N-heterocyclic carbene catalyzed trifluoromethylation of carbonyl compounds

Article abstract of DOI:10.1021/ol050568i

(Chemical Equation Presented) A novel N-heterocyclic carbene (NHC) catalyzed trifluoromethylation reaction of carbonyl compounds was discovered. Both enolizable and nonenolizable aldehydes and α-keto esters undergo facile trifluoromethylation with TMSCF₃ at room temperature in the presence of only 0.5-1 mol % of the commercially available NHC (1), providing CF₃-substituted alcohols in good yields. Selective trifluoromethylation of aldehydes over ketones can be achieved under NHC catalysis. These conditions are mild and simple and tolerate a variety of functional groups.

Full text of DOI:10.1021/ol050568i

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2193-2196
N-Heterocyclic Carbene Catalyzed
Trifluoromethylation of Carbonyl
Compounds
Jinhua J. Song,* Zhulin Tan, Jonathan T. Reeves, Fabrice Gallou,
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 March 15, 2005
ABSTRACT
A novel N-heterocyclic carbene (NHC) catalyzed trifluoromethylation reaction of carbonyl compounds was discovered. Both enolizable and
nonenolizable aldehydes and -keto esters undergo facile trifluoromethylation with TMSCF3 at room temperature in the presence of only 0.5
r
−1
mol % of the commercially available NHC (1), providing CF3-substituted alcohols in good yields. Selective trifluoromethylation of aldehydes
over ketones can be achieved under NHC catalysis. These conditions are mild and simple and tolerate a variety of functional groups.
Trifluoromethyl-containing molecules are finding increasing
applications in drug discovery research as well as synthesis
of agrochemicals and polymers.1 Incorporation of a triflu-
oromethyl group often leads to desirable changes in physi-
cochemical properties of organic molecules. One of the most
straightforward methods to introduce a CF3 group into a
molecule involves the direct trifluoromethylation of carbonyl
compounds. In the past 15 years, many useful trifluorom-
ethylation methodologies have been invented.2 By far the
most convenient and widely utilized method is the fluoride-
induced (e.g., TBAF or CsF) nucleophilic trifluoromethyla-
tion with TMSCF3.2j-l This transformation is believed to
involve the initial reaction of fluoride with TMSCF3 to form
Me3SiF and a CF3 anion. The trifluoromethide anion reacts
with the carbonyl compound R1COR2 to generate the alk-
oxide intermediate R1R2(CF3)CO- that propagates the sub-
sequent reactions.2j This proposed mechanism was supported
by the observation that the reaction can also be initiated by
using simple alkoxides such as t-BuOK or Me3SiONa.
Trifluoromethyl transfer from TMSCF3 was also catalyzed
by Lewis bases via a different mechanistic pathway. In this
case, the Lewis base is the true catalyst that is turned over
in catalytic cycles.2c This approach avoids the use of strong
bases such as fluoride or alkoxides and is more applicable
to base-sensitive substrates. Fuchikami et al. have shown that
a variety of Lewis bases, such as dibutylamine, triethylamine,
pyridine, PPh3, AsPh3, and SbPh3, can catalyze CF3 addition
reactions to aldehydes and certain activated ketones, although
with low efficiencies.3 More recently, Prakash et al. described
(1) Olah, G. A., Chambers, R. D., Prakash, G. K. S., Eds. Synthetic
Fluorine Chemistry; John Wiley & Sons: New York, 1992.
(2) (a) Roussel, S.; Billard, T.; Langlois, B. R.; Saint-Jalmes, L. Synlett
2004, 12, 2119. (b) Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2003,
5, 3253. (c) Prakash, G. K. S.; Mandal, M.; Panja, C.; Mathew, T.; Olah,
G. A. J. Fluorine Chem. 2003, 123, 61. (d) Prakash, G. K. S.; Mandal, M.
J. Fluorine Chem. 2001, 112, 123. (e) Aiet-Mohand, S.; Takechi, N.;
Medebielle, M.; Dolbier, W. R., Jr. Org. Lett. 2001, 3, 4271. (f) Billard,
T.; Burns, S.; Langlois, B. R. Org. Lett. 2000, 2, 2101. (g) Large, S.; Roques,
N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848. (h) Singh, R. P.; Shreeve,
J. M. Tetrahedron 2000, 56, 7613. (i) Singh, R. P.; Cao, G.; Kirchmeier,
R. L.; Shreeve, J. M. J. Org. Chem. 1999, 64, 2873. (j) Prakash, G. K. S.;
Yudin, A. K. Chem. ReV. 1997, 97, 757. (k) Krishnamurthi, R.; Bellew, D.
R.; Prakash, G. K. S. J. Org. Chem. 1991, 56, 984. (l) Prakash, G. K. S.;
Krishnamurthi, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393. (m)
McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555. (n)
Umemoto, T. Chem. ReV. 1996, 96, 1757. (o) Umemoto, T.; Ishihara, S. J.
Am. Chem. Soc. 1993, 115, 2156. (p) Umemoto, T.; Goto, Y. Bull. Chem.
Soc. Jpn. 1987, 60, 3307. (q) Shreeve, J. M.; Yang, J.-J.; Kirchmeier, R. L.
US Patent 6215021 (2001). (r) Dolbier, W. R., Jr. Chem. ReV. 1996, 96,
1557. (s) Dolbier, W. R., Jr. Top. Curr. Chem. 1997, 192, 97.
10.1021/ol050568i CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/05/2005

a triethylamine N-oxide catalyzed trifluoromethylation reac-
tion with aldehydes.2c However, the aforementioned Lewis
bases exhibited low catalytic activities in trifluoromethylation
reactions and required high catalyst loadings (10-50 mol
%) as well as long reaction times. In this paper, we report
the discovery of a novel N-heterocyclic carbene (NHC)
catalyzed trifluoromethylation reaction of carbonyl com-
pounds using as little as 0.5-1 mol % catalyst loading.
N-Heterocyclic carbenes have received considerable at-
tention in recent years. They have been successfully em-
ployed as ligands in a wide range of transition-metal-
catalyzed processes.4 In contrast, there has been limited
application of N-heterocyclic carbenes in nucleophilic ca-
talysis.5 N-Heterocyclic carbenes have been used to catalyze
organic transformations such as nucleophilic substitutions,6
benzoin, and Stetter reactions.7 Recently, N-heterocyclic
carbene catalyzed transesterification reactions were de-
scribed.8 Louie also demonstrated that NHCs are effective
catalysts for trimerization of isocyanates.9 In search for a
more efficient and milder Lewis base catalyst for trifluo-
romethylation reactions, we envisioned that we could exploit
the strong σ-donating property of NHCs to effect reactions
between TMSCF3 and carbonyl compounds.
HCl), the desired alcohol 6a was obtained. Encouraged by
this promising result, a number of solvents were then
screened. DMF was found to be another effective solvent2b,f,3
for this reaction giving complete conversion within 20 min
at ambient temperature in the presence of 10 mol % of the
catalyst (entry 2). Use of toluene, methylene chloride or
MTBE as solvents all resulted in sluggish reactions.
Further optimization focused on minimizing the catalyst
loading. When the reaction was carried out in THF with 0.5
mol % of catalyst, the reaction became slower and a 79%
conversion was achieved after 5 h (entry 3). On the other
hand, with DMF as the reaction solvent, the catalyst loading
can be reduced to 0.5 mol % and the reaction reached 98%
conversion within 45 min (entry 4). Further decrease of the
catalyst amount to 0.1 mol % significantly slowed the
reaction (62% conversion after 24 h at room temperature,
entry 5). Three other readily available NHCs (2 to 4) were
briefly tested at 0.5 mol % catalyst loading level and were
found to be equally effective (entries 6-8). The observed
high catalytic activity of NHC is remarkable compared to
the previously reported Lewis bases for the same or similar
transformations. For example, triethylamine-catalyzed trif-
luoromethylation of benzaldehyde proceeded to only 59-
66% conversion after 10 h at room temperature with 10-50
mol % catalyst loadings3 and the more recent triethylamine
N-oxide catalyzed reactions also necessitate 50 mol %
catalyst loading and ∼12 h of reaction time.2c,11
Our studies commenced with the trifluoromethylation
reaction with benzaldehyde (Table 1). Adamantyl-substituted
The scope of N-heterocyclic carbene catalyzed trifluoro-
methylation reactions was explored using a variety of car-
bonyl compounds (Table 2). Aromatic aldehydes with either
electron-withdrawing or electron-donating groups (entries
1-4)12-14 all gave products in good to excellent yields. When
trans-cinnamaldehyde was subjected to our reaction condi-
tions, 1,2-addition product was obtained in 89% isolated yield
(entry 5).13 Trifluoromethyl addition to sterically demanding
aldehyde 5f was also successful (entry 6).
Table 1. Trifluoromethylation of Benzaldehyde
entry
solvent
cat. (loading)
time
1 h
20 min
5 h
45 min
24 h
30 min
30 min
20 min
conversion (%)
1
2
3
4
5
6
7
8
THF
DMF
THF
DMF
DMF
DMF
DMF
DMF
1 (10 mol %)
1 (10 mol %)
1 (0.5 mol %)
1 (0.5 mol %)
1 (0.1 mol %)
2 (0.5 mol %)
3 (0.5 mol %)
4 (0.5 mol %)
100
100
79
98
62
93
100
100
(5) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43,
5130.
(6) (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.
(7) (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,
6205. (c) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743.
(d) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
10298. (e) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim.
Acta 1996, 79, 1899. (f) Enders, D.; Breuer, K.; Teles, J. H. HelV. Chim.
Acta 1996, 79, 1217. (g) 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.
carbene 1 was first chosen for our study because it is
commercially available and has good thermal stability.10
A
(8) (a) Grasa, G. A.; Guveli, T.; Singh, R.; Nolan, S. P. J. Org. Chem.
2003, 68, 2812. (b) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S.
P. J. Org. Chem. 2004, 69, 209. (c) Grasa, G. A.; Kissling, R. M.; Nolan,
S. P. Org. Lett. 2002, 4, 3583. (d) Nyce, G. W.; Lamboy, J. A.; Connor, E.
F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587. (e) Nyce, G.
W.; Glauser, T.; Connor, E. F.; Mock, A.; Waymouth, R. M.; Hedrick, J.
L. J. Am. Chem. Soc. 2003, 125, 3046. (f) Connor, E. F.; Nyce, G. W.;
Myers, M.; Mock, A.; Hedrick, J. L. J. Am. Chem. Soc. 2002, 124, 914. (g)
Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347.
(9) Duong, H. A.; Cross, M. J.; Louie, J. Org. Lett. 2004, 6, 4679.
(10) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361.
solution of benzaldehyde and TMSCF3 (3 equiv) in THF at
0 °C was treated with 10 mol % of NHC 1. After only 1 h
at room temperature, the reaction reached completion (entry
1). After cleavage of TMS ether by acid hydrolysis (2 N
(3) (a) Hagiwara, T.; Kobayashi, T.; Fuchikami, T. Main Group Chem.
1997, 2, 13. (b) Fuchikami, T.; Hagiwara, T. Jpn. Kokai Tokkyo Koho JP
07118188 A2 19950509, 1995.
(4) (a) Herrmann, W. A.; Ofele, K.; von Preysing, D.; Schneider, S. K.
J. Organomet. Chem. 2003, 687, 229. (b) Yong, B. S.; Nolan, S. P.
Chemtracts 2003, 16, 205. (c) Navarro, O.; Kelly, R. A., III; Nolan, S. P.
J. Am. Chem. Soc. 2003, 125, 16194. (d) Littke, A. F.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 4176. (e) Herrmann, W. A. Angew. Chem., Int.
Ed. 2002, 41, 1290.
(11) As a comparison, we have carried out the fluoride-initiated
trifluoromethylation of benzaldehyde using 0.5 mol % TBAF and TMSCF3
(3 equiv). The reaction went to completion in 30 min at room temperature
with either THF or DMF as the reaction solvent.
2194
Org. Lett., Vol. 7, No. 11, 2005

tection of the acid as its TMS ester by reaction with TMSCF3
followed by the addition of the NHC catalyst (entry 10).18
R-Keto esters are an important class of carbonyl com-
pounds that are being widely utilized in organic synthesis.19
Lewis base catalyzed trifluoromethylation of R-keto esters,
however, has not been reported.2c,3 Using NHC catalysis, we
were able to expand the substrate scope to include R-keto
esters. Both c-hexyl pyruvate (5k) and ethyl 2-oxo-4-
phenylbutyrate (5l) underwent reactions with TMSCF3 in the
presence of 1 mol % NHC (1) to furnish the CF3-substituted
tertiary alcohols (entries 11 and 1220).
Table 2. Trifluoromethylation Catalyzed by NHCs
Acetophenone gave <1% conversion under the catalysis
of carbenes 1-3. However, reactions with a more reactive
ketone 5m did proceed in the presence of 10 mol % of NHC
3 to give trifluoromethyl substituted tertiary alcohol in 75%
yield (entry 13). The significant reactivity gap between
aldehydes and ketones provides an opportunity to selectively
trifluoromethylate an aldehyde in the presence of a ketone
functionality. This was illustrated using p-acetyl benzalde-
hyde (5n) as a test substrate (entry 14). Even with a large
excess of TMSCF3 (5 equiv), clean conversion to the mono-
trifluoromethylated product 6n was achieved using 0.5 mol
% of adamantyl-substituted carbene 1 as the catalyst. In con-
trast, the TBAF-initiated trifluoromethylation of 5n gave a mix-
ture of 6n and double-addition product even if only 1 equiv
of TMSCF3 was used. The ratio between 6n and double addi-
tion product from fluoride initiated reactions was 1.9:1 in
DMF, 3.6:1 in THF, and 1:2.1 in toluene as determined by
HPLC.
In conclusion, we have discovered a novel N-heterocyclic
carbene catalyzed trifluoromethylation reaction of carbonyl
compounds. Both enolizable and nonenolizable aldehydes
and R-keto esters undergo facile trifluoromethylation at room
temperature in the presence of only 0.5-1 mol % of the
commercially available NHC (1), providing CF3 substituted
alcohols in good yields. Selective trifluoromethylation of
aldehydes over ketones can be achieved under NHC catalysis.
These conditions are extremely mild and simple and tolerate
a variety of functional groups. Importantly, compared to the
previously reported Lewis base-catalyzed trifluoromethyla-
tion protocols, our new method offers much greater catalytic
efficiency as well as broader substrate scope. This methodol-
ogy exemplifies the ability of NHCs to serve as nucleophilic
catalysts for fundamental organic reactions. Efforts to extend
NHC catalysis to other organic transformations, including
(12) Sibille, S.; McHarek, S.; Perichon, J. Tetradedron 1989, 45, 1423.
(13) Tordeux, M.; Francese, C.; Wakselman, C. J. Chem. Soc., Perkin
Trans. 1 1990, 1951.
(14) Ishii, A.; Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65,
1597.
(15) Enolizable carbonyl compounds can be trifluoromethylated using
fluoride initiated reactions with TMSCF3 (see ref 2j). However, enolizable
aldehydes were reported to present problems for some other trifluorom-
ethylation methods (for examples, see ref 2b,c,f).
(16) Hamada, H.; Shiromoto, M.; Funahashi, M.; Itoh, T.; Nakamura,
K. J. Org. Chem. 1996, 61, 2332.
(17) Kuroki, Y.; Sakamaki, Y.; Iseki, K. Org. Lett. 2001, 3, 457.
(18) Fujisawa, T.; Ichikawa, K.; Shimizu, M. Tetradedron: Asymmetry
1993, 4, 1237.
(19) For a recent example, see: Ramon, D. J.; Yus, M. Angew. Chem.,
Int. Ed. 2004, 43, 284.
(20) Blay, G.; Fernandez, I.; Marco-Aleixandre, A.; Monje, B.; Pedro,
J. R.; Ruiz, R. Tetradedron 2002, 58, 8565.
It is noteworthy that enolizable aldehydes, which often pre-
sent problems in trifluoromethylation reactions,15 worked
very well under our standard conditions to produce the desir-
ed CF3 adducts in high yields (entries 7-9).16,17 The 4-car-
boxobenzaldehyde (5j) was trifluoromethylated via in situ pro-
Org. Lett., Vol. 7, No. 11, 2005
2195

carbene-catalyzed asymmetric trifluoromethylation processes
are ongoing.
isolated compounds 6a-n, as well as 13C NMR and HRMS
data for new compounds 6f,k,m,n. This material is available
free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
1
1
cedures, H NMR data, copies of H NMR spectra for
OL050568I
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