Transition-metal-free synthesis of primary to tertiary carboxamides: A quick access to prodrug-pyrazinecarboxamide

Article abstract of DOI:10.1016/j.tetlet.2017.11.006

One-pot expedient and direct carbamoylation of heterocyclics is described. The transformation is realized via direct dehydrogenative aminocarbonylation of heterocyclic compounds under transition-metal-free conditions. This method is regioselective and the protocol is proved to be scalable on a gram scale. Further, the therapeutically useful antitubercular agent pyrazinecarboxamide is successfully synthesized by employing this protocol.

Full text of DOI:10.1016/j.tetlet.2017.11.006

Accepted Manuscript
Transition-Metal-Free Synthesis of Primary to Tertiary Carboxamides: A Quick
Access to Prodrug-Pyrazinecarboxamide
Trimbak B. Mete, Ankit Singh, Ramakrishna G. Bhat
PII:
S0040-4039(17)31400-4
https://doi.org/10.1016/j.tetlet.2017.11.006
TETL 49449
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 September 2017
2 November 2017
5 November 2017
Please cite this article as: Mete, T.B., Singh, A., Bhat, R.G., Transition-Metal-Free Synthesis of Primary to Tertiary
Carboxamides: A Quick Access to Prodrug-Pyrazinecarboxamide, Tetrahedron Letters (2017), doi: https://doi.org/
1
0.1016/j.tetlet.2017.11.006
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2
Graphical Abstract
Transition-Metal-Free Synthesis of Primary to Leave this area blank for abstract info.
Tertiary Carboxamides: A Quick Access to
Prodrug-Pyrazinecarboxamide
*
Trimbak B. Mete, Ankit Singh and Ramakrishna G. Bhat

1
Tetrahedron Letters
journal homepage: www.els evier.com
Transition-Metal-Free Synthesis of Primary to Tertiary Carboxamides: A Quick
Access to Prodrug-Pyrazinecarboxamide
a
Trimbak B. Mete , Ankit Singh and Ramakrishna G. Bhat *
a
a
a
Department of Chemistry, Indian Institute of Science Education & Research (IISER), Pune, 411008, Maharashtra, India. Fax: +91-(20)-25899790;Tel:+91-
0
20-25908092; E-mail: rgb@iiserpune.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
One-pot expedient and direct carbamolyation of heterocyclics is described. The transformation is
realized via direct dehydrogenative aminocarbonylation of heterocyclic compounds under
transition-metal-free conditions. This method is regioselective and the protocol is proved to be
scalable on a gram scale. Further, the therapeutically useful antitubercular agent
pyrazinecarboxamide is successfully synthesized by employing this protocol.
Received in revised form
Accepted
Available online
Keywords:
Transition-Metal-Free
Caboxamide
2009 Elsevier Ltd. All rights reserved.
Carbamolyation
Potassium persulfate
Heteroaromatic
Introduction
methods did not work on quinoline and other heteroaromatics.
Although aminocarbonylation via direct activation of N-protected
4
formamide is known yet the transition-metal-free
Carboxamide is a very important and useful functional group
and heterocyclic carboxamides are significant structural scaffolds
in many materials, natural products and bioactive compounds.
They are also useful synthetic building blocks for many
pharmaceuticals and agrochemicals. Along with traditional or
conventional condensation reactions of carboxylic
acids/carboxylic acid derivatives and amines under harsher basic
conditions or using coupling reagents, many alternative strategies
have been developed for the synthesis of carboxamides in the
recent years. Some of various strategies including cross-
dehydrogenative coupling, amine dehydrogenation or oxidation
reactions, transamidation reactions, aldehyde-amine coupling
reactions, and C-N coupling reactions have been developed for
carboxamide synthesis in recent years. Alternatively, transition
metal (Pd, Co, Ag, Ti) catalyzed protocols such as
aminocarbonylation of aromatic and heteroaromatic halides,
direct carbamolyation of pyridines, and hydration of nitriles have
been developed in pursuit of achieving newer methods.
However, these methods rely on transition metal salts and some
of these methods require the use of toxic and corrosive gases
such as carbon monoxide and ammonia or alternatively ammonia
equivalents such as aqueous ammonia, ammonium carbamate and
other amine bases. All these methods require the use of
carbamoylation of heteroaromatics via direct activation of
formamide and N, N-dimethylformamide has not been much
successful till date. Some of the examples of direct
aminocarbonylation suffer from lower yields and afford the
mixture of aminocarbonylated and domintating α-amidoalkylated
side products. Methods are also limited to fewer substrate scopes
1
2
(mostly with pyridines and formamide) with lower
chemoselectivity and moreover these have not been studied in a
great detail.
5
Practical and expedient transition-metal-free protocols are
gaining a great importance and are promising alternatives to the
6
2
traditional methods as the contamination due to the residual
transition metals can be avoided at lower costs. Thus it is more
desirable to develop sustainable transition-metal-free practical
protocol for the direct access of primary to tertiary carboxamides
of different heteroaromatics. We have shown considerable
3
7
interest in developing transition-metal-free protocols and our
ongoing research activities prompted us to evaluate the method
for the direct aminocarbonylation using formamide, N-
methylformamide and N, N-dimethylformamide by
8
functionalizing the C-H bond. Based on the earlier literature, it
is known that persulfate is an efficient oxidant and a very good
radical initiator and it could be explored for the homolytic
cleavage of formamide. Interestingly, persulfates are known to be
transition metals and most of them need pre-activated
aryl/heteroaryl halides. The limitation of some of these methods
is that they are confined to primary carboxamides only with
limited scope on pyridines and found to be not suitable for the
synthesis of secondary and tertiary carboxamides. Likewise,
9
mild and benign and eco-friendly low cost reagents.
As a part of our ongoing research programme on transition-
metal-free protocols, we herein, report the direct

2
aminocarbonylation of heteroaromatics via cross-
dehydrogenative coupling approach. This simple and user
friendly protocol for aminocarbonylation uses potassium
persulfate and formamide/N-methylformamide (NMF)/DMF as
reagents to access primary to tertiary carboxamides with high
selectivity.
substrates with secondary and tertiary formamides. Under the
standardized reaction conditions, substrates (1a-b, 1e-f) reacted
smoothly with the N-methyl formamide (NMF) 2b to afford the
corresponding secondary carboxamides (3ab, 3bb, 3eb, 3fb) in
very good yields (see Table 2).
a-d
Result and Discussion
Table 2. Synthesis of primary to tertiary heteroaryl caboxamides
We commenced our initial work with pyridine 1a and
formamide 2a as model substrates (Table 1). The initial reaction
of 1a and formamide 2a in presence of K S O (2 equiv.) in DCE
2 2 8
at room temperature (both in air and inert condition) did not work
even after prolonged reaction condition (entry 1, Table 1).
However, at 50 C trace amount of product 3aa formed (entry 2,
o
o
Table 1). While, heating the reaction mixture at 70 C afforded
modest yield of the desired product 3aa (entry 3, Table 1).
Interestingly, when formamide 2a was used as solvent as well as
substrate the reaction proceeded smoothly at elevated
o
temperature (70 C), to afford the desired product 3aa in 79%
isolated yield (Table 1, entry 6) in 12 h.
Table 1. Condition screening and Optimization of aminocarbonylation of
pyridine
O
H
H
K2S2O8
Solvent
+
H
N
H
N
N
H
N
70°C, 12h
O
1a
2a
3aa
Temp
°C)
Time
(h)
c
Entry Solvent
Yield (%)
(
d
1
2
3
4
5
6
7
8
9
1
DCE
DCE
DCE
rt
12
12
12
12
12
12
12
6
NR
50
70
rt
trace
40
b
Formamide
Formamide
NR
50
b
50
70
70
70
70
100
b
Formamide
79
H
2
O
30
THF
CH CN
Formamide
24
3
12
12
45
0
Decomposed
a
Reaction Conditions: Pyridine 1a (1 equiv.), Formamide (10 equiv.)
potassium persulfate (2 equiv.), solvent (2 mL) under aerial atmosphere for
a
Reaction Conditions: Pyridine 1a (1 equiv.), Formamide or NMF or
DMF (20 equiv.) potassium persulfate (2 equiv.) under aerial atmosphere
b
2 h, Formamide was used as substrate as well as solvent (20 equiv.),
1
c
d
Isolated yield after purification by column chromatography. reactions did
not work at rt.
b
for 12 h, Formamide/NMF/DMF were used as substrate as well as
c
solvent (20 equiv.), Isolated yield after purification by column
d
chromatography. 3ca’(5-methylpicolinamide) was obtained as
regioisomer along with 3ca (3ca:3ca’ 58:42)
While, solvents such as water, THF and acetonitrile were
found to be not good solvents for the desired transformation.
After screening several solvents and temperature conditions
Further, the protocol was explored on quinoline and its
derivative, and pyrazine (1l, 1m, 1n) with NMF 2b under the
reaction conditions to afford the secondary carboxamides (3lb,
optimum reaction condition was emerged as pyridine 1a (1
o
(2 equiv.) at 70 C and formamide (20 equiv,
equiv.), K
2
S
2
O
8
solvent as well as reagent) under aerial atmosphere (entry 6,
Table 1) in 12 h. With this optimized result in hand, we explored
the substrate scope of the method with different substrates and
primary to tertiary amides.
3
mb, 3nb) in very good yields (up to 85% yield). Further, the
strength of the protocol was explored for the access of tertiary
carboxamides using DMF. Earlier, in the literature it was
observed that DMF is relatively unreactive towards the
Under optimal reaction conditions, substrates (1a-1m)
possessing the electron-donating as well as electron withdrawing
groups reacted smoothly with formamide 2a to afford the
corresponding carboxamides (3aa-3ma) in moderate to good
yields (Scheme 1). Encouraged by this success we planned to
explore the generality of the protocol by exploring various
aminocarbonylation and known to give side products emanating
from α-amidoalkylation as major products. Different substrates
1a, 1e-g, 1l-1m, 1o-p (pyridine, quinoline, bipyridyl derivatives)
were treated with the DMF 2c under optimal reaction conditions
to afford the corresponding tertiary carboxamides (3ac, 3ec, 3fc,
3gc, 3lc, 3mc, 3oc, 3pc) in moderate yields. It is very important

3
to note that we did not observe any α-amidoalkylation side
products. The position of the substituents on the ring had no
significant and noticeable effect on the reaction rate and yields.
Different functional group such as bromo, chloro, methoxy and
cyano were well tolerated under the reaction conditions. Method
proved to be regio- and chemoselective for the α-
access to primary to tertiary carboxamides employing user
friendly and less expensive K as reagent. Protocol works
well with usually unreactive substrates such as NMF, DMF and
quinoline and other heterocycles. Moreover, the protocol is clean
and did not give any side products eminating from competing α-
amidoalkylation. Pyrazinecarboxamide a prescribed drug has
been synthesized using this protocol and the practicality of the
protocol was demonstrated on a gram scale for the wider
application.
2 2 8
S O
aminocarbonylation only and we did not observe any γ-
carboxamides and α-amidoalkylated side products.
It is very significant to note that protocol gave access to
primary to tertiary carboxamides on various substrates including
DMF and quinolines. Pyrazine carboxamide is known as Rifater
or Tebrazid and is a prescribed prodrug for the tuberculosis
worldwide. In order to make this protocol practical and for the
wider applicability we demonstrated the synthesis of pyrazine
carboxamide 3na (86% yield) starting from 1n and formamide 2a
using optimal reaction conditions. Further, we synthesized
pyrazine carboxamide 3na in a gram scale and the method
proved to be scalable. The method is simple and straightforward
unlike the conventional methods such as coupling of pyrazine
carboxylic acid and formamide via the activation either by acid
Acknowledgments
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of India
for the generous research grant. Authors also thank Indian
Institute of Science Education and Research (IISER), Pune for
the financial support. T. B. M. thank CSIR, New Delhi, India and
A. S. thank IISER-P for the fellowship.
Supplementary Material
1
13
.
Experimental details and H, C-NMR spectra of compounds 3
are available. The material is available free of charge via the
internet at
chloride or by coupling agents such as DCC/EDC HCl.
In order to understand and to gain further insight into the
mechanism, pyridine 1a and formamide 2a were treated with
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) under standard
optimal conditions. We observed that reaction did not proceed
even after prolonged reaction time thus indicating that the
possible radical pathway was inhibited by the TEMPO (Scheme
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Highlights
Highlights of this manuscript are as follows:
•
•
Direct acess to Primary to
Tertiary Carboxamides
One Pot Transition-metal-free
synthesis
•
•
Selective α-carbamoylation
Synthesis of
Pyrazinecarboxamide-Prodrug for
Tuberculosis
•
Successfully demonstrated gram
scale synthesis