A novel oxidative transformation of alcohols to nitriles: An efficient utility of azides as a nitrogen source

Article abstract of DOI:10.1039/c2cc31256e

An efficient methodology to oxidize benzylic and cinnamyl alcohols to their corresponding nitriles in excellent yields has been developed. This methodology employs DDQ as an oxidant and TMSN₃ as a source of nitrogen in the presence of a catalytic amount of Cu(ClO₄)₂·6H ₂O.

Full text of DOI:10.1039/c2cc31256e

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 5506–5508
www.rsc.org/chemcomm
COMMUNICATION
A novel oxidative transformation of alcohols to nitriles: an efficient
utility of azides as a nitrogen sourcew
Balaji V. Rokade, Sanjeev K. Malekar and Kandikere Ramaiah Prabhu*
Received 20th February 2012, Accepted 11th April 2012
DOI: 10.1039/c2cc31256e
An efficient methodology to oxidize benzylic and cinnamyl
alcohols to their corresponding nitriles in excellent yields has
been developed. This methodology employs DDQ as an oxidant
and TMSN3 as a source of nitrogen in the presence of a catalytic
amount of Cu(ClO4)2Á6H2O.
Attempts in this direction to synthesize nitriles directly from
alcohols12 require forcing conditions.16 Recently, we have
reported the transformation of benzylic azides to nitriles using
CuI and TBHP (tert-butyl hydroperoxide).17 In continuation of
our investigation,18 herein we report an elegant strategy to trans-
form cinnamyl and benzyl alcohols to their corresponding nitriles
using TMSN3 (trimethylsilyl azide) as a nitrogen source with a
catalytic amount of Cu(ClO4)2Á6H2O in the presence of DDQ.
Initial optimization studies were carried out using cinnamyl
alcohol (1a) and Cu(ClO4)2Á6H2O with a variety of oxidants
(Table 1). Preliminary experiments indicated that TMSN3 is a
suitable source of nitrogen under the present reaction condi-
tions. Contrary to our expectation sodium azide (NaN3) did
not furnish the desired product.19 Therefore, further studies
were carried out using TMSN3, Cu(ClO4)2Á6H2O and a variety of
oxidants (Table 1). Interestingly, atmospheric air or molecular
oxygen as oxidants furnished the corresponding azide 3a as the
major product (entries 1 and 2, Table 1), whereas, a similar
reaction with H2O2 was unsuccessful (entry 3). Reaction of
cinnamyl alcohol 1a with TBHP, benzoquinone, di-tert-butyl
peroxide (DTBP), or chloranil resulted in the formation of a
The azide functionality is one of the valuable intermediates in
organic synthesis.1 Utility of azides2a–c is demonstrated in
insertion of nitrogen into hydrocarbons to obtain tetrazoles,2d
amides2e or transform allylarenes to alkenyl nitriles2f,g and in
click chemistry.3 Ammonia or its alternatives have been used
as the source of nitrogen to synthesize amines, amides, nitriles
etc.,4 which require harsh conditions such as high pressure
and/or temperature. Nevertheless, these reactions have paved
new avenues of utility of azides in the synthesis of nitrogen-
containing heterocyclic compounds by C–H or C–C bond
cleavage.5 The nitrile functionality is special in organic synthesis6
as it occurs in several natural products7 and can be trans-
formed into a variety of functional groups such as amines,
ketones, acids, amides etc. Aliphatic nitriles are synthesized
using corresponding halides and metal cyanides,8 whereas
aromatic nitriles are synthesized by employing the classical
Sandmeyer reaction.9 Dehydration of amides,10 oximes11 and
oxidative conversion of alcohols12 or amines13 are a few more
methods reported to accomplish synthesis of nitriles. C–H
functionalization of methyl arenes to corresponding nitriles
has been reported by Jiao and co-workers,14 which requires
activated precursors. The utility of azides to synthesize aryl, alkyl
or alkenyl nitriles has been reported by various groups.2,15
Interestingly, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)
is known to oxidize cinnamyl azide to cinnamonitrile.2f,g Further,
azides are easily accessed by azidation of either allylic alcohols2h
or allylic acetates.2i As alcohols are inexpensive and easily
available or prepared, it is advantageous to synthesize nitriles
directly from alcohols. It is important to note that most of the
methods for synthesizing nitriles employ halides, acetates or azides,
which are generally obtained from their corresponding alcohols.
Table 1 Optimization studies of oxidantsa
Yieldb (%)
Entry
Oxidant
2a
3a
4a
1a
1
2
3
4
5
6
7
8
Air
O2
H2O2
Aq. TBHP(70%)
TBHP in decane
Benzoquinone
DTBP
Chloranil
DDQ
DDQ
nd
nd
nd
nd
95
75
nd
52
nd
nd
nd
5
nd
25
100
43
Inseparable mixture
Inseparable mixture
nd
32
100
100
42
14
nd
nd
nd
54
nd
nd
58
nd
nd
nd
9
10c
a
Reaction conditions: alcohol (0.50 mmol), TMSN3 (1.0 mmol),
Cu(ClO4)2Á6H2O (0.05 mmol), oxidant (1.5 mmol), 1,2-dichloroethane
Department of Organic chemistry, Indian Institute of Science,
Bangalore 560 012, Karnataka, India.
E-mail: prabhu@orgchem.iisc.ernet.in; Fax: +91-80-23600529
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and NMR spectra for all products.
See DOI: 10.1039/c2cc31256e
b
(2 ml), RT. Yields were determined by 1H NMR analysis with respect
c
to the starting material. Reaction carried out at 60 1C for 1 h.
nd = not detected (o1%).
c
5506 Chem. Commun., 2012, 48, 5506–5508
This journal is The Royal Society of Chemistry 2012

View Online
Table 2 Catalyst screening
Table 3 Conversion of cinnamyl alcohols to nitrilesa,b
Yielda (%)
Entry
Catalyst
2a
4a
1
2
3
4
5
6
CuI
CuCl
93
58
88
75
78
91
7
42
12
25
22
9
CuBr
CuCl2Á2H2O
CuO
Cu2O
7
8
9
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2Á1H2O
Cu(NO3)2Á3H2O
CuSO4Á5H2O
Cu powder
Cu(OTf)2
Cu(ClO4)2Á6H2O
None
67
87
75
89
33
13
25
11
50
nd
nd
37
50
100
100
63
a
Reaction conditions: TMSN3 (0.75 mmol), alcohol (0.5 mmol),
Cu(ClO4)2Á6H2O (0.025 mmol), DDQ (1.1 mmol) in DCE (2 mL) at
b
c
60 1C. Isolated yields. Mixture of E and Z diastereomers (8.9 : 1.1,
based on HNMR).
a
Yields were determined by1H NMR with respect to the starting
1
material. nd = not detected (o1%).
the corresponding nitriles 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i and
2j21 respectively, in good to excellent yields (Table 3).
mixture of products (entries 4–8, Table 1). Finally, it was
satisfying to find that a catalytic amount of Cu(ClO4)2Á6H2O
and TMSN3 in the presence of DDQ was a suitable system to
transform cinnamyl alcohol 1a to cinnamonitrile 2a at room
temperature in almost quantitative yield (3 h, entry 9, Table 1).
Further, it was found that the same reaction proceeds well at
60 1C in shorter duration (1 h) to furnish cinnamonitrile 2a in
quantitative yield (entry 10, Table 1).
To extend the scope of this reaction, a variety of benzylic
alcohols were subjected to similar reaction conditions (Table 4). As
seen in the table, this method is proved to be versatile as a variety of
benzylic alcohols with electron-withdrawing and electron-donating
substituents on the phenyl ring were converted to their corres-
ponding nitriles (6a–6s) in good yields. However, 2-phenylethanol
did not produce the corresponding nitrile, which may be due to the
lack of conjugation (6t, Table 4). The salient feature of the above
reaction is that this transformation is selective as a variety of
functional groups such as allylic, propargylic, O-benzylic, ester
groups, which are prone to oxidation, were inert under the reaction
conditions. Additionally, the reaction tolerates the protecting
groups such as TBDPS, TBDMS and benzylic which are prone
to undergo deprotection under milder reaction conditions.
Based on a few control experiments (see Scheme S1, ESIw)
and literature precedence,22–24 we believe that Cu(ClO4)2Á6H2O,
which is a Lewis acid, activates the alcohol (or aldehyde) and
assists the nucleophilic attack of TMSN3 to form the corres-
ponding azide, which further reacts with DDQ to form allylic
or benzylic carbocation I, which furnishes the corresponding
nitrile as presented in Scheme 1. Further work is underway in
our laboratory.
Further studies revealed that copper catalysts such as copper
halides, copper oxides, copper acetate, copper nitrate, copper
sulphate and copper powder under the identical reaction condi-
tions are not suitable catalysts as they resulted in the formation
of mixtures of corresponding nitriles and aldehydes (entries 1–11,
Table 2). However, Cu(OTf)2 and Cu(ClO4)2Á6H2O were found
to be the most suitable catalysts, as these reactions furnished the
quantitative yield of 2a (entries 12 and 13, Table 2). The
reaction also proceeded in the absence of copper catalysts but
unfortunately furnished the mixture of corresponding nitrile
and aldehyde (entry 14, Table 2). In the solvent screening
studies, it was found that dichloroethane (DCE), toluene and
CH3CN were suitable solvents for conversion of alcohol 1a to
the corresponding nitrile 2a, whereas the reaction in THF
resulted in lower yield of the product. No reaction was
observed in MeOH or water as solvent (see Table S1 in ESIw).
With the help of additional screening studies (Table S2, ESIw),
it was found that 5 mol% Cu(ClO4)2Á6H2O, 1.5 equiv.
TMSN3, and 2.2 equiv. of DDQ are required for the efficient
conversion of cinnamyl alcohol 1a to cinnamonitrile 2a.20
Under the optimized reaction conditions, the scope and
limitation of the reaction was investigated and the results have
been compiled in Table 3. As can be seen in Table 3, a variety
of substituted cinnamyl alcohols were converted to their
corresponding nitriles in excellent yields. It is evident from the
table that neither electron-donating substituents nor electron-
withdrawing substituents have any effect on the outcome of
the reaction and the reaction proceeded well to furnish
In conclusion, we have demonstrated a novel, efficient and
useful methodology to oxidize benzylic and cinnamyl alcohols
to their corresponding nitriles in excellent yields by employing
DDQ as an oxidant and TMSN3 as a source of nitrogen in the
presence of a catalytic amount of Cu(ClO4)2Á6H2O. Further, this
method tolerates a variety of oxidizable functional groups and a
few useful protecting groups. Additionally, it was also observed
that cinnamyl azide can be synthesized using cinnamyl alcohol,
TMSN3 and Cu(ClO4)2Á6H2O which is also under investigation.
We are grateful to Indian Institute of Science, CSIR,
New Delhi (no. 01(2415)/10/EMR-II), for financial assistance,
and Dr A. R. Ramesha for useful discussions. BVR thanks
CSIR, New Delhi, for a research fellowship.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5506–5508 5507

View Online
Table 4 Conversion of benzylic alcohols to nitrilesa,b
L. Zhang and N. Jiao, Org. Lett., 2010, 12, 2888; (h) M. Rueping,
C. Vila and U. Uria, Org. Lett., 2012, 14, 768; (i) B. Sreedhar,
P. S. Reddy and N. S. Kumar, Tetrahedron Lett., 2006, 47, 3055.
3 (a) L. Ackermann and H. K. Potukuchi, Org. Biomol. Chem., 2010,
8, 4503; (b) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302.
4 J. L. Klinkenberg and J. F. Hartwig, Angew. Chem., Int. Ed., 2011,
50, 86.
5 K. Banert, The Chemistry of Vinyl, Allenyl, and Ethynyl Azides, in
Organic Azides – Syntheses and Applications, ed. S. Brase and
¨
K. Banert, John Wiley & Sons Ltd., Chichester, 2010, pp. 115–166.
6 (a) The Chemistry of the Cyano Group, ed. Z. Rappoport, Interscience,
New York, 1970; (b) S. Arseniyadis, K. S. Kyler and D. S. Watt, in
Organic Reactions, ed. W. G. Dauben, Wiley, New York, 1984,
vol. 31, pp. 1–374; (c) A. J. Fatiadi, in Preparation and Synthetic
Applications of Cyano Compounds, ed. S. Patai and Z. Rappaport,
Wiley, New York, 1983; (d) R. C. Larock, Comprehensive Organic
Transformations, VCH, New York, 1989; (e) J. S. Miller and
J. L. Manson, Acc. Chem. Res., 2001, 34, 563.
7 (a) R. C. Larock, Comprehensive Organic Transformations, VCH,
Weinheim, 1989, p. 819; (b) C. Grundmann, in Houben-Weyl:
Methoden der organischenChemie, ed. J. Falbe, Thieme, Stuttgart,
4th edn, 1985, vol. E5, p. 1313.
8 (a) M. Sundermeier, A. Zapf and M. Beller, Chem. Commun., 2004,
1388; (b) H.-J. Cristau, A. Ouali, J.-F. Spindler and M. Taillefer,
Chem.–Eur. J., 2005, 11, 2483; (c) J. Zanon, A. Klapars and
S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 2890.
9 T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1885, 18, 1946.
10 (a) C.-W. Kuo, J.-L. Zhu, J.-D. Wu, C.-M. Chu, C.-F. Yao and K.-S.
Shia, Chem. Commun., 2007, 301; (b) K. Mai and G. Patil, Tetrahedron
Lett., 1986, 27, 2203; (c) S. Enthaler, Chem.–Eur. J., 2011, 17, 9316.
11 (a) E. Choi, C. Lee, Y. Na and S. Chang, Org. Lett., 2002, 4, 2369;
(b) K. Yamaguchi, H. Fujiwara, Y. Ogasawara, M. Kotani and
N. Mizuno, Angew. Chem., Int. Ed., 2007, 46, 3922.
12 (a) S. Iida and H. Togo, Tetrahedron, 2007, 63, 8274; (b) N. Mori
and H. Togo, Synlett, 2005, 1456; (c) S. Iida and H. Tago, Synlett,
2007, 407; (d) S. Yamazaki and Y. Yamazaki, Chem. Lett., 1990,
571; (e) G. D. McAllister, C. D. Wilfred and R. J. K. Taylor,
Synlett, 2002, 1291; (f) F.-E. Chen, Y.-Y. Li and H.-Q. Jia,
Synthesis, 2002, 1804.
a
Reaction conditions: TMSN3 (0.75 mmol), alcohol (0.5 mmol),
Cu(ClO4)2Á6H2O (0.025 mmol), DDQ (1.1 mmol) in DCE (2 mL) at
b
13 (a) H. Veisi, Synthesis, 2010, 2631; (b) C. Zhu, C. Sun and Y. Wei,
Synthesis, 2010, 4235.
60 1C. Isolated yields.
14 W. Zhou, L. Zhang and N. Jiao, Angew. Chem., Int. Ed., 2009, 48, 7094.
15 (a) R. Sasson and S. Rozen, Org. Lett., 2005, 7, 2177; (b) S. Chiba,
L. Zhang, G. Y. Ang and B. W.-Q. Hui, Org. Lett., 2010, 12, 2052;
(c) W. Zhou, J. Xu, L. Zhang and N. Jiao, Synlett, 2011, 887;
(d) J. He, K. Yamaguchi and N. Mizuno, J. Org. Chem., 2011,
76, 4606; (e) R. Hernandez, E. I. Leon, P. Moreno, R. F. Concepcion
and E. Suarez, J. Org. Chem., 2004, 69, 8437; (f) H. Hayashi,
A. Ohno and S. Oka, Bull. Chem. Soc. Jpn., 1976, 49, 506.
16 (a) T. Oishi, K. Yamaguchi and N. Mizuno, Angew. Chem., Int. Ed.,
2009, 48, 6286; (b) T. Oishi, K. Yamaguchi and N. Mizuno, Top.
Catal., 2010, 53, 479.
17 M. Lamani and K. R. Prabhu, Angew. Chem., Int. Ed., 2010,
49, 6622.
18 (a) M. Maddani and K. R. Prabhu, Tetrahedron Lett., 2008,
49, 4526; (b) M. Maddani, S. R. K. Moorthy and K. R. Prabhu,
Tetrahedron, 2010, 66, 329; (c) M. Maddani and K. R. Prabhu,
J. Chem. Sci., 2010, 90, 287; (d) K. Alagiri and K. R.
Prabhu, Tetrahedron, 2011, 67, 8544; (e) M. Lamani, P. Devadig
and K. R. Prabhu, Org. Biomol. Chem., 2012, 10, 2753.
19 The reaction of cinnamyl alcohol with Cu(ClO4)2Á6H2O, NaN3 and
DDQ produced quantitative yield of cinnamaldehyde.
20 Reaction of cinnamyl alcohol (1a) with DDQ (1.2 equiv.), TMSN3
(1.5 equiv.) and Cu(ClO4)2Á6H2O (5 mol%) furnished cinnamonitrile
in major amounts (85–90%), along with a minor amount of aldehyde
(10%). To circumvent this problem, 2.2 equiv. of DDQ was employed
which furnished cinnamonitrile (2a) exclusively in good yield (99%).
21 This reaction has produced the mixture of E and Z diastereomers
in the ratio of 8.9 : 1.1 (based on 1H NMR).
Scheme 1 A tentative mechanism.
Notes and references
1 (a) E. F. V. Scriven and K. Turnbull, Chem. Rev., 1988, 88, 297;
(b) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596; (c) S. Brase, C. Gil,
K. Knepper and V. Zimmermann, Angew. Chem., Int. Ed., 2005,
44, 5188; (d) S. Lang and J. Murphy, Chem. Soc. Rev., 2006, 35, 146;
(e) E. Leemans, M. D’Hooghe and N. D. Kimpe, Chem. Rev., 2011,
111, 3268; (f) T. Pasinszki, M. Krebsz and O. Wagner, Curr. Org.
Chem., 2011, 15, 1700.
2 (a) W. Q. Tian and Y. A. Wang, J. Org. Chem., 2004, 69, 4299;
(b) F. L. Lin, H. M. Hoyt, H. V. Halbeek, R. G. Bergman and
C. R. Bertozzi, J. Am. Chem. Soc., 2005, 127, 2686; (c) E. Arstad,
A. G. M. Barrett, B. T. Hopkins and J. Kobberling, Org. Lett.,
2002, 4, 1975; (d) C. Qin, W. Zhou, F. Chen, Y. Ou and N. Jiao,
Angew. Chem., Int. Ed., 2011, 50, 12595; (e) F. Chen, C. Qin, Y. Cui
and N. Jiao, Angew. Chem., Int. Ed., 2011, 50, 11487; (f) C. Qin and
N. Jiao, J. Am. Chem. Soc., 2010, 132, 15893; (g) W. Zhou, J. Xu,
22 K. Nishiyama, M. Oba and A. Watanabe, Tetrahedron, 1987,
43, 693.
23 K. Banert, C. Berndt, S. Firdous, M. Hagedorn, Y.-H. Joo,
T. Ruffer and H. Lang, Angew. Chem., Int. Ed., 2010, 49, 10206.
24 G. I. Koldobskii, V. A. Ostrovskii and B. V. Gidaspov, Russ.
Chem. Rev., 1978, 47, 1084.
c
5508 Chem. Commun., 2012, 48, 5506–5508
This journal is The Royal Society of Chemistry 2012