LETTER
1291
Versatile and Fluoride-Free Cyanation of Alkyl Halides and Sulfonates with
Trimethylsilyl Cyanide
Cyanation of
A
lky
s
l
H
alides
a
and Sulfona
m
te
s
w
ith Trimethyls
u
ilyl Cyanide Yabe, Hideya Mizufune, Tomomi Ikemoto*
Chemical Development Laboratories, CMC Center, Pharmaceutical Production Division, Takeda Pharmaceutical Company Limited,
2-17-85, Jusohonmachi, Yodogawa-ku, Osaka, 532-8686, Japan
Fax +81(6)63006251; E-mail: Ikemoto_Tomomi@takeda.co.jp
Received 8 January 2009
compounds from alkyl halides and sulfonates with
Abstract: Cyanation of biphenyl-4-ylmethyl methanesulfonate
TMSCN using fluoride-free inorganic salts.
with trimethylsilyl cyanide using fluoride-free inorganic salts, such
as Cs2CO3, K2CO3, and LiOH·H2O, as additives in MeCN quantita-
tively gave biphenyl-4-ylacetonitrile. This methodology was ap-
plied to various alkyl halides to give the corresponding nitrile
compounds in good to excellent yields. Of note, 4-(hydroxymeth-
yl)benzyliodide O-protected by the silyl group was converted into
phenylacetonitrile derivative in 99% yield without desilylation.
Preliminarily, fluoride compounds as an additive (1.2
equiv) were re-examined in the cyanation of biphenyl-4-
ylmethyl methanesulfonate (1a) as a model substrate with
TMSCN (1.2 equiv). Compound 1a was treated with
TBAF in MeCN at room temperature for 6 hours to give 2
in 96% yield according to methods described in the liter-
ature.12 Although the reported example was the secondary
methanesulofonate,13 the treatment of 1a with CsF in
MeCN for 24 hours at room temperature gave 2 in 99%
yield. Comparatively, KF provided 2 after 6 days in 73%
yield. Differences in reactivity with the species of fluoride
and metals in the inorganic fluoride salt were found from
these results, which led us to investigate inorganic and or-
ganic salts other than fluoride salts.
Key words: cyanation, trimethylsilyl cyanide, fluoride-free inor-
ganic salt
Cyanation is an important means of constructing C–C
bonds in organic synthesis. The resulting products can be
further transformed to a wide range of important synthetic
intermediates including amines,1 carboxylic acids,2 and
heterocycles.3 Trimethylsilyl cyanide (TMSCN) is a use-
ful reagent as a stabilized hydrogen cyanide, and is often
used in combination with an additive (Lewis acid,4–10 met-
al oxide,11 and fluoride compound11–13). For ring-opening
reaction of epoxides11a,14,15 and the hydrocyanation of car-
bonyl compounds,16–18 many reactions have been ex-
plored because various additives have afforded
regiospecific, chemoselective, and asymmetric reactions.
In contrast, the substitution reaction of alkyl halides with
TMSCN, using Lewis acid (TiCl4,9 SnCl4,10 and
AgClO419) and CsF13 as an additive, has received relative-
ly less attention because treatment of alkyl halides with
TMSCN using Lewis acid was limited to the synthesis of
secondary and tertiary compounds as substrates.9,10 Al-
though the reaction of primary halides with Lewis acid
gave isocyanides or a mixture of polymeric products,9 De-
shong’s group reported an efficient TMSCN-promoted
cyanation of primary alkyl halides by employing tetra-
n-butylammonium fluoride (TBAF) as an additive in
1999.12 However, substrates protected by the silyl group
cannot be used because the fluoride anion affords desilyl-
ation.20 In addition, fluoride anion generally causes the
difficulty to waste and the limitation of vessel’s material
considering the preparation for large scale. Therefore, it is
important to explore versatile and practical alternatives to
cyanide. Here, we describe a method for preparing nitrile
The cyanation of 1a with TMSCN (1.2 equiv) using
Cs2CO3 or K2CO3 as an additive (1.2 equiv) in MeCN at
room temperature was carried out, as shown in Table 1.
Surprisingly, the two fluoride-free reactions proceeded.
Thus, although Cs2CO3 system required 24 hours to com-
plete the reaction (entry 1, 99% yield), the reaction with
K2CO3 provided a similar result to TBAF, giving 2 after 8
hours in 98% yield (entry 2).21 KHCO3 converted 1a into
2 in 90% yield, however, the reaction took 7 days (entry
3). Other heterogeneous bases, such as LiOH·H2O,
NaOH, K3PO4, and KOAc, also afforded more than 90%
yield after 24 hours (entries 4–7). In the case of organic
salts, NaOMe gave 2 in 85% yield, whereas NaSMe gave
a mixture of 2 and methyl thioether (entries 8 and 9). Of
note, neither KOAc nor NaOMe afforded the correspond-
ing acetate or ether (entries 7 and 8). Changing the solvent
from MeCN to EtOAc, acetone, THF, and DMSO resulted
in a slower reaction and less selectivity compared to that
in MeCN (entries 10–13). In the case of MeOH, the corre-
sponding methyl ether was obtained in 54% yield (entry
14).
The reaction of alkyl bromide 1b and alkyl chloride 1c as
substrates with TMSCN and K2CO3 in MeCN also gave 2
in 99 and 90% yield, respectively (entries 15 and 18). In
the case of 1b, the rate of cyanation was higher with
LiOH·H2O than with K2CO3 (entries 15 vs. 16). Interest-
ingly, the reaction of 1b with NaOH at 50 °C for 13 hours
in MeCN proceeded smoothly, giving 2 in 94% yield
without hydroxylation (entry 17). From these results, it is
thought that the bases could coordinate to TMSCN, simi-
SYNLETT 2009, No. 8, pp 1291–1294
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Advanced online publication: 08.04.2009
DOI: 10.1055/s-0028-1088129; Art ID: U00209ST
© Georg Thieme Verlag Stuttgart · New York
Yabe, Osamu
