Clean synthesis of primary to tertiary carboxamides by CsOH-catalyzed aminolysis of nitriles in water

Article abstract of DOI:10.1039/c6gc01565d

Using CsOH as the only catalyst and utilizing its "cesium effect", a clean synthesis of a wide range of primary, secondary, and tertiary carboxamides was achieved by aminolysis reactions of nitriles with ammonia, primary, or secondary amines in water. Studies on the control reactions revealed that the reactions with ammonia most probably proceed via an aminolysis path by the initial addition of ammonia to Cs-activated nitriles to form unsubstituted amidine intermediates, while the reactions with primary or secondary amines may proceed via a hydration/transamidation path by the initial hydration of the Cs-activated nitriles to form primary carboxamide intermediates followed by their transamidation with amines through the formation of substituted amidine intermediates.

Full text of DOI:10.1039/c6gc01565d

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Clean Synthesis of Primary to Tertiary Carboxamides by CsOH-
Catalyzed Aminolysis of Nitriles in Water†
a
a
a
a
a,b
Yang Li,‡ Haonan Chen,‡ Jianping Liu, * Xujun Wan, and Qing Xu *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A) Nitrile hydration: limited to primary carboxamides
Using CsOH as the only catalyst and utilizing its “cesium effect”, a
clean synthesis of a wide range of primary, secondary, and tertiary
carboxamides was achieved by aminolysis reactions of nitriles
with ammonia, primary, or secondary amines in water. Studies of
the control reactions revealed that the reactions with ammonia
most probably proceeds via an aminolysis path by initial addition
of ammonia to Cs-activated nitriles to form unsubstituted amidine
intermediates; while the reactions with primary or secondary
amines may proceed via hydration/transamidation path by initial
hydration of the Cs-activated nitriles to form primary carboxamide
intermdiates followed by its transamidation with amines through
the formation of substituted amidine intermdiates.
Method a: cat. TM
O
Method b: TMꢀfree methods
R
N + H O
2
Method c: NHase enzyme
Method d: cat. CsOH/DMSO
R
NH
2
B) TMꢀcatalyzed nitrile aminolysis
R2
O
cat. TM
R2
R1
N
H
R1
+
3N
N
R3
R
C) Addition of magnesium amides to aryl nitriles
NMgBr
O
R
2
NH/EtMgBr
HCl
Ar
N
Ar
NR
2
Ar
NR
2
D) This work: TM-free CsOH-catalyzed nitrile aminolysis
(suitable for preparation from primary to tertiary carboxamides)
Carboxamide structures are significant functional groups in
organic chemistry, biochemistry, natural products, and
NH
or
3
O
O
O
cat. CsOH only, H
2
O
R1
N +
R2
R2
1
materials. They are also versatile synthons in organic and
R2
R1
no additive
R1
R1
NH
2
N
N
R3
3N H no organic solvent
H
1
,2
pharmaceutical synthesis.
In addition to conventional
R
R1 = aryl, heteroaryl, alkyl, cycloalkyl, vinyl
, R = H, benzyl, alkyl, cycloalkyl
condensation reactions of carboxylic acid derivatives with
1
amines under harsh conditions or using activating reagents,
,2
R
2
3
Scheme 1. General Methods for Carboxamide Synthesis from
various greener new strategies such as dehydrogenative or
oxidative alcohol-amine and aldehyde-amine coupling
reactions, amine dehydrogenation or oxidation reactions,
Nitriles.
5
h
transamidation reactions, and C-N coupling reactions have also water (Scheme 1A, method d), which, we found out, utilizes
2
8
the “cesium effect” to activate the nitrile and effect an
been developed for carboxamide synthesis in recent years.
Even though, the nitrile hydration reaction is still an attractive efficient hydration process as well as the in situ generated
9
alternative for carboxamide synthesis (Scheme 1A) due to the dimethylsulfinyl anion to avoid over hydrolysis of the nitriles.
3
-6
effectiveness, atom efficiency, straightforwardness, and However, a limitation of the nitrile hydration methods is that
3
sustainable features of the method. Hence various methods they are confined to primary carboxamides only, but not
3
,4
mainly the transition metal (TM) catalysis,
3
TM-free suitable for substituted secondary and tertiary carboxamides.
methods including the text book methodology using H O as One solution to this limitation may be the aminolysis of nitriles
,5
2
2
5
a-d
6
the reagent, and enzymatic methods have been developed with amines. However, although nitrile aminolysis is
in recent years. Our group has focused on amine and amide theoretically a promising method for substituted carboxamide
derivatives in the past few years. We also described a synthesis, it received little attention in the past. To our
7
10
CsOH/DMSO-catalyzed selective nitrile hydration reaction in
2
knowledge, H S was once used as the catalyst by De Benneville
1
1
and co-workers 60 years ago, but clearly this method has
severe drawbacks. Only in recent years, a few transition metal
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
Zhejiang 325035, P. R. China. E-mail: qing-xu@wzu.edu.cn; Fax: (+)-86-577-
(
TM)-catalyzed methods using Pt, Ru, Zn, Cu, Ce, Fe, or Co
12
catalysts were reported (Scheme 1B), but some methods still
require harsh reaction conditions and/or complex catalytic
systems. TM-free methods, which should be promising
8
6689302; Tel: (+)-86-138-57745327
School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou,
b
Jiangsu 225002, China
Electronic Supplementary Information (ESI) available: Experimental details,
†
1
product characterization, details of the control experiments, and copies of H NMR, alternatives because the TM residue and contamination in the
13
C NMR and HRMS spectra of the products. See DOI: 10.1039/x0xx00000x
These two authors contributed equally to this work.
final carboxamides can be avoided by not using the TM
‡
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catalysts, were even rare in the literature. Only the aromatic nitriles (runs 2-12), except 3-nitrobenzonitrile (run
Bhattacharya group in 2006 employed magnesium amides, 11)
prepared in situ by deprotonation of amines by Table 1. Condition Screening and Optimization for Nitrile Aminolysis
a
with Ammonia.
ethylmagnesium bromide, to react with nitriles to obtain the
1
3
substituted carboxamides (Scheme 1C), and this method is
limited to aryl nitriles and requires the reactive Grignard
reagents for the pre-preparation of the magnesium amides
from amines and the anhydrous conditions. Therefore, there is
still a great need in the field to develop more sustainable and
efficient methods for clean synthesis of the primary to tertiary
carboxamides from nitriles and amines. Herein we report that,
O
CN
NH
3
—H
2
O
cat.
NH
2
+
or
H O
2
under air, T, t
1
a
2a
b
c
run
1
cat. (mol%)
CsOH (10)
CsOH (10)
CsOH (10)
CsOH (10)
KOH (10)
reactant
H O
T, t
2a%
o
d
100 C, 24 h
61
2
by using CsOH as the only catalyst and utilizing again the
8
cesium effect” to activate the nitriles via coordination, a
o
e
2
H
O
100 C, 2 h
57
2
“
o
f
3
H O
100 C, 1 h
48
clean synthesis of primary, secondary, and tertiary
carboxamides can be achieved by aminolysis of nitriles with
ammonia, primary, or secondary amines in water (Scheme 1D).
As shown in Table 1, hydration of benzonitrile (1a) in
water catalyzed by 10 mol% CsOH was initially tested under
2
o
4
NH ·H O
100 C, 1 h
>99 (94)
3
2
o
5
NH ·H O
100 C, 2 h
64
80
60
81
0
3
2
o
6
NaOH (10)
NH ·H O
100 C, 2 h
3
2
o
5
h
7
t-BuOK (10)
t-BuONa (10)
Cs CO (10)
NH
3
·H
2
O
100 C, 2 h
air. Incomplete conversion of 1a and inevitable over
o
hydrolysis to benzoic acid PhCOOH led to only a moderate
o
yield of the target benzamide (2a) at 100 C (run 1). Shortening
8
NH ·H O
100 C, 2 h
3
3
2
o
9
NH
NH
NH
NH
NH
·H
·H
·H
·H
·H
2
O
O
O
O
O
100 C, 5 h
2
3
the reaction time to 2 h or even 1 h to avoid the over
hydrolysis gave no enhancement but only led to slight
decrease of the product yield (runs 2-3). Even within the short
reaction times such as 1-2 h (runs 2-3), over hydrolysis of PhCN
to PhCOOH is still inevitable. The similar yields in prolonged
reaction times from 2 to 24 h (runs 1-2) also suggested that
o
1
0
1
CsF (10)
--
3
3
3
3
2
2
2
2
100 C, 5 h
0
o
1
100 C, 24 h
0
o
12
CsOH (10)
CsOH (5)
80 C, 6 h
96
80
o
13
100 C, 24 h
a
The mixture of 1a (1.0 mmol) and catalyst in aqueous ammonia (25 wt%
progress of the nitrile hydration reaction was most probably NH in water) or distilled water (0.5 mL) was directly sealed under air in a
3
b
2
terminated by disappearance of CsOH due to its neutralization Schlenk tube and then heated and monitored by GC-MS/TLC. CsOH·H O
c
was used and abbreviated. GC yields (isolated yield in parenthesis) based
by PhCOOC generated by over hydrolysis of 1a. In contrast,
when aqueous ammonia (25 wt% NH in water) was used
d
e
on 1a. 28% PhCN and 11% PhCOOH were detected. 33% PhCN and 10%
3
f
PhCOOH were detected. 44% PhCN and 8% PhCOOH were detected.
instead of water, complete conversion of 1a without
observation of over hydrolysis was achieved. The reaction was
so fast that the time could be shortened to 1 h only but still
give a high 94% isolated yield of 2a (run 4). The results
obtained from water and from aqueous ammonia (runs 3-4)
clearly suggested that addition of ammonia to nitrile as well as
the whole nitrile aminolysis process is far more efficient than
which is as reactive as 1a (run 1), are found generally less
reactive than 1a (run 1). Thus the reactions usually required
longer time than 1 h to complete, giving the target
carboxamides in moderate to high yields. In addition to those
with inert substituents (runs 1-3,12), the reactive amino,
hydroxy, fluoro, chloro, bromo, and nitro groups could also be
tolerated under the basic conditions to afford the target
carboxamides (runs 4-11), which may be transformed further
into other useful chemicals by utilizing these reactive groups.
1
4
the hydration reaction under the same conditions. Other
inorganic bases and cesium salts were also screened (runs 5-
10). The normal bases such as NaOH, KOH, t-BuONa, and t-
BuOK showed moderate to good catalytic activity in the
reaction (runs 5-8). Unlike CsOH, weak basic cesium salts
4
-Hydrobenzonitrile required 120 mol% of CsOH (run 5), most
possibly because the acidic hydroxyl moiety consumed 1 equiv.
of CsOH to form the corresponding phenoxide during the
reaction. Most heteroaryl nitriles are similarly reactive as 1a
under the standard conditions (runs 13-18), giving good to
high yields of the products in 1 h. In addition to aryl and
heteroaryl nitriles, the less reactive aliphatic alkyl and vinyl
nitriles are also good substrates for the CsOH-catalyzed
aminolysis (runs 19-20). Thus, acetonitrile and cyclopropyl
nitrile gave the target carboxamides in 60-80 yields of the
products under the standard conditions (runs 19-20). Benzylic
and longer-chain alkyl and vinyl nitriles are less reactive. The
reactions required a higher loading of the catalyst and a higher
temperature to give moderate to good yields of the products
2 3
Cs CO and CsF was not effective at all (runs 9-10). Similarly,
without the addition of any alkali base, no reaction occurred at
all in aqueous ammonia even after heating the mixture for 24
h (run 11). The above results that CsOH is far more active than
other base catalysts also revealed cesium’s exceptional effect
in the nitrile aminolysis reaction, most possibly by activating
5
h,15
the nitrile through coordination.
Further attempts to
optimize the reaction conditions by reducing the reaction
temperature or catalyst loading only led to incomplete
conversion of 1a and lower yields of 2a (runs 12-13).
With the optimal reaction conditions in hand, we then
applied it to other nitriles to test the scope of the method. As
shown in Table 2, substituted electron-rich and -deficient
(runs 21-24).
2
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the amine loading (run 8) or using DMSO as the additive (runs
-10) gave no better results.
9
Table 2. Substrate Extension for CsOH-Catalyzed Nitrile Table 3. Condition Screening and Optimization for CsOH-Catalyzed
a
a
Nitrile Aminolysis with Benzyl Amine.
Aminolysis with Ammonia.
O
CsOH (10 mol%)
under air, 100 oC, t
R
CN + NH
3
—H
2
O
O
R
NH2
CN
1
2
NH
2
CsOH (10 mol%)
solvent, N , T, t
N
+
H
2
1a
3a
4aa
O
(3)
O
O
(1)
(2)
(4)
O
Me
run
solvent (mL)
T, t
1a conversion
NH
2
NH2
NH
2
Ph
NH
2
b
(
4aa% yield)
Me
NH
2
2
a: 1 h, 94%
2
b: 6 h, 80%
2c: 6 h, 89%
2d: 4 h, 71%
o
1
2
3
NH
NH
NH
NH
-
3
3
3
3
·H
·H
·H
·H
2
O (0.5)
2
O (0.5)
2
O (0.5)
2
O (0.5)
100 C, 24 h
0
(
5)
(6)
(8)
Cl
O
O
(7)
O
O
o
130 C, 24 h
18
NH
2
NH
2
NH
2
NH2
o
HO
F
Cl
160 C, 48 h
77
2g: 12 h, 70%c
2
e: 24 h, 50%b
2f: 2 h, 85%
2h: 3 h, 75%
c
4
o
160 C, 48 h
0
(
9)
O
(10)
(11)
O
(12)
O
o
O
5
6
7
160 C, 48 h
42
NH
2
NH
NH2
2
NH
2
o
2
H O (0.25)
160 C, 48 h
72
Cl
Br
O N
2
2
i: 3 h, 75%
2j: 6 h, 66%
2k: 1 h, 75%
o
2
l: 6 h, 75%
H
2
O (0.5)
160 C, 48 h
98 (68)
98
(
13)
O
d
8
o
O
(14)
(
15)
O
(16)
Cl
O
H
2
O (0.5)
160 C, 48 h
N
NH
2
N
NH
2
o
NH
2
NH
2
9
2
H O (0.5)/DMSO (1.0 equiv.)
160 C, 24 h
6
N
N
o
2
m: 1 h, 79%
2n: 1 h, 74%
2p: 1 h, 89%
10
H
2
O (2.0 equiv.)/DMSO (0.5) 160 C, 24 h
trace
2
o: 1 h, 73%
a
(
17)
O
Unless otherwise noted, the mixture of 1a (1.0 mmol), 3a (1.2 mmol, 1.2
equiv.), and CsOH·H O (10 mol%) in the solvent was sealed in a Schlenk tube
under N
isolated yield in parenthesis) based on 1a. Without CsOH·H
of 3a.
(
18)
O
(19)
(20)
(24)
O
O
2
N
NH
2
b
NH
2
NH2
and then heated and monitored by GC-MS/TLC. GC yields
N
H
3
C
NH
2s: 12 h, 60%
23)
2
2
S
c
d
(
2
O. 2.0 equiv.
2q: 1 h, 75%
2t: 3 h, 80%
2
r: 3 h, 77%
(
21)
(22)
Cl
(
O
O
O
O
NH
2
NH
2
NH
2
The optimized conditions (Table 3, run 7) were then
employed for substituted carboxamide synthesis. As shown in
Table 4, benzylamine (3a) could react with electron-rich and –
deficient aryl and heteroaryl nitriles (runs 1-8) including those
with reactive halo groups (runs 4,5,7), and the less reactive
aliphatic nitriles (runs 9-12) to give moderate to good yields of
the target secondary carboxamides under the standard
conditions. Similarly, substituted electron-rich and –deficient
NH
2v: 24 h, 55%d
2
2x: 24 h, 68%d
u: 24 h, 70%d
2w: 24 h, 50%d
2
a
Unless otherwise noted, the mixture of 1 (1.0 mmol) and CsOH·H
mol%) in aqueous ammonia (25 wt% NH in water, 0.5 mL) was directly
sealed under air in a Schlenk tube and then heated and monitored by GC-
2
O (10
3
b
c
2
MS/TLC. Isolated yields based on 1. 120 mol% CsOH·H O. 20 mol%
d
o
2 2
CsOH·H O. 20 mol% CsOH·H O, 160 C.
The same catalytic method was then applied to aminolysis benzylic amines (runs 13-17) including those with reactive halo
of nitriles with primary and secondary amines for substituted groups (runs 15-17) and sterically more bulky ones with ortho-
carboxamide synthesis (Table 3). When the model reaction of substituents (runs 14, 17), and primary aliphatic amines (runs
benzonitrile (1a) and benzylamine (3a) was initially tested 18-24) including the sterically more bulky ones with secondary
under the same conditions as the preceding aminolysis alkyl groups (runs 19, 22, 24) all reacted smoothly with
reactions under air, considerable amounts of imine byproduct benzonitrile (1a) to give the target carboxamides in generally
was detected, which was most possibly generated by aerobic moderate to good yields. The amines with the amino group
amine oxidation by air at heating. To avoid the formation directly connected to secondary alkyl groups gave much lower
byproduct imines, the reactions were then performed under yields of the products mostly due to the steric hindrance from
an atmosphere of pure nitrogen. As shown in Table 3, initially the substrates themselves (runs 22, 24). In the reaction of an
o
no target 4aa was detected at 100 C under nitrogen (run 1). aminoalcohol (run 23), the carboxamide product 4al was
Enhancing the reaction temperature worked to give improved obtained as the single product without detecting the
yields of 4aa (runs 2-3). No reaction occurred without CsOH corresponding ester product. This revealed again that, under
(
run 4). A low yield of 4aa could also be detected in a neat the present reaction conditions, amines including the
reaction of 1a and 3a (run 5), suggesting that aqueous ammonia are more nucleophilic and tend to react with nitriles
ammonia is not essential for the reaction. Water was then more easily than the O-nucleophiles such as the water (Table 1)
used as the solvent, giving an improved yield of the product and alcohol (Table 4, run 23). In addition to primary amines,
(
run 6). It was then found in 0.5 mL water full conversion of cyclic secondary amines such as pyrrolidine and morpholine
the reaction can be achieved to give the best result (run 7). could also react with nitriles to give the target carboxamides
Further attempts to improve the product yield by enhancing under the standard conditions, although in some cases the
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12
product yields were not satisfactory (runs 25-30). Moreover, known nitrile aminolysis methods, and most reactions were
1
2
although we tried many times, the reactions of acylic reported to proceed via the aminolysis path (path a). In
secondary amines or anilines with nitriles were not successful present CsOH-catalyzed reactions, as shown in condition
under the standard conditions at present, most possibly due to screening section of the nitrile aminolysis reaction, the
the steric repulsion generated during the addition of the reaction with ammonia (Table 1, run 4) was found faster and
secondary amino moiety to the nitrile and the less nucleophilic more efficient than the reactions with water (Table 1, runs 1-3),
nature of the anilines than the alkyl amines.
with the latter one being inevitably accompanied by over
hydrolysis of the nitrile to give acid byproducts. The high yield
Table 4. Substrate Extension for CsOH-Catalyzed Nitrile Aminolysis of target 2a and no detection of acid byproduct in the
a
with Primary or Secondary Amines.
aminolysis reaction (Table 1, run 4) suggested that nitrile over
hydrolysis can be successfully inhibited by addition of
ammonia. Besides, the control reaction of PhCOOH and
ammonia under the same conditions giving no target 2a (eq. 1)
also suggested that over hydrolysis path (path c) can be
excluded in the present reaction. Moreover, since amines are
usually more nucleophilic than O-nucleophiles such as the
water under the same conditions and the aminolysis reaction
was found faster and more efficient (Table 1, run 4), nitriles
may first react selectively with ammonia to effectively afford
O
R2
R3NH
R2
R1 CN
CsOH (10 mol%)
O, N
, 160 oC, 2 d
+
R1
N
H
2
2
R3
1
3
4
(
1)
Ph
O
(2)
O
(3)
O
(4)
Cl
O
Me
N
Ph
N
Ph
N
Ph
Ph
N
Ph
H
H
H
H
Me
(6)
4
aa: 68%
4ba: 65%
4ca: 70%
4ha: 70%
(
8)
O
(5)
O
O
(7)
O
Cl
N
H
Ph
N
N
Ph
N
H
Ph
target carboxiamdes
2 via the formation of an unsubstituted
H
S
H
N
N
2
5 (path a, R = R = H), rendering the
3
Br
9)
amidine intermediate
4
ja: 65%
4oa: 83%
4pa: 60%
ra: 70%b
4
(
O
(10)
(12)
hydration path (path b) not the dominant one in the reaction.
Eventhough, path b cannot be excluded completely at present
since moderate yields of 2a could also be obtained under the
O
(11)
Ph
O
O
H
3
C
N
Ph
N
H
Ph
N
Ph
4ua: 45%
(15)
N
H
Ph
H
H
sa: 75%c
4wa: 60%
4
4ta: 70%
1
5
hydration conditions.
(13)
(16)
Ph
O
O
(14)
O
Me
O
Cl
N
H
O
Ph
N
Ph
O
N
Ph
N
H
H
H
2
H O
R2
R1
cat. CsOH
NH
NH
3
N
R1
2,4
Me
(18)
F
R2
N
R3
path a
, R = H)
4
ab: 69%
4ac: 70%
b
4ad: 70%
(20)
4ae: 72%
1
R
2
3
R1
N
(R
2
3
3N
H
(17)
O
Cl
(19)
Ph
Cs
R
5
R
3
O
O
NH
3
Ph
N
H
Ph
N
N
Ph
N
R
C
N: Cs
cat. CsOH
H
H
H
2
H O
R3
2
7
R
4
ai: 70%
(24)
Ph
O
R2
4
af: 65%
4ag: 74%
4ah: 68%
(23)
H
2
O
3N
H
3
N
path b
cat. CsOH
R
(
21)
Ph
O
(22)
O
O
R1
(R2 and/or R ≠ H)
3
O
NH
2
ꢀ
H
2
O
R1
2
NH
2
Ph
OH
transamidation
N
Ph
N
Ph
Ph
N
N
6
H
H
H
H
cat. CsOH, H O
2
b
4al: 75%b
4am: 39%b
4
aj: 51%b
4ak: 35%
cat. CsOH
R2
over hydrolysis
O
(25)
O
N
(26)
(27)
O
N
(28)
O
O
O
R3N
H
3
R2
R1
2,4
N
R3
Ph
Ph
N
N
R1
path c
OH
ꢀ
H O
2
O
N
O
O
Cl
condensation
4
an: 65%
4ao: 37%
4io: 28%
4mo: 64%
(29)
O
(30)
O
Scheme 2. Potential reaction paths for CsOHꢀcatalyzed nitrile
N
N
N
N
O
aminolysis with ammonia or amines in water.
N
O
4oo: 65%
4qo: 40%
a
O
CsOH (10 mol%)
Unless otherwise noted, the mixture of 1 (1.0 mmol), 3 (1.2 mmol, 1.2
equiv.), CsOH·H O (10 mol%) in distilled water (0.5 mL) was stirred under
nitrogen and then monitored by GC-MS/TLC. Isolated yields based on 1. 1.5
PhCOOH
+
3 2
NH —H O
under air, 100 oC, 1 h
Ph
NH2
(1)
2
2a
b
not detected by both TLC and GC
c
3
equiv. of 3. 4.0 equiv. of CH CN; yield based on 3a.
O
O
CsOH (10 mol%)
O (0.5 mL)
Ph CN+ Ph
NH
2+Ph
NH
N
H
4aa
Ph+PhCOOH (2)
GC
2
As to the possible reaction paths of the present nitrile
aminolysis reactions, there are generally three potential paths
H
2
Ph
3a
1a
, 160 o
N
2
C
2a
1
) 1 h, 1a/2a/4aa/PhCOOH = 4/86/0/10
that may afford the final carboxamide products
2
and
4
) 6 h, 1a/2a/4aa/PhCOOH = 3/89/5/3GC
2
(Scheme 2), i.e., the aminolysis path involving formation of
amidine intermdiates
5 by direct addition of amines to nitriles
The circumstances in aminolysis reactions with primary or
secondary amines may be different, as the reactions require
longer time and a higher temperature. The reaction of 1a and
(path a), the hydration/transamidation path involving
formation of primary carboxamides
formation of amidine intermdiates
2
6
by nitrile hydration and
(path b), and the over
3a was then re-investigated in shorter reaction times to clarify
15
the reaction intermediates. As shown in eq. 2, the reaction
hydrolysis path involving condensation of the byproduct acids
with the amines (path c). Path a and b have been proposed in
initially (run 1, in 1 h) afforded primary amide 2a as the major
4
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product and a small amount of PhCOOH, without detection of In conclusion, we have developed a clean synthesis of the
target 4aa at this point. After heating for 6 h, a low yield of 4aa primary, secondary, and tertiary carboxamides by CsOH-
was then observed in the reaction (run 2). These results catalyzed aminolysis reactions of nitriles with ammonia,
suggested that the hydration path may be the dominant one in primary, or secondary amines in water. This new method
nitrile aminolysis reactions with primary and secondary requires no any organic solvents as the co-solvent or any
amines, followed by
a
transamidation reaction of additives and can be applied to a wide scope of substrates
intermediates 2 with amines (vide infra). Indeed, the such as aryl, alkyl, and vinyl nitriles, and ammonia, primary
transamidation reaction of 2a and 3a under the standard benzylic, alkyl, and cycloalkyl amines, and cyclic secondary
conditions readily afforded 61% isolated yield of 4aa (eq. 3), amines, being a practical and useful method for primary to
supporting the transamidation step as well as path b.
O
tertiary carboxamide synthesis. Most possibly due to the
“cesium effect” to activate the nitriles via Cs-nitrile
coordination, CsOH is a more active catalyst for the reaction
than other base catalysts. Control reactions revealed that the
aminolysis reactions of nitriles with ammonia most probably
proceeds via the aminolysis path by initial addition of
ammonia to Cs-activated nitriles to form unsubstituted
amidine intermediates. However, different to the known nitrile
aminolysis reactions that mostly supporting the aminolysis
O
CsOH (10 mol%)
+
Ph
NH2
Ph
N
H
4aa
Ph
(3)
Ph
NH
2
H
2
O (0.5 mL)
3
a
2
a
, 160 oC, 48 h
N
2
61% isolated yield
O
CsOH (10 mol%)
PhCOOH
+
Ph
NH2
Ph
N
H
Ph
(4)
H
2
O (0.5 mL)
, 160 oC, 48 h
2
3
a
N
4
aa
not detected by TLC
trace detected by GC
12
path, the reactions of nitriles with primary and secondary
amines
are more
likely
to
proceed
via the
hydration/transamidation path by an initial nitrile hydration to
primary carboxamide intermediates followed by a subsequent
transamidation with amines to give the final products. Further
applications of these CsOH-catalyzed hydration and aminolysis
reactions are underway.
To verify the possibility of path c, a control reaction of
PhCOOH and 3a was also investigated under the standard
conditions, but only trace 4aa could be detected (eq. 4). This
suggested that, just like the condensation of the acid with
ammonia (eq. 1), the same reaction of the acid byproducts
with amines is also not an efficient process in the present
reactions. Hence, the over hydrolysis/condensation path (path
c) is unlikely to proceed in nitrile aminolysis reactions with
both ammonia and primary/secondary amines eventhough
acid byproducts may be generated.
Acknowledgment
We thank Natural Science Foundation of Zhejiang Province for
Distinguished
Postgraduate Innovation Foundation of Wenzhou University
3162015040) for financial support.
Young
Scholars
(LR14B020002)
and
Based on above results, the literature on nitrile aminolysis
1
2
reactions,
and our previous findings in CsOH/DMSO-
5
(
h
catalyzed nitrile hydration reactions, the possible reaction
paths for the present CsOH-catalyzed nitrile aminolysis
reactions are outlined in Scheme 2. Thus, the reaction may Notes and references
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1
(a) The Chemistry of Amides, (ed.: J. Zabicky), Wiley-
8
5h,16
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intermdiates
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| J. Name., 2012, 00, 1-3
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Table of Contents
Clean Synthesis of Primary to Tertiary Carboxamides by CsOH-Catalyzed Aminolysis of Nitriles in Water
Yang Li, Haonan Chen, Jianping Liu,* Xujun Wan, and Qing Xu*
NH3
or
R2
R3N H
O
O
O
cat. CsOH only, H O
2
R2
R2
R1
R1
N +
R1
N
R1
NH
no additive
no organic solvent
2
N
R3
H
54 examples
up to 94% isolated yield
1
R = aryl, heteroaryl, alkyl, cycloalkyl, vinyl
2
3
R , R = H, benzyl, alkyl, cycloalkyl
Using CsOH as the only catalyst and utilizing its “cesium effect”, a clean synthesis of a wide range of primary,
secondary, and tertiary carboxamides was achieved by aminolysis reactions of nitriles with ammonia, primary, or
secondary amines in water. Studies of the control reactions revealed that the reactions with ammonia most
probably proceeds via an aminolysis path by initial addition of ammonia to Cs-activated nitriles to form
unsubstituted amidine intermediates; while the reactions with primary or secondary amines may proceed via
hydration/transamidation path by initial hydration of the Cs-activated nitriles to form primary carboxamide
intermdiates followed by its transamidation with amines through the formation of substituted amidine intermdiates.