A one-pot method for the efficient preparation of aromatic nitriles from aldehydes using ammonia, magnesium sulfate, and manganese dioxide

Article abstract of DOI:10.1055/s-2001-10781

A one-pot and efficient preparation of aromatic nitriles from the corresponding aldehydes was accomplished by treatment with 2 M ammonia solution in 2-propanol, magnesium sulfate, and manganese dioxide in THF at room temperature. This method was found to be compatible with a variety of functionalities such as hydroxyl, ester, and amide.

Full text of DOI:10.1055/s-2001-10781

230
LETTER
A One-Pot Method for the Efficient Preparation of Aromatic Nitriles from
Aldehydes Using Ammonia, Magnesium Sulfate, and Manganese Dioxide
Gaifa Lai,*,1 Nana K. Bhamare, Wayne K. Anderson
Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260, USA
Fax+1-732-422-0156; E-mail: glai@pharmacop.com
Received 6 December 2000
R
Abstract: A one-pot and efficient preparation of aromatic nitriles
from the corresponding aldehydes was accomplished by treatment
with 2 M ammonia solution in 2-propanol, magnesium sulfate, and
manganese dioxide in THF at room temperature. This method was
found to be compatible with a variety of functionalities such as hy-
N
H
MeO
droxyl, ester, and amide.
O
Key words: aromatic nitriles, aldehydes, manganese dioxide
1a R = CHO
1b R = CONH2
1c R = CN
Nitriles are widely used as important intermediates in or-
ganic synthesis. For example, nitriles were readily con-
verted to heterocyclic compounds such as tetrazoles,2
thiazoles,3 oxazoles,4 and 2-oxazolines.5 It has also been
the reaction was detected by 1H NMR or TLC analyses.17
well documented that the cyano group itself is present in
This one-pot procedure was compatible with a variety of
substituents such as hydroxyl, ether, ester, and amide. The
reaction of 4-hydroxybenzaldehyde, for example, cleanly
furnished the product 4-cyanophenol in 90% yield (entry
5). Heterocyclic aromatic aldehydes also reacted effi-
ciently (entries 8-10). The dialdehyde 3a was readily con-
verted into the dinitrile 3b,18 which was isolated as a white
solid in 93% yield (entry 12). The reaction of the 2-biphe-
nylcarboxaldehyde 4a proceeded smoothly under the
same conditions to afford the expected nitrile compound
4b19 in 88% yield after purification (entry 13).
HIV protease inhibitors,6a 5-lipoxygenase inhibitors,6b
and many other biologically significant molecules. There
have been quite a number of methods reported in the liter-
ature for the preparation of nitriles from aldehydes via the
dehydration of the corresponding aldoximes7,8 or using
such reagents as trimethylsilyl azide,9 triazidochlorosi-
lane,10 sodium azide and aluminum chloride,11 1-nitropro-
pane and ammonium hydrogenphosphate,12 N,N-
dimethylhydrazine and magnesium monoperoxyphthalate
hexahydrate,13 and ammonia and iodine14a or lead tetraac-
etate.14b However, many of these methods met with some
limitations, including low yields, laborious procedures,
requiring drastic reaction conditions, and using corrosive
or toxic reagents. In the course of investigating the trans-
formation of the advanced intermediate aldehyde 1a to the
desired amide 1b by treatment with ammonia, sodium cy-
anide, and manganese dioxide in 2-propanol, we isolated
a small amount of the byproduct 3-cyanoindole 1c (5%) as
well as the amide 1b (76%).15 The formation of this
byproduct proceeded presumably through the oxidation of
the resulting aldimine from the aldehyde 1a and ammonia.
It occurred to us that the substitution of magnesium sul-
fate for sodium cyanide would facilitate such a side reac-
tion because of its favoring the aldimine formation. We
therefore decided to examine a new, one-pot procedure
for the preparation of aromatic nitriles from the corre-
sponding aldehydes using ammonia, magnesium sulfate,
and manganese dioxide.
A representative experimental procedure is described for
the preparation of the nitrile 2b. To a stirred solution of 3-
(4-methoxybenzyloxy)benzaldehyde (2a, 200 mg, 0.825
mmol) in THF (3 mL) were added 2 M ammonia solution
in 2-propanol (6.2 mL, 12.4 mmol, 15 equiv) and anhy-
drous magnesium sulfate (1.49 g, 12.38 mmol, 15 equiv).
After 15 min, manganese dioxide (Aldrich, 85%, 1.27 g,
12.41 mmol, 15 equiv) was added in small portions. The
resulting mixture was stirred at room temperature for 20 h
and then diluted with CH2Cl2 (20 mL). The mixture was
filtered through a layer of Celite and the filtrate was con-
centrated under reduced pressure. The solid residue was
purified by column chromatography (silica gel, EtOAc-
hexanes, 1:9) to give 181 mg (91%) of 3-(4-methoxyben-
zyloxy)benzonitrile (2b) as a white solid: mp 94-96 °C; Rf
0.30 (EtOAc-hexanes, 1:9); 1H NMR (CDCl3) δ 7.48-7.42
(m, 3 H), 7.39-7.29 (m, 3 H), 7.04 (d, J = 8.6 Hz, 2 H),
5.12 (s, 2 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ 160.1 (C),
159.2 (C), 130.7 (CH), 160.1 (C), 159.2 (C), 130.7 (CH),
129.7 (CH), 128.2 (C), 125.0 (CH), 120.5 (CH), 119.1
(CN), 118.2 (CH), 114.5 (CH), 113.5 (C), 70.5 (CH2),
55.7 (CH3); IR (KBr) 2225, 1612, 1601, 1573, 1515 cm-1.
To our delight, treatment of aromatic aldehydes with 2 M
ammonia solution in 2-propanol (15 equiv), magnesium
sulfate (15 equiv), and manganese dioxide (15 equiv) in
THF at room temperature for 16-22 h indeed gave the de-
sired nitriles16 in high yields (Table). The completion of
Synlett 2001, No. 2, 230–231 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A One-Pot Method for the Efficient Preparation of Aromatic Nitriles from Aldehydes
231
(4) (a) Moody, C. J.; Doyle, K. J. Prog. Heterocyclic Chem. 1997,
9, 1. (b) Ducept, P. C.; Marsden, S. P. Synlett 2000, 692.
(5) Jnaneshwara, G. K.; Deshpande, V. H.; Lalithambika, M.;
Ravindranathan, T.; Bedekar, A. V. Tetrahedron Lett. 1998,
39, 459.
Table One-Pot Preparation of Aromatic Nitriles by Treatment of
Aldehydes with NH3, MgSO4, and MnO2
Entry
Aldehyde
Nitrile
Time(h) Yield(%)a
Benzaldehyde
Benzonitrile
16
20
20
89
87
86
93
1
2
(6) (a) Janakiraman, M. N.; Watenpaugh, K. D.; Tomich, P. K.;
Chong, K.-T.; Turner, S. R.; Tommasi, R. A.; Thaisrivongs,
S.; Strohbach, J. W. Bioorg. Med. Chem. Lett. 1998, 8, 1237.
(b) Dube, D.; Blouin, M.; Brideau, C.; Chan, C.-C.;
Desmarais, S.; Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.;
Girard, M.; Girard, Y.; Guay, J.; Riendeau, D.; Tagari, P.;
Young, R. N.; Bioorg. Med. Chem. Lett. 1998, 8, 1255.
(7) March, J. Advanced Organic Chemistry; John Wiley & Sons:
New York, 1992 pp. 1038-1039, and references cited therein.
(8) For recent reports, see: (a) Wang, E.-C.; Lin, G.-J.
Tetrahedron Lett. 1998, 39, 4047. (b) Bose, D. S.; Narsaiah,
A. V. Tetrahedron Lett. 1998, 39, 6533. (c) Jose, B.; Sulatha,
M. S.; Pillai, P. M.; Prathapan, S. Synth. Commun. 2000, 30,
1509. (d) Desai, D. G.; Swami, S. S.; Mahale, G. D. Synth.
Commun. 2000, 30, 1623. (e) Bajpai, A. R.; Deshpande, A. B.;
Samant, S. D. Synth. Commun. 2000, 30, 2785. (f) Veverkova,
E.; Toma, S. Synth. Commun. 2000, 30, 3109. (g) Miller, C. P.;
Kaufman, D. H. Synlett 2000, 1169. (h) Das, B.; Ramesh, C.;
Madhusudhan, P. Synlett 2000, 1599.
2-Naphthaldehyde
2-Cyanonaphthalene
3-Bromobenzonitrile
3
4
3-Bromobenzaldehyde
2,6-Dichlorobenzaldehyde 2,6-Dichlorobenzonitrile 17
4-Hydroxybenzaldehyde
3-Methoxybenzaldehyde
Methyl 4-formylbenzoate
Pyridine-3-carboxaldehyde
Indole-3-carboxaldehyde
4-Cyanophenol
22
17
16
17
16
5
6
90
91
86
76
84
3-Methoxybenzonitrile
Methyl 4-cyanobenzoate
7
8
9
3-Cyanopyridine
Indole-3-carbonitrile
17
1a
1c
10
82
CN
CHO
91
20
11
O
O
MeO
MeO
2b
2a
CHO
CN
(9) Nishiyama, K.; Oba, M.; Watanabe, A. Tetrahedron 1987, 43,
693.
N
N
12
22
93
(10) Elmorsy, S. S.; El-Ahl, A.-A. S.; Soliman, H.; Amer, F. A.
Tetrahedron Lett. 1995, 36, 2639.
(11) Suziki, H.; Nakaya, C. Synthesis 1992, 641.
CHO
CN
3a
3b
(12) (a) Blatter, H. M.; Lukaszewski, H.; De Stevens, G. J. Am.
Chem. Soc. 1961, 83, 2203. (b) Blatter, H. M.; Lukaszewski,
H.; De Stevens, G. Org. Synth. 1973, Coll. Vol. V, 656.
(13) Fernandez, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M.;
Vazquez, J. Tetrahedron Lett. 1993, 34, 141.
O
H
O
H
N
NHEt
N
NHEt
N
H
N
H
O
O
13
22
88
N
N
(14) (a) Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. Jpn. 1966,
39, 854. (b) Parameswaran, K. N.; Friedman, O. M. Chem.
Ind. 1965, 988.
(15) Lai, G.; Anderson, W. K. Tetrahedron 2000, 56, 2583.
(16) All nitriles obtained were identified by 1H and 13C NMR
spectral data and, for known nitriles, comparison with those
previously reported.
CHO
4a
CN
4b
a Yields refer to single runs and are given for isolated products.
(17) TLC analysis showed that the nitriles and the corresponding
starting aldehydes had very similar Rf’s in most cases (entries
1-3, 5-7, 11 and 13 in the Table).
In summary, we have demonstrated a one-pot and effi-
cient preparation of aromatic nitriles from aldehydes em-
ploying ammonia, magnesium sulfate, and manganese
dioxide. Prominent among the advantages of this new
method are its mild and neutral reaction conditions, oper-
ational simplicity, and high yields.
(18) 4,4’-Dicyanotriphenylamine (3b) as a white solid: mp 191-
193 °C; Rf 0.41 (EtOAc-hexanes, 1:4); 1H NMR (CDCl3) δ
7.65 (d, J = 8.7 Hz, 4 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.39 (m, 1
H), 7.25-7.19 (m, 2 H), 7.21 (d, J = 8.8 Hz, 4 H); 13C NMR
(CDCl3) δ 150.6, 145.4, 133.9, 130.7, 127.3, 126.9, 123.2,
119.3 (CN), 106.2; IR (KBr) 2220, 1592, 1501 cm-1.
(19) 4b as a white solid: mp 201-203 °C; Rf 0.34 (MeOH-CH2Cl2,
1:9);1H NMR (DMSO-d6) δ 8.62 (m, 1 H), 8.45 (m, 1 H), 7.96
(m, 1 H), 7.82 (m, 1 H), 7.61 (m, 3 H), 7.51 (d, J = 8.6 Hz, 2
H), 7.41 (d, J = 8.5 Hz, 2 H), 7.39 (m, 1 H), 4.58 (m, 1 H), 4.39
(q, J = 7.2 Hz, 2 H), 3.05 (m, 4 H), 1.06 (t, J = 7.2 Hz, 3 H);
13C NMR (DMSO-d6) δ 173.1, 158.3, 149.3, 148.6, 145.1,
139.3, 136.6, 135.9, 135.6, 134.5, 134.1, 130.7, 130.3, 129.1,
128.7, 124.1, 119.3 (CN), 110.8, 55.1, 48.6, 38.9, 34.7, 15.9;
IR (KBr) 3361, 3308, 3241, 2223, 1650, 1632, 1561 cm-1; MS
(CI) m/z 428 (MH+), 357.
References and Notes
(1) Address for correspondence: 8-7B Koster Blvd., Edison, NJ
08837, USA.
(2) (a) Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58,
4139. (b) Bailey, T. R.; Diana, G. D.; Kowalczyk, P. J.;
Akullian, V.; Eissenstat, M. A.; Cutcliffe, D.; Mallamo, J. P.;
Carabateas, P. M.; Pevear, D. C. J. Med. Chem. 1992, 35,
4628. (c) Kadaba, P. K. Synthesis 1973, 71.
(3) (a) Gu. X.-H.; Wan, X.-Z.; Jiang, B. Bioorg. Med. Chem. Lett.
1999, 9, 569. (b) 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.
Article Identifier:
1437-2096,E;2001,0,02,0230,0231,ftx,en;S08300ST.pdf
Synlett 2001, No. 2, 230–231 ISSN 0936-5214 © Thieme Stuttgart · New York