Transformation of aromatic bromides into aromatic nitriles via formations of grignard reagents and their DMF adducts

Article abstract of DOI:10.1016/j.tetlet.2011.02.110

Various aromatic bromides were efficiently transformed into the corresponding aromatic nitriles in good yields via the formations of Grignard reagents and subsequently N,N-dimethyl formamide (DMF) adducts, followed by treatment with molecular iodine (I₂) in aq NH₃ at room temperature. The present reaction is an easy and practical method for the preparation of aromatic nitriles from aromatic bromides with less toxic reagents, such as Mg, DMF, I₂, and aq NH₃.

Full text of DOI:10.1016/j.tetlet.2011.02.110

Tetrahedron Letters 52 (2011) 2404–2406
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Transformation of aromatic bromides into aromatic nitriles via formations
of grignard reagents and their DMF adducts
⇑
Genki Ishii, Katsuhiko Moriyama, Hideo Togo
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Various aromatic bromides were efficiently transformed into the corresponding aromatic nitriles in good
yields via the formations of Grignard reagents and subsequently N,N-dimethyl formamide (DMF) adducts,
followed by treatment with molecular iodine (I2) in aq NH3 at room temperature. The present reaction is
an easy and practical method for the preparation of aromatic nitriles from aromatic bromides with less
toxic reagents, such as Mg, DMF, I2, and aq NH3.
Received 4 February 2011
Revised 22 February 2011
Accepted 25 February 2011
Available online 3 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Aromatic nitriles are one of the most important synthetic pre-
cursors for organic synthesis because they can be easily trans-
formed into esters, amides, carboxylic acids, amines, amidines,
ketones, and nitrogen-containing heterocycles, such as tetrazoles,
oxazoles, and natural products. Moreover, aromatic nitriles are
used as pharmaceuticals, liquid crystals, dyes, and synthetic inter-
mediates for agrochemicals, pharmaceuticals, and functional mate-
rials.1 For example, Citalopram hydrobromideÒ (treatment of
alcohol dependency), PericiazineÒ (anti-psychotic drug), Fadroz-
oleÒ (oncolytic drug), LetrozoleÒ (breast cancer therapy), Bicaluta-
mide (prostate cancer and breast cancer therapies), and Etravirine
(anti-HIV) are pharmaceutically important aromatic nitriles,2 and
4-cyano-40-pentylbiphenyl is a typical liquid crystal material. The
most general methods for the preparation of aromatic nitriles in-
clude the dehydration of aromatic amides (primary amides) with
SOCl2, TsCl/Py, P2O5, POCl3, COCl2, or Ph3P/CCl4.3 Aromatic alde-
hydes can be also used for the preparation of aromatic nitriles
via the dehydration of the corresponding aldoximes formed.4 Other
general and conventional methods for the preparation of aromatic
nitriles are the Sandmeyer reaction of aromatic diazonium ion with
toxic CuCN3a,5 and the Rosenmund–von Braun reaction with aro-
matic halides and toxic CuCN at high temperature.6 Recently, the
latter reaction has been actively studied and the reaction condi-
tions have been improved as follows: aromatic bromides were
converted into the corresponding aromatic nitriles with CuCN at
DMF refluxing temperature,7a Pd(OAc)2ꢀK4[Fe(CN)6] at 120 °C,7b
Pdꢀ(binaphthyl)P(But)2ꢀZn(CN)2ꢀZn at 80–95 °C,7c Pd2(dba)3ꢀZn-
(CN)2ꢀDPPF at 80–120 °C,7d Pd(tmhd)2ꢀK4[Fe(CN)6] at 80 °C,7e
Zn(CN)2ꢀPd2(dba)3 at 100 °C,7f Pd/CꢀCuIꢀK4[Fe(CN)6]ꢀ3H2O at
130–140 °C,7g CuIꢀalkylimidazoleꢀPd/CꢀCuIꢀK4[Fe(CN)6] at 140–
180 °C,7h Zn(CN)2ꢀPd2(dba)3ꢀdppfꢀZnꢀZnBr2 at 95 °C,7i CuOꢀPdꢀK4
[Fe(CN)6] at 120 °C,7j Pd(OAc)2ꢀCu(OAc)2ꢀK4[Fe(CN)6]7k at 130 °C,
and CuIꢀK4[Fe(CN)6]7l at 175 °C, most of which require toxic metal
cyanides. The direct and catalytic cyanation of aromatics contain-
ing a 2-pyridyl group via C–H bond cleavage with Cu(OAc)2ꢀTMSC-
N8a and Pd(OAc)2ꢀCuBrꢀCuCN,8b which also requires toxic metal
cyanides again, and with Pd(OAc)2ꢀCuBr2ꢀDMFꢀaq NH3 at 130 °C,8c
has been reported. Moreover, the direct and catalytic cyanation
of heteroaromatics, such as indoles and benzothiazoles, with
CuCNꢀI2ꢀNaCNꢀphenanthroline at 110 °C8d, Pd(OAc)2ꢀCuCNꢀCuBr2
at 130 °C8e, and Pd(OAc)2ꢀK4[Fe(CN)6]ꢀCu(OAc)2 at 130 °C8f was also
reported recently. To the best of our knowledge, methods for prep-
arations of aromatic nitriles from aromatic bromides under mild
conditions with less toxic reagents are extremely limited. Very re-
cently, an attractive method for the preparation of aromatic nitriles
from aromatic bromides via the formation of Grignard reagents,
followed by the reaction with N-cyanobenzimidazole as a cyano
group source, was reported.9 However, N-cyanobenzimidazole is
not easily available and must be prepared. Thus, there are still no
easy, practical, and general methods for the environmentally be-
nign and efficient preparation of aromatic nitriles from aromatic
bromides. On the other hand, molecular iodine (I2) is one of the
simplest oxidants currently available. It is highly affordable and
has very low toxicity. In view of environmentally benign organic
synthesis, I2 has been used in various organic reactions, including
the oxidation of alcohols or aldehydes to esters, the oxidation of
sulfides to sulfoxides, the introduction of protecting groups, the
deprotection of protecting groups, iodocyclization, carbon–carbon
bond formation, and the formation of heterocycles.10
Recently, we reported a direct, efficient, practical, and low-tox-
icity method for the oxidative conversion of benzylic alcohols and
benzylic halides into the corresponding aromatic nitriles using I2 in
aq NH3.11g–i In those reactions, aromatic aldehydes could be also
smoothly converted into the corresponding aromatic nitriles with
I2 in aq NH3 at room temperature.11b,g,12 Moreover, very recently,
we reported the first practical metal-free one-pot conversion of
electron-rich aromatics into the corresponding aromatic nitriles
⇑
Corresponding author.
E-mail address: togo@faculty.chiba-u.jp (H. Togo).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.110

G. Ishii et al. / Tetrahedron Letters 52 (2011) 2404–2406
2405
Table 1
in good yields, via the formation of aromatic N,N-dimethyliminium
salts with POCl3 and, followed by the treatment with I2 in aq NH3.13
Another method is the preparation of aromatic nitriles by the reac-
tion of aromatic bromides and aromatics with n-BuLi and subse-
quently DMF, followed by the treatment with I2 in aq NH3.14
However, the latter method is not so practical for large scale exper-
iment because it is not so easy to control the reaction mixture at
low temperature (ꢁ70 °C) and to handle a large amount of n-BuLi.
As part of our studies on the use of I2 for organic synthesis,11 we
would like to report herein an easy and practical transformation
of aromatic bromides into the corresponding aromatic nitriles.
The reaction was conducted as follows.15 To a flask containing
Mg turnings was added p-bromotoluene in THF at room tempera-
ture. After the formation of Grignard reagent, DMF was added to
the reaction mixture. The obtained mixture was stirred for 2 h at
room temperature. Then, aq NH3 (28–30%) and I2 were added to
the reaction mixture. After being stirred overnight, the mixture
was poured into aq sat. Na2SO3 solution and extracted with CHCl3.
After removal of solvent and short column chromatography, p-tol-
unitrile was obtained in 67% yield, as shown in Table 1 (entry 1).
The same treatment of m-bromotoluene, o-bromotoluene,
Transformation of aromatic bromides into aromatic nitriles
Entry
1
Ar–
Yielda (%)
67
73
2
3
67
62
4
5
6
74
80
1-bromo-2,4-dimethylbenzene,
1-bromo-3,4-dimethylbenzene,
1-bromo-2,5-dimethylbenzene, 1-bromo-2,4,6-trimethylbenzene,
p-bromoanisole, 1-bromo-2,4-dimethoxybenzene, 1-bromo-2,4,6-
trimethoxybenzene, p-bromo-N,N-dimethylaniline, 1-bromonaph-
thalene, 2-bromonaphthalene, and 4-bromobiphenyl with Mg
and subsequently DMF, followed by the reaction with I2 and aq
NH3, generated the corresponding aromatic nitriles in good yields
(entries 2–14). 1-Bromo-4-chlorobenzene and 1-bromo-4-fluoro-
benzene bearing an electron-withdrawing group were also treated
with Mg, DMF, I2, and aq NH3 to provide 4-chlorobenzonitrile and
4-fluorobenzonitrile, respectively, in good yields (entries 15 and
16). The same treatment of p-iodotoluene and 2-bromothiophene
with Mg and subsequently DMF, followed by the reaction with I2
and aq NH3 provided p-tolunitrile and 2-cyanothiophene in good
yields (entries 17 and 20). However, p-tolunitrile was not obtained
at all by the reaction of p-chlorotoluene with Mg, DMF, I2, and aq
NH3 under the same conditions (entry 18), and the starting mate-
rial was recovered. Treatment of 1-bromo-3-cyanobenzene, which
has an electron-withdrawing group, with i-PrMgCl16 and subse-
quently DMF, followed by the reaction with I2 and aq NH3 gave
1,3-dicyanobenzene in good yield (entry 19). Aliphatic nitriles,
such as 1-bromoadamantane, 1-bromooctane, could be also trans-
formed into the corresponding nitriles in moderate yields, using
the present method (entries 21 and 22). The present method can
be used for large scale experiment. Practically, p-tolunitrile was
obtained in 75% yield starting from 30 mmol of p-bromotoluene
under the same conditions.
7
79
8
9
84
77
10
64
11
12
62
62
13
14
65
64
15
61
69
80
16
Plausible reaction mechanism is shown in Scheme 1. Thus, after
the formation of Grignard reagent (a), it reacts with DMF to give
adduct (b). The addition of I2 and aq NH3 induces the formation
of aromatic aldehyde (d) and aromatic imine (e), and (e) further
reacts with I2 to form N-iodo aromatic imine (f). Once N-iodo
aromatic imine (f) is formed, HI elimination smoothly occurs by
the reaction with NH3 to give aromatic nitrile. As mentioned
before,11b,g,12 aromatic aldehydes could be smoothly transformed
into the corresponding aromatic nitriles by the reaction with I2
and aq NH3 at room temperature.
17b
18c
0
19
20
71
70
In conclusion, various aromatic bromides, such as bromotolu-
enes, bromodimethylbenzenes, bromotrimethylbenzene, bromo-
anisole, bromodimethoxybenzenes, bromotrimethoxybenzene,
bromonaphthalenes, bromobiphenyl, and bromothiophene could
be smoothly transformed into the corresponding aromatic nitriles
in good yields at room temperature by treatment with Mg and sub-
sequently with DMF, followed by a treatment with I2 in aq NH3.
Aliphatic bromides could be also transformed into the correspond-
21
61
60
22
CH3(CH2)7–
a
Isolated yield.
b
p-Iodotoluene instead of p-bromotoluene was used, and LiBr (1.2 equiv) was
added at first.
c
p-Chlorotoulene instead of p-bromotoluene was used.

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G. Ishii et al. / Tetrahedron Letters 52 (2011) 2404–2406
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ing aliphatic nitirles in good yields by the same treatment with Mg,
DMF, I2, and aq NH3. The present reaction is an easy and practical
method for the preparation of nitriles from various aromatic and
aliphatic bromides through the formation of Grignard reagents
and their DMF adducts, and can be used for large scale experi-
ments. Further synthetic study of the present reaction is under
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Acknowledgments
Financial support in the form of a Grant-in-Aid for Scientific
Research (No. 20550033) from the Ministry of Education, Culture,
Sports, Science, and Technology in Japan, Iodine Research Project
in Chiba University, Academia Showcase Research Grant from the
Japan Chemical Innovation Institute (JCII), and Futaba Electronics
Memorial Foundation is gratefully acknowledged.
13. Ushijima, S.; Togo, H. Synlett 2010, 1067.
14. Ushijima, S.; Togo, H. Synlett 2010, 1562.
15. Typical experimental procedure for the transformation of aromatic bromides into
aromatic nitriles: To a flask containing Mg turnings (0.28 g, 14 mmol) was
added p-bromotoluene (1.38 g, 8.0 mmol) in THF (8 mL) at room temperature.
After being stirred for 2 h, DMF (1.3 mL, 12 mmol) was added to the reaction
mixture. The obtained mixture was stirred for 2 h at room temperature. Then,
aq NH3 (7 mL, 28–30%) and I2 (4.06 g, 1.6 mmol) were added to the reaction
mixture. After being stirred overnight, the reaction mixture was poured into aq
sat. Na2SO3 solution and extracted with CHCl3 (3 ꢂ 30 mL). The organic layer
was dried over Na2SO4 and filtered. After removal of the solvent, the residue
was purified by short column chromatography on silica gel (eluent: hexane /
ethyl acetate = 9:1, v/v) to provide pure p-tolunitrile (0.77 g) in 67% yield. Most
aromatic nitriles mentioned in this work are commercially available and were
identified by comparison with the authentic samples.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.110.
References and notes
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4-methylbenzonitrile: Mp 26–28 °C (commercial, Mp 26–28 °C); IR: 2227 cmꢁ1
;
1H NMR (CDCl3: 500 MHz) d = 2.41 (s, 3H), 7.26 (d, J = 8.1 Hz, 2H), 7.52 (d,
J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) d = 21.7, 109.2, 119.1, 129.7, 131.9,
143.6.
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