An efficient and green protocol for the preparation of cycloalkanols: A practical synthesis of venlafaxine

Article abstract of DOI:10.1016/j.tetlet.2004.08.018

The condensation of arylacetonitriles with cyclic ketones using aqueous NaOH or KOH under phase transfer catalysis gives almost quantitative yields of cycloalkanols. This protocol is utilized for a practical synthesis of the antidepression drug, venlafaxine 1.

Full text of DOI:10.1016/j.tetlet.2004.08.018

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7291–7295
An efficient and green protocol for the preparation of
cycloalkanols: a practical synthesis of venlafaxine
Subhash P. Chavan,* Dushant A. Khobragade, Subhash K. Kamat, Latha Sivadasan,
Kamalam Balakrishnan, T. Ravindranathan, Mukund K. Gurjar and Uttam R. Kalkote
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 9 June 2004; revised 27 July 2004; accepted 3 August 2004
Available online 19 August 2004
Abstract—The condensation of arylacetonitriles with cyclic ketones using aqueous NaOH or KOH under phase transfer cataly-
sis gives almost quantitative yields of cycloalkanols. This protocol is utilized for a practical synthesis of the antidepression drug,
venlafaxine.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
CN
CN
NMe2
R3
Venlafaxine1,2 1 is a new generation antidepression
drug, quite different from other antidepressants having
a unique structure and morphological effects. The earlier
patented methods for its synthesis involve the use of
strong bases such as n-BuLi,3,4 LDA,5 NaOMe, NaOEt,
NaNH2, NaH,6 etc., for coupling p-methoxyphenyl-
acetonitrile 2 with cyclohexanone 3 under anhydrous
conditions, at À78ꢁC, to give the 1-[cyano(4-methoxy-
phenyl)methyl]cycloalkanol 4. The yields under these
conditions are low and are not ideally suited to large
scale industrial synthesis.
R1
R3
R3
R1
R1
R2
R2
R2
Venlafaxine 1
R1=R3=H, R2=OMe
Scheme 1.
ditions. In addition, this protocol can be successfully
employed for the synthesis of a wide variety of other
natural products7h and commercially important
pharmaceuticals.7i
2. Results and discussion
Our interest in developing mild and green proto-
cols7a,b,f–r led us to undertake a practical and efficient
synthesis of this commercially important drug. Cyclo-
alkanols serve as important intermediates for the syn-
thesis of potent drugs like venlafaxine. In pursuit of
methods for forming C–C bonds and functional group
transformations under aqueous conditions7f–r we have
developed a very mild, general and efficient method
for the synthesis of such cycloalkanols (see Scheme 1).
Our protocol employs simple bases such as NaOH and
KOH in an aqueous medium under phase transfer con-
Thus, the condensation of p-methoxyphenylacetonitrile
2 with cyclohexanone 3 was carried out using 10% aque-
ous NaOH or KOH in the presence of tetrabutylammo-
nium hydrogen sulfate (TBAHSO4) as phase transfer
catalyst at 0–15ꢁC to give almost quantitative yields of
1-[cyano(4-methoxyphenyl)methyl]cycloalkanol 4 with-
in 30min–1h. The product precipitated from the aque-
ous medium, and was filtered off to obtain the pure
product. The reaction could also be carried out using
powdered NaOH or KOH, at 0–15ꢁC without a phase
transfer catalyst to furnish 4 in 87% yield within
30min. The reaction can also be performed using poly-
ethylene glycol (MW-6000) as the phase transfer catalyst
when yields of up to 73% were obtained, albeit in 48h.
Thus, the process eliminates the use of organic solvents
Keywords: Condensation; Cycloalkanols; Phase transfer catalyst.
*
Corresponding author. Tel./fax: +91 20 5893614; e-mail: spchavan@
dalton.ncl.res.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.018

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S. P. Chavan et al. / Tetrahedron Letters 45 (2004) 7291–7295
Table 1.
Entry
Nitrile
Ketone
Product
PTCa
Time
1h
%Yield
97
OMe
OMe
O
1
2
3
TBAHSO4
3
CN
OH
4
CN
2
O
TBAHSO4
TBAHSO4
1h
1h
87
95
CN
OH
6 OMe
CN
5
3
OMe
OMe
OMe
O
CN
OH
CN
7
3
8
OMe
OMe
MeO
OMe
MeO
OMe
O
4
5
6
7
TBAHSO4
TBAHSO4
TBAHSO4
TBAId
1h
90b
CN
CN
OH
10
9
3
Cl
Cl
O
45min
45min
1h
87
CN
CN
OH
12
Cl
11
3
Cl
O
73c
CN
CN
OH
11
13
14
OMe
OMe
O
83
CN
CN
OH
13
2
15
NC
O
OMe
OMe
HO
NC
8
TBAHSO4
45min
56e
NC
OMe
OMe
OMe
OMe
CN
2
5
16
17
O
9
TBAId
TBAId
1h
2h
96
66
CN
OH
CN
13
18
OMe
OMe
O
O
O
O
10
CN
CN
OH
19
3
20
OMe
OMe
O
O
11
TBAHSO4
2h
96
CN
CN
OH
19
13
21

S. P. Chavan et al. / Tetrahedron Letters 45 (2004) 7291–7295
7293
Table 1 (continued)
Entry
Nitrile
Ketone
Product
NRf
PTCa
Time
%Yield
––
O
CN
12
13
TBAHSO4
Overnight
MeO
3
OMe
22
OMe
O
NRf
TBAHSO4
Overnight
––
MeO
OMe
23
CN
2
OMe
O
14
15
NRf
TBAHSO4
TBAHSO4
Overnight
30min
––
77
24
CN
2
NC
CN
O
NC
CN
25
3
26
a PTC = phase transfer catalyst.
b Powdered nitrile was used.
c About 10% dehydrated product was obtained.
d TBAI = tetrabutylammonium iodide.
e Powdered ketone was used.
f No reaction observed even at room temperature.
either as the reaction medium or in the workup (extrac-
tion), employing water as the reaction medium, thereby
making it a simpler, cleaner and ÔgreenerÕ process. In
order to generalize this reaction, a wide variety of aryl-
acetonitriles were treated with different ketones. The
results are listed in Table 1.
formed inevitably, over the same period of time,
exclusively!
Having developed a mild protocol for the condensation
of arylacetonitriles with ketones, the key intermediate 4
was synthesized in an almost quantitative yields. The
second step in the patent3 involves the use of the expen-
sive catalyst, Rh/Al2O3. Further simplifying the process,
reduction of the nitrile to venlafaxine was performed un-
der a hydrogen atmosphere (200psi) using Raney nickel
as the catalyst in the presence of formalin7b to furnish
venlafaxine 1. This novel procedure for reduction of a
nitrile to an amine and subsequent N,N-dimethylation
was performed in one-pot (Scheme 2).
From the table it is evident that a wide variety of aryl-
acetonitriles undergo C–C bond formation with cyclic
ketones to give good to excellent yields of the corre-
sponding cycloalkanols. Both cyclohexanone as well as
cyclopentanone were shown to react efficiently under
these conditions. An a-substituted arylacetonitrile (entry
12) however, did not react with cyclohexanone under
these conditions. Aromatic and acyclic ketones (entries
13 and 14) also failed to undergo the reaction. Even mal-
ononitrile (entry 15) was shown to undergo facile C–C
bond formation with cyclohexanone. However, it was
found that when the reaction is carried out at room tem-
perature, the corresponding dehydrated product was
Although, the yield of this reaction is 30%, 60% of the
starting material was recovered and could be recycled
which becomes attractive from an industrial point of
view. Thus, in the second step, the expensive catalyst
was replaced by a cheaper catalyst viz Raney nickel.
OMe
OMe
CN
O
a
b
+
NMe2
OH
Venlafaxine 1
3
CN
OMe
2
OH
4
Scheme 2. Reagents and conditions: (a) 10% aqueous NaOH, TBAHSO4, 0–15ꢁC, 30min–1h, quantitative yield; (b) H2, 280psi, formalin, MeOH,
100ꢁC, 30% (60% cycloalkanol is recovered).

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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
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in a measuring cylinder, washed three–four times with
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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

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