LETTER
p-Alkenylbenzonitriles
1617
Table Reactions of 1– or 12– with Alkenyl Bromides 2
4-(But-3-enyl)benzonitrile (3d, Entry 8)4a,13a,b
Starting with 12– sodium salt (6.1 mmol) and 2d (6.7 mmol), 3d
(0.70 g, 73%) was isolated by TLC (Rf = 0.5; hexane–Et2O, 9:1) as
a pale yellow oil.
Entry
Anionic
reagent
Alkenyl
bromide
Temp
(°C)
Main products
(yield, %)b
1
2
1• – Li+/Na+
2a
–33
–70
–33
–33
–70
–78
–33
–33
–33
–33
–33
–33
3a (50/53)
3a (57/60)
3a (80)
4-(Pent-4-enyl)benzonitrile (3e, Entry 10)14a,c
Starting with 12– sodium salt (6.0 mmol) and 2e (6.6 mmol), 3e
(0.75 g, 73%) was isolated by TLC (Rf = 0.4; hexane–Et2O, 9:1) as
a pale yellow oil.
12– 2 (Li+/Na+) 2a
3c
4
12– 2 Na+
1• – Na+
2a
2b
2b
2c
2d
2d
2e
2e
2f
4-(Hex-5-enyl)benzonitrile (3f, Entry 12)4c
Starting with 12– sodium salt (3.0 mmol) and 2f (3.5 mmol), 3f (0.44
g, 79%) was isolated by TLC (Rf = 0.6; hexane–Et2O, 9:1) as a pale
yellow oil.
3b (65)
5
12– 2 Na+
12– 2 Na+
1• – Na+
3b (75)
6d
7
3c (16)
The ‘Inverted’ Mixing Procedure (Entry 3)
3d (50)
The NH3 (50 mL) was condensed to dinitrile 1 (0.64 g 5.0 mmol) in
a cooled (–70 °C) dropping funnel equipped with a pressure-equal-
ization arm, a stirrer and a gas vent, and Na (0.24 g, 10.3 mmol) was
added. Then, the suspension of the 12– salt was added dropwise to
stirred precooled (–30 °C) allylbromide (2a, 0.9 mL, 10.4 mmol) in
THF (4 mL) during 15 min. After 10 min the reaction mixture was
worked up as described above and separated by column chromatog-
raphy (cyclohexane–EtOAc, 20:1) to provide 4-allylbenzonitrile
(3a)11b (0.57 g, 80%, Rf = 0.24) as a pale yellow oil.
8
12– 2 Na+
1• – Na+
3d (73)
9c
10
11
12
3e (24)
12– 2 Na+
1• – Na+/K+
3e (73)
3f (48/56)
3f (79/834c)
12– 2 (Na+/K+) 2f
a Unless otherwise stated, reactions were performed in liquid NH3,
concentration of 1• – or 12– salt was 0.1–0.2 M, molar ratio of 1• – to
alkenyl bromide 2:1, of 12– to alkenyl bromide 1:1.15, reaction time
of 30–50 min.
4-(2-Fluoroallyl)benzonitrile (3c, Entry 6)
THF (30 mL) was added under argon to nitrile 1 (0.38 g, 3.0 mmol).
Then, at –70 °C and continuous stirring NH3 (30 mL) was con-
densed into the mixture, Na (0.14 g, 6.1 mmol) was added, and NH3
was evaporated. The suspension of 12– salt in THF was cooled to
–78 °C in an argon flow and fluoroallylbromide (2c)8 (0.37 mL, 3.2
mmol) was added. The reaction mixture was stirred for 45 min and
worked up as described above. The product mixture was separated
by column chromatography (cyclohexane–EtOAc, 20:1) and HPLC
(cyclohexane–EtOAc, 30:1) providing 3c (0.08 g, 16%) as a color-
less oil. 1H NMR (300.13 MHz, CDCl3): d = 3.42 (2 H, d, J = 16.4
Hz), 4.00 (1 H, dd, J = 48.7, 3.0 Hz), 4.54 (1 H, dd, J = 17.0, 3.0
Hz), 7.36 (2 H, d, J = 8.4 Hz), 7.59 (2 H, d, J = 8.4 Hz). 13C NMR
(75.47 MHz, CDCl3): d = 26.9, 35.8, 92.4, 111.0, 118.7, 129.7,
132.4, 141.5. 19F NMR (282.4 MHz, CDCl3): d = –94.75 (1 F, ddt,
J = 48.7, 17.0, 16.4 Hz). MS (EI): m/z (%) = 161 (100) [M+], 141
(55), 133 (43), 116 (6), 114 (10), 89 (6), 63 (5).
b Isolated yield. For 1• – reactions, yield is given taking into account
that two equiv of 1• – are required to form one equiv of alkylated
product.
c ‘Inverted’ mixing experiment.
d The reaction was performed in THF.
In summary, reactions of 1• – or 12– with alkenyl bromides
2 provide a new convenient one-pot synthesis of 4-allyl-
and 4-(w-alkenyl)benzonitriles 3 in good yields. The pro-
tocol of 12– alkylation is comparable or superior to those
described in literature11–15 both in product yields, avail-
ability of starting materials, and experimental simplicity.
Acknowledgment
The ‘Regular’ Procedure of 1• – or 12– Alkylation
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG), grant no. 436 RUS 17/107/05, and the Russian Foundation
for Basic Research (RFBR), grant no. 05-03-32309a.
The alkylating reagent 2 was added dropwise to a stirred solution of
the 1• – salt or suspension of the 12– salt generated by the addition of
alkali metal (for 1• – ca. 0.95 equiv, for 12– ca. 2.1 equiv)4a–c to a sus-
pension of 1 in liquid NH3 (50–100 mL). The mixture was stirred
under an atmosphere of evaporating NH3 at desired temperature for
30–50 min. Then, Et2O (50 mL) was added and the mixture was
stirred until NH3 has evaporated completely and r.t. has been
reached. Afterwards, H2O (50 mL) was added to the residue. The
solid dinitrile 1 was filtered off, washed sequentially with Et2O and
H2O and air-dried. The combined liquid phases were separated and
the aqueous layer was extracted with Et2O (3 × 25 mL). The com-
bined ethereal layer was washed with H2O (3 × 25 mL), dried
(MgSO4), and the solvent was evaporated. The individual products
were isolated by TLC (fixed layer of silica gel) or by column
chromatography.
References
(1) (a) Meyer, O. G. J.; Fröhlich, R.; Haufe, G. Synthesis 2000,
1479. (b) Rosen, T. C.; Haufe, G. Tetrahedron: Asymmetry
2002, 13, 1396.
(2) (a) Csuk, R.; Schabel, M. J.; von Scholz, Y. Tetrahedron:
Asymmetry 1996, 7, 3505. (b) Nishii, Y.; Maryjama, N.;
Wakasugi, K.; Tanabe, U. Bioorg. Med. Chem. 2001, 11,
33. (c) Kumar, J. S.; Roy, S.; Datta, A. Bioorg. Med. Chem.
1999, 9, 513. (d) Rosen, T. C.; Yoshida, S.; Kirk, K. L.;
Haufe, G. ChemBioChem 2004, 5, 1033.
(3) (a) Schultz, A. G. Chem. Commun. 1999, 1263. (b) Birch,
A. J. Pure Appl. Chem. 1996, 68, 553. (c) Rabideau, P. W.;
Marcinow, Z. Org. React. 1992, 42, 1.
4-(2-Methylallyl-benzonitrile (3b, Entry 5)15,16
Starting with 12– sodium salt (10.0 mmol) and 2b (11.4 mmol), 3b
(1.17 g, 75%) was isolated by column chromatography (Rf = 0.20;
cyclohexane–EtOAc, 10:1) as a pale yellow oil.
Synlett 2007, No. 10, 1616–1618 © Thieme Stuttgart · New York