An efficient oxidation of primary azides catalyzed by copper iodide: A convenient method for the synthesis of nitriles

Article abstract of DOI:10.1002/anie.201002635

A wide range of primary azides have been efficiently oxidized by a catalytic amount of CuI and TBHP into their corresponding nitriles in aqueous solution. A variety of oxidizable functional groups were well tolerated under the reaction conditions, and oxidation of secondary azides furnished their corresponding ketones (see scheme; TBHP=tert-butyl hydroperoxide).

Full text of DOI:10.1002/anie.201002635

Communications
DOI: 10.1002/anie.201002635
Oxidation of Azides
An Efficient Oxidation of Primary Azides Catalyzed by Copper Iodide:
A Convenient Method for the Synthesis of Nitriles**
Manjunath Lamani and Kandikere Ramaiah Prabhu*
The nitrile group is an important functional group in organic
Table 1: Optimization of the reaction conditions.
synthesis.[1] Therefore, the development of newer methods for
the synthesis of nitriles is of significant interest among organic
chemists.[2] Typical methods for the synthesis of nitriles
include the cyanation of halides,[3,4] the Sandmeyer reaction
(for aromatic nitriles),[5] dehydration of aryl oximes,[6] and
other methods.[7–11] Although some of these methods are
attractive, they suffer from the limitations of using extreme
conditions and large amounts of reagents. Therefore, the
development of convenient and user-friendly procedures for
the synthesis of nitriles is highly desirable. Recently, an
interesting conversion of methyl arenes into aryl nitriles using
phenyliodonium diacetate (PIDA) has been reported by Jiao
and co-workers;[12] whilst the use of azides in the synthesis of
nitriles has also been documented.[12,13] For example, con-
version of organic azides into nitriles using bromine trifluor-
ide was reported by Sasson and Rozen.[14] Furthermore, Chiba
Entry
Oxygen source
Solvent
Yield [%][a,b]
1
2
3
4
5
6
7
8
None
O2
NMO
TEMPO+O2
H2O2
NaBO3·4H2O
TBHP (aq 70%)
TBHP (aq 70%)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
toluene
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
92[c]
89[c]
[a] Reaction conditions: 1a (1 mmol), CuI (1 mmol), water or toluene
(2 mL), reflux, 20 h. [b] Yield of isolated product. [c] Reaction completed
in 1 h. TBHP=tert-butyl hydroperoxide, n.r. =no reaction.
et al.[15] reported the C C bond cleavage of a-azido carbonyl
À
compounds to furnish nitriles and carboxylic acid. In the
above reactions, the use of NH3, azides, or metal cyanides as
the nitrogen source are required, depending upon the strategy
adopted.
with the azide 1a under refluxing conditions in aqueous
solution to furnish the corresponding nitrile 2a in excellent
yield (92%, 1 h; Table 1, entry 7). The reaction proceeded
well in toluene to yield 2a in 89% (1 h; Table 1, entry 8).
In order to optimize the catalyst loading, a number of
copper catalysts were screened. As seen in Table 2, the
reaction did not proceed in the absence of a catalyst (entry 1,
Table 2). The reaction of 1a with catalytic amounts of copper
In continuation of our research on green chemistry[16] and
the utility of organic azides,[17] we found that a variety of
primary azides are efficiently oxidized into nitriles by a
catalytic amount of CuI and tert-butyl hydroperoxide
(TBHP). During the optimization studies, para-methoxyben-
zyl azide 1a was reacted with stoichiometric amounts of
copper iodide in the presence of a variety of oxygen sources.
As shown in Table 1, the preliminary reaction of 1a with CuI
in the absence of an oxygen source or with several other
oxygen sources, such as molecular oxygen, N-methylmorpho-
line-N-oxide (NMO), 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) with oxygen, H2O2, or sodium perborate did not
produce any significant amount of the product and the
starting material was recovered (Table 1, entries 1–6). Sub-
sequently, we found that CuI (stoichiometric amount) with
excess of TBHP (70% solution in water, 2.5 equiv) reacted
Table 2: Catalytic oxidation by copper reagents.
Entry
Catalyst
(mol%)
TBHP
[equiv]
t
[h]
Yield [%][a,b]
2a
3a
1
2
3
4
5
6
7
8
9
none
CuCl (5)
CuBr (5)
[Cu(acac)2] (5)
Cu (OAc)2·H2O (5)
CuSO4·5H2O (5)
CuI (5)
CuI (10)
CuI (5)
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.5
40
1
1
1
1
1
1
1
24
n.r.
n.r.
[*] M. Lamani, Dr. K. R. Prabhu
65 (62)
63 (60)
70 (68)
73 (70)
73 (71)
92 (89)
92 (90)
92 (90)
25 (25)
22 (20)
20 (18)
22 (20)
22 (18)
0 (0)
Department of Organic Chemistry, Indian Institute of Science
Bangalore 560 012, Karnataka (India)
Fax: (+91)80-2360-0529
E-mail: prabhu@orgchem.iisc.ernet.in
[**] We thank the Indian Institute of Science and Ray Chemicals for
financial support of this investigation, Dr. A. R. Ramesha for useful
discussions, and Prof. Sosale Chandrasekhar and Mr. Anjan Roy for
their encouragement. M.L. thanks the CSIR, New-Delhi for a junior
research fellowship.
0 (0)
0 (0)
[a] Reaction condition: 1a (1 mmol), copper catalyst (0.05 mmol), water
or toluene (2 mL), reflux, 1 h. [b] Yield of isolated product. Yields in
parenthesis refer to the reaction in toluene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002635.
6622
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Chemie
Table 3: Oxidation of primary azides.
reagents, such as CuCl, CuBr, [Cu(acac)2] (acac =
acetylacetonate), Cu(OAc)2·H2O (Ac = acetyl), or
CuSO4·5H2O[18] and TBHP produced mixtures of
para-methoxybenzonitrile 2a and para-methoxy-
benzoic acid 3a (Table 2, entries 2–6). Reaction of
1a with TBHP (2.5 equiv) in the presence of CuI
(5 mol%) was found to be the optimum conditions,
furnishing para-methoxybenzonitrile 2a in excel-
lent yield (92%, 1 h; Table 2, entry 7). Increasing
the amount of catalyst to 10 mol% did not alter the
yield of the product (Table 2, entry 8); at the same
time, decreasing the amount of TBHP to 1.5 equiv-
alents resulted in a much longer reaction time (24 h)
without affording any change in the yield of the
product (Table 2, entry 9). As seen from Table 1
and Table 2, the reaction proceeds well in both
toluene and water, and as such we continued our
investigation by using water as the solvent as it is
environmentally benign.
Entry
1
Substrate
t [h]
Product
Yield [%][b]
80
1b
1c
1
2b
2c
2
1
75
3
4
1d
1e
1
6
2d
2e
85
84
5
6
7
1 f
1g
1h
1
1
2
2 f
2g
2h
82
76
75
Next, we investigated the scope of the reaction
and found that a variety of primary azides were
smoothly transformed into the corresponding
nitriles in good to excellent yields (Table 3 and
Table 4). Benzylic azides bearing electron-donating
and electron-withdrawing groups underwent
a
smooth oxidation to provide the corresponding
benzonitriles in high yields (Table 3, entries 1–5).
2-(Azidomethyl)naphthalene 1 f gave the corre-
sponding nitrile 2 f in 82% yield (Table 3, entry 5).
Interestingly, the oxidation of benzylic azides bear-
ing several oxidizable functional groups resulted in
the formation of the corresponding nitriles in good
yields. Cinnamyl azide 1g, underwent a facile
oxidation to yield cinnamonitrile 2g in 76% yield
(Table 3, entry 6). Similarly, azido-derivatives bear-
ing allylic ether (1h) and ester functionality (1i)
furnished the corresponding nitriles 2h and 2i in
good yields (Table 3, entries 7 and 8). Interestingly,
diazide derivative 1,4-bis(azidomethyl)benzene 1j
was oxidized into its corresponding dinitrile 2j in
good yield (87%; Table 3, entry 9). Under the
optimized oxidation conditions, para-acetyl benzyl
azide 1k gave the corresponding nitrile 2k in
moderate yield (51%; Table 3, entry 10).[19] 2-(Azi-
domethyl)pyridine 1l reacted smoothly to afford
the corresponding nitrile 2l in 53% yield.[19] Ali-
phatic primary azides,[20] such as 1m, 1n, and 1o
reacted well to form the corresponding nitriles in
good yields (70–73%; Table 3, entries 12–14).
8
1i
1j
1k
1l
6
2
6
8
2i
2j
2k
2l
76
9
87
10
11
51[b]
53[b]
12
13
1m
1n
27
24
2m
2n
70[c,d]
73[c]
14
1o
14
2o
71
[a] Yield of isolated product. [b] 1k was recovered in 25%, 1l was recovered in 20%.
[c] Yield determined by GC analysis. [d] With 4 equivalents of TBHP.
The scope of this reaction was further demon-
strated in the oxidation of the secondary benzylic azides, such
as 1-phenylethyl azide (1p), diphenylmethyl azide (1q), 1-(2-
napthyl)ethyl azide (1r), and 1-(para-methylphenyl)1-azido-
ethane (1s) resulted in the formation of their corresponding
ketones in very good yields (2p–2s, 91–94%; Table 4,
entries 1–4). a-Azido carbonyl compound ethylÀ2-azido-2-
(naphthalen-1-yl)acetate (1t) underwent smooth oxidation to
produce the corresponding a-ketoester 2t in moderate yield
(53%; Table 4, entry 5). It is noteworthy that the reaction of
1t with copper acetate under an oxygen atmosphere resulted
À
in cleavage of the C C bond to furnish the corresponding
nitrile and carboxylic acid,[15] whereas in the present reaction,
[21]
À
cleavage of the C C bond is not observed.
To get an insight into the reaction mechanism, the
reaction of CuI and TBHP with 1a was performed under an
argon atmosphere and confirmed that nitrogen gas was
generated during the reaction.[22] Furthermore, it was found
that the addition of a radical inhibitor (hydroquinone) had no
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Communications
Table 4: Oxidation of secondary azides to ketones.
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Entry
1
Substrate
t [h]
Product
Yield [%][a]
94
1p
1q
1r
1
2p
2q
2r
2
3
4
1
1
1
92
91
92
1s
2s
5
1t
24
2t
53[b]
[a] Yield of isolated product. [b] Reaction carried out at 08C, 1t was recovered
in 25%.
effect on the oxidation reaction of 1a and proceeded
smoothly to form 2a, thus indicating that the reaction did
not proceed through a radical intermediate.[23] A detailed
mechanistic study is currently underway within the group.
In summary, we have demonstrated that a variety of
primary azides are efficiently oxidized by TBHP and CuI
(5 mol%) into their corresponding nitriles in aqueous solu-
tion. This synthesis is suitable for a wide range of primary
benzylic azides that contain electron-donating and electron-
withdrawing functional groups. The oxidation is selective and
a number of oxidizable functional groups were well-tolerated
during the reaction conditions. Furthermore, oxidation of
secondary azides furnished the corresponding ketones in
excellent yields.
[5] a) T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1885, 18, 1946; b) T.
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[11] For other methods see: a) T. Oishi, K. Yamaguchi, N. Mizuno,
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47, 8969.
Experimental Section
Typical procedure for para-methoxybenzonitrile (2a): Aqueous
TBHP (70% solution in water, 0.344 mL, 2.5 mmol) was added to a
stirred suspension of 1-(azidomethyl)-4-methoxybenzene (1a,[16a]
163 mg, 1 mmol) and CuI (9.5 mg, 0.05 mmol) in water (2 mL). The
reaction mixture was heated at reflux until the reaction had gone to
completion (1 h, monitored by TLC), cooled to room temperature,
and extracted with ethyl acetate (3 ꢀ 15 mL); the combined organic
layer was washed with water (2 ꢀ 50 mL), dried over sodium sulfate,
and the solvent was removed under vacuum. The residue was purified
by column chromatography on silica gel (EtOAc/hexane 1:19 to 1:9)
to furnish 123 mg (92%) of 2a as a colorless solid; m.p.: 55–578C
(lit.[24] 56–57).
Received: May 2, 2010
Published online: August 2, 2010
[12] W. Zhou, L. Zhang, N. Jiao, Angew. Chem. 2009, 121, 7228;
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Maier, Tetrahedron 2008, 64, 5645.
[14] R. Sasson, S. Rozen, Org. Lett. 2005, 7, 2177.
[15] S. Chiba, L. Zhang, G. Y. Ang, B. W.-Q. Hui, Org. Lett. 2010, 12,
2052.
Keywords: azides · copper · nitriles · oxidation ·
tert-butyl hydroperoxide
.
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[16] a) M. Maddani, S. K. Moorthy, K. R. Prabhu, Tetrahedron 2010,
66, 329; b) M. Maddani, K. R. Prabhu, J. Org. Chem. 2010, 75,
2327.
65% and 25% yields, respectively (Table 2, entry 2). It is
important to note that the method developed by Jiao and co-
workers uses PIDA as the oxidant at room temperature, whereas
the method described here uses aqueous TBHP as the oxygen
source under refluxing conditions in water.
[17] a) M. Maddani, K. R. Prabhu, Tetrahedron Lett. 2007, 48, 7151;
b) M. Maddani, K. R. Prabhu, Tetrahedron Lett. 2008, 49, 4526.
[18] Jiao and co-workers recently proposed an azide intermediate in
the conversion of methyl arenes into aryl nitriles with PIDA,
CuSO4·5H2O, and NaN3 (see Ref [12]). This reaction appeared
to be an oxidation catalyzed by PIDA, as the reaction proceeded
in the absence of copper reagents (see the Supporting Informa-
tion, S2; also see Ref. [12]) at À408C. However, addition of
CuSO4·5H2O resulted in a nominal increase in the yield of the
nitrile obtained (see the Supporting Information, S2; also see
Ref. [12]). Furthermore, para-methoxybenzyl azide (1a) fur-
nished trace amounts of the corresponding nitrile (2a) from the
reaction with PIDA (2 equiv) and CuCl (10 mol%) under a N2
atmosphere in CH3CN, with the recovery of para-methoxybenzyl
azide (1a) in 99% yield (see the Supporting Information, S6).
Contrary to this observation, our studies revealed that the
reaction of para-methoxybenzyl azide (1a) with CuCl (5
mol%)and TBHP (2.5 equiv) in water (or toluene) heated to
reflux afforded the corresponding nitrile (2a) and acid (3a) in
[19] 1k was recovered in 25%; 1l was recovered in 20%.
[20] In the oxidations of aliphatic azides, such as 1m and 1n, 4 equiv
of TBHP was needed to furnish 2m and 2n in good yields.
[21] The reaction of a-azido carbonyl compound ethyl À2-azido-2-
(naphthalen-1-yl) acetate (1r) was performed at 08C as the azido
ester 1t was not stable under the standard reaction conditions.
[22] The reaction of 1a with CuI (5 mol%) and TBHP (2.5 equiv) in
water was performed under an argon atmosphere and the gas
generated during the reaction analyzed by GC to find that
nitrogen gas was generated during the reaction.
[23] The reaction of 1a with CuI and TBHP in the presence of radical
inhibitors, such as hydroquinones, had no effect on the oxidation
reaction, and was complete in 1 h, thus providing 2a in good
yield.
[24] a) B. Movassagh, S. Shokari, Tetrahedron Lett. 2005, 46, 6923;
b) A. V. Narsaiah, K. Nagaiah, Adv. Synth. Catal. 2004, 346,
1271.
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