# Patent

## Title
Cyclopropanation

## Abstract

A method of preparing a cyclopropane ring-bearing compound of the formula I




in which R1 and R2 are independently selected from C1-C10 alkyl, optionally substituted, or R1 and R2, together with the bonds linking them to the cyclopropane ring, form a monocyclic or bicyclic ring system, which may comprise at least one hetero-atom, comprising the reaction of a compound of formula II

R1—CH═CH—R2  II

in which R1 and R2 have the significances hereinabove defined, with a compound of formula III

X—CH2—Y  III

in which X is a nucleofuge selected from halides and pseudohalides and Y is an electrofuge selected from boranes and borates, in the presence of a metal catalyst complex selected from those useful for catalytic cyclopropanation and those useful for catalyzing Heck coupling. The method provides a particularly easy and non-hazardous method of cyclopropanation.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a national stage application of International Application No. PCT/EP2014/073932, filed 6 Nov. 2014, which claims priority from Great Britain Patent Application No. 1319677.9, filed 7 Nov. 2013, which applications are incorporated herein by reference.
The work leading to this invention has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. PIEF-GA-2010-275400. and the Swiss National Science Foundation under grant 200020_137505.
This disclosure relates to cyclopropanation and to compounds for use therein.
Cyclopropanation, the conversion of a carbon-carbon double bond to a cyclopropane ring, is a chemical transformation used commonly in the synthesis of organic chemical compounds, in particular in the pharmaceutical, agrochemical, and flavors and fragrances industries. Cyclopropanation on a laboratory scale is commonly performed with the aid of diazo compounds, for example, diazomethane for methylenation reactions, and transition metal catalysts typically comprising copper or rhodium complexes. A wide variety of suitable catalysts is described in the review of Dzhemilev et at (Russian Chemical Bulletin, 1989, 38(8), 1707-1714).
On a larger, preparative scale relevant to production of commercially-significant quantities of cyclopropanated compounds, diazo compounds are avoided because of safety problems associated with their instability with respect to explosion, as well as the carcinogenicity of some of the best chemical precursors to diazo compounds.
One widely-exploited cyclopropanation reaction is the Simmons-Smith reaction (J.Am.Chem.Soc. 1958, 80, 5323, 1959, 81, 4256). This has the major advantage of being effective on a commercial scale, and it can deliver good-to-excellent yields. However, it produces more than stoichiometric amounts of zinc-containing waste, and furthermore typically requires diiodomethane, an expensive and potentially dangerous reagent.
It has now been found that it is possible to cyclopropanate carbon-carbon double bonds by a method that avoids the disadvantages of the prior art. There is therefore provided a method of preparing a cyclopropane ring-bearing compound of the formula I




in which R1 and R2 are independently selected from C1-C10 alkyl, optionally substituted, or R1 and R2, together with the bonds linking them to the cyclopropane ring, form a monocyclic or bicyclic ring system, which may comprise at least one hetero-atom, comprising the reaction of a compound of formula II

R1—CH═CH—R2  II

in which R1 and R2 have the significances hereinabove defined, with a compound of formula III

X—CH2—Y  III

in which X is selected a nucleofuge selected from halides and pseudohalides and Y is an electrofuge selected from boranes and borates, in the presence of a metal catalyst complex selected from those that are useful for catalytic cyclopropanation and those useful for catalyzing Heck coupling.

It is particularly unexpected that a compound of the formula III can perform this function under these conditions.
The moieties R1 and R2 in Formulae I and II may be selected from

    
    
        (a) C1-C10 alkyl, optionally substituted;
        (b) R1 and R2, together with the bonds linking them to the cyclopropane ring, form a monocyclic or bicyclic ring system, which may comprise at least one hetero-atom.
    
    


Particular examples of case (a) include 4-phenyl-1-butene, and styrene.
Particular example of case (b) include (left to right below) norbornene and cis cyclooctene:




In the case of Formula III, the terms “nucleofuge” and “electrofuge” have their normal meanings, that is, respectively, a leaving group that retains the electron bonding pair from its previous bonding, and a leaving group that does not retain the bonding pair.
Typical examples of nucleofuge X include halogens and pseudohalogens (that is, compounds that are only partially halogen, or completely halogen-free). Examples of these include iodine and bromine. A particular example of a pseudohalogen includes acetate.
Typical examples of electrofuge Y include the trifluoroborate salts of alkali metals, such as sodium and potassium, and pinacol borane (4,4,5,5-tetramethyl-1,3,2-dioxaborolane).
The catalyst may be selected from any suitable catalyst known to be useful either for the cyclopropanation of olefins, or for use in the Heck reaction (see Zapf et al, Topics in Catalysis, 2002, 19, 101-109).
Particular examples are those complexes of metals of Group 10 (nickel, palladium, platinum) of the Periodic Table in the 0 or +2 oxidation state. A particular example is palladium.
A particular example of a catalyst is the Herrmann catalyst. This catalyst, trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II), has the formula:




(see Angew. Chem. Int. Ed. Engl. 1995, 34, 1844-1848).

and is readily commercially available.

A wide variety of conditions and reactants are possible. Typical solvents are dimethylformamide (DMF) and dimethylacetamide (DMA), optionally with added water and/or methanol. Tetrahydrofuran has also been found to work in some cases. In some cases, added bases, such as carbonate or fluoride salts, can be useful. However, the skilled person can, by simple, non-inventive experimentation, easily provide a suitable method with suitable conditions and reactants in every case.
The process provides a relatively easy method of cyclopropanating olefinic bonds. It is especially effective in cyclopropanating in-ring olefinic bonds, and this permits the ready synthesis of a considerable number of interesting compounds that previously could only be made with difficulty. Such compounds are useful as intermediates in other chemical processes, or as final products, and they are useful in a wide variety of chemical fields, such as pharmaceuticals, dyestuffs, flavours and fragrances.
This disclosure is further described with reference to the following non-limiting examples.
A number of preparations were made, and the results are shown in the following tables.


GENERAL PROCEDURE
In the glove box, a 5 mL Young Schlenk (approximately 10 mL total volume) was equipped with a glass coated stir bar. In the glove box, base (1.5 equiv), methylenation reagent (1.5 equiv), olefin (1 equiv), and catalyst (5 mol %) were transferred to the vial. A degassed solvent mixture of a polar solvent (16 mL/mmol substrate) and a ROH solvent (2 mL/mmol substrate) were added and the Schlenk was closed. After transferring the Schlenk outside the glove box, the reaction mixture was heated to 90° C. in an oil bath and stirred for 16 h. Then the reaction mixture was rapidly cooled to 0° C. in an ice bath. Consecutively undecane (0.4 equiv) as internal standard, Et2O (45 mL/mmol substrate) and water (45 mL/mmol substrate) were then added. The phases were separated and the aqueous phase was extracted with Et2O (45 mL/mmol substrate). The combined organic phases were washed with brine (45 mL/mmol substrate), dried over MgSO4 and analyzed by GC-MS.
Procedure for Standard Reaction:
In the glove box, a 5 mL Young Schlenk (approximately 10 mL total volume) was equipped with a glass coated stir bar. In the glove box, K2CO3 (25.1 mg, 0.182 mmol), KBF3CH2I (43.1 mg, 0.174 mmol), norbornene (11.0 mg, 0.117 mmol), and Hermann PdII-catalyst (2.74 mg, 0.00292 mmol, dimer so 5.0 mol % PdII) were transferred to the vial. A degassed solvent mixture of DMF (2 mL) and H2O (0.25 mL) were added and the Schlenk was closed. After transferring the Schlenk outside the glove box, the reaction mixture was heated to 90° C. in an oil bath and stirred for 16 h. Then the reaction mixture was rapidly cooled to 0° C. in an ice bath. Consecutively undecane (10 μL, 7.4 mg, 0.047 mmol) as internal standard, Et2O (5 mL/mmol substrate) and water (5 mL/mmol substrate) were then added. The phases were separated and the aqueous phase was extracted with Et2O (5 mL/mmol substrate). The combined organic phases were washed with brine (5 mL), dried over MgSO4 and analyzed by GC-MS (method: 40° C. for 2 min, then from 40° C. to 300° C. in 17 min 20 sec [ramp: 15° C./min]). The tricyclo[3.2.1.0-2,4]octane was obtained in 98% yield according to GC-MS (standardized).
tricyclo[3.2.1.02,4]octane (compared to authentic sample, identical fragmentation pattern [GC-MS])—retention time: 5.81 min, area: 20343140, correction factor: 1.304/1.00 tricyclo[3.2.1.0-2,4]octane/undecane;
undecane—retention time: 8.65 min, area: 15889470.
The results are set forth in the following tables. Table 1 shows the screening of catalysts using norborene as the test olefin, and Table 2 shows the optimization of solvent, additives, and the electrofuge/nucleofuge combinations. Table 3 shows results for olefins other than norbornene.







TABLE 1







Screening of catalysts for the methylenation of norbornene.a








 








 










entry
catalyst
yield
remaining 1b





1 
none
 0%
80%


2 
Pd0(PPh3)4
 6%
71%


3c
Pd0(dba)2 + IPr
 2%
81%


4 
Pd0(IPr)2
37%
45%


5 
Pd0(P(tBu)3)2
85%
15%


6 
PdII-Herrmann
98%
 0%


7 
PdIIIPrCl2-dimer
88%
 4%





aConditions: scale 0.117 mmol 1, 0.06 M concentration of 1.


bStandardized GC-yield and recovery of 1.


cPd0(dba)2 (5 mol %) and IPr ligand (6 mol %) were used.













TABLE 2







Optimization of norbornene methylenation using the Herrmann (4) and


Pd0(P(tBu)3)2 (5) catalysts.a








 













#
cat
XCH2’B’
base
DMF/H2O
yieldb
rem. 1b





 1 
4
ICH2BF3K (2)
K2CO3
8/1
98%
 0%


 2 
5
ICH2BF3K (2)
K2CO3
8/1
85%
15%


 3 
4
ICH2BF3K (2)
K2CO3
DMF only
25%
56%


 4 
5
ICH2BF3K (2)
K2CO3
DMF only
47%
42%


 5 
4
ICH2BF3K (2)
none
8/1
24%
54%


 6 
5
ICH2BF3K (2)
none
8/1
35%
52%


 7 
4
ICH2BF3K (2)
none
DMF only
 1%
73%


 8 
5
ICH2BF3K (2)
none
DMF only
87%
 7%


 9c
4
ICH2BF3K (2)
K2CO3
8/1
38%
37%


10c
5
ICH2BF3K (2)
K2CO3
8/1
66%
17%


11 
5
BrCH2BF3K
none
DMF only
 7%
73%


12 
5
ICH2B(OR)2d
CsFe
DMF only
70%
16%


13 
5
ICH2B(OR)2d
K2CO3 + CsFe
8/1
92%
 8%





aConditions: scale 0.117 mmol 1, 0.06 M concentration of 1.


bStandardized GC-yield and recovery of 1.


cBefore addition of 1 and the catalyst the B-reagent 2 was preactivated at 90° C. for 30 min.


d2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used.


e3.0 equiv of CsF was used.













TABLE 3







Methylenation of several electron-rich olefins using Herrmann catalyst 4.a








 











#
substrate
cyclopropaneb
β-H elimination productb
remaining 7b





1












58%


 


2












43%


 


3












39%





aConditions: scale 0.113-0.117 mmol, 0.06 M concentration of 7.


bStandardized GC-yield and recovery of 7.


cA mixture of several olefins was obtained.

## Claims

1. A method of preparing a cyclopropane ring-bearing compound of the formula I



in which R1 and R2 are independently selected from C1-C10 alkyl, optionally substituted, or R1 and R2, together with the bonds linking them to the cyclopropane ring, form a monocyclic or bicyclic ring system, which optionally comprises at least one hetero-atom, comprising the reaction of a compound of formula II


R1—CH═CH—R2  II


in which R1 and R2 have the significances hereinabove defined, with a compound of formula III


X—CH2—Y  III


in which X is a nucleofuge selected from halides and pseudohalides and Y is an electrofuge selected from boranes and borates, in the presence of a metal catalyst complex selected from those useful for catalytic cyclopropanation and those useful for catalyzing Heck coupling.

2. The method according to claim 1, in which the nucleofuge is selected from halogens and pseudohalogens.

3. The method according to claim 1, in which the electrofuge is selected from trifluoroborate salts of alkali metals, and pinacol borane.

4. The method according to claim 1 in which the catalyst is a Herrmann catalyst.