2936
R. Sengupta, S. M. Weinreb
PAPER
IR (thin film): 3266, 2958, 1703, 1461 cm–1.
2-[4-(Dimethylamino)phenyl]-3-methylbutanenitrile (4f)
Tan solid; yield: 22 mg (73%); Rf = 0.43 (hexanes–EtOAc, 7:1).
1H NMR (300 MHz, CDCl3): δ = 8.80 (br s, 1 H), 7.56 (s, 0.6 H),
7.36 (s, 0.4 H), 2.48–2.43 (m, 1 H), 2.15–0.95 (m, 8 H), 0.87 (s, 5.4
H), 0.80 (s, 3.6 H).
13C NMR (75 MHz, CDCl3): δ = 155.0 (CH), 152.7 (CH), 70.6 (C),
68.8 (C), 47.5 (CH), 47.3 (CH), 40.0 (CH2), 37.6 (CH2), 32.8 (C),
32.7 (C), 27.9 (CH3), 27.8 (CH3), 25.9 (CH2), 22.5 (CH2).
IR (thin film): 2928, 2802, 2361, 2336, 1612, 1514 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 8.6 Hz, 2 H), 6.70 (d,
J = 8.4 Hz, 2 H), 3.55 (d, J = 6.4 Hz, 1 H), 2.95 (s, 6 H), 2.09–2.04
(m, 1 H), 1.03 (d, J = 2.3 Hz, 3 H), 1.02 (d, J = 2.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.5 (C), 129.0 (CH), 122.7 (C),
120.9 (C), 112.8 (CH), 44.6 (CH), 40.9 (CH3), 34.2 (CH), 21.1
(CH3), 19.4 (CH3).
α-Aryl Nitriles; General Procedure
To a 25-mL round-bottomed flask flushed with argon was added
powdered CuCN (30 mg, 0.33 mmol). The flask was sealed with a
rubber septum and a needle connected to an argon line was intro-
duced through the septum. The flask was charged with anhyd THF
(1.5 mL) and the mixture was cooled to –10 °C. A hexane–Et2O
soln (~1:2–2:1, ~0.5–1.0 M) of the freshly prepared aryllithium
(0.37 mmol)13 was added slowly by a syringe to the mixture at
–10 °C. Upon the addition of the organolithium reagent, the con-
tents of the flask changed from a gray suspension to a colorless
solution or to one with a greenish tinge. The solution was cooled to
–30 °C and stirred for 5 min at this temperature. The α-chloro al-
doxime (0.15 mmol) in THF (1.5 mL) was added dropwise to the
mixture at –30 °C; as the α-chloro aldoxime was added, the clear so-
lution slowly became turbid and the color slowly changed to bright
yellow. After the addition was complete, the solution was stirred for
20 min at this temperature. Concd H2SO4 (0.04 mL, 0.72 mmol) was
added to the mixture at –30 °C, followed by CH2Cl2 (1.5 mL).
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2: 203.1548; found:
203.1543.
2-(4-Chlorophenyl)-3-methylbutanenitrile (4g)
Tan oil; yield: 20 mg (70%); Rf = 0.55 (hexanes–EtOAc, 7:1).
IR (thin film): 2966, 2932, 2240, 1727, 1597, 1490 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 8.3 Hz, 2 H), 7.24 (d,
J = 8.3 Hz, 2 H), 3.64 (d, J = 6.2 Hz, 1 H), 2.13–2.04 (m, 1 H),
1.06–1.01 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 133.8 (C), 129.6 (CH), 129.5
(CH), 128.6 (C), 119.8 (C), 45.0 (CH), 34.2 (CH), 21.1 (CH3), 19.1
(CH3).
HRMS (EI): m/z [M+] calcd for C11H12ClN: 193.0658; found:
193.0670.
The reaction mixture was warmed to r.t. and anhyd pyridine (0.15
mL, 1.86 mmol) was added followed by anhyd Et3N (0.2 mL, 1.43
mmol). Solid DCC (250 mg, 1.2 mmol) was added and the resulting
mixture was stirred at r.t. After 12 h, the reaction mixture was
poured into a separatory funnel containing ethylenediamine (2 mL)
dissolved in H2O (100 mL), and the mixture was extracted with
Et2O (25 mL). The organic layer was washed with H2O (100 mL),
followed by a formic acid soln [100 mL; 96% HCOOH (2 mL) in
H2O (100 mL)]. The organic layer was washed with brine (100 mL)
and dried over anhyd MgSO4. The organic solution was concentrat-
ed under reduced pressure and the product was purified by flash col-
umn chromatography on silica gel [CH2Cl2–hexanes, 1:9; followed
by EtOAc–hexanes gradient (7–15% EtOAc in hexanes)].
Acknowledgment
We are grateful to the National Science Foundation (CHE-
1105653) for financial support of this research.
Supporting Information for this article is available online at
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References
(1) See, for example: Caron, S.; Vazquez, E.; Wojcik, J. M.
J. Am. Chem. Soc. 2000, 122, 712; and references cited
therein.
(2) Jeffery, P. Pulm. Pharmacol. Ther. 2005, 18, 9.
(3) Prisant, L. M. Heart Dis. 2001, 3, 55.
(4) For lead references, see: (a) Friedrich, K.; Wallenfels, K.
The Chemistry of the Cyano Group; Wiley-Interscience:
New York, 1970. (b) Larock, R. C. Comprehensive Organic
Transformations, 2nd ed.; Wiley-VCH: New York, 1999.
(5) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 9330. (b) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 15824.
α-Aryl nitriles 4a, 4b, 4c, 4h, 4i, 4j, 4k and 7 are commercially
available or have previously been reported.16
3-Methyl-2-phenylbutanenitrile (4d)
Tan oil; yield: 21 mg (87%); Rf = 0.55 (hexanes–EtOAc, 7:1).
IR (thin film): 2960, 2932, 2867, 2239, 2035, 1731, 1599, 1489,
1459, 1374 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H), 3.67 (d,
J = 6.2 Hz, 1 H), 2.19–2.08 (m, 1 H), 1.05 (t, J = 7.4 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 135.0 (C), 128.9 (CH), 128.1
(CH), 128.0 (CH), 120.0 (C), 45.2 (CH), 33.9 (CH), 20.9 (CH3),
18.9 (CH3).
(6) You, J.; Verkade, J. G. Angew. Chem. Int. Ed. 2003, 42,
5051.
(7) (a) Korboukh, I.; Kumar, P.; Weinreb, S. M. J. Am. Chem.
Soc. 2007, 129, 10342. (b) Majireck, M. M.; Witek, J. A.;
Weinreb, S. M. Tetrahedron Lett. 2010, 51, 3555. (c) Witek,
J. A.; Weinreb, S. M. Org. Lett. 2011, 13, 1258. (d) Kumar,
P.; Li, P.; Korboukh, I.; Wang, T. L.; Yennawar, H.;
Weinreb, S. M. J. Org. Chem. 2011, 76, 2094. (e) Sengupta,
R.; Witek, J. A.; Weinreb, S. M. Tetrahedron 2011, 67,
8229.
(8) For reviews of nitrosoalkenes, see: (a) Gilchrist, T. L. Chem.
Soc. Rev. 1983, 12, 53. (b) Lyapkalo, I. M.; Ioffe, S. L. Russ.
Chem. Rev. 1998, 67, 467.
(9) (a) Hassner, A.; Maurya, R. Tetrahedron Lett. 1989, 30,
5803. (b) Artman, G. D. III; Waldman, J. H.; Weinreb, S. M.
Synthesis 2002, 2057.
HRMS (EI): m/z [M+] calcd for C11H13N: 159.1048; found:
159.1045.
2-(4-Methoxyphenyl)-3-methylbutanenitrile (4e)
Tan oil; yield: 28 mg (98%); Rf = 0.45 (hexanes–EtOAc, 7:1).
IR (thin film): 2964, 2238, 1611, 1511, 1462 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.21 (d, J = 8.6 Hz, 2 H), 6.89 (d,
J = 8.7 Hz, 2 H), 3.81 (s, 3 H), 3.59 (d, J = 6.3 Hz, 1 H), 2.09–2.05
(m, 1 H), 1.02 (t, J = 5.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 159.7 (C), 129.4 (CH), 127.3 (C),
120.6 (C), 114.6 (CH), 55.8 (CH3), 44.8 (CH), 34.2 (CH), 21.1
(CH3), 19.3 (CH3).
HRMS (EI): m/z [M+] calcd for C12H15NO: 189.1154; found:
189.1156.
(10) (a) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jorgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790.
Synthesis 2012, 44, 2933–2937
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