Practical one-pot transformation of electron-rich aromatics into aromatic nitriles with molecular iodine and aq NH3 using Vilsmeier-Haack reaction

Article abstract of DOI:10.1016/j.tet.2012.04.034

Various electron-rich aromatics could be efficiently transformed into the corresponding aromatic nitriles in good to moderate yields by treatment with DMF and POCl₃, followed by the reaction with molecular iodine or 1,3-diiodo-5,5-dimethylhydantoin (DIH) in aq NH₃. Some of less reactive aromatics, such as anisole, 1,2-dimethoxybenzene, 1,4-dimethoxybenzene, and mesityrene, could be also transformed into the corresponding aromatic nitriles in good to moderate yields using N-methylformanilide and O(POCl ₂)₂, followed by the reaction with molecular iodine in aq NH₃. Moreover, propiophenone derivatives could be successfully transformed into the corresponding β-chlorocinnamonitriles by the reaction with DMF and POCl₃, followed by the reaction with molecular iodine and aq NH₃. These reactions are novel metal-free one-pot methods for the preparation of aromatic nitriles from electron-rich aromatics and β-chlorocinnamonitriles from propiophenones.

Full text of DOI:10.1016/j.tet.2012.04.034

Tetrahedron 68 (2012) 4588e4595
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Practical one-pot transformation of electron-rich aromatics into aromatic nitriles
with molecular iodine and aq NH3 using VilsmeiereHaack reaction
*
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 electron-rich aromatics could be efficiently transformed into the corresponding aromatic nitriles
in good to moderate yields by treatment with DMF and POCl3, followed by the reaction with molecular
iodine or 1,3-diiodo-5,5-dimethylhydantoin (DIH) in aq NH3. Some of less reactive aromatics, such as
anisole, 1,2-dimethoxybenzene, 1,4-dimethoxybenzene, and mesityrene, could be also transformed into
the corresponding aromatic nitriles in good to moderate yields using N-methylformanilide and
O(POCl2)2, followed by the reaction with molecular iodine in aq NH3. Moreover, propiophenone de-
Received 15 March 2012
Received in revised form 7 April 2012
Accepted 9 April 2012
Available online 14 April 2012
rivatives could be successfully transformed into the corresponding b-chlorocinnamonitriles by the re-
action with DMF and POCl3, followed by the reaction with molecular iodine and aq NH3. These reactions
are novel metal-free one-pot methods for the preparation of aromatic nitriles from electron-rich aro-
matics and b-chlorocinnamonitriles from propiophenones.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
at 130e140 ꢀC,6g CuIꢁalkylimidazoleꢁPd/CꢁCuIꢁK4[Fe(CN)6] at
140e180 ꢀC,6h Zn(CN)2ꢁPd2(dba)3ꢁdppfꢁZnꢁZnBr2 at 95 ꢀC,6i
CuOꢁPdꢁK4[Fe(CN)6] at 120 ꢀC,6j K4Fe(CN)6ꢁCuI/microwave,6k
Pd(OAc)2ꢁCu(OAc)2ꢁ K4[Fe(CN)6] at 130 ꢀC,6l Pd/CꢁdppfꢁZn(CN)2 at
100e120 ꢀC,6m Pdꢁt-Bu3PꢁNaCN at 70 ꢀC,6n Pd(dba)2ꢁ K4[Fe(CN)6]ꢁt-
Aromatic nitriles are important synthetic transformation pre-
cursors because they can be easily transformed into amides, esters,
primary amines, carboxylic acids, and nitrogen-containing heterocy-
cles, such as tetrazoles and oxazoles, and are also used as synthetic
intermediates for agrochemicals, pharmaceuticals, and functional
materials.1 Practically, Citalopram hydrobromideÒ (treatment of al-
cohol dependency), PericiazineÒ (anti-psychotic drug), FadrozoleÒ
(oncolytic drug), and LetrozoleÒ (breast cancer therapy) are pharma-
ceutically important aromatic nitriles, and 4-cyano-40-pentylbiphenyl
is a typical liquid crystal material.2 The most typical methods for the
preparation of aromatic nitriles are the dehydration of aromatic pri-
mary amides3,4 with SOCl2, TsCl/Py, P2O5, POCl3, COCl2, (EtO)3P/I2,
Ph3P/CCl4, (COCl)2/DMSO, (CH2O)n/HCO2H, (CF3SO2)2O/Et3N, or
Bu2SnO, the condensation of carboxylic acids with NH3/silica gel or
NH3/ethyl polyphosphate, the reaction of esters with Me2AlNH2,4
and the Sandmeyer reaction of aromatic diazonium ion with toxic
CuCN.4,5 On the other hand, recently, the direct transformation of
aromatic bromides into the corresponding aromatic nitriles has been
actively studied with CuCN in N,N-dimethylformamide (DMF) at
153 ꢀC (the Rosenmundevon Braun reaction),6a Pd(OAc)2ꢁK4[Fe(CN)6]
at 120 ꢀC,6b Pdꢁ(binaphthyl)P(But)2ꢁZn(CN)2ꢁZn at 80e95 ꢀC,6c
Pd2(dba)3ꢁZn(CN)2ꢁDPPF at 80e120 ꢀC,6d Pd(tmhd)2ꢁK4[Fe(CN)6]
at 80 ꢀC,6e Zn(CN)2ꢁPd2(dba)3 at 100 ꢀC,6f Pd/CꢁCuIꢁK4[Fe(CN)6]ꢁ3H2O
BuOK at 50 ꢀC,6o Pd{C6H4[CH2N(CH2Ph)2]}(
m-Br)2ꢁK4[Fe(CN)6] at
130 ꢀC,6p and Pd(Ph3P)4ꢁK4[Fe(CN)6] at 85 ꢀC,6q all of which require
toxic metalcyanides. The direct cyanation of aromatics containing a 2-
pyridyl group via CeH bond cleavage with Cu(OAc)2ꢁTMSCN7a
and Pd(OAc)2ꢁCuBrꢁCuCN7b at 130 ꢀC, the cyanation of indoles at 3-
position with Pd(OAc)2ꢁCu(OAc)2ꢁK4[Fe(CN)6],6l the cyanation of
benzothiazole with CuCNꢁphenanthrolineꢁI2ꢁNaCNꢁt-BuOLi at
110 ꢀC,7c and the cyanation of indoles and aromatics bearing a 2-
pyridyl group with FeI2ꢁCuCNꢁPhI(OAc)2,7d all of which require toxic
metal cyanides as well, were reported. In addition, the cyanation of
aromatics bearing a 2-pyridyl group with Pd(OAc)2ꢁCuBr2ꢁDMF at
130 ꢀC,8a the cyanation of aromatic bromides and iodides in the
presence of Cu(OAc)2 in DMF at 150 ꢀC,8b and the cyanation of indoles
at 3-position with Pd(OAc)2ꢁCuBr2ꢁFeCl2ꢁDMF at 130 ꢀC,8c under
cyanide-free conditions were reported. Moreover, the metal-free
cyanation of indoles and pyrroles with PhI(O2CCF3)2 and TMSCN
in the presence of BF3ꢁEt2O9a and GaCl3-catalyzed cyanation of
electron-rich aromatics with BrCN9b were also reported. However,
most of the methods mentioned above required toxic transition
metals and/or cyanides. Thus, a transition-metal-free and cyanide-
free, and therefore environmentally benign and economical ap-
proach for the transformation of aromatics into the corresponding
aromatic nitriles is greatly required. To the best of our knowledge,
* Corresponding author. E-mail address: togo@faculty.chiba-u.jp (H. Togo).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.034

S. Ushijima et al. / Tetrahedron 68 (2012) 4588e4595
4589
Table 1
studies on the one-pot transformation of aromatics into the corre-
sponding aromatic nitriles using less toxic reagents are extremely
limited. Typical methods are the reaction of electron-rich aromatics
with chlorosulfonylisocyanate to form N-chlorosulfonyl amides and
the subsequent treatment with DMF to provide aromatic nitriles, to-
gether with the evolution of SO3 and HCl,10a,b and the reaction of in-
doles or pyrroles with triphenylphospineethiocyanogen (TPPT).10c
Another method reported by us recently is the reaction of methox-
ybenzenes and fluorobenzenes with n-BuLi and subsequently DMF,
followed by the reaction with molecular iodine and aq NH3.11
Here, as part of our ongoing studies on the use of molecular
iodine for organic synthesis,12 we would like to report one-pot
transformation of aromatics into the corresponding aromatic ni-
triles and related reactions as a full paper.13
Optimization of the second-step reaction for one-pot transformation of 1-
methoxynaphthalene into 1-cyano-4-methoxynaphthalene
2. Results and discussion
Entry
Reagent
Aq NH3 (x ml)
Time (h)
Yield (%)
The VilsmeiereHaack reaction is an efficient method for the
transformation of electron-rich aromatics into the corresponding
aromatic aldehydes using POCl3 and DMF.14,15 Based on this re-
action and our previous study on the use molecular iodine for the
transformation of benzylic halides and benzylic alcohols into aro-
matic nitriles,12iel we recently reported a one-pot transformation of
electron-rich aromatics into the corresponding aromatic nitriles
using POCl3 and DMF, followed by the reaction with molecular io-
dine and aq NH3.13 To further extend the application of this novel
metal-free and cyanide-free introduction of a cyano group into
aromatics, the details and limitations of the reaction were studied.
As the first step, 1-methoxynaphthalene (6 mmol) was treated
with POCl3 (1.1 equiv) and DMF (4.0 equiv) at 100 ꢀC for 2 h to form
N,N-dimethyliminium salt quantitatively. Then, molecular iodine
and aq NH3 (28e30%) were added to the formed N,N-dimethyli-
minium salt at room temperature as the second step, as shown in
Table 1 (entries 1e5). Optimization studies indicated that treat-
ment of the N,N-dimethyliminium salt with molecular iodine
(2.0 equiv) and aq NH3 (12 mL) for 3 h at room temperature gave 4-
methoxy-1-cyanonaphthalene in 99% yield (entry 5). When mo-
lecular iodine was not added to the N,N-dimethyliminium salt at
the second step, 4-methoxy-1-cyanonaphthalene was not obtained
at all and instead, 4-methoxy-1-naphthaldehyde was obtained
quantitatively (entry 6). On the other hand, when N-chlor-
osuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccini-
mide (NIS), and 1,3-diiodo-5,5-dimethylhydantoin (DIH) were
used instead of molecular iodine, NCS did not work at all, NBS
gave 4-methoxy-1-cyanonaphthalene in moderate yield, and NIS
and DIH showed high reactivity to provide 4-methoxy-1-
cyanonaphthalene in good yields (entries 7e10).
Thus, the use of molecular iodine or iodine-containing reagents,
such as NIS and DIH, is the key to furnish 4-methoxy-1-
cyanonaphthalene in good yields. Here, DIH has two NeI bonds
and therefore, it works as 2 equiv of molecular iodine. Based
on these results, various electron-rich aromatics, such as 1,3-
dimethoxybenzene, 1,3,5-trimethoxybenzene, 1,2,3-trimethoxy-
benzene, 1-methoxynaphthalene, 2-methoxynaphthalene, 1,5-
dimethoxynaphthalene, and N,N-dimethylaniline, were treated
with POCl3 and DMF, followed by the reaction of molecular iodine
(2.0 equiv) or DIH (1.0 equiv), and aq NH3 (12 mL) at room tem-
perature for 3 h to provide the corresponding aromatic nitriles in
good yields with high regioselectivity, as shown in Table 2 (entries
1e8). There is little difference in the yields of aromatic nitriles
between molecular iodine and DIH. The same treatment of heter-
oaromatics, such as indole, N-methylindole, N-methylcarbazole,
thiophene, 2-decylthiophene, and 2-decylfuran, gave also the cor-
responding heteroaromatic nitriles in good to moderate yields with
high regioselectivities (entries 9e11, 13e15). Treatment of N-ben-
zylpyrrole with POCl3 and DMF, followed by the reaction with
1
2
3
4
5
6
7
8
9
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.5 equiv)
I2 (2.0 equiv)
d
6
6
3
18
3
3
3
3
3
3
3
41
38
66
71
99
0
Trace
43
89
89
12
12
12
12
12
12
12
12
NCS (2.0 equiv)
NBS (2.0 equiv)
NIS (2.0 equiv)
DIH (1.25 equiv)
10
3
molecular iodine or DIH, and aq NH3 gave two regioisomers, N-
benzyl-2-cyanopyrrole and N-benzyl-3-cyanopyrrole, in good
yields; in this case, the former nitrile was the major product (en-
try 12). Meanwhile, the same treatment of benzothiophene and
benzofuran did not generate the corresponding heteroaromatic
nitriles at all. Then, less reactive aromatics, such as anisole,
1,2-dimethoxybenzene, 1,4-dimethoxybenzene, and mesitylene,
for the VilsmeiereHaack reaction were used as substrates for
the present reaction. Anisole, 1,2-dimethoxybenzene, 1,4-
dimethoxybenzene, and mesitylene did not react with POCl3 and
DMF effectively and therefore, the corresponding aromatic nitriles
were formed in extremely low yields, as shown in Table 3 (Method
A, entries 1, 4, 7, 16). However, when anisole, 1,2-dimethoxy-
benzene, and 1,4-dimethoxybenzene were treated with O(POCl2)2
and N-methylformanilide (NMFA) (Method B) at 100 ꢀC for 10e13 h
in the first step,15 and then, molecular iodine and aq NH3 were
added to the reaction mixture, 1-cyano-4-methoxybenzene, 1-
cyano-3,4-dimethoxybenzene, and 1-cyano-2,5-dimethoxyben-
zene were furnished in good yields with high regioselectivities,
respectively (entries 2, 5, 8). Treatment of 1,2,3-trimethoxybenzene
and anthracene with POCl3 and DMF (Method A), followed by the
reaction with molecular iodine and aq NH3 gave the corresponding
aromatic nitriles in moderate yields, while the same reactions with
O(POCl2)2 and NMFA, followed by the reaction with molecular io-
dine and aq NH3 gave 1-cyano-2,3,4-trimethoxybenzene and 9-
cyanoanthracene in good yields with high regioselectivities, re-
spectively, (entries 10, 11, 13, 14). This is due to the formation of
highly electrophilic iminium species from the reaction of NMFA and
O(POCl2)2. Treatment of 1,2-dimethoxybenzene, 1,4-dimethoxy-
benzene, anthracene, and mesitylene with (CF3SO2)2O and DMF,16

4590
S. Ushijima et al. / Tetrahedron 68 (2012) 4588e4595
Table 2 (continued)
Table 2
One-pot transformation of aromatics into aromatic nitriles
Entry
AreH
Temp
(ꢀC)
Time
(h)
Yield (%)
I2
DIH
15
80
2
6
91
0
81
Entry
AreH
Temp
(ꢀC)
Time
(h)
Yield (%)
I2
16
100
d
DIH
92
a
DIH (1.25 equiv) was used.
1
2
40
40
3
3
74
99
followed by the reaction with molecular iodine and aq NH3 gen-
erated the corresponding aromatic nitriles in moderate yields, re-
spectively, (entries 6, 9, 15, 17). However, the introduction of
a cyano group into naphthalene, benzothiophene, and benzofuran
with methods AeC did not succeed because the introduction of the
N,N-dimethyliminium group to the aromatics (the first step) did not
occur.
99
3
4
5
6
100
100
100
80
4
2
6
4
59
99
90
91
67
When the previous method11 and the present method were
compared in terms of the introduction of a cyano group into 1,3-
dimethoxybenzene and N-methylindole, the complementary in-
troduction of the cyano group could be achieved, as shown in
Scheme 1.
Thus, when 1,3-dimethoxybenzene and N-methylindole were
treated with POCl3 and DMF, followed by the reaction with mo-
lecular iodine and aq NH3, 1-cyano-2,4-dimeth oxybenzene and N-
methyl-3-cyanoindole were obtained in good yields with high
regioselectivities, respectively. On the other hand, when 1,3-
dimethoxybenzene and N-methylindole were treated with n-BuLi
and subsequently DMF, followed by the reaction with molecular
iodine and aq NH3, 2-cyano-1,3-dimethoxybenzene and N-methyl-
2-cyanoindole were obtained in good yields with high regiose-
lectivities, respectively.
89a
90a
99a
Then, as a synthetic application of the present method, aro-
matic ketones were used as the substrate. When propiophenone
was treated with POCl3 (1.6 equiv) and DMF (1.6 equiv) at 60 ꢀC
7
8
100
80
10
2
67
86
d
for 3 h,
b-chloro-a-methylcinnamonitrile was obtained in 93%
86a
yield with E/Z¼83/17 ratio. Based on this result,
p-methylpropiophenone, p-methoxypropiophenone, p-chlor-
opropiophenone, p-fluoropropiophenone, n-nonanophenone,
a-
tetralone, and 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one
were treated with POCl3 and DMF, followed by the reaction
with molecular iodine and aq NH3 to provide the corresponding
9
rt
3
81
65
b
-chlorocinnamonitrile derivatives in good yields, respectively, as
shown in Table 4.
10
11
40
3
1
99
99
92
A plausible reaction mechanism for the one-pot transformation
of electron-rich aromatics into aromatic nitriles is proposed, as
shown in Scheme 2. The initial step involves the VilsmeiereHaack
reaction to form aromatic N,N-dimethyliminium salt (a). Once ar-
omatic N,N-dimethyliminium salt (a) is formed, it reacts smoothly
with aq NH3 to form the corresponding aromatic imine (b), which
further reacts with molecular iodine to generate the corresponding
aromatic N-iodoimine (c). Once N-iodoimine (c) is formed, elimi-
nation of HI rapidly occurs in aq NH3 to provide the corresponding
aromatic nitrile.
100
98a
12
40
1
87
86
(
a
:
b
¼72:15)
(a
:
b
¼62:24)
3. Conclusion
13
14
80
80
4
2
45
76
54
81
In conclusion, various electron-rich aromatics, such as
1,3-dimethoxybenzene, 1,3,5-trimethoxybenzene, 1-methoxynap-
hthalene, 2-methoxynaphthalene, 1,5-dimethoxynaphthalene,
anthracene, N,N-dimethylaniline, indole, 2-decylthiophene,

S. Ushijima et al. / Tetrahedron 68 (2012) 4588e4595
4591
Table 3
One-pot transformation of aromatics into aromatic nitriles with modefied Vils-
meiereHaack reaction
Entry
1
AreH
Method
A
Temp (ꢀC)
100
Time (h)
10
Yield (%)
11
2
3
B
C
100
100
13
13
69
19
Scheme 1. Complementary one-pot introduction of cyano group with (1) POCl3/DMF,
(2) I2/aq NH3 system and (1) n-BuLi, (2) DMF, (3) I2/aq. NH3 system.
4
A
100
5
11 (35)a
5
6
B
C
100
100
10
10
92
53
Table 4
One-pot transformation of alkyl aryl ketones into
derivatives
b-chlorocinnamonitrile
7
A
100
6
0 (98)a
8
9
B
C
100
100
10
10
71 (19)a
32 (39)a
10
A
100
4
59
11
12
B
C
100
100
12
12
82
78 (8)a
13
A
100
10
67
14
15
B
C
100
100
10
10
99
32 (41)a
16
17
18
19
20
A
Cb
A
100
5
65
8
0 (62)a
52
120e130
90
0 (76)a
0 (39)a
12
C
100
20
6
A
100
21
22
B
C
100
100
13
13
24
24
23
A
100
6
0
24
25
B
C
100
100
13
13
35c
4 (49)a
2-decylfuran, and pyrrole, could be smoothly transformed into the
corresponding aromatic nitriles and heteroaromatic nitriles in good
yields, respectively, by treatment with POCl3 and DMF, followed by
the reaction with molecular iodine in aq NH3. However, the in-
troduction of cyano group to less reactive aromatics, such as ben-
zothiophene, benzofuran, naphthalene, and benzene, did not
a
Yield of starting material.
b
c
Tf2O (2.2 equiv) and DMF (2.2 equiv) were used.
Ratio of was 45:55.
a:b

4592
S. Ushijima et al. / Tetrahedron 68 (2012) 4588e4595
(3045.7 mg, 12 mmol) and aq NH3 (12 mL, 28e30%) were added to
the reaction mixture. The obtained mixture was stirred for 3 h at rt.
After the reaction, the mixture was poured into aq satd Na2SO3 so-
lution and extracted with CHCl3 (3ꢂ20 mL). The organic layer was
dried over Na2SO4, filtered, and evaporated to provide almost pure
2,4,6-trimethoxybenzonitrile (1156.1 mg) in 99% yield. If necessary,
it was recrystallized from a mixture of hexane and EtOAc (1:1).
4.3. Typical experimental procedure for the transformation
of aromatics into aromatic nitriles with DIH and aq NH3 using
the VilsmeiereHaack reaction
To a flask containing 1,3,5-trimethoxybenzene (1009.1 mg,
6 mmol) were added POCl3 (1011.9 mg, 6.6 mmol) and DMF
(1754.1 mg, 24 mmol) at 0 ꢀC. After being stirred for 3 h at 40 ꢀC,
DIH (2279.5 mg, 6 mmol) and aq ammonia (12 mL, 28e30%) were
added to the reaction mixture. The obtained mixture was stirred for
3 h at rt. After the reaction, the mixture was poured into aq satd
Na2SO3 solution and extracted with CHCl3 (3ꢂ20 mL). The organic
layer was dried over Na2SO4, filtered, and evaporated to provide
almost pure 2,4,6-trimethoxybenzonitrile (1156.1 mg) in 99% yield.
If necessary, it was recrystallized from a mixture of hexane and
EtOAc (1:1).
Scheme 2. Reaction mechanism for nitrile from aromatics.
4.4. Typical experimental procedure for transformation
of 1,2-dimethoxybenzene to 3,4-dimethoxybenzonitrile with
I2 and aq NH3 using NMFA and O(POCl2)2 system
succeed, because the corresponding aromatic N,N-dimethylimi-
nium salts were not formed from these aromatics with a POCl3 and
DMF system and a NMFA and O(POCl2)2 system, respectively. The
same treatment of propiophenones with POCl3 and DMF, followed
by the reaction with molecular iodine and aq NH3 gave the corre-
b-chlorocinnamonitrile derivatives in good yields, re-
spectively. The present reactions are novel metal-free one-pot
transformations of electron-rich aromatics and propiophenones
To an ice cooled solution of N-methylformanilide (2.2 mmol)
was added dropwise diphosphoryl chloride (2.2 mmol). The solu-
tion was stirred for 30 min at 0 ꢀC, and then 1,2-dimethoxybenzene
(276.3 mg, 2 mmol) in DMF (1.0 mL) was added dropwise. After
being stirred for 10 h at 100 ꢀC, I2 (1015.2 mg, 4 mmol), aq NH3
(4 mL, 28e30%) and THF (1 mL) were added to the reaction mixture.
The obtained mixture was stirred for 3 h at rt. After the reaction, the
mixture was poured into aq satd Na2SO3 solution and extracted
with CHCl3 (3ꢂ20 mL). The organic layer was dried over Na2SO4,
filtered, and evaporated. The product was purified by flash short
column chromatography (Hexane:AcOEt¼3:1) to afford 3,4-
dimethoxybenzonitrile as a white solid in 92% yield.
sponding
into the corresponding aromatic nitriles and b-chlorocinnamoni-
triles. The advantages of the present reaction are operational sim-
plicity, low cost, low toxicity, and easy availability of reaction
materials. Therefore, we believe the present reactions are useful
and environmentally benign methods for the preparation of aro-
matic nitriles from aromatics and
propiophenones.
b-chlorocinnamonitriles from
4.5. Typical experimental procedure for conversion
of mesityrene to 2,4,6-trimethylbenzonitrile with I2 and aq
NH3 using (Tf)2O and DMF system
4. Experimental section
4.1. General
To an ice cooled solution of DMF (4.4 mmol) was added drop-
wise Tf2O (4.4 mmol) in a screw-capped glass vial (10 mL). The
solution was stirred for 0.5 h at 0 ꢀC.Then, 1,3,5-trimethylbenzene
(240.4 mg, 2 mmol) in DMF (1.0 ml) was added dropwise. After
being stirred for 65 h at 120e130 ꢀC, I2 (1015.2 mg, 4 mmol), aq NH3
(4 mL, 28e30%), and THF (1 mL) were added to the reaction mix-
ture, and the obtained mixture was stirred for 3 h at rt. After the
reaction, the mixture was poured into aq satd Na2SO3 solution and
extracted with CHCl3 (3ꢂ20 mL). The organic layer was dried over
Na2SO4, filtered, and evaporated. The product was purified by flash
short column chromatography (Hexane:AcOEt¼9:1) to give 2,4,6-
trimethylbenzonitrile as a white solid in 52% yield.
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, MS-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 p-TLC.
4.5.1. 2ꢀ,4-Dimethoxybenzonitrile. Mp 93e94 ꢀC (commercial, mp
93e94 C); IR (Nujol) 2219 cmꢃ1; 1H NMR (500 MHz, CDCl3):
d
3.86
€
4.2. Typical experimental procedure for the transformation
of aromatics into aromatic nitriles with I2 and aq NH3 using
the VilsmeiereHaack reaction
(s, 3H), 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):
d 55.6, 55.9, 93.8, 98.4,
105.7, 116.9, 134.8, 162.8, 164.6.
To a flask containing 1,3,5-trimethoxybenzene (1009.1 mg,
6 mmol) were added POCl3 (1011.9 mg, 6.6 mmol) and DMF
(1754.1 mg, 24 mmol) at 0 ꢀC. After being stirred for 3 h at 40 ꢀC, I2
4.5.2. 2,4,6-Trimethoxybenzonitrile. Mp 139e140 ꢀC (commercial,
mp 143e145 C); IR (Nujol) 2212 cmꢃ1; 1H NMR (500 MHz, CDCl3):
ꢀ
€

S. Ushijima et al. / Tetrahedron 68 (2012) 4588e4595
4593
d
d
3.86 (s, 3H), 3.89 (s, 6H), 6.07 (s, 2H); 13C NMR (100 MHz, CDCl3)
55.6, 56.0, 83.7, 90.2, 114.6, 163.6, 165.3.
126.6, 127.3, 128.3, 128.9, 135.9; HRMS(FAB) [MþH]þ, calcd for
C12H11N2¼183.0922, found¼183.0927.
4.5.3. 2,3,4-Trimethoxybenzonitrile. Mp 55e56 ꢀC (commercial, mp
4.5.13. 3-Cyano-N-benzylpyrrole. Oil; IR (neat) 2224 cmꢃ1; 1H NMR
56e57 C); IR (Nujol) 2226 cmꢃ1; 1H NMR (400 MHz, CDCl3):
d
3.87
(500 MHz, CDCl3):
d
5.06 (s, 2H), 6.44 (d, J¼1.7 Hz, 1H), 6.65 (s, 1H),
ꢀ
€
(s, 3H), 3.92 (s, 3H), 4.06 (s, 3H), 6.70 (d, J¼8.7 Hz, 1H), 7.29 (d,
7.11e7.17 (m, 3H), 7.33e7.41 (m, 3H); 13C NMR (125 MHz,
J¼8.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
56.1, 60.9, 61.6, 98.9,
CDCl3) d 54.0, 104.6, 112.5, 119.0, 122.3, 127.3, 128.1, 128.4,
107.4, 116.4, 128.6, 141.7, 155.7, 157.9.
129.0, 135.8; HRMS(FAB) [MþH]þ, calcd for C12H11N2¼183.0922,
found¼183.0927.
4.5.4. 4-Methoxy-1-cyanonaphthalene. Mp ꢃ1100e102 ꢀC (commer-
ꢀ
€
cial, mp 100e102 C); IR (Nujol) 2213 cm
;
1H NMR (400 MHz,
4.5.14. 2-Cyanothiophene. Oil (commercial, oil); IR (neat)
CDCl3):
d
4.07 (s, 3H), 6.84 (d, J¼8.2 Hz, 1H), 7.59 (t, J¼8.2 Hz, 1H),
2222 cmꢃ1; 1H NMR (500 MHz, CDCl3):
d
7.14 (dd, J¼5.2, 3.7 Hz,1H),
7.69 (t, J¼8.2 Hz, 1H), 7.86 (d, J¼8.2 Hz, 1H), 8.17 (d, J¼8.2 Hz, 1H),
7.62 (d, J¼5.2 Hz, 1H), 7.64 (d, J¼3.7 Hz, 1H); 13C NMR (125 MHz,
8.32 (d, J¼8.2 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
56.0, 101.9,
CDCl3) d 109.8, 114.1, 127.6, 132.5, 137.3.
103.3, 118.5, 122.7, 124.8, 125.1, 126.7, 128.9, 133.4, 134.0, 159.3.
4.5.15. 5-Decylthiophene-2-carbonitrile. Oil; IR (neat) 2218 cmꢃ1
1H NMR (500 MHz, CDCl3):
;
4.5.5. 2-Methoxy-1-cyanonaphthalene. Mp 96e97 ꢀC (lit.17 mp
d
0.88 (t, J¼7.1 Hz, 3H), 1.23e1.38 (m,
95e96 C); IR (Nujol) 2211 cmꢃ1; 1H NMR (400 MHz, CDCl3):
d
4.08
14H), 1.67 (quintet, J¼7.5 Hz, 2H), 2.83 (t, J¼7.5 Hz, 2H), 6.78 (d,
ꢀ
€
(s, 3H), 7.28 (d, J¼8.7 Hz, 1H), 7.45 (t, J¼8.0 Hz, 1H), 7.64 (t, J¼8.0 Hz,
J¼3.6 Hz, 1H), 7.43 (d, J¼3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
1H), 7.83 (d, J¼8.0 Hz, 1H), 8.04 (d, J¼8.7 Hz, 1H), 8.09 (d, J¼8.0 Hz,
d
13.9, 22.5, 28.8, 29.0, 29.1, 29.3, 29.6, 29.9, 31.2, 31.7, 106.6, 114.3,
1H); 13C NMR (100 MHz, CDCl3)
d
56.5, 95.0, 111.9, 115.7, 123.9,
124.7, 137.4, 154.2; HRMS (FAB) [MþH]þ, calcd for
C15H24NS¼250.1629, found¼250.1636.
125.0, 127.9, 128.4, 129.1, 133.4, 135.0, 161.5.
4.5.6. 4,8-Dimethoxy-1-cyanonaphthalene. Mp 126e129 ꢀC; IR
4.5.16. 5-Decylfuran-2-carbonitrile. Oil; IR (neat) 2229 cmꢃ1
;
1H
ꢃ1
(Nujol) 2211 cm
;
1H NMR (400 MHz, CDCl3):
d
4.05 (s, 6H), 6.85
NMR (500 MHz, CDCl3):
d
0.88 (t, J¼7.0 Hz, 3H), 1.21e1.38 (m, 14H),
€
(d, J¼8.2 Hz,1H), 6.99 (d, J¼7.7 Hz,1H), 7.47 (t, J¼7.7 Hz,1H), 7.86 (d,
1.65 (quintet, J¼7.1 Hz, 2H), 2.66 (t, J¼7.1 Hz, 2H), 6.11 (d, J¼3.4 Hz,
J¼8.2 Hz, 1H), 7.89 (d, J¼7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
1H), 6.99 (d, J¼3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 14.0, 22.6,
d
55.6, 55.9, 98.3, 103.9, 107.5, 114.8, 120.8, 124.9, 126.7, 126.8, 136.2,
27.5, 28.1, 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.
154.6, 158.8; HRMS (ESI) [M]þ, calcd for C13H11O2N¼213.0784,
found¼213.0780.
4.5.7. 9-Cꢀyanoanthracene. Mp 173e175 ꢀC (commercial, mp
4.5.17. 4-Methoxybenzonitrile. Mp 54e55 ꢀC (commercial, mp
ꢃ1
1H NMR (500 MHz, CDCl3):
57e59 C); IR (Nujol) 2216 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d 3.86
ꢀ
€
€
173e177 C); IR (Nujol) 2212 cm
;
d
7.59 (t, J¼8.5 Hz, 2H), 7.73 (t, J¼8.5 Hz, 2H), 8.09 (d, J¼8.5 Hz, 2H),
(s, 3H), 6.95 (d, J¼8.9 Hz, 2H), 7.59 (d, J¼8.9 Hz, 2H); 13C NMR
8.43 (d, J¼8.5 Hz, 2H), 8.69 (s, 1H); 13C NMR (125 MHz, CDCl3)
(125 MHz, CDCl3) d 55.5, 103.8, 114.7, 119.2, 133.9, 162.8.
d
105.4, 117.2, 125.2, 126.3, 128.9 (2C), 130.6, 132.7, 133.3.
4.5.18. 3,4-Dimethoxybenzonitrile. Mp 65e67 ꢀC (commercial, mp
4.5.8. 4-(N,N-Dimethyamino)benzonitrile. Mp 74e75 ꢀC (commer-
68e70 C); IR (Nujol) 2223 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d 3.91
ꢀ
€
ꢃ1
ꢀ
€
cial, mp 75 C); IR (Nujol) 2210 cm
d
;
1H NMR (500 MHz, CDCl3)
(s, 3H), 3.94 (s, 3H), 6.90 (d, J¼8.4 Hz, 1H), 7.08 (d, J¼2.0 Hz, 1H),
3.04 (s, 6H), 6.64 (d, J¼9.1 Hz, 2H), 7.47 (d, J¼9.1 Hz, 2H); 13C NMR
7.29 (dd, J¼8.4 Hz, J¼2.0 Hz,1H); 13C NMR (125 MHz, CDCl3)
d 55.92,
(100 MHz, CDCl3)
d
39.9, 97.2, 111.3, 120.7, 133.3, 152.4.
55.94, 103.7, 111.1, 113.7, 119.1, 126.3, 149.0, 152.7.
4.5.9. 3-Cyanoindole. Mp
177e179
ꢀC
(commercial,
mp
4.5.19. 2,5-Dimethoxybenzonitrile. Mp 79e82 ꢀC (commercial, mp
179e182 C); IR (Nujol) 2227 cmꢃ1; 1H NMR (500 MHz, DMSO-d6):
81e85 C); IR (Nujol) 2224 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d 3.78
ꢀ
ꢀ
€
€
d
7.20e7.29 (m, 2H), 7.56 (d, J¼8.0 Hz, 1H), 7.64 (d, J¼8.0 Hz, 1H),
(s, 3H), 3.89 (s, 3H), 6.91 (d, 1H, J¼9.0), 7.05e7.11 (m, 2H), 13C NMR
8.24 (s, 1H), 12.20 (br, 1H); 13C NMR (125 MHz, DMSO-d6): 84.3,
(400 MHz, CDCl3)
148.7.
d 48.9, 49.3, 94.7, 105.5, 109.3, 110.5, 113.8, 146.1,
113.0, 116.4, 118.4, 121.7, 123.4, 126.8, 134.5, 135.2.
4.5.10. N-Methyl-3-cyanolindole. Mp 60e61 ꢀC (lit.18 mp
4.5.20. 2,4,6-Trimethylbenzonitrile. Mp 50e51 ꢀC (lit.12l mp
ꢃ1
60.5e61.5 C); IR (Nujol) 2219 cm
;
1H NMR (500 MHz, CDCl3):
54e55 C); IR (Nujol) 2218 cmꢃ1; 1H NMR (500 MHz, CDCl3)
(s, 3H), 2.47 (s, 6H), 6.92 (s, 2H); 13C NMR (500 MHz, CDCl3)
21.5, 110.2, 117.6, 128.1, 141.9, 142.7.
d 2.32
ꢀ
ꢀ
€
€
d
3.75 (s, 3H), 7.25 (t, J¼6.4 Hz, 1H), 7.28e7.35 (m, 2H), 7.44 (s, 1H),
d
20.6,
7.68 (d, J¼7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 33.2, 84.5, 110.1,
115.8, 119.1, 121.7, 123.4, 127.3, 135.4, 135.6.
4.6. Typical experimental procedure for transformation
of propiophenone to b-chloro-a-methylecinnamonitrile
4.5.11. 9-Methyl-9H-carbazole-3-carbonitrile. Mp 90e92 ꢀC (lit.19
ꢃ1
;
1H NMR (500 MHz, CDCl3):
ꢀ
€
mp 91e93 C); IR (Nujol) 2212 cm
3.83 (s, 3H), 7.31 (t, J¼7.8 Hz, 1H), 7.37 (d, J¼8.6 Hz, 1H), 7.42 (d,
d
Propiophenone (268.4 mg, 2 mmol) was added to POCl3
(490.7 mg, 3.2 mmol) and DMF (233.9 mg, 3.2 mmol) at 0 ꢀC. After
being stirred for 3 h at 60 ꢀC, I2 (609.1 mg, 2.4 mmol), aq NH3 (4 mL,
28e30%) and THF (2 mL) were added to the reaction mixture. The
obtained mixture was stirred for 3 h at rt. After the reaction, the
mixture was poured into aq satd Na2SO3 solution and extracted
with CHCl3 (3ꢂ20 mL). The organic layer was dried over Na2SO4,
filtered, and evaporated. The product was purified by flash short
J¼8.0 Hz, 1H), 7.55 (t, J¼8.0 Hz, 1H), 7.66 (d, J¼8.6 Hz, 1H), 8.04 (d,
J¼7.8 Hz, 1H), 8.30 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 28.9, 101.0,
108.7, 108.8, 120.1, 120.3, 120.4, 121.3, 122.4, 124.6, 126.9, 128.4,
141.1, 142.0.
4.5.12. 2-Cyano-N-benzylpyrrole. Oil; IR (neat) 2215 cmꢃ1; 1H NMR
(400 MHz, CDCl3):
6.80e6.86 (m, 2H), 7.18 (d, J¼7.4 Hz, 2H), 7.31e7.38 (m, 3H);
13C NMR (125 MHz, CDCl3)
52.3, 104.0, 109.9, 113.7, 120.2,
d
5.19 (s, 2H), 6.19 (dd, J¼2.9, 2.7 Hz, 1H),
column chromatography (Hexane:AcOEt¼12:1) to afford (E)-
b-
d
chloro- -methylcinnamonitrile as a white solid in 77% yield, and
a

4594
S. Ushijima et al. / Tetrahedron 68 (2012) 4588e4595
(Z)-
b
-chloro-
a
-methylecinnamonitrile as a colorless oil in 16%
J¼8.6 Hz, 2H), 7.37e7.42 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 18.6,
(83:17, E/Z ratio).
108.9, 115.8 (d, JCꢃF¼21.6 Hz), 117.7, 130.7 (d, JCꢃF¼8.4 Hz), 131.0 (d,
JCꢃF¼3.6 Hz), 144.0, 163.4 (d, JCꢃF¼251.9 Hz); HRMS (ESI) [MþH]þ,
calcd for C10H8NClF¼196.0324, found¼196.0327. (NOE of aromatic
group based on Me group; 0.82%).
4.6.1. (E)-
b
-Chloro-
a
-methylcinnamonitrile. Oil; IR (neat) 1606,
2.20 (s, 3H), 7.37e7.45 (m,
19.2, 106.8,
2216 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
3H), 7.58e7.63 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
118.1, 128.37, 128.41, 130.6, 135.9, 149.5; HRMS (ESI) [MþNa]þ, calcd
for C10H8NClNa¼200.0237, found¼200.0240.
4.6.11. (E)-
b
-Chloro-
a-heptylcinnamonitrile. Oil; IR (neat) 1595,
2215 cmꢃ1
;
1H NMR (500 MHz, CDCl3)
d
0.90 (t, J¼7.2 Hz, 3H),
1.25e1.48 (m, 8H),1.68 (quintet, J¼7.5 Hz, 2H), 2.57 (t, J¼7.7 Hz, 2H),
4.6.2. (Z)-
b-Chloro-
a
-methylcinnamonitrile. Oil; IR (neat) 1616,
2.01 (s, 3H), 7.35e7.39 (m,
18.5, 108.6,
7.40e7.44 (m, 3H), 7.59e7.63 (m, 2H); 13C NMR (125 MHz,
2219 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
CDCl3) d 14.0, 22.6, 27.3, 28.86, 28.91, 31.7, 32.7, 112.6, 117.7, 128.45,
2H), 7.40e7.47 (m, 3H); 13C NMR (125 MHz, CDCl3)
d
128.51, 130.6, 136.2, 148.8; HRMS (ESI) [MþNa]þ, calcd for
C16H20NClNa¼284.1176, found¼284.1164.
117.8, 128.4, 128.6, 130.3, 135.0, 149.6; HRMS (ESI) [MþNa]þ, calcd
for C10H8NClNa¼200.0237, found¼200.0240.
4.6.12. (Z)-
b
-Chloro-
a-heptylcinnamonitrile. Oil; IR (neat) 1677,
4.6.3. (E)-
b-Chloro-
a
-methyl-p-methylcinnamonitrile. Mp 39e42 ꢀC;
2218 cmꢃ1
;
1H NMR (500 MHz, CDCl3)
d
0.85 (t, J¼7.2 Hz, 3H),
IR (Nujol) 1606, 2215 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
2.01 (s, 3H),
1.15e1.41 (m, 8H), 1.59 (quintet, J¼7.5 Hz, 2H), 2.26 (t, J¼7.7 Hz, 2H),
€
2.39 (s, 3H), 7.23 (d, J¼7.9 Hz, 2H), 7.28 (d, J¼8.4 Hz, 2H); 13C NMR
7.33e7.37 (m, 2H), 7.42e7.45 (m, 3H); 13C NMR (125 MHz, CDCl3)
(100 MHz, CDCl3)
d
18.6. 21.4. 107.9. 118.0. 128.5. 129.2. 132.1. 140.8.
d 14.0, 22.5, 28.3, 28.6, 28.7, 31.56, 31.68, 114.9, 117.1, 128.3, 128.6,
145.4; HRMS (ESI) [MþNa]þ, calcd for C11H10NClNa¼214.0394,
found¼214.0394.
130.2, 135.4, 144.8; HRMS (APCI) [MþH]þ, calcd for
C16H21NCl¼262.1357, found¼262.1355.
4.6.4. (Z)-
b
-Chloro-
a
-methyl-p-methylcinnamonitrile. Oil; IR (neat)
4.6.13. 1-Chloro-3,4-dihydronaphthalene-2-carbonitrile. Mp 54e55 ꢀC
1608, 2218 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
2.21 (s, 3H), 2.39 (s,
; IR (Nujol) 1605, 2212 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
2.63e2.67
€
3H), 7.23 (d, J¼7.9 Hz, 2H), 7.52 (d, J¼8.4 Hz, 2H); 13C NMR
(m, 2H), 2.91e2.95 (m, 2H), 7.19 (d, J¼6.2 Hz, 1H), 7.30e7.38 (m, 2H),
(100 MHz, CDCl3)
d
19.3, 21.4, 106.0, 118.5, 128.4, 129.1, 133.2, 141.1,
7.69 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 26.3, 26.8, 107.9,
149.9; HRMS (ESI) [MþNa]þ, calcd for C11H10NClNa¼214.0394,
found¼214.0397.
117.3, 126.1, 127.3, 127.7, 130.3, 131.1, 136.4, 143.4; HRMS (ESI) [MþH]þ,
calcd for C11H9NCl¼190.0418, found¼190.0418.
4.6.5. (E)-
b
-Chloro-
a
-methyl-p-methoxycinnamonitrile. Mp 74e75 ꢀC;
4.6.14. 3-Chloro-4-cyano-1,3-benzocycloheptadiene. Oil; IR (neat)
IR (Nujol) 1604, 2212 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
2.21 (s, 3H),
1604, 2214 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
2.20 (t, J¼7.0 Hz, 2H),
€
2.39 (s, 3H), 7.23 (d, J¼7.9 Hz, 2H), 7.52 (d, J¼8.4 Hz, 2H); 13C NMR
2.28 (q, J¼6.8 Hz, 2H), 2.68 (t, J¼7.0 Hz, 2H), 7.24e7.26 (m, 1H),
(125 MHz, CDCl3)
d 19.3, 21.4, 106.0, 118.5, 128.4, 129.1, 133.2, 141.1,
7.34e7.38 (m, 2H), 7.55e7.59 (m, 1H); 13C NMR (100 MHz, CDCl3)
149.9; HRMS (ESI) [MþNa]þ, calcd for C11H10ONClNa¼230.0343,
found¼230.0339. (NOE of aromatic group based on Me group; 0.19%).
d 28.9, 31.4, 34.1, 111.4, 117.7, 126.8, 128.5, 129.1, 130.7, 135.6, 140.4,
145.2; HRMS (ESI) [MþH]þ, calcd for C12H11NCl¼204.0575,
found¼204.0579.
4.6.6. (Z)-
b
-Chloro-
a
-methyl-p-methoxycinnamonitrile. Oil;
IR
(neat) 1604, 2213 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 2.03 (s, 3H),
3.85 (s, 3H), 6.94 (d, J¼8.8 Hz, 2H), 7.34 (d, J¼8.8 Hz, 2H); 13C NMR
Acknowledgements
(100 MHz, CDCl3)
d 18.7, 55.4, 107.2, 113.9, 118.2, 127.1, 130.3, 145.2,
161.0; HRMS (ESI) [MþNa]þ, calcd for C11H10ONClNa¼230.0343,
found¼230.0344. (NOE of aromatic group based on Me group;
1.13%).
Financial support in the forms of a Grant-ineAid for Scientific
Research (No. 20550033) from the Ministry of Education, Culture,
Sports, Science, and Technology in Japan, Iodine Research Project in
Chiba University, and Futaba Electronics Memorial Foundation is
gratefully acknowledged.
4.6.7. (E)-b-Chloro-a
-methyl-p-chlorocinnamonitrile. Mp 75e78 ꢀC;
IR (Nujol) 1591, 2212 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
2.22 (s, 3H),
€
7.41 (d, J¼8.6 Hz, 2H), 7.57 (d, J¼8.9 Hz, 2H); 13C NMR (125 MHz,
References and notes
CDCl3)
d 19.3, 107.5, 118.0, 128.8, 129.8, 134.4, 136.8, 148.3; HRMS
(APCI) [MþH]þ, calcd for C10H8NCl2¼212.0028, found¼212.0030.
1. (a) Sandler, S. R.; Karo, W. In Nitriles (Cyanides); Wasserman, H. H., Ed.; Organic
Functional Group Preparations; Academic.: San Diego, 1983; vol. 12-I; of Organic
Chemistry, Chapter 17; (b) Fabiani, M. E. Drug News Perspect. 1999, 12, 207.
2. (a) Friedrick, K.; Wallensfels, K. In The Chemistry of the Cyano Group; Rappoport,
Z., Ed.; Wiley-Interscience: New York, 1970; (b) North, M. In Comprehensive
Organic Functional Group Transformation; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Pergamon: Oxford, 1995; (c) Murahashi, S. eI. Synthesis from ni-
triles with retention of the cyano group. In Science of Synthesis; Georg Thieme:
2004; vol. 19, pp 345e402; (d) Collier, S. J.; Langer, P. Application of nitriles as
reagents for organic synthesis with loss of the nitrile functionality In. Science of
Synthesis; Georg Thieme: 2004; vol. 19, pp 403e425.
3. (a) Reisner, D. B.; Coring, E. C. Org. Synth. Coll. 1963, Vol. IV, 144; (b) Krynitsy, J.
A.; Carhart, H. W. Org. Synth. Coll. 1963, Vol. IV, 436; (c) Humber, J. G.; Davis, M.
A. Can. J. Chem. 1966, 44, 2113; (d) Yamato, E.; Sugasawa, S. Tetrahedron Lett.
1970, 4348; (e) Lehnert, W. Tetrahedron Lett. 1971, 1501; (f) Campagna, F.; Caroti,
A.; Casini, G. Tetrahedron Lett. 1977, 1813; (g) Mai, K.; Patal, G. Tetrahedron Lett.
1986, 27, 2203; (h) Claremon, D. A.; Phillips, B. Tetrahedron Lett. 1988, 29, 2155;
(i) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem. 1990, 55, 4515; (j)
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therein; (l) Heck, M.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1996, 61, 6486;
(m) Nakajima, N.; Ubukata, M. Tetrahedron Lett. 1997, 38, 2099; (n) Bose, D. S.;
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4.6.8. (Z)-b-Chloro-a-methyl-p-chlorocinnamonitrile. Oil; IR (neat)
1592, 2221 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d 2.02 (s, 3H), 7.33 (d,
J¼8.6 Hz, 2H), 7.57 (d, J¼8.9 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
18.6, 109.2, 117.5, 128.9, 129.9, 133.3, 136.5, 143.8; HRMS (APCI)
[MþH]þ, calcd for C10H8NCl2¼212.0028, found¼212.0033.
4.6.9. (E)-b-Chloro-a
-methyl-p-fluorocinnamonitrile. Mp 66e69 ꢀC;
IR (Nujol) 1604, 2212 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
2.22 (s, 3H),
€
7.12 (t, J¼8.6 Hz, 2H), 7.60e7.65 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
19.3,107.1,115.7 (d, JCꢃF¼21.6 Hz),118.1,130.7 (d, JCꢃF¼8.4 Hz),132.1
(d, JCꢃF¼3.6 Hz), 148.4, 163.8 (d, JCꢃF¼251.9 Hz); HRMS (APCI)
[MþH]þ, calcd for C10H8NClF¼196.0324, found¼196.0325. (NOE of
aromatic group based on Me group; 0.14%).
4.6.10. (Z)-
b
-Chloro-
a-methyl-p-fluorocinnamonitrile. Oil; IR (neat)
1602, 2220 cmꢃ1
;
1H NMR (500 MHz, CDCl3)
d
2.02 (s, 3H), 7.14 (t,

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