Direct transformation of aldehydes to nitriles using iodine in ammonia water

Article abstract of DOI:10.1016/S0040-4039(00)02195-X

Treatment of aromatic, heterocyclic, aliphatic, conjugated, and polyhydroxy aldehydes with iodine in ammonia water at room temperature for a short period gave the corresponding nitriles in high yields.

Full text of DOI:10.1016/S0040-4039(00)02195-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1103–1105
Direct transformation of aldehydes to nitriles using iodine in
ammonia water
Sanjay Talukdar, Jue-Liang Hsu, Tzu-Chi Chou and Jim-Min Fang*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, Republic of China
Received 29 November 2000; accepted 30 November 2000
Abstract—Treatment of aromatic, heterocyclic, aliphatic, conjugated, and polyhydroxy aldehydes with iodine in ammonia water
at room temperature for a short period gave the corresponding nitriles in high yields. © 2001 Elsevier Science Ltd. All rights
reserved.
Formation of nitriles from the corresponding aldehydes
is an important functional group transformation.1
Many methods involve the initial conversion of alde-
hydes to aldoximes, which are subjected to dehydration
to give nitriles.2 Direct conversion of aldehydes into
nitriles without isolation of nitrogen-containing inter-
Table 1. Conversion of aldehydes to nitriles by using iodine in ammonia water
Substrate
Cosolvent
Reaction time (min)
Nitrile (yield %)
Yield (%) via other methodsa,b,c,d,e,f
PhCHO
4-BrC6H4CHO
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
None
None
30
45
20
30
10
7
1 (96)
2 (95)
3 (95)
4 (96)
5 (89)
6 (88)
7 (97)
8 (85)
9 (90)
10 (94)
11 (96)
12 (57)k
13 (83)m
14 (85)
79a; 68b; 50c; 74d; 73e; 32f
90b,g; 45d; 68e,g
4-MeOC6H4CHO
4-O2NC6H4CHO
4-NCC6H4CHO
2-Furaldehyde
2-Thiophenecarboxaldehyde
2-Pyridinecarboxaldehyde
CH3(CH2)7CHO
c-C6H11CHO
82a; 50c; 83d; 90e; 48f
81b; complicatede
<10a; 37b; tracee
5
15
73
10
5
60
30
30
63a,h; 59b,h; 26c,h; 66e,i; 14f,j
48e
Cinnamaldehyde
Crotonaldehyde
2-Deoxy-
55a; 89b; 10c; 76f
Tracea,l
D
-ribose
-glucose
Perbenzyl-
D
a Method A (Ref. 6a) uses NH3/O2/CuCl2·2H2O/MeONa in MeOH.
b Method B (Ref. 6b) uses NH3/Pb(OAc)4 in dry benzene.
c Method C (Ref. 6c) uses NH3/I2/MeONa in MeOH.
d Method D (Ref. 6d) uses NH3/S8/NaNO2.
e Method E (Ref. 6e) uses NH3/KI/MeONa in MeOH on electrooxidation.
f Method F (Ref. 6f) uses NH3/H2O2/CuCl in 2-propanol.
g The yield for the reaction of 4-ClC6H4CHO.
h The yield for the reaction of heptanenitrile.
i The yield for the reaction of octanenitrile.
j The yield for the reaction of undecanenitrile.
k Crotononitrile was the exclusive product according to the 1H NMR analysis. Due to high volatility of crotononitrile, Et2O was used as the
solvent instead of THF. The isolated yield decreased to 57% on evaporation.
l The result for the reaction of acrylonitrile.
m The yield for the peracetylation derivative.
Keywords: aldehydes; nitriles; solvents and solvent effects.
* Corresponding author. Fax: (886-2)-2363-6359; e-mail: jmfang@mail.ch.ntu.edu.tw
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02195-X

1104
S. Talukdar et al. / Tetrahedron Letters 42 (2001) 1103–1105
mediates has also been explored.3 In most cases, aro-
matic aldehydes are preferably converted to aromatic
nitriles, whereas the transformations of enolizable
aliphatic aldehydes often give unsatisfactory yields of
aliphatic nitriles. The problem can be somewhat cir-
cumvented by using less available reagents4 (e.g. sulfi-
mide) or unconventional approaches5 (e.g. microwave
irradiation).
(1.1 molar proportions) in ammonia water (28% solu-
tion) at room temperature for a short period afforded
the desired nitriles in very high yields (Eq. (1) and
Table 1). According to the previous reports,6e,7 we
speculated that the reaction proceeded via oxidation of
aldimine with iodine to give an N-iodo aldimine inter-
mediate, which eliminated an HI molecule in ammonia
solution to afford the nitrile product. The aldehydes
examined in this study included benzaldehydes, hetero-
cyclic aromatic aldehydes, a,b-unsaturated aldehydes,
aliphatic aldehydes, and saccharide aldehydes.
The use of ammonia combined with appropriate oxi-
dants is considered as an expedient method for the
transformation of aliphatic and aromatic aldehydes to
their corresponding nitriles. Indeed, six processes
(methods A–F)6 using such an approach have been
reported (Table 1). Method A6a is conducted by stirring
an appropriate aldehyde with NH3 and O2 in MeOH
using CuCl2 and MeONa as the promoters. This
method provides modest yields (55–82%) of aromatic
and aliphatic nitriles, but low yields (<10%) of acryloni-
trile and furonitrile. Method B6b is performed in dry
benzene by slow bubbling with NH3 gas and the por-
tionwise addition of Pb(OAc)4 in a simultaneous man-
ner. This procedure is tedious, and only small-scale
reactions are demonstrated to give benzonitrile (68%),
furonitrile (37%), and heptanenitrile (59%). Using
method C,6c benzonitrile (50%), p-chlorobenzonitrile
(68%), p-methoxybenzonitrile (50%), cinnamononitrile
(10%), and heptanenitrile (26%) are obtained from their
corresponding aldehydes on treating with iodine and
MeONa in NH3 gas saturated MeOH solution. This
method is complicated by the presence of MeONa to
give some methyl esters. Method D,6d using elemental
sulfur and NaNO2 in liquid NH3 at 100°C, is limited to
the transformation of aromatic aldehydes. Method E6e
converts aldehydes to nitriles by electrooxidation in
methanolic NH3 solution containing KI and MeONa.
This method fails to prepare p-nitrobenzonitrile or
furonitrile due to complications from other reactions.
Using method F,6f a mixture of aldehyde and H2O2
(50% solution) are slowly added (dropwise over 2.5–4
h) into NH3 gas saturated 2-propanol solution contain-
ing CuCl. This method is applicable to large-scale
reactions (e.g. 1.5 mol) by using excessive amounts of
H2O2 (e.g. 3.35 mol) with cautious cooling. Benzalde-
hydes and conjugated aldehydes are thus converted to
the corresponding nitriles in variable yields (32–87%),
as shown by the six examples. However, the reaction of
enolizable aldehydes (undecanal and citronellal) is ine-
fficient, giving the nitrile products in low yields (14 and
8%, respectively, according to the GC analyses).
CHO
H
CN
H
H
H
H
H
H
H
i) I2, aq. NH3, r.t.
ii) Ac2O, pyridine
OH
OAc
OAc
(2)
OH
CH2OH
CH2OAc
13
CN
CHO
H
OBn
H
OBn
I2, aq. NH3, r.t.
BnO
H
H
BnO
H
H
OBn
OBn
OBn
(3)
H
H
OBn
CH2OBn
CH2OBn
14
The following procedure is typical. Iodine (1.1 mmol)
was added to a stirring solution of aldehyde (1 mmol)
in ammonia water (10 mL of 28% solution) and THF (1
mL) at room temperature. The dark solution became
colorless (or light gray in some cases) after stirring for
5–73 min, an indication that the reaction was complete.
The reaction mixture was charged with aqueous
Na2S2O3 (5 mL of 5% solution), followed by extraction
with ether (2×15 mL), to give a practically pure nitrile
product.
CAUTION: It is known that iodine reacts with ammo-
nia water under certain conditions to give a black
powder of nitrogen triiodide monoamine (NI3·NH3).8
The dry powder explodes readily by mechanical shock,
heat or irradiation. Although we did not have any
incidents when handling the reactants in this study, one
should avoid using excess reagent.
By comparison with the closely related methods C and
E, our current method exhibited distinct advantages.
First, we utilized the readily available ammonia water
instead of ammonia gas saturated methanol. The opera-
tion of such a reaction using our method became simple
and efficient. Second, we omitted MeONa in the reac-
tion media so that the complication of side reactions
(e.g. formation of methyl ester) found in the previous
methods was avoided. In the absence of MeONa, trans-
formation of aldehydes to nitriles still proceeded
rapidly according to our study. These two small
changes did improve the yields of nitriles to a great
extent, especially in the preparation of p-nitrobenzalde-
hyde (96%), furonitrile (88%), cinnamononitrile (97%),
and aliphatic nitriles (>90%). It was also noted that our
method was ideal for water-soluble substrates, such as
I2, aq. NH3, r.t.
O
(1)
R C
R C N
H
R = C6H5
R = p-BrC6H4
R = p-MeOC6H4
1
2
5
8
3
6
9
R = 2-furyl
R = Me(CH2)7
R = p-O2NC6H4
R = 2-thienyl
R = p-NCC6H4
R = 2-pyridyl
4
7
R = cyclohexyl
10
11 R = PhCH=CH
12 R = MeCH=CH
On the basis of NH3/oxidant protocols, we wish to
develop a practical and environmentally benign method
for direct transformation of aldehydes to nitriles. We
found that treatment of various aldehydes with iodine

S. Talukdar et al. / Tetrahedron Letters 42 (2001) 1103–1105
1105
the carbohydrates shown in Eqs. (2) and (3). Thus,
2-deoxy- -ribose was treated with I2 in ammonia water
at room temperature for 30 min to give an 83% yield of
(3,4,5-triacetoxy)pentanenitrile9 (13) after subsequent
acetylation (Ac2O/pyridine). By a similar procedure,
1981, 739; (d) Saednya, A. Synthesis 1982, 190; (e) Gan-
boa, I.; Palomo, C. Synth. Commun. 1983, 13, 219; (f)
Capdevielle, P.; Lavigne, A.; Maumy, M. Synthesis 1989,
451; (g) Bose, D. S.; Narsaiah, A. V. Tetrahedron Lett.
1998, 39, 6533; (h) Kumar, H. M. S.; Reddy, B. V. S.;
Reddy, P. T.; Yadav, J. S. Synthesis 1999, 586.
D
2,3,4,5,6-penta-O-benzyl-D-glucose was smoothly con-
verted to 2,3,4,5,6-penta-O-benzyl-
D
-glucononitrile10
4. (a) Pomeroy, J. H.; Craig, C. A. J. Am. Chem. Soc. 1959,
81, 6340; (b) Gelas-Mialhe, Y.; Vessie`re, R. Synthesis
1980, 1005; (c) Furukawa, N.; Fukumura, M.; Akasaka,
T.; Yoshimura, T.; Oae, S. Tetrahedron Lett. 1980, 21,
761; (d) Georg, G. I.; Pfeifer, S. A. Tetrahedron Lett.
1985, 26, 2739; (e) Nishiyama, K.; Oba, M.; Watanabe,
A. Tetrahedron 1987, 43, 693; (f) Suzuki, H.; Nakaya, C.
Synthesis 1992, 641.
5. (a) Villemin, D.; Lalaoui, M.; Alloum, A. B. Chem. Ind.
(London) 1991, 176; (b) Delgado, E.; Cano, A. C.; Gar-
cia, O.; Alvarado, J.; Velasco, L.; Alvarez, C.; Rudler, H.
Synth. Commun. 1992, 2125; (c) Feng, J.-C.; Liu, B.; Dai,
L.; Bian, N.-S. Synth. Commun. 1998, 28, 3765; (d) Das,
B.; Madhusudhan, P.; Venkataiah, B. Synlett 1999, 1569.
6. (a) Brackman, W.; Smit, P. J. Recl. Trav. Chim. 1963, 82,
757; (b) Parameswaran, K. N.; Friedman, O. M. Chem.
Ind. (London) 1965, 988; (c) Misono, A.; Osa, T.; Koda,
S. Bull. Chem. Soc. Jpn. 1966, 39, 854; (d) Sato, R.; Itoh,
K.; Itoh, K.; Nishina, H.; Goto, T.; Saito, M. Chem.
Lett. 1984, 1913; (e) Okimoto, M.; Chiba, T. J. Org.
Chem. 1988, 53, 218; (f) Erman, M. B.; Snow, J. W.;
Williams, M. J. Tetrahedron Lett. 2000, 41, 6749.
7. Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. Jpn.
1967, 40, 2875.
(14) in 85% yield.
In summary, a variety of aldehydes were successfully
transformed into nitriles by treatment with iodine in
ammonia water. This method is simple, economic, and
environmentally benign. This method is especially use-
ful for the transformation of water-soluble aldehydes
such as carbohydrates.
Acknowledgements
We thank the National Science Council for financial
support. We also thank Dr. Chun-Hung Lin (Institute
of Biochemistry, Academia Sinica) for helpful discus-
sion and providing the sample of 2,3,4,5,6-penta-O-
benzyl-D-glucose.
References
1. (a) Mowry, D. T. Chem. Rev. 1948, 42, 250; (b) Friedrich,
K.; Wallensfels, K. In The Chemistry of the Cyano Group;
Rappoport, Z., Ed.; Wiley-Interscience: New York, 1970;
(c) North, M. In Comprehensive Organic Functional
Group Transformations; Katrizky, A. R.; Meth-Conn, O.;
Rees, C. W., Eds.; Pergamon: Oxford, 1995; pp. 617–618.
2. (a) Findlay, J. A.; Tang, C. S. Can. J. Chem. 1967, 45,
1014; (b) Forey, H. G.; Datlon, D. R. J. Chem. Soc.,
Chem. Commun. 1973, 628; (c) Kukhar, V. P.; Pasternak,
V. I. Synthesis 1974, 563; (d) Shinozaki, H.; Imaizumi,
M.; Tajima, M. Chem. Lett. 1983, 929; (e) Meshram, H.
M. Synthesis 1992, 943; (f) Katritzky, A. R.; Zhang, G.
F.; Fan, W. Q. Org. Prep. Proc. Int. 1993, 25, 315.
3. (a) Blatter, H. M.; Lukaszewski, H.; de Stevens, G. J.
Am. Chem. Soc. 1961, 83, 2203; (b) Olah, G. A.; Keumi,
T. Synthesis 1979, 112 and references cited therein; (c)
Dauzonne, D.; Demerseman, P.; Royer, R. Synthesis
8. Roesky, H. W.; Mo¨ckel, K. Chemical Curiosities; VCH:
Weinheim, 1996; pp. 292–293.
9. (3,4,5-Triacetoxy)pentanenitrile (13): [h]2D5=+7.3 (c=2.5,
CHCl3); IR (neat) 2263 cm−1 1H NMR (300 MHz,
;
CDCl3) l 2.02 (3 H, s), 2.09 (6 H, s), 2.65–2.81 (2 H, m),
4.13 (1 H, dd, J=12.5, 4.2 Hz), 4.29 (1 H, dd, J=12.5,
3.2 Hz), 5.17–5.22 (2 H, m); 13C NMR (CDCl3, 50 MHz)
l 19.6 (CH2), 20.6 (CH3×2), 20.7 (CH3), 61.2 (CH2), 66.4
(CH), 70.4 (CH), 121.7 (C), 169.4 (C), 169.5 (C), 170.2
(C). HR-FAB-MS: calcd for C11H16NO6 (M++1) m/z
258.0978; found m/z 258.0981.
10. Yokoyama, M.; Kobayashi, N.; Hachiya, T.; Kubo, M.;
Togo, H. Bull. Chem. Soc. Jpn. 1996, 69, 2989. The
reaction of 2,3,4,5,6-penta-O-benzyl-
Me3SiN3/BF3·OEt2 in CH2Cl2 solution gives 2,3,4,5,6-
penta-O-benzyl- -glucononitrile (27%) and 1,1-diazido-
2,3,4,5,6-pentabenzyloxyhexane (47%).
D-glucose with
D
.