Direct oxidative conversion of alkyl halides into nitriles with molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin in aq ammonia

Article abstract of DOI:10.1016/j.tet.2009.05.001

Various benzylic halides were smoothly and directly converted into the corresponding aromatic nitriles in high yields using molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin, respectively, in aq ammonia. Similarly, primary alkyl halides were also converted into corresponding nitriles in moderate to good yields using molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin in aq ammonia, although a long reaction time was required. The present reaction is a new method for the preparation of aromatic nitriles from benzylic halides and a new method for the conversion of alkyl halides into corresponding nitriles with retention of the number of carbon atoms.

Full text of DOI:10.1016/j.tet.2009.05.001

Tetrahedron 65 (2009) 6257–6262
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct oxidative conversion of alkyl halides into nitriles with molecular
iodine and 1,3-diiodo-5,5-dimethylhydantoin in aq ammonia
Shinpei Iida, Ryosuke Ohmura, 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:
Received 2 April 2009
Received in revised form 1 May 2009
Accepted 1 May 2009
Available online 8 May 2009
Various benzylic halides were smoothly and directly converted into the corresponding aromatic nitriles
in high yields using molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin, respectively, in aq ammo-
nia. Similarly, primary alkyl halides were also converted into corresponding nitriles in moderate to good
yields using molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin in aq ammonia, although a long
reaction time was required. The present reaction is a new method for the preparation of aromatic nitriles
from benzylic halides and a new method for the conversion of alkyl halides into corresponding nitriles
with retention of the number of carbon atoms.
Keywords:
Molecular iodine
Ó 2009 Elsevier Ltd. All rights reserved.
1,3-Diiodo-5,5-dimethylhydantoin
Aq ammonia
Aromatic nitrile
Aliphatic nitrile
Benzylic halide
Alkyl halide
1. Introduction
highly toxic metal cyanide via a nucleophilic pathway. However, this
reaction induces one-carbon homologation. Consequently, nitriles
Molecular iodine is one of the simplest oxidants currently
available. It is highly affordable and has relatively low toxicity.
Considered to be an environmentally benign oxidizing agent for
organic synthesis, molecular iodine is used in various organic
reactions, including the oxidation of alcohols or aldehydes to esters,
the oxidation of sulfides to sulfoxides, the oxidation of cyclo-
hexenones to benzene rings, the introduction of protecting groups,
the deprotection of protecting groups, iodocyclization, carbon–
are generally prepared by the dehydration of amides with SOCl
TsCl/Py, P , POCl , COCl , (EtO) P/I , or Ph P/CCl , by the con-
densation of carboxylic acids with NH /silica gel or NH /ethyl poly-
phosphate, and by the reaction of esters with Me AlNH
can also be easily obtained by the oxidation of primary amines using
2
,
2
O
5
3
2
3
2
3
4
3
3
5
2
2
. Nitriles
AgO, Pb(OAc)
4
, cobalt peroxide, Na
2
S
2
O
8
or (Bu
4
N)
2
2
S O
8
with
metals, NaOCl, K
3
Fe(CN) , Cu(I) or Cu(II) with oxygen, RuCl
6
3
or re-
6
lated Ru reagents, PhIO, and trichloroisocyanuric acid with TEMPO.
However, to the best of our knowledge, the direct oxidative con-
version of alkyl halides into corresponding nitriles with retention of
1
carbon bond formation, and the formation of heterocycles. Syn-
thetic studies of 1,3-diiodo-5,5-dimethylhydantoin (DIH) are
2
7
extremely limited, although its structure is similar to that of N-
the number of carbon atoms has never been reported. As part of our
iodosuccinimide (NIS). However, as DIH (MW¼380) has two N–I
bonds, it can be expected that 1 equiv of DIH has the same oxidative
ability as 2 equiv of molecular iodine (MW¼254) or NIS (MW¼225).
Thus, DIH is highly efficient and economical. On the other hand,
nitriles are one of the most important synthetic transformation
precursors because they can be easily converted into esters, amides,
carboxylic acids, amines, and nitrogen-containing heterocycles,
ongoing studies on the use of molecular iodine and DIH for organic
synthesis, we would like to report the direct oxidative conversion
of benzylic halides and primary alkyl halides into corresponding
aromatic nitriles and aliphatic nitriles with molecular iodine and
DIH, respectively, in aq ammonia.
8
3
2. Results and discussion
particularly tetrazoles that have potent biological activity, and have
been used as synthetic intermediates for agricultural chemicals,
pharmaceuticals, and functional materials. The most typical
preparation method of nitriles is the reaction of alkyl halides with
4
2.1. Direct oxidative conversion of benzylic halides
and alkyl halides into corresponding nitriles with
molecular iodine in aq ammonia
7
*
Corresponding author.
E-mail address: togo@faculty.chiba-u.jp (H. Togo).
Recently, we reported the direct, efficient, practical, and less
toxic oxidative conversion of primary alcohols and amines into
0
040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.001

6258
S. Iida et al. / Tetrahedron 65 (2009) 6257–6262
corresponding nitriles using molecular iodine in aq ammonia.9
Based on the results of that study, we planned to perform the direct
oxidative conversion of primary alkyl halides into corresponding
nitriles using molecular iodine in aq ammonia. Primary alkyl ha-
Table 1
2 3
Conversion of benzylic halides into aromatic nitriles with I in aq NH
I2, aq.NH (3.0 mL)
3
Ar CH2X
Ar CN
60 °C
N
lides should react with ammonia via the S 2 nucleophilic pathway
Entry
X
Ar
I
2
(equiv)
Time (h)
Yielda (%)
to form corresponding primary amines that can be smoothly oxi-
dized to corresponding nitriles by molecular iodine in a one-pot
manner. Practically, the reaction was carried out by treating benzyl
chloride (1 mmol) with molecular iodine (2.1 mmol, 2.1 equiv)
1
2
3
4
5
Cl
Cl
Cl
Cl
Cl
C
6
H
5
2.1
2.1
2.1
2.1
2.1
4
10
4
2
4
73
73
92
82
88
p-ClC
p-O NC H
p-CH
p-CH
6 4
H
2
6 4
ꢀ
3
C
6
H
4
smoothly in aq ammonia (28–30%, 3 mL) at 60 C in a standard
3
OC
6
H
4
reactor under an empty balloon to provide benzonitrile in good
yield, as shown in Table 1 (entry 1). p-Chlorobenzyl, p-nitrobenzyl,
p-methylbenzyl, p-methoxybenzyl, and 1-naphthylmethyl chlo-
rides could be also converted into corresponding nitriles in good
yields under the same conditions (entries 2–6). Benzyl, p-chloro-
benzyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, and
6
7
Cl
Cl
2.1
2.1
4
83
60
4b
S
1
-naphthylmethyl bromides could be also converted into corre-
sponding nitriles in good yields under the same conditions using
.4 mmol of molecular iodine (entries 11–16). The same treatment
8
9
Cl
2.1
4
61
N
Ts
2
of benzyl iodide provided benzonitrile in good yield (entry 19). 3-
Chloromethyl-1-tosylindole and 2,4,6-trimethylbenzyl chloride
could also be converted into corresponding nitriles in good yields
under the same conditions (entries 8 and 9). When the same re-
action was carried out with 2-halomethylthiophene as substrate,
the yield of 2-cyanothiophene was low. However, after treating 2-
halomethylthiophene with aq ammonia for 2 h at rt, adding mo-
lecular iodine to the reaction mixture, and warming the obtained
CH3
Cl
Cl
CH3
2.1
4.2
4
4
86
81
CH3
10
ꢀ
11
Br
Br
Br
Br
Br
C
H
6 5
2.4
2.4
2.4
2.4
2.4
4
8
4
4
4
78
78
88
88
84
mixture at 60 C, 2-cyanothiophene was obtained in moderate
1
2
p-ClC
6 4
H
yields (entries 7 and 17). One of the reasons why the yield of 2-
cyanothiophene was lower than that of the other aromatic nitriles
may be the low boiling point of 2-cyanothiophene. Treatment of
1
3
p-O NC
2
6
H
4
14
15
p-CH C H
p-CH
3
6
4
3
OC
6
H
4
1,3-bis(chloromethyl)benzene and 1,3-bis(bromomethyl)benzene
with molecular iodine (4.2 equiv and 4.8 equiv) in aq ammonia
gave 1,3-dicyanobenzene in good yields (entries 10 and 18).
Clearly, the present reaction is a good method for the prepara-
tion of aromatic nitriles from benzylic halides directly. That means
we do not need to use the Sandmeyer reaction of diazonium with
toxic CuCN or the dehydration of aromatic amides with dehydrat-
ing agents.
16
Br
Br
Br
2.4
2.4
4.8
4
4b
4
87
49
74
17
S
18
When the same reaction was carried out under the same con-
ditions with 1-iodododecane (1 mmol) as substrate, corresponding
lauronitrile was not formed at all and the starting material was
quantitatively recovered. Then, we examined the effect of additives
as cosolvent, such as THF, dioxane, DMSO, or DMF, on promoting the
nucleophilic reaction of ammonia with 1-iodododecane, and after
several trials, we found that the addition of a small amount of DMF
in a screw-capped glass vial (10 mL), instead of the use of a standard
reactor under a balloon, improved the yield of lauronitrile. We be-
lieve that the evolution of ammonia gas from the reaction mixture
under the present conditions is restrained by using a screw-capped
glass vial, since the reaction of aliphatic primary alkyl halides with
ammonia proceeds rather slowly compared with that of benzylic
halides with ammonia. Thus, DMF (0.01 mL) was added to a mixture
of 1-iodododecane in aq ammonia (1 mL) in a screw-capped glass
1
9
I
p-ClC
6
H
4
2.4
8
78
a
Isolated yield.
I was added after 2 h.
2
b
efficiently converted into corresponding nitriles in good yields
without DMF (entries 9–17). 1,10-Diiododecane and 1,10-dibromo-
decane provided the corresponding sebaconitrile in moderate
yields by using 6 equiv of molecular iodine under the same condi-
tions (entries 7 and 8). In contrast, cyclohexylmethyl halides were
less reactive and adamantylmethyl halides did not react at all due to
steric hindrance of the initial conversion into corresponding amines
N
via the S 2 reaction pathway with ammonia (entries 4–6) (Table 2).
As a result, the present reaction is a novel means to convert alkyl
halides into the corresponding nitriles, with retention of the
number of carbon atoms.
ꢀ
vial, and the obtained mixture was warmed at 60 C for 72 h. Then,
molecular iodine (3 equiv) and aq ammonia (6 mL) were added to
ꢀ
the reaction mixture and again the mixture was warmed at 60 C for
4
h to provide lauronitrile in 75% yield (entry 1). Based on these
2.2. Direct oxidative conversion of benzylic halides and alkyl
halides into corresponding nitriles with DIH in aq ammonia
results, 1-bromododecane and 1-chlorododecane were also treated
with molecular iodine in aq ammonia and a small amount of DMF to
form corresponding lauronitrile in good to moderate yields under
the same conditions (entries 2 and 3). The reactivity depends on the
alkyl halides, i.e., primary alkyl chlorides are less reactive than pri-
mary alkyl bromides and iodides. On the other hand, other primary
alkyl-chain halides, such as 3-phenylpropyl halides, 4-phenylbutyl
halides, 5-phenylpentyl halides, and 11-haloundecanoic acids, were
The use of 1,3-diiodo-3,3-dimethylhydantoin (DIH) in the io-
2
dination of aromatics was first reported in 1965. However, to the
best of our knowledge, it has been never used in organic synthesis.
We have reported the direct, efficient, practical, and less toxic ox-
idative conversion of primary alcohols and amines into corre-
9
c
sponding nitriles using DIH in aq ammonia. Thus, based on the

S. Iida et al. / Tetrahedron 65 (2009) 6257–6262
6259
Table 2
2 3
Conversion of primary alkyl halides into aliphatic nitriles with I in aq NH
1
2
. aq. NH , cosolvent
3
. I2 (3.0 eq.), aq. NH , 60 °C
3
R
CH X
R
CN
2
Entry
1b
R
X
Cosolvent
First step
Second step
Yielda (%)
ꢀ
aq NH
3
(mL)
Temp ( C)
Time (h)
aq NH
3
(mL)
Time (h)
nC11
H
I
Br
Cl
DMF 0.01 mL
DMF 0.03 mL
DMF 0.03 mL
1.0
1.0
1.0
60
60
100
72
72
72
6.0
6.0
6.0
4
4
4
75
69
23
–
b
2
b
c
3
49 (19 )
4b
5
I
Br
DMF 0.01 mL
DMF 0.01 mL
1.0
1.0
100
100
24
24
6.0
6.0
4
4
48
39 (7 )
b
c
6b
I
DMF 0.01 mL
1.0
100
24
6.0
4
0 (99c)
b,d
7
2
–(CH )
8
–
I
Br
None
None
3.0
3.0
60
60
4
24
6.0
6.0
6
6
54
58
b,d
8
9e
I
Br
Cl
None
None
None
3.0
5.0
3.0
60
60
100
12
24
24
3.0
3.0
3.0
4
4
4
70
73
65
1
0
b
11
1
13
2b,e
I
Br
None
None
3.0
5.0
60
60
4
48
3.0
3.0
4
4
56
68
b,e
b
1
15
4
I
Br
None
None
3.0
5.0
60
60
4
24
3.0
3.0
4
4
63
76
1
17
6
2
HO C(CH
2
)
9
–
I
Br
None
None
3.0
5.0
60
60
4
4
3.0
3.0
4
12
53
56
a
Isolated yield.
A screw-capped glass vail (10 mL) was used.
Yield of the starting material.
b
c
d
e
I
2
(6.0 equiv) was used.
First step was carried out under dark condition.
Table 3 (continued)
Entry
X
Ar
Time (h)
Yielda (%)
90
Table 3
Conversion of benzylic halides into aromatic nitriles with DIH in aq NH
3
DIH (1.2 eq.), aq.
16
Br
4
NH (3.0 mL)
3
Ar CH X
Ar CN
2
6
0 °C
4b
17
Br
Br
39
S
Entry
X
Ar
Time (h)
Yielda (%)
1
2
3
4
5
Cl
Cl
Cl
Cl
Cl
C
6
H
5
4
8
4
2
4
73
74
84
77
91
4c
18
75
82
p-ClC
6 4
p-O NC H
6 4
H
2
p-CH
p-CH
3
C
6
H
4
19
I
p-ClC
6
H
4
8
3 6 4
OC H
a
Isolated yield.
DIH was added after 2 h.
DIH (2.4 equiv) was used.
b
c
6
7
Cl
Cl
4
83
50
4b
above reactions of benzylic halides with molecular iodine in aq
ammonia, benzyl chloride was treated with 1.2 equiv of DIH in aq
ammonia (3 mL) for 4 h at 60 C in a standard reactor under an
S
ꢀ
8
9
Cl
4
60
empty balloon to provide benzonitrile in good yield, as shown in
Table 3 (entry 1). Similar to the reactions with molecular iodine, p-
chlorobenzyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl,
and 1-naphthylmethyl chlorides could be also converted into cor-
responding nitriles in good yields under the same conditions (en-
tries 2–6). The reactivity of DIH is almost the same as that of
molecular iodine. Benzyl, p-chlorobenzyl, p-nitrobenzyl, p-methyl-
benzyl, p-methoxybenzyl, and 1-naphthylmethyl bromides could
be also converted into corresponding nitriles in good yields under
the same conditions using 1.2 equiv of DIH (entries 11–16). The
same treatment of benzyl iodide provided benzonitrile in good
yield (entry 19). 3-Chloromethyl-1-tosylindole and 2,4,6-trime-
thylbenzyl chloride could be also converted into corresponding
nitriles in moderate yields under the same conditions (entries 8 and
N
Ts
CH3
Cl
Cl
CH3
4
53
70
CH3
4c
10
1
1
Br
Br
Br
Br
Br
C
6
H
5
4
8
4
4
4
77
80
88
88
85
1
2
p-ClC
6 4
H
1
3
p-O NC
2
6
H
4
1
4
p-CH
p-CH
3
6
C H
4
15
3 6 4
OC H

6260
S. Iida et al. / Tetrahedron 65 (2009) 6257–6262
Table 4
Conversion of primary alkyl halides into aliphatic nitriles with DIH in aq NH
3
1
. aq. NH , cosolvent
3
2
. DIH (2.0 eq.), aq. NH , 60 °C
3
R
CH X
R
CN
2
Entry
1b
R
X
Cosolvent
First step
Second step
Yielda (%)
ꢀ
aq NH
3
(mL)
Temp ( C)
Time (h)
aq NH
3
(mL)
Time (h)
nC11
H
–
I
Br
DMF 0.01 mL
DMF 0.03 mL
1.0
1.0
60
60
72
72
6.0
6.0
4
4
76
69
23
b
2
3b
4
I
Br
DMF 0.01 mL
DMF 0.03 mL
1.0
1.0
100
100
24
24
6.0
6.0
4
4
43
36
b
b,c
5
–(CH
2
)
8
–
I
Br
None
None
3.0
3.0
60
60
4
24
3.0
3.0
6
6
67
59
b,c
6
b,d
7
I
Br
None
None
3.0
3.0
60
60
12
24
3.0
3.0
4
4
74
72
b
8
b,d
9
1
I
Br
None
None
3.0
3.0
60
60
4
24
3.0
3.0
4
4
59
66
0b
b,d
1
1
1
I
Br
None
None
3.0
3.0
60
60
4
24
3.0
3.0
4
4
60
64
2b
1
14
3
HO
2
C(CH
2
)
9
–
I
Br
None
None
3.0
3.0
60
60
4
4
3.0
3.0
4
12
57
56
a
Isolated yield.
A screw-capped glass vail (10 mL) was used.
DIH (4 equiv) was used.
b
c
d
First step was carried out under dark condition.
A possible reaction pathway for the conversion of benzylic halides
and primary alkyl halides into corresponding aromatic nitriles and
aliphatic nitriles, respectively, with molecular iodine and DIH in aq
ammonia is shown in Scheme 1. The initial nucleophilic reaction of
ammonia with benzylic or alkyl halide occurs to generate corre-
sponding primary amine (a). N-Iodination of amine (a) with mole-
cular iodine or DIH takes place to provide N-iodo compound (b),
I2 or DIH
aq. NH3
R
CH2
X
R
R
C N
(
S 2)
N
( -HI )
NH ( -HX )
3
I
R
CH NH2
C N
2
a)
(
H
(d)
followed by
c). Then,aldemine(c)reactswithmoleculariodineorDIHtogenerate
N-iodo compound (d), and this isfollowed by -elimination of HI with
ammonia to give corresponding nitrile. NH
b-elimination of HI with ammonia to provide aldemine
I2 or DIH ( -HX )
(
I2 or DIH ( -HX)
b
H
n
I
3-n (n¼2,1, 0) formed by
R
CH NH
c)
R
CH NH
b)
(
-HI )
the reaction of ammoniawith molecular iodine or DIH, mayalsowork
as effective N-iodonation species of amine and aldemine.
(
(
I
CH3
O
DIH : CH3
N
I
N
3. Conclusion
I
O
Scheme 1. Possible reaction pathway for nitrile.
In conclusion, benzylic halides and primary alkyl halides could
be easily and directly converted into corresponding aromatic ni-
triles and aliphatic nitriles, respectively, in good yields with re-
tention of the number of carbon atoms, using molecular iodine and
DIH in aq ammonia. The present reaction is not only a novel method
for the preparation of aromatic nitriles from benzylic halides, but
also a conversion method of primary alkyl halides into corre-
sponding aliphatic nitriles, with retention of the number of carbon
atoms. As is well known, the advantages of molecular iodine are
operational simplicity, low cost, low toxicity, and availability, DIH is
also a useful reagent because it is a pale yellow solid, has low tox-
icity, and does not sublimate like molecular iodine. Therefore, the
present reactions should be a useful and environmentally benign
method for the preparation of aromatic nitriles and aliphatic nitriles
from benzylic halides and primary alkyl halides, respectively.
9
). The same treatment of 1,3-bis(chloromethyl)benzene and 1,3-
bis(bromomethyl)benzene with DIH (2.4 equiv) in aq ammonia
gave 1,3-dicyanobenzene in good yields (entries 10 and 18).
For primary alkyl iodides and bromides, the reaction did not
proceed under the same conditions, similar to the case of molecular
iodine. Thus, DMF (0.01 mL) was added to a mixture of 1-iododo-
decane in aq ammonia (1 mL) in a screw-capped glass vial, and the
obtained mixture was warmed at 60 C for 72 h. Then, DIH (2 equiv)
and aq ammonia (6 mL) were added to the reaction mixture, and
again the mixture was warmed at 60 C for 4 h to provide laur-
onitrile in 76% yield as shown in Table 4 (entry 1). 1-Bromodode-
cane was treated with DIH in aq ammonia and a small amount of
DMF to form corresponding lauronitrile in good yield under the
same conditions (entry 2). On the other hand, 3-phenylpropyl ha-
lides, 4-phenylbutyl halides, 5-phenylpentyl halides, and 11-halo-
undecanoic acids, were efficiently converted into corresponding
nitriles in good yields without DMF (entries 7–14). The same
treatment of 1,10-diiododecane and 1,10-dibromodecane provided
the corresponding sebaconitrile in moderate to good yields by us-
ing 4 equiv of DIH under the same conditions (entries 5 and 6).
ꢀ
ꢀ
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were obtained with JEOL-JNM-
GSX-400, JEOL-JNM-LA-400, and JEOL-JNM-LA-500 spectrometers.

S. Iida et al. / Tetrahedron 65 (2009) 6257–6262
6261
Chemical shifts are expressed in parts per million downfield from
TMS in units. Mass spectra were recorded on JEOL-HX-110 and
(3ꢁ15 mL). The organic layer was washed with brine and dried over
Na SO to provide 3-phenylpropionitrile in 72% yield in an almost
d
2
4
JEOL-JMS-ATII15 spectrometers. IR spectra were measured with
a JASCO FT/IR-4100 spectrometer. Melting points were determined
with a Yamato Melting Point Apparatus Model MP-21. Silica gel 60
pure state. If necessary, the product was purified by column chro-
matography (silica gel; hexane/EtOAc¼4:1) to give pure 3-phenyl-
ꢂ1
1
propanenitrile as colorless oil. IR (NaCl): 2250 cm
. H NMR
(
Kanto Kagaku Co.) was used for column chromatography and
(CDCl
3
, TMS):
d
¼7.34 (2H, t, J¼8.2 Hz), 7.28 (1H, t, J¼8.2 Hz), 7.23
Wakogel B-5F was used for preparative TLC.
(2H, d, J¼8.2 Hz), 2.96 (2H, d, J¼7.9 Hz), 2.62 (2H, d, J¼7.9 Hz).
All nitrile products mentioned in this work, except 10-cyano-
decanoic acid and 1-(p-toluenesulfonyl)indole-3-carbonitrile, were
identified by comparing with commercially available authentic
samples.
4
.2. Typical procedure for oxidative conversion of benzyl
halides into nitriles with I
2
To a mixture of 4-methylbenzyl chloride (140.6 mg,1 mmol) and
aq NH
3
(3.0 mL, 45 mmol) was added I
2
(533.0 mg, 2.1 mmol) at rt
4.5.1. Benzonitrile
ꢀ
ꢂ1 1
under an empty balloon. The obtained mixture was stirred at 60 C.
Oil. IR (neat): 2230 cm . H NMR (CDCl
3
, TMS):
d
¼7.67 (2H, d,
After 4 h at the same temperature, the reaction mixture was
J¼7.7 Hz), 7.61 (1H, t, J¼7.7 Hz), 7.48 (2H, t, J¼7.7 Hz).
ꢀ
quenched with H
was extracted with Et
with brine and dried over Na
2
O (10 mL) and satd aq Na
2
SO
3
(2 mL) at 0 C, and
2
O (3ꢁ15 mL). The organic layer was washed
4.5.2. 4-Chlorobenzonitrile
SO to provide p-tolunitrile in 82%
4
Mp 90–91 C. IR (neat): 2225 cm . 1H NMR (CDCl
ꢀ
ꢂ1
3
, TMS):
2
yield in an almost pure state. If necessary, the product was purified
d
¼7.61 (2H, d, J¼8.5 Hz), 7.47 (2H, d, J¼8.5 Hz).
by column chromatography (silica gel; hexane/EtOAc¼4:1) to give
ꢀ
pure p-tolunitrile as a colorless solid; mp 25–26 C. IR (NaCl):
4.5.3. 4-Methoxybenzonitrile
ꢂ1
1
Mp 55–57 C. IR (neat): 2224 cm . 1H NMR (CDCl
ꢀ
ꢂ1
2
230 cm
.
H NMR (CDCl
3
, TMS):
d
¼7.55 (2H, d, J¼7.9 Hz), 7.27
3
, TMS):
(
2H, d, J¼7.9 Hz), 2.42 (3H, s).
d¼7.59 (2H, d, J¼8.9 Hz), 6.96 (2H, d, J¼8.9 Hz), 3.86 (3H, s).
4
.5.4. 2-Cyanothiophene
Oil. IR (neat): 2224 cm . H NMR (CDCl
4
.3. Typical procedure for oxidative conversion of alkyl
ꢂ1 1
3
, TMS):
d
¼7.65 (1H, d,
halides into nitriles with I
2
J¼3.8 Hz), 7.62 (1H, d, J¼5.0 Hz), 7.75 (1H, dd, J¼5.0 and 3.8 Hz).
A mixture of 3-phenylpropyl bromide (199.1 mg, 1 mmol) and
4
.5.5. 1-Naphthonitrile
aq NH
3
(5.0 mL, 75 mmol) in a screw-capped glass vial (10 mL) was
Mp 34–35 C. IR (neat): 2222 cm . 1H NMR (CDCl
ꢀ
ꢂ1
ꢀ
3
, TMS):
stirred at 60 C for 24 h. Then, aq NH
3
(3.0 mL, 45 mmol) and I
2
d
¼8.22 (1H, d, J¼8.2 Hz), 8.06 (1H, d, J¼8.2 Hz), 7.91 (1H, d,
(
761.4 mg, 3.0 mmol) were added. After 4 h at the same tempera-
ture, the reaction mixture was quenched with H O (10 mL) and satd
(2 mL) at 0 C, and was extracted with Et
O (3ꢁ15 mL).
The organic layer was washed with brine and dried over Na SO to
J¼7.9 Hz), 7.89 (1H, d, J¼7.9 Hz), 7.67 (1H, t, J¼8.2 Hz), 7.60 (1H, t,
J¼8.2 Hz), 7.50 (1H, t, J¼7.9 Hz).
2
ꢀ
aq Na
2
SO
3
2
2
4
4.5.6. 2,4,6-Trimethylbenzonitrile
provide 3-phenylpropionitrile in 73% yield in an almost pure state.
If necessary, the product was purified by column chromatography
Mp 54–55 C (lit. mp 55 C). IR (neat): 2220 cm . 1H NMR
ꢀ
10
ꢀ
ꢂ1
(CDCl , TMS):
3
d¼6.93 (2H, s), 2.48 (6H, s), 2.32 (3H, s).
(
silica gel; hexane/EtOAc¼4:1) to give pure 3-phenylpropanenitrile
ꢂ1
1
as a colorless oil. IR (NaCl): 2250 cm
3
. H NMR (CDCl , TMS):
4
.5.7. Lauronitrile
Oil. IR (neat): 2247 cm . H NMR (CDCl
J¼7.2 Hz), 1.66 (2H, quintet, J¼7.2 Hz), 1.44 (2H, quintet, J¼7.2 Hz),
.35–1.25 (14H, br), 0.88 (3H, t, J¼7.2 Hz).
d
¼7.34 (2H, t, J¼8.2 Hz), 7.28 (1H, t, J¼8.2 Hz), 7.23 (2H, d, J¼8.2 Hz),
ꢂ1 1
3
, TMS):
d
¼2.34 (2H, t,
2
.96 (2H, d, J¼7.9 Hz), 2.62 (2H, d, J¼7.9 Hz).
1
4
.4. Typical procedure for oxidative conversion of benzyl
halides into nitriles with DIH
4
.5.8. Cyclohexanecarbonitrile
Oil. IR (neat): 2218 cm . H NMR (CDCl
ꢂ1 1
3
, TMS):
d
¼2.62 (1H, m),
To a mixture of 4-methylbenzyl chloride (140.6 mg,1 mmol) and
1.85 (2H, m), 1.72 (4H, m), 1.55–1.37 (4H, m).
aq NH
3
(3.0 mL, 45 mmol) was added DIH (439.1 mg,1.2 mmol) at rt
ꢀ
under an empty balloon. The obtained mixture was stirred at 60 C.
After 4 h at the same temperature, the reaction mixture was
4
.5.9. 1-Cyanoadamantane
ꢀ
Mp 190–191 C. IR (neat): 2229 cmꢂ1. 1H NMR (CDCl
3
, TMS):
ꢀ
quenched with H
was extracted with Et
with brine and dried over Na
2
O (10 mL) and satd aq Na
2
SO
3
(2 mL) at 0 C, and
d¼2.04 (9H, br), 1.74 (6H, br).
2
O (3ꢁ15 mL). The organic layer was washed
2
SO to provide p-tolunitrile in 77%
4
4
.5.10. Sebaconitrile
Oil. IR (neat): 2245 cm . H NMR (CDCl
J¼7.1 Hz), 1.66 (4H, quintet, J¼7.1 Hz), 1.46 (4H, m), 1.35 (4H, m).
yield in an almost pure state. If necessary, the product was purified
ꢂ1 1
3
, TMS):
d¼2.35 (4H, t,
by column chromatography (silica gel; hexane/EtOAc¼4:1) to give
ꢀ
pure p-tolunitrile as a colorless solid; mp 25–26 C. IR (NaCl):
ꢂ1
1
2
230 cm
.
H NMR (CDCl
3
, TMS):
d
¼7.55 (2H, d, J¼7.9 Hz), 7.27
4
.5.11. 1,3-Dicyanobenzene
Mp 160–161
C. IR (KBr): 2240 cm . 1H NMR (CDCl , TMS):
¼7.97 (1H, s), 7.92 (2H, d, J¼8.1 Hz), 7.67 (1H, t, J¼8.1 Hz).
ꢀ
ꢂ1
(
2H, d, J¼7.9 Hz), 2.42 (3H, s).
3
d
4
.5. Typical procedure for oxidative conversion of alkyl
halides into nitriles with DIH
4.5.12. 4-Nitrobenzonitrile
Mp 140–142 C. IR (neat): 2233 cm . 1H NMR (CDCl
ꢀ
ꢂ1
, TMS):
3
A mixture of 3-phenylpropyl bromide (199.1 mg, 1 mmol) and
d¼8.37 (2H, d, J¼8.9 Hz), 7.90 (2H, d, J¼8.9 Hz).
ꢀ
aq NH
3
(3.0 mL, 45 mmol) was stirred at 60 C for 24 h in a screw-
capped reactor, then to the mixture were added aq NH
3
(3.0 mL,
4.5.13. 4-Phenylbutanenitrile
Oil. IR (neat): 2246 cm . 1H NMR (CDCl
ꢂ1
, TMS):
d¼1.99 (2H,
4
5 mmol) and DIH (731.9 mg, 2.0 mmol). After 4 h at the same
3
temperature, the reaction mixture was quenched with H
2
O (10 mL)
quintet, J¼7.2 Hz), 2.32 (2H, t, J¼7.2 Hz), 2.78 (2H, t, J¼7.2 Hz), 7.18
(2H, d, J¼7.3 Hz), 7.23 (1H, t, J¼7.3 Hz), 7.32 (2H, t, J¼7.3 Hz).
ꢀ
and satd aq Na
2
SO
3
(2 mL) at 0 C, and was extracted with Et
2
O

6
262
S. Iida et al. / Tetrahedron 65 (2009) 6257–6262
3. (a) Friedrick, K.; Wallensfels, K. In The Chemistry of the Cyano Group; Rappoport,
4
2
4
.5.14. 5-Phenylpentanenitrile
Oil. IR (neat): 2246 cm . H NMR (CDCl
.35 (2H, t, J¼7.0 Hz), 2.66 (2H, t, J¼7.5 Hz), 7.24 (5H, m).
ꢂ1 1
Z., Ed.; Wiley-Interscience: New York, NY, 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.-I. Synthesis from Nitriles
with Retention of the Cyano Group. In Science of Synthesis; Georg Thieme:
Stuttgart, 2004; Vol. 19, pp 345–402; (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: Stuttgart, 2004; Vol. 19, pp 403–425.
4. Fabiani, M. E. Drug News Perspect 1999, 12, 207.
3
, TMS):
d
¼1.74 (4H, m),
.5.15. 1-(p-Toluenesulfonyl)indole-3-carbonitrile
ꢀ
ꢂ1
1H NMR (CDCl
.
Mp 155–157 C. IR (neat): 2231 cm
¼8.11 (1H, s), 8.00 (1H, d, J¼7.9 Hz), 7.83 (2H, d, J¼8.4 Hz), 7.69 (1H,
d, J¼7.9 Hz), 7.44 (1H, t, J¼7.9 Hz), 7.38 (1H, t, J¼7.9 Hz), 7.31 (2H, d,
3
, TMS):
d
5
. Comprehensive Organic Transformation; Larock, R. C., Ed.; VCH: New York, NY,
989; pp 976–993.
1
1
3
J¼8.4 Hz), 2.38 (3H, s). C NMR (CDCl
3
, TMS):
d
¼146.3, 133.9, 133.5,
6
. (a) Clarke, T. G.; Hampson, N. A.; Lee, J. B.; Morley, J. R.; Scanlon, B. Tetrahedron Lett.
1968, 5685; (b) Vargha, L.; Remenyi, M. J. Chem. Soc. 1951, 1068; (c) Cason, J. Org.
Synth.; Wiley: New York, NY, 1955; Coll. Vol. III, p 3; (d) Mihailovic, M. L.; Sto-
jiljkovic, A.; Andrejevic, V. Tetrahedron Lett. 1965, 461; (e) Stojiljkovic, A.; An-
drejevic, V.; Mihailovi, M. L. Tetrahedron 1967, 23, 721; (f) Below, J. S.; Garza, C.;
Mathieson, J. W. J. Chem. Soc., Chem. Commun. 1970, 634; (g) Troyanskii, E. I.;
Svitanko, I. V.; Ioffe, V. A.; Nikishin, G. I. Izv. Akad. Nauk SSSR, Ser. Khim.1982, 2180;
1
33.1, 130.0, 128.2, 127.1, 126.4, 124.7, 120.2, 113.7, 113.4, 93.5, 21.6.
HRMS: calcd for C16
H
13
O
2
N
2
S: 297.0698; found: 297.0687.
4
.5.16. 10-Cyanodecanoic acid
Mp 42–44 C. IR (neat): 2243, 1690 cm . H NMR (CDCl , TMS):
3
ꢀ
ꢂ1 1
(h) Yamazaki, S.; Yamazaki, Y. Bull. Chem. Soc. Jpn. 1990, 63, 301; (i) Biondini, D.;
d
¼2.35 (t, J¼7.4 Hz, 2H), 7.34 (t, J¼7.2 Hz, 1H), 1.64 (m, 4H), 1.44 (br,
Brinchi, L.; Germani, R.; Goracci, L.; Savelli, G. Eur. J. Org. Chem. 2005, 3060; (j)
Chen, E.; Peng, Z.; Fu, H.; Liu, J.; Shao, L. J. Chem. Res., Synop.1999, 726; (k) Lee, G. A.;
Freedman, H. H. Tetrahedron Lett.1976,1641; (l) Yamazaki, S. Synth. Commun.1997,
2
2
1
H) 1.32 (br, 9H). 13C NMR (CDCl
9.0, 28.72, 28.66, 25.4, 24.7, 17.2. HRMS: m/z calcd for C11
3
, TMS):
d
¼179.7, 119.9, 34.0, 29.1,
19 2
H O
N:
27; (m) Jursic, B. J. Chem. Res., Synop.1988, 168; (n) Nikishin, G. I.; Troyanskii, E. I.;
98.1494; found: 198.1484.
Joffe, V. A. Izv. Akad. Nauk SSSR, Ser. Khim. 1982, 2758; (o) Kametani, T.; Takahashi,
K.; Ohsawa, T.; Ihara, M. Synthesis 1977, 245; (p) Capdevielle, P.; Lavigne, A.;
Maumy, M. Synthesis 1989, 453; (q) Capdevielle, P.; Lavigne, A.; Sparfel, D.; Bar-
anne-Lafont, J.; Nguyen, K. C.; Maumy, M. Tetrahedron Lett. 1990, 31, 3305; (r)
Maeda, Y.; Nishimura, T.; Uemura, S. Bull. Chem. Soc. Jpn. 2003, 76, 2399; (s) Tang,
R.; Diamond, S. E.; Neary, N.; Mares, F. J. Chem. Soc., Chem. Commun. 1978, 562; (t)
Schroder, M.; Griffith, W. P. J. Chem. Soc., Chem. Commun. 1979, 58; (u) Bailey, A. J.;
James, B. R. Chem. Commun. 1996, 2343; (v) Mori, K.; Yamaguchi, K.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Chem. Commun. 2001, 461; (w) Yamaguchi, K.; Mizuno, N.
Angew. Chem., Int. Ed. 2003, 42,1480; (x) Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.;
Ochiai, M.; Inenaga, M.; Nagao, Y. Tetrahedron Lett. 1988, 29, 6913; (y) Chen, F.;
Kuang, Y.; Dai, H.; Lu, L.; Huo, M. Synthesis 2003, 2629.
Acknowledgements
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, Japan is gratefully acknowledged.
The authors thank Nippoh Chemical Co. for the gift of DIH.
7. As a preliminary report: Iida, S.; Togo, H. Synlett 2008, 1639.
8
. (a) Mori, N.; Togo, H. Synlett 2004, 880; (b) Mori, N.; Togo, H. Tetrahedron 2005,
61, 5915; (c) Ishihara, M.; Togo, H. Synlett 2006, 227; (d) Ishihara, M.; Togo, H.
Tetrahedron 2007, 63, 1474.
References and notes
1
. Review: (a) Togo, H.; Iida, S. Synlett 2006, 2159; (b) Togo, H. J. Synth. Org. Chem.
9. (a) Mori, N.; Togo, H. Synlett 2005, 1456; (b) Iida, S.; Togo, H. Synlett 2006, 2633;
(c) Iida, S.; Togo, H. Tetrahedron 2007, 63, 8274.
10. Houben, J.; Fischer, W. Ber. 1933, 66B, 339.
2008, 66, 652.
2
. Orazi, O. O.; Corral, R. A.; Bertorello, H. E. J. Org. Chem. 1965, 30, 1101.