Oxidative conversion of primary alcohols, and primary, secondary, and tertiary amines into the corresponding nitriles with 1,3-diiodo-5,5- dimethylhydantoin in aqueous NH3

Article abstract of DOI:10.1055/s-2007-967954

Various primary alcohols, and primary, secondary, and tertiary amines were oxidatively and efficiently converted into the corresponding nitriles in good yields, by 1,3-diiodo-5,5-dimethylhydantoin (DIH) in aqueous ammonia (NH ₃) at 60°C. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967954

LETTER
407
Oxidative Conversion of Primary Alcohols, and Primary, Secondary, and
Tertiary Amines into the Corresponding Nitriles with 1,3-Diiodo-5,5-dime-
thylhydantoin in Aqueous NH3
C
S
onversionof
h
A
lcohols an
i
A
min
n
es to
N
itrile sp ei Iida, Hideo Togo*
Graduate School of Science and Technology, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
Received 27 November 2006
report another direct, efficient, practical and less toxic
oxidative conversion of primary alcohols, and primary,
secondary, and tertiary amines into the corresponding
nitriles, using 1,3-diiodo-5,5-dimethylhydantoin (DIH) in
aqueous ammonia. Today, to the best of our knowledge,
synthetic use of DIH is extremely limited, whereas the
iodination of aromatics with DIH has been reported.7
Abstract: Various primary alcohols, and primary, secondary, and
tertiary amines were oxidatively and efficiently converted into the
corresponding nitriles in good yields, by 1,3-diiodo-5,5-dimethyl-
hydantoin (DIH) in aqueous ammonia (NH ) at 60 °C.
3
Key words: primary alcohols, primary amines, secondary amines,
tertiary amines, 1,3-diiodo-5,5-dimethylhydantoin, nitriles, aque-
ous ammonia
Thus, the present reaction was carried out very simply by
treatment of dodecanol and dodecylamine (1 mmol) with
Nitriles are very useful intermediates in synthetic organic DIH (2.0 mmol for dodecanol and 1.2 mmol for dodecyl-
1
chemistry, especially in reactions for ready conversion amine) in aqueous ammonia (28-30%, 3 mL) at 60 °C
into many biologically important compounds, such as ox- under dark conditions to provide the corresponding
2
a-c
2d,e
2f-i
8
azoles,
thiazoles, tetrazoles, triazolo[1,5-c]pyri- lauronitrile in 97% and 88% yields, respectively, as
2k
2
j
midines, and 1,2-diarylimidazoles. Typical one-carbon shown in Table 1 (entries 1 and 5). When the same reac-
homologated nitriles are obtained by the reaction of alkyl tion was carried out with NIS (4.0 mmol for dodecanol
halides with toxic cyanide. On the other hand, dehydration and 2.4 mmol for dodecylamine) in aqueous ammonia,
of amides and aldoximes, and oxidation of primary lauronitrile was also obtained (entries 2 and 6). However,
amines provide the corresponding nitriles, keeping the the yields were lower as compared with that obtained with
number of carbon atoms constant. Thus, nitriles are DIH. On the other hand, NCS and NBS did not provide the
generally prepared by the dehydration of amides with corresponding lauronitrile at all, and the starting materials
SOCl , TsCl-pyridine, P O , POCl , COCl , (EtO) P/I , were recovered (entries 3, 4, 7, and 8).
2
2
5
3
2
3
2
3
and Ph P/CCl . Nitriles are also prepared by the conden-
3
4
sation of carboxylic acids with NH /silica gel, NH /ethyl Table 1 Oxidative Conversion of Dodecanol and Dodecylamine into
3
3
Lauronitrile with DIH and Related Reagents in Aqueous Ammonia
polyphosphate, etc., and by the reaction of esters with
Me AlNH . Oxidative conversion of primary amines into
the corresponding nitriles has been also studied well,
3
reagent, aq NH3
2
2
C11H23CH2X
C11H23CN
60 °C, dark
4
a
4b-e
4f
using AgO, Pb(OAc)4,
cobalt peroxide, nickel
Time (h) Yield (%)a
4
g
4h-k
Entry
X
Reagent
Equiv
peroxide, Na S O or (Bu N) S O with metals,
2
2
8
4
2
2
8
4
l-n
4o
4p-s
NaOCl,
RuCl3 and related Ru reagents,
chloroisocyanuric acid with 2,2,6,6-tetramethylpiperidi-
K Fe(CN) , Cu(I) or Cu(II) with oxygen,
3 6
1
2
3
4
OH
DIH
NIS
NBS
NCS
2.0
4.0
4.0
4.0
32
32
32
32
97
4
t–x
4y
b
b
b
PhIO, and tri-
65 (16)
0 (99)
0 (99)
4
z
nooxy (TEMPO). However, there are only a few reports
on the direct oxidative conversion of alcohols as starting
materials into nitriles in a one-pot procedure, i.e. using
NH HCO , (Bu N) S O , and a catalytic amount of
5
6
7
8
NH2
DIH
NIS
NBS
NCS
1.2
2.4
2.4
2.4
6
6
6
6
88
71
0 (57)
0 (51)
b
b
4
3
4
2
2
8
5
a
Cu(HCO ) ·Ni(HCO ) in aqueous KOH and i-PrOH,
2
2
2 2
and MnO , NH , and MgSO in THF and i-PrOH for
benzylic and cinnamic alcohols.
a
2
3
4
Isolated yield.
Recovered starting material.
5
b
b
As a part of our basic study of molecular iodine and relat-
ed reagents for organic synthesis, we previously reported
Various primary alcohols and benzylic alcohols were
6a
an efficient preparation of nitriles from the alcohols and
treated with DIH (1.5-2.0 equiv) in aqueous ammonia un-
6
b
amines using molecular iodine. Here, we would like to
8
der the same conditions, as shown in Table 2. Yields of
the reaction in which the flask was protected from room
light with aluminum foil, was slightly better than those in
which the flask was not protected from room light (entries
SYNLETT 2007, No. 3, pp 0407–0410
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-967954; Art ID: U14106ST
1
5.
0
2.
2
0
0
7
1
and 2). The reactivity depends on the alcohols used; thus
©
Georg Thieme Verlag Stuttgart · New York

4
08
S. Iida, H. Togo
LETTER
Table 2 Oxidative Conversion of Alcohols into Nitriles with DIH in
Table 3 Oxidative Conversion of Amines into Nitriles with DIH in
Aqueous Ammonia
Aqueous Ammonia
DIH, aq NH3
DIH, aq NH3
RCH2OH
RCN
RCH NR'
RCN
2
2
60 °C, dark
60 °C, dark
Entry
R
DIH (equiv) Time (h)
Yield (%)a
Entry R
NR¢
2
DIH
Time Yield
(
equiv) (h)
(%)a
1
2
3
1.5b
1.5
2.0
24
24
24
63
69
77
1
2
3
4
Me(CH
)
CH
-
NH
NH
1.1
1.2
1.2
1.5
4
4
6
4
84
85
88
88
2
9
2
2
2
NH2
NH2
4
5
-Me(CH ) CH -
2.0
2.0
32
32
97
82
2
9
2
5
6
7
NH2
NH2
NH2
1.2
1.2
1.2
2
2
3
79
92
72
6
7
-CH (CH ) CH -
4.0c
3.0c
24
4
94
95
2
2 4
2
Me
8
9
0
1
1.1
1.3
1.5
1.7
3
3
3
3
66
77
84
83
Cl
1
1
8
9
NH2
NH2
1.2
1.2
4
4
93
98
Me
OMe
1
2
1.5
5
71
O2N
13
1.5
3
81
1
1
1
0
1
2
-CH (CH ) CH -
NH2
2.4b
1.7
6
65
76
80
2
2 6
2
Cl
Me(CH ) CH
2
NHMe
NMe2
6
2
9
1
1
1
4
5
6
1.5
1.5
1.5
12
3
89
91
92
1.7b
0.5
O2N
1
1
3
4
NHMe
NMe2
1.7
2.5
3
2
79
72
b
Cl
MeO
1
1
1
5
6
7
Me(CH ) CH -
NH(CH R)
2.4
3.6c
2.4
10
84
84
2
9
2
2
8
N(CH R)
6
2
2
NH(CH R)
N(CH R)
6
48
84
85
2
d
a
b
c
18
4.2
Isolated yield.
Flask was not covered with aluminum foil.
Double amount of aq NH was used.
2
2
Cl
3
a
Isolated yield.
Aqueous NH (6 mL) was used.
Aqueous NH (9 mL) was used.
Aqueous NH (3 mL) was added again after 24 h.
b
c
d
3
3
benzylic alcohols were smoothly converted into the corre-
sponding nitriles in good yields, using 1.5 equivalents of
DIH, while aliphatic primary alcohols required 2 equiva-
3
lents of DIH and longer reaction time. The treatment of and tris(dodecyl)amine (1 mmol), were treated with 2.4
,8-octanediol and p-xylene glycol in an analogous man- equivalents and 3.6 equivalents of DIH, in aqueous am-
ner provided the corresponding dinitriles in good yields monia under the same conditions to provide the corre-
1
(
entries 6 and 7). Then the reactions of primary, second- sponding lauronitrile in 84% and 84% yields, respectively
ary, and tertiary amines with DIH in aqueous NH were (entries 15 and 16).
carried out as shown in Table 3. Primary and benzylic
amines smoothly reacted with DIH in aqueous NH to
give the corresponding nitriles in good yields. Decan-
1
2
ondary amines and N,N-dimethyl tertiary amines were
treated with DIH under the same conditions, the corre-
sponding nitriles could be again obtained in good yields
3
A plausible reaction pathway for the conversion of prima-
3
ry alcohol and primary amine into nitrile is shown in
Scheme 1. According to this pathway, the initial O-iodi-
nation and N-iodination of alcohol and amine with DIH
occurs to form the O-iodo and N-iodo compounds (a),
respectively, followed by b-elimination of HI by am-
monia to form aldehyde and aldimine (b), respectively.
Here the aldehyde reacts with ammonia to form aldimine
8
,11-diamine generated the corresponding dinitrile using
.4 equivalents of DIH (entry 10). When N-methyl sec-
(
entries 11-14). Moreover, bis(dodecyl)amine (1 mmol),
(
c). Then, aldimine (c) reacts with DIH in the presence of
Synlett 2007, No. 3, 407–410 © Thieme Stuttgart · New York

LETTER
Conversion of Alcohols and Amines into Nitriles
409
ammonia to form N-iodo aldimine (d), followed by b-
Yokokawa, F. Tetrahedron Lett. 1998, 39, 2223.
(
c) Ducept, P. C.; Marsden, S. P. Synlett 2000, 692.
elimination of HI by ammonia to generate the correspond-
6
(d) Chihiro, M.; Nagamoto, H.; Takemura, I.; Kitano, K.;
Komatsu, H.; Sekiguchi, K.; Tabusa, F.; Mori, T.;
Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1995, 38, 353.
ing nitrile. Practically, aldehydes react with DIH smooth-
ly at room temperature in aqueous ammonia to provide the
corresponding nitriles in good yields. Imines also react
with DIH in aqueous ammonia to form the corresponding
nitriles in good yields.
(
e) Gu, X.-H.; Wan, X.-Z.; Jiang, B. Bioorg. Med. Chem.
Lett. 1999, 9, 569. (f) Kadaba, P. K. Synthesis 1973, 71.
(g) Diana, G. D.; Cutcliffe, D.; Volkots, D. L.; Mallamo, J.
P.; Bailey, T. R.; Vescio, N.; Oglesby, R. C.; Nitz, T. J.;
Wetzel, J.; Giranda, V.; Pevear, D. C.; Dutko, F. J. J. Med.
Chem. 1993, 36, 3240. (h) Wittenberger, S. J.; Donner, B.
G. J. Org. Chem. 1993, 58, 4139. (i) Shie, J.-J.; Fang, J.-M.
J. Org. Chem. 2003, 68, 1158. (j) Medwid, J. B.; Paul, R.;
Baker, J. S.; Brockman, J. A.; Du, M. T.; Hallett, W. A.;
Hanifin, J. W.; Hardy, R. A. Jr.; Tarrant, M. E.; Torley, L.
W.; Wrenn, S. J. Med. Chem. 1990, 33, 1230. (k) Khanna,
I. K.; Weier, R. M.; Yu, Y.; Xu, X. D.; Koszyk, F. J.; Collins,
P. W.; Koboldt, C. M.; Veenhuizen, A. W.; Perkins, W. E.;
Casler, J. J.; Masferrer, J. L.; Zhang, Y. Y.; Gregory, S. A.;
Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1634.
(3) Comprehensive Organic Transformation; Larock, R. C.,
Ed.; VCH Publishers, Inc.: New York, 1989, 976–993.
(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.
R
CH2 XH
R
C≡N
HI
X = O, NH
DIH – HI
–
I
H
R
C
H
(d)
N
R
R
CH X
[
X = NH]
DIH
(a)
I
–
HI
–
HI
DIH – HI
[
X = O]
NH3
CH
b)
X
R
CH NH
c)
–
H2O
O
(
(
I
Me
N
DIH :
Me
N
O
I
Scheme 1 Plausible reaction pathway for nitrile
(
d) Mihailovic, M. L.; Stojiljkovic, A.; Andrejevic, V.
Tetrahedron Lett. 1965, 461. (e) Stojiljkovic, A.;
Andrejevic, V.; Mihailovic, M. L. Tetrahedron 1967, 23,
In summary, DIH can be used as an efficient reagent for
the conversion of primary alcohols, and primary, second-
ary, and tertiary amines into the corresponding nitriles in
good yields in aqueous ammonia. DIH has almost the
same reactivity as molecular iodine. However, DIH is a
pale yellow solid and does not sublimate like molecular
iodine. So it is more convenient to operate the reaction
with DIH. The present method using DIH may become
another simple and useful method for the direct oxidative
conversion of primary alcohols, and primary, secondary,
and tertiary amines into the corresponding nitriles, along
with molecular iodine. Further synthetic study of DIH is
underway in this laboratory.
721. (f) Below, J. S.; Garza, C.; Mathieson, J. W. Chem.
Commun. 1970, 634. (g) Nakagawa, K.; Tsuji, T. Chem.
Pharm. Bull. 1963, 11, 296. (h) Troyanskii, E. I.; Svitanko,
I. V.; Ioffe, V. A.; Nikishin, G. I. Izv. Akad. Nauk SSSR, Ser.
Khim. 1982, 2180. (i) Yamazaki, S.; Yamazaki, Y. Bull.
Chem. Soc. Jpn. 1990, 63, 301. (j) Biondini, D.; Brinchi, L.;
Germani, R.; Goracci, L.; Savelli, G. Eur. J. Org. Chem.
2005, 3060. (k) Chen, E.; Peng, Z.; Fu, H.; Liu, J.; Shao, L.
J. Chem. Res., Synop. 1999, 726. (l) Lee, G. A.; Freedman,
H. H. Tetrahedron Lett. 1976, 1641. (m) Yamazaki, S.
Synth. Commun. 1997, 27, 27. (n) Jursic, B. J. Chem. Res.,
Synop. 1988, 168. (o) Nikishin, G. I.; Troyanskii, E. I.;
Joffe, V. A. Izv. Akad. Nauk SSSR, Ser. Khim. 1982, 2758.
(p) Kametani, T.; Takahashi, K.; Ohsawa, T.; Ihara, M.
Synthesis 1977, 245. (q) Capdevielle, P.; Lavigne, A.;
Maumy, M. Synthesis 1989, 453. (r) Capdevielle, P.;
Lavigne, A.; Sparfel, D.; Baranne-Lafont, J.; Nguyen, K. C.;
Maumy, M. Tetrahedron Lett. 1990, 31, 3305. (s) Maeda,
Y.; Nishimura, T.; Uemura, S. Bull. Chem. Soc. Jpn. 2003,
Acknowledgment
Financial support from Forum on Iodine Utilization is gratefully
acknowledged. The authors thank Nippoh Chemicals Co. for the
gift of DIH.
76, 2399. (t) Tang, R.; Diamond, S. E.; Neary, N.; Mares, F.
J. Chem. Soc., Chem. Commun. 1978, 562. (u) Schröder,
M.; Griffith, W. P. J. Chem. Soc., Chem. Commun. 1979,
References and Notes
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(
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(z) Chen, F.; Kuang, Y.; Dai, H.; Lu, L.; Huo, M. Synthesis
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(c) Murahashi, S.-I. Synthesis from Nitriles with Retention of
the Cyano Group, In Science of Synthesis, Vol. 19; Georg
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Synlett 2007, No. 3, 407–410 © Thieme Stuttgart · New York

4
10
S. Iida, H. Togo
LETTER
was identified by comparison with the commercially
(
8) Typical Experimental Procedure for Oxidative
9
Conversion of Primary Alcohols into Nitriles: To a
available authentic compound.
mixture of dodecanol (186.3 mg, 1 mmol) and aq NH (3.0
mL, 45 mmol) was added DIH (731.9 mg, 2.0 mmol) at r.t.
under an empty balloon. The obtained mixture was stirred at
Typical Experimental Procedure for Oxidative
Conversion of Primary Amines into Nitriles: To a
mixture of dodecylamine (185.4 mg, 1 mmol) and aq NH3
(3.0 mL, 45 mmol) was added DIH (439.1 mg, 1.2 mmol) at
r.t. under an empty balloon. The obtained mixture was
stirred at 60 °C. After 6 h at the same temperature, the
3
9
6
0 °C. After 32 h at the same temperature, the reaction
mixture was quenched with H O (20 mL) and sat. aq Na SO
3
2
2
(
3 mL) at 0 °C, and was extracted with Et O (3 × 15 mL).
2
The organic layer was washed with brine and dried over
Na SO to provide lauronitrile in 97% yield in an almost
reaction mixture was quenched with H O (20 mL) and sat. aq
2
Na SO (3 mL) at 0 °C, and was extracted with Et O (3 × 15
2
4
2
3
2
pure state. If necessary, the product was purified by column
chromatography on silica gel (hexane-EtOAc, 4:1) to give
pure lauronitrile in 97% yield as a colorless oil. IR (NaCl):
mL). The organic layer was washed with brine and dried
over Na SO to provide lauronitrile in 88% yield in an
2
4
almost pure state. If necessary, the product was purified by
column chromatography on silica gel (hexane-EtOAc, 4:1)
to give pure lauronitrile as a colorless oil.
-
1 1
2
250 cm . H NMR (400 MHz, CDCl ): d = 0.88 (t, J = 7.0
3
Hz, 3 H), 1.29 (br, 14 H), 1.45 (quin, J = 7.1 Hz, 2 H), 1.66
quin, J = 7.1 Hz, 2 H), 2.34 (t, J = 7.1 Hz, 2 H). The product
(
(9) All nitriles gave satisfactory spectroscopic data and were
identified by comparison with commercially available
authentic materials.
Synlett 2007, No. 3, 407–410 © Thieme Stuttgart · New York