2011.12.20. Yuya Morita (B4)

Combining transition metal catalysis andorganocatalysis~for dual activation of carboxylic acids
by transition metal and boron catalysts~

New method for C-C bond formation

dual activationtransition metal catalysis

Cu

organocatalysis
HNAg

O

CO2H

N

Co
Au
Sc

Ar

PdRh

Ph

Ru
NiO
O

N
H

O
POH

ArContents
1. Combining transition metal catalysts and aminocatalysts
2. Boron compounds as catalysts
3. Dual activation of carboxylic acids by combining transition metaland boron catalysts

1. Combining transition metal catalysts and aminocatalysts
0. introduction
two types of activation mode by aminocatalysts

enamine - bifunctional catalyst
Proline has been playing a major role in enamine-based catalysis.
In this view, proline can be regarded as a Lewis base/Brønsted acid "bifunctional catalyst".
"replace" the Brønsted acid with a metal Lewis acida novel class of metal Lewis acid-enamine bifunctional catalysts with the intention tobridge more traditional transition-metal catalysis with the newly established prosperous
area of organocatalysis
the Challenging Problem
the acid-base self-quenching reaction leading to catalyst inactivation•finetuning the reaction conditions and catalystse.g.) using a "soft" Lewis acid (metal such as Cu(I), Ag(I), Au(I), and Pd(0)) anda "hard" Lewis base (amine)
1. combining enamine catalysis and -allyl palladium complexes
2. combining enamine catalysis and -activation of C-C triple bond
4. combining enamine catalysis and SOMO photoredox catalysis
5. combining enamine catalysis and Rhodium-catalyzed hydroformylation•using a tridentate (or bidentate) ligand tethered with a chiral amine(the Lewis acid and Lewis base are incorporated into one molecule)

A large number of metals
can be introduced.

3. combining enamine catalysis and metal activating carbonyl groups
This new concept aims to achieve organic transformations that cannot
be accessed by organocatalysis or metal catalysis alone.

1. combining enamine catalysis and π-allyl palladium complexes
enamine catalysis
nucleophilic activation

π-allyl palladium complexes
electrophilic activation

1-1. Direct Intermorecular α-Allylic Alkylation of Aldehydes and Cyclic Ketones

A. Cóldova, et al. Angew. Chem. Int. Ed. 2006, 45, 1952

The first example of the one-pot combination of transition metal and enamine catalysis!!
screening of amine catalysts

mechanism

This is the first direct intermoleculer α-alkylation of aldehydes.
conventional method...
(stoichiometric amounts of metal, preactivated aldehydes...)
But...
The satisfactory results are not obtained in asymmetric version of this reaction

1-2. Intramorecular α-Allylic Alkylation of Aldehydes

R. N. Saicic, et al. Org. Lett. 2007, 9, 5063

catalytic asymmetric cyclization•using chiral amine catalysts
MacMillan's catalyst, (S)-proline, (S)-2-diphenylprolinol
did not catalyze the reaction. (S)-2-methoxymethyl
pyrrolidine failed to effect the asymmetric induction.
•using the chiral metal complex

R. N. Saicic, et al. Tetr ahedron. 2009, 65, 10485

1-3. α-Allylic Alkylation of Aldehydes with Allylic Alcohols

B. Br eit, et al. Or g. Lett. 2009, 11, 1453

But...
The satisfactory results are not obtained in asymmetric version of this reaction

2. combining enamine catalysis and π-activation of C-C triple bondenamine catalysis
nucleophilic activation

π-acid-activated alkynes
electrophilic activation

2-1. 1,2-Dihydroisoquinoline Synthesis

Q. Ding and J. W u, Org. Lett. 2007, 9, 4959

mechanism

This is the first example of combination ofenamine catalysis and π acidic transition
metal catalysts.

2-2. Direct Carbocyclization of Aldehydes with Alkynes(α-substituted aldehydes)(unbranched aldehydes)
S. F. Kirsch, et al. Org. Lett. 2008, 10, 1025

possible mechanism•AgOTfEtN(i-Pr)2 gave TM is 73% isolated yield.
mechanism B•[(Ph3PAu)3O]BF4EtN(i-Pr)2 failed to give significant amount of TM.
mechanism A

2-3. A Carboannulation for the Synthesis of Cyclopentene
mechanism

D. J. Dixon, et al. Chem. Commun. 2008, 2923

But...
Good enantioselectivity was not observed in this type of reaction.

3. combining enamine catalysis and metal activating carbonyl groups

enamine catalysis
nucleophilic activation

metal activating calbonyl groups
electrophilic activation

3-1. Direct Asymmetric Aldol Reaction of Ketones

H. W ang, et al. Eur . J. Org. Chem. 2009, 4581

tridentate ligands

the catalysts were prepared by stirring the ligand and themetal salt in solvent for 2-4 hours at room temperature
before addition of the substrates

proposed trasition state

The tethered pyrrolidine moiety in the ligand did not participate in the coordination to
the metal and the acid-base self-quenching reaction did not happen as expected!!

3-2. Asymmetric Inverse-Erectron-Demand Hetero-Diels-Alder Reaction

H. W ang, et al. Angew. Chem. Int. Ed. 2011, 50, 3484

The competing reactions of cyclohexanone with enone 3a in the presence of an amine catalyst•a highly enantioselective aldol reaction occurs in thepresence of a proline-derived catalyst•a novel asymmetric formal [3+3] annulation reaction
occurs in the presence of another proline-derived catalyst

optimization of HDA reaction[a]proposed catalytic cycle

the catalysts were prepared by stirring the ligand and themetal salt in solvent for 1-4 hours before addition of thesubstrates

ligand screening

proposed transition state

The big R (tert-butyl) group shields the Re face of theenamine, thus the activated enone attacks from the Siface.

4. combining enamine catalysis and SOMO photoredox catalysis
SOMO activation strategy•single-electron oxidation of a transient chiral enamine intermediate was achieved on treatment of enamines
with suitable metal oxidants (such as CAN)
CAN=Ce(NH4)2(NO3)6•the enamine nucleophiles were transformed into radical cationic electrophiles

4-1. Direct Asymmetric Alkylation of Aldehydes

radical-cation intermediate•reactivity to unactivated olefins•experiments of the radical clock
D. W . C. MacMillan, et al. Science, 2007, 316, 582

4-2. combining enamine catalysis and photoredox catalysis

The experiment of radical clock indicatesthat a 3π electron SOMO activatedintermediate is not operative in theorganocatalytic cycle.

D. W . C. MacMillan, et al. Science, 2008, 322, 77

5. combining enamine catalysis and Rhodium-catalyzed hydroformylation
5-1. Tandem Hydroformylation/Enantioselective Aldol Reactions

B. Br eit, et al. Adv. Synth. Catal. 2007, 349, 1891

The difficulty of this cross-aldol reaction between two non-equivaent aldehydes•two aldehyde have to show significant rate differences in enamine formation•the homo-aldol of the aldehyde component has to be suppressedtandem hydroformylation/organocatalytic aldol reaction
generate the donor aldehyde in a low stationary concentration by the hydroformylationof alkenes
ligands

A crucial factor for success of this reaction is thecorrect adjustment of the hydroformylation rate to
the rate of proline-catalyzed aldol addition sinceaccumulation of the donor aldehyde would
facilitate undesired homodimerization.
*In case of the more electrophilic aryl aldehydes,
the more reactive hydroformylation catalyst basedon L1 gave optimal results.
Application to terminal alkenes

5-2. Tandem Hydroformylation/Enantioselective Mannich Reactions

P. Eilbr acht, et al. Adv. Synth. Catal. 2009, 351, 339

2. Boron compounds as catalysts
1. combined acid catalysis
combined acids system (Lewis acid and Brønsted acid)an effective asymmetric environmentby more-organized structures

more reactivity
by associative interactione.g.) HSO3F•SbF5 (magic acid)

The concept of combined acids can be a particularly useful tool for the design ofasymmetric catalysis.

H. Y amamoto, K. Futatsugi, Angew. Chem. Int. Ed. 2008, 47, 2876**

1-1. a chiral boron reagnet (BLA)

Y amamoto, H. et al. Tetrahedr on Lett. 1986, 27, 4895

The intramolecular hydrogen bonding between
the hydrogen atom on the amide and the oxygen
atom attached to the boron center increases theLewis acidity of boron.

But...
1.2 equiv of boron reagent is required in this reaction.

1-2. CAB (chiral acyloxyborane) catalysts (BLA)

Mechanism studies of a CAB-catalyzed
asymmetric diel-Alder reactions

Y amamoto, H. et al. J. Am. Chem. Soc. 1993, 115, 10412

CAB-methacrolein and CAB-crotonaldehyde complex

Based on the NOE experiments, it wasestablished that the effective shielding of
the CAB-coordinated aldehydes arises
from π stacking of 2,6diisopropoxybanzaldehyde ring and thecoordinated aldehyde.

1-3. π-π donor-acceptor interaction (BLA)
Y amamoto, H. et al. J. Am. Chem. Soc. 1998, 120, 6920

The coordination of a proton of the 2-hydroxyphenylgroup with an oxygen of the adjacent B-O bond incomplex plays an important role.
hydrogen bonding interaction via a Brønsted acid•increase the Lewis acidity of boron•increase the π-basicity of the phenoxy moiety

Asymmetric Diels-Alder reactions catalyzed by BLA 2

The attractive π-π donor-acceptor interaction
between a dienophile and a chiral ligand ishighly effective for inducing asymmetry.

synthesis of BLA catalysts*THF and additional water are required for the preparation of a sufficient amount of BLA2.

1-4. oxazaborolidine (BLA)
asymmetric Diels-Alder reaction

transition state

NO
B

HTfO
CHO

S

CHO

CH2Cl2, -95 oC
1-2 h

E. J. Corey, et al. J. Am. Chem. Soc. 2002, 124, 3808

1-5. oxazaborolidine (LLA)asymmetric Diels-Alder reaction

H. Y amamoto, et al., Angew. Chem. Int. Ed. 2005, 44, 1484

The reactivity and asymmetric induction ability canbe maintainted even in the presence of a small
amount of water as well as other Lewis bases
by adding a slightly larger amount of SnCl4.

1-6. dioxaborolane (LLA)transition state
PhR3
R1BO

H

R4

OH

Sc(OTf)3(10 mol%)OO

H

CH2Cl2, -78 oC

R3R4
R1 R 2

R2

A close investigation pointed to electrophilic activationby coordination of the metal ion to one of the boronate
oxygens in a closed bimolecular transition state.
D. G. Hall, et al. J. Am. Chem. Soc. 2004, 126, 4518

2. activation of carboxylic acid
OR[B]
OHO
R
O [B]
activation

2-1. boron compound-catalyzed amide condensation
1. arylboronic acid

Y amamoto, H. et al. J. Org. Chem. 1996, 61, 4196

proposed catalytic cycle

arylboronic acids with electron-withdrawing substituents at the aryl group•water-, acid-, and base-torelant•thermally stable and can be readily handled in air•strong Lewis acidity enhances the rate of the generation of acyloxyborane species andtheir reactivity with amines
only catalytic amount of boronic acids are required!!

But...
Catalytic activities of these neutral boronic acids are greatly diminished in polar solvents.
This solvent limitation restricts the scope of substrates.

2. N-Alkyl-2-boronopyridinium Salt

Y amamoto, H. et al. Org. Lett. 2005, 7, 5043

•4-borono-N-methylpyridinium iodide (2) is effective in polar solvents.
•A catalyst 2 can be reused through the use of ionic liquid-toluene biphasic solvents.
•Catalysts 5 are reusable without the need for ionic liquids.

1-ethyl-3-methylimidazolium
trifluoromethanesulfonate [emim][OTf]plays an important role in suppressing
the condensation of 2 to [2]12.

3. catecholborane

Ganem's amide condensation

Ganem, B. et al. J. Or g. Chem. 1978, 43, 4393

Under this condition, benzo[d][1,3,2]dioxaborol-2-ol(3) is inert as a condensing reagent.

How can we use 3 as a condensing reagent??

3 serves as a dehydrative catalyst under azeotropic reflux conditions
with the removal of water in less polar solvents!!
Y amamoto, H. et al. Org. Lett. 2006, 8, 1431

But...
These catalysts(1~3) required heating at reflux in solvent at temperatures over 110 oC.

4. o-halophenylboronic acid
D. G. Hall, et al. Angew. Chem. Int. Ed. 2008, 47, 2876

*MS4Å is essential to scavenge the waterby-product of the reaction.

Why is the catalyst 2 so effective?
•para isomer is significantly less effective•o,o'-dihaloarylboronic acids are less reactive•inductive effects alone cannot account for
The reason is unclear at present...

Catalyst 2 functions under practical and mild conditions at room temperature!!
2-2. boron compound-catalyzed ester condensation
ester condensation of α-hydroxycarboxylic acids
Y amamoto, H. et al. Tetr ahedron. 2007, 63, 8645

F3C
B(OH)2N

B(OH)2I
F3C

12•Boric acid was the most active catalyst with a molar
ratio of mandelic acid/butanol of >1:2.
•2 was the most active catalyst with a molar ratio ofmandelic acid/butanol of <1:3.

B(OH)3 with a higher ratio of
α-hydroxycarboxylic acid
B(OH)3 in excess alcohol

Not only α-hydroxycarboxylic acids but alsoβ-hydroxycarboxylic acids were condensed.
limitation of this reaction
Boron(III) compounds were much less effective forthe esterification of simple carboxylic acids.
This is because an alkoxyborane species is preferentially
produced rather than the desired acyloxyborane species.

Amide condensation issuppressed in thepresence of alcohol.

chemoselective esterificationof α-hydroxycarboxylic acids

2-3. boron compound-catalyzed Diels-Alder reaction
1. CAB (chiral acyloxyborane) catalysts
OO

H
OO

O
R

HBO

CAB

O

Y amamoto, H. et al. J. Am. Chem. Soc. 1988, 110, 6254
CAB

catalytic cycle

2. boronic acid
OArB(OH)2 (20 mol%)OH

CH2Cl2, 25-30 oCOHOOO
B

ArOH

D. G. Hall, et al. Angew. Chem. Int. Ed. 2008, 47, 2876

selective activation of carboxylic acid

A remarkable selectivity of carboxylic acids over the corresponding esters!!

3. Dual activation of carboxylic acids by combining transition metal
and boron catalysts
0. conceptketones, aldehydes

carboxylic acids

amines as organocatalysts

boron compounds as organocatalysts

transition metaltransition metal

1. motivation
Some boron compounds-catalyzed reactions using carboxylic acids as substrates
were reported.
•amide condensation•ester condensation•Diels-Alder reaction(see Chapter 2-2)

But the reaction using carboxylic acids as nucleophiles seemed to be difficult so far.
dual activation by transition metal
and boron catalysts

These reactions (such as Michael addition, aldol reaction...) will be possible.
OEWG

boron catalysts
OHOEWGOH

metal, base

RRM

MOO
EWG

Hbase

O [B]

O [B]RR*boron catalysts, metal, and base(NEt3 etc.) can coexist (see p.14)

2. advantage
Boron compounds can selectively activate carboxylic acids. (see p.20)
carboxylic acids are activated enough to be
deprotonated the α-proton by weak baseChemoselective nucleophilic addition of carboxylic acids will be possible.

3. catalyst design•using a bidentate (or tridentate) ligand tethered with a boron compoundactive species

NN

M

O

N

N
HB

O
O

B
O

R

catalyst

HN
R'HN

N
R'O

N

NH

O

O
M

NHOO

O

N

B
O
R

catalyst

NH

B