# Patent

## Title
Processes for the preparation of pyrrolidine intermediates

## Abstract

The present invention relates to processes for the enantio-selective preparation of spyrrolidine derivatives useful in the manufacture of pesticidally active compounds, as well as to intermediates in the processes. The processes include those comprising
(a-i) reacting a compound of formula Ia




wherein

P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a source of cyanide in the presence a chiral catalyst to give a compound of formula IIa





wherein P, R1 and R2 are as defined for the compound of formula Ia; and

(a-ii) oxidizing the compound of formula IIa with a peroxy acid, or peroxide in the presence of an acid to give a compound of formula VI





wherein R1 and R2 are as defined for the compound of formula Ia.

## Background
This application is a 371 filing of International Application No. PCT/EP2012/069171, filed Sep. 28, 2012, which claims priority benefit to International Application No. PCT/EP2011/067224 filed Oct. 3, 2011 and U.S. Provisional Patent Application No. 61/576,135 filed Dec. 15, 2011, the contents of all of which are incorporated herein by reference.


The present invention relates to the synthesis of intermediates useful for the preparation of substituted pyrrolidine derivatives, including those having pesticidal activity. The invention relates more particularly to the stereoselective syntheses of these intermediates
Certain pyrrolidine derivatives with insecticidal properties are disclosed in, for example WO2008/128711, WO2010043315, WO2011/080211. Such pyrrolidine derivatives include at least one chiral centre at one of the ring members of the pyrrolidine moiety. The present invention provides a process for selectively synthesizing enantiomers of such compounds as well as intermediates that can be used in the synthesis of such compounds.
A route to enantio-enriched intermediates is desirable in view of the differential biological activity of the enantiomers. Use of enantio-enriched intermediates can therefore reduce the amount of active ingredient needed to control key pests, thereby reducing costs and impact on the environment.
Accordingly, in a first aspect the invention provides a process for the enantio-selective preparation of a pyrrolidine derivative comprising
(a-i) reacting a compound of formula Ia




wherein

P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a source of cyanide in the presence a chiral catalyst to give a compound of formula IIa





wherein P, R1 and R2 are as defined for the compound of formula Ia; and

(a-ii) oxidising the compound of formula IIa with a peroxy acid, or peroxide in the presence of an acid, preferably a strong acid, to give a compound of formula VI





wherein R1 and R2 are as defined for the compound of formula Ia.

The ability to prepare compounds of formula VI from compounds of formula IIa via the Baeyer-Villiger oxidation reaction was unexpected and provides an efficient route to enantio-enriched pyrrolidine derivatives, and can also be applied to reactions with racemic mixtures.

In one embodiment step (a-ii) comprises oxidising the compound of formula IIa with a peroxide in the presence of a strong acid to give a compound of formula VI.

In addition, the reaction optionally comprises

(a-iii-1) reducing the compound of formula VI with a suitable reducing agent to give a compound of formula IX





wherein R1 and R2 are as defined for the compound of formula Ia.

and optionally

(a-iv-1) reacting the compound of formula IX with a compound of formula (XIII)

XB-A′  (XIII)

wherein XB is a leaving group such as halogen, and A′ is optionally substituted aryl or optionally substituted heteroaryl to give a compound of formula XVI





wherein R1 and R2 are as defined for the compound of formula Ia and A′ is as defined for the compound of formula XIII;

or the reaction optionally comprises

(a-iii-2) reacting the compound of formula VI with a compound of formula XIII to give a compound of formula XII





wherein R1 and R2 are as defined for the compound of formula Ia and A′ is as defined for the compound of formula XIII;

and optionally

(a-iv-2) reducing the compound of formula XII with a suitable reducing agent to give a compound of formula XVI.

In a further aspect the invention provides a process for the enantio-selective preparation of a pyrrolidine derivative comprising

(a-1) reacting a compound of formula Ia





wherein

P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a source of cyanide in the presence a chiral catalyst to give a compound of formula IIa





wherein P, R1 and R2 are as defined for the compound of formula Ia; and

(a-2) oxidizing the compound of formula II a with a peroxide to give a compound of formula XVIII





wherein P, R1 and R2 are as defined for the compound of formula Ia; and

(a-3) reducing the compound of formula XVIII with a suitable reducing agent to give a compound of formula III





wherein R1 and R2 are as defined for the compound of formula Ia; and

and wherein the reaction optionally comprises

(a-4-1) reducing the compound of formula III with a suitable reducing agent

to give a compound of formula IX





wherein R1 and R2 are as defined for the compound of formula Ia;

and optionally

(a-5-1) reacting the compound of formula IX with a compound of formula (XIII)

XB-A′  (XIII)

wherein XB is a leaving group such as halogen, and A′ is optionally substituted aryl or optionally substituted heteroaryl to give a compound of formula XVI





wherein R1 and R2 are as defined for the compound of formula Ia and A′ is as defined for the compound of formula XIII;

or the reaction optionally comprises

(a-4-2) reacting the compound of formula III with a compound of formula (XIII) to give a compound of formula XVII





wherein R1 and R2 are as defined for the compound of formula Ia and A′ is as defined for the compound of formula XIII;

and optionally

(a-5-2) reducing the compound of formula XVII with a suitable reducing agent to give a compound of formula XVI.

In a further aspect the invention provides a process for the enantio-selective preparation of a pyrrolidine derivative comprising

(b-i) reacting a compound of formula Ib





wherein

P is optionally substituted heteroaryl, and wherein the heteroaryl contains at least one ring nitrogen or oxygen atom, wherein the heteroaryl is connected at P via a ring carbon atom;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a source of cyanide in the presence a chiral catalyst to give a compound of formula IIb





wherein P, R1 and R2 are as defined for the compound of formula Ib; and

(b-ii-1) oxidatively cleaving the compound of formula IIb to give a compound of formula XIX





wherein R1 and R2 are as defined for the compound of formula Ib; and

(b-ii-2) hydrolysing and dehydrating the compound of formula XIX to give a compound of formula VI





wherein R1 and R2 are as defined for the compound of formula Ib;

wherein dehydration is performed in the presence of acid; or

(b-ii) reductively cyclising the compound of formula IIb with a suitable reducing agent to give a compound of formula III





wherein R1 and R2 are as defined for the compound of formula I.

In a further aspect the invention provides a process for the enantio-selective preparation of a pyrrolidine derivative comprising

(c-ii) reductively cyclising the compound of formula IIb with a suitable reducing agent to give a compound of formula III





wherein R1 and R2 are as defined for the compound of formula I;

(c-i) reacting a compound of formula I





wherein

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a source of cyanide in the presence a chiral catalyst to give a compound of formula II





wherein P, R1 and R2 are as defined for the compound of formula I; and

(c-ii) reductively cyclising the compound of formula II with a suitable reducing agent to give a compound of formula III





wherein R1 and R2 are as defined for the compound of formula I; or

(c-iii-1) partially hydrolysing the compound of formula II to give a compound of formula V





wherein P, R1 and R2 are as defined for the compound of formula I; and

(c-iii-2) cyclising the compound of formula V, e.g. by heating, to give a compound of formula VI





wherein R1 and R2 are as defined for the compound of formula I; or

(c-iv-1) hydrolysing the compound of formula II to give a compound of formula VII





wherein R1 and R2 are as defined for the compound of formula I; and

(c-iv-2) cyclising the compound of formula VII, e.g. by heating, to give a compound of formula VI





wherein R1 and R2 are as defined for the compound of formula I; or

(c-v-1) reducing the compound of formula II with a suitable reducing agent to give a compound of formula VIII





wherein R1 and R2 are as defined for the compound of formula I; and

(c-v-2) treating the compound of formula VIII with a suitable activating agent to give a compound of formula IX





wherein R1 and R2 are as defined for the compound of formula I; or

(c-vi-1) hydrolysing the compound of formula II to give a compound of formula X





wherein R1 and R2 are as defined for the compound of formula I; and

(c-vi-2) reacting the compound of formula X with a compound of formula XI

H2N-A′  (XI)

wherein A′ is optionally substituted aryl or optionally substituted heteroaryl to give a compound of formula XII





wherein R1 and R2 are as defined for the compound of formula I and A′ is as defined for the compound of formula XI; or

(c-vii-1) reducing the compound of formula I with a suitable reducing agent to give a compound of formula IV





wherein P, R1 and R2 are as defined for the compound of formula I; and

(c-vii-2) reacting the compound of formula IV with a compound of formula XIII

XB-A′  (XIII)

wherein A′ is as defined for the compound of formula XII and XB is a leaving group, e.g. halogen such as bromo, to give a compound of formula XIV





wherein P, R1 and R2 are as defined for the compound of formula I and A′ is as defined for the compound of formula XII; and

(c-vii-3) reducing the compound of formula XIV with a suitable reducing agent to give a compound of formula XV





wherein R1 and R2 are as defined for the compound of formula I and A′ is as defined for the compound of formula XII; and

(c-vii-4) treating the compound of formula XV with a suitable activating agent to give a compound of formula XVI





wherein R1 and R2 are as defined for the compound of formula I and A′ is as defined for the compound of formula XII; or

(c-viii-1) preparing a compound of formula XIV as described in a-vii-2;

(c-viii-2) cyclising the compound of formula XIV, e.g. by heating, to give a compound of formula XVII





wherein R1 and R2 are as defined for the compound of formula I and A′ is as defined for the compound of formula XII.

In a further aspect the invention provides a process for the enantio-selective preparation of a pyrrolidine derivative comprising

(d-i) reacting a compound of formula II





wherein

P is hydroxy, alkoxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a nitromethane in the presence a chiral catalyst to give a compound of formula XX.





wherein P, R1 and R2 are as defined for the compound of formula I; and

(d-ii-1) reducing the compound of formula XX with a suitable reducing agent to give a compound of formula IV





wherein P, R1 and R2 are as defined for the compound of formula I; and

(d-ii-2) cyclising the compound of formula IV, e.g. by heating, to give a compound of formula III





wherein R1 and R2 are as defined for the compound of formula I; or

(d-iii-1) reducing the compound of formula XX with a suitable reducing agent to give a compound of formula VIII





wherein R1 and R2 are as defined for the compound of formula I; and

(d-iii-2) treating the compound of formula VIII with an activating agent to give a compound of formula IX





wherein R1 and R2 are as defined for the compound of formula I.

In a further aspect the invention provides a process for the enantio-selective preparation of a pyrrolidine derivative comprising

(e-i) reacting a compound of formula XXI





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a compound of formula XXII





P is hydroxy, alkoxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom; and

(e-ii-1) reducing the compound of formula XX with a suitable reducing agent to give a compound of formula IV





wherein P, R1 and R2 are as defined for the compound of formula I; and

(e-ii-2) cyclising the compound of formula IV, e.g. by heating, to give a compound of formula III





wherein R1 and R2 are as defined for the compound of formula I; or

(e-iii-1) reducing the compound of formula XX with a suitable reducing agent to give a compound of formula VIII





wherein R1 and R2 are as defined for the compound of formula I; and

(e-iii-2) treating the compound of formula VIII with an activating agent, such as SOCl2 to give a compound of formula IX





wherein R1 and R2 are as defined for the compound of formula I.

In a further aspect the invention provides a process for the enantio-selective preparation of a pyrrolidine derivative comprising
(f-i) reacting a compound of formula XXI




wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a compound of formula XXIII





wherein R100 is alkyl, aryl or heteroaryl, each optionally substituted;

in the presence of a chiral catalyst to give a compound of formula XXIV





wherein R1, R2 are as defined for the compound of formula XXI and R100 is as defined for the compound of formula XXIII; and

(f-ii) reductively cyclising the compound of formula XXIV with a suitable reducing agent to give a compound of formula XXV





wherein R1, R2 are as defined for the compound of formula XXI and R100 is as defined for the compound of formula XXIII; and

(f-iii) treating the compound of formula XXV with base followed by treatment with acid to give a compound of formula III





wherein R1 and R2 are as defined for the compound of formula XXI.

The processes of the invention may also comprise one or more of the following:

    
    
        reducing a compound of formula III to a compound of formula IX with a suitable reducing agent;
        reducing a compound of formula IV to a compound of formula III with a suitable reducing agent;
        reducing a compound of formula IV to a compound of formula IX with a suitable reducing agent;
        reducing a compound of formula XII to a compound of formula XVII with a suitable reducing agent;
        reducing a compound of formula XII to a compound of formula XVI with a suitable reducing agent;
        reducing a compound of formula XVII to a compound of formula XVI with a suitable reducing agent.
    
    


Suitable reducing agents for the above processes will be apparent to the person skilled in the art, and are examples are described in more detail below.
In a further aspect the invention provides a compound of formula IIc




wherein

P is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, or arylsulfinyl, each optionally substituted;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula III





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula IV





wherein

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula V





wherein

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula VI





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula VII





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula VIII





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula IX





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula X





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula XII





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula XIV





wherein

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula XV





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula XVI





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula XVII





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula XVIII





wherein

P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of IIc and a compound of formula IIIA





wherein

P is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, or arylsulfinyl, each optionally substituted;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula IIc.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula III and a compound of formula IIIA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula III.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula IV and a compound of formula WA





P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula V and a compound of formula VA





wherein

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted wherein the mixture is enriched for the compound of formula V.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula VI and a compound of formula VIA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula VI.

In a further aspect the invention provides a mixture comprising a compound of formula VII and a compound of formula VIIA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula VII.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula VIII and a compound of formula VIIIA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula VIII.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula IX and a compound of formula IXA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula IX.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula X and a compound of formula XA





R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula X.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula XII and a compound of formula XIIA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl; wherein the mixture is enriched for the compound of formula XII.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula XIV and a compound of formula XIVA





wherein

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl;

wherein the mixture is enriched for the compound of formula XIV.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula XV and a compound of formula XVA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl;

wherein the mixture is enriched for the compound of formula XV.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula XVI and a compound of formula XVIA





wherein

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl;

wherein the mixture is enriched for the compound of formula XVI.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula XVII and a compound of formula XVIIA





R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

A′ is optionally substituted aryl or optionally substituted heteroaryl;

wherein the mixture is enriched for the compound of formula XVII.

Preferred substituent definitions are given below.

In a further aspect the invention provides a mixture comprising a compound of formula XVIII and a compound of formula XVIIIA





wherein

P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

wherein the mixture is enriched for the compound of formula XVIII.

Preferred substituent definitions are given below.

In a further aspect the invention provides a compound of formula XXIX.

In a further aspect the invention provides a compound of formula XXX.

In a further aspect the invention provides a compound of formula XXXI.

In a further aspect the invention provides a compound of formula XXXII.

In a further aspect the invention provides a compound of formula XXXIII.





In the above compounds R1 and R2 are as defined for the compound of formula IIa.

In a further aspect the invention provides a mixture comprising a compound of formula XXIX and a compound of formula XXIXA, wherein the mixture is enriched for the compound of formula XXIX.

In a further aspect the invention provides a compound of formula XXX and a compound of formula XXXA wherein the mixture is enriched for the compound of formula XXX.

In a further aspect the invention provides a compound of formula XXXI and a compound of formula XXXIA wherein the mixture is enriched for the compound of formula XXXI.

In a further aspect the invention provides a compound of formula XXXII and a compound of formula XXXIIA wherein the mixture is enriched for the compound of formula XXXII.

In a further aspect the invention provides a compound of formula XXXIII and a compound of formula XXXIIA wherein the mixture is enriched for the compound of formula XXXII.

The compound of formula XXIXA, XXXA, XXXIA, XXXIIA and XXXIIIA have the opposite stereochemistry to XXIX, XXX, XXXI, XXXII and XXXIII at the carbon bonded to R1 and R2.

In a further aspect the invention provides a process for preparing pyrrolidine derivatives comprising

(a-i) reacting a compound of formula Ia





wherein

P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom;

R1 is chlorodifluoromethyl or trifluoromethyl;

R2 is aryl or heteroaryl, each optionally substituted;

with a source of cyanide to give a compound of formula IIa





wherein P, R1 and R2 are as defined for the compound of formula Ia; and

(a-ii) oxidising the compound of formula IIa with a peroxide in the presence of strong acid to give a compound of formula VI-1





wherein R1 and R2 are as defined for the compound of formula Ia.

The cyanide addition can be done in presence of a base and/or a catalyst. Examples of bases include triethyl amine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.

Examples of chiral catalysts include crown ethers and phase transfer catalysts such as tetrabutylammonium bromide.

In addition, the reaction optionally comprises

(a-iii-1) reducing the compound of formula VI-1 with a suitable reducing agent to give a compound of formula IX-1





wherein R1 and R2 are as defined for the compound of formula Ia.

and optionally

(a-iv-1) reacting the compound of formula IX with a compound of formula (XIII)

XB-A′  (XIII)

wherein XB is a leaving group such as halogen, and A′ is optionally substituted aryl or optionally substituted heteroaryl to give a compound of formula XVI-1





wherein R1 and R2 are as defined for the compound of formula Ia and A′ is as defined for the compound of formula XIII;

or the reaction optionally comprises

(a-iii-2) reacting the compound of formula VI-1 with a compound of formula XIII-1 to give a compound of formula XII-1





wherein R1 and R2 are as defined for the compound of formula Ia and A′ is as defined for the compound of formula XIII;

and optionally

(a-iv-2) reducing the compound of formula XII-1 with a suitable reducing agent to give a compound of formula XVI-1.

In a further aspect the invention provides a compound of formula VI-1.

In a further aspect the invention provides a compound of formula XXIX-1.

In a further aspect the invention provides a compound of formula XXX-1.

In a further aspect the invention provides a compound of formula XXXI-1.

In a further aspect the invention provides a compound of formula XXXII-1.

In a further aspect the invention provides a compound of formula XXXIII-1.





In the compounds above R1 and R2 are as defined for the compound of formula Ia.

In enantiomerically enriched mixtures of the invention, the molar proportion of the enriched compound in the mixture compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.
Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl- or alkoxycarbonyl-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methyl-prop-1-yl or 2-methyl-prop-2-yl. The alkyl groups are, unless indicated to the contrary, preferably C1-C6, more preferably C1-C4, most preferably C1-C3 alkyl groups.
Alkylene groups can be in the form of a straight or branched chain and are, for example, —CH2—, —CH2—CH2—, —CH(CH3)—, —CH2—CH2—CH2—, —CH(CH3)—CH2—, or —CH(CH2CH3)—. The alkylene groups are, unless indicated to the contrary, preferably C1-C6, more preferably C1-C3, more preferably C1-C2, most preferably C1 alkylene groups.
Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are, unless indicated to the contrary, preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkenyl groups.
Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are, unless indicated to the contrary, preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkynyl groups.
Halogen is fluorine, chlorine, bromine or iodine.
Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl-, haloalkylsulfonyl-, haloalkylcarbonyl- or haloalkoxycarbonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.
Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or 1,2-dichloro-2-fluoro-vinyl.
Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 1-chloro-prop-2-ynyl.
Cycloalkyl groups can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are, unless indicated to the contrary, preferably C3-C8, more preferably C3-C6 cycloalkyl groups.
Aryl groups are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
Heteroaryl groups are aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl and benzotriazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
Heterocyclyl groups are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl, [1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl, and morpholinyl or their oxidised versions such as 1-oxo-thietanyl and 1,1-dioxo-thietanyl. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[1,3]dioxolanyl, and 2,3-dihydro-benzo[1,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
Unless stated otherwise where groups are optionally substituted they may be substituted e.g. by one to five groups, e.g. by one to three groups, preferably independently selected from nitro, cyano, hydroxy, halogen, mercapto, isocyano, cyanate, isothiocyanate, carboxy, carbamoyl, aminosulfonyl, monoalkylamino, dialkylamino, N-alkylcarbonylamino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, SF5, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, alkoxy-carbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkylthio, cycloalkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylsulfenyl, alkylsulfinyl including isomers, alkylsulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylphosphinyl, alkylphosphonyl, alkylphosphinyl including isomers, alkylphosphonyl including isomers, N-alkyl-aminocarbonyl, -dialkyl-aminocarbonyl, N-alkylcarbonyl-aminocarbonyl, N-alkylcarbonyl-N-alkylaminocarbonyl, aryl, aryloxy, benzyl, benzyloxy, benzylthio, arylthio, arylamino, benzylamino, trialkylsilyl, alkoxyalkyl, alkylthioalkyl, alkylthioalkoxy, alkoxyalkoxy, phenethyl, benzyloxy, haloalkyl, haloalkoxy, haloalkylthio, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkoxyalkoxy, haloalkoxyalkylthio, haloalkoxyalkylcarbonyl or haloalkoxyalkyl, cycloalkylamino-carbonyl, alkylsulfinylimino, alkylsulfonylimino, alkoxyimino, and a heterocyclic group;
preferably nitro, cyano, hydroxy, mercapto, isocyano, cyanate, isothiocyanate, carboxy, carbamoyl, aminosulfonyl, mono-C1-C12alkylamino, di-C2-C24alkylamino, N—C1-C12alkylcarbonylamino, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, SF5, C1-C12alkoxy, C2-C6alkenyloxy, C2-C6alkynyloxy, C3-C8cycloalkyloxy, C3-C8cycloalkenyloxy, C1-C12alkoxycarbonyl, C2-C6alkenyloxycarbonyl, C2-C6alkynyloxycarbonyl, aryloxycarbonyl, C1-C12alkylcarbonyl, C2-C6alkenylcarbonyl, C2-C6alkynylcarbonyl, arylcarbonyl, C1-C12alkylthio, C3-C8cycloalkylthio, C2-C6alkenylthio, C3-C8cycloalkenylthio, C2-C6alkynylthio, C1-C12alkylsulfenyl, C1-C12alkylsulfinyl including isomers, C1-C12alkylsulfonyl, mono-C1-C12alkylaminosulfonyl, di-C2-C24alkylaminosulfonyl, C1-C12alkylphosphinyl, C1-C12alkylphosphonyl, C1-C12alkylphosphinyl including isomers, C1-C12alkylphosphonyl including isomers, N—C1-C12alkyl- aminocarbonyl, -di-C2-C24alkyl-aminocarbonyl, N—C1-C12alkylcarbonyl-aminocarbonyl, N—C1-C12alkylcarbonyl-N—C1-C12alkylaminocarbonyl, aryl, aryloxy, benzyl, benzyloxy, benzylthio, arylthio, arylamino, benzylamino, trialkylsilyl, C1-C12alkoxyalkyl, C1-C12alkylthioalkyl, C1-C12alkylthioalkoxy, C1-C12alkoxyalkoxy, phenethyl, benzyloxy, C1-C12haloalkyl, C1-C12haloalkoxy, C1-C12haloalkylthio, C1-C12haloalkylcarbonyl, C1-C12haloalkoxycarbonyl, C1-C12haloalkoxyalkoxy, C1-C12haloalkoxyC1-C12alkylthio, C1-C12haloalkoxyC1-C12alkylcarbonyl or C1-C12haloalkoxy-C1-C12alkyl, C3-C8cycloalkylamino-carbonyl, C1-C12alkylsulfinylimino, C1-C12alkylsulfonylimino, C1-C12alkoxyimino, and a heterocyclic group, wherein aryl is phenyl and heterocyclic groups are heteroaryl groups as defined above. Preferred optional substituents are cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy.
Bearing in mind the stereocentre which is the subject of the invention, the invention otherwise includes all isomers of compounds of formula I, salts and N-oxides thereof, including enantiomers, diastereomers and tautomers. Tautomers of the compounds of formula I include the enamine form, for example. These are covered by the invention.
Preferred substituent values in compounds of formula I are as follows, which may be combined in any order. These preferred substituent values also apply to other compounds of the invention in which the same substituents are present.
Preferably R1 is trifluoromethyl.
Preferably R2 is aryl or aryl substituted by one to five Q1, or heteroaryl or heteroaryl substituted by one to five Q1. Preferably R2 is group A




wherein B1, B2, B3, B4 and Q1 are as defined below. More preferably R2 is group A1 or A2





More preferably R2 is group A3 or A4




B1, B2, B3, B4 are independently C-Q1 or nitrogen.
Q1, Q2, Q3, Q4, and Q5 are independently hydrogen, halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, hydroxy, C1-Cgalkylamino, C1-C8alkoxy, C1-C8haloalkoxy, mercapto, C1-C8alkylthio, C1-C8haloalkylthio, C1-C8alkylsulfinyl, C1-C8haloalkylsulfinyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, optionally substituted aryl or optionally substituted heterocyclyl. Preferably, Q1, Q2, Q3, Q4, and Q5 are each independently hydrogen, halogen, cyano, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy or C1-C8haloalkoxy, more preferably bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy, preferably bromo, chloro or trifluoromethyl. Preferably at least two of Q1, Q2, Q3, Q4, and Q5 are not hydrogen.
When P is defined as hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom, then P is preferably hydroxy, C1-C12alkoxy, C1-C12haloalkoxy phenyloxy, C1-C12sulfinyl, phenylsulfinyl or heteroaryl, wherein phenyl (including phenyloxy) and heteroaryl are optionally substituted by one to five groups independently selected from cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy, and heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl or benzotriazolyl, more preferably P is hydroxyl, C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl, or C1-C6alkylsulfinyl.
When P is defined as alkyl, aryl or heteroaryl, each optionally substituted (and e.g. wherein the heteroaryl is connected to at P via a ring carbon atom), then preferably P is C1-C12alkyl, C1-C12haloalkyl, phenyl or heteroaryl, and heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl or benzotriazolyl, e.g. wherein phenyl and heteroaryl are each optionally substituted by one to five groups independently selected from cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy.
When P is defined as optionally substituted heteroaryl, and wherein the heteroaryl contains at least one ring nitrogen or oxygen atom, wherein the heteroaryl is connected at P via a ring carbon atom, then preferably P is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl or benzotriazolyl, each optionally substituted by one to five groups independently selected from cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy.
When P is defined as P is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, or arylsulfinyl, each optionally substituted, then preferably P is C1-C12alkyl, C1-C12haloalkyl, hydroxy, C1-C12alkoxy, C1-C12haloalkoxy, phenyloxy, C1-C12sulfinyl, phenylsulfinyl, wherein phenyl is optionally substituted by one to five groups independently selected from cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy.
Preferably A′ is selected from P1 to P6




In one group of compounds A′ is P1. In another group of compounds A′ is P2. In another group of compounds A′ is P3. In another group of compounds A′ is P4. In another group of compounds A′ is P5. In another group of compounds A′ is P6. In another group of compounds A′ is selected from P3 to P5. When P is P2 to P5, P is preferably P7 to P22







A1, A2 and A3 are independently of each other C—H, C—R5, or nitrogen. Preferably no more than two of A1, A2 and A3 are nitrogen. In one group of compounds A1, A2 and A3 are each C—R5. In one group of compounds A1 is nitrogen and A2 and A3 are both C—R5. In another group of compounds A2 is nitrogen and A1 and A3 are both C—R5. In another group of compounds A1 and A2 are both nitrogen and A3 is C—R5. In one group of compounds A1, A2 and A3 are each C—H. In one group of compounds A1 is nitrogen and A2 and A3 are both C—H. In another group of compounds A2 is nitrogen and A1 and A3 are both C—H. In another group of compounds A1 and A2 are both nitrogen and A3 is C—H. Preferably A1, A2 and A3 are each C—H.
A1′, A2′, A3′, A4′, A5′ and A6′ are independently of each other C—H, C—R5 or nitrogen provided that no more than two of A1′, A2′, A3′, A4′, A5′ and A6′ are nitrogen. Preferably A1′, A2′, A3′, A4′, A5′ and A6′ are C—H.
The ring formed by A1, A2, and A3, or A1′, A2′, A3′, A4′, A5′ and A6′ may, for example, be phenyl, pyridyl, pyrimidine, pyrazine, pyridazine, naphthyl or quinoline.
Each R5 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C3-C10cycloalkyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylthio, C1-C8haloalkylthio, C1-C8alkylsulfinyl, C1-C8haloalkylsulfinyl, C1-C8alkylsulfonyl or C1-C8haloalkylsulfonyl. Preferably, each R5 is independently halogen, C1-C8alkyl, C1-C8haloalkyl or C2-C8alkenyl. More preferably, each R5 is independently bromo, chloro, fluoro, methyl, trifluoromethyl or vinyl, most preferably each R5 is methyl.
Q is hydrogen, halogen, nitro, NH2, cyano, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C3-C8haloalkynyl, C3-C10cycloalkyl, C1-C8alkylthio, C1-C8haloalkylthio, C1-C8alkylsulfinyl, C1-C8haloalkylsulfinyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, arylsulfonyl or arylsulfonyl substituted by one to five groups independently selected from C1-C4alkyl and nitro, —N(R6)R7b, —C(W5)N(R6)R7, —C(R15)(R16)N(R17)R18, C(═W5)OR7a, —C(═W5)R13, —OR14, aryl or aryl substituted by one to five Z1, heterocyclyl or heterocyclyl substituted by one to five Z1. Preferably, Q is cyano, halogen, nitro, NH2, arylsulfonyl or arylsulfonyl substituted by one to five groups independently selected from C1-C4alkyl and nitro, heterocyclyl or heterocyclyl substituted by one to five Z1, —OR14, —C(═O)N(R6)R7, —CO(═O)R7a, —C(═O)R13, or —C(R15)(R16)N(R17)R18. More preferably, Q is cyano, halogen, nitro, NH2, phenylsulfonyl or phenylsulfonyl substituted by one to five groups independently selected from C1-C4alkyl and nitro, —OR14, —C(═O)N(R6)R7, —CO(═O)R7a, —C(═O)R13, —C(R15)(R16)N(R17)R18, or a heterocycle selected from H1 to H9




Even more preferably, Q is cyano, halogen, nitro, NH2, C1-C8alkoxy, phenylsulfonyl or phenylsulfonyl substituted by one to five groups independently selected from C1-C4 alkyl and nitro, —C(═O)N(R6)R7, —CO(═O)R7a, —C(═O)R13, —C(R15)(R16)N(R17)R18, or a heterocycle selected from H1 to H9.
k is 0, 1, or 2, preferably 0.
R6 is hydrogen, C1-C8alkyl, C1-C8alkoxy, C2-C8alkenyl, C2-C8alkynyl, C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C4alkylene, C1-C8alkylcarbonyl or C1-C8alkoxycarbonyl. Preferably, R6 is hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylcarbonyl, or C1-C8alkoxycarbonyl. More preferably, R6 is hydrogen, methyl, ethyl, methylcarbonyl or methoxycarbonyl, more preferably hydrogen, methyl or ethyl, most preferably hydrogen.
R7 is hydrogen, alkyl or alkyl substituted by one to five R8, alkenyl or alkenyl substituted by one to five R8, alkynyl or alkynyl substituted by one to five R8, C3-C10cycloalkyl or C3-C10cycloalkyl substituted by one to five R9, C3-C10cycloalkyl-C1-C4alkylene or C3-C10cycloalkyl-C1-C4alkylene wherein the cycloalkyl moiety is substituted by one to five R9, C1-C8alkyl-N(R6)—C(═O)—C1-C4alkylene, C1-C8haloalkyl-N(R6)—C(═O)—C1-C4alkylene, C3-C8cycloalkyl-aminocarbonyl-C1-C4alkylene, C1-C6alkyl-O—N═CH—, C1-C6haloalkyl-O—N═CH—, aryl-C1-C6alkylene or aryl-C1-C6alkylene wherein the aryl moiety is substituted by one to five R10, heterocyclyl-C1-C6alkylene or heterocyclyl-C1-C6alkylene wherein the heterocyclyl moiety is substituted by one to five R10 and wherein each heterocyclyl moiety contains one or more ring members independently selected from O, N, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 and SO═N—R12, aryl or aryl substituted by one to five R10, heterocyclyl or heterocyclyl substituted by one to five R10 and wherein each heterocyclyl moiety contains one or more ring members independently selected from O, N, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 and SO═N—R12. Preferably, R7 is hydrogen, C1-C5alkyl or C1-C5alkyl substituted by one to five R8, C3-C10cycloalkyl or C3-C10cycloalkyl substituted by one to five R9, aryl-C1-C6alkylene or aryl-C1-C6alkylene wherein the aryl moiety is substituted by one to five R10, heterocyclyl-C1-C6alkylene or heterocyclyl-C1-C6alkylene wherein the heterocyclyl moiety is substituted by one to five R10 and wherein each heterocyclyl moiety contains one or more ring members independently selected from O, N, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 and SO═N—R12, aryl or aryl substituted by one to five R10, heterocyclyl or heterocyclyl substituted by one to five R10 and wherein each heterocyclyl moiety contains one or more ring members independently selected from O, N, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 and SO═N—R12, C1-C8alkyl-N(R6)—C(═O)—C1-C4 alkylene, C1-C8haloalkyl-N(R6)—C(═O)—C1-C4alkylene, C3-C8cycloalkylaminocarbonyl-C1-C4alkylene, C1-C6alkyl-O—N═CH—, or C1-C6haloalkyl-O—N═CH—. More preferably, R7 is hydrogen, C1-C8alkyl, C1-C8haloalkyl, phenyl-C1-C6alkylene or phenyl-C1-C6alkylene wherein the phenyl moiety is substituted by one to five R10, pyridyl-C1-C6alkylene or pyridyl-C1-C6alkylene wherein the pyridyl moiety is substituted by one to four R10, thiazolyl-C1-C6alkylene or thiazolyl-C1-C6alkylene wherein the thiazolyl moiety is substituted by one or two R10, phenyl or phenyl substituted by one to five R10, pyridyl or pyridyl substituted by one to four R10, thiazolyl or thiazolyl substituted by one or two R10, C3-C6cycloalkyl or C3-C6cycloalkyl wherein one ring atom is replaced by O or S, C1- C4alkyl-O—N═CH—, C1-C4haloalkyl-O—N═CH—, C1-C4alkyl-N(R6)—C(═O)—CH2—, C1-C4haloalkyl-N(R6)—C(═O)—CH2—, or a group of formula (Y)




In one group of compounds R7 is not a group of formula (Y)
L is a single bond or C1-C6alkylene;
Y1, Y2 and Y3 are independently of another O, CR21R22, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 or SO═N—R12, provided that at least one of Y1, Y2 or Y3 is not CR21R22, C═O or C═N—OR12. In the group of formula (Y), preferably two of Y1, Y2 and Y3 are CR21-22, x and the other is O, N—R12, S, SO, SO2, S═N—R12 or SO═N—R12, more preferably two of Y1, Y2 and Y3 are CH2 and the other is S, SO or SO2. When L is a bond Y1 and Y3 are preferably CH2 and Y2 is S, SO, SO2, S═N—R12 or SO═N—R12. When L is alkylene, Y1 is preferably S, SO, SO2, S═N—R12 or SO═N—R12 and Y2 and Y3 are CH2.
R7a is hydrogen, alkyl or alkyl substituted by one to five R8, alkenyl or alkenyl substituted by one to five R8, alkynyl or alkynyl substituted by one to five R8, cycloalkyl or cycloalkyl substituted by one to five R9, aryl-alkylene or aryl-alkylene wherein the aryl moiety is substituted by one to five R10, heteroaryl-alkylene or heteroaryl-alkylene wherein the heteroaryl moiety is substituted by one to five R10, aryl or aryl substituted by one to five R10, or heteroaryl or heteroaryl substituted by one to five R10. Preferably, R7a is hydrogen, C1-C15alkyl or C1-C15alkyl substituted by one to five R8, C2-C15alkenyl or C2-C15alkenyl substituted by one to five R8, C2-C15alkynyl or C2-C15alkynyl substituted by one to five R8, C3-C10cycloalkyl or C3-C10cycloalkyl substituted by one to five R9, aryl-C1- C6alkylene or aryl-C1-C6alkylene wherein the aryl moiety is substituted by one to five R10, heteroaryl-C1-C6alkylene or heteroaryl-C1-C6alkylene wherein the heteroaryl moiety is substituted by one to five R10, or heteroaryl or heteroaryl substituted by one to five R10. More preferably R7a is hydrogen, C1-C15alkyl, C1-C15haloalkyl C2-C15alkenyl, C2-C15haloalkenyl, C2-C15alkynyl, C2-C15haloalkynyl, phenyl-C1-C4alkylene or phenyl-C1-C4alkylene wherein the phenyl moiety is substituted by one to five halogen, pyridyl-C1-C4alkyl or pyridyl-C1-C4alkyl wherein the pyridyl moiety is substituted by one to four halogen, pyridyl or pyridyl substituted by one to four R10, most preferably R7a is C1-C15alkyl, C1-C15haloalkyl, C2-C15alkenyl, C2-C15haloalkenyl, pyridyl or benzyl.
R7b is hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl cycloalkyl, halocycloalkyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or benzyl, more preferably R7b is hydrogen, C1-C15alkyl, C1-C15haloalkyl, C2-C15alkenyl, C2-C15haloalkenyl, C2-C15alkynyl, C2-C15haloalkynyl, C3-C10cycloalkyl, C1-C15alkylcarbonyl or C1-C15alkoxycarbonyl; most preferably R7b is C1-C15alkyl, C1-C15haloalkyl, C2-C15 alkenyl or C2-C15haloalkenyl.
Each R8 is independently halogen, cyano, nitro, hydroxy, NH2, mercapto, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylthio, C1-C8haloalkylthio, C1-C8alkylsulfinyl, C1-C8haloalkylsulfinyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, C1-C8alkylamino, C2-C8dialkylamino, C3-C8cycloalkylamino, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8alkylaminocarbonyl, C1-C8dialkylaminocarbonyl, C1-C8haloalkylcarbonyl, C1-C8haloalkoxycarbonyl, C1-C8haloalkylaminocarbonyl, C1-C8halodialkylaminocarbonyl. Preferably, each R8 is independently halogen, cyano, nitro, hydroxy, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, mercapto, C1-C8alkylthio, C1-C8haloalkylthio, C1-C8alkylsulfinyl, C1-C8haloalkylsulfinyl, C1-C8alkylsulfonyl. More preferably, each R8 is independently halogen, cyano, nitro, hydroxy, C1-C8alkoxy, C1-C8haloalkoxy, mercapto, C1-C8alkylthio, C1-C8haloalkylthio, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy.
Each R9 is independently halogen or C1-C8alkyl. Preferably, each R9 is independently chloro, fluoro or methyl, most preferably each R9 methyl.
Each R10 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, hydroxy, C1-C8alkoxy, C1-C8haloalkoxy, mercapto, C1-C8alkylthio, C1-C8haloalkylthio, C1-C8alkylsulfinyl, C1-C8haloalkylsulfinyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, aryl or aryl substituted by one to five R11, or heterocyclyl or heterocyclyl substituted by one to five R11. Preferably each R10 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy, more preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, most preferably bromo, chloro, fluoro, cyano or methyl.
Each R4 and R11 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy or C1-C8alkoxycarbonyl; more preferably each R4 and R11 is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro or methyl, most preferably each R4 and R11 is independently chloro, fluoro or methyl.
Each R12 is independently hydrogen, cyano, cyano-C1-C8alkyl, C1-C8alkyl, C1-C8haloalkyl, C3-C8cycloalkyl, C3-C8cycloalkyl where one carbon atom is replaced by O, S, S(O) or SO2, or C3-C8cycloalkyl-C1-C8alkylene, C3-C8cycloalkyl-C1-C8alkylene where one carbon atom in the cycloalkyl group is replaced by O, S, S(O) or SO2, or C3-C8cycloalkyl-C1-C8haloalkylene, C1-C8hydroxyalkyl, C1-C8alkoxy-C1-C8alkylene, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, aryl or aryl substituted by one to three R11, C1-C8alkylcarbonyl, C1-C8haloalkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8haloalkoxycarbonyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, aryl-C1-C4alkylene or aryl-C1-C4alkylene where the aryl moiety is substituted by one to three R11, or heteroaryl-C1-C4alkylene or heteroaryl-C1-C4alkylene where the heteroaryl moiety is substituted by one to three R11, or C1-C4alkyl-C1-C4alkyl-O—N═)C—CH2—. Preferably, each R12 is independently hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylcarbonyl, C1-C8haloalkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8haloalkoxycarbonyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, aryl-C1-C4alkylene or aryl-C1-C4alkylene where the aryl moiety is substituted by one to three R11, or heteroaryl-C1-C4alkylene or heteroaryl-C1-C4alkylene where the heteroaryl moiety is substituted by one to three R11. More preferably, each R12 is independently hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylcarbonyl, C1-C8haloalkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8haloalkoxycarbonyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, phenyl-C1-C4alkylene or phenyl-C1-C4alkylene where the phenyl moiety is substituted by one to three R11, or pyridyl-C1-C4alkylene or pyridyl-C1-C4alkylene where the pyridyl moiety is substituted by one to three R11.
R13 is halogen or imidazole, preferably chloro, fluoro or bromo.
Each R14 is independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C10cycloalkyl, C1-C6alkyl-C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C6alkylene, C1-C10alkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, or arylsulfonyl or arylsulfonyl substituted by one to five groups independently selected from C1-C4alkyl and nitro; more preferably each R14 is independently hydrogen, C1-C8alkyl, phenylsulfonyl or phenylsulfonyl substituted by one to five groups independently selected from C1-C4alkyl and nitro.
R15 and R16 are each independently hydrogen, C1-C12alkyl or C1-C12alkyl substituted by one to five R8, C3-C8cycloalkyl or C3-C8cycloalkyl substituted by one to five R9, C2-C12alkenyl or C2-C12alkenyl substituted by one to five R8, C2-C12alkynyl or C2-C12alkynyl substituted by one to five R8, cyano, C1-C12alkoxycarbonyl or C1-C12alkoxycarbonyl substituted by one to five R8, C1-C12alkoxythiocarbonyl or C1-C12alkoxythiocarbonyl substituted by one to five R8, or R15 and R16 together with the carbon atom to which they are attached may form a 3 to 6-membered carbocyclic ring. Preferably, R15 and R16 are each independently hydrogen, C1-C1 alkyl, C1-C12haloalkyl, C3-C8cycloalkyl, C3-C8halocycloalkyl, C2-C12alkenyl or C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl cyano, C1-C12alkoxycarbonyl, C1-C12haloalkoxycarbonyl, C1-C12alkoxythiocarbonyl, C1-C12haloalkoxythiocarbonyl, or R15 and R16 together with the carbon atom to which they are attached may form a 3 to 6-membered carbocyclic ring. Preferably, R15 and R16 are each independently hydrogen, halogen, cyano, C1-C4alkyl or C1-C4haloalkyl.
R17 is hydrogen, NH2, hydroxyl, C1-C12 alkoxy or C1-C12alkoxy substituted by one to five R8, C1-C12alkylcarbonylamino or C1-C12alkylcarbonylamino wherein the alkyl is substituted by one to five R8, C1-C12alkylamino or C1-C12alkylamino wherein the alkyl is substituted by one to five R8, C1-C12alkyl or C1-C12alkyl substituted by one to five R8, C3-C8cycloalkyl or C3-C8cycloalkyl substituted by one to five R9, cyano, C2-C12alkenyl or C2-C12alkenyl substituted by one to five R8, C2-C12alkynyl or C2-C12alkynyl substituted by one to five R8, C1-C12alkylcarbonyl or C1-C12alkylcarbonyl substituted by one to five R8, C1-C12alkoxycarbonyl or C1-C12alkoxycarbonyl substituted by one to five R8 or is selected from CH2—R25, C(═O)R19 and C(═S)R19. Preferably, R17 is hydrogen, NH2, hydroxyl, C1-C12alkoxy, C1-C12haloalkoxy, C1-C12alkylcarbonylamino, C1-C12haloalkylcarbonylamino, C1-C12alkylamino, C1-C12haloalkylamino, C1-C12alkyl, C1-C12haloalkyl, C3- C8cycloalkyl, C3-C8halocycloalkyl, cyano, C1-C12alkenyl, C1-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl, C1-C12alkylcarbonyl, C1-C12haloalkylcarbonyl, C1-C8alkoxycarbonyl, or C1-C8haloalkoxycarbonyl. More preferably, R17 is hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylcarbonyl, or C1-C8alkoxycarbonyl.
R18 is hydrogen, cyano, carbonyl, thiocarbonyl, C1-C12alkylcarbonyl or C1-C12 alkylcarbonyl substituted by one to five R8, C1-C12alkylthiocarbonyl or C1-C12alkylthiocarbonyl substituted by one to five R8, C1-C12alkylaminocarbonyl or C1-C12alkylaminocarbonyl wherein the alkyl is substituted by one to five R8, C1-C12alkylaminothiocarbonyl or C1-C12alkylaminothiocarbonyl wherein the alkyl is substituted by one to five R8, C2-C24 (total carbon number) dialkylaminocarbonyl or C2-C24 (total carbon number) dialkylaminocarbonyl wherein one or both alkyl is substituted by one to five R8, C2-C24 (total carbon number) dialkylaminothiocarbonyl or C2-C24 (total carbon number) dialkylaminothiocarbonyl wherein one or both alkyl is substituted by one to five R8, C1-C12alkoxyaminocarbonyl or C1-C12alkoxyaminocarbonyl wherein the alkoxy is substituted by one to five R8, C1-C12alkoxyaminothiocarbonyl or C1-C12alkoxyaminothiocarbonyl wherein the alkoxy is substituted by one to five R8, C1-C12alkoxycarbonyl or C1-C12alkoxycarbonyl substituted by one to five R8, C1-C12alkoxythiocarbonyl or C1-C12alkoxythiocarbonyl substituted by one to five R8, C1-C12thioalkoxycarbonyl or C1-C12thioalkoxycarbonyl substituted by one to five R8, C1-C12thioalkoxythiocarbonyl or C1-C12thioalkoxythiocarbonyl substituted by one to five R8, C1-C12alkylsulfonyl or C1-C12alkylsulfonyl substituted by one to five R8, C3-C12cycloalkylcarbonyl or C3-C12cycloalkylcarbonyl substituted by one to five R9, C2-C12alkenylcarbonyl or C2-C12alkenylcarbonyl substituted by one to five R8, C2-C12alkynylcarbonyl or C2-C12alkynylcarbonyl substituted by one to five R8, C3-C12cycloalkyl-C1-C12alkylcarbonyl or C3-C12cycloalkyl-C1-C12alkylcarbonyl substituted by one to five R9, C1-C12alkylsulfenyl-C1-C12alkylcarbonyl or C1-C12alkylsulfenyl-C1-C12alkylcarbonyl substituted by one to five R8, C1-C12alkylsulfinyl-C1-C12alkylcarbonyl or C1-C12alkylsulfinyl-C1-C12alkylcarbonyl substituted by one to five R8, C1-C12 alkylsulfonyl-C1-C12alkylcarbonyl or C1-C12alkylsulfonyl-C1-C12alkylcarbonyl substituted by one to five R8, C1-C12alkylcarbonyl-C1-C12alkylcarbonyl or C1-C12alkylcarbonyl-C1-C12alkylcarbonyl substituted by one to five R8, C3-C12cycloalkylaminocarbonyl or C3-C12cycloalkylaminocarbonyl wherein the cycloalkyl is substituted by one to five R9, C2-C12alkenylaminocarbonyl or C2-C12alkenylaminocarbonyl wherein the alkenyl is substituted by one to five R8, C2-C12alkynylaminocarbonyl or C2-C12alkynylaminocarbonyl wherein the alkynyl is substituted by one to five R8, or is selected from C(═O)R19 and C(═S)R19. Preferably R18 is hydrogen, cyano, carbonyl, thiocarbonyl, C1-C12alkylcarbonyl, C1-C12haloalkylcarbonyl, C1-C12alkylthiocarbonyl, C1-C12haloalkylthiocarbonyl, C1-C12alkylaminocarbonyl, C1-C12alkylaminothiocarbonyl, C2-C24 (total carbon number) dialkylaminocarbonyl, C2-C24 (total carbon number) dialkylaminothiocarbonyl, C1-C12alkoxyaminocarbonyl, C1-C12alkoxyaminothiocarbonyl, C1-C12alkoxycarbonyl, C1-C12haloalkoxycarbonyl, C1-C12alkoxythiocarbonyl, C1-C12haloalkoxythiocarbonyl, C1-C12thioalkoxycarbonyl, C1-C12thioalkoxythiocarbonyl, C1- C12alkylsulfonyl, C1-C12haloalkylsulfonyl, C3-C12cycloalkylcarbonyl, C3-C12halocycloalkylcarbonyl, C2-C12alkenylcarbonyl, C2-C12haloalkenylcarbonyl, C2-C12 alkynylcarbonyl, C2-C12haloalkynylcarbonyl, C3-C12cycloalkyl-C1-C12alkylcarbonyl, C3-C12halocycloalkyl-C1-C12alkylcarbonyl, C2-C12alkylsulfenyl-C1-C12alkylcarbonyl, C2-C12haloalkylsulfenyl-C1-C12alkylcarbonyl, C1-C12alkylsulfinyl-C1-C12alkylcarbonyl, C1-C12haloalkylsulfinyl-C1-C12alkylcarbonyl, C1-C12alkylsulfonyl-C1-C12alkylcarbonyl, C1-C12haloalkylsulfonyl-C1-C12alkylcarbonyl, C1-C12alkylcarbonyl-C1-C12alkylcarbonyl, C1-C12haloalkylcarbonyl-C1-C12alkylcarbonyl, C3-C12cycloalkylaminocarbonyl, C2-C12alkenylaminocarbonyl, C2-C12alkynylaminocarbonyl. More preferably, R18 is C1-C4alkylcarbonyl or C1-C4alkylcarbonyl substituted by one to five R8, C3-C6 cycloalkylcarbonyl or C3-C6cycloalkylcarbonyl wherein the cycloalkyl is substituted by one to five R9; even more Preferably, R18 is C1-C4alkylcarbonyl, C1-C4haloalkylcarbonyl, C3-C6cycloalkylcarbonyl or C3-C6halocycloalkylcarbonyl.
R17 and R18 together with the nitrogen atom to which they are bound may form a 3- to 6-membered heterocyclic ring which may be substituted by one to five R11, or may be substituted with a keto, thioketo or nitroimino group.
R19 is aryl or aryl substituted by one to five R11, heterocyclyl or heterocyclyl substituted by one to five R11. The aryl is preferably phenyl and the heterocyclyl is preferably pyridyl.
R20 is hydrogen or C1-C5alkyl.
Each R21 and R22 is independently hydrogen, halogen, C1-C5alkyl or C1-C8haloalkyl.
Each Z1 is independently halogen, C1-C12alkyl or C1-C12alkyl substituted by one to five R8, nitro, C1-C12alkoxy or C1-C12alkoxy substituted by one to five R8, cyano, C1-C12alkylsulfinyl, C1-C12 alkylsulfonyl, C1-C12haloalkylsulfinyl, C1-C12haloalkylsulfonyl, hydroxyl or thiol.
Preferably each Z1 is independently halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, or C1-C4haloalkoxy, more preferably each Z1 is independently hydrogen, halogen, methyl, halomethyl, methoxy or halomethoxy.
R26 is hydrogen, azido, halogen, hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkoxycarbonyl or —CO2H, more preferably —N(R28)(R29), halogen, hydroxy, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkoxycarbonyl, C1-C8haloalkoxycarbonyl, or —CO2H.
R27 is hydrogen, halogen, hydroxy, optionally substituted amino, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aloxycarbonyl, more preferably hydrogen, halogen, hydroxy, hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C8haloalkoxy, more preferably hydrogen, C1-C8alkyl, C1-C8alkoxy, or C1-C8haloalkoxy.
R26 and R27 may together be oxo, optionally substituted oxime, optionally substituted imine and optionally substituted hydrazone
R28 is hydrogen, cyano, formyl, thioformyl, alkylcarbonyl, haloalkylcarbonyl, alkyl-thiocarbonyl, haloalkyl-thiocarbonyl, mono- or di-alkylaminocarbonyl, mono- or di-alkylamino-thiocarbonyl, alkoxyaminocarbonyl, alkoxyamino-thiocarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxy-thiocarbonyl, alkylthio-carbonyl, alkylthio-thiocarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkynylalkylcarbonyl, cycloalkyl-alkylcarbonyl, alkylthioalkyl-carbonyl, alkylsulfinylalkylcarbonyl, alkylsulfonylalkylcarbonyl, alkylcarbonylalkylcarbonyl, cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, —CH2—R30, —C(O)R30 or —C(S)R30, and each group from alkylcarbonyl to alkynylaminocarbonyl among the definitions of R8 may be substituted; preferably R28 is hydrogen, cyano, formyl, thioformyl, C1-C12alkylcarbonyl, C1-C12haloalkyl-carbonyl, C1-C12alkyl-thiocarbonyl, C1-C12haloalkyl-thiocarbonyl, mono-C1-C12 or di-C2-C24alkyl-aminocarbonyl, mono-C1-C12 or di-C2-C24alkylamino-thiocarbonyl, C1-C12alkoxy-aminocarbonyl, C1-C12alkoxyamino-thiocarbonyl, C1-C12alkoxy-carbonyl, C1-C12alkoxy-C1-C12alkyl-carbonyl, C1-C12alkoxy-thiocarbonyl, C1-C12alkylthio-carbonyl, C1-C12alkylthio-thiocarbonyl, C1-C12alkylsulfonyl, C1-C12haloalkylsulfonyl, C3-C8cycloalkyl-carbonyl, C2-C6alkenyl-carbonyl, C2-C6alkynyl-carbonyl, C2-C6alkynyl-C1-C12alkyl-carbonyl, C3-C8cycloalkyl-C1-C12alkyl-carbonyl, C1-C12alkylthio-C1-C12alkyl-carbonyl, C1-C12alkyl-sulfinyl-C1-C12alkyl-carbonyl, C1-C12alkylsulfonyl-C1-C12alkyl-carbonyl, C1-C12alkylcarbonyl-C1-C12alkyl-carbonyl, C3-C8cycloalkylamino-carbonyl, C2-C6alkenylamino-carbonyl, C2-C6alkynylamino-carbonyl, —CH2—R10, —C(O)R10, or —C(S)R10, and each group from C1-C12alkyl-carbonyl to C2-C6alkynyl-amino-carbonyl, among the definitions of R8 may be optionally substituted; more preferably R28 is hydrogen, cyano, carbonyl, thiocarbonyl, C1-C6alkyl-carbonyl, C1-C6haloalkyl-carbonyl, C1-C6alkyl-thiocarbonyl, C1-C6haloalkyl-thiocarbonyl, mono-C1-C6 or di-C2-C12) alkyl-aminocarbonyl, mono-C1-C6 or di-C2-C12)alkylamino-thiocarbonyl, C1-C6alkoxy-aminocarbonyl, C1-C6alkoxyamino-thiocarbonyl, C1-C6alkoxy-carbonyl, C1-C6alkoxy-C1-C6alkyl-carbonyl, C1-C6alkoxy-thiocarbonyl, C1-C6alkylthio-carbonyl, C1-C6alkylthio-thiocarbonyl, C1-C6alkylsulfonyl, C1-C6haloalkylsulfonyl, C3-C6cycloalkyl-carbonyl, C2-C4 alkenyl-carbonyl, C2-C4alkynyl-carbonyl, C2-C4alkynyl-C1-C2alkyl-carbonyl, C3-C6cycloalkyl-C1-C2alkyl- carbonyl, C1-C6alkylthio-C1-C6alkyl-carbonyl, C1-C6alkylsulfinyl-C1-C6alkyl-carbonyl, C1-C6 alkylsulfonyl-C1-C6alkyl-carbonyl, C1-C6alkylcarbonyl-C1-C6alkyl-carbonyl, C3-C6cycloalkylamino-carbonyl, C2-C4 alkenylamino-carbonyl, C1-C6alkynylamino-carbonyl, —CH2—R30-, —C(O)R30 or —C(S)R30 and each group from C1-C6alkyl-carbonyl to C1-C6alkynylamino-carbonyl among the definitions of R28 may be optionally substituted. In one group of compounds R8 is C1-C6alkyl-carbonyl, C1-C6haloalkyl-carbonyl, C3-C6cycloalkyl-C1-C2alkyl-carbonyl or C3-C6cycloalkyl-carbonyl.
R29 is hydrogen, amino, hydroxy, cyano, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, alkylimino, alkoxy, alkylcarbonyl, alkylcarbonylamino, alkoxyalkyl, cyanoalkyl, alkoxycarbonylalkyl, —CH2—R30, —C(O)R30 or —C(S)R30, and each group from alkyl to alkylcarbonylamino among the definitions of R9 may be substituted;
preferably R29 is hydrogen, amino, hydroxy, cyano, C1-C12alkyl, C1-C12haloalkyl, C3-C8cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C12alkylimino, C1-C12alkoxy, C1-C12alkyl-carbonyl, C1-C12alkyl-carbonylamino, C1-C12alkoxy-C1-C12alkyl, C1-C12cyanoalkyl, C1-C12alkoxycarbonyl-C1-C12alkyl, —CH2—R30, —C(O)R30, or —C(S)R30 and each group from C1-C12alkyl alkyl to C1-C12alkoxycarbonyl-C1-C12alkyl among the definitions of R29 may be optionally substituted; preferably R29 is hydrogen, amino, hydroxy, cyano, C1-C6alkyl, C1-C12haloalkyl, C3-C6 cycloalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6alkylimino, C1-C6alkoxy, C1- C6alkyl-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-C1-C6alkyl, C3-C6cyanoalkyl, C1-C6alkoxycarbonyl-C1-C6alkyl, —CH2—R30, —C(O)R30 or —C(S)R30, and each group from C1-C6alkyl to C1-C6alkoxycarbonyl-C1-C6alkyl, among the definitions of R29 may be optionally substituted. In one group of compounds R9 is hydrogen, C1-C6alkoxy or benzyl.
R28 and R29, together with the N atom to which they are bound, may form a 3- to 6-membered heterocyclic ring which may be substituted and may further comprise N, O or S.
R30 is phenyl which may be substituted, a 5- to 6-membered heterocyclic group which may be substituted and comprises at least one of N, O and S, optionally substituted C1-C12alkyl, amino, mono-C1-C12 or di(C2-C24)alkylamino; preferably optionally substituted phenyl, pyridyl, pyrimidinyl, or a group (H1) to (H9), or an optionally substituted C1-C6alkyl, amino, mono-C1-C6 or di(C1-C12)alkylamino group.
Preferably R100 is C1-C12 alkyl, phenyl or heteroaryl as defined above, optionally substituted with one to five groups independently selected from cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy, more preferably C1-C6alkyl, most preferably ethyl.
In one group of compounds, group A1 (applicable to all compounds of the invention bearing a group R1 and R2):
R1 is trifluoromethyl.
R2 is group A




B1, B2, B3, B4 are independently C-Q1 or nitrogen;
each Q1 is independently hydrogen, halogen, cyano, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy or C1-C8haloalkoxy.
In one group of compounds, group A2, (applicable to all compounds bearing the group A′) A′ is selected from P1 to P6;
A1, A2, A3, and A4 are independently of each other C—H, C—R5, or nitrogen;
A1′, A2′, A3′, A4′, A5′ and A6′ are independently of each other C—H, C—R5 or nitrogen provided that no more than two of A1′, A2′, A3′, A4′, A5′ and A6′ are nitrogen;
each R5 is independently hydrogen, halogen, C1-C8alkyl, C1-C8haloalkyl or C2-C8alkenyl;
Q is cyano, halogen, nitro, NH2, arylsulfonyl or arylsulfonyl substituted by one to five groups independently selected from C1-C4alkyl and nitro, heterocyclyl or heterocyclyl substituted by one to five Z1, —OR14, —C(═O)N(R6)R7, —CO(═O)R7a, —C(═O)R13, or —C(R15)(R16)N(R17)R18;
k is 0, 1, or 2;
R6 is hydrogen, methyl, ethyl, methylcarbonyl or methoxycarbonyl;
R7 is hydrogen, C1-C8alkyl or C1-C8alkyl substituted by one to five R8, C3-C10cycloalkyl or C3-C10cycloalkyl substituted by one to five R9, aryl-C1-C6alkylene or aryl-C1-C6alkylene wherein the aryl moiety is substituted by one to five R10, heterocyclyl-C1-C6alkylene or heterocyclyl-C1-C6alkylene wherein the heterocyclyl moiety is substituted by one to five R10 and wherein each heterocyclyl moiety contains one or more ring members independently selected from O, N, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 and SO═N—R12, aryl or aryl substituted by one to five R10, heterocyclyl or heterocyclyl substituted by one to five R10 and wherein each heterocyclyl moiety contains one or more ring members independently selected from O, N, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 and SO═N—R12, C1-C8 alkyl-N(R6)—C(═O)—C1-C4 alkylene, C1-C8haloalkyl-N(R6)—C(═O)—C1-C4alkylene, C3-C8cycloalkylaminocarbonyl-C1-C4alkylene, C1-C6alkyl-O—N═CH—, or C1-C6haloalkyl-O—N═CH;
R7a is hydrogen, C1-C15alkyl or C1-C15alkyl substituted by one to five R8, C2-C15alkenyl or C2-C15alkenyl substituted by one to five R8, C2-C15alkynyl or C2-C15alkynyl substituted by one to five R8, C3-C10cycloalkyl or C3-C10cycloalkyl substituted by one to five R9, aryl-C1-C6alkylene or aryl-C1-C6alkylene wherein the aryl moiety is substituted by one to five R10, heteroaryl-C1-C6alkylene or heteroaryl-C1-C6alkylene wherein the heteroaryl moiety is substituted by one to five R10, or heteroaryl or heteroaryl substituted by one to five R10;
R7b is hydrogen, C1-C15 alkyl, C1-C15haloalkyl, C2-C15 alkenyl, C2-C15haloalkenyl, C2-C15 alkynyl, C2-C15haloalkynyl, C3-C10cycloalkyl, C1-C15 alkylcarbonyl or C1-C15alkoxycarbonyl;
each R8 is independently halogen, cyano, nitro, hydroxy, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, mercapto, C1-C8alkylthio, C1-C8haloalkylthio, C1-C8 alkylsulfinyl, C1-C8haloalkylsulfinyl, C1-C8alkylsulfonyl;
each R9 is independently halogen or C1-C8alkyl. Preferably, each R9 is independently chloro, fluoro or methyl;
each R10 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy;
each R11 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy or C1-C8alkoxycarbonyl;
each R12 is independently hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylcarbonyl, C1-C8haloalkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8haloalkoxycarbonyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, aryl-C1-C4alkylene or aryl-C1-C4alkylene where the aryl moiety is substituted by one to three R11, or heteroaryl-C1-C4alkylene or heteroaryl-C1-C4alkylene where the heteroaryl moiety is substituted by one to three R11;
R13 is halogen or imidazole;
each R14 is independently hydrogen, C1-C8alkyl, phenylsulfonyl or phenylsulfonyl substituted by one to five groups independently selected from C1-C4alkyl and nitro;
R15 and R16 are each independently hydrogen, C1-C12alkyl, C1-C12haloalkyl, C3-C8cycloalkyl, C3-C8halocycloalkyl, C2-C12alkenyl or C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl cyano, C1-C12alkoxycarbonyl, C1-C12haloalkoxycarbonyl, C1-C12alkoxythiocarbonyl, C1-C12haloalkoxythiocarbonyl, or R15 and R16 together with the carbon atom to which they are attached may form a 3 to 6-membered carbocyclic ring;
R17 is hydrogen, NH2, hydroxyl, C1-C12alkoxy, C1-C12haloalkoxy, C1-C12alkylcarbonylamino, C1-C12haloalkylcarbonylamino, C1-C12alkylamino, C1-C12haloalkylamino, C1-C12alkyl, C1-C12haloalkyl, C3-C8cycloalkyl, C3-C8halocycloalkyl, cyano, C1-C12alkenyl, C1- C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl, C1-C12alkylcarbonyl, C1-C12haloalkylcarbonyl, C1-C8alkoxycarbonyl, or C1-C8haloalkoxycarbonyl;
R18 is hydrogen, cyano, carbonyl, thiocarbonyl, C1-C12alkylcarbonyl, C1-C12haloalkylcarbonyl, C1-C12alkylthiocarbonyl, C1-C12haloalkylthiocarbonyl, C1-C12alkylaminocarbonyl, C1-C12alkylaminothiocarbonyl, C2-C24 (total carbon number) dialkylaminocarbonyl, C2-C24 (total carbon number) dialkylaminothiocarbonyl, C1-C12alkoxyaminocarbonyl, C1-C12alkoxyaminothiocarbonyl, C1-C12alkoxycarbonyl, C1-C12haloalkoxycarbonyl, C1-C12alkoxythiocarbonyl, C1-C12haloalkoxythiocarbonyl, C1-C12thioalkoxycarbonyl, C1-C12thioalkoxythiocarbonyl, C1-C12alkylsulfonyl, C1-C12haloalkylsulfonyl, C3-C12cycloalkylcarbonyl, C3-C12halocycloalkylcarbonyl, C2-C12alkenylcarbonyl, C2-C12haloalkenylcarbonyl, C2-C12 alkynylcarbonyl, C2-C12haloalkynylcarbonyl, C3-C12cycloalkyl-C1-C12alkylcarbonyl, C3-C12halocycloalkyl-C1-C12alkylcarbonyl, C2-C12alkylsulfenyl-C1-C12alkylcarbonyl, C2-C12haloalkylsulfenyl-C1-C12alkylcarbonyl, C1-C12alkylsulfinyl-C1-C12alkylcarbonyl, C1-C12haloalkylsulfinyl-C1-C12alkylcarbonyl, C1-C12alkylsulfonyl-C1-C12alkylcarbonyl, C1-C12haloalkylsulfonyl-C1-C12alkylcarbonyl, C1-C12alkylcarbonyl-C1-C12alkylcarbonyl, C1-C12haloalkylcarbonyl-C1-C12alkylcarbonyl, C3-C12cycloalkylaminocarbonyl, C2-C12alkenylaminocarbonyl, C2-C12alkynylaminocarbonyl. More preferably, R18 is C1-C4alkylcarbonyl or C1-C4alkylcarbonyl substituted by one to five R8, C3-C6 cycloalkylcarbonyl or C3-C6cycloalkylcarbonyl wherein the cycloalkyl is substituted by one to five R9; even more Preferably, R18 is C1-C4alkylcarbonyl, C1-C4haloalkylcarbonyl, C3-C6cycloalkylcarbonyl or C3-C6halocycloalkylcarbonyl;
R17 and R18 together with the nitrogen atom to which they are bound may form a 3- to 6-membered heterocyclic ring which may be substituted by one to five R11, or may be substituted with a keto, thioketo or nitroimino group;
R19 is aryl or aryl substituted by one to five R11, heterocyclyl or heterocyclyl substituted by one to five R11 wherein aryl is phenyl and the heterocyclyl is preferably pyridyl;
R20 is hydrogen or C1-C8alkyl;
each R21 and R22 is independently hydrogen, halogen, C1-C8alkyl or C1-C8haloalkyl;
each Z1 is independently halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, or C1-C4haloalkoxy;
R26 is —N(R28)(R29), halogen, hydroxy, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkoxycarbonyl, C1-C8haloalkoxycarbonyl, or —CO2H;
R27 is hydrogen, halogen, hydroxy, hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C8haloalkoxy, more preferably hydrogen, C1-C8alkyl, C1-C8alkoxy, or C1-C8haloalkoxy;
R26 and R27 may together be oxo, optionally substituted oxime, optionally substituted imine and optionally substituted hydrazone;
R28 is hydrogen, cyano, formyl, thioformyl, C1-C12alkylcarbonyl, C1-C12haloalkyl-carbonyl, C1-C12alkyl-thiocarbonyl, C1-C12haloalkyl-thiocarbonyl, mono- C1-C12 or di-C2-C24alkyl-aminocarbonyl, mono-C1-C12 or di-C2-C24alkylamino-thiocarbonyl, C1-C12alkoxy-aminocarbonyl, C1-C12alkoxyamino-thiocarbonyl, C1-C12alkoxy-carbonyl, C1-C12alkoxy-C1-C12alkyl-carbonyl, C1-C12alkoxy-thiocarbonyl, C1-C12alkylthio-carbonyl, C1-C12alkylthio- thiocarbonyl, C1-C12alkylsulfonyl, C1-C12haloalkylsulfonyl, C3-C8cycloalkyl-carbonyl, C2-C6alkenyl-carbonyl, C2-C6alkynyl-carbonyl, C2-C6alkynyl-C1-C12alkyl-carbonyl, C3-C8cycloalkyl-C1-C12alkyl-carbonyl, C1-C12alkylthio-C1-C12alkyl-carbonyl, C1-C12alkyl-sulfinyl-C1-C12alkyl-carbonyl, C1-C12alkylsulfonyl-C1-C12alkyl-carbonyl, C1-C12alkylcarbonyl-C1-C12alkyl-carbonyl, C3-C8cycloalkylamino-carbonyl, C2-C6alkenylamino-carbonyl, C2-C6alkynylamino-carbonyl, —CH2—R10, —C(O)R10, or —C(S)R10, and each group from C1-C12alkyl-carbonyl to C2-C6alkynyl-amino-carbonyl, among the definitions of R8 may be optionally substituted;
R29 is hydrogen, amino, hydroxy, cyano, C1-C12alkyl, C1-C12haloalkyl, C3-C8cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C12alkylimino, C1-C12alkoxy, C1-C12alkyl-carbonyl, C1-C12alkyl-carbonylamino, C1-C12alkoxy-C1-C12alkyl, C1-C12cyanoalkyl, C1-C12alkoxycarbonyl-C1-C12alkyl, —CH2—R30, —C(O)R30, or —C(S)R30 and each group from C1-C12alkyl alkyl to C1-C12alkoxycarbonyl-C1-C12alkyl among the definitions of R29 may be optionally substituted;
R28 and R29, together with the N atom to which they are bound, may form a 3- to 6-membered heterocyclic ring which may be substituted and may further comprise N, O or S;
optionally substituted phenyl, pyridyl, pyrimidinyl, or a group (H1) to (H9), or an optionally substituted C1-C6alkyl, amino, mono-C1-C6 or di(C1-C12)alkylamino group;
wherein unless otherwise stated optionally substituents are independently selected from cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy.
In one group of compounds, group A3, (applicable to all compounds of the invention bearing group A′) A′ is P1 or P2;
A1, A2 and A3 are C—H;
Q is cyano, halogen, nitro, NH2, C1-C8alkoxy, phenylsulfonyl or phenylsulfonyl substituted by one to five groups independently selected from C1-C4 alkyl and nitro, —C(═O)N(R6)R7, —CO(═O)R7a, —C(═O)R13, —C(R15)(R16)N(R17)R18, or a heterocycle selected from H1 to H9;
k is 0, 1 or 2, preferably 0;
each R5 is independently halogen, C1-C8alkyl, C1-C8haloalkyl or C2-C8alkenyl;
R6 is hydrogen;
R7 is hydrogen, C1-C8alkyl, C1-C8haloalkyl, phenyl-C1-C6alkylene or phenyl-C1-C6alkylene wherein the phenyl moiety is substituted by one to five R10, pyridyl-C1-C6alkylene or pyridyl-C1-C6alkylene wherein the pyridyl moiety is substituted by one to four R10, thiazolyl-C1-C6alkylene or thiazolyl-C1-C6alkylene wherein the thiazolyl moiety is substituted by one or two R10, phenyl or phenyl substituted by one to five R10, pyridyl or pyridyl substituted by one to four R10, thiazolyl or thiazolyl substituted by one or two R10, C3-C6cycloalkyl or C3-C6cycloalkyl wherein one ring atom is replaced by O or S, C1-C4alkyl O—N═CH—, C1-C4haloalkyl-O—N═CH—, C1-C4alkyl-N(R6)—C(═O)—CH2—, C1-C4haloalkyl-N(R6)—C(═O)—CH2—, or a group of formula (Y)




L is a single bond or C1-C6alkylene, preferably a bond;
Y1, Y2 and Y3 are independently of another O, CR21R22, C═O, C═N—OR12, N—R12, S, SO, SO2, S═N—R12 or SO═N—R12, provided that at least one of Y1, Y2 or Y3 is not CR21R22, C═O or C═N—OR12, preferably two of Y1, Y2 and Y3 are CH2 and the other is S, SO or SO;
R7a is C1-C15alkyl, C1-C15haloalkyl, C2-C15alkenyl, C2-C15haloalkenyl, pyridyl or benzyl;
each R8 is independently halogen, cyano, nitro, hydroxy, C1-C8alkoxy, C1-C8haloalkoxy, mercapto, C1-C8alkylthio, C1-C8haloalkylthio;
each R9 is independently halogen or C1-C8alkyl;
each R10 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy;
each R11 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy or C1-C8alkoxycarbonyl;
each R12 is independently hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylcarbonyl, C1-C8haloalkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8haloalkoxycarbonyl, C1-C8alkylsulfonyl, C1-C8haloalkylsulfonyl, phenyl-C1-C4alkylene or phenyl-C1-C4alkylene where the phenyl moiety is substituted by one to three R11, or pyridyl-C1-C4alkylene or pyridyl-C1-C4alkylene where the pyridyl moiety is substituted by one to three R11;
R13 is halogen or imidazole, preferably chloro, fluoro or bromo;
R15 and R16 are each independently hydrogen, halogen, cyano, C1-C4alkyl or C1-C4haloalkyl;
R17 is hydrogen, C1-C5alkyl, C1-C5alkoxy, C1-C5alkylcarbonyl, or C1-C5alkoxycarbonyl;
R18 is C1-C4alkylcarbonyl or C1-C4alkylcarbonyl substituted by one to five R8, C3-C6 cycloalkylcarbonyl or C3-C6cycloalkylcarbonyl wherein the cycloalkyl is substituted by one to five R9;
R20 is hydrogen or C1-C5alkyl, preferably hydrogen;
each Z1 is independently hydrogen, halogen, methyl, halomethyl, methoxy or halomethoxy;
R26 is —N(R28)(R29), halogen, hydroxy, C1-C5alkoxy, C1-C8haloalkoxy, C1-C5alkoxycarbonyl, C1-C5haloalkoxycarbonyl, or —CO2H;
R27 is hydrogen, C1-C5alkyl, C1-C5alkoxy, or C1-C8haloalkoxy.
R28 is C1-C6alkyl-carbonyl, C1-C6haloalkyl-carbonyl, C3-C6cycloalkyl-C1-C2alkyl-carbonyl or C3-C6cycloalkyl-carbonyl;
R29 is hydrogen, C1-C6alkoxy or benzyl.
In one group of compounds, group A4, applicable to all compounds of the invention bearing a group R1, R2 and A′, R1 and R2 are as defined in group A1 and A′ is as defined in group A2.
In one group of compounds, group A5, applicable to all compounds of the invention bearing a group R1, R2 and A′, R1 and R2 are as defined in group A1 and A′ is as defined in group A3.
In one group of compounds, group A6, applicable to all compounds of the invention bearing a group P, P is C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2,4-triazolyl, N-benzotriazolyl, or C1-C6alkylsulfinyl.
In one group of compounds, group A7, applicable to all compounds of the invention bearing a group P, optionally P is not C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2,4-triazolyl, N-benzotriazolyl, or C1-C6alkylsulfinyl.
In one group of compounds, group A8, applicable to all compounds of the invention bearing a group R2, R2 is aryl or aryl substituted by one to five R70, or heteroaryl or heteroaryl substituted by one to five R70, preferably phenyl or phenyl substituted by one to five R70, more preferably phenyl substituted by one to three R70, even more preferably R2 is 3-chloro-5-trifluoromethyl-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,5-dichloro-4-fluoro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-, most preferably 3,5-dichloro-phenyl; each R70 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, hydroxy, C1-C8alkoxy-, C1-C8haloalkoxy-, mercapto, C1-C5alkylthio-, C1-C8haloalkylthio-, C1-C8alkylsulfinyl-, C1-C8haloalkylsulfinyl-, C1-C5alkylsulfonyl-, C1-C8haloalkylsulfonyl-, C1-C5alkylcarbonyl-, C1-C5alkoxycarbonyl-, aryl or aryl substituted by one to five R71, or heterocyclyl or heterocyclyl substituted by one to five R71; preferably halogen, cyano, C1-C5alkyl, C1-C8haloalkyl or C1-C8alkoxy-, more preferably bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy, preferably bromo, chloro, fluoro or trifluoromethyl, most preferably bromo or chloro; each R71 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy-, C1-C8haloalkoxy- or C1-C8alkoxycarbonyl-, preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro or methyl, most preferably chloro, fluoro or methyl.
In one group of compounds, group A9, applicable to all compounds of the invention bearing a group R2, optionally R2 is not aryl or aryl substituted by one to five R70, or heteroaryl or heteroaryl substituted by one to five R70, each R70 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2- C8alkynyl, C2-C8haloalkynyl, hydroxy, C1-C8alkoxy-, C1-C8haloalkoxy-, mercapto, C1-C8alkylthio-, C1-C8haloalkylthio-, C1-C8alkylsulfinyl-, C1-C8haloalkylsulfinyl-, C1-C8alkylsulfonyl-, C1-C8haloalkylsulfonyl-, C1-C8alkylcarbonyl-, C1-C5alkoxycarbonyl, aryl or aryl substituted by one to five R71, or heterocyclyl or heterocyclyl substituted by one to five R71; each R71 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy-, C1-C8haloalkoxy- or C1-C8alkoxycarbonyl-.
In one group of compounds, group A10, applicable to all compounds of the invention bearing a group R2, R2 is phenyl substituted by one to three R7; each R7 is independently halogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C1-C8alkoxy-;
In one group of compounds, group A11, applicable to all compounds of the invention bearing a group R2, optionally R2 is not phenyl substituted by one to three R70; each R70 is independently halogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C1-C8alkoxy-;
In one group of compounds, group A12, applicable to all compounds of the invention bearing a group R2, R2 is 3-chloro-5-trifluoromethyl-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,5-dichloro-4-fluoro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-.
In one group of compounds, group A13, applicable to all compounds of the invention bearing a group R2, optionally R2 is not 3-chloro-5-trifluoromethyl-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,5-dichloro-4-fluoro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-.
In one group of compounds, group A14, applicable to all compounds of the invention bearing a group R2, R2 is aryl or aryl substituted by one to five R70, or heteroaryl or heteroaryl substituted by one to five R70, preferably phenyl or phenyl substituted by one to five R7; each R70 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, hydroxy, C1-C8alkoxy-, C1-C8haloalkoxy-, mercapto, C1-C8alkylthio-, C1-C8haloalkylthio-, C1-C8alkylsulfinyl-, C1-C8haloalkylsulfinyl-, C1-C8alkylsulfonyl-, C1-C8haloalkylsulfonyl-, C1-C5alkylcarbonyl-, C1-C8alkoxycarbonyl-, aryl or aryl substituted by one to five R71, or heterocyclyl or heterocyclyl substituted by one to five R71; each R71 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy-, C1-C8haloalkoxy- or C1-C8alkoxycarbonyl-.
In one group of compounds, group A15, applicable to all compounds of the invention bearing a group R2, optionally R2 is not aryl or aryl substituted by one to five R70, or heteroaryl or heteroaryl substituted by one to five R70, preferably phenyl or phenyl substituted by one to five R7; each R70 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, hydroxy, C1-C8alkoxy-, C1-C8haloalkoxy-, mercapto, C1-C8alkylthio-, C1-C8haloalkylthio-, C1-C8alkylsulfinyl-, C1-C8haloalkylsulfinyl-, C1-C8alkylsulfonyl-, C1-C8haloalkylsulfonyl-, C1-C8alkylcarbonyl-, C1-C8alkoxycarbonyl-, aryl or aryl substituted by one to five R71, or heterocyclyl or heterocyclyl substituted by one to five R71; each R71 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8halo alkyl, C1-C8alkoxy-, C1-C8haloalkoxy- or C1-C8alkoxycarbonyl-.
In one group of compounds, group A16, applicable to all compounds of the invention bearing a group A′, A′ may be group C




A1a, A2a, A3a and A4a are independently of each other C—H, C—R5a or nitrogen;

G1a is oxygen or sulfur;

R1a is hydrogen, C1-C8alkyl, C1-C8alkoxy-, C1-C8alkylcarbonyl-, C1-C8alkoxycarbonyl- or C1-C8haloalkoxycarbonyl-;

R2a is a group of formula D




where

La is a single bond or C1-C6alkylene; and

Y1a, Y2a and Y3a are independently of another CR8aR9a, C═O, C═N—OR10a, N—R10a, S, SO, SO2, S═N—R10a or SO═N—R10a, provided that at least one of Y1a, Y2a or Y3a is not CR8aR9a, C═O or CN—OR10a, preferably thietan-3-yl-, 1-oxo-thietan-3-yl-, 1,1-dioxo-thietan-3-yl- or 3-methyl-thietan-3-yl-, more preferably thietan-3-yl-, 1-oxo-thietan-3-yl-, or 1,1-dioxo-thietan-3-yl-;
each R5a is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C3-C10cycloalkyl, C1-C8alkoxy-, C1-C8haloalkoxy-, C1-C8alkylthio-, C1-C8haloalkylthio-, C1-C8alkylsulfinyl-, C1-C8haloalkylsulfinyl-, C1-C8alkylsulfonyl- or C1-C8haloalkylsulfonyl-, or
two R5a on adjacent carbon atoms together form a —CH═CH—CH═CH— bridge;
R6a is hydrogen, C1-C8haloalkyl or C1-C8alkyl;
each R8a and R9a is independently hydrogen, halogen, C1-C8alkyl or C1-C8haloalkyl;
each R10a is independently hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylcarbonyl-, C1-C8haloalkylcarbonyl-, C1-C8alkoxycarbonyl-, C1-C8haloalkoxycarbonyl-, C1-C8alkylsulfonyl-, C1-C8haloalkylsulfonyl-, aryl-C1-C4alkylene- or aryl-C1-C4alkylene where the aryl moiety is substituted by one to three R12a, or heteroaryl-C1-C4alkylene- or heteroaryl-C1-C4alkylene- where the heteroaryl moiety is substituted by one to three R12a;
each R11a and R12a is independently halogen, cyano, nitro, C1-C5alkyl, C1-C8haloalkyl, C1-C8alkoxy-, C1-C8haloalkoxy- or C1-C5alkoxycarbonyl-.
In one group of compounds, group A17, applicable to all compounds of the invention bearing a group A′, optionally A′ is not A′ as defined in group A16.
Examples of chiral catalysts include chiral cinchona alkaloid derivatives, chiral thiourea derivatives, chiral urea derivatives, chiral aza-crown ether derivatives, chiral metal complexes, chiral amidine and guanidine derivatives, chiral pyrrolidine and imidazolidine derivatives, chiral scandium III complexes, chiral naphthyl phase transfer catalysts, chiral galodinium or strontium catalysts, chiral crown ether derivatives and chiral ligands for alkaline earth metals.
Chiral cinchona alkaloid derivatives are preferred and include alkaloid derivatives of the quaternary ammonium salts, tertiary amine derivatives, urea derivatives, thiourea derivatives and squaramide derivatives.
The term “chiral cinchona alkaloid derivatives” may overlap with the terms “chiral thiourea derivative” and “chiral urea derivative”. Accordingly, the term “Chiral cinchona alkaloid derivatives” may in some embodiments exclude chiral thiourea derivatives and chiral urea derivatives. However, unless explicitly indicated the term “Chiral cinchona alkaloid derivatives” will include the relevant chiral thiourea derivatives and chiral urea derivatives.
In one embodiment the chiral catalysts are thiourea derivatives and chiral urea derivatives, in particular those that contain in the molecule a basic nitrogen atom in addition to the two nitrogen atoms of the urea or thiourea moiety, e.g. a primary, secondary or tertiary amine Examples include chiral cinchona alkaloid thiourea derivatives, chiral cinchona alkaloid urea derivatives, thiourea derivatives of cyclohexanediamine and urea derivatives of cyclohexanediamine Chiral cinchona alkaloid thiourea derivatives and thiourea derivatives of cyclohexanediamine are preferred.
For the nitromethane addition the preferred chiral catalysts are cinchona alkaloid derivatives, chiral thiourea derivatives and chiral metal complexes. These catalysts include those from groups 1, 2, 3, 4, 5, 7 and 11 below. Particularly preferred catalysts for are chiral cinchona alkaloid derivatives, particularly cinchona alkaloid derivatives of quaternary ammonium salts, cinchona alkaloid urea derivatives, cinchona alkaloid thiourea derivatives, and cinchona alkaloid squaramide derivatives. Even more preferred are cinchona alkaloid urea derivatives, cinchona alkaloid thiourea derivatives, most preferred being cinchona alkaloid thiourea derivatives.
For the cyanide addition the preferred catalysts are cinchona alkaloid derivatives, chiral ruthenium catalysts as well as gadolinium and strontium catalysts. These catalysts include those from groups 1, 2, 3, 4, 7 and 13. Most preferred catalysts are derivatives of cinchona alkaloid quaternary ammonium salts.
Examples of cinchona alkaloid quaternary ammonium salt derivatives include compounds of formula 1 (group 1)




wherein

W1 is ethyl or vinyl; R30 is hydrogen or C1-C4alkoxy; R31 is hydroxyl, C1-C4alkoxy, C2-C4alkenyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy or optionally substituted benzyloxy; R32 is optionally substituted aryl or optionally substituted heteroaryl; X is an anion.
Preferably W1 is vinyl.
Preferably R30 is methoxy.
Preferably R31 is hydroxyl, C1-C4alkoxy, C2-C4alkenyloxy, optionally substituted heteroaryloxy or benzyloxy, more preferably hydroxyl, optionally substituted pyrimidinyloxy or benzyloxy, most preferably hydroxyl.
Preferably X is a halogen, more preferably chloride or bromide. Preferably R32 is phenyl or phenyl substituted by one to five R33, naphthyl or naphthyl substituted by one to five R33, anthracenyl or anthracenyl substituted by one to five R33, or heteroaryl or heteroaryl substituted by one to four R33; more preferably R32 is phenyl or phenyl substituted by one to five R33, naphthyl or naphthyl substituted by one to five R33, anthracenyl or anthracenyl substituted by one to five R33, pyrimidinyl or pyrimidinyl substituted by one to three R33, or pyridyl or pyridyl substituted by one to four R33; more preferably phenyl or phenyl substituted by one to five R33, naphthyl or naphthyl substituted by one to five R33, anthracenyl or anthracenyl substituted by one to five R33, or pyridyl or pyridyl substituted by one to four R33; more preferably R32 is phenyl or phenyl substituted by one to five R33, anthracenyl or anthracenyl substituted by one to five R33, or pyridyl or pyridyl substituted by one to four R33; even more preferably R32 is phenyl or phenyl substituted by one to five substituents independently selected from halogen, methyl and methoxy, anthracenyl or anthracenyl substituted by one to five substituents independently selected from halogen, methyl and methoxy, pyridyl or pyridyl substituted by one to four halogen atoms, or group B




or group B substituted by one to four substituents independently selected from halogen, methyl and methoxy, even more preferably phenyl substituted by one to five substituents independently selected from halogen methyl and methoxy, anthracenyl or anthracenyl substituted by one to five substituents independently selected from halogen, methyl and methoxy or pyridyl or pyridyl substituted by one to four halogen atoms, even more preferably phenyl substituted by one to five substituents independently selected from halogen methyl and methoxy or anthracenyl. Each R33 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy, C3-C8cycloalkyl, phenyl or phenyl substituted by one to five halogen, and wherein two R33 substituents on adjacent carbon atoms may together form a partially saturated 5-7 membered ring containing one or two heteroatoms independently selected from O, N(R34) and S; and each R34 is independently hydrogen or C1-C4 alkyl. Preferably each R33 is independently halogen, cyano, nitro, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, aryl or C1-C4haloalkoxy, and wherein any two R33 substituents on adjacent carbon atoms may together form a partially saturated 5 membered ring containing one or two O atoms, more preferably each R33 is independently halogen, methyl, halomethyl, methoxy, phenyl or halomethoxy, and wherein any two R33 substituents on adjacent carbon atoms may together form a partially saturated 5 membered ring containing one or two O atoms, more preferably each R33 is independently halogen, methyl, phenyl or methoxy, most preferably each R33 is independently fluorine, methyl, phenyl or methoxy.

Examples include




























wherein X is an anion, preferably halogen, more preferably chloride or bromide.

Examples of cinchona alkaloid quaternary ammonium salt derivatives are described for example in Arai et al., Tet. Lett. 1999, 4215; S. Colonna, H. Hiemstra, H. Wynberg, J. Chem. Soc. Chem. Commun. 1978, 238; E. J. Corey, F. Y. Zhang, Org. Lett. 2000, 2, 4257; D. Y. Kim, S. C. Huh, Tetrahedron 2001, 57, 8933; M. Hua, H. Cui, L. Wang, J. Nie, J. Ma, Angew. Chem. 2010, 122, 2832; Angew. Chem. Int. Ed. 2010; and T. Ooi, K. Maruoka, Acc. Chem. Res. 2004, 37, 526; Provencher, B. A., Bartelson, K. J., Liu, Y., Foxman, B., Deng, L. Angew. Chem. Int. Ed. 2011, 50, 10565; Liu, Y., Provencher, B. A., Bartelson, K. J., Deng, L. Chem. Sci. 2011, 2, 1301
Examples of cinchona alkaloid tertiary amine derivatives include compounds of formula 2 (group 2)




W2 is ethyl or vinyl; R35 is hydrogen or C1-C4alkoxy; R36 is hydroxyl, C1-C4alkoxy, C2-C4alkenyloxy or optionally substituted benzyloxy.

Preferably W2 is vinyl.
Preferably R35 is methoxy.
Preferably R36 is hydroxyl, C1-C4alkoxy, C2-C4alkenyloxy or benzyloxy, most preferably hydroxyl.
Examples include:




as described in A. Latvala, S. Stanchev, A. Linden, M. Hesse, Tet. Asym. 1993, 2, 173.

Examples of cinchona alkaloid urea and thiourea derivatives include compounds of formula 3 (group 3)




Y is S or O, W3 is ethyl or vinyl; R37 is hydrogen or C1-C4alkoxy; R38 is optionally substituted aryl or optionally substituted C3-C10cycloalkyl.

Preferably Y is S.
Preferably W3 is vinyl or ethyl.
Preferably R37 is methoxy.
Preferably R38 is phenyl optionally substituted by one to five R39 or C5-C6cycloalkyl optionally substituted by R40, more preferably phenyl optionally substituted by one to five R39.
R39 is halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, preferably C1-C4 haloalkyl, more preferably C1-C4haloalkyl.
R40 is NH2, halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, preferably NH2.
Examples include




as described in B. Vakulya, S. Varga, A. Csampai, T. Soós, Org. Lett. 2005, 7, 1967; B. Vakulya, S. Varga, T. Soós, J. Org. Chem. 2008, 73, 3475; P. Li, Y. Wang, X. Liang, J. Ye, Chem. Commun. 2008, 3302; and C. Oliva, A. Silva, F. Paz, J. Calvaleiro, Synlett, 2010, 7, 1123-1127.

Examples of squaramide catalysts include compound of formula 4 (group 4)




wherein W4 is ethyl or vinyl; R54 is hydrogen or C1-C4alkoxy; R55 is optionally substituted aryl.

Preferably W4 is vinyl
Preferably R54 is methoxy.
Preferably R55 is phenyl optionally substituted by one to five R56 or C5-C6cycloalkyl optionally substituted by R40.
R56 is halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, preferably C1-C4haloalkyl.
Examples include those wherein in the compound of formula X, R54 is H or OMe and R55 is 4-CF3—C6H4 or 3,5-(CF3)2—C6H3 as described in Yang, W.; Du, D. Org. Lett., 2010, 12 (23), 5450-5453.
Examples of thiourea derivatives of cyclohexanediamine or diamines (group 5) include the following




Examples of thiourea derivatives of cyclohexanediamine are described in K. Mei, M. Jin, S. Zhang, P. Li, W. Liu, X. Chen, F. Xue, W. Duan, W. Wang, Org. Lett. 2009, 11, 2864, and B. Vakulya, S. Varga, T. Soós, J. Org. Chem. 2008, 73, 3475.
Examples of thiourea derivatives of diamines are described in He, Tianxiong; Qian, Jing-Ying; Song, Hong-Liang; Wu, Xin-Yan Synlett 2009, 19, 3195-319 and Kokotos, C. G.; Kokotos, G., Advanced Synthesis & Catalysis 2009, 351(9), 1355-1362 and Manzano, R.; Andres, J. M.; Alvarez, R.; Muruzabal, M. D.; de Lera, A. R.; Pedrosa, R. Chem. Eur. J. 2011, 17, 5931.
Examples of aza-crown ethers (group 6) include compound of formula 5




R41 is hydrogen, C1-C10alkyl, C1-C10hydroxyalkyl C1-C5alkoxy-C1-C5alkyl, C1-C8alkoxycarbonyl, C1-C8alkyl optionally substituted aryl, aryl-C1-C4alkyl wherein the aryl is optionally substituted, (aryl)2P(O)C1-C4 alkyl wherein each aryl is optionally substituted.

Preferably R41 is hydrogen, C1-C10alkyl, C1-C10hydroxyalkyl, C1-C5alkoxy-C1-C5alkyl, C1-C8alkoxycarbonyl-C1-C5alkyl, phenyl, phenyl-C1-C4alkyl, (phenyl)2P(O)C1-C4 alkyl.
Examples of aza crown ethers include those wherein R41 is C6H5, CH2C6H5, CH3— (CH2)3, CH3—(CH2)9, CH2CH2OH, C6H11, CH2CO2CH3, hydrogen, CH2CH2OCH3, (CH2)4P(O)Ph2.
Examples of aza-crown ethers are described in P. Bakó, A. Szöllösy, P. Bombicz, L. Töke, Synlett 1997, 291 and T. Bakó, P. Bakó, A. Szöllösy, M. Czugler, G. Keglevich, L. Töke, Tet. Asym. 2002, 203.
Examples of chiral metal complexes (group 7) include the following




as described in G. Sundararajan, N. Prabagaran, Org. Lett. 2001, 3, 389;





as described in Kurono, N.; Nii, N.; Sakaguchi, Y.; Uemura, M.; Ohkuma, T. Angew. Chem. Int. Ed. 2011, 50, DOI: 10.1002/anie.201100939





as described in. Keller, N. Veldman, A. L. Spek, B. L. Feringa, Tetrahedron: Asymmetry 1997, 8, 3403; LaK3tris((R)-binaphthoxide)) as described in K. Funabashi, Y. Saida, M. Kanai, T. Arai, H. Sasai, M. Shibasaki, Tetrahedron Lett. 1998, 39, 7557; and





(S,S)-(salen)A1
variations thereof include [(S,S)-(salen)Al]2O, (S,S)-(salen)AlMe, (S,S)-(salen)AlCl and are described in M. S. Taylor, D. N. Zalatan, A. M. Lerchner, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 1313;




in combination with an achiral amine, e.g. 2,2,6,6-tetramethylpiperidine, as described in K. Itoh, S. Kanemasa, J. Am. Chem. Soc. 2002, 124, 13394.

Examples of chiral amidines and guanidines (group 8) include compounds of formula 6




wherein each R42 is C(H)Ph2, or CH2OR43, wherein R43 is t-BuPh2Si, H or benzyl, e.g. as described in A. P. Davis, K. J. Dempsey, Tetrahedron: Asymmetry 1995, 6, 2829;





as described in Zhang, G.; Kumamoto, T.; Heima, T.; Ishikawa, T. Tetrahedron Lett. 2010, 51, 3927.





Where X is a halogen or BF4 of PF6, most preferably chloride as described in Ma, T.; Fu, X.; Kee, C. W.; Zong, L.; Pan, Y.; Huang, K.; Tan, C. J. Am. Chem. Soc. 2011, 133, 2828 and





wherein R44 and R45 are independently C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, TBDMS-C1-C4 alkyl or TBDPS-C1-C4 alkyl, preferably both R44 and R45 are either hydroxymethyl, TMDMS-methyl or TBDPS-methyl, and wherein X is an anion, preferably halogen or BF4—, more preferably chloride or BF4—, e.g. as described in M. T. Allingham, A. Howard-Jones, P. J. Murphy, D. A. Thomas, P. W. R. Caulkett, Tetrahedron Lett. 2003, 44, 8677.

Examples of the pyrrolidine derivatives as chiral catalysts (group 9) include proline, e.g. in combination with trans-2,5-dimethylpiperazine as described in S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975;




as described in C. E. T. Mitchell, S. E. Brenner and S. V. Ley, Chem. Commun., 2005, 5346 and C. E. T. Mitchell, S. E. Brenner, J. Garcia-Fortanet and S. V. Ley, Org. Biomol. Chem., 2006, 4, 2039;





as described in N. Halland, R. G. Hazell, K. A. Jorgensen, J. Org. Chem. 2002, 67, 8331;





as described in C. Oliva, A. Silva, F. Paz, J. Calvaleiro, Synlett, 2010, 7, 1123-1127; and





as described in Xu, D.; Shi, S.; Wang, Y. European Journal of Organic Chemistry 2009, (28), 4848-4853.

Examples of chiral imidazoline catalysts (group 10) include




as described in N. Halland, R. G. Hazell, K. A. Jorgensen, J. Org. Chem. 2002, 67, 8331; and





as described in A. Prieto, N. Halland, K. A. Jøorgensen, Org. Lett. 2005, 7, 3897.

Examples of chiral N,N′-dioxide-scandium III complexes (group 11) include ligand-Sc(OTf)3 complexes wherein the ligand is a compound of formula 7 or 8




wherein R46 and R47 are phenyl optionally substituted by one to five halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and wherein n is 1 or 2;

Examples include those wherein n is 1 and R46 is 2,6-iPr2C6H3; n is 1 and R46 is C6H5; n is 1 and R46 is 2-MeC6H4; n is 2 and R46 is 2,6-iPr2C6H3; R47 is 2,6-iPr2-C6H3; as described in L. Wang, Q. Zhang, X. Zhou, X. Liu, L. Lin, B. Qin, X. Feng, Chemistry-A European Journal, 2010, 16, (26), 7696-7699,

Chiral binaphthyl phase transfer catalysts (group 12) include compounds of formula 11, 12, 13 and 14




wherein R48, R29, R50 and R52 are each independently phenyl or naphthyl optionally substituted by one to five halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy; each R51 is C1-C5 alkyl or C1-C8haloalkyl, R53 is a bond or C1-C8 alkylene and X is an anion, e.g. a halogen, preferably chlorine or bromine Examples include those wherein each R48 is 3,5-(CF3)2(C6H3); each R48 is 3,4,5-F3C6H2; each R49 is 3,5-(CF3)2(C6H3); each R49 is 3,4,5-F3C6H2; each R50 is 3,5-(CF3)2(C6H3); each R50 is 3,4,5-F3C6H2; each R51 is n-butyl; each R52 is H and R53 is a bond; each R52 is H and R53 is ethylene; each R52 is H and R53 is propylene; each R52 is phenyl and R53 is a bond; each R52 is phenyl and R53 is ethylene; each R52 is phenyl and R53 is propylene; each R52 is 3,4,5-F3C6H2 and R53 is a bond; each R52 is 3,4,5-F3C6H2 and R53 is ethylene; each R52 is 3,4,5-F3C6H2 and R53 is propylene; each R52 is, 5-(CF3)2C6H2 and R53 is a bond; each R52 is, 5-(CF3)2C6H2 and R53 is ethylene; each R52 is 3,5-(CF3)2C6H2 and R53 is propylene; each R48 is 2-naphthyl as described in M. Hua, H. Cui, L. Wang, J. Nie, J. Ma, Angew. Chem. 2010, 122, 2832 and T. Ooi, K. Maruoka, Acc. Chem. Res. 2004, 37, 526.

Examples of ligands for galodinium or strontium catalysis (group 13) include compounds of formula 15 and 16




wherein R57 is CN or F, R58 is H or F; each R59 is phenyl or p-tolyl; R60 is OH, OMe or Oi-Bu as described in Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072; Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 8862.

Examples of crown ether phase transfer catalysis (group 14) include compounds of formula XXI




wherein each R61 is is H or benzyl as described in Dehmlow, D. E.; Sauerbier, C. Liebigs Ann. Chem. 1989, 181-185.

Examples of ligands for alkaline earth metal catalysis (group 15) include




as described in Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364; Tsubogo, T.; Saibo, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321; Kobayashi, S.; Tsubogo, T.; Saito, S.; Yamashita, Y. Org. Lett. 2008, 10, 807

It will be clear to the person skilled in the art that in order to prepare the compounds of the invention with the indicated stereochemistry, the stereochemistry of the compound of formula II must be matched with the corresponding stereochemistry of the catalyst. It is understood that the stereochemistry of the catalysts depicted above is appropriate for a compound of formula IA:




The following schemes describe the processes of the invention in more detail. In the schemes below the stereochemistry at * corresponds to the stereochemistry in the claims. The substituent definitions are as defined herein.





1) Enantioenriched compounds of formula (II) can be prepared by reacting a compound of formula (I) with a suitable cyanide source in the presence of a chiral catalyst. Suitable cyanide sources include, but are not limited to alkali metal cyanides, trimethylsilyl and tert-butyldimethylsilyl cyanides, hydrogen cyanide, CNCO2Et and acetone cyanohydrin. Depending from the catalyst used, suitable solvents include dioxane, tetrahydrofuran, dichloromethane, t-butylmethyl ether, 1,2-dichloroethane, dimethoxyethane, xylenes and toluene. In certain cases additives such as cesium fluoride, cesium chloride, lithium phenolate or 2,6-dimethylphenol are often required. In most cases it is advantageous to conduct the reaction in a suitable solvent at dilution between 0.1 M to 1 M, preferably 0.3 M to 0.5 M. The reaction temperature could be from −40° C. to 100° C., preferably between −20° C. and 50° C. The reaction time is usually between 1 hour and 96 hours, preferably between 6 hours and 24 hours. The amount of catalyst is usually between 0.02 and 0.2 molar equivalents, preferably between 0.05 and 0.1 molar equivalents. Certain catalysts require a presence of a Lewis acid, such as galodinium trifluoromethansulfonate or strontium trifluoromethanesulfonate. If chiral phase transfer catalysts of group I are used the addition of small amounts of water (between one and four molar equivalents) is often beneficial. Conducting the reaction in a biphasic system (water/suitable organic solvent) is, however, usually detrimental to chemical reactivity. Suitable conditions for this asymmetric reaction are disclosed in the literature: (a) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928. (c) Mazet, C.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2008, 47, 1762. (d) Madhavana, N.; Weck, M. AdV. Synth. Catal. 2008, 350, 419. (e) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514. (f) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanaia, M.; Shibasaki, M. Tetrahedron 2007, 63, 5820. (g) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072. (h) Bernardi, L.; Fini, F.; Fochi, M.; Ricci, A. Synlett 2008, 1857. (i) Jun Wang, Wei Li, Yanling Liu, Yangyang Chu, Lili Lin, Xiaohua Liu, and Xiaoming Feng Organic Letters (2010), 12, (6), 1280-1283. (j) anaka, Yuta; Kanai, Motomu; Shibasaki, Masakatsu, Journal of the American Chemical Society 2010, 132, (26), 8862-8863. (k) Brian A. Provencher, Keith J. Bartelson, Yan Liu, Bruce M. Foxman, Li Deng, Angewandte Chemie International Edition.




2) Enantioenriched compounds of formula (V) can be prepared by cyclization of enantioenriched compounds of formula (IV) wherein P is hydroxyl, C1-C6alkoxy, N-pyrrolyl, N-azolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl, C1-C6alkylsulfinyl under standard acidic or basic conditions.
3) Enantioenriched compounds of formula (IV) wherein P is e.g. hydroxyl, C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl, C1-C6alkylsulfinyl can be prepared by selective reduction of enantioenriched compounds of formula (II) wherein P is e.g. hydroxyl, C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl, C1-C6alkylsulfinyl. Suitable reducing agents include iron and zinc in the presence of a strong acid, Raney nickel under the atmosphere of hydrogen, a mixture of titanium (IV) chloride with zinc or titanium (III) chloride and a mixture of cobalt (II) or nickel (II) chloride with sodium borohydride. A reduction with Raney nickel is performed in a suitable alcoholic solvents, such as methanol or ethanol at dilution between 0.1 M to 1 M and in most cases it is advantageous to conduct the reaction between 0.3 M to 0.5 M, at temperatures from 20° C. to 60° C. Hydrogen pressure used is from 1 bar to 20 bars and the amount of catalyst used is between 5 and weight percent. The reaction time is usually between 10 min and 6 hours, preferably between 30 min and 2 hours. The extent of reduction could potentially be controlled by varying temperature and pressure of hydrogen. A reduction with zinc and acid is carried out in suitable polar solvents, such as dimethylformamide, which are miscible with water. The pH of a solution is kept at 1-2 and the amount of zinc powder used is between 2 and 10 molar equivalents, preferably between 2 and 4 molar equivalents. The reaction time is usually between 30 min and 4 hours, preferably between 30 min and 1 hour. The reduction with cobalt (II) chloride and sodium borohydride is carried out in a suitable alcoholic solvent and the amount of sodium borohydride used is between 2 and 10 molar equivalents, preferably between 2 and 4 molar equivalents, amount of cobalt (II) chloride hexahydrate used is between 1 and 10 molar equivalents. The reaction time is usually between 30 min and 6 hours, preferably between 30 min and 2 hours.
4) Alternatively enantioenriched compounds of formula (V) can be directly obtained by a reductive cyclization of enantioenriched compound of formula (II) under the conditions described above.




5) Enantioenriched Compounds of formula (VI) can be obtained by a cyclization of enantioenriched compound of formula (V) wherein P is e.g. C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl, C1-C6alkylsulfinyl under basic conditions such as those described in Tetrahedron, 39(19), 3055-7; 1983.
6) Enantioenriched Compounds of formula (V) can be obtained by a selective hydrolysis of the nitrile function in Enantioenriched compounds of formula (II) by acidic or basic hydrolysis.




7) Enantioenriched compounds of formula (VI) can be obtained by a cyclization of enantioenriched compounds of formula (VII) by a dehydrating reaction such as those described in Chemistry—A European Journal, 9(14), 3270-3281; 2003.
8) Enantioenriched Compounds of formula (VII) can be obtained by complete hydrolysis of enantioenriched compound of formula (II) under basic aqueous conditions.




9) Enantioenriched Compounds of formula (IX) can be obtained by treating an enantioenriched compound of formula (II) with an activating agent under the conditions described in J. Org. Chem. 2008, 73, 312-315. Suitable activating agents include sulfonyl molecules e.g. SOCl2 and HCl, trichlorophosphate, triphenylphosphine and diethylazodicarboxylate, 1H-imidazole and bromine and triphenylphosphine, phosphoric acid or catalysts such as dihydridotetrakis(triphenylphosphine)ruthenium(II).
10) Enantioenriched Compounds of formula (VIII) can be obtained by complete reduction of enantioenriched compounds of formula (II) wherein P is e.g. C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl or C1-C6alkylsulfinyl for example with a metal hydride such as lithium aluminum hydride (LiAlH4). For instance according to a method developed in the literature in Journal of Medicinal Chemistry, 51(22), 7144-7153; 2008. Alternatively, suitable conditions involve the treatment of Enantioenriched compounds of formula (II) under an atmosphere of hydrogen gas in the presence of a metal catalyst, such as those described in the literature in Bioorganic Chemistry, 36(5), 241-251; 2008.




10) Enantioenriched Compounds of formula (XII) can be obtained by reacting a enantioenriched compound of formula (X) and an enantioenriched compound of formula (II) in the presence of a suitable dehydrating agent such as thionyl chloride (SOCl2). For instance according to a method described in Asian Journal of Chemistry, 19(6), 4939-4941; 2007.
11) Enantioenriched Compounds of formula (X) can be obtained by hydrolysis of a enantioenriched compound of formula (II) wherein P is e.g. C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl or C1-C6alkylsulfinyl in the presence of aqueous mineral acid, such as aqueous sulphuric acid between 1% and 100% weight/weight, or hydrochloric acid between 1% and 100% weight/weight between 0.1 M to 5 M. In most cases it is advantageous to conduct the reaction preferably 0.3 M to 0.5 M, at temperatures from 20° C. to 120° C.




12) Enantioenriched Compounds of formula (XVI) can be obtained by treating a enantioenriched compound of formula (XV) with a suitable activating agent under the conditions described in the literature, such as in J. Org. Chem. 2008, 73, 312-315. Suitable activating agents include sulfonyl molecules e.g. SOCl2, mesylate, tosylate, triflate etc
13) Enantioenriched compounds of formula (XV) can be obtained by reducing an enantioenriched compound of formula (XIV) wherein P is e.g. C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl or C1-C6alkylsulfinyl with a suitable metal hydride such as Lithium aluminum hydride, for instance according to a method described in the literature in Journal of Medicinal Chemistry, 49(1), 399-406; 2006.
14) Enantioenriched Compounds of formula (XIV) can be obtained by reacting a enantioenriched compound of formula (IV) wherein P is e.g. C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl or C1-C6alkylsulfinyl and a compound of formula (XIII) in the presence of a metal catalyst and a base. Suitable conditions can be found in the literature in Organic Letters, 11(6), 1449-1452; 2009 and in Journal of the American Chemical Society, 132(1), 413-426; 2010.




15) Enantioenriched compounds of formula (XVII) can be obtained by cyclising an enantioenriched compound of formula (XIV) wherein P is e.g. C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl or C1-C6alkylsulfinyl under neutral conditions, such as those described in the literature in Bioorganic & Medicinal Chemistry Letters, 19(16), 4733-4739; 2009, or under basic conditions such as those described in Synlett, (4), 591-594; 2006.




16) Enantioenriched compounds of formula (XVIII) can be obtained by carrying out a Baeyer-Villiger reactions (M. B. Smith, J. March: March's advanced organic chemistry. Wiley, New York 2001.) on compounds (IIa) wherein P is e.g. an optionally substituted aryl or an optionally substituted heteroaryl or optionally substituted alkyl. Suitable reagents for the reaction include, but are not limited to m-chloro peroxybenzoic acid and trifluoro peroxyacetic acid. The reaction can be conducted neat or in a suitable solvent such as dichloromethane, chloroform, 1,2-dichloroethane, acetic acid, acetonitrile, methanol, trifluoroacetic acid, 1,4-dioxane, benzene, tert-butyl alcohol. The reaction temperature could be from −50° C. to 150° C., preferably between −20° C. and 100° C. The reaction time is usually between 1 hour and 96 hours, preferably between 1 hour and 24 hours.
17) Enantioenriched compounds of formula (III) could be obtained by reductive cyclization of compounds of formula (XVIII) wherein P is as defined for compounds of formula (Ha). Suitable reducing agents include iron a late transition metal selected from Pd, Pt, Ni and Co and a source of hydride such as hydrogen gas, a borohydride salt or borane. A reduction with Raney nickel is performed in suitable alcoholic solvents, such as methanol or ethanol, at temperatures from 20° C. to 60° C. Hydrogen pressure used is from 1bar to 20 bar and the amount of catalyst used is between 5 and 20 weight percent. The reaction time is usually between 10 min and 6 hours, preferably between 30 min and 2 hours.
Alternatively, the reductive cyclization can be carried out in the presence of a borohydride salt, such as sodium borohydride, in the presence of a cobalt salt, such as cobalt(II) dichloride, in a suitable alcoholic solvent, such as methanol or ethanol, according to the conditions described in the literature Bioorganic & Medicinal Chemistry Letters, 20(2), 704-708; 2010
18) Alternatively the reductive cyclization can be carried out by reacting compounds of formula (XVIII) with borane complexed with a suitable acceptor such as dimethylsulfide or tetrahydrofuran. Suitable solvents induce tetrahydrofuran and 1,4-dioxane and the reaction temperature can range between 25 C and 100 C. Appropriate conditions are described in the literature Journal of the American Chemical Society (1988), 110(6), 1679-90.




19) Enantioenriched Compounds of formula (VI) can be obtained by carrying out a Baeyer-Villiger oxidation reaction on enantioenriched compounds of formula (IIc) wherein P is e.g. an optionally substituted aryl or an optionally substituted heteroaryl. Suitable reagents for the reaction include, but are not limited to m-chloro peroxybenzoic acid, trifluoro peroxyacetic acid and peroxy sulfuric acid. Particularly preferred reagent is peroxysulfuric acid. Between 1 and 100 equivalents of the reagent is typically used (e.g. at least 1 equivalent, e.g. up to 100 equivalents).
Alternatively, a suitable reagent is peroxide in the presence of acid, preferably a strong acid. Peroxides include, but are not limited to hydrogen peroxide, sodium peroxide, sodium perborate, sodium percarbonate, sodium persulfate, potassium persulfate. Particularly preferred is hydrogen peroxide. The concentration of hydrogen peroxide can be between 5% and 90%, preferably between 20-40% (e.g. at least 5%, at least 20%, e.g. up to 90%, up to 40%). (% refers to v/v.). Between 1 and 100 molar equivalents of the reagent is typically used (e.g. at least 1 molar equivalent, e.g. up to 100 molar equivalents).
Strong acids are e.g. any acid with pKa lower then acetic acid. Strong acids include, but are not limited to trifluoroacetic acid, nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, Nafion-H. Particularly preferred is sulphuric acid. The concentration of acid, which is preferably sulphuric acid, can be between 10% and 99%, preferably between 50-97% (e.g. at least 10%, at least 50%, e.g. up to 99%, up to 97%) (% refers to v/v.) Between 1 and 100 molar equivalents of the reagent is typically used (e.g. at least 1 molar equivalent, e.g. up to 100 molar equivalents).
The reaction can be conducted neat or in a suitable solvent. Suitable reagents for the reaction include, but are not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride, acetic acid. The reaction temperature could be from −50° C. to 150° C., preferably between −20° C. and 100° C. (e.g. at least −50° C., at least −20° C., e.g. up to 150° C., up to 100° C.). The reaction time is usually between 1 hour and 96 hours, preferably between 1 hour and 24 hours (e.g. at least 1 hour, e.g. up to 96 hours, up to 24 hours).




20) Enantioenriched Compounds of formula (VI) can be obtained by hydrolysis of the nitrile function in Enantioenriched compounds of formula (XIX) by acidic or basic hydrolysis followed by a dehydration reaction.
21) Enantioenriched Compounds of formula (XIX) can be obtained by hydrolysis of Enantioenriched compound of formula (II) under basic aqueous conditions.




22) Enantioenriched Compounds of formula (III) can be prepared by cyclization of a enantioenriched compound of formula (IV) under basic, acidic or neutral conditions.
23) Enantioenriched Compounds of formula (IV) can be prepared by reducing a enantioenriched compound of formula (XX). Suitable reducing agents include iron and zinc in the presence of a strong acid, a mixture of titanium (IV) chloride with zinc or titanium (III) chloride, or a late transition metal selected from Pd, Pt, Ni and Co and a source of hydride such as hydrogen gas, a silane, formic acid, a formate salt, or a borohydride salt. A reduction with Raney nickel is performed in suitable alcoholic solvents, such as methanol or ethanol, at temperatures from 20° C. to 60° C. Hydrogen pressure used is from 1bar to 20 bar and the amount of catalyst used is between 5 and 20 weight percent. The reaction time is usually between 10 min and 6 hours, preferably between 30 min and 2 hours. The extent of reduction could potentially be controlled by varying temperature and pressure of hydrogen. A reduction with zinc and acid is carried out in suitable polar solvents, such as dimethylformamide, which are miscible with water. The pH of a solution is kept at 1-2 and the amount of zinc powder used is between 2 and 10 molar equivalents, preferably between 2 and 4 molar equivalents. The reaction time is usually between 30 min and 4 hours, preferably between 30 min and 2 hours.
24) Alternatively, the reduction can be carried out in the presence of a silane, such as triethylsilane, in the presence of a source of palladium, such as palladium supported on charcoal, in a suitable alcoholic solvent, such as methanol or ethanol, according to the conditions described in the literature in Journal of Organic Chemistry, 72(17), 6599-6601; 2007.
25) Alternatively, the reduction can be carried out in the presence of formic acid or a formate salt, such as ammonium formate, in the presence of a source of palladium, such as palladium supported on charcoal, in a suitable alcoholic solvent, such as methanol or ethanol, according to the conditions described in the literature in Synthesis (1986), (2), 133-5 and in Organic Letters, 3, 3153-3155; (2001).
26) Alternatively, the reduction can be carried out in the presence of a borohydride salt, such as sodium borohydride, in the presence of a nickel salt, such as nickel(II) dichloride hexahydrate, in a suitable alcoholic solvent, such as methanol or ethanol, according to the conditions described in the literature in Organic Letters, 3, 1825-1827; (2001).
27) Alternatively, the reduction can be carried out in the presence of a borohydride salt, such as sodium borohydride, in the presence of a cobalt salt, such as cobalt(II) dichloride, in a suitable alcoholic solvent, such as methanol or ethanol, according to the conditions described in the literature in Journal of Organic Chemistry, 62(24), 8565-8568; 1997.
28) Alternatively enantioenriched compounds of formula (III) can be prepared by reducing and cyclizing enantioenriched compounds of formula (XX) under the reduction conditions described above.
29) Enantioenriched compounds of formula (XX) can be prepared by reacting a compound of formula (I) with nitromethane in an asymmetric fashion, in the presence of a chiral catalyst. Reaction with some chiral catalysts, notably bifunctional thiourea or urea catalysts, do not require any additives. The amount of catalyst is usually between 0.02 and 0.2 molar equivalents, preferably between 0.05 and 0.1 molar equivalents. In some instances an additional proton source such as 4-nitrophenol or t-butanol is needed or useful. Such methods have been described in the literature: (a) Benedek Vakulya, Szilárd Varga and Tibor Soós, Journal of Organic Chemistry (2008), 73, (9), 3475-3480. (b) Tetrahedron Letters (2008), 49, (35), 5220-5223. (c) Roberto Ballini, Giovanna Bosica, Dennis Fiorini, Alessandro Palmieri, and Marino Petrini, Chem Rev 2005, 105, 933.
In most other cases, however, it is necessary or useful to add a base to the reaction media. Suitable bases include amines, such as triethylamine, 2,5-dimethylpiperazine, tetramethylpiperidine, 4-dimethylamino pyridine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, metal alkoxides, such as sodium t-butoxide, metal carbonates, such as potassium carbonate or metal fluorides, such as cesium fluoride or cesium chloride and tetrabutylammonium fluoride. In most cases it is advantageous to conduct the reaction using nitromethane as a solvent at dilution between 0.1 M to 1 M, preferably 0.3 M to 0.5 M. Alternatively suitable organic solvents could be used, for example toluene, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, methanol or ethyl acetate at a temperature from 0° C. to 100° C., preferably between 40 and 100° C., and at dilution of e.g. between 0.1 M to 1 M. The reaction time is usually between 12 and 96 hours, preferably between 24 and 72 hours. If a solvent other than nitromethane is used, the amount of nitromethane added is between 1.5 and 20 molar equivalents, preferably between 1.5 and 5 molar equivalents.




30) Enantioenriched compounds of formula (IV) can be prepared by reacting a compound of formula (XXI) with an acetophenone of formula (XXII) in the presence of a chiral catalyst. Compounds of formula (XXII) are known in the literature or can be prepared using methods known to a person skilled in the art (see for example Journal of the American Chemical Society (2008), 130(42), 13862-13863) and compounds of formula (XXI) are known in the literature or can be prepared using methods known to a person skilled in the art (see for example WO2009/080250). In most cases it is advantageous to conduct the reaction using suitable organic solvents, for example toluene, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, methanol or ethyl acetate. The temperature is usually between 0° C. and 100° C., preferably between 40 and 100° C. Where a solvent is used the reactants are usually at a dilution of e.g. between 0.1 M to 1 M. The reaction time is usually between 1 and 96 hours, preferably between 1 and 24 hours. The amount of catalyst is usually between 0.02 and 0.2 molar equivalents, preferably between 0.05 and 0.1 molar equivalents. Reaction with some chiral catalysts, notably bifunctional thiourea or urea catalysts, do not require any additives. In some cases, however, it is necessary or useful to add an acid to the reaction media. Suitable acids are benzoic acids. In some instances an additional proton source such as 4-nitrophenol, phenols, naphthalenol or t-butanol is needed or useful.




31) Enantioenriched compounds of formula (III) can be prepared by reacting compounds of formula (XXV) with an aqueous base followed by acidification. Suitable bases include but are not limited to alkali metal hydroxides. The reaction temperature could be between 25 C and 100 C, preferably between 40 C and 80 C. Between 1 and 5 equivalents of alkali metal hydroxide are used. Suitable solvents include, but are not limited to alcohols (such as ethanol), water and tetrahydrofuran. Suitable acids include sulphuric acid, hydrochloric acid, phosphoric acid and p-toluene sulfonic acid. In some cases heating in a nonpolar solvent such as toluene is sufficient for decarboxylation.
32) Enantioenriched compounds of formula (XXV) can be prepared by a reductive cyclization of compounds of formula (XXIV). Suitable reducing agents include iron and zinc in the presence of a strong acid, a mixture of titanium (IV) chloride with zinc or titanium (III) chloride, or a late transition metal selected from Pd, Pt, Ni and Co and a source of hydride such as hydrogen gas, a silane, formic acid, a formate salt, or a borohydride salt. A reduction with Raney nickel is performed in suitable alcoholic solvents, such as methanol or ethanol, at temperatures from 20° C. to 60° C. Hydrogen pressure used is from 1bar to 20 bar and the amount of catalyst used is between 5 and 20 weight percent. The reaction time is usually between 10 min and 6 hours, preferably between 30 min and 2 hours. The extent of reduction could potentially be controlled by varying temperature and pressure of hydrogen. A reduction with zinc and acid is carried out in suitable polar solvents, such as dimethylformamide, which are miscible with water. The pH of a solution is kept at 1-2 and the amount of zinc powder used is between 2 and 10 molar equivalents, preferably between 2 and 4 molar equivalents. The reaction time is usually between 30 min and 4 hours, preferably between 30 min and 2 hours. Suitable conditions for similar reductive cyclizations have been describe in the literature, for example: (a) Okino, Tomotaka; Hoashi, Yasutaka; Furukawa, Tomihiro; Xu, Xuenong; Takemoto, Yoshiji. J. Am. Chem. 1 Soc. (2005), 127(1), 119-125; (b) Ji, Jianguo; Barnes, David M.; Zhang, Ji; King, Steven A.; Wittenberger, Steven J.; Morton, Howard E. J. Am. Chem. Soc. (1999), 121(43), 10215-10216
33) Enantioenriched compounds of formula XXIV can be prepared can be prepared by reacting compounds of formula XXI with compounds of formula XXII in the presence of a chiral catalyst. Depending from the catalyst used, suitable solvents include dioxane, tetrahydrofuran, dichloromethane, acetonitrile, t-butylmethyl ether, 1,2-dichloromethane, xylenes and toluene. In most cases it is advantageous to conduct the reaction in a suitable solvent at dilution between 0.1 M to 1 M, preferably 0.3 M to 0.5 M. The reaction temperature could be from −40° C. to 100° C., preferably between −20° C. and 50° C. The reaction time is usually between 1 hour and 96 hours, preferably between 6 hours and 24 hours. The amount of catalyst is usually between 0.02 and 0.2 molar equivalents, preferably between 0.05 and 0.1 molar equivalents.
34) Suitable catalysts and conditions for this asymmetric step are well described in the literature. Representative examples include: (a) Ji, Jianguo; Barnes, David M.; Zhang, Ji; King, Steven A.; Wittenberger, Steven J.; Morton, Howard E. Journal of the American Chemical Society (1999), 121(43), 10215-10216. (b) Cooey, S. H.; Conno, S. J. Angew. Chem. Int. Ed. 2005, 6367. (c) Ye, J.; Dixon, J.; Hynes, P. Chem. Comm 2005, 448




35) Enantioenriched compounds of formula (XVI) can be prepared by reduction of Enantioenriched compounds of formula (XVII) with a metal hydride, for instance according to a method developed in the literature: Journal of Pharmaceutical Sciences (1978), 67(7), 953-6.
36) Enantioenriched Compounds of formula (XVII) can be prepared by reaction of Enantioenriched compound of formula (III) with a compound of formula (Va) wherein XB is a leaving group, for example a halogen, such as bromo, as described above).
37) Enantioenriched Compounds of formula (XVI) can be prepared by reduction of enantioenriched compounds of formula (XII) with a metal hydride, for instance according to a method developed in the literature (ARKIVOC, 2003, 5, And U.S. Pat. No. 4,524,206).
Suitable reagents for the reaction include, but are not limited to . . . metal hydride
The reaction can be conducted neat or in a suitable solvent The reaction temperature could be from −50° C. to 150° C., preferably between −20° C. and 100° C. The reaction time is usually between 1 hour and 96 hours, preferably between 1 hour and 24 hours. The reduction of such succinimides are known to proceed through one or several intermediates of formula (XXVI), (XXVII), and (XXVIII), which may be optionally isolated.








38) Enantioenriched compounds of formula (XI), can be prepared by reaction of enantioenriched compound of formula (XIII) wherein XB is a leaving group, for example a halogen, such as bromo, with a compound of formula (III) in the absence or the presence of a catalyst, such as palladium(II) acetate or bis(triphenylphosphine)palladium(II) dichloride, optionally in the presence of a ligand, such as triphenylphosphine, and a base, such as sodium carbonate, pyridine, triethylamine, 4-(dimethylamino)-pyridine (“DMAP”) or diisopropylethylamine (Hunig's base), in a solvent, such as water, N,N-dimethylformamide or tetrahydrofuran. The reaction is carried out at a temperature of from 50° C. to 200° C., preferably from 100° C. to 150° C. The reaction is carried out at a pressure of from 50 to 200 bar, preferably from 100 to 150 bar.




39) Enantioenriched Compounds of formula (VIII) can be obtained by reduction of Enantioenriched compound of formula (XX) wherein P is e.g. C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl or C1-C6alkylsulfinyl using conditions described above.




40) Enantioenriched compounds of formula (IX) can be prepared by reduction of Enantioenriched compounds of formula (III) or (VI). Suitable reagents for the reaction include, but are not limited to metal hydride The reaction can be conducted neat or in a suitable solvent. The reaction temperature could be from −50° C. to 150° C., preferably between −20° C. and 100° C. The reaction time is usually between 1 hour and 96 hours, preferably between 1 hour and 24 hours. The reduction of such succinimides are known to proceed through one or several intermediates of formula (XXIX), (XXX), (XXXI), (XXXIII) and ($$), which may be optionally isolated.








41) Enantioenriched Compounds of formula (I′′) wherein P is hydroxyl, C1-C6alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl, N-benzotriazolyl or C1-C6alkylsulfinyl can be obtained by carrying out a Baeyer-Villiger oxidation reaction on enantioenriched compounds of formula (I′) wherein P is an optionally substituted aryl or an optionally substituted heteroaryl. Suitable reagents for the reaction include, but are not limited to m-chloro peroxybenzoic acid, trifluoro peroxyacetic acid and peroxy sulfuric acid. The reaction can be conducted neat or in a suitable solvent. The reaction temperature could be from −50° C. to 150° C., preferably between −20° C. and 100° C. The reaction time is usually between 1 hour and 96 hours, preferably between 1 hour and 24 hours.
In the above schemes a leaving group may before example a halogen, C1-C8alkoxy, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C5 arylsulfonyloxy, optionally substituted C1-C8arylsulfonyloxy (aryl is preferably phenyl), diazonium salts (e.g. XB is —N2+Cl−, —N2+BF4−, —N2+Br−, —N2+PF6−), phosphonate esters (e.g. —OP(O)(OR)2, wherein R is methyl or ethyl), preferably bromo, iodo, chloro, trifluoromethylsulfoxy, p-toluenesulfoxy, diazonium chloride.
In the above schemes, where a reaction condition, e.g. temperature, time, concentration, is given as a range, e.g. value X to value Y, the skilled person will understand that these values serve as guidelines and that it may be possible to perform the reactions outside the given values. In addition, where such ranges are given, in each case these include separate disclosures of “at least X”, and “Y or less”. For example a range of 50° C. to 150° C. includes s disclosure of “at least 50° C.” and a disclosure of “150° C. or less”.
The following tables A to M illustrate compounds relating to the invention. In the compounds disclosed in Tables A to M the stereochemistry at * corresponds to that of formula II.







TABLE A







Compounds of formula A











(A)













 












Comp






No.
Q2
B2
Q4
















1
Cl
C—Cl
Cl



2
Cl
C—H
Cl



3
CF3
C—H
CF3



4
Cl
C—H
CF3



5
Br
C—H
CF3



6
Cl
C—F
H



7
F
C—Cl
H



8
Cl
C—Cl
H



9
Cl
C—F
Cl



10
Cl
C—Br
Cl



11
Cl
C—I
Cl



12
F
C—F
F



13
Cl
C—H
Br



14
Cl
C—H
F



15
Cl
C—Cl
CF3



16
CF3
C—Cl
CF3



17
CF3
C—H
H



18
Cl
N
Cl



19
Cl
N
H



20
CF3
N
CF3



21
CF3
N
H

















TABLE B







Compounds of formula B











(B)













 












Comp






No.
Q2
B2
Q4
















1
Cl
C—Cl
Cl



2
Cl
C—H
Cl



3
CF3
C—H
CF3



4
Cl
C—H
CF3



5
Br
C—H
CF3



6
Cl
C—F
H



7
F
C—Cl
H



8
Cl
C—Cl
H



9
Cl
C—F
Cl



10
Cl
C—Br
Cl



11
Cl
C—I
Cl



12
F
C—F
F



13
Cl
C—H
Br



14
Cl
C—H
F



15
Cl
C—Cl
CF3



16
CF3
C—Cl
CF3



17
CF3
C—H
H



18
Cl
N
Cl



19
Cl
N
H



20
CF3
N
CF3



21
CF3
N
H

















TABLE C







Compounds of formula C











(C)













 












Comp






No.
Q2
B2
Q4
















1
Cl
C—Cl
Cl



2
Cl
C—H
Cl



3
CF3
C—H
CF3



4
Cl
C—H
CF3



5
Br
C—H
CF3



6
Cl
C—F
H



7
F
C—Cl
H



8
Cl
C—Cl
H



9
Cl
C—F
Cl



10
Cl
C—Br
Cl



11
Cl
C—I
Cl



12
F
C—F
F



13
Cl
C—H
Br



14
Cl
C—H
F



15
Cl
C—Cl
CF3



16
CF3
C—Cl
CF3



17
CF3
C—H
H



18
Cl
N
Cl



19
Cl
N
H



20
CF3
N
CF3



21
CF3
N
H

















TABLE D







Compounds of formula D











(D)













 












Comp






No.
Q2
B2
Q4
















1
Cl
C—Cl
Cl



2
Cl
C—H
Cl



3
CF3
C—H
CF3



4
Cl
C—H
CF3



5
Br
C—H
CF3



6
Cl
C—F
H



7
F
C—Cl
H



8
Cl
C—Cl
H



9
Cl
C—F
Cl



10
Cl
C—Br
Cl



11
Cl
C—I
Cl



12
F
C—F
F



13
Cl
C—H
Br



14
Cl
C—H
F



15
Cl
C—Cl
CF3



16
CF3
C—Cl
CF3



17
CF3
C—H
H



18
Cl
N
Cl



19
Cl
N
H



20
CF3
N
CF3



21
CF3
N
H

















TABLE E







Compounds of formula E











(E)













 












Comp






No.
Q2
B2
Q4
















1
Cl
C—Cl
Cl



2
Cl
C—H
Cl



3
CF3
C—H
CF3



4
Cl
C—H
CF3



5
Br
C—H
CF3



6
Cl
C—F
H



7
F
C—Cl
H



8
Cl
C—Cl
H



9
Cl
C—F
Cl



10
Cl
C—Br
Cl



11
Cl
C—I
Cl



12
F
C—F
F



13
Cl
C—H
Br



14
Cl
C—H
F



15
Cl
C—Cl
CF3



16
CF3
C—Cl
CF3



17
CF3
C—H
H



18
Cl
N
Cl



19
Cl
N
H



20
CF3
N
CF3



21
CF3
N
H

















TABLE F







Compounds of formula F











(F)













 












Comp






No.
Q2
B2
Q4
















1
Cl
C—Cl
Cl



2
Cl
C—H
Cl



3
CF3
C—H
CF3



4
Cl
C—H
CF3



5
Br
C—H
CF3



6
Cl
C—F
H



7
F
C—Cl
H



8
Cl
C—Cl
H



9
Cl
C—F
Cl



10
Cl
C—Br
Cl



11
Cl
C—I
Cl



12
F
C—F
F



13
Cl
C—H
Br



14
Cl
C—H
F



15
Cl
C—Cl
CF3



16
CF3
C—Cl
CF3



17
CF3
C—H
H



18
Cl
N
Cl



19
Cl
N
H



20
CF3
N
CF3



21
CF3
N
H

















TABLE G







Compounds of formula G











(G)













 












Comp






No.
Q2
B2
Q4
















1
Cl
C—Cl
Cl



2
Cl
C—H
Cl



3
CF3
C—H
CF3



4
Cl
C—H
CF3



5
Br
C—H
CF3



6
Cl
C—F
H



7
F
C—Cl
H



8
Cl
C—Cl
H



9
Cl
C—F
Cl



10
Cl
C—Br
Cl



11
Cl
C—I
Cl



12
F
C—F
F



13
Cl
C—H
Br



14
Cl
C—H
F



15
Cl
C—Cl
CF3



16
CF3
C—Cl
CF3



17
CF3
C—H
H



18
Cl
N
Cl



19
Cl
N
H



20
CF3
N
CF3



21
CF3
N
H

















TABLE H





Compounds of formula H






















(H)










Table H discloses 630 compounds of formula H, wherein Q2, B2, Q4 and P have the values as defined in Table X.








TABLE J





Compounds of formula J






















(J)










Table J discloses 630 compounds of formula J, wherein Q2, B2, Q4 and P have the values as defined in Table X.








TABLE K





Compounds of formula K






















(K)










Table K discloses 630 compounds of formula K, wherein Q2, B2, Q4 and P have the values as defined in Table X.








TABLE L





Compounds of formula L






















(L)










Table L discloses 630 compounds of formula L, wherein Q2, B2, Q4 and P have the values as defined in Table X.








TABLE M





Compounds of formula M






















(M)










Table M discloses 630 compounds of formula M, wherein Q2, B2, Q4 and P have the values as defined in Table X.












TABLE X






Q2
B2
Q4
P





















X.1
Cl
C—Cl
Cl
P1



X.2
Cl
C—H
Cl
P1



X.3
CF3
C—H
CF3
P1



X.4
Cl
C—H
CF3
P1



X.5
Br
C—H
CF3
P1



X.6
Cl
C—F
H
P1



X.7
F
C—Cl
H
P1



X.8
Cl
C—Cl
H
P1



X.9
Cl
C—F
Cl
P1



X.10
Cl
C—Br
Cl
P1



X.11
Cl
C—I
Cl
P1



X.12
F
C—F
F
P1



X.13
Cl
C—H
Br
P1



X.14
Cl
C—H
F
P1



X.15
Cl
C—Cl
CF3
P1



X.16
CF3
C—Cl
CF3
P1



X.17
CF3
C—H
H
P1



X.18
Cl
C—Cl
Cl
P2



X.19
Cl
C—H
Cl
P2



X.20
CF3
C—H
CF3
P2



X.21
Cl
C—H
CF3
P2



X.22
Br
C—H
CF3
P2



X.23
Cl
C—F
H
P2



X.24
F
C—Cl
H
P2



X.25
Cl
C—Cl
H
P2



X.26
Cl
C—F
Cl
P2



X.27
Cl
C—Br
Cl
P2



X.28
Cl
C—I
Cl
P2



X.29
F
C—F
F
P2



X.30
Cl
C—H
Br
P2



X.31
Cl
C—H
F
P2



X.32
Cl
C—Cl
CF3
P2



X.33
CF3
C—Cl
CF3
P2



X.34
CF3
C—H
H
P2



X.35
Cl
C—Cl
Cl
P3



X.36
Cl
C—H
Cl
P3



X.37
CF3
C—H
CF3
P3



X.38
Cl
C—H
CF3
P3



X.39
Br
C—H
CF3
P3



X.40
Cl
C—F
H
P3



X.41
F
C—Cl
H
P3



X.42
Cl
C—Cl
H
P3



X.43
Cl
C—F
Cl
P3



X.44
Cl
C—Br
Cl
P3



X.45
Cl
C—I
Cl
P3



X.46
F
C—F
F
P3



X.47
Cl
C—H
Br
P3



X.48
Cl
C—H
F
P3



X.49
Cl
C—Cl
CF3
P3



X.50
CF3
C—Cl
CF3
P3



X.51
CF3
C—H
H
P3



X.52
Cl
C—Cl
Cl
P4



X.53
Cl
C—H
Cl
P4



X.54
CF3
C—H
CF3
P4



X.55
Cl
C—H
CF3
P4



X.56
Br
C—H
CF3
P4



X.57
Cl
C—F
H
P4



X.58
F
C—Cl
H
P4



X.59
Cl
C—Cl
H
P4



X.60
Cl
C—F
Cl
P4



X.61
Cl
C—Br
Cl
P4



X.62
Cl
C—I
Cl
P4



X.63
F
C—F
F
P4



X.64
Cl
C—H
Br
P4



X.65
Cl
C—H
F
P4



X.66
Cl
C—Cl
CF3
P4



X.67
CF3
C—Cl
CF3
P4



X.68
CF3
C—H
H
P4



X.69
Cl
C—Cl
Cl
P5



X.70
Cl
C—H
Cl
P5



X.71
CF3
C—H
CF3
P5



X.72
Cl
C—H
CF3
P5



X.73
Br
C—H
CF3
P5



X.74
Cl
C—F
H
P5



X.75
F
C—Cl
H
P5



X.76
Cl
C—Cl
H
P5



X.77
Cl
C—F
Cl
P5



X.78
Cl
C—Br
Cl
P5



X.79
Cl
C—I
Cl
P5



X.80
F
C—F
F
P5



X.81
Cl
C—H
Br
P5



X.82
Cl
C—H
F
P5



X.83
Cl
C—Cl
CF3
P5



X.84
CF3
C—Cl
CF3
P5



X.85
CF3
C—H
H
P5



X.86
Cl
C—Cl
Cl
P6



X.87
Cl
C—H
Cl
P6



X.88
CF3
C—H
CF3
P6



X.89
Cl
C—H
CF3
P6



X.90
Br
C—H
CF3
P6



X.91
Cl
C—F
H
P6



X.92
F
C—Cl
H
P6



X.93
Cl
C—Cl
H
P6



X.94
Cl
C—F
Cl
P6



X.95
Cl
C—Br
Cl
P6



X.96
Cl
C—I
Cl
P6



X.97
F
C—F
F
P6



X.98
Cl
C—H
Br
P6



X.99
Cl
C—H
F
P6



X.100
Cl
C—Cl
CF3
P6



X.101
CF3
C—Cl
CF3
P6



X.102
CF3
C—H
H
P6



X.103
Cl
C—Cl
Cl
P7



X.104
Cl
C—H
Cl
P7



X.105
CF3
C—H
CF3
P7



X.106
Cl
C—H
CF3
P7



X.107
Br
C—H
CF3
P7



X.108
Cl
C—F
H
P7



X.109
F
C—Cl
H
P7



X.110
Cl
C—Cl
H
P7



X.111
Cl
C—F
Cl
P7



X.112
Cl
C—Br
Cl
P7



X.113
Cl
C—I
Cl
P7



X.114
F
C—F
F
P7



X.115
Cl
C—H
Br
P7



X.116
Cl
C—H
F
P7



X.117
Cl
C—Cl
CF3
P7



X.118
CF3
C—Cl
CF3
P7



X.119
CF3
C—H
H
P7



X.120
Cl
C—Cl
Cl
P8



X.121
Cl
C—H
Cl
P8



X.122
CF3
C—H
CF3
P8



X.123
Cl
C—H
CF3
P8



X.124
Br
C—H
CF3
P8



X.125
Cl
C—F
H
P8



X.126
F
C—Cl
H
P8



X.127
Cl
C—Cl
H
P8



X.128
Cl
C—F
Cl
P8



X.129
Cl
C—Br
Cl
P8



X.130
Cl
C—I
Cl
P8



X.131
F
C—F
F
P8



X.132
Cl
C—H
Br
P8



X.133
Cl
C—H
F
P8



X.134
Cl
C—Cl
CF3
P8



X.135
CF3
C—Cl
CF3
P8



X.136
CF3
C—H
H
P8



X.137
Cl
C—Cl
Cl
P9



X.138
Cl
C—H
Cl
P9



X.139
CF3
C—H
CF3
P9



X.140
Cl
C—H
CF3
P9



X.141
Br
C—H
CF3
P9



X.142
Cl
C—F
H
P9



X.143
F
C—Cl
H
P9



X.144
Cl
C—Cl
H
P9



X.145
Cl
C—F
Cl
P9



X.146
Cl
C—Br
Cl
P9



X.147
Cl
C—I
Cl
P9



X.148
F
C—F
F
P9



X.149
Cl
C—H
Br
P9



X.150
Cl
C—H
F
P9



X.151
Cl
C—Cl
CF3
P9



X.152
CF3
C—Cl
CF3
P9



X.153
CF3
C—H
H
P9



X.154
Cl
C—Cl
Cl
P10



X.155
Cl
C—H
Cl
P10



X.156
CF3
C—H
CF3
P10



X.157
Cl
C—H
CF3
P10



X.158
Br
C—H
CF3
P10



X.159
Cl
C—F
H
P10



X.160
F
C—Cl
H
P10



X.161
Cl
C—Cl
H
P10



X.162
Cl
C—F
Cl
P10



X.163
Cl
C—Br
Cl
P10



X.164
Cl
C—I
Cl
P10



X.165
F
C—F
F
P10



X.166
Cl
C—H
Br
P10



X.167
Cl
C—H
F
P10



X.168
Cl
C—Cl
CF3
P10



X.169
CF3
C—Cl
CF3
P10



X.170
CF3
C—H
H
P10



X.171
Cl
C—Cl
Cl
P11



X.172
Cl
C—H
Cl
P11



X.173
CF3
C—H
CF3
P11



X.174
Cl
C—H
CF3
P11



X.175
Br
C—H
CF3
P11



X.176
Cl
C—F
H
P11



X.177
F
C—Cl
H
P11



X.178
Cl
C—Cl
H
P11



X.179
Cl
C—F
Cl
P11



X.180
Cl
C—Br
Cl
P11



X.181
Cl
C—I
Cl
P11



X.182
F
C—F
F
P11



X.183
Cl
C—H
Br
P11



X.184
Cl
C—H
F
P11



X.185
Cl
C—Cl
CF3
P11



X.186
CF3
C—Cl
CF3
P11



X.187
CF3
C—H
H
P11



X.188
Cl
C—Cl
Cl
P12



X.187
Cl
C—H
Cl
P12



X.190
CF3
C—H
CF3
P12



X.191
Cl
C—H
CF3
P12



X.192
Br
C—H
CF3
P12



X.193
Cl
C—F
H
P12



X.194
F
C—Cl
H
P12



X.195
Cl
C—Cl
H
P12



X.196
Cl
C—F
Cl
P12



X.197
Cl
C—Br
Cl
P12



X.198
Cl
C—I
Cl
P12



X.199
F
C—F
F
P12



X.200
Cl
C—H
Br
P12



X.201
Cl
C—H
F
P12



X.202
Cl
C—Cl
CF3
P12



X.203
CF3
C—Cl
CF3
P12



X.204
CF3
C—H
H
P12



X.205
Cl
C—Cl
Cl
P13



X.206
Cl
C—H
Cl
P13



X.207
CF3
C—H
CF3
P13



X.208
Cl
C—H
CF3
P13



X.209
Br
C—H
CF3
P13



X.210
Cl
C—F
H
P13



X.211
F
C—Cl
H
P13



X.212
Cl
C—Cl
H
P13



X.213
Cl
C—F
Cl
P13



X.214
Cl
C—Br
Cl
P13



X.215
Cl
C—I
Cl
P13



X.216
F
C—F
F
P13



X.217
Cl
C—H
Br
P13



X.218
Cl
C—H
F
P13



X.219
Cl
C—Cl
CF3
P13



X.220
CF3
C—Cl
CF3
P13



X.221
CF3
C—H
H
P13



X.222
Cl
C—Cl
Cl
P14



X.223
Cl
C—H
Cl
P14



X.224
CF3
C—H
CF3
P14



X.225
Cl
C—H
CF3
P14



X.226
Br
C—H
CF3
P14



X.227
Cl
C—F
H
P14



X.228
F
C—Cl
H
P14



X.229
Cl
C—Cl
H
P14



X.230
Cl
C—F
Cl
P14



X.231
Cl
C—Br
Cl
P14



X.232
Cl
C—I
Cl
P14



X.233
F
C—F
F
P14



X.234
Cl
C—H
Br
P14



X.235
Cl
C—H
F
P14



X.236
Cl
C—Cl
CF3
P14



X.237
CF3
C—Cl
CF3
P14



X.238
CF3
C—H
H
P14



X.239
Cl
C—Cl
Cl
P15



X.240
Cl
C—H
Cl
P15



X.241
CF3
C—H
CF3
P15



X.242
Cl
C—H
CF3
P15



X.243
Br
C—H
CF3
P15



X.244
Cl
C—F
H
P15



X.245
F
C—Cl
H
P15



X.246
Cl
C—Cl
H
P15



X.247
Cl
C—F
Cl
P15



X.248
Cl
C—Br
Cl
P15



X.249
Cl
C—I
Cl
P15



X.250
F
C—F
F
P15



X.251
Cl
C—H
Br
P15



X.252
Cl
C—H
F
P15



X.253
Cl
C—Cl
CF3
P15



X.254
CF3
C—Cl
CF3
P15



X.255
CF3
C—H
H
P15



X.256
Cl
C—Cl
Cl
P16



X.257
Cl
C—H
Cl
P16



X.258
CF3
C—H
CF3
P16



X.259
Cl
C—H
CF3
P16



X.260
Br
C—H
CF3
P16



X.261
Cl
C—F
H
P16



X.262
F
C—Cl
H
P16



X.263
Cl
C—Cl
H
P16



X.264
Cl
C—F
Cl
P16



X.265
Cl
C—Br
Cl
P16



X.266
Cl
C—I
Cl
P16



X.267
F
C—F
F
P16



X.268
Cl
C—H
Br
P16



X.269
Cl
C—H
F
P16



X.270
Cl
C—Cl
CF3
P16



X.271
CF3
C—Cl
CF3
P16



X.272
CF3
C—H
H
P16



X.273
Cl
C—Cl
Cl
P17



X.274
Cl
C—H
Cl
P17



X.275
CF3
C—H
CF3
P17



X.276
Cl
C—H
CF3
P17



X.277
Br
C—H
CF3
P17



X.278
Cl
C—F
H
P17



X.279
F
C—Cl
H
P17



X.280
Cl
C—Cl
H
P17



X.281
Cl
C—F
Cl
P17



X.282
Cl
C—Br
Cl
P17



X.283
Cl
C—I
Cl
P17



X.284
F
C—F
F
P17



X.285
Cl
C—H
Br
P17



X.286
Cl
C—H
F
P17



X.287
Cl
C—Cl
CF3
P17



X.288
CF3
C—Cl
CF3
P17



X.289
CF3
C—H
H
P17



X.290
Cl
C—Cl
Cl
P18



X.291
Cl
C—H
Cl
P18



X.292
CF3
C—H
CF3
P18



X.293
Cl
C—H
CF3
P18



X.294
Br
C—H
CF3
P18



X.295
Cl
C—F
H
P18



X.296
F
C—Cl
H
P18



X.297
Cl
C—Cl
H
P18



X.298
Cl
C—F
Cl
P18



X.299
Cl
C—Br
Cl
P18



X.300
Cl
C—I
Cl
P18



X.301
F
C—F
F
P18



X.302
Cl
C—H
Br
P18



X.303
Cl
C—H
F
P18



X.304
Cl
C—Cl
CF3
P18



X.305
CF3
C—Cl
CF3
P18



X.306
CF3
C—H
H
P18



X.307
Cl
C—Cl
Cl
P19



X.308
Cl
C—H
Cl
P19



X.309
CF3
C—H
CF3
P19



X.310
Cl
C—H
CF3
P19



X.311
Br
C—H
CF3
P19



X.312
Cl
C—F
H
P19



X.313
F
C—Cl
H
P19



X.314
Cl
C—Cl
H
P19



X.315
Cl
C—F
Cl
P19



X.316
Cl
C—Br
Cl
P19



X.317
Cl
C—I
Cl
P19



X.318
F
C—F
F
P19



X.319
Cl
C—H
Br
P19



X.320
Cl
C—H
F
P19



X.321
Cl
C—Cl
CF3
P19



X.322
CF3
C—Cl
CF3
P19



X.323
CF3
C—H
H
P19



X.324
Cl
C—Cl
Cl
P20



X.325
Cl
C—H
Cl
P20



X.326
CF3
C—H
CF3
P20



X.327
Cl
C—H
CF3
P20



X.328
Br
C—H
CF3
P20



X.329
Cl
C—F
H
P20



X.330
F
C—Cl
H
P20



X.331
Cl
C—Cl
H
P20



X.332
Cl
C—F
Cl
P20



X.333
Cl
C—Br
Cl
P20



X.334
Cl
C—I
Cl
P20



X.335
F
C—F
F
P20



X.336
Cl
C—H
Br
P20



X.337
Cl
C—H
F
P20



X.338
Cl
C—Cl
CF3
P20



X.339
CF3
C—Cl
CF3
P20



X.340
CF3
C—H
H
P20



X.341
Cl
C—Cl
Cl
P21



X.342
Cl
C—H
Cl
P21



X.343
CF3
C—H
CF3
P21



X.344
Cl
C—H
CF3
P21



X.345
Br
C—H
CF3
P21



X.346
Cl
C—F
H
P21



X.347
F
C—Cl
H
P21



X.348
Cl
C—Cl
H
P21



X.349
Cl
C—F
Cl
P21



X.350
Cl
C—Br
Cl
P21



X.351
Cl
C—I
Cl
P21



X.352
F
C—F
F
P21



X.353
Cl
C—H
Br
P21



X.354
Cl
C—H
F
P21



X.355
Cl
C—Cl
CF3
P21



X.356
CF3
C—Cl
CF3
P21



X.357
CF3
C—H
H
P21



X.358
Cl
C—Cl
Cl
P22



X.359
Cl
C—H
Cl
P22



X.360
CF3
C—H
CF3
P22



X.361
Cl
C—H
CF3
P22



X.362
Br
C—H
CF3
P22



X.363
Cl
C—F
H
P22



X.364
F
C—Cl
H
P22



X.365
Cl
C—Cl
H
P22



X.366
Cl
C—F
Cl
P22



X.367
Cl
C—Br
Cl
P22



X.368
Cl
C—I
Cl
P22



X.369
F
C—F
F
P22



X.370
Cl
C—H
Br
P22



X.371
Cl
C—H
F
P22



X.372
Cl
C—Cl
CF3
P22



X.373
CF3
C—Cl
CF3
P22



X.374
CF3
C—H
H
P22



X.375
Cl
C—Cl
Cl
P23



X.376
Cl
C—H
Cl
P23



X.377
CF3
C—H
CF3
P23



X.378
Cl
C—H
CF3
P23



X.379
Br
C—H
CF3
P23



X.380
Cl
C—F
H
P23



X.381
F
C—Cl
H
P23



X.382
Cl
C—Cl
H
P23



X.383
Cl
C—F
Cl
P23



X.384
Cl
C—Br
Cl
P23



X.385
Cl
C—I
Cl
P23



X.386
F
C—F
F
P23



X.387
Cl
C—H
Br
P23



X.388
Cl
C—H
F
P23



X.389
Cl
C—Cl
CF3
P23



X.390
CF3
C—Cl
CF3
P23



X.391
CF3
C—H
H
P23



X.392
Cl
C—Cl
Cl
P24



X.393
Cl
C—H
Cl
P24



X.394
CF3
C—H
CF3
P24



X.395
Cl
C—H
CF3
P24



X.396
Br
C—H
CF3
P24



X.397
Cl
C—F
H
P24



X.398
F
C—Cl
H
P24



X.399
Cl
C—Cl
H
P24



X.400
Cl
C—F
Cl
P24



X.401
Cl
C—Br
Cl
P24



X.402
Cl
C—I
Cl
P24



X.403
F
C—F
F
P24



X.404
Cl
C—H
Br
P24



X.405
Cl
C—H
F
P24



X.406
Cl
C—Cl
CF3
P24



X.407
CF3
C—Cl
CF3
P24



X.408
CF3
C—H
H
P24



X.409
Cl
C—Cl
Cl
P25



X.410
Cl
C—H
Cl
P25



X.411
CF3
C—H
CF3
P25



X.412
Cl
C—H
CF3
P25



X.413
Br
C—H
CF3
P25



X.414
Cl
C—F
H
P25



X.415
F
C—Cl
H
P25



X.416
Cl
C—Cl
H
P25



X.417
Cl
C—F
Cl
P25



X.418
Cl
C—Br
Cl
P25



X.419
Cl
C—I
Cl
P25



X.420
F
C—F
F
P25



X.421
Cl
C—H
Br
P25



X.422
Cl
C—H
F
P25



X.423
Cl
C—Cl
CF3
P25



X.424
CF3
C—Cl
CF3
P25



X.425
CF3
C—H
H
P25



X.426
Cl
C—Cl
Cl
P26



X.427
Cl
C—H
Cl
P26



X.428
CF3
C—H
CF3
P26



X.429
Cl
C—H
CF3
P26



X.430
Br
C—H
CF3
P26



X.431
Cl
C—F
H
P26



X.432
F
C—Cl
H
P26



X.433
Cl
C—Cl
H
P26



X.434
Cl
C—F
Cl
P26



X.435
Cl
C—Br
Cl
P26



X.436
Cl
C—I
Cl
P26



X.437
F
C—F
F
P26



X.438
Cl
C—H
Br
P26



X.439
Cl
C—H
F
P26



X.440
Cl
C—Cl
CF3
P26



X.441
CF3
C—Cl
CF3
P26



X.442
CF3
C—H
H
P26



X.443
Cl
C—Cl
Cl
P27



X.444
Cl
C—H
Cl
P27



X.445
CF3
C—H
CF3
P27



X.446
Cl
C—H
CF3
P27



X.447
Br
C—H
CF3
P27



X.448
Cl
C—F
H
P27



X.449
F
C—Cl
H
P27



X.450
Cl
C—Cl
H
P27



X.451
Cl
C—F
Cl
P27



X.452
Cl
C—Br
Cl
P27



X.453
Cl
C—I
Cl
P27



X.454
F
C—F
F
P27



X.455
Cl
C—H
Br
P27



X.456
Cl
C—H
F
P27



X.457
Cl
C—Cl
CF3
P27



X.458
CF3
C—Cl
CF3
P27



X.459
CF3
C—H
H
P27



X.460
Cl
C—Cl
Cl
P28



X.461
Cl
C—H
Cl
P28



X.462
CF3
C—H
CF3
P28



X.463
Cl
C—H
CF3
P28



X.464
Br
C—H
CF3
P28



X.465
Cl
C—F
H
P28



X.466
F
C—Cl
H
P28



X.467
Cl
C—Cl
H
P28



X.468
Cl
C—F
Cl
P28



X.469
Cl
C—Br
Cl
P28



X.470
Cl
C—I
Cl
P28



X.471
F
C—F
F
P28



X.472
Cl
C—H
Br
P28



X.473
Cl
C—H
F
P28



X.474
Cl
C—Cl
CF3
P28



X.475
CF3
C—Cl
CF3
P28



X.476
CF3
C—H
H
P28



X.477
Cl
C—Cl
Cl
P29



X.478
Cl
C—H
Cl
P29



X.479
CF3
C—H
CF3
P29



X.480
Cl
C—H
CF3
P29



X.481
Br
C—H
CF3
P29



X.482
Cl
C—F
H
P29



X.483
F
C—Cl
H
P29



X.484
Cl
C—Cl
H
P29



X.485
Cl
C—F
Cl
P29



X.486
Cl
C—Br
Cl
P29



X.487
Cl
C—I
Cl
P29



X.488
F
C—F
F
P29



X.489
Cl
C—H
Br
P29



X.490
Cl
C—H
F
P29



X.491
Cl
C—Cl
CF3
P29



X.492
CF3
C—Cl
CF3
P29



X.493
CF3
C—H
H
P29



X.494
Cl
C—Cl
Cl
P30



X.495
Cl
C—H
Cl
P30



X.496
CF3
C—H
CF3
P30



X.497
Cl
C—H
CF3
P30



X.498
Br
C—H
CF3
P30



X.499
Cl
C—F
H
P30



X.500
F
C—Cl
H
P30



X.501
Cl
C—Cl
H
P30



X.502
Cl
C—F
Cl
P30



X.503
Cl
C—Br
Cl
P30



X.504
Cl
C—I
Cl
P30



X.505
F
C—F
F
P30



X.506
Cl
C—H
Br
P30



X.507
Cl
C—H
F
P30



X.508
Cl
C—Cl
CF3
P30



X.509
CF3
C—Cl
CF3
P30



X.510
CF3
C—H
H
P30



X.511
Cl
N
Cl
P1



X.512
Cl
N
H
P1



X.513
CF3
N
CF3
P1



X.514
CF3
N
H
P1



X.515
Cl
N
Cl
P2



X.516
Cl
N
H
P2



X.517
CF3
N
CF3
P2



X.518
CF3
N
H
P2



X.519
Cl
N
Cl
P3



X.520
Cl
N
H
P3



X.521
CF3
N
CF3
P3



X.522
CF3
N
H
P3



X.523
Cl
N
Cl
P4



X.524
Cl
N
H
P4



X.525
CF3
N
CF3
P4



X.526
CF3
N
H
P4



X.527
Cl
N
Cl
P5



X.528
Cl
N
H
P5



X.529
CF3
N
CF3
P5



X.530
CF3
N
H
P5



X.531
Cl
N
Cl
P6



X.532
Cl
N
H
P6



X.533
CF3
N
CF3
P6



X.534
CF3
N
H
P6



X.535
Cl
N
Cl
P7



X.536
Cl
N
H
P7



X.537
CF3
N
CF3
P7



X.538
CF3
N
H
P7



X.539
Cl
N
Cl
P8



X.540
Cl
N
H
P8



X.541
CF3
N
CF3
P8



X.542
CF3
N
H
P8



X.543
Cl
N
Cl
P9



X.544
Cl
N
H
P9



X.545
CF3
N
CF3
P9



X.546
CF3
N
H
P9



X.547
Cl
N
Cl
P10



X.548
Cl
N
H
P10



X.549
CF3
N
CF3
P10



X.550
CF3
N
H
P10



X.551
Cl
N
Cl
P11



X.552
Cl
N
H
P11



X.553
CF3
N
CF3
P11



X.554
CF3
N
H
P11



X.555
Cl
N
Cl
P12



X.556
Cl
N
H
P12



X.557
CF3
N
CF3
P12



X.558
CF3
N
H
P12



X.559
Cl
N
Cl
P13



X.560
Cl
N
H
P13



X.561
CF3
N
CF3
P13



X.562
CF3
N
H
P13



X.563
Cl
N
Cl
P14



X.564
Cl
N
H
P14



X.565
CF3
N
CF3
P14



X.566
CF3
N
H
P14



X.567
Cl
N
Cl
P15



X.568
Cl
N
H
P15



X.569
CF3
N
CF3
P15



X.570
CF3
N
H
P15



X.571
Cl
N
Cl
P16



X.572
Cl
N
H
P16



X.573
CF3
N
CF3
P16



X.574
CF3
N
H
P16



X.575
Cl
N
Cl
P17



X.576
Cl
N
H
P17



X.577
CF3
N
CF3
P17



X.578
CF3
N
H
P17



X.579
Cl
N
Cl
P18



X.580
Cl
N
H
P18



X.581
CF3
N
CF3
P18



X.582
CF3
N
H
P18



X.583
Cl
N
Cl
P19



X.584
Cl
N
H
P19



X.585
CF3
N
CF3
P19



X.586
CF3
N
H
P19



X.587
Cl
N
Cl
P20



X.588
Cl
N
H
P20



X.589
CF3
N
CF3
P20



X.590
CF3
N
H
P20



X.591
Cl
N
Cl
P21



X.592
Cl
N
H
P21



X.593
CF3
N
CF3
P21



X.594
CF3
N
H
P21



X.595
Cl
N
Cl
P22



X.596
Cl
N
H
P22



X.597
CF3
N
CF3
P22



X.598
CF3
N
H
P22



X.599
Cl
N
Cl
P23



X.600
Cl
N
H
P23



X.601
CF3
N
CF3
P23



X.602
CF3
N
H
P23



X.603
Cl
N
Cl
P24



X.604
Cl
N
H
P24



X.605
CF3
N
CF3
P24



X.606
CF3
N
H
P24



X.607
Cl
N
Cl
P25



X.608
Cl
N
H
P25



X.609
CF3
N
CF3
P25



X.610
CF3
N
H
P25



X.611
Cl
N
Cl
P26



X.612
Cl
N
H
P26



X.613
CF3
N
CF3
P26



X.614
CF3
N
H
P26



X.615
Cl
N
Cl
P27



X.616
Cl
N
H
P27



X.617
CF3
N
CF3
P27



X.618
CF3
N
H
P27



X.619
Cl
N
Cl
P28



X.620
Cl
N
H
P28



X.621
CF3
N
CF3
P28



X.622
CF3
N
H
P28



X.623
Cl
N
Cl
P29



X.624
Cl
N
H
P29



X.625
CF3
N
CF3
P29



X.626
CF3
N
H
P29



X.627
Cl
N
Cl
P30



X.628
Cl
N
H
P30



X.629
CF3
N
CF3
P30



X.630
CF3
N
H
P30









The values of P1 to P30 in Table X are shown in Table P.











TABLE P









P1 
—OCH3



P2 
—OCH2CH3



P3 
—OtBu



P4 
—NMe2



 



P5 







 



P6 







 



P7 







 



P8 







 



P9 







 



P10
OPh



P11
Ph



 



P12







 



P13







 



P14







 



P15
tBu



 



P16







 



P17







 



P18







 



P19







 



P20







 



P21







 



P22







 



P23







 



P24







 



P25
—CH(CH3)2



 



P26







 



P27







 



P28







 



P29
OCH2Ph



P30
OH












PREPARATION EXAMPLES
The following abbreviations were used in this section: s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; M.p.=melting point; RT=retention time, [M+H]+=molecular mass of the molecular cation, [M−H]−=molecular mass of the molecular anion.
The following LC-MS methods were used to characterize the compounds:










Method C
















MS
ZQ Mass Spectrometer from Waters (single quadrupole mass



spectrometer), ionization method: electrospray, polarity: positive



ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V)



3.00, source temperature (° C.) 100, desolvation temperature



(° C.) 200, cone gas flow (L/Hr) 200, desolvation gas flow (L/Hr)



250, mass range: 150 to 800 Da.


LC
1100er Series HPLC from Agilent: quaternary pump, heated



column compartment and diode-array detector.



Column: Waters Atlantis dc18, length (mm) 20, internal



diameter (mm) 3, particle size (μm) 3, temperature (° C.)



40, DAD wavelength range (nm): 200 to 500, solvent gradient:



A = 0.1% v/v formic acid in water and B = 0.1% v/v formic



acid in acetonitrile.












Time (min)
A %
B %
Flow (ml/min)



0.0
90
10
1.7



5.5
0.0
100
1.7



5.8
0.0
100
1.7



5.9
90
10
1.7



















Method D
















MS
ZMD Mass Spectrometer from Waters (single quadrupole mass



spectrometer), ionization method: electrospray, polarity: positive



ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V)



3.00, source temperature (° C.) 150, desolvation temperature



(° C.) 320, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr)



400, mass range: 150 to 800 Da.


LC
Alliance 2795 LC HPLC from Waters: quaternary pump, heated



column compartment and diode-array detector.



Column: Waters Atlantis dc18, length (mm) 20, internal



diameter (mm) 3, particle size (μm) 3, temperature (° C.)



40, DAD wavelength range (nm): 200 to 500, solvent gradient:



A = 0.1% v/v formic acid in water and B = 0.1% v/v formic



acid in acetonitrile.












Time (min)
A %
B %
Flow (ml/min)



0.0
80
20
1.7



2.5
0.0
100
1.7



2.8
0.0
100
1.7



2.9
80
20
1.7



















Method F
















MS
ZQ Mass Spectrometer from Waters (single quadrupole mass



spectrometer), ionization method: electrospray, polarity: negative



ionization, capillary (kV) 3.00, cone (V) 45.00, source



temperature (° C.) 100, desolvation temperature (° C.) 250,



cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass



range: 150 to 1000 Da.


LC
HP 1100 HPLC from Agilent: solvent degasser, binary pump,



heated column compartment and diode-array detector.



Column: Phenomenex Gemini C18, length (mm) 30, internal



diameter (mm) 3, particle size (μm) 3, temperature (° C.)



60, DAD wavelength range (nm): 200 to 500, solvent gradient:



A = 0.05% v/v formic acid in water and B = 0.04% v/v formic



acid in acetonitrile/methanol (4:1).












Time (min)
A %
B %
Flow (ml/min)



0.0
95
5.0
1.7



2.0
0.0
100
1.7



2.8
0.0
100
1.7



2.9
95
5.0
1.7



3.1
95
5
1.7









Example 1
Preparation of enantioenritched 4-[(3R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester




Potassium cyanide (6.465 g, 99.283 mmol) and acetone cyanohydrin (23.9 ml, 261.272 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (40.000 g, 87.091 mmol) in toluene (600.0 ml). To this vigorously stirred suspension was added 9-anthrylmethyl quininium chloride (7.200 g, 13.064 mmol). The reaction mixture was stirred at 60° C. for 2 hours and at room temperature during 63 hours. At this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (35.80 g, 67.6%) as a white amorphous solid. Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=98:2 1 ml/min): retention time 8.11 minutes (minor enantiomer, 5%), 9.95 minutes (major enantiomer, 95%)

1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.78-7.72 (m, 2H), 7.48 (s, 2H), 7.46-7.42 (m, 1H), 4.17 (d, 1H), 4.02 (d, 2H), 2.62 (s, 3H), 1.62 (s, 9H)
Example 2
Preparation of 9-anthrylmethyl quinidinium chloride
A solution of 9-chloromethyl-anthracene (0.91 g, 1.3 eq, 0.40 mmol) and quinidine [CAS=56-54-2] (1 g, 0.38) in toluene (10 ml) was heated at 90° C. for 18 hours. The reaction mixture was filtered, washed with n-heptane. The solid was recrystallised from chloroform and n-heptane to afford the title product (1.69 g) as a yellow solid. Preparation of this compound is also reported in dissertation: contributions to the asymmetric catalysis of c-c couplings, and to the chemical induction of cardiomyogenesis from embryonic stem cells, bianca seelig, university köhl 2009.
Example 3
Preparation of enantioenritched 4-[(3S)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester




Potassium cyanide (0.021 g, 0.32 mmol) and acetone cyanohydrin (0.086 mg, 1.01 mmol) were added to a solution tert-butyl 4-[(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzo (0.150 mg, 0.326 mmol) in toluene (1.0 ml). To this vigorously stirred suspension was added 9-anthrylmethyl quinidinium chloride (0.054 g, 0.098 mmol). The reaction mixture was stirred at 45° C. for 18 hours. At this time water was added and the reaction mixture was extracted with toluene (3×). The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford tert-butyl 4-[(3S)-3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoyl]-2-methyl-benzoate (0.080 g, 50%) as a white foam.

Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=98:2 1 ml/min): retention time 7.64 minutes (major enantiomer, 78.5%), 9.53 minutes (minor enantiomer, 21.5%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.78-7.72 (m, 2H), 7.48 (s, 2H), 7.46-7.42 (m, 1H), 4.17 (d, 1H), 4.02 (d, 2H), 2.62 (s, 3H), 1.62 (s, 9H)

Example 4
Preparation of enantioenritched (3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-2,5-dione




Hydrogen peroxide (aq. 30%, 2.0 mL) was added to sulfuric acid (96%, 15.0 mL) slowly at <0° C. followed by tert-butyl 4-[(3R)-3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoyl]-2-methyl-benzoate (600 mg) in dichloromethane (6.0 mL). The reaction mixture was stirred for 30 min. at 0° C. The reaction mixture was added on ice, treated with saturated aq. Na2SO3 and extracted with dichloromethane (3×). The combined organic phase were dried (Na2SO4), evaporated giving 1.03 g of yellowish foam. It was dissolved in methanol (8 mL) and treated with 8M sodium hydroxide (3 mL). The reaction mixture was stirred at 30 min at RT, acidified with conc. HCl and extracted with dichloromethane. The organic phase was washed with water, NaHCO3 (aq., sat.), water. It was dried (Na2SO4) and evaporated giving the title compound as a white solid 450 mg (70%).

1H-NMR (400 MHz, CDCl3): δ 3.49 (d, J=18.5 Hz), 3.25 (d, J=18.5 Hz), 7.47 (s, 1H), 7.57 (s, 2H), 8.53 (bs, 1H) ppm.
13C-NMR (101 MHz, CDCl3): δ 39.0, 56.8 (q, J=27 Hz), 123.7 (q, J=284 Hz), 126.6), 130.14, 134.4, 136.0, 170.4, 171.6 ppm.
19F-NMR (377 MHz, CDCl3): δ −71.6 ppm.
LC/MS (ES-): 310 (M−H)−, Rt=1.72 min
GC/MS (CI): 312 (M+H)+, Rt=6.25 min
m.p.=138-141° C.
Example 5
Preparation of (3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine




To a solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-2,5-dione (0.02 g) in dry THF (0.5 ml) were added sequentially BF3 etherate (0.109 g, 6 equiv.) and borane-THF complex 1M in THF (1.4 g, 24 equiv.) The reaction stirred at 40° C. for 18 h. After cooling to room temperature, HCl (aq. 4M solution, 1 ml) was added to the mixture and heated for additional 30 minutes at 40° C. After cooling to room temperature, the reaction mixture was washed with Et2O. The aqueous phase was basified to pH-10 with NaOH and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried (Na2SO4) and evaporated. The crude product was purified by column chromatography (silica, eluent: AcOEt with 1% Et3N and 1% MeOH) giving 3.5 mg (19%) of the title compound as a colorless solid.

Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=70:30:0.1, 1 ml/min): retention time 5.15 minutes (minor enantiomer, <15%), 6.96 minutes (major enantiomer, >75%).

1H-NMR (400 MHz, CDCl3): δ=7.36 (t, 1H); 7.26 (d, 2H, 0.73 Hz); 3.76 (d, 1H, 12.8 Hz); 3.32-3.21 (m, 2H); 3.10-3.01 (m, 1H); 2.60-2.51 (m, 1H); 2.36-2.26 (m, 1H) ppm. LC/MS (ES-): 284 (M+H)+, Rt=1.07 min
Example 6
Preparation of enantioenritched (3R)-3-(3,5-dichlorophenyl)-1-methyl-3-(trifluoromethyl)pyrrolidine-2,5-dione




In a dried flask, under argon, to a solution of (3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-2,5-dione (99 mg) in dry DMF, was added potassium carbonate (0.117 g, 0.84 mmol), followed by iodomethane (0.1213 g, 0.84 mmol). The reaction mixture was stirred for 2 hours at from temperature. Water was added to the reaction mixture and it was extracted with Et2O. The organic phase was washed one time with HCl solution (0.5N), dried over Na2SO4 and evaporated in vacuum to give 62 mg (60%) as a yellow oil

1H-NMR (400 MHz, CDCl3): δ 3.12 (s, 3H); 3.22 (d, 1H, J=18.3 Hz), 3.44 (d, 1H, J=18 Hz), 7.45 (t, 1H), 7.58 (s, 2H), ppm.
GC/MS: RT=5.72 min; 326 (M+H)+
Example 7
Preparation of enantioenritched (3R)-3-(3,5-dichlorophenyl)-1-methyl-3-(trifluoromethyl)pyrrolidine




To a solution of (3R)-3-(3,5-dichlorophenyl)-1-methyl-3-(trifluoromethyl)pyrrolidine-2,5-dione (0.05 g) in dry THF (1 ml) were added sequentially BF3 etherate (0.271 g, 0.975 mmol, 6 equiv.) and borane-THF complex 1M in THF (3.4 g, 24 equiv.) The reaction stirred at 40° C. for 18 h. After cooling to room temperature, HCl (aq. 4M solution, 1 ml) was added to the mixture and heated for additional 30 minutes at 40° C. After cooling to room temperature, the reaction mixture was washed with Et2O. The aqueous phase was basified to pH ̃10 with NaOH and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried (Na2SO4) and evaporated giving the desired product 10 mg (21%).

1H-NMR (400 MHz, CDCl3): δ 7.62 (S, 2H); 7.39 (t, 1H); 3.74-3.68 (m, 1H); 3.47-3.39 (m, 2H); 3.35-3.27 (m, 1H); 2.97 (s, 3H); 2.84-2.75 (m, 1H); 2.60-2.52 (m, 1H);
LC/MS (ES-): 298 (M+H)+, Rt=1.14 min
Example 8
Preparation of (E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(2-furyl)but-2-en-1-one




A flask was charged with starting material 1-(2-furyl)ethanone (5.00 g), 1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethanone (12.39 g), potassium carbonate (7.00 g), triethylamine (0.46 g) and 1,2-dichloroethane (50 mL). The reaction mixture was stirred and heated to reflux for 12 hours. Then potassium carbonate (6.00 g) was added and heating was continued for another 12 hours. The reaction mixture was diluted with dichloromethane, washed with water (2×) and the organic phase was dried over Na2SO4 and evaporated. Purification of the crude product via column chromatography (silica, n-heptane/ethyl acetate gradient) gave 10.8 g (71%) of the desired product.

1H-NMR (400 MHz, CDCl3): δ 7.66-7.64 (m, 1H); 7.42-7.39 (m, 2H); 7.26 (d, 1H, J=3.7 Hz); 7.18 (d, 2H, J=1.47 Hz) ppm.
13C-NMR (101 MHz, CDCl3): δ 176.5; 152.5; 147.7; 138.8 (q); 135.0; 133.6; 129.5; 128.4 (q); 127.4; 122.1 (q); 119.5; 113.1 ppm.
25 19F-NMR (377 MHz, CDCl3): δ −67.09 ppm.
GC/MS (CI): 335 (M+H)+, Rt=5.73 min
m.p.=72-76° C.
Example 9
Preparation of enantioenritched 2-(3,5-dichlorophenyl)-4-(2-furyl)-4-oxo-2-(trifluoromethyl)butanenitrile




To a solution of (E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(2-furyl)but-2-en-1-one (0.200 g, 0.597 mmol) in toluene (3 mL) were added (R)-[1-(9-anthrylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl)methanol chloride (0.066 g, 0.119 mmol), acetone cyanohydrin (0.165 mL, 1.802 mmol) and potassium carbonate (0.09206 g, 0.657 mmol) sequentially. The reaction mixture was vigorously stirred at room temperature for 2 h. At this time aqueous solution of NH4Cl was added and the reaction mixture was extracted with AcOEt, dried (Na2SO4) and evaporated. Purification of the crude product via column chromatography (silica, n-heptane/ethyl acetate gradient) gave 165 mg (76%) of the desired product as white semisolid.

Chiral HPLC analysis (Chiralpack AS-R3, Acetonitrile:MeOH:Water=45:5:50, 1 ml/min): retention time 56.73 minutes (minor enantiomer, 13.4%), 59.31 minutes (major enantiomer, 86.6%). (The identity of the stereochemistry was not determined. It is expected that the alternative isomer could be produced in enantiomeric excess with use an appropriate catalyst with reversed stereochemistry.)

1H-NMR (400 MHz, CDCl3): δ 7.68-7.67 (m, 1H); 7.51 (s, 2H); 7.46 (t, 1H); 7.30-7.27 (m, 1H); 6.64 (dd, 1H, J=1.83 Hz, J=3.67 Hz); 4.48 (d, 1H, J=18.3 Hz); 3.89 (d, 1H, J=18.3 Hz) ppm
GC/MS (CI): 362 (M+H)+, Rt=6.60 min
Example 10
Preparation of enantioenritched 3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoic acid




2-(3,5-dichlorophenyl)-4-(2-furyl)-4-oxo-2-(trifluoromethyl)butanenitrile (0.150 g, 0.414 mmol) was dissolved in a mixture of dichloromethane, acetonitrile and water (1:1:2). Sodium periodate (0.627 g, 2.900 mmol) was added, followed by ruthenium chloride hydrate (0.003 g, 0.035 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with CH2Cl2; the organic phase was washed with H2O and dried over Na2SO4 giving 53 mg of violet solid.

1H-NMR (400 MHz, CDCl3): δ 7.49 (s, 1H); 7.46 (s, 2H); 3.42 (s, 2H) ppm
LC/MS: Rt=1.83 min; 310 (M−H)−,
Example 11
Preparation of (E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-pyrrol-1-yl-but-2-en-1-one




A suspension of sodium hydride (0.117 g) in 1,2-dimethoxyethane (5 ml) was cooled to 0° C. and a solution of 2-diethoxyphosphoryl-1-pyrrol-1-yl-ethanone (0.754 g) in 1,2-dimethoxyethane (2 ml) was added drop-wise and stirred for 20 min. To the reaction mixture was added drop-wise a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethanone (0.503 g) in 1,2-dimethoxyethane (2 ml). The reaction was stirred for a further 30 min at 0° C., then allowed to warm to RT and stirred for a further 2 h. The reaction mixture was quenched by cautious addition of saturated NH4Cl(10 ml) solution over ice and extracted with ethyl acetate (3×15 ml). The combined organics were passed through a PTFE membrane and concentrated in vacuo to give a turbid orange oil, which was taken up in toluene and purified by column-chromatography on a pre-packed silica column eluting with heptanes/ethyl acetate to give the title compound as a pale yellow oil (0.313 g)

1H-NMR: (400 MHz, CDCl3) δH ppm 7.40 (m, 2H), 7.20 (m, 3H), 7.18-7.19 (m, 1H), 6.33-6.35 (m, 2H).
Example 12
Preparation of enantioenritched 2-(3,5-dichlorophenyl)-4-oxo-4-pyrrol-1-yl-2-(trifluoromethyl)-butanenitrile




To a suspension of potassium carbonate (0.144 g) and (R)-(6-methoxy-4-quinolyl)-[(2S,4S,5R)-1-[(2,3,4,5,6-pentafluorophenyl)methyl]-5-vinyl-quinuclidin-1-ium-2-yl]methanol bromide (0.126 g) in toluene (4 ml) was added a solution of (E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-pyrrol-1-yl-but-2-en-1-one (0.313 g) in toluene (2 ml) followed by 2-hydroxy-2-methyl-propanenitrile (100 μl) in toluene (2 ml). The reaction mixture was heated to 45° C. overnight before potassium cyanide (0.077 g), a drop of water and a further aliquot of the 2-hydroxy-2-methyl-propanenitrile (100 μl) were added and the reaction mixture heated to 60° C. for a further 4 h. The reaction was poured onto saturated NH4Cl solution and extracted with dichloromethane (3×25 ml). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a dark amber gum, which was purified by column-chromatography on a pre-packed silica column eluting with heptanes/ethyl acetate to give the title compound as a pale yellow oil (0.084 g). Chiral HPLC analysis (Chiralpack IA, Heptane:isopropanol=95:5, 1 ml/min): retention time 6.09 minutes (minor enantiomer, 34%), 6.96 minutes (major enantiomer, 66%). (The identity of the stereochemistry was not determined. It is expected that the alternative isomer could be produced in enantiomeric excess with use of an appropriate catalyst with reversed stereochemistry)

1H-NMR (400 MHz, CDCl3) δH ppm 7.48-7.51 (m, 2H), 7.45-7.48 (m, 1H), 7.21-7.26 (m, 2H), 6.37 (m, 1H), 3.90 (m, 1H).
Example 13
Preparation of enantioenritched methyl 3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoate




Enantioenritched 2-(3,5-Dichlorophenyl)-4-oxo-4-pyrrol-1-yl-2-(trifluoromethyl)butanenitrile (22 mg) was taken up in methanol (2 ml) and sodium methoxide (33 mg) was added. The reaction was stirred at ambient temperature for 1 h before saturated NH4Cl solution (4 ml) was added and the mixture extracted with EtOAc (3×8 ml). The organic portions were combined, passed through a PTFE membrane and concentrated in vacuo to give a colourless semi-solid, which was then taken up in toluene and purified by column-chromatography on silica, eluting with cyclohexane/EtOAc to give the title compound as a colourless oil (7 mg).

1H-NMR (400 MHz, CHLOROFORM-d): δH ppm 7.45-7.49 (m, 3H), 3.68 (s, 3H), 3.36-3.39 (m, 1H).
Example 14
Preparation of enantioenritched 4-(3,5-dichlorophenyl)-4-(trifluoromethyl)pyrrolidin-2-one




To a solution of methyl enantioenritched 3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoate (7 mg) in methanol (0.75 ml) was added cobalt (II) chloride hexahydrate (17 mg) followed by sodium borohydride (12 mg). The reaction mixture was stirred for 2 h at ambient temperature before it was concentrated in vacuo and the residue was taken up in dichloromethane (2 ml) and filtered through Celite. The filter cake washed with further dichloromethane (3×2 ml) and the combined filtrates were concentrated in vacuo to give a black film, which was purified by column-chromatography on silica, eluting with 5-10% methanol/dichloromethane to give the title compound as a colourless oil (6 mg)

1H-NMR (400 MHz, CDCl3): δH ppm 7.41 (t, 1H), 7.15-7.18 (m, 2H), 5.91 (br.s., 1H), 4.12 (dd, 2H), 3.81 (d, 2H).
Example 15
Preparation of methyl 4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoate




To a degassed solution of (3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (100.0 mg) and methyl 4-bromo-2-methyl-benzoate (88.7 mg) in dry toluene (1.8 mL) were added sequentially sodium tert-butoxide (34.9 mg), Xantphos (12.6 mg) and Pd2(dba)3.CHCl3 (6.6 mg). The reaction mixture was stirred under argon at 80° C. overnight. The reaction mixture was diluted with AcOEt and washed two times with water and brine. The organic phase was dried (Na2SO4), filtered and evaporated to give 150 mg of red orange oil. The crude product was purified by silica gel column chromatography (Heptane in 0-100% of AcOEt) giving 51 mg (33%) of a white solid.

1H-NMR (400 MHz, CDCl3): δ 7.93 (d, 1H, J=8.5 Hz); 7.40 (t, 1H, J=2 Hz); 7.30 (s, 2H); 6.45-6.38 (m, 2H), 4.13 (d, 1H, J=10.6 Hz); 3.85 (s, 3H); 3.82 (d, 1H, J=10.6 Hz); 3.66-3.48 (m, 2H); 2.92-2.82 (m, 1H); 2.63 (s, 3H); 2.60-2.49 (m, 1H) ppm.
19F-NMR (400 MHz, CDCl3): 6-73.11 ppm.
13C-NMR (400 MHz, CDCl3): δ 167.74; 148.89; 142.98; 140.46; 135.30; 133.02; 128.87; 126.83; 117.39; 114.25; 108.78; 54.47; 53.17; 51.21; 46.40; 31.72; 22.71 ppm.
Example 16
Preparation of 4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoic acid




Methyl 4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoate (31.0 mg) was dissolved in tetrahydrofuran (0.36 mL). Potassium hydroxide (300 mg) in MeOH/H2O (0.36 ml/0.36 ml) was added at RT. The reaction was stirred at 40° C. for 72 h. The aqueous layer was extracted with ether, then it was acidified until pH=1 with aq. HCl and extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered and evaporated in vacuum to give 26 mg (85%) of the desired product as a white solid.

1H-NMR (400 MHz, CDCl3): δ 8.01 (d, 1H, J=8 Hz); 7.40 (t, 1H, J=2 Hz); 7.30 (s, 2H); 6.48-6.40 (m, 2H), 4.13 (d, 1H, J=11 Hz); 3.82 (d, 1H, J=11 Hz); 3.66-3.48 (m, 2H); 2.92-2.82 (m, 1H); 2.65 (s, 3H); 2.62-2.48 (m, 1H) ppm.
Example 17
Preparation of 4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-N-(1,1-dioxothietan-3-yl)-2-methyl-benzamide




To a suspension of 4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoic acid (20.0 mg) in dry dichloromethane (1 mL) were added sequentially 3-hydroxytriazolo[4,5-b]pyridine (7.2 mg, 1.100), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (10.1 mg) and a solution of 1,1-dioxothietan-3-amine hydrochloride (9.1 mg) and triethylamine (14.5 mg) in dichloromethane. The yellow solution stirred under argon for 20 h at RT. The reaction mixture was diluted with DCM, washed with a saturated solution of NH4Cl and brine. The organic phase was dried (Na2SO4), filtered and evaporated in vacuum to give 16 mg (65%) of white solid.

1H-NMR (400 MHz, CDCl3): δ 7.42-7.38 (m, 2H); 7.31-7.29 (m, 2H); 6.44-6.39 (m, 2H); 6.33 (d, 1H, 6.6 Hz); 4.91-4.83 (m, 1H); 4.66-4.57 (m, 2H); 4.10 (d, 1H, J=10.6 Hz); 4.06-3.98 (m, 2H); 3.82 (d, 1H, J=10.6 Hz); 3.64-3.45 (m, 2H); 2.92-2.84 (m, 1H); 2.61-2.53 (m, 1H); 2.60 (s, 3H) ppm.
Chiral HPLC analysis (Chiralpack® IA 0.46 cm×10 cm, Heptane:2-propanol:diethylamine=70:30:0.1, Flow rate: 1 ml/min; Detection: 288 nm): retention time 5.61 minutes (major enantiomer, >99%), 8.46 minutes (minor enantiomer, not observed).
Example 18 (Reference)
Preparation of (3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine and (3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine




Preparative Method:

Column: 250×30 mm CHIRALPAK® ID 5 μm

Mobil phase: Carbon dioxide (Methanol+1% Diethylamine) 95/5

Flow rate: 120 mL/min

Detection: UV 220 nm

Outlet Pressure: 130 bar

Temperature: 25° C.

Analytical Method:

Column: 250×4.6 mm CHIRALPAK® IA 5 μm

Mobil phase: Heptane:2-propanol: diethylamine=70:30:0.1

Flow rate: 1 mL/min

Detection: UV 270 nm

Temperature: 25° C.

Retention time 5.15 minutes (S-enantiomer), 6.96 minutes (R-enantiomer)

391 mg of (3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (first eluting enantiomer, >99% enantiomeric excess) and 400 mg of (3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (second eluting enantiomer, >98% enantiomeric excess were prepared from 958 mg of racemic 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine.

(Enantiomeric excess is defined as the absolute difference between the mole fraction of each enantiomer.)

## Claims

1. A compound, wherein the compound is a compound of formula IIc,



wherein
P is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, or arylsulfinyl, each optionally substituted,
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula III,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula IV,




wherein
P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula V,




wherein
P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula VI,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula VII,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula VIII,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula X,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted;
a compound of formula XIV,




wherein
P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
A′ is optionally substituted aryl or optionally substituted heteroaryl;
a compound of formula XV,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
A′ is optionally substituted aryl or optionally substituted heteroaryl;
a compound of formula XVIII,




wherein
P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom,
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted; or
a compound of formula XII,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
A′ is optionally substituted aryl or optionally substituted heteroaryl.

2. A compound of claim 1, wherein the compound is of formula XII,



wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
A′ is optionally substituted aryl or optionally substituted heteroaryl.

3. A mixture comprising a compound of IIc and a compound of formula IIcA,



wherein
P is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, or arylsulfinyl, each optionally substituted,
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula IIc;
a mixture comprising a compound of formula III and a compound of formula IIIA,




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula III;
a mixture comprising a compound of formula IV and a compound of formula IVA,




P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula IV;
a mixture comprising a compound of formula V and a compound of formula VA,




wherein
P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and wherein the mixture is enriched for the compound of formula V;
a mixture comprising a compound of formula VI and a compound of formula VIA




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula VI;
a mixture comprising a compound of formula VII and a compound of formula VIIA




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula VII;
a mixture comprising a compound of formula VIII and a compound of formula VIIIA




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula VIII;
a mixture comprising a compound of formula X and a compound of formula XA




R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula X;
a mixture comprising a compound of formula XII and a compound of formula XIIA




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted,
A′ is optionally substituted aryl or optionally substituted heteroaryl, and wherein the mixture is enriched for the compound of formula XII;
a mixture comprising a compound of formula XIV and a compound of formula XIVA




wherein
P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl, each optionally substituted, and wherein the heteroaryl contains at least one ring nitrogen atom, and the heteroaryl is connected at P via a ring nitrogen atom,
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted,
A′ is optionally substituted aryl or optionally substituted heteroaryl, and
wherein the mixture is enriched for the compound of formula XIV;
a mixture comprising a compound of formula XV and a compound of formula XVA




wherein
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted,
A′ is optionally substituted aryl or optionally substituted heteroaryl, and
wherein the mixture is enriched for the compound of formula XV;
a mixture comprising a compound of formula XVIII and a compound of formula XVIIIA




wherein
P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom,
R1 is chlorodifluoromethyl or trifluoromethyl,
R2 is aryl or heteroaryl, each optionally substituted, and
wherein the mixture is enriched for the compound of formula XVIII; or
a compound of formula XXIX, XXX, XXXI, XXXII, or XXXIII




wherein
R1 is chlorodifluoromethyl or trifluoromethyl, and
R2 is aryl or heteroaryl, each optionally substituted.