Aminomethylation of imidazopyridines using N,N-dimethylformamide as an aminomethylating reagent under Cu(II)-catalysis

Article abstract of DOI:10.1016/j.tetlet.2020.152581

N,N-Dimethylformamide has been explored as an aminomethylating reagent in the functionalization of imidazopyridine under Cu(II)-catalysis. A library of aminomethylated imidazopyridines with broad functionalities was synthesized in good yields.

Full text of DOI:10.1016/j.tetlet.2020.152581

Journal Pre-proofs
Aminomethylation of imidazopyridines using N,N-dimethylformamide as an
aminomethylating reagent under Cu(II)-catalysis
Payel Ghosh, Sadhanendu Samanta, Sumit Ghosh, Sourav Jana, Alakananda
Hajra
PII:
S0040-4039(20)31080-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152581
TETL 152581
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 September 2020
16 October 2020
19 October 2020
Please cite this article as: Ghosh, P., Samanta, S., Ghosh, S., Jana, S., Hajra, A., Aminomethylation of
imidazopyridines using N,N-dimethylformamide as an aminomethylating reagent under Cu(II)-catalysis,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152581
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Aminomethylation of Imidazopyridines
using N,N-Dimethylformamide as an
Aminomethylating Reagent under Cu(II)-
Catalysis
Leave this area blank for abstract info.
Payel Ghosh, Sadhanendu Samanta, Sumit Ghosh, Sourav Jana, and Alakananda Hajra*
Me
Me
N
N
R
Cu(OTf)2/TBHP
90 °C, 12 h
N
N
CHO
+
N
R
N
Me
Me
upto 92% yield

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Aminomethylation of Imidazopyridines using N,N-Dimethylformamide as an
Aminomethylating Reagent under Cu(II)-Catalysis
Payel Ghosh, Sadhanendu Samanta, Sumit Ghosh, Sourav Jana, and Alakananda Hajra*
a
Department of Chemistry; Visva-Bharati (A Central University), Santiniketan 731235, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
N,N-Dimethylformamide has been explored as an aminomethylating reagent in the
functionalization of imidazopyridine under Cu(II)-catalysis. A library of aminomethylated
imidazopyridines with broad functionalities was synthesized in good yields.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Aminomethylation
Imidazopyridine
DMF
Cu(II)-Catalysis
Radical
Et
Cl
N,N-Dimethylformamide (DMF) is a readily available high
boiling polar solvent. The solvent properties of DMF are
attractive due to its high dielectric constant and aprotic in nature.
Moreover, apart from solvent property in various reactions DMF
have been explored as different building block units such as CO,
CN, NMe2, CONMe2, Me, CHO, CH2, NH2 etc (Figure 1).1
Recently, DMF has gained considerable attention to introduce as
methylene2 and also dimethylamino3 groups.
N
N
N
N
N
Me
N
N
N
tBu
nPr
N
N
Me
Me
Me
OH
O
O
I
II
Necopidem ( )
Saripidem ( )
N
-CN
-CHO
Cl
Me
-CO
N
Me
-CONMe2
-NMe2
N
N
O
N
N
O
V
GSK812397 ( )
-Me
DMF
N(nPr)
NMe2
IV
Cl
2 Me
III
Alpidem (
)
Zolpidem (
)
NMe2
Figure 2: Imidazo[1,2-a]pyridine containing bioactive molecules.
-H
-O-
On the other hand, amines are interesting organic compounds
in synthetic and pharmaceutical chemistry.9 Moreover, tertiary
N,N-dimethylamines have been also used as ligands for the
preparation of metallic complexes, buffers in the sequential
analysis of proteins and peptides, modifiers for reversed-phase
chromatography, dehydrating agent and reducing agent.10 So, the
synthesis of tertiary amines becomes an important area in pure
and applied chemistry.3,11 Thus development of easy protocol for
the synthesis of tertiary amines has gained much attention from
the synthetic chemists. In continuation of our research on
synthesis12 and functionalization13 of imidazo[1,2-a]pyridines,
herein we report a synthesis of trisubstituted amines via
aminomethylation of imidazopyridine using DMF in presence of
Cu(II)-salt and TBHP (Scheme 1). To the best of our knowledge
-CH2
Figure 1: N,N-Dimethylformamide as building block.
Imidazo[1,2-a]pyridine is an important class of heterocyclic
scaffold.4 This scaffold has been found in a number of
biologically active pharmaceutical products5 and material
sciences.6 Several bioactive compounds such as necopidem (I),
saripidem (II) and alpidem (III) work as an anxiolytic agent.
Moreover, zolpidem (IV) is used in the treatment of insomnia
and GSK812397 (V) is used for the treatment of HIV infection.4,5
Many of these compounds contain 3-alkyl amine substituted
imidazo[1,2-a]pyridine moiety as the core structure (Figure 2).
The pharmacological activity of this moiety is dependent on its
substituent. Therefore, there is a continuous efforts of chemist for
the construction of functionalized imidazo[1,2-a]pyridines.7,8

2
Tetrahedron Letters
nrc
nrc
nrc
16c
52
82
64
80
there is no report for the aminomethylation (-CH2NMe2) using
12
13
14
15
16
17
18
19
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (15)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
1,2-DCB
xylene
DMA
H2O
90
90
90
90
90
90
80
100
dimethylformamide as a synthon.
N
N
CHO Cu(II)-cat
N
DMF
R
+
Me
N
R
DMF
N
TBHP
Me
Me
DMF
N
DMF
Me
aReaction conditions: 1a (0.2 mmol), Cu(OTf)2 (7.2 mg, 10
mol%) in DMF (2a, 1.5 mL) with 6 equiv of TBHP solution (5.5-
6.0 M in decane) at 25 °C for 5 min, then the temperature was
increased at 90 °C and stirred for 12 h. bIsolated yields. c10 Equiv
of DMF was added. nr = No reaction.
Scheme 1. Aminomethylation of imidazopyridines.
We commenced our study reacting 2-phenylimidazo[1,2-
a]pyridine (1a) with N,N-dimethylformamide (2a) in the
presence of 10 mol% Cu(OTf)2, and 3 equiv TBHP, and the
reaction mixture was stirred at 25 °C for 5 min. Then the
temperature was increased at 90 °C and stirred for 12 h (Table 1,
entry 1). Interestingly, the aminomethylated product 3aa was
isolated in 29% yield after 12 h. To determine the optimal
reaction conditions, the amount of oxidant was increased from 3
equiv to 6 equiv. The yield of 3aa was improved to 81% (Table
1, entry 2). An almost similar result was obtained with 9 equiv of
TBHP (Table 1, entry 3). Other common Cu salts like CuCl2,
CuBr2, CuI and Cu(OAc)2.H2O were employed as the catalyst,
but these were not so effective like Cu(OTf)2 (Table 1, entries 4-
7). However, the amiomethylated product was not obtained in
absence of Cu(OTf)2 or TBHP (Table 1, entries 8 and 9) which
implies the necessity of both in this transformation. Common
Lewis acid like FeCl3 and oxidant like DTBP were also tested but
they did not produce any aminomethylated product (Table 1,
entries 10 and 11). Further the reaction was screened with several
common solvents like 1,2-DCB, xylene, DMA and H2O (Table 1,
entries 12-15) in the presence of 10 equiv of DMF and all these
cases the desired product was not formed. However, significant
decrease of the yield was observed on decreasing the catalyst
loading. Moreover increment of the catalyst loading from 10
mol% to 15 mol% did not improve yield of the reaction (Table 1,
entries 16 and 17). With decreasing the reaction temperature to
80 °C, much lower yield was obtained (Table 1, entry 18).
Furthermore, at higher temperature (100 °C), no observable
change was noticed (Table 1, entry 19). Thus, a combination of
10 mol% Cu(OTf)2, 6 equiv of TBHP at 90 °C for 12 h was
found to represent the optimized reaction conditions affording
81% yield of the aminomethylated product (Table 1, entry 2).
After getting the optimized reaction conditions, various
substituted imidazo[1,2-a]pyridines were introduced to prove the
general applicability of this protocol. At first, the effect of the
substituent on phenyl ring of imidazopyridine was studied and
the results are summarized in Table 2. Electron donating like -
Me, -OMe substituted imidazopyridines gave the desired
products in excellent yields (3ba and 3ca). Halogen substituted
imidazopyridines were also well tolerated under the present
reaction conditions (3da and 3ea). Interestingly commercially
available drug zolimidine was also aminomethylated under the
present reaction conditions with 72% yield (3fa). Imidazo[1,2-
a]pyridine with strong electron-withdrawing -CF3 and -NO2
groups reacted well to give the corresponding products 3ga and
3ha in 74% and 75% yields respectively. 2-Naphthyl and
heteroaryl like 2-thiophenyl substituted imidazo[1,2-a]pyridines
also produced the desired aminomethylated products in good
yields (3ia and 3ja). But, 2-pyridyl substituted imidazo[1,2-
a]pyridine produced an inseparable mixture of products.
Moreover, unsubstituted imidazo[1,2-a]pyridine regioselectively
produced 3-aminomethylated product in 86% yield (3ka).
However, aliphatic substituted as well as C-3 substituted
imidazo[1,2-a]pyridines (1l and 1m) were unreacted under the
present reaction conditions. This observation illustrated that the
reaction selectively took place at the C-3 position because of
being more electron rich center.
Table 2. Substrate scope: Variation of C-2 substituents on
imidazo[1,2-a]pyridinesa
Table 1. Evaluation of the reaction conditionsa,b
N
N
N
Cu(II), TBHP
temp, time
DMF
+
N
NMe2
3aa
1a
2a
entry
catalyst
(mol%)
oxidant
(equiv)
solvent
temp
yield
(oC)
(%)
29
81
81
32
37
21
nr
1
2
3
4
5
6
7
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
CuCl2 (10)
TBHP (3)
TBHP (6)
TBHP (9)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
90
90
90
90
90
90
90
CuBr2 (10)
CuI(10)
Cu(OAc)2.H2O
(10)
8
9
---
TBHP (6)
---
DMF
DMF
DMF
DMF
90
90
90
90
nr
nr
nr
nr
Cu(OTf)2 (10)
FeCl3 (10)
10
11
TBHP (6)
DTBP (6)
Cu(OTf)2 (10)

3
Table 3. Substrate scope: Variation of substituents on
imidazo[1,2-a]pyridine at pyridine ringa
R
+
R
Cu(OTf)2 (10 mol%)
TBHP (6 equiv)
90 oC, 12 h
N
N
N
N
DMF
NMe2
Cu(OTf)2 (10 mol%)
N
N
N
N
1a 1k
-
2a
3aa 3ka
-
TBHP (6 equiv)
90 oC, 12 h
DMF
+
Me
OMe
NMe2
R
R
NMe2
NMe2
N
N
1n 1p
2a
3na 3pa
N
N
N
-
-
NMe2
NMe2
NMe2
N
N
N
N
N
Me
Br
3aa
3ba
, 83%
3ca
, 81%
, 89%
SO2Me
NMe2
NMe2
, 79%
F
Cl
N
N
Me
3na
3pa
, 86%
3oa
, 81%
N
N
N
N
N
N
NMe2
NMe2
, 84%
NMe2
N
N
MeO
3da
, 86%
3ea
3fa
, 72%
3qa
, 77%
CF3
aReaction conditions: 1 (0.2 mmol), Cu(OTf)2 (10 mol%) in
DMF (2a, 1.5 mL) with 6 equiv of TBHP solution (5.5-6.0 M in
decane) at 25 °C for 5 min, then the temperature was increased at
90 °C and stirred for 12 h.
N
N
N
N
NO2
NMe2
NMe2
NMe2
, 92%
N
N
b
b
3ga
3ha
3ia
, 74%
, 75%
Unreacted Imidazopyridine
S
Me
Me
The gram-scale reaction was also performed to show the
practical applicability of the present protocol and the result are
summarized in Scheme 2. The reaction between 2-
phenylimidazo[1,2-a]pyridine (1a) and N,N-dimethylformamide
(2a) was carried out and the desired product, N,N-dimethyl-1-(2-
phenylimidazo[1,2-a]pyridin-3-yl)methanamine was obtained in
77% yield (1.116 g, 3aa).
N
N
N
N
N
N
NMe2
NMe2
N
N
b
3ja
3ka
, 87%
, 86%
3l
3m
aReaction conditions: 1 (0.2 mmol), Cu(OTf)2 (10 mol%) in
DMF (2a, 1.5 mL) with 6 equiv of TBHP solution (5.5-6.0 M in
decane) at 25 °C for 5 min, then the temperature was increased at
90 °C and stirred for 12 h. bReaction time 18 h.
N
N
N
N
Standard Condition
+
DMF
NMe2
Next the effects of substituents present on the pyridine ring of
imidazo[1,2-a]pyridine were examined and the results are
summarized in Table 3. Imidazopyridines containing methyl
substituent at different position of pyridine ring and bromo
substituted derivative were successfully afforded the
corresponding aminomethylated products with good to excellent
yields (3na, 3oa and 3pa). 7-methoxy-2-phenylimidazo[1,2-
a]pyridine (1q) also well tolerable for this transformation and
2a
9.0 mL
1a
3aa
, 77%
1.1 g
, 6 mmol
1.1 g
Gram-scale synthesis
Scheme 2. Gram-scale reaction.
Few control experiments were performed to understand the
plausible reaction mechanism (Scheme 3). At first the reactions
were carried out in presence of radical scavengers such as
2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and butylated
hydroxytoluene (BHT). The yield of 3aa decreased that signifies
the reaction possibly proceeds through the radical pathway
(Scheme 3, eq A). However, N,N-diethylformamide (2b) did not
respond to this reaction (Scheme 3, eq B).
produced
1-(7-methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)-
N,N-dimethylmethanamine (3qa) in 77% yields.
N
N
N
N
CHO
N
Standard Condition
+
(A)
NMe2
3aa
Radical Scavenger
(3 equiv)
Me
Me
1a
2a
i) TEMPO:
, 31%
3aa
ii) BHT:
, 26%
Cl
Cl
N
N
N
N
CHO
(B)
Standard Condition
+
N
NEt2
, 0%
Et
Et
1e
2b
3eb

4
Tetrahedron Letters
species E via radical pathway through sequential formation of
Scheme 3. Control experiments.
few intermediates as proposed by Ge3b and Lin.3c Then, the
aromatic electrophilic substitution occurs with electron rich
imidazopyridine to form intermediate F. Finally, deprotonation
of intermediate F affords the desired aminomethylated product
3aa.
On the basis of literature reports14 and our previous
experiences,15 the probable mechanism for this transformation is
outlined in Scheme 4. In the presence of Cu(II) and oxidant,
possibly DMF is oxidized to produce the reactive iminium
H
O
Me
Me
Me
N
Me
Cu(II)/[O]
N Me
N CHO
N
N CHO
H2C
Me
Me
H2C
E
Me
H
O
H
A
C
N
Me
N
Me
-CO
N
Me
D
N
H
Ph
B
1a
Ph
H
N
N
N
N
Me
-H+
N
N
Ph
F
Me
Me
Me
3aa
Scheme 4. Probable mechanistic pathway.
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In summary, we have successfully explored DMF as an
aminomethylating agent in the synthesis of aminomethylated
imidazopyridines through Cu(II)-catalyzed coupling between
DMF and imidazo[1,2-a]pyridine. To the best of our knowledge,
this is the first report for the use of DMF as an
aminomethylenating reagent in the synthesis of functionalized
imidazoheterocycles. We believe that the present finding of
aminomethylation using DMF will gain useful applications in
pharmaceuticals and material sciences.
8.
Acknowledgments
A.H. acknowledges the financial support from CSIR, New Delhi
(Grant No. 02(0307)/17/EMR-II)), P.G. thanks UGC-New Delhi
(UGC-JRF) for her fellowship.
9.
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S. A. Amines: Synthesis Properties and Applications, Cambridge
University Press, Cambridge, 2004. (c) Amino Group Chemistry.
From Synthesis to the Life Sciences, (Ed.: A. Ricci), Wiley-VCH,
Weinheim, 2008.
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15. Kibriya, G.; Bagdi, A. K.; Hajra, A. Org. Biomol. Chem. 2018, 16,
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