Synthesis of Indolizines through Oxidative Linkage of C-C and C-N Bonds from 2-Pyridylacetates

Article abstract of DOI:10.1021/acs.joc.5b00477

Synthesis of indolizine-1-carboxylates through the Ortoleva-King reaction of 2-pyridylacetate followed by the Aldol condensation under mild reaction conditions has been described. This protocol is compatible with a broad range of functional groups, and it has been also successfully extended to unsaturated ketones, bringing about the regioselective formation of benzoyl-substituted indolizines through Michael addition followed by C-N bond formation, which are difficult to prepare by previous methods in a single step.

Full text of DOI:10.1021/acs.joc.5b00477

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Note
Synthesis of Indolizines Through Oxidative Linkage
of C-C and C-N bonds from 2-Pyridylacetates
Darapaneni Chandra Mohan, Chitrakar Ravi, Venkatanarayana Pappula, and Subbarayappa Adimurthy
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 Jun 2015
Downloaded from http://pubs.acs.org on June 5, 2015
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Synthesis of Indolizines Through Oxidative Linkage of C-
C and C-N bonds from 2-pyridylacetates
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Darapaneni Chandra Mohan,a Chitrakar Ravi,a Venkatanarayana Pappulaa and
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Subbarayappa Adimurthya*
aAcademy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
*E-mail: adimurthy@csmcri.org
Abstract:
Synthesis of indolizine-1-carboxylates through the Ortoleva−King reaction of 2-
pyridylacetate followed by the Aldol condensation under mild reaction conditions has been
described. This protocol is compatible with a broad range of functional groups, and it has
been also successfully extended to unsaturated ketones, bringing about the regioselective
formation of benzoyl-substituted indolizines through Michael addition followed by C-N bond
formation, which are difficult to prepare by previous methods in a single step.
Indolizines are the most privileged structural units of heterocycles, and considerable attention
has been paid in modern organic synthesis.1-3 Several molecules bearing the indolizine
scaffold have been proved to exhibit remarkable biological activities (Fig. 1) like
antimicrobial, anti-tubercular,4 antiinflammatory,5 anti-fungal,6 antioxidants,7 anticancer,8
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and inhibitor for vascular endothelial growth factor (VEGF).9-10 Substituted indolizines have
been also used in material science due to their rich luminescent properties.11-13
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Figure 1 Biologically active Indolizines
Considering the wide range of biological activities, indolizine derivatives are being used as
valuable leads for the design and synthesis of new biologically-active analogues. Because of
the importance of these molecules, some graceful methods have been developed, which
includes 1,3-dipolar cycloaddition of pyridinium N-methylides with electron-deficient
alkynes or alkenes,14-17 transition-metal-catalyzed intramolecular cycloisomerization of
pyridines,18-22 copper-catalyzed [3+2] cyclization of pyridines with alkenyldiazoacetates,23
multicomponent approaches,24-28 copper catalyzed annulation of 2-alkylazaarenes with α,β-
unsaturated carboxylic acids29 and I2-mediated oxidative cyclization30 and cyclization of
pyridine derivatives.31 Recently, we have reported copper-catalyzed aerobic oxidative
synthesis of imidazo[1,2-a]pyridines from pyridine derivatives.32 In continuation of our
interest on the synthesis of heterocycles, herein we describe the direct synthesis of
unsubstituted and substituted indolizine derivatives from commercially accessible pyridines,
acetophenones and chalcones (Scheme 1). The present method features a much broader scope
on indolizine synthesis, and eliminates the requirement of pyridinium N-methylides
derivatives.
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Scheme 1
In continuation of our studies on the synthesis of nitrogen-heterocycles33-38 we investigated
the reaction of 2-pyridylacetates and acetophenones as these starting substrates are
commercially available. Initially, we performed the reaction of 2-pyridyl ethyl ester 1a with
4-chloro acetophenone 2a with catalytic amount of copper(I) iodide and BF3·Et2O as additive
based on our previous results,32 only 5% of product 3a formation was observed in 5h in open
air (Table 1, entry 1). Traces of product formation were observed under oxygen atmosphere
(entry 2) and with other additives (entries 3 and 4). The reaction under neat conditions, 20%
of 3a was obtained (entry 5). Further, with other additives, the yield was raised to 32%
(entries 6 and 7). No improvement of yield was observed in absence of CuI, with other
oxidant (DTBP) and increase of temperature to 80° C (entries 8-11). However, using
elemental iodine as catalyst in place of copper iodide and DTBP as oxidant at 80° C, 68% of
3a was isolated (Table 1, entry 12). Under the same conditions but, without additive (CuBr2)
the yield was dropped to 10% (entry 13). By increasing the amount of iodine, with other
iodine sources, (KI, and TBAI), oxidants (TBHP, TBBP, K2S2O8 and H2O2) and other
solvents tested were either poorly effective or entirely ineffective for the present
transformation (Table 1, entries 14−24). As the co-operation of (I2−CuBr2) source showed the
best reactivity, it was chosen as the best combination for further reactions (Table 1, entry 12).
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Table 1. Optimization of conditions for 3aa
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a Conditions: 1a (0.30 mmol), 2a (0.90 mmol), catalyst, additive, solvent (0.50 mL), in an oil bath 5 h in argon
balloon, isolated yield
To demonstrate the efficiency and to explore the scope of the optimized conditions for the
synthesis of indolizines, different 2-pyridylacetates were investigated with acetophenone
derivatives (Table 2). The oxidative annulation of other 2-pyridylacetates such as –COOMe,
-COOiPr, -COOnBu, -COOtBu, and -COOCy, reacted well with 4-chloroacetophenone and
produced the corresponding indolizine esters 3b-3f in moderate to good yields. One of the
product 3b was further confirmed by single crystal XRD analysis (Fig 2). Although this route
was only realized for a particular class of substrates (2-pyridylacetate based), for the
formation of C-N bonds it represents a major development for the annulation strategy to
obtain indolizine derivatives under mild conditions without the requirement of pyridinium-N-
methylides.
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Figure 2. The crystal structure of 3b (40% probability factor for the thermal ellipsoids)
Table 2. Substrate scope of various 2-pyridylacetate and different acetophenonesa
a Conditions: 1 (0.30 mmol), 2 (0.90 mmol), I2 (20 mol%), CuBr2 (10 mol%), DTBP (0.30 mmol) in an oil bath
5 h, at 80 ᵒC h in argon balloon, isolated yield.
Then, the generality of this reaction was extended with more functionalized acetophenones 2
with various 2-pyridylacetate 1. The reaction was found to be very facile with both electron
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rich and electron-deficient acetophenones. The reaction of ethyl 2-(pyridin-2-yl) acetate (1a),
with neutral, electron rich and deficient groups at para-position of acetophenone (Me, Et,
OMe, Br) provided the desired products 3g-3k in moderate yields. There was no steric effect
was observed in case of 2, 6-methoxy acetophenone as it also gave 57% yield of desired
product 3l. Attempts were made with substrates having halogens at ortho position of
acetophenones, and obtained corresponding halo products 3m-3r in 52-76% yields. It may be
noted that, halide (Cl, Br and F) substituted indolizine derivatives were well tolerated, and
these products could be further useful in traditional cross-coupling reactions. We found that,
the present system is applicable to 2-acetylthiophene, to afford the desired products 3s in
moderate yield. Delightfully the present system is also applicable to 2-(pyridin-2-yl)
acetonitrile, and the nitrile substituted products 3t and 3u was obtained in 50% and 54%
yield. Reaction of 1a with propiophenone gave the desired product 3v in moderate yield. In
the case of aliphatic ketone like acetone, no reaction was observed 3w (the substrate
decomposed).
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Scheme 2. Control experiments
Then, to establish the reaction mechanism, some control experiments were performed
(Scheme 2). When the reaction of 2-ethylpyridine 6 was reacted with acetophenone 2a under
the optimized conditions, no product formation was observed. When the same reaction was
carried out in the presence of 1.0 equivalent I2, it resulted < 5% of yield. Further the reaction
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was performed by the addition of AgOAc under optimised conditions, to confirm the role of
catalytic iodine, but no product formation was observed. To confirm whether α-
bromo/iodoacetophenone gives the desired product under the optimized reaction conditions,
we performed the reaction of 1a with both α-iodoacetophenone (2aa) and α-Bromo
acetophenone (2ab) respectively, in the former case 70% of 3a was isolated and in the later
one traces of product was observed. These observations indicate that, catalytic iodine plays
crucial role to generate α-iodoacetophenone as intermediate in the present transformation.
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Based on the above control experiments and literature reports,39-41 we proposed a plausible
reaction mechanism as shown in scheme 3. Initially, acetophenone 2 reacts with molecular
iodine and generates α-iodoacetophenone A in situ, which will react with 2-pyridylactate 1
and generates another intermediate B through Ortoleva−King reaction. The intermediate B
undergoes aldol condensation and yield the desired product 3. The eliminated iodide ion (I-)
gets converted to molecular iodine to continue the cycle in presence of copper and oxidant.
Scheme 3. Plausible reaction mechanism
Scheme 4. Functionalization of 3-unsubstituted indolizines
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As the handful of indolizines were obtained under mild conditions, we thought of introducing
substituents regioselectively at C-3 position of 3a, to obtain the corresponding functionalized
indolizine derivatives 5 and 6 (Scheme 4).
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Generally, the insertion of acyl/benzoyl groups to azo-heterocycles is a difficult task and
often requires forcible reaction conditions.42-44 To overcome these difficulties, we took on the
challenge to obtain directly benzoylated indolizines from chalcones and 2-pyridylacetates
under copper catalysis (for detailed investigation see Table S2) and good yields of desired
products were obtained under these optimised conditions (Table 3).
Table 3. Substrate scope of various 2-pyridylacetates with different chalconesa
aConditions: 1 (0.60 mmol), 8 (0.20 mmol), catalyst,(0.04 mmol) oxidant (0.40 mmol), solvent (1.0 mL), in an
oil bath 12 h at 110 ᵒC in argon balloon, isolated yield.
To the best of our knowledge, no reports exist to access these highly substituted indolizines
from commercially available starting substrates in one pot under mild conditions. Chalcone
8a was reacted with different 2-pyridylacetates such as–COOEt, –COOMe, –COOiPr, –
COOnBu, –COOtBu, and –COOCy, and obtained the corresponding indolizines 9a-9f in
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moderate to good yields. The product 9a was further confirmed by single crystal XRD
analysis (Fig S1). The presences of electron donating and withdrawing substituents in both
the phenyl rings of chalcones reacted well with 2-pyridylacetate and afford the corresponding
products 9g-9n in good yields (62% – 86%). The heteroatom substituted chalcone (E)-1-
phenyl-3-(thiophen-2-yl)prop-2-en-1-one also reactive and produced the substituted
indolizine 9o in moderate yield. Unfortunately the present system is not applicable for
ethylcinnamate (9p) and it was not included in Table 3.
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In conclusion, we have developed a new method for the synthesis of indolizine-1-
carboxylates by the co-operative (I2−CuBr2) catalysis under mild reaction conditions. This
protocol is compatible with a broad range of functional groups, and these molecules were
selectively functionalised at C-3 position to obtain sulfenylated and arylated products. In
addition, copper-catalyzed synthesis of aroylated indolizines in a single step was also
investigated.
Experimental Section:
General Experimental Section: All commercially available chemicals and reagents were
1
used without any further purification unless otherwise indicated. H and 13C NMR spectra
were recorded at 500 and 125 MHz respectively. The spectra were recorded in CDCl3 as
solvent. Multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); m
(multiplet); dd (doublet of doublets), etc. and coupling constants (J) were given in Hz.
Chemical shifts are reported in ppm relative to TMS as an internal standard. The peaks
1
around delta values of H NMR (7.26), and 13C NMR (77.0) are correspond to deuterated
solvent chloroform. The mass analyser type TOF used for the HRMS measurements. Mass
spectra were obtained using electrospray ions impact (ESI) ionization method. Progress of the
reactions was monitored by thin layer chromatography (TLC). All products were purified
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through column chromatography using silica gel 100-200 mesh size using hexane/ethyl
acetate as eluent unless otherwise indicated.
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Typical procedure for the synthesis of Ethyl 2-(4-chlorophenyl)indolizine-1-carboxylate
(3a): 49.5 mg (0.300 mmol) of ethyl 2-(pyridin-2-yl)acetate 1a, 138.6 mg (0.900 mmol) of 4-
chloroacetophenone (2a), I2 (0.060 mmol, 15.2 mg), CuBr2 (0.030 mmol, 6.6 mg), and DTBP
(0.300 mmol) were placed in a reaction tube. The tube containing the above mixture was
heated in an oil bath at 75-80 ᵒC for 5 h under an argon atmosphere (balloon). After
completion of the reaction, it was allowed to attain room temperature and add 20 mL of
saturated (Na2S2O3) hypo solution, extracted with EtOAc (20 mL X 2) and the solvent was
removed under reduced pressure. The left out crude product was then purified through
column chromatography using silica gel (5 % EtOAc/hexane) to afford 3a; 68% (60.5 mg)
yield:
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1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.45 (d, J =
8.0 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.22 (s, 1H), 7.07 (t, J = 6.5 Hz, 1H). 6.73 (t, J = 6.5
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Hz, 1H), 4.27 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3) δ
164.7, 136.7, 133.4, 133.0, 131.4, 131.1, 127.6. 125.6, 120.3, 113.6, 112.7, 101.4, 59.4, 14.3.
HRMS calcd for C17H15ClNO2 : 300.0791. Found: 300.0784.
Methyl 2-(4-chlorophenyl)indolizine-1-carboxylate (3b)
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(Eluent: 5% EtOAc/hexane); 54% yield (46 mg); H NMR (500 MHz, CDCl3) δ 8.23 (d, J =
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9.5 Hz, 1H), 7.98 (d, J = 6.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.23
(s, 1H), 7.10-7.07 (m, 1H), 6.74 (t, J = 6.5 Hz, 1H), 3.78(s, 3H). 13C NMR (125 MHz,
CDCl3) δ 165.2, 136.8, 133.4, 133.1, 131.5, 131.1, 127.8, 125.5, 122.7, 120.3, 113.7, 112.8,
101.1, 50.6. HRMS calcd for C16H13ClNO2: 286.0635. Found: 286.0638.
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Isopropyl 2-(4-chlorophenyl)indolizine-1-carboxylate (3c)
(Eluent: 5% EtOAc/hexane); 65% yield (60.7 mg); 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J
= 9.0 Hz, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H),
7.20 (s, 1H), 7.07-7.04 (m, 1H), 6.71 (t, J = 6.5 Hz, 1H), 5.5(septet, J = 6.5 Hz, 1H), 1.24 (d,
J = 6.5 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 163.3, 135.6, 132.5, 131.9, 130.2, 126.5,
124.5, 121.5, 119.3, 112.5, 111.7, 100.8, 65.7, 21.0. HRMS calcd for C18H17ClNO2:
314.0948. Found: 314.0952.
Tert-butyl 2-(4-chlorophenyl)indolizine-1-carboxylate (3d)
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(Eluent: 5% EtOAc/hexane); 66% yield (65.4 mg); H NMR (500 MHz, CDCl3) δ 8.13 (d, J
= 9.0 Hz, 1H), 7.86 (d, J = 7.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H),
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7.09 (s, 1H), 6.95 (t, J = 6.5 Hz, 1H), 6.61 (t, J = 6.5 Hz, 1H), 1.37(s, 9H). C NMR (125
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MHz, CDCl3) δ 163.2, 135.5, 132.8, 131.8, 130.2, 130.1, 126.8, 124.4, 121.3, 119.2, 112.3,
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111.8, 27.4. HRMS calcd for C19H19ClNO2: 328.1104. Found: 328.1092.
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Butyl 2-(4-chlorophenyl)indolizine-1-carboxylate (3e)
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(Eluent: 5% EtOAc/hexane); 67% yield (66.1 mg); 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J =
9.0 Hz, 1H), 7.87 (d, J = 7.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.10
(s, 1H), 6.99-6.96 (m, 1H), 6.79 (t, J = 6.5 Hz, 1H). 4.10 (t, J = 6.5 Hz, 2H), 1.49 (sextet, J =
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6.5 Hz, 2H), 1.19 (sextet, J = 6.5 Hz, 2H). 0.79 (t, J = 6.5 Hz, 3H). C NMR (125 MHz,
CDCl3) δ 164.8, 136.7, 133.5, 132.9, 131.3, 131.1, 127.6, 125.4, 122.6, 120.3, 113.6, 112.7,
101.4, 63.3, 30.7, 19.2, 13.6. HRMS calcd for C19H19ClNO2: 328.1104. Found: 328.1093.
Cyclohexyl 2-(4-chlorophenyl)indolizine-1-carboxylate (3f)
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(Eluent: 5% EtOAc/hexane); 61% yield (65.4 mg); H NMR (500 MHz, CDCl3) δ 8.24 (d, J
= 9.0 Hz, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.5 Hz, 2H),
7.19 (s, 1H), 7.06-7.03 (m, 1H), 6.70 (t, J = 6.5 Hz, 1H). 4.49 (septet, J = 4.0 Hz, 1H), 1.89-
1.86 (m, 2H), 1.63-1.60 (m, 2H), 1.52-1.49 (m, 2H), 1.44-1.30 (m, 4H), 1.26-1.22 (m, 2H).
13C NMR (125 MHz, CDCl3) δ 164.2, 136.6, 133.5, 132.9, 131.4, 131.1, 127.4, 125.4, 122.9,
120.3, 113.5, 112.6, 101.8, 71.7, 31.8, 15.4, 13.7. HRMS calcd for C21H21ClNO2 : 354.1261.
Found: 354.1254.
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Ethyl 2-phenylindolizine-1-carboxylate (3g)
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(Eluent: 5% EtOAc/hexane); 57% yield (45 mg); H NMR (500 MHz, CDCl3) δ 8.24 (d, J =
9.0 Hz, 1H), 7.99 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.0 Hz, 2H), 7.31
(t, J = 7.0 Hz, 1H), 7.20 (s, 1H), 7.03 (t, J = 7.5 Hz, 1H). 6.68 (t, J = 6.5 Hz, 1H), 4.25 (q, J =
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7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3) δ 164.9, 136.7, 134.9,
132.6, 129.8, 127.4, 126.9, 125.4 122.3, 120.2, 113.6, 112.5, 101.5, 59.2, 14.2. HRMS calcd
for C17H16NO2 : 266.1181. Found: 266.1188.
Ethyl 2-(p-tolyl)indolizine-1-carboxylate (3h)
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(Eluent: 5% EtOAc/hexane); 56% yield (47 mg); H NMR (500 MHz, CDCl3) δ 8.23 (d, J =
9.0 Hz, 1H), 7.84 (d, J = 6.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.14-7.09 (m, 3H), 6.93 (t, J
= 7.0 Hz, 1H), 6.58 (t, J = 6.5 Hz, 1H). 4.25 (q, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.21 (t, J = 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.9. 136.6, 132.6, 131.8, 129.7, 128.2, 125.4,
122.2, 120.2, 113.5, 112.4, 101.4, 59.2, 21.1, 14.2. HRMS calcd for C18H18NO2: 280.1338.
Found: 280.1324.
Ethyl 2-(4-ethylphenyl)indolizine-1-carboxylate (3i)
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(Eluent: 5% EtOAc/hexane); 51% yield (45.1 mg); H NMR (500 MHz, CDCl3) δ 8.24 (d, J
= 9.0 Hz, 1H), 7.84 (d, J = 6.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.13-7.11 (m, 3H), 6.95-
6.92 (m, 1H), 6.58 (t, J = 6.5 Hz, 1H), 4.18 (q, J = 7.5 Hz, 2H), 2.60 (q, J = 7.5 Hz, 2H).
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1.20-1.14 (m, 6H). C NMR (125 MHz, CDCl3) δ 164.9, 143.0, 136.6, 132.0, 129.7, 127.0,
125.4, 122.2, 120.2, 113.5, 112.4, 101.4, 59.2, 28.5, 15.5, 14.2. HRMS calcd for C19H20NO2:
294.1494. Found: 294.1490.
Ethyl 2-(4-methoxyphenyl)indolizine-1-carboxylate (3j)
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(Eluent: 5% EtOAc/hexane); 55% yield (48.6 mg); H NMR (500 MHz, CDCl3) δ 8.23 (d, J
= 9.0 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.19 (s, 1H), 7.03 (t, J = 6.5
Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.69 (t, J = 6.5 Hz, 1H), 4.27 (q, J = 7.5 Hz, 2H), 3.83 (s,
3H), 1.26 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.9, 158.8, 136.6, 130.9,
127.1, 125.4, 122.2, 120.2, 113.4, 113.0, 112.4, 101.3, 59.2, 52.2, 14.3. HRMS calcd for
C18H18NO3: 296.1287. Found: 296.1275.
Ethyl 2-(4-bromophenyl)indolizine-1-carboxylate (3k)
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(Eluent: 5% EtOAc/hexane); 65% yield (66.7 mg); 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J =
8.0 Hz, 1H), 7.94 (d, J = 6.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.19
(s, 1H), 7.06-7.03 (m, 1H), 6.71 (t, J = 6.5 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 1.25 (t, J = 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.7, 136.7, 133.8, 130.5, 125.4, 122.6, 121.1,
120.2, 113.5, 112.7, 101.2, 59.3, 14.2. HRMS calcd for C17H15BrNO2: 344.0286. Found:
344.0298.
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Ethyl 2-(2,6-dimethoxyphenyl)indolizine-1-carboxylate (3l)
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(Eluent: 5% EtOAc/hexane); 57% yield (56.6mg); H NMR (500 MHz, CDCl3) δ 8.10 (d, J =
9.0 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.13(s, 1H), 6.91 (t, J = 7.0
Hz, 1H), 6.79-6.76 (m, 3H), 6.5 (t, J = 6.5 Hz, 1H), 4.08 (t, J = 7.5 Hz, 2H). 3.68 (s, 3H),
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3.61 (s, 3H), 1.05 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3) δ 164.8, 151.6, 136.0,
127.9, 125.4, 125.3, 121.9, 119.9, 117.2, 113.6, 112.6, 112.2, 111.2, 102.9, 58.9, 55.9, 55.5,
14.0. HRMS calcd for C19H20NO4: 326.1394. Found: 326.1383.
Ethyl 2-(2-fluorophenyl)indolizine-1-carboxylate (3m)
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(Eluent: 5% EtOAc/hexane); 76% yield (61.1 mg); H NMR (500 MHz, CDCl3) δ 8.23 (d, J
= 9.5 Hz, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.38-7.29 (m, 2H), 7.24 (s, 1H0, 7.16-7.08 (m, 2H),
7.05-7.02 (m, 1H), 6.68 (t, J = 6.5 Hz, 2H), 4.22 (q, J = 7.5 Hz, 2H), 1.63 (t, J = 7.5 Hz, 3H).
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13C NMR (125 MHz, CDCl3) δ 164.7, 161.3, (d, J = 245 Hz), 136.3, 131,.8, 128.9, (d, J = 7.7
Hz), 125.5, 125.3, 123.2, 123.0, 122.3, 120.1, 115.0, (d, J = 22.5 Hz),113.9, 112.5, 102.6,
59.2, 14.0. HRMS calcd for C17H15FNO2: 284.1087. Found: 284.1081.
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Ethyl 2-(2-bromophenyl)indolizine-1-carboxylate (3n)
(Eluent: 5% EtOAc/hexane); 60% yield (61.5 mg); 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J =
9.0 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.33-7.29 (m, 2H), 7.21-7.17
(m 2H), 7.07-7.04 (m, 1H), 6.71 (t, J = 6.5 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 1.07 (t, J = 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.5, 136.8, 135.9, 131.9, 131.5, 130.8, 128.5,
126.4, 125.6, 124.7, 122.4, 120.1, 113.5, 112.6, 102.8, 59.1, 13.9. HRMS calcd for C17H15Br
NO2: 344.0286. Found: 344.0298.
Ethyl 2-(2-chlorophenyl)indolizine-1-carboxylate (3o)
(Eluent: 5% EtOAc/hexane); 70% yield (62.6 mg); 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J =
9.0 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.33-7.24 (m, 3H), 7.20 (s,
1H), 7.05 (t, J = 7.5 Hz, 1H), 6.70 (t, J = 7.0 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 1.21 (t, J =
13
7.0 Hz, 3H). C NMR (125 MHz, CDCl3) δ 164.6, 136.0, 134.6, 134.3, 131.5, 129.0, 128.8,
128.4, 125.8, 125.6, 122.4, 120.0, 113.6, 112.6, 102.8, 59.1, 13.9. HRMS calcd for C17H15Cl
NO2: 300.0791. Found: 300.0782.
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Isopropyl 2-(2-fluorophenyl)indolizine-1-carboxylate (3p)
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(Eluent: 5% EtOAc/hexane); 56% yield (49.5 mg); 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J =
9.0 Hz, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.38-7.30 (m, 2H), 7.24 (s, 1H), 7.16-7.08 (m, 2H),
7.04 (t, J = 7.0 Hz, 1H), 6.68 (t, J = 6.5 Hz, 1H), 5.13(Septet, J = 6.0 Hz, 1H), 1.16 (d, J = 6.0
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Hz, 6H). C NMR (125 MHz, CDCl3) δ 164.2, 161.3, (d, J = 244 Hz), 136.2, 131.8, 128.8,
(d, J = 7.7 Hz), 125.4, 125.3, 123.4, 123.2, 123.2, 122.2, 120.1, 115.0, (d, J = 22.2 Hz),
113.7, 112.5, 103.0, 67.4, 21.8. HRMS calcd for C18H17FNO2: 298.1243. Found: 298.1231.
Butyl 2-(2-bromophenyl)indolizine-1-carboxylate (3q)
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(Eluent: 5% EtOAc/hexane); 52% yield (58 mg); H NMR (500 MHz, CDCl3) δ 8.27 (d, J =
9.0 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.32-7.29 (m, 2H), 7.21-7.18
(m, 2H), 7.08-7.05 (m, 1H), 6.73 (t, J = 6.5 Hz, 1H), 4.10 (t, J = 6.5 Hz, 2H), 1.39 (q, J = 6.5
Hz, 2H). 1.10 (sextet, J = 6.5 Hz, 2H), 0.79 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)
δ 164.8, 136.9, 136.0, 132.0, 131.5, 130.7, 128.5, 126.4, 125.6, 124.7, 122.4, 120.1, 113.5,
112.6, 102.8, 63.2, 30.5, 19.1, 13.7. HRMS calcd for C19H19BrNO2Na: 395.0497. Found:
395.0497.
Butyl 2-(2-chlorophenyl)indolizine-1-carboxylate (3r)
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(Eluent: 5% EtOAc/hexane); 63% yield (62.2 mg); 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J =
9.0 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.544-7.42 (m, 1H), 7.34-7.32 (m, 1H), 7.39-7.24 (m,
2H0, 7.18 (s, 1H), 7.06 (t, J = 7.0 Hz, 1H), 6.70 (t, J = 7.0 Hz, 1H), 4.10 (t, J = 6.5 Hz, 2H),
1.14 (d, J = 6.5 Hz, 2H). 1.12 (sextet, J = 6.5 Hz, 2H), 0.80 (t, J = 6.5 Hz, 3H).13C NMR (125
MHz, CDCl3) δ 164.8, 136.1, 134.7, 134.3, 131.5, 128.9, 128.8, 128.3, 125.8, 125.5, 124.4,
120.0, 113.6, 112.6, 102.9, 63.2, 30.5, 19.0, 13.6. HRMS calcd for C19H19ClNO2: 328.1104.
Found: 328.1111.
Ethyl 2-(thiophen-2-yl)indolizine-1-carboxylate (3s)
Eluent: 5% EtOAc/hexane); 26% yield (20.8 mg); 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J =
9.0 Hz, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 3.5 Hz, 1H), 7.36 (s, 1H), 7.31(d, J = 5.0
Hz, 1H), 7.08-7.02 (m, 2H), 6.69 (t, J = 7.0 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H). 1.34 (t, J = 7.0
Hz, 3H).13C NMR (125 MHz, CDCl3) δ 164.7, 136.8, 135.5, 127.8, 126.6, 125.3, 124.8,
122.5, 120.3, 114.0, 112.8, 102.4, 59.4, 14.4. HRMS calcd for C15H14NO2S: 272.0745.
Found: 272.0738.
2-phenylindolizine-1-carbonitrile (3t)
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(Eluent: 5% EtOAc/hexane); 50% yield (33 mg); H NMR (500 MHz, CDCl3) δ 8.00 (d, J =
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= 7.5 Hz, 1H), 7.07-7.04 (m, 1H), 6.75 (t, J = 7.0 Hz, 1H), C NMR (125 MHz, CDCl3) δ
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139.0, 132.2, 131.7, 128.9, 128.0, 127.3, 126.0, 122.5, 117.7, 117.0, 113.2, 111.1, 80.0.
HRMS calcd for C15H11N2: 219.0922. Found: 219.0910.
2-(4-Chlorophenyl)indolizine-1-carbonitrile (3u)
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(Eluent: 5% EtOAc/hexane); 53% yield (40 mg); H NMR (500 MHz, CDCl3) δ 7.92 (d, J =
7.0 Hz, 1H), 7.60-7.59 (m, 2H), 7.54 (d, J = 9.0 Hz, 1H), 7.33-7.31 (m, 3H), 6.99 (t, J = 7.0
Hz, 1H), 6.68 (t, J = 6.5 Hz, 1H), 13C NMR (125 MHz, CDCl3) δ 139.0, 133.9, 130.7, 130.5,
129.1, 128.4, 126.0, 122.8, 117.7, 116.8, 113.4, 111.1, 80.0. HRMS calcd for C15H10ClN2:
253.0533. Found: 253.0536.
Ethyl 3-methyl-2-phenylindolizine-1-carboxylate (3v)
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(Eluent: 5% EtOAc/hexane); 32% yield (27 mg); H NMR (500 MHz, CDCl3) δ 8.22 (d, J =
9.0 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.33-7.26 (m, 5H), 7.00 (t, J = 8.5 Hz, 1H), 6.73 (t, J =
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6.5 Hz, 1H), 4,09 (q, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H). C NMR (125
MHz, CDCl3) δ 165.0, 135.5, 135.4, 130.6, 1289.6, 127.2, 126.6, 122.5, 121.4, 120.0, 119.5,
112.4, 101.6, 59.0, 14.1, 9.7. HRMS calcd for C18H18NO2: 280.1334. Found: 280.1336.
Ethyl 2-(4-chlorophenyl)-3-(phenylthio)indolizine-1-carboxylate (5) 45
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To a round-bottomed flask containing organic disulfide (0.10 mmol), appropriate 3a (0.20
mmol), CuI (3.0 mol %), was added DMSO (0.5 mL). The reaction mixture was allowed to
stir at 110 ᵒC for 10 h under atmospheric air the solutions were cooled to room temperature,
diluted with ethyl acetate (10 mL), and washed with water (3 X 10 mL). The organic phase
were separated, dried over MgSO4, and concentrated under vacuum. The residues were
purified by chromatography on silica gel using 3% ethyl acetate/hexane as the eluent and to
afford 5; 92% (75 mg) yield
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1H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 7.0 Hz, 1H), 7.33-7.29
(m, 5H), 7.23 (t, J = 8.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.84-6.79
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(m, 3H), 4.23(q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3) δ
164.2, 139.0, 138.4, 135.7, 133.48, 133.40, 133.7, 131.7, 129.2, 127.5, 127.4, 125.7, 125.3,
124.7, 124.6, 124.5, 120.0, 113.5, 110.1, 103.2, 59.5, 14.1. HRMS calcd for C23H19ClNO2 S:
408.0825. Found: 408.0811.
Ethyl 2-(4-chlorophenyl)-3-phenylindolizine-1-carboxylate (6) 46
A mixture of 3a (0.300 mmol), Iodobenzene (0.300 mmol), Pd(OAc)2 (3.0 mg, 5 mol%),
AgOAc (50.0 mg, 0.300 mmol), KOAc (59.0 mg, 0.600 mmol) in DMF (2 mL) was stirred at
90 °C under N2 for 12 h. Afterward, the mixture was cooled to room temperature and filtered
through a pad of celite. The crude product was dissolved in Et2O (20 mL), washed with water
(2 × 10 mL) and brine (10 mL), then dried over MgSO4. The solvent was evaporated under
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reduced pressure, and the residue was subjected to column chromatography to obtain the
desired product. (Eluent: 5% EtOAc/hexane); 71% yield (79.5 mg) isolated.
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1H NMR (500 MHz, CDCl3) δ 8.24 (t, J = 7.5 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.30-7.24
(m, 3H), 7.71-7.08 (m, 6H). 7.04-7.01 (m, 1H), 6.61 (t, J = 6.5 Hz, 1H), 4.15 (q, J = 7.0 Hz,
2H), 1.11 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.9, 136.0, 133.4, 132.5,
132.2, 130.8, 129.8, 129.1, 128.9, 128.2, 127.4, 127.3, 124.7, 123.2, 122.8, 122.7, 120.2,
112.7, 102.4, 59.3, 14.2. HRMS calcd for C23H19ClNO2 S: 376.1104. Found: 376.1103.
Typical procedure for the synthesis of ethyl 3-benzoyl-2-phenylindolizine-1-carboxylate
(9a): 99.0 mg (0.600 mmol) of ethyl 2-(pyridin-2-yl)acetate 1a, 41.6 mg (0.200 mmol) of
(E)-chalcone (8a), Cu(OAc)2 (0.040 mmol), FeCl2.4H2O (0.400 mmol), and dichlorobenzene
(1.0 mL), were placed in a reaction tube. The tube containing the above mixture was heated
in an oil bath at 110 ᵒC for 12 h under an argon atmosphere (balloon). After completion of the
reaction, it was allowed to attain room temperature and filtered the reaction mixture using
celite pad and washed with EtOAc. The crude product left our after the removal solvent of
under reduced pressure, was purified through column chromatography using silica gel (10 %
EtOAc/hexane) to afford 9a; 89% yield (68 mg).
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1H NMR (500 MHz, CDCl3) δ 9.61 (d, J = 6.5 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 7.40 (t, J =
8.5 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.14(t, J = 7.0 Hz, 1H), 7.08 (t, J = 3.5 Hz, 2H). 7.03-
6.98 (m, 6H), 4.16 (q, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)
δ 188.2, 164.3, 140.2, 139.2, 139.1, 133.8, 131.1, 130.8, 129.0, 128.0, 127.3, 127.0, 126.9,
126.6, 122.2, 119.6, 114.7, 104.7, 59.6, 13.4. HRMS calcd for C24H20NO3: 370.1443. Found:
370.1441.
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Methyl 3-benzoyl-2-phenylindolizine-1-carboxylate (9b)
(Eluent: 10% EtOAc/hexane); 67% yield (47.5 mg); 1H NMR (500 MHz, CDCl3) δ 9.52 (d, J
= 7.5 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.0 Hz, 2H),
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7.03 (t, J = 7.5 Hz, 1H), 7.02-7.00 (m, 2H), 6.96-6.91 (m, 6H), 3.67 (s, 3H). C NMR (125
MHz, CDCl3) δ 188.3, 164.6, 140.2, 139.2, 139.0, 133.6, 131.1, 131.0, 129.1, 128.0, 127.3,
127.1, 126.7, 122.3, 119.7, 114.8, 104.3, 51.8. HRMS calcd for C23H18NO3: 356.1287.
Found: 356.1295.
Isopropyl 3-benzoyl-2-phenylindolizine-1-carboxylate (9c)
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(Eluent:10% EtOAc/hexane); 69% yield (53 mg); H NMR (500 MHz, CDCl3) δ 9.62 (d, J =
7.0 Hz, 1H), 8.48(d, J = 9.0 Hz, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.35 (d, J = 7.0 Hz, 2H),
7.13(t, J = 7.5 Hz, 1H), 7.08-7.06 (m, 2H), 7.03-6.97 (m, 6H), 5.07(septet, J = 6.0 Hz, 2H).
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1.07 (d, J = 6.0 Hz, 6H). C NMR (125 MHz, CDCl3) δ 188.2, 163.8, 140.1, 139.3, 139.1,
134.0, 131.1, 130.8, 122.1, 119.6, 114.7, 105.2, 67.0, 21.6. HRMS calcd for C25H22NO3:
384.1600. Found: 384.1579.
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Butyl 3-benzoyl-2-phenylindolizine-1-carboxylate (9e)
(Eluent: 10% EtOAc/hexane); 81% yield (64 mg); 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J =
7.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 7.0 Hz, 2H), 7.14
(t, J = 7.5 Hz, 1H), 7.08-7.07 (m, 2H), 7.03-6.97 (m, 6H), 4.09 (t, J = 6.5 Hz, 2H). 1.39
(quintet, J = 6.5 Hz, 2H), 1.09 (sextet, J = 6.5 Hz, 3H), 0.78 (t, J = 6.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 188.2, 164.5, 140.1, 139.2, 133.9, 131.0, 130.8, 129.0, 127.9, 127.3,
127.1, 126.9, 126.6, 122.2, 119.6, 114.8, 104.7, 63.6, 30.4, 19.0, 13.6. HRMS calcd for
C26H24NO3: 398.1756. Found: 398.1758.
Cyclohexyl 3-benzoyl-2-phenylindolizine-1-carboxylate (9f)
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(Eluent: 10% EtOAc/hexane); 78% yield (66 mg); H NMR (500 MHz, CDCl3) δ 9.61 (d, J
= 7.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 7.40 (t, J = 7.0 Hz, 1H), 7.34 (d, J = 7.5 Hz, 2H),
7.14 (t, J = 7.5 Hz, 1H), 7.08-7.07 (m, 2H), 7.03-6.97 (m, 6H), 4.88-4.85 (m, 1H), 1.75-1.73
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(m, 2H), 1.48-1.42 (m, 2H), 1.26-1.11(m, 6H), 13C NMR (125 MHz, CDCl3) δ188.2, 163.8,
141.1, 139.3, 139.1, 134.0, 131.1, 130.8, 129.0, 127.9, 127.8, 127.0, 126.9, 126.7, 122.2,
119.7, 114.7,105.1, 72.1, 31.4, 25.2, 23.5. HRMS calcd for C28H26NO3: 424.1913. Found:
424.1897.
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Ethyl 3-benzoyl-2-(4-chlorophenyl)indolizine-1-carboxylate (9g)
(Eluent: 10% EtOAc/hexane); 80% yield (64.5 mg); 1H NMR (500 MHz, CDCl3) δ 9.62 (d, J
= 7.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H),
7.22 (t, J = 7.5 Hz, 1H), 7.06-6.94 (m, 7H), 4.18 (q, J = 7.0 Hz, 2H), 1.12 (t, J = 7.0 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 188.0. 164.0, 139.2, 139.1, 138.9, 133.0, 132.4, 132.3, 130.9,
128.9, 128.0, 127.5, 127.3, 126.8, 122.2, 119.7, 115.0, 104.6, 59.7, 13.9 HRMS calcd for
C24H19ClNO3: 404.1053. Found: 404.1056.
Ethyl 3-benzoyl-2-(4-fluorophenyl)indolizine-1-carboxylate (9h)
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(Eluent: 10% EtOAc/hexane); 86% yield (66.5 mg); H NMR (500 MHz, CDCl3) δ 9.62 (d,
J = 7.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.0 Hz, 2H),
7.20 (t, J = 7.5 Hz, 1H), 7.05-7.02 (m, 5H), 6.68 (t, J = 5.5 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H),
1.11 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 188.0. 164.1, 162.8, (d, J = 245
Hz),, 139.2, 139.1, 132.78, (d, J = 7.8 Hz), 131.1, 131.0, 129.8, 129.0, 128.0, 127.4, 127.2,
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122.3, 119.7, 114.9, 113.7, (d, J = 21.5 Hz),, 104.6, 59.6, 13.9. HRMS calcd for C24H19FNO3:
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388.1349. Found: 388.1364.
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Ethyl 3-benzoyl-2-(4-cyanophenyl) indolizine-1-carboxylate (9i)
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(Eluent: 10% EtOAc/hexane); 73% yield (58 mg); 1H NMR (500 MHz, CDCl3) δ 9.63 (d, J =
7.0 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H), 7.93-7.88 (m, 1H), 7.48-7.45 (m, 2H), 7.30-7.27 (m,
4H), 7.24-7.18 (m, 3H), 7.10-7.02 (m, 3H), 4.17 (q, J = 7.0 Hz, 2H), 1.10 (t, J = 7.0 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 187.6, 163.7, 139.3, 139.1, 139.0, 137.9, 131.7, 131.3, 130.1,
128.9, 128.6, 128.1, 127.9, 127.6, 122.1, 119.8, 118.7, 115.3, 110.5, 104.6, 59.9, 13.9. HRMS
calcd for C25H19N2O3: 395.1396. Found: 395.1402.
Ethyl 3-benzoyl-2-(4-nitrophenyl)indolizine-1-carboxylate (9j)
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(Eluent: 10% EtOAc/hexane); 62% yield (51.5 mg); H NMR (500 MHz, CDCl3) δ 9.64 (d, J
= 7.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.0 Hz, 1H),
7.32 (d, J = 7.0 Hz, 2H), 7.25 (d, J = 7.5 Hz, 2H), 7.16 (t, J = 7.0 Hz, 1H), 7.10 (t, J = 7.0
Hz, 1H), 7.02(t, J = 7.5 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 187.6, 163.7, 146.4, 141.4, 139.1, 139.0, 137.5, 132.1, 131.9, 131.3,
128.9, 128.1, 127.7, 127.6, 122.1, 121.7, 119.8, 115.4, 104.6, 59.9, 13.9. HRMS calcd for
C24H19N2O5: 415.1294. Found: 415.1310.
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Ethyl 3-(4-methylbenzoyl)-2-phenylindolizine-1-carboxylate (9k)
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(Eluent: 10% EtOAc/hexane); 76 % yield (58 mg); 1H NMR (500 MHz, CDCl3) δ 9.51 (d, J =
7.0 Hz, 1H), 8.45 (d, J = 9.0 Hz, 1H), 7.37 (t, J = 7.0 Hz, 1H), 7.27(d, J = 7.0 Hz, 2H), 7.09-
6.98 (m, 5H), 6.80 (d, J = 7.0 Hz, 2H), 4.16 (q, J = 7.0 Hz, 2H), 2.18 (s, 3H), 1.17 (t, J = 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 188.1, 164.4, 140.5, 139.7, 139.0, 136.5, 134.0,
131.2, 129.3, 128.0, 127.9, 126.8, 126.7, 122.5, 119.7, 114.6, 104.4, 59.6, 21.3, 13.9. HRMS
calcd for C25H22NO3: 384.1600. Found: 384.1611.
Ethyl 3-(4-ethylbenzoyl)-2-phenylindolizine-1-carboxylate (9l)
(Eluent: 10% EtOAc/hexane); 77 % yield (61.5 mg); 1H NMR (500 MHz, CDCl3) δ 9.48 (d, J
= 7.0 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.0 Hz, 2H),
7.00-6.98 (m, 2H), 6.93-6.88 (m, 4H), 6.73 (d, J = 7.0 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H),
2.40 (q, J = 7.0 Hz, 2H), 1-03-0.98 (m, 6H).13C NMR (125 MHz, CDCl3) δ 188.1, 164.3,
147.6, 139.9, 139.0, 136.7, 134.0, 131.1, 129.3, 127.9, 126.8, 126.6, 122.4, 119.6, 114.6,
104.5, 59.6, 28.7, 15.2, 13.8. HRMS calcd for C26H24NO3: 398.1756. Found: 398.1762.
Ethyl 3-(4-chlorobenzoyl)-2-phenylindolizine-1-carboxylate (9m)
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(Eluent: 10% EtOAc/hexane); 77% yield (63 mg); 1H NMR (500 MHz, CDCl3) δ 9.63 (d, J =
7.0 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 2H),
7.09-7.00 (m, 5H), 6.96 (d, J = 8.5 Hz, 2H), 4.16 (q, J = 7.0 Hz, 2H), 1.16 (t, J = 7.0 Hz,
3H). 13C NMR (125 MHz, CDCl3) δ 186.7, 164.4, 140.4, 139.3, 137.7, 137.6, 133.1, 130.3,
128.0, 127.5, 127.4, 127.1, 126.8, 122.0, 119.7, 115.0, 104.9, 59.7, 13.8. HRMS calcd for
C24H19ClNO3: 404.1053. Found: 404.1052.
Ethyl 3-(4-nitrobenzoyl)-2-phenylindolizine-1-carboxylate (9n)
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(Eluent: 5% EtOAc/hexane); 83% yield (70 mg); H NMR (500 MHz, CDCl3) δ 9.85 (d, J =
7.0 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.52 (t, J = 7.0 Hz, 1H), 7.39
(d, J = 7.5 Hz, 2H), 7.13 (t, J = 7.0 Hz, 1H), 7.03-6.96 (m, 5H), 4.14 (q, J = 7.0 Hz, 2H),
1.13 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 185.6, 163.9, 148.1, 145.3, 141.3,
139.8, 133.6, 131.0, 129.5, 128.5, 128.4, 127.5, 126.9, 124.4, 121.7, 119.8, 115.0, 105.8,
59.8, 13.8. HRMS calcd for C24H19N2O5: 415.1294. Found: 415.1302.
Ethyl 3-benzoyl-2-(thiophen-2-yl)indolizine-1-carboxylate (9o)
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(Eluent: 5% EtOAc/hexane); 42% yield (32 mg); H NMR (500 MHz, CDCl3) δ 9.47 (d, J =
7.0 Hz, 1H), 8.43 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 727-
7.24 (m, 1H), 7.14-7.08 (m, 3H), 7.01 (t, J = 7.0 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.60-
6.58 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 188.2, 164.0, 139.3, 138.9, 133.8, 131.4, 131.2, 130.7, 128.7, 127.59, 127.51,
126.9, 125.9, 123.0, 119.7, 114.8, 105.2, 59.8, 14.0. HRMS calcd for C22H18NO3S:
376.1007. Found: 376.1014.
ACKNOWLEDGMENT
CSIR-CSMCRI Communication No. 025/2015. D.C.M, C. R, & V.P. are thankful to AcSIR
for their Ph.D. enrollment and the “Analytical Discipline and Centralized Instrumental
Facilities” for providing instrumentation facilities. D.C.M. and V.P are also thankful to UGC,
New Delhi for their fellowships. We thank DST, Government of India (SR/S1/OC-13/2011),
for financial support. We also thank CSIR-CSMCRI (OLP-0076) for partial assistance.
1
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Supporting Information H and C NMR spectra for all compounds and Crystallographic
data for compound 3b (CCDC-1017738) and 9a (CCDC-1051936) can be obtained free of
charge
from
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif. This material is available free of charge via the
Internet at http://pubs.acs.org.
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