One-pot transformation of methylarenes into aromatic nitriles with inorganic metal-free reagents

Article abstract of DOI:10.1002/ejoc.201402270

Various methylarenes were transformed into the corresponding aromatic nitriles in good to moderate yields by the treatment with aq. HBr and aq. H ₂O₂, followed by reaction with molecular iodine and aq. ammonia in a one-pot procedure. The present reaction is a useful, practical, transition-metal-free, and organic-reagent-free method for the preparation of aromatic nitriles from methylarenes. Various methylarenes were treated with aq. HBr and aq. H₂O₂ under warming conditions and/or irradiation conditions, followed by the reaction with molecular iodine and aq. ammonia, to provide the corresponding aromatic nitriles, in a one-pot procedure. The present reaction was carried out under metal-free and organic-reagent-free conditions. Copyright

Full text of DOI:10.1002/ejoc.201402270

FULL PAPER
DOI: 10.1002/ejoc.201402270
One-Pot Transformation of Methylarenes into Aromatic Nitriles with
Inorganic Metal-Free Reagents
Yuhsuke Kawagoe,[a] Katsuhiko Moriyama,[a] and Hideo Togo*[a]
Keywords: Synthetic methods / Oxidation / Bromine / Iodine / Aromatic nitriles
Various methylarenes were transformed into the correspond- The present reaction is a useful, practical, transition-metal-
ing aromatic nitriles in good to moderate yields by the treat-
ment with aq. HBr and aq. H2O2, followed by reaction with
molecular iodine and aq. ammonia in a one-pot procedure.
free, and organic-reagent-free method for the preparation of
aromatic nitriles from methylarenes.
for electron-rich methylarenes. A third transformation
method, which was reported very recently, involves the
treatment of methylarenes with N-hydroxyphthalimide and
tert-butylnitrite in the presence of Pd(OAc)2 catalyst, an ex-
pensive transition-metal reagent, at 70 °C for 24 h.[6c] We
have previously reported a cyanide-free and transition-
metal-free one-pot conversion of methylarenes into aro-
matic nitriles by treatment with N-bromosuccinimide (NBS)
or 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the
presence of a catalytic amount of benzoyl peroxide (BPO)
or 2,2Ј-azobis(isobutyronitrile) (AIBN), followed by the re-
action with molecular iodine in aq. ammonia.[7] However,
because this reaction requires organic molecules, such as
NBS or DBDMH and AIBN or BPO, stoichiometric
amounts of organic molecules, such as succinimide or 5,5-
dimethylhydantoin, and other organic compounds derived
from the radical initiator, are formed and those organic co-
products must be removed carefully from the reaction mix-
ture by column chromatography. In addition, this method
is not suitable for large-scale reactions. Here, to establish
a practical, transition-metal-free, and organic-reagent-free
preparation of aromatic nitriles from methylarenes. We re-
port the transformation of methylarenes into aromatic
nitriles through the reaction with aq. HBr and aq. H2O2,
followed by the reaction with molecular iodine and aq.
ammonia.
Introduction
Aromatic nitriles are one of the most important organic
compounds because they serve as building blocks in organic
synthesis, especially for the preparation of pharmaceuticals,
agrochemicals, natural products, dyes, and herbicides.[1] Cit-
alopram hydrobromide® (treatment of alcohol depen-
dency), Periciazine® (antipsychotic drug), Fadrozole® (on-
colytic drug), and Letrozole® (breast cancer therapy) are
pharmaceutically important aromatic nitriles, and 4-cyano-
4Ј-pentylbiphenyl is a typical liquid-crystal material.[2] In
general, aromatic nitriles are prepared by the dehydration
of primary aromatic amides[3] or by the Sandmeyer reaction
of an aromatic diazonium ion with toxic CuCN.[4] Recently,
the direct transformation of aromatic bromides into the
corresponding aromatic nitriles with CuCN in N,N-dimeth-
ylformamide (DMF) under heating conditions (the Rosen-
mund-von Braun reaction) has been studied,[5a] and many
other related reactions with palladium and metal cyanide
under heating conditions have been actively studied as
well.[5b–5r] All of those reactions require toxic metal cya-
nides, however, the one-pot oxidative transformation of
methylarenes into aromatic nitriles is very attractive be-
cause various methylarenes are easily available. However, to
the best of our knowledge, studies of the one-pot transfor-
mation of methylarenes into aromatic nitriles are quite lim-
ited. One transformation method requires high tempera-
tures (360–460 °C) and uses ammonia and oxygen in the
presence of (VO)2P2O7 catalyst.[6a] A second transformation
method involves the reaction of methylarenes with excess
toxic NaN3 and (diacetoxyiodo)benzene in the presence of
CuSO4 catalyst at room temperature,[6b] and is only effective
Results and Discussion
The effective transformation of benzylic halides into aro-
matic nitriles with molecular iodine (2.1–2.5 equiv.) and aq.
ammonia (28–30%, 3 mL) at 60 °C was previously reported
by us.[8] Based on those results, 4-bromotoluene (1a) was
treated with aq. HBr (1.0 equiv., 3.0 equiv., and 4.0 equiv.)
and aq. H2O2 (ca. 30% in water; 2.0 equiv. and 4.0 equiv.)
at 60 °C or 80 °C for a few hours in water, nitromethane,
acetonitrile, 1,2-dichloroethane (DCE), carbon tetrachlor-
[a] Graduate School of Science, Chiba University,
Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
http://reaction-2.chem.chiba-u.jp/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402270.
Eur. J. Org. Chem. 2014, 4115–4122
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. Kawagoe, K. Moriyama, H. Togo
FULL PAPER
ide, or without solvent (neat), followed by the reaction whereas in the previous method, organic wastes, such as
with molecular iodine (2.5 equiv.) and aq. ammonia (28– succinimide or 5,5-dimethylhydantoin, and co-products de-
30%, 3 mL) at 60 °C for 4 h, as shown in Table 1, Entries 1– rived from the radical initiators used had to be carefully
10. As a result, treatment of 4-bromotoluene (1a) with aq. removed by column chromatography, with NBS or
HBr (3.0 equiv.) and aq. H2O2 (2.0 equiv.) in water at 60 °C DBDMH and AIBN or BPO.[7] Here, after the first reaction
for 1 h, followed by the reaction with molecular iodine step that involves 4-bromotoluene (1a), aq. HBr
(2.5 equiv.) and aq. ammonia (3 mL) at 60 °C for 4 h pro- (3.0 equiv.), and aq. H2O2 (2.0 equiv.) at 60 °C for 1 h, 4-
vided 4-bromobenzonitrile (2a) in 91% yield (Table 1, En- bromobenzyl bromide was obtained in 85% isolated yield.
try 4; Method A) with high purity by simple extraction of Thus, the reaction intermediate after the first reaction step
the reaction mixture with chloroform. In the present case, was 4-bromobenzyl bromide, and it was smoothly trans-
4-bromobenzonitrile (2a) was obtained in high yield with formed into 4-bromobenzonitrile (2a) by reaction with mo-
high purity by simple extraction of the reaction mixture, lecular iodine and aq. ammonia at 60 °C for 4 h. When
other bromide sources, such as LiBr, KBr, MgBr2, and tet-
rabutylammonium bromide (TBAB), were used under the
Table 1. One-pot transformation of 4-bromotoluene to 4-bromo-
same procedure and conditions, 4-bromobenzonitrile (2a)
benzonitrile.
was not obtained at all (Table 1, Entries 11–14). However,
when aq. H2O2 was replaced with tert-butyl hydrogen per-
oxide (TBHP), K2S2O8, di-tert-butyl peroxide (DTBP), or
tBuOCl under the same procedure and conditions, 4-
bromobenzonitrile (2a) was obtained in low yield with
TBHP and tBuOCl, and in moderate yield with K2S2O8,
Entry Oxidant
“Br”
Solvent Temp. Time Yield
but was not obtained at all with DTBP (Table 1, Entries 15–
18). Finally, when HCl was used under the same procedure
and conditions, 4-bromobenzonitrile (2a) was not obtained
at all (Table 1, Entry 19). In addition, when aq. HBr or aq.
H2O2 was not used under the same procedure and condi-
tions, 4-bromobenzonitrile (2a) was again not obtained at
[°C]
[h]
[%]
1
aq. H2O2
aq. HBr
H2O
H2O
H2O
H2O
H2O
neat
80
1
85
(4.0 equiv.) (4.0 equiv.)
aq. H2O2 aq. HBr
(4.0 equiv.) (4.0 equiv.)
aq. H2O2 aq. HBr
(4.0 equiv.) (4.0 equiv.)
aq. H2O2 aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 aq. HBr
(2.0 equiv.) (1.0 equiv.)
aq. H2O2 aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 LiBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 KBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 MgBr2
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 TBAB
(2.0 equiv.) (3.0 equiv.)
TBHP aq. HBr
(2.0 equiv.) (3.0 equiv.)
K2S2O8 aq. HBr
(2.0 equiv.) (3.0 equiv.)
DTBP aq. HBr
(2.0 equiv.) (3.0 equiv.)
tBuOCl aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 aq. HCl
(2.0 equiv.) (3.0 equiv.)
2
80
80
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
3
5
1
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
80
75
91
63
90
0
3
4
Table 2. One-pot transformation of 4-methoxytoluene to 4-meth-
oxybenzonitrile.
5
6
7
MeNO2
MeCN
DCE
CCl4
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
8
13
38
45
0
9
10
11
12
13
14
15
16
17
18
19
20
21
Entry Oxidant
“Br”
Solvent
Time
[h]
Yield
[%]
2r
2s
0
1[a]
2
aq. H2O2 aq. HBr
(2.0 equiv.) (3.0 equiv.)
aq. H2O2 aq. HBr
H2O
CCl4
1
2
Ͻ5
63
87
16
0
Ͻ5
0
0
0
(2.0 equiv.) (3.0 equiv.) (0.25 m)
aq. H2O2 aq. HBr CCl4
(2.0 equiv.) (3.0 equiv.) (0.25 m)
aq. H2O2 aq. HBr CH2Cl2
(2.0 equiv.) (3.0 equiv.) (0.25 m)
aq. H2O2 aq. HBr CCl4
(2.0 equiv.) (3.0 equiv.) (2.0 m)
aq. H2O2 LiBr CCl4
(2.0 equiv.) (3.0 equiv.) (0.25 m)
aq. H2O2 KBr CCl4
(2.0 equiv.) (3.0 equiv.) (0.25 m)
TBHP aq. HBr CCl4
(2.0 equiv.) (3.0 equiv.) (0.25 m)
K2S2O8 aq. HBr CCl4
(2.0 equiv.) (3.0 equiv.) (0.25 m)
0
3
0.5
1
14
62
0
4
81
99
0
5
1
6
1
0
31
0
7
1
0
0
8
1
16
Ͻ5
0
aq. H2O2
(2.0 equiv.)
–
–
0
9
1
0
aq. HBr
(3.0 equiv.)
0
[a] The first reaction step was carried out at 60 °C for 1 h, instead
of irradiation with a tungsten lamp.
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One-Pot Transformation of Methylarenes into Aromatic Nitriles
all (Table 1, Entries 20 and 21). Thus, the present reaction chloride, 4-methoxybenzonitrile (2r) was obtained in mod-
requires both aq. HBr and aq. H2O2 for the formation of erate yield, as shown in Table 2, Entry 2). Thus, when 4-
4-bromobenzyl bromide. When 4-methoxytoluene (1r), methoxytoluene (1r) was treated with aq. HBr (3.0 equiv.)
which has an electron-rich aromatic ring, was treated with and aq. H2O2 (2.0 equiv.) in carbon tetrachloride (0.25 m,
aq. HBr (3.0 equiv.) and aq. H2O2 (2.0 equiv.) at 60 °C for diluted conditions) at 20 °C for 0.5 h, followed by reaction
1 h, and then treated with molecular iodine (2.5 equiv.) and with molecular iodine (2.5 equiv.) and aq. ammonia, 4-
aq. ammonia (3 mL) at 60 °C for 4 h (Method A), the yield methoxybenzonitrile (2r) was obtained in 87% yield as a
of 4-methoxybenzonitrile (2r) was trace owing to bromina- single product with high purity by simple extraction of the
tion of the aromatic ring of 4-methoxytoluene as the first reaction mixture with chloroform (Table 2, Entry 3;
reaction step to form 3-bromo-4-methoxytoluene and con- Method B). When dichloromethane was used instead of
sumption of the bromide source (Table 2, Entry 1). How- carbon tetrachloride and the reaction was performed under
ever, when the reaction was carried out under irradiation the same procedure and conditions, 3-bromo-4-methoxy-
conditions with a tungsten lamp at 20 °C and the solvent benzonitrile (2s) was obtained in 81% yield, together with
was changed to a less polar solvent, such as carbon tetra- 4-methoxybenzonitorile (2r) in 16% yield (Table 2, En-
Table 3. One-pot transformation of methylarenes to aromatic nitriles.
[a] The reaction was carried out under concentrated conditions (2.0 m solution of substrate). [b] I2 (5.0 equiv.) was added in the second
reaction step. [c] The first reaction step was carried out at 80 °C. [d] I2 (4.0 equiv.) was added in the second reaction step. [e] The second
reaction step was carried out at 80 °C. [f] I2 (6.0 equiv.) was added in the second reaction step. [g] The first reaction step was carried out
in diluted concentration (0.1 m solution of substrate). [h] H2O2 (1.5 equiv.) and aq. HBr (2.0 equiv.) were added. [i] At the second reaction
step, aq. NH3 was added and the mixture was stirred for 4 h at 60 °C, and then, I2 (5.0 equiv.) was added and the mixture was stirred
for 15 h at 60 °C. [j] H2O2 (3.0 equiv.) and aq. HBr (4.5 equiv.) were added in the first reaction step.
Eur. J. Org. Chem. 2014, 4115–4122
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Y. Kawagoe, K. Moriyama, H. Togo
FULL PAPER
try 4). This is owing to the bromination of the aromatic in carbon tetrachloride in 2.0 m solution of substrate (0.1 m
ring of 4-methoxytoluene (1r) and the subsequent radical solution for 3,4-dimethoxytoluene) under irradiation with a
bromination of the benzylic position in dichloromethane, tungsten lamp at 20 °C (Method B), followed by treatment
which is more polar than carbon tetrachloride, in the first with molecular iodine and aq. ammonia, 4-bromo-1-cyano-
reaction step. When 4-methoxytoluene (1r) was treated with naphthalene (2o), 5-bromo-2-methoxybenzonitrile (2u), and
aq. HBr (3.0 equiv.) and aq. H2O2 (2.0 equiv.) in carbon 2-bromo-4,5-dimethoxybenzonitrile (2v) were obtained in
tetrachloride (2 m, concentrated conditions) at 20 °C for high yields, respectively (Table 3, Entries 15, 21, and 22).
1 h, followed by the reaction with molecular iodine Heteroaromatics that bear a methyl group, such as 1-phen-
(2.5 equiv.) and aq. ammonia, 3-bromo-4-methoxybenzo- ylsulfonyl-3-methylindole (1x) and 3-methylbenzothiophene
nitrile (2s) was obtained in 99% yield as a single product (1y), could be also transformed into the corresponding het-
with high purity by simple extraction of the reaction mix- eroaromatic nitriles in moderate yields, respectively, with
ture with chloroform (Table 2, Entry 5). Thus, 4-methoxy- Method B followed by reaction with molecular iodine and
benzonitrile (2r) and 3-bromo-4-methoxybenzonitrile (2s) aq. ammonia (Table 3, Entries 24, 25). Finally, 4,4Ј-dimeth-
can be prepared with high selectivity, respectively, by the ylbenzophenone (1z), m-xylene, and p-xylene could be also
same procedure with different concentrations of the sub- transformed into corresponding aromatic dinitriles 2z, 2aa,
strate in the case of Method B. When aq. HBr was changed and 2g in good to moderate yields, respectively, with
to LiBr or KBr, or aq. H2O2 was changed to TBHP or Method B (aq. HBr: 4.5 equiv. and aq. H2O2: 3.0 equiv.)
K2S2O8, and the reaction was performed under the same followed by reaction with molecular iodine and aq. ammo-
procedure and conditions, 4-bromobenzonitrile (2r) was not nia. A plausible reaction pathway is shown in Scheme 1.
obtained (Table 2, Entries 6–9).
Methylarene reacts with molecular bromine, which is
Based on the fundamental studies, various methylarenes formed in situ by the reaction of hydrogen bromide with
bearing bromo, chloro, iodo, benzoyl, cyano, methylsulf- hydrogen peroxide, to give a benzylic bromide through the
onyl, nitro, hydroxycarbonyl, and ethoxycarbonyl groups, formation of benzylic radical. This is the Wohl–Ziegler re-
as well as methylnaphthalenes, were treated with aq. HBr action[9] with hydrogen bromide and hydrogen peroxide,
and aq. H2O2 under warming conditions (60 °C) in water which generates a small amount of molecular bromine in
(Method A) or irradiation conditions with a tungsten lamp solution, instead of NBS or DBDMH with AIBN or BPO
in carbon tetrachloride at 20 °C (Method B), followed by as the radical initiator. Once benzylic bromide is formed, it
the reaction with molecular iodine and aq. ammonia to smoothly reacts with ammonia to give a primary benzylic
provide the corresponding aromatic nitriles, as shown in amine, which further reacts with molecular iodine to pro-
Table 3. 4-Chlorotoluene (1d) was transformed into 4- vide an aromatic nitrile through the formation of an imine,
chlorobenzonitrile (2d) in good yield by using Method A N-iodo imine, and then its β-elimination. Practically, benz-
and the subsequent treatment with molecular iodine and ylic bromides could be obtained in over 85% yields by the
aq. ammonia, although the same reaction with Method B reaction of methylarenes with aq. HBr and aq. H2O2 under
provided the corresponding aromatic nitrile in low yield warming conditions at 60 °C or irradiation conditions with
(Table 3, Entry 4). For 2-bromotoluene (1b), 3-bromotolu- a tungsten lamp at 20 °C.
ene (1c), 4-iodotoluene (1e), 4-cyanotoluene (1g), and 4-
nitrotoluene (1i), both Method A and Method B could be
used to give the corresponding aromatic nitriles in good to
moderate yields, respectively, after subsequent treatment
with molecular iodine and aq. ammonia (Table 3, Entries 2,
3, 5, 7, and 9). In contrast, treatment of 4-benzoyltoluene
(1f), 4-(methylsulfonyl)toluene (1h), 4-methylbenzoic acid
(1j), ethyl 4-methylbenzoate (1k), toluene (1l), 2-methyl-
anthraquinone (1m), 1-methylnaphthalene (1n), 2-methyl-
naphthalene (1p), 4-phenyltoluene (1q), 2-methoxytoluene
(1t), and 4-tert-butyltoluene (1w) with aq. HBr and aq.
H2O2 in carbon tetrachloride under irradiation conditions
with a tungsten lamp at 20 °C (Method B), followed by re-
action with molecular iodine and aq. ammonia provided
corresponding aromatic nitriles 2f, 2h, 2j, 2k, 2l, 2m, 2n,
2p, 2q, 2t, and 2w in good to moderate yields, respectively,
although the same reactions under warming conditions at
60 °C (Method A), instead of irradiation with a tungsten
lamp, did not give aromatic nitriles (Table 3, Entries 6, 8,
Scheme 1. Plausible reaction pathway.
10–14, 16, 17, 20, and 23). Moreover, when electron-rich
methylarenes, such as 1-methylnaphthalene (1n), 2-meth-
oxytoluene (1t), and 3,4-dimethoxytoluene (1v), were
Finally, the present method was used for the preparation
treated with aq. HBr (3.0 equiv.) and aq. H2O2 (2.0 equiv.) of Letrozole®[1d] from 4,4Ј-dimethylbenzophenone (1z).
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One-Pot Transformation of Methylarenes into Aromatic Nitriles
Scheme 2.
HBr (concentration: 47.0–49.0%, 3.0 mmol, 0.5 mL) at room tem-
perature, and the mixture was stirred for 20 min at 60 °C. Then, aq.
H2O2 (concentration: 30.0–35.5%, 2.0 mmol, 0.23 mL) was added
dropwise, and the mixture was stirred for 1 h at 60 °C. After cool-
ing to room temperature, CH3CN (2.0 mL), aq. NH3 (concentra-
tion: 28.0–30.0 mL, 3.0 mL), and I2 (2.5 mmol, 634.5 mg) were
added to the mixture at room temperature, and stirred for 4 h at
60 °C. The reaction mixture were cooled to room temperature and
quenched by satd. aq. Na2SO3 (15 mL). The mixture was extracted
with CHCl3 (20 mL ϫ 3) and then, the organic layer was dried
with Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by short column chromatography on silica
gel (EtOAc/hexane = 1:9) to afford 4-bromobenzonitrile (2a) in
91% yield (165.6 mg).
Compound 1z was transformed into 4,4Ј-dicyanobenzo-
phenone (2z) by the present method in 74% yield. Then, 2z
was reduced to alcohol 3 in 100% yield by reduction with
NaBH4, and alcohol 3 was treated with MsCl and Et3N to
form mesylate 4. Finally, Letrozole® (5) was obtained in
67% yield (two steps) by reaction of mesylate 4 with tri-
azole in the presence of K2CO3, as shown in Scheme 2.
Conclusions
Various methylarenes were transformed into the corre-
sponding aromatic nitriles in good to moderate yields by
treatment with aq. HBr and aq. H2O2 under warming con-
ditions at 60 °C in water (Method A) or under irradiation
conditions with a tungsten lamp in carbon tetrachloride
(Method B), followed by the reaction with molecular iodine
and aq. ammonia in a one-pot procedure. Overall, Method
B is a better choice than Method A to give the correspond-
ing aromatic nitriles in good yields, from methylarenes. Fi-
nally, Method B was used for the preparation of Letrozole®
from 4,4Ј-dimethylbenzophenone in good yield. The present
reaction is a useful, practical, transition-metal-free, and or-
ganic-reagent-free method for the preparation of aromatic
nitriles from methylarenes.
General Procedure. Method B: To a solution of 4-methoxytoluene
(1r; 1.0 mmol, 122.2 mg) and aq. HBr (concentration: 47.0–49.0%,
3.0 mmol) in CCl4 (4.0 mL) was added dropwise aq. H2O2 (concen-
tration: 30.0–35.5%, 2.0 mmol, 0.23 mL) at room temperature
slowly, and the mixture was stirred for 30 min under irradiation
with a tungsten lamp (200 W) at 20 °C. Then, CH3CN (2.0 mL),
aq. NH3 (concentration: 28.0–30.0 mL, 3.0 mL), and I2 (2.5 mmol,
634.5 mg) were added to the mixture at room temperature, and
stirred for 4 h at 60 °C. The reaction mixture were cooled to room
temperature and quenched by satd. aq. Na2SO3 (15 mL). The mix-
ture was extracted with CHCl3 (20 mL ϫ 3) and then, the organic
layer was dried with Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by short column
chromatography on silica gel (EtOAc/hexane = 1:9) to afford 4-
methoxybenzonitile (2r) in 87% yield (115.8 mg).
Experimental Section
4-Bromobenzonitrile (2a, commercially available): Yield, Method A:
165.6 mg (91%), Method B: 45.5 mg (25%). White solid, m.p. 111–
General: 1H NMR and 13C NMR spectra were obtained with
JEOL-JNM-ECX400, JEOL-JNM-ECS400, and JEOL-JNM-
ECA500 spectrometers. Chemical shifts are expressed in ppm
downfield from TMS. Mass spectra were recorded with JMS-
T100GCV, JMS-HX110, and Thermo LTQ Orbitrap XL spectrom-
eters. IR spectra were measured with a JASCO FT/IR-4100 spec-
trometer. Melting points were determined with a Yamato Melting
Point Apparatus Model MP-21. Silica gel 60F254 (Merck) was used
for TLC and Silica gel 60 (Kanto Kagaku Co.) was used for short
column chromatography.
1
112 °C. IR (neat): ν = 2224 cm–1. H NMR (500 MHz, CDCl ): δ
˜
3
= 7.53 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 8.4 Hz, 2 H) ppm. 13C
NMR (125 Hz, CDCl3): δ = 111.18, 118.04, 127.99, 132.61,
133.37 ppm.
2-Bromobenzonitrile (2b, commercially available): Yield, Method A:
118.3 mg (65%), Method B: 176.6 mg (97%). White solid, m.p. 55–
56 °C. IR (neat): ν = 2224 cm–1. 1H NMR (500 MHz, CDCl ): δ =
˜
3
7.42–7.49 (m, 2 H), 7.65–7.71 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 115.71, 117.14, 125.25, 127.60, 133.18, 133.87,
134.31 ppm.
General Procedure. Method A: To a solution of 4-bromotoluene
(1a; 1.0 mmol, 171.0 mg) in distilled water (1.0 mL) was added aq.
Eur. J. Org. Chem. 2014, 4115–4122
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4119

Y. Kawagoe, K. Moriyama, H. Togo
FULL PAPER
3-Bromobenzonitrile (2c, commercially available): Yield, Method A:
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 112.26, 118.75, 129.01,
100.1 mg (55%), Method B: 134.7 mg (74%). White solid, m.p. 38–
132.01, 132.68 ppm.
39 °C. IR (neat): ν = 2233 cm–1. 1H NMR (500 MHz, CDCl ): δ =
˜
3
9,10-Dioxo-9,10-dihydroanthracene-2-carbonitrile (2m, commer-
7.37 (t, J = 7.9 Hz, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.74–7.76 (m,
1 H), 7.80 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 114.15,
117.25, 122.86, 130.67, 130.67, 134.71, 136.08 ppm.
cially available): Yield, Method A: – (0%), Method B: 135.3 (58%).
Yellow solid, m.p. 207–209 °C. IR (neat): ν = 1673, 2232 cm–1. H
1
˜
NMR (500 MHz, CDCl3): δ = 7.86–7.89 (m, 2 H), 8.07 (dd, J =
8.0, 1.5 Hz, 1 H), 8.31–8.36 (m, 2 H), 8.43 (d, J = 8.0 Hz, 1 H),
8.60 (dd, J = 1.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
117.17, 117.72, 127.57 (2 C), 128.01, 131.27, 132.94, 133.07, 133.79,
134.82, 134.84, 135.60, 136.61, 181.17, 181.65 ppm.
4-Chlorobenzonitrile (2d, commercially available): Yield, Method A:
119.7 mg (87%), Method B: 24.8 mg (18%). White solid, m.p. 90–
91 °C. IR (neat): ν = 2225 cm–1. 1H NMR (500 MHz, CDCl ): δ =
˜
3
7.47 (d, J = 8.6 Hz, 2 H), 7.61 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 110.75, 117.94, 129.67, 133.35, 139.52 ppm.
1-Naphthonitrile (2n, commercially available): Yield, Method A:
– (0%), Method B: 111.8 mg (73%). White solid, m.p. 36–37 °C.
4-Iodobenzonitrile (2e, commercially available): Yield, Method A:
91.6 mg (40%), Method B: 148.9 mg (65%). White solid, m.p. 125–
1
IR (neat): ν = 2224 cm–1. H NMR (500 MHz, CDCl ): δ = 7.53
˜
3
1
126 °C. IR (neat): ν = 2226 cm–1. H NMR (500 MHz, CDCl ): δ
(t, J = 7.8 Hz, 1 H), 7.60–7.72 (m, 2 H), 7.90–7.93 (m, 2 H), 8.08
(d, J = 8.3 Hz, 1 H), 8.24 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 109.96, 117.68, 124.76, 124.92, 127.39,
128.43, 128.52, 132.15, 132.45, 132.73, 133.13 ppm.
˜
3
= 7.32 (d, J = 8.3 Hz, 2 H), 7.85 (d, J = 8.3 Hz, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 100.30, 111.73, 118.22, 133.15,
138.50 ppm.
4-Bromo-1-naphthonitrile (2o, commercially available): Yield,
4-Cyanobenzophenone (2f, commercially available): Yield, Method
Method A: – (trace), Method B: 185.7 mg (80%). White solid, m.p.
A: 12.4 mg (6%), Method B: 172.0 mg (83%). White solid, m.p.
100–101 °C. IR (neat): ν = 2217 cm–1. 1H NMR (500 MHz,
˜
1
110–111 °C. IR (neat): ν = 1650, 2226 cm–1. H NMR (500 MHz,
˜
CDCl3): δ = 7.71–7.77 (m, 3 H), 7.85 (d, J = 7.7 Hz, 1 H), 8.24 (d,
J = 7.4 Hz, 1 H), 8.32 (d, J = 7.4 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 110.13, 117.23, 125.69, 128.03, 128.96 (2
C), 129.24, 129.42, 131.84, 132.31, 133.13 ppm.
CDCl3): δ = 7.52 (dd, J = 7.5, 8.0 Hz, 2 H), 7.63–7.66 (m, 1 H),
7.78–7.81 (m, 4 H), 7.88 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 115.65, 117.99, 128.61, 130.04, 130.20,
132.14, 133.30, 136.31, 141.21, 195.01 ppm.
2-Naphthonitrile (2p, commercially available): Yield, Method A:
– (0%), Method B: 104.2 mg (68%). White solid, m.p. 65–66 °C.
Terephthalonitrile (2g, commercially available): Yield, Method A:
64.1 mg (50%), Method B: 126.8 mg (99%) from 4-cyanotoluene,
yield Method A: 7.7 mg (6%), Method B: 78.2 mg (61%) from p-
1
IR (neat): ν = 2225 cm–1. H NMR (500 MHz, CDCl ): δ = 7.60–
˜
3
7.67 (m, 3 H), 7.89–7.93 (m, 3 H), 8.24 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 109.36, 119.25, 126.33, 127.64, 128.04,
128.40, 129.02, 129.18, 132.23, 134.14, 134.63 ppm.
xylene. White solid, m.p. 219–220 °C. IR (neat): ν = 2231 cm–1. 1H
˜
NMR (500 MHz, CDCl3): δ = 7.80 (s, 4 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 116.70, 116.98, 132.77 ppm.
[1,1Ј-Biphenyl]-4-carbonitrile (2q, commercially available): Yield,
4-Methylsulfonylbenzonitrile (2h, commercially available): Yield,
Method A: – (0%), Method B: 179.2 mg (Ͼ99%). White solid, m.p.
Method A: 14.5 mg (8%), Method B: 163.1 mg (90%). White solid,
1
85–86 °C. IR (neat): ν = 2225 cm–1. H NMR (500 MHz, CDCl ):
˜
3
1
m.p. 141–142 °C. IR (neat): ν = 1146, 1327, 2237 cm–1. H NMR
˜
δ = 7.41 (t, J = 7.7 Hz, 1 H), 7.48 (dd, J = 7.7, 7.2 Hz, 2 H), 7.58
(d, J = 7.2 Hz, 2 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 110.78, 118.87, 127.13,
127.64, 128.60, 129.02, 132.50, 139.05, 145.55 ppm.
(500 MHz, CDCl3): δ = 3.10 (s, 3 H), 7.90 (d, J = 8.6 Hz, 2 H),
8.01 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
44.24, 117.01, 117.62, 128.20, 133.19, 144.44 ppm.
4-Nitrobenzonitrile (2i, commercially available): Yield, Method A:
4-Methoxybenzonitrile (2r, commercially available): Yield, Method
106.6 mg (72%), Method B: 74.6 mg (50%). Yellow solid, m.p. 145–
A: – (0%), Method B: 115.8 mg (87%). White solid, m.p. 58–59 °C.
146 °C. IR (neat): ν = 1346, 1521, 2233 cm–1. 1H NMR (500 MHz,
˜
1
IR (neat): ν = 2216 cm–1. H NMR (500 MHz, CDCl ): δ = 3.86
˜
3
CDCl3): δ = 7.90 (d, J = 8.9 Hz, 2 H), 8.34 (d, J = 8.9 Hz, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 116.75, 118.30, 124.25,
133.44, 150.02 ppm.
(s, 3 H), 6.95 (d, J = 8.9 Hz, 2 H), 7.59 (d, J = 8.9 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 55.48, 103.88, 114.69, 119.17,
133.91, 162.78 ppm.
4-Cyanobenzoic Acid (2j, commercially available): Yield, Method A:
3-Bromo-4-methoxybenzonitrile (2s, commercially available): Yield,
Method A: – (0%), Method B: 212.0 mg (Ͼ99%). White solid, m.p.
10.3 mg (7%), Method B: 110.3 mg (75%). White solid, m.p. 215–
1
216 °C. IR (neat): ν = 1685, 2231cm–1. H NMR (500 MHz, [D ]-
120–121 °C. IR (neat): ν = 2224 cm–1. 1H NMR (500 MHz,
˜
6
˜
DMSO): δ = 7.92 (d, J = 8.5 Hz, 2 H), 8.04 (d, J = 8.5 Hz, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 115.15, 118.23, 129.96,
132.67, 134.87, 166.11 ppm.
CDCl3): δ = 3.97 (s, 3 H), 6.95 (d, J = 8.6 Hz, 1 H), 7.60 (dd, J =
8.6, 2.0 Hz, 1 H), 7.83 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 56.54, 105.23, 111.87, 112.31, 117.72,
133.13, 136.67, 159.41 ppm.
Ethyl 4-Cyanobenzoate (2k, commercially available): Yield, Method
A: – (0%), Method B: 113.9 mg (65%). White solid, m.p. 52–54 °C.
2-Methoxybenzonitrile (2t, commercially available): Yield, Method
IR (neat): ν = 1185, 1715, 2229 cm–1. 1H NMR (500 MHz, CDCl ):
˜
A: – (trace), Method B: 97.2 mg (73%). Colorless oil. IR (neat): ν
3
˜
= 2225 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.94 (s, 3 H), 6.97–
7.03 (m, 2 H), 7.53–7.56 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 55.92, 101.69, 111.21, 116.46, 120.69, 133.68, 134.34,
161.16 ppm
δ = 1.42 (t, J = 7.1 Hz, 3 H), 4.43 (q, J = 7.1 Hz, 2 H), 7.67 (d, J
= 8.6 Hz, 2 H), 8.15 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.03, 61.60, 116.04, 117.80, 129.85,
131.99, 134.08, 164.70 ppm.
Benzonitrile (2l, commercially available): Yield, Method A: 37.1 mg
5-Bromo-2-methoxybenzonitrile (2u, commercially available): Yield,
(36%), Method B: 72.2 mg (70%). Colorless oil. IR (neat): ν =
Method A: – (0%), Method B: 161.2 mg (72%). White solid, m.p.
˜
2228 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.48 (dd, J = 8.1,
7.5 Hz, 2 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.65 (d, J = 8.1 Hz, 2
90–91 °C. IR (neat): ν = 2227 cm–1. H NMR (500 MHz, CDCl ):
1
˜
3
δ = 3.93 (s, 3 H), 6.87 (d, J = 8.9 Hz, 1 H), 7.64 (dd, J = 8.9,
4120
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4115–4122

One-Pot Transformation of Methylarenes into Aromatic Nitriles
2.5 Hz, 1 H), 7.66 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR (125 MHz,
To a solution of 4,4Ј-dicyanobenzophenone (2z, 0.25 mmol,
CDCl3): δ = 56.25, 103.31, 112.06, 113.0, 114.85, 135.55, 137.12, 58.1 mg) in dry MeOH (1.5 mL) was added NaBH4 (0.375 mmol,
160.18 ppm.
15.4 mg) at 0 °C, and the mixture was stirred for 30 min. The reac-
tion mixture was quenched by the addition of cooled water
(5.0 mL), and was extracted with EtOAc (20.0 mL ϫ 3). The or-
ganic layer was washed with brine (20.0 mL) and dried with
Na2SO4. After removal of solvent under reduced pressure, the resi-
due was purified by short column chromatography on silica gel
(eluent: EtOAc) to afford bis(4-cyanophenyl)methanol (3) in quan-
2-Bromo-4,5-dimethoxybenzonitrile (2v): Yield, Method A: – (0%),
Method B: 174.3 mg (72%). White solid, m.p. 115–117 °C. IR
(neat): ν = 2229 cm–1. H NMR (500 MHz, CDCl ): δ = 3.89 (s, 3
1
˜
3
H), 3.94 (s, 3 H), 7.05 (s, 1 H), 7.08 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 56.30, 56.43, 106.79, 115.14, 115.40,
117.51, 117.58, 148.42, 153.10 ppm. HRMS (APCI): calcd. for
C9H879BrNO2 [M]+ 240.9733; found 240.9727.
titative yield (58.7 mg). White solid, m.p. 156–157 °C. IR (neat): ν
˜
1
= 2225, 3423 cm–1. H NMR (500 MHz, CDCl3): δ = 3.05 (d, J =
4-tert-Butylbenzonitrile (2w, commercially available): Yield, Method
0.3 Hz, 1 H), 5.91 (d, J = 0.3 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 4 H),
7.61 (d, J = 8.0 Hz, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
74.68, 111.62, 118.43, 127.10, 132.47, 147.79 ppm.
A: 76.4 mg (48%), Method B: 143.3 mg (90%). Pale yellow oil. IR
(neat): ν = 2227 cm–1. H NMR (500 MHz, CDCl ): δ = 1.36 (s, 9
1
˜
3
H), 7.49 (d, J = 8.6 Hz, 2 H), 7.58 (d, J = 8.6 Hz, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 30.83, 35.15, 109.17, 119.05, 126.07,
131.85, 156.52 ppm
To
a solution of bis(4-cyanophenyl)methanol (3, 1.0 mmol,
234.3 mg) in dry CH2Cl2 (10.0 mL) were added methanesulfonyl
chloride (2.0 mmol, 0.16 mL) and triethylamine (2.0 mmol,
0.28 mL), and the mixture was stirred for 8 h at room temperature.
After the reaction, the solvent was removed under reduced pres-
sure. The obtained residue including bis(4-cyanophenyl)methyl
methanesulfonate (4) was dissolved in dry CH3CN (10.0 mL). To
the mixture were added triazole (4.0 mmol, 281.9 mg) and K2CO3
(4.0 mmol, 552.5 mg). The mixture was stirred for 24 h at 60 °C.
After cooling to room temperature, the reaction mixture was
quenched with water (10.0 mL) and extracted with CH2Cl2
(20.0 mL ϫ 3). The organic layer was washed with brine (20.0 mL)
and dried with Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by short column chromatography
on silica gel (EtOAc/hexane = 5:1) to afford Letrozole (5) in 67%
yield (191.2 mg) in two steps.
1-(Phenylsulfonyl)-1H-indole-3-carbonitrile (2x): Yield, Method B:
135.5 mg (48%). Pale yellow solid, m.p. 148–149 °C. IR (neat): ν =
˜
1136, 1376, 2225 cm–1. H NMR (500 MHz, CDCl3): δ = 7.39 (t,
1
J = 8.2 Hz, 1 H), 7.46 (t, J = 8.2 Hz, 1 H), 7.53 (t, J = 8.3 Hz, 2
H), 7.64 (t, J = 8.3 Hz, 1 H), 7.71 (d, J = 8.2 Hz, 1 H), 7.96 (d, J
= 8.3 Hz, 2 H), 8.01 (d, J = 8.2 Hz, 1 H), 8.11 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 93.93, 113.37, 113.73, 120.33,
124.87, 126.62, 127.13, 128.29, 129.77, 133.06, 133.64, 134.90,
137.08 ppm. HRMS (ESI): calcd. for C15H10N2O2SNa [M]+
305.0355; found 305.0351.
Benzo[b]thiophene-3-carbonitrile (2y, commercially available): Yield,
Method B: 100.3 mg (63%). Colorless solid, m.p. 72–73 °C. IR
(neat): ν = 2222 cm–1. H NMR (500 MHz, CDCl ): δ = 7.50 (dd,
1
˜
3
J = 8.0, 0.9 Hz, 1 H), 7.55 (dd, J = 8.0, 7.8 Hz, 1 H), 7.92 (dd, J
= 8.3, 0.9 Hz, 1 H), 8.01 (dd, J = 8.3, 7.8 Hz, 1 H), 8.13 (s, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 107.07, 114.31, 122.52,
122.81, 125.96, 126.16, 137.23, 137.54, 138.46 ppm.
Letrozole 5: Yield 191.1 mg (67%). White solid, m.p. 183–185 °C
(commercially available). IR (neat): ν = 2229 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 6.81 (s, 1 H), 7.29 (d, J = 8.5 Hz, 4 H),
7.71 (d, J = 8.5 Hz, 4 H), 8.07 (s, 1 H), 8.09 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 66.36, 113.28, 117.82, 128.90,
132.91, 141.75, 143.67, 153.06 ppm.
4,4Ј-Dicyanobenzophenone (2z, commercially available): Yield,
Method A: 32.5 mg (14%), Method B: 171.9 mg (74%). White so-
lid, m.p. 160–161 °C. IR (neat): ν = 1665, 2226 cm–1. 1H NMR
˜
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H NMR and 13C NMR spectra of all aromatic
nitriles 2, compound 3, and Letrozole (5).
(500 MHz, CDCl3): δ = 7.84 (d, J = 8.6 Hz, 4 H), 7.89 (d, J =
8.6 Hz, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 116.42,
117.60, 130.17, 132.38, 139.66, 193.37 ppm.
Isophthalonitrile (2aa, commercially available): Yield, Method A:
Acknowledgments
– (0%), Method B: 51.3 mg (40%). White solid, m.p. 159–160 °C.
1
IR (neat): ν = 2233 cm–1. H NMR (500 MHz, CDCl ): δ = 7.67
˜
3
Financial support by the Ministry of Education, Culture, Sports,
Science, and Technology in Japan in the form of a Grant-in-Aid
for Scientific Research (grant number 25105710) and by Chiba
University (Iodine Research Project) is gratefully acknowledged.
(t, J = 7.8 Hz, 1 H), 7.91 (dd, J = 7.8, 1.5 Hz, 2 H), 7.97 (t, J =
1.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 114.12,
116.59, 130.31, 135.38, 135.97 ppm.
Preparation of Letrozole 5: To a solution of 4,4Ј-dimethylbenzo-
phenone (1z, 1.0 mmol, 210.3 mg) and aq. HBr (concentration:
47.0–49.0%, 4.5 mmol, 0.75 mL) in CCl4 (4.0 mL) was added aq.
H2O2 (concentration: 30.0–35.5%, 3.0 mmol, 0.35 mL) at room
temperature slowly, and the mixture was stirred for 2 h under irra-
diation with a tungsten lamp (200 W) at 20 °C. Then, CH3CN
(2.0 mL), aq. NH3 (concentration: 28.0–30.0 mL, 3.0 mL), and I2
(6.0 mmol, 1.521 g) were added at room temperature, and the mix-
ture was stirred for 48 h at 60 °C. The reaction mixture was cooled
to room temperature and quenched by the addition of satd. aq.
Na2SO3 (15.0 mL). The mixture was extracted with CHCl3
(20.0 mL ϫ 3) and then, the organic layer was dried with Na2SO4.
After removal of the solvent under reduced pressure, the residue
was purified by short column chromatography on silica gel (EtOAc/
hexane = 1:4) to afford 4,4Ј-dicyanobenzophenone (2z) in 74%
yield (171.9 mg).
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4121

Y. Kawagoe, K. Moriyama, H. Togo
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Received: March 16, 2014
Published Online: May 19, 2014
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