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"up. w surf w. , . .. - n v 2.. ima‘ .‘3, n «WWNT ””””””””””””””” 1121512550 311293006\120 ,. w... LIBRAR t Michigan Stat: University This is to certify that the dissertation entitled SYNTHESIS OF 2,2' :5' ,2"-TERPYRROLE. 2,5-BIS(2-PYRRYL)THIOPHENE AND SUBSTITUTED ANALOGS presented by Bryon Anderson Merrill has been accepted towards fulfillment of the requirements for Ph.D. degreein Organic Chemistry @«W Date /é‘/M /9'yfl MSUbuWnAcn‘on/Eqd “may Institution 0-1217! PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or More data due. DATE DUE , DATE DUE DATE DUE on 2 5 1993; '7I___[——} I w L __J ”WT—i MSU Is An Affirmative ActionlEqual Opportunity Insthuflon '— |_ SYNTHESIS OF 2,2':5',2'-TERPYRROLE, 2,5-BlS(2-PYRRYL)THlOPHENE AND SUBSTITUTED ANALOGS BY Bryon Anderson Merrill A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1990 ABSTRACT SYNTHESIS OF 2,2':5',2”-TERPYRROLE, 2,5-BlS(2—PYRRYL)THIOPHENE AND SUBSTITUTED ANALOGS By Bryon Anderson Merrill Linear heteroaromatic tricycles are important precursors for the preparation of organic conductive polymers and expanded-porphyrin macrocycles. An efficient route to a series of these compounds has been achieved. The key step involves a Stetter reaction between an electron deficient pyrrole aldehyde and divinyl sulfone. The resulting 1,4-diketone is used as a common precursor for the synthesis of tricycles of different heteroatom composition. N-sulfonyl protected 2-formylpyrroles were utilized in the preparation of 2,2':5',2"-terpyrrole (3a) and 2,5-bis(2-pyrryl)thiophene (3b). Condensation of the 1,4-diketone intermediate with an ammonium salt followed by hydrolytic deprotection provided 3a. Reaction of the 1,4-diketone intermediate with Lawesson's reagent followed by hydrolytic deprotection provided 3b. Compound 3b is a new tricycle. The alkyl substituted analogs 2,5-bis(4-methyl-2—pyrryl)pyrrole (59) and 2,5-bis(4-methyl-2-pyrryl)thiophene (60) were prepared using 2-formyI-3,5- diethoxycarbonyI-4-methylpyrrole as the electron deficient starting material. Initial reactions of 1,4-diketones with 1,4-phenylenediamine provided low yields of N,N'-phenyl-bridged tricyclic dimers. Electrochemical polymerization of tricycles 3b and 60 yielded thin films which exhibited excellent electrochemical response and high conductivity values. The attempted synthesis of a [1,4,1 ,4]tetraazadithioplatyrin (73), an expanded-porphyrin, resulted in the recovery of a linear, dimeric product. This thesis is dedicated with love to my Mom, Mark and Tonya and in loving memory of my grandmother, Martha Anderson (Granny). ACKNOWLEDGEMENTS I am pleased to express my deep appreciation to Professor Eugene LeGoff for his guidance, enthusiasm and friendship. Under his direction, my studies have been both fun and exciting. I am equally grateful to Eric Lind, Thungmei Luo and Wai-Yee Leung for passing on the oral history of the LeGoff research group. Most of my laboratory expertise was acquired by watching and questioning these three scientists. I am indebted to Professor John Gaudiello and Evaldo DeArmas for investigating the electrochemical properties of some of the compounds in this thesis. Professor Gaudiello's willingness to explain and discuss his results greatly expanded my understanding of this project and its scientific importance. Financial support for this work was generously supplied by Michigan State University and is gratefully acknowledged (i.e., Lawrence Quill Fellowship (1984-87), College of Natural Science Fellowship (1984-85, 88-89), H.T. Graham Fellowship (1988-89), William R. Yates Fellowship (1989), All- University Research Initiation Grant (1988)). I would like to thank Mark McMills, Jeff Raggon, Rick Olsen and Paul Weipert for many enthusiastic discussions on organic synthesis, as well as many unforgettable moments on the golf course. Additional thanks go to my non-golfing colleagues and friends, Vinod and Tutul. Professor Ron Starkey (University of Wisconsin - Green Bay) and Dr. John Davison (Oak Park-River Forest High School) merit special mention as teachers whose enthusiasm for chemistry resulted in my decision to become a chemist. Special thanks go to my Mom and my brother, Mark, for their love, support and confidence in me. I have missed being near them the past five years. I always looked forward to going home to Baileys Harbor and to having them visit me on campus (mainly Forest Akersl). Finally, I am extremely fortunate to have studied chemistry at Michigan State for it is here that I found and fell in love with my wife, Tonya. TABLE OF CONTENTS Ease LIST OF TABLES ............................................ vii LIST OF FIGURES ........................................... viii LIST OF SCHEMES .......................................... xiii I. INTRODUCTION ........................................... 1 A. SYNTHESIS OF HETEROAROMATIC CONDUCTIVE POLYMERS ........................................... 1 B. SYNTHESIS OF EXPANDED PORPHYRIN-LIKE HETEROANNULENES ................................. 15 ll. RESULTS AND DISCUSSION .............................. 31 A SYNTHESIS OF a—TERPYRROLE AND MIXED HETEROAROMATIC TRICYCLES ........................ 31 1. Attempted Synthesis of 3a by Portoghese's Method ..... 34 2. Synthesis of 3a-c From 1-4-Diketone Precursors ........ 41 3. Electrochemical Studies of 3b and 60 ................. 58 4. Synthesis of Phenyl-Bridged Tricycles ................. 65 B. STUDIES DIRECTED TOWARD THE SYNTHESIS OF [1 ,4,1,4]TETRAAZADITHIOPLATYRIN 73 .................. 70 CONCLUSIONS .............................................. 73 EXPERIMENTAL SECTION .................................... 75 APPENDIX ................................................... 95 LIST OF REFERENCES ....................................... 144 vi Table Table Table Table Table Table LIST OF TABLES Representative Organic Conductive Polymers ........... Oxidation Potential and Conductivity Data of Substituted Systems ............................................ Physical Properties of1a-d and 2a-d ................. Eml Values of Tricyclic Monomers ...................... Substituent Effects on the Epa of Heteroaromatic Monomers ........................................... Conductivity Values of Heteroaromatic Polymers ......... vii E395 2 9 13 61 62 64 LIST OF FIGURES Bade Figure 1 Conjugated n-Electron Structure of Organic Conductive Polymers .......................... 2 Figure 2 INDO Molecular Orbital Calculations of Unpaired Electron Distribution ........................... 6 Figure 3 Energy Level Diagram of the 'Aromatic' Phase and the 'Ouinoid' Phase of Heteroaromatic Polymers ..................................... 7 Figure 4 Proposed [1 ,4,1,4]Platyrins ..................... 15 Figure 5 Dewar Calculation of Delocalization Energy ...... 16 Figure 6 Representative Large Aromatic Heteroannulenes. . 18 Figure 7 Mertes' Hybrid Porphyrin-Like Bimetallic Ring ..... 19 Figure 8 Organic Conductive Macrocycles ................ 22 Figure 9 Averaged Crystallographic Parameters of Octaethylporphyrin ............................. 24 Figure 10 Calculated Lowest Energy Conformation of 5a . . . . 24 Figure 11 Calculated Lowest Energy Conformation of 7a . . . . 25 Figure 12 Calculated Lowest Energy Conformation of 5c ..... 25 Figure 13 Calculated Lowest Energy Conformation of 7c ..... 26 Figure 14 Calculated Lowest Energy Conformation of 5b ..... 26 Figure 15 Calculated Lowest Energy Conformation of 7b ..... 27 Figure 16 Space-Filling Representation of Porphine ......... 27 Figure 17 Space-Filling Representation of 5a ............... 28 viii E395 Figure 18 Space-Filling Representation of 7a .............. 28 Figure 19 Space-Filling Representation of 5c .............. 29 Figure 20 Space-Filling Representation of 7c .............. 29 Figure 21 Space-Filling Representation of 5b .............. 30 Figure 22 Space-Filling Representation of 7b .............. 30 Figure 23 Cyclic Voltammogram (CV) of 3b ............... 60 Figure 24 Cyclic Voltammogram (CV) of 60 ............... 60 Figure 25 Surface Wave Cyclic Voltammogram of 4b ....... 63 Figure 26 Surface Wave Cyclic Voltammog ram of 66 ....... 63 Figure 27 Hydrogen-Bond Stabilized Conformation of 56 . . . 67 Figure A1 250 MHz 1H-NMR spectrum of 1-methanesulfonyl- 2-formylpyrrole (46b) .......................... 95 Figure A2 62.9 MHz 13C-NMR spectrum of 1-methane- sulfonyl-2-formylpyrrole (46b) ................... 96 Figure A3 300 MHz 1H-NMR spectrum of 1,4-bis(1-benzene- sulfonyI-2-pyrryl)-1,4-butanedione (47a) .......... 97 Figure A4 75.4 MHz 13C-NMR spectrum of 1,4-bis(1- ‘ benzenesulfonyl-2-pyrryl)-1,4-butanedione (47a) ......................................... 98 Figure A5 300 MHz 1H-NMR spectrum of 1,4-bis(1-methane- sulfonyl-2-pyrryI)-1,4-butanedione (47b) .......... 99 Figure A6 75.4 MHz 13C-NMR spectrum of 1,4-bis(1-methane- sulfonyl-2-pyrryl)-1 ,4-butanedione (47b) .......... 100 Figure A7 250 MHz 1H-NMR spectrum of 2,5-bis(1-benzene- sulfonyI-2-pyrryl)pyrrole (483) .................... 101 Figure A8 75.4 MHz 13C-NMR spectrum of 2,5-bis(1-benzene- squonyl-2-pyrryl)pyrrole (48a) ................... 102 Figure A9 250 MHz 1H--NMR spectrum of 2,5-bis(1-methane- sulfonyl-2-pyrryl)pyrrole (48b) ................... 103 Figure A10 Figure A11 Figure A12 Figure A13 Figure A14 Figure A15 Figure A16 Figure A17 Figure A18 Figure A19 Figure A20 Figure A21 Figure A22 Figure A23 Figure A24 Figure A25 E399 62.9 MHz 13C-NMR spectmm of 2,5-bis(1- methanesuIfonyl-2-pyrryl)pyrrole (48b) .......... 104 250 MHz 1H-NMR spectrum of 2,2':5',2"-terpyrrole (3a) .......................................... 105 62.9 MHz 130-NMR spectrum of 2,2':5',2"-terpyrrole (3a) .......................................... 106 300 MHz 1H-NMR spectrum of 2,5-bis(1-benzene- sulfonyl-2—pyrryl)thiophene (49a) ................ 107 75.4 MHz 1Cic-NMR spectrum of 2,5-Bis(1- benzenesuIfonyI-2-pyrryl)thiophene (49a) ........ 108 250 MHz 1H-NMR spectrum of 2,5-bis(1-methane- suIfonyI-2-pyrryl)thiophene (49b) ................ 109 62.9 MHz 13C-NMR spectrum of 2,5-bis(1-methane- sulfonyI-2-pyrryl)thiophene (49b) ................ 1 10 300 MHz 1H-NMR spectrum of 2,5-bis(1-benzene- sulfonyI-2-pyrryl)furan (50) ...................... 1 1 1 62.9 MHz 13C-NMR spectrum of 2,5-bis(1-benzene- sulfonyI-2-pyrryl)furan (50) ...................... 1 12 300 MHz 1H-NMR spectrum of 2,5-bis(2-pyrryl)- thiophene (3b) ................................. 1 13 75.4 MHz 13C-NMR spectrum of 2,5-bis(2-pyrryl)- thiophene (3b) ................................. 1 14 300 MHz 1H-NMR spectrum of 2-(5-formyI-2-pyrryl)- 5-(2-pyrryl)thiophene (52) ....................... 1 15 62.9 MHz 13C-NMR spectrum of 2-(5-formyI-2-pyrryl)- 5(2-pyrryl)thiophene (52) ...................... 1 16 250 MHz 1H-NMR spectrum of 2,5-bis(5-formyl-2- pyrryl)thiophene (53) ........................... 1 17 62.9 MHz 1i’rC-NMR spectrum 012,5—bis(5-formyI-2- pyrryl)thiophene (53) ........................... 1 18 300 MHz 1H-NMR spectrum of 1,4-bis(3,5-diethoxy- carbonyl-4-methyI-2-pyrryl)-1,4-butanedione (55). . 119 Figure A26 Figure A27 Figure A28 Figure A29 Figure A30 Figure A31 Figure A32 Figure A33 Figure A34 Figure A35 Figure A36 Figure A37 Figure A38 Figure A39 Figure A40 75.4 MHz 13C-NMR spectrum of 1,4-bis(3,5~diethoxy- carbonyl-4-methyl-2-pyrryl)-1,4-butanedione (55). . 250 MHz 1H-NMR spectrum of 2,5-bis(3,5-diethoxy- carbonyI-4-methyl-2-pyrryl)pyrrole (56) ........... 62.9 MHz 130-NMR spectrum of 2,5—bis(3,5-diethoxy- carbonyI-4-methyl-2-pyrryl)pyrrole (56) ........... 300 MHz 1H-NMR spectrum of 2,5-bis(3,5-diethoxy- carbonyl-4-methyI-2-pyrryl)thiophene (57) ........ 62.9 MHz 13C-NMR spectrum of 2,5-bis(3,5-diethoxy- carbonyI-4-methyl-2-pyrryl)thiophene (57) ........ 250 MHz 1H-NMR spectrum of 2,5-bis(3,5-diethoxy- carbonyl-4-methyl-2-pyrryl)furan (58) ............. 62.9 MHz 1i’rC-NMR spectrum of 2,5-bis(3,5-diethoxy- carbonyl-4-methyI-2-pyrryI)furan (58) ............. 250 MHz 1H-NMR spectrum of 2,5-bis(4-methyl-2- pyrryl)pyrrole (59) .............................. 62.9 MHz 13C-NMR spectrum of 2,5-bis(4-methyI-2- pynyl)pyrrole (59) .............................. 250 MHz 1H-NMR spectrum of 2,5-bis(4-methyI-2- pyrryl)thiophene (60) ........................... 62.9 MNz 13C-NMR spectrum of 2,5-bis(4-methyI-2- pyrryl)thiophene (60) ........................... 300 MHz 1H-NMR spectrum of 1,4-bis(5-ethoxy- carbonyl-3,4-dimethyl-2-pyrryI)-1 ,4-butanedione (63) .......................................... 75.4 MHz 13C-NMR spectrum of 1,4-bis(5-ethoxy- carbonyl-3,4-dimethyl-2-pyrryl)-1 ,4-butanedione (63) .......................................... 300 MHz 1H-NMR spectrum of 2,5-bis(5-ethoxy- carbonyl-3,4-dimethyl-2—pyrryl)thiophene (64) . . . . 62.9 MHz 13C-NMR spectrum of 2,5-bis(5-ethoxy- carbonyl-3,4—dimethyl-2-pyrryl)thiophene (64) . . . . xi Base 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 E393 Figure A41 250 MHz 1H-NMR spectrum of 2,5—bis(5-ethoxy- carbonyl-3,4-dimethyl-2-pyrryl)furan (65) ......... 135 Figure A42 250 MHz 1H-NMR spectrum of compound 69 ...... 136 Figure A43 62.9 MHz 130-NMR spectrum of compound 69 ..... 137 Figure A44 250 MHz 1H-NMR spectrum of compound 70 ...... 138 Figure A45 75.4 MHz 13C—NMR spectrum of compound 70 ..... 139 Figure A46 300 MHz 1H-NMR spectrum of compound 71 ...... 140 Figure A47 75.4 MHz 1(’1C-NMR spectrum of compound 71 ..... 141 Figure A48 300 MHz 1H-NMI'PI spectrum of compound 72 ...... 142 Figure A49 75.4 MHz 13C-NMR spectrum of compound 72 ..... 143 xii LIST OF SCHEMES E302 Scheme 1 Mechanism of the Electrochemical Polymerization Reaction ...................................... 4 Scheme 2 Charge Carrier Formation ...................... 7 Scheme 3 Naitoh's Copolymer Synthesis ................... 12 Scheme 4 Ferraris' Cepolymer Synthesis ................... 13 Scheme 5 Proposed Copolymer Synthesis .................. 14 Scheme 6 Potts' and Smith's Synthesis of 2,2':5',2"-Terpyrrole (3a) ........................................... 32 Scheme 7 Chieici's and Cella‘s Synthesis of 3a ............. 33 Scheme 8 Rapoport's Synthesis of 3a ...................... 34 Scheme 9 Portoghese's Pyrrole Synthesis .................. 35 Scheme 10 Piloty-Robinson Pyrrole Synthesis ................ 36 Scheme 11 Acid Chloride Induced Piloty-Robinson Pyrrole Synthesis ..................................... 36 Scheme 12 Portoghese's Proposed Mechanism .............. 37 Scheme 13 The Portoghese Procedure with 2-Acetylpyrrole (27) and 2-Acetylthiophene (30): Formation of Azines. . 38 Scheme 14 Reaction of Acylhydrazine 32 Under Portoghese's Reaction Conditions ............................ 39 Scheme 15 Yoshida’s Anionic Synthesis of Pyrrole ........... 40 Scheme 16 Acid Chloride Activation of Azine Rearrangements. . 40 xiii Scheme 17 Scheme 18 Scheme 19 Scheme 20 Scheme 21 Scheme 22 Scheme 23 Scheme 24 Scheme 25 Scheme 26 Scheme 27 Scheme 28 Scheme 29 Scheme 30 Scheme 31 Scheme 32 Scheme 33 Scheme 34 The Reaction of Cyclohexanone under Portoghese's Conditions ........................ Formation of 38-0 from 1,4-Bis(2-pyrryI)-1,4- butanedione (35) .............................. The Stetter Reaction ............................ Mechanism of the Stetter Reaction ................ Acyloin and Cyanohydrin Reactions of 2-Formyl- pyrrole (36) .................................... EWG-Substituent Activation of the Acyloin Condensation .................................. Jones’ Thiazolium Salt-Catalyzed Michael Reaction The Stetter Reaction with N-EWG Substituted 2- Formylpyrroles .................................. Synthesis of 1 ,4-Bis(1-benzenesuIfonyl-2-pyrryI)-1,4- butanedione (47a) ............................. Initial Attempts at the PaaI-Knorr Reaction ......... Ultrasound Activation of the PaaI-Knorr Reaction . . . Summary of the 2,2':5',2"-Terpyrrole (38) Synthesis Preparation of 1-MethanesulfonyI-2-formylpyrrole (46b) ......................................... Synthesis of 2,5-Bis(2-pyrryl)thiophene (3b) ....... Synthesis of 2,5-Bis(1-benzenesulfonyl-Z-pyrryl)- furan (50) ..................................... Synthesis of 2-(5-FormyI-2-pyrryl)-5-(2-pyrryl)thio- phene (52) ................................... Synthesis of 2,5-Bis(5-formyI-2-pyrryl)thiophene (53) ........................................... Synthesis of 4,4"-Dimethylsubstituted Analogs of 3a-c .......................................... xiv Race 41 42 43 43 44 45 45 46 47 48 49 50 51 52 53 54 54 55 Scheme 35 Scheme 36 Scheme 37 Scheme 38 Scheme 39 Scheme 40 Scheme 41 Scheme 42 Scheme 43 Synthesis of 3,4:3",4"-Tetramethylsubstituted Analogs of 3a-c .............................. Electrochemical Polymerization of 3b and 60 . . . . Retrosynthesis of PhenyI-Bridged Tricycles ....... One-Step Synthesis of Compound 70 .......... Alternate One-Step Synthesis of 70 ............ Two-Step Synthesis 0170 ..................... Lindsey's Synthesis of Tetraphenyl Porphyrin . . . . Proposed Route to [1 ,4,1 ,4]Tetraazadithioplatyrin 73 .......................................... Attempted Synthesis of 73 .................... XV 58 59 66 67 68 69 70 71 71 INTRODUCTION INTRODUCTION A. L n 0 I 30.13.“; .L. '0 n In the past decade, a small number of organic polymers have been reported which exhibit high electrical conductivity when submitted to oxidative or reductive conditions ('doping'). Conductivity values as high as several hundred ohm-1cm-1 (S cm-I) have been recorded. The typical conductivity range lies from 102 to 10'4 S cm‘1 which places the 'doped' organic polymers approximately at the midpoint between traditional metal conductors (i.e., copper 106 S cm-I) and insulators (i.e., polyvinyl chloride 1040 S cm-‘).1 A substantial effort has been undertaken by chemists, physicists, and material scientists to investigate the theoretical, synthetic design, and technological applications of these unique materials. A consistent structural property of all known organic conductive polymers is the presence of a conjugated rt-electron system. Highly conjugated materials are able to either gain or lose electrons with relative ease via the rr-system, while still maintaining the structural integrity of the polymer through the sigma bonds.2 Polyacetylene, an intrinsic insulator (approximately 10'9 S cm-I), was the first and most robust electrical conductor discovered. Maximum conductivity values of 103 to 105 S cm-1 have been recorded for both oxidatively or reductively 'doped' polyacetylene. Unfortunately, the usefulness of polyacetylene in practical applications has been limited by its low stability in air and its poor mechanical integrity.3 2 In contrast, electrochemical oxidative polymerization of the heteroaromatic monomers pyrrole, thiophene, and furan yields thin films which exhibit good electrical conductivity and environmental stability (Table 1).4 The electrochemical method of polymerization allows for a simple and clean method of sample preparation. Figure 1 shows that the conjugated n-electron structure is maintained in the polyheteroaromatics. The heteroatoms (X=NH, S, 0) hold the trans-polyacetylene structure in a rigid trans-cisoid conformation. Both polypyrrole and polythiophene exhibit excellent electrochemical response. The polymer films can be cycled repeatedly between the oxidized conducting state and the neutral insulating state with no apparent degradation of the sample.“-5 Table 1. Representative Organic Conductive Polymers Maximum (S cm’l) WM polyacetylene 103-105 3a,b polypyrrole 102-103 4a,b polythiophene 102 4c polyfuran 102 4f Figure 1. Conjugated n-Electron Structure of Organic Conductive Polymers polyacetylene : \ \ \ polyheteroaromatic : X=NH,S,O 3 A number of important technological applications of the heteroaromatic polymers have been tested and/or postulated. In addition, due to the rapid pace of discoveries in this field, new uses are continuously being reported. Some of the areas in which these materials show promise include light-weight all-polymer batteries“, information storage devices", protection of semi- conductor anodesa, electro-optical display devices9, and remote environmental sensors”. The conductivity values observed for the heteroaromatic polymers can vary over several orders of magnitude depending upon the method of polymerization and 'doping', as well as the counter anion employed.4a These are experimental factors which are independent of the monomer composition. Under a set of standard reaction conditions, however, it should be possible to investigate the effect of changes in the structure of the monomer on the electrical response of the polymer. The ability to alter the heteroatom composition, sequence distribution, and peripheral substituent pattern of the polymer via synthetic alteration of the monomer units may allow for a systematic modification of the electronic properties of the polymer. The ultimate result would be the designed synthesis of a series of polymers exhibiting a continuum of electrical and mechanical properties. By adjusting structural features, physical parameters such as ionization potential, band gap energy, and it-electron bandwidth may be able to be 'tuned' to meet a specific need.‘1 In order to determine the synthetic design factors which will result in the desired modifications, the mechanistic aspects of the electropolymerization and 'oxidative doping' reactions need to be understood. The electrochemical preparation of heteroaromatic polymers is believed to involve a series of radical cation coupling reactions at the electrode 4 surface.12 The polymerization of pyrrole (Scheme 1) is representative of the reaction sequence. The coupling step produces an intermediate dihydro- oligomer dication which forms the neutral oligomer after the loss of two protons (Step 2). The return to a conjugated aromatic structure drives the elimination step. Film formation is stoichiometric with two electrons per monomer unit being involved in the reaction. The high concentration of radical cation monomer (R+-) maintained near the electrode allows for the continued coupling of R1“ with the oligomer radical cations supported on the electrode surface (Steps 3 and 4). The overall process is referred to as an E(CE)n reaction sequence. An electron transfer step (E) is followed by a chemical reaction (C) and another electron transfer step (E). Polymer formation results from a cascade of ECE reactions. Scheme 1. Mechanism of the Electrochemical Polymerization Reaction H H — H H + H H 2) 2 Q. 9 _2__. /N\ N 0H 0H H H I 3) 5 __'_°'___. / 93 N N ' H \ E" H H _ H H — ¢ 4) 0N .0 ___~ / 9 2H N N ' + "G N "G N N H — H H -- H H H / H Overall Reaction : H (X+2) é~§ ——- l \ N /N\ + (2Xri-2)H+ + (2X+2)e° H 5 The idealized structure of the heteroaromatic conductive polymers consists of a series of a,a'-Iinked monomeric units. This structure has been proposed due to the fact that 2-substituted heteroaromatic monomers only form dimeric products.13 INDO (intermediate neglect of differential overlap) molecular orbital calculations on pyrrole, thiophene, and furan show that the at positions do contain the highest unpaired electron density.“ However, as the oligomers grow in size, delocalization of the radical cation through the extended n-system causes the distribution of unpaired electron density to become more diffuse (see Figure 2 for an example with pyrrole oligomers). After a certain point, neither the 01 nor the [3 positions of the oligomer are strongly favored in the coupling process. As a result. a number of a,B'-cross-Iinks can be expected in the polymer. X-ray photoemission studies confirm that the actual polymers possess increased structural disorder relative to the ideal structure. As many as one-third of the rings in polypyrrole contain a structural defect and much of the disorder can be attributed to a,8'-cross-links in the chain.15 These defects from the idealized structure are important, because the undesired cross links are known to diminish the conductive properties of the polymer by creating an increase in the band gap and a decrease in the bandwidth.16 6 Figure 2. INDO Molecular Orbital Calculations of Unpaired Electron Distribution , 0.0012 N H \ 0.0094 -0.0043 / \ 3/ 0.0139 N / H / \ 0.0049 0.0093 0.0078 -0.0043 / \ n / \<—0.0083 fl \ / ”\00017 0.0024 The neutral polymer is non-conductive. Electrons cannot move through the polymer chain due to a lack of charge carriers. In the heteroaromatic polymers, charge carriers are created by two electron oxidations to form a series of bipolarons (dications)2-17. Oxidation results in a structural transformation of the polymer from an 'aromatic' conformation (A) to a 'quinoid' conformation (8) (Scheme 2). The oxidized 'quinoid' structure has a lower ionization potential and higher electron affinity than the 'aromatic' structure. As a result, the HOMO and LUMO bands of the bipolaron lie within the bandgap region of the 'aromatic' structure. The energy level diagram in Figure 3 allows for the spinless bipolarons to act as the charge carriers upon application of an electric field.17 7 Scheme 2. Charge Carrier Formation neutral: - e' + e polaron: - e' + e' bipolaron: Flgure 3. Energy Level Diagram of the 'Aromatic' Phase and the'Quinoid' Phase of Heteroaromatc Polymers .cTIfin' ,In.'l'."..o'n \' __ Oulnoid Phase Phase 8 The requirement of a 'quinoid' conformation for conduction provides a structural reason for the previously discussed observation that a,B'-cross-links in the polymer tend to diminish the conductivity values. The disordered structure in the cross-linked material inhibits the capacity of two radical cations to combine and form a bipolaron.2 The addition of substituents to the carbon skeleton has proven to be an effective method for modification of the redox chemistry and conductive properties of the heteroaromatic polymers.18 The influence of a substituent can involve either an electronic or a steric effect. Electron-donating substituents stabilize the radical cation intermediate and thus lead to lower oxidation potentials (Epa) for both the monomer and the polymer. This is a desirable effect, since lower oxidation potentials minimize the possibility of side reactions between the monomer and other species. Electron-withdrawing substituents destabilize the radical cation intermediate. This leads to higher oxidation potentials and poor quality films. The very reactive destabilized intermediates tend to undergo indiscriminate reactions with solvent or anions to form soluble products. In general, small alkyl groups provide the most positive influence on the electrochemistry of the monomers. Table 2 shows that both 3-methylthiophene and N-methylpyrrole have lower oxidation potentials than the parent unsubstituted monomer. 3-Bromo and 3-iodo substituted thiophenes provide films with poor physical and electrical properties, while thiophenes containing the strong electron-withdrawing substituents 3-cyano and 3—nitrothiophene do not form films.‘9a 9 Table 2. Oxidation Potential and Conductivity Data of Substituted Systems 4b.12b.19,21 Monomer Polymer Polymer(S cm'l) Hangman. E2a1ML______EQgl¥L________QQnduQLixiL¥ thiophene 2.06 0.96 104-1 3-methy1thiophene 1.86 0.72 100 3-bromothiophene 2.10 1.06 ** 3-iodothiophene 2.03 **** ** 3-cyanothiophene 2.46 **** ** 3-nitrothiophene 2.69 **** ** pyrrole 1.20 -0.15 102-103 N-methylpyrrole 1.12 0.50 10‘3 3-methylpyrrole **** -O.25 4 Steric factors (Table 2) have little effect on the electrooxidation of the monomer, but they do exert a substantial influence on the properties of the polymer where a planar or near planar conformation is required for efficient electrical conductivity. The positioning of a stabilizing substituent on the 3- position of the monomer should increase the number of a,a'-bonds and thus create a more ordered (more conductive) polymer.20 This hypothesis is confirmed for poly-3-methylthiophene which displays a 102- to 103-fold enhancement in conductivity over polythiophene, when the films are prepared under the same conditions.”b However, the analysis is not so simple. The conductivity values of poly-3-methylpyrrole and poly-N-methylpyrrole are decreased by factors of 102-103 and 105-106, respectively, relative to polypyrroleJZbr21 The dramatic dichotomy of methyl group influence in the thiophene and pyrrole systems is explained by different levels of steric strain in the two polymers. Poly-3-methylthiophene is believed to be able to achieve a coplanar 10 or near coplanar conformation in the oxidized state“, while poly-3- methylpyrrole and poly-N-methylpyrrole are thought to be in a twisted conformation.21 If steric interference results in a deviation from coplanarity of greater than 40%, a significant reduction in conductivity is observed.22 The steric interference argument is supported by experimental results from the electrochemical copolymerization of pyrrole and N-methylpyrrole. The conductivity of the copolymer (approximately 1 S cm-l) is midway between the conductivity values of the two parent polymers.23 This is consistent with the idea of the unsubstituted pyrrole units acting as spacers to decrease the undesired steric interactions of the N-methyl group. It is evident from the above example that both electronic and steric properties of the substituents need to be considered in the design of new conductive polymers. The results obtained for one heteroaromatic system do not necessarily correspond to those obtained for another system. Small and seemingly minor structural modifications can lead to major changes in the physical properties of a material. In addition to control over substituent composition and ring fusion selectivity, manipulation of the heteroarom composition stands as an area of potential importance. The preparation of copolymers containing a mixture of pyrrole, thiophene, and furan monomers has been investigated to only a very limited extent. It is hoped that the unique physical, chemical, and electronic properties of the individual heterocycles can be transferred throughout the polymer via the conjugated n-system. Theoretical calculations indicate that the electronic properties of a copolymer are influenced by the heteroatom composition. As expected, the calculated properties of the heteroaromatic copolymers are intermediate between those of the corresponding homopolymers.24 For example, the polymers of pyrrole, thiophene, and furan 11 each possess unique oxidation potentials. Copolymers containing a range of heterocycle stoichiometries are predicted to provide a continuum of intermediate IEpa values. Of equal importance, the conductivity of the heteroaromatic polymers depends upon their ability to form a 'quinoidal' conformation. The band gap has been calculated to decrease linearly with the amount of 'quinoid' Structure in the doped polymer!“ Since the ability to form the 'quinoid' structure depends upon the 'aromatic' character of each heteroaromatic unit, it may be possible to control ('tune') the size of the band gap by altering the monomer composition. For example, the energy required to form the 'quinoid' conformation from the 'aromatic' conformation is 16.1 KcaI/mole per ring for thiophene, but only 14.4 Kcal/mole per ring for pyrrole.25 Consequently, an increase in pyrrole concentration in the polymer should lead to increased conductivity, while an increase in thiophene concentration should result in decreased conductivity. Experimental investigations need to be conducted to show if such relationships exist and if they are linear with respect to monomer concentration. The synthesis of copolymers has been limited by experimental factors. For example, direct electrochemical copolymerization of pyrrole and thiophene is difficult due to the large difference in their individual oxidation potentials (Em| pyrrole = 1.20V21, Epa thiophene = 2.06Vl9). Films of low quality are formed and no control over either the stoichiometry or sequence distribution of the monomeric units is possible. In contrast, a—terthiophene (Epal 1.05V25) has an oxidation potential similar to that of pyrrole and conductive copolymers (1.0 S cm'l) of pyrrole and a-terthiophene have been produced.27 However,the composition of the copolymer is once again unknown. 12 A few copolymers have been synthesized in which the mixed system is incorporated into a bicyclic or tricyclic monomer. Naitoh reported the synthesis of a polymer consisting of an equal mixture of pyrrole and thiophene units by the electrochemical polymerization of 2-(2-thienyl)pyrrole (Scheme 3).28 Due to the lack of symmetry in the monomer, the sequence distribution of the copolymer is variable. Both alternating and random arrangements of the pyrrole and thiophene units are possible. The Epa of the polymer (Epa 0.50V) lies midway between that of polypyrrole (Em.l -0.15V) and polythiophene (Epa 0.96V). No conductivity measurement was reported. Scheme 3. Naitoh's Copolymer Synthesis 23: mil E... /\ S \/ 2-(2—thienyl)pyrrole II I \ (D \ / The interesting tricycles 1a-d were synthesized by Wynberg29 and used by Ferraris as monomers for the preparation of the mixed polymer system 2a-d (Scheme 4).30 Since monomers 1a-d are symmetrical, the resulting polymers posses a known stoichiometry and sequence distribution of heteroaromatic units. A range of electrical properties are obtained depending upon the nature of the heteroatom X (Table 3). The peak oxidation potentials for both the monomeric and polymeric materials span a range of 0.6 to 1V. Conductivity values vary over four orders of magnitude. The high oxidation potential and low conductivity of 2b is indicative of undesirable steric effects. 13 Scheme 4. Ferraris' Copolymer Synthesis Q—O—Q Er X 18. X=NH J b. X=NCH3 c. X=O x S X 9 28-6 n Table 3. Physical Properties of 1a-d and 2a-d 3° Monomer Polymer Polymer (S cm‘l) Manama—JEN) .8me 1a 0.66 0.59-0.61 280 1b 0.74 0.94-0.98 1 1c 0.94 0.81-0.83 0.3 1d 1.01 0.88-0.91 20 It is difficult to comment on whether the two a,a' linkages incorporated into the monomer increase the order of the polymer. Two reports in the literature present opposite experimental findings as to whether an increase in the number of rings in the monomer increases the degree of conjugation in the resulting polymerfi’rl-‘i2 From a statistical point of view, approximately two-thirds of the linkages are guaranteed to be 01,012 However, as discussed earlier, the oligomeric structures (i.e., tricycles) exhibit a lower preference for a-coupling due to delocalization of the radical cation throughout the rc-system.“ The limited experimental results of Ferraris indicate that variation of the heteroatom composition does result in changes in the electrical properties of the polymer. 14 In this study, an alternate series of symmetrical tricycles 3a-c (Scheme 5) will be synthesized and investigated for their potential as monomers in the electrochemical formation of conductive polymers. The defined stoichiometry (two nitrogen atoms to one variable heteroatom) of tricycle 3 nicely complements that of tricycle 1 (two sulfur atoms to one variable heteroatom). Since pyrrole exhibits a lower oxidation potential than thiophene, a range of polymer Epa's below the values obtained by Ferraris are expected. Compounds 3a-c will provide additional polymers (4a-c) in which the substituent stoichiometry and sequence distribution is known. Well defined polymer samples such as 4a-c are required, if a pattern between polymer structure and electrical response is to be determined. Scheme 5. Proposed Copolymer Synthesis 39. x-NH b. X-S c. X-O 15 B. L n 0 L'ALI ...:-I :L- L - ZCALL L In addition to the synthesis of the linear copolymers discussed in the previous section, tricycles 3a-c are of interest as precursors for the construction of the novel heteroannulenes 5-7 (Figure 4). Macrocycles 5-7 are classified as expanded porphyrin-Iike compounds. Ring expansion is achieved by the incorporation of two heteroaromatic rings of variable composition (i.e., pyrrole, thiophene, or furan) into a tetrapyrrolic ring system. The name [1,4,1,4]platyrin describes the general ring structure of 5-7. The bracketed numbers represent the number of methine carbons separating each of the four pyrrole rings. The middle ring in each tricyclic unit acts as a four- carbon spacer. The word platyrin was coined in this laboratory as a designation for 'wide or broad porphyrin'.33 Flgure 4. Proposed [1 ,4,1,4jPIatyrins 22 u-electron annulene 241: - electron annulene 261p electron annulene 5‘X'NH sax-NH 7ax-NH b X - S b X - S b X - S c X - O c x - o c X - 0 Due to the unusual electronic properties which they exhibit, planar compounds with an extended n-electron network are of current interest in a number of scientific disciplines. For example, the physical and spectral properties of 5-7 are of interest in theoretical chemistry to confirm the current 16 understanding of aromaticity.34 The metal complexes of compounds similar to 5-7 have been used in biological chemistry as synthetic models to mimic oxygen transport and oxidase activity.35 Derivatives of the metalloporphine skeleton have been shown to act as electrical conductors in the field of solid state chemistry.36 Thus, the synthesis of macrocycles 5-7 should provide information of both theoretical and practical importance. The target compounds have the potential to form cyclic, conjugated 1c- electron systems in three distinct oxidation states (2211:- (5), 241r- (6), and 261:- electrons (7)). According to Hiickel (4n+2) theory, compounds 5 and 7 should be aromatic, while compound 6 should be anti-aromatic.37 However, Dewar has used semiempirical molecular orbital calculations (Pople-Pariser-Parr (PPP) approximation) to determine that conjugated cyclic polyenes no longer exhibit aromatic or anti-aromatic properties above 221c-electrons (Figure 5).38 Thus, it is predicted that compound 5 should be aromatic, but compounds 6 and 7 should be non-aromatic. Figure 5. Dewar Calculation of Delocalization Energy l I o 1 0 20 30 number of n-electrons Delocalization energy ( in B ) calculated by the Pople-Pariser-Parr (PPP) approximation 17 A number of annulenes containing 221t-electrons and greater have been prepared to test Dewar's calculations. The presence of a diamagnetic ring current in the 1H-NMR spectrum has been used as a qualitative diagnostic test for aromatic character, while the presence of a paramagnetic ring current has been used to identify anti-aromatic character.34 In the 1960's, Sondheimer prepared a series of large annulenes and dehydroannulenes.39 As predicted, the 14-, 18-, and 221t-electron systems exhibited a diamagnetic ring current and the 16-, 20-, and 241c-electron systems showed a paramagnetic ring current. Conflicting data was acquired for larger rings. Tridehydro[26]annulene and tridehydro[30]annulene displayed localized bonding.40 However, contrary to the calculations of Dewar, monodehydro[26]annulene displayed a diamagnetic ring current.41 The discrepancy in ring current values for the large dehydroannulenes may be due to the increased level of conformational flexibility in these large ring systems. A planar or near planar conjugated ring system is required for bond delocalization. As a result, heteroannulenes have been utilized to build the desired conjugated ring system. By replacing pairs of internal hydrogens in the annulene with heteroatoms, a significant increase in the conformational rigidity of the macrocycle is obtained. Porphine, a tetraaza[18]annulene, is the best known member of this class of compounds. The diamagnetic ring current of the octaethyl substituted derivative 8 (Figure 6), as evidenced by the 1H- NMR resonances, is representative of all members of the porphyrin family.“2 Recent syntheses of expanded porphyrin ring systems are shown in Figure 6. [1 ,3,1,3]Platyrin (9)33, pentaphyrin (10)43, sapphyrin (11)“, and texaphyrin (12)45 are 221t-electron systems which exhibit diamagnetic ring currents. The 26n-electron heteroannulenes hexaphyrin (13)“, [26]porphyrin (14)", and [1,5,1 ,5]platyrin (15)“, also display diamagnetic ring currents. The 18 actual data obtained for 13-15 shows that Zen-electron systems are aromatic and disputes the theoretical calculations of Dewar. Figure 6. Representative Large Aromatic Heteroannulenes ‘- -5.6 H, 11.0 Texaphyrin (1 2) Hexaphyrin (1 3) confinued ......... 19 Flgure 6, continued ....... ‘8 13.67 8 4"“ INIPOIPIIW" (1 4) Il-5-1-5IP'M0 (1 5) The similarity in structure of compounds 5-7 to compounds 9-15 indicates that 5-7 are excellent candidates for the testing of bond delocalization. Their synthesis and characterization will add to the limited set of data available on the aromatic properties of large ring macrocycles. In addition to their theoretical importance, macrocycles 5-7 are of potential biological interest. They are structurally similar to the hybrid porphyrin-like bimetallic ring system 16 which has been synthesized by Mertes to mimic biological oxygen transport and oxidase activity (Figure 7).35 Flgure 7. Mertes' Hybrid Porphyrin-Like Bimetallic Ring 20 Since both bimetallic systems (such as cuproproteins49) and metalloporphyrins5° play an important role in the activation of molecular oxygen, Mertes hoped to develop a hybrid biomimetic model. The two keys to the design of compound 16 are that the internal cavity is large enough to hold two metal cations and that a planar ring structure is possible. Mertes did succeed in isolating bimetallic Pb(ll), Zn(ll) and Cu(ll) complexes of 16. However, the ring system was not planar. The ligand folds so that the two dipyrrylmethene units are nearly parallel. Even so, the biomimetic capabilities of the dicopper complex were encouraging as the complex was shown to activate molecular oxygen in the oxidation of 3,5-di-tert-butylcatechol. Compounds 5-7 should possess an internal cavity large enough to complex two small cations. Of greater importance, the rigidity of the conjugated system in the macrocycles should guarantee a planar conformation and consequently a structure which bears a greater similarity to the natural porphyrin systems than Mertes' non-conjugated ligand. By placing the bimetallic system in a rigid , planar conformation, a less hindered approach to substrate molecules is available. A second potential biological use of compounds 5-7 is as photo- therapeutic agents. For many years, hematoporphyrin derivatives have been used to selectively destroy tumor cells which lie close to the body surface.51 Hematoporphyrins localize in tumor cells. Activation of the hematoporphyrin with light results in the production of singlet oxygen which rapidly oxidizes and destroys adjacent tumor cells. A drawback to this procedure is that the absorption maximum of hematoporphyrin is close to that of hemoglobin. Consequently, irradiation results in the undesired destruction of hemoglobin.52 The expanded porphyrin ring systems such as 5-7, however, will absorb light at longer wavelengths than hematoporphyrin. By utilizing these larger ring 21 systems, the possibility exists for the production of singlet oxygen, without the undesired photo-decomposition of hemoglobin. A recent report has indicated that hematoporphyrin phototherapy is also successful in the eradication of the herpes simplex vims (HSV-1) and the human immune-deficiency virus (HIV) in blood samples.53 Once again, the more highly conjugated ring systems may be able to provide the same results with fewer negative side reactions. The final potential use of macrocycles 5-7 is as organic conductors. Hoffman and lbers have reported that crystals of nickel porphyrin (17) and nickel phthalocyanine complexes (18) are intrinsic insulators (10'10 S cm'l), but upon doping with iodine, the conductivity values increase to approximately 102 S cm'1 (Figure 8).36 The ability of these metalloporphyrin macrocycles to express such high conductivity has been attributed to two basic factors. First, the individual molecules are well organized in the solid state so that strong intermolecular interactions can be attained. Second, the ring systems can adopt a non-integral or partial oxidation state. Since compounds 5-7 are simply ring-expanded analogs of 17 and 18, their mono or bimetallic complexes should also exhibit high conductivity upon doping. Like 17 and 18, the individual heterocycle rings lock macrocycles 5-7 into planar conformations for efficient molecular stacking and the delocalized n-electron systems allow for a number of possible oxidation states. 22 Flgure 8. Organic Conductive Macrocycles 0H, CH, CH, 17 Molecular mechanics calculations of the 22n- and 261t-electron structures 5a-c and 7a-c were performed in order to calculate both the strain in the macrocyclic rings and the size of the internal cavity.54 Both the hexaazaplatyrins (5a,7a) and the tetraazadioxoplatyrins (5c,7c) provide the desired planar conformations as the energy minimized structures. All of the dihedral angles are found to be 0°. Figures 10-13 show that reasonable internal bond angles for the methylene bridges exist. The calculated angles range from 124° to 126°. These values are close to the 127° bond angle which has been observed in the stable porphyrin ring system (Figure 9).55 The average internal cavity size of structures 5a,7a and 5c,7c is approximately 1.8 times greater than that of porphyrin. The outer nitrogens in the expanded ring systems define a rectangle of dimensions 3.0 A x 5.3 A, while the four nitrogens of the porphyrin ring define a square with an NN distance of 2.9 A55 The cavities are large enough so that two small metal cations (i.e., Ni(ll), Mg(ll), Cu(ll), Zn(ll), etc.)56 may be incorporated to form planar bimetallic complexes. In addition, small metal-metal bonded systems such as dirhodium and diruthenium complexes may be able to be synthesized.57 A comparison of the space-filling representations of the 23 porphyrin ring system (Figure 16) and of the hexaaza- and tetraazadioxoplatyrins (Figures 17-20) provides a dramatic view of the differences in cavity size. In the 26-1: electron tetraazadithioplatyrin (7b), however, steric strain is evident and the energy minimized structure is twisted from a planar conformation. The calculated dihedral angle about the methylene bridges for 7b is 7° (Figure 15). Compound 5b, the 22n-electron analog, is much less strained and is actually calculated to prefer a near planar conformation (Figure 14). Space filling models of 5b and 7b (Figures 21 and 22) reveal that the strain in 7b is the result of a steric interaction between the large sulfur atoms and the protons on nitrogen. Oxidation of 7b to 5b removes the two protons and a planar structure can be formed. The internal cavity of the tetraazadithioplatyrins (5b,7b) is greatly reduced relative to the hexaaza(5a,7a) and tetraazadioxo(5c,7c) structures. The calculated interatomic distance between the two sulfur atoms (approx. 3.8 A) is about 1.2 A shorter than when a pair of nitrogen or oxygen atoms are placed in the same positions (approx. 5.0 A). Since the calculations show that even protons inside the cavity of the tetraazadithioplatyrin ring cause steric interference, it is anticipated that metal complexes of the ring will not form planar structures. Any metals that do coordinate should lie out of the plane of the ring. 24 Figure 9. Averaged Crystallographic Parameters of Octaethylporphyrin 25 Flgure 11. Calculated Lowest Energy Conformation of 7a 26 Flgure 13. Calculated Lowest Energy Conformation of 7c 27 Figure 15. Calculated Lowest Energy Conformation of 7b 28 Flgure 17. Space-Filling Representation of 5a Figure 19. Space-Filling Representation of 5c Figure 20. Space-Filling Representation of 7c 30 Flgure 21. Space-Filling Representation of 5b RESULTS AND DISCUSSION RESULTS AND DISCUSSION A. L'- . 1" :- 33. AL'HL .I=I.E.AE.UA IBlDlQLES The heteroaromatic tricycle 3 is the key intermediate in the formation of both the heteroaromatic polymers 4a-c and the expanded porphyrin annulenes 5-7. To date, no syntheses of 2,5-bis(2-pyrryl)thiophene (3b) or 2,5-bis(2-pyrryl)furan (30) have been reported in the literature.58 2,2':5',2"- terpyrrole (3a) is known.59°61 However, the literature procedures of the preparation of 3a suffer from low overall yields and/or the use of expensive reagents. H H Bax-NH bX-S cX-O H x :1 n x x N N 3 E e H lax-NH n bX-S cX-O arr-electron annulene 241t- electron annulene 261p electron annulene Sax-NH Sax-NH “lax-NH bx-s bX-S bX-S cX-O cX-O cX-O 31 In 32 The simplest route to 39 is shown in Scheme 6. Potts and Smith reported that pyrrole undergoes extremely rapid trimerization to form 2,5-bis(2- pyrryl)pyrrolidine (19) in moderate yield.59 The difference of a few seconds in quenching the reaction can lead to a significantly lowered yield. Catalytic dehydrogenation of 19 produces 3a in very low yield.60 The combination of difficult reproducibility in step one and low yield in step two makes this reaction sequence inadequate for large-scale preparations. SCHEME 6. Potts' and Smith's Synthesis of 2,2':5',2"-Terpyrrole (3a) i E 20% aq. HCI, 0°c \ / \ Pd IC (10 mole%) N 30 sec., 40% 7 N reflux, p-cymene, 14% H H 12 12 19 /\l /\ 1:2 12 12 3a Chieici and Cella have developed an alternate two-step route to 38 (Scheme 7) which utilizes the reaction of the pyrrole Gn’gnard reagent with diethylsuccinate to provide the corresponding 1,4-diket0ne (20) in low yield (22%). Closure of the 1,4-diketone to a pyrrole under Paal-Knorr rection conditions was reported. However, no yield of 3a was indicated!51 SI Ill DE 311 SL‘ V8 SI: 33 SCHEME 7. Chieici's and Cella's Synthesis of 3a 0 / \ + 0., 22% g / \ / \ C? .OJK/Y . . O MgBr 2 0 12 12 The final and most reliable literature route to 3a was reported by Rapoport (Scheme 8).50 The synthesis relies on an initial Vilsmeier-Haack condensation of methyl pyroglutamate with pyrrole, followed by dehydrogenation to form bipyrrole 21. A second condensation- dehydrogenation sequence provides terpyrrole 22. Saponification followed by decarboxylation yields the desired product 3a. Two distinct disadvantages of this reaction sequence exist for the synthesis of 3a on a preparative scale. First, the strategy of forming one ring of the tricycle at a time results in a lengthy synthesis with low overall yield (7 steps, 2.4% overall yield). The low yield of the final dehydrogenation (15.4%), which occurs late in the synthesis, is particuarly damaging. Second, the two dehydrogenation steps require stoichiometric, rather than catalytic, amounts of palladium. This results in a substantial increase in the cost of the synthesis. Due to the electron-rich nature of the unsubstituted pyrrole rings, 3a is a very labile molecule. Rapoport has reported that solutions of 3a in methanol slowly turn green upon exposure to air and light. A black precipitate is formed 34 after 24 hours. However, the crystalline material is stable at low temperatures in the absence of air and light. SCHEME 8. Rapoport's Synthesis of 3a \ POC|3 \ + \ N O N COZCH3 51% N N 9020“: H H H Pd/C (100 mole%) CH H. HCI J 3%., 200°C, 71% [pyroglutamic acid] ° II / \ / \ 90013. 04370026”: H / \ / \ 01-13020 N N \N 002013 t N N cozcu, H H 76%: H H 21 Pd/C(100mole%) 200°c,1s.4°/. 1 N CH, CH OH, 82.5% /\/\/\ ’a 3 -/\/\/\ CH3°20 N N N CO2CH3 2) sublimation, 73% N N N H H H H H H 22 33 LAMWWMM The lack 01a satisfactory preparation of 3a and no reported syntheses of the tricycles 3b and 3c resulted in an effort to design new and efficient , synthetic routes to these compounds. The initial strategy for the synthesis of 3a was inspired by a 1986 report of Portoghese which described a mild, one- pot synthesis of symmetrical pyrroles via the reaction of an a-free ketone and an N-aminoimide (23) (or the ring-opened hydrazine-ester (24)).‘52 The report 35 was limited to the synthesis of four dimeric morphinans containing a connecting pyrrole ring (Scheme 9). SCHEME 9. Portoghese's Pyrrole Synthesis NR1 R2 0 . . . ,3" N - amInOImIde , DMF O : 90 ° C , 0.5 h OH“ R1 R2 R3 Yield (%) a) allyl OH H 60 b) CH3 OH H 60 c) CH3 H H 48 d) CH3 H H 52 This procedure is very attractive, because it stands as a mild, high yield alternative to the traditional Piloty-Robinson synthesis of symmetrical pyrroles from ketones. Under Piloty-Robinson conditions, the acid-catalyzed rearrangement of a keto-azine provides the pyrrole adduct.63 The reaction is thought to occur by a Cope rearrangement of the bisenamine form of the azine (Scheme 10). The general utility of the reaction is limited by the high temperatures required to induce cyclization. Somewhat milder conditions are possible when an acid chloride is used to activate the azine (Scheme 11).64 36 SCHEME 10. Piloty-Robinson Pyrrole Synthesis R R HCl or ZnClz A R \ / R = R N R N—N H A (approx.180°C) l R t R R RH C: R RH Men—L— 1% =1? 3an R R N—N HH SCHEME 11. Acid Chloride Induced Piloty-Robinson Pyrrole Synthesis 0* ii OH,C(omI. dioxane, reflux ./ \. N’ \ t .I N \O A 82% o \N’“ PhC(O)Cl, xylene, reflux; A NHzNHz- l30propanolA A -- Y ] reflux H 0 Ph 30% Although it yields identical products and uses similar reagents to the Piloty-Robinson reaction, Portoghese reported that the reaction in Scheme 9 does not proceed via an azine intermediate. Instead a mechanism was proposed (Scheme 12) in which the key carbon-carbon bond is formed between two diacylhydrazone intermediates (25 to 26). The driving force for bond formation is suggested to be the capacity of the imide to act as a leaving group. The mechanism is surprising, since it is unusual for the same functional 37 group to act as both an electron donor and an electron acceptor in an intermolecular substitution reaction. SCHEME 12. Portoghese's Proposed Mechanism / \ = 0 NH @% (.76) \ N/NK 2 6 H0 H9 2 steps 3 " HR R R R HR R R N\ R / \ m : HzNg H R u R i R (“(9 R ( O '!‘ 0 H3 H NH? v oxiro Regardless of the mechanism, it appeared that this procedure could be extended to the synthesis of 3a by the submission of 2-acetylpyrrole (27) to the reaction conditions. Unfortunately, reaction of 27 with succinylhydrazine methyl ester hydrochloride (28) resulted in a 65% recovery of 27 and a 10% yield of the corresponding azine 29 as a mixture of geometrical isomers (Scheme 13). Reaction of 2-acetylthiophene (30) with 28 also resulted in a high yield of the corresponding azine 31 as a mixture of geometrical isomers (Scheme 13). 38 SCHEME 13. The Portoghese Procedure with 2—Acetylpyrrole (27) and 2-Acetylthiophene (30): Formation of Azines 28.DMF,90°C,5h " / \ IN = “WNW + 27 u " (65%) 29 . ( 10%) mlxture of dlastereomers 3 \N’fi\ I \ 28 . OH,CH (anhydrous) : Mu’fiw + l . 3 reflux , 4 days \ l / S 0 31e(52%) 31b(41%) 3° (E,E)-azine (Z,E)-azlne Similar yields of 31 were obtained using various combinations of solvent (i.e., methanol, ethanol, dimethylformamide, acetonitrile) and nitrogen reagent (i.e., succinylhydrazine methyl ester hydrochloride, succinylhydrazine ethyl ester hydrochloride, succinylhydrazine carboxylic acid hydrochloride, N- aminophthalimide hydrochloride). Thus, it appears that contrary to the statements of Portoghese, the N- aminoimide (or hydrazine-ester) reagent acts as a source of hydrazine to form the intermediate of the Piloty-Robinson reaction. As a result, a number of tactics were tried to induce formation of the required bisenamine cyclization precursor. 2-Acetylthiophene (30) was used as the model for the heteroaromatic ketones. due to the higher yields of azine intermediate obtained. Attempts to drive the reaction to pyrrole formation by the addition of acid catalysts (i.e., acetic acid, amberlyst-15 ion exchange resin, triethylamine hydrochloride, and trifluoroacetic acid) resulted in azine products (31).64b 39 The reaction of 31a with a number of Lewis acid catalysts (i.e., zinc chloride, ethylaluminum dichloride, dimethylaluminum chloride, titanium tetrachloride) resulted solely in isomerization of 31a to a mixture of 31a and 31b. The acylhydrazine 32 is analogous to the key intermediate 25 in the Portoghese mechanism. However, reaction of 32 in DMF at 90°C provided a 73% recovery of 32 (Scheme 14). SCHEME 14. Reaction of Acylhydrazine 32 under Portoghese's Reaction Conditions I \ DMF , 90°C 5 | 0 = 73% recovery of 3 2 -.N "Ml/OCHZCHS 4 days 32 H o Rearrangement of 31a was attempted under anionic conditions. Yoshida reported that the reaction of propiophenone azine (33) with 2.2 equivalents of lithium diisopropylamide (LDA) in tetrahydrofuran (THF) gave 3,4-dimethyl-2,5-diphenylpyrrole (34) in 52% yield (Scheme 15).65 Submission of 31a to the same conditions (and at -20°C) resulted in polymer formation. When the reaction was quenched after one hour (-20°C to room temperature) with 020, the 1H-NMR spectrum showed a 2:3 ratio of methyl to thiophene protons. Thus, initial dianion formation did occur. 40 SCHEME 15. Yoshida‘s Anionic Synthesis of Pyrrole 0*? TQ—fi LDA, THF polymer room temp. Attempted activation of 31a with acetyl chloride led solely to the isomerization of 31a (Scheme 16). However, the previously reported formation of N-acetyl-1,2,3,4,5,6,7,8-octahydrocarbazole (Scheme 16) under the same reaction conditions was repeated and confirmed (80%, lit. 82%, Scheme 11).643 These results indicate that rearrangement of the azine is substrate dependent. SCHEME 16. Acid Chloride Activation of Azine Rearrangements CH3C(O)CI, dioxane, reflux, 50h 31a = 31a (49%) + 31b(45%) N- CH30(O)CI, dioxane, reflux, 0.5h W N’\ ‘. r N 80% O 41 The inconsistent nature of pyrrole formation via the rearrangement of azines is well documented. For example, the rearrangement of cyclohexanone azine occurs in 79% yield using standard Piloty-Robinson cyclization conditions (ZnClz (cat.), neat, 220-2300C). However, the same reaction fails for the azines of acetone, butyraldehyde, isovaleraldehyde, cyclopentanone, butanone, and acetophenone.648 In a final test, Poroghese's reaction conditions were examined with cyclohexanone. Cyclohexanone is a more representative model of the morphinan ketones used in the original report. Indeed, reaction of cyclohexanone with 28 produced the desired 1,2,3,4,5,6,7,8-octa- hydrocarbazole in 20% yield (Scheme 17). The results of this study seem to provide additional confirmation to the literature reports that the synthesis of pyrroles from keto-azines lacks generality. SCHEME 17. The Reaction of Cyclohexanone under Portoghese's Conditions 0 DMF,90°C,2h . . . + 28 = M * N H 1,2,3,4,5.6,7,8 - octahydrocarbazole ( 20%) A second route to the heteroaromatic tricycles 3a-c was attempted using a 1,4-diketone as the key intermediate (Scheme 18). This is an attractive pathway, since all three tricycles can be synthesized from a common precursor. 42 Acid-catalyzed condensation of ammonia (NH4+) with 1,4-bis(2-pyrryl)-1,4- butanedione (35) should provide 3a (Paal-Knorr reaction).66 Phosphorus pentasulfide (P285) or Lawesson's reagent are known to react with 1,4- diketones to provide thiophenes (3b).29.67 Acid-catalyzed dehydration of 1,4- diketones is, likewise, a standard technique for the preparation of furans (3c).68 SCHEME 18. Formation of 3a-c from 1,4-Bis(2-pyrryl)-1,4-butanedione (35) [I \S Stetter Reaction = / \ / \ N cHo N N H H 00 H 35 N|"l4+ P2 85 H* ( 'H20 ) v /\/\/\ /\/\/\ /\/\l\ N N N N o N H H H H 3a 3b 3c The preparation of symmetrical 1,4-diketones via the thiazolium salt- catalyzed addition of heteroaromatic aldehydes to divinyl sulfone has been reported by Stetter for a number of aromatic aldehydes (Scheme 19).69 In this laboratory, Luo and Leung have extensively investigated the Stetter reaction for 2-thienyl and 2-furyl aldehydes, respectively.70 However, there has been no report of 2-formylpyrrole (36) as a reactant in the Stetter reaction and, indeed, submission of 36 to the reaction conditions resulted only in the recovery to starting material. The failure of the pyrrole 43 aldehyde to react is not unexpected, if the mechanism of the Stetter reaction is considered (Scheme 20).69 SCHEME 19. The Stetter Reaction thiazolium salt (cat.), NaOAc Ar-CHO > Ar Ar divinyl sulfone, EtOH, reflux O O W R (+3 phenyl 46 thiazolium salt = “L X G 4wtoluy| 35 I > 2-thienyl 48 HO S 2le 75 catalyst 1 : R = PhCl-lz, X = Cl Z’PYW' "Ot reported catalyst2: R = CH3 . X=| SCHEME 20. Mechanism of the Stetter Reaction R R R ad (9') 09 6)") 0H Ar—CHO + /\>£\)e 3_'—’ JHH JHG 37 Ho 3 HO 5 Ar Ho 3 Ar 3 8 3 9 0 divinyl sulfone Ar’lk/‘SOA 1 base 0 ”JV + BH (‘9 9 ozs/\ + 37 + divinylsulfone + 3 8 " base 44 The non-reactivity can be attributed to the destabilization of the acyl anion 39 by the electron-rich u-system of the pyrrole ring. The inability of 2- formylpyrrole to undergo the acyloin condensation or form the cyanohydrin product on reaction with hydrogen cyanide provides evidence to support this reasoning (Scheme 21).71 SCHEME 21. Acyloin and Cyanohydrin Reactions of 2-Formylpyrrole (36) (M9) U X—> ’ ‘”° Ll CH0 No Reaction 3 \ I (Me)36 (Me) 0 HCN 0“ x_. man No Reaction N H H The reactions in Scheme 21 fail even when the acidic pyrrole (N-H) hydrogen is replaced with a methyl group. The attachment of an electron withdrawing group(s) (EWG) on the pyrrole ring has been shown to stabilize the acyl anion to the point where productive nucleophilic reactions can occur. For example, 3-ethoxycarbonyl-2-formyl-1-methylpyrrole (40) is converted to the tetracyclic compound 42 via the acyloin 41 (Scheme 22).72 Jones has recently shown that EWG-substituted 2-formyl pyrroles react with methyl vinyl ketone in thiazolium salt-catalyzed Michael reactions (Scheme 23).73 45 SCHEME 22. EWG-Substituent Activation of the Acyloin Condensation 41,, 03:40 E - ethyl ester 42(16%) 0 SCHEME 23. Jones' Thiazolium Salt-Catalyzed Michael Reaction a thiazolium salt (cat.), / \ EtOH, EtsN. reflux M N CHO + N = N O 6479 O O Sth $02Ph E E thiazolium salt (cat.), I \ + / EtOH, EtaN, reflux / \ E N CHO /\n/ : E N o o H 0 80%: H E - Ethyl ester In this study, initial investigations of the Stetter reaction for symmetrical 1,4-diketone formation involved the reaction of a number of N-EWG substituted 2-formylpyrroles. Submission of N-acyl substituted compounds (i.e., N-benzoyl (43), N-t-butoxycarbonyl (N-BOC, 44), and N-carbobenzyloxy (N-CBZ, 45) to 46 the Stetter conditions resulted in the formation of a mixture of undesired products. The major products included recovered starting material, deprotection of the pyrrole nitrogen, and/or Cannizzaro reaction products (Scheme 24). SCHEME 24. The Stetter Reaction with N-EWG Substituted 2- Formylpyrroles [3V [3‘00 0025‘ d’ ' I n 74°/ ‘5 HOLUCHOT 134-G + Ithysuone( o) 4 4°)?" " 35% CW”?! 5% 44% b [Acne + benzoic anhydride (47%) 6mm: 43% [aim ' aucHo + <—-)\4:H(013t)2 3°C 25% 3°C 8% foe 4 \4 U N CH0 method a : EtOH, thiazolium salt, NaOAc, divinyl sulfone éoc 58% method b : DMF, thiazolium salt, Et3N, divinyl sulfone method 0 : dioxane, thiazolium salt, Et3N, divinyl sulfone QCHOZ _. intractable material (:82 \ The lability of N-acyl substituents under mild solvolytic conditions was evidenced by the high degree of deprotection which occurred when ethanol was used as the solvent. The lability of the N-CBZ group was confirmed when an NMR sample of 45 decomposed within minutes in methanol-d4. N-alkyl-like activating groups (i.e., benzyl, pyridylethyl74) led solely to the recovery of starting material. Two C-EWG substituted 2-formylpyrroles (i.e., 3- 47 iodo75 and 5-cyanovinyl76) produced none of the desired 1,4-diketone product. In both cases, polymeric material was formed. In contrast, 1-benzenesulfonyI-2-formylpyrrole77 (463) formed the 1,4- diketone 47a in 70% yield (Scheme 25). Compound 47a precipitated out of the boiling ethanol solution as a fine tan powder. 1H-NMR spectroscopy revealed that the precipitate was greater than 95% pure. Due to its insolubility in common organic solvents, 478 was used without further purification. The high yield of product parallels the electron-withdrawing strength of the benzenesulfonyl substituent. The sulfonyl group is one of the strongest electron-withdrawing groups known.78 SCHEME 25. Synthesis of 1,4-Bis(1-benzenesulfonyl-2-pyrryl)-1,4-butane- dione (47a) (1 thiazolium salt ( cat. ), NaOAc / \ / \ N CH0 divinyl sulfone, EtOH, reflux I? o o if sozph Sth Sth 458 4 7 a ( 70% ) Condensation of 47a to a pyrrole using standard Paal-Knorr reaction conditions proved to be more difficult than anticipated (Scheme 26). Treatment of 47a with ammonium acetate (NH4OAc) in refluxing acetic acid with acetic anhydride (A020) acting as a water scavenger resulted in a 90% recovery of the starting material 473.29 Replacement of acetic acid (bp 118°C) with the higher boiling solvent propionic acid (bp 140°C) provided 48a in low yield (17%, 73% of 47a recovered). Reaction of 47a with ammonium carbonate in refluxing DMF, according to the procedure of Wasserman, yielded 80% of starting 1,4-diketone (47a).79 48 The Leuckart reaction”, compound 47a in refluxing formamide (bp 210°C), resulted in decomposition products. The use of the primary amine benzylamine as the nitrogen source also led to the recovery of starting material (46%). The low solubility of 47a in the reaction solvents was seen as a probable cause for the poor reactivity. For example, 47a exhibited only partial solubility even in hot propionic acid. As a result, the use of a cosolvent was investigated. Surprisingly, 47a was insoluble in sulfolane, but it was completely soluble in dimethyl sulfoxide (DMSO). However, the use of a propionic acid/DMSO (2:1) solvent system yielded none of the desired product (Scheme 26). SCHEME 26. Initial attempts at the Paal-Knorr Reaction / \ NH40Ac, HOAc, Ac20 W t 96% recovery of 47a go 0 O é reflux, 24h 2Ph "a 02Ph NH40AC, 02H§002H, A020; / \ / \ / 478 reflux, 40h N N N (73% ) Sth H $0,”. 488 ( 17%») ammonium carbonate, DMF = 77% recovery of 47a 100° 0, 18h formamide, reflux, 2h , _ : decomposition Leuckart Rxn. PhCH2 NHZ, toluene — 46% recovery of 47a HOAc ( cat. ), reflux, 16h HOAc/ DMSO (2:1 ), 140° C = no product NH40AC , A020, 15h 49 Ultrasonic irradiation has been reported to induce rate enhancements in a number of heterogeneous (non-organometallic) reactions.81 Consequently, ultrasound treatment of 47a in propionic acid was attempted as a method to create a more reactive medium. Irradiation of a mixture of 47a, NH4OAc, A020, and propionic acid produced a fine dispersion, which upon subsequent heating, formed the desired terpyrrole 48a in 46% yield. The use of hexamethyldisilazane (HMDS) in place of NH4OAc as the nitrogen source resulted in a comparable 44% yield of 483 (Scheme 27).82 In this case, the ultrasound treatment provided a significant increase in product yield. SCHEME 27. Ultrasound Activation of the Paal-Knorr Reaction / \ / \ ° °' b t / \ / \ / \ N N '3' ° 0 l '3' H l SOzPh SOzPh SOzPh SOzPh 47a 48a method a : 1. NH4OAc,Ac20,CzH5002H, ultrasound 2. reflux, 10h (46% yield) method b : 1. A020,C2HSCOZH, ultrasound 2. HMDS,CF3002H (cat.), reflux, 11h (44% yield) Base hydrolysis of 48a (NaOH/methanol) provided 33 in 75% yield after purification.83 The presence of an alkaline medium in the deprotection step is highly desirable due to the acid-sensitive nature of the unsubstituted terpyrrole ring system. The complete synthetic route (four steps, 23% overall yield) is summarized in Scheme 28 and compares very favorably with Rapoport's previously reported synthesis (seven steps, 2.4% overall yield). The melting point, 1H-NMR spectra, and ultraviolet spectra of 33 match the literature 50 values.‘50 In addition the 13C-NMR and high resolution mass spectra (HRMS) are consistent with the assigned sthcture. Although the use of the N-phenylsulfonyl group to temporarily activate 2- formylpyrrole provided a facile route to 3a, the high molecular weight of the protecting group posed a practical Inconvenience. While the conversion of 48a to 3a occurs in 75% yield on the molar scale, the mass yield for the reaction is only 31%. Thus, the use of the methanesulfonyl group as a lower molecular weight activating substitutent was investigated. Scheme 28 shows that comparable yields were obtained for each step when the methanesulfonyl group replaced the benzenesulfonyl group. The conversion of 48b to 3a occurs in 72% on the molar scale which results in a 40% mass yield. SCHEME 28. Summary of the 2,2':5',2"-Terpyrrole (38) Synthesis [1 _a_../\ /\ b. /\/\/\ N CHO N \00/ N N N I|3wc flaws N l l H l EWG ewe ewe 46a. EWG-Ph802 47a. 70% :3: 23:: 46b. EWG-CHaso2 47b. 74% ' l. /\ /\ /\ N N N H H H 30 75% from 480 72% from 48!: a. thlazollum salt (cat.), NaOAc, dlvlnyl sulfone. EtOH, reflux b. NH4OAc, A020, CszcOZH, ultrasound followed by reflux c. NaOH-Cl-IaoH, reflux 51 The only deviation occurred in the synthesis of 46b. While 46a was formed in high yield (96%) by the addition of benzenesulfonyl chloride to 2- formylpyrrole according to the phase transfer conditions of Jones", the same conditions provided only a modest amount of 46b (42%). An optimized yield of 46b (61%) was obtained by the slow addition of methanesulfonyl chloride to the preformed pyrrole anion (NaH, ether) (Scheme 29). The difficulty in formation of 46b relative to 46a may be due to the presence of acidic protons on the methyl group of methanesulfonyl chloride. For example, the production of sulfene (CH2=802) by mono-deprotonation of either methanesulfonyl chloride or 46b may result in competitive dimerization and oligomerization reactions.84 SCHEME 29. Preparation of 1-MethanesuIfonyl-2-formylpyrrole (46b) / \ PhSO Cl, CH 012.30% NaOH(aq.),(Bu) NBr QCHO 2 2 ‘ > [k N N CHO H 36 | Sth 468 ( 96% ) CHasOZCI. CHZCIZ, 30% NaOH ( 8C).), ( BU )4NOH [x > N CHO $02CH3 46b ( 42% ) 1. NaH, ether [x : CHO 2. CH3800l, ether N SOZCHa 46b (61%) 52 As mentioned previously, the additional advantage of the 1,4-diketone intermediate is that it allows for the synthesis of the novel mixed heteroaromatic tricycles 3b and 3c. Closure of the 1,4-diketone 47 to a thiophene 49 was accomplished in 65% yield with Lawesson's reagent (Scheme 30)."’9-67a35 Both of the sulfonyl protected diketones 47a and 47b gave the same yield. Ultrasound irradiation was not required as ring formation proceeded smoothly in refluxing toluene. Base hydrolysis of the sulfonyl groups provided 2,5—bis(2- pyrryl)thiophene (3b) in high yield (93% from 498 and 86% from 49b). SCHEME 30. Synthesis of 2,5-Bis(2-pyrryl)thiophene (3b) [1 a. /\ /\ b. /\ /\ /\ N 0H0 N \00/ N N s N I'swe éwe Ilswe Ilswe l EWG 46a. EWG-PhSOz 47a. 70% 2:: 22°: 46b. ewe-CHaso2 47b. 74% ' l. / \ / \ / \ N s N H H 3b 93% from 498 a. thiazolium salt (cat.), NaOAc, divinyl sulfone, EtOH, reflux 86% from 49b b. Lawesson's reagent, toluene, reflux c. NaOHCHsoH, reflux A room temperature conversion of 47a to 49a was effected by the ultrasound treatment of 47a with an excess of P285 (5.5 equivalent) in tetrahydrofuran!“5 The 58% yield of 49a was only slightly less than that obtained with Lawesson's reagent at 110°C. However, the presence of excess 53 sulfur reagent made sample purification much more difficult. No reaction occurred when 478 was treated with Lawesson's reagent under the room temperature ultrasound conditions. A low-yield (11%) of 2,5-bis(1-benzenesulfonyI-2-pyrryl)furan 50 was obtained when a mixture of 47a, acetic anhydride, and propionic acid was irradiated with ultrasound, followed by reflux (Scheme 31). Due to the low yield of 50, solvolytic deprotection to produce 2,5-bis(2-pyrryl)furan (30) was not attempted. SCHEME 31. Synthesis of 2,5-Bis(1-benzenesuIfonyl-2-pyrryl)furan (50) 1. Aczo , propionic acid , /\ /\ ”'"mum'ah =/\/\/\ N o o N 2. reflux , 48h 8" o T 502% 5021311 sozPh SOzPh 478 50 (11%) A number of additional syntheses were undertaken to produce substituted analogs of 3a,b,c. 2,5-Bis(2-pyrryl)thiophene (3b) was monoformylated at the expected a- position using Clezy's modification of the Vilsmeier reagent (Scheme 32).87 Room temperature reactions with up to an 8.5 molar excess of reactive intermediate 51 resulted solely in monoformylation. G) H c OclolPh 3 >N=C< Cl 9 H30 H 51 54 SCHEME 32. Synthesis of 2-(5-Formyl-2-pyrryI)-5-(2-pyrryl)thiophene (52) W 1.DMF,PhC(0)C|(Z3OQ-) t / \ / \ / \ N s N 2. News-3°“ N s N CH0 H H H H 3b 52(72%) \. DMF, PhC(O)Cl(8.5 sq.) _ 52 (73%) 2. M200, . EtOH Reaction of 3b with an excess of Vilsmeier reagent (8.5 equivalents) at elevated temperature (80°C, 6h) provided the symmetrical bis-formylated product 53 (47%, Scheme 33). Recrystallization from acetonitrile produced dark green needles which exhibited low solubility in common organic solvents. This property is in accord with the physical characteristics of other linear, heteroaromatic dialdehydes.7° SCHEME 33. Synthesis of 2,5-Bis(5-formyl-2-pyrryl)thiophene (53) / \ / \ / \ 1.DMF,PhC(O)CI(8.Seq,),80oC’6h 5 N 2- N21200:, . EtOl-I , reflux N H H 3b /\ /\ /\ OHCN S NCH0 H H 53 (47%) 4,4“-Dimethyl-substituted analogs of 3a-c were synthesized by the use of 2-f0rmyl-3,5-dieth0xycarbonyl-4-methylpyrrole (54) as the activated aldehyde in the general four-step procedure (Scheme 34). Compound 54 was conveniently prepared by the sulfuryl chloride oxidation of readily available 55 SCHEME 34. Synthesis of 4,4'-Dimethylsubstituted Analogs.of 3a-c 5 4 5 5 E . ethyl ester b, 75% c, 76% d. 68% II E E E E E E \ / \ / \ / \ / \ / \ / \ / \ / \ E N N N E E N s N E E N N E H H H H H H H 56 57 58 e,22%| 9,52%l e *( / / \ / \ / \ / \ / \ \ \ / \ N N N N s N N N H H H H H H H 59 60 61 a) thiazolium salt (cat.), Eth, divinyl sulfone, dioxane, 80°C b) NH4OAc, HOAc, Ac20, reflux c) Lawesson's reagent, toluene, reflux d) HOAc,A020, reflux e) 1. NaOH, EtOH,requx; 2. sublimation Knorr's pyrrole (2,4-diethoxycarbonyl-3,5-dimethylpyrrole).38 In this case, the electron density of the pyrrole ring was reduced by the addition of two ethyl ester substituents on the C-3 and C-5 positions of the aldehyde. The capricious nature of the Stetter reaction was evidenced when submission of 54 to the standard reagents (i.e., NaOAc, ethanol, 3-benzyl-5-(2- hydroxyethyl)-4-methyI-1,3-thiazolium chloride) yielded no product. However, 56 alternative reaction conditions (i.e., triethylamine, 1,4-dioxane, 5-(2-hydroxy- ethyl)3,4-dimethyl-thiazolium iodide) provided the 1,4-diketone 55 in good yield (60%). Closure of 55 to the corresponding pyrrole (56, 75%), thiophene (57, 76%), and furan (58, 68%) rings proceeded without incident using the standard conditions. Since 55 was soluble in hot acetic acid, ultrasonic treatment was not required for the preparation of either 56 or 58. The increased solubility of 55 compared to the sulfone-protected diketones 47a,b is also reflected in the higher yields of tricyclic products. Saponification of tetra-ester 56 and subsequent thermal decarboxylation (sublimation) of the resulting tetra-acid provided the 4,4“- dimethyI-substituted terpyrrole 59 in 22% yield. Identical treatment of 57 produced 60 in 52% yieldfi9 The yields are respectable considering that the removal of four ester groups was required and that the hydrolysis of beta carboxylic esters is known to be sluggishfi’o In addition, the two electron- donating methyl substituents in 59 act to increase the lability of the already sensitive terpyrrole structure. The inability to successfully decarboxylate 58 is not surprising, since furan possesses less aromatic stability than either pyrrole or thiophene.91 As a result, 2,5-bis(4-methyl-2-pyrryl)furan (61) is expected to be very susceptible to aerial oxidation and other decomposition reactions. 2-F0rmyl-5-ethoxycarbonyl-3,4-dimethylpyrrole (62) was used as the activated aldehyde in the attempted synthesis of 3,4:3",4"-tetramethyl- substituted analogs of 3a-c (Scheme 35).92 The required 1,4-diketone intermediate 63 was synthesized in low yield (33%) under the standard reaction conditions (i.e., NaOAc, ethanol, 3-benzyI-5-(2-hydroxyethyI)-4- methyl-1,3—thiazolium chloride). The alternate reaction conditions used in the 57 synthesis of 55 were unsuccessful in this situation. The dramatic two-to-one difference in 1,4-diketone yield for aldehydes 54 and 62 reveals the dominating effect of electron-withdrawing group(s) strength on the efficiency of the Stetter reaction. Treatment of 63 with Lawesson's reagent in refluxing toluene provided 2,5-bis(5-ethoxycarbonyl-3,4-dimethyl-2-pyrryl)thiophene 64 in good yield (73%) Submission of 63 to the previous conditions for pyrrole formation (i.e. NH4(OAc) excess, HOAc, A020, reflux) resulted in the unusual formation of 2,5- bis(5-ethoxycarbonyI-3,4-dimethyl-2-pyrryl)furan 65 (39%). The exclusive formation of furan was confirmed by high resolution mass spectrometry (398.1842 u calculated, found 398.1849). Due to the low yield obtained in the synthesis of 63, only small samples of 64 and 65 were available. Consequently, decarboxylation of these compounds was not attempted. 58 SCHEME 35. Synthesis of 3,4:3",4"-Tetramethylsubstituted Analogs of 3a-c M “3% , / \ / \ E CHO N E N o o N E H H H 62 63 E- ethyl ester b,73% 0,39% ll / \ / \ / \ / \ / \ / \ E N s N E E N 0 N E H H H H 64 65 a) thiazolium salt (cat.), NaOAc, divinyl sulfone, EtOH, reflux b) Lawesson's reagent, toluene, reflux c) NH4OAc, Ac20, HOAc, reflux aElectrocbemioaLSjudiesflandfin Electrochemical polymerization experiments on the novel tricycles 3b and 60 were performed by DeArmas, Gaudiello and LeGoff to produce the copolymeric structures 4b and 66 (Scheme 36). The polymer films were prepared in a two-compartment cell on an indium-tin oxide (ITO) anode. Acetonitrile containing 0.1M tetra-n-butylammonium tetrafluoroborate (TBATFB) was used as the solvent-electrolyte system. A sodium-saturated calomel electrode (SSCE) served as the reference electrode. 59 SCHEME 36. Electrochemical Polymerization of 3b and 60 N s N ' H 3., H The corresponding cyclic voltammograms (Figures 23 and 24) show that both monomers 3b and 60 form films by irreversible electrooxidation. Polymer growth occurs via the expected electron transfer followed by chemical reaction mechanism (E(CE)n).14 The peak oxidation potential (Epa) of 3b (pyrrole to thiophene ratio 2:1) lies slightly less than half way between the Epa's of the parent monomers tat-terpyrrole (3a) and a-terthiophene (Table 4).2°-93 60 FIGURE 23. Cyclic Voltammogram (CV) of 3b EXP. CONDITIONS: 1.55 2 .. tut! (nth-.4 HIGH IM- .0 L011 EIVI--.e FINAL (1V)°-.‘ IE 2 _ v leV/SECI - so ‘N‘! O/- -0 M It". l-Vl- 3.1 3 d .552 .. Q o e. s. 5 U at 2 P -.6 - 8 Potential V vs 5 '.SE 2 h ( ) SCE -tEZ -t.5£ 2 I. -ZE 2 ,. FIGURE 24. Cyclic Voltammogram (CV) of 60 EXP. CONOXTIONS; 1.x I >- lutt “VP-.4 N15” (In. .. L011 (Mo-.4 FINAL (IVl'-.4 :E 1 l" V (IV/SEC, ' 5. ’N!‘ 0" I. m D". la"- 3.!!! Current (.4) Potential (V) vs SSCE 'tE 1 ~t.SE I . l -25 5 )- 61 Table 4. Epal Values of Tricyclic Monomers Mammar— EonJXL / \ / \ / \ 1.05.. S S S N S N H 3b H / \ / \ / \ 0.26.. N N N H H H The lower Epa of 60 compared to 3b (Epa shifted 0.12V cathodic) is consistent with previous experimental and theoretical results. The 4,4"-methyl substituents cause minimal steric disruption of the n-system, while providing beneficial electronic stabilization of the radical cation intermediate. As discussed in the introduction, this phenomenon has been reported in the polythiophene series.19 Small electron-donating groups decrease the EM of the thiophene monomer. Conversely, small electron-withdrawing groups increase the Epa of the monomer (Table 5). 62 Table 5. Substituent Effects on the Epa of Heteroaromatic Monomers Monomer. Eea_L_l_V / \ / \ / \ 0.52 N s N H 3., H /\/\/\ 0.40 N S N H 60 H thiophene 2.06“ 3 - methylthiophene 1.86" 3 — cyanothiophene 2.46" 3 - nitrothiophene 2.69“ pyrrole 1 .20"’1 N- methylpyrrole 1.122‘ The polymer-coated anodes were washed free of residual monomer and resubmitted to new electrochemical cells in order to obtain the surface wave cyclic voltammograms (Figure 25 and 26). The Epa's of 4b and 66 were recorded at -0.02 V and 0.21 V, respectively. Both films exhibited reversible electrochromic behavior as they cycled between a pale yellow color in the neutral state and a dark green color in the oxidized state. In addition, both polymers exhibited a large increase in capacitance when cycled to the oxidized state. This is indicative of the presence of a conductive material on the anode surface. 63 FIGURE 25. Surface Wave Cyclic Voltammogram of 4b EXP. MITIONS: “5 ‘ )' um eon—.0 H191 EM. .5 L0! EM-J FINAL CM~.3 t! 1 . v (av/sect - to {NIT O/- .0 A f M W. 100- ."80417 d e! 5 b a U I. I. 8 a ‘ L A 1 1 A n J 1 .A/L 1 l5 s .4 .3 .2 .t o -.t -.g,/.f'f-.4 -.s -.6 Potential (V) vs SSCE -0! t b ‘5‘ 8 I- -‘I! t I- i i )- FIGURE 26. Surface Wave Cyclic Voltammogram of 66 EXP. CONDITIONS: 1.551 I. tun Etta—.4 mu em- .0 Lou Inn-me FINAL “VI—.4 v t-vxsect - ee ‘6‘ ' tun e/-- « sun mt. tth- .7012”: A 3 .5. . 15 E I -.6 - a Potential (V) vs SSCE fig 3 l- -‘E 3 r- -‘ei 5 y. 45 t i 64 The dc. conductivity measurements of polymers 4b and 66 were determined by the four-probe method.94 The polymers were doped for five minutes in acetonitrile with TBATFB as the electrolyte. Unsubstituted polymer 4b displayed an electrical conductivity of 17 S cm-l. Methyl-substituted polymer 66 exhibited a ten-fold increase in conductivity at 216 S cm-l. Thus, both polymers display excellent electrical conductivity in the oxidized state. The conductivity values measured are similar to those reported for other heteroaromatic polymers (Table 6).30 Table 6. Conductivity Values of Heteroaromatic Polymers Polymer Monomer. Conductivity ( S cm'1 ) \ / \ 280” s N s H We 0) 21° N s N H H / 17 W (an) N H H [LU—Q 1" S N CH. / \ 0.3” S S thiophene >100' pyrrole >100‘ furan 301 N-methylpyrrole <0.001 ' 65 The enhanced conductivity of 66 relative to 4b is representative of a more highly ordered structure in 66. This finding is consistent with the initial hypothesis that substitution of the 4 and 4" positions with methyl groups should increase the percentage of a,a'-linkages and thus create a more uniform distribution of polymer chains. This trend has been observed by others in polythiophenes. The addition of a 3-methyl substituent increases the electrical conductivity of polythiophene by a factor of 10 to 1000 depending upon the doping conditions and the counter anion employed.19b Overall, electrochemical measurements of monomers 3b and 60 have shown that they exhibit the desired physical properties. Both monomers provide films of excellent conductivity and electrochemical response. The synthetically designed tricyclic structure of the monomers allows for the preparation of a new class of copolymers of known stoichiometry and sequence distribution. In addition, the structural order of the polymers is increased first by the presence of two a,a'-linkages designed into each monomer and second by the use of B-substituents to block competitive coupling at non-ot-positions. The results of this study and of other studies (Tables 4-6) show that by altering either the heteroatom composition and/or substituent composition of the monomer, materials possessing a continuum of electronic properties can be prepared. 4.5 || .. [El l-B'l II' I Heteroaromatic polymers such as polypyrrole, polythiophene, 4b, and 66 form linear, one»dimensional chains. Monomers such as 67 (Scheme 37), in which two heteroaromatic tricycles are held together by a phenyl bridge, 66 could form two-dimensional or even three-dimensional heteroaromatic polymers. The preparation and electrical properties of two- and three- dimensional polymers have not been previously explored. A retrosynthetic analysis (Scheme 37) indicates that structures such as 67 may be synthesized from p-phenylenediamine (68) and the heteroaromatic 1,4-diketones prepared by the Stetter reaction. SCHEME 37. Retrosynthesis of Phenyl-Bridged Tricycles /\ /\ \/ /\/\/\ " °° " x N x NH2 ::;> x N x NH; \/\/\/ x 00 x /\ 67 \/ \/ X-NH,S,O An initial investigation into the synthesis of this class of compounds was begun with the previously synthesized diketone 55. Condensation of 55 with 68 provided amide 69 as the major product (42%) and only a small amount of the desired phenyl-bridged dimer 70 (16%) (Scheme 38). The formation of a carboxylic amide by direct reaction of an amine with an acid is generally a very slow reaction. Thus, it is surprising that amide formation competes with the synthetically more facile reaction of an amine with a ketone. This indicates that the condensation to form the second pyrrole moiety is quite sluggish. 67 SCHEME 38. One-Step Synthesis of Compound 70 E N N N E E N N N E E H H H H W 68(05 eq.),HOAc ¢ + E E : N N reflux, 4 days H H H 55 E N N N E HN E-ethylester W E E 70 (16%) 68(42%) The electronic spectra of 69 ( lmax. 299nm) and 70 (lmax. 293nm) undergo a dramatic hypsochromic shift compared to the parent N-unsubstituted tricycle 56 (lmax. 367nm). The large shift can be rationalized by two factors. First, the phenyl group may interfere with the ability of the aromatic rings to achieve a coplanar structure. Second, hydrogen-bonding between an ethyl ester carbonyl and the hydrogen on the middle pyrrole nitrogen may hold 56 in a planar conformation (Figure 27). The hydrogen-bond stabilized conformer is not available in the N-phenyl substituted structure. Flgure 27. Hydrogen-bond Stabilized Conformation of 56 56 , E . ethyl ester 68 The reaction of 55 with 68 (2:1 ratio) in refluxing toluene with a catalytic amount of p—toluenesulfonic acid (pTSA) yielded only 16% of the mono- condensed product 71 (max, 299nm). Prolonged heating (40h) provided 5% of the desired product 70 (Scheme 39). Again, the sluggish nature of the second Paal-Knorr reaction is evidenced. SCHEME 39. Alternate One-Step Synthesis of 70 E E E N N N E 68 0. . . TSA W “seq” =55<47%)+ H H E N N E toluene, reflux, 18h H 55 NH2 7 1 (16%) E s ethyl ester O. .8 I. M ’ 40 h ‘ 70(5°/o) In an attempt to improve the low yields obtained for 70 with a stoichiometric ratio of reagents, a two-step procedure was implemented which utilized excess quantities of each reactant. Reaction of 55 with an excess of diamine reagent (3.5 equiv.) provided a 72% yield of mono-condensed product (71). Submission of 71 to a three-fold excess of 55 gave 70 in 42% yield. Thus, the two-step procedure resulted in a 30% overall yield of 70 (Scheme 40). 69 SCHEME 40. Two-Step Synthesis of 70 E E 68 3. . , TSA /\ (seq’p = 71(72%) E N N E toluene, reflux, 20h H 55 H 55 (3eq).toluene g pTSA(cat.) E ”M 93“” reflux, 18h ll E E W EN N NE ”OH H H 5N N NE l\/\/ E E 70(42%) The use of the sulfone-protected diketones 47a and 47b led solely to the recovery of starting material. 1.1: nd,CH H.7h + 53 ”m" ”002 : 47a(95%) 2. reflux, 18h 1. , TS lt d, 7h + 68 xylene p A, u rasoun _ 47b(73%) N o N 2. reflux, 3 days The attempted preparation of the [1,4,1 ,4]tetraazadithi0platyrin 73 was patterned after Lindsey's modification of the well-studied Alder-Longo synthesis of porphyrins.95 The reaction involves an acid-catalyzed condensation between pyrrole and an aldehyde (Scheme 41). SCHEME 41. Lindsey's Synthesis of Tetraphenylporphyrin R H R Bl::3(05t)2 H R oxidation [I 3 + nono o —- n R N 25 C R H H H R R porphyrinogen Tetraphenylporphyrin R a phenyl ( 45%) This method is perhaps the most convenient and reliable route for the preparation of synthetic porphyrins. The reaction conditions are designed to favor cyclization over linear polymerization. The analogous reaction for the preparation of 73 is shown in Scheme 42. Reaction of 3b with p-tolualdehyde and BF3(OEt)2 at room temperature, however, provided the linear methane-bridged dimer 72 in 18% yield (Scheme 43). Tricycle 3b was recovered in 40% yield. The remaining products appeared to be long-chain linear polymers. Increasing the temperature of the (n DO!) tfac 71 reaction to 40°C (reflux, CHzclz) resulted in a decrease in the yield of 72 (10%) and a 42% recovery of 3b. No cyclized material was isolated. SCHEME 42. Proposed Route to [1,4,1,4]Tetraazadithioplatyrin 73 3510502 Ar Ar oxidation W . m... .. H N s N 20 H 3b H so [26]annu|ene ( 7 3 ) SCHEME 43. Attempted Synthesis of 73 H H at, 35(03): 4.. Hac—Q—CHO A change in the acid catalyst from BF3(OEt)2 to CF3002H yielded only CHZCIZ. 5 days polymeric products. Thin-layer chromatography (TLC) analysis showed no trace of starting materials, dimer 72, or cyclized product. 72 Future approaches to the synthesis of the [1 ,4,1 ,4]tetraazadithioplatyrin ring system may include the following: 1) the study of different Lewis acid catalysts; 2) the use of B—substituted analogs of 3b to reduce competitive side reactions; and 3) the use of monoformylated tricycle (52) as the starting material in a one-step synthesis. CONCLUSIONS CONCLUSIONS A general synthetic route to the linear heteroaromatic tricycles 2,2':5',2"- terpyrrole (3a) and 2,5—bis(2-pyrryl)thiophene (3b) has been described. The synthesis depends upon the formation of a symmetrical 1,4-diketone via the reaction of an N-sulfonyl substituted 2-formylpyrrole and divinyl sulfone (Stetter reaction). The utilization of a 1,4-diketone as an intermediate in the synthetic strategy allows for both systems to be obtained from a common precursor. The preparation of 3a in four steps and 23% overall yield is a significant improvement over the presently employed synthetic route of Rapoport5° (seven steps, 2.4% overall yield). The novel mixed tricycle 3b is formed in 41% overall yield. The 4,4”-dimethyl substituted analogs of 3a and 3b, 2,5-Bis(4-methyl-2- pyrryl)pyrrole (59, 9% overall yield) and 2,5-bis(4-methyl-2-pyrryl)thiophene (60, 21% overall yield), are obtained starting with 2-formyl-3,5- diethoxycarbonyl-4-methylpyrrole (54) as the electron deficient aldehyde. The use of 3b and 60 as monomers in the synthesis of heteroaromatic polymers has yielded copolymers with a known stoichiometry and sequence distribution of heterocycle units. The presence of two a,a'-linkages in the monomer may lead to a more ordered polymeric structure. The copolymers derived from both 3b and 60 exhibit excellent stability and electrochemical response, as well as, high conductivity. As predicted, the electronic properties 73 74 of the copolymer derived from 3b are intermediate between those of the corrsponding homopolymers. Electrochemical polymerization of monomer 60 provides a copolymer of higher conductivity (216 S cm'1) than that obtained from monomer 3b (17 S cm”). The difference in the two conductivity values can be attributed to the presence of B-methyl substituents in 60. The methyl groups block the undesired competitive a,B'- an B,B'-coupling reactions. As a result, a more highly ordered and consequently more conductive a, a'-linked copolymer is prepared. Initial investigations into the use of 3a and 3b as precursors for the synthesis of novel expanded-porphyrin heteroannulenes have been attempted. Condensations of 3b with p-tolualdehyde have so far resulted in the recovery of a linear, dimeric mono-condensation product (72), rather than the desired [1,4,1,4]tefraazadithioplatyrin (73). Additional condensation reactions need to be attempted before the feasibility of product formation can be determined. EXPERIMENTAL EXPERIMENTAL SECTION General. Toluene and diethyl ether were dried by distillation under argon from sodium-benzophenone ketyl. Acetic anhydride, triethylamine (TEA) and methanesulfonyl chloride were dried by distillation under argon from calcium hydride. Ethanol was dried by distillation under argon from magnesium. Acetic acid (HOAc) was dried by distillation under argon from triacetyl borate.95 Anhydrous N,N-dimethylformamide (DMF) and 1,4-dioxane were purchased from Aldrich Chemical Company, Milwaukee, WI and used as received. Ammonium acetate (NH4OAc) and sodium acetate (NaOAc) were dried in a vacuum oven at 50°C and 100°C, respectively. All reactions were performed under an argon atmosphere unless otherwise mentioned. Melting points were determined on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Ultrasonic processing was performed with a Vibra Cell VC500. Proton nuclear magnetic resonance (lH-N MR) spectra were obtained on a Bruker WM-250 (250 MHz), Varian VXR (300 MHz) or Varian Gemini (300 MHz) spectrometer. Chemical shifts are reported in parts per million (8) using the residual solvent proton resonance as the internal reference (acetone, 6 2.04; acetonitrile, 1.93; chloroform, 7.24; dichloromefhane, 5.32; DMSO, 2.49; methanol, 3.30; tetrahydrofuran, 1.73). 1H-NMR data are tabulated as follows: chemical shift multiplicity (s, singlet; br s, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; m, multiplet), coupling constant (Hz), number of hydrogens. ‘30 nuclear magnetic 75 76 resonance (13C-NMR) spectra were recorded on a Bruker WM-250 (62.9 MHz), Varian VXR (75.4 MHz), or Varian Gemini (75.4 MHz). Chemical shift values are reported in parts per million using the solvent peak as the internal reference (acetone, 529.8; chloroform, 77.0; DMSO, 39.5; methanol, 49.0; tetrahydrofuran, 67.4). Infrared (IR) spectra were recorded on a Nicolet lR/42 spectrometer. Ultraviolet (UV) spectra were obtained on a Hitachi U-2000 spectrometer. Electron impact mass spectra (El-MS) were recorded on a Finnigan 4000 with an INCOS 4021 data system. High-resolution mass spectra (HRMS) were determined on a JOEL HX110 spectrometer at the Michigan State University Regional Mass Spectroscopy Facility, Department of Biochemistry, East Lansing, MI. Flash column chromatography was performed according to the procedure of Still, et.al.97 Chromatography parameters are reported as follows: 9 of solid phase, column outer diameter (od), eluent, R1. (E,E)-Methyl(2-thlenyl)ketazine (31a) and (E,Z)-Methyl(2- thlenyl)ketazlne (31 b). A solution of succinylhydrazine methyl ester hyrdochloride (0.75 g, 4.2 mmole) and 2-acetyl thiophene (0.54 ml, 5 mmole) in dry methanol (10 ml) was heated to a gentle reflux for four days. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resulting residue was extracted from water with ether (3x), dried over M9804, and concentrated in vacuo. Flash column chromatography of the crude sample (50 g of 230-400 mesh silica gel, 30 mm od column, CHZCIZ-hexane (80:20)) provided 0.268 g (52%) of 31a as a bright yellow solid (mp 91.5-92.500, lit 93°C”) and 0.212 g (41%) of 31b as a bright yellow solid (mp 72.5-73.000). Compound 31a: R, 0.52 (CHZCIZ-hexane (80:20)); 1H-NMR (CDCI3) 5 7.42 (dd, J=3.7, 1.1 Hz, 2H), 7.39 (dd, J=5.1, 1.0 Hz, 2H), 7.08 (dd, J=5.1, 3.7 Hz, 77 2H), 2.46 (s, 6H); 13C-NMR (CDCI3) 8157.5, 144.8, 128.9, 127.7, 127.4, 14.9; IR (CHCI3) 1595, 1432, 1369, 1359, 1295, 1235, 1089, 1060, 855, 832 cm"; El- MS (70eV), m/z (relative intensity) 250 (M42, 3.1), 249 (M+1, 5.8), 248 (W, 30.3), 233 (19.5), 215 (14.4), 192 (4.2), 138 (6.4), 124 (34.5), 110 (20.6), 109 (31.6), 97 (19.2), 84 (13.5), 66 (22.8), 65 (22.2). Compound 31b: R; 0.23 (CHZClz-hexane (80:20)); 1H-NMR (CDCIa) 57.64- 7.48 (m, 4H), 7.11 (m, 2H), 2.59 (s, 3H), 2.45 (s, 3H); 13c-NMR (00013) 5 157.6, 153.0, 144.6, 134.6(2), 130.8, 130.1,128.s, 127.8, 126.3, 23.2, 15.2; IR (CHCI3) 1590, 1430, 1367, 1295, 1235, 1089, 1060, 855, 832 cm-1; El-MS (70eV), m/z (relative intensity) 250 (M+2, 6.8), 249 (M+1, 18.2), 248 (W, 53.1), 233 (33.0), 215 (28.5), 192 (8.6), 138 (10.4), 124 (65.1), 110 (36.7), 109 (56.8), 97 (35.9), 84 (22.0), 66 (33.5), 65 (33.6). 1-Methanesulfonyl-2-formylpyrrole (46b). A suspension of NaH (1.0 g, 25 mmole, 60% in oil washed with 3 x 50 ml portions of dry ether) in ether (50 ml) was slowly charged with 2-formylpyrrole 36 (20 ml of 1.37 M ether solution, 27 mmole) and the flask was heated to a gentle reflux for 2.5 h. Methanesulfonyl chloride (8 ml of 3.72 M other solution, 30 mmole) was added dropwise at 0°C and the resulting tan suspension was stirred for 5 h at 0°C followed by 35 h at room temperature. The mixture was filtered, washed with CHZClz and the filtrate was concentrated in vacuo to provide a brown oil. The crude product was purified by flash column chromatography (200 g of 230-400 mesh silica gel, 50 mm od column, CH2CI2-ethyl acetate (99:1), R;0.45) to yield 2.65 g (61%) of 46b as a pale yellow oil which solidifies upon standing, mp 43- 44°C. 1H-NMR (acetone-d5) 89.76 (d, J=0.8 Hz, 1H), 7.61 (ddd, J=3.1, 1.8, 0.8 Hz, 1H), 7.35 (dd, J=3.9, 1.8 Hz, 1H), 6.48 (dd, J=3.9, 3.1 Hz, 1H), 3.73 (s, 3H); ‘30- 78 NMR (acetone-d5) 5179.2, 134.2, 130.8, 128.4, 1122.430; IR (Nujol) 3140, 3128,1674,1445,1408,1362,1339,1327,1236,1177,1142,1061,1019, 970, 779, 772 cm"; EI-MS (70eV), m/z (relative intensity) 173 (W, 10.0), 94 (73.4), 79 (22.6), 66 (20.3). 1,4-Bls(1-benzenesuIfonyI-2-pyrryI)-1,4-butanedlone (476). A mixture of 468 (21.0 g, 89.4 mmole) in absolute ethanol (120 ml) was charged with 3-benzyI-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (3.7 g, 13.6 mmol) and anhydrous NaOAc (2.3 g, 23.0 mmol). The mixture was heated to a gentle reflux and divinyl sulfone (4.5 ml, 43.8 mmole) was added dropwise. The solution was refluxed for an additional 12 h. A light tan precipitate was filtered from the orange solution and washed with cold water, ethanol and ether. The precipitate was air dried to yield 15.6 g (70%) of 476 as a fine powder (> 95% pure by 1H-NMR). Flash column chromatography (230-400 mesh silica gel, CHZCIZ, R; 0.31) provided an analytical sample of 476 as a white solid, mp 206-207°C. 1H-NMR (CDCIa) 8 7.95 (d, J=7.7 Hz, 4H), 7.80 (m, 2H), 7.57-7.45 (m, 6H), 7.12 (dd, J=3.8, 1.6 Hz, 2H), 6.35 (t, J=3.4 Hz, 2H), 3.03 (s, 4H); 130-NMR (CDCI3) 8 186.6, 138.9, 133.6, 132.8, 130.2, 128.7, 128.0, 123.8, 110.5, 33.0; lR (Nujol) 1674, 1358, 1290, 1175, 1144, 1111, 1063, 1046, 964, 773, 748, 680 cm"; El- MS (706V), m/z (relative intensity) 496 (M+, 2.2), 339 (6.1), 262 (21.6), 234 (68.9), 141 (32.1), 94 (30.4), 77 (base); HRMS (FAB) calod for C24H20N20632 (M+H) 497.0841, found 497.0835. 1,4-Bls(1-methanesulfonyI-2-pyrryl)-1,4-butanedlone (47b). The same general procedure as for the formation of 478 was used. Compound 46b (2.0 g, 12 mmole), divinyl sulfone (0.57 ml, 5.6 mmole), NaOAc (0.3 g, 3.6 79 mmole), 3-benzyl-5—(2-hydroxyethyI)-4-methyl-1,3-thiazolium chloride (0.48 g, 1.8 mmole), and absolute ethanol were combined to yield 1.56 g (74%) of 47b as a light tan solid (>95% pure by 1H-NMR). Flash column chromatography (230-400 mesh silica gel, CHzclz, R; 0.27) provided an analytical sample of 47b as a white solid, mp 195-197°C. 1H-NMR (CDZCIZ) 8 7.57 (dd, J=3.3, 1.7 Hz, 2H), 7.30 (dd, J=3.6, 1.7 Hz, 2H), 6.35 (dd, J=3.6, 3.3 Hz, 2H), 3.65 (s, 6H), 3.27 (s, 4H); 13C-NMR (DMSO-d5) 8 188.0, 132.2, 129.8, 124.8, 110.3, 42.5, 32.6; IR (Nujol) 1659, 1366, 1288, 1109, 1040, 947 cm°1; El-MS (706V), m/z (relative intensity) 372 (M+, 1.7), 200 (16.7), 172 (55.9), 94 (base), 79 (28.9); HRMS (FAB) calod for C14H16N20582 (M+H) 373.0528, found 373.0529. 2,5-Bls(1-benzenesulfonyl-2-pyrryl)pyrrole (488). A suspension of 476 (0.401 g, 0.81 mmole) in dry propionic acid (6 ml) was charged with anhydrous NH4OAc (1.71 g, 22.2 mmole) and acetic anhydride (1.20 ml, 12.7 mmole). The reaction mixture was cooled in a water bath and sonicated with a direct immersion ultrasonic horn until a fine dispersion was obtained.25 The water bath temperature never exceeded 30°C. The tan dispersion was quickly decanted into a round bottorn flask fitted with a condenser and heated to a gentle reflux for 10 h. After cooling to room temperature, a majority of the propionic acid and acetic anhydride was removed by vacuum distillation. Water (20 ml) was added to the residue and this solution was neutralized with 2N NaOH. The aqueous solution was extracted with CHZCIZ and the combined organic fractions were washed with 10% sodium bicarbonate (2x), brine (1x), dried over Na2804, and concentrated in vacuo. Flash column chromatography (15 g of 230-400 mesh silica gel, 20 mm od column, Cchlz-hexane (75:25), R; 0.44) provided 0.178 g (46%) of 488 as a pale yellow solid, mp 151-152°C. 80 1H-NMR (acetone-d6) 89.95 (br s, 1H), 7.67-7.44 (m, 12H), 6.35 (m, 4H), 6.21 (d, J=2.6 Hz, 2H); 13C-NMR (acetone-d5) 8139.2, 134.9, 130.0, 128.7, 127.9, 124.6, 122.9, 116.6, 113.0, 112.4; El-MS (258V), m/z (relative intensity) 477 (M+, 10.7), 336 (68.7), 195 (base); UV (methanol) 288 (log 6 4.06), 275 (4.07), 224 nm (4.33); HRMS (El) calcd for CZ4H19N304SZ 477.0817, found 477.0797. 2,5-Bls(1-methanesuIfonyI-2-pyrryl)pyrrole (48b). The same procedure as for the formation of 488 was used. Compound 47b (0.507 g, 1.4 mmole), NH40Ac (2.82 g, 36 mmole), acetic anhydride (1.9 ml, 20 mmole), and propionic acid (11 ml) were combined. Flash column chromatography of the crude product (30 g of 230-400 mesh silica gel, 30 mm od column, CHzclz, R; 0.42) yielded 0.207 g (43%) of 48b as a white solid, mp 107-108°C. 1H-NMR (acetone-d6) 810.19 (br s, 1H), 7.26 (dd, J=3.4, 1.8 Hz, 2H), 6.50 (m, 4H), 6.36 (t, J=3.4 Hz, 2H), 3.18 (s, 6H); 13C-NMR (acetone-d5) 8127.5, 123.8, 123.3, 116.2, 112.5, 111.8, 42.1; El-MS (25eV), m/z (relative intensity) 353 (M+, base), 274 (47.0), 196 (98.2); uv (methanol) 290 nm (log e 4.13); HRMS (FAB) calod for C14H15N30482 (M+H) 354.0582, found 354.0590. 2,2':5',2"-Terpyrrole (38). A deaerated solution of NaOH (SN, 2 ml) in methanol (7 ml) was charged with 488 (0.200 g, 0.42 mmole) and heated to a gentle reflux for 70 min. The reaction was cooled to room temperature and extracted from NH4CI (sat.) with Cchlg. The combined organic fractions were washed with water (2x), dried over NaZSO4, and concentrated in vacuo. The dark gray residue was immediately purified by flash column chromatography (6 g of 230-400 mesh silica gel, 15 mm od column, argon pressure, deaerated CH2Clg-ethyl acetate (98:2), R; 0.36) to provide 62 mg (75%) of 38 as a light gray solid. Sublimation (180°C, 0.1 mm Hg) provided an analytical sample of 81 38 as a white solid, mp 241-242°C (lit.6° mp 242°C). Compound 38 was stored at -15°C under an argon atmosphere. The 1H-NMR and UV spectra of 38 are consistent with literature values.60 1H-NMR (methanol-d4) 86.66 (dd, J=2.6, 1.5 Hz, 2H), 6.27 (dd, J=3.4, 1.5 Hz, 2H), 6.18 (s, 2H), 6.08 (dd, J=3.4, 2.6 Hz, 2H); 13C-NMR (methanol-d4) 5127.5, 127.2, 117.9, 109.3, 104.5, 103.5; EI—MS (256V), m/z (relative intensity) 197 (M+, base), 196 (46.3), 169 (21.5); UV (methanol) 345 sh (log 64.07), 326 (4.37), 319 nm (4.38); HRMS (El) calcd for C12H11N3 197.0953, found 197.1010. 2,5-Bls(1-benzenesuIfonyl-2-pyrryl)thlophene (498). A mixture of 478 (8.0 g, 16 mmole) in dry toluene (225 ml) was charged with Lawesson's reagent (4.6 g, 11 mmol) and heated to a gentle reflux for 6 h. The green solution was cooled to room temperature and concentrated to one-half its original volume in vacuo. Methanol was slowly added to the toluene solution until a precipitate appeared. Filtration yielded 5.5 g of a light tan solid. Flash column chromatography of the crude product (300 g of 230-400 mesh silica gel, 50 mm od column, CHZClz-hexane (60:40), R; 0.48) provided 5.2 g (65%) of 498 as a white solid, mp 151-152°C. IH-NMR (CDCI3) 57.57-7.38 (m, 12H), 6.95 (s, 2H), 6.27 (m, 4H); ‘3C-NMR (CDCI3) 8138.4, 133.8, 132.5, 129.9, 129.1, 127.3, 126.8, 124.8, 117.7, 111.9; EI-MS (70eV), m/z (relative intensity) 494 (M+, 5.1 ), 353 (30.5), 212 (base), 141 (11.4), 77 (82.2); UV (methanol) 298 (log 6 4.0), 275 (3.94), 268 (3.92), 217 nm (4.31); HRMS (El) calcd for Cz4H13N20433 494.0429, found 494.0396. 2,5-Bls(1-methanesulfonyl-2-pyrryl)thIophene (49b). The same general procedure as for the formation of 498 was used. Compound 47b 82 (0.201 g, 0.54 mmole), Lawesson's reagent (0.153 g, 0.38 mmole), and toluene (10 ml) were heated to a gentle reflux for 4 h. Flash column chromatography of the crude product (20 g of 230-400 mesh silica gel, 20 mm od column, CH2CI2, R; 0.46) yielded 0.130 g (65%) of 49b as a white solid, mp 155-157°C. 1H-NMR (acetone-d5) 8 7.35 (dd, J=3.4, 1.8 Hz, 2H), 7.31 (s, 2H), 6.54 (dd, J=3.5, 1.8 Hz, 2H), 6.39 (t, J=3.4 Hz, 2H), 3.23 (s, 6H); 13C-NMR (acetone-d5) 5 133.8, 130.6, 126.8, 125.1, 118.2, 112.0, 42.6; El-MS (70eV), m/z (relative intensity) 372 (M+2, 1.4), 371 (M+1, 197), 370 (M+, 12.8), 291 (35.3), 212 (base), 79 (43.6); UV (methanol) 303 nm (log 64.10); HRMS (FAB) calcd for C14H14N20483 (M+H) 371.0194, found 371.0196. 2,5-Bls(1-benzenesuIfonyl-2-pyrryl)fur8n (50). A suspension of 478 (0.400 g, 0.80 mmole) in dry propionic acid (7 ml) was charged with acetic anhydride (2.3 ml, 24 mmole). The reaction mixture was cooled in a water bath and sonicated with a direct immersion ultrasonic horn until a fine dispersion was obtained (8 h). The water bath temperature never exceeded 30°C. The tan dispersion was quickly decanted into a round bottom flask fitted with a condenser and heated to a gentle reflux for 48 h. After cooling to room temperature, a majority of the propionic acid and acetic anhydride was removed by vacuum distillation. Water was added to the residue and this solution was neutralized with 2N NaOH. The aqueous solution was extracted from NaHCOa (50% solution) with CHZCIZ and the combined organic fractions were washed with water (2x), brine (1x), dried over M9804, and concentrated in vacuo. Flash column chromatography (20 g of 230-400 mesh silica gel, 30 mm od column, CH2Cl2-hexane (70:30), R; 0.44) provided 44 mg (11%) of 50 as a clear oil. 83 1H-NMR (acetone-d5) 8 7.60-7.31 (m, 12H), 6.68 (s, 2H), 6.38 (dd, J=3.3, 1.7 Hz, 2H), 6.32 (t, J=3.3 Hz, 2H); 1StC-NMR (CDCI3) 8 144.2, 138.4, 133.7, 129.1, 127.1, 125.2, 124.8, 117.0, 112.3, 112.0; El-MS (706V), m/z (relative intensity) 479 (M+1, 4.9), 478 (M+, 17.6), 337 (base), 196 (59.4), 149 (18.2). 2,5-Bls(2-pyrryl)thIophene (3b). The same general procedure as for the formation of 38 was used. Compound 498 (0.203 g, 0.4 mmole), NaOH (2 ml, 5N), and methanol (5 ml) were refluxed for 1.5 h to achieve the desired hydrolytic deprotection. Column chromatography with neutral alumina (9 g of 80-200 mesh, 15 mm od column, deaerated Cchlz-ethyl acetate (9723), R; 0.36) provided 82 mg (93%) of 3b as a pale green solid, mp 194-196°C dec. 1H-NMR (acetone-d6) 810.40 (br s, 2H), 7.05 (s, 2H), 6.80 (m, 2H), 6.30 (m, 2H), 6.12 (m, 2H); 13C-NMR (acetone-d6) 8134.3, 127.3, 121.6, 119.6, 110.0, 106.8; EI-MS (706V), m/z (relative intensity) 216 (M+2, 5.0), 214 (M+, base), 186 (19.3), 107 (9.6); UV (methanol) 377 sh (log 6 4.11), 353 (4.40), 226 nm (4.01); HRMS (El) calcd for c12H1ost 214.0565, found 214.0572. 2-(5-Formyl-2-pyrryl)-5-(2-pyrryl)thlophene (52). A magnetically stirred solution of 3b (0.200 g, 0.93 mmole) in anhydrous DMF (4 ml) was cooled to 0°C and slowly charged with benzoyl chloride (5 ml of 1.6M DMF solution, 8 mmole). The solution was stirred at room temperature for 17 h. Toluene (10 ml) was added and the resulting precipitate was transferred to a flask containing N82003 (0.3 g) in aqueous ethanol (70%, 13 ml). The ethanol solution was heated at reflux temperature for 0.5 h followed by stirring at room temperature overnight. Removal of ethanol in vacuo provided a fluorescent green aqueous residue which was extracted with CHZCI2 (3x). The combined organic fractions were washed with water (2x), dried over Na2804, and 84 concentrated. Flash column chromatography of the crude product (27 g of 230- 400 mesh silica gel, 30 mm od column, CHzclz-ethyl acetate (80:20), R; 0.51) yielded 0.165 g (73%) of 52 as a yellow solid, mp 190-192°C dec. 1H-NMR (acetone-d5) 8 11.30 (br s, 1H), 10.58 (br s, 1H), 9.48 (s, 1H), 7.55 (d, J=3.9 Hz, 1H), 7.17 (d, J=3.9 Hz, 1H), 7.03 (d, J=4.0 Hz, 1H), 6.87 (m, 1H), 6.52 (d, J=3.9 Hz, 1H), 6.40 (m, 1H), 6.16 (m, 1H); 13C-NMR (methanol-d4) 8 179.8, 138.9, 137.0, 134.5, 131.1, 127.1, 126.4, 124.4, 121.9, 120.4, 110.3, 110.0, 107.5; IR (Nujol) 3410, 3364, 3262, 1650, 1262, 1200, 1050, 1035, 820, 788 cm‘I; EI-MS (706V), m/z (relative intensity) 242 (W, 10.6), 213 (3.5), 149 (6.3), 86 (30.3), 84 (48.3); UV (methanol) 390 (log 6 4.40), 302 (3.72), 234 nm (4.00); HRMS (El) calcd for C13H10NZOS 242.0514, found 242.0525. 2.5-BIs(5-formyl-2-pyrryl)thIophene (53). A magnetically stirred solution of 3b (0.100 g, 0.47 mmole) in anhydrous DMF (3 ml) was cooled to 0°C and slowly charged with benzoyl chloride (3.5 ml of 1.2M DMF solution, 4.2 mmole). The solution was stirred at 0°C for 1 h and then warmed to 80°C for 6 h. After cooling to room temperature, toluene (5 ml) was added to the reaction. The resulting precipitate was collected and transferred to a flask containing N82003 (0.15 g) in aqueous ethanol (70%, 10 ml). The green solution was heated at reflux temperature for 0.5 h followed by stirring at room temperature for 7 h. Removal of the ethanol in vacuo provided an aqueous residue which was extracted with CH20I2. The combined organic fractions were washed with water (2x), dried over N82304, and concentrated to yield a yellow solid (14 mg). In addition, filtration of an emulsion at the water/CH2Cl2 interface yielded a dark green solid (57 mg). The crude samples were combined. Recrystallization from acetonitrile provided 59 mg (47%) of 53 as dark green needles, mp 275-276°C. 85 1H-NMR (DMSO-d5) 812.58 (br s, 2H), 9.49 (s, 2H), 7.68 (s, 2H), 7.07 (d, J=4.0 Hz, 2H), 6.57 (d, J=4.0 Hz, 2H); 13c-NMR (DMSO-d6) 5178.7, 133.6, 133.4, 133.3, 125.7, 122.1, 109.2; IR (Nujol) 3262, 1637, 1273, 1049, 1041, 829, 781, 771 cm'l; El-MS (256V), m/z (relative intensity) 272 (M+2, 5.3), 271 (M+1, 14.7), 270 (M+, base), 271 (12.7), 214 (20.7), 213 (22.2), 186 (11.2); uv (acetonitrile) 409 sh (log e 4.42), 392 (4.55), 375 sh (4.49), 245 (4.05). 222 nm (4.10); HRMS (FAB) calcd for C14H10N2028 (M+H) 271.0541, found 271.0523. 1 ,4-BIs(3,5-dIethoxycarbonyl-4-methyI-2-pyrryl)-1 ,4-butanedlone (55). A solution of 54 (8.5 g, 33 mmole) in anhydrous 1,4-dioxane (70 ml) was charged with 3,4-dimethyl-5-(2-hydroxyethy|)-thiazolium iodide (1.4 g, 5 mmole) and triethylamine (1.4 ml, 10 mmole). The mixture was heated to 85°C and divinyl sulfone (1.6 ml, 16 mmole) was added dropwise. The solution was stirred at 85-90°C for an additional 20 h. The reaction was cooled, filtered and the filtrate concentrated in vacuo. The bright orange residue was extracted from water with CHZCIZ. The combined organic fractions were washed with water (2x), dried over MgSO4, and concentrated. The crude product was dissolved in a minimum amount of CH20I2 and dropwise addition of ether resulted in the precipitation of 5.1 g (60%) of 55 as a light tan powder (>95% pure by 1H-NMR). Flash column chromatography (230-400 mesh silica gel, hexane-ethyl acetate (70:30), R; 0.30) provided an analytical sample of 55 as a white solid, mp 153-154°C. 1H-NMR (CDCI3) 89.97 (br s, 2H), 4.41 (q, J=7.1 Hz, 4H), 4.35 (q, J=7.1 Hz, 4H), 3.40 (s, 4H), 2.48 (s, 6H), 1.39 (t, J=7.1 Hz, 6H), 1.34 (t, J=7.1 Hz, 6H); 13C- NMR (CDCI3) 8190.1, 163.9, 159.4, 130.8, 128.5, 121.2, 118.9, 60.2, 60.0, 34.1, 13.3, 13.2, 10.4; IR (Nujol) 3277, 1701, 1665, 1556, 1337, 1281, 1250, 1184, 1130, 1024, 870, 792, 775 cm'I; El-MS (70eV), m/z (relative intensity) 86 532 (M+, 1.2), 440 (10.7), 261 (13.8), 252 (68.6), 234 (base), 206 (68.8), 188 (56.6), 178 (65.8); HRMS (FAB) calcd for CzeHazNsz (M+H) 533.2135, found 533.2129. 2,5-BIs(3,5-dIethox’ycarbonyI-4-methyl-2-pyrryl)pyrrole (56). The same general procedure as for the formation of 488 was used. A major change in the experimental procedure was the elimination of the ultrasound treatment. Compound 55 is soluble in hot HOAc. Compound 55 (4.0 g, 7.5 mmole), NH4OAc (14.4 g, 187 mmole), acetic anhydride (5.9 ml, 62 mmole), and HOAc (100 ml) were heated at reflux for 12 h. Flash column chromatography of the crude product (200 g of 230-400 mesh silica gel, 50 mm od column, hexane-ethyl acetate (70:30), R; 0.31) yielded 2.9 g (75%) of 56 as a yellow solid, mp 163-164°C. 1H-NMR (acetone-d5) 812.57 (br s, 1H), 10.80 (br s, 2H), 6.88 (d, J=2.3 Hz, 2H), 4.33 (q, J=7.1 Hz, 4H), 4.29 (q, J=7.1 Hz, 4H), 2.60 (s, 6H), 1.32 (t, J=7.2 Hz, 12H); 13C-NMR (acetone-d5) 5166.7, 161.6, 133.5, 131.4, 124.9, 120.6, 112.9, 111.4, 61.0, 60.7, 14.7, 14.6, 12.6; IR (Nujol) 3320, 3243, 1695, 1657, 1576, 1253 cm°‘; EI-MS (706V), m/z (relative intensity) 513 (M+, 52.7), 467 (55.5), 421 (base), 330 (13.7), 274 (28.5), 165 (26.0); UV (methanol) 367 (log 6 4.46), 303.5 (4.19), 220 (4.53); HRMS (El) calcd for Cst31N309 513.2111, found 513.2057. 2,5-BIs(3,5-dIethoxycarbonyI-4-methyl-2-pyrryl)thIophene (57). The same general procedure as for the formation of 498 was used. Compound 55 (4.2 g, 7.9 mmole), Lawesson's reagent (2.1 g, 5.2 mmol), and toluene (80 ml) were heated to a gentle reflux for 4 h. Flash column chromatography of the cmde product (300 g of 230-400 mesh silica gel, 50 mm 87 od column, CHZCIZ-ethyl acetate (95:5), R; 0.36) yielded 3.2 g (76%) of 57 as a pale yellow solid, mp 146-147°C. 1H-NMR (CDCI3) 89.11 (br s, 2H), 7.42 (s, 2H), 4.32 (q, J=7.1 Hz, 4H), 4.27 (q, J=7.1 Hz, 4H), 2.59 (s, 6H), 1.34 (t, J=7.1 Hz, 6H), 1.30 (t, J=7.1 Hz, 6H); 130» NMR (CDCI3) 8164.7, 161.1, 133.8, 131.7, 130.9, 128.3, 120.2, 114.9, 60.7, 60.2, 14.4, 14.3, 12.0; IR (Nujol) 3436, 3326, 1709, 1682, 1269, 1250, 1128, 1101, 1065, 1024, 783 cm'l; El-MS (70eV), m/z (relative intensity) 530 (M+, 6.2), 484 (10.1), 438 (12.3); UV (methanol) 340 (log 64.28), 275 nm (4.21); HRMS (El) calcd for CzaHaoNanS 530.1722, found 530.1694. 2.5-Bls(3,5-diethoxycarbonyI-4-methyl-2-pyrryl)furan (58). A mixture of 55 (0.150 g, 0.28 mmole), HOAc (5 ml), and acetic anhydride (0.8 ml, 8.5 mmole) was heated to a gentle reflux for 20 h. The golden yellow solution displayed a fluorescent purple meniscus. HOAc and acetic anhydride were removed by vacuum distillation. The resulting bright yellow solid was dissolved in CH2CI2, washed with 25% NaHCOa (3x), water (1x), brine (1x), dried over M9804. and concentrated in vacuo. Flash column chromatography of the crude sample (12 g of 230-400 mesh silica gel, 20 mm od column, hexane-ethyl acetate (70:30), R; 0.24) provided 99 mg (68%) of 58 as a bright yellow solid, mp 144-145°C. 1H-NMR (acetone-d6) 811.03(br s, 2H), 7.53 (s, 2H), 4.34 (q, =7.1 Hz, 4H), 4.33 (q, J=7.1 Hz, 4H), 2.57 (s, 6H), 1.37 (t, J=7.1 Hz, 6H), 1.36 (t, J=7.1 Hz, 6H);13C-NMR (acetone-d6) 5164.9, 161.5, 145.7, 130.9, 129.6, 121.1, 115.2, 114.1, 61.0, 60.6, 14.7, 14.6, 12.4; IR (Nujol) 3324, 3254, 1701, 1670, 1286, 1259, 1140, 1101, 1074, 1024 cm'l; El-MS (706V), m/z (relative intensity) 514 (M+, 63.5), 468 (base), 422 (30.0), 321 (10.8), 249 (11.6), 166 (21.3), 149 (32.5); UV (methanol) 397 sh (log 6 4.30), 379 (4.48), 362 sh (4.41), 279 (4.40), 88 256 nm (4.35); HRMS (FAB) calcd for CzeHaoNzOg (M+H) 515.2028, found 515.2039. 2,5-BI3(4-methyI-2-pyrryl)pyrrole (59). A deaerated solution of NaOH (3N, 15 ml) in ethanol (25 ml) was charged with 56 (0.600 g, 1.2 mmole) and heated to a gentle reflux for 12 h. The reaction was cooled to room temperature and ethanol was removed in vacuo. Water and CH2CI2 were added. The aqueous layer was separated, cooled in an ice bath, and slowly acidified to pH 4 with HOAc. The resulting mixture was filtered to yield 540 mg of a black percipitate (crude tetraacid). The crude product was dried on a mechanical vacuum pump (0.05 mm Hg) overnight. Sublimation of the dry solid (200°C, 0.1 mm Hg) provided 57 mg (22%) of 59 as a white powder, mp 229-231°C. 1H-NMR (acetonitrile-dg) 8 9.15 (br s, 2H), 8.91 (br s, 1H), 6.47 (s, 2H), 6.14 (d, J=2.6 Hz, 2H), 6.10 (s, 2H), 2.06 (s, 6H); 13C-NMR (methanol-d4) 8127.3, 127.0, 119.7, 115.6, 104.9, 104.2, 11.7; El-MS (256V), m/z (relative intensity) 225 (M+, base), 210 (14.8), 111 (13.3), 97 (19.0); UV (methanol) 325 nm (log 6 4.46); HRMS (El) calcd for C14H15N3 225.1266, found 225.1281. 2,5-BIs(4-methyI-2-pyrryl)thIophene (60). The same general procedure as for the formation of 59 was used. Saponification of 57 (0.350 g, 0.56 mmole) yielded 0.285 g of crude tetraacid as a dark green solid. Sublimation (200°C, 0.1 mm Hg) provided 83 mg (52%) of 60 as a pale yellow powder, mp 237-238°C. 1H-NMR (THF-dg) 8 9.96 (br s, 2H), 6.85 (s, 2H), 6.47 (s, 2H), 6.10 (s, 2H), 2.06 (s,6H);13C-NMR (THF-dg) 5134.6, 127.5, 120.7, 120.1, 117.2, 108.1, 12.0; El- MS (256V), m/z (relative intensity) 244 (M+2, 5.7), 243 (M+1, 17.3), 242 (M+, 89 base), 149 (10.6); uv (methanol) 362 nm (log 6 4.41); HRMS (FAB) calcd for c14H14st (M+H) 243.0956, found 243.0939. 1 ,4-BIs(5-ethoxycarbonyl-3,4-dlmethyl-2-pyrryI)-1 ,4-butanedlone (63). The same general procedure as for the formation of 478 was used. A solution of 2-formyI-5-ethoxycarbonyl-4-methylpyrrole (62) (0.313 g, 1.6 mmole) in absolute ethanol (4 ml) was charged with 3,4-dimethyI—5-(2- hydroxyethyl)-thiazolium iodide (0.065 g, 0.23 mmole) and triethylamine (0.06 ml, 0.43 mmole). The mixture was heated to a gentle reflux and divinyl sulfone (0.074 ml, 0.74 mmole) was added. After refluxing for an additional 22 h, the reaction was cooled to room temperature and filtered to provide 88 mg of 63 as a white powder (>95% pure by 1H-NMR). The filtrate was extracted from water with CHCIa. The combined organic fractions were washed with water (2x), brine (1x), dried over N82804, and concentrated in vacuo. Flash column chromatography of the crude residue (22 g of 230-400 mesh silica gel, 30 mm od column, hexane-ethyl acetate (77:23)) yielded 56 mg (18%) of recovered 62, 17 mg (4%) of 2,5-diethoxycarbonyI-3,4-dimethylpyrrole, and 15 mg of 63 (R; 0.25, mp 173-174°C). Total yield of 63: 103 mg (33%). Compound 63: 1H-NMR (CDCI3) 8 9.55 (br s, 2H), 4.32 (q, J=7.1 Hz, 4H), 3.22 (s, 4H), 2.32 (s, 6H), 2.26 (s, 6H), 1.34 (t, J=7.1 Hz, 6H); 13C-NMR (CDCI3) 8 189.7, 161.0, 130.1, 127.4, 125.8, 122.5, 60.6, 34.2, 14.4, 11.3, 10.0; IR (CDCI3) 3440, 1698, 1647, 1453, 1257, 1245, 1189 cm'I; EI-MS (708V), m/z (relative intensity) 416 (M+, 2.6), 368 (4.3), 250 (7.8), 222 (19.9), 176 (20.1), 148 (31.3), 115 (29.1), 73 (base); IRMS (El) calcd for 022H28N205 416.1947, found 416.1949. 90 2.5-BIs(5-ethoxycarbonyl-3,4-dImethyl-2-pyrryl)thlophene (64). The same general procedure as for the formation of 498 was used. Compound 63 (0.041 g, 9.8 x 10'2 mmole), Lawesson's reagent (0.026 g, 6.4 x 10’2 mmole), and toluene (5 ml) were heated to a gentle reflux for 5 h. Flash column chromatography of the crude product (5 g of 230-400 mesh silica gel, 15 mm od column, hexane-ethyl acetate (77:23), R;0.33) yielded 30 mg (73%) of 64 as a golden yellow solid, mp 200-201°C. 1H-NMR (CDCI3) 58.82 (br s, 2H), 7.10 (s, 2H), 4.32 (q, J=7.1 Hz, 4H), 2.29 (s, 6H), 2.17 (s, 6H), 1.35 (t, J=7.1 Hz, 6H); 1i’tC-NMR (CDCI3) 8 161.6, 133.5, 128.2, 126.5, 124.3, 119.0, 118.9, 60.1, 14.6, 10.5, 10.2; IR (CHCI3) 3450, 1678, 1519, 1270 cm°1; EI-MS (706V), m/z (relative intensity) 416 (M+2, 1.3), 414 (M+, 51.4), 368 (68.2), 322 (65.3), 171 (39.2), 169 (37.7), 129 (26.0), 103 (51.1), 97 (32.9), 85 (41.8), 73 (71.5), 57 (base); UV (methanol) 366 (log 6 4.30), 252 (3.90), 237 (4.04), 219 nm (4.08); HRMS (El) calcd for 022H26N204s 414.1613, found 414.1598. Attempted Preparation of 2,5-Bls(5-ethoxycarbonyl-3,4-dlmethyl-2- pyrryl)pyrrole. Synthesis of 2,5-BIs(5-ethoxycarbonyI-3,4-dImethyl- 2-pyrryl)furan (65). The same general procedure as for the formation of 56 was used. 1,4-Diketone 63 (0.038 g, 9.2 x 10'2 mmole), NH4OAc (0.148 g, 1.9 mmole), acetic anhydride (0.18 ml, 1.9 mmole), and HOAc (5 ml) were heated at reflux for 12 h. The reaction was cooled to room temperature and then to 0°C. Cold NaOH (2.5 N) was slowly added to neutralize the solution. 30 mg of a pale green solid precipitated out and was collected by filtration. Flash column chromatography of the crude product (3 g of 230-400 mesh silica gel, 15 mm od column, hexane-ethyl acetate (85:15 to 75:25)) yielded 14.3 mg 91 (39%) of 65 as a white solid, mp 154-156°C dec. 9 mg (23%) of 63 was recovered. Compound 65: R; 0.44 (hexane-ethyl acetate (85:15)); 1H-NMR (acetone-d5) 8 10.42 (br s, 2H), 6.74 (s, 2H), 4.28 (q, J=7.1 Hz, 4H), 2.28 (s, 6H), 2.17 (s, 6H), 1.32 (t, J=7.1 Hz, 6H); 13C-NMR (acetone-d6) 5 161.7, 146.4, 127.7, 124.7, 119.7, 118.0, 108.6, 60.0, 14.6, 10.3, 9.9; El-MS (706V), m/z (relative intensity) 399 (M+1, 22.2), 398 (M+, 89.6), 352 (base), 306 (85.2), 149 (10.0), 105 (9.73); UV (methanol) 397 (sh), 375, 274 nm; HRMS (El) calcd for szstNgos 398.1842, found 398.1849. Condensation of 1,4-BIs(3,5-diethoxycarbonyl-4-methyI-2-pyrryl)- 1,4-butanedlone (55) with 1,4-Phenylenedlamlne (Method A). A mixture of 55 (0.250 g, 0.47 mmole), HOAc (11 ml) and 1,4-phenylenediamine (0.024 g, 0.22 mmole) was heated at a gentle reflux for four days. The fluorescent green solution was cooled to room temperature and the majority of HOAc was removed by vacuum distillation. The residue was extracted from NaHCOa (sat.) with CHZCIZ. The combined organic fractions were washed with NaHCOa (sat., 1x), water (2x), dried over M9804, and concentrated in vacuo. Flash column chromatography of the crude sample (30 g of 230-400 mesh silica gel, 30 mm od column, gradient elution hexane-ethyl acetate (75:25 to 20:80) provided 38 mg (16%) of 70 as a white solid (mp 244.5-245.5°C) and 60 mg (42%) of 69 as a light tan solid. Compound 70: R; 0.30 (hexane-ethyl acetate (60:40)); 1H-NMR (acetone-d6) 8 10.96 (br s, 4H), 6.70 (s, 4H), 6.27 (s, 4H), 4.26 (q, J=7.1 Hz, 8H), 3.80 (q, J=7.1 Hz, 8H), 2.48 (s, 12H), 1.30 (t, J=7.1 Hz, 12H), 1.02 (t, J=7.1 Hz, 12H); 13C-NMR (acetone-d6) 8 164.0, 161.5, 137.8, 131.7, 130.5, 126.7, 126.6, 120.8, 117.4, 112.6, 60.5, 59.6, 14.7, 14.6, 11.9; FAB-MS, m/z (relative 92 intensity) 1100 (M+, 35), 460 (10), 307 (54), 154 (base); uv (acetonitrile) 293 (sh), 269, 216 nm; HRMS (El) calcd for CsaH54N3016 1100.4378, found 1100.4377. Compound 69: R; 0.46 (hexane-ethyl acetate (30:70)); 1H-NMR (acetone-d5) 8 10.90 (br s, 2H), 9.09 (br s, 1 H), 7.42 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 6.41 (s, 2H), 4.24 (q, J=7.1 Hz, 4H), 3.95 (q, J=7.1 Hz, 4H), 2.42 (s, 6H), 2.00 (s, 3H), 1.28 (t, J=7.1 Hz, 6H), 1.11 (t, J=7.1 Hz, 6H); 1‘fC-NMR (acetone-d6) 8 168.8, 164.4, 161.4, 139.4, 134.0, 131.9, 129.9, 128.5, 126.9, 120.6, 119.0, 117.3, 112.4, 60.5, 59.8, 24.2, 14.65, 14.60, 11.8; El-MS (259V), m/z (relative intensity) 647 (M+1, 4.4), 379 (6.9), 149 (24.3), 129 (25.1), 111 (25.8), 97 (46.9), 85 (72.1); UV (acetonitrile) 299, 264, 249, 214, 204 nm. Two-Step Preparation of 70 (Method B). A solution of 55 (0.100 g, 0.19 mmole) in toluene (8 ml) was charged with a catalytic amount of anhydrous p- toluene sulfonic acid (0.015 g, 0.088 mmole), an excess of 1,4- phenylenediamine (0.070 g, 0.65 mmole) and heated at a gentle reflux for 20 h. A precipitate formed upon cooling the solution to room temperature. Filtration provided 0.105 g of a tan solid which was cast into hexanezethyl acetate (60:40). A small amount of compound did not dissolve and the sample was filtered a second time. The resulting tan powder was identified as starting material 55 (20 mg, 20%). The filtrate was concentrated in vacuo and purified by flash column chromatography (12 g of 230-400 mesh silica gel, 20 mm od column, hexane-ethyl acetate (60:40)) to provide 81 mg (72%) of 71 as a white solid, mp 191-193°C. Compound 71: R; 0.32 (hexane-ethyl acetate (60:40)); 1H-NMR (acetone-d5) 8 10.5 (br s, 2H), 6.69 (m, 2H), 6.42 (m, 2H), 6.40 (s, 2H), 4.65 (br s, 2H), 4.21 (q, J=7.1 Hz, 4H), 4.00 (q, J=7.1 Hz, 4H), 2.43 (s, 6h), 1.27 (t, J=7.1 Hz, 6H),. 93 1.16 (t, J=7.1 Hz, 6H); 13C-NMR (acetone-d6) 8 164.7, 161.3, 148.6, 132.1, 129.9, 129.0, 128.3, 127.0, 120.3, 117.2, 114.5, 112.2, 60.5, 59.8, 14.6, 14.5, 11.8; El-MS (25eV), m/z (relative intensity) 604 (M+, 6.6), 558 (2.2), 512 (0.2), 85 (base); UV (acetonitrile) 298,274, 245, 213, 202 nm. A solution of 71 (0.070 g, 0.12 mmole) in toluene (6 ml) was charged with a catalytic amount of p-toluenesulfonic acid (0.007 g, 0.004 mmole) and an excess of 55 (0.185 9, 0.35 mmole) and heated at a gentle reflux for 18 h. Flash column chromatography provided 53 mg (42%) of 70 as a white solid (mp 244.5-245.5°C) and 11 mg (16%) of recovered 71. Overall yield of 70 by the two-step procedure: 30%. Condensation of 3b to 72. A deaerated solution of 3b (0.084 g, 0.39 mmole) in CHQCIZ (60 ml) was charged sequentially with p-tolualdehyde (0.046 ml, 0.39 mmole) and BF3(0Et)2 (0.07 ml of 0.25M solution, 1.8 x 10'2 mmole). The solution slowly turned from a golden yellow color to a transparent forest green color. The reaction was allowed to stir at room temperature for five days with periodic monitoring of the reaction by thin-layer chromatography (tlc). A new spot formed on the tlc plate, but a significant amount of starting material remained. The reaction was cast into H20 and extracted with CHZCIZ (2x). The combined organic fractions were dried over M9804 and then concentrated in vacuo. Flash column chromatography of the crude sample (10 9 of 230-400 mesh silica gel, 20 mm od column, CHZCIZ) provided 34 mg (40%) of recovered 3b and 19 mg (18%) of 72 as a light green solid. Compound 72: R;0.33 (CHZCIZ); 1H-NMR (acetone-d6) 8 10.40 (br s, 2H), 10.28 (br s, 2H), 7.13 (s, 2H), 7.12 (s, 2H), 7.0 (s, 4H), 6.79 (m, 2H), 6.27 (m, 2H), 6.21 (m, 2H), 6.11 (m, 2H), 5.72 (m, 2H), 5.41 (s, 1H), 2.30 (s, 3H); 130- NMR (acetone-d6) 8 141.0, 137.0, 136.3, 134.8, 134.3, 129.9, 129.6, 127.7, 94 127.3, 121.9, 121.6, 119.8, 110.3, 109.8, 107.0, 106.9, 44.6, 21.0; FAB-MS, m/z (relative intensity) 532 (M42, 6), 531 (M+1, 12), 530 (M+, 17), 460 (5), 317 (16), 307 (37), 289 (11), 154 (base); UV (acetonitrile) 386 (sh), 365, 234 (sh), 210 nm. 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"-1 ”film..— Lora-’— 140 K 252.685 6252.... 122-1. ~12 eem .m4< 4521 2&0 F.—....—..-—-....-..— .- 0 Ow « ..—.... ”En-m...-[rm-eeupmpmw fl \II‘ J W , M u __ a .4 U a 19 J 0 fl .- 19 ._|\\\II t \ 141 .u. :- 25868 5 62525 122-02 ~12 4mm 00 00. 0.6.. 0: 00. 00a .54... Seer. 000 000 142 ~0- 9.581.008 1.2.02.0 1.22-1. ~15. com .e4< 552“. 143 u.- 25868 5 62525 122-02 ~12 4.? 2n... 0 00 02 00 00 00. 0.... 0... 00— 00. .8... 552“. 00w 000 53.. 54412.44fi43. I .1... e453 24 .. .5... _._... a 3433...... 2.514.... 24.44.... LIST OF REFERENCES LIST OF REFERENCES (a)Skotheim TA Ed MW Dekker: New York, 1986; (b) Cowan, 0.0.; Wiygul, F. M. Chem Eng. News, July 21, 1986, pp 28-45; (c) Reynolds, J. R. Chemtech, 1988, 18,440. Brédas, J.L.; Street, G.B. Aoc. Chem. Res. 1985, 18,309. (a) Chiang, C.K.; Drury, M.A.; Gau, S.C.; Heeger, A.J.; Louis, E.J.; MaoDiarmid, A.G.; Park, Y.W.; Shirakawa, H. J. Am. Chem. Soc. 1978, 100,1013;(b)BasescuN.;Liu,Z.-.;X Moses, 0.; Heeger, A..;J Naarmann, H.; Theophilou, N. 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