Tandem approach for the synthesis of 3-sulfenylimidazo[1,5-: A] pyridines from dithioesters

Article abstract of DOI:10.1039/c6ra03771b

Iodine-mediated synthesis of 3-sulfenylimidazo[1,5-a]pyridines via C-H functionalization has been achieved using dithioesters, 2-methylaminopyridines and sulfonyl hydrazides. A library of 3-sulfanylimidazopyridines and imidazopyridines with broad function

Full text of DOI:10.1039/c6ra03771b

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Tandem Approach for the Synthesis of 3-Sulfenylimidazo[1,5-
a]pyridines from Dithioesters
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
Ajjahalli. B. Ramesha, Chottanahalli. S. Pavan Kumar, Nagarakere. C. Sandhya, Manikyanahalli.
c
a
a
N. Kumara, Kempegowda Mantelingu * and Kanchugarakoppal. S. Rangappa, *
DOI: 10.1039/x0xx00000x
www.rsc.org/
Iodine-mediated synthesis of 3-sulfenylimidazo[1,5-a]pyridines via
C–H functionalization has been achieved using dithioesters, 2-
methylaminopyridines and sulfonyl hydrazides. A library of 3-
sulfanylimidazopyridines and imidazopyridines with broad
functionalities are synthesized under metal-free reaction
conditions.
S
S
EtOOC
S
COOEt
O
N
OH
O
Me
N
H
Me
a
b
Fig.
1 Biologically active Sulfenylated heteroarenes; (a) 5-
The development of C−S bond formaꢀon has gained much
attention in the organic synthesis due to the occurrence of the C-S
lipoxygenase inhibitor and (b) Inhibitor HIV-1 Integrase
1
bond in biologically and pharmaceutically active organic materials.
Sulfenylated heteroarenes can be found in molecules such as
2
AZD4407,
materials
a
5-lipoxygenase inhibitor, and thienoacene-based
applicability.
3
(Figure
1).
Pharmacological
properties
of
Sulfonyl hydrazides are readily accessible and exist as stable
Imidazopyridines are mainly dependent on the nature of the
substituent’s, and introduction of sulfenyl or selenyl groups on the
aza-aromatic rings could impart marked biological properties to the
compounds; for example, 3-sulfenyl indoles, 3-sulfenyl pyrroles,
and 3-sulfenylimidazopyridines are of considerable therapeutic
solids, and they have been widely employed to form hydrazones
10
and heterocycles which have versatile applications. Moreover,
11
sulfonyl hydrazides can be utilized as reductants and sulfonyl
12
sources through the cleavage of their sulfur–nitrogen bonds, and
very recently as aryl sources through the cleavage of their carbon–
4
value against a variety of diseases. 3-Sulfenylimidazopyridines are
13
sulfur bonds. Thus, it is highly desirable to develop an alternate
usually prepared by sulfenylation of imidazopyridines prior-
method for the sulfenylation of imidazo[1,5-a]pyridines under
transition metal free condition. Tian and coworkers first reported
the thiolation of indoles employing sulfonyl hydrazides as a thiol
synthesized. Direct formation of
a
C–S bond via C–H
functionalization of heterocycles has received considerable
5
6
7
attention in recent years. Thiols, disulfides, N-thioimides,
14
surrogate. Subsequently, Singh et al. also reported the synthesis
8
9
arylsulfonyl chlorides, sulfonium salts etc. have been used as the
sulfenylating agents. The use of these reagents has some practical
limitations such as thiols are foul-smelling, volatile, and toxic, where
as disulfides are expensive, moisture sensitive and unstable. In
addition, these methodologies suffer from some drawbacks like the
use of a transition metal catalyst, stoichiometric amounts of
oxidants and bases, harsh reaction conditions, and limited
of vinyl sulfides and diaryl thioethers using sulfonyl hydrazides
15
under microwave irradiation. Very recently Hajra and co-workers
reported the thiolation of imidazo[1,2-a]pyridines using sulfonyl
16
hydrazides. So far, the use of sulfonyl hydrazides as sulfenylating
agents is limited. Recently, we have reported a method for the
synthesis of functionalized imidazopyridine derivatives employing
17
18
novel method. Based on our experiences on dithioesters and
inspired by Tian’s pioneering work, we have envisaged that
imidazo[1,5-a]pyridines could be sulfenylated at the 3-position
under mild conditions. In continuation of our work on synthesis of
a.
Synthetic Laboratory, DOS in Chemistry, University of Mysore, Manasagangotri,
Mysore-570006, Karnataka, India
Sharada Vilas Collegue, Mysuru.
Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore
b.
19
c.
heterocyclic compounds herein, we report a new iodine-mediated
5
70005, Karnataka, India
Corresponding authors.
Electronic Supplementary Information (ESI) available: [[CCDC 4h- 1451828, H NMR
convenient and tandem approach for the synthesis of 3-
sulfenylimidazo[1,5-a]pyridines under mild conditions by sulfonyl
hydrazides as a thiol surrogate in.
*
1
13
and C NMR]. See DOI: 10.1039/x0xx00000x
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Journal Name
a
Table 1. Reaction optimization of 4a
Scheme
1
Substrate scope for the synthesis of 3-
sulfenylimidazo[1,5-a]pyridines
No.
Additives
Solvent
Time Temperature Yield
in h
12h
%
-
1
2
3
4
5
6
7
8
9
I
I
I
I
I
2
2
2
2
2
(1.0 eq)
(1.0 eq)
(2.2 eq)
(2.5 eq)
(2.2 eq)
Ethanol
Ethanol
Ethanol
Ethanol
methanol
THF
rt
o
20 h
14 h
12 h
24 h
24 h
24 h
24 h
20 h
70 C
48
87
86
75
81
60
78
67
o
80 C
o
80 C
o
80 C
o
I2 (2.2 eq)
80 C
o
I
I
I
2
2
2
(2.2 eq)
(2.2 eq)
(2.2 eq)
DMF
80 C
o
CH
3
CN
80 C
o
Ethyl
80 C
acetate
o
1
1
1
1
0
1
2
3
I
I
2
2
(2.2 eq)
(2.2 eq)
CHCl
3
18 h
24 h
24 h
24 h
80 C
55
30
55
43
o
CH Cl
2
2
80 C
o
TBAI(2.0eq)
NIS (2.0 eq)
Ethanol
Ethanol
80 C
o
80 C
a
Reactions were performed with 1.1 mmol of 1a and 1.0 mmol of 2a. Yields are isolated
yields of chromatographically purified compounds
Result and discussion
We set out to identify the possible mild reaction conditions for
the model reaction between 2-methylaminopyridine, p-
toluenesulfonyl hydrazide and phenyl and results are listed in Table
1.
2
Initially the reaction was carried out using 1.0 eq of I as an
additive at room temperature. Gratifyingly, the 2-
phenylimidazo[1,5-a]pyridine was obtained with 46% yield after 12
h. Inspired by this result, the reaction of p-toluenesulfonyl
hydrazide, phenyl dithioester and 2-methylaminopyridine was
(
Table 1, entries 12 and 13). Thus the highest yield (87%) was
obtained in the presence of 2.2 eq of I in ethanol at 80 °C
Table 1, entry 3).
With the optimized reaction conditions in hand, the
2
(
o
stirred at 50 C for 12 h which again formed 2-phenylimidazo[1,5-
substrate scope was investigated and the results are shown in
Scheme 1. Remarkable tolerance toward electronic demands
of substituents on both dithioesters and p-toluenesulfonyl
hydrazide were studied under optimized reaction conditions.
Dithioesters bearing various substituents like –Me, –F at
different positions on the benzene ring was efficiently reacted
with p-toluenesulfonyl hydrazide to afford the desired
products with high to excellent yields (4a-4n). Dithioesters
with electron donating group (4b and 4j) and electron
a]pyridine with 55% but failed to produce sulfonated product. The
desired sulfonated product 3-sulfenylimidazo[1,5-a]pyridine was
o
obtained in 48% yield when the temperature was raised to 70 C
(Table 1, entry 2). Optimisation of additive loading was carried out
to improve the yield of 4a. On increasing the additive loading to 2.2
eq, the desired product was obtained with 87% yield respectively
(Table 1, entry 3). The additive failed to induce any positive impact
on the yield with further enhancement of its amount to 2.5 eq
(Table 1, entry 4). Thus the additive loading was optimized at 2.2 withdrawing groups (4d) on the phenyl ring were well
eq. The reaction was then performed in different common solvents tolerated. The sulfonyl hydrazide bearing electron –donating
like MeOH, THF, DMF, MeCN, ethyl acetate, CHCl
3
, CH
2
Cl
2
etc. groups (Me, O-Me) and electron withdrawing groups (F, NO
2
(
Table 1, entries 5–11). The better result was obtained in ethanol. and CF
3
) produced the desired product with high yields
Other iodide sources like TBAI and NIS were not as effective as I2
(scheme 1, 4g-4l).
2
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Scheme 2 Substrate scope for the synthesis of imidazolo[1,5-
a]pyridines and [1,2,4]-triazolo[4,3-a]pyridines
Scheme 3 A plausible reaction mechanism for the formation of
imidazolo[1,5-a]pyridines
novel method for the synthesis of imidazolopyridine in high yields
under mild condition and simple work up procedures.
N
N
N
N
N
N
N
N
Insight of this and as result of great importance of
functionalized imidazopyridines among natural and pharmaceutical
products, we explored out a procedure with several kinds of
substrates and the results are shown in Scheme 2.
F
F
5
a, (85%)
5b, (76%)
(rt, 4h)
5
c, (83%)
5d, (88%)
(rt, 2h)
A plausible mechanism for the the cyclization reaction leading
to imidazolo[1,5-a]pyridines is displayed in scheme 3. The reaction
of 2-methylaminopyridine 2 with phenyl dithioester 1 gives N-2-
pyridylmethyl thioamide A followed by the iodination at sulfur
generates intermediate B. Subsequent iodination again at sulfur
takes place to form an electrophilic intermediate C, which
undergoes intramolecular substitution by the pyridine nitrogen at
the immino carbon to form D. Finally, the aromatization of D takes
place to yield the product 5.
(
rt, 2h)
(
rt, 2.5h)
N
N
N
N
N
N
S
N
N
N
N
O
5e, (89%)
5f, (81%)
(rt, 3h)
5g, (80%)
(rt, 4h)
5h, (78%)
(rt, 3 h)
(rt, 3h)
Conclusions
2
An efficient I -mediated three-component reaction in one pot
N
N
has been developed for the synthesis of 3-sulfenylimidazopyridines
from dithioesters, 2-aminopyridines, and sulfonyl hydrazides. This
tandem reaction process involves a C–H bond functionalization
strategy for the formation of C–N and C–S bonds without any
oxidants. The reaction proceeds through the cleavage of sulfur–
nitrogen and sulfur–oxygen bonds by sulfonyl hydrazides as a thiol
surrogate in. This methodology is applicable to both alkyl and aryl
sulfonyl hydrazides, and various imidazopyridines having broad
functionalities. Simple, one pot, broad substrate scope, transition
metal free and mild reaction conditions are the attractive features
of the present protocol. In addition, imidazopyridines can also be
formed under the optimized reaction conditions without the use of
disulfides.
N
N
O
5
i, (76%)
5j, (73%)
(rt, 3h)
(
rt, 3h)
The aliphatic sulfonyl hydrazides were successfully underwent the
current reaction giving desired products under optimized reaction
condition (scheme 1, 4m and 4n). The structure is also confirmed by
single X-ray crystal studies for the compound 4h.
To extend the scope of the methodology, a variety of
dithioesters were allowed to react with 2- methylamino pyridine or
hydrazine pyradine. Without the use of phenyl sulfonyl hydrazides,
Acknowledgements
iodine mediated reaction of dithioesters and methylaminopyridine Financial support from the DST-Fastrack, New Delhi (grant No.
easily afforded the intermediate imidazo[1,5-a]pyridines without SERB/F/5061/2013-14
dated 31-10-2013) is gratefully
any oxidant. Number of protocols has been developed to synthesize acknowledged. We also thank NMR Facility, Institute of Excellence,
2
0-23
imidazopyridines,
which suffers from disadvantages like the use University of Mysore, Manasagangotri, Mysuru-570006, India for
2
0a
20b
of strong acidic, corrosive reagents such as POCl
3
,
SOCl
2
21b
,
spectral data.
21a
Lawesson’s reagent and a modified Mitsunobu reaction. In
Notes and references
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Tandem Approach for the Synthesis of 3-Sulfenylimidazo[1,5-a]pyridines from Dithioesters
a
a
a
b
Ajjahalli. B. Ramesha, Chottanahalli. S. Pavan Kumar, Nagarakere. C. Sandhya, Manikyanahalli. N. Kumara, Kempegowda
a
a
Mantelingu * and Kanchugarakoppal. S. Rangappa, *