Nucleophilic Carbenes in Organocatalysis

1
Nucleophilic Carbenes in Organocatalysis
Rawal Group Literature Meeting
Enders, D. Balensiefer, T. Acc. Chem. Res. 2004,
37, 534.

• Apurva H. Dave
• April 11, 2005

2
Carbenes 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.
3
Carbenes 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.
4
N-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.
5
Stable 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.
6
Organocatalyzed Reactions by NHC
Benzoin Condensation
Stetter Reaction
Homoenolate/ Internal Redox
7
Organocatalyzed Reactions by NHC
Transesterification/ Acylation
Kinetic Resolution
Ring Opening Polymerization
8
The 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.
9
Benzoin 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
10
Benzoin 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.
11
Benzoin 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.
12
Benzoin 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.
13
Benzoin 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.
14
Benzoin 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.
15
Benzoin 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
16
Intramolecular 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.
17
Benzoin 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.
18
Sila-Benzoin Condensation Proposed Mechanism
Matteson, A. E. Scheidt, K. A. Org. Lett. 2004,
6. 4363.
19
The 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.
20
Stetter 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.
21
Stetter 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.
22
Stetter 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.
23
Stetter 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.
24
Stetter 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.
25
Sila-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.
26
Homoenolate 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.

27
Homoenolate 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.
28
Homoenolate 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.
29
Homoenolate 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.
30
Internal 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.
31
Internal 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.
32
Internal 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.
33
Transesterification/Acylation Reactions

• NHC catalysis of transesterification reactions
  proceed in a mechanistically
• similar fashion as phospines and DMAPs.

34
Transesterification/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.
35
Transesterification/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.
36
Transesterification/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.
37
Transesterification/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.
38
Kinetic 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.

39
Kinetic 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.
40
Kinetic 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.
41
Ring-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.