THE REDUCTIVE CONDENSATION OF 2,5-DISUBSTITUTED PYRROLES by James David White B,A., Cambridge University, 1959 A TRESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE In the Department of CHEMISTRY We accept this thesis as conforming to the required standard THE,UNIVERSITY OF BRITISH COLUMBIA June, 196l In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be alloived without my written permission. Department ofChemistry The University of British Columbia, Vancouver 8, Canada. Date Ju*e ^ 1961 ABSTRACT The problem initially presented was the structural elucidation of a compound obtained when 2,5-dimethylpyrrole was subjected to conditions of acidic reduction. Previous workers had assigned a molecular formula C^H^N to this product and a partial structure had been put forward based on the indolenine system. In the course of this work it was found that the compound obtained by these earlier workers was the result of a reductive self-condensation of 2,5>-diraethylpyrrole, and Its structure was conclusively established as 1,3»h»7-tetramethyl- isoindoline. The methods used in the structural elucidation of this product included elemental analysis of its derivatives, measurement of its basicity and equivalent weight, infrared and ultraviolet spectroscopic evidence, oxidative degradation, and its proton magnetic resonance spectrum. Two related isoindolines were prepared by different routes. 2J4., 7-trimethylisoindoline was synthesised by methods analogous to those already known, and the ultraviolet.spectrum of its methiodide, when compared with that of the raethiodide from 1>3»K»7-tetramethylisoindoline, reinforced the structural assign• ment of the latter. 1, 3-diphenyl-l|., 7-dimethylisoindoline was obtained by the reductive condensation of acetonylacetone with 2,5-diphenylpyrrole (which did not undergo self-condensation). ii The favourable result of this reaction suggested that a similar condensation may have occurred to give the 1, 3, k-» 7-tetramethyl- isoindoline and also admitted the possibility of a general synthesis of substituted isoindolines by this route. An attempt was made to resolve the mechanism of the 2,5-diraethylpyrrole condensation, for which either a Diels-Alder reaction or a ring-opening process may be postulated. The failure of the dimethylpyrrole to show dienic character, even in the presence of very strong dienophiles, together with positive evidence for ring-opening and ketone-pyrrole condensation argued forcibly for the latter mechanism. iii TABLE OP CONTENTS CHAPTER PAGE Ic INTRODUCTIONO oooooooeoao9«oooe«oooo 1 Ho REDUCTIVE CONDENSATION OP 2,5-DIMETHYLPYRR0LE 9 Structural Elucidation of the Product . 10 Preparation and Analysis of Derivatives ..... 10 N-Methylation .... ......... 10 Infrared Spectrum ,...10 Ultraviolet Spectrum. 13 Electrometric Titration ............. lif Oxidative Degradation .............. llj. Proton Magnetic Resonance Spectrum. ....... 15 Stereochemistry of the Product. ...........16 III. RELATED ISOINDOLINES. ......... ... 17 2,1^7-Trimethylisoindoline. .............17 1,3~I)iphenyl-i|j,7-dimethylisoindoline. ........ 21 DOI* iV3- t X V G S 0000000004000000006 23 Infrared Spectrum ....... 2I4. Ultraviolet Spectrum. ..............214. IV. THE MECHANISM OP THE 2,5-DIMETHYLPYRROLE CONDENSATION . 26 Diels-Alder Mechanism ................26 Ring-opening Mechanism. ...............31 V. EXPERIMENTAL, ...aooo............... 37 REFERENCES oo«ooao...ooo.ooo...oo.» iv LIST OP TABLES TABLE PAGE I. Chief Features of the Infrared Spectrum of 1,3J,I(.i,7-Tetramethylisoindpline. ........... 12 II. The Ultraviolet Spectra of 1,3,1].,7-Tetramethyl- isoindoline and Related Compounds .......... 13 III. pK Values of 1,3,lj.,7-Tetramethylisoindoline and Related Compounds .................. llf IV. The Proton Magnetic Resonance Spectrum of 1n3>sh» 7-Tetramethylisoindoline. ........... 15 V. The Ultraviolet Spectrum of 1,3-Diphenyl-lj., 7-d.imethyl- isoindoline and Related Compounds .......... 2I4. v LIST OP FIGURES FIGURE ' PAGE 1, The Pyrrole Trimer. eooooooeooooooo 2. Reaction Sequence in the Condensation of 2,3-Disubstituted Pyrroles. oeoooooooooo 3« Schemes Proposed for the Condensation of 2,ij.-Dimethylpyrrole .................. 4 Ij.. Plancher's Scheme for the Reductive Condensation of 2,5-Dimethylpyrrole ... ........ 6 5° The Reductive Condensation of 2,5-Dimethylpyrrolej Derivatives and Oxidative Degradation of the P^OdUCt «ooooooooooooooooooooooo^]]_ 6. The Synthesis of 2,I(.,7-Trimethylisoindoline ....... 18 7«. The Synthesis of 1, 3-Diphenyl-lj.j, 7-dimethyllsoindollne cLXlCl ID©!1 lV&tlV6S o o e o o « o o o o o o e o o o o © o o 22 8. A Proposed Diels-Alder Mechanism for the Reductive Condensation of 2,5-Dimethylpyrrole .......... 27 9. Products of the Reaction of Certain Pyrroles with «Dl QX10 jptl ii © S 0000000400000000000000 2^ 10. A Proposed Ring-opening Mechanism for the Reductive Condensation of 2S5-Dimethylpyrrole .......... 32 11. The Condensation of Acetonylacetone with 2,5>-Dimethyl- "t 111 Gjptl 0I"1© oooo9oooooooo«ooaoe6ooo3^~ 12. The Condensation Product of Acetone and 2 = 5>-Dimethyl- P Old o oeooo eooooooeoooooooooo3^" vi ACKNOWLEDGMENT The writer would like to express his thanks to Dr. R. Bonnett who provided much helpful advice and guidance in the course of this research. Thanks are also due to Dr. D. McGreer for deter• mining the N.M.R. spectra. Analyses were carried out by A. Bernhardt, Mulheim. vii CHAPTER I INTRODUCTION The importance of pyrrole compounds in plant and animal life is well established and their chemistry has attracted a proportionately large share of the attention devoted to heterocyclic compounds. The incorporation of the pyrrole nucleus in the macrocyclic porphyrin systems of such molecules as chlorophyll and hemin testifies to the significant part which it plays in living processes. Other examples of biologically important pyrrole compounds include the enzyme catalase, the bile pigment bilirubin and the mould pigment prodigiosino The parent compound, pyrrole, has been known for some time as a constituent of bone-oil and its earliest preparations consisted of distillation of coal tar, bones, and horn. Runge, in lQ3k-> described a method for detecting pyrrole prepared in this way using a pine-splinter moistened with hydrochloric acid (1). The pine-splinter turned bright red in the presence of pyrrole and the name of this class of compounds derives from the Greek equivalent for this colour. Pyrrole is generally regarded as intermediate in aromaticity between furan and thiophene, although pyrrole itself is unstable in air, turning rapidly yellow and then orange. The presence of alkyl groups on the ring accelerates this deter• ioration while electron-withdrawing substituents inhibit the 2 Figure 2. Reaction sequence in the condensation of 2,3-disubstituted pyrroles. 3 effect. Among the reactions of pyrrole is one, first reported in 1888, in which pyrrole is treated with acid to give a trimer (2). After several incorrect assignments, the structure of the trimer was eventually established as (I) (3). Acid treatment of 2-methylpyrrole was found to give a product, C]_oHnN, which Dennstedt concluded to be 2,1^-dimethyl- indole (IV; R = CH3, R! = H) (ij.). A similar reaction occurred with 2,3-dimethylpyrrole giving the dipyrrole (II; R = R' = CH3) and subsequently 2,3*4s5-tetramethylindole (5), although later workers proposed a bis structure for this compound (6). Allen, in 1938> suggested that condensation to form indoles was a general reaction of 2,3-disubstituted pyrroles (7)» Allen's scheme consisted of an initial linkage at the free (^-positions to give the dipyrrole (II). Ring-closure, giving the bridge- compound (III), followed by elimination of ammonia would result in the 2,3>lw5-substituted indole. In the case of 2-phenylpyrrole it was found that the dipyrrole (II; R = Ph, R' = H) was formed but no further reaction occurred (8). It was first thought that the condensation of 2,l).-dialkylpyrroles follov*red the pattern of the 2,3-disubstituted pyrroles. Plancher, on treating 2,k-dimethylpyrrole with zinc and acetic acid, obtained a solid for which analysis indicated a molecular formula C^H^N (9). On the basis of an initial o^ot'-linkage giving the dipyrrole (VII), Plancher proposed that ring-closure occurred between the substituted ^-position of one pyrrole nucleus and the free /3-position of the other ((a) In Figure 3)« Upon elimination of ammonia this would give the Figure 3. Schemes proposed for the condensation of 2,4-dimethylpyrrole. 5 bicyclic structure (VIII) (10). This structure was later revised to an indolenine (IX) which, ©lancher claimed, better accounted for the basicity of his product and also afforded a closer analogy with a reaction between acetonylacetone and pyrrole which gave [[.,7-dimethylindole (II). The indolenine would result from cyclisation of the dipyrrole (VII) by means of the bond (b) in Figure 3° Since the structure of the intermediate dipyrrole was not known (although (VII) would be most likely on steric grounds) the possibility of three other isomers of the indolenine had to be