Activation of TMSCN by N-heterocyclic carbenes for facile cyanosilylation of carbonyl compounds

Article abstract of DOI:10.1021/jo052206u

N-Heterocyclic carbenes were found to be highly effective organocatalysts in activating TMSCN for facile cyanosilylation of carbonyl compounds. Cyano transfer from TMSCN to aldehydes and ketones proceeds at room temperature in the presence of only 0.01-0.

Full text of DOI:10.1021/jo052206u

an NHC-acyl intermediate was suggested by Waymouth and
Hedrick.6e In a recently reported NHC-catalyzed amide bond
formation8 reaction, it was proposed that NHC functions as a
carbon-centered Brφnsted base.
Activation of TMSCN by N-Heterocyclic
Carbenes for Facile Cyanosilylation of Carbonyl
Compounds
Recently, we have reported our discovery of an efficient
NHC-catalyzed trifluoromethyl transfer reaction from TMSCF3
to carbonyl compounds.9 To our best knowledge, this reaction
serves as the first example to show that a silicon-based reagent
such as TMSCF3 can be activated by N-heterocyclic carbenes
for nucleophilic addition reactions. As part of our continued
efforts to gain more insight into this unprecedented mode of
reactivity for NHCs, we now wish to disclose a facile NHC-
catalyzed cyanation reaction between TMSCN and carbonyl
compounds using as little as 0.01-0.5 mol % catalyst loadings.
Cyanohydrins represent one of the most valuable synthons
that can be elaborated into a variety of useful synthetic building
blocks, such as R-hydroxy acids, R-hydroxy aldehydes, 1,2-
diols, and R-amino alcohols.10 Because of their importance in
organic synthesis and life science research, a large body of work
has been devoted to the development of cyanohydrin synthesis.
The most commonly used method to prepare cyanohydrins
involves the cyanosilylation of carbonyl compounds using
TMSCN. Transfer of a cyano group from TMSCN to carbonyl
compounds can be catalyzed by a plethora of reagents11-13
including Lewis acids, Lewis bases, metal alkoxides, bifunc-
tional catalysts, iodine, and inorganic salts. Among these
methods, the metal-free, organic-molecule-catalyzed processes
are particularly attractive because of the mildness of the reaction
conditions and the potential for the development of an asym-
metric version of this transformation. However, there are only
a limited number of such examples existing in the literature.12,13
For example, it has been reported that Lewis bases such as
triethylamine, tributylphosphine, triphenylarsine, trisaminophos-
phines, and triphenylantimony catalyze cyanosilylation of car-
Jinhua J. Song,* Fabrice Gallou, Jonathan T. Reeves,
Zhulin Tan, 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 October 23, 2005
N-Heterocyclic carbenes were found to be highly effective
organocatalysts in activating TMSCN for facile cyanosi-
lylation of carbonyl compounds. Cyano transfer from
TMSCN to aldehydes and ketones proceeds at room tem-
perature in the presence of only 0.01-0.5 mol % of
N-heterocyclic carbene (1), leading to a range of trimethyl-
silylated cyanohydrins in very good to excellent yields. These
conditions are extremely mild and simple and tolerate various
functional groups.
N-Heterocyclic carbenes (NHCs) have attracted considerable
attention in recent years. They have been extensively studied
and employed as ligands in a variety of transition-metal-
catalyzed processes.1 Owing to their strong σ-donating proper-
ties, N-heterocyclic carbenes can also act as organocatalysts.2
N-Heterocyclic carbenes have been used to catalyze organic
transformations such as nucleophilic substitutions,3 benzoin- and
Stetter-type reactions,4 homoenolate formations,5 transesterifi-
cation reactions,6 and trimerization of isocyanates.7 It was
believed that the key step in the NHC-catalyzed nucleophilic
substitutions or benzoin- or Stetter-type reactions involves the
attack of the carbene at the carbonyl group of the aldehydes to
form the “Breslow intermediate” which functions like an acyl
anion equivalent (Umpolung). For transesterification reactions,
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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.
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Myers, M.; Mock, A.; Hedrick, J. L. J. Am. Chem. Soc. 2002, 124, 914. (g)
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10.1021/jo052206u CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/04/2006
J. Org. Chem. 2006, 71, 1273-1276
1273

bonyl compounds with TMSCN.12d,f,i,j Guanidine was also
successfully employed as a catalyst for this reaction.12h,k More
recently, certain amine N-oxides have been shown to be effective
catalysts for the cyanide addition to both aldeydes and ketones
using TMSCN as the cyanide source.12a-c,e,g In these reactions,
nucleophilic activation of TMSCN by amine N-oxides was
proposed as a key step in the catalytic cycle.12c During our
search for a new type of organocatalyst for this transformation,
we decided to investigate the possibility of using nucleophilic
N-heterocyclic carbenes to catalyze cyanosilylation of carbonyl
compounds with TMSCN.
TABLE 1. Cyanosilylation of Benzaldehyde and Acetophenone
% conversion
entry
R
solvent catalyst loading
time
(% isolated yield)
1
2
3
4
H
THF
THF
DMF
DMF
0.5 mol %
0.01 mol %
0.5 mol %
0.1 mol %
10 min
4 h
99 (91)
97 (83)
95 (80)
95 (74)
H
Me
Me
1 h
16 h
On the basis of our experience with NHC-catalyzed triflu-
oromethyl addition reactions with TMSCF3,9 we postulated that
the carbon-silicon bond in TMSCN could be activated by
NHCs for cyano transfer in an analogous fashion. Indeed, when
a THF solution of benzaldehyde and TMSCN was treated with
0.5 mol % of 1,3-di-tert-butylimidazol-2-ylidene (1, ItBu, Table
1) at room temperature, the cyanide addition occurred almost
instantaneously to give trimethylsilylated cyanohydrin 3a with
99% conversion in 10 min (entry 1). 1,3-Di-(1-adamantyl)-
imidazol-2-ylidene (IAd) was found to exhibit similar catalytic
activity. Both ItBu and IAd carbenes have good thermal
stability14 and can be easily handled in the laboratories. NHC-
catalyzed cyanide addition to benzaldehyde also proceeded
smoothly in a number of other solvents such as methylene
chloride, MTBE, and acetonitrile. The catalyst loading was
studied on a ∼100 mmol scale, and we were delighted to find
that only a minute amount of NHC 1 (0.01 mol %) was required
to catalyze the cyanation of benzaldehyde at room temperature
in THF (97% conversion within 4 h, entry 2).
An NHC-catalyzed reaction between acetophenone and
TMSCN is very sluggish in THF. Switching the reaction solvent
to DMF greatly accelerated the rate of the reaction, giving 95%
conversion within 1 h at room temperature in the presence of
0.5 mol % of the catalyst 1 (entry 3). When 0.1 mol % of NHC
1 was used in the cyanation of acetophenone in DMF, the same
conversion (95%) was achieved after 16 h at room temperature
(entry 4). It should be noted that in the absence of NHC (1) no
reaction occurs between benzaldehyde and TMSCN in THF or
between acetophenone and TMSCN in DMF after 17 h at room
temperature. The low catalyst loading that is needed for this
reaction underscores the extraordinary catalytic activity of NHCs
in activating silicon-based reagents such as TMSCN. In contrast,
for the previously reported organocatalysts, 5 mol % of phenolic
amine N-oxide (6 h at room temperature)12a or 30 mol % NMO
(8 h at room temperature)12b was employed to promote complete
conversion of acetophenone to the corresponding trimethylsi-
lylated cyanohydrin 3b.
The scope of this method was examined by using a number
of representative carbonyl compounds (Table 2). For these
preparative experiments, 0.5 mol % catalyst loading was used.
Benzaldehyde as well as enolizable aliphatic aldehydes (entries
1-3) underwent NHC-catalyzed cyanosilylation in excellent
yields. Cyanide addition to the sterically hindered pivalaldehyde
occurred rapidly at room temperature (entry 4).
Cyanosilylation reactions of ketones were carried out at room
temperature by using DMF as the solvent. R-Keto ester 2f was
subjected to the NHC-catalyzed cyanation reaction to afford
product 3f in 79% yield (entry 5). Acetophenone and p-
nitroacetophenone (entries 6-7) were smoothly converted into
the corresponding tertiary trimethylsilylated cyanohydrins under
NHC catalysis. Cyanation of cyclic and acyclic aliphatic ketones
(entries 8-9) was found to proceed efficiently. It is of particular
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1274 J. Org. Chem., Vol. 71, No. 3, 2006

TABLE 2. NHC-Catalyzed Cyanosilylation of Carbonyl
Compounds
FIGURE 1. Proposed reaction pathway.
conditions (0.5 mol % NHC 1, room temperature, 2 h). As a
comparison, amine N-oxide-catalyzed cyanosilylation of R-te-
tralone (2k) required a long reaction time (∼15 h at room
temperature) as well as significantly higher catalyst loading.12a,b
Finally, we have shown that cyanide addition to 2-bromo-
acetophenone was also successful (entry 13).
We propose that the NHC-catalyzed cyanosilylation reaction
follows a nucleophilic catalysis pathway, as illustrated in Figure
1.12c,19 NHC interacts with TMSCN to form a reactive pentava-
lent silicon complex 4 which transfers a cyano group to the
carbonyl compound. Subsequently, the intermediate 5 fragments
to furnish the desired product while regenerating the carbene
catalyst.
In conclusion, we have described a highly efficient cyanosi-
lylation reaction of carbonyl compounds by using N-heterocyclic
carbene 1 as an organocatalyst. Ketones and aldehydes undergo
facile cyanosilylation at room temperature in the presence of
only 0.01-0.5 mol % of NHC 1, leading to a range of
trimethylsilylated cyanohydrins in very good to excellent yields.
Compared to the previously reported organocatalysts for cy-
anosilylation reactions with TMSCN,12 N-heterocyclic carbene
has exhibited higher catalytic activity as evidenced by the shorter
reaction time and much lower catalyst loading. These conditions
are metal-free, extremely mild, and simple and tolerate various
functional groups. Importantly this methodology further exem-
plifies the remarkable ability of NHCs to activate silicon-based
reagents such as TMSCN and TMSCF3. Efforts to further extend
NHC catalysis to other fundamental organic transformations are
ongoing.
Experimental Section
General Procedures. All reactions were performed in oven-
dried glassware under nitrogen with magnetic stirring. All com-
mercial reagents were used as received. Flash chromatography was
performed using 230-400 mesh silica gel.
Cyanosilylation of Benzaldehyde. A dry flask with a stir bar
was purged with N2 and charged with anhydrous THF (6 mL),
benzaldehyde (1.0 mL, 10.0 mmol, 1.0 equiv), and finally TMSCN
(1.3 mL, 10.0 mmol, 1.0 equiv). 1,3-Di-tert-butylimidazol-2-ylidene
(9 mg, 0.05 mmol, 0.005 equiv) was added at room temperature.
After 10 min, HPLC analysis shows the complete consumption of
benzaldehyde. The reaction mixture was concentrated and loaded
directly onto a silica gel column (eluting with 90:10 hexanes/
MTBE) to give 3a (1.87 g, 91%) as a colorless oil.
a Method A: To a THF solution of aldehyde and TMSCN (1.0 equiv) at
room temperature was added carbene (1, 0.5%), and the reaction was stirred
at room temperature for the time indicated above. b Method B: To a DMF
solution of ketone and TMSCN (1.1 equiv) at room temperature was added
carbene (1, 0.5 mol %), and the reaction was stirred at room temperature
for the time indicated above.
interest to note that cyanosilylation of sterically hindered ketone
2j (entry 10) and relatively unreactive ketones 2k and 2l (entries
11-12) was readily achieved under our standard reaction
Cyanosilylation of Acetophenone. A dry flask with a stir bar
was purged with N2 and charged with anhydrous DMF (5 mL),
acetophenone (0.59 mL, 5.0 mmol, 1.0 equiv), and finally TMSCN
(0.73 mL, 5.5 mmol, 1.1 equiv). 1,3-Di-tert-butylimidazol-2-ylidene
(4.5 mg, 0.025 mmol, 0.005 equiv) was added at room temperature.
(19) Prakash, G. K. S.; Mandal, M.; Panja, C.; Mathew, T.; Olah, G. A.
J. Fluorine Chem. 2003, 123, 61.
J. Org. Chem, Vol. 71, No. 3, 2006 1275

After 1 h, HPLC analysis shows the complete consumption of
acetophenone. The reaction mixture was diluted with MTBE (40
mL) and washed with water (20 mL) and brine (20 mL). The
organic layer was dried over MgSO4, concentrated, and loaded onto
a silica gel column (eluting with 90:10 hexanes/EtOAc) to give 3b
(0.88 g, 80%) as a colorless oil.
Supporting Information Available: 1H NMR and 13C NMR
data as well as copies of H NMR spectra for isolated products
3a-m. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
JO052206U
1276 J. Org. Chem., Vol. 71, No. 3, 2006