Ruthenium(II)-Catalyzed Regioselective Ortho Amidation of Imidazo Heterocycles with Isocyanates

Article abstract of DOI:10.1021/acs.joc.6b02282

Direct ortho amidation at the phenyl ring of 2-phenylimidazo heterocycles with aryl isocyanates has been achieved via a chelation-assisted cationic ruthenium(II) complex catalyzed mechanism. The methodology provides a straightforward, high-yielding regios

Full text of DOI:10.1021/acs.joc.6b02282

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Article
Ruthenium(II) Catalyzed Regioselective o-
Amidation of Imidazo-heterocycles with Isocyanates
S. M. ABDUL SHAKOOR, Santosh Kumari, Sadhika
Khullar, Sanjay K. Mandal, Anil Kumar, and Rajeev Sakhuja
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02282 • Publication Date (Web): 18 Nov 2016
Downloaded from http://pubs.acs.org on November 19, 2016
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Ruthenium(II) Catalyzed Regioselective o-Amidation of
Imidazo-heterocycles with Isocyanates
a
a
b
b
a
S. M. Abdul Shakoor, Santosh Kumari, Sadhika Khullar , Sanjay K. Mandal, Anil Kumar,
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a,
Rajeev Sakhuja *
a
Department of Chemistry, Birla Institute of Technology & Science, Pilani, Rajasthan, 333031, India
Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Sector
b
8
1, S.A.S. Nagar, Manuali P.O., Punjab 140306, India
Fax: 91ꢀ1596ꢀ244183, Tel: 91 5196ꢀ5155663
Eꢀmail: sakhuja.rajeev@gmail.com
N
H
Y
N
N
R1
O
[
RuCl (p-Cymene)] [5 mol %]
Y
N
R1
2
2
NH
Imidazo-pyridine, imidazo-pyrimidine
imidazo-thiazole, imidazo-benzothiazole
KPF [30 mol %]
DCE, 100 C, N atm.
6
Ar
3 Examples
Upto 80% yield
2
2
Ar N C O
*
C-H Activation at remote site without
protecting an active site in IP
Regioselective synthesis)
Wide Substrate Scope
Good Yields
* Gram Scale Applicability
subst. phe, naphthyl, furyl
N
X
(
N
X
N
*
N
*
O
H
NH
Ph
*
Mechanistic Studies for proposed
catalytic cycle
X= S, O
2
7
Examples
0-73% yield
Abstract: Direct oꢀamidation at the phenyl group of 2ꢀphenylimidazoꢀheterocycles with aryl
isocyanates has been achieved via chelationꢀassisted cationic ruthenium(II) complexꢀcatalyzed
mechanism. The methodology provides a straightforward, highꢀyielding regioselective approach
towards the synthesis of an array of oꢀamidated phenylimidazoꢀheterocycles without prior
2
activation of C(sp )ꢀH. This also reports the first method for coupling of aryl isocyanates with
imidazo[1,2ꢀa]pyridine system via penta cyclometalated intermediate. The methodology is found
to be easily scalable and could be applied towards selective oꢀamidation of 2ꢀ
heteroarylimidazo[1,2ꢀa]pyridine frameworks.
Keywords:
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2
ꢀPhenylimdazo[1,2ꢀa]pyridine ; Aryl isocyanate; Ruthenium catalyst; oꢀAmidation; CꢀH
Activation
Introduction
Transition metalꢀcatalyzed direct CꢀH activation of nonꢀactivated CꢀH bonds with various
coupling partners via chelationꢀassisted activation has streamlined the chemical synthesis by
ceasing tedious and expensive substrate preꢀactivation steps. Within the same domain, immense
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progress has been recently documented towards the development of pivotal CꢀC bonds.
Chelationꢀassisted direct C−H bond activation via directing group was initially showcased by Pd
2
or Rh catalysts, however, at present the usage of a large variety of other metal catalysts
3
including the environmentally benign Ru catalysts are well exemplified. A multitude of
functionalities, including amides, amines, ketones, esters, alcohols and azo group have acted as
4
directing groups in C–H functionalization via metal chelationꢀactivation strategy. In 1993,
Murai’s group utilized a Ru(0)ꢀcatalyst precursor for chelationꢀassisted oꢀalkylation of aromatic
5
ketones with alkenes via C–H bond activation. Ever since this work, chelationꢀassisted Ru(II)ꢀ
catalyzed addition to CꢀC πꢀbonds via cyclometalationꢀmigratory insertion mechanism has
6
witnessed enormous progress over Rh or Re catalysis. However, such reactions have not been
extended to systems incorporating polar CꢀN bond, and only proceed in presence of strongly
7
coordinating aryl pyridines or aryl pyrazoles.
Along this line, the direct insertion of activated or nonꢀactivated C−H bonds into the polar C−N
πꢀbond of isocyanates is a highly auspicious methodology for providing synthetically and
biologically important amides. Pioneering efforts have been made by Ackermann, Kuninobu and
7
ꢀ8
Takai, Bergman and Ellman, Cheng and Li towards introducing amide functionalities on
various biologically important heterocyclic scaffolds, by virtue of versatile directing groups. In
most strategies, the directing group (DG) is introduced in the parent moiety to accomplish its oꢀ
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7b,8aꢀd,8f
amidation,
while in very few substrateꢀdirected motifs, the oꢀamidation proceeds through
7
,8g
an inbuilt coordinating site. (Figure 1).
Directing Group
mediated o-amidation
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O
[
Rh] or [Mn]
[Rh] Catalysed
Kim's work, 2015
N
DG
HN Ar
N
ArNCO
[Mn] Catalysed
DG
DG; pyridyl, pyrimidyl
Ackermann's work, 2015
DG
DG
[Ru]
O
ArNCO
[Ru] Catalysed
Ackermann's work, 2014
N
N
HN Ar
DG: pyrrolidinyl amide
Previous Works
Substrate-Directed
o-amidation
[
RuCl (p-Cymene)]
N
2
2
N
N
KPF6
N
ArNCO
O
NH
Present Work
Ar
Figure 1. Few examples of Chelationꢀassisted oꢀamidation of heterocycles (Previous and Present
work)
Imidazo[1,2ꢀa]pyridine (IP) is an example of privileged heterocyclic motif that has been
immensely highlighted in recent literature due to its versatile biological profile including,
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antiviral, antimicrobial, antitumor, antiꢀinflammatory, antiparasitic, hypnotic activities. In
addition, numerous commercially available drugs such as Alpidem, Zolpidem, Olprinone,
minodronic acid, Zolimidine, Nicopidem and optically active GSK812397 candidates are IP
functionalized derivatives. In particular, amido functionalized imidazo[1,2ꢀa]pyridine scaffold
constitute the core skeleton of numerous marketed drugs such as Alpidem, Zolpidem, Saripidem
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9ꢀ10
and others (DSꢀ1, CJꢀ033466, Q203) that are under clinical trials (Figure 2).
This allude our
interest towards the synthesis of new amido functionalized IPs as potential drug
pharmacophores.
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N
N
N
Cl
N
N
O
Cl
Cl
N
N
O
N
O
N
Alpidem
Zolpidem
Saripidem
Sedative & anxiolytic agent)
(
anxiolytic agent)
(treatment of insomnia)
(
Br
N
S
N
H
N
N
O
N
O
Br
N
NH
Cl
N
O
N
HN
Cl
N
OCF3
NH2
Q203
DS-1
Cl
CJ-033466
Selective 5-HT4 agonist
Anti-tuberculosis agent
under Phase 2 clinical trial
positive allosteric modulator
Figure 2. Some examples of biologically active amido functionalized imidazo[1,2ꢀa]pyridines
To the best of our knowledge, there is no report for the direct oꢀamidation of 2ꢀarylimidazo[1,2ꢀ
a]pyridines with isocyanate under any metalꢀcatalyzed conditions. Within our program for
1
1
synthesizing functionalized imidazo[1,2ꢀa]pyridines, and hypothesizing it to be selfꢀdirecting
motif, we developed a convergent regioselective Ru(II)ꢀcatalyzed approach towards direct oꢀ
amidation of 2ꢀarylimidazo[1,2ꢀa]pyridine with aryl isocyanates.
Results and Discussion
Our initial investigation commenced with the identification of a suitable catalyst and
appropriate reaction conditions that would allow selective oꢀamidation on the phenyl ring of 6ꢀ
bromoꢀ2ꢀphenylimidazo[1,2ꢀa]pyridine (1a) using phenyl isocyanate (2a). To identify an
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efficient catalyst for developing the above strategy, we initially employed 5 mol % of [RuCl (pꢀ
2
cymene)] in a variety of solvents such as dichloromethane, toluene, xylene, 1,2ꢀdichloroethane
2
etc. under reflux conditions (entry 1). However, the reaction failed to furnish the expected
product (3a) under any of these conditions, in absence or presence of a variety of additives such
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as NaOAc, KOAc and CsOAc (Table 1, entry 1ꢀ4). Delightfully, the use of AgSbF (30 mol%)
6
with [RuCl (pꢀcymene)] (5 mol%) gave 56% of the expected mono oꢀamidated product (3a)
2
2
o
along with 25% of bis oꢀamidated product (3a') using DCE at 100 C in 18 h (Table 1, entry 5).
Replacing AgSbF with Cu(OAc) also resulted in similar yields of 3a and 3a' (Table 1, entry 6).
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2
Interestingly, an employment of comparatively cheaper and stable KPF (30 mol%) resulted in
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the formation of 3a and 3a' in 62% and 20% yields respectively after 18 h (Table 1, entry 7).
Gratifyingly, conducting the above reaction for lesser time period (14 h) yielded 72% of 3a as a
major product (Table 1, entry 8). An increment in the catalyst loading from 5 mol % to 10 mol
%
or additive loading to 50 mol % did not show any noticeable amelioration in the yield of 3a
Table 1, entry 9ꢀ10). On the other hand, reduction in the yield of 3a was observed when 20 mol
of KPF was used with 5 mol % of the ruthenium catalyst (Table 1, entry 11). Further, an
(
%
6
enhancement in the yield of 3a up to 75% was observed by using 1.5 equivalents of phenyl
isocyanate possibly due to the unstable behavior of isocyanate (Table 1, entry 12). Albeit, the
change of solvents to toluene, benzene and dichloromethane were less effective for the catalytic
reaction giving 3a in 54, 46 and 48% yields, respectively (Table 1, entries 13ꢀ15). The use of
other ruthenium catalyst such as RuCl (PPh ) and RuCl xH O and other available transition
2
3 3
3.
2
metal catalyst including Rh(OAc) and Pd(OAc) were found to be completely inactive for the
2
2
above transformation (Table 1, entries 16ꢀ19).
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a
Table 1. Selected Optimization of Reaction Conditions for synthesis of 3a
NH
O
O
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
N
NCO
N
N
N
Br
Catalyst/Additive
Br
O
N
Solvent
NH
Br
NH
Reaction Condition
3a
1a
2a
3a'
N atm.
2
Entry
Catalyst
Additive
Solvent
Yield
Yield
%) 3a (%) 3a'
(
1
2
3
[RuCl (pꢀcymene)]2
ꢀ
DCE/DCM/xylene/toluene, Reflux, 24 h
DCE/ xylene, 100 °C, 24 h
DCE/ xylene, 100 °C, 24 h
DCE/ xylene, 100 °C, 24 h
DCE, 100 °C, 18 h
NR
NR
NR
NR
56
ꢀ
2
[RuCl (pꢀcymene)]2
NaOAc
KOAc
CsOAc
AgSbF6
Cu(OAc)2
KPF6
ꢀ
2
[RuCl (pꢀcymene)]2
ꢀ
2
a
4
[RuCl (pꢀcymene)]2
ꢀ
2
5
6
7
8
[RuCl (pꢀcymene)]2
25
2
[RuCl (pꢀcymene)]2
DCE, 100 °C, 18 h
55
22
2
[RuCl (pꢀcymene)]2
DCE, 100 °C, 18 h
62
20
2
[RuCl (pꢀcymene)]2
KPF6
DCE, 100 °C, 14 h
72
trace
trace
trace
trace
trace
trace
trace
15
2
b
9
[RuCl (pꢀcymene)]2
KPF6
DCE, 100 °C, 14 h
73
2
c
1
0
[RuCl (pꢀcymene)]2
KPF6
DCE, 100 °C, 14 h
70
2
d
e
e
e
e
e
e
11
[RuCl (pꢀcymene)]2
KPF6
DCE, 100 °C, 14 h
62
2
1
2
[RuCl (p-cymene)]2
KPF6
KPF6
DCE, 100 °C, 14 h
75
2
13
[RuCl (pꢀcymene)]2
Toluene, 100 °C, 14 h
Benzene, 80 °C, 14 h
DCM, 40 °C, 14 h
54
2
1
4
[RuCl (pꢀcymene)]2
KPF6
46
2
15
[RuCl (pꢀcymene)]2
KPF6
48
2
1
6
RuCl (PPh )
KPF6
DCE, 100 °C, 14 h
NR
NR
ꢀ
2
3 3
17
RuCl3.
x
H O
2
KPF6
DCE, 100 °C, 14 h
ꢀ
e
e
1
1
8
Rh(OAc)2
Pd(OAc)2
KPF6
KPF6
DCE, 100 °C, 14 h
DCE, 100 °C, 14 h
NR
NR
ꢀ
ꢀ
9
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), catalyst (5 mol %), additive (30 mol %), solvent (4 mL). The
reactions were performed as per the conditions mentioned; 10 mol % of [RuCl (pꢀcymene)] ; 50 mol % of KPF ; 20 mol
b
c
d
2
2
6
e
%
of KPF ; 2a (0.37 mmol); NR: No Reaction
6
With the optimized conditions in hand, the scope of the developed transformation was applied to
a variety of aryl isocyanates and a wide range of 2ꢀarylimidazo[1,2ꢀa]pyridines (Scheme 1).
Among the isocyanates used, chloro substituted phenyl isocyanates (2b-2e) showed fairly good
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reactivity with the substituted and unsubstituted imidazo[1,2ꢀa]pyridines. For example,
4ꢀchlorophenyl isocyanate (2b) resulted in the formation of corresponding imidazo[1,2ꢀ
a]pyridinꢀ2ꢀyl benzamides (3b, 3c and 3d), in 74%, 76% and 72% isolated yields, respectively.
While, 3ꢀchlorophenyl isocyanate (2c) showed slightly lower reactivity affording 3e and 3f in
66% and 69% isolated yields with 1e and 1a respectively. The use of 2,5ꢀdichlorophenyl
isocyanate (2d) gave comparatively better yield of the desired oꢀamidated product (3h, 77%) as
compared to 2,3ꢀdichlorophenyl isocyanate (2e). A reduction in the yield of amidated product
(3i, 59%) was noticed when 2ꢀfluorophenyl isocyanate (2f) was allowed to react with 1a as
compared to phenyl isocyanate (2a). 4ꢀMethoxyphenyl isocyanate (2g) showed comparative
reluctance to react with 1g-h under the optimized reaction conditions, resulting 3j and 3k in 50%
and 58% yields respectively. 1ꢀNapthyl isocyanate (2h) also reacted well with 1i to give the
corresponding product, 3l in 65% isolated yield. The presence of an electron donating groups
such as methyl and methoxy on the aryl ring of 2ꢀarylimidazo[1,2ꢀa]pyridines underwent oꢀ
amidation affording 3m-p in fairly good yields. 2ꢀNaphthyl imidazo[1,2ꢀa]pyridine (1j) also
showed similar affinity towards the formation of desired product 3r in 70% isolated yield.
Imidazo[1,2ꢀa]pyridine (1k) bearing bromo substitution on the aryl ring showcased retardation in
its reactivity resulting in 60% of 3s. Albeit, 3t was isolated in poor yield when 2ꢀfuryl isocyanate
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57
58
59
60
(synthesized inꢀsitu) was used under similar conditions. Unfortunately nitro substituted
imidazo[1,2ꢀa]pyridine (1l) failed to yield the desired amidated product (3u) under our optimized
conditions.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
N
N
N
N
Br
Cl
O
O
O
O
NH
NH
NH
NH
3a
75%
3
7
b
4%
3c
3d
76%
72%
Cl
N
Cl
Cl
N
N
N
OMe
OMe
N
N
N
N
Br
O
O
O
O
NH
Cl
NH
Cl
NH
Cl
NH
Cl
3
6
f
3
6
e
3g
3h Cl
9%
6%
72%
7
7%
Cl
N
N
N
N
OMe
N
N
N
N
Br
O
O
O
O
NH
NH
NH
NH
3i
F
3j
5
3k
3l
0%
5
9%
58%
MeO
65%
MeO
N
N
N
N
N
O
OMe
N
N
N
O
O
O
O
NH
NH
NH
NH
3
6
o
6%
3p
78%
3n
3m
70%
6
8%
N
N
N
N
N
Br
NO2
N
N
N
N
N
Cl
O
O
O
O
O
NH
O
NH
NH
NH
NH
3
q
3r
0%
3s
60%
3t
30%
3u
0%
65%
7
Scheme 1. Substrate scope of imidazo[1,2ꢀa]pyridines and isocyanates
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All the synthesized compounds were isolated by column chromatography and characterized by
1
detailed spectroscopic analysis. The H NMR spectrum of 3a showed three characteristic
singlets, for one proton each at
δ 10.28, 8.39 and 7.92 for the amidic (NꢀH), Cꢀ5 H and Cꢀ3 H
10
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respectively with other expected signals evidencing the presence of an amidic group at the 2ꢀ
phenyl ring suggesting the correct structure of the desired compound 3a. As a representative
example, single crystals of 3d were grown by ethyl acetate/hexanes for the Xꢀray diffraction
12
studies. 3d crystallizes in the Monoclinic P2 /c space group. An ORTEP diagram of 3d (CCDC
1
No. 1501223) is shown in Figure 2S (Supporting information file).
The scope of the reaction was further explored towards the selective oꢀamidaton of 2ꢀ
thiophenylimidazo[1,2ꢀa]pyridine (4a) and 2ꢀfurylimidazo[1,2ꢀa]pyridine (4b) to afford the
corresponding oꢀamidated products 5a and 5b in 73% and 70% yields, respectively (Scheme 2).
Scheme 2. oꢀAmidation of 2ꢀheteroaryl imidazo[1,2ꢀa]pyridines with isocyanate
To extend the scope of our methodology, few other imidazoheterocyles such as
imidazo[2,1ꢀb]thiazole (6a), and benzo[d]imidazo[2,1ꢀb]thiazole (6b) were reacted with phenyl
isocyanate (2a) under optimized experimental conditions to give their corresponding amidated
products 7a and 7b in 67% and 70% yields, respectively (Scheme 3). In addition, it was observed
that imidazo[2,1ꢀb]thiazole (6a) showed excellent reactivity and heating for 14 h resulted in the
isolation of bis oꢀamidated product (7a') in 18% yield along with 7a.
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Scheme 3. oꢀAmidation of 2ꢀphenylimidazolyl thiazoles with isocyanate
It is noteworthy that attempts to undergo oꢀamidation of 2ꢀarylimidazo[1,2ꢀa]pyrimidine
(8a) with phenyl isocyanate under similar experimental conditions resulted in predominant
formation of bis oꢀamidated product 9a' in 80% yield even in 10 h. This could possibly be due to
presence of an extra nitrogen in the chelating vicinity that enhances its reactivity and restrains
the reaction to stop after mono oꢀamidation (Scheme 4).
Scheme 4. oꢀAmidation of 2ꢀphenylimidazo[1,2ꢀa]pyrimidine with isocyanate
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To assess the scalability of this Ru(II)ꢀcatalyzed C−H bond amidation process, a gram scale
reaction was performed between 1f and 2a under optimized conditions to yield the desired oꢀ
amidated product 3p in 70% (1.05g) yield, which was a similar to that obtained on a smaller
scale (Scheme 5).
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Scheme 5. Gram scale synthesis of 3p
To gain some insights into mechanism, a few control experiments were performed.
Stoichiometric reaction between 6ꢀmethylꢀ2ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridine (1d) with phenyl
isocyanate (2a) under catalystꢀfree conditions failed to yield either Cꢀ3 amidated or oꢀamidated
product, thereby suggesting a vital role of catalyst and additive (Scheme 6i). The inability of
imidazo[1,2ꢀa]pyridine (1m) to give any amidated product with 2a under optimized condition
further affirmed the nonꢀreactivity of Cꢀ3 centre under ruthenium catalyzed conditions (Scheme
6
ii). Reaction of 1d with [RuCl (pꢀcymene)] in the presence of KPF (3 equiv.) in 1,2ꢀ
2 2 6
dichloroethane resulted in the formation of cyclometalated complex (C ) (Scheme 6iii).
3
Formation of C was confirmed by ESIꢀMS analysis (Fig. 1S, Supporting information file),
3
however, it was only partially purified by repeated diethyl ether wash. Attempts to purify C by
3
undertaking column chromatography (using silica gel or neutral alumina as adsorbents) were
unsuccessful probably due to the instability of the complex. The proposed structure of C is in
3
8
a
accordance with the literature reports. Employing catalytic amounts of the complex C for
3
coupling reaction between 1d and 2a in the presence of KPF under optimized conditions, the
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desired product 3o was obtained in comparable yields (Scheme 6iv). Finally attempting
stoichiometric reaction between C and 1d also resulted in the formation of 3o in 40% yield
3
(
Scheme 6v), thereby suggesting C to be an intermediate and a reservoir of active species C in
3
2
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the catalytic process.
Scheme 6. Control Experiments
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8a,13
From the control experiments and literature reports
it is proposed that the plausible catalytic
process is initiated by the dissociation of the [RuCl (pꢀcymene)] dimer (C ) into cationic
2
2
1
ꢀ
ruthenium monomeric species C (active catalyst), most likely by substitution of Cl ligand by
2
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PF . Thereafter, reversible CꢀH ruthenation at the oꢀposition of phenyl ring on 2ꢀ
6
phenylimidazo[1,2ꢀa]pyridine leads to formation of a cationic intermediate complex C3.
Coordination of isocyanate 2a to C , followed by migratory insertion provides C via C which
3
5
4,
on protoꢀdemetalation affords oꢀamidated product, along with the regeneration of the cationic
ruthenium species C that continues the catalytic process (Scheme 7).
2
Ph
NH
O
+
N
i-Pr
N
N
X]n-
[
3o
RuXn
N
C2
1d
X = Cl or PF6
C-H -Ruthenation
Proto-Demetallation
HX
HX
KPF6
[
RuCl (p-Cymene)]
2
2
Cl
C
1
i-Pr
L
Ru
Ru
i-Pr
Ph
N
N
N
O
N
N
C3
C5
Ph N C O
Coordination
Migratory Insertion
2a
Ph
N C O
i-Pr
L
N
L
N
C4
Scheme 7. Plausible catalytic pathway for oꢀamidation of 2ꢀphenylimidazo[1,2ꢀa]pyridine with
isocyanate
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Conclusions
In summary, we have described a convergent and straightforward method for the regioselective
2
synthesis of oꢀamidated imidazoꢀheterocycles via C(sp )–H bond functionalization with aryl
0
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isocyanates employing [RuCl (pꢀcymene)] and KPF in catalytic amounts. An array of oꢀ
2
2
6
amidatedꢀphenyl imidazo[1,2ꢀa]pyridines derivatives with broad functionalities were synthesized
in moderate to good yields. The developed protocol was also applicable for the selective oꢀ
amidation of other imidazoꢀfused heterocycles such as imidazo[2,1ꢀb]thiazole,
benzo[d]imidazo[2,1ꢀb]thiazole and imidazo[1,2ꢀa]pyrimidine. This the first report for the direct
oꢀamidation on imidazo[1,2ꢀa]pyridine scaffold using aryl isocyanates.
Experimental Section
General
Commercially available reagents were used without purification. Commercially available
solvents were dried by standard procedures prior to use. Nuclear magnetic resonance spectra
were recorded on 400 MHz spectrometer and chemical shifts are reported in δ units, parts per
million (ppm), relative to residual chloroform (7.26 ppm) or DMSO (2.5 ppm) in the deuterated
solvent. The following abbreviations were used to describe peak splitting patterns when
appropriate: s = singlet, d = doublet, t = triplet, dd = doublet of doublet and m = multiplet.
1
3
Coupling constants J were reported in Hz. The C NMR spectra were reported in ppm relative to
deuterochloroform (77.0 ppm) or [d ] DMSO (39.5 ppm). Melting points were determined on a
6
capillary point apparatus equipped with a digital thermometer and are uncorrected. High
resolution mass spectra were recorded with a TOF analyzer spectrometer by using electrospray
mode.
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General procedure for o-amidation of imidazoheterocycles
A mixture of imidazoheterocycles (1a-k, 4a-b, 6a-b and 8a) (0.37 mmol), aryl isocyanates (2a-
h) (0.56 mmol), [RuCl (pꢀcymene)] , (0.02 mmol), KPF (0.11 mmol) in dichloroethane (10
2
2
6
10
11
12
13
14
15
16
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22
23
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60
mL) were heated at 100 °C under nitrogen atmosphere for 14ꢀ 20 h. On completion of reaction as
indicated by TLC, the reaction mixture was filtered, evaporated and was directly subjected to
silica gel column chromatography [SiO (100ꢀ200 mesh), Hexane/EtOAc, 8:2] to yield the oꢀ
2
amidated products (3a-s, 5a-b, 7a-b). In few cases, the bis oꢀamidated product (3a', 7a', 9a')
were also isolated.
2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)-N-phenylbenzamide (3a): White solid; yield: 109
1
mg (75%); mp: 198–201 °C; H NMR (400 MHz, CDCl )
δ 10.28 (s, 1H), 8.39 (s, 1H),
3
7.99 (d,
J
= 7.8 Hz, 1H), 7.92 (s, 1H), 7.67 – 7.63 (m, 2H), 7.52 – 7.44 (m, 2H), 7.41 –
.35 (m, 2H), 7.23 (t, = 7.9 Hz, 2H), 7.15 (dd, = 9.5, 1.8 Hz, 1H), 7.00 (t, = 7.4 Hz,
H); C NMR (100 MHz, CDCl ) δ 173.4, 148.6, 147.9, 144.3, 141.7, 135.9, 134.4, 134.2,
7
1
J
J
J
1
3
3
133.5, 132.9, 132.7, 132.6, 131.9, 128.6, 125.1, 122.6, 116.3, 111.2; HRMS (ESIꢀTOF) (m/z)
+
+
calculated C H BrN O : 392.0398; found 392.0405 [M+H] .
2
0
15
3
N-(4-Chlorophenyl)-2-(imidazo[1,2-a]pyridin-2-yl)benzamide (3b): White solid; yield: 95
1
mg (74%); mp 225–227 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.59 (s, 1H), 8.56 (dd, J = 6.8,
6
1.0 Hz, 1H), 8.09 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.61 – 7.56 (m, 1H),
7.54 – 7.50 (m, 2H), 7.48 – 7.45 (m, 1H), 7.39 (d, J = 8.9 Hz, 2H), 7.25– 7.19 (m,1H), 6.88 –
13
6
.84 (m,1H); C NMR (100 MHz, DMSOꢀd ) δ 168.9, 144.7, 143.0, 138.7, 136.7, 131.7, 129.8,
6
129.4, 128.9, 128.0, 127.8, 127.4, 125.3, 121.8, 120.2, 117.0, 112.6, 111.0; HRMS (ESIꢀTOF)
+
+
(
m/z) calculated C H ClN O : 348.0903; found 348.0910 [M+H] .
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2
-(6-Chloroimidazo[1,2-a]pyridin-2-yl)-N-(4-chlorophenyl)benzamide (3c): White solid;
1
yield: 107 mg (76%); mp 165–166 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.58 (s, 1H), 8.90
6
(dd, J = 2.0, 0.8 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.74 – 7.69 (m, 2H), 7.61 – 7.55
0
1
2
3
4
5
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7
8
9
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1
2
3
4
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7
8
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2
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7
8
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2
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4
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7
8
9
0
13
(m, 2H), 7.53 – 7.47 (m, 2H), 7.41 – 7.37 (m, 2H), 7.28 (dd, J = 9.6, 2.1 Hz, 1H); C NMR (100
MHz, DMSOꢀd ) δ 168.8, 144.1, 143.1, 136.7, 131.2, 130.1, 129.4, 129.0, 128.3, 128.2, 127.6,
6
1
26.4, 125.4, 121.9, 120.3, 119.5, 117.9, 111.7; HRMS (ESIꢀTOF) (m/z) calculated
+
+
C H Cl N O : 382.0513; found 382.0521 [M+H] .
20
14
2
3
N-(4-Chlorophenyl)-5-methyl-2-(6-methylimidazo[1,2-a]pyridin-2-yl)benzamide
(3d):
1
White solid; yield: 100 mg (72%); mp 230–232 °C; H NMR (400 MHz, CDCl ) δ 10.72 (s,
3
1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H), 7.50 (t, J = 8.3 Hz, 2H),
7.28 – 7.26 (m, 2H), 7.25 – 7.22 (m, 1H), 7.10 (dd, J = 9.2, 1.4 Hz, 1H), 2.38 (s, 3H), 2.34 (s,
13
3H) ; C NMR (100 MHz, CDCl ) δ 167.7, 144.2, 143.4, 138.3, 137.6, 135.4, 131.0,130.6,
3
1
30.4, 128.9, 128.8, 128.7,128.1, 123.5, 122.7, 121.0, 116.1, 110.9, 21.1, 18.1; HRMS (ESIꢀ
+
+
TOF) (m/z) calculated C H ClN O : 376.1216; found 376.1235 [M+H] .
2
2
19
3
N-(3-Chlorophenyl)-2-(imidazo[1,2-a]pyridin-2-yl)-5-methylbenzamide (3e): White Solid;
1
yield: 88 mg (66%); mp 220
–
221 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.62 (s, 1H), 8.56 (d,
6
J = 6.7 Hz, 1H), 8.07 (s, 1H), 7.98 – 7.90 (m, 2H), 7.58 – 7.46 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H),
.35 (t, J = 8.0 Hz, 2H), 7.24 – 7.18 (m, 1H), 7.14 (d, J = 7.86 Hz, 1H), 6.84 (t, J = 6.6 Hz, 1H),
7
1
3
2.40 (s, 3H); C NMR (100 MHz, DMSOꢀd ) δ 169.2, 144.6, 143.1, 141.3, 137.5, 136.4, 133.4,
6
1
30.8, 130.7, 129.4, 128.9, 128.5, 127.5, 125.4, 123.6, 119.7, 118.6, 116.9, 112.6, 110.7, 21.0 ;
+
+
HRMS (ESIꢀTOF) (m/z) calculated C H ClN O : 362.1060; found 362.1079 [M+H] .
21 17
3
2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)-N-(3-chlorophenyl)benzamide (3f): White solid;
1
yield: 108 mg (69%); mp 217–219 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.62 (s, 1H), 8.98
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(
d, J = 1.0 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.93 (s, 1H), 7.65 – 7.56 (m, 1H), 7.56
1
3
–
7.45 (m, 4H), 7.35 (dd, J = 9.3, 7.1 Hz, 2H), 7.15 (dd, J = 7.9, 1.1 Hz, 1H); C NMR (100
MHz, DMSOꢀd ) δ 169.0, 143.8, 143.2, 141.1, 136.6, 133.5, 131.2 130.8, 130.1, 129.4, 128.4,
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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54
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59
60
1
28.3, 128.2, 127.6, 123.7, 119.8, 118.7, 118.1, 111.5, 106.4; HRMS (ESIꢀTOF) (m/z) calculated
+
+
C H BrClN O : 426.0008; found 426.0023 [M+H] .
20
14
3
N-(2,3-Dichlorophenyl)-5-methoxy-2-(7-methylimidazo[1,2-a]pyridin-2-yl)benzamide (3g):
1
White solid; yield: 113 mg (72%); mp 238–240 °C; H NMR (400 MHz, CDCl ) δ 9.50 (d, J
3
= 7.1 Hz, 1H), 8.50 (dd, J = 8.2, 1.5 Hz, 1H), 8.28 (s, 1H), 7.72 – 7.61 (m, 2H), 7.50 (s, 1H),
7.23 (t, J = 8.1 Hz, 1H), 7.17 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.90 (dd, J =
13
7.2, 1.6 Hz, 1H), 3.90 (s, 3H), 2.50 (s, 3H); C NMR (100 MHz, CDCl + DMSOꢀd ) 160.7,
3
6
159.5, 149.1, 146.7, 139.4, 137.0, 132.3, 131.4, 128.6, 127.1, 126.1, 126.1, 121.9, 116.9, 115.7,
+
114.8, 113.9, 55.8, 21.3; HRMS (ESIꢀTOF) (m/z) calculated C H Cl N O : 426.0776 ; found
2
2
18
2
3
2
+
426.0793 [M+H] .
N-(2,5-Dichlorophenyl)-5-methoxy-2-(7-methylimidazo[1,2-a]pyridin-2-yl)benzamide (3h):
1
White solid; yield: 121 mg (77%); mp 217–218 °C; H NMR (400 MHz, CDCl ) δ 9.50 (d, J
3
= 7.1 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.50 (s, 1H), 7.16
(d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.97 (dd, J = 8.5, 2.4 Hz, 1H), 6.94 – 6.86 (m, 1H),
1
3
3.89 (s, 3H), 2.51 (s, 3H). ; C NMR (100 MHz, CDCl ) δ 161.1, 159.1, 150.2, 147.4, 139.6,
3
135.8, 133.3, 131.4, 129.6, 127.6, 125.6, 123.9, 120.8, 120.2, 116.7, 115.9, 114.9, 113.7, 55.5,
+
+
21.5; HRMS (ESIꢀTOF) (m/z) calculated C H Cl N O : 426.0776; found 426.0798 [M+H] .
22 18 2 3 2
2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)-N-(2-fluorophenyl)benzamide (3i): White solid;
1
yield: 89 mg (59%); mp 225–227 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.25 (s, 1H), 9.00
6
(d, J = 1.1 Hz, 1H), 8.17 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.84 (dd, J = 9.0, 6.5 Hz, 1H), 7.59 (d,
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5
5
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J = 7.3 Hz, 1H), 7.57 – 7.53 (m, 2H), 7.48 (t, J = 7.0 Hz, 1H), 7.37 (dd, J = 9.5, 1.9 Hz, 1H),
1
3
7
1
1
.24 (dd, J = 8.0, 5.5 Hz, 3H); C NMR (100 MHz, DMSOꢀd ) δ 169.0, 156.6, 154.2, 143.9,
6
43.1, 136.5, 131.3, 130.0, 129.4, 128.4, 128.2, 127.5, 126.8, 126.7, 126.3, 124.7, 118.1, 116.2,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
11.7, 106.4; HRMS (ESIꢀTOF) (m/z) calculated C H BrFN O : 410.0304; found 410.0327
20
14
3
+
[M+H] .
N-(4-Methoxyphenyl)-5-methyl-2-(7-methylimidazo[1,2-a]pyridin-2-yl)benzamide
(3j):
1
White solid; yield: 68 mg (50%); mp 192–194 °C; H NMR (400 MHz, CDCl ) δ 9.91 (s,
3
1H), 7.96 (d, J = 6.9 Hz, 1H), 7.65 (s, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H),
7.36 (s, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.65 (d, J = 6.9 Hz, 1H), 3.81 (s,
13
3
H), 2.43 (s, 3H), 2.40 (s, 3H ); C NMR (100 MHz, CDCl ) δ 167.6, 156.1, 144.9, 144.0,
3
138.2, 136.5, 135.8, 132.1, 130.8, 130.4, 130.0, 128.1, 125.0, 121.5, 115.4, 115.3, 114.1, 110.5,
+
2
5
5.5, 21.5, 21.1;HRMS (ESIꢀTOF) (m/z) calculated C H N O : 372.1712; found 372.1730
2
3
22
3
+
[
M+H] .
2-(Imidazo[1,2-a]pyridin-2-yl)-5-methoxy-N-(4-methoxyphenyl)benzamide (3k): White
1
solid; yield: 80 mg (58%); mp 198–201 °C; H NMR (400 MHz, MeOHꢀd ) δ 8.34 (d, J = 6.8
4
Hz, 1H), 7.88 (d, J = 10.4 Hz, 2H), 7.53 (d, J = 9.2 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.30 (dd, J =
6.8, 2.2 Hz, 1H), 7.20 – 7.11 (m, 2H), 6.89 (dd, J = 7.1, 2.0 Hz, 2H), 6.86 (dd, J = 4.7, 2.2 Hz,
1
3
1
H), 3.90 (s, 3H), 3.78 (s, 3H); C NMR (100 MHz MeOHꢀd ) δ 169.3, 159.5, 156.8, 144.9,
4
142.6, 137.5, 131.3, 130.8, 126.4, 125.6, 121.9, 121.4, 115.6, 115.2, 113.7, 113.6, 112.7, 110.2,
+
3
5
4.7, 54.4; HRMS (ESIꢀTOF) (m/z) calculated C H N O : 374.1504; found 374.1523
2
2
20
3
+
[
M+H] .
2-(7-Methylimidazo[1,2-a]pyridin-2-yl)-N-(naphthalen-1-yl)benzamide (3l): White solid;
1
yield: 90 mg (65%); mp 199–203 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.41 (s, 1H), 8.43
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(
d, J = 6.7 Hz, 1H), 8.09 (s, 1H), 8.01 – 7.75 (m, 5H), 7.68 (d, J = 7.1 Hz, 1H), 7.62 – 7.47 (m,
1
3
4
H), 7.36 (s, 1H), 7.30 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 6.6 Hz, 1H), 2.36 (s, 3H); C NMR (100
MHz, DMSOꢀd ) δ 169.7, 145.2, 143.3, 137.3, 135.9, 134.1, 132.1, 129.8, 129.6, 129.2, 128.3,
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
27.9, 127.1, 126.8, 126.8, 126.0, 126.0, 123.7, 123.5, 115.2, 110.7, 21.3; HRMS (ESIꢀTOF)
+
+
(m/z) calculated C H N O : 378.1606; found 378.1614 [M+H] .
2
5
20
3
2-(Imidazo[1,2-a]pyridin-2-yl)-5-methyl-N-phenylbenzamide (3m): White solid; yield: 82
1
mg (68%); mp 188–190 °C; H NMR (400 MHz, CDCl ) δ 9.80 (s, 1H), 8.10 (d, J = 6.8 Hz,
3
1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.68 – 7.61 (m, 4H), 7.33 (d, J = 7.7 Hz, 3H), 7.26 – 7.21 (m,
13
1H), 7.10 (t, J = 7.4 Hz, 1H), 6.83 (t, J = 6.8 Hz, 1H), 2.44 (s, 3H); C NMR (100 MHz, CDCl )
3
δ 168.0, 144.6, 138.7, 138.4, 135.8, 131.0, 130.5, 130.0, 129.0, 128.1, 125.9, 125.4, 124.2, 123.2,
+
120.0, 119.9, 117.0, 112.8, 21.1; HRMS (ESIꢀTOF) (m/z) calculated C H N O : 328.1449;
21
18
3
+
found 328.1455 [M+H] .
2-(Imidazo[1,2-a]pyridin-2-yl)-5-methoxy-N-phenylbenzamide (3n): White solid; yield: 89
1
mg (70%); mp 179–181 °C; H NMR (400 MHz, CDCl ) δ 10.07 (s, 1H), 8.12 (d, J = 6.6 Hz,
3
1H), 7.71 (s, 1H), 7.63 (d, J = 7.3 Hz, 3H), 7.46 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H),
7.25 (d, J = 8.3 Hz, 1H), 7.22 – 7.16 (m, 1H), 7.11 – 7.03 (m, 2H), 6.85 (t, J = 6.6 Hz, 1H), 3.91
1
3
(s, 3H); C NMR (100 MHz, CDCl ) δ 167.2, 159.6, 144.4, 138.7, 137.1, 132.3, 128.9, 128.8,
3
125.9, 125.6, 124.1, 119.8, 119.6, 116.9, 116.8, 114.2, 112.9, 111.0, 55.5; HRMS (ESIꢀTOF)
+
2
+
(m/z) calculated C H N O : 344.1399; found 344.1406 [M+H] .
2
1
18
3
5-Methyl-2-(6-methylimidazo[1,2-a]pyridin-2-yl)-N-phenylbenzamide (3o): White solid;
1
yield: 75 mg (66%); mp 174–176 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.44 (s, 1H), 7.96 (s,
6
1H), 7.88 (dd, J = 7.9, 2.1 Hz, 1H), 7.79 (dd, J = 8.4, 2.4 Hz, 1H), 7.65 (d, J = 7.1 Hz, 2H), 7.36
(d, J = 9.1 Hz, 1H), 7.30 (s, 1H), 7.28 – 7.17 (m, 3H), 7.04 – 6.93 (m, 2H), 2.36 (s, 3H), 2.21 (s,
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
3
H); C NMR (100 MHz, DMSOꢀd ) δ 168.9, 143.7, 142.9, 139.4, 137.2, 136.4, 130.3, 129.4,
6
1
28.8, 128.6, 128.5, 128.2, 124.0, 123.8, 121.9, 120.1, 116.2, 110.3, 21.1, 18.0; HRMS (ESIꢀ
+
+
TOF) (m/z) calculated C H N O : 342.1606; found 342.1612 [M+H] .
2
2
20
3
0
1
2
3
4
5
6
7
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9
0
1
2
3
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0
1
2
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9
0
1
2
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
-Methoxy-2-(7-methylimidazo[1,2-a]pyridin-2-yl)-N-phenylbenzamide (3p): White solid;
1
yield: 102 mg (78%); mp 189–191 °C; H NMR (400 MHz, CDCl ) δ 10.49 (s, 1H), 8.40 (d, J
3
=
6.9 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.89 (s, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.32 (t, J = 7.8 Hz,
2
H), 7.28 (s, 1H), 7.13 (dd, J = 8.7, 2.6 Hz, 1H), 7.10 – 7.01 (m, 2H), 6.66 (d, J = 6.9 Hz, 1H),
1
3
3.84 (s, 3H), 2.31 (s, 3H); C NMR (100 MHz, CDCl ) δ 173.2, 163.6, 149.6, 147.5, 144.5,
3
1
42.6, 140.4, 135.6, 133.9, 131.3, 129.0, 128.8, 125.1, 120.4, 119.9, 119.7, 117.9, 114.4, 60.7,
+
2
+
2
6.0; HRMS (ESIꢀTOF) (m/z) calculated C H N O : 358.1555; found 358.1560 [M+H] .
22 20
3
2-(Imidazo[1,2-a]pyridin-2-yl)-N-phenylbenzamide (3q): White solid; yield: 75 mg (65%);
1
mp 184–186 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.48 (s, 1H), 8.58 (d, J = 6.1 Hz, 1H), 8.11
6
(
s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.53 (m, 4H), 7.33 (t, J = 7.1 Hz, 2H),
13
7
.28 – 7.23 (m, 1H), 7.08 (t, J = 6.8 Hz, 1H), 6.87 (t, J = 5.9 Hz, 1H); C NMR (100 MHz,
DMSOꢀd ) δ 168.8, 144.5, 142.9, 139.7, 137.0, 131.4, 129.9, 129.4, 129.1, 128.1, 128.0, 127.9,
6
+
125.8, 124.0, 120.3, 117.0, 112.8, 111.1; HRMS (ESIꢀTOF) (m/z) calculated C H N O :
2
0
16
3
+
3
14.1293; found 314.1303 [M+H] .
3
-(Imidazo[1,2-a]pyridin-2-yl)-N-phenyl-2-naphthamide (3r): White solid; yield: 94 mg
1
(70%); mp 190–193 °C; H NMR (400 MHz, CDCl ) δ 9.81 (s, 1H), 8.12 (d, J = 7.4 Hz, 2H),
3
8
7
1
.04 (s, 1H), 7.84 (s, 1H), 7.81 – 7.74 (m, 1H), 7.67 (d, J = 7.6 Hz, 3H), 7.60 (d, J = 8.4 Hz, 1H),
.50 (dd, J = 5.9, 2.8 Hz, 2H), 7.38 – 7.29 (m, 3H), 7.12 (t, J = 7.3 Hz, 1H), 6.87 (t, J = 6.7 Hz,
1
3
H); C NMR (100 MHz, DMSOꢀd ) δ 206.9, 139.0, 135.7, 133.3, 131.8, 128.76, 128.7, 128.7,
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28.2, 127.9, 127.4, 126.9, 126.1, 125.6, 124.2, 123.9, 119.9, 117.6, 116.6, 112.7, 111.2, 111.2;
+
+
HRMS (ESIꢀTOF) (m/z) calculated C H N O : 364.1449; found 364.1454 [M+H] .
24 18
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5-Bromo-2-(imidazo[1,2-a]pyridin-2-yl)-N-phenylbenzamide (3s): White solid; yield: 87 mg
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(
60%); mp 200–203 °C; H NMR (400 MHz, CDCl ) δ 10.39 (s, 1H), 8.08 (d, J = 6.8 Hz, 1H),
3
7.87 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 8.4 Hz, 2H), 7.47 (dd,
J = 8.3, 2.1 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.28 – 7.23 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H), 6.84
13
(
m, 1H); C NMR (100 MHz, CDCl ) δ 166.4, 144.6, 142.9, 138.6, 137.4, 132.9, 132.1, 131.6,
3
129.1, 125.9, 125.9, 124.4, 122.2, 119.9, 117.0, 113.2, 111.3; HRMS (ESIꢀTOF) (m/z) calculated
+
+
C H BrN O : 392.0398; found 392.0403 [M+H] .
20
15
3
Procedure for the o-amidation of 1c with furyl isocyanate (2i)
1
4
Furyl isocyanate was synthesized inꢀsitu by heating furanꢀ2ꢀcarbonyl azide (0.150 g) in 1,2ꢀ
dichloroethane at 100 °C for about 45 minutes under nitrogen atmosphere via curtius
rearrangement. Furyl isocyanate (assuming 100% conversion) was directly used for the oꢀ
amidation of 1c (0.100 g, 0.43 mmol) following earlier described procedure to yield 3t.
2
-(6-Chloroimidazo[1,2-a]pyridin-2-yl)-N-(furan-2-yl)benzamide (3t): Yellow solid; yield:
1
66 mg (30%); mp 200–203 °C; H NMR (400 MHz, CDCl ) δ 8.35 (s, 1H), 7.89 (s, 1H), 7.65
3
(
s, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.47 – 7.40 (m, 3H), 7.36 (dd, J = 7.3, 5.3 Hz, 2H), 7.27 – 7.24
13
(
m, 1H), 7.23 – 7.19 (m, 1H), 6.69 (dd, J = 3.4, 1.7 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
157.3, 146.5, 145.5, 129.8, 128.8, 128.5, 127.3, 125.2, 121.3, 120.3, 120.3, 117.8, 117.2, 112.9;
+
2
+
HRMS (ESIꢀTOF) (m/z) calculated C H ClN O : 338.0696; found 338.0675 [M+H] .
1
8
13
3
2
-(Imidazo[1,2-a]pyridin-2-yl)-N-phenylthiophene-3-carboxamide (5a): White solid; yield:
1
8
6 mg (73%); mp 221–223 °C; H NMR (400 MHz, DMSOꢀd ) δ 11.52 (s, 1H), 8.65 – 8.60
6
(
m, 1H), 8.43 (s, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.68 (dd, J = 9.1, 0.7 Hz, 1H), 7.63 (d, J = 5.3
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5
5
5
5
6
Hz, 1H), 7.51 (d, J = 5.3 Hz, 1H), 7.42 – 7.30 (m, 3H), 7.14 – 7.08 (m, 1H), 6.96 (td, J = 6.8, 1.0
1
3
Hz, 1H); C NMR (100 MHz, DMSOꢀd ) δ 162.7, 144.3, 139.7, 138.3, 137.9, 133.6, 130.6,
6
129.3, 127.7, 126.7, 125.7, 124.1, 120.3, 116.7, 113.4, 111.9; HRMS (ESIꢀTOF) (m/z) calculated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
C H N OS : 320.0857; found 320.0885 [M+H] .
18
14
3
2-(Imidazo[1,2-a]pyridin-2-yl)-N-phenylfuran-3-carboxamide (5b): White solid; yield: 75
1
mg (67%); mp 180–182 °C; H NMR (400 MHz, DMSOꢀd ) δ 13.77 (s, 1H), 8.69 (m, 1H),
6
8.53 (d, J = 0.5 Hz, 1H), 7.94 – 7.86 (m, 4H), 7.50 (m, 1H), 7.46 – 7.40 (m, 2H), 7.16 – 7.09 (m,
13
2H), 7.05 (d, J = 1.9 Hz, 1H); C NMR (100 MHz, DMSOꢀd ) δ 164.7, 151.4, 148.9, 147.8,
6
147.7, 144.9, 140.3, 134.3, 132.6, 128.5, 124.9, 124.4, 121.5, 119.1, 118.9, 117.2; HRMS (ESIꢀ
+
+
TOF) (m/z) calculated C H N O : 304.1086; found 304.1092 [M+H] .
18 14
3
2
2-(Imidazo[2,1-b]thiazol-6-yl)-N-phenylbenzamide (7a): Yellow solid; yield: 80 mg (67%);
1
mp 195–198 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.45 (s, 1H), 7.96 (t, J = 6.7 Hz, 2H), 7.92
6
(s, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.56 – 7.50 (m, 1H), 7.46 (d, J = 6.5 Hz, 1H), 7.40 (t, J = 7.0
13
Hz, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.24 (d, J = 4.4 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H); C NMR
(
100 MHz, DMSOꢀd ) δ 169.0, 149.2, 144.7, 139.8, 136.2, 131.7, 129.8, 129.1, 128.7, 128.0,
6
+
127.4, 124.0, 120.6, 120.2, 113.6, 111.4; HRMS (ESIꢀTOF) (m/z) calculated C H N OS :
18
14
3
+
3
20.0857; found 320.0864 [M+H] .
2-(Benzo[d]imidazo[2,1-b]thiazol-2-yl)-N-phenylbenzamide (7b): White solid; yield: 95 mg
1
(70%); mp 145–147 °C; H NMR (400 MHz, CDCl ) δ 9.16 (s, 1H), 7.92 (s, 1H), 7.80 – 7.72
3
(m, 2H), 7.66 (dd, J = 7.3, 4.7 Hz, 3H), 7.55 (d, J = 7.9 Hz, 1H), 7.48 – 7.41 (m, 2H), 7.36 (m,
1
3
4
1
1
H), 7.13 (t, J = 7.4 Hz, 1H); C NMR (100 MHz, CDCl ) δ 168.1, 147.5, 145.4, 138.5, 135.6,
3
32.0, 131.0, 130.2, 130.1, 129.8, 129.0, 128.9, 128.9, 128.0, 126.4, 125.2, 124.3, 120.0, 113.0,
+
+
10.2; HRMS (ESIꢀTOF) (m/z) calculated C H N OS : 370.1014; found 370.1022 [M+H] .
2
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-(6-Bromoimidazo[1,2-a]pyridin-2-yl)-N ,N -diphenylisophthalamide (3a') : White solid;
(Table 1, entry 5)
1
yield
: 25%; mp 240–242 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.30 (s, 2H),
6
8
.97 (d, J = 1.1 Hz, 1H), 8.03 (s, 1H), 7.70 – 7.67 (m, 2H), 7.63 – 7.59 (m, 1H), 7.54 (d, J = 7.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
28
29
30
31
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33
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz, 4H), 7.39 (d, J = 9.6 Hz, 1H), 7.29 – 7.24 (m, 5H), 7.04 (t, J = 7.4 Hz, 2H); C NMR (100
MHz, DMSOꢀd ) δ 167.7, 142.7, 142.6, 139.5, 139.3, 129.8, 129.0, 128.9, 128.3, 127.9, 127.3,
6
+
1
23.9, 120.3, 118.1, 112.8, 106.3; HRMS (ESIꢀTOF) (m/z) calculated C H BrN O
2
:
2
7
20
4
+
5
11.0769; found 511.0778 [M+H] .
1
3
2-(Imidazo[2,1-b]thiazol-6-yl)-N ,N -diphenylisophthalamide (7a'): Yellow solid; yield:
1
0
.024 mg (18%); mp 224–225 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.27 (s, 2H), 7.92 (d, J
6
=
4.5 Hz, 1H), 7.83 (d, J = 3.8 Hz, 1H), 7.64 – 7.60 (m, 2H), 7.60 – 7.52 (m, 5H), 7.28 (t, J = 7.9
13
Hz, 4H), 7.16 (d, J = 4.5 Hz, 1H), 7.05 (t, J = 7.4 Hz, 2H); C NMR (100 MHz, DMSOꢀd6) δ
1
1
67.9, 148.5, 142.8, 139.6, 139.0, 130.0, 128.9, 128.7, 127.6, 123.8, 120.3, 120.2, 113.2,
+
+
12.6; HRMS (ESIꢀTOF) (m/z) calculated C H N O S : 439.1228; found 439.1236 [M+H] .
25 19
4
2
1
3
2
-(Imidazo[1,2-a]pyrimidin-2-yl)-N ,N -diphenylisophthalamide (9a'): Yellow solid; yield:
1
1
27 mg (80%); mp 273–275 °C; H NMR (400 MHz, DMSOꢀd ) δ 10.40 (s, 2H), 9.04 – 8.98
6
(m, 1H), 8.42 (d, J = 1.9 Hz, 1H), 8.00 (s, 1H), 7.70 (d, J = 7.4 Hz, 2H), 7.66 – 7.61 (m, 1H),
.57 (d, J = 7.9 Hz, 4H), 7.27 (t, J = 7.7 Hz, 4H), 7.04 (t, J = 7.3 Hz, 2H), 6.98 (dd, J = 6.5, 4.2
7
1
3
Hz, 1H); C NMR (100 MHz, DMSOꢀd ) δ 167.7, 150.5, 147.4, 143.0, 139.6, 139.4, 135.4,
6
130.0, 129.0, 128.9, 128.4, 124.0, 120.3, 110.7, 109.3; HRMS (ESIꢀTOF) (m/z) calculated
+
+
C H N O : 434.1617; found 434.1625 [M+H] .
26
20
5
2
Procedure for Synthesis of Complex C . A mixture of 6ꢀmethylꢀ2ꢀ(pꢀtolyl)imidazo[1,2ꢀ
3
a]pyridine (1d) (0.17 mmol, 0.040 g), [RuCl ꢀ(pꢀcymene)] , (0.11 mmol, 0.070 g), KPF (3
2
2
6
equiv.) in dichloroethane (5 mL) under nitrogen atmosphere was stirred for 12 h. After filtration
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through celite, the solvent was concentrated under reduced pressure and the residue was washed
with Et O (15 mL×5) to afford partially purified complex C . ESIꢀMS (m/z) calculated
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3
+
+
C H N Ru : 457.1217; found 457.1382 [MꢀCl]
.
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Acknowledgments
The authors acknowledge Department of Science & Technology (DST), New Delhi for
providing research grant (SB/FT/CSꢀ033/2012) for the work. We also thank BITS Pilani for
providing research grant (BITS additional research grant) for the work. The authors SMAS and
SK thank BITS Pilani and UGC, New Delhi, respectively, for providing Senior Research
Fellowships. The use of Xꢀray facility at IISER Mohali is gratefully acknowledged.
SUPPORTING INFORMATION
Copies of NMR data, ESIꢀMS of C single crystal Xꢀray analysis data table for 3d and
3
,
ORTEP diagram of 3d. A CIF file for 3d which is deposited with Cambridge Crystallographic
Data Centre (CCDC No. 1501223) is provided.
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0
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(
12) Crystal data for 3d: C H ClN O, M = 375.84, Monoclinic, space group P2 /c, a =
22
18
3
1
10.8372(10) Å, b = 10.5719(5) Å, c = 16.5469(8) Å, α = 90°, β = 90.413(1)°, γ = 90°, V =
3
3
ꢀ1
1
895.7(2) Å , Z = 4, D =1.317 Mg/cm ,
ꢀ
(MoꢀKα) = 0.218 mm , T = 296(2) K, 48825
c
reflections collected. Refinement of 2619 reflections (246 parameters) with I>2σ(I) converged at
a final R = 0.046, wR = 0.1098, gof = 1.057.
1
2
(13) (a) Chinnagolla, R. K.; Vijeta, A.; Jeganmohan, M. Chem. Commun. 2015, 51, 12992. (b)
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