PAPER
Reductive Alkylation and Addition of Aromatic and Heteroaromatic Nitriles
4249
for 16 h, then quenched with sat. aq NH4Cl (8 mL), and extracted
with Et2O (3 × 15 mL). The combined organic extracts were washed
with brine (15 mL) and concentrated. The crude product was sub-
jected to chromatographic purification on silica gel (hexane–
EtOAc, 50:1) to give 3f as a white solid (150 mg, 68%); mp 76–
77 °C.
104.4 (C), 90.3 (CH), 38.5 (CH2), 34.1 (CH2), 32.3 (CH2), 21.6
(CH2), 13.6 (CH3).
HRMS-EI: m/z [M]+ calcd for C23H26S: 334.1755; found: 334.1748.
Reductive Alkylation of 2-Thienyldialkylacetonitriles; 2-(1,1-
Dibenzylpentyl)thiophene (6a); Typical Procedure
IR (neat): 2934, 1600, 1496 cm–1.
To a stirred solution of 1s (200 mg, 0.66 mmol) in THF (8 mL) pre-
cooled at –100 °C was slowly added lithium naphthalenide in THF
(0.5 M, 3.95 mL, 1.98 mmol) in 5 min via a syringe under an argon
atmosphere. The resulting dark green solution was stirred at
–100 °C for 40 min and treated with 1-bromobutane (0.28 mL, 2.64
mmol). The reaction mixture was stirred at –100 °C for 1 h,
quenched with sat. aq NH4Cl (8 mL) and extracted with Et2O
(2 × 20 mL). The combined organic extracts were washed with
brine (10 mL) and concentrated. Chromatographic purification on
silica gel (hexane–EtOAc, 30:1) gave 6a as a white solid (154 mg,
70%); mp 61–63 °C.
1H NMR (400 MHz, CDCl3): d = 7.33–7.26 (m, 6 H), 3.87–6.83 (m,
3 H), 7.14–7.12 (m, 6 H), 3.17 (d, J = 13.6 Hz, 2 H), 3.10 (d,
J = 13.6 Hz, 2 H), 1.64–1.60 (m, 2 H), 1.50–1.42 (m, 2 H), 1.30 (tq,
J = 7.0, 7.6 Hz, 2 H), 0.91 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 145.9 (C), 138.4 (2 × C), 130.4
(4 × CH), 127.8 (2 × CH), 127.5 (4 × CH), 127.4 (2 × CH), 125.8
(2 × CH), 125.6 (CH), 45.7 (C), 44.9 (2 × CH2), 33.5 (CH2), 26.0
(CH2), 23.1 (CH2), 14.1 (CH3).
HRMS-EI: m/z [M]+ calcd for C25H28: 328.2191; found: 328.2184.
IR (neat): 3028, 2934, 1602, 1495, 1455 cm–1.
Reductive Addition with Oxygen to Pyridyldialkylacetonitriles;
1-Phenyl-2-pyridin-3-ylhexan-2-ol (4p); Typical Procedure
To a stirred solution of 2e (200 mg, 0.76 mmol) in THF (10 mL)
precooled at –40 °C was slowly added lithium naphthalenide in
THF (0.5 M, 4.6 mL, 2.30 mmol) in 5 min via a syringe under an
argon atmosphere. The resulting dark green solution was stirred at
–40 °C for 40 min, then cooled to –78 °C and purged with O2 for 1
h. The reaction mixture was then quenched with sat. aq NH4Cl (10
mL) and extracted with Et2O (3 × 20 mL). The combined organic
extracts were washed with brine (15 mL) and concentrated. Chro-
matographic purification on silica gel (hexane–EtOAc, 3:1) yielded
4p as a yellowish oil (93 mg, 48%).
1H NMR (400 MHz, CDCl3): d = 7.29–7.20 (m, 7 H), 7.07–6.91 (m,
5 H), 6.55 (d, J = 3.6 Hz, 1 H), 3.14 (d, J = 13.6 Hz, 2 H), 3.02 (d,
J = 13.6 Hz, 2 H), 1.62–1.25 (m, 6 H), 0.91 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 152.3 (C), 137.8 (2 × C), 130.3
(4 × CH), 127.5 (4 × CH), 126.2 (CH), 126.1 (2 × CH), 124.5 (CH),
122.9 (CH), 46.8 (CH2), 45.8 (C), 35.1 (CH2), 25.9 (CH2), 23.0
(CH2), 14.1 (CH3).
HRMS-EI: m/z [M]+ calcd for C23H26S: 334.1755; found: 334.1755.
Following the same procedure, 6a was also prepared from 2g and
benzyl bromide in 56% yield.
IR (neat): 3231, 2955, 1590, 1576 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.56 (d, J = 1.6 Hz, 1 H), 8.42 (d,
J = 4.4 Hz, 1 H), 7.63 (dt, J = 8.0, 1.6 Hz, 1 H), 7.22 (dd, J = 8.0,
4.4 Hz, 1 H), 7.18-7.13 (m, 3 H), 6.95–6.91 (m, 2 H), 3.10 (d,
J = 13.6 Hz, 1 H), 3.05 (d, J = 13.6 Hz, 1 H), 1.93 (dt, J = 12, 3.6
Hz, 1 H), 1.79 (dt, J = 12, 3.6 Hz, 1 H), 1.32–1.16 (m, 3 H), 1.01–
0.91 (m, 1 H), 0.79 (t, J = 7.2 Hz, 3 H).
Acknowledgment
We are grateful to the National Science Council of Republic of
China (Taiwan), National Tsing Hua University, and National Dong
Hwa University for financial support.
13C NMR (100 MHz, CDCl3): d = 147.1 (CH), 147.0 (CH), 141.4
(C), 135.6 (C), 133.8 (CH), 130.6 (CH), 128.2 (CH), 126.8 (CH),
122.9 (CH), 75.5 (C), 49.5 (CH2), 41.5 (CH2), 25.5 (CH2), 22.9
(CH2), 13.9 (CH3).
HRMS-EI: m/z [M]+ calcd for C17H21NO: 255.1623; found:
255.1613.
References
(1) House, H. O. In Modern Synthetic Reactions, 2nd ed.; W. A.
Benjamin Inc.: New York, 1972, 492–628.
(2) Schaefer, F. C. In The Chemistry of the Cyano Group;
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(3) Mattalia, J.-M.; Marchi-Delapierre, C.; Hazimeh, H.;
Chanon, M. ARKIVOC 2006, (iv), 90.
Generation of 1-Alkylsulfanyl-1,3,4-triene from 2-Thienyl-
dialkylacetonitriles; (5-Benzyl-6-phenylhexa-1,3,4-trienyl)(bu-
tyl)sulfane (5a); Typical Procedure
(4) For recent examples, see: (a) Morin, M. D.; Rychnovsky, S.
D. Org. Lett. 2005, 7, 2051. (b) Burke, Y. A. M.; Kotani, S.
J.; Ziller, W.; Rychnovsky, S. D. Org. Lett. 2010, 12, 72.
(5) (a) Shia, K. S.; Chang, N. Y.; Yip, J.; Liu, H. J. Tetrahedron
Lett. 1997, 38, 7713. (b) Liu, H. J.; Zhu, J. L.; Shia, K. S.
Tetrahedron Lett. 1998, 39, 4183. (c) Zhu, J. L.; Shia, K. S.;
Liu, H. J. Chem. Commun. 2000, 1599. (d) Liu, H. J.; Yip, J.
Synlett 2000, 1119. (e) Liu, H. J.; Ly, T. W.; Tai, C. L.; Wu,
J. D.; Liang, J. K.; Guo, J. C.; Tseng, N. W.; Shia, K. S.
Tetrahedron 2003, 59, 1209. (f) Wu, J. D.; Shia, K. S.; Liu,
H. J. Tetrahedron Lett. 2001, 42, 4207. (g) Liu, H. J.; Ho,
Y. L.; Wu, J. D.; Shia, K. S. Synlett 2001, 1805. (h) Tsia, T.
Y.; Shia, K. S.; Liu, H. J. Synlett 2003, 97. For our recent
publications in this area, see: (i) Ko, Y. C.; Zhu, J. L.
Synthesis 2007, 3659. (j) Amancha, P. K.; Lai, Y. C.; Chen,
I. C.; Liu, H. J.; Zhu, J. L. Tetrahedron 2010, 66, 871.
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1982, 104, 2198.
To a stirred solution of 1s (100 mg, 0.33 mmol) in THF (5 mL) pre-
cooled at –78 °C was slowly added lithium naphthalenide in THF
(0.5 M, 1.98 mL, 0.99 mmol) in 5 min via a syringe under an argon
atmosphere. The resulting dark green solution was stirred at –78 °C
for 40 min and treated with 1-bromobutane (0.14 mL, 1.32 mmol).
The reaction mixture was stirred at –78 °C for 1 h, quenched with
sat. aq NH4Cl (4 mL) and extracted with Et2O (2 × 15 mL). The
combined organic extracts were washed with brine (5 mL) and con-
centrated. The purification of the crude products on silica gel (hex-
ane–EtOAc, 20:1) provided 5a as a yellowish oil (39 mg, 35%).
IR (neat): 3027, 2956, 2929, 1942, 1602 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.29–7.10 (m, 10 H), 6.10–5.89
(m, 3 H), 3.28 (s, 4 H), 2.68 (t, J = 7.2 Hz, 2 H), 1.62–1.36 (m, 4 H),
0.91 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 207.2 (C), 139.1 (C), 129.0
(3 × CH), 128.2 (3 × CH), 126.2 (2 × CH), 125.8 (CH), 123.1 (CH),
(7) March, J. In Advanced Organic Chemistry 4th ed., Wiley-
Interscience: New York, 1992, 26–74.
Synthesis 2010, No. 24, 4242–4250 © Thieme Stuttgart · New York