Facile one-pot transformation of arenes into aromatic nitriles under metal-cyanide-free conditions

Article abstract of DOI:10.1002/ejoc.201403672

Electron-rich arenes bearing methyl or methoxy groups on the aromatic ring were treated with dichloromethyl methyl ether and ZnBr₂, and then with molecular iodine and aq. ammonia to give the corresponding aromatic nitriles in good yields. Using this method, febuxostat was efficiently prepared from 4-bromophenol in four steps. The method can be used for the preparation of aromatic nitriles from arenes in one pot under metal-cyanide-free conditions. Various electron-rich arenes could be effectively converted into the corresponding aromatic nitriles in good yields, by treatment with ZnBr₂ and dichloromethyl methyl ether, followed by reaction with molecular iodine and aq. ammonia.

Full text of DOI:10.1002/ejoc.201403672

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201403672
Facile One-Pot Transformation of Arenes into Aromatic Nitriles under
Metal-Cyanide-Free Conditions
Toshiyuki Tamura,[a] Katsuhiko Moriyama,[a] and Hideo Togo*[a]
Keywords: Synthetic methods / Oxidation / Aromatic substitution / Cyanides / Iodine
Electron-rich arenes bearing methyl or methoxy groups on
the aromatic ring were treated with dichloromethyl methyl
yields. Using this method, febuxostat was efficiently pre-
pared from 4-bromophenol in four steps. The method can be
ether and ZnBr2, and then with molecular iodine and aq. am- used for the preparation of aromatic nitriles from arenes in
monia to give the corresponding aromatic nitriles in good
one pot under metal-cyanide-free conditions.
120 °C,[6g] Pd(OAc)2/Cu(OAc)2/K4[Fe(CN)6] at 130 °C,[6h]
CuI/K4[Fe(CN)6] at 175 °C,[6i] Pd(dba)2/K4[Fe(CN)6] at
Introduction
Aromatic nitriles are some of the most important com-
pounds for organic synthesis.[1,2] They are intermediates in
the synthesis of aromatic amides, carboxylic acids, amines,
aldehydes, ketones, and nitrogen-containing heterocycles[2]
such as tetrazoles, imidazoles, oxazoles, thiazoles, and selen-
azoles. Moreover, some important pharmaceuticals are aro-
matic nitriles,[2] and examples include Citalopram hydro-
bromide (treatment of alcohol dependency), Periciazine
(antipsychotic drug), Fadrozole (oncolytic drug), Letrozole
(breast cancer therapy), Bicalutamide (prostate cancer and
breast cancer therapy), and Etravirine (anti-HIV). 4-Cyano-
4Ј-pentylbiphenyl is one of the typical liquid-crystal materi-
als.
The most well-known methods for the preparation of
aromatic nitriles include the dehydration of primary aro-
matic amides with SOCl2, TsCl/pyridine, P2O5, POCl3,
COCl2, or Ph3P/CCl4,[3] and the Sandmeyer reaction, which
requires aromatic diazonium halides and toxic CuCN.[3,4]
Recently, the direct conversion of aromatic bromides into
the corresponding aromatic nitriles, i.e., the Rosenmund–
von Braun reaction[5] using CuCN in refluxing DMF, and
related reactions using Pd and metal cyanides at high tem-
perature[1c,6] have been actively studied. In recent studies,
various reagents and conditions were reported for the reac-
tions of aromatic halides, including Zn(CN)2/Pd2(dba)3
(dba = dibenzylideneacetone) at 100 °C,[6c] Pd–C/CuI/
K4[Fe(CN)6]/3H2O at 130–140 °C,[6d] CuI/alkylimidazole/
Pd–C/CuI/K4[Fe(CN)6] at 140–180 °C,[6e] Zn(CN)2/
Pd2(dba)3/dppf/Zn/ZnBr2 [dppf = 1,1Ј-bis(diphenylphos-
phino)ferrocene] at 95 °C,[6f] CuO/Pd/K4[Fe(CN)6] at
50 °C,[6j]
P[(NC5H10)(C6H11)2]2PdCl2/K4[Fe(CN)6]
at
140 °C,[6k] Pd(Ph3P)4/DBU/K4[Fe(CN)6] (DBU = 1,8-diaza-
bicycloundec-7-ene) at 85 °C,[6l] Pd{C6H4[CH2N(CH2Ph)2]-
(μ-Br)2}/K4[Fe(CN)6] at 130 °C,[6m] and ZnO/Pd nanopar-
ticles/K4[Fe(CN)6] at 130 °C[6o] were reported. However,
these reactions require toxic metal cyanides and/or expens-
ive rare metals, such as Pd, and high temperatures. Some
metal-cyanide-free methods have also been reported. These
include the reaction of aryl bromides with Cu(OAc)2/DMF/
TMEDA (tetramethylethylenediamine) at 150 °C,[7a] the re-
action of 3-iodoindoles with Cu(CF3CO2)2/DMF at
130 °C,[7b] the reaction of aryl bromides with Cu(OAc)2/
Ag2O/Ph3PO/CH3CN at 125 °C,[7c] the reaction of indoles
and pyridines with Pd(OAc)2/Cu(CF3CO2)2/tBuNC at
70 °C,[7d] the CaCl3-catalysed cyanation of electron-rich ar-
enes with BrCN at 120 °C,[7e] the reaction of indoles and
pyrroles with PhI(CF3CO2)2 and TMSCN (TMS = trimeth-
ylsilyl) in the presence of BF3·Et2O at room temperature,[7f]
and the FeII-catalysed cyanation of arenes with aryl(cyano)-
iodonium triflates,[8] prepared from bis(trifluoroacetoxy)-
iodoarenes with TMSCN and TMSOTf.
We recently reported two metal-cyanide-free and transi-
tion-metal-free methods. Aryl bromides underwent a halo-
gen–metal exchange reaction by treatment with nBuLi or
Mg, and this was followed by treatment with DMF and
then reaction with molecular iodine and aq. ammonia to
generate the corresponding aromatic nitriles in good
yields.[9] Electron-rich aromatics underwent a Vilsmeier–
Haack reaction with POCl3 and DMF, and this was fol-
lowed by treatment with molecular iodine and aq. ammonia
to give the aromatic nitriles in good yields.[10] The latter
reaction is very useful, because it can be used for the one-
pot introduction of a cyano group into rather electron-rich
arenes under mild reaction conditions, such as at room tem-
perature or with warming, without using metal cyanides.
[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.201403672.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
T. Tamura, K. Moriyama, H. Togo
FULL PAPER
However, there are still disadvantages. For example, the in- (1.3 equiv.) in dichloromethane for 8 h at room temperature,
troduction of a cyano group into m-xylene, benzothiophene, followed by reaction with molecular iodine and aq. ammo-
or naphthalene is difficult, because the initial Vilsmeier– nia gave 1-cyano-2-methoxynaphthalene (2a) in 92% yield
Haack reaction of those arenes with DMF and POCl3 does (Table 1, entry 4). ZnI2 was also an effective catalyst under
not occur efficiently.[10] In addition, the introduction of a the same conditions, giving nitrile 2a in good yield (Table 1,
cyano group into allyl phenyl ether, bearing an olefinic entries 7–10). On the other hand, the same treatment of 2-
group, did not give the desired aromatic nitrile. Thus, it is methoxynaphthalene (1a) in the absence of ZnBr2 yielded
difficult to introduce a cyano group into certain arenes with none of nitrile 2a at all (Table 1, entry 11). AlCl3, FeCl3,
the POCl3 and DMF system.
and AgOTf were not effective Lewis acids for this reaction.
The introduction of a formyl group into electron-rich ar- Moreover, when iodoform, bromoform, chloroform, or tri-
enes using dichloromethyl methyl ether and a Lewis acid, methyl orthoformate, all of which represent equivalent
such as TiCl4,[11a] AlCl3,[11b,11c] AgOTf,[11d] or SnCl4,[11e] is synthons to dichloromethyl methyl ether, were used instead
a very attractive alternative, because the formylation pre- of dichloromethyl methyl ether under the same conditions,
cursor is formed from the Lewis acid and dichloromethyl nitrile 2a was not obtained at all (Table 1, entries 12–15).
methyl ether. In this article, as part of our research into Thus, initial treatment of 2-methoxynaphthalene (1a) with
applications of molecular iodine for organic synthesis,[12] we dichloromethyl methyl ether (2.0 equiv.) in the presence of
report a mild one-pot transformation of electron-rich ar- ZnBr2 (1.3 equiv.) in dichloromethane at room temperature,
enes into the corresponding aromatic nitriles by treatment followed by reaction with molecular iodine and aq. ammo-
with ZnBr2 and dichloromethyl methyl ether, followed by nia gave 1-cyano-2-methoxynaphthalene (2a) in the best
reaction with molecular iodine and aq. ammonia.
yield. Based on those results, 2-methylnaphthalene (1b), 1-
methoxynaphthalene (1c), and 1-methylnaphthalene (1d)
were treated with dichloromethyl methyl ether in the pres-
ence of ZnBr2 in dichloromethane at room temperature for
8–18 h, followed by treatment with molecular iodine and
aq. ammonia. This gave 1-cyano-2-methylnaphthalene (2b),
4-cyano-1-methoxynaphthalene (2c), and 4-cyano-1-methyl-
naphthalene (2d) in 73, 94, and 65% yields, respectively
(Table 2).
Results and Discussion
Treatment of a mixture of 2-methoxynaphthalene (1a)
and dichloromethyl methyl ether (2.0 equiv.) in the presence
of ZnBr2 or ZnCl2 in chloroform, 1,2-dichloroethane, and
dichloromethane at room temperature, followed by reaction
with molecular iodine and aq. ammonia gave 1-cyano-2-
methoxynaphthalene (2a), whereas the same reaction in
THF did not give 1-cyano-2-methoxynaphthalene (2a) at all
(Table 1, entries 1–5).
Similar treatment of naphthalene (1e), which was inert to
the POCl3/DMF system at 100 °C,[10] with dichloromethyl
methyl ether in the presence of ZnBr2 at room temperature,
followed by reaction with molecular iodine and aq. ammo-
nia at room temperature gave 1-cyanonaphthalene (2e) in
68% yield. The same treatment of 1,2,3,5-tetramethylbenz-
ene (1f), 1,2,4,5-tetramethylbenzene (1g), 1,2,3-trimethoxy-
benzene (1h), 1,2-dimethoxy-4-methylbenzene (1j), 1,3,5-tri-
methoxybenzene (1k), 1,3,5-trimethylbenzene (1l), 1,3-di-
methoxybenzene (1m), 3-methyl-1-methoxybenzene (1n),
1,3-dimethylbenzene (1o; inert to the POCl3/DMF system
at 100 °C), 4-methyl-1-methoxybenzene (1p), and 2-methyl-
1-methoxybenzene (1q) gave the corresponding nitriles (i.e.,
2f, 2g, 2h, 2j, 2k, 2l, 2m, 2n, 2o, 2p, and 2q) in good yields.
However, the same treatment of methyl 2,4-dimethoxy-
benzoate (1i), which has an electron-withdrawing ester
group, gave methyl 5-cyano-2,4-dimethoxybenzoate (2i) in
57% yield. When the procedure was scaled up (15 mmol)
with 1,3,5-trimethylbenzene (1l) under the same conditions,
2,4,6-trimethylbenzonitrile (2l) was obtained in 82% yield.
Thus, this reaction can be used for the semi-large-scale
preparation of aromatic nitriles from arenes. The same
treatment of 1-chloro-4-methoxybenzene (1r) and 1-bromo-
4-methoxybenzene (1s) provided the corresponding nitriles
(i.e., 2r and 2s) both in 68% yield. Similarly, treatment of
1,2-methylenedioxybenzene (1t) and 1,2-dimethoxybenzene
(1u) with dichloromethyl methyl ether in the presence of
ZnBr2 at room temperature, followed by reaction with
Table 1. One-pot transformation of 2-methoxynaphthalene into 1-
cyano-2-methoxynaphthalene.
Entry Lewis acid Additive
Solvent
Yield [%]
1
2
ZnBr2
ZnCl2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnI2
ZnI2
ZnI2
ZnI2
–
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
Cl2CHOCH3
CHI3
CHCl3
14
30
28
92
n.r.
69[b]
54
64
87
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
THF
CH2Cl2
ClCH2CH2Cl
CH2Cl2
CH2Cl2
THF
ClCH2CH2Cl
CH2Cl2
3
4[a]
5
6[b]
7
8
9[a]
10
11
12
13
14
15
ZnBr2
ZnBr2
ZnBr2
ZnBr2
CHBr3
CHCl3
CH(OCH3)3
CH2Cl2
CH2Cl2
CH2Cl2
[a] Reaction time for the first step was 8 h. [b] ZnBr2 (1.0 equiv.)
was used; n.r.: no reaction.
Treatment of a mixture of 2-methoxynaphthalene (1a) molecular iodine and aq. ammonia gave piperonylonitrile
and dichloromethyl methyl ether (2.0 equiv.) with ZnBr2 (2t) and 3,4-dimethoxybenzonitrile (2u), respectively, in
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
Transformation of Arenes into Aromatic Nitriles
Table 2. One-pot transformation of arenes into aromatic nitriles.
and allyl 4-methylphenyl ether (1x) also generated the cor-
responding nitriles (i.e., 2v, 2w, and 2x) in good yields. Fi-
nally, the same treatment of benzothiophene (1y), which
was inert to the POCl3/DMF system at 100 °C, and N-
methylindole (1z) gave nitriles 2y and 2z, respectively, in
good yields. Thus, this method can be used for the transfor-
mation of electron-rich arenes bearing functional groups,
such as methoxy, ester, halogen, and acetal groups, and car-
bon–carbon double bonds, into the corresponding aromatic
nitriles in good to moderate yields in a one-pot manner.
Finally, as a synthetic application of the present method,
febuxostat (a xanthine oxidase inhibitor that is well used for
the medical treatment of gout)[13] was efficiently prepared in
four steps from 4-bromophenol and also from 4-iodo-
phenol, as shown in Scheme 1. Treatment of 4-bromophenyl
isobutyl ether (1v) or 4-iodophenyl isobutyl ether (1w) with
dichloromethyl methyl ether in the presence of ZnBr2 in 1,2-
dichloroethane at 50 °C for 16 h, followed by reaction with
molecular iodine and aq. ammonia gave the corresponding
nitriles (i.e., 2v and 2w) in 65 and 60% yields, respectively.
Furthertreatmentofbromide2vandiodide2wwith5-(tert-but-
oxycarbonyl)-4-methylthiazole and tBuOLi in the presence
of Ni(OAc)2 gave the coupling product 3 in 53 and 60%
yields, respectively. Deprotection of compound 3 by treat-
ment with CF3CO2H gave febuxostat in 93% yield.
[a] 1,2-Dichloroethane was used as the solvent, and the reaction
temperature was 50 °C for the first step. [b] 1l (15 mmol) and
CH2Cl2 (30 mL) were used in the first step; aq. NH3 (10 mL) and
THF (15 mL) were used in the second step. [c] The reaction tem-
perature was –20 °C for the first step, and 0 °C for the second step.
Scheme 1. Preparation of febuxostat.
A possible mechanism for the reaction is shown in
Scheme 2. The electrophilic species formed from the reac-
tion of dichloromethyl methyl ether with ZnBr2 reacts with
good yields. Moreover, the same treatment of 4-bromo- aromatic ring by an SEAr pathway. The resulting (dichloro-
phenyl isobutyl ether (1v), 4-iodophenyl isobutyl ether (1w), methyl)arene reacts with aq. ammonia to form an aromatic
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
T. Tamura, K. Moriyama, H. Togo
FULL PAPER
solvent was removed under reduced pressure, and the residue was
purified by short column chromatography on silica gel to give the
corresponding aromatic nitriles.
imine. Once the imine is formed, it smoothly reacts with
molecular iodine to form the N-iodoimine. Subsequent eli-
mination of HI takes place to give the aromatic nitrile.
Here, formation of (dichloromethyl)arenes was observed by General Procedure for Arenes 1r, 1s, 1v, and 1w: A solution of
dichloromethyl methyl ether (2.0 mmol) in ClCH2CH2Cl (1.0 mL)
was added to a solution of arene (1.0 mmol) and dry ZnBr2
(1.3 mmol) in ClCH2CH2Cl (3.0 mL), and the mixture was stirred
for 15–16 h at 50 °C. The solvent was removed, and then NaOH
(4 n aq.; 1 mL) and dioxane (4 mL) were added. The resulting mix-
ture was stirred at 100 °C for 14 h. Finally, NH3 (28% aq.; 4 mL)
and iodine (2.5 mmol) were added to the reaction mixture, and the
resulting mixture was stirred for 6 h at room temperature. The reac-
tion mixture was quenched with satd. aq. Na2SO3 (10 mL). The
mixture was extracted with CHCl3 (3ϫ 20 mL), and then the com-
bined organic extracts were dried with Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified by
short column chromatography on silica gel to give the correspond-
ing aromatic nitriles.
NMR spectroscopy in high yields when the solvent was re-
moved after the reaction of arenes with dichloromethyl
methyl ether and ZnBr2.
2-Methoxynaphthonitrile (2a): Yield 168.5 mg (92%), solid, m.p.
94–95 °C. IR (chloroform): ν = 2213 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 4.04 (s, 3 H), 6.79 (d, J = 8.4 Hz, 1 H), 7.56 (t, J =
7.2 Hz, 1 H), 7.66 (t, J = 7.2 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H),
8.14 (d, J = 8.4 Hz, 1 H), 8.30 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 55.9, 101.7, 103.2, 118.4, 122.7, 124.8,
125.1, 126.6, 128.8, 133.3, 133.9, 159.3 ppm. HRMS (APCI): calcd.
for C12H10ON [M + H]+ 184.0753; found 184.0757.
Scheme 2. Plausible reaction mechanism.
Conclusions
Various electron-rich arenes bearing methyl, methoxy,
chloro, bromo, ester, or acetal, groups, or carbon–carbon
double bonds, etc. could be smoothly transformed into the
corresponding aromatic nitriles in good to moderate yields,
by treatment with dichloromethyl methyl ester in the pres-
ence of ZnBr2, followed by treatment with molecular iodine
and aq. ammonia. This method could be used for the prep-
aration of febuxostat from 4-bromophenol or 4-iodophenol
in four steps. We believe that this method is useful for the
preparation of aromatic nitriles from arenes, because the
reaction can be carried out under mild reaction conditions
without the use of toxic metal cyanides.
2-Methylnaphthonitrile (2b): Yield 122.0 mg (73%), solid, m.p. 85–
86 °C. IR (chloroform): ν = 2214 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 2.74 (s, 3 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.54 (t, J =
7.2 Hz, 1 H), 7.65 (t, J = 7.2 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H),
7.94 (d, J = 8.4 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.2, 109.2, 117.0, 124.8, 126.5, 127.6,
128.3, 128.5, 131.1, 132.5, 132.7, 142.9 ppm. HRMS (APCI): calcd.
for C12H10N [M + H]+ 168.0806; found 168.0808.
4-Methoxynaphthonitrile (2c): Yield 172.1 mg (94%), solid, m.p.
100–102 °C. IR (chloroform): ν = 2212 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 4.06 (s, 3 H), 6.82 (d, J = 8.0 Hz, 1 H), 7.57 (t, J =
8.4 Hz, 1 H), 7.68 (t, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 1 H),
8.15 (d, J = 8.4 Hz, 1 H), 8.30 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 55.9, 101.8, 103.2, 118.4, 122.7, 124.8,
125.1, 126.6, 128.9, 133.4, 134.0, 159.3 ppm. HRMS (APCI): calcd.
for C12H10ON [M + H]+ 184.0754; found 184.0757.
Experimental Section
General Remarks: 1H 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 tetramethylsilane in δ units. Mass spectra were re-
corded with JMS-T100GCV, JMS-HX110, and Thermo LTQ Or-
bitrap XL spectrometers. IR spectra were measured with a JASCO
FTIR-4100 spectrometer. Melting points were determined with a
Yamato MP-21 melting-point apparatus. Silica gel 60F254 (Merck)
was used for TLC, and silica gel 60 (Kanto Kagaku Co.) was used
for short column chromatography.
4-Methylnaphthonitrile (2d): Yield 108.6 mg (65%), solid, m.p. 52–
53 °C. IR (chloroform): ν = 2220 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 2.75 (s, 3 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.65 (t, J =
8.4 Hz, 1 H), 7.70 (t, J = 8.4 Hz, 1 H), 7.81 (d, J = 7.6 Hz, 1 H),
8.08 (d, J = 7.6 Hz, 1 H), 8.26 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 19.9, 108.3, 118.1, 124.7, 125.7, 125.8,
127.3, 128.1, 132.2, 132.3, 132.4, 140.9 ppm. HRMS (APCI): calcd.
for C12H10N [M + H]+ 168.0806; found 168.0808.
1-Naphthonitrile (2e): Yield 104.1 mg (68%), solid, m.p. 34–35 °C.
IR (chloroform): ν = 2222 cm–1. 1H NMR (400 MHz, CDCl ): δ =
˜
3
General Procedure: A solution of dichloromethyl methyl ether
(2.0 mmol) in CH2Cl2 (1.0 mL) was added to a solution of arene
(1.0 mmol) and dry ZnBr2 (1.3 mmol) in CH2Cl2 (3.0 mL) at room
temperature, and the mixture was stirred for 0.5–21 h at room tem-
perature or 50 °C, depending on the substrate. Then, NH3 (28%
aq.; 4 mL) and iodine (2.5 mmol) were added to the reaction mix-
ture, and the resulting mixture was stirred for 6 h at room tempera-
ture. The reaction mixture was quenched with satd. aq. Na2SO3
(10 mL). The mixture was extracted with CHCl3 (3ϫ 20 mL), and
then the combined organic extracts were dried with Na2SO4. The
7.52 (t, J = 8.7 Hz, 1 H), 7.62 (t, J = 8.2 Hz, 1 H), 7.70 (t, J =
8.2 Hz, 1 H), 7.92 (m, 2 H), 8.08 (d, J = 8.4 Hz, 1 H), 8.24 (d, J =
8.4 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 110.1, 117.8,
124.9, 125.1, 127.5, 128.5, 128.6, 132.3, 132.6, 132.9, 133.2 ppm.
HRMS (APCI): calcd. for C11H8N [M + H]+ 154.0649; found
154.0651.
2,3,4,6-Tetramethylbenzonitrile (2f): Yield 138.5 mg (87%), solid,
m.p. 62–64 °C. IR (chloroform):
ν =
˜
2214 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.16 (s, 3 H), 2.29 (s, 3 H), 2.45 (s, 3 H),
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
Transformation of Arenes into Aromatic Nitriles
2.47 (s, 3 H), 6.94 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ CDCl3): δ = 20.2, 21.6, 109.6, 118.4, 126.9, 130.9, 132.3, 141.7,
= 15.3, 18.7, 20.4, 21.0, 118.2, 128.1, 129.1, 133.2, 138.8, 139.9,
143.4 ppm. HRMS (APCI): calcd. for C9H10N [M + H]+ 132.0808;
H]+ found 132.0808.
141.3 ppm. HRMS (APCI): calcd. for C11H14N [M
160.1118; found 160.1121.
+
2-Methoxy-5-methylbenzonitrile (2p): Yield 120.5 mg (82%), oil. IR
(chloroform): ν = 2225 cm–1. 1H NMR (400 MHz, CDCl3): δ =
2,3,5,6-Tetramethylbenzonitrile (2g): Yield 140.1 mg (88%), solid,
m.p. 75–76 °C. IR (chloroform):
2216 cm–1, 1H NMR
˜
ν
˜
=
2.30 (s, 3 H), 3.90 (s, 3 H), 6.86 (d, J = 8.6 Hz, 1 H), 7.33 (dd, J =
8.6, 2.3 Hz, 1 H), 7.34 (d, J = 2.3 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 20.0, 55.9, 101.3, 111.1, 116.6, 130.2, 133.6,
134.9, 159.2 ppm. HRMS (APCI): calcd. for C9H10ON [M + H]+
148.0753; found 148.0757.
(400 MHz, CDCl3): δ = 2.23 (s, 6 H), 2.42 (s, 6 H), 7.10 (s, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 17.8, 19.5, 113.8, 118.3,
134.4, 135.2, 137.6 ppm. HRMS (APCI): calcd. for C11H14N [M +
H]+ 160.1120; found 160.1121.
2,3,4-Trimethoxybenzonitrile (2h): Yield 158.4 mg (82%), solid,
4-Methoxy-3-methylbenzonitrile (2q): Yield 120.5 mg (82%), solid,
2226 cm–1. 1H NMR
m.p. 48–49 °C. IR (chloroform):
ν =
˜
2224 cm–1. 1H NMR
m.p. 54–55 °C. IR (chloroform):
ν =
˜
(400 MHz, CDCl3): δ = 3.89 (s, 3 H), 3.92 (s, 3 H), 4.05 (s, 3 H),
6.70 (d, J = 8.9 Hz, 1 H), 7.28 (d, J = 8.9 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 56.1, 60.9, 61.6, 98.9, 107.4, 116.4, 128.6,
141.7, 155.8, 157.9 ppm. HRMS (APCI): calcd. for C10H12O3N [M
+ H]+ 194.0808; found 194.0812.
(400 MHz, CDCl3): δ = 2.21 (s, 3 H), 3.90 (s, 3 H), 6.86 (d, J =
8.6 Hz, 1 H), 7.39 (s, J = 2.0 Hz, 1 H), 7.50 (dd, J = 8.6, 2.0 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 15.9, 55.5, 103.3, 110.0,
119.4, 128.1, 131.9, 133.8, 161.0 ppm. HRMS (APCI): calcd. for
C9H10N [M + H]+ 148.0753; found 148.0757.
Methyl 5-Cyano-2,4-dimethoxybenzoate (2i): Yield 126.0 mg (57%),
5-Chloro-2-methoxybenzonitrile (2r): Yield 113.5 mg (68%), solid,
1
solid, m.p. 116–117 °C. IR (chloroform): ν = 2223 cm–1. H NMR
m.p. 92–93 °C. IR (chloroform):
ν =
˜
2229 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 3.86 (s, 3 H), 3.99 (s, 6 H), 6.46 (s, 1 H),
8.13 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 52.0, 56.3 (2
C), 93.6, 95.2, 112.8, 115.7, 138.1, 164.1, 164.6, 165.3 ppm. HRMS
(APCI): calcd. for C11H12O4N [M + H]+ 222.0756; found 222.0761.
(400 MHz, CDCl3): δ = 3.93 (s, 3 H), 6.92 (d, J = 8.2 Hz, 1 H),
7.48 (d, J = 2.4 Hz, 1 H), 7.52 (dd, J = 8.2, 2.4 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 56.3, 103.1, 112.5, 115.1, 125.6,
132.9, 134.3, 159.8 ppm. HRMS (APPI): calcd. for C8H7ONCl [M
+ H]+ 168.0206; found 168.0211.
4,5-Dimethoxy-2-methylbenzonitrile (2j): Yield 154.1 mg (87%), so-
lid, m.p. 78–79 °C. IR (chloroform): ν = 2214 cm–1. 1H NMR
˜
5-Bromo-2-methoxybenzonitrile (2s): Yield 143.4 mg (68%), solid,
m.p. 85–86 °C. IR (chloroform):
ν =
˜
2228 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.49 (s, 3 H), 3.87 (s, 3 H), 3.91 (s, 3 H),
6.74 (s, 1 H), 6.99 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
20.0, 55.9, 56.1, 103.4, 112.6, 113.8, 118.5, 136.3, 147.0, 152.4 ppm.
HRMS (APCI): calcd. for C10H12O2N [M + H]+ 178.0860; found
178.0863.
(400 MHz, CDCl3): δ = 3.92 (s, 3 H), 6.87 (d, J = 8.9 Hz, 1 H),
7.64 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 56.3, 103.6,
112.2, 113.0, 114.9, 135.8, 137.2, 160.3 ppm. HRMS (ESI): calcd.
for C8H7ONBr [M + H]+ 211.9702; found 211.9706.
2,4,6-Trimethoxybenzonitrile (2k): Yield 175.6 mg (91%), solid,
Piperonylonitrile (2t): Yield 114.6 mg (78%), solid, m.p. 87–89 °C.
m.p.140–141 °C. IR (chloroform): ν = 2217 cm–1. 1H NMR
1
IR (chloroform): ν = 2221 cm–1. H NMR (400 MHz, CDCl ): δ =
˜
˜
3
(400 MHz, CDCl3): δ = 3.86 (s, 3 H), 3.88 (s, 6 H), 6.06 (s, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 55.6, 56.0, 83.9, 90.2,
114.5, 163.7, 165.2 ppm. HRMS (APCI): calcd. for C10H12O3N [M
+ H]+ 194.0807; found 194.0812.
6.07 (s, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 7.04 (d, J = 1.6 Hz, 1 H),
7.20 (dd, J = 8.2, 1.6 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 102.1, 104.9, 109.1, 111.4, 118.8, 128.2, 148.0, 151.5 ppm.
HRMS (APCI): calcd. for C8H6O2N [M + H]+ 148.0390; found
148.0393.
2,4,6-Trimethylbenzonitrile (2l): Yield 127.6 mg (88%), solid, m.p.
51–52 °C. IR (chloroform): ν = 2219 cm–1. 1H NMR (400 MHz,
˜
3,4-Dimethoxybenzonitrile (2u): Yield 136.9 mg (84%), solid, m.p.
CDCl3): δ = 2.32 (s, 3 H), 2.49 (s, 6 H), 6.94 (s, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 20.6, 21.5, 110.2, 117.6, 128.1, 141.9,
66–67 °C. IR (chloroform): ν = 2224 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 3.91 (s, 3 H), 3.94 (s, 3 H), 6.91 (d, J = 8.2 Hz, 1 H),
7.08 (s, 1 H), 7.29 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 55.9, 56.0. 103.7, 111.1, 113.7, 119.1, 126.3, 149.0,
152.7 ppm. HRMS (APCI): calcd. for C9H10O2N [M + H]+
164.0704; found 164.0706.
142.7 ppm. HRMS (APCI): calcd. for C10H12N [M
146.0961; found 146.0964.
+
H]+
2,4-Dimethoxybenzonitrile (2m): Yield 138.6 mg (85%), solid, m.p.
93–94 °C. IR (chloroform): ν = 2218 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 3.85 (s, 3 H), 3.90 (s, 3 H), 6.47 (d, J = 2.4 Hz, 1 H),
6.51 (dd, J = 8.4, 2.4 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 55.6, 55.9, 93.9, 98.4, 105.6, 116.9,
134.8, 162.8, 164.5 ppm. HRMS (APCI): calcd. for C9H10O2N [M
+ H]+ 164.0702; found 164.0706.
5-Bromo-2-isobutoxybenzonitrile (2v): Yield 164.4 mg (65%), liquid.
1
IR (chloroform): ν = 2229 cm–1. H NMR (400 MHz, CDCl ): δ =
˜
3
1.05 (d, J = 6.9 Hz, 6 H), 2.10–2.19 (m, 1 H), 3.80 (d, J = 6.2 Hz,
2 H), 6.83 (d, J = 8.8 Hz, 1 H), 7.59 (dd, J = 8.6, 2.5 Hz, 1 H),
7.63 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
18.9, 28.0, 75.5, 103.7, 111.8, 113.8, 114.8, 135.6, 137.0, 159.0 ppm.
HRMS (ESI): calcd. for C11H13ONBr [M + H]+ 254.0170; found
254.0175.
4-Methoxy-2-methylbenzonitrile (2n): Yield 129.4 mg (88%), solid,
m.p. 52–53 °C. IR (chloroform):
ν =
˜
2218 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.51 (s, 3 H), 3.84 (s, 3 H), 6.76 (dd, J =
8.8, 2.5 Hz, 1 H), 6.79 (d, J = 2.5 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.6, 55.4, 104.5, 112.0,
115.6, 118.5, 134.1, 144.0, 162.6 ppm. HRMS (APPI): calcd. for
C9H10ON [M + H]+ 148.1754; found 148.1757.
5-Iodo-2-isobutoxybenzonitrile (2w): Yield 180.6 mg (60%), oil. IR
(chloroform): ν = 2228 cm–1. 1H NMR (400 MHz, CDCl3): δ =
˜
1.05 (d, J = 6.8 Hz, 6 H), 2.10–2.19 (m, 1 H), 3.80 (d, J = 6.4 Hz,
2 H), 6.72 (d, J = 9.2 Hz, 1 H), 7.75 (dd, J = 9.2, 2.3 Hz, 1 H),
7.78 (d, J = 2.3 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
2,4-Dimethylbenzonitrile (2o): Yield 89.1 mg (68%), solid, m.p. 23–
25 °C. IR (chloroform): ν = 2220 cm–1. 1H NMR (400 MHz, 18.9, 28.0, 75.3, 80.8, 104.2, 114.3, 114.6, 141.3, 142.8, 160.5 ppm.
˜
CDCl3): δ = 2.37 (s, 3 H), 2.49 (s, 3 H), 7.06 (d, J = 8.0 Hz, 1 H),
HRMS (ESI): calcd. for C11H13ONI [M + H]+ 302.0028; found
302.0036.
7.11 (s, 3 H), 7.48 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
T. Tamura, K. Moriyama, H. Togo
FULL PAPER
5-Methyl-2-allyloxybenzonitrile (2x): Yield 102.1 mg (59%), oil. IR
Acknowledgments
(chloroform): ν = 2226 cm–1. 1H NMR (400 MHz, CDCl3): δ =
˜
2.29 (s, 3 H), 4.61–4.64 (m, 2 H), 5.32 (dq, J = 10.8, 1.2 Hz, 1 H),
5.47 (dq, J = 17.6, 1.6 Hz, 1 H), 5.98–6.05 (m, 1 H), 6.84 (d, J =
8.4 Hz, 1 H), 7.27 (dd, J = 8.4, 2.2 Hz, 1 H), 7.34 (d, J = 2.2 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.0, 69.4, 101.8,
112.5, 116.5, 118.0, 130.4, 132.0, 133.7, 134.8, 158.2 ppm. HRMS
(APCI): calcd. for C11H12ON [M + H]+ 174.0911; found 174.0913.
Financial support in the form of a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science,
and Technology in Japan (No. 25105710), and also from the Iodine
Research Project in Chiba University is gratefully acknowledged.
[1] a) S. R. Sandler, W. Karo, Nitriles (Cyanides), in: Organic
Functional Group Preparations (Ed.: H. H. Wasserman), Aca-
demic Press, Inc., San Diego, 1983, vol. 12-I, chapter 17; b)
M. E. Fabiani, Drug News Perspect. 1999, 12, 207–215; c) J.
Kim, H. J. Kim, S. Chang, Angew. Chem. Int. Ed. 2012, 51,
11948–11959; Angew. Chem. 2012, 124, 12114–12125; d) F. F.
Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C. Shook, J.
Med. Chem. 2010, 53, 7902–7919.
3-Cyanobenzothiophene (2y): Yield 130.5 mg (82%), solid, m.p. 72–
73 °C. IR (chloroform): ν = 2227 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 7.48 (t, J = 7.2 Hz, 1 H), 7.54 (t, J = 7.2 Hz, 1 H),
7.91 (d, J = 8.2 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 1 H), 8.11 (s, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 107.0, 114.2, 122.5, 122.8,
125.9, 126.1, 137.2, 137.5, 138.4 ppm. HRMS (APCI): calcd. for
C9H6NS [M + H]+ 160.0213; found 160.0215.
[2] a) K. Friedrick, K. Wallensfels, in: The Chemistry of the Cyano
Group (Ed.: Z. Rappoport), Wiley-Interscience, New York,
1970; b) M. North, in: Comprehensive Organic Functional
Group Transformation (Eds.: A. R. Katritzky, O. Meth-Cohn,
C. W. Rees), Pergamon, Oxford, UK, 1995; c) S.-I. Murahashi,
Synthesis from Nitriles with Retention of the Cyano Group, in:
Science of Synthesis vol. 19, Thieme, Stuttgart, Germany, 2004,
p. 345–402; d) S. J. Collier, P. Langer, Application of Nitriles as
Reagents for Organic Synthesis with Loss of the Nitrile Func-
tionality, in: Science of Synthesis vol. 19, Thieme, Stuttgart,
Germany, 2004, p. 403–425; e) J. B. Medwid, R. Paul, J. S.
Baker, J. A. Brockman, M. T. Du, W. A. Hallett, J. W. Hanifin,
R. A. Hardy Jr., M. E. Tarrant, L. W. Torley, S. Wrenn, J. Med.
Chem. 1990, 33, 1230–1241; f) G. D. Diana, D. Cutcliffe, D. L.
Volkots, J. P. Mallamo, T. R. Bailey, N. Vescio, R. C. Oglesby,
T. J. Nitz, J. Wetzel, V. Giranda, D. C. Pevear, F. J. Dutko, J.
Med. Chem. 1993, 36, 3240–3250; g) S. J. Wittenberger, B. G.
Donner, J. Org. Chem. 1993, 58, 4139–4141; h) P. Wipf, Chem.
Rev. 1995, 95, 2115–2134; i) M. Chihiro, H. Nagamoto, I. Take-
mura, K. Kitano, H. Komatsu, K. Sekiguchi, F. Tabusa, T.
Mori, M. Tominaga, Y. Yabuuchi, J. Med. Chem. 1995, 38,
353–358; j) I. K. Khanna, R. M. Weier, Y. Yu, X. D. Xu, F. J.
Koszyk, P. W. Collins, C. M. Koboldt, A. W. Veenhuizen, W. E.
Perkins, J. J. Casler, J. L. Masferrer, J. Y. Zhang, S. A. Gregory,
K. Seibert, P. C. Isakson, J. Med. Chem. 1997, 40, 1634–1647;
k) P. Wipf, F. Yokokawa, Tetrahedron Lett. 1998, 39, 2223–
2226; l) X. Gu, X. Wan, B. Jiang, Bioorg. Med. Chem. Lett.
1999, 9, 569–572; m) P. C. Ducept, S. P. Marsden, Synlett 2000,
692–694; n) J.-J. Shie, J.-M. Fang, J. Org. Chem. 2003, 68, 1158–
1160.
1-Methyl-3-cyanoindole (2z): Yield 101.5 mg (65%), oil. IR (chloro-
1
form): ν = 2219 cm–1. H NMR (400 MHz, CDCl ): δ = 3.83 (s, 3
˜
3
H), 7.27–7.44 (m 3 H), 7.58 (s 1 H), 7.75 (d, J = 7.6 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 33.5, 85.3, 110.2, 115.8, 119.7,
122.0, 120.7, 127.6, 135.4, 135.9 ppm. HRMS (APCI): calcd. for
C10H9N2 [M + H]+ 157.0757; found 157.0760.
tert-Butyl 2-(3Ј-Cyano-4Ј-isobutoxyphenyl)-4-methylthiazole-5-carb-
oxylate (3): A glass vessel containing a magnetic stirrer bar,
Ni(OAc)2·4H2O (0.2 mmol, 50.6 mg), and MgSO4 (2.0 mmol,
240.6 mg) was dried under vacuum with a heat gun, and was then
filled with argon gas after cooling to room temperature. 2,2Ј-Bi-
pyridyl (0.2 mmol, 31.3 mg), 5-bromo-2-isobutoxybenzonitrile
(1.0 mmol, 253.0 mg) or 5-iodo-2-isobuthoxybenzonitrile (1.0 mmol,
301.0 mg), tert-butyl 4-methylthiazole-5-carboxylate (2.0 mmol,
398.6 mg), LiOtBu (5.0 mmol, 400.0 mg), and dry dioxane (6.0 mL)
were added to the vessel at room temperature, and the resulting
mixture was stirred for 40 h at reflux. The mixture was allowed to
cool to room temperature, then it was passed through a short pad
of silica gel, which was washed wth EtOAc. The filtrate was concen-
trated, and the residue was purified by preparative TLC (3ϫ;
EtOAc/hexane, 1:6) to give compound 3 (197.2 mg, 53% from 2v;
or 223.2 mg, 60% from 2w) as a solid, m.p. 108–110 °C. IR (chloro-
1
form): ν = 1712 cm–1. H NMR (400 MHz, CDCl ): δ = 1.09 (d, J
˜
3
= 6.8 Hz, 6 H), 1.59 (s, 9 H), 2.18–2.23 (m, 1 H), 2.73 (s, 3 H), 3.89
(d, J = 6.8 Hz, 2 H), 7.00 (d, J = 8.9 Hz, 1 H), 8.08 (dd, J = 8.9,
2.3 Hz, 1 H), 8.17 (d, J = 2.3 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 17.3, 19.0, 28.1, 28.2, 75.6, 82.5, 102.8, 112.5, 115.4,
123.7, 126.1, 131.9, 132.4, 160.1, 161.3, 162.3, 166.5 ppm.
[3] a) R. C. Larock, Nitriles, Carboxylic Acids and Derivatives, in:
Comprehensive Organic Transformations, 2nd ed., Wiley, New
York, 1999, p. 1621–1996; b) K. Ouchaou, D. Georgin, F. Ta-
ran, Synlett 2010, 2083–2086.
[4] T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17, 1633, 2650–
2653.
[5] a) K. W. Rosenmund, E. Struck, Ber. Dtsch. Chem. Ges. 1916,
52, 1749–1756; b) J. von Braun, G. Manz, Justus Liebigs Ann.
Chem. 1931, 488, 111–126; c) C. F. Koelsch, A. G. Whitney, J.
Org. Chem. 1941, 6, 795–803; d) J. X. Wu, B. Beck, R. X. Ren,
Tetrahedron Lett. 2002, 43, 387–389.
Febxostat: CF3COOH (5.0 mL) was added to a solution of
2-(3Ј-cyano-4Ј-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (3;
0.5 mmol, 186.1 mg) in dry CH2Cl2 (5.0 mL). The mixture was
stirred for 18 h at room temperature. Then the solvent was removed
under reduced pressure, toluene (3ϫ 3.0 mL) was added to the resi-
due, the toluene was removed under reduced pressure, and finally
[6] For recent reviews, see: a) S. Sundermeier, A. Zapf, M. Beller,
Eur. J. Inorg. Chem. 2003, 3513–3526; b) P. Anbarasan, T.
Schareina, M. Beller, Chem. Soc. Rev. 2011, 40, 5049–5067; for
articles, see: c) Z. Iqbal, A. Lyubimtsev, M. Hanack, Synlett
2008, 2287–2290; d) G. Chen, J. Weng, Z. Zheng, X. Zhu, Y.
Cai, J. Cai, Y. Wan, Eur. J. Org. Chem. 2008, 3524–3528; e) T.
Schareina, A. Zapf, A. Cotte, N. Müller, M. Beller, Synthesis
2008, 3351–3355; f) F. G. Buono, R. Chidambaram, R. H.
Mueller, R. E. Waltermire, Org. Lett. 2008, 10, 5325–5328; g)
K. Chattopadhyay, R. Dey, B. C. Ranu, Tetrahedron Lett. 2009,
50, 3164–3167; h) G. Yan, C. Kuang, Y. Zhang, J. Wang, Org.
Lett. 2010, 12, 1052–1055; i) C. DeBlase, N. E. Leadbeater, Tet-
rahedron 2010, 66, 1098–1101; j) P. Y. Yeung, C. P. Tsang, F. Y.
filtration with hexane gave febuxostat (147.0 mg, 93%) as a solid,
1
m.p. 205–208 °C. IR (chloroform): ν = 1688, 2230, 2961 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.09 (d, J = 6.7 Hz, 6 H), 2.18–2.23
(m, 1 H), 2.79 (s, 3 H), 3.90 (d, J = 6.7 Hz, 2 H), 7.02 (d, J =
8.9 Hz, 1 H), 8.08 (dd, J = 8.9, 2.3 Hz, 1 H), 8.16 (d, J = 2.3 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.62, 19.01, 28.12,
75.69, 102.93, 112.62, 115.28, 125.64, 128.18, 128.99, 132.14,
132.68, 162.64, 162.85, 168.50 ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for all the aromatic
nitriles and febuxostat.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
Transformation of Arenes into Aromatic Nitriles
Kwong, Tetrahedron Lett. 2011, 52, 7038–7041; k) R. Gerber,
M. Oberholzer, C. M. Frech, Chem. Eur. J. 2012, 18, 2978–
2986; l) D. Zhang, H. Sun, L. Zhang, Y. Zhou, C. Li, H. Jiang,
K. Chen, H. Liu, Chem. Commun. 2012, 48, 2909–2911; m)
A. R. Hajipour, R. Rafiee, A. E. Ruoho, Tetrahedron Lett.
2012, 53, 526–529; n) T. Chatterjee, R. Dey, B. C. Ranu, J. Org.
Chem. 2014, 79, 5875–5879.
Mori, H. Togo, Tetrahedron 2005, 61, 5915–5925; e) M. Ishih-
ara, H. Togo, Synlett 2006, 227–230; f) S. Iida, H. Togo, Synlett
2006, 2633–2635; g) M. Ishihara, H. Togo, Tetrahedron 2007,
63, 1474–1480; h) S. Iida, H. Togo, Synlett 2007, 407–410; i) S.
Iida, H. Togo, Synlett 2008, 1639–1642; j) S. Iida, R. Ohmura,
H. Togo, Tetrahedron 2009, 65, 6257–6262; k) R. Ohmura, M.
Takahata, H. Togo, Tetrahedron Lett. 2010, 51, 4378–4371; l)
Y. Suzuki, Y. Ishiwata, K. Moriyama, H. Togo, Tetrahedron
Lett. 2010, 51, 5950–5953; m) S. Takahashi, H. Togo, Heterocy-
cles 2010, 82, 593–601; n) Y. Suzuki, T. Yoshino, K. Moriyama,
H. Togo, Tetrahedron 2011, 67, 3809–3814; o) H. Baba, K. Mo-
riyama, H. Togo, Tetrahedron Lett. 2011, 52, 4303–4307; p) Y.
Suzuki, K. Moriyama, H. Togo, Tetrahedron 2011, 67, 7956–
7962; q) S. Ushijima, S. Dohi, K. Moriyama, H. Togo, Tetrahe-
dron 2012, 68, 1436–1442; r) H. Baba, K. Moriyama, H. Togo,
Synlett 2012, 23, 1175–1180; s) S. Ushijima, K. Moriyama, H.
Togo, Tetrahedron 2012, 68, 4701–4709; t) S. Dohi, K. Mori-
yama, H. Togo, Tetrahedron 2012, 68, 6557–6564; u) H. Kikui,
K. Moriyama, H. Togo, Synthesis 2013, 45, 791–797; v) G.
Ishii, R. Harigae, K. Moriyama, H. Togo, Tetrahedron 2013,
69, 1462–1469; w) H. Shimojo, K. Moriyama, H. Togo, Synthe-
sis 2013, 45, 2155–2164; x) K. Miyagi, K. Moriyama, H. Togo,
Eur. J. Org. Chem. 2013, 5886–5892; y) D. Tsuchiya, Y. Ka-
wagoe, K. Moriyama, H. Togo, Org. Lett. 2013, 15, 4194–4197;
z) S. Dohi, K. Moriyama, H. Togo, Eur. J. Org. Chem. 2013,
7815–7822; Y. Kawagoe, K. Moriyama, H. Togo, Eur. J. Org.
Chem. 2014, 4115–4122.
[7] a) C. Zhang, X. Ren, J. Chen, M. Hu, J. Cheng, Org. Lett.
2011, 13, 5004–5007; b) J. Kim, H. Kim, S. Chang, Org. Lett.
2012, 14, 3924–3927; c) R. Song, J. Wu, Y. Liu, G. Deng, C.
Wu, W. Wei, J. Li, Synlett 2012, 23, 2491–2496; d) J. Peng, J.
Zhao, Z. Hu, D. Liang, J. Huang, Q. Zhu, Org. Lett. 2012, 14,
4966–4969; e) K. Okamoto, M. Watanabe, M. Murai, R. Hat-
ano, K. Ohe, Chem. Commun. 2012, 48, 3127–3129; f) T. Dohi,
K. Morimoto, Y. Kiyono, H. Tohma, Y. Kita, Org. Lett. 2005,
7, 537–540.
[8] Z. Shu, W. Ji, X. Wang, Y. Zhou, Y. Zhang, J. Wang, Angew.
Chem. Int. Ed. 2014, 53, 2186–2189; Angew. Chem. 2014, 126,
2218–2221.
[9] a) S. Ushijima, H. Togo, Synlett 2010, 1562–1566; b) S. Ushi-
jima, K. Moriyama, H. Togo, Tetrahedron 2011, 67, 958–968;
G. Ishii, R. Harigae, K. Moriyama, H. Togo, Tetrahedron 2013,
69, 1462–1469.
[10] a) S. Ushijima, H. Togo, Synlett 2010, 1067–1070; b) S. Ushi-
jima, K. Moriyama, H. Togo, Tetrahedron 2012, 68, 4588–4595.
[11] a) O. Meth-Cohn, M. Ashton, Tetrahedron Lett. 2000, 41,
2749–2752; b) A. P. Yakubov, D. V. Tsyganov, L. I. Belen’kii,
M. M. Krayushkin, Tetrahedron 1993, 49, 3397–3404; c) P.
Dhankher, T. D. Sheppard, Synlett 2014, 25, 381–384; d) K.
Ohsawa, M. Yoshida, T. Doi, J. Org. Chem. 2013, 78, 3438–
3444; e) O. Kundrat, H. Dvorakova, V. Eigner, P. Lhotak, J.
Org. Chem. 2010, 75, 407–411, and references cited therein.
[12] For reviews, see: a) H. Togo, S. Iida, Synlett 2006, 2159–2175;
b) H. Togo, J. Synth. Org. Chem. Jpn. 2008, 66, 652–663; for
articles, see: c) N. Mori, H. Togo, Synlett 2004, 880–882; d) N.
[13]
a) K. Okamoto, B. T. Eger, T. Nishuno, S. Kondo, E. F. Pai, T.
Nishino, J. Biol. Chem. 2003, 278, 1848–1855; b) J. Yamaguci,
K. Mutou, K. Amaike, T. Yamamoto, K. Itami, J. Synth. Org.
Chem. Jpn. 2013, 71, 576–587; c) J. Canivel, J. Yamaguchi, I.
Ban, K. Itami, Org. Lett. 2009, 11, 1733–1736.
Received: December 23, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43672
/KAP1
Date: 09-02-15 12:56:18
Pages: 8
T. Tamura, K. Moriyama, H. Togo
FULL PAPER
Aromatic Nitriles
Various electron-rich arenes could be effec-
tively converted into the corresponding
aromatic nitriles in good yields, by treat-
ment with ZnBr2 and dichloromethyl
methyl ether, followed by reaction with
molecular iodine and aq. ammonia.
T. Tamura, K. Moriyama,
H. Togo* ........................................... 1–8
Facile One-Pot Transformation of Arenes
into Aromatic Nitriles under Metal-Cyan-
ide-Free Conditions
Keywords: Synthetic methods / Oxidation /
Aromatic substitution / Cyanides / Iodine
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0