One-pot conversion of aromatic bromides and aromatics into aromatic nitriles via aryllithiums and their DMF adduct

Article abstract of DOI:10.1016/j.tet.2010.11.109

Various aromatic bromides and iodides were smoothly converted into the corresponding aromatic nitriles in good to moderate yields by the treatment with n-butyllithium and subsequently DMF, followed by treatment with molecular iodine in aq NH₃. The same treatment of typical aromatics and heteroaromatics with n-butyllithium and subsequently DMF, followed by treatment with molecular iodine in aq NH₃ also provided the corresponding aromatic nitriles in good yields. Moreover, the same treatment of aromatic bromides and aromatics with half amount of DIH (1,3-diiodo-5,5- dimethylhydantoin) instead of molecular iodine worked effectively to give the corresponding aromatic nitriles, respectively, in good yields. These reactions are novel and environmentally benign one-pot methods for the preparation of aromatic nitriles from aromatic bromides and aromatics, respectively, through the formation of aryllithiums and their DMF adducts.

Full text of DOI:10.1016/j.tet.2010.11.109

Tetrahedron 67 (2011) 958e964
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot conversion of aromatic bromides and aromatics into aromatic nitriles via
aryllithiums and their DMF adduct
*
Sousuke Ushijima, 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 and iodides were smoothly converted into the corresponding aromatic ni-
triles in good to moderate yields by the treatment with n-butyllithium and subsequently DMF, followed
by treatment with molecular iodine in aq NH3. The same treatment of typical aromatics and hetero-
aromatics with n-butyllithium and subsequently DMF, followed by treatment with molecular iodine in aq
NH3 also provided the corresponding aromatic nitriles in good yields. Moreover, the same treatment of
aromatic bromides and aromatics with half amount of DIH (1,3-diiodo-5,5-dimethylhydantoin) instead of
molecular iodine worked effectively to give the corresponding aromatic nitriles, respectively, in good
yields. These reactions are novel and environmentally benign one-pot methods for the preparation of
aromatic nitriles from aromatic bromides and aromatics, respectively, through the formation of ar-
yllithiums and their DMF adducts.
Received 8 November 2010
Received in revised form 29 November 2010
Accepted 30 November 2010
Available online 7 December 2010
Keywords:
Molecular iodine
Aq ammonia
n-Butyllithium
Aryllithium
Aromatic nitrile
DMF
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the corresponding aldoximes formed.5 Recently, the direct conver-
sion of aromatic bromides into the corresponding aromatic nitriles
Aromatic nitriles are one of the most important synthetic trans-
formation precursors because they can be easily converted into es-
ters, amides, carboxylic acids, amines, amidines, ketones, and
nitrogen-containing heterocycles, such as tetrazoles, and are used as
pharmaceuticals and liquid crystals, and as synthetic intermediates
for agricultural chemicals, pharmaceuticals, and functional mate-
rials.1 For example, Citalopram hydrobromideÒ (treatment of alcohol
dependency), PericiazineÒ (anti-psychotic drug), FadrozoleÒ (onco-
lytic drug), LetrozoleÒ (breast cancer therapy), Bicalutamide (pros-
tatic cancer and breast cancer therapy), and Etravirine (anti-HIV) are
pharmaceutically important aromatic nitriles,2 and 4-cyano-40-
pentylbiphenyl is a typical liquid crystal material. The general
methods for the preparation of aromatic nitriles include the de-
hydration of aromatic amides with SOCl2, TsCl/Py, P2O5, POCl3, COCl2,
or Ph3P/CCl4, the reaction of carboxylic acids with chlor-
osulfonylisocyanate (ClSO2NCO) and DMF,3a palladium-catalyzed
decarboxylative conversion of arenecarboxylic acids into aromatic
nitriles with Pd(OTf)2, Ag2CO3, and cyanhydrin,3b the reaction of
esters with Me2AlNH2,3a and the Sandmeyer reaction of aromatic
diazonium ion with toxic CuCN.3a,4 Aromatic aldehydes can be also
used for the preparation of aromatic nitriles via the dehydration of
has been actively studied with CuCN at DMF refluxing temperature,6a
Pd(OAc)2$K4[Fe(CN)6] at 120 ꢀC,6b Pd$(binaphthyl)P(tBu)2$Zn
(CN)2$Zn at 80e95 ꢀC,6c Pd2(dba)3$Zn(CN)2$DPPF at 80e120 ꢀC,6d Pd
(tmhd)2$K4[Fe(CN)6] at 80 ꢀC,6e Zn(CN)2$Pd2(dba)3 at 100 ꢀC,6f Pd/
C$CuI$K4[Fe(CN)6]$3H2O at 130e140 ꢀC,6g CuI$alkylimidazole$Pd/
C$CuI$ K4[Fe(CN)6] at 140e180 ꢀC,6h Zn(CN)2$Pd2(dba)3$
dppf$Zn$ZnBr2 at 95 ꢀC,6i CuO$Pd$K4[Fe(CN)6] at 120 ꢀC,6j Pd
(OAc)2$Cu(OAc)2$K4[Fe(CN)6]6k at 130 ꢀC, and CuI$K4[Fe(CN)6]6l at
175 ꢀC, all of which require toxic metal cyanides. More recently, the
direct and catalytic cyanation of aromatics containing a 2-pyridyl
group via CeH bond cleavage with Cu(OAc)2$TMSCN,7a Pd
(OAc)2$CuBr$CuCN,7b which requires toxic metal cyanides again, and
Pd(OAc)2$CuBr2$DMF$aq NH3 at 130 ꢀC,7c was reported. The another
one-pot cyanation of arenes via iridium-catalyzd CeH borylation of
arenes and copper-mediated cyanation was reported recently with
B2pin2, [Ir(cod)OMe]2, followed by treatment with Cu(NO3)2 and Zn
(CN)2 at 100 ꢀC.7d To the best of our knowledge, one-pot preparations
of aromatic nitriles from aromatics are extremely limited. One well-
established method is the reaction of highly electron-rich aromatics
with ClSO2NCO to form N-chlorosulfonyl amides and the subsequent
treatment with DMF to provide aromatic nitriles, together with the
evolution of SO3 and HCl.8 However, its synthetic utility is limited to
highly electron-rich aromatics alone. Thus, today, there are no prac-
tical and general methods for the environmentally benign and effi-
cient one-pot preparation of aromatic nitriles from aromatic
* Corresponding author. E-mail address: togo@faculty.chiba-u.jp (H. Togo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.109

S. Ushijima et al. / Tetrahedron 67 (2011) 958e964
959
Table 1
bromides and aromatics. Clearly an environmentally benign, eco-
Conversion of aromatic bromides into aromatic nitriles
nomical, and efficient approach for the one-pot preparation of aro-
matic nitriles from aromatic bromides and aromatics is urgently
required. On the other hand, molecular iodine is one of the simplest
oxidants currently available. It is highly affordable and has very low
toxicity. In view of environmentally benign organic synthesis, mo-
lecular iodine has been used in various organic reactions, including
the oxidation of alcohols or aldehydes to esters, the oxidation of
sulfides to sulfoxides, the oxidation of cyclohexenones to benzene
rings, the introduction of protecting groups, the deprotection of
protecting groups, iodocyclization, carbonecarbon bond formation,
and the formation of heterocycles.9
Entry
Ar-X
Time A (h)
Yields (%)a
I2
DIH
Recently, we reported a direct, efficient, practical, and low-
toxicity method for the oxidative conversion of benzylic alcohols
and benzylic halides into the corresponding aromatic nitriles
using molecular iodine in aq NH3.10gei In those reactions, aro-
matic aldehydes could be also smoothly converted into the
corresponding aromatic nitriles with molecular iodine in aq
NH3.10b,10g,11 As part of our studies on the use of molecular io-
dine for organic synthesis,10 we would like to report herein
a facile and environmentally benign one-pot conversion of ar-
omatic bromides and aromatics into the corresponding aromatic
nitriles in detail. Very recently, we reported the first practical
metal-free one-pot conversion of electron-rich aromatics into
the corresponding aromatic nitriles in good yields, via the for-
mation of aromatic N,N-dimethyliminium salts with POCl3 and
DMF, followed by the treatment with molecular iodine in aq
NH3.12 However, that reaction required highly electron-rich ar-
omatics, such as dimethoxybenzenes, trimethoxybenzenes,
methoxynaphthalenes, indoles, 2-alkylfurans, and 2-alkylth-
iophenes, because the first step involves the formation of aro-
matic N,N-dimethyliminium salts via electrophilic substitution
on aromatics, using POCl3 and DMF (the VilsmeiereHaack re-
action), and in one case, the introduction of cyano group into
benzothiophene and benzofuran was not successful. Therefore,
we designed an environmentally benign one-pot conversion of
aromatic bromides and aromatics into the corresponding aro-
matic nitriles via aryllithium, using DMF and molecular iodine in
aq NH3.
1
0.5
80
75
2
3
0.5
0.5
0
0
70
68
4
5
0.5
0.5
76
68
70
73
6
0.5
62 (15)b
62 (16)b
7
8
0.25
0.5
74 (20)c
62
61 (18)c
64
9
0.5
99d
80d
10
11
0.5
0.5
76
70
81
2. Results and discussion
d
n-Butyllithium (1.67 M solution in hexane) was added dropwise
to a solution of p-bromotoluene in THF at ꢁ70 ꢀC. After 30 min, the
resulting mixture was warmed at 0 ꢀC and stirred for 5 min. Then,
DMF was added and the obtained mixture was stirred at 0 ꢀC. After
1 h at the same temperature, aq NH3 (28e30%) and I2 were added
and the obtained mixture was stirred for 2 h at rt to provide 4-
methylbenzonitrile in 80%yield, as showninTable 1 (entry1).13 After
removal of ether from the ether extract of reaction mixture, the
purity of 4-methylbenzonitrile was over 80%. The same treatment
of 3-methylbromobenzene, 2-methylbromobenzene, 2,4-dime-
thylbromobenzene, 3,4-dimethylbromobenzene, 2,5-dimethyl-
bromobenzene, 2,4,6-trimethylbromobenzene, p-bromoanisole,
12
13
14
0.5
0.5
2.0e
95d
59
83d
61
86
79
2,4-dimethoxybromobenzene,
2,4,6-trimethoxybromobenzene,
and 4-(dimethylamino)bromobenzene gave the corresponding ar-
omatic nitriles, respectively, in good to moderate yields (Table 1,
entries 4e10, 12e14). After removal of ether from the ether extracts
of reaction mixtures, the purity of aromatic nitriles was in the range
of 65e80%. When 2,4-dimethylbromobenzene and 3,4-dimethyl-
bromobenzene were used, 2,6-dimethylbenzonitrile and 2,3-
dimethylbenzonitrile were formed as by-product via the isomeri-
zation of the formed carbanions, respectively (entries 6, 7). Using the
same procedure, 1-bromonaphthalene, 2-bromonaphthalene, and
4-bromobiphenyl also provided the corresponding aromatic nitriles
in good yields (Table 1, entries 15, 17, 18). 2-Bromopyridine gave
15
16
0.5
0.5
60d
64d
51d
61d
17
18
0.5
0.5
83
64
60
63
(continued on next page)

Table 2
Conversion of aromatic into aromatic nitriles
Table 1 (continued )
Entry
Ar-X
Time A (h)
Yields (%)a
I2
DIH
19
0.5
66
67
47f
Entry
Ar-CN
Temp.
Yields (%)a
20
0.5
55
I2
DIH
a
Reaction was performed on a 5 mmol scale. Isolated yield.
Yield of 2,6-dimethylbenzonitrile.
Yield of 2,3-dimethylbenzonitrile.
DMF (1.5 equiv) was added.
I2 (1.5 equiv) or DIH (1.0 equiv) was added and the third step was 4 h.
DIH (1.0 equiv) was added.
1
0
0
ꢀC
74
91
68
b
c
d
e
f
2
3
4
ꢀC
94
79
91
0
0
ꢀC
61
92
2-cyanopyridine in good yield using the same procedure (Table 1,
entry 19). Under the present conditions, p-chlorotoluene did not
provide 4-methylbenzonitrile at all (entry 2), while the same
treatment of p-iodotoluene, p-iodoanisole, and 1-iodonaphthalene
gave the corresponding aromatic nitriles in good yields (Table 1,
entries 3, 11, 16). Therefore, the same reaction of p-bromo-
chlorobenzene with n-butyllithium, and subsequently DMF, fol-
lowed by treatment with I2 in aq NH3 gave p-chlorobenzonitrile in
good yield, as shown in Table 1 (entry 20).
1,3-Diiodo-5,5-dimethylhydantoin (DIH) has two NeI bonds and
therefore, a half amount of DIH, instead of I2, in aq NH3 provided the
corresponding aromatic nitriles in good to moderate yields, as shown
inTable 1 (right column). Thus, n-butyllithiumwasadded dropwise to
a solution of p-bromotoluene in THF at ꢁ70 ꢀC. After 30 min, the
resulting mixture was warmed at 0 ꢀC and stirred for 5 min. Then,
DMF wasadded and the obtained mixturewasstirred at0 ꢀC. After 1 h
at the same temperature, aq NH3 and DIH were added and the
obtained mixture was stirred for 2 h at rt to provide 4-methyl-
benzonitrile in 75% yield, as shown in Table 1 (entry 1, right column).
The reactivity of DIH is almost the same as that of molecular iodine.
When 2,4-dimethylbromobenzene and 3,4-dimethylbromobenzene
were used, 2,6-dimethylbenzonitrile and 2,3-dimethylbenzonitrile
were formed again as by-product via the isomerization of formed
carbanions, respectively (entries 6, 7, right column).
ꢀC
5
6
0
ꢀC
76
42
56
41
rtb
7
8
0
0
ꢀC
rt
65
68
63
75
ꢀCd
The one-pot conversion of dialkylbenzenes, trialkylbenzenes,
anisoles, benzothiophene, benzofuran, and pyridine into the
corresponding aromatic nitriles with the previous methods
(POCl3$DMF, and I2 in aq NH3)12 did not succeed at all. There-
fore, the present method should be very useful for the conver-
sion of aromatic bromides and iodides into the corresponding
aromatic nitriles, using n-butyllithium, DMF, and molecular io-
dine or DIH in aq NH3, as aromatic bromides and iodides can be
prepared directly from aromatics. Moreover, known one-pot
methods for the preparation of aromatic nitriles from aromatic
bromides have drawbacks, thus they require expensive Pd and
toxic metal cyanide, and the reactions are conducted at high
temperature.6
Then, n-butyllithium was added dropwise into a solution of
1,3-dimethoxybenzene in THF at 0 ꢀC and the obtained mixture
was stirred for 2 h at the same temperature. Thereafter, DMF was
added and the obtained mixture was stirred at 0 ꢀC. After 2 h at
the same temperature, aq NH3 and I2 were added and the re-
action mixture was stirred for 2 h at rt to give 2,6-dimethox-
ybenzonitrile in 91% yield, as shown in Table 2 (entry 2). After
removal of ether from the ether extract of reaction mixture, the
9
0
0
0
ꢀC
70
51
10
11
ꢀCd
49 (20)c
90
47 (21)c
74
ꢀC
12
0
0
ꢀCd
65
79
53
74
13
ꢀC
a
Reaction was performed on a 4 mmol scale. Isolated yield.
LDA (2.2 equiv) was added instead of n-BuLi.
Yield starting material.
b
c
d
The third step was 4 h, and I2 (1.5 equiv) or DIH (0.75 equiv) was used.

S. Ushijima et al. / Tetrahedron 67 (2011) 958e964
961
purity of 4-methylbenzonitrile was over 80%. Under the same
conditions, anisole, 1,3,5-trimethoxybenzene, 1,4-dimethoxy-
benzene, 1,2-dimethoxybenzene, N-tosylindoles, N-methylindole,
benzofuran, benzothiophene, 2-decylfuran, 2-decylthiophene, and
2-methoxynaphthalene could be converted into the correspond-
ing aromatic nitriles in good to moderate yields (Table 2, entries
1, 3e5, 7e13). After removal of ether from the ether extracts of
reaction mixtures, the purity of aromatic nitriles was in the range
of 60e80%. 1,3-Difluorobenzene was also converted into the
corresponding aromatic nitrile containing fluorine atoms in
moderate yield, by the present procedure using LDA instead of
n-butyllithium (Table 2, entry 6). The reactivity of DIH is again
almost the same as that of I2 (Table 2, right column).
Then, the synthetic application of the present reactions was
carried out. 4-Cyano-40-pentylbiphenyl, which is a typical liquid
crystal material, was prepared in good yield from the reactions of
4-bromo-40-pentylbiphenyl with n-butyllithium at ꢁ70 ꢀC, and
subsequently DMF at 0 ꢀC, followed by the reaction with mo-
lecular iodine or DIH in aq NH3 at rt, as shown in Scheme 1. The
hydroxy group of p-cresol was protected with an MOM group,
and O-MOM protected p-cresol was treated with n-butyllithium
at 0 ꢀC and subsequently DMF. This was followed by the reaction
with molecular iodine or DIH in aq NH3 and then methanolysis
with p-TsOH in methanol to provide 2-cyano-4-methylphenol in
good yield.
Scheme 2. Possible Reaction Pathway for Nitrile.
3. Conclusion
Various electron-rich and electron-deficient aromatic bromides,
such as bromotoluenes, bromodimethylbenzenes, bromotri-
methylbenzene, bromoanisole, bromonaphthalenes, bromobi-
phenyl, and bromopyridine could be smoothly converted into the
corresponding aromatic nitriles in good to moderate yields by
treatment with n-butyllithium and subsequently DMF, followed by
treatment with molecular iodine or DIH in aq NH3. The same
treatment of typical aromatics and heteroaromatics, such as ani-
sole, dimethoxybenzenes, trimethoxybenzenes, benzothiophene,
N-methylindole, N-tosylindole, benzofuran, alkylthiophene, and
alkylfuran with n-butyllithium and subsequently DMF, followed by
treatment with molecular iodine or DIH in aq NH3 provided the
corresponding aromatic nitriles in good yields. The present re-
actions are novel and practical one-pot methods for the preparation
of aromatic nitriles from aromatic bromides and aromatics through
the formation of aryllithiums and their DMF adducts.
4. Experimental section
4.1. General
1H NMR spectra were recorded with JEOL-JNM-ECX400, JEOL-
JNM-ECS400, and JEOL-JNM-ECA500 spectrometers. Chemical
shifts are expressed in parts per million downfield from TMS in
d
units. Mass spectra were recorded on JMS-HX110, JMS-T100GCV,
and Thermo LTQ Orbtrap spectrometers. IR spectra were measured
with a JASCO FT-IR4100 spectrometer. Melting points were de-
termined on a YAMATO Melting Point electrothermal apparatus
MP-21 in open capillary tubes and are uncorrected. Kieselgel 60
F254 was used for TLC, Silica gel 60 (Kanto Kagaku Co.) was used for
column chromatography, and Wakogel B-5F was used for pre-
parative pTLC.
Scheme 1. Synthetic Application.
A plausible reaction mechanism is shown in Scheme 2. The
initial step is the formation of aryllithium (a) by the reaction of
aromatic bromide or aromatics with n-butyllithium. Then, aryl-
lithium (a) reacts with DMF to generate adduct (b). The addition of
molecular iodine or DIH, and aq NH3 induces the formation of ar-
omatic imine (c), which further reacts with molecular iodine or DIH
to form N-iodo aromatic imine (d). Once N-iodo aromatic imine (d)
is formed, HI elimination smoothly occurs by NH3 to generate ar-
omatic nitrile.10gej
4.2. Typical experimental procedure for the conversion of
aromatic bromides into aromatic nitriles with I2
n-Butyllithium (1.67 M solution in hexane, 3.3 mL, 5.5 mmol)
was added dropwise to a solution of p-bromotoluene (855 mg,
5.0 mmol) in THF (5 mL) at ꢁ70 ꢀC. After 30 min, the resulting

962
S. Ushijima et al. / Tetrahedron 67 (2011) 958e964
mixture was warmed and stirred for 5 min at 0 ꢀC. Then, DMF
(0.43 mL, 5.5 mmol) was added and the obtained mixture was
stirred at 0 ꢀC. After 1 h at the same temperature, aq NH3 (10 mL,
150 mmol) and I2 (1.40 g, 5.5 mmol) were added and the obtained
mixture was stirred for 2 h at rt. The reaction mixture was
quenched with satd aq Na2SO3 (15 mL) and extracted with Et2O
(3ꢂ20 mL). The organic layer was washed with brine and dried over
Na2SO4 to provide 4-methylbenzonitrile in over 80% purity. The
product was purified by a short column chromatography on silica
gel (Hexane/EtOAc¼9:1) to give pure 4-methylbenzonitrile in 80%
yield as a colorless solid.
6.95 (d, J¼8.9 Hz, 2H), 7.59 (d, J¼8.9 Hz, 2H); 13C NMR (125 MHz,
CDCl3)
d¼55.5, 103.8, 114.7, 119.2, 133.9, 162.8.
4.3.9. 2,4-Dimethoxybenzonitrile. Mp 93e94 ꢀC (commercial, Mp
93e94 ꢀC); IR: 2219 cmꢁ1; 1H NMR (CDCl3, 500Hz),
¼3.86 (s, 3H),
d
3.90 (s, 3H), 6.46 (s, 1H), 6.51 (d, J¼8.5 Hz, 1H), 7.48 (d, J¼8.5 Hz,
1H); 13C NMR (100 MHz, CDCl3):
116.9, 134.8, 162.8, 164.6.
d¼55.6, 55.9, 93.8, 98.4, 105.7,
4.3.10. 2,4,6-Trimethoxybenzonitrile. Mp 139e140 ꢀC (commercial,
Mp 143e145 ꢀC); IR: 2212 cmꢁ1; 1H NMR (CDCl3:500 MHz)
(s, 3H), 3.89 (s, 6H), 6.07 (s, 2H); 13C NMR (100 MHz, CDCl3)
56.0, 83.7, 90.2, 114.6, 163.6, 165.3.
d
¼3.86
d
¼55.6,
4.3. Typical experimental procedure for the conversion of
aromatic bromides into aromatic nitriles with DIH
4.3.11. 4-(N,N-dimethyamino)benzonitrile. Mp 74e75 ꢀC (commer-
n-Butyllithium (1.67 M solution in hexane, 3.3 mL, 5.5 mmol) was
added dropwise to a solution of p-bromotoluene (0.86 g, 5.0 mmol)
in THF (5 mL) at ꢁ70 ꢀC. After 30 min, the resulting mixture was
stirred for 5 min at 0 ꢀC and then DMF (4.25 mL, 5.5 mmol) was
added and the obtained mixture was stirred at 0 ꢀC. After 1 h at the
same temperature, aq NH3 (10 mL, 150 mmol) and DIH (1.14 g,
3.0 mmol) were added and the resulting mixture was stirred for 2 h
at rt. The reaction mixture was quenched with satd aq Na2SO3
(15 mL) and extracted with ether (3ꢂ20 mL). The organic layer was
washed with brine and dried over Na2SO4 to provide 4-methyl-
benzonitrile in over 75% purity. The product was purified by a col-
umn chromatography on silica gel (Hexane/EtOAc¼9:1) to give pure
4-methylbenzonitrile in 75% yield as a colorless solid.
cial, Mp 75 ꢀC); IR: 2210 cmꢁ1; 1H NMR (CDCl3:500 MHz)
d
¼3.04 (s,
6H), 6.64 (d, J¼9.1 Hz, 2H), 7.47 (d, J¼9.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d
¼39.9, 97.2, 111.3, 120.7, 133.3, 152.4.
4.3.12. 1-Naphthonitrile. Mp 35e36 ꢀC (commercial, Mp
36e38 ꢀC); IR: 2219 cmꢁ1 1H NMR (CDCl3:500 MHz)
;
d
¼7.49 (t,
J¼7.9 Hz, 1H), 7.59 (t, J¼8.2 Hz, 1H), 7.67 (t, J¼8.2 Hz, 1H), 7.89 (d,
J¼7.9 Hz, 1H), 7.91 (d, J¼7.9 Hz, 1H), 8.05 (d, J¼8.2 Hz, 1H), 8.22 (d,
J¼8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼110.0, 117.7, 124.8,
d
124.9, 127.4, 128.4, 128.5, 132.2, 132.5, 132.8, 133.2.
4.3.13. 2-Naphthonitrile. Mp 68e70 ꢀC (commercial, Mp
66e70 ꢀC); IR: 2225 cmꢁ1; 1H NMR (CDCl3:500 MHz)
d
¼7.58e7.68
Most aromatic nitriles mentioned in this work are commercially
available and were identified by comparison with the authentic
samples.
(m, 3H), 7.88e7.93 (m, 3H), 8.24 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
¼109.3, 119.2, 126.3, 127.6, 128.0, 128.4, 129.0, 129.2, 132.2, 134.1,
134.6.
4.3.1. 4-Methylbenzonitrilꢁe1. Mp 26e28 ꢀC (commercial, Mp
4.3.14. 4-Cyanobiphenyl. ꢁM1 p 85e88 ꢀC (commercial, Mp
26e28 ꢀC); IR: 2227 cm
;
1H NMR (CDCl3:500 MHz)
d
¼2.41 (s,
85e87 ꢀC); IR: 2225 cm
;
1H NMR (CDCl3, 500 MHz)
d
¼7.44 (t,
3H), 7.26 (d, J¼8.1 Hz, 2H), 7.52 (d, J¼8.1 Hz, 2H); 13C NMR
J¼7.3 Hz, 1H), 7.49 (t, J¼7.3 Hz, 2H), 7.59 (d, J¼7.3 Hz, 2H), 7.69 (d,
(125 MHz, CDCl3)
d
¼21.7, 109.2, 119.1, 129.7, 131.9, 143.6.
J¼8.8 Hz, 2H), 7.73 (d, J¼8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d¼110.8, 118.9, 127.1, 127.6, 128.6, 129.0, 132.5, 139.0, 145.6.
4.3.2. 3-Methylbenzonitrile. Oil (commercial); IR: 2229 cmꢁ1 1H
;
NMR (CDCl3:500 MHz)
(125MHz, CDCl3)
d
¼2.38 (s, 3H), 7.32e7.47 (m, 4H); 13C NMR
4.3.15. 2-Cyanopyridine.ꢁM1 p 24e25 ꢀC (commercial, Mp
d
¼20.8,111.9,118.8,128.8,129.0,132.2,133.4,139.0.
24e27 ꢀC); IR: 2236 cm
;
1H NMR (CDCl3, 500 MHz)
d
¼7.56 (dd,
J¼7.8 and 4.6 Hz, 1H), 7.73 (d, J¼7.8 Hz, 1H), 7.88 (t, J¼7.8 Hz, 1H),
4.3.3. 2-Methylbenzonitrile. Oil (commercial); IR: 2225 cmꢁ1
;
1H
8.74 (d, J¼4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼117.0, 126.9,
d
NMR (CDCl3:500 MHz)
d
¼2.54 (s, 3H), 7.26 (t, J¼7.6 Hz, 1H), 7.31 (d,
128.3, 133.4, 136.9, 150.8.
J¼7.6 Hz, 1H), 7.48 (t, J¼7.6 Hz, 1H), 7.58 (d, J¼7.6 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
d
¼20.0,112.3,117.8,126.0,130.0,132.1,132.3,141.5.
4.3.16. 4-Chlorobenzonitrile. Mp 92e95 ꢀC (commercial, Mp
90e93 ꢀC); IR: 2226 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼7.48 (d,
4.3.4. 2,4-Dimethylbenzonitrile. Mp 23e24 ꢀC (commercial, Mp
23e25 ꢀC); IR: 2221 cmꢁ1; 1H NMR (CDCl3:500 MHz)
J¼8.8 Hz, 2H), 7.61 (d, J¼8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d
¼2.36 (s, 3H),
d¼110.7, 117.9, 129.6, 133.3, 139.5.
2.47 (s, 3H), 7.05 (d, J¼8.0 Hz, 1H), 7.10 (s, 1H) 7.43 (d, J¼8.0 Hz, 1H).
4.3.5. 3,4-Dimethylbenzonitrile. Mp 63e64 ꢀC (commercial, Mp
4.4. Typical experimental procedure for the conversion of
aromatics into aromatic nitriles with I2
64e67 ꢀC); IR: 2224 cmꢁ1; 1H NMR (CDCl3:500 MHz)
d¼2.29 (s, 3H),
2.32 (s, 3H), 7.21 (d, J¼7.8 Hz, 1H), 7.39 (d, J¼7.8 Hz, 1H), 7.41 (s, 1H).
n-Butyllithium (1.67 M solution in hexane, 2.9 mL, 4.8 mmol) was
added dropwise into a solution of 1,3-dimethoxybenzene (0.55 g,
4.0 mmol) in THF (5 mL) at 0 ꢀC and the mixture was stirred for 2 h at
the same temperature. Then, DMF (0.34 mL, 4.4 mmol) was added to
the mixture and the obtained mixture was stirred at 0 ꢀC. After 2 h at
the same temperature, aq NH3 (8 mL, 120 mmol) and I2 (1.12 g,
4.4 mmol) were added and stirred for 2 h at rt. The reaction mixture
was quenched with satd aq Na2SO3 (15 mL) and was extracted with
Et2O (3ꢂ20 mL). The organic layer was washed with brine and dried
over Na2SO4 to provide 2,6-dimethoxybenzonitrile in over 80% pu-
rity. The product was purified by a short column chromatography on
silica gel (Hexane/EtOAc¼3:1) to give pure 2,6-dimethoxybenzoni-
trile in 91% yield as a colorless solid.
4.3.6. 2,5-Dimethylbenzonitrile. Oil (commercial); IR: 2227 cmꢁ1
;
1H NMR (CDCl3:500 MHz)
d
¼2.33 (s, 3H), 2.48 (s, 3H), 7.18 (d,
J¼7.9 Hz, 1H), 7.27 (d, J¼7.9 Hz, 1H), 7.36 (s, 1H); 13C NMR (125 MHz,
CDCl3)
d
¼19.6, 20.3, 112.2, 118.0, 129.8, 132.3, 133.3, 135.8, 138.4.
4.3.7. 2,4,6-Trimethylbenzonitrile. Mp 50e51 ꢀC (lit.10i Mp
54e55 ꢀC); IR: 2218 cmꢁ1; 1H NMR (CDCl3:500 MHz)
d
¼2.32 (s, 3H),
2.47 (s, 6H), 6.92 (s, 2H); 13C NMR (125 MHz, CDCl3)
110.2, 117.6, 128.1, 141.9, 142.7.
d
¼20.6, 21.5,
4.3.8. 4-Methoxybenzonitrile. Mp 54e55 ꢀC (commercial, Mp
57e59 ꢀC); IR: 2216 cmꢁ1; 1H NMR (CDCl3:500 MHz)
¼3.86 (s, 3H),
d

S. Ushijima et al. / Tetrahedron 67 (2011) 958e964
963
4.5. Typical experimental procedure for the conversion of
aromatics into aromatic nitriles with DIH
2H), 7.68 (d, J¼7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d
¼111.8,
112.0, 118.4, 122.5, 124.5, 125.4, 127.2, 128.4, 155.6.
n-Butyllithium (1.67 M solution in hexane, 2.9 mL, 4.8 mmol)
was added dropwise to a solution of 1,3-dimethoxybenzene
(0.55 g, 4.0 mmol) in THF (5 mL) at 0 ꢀC. After 2 h, DMF (0.34 mL,
4.4 mmol) was added to the mixture and the obtained mixture
was stirred at 0 ꢀC. After 2 h at the same temperature, aq NH3
(8 mL, 120 mmol) and DIH (0.91 g, 2.4 mmol) were added and
the resulting mixture was stirred for 2 h at rt. The reaction
mixture was quenched with satd aq Na2SO3 (15 mL) and was
extracted with ether (3ꢂ20 mL). The organic layer was washed
with brine and dried over Na2SO4 to provide 2,6-dimethox-
ybenzonitrile in over 80% purity. The product was purified by
a column chromatography on silica gel (Hexane/EtOAc¼3:1) to
give pure 2,6-dimethoxybenzonitrile in 94% yield as a colorless
solid.
4.5.10. Benzothiophene-2-carbonitrile. Oil (commercial, Mp 24e
28 ꢀC); IR: 2217 cmꢁ1
;
1H NMR (CDCl3, 500 MHz)
d
¼7.43 (t,
J¼7.6 Hz, 1H), 7.48 (t, J¼7.6 Hz, 1H), 7.77e7.85 (m, 3H); 13C NMR
(125 MHz, CDCl3):
137.2, 141.0.
d
¼109.4, 114.3, 122.2, 125.1, 125.6, 127.7, 134.8,
4.5.11. 5-Decylfuran-2-carbonitrile. Oil; IR: 2229 cmꢁ1
;
1H NMR
(CDCl3, 500 MHz)
d
¼0.88 (t, J¼7.0 Hz, 3H), 1.21e1.38 (m, 14H), 1.65
(quintet, J¼7.1Hz, 2H), 2.66(t,J¼7.1Hz, 2H), 6.11(d, J¼3.4Hz,1H), 6.99
(d, J¼3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
¼14.0, 22.6, 27.5, 28.1,
d
28.9, 29.1, 29.2, 29.4, 29.5, 31.8,106.9,111.9,123.0,124.2,162.5; HRMS
(FAB) [MþH]þ, calcd for C15H24NO¼234.1858, found¼234.1861.
4.5.12. 5-Decylthiophene-2-carbonitrile. Oil; IR: 2218 cmꢁ1
;
1H
NMR (500 MHz, CDCl3):
d
¼0.88 (t, J¼7.1 Hz, 3H),1.23e1.38 (m,14H),
4.5.1. 2-Methoxybenzonitrile. Oil (commercial); IR: 2228 cmꢁ1
;
1H
1.67 (quintet, J¼7.5 Hz, 2H), 2.83 (t, J¼7.5 Hz, 2H), 6.78 (d, J¼3.6, Hz,
NMR (400 MHz, CDCl3)
d
¼3.92 (s, 3H), 6.96e7.04 (m, 2H), 7.51e7.57
1H), 7.43 (d, J¼3.6 Hz,1H); 13C NMR (100 MHz, CDCl3):
¼13.9, 22.5,
d
(m, 2H); 13C NMR (125 MHz, CDCl3):
120.6, 133.4, 134.3, 161.0.
d
¼55.8, 101.3, 111.1, 116.3,
28.8, 29.0, 29.1, 29.3, 29.6, 29.9, 31.2, 31.7, 106.6, 114.3, 124.7, 137.4,
154.2; HRMS(FAB) [MþH]þ, calcd for C15H24NS¼250.1629,
found¼250.1636.
4.5.2. 2,6-Dimethoxybenzonitrile. Mp 117e119 ꢀC (commercial, Mp
119e123 ꢀC); IR: 2220 cmꢁ1; 1H NMR (CDCl3, 500 MHz)
d
¼3.90 (s,
4.5.13. 3-Methoxy-2-naphthonitrile. Mp 123e125 ꢀC (lit.16 Mp
6H), 6.56 (d, J¼8.5 Hz, 2H), 7.44 (t, J¼8.5 Hz, 1H); 13C NMR
125 ꢀC); IR: 2224 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d¼4.02 (s, 3H),
(100 MHz, CDCl3):
d
¼56.1, 91.2, 103.4, 114.0, 134.7, 162.6.
7.19 (s,1H), 7.43 (dd, J¼6.8 and 7.2 Hz,1H), 7.58 (dd J¼6.8 and 7.2 Hz,
1H), 7.75 (d, J¼8.2 Hz, 1H), 7.79 (d, J¼8.2 Hz, 1H), 8.15 (s, 1H); 13C
4.5.3. 2,4,6-Trimethoxybenzonitrile. Mp 139e140 ꢀC (commercial
NMR (100 MHz, CDCl3):
d
¼55.9, 103.3, 106.2, 116.4, 125.0, 126.8,
Mp 143e145 ꢀC); IR: 2212 cmꢁ1; 1H NMR (400 MHz, CDCl3):
(s, 3H), 3.89 (s, 6H), 6.07 (s, 2H); 13C NMR (100 MHz, CDCl3):
56.0, 83.7, 90.2, 114.6, 163.6, 165.3.
d
¼3.86
127.3, 128.1, 129.3, 135.9, 136.1, 156.0.
d¼55.6,
4.5.14. 4-Cyano-40-pentylbiphenyl. Oil (commercial); IR: 2226
cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼0.89 (t, J¼6.8 Hz, 3H),
4.5.4. 2,5-Dimethoxybenzonitrile. Mp 79e82 ꢀC (commercial, Mp
1.28e1.38 (m, 4H), 1.58e1.68 (m, 2H), 2.62 (t, J¼7.7 Hz, 2H), 7.25 (d,
81e85 ꢀC); IR: 2224 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
¼3.78 (s,
J¼8.2 Hz, 2H), 7.46 (d, J¼8.2 Hz, 2H), 7.57e7.65 (m, 4H); 13C NMR
3H), 3.89 (s, 3H), 6.91 (d, J¼9.0 Hz, 1H), 7.05e7.11 (m, 2H); 13C NMR
(100 MHz, CDCl3):
127.2, 129.0, 132.3, 136.2, 143.6, 145.3.
d
¼13.9, 22.4, 30.9, 31.3, 35.4, 110.3, 118.8, 126.9,
(100 MHz, CDCl3):
148.7.
d¼48.9, 49.3, 94.7, 105.5, 109.3, 110.5, 113.8, 146.1,
4.5.15. 2-(methoxymethoxy)-5-methylbenzonitrile. Mp 59e61 ꢀC;
4.5.5. 2,3-Dimethoxybenzonitrile. Mp 41e42 ꢀC (commercial, Mp
43e46 ꢀC); IR: 2228 cmꢁ1 1H NMR (CDCl3, 500 MHz)
¼3.89 (s,
3H), 4.03 (s, 3H), 7.07e7.16 (m, 3H); 13C NMR (100 MHz, CDCl3):
¼56.0, 61.7, 107.0, 116.3, 116.9, 124.4, 124.5, 151.7, 152.6.
IR: 2225 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d¼2.31 (s, 3H), 3.52 (s,
;
d
3H), 5.26 (s, 2H), 7.12 (d, J¼8.6 Hz,1H), 7.31 (d, J¼8.6 Hz, 1H), 7.36 (s,
1H); 13C NMR (125 MHz, CDCl3)
d¼20.2, 56.5, 94.8, 102.6, 114.9,
d
116.5, 131.6, 133.5, 135.0, 157.0; HRMS(ESI)[MþH]þ, calcd for
C10H12O2N¼178.0863, found¼178.0861.
4.5.6. 2,6-Difluorobenzonitrile. Oil (commercial Mp 25e28 ꢀC); IR:
2241 cmꢁ1 1H NMR (400 MHz, CDCl3):
¼7.05e7.10 (m, 2H),
7.58e7.67 (br, 1H); 13C NMR (100 MHz, CDCl3):
¼92.5 (s), 109.1 (s),
112.2 (dd, J1¼6.2, J2¼3.8 Hz),135.5 (t, J¼10.5 Hz),163.3 (J¼257.5 Hz).
;
d
4.5.16. 2-Hydroxy-5-methylbenzonitrile. Mp 100e102 ꢀC; IR:
d
2234 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼2.28 (s, 3H), 6.12e6.65
(br, 1H), 6.90 (d, J¼8.6 Hz, 1H), 7.24e7.3(m, 2H); 13C NMR (125 MHz,
CDCl3):
d¼20.1, 90.0, 116.5, 130.5, 132.5, 135.6, 156.5; HRMS(ESI)
4.5.7. 2-Cyano-N-tosylindole. Mp 160e161 Mp
ꢀC (lit.14
[MþH]þ, calcd for C8H8ON¼134.0600, found¼134.0603.
160e162 ꢀC); IR: 1173, 1377, 2227 cmꢁ1; 1H NMR (CDCl3, 500 MHz)
d
¼2.37 (s, 3H), 7.27 (d, J¼8.2 Hz, 2H), 7.32e7.38 (m, 2H), 7.52e7.60
Acknowledgements
(m, 2H), 7.90 (d, J¼8.4 Hz, 2H), 8.21 (d, J¼8.4 Hz, 1H); 13C NMR
(125 MHz, CDCl3):
127.1, 127.4, 128.6, 130.2, 134.3, 136.6, 146.1.
d¼21.6, 108.9, 112.2, 114.5, 122.5, 123.0, 124.7,
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 Ja-
pan Chemical Innovation Institute (JCII), and Futaba Electronics
Memorial Foundation, is gratefully acknowledged.
4.5.8. 2-Cyano-N-methylindole. Mp 70e73 ꢀC; IR: 2223 cmꢁ1 1H
;
NMR (CDCl3:500 MHz)
d¼3.91 (s, 3H), 7.16 (s, 1H), 7.21 (t, J¼6.8,1H),
7.34e7.44 (m, 2H), 7.66 (d, J¼8.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3):
d¼31.4, 110.0, 110.1, 112.6, 113.6, 121.3, 122.2, 125.7, 126.0,
137.9; HRMS(APCI) [M]þ, calcd for C10H8N2¼156.0682,
found¼156.0681.
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4.5.9. Benzofuran-2-carbonitrile. Oil (lit.15); IR: 2227 cmꢁ1; 1H NMR
(CDCl3:500 MHz)
d¼7.36 (t, J¼7.5 Hz,1H), 7.46 (s, 1H), 7.49e7.58 (m,

964
S. Ushijima et al. / Tetrahedron 67 (2011) 958e964
€
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