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Beilstein Journal of Organic Chemistry
Preliminary Communication
Open Access

Efficient synthesis of 5-substituted 2-aryl-6cyanoindolizines via nucleophilic substitution reactions
Eugene V Babaev*, Natalya I Vasilevich and Anna S Ivushkina
Address: Department of Chemistry, Moscow State University, 119992, Moscow, Russia Email: Eugene V Babaev* - babaev@org.chem.msu.su; Natalya I Vasilevich - nikto25@hotmail.com; Anna S Ivushkina - anna@hotmail.ru * Corresponding author

Published: 07 October 2005 Beilstein Journal of Organic Chemistry 2005, 1:9 doi:10.1186/1860-5397-1-9

Received: 11 June 2005 Accepted: 07 October 2005

This article is available from: http://bjoc.beilstein-journals.org/content/1/1/9 © 2005 Babaev et al; licensee Beilstein-Institut. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
2-Aryl-6-cyano-7-methyl-5-indolizinones were successfully converted into 2-aryl-5-chloro-6cyano-7-methylindolizines. The obtained 5-chloroindolizines readily underwent nucleophilic substitution at position 5 leading in high yields to novel 5-functionalised indolizines.

Indolizines are an important class of heterocyclic compounds since many natural alkaloids contain in their structure a saturated (swainsonine) or aromatic (camptothecin) indolizine moiety. While the chemistry of indolizines has been widely investigated[1] the chemistry of 5-substituted indolizines remains very poor because there are only a few reliable ways for their synthesis. 8-Nitroindolizines may undergo amination at position 5 (SNH substitution) under the action of secondary amines.[2] 2-Phenylindolizine can be lithiated at position 5, and the resulting indolizyl lithium can react with some electrophiles (CO2, PhCHO, PhCN, Me3SiCl, MeI) leading to variety of new products in good yields.[3] An interesting method for preparing 5-substitutied indolizines by recyclization of oxazolo[3,2-a]pyridinium salts was developed in our laboratory.[4,5] Using this strategy a series of 5-substituted indolizines have been prepared in good yields, but (although the method seems to be quite reliable) it is currently restricted only by secondary amines.

In seeking for a synthetic approach to 5-substituted indolizines we have assumed that indolizines bearing an appropriate leaving group (e.g. halogen) at position 5 may undergo nucleophilic substitution. Herein we discuss the synthesis of previously unknown 5-chloroindolizines and their use as precursors to novel 5-substituted indolizines via nucleophilic displacement reactions. The synthesis of 2-aryl-5-chloro-6-cyano-7-methylindolizines 2 is shown in Scheme 1. 2-Aryl-6-cyano-7methyl-5-indolizinones 1 a d were prepared according to protocol of Gevald.[6] Our modification of the original method included separation of N- and O-isomers of phenacyl pyridines before cyclization (using the difference in their solubility in chloroform). Although 1H-NMR (see Additional file 2) and Nuclear Overhauser Effect confirmed the structure A for indolizinones 1, we assumed the existence of tautomerism between forms A and B involving hydrogen interchange between oxygen and C-3 carbon (Scheme 1). Although the amount of tautomer B is negligibly small, one would expect that treatment of

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CN
N H

1. EtONa/EtOH 2. Ar C(O)CH2Br N

CN + O O Ar EtONa/EtOH refluxing 5 min POCl3, 80 100oC N

CN O O Ar

O

NC

N O 1a - d

Ar NC

N

Ar

1 1 1 1

a: b: c: d:

Ar Ar Ar Ar

= = = =

p p p p

F C6H4 Cl C6H4 Br C6H4 Me C6H4

2 2 2 2

a: b: c: d:

Cl 2a-d Ar = p F C6H4 Ar = p Cl C6H4 Ar = p Br C6H4 Ar = p Me C6H4

NC O
A

N

Ar NC

N
OH B

Ar

Scheme 1: Synthesis of 2-aryl-5-chloro-6-cyano-7-methylindolizines 2. Possible tautomeric structures A and B for 2-aryl-6-cyano-7methyl-5-indolizinones 1.

1 a d with phosphorous oxychloride may lead to substitution of oxo/oxy-group to chlorine giving the products 2 a d. (It is well known that analogous 2-hydroxypyridines which exist in the pyridone tautomeric form can be easily converted to 2-chloroderivatives by reaction with POCl3.).[7] Indeed, heating of indolizinones 1 a d in POCl3 at 80100°C during 10 hours without any solvent followed by pouring into a mixture of ice/sodium acetate and filtration of the green precipitate afforded crude 5-chloroindolizines. After column chromatography (eluent carbon tetrachloride) yellow solids were obtained. Performing this reaction in the presence of twofold molar excess of trimethylbenzylammonium chloride or TEBAC increased the yields of 2 a d up to 3075%. In the 1H NMR spectra of these products the initial signal of 3-CH2 group at ~5 ppm (intensity 2H) disappeared, and a new aromatic signal 3-CH (with intensity 1H) appeared at 7.99 8.11 ppm. The halogen atom in 5-chloro-6-cyanoindolizines 2 should be activated to nucleophilic substitution reactions by the suitable ortho-arrangement of the nitrogen atom of the pyridine ring and electron-withdrawing cyano-group. The pattern strongly resembled 2-chloro-3-cyanopyridine,

that is why we anticipated successful substitution in reactions of 2 with oxygen, nitrogen, and sulfur nucleophiles. Indeed, 5-chloroindolizines readily underwent nucleophilic substitution to produce previously unknown compounds 3 6 in good to excellent yields (Scheme 2). These products are detailed in Table 2. Thus, 5-methoxyindolizines 3 a c were formed after refluxing 2 b d in solution of sodium methoxide in methanol overnight in good yields (Scheme 2). Treatment of 2a, d with excess of amines without any solvent gave 5-amino derivatives 4 a h. In the case of secondary amines (4 a c, e g) the reaction proceeded at room temperature, but reaction with less nucleophilic benzylamine (4 d, h) required heating for 30 min. Nucleophilic substitution also occured with sulfur nucleophiles. Thus, 2d reacted with mercaptoethanol under basic conditions leading to 5a. Conversion 2a into 5b was conveniently achieved with ethyl mercaptoacetate in ethanolic sodium hydroxide. Interestingly, 2a reacted also with thiourea in refluxing butanol giving indolizinethione 6. The product 6 seems to be the result of decomposition of unstable isothiouronium salt, and the process resembles the known conversion of 2chloro-3-cyanopyridines to 3-cyanopyridinethiones under the same conditions via a similar intermedi-

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ate.[8]1H NMR spectrum of 6, which was very similar to the spectra of 1, indicated disappearance of aromatic proton signal H3 and appearance of a signal at 5.35 ppm with intensity 2H. In conclusion, we are the first to obtain 2-aryl-5-chloro-6cyano-7-methylindolizines from 2-aryl-6-cyano-7methyl-5-indolizinones and to prove the possibility to employ them in nucleophilic substitution reactions. Moreover, these reactions are the first examples of preparative nucleophilic substitution in indolizines, and our findings open a new way to functionalize the C-5 position (in most cases considered as inactive). The studies of further cyclizations of 5-substituted indolizines involving neighbouring cyano-group and ring position C3 is underway.

Table 1: Properties of 5-substituted 2-aryl-6-cyano-7methylindolizines

NC

N X 5-X*

Ar

N o. 2 2 2 2 3 3 3 4 4 4 4 4 4 4 4 5 5 a b c d a b c a b c d e f g h a b

R in 2-Ar p-F p-Cl p-Br p-Me p-Cl p-Br p-Me p-F p-F p-F p-F p-Me p-Me p-Me p-Me p-Me p-F

Yield % 30 65 54 74 50 71 73 99 91 88 58 74 71 85 83 71 70

m.p., °C 173175 198200 229230 157158 169172 197200 170173 189190 205209 186188 190194 228230 212215 213216 185187 132135 142145

Note
*Characteristics of parent indolizinones 1 a d were identical to those described in literature.[9]

Supporting information

Cl Cl Cl Cl OMe OMe OMe pyrrolidyl piperidyl hexamethy-lenimino benzylamino pyrrolidyl piperidyl hexamethy-lenimino benzylamino S(CH2)2OH SCH2CO2Et

MeONa/MeOH 2b-d

NC

N O 3a-c

Ar

Additional material Additional File 1

2 a, d

NHR1R2

NC

N NR1R2 4a-h

Ar

Supporting tables Click here for file [http://www.biomedcentral.com/content/supplementary/18605397-1-9-S1.doc]

2d

HS(CH2)2OH NaOH/MeOH

Additional File 2
Ar

NC

N

S(CH2)2OH
5a 2a HSCH2COOEt NaOH/EtOH

Supporting information Click here for file [http://www.biomedcentral.com/content/supplementary/18605397-1-9-S2.pdf]

NC

N

Ar

SCH2COOEt 5b
2a (NH2)2CS

Acknowledgements
This work was supported by Russian Foundation of Basic Research (grant 04-0332823).

NC H2N

N S
NH HCl

Ar

References
1. 2. 3. 4. Flitch W: Pyrroles with fused six-membered heterocyclic rings: afused. In Comprehensive Heterocyclic Chemistry Volume 4. Edited by: Katritzky AR, Rees CW. London: Pergamon Press; 1984:443-478. Kost AN, Sagitullin RS, Gromov SP: Heterocycles 1977, 7:997-1001. Renard M, Gubin J: Tetrahedron Lett 1992, 33:4433-4434. Babaev EV, Efimov AV, Maiboroda DA, Jug K: Eur J Org Chem 1998, 1:193-196. Babaev EV: J Heterocycl Chem 2000, 37:519-526. Gevald K, Jansch HJ: J Prakt Chem 1976, 318:313-320. Kwok R: J Heterocycl Chem 1978, 15:877-880. Kitaygorodova EA, Konyushkin LD, Mikhaychenko SN: Khim Geterotsikl Soedin 1999, 3:337-341. (Rus) Lin CF, Lin YF, Lo YC, Chen KT, Su TL: Heterocycles 2000, 1:15-26.

CN S

N
6

Ar

5. 6. 7. 8. 9.

Scheme 2: Nucleophilic substitution in 2-aryl-5-chloro-6-cyano-7methylindolizines.

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