Title: Nucleophilic Carbenes in Organocatalysis
1Nucleophilic Carbenes in Organocatalysis
Rawal Group Literature Meeting
Enders, D. Balensiefer, T. Acc. Chem. Res. 2004,
37, 534.
- Apurva H. Dave
- April 11, 2005
2Carbenes A Brief Introduction
- Carbenes are two-coordinate carbon compounds that
have two nonbonding electrons and no formal
charge on the carbon.
- It is reported that the term carbene, as we now
know it, was conceived in the middle of the night
by W. von E. Doering, S. Winstein, and R. B.
Woodward while riding in a Chicago taxi that
delivered them to Boston the next day.
Doering, W. von E. Knox, L. H. J. Am. Chem. Soc.
1956, 78, 4947 footnote 9.
3Carbenes A Brief Introduction
- Fischer Carbenes - electophilic, heteroatom
stabilized.
- Schrock Carbenes - nucleophilic, methylene or
alkylidene.
Metathesis by Electrophilic Carbene Complexes
Grubbs 2nd Generation Ru Catalyst
Schrock Mo Catalyst
These catalysts have had a major impact on
methodology by allowing olefins to be used in C-C
bond formation.
Hegedus, L. S. Transition Metals in the Synthesis
of Complex Organic Molecules University Science
Books Sausalito 1999 Chapter 6. Trnka, T. M.
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
4N-Heterocyclic Carbenes (NHC)
- Wanzlick Type Carbenes Dimers that dissociate
to give nucleophilic carbenes in situ.
Wanzlick, H. W. Angew. Chem. Int. Ed. 1962, 1, 75.
- Stable Carbenes- isolable in the absence of
oxygen and moisture.
Arduengo, A. J. III Harlow, R. L. Kline, M. K.
J. Am. Chem. Soc. 1991, 113, 361.
- Large singlet-triplet energy gap (336kJ/mol)
- p-interactions in the imidazole ring
- Electronegativity of nitrogen atoms
- Steric effects of adamantyl groups
Arduengo, A. J. III Dias, H. V. R. Harlow, R.
L. Kline, M. K. J. Am. Chem. Soc. 1992, 114,
5530.
5Stable NHCs More Examples
This triazole heterocycle NHC was the first
commercially available carbene, but is sensitive
to air and moisture.
Enders, D. Breuer, K. Raabe, G. Runsink, J.
Teles, J. H. Melder, J.-P. Ebel, K. Brode, S.
Angew. Chem. Int. Ed. 1995, 34, 2021.
NHC 1 shown to be air-stable for at least 2 days.
Arduengo, A. J. III Davidson, F. Dias, H. V.
R. Goerlich, J. R.Khasnis, D. Marshall, W.
J. Prakasha, T. K. J. Am. Chem. Soc. 1997, 119,
12742.
NHC 2 shown to be air-stable indefinitely.
Cole, M. L. Jones, C. Junk, P. C. New J. Chem.
2002, 26, 1296.
6Organocatalyzed Reactions by NHC
Benzoin Condensation
Stetter Reaction
Homoenolate/ Internal Redox
7Organocatalyzed Reactions by NHC
Transesterification/ Acylation
Kinetic Resolution
Ring Opening Polymerization
8The Benzoin Condensation
1832 Wöhler and Liebig discovered benzoin
condensation catalyzed by cyanide anion.
1903 Lapworth proposes mechanism that would
proceed via a carbanion, representing an
inverted (i.e., nucleophilic) reactivity of the
carbonyl carbon (Umpolung concept by Seebach in
1979).
1943 Ukai et al. reported thiazolium salts can
also be used as catalysts in benzoin
condensation.
1954 Mizuhara et al, reported the catalytic
activity of thiamine is based on thiazolium unit.
9Benzoin Condensation NHC Mechanism
1958 Breslow presents mechanistic model for the
thiazolium salt catalyzed benzoin condensation
which is based on the Lapworth mechanism.
Think of this intermediate as an enamine
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719
10Benzoin Condensation Asymmetric Variations
The product of the benzoin condensation generates
a new stereogenic center.
Sheehan, J. Hara, T. J. Org. Chem. 1974, 39,
1196.
Sheehan, J. Hunnemann, D. H. J. Am. Chem. Soc.
1966, 88, 3666.
Dvorak, C. A. Rawal, V. H. Tetrahedron Lett.
1998, 39, 2925.
11Benzoin Condensation Asymmetric Variations
- Enders et al, reported the most active catalyst
which gave benzoin from - benzaldehyde in 66 yield, 75 ee.
- Electron-rich aromatic aldehydes gave up to 86
ee, but lower yields.
- Electron-poor aromatic aldehydes gave lower
asymmetric induction, - but higher yields.
- Reactions had to be carried out in the absence of
air and water, otherwise the - intermediate carbene was oxidized or suffered
hydrolysis.
Enders, D. Breuer, K. Teles, J. H. Helv. Chim.
Acta 1996, 79, 1217. Enders, D. Breuer, K.
Addition of Acyl Carbanion Equivalents to
Carbonyl Groups and Enones. In Comprehensive
Asymmetric Catalysis, Springer-Verlag
Heidelberg, 1999 Vol. 3, pp 1093. Teles, J. H.
Breuer, K. Enders, D. Gielen, H. Synth. Commun.
1999, 29, 1.
12Benzoin Condensation Asymmetric Variations
- Attempts to apply catalyst A to the synthesis of
aliphatic acyloins gave low - yields and enantioselectivities.
- Catalyst B was shown to be the best for the
condensation of aliphatic - aldehydes, giving moderate yields and up to 26
ee.
Breuer, K. Ph.D. Thesis, Technical University of
Aachen, 1997.
13Benzoin Condensation Asymmetric Variations
- Leeper et al, reported the use of a constrained
triazole catalyst which gave - the benzoin condensation of benaldehyde in 45
yield and 80 ee,
- The condensation of other aromatic aldehydes gave
poor to moderate yields with moderate to good ee.
Knight, R. L. Leeper, F. J. J. Chem. Soc. Perkin
Trans I 1998, 1891.
14Benzoin Condensation Asymmetric Variations
- Enders et al, reported the use of a different
constrained triazole catalyst which - gave the benzoin condensation of benaldehyde in
83 yield and 90 ee, - the best reported thus far.
- The condensation of other aromatic aldehydes gave
moderate to good yields with up to 95 ee.
- Electron-rich aromatic aldehydes gave the highest
ee but lower yields.
Enders, D. Kallfass, U. Angew. Chem. Int. Ed.
2002, 41. 1743.
15Benzoin Condensation Possible Transition States
- Since the E/Z geometry of the Breslow
intermediate has not been determined, these
possible transition states have been proposed to
explain the stereochemical outcome of the
previous reaction.
Enders, D. Kallfass, U. Angew. Chem. Int. Ed.
2002, 41. 1743. Dudding, T. Houk, K. N. Prod.
Nat. Acad. Sci. U.S.A., 2004, 101, 5770
16Intramolecular Cross Benzoin Condensation
- Suzuki et al, reported the first example of a
crossed aldehyde-ketone benzoin condensation
giving good to excellent yields.
Hachisu, Y. Bode, J. W. Suzuki, K. J. Am. Chem.
Soc. 2003, 125. 8432.
17Benzoin Condensation Addition of Acylsilanes to
Imines
- Schiedt et al, reported a variation of the
Benzoin condensation by condensing aliphatic
acylsilanes with imines in moderate to good
yields.
- Acylsilanes, unlike aldehydes, avoids benzoin
(self-condensation) product.
Matteson, A. E. Scheidt, K. A. Org. Lett. 2004,
6. 4363.
18Sila-Benzoin Condensation Proposed Mechanism
Matteson, A. E. Scheidt, K. A. Org. Lett. 2004,
6. 4363.
19The Stetter Reaction
1970s Stetter et al, extended cyanide and
thiazolium catalyzed reaction of nucleophilic
acylation of aldehydes to Michael acceptors.
Thiazolium catalyzed mechanism is proposed to
proceed via Breslow intermediate, which then adds
in a conjugate fashion to an ?-? unsaturated
aldehyde.
Stetter, H. Angew. Chem. Int. Ed. 1976, 15, 639.
20Stetter Reaction IntermolecularAsymmetric
Variations
The product of the Stetter reactions a new
stereogenic center and is amenable to
NHC-catalyzed asymmetric acylations.
- Enders et al, attempts at intermolecular
asymmetric reactions gave 29 yield - and 30 ee.
- In general, the catalytic activity of thiazolium
and triazolium salts was low.
Enders, D. Breuer, K. Addition of Acyl Carbanion
Equivalents to Carbonyl Groups and Enones. In
Comprehensive Asymmetric Catalysis,
Springer-Verlag Heidelberg, 1999 Vol. 3, pp
1093, and refs within.
21Stetter Reaction IntramolecularAsymmetric
Variation
- Enders et al, reported triazole catalyzed
intramolecular asymmetric Stetter reaction giving
up to 73 yield 74 ee.
Enders, D. Breuer, K. Runsink, J. Teles, J. H.
Helv. Chim. Acta 1996, 79, 1899. Enders, D.
Breuer, K. Addition of Acyl Carbanion Equivalents
to Carbonyl Groups and Enones. In Comprehensive
ASymmetric Catalysis, Springer-Verlag
Heidelberg, 1999 Vol. 3, pp 1093.
22Stetter Reaction IntramolecularAsymmetric
Variation
- Rovis et al, reported an improvement of the
intramolecular asymmetric Stetter reaction with
up to 95 yield and up to 97 ee, using
constrained triazole catalyst 33.
- An example was reported with an aliphatic
aldehyde forming the cyclo- - pentanone product in 81 yield and 95 ee.
- While the scope of the reaction has been extended
from the examples of Enders - et al, of the reaction has been expanded, but it
is restricted to E-alkenes.
Kerr, M. S. Read de Alaniz, J. Rovis, T. J. Am.
Chem. Soc. 2002, 124, 10298.
23Stetter Reaction IntramolecularAsymmetric
Variation
- Rovis et al, reported the enantioselective
synthesis of quaternary centers via the
asymmetric Stetter reaction, with up to 96 yield
and in excellent ee with pentafluorophenyl
triazole catalyst shown.
- The scope of the reaction includes both aromatic
and aliphatic aldehydes with - E-alkene geometry.
- The authors note the apparent reversal in
stereoinduction between the aliphatic - and aromatic compounds. This result is
currently under investigation.
Kerr, M. S. Rovis, T. J. Am. Chem. Soc. 2004,
126, 8877.
24Stetter Reaction Acylimine Acceptors
- Reider et al, reported the synthesis of ?-amido
ketones in the reaction of aldehydes and
acylimines, catalyzed by the thiazolium salt
shown.
- The acylimine is formed in situ from
arylsulfonamide and serves as the - Michael acceptor.
Murry, J. A. Frantz, D. E. Soheili, A.
Tillyer, R. Grabowski, E. J. J. Reider, P.
J. J. Am. Chem. Soc. 2001, 123, 9696.
25Sila-Stetter Reaction
Mattson, A. E. Bharadwaj, A. R. Scheidt, K. A.
J. Am. Chem. Soc. 2004, 126, 2314.
- Scheidt et al, reported moderate to high yields
for the conjugate addition of acylsilanes to
unsaturated esters and ketones.
- The mechanism is proposed to proceed via a Brook
rearrangement, similar to the Sila-Benzoin
condesation mechanism presented earlier.
- The Sila-Stetter methodology was used in a
multicomponent synthesis of highly substituted
pyrroles in good yields
Bharadwaj, A. R. Scheidt, K. A. Org. Lett. 2004,
6, 2465.
26Homoenolate Chemistry/Internal Redox Reactions
- Under normal conditions, the ?-position is
electrophilic. With Homoenolate chemistry, a
nucleophile is generated at the ?-position.
- Mechanistically, there are two possible
nuclephiles, the carbonyl carbon - (leading to a Benzoin or Stetter-like product)
and the ?-carbon. By varying - the bulk of the R groups on the NHC catalyst,
the homoenolate - intermediate can be favored.
- This reaction can be thought of as an internal
redox reaction, that is the - unsaturated aldehyde is oxidized to an ester,
and the aldehyde is reduce - to an alcohol.
27Homoenolate Chemistry ?-butryolactone Synthesis
- The synthesis of ?-butyrolactones, catalyzed by
NHCs, was published by two groups.
- A variety of enals and aldehydes were coupled in
good yield and - stereoselectivities.
Burstein, C. Glorius, F. Angew. Chem. Int. Ed.
2004, 43, 6205.
Sohn, S. B. Rosen, E. L. Bode, J. W. J. Am.
Chem. Soc. 2004, 126, 14370.
28Homoenolate Proposed Mechanism
- Cis-enal gave the identical stereochemical
outcome as the trans-enal, - implicating a homoenolate isomerization
- t-BuOD gave stereoselective deuterium
incorporation at the ?-position - of the lactone, thus tautomerization to
activated carboxylated occurs after - homoenolate addition to aldehyde.
- No observed deuterium incorporation at
?-position, thus quenching - homoenolate is not a major pathway.
Sohn, S. B. Rosen, E. L. Bode, J. W. J. Am.
Chem. Soc. 2004, 126, 14370.
29Homoenolate Chemistry Converting ?-?-Unsaturated
Aldehydes into Saturated Esters
- Scheidt et al, reported the conversion of
cinnamaldehyde to the corresponding - saturated ester using an imidazolium catalyst
with a variety of primary and - secondary alcohols in good yields
- Examples for the conversion of several
?-?-unsaturated aldehydes into - the corresponding benzyl ester was reported in
good to excellent yields.
Chan, A. Scheidt, K. A. Org. Lett. 2005, 7, 905.
30Internal Redox Reactions ?-Hydroxyesters from
Epoxyaldehydes
- Bode et al, reported the generation of
?-hydroxyesters from epoxyaldehydes, - using a thiazolium catalyst, in good yields and
dr.
- Several primary and secondary alcohols were
functional in the reaction.
- An example of an ?-?-aziridinylaldehyde was shown
to give the corresponding - ?-aminoester in 53 yield, pointing to a broader
scope for this reaction.
Chow, K, Y-K. Bode, J. J. Am. Chem. Soc. 2004,
126, 8126.
31Internal Redox Reactions Converting?-Haloaldehyd
es into Acylating Reagents
- Rovis et al, reported the conversion of
?-haloaldehydes into acylating reagents in
moderate to excellent yields with a variety of
primary and secondary alcohols (including chiral
examples) and aniline.
- The desymmetrization of meso-hydrobenzoin was
demonstrated with a chiral - triazole catalyst developed in the course of the
intramolecular Stetter reaction.
Reynolds, N. T. Read de Alaniz, J. Rovis, T. J.
Am. Chem. Soc. 2004, 126, 9518.
32Internal Redox Reactions Proposed Mechanism
- The reaction is similar in concept to the work of
Bode et al. The proposed - mechanism proceeds via Breslow intermediate II
which then eliminates the - ?-halide giving III, which is then protonated.
Intermediate IV undergoes - nucleophilic attack and regenrates the catalyst.
Reynolds, N. T. Read de Alaniz, J. Rovis, T. J.
Am. Chem. Soc. 2004, 126, 9518.
33Transesterification/Acylation Reactions
- NHC catalysis of transesterification reactions
proceed in a mechanistically - similar fashion as phospines and DMAPs.
34Transesterification/Acylation Reactions
- Nolan et al, reported transesterification
reactions using different enol esters and - primary alcohols such as benzyl alcohol,
geraniol alcohol, and cinnamyl - alcohol.
- Also reported was the selective acylation of
benzyl alcohol over 2-butanol.
Grasa, G. A. Kissling, R. M. Nolan, S. P. Org.
Lett. 2002, 4, 3583. Grasa, G. A. Güveli, T.
Singh, R. Nolan, S. P. J. Org. Chem. 2003, 68,
2812.
35Transesterification/Acylation ReactionsTranseste
rification of Methyl Esters
- Nolan et al, also reported the transesterification
of a variety of methyl esters - with several primary and secondary alcohols in
excellent yields.
- Notably, catalysts such as DMAP, DABCO, and DBU
gave poor to low yields - methyl acetate and benzyl alcohol.
- This transformation is very useful, as it
demonstrates a mild method for the - conversion of methyl esters to other esters with
a variety of alcohols.
Grasa, G. A. Kissling, R. M. Nolan, S. P. Org.
Lett. 2002, 4, 3583. Grasa, G. A. Güveli, T.
Singh, R. Nolan, S. P. J. Org. Chem. 2003, 68,
2812.
36Transesterification/Acylation ReactionsAcylation
of Secondary Alcohols
- Nolan et al, reported the acylation of several
secondary alcohols using ICy - catlayst with methyl acetate and ethyl acetate
in good to excellent yields
- The selective acylation of a diol was
demonstrated, favoring acylation at the - primary alochol.
Singh, R. Kissling, R. M. Letellier, M-A.
Nolan, S. P. J. Org. Chem. 2004, 69, 209.
37Transesterification/Acylation ReactionsAcylation
of Arylfluorides
- Suzuki et al, reported the nucleophilic acylation
of arylfluoride catalyzed by - imidazolium catalysts in moderate yields.
- Several electron-withdrawing and
electron-donating arylfluorides were shown - to be effective in this reaction, with the
electron-rich aryl group giving the best - yield.
Suzuki, Y. Toyota, T. Imada, F. Sato, M.
Miyashita, A. Chem. Comm. 2003, 1314.
38Kinetic Resolution
- With several successful examples of
transesterification and acylation with - carbene catalysts, a logical extension of this
chemistry is to use a chiral - catalyst for the kinetic resolution of secondary
alcohols.
- Nonenzymatic enantioselective acylation of
secondary alcohols is known to be catalyzed by
various organic compounds such as chiral
4-aminopyridines, diamines, peptides and
phosphines.
39Kinetic Resolution
- Maruoka et al, described the application of
chiral NHC for the enantioselective - acylation of secondary alcohols in good
conversion and selectivities.
- Neither electron-donating of electron-withdrawing
groups on the aromatic ring - of the secondary alcohols affected the
enantioselectivity of the reaction.
- This reaction proceeds via transesterification
rather than acylation with acid - chlorides or anhydrides which is the method used
with DMAP derivatives. This - method avoids the use of a stoichiometric amount
of base.
Kano, T. Sasaki, K. Maruoka, K. Org. Lett.
2005, ASAP.
40Kinetic Resolution
- Scheidt et al, in conjunction with their
homoenolate chemistry, reported one - example of a kinetic resolution using a chiral
homoenolate intermediate, which - upon protonation gives an acylating agent.
- For this example, cinnamaldehyde was used to
acylate 1-phenylethanol, - giving a 40 conversion at s4.8.
Chan, A. Scheidt, K. A. Org. Lett. 2005, 7, 905.
41Ring-Opening Polymerization (ROP)
- An additional application of the
transesterification mechansim was demonsrated by
Hendrick et al, who reported the use of IMes
carbene catalyst for ring-opening polymerization
reaction.
- By varying the monomer and alcohol initiator, a
PDI of 1.05 was obtained, - indicating polymers of nearly uniform molecular
weight.
- Current work focuses on the application of
different carbene catalysts, such a - those used in the previous reactions, to ROP.
Connor, E. F. Nyce, G. W. Myers, M. Möck, A.
Hedrick, J. L. J. Am. Chem. Soc. 2002, 124,
914. Nyce, G. W. Glausser, T. Connor, E. F.
Möck, A. Waymouth, R. M. Hedrick, J. L. J. Am.
Chem. Soc. 2003, 125, 3046.