Synthesis of diverse libraries of carboxamides via chemoselective N-acylation of amines by carboxylic acids employing Br?nsted acidic IL [BMIM(SO3H)][OTf]

Article abstract of DOI:10.1016/j.tetlet.2019.151159

Chemoselective N-acylation of amines with carboxylic acids as acyl electrophiles and Br?nsted acidic IL [BMIM(SO₃H)][OTf] as promoter is reported under both thermal and microwave irradiation to produce libraries of carboxamides in good to excellent yields after a simple workup. The protocol is compatible with structurally diverse 1° and 2° amines and works in the presence of sensitive functional groups such as thiols and phenols. The potential for recycling and reuse of the IL is also demonstrated.

Full text of DOI:10.1016/j.tetlet.2019.151159

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Synthesis of diverse libraries of carboxamides via chemoselective
N-acylation of amines by carboxylic acids employing Brønsted acidic
IL [BMIM(SO3H)][OTf]
Hemantkumar M. Savanur a, Shruti S. Malunavar a, Pavankumar Prabhala a, Suraj M. Sutar a,
Rajesh G. Kalkhambkar a, , Kenneth K. Laali b,
⇑
⇑
a Department of Chemistry, Karnatak University’s Karnatak Science College, Dharwad, Karnataka 580001, India
b Department of Chemistry, University of North Florida, 1, UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemoselective N-acylation of amines with carboxylic acids as acyl electrophiles and Brønsted acidic IL
[BMIM(SO3H)][OTf] as promoter is reported under both thermal and microwave irradiation to produce
libraries of carboxamides in good to excellent yields after a simple workup. The protocol is compatible
with structurally diverse 1° and 2° amines and works in the presence of sensitive functional groups such
as thiols and phenols. The potential for recycling and reuse of the IL is also demonstrated.
Ó 2019 Elsevier Ltd. All rights reserved.
Received 4 July 2019
Revised 11 September 2019
Accepted 15 September 2019
Available online xxxx
Keywords:
[BMIM(SO3H)][OTf]
N-Acylation
Amines
Carboxylic acids
Microwave
Transformation of amines to carboxamides by N-acylation is
fundamental to both chemistry and biology, and the ability to per-
form this important step in a selective manner in the presence of
other functional groups such as thiols and phenols by using readily
available reagents and catalysts is highly desirable.
Continuing our interest in application of task-specific ILs as cat-
alysts in synthetic method development [10], we report here on
the efficacy of [BMIM(SO3H)][OTf] as a Brønsted-acidic IL to pre-
pare diverse libraries of carboxamides via chemoselective N-Acyla-
tion of aromatic, heterocyclic, alicyclic, and aliphatic amines using
readily available carboxylic acids as acyl electrophiles (Scheme1).
Initial optimization studies (Table 1) with parent aniline using
acetic acid and [BMIM(SO3H)][OTf] (Table 1) showed that high con-
versations are achievable provided sufficient volume of the IL is
employed. Similar conversions could be achieved under microwave
heating at lower temperatures and with shorter reaction times
(entries 6 and 7 versus 13 and 14).
These optimal conditions were then employed for a survey
study (Table 2) with diversely substituted anilines bearing activat-
ing and deactivating substituents (entries 1–17), as well as repre-
sentative examples of heterocyclic (entries 18–20), alicyclic
(entries 25–26), aliphatic (entries 28–29), and benzylic (entry 27)
There have been numerous literature reports on the use of acid
chlorides and anhydrides as acyl electrophiles under basic or acidic
conditions. Reactions are typically mediated by Lewis basic, Lewis
acidic, or Brønsted acidic additives, or by metal catalysts such as
copper sulfate, zinc oxide, and oxomolybdenum species, and in
some cases carried out without additives [1–6]. In comparison,
the readily available and easier to use carboxylic acids have less
frequently been used as acyl electrophiles due to their lower reac-
tivity. The N-acylation of anilines, especially those bearing elec-
tron-withdrawing substituents, is more challenging often
requiring thermal or microwave activation. N-Acyl-benzotriazoles
under neutral or in acid, and [N-acyl-DBN] [BPh4] salts have been
employed in several studies as alternatives to acyl halides for
selective N-acylation of aromatic amines [7–9]. However, these
N-acyl transfer reagents are not widely available and some have
limited stability.
amines, as well as N-methylaniline (entry 24), and o-phenylenedi-
amine (entry 23). Entries 21 and 22 provide test examples to
demonstrate chemoselectivity in the presence of OH and SH groups
(entries 21–22). Microwave-assisted reactions were superior since
similar conversions were reached at significantly lower tempera-
tures and shorter reaction times.
⇑
Corresponding authors.
E-mail address: Kenneth.Laali@UNF.edu (K.K. Laali).
https://doi.org/10.1016/j.tetlet.2019.151159
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: H. M. Savanur, S. S. Malunavar, P. Prabhala et al., Synthesis of diverse libraries of carboxamides via chemoselective N-acylation of
amines by carboxylic acids employing Brønsted acidic IL [BMIM(SO3H)][OTf], Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151159

2
H.M. Savanur et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. [BMIM(SO3H)][OTf] catalyzed chemoselective N-acylation of amines.
Table 1
Table 3 presents a survey study employing structurally diverse
Optimization of the reaction conditions.
carboxylic acids for selective N-acylation under mild heating to
prepare libraries of aromatic, alicyclic, and aliphatic carboxamides
in acceptable isolated yields (entries 30–42).
Given the quantities of the [BMIM(SO3H)][OTf] needed to
achieve high conversions, a recycling/reuse procedure was devel-
oped (see supplementary information for the recovery procedure
and Fig. S1 for its efficiency in separate attempts), and the efficacy
of the method was demonstrated in chemoselective N-acylation
using HOAc under thermal condition, by repeating entries 1, 2, 7
and 8 out of Table 2, employing recovered IL for up to three cycles.
The outcomes summarized in Table S1 and Fig. S2 (supplementary
information) show a gradual (but not dramatic) decrease in the
conversions.
In conclusion, we have found an atom economical approach for
N-acylation of structurally diverse amines with carboxylic acids, by
using [BMIM(SO3H)][OTf] as promoter under conventional or
microwave heating, that provides a practical alternative to the
existing N-acylation methods. The ability to use readily available
and easier to use carboxylic acids as acyl electrophiles, coupled
to the potential for the recovery and reuse of the Brønsted-acidic
IL while still achieving acceptable yields, are notable attributes of
the present method.
Entry
Catalyst load (mol %)
Temp
0C
Time
(h/min)
Yielda
%
1
2
3
4
5
6
7
8
5
25
50
50
80
24 h
18 h
24 h
18 h
8 h
3 h
5 h
5 h
15 min
12 min
10 min
8 min
8 min
5 min
8 min
10 min
–
10
10
20
30
45
50
60
15
20
30
40
45
50
50
65
NI
NI
54
61
91
90
90
62
71
81
90
93
79
92
92
90
103
105
78
9
50b
60b
58b
60b
60b
65b
65b
72b
10
11
12
13
14
15
16
NI – Not Isolated, NR – No Reaction.
a
Isolated yield of pure product.
Reaction was carried under microwave irradiation.
b
Table 2
Chemoselective N-acylation of structurally diverse amines with acetic acid as acyl electrophile.
Entry
1
Substrate
Product
Microwave (MW)
Thermal (
Hours
3
D)
Minutes
8
Yielda
94
%
Yielda
90
%
NH2
H
N
O
2
8
92
4
88
NH2
H
N
O
Please cite this article as: H. M. Savanur, S. S. Malunavar, P. Prabhala et al., Synthesis of diverse libraries of carboxamides via chemoselective N-acylation of
amines by carboxylic acids employing Brønsted acidic IL [BMIM(SO3H)][OTf], Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151159

H.M. Savanur et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2 (continued)
Entry
Substrate
Product
Microwave (MW)
Thermal (
Hours
3.5
D)
Minutes
10
Yielda
92
%
Yielda
86
%
3
NH2
H
N
O
O
O
4
5
6
10
10
10
88
86
78
4
4
5
85
86
77
NH2
H
N
Cl
F
O
Cl
NH2
H
N
O
F
H
N
O
O2N
7
8
9
10
10
9
80
90
82
5
90
89
85
NH2
H
N
O
6
O
Cl
Br
F
NH2
H
O
Cl
N
O
5.5
NH2
NH2
H
N
O
10
11
12
13
–
–
4
6
5
6
82
79
86
89
H
N
Br
F
O
10
10
10
83
80
75
NH2
H
N
O
H
N
NH2
O
O
Cl
F
O
Cl
F
H
N
NH2
O
O
O
14
15
16
17
10
–
86
–
5
87
84
83
91
H
N
NH2
NH2
5
H
N
–
–
3.5
7
Br
Br
H
N
NH2
NH2
O
O
10
88
H
N
18
–
–
7
85
N
NH2
H
N
N
O
(continued on next page)
Please cite this article as: H. M. Savanur, S. S. Malunavar, P. Prabhala et al., Synthesis of diverse libraries of carboxamides via chemoselective N-acylation of
amines by carboxylic acids employing Brønsted acidic IL [BMIM(SO3H)][OTf], Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151159

4
H.M. Savanur et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 2 (continued)
Entry
Substrate
Product
Microwave (MW)
Thermal (
Hours
5
D)
Minutes
10
Yielda
80
%
Yielda
90
%
19
20
21
NH2
H
N
S
S
O
10
6
75
78
5
6
80
78
NH2
H
N
N
N
O
OH
OH
SH
H
NH2
N
O
22
5
80
5
80
SH
H
N
NH2
O
23
24
–
–
7
7
85
90
NH2
NH2
NHCOCH3
NHCOCH3
10
86
H
N
N
O
25
26
27
8
9
–
88
86
–
7
6
6
91
81
88
NH
N
N
O
O
NH
O
O
O
NH2
N
H
28
29
8
–
88
–
7
7
90
90
NH2
H
N
O
H
NH2
N
O
a
Isolated yield of pure product.
Table 3
Chemoselective synthesis of N-aryl-carboxamides using structurally diverse carboxylic acids.
NH2
R
O
O
Aliphatic,
Alicyclic,
Aromatic
[BMIM(SO3H)]OTf
96-100 0C
Aliphatic,
Alicyclic,
Aromatic
OH
NH
R
Entry
30
RCOOH
Product
Time
h
Yielda
%
3
77
O
O
OH
O
N
H
31
5
79
O
OH
N
H
Please cite this article as: H. M. Savanur, S. S. Malunavar, P. Prabhala et al., Synthesis of diverse libraries of carboxamides via chemoselective N-acylation of
amines by carboxylic acids employing Brønsted acidic IL [BMIM(SO3H)][OTf], Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151159

H.M. Savanur et al. / Tetrahedron Letters xxx (xxxx) xxx
5
Table 3 (continued)
Entry
RCOOH
Product
Time
h
Yielda
%
32
33
6
52
O
O
OH
N
H
5
62
O
O
OH
N
H
34
2
63
O
O
F
F
F
N
OH
F
H
F
F
35
36
7
8
42
67
O
O
OH
N
H
O
O
OH
OH
N
H
37
38
8
9
71
54
O
O
N
H
O
O
OH
N
H
39
1
79
O
O
OH
N
H
Entry
40
RCOOH
Product
Time
h
Yielda
%
2
72
O
O
N
H
OH
Cl
Cl
41
42
24
21
NI
NI
O
O
O
N
OH
H
O
OH
N
H
NI: not isolated.
a
Isolated yield of pure product
Acknowledgements
Appendix A. Supplementary data
The authors thank the University Sophisticated Instrument Cen-
ter, KUD for IR, GC, and GC-MS, They also thank NMR Research
Center, Indian Institute of Science, Bangalore for 1H NMR and 13C
NMR. Financial assistance through Project No. VGST-RGS/F-GRD-
742/2017-18/2018-19 by Vision Group on Science and Technology,
Govt. of Karnataka, Bangalore is gratefully acknowledged. K. K. L.
thanks University of North Florida for the Outstanding Faculty
Scholarship and Presidential Professorship awards, Faculty scholar-
ship and UNF Foundation Board grants, and the Dean’s Leadership
Council award.
Supplementary data (experimental procedures, analytical and
spectral data) to this article can be found online at https://doi.
org/10.1016/j.tetlet.2019.151159.
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Please cite this article as: H. M. Savanur, S. S. Malunavar, P. Prabhala et al., Synthesis of diverse libraries of carboxamides via chemoselective N-acylation of
amines by carboxylic acids employing Brønsted acidic IL [BMIM(SO3H)][OTf], Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151159