I Synthesis of benzo-fused heterocycles using isomerization and ring-closing metathesis reactions Lee Gavin Madeley Supervised by Prof. W.A.L. van Otterlo A dissertation submitted in the School of Chemistry to the Faculty of Science, University of the Witwatersrand, in fulfilment of the requirements for the Degree of Master of Science March 2010 II Declaration I declare that the work presented in this dissertation is my own, unaided work and was carried out under the supervision of Prof. W.A.L. van Otterlo. It is being submitted for the Degree of Master of Science in the University of the Witwatersrand, Johannesburg. It has not been submitted before for any degree or examination in any other University. __________________________ Lee Gavin Madeley March 2010 III Abstract The first part of the dissertation involves the use of ruthenium mediated isomerization (RMI) followed by ring-closing metathesis (RCM) on a selection of phenols and naphthol-1-ol precursors – that had been subjected to allylation; followed by a heat initiated Claisen rearrangement; followed by re-allylation – to form a selection of benzofurans. This procedure, to the best of our knowledge, represents a novel method for the synthesis of benzofurans, with very good average yields of around 90% overall for the RMI/RCM and allylation steps. The lowest yield of the five synthetic steps, were for the Claisen rearrangements with a range of yields between 50% and 86%, indicating the potential to optimise the yields of these reactions, which were carried out using both conventional and microwave heating. The following five-membered oxygen-containing heterocycles were thus obtained: 4,7-dimethoxybenzofuran, 5-bromobenzofuran, 5-tert-butyl-benzofuran, 7- phenyl-1-benzofuran and naphtho[1,2-b]furan. The second part of the dissertation involves the use of RMI and RCM on di-allylated; di- allylated di-isomerised; and di-allylated mono-isomerized O,N- (aminophenol) and N,N- (benzene-1,2-diamine) protected precursors. This resulted in the formation of six-, seven- and eight-membered benzo-fused heterocycles respectively. Except in the case of the mono- and di-isomerised N,N-precursor, which failed to undergo RCM, despite several attempts. This failure, which is not unprecedented, is most likely due to the interaction of nitrogen‟s lone pairs and the adjacent saturated bonds of the precursor with the GII catalyst, resulting in de- allylation. Of those reactions that were successful, the average yields for the RMI/RCM steps were in the region of 82% for the N,N-precursors and 95% for the O,N-precursors. All precursors readily submitted to allylation and isomerization, with an average yield of 94%. The following benzo-fused heterocycles were thus obtained: six-membered: 4H-1,4- benzoxazin-4-yl(phenyl) methanone; seven-membered: 1,5-benzoxazepin-5(4H)- yl(phenyl)methanone; eight-membered: 2,5-dihydro-6H-1,6-benzoxazocin-6-yl(phenyl) methanone and 1,1'-[(3Z)-2,5-dihydro-1,6-benzodiazocine-1,6-diyl]diethanone. IV Acknowledgements I would like to thank my supervisor Willem van Otterlo and the Head of School Jo Michael; my family; and my friends – especially Shaun and Warren. All your indulgences are appreciated. After much consideration, I have included a quote which follows, it may be wasted next to such a lean work, but my intentions are most humble and I‟m sure that this was the spirit in which it was intended: “We are nothing without the work of others our predecessors, others our teachers, others our contemporaries. Even when, in the measure of our inadequacy and our fullness, new insight and new order are created, we are still nothing without others. Yet we are more.” J. Robert Oppenheimer, Reith Lecture, 20 December 1953 V Table of Contents Declaration II Abstract III Acknowledgments IV Table of contents V List of Abbreviations XII Chapter 1: Introduction 1 1.1 Project overview 2 1.2 Metathesis reactions (RCM) 3 1.2.1 Metathesis catalysts 3 1.2.2 Metathesis mechanism 4 1.2.3 Metathesis catalyst used in this project 7 1.3 Ruthenium mediated isomerization (RMI) 9 1.3.1 Isomerization reaction 9 1.3.2 Isomerization mechanism 11 1.3.3 Isomerization catalyst used in this project 13 1.4 Claisen rearrangements 14 1.5 Conclusion 15 Chapter 2: Relevance of the research 17 2.1 5-membered oxygen containing benzo-fused heterocycles 17 2.1.1 Previous benzofuran synthetic strategies 19 2.1.1.1 Non-metathesis ring-closure (RC) reactions 19 2.1.1.1.1 RC by the formation of the O-C(2) bond 19 2.1.1.1.2 RC by the formation of the Ar-C(3) bond 20 2.1.1.1.3 RC by the formation of the C(2)-C(3) bond 20 2.1.1.1.4 RC by the formation of the Ar-O bond 21 VI 2.1.1.2 Synthesis from furans and dihydrofurans 22 2.1.1.3 Use of the Perkin rearrangement 22 2.1.1.4 Resin based benzofuran combinatorial approaches 23 2.1.1.4.1 The Habermann approach 23 2.1.1.4.2 The Fancelli approach 24 2.1.1.4.3 The Nicolaou approach 25 2.2 6-, 7- and 8-membered O, N-benzo-fused heterocycles 27 2.2.1 6-membered O-N-benzo-fused heterocycles 27 2.2.1.1 Previous synthetic strategies for the 1,4-benzoxazines 29 2.2.1.1.1 The Synthetic strategy of Buon 29 2.2.2 7-membered O-N-benzo-fused heterocycles 30 2.2.2.1 Previous synthetic strategies for the 1,5-benzoxapines 32 2.2.2.1.1 Sequential N-acylamide RCM 32 2.2.2.1.2 The reduction of chromanone Oximes 32 2.2.3 8-membered O-N-benzo-fused heterocycles 33 2.2.3.1 Previous synthetic strategies for the 1,6-benzoxacines 35 2.2.3.1.1 The RCM enyne metathesis strategy of Mori 35 2.3 6-, 7- and 8-membered N, N-benzo-fused heterocycles 36 2.3.1 6-membered N,N-benzo-fused heterocycles 36 2.3.1.1 Previous synthetic strategies for the 1,4-quinoxalines 38 2.3.1.1.1 Reduction involving quinoxaline 38 2.3.1.1.2 Oxalate addition involving di-amines 38 2.3.1.1.3 Beirut methodologies involving benzofuroxans 40 2.3.2 7-membered N,N-benzo-fused heterocycles 41 2.3.2.1 Previous synthetic strategies for the 1,5-benzodiazapines 43 2.3.2.1.1 o-Phenylenediamines with unsaturated carbonyls 43 2.3.2.1.2 The one-pot three-component strategy 44 2.3.2.1.3 Synthesis involving zeolites 45 2.3.3 8-membered N,N-benzo-fused heterocycles 45 VII 2.3.3.1 Previous synthetic strategies for the 1,6-benzodiazacines 47 2.3.3.1.1 Di-amines with cis-1,4-dichloro-2-butene 47 2.3.3.1.2 RCM of allylated 1,2-benzodiamines 47 2.4 Conclusion 48 Chapter 3: Results and discussion 49 3.1 The Wits RMI RCM approach to benzofurans 50 3.1.1 Retro-synthetic analysis of the benzofurans 50 3.1.2 General methodology towards the benzofurans 51 3.1.3 Substituted phenols and naphthalene-1-ol precursors 53 3.1.4 Results and analysis of the individual reaction steps 53 3.1.4.1 Allylation of the phenols and naphthalene-1-ol 53 3.1.4.1.1 Yield and characterization data 55 3.1.4.2 Claisen reactions of the allylated precursors 56 3.1.4.2.1 Yield and characterization data 57 3.1.4.3 Re-allylation of the Claisen products 60 3.1.4.3.1 Yield and characterization data 61 3.1.4.4 Di-isomerization of the di-allylated compounds 63 3.1.4.4.1 Yield and characterization data 64 3.1.4.5 RCM of the di-isomerized compounds 65 3.1.4.5.1 Yield and characterization data 67 3.1.5 Conclusion regarding benzofuran RMI RCM methodology 69 3.2 The Wits RMI RCM approach to the 6-, 7- and 8-membered O, N and N, N benzo-fused heterocycles 70 3.2.1 Retro-synthetic analysis 70 3.2.2 General synthetic methodologies implemented towards: 71 3.2.2.1 The O,N benzo-fused heterocycles 72 3.2.2.2 The N,N benzo-fused heterocycles 74 VIII 3.3 Results obtained for the individual reaction steps 76 3.3.1 Protection of the heterocyclic precursors 76 3.3.1.1 Protection of 2-aminophenol 76 3.3.1.2 Protection benzene-1,2-diamine 77 3.3.2 Sequential and dual allylation protocols 78 3.3.2.1 Mono- and di-allylations performed on precursors 79 3.3.2.1.1 Characterization of allylation products 80 3.3.2.2 Allylations performed on the ‘isomerized’ precursors 82 3.3.2.2.1 Characterization of allylation products 83 3.3.3 Isomerization (RMI) protocol 85 3.3.3.1 Yield and characterization data 86 3.3.4 RCM protocol 89 3.3.4.1 Yield and characterization of successful RCM products 91 3.3.4.2 Data regarding the un-successful RCM products 93 3.4 Conclusion regarding the O,N- and N,N-benzofused heterocycles 94 Chapter 4: Conclusions and future work 95 4.1 Conclusions and future work regarding the benzofurans 96 4.2 Conclusions and future work regarding the O,N-benzo-fused heterocycles 97 4.3 Conclusions and future work regarding the N,N-benzo-fused heterocycles 98 Chapter 5: Experimental 101 5.0 General experimental procedures 102 5.1 The benzofurans 104 5.1.1 Mono-allylation of the precursors 104 5.1.1.1 1,4-Dimethoxy-2-(prop-2-en-1-yloxy)benzene 141a 104 IX 5.1.1.2 1-Bromo-4-(prop-2-en-1-yloxy)benzene 141b 105 5.1.1.3 1-tert-Butyl-4-(prop-2-en-1-yloxy)benzene 141c 105 5.1.1.4 2-(Prop-2-en-1-yloxy)biphenyl 141d 106 5.1.1.5 1-(Prop-2-en-1-yloxy)naphthalene 141e 107 5.1.2 Claisen reactions on the mono-allylated precursors 108 5.1.2.1 3,6-Dimethoxy-2-(prop-2-en-1-yl)phenol 142a 108 5.1.2.2 4-Bromo-2-(prop-2-en-1-yl)phenol 142b 109 5.1.2.3 4-tert-Butyl-2-(prop-2-en-1-yl)phenol 142c 109 5.1.2.4 3-(Prop-2-en-1-yl)biphenyl-2-ol 142d 110 5.1.2.5 2-(Prop-2-en-1-yl)naphthalen-1-ol 142e 111 5.1.3 Re-allylation of the Claisen precursors 112 5.1.3.1 1,4-Dimethoxy-2-(prop-2-en-1-yl)-3-(prop-2-en-1-yloxy)benzene ……………………………………………………………………...143a 112 5.1.3.2 4-Bromo-2-(prop-2-en-1-yl)-1-(prop-2-en-1-yloxy)benzene 143b 113 5.1.3.3 4-tert-Butyl-2-(prop-2-en-1-yl)-1-(prop-2-en-1-yloxy)benzene 143c 114 5.1.3.4 3-(Prop-2-en-1-yl)-2-(prop-2-en-1-yloxy)biphenyl 143d 115 5.1.3.5 2-(Prop-2-en-1-yl)-1-(prop-2-en-1-yloxy)naphthalene 143e 116 5.1.4 Di-isomerization of the di-allylated precursors 117 5.1.4.1 1,4-Dimethoxy-2-(prop-1-en-1-yl)-3-(prop-1-en-1-yloxy)benzene …………………………………………………………………….