Direct oxidative conversion of alcohols and amines to nitriles with molecular iodine and DIH in aq NH3

Article abstract of DOI:10.1016/j.tet.2007.05.106

Simple and high-yield procedures for the direct oxidative conversion of various primary alcohols, and primary, secondary, and tertiary amines to the corresponding nitriles were successfully carried out with molecular iodine in aq ammonia and 1,3-diiodo-5,5-dimethylhydantoin in aq NH₃, respectively.

Full text of DOI:10.1016/j.tet.2007.05.106

Tetrahedron 63 (2007) 8274–8281
Direct oxidative conversion of alcohols and amines to
nitriles with molecular iodine and DIH in aq NH3
*
Shinpei Iida and Hideo Togo
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
Received 8 May 2007; revised 24 May 2007; accepted 25 May 2007
Available online 2 June 2007
Abstract—Simple and high-yield procedures for the direct oxidative conversion of various primary alcohols, and primary, secondary, and
tertiary amines to the corresponding nitriles were successfully carried out with molecular iodine in aq ammonia and 1,3-diiodo-5,5-dimethyl-
hydantoin in aq NH , respectively.
3
Ó 2007 Published by Elsevier Ltd.
1. Introduction
2. Results and discussion
Nitriles are one of the most important synthetic transforma-
tion precursors, especially into esters, amides, carboxylic
acids, amines, and nitrogen-containing heterocycles.
2.1. Conversion of primary alcohols, and primary, sec-
ondary, and tertiary amines to nitriles with molecular
iodine in aq NH3
1
Therefore, they have been used as synthetic intermediates
for agricultural chemicals, pharmaceutical chemicals, and
functional material chemicals. The most typical synthetic
Molecular iodine is a mild, cheap, and easily available oxi-
dizing reagent, and it is useful because it is solid form and is
less toxic than other halogens such as molecular bromine
and chlorine. Previously, simple conversion of aldehydes
to the corresponding nitriles using molecular iodine in aq
2
method is the reaction of alkyl halides with very toxic metal
cyanide via nucleophilic pathway, though one carbon is in-
creased. Consequently, nitriles are generally prepared by
the dehydration of amides with SOCl , TsCl/Py, P O ,
6
NH and CH OH or THF was reported. Today, to the best
3
2
2
5
3
POCl , COCl , (EtO) P/I , Ph P/CCl , etc., by the conden-
3
of our knowledge, direct oxidative conversion of alcohol
to the corresponding nitriles in one-pot manner is extremely
limited, i.e. using NiSO4 and K S O in aq NaOH,
2 2 8
2
3
2
3
4
sation of carboxylic acids with NH /silica gel, NH /ethyl
3
3
7
a
polyphosphate, etc., and by the reaction of esters with
Me AlNH . On the other hand, oxidative conversion of pri-
mary amines to the corresponding nitriles has been well
3
NH HCO , (Bu N) S O , and a catalytic amount of
4 3 4 2 2 8
2
2
i
7b
Cu(HCO ) $Ni(HCO ) in aq KOH and PrOH, and
2 2 2 2
4
a
4b–4e
4f
i
studied using AgO, Pb(OAc)4,
Na S O or (Bu N) S O with metals,
cobalt peroxide,
NaOCl,
MnO , NH , and MgSO in THF and PrOH for benzylic
2 3 4
4
g–4j
4k–4m
7c
and cinnamic alcohols.
2
2
8
4
2 2 8
4
n
4o–4r
K Fe(CN) , Cu(I) or Cu(II) with oxygen,
6
RuCl and
3
3
4
s–4w
4x
related Ru reagents,
PhIO, and trichloroisocyanuric
At first, a direct, efficient, practical, and less toxic oxidative
conversion of primary alcohols to the corresponding nitriles,
4
y
acid with TEMPO. Here, as a part of our study for the syn-
thetic use of molecular iodine and related reagents for or-
ganic synthesis, we would like to report for the direct
8
using molecular iodine in aq NH was studied. Thus, when
3
5
3-phenylpropanol (1 mmol) was treated with molecular io-
dine in aq NH , changing the amounts of molecular iodine
oxidative conversion of primary alcohols, and primary, sec-
ondary, and tertiary amines to the corresponding nitriles with
molecular iodine and related reagents.
3
and aq NH under empty balloon, 3-phenylpropionitrile
3
was formed as shown in Table 1. When the reaction was car-
ried out in a sealed tube, the amount of aq NH could be re-
3
duced (entries 7–10). However, it is not so practical. The
results indicate that the reaction with 3.0 equiv of molecular
iodine and 45 equiv of aq NH (3 mL, 28–30%) under empty
balloon at 60 C gave 3-phenylpropionitrile in the best yield
(entry 5).
3
Keywords: Primary alcohol; Primary amine; Secondary amine; Tertiary
amine; Iodine; 1,3-Diiodo-5,5-dimethylhydantoin; Nitrile; Aq NH .
3
ꢀ
*
Corresponding author. E-mail: togo@faculty.chiba-u.jp
0
040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.05.106

S. Iida, H. Togo / Tetrahedron 63 (2007) 8274–8281
Table 1. Oxidative conversion of 3-phenylpropanol to 3-phenylpropionitrile Table 3. Oxidative conversion of alcohol to nitriles with I
8275
/aq NH
2 3
with I
2 3
/aq NH
I2 (3.0 eq.)
aq.NH3 (3.0 mL), 60 °C
R−CH OH
R−CN
I2, aq. NH
3
2
Ph(CH ) CH OH
Ph(CH ) CN
2 2
2
2
2
2
4h
Entry
Re
Time Yield Entry
(
Re
Time Yield
(h) (%)
ꢀ
Entry
I
2
/aq NH
3
(equiv)
Temp. ( C)
Yield (%)
h) (%)
a
14 (86 )
1
2
3
4
5
2.5/10
2.5/10
2.5/20
2.5/45
3.0/45
3.0/10
3.0/5
3.0/10
3.0/15
3.0/20
rt
CH3
CH3
a
62 (28 )
50
50
50
60
60
60
60
60
60
a
74 (20 )
a
1
2
2
86
95
11
CH3
30 68
a
67 (29 )
91
51 (34 )
b
a
6
c
a
31 (53 )
Cl
2
12
4
2
42
99
7
c
a
48 (31 )
8
c
a
81 (12 )
9
c
a
85 (12 )
10
b
13
3
4
3
3
92
77
a
b
c
O2N
Yield of the starting material.
CO (2.0 equiv) was added.
Reaction was carried out in a sealed tube.
K
2
3
14
24 91
42 90
21 63
N
When the reactivity of molecular iodine was compared with
those of N-bromosuccinimide (NBS), N-chlorosuccinimide
c
5
6
7
8
9
CH3O
CH3O
CH3O
CH3O
2
2
3
4
4
99
97
67
66
80
15
16
17
18
19
(
NCS), N-iodosuccinimide (NIS), ICl, and Ca(OCl) in aq
2
NH3 using p-methoxybenzyl alcohol and 1-dodecanol,
NBS and NCS did not work, and NIS and ICl gave the cor-
responding nitriles in good to moderate yields as shown in
Table 2. However, the yields with molecular iodine were bet-
ter than those with NIS and ICl, and practically NIS is expen-
sive and ICl is not so easy to operate. Based on these results,
various primary alcohols such as benzylic alcohols, straight-
chained alcohols, adamantylmethanol were treated with
CH3O
S
CH (CH
3
2
)
11
–
8
8
6
91
68
90
N
Ts
molecular iodine in aq NH to provide the corresponding
3
nitriles in good yields, except for cinnamyl alcohol, which
induced further addition reaction to the formed cinnamoni-
trile by ammonia in aq NH under the warming temperature
3
as shown in Table 3. The reaction could be also carried out
in preparative scale without any problem to give the corre-
sponding nitrile in good yield (entry 15). Diols could
be also transformed to the corresponding dinitriles using
CH3
b
20
1
0
6
80
–(CH
2
)
8
–
24 99
CH3
twice the amount of molecular iodine and aq NH (entries
3
a
ꢀ
Reaction was carried out at 80 C and I
4 h.
(6.0 equiv) and aq NH
Reaction was carried out using 10 mmol (1.36 g) of alcohol.
2
(1.5 equiv) was added again after
1
3 and 20).
2
b
c
I
2
3
(6.0 mL) were used.
Today, some outline work on the reaction of benzylamine
with molecular iodine in acetonitrile to form imine, N-
benzylidenebenzylamine, benzonitrile, etc., was reported.
9
the reaction was very simply carried out by treatment of
benzylic and aliphatic primary amines (1 mmol) with mole-
cular iodine (2.1–3.0 mmol) in aq NH (28–30%, 3 mL) at
60 C to provide the corresponding nitriles in good yields
as shown in Table 4. When the same reaction was carried
However, detailed study for the reaction of amines with
molecular iodine in aq NH has not been carried out. Thus,
3
3
ꢀ
1
0
Table 2. Oxidative conversion of alcohols to nitriles with halogen reagents
in aq NH
t
out in water or BuOH in the presence of K CO , instead of
3
2
3
aq ammonia, the yield of nitrile was decreased as shown in
entries 5 and 6. Diamines were also converted to the corre-
sponding dinitriles in good yields (entries 14–17). DL-2-phe-
nylglycine was converted to benzonitrile through oxidative
decarboxylation (entries 18 and 19).
Reagent, aq. NH3 (3.0 mL)
R−CH OH
R−CN
2
60 °C
Entry
Re
Reagent
(3.0 equiv)
Time (h) Yield (%)
1
2
3
4
5
6
I
2
2
2
2
2
2
2
99
a
2 (88 )
NBS (3.0 equiv)
NCS (3.0 equiv)
NIS (3.0 equiv)
ICI (3–6 equiv)
a
0 (99 )
When N-methyl secondary amines and N,N-dimethyl
tertiary amines were treated with molecular iodine under
the same conditions, the corresponding nitriles could be
again obtained in good yields as shown in Table 5. Moreover,
bis(dodecyl)amine (1 mmol), bis(4-methylbenzyl)amine
CH3O
a
92 (8 )
97
a
0 (94 )
Ca(OCI)
2
(1.5 equiv)
7
8
9
CH
3
(CH
2
)
10
–
I
2
(3.0 equiv)
8
8
8
91
60 (40 )
a
NIS (3.0 equiv)
ICI (3–6 equiv)
(1 mmol), tris(dodecyl)amine (1 mmol), and tris(4-methyl-
a
67 (31 )
benzyl)amine (1 mmol) were treated with 4.5 equiv,
4.5 equiv, 6.5 equiv, and 6.5 equiv of molecular iodine, in
a
Yield of the starting material.

8276
S. Iida, H. Togo / Tetrahedron 63 (2007) 8274–8281
Table 4. Oxidative conversion of primary amines to nitriles with I
2
/aq NH
3
Table 5. Oxidative conversion of secondary and tertiary amines to nitriles
2 3
with I /aq NH
I2, aq. NH3 (3.0 mL)
R−CH NH
R−CN
2
2
I2
60 °C
R−CH X
R−CN
2
aq. NH3 (3 mL), 60 °C
Entry
Re
I
2
(equiv)
Time (h)
Yield (%)
Entry
Re
X
2
I (equiv) Time (h) Yield (%)
1
2
2.1
3.0
1
1
56
68
1
2
3
4
5
6
NH(CH
NH(CH
NH(CH
N(CH
N(CH
N(CH
3
3
3
2
2
2
)
)
)
2.1
3.5
4.0
2.1
3.5
4.0
4
4
4
0.5
0.5
0.5
49
71
71
41
71
74
3
4
5
6
2.1
3.0
3.0
3.0
2
2
2
8
80
81
30
a
3
3
3
)
)
)
CH3
b
c
50 (20 )
7
8
2.1
3.0
2
2
78
87
7
8
CH (CH
3
2
)
10
–
NH(CH
N(CH
3
)
)
3.5
3.5
4
0.5
76
73
Cl
)
3
2
9
1
NH(CH
N(CH
3
3.5
4.0
1
1
81
67
9
1
2.1
3.0
1
1
77
82
0
3
)
2
0
OCH3
1
1
1
2
NH(CH
N(CH
3
)
3.5
4.0
1
1
84
77
1
1
1
2
CH
3
(CH
2
)
10
–
2.1
3.0
4
4
75
83
3
)
2
CH3
Cl
TsHN
1
3
3.0
2
72
1
1
3
4
NH(CH
N(CH
3
)
)
3.5
5.0
2
2
77
72
3
)
2
d
d
1
1
4
5
4.2
6.0
2
2
79
90
15
16
NH(CH
N(CH
3
3.5
5.0
2
6
96
76
d
3
)
1
1
6
7
–(CH
2
)
8
–
4.2
6.0
4
4
61
61
O N
2
2
d
1
18
7a
CH (CH
3
2
)
10
–
NH(CH
N(CH
2
R) 4.5
6.5
4
6
84
71
e
1
1
8
9
-
2.1
3.0
1
1
80
95
COO
Ph
2
R)
2
e
H
+
19
2
NH(CH
R) 4.5
6.5
8
4
91
83
NH3
2
0
N(CH R)
2
2
a
b
c
d
e
CH3
H
2
O (3.0 mL) and K
BuOH (3.0 mL) and K
2
CO
3
(3.0 equiv) were used instead of aq NH .
(3.0 equiv) were used instead of aq NH
3
t
2
CO
3
3
.
a
Aq NH (9 mL) was used.
3
Yield of the starting material.
Double amount of aq NH
Product was benzonitrile.
3
was used.
Table 6. Oxidative conversion of 1-dodecanol and 1-dodecylamine with
DIH in aq NH
3
Reagent,
aq.NH (3.0 mL)
aq NH under the same conditions to give the corresponding
3
lauronitrile (1.67 mmol), p-tolunitrile (1.82 mmol), lauroni-
trile (2.14 mmol), and p-tolunitrile (2.53 mmol) in 84%,
3
C11H23 CH X
C11H23 CN
2
60 °C, dark
Entry
X
Reagent
Equiv
Time (h)
Yield (%)
97
65 (16 )
9
1%, 71%, and 83% yields, respectively (entries 17–20).
1
2
3
4
OH
DIH
NIS
NBS
NCS
2.0
4.0
4.0
4.0
32
32
32
32
a
2
.2. Conversion of primary alcohols, and primary,
a
0 (99 )
0 (99 )
secondary, and tertiary amines to nitriles with DIH
in aq NH3
a
5
6
7
8
NH
2
DIH
NIS
NBS
NCS
1.2
2.4
2.4
2.4
6
6
6
6
88
71
0 (57 )
0 (51 )
1
,3-Diiodo-5,5-dimethylhydantoin (DIH) was also studied
a
as another direct, efficient, practical, and less toxic oxidative
reagent for the conversion of primary alcohols to the corre-
sponding nitriles in aq NH . Today, to the best of our knowl-
a
a
Yield of the starting material.
3
edge, synthetic use of DIH is extremely limited, while the
iodination of aromatics with DIH has been reported.
1
1
Based on these results, various primary alcohols and primary
amines were treated with DIH in aq NH to form the corre-
3
Thus, the reaction was very simply carried out by treatment
of 1-dodecanol (1 mmol) and 1-dodecylamine (1 mmol)
with DIH (2.0 mmol for 1-dodecanol and 1.2 mmol for 1-
sponding nitriles in good yields (Tables 7 and 8). The reac-
tivity depends on the alcohols used, thus benzylic alcohols
were smoothly converted to the corresponding nitriles in
good yields, using 1.5 equiv of DIH (entries 8–16 in Table
7), while aliphatic primary alcohols required 2.0 equiv of
DIH and long reaction time (entries 1–6 in Table 7). The
same treatment of 1,8-octanediol and p-xylene glycol pro-
vided the corresponding dinitriles in good yields, respec-
tively (entries 7 and 17 in Table 7). The reaction could be
also carried out in preparative scale without any problem
to provide the corresponding nitrile in good yield (entry 5
in Table 7). Secondary and tertiary amines were also con-
verted to the corresponding nitriles in good yields (entries
ꢀ
dodecylamine) in aq NH (28–30%, 3 mL) at 60 C under
3
dark conditions to provide the corresponding lauronitrile
in 97% and 88% yields, respectively, as shown in Table 6
1
2
(
with NIS (4.0 mmol for 1-dodecanol and 2.4 mmol for 1-do-
entries 1 and 5). When the same reaction was carried out
decylamine) in aq NH , lauronitrile was also obtained
3
(
entries 2 and 6). However, the yields tend to decrease as
compared with DIH. On the other hand, NCS and NBS did
not provide the corresponding lauronitrile at all, and the
starting materials remained mainly (entries 3, 4, 7, and 8).

S. Iida, H. Togo / Tetrahedron 63 (2007) 8274–8281
8277
Table 7. Oxidative conversion of alcohols to nitriles with DIH/aq NH
3
Table 8. Oxidative conversion of amines to nitriles with DIH/aq NH
3
DIH, aq. NH3 (3.0 mL)
DIH, aq. NH3 (3.0 mL)
60 °C, dark
R−CH OH
R−CN
R−CH NX
R−CN
2
2
60 °C, dark
Entry
a
Re
DIH (equiv)
Time (h)
Yield (%)
Entry
Re
NX
DIH (equiv) Time (h) Yield (%)
1
1.5
1.5
2.0
24
24
24
63
69
77
1
2
3
4
CH (CH
3
2
)
10
–
NH
NH
NH
NH
2
2
2
2
1.1
1.2
1.2
1.5
4
4
6
4
84
85
88
88
2
3
4
5
CH
3
(CH
2
)
10
–
2.0
2.0
32
32
97
95
b
5
6
7
8
9
NH
NH
NH
NH
2
2
2
2
1.2
1.2
1.2
1.2
2
2
3
4
79
92
72
93
6
2.0
32
82
c
7
2
–(CH )
6
–
4.0
24
94
Me
8
9
1.1
1.3
1.5
1.7
3
3
3
3
66
77
84
83
1
1
0
1
Me
Cl
12
1.5
5
71
OMe
13
1.5
3
81
NH
2
1.2
2.4
4
6
98
65
Cl
O N
2
1
1
1
4
5
6
1.5
1.5
1.5
12
3
89
91
92
a
a
a
1
0
2 8
–(CH ) –
NH
2
O N
2
1
1
1
2
CH (CH
3
2
)
10
–
–
NH(CH
N(CH
3
)
)
1.7
1.7
6
0.5
76
80
3
)
2
MeO
13
1
NH(CH
N(CH
1.7
2.5
3
2
79
72
3
4
3
)
2
Cl
CH
8
1
1
5
6
3
(CH
2
)
10
NH(CH
2
R) 2.4
10
6
84
84
b
N(CH
NH(CH
N(CH R)
2
R)
R) 2.4
4.2
2
3.6
1
1
7
8
2
6
48
84
85
c
2
2
17
3.0
4
95
Cl
a
b
c
a
b
c
Aq NH
Aq NH
Aq NH
(6 mL) was used.
(9 mL) was used.
(3 mL) was added again after 24 h.
3
Flask was not covered with Alumi-foil.
Reaction was carried out using 10 mmol of alcohol.
Double amount of aq NH was used.
3
3
3
11–18 in Table 8). Today, it is known that aldehydes
smoothly react with molecular iodine in aq NH to provide
Table 9. Oxidative conversion of aldehydes to nitriles with DIH/aq NH
3
3
DIH (0.6 equiv.)
6
the corresponding nitriles. DIH also reacts with aldehydes
including cinnamaldehyde in aq NH at room temperature
aq. NH (3.0 mL)
3
R−CHO
Re
R−CN
3
r.t.
to provide the corresponding nitriles in good yields as shown
in Table 9.
Entry
1
Time (h)
1
Yield (%)
89
Treatment of imines, which were prepared from the corre-
sponding aldehydes with primary amines, with molecular
Me
ꢀ
iodine and DIH in aq NH at 60 C gave the corresponding
3
2
3
MeO
1
2
90
78
nitriles, respectively, in good yields as shown in Table 10.
Based on these results, a plausible reaction pathway for
the conversion of primary alcohol and primary amine to
the corresponding nitrile with molecular iodine and DIH is
shown in Scheme 1. Thus, the initial O-iodination and N-
iodination of alcohol and amine with molecular iodine and
DIH occurred to form O-iodo and N-iodo compounds (a), re-
O N
2
4
2
3
1
94
73
88
a
5
spectively, followed by b-elimination of HI by NH to form
3
aldehyde and aldimine (b), respectively. Here aldehyde
smoothly reacts with NH to form aldimine (c). Then, ald-
6
3
imine (c) reacts with molecular iodine and DIH in the pres-
ence of NH to form N-iodo aldimine (d), followed by
b-elimination of HI by NH to generate the corresponding
3
3
b
7
1
77
nitrile. Practically, aldehydes react with molecular iodine
and DIH smoothly at room temperature in aq NH to provide
the corresponding nitriles in good yields. Imines also react
a
3
3
DIH (1.2 equiv) and aq NH (6.0 mL) were used.
THF (1 mL) was used and reaction was carried out at 0 C.
b
ꢀ

8278
S. Iida, H. Togo / Tetrahedron 63 (2007) 8274–8281
Table 10. Oxidative conversion of imines to nitriles with DIH/aq NH
3
downfield from tetramethylsilane (TMS) in d units. Mass
spectra were recorded on JEOL-HX-110 and JEOL-JMS-
ATII15 spectrometers. Melting points were determined on
Yamato melting point apparatus Model MP-21. Silica
gel 60 (Kanto Kagaku Co.) was used for column chro-
matography and Wakogel B-5F was used for preparative
TLC.
Reagent
aq.NH3 (3.0 mL)
R−C N CH R'
R−CN +
R'−CN
2
H
60 °C
Reagent
0
Entry
Re
R e
Time Yields (%)
(
h)
0
RꢂCN R ꢂCN
1
2
I
2
(4.0 equiv) 16
6
79
79
80
75
Most of the nitriles mentioned in this work were identified
with commercially available authentic samples, except
for 1-(p-toluenesulfonyl)indole-3-carbonitrile and 3-(p-
toluenesulfonyl)aminomethylbenzonitrile.
CH
3
(CH
2
)
10
–
DIH (2.0 equiv)
Me
Me
3
4
I
2
(4.0 equiv) 16
3
79
94
72
79
DIH (2.0 equiv)
Cl
4.2. Typical procedure for oxidative conversion
of primary alcohols to nitriles with I2
5
6
I
2
(4.0 equiv) 16
DIH (2.0 equiv) 10
95
94
81
72
CH
3
2
(CH )
10
–
O N
2
7
8
I
2
(4.0 equiv) 16
96
97
70
80
To a mixture of 3-phenylpropanol (136.2 mg, 1 mmol) and
aq NH (3 mL, 45 mmol) was added I (761 mg, 3 mmol)
DIH (2.0 equiv)
4
3
2
O N
Cl
2
at room temperature under empty balloon. Empty balloon
was used to reduce the escape of ammonia gas from the re-
ꢀ
ꢀ
with molecular iodine and DIH in aq NH at 60 C to form
3
action mixture. The mixture obtained was stirred at 60 C.
the corresponding nitriles in good yields.
After 24 h at the same temperature, the reaction mixture
was quenched with H O (20 mL) and satd aq Na SO
3
2
2
IX
ꢀ
(
3 mL) at 0 C, and was extracted with Et O (3ꢁ20 mL).
R
CH2 XH
R
R
C
N
2
aq. NH3
The organic layer was washed with brine and dried over
Na SO to provide 3-phenylpropionitrile in 91% yield in
IX ( -HX )
X = O, NH
( -HI )
2
4
I
an almost pure state. If necessary, the product was purified
by flash column chromatography on silica gel (hexane/
H
C
H
N
R
R
CH
X
I
[
X = NH ]
IX
EtOAc¼4:1) to give pure 3-phenylpropionitrile as a colorless
(
a)
(d)
ꢂ1 1
oil. IR (NaCl): 2250 cm . H NMR (CDCl ): d¼7.34 (2H,
(
-HX)
3
(
-HI )
t, J¼8.2 Hz), 7.28 (1H, t, J¼8.2 Hz), 7.23 (2H, d, J¼8.2 Hz),
IX ( -HX)
[
X = O ]
2
.96 (2H, t, J¼7.4 Hz), 2.62 (2H, t, J¼7.4 Hz).
NH
3
CH
b)
X
R
CH NH
(c)
(
-H O)
2
(
4
.3. Typical procedure for oxidative conversion
O
CH3
I
of primary amines to nitriles with I
2
N
IX: I
I
or
CH3
N
I
O
To a mixture of 4-methylbenzylamine (121.2 mg, 1 mmol)
and aq NH (3.0 mL, 45 mmol) was added I (533.0 mg,
2.1 mmol) at room temperature under an empty balloon.
3
2
Scheme 1. Plausible reaction pathway for nitrile.
ꢀ
The resulting mixture was stirred at 60 C. After 2 h at the
same temperature, the reaction mixture was quenched with
ꢀ
3. Conclusion
H O (20 mL) and satd aq Na SO (3 mL) at 0 C, and was
2
2
3
extracted with Et O (3ꢁ15 mL). The organic layer was
2
In summary, primary alcohols, and primary, secondary, and
tertiary amines could be easily and efficiently converted to
the corresponding nitriles in good yields, using molecular
washed with brine and dried over Na SO to provide p-
2
4
tolunitrile in 80% yield in an almost pure state. If necessary,
the product was purified by column chromatography (silica
gel; hexane/EtOAc¼4:1) to give pure p-tolunitrile as a color-
iodine and DIH in aq NH . As is well known, the advantages
3
ꢀ
ꢂ1
1
of molecular iodine are operational simplicity, low cost, and
low toxicity. DIH can be also used for the same oxidative
conversion of primary alcohols, and primary, secondary,
and tertiary amines to the corresponding nitriles in good
yields. DIH is a pale yellow solid and does not sublimate,
like molecular iodine. So it is more convenient to operate
the reaction with DIH.
less solid; mp 25 C. IR (NaCl): 2230 cm . H NMR
(CDCl ): d¼7.55 (2H, d, J¼7.9 Hz), 7.27 (2H, d, J¼7.9 Hz),
3
2.42 (3H, s).
4.4. Typical procedure for oxidative conversion
of tertiary amines to nitriles with I2
To
a
163.2 mg, 1 mmol) and aq NH (3.0 mL, 45 mmol) was
mixture of N,N-dimethyl-3-phenylpropylamine
(
added I (888.3 mg, 3.5 mmol) at room temperature under
3
4
. Experimental section
2
an empty balloon. The resulting mixture was stirred at
60 C. After 0.5 h at the same temperature, the reaction
ꢀ
mixture was quenched with H O (20 mL) and satd aq
4
.1. General
2
1
13
ꢀ
H and C NMR spectra were obtained with JEOL-JNM-
LA-400, JEOL-JNM-LA-400s, JEOL-JNM-LA-500 spec-
trometers. Chemical shifts are expressed in parts per million
Na SO (3 mL) at 0 C, and was extracted with Et O
2
3
2
(3ꢁ15 mL). The organic layer was washed with brine and
dried over Na SO to provide 3-phenylpropionitrile in
2
4

S. Iida, H. Togo / Tetrahedron 63 (2007) 8274–8281
8279
7
1% yield in an almost pure state. If necessary, the product
for 1 h. The reaction mixture was quenched with H O
2
ꢀ
was purified by column chromatography on silica gel (hex-
ane/EtOAc¼4:1) to give pure 3-phenylpropionitrile as a
colorless oil.
(20 mL) and satd aq Na SO (1 mL) at 0 C, and was ex-
3
2
tracted with Et O (3ꢁ15 mL). The organic layer was washed
2
with brine and dried over Na SO to provide p-tolunitrile in
2
4
89% yield in an almost pure state. If necessary, the product
4.5. Oxidative conversion of tris(4-methylbenzyl)amine
to p-tolunitrile with I2
was purified by column chromatography on silica gel (hex-
ane/EtOAc¼4:1) to give pure p-tolunitrile as a colorless
solid.
To a mixture of tris(4-methylbenzyl)amine (329.5 mg,
1
mmol) and aq NH (3.0 mL, 45 mmol) was added I2
3
4.9. Typical procedure for oxidative conversion of imines
to nitriles with I2
(
balloon. The resulting mixture was stirred at 60 C. After
1.650 g, 6.5 mmol) at room temperature under an empty
ꢀ
h at the same temperature, the reaction mixture was
4
quenched with H O (20 mL) and satd aq Na SO (3 mL)
To a mixture of N-(4-methylbenzylidene)-1-dodecylamine
(287.5 mg, 1 mmol) and aq NH (3.0 mL, 45 mmol) was
2
2
3
3
ꢀ
ganic layer was washed with brine and dried over Na SO
at 0 C, and was extracted with Et O (3ꢁ15 mL). The or-
added I (1.015 g, 4.0 mmol) at room temperature under
2
2
an empty balloon. The obtained mixture was stirred at
ꢀ
2
4
to provide p-tolunitrile in 84% yield in an almost pure state.
If necessary, the product was purified by column chromato-
graphy (silica gel; hexane/EtOAc¼4:1) to give pure p-
tolunitrile as a colorless solid.
60 C. After 16 h at the same temperature, the reaction mix-
ture was quenched with H O (20 mL) and satd aq Na SO
3
2
2
ꢀ
The organic layer was washed with brine and dried over
(3 mL) at 0 C, and was extracted with Et O (3ꢁ15 mL).
2
Na SO to provide p-tolunitrile and lauronitrile in 79%
2
4
4
.6. Typical procedure for oxidative conversion
of primary alcohols to nitriles with DIH
and 80%, respectively. The products were separated by col-
umn chromatography on silica gel (hexane/EtOAc¼4:1) to
give pure p-tolunitrile as a colorless solid and lauronitrile
as a colorless oil.
To a mixture of 1-dodecanol (186.3 mg, 1 mmol) and aq
NH3 (3.0 mL, 45 mmol) was added DIH (731.9 mg,
ꢂ1
1
2
.0 mmol) at room temperature under an empty balloon.
ꢀ
4.9.1. Benzonitrile. IR (neat): 2230 cm
.
H NMR
The obtained mixture was stirred at 60 C. After 32 h at
the same temperature, the reaction mixture was quenched
(CDCl ): d¼7.67 (2H, d, J¼7.7 Hz), 7.61 (1H, t, J¼
3
7.7 Hz), 7.48 (2H, t, J¼7.7 Hz).
ꢀ
with H O (20 mL) and satd aq Na SO (3 mL) at 0 C, and
2
2
3
ꢂ1
1
was extracted with Et O (3ꢁ15 mL). The organic layer
4.9.2. 4-Chlorobenzonitrile. IR (neat): 2225 cm . H
NMR (CDCl ): d¼7.61 (2H, d, J¼8.5 Hz), 7.47 (2H, d, J¼
2
was washed with brine and dried over Na SO to provide
2
4
3
lauronitrile in 97% yield in an almost pure state. If necessary,
the product was purified by column chromatography on
silica gel (hexane/EtOAc¼4:1) to give pure lauronitrile as
8.5 Hz).
ꢂ1 1
4.9.3. 3-Nitrobenzonitrile. IR (neat): 2237 cm . H NMR
(CDCl ): d¼8.55 (1H, s), 8.49 (1H, d, J¼8.1 Hz), 8.02 (1H,
ꢂ1
1
a colorless oil. IR (NaCl): 2250 cm . H NMR (CDCl ):
3
3
d¼2.34 (2H, t, J¼7.1 Hz), 1.66 (2H, quintet, J¼7.1 Hz),
d, J¼8.1 Hz), 7.75 (1H, t, J¼8.1 Hz).
1
.45 (2H, quintet, J¼7.1 Hz), 1.29 (14H, br), 0.88 (3H, t,
ꢂ1
1
J¼7.0 Hz).
4.9.4. 3-Cyanopyridine. IR (neat): 2235 cm . H NMR
CDCl ): d¼8.91 (1H, s), 8.84 (1H, d, J¼4.8 Hz), 7.99
(
3
4.7. Typical procedure for oxidative conversion
of primary amines to nitriles with DIH
(1H, d, J¼8.0 Hz), 7.75 (1H, dd, J¼8.0 and 4.8 Hz).
ꢂ1
1
4
.9.5. 4-Methoxybenzonitrile. IR (neat): 2224 cm . H
To a mixture of 1-dodecylamine (185.4 mg, 1 mmol) and aq
NH3 (3.0 mL, 45 mmol) was added DIH (439.1 mg,
NMR (CDCl ): d¼7.59 (2H, d, J¼8.9 Hz), 6.96 (2H, d,
3
J¼8.9 Hz).
1
.2 mmol) at room temperature under an empty balloon.
ꢀ
The obtained mixture was stirred at 60 C. After 6 h at the
same temperature, the reaction mixture was quenched with
4.9.6.
3,4,5-Trimethoxybenzonitrile.
IR
(neat):
ꢂ1 1
2225 cm . H NMR (CDCl ): d¼6.87 (2H, s), 3.90 (3H, s),
3
ꢀ
H O (20 mL) and satd aq Na SO (3 mL) at 0 C, and was
2
3.88 (6H, s).
2
3
extracted with Et O (3ꢁ15 mL). The organic layer was
2
ꢂ1
1
washed with brine and dried over Na SO to provide lauro-
2
4.9.7. 2-Cyanothiophene. IR (neat): 2224 cm . H NMR
(CDCl ): d¼7.65 (1H, d, J¼3.8 Hz), 7.62 (1H, d,
4
nitrile in 88% yield in an almost pure state. If necessary, the
product was purified by column chromatography on silica
gel (hexane/EtOAc¼4:1) to give pure lauronitrile as a color-
less oil.
3
J¼5.0 Hz), 7.75 (1H, dd, J¼5.0 and 3.8 Hz).
ꢂ1
1
4.9.8. 1-Naphthonitrile. IR (neat): 2222 cm . H NMR
(
CDCl ): d¼8.22 (1H, d, J¼8.2 Hz), 8.06 (1H, d, J¼
3
4.8. Typical procedure for oxidative conversion
of aldehydes to nitriles with DIH
8.2 Hz), 7.91 (1H, d, 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).
To a mixture of p-tolualdehyde (120.2 mg, 1 mmol) and aq
NH3 (3.0 mL, 45 mmol) was added DIH (219.6 mg,
0.6 mmol) at room temperature under an empty balloon.
The obtained mixture was stirred at the same temperature
ꢂ1
1
4.9.9. 2,5-Dimethylbenzonitrile. IR (KBr): 2230 cm . H
NMR (CDCl ): d¼7.39 (1H, s), 7.28 (1H, d, J¼7.9 Hz), 7.19
3
(1H, d, J¼7.9 Hz), 2.50 (3H, s), 2.34 (3H, s).

8
280
S. Iida, H. Togo / Tetrahedron 63 (2007) 8274–8281
ꢂ1
1
4
.9.10. 2,4,6-Trimethylbenzonitrile. IR (neat): 2220 cm
.
H NMR (CDCl ): d¼7.73 (2H, d, J¼8.1 Hz), 7.54 (1H,
3
1
H NMR (CDCl ): d¼6.93 (2H, s), 2.48 (6H, s), 2.32 (3H, s).
d, J¼7.8 Hz), 7.52 (1H, d, J¼7.8 Hz), 7.42 (1H, s), 7.41
13
3
(
1H, t, J¼7.8 Hz), 7.32 (2H, d, J¼8.1 Hz), 4.80 (1H, br s),
ꢂ1
1
4
.9.11. Cinnamonitrile. IR (neat): 2216 cm . H NMR
4.19 (1H, br d, J¼6.5 Hz), 2.45 (3H, s). C NMR (CDCl ,
3
(
5
CDCl ): d¼7.48–7.38 (5H, m), 7.41 (1H, d, J¼16.7 Hz),
ppm): d¼143.9, 138.1, 136.6, 132.2, 131.3, 131.1, 129.8,
129.4, 127.0 118.4, 112.5, 46.2, 21.5. HRMS (FAB): calcd
for C H O N S: 287.0854; found: M+1¼287.0853.
3
.89 (1H, d, J¼16.7 Hz).
1
5 15 2 2
ꢂ1 1
4
.9.12. Terephthalonitrile. IR (neat): 2229 cm . H NMR
(
CDCl ): d¼7.80 (4H, s).
3
Acknowledgements
4
2
6
.9.13. 3-(4-Methoxyphenyl)propionitrile. IR (neat):
250 cm . H NMR (CDCl ): d¼7.15 (2H, d, J¼8.8 Hz),
ꢂ1
1
FinancialsupportfromaGrant-in-Aid forScientificResearch
(No. 16655012) from the Ministry of Education, Science,
Sports, and Culture of Japan is gratefully acknowledged.
The authors thank Nippoh Chemicals Co. for the gift of DIH.
3
.87 (2H, d, J¼8.8 Hz), 3.80 (3H, s), 2.90 (2H, t,
J¼7.4 Hz), 2.58 (2H, t, J¼7.4 Hz).
ꢂ1
1
4
.9.14. Tridecanenitrile. IR (neat): 2247 cm . H NMR
(
CDCl ): d¼2.34 (2H, t, J¼7.2 Hz), 1.66 (2H, quintet,
3
J¼7.2 Hz), 1.44 (2H, quintet, J¼7.2 Hz), 1.35–1.25 (16H,
References and notes
br), 0.88 (3H, t, J¼7.2 Hz).
1
. (a) Friedrick, K.; Wallensfels, K. The Chemistry of the Cyano
Group; Rappoport, Z., Ed.; Wiley-Interscience: New York,
NY, 1970; (b) North, M. 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. Science of Synthesis; Georg Thieme: 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. Science of Synthesis; Georg Thieme:
2004; Vol. 19, pp 403–425.
ꢂ1 1
.9.15. Cyclohexanecarbonitrile. IR (neat): 2218 cm . H
4
NMR (CDCl ): d¼2.62 (1H, m), 1.85 (2H, m), 1.72 (4H, m),
3
1
.55–1.37 (4H, m).
ꢂ1
1
4
.9.16. 1-Cyanoadamantane. IR (neat): 2229 cm . H
NMR (CDCl ): d¼2.04 (9H, br), 1.74 (6H, br).
3
ꢂ1
1
4
(
.9.17. Sebaconitrile. IR (neat): 2245 cm
.
H NMR
CDCl ): d¼2.35 (4H, t, J¼7.1 Hz), 1.66 (4H, quintet,
3
J¼7.1 Hz), 1.46 (4H, m), 1.35 (4H, m).
2
. Fabiani, M. E. Drug News Perspect. 1999, 12, 207.
ꢂ1
1
4
.9.18. 2-Chlorobenzonitrile. IR (KBr): 2230 cm . H
3. Comprehensive Organic Transformation; Larock, R. C., Ed.;
VCH: 1989; pp 976–993.
NMR (CDCl ): d¼7.69 (1H, d, J¼7.7 Hz), 7.58–7.51 (2H,
3
m), 7.38 (1H, dd, J¼7.7 and 6.7 Hz).
4. (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., Coll. Vol. III; Wiley: New York, NY, 1955; p 3; (d)
Mihailovic, M. L.; Stojiljkovic, A.; Andrejevic, V.
Tetrahedron Lett. 1965, 461; (e) Stojiljkovic, A.; Andrejevic,
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; (h) Yamazaki, S.; Yamazaki, Y. Bull. Chem. Soc.
Jpn. 1990, 63, 301; (i) Biondini, D.; Brinchi, L.; Germani,
R.; Goracci, L.; Savelli, G. Eur. J. Org. Chem. 2005, 3060;
ꢂ1
1
4
.9.19. 2-Methoxybenzonitrile. IR (neat): 2230 cm . H
NMR (CDCl ): d¼7.59–7.52 (2H, m), 7.01 (1H, t,
3
J¼7.5 Hz), 6.98 (1H, d, J¼8.4 Hz).
ꢂ1
1
4
.9.20. Isophthalonitrile. IR (KBr): 2240 cm . H NMR
(
(
CDCl ): d¼7.97 (1H, s), 7.92 (2H, d, J¼8.1 Hz), 7.67
3
1H, t, J¼8.1 Hz).
ꢂ1
1
4
.9.21. 4-Nitrobenzonitrile. IR (neat): 2233 cm
.
H
NMR (CDCl ): d¼8.37 (2H, d, J¼8.9 Hz), 7.90 (2H, d,
3
J¼8.9 Hz).
(
j) Chen, E.; Peng, Z.; Fu, H.; Liu, J.; Shao, L. J. Chem. Res.,
ꢂ1
1
4
(
.9.22. Suberonitrile. IR (neat): 2250 cm
.
H NMR
Synop. 1999, 726; (k) Lee, G. A.; Freedman, H. H.
Tetrahedron Lett. 1976, 1641; (l) Yamazaki, S. Synth.
Commun. 1997, 27; (m) Jursic, B. J. Chem. Res., Synop.
CDCl ): d¼2.37 (4H, t, J¼7.0 Hz), 1.70 (4H, quintet,
3
J¼7.0 Hz), 1.52 (4H, m).
1
988, 168; (n) Nikishin, G. I.; Troyanskii, E. I.; Joffe, V. A.
4
1
8
8
7
.9.23. 1-(p-Toluenesulfonyl)indole-3-carbonitrile. Mp
ꢀ
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.; Baranne-
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,
ꢂ1
1
55–157 C. IR (neat): 2231 cm . H NMR (CDCl ): d¼
3
.11 (1H, s), 8.00 (1H, d, J¼7.9 Hz), 7.83 (2H, d, J¼
.4 Hz), 7.69 (1H, d, J¼7.9 Hz), 7.44 (1H, t, J¼7.9 Hz),
.38 (1H, t, J¼7.9 Hz), 7.31 (2H, d, J¼8.4 Hz), 2.38 (3H,
13
s). C NMR (CDCl , ppm): d¼146.3, 133.9, 133.5, 133.1,
3
1
9
2
30.0, 128.2, 127.1, 126.4, 124.7, 120.2, 113.7, 113.4,
3.5, 21.6. HRMS (FAB): calcd for C H O N S:
97.0698; found: M+1¼297.0687.
.9.24. 4-(p-Toluenesulfonyl)aminomethylbenzonitrile.
1
6 13 2 2
4
Mp 110–112 C (lit. 112–114 C). IR (neat): 2231 cm
ꢀ
13
ꢀ
ꢂ1
.

S. Iida, H. Togo / Tetrahedron 63 (2007) 8274–8281
8281
4
2
61; (w) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed.
003, 42, 1480; (x) Moriarty, R. M.; Vaid, R. K.; Duncan,
7. (a) Yamazaki, S.; Yamazaki, Y. Chem. Lett. 1990, 571; (b)
Chen, F.; Li, Y.; Xu, M.; Jia, H. Synthesis 2002, 1804; (c)
McAllister, G. D.; Wilfred, C. D.; Taylor, R. J. K. Synlett
2002, 1291.
8. Mori, N.; Togo, H. Synlett 2005, 1456.
9. Goosen, A.; McCleland, C. W.; Sipamla, A. M. J. Chem.
Res. (M) 1995, 311.
M. P.; Ochiai, M.; Inenaga, M.; Nagao, Y. Tetrahedron Lett.
988, 29, 6913; (y) Chen, F.; Kuang, Y.; Dai, H.; Lu, L.;
Huo, M. Synthesis 2003, 2629.
1
5
6
. (a) Mori, N.; Togo, H. Synlett 2004, 880; (b) Mori, N.; Togo, H.
Tetrahedron 2005, 61, 5915; (c) Ishihara, M.; Togo, H. Synlett
2
1
006, 227; (d) Ishihara, M.; Togo, H. Tetrahedron 2007, 63,
474.
10. Iida, S.; Togo, H. Synlett 2006, 2633.
11. Orazi, O. O.; Corral, R. A.; Bertorello, H. E. J. Org. Chem.
1965, 30, 1101.
12. Iida, S.; Togo, H. Synlett 2007, 407.
13. Bookser, B. C.; Bruice, T. C. J. Am. Chem. Soc. 1991, 113,
4208.
. (a) Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. Jpn. 1966,
9, 854; (b) Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc.
3
Jpn. 1967, 40, 2875; (c) Talukdar, S.; Hsu, J.; Chou, T.; Fang,
J. Tetrahedron Lett. 2001, 42, 1103.