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Synthesis of Indole and Oxindole Derivatives Incorporating Pyrrolidino, Pyrrolo Or Imidazolo Moieties

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Synthesis of Indole and Oxindole Derivatives Incorporating Pyrrolidino, Pyrrolo Or Imidazolo Moieties From DEPARTMENT OF BIOSCIENCES AT NOVUM Karolinska Institutet, Stockholm, Sweden SYNTHESIS OF INDOLE AND OXINDOLE DERIVATIVES INCORPORATING PYRROLIDINO, PYRROLO OR IMIDAZOLO MOIETIES Stanley Rehn Stockholm 2004 All previously published papers have been reproduced with permission from the publishers. Published and printed by Karolinska University Press Box 200, SE-171 77 Stockholm, Sweden © Stanley Rehn, 2004 ISBN 91-7140-169-5 Till Amanda Abstract The focus of this thesis is on the synthesis of oxindole- and indole-derivatives incorporating pyrrolidins, pyrroles or imidazoles moieties. Pyrrolidino-2-spiro-3’-oxindole derivatives have been prepared in high yielding three-component reactions between isatin, α-amino acid derivatives, and suitable dipolarophiles. Condensation between isatin and an α-amino acid yielded a cyclic intermediate, an oxazolidinone, which decarboxylate to give a 1,3-dipolar species, an azomethine ylide, which have been reacted with several dipolarophiles such as N- benzylmaleimide and methyl acrylate. Both N-substituted and N-unsubstituted α- amino acids have been used as the amine component. 3-Methyleneoxindole acetic acid ethyl ester was reacted with p- toluenesulfonylmethyl isocyanide (TosMIC) under basic conditions which gave (in a high yield) a colourless product. Two possible structures could be deduced from the analytical data, a pyrroloquinolone and an isomeric ß-carboline. To clarify which one of the alternatives that was actually formed from the TosMIC reaction both the ß- carboline and the pyrroloquinolone were synthesised. The ß-carboline was obtained when 3-ethoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester was treated with a tosylimine. An alternative synthesis of the pyrroloquinolone was performed via a reduction of a 2,3,4-trisubstituted pyrrole obtained in turn by treatment of a vinyl sulfone with ethyl isocyanoacetate under basic conditions. This molecule (the pyrroloquinolone), obtained in a low yield by a multistep procedure, proved to be identical with the product obtained easily via the TosMIC route. The reaction between 3-aminocrotonates and 3-acetonylideneoxindole in refluxing toluene resulted in 2-pyrrolo-3’-yloxindoles in high yields, (around 90 %). At room temperature the 2-pyrrolo-3’-yloxindoles exist as a mixture of keto-enol tautomers. Treatment with POCl3 yielded the corresponding 2-chloro-3-pyrrolyl indole, which gave a pyrrolo annulated indolopyrane upon basic hydrolysis of the ester function of the methyl ester. 3-Imidazolylindoles were synthesised in good yields from the corresponding benzylimine and TosMIC. Treatment of cyclohexanone benzylimine with α- chloroacrylonitrile yielded, after expulsion of HCN by refluxing in ethanol, 1-benzyl- 4,5,6,7-tetrahydroindole. Formylation and benzylimine formation followed by treatment with TosMIC furnished the desired 2-imidazolyltetrahydroindole. Keywords: isatin, three-component reaction, α-amino acid, azomethine ylide, pyrrolidino-3-spiro-3’-oxindole derivatives, 3-methyleneoxindole derivatives, pyrroloquinolone, TosMIC, β-carboline, tosylimine, pyrrole, keto-enol tautomerism, indolopyran-2-one, imidazole, benzylimine, tetrahydroindole. iv List of publications The thesis is based on the following papers, referred to in the text by the Roman numerals I-IV: I. The Three-Component Reaction between Isatin, α-Amino Acids, and Dipolarophiles. Rehn, S.; Bergman, J.; Stensland, B. Eur. J. Org. Chem, 2004, 413-418. II. Synthesis of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester and its isomer 1-oxo-2,9-dihydro-1H-β-carboline-4-carboxylic acid ethyl ester. Bergman, J.; Rehn, S. Tetrahedron, 2002, 45, 9179-9185. III. The reaction between 3-aminocrotonates and oxindole 3-ylidene derivatives: synthesis of highly substituted pyrroles. Rehn, S.; Bergman, J. Tetrahedron, accepted. IV. Synthetic studies towards the alkaloid granulatimide: synthesis of 3- imidazolylindole and 2-imidazolyltetrahydroindole. Rehn, S.; Bergman, J. Manuscript v Contents Abstract…….………………...……………………………………………………….iv List of papers………………………………………………………………………….v Contents……………………….………………………………………………………vi 1 Introduction to isatin chemistry .............................................................................1 1.1 Synthesis of isatin ..............................................................................................1 1.2 Fundamental reactivity of isatins.......................................................................2 1.2.1 Aromatic substitution.....................................................................................2 1.2.2 N-Alkylation and N-acylation.......................................................................3 1.2.3 Carbonyl reactions .........................................................................................3 2 Pyrrolidino-2-spiro-3’-oxindole..............................................................................9 2.1 Naturally occuring 3-spiro-oxindoles................................................................9 2.2 Ninhydrin and the Strecker degradation............................................................9 2.3 Azomethine ylides...........................................................................................10 2.3.1 1,2-prototropic shift .....................................................................................10 2.3.2 Decarboxylative condensation ....................................................................11 2.3.3 Three-component reactions (paper I) ..........................................................12 3 Reactions on 3-methyleneoxindole derivatives...................................................15 3.1 3-Methyleneoxindole acetic acid ethyl ester...................................................15 3.1.1 Isocyanides...................................................................................................16 3.2 Addition of TosMIC to 3-methyleneoxindole derivatives (paper II).............16 3.2.1 Mechanistic aspects .....................................................................................17 3.2.2 β-Carbolines.................................................................................................18 3.2.3 Pyrroloquinolones........................................................................................20 3.3 3-(Pyrrol-4-yl)-oxindole (paper III) ................................................................22 3.3.1 Introduction..................................................................................................22 3.3.2 3-Aminocrotonates and 3-methyleneoxindole acetic acid ethyl ester........23 3.3.3 3-Aminocrotonates and 3-acetonylideneoxindole ......................................24 3.3.4 Chlorination of pyrrolo-oxindoles with POCl3 ...........................................26 4 Synthetic studies towards the alkaloid granulatimide (paper IV) ...................28 4.1 Introduction to imidazolyl indoles...................................................................28 4.2 3-(Imidazolyl)-indoles .....................................................................................29 4.3 2-(Imidazolyl)-tetrahydroindoles ....................................................................29 4.3.1 Published procedures to granulatimide .......................................................29 4.3.2 Retrosynthesis of granulatimide..................................................................30 4.3.3 Synthesis of 2-imidazolyltetrahydroindole .................................................31 5 Acknowledgements.................................................................................................33 6 Appendix: supplementary material .....................................................................34 6.1 Experimental part to section 4 .........................................................................34 7 Abbreviations..........................................................................................................38 vi 1 Introduction to isatin chemistry Isatin 1 (indole-2,3-dione)1 has been known since 1841 when Erdmann and Laurent prepared it by oxidation of indigo 2 by nitric and chromic acids. Although known as a synthetic molecule for almost 140 years, isatin was later found in nature, for instance in the fruits of the cannon ball tree, Couroupita quianensis Aubl.2 In man, isatin has been found to function as an endogenous monoamine oxidase inhibitor.3 4 O O 3 H 5 2 N O 6 N1 N H H 7 O 1 2 Figure 1. Isatin 1 and indigo 2. 1.1 Synthesis of isatin The importance of indigo as a possible synthetic dyestuff whithin the textile industry led to intense research in the area of indigo chemistry. As an offspring to the efforts in indigo research, the chemistry of isatin was explored, and several synthetic pathways to isatin were developed. The oldest and the most important method of synthesising isatin is the Sandmeyer methodology that starts from an aniline 3, which reacts with chloral hydrate and hydroxylamine hydrochloride in water containing sodium sulfate to form an isonitrosoacetanilide 4. The isolated isonitrosoanilide 4 is then treated with concentrated sulfuric acid to yield the isatin 5. O NOH a b R R R O c NH2 N O N H H 34 5 Scheme 1. The Sandmeyer synthesis. a) Cl3CCH(OH)2, H2NOH·HCl, Na2SO4. b) H2SO4. c) H2O. Second to Sandmeyer’s procedure of isatin synthesis is the method of Stollé whereby the aniline (usually as its hydrochloride) is reacted with oxalyl chloride to form an intermediate, chlorooxalyl anilide, which in turn can
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