A facile and efficient one-pot synthesis of nitriles from carboxylic acids

Article abstract of DOI:10.1055/s-2005-871967

Direct transformation of aliphatic carboxylic acids to the corresponding nitriles can be easily performed with acetonitrile in the presence of sulfuric acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871967

LETTER
2089
A Facile and Efficient One-Pot Synthesis of Nitriles from Carboxylic Acids
O
K
ne-PotSynthesis
a
of
N
itrile
s
ta Mlinarić-Majerski,* Renato Margeta, Jelena Veljković
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, P. O. Box 180, 10002 Zagreb, Croatia
Fax +385(1)4680195; E-mail: majerski@irb.hr
Received 26 May 2005
Our studies involved a series of compounds such as 1a–8a
Table 1). The starting acids were prepared according to
literature procedures.
Abstract: Direct transformation of aliphatic carboxylic acids to the
corresponding nitriles can be easily performed with acetonitrile in
the presence of sulfuric acid.
(
8
Key words: carboxylic acids, nitriles, acetonitriles, adamantane The results indicate that this methodology gives the corre-
derivatives, one-pot procedure
sponding nitriles in good to moderate yields (Table 1).
When aromatic acid 8a was used under the same reaction
conditions, a mixture of three products (cyanide, dicarb-
oxamide, and amide) was obtained in a ratio of 3:3:1. Pro-
longing the reaction time to eight hours gave the same
reaction mixture in a 5:2:1 ratio (Table 1, entry 8). Closer
inspection of the reaction of 1a and 4a (Table 1, entries 9
and 10) using a different ratio of carboxylic acid/sulfuric
acid or a lower temperature, gave a similar result. The
lower temperature provided a good compromise between
complete conversion of carboxylic acid and formation of
all three products, corresponding nitrile, dicarboxamide,
and amide.
Introduction of a cyano group into a molecule, or transfor-
mation of an acid into the corresponding nitrile, is not al-
ways a simple procedure. In connection with this, the
1
dehydratation of primary alkyl or aryl amides to their cor-
responding nitriles has been thoroughly documented in
1
b
the literature. Decarboxylative cyanation of Barton’s es-
ter and addition of toluensulfonylcyanide to the carbon–
2
carbon double bond, as well as radical cyanation of alkyl
3
iodides, or cyanation of aldehydes with hydroxylamine
4
hydrochloride in the presence of graphite or in the pres-
ence of a catalytic amount of sodium iodide have been re-
5
We believe that reaction starts with protonation, and more
or less simultaneously, the reaction with the carboxylic
group occurs to give isoamide intermediate, which then
rearranges to dicarboxamide A, followed by a second pro-
tonation, and formation of amide B. Dehydration of amide
B should give the expected nitrile (Scheme 2). In the con-
trol experiment (the same reaction conditions, 95 °C, 4 h)
amide 10 gave 1b in a high yield.9
ported previously. Furthermore, it has been shown that
acyl chlorides can be converted into the corresponding ni-
triles via their reaction with 2,4-dinitrobenzenesulfona-
6
mide. A procedure that can be used to convert carboxylic
7
a
acids into nitriles at very high temperatures or via N-
acylurea intermediates by using arylboronic acid and
rhenium(VII) oxo complexes as active catalysts has also
been published.
7
b
a
O
In connection with our recent interest in the synthesis of
novel cage-annulated amino acids analogues we have
found a very simple and efficient one-pot transformation
of various types of carboxylic acids into nitriles by their
treatment with acetonitrile in the presence of sulfuric acid
O
H+
R
C
O
C
+ H+
R
C N
OH + CH3C
HN
CH3
(
Scheme 1), and we report that herein.
O
O
O
H+
R
C
NH2
R
C
NH
C
CH3
B
A
A
X
–
H2O
N
CH3CN / H2SO4
R
C
B
Y
Scheme 2
1
a A = H; B = COOH
a A = Br; B = COOH
a A = B = COOH
1b X = H; Y = CN
2b X = NHCOCH3; Y = CN
3b X = Y = CN
4b X = H; Y = CH2CN
5b X = Y = CH2CN
6b C6H11CN
7b CH3(CH2)12CN
8b PhCN
2
3
4
5
6
7
8
The formation of dicarboxamide is in accord with the re-
sults of Davidson and Skovronek which show that the
isoamide is, indeed, in equilibrium with dicarboximide,
nitrile, and carboxylic acid.9b
a A = H; B = CH2COOH
a A = B = CH2COOH
a C6H11COOH
a CH3(CH2)12COOH
a PhCOOH
In conclusion, the efficient and very simple method for the
one-pot conversion of carboxylic acids into nitriles has
been developed and the mechanism of this reaction has
been elucidated. The possibility of isolating intermediate
amides and dicarboxamides is an additional practical ben-
efit for the synthesis of these types of compounds.
Scheme 1
SYNLETT 2005, No. 13, pp 2089–2091
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-871967; Art ID: G13705ST
1
9
.0
8
.2
0
0
5
©
Georg Thieme Verlag Stuttgart · New York

2
090
Kata Mlinarić-Majerski et al.
Table 1 One-Pot Transformation of Various Carboxylic Acids into Nitriles by their Treatment with Acetonitrile in the Presence of Sulfuric
Acid10
Yield (%) Productb
a
Entry Acid (1 mmol)
Tempera- Time H SO
2
4
ture (°C) (h)
[mmol]
1
95
4
10
7111
COOH
COOH
CN
1
a
a
1b
2
3
Br
95
4
10
5412
NHCOCH3
CN
2
2b
95
4
20
6213
CN
COOH
COOH
CN
3
a
a
3b
4
5
95
95
4
4
10
20
6314,15
CH2COOH
2
CH CN
4
4bc
4116
CH COOH
2
2
CH CN
CH2COOH
CH CN
2
5
a
a
5b
6b
6
95
4
10
5917
COOH
CN
6
7
CH (CH ) COOH
95
95
4
8
10
20
4118
56
CH (CH ) CN
7b
3
2 12
3 2 12
7a
8d
O
O
O
COOH
CN
+
N
+
+
NH2
H
8
a
8
b
5
:
2
:
1
9d
40
40
18
18
20
20
5519,20
O
O
O
COOH
+
NH2
N
CN
H
1
a
a
1
b
9
1
10
1
1
:
:
0d
5215,21,22
1
O
O
O
CN +
+
CH2COOH
N
NH2
H
4
4
b
11
12
2
:
2
:
1
a
b
c
d
Yields refer to isolated products.
All products were characterized by IR, H and 13C NMR spectroscopic data.
1
Besides 4b traces of unidentified product was observed.
The ratio of products was determined from 13C NMR spectra of crude reaction mixture.
Synlett 2005, No. 13, 2089–2091 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Nitriles
2091
Acknowledgment
(11) 1b: IR (KBr): 2919 (s), 2856 (m), 2252 (w), 2226 (w), 1453
–
1 1
(
2
m), 1103 (m) cm ; H NMR: d = 1.71–1.77 (6 H, m), 2.00–
.08 (9 H, m); C NMR: d = 26.92 (d), 35.56 (t), 39.75 (t),
We thank the Ministry of Science, Education and Sport of the
Republic of Croatia for financial support of this study (Project
13
125.01 (s).
0
098052).
(
(
(
12) Mella, M.; Freccero, M.; Soldi, T.; Fasani, E.; Albini, A. J.
Org. Chem. 1996, 61, 1413.
13) Bridson, J. N.; Schriver, M. J.; Zhu, S. Can. J. Chem. 1995,
References
7
3, 212.
1
5
14) 4b: Mp 73–76 °C (lit. 73–74 °C); IR (KBr): 2903 (s), 2850
(
1) (a) Friedrich, K.; Wallenfels, K. In Introduction of the Cyano
Group into the Molecule; Patai, S.; Rappoport, Z., Eds.; John
Wiley & Sons: New York, 1970, 67–122. (b) Larock, R. C.
Comprehensive Organic Transformation; VCH Publishers:
New York, 1989.
–
1 1
(m), 2236 (w), 1442 (m), 1347 (m) cm ; H NMR: d = 1.58–
1
3
1
.77 (12 H, m), 2.00–2.06 (3 H, m), 2.09 (2 H, s, CH2);
C
NMR: d = 28.14 (d), 31.98 (s), 32.12 (t), 36.14 (t), 41.62 (t),
17.74 (s).
1
(
(
15) Lauria, F.; Vecchietti, V.; Bergamaschi, M. Farmaco Ed.
Sci. 1967, 22, 681.
(
2) (a) Barton, D. H. R.; Jaszberenyi, J. Cs.; Theodorakis, E. A.
Tetrahedron 1992, 48, 2613. (b) Barton, D. H. R.;
Jaszberenyi, J. Cs.; Theodorakis, E. A. Tetrahedron Lett.
1
16) (a) 5b: H NMR: d = 1.42–1.61 (12 H, m), 2.10–2.19 (6 H,
1
3
m, with a distinguishable singlet at 2.11); C NMR:
1991, 32, 3321.
d = 28.17 (d), 31.44 (t), 32.74 (s), 34.78 (t), 40.40 (t), 45.58
(
(
(
(
(
3) Kim, S.; Song, H.-J. Synlett 2002, 2110.
(
t), 117.09 (s); (b) For IR data of 5b see: Aigami, K.;
Inamoto, Y.; Takaishi, N.; Hattori, K. J. Med. Chem. 1975,
8, 713.
4) Sharghi, H.; Hosseini Sarvari, M. Synthesis 2003, 243.
5) Ballini, R.; Fiorini, D.; Palmieri, A. Synlett 2003, 1841.
6) Huber, V. J.; Bartsch, R. A. Tetrahedron 1998, 54, 9281.
7) (a) Vinokurov, V. A.; Ananiev, N. P.; Gaevoj, E. G.;
Kuznecova, L. A.; Morsumzade, E. M.; Karahanov, R. A.
Zh. Org. Khim. 1985, 21, 1806. (b) Ishihara, K.; Furuya, Y.;
Yamamoto, H. Angew. Chem. Int. Ed. 2002, 41, 2983.
8) (a) 1a: Stetter, H.; Schwarz, M.; Hirschhorn, A. Chem. Ber.
1
(17) Wender, P. A.; Eissenstat, M. A.; Sapuppo, N.; Ziegler, F. E.
Org. Synth., Coll. Vol. 6 1988, 334–337.
(18) Taber, D. F.; Kong, S. J. Org. Chem. 1997, 62, 8575.
(
19) 9: Mp 154–156 °C; R 0.44 (silica gel, EtOAc–hexane, 1:1).
f
IR (KBr): 3273 (m), 2907 (s), 2856 (m), 1727 (s), 1696 (s),
(
1
671 (s), 1470 (m), 1377 (m), 1289 (m), 1207 (m), 1016 (m)
1959, 92, 1629. (b) 2a: Stetter, H.; Mayer, J. Chem. Ber.
1962, 95, 667. (c) 3a: Stetter, H.; Wulff, C. Chem. Ber.
1960, 93, 1366. (d) 4a and 5a: Bott, K. Chem. Ber. 1968,
101, 564.
–
1 1
cm . H NMR: d = 1.68–1.79 (6 H, m), 1.86–1.89 (6 H, m),
2
.06–2.12 (3 H, m), 2.48 (3 H, s, CH ), 8.26 (1 H, br s, NH).
C NMR: d = 25.45 (q, 1 C), 27.69 (d, 3 C), 36.03 (t, 3 C),
3
1
3
38.48 (t, 3 C), 41.80 (s, 1 C), 173.51 (s, 1 C), 176.55 (s, 1 C).
(
9) (a) Similarly, when dicarboxamide 11 was subjected to the
same reaction conditions, but the reaction time was reduced
to 2 h, the mixture of 11, 12, and 4b was obtained in a 1:3:3
ratio. (b) Davidson, D.; Skovronek, H. J. Am. Chem. Soc.
Anal. Calcd for C H NO : C, 70.56; H, 8.65; N, 6.33.
13 19
2
Found: C, 70.83; H, 8.63; N, 6.46.
20) 10: Stetter, H.; Mayer, J.; Schwarz, M.; Wulff, K. Chem.
Ber. 1960, 93, 226.
(
(
1958, 80, 376.
21) 11: Mp 142–144 °C; R 0.40 (silica gel, EtOAc–hexane,
(
10) General Procedure for the One-Pot Preparation of
Nitriles. Concd H SO (10 mmol) was added dropwise at r.t.
f
1
:1); IR (KBr): 3268 (m), 3175 (m), 2902 (s), 2845 (m),
2
4
–
1 1
1732 (s), 1531 (m), 1500 (m), 1238 (m), 1135 (m) cm ; H
to a well-stirred suspension of acid (1 mmol) in MeCN (5
mL) and then the mixture was stirred under reflux for the
appropriate time (Table 1). The excess of acetonitrile was
then evaporated and CH Cl (15 mL) and H O (15 mL) were
added. The layers were separated and the water layer was
extracted with a fresh portion of CH Cl . The combined
organic layers were washed with brine, dried over MgSO4,
and evaporated under reduced pressure to give the crude
product, which was purified by chromatography using
EtOAc–hexane as eluent.
NMR: d = 1.60–1.75 (12 H, m), 1.98 (3 H, br s), 2.20 (2 H,
1
3
s, CH ), 2.42 (3 H, s, CH ), 8.78 (1 H, br s, NH); C NMR:
2
3
d = 25.17 (q, 1 C), 28.43 (d, 3 C), 33.32 (s, 1 C), 36.51 (t, 3
C), 42.27 (t, 3 C), 51.50 (t, 1 C), 171.07 (s, 1 C), 172.67 (s,
2
2
2
1
C); Anal. Calcd for C H NO : C, 71.46; H, 8.99; N, 5.95.
14 21 2
2
2
Found: C, 71.84; H, 8.88; N, 6.04.
(
22) 12: Anderson, G. L. US 6,348,625 B1, 2002.
Synlett 2005, No. 13, 2089–2091 © Thieme Stuttgart · New York