7294
S. P. Chavan et al. / Tetrahedron Letters 45 (2004) 7291–7295
Alternatively, cycloalkanol 4 could be reduced with
LiAlH4/AlCl3 to give the corresponding amine (quanti-
tative yield), which could be further N,N-dimethylated
using formalin and formic acid in the presence of a large
excess of water8 to furnish 1 (85–90% yield). Thus, novel
conditions were developed where water is used as the
reaction medium and mild, readily and cheaply available
bases are employed in the key step. The use of an expen-
sive catalyst was avoided and the reaction could be per-
formed employing a cheaper catalyst instead.
was then dissolved in ethyl acetate and partitioned
between 10% aq HCl. The aqueous layer was washed
with ethyl acetate, basified using 10% aq NaOH soln, sat-
urated with NaCl, and the product extracted into ethyl
acetate, washed with brine (2 · 25mL), dried over anhy-
drous Na2SO4 and concentrated in vacuo to give a bright
white solid (1.69g, 30%, mp 74–76ꢁC). The first ethyl
acetate fraction after washing with water (2 · 25mL),
drying over anhydrous Na2SO4 and concentration under
reduced pressure returned unreacted nitrile 4 (3g, 60%).
The hydrochloride salt of venlafaxine 1 was prepared
using isopropanol saturated with HCl gas to give bright
white crystals (mp 224–226ꢁC, lit.3 mp 225–226ꢁC).
The hydrochloride salt of 1 was prepared using isopro-
panol saturated with HCl gas followed by recrystalliza-
tion from ethyl acetate.
Acknowledgements
3. Conclusion
D.A.K. thanks CSIR, New Delhi, India for financial
assistance. Funding, in part, from CSIR under YSA,
New Delhi, India, to S.P.C. is also gratefully
acknowledged.
In conclusion, we have developed a novel protocol for the
condensation of arylacetonitriles with cyclic ketones in an
aqueous medium and utilized it for the synthesis of the
commercially important drug, venlafaxine. The process
is simple to operate, and eliminates cumbersome purifica-
tion techniques such as column chromatography, making
it very attractive from a commercial point of view.
References and notes
1. Carmen, A. A.; Bosch, J.; Camps, G. P.; Maria del Carmen,
O. M.; Nuria, S. M. WO 2001007397; Chem. Abstr. 2001,
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Pharm. Univ. 1999, 30, 249–250.
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U.S. Patent US 4,535,186; Chem. Abstr. 1985, 102, 5895.
4. Souvetre, R.; Claude, M.; Schmitt, R.; Penne, J. S.
Tetrahedron 1978, 34, 2135–2140.
4. Experimental
4.1. A typical procedure for the preparation of
cycloalkanols
1-[Cyano(4-methoxyphenyl)methyl]cycloalkanol (4): An
ice-cooled mixture of p-methoxyphenylacetonitrile
(100g, 0.680mol), 10% aq NaOH soln (100mL,
0.250mol) and tetrabutylammonium hydrogen sulfate
(5g, 0.014mol) was stirred for 30min. A dark red colour
was observed due to the anion. To this was added cyclo-
hexanone (67g, 0.680mol) in small portions, at 0ꢁC,
with vigorous stirring, such that the temperature did
not rise above 15ꢁC. After 30min–1h, a white solid
formed. The solid was crushed and the reaction mixture
was again stirred vigorously at room temperature for a
further 1h. The solid was filtered, washed with water
until neutral to pH paper and dried. Crystallization
from ethyl acetate–petroleum ether (500:350, v/v) gave
a bright white solid (161.66g, 97%; mp 125–126ꢁC,
lit.3 mp 125–127ꢁC).
5. Shepherd, P. G. U.K. Patent GB 2,227,743A; Chem. Abstr.
1991, 114, 81228.
6. Guohou, C.; Chao, Z. Chinese Patent CN 1,225,356A;
Chem. Abstr. 2000, 133, 17266.
7. (a) Chavan, S. P.; Kamat, S. K.; Sivadasan, L.; Balakrishnan,
K.; Khobragade, D. A.; Ravindranathan, T.; Gurjar, M. K.;
Kalkote, U. R. U.S. Patent US 6,350,912B1, Chem. Abstr.
2002, 136, 200009; (b) For related work please see references:
(c), (d) and (e). Chavan, S. P.; Kamat, S. K.; Sivadasan, L.;
Balakrishnan, K.; Khobragade, D. A.; Ravindranathan, T.;
Gurjar, M. K.; Kalkote, U. R. U.S. Patent US 6,504,044B2,
2003; (c) Ekkundi; Vadiraj S.; Mumbaikar, V. N.; Paingan-
kar, N.; Van Der Schaaf; Adriaan, P. U.S. Patent US
6,620,96, 2003; (d) Basappa, C. V.; Kavitha; Rangappa, R. S.
Bioorg. Med. Chem. Lett. 2004, 14, 3279–3281; (e) Kim, K.;
Kim, K.; Lee, S.; Park, J.-s.; Chai, K. WO 2003000652A1;
Chem. Abstr. 2003, 138, 73016; (f) Kalkote, U. R.; Sathe, V.
T.; Kharul, R. K.; Chavan, S. P.; Ravindranathan, T.
Tetrahedron Lett. 1996, 37, 6785–6786; (g) Chavan, S. P.;
Dantale, S. W.; Kalkote, U. R.; Jyothirmai, V. S.; Kharul, R.
K. Synth. Commun. 1998, 28, 2789–2792; (h) Chavan, S. P.;
Khobragade, D. A.; Pathak, A. B.; Kalkote, U. R. Tetrahe-
dron Lett. 2004, 45, 5263–5265; (i) Unpublished work from
our lab; (j) Chavan, S. P.; Soni, P. B.; Kamat, S. K. Synlett,
2001, 1251–1252; (k) Chavan, S. P.; Anand, R.; Pasupathy,
K.; Rao, B. S. Green Chem. 2001, 3, 320–322; (l) Chavan, S.
P.; Dantale, S. W.; Govande, C. A.; Venkatraman, M. S.;
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4.2. Reduction of the nitrile
2-[Dimethylamino(4-methoxyphenyl)ethyl]cyclohexanol
(1): To a solution of cycloalkanol 4 (5g, 0.02mol) in
methanol (100mL) was added formalin (35% soln,
25mL) and Raney nickel (2.5mL aqueous suspension,
in a measuring cylinder, washed three–four times with
methanol to remove water). The mixture was subjected
to reduction using Raney nickel under a H2 atmosphere
(200psi) at 60ꢁC, for 6h. The reaction mixture was
allowed to cool to room temperature and filtered. The
catalyst was thoroughly washed with methanol
(4 · 25mL). The combined filtrate was concentrated
under reduced pressure to afford an oily residue, which