N-heterocyclic carbene-catalyzed Mukaiyama aldol reactions

Article abstract of DOI:10.1021/ol0630494

(Chemical Equation Presented) N-Heterocyclic carbenes were shown to be highly effective catalysts to promote Mukaiyama aldol reactions. In the presence of only 0.5 mol % of N-heterocyclic carbene (5), various aldehydes and 2,2,2-trifluoroacetophenone unde

Full text of DOI:10.1021/ol0630494

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1013-1016
N-Heterocyclic Carbene-Catalyzed
Mukaiyama Aldol Reactions
Jinhua J. Song,* Zhulin Tan, Jonathan T. Reeves, Nathan K. Yee, and
Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
900 Old Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut 06877-0368
jsong@rdg.boehringer-ingelheim.com
Received December 17, 2006
ABSTRACT
N-Heterocyclic carbenes were shown to be highly effective catalysts to promote Mukaiyama aldol reactions. In the presence of only 0.5 mol
% of N-heterocyclic carbene (5), various aldehydes and 2,2,2-trifluoroacetophenone underwent Mukaiyama aldol reactions in THF with trimethylsilyl
ketene acetal (2) at 23
°C as well as with trimethylsilyl enol ether (7) at 0 °C to afford aldol adducts in good yields. These conditions are
extremely mild and operationally simple and tolerate various functional groups.
The use of N-heterocyclic carbenes (NHCs) as organocata-
lysts has attracted considerable attention in recent years.1
NHCs have been employed to catalyze organic reactions such
as nucleophilic substitutions,2 benzoin and Stetter-type
reactions,3 homoenolate formations,4 Diels-Alder reactions,5
formylcyclopropane ring opening,6 and redox processes.7 It
is believed that the common step in these transformations
involves initial reaction of the NHC with aldehydes to form
the “Breslow intermediate” which can lead into various
subsequent reaction pathways. NHCs were also used for
trimerization of isocyanates8 and transesterification reactions,9
for which the intermediacy of an NHC-acyl species was
hypothesized. For a reported NHC-catalyzed amide bond
formation reaction, it was proposed that the NHC acted as a
carbon-centered Brφnsted base.10 NHCs were also found to
catalyze an intramolecular alkylation reaction.11
Recently, we have discovered a new mode of reactivity
for NHCs where certain silicon-carbon bonds, such as in
TMSCN and TMSCF3, could be effectively activated by
(3) (a) Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2431. (b) Kerr,
M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298.
(c) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim. Acta 1996,
79, 1899. (d) Enders, D.; Breuer, K.; Teles, J. H. HelV. Chim. Acta 1996,
79, 1217. (e) Teles, J. H.; Melder, J.-P.; Ebel, K.; Schneider, R.; Gehrer,
E.; Harder, W.; Brode, S.; Enders, D.; Breuer, K.; Raabe, G. HelV. Chim.
Acta 1996, 79, 61. (f) Myers, M. C.; Bharadwaj, A. R.; Milgram, B. C.;
Scheidt, K. A. J. Am. Chem. Soc. 2005, 127, 14675. (g) Kerr, M. S.; Rovis,
T. J. Am. Chem. Soc. 2004, 126, 8876. (h) Chow, K. Y. K.; Bode, J. W. J.
Am. Chem. Soc. 2004, 126, 8126. (i) Mattson, A. E.; Bharadwaj, A. R.;
Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71, 5715. (j) Myers, M.
C.; Bharadwaj, A. R.; Milgram, B. C.; Scheidt, K. A. J. Am. Chem. Soc.
2005, 127, 14675. (k) Enders, D.; Niemeier, O.; Balensiefer, T. Angew.
Chem., Int. Ed. 2006, 45, 1463. (l) Enders, D.; Kallfass, U. Angew. Chem.,
Int. Ed. 2002, 41, 1743. (m) Moore, J. L.; Kerr, M. S.; Rovis, T. Tetrahedron
2006, 62, 11477. (n) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552.
(o) Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284.
(1) (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534. (b)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Nair,
V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130.
(2) (a) Suzuki, Y.; Toyota, T.; Imada, F.; Sato, M.; Miyashita, A. Chem.
Commun. 2003, 1314. (b) Miyashita, A.; Suzuki, Y.; Iwamoto, K.-I.; Oishi,
E.; Higashino, T. Heterocycles 1998, 49, 405. (c) Miyashita, A.; Suzuki,
Y.; Iwamoto, K.-I.; Higashino, T. Chem. Pharm. Bull. 1998, 46, 390.
10.1021/ol0630494 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/13/2007

NHCs for nucleophilic addition reactions. In this context,
we have described an efficient NHC-catalyzed trifluoro-
methyl transfer reaction from TMSCF3 to carbonyl com-
pounds12 as well as an NHC-catalyzed cyanation reaction
between TMSCN and carbonyl compounds using very low
catalyst loadings (0.01-1 mol %).13 Analogous NHC-
catalyzed cyanation reactions were also independently dem-
onstrated by three other research groups.14 More recently,
an interesting NHC-catalyzed aziridine ring-opening reaction
with silylated nucleophiles was reported.15 As part of our
ongoing research program on NHC catalysis, we now wish
to report that NHCs are also capable of catalyzing Mu-
kaiyama aldol reactions with as low as 0.05-0.5 mol %
catalyst loadings.
The Mukaiyama aldol reaction, i.e., reaction of an enoxy-
silane with a carbonyl compound, is one of the most
fundamental organic transformations and has been the subject
of intensive investigations for the past three decades.16 The
Mukaiyama aldol reaction can be catalyzed either by Lewis
acids via activation of the electrophiles (i.e., carbonyl
compounds) or by Lewis bases via activation of the nucleo-
philes (i.e., enoxysilanes, Figure 1). For example, reactions
acetate,21 lithium alkoxides,22 N-oxides,23 or N-methylimid-
azole24 with 5-20 mol % catalyst loadings. It was also
reported that Mukaiyama aldol reactions could proceed
without added catalysts in some highly polar solvents such
as DMF, DMSO, ionic liquids, water, or DBU.25 Denmark
has shown that Mukaiyama aldol reactions using the more
reactive enoxytrichlorosilanes could be effectively catalyzed
by phosphoramides or N-oxides.26 It is generally accepted
that, for these Lewis base catalyzed Mukaiyama aldol
reactions, the key step involves the activation of Si-O bonds
through interaction of Si with Lewis basic heteroatom centers
(e.g., N, O, or P, etc.).27
As part of our efforts to expand the scope of NHC
catalysis, we proposed that NHCs could potentially be
utilized as carbon-centered nucleophilic catalysts for activat-
ing the Si-O bonds in enoxysilanes, thereby catalyzing
Mukaiyama aldol reactions. As a test case, we carried out a
series of reactions between 2-naphthaldehyde (1a) and
trimethylsilyl ketene acetal 2 (1.2 equiv) in THF at 23 °C
by using four readily available NHC catalysts (3, 4a, 4b,
and 5, Table 1). We were glad to find that, in the presence
of 0.5 mol % of 1,3-di-tert-butylimidazol-2-ylidene (3), the
desired aldol adduct 6a28 was obtained in 78% yield (after
desilylation) within 3 h at 23 °C (entry 1). Aryl-substituted
imidazol-2-ylidenes were found to be less effective for this
reaction. For example, reaction using 1,3-bis(2,6-diisopro-
(12) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2005, 7, 2193.
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Chem. Pharm. Bull. 2006, 54, 397. (c) Fukuda, Y.; Maeda, Y.; Kondo, K.;
Aoyama, T. Synthesis 2006, 1937. (d) Fukuda, Y.; Kondo, K.; Aoyama, T.
Synthesis 2006, 2649. (e) Suzuki, Y.; Abu Bakar, M. D.; Muramatsu, K.;
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Figure 1. Lewis base catalyzed Mukaiyama aldol reactions.
between enoxysilanes and aldehydes could be catalyzed by
fluoride,17 phosphines,18 CaCl2,19 lithium amides,20 lithium
(4) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370. (b) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
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Org. Lett., Vol. 9, No. 6, 2007

superior catalytic capability compared to these commonly
employed nucleophilic catalysts.
Table 1. NHC-Catalyzed Mukaiyama Aldol Reactions
The scope of the NHC-catalyzed Mukaiyama aldol reac-
tions was explored using a range of substrates as illustrated
in Table 2. Aromatic aldehydes with electron-donating or
electron-withdrawing groups were well tolerated (entries
Table 2. Mukaiyama Aldol with Silyl Ketene Acetal Catalyzed
by NHC
pylphenyl)imidazol-2-ylidene (4a) gave 32% yield after 3 h
(entry 2) and 70% yield after 6.5 h at 23 °C (entry 3).
Similarly, the use of carbene 4b (Ar ) 2,4,6-trimethylphe-
nyl)9 gave 60% yield of aldol product after 6 h (entry 4).
Bulky adamantyl-substituted carbene 5 exhibited good
catalytic activity to give 77% yield of 6a after 3 h at 23 °C
(entry 5). NHC 5 was used for all subsequent experiments
because it possesses good thermal stability29 and is easy to
handle in laboratories. Further optimization revealed that the
catalyst loading could be lowered to 0.05 mol % without a
decrease in yield, and the reaction did take longer (22.5 h)
to complete (entry 6). Finally, it was shown in a control
experiment that, without the addition of the carbene catalyst,
no aldol product was formed in THF after 16 h at 23 °C
(entry 7). A few solvents were briefly screened, and it was
found that the reaction was slower in ether and that no
reaction occurred in toluene (entries 8 and 9). As a
comparison, we carried out the same Mukaiyama aldol
reaction using some other charge-neutral Lewis base cata-
lysts. It has been reported that tris(2,4,6-trimethoxyphenyl)-
phosphine (TTMPP)18 could be used to promote Mukaiyama
aldol reactions with various aldehydes in THF at a 20 mol
% catalyst loading level, giving aldol products in 48-93%
yield after 3 h at room temperature. However, when a much
lower catalyst loading (0.5 mol % of TTMPP) was used for
the aldol reaction between 1a and 2, only 36% yield was
obtained after 22.5 h at 23 °C (entry 10, cf. entries 5 and 6).
Furthermore, reactions using 10 mol % of N-methylimidazole
or pyridine oxide as catalysts gave no aldol addition products
after 21 h at 23 °C in THF (entries 11 and 12).30 These
observations in our study have indicated that NHCs possess
(29) (a) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem.
Soc. 1991, 113, 361. (b) Arduengo, A. J., III; Bock, H.; Chen, H.; Denk,
M.; Dixon, D. A.; Green, J. C.; Herrmann, W. A.; Jones, N. L.; Wagner,
M.; West, R. J. Am. Chem. Soc. 1994, 116, 6641.
Org. Lett., Vol. 9, No. 6, 2007
1015

1-8), and they all gave good yields of aldol products20,28
under our standard reaction conditions (3 h, 23 °C). Reaction
with trans-cinnamaldehyde proceeded uneventfully to furnish
â-hydroxy ester 6i in 74% yield (entry 9).20 The sterically
demanding pivalaldehyde as well as enolizable isobutyr-
aldehyde were found to be suitable substrates giving products
in moderate yields (entries 10 and 11).31 Attempts to effect
Mukaiyama aldol addition to acetophenone were unsuccess-
ful. However, it is interesting to note that reaction between
2 and 2,2,2-trifluoroacetophenone took place in 87% yield
to afford compound 6m, which contains two contiguous
quarternary carbon centers (entry 12).
the reaction was initially carried out at 23 °C for ∼2 h, the
desired aldol adduct was observed along with significant
byproduct formation. Lowering the reaction temperature to
0 °C slowed down the aldol addition but effectively
suppressed byproduct formation. Thus, reaction of p-tolu-
aldehyde with trimethylsilyl enol ether 7 (1.2 equiv) at 0 °C
for 65 h under the influence of 0.5 mol % of NHC 5 gave
74% yield of compound 8d (entry 1).32 Without the addition
of the NHC catalyst, no aldol product formation was
observed after 65 h at 0 °C (entry 2). Reaction of silyl enol
ether 7 with the electron-rich p-anisaldehyde gave only 10%
yield (entry 3).33 On the other hand, electron-deficient
substrates such as p-chlorobenzaldehyde and p-nitrobenz-
aldehyde proved to be much better aldol acceptors with 60%
and 84% yields, respectively (entries 4 and 5).33,34 Reaction
with hydrocinnamaldehyde proceeded poorly giving only
25% yield (entry 6).35 To our delight, 2,2,2-trifluoro-
acetophenone was found to be an excellent substrate for this
reaction and compound 8m was isolated in 95% yield (entry
7).36
Next, we investigated Mukaiyama aldol reactions with
trimethylsilyl enol ether 7 (Table 3). Because of the relatively
Table 3. Mukaiyama Aldol with Silyl Enol Ether Catalyzed by
NHC
We propose that, analogous to other Lewis base cata-
lyzed12,13,27 Mukaiyama aldol reactions, NHC-catalyzed aldol
additions proceed through a possible pentavalent silicon
complex that is formed by initial attack of NHC on the Si
atom in enoxysilanes.
In summary, we have demonstrated that NHCs can serve
as highly efficient organocatalysts for Mukaiyama aldol
reactions. In the presence of only 0.5 mol % of N-
heterocyclic carbene 5, a range of aldehydes underwent
Mukaiyama aldol reactions in THF with trimethylsilyl ketene
acetal 2 at 23 °C as well as with trimethylsilyl enol ether 7
at 0 °C to afford aldol adducts in good yields. 2,2,2-
Trifluoroacetophenone was also found to be a suitable
substrate for these reactions. These new conditions are metal-
free, extremely mild, and operationally simple and tolerate
various functional groups. Importantly, this methodology
further illustrates the remarkable ability of NHCs to activate
silicon-based reagents for nucleophilic C-C bond-forming
reactions. Efforts to further explore potential NHC catalysis
for other fundamental organic transformations are underway.
Supporting Information Available: Experimental pro-
cedures and data for compounds 6a-k, 6m, 8d-f, 8h, 8m,
1
and 8n, including copies of H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0630494
(30) Both pyridine oxide and N-methylimidazole have been used to
catalyze Mukaiyama aldol reactions in DMF, which is a much more polar
solvent than THF. See refs 23 and 24.
(31) Wessjohann, L.; Gabriel, T. J. Org. Chem. 1997, 62, 3772.
(32) Komoto, I.; Kobayashi, S. J. Org. Chem. 2004, 69, 680.
(33) Jankowska, J.; Mlynarski, J. J. Org. Chem. 2006, 71, 1317.
(34) Wang, G.-W.; Zhang, Z.; Dong, Y.-W. Org. Process Res. DeV. 2004,
8, 18.
(35) Shimizu, M.; Kobayashi, F.; Hayakawa, R. Tetrahedron 2001, 57,
9591.
(36) Sokeirik, Y. S.; Sato, K.; Omote, M.; Ando, A.; Kumadaki, I.
Tetrahedron Lett. 2006, 47, 2821.
low reactivity of silyl enol ethers compared to silyl ketene
acetals, this reaction turned out to be quite challenging. When
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