Hydrocyanations of arylalkenes provide a direct path to
such benzylic nitriles and, moreover, have the advantage of
easy access to starting materials. Transition-metal-free hy-
drocyanations had long been realized, with the only difficulty
being a requirement of extremely high temperatures and
pressures.9 Transition-metal (Co, Ni, Pd) catalyzed hydro-
cyanations of alkenes to form primary or secondary nitriles
have been established by both academia and industry.10
However, their application to substituted aryl alkenes had
been very limited.11 In addition, most of the above proce-
dures require handling of hazardous hydrogen cyanide, which
critically limits applications for fine chemical synthesis.
In the course of synthetic study of a PDE 4 inhibitor (3),4c
which featured a tertiary benzylic nitrile, we envisioned that
1-arylcyclohexene derivative 1 might be converted to nitrile
2 in presence of an appropriate Brønsted acid and cyanide
source, despite the fact that such acid-promoted hydrocya-
nation has been very rare (Scheme 1).12 This idea was based
Supporting Information) and trimethylsilyl cyanide (Me3-
SiCN), selected as an easily handled cyanide source, each
of several Brønsted acids was added at room temperature.
Both acids and trimethylsilyl cyanide were used in large
excess (ca. 100 equiv) for the purpose of testing the concept.
Use of inorganic acids (e.g., 36% HCl, 47% HBr, H3PO4,
PPA) only gave recovered starting material. Sulfuric acid
caused decomposition of substrate. With TFA, a trace of
desired nitrile 2 was detected by HPLC. Both 60% HClO4
and methanesulfonic acid gave 2 in moderate conversion.
Finally, triflic acid (TfOH) was identified as the most
effective promoter to provide 2 with high conversion.
Encouraged with this result, we moved on to solvent
optimization employing 2.0 equiv of triflic acid and 1.5 equiv
of trimethylsilyl cyanide. As shown in Table 1, the use of
Table 1. Solvent Effectsa
assay yieldb (%)
(cis/trans)c
Scheme 1. Retrosynthesis of a PDE 4 Inhibitor (3)
entry
solvent
time (h)
1
2
1
2
3
4
5
6
7
8
DMSO
DMF
EtOH
DME
EtOAc
CH3CN
TFA
Hexane
Toluene
EDCd
72
72
24
24
24
5
9
2
2
2
81
82
84
78
65
2
4
5
0
0
0
0
0
0
3
14
23
29
36
45
54
56
(52/48)
(65/35)
(66/34)
(63/37)
(70/30)
(62/38)
(63/37)
(63/37)
9
10
11
12
PhCF3
CH2Cl2
2
2
0
0
first on the assumption that the possible intermediate benzylic
cation should be stabilized by the electron-donating substit-
uents of 1. In this paper, we describe a discovery and
optimization of a Brønsted acid-promoted hydrocyanation
of arylalkenes which provides a new and practical synthetic
approach to tertiary benzylic nitriles.
a Conditions: 1 (0.05 mmol), Me3SiCN (1.5 equiv), TfOH (2.0 equiv),
solvent (0.5 mL), rt. b HPLC yield. c Ratio of cis/trans isomers of 2 was
determined by HPLC. d Ethylene dichloride.
Our study began with exploration of a Brønsted acid. To
a dichloromethane solution of cyclohexene 1 (see the
polar solvents such as DMSO did not provide 2 (entries
1-5). Hydrocarbon solvents afforded a moderate yield of 2
(entries 8 and 9) but seemed unsuitable because of the
forming heterogeneous reaction mixture. Halogenated sol-
vents such as dichloromethane gave the best results (entries
10-12). Trifluorotoluene (entry 11) was selected for further
optimization, particularly from an environmental viewpoint.13
Optimal stoichiometry of triflic acid and trimethylsilyl
cyanide was examined (Table 2). Triflic acid treatment
(absence of trimethylsilyl cyanide) caused degradation of 1,
mainly giving a dimer 4 (entry 1).14 Minimizing exposure
to triflic acid, solution of 1 was added last and slowly (entries
2-6). Use of a slightly excess equivalent of triflic acid
compared to trimethylsilyl cyanide was essential for reducing
dimer formation and provided a higher yield of 2, which
implies that residual triflic acid plays a key role. Alternative
cyanide sources were also examined. Acetone cyanohydrin,
a less expensive cyanide source, provided a lower yield and
slower reaction rate (entry 9), while sodium cyanide and zinc
(8) (a) Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 4641–4642. (b) Culkin, D. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 9330–9331. (c) Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234–245. (d) You, J.; Verkade, J. G. Angew. Chem.,
Int. Ed. 2003, 42, 5051–5053. (e) You, J.; Verkade, J. G. J. Org. Chem.
2003, 68, 8003–8007.
(9) Mowry, D. T. Chem. ReV. 1948, 42, 189–283.
(10) (a) NorthM. In ComprehensiVe Organic Functional Group Trans-
formations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon:
Oxford, 1995; Vol. 3, p 614. (b) Arthur, P., Jr.; England, D. C.; Pratt, B. C.;
Whitman, G. M. J. Am. Chem. Soc. 1954, 76, 5364–5367. (c) Tolman, C. A.;
Mckinney, R. J.; Seidel, W. C.; Druliner, J. D.; Stevens, W. R. AdV. Catal.
1985, 33, 1–46. (d) Nugent, W. A.; McKinney, R. J. J. Org. Chem. 1985,
50, 5370–5372. (e) RajanBabu, T. V.; Casalnuovo, A. L. J. Am. Chem.
Soc. 1992, 114, 6265–6266. (f) Casalnuovo, A. L.; RajanBabu, T. V.; Ayers,
T. A.; Warren, T. H. J. Am. Chem. Soc. 1994, 116, 9869–9882. (g) Horiuchi,
T.; Shirakawa, E.; Nozaki, K.; Takaya, H. Tetrahedron: Asymmetry 1997,
8, 57–63. (h) Yan, M.; Xu, Q.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry
2000, 11, 845–849. (i) Goertz, W.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M.; Vogt, D. Chem.sEur. J. 2001, 7, 1614–1618. (j) Morgan,
T. A. U.S. Patent 4,810,814, 1989.
(11) Only a few patents have appeared that use Pd catalyst and hydrogen
cyanide under high temperature (130 °C) in an autoclave: Eidenschink, R.;
Haas, G.; Pohl, L.; Ro¨mer, M.; Scheuble, B.; Weber, G. U.S. Patent
4,510,069, 1985.
(12) AlCl3/HCl-mediated hydrocyanation of 1,1-diphenylethylene was
described in ref 9.
(13) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450–451.
(14) Chaudhuri, B. Org. Process Res. DeV. 1999, 3, 220–223.
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