Base-mediated 1,3-dipolar cycloaddition of pyridinium bromides with bromoallyl sulfones: a facile access to indolizine scaffolds

Article abstract of DOI:10.1039/d0ob01696a

An expedient and transition-metal-free synthetic strategy has been developed for the construction of substituted indolizines from a unique combination of pyridinium salts and 2-bromoallyl sulfones. This approach does not compromise with the diverse substitutions on both the pyridinium salts and 2-bromoallyl sulfones. Wide substrate scope, operational simplicity, milder reaction conditions and good to moderate yields are the merits associated with the current approach. Moreover, this method provides two products which are amenable for the generation of a library of key indolizine building blocks. This journal is

Full text of DOI:10.1039/d0ob01696a

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DOI: 10.1039/D0OB01696A
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ARTICLE
Base-mediated 1,3-dipolar cycloaddition of pyridinium bromides
with bromoallyl sulfones: A facile access to indolizine scaffolds
Received 00th January 20xx,
Accepted 00th January 20xx
Chetna Jadala,‡, a Velma Ganga Reddy,‡, b,c Namballa Hari Krishna,a,b,d Nagula Shankaraiah,*a and
Ahmed Kamal*a, b, e
DOI: 10.1039/x0xx00000x
An expedient and transition-metal-free synthetic strategy has been developed for the construction of substituted
indolizines from a unique combination of pyridinium salts and 2-bromoallyl sulfones. This approach does not compromise
with the diverse substitutions on both the pyridinium salts and 2-bromoallyl sulfones. Wide substrate scope, operational
simplicity, milder reaction conditions and good to moderate yields are the merits associated with the current approach.
Moreover, this method provides two products which is amenable for the generation of a library of key indolizine building
blocks.
www.rsc.org/
condensation reaction of 2-pyridinecarbaldehyde with 1,3-
dicarbonyl compounds,7d intramolecular cyclization of
appropriately substituted pyridines,8-13 multi-component
coupling reactions (MCRs) on pyridine,14 and cross-
coupling/cyclization of pyridine derivatives and alkynes.15
However, aforementioned strategies are associated with usage
of expensive and toxic metals such as copper,9 platinum,10
silver,11 gold,12 and palladium13 as catalysts. Therefore, more
straightforward, cost effective and environmentally friendly
strategies to construct indolizines are highly needed.
Introduction
Aza-heteroarene compounds have always been recognized
as the frameworks of interest owing to their importance in the
field of organic and medicinal chemistry. In particular,
indolizine skeleton enjoyed a rich history as a significant
subclass of N-fused heterocycles, which is featured as a
valuable structural motif in numerous bioactive natural
products1 such as swainsonine, castanospermine and is a
central pharmacophore of pharmaceuticals2 like topotecan
(Fig. 1), exhibiting broad range of pharmacological activities
including anticancer, antiviral, antifungal, antihypertensive,
calcium channel blocking, anti-inflammatory, antioxidant, anti-
convulsant and phosphatase inhibitory activities etc. (Fig. 1).3
In addition to their pharmacological properties, indolizine
derivatives have profound applications in material sciences as
fluorescent materials and dyestuffs because of their
luminescent properties.4 These facts demand burgeoning
interest in the synthetic community towards the development
of simple and flexible methods for the efficient construction of
this motif.
OH
O
OH
OH
OH
N
H
H
HO
HO
N
)
OH
HO
O
N
N
N
O
HO
I
II
III
Topotecan (
(-)-swainsonine ( ) (+)-castanospermine ( )
O
O
O
O
S
N
HN
N
N
O
O
Over the past decade, tremendous efforts have been
diverted towards the efficient, versatile and concise
construction of indolizine chemotypes.5-18 Various traditional
synthetic strategies include: chichibabin reaction,6 cyclisation
on pyridine with 2,3-diarylcyclopropenone,7c Perkin
IV
V
)
Anticancer (
)
Anticonvulsant (
NC
Fig. 1 Structures of drugs and drug candidates containing indolizine ring
Recently, pyridinium ylides have been extensively exploited
as 1,3-dipolar cycloaddition partners in the construction of
various aza-heterocycles due to their efficiency and
a. Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Hyderabad-500 037, India, email:
ahmedkamal@iict.res.in, shankar@niperhyd.ac.in
environmental friendly features.16 Therefore,
a
few
b. Medicinal Chemistry
& Pharmacology, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India.
approaches have been evolved for the successful construction
of substituted indolizines utilizing pyridinium ylides.17 For
example, TEMPO-mediated cyclisation of pyridinium ylides
with electron deficient alkynes was described by Shi et al.,
c. Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science,
RMIT University, GPO Box 2476, Melbourne 3001, Australia.
d. Department of Chemistry, Hunter College, City University of New York, 695 Park
Avenue, NY 10065, USA.
e. School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New
Delhi, 110062, India.
‡Both the authors share equal authorship
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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(Scheme 1a).14c Recently, Iron (III)-catalyzed multi-component forced us to optimize the reaction parameters such as base,
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DOI: 10.1039/D0OB01696A
synthesis by the combination of pyridine, diazo compound and solvent, temperature and duration of the reaction in detail.
alkynes via an in situ generated pyridinium ylides was achieved During the attempts of base optimization for this
by Douglas et al., (Scheme 1b).18 In spite of the considerable transformation, a little improvement in the yield of 5a along
efforts made a more practical and convenient approach with unavoidable amounts of 5a’ was observed when Na2CO3
avoiding metal catalyst is always highly desirable considering was replaced with K2CO3 under similar reaction conditions
the ubiquity and importance of indolizine frameworks.
(entry 3, Table 1). In this perspective, we thought of balancing
On the other hand, allenyl sulfones captivated as a 2 the yields of both the products and isolate them. It is also clear
carbon electrophilic building blocks in the cycloaddition that bases such as NaHCO3, NaOAc and K3PO4 had virtually no
reactions.19 As a part of our ongoing research in the incremental effect on the yields of the reaction (entries 4, 5, &
development of new synthetic methodologies on cycloaddition 6, Table 1). Fortunately, Cs2CO3 was identified to be the best
reactions,20 we hypothesized that if pyridinium ylides and base of choice as we could observe a significant increase in the
sulfonyl allenes were generated in situ, then it would lead to a yields of the products 5a and 5a’ (entry 7-9, Table 1). However,
[3+2] cycloaddition, ultimately rendering the indolizine increase in the base load from 1.1 equiv. to 1.5 equiv. had no
scaffolds. Herein, we report our efforts towards a base significant improvement in the yield of the products (entry 10,
promoted cycloaddition on pyridinium bromides with Table 1). Moreover, a model reaction in the absence of base
bromoallyl sulfones towards the construction of substituted did not deliver any desired products even in trace amounts
indolizines (Scheme 1c).
(entry 11, Table 1).
Table 1. Optimization of the reaction conditions for 5a and 5a’a
CONMe2
Shi et al., 2016
R1
O
TEMPO
EWG
(a)
R2
N
N
Br
Ph
Br
O
O
S
Ph
O
O
Douglas et al., 2017
base, solvent
time, temp.
Br-
O
S
O
N
N
R3
N2
N
Fe(TPP)Cl
16 h
R1
R3
(b)
N
R2O2C
O
N
O
R2O2C
SO2PhR1
3a
4a
5a'
5a
Br
O
Our work:
yield (%)b
5a 5a’
ndc
temp
(oC)
rt
time
(h)
12
12
12
12
12
12
12
12
8
O
Cs2CO3
entry
base(mmol) solvent
O
S
N
(c)
N
N
CH3CN, rt, 8 h
Br
O
O
1
2
Na2CO3(1.1)
Na2CO3(1.1)
K2CO3(1.1)
NaHCO3(1.1)
NaOAc(1.1)
K3PO4(1.1)
Cs2CO3(1.1)
Cs2CO3(1.1)
Cs2CO3(1.1)
Cs2CO3(1.5)
-
DMF
DMF
ndc
11
30
30
28
30
45
65
66
65
ndc
R
R
R
R1
100
100
100
100
100
100
100
80
4
10
3
DMF
Scheme 1. Comparison of previous approaches with the present protocol towards the
synthesis of indolizines.
4
DMF
trace
16
5
DMF
6
DMF
14
Results and discussion
7
DMF
28
At the outset, we focused our attention on the synthesis of
model substrates 3a (treating pyridine with p-methoxy
bromoacetophenone) and 4a using earlier reports.21,22 Initially,
we presumed to use the purified allenyl sulfones obtained
after the treatment of bromoallyl sulfones with cesium
carbonate. However, an inseparable mixture of allenyl sulfone
and propargyl sulfones was resulted after work-up and column
purification, therefore, utilization of bromoallyl sulfones (4a)
as such without any functionalization appeared to be more
appropriate, which aids in pot-economy and efficacy aspects.
To test the hypothesis, we commenced our initial investigation
by treating 3a (0.5 mmol) with 4a (0.5 mmol) in the presence
of Na2CO3 (1.1 mmol) in DMF (4 mL) at room temperature,
which resulted in formation of no desired product even after
stirring for 12 h (entry 1, Table 1). As the reaction was sluggish
at room temperature, an attempt at elevated temperature
(100 oC) under the similar reaction conditions resulted in
formation of the desired products (5a and 5a’), albeit in low
yields (11 and 4%, entry 2, Table 1). These encouraging results
8
DMF
30
9
CH3CN
CH3CN
CH3CN
32
10
11
rt
8
32
rt
12
ndc
aReactions were performed with 3a (0.5 mmol), 4a (0.5 mmol) bIsolated yields.
cn.d = not detected.
After identifying the suitable base for this transformation,
we diverted our attention towards the optimization of other
reaction parameters such as solvent, reaction time and
temperature (Table 1). Substitution of DMF with easier to
handle solvent CH3CN resulted in considerable improvement in
the yield of the products (5a and 5a’) when the reaction was
performed at 80 C for 8 h (entry 9, Table 1). After a brief
optimization, we are delighted to conclude that the reaction
can also be conducted equally well at room temperature
o
2 | J. Name., 2012, 00, 1-3
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omitting the reflux conditions, using Cs2CO3 as a base in CH3CN tolerated with all pyridinium ylides bearing electVrioewn-AdrtoiclneaOtnilninge
(entry 10, Table 1).
and electron-withdrawing substituenDtOs I: 1t0o.1039d/eDl0ivOeBr016t9h6Ae
Having optimized reaction conditions in hand, we sought to corresponding products in good yields. In consistent with the
explore the substrate scope of various pyridinium bromides simple 2-bromoallyl sulfone and good yields were observed
and 2-bromoallyl sulfones. Initially, the substrate scope of with pyridinium bromides containing electron donating
pyridinium bromides was examined by treating variously substitutions such as methyl (6b), methoxy (6c) and phenyl
substituted pyridinium ylides with simple 2-bromoallyl (6g). However, comparably lesser yields were observed with
sulfones (Table 2). A wide array of electron-donating and electron-withdrawing substituents such as F, Cl, CN and NO2
electron-withdrawing substituents on different positions of the (6d, 6e, 6f and 6h, Table 3).
aryl ring of the pyridinium bromides underwent very smooth
Table 3. Substrate scope of the pyridinium bromides and 2-bromoallyl sulfones for the
1,3-dipolar cycloaddition to render corresponding products
synthesis of substituted indolizinesa
5a‒5h’ in moderate to very good yields (Table 2). However,
the electronic effects of the substituents have considerable
impact on the reaction efficacy and yields. In general,
pyridinium bromides bearing electron-donating substituents
Br
O
O
S
O
such as methyl (5b), methoxy (5c), and phenyl (5g) on the aryl
Cs2CO3 (1.1 mmol)
Br-
O
S O
N
N
N
ring were well tolerated to provide the desired products in
moderate to good yields (Table 2). In contrast, pyridinium
bromides with electron-withdrawing groups like CN and NO2
on the aryl ring of pyridinium bromide were less tolerated
yielding corresponding products in lesser yields. It is worth
mentioning that, substrates bearing halo substituents (F, Cl)
were also amenable with the optimized reaction conditions to
deliver the corresponding products in good yields (5d and 5e,
Table 2).
CH3CN, rt, 8 h
R
O
O
R
3a-h
4b
R
5a'-h'
6a-h
O
O
O
S
O
N
S
S
S
O
O
O
O
N
N
N
O
O
O
O
O
F
6b
5b':
6c
5c':
6d
5d':
: 60%,
29%
: 58%,
31%
: 43%, 35%
6a
5a':
: 62%,
31%
Table 2. Substrate scope of the pyridinium bromides and 2-bromoallyl sulfones for the
synthesis of substituted indolizinesa
O
S
O
O
S
O
O
O
S
S
O
O
Br
N
O
O
S
N
N
N
O
O
Cl
Cs2CO3 (1.1 mmol)
O
Br-
O
S
O
NO2
N
O
CN
25%
O
Ph
22%
N
N
CH3CN, rt, 8 h
R
6e
5e':
32%
: 42%,
6g
5g':
6f:
5f':
: 45%,
38%,
6h
: 39%,
5h':
24%
O
O
aReactions were performed with 3a (0.5 mmol), 4b (0.5 mmol) with 1.1 mmol of
Cs2CO3, bIsolated yields.
R
3a-h
4a
5a'-h'
R
5a-h
O
N
O
S
O
S
S
O
O
O
The mechanistic rationale for the base mediated 1,3-
dipolar cycloaddition of pyridinium bromide with bromoallyl
sulfones for the synthesis of indolizine derivatives is proposed
in Scheme 2. Initially, a base promoted generation of allenyl
sulfone (iii) and pyridinium ylide (ii) intermediates was
assumed from the corresponding starting materials, which
undergo 1,3-dipolar cycloaddition to deliver intermediate iv.
The intermediate iv undergoes subsequent isomerization (1,3-
H shift) to afford intermediate v which further undergoes
transformation by either aerial oxidation/oxidative
aromatization or extrusion of sulfonyl group as phenyl/tolyl
sulfinate to afford corresponding desired products 5a and 5a’
respectively.
N
N
N
N
N
O
O
O
O
O
O
O
O
5b: 62%
5b'
: 30%
5a: 63%
5c: 60%
5c'
: 32%
5a': 33%
O
S
O
O
S
S
O
O
O
N
N
O
N
N
N
N
O
O
CN
O
F
O
O
Cl
CN
F
Cl
5d': 33%
5e': 28%
5d: 43%
5e: 45%
5f: 40%
5f':
22%
O
S
O
S
O
O
N
N
N
O
N
O
Ph
O
NO2
NO2
O
Ph
5g: 39%
5h': 29%
5h: 41%
5g': 23%
aReactions were performed with 3a (0.5 mmol), 4a (0.5 mmol) with 1.1 mmol of
Cs2CO3, bIsolated yields.
The feasibility of this method was further extended to
evaluate the substrate scope of 2-bromoallyl sulfones.
Accordingly, 2-bromoallyl sulfones substituted with a methyl
group on the sulfone ring was made to react with differentially
substituted pyridinium bromides (Table 3), which is well
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Br
O
Br
O
pressure using freshly distilled solvents. All evVaiepwoArratitcileoOnnlionef
solvents was carried out under reducedDpOrIe: s10su.1r0e39o/Dn0HOeB0id1o69lp6hA
rotary evaporator below 45 °C.
O
O
C
Cs2CO3
CsBr
O
S
O
S
O
S
Base
N
N
O
Br
General procedure for the synthesis of 1-(2-oxo-2-
phenylethyl)pyridin-1-ium bromide (3a-i):
iii
(
)
ii
( )
4a
i
( )
3a
O
O
O
A mixture of phenacyl bromide (1, 10 mmol) and pyridine (2,
10 mL) was taken in a 50 mL round bottomed flask and stirred
at rt until the completion of reaction. After confirmed by TLC,
the reaction mixture was filtered through vacuum and the
residue was washed with hexane (20 mL) then dried over
vacuum to afford the desired products 3a-h.
a
N
N
N
H
b
H
Aerial
oxidation
(O)
O
S
O
O
O
S
O
S
O
v
( )
iv
(
)
5a
O
S
General
bromoallyl)sulfonyl)benzene
bromoallyl)sulfonyl)-4-methylbenzene (4b):
procedure
for
the
synthesis
of
((2-
1-((2-
-O
a
(4a)
and
O
N
Sodium benzenesulfinate or sodium p-toluenesulfinate (10
mmol) was added to DMF (10 mL) in a round-bottom flask and
left to stir for 20 min. To this suspension, 2,3-dibromopropene
(1.22 mL, 10 mmol) was added, and the mixture was stirred at
room temperature under nitrogen atmosphere for 12 h. After
completion of the reaction, ice and ethyl acetate (20 mL) were
added and the mixture was stirred for 15 min. Water (20 mL)
was added, and the organic layer was separated in a
separatory funnel. The aqueous layer was extracted with ethyl
acetate (2×15 mL); the organic layers were combined, and the
solvent was evaporated on a rotavapor. The residue obtained
was purified by column chromatography on silica gel using
ethyl acetate/hexane mixtures as the eluent to obtain pure
samples of 4a or 4b.23
5a'
Scheme 2. Plausible reaction pathway.
Conclusion
In summary, we have developed a simple, efficient and
practical transition-metal-free approach for the synthesis of
densely functionalized (2-methyl-1-(phenylsulfonyl)indolizin-3-
yl)(phenyl) methanones from pyridinium bromides and
bromoallyl sulfones via in situ generation of pyridinium ylides
and electrophilic allenes under basic conditions. Broad
substrate scope, compatibility with many functional groups,
and simple experimental procedure with satisfactory yields are
the salient features of the current protocol. These novel
molecules synthesized in environmental friendly manner may
showcase advancement in potential applications in the drug
discovery and development.
General procedure for the synthesis of (2-methyl-1-
(phenylsulfonyl)indolizin-3-yl)(phenyl)methanone (5a-h’ and
6a-h):
A mixture of allyl sulfones (0.5 mmol) and CH3CN was taken in
a 25 mL round bottomed flask and stirred for 5 min; later
pyridinium salt (0.5 mmol) and cesium carbonate (1.1 mmol)
was added and left until the completion of reaction. After
confirmed by TLC, the reaction mixture evaporated to remove
CH3CN then was quenched with water and extracted with
EtOAc (25 mL×2), washed with brine (10 mL) and dried over
anhydrous Na2SO4, filtered and concentrated in vacuo to give
the crude products, which was further purified by silica gel
chromatography using an ethyl acetate/petroleum ether
gradient mixture to afford the desired products 5a-5h’ and 6a-
h
Experimental section
General information
Unless otherwise specified, all solvents and other reagents are
commercially available and used without further purification.
All reagents were weighed and handled in air at room
temperature. Column chromatography was performed on
silica gel (60-120 and 100-200 mesh). NMR spectra were
recorded on Bruker 500 NMR spectrometer Chemical shifts
were mentioned in parts per million (ppm, δ). Proton coupling
patterns are described as singlet (s), doublet (d), triplet (t),
quartet (q), doublet of doublet (dd), doublet triplet (dt) and
multipet (m). HRMS were determined in positive mode with
Agilent QTOF mass spectrometer 6540 series instrument.
Melting points are determined on an Electro thermal melting
point apparatus and are uncorrected. The names of all
compounds given in the experimental section were taken from
Chem. ultra, version 12.0. The reactions wherever anhydrous
conditions required are carried under nitrogen positive
(2-Methyl-1-(phenylsulfonyl)indolizin-3-
yl)(phenyl)methanone (5a). White solid, yield 63%; mp: 138–
141 °C; FT-IR (cm−1): 2957.4, 2921.1, 2851.5, 1600, 1492.4,
1386.3, 1082.8, 720.4; 1H NMR (500 MHz, DMSO-d6): δ 9.27 (d,
J = 7.1 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 7.94 – 7.90 (m, 2H), 7.66
(d, J = 9.0 Hz, 4H), 7.61 – 7.56 (m, 2H), 7.54 (d, J = 7.6 Hz, 3H),
7.22 (td, J = 7.0, 1.2 Hz, 1H), 2.06 (s, 3H).; 13C NMR (125 MHz,
DMSO-d6): δ 187.3, 147.5, 143.7, 140.4, 137.0, 133.6, 133.4,
132.8, 130.0, 129.6, 129.4, 129.3, 129.1, 128.8, 128.1, 126.3,
124.8, 122.9, 117.9, 115.9, 111.5, 13.0; HRMS (ESI): m/z calcd
4 | J. Name., 2012, 00, 1-3
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for C22H17NO3S 376.0963; found 376.0987 [M+H]+.;ESI(MS): 2H), 7.69–7.63 (m, 2H), 7.58 (t, J = 7.6 Hz, 2H), 7.28 (td, J = 7.0,
View Article Online
13
[M+H]+ 375.99.
1.2 Hz, 1H), 2.03 (s, 3H); C NMR (125 MHz, DMSO-d6): δ
185.7, 147.8, 144.6, 143.2, 137.1, 134.4, 133.0, 133.8, 130.2,
129.7, 129.5, 129.1, 129.9, 128.5, 126.8, 122.3, 118.72, 117.6,
116.7, 114.1, 111.1, 13.6; HRMS (ESI): m/z calcd for
C23H16N2O3S 401.0915; found 401.0930 [M+H]+..
DOI: 10.1039/D0OB01696A
(2-Methyl-1-(phenylsulfonyl)indolizin-3-yl)(p-
tolyl)methanone (5b). White solid, yield 62%; mp: 210–213 °C;
FT-IR (cm−1): 2968.3, 2926.8, 2856.8, 1738.9, 1598.4, 1380.4,
1230.6, 1082.9, 941.7, 764.4;1H NMR (500 MHz, DMSO-d6): δ
9.17 (d, J = 7.2 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 7.6 [1,1'-Biphenyl]-4-yl(2-methyl-1-(phenylsulfonyl)indolizin-3-
Hz, 2H), 7.70–7.53 (m, 6H), 7.36 (d, J = 8.0 Hz, 2H), 7.23–7.16 yl)methanone (5g). White solid, yield 55%; mp: 230–233 °C;
(m, 1H), 2.46–2.39 (m, 3H), 2.15–2.07 (m, 3H); 13C NMR (125 FT-IR (cm−1): 3023.2, 2951.1, 2856.3, 1738.6, 1616.2, 1334.5,
MHz, DMSO-d6): δ 187.6, 147.8, 143.5, 143.4, 137.5, 136.9, 1082.6, 968.2, 725.8; 1H NMR (500 MHz, DMSO-d6): δ 9.24 (d, J
133.8, 132.3, 130.8, 129.7, 129.6, 129.5, 129.2, 128.9, 128.6, = 7.0 Hz, 1H), 8.34 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H),
126.1, 123.0, 117.7, 115.9, 110.9, 21.6, 13.3; HRMS (ESI): m/z 7.86 (d, J = 8.3 Hz, 2H), 7.76 (dd, J = 11.7, 7.9 Hz, 4H), 7.65 (t, J
calcd for C23H19NO3S 390.1119; found 390.1129 [M+H]+.;ESI = 7.3 Hz, 1H), 7.59 (q, J = 6.9 Hz, 3H), 7.52 (t, J = 7.6 Hz, 2H),
(MS): [M+H]+ 389.95.
7.44 (t, J = 7.3 Hz, 1H), 7.24–7.19 (m, 1H), 2.17 (d, J = 14.9 Hz,
3H); 13C NMR (125 MHz, DMSO-d6): δ 186.3, 147.6, 144.8,
143.1, 139.1, 139.9, 138.3, 137.2, 135.6, 133.1, 133.0, 130.0,
130.5, 129.7, 129.6, 129.5, 128.5, 128.9, 128.8, 127.3, 127.9,
126.4, 123.0, 117.1, 115.3, 110.9, 13.6; HRMS (ESI): m/z calcd
for C28H21NO3S 452.1276; found 452.1292 [M+H]+..
(4-Methoxyphenyl)(2-methyl-1-(phenylsulfonyl)indolizin-3-
yl)methanone (5c). White solid, yield 60%; mp: 192–194 °C;
FT-IR (cm−1): 3006.2, 2961.2, 2851.3, 1738.5, 1592.2, 1465.1,
1337.1, 1018.9, 962.6, 764.2; 1H NMR (500 MHz, DMSO-d6): δ
9.06 (s, 1H), 8.30 (d, J = 7.1 Hz, 1H), 7.94 (s, 2H), 7.64 (d, J =
41.5 Hz, 6H), 7.13 (d, J = 29.2 Hz, 3H), 3.87 (s, 3H), 2.16 (s, 3H); (2-Methyl-1-(phenylsulfonyl)indolizin-3-yl)(2-
13C NMR (125 MHz, DMSO-d6): δ 186.5, 163.4, 147.3, 143.2, nitrophenyl)methanone (5h). White solid, yield 41%; mp: 150–
136.3, 133.5, 132.5, 131.3, 130.8, 129.7, 129.5, 129.4, 129.1, 151 °C; FT-IR (cm−1): 3004.1, 2968.1, 2836.3, 1737.6, 1623.2,
1
128.2, 128.4, 126.9, 123.3, 117.5, 115.5, 114.0, 110.7, 56.5, 1396.5, 1082.6, 948.2, 752.8; H NMR (500 MHz, DMSO-d6): δ
13.1; HRMS (ESI): m/z calcd for C23H19NO4S 406.1068; found 9.80 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.25 (dd, J = 8.2,
406.1088 [M+H]+..;ESI(MS): [M+H]+ 405.90.
0.9 Hz, 1H), 7.94–7.90 (m, 3H), 7.83 (ddd, J = 8.2, 6.3, 1.4 Hz,
1H), 7.76–7.72 (m, 2H), 7.65 (ddd, J = 6.6, 3.8, 1.2 Hz, 1H),
(4-Fluorophenyl)(2-methyl-1-(phenylsulfonyl)indolizin-3-
yl)methanone (5d). White solid, yield 43%; mp: 201–204 °C;
FT-IR (cm−1): 2924.0, 2851.9, 1738.3, 1617.4, 1598.0, 1379.6,
1229.3, 1008.8, 940.7, 727.0; 1H NMR (500 MHz, DMSO-d6): δ
9.22 (d, J = 7.0 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 7.5
Hz, 2H), 7.75 (dd, J = 8.5, 5.6 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H),
7.62–7.56 (m, 3H), 7.38 (t, J = 8.8 Hz, 2H), 7.21 (t, J = 6.6 Hz,
1H), 2.09 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 185.9, 165.0 (2-Methyl-1-tosylindolizin-3-yl)(phenyl)methanone
(d, JCF = 250.7 Hz), 143.78, 137.0, 136.9, 133.6, 133.3, 132.1 White solid, yield 62%; mp: 192–194 °C; FT-IR (cm−1): 3140.4,
(d, JCF = 9.2 Hz), 130.0, 129.7, 128.7, 128.2, 126.3, 122.1, 2971.1, 2889.5, 1738.3, 1608.3, 1446.5, 1398.3, 1228.8,
7.60–7.56 (m, 2H), 7.37 (td, J = 7.0, 1.3 Hz, 1H), 1.97 (s, 3H); 13
C
NMR (125 MHz, DMSO-d6): δ 185.1, 146.4, 143.7, 141.6, 137.4,
133.2, 132.5, 132.8, 131.5, 129.7, 129.6, 129.1, 128.5, 128.5,
126.9, 123.2, 117.2, 116.2, 116.5, 115.9, 114.4, 111.2, 21.4;
HRMS (ESI): m/z calcd for C22H16N2O5S 421.0813; found
421.0834 [M+H]+..
(6a).
1
117.9, 116.3 (d, JCF = 22.0 Hz), 115.5, 111.4, 13.2; HRMS (ESI): 1084.8, 758.4; H NMR (500 MHz, DMSO-d6): δ 9.27 (d, J = 7.0
m/z calcd for C22H16FNO3S 394.0868; found 394.0898 [M+H]+..; Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.65 (d,
ESI(MS): [M+H]+ 393.90.
J = 7.2 Hz, 3H), 7.62 – 7.57 (m, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.37
(d, J = 8.0 Hz, 2H), 7.21 (t, J = 6.9 Hz, 1H), 2.34 (s, 3H), 2.05 (s,
3H). 13C NMR (125 MHz, DMSO-d6): δ 187.3, 147.4, 144.0,
141.2, 140.46, 139.0, 138.5, 136.1, 133.7, 132.5, 130.9, 129.5,
129.8, 128.5, 128.6, 126.9, 124.5, 122.0, 117.2, 115.2, 111.2,
21.2, 13.1; HRMS (ESI): m/z calcd for C23H19NO3S 390.1119;
found 390.1129 [M+H]+..;ESI(MS): [M+H]+ 389.95.
(4-Chlorophenyl)(2-methyl-1-(phenylsulfonyl)indolizin-3-
yl)methanone (5e). White solid, yield 45%; mp: 210–215 °C;
FT-IR (cm−1): 3057.2, 3010.7, 2963.4, 1738.4, 1604.2, 1496.4,
1336.3, 1147.9, 1030.3, 750.4; 1H NMR (500 MHz, DMSO-d6): δ
9.27 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 7.94–7.90 (m,
2H), 7.69 (d, J = 8.3 Hz, 3H), 7.65–7.56 (m, 5H), 7.23 (t, J = 7.0
Hz, 1H), 2.10 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 186.4, (2-Methyl-1-tosylindolizin-3-yl)(p-tolyl)methanone
143.3, 137.7, 133.6, 131.3, 130.1, 129.0, 129.7, 128.1, 126.4, White solid, yield 60%; mp: 220–223 °C; FT-IR (cm−1): 2964.5,
(6b).
117.0, 115.9, 13.4; HRMS (ESI): m/z calcd for C22H16ClNO3S 2919.6, 2850.7, 1738.5, 1619.7, 1567.2, 1487.4, 1298.3,
1
411.0510; found 411.0510 [M+H]+..;ESI(MS): [M+H]+ 409.85.
1082.5, 721.9; H NMR (500 MHz, DMSO-d6): δ 9.16 (dd, J =
6.1, 1.0 Hz, 1H), 8.34–8.27 (m, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.56
(ddd, J = 8.0, 6.7, 1.7 Hz, 3H), 7.41–7.33 (m, 4H), 7.17 (td, J =
7.0, 1.3 Hz, 1H), 2.42 (d, J = 11.8 Hz, 3H), 2.35 (d, J = 11.9 Hz,
3H), 2.13–2.07 (m, 3H); 13C NMR (125 MHz, DMSO-d6): δ 187.4,
147.4, 144.3, 143.0, 141.8, 137.8, 136.5, 132.2, 130.8, 129.1,
129.2, 128.6, 128.1, 126.7, 124.4, 122.3, 117.9, 115.2, 114.5,
112.2, 111.6, 21.5, 21.2, 13.2; HRMS (ESI): m/z calcd for
4-(2-Methyl-1-(phenylsulfonyl)indolizine-3-
carbonyl)benzonitrile (5f). White solid, yield 40%; mp: 212–
215 °C; FT-IR (cm−1): 2961.2, 2853.3, 2224.5, 1738.5, 1576.2,
1496.2, 1339.3, 1234.6, 1082.5, 748.3; 1H NMR (500 MHz,
DMSO-d6): δ 9.43 (d, J = 7.1 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H),
8.02 (d, J = 8.3 Hz, 2H), 7.95–7.90 (m, 2H), 7.81 (d, J = 8.3 Hz,
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C24H21NO3S 404.1276; found 404.1289 [M+H]+..;ESI(MS): = 9.0, 6.9, 1.1 Hz, 1H), 7.55–7.50 (m, 2H), 7.47–7.43 (m, 1H),
View Article Online
[M+H]+ 403.95.
7.38 (d, J = 8.0 Hz, 2H), 7.21 (td, J = 7.0, 1.3 Hz, 1H), 2.36 (d, J =
7.4 Hz, 3H), 2.15 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ
186.8, 144.0, 141.0, 139.1, 136.8, 133.0, 130.5, 130.0, 129.6,
128.6, 127.4, 127.4, 126.2, 117.4, 115.6, 111.4, 21.4, 13.3;
HRMS (ESI): m/z calcd for C29H23NO3S 466.1432; found
466.1465 [M+H]+..;ESI(MS): [M+H]+ 465.90, 180.90, 285.85,
370.90, 445.0 and 466.90.
DOI: 10.1039/D0OB01696A
(4-Methoxyphenyl)(2-methyl-1-tosylindolizin-3-
yl)methanone (6c). White solid, yield 58%; mp: 201–203 °C;
FT-IR (cm−1): 3012.2, 2958.2, 2856.2, 1738.4, 1598.1, 1464.0,
1339.3, 1082.9, 968.6, 765.2; H NMR (500 MHz, DMSO-d6): δ
9.04 (d, J = 6.4 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 7.5
Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.59–7.48 (m, 1H), 7.37 (d, J =
1
7.4 Hz, 2H), 7.13 (d, J = 6.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 3.86 (2-Methyl-1-tosylindolizin-3-yl)(2-nitrophenyl)methanone
(s, 3H), 2.34 (s, 3H), 2.14 (s, 3H); 13C NMR (125 MHz, DMSO-d6): (6h). Off White solid, yield 39%; mp: 220–223 °C; FT-IR (cm−1):
δ 186.2, 163.0, 147.6, 143.6, 141.7, 138.4, 136.9, 132.7, 131.9, 2989.5, 2968.1, 2856.3, 1738.6, 1623.2, 1386.5, 1082.6, 954.2,
1
131.2, 130.6, 129.5, 129.2, 128.6, 128.9, 126.15, 123.3, 117.7, 752.8; H NMR (500 MHz, DMSO-d6): δ 9.44 (d, J = 7.1 Hz, 1H),
115.6, 114.8, 110.5, 56.2, 21.1, 13.9; HRMS (ESI): m/z calcd for 8.35 (d, J = 9.0 Hz, 1H), 8.05–7.99 (m, 2H), 7.84–7.78 (m, 3H),
C24H21NO4S 420.1225; found 420.1265 [M+H]+..
7.66 (ddd, J = 9.0, 5.6, 2.1 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.37
(t, J = 8.1 Hz, 2H), 7.27 (ddd, J = 7.0, 5.6, 1.3 Hz, 1H), 2.35 (s,
3H), 2.02 (s, 3H); HRMS (ESI): m/z calcd for C23H18N2O5S
434.4644; found 434.4658 [M+H]+..
(4-Fluorophenyl)(2-methyl-1-tosylindolizin-3-yl)methanone
(6d). White solid, yield 43%; mp: 210–215 °C; FT-IR (cm−1):
2956.7, 2918.4, 2850.3, 1714.2, 1599.1, 1489.4, 1398.3,
1229.3, 966.0, 725.4;1H NMR (500 MHz, DMSO-d6): δ 9.22 (d, J (2-Methylindolizin-3-yl)(phenyl)methanone (5a’). White solid,
= 7.1 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), yield 33%; mp: 140–143 °C; FT-IR (cm−1): 2948.4, 2924.1,
7.77–7.72 (m, 2H), 7.58 (dd, J = 12.0, 4.0 Hz, 1H), 7.40–7.35 (m, 2856.5, 1612, 1498.4, 1339.3, 1082.5, 728.4; 1H NMR (500
4H), 7.20 (td, J = 7.0, 1.1 Hz, 1H), 2.34 (s, 3H), 2.08 (s, 3H); 13
C
MHz, DMSO-d6): δ 9.63 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 8.8 Hz,
NMR (125 MHz, DMSO-d6): δ 185.9, 164.9 (d, JCF = 250.8 Hz), 1H), 7.58–7.49 (m, 5H), 7.29–7.23 (m, 1H), 6.99 (t, J = 6.6 Hz,
144.0, 141.0, 136.9, 133.2, 132.1 (d, JCF = 9.3 Hz), 130.5, 128.7, 1H), 6.48 (s, 1H), 1.83 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ
128.5, 126.2, 122.7, 117.4, 116.3 (d, JCF = 21.9 Hz), 115.6, 185.9, 142.2, 138.4, 134.3, 131.3, 129.5, 128.3, 128.5, 125.6,
111.5, 21.4, 13.2; HRMS (ESI): m/z calcd for C24H21NO4S 122.5, 121.8, 118.9, 113.1, 105.4, 15.3; HRMS (ESI): m/z calcd
408.1025; found 408.1035 [M+H]+..;ESI(MS): [M+H]+ 407.90.
for C16H13NO 236.1031; found 236.1043 [M+H]+..;ESI (QToF):
[M+H]+ 235.95.
(4-Chlorophenyl)(2-methyl-1-tosylindolizin-3-yl)methanone
(6e). White solid, yield 42%; mp: 218–220 °C; FT-IR (cm−1): (2-Methylindolizin-3-yl)(p-tolyl)methanone (5b’). White solid,
2958.3, 2921.8, 2852.0, 1738.4, 1631.1, 1463.9, 1380.0, yield 30%; mp: 202–205 °C; FT-IR (cm−1): 2961.4, 2923.0,
1230.6, 1029.9, 752.4; 1H NMR (500 MHz, DMSO-d6): δ 9.27 (d, 2853.0, 1738.4, 1586.2, 1494.4, 1339.3, 1229.6, 1134.9, 758.4;
J = 7.1 Hz, 1H), 8.36 – 8.28 (m, 1H), 7.80 (d, J = 8.3 Hz, 2H), 1H NMR (500 MHz, DMSO-d6): δ 9.54 (d, J = 7.0 Hz, 1H), 7.69–
7.69–7.66 (m, 2H), 7.61 (dq, J = 5.9, 2.1 Hz, 3H), 7.38 (d, J = 8.0 7.57 (m, 1H), 7.54–7.44 (m, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.23
Hz, 2H), 7.22 (td, J = 7.0, 1.3 Hz, 1H), 2.35 (s, 3H), 2.08 (s, 3H); (dd, J = 10.5, 4.9 Hz, 1H), 6.95 (dd, J = 9.6, 4.1 Hz, 1H), 6.47 (s,
13C NMR (125 MHz, DMSO-d6): δ 186.1, 147.4, 144.0, 140.8, 1H), 2.40 (s, 3H), 1.87 (t, J = 11.4 Hz, 3H); 13C NMR (125 MHz,
139.4, 137.2, 137.0, 133.4, 133.10, 130.0, 129.8, 129.2, 128.4, DMSO-d6): δ 185.0, 143.3, 141.3, 139.3, 137.1, 134.8, 129.4,
128.6, 126.1, 124.5, 122.6, 119.7, 117.4, 115.1, 114.3, 111.7, 128.1, 127.9, 126.7, 124.7, 121.6, 118.7, 113.8, 105.6, 21.4,
21.3, 13.3; HRMS (ESI): m/z calcd for C24H21NO4S 425.0666; 15.1; HRMS (ESI): m/z calcd for C17H15NO 250.1187; found
found 425.0685 [M+H]+..;ESI(MS): [M+H]+ 423.85, 425.85 and 250.1198 [M+H]+..;ESI(MS): [M+H]+ 249.95.
426.80.
(4-Methoxyphenyl)(2-methylindolizin-3-yl)methanone (5c’).
4-(2-Methyl-1-tosylindolizine-3-carbonyl)benzonitrile
(6f). White solid, yield 70.8%; mp: 150–151 °C; FT-IR (cm−1): 3008.8,
White solid, yield 38%; mp: 230–234 °C; FT-IR (cm−1): 2956.2, 2968.3, 2846.3, 1738.3, 1567.2, 1455.1, 1337.1, 1021.9, 962.8,
2848.3, 2221.5, 1738.3, 1598.1, 1498.2, 1343.3, 1230.6, 764.1; 1H NMR (500 MHz, DMSO-d6): δ 9.42 (d, J = 7.0 Hz, 1H),
1
1082.2, 752.3; H NMR (500 MHz, DMSO-d6): δ 9.44 (d, J = 7.1 7.66–7.52 (m, 3H), 7.18 (t, J = 7.4 Hz, 1H), 7.12–7.01 (m, 2H),
Hz, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.05–7.99 (m, 2H), 7.84–7.78 6.91 (t, J = 6.8 Hz, 1H), 6.46 (s, 1H), 3.85 (d, J = 1.8 Hz, 3H), 1.95
(m, 3H), 7.66 (ddd, J = 9.0, 5.6, 2.1 Hz, 1H), 7.47 (d, J = 7.9 Hz, (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 185.8, 162.9, 143.5,
1H), 7.37 (t, J = 8.1 Hz, 2H), 7.27 (ddd, J = 7.0, 5.6, 1.3 Hz, 1H), 137.2, 134.8, 133.9, 130.4, 129.6, 127.1, 124.6, 121.0, 118.7,
2.35 (s, 3H), 2.02 (s, 3H) ; HRMS (ESI): m/z calcd for 114.8, 113.7, 105.0, 55.4, 15.8; HRMS (ESI): m/z calcd for
C24H18N2O3S 415.1072; found 415.1097 [M+H]+..
C17H15NO2 266.1136; found 266.1158 [M+H]+..;ESI(MS): [M+H]+
265.95.
[1,1'-Biphenyl]-4-yl(2-methyl-1-tosylindolizin-3-
yl)methanone (6g). White solid, yield 52%; mp: 240–243 °C; (4-Fluorophenyl)(2-methylindolizin-3-yl)methanone
(5d’).
FT-IR (cm−1): 2964.5, 2920.7, 2851.3, 1712.8, 1603.1, 1464.3, White solid, yield 32%; mp: 183–185 °C; FT-IR (cm−1): 2961.3,
1
1254.1, 1082.3, 749.4; H NMR (500 MHz, DMSO-d6): δ 9.26– 2923.5, 2852.7, 1738.6, 1597.1, 1497.4, 1338.3, 1024.2, 963.6,
9.22 (m, 1H), 8.32 (dt, J = 9.1, 1.2 Hz, 1H), 7.89–7.85 (m, 2H), 739.;1H NMR (500 MHz, DMSO-d6): δ 9.22 (d, J = 7.1 Hz, 1H),
7.83–7.79 (m, 3H), 7.78 (s, 1H), 7.77–7.74 (m, 2H), 7.59 (ddd, J 8.31 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.77–7.72 (m,
6 | J. Name., 2012, 00, 1-3
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2H), 7.58 (dd, J = 12.0, 4.0 Hz, 1H), 7.40–7.35 (m, 4H), 7.20 (td,
J = 7.0, 1.1 Hz, 1H), 2.34 (s, 3H), 2.08 (s, 3H); 13C NMR (125
MHz, DMSO-d6): δ 184.3, 163.9 (d, JCF = 247.9 Hz), 138.6,
138.1, 134.8, 130.9 (d, JCF = 8.8 Hz), 128.1, 125.1, 121.1, 118.4,
115.9 (d, JCF = 21.7 Hz), 113.8, 105.8, 15.7; HRMS (ESI): m/z
calcd for C16H12FNO 254.0936; found 254.0968 [M+H]+..;ESI
(MS): [M+H]+ 253.95.
Acknowledgement
View Article Online
DOI: 10.1039/D0OB01696A
We are thankful to the Department of pharmaceuticals (DoP),
the Ministry of Chemicals and Fertilizers Govt. of India, New
Delhi for the award of NIPER Fellowship. NIPER research
communication No. NIPER-H/2020/M055.
References
(4-Chlorophenyl)(2-methylindolizin-3-yl)methanone
(5e’).
White solid, yield 28%; mp: 202–205 °C; FT-IR (cm−1): 2957.4,
2921.3, 2851.0, 1743.4, 1592.2, 1462.6, 1377.1, 1229.9,
1
(a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 139; (b) J. P.
Michael, Nat. Prod. Rep., 2007, 24, 191; (c) J. P. Michael, Nat.
Prod. Rep., 2005, 22, 603; (d) E. F. Duran-Lara,
1
N
1088.7, 720.4; H NMR (500 MHz, DMSO-d6): δ 9.27 (d, J = 7.1
.Shankaraiah, D. Geraldo, L. S. Santos, J. Braz. Chem. Soc.,
2009, 20, 813.
Hz, 1H), 8.36 – 8.28 (m, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.69–7.66
(m, 2H), 7.61 (dq, J = 5.9, 2.1 Hz, 3H), 7.38 (d, J = 8.0 Hz, 2H),
7.22 (td, J = 7.0, 1.3 Hz, 1H), 2.35 (s, 3H), 2.08 (s, 3H); 13C NMR
(125 MHz, DMSO-d6): δ 186.1, 144.0, 139.4, 137.6, 133.4,
129.8, 129.2, 128.4, 128.6, 126.1, 122.1, 117.3, 115.1, 111.7,
21.3, 13.3; HRMS (ESI): m/z calcd for C16H12ClNO 271.0578;
found 271.05698 [M+H]+..;ESI(MS): [M+H]+ 269.95, 271.90.
2
(a) V. Sharma, V. Kumar, Med. Chem. Res., 2014, 23, 3593;
(b) S. P. Gupta, A. N. Mathur, A. N. Nagappa, D. Kumar, S.
Kumaran, Eur. J. Med. Chem., 2003, 38, 867; (c) K. M.
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3
4-(2-Methylindolizine-3-carbonyl)benzonitrile (5f’). White
solid, yield 22%; mp: 198–200 °C; FT-IR (cm−1): 2971.2, 2856.3,
2227.5, 1738.5, 1576.2, 1494.6, 1337.3, 1246.6, 1060.5, 747.3;
1H NMR (500 MHz, DMSO-d6): δ 9.73 (d, J = 7.1 Hz, 1H), 7.98
(d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.8 Hz,
1H), 7.36–7.29 (m, 1H), 7.05 (td, J = 6.9, 1.3 Hz, 1H), 6.52 (s,
1H), 1.79 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 185.6,
146.3, 143.5, 138.7, 133.1, 129.6, 129.0, 128.7, 128.4, 126.0,
118.4, 114.4, 113.1, 106.5, 79.7, 15.8; HRMS (ESI): m/z calcd
for C16H12ClNO 261.0983; found 261.0999 [M+H]+..;ESI(MS):
[M+H]+ 260.95.
4
[1,1'-Biphenyl]-4-yl(2-methylindolizin-3-yl)methanone (5g’).
White solid, yield 23%; mp: 225–228 °C; FT-IR (cm−1): 3029.1,
2971.1, 2836.3, 1737.6, 1600.2, 1334.5, 1029.6, 962.2, 727.8;
1H NMR (500 MHz, DMSO-d6): δ 9.61 (dd, J = 7.1, 0.7 Hz, 1H),
7.85–7.81 (m, 2H), 7.79–7.75 (m, 2H), 7.68–7.63 (m, 3H), 7.52
(dd, J = 10.5, 4.8 Hz, 2H), 7.46–7.41 (m, 1H), 7.26 (ddd, J = 8.7,
6.8, 1.0 Hz, 1H), 6.99 (td, J = 6.9, 1.3 Hz, 1H), 6.50 (s, 1H), 1.93
(s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 185.9, 147.4, 142.6,
140.9, 139.8, 138.3, 134.6, 129.5, 129.0, 128.2, 128.2, 127.2,
127.1, 126.5, 125.2, 124.3, 121.2, 119.6, 118.2, 113.8, 105.1,
15.2; HRMS (ESI): m/z calcd for C22H17NO 312.1344; found
312.1367 [M+H]+..;ESI(MS): [M+H]+ 312.00.
5
(2-Methylindolizin-3-yl)(2-nitrophenyl)methanone
(5h’).
6
7
8
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White solid, yield 53%; mp: 205–209 °C; FT-IR (cm−1): 3003.1,
2971.1, 2856.3, 1738.6, 1628.2, 1356.5, 1082.6, 950.2, 752.8;
1H NMR (500 MHz, DMSO-d6): δ 9.46 (d, J = 7.1 Hz, 1H), 8.39–
8.35 (m, 3H), 7.70–7.64 (m, 2H), 7.58 (dd, J = 10.5, 4.8 Hz, 2H),
7.29 (tt, J = 5.0, 2.5 Hz, 1H), 2.05 (s, 3H); ); 13C NMR (125 MHz,
DMSO-d6): δ 184.1, 143.0, 138.4, 137.6, 133.4, 129.8, 129.2,
128.3, 128.7, 126.1, 123.1, 115.3, 115.1, 112.7, 21.4, 13.5;
HRMS (ESI): m/z calcd for C16H12N2O3 280.2781; found
271.2790 [M+H]+..
Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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RMIT Classification: Trusted
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8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01696A
Base-mediated 1,3-dipolar cycloaddition of pyridinium bromides with
bromoallyl sulfones: A facile access to indolizine scaffolds
Chetna Jadala,‡, a Velma Ganga Reddy,‡, b,c Namballa Hari Krishna,a,b,d Nagula Shankaraiah,*a
and Ahmed Kamal*a, b, e
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Hyderabad 500037, India.
bMedicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500007, India.
cCentre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT
University, GPO Box 2476, Melbourne 3001, Australia
dDepartment of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY
10065, USA
eSchool of Pharmaceutical Education and Research (SPER) Jamia Hamdard, New Delhi,
110062, India.
‡ Both the authors share equal authorship
*Corresponding authors: Dr. Ahmed Kamal, E-mail.: ahmedkamal@iict.res.in and Dr. Nagula
Shankaraiah, E-mail.: shankar.niperhyd@gov.in
A mild, transition-metal-free strategy has been described for the construction of substituted indolizines by 1,3-dipolar
cycloaddition of pyridinium bromides with bromoallyl sulfones in the presence of base.