Facile preparation of α-aryl nitriles by direct cyanation of alcohols with TMSCN under the catalysis of InX3

Article abstract of DOI:10.1021/ol801812a

(Chemical Equation Presented) A convenient and efficient synthesis of α-aryl nitrites was developed by direct cyanation of alcohols with TMSCN under the catalysis of Lewis acid. Using 5-10 mol % of InBr₃ as the catalyst, a variety of benzylic alcohols can be converted to the corresponding nitriles in 5-30 min with yields of 46-99%.

Full text of DOI:10.1021/ol801812a

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4573-4576
Facile Preparation of r-Aryl Nitriles by
Direct Cyanation of Alcohols with
TMSCN Under the Catalysis of InX3
Gang Chen, Zheng Wang, Jiang Wu, and Kuiling Ding*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
kding@mail.sioc.ac.cn
Received August 5, 2008
ABSTRACT
A convenient and efficient synthesis of r-aryl nitriles was developed by direct cyanation of alcohols with TMSCN under the catalysis of Lewis
acid. Using 5-10 mol % of InBr3 as the catalyst, a variety of benzylic alcohols can be converted to the corresponding nitriles in 5-30 min
with yields of 46-99%.
R-Aryl nitriles represent one class of important compounds
with extensive biological activities and utility in organic
synthesis. For example, verapamil (1)1 is used clinically for
the treatment of chronic obstructive pulmonary disease and
hypertension. As synthetic intermediates, R-aryl nitriles are
potentially valuable precursors for the synthesis of well-
known drugs such as indoprofen (2),2 cicloprofen (3),3 and
naproxen (4)4 as shown in Figure 1. Furthermore, R-aryl
nitriles are also versatile building blocks for constructing the
corresponding amides, aldehydes, ketones, primary amines,
and heterocycles.5 Accordingly, several useful strategies for
Figure 1. Verapamil and some derivatives of R-aryl nitriles.
the synthesis of R-aryl nitriles have been developed over
the decades, typically including nucleophilic substitution of
a benzylic halide,6 photochemical aromatic cyanomethyla-
tion,7 dehydration of amides,8 hydrocyanation of olefins,9
acylations of silyl ketene imines,10 and coupling reactions
of nitriles with aryl halides,11 among others.12 When an
alcohol is used as the starting material for the synthesis of
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10.1021/ol801812a CCC: $40.75
Published on Web 09/23/2008
2008 American Chemical Society

the corresponding nitrile, at least two viable synthetic routes
can be envisaged, i.e., a prior transformation of the alcohol
into the corresponding halide or related compounds that have
good leaving potential followed by cyanation or, alterna-
tively, via direct conversion of the corresponding alcohols
using various cyanating reagent systems.13 Although direct
cyanation of alcohols constitutes a particularly attractive
synthetic route to nitriles in terms of both starting material
accessibility and economy concerns, unfortunately many of
the direct cyanation protocols developed suffered from
shortcomings such as the use of stoichiometric activating
reagents and (or) tedious workup procedures, which would
to some extent hamper their practical utilizations.13
as FeX3, BiX3, or InX3, etc. X ) Cl, Br, or OTf) have been of
much research interest. In these reactions, the hydroxyls in
alcohols can be directly substituted by the desired nucleophiles
without the need for prior transformation into the groups that
have good leaving potentials. It has been assumed that at least
in some of these reactions the alcohols are activated toward
nucleophilic substitution by interaction with the oxophilic Lewis
acids.14c Inspired by these results, we envisaged that a direct
transformation of alcohols to the corresponding R-aryl nitriles
might also be feasible in the presence of a suitable Lewis acidic
catalyst/cyanating agent combination. Herein, we report an
InX314a-c,15a,19 catalyzed cyanation protocol for R-aryl al-
cohols using TMSCN (trimethylsilyl cyanide) as the cyanat-
ing agent, affording the corresponding R-aryl nitriles effi-
ciently in high yields under mild reaction conditions.
The work was started by testing the cyanation of allylic
alcohol 5a with TMSCN in dichloromethane in the presence
of a catalytic amount (10 mol %) of FeCl3. The reaction
proceeds smoothly at room temperature with complete substrate
conversion in 30 min, albeit with only a moderate yield of
isolated allylic cyanide 6a (41%). Encouraged by this result,
various Lewis acids as well as the reaction conditions were
further screened for the catalysis (Table 1). As shown in Table
Recently, direct substitutions of the hydroxyl group in
alcohols by various nucleophiles such as allyl-, alkynyl-, and
propargylsilanes,14 1,3-dicarbonyl compounds,15 amides16 or
amines,17 and so on18 under the catalysis of Lewis acids (such
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Table 1. Optimization of the Reaction Conditions for Lewis
Acid Catalyzed Cyanation of 5aa
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855–856. (b) Biogegrain, R.; Castro, B. R.; Selve, C. Tetrahedron Lett. 1975,
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1988, 18, 445–452. (d) Davis, R.; Untch, K. G. J. Org. Chem. 1981, 46,
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Org. Chem. 2004, 69, 2562–2564. (i) Kanai, T.; Kanagawa, Y.; Ishii, Y. J.
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B.; Mami, I. J. Org. Chem. 1976, 41, 2502–2503. (l) Soltani Rad, M. N.;
Khalafi-Nezhad, A.; Behrouz, S.; Faghihi, M. A. Tetrahedron Lett. 2007,
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TMSCN
(equiv)
time
(h)
yield
(%)b
entry
cat.
solvent
CH2Cl2
1
FeCl3
BiCl3
BiBr3
AuCl3
In(OTf)3
InCl3
InBr3
/
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
2
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
0.5
0.5
0.5
2
41
88
73
82
78
93
98
0
67
trace
23
81
99
87
41
95
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
dioxane
toluene
ClCH2CH2Cl
CH3CN
n-hexane
CH2Cl2
3
4
5
2
6
0.5
0.1
10
0.5
2
7
(14) (a) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int.
Ed. 2004, 43, 1414–1416. (b) Saito, T.; Yasuda, M.; Baba, A. Synlett 2005,
1737–1739. (c) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org.
Chem. 2006, 71, 8516–8522. (d) Georgy, M.; Boucard, V.; Campagne, J. M.
J. Am. Chem. Soc. 2005, 127, 14180–14181. (e) Braun, M.; Kotter, W.
Angew. Chem., Int. Ed. 2004, 43, 514–517. (f) Zhan, Z. P.; Yang, W. Z.;
Yang, R. F.; Yu, J. L.; Li, J. P.; Liu, H. J. Chem. Commun. 2006, 3352–
3354. (g) Zhan, Z. P.; Yu, J. L.; Liu, H. J.; Cui, Y. Y.; Yang, R. F.; Yang,
W. Z.; Li, J. P. J. Org. Chem. 2006, 71, 8298–8301. (h) Rubin, M.;
Gevorgyan, V. Org. Lett. 2001, 3, 2705–2707.
8
9
10
11
12
13
14
15
16c
2
0.5
0.5
0.5
5
1
(15) (a) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006,
45, 793–796. (b) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. AdV.
Synth. Catal. 2006, 348, 1033–1037. (c) Liu, P. N.; Zhou, Z. Y.; Lau, C. P.
Chem.-Eur. J. 2007, 13, 8610–8619. (d) Noji, M.; Konno, Y.; Ishii, K. J.
Org. Chem. 2007, 72, 5161–5167. (e) Rueping, M.; Nachtsheim, B. J.;
Kuenkel, A. Org. Lett. 2007, 9, 825–828. (f) Jana, U.; Biswas, S.; Maiti, S.
Tetrahedron Lett. 2007, 48, 4065–4069. (g) Huang, W.; Wang, J.; Shen,
Q.; Zhou, X. Tetrahedron Lett. 2007, 48, 3969–3973.
a All the reactions were carried out by dropwise addition of a solution
of 5a in the specified solvent to a stirred suspension of TMSCN and the
metal salt (10 mol %) in the same solvent over 30 min (or less), and the
resulting mixtures were stirred therein at room temperature for the specified
time periods. b Yield of the isolated product. c 0.05 equiv of InBr3 was used.
(16) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409–413.
1, the bismuth(III) halides (BiCl3 or BiBr3) are more efficient
for the reaction than FeCl3, affording the target nitrile in good
(17) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew.
Chem., Int. Ed. 2007, 46, 3139–3143.
(18) (a) Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A. J. Am. Chem.
Soc. 2004, 126, 7186–7187. (b) Liu, J.; Muth, E.; Flo¨rke, U.; Henkel, G.;
Merz, K.; Sauvageau, J.; Schwake, E.; Dyker, G. AdV. Synth. Catal. 2006,
348, 456–462. (c) Vicennati, P.; Cozzi, P. G. Eur. J. Org. Chem. 2007,
224, 8–2253. (d) Toshimitsu, A.; Nakano, K.; Mukai, T.; Tamao, K. J. Am.
Chem. Soc. 1996, 118, 2756–2757.
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Loh, T. P. J. Am. Chem. Soc. 2003, 125, 13042–13043. (b) Zhao, J. F.;
Zhao, Y. J.; Loh, T. P. Chem. Commun. 2008, 1353–1355. (c) Liu, F.; Loh,
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4574
Org. Lett., Vol. 10, No. 20, 2008

Table 2. InBr3-Catalyzed Direct Cyanation of Alcohols 5a-5u with TMSCNa
a Reaction conditions: a solution of 5 (0.25 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a suspension of TMSCN (0.5 mmol) and InBr3 (10 mol
%) in CH2Cl2 (0.5 mL) over the specified time period (<30 min) at room temperature, followed by stirring the resulting mixture for an extended time period
or immediate workup. b InCl3 was used as the catalyst instead of InBr3.
yields under identical conditions (entries 2 and 3). AuCl3 and
In(OTf)3 were also found to be effective catalysts for the
reaction, giving the cyanation product in good yields (78-80%)
in somewhat prolonged reaction periods (entries 4 and 5).
Among the examined metal salts, InCl3 and InBr3 turned out
to be optimal in terms of reaction efficiency, affording the
cyanation product in excellent yields within short reaction
periods (entries 6 and 7), presumably as a result of the moderate
Lewis acidity and water/alcohol tolerance of the indium(III)
species.14c,20 A control experiment indicated that under the
(20) Auge´, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739–1764
.
Org. Lett., Vol. 10, No. 20, 2008
4575

test conditions the reaction was negligible in the absence of
a catalyst (entry 8). Lowering the amount of the nucleophile
TMSCN from 2 equiv (relative to that of the alcohol) to 1 is
obviously unfavorable for the reaction, as the yield of the
desired product decreased considerably, probably owing to
more side product formation (chalcone and 1,3-diphenyl-
propene were isolated from the reaction system as the
byproducts due to the disproportionation of 5a under the
experimental conditions) by competing reactions under lower
nucleophile concentration (entries 9 vs 7). Screening the
solvents for InBr3-catalyzed reaction revealed that CH2Cl2
or 1,2-dichloroethane (DCE) was optimal (entries 7 and 13),
whereas coordinating solvents such as THF or dioxane were
deleterious to the catalysis (entries 10 and 11). Furthermore,
when the catalyst loading of InBr3 was reduced to 5 mol %,
the cyanation product could still be obtained in high yield
within a slightly prolonged reaction period (entry 16).
Subsequently, we proceeded to examine the substrate
scope of the alcohol cyanation protocol for the preparation
of R-aryl nitriles with InBr3 as the catalyst (Table 2). As
shown in the table, most of the tested benzylic alcohols can
smoothly react with TMSCN in high efficiency (usually less
than 10 min) under the optimized conditions, giving the
corresponding nitriles in good to excellent yields. For the
reaction involving the dissymmetric allylic alcohol 5b, only
one of the two potential isomers was isolated in good yield
(entry 2).21 While only moderate yield of the nitrile was
obtained for the cyanation of ortho-methoxy substituted
1-phenyl ethanol 5d (entry 4), the presence of the same
substituent at the para-position of the R-phenyl ring of the
substrate was obviously beneficial for the reaction (entry 5).
Although the exact reason for such a dramatic difference in
reactivity is unclear, the electronic and/or steric effect of the
ortho-methoxy group in substrate 5d should be responsible
for the result observed. For the reactions of other analogous
substrates, it is obvious that the electron-donating groups at
the para-position of benzylic alcohols consistently gave the
corresponding nitriles in high yields (entries 6-14). Fur-
thermore, for the cyanation of the sterically more demanding
tertiary alcohols, which are known to be difficult substrates
for other cyanation approaches, good to excellent yields of
nitriles were obtained (entries 15-17). To our delight, the
precursors for cicloprofen and indoprofen, respectively, can
also be efficiently obtained in high yields by this protocol
(entries 18 and 19). Intriguingly, when alcohol 5t was
subjected to the cyanation condition with InBr3 as the
catalyst, an intractable mixture was obtained. Further screen-
ing of a variety of Lewis acids revealed that InCl3 was an
effective catalyst for the transformation of 5t, affording the
nitrile product 6t, a key intermediate, in 56% yield (entry
20). Therefore, the present protocol has provided an alterna-
tive facile synthesis of verapamil.10,11a
However, it is worth noting that alcohol substrates
including primary alcohols, such as PhCH2OH,
4-MeOC6H4CH2OH, or (E)-3-PhCHdCHCH2OH, and sec-
ondary 1-phenyl ethanol were found to be not amenable to
this catalytic cyanation protocol. In the reactions of alcohols
bearing electron-deficient aryl substituents, such as 1-(4-
fluorophenyl)ethanol, 1-(4-nitrophenyl)ethanol, or 1-(pyridin-
2-yl)ethanol, the corresponding cyanation products were not
obtained under otherwise identical reaction conditions, which
might be attributed to the difficulty in the formation of a
carbo-cationic intermediate.
Although the exact mechanism of this In(III)-catalyzed
cyanation reaction is unclear at the present stage, we
speculate that the catalytic cycle might involve some type
of carbenium intermediates14c,15d formed by the heterolytic
cleavage of the C-O bond of the alcohols with the assistance
of Lewis acidic In(III) (and TMSCN). Experimental evidence
in support of this proposal was observed in the cyanation of
enantioenriched (S)-5e (90% ee), where racemic cyanation
product 6e was isolated in high yield (92%). In addition,
when (E)-1-phenylbut-2-en-1-ol (5u), a regioisomer of 5b,
was submitted to the cyanation reaction, the essentially
identical yield of 6b (entry 2 vs 21 in Table 2) and
regioisomer distribution21 of cyanation products to the case
of 5b were observed (see also pp S54-55 in Supporting
Information), indicating the involvement of a delocalized
carbocation in the catalytic process.
In summary, we have developed a new and efficient
catalytic protocol for the preparation of R-aryl nitriles via
a direct cyanation of appropriate alcohols. Using InX3 (X
) Br or Cl) as the catalyst, a variety of R-aryl alcohols
can be converted to the corresponding nitriles commonly
within 5-30 min in good to excellent yields under mild
reaction conditions. Of special importance, the method
was demonstrated to be very convenient for the synthesis
of the key nitrile precursors for some clinically important
compounds such as verapamil (1), indoprofen (2), ciclo-
profen(3), and naproxen (4). Further development of a
catalytic asymmetric version of this method is in progress
in our laboratory.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (No. 20532050,
20632060), the Chinese Academy of Sciences, the Major
Basic Research Development Program of China (Grant
No.2006CB806106), the Science and Technology Commis-
sion of Shanghai Municipality, and Merck Research Labo-
ratories.
Supporting Information Available: A general experi-
mental procedure and spectroscopic data of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) 1H NMR spectrum of the crude reaction products indicated that a
regioisomer of 6b is also formed as the minor product (14%) (see page
S55 in Supporting Information).
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