Direct transformation of methyl arenes to aryl nitriles at room temperature

Full text of DOI:10.1002/anie.200903838

Communications
DOI: 10.1002/anie.200903838
Aryl Nitriles
Direct Transformation of Methyl Arenes to Aryl Nitriles at Room
Temperature**
Wang Zhou, Liangren Zhang, and Ning Jiao*
The development of novel methods for the preparation of aryl
nitriles is of long-standing interest to organic chemists
because of the importance of these compounds in chemistry
and biology. Moreover, they are also versatile building blocks
in the synthesis of natural products, pharmaceuticals, agricul-
tural chemicals, materials, and dyes.[1] In the past several
decades, three general strategies for the synthesis of aryl
Table 1: The direct transformation of para-methylanisole (1a) to
nitriles have been developed: 1) the replacement approach, in
which aryl nitriles are obtained by introducing a nitrile group
through Sandmeyer reaction[1] of aryldiazonium salts or by
the transition-metal-mediated cyanation of aryl halides with a
cyanide source which generally is toxic;[2] 2) the dehydration
approach, for example, dehydration of aryl amides[3a,b] or
oximes,[3c,d] or oxidative dehydration of benzylic amines or
4-methoxybenzonitrile (2a).[a]
Entry NaN3
[equiv]
PIDA
[equiv]
Additive (equiv)
t [h] Yield of
2a [%][b]
1
2
3
4
0
3.2
0
none
none
none
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuSO4·5H2O(0.05)
CuSO4·5H2O(0.05)
CuSO4·5H2O(0.05)
none
12
12
3
0
0
42
55
alcohols with ammonia;[3e,f] and 3) direct C H functionaliza-
À
4.0
4.0
4.0
4.0
4.0
0
tion, one of the most exciting topics in concise and economical
organic synthesis.[4] In this context an even more attractive but
challenging issue is the direct ammoxidation of substituted
methyl arenes.[5] However, the low selectivity and harsh
reaction conditions (reaction temperatures of 630–730 K)
3.2
3.2
3.2
3.2
3.2
3.2
3.2
3.2
6.4
2
5[c]
6[d]
7[e]
8
12 trace
3
3
3
6
6
6
53
8
(58)
70 (71)
(60)
(64)
4.0
4.0
À
9[f]
required because of the high C H bond dissociation energy
10[f] 4.0
11[f] 8.0
limit their application in organic synthesis. Hence, the direct
transformation of methyl arenes to aromatic nitriles under
mild conditions still remains of great value. Herein, we
demonstrate a novel and efficient copper-promoted trans-
formation of substituted methyl arenes to aryl nitriles by the
none
[a] Reaction conditions: 1a (0.5 mmol), NaN3, PIDA, additive in
acetonitrile at 258C under N2. [b] Yields determined by GC using
n-dodecane as the internal standard, the number in parentheses refers to
the yield of isolated product. [c] The reaction was carried out at 08C.
[d] The reaction was carried out at 508C. [e] Me3SiN3 was used instead of
NaN3. [f] NaN3 and PIDA were added in three portions.
À
cleavage of three C H bonds under mild and neutral
conditions [Eq. (1)].
We began our evaluation of this direct transformation
with the reaction of para-methylanisole (1a; Table 1). Grat-
ifyingly, when NaN3 was chosen as the nitrogen source, the
reaction in the presence of phenyliodonium diacetate (PIDA)
in acetonitrile at room temperature provided 4-methoxyben-
zonitrile (2a) in 42% yield (Table 1, entry 3). This product
was not observed when the reaction was carried out in the
absence of either NaN3 or PIDA (Table 1, entries 1 and 2).
Notably, catalytic amounts of CuCl facilitated this trans-
formation, giving 2a in 55% yield (cf. Table 1, entries 3 and
4). The oxidant played an essential role in this transformation.
Attempts at using other organic or inorganic oxidants such as
ceric ammonium nitrate (CAN), Mn(OAc)3, and PhIO were
not successful (see Table S3 in the Supporting Information).
The yield of 2a decreased to 8% when Me3SiN3 was used
instead of NaN3 (Table 1, entry 7). Further studies indicated
that the efficiency of this transformation was not affected by
the addition of water, base, or Lewis acid (see Tables S3 and
S4 in the Supporting Information). We screened a number of
different parameters (see the Supporting Information) and
found that the direct transformation facilitated by
[*] W. Zhou, Dr. L. Zhang, Dr. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Road 38, Beijing 100191 (China)
Fax: (+86)10-8280-5297
E-mail: jiaoning@bjmu.edu.cn
Dr. N. Jiao
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
[**] Financial support from Peking University, the National Science
Foundation of China (nos. 20702002, 20872003), and the National
Basic Research Program of China (973 Program; grant no.
2009CB825300) is greatly appreciated. We thank Chun Zhang for
reproducing the results of entries 4 and 9 in Table 2.
.
CuSO4 5H2O using acetonitrile as the solvent at room
temperature was the most efficient (58% yield, Table 1,
entry 8). The optimized conditions providing the highest yield
(71%) are listed in entry 9, Table 1. The yields decreased
when the salts of other metals such as Co, In, Zn, or Fe were
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903838.
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employed instead of CuSO4·5H2O (see Table S4 in the
Supporting Information). Even with loadings of 8.0 equiv
NaN3 and 6.4 equiv PIDA, the yield did not increase
significantly in the absence of the copper salt (cf. Table 1,
entries 9–11).
As this reaction proceeds under mild and neutral con-
ditions, it may be useful for the preparation of functionalized
aryl nitriles from the corresponding toluenes avoiding the
decomposition of the functional group. To explore the
substrate scope, we examined a wide range of substituted
toluenes. Reactions of para-heteroatom-substituted toluenes
with electron-donating groups proceeded efficiently
(Table 2). Substrates with substituents at the meta and ortho
positions could be smoothly transformed into the correspond-
ing aryl nitriles, which indicated that steric interactions did
not significantly affect the reactivity (Table 2, entries 3–7 and
11). It is noteworthy that the para substituents, which serve as
the directing groups, are important for this transformation.
Hence, 1g reacted highly regioselectively to give 2g, in which
the meta methyl group is untouched, in 76% yield (Table 2,
entry 7). Furthermore, para hydroxy groups protected as
methoxymethyl (MOM) and tert-butyldiphenylsilyl (TBDPS)
ethers, protecting groups that are easily cleaved, are ame-
nable to further functional group transformations and can
serve as efficient directing groups (Table 2, entries 9 and 10).
Moreover, halogen-substituted toluenes are also suitable
substrates leading to halogen-substituted aryl nitriles
(Table 2, entry 11). Intriguingly, protected para-toluidines
reacted smoothly (2m was formed in 44% yield; Table 2,
entry 13); in contrast, the synthesis of these para-amino-
benzonitriles by other methods from simple and inexpensive
starting materials would normally require at least three steps.
Notably, para-methylbiphenyl also exhibited good reactivity,
and 4-phenylbenzonitrile (2n) was obtained in 45% yield
(Table 2, entry 14).
Table 2: Direct transformation of methyl arenes 1 to aryl nitriles 2.[a]
This transformation provides diverse opportunities for
application to organic synthesis. For example, tetrazole
analogue 6 related to Disoxaril[6] (Scheme 1) has broad-
Entry
Substrate
Product
Yield [%][b]
1
2
71
65
3
4
86
96
5
52
6
7
31
76
8
83
50
95
Scheme 1. Synthesis of a tetrazole analogue related to Disoxaril.
Reagents and conditions: a) 1. TsCl, pyridine, À20 to À108C, 96%;
2. 2,4,6-trimethylphenol, K2CO3, butan-2-one, reflux, 90%; b) n-
9
=
C3H7CH NOH, N-chlorosuccinimide, pyridine, CHCl3, 75%; c) NaN3,
PIDA, CuSO4·5H2O, CH3CN, 258C, 32%; d) 1. NaN3, NH4Cl, DMF,
1208C; 2. CH3I, K2CO3, CH3CN, 608C, 50% for 2 steps. Ts=toluene-
sulfonyl.
10
11
12
29
77
spectrum antipicornavirus activity, exhibiting MIC80 values on
the order of 0.20 mm for 15 rhinovirus serotypes. In the
reported method, tetrazole analogue 6 was prepared from
4-hydroxy-3,5-dimethylbenzonitrile.[6] Alternatively, we envi-
sioned that 6 could be synthesized with our presented
transformation as the key step from inexpensive and easily
available 2,4,6-trimethylphenol.[7] The aryl nitrile intermedi-
ate 5 was prepared with high regioselectivity from the
functionalized methyl arene 4 as the key step; this trans-
13
14
44
45
[a] Reaction conditions:
(1.6 mmol), CuSO4·5H2O (0.025 mmol) in acetonitrile (4 mL) at 258C
under N2. [b] Yield of isolated product. Boc=tert-butoxycarbonyl.
1 (0.5 mmol), NaN3 (2.0 mmol), PIDA
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Communications
formation could hardly be realized by the gas-phase ammox-
(SET)[11] of 12 oxidated by PIDA.[8a] Then cation 13, which is
stabilized by the a-N3 and para substituent on the aromatic
ring, undergoes a rearrangement like the Schmidt reaction[12]
to afford product 2.
Some deliberate reactions for an in-depth understanding
of the mechanism have been investigated (see Scheme 3 and
the Supporting Information). When the reaction of para-
methylanisole (1a) was conducted under O2, 4-methoxybenz-
aldehyde (15) was obtained in 16% yield along with a trace of
benzylic azide 7a (Scheme 3); the transformation of 1a was
idation of methyl arenes with ammonia and molecular
oxygen.[5] Tetrazole analogue 6 was prepared in an overall
yield of 10%, which is similar to that of the reported method
from 4-hydroxy-3,5-dimethylbenzonitrile;[6] however, in the
former case the starting material (2,4,6-trimethylphenol) is
much cheaper than 4-hydroxy-3,5-dimethylbenzonitrile.[7]
During this process, small amounts of benzylic azide 7
were observed. To probe the reaction mechanism, 7a and 8a
were subjected to the optimized conditions. Interestingly, 7a
was cleanly converted to 2a [Eq. (2)]. However, 8a provided
2a in 56% yield with 44% recovery of 8a [Eq. (3)].
Scheme 3. The reaction of para-methylanisole (1a) in the presence of
O2.
On the basis of these preliminary results, a reasonable
mechanism of this transformation is hypothesized
(Scheme 2). Radical species 9 and 10 are initially produced
completely inhibited by dioxygen. On the other hand, the
formation of 4-methoxybenzaldehyde (15) implicates that
the process proceeds via radical intermediate 11a. Radical
11a is then trapped by dioxygen to provide peroxy radical
14,[13] which is eventually converted into 4-methoxyben-
zaldehyde (Scheme 3).[14] Neither 2a nor 15 were observed
in the absence of NaN3 (see the Supporting Information).
In summary, we have developed a unique and novel
method for the direct transformation of methyl arenes to
aryl nitriles at room temperature. To the best of our
knowledge, this is the first direct conversion of a methyl
group to a cyano group under mild and neutral conditions.
À
During this transformation, three C H bonds are cleaved.
This observation not only provides a new synthetic tool for
constructing synthetically and medicinally important aryl
À
nitriles, but also offers an opportunity to achieve C H
Scheme 2. Proposed mechanism for the direct transformation.
functionalization under mild conditions. Further studies on
the reaction scope and synthetic applications are ongoing
in our group.
through the reaction of PIDA and NaN3.[8] Then the azide
radical 9 attacks substrate 1 to generate the benzylic radical
11, followed by the formation of benzylic azide 7.[9] Since the
conversion of 7a to 2a was not observed in the absence of
PIDA or NaN3 (see Equations S1 and S2 in the Supporting
Information), these results indicate that the reaction between
PIDA and NaN3 generating radical species 9 and 10 is
important for this transformation. We hypothesize that
further abstraction of a proton from benzylic azide 7 by the
radical 9 forms radical 12. Although path Avia intermediate 8
is possible,[10] we consider that the transformation is more
likely to occur through path B, because 8 was not detected
during this transformation and the result of Equation (3) is
also unreasonable. In path B the benzylic cation 13 is
produced through copper-promoted single electron transfer
Experimental Section
4-methoxybenzonitrile (2a):[15] 4-Methoxytoluene (1a) (0.5 mmol,
61 mg) was added to a mixture of PIDA (0.53 mmol, 172 mg), NaN3
(0.67 mmol, 44 mg), and CuSO4·5H2O (0.025 mmol, 6.2 mg) in
acetonitrile (4 mL) at À408C under N2, and then the reaction mixture
was degassed. The reaction mixture was stirred at room temperature
for 2 h, then two further portions of PIDA (171 mg each time) and
NaN3 (44 mg each time) were added, once every 2 h. After further
2 h, the resulting mixture was filtered, concentrated to dryness, and
purified by flash chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1) to afford 47 mg (71%) of 2a as a solid:
1H NMR (CDCl3, 300 MHz): d = 7.51 (d, J = 8.9 Hz, 2H), 6.87 (m, J =
8.9 Hz, 2H), 3.78 ppm (s, 3H); 13C NMR (CDCl3, 75 MHz): d = 162.8,
~
133.9, 119.2, 114.7, 103.9, 55.5 ppm; IR (neat): n = 2924, 2219, 1606,
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1510, 1461, 1260, 1176, 1024, 832 cmÀ1; MS (70 eV): m/z (%) 133.1
(M+, 100).
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Received: July 14, 2009
Published online: August 24, 2009
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À
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