Regioselective synthesis of indolizines, pyrrolo[2,1-a ]isoquinolines, and quinolines

Article abstract of DOI:10.1080/00397911.2015.1092550

Convenient and regioselective synthesis of indolizine and pyrrolo[2,1-a]isoquinoline/quinoline derivatives by one-pot multicomponent reaction of N-substituted pyridinium and isoquinolinum/quinolinium salts with alkyl propiolates in the presence triphenylp

Full text of DOI:10.1080/00397911.2015.1092550

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Regioselective Synthesis of Indolizines, Pyrrolo[2,1-
a]isoquinolines, and Quinolines
Seyed Abolghasem Hashemi & Gholamhossein Khalili
To cite this article: Seyed Abolghasem Hashemi & Gholamhossein Khalili (2015)
Regioselective Synthesis of Indolizines, Pyrrolo[2,1-a]isoquinolines, and Quinolines, Synthetic
Communications, 45:21, 2491-2497, DOI: 10.1080/00397911.2015.1092550
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1092550
View supplementary material
Published online: 27 Oct 2015.
Submit your article to this journal
Article views: 10
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [Central Michigan University]
Date: 01 November 2015, At: 22:22

Synthetic Communications1, 45: 2491–2497, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1092550
REGIOSELECTIVE SYNTHESIS OF INDOLIZINES,
PYRROLO[2,1-a]ISOQUINOLINES, AND QUINOLINES
Seyed Abolghasem Hashemi and Gholamhossein Khalili
Chemistry Department, Islamic Azad University, Bushehr, Iran
GRAPHICAL ABSTRACT
Abstract Convenient and regioselective synthesis of indolizine and pyrrolo[2,1-a]
isoquinoline=quinoline derivatives by one-pot multicomponent reaction of N-substituted
pyridinium and isoquinolinum=quinolinium salts with alkyl propiolates in the presence
triphenylphosphine is described.
Keywords Indolizine; pyrrolo[2,1-a]isoquinoline; pyrrolo[2,1-a]quinoline; regioselective
synthesis
INTRODUCTION
The development of efficient and versatile strategies for the synthesis of
heterocycles is one of the top challenges in organic synthesis because most of the
biologically active compounds produced by nature contain a heterocyclic scaffold
as a fundamental unit in their structure.[1] Of these heterocycles, the indolizine motif
is a bicyclic system in natural products, pharmaceuticals, and biologically active
molecules such as aromatase inhibitory,[2] anti-inflammatory,[3] antitumor,[4] and
antitubercular pharmaceuticals.[5] On the other hand, these azabicyclic compounds
exhibit interesting electronic properties and are attractive molecules in theoretical
chemistry.[6] Indolizines have emerged as important synthetic targets because of their
potential applications. As a consequence, the development of new and general
Received August 17, 2015.
Address correspondence to Seyed Abolghasem Hashemi, Chemistry Department, Islamic Azad
University, Bushehr Branch, P.O. Box 7519619555, Bushehr, Iran. E-mail: abolghasem.hashemy@
gmail.com
2491

2492
S. A. HASHEMI AND G. KHALILI
methods for their preparation is of significant interest.[7] The most important
methods for the preparation of indolizine rings can be classified mainly as the
cycloaddition reaction,[8] Tschirschibabin reaction,[9] and transition-metal-catalyzed
cycloisomerization.[10] Among the currently used strategies to develop the new
heterocyclic compounds, multicomponent condensation reactions offer a valuable
solution for this area because of their inherent atom efficiency, time and energy
savings, diversity with minimum waste, and ease of implementation.[11] Of the pre-
viously reported methods for the synthesis of indolizines and pyrrolo[2,1-a]isoquino-
lines=quinolines, the reaction pyridinium, isoquinolinum, or quinolinium salts with
alkenes using ion-exchange resin as the base in the presence of oxidizing agent in
a one-pot reaction is one of the most attractive routes because of biological applica-
tions of this new reaction products.[12] Therefore, in continuation of our interest in
the development of new methods for the synthesis of these heterocyclic systems,
we now describe a regioselective synthesis of the functionalized indolizines,
pyrrolo[1,2-a]isoquinolines, and pyrrolo[2,1-a]quinolines in a new multicomponent
reaction from simple starting materials, which proceeds in good yields.
RESULTS AND DISCUSSION
In a pilot experiment, a solution of alkyl propiolates 2 and N-substituted
pyridinium (1), isoquinolinum (4), or quinolinium (5) salts in dimethylformamide
(DMF) were reacted with a stoichiometric amount of triphenylphosphine at room
temperature for 12 h (Scheme 1). After screening with various amounts of triphenyl-
phosphine, the best results were obtained in DMF at rt for 12 h in the presence of
stoichiometric amounts of PPh3. Purification of the reaction mixtures by SiO2
column chromatography afforded the functionalized indolizines 3, pyrrolo[2,1-a]iso-
quinolines 6, or pyrrolo[1,2-a]quinolines 7 (Fig. 1). The structures of the indolizines
and pyrrolo[1,2-a]isoquinoline=quinoline derivatives were established on the basis of
their infrared (IR), 1H NMR, and 13C NMR spectra. For example, the IR spectrum
of 3a exhibited characteristic ester carbonyl bands at 1725 cmꢀ1. Characteristic sig-
1
nals in H NMR spectrum of 3a showed ethoxy group at 4.28 as a quartet (3J ¼
7.2 Hz) and methoxy group at 3.83 as singlet. The aryl protons exhibited character-
istic signals in the aromatic region of the spectrum. The 13C resonance signals of the
Scheme 1.

REGIOSELECTIVE SYNTHESIS OF INDOLIZINE
2493
Figure 1.
two carbonyl groups were seen at δ 160.7 and 164.5 whereas the methyl signal was
observed at 22.6 ppm. Partial assignment of these data is given in the experimental
section.
A possible mechanistic pathway for the formation of products 3 is shown in
Scheme 2. The initial addition results in the formation of zwitterion 8 from the tri-
phenylphosphine and alkyl propiolate 2, which is subsequently protonated by pyri-
dinium salt 1. Next, the positively charged ion 10 is attacked by nucleophilic addition
of pyridinium ylide 9 to form 11, which then undergoes cyclization to produce the
primary adduct 13 by eliminiation of PPh3 and proton from cation 12. The aroma-
tization completes the reaction sequence, leading to the final product 3 via eliminia-
tion of hydrogen molecule.
In conclusion, we have devised a novel synthesis of functionalized indolizines
and pyrrolo[1,2-a]isoquinolines=quinolines by triphenylphosphine-mediate reaction
of N- functionalized pyridinium, isoquinolinum, or quinolinium salts with alkyl pro-
piolates. The simple purification, high regioselectivity, and good yield of products
are advantages of this new method. It is conceivable that the regioselective synthesis
of substituted indolizine derivatives may be amenable to a number of potentially use-
ful synthetic transformations.

2494
S. A. HASHEMI AND G. KHALILI
Scheme 2.
EXPERIMENTAL
All reactions were carried out in oven-dried glassware. Progress of the reaction
was monitored by thin-layer chromatography (TLC), while the reaction mixture was
purified by column chromatography, using silica gel (Merck 230–240 mesh). Melting
points were determined on an Electrothermal-9100 apparatus. IR spectra were
recorded on a Shimadzu-IR-460 spectrometer, absorbances are reported in cmꢀ1
.
The 1H and 13C NMR spectra were measured (CDCl3 solvent) with a Bruker
DRX-400 Avance instrument at 400.1 and 100.6 MHz, respectively. Elemental analy-
sis was carried out using a Vario EL III CHNOS elemental analyzer. Mass spectra
were recorded on a Finnigan-MAT-8430EI-MS mass spectrometer.
General Procedure for the Preparation of 3, 6, and 7
A solution of alkyl propiolate 2 (1 mmol) in 2 mL DMF was added to a
magnetically stirred solution of N-functionalized pyridinium, isoquinolinum, or

REGIOSELECTIVE SYNTHESIS OF INDOLIZINE
2495
quinolinium salt 1, 4, or 5 (1 mmol) and triphenylphosphine (1 mmol) in 3 mL DMF
at ꢀ5 to 0 °C temperature. The reaction mixture was stirred for 12 h, and then the
mixture was poured onto H2O (5 mL), extracted with AcOEt (15 mL), and dried
(MgSO4). The solvent was removed under reduced pressure. The residue was
separated by silica gel (Merck 230–240 mesh) column chromatography using
hexane–ethyl acetate mixture as eluent. In addition, Compounds 3 g, 3 h, 6, and 7
have been reported in the literature.[12]
3-Ethyl 2-Methyl-5-methylindolizine-2,3-dicarboxylate (3a)
1
Colorless oil. yield: 0.17 g (68%). IR (KBr) (nmax=cmꢀ1): 1725 (COO). H
3
NMR (400.1 MHz, CDCl3): d ¼ 1.34 (3 H, t, J ¼ 7.2 Hz, Me), 2.64 (3 H, s, Me),
3.83 (3 H, s, OMe), 4.28 (2 H, q,3J ¼ 7.2 Hz, OCH2), 6.71 (1 H, d,3J ¼ 7.2 Hz,
CH), 7.19–7.22 (1 H, m, CH), 7.89 (1 H, s, CH), 8.21 (1 H, d,3J ¼ 8.8 Hz, CH).
13C NMR (100.6 MHz, CDCl3): d ¼ 14.3 (Me), 22.6 (Me), 51.1 (OMe), 60.8
(OCH2), 104.5 (C), 116.2 (CH), 117.2 (CH), 126.1 (CH), 126.7 (CH), 134.6 (C),
138.8 (C), 141.2 (C), 160.7 (C=O), 164.5 (C=O). MS m=z 261 (Mþ, 28), 131 (38),
117(100). Anal. calcd. for C14H15NO4(261.28): C 64.36, H 5.79, N 5.36%. Found:
C 64.74, H 5.68, N 5.42%.
Ethyl 3-Benzoyl-7-methylindolizine-2-carboxylate (3b)
White powder, mp 87–89°C. yield: 0.21 g (70%). IR (KBr) (nmax=cmꢀ1): 1714
1
(COO), 1675 (CO). H NMR (400.1MHz, CDCl3): d ¼ 1.41 (3 H, t,3J ¼ 7.2 Hz, Me),
2.51 (3 H, s, Me), 4.40 (2 H, q,3J ¼ 7.2 Hz, OCH2), 6.94 (1 H, dd,3J ¼ 6.8 Hz,4J ¼ 2.4 Hz,
CH), 7.50-7.58 (3 H, m, 3 CH), 7.79 (1 H, s, CH), 7.82–7.84 (2 H, m, 2 CH), 8.21 (1 H, s,
3
CH), 9.88 (1 H, d, J ¼ 6.8 Hz, CH). 13C NMR (100.6 MHz, CDCl3): d ¼ 14.5 (Me),
22.7 (Me), 59.9 (OCH2), 114.0 (C), 117.7 (CH), 118.2 (CH), 128.3 (2 CH), 128.6
(CH), 128.9 (2 CH), 129.2 (CH), 131.3 (CH), 139.2 (C), 139.4 (C), 140.0 (C), 140.4
(C), 164.2 (C=O), 185.2 (C=O). MS m=z 307 (Mþ, 25), 262 (40), 77 (100). Anal. calcd.
for C19H17NO3(307.34): C 74.25, H 5.58, N 4.56%. Found: C 74.65, H 5.42, N 4.60%.
Diethylindolizine-2,3-dicarboxylate (3c)
1
Colorless oil. Yield: 0.17 g (66%). IR (KBr) (nmax=cmꢀ1): 1709 (COO). H
NMR (400.1 MHz, CDCl3): d ¼ 1.32–1.37 (6 H, m, 2 Me), 4.29–4.35 (4 H, m, 2
OCH2), 6.88–6.92 (1 H, m, CH), 7.22–7.26 (1 H, m, CH), 7.92 (1 H, s, CH), 8.25–
8.28 (1 H, m CH), 9.45 (1 H, d,3J ¼ 7.2 Hz, CH). 13C NMR (100.6 MHz, CDCl3): d
¼ 14.1 (Me), 14.2 (Me), 59.9 (OCH2), 60.2 (OCH2), 114.3 (CH), 119.5 (CH), 124.2
(CH), 125.5 (CH), 127.9 (CH), 132.0 (C), 133.0 (C), 139.0 (C), 161.2 (C=O), 164.2
(C=O). MS m=z 261 (Mþ, 15), 117 (100). Anal. calcd. for C14H15NO4(261.27): C
64.36, H 5.79, N 5.36%. Found: C 64.49, H 5.64, N 5.41%.
Diethyl 5-Methylindolizine-2,3-dicarboxylate (3d)
Colorless oil. yield: 0.17 g (63%). IR (KBr) (nmax=cmꢀ1): 1709 (CO). 1H NMR
(400.1 MHz, CDCl3): d ¼ 1.34 (6 H, t,3J ¼ 7.2 Hz, 2 Me), 2.63 (3 H, s, Me), 4.25–4.37

2496
S. A. HASHEMI AND G. KHALILI
(4 H, m, 2 OCH2), 6.71 (1 H, d,3J ¼ 6.8 Hz, CH), 7.21 (1 H, t,3J ¼ 7.2 Hz, CH), 7.90
(1 H, s, CH), 8.23 (1 H, d,3J ¼ 8.4 Hz, CH). 13C NMR (100.6 MHz, CDCl3): d ¼ 14.4
(Me), 14.5 (Me), 22.6 (Me), 59.8 (OCH2), 60.8 (OCH2), 116.2 (CH), 117.2 (CH),
126.0 (CH), 126.7 (CH), 128.5 (C), 134.4 (C), 138.8 (C), 141.2 (C), 160.7 (C=O),
164.1 (C=O). MS m=z 275 (Mþ, 18), 131 (45), 117 (100). Anal. calcd. for
C15H17NO4(275.30): C 65.44, H 6.22, N 5.09%. Found: C 65.71, H 6.27, N 5.13%.
3-Ethyl 2-Methylindolizine-2,3-dicarboxylate (3e)
1
Colorless oil. Yield: 0.14 g (60%). IR (KBr) (nmax=cmꢀ1): 1715 (COO). H
NMR (400.1 MHz, CDCl3): d ¼ 1.33 (3 H, t,3J ¼ 7.2 Hz, Me), 3.84 (3 H, s, OMe),
4.31 (2 H, q,3J ¼ 7.2 Hz, OCH2), 6.89–6.92 (1 H, m, CH), 7.22–7.26 (1 H, m, CH),
7.92 (1 H, s, CH), 8.26 (1 H, d,3J ¼ 8.8 Hz, CH), 9.45 (1 H, d,3J ¼ 7.2 Hz, CH).
13C NMR (100.6 MHz, CDCl3): d ¼ 14.1 (Me), 51.2 (OMe), 60.3 (OCH2), 114.4
(CH), 119.5 (CH), 124.2 (CH), 125.6 (CH), 127.9 (CH), 130.8 (C), 134.6 (C), 139.0
(C), 161.1 (C=O), 164.6 (C=O). MS m=z 247 (Mþ, 20), 216 (35), 117 (100). Anal.
calcd. for C13H13NO4(247.25): C 63.15, H 5.30, N 5.67%. Found: C 63.26, H
5.24, N 5.72%.
Ethyl 3-Benzoyl-5-methylindolizine-2-carboxylate (3f)
White powder, mp 86–89 °C. Yield: 0.22 g (72%). IR (KBr) (nmax=cmꢀ1): 1710
(COO), 1680 (CO). 1H NMR (400.1 MHz, CDCl3): d ¼ 1.39 (3 H, t,3J ¼ 7.2 Hz, Me),
2.62 (3 H, s, Me), 4.37 (2 H, q,3J ¼ 7.2 Hz, OCH2), 6.93 (1 H, d,3J ¼ 6.8 Hz, CH),
7.28–7.44 (1 H, m, CH), 7.52–7.56 (2 H, m, 2 CH), 7.62–7.66 (1 H, m, CH), 7.75
(1 H, s, CH), 8.04–8.07 (2 H, m, 2 CH), 8.39 (1 H, d,3J ¼ 8.4 Hz, CH). 13C NMR
(100.6 MHz, CDCl3): d ¼ 14.5 (Me), 23.2 (Me), 59.9 (OCH2), 105.4 (C), 116.7
(CH), 117.1 (CH), 125.4 (C), 127.4(CH), 128.4 (2 CH), 129.6 (CH), 130.2 (2 CH),
132.5 (CH), 138.5 (C), 139.8 (C), 141.8 (C), 164.1 (C=O), 182.9 (C=O). MS m=z
307 (Mþ, 41), 77 (100). Anal. calcd. for C19H17NO3(307.12): C 74.25, H 5.58, N
4.56%. Found: C 74.63, H 5.45, N 4.38%.
SUPPLEMENTAL MATERIAL
1
Full experimental details and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.
REFERENCES
1. Katritzky, A. R.; Rees, C. W.; Bird, C. W.; Cheeseman, G. W. H. (Eds.); Comprehensive
Heterocyclic Chemistry; Pergamon Press: New York, 1987; p. 1.
2. Sonnet, P.; Dallemagne, P.; Guillon, J.; Enguehard, C.; Stiebing, S.; Tanguy, J.; Bureau,
R.; Rault, S.; Auvray, P.; Moslemi, S.; Sourdaine, P.; Seralini, G. E. New aromatase inhi-
bitors: Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine deri-
vatives. Bioorg. Med. Chem. 2000, 8, 945–955.
3. Kalman, R.K.; Doerge, R. F. p-Substituted 1,2-diphenylindolizines as anti-inflammatory
agents. Pharm. Sci. 1972, 61, 949–951.

REGIOSELECTIVE SYNTHESIS OF INDOLIZINE
2497
4. Humphries, M. J.; Matsumoto, K.; White, S. L.; Olden, K. Inhibition of experimental
metastasis by castanospermine in mice: Blockage of two distinct stages of tumor coloniza-
tion by oligosaccharide processing inhibitors. Cancer Res. 1986, 46, 5215–5222.
5. Gundersen, L.-L.; Charnock, C.; Negussie, A. H.; Rise, F.; Teklu, S. Synthesis of indoli-
zine derivatives with selective antibacterial activity against Mycobacterium tuberculosis.
Eur. J. Pharm. Sci. 2007, 30, 26–35.
6. Swinbourne, F. T.; Hunt, J. H.; Klinkert, K.; Katritzky, A. R.; Boulton, A. J. (Eds.);
Advances in Heterocyclic Chemistry, Vol. 23; Academic Press: New York, 1978; p. 103.
7. Katrizky, A. R.; Qui, G.; Yang, B.; He, H-Y. Novel syntheses of indolizines and pyrrolo
[2,1-a]isoquinolines via benzotriazole methodology. J. Org. Chem. 1999, 64, 7618–7621.
8. Fang, X.; Wu, Y.-M.; Deng, J.; Wang, S.-W. Synthesis of monofluorinated indolizines
and their derivatives by the 1,3-dipolar reaction of N-ylides with fluorinated vinyl tosy-
lates. Tetrahedron 2004, 60, 5487–5493.
9. Gubin, J.; Lucchetti, J.; Mahaux, J.; Nisato, D.; Rosseels, G.; Clinet, M.; Polster, P.;
Chatelain, P. A novel class of calcium-entry blockers: the 1-[[4-(aminoalkoxy)phenyl]
sulfonyl]indolizines. J. Med. Chem. 1992, 35, 981–988.
10. Hardin, N. A. R.; Sarpong, R. Remarkable facilitation of hetero-cycloisomerizations with
water and other polar protic solvents: Metal-free synthesis of indolizines. Green Chem.
2010, 12, 1556–1559.
11. Bhunia, A.; Kaicharla, T.; Porwal, D.; Gannade, R. G.; Biju, A. T. Multicomponent reac-
tions involving phosphines, arynes, and aldehydes. Chem. Commun. 2014, 50, 11389–
11392.
12. Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira, R.; Sahu, P.; Pair, K. B.;
Ghosh, S.; Sinha, C.; Samanta, A.; Banerjee, S.; Mondal, N. B. Amberlite–IRA-402 (OH)
ion exchange resin–mediated synthesis of indolizines, pyrrolo [1,2-a] quinolones, and iso-
quinolines: Antibacterial and antifungal evaluation of the products. Eur. J. Med. Chem.
2011, 46, 2132–2140.