Cs2CO3 in pyrrolidinone promoted hydration of functionalized (hetero)aryl nitriles under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.03.117

An efficient hydration reaction of various (hetero)aryl nitriles using Cs₂CO₃ in pyrrolidinone is described. This new metal-free protocol proved to be highly effective and general to synthesize a variety of (hetero)aryl amides.

Full text of DOI:10.1016/j.tetlet.2012.03.117

Tetrahedron Letters 53 (2012) 2860–2863
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cs CO in pyrrolidinone promoted hydration of functionalized (hetero)aryl
2
3
nitriles under metal-free conditions
⇑
⇑
Sophian Sahnoun, Samir Messaoudi , Jean-François Peyrat, Jean-Daniel Brion, Mouad Alami
Univ Paris-Sud, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-92296, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient hydration reaction of various (hetero)aryl nitriles using Cs CO3 in pyrrolidinone is described.
2
Received 9 March 2012
Revised 27 March 2012
Accepted 28 March 2012
Available online 1 April 2012
This new metal-free protocol proved to be highly effective and general to synthesize a variety of
(hetero)aryl amides.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Nitriles
Hydration
Amides
Metal-free procedure
The direct addition of O–H bonds to nitriles, known as hydra-
tion, is one of the most simple and powerful tools to convert ni-
triles into amides. These compounds exhibit a quite broad range
the arylated adenine with concomitant hydration of nitrile func-
tion (Scheme 1). The formation of amide as the main product
led us to consider whether this reaction could provide general ac-
cess to amides as a complement to existing procedures. Therefore
9
1
of applications in academia and industry. In addition, they are
useful intermediates in organic synthesis, for instance in transi-
2 2 3
the role played by reactants (Pd(OH) /C, CuI, Cs CO and NMP) in
promoting the conversion of 4-chlorobenzonitrile 1a, as a model
tion-metal catalyzed C–N bond forming reactions.2 Classically the
hydration was carried out with strong acids or bases (e.g., H
NaOH). These methods suffer from drawbacks, such as the use
of drastic conditions which frequently resulted in over-hydrolysis
2
SO
4
,
substrate into the corresponding amide was investigated (Table 1).
We found that Cs CO in pyrrolidinone promoted efficient hydra-
2 3
3
tion of nitriles to provide various functionalized (hetero)aryl
amides under a metal-free procedure. A recent work concerning
transition metal-free catalytic hydration of organonitriles to
to form undesirable carboxylic acids. Systems related to the use
4
of urea hydrogen peroxide (UHP) in the presence of K
2
CO
3
, N,N-
5
6
10
disubstituted hydroxylamine, or microorganisms have also been
reported. In recent years, considerable effort has been expended to
extend the hydration reaction to applications in fine chemicals, and
amides prompted us to report the results of our study.
As outlined in Table 1, a variety of reaction conditions were
screened. The result of entry 1 showed that the presence of both
7
7a–d
7e–f
to use new metal-transition catalysts, including Ru,
Rh,
Pd(OH)
of 1a efficiently occurred in the presence of Cs
at 160 °C leading to amide 2a in 79% yield. The screening reaction
was continued with respect to the base. The use of Cs CO was
or LiOH led to amide
2
/C and CuI was unnecessary, since the hydration reaction
7
g
7i
7j–l
Ni, Cu and Pd
which assisted activation of the nitrile func-
2
CO alone in NMP
3
tion, and thus enhancing the hydration rate. Although these me-
tal-catalyzed reactions are suitable procedures for the synthesis
of amides, however, the use of expensive metal-transition catalysts
limits the exploitation of these methods. Therefore, the develop-
ment of a metal-free protocol is an appealing challenge in chemical
research.
2
3
found to be optimal since reactions with K
2
CO
3
NH2
N
NH2
N
Cl
CN
1a
Previously, during our search on the palladium-catalyzed C–H
N
N
N
N
O
8
N
N
arylation of free-(NH
2
) adenines to prepare 8-aryl adenines, we
unexpectedly observed when using 4-chlorobenzonitrile 1a as
the coupling partner, that the C–H arylation provided in 77% yield
Pd(OH)
2
/C (5 mol% )
NH2
CuI (1 equiv)
Cs CO (2equiv)
2
3
NMP, 160 °C
77%
⇑
Corresponding authors. Tel.: +33 1 46 83 58 87; fax: +33 1 46 83 58 28.
E-mail addresses: samir.messaoudi@u-psud.fr (S. Messaoudi), mouad.alami@
MeO
MeO
u-psud.fr (M. Alami).
Scheme 1. Concomitant C–H arylation of adenine and nitrile hydration.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.117

S. Sahnoun et al. / Tetrahedron Letters 53 (2012) 2860–2863
2861
Table 1
Optimization hydration reaction of 4-chlorobenzonitrile 1a under various conditions
a
Base
O
Solvent
Cl
CN
Cl
T (°C), Time (h)
NH2
1
a
2a
Time (h)
Entry
Base
Cs CO
CO
LiOH
Na CO
Li CO
Solvent
T (°C)
Conv.b (%)
Yieldc (%)
1
2
3
4
5
6
7
8
9
2
3
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Pyrrolidinone
DMF
DMA
tBuOH
Toluene
160
160
160
160
160
160
160
160
160
160
160
160
160
130
130
16
16
16
16
16
16
16
16
16
16
16
16
16
2
100
81
100
<10
<10
0
79
61
65
nd
nd
nd
nd
nd
82
71
70
54
0
K
2
3
2
3
2
3
Ba
Ca
2
CO
CO
3
2
3
0
3
K PO
4
49
100
94
92
78
0
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
CO
3
3
3
3
3
10
11
12
13
14
15
d
CO
CO
3
Pyrrolidinone
Pyrrolidinone
100
90
e
3
2
76
nd
a
b
c
Unless otherwise stated, all reactions were heated in the solvent using 1a (1.0 equiv) and base (2 equiv).
The conversion was determined by H NMR in the crude reaction mixture and was based on remaining 1a.
Yield of isolated product.
1
d
e
Best conditions were found to require: 1a (1.0 equiv) and Cs
equiv of Cs CO was used.
2
CO
3
(1.5 equiv), 130 °C, 2 h.
1
2
3
Table 2
Hydration of various functionalized (hetero)aryl nitriles 1
1
2
Entry
(Hetero)aryl nitriles 1
Amide 3
Yielda (%)
90
O
Cl
Br
I
CN
CN
Cl
1
1a
1b
1c
1d
2a
2b
2c
2d
NH2
O
Br
I
2
3
4
85
77
61
NH2
O
CN
NH2
O
O N
CN
2
O N
2
NH2
O
CN
5
6
1e
1f
2e
2f
83
95
NH2
Cl
Cl
O
CN
NH2
F3C
F3C
O
CN
7
8
9
1g
1h
1i
2g
2h
2i
65
NH2
Cl
Cl
O
Me
CN
Me
71b
88
NH2
CN
O
NH2
CN
O
1
0
1j
NH
2
2j
75
N
N
(
continued on next page)

2
862
S. Sahnoun et al. / Tetrahedron Letters 53 (2012) 2860–2863
Table 2 (continued)
Entry
(Hetero)aryl nitriles 1
Amide 3
Yielda (%)
86
NH2
11
12
13
1k
2k
2l
N
CN
N
O
O
N
CN
N
1l
77
72
NH2
O
N
CN
N
1m
2m
NH2
NH2
Cl
Cl
1
1
4
5
CN
CN
1n
1o
2n
2o
97
99
O
S
O
O
NH2
S
O
a
Yield of isolated product.
b
3
2 3
equiv of Cs CO were used.
O
2
a in slightly lower yields (entries 2 and 3), or were ineffective with
Na CO , Li CO , Ba CO , Ca CO , and K PO as the base (entries 4–
). Next, solvent screening study was undertaken and revealed that
Cs
N
O
2
3
2
3
2
3
2
3
3
4
Cs O
OCs
Cs
8
Ar
C
O
N
Ar
O
O
Pyrrolidinone
the hydration in pyrrolidinone also was effective providing 2a in a
good 82% yield (entry 9). Using other polar solvents, including DMF,
DMA or tBuOH induced a lowering of the conversion rate (entries
I
-
CO2
1
0–12). Switching into non polar solvent, such as toluene failed
and only starting material was recovered unchanged (entry 13).
Finally, pyrrolidinone was chosen as the solvent to evaluate the
effect of other parameters reaction, including temperature, reaction
Cs
NH
OH
"
H "
+
N
Cs
Ar
NH2
O
Ar
Ar
time, and amount of Cs
Table 1), the best result was obtained at 130 °C for 2 h using Cs
1.5 equiv) as the base. Under these conditions, amide 2a was
2
3
CO . After a series of assays (not shown in
II
2
CO
3
(
2 3
Scheme 2. Plausible mechanism of the Cs CO addition to nitrile.
formed in an excellent 90% yield (entry 14), and no corresponding
acid was detected. It should be noted that decreasing the amount
of Cs
from 1.5 to 1 equiv11 resulted in a lowering of the conver-
2
CO
3
the nitrile carbon atom occurs at first to give the intermediate I.
This latter would evolve through a decarboxylative mechanism
to cesium benzimidate II which, after workup, would give the cor-
responding amide.
In summary, we have developed an efficient metal-free hydra-
2 3
tion protocol of (hetero)aryl nitriles based on the use of Cs CO
in pyrrolidinone. Accordingly, a variety of (hetero)aryl amides
has been successfully prepared in good to excellent yields. Owing
to the practical advantages and low environmental impact, we
believe that the reaction described here could be an attractive
alternative for the preparation of various functionalized amides
and should find broad applications in synthetic organic chemistry
and pharmaceutical sciences.
sion rate (76% conversion, entry 15).
Prompted by these results, we subsequently investigated fifteen
aryl and heteroaryl nitriles to demonstrate the general applicability
of our protocol. Results summarized in Table 2 show that the opti-
mized conditions described above proved to be general for the for-
mation of various amides 2 from a large series of functionalized
benzonitriles. The reaction worked well with meta and para elec-
tron-poor benzonitriles and exhibited chemical compatibility with
some functional groups, including halides, –CF
entries 1–6). On switching the substituent to the ortho position,
the amide product 2g was formed in an acceptable 65% yield (entry
), indicating that steric hindrance appears to play an important
3
, and nitro groups
(
7
role. Substrates bearing electron-withdrawing groups were more
reactive than those with electron-donating groups, as for 4-meth-
Acknowledgments
2 3
ylbenzonitrile 1h, 3 equiv of Cs CO and 4 h heating were required
to achieve satisfying conversion and yield (entry 8). Remarkably,
this hydration reaction also proceeded successfully in the case of
several heteroaryl nitriles, such as pyridine, furan and thiophene
derivatives. Under our optimized conditions, nicotinonitrile 1j was
converted into nicotinamide 2j in 75% yield (entry 10). Moreover,
The CNRS is gratefully acknowledged for financial support of
this research and the MNSER for a doctoral fellowship to S.S.
Thanks to A. Solgadi for performing mass spectra analysis (SAMM
platform, Châtenay-Malabry). Our laboratory BioCIS-UMR 8076 is
a member of the laboratory of Excellence LERMIT supported by a
Grant from ANR (ANR-10-LABX-33).
2
- and 4-cyanopyridines 1k–m gave the corresponding amides
k–m in good yields, regardless of the nitrile position, or the nature
2
of the substituent on the pyridine ring (entries 11–13). Finally, 2-
furancarbonitrile 1n and 2-thiophenecarbo nitrile 1o could be easily
hydrated in almost quantitative yields (entries 14 and 15).
The plausible reaction mechanism could be proposed as shown
References and notes
1.
(a) Thallaj, N. K.; Przybilla, J.; Welter, R.; Mandon, D. J. Am. Chem. Soc. 2008, 130,
414–2415; (b) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
2
Wiley-VCH: New York, 1999. p. 1988; (c) Kukushkin, V. Y.; Pombeiro, A. J. L.
in Scheme 2. Nucleophilic addition of carbonate group of Cs
2
CO
3
to
Chem. Rev. 2002, 102, 1771–1802. and references cited therein; (d) Bokach, N.

S. Sahnoun et al. / Tetrahedron Letters 53 (2012) 2860–2863
2863
A.; Kukushkin, V. Y. Russ. Chem. Rev. 2005, 74, 153–170; (e) Kukushkin, V. Y.;
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Buchwald, S. L. Org. Lett. 2003, 5, 3667–3669;(c)Fors, B. P.; Dooleweerdt, K.; Zeng,
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Messaoudi, S.; Audisio, D.; Brion, J.-D.; Alami, M. Tetrahedron 2007, 63, 10202–
11. By adding H
Cs CO (1.0 equiv) in pyrrolidinone at 130 °C for 2 h, led to the amide 2a in 65%
yield.
2
O (1 equiv) to the reaction of 1a (1.0 equiv) in the presence of
2
3
12. General procedure for hydration of (hetero)aryl nitriles 1: A flame-dried
resealable 2–5 mL Pyrex reaction vessel was charged with the solid reactant(s):
(hetero)aryl nitriles 1 (1.0 mmol) and Cs CO (1.5 mmol). The reaction vessel
2 3
was capped with a rubber septum, and pyrrolidinone (2 mL per mmol [0.5 M])
was added through the septum. The septum was replaced with a teflon
screwcap. The reaction vessel was sealed and heated at 130 °C for 2 h. The
resulting suspension was cooled to room temperature and filtered through a
1
0210; (g) Audisio, D.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. J. Org.
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O.; Brion, J.-D.; Alami, M. Eur. J. Org. Chem. 2011, 5077–5088.
3
.
For the hydration of nitriles to amides catalyzed by strong acids or bases, see:
2 2
pad of celite eluting with CH Cl /MeOH (7:3), and the inorganic salts were
(
a) Moorthy, J. N.; Singhal, N. J. Org. Chem. 2005, 70, 1926–1929. and references
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removed. The filtrate was concentrated and purification of the residue by silica
gel column chromatography gave the desired product.
f 2
0.22 (Et
O); mp = 179–181 °C; 1H NMR
9
Compound 2a: Yield: 90%; TLC: R
(DMSO d , 300 MHz): 8.04 (s, 1H), 7.88 (d, 2H, H, J = 8.2 Hz), 7.52 (d, 2H,
J = 8.2 Hz), 7.46 (s, 1H); C NMR (DMSO d
(2C), 128.3 (2C); m/z MS (ES+) 156.0 (M+H) .
Compound 2g: Yield: 65%; TLC: R 0.29 (Et
(DMSO d
(DMSO d
R.; Pombeiro, A. J. L. Inorg. Chem. 2002, 41, 4798–4804; (d) Hall, J. H.; Gisler, M.
J. Org. Chem. 1976, 41, 3769–3770; (e) Sharghi, H.; Sarvari, M. H. Synth.
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Chem. 1994, 59, 3769–3774; (g) McIsaac, J. E., Jr.; Ball, R. E.; Behrman, E. J. J. Org.
Chem. 1971, 36, 3048–3050; (h) Merchant, K. J. Tetrahedron Lett. 2000, 41,
6
13
6
, 75 MHz): 166.8, 136.1, 133.0, 129.4
+
1
f
2
O); mp = 142–144 °C; 1 H NMR
3
6
, 300 MHz): 7.86 (s, 1H), 7.58 (s, 1H), 7.52–7.27 (m, 4H); C NMR
3
747–3749.
6
, 75 MHz): 168.1, 137.1, 130.5, 129.6, 129.6, 128.6, 127.0; m/z MS
+
4
5
6
.
.
.
Balicki, R.; Kaczmarek, L. Synth. Commun. 1993, 23, 3149–3155.
Ma, X. Y.; Lu, M. J. Chem. Res. 2011, 35, 480–483.
(ES+) 156.0 (M+H) .
Compound 2j: Yield: 75%; TLC: R
f
0.10 (EtOAc); mp = 130–132 °C; 1H NMR
(a) Mascharak, P. K. Coord. Chem. Rev. 2002, 225, 201–214; (b) Black, G. W.;
Gregson, T.; McPake, C. B.; Perry, J. J.; Zhang, M. Tetrahedron Lett. 2010, 51,
(DMSO
J = 7.9 Hz), 8.14 (s, 1H), 7.58 (s, 1H), 7.49 (dd, 1H, J
4H); 13C NMR (DMSO d
, 75 MHz): 166.4, 151.9, 148.6, 135.1, 129.6, 123.4; m/z
d
6
,
300 MHz): 9.03 (s, 1H), 8.69 (d, 1H, J = 4.5 Hz), 8.20 (d, 1H,
1
= 7.8 Hz, J = 4.8 Hz), (m,
2
1
639–1641.
6
+
7
.
For the metal-assisted hydration of nitrile to amide, see: (a) Cadierno, V.;
Francos, J.; Gimeno, J. Chem. Eur. J. 2008, 14, 6601–6605; (b) Polshettiwar, V.;
Varma, R. S. Chem. Eur. J. 2009, 15, 1582–1586; (c) Yi, C. S.; Zeczycki, T. N.;
Lindeman, S. V. Organometallics 2008, 27, 2030–2035; (d) Leung, C. W.; Zheng,
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Compound 2l: Yield: 77%; TLC: R
(DMSO d , 300 MHz): 8.71 (s, 2H), 8.24 (s, 1H), 7.81–7.73 (m, 2H); 7.71 (s, 1H);
C NMR (DMSO d , 75 MHz): 166.3, 150.2, (2C),141.3, 121.4 (2C); m/z MS (ES+)
0.14 (EtOAc); mp = 154–160 °C; 1H NMR
f
6
13
6
+
123.0 (M+H) .
Compound 2m: Yield: 72%; TLC: R
(DMSO d
1H, J = 5.1 Hz); C NMR (DMSO d
121.0; m/z MS (ES+) 157.0 (M+H) .
Compound 2n: Yield: 97%; TLC: R
f
0.44 (EtOAc); mp = 202-204 °C; 1H NMR
, 300 MHz): 8.56 (d, 1H, J = 5.1 Hz), 8.32 (s, 1H), 7.87 (s, 2H), 7.77 (d,
f
6
13
6
+, 75 MHz): 164.8, 150.9, 150.7, 144.9, 122.1,
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2975; (k) Kim, E. S.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2009, 50, 6286–6289.
0.3 (c-hexane/EtOAc: 2:8); mp = 140–
1
142 °C; H NMR (DMSO d , 300 MHz): 7.80 (s, 1H), 7.76 (s, 1H), 7.36 (s, 1H),
6
13
7.17–6.96 (m, 1H), 6.74–6.47 (m, 1H); C NMR (DMSO d
148.1, 145.0, 113.6, 111.8; m/z MS (ES+) 112.0 (M+H) .
6
, 75 MHz): 159.4,
+
For the Pd-catalyzed dehydration of aldoxime to nitrile, see:; (l) Kim, H. S.; Kim,
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Compound 2o: Yield: 99%; TLC: R
f
0.4 (c-hexane/EtOAc: 2:8); mp = 179–
1
8
.
.
181 °C; H NMR (DMSO d , 300 MHz): 7.76 (s, 1H), 7.75–7.71 (m, 2H), 7.37 (s,
6
13
6097–6102; (b) Messaoudi, S.; Brion, J.-D.; Alami, M. Eur. J. Org. Chem. 2010,
6495–6516; (c) Sahnoun, S.; Messaoudi, S.; Brion, J.-D.; Alami, M. ChemCatChem
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1H), 7.16–7.09 (m, 1H), 6.74–6.47 (m, 1H); C NMR (DMSO d
140.3, 131.0, 128.6, 127.9; m/z MS (ES+) 128.0 (M+H) .
6
, 75 MHz): 162.9,
+
9
(a) Sahnoun, S.; Messaoudi, S.; Brion, J.-D.; Alami, M. Org. Biomol. Chem. 2009, 7,
271–4278; (b) Sahnoun, S.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.
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4