Direct and facile oxidative conversion of primary, secondary, and tertiary amines to their corresponding nitriles

Article abstract of DOI:10.1055/s-2006-951491

Molecular iodine in aqueous ammonia at 60 °C efficiently oxidized various primary, secondary, and tertiary amines to their corresponding nitriles in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951491

LETTER
2633
Direct and Facile Oxidative Conversion of Primary, Secondary, and Tertiary
Amines to Their Corresponding Nitriles
D
irec
t
and
F
ac
h
ile
O
xidative
i
Conve
n
rsionof
A
m
p
ines totheir
e
Correspond
i
ingNitriles Iida,a Hideo Togo*a,b
a
Graduate School of Science and Technology, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
b
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
Received 14 July 2006
to provide the corresponding nitriles in good yields, as
shown in Table 1. When the same reaction was carried out
in water or t-BuOH in the presence of K2CO3, instead of
aqueous NH3, the yield of nitrile decreased (Table 1,
entries 5 and 6). Diamines were also converted into the
corresponding dinitriles in good yields (Table 1, entries
14–17). D/L-2-Phenylglycine was converted into benzo-
nitrile through oxidative decarboxylation (Table 1, entries
18 and 19)
Abstract: Molecular iodine in aqueous ammonia at 60 °C efficient-
ly oxidized various primary, secondary, and tertiary amines to their
corresponding nitriles in good yields.
Key words: amines, iodine, nitriles , aqueous ammonia
Nitriles are one of the most important precursors of esters,
amides, and carboxylic acids.1 Therefore, they have been
used as synthetic intermediates for agricultural chemicals,
pharmaceutical chemicals, and functional materials.2 A
typical method is the reaction of alkyl halides with very
toxic cyanide via nucleophilic pathway; the length of the
carbon chain is increased by one during this process. Due
to the toxicity of cyanide, nitriles are generally prepared
by the dehydration of amides with SOCl2, TsCl/pyridine,
P2O5, POCl3, COCl2, (EtO)3P/I2, or Ph3P/CCl4.3 Nitriles
have also been prepared by the condensation of carboxylic
acids with NH3/silica gel or NH3/ethyl polyphosphate. Es-
ters can also furnish nitriles by reaction with Me2AlNH2.3
The oxidation of primary amines to their corresponding
nitriles has been extensively investigated; a range of
reagents have been successful, including AgO,4a
Pb(OAc)4,4b–e cobalt peroxide,4f Na2S2O8 or (Bu4N)S2O8
with metals,4g–j NaOCl,4k–m K3Fe(CN)6,4n Cu(I) or Cu(II)
with oxygen,4o–r RuCl3 and related Ru reagents,4s–w
PhIO,4x or trichloroisocyanuric acid with TEMPO.4y
Table 1 Oxidative Conversion of Primary Amines to Nitriles9
I2
R
CH2NH2
R
CN
aq NH3 (3 mL), 60 °C
Entry
R
I2 (equiv)
Time (h)
Yields (%)a
1
2
2.1
3.0
1
1
56
68
3
4
5
6
2.1
2
2
2
8
80
81
30
50
3.0
3.0b
3.0c
Me
7
8
2.1
3.0
2
2
78
87
Cl
9
10
2.1
3.0
1
1
77
82
OMe
Recently we have investigated the application of molecu-
lar iodine to organic synthesis, and have reported its suc-
cessful application in the conversion of alcohols to esters5
and nitriles.6 Very recently we reported the preparation of
2-imidazolines and 2-imidazoles from aldehydes with
molecular iodine and (diacetoxyiodo)benzene.7 Just over
ten years ago some outline work on the reaction of benzyl-
amine with molecular iodine in acetonitrile to form imi-
nes, N-benzylidenebenzylamine, and benzonitrile was
reported.8 Here, we would like to report a direct, efficient,
and practical oxidation of primary, secondary, and tertiary
amines to their corresponding nitriles, using molecular
iodine in aqueous NH3.
11
12
2.1
3.0
4
4
75
83
Me
9
NHTs
13
3.0
2
72
14
15
4.2d
6.0d
2
2
79
90
16
17
4.2d
6.0d
4
4
61
61
8
–
CO2
18
2.1
3.0
1
1
80e
95e
H
Ph
+
The oxidation was carried out by treating benzylic and 19
aliphatic primary amines (1 mmol) with molecular iodine
NH3
(2.1–3.0 mmol) in aqueous NH3 (28–30%, 3 mL) at 60 °C
a Isolated yield.
b H2O (3 mL) and K2CO3 (3 equiv) were used instead of aq NH3.
c tBuOH (3 mL) and K2CO3 (3 equiv) were used instead of aq NH3.
d The double amount of aq NH3 was used.
SYNLETT 2006, No. 16, pp 2633–2635
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951491; Art ID: U08506ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
6
e Product is benzonitrile.

2634
S. Iida, H. Togo
LETTER
Table 2 Oxidative Conversion of Secondary and Tertiary Amines
tion of HI to form imino compound b. Once imino com-
pound b is formed, it reacts with NH3 to form 1,1-diamino
compound c, which smoothly decomposes to primary
amine d and imine f. Primary amine d reacts with molec-
ular iodine to form N-iodoamine e, followed by b-elimi-
nation of HI to generate imine f. Imine f also reacts with
molecular iodine to form N-iodo imine g, and finally elim-
ination of HI by NH3 occurs to provide the corresponding
nitrile.6
to Nitriles9
I2
R
CH2X
R
CN
aq NH3 (3 mL), 60 °C
Entry
R
X
I2
Time Yield
(equiv) (h)
(%)a
1
2
3
NH(Me)
NH(Me)
NH(Me)
2.1
3.5
4.0
4
4
4
49
71
71
H
4
5
6
N(Me)2
N(Me)2
N(Me)2
2.1
3.5
4.0
0.5
0.5
0.5
41
71
74
R
CH2
N
CH2R
(– HI)
2 R
C
(a)
N
I2
H
(– HI)
7
8
NH(Me)
N(Me)2
3.5
3.5
4
0.5
76
73
R
CH N CH2R
Me
9
I
(a)
H
I
R
(g)
C
H
N
(– HI)
CH2R
R
CH NH
9
10
NH(Me)
N(Me)2
3.5
4.0
1
1
81
67
(e)
I
R
R
CH
(b)
NH3
N
(– HI)
(– HI)
I2
11
12
NH(Me)
N(Me)2
3.5
4.0
1
1
84
77
I2 (– HI)
Me
+
CH NH CH2R
R
CH2 NH2
(d)
R
CH NH
(f)
13
14
NH(Me)
N(Me)2
3.5
5.0
2
2
77
72
NH2
(c)
Cl
Scheme 2 Plausible reaction pathway for the conversion of
secondary amines into nitriles
15
16
NH(Me)
N(Me)2
3.5
5.0
2
6
96
76
NO2
In summary, primary, secondary, and tertiary amines
could be easily and efficiently converted into the corre-
sponding nitriles in good yields. Molecular iodine was
employed which has the advantages of operational sim-
plicity, low cost, and low toxicity; this suggest that the
application of molecular iodine in organic synthesis
should be broadened. Further investigations on the appli-
cation of molecular iodine to the reactions described here
are underway.
a Isolated yields.
When N-methyl secondary amines and N,N-dimethyl
tertiary amines were treated with molecular iodine under
the same conditions, the corresponding nitriles were again
obtained in good yields as shown in Table 2. Moreover,
we found that sterically hindered amines also provided
the corresponding nitriles. Bis(4-methylbenzyl)amine,
bis(dodecyl)amine,
and
tris(4-methylbenzyl)amine
Acknowledgment
reacted with molecular iodine in aqueous NH3 under the
same conditions to provide p-tolunitrile and lauronitrile
(Scheme 1).
Financial support from a Grant-in-Aid for Scientific Research (No.
16655012) from the Ministry of Education, Science, Sports, and
Culture of Japan and Forum of Iodine Utilization is gratefully
acknowledged.
I2 (4.5 equiv)
2
Me
CN
Me
CH2 NH
2
aq NH3 (3 mL),
60 °C, 8 h
91%
References and Notes
I2 (4.5 equiv)
(1) (a) Cohen, M. A.; Sawden, J.; Turner, N. J. Tetrahedron Lett.
1990, 31, 7223. (b) Murahashi, S.-I. Synthesis from Nitriles
with Retention of the Cyano Group, In Science of Synthesis,
Vol. 19; Murahashi, S.-I., Ed.; Georg Thieme Verlag:
Stuttgart, 2004, 345–402. (c) Collier, S. J.; Langer, P.
Applications of Nitriles as Reagents for Organic Synthesis
with Loss of the Nitrile Functionality (Including
Cycloaddition Reactions), In Science of Synthesis, Vol. 19;
Murahashi, S.-I., Ed.; GeorgThieme Verlag: Stuttgart, 2004,
403–425.
2 C11H23CN
84%
(C12H25)2NH
aq NH3 (3 mL),
60 °C, 4 h
I2 (6.5 equiv)
3
Me
CH2
N
Me
CN
3
aq NH3 (3 mL),
60 °C, 4 h
84%
Scheme 19
(2) Fabiani, M. E. Drug News Perspect. 1999, 12, 207.
(3) Comprehensive Organic Transformation; Larock, R. C.,
Ed.; VCH Publishers, Inc./VCH Verlagsgesellschaft: New
York/Weinheim, 1989, 976–993.
Based on these results, a plausible reaction pathway for
the conversion of secondary amines into nitriles is shown
in Scheme 2. Thus, initial N-iodonation of amine occurred
to give N-iodo secondary amine a, followed by b-elimina-
Synlett 2006, No. 16, 2633–2635 © Thieme Stuttgart · New York

LETTER
Direct and Facile Oxidative Conversion of Amines to their Corresponding Nitriles
2635
(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, 1955, 3.
(20 mL) and a sat. aq solution of Na2SO3 (3 mL) at 0 °C. The
product was extracted with Et2O (3 × 15 mL). The organic
layer was washed with brine and dried over Na2SO4 to
provide p-tolunitrile in 80% yield in an almost pure state. If
necessary, the product was purified by column
chromatography (silica gel; hexane–EtOAc, 4:1) to give
pure p-tolunitrile as a colorless solid; mp 25 °C. IR (NaCl):
2230 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.42 (3 H, s),
7.27 (2 H, d, J = 7.9 Hz), 7.55 (2 H, d, J = 7.9 Hz). The
identity of the product was confirmed by comparison of its
analytical data with a sample of the commercially available
authentic compound.
(d) Mihailović, M. L.; Stojiljković, A.; Andrejević, V.
Tetrahedron Lett. 1965, 461. (e) Stojiljković, A.;
Andrejević, V.; Mihailović, M. L. Tetrahedron 1967, 23,
721. (f) Below, J. S.; Garza, C.; Mathieson, J. W. J. Chem.
Soc. D 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. (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, 27. (m) Jursic, B. J. Chem. Res., Synop.
1988, 168. (n) Nikishin, G. I.; Troyanskii, E. I.; 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.; 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) Schröder,
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.
Oxidative Conversion of Tertiary Amines to Nitriles;
Typical Procedure: To a mixture of N,N-dimethyl-3-
phenylpropylamine (163.2 mg, 1 mmol) and aq NH3 (3.0
mL, 45 mmol) under an empty balloon was added I2 (888.3
mg, 3.5 mmol) at r.t. The resulting mixture was stirred at
60 °C. After 0.5 h at the same temperature, the reaction
mixture was quenched with H2O (20 mL) and a sat. aq
solution of Na2SO3 (3 mL) at 0 °C. The product was
extracted with Et2O (3 × 15 mL). The organic layer was
washed with brine and dried over Na2SO4 to provide 3-
phenylpropionitrile in 71% yield in an almost pure state.
If necessary, the product was purified by column chromatog-
raphy (silica gel; (hexane–EtOAc, 4:1) to give pure 3-
phenylpropionitrile as a colorless oil. IR (NaCl): 2250 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.62 (2 H, t, J = 7.4 Hz),
2.96 (2 H, t, J = 7.4 Hz), 7.23 (2 H, d, J = 8.1 Hz), 7.28 (1 H,
t, J = 8.2 Hz) 7.34 (2 H, t, J = 8.2 Hz). The identity of the
product was confirmed by comparison of its analytical data
with a sample of the commercially available authentic
compound.
Oxidative Conversion of Tris(4-methylbenzyl)amine to
p-Tolunitrile: To a mixture of tris(4-methylbenzyl)amine
(329.5 mg, 1 mmol) and aq NH3 (3.0 mL, 45 mmol) under an
empty balloon was added I2 (1.650 g, 6.5 mmol) at r.t. The
resulting mixture was stirred at 60 °C. After 4 h at the same
temperature, the reaction mixture was quenched with H2O
(20 mL) and a sat. aq solution of Na2SO3 (3 mL) at 0 °C. The
product was extracted with Et2O (3 × 15 mL). The organic
layer was washed with brine and dried over Na2SO4 to
provide p-tolunitrile in 84% yield in an almost pure state. If
necessary, the product was purified by column chromatog-
raphy (silica gel; hexane–EtOAc, 4:1) to give pure p-tolu-
nitrile as a colorless solid; mp 25 °C. IR (NaCl): 2230 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.42 (3 H, s), 7.27 (2 H, d,
J = 7.9 Hz), 7.55 (2 H, d, J = 7.9 Hz).
(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.
(5) (a) Mori, N.; Togo, H. Synlett 2004, 880. (b) Mori, N.;
Togo, H. Tetrahedron 2005, 61, 5915.
(6) Mori, N.; Togo, H. Synlett 2005, 1456.
(7) Ishihara, M.; Togo, H. Synlett 2006, 227.
(8) Goosen, A.; McCleland, C. W.; Sipamla, A. M. J. Chem.
Res. (M) 1995, 311.
(9) Oxidative Conversion of Primary Amines to Nitriles;
Typical Procedure: To a mixture of 4-methylbenzylamine
(121.2 mg, 1 mmol) and aq NH3 (3.0 mL, 45 mmol) under an
empty balloon was added I2 (533.0 mg, 2.1 mmol) at r.t. The
resulting mixture was stirred at 60 °C. After 2 h at the same
temperature, the reaction mixture was quenched with H2O
Synlett 2006, No. 16, 2633–2635 © Thieme Stuttgart · New York