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"a. ‘14-}; 1" ll‘ 20(03633 LIBRARY Michigan State University This is to certify that the dissertation entitled SYNTHESIS OF LINEAR a—POLYFURANS AND SYNTHETIC APPROACHES TO POLYFURAN MACROCYCLES presented by Wai—Yee Leung has been accepted towards fulfillment of the requirements for Ph.D degree in ChemistQL [gm/W / Major profetgor Date / @MSZ _/7¢€) )2 MSU is an Affirmative Action/Equal Opportunity Institution 012771 1V1ESI~J RETURNING MATERIALS: Place in book drop to LJBRARJES remove this checkout from .—:—. your record. FINES will be charged if book is returned after the date stamped.below. SYNTHESIS OF LINEAR a-POLYFURANS AND SYNTHETIC APPROACHES TO POLYFURAN MACROCYCLES BY Wai-Yee Leung A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1988 ABSTRACT SYNTHESIS or LINEAR a-POLYFURANS SYNTHETIC APPROACHES TgDPOLYEURAN MACROCYCLES By Wai-Yee Leung The synthesis and the Chemical properties of a-polyfurans are described. The conversion of a-terfuran 12 to the [26]annulene hexoxide 9 and macrocyclic a-polyfuran 10 has been investigated. The 1,4-diketone precursors to a—polyfurans were prepared in the following ways: 1) Michael addition of aldehydes to Mannich bases, 2) Michael addition of aldehydes to vinyl sulfone and 3) nucleophilic addition of organolithium compounds to N,N,N',N'-tetramethylsuccinamide 19. Cyclization of the 1,4—diketones by acid catalyst gave the a-polyfurans in fair yields. The a—polyfurans showed electrophilic and nucleo- philic properties from which various monosubstituted and disubstituted derivatives can be obtained. Condensation of the open-Chain furan compound 55a with benzaldehyde or 55b with anisaldehyde in the presence of Lewis acid yielded a mixture of macrocyclic oligomers 42c or 42d. Oxidation of 42c or 42d to the 26 weelectron annulene hexoxide 9 was not successful. Due to the solubility problem of the oligomeric intermediate which decreased rapidly as the molecular weight Wai-Yee Leung increases, the synthesis of the macrocyclic a-polyfuran 10 from the simple precursors was also not successful. To my wife, Ching-ying for her love, support and understanding. iv ACKNOWLEDGEMENTS The author is greatly indebted to Professor Eugene LeGoff for his patience, guidance and encouragement during the course of research. He is also thankful to Michigan State University for the financial support in the form of teaching assistantship and to Professor Eugene LeGoff for the research assistantship during the last two summer terms. TABLE OF CONTENTS LIST OF TABLES . . . . . . . . . . . . . . LIST OF FIGURES. . . . . . . . . . . . . . INTRODUCTION . . . . . . . . . . . . . . . Scheme 1 . . . . . . . . . . . . . . . Scheme 2 . . . . . . . . . . . . . . . Scheme 3 . . . . . . . . . . . . . . . RESULTS AND DISCUSSION A. Synthesis of linear a-polyfurans. Scheme 4 . . . . . . . . . . . . . . . Scheme 5 . . . . . . . . . . . . . . . Scheme 6 . . . . . . . . . . . . . . . Scheme 7 . . . . . . . . . . . . . . . Scheme 8 . . . . . . . . . . . . . . . Scheme 9 . . . . . . . . . . . . . . . Scheme 10. . . . . . . . . . . . . . . Scheme 11. . . . . . . . . . . . . . . Scheme 12. . . . . . . . . . . . . . . Scheme 13. . . . . . . . . . . . . . . Scheme 14. . . . . . . . . . . . . . . Scheme 15. . . . . . . . . . . . . . . SCheme 1 6 O O O O O O O O O O O O O O 0 vi PAGE xiii xiv 10 11 13 13 18 19 19 20 20 23 24 25 PAGE Scheme 17. . . . . . . . . . . . . . . . . . . . . 25 Scheme 18. : . . . . . . . . . . . . . . . . . . .g 27 B. Synthesis of novel macrocyclic a-polyfurans I. Studies towards the synthesis of [26]annulene hexoxide 9 . . . . . . . . . . . 29 Scheme 19. . . . . . . . . . . . . . . . . . . . . 29 Scheme 20. . . . . . . . . . . . . . . . . . . . . 30 Scheme 21. . . . . . . . . . . . . . . . . . . . . 31 Scheme 22. . . . . . . . . . . . . . . . . . . . . 31 Scheme 23. . . . . . . . . . . . . . . . . . . . . 32 Scheme 24. . . . . . . . . . . ... . . . . . . . . 33 Scheme 25. . . . . . . . . . . . . . . . . . . . . 33 Scheme 26. . . . . . . . . . . . . . . . . . . . . 34 Scheme 27. . . . . . . . . . . . . . . . . . . . . 35 Scheme 28. . . . . . . . . . . . . . . . . . . . . 37 Scheme 29. . . . . . . . . . . . . . . . . . . . . 40 Scheme 30. . . . . . . . . . . . . . . . . . . . . 41 Scheme 31. . . . . . . . . . . . . . . . . . . .». 42 Scheme 32. . . . . . . . . . . . . . . . . . . . . 43 Scheme 33. . . . . . . . . . . . . . . . . . . . . 53 II. Studies towards the synthesis of cyclic a-polyfuran 10 . . . . . . . . . . . . . . . 54 Scheme 34. . . . . . . . . . . . . . . . . . . . . 55 Scheme 35. ... . . . . . . . . . . . . . . . . . . 55 Scheme 36. . . . . . . . . . . . . . . . . . . . . 56 CONCLUSION . . . . . . . . . . . . . . . . . . . . . . S7 vii PAGE EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . 58 General Methods . . . . . . . . . . . . . . . . .7 58 N,N,N',N'-Tetramethylsuccinamide 19 . . . . . . . 59 Methyl N,N-dimethylcarbamate 38 . . . . . . . . . 6O 3—Dimethylamino-1-(2-furyl)-propanone 15a . . . . 6O 3-Dimethylamino-1-(5-2,2'-bifuryl)-pr0panone 15b . 61 General Procedure . . . . . . . . . . . . . . . . 62 5,8-Dodecanedione 20 . . . . . . . . . . . . . . . 62 1,4-Diphenyl-1,4—butanedione 21 . . . . . . . . . 63 1,4-Bis(2—thienyl)-1,4—butanedione 22 . . . . . . 63 1,4-Bis(2—furyl)—1,4-butanedione 16a . . . . . . . 63 1—(2-Furyl)—4-(5-2,2'—bifuryl)-1,4-butanedione 16b. 64 1,4-Bis(5-2,2'-bifuryl)-1,4abutanedione 16c . . . 6S 1-(2-Furyl)-4-(5-2,2':5',2"-terfuryl)- 1,4-butanedione 16d . . . . . . . . . . . . . . . 57 1-(5-2,2'-Bifuryl)—4-(5-2,2':5',2"-terfuryl)- 1,4-butanedione 16e . . . . . . . . . . . . . . . 68 1-(2-Fury1)-4-(5-2,2':5',2":5",2"'-quaterfuryl)- 1,4-butanedione 16f . . . . . . . . . . . . . . . 68 1-(5-2,2'-Bifuryl)-4—(5-2,2':5',2":5",2"'- quaterfury1)-1,4-butanedione 169 . . . . . . . . 69 1,4-Bis(5-2,2':5',2"-terfuryl)- 1,4-butanedione 16h . . . . . . . . . . . . . . . 70 1,4-Bis(5-2,2':5',2":5",2"'—quaterfuryl)- 1,4-butanedione 161 . . . . . . . . . . . . . . . 71 viii PAGE 2,2'-Bifuran 11 . . . . . . . . . . . . . . . . . 72 2,2':5',2"-Terfuran 12 . . . . . . . . . . . . . . 72 2,2':5',2":5",2"'-Quaterfuran 13 . . . . . . . . 73 2,2':5',2":5",2"':5"',2""-Quinquefuran 23 . . 74 2,2':5',2":S",2"':5"',2"":5'"',2""'- seXifuran 24 O O O C O O O O O O . O O . C . O O O 75 2,2':5',2":5",2"':5"',2"":5"",2""' 5""',2"""-Septifuran 25 . . . . . . . . . . . 77 2,5-Bis(2-furyl)-thiophene 26 . . . . . . . . . . . 77 2,5-Bis(5-2,2'—bifuryl)-thiophene 27 . . . . . . . 78 2,5-Bis(5-2,2':5',2"-terfuryl)-thiophene 28 . . . 78 2,5-Bis(2-furyl)-Pyrrole 29 . . . . . . . . . . . 79 2,5-Bis(5-2,2'-bifuryl)—pyrrole 30 . . . . . . . . 79 2,5-Bis(5-2,2':5',2"-terfuryl)-pyrrole 31 . . . . 30 S-Formyl-2,2'-bifuran 14b . . . . . . . . . . . . 31 5-Formyl-2,2':5',2"-terfuran 14c . . . . . . . . . 82 5-Formyl-2,2':5',2":5",2"'-quaterfuran 14d . . . 83 5-Formyl-2,2':5',2":5",2"':5"',2""- quinquefuran 14e . . . . . . . . . . . . . . . . . 84 5-Bromo-5'-formyl-2,2'-bifuran 32a . . . . . . . . 84 S-Bromo-S"-formyl-2,2':S',2"-terfuran 32b . . . . 85 5-Bromo-5"'-formyl-2,2':5',2":5",2"'- quaterfuran 32c . . . . . . . . . . . . . . . . . 86 5-Bromo-5"'1-formyl-2,2':5',2":5",2"':5"',2""- quinquefuran 32d . . . . . . . . . . . . . . . . . 87 5,5'-Diformyl-2,2'—bifuran 33a . . . . . . . . . . 87 ix 5,5"-Diform l-2,2':5',2"-terfuran 33b . Y 5,5"'-Diformy1-2,2':S',2":5",2'"-quaterfuran 33C 0 O O O O O C O O C C C O O O O C O . O . S'slIiI_Diformyl-2'2l:sl'211:5!l'21li:slUI’ZOIII_ QUinquefuran 33d 0 o o o o o o o o O o 0 5,5'-Dibromo-2,2'-bifuran 34a . . . . . . 5,5"-Dibromo-2,2':5',2"-terfuran 34b . 5,5"'-Dibromo-2,2':5',2":5",2'"-quaterfuran 5-Acetyl-2,2'-bifuran 17b and 5,5'-diacetyl—2,2'-bifuran 37a . . . . . S—Acetyl—2,2':5',2"-terfuran 17c and 5,S"-diacetyl-2,2':5',2"-terfuran 37b . 5-Benzoyl-2,2'-bifuran 36a and 5,5'-dibenzoyl-2,2'—bifuran 37c . . . . 5-Benzoyl-2,2':S',2"-terfuran 36b and 5,S"-dibenzoyl-2,2':5',2"-terfuran 37d 5-(4-Methoxybenzoyl)-2,2'-bifuran 36c and 5,5'-di-(4-methoxybenzoyll-2,2'-bifuran 37e 5-(4-Methoxybenzoyl)-2,2':5',2"-terfuran 36d and 5,5"-di-(4-methoxybenzoyl)-2,2‘:5'2"-terfuran Bis(5-2,2'-bifuryl) ketone 39a . . . . . Bis(5-2,2':S',2"-terfuryl) ketone 39b . 5,5'-d-2,2'-Bifuran 40a . . . . . . . . 5,5"-d-2,2':5',2"-Terfuran 40b . . . . 5,5"'-d-2,2':5',2":5",2"'-Quaterfuran S,5'-Dimethyl-2,2'-bifuran 41a . . . . . X 37f. PAGE 88 88 89 90 90 91 91 93 94 95 96 98 99 100 100 101 101 102 5,5"-Dimethyl-2,2':S',2"-terfuran 41b . . . . . 5,5'"-Dimethyl-2,2':5',2":S",2"'-quaterfuran 41c . . . . . . . . . . . . . . . . . . . . . . . 5,S"-Dibenzoyl-2,2':5',2"—terfuran 37d . . . . 2,2-Bis(S-formyl-Z-furyllpropane 44 . . . . . . . 2,2—Bis(S-acetyl-Z-furyl)propane 47 . . . . . . . Bis-Mannich base 45 . . . . . . . . . . . . . . 2-Furyl-(S—formyl-Z-furyll-Z,2—propane 50 . . . . 1,4-Bis(2,2-difurylpropane)-1,4-butanedione S1. . PAGE . 103 . 103 . 104 . 104 . 105 . 106 .107 .108 5,5"-Bis(dimethylfurfuryl)2,2':5',2"—terfuran 52,109 5,5"-Bis(S-formyl-dimethylfurfuryl)-2,2':5',2" terfuran 48 . . . . . . . . . . . . . . . . . . . 5,5"-Bis(S-acetyl-dimethylfurfuryl)-2,2':5',2" terfuran 53 . . . . . . . . . . . . . . . . . . . Cyclization of 14c to 42b . . . . . . . . . . . . Cyclization of a—terfuran 12 with benzaldehyde to 42c . . . . . . . . . . . . . . . . . . . . . Phenylbis(5-2,2':5',2"-terfuryl)methane 55a and 5,5"-bis(pheny1(5-2,2':5',2"-terfuryl)methyl)— terfuran 56a . . . . . . . . . . . . . . . . . . 4-Methoxyphenylbis(S-2,2':5',2"-terfuryl)methane 55b and 5,5"-bis(4-methoxyphenyl-(5-2,2':5',2"- terfuryl)methyl)—terfuran 56b . . . . . . .l. . . Cyclization of 55a with benzaldehyde to 42c . . . Cyclization of 55b with 4-methoxybenzaldehyde to 42d 0 O O O O O O O O O O O C O O O O O O O O O 0 xi ~109 .110 .112 113 .114 .115 APPENDIX . . . . . LIST OF REFERENCES xii TABLE LIST OF TABLES PAGE 1,4-Diketones from aldehyde and Mannich base. . . 12 1,4-Diketones from aldehyde and vinyl sulfone . . 14 Yields of products from the reaction bewteen organolithium compounds with N,N,N',N'-tetramethyl- diamide . . . . . . . . . . . . . . . . . . . . 15 Yields of products from the reaction bewteen organolithium compounds with N,N,N',N'-tetramethyl- succinamide 19 . . . . . . . . . . . . . . . . . 15 Polyfurans by ring closure of 1,4-diketone . . . 18 UV spectrum data (the highest xmax value) of a-polyfurans . . . . . . . . . . . . . . . . . . 21 UV Spectrum data (the highest Améx value) of appolyaryls . . . . . . . . . . . . . . . . . . . 22 Yields of monoketones and diketones from the reaction bewteen the lithiated compounds of a-bi and a-terfuran with N,N-dimethylamides . . . 26 Yields of disubstituted products from the reaction bewteen the dianion of a-polyfurans with various electrophiles. . . . . . . . . . . . 28 xiii FIGURE 1 10 11 A1 LIST OF FIGURES The delocalization energy (in13) calculated by the HMO and Pople-Pariser-Par approximations for monocyclic conjugated systems . . . . . . . 250 MHz 1H NMR spectrum of 42b . . . . ... . . 62.9 MHz 13C NMR spectrum of 42b . . . . . . . 250 MHz 1H NMR spectrum of PhenylbiS(5—2,2':5',2"—terfuryl)methan _55a . 250 MHz 1H NMR spectrum of 42c . . . . . . . . 62.9 MHz 13C NMR spectrum of phenylbis(5-2,2':5',2"-terfuryl)methane 55a . 62.9 MHz 13C NMR spectrum of 42c . . . . . . . 250 MHz 1H NMR spectrum of PAGE 44 , 46 4-methoxyphenylbis(5-2,2':5',2"-terfuryl)methane 55b O O O O O O O O O O O O O O O O O O O O O O 250 MHz 1H NMR Spectrum of 42d . . . . . . . . 62.9 MHz 13C NMR spectrum of . 49 . 50 4-methoxyphenylbis(5-2,2':5',2"-terfury1)methane 55b O O O O O O O O O O, O O O O O O O O O O O O 13 62.9 MHz C NMR spectrum of 42d . . . . . . . 250 MHz 1H NMR spectrum of 1-(2-fury1)- 4-(5-2,2'-bifuryl)-1,4-butanedione 16b . . . . xiv . 51 . 52 .116 FIGURE PAGE A2 250 MHz 1H NMR spectrum of 1,4-bis(5-2,2'- bifuryl)-1,4—butanedione 16c . . . . . . . . . . 117 1 A3 250 MHz H NMR spectrum of 1—(2-furyl)- 4-(5-2,2':5',2"-terfuryl)-1,4-butanedione 16d . 118 1 A4 250 MHz H NMR spectrum of 1-(5-2,2'-bifuryl)- 4-(5-2,2':5',2"—terfuryl)-1,4-butanedione 16e . 119 AS 250 MHz 1H NMR spectrum of 1-(2-furyl)— 4-(5-2,2':5',2":5",2"'-quaterfuryl)- 1,4-butanedione 16f . . . . . . . . . . . . . . 120 A6 250 MHz 1H NMR spectrum of 1—(5-2,2'-bifuryl)- 4-(5-2,2':5',2":5",2"'-quaterfuryl)- 1,4-butanedione 16g . . . . . . . . . . . . . . 121 1 A7 250 MHz H NMR spectrum of 1,4-bis(5-2,2':5',2"- terfuryll-l,4-butanedione 16h . . . . . . . . . 122 A8 250 MHz 1H NMR spectrum of 2,2':5',2":5",2"'- quaterfuran 13 . . . . . . . . . . . . . . . . . 123 1 A9 250 MHz H NMR spectrum of 2,2':5',2":5",2"' 5"',2""-quinquefuran 23 . . . . . . . . . . . 124 1 A10 250 MHz H NMR spectrum of 2,2':5',2":5",2"' 5"‘,2"":5"",2""'-S€Xifuran 2‘ o o o o o o 125 A11 250 MHz 13 NMR spectrum of 2,5-bis(2-fury1)- thiophene 26 . . . . . . . . . . . . . . . . . 126 A12 250 MHz 1H NMR spectrum of 2,5-bis(5-2,2'- bifurYI)-thiophene 27 o o o o o o o o o o o o o 127 A13 250 MHz 1 H NMR spectrum of 2,5-bis(S—2,2':5',2"_ terfuryl)-thiophene 28 . . . . . . . . , , , , . 123 XV FIGURE A14 A15 A16 A17 A18 A19 A20 A21 A22 A23 PAGE 250 MHz 1H NMR spectrum of 2,5-bis(2-furyl)- pyrrole 29 . . . . . . . . . . . . . . . . . . . 129 250 MHz 1H NMR spectrum of 2,5-bis(5-2,2'- bifury1)-pyrr01e 30 o o o o o o o o o 0 o o o o 130 1 250 MHz H NMR spectrum of 2,5-bis(5-2,2'- bifuryl)-pyrrole 30 in DMSO-d . . . . . . . 131 1 6 O O 250 MHz H NMR spectrum of 2,5—bis(5-2,2':5',2"- terfuryl)-pyrrole 31 in DMSO-d6 . . . . . . . . 132 1 250 MHz H NMR spectrum of 5,5'-bis(5—formyl- dimethylfurfurylk2,2':5',2'tterfuran 48 . . . . 133 1 250 MHz H NMR spectrum of 5,5'-bis(S-acetyl- dimethylfurfuryl)-2,2':S',2"-terfuran 53 .. . . 134 1 250 MHz H NMR spectrum of 42c from the reaction bewteen a-terfuran 12 and benzaldehyde at 1X10-2 M O O O O O O O O O O O O O O O O O O 135 13 62.9 MHz C NMR spectrum of 42c from the reaction bewteen a-terfuran 12 and benzaldehyde at 1X10-2 M O O O O O O O O O O O O O O O O O O 136 1 250 MHz H NMR spectrum of 1,4-bis(2,2- difurylpropanel-1,4-butanedione 51 . . . . . . . 137 1 250 MHz H NMR Spectrum 5,5"-bis(dimethy1- furfuryl)-2,2':5',2"-terfuran 52 . . . . . . . 138 xvi INTRODUCTION At an early stage in organic chemistry the Characteristic differences in physical properties and chemical reactivity bewteen benzenoid hydrocarbons and their acyclic analogues led Kekule1 to make his fundamental studies on the structure of benzene. Since that time, the theory of "aromatic Character" has attracted the interest of organic chemists to an ever increasing degree. Alongside the benzenoid compounds numerous non-benzenoid heterocyclic and carbocyclic systems with very similar properties have appeared, which have robbed the Classical aromatic substance, benzene, of its special position and have necessitated a wider and deeper definition of the concept of ”aromatic character". The theory of "aromatic character" has thereby undergone manifold changes. The empirical generalization of the "aromatic sextet"2 was followed by Huckel's rule,3 which was based upon quantum mechanical considerations. According to this rule, it predicts that those fully conjugated, planar, monocyclic polyolefins with [4n+2] 1r-electrons, where n is an integer, will have properties similar to those of benzene whereas those with [4n] r-electrons will not possess any aromatic stability. A shortcoming of this HMO theory is that it also predicts a sizable resonance energy for 1 2 cyclobutadiene and cyclooctatetraene even though this is not the case as proved experimentally [Figure 1]. Figure 1. The delocalizatioa energy (infi) calculated by the HMO and Pople- Pariser-Parr approximations for monocyclic conjugated systems. To solve the quantitative discrepancies bewteen the theoretical and experimental results from the HMO method, Dewar4 derived the resonance energy by using the Pople- Pariser-Par (PPP) approximation. From this calculation, 3 the [4n] system now have negative resonance energy and localized double bond whereas the [4n+2] system possesses positive resonanCe energy and is delocalized [Figure 1]. It also indicates that the Huckel's rule should break down at higher value of n, with the onset of bond alternations and zero resonance energy, and it has been predicted that the limit should lie bewteen [22] and [26]annulenes.4 In order to provide an experimental test of these predictions, Sondheimer and his collaborators began, in 1965, to investigate the preparation of a number of annulenes. Using the proton NMR as the diagnostic test for aromaticity, 6 [18]7 and [22]8 annulenes were it was found that [14], diatropic while [24]annulene9 was paratropic. The [26] and [28]annulenes have not been synthesised and although [30]annulene1O has been prepared, its NMR spectrum was not studied. A monodehydro[26]annulene11 has been synthesized and this compound did show a diamagnetic ring current. However, a tridehydrol26lannulene12 has also been synthesized which showed no ring current effect. So there is still some argument as to whether or not a 26 r-electron system is aromatic. A problem associated with these large ring monocyclic compounds is their conformational mobility which might not give any diatropic effect if the molecules are in a non-planar conformation. An ideal molecule for aromatic study should have a rigid and planar framework. This can be achieved if pairs of internal hydrogen atoms in the annulenes are replaced by 4 heteroatoms. In this case, the peripheral conjugation is not perturbed significantly and again systems containing [4n+2] peripheral reelectrons exhibit aromaticity. Perhaps the best known example for this class is the porphrin molecule 1. Porphyrins are stable 18 r-electron systems and aromatic in character. The expansion of the porphyrin macrocycle to [22] and [26]platyrins, 213 and 314, by formally inserting three and five carbons atoms between the pyrrolic rings has been reported from this laboratory. Both 2 and 3 Showed signifi- cant diamagnetic ring current in an applied magnetic field. Besides nitrogen, the use of oxygen as the bridging atom has 5 and the also been studied. The [18]annulene trioxide 41 [18]annulene dioxide 516 have proved to be aromatic while the [24]annulene mazaoxide 617 was anti-aromatic. Macrocycles 7 and 8 that contained furan and pyrrole rings have been synthesized18 and also found to be diatropic. Because the literature contains so few 26 or more r—electron systems, a study of their synthesis would provide a better understanding of the concept of aromaticity. The compounds of interest in the present study are the [26]annulene hexoxide 9 and cyclic a-polyfuran 10. While the furan ring imposes the rigidity to the carbon framework, molecular model of 9 reveals that the compound can adapt a planar conformation without much steric and angle strain, hence this might lead to cyclic delocalization and a peripheral diamagnetic ring current. For the class of compounds such as 10, they might provide some insight as to Me No R R R R R R R MC 7 R=Me, Et 8 R=Me, Et what stage (if at all) a [4n] r-electron system will cease to be paratropic. R = H, alkyl or aryl \ C _. I A Closer look at 9 shows that it consists of the a-terfuran structural unit while 10 actually is the cyclic form of linear a-polyfuran, so a logical synthetic approach to 9 and 10 would come from the linear a-polyfuran. Unlike its heavy congener, the a-polythienyls, that has been studied in great detail due to their bioactivities 19'20 the linear a-polyfuran and physicochemical properties, only received little attention in the literature. A few studies on the syntheses of a—bi, a-ter and a-quater- furans have been reported,21 but a-quinque, a-sexi and a-septifurans are still unknown. The a-bifuran 11 was basically prepared from the oxidative coupling of the furylmetallic compound in the presence of catalytic or stiochiometric amount of transition metal salt [Scheme 1]. O O (3 11 X M 11(%) Ref HgOAC Cu, PdCl2 86 21a HgCl [Cth(CO)2]2, LiCl 70 21b Li CuCl2 85 21c MgI CoCl2 30 21d Scheme 1 The extension of this oxidation coupling reaction by copper(II) Chloride has led to the synthesis of a-terfuran 12 and a-quaterfuran 13 4[;)L4:;}|J + (ZESLJ CMNZ 21c Scheme 2 [Scheme 2]. 12 (16%) QQ 4.390- 13 40-00 m 0 o o’ (27%) 8 Recently, Descote521f reported the addition of vinyl sulfone to furfural in the presence of a thiazolium salt to give the 1,4-diketone 16a which undergo dehydrative cyclization to a-terfuran 12 in 33% overall yield [Scheme 3]. + N1. / \ H Ho Q) o EtOH, NaOAc o oo o 51% 163 (CH3CO)ZO HCI 69% 12 Scheme 3 Because of such little and scattered studies, the potential of a-polyfurans as an organic conductor remains totally unexplored. There are two goals in this work. Firstly, the synthesis of the linear a-polyfurans and the study of some of their chemistry. Secondly, the incorporation of the linear cz-polyfurans into large ring macrocycles which may ultimately lead to 9 and 10. RESULTS AND DISCUSSION A. Synthesis of linear a—polyfurans In this study, the synthetic approach to the linear a-polyfurans is based on the dehydrative cyclization of the 1,4-dicarbonyl compounds [Scheme 4]. We believe this is the general approach to both odd and eygn number of a-polyfurans. Furthermore, the presence of many dehydration methods22 that might effect this cyclization also makes this approach more attractive. So the problem remaining is the preparation of the symmetrical (m=n) and unsymmetrical (min) 1,4-butanedione precursors. m+n+l>3 Scheme 4 Although there is a large number of synthetic methods for the 1,4-diketones in the literature,23 only three different approaches that are suitable in the present study have been investigated. Their net transformations are summarized in Scheme 5. The first approach provides the 1,4-diketones from the Michael addition of aldehydes to the Mannich bases [Eq.1]. 9 10 The second approach involves the Michael addition of aldehydes to vinyl sulfone [Eq. 2]. The third approach to the 1,4-diketones comes from the reaction of the organolithium compounds with the N,N,N',N'—tetramethylsuccinamide [Eq. 3]. One obvious point can be made immediately from these different synthetic pathways, namely the first approach may provide access to both symmetrical (R=R') and unsymmetrical (R¥R') 1,4-dicarbonyl compounds while both the second and third approaches give convenient entry to the symmetrical O 0 RIM. * WWK ——R—[Ww (Hg. 11 O 21.in + AsozA “ROW. 12:21.21 aW—E [Eq. 3] 0 / \ N\ 211 u + N 0 ’ 0 Scheme 5 The Michael addition of aldehydes to a,fi-unsaturated ketones or Mannich bases in the presence of cyanide as catalyst has been utilized by Stetter for the general 24 synthesis of 1,4-diketones. Indeed, we have already used this method as an efficient way to the synthesis of 11 a-polythienyls with excellent yields.25 So an extension of this method to the preparation of a-polyfurans via the 1,4-diketones is'worth studying. m 0 0 n 143 m=l lSa n=l 16a m=n=1 (9%) 14b m=2 le n=2 16b m=2. n=l (63%) 14c m=3 16c m=n=2 (68%) 14d m=4 16d =3. n=l (59%) 161: “1:3. “=2 (53%) lfif‘matmfl.0w%0 16; that , n=2 (51%) 0 Scheme 6 The furfural 14a reacted with the 3-dimethy1amino- 1-(2-furyl)-propanone 15a in dry DMF in the presence of KCN at room temperature gave the 1,4-diketone 16a in disappoint- ing low yield (9%). Surprisingly, this Mannich base 15a reacted with other aldehydes 14b-14d to give the corresponding 1,4-diketones (16b, 168, 16f) in fair to good yields [Scheme 6]. The 1,4-diketone compounds (16c, 16e, 169) were also obtained in comparable yields when the Mannich base was changed to 3-dimethylamino-1-(5-2,2'-bifuryl)-propanone 15b [Scheme 6]. The structures and the melting points of the 1,4-diketones were shown in Table 1. The reason for the low yield of the reaction bewteen furfural 14a and the Mannich base 15a is unclear. Stetter 12 Table 1 l.4oDiketoncs from Aldehyde and Mannich base 1.4-dikctone mp, (°C) W mm 00 O O 161 W 98-99 0 O O O 0 16b 00 O O o 0 16¢ z3£§[§<>zs 137-139 0 000 O 0 16d 0 O O o o o o 160 QQQQQQ 1...... O O O O O O O 16! (§()!)l§‘>£>ls 165(dcc) O O O 0 000 0 16¢ has mentioned this reaction in a review paper24a but the yield was not reported. The Mannich bases, 15a and 15b, used in here were synthesized from the reaCtion of Z-acetylfuran 17a or S-acety1-2,2'-bifuran 17b with paraformaldehyde, dimethyl- amine hydrochloride and concentrated hydrochloric acid in ethanol solution [Scheme 7]. An attempt to prepare the Mannich base from 5-acetyl-2,2':5',2"—terfuran 17c failed. 13 Only 17c was recovered quantitatively after the reaction. The necessary aldehydes, 14b-14d, were synthesized from the Vilsmeier reaction of the corresponding a-polyfurans (Vida inflaa). 0 II (CH)NH.HC1 1 II H/ NH40H n—m'EOCH. (“CLAW ELOH * "—1:le CCHzCHzN\+ CT 15a or 15b Conc. H0 183 m=1 (68%) =1 "3 m 186 m=2 (45%) 17b m=2 17c m=3 Scheme 7 At first, we Anticipate to prepare both symmetrical and unsymmetrical 1,4-diketones from this cyanide catalyzed Michael addition reaction. But the low yield of 16a and the failure to prepare the Mannich base from 17c prompted us to make the symmetrical 1,4-diketones by other means. (mesolution to the symmetrical 1,4-diketones came from the thiazolium salt catalyzed addition of aldehydes to vinyl sulfone [Scheme 8], a reaction that was also well studied 26 by Stetter. This reaction is mechanistically parallel to the cyanide catalyzed 1,4-diketone synthesis except in this fA / N 3 H-[Qlfiw ”9°24 33}? Tillmmmx ' 143 m=1 163 m=l 14b m=2 16¢ “=2 14c m=3 16h m= 14d m=4 151 that Scheme 8 14 case, the thiazolium salt exerts the catalytic effect in the presence of a base. In this reaction, the vinyl sulfone was added dropwise to a hot ethanolic solution containing the aldehyde, thiazolium salt (3-benzyl-5-(2-hydroxyethyl)- 4-methyl-thiazolium chloride) and sodium acetate. After the mixture was refluxed overnight or 24h, the desired 1,4-diketones can be isolated in fair to good yields [Table 2]. The side product polysulfone can be separated easily by simple fil- tration. This reaction did not work when applied to 5-bromofurfural, thus limited access to S,S'-disubstituted 1,4-diketone. Table 2. 1.4-Diketones from aldehydes and vinyl sulfone l.4-dikctone yield (‘5) mp. (°C) (5‘ 5!; 66 130-131 0 oo o 16: O o oo 0 0 16¢ QQQQQQQ .. mo 0 o oo o o 0 [Gt 0 O O 0 [6| Unlike the above two methods which led to the 1,4-diketones from the furan derivatives, the second way to the symmetrical 15 1,4-diketones derived directly from the heteroaromatic nucleus. At the beginning, we were interested in the synthesis of 1,4-diketones from the Lewis acid catalyzed reaction bewteen succinyl chloride or fumaryl Chloride with furan. Due to the acid sensitive nature of furan, the Lewis acid employed was alkylaluminum Chloride which can also function as proton scavenger. Unfortunately, this study gave fruitless results under various reaction conditions (-78°C up to room temperature in dichloromethane or ether as solvent). Only in one case could a small amount of ethyl 3-furoyl- propionate be isolated from the reaction in ether bewteen furan and succinyl chloride in the presence of ethylaluminum dichloride. Our attention was then drawn to a report published in 1973 which disclosed the synthesis of 1,4- and 1,5-diketones from the reaction of N,N,N',N'-tetramethy1diamides with 27 organolithium reagents at -78°C. The results of this study are shown in Table 3. In view of these results, the prospect Table 3. Yields of products from the reaction -78°C 2 NJ + MqNCO(CHz)nCONMe¢ RCO(CH2),,COR R n Yield(%) Solvent Time(h) Phenyl 2 4 Ether 24 6-Bromo-2-pyndyl 2 71 Ether 3 i 2- 'd 1 2 20 ‘ Ether - Py-n y . 2 33 THF - 24 2-Tluenyl Phenyl 3 50 Ether 24 6-Bromo-2-pyridyl 3 76 Ether 3 2-Pyridyl 3 20 5*“ 3'4 ' e 3 24 THE 24 2-‘I‘luenyl 2 n-Butyl 3 19 Em“ ' Run with 4 equiv of 2-thienyllithium 16 of this method for 1,4—diketone synthesis did not look promising as we can see that the yields of the 1,5-diketones were generally higher than those of 1,4-diketones. In the case of phenyllithium, only a 4% yield of 1,4—diphenyl- butanedione was formed in the reaction with N,N,N',N'- tetramethylsuccinamide 19. Furthermore, it was reported that n-butyllithium gave a very complex mixture with the diamide 19. However, when this reaction was performed by adding the diamide 19 in one portion to the organolithium reagent at 00C and then stirring at room temperature for a further 24h, Table 4. Yields of 1,4-diketones from the reaction Eizo 19 0°C "fl 20-42 163, 16c, 1611 R Time(h) Product Yield(%) n-Butyl 24 20 20 U 24 (36)” 22 22 (25)” S n 24 16a 50 0 an 24 16c 61 0 <3 (1 24 16h 49 C) O O ' Added as ether-a1 PhLi.LiBr Solution. b Reaction at room temperature for 3611 with 25% yield. the yield of 1,4-dipheny1butanedione 21 was increased 17 approximately twelve times to 47% while n-butyllithium gave 5,8-dodecanedione 20 in a 20% yield [Table 4]. Similarly, both 2-furyllithium and Z-thienyllithium gave the corresponding 1,4—diketones in 50% and 22% yields respectively [Table 4]. For the case of 2-thienyllithium, using excess lithium reagent or longer reaction time did not improve the yield. This yield was somewhat lower than the result from the literature which has 33% optimal yield when the reaction was done in THF at -78°C [Table 3]. The extension of this reaction to the organolithium reagents derived from a-bifuran 11 and a-terfuran 12 also gave the symmetrical 1,4-diketones 16c and 16d in modest yields [Table 4]. In summary, three different approaches are available for the synthesis of 1,4-diketone precursors to a-polyfurans. While the Mannich base method is good for the synthesis of unsymmetrical 1,4-diketones, the other two methods (vinyl sulfone and diamide) are complement to it for the preparation of symmetrical 1,4-butanediones. All the structures of the 1,4-diketones were confirmed by their spectra (see Experimental). For the unsymmetrical 1,4-diketones such as 16b, 16d, 16f and 16g, their 13C NMR spectra clearly Showed two distinct signals for the two carbonyl carbons or two a-methylene carbons or both. The IR absorptions in the range of 1640-1670 cm-1 were obtained for the 1,4—diketones. With the 1,4—diketones in hand, the time has come to study their ring Closure to a-polyfurans. It was found that 18 H-mlflflgti (CHSCOW L. H‘[fl]‘H HCl m+n61 Scheme 9 most of these 1,4-diketones readily gave the a-polyfurans upon treatment with acetic anhydride in the presence of a catalytic amount of concentrated hydrochloric acid [Scheme 9]. Oligomers possessing three, four, five and six furan rings were prepared in this manner in fair yields [Table 5]. Table 5. Polyfurans by ring closure ol 1.4-diketones 1,4-diketone Polyfurans Yieldm) [;>1—34:} FPBC}qu 63 OO 3 16. 1 2 W .10]... .2 oo o 4 1 6b 1 3 W .953]... .0 oo 5 1 Ge 2 3 W ~-[Q]—~ .. oo 5 166 2 3 W ~10}: 2° 19 However, the diketone 16h resisted the dehydration under the same condition or gave unidentified products under other dehydration conditions (DMSO, polyphosphoric ester, P205, HMPA and p-TsOH in CHC13). But the a-septifuran 25 was obtained in very small yield when a solution of the diketone 16h in acetic acid and acetic anhydride was refluxed for 48h [Scheme 10]. / ¥/\ \/ CWCOzH mm 00 0 (CH3CO)2O 7 15" 17% 25 Scheme 10 Due to their limited amount available or low solubility, the dehydration of 16f, 169 and 161 was not studied. Attempts have been made to improve the yield by doing the dehydration under neutral condition, but this resulted in very poor yields [Scheme 11]. W ”[4313“ 16. 15.4% (100°C, 2411) 2.1% (70-30%. 5 days) P--Mo - Methyl ester of phosphorlc acid Scheme 11 Besides the dehydration of 1,4-diketone 16e, the 20 a-sexifuran 24 can also be prepared from the oxidative coupling of a-terfuryllithium by anhydrous copper(II) chloride but only in a 5.3% yield [Scheme 12]. Scheme 12 We have completed the syntheses of a-polyfurans from the 1,4-diketones and also proved that this is a general approach to both the odd and 2322 number of a-polyfurans. In addition to a-polyfurans, this 1,4-diketone synthesis is also useful in providing a facile route to the mixed a—polyaryls. To demonstrate this point, we have prepared a 26 mall (56%) 27 11:82 (57%) 28 111-3 (40%) @W@: 16: 111-1 16c maZ 1,... ”mm: 29 0181 (22%) 3o 111:2 (51%) 31 m=3 (15%) Scheme 13: a) Lawcsson's reagent. toluene; b) NH4OAC. CH3C02H. (013C050 21 several linear mixed a—furylthiophenes 26-28 and a-furyl- pyrroles 29-31 from three symmetrical 1,4-diketones [Scheme 13]. While there were some difficulties in synthesis the a-septifuran 25, its mixed counterparts 28 and 31 can be easily prepared in high yields. A study and comparison of the UV spectrum data of a-polyfurans [Table 6] and a-polyaryls [Table 7] reveals some interesting points. For the linear a-polyfurans, the data showed a decreasing incremental bathochromic shift of the longest wavelength absorption as the molecule increases in length. In fact the bathochromic shift observed on going from a-sexifuran 24 to a-septifuran 25 is only 5 nm and this indicates that there might exist a limit to the conjugation bewteen the furans rings in the vicinity of six or seven furan rings. When one of the furan rings in a-polyfuran is replaced by a pyrrole ring, the longest wavelength absorption of the resulting a—furylpyrroles remains nearly the same as its counterparts from a-polyfurans. However, when the furan Table 6 UV spectrum data (the highest Am“ value) 01 a-polyfurans 0 n CHCI3 (um) Am 350 390 415 436 441 22 Table 7 UV spectrum data (the highest Am“ value) of a-polyaryls m 1 2 3 X=NH 345 411 441 M::%(mm XaS 369 432 464 ring is replaced by the thiophene ring, the highest Amax of the a-furylthiophenes shifts to longer wavelength by about 20 nm compares to its counterparts from a-polyfurans and a-furylpyrroles. Such phenomenon is in agreement with the general observation that the thiophene compounds are usually absorbed at longer wavelength than structurally similar furan and pyrrole compounds, possibly due to the thiophene is more aromatic in character or the participation of the low lying d-orbitals in bond interaction. Although the syntheses of a-polyfurans (up to a-quaterfuran) have been reported,21 their chemistry has not been well studied.21c' 21d! 219: 28 So we undertook to study the chemistry of the a-polyfurans for two reasons. Firstly, the studies would enrich our understanding of the properties of this type of compounds. Secondly, the results from these studies might be useful to accomplish our second goal, i.e. the synthesis of the polyfuran macrocycles 9 and 10. 23 The a-polyfurans (11-13 and 23) were easily formylated by the Vilsmeier-Haack method to give the corresponding S-formyl derivatives, 14b-14e, in good to excellent yields [Scheme 14]. These monoaldehydes (14b-14d) have been used to synthesiz the 1,4-diketones either by reacting with Mannich bases or vinyl sulfone (Vida aupaa). Treatment of these monoaldehydes (14b-14e) with N-bromosuccinimide (NBS) in dimethylformamide (DMF) gave the corresponding bromoaldehydes, 32a-3Zd, in good yields [Scheme 14]. However, the use of pyrindine hydrobromide as brominating agent in chloroform only led to the destruction of the aldehydes. 1.?OC13.DMF H'[[/ >\]'H t H-[[/ \>]C|~O ——-’ Br-I: \ 'Cl-D O n 2.NaOAc Q n DMF 0 n 14b 11:2 (91%) 323 "=2 (88%) u at: 14c n=3 (97%) 32b n=3 (68%) 12 n- 1411 n=4 (66%) 32c n=4 (74%) i: “=2 14¢ n=5 (46%) 32d n=5 (72%) [1: Scheme 14 When the a—bifuran 11 and a-terfuran 12 were treated with more than 2 equivalents of Vilsmeier reagent (P0C13, DMF), only the corresponding monosubstitution products, 14b and 14c, were isolated, no dialdehyde compounds were detected. 21e This was consistent with a report in which the Gattermann reaction of a-bifuran 11 gave only the monoaldehyde 14b 24 even when a large excess of the reagent (HCN, HCl) was employed. It would appear from this evidence that the deactivating effect of an electrophilic group (in this instance CHO) is transferred through the extended conjugated system of a-bifuran and a-terfuran, thereby inhibiting the introduction of second formyl group to the remainingcxposit- ion. This trend of deactivation is expected to carry on to other a—polyfurans. But we were surprised to find that treating the a—quaterfuran 13 and a-quinquefuran 23 with excess Vilsmeier reagent gave the corresponding dialdehydes 33c and 33d exclusively in modest yields [Scheme 15]. These results might reflect that the furan rings in larger a-polyfurans behave more like an individual unit than an extended conjugated system, thus diminishes the deactivating effect of the first formyl group. mm]; H m ; (MC-[Q]- GHQ 13 n=4 33c n=4 (65%) 23 n=5 3311 "=5 (57%) Scheme 15: a) Excess Vilsmeyer reagent; b) NaOAc The dibromides, 34a-34c, were readily obtained by brominating the corresponding a-polyfurans, 11-13, with NBS in DMF in fair to good yields [Scheme 16]. These dibromides are slowly decomposed at room temperature but stable for a long time if kept at 0°C. 25 “14—31;,” N83 (2“!) * Brim]? O DMF O 11 n=2 34a n=2 (56%) 12 n=3 34b n=3 (72%) [3 n=4 34c n=4 (77%) Scheme 16 The preparation of the ketone derivatives from a-bifuran and a-terfuran by acylation with acetic anhydride in the presence of an acid (H3PO4) or a Lewis acid catalyst (BF .OEt) 3 led only to the decomposition of the starting material. Fortunately,the successful synthesis of 1,4-diketones from organolithium reagent and N,N,N',N'-tetramethyldiamide 19 provides an alternative route to make the ketone compounds. Based on competition experiments, Kauffmann et a1.21C has found that the acidity of a-hydrogen from the a-polyfurans against n-butyllithium decreases in the following sequence: a-terfuran > a-bifuran > furan. So while the 2-furyllithium. in ether was usually prepared by refluxing a solution of 29 furan and n-butyllithium for 4 hours, the corresponding H-lUl-H + n-BuLi B20 ; H-[fli-Li 11 n22 353 MHZ 12 n=3 35b n=3 Scheme 17 26 a-lithiated compounds, 353 and 35b, from a-bifuran 11 and a-terfuran 12 were easily obtained by stirring a solution of a-polyfuran and n-butyllithium at room temperature for 2 hours [Scheme 17]. These organolithium compounds, 35a and 35b, readily reacted with various N,N-dimethylamides to give the ketones together with a small amount of diketones. The results are summarized in Table 8. The yields of the ketones from a-bifuran are generally better than those from a—terfuran, a Table 8 Yields of monoketone and diketone from the reaction H-QLU + R-E-Ni E90 wwlrpon + soc-[QLOOR 35a n=2 1711. 171: 378-371 351) n=3 36a . 366 Product Yield (%) “ R Monoketone Diketone 11 or 36 : 37 2 CH: 176 37: so 1 3 CH; 17c 37]) 47 : 6 2 QB, 36. 37c 59 6 3 C63, 36:. 37d 42 6 2 p-W 35.; 37c 56 6 3 p-Mcoqm 36d 37: 46 s result that is presumably due to steric effect. The ketone compound 17b, prepared in this manner, has been used to make the Mannich base 15b for 1,4-diketone synthesis (Vida aupaa). Besides the amides, the methyl N,N-dimethylcarbamate 38 27 also reacted with the organolithium compounds to give the symmetrical ketones, 39a and 39b in modest yields [Scheme 18]. H-[[)]-u + :~-§-OM. __‘Lmeflmh O n 0 n O n 358 n=2 38 39a n=2 (49%) 3st) n=3 39b n=3 (40%) Scheme 18 The formation of the diketones from the above nucleo- philic reactions suggests that treating the a-polyfurans with 2 molar equivalents of n-butyllithium under the same condition could generate the dianion. This is shown to be the case by trapping the dianion with D O or methyl iodide [Table 9]. 2 In all cases (entries 1-6), only the disubstituted products 18 and 13C NMR spectra (see Experimental). For example, their 1H NMR (40-41) were formed and this is supported by their spectra showed the absence of the a—hydrogen signal around 7.4-7.5 ppm and 13 C NMR spectra of the deuterated derivatives (doe-40c) showed triplet for the free a-carbon while the free abcarbon was shifted downfield by 10 ppm in the dimethyl compounds (41a-41c). The exclusive formation of dimethyl compound 41a from a-bifuran 11 in ether is contrast to a 28 Table 9 Yields of disubstituted products from the reaction H_[/ \]_H L mBUU(2an/qu: E-£[_§J-E On 2.13 On Entry n E Product Yield (‘70) MCI Me- LII \>l ' M6 ’ 48 ,(I 1]- 6 4 Mel Me 1. 0 4M9 9 8 3 DMF G—iC-[Q];C1'D 39 ° {—1, 11 report28a that treating the bifuran 11 with two molar equivalents of n-butyllithium in THF gave a mixture of starting material, methyl and dimethyl derivatives in 76% total 29 yield. The poor yields of the disubstituted products, 40c and 41c, from a-quaterfuran may be due to the decomposition of the starting material during the dianion formation because substantial amount of insoluble black solid was observed during work-up. The reason for this decomposition is not clear. Although the yield of the dialdehyde 33a is disappo— inting, the reaction bewteen the dianions from a-bifuran and a-terfuran with DMF (entries 7 and 8) provides a way to synthesiz the dialdehydes, 33a and 33b, which cannot be obtained from the corresponding a—polyfurans with excess Vilsmeier reagent. Finally, the dianion from a-terfuran also reacted with N,N-dimethylbenzamide to give the diketone 37d in 30% yield (entry 9). B. Synthesis of novel macrocyclic a-polyfurans I. Studies towards the synthesis of [26]annulene hexoxide 9 Retrosynthetic analysis of 9 suggests that compound 42 is a potential precursor since oxidation of 42 (R'=H) might afford the [26]annulene hexoxide 9 [Scheme 19]. Consequently, R-fldlkyloru'yl Scheme 19 3O efforts have been made to construct the ring compound 42. At the beginning, a model compound 42a (R=R'=CH3) is made so as to test the feasibility of various synthetic approaches to the macrocyclic ring structure. The first retrosynthetic analysis of 42a suggests it may come from the dehydrative cyclization of the tetraketone 43 which in turn may involve an intermolecular catalyzed addition of the dialdehyde 44 to vinyl sulfone or the bis-Mannich base 45 [Scheme 20]. O 0 ¢::: 0 o ‘ OO 0 / \ O N\ 428 43 o + 44 ~< o 45 Scheme 20 The dialdehyde 44 was readily obtained in excellent yield 30 by treating the 2,2-difurylpropane 46 with Vilsmeier reagent (POC1 DMF) [Scheme 21]. The desired bis-Mannich 3' base 45 was prepared from the diketone compound 47 which in turn was synthesized by reacting 46 with acetic anhydride in the presence of a catalytic amount of boron trifluoride etherate [Scheme 21]. 31 1. P003. DMF OCH CH C1 0"[ >\ 2 2 r " \ PM” 0 0 .2. NaOAc O O o O 46 39% 44 (CH,CO)2O BF,.OEt 49% (ECHO). (CH ) NHHCI + + ”“40” I \ [_m 32 : c1- “(WI-0W“: Ct 45 o 0 Conc.HC1 ’ o 0 O 0 E1011 0 O 47 40% Scheme 21 Unfortunately, the dialdehyde 44 gave rise to a plethora of unidentified products upon treatment with the vinyl sulfone. The dialdehyde 44 was the only detectable compound in minute amount after its reaction with the bis-Mannich base 45. Our second synthetic approach to 42a is based on the intramolecular catalyzed addition of the dialdehyde 48 to the vinyl sulfone [Scheme 22]. Since the dialdehyde 48 consists all but two carbon atoms of the macrocyclic framework, it was anticipated that 48 is more readily to form the cyclic 1,4-diketone 49 with vinyl sulfone. 42: C: <= YUIWIW" O O 48 49 Scheme 22 32 The preparation of the dialdehyde 48 is shown in Scheme 23. Vilsmeier-Haack reaction of 46 gave the aldehyde 50 in excellent yield. The thiazolium salt catalyzed addition of 50 to vinyl sulfone gave the 1,4-diketone 51 which in turn was dehydrated with acetic anhydride to give the furan compound 52. Treatment of 52 with 2 molar equivalents of Vilsmeier reagent gave the desired dialdehyde 48. b c CW?) :7?- QIQy" —;.;—- QIQQQIQ 4‘ so 0 51 d 58% leWQlfl" 2'; QIWCHQ O 52 48 Scheme 23: a) DMF. POCl-,. (210130-120; b) NaOAc; c) Vinyl sulfone. thiazolium salt. NaOAC. EtOH: d)(CH3CO)10.HCl; e) Excess Vilmeyet mum Like 44, the dialdehyde 48 only gave a complex mixture of unidentified products when reacted with the vinyl sulfone. The formation of 1,4-diketone from organolithium and diamide 19 prompts us to study the synthesis of 49 from the furan compound 52 [Scheme 24].. However, under the conditions (n-BuLi or LDA in ether) studied, the cyclic diketone 49 was not detected. 33 0 <= QIQQOIO + >NW< 49 Scheme 24 There is a report of the synthesis of 1,4-diketones by oxidative coupling of ketone enolates with anhydrous copper(II) chloride.23d The application of this synthetic methodology to the cyclic 1,4-diketone 49 from the diketone compound 53 is very attractive [Scheme 25]. Unlike the previous synthetic approaches to 49 that involves formation of two carbon-carbon bonds, the present approach needs to form only one carbon-carbon bond because the diketone 53 has all the carbon atoms of the macrocyclic 1,4-diketone 49. 0001 W 0100010 0 I o 0 0 0 8133.051 0 O o o O O O 22% 53 52 l. LDA. THF 49 :/\ LCMM Scheme 25 The diketone 53 was obtained by the Lewis acid catalyzed 34 reaction of 52 with acetic anhydride. But to our disappoint- ment, the dienolate, generated by treating 53 with LDA, gave a plethora of unidentified products upon treatment with copper(II) chloride. In view of the above results, the 1,4-diketone synthesis is an ineffective approach to the macrocycle 42. Therefore, other ways have to be devised for making 42. It has been demonstrated that a-terfuran 12 gave dianion efficiently by treating with 2 molar equivalents of n-BuLi and also the monolithiated derivative 35b of a-terfuran 12 reacted with carbamate 38 to give the symmetrical ketone 39b in modest yield (Vida éupaa). Retrosynthetic analysis of 42 suggests the symmetrical and cyclic diketone 54 as a possible precursor which may obtain from a-terfuran 12 and carbamate 38 [Scheme 26]. 42 54 Scheme 26 The dianion from 12 did react with 38 and give a reddish brown solid as major product together with small amount of 12 and 39b. Unfortunately, the solid was insoluble in any 35 solvent system and was assumed to be a linear polymeric ketone because its IR spectrum showed carbonyl group absorption. However, the mass spectrum of the solid did not give any additional information as no peak greater than m/e 250 was observed. Another retrosynthetic analysis suggests 42 might come from the self cyclization of 5"-formyl-2,2':5',2"-terfuran 14c [Scheme 27]. Scheme 27 Efforts to accomplish this cyclization in ethanol or benzene with various protonic acids (concentrated HCl, gaseous HCl, p-TsOH and CF COZH) were all in vain. For each 3 case, either the starting material or intractable material was obtained. We think these reaction conditions may be too harsh so that the product hydrolyzed or decomposed rapidly after its formation. So this cyclization reaction has been studied under mild condition by employing a Lewis acid in aprotic solvent. The use of some common Lewis acids such as BF3.OEt, 36 SnCl4, MgBr .OEt and POCl3 in dichloromethane did not cyclize 2 the aldehyde 14c. In both BF3.OEt and SnCl4 cases, addition of the Lewis acid to the dichloromethane solution of 14c resulted in the formation of a quantitative amount of red precipitate. Quenching the solution with saturated NH4C1 solution and usual work-up gave back 14c near quantitatively. A similar situation occurred with MgBr2.OEt except a yellow precipitate in this case. These results indicated the Lewis acids may form an insoluble complex with 14c, thereby inhibited the cyclization. Although there was no precipitation from POCl3 as Lewis acid, no reaction occurred as 14c was recovered quantitatively. Attention was then turned to the alkylaluminum chloride reagents for the cyclization of 14c. The alkylaluminum chloride reagents have an advantage over other Lewis acids because the alkyl group can function as proton scavenger so that any side reaction caused by the presence of adventitious protons can be avoided. This is particularly true in this work as the furan nucleus is extremely sensitive to acidic medium. We were delighted to find that the diethylaiuminum chloride (EtzAlCl) in dichloromethane caused the aldehyde 14c to cyclize [Scheme 28]. The cyclization reaction did not go to completion but this gave us no problem as the cyclized product 42b can be easily separated from the starting material by flash column chromatography. Evidence for the cyclization comes from the 1H and 13C NMR spectra of 37 emu [/ \5 [/ i [’1‘] ____. o o o o H Clip, 0 0 El 0 u c an Scheme 28 the product 42b. Besides indicating the absence of the oehydrogen at 7.40-7.50 ppm for the cyclic structure of 42b, the 1H NMR spectrum [Figure 2] also showed that there was an ethyl group transferred from the Lewis acid so that the bridging carbon has an ethyl group instead of the hydroxyl group. Such an alkyl group transfer from the alkylaluminum chloride reagent is known.31 The centrosymmetrical formulation for 42b is also indicated by the presence of 9 peaks in its 13C NMR spectrum [Figure 3]. However, the EI mass spectrum of 42b at 20 eV showed that the compound is the cyclic trimer (n=3) with parent ion at m/e 720. But by comparison to other cyclization study below, we believe 42b is a mixture of cyclic oligomers (n=2, 3, 4...etc) and diastereomers with the cyclic trimer (n=3) as the major product. Attempts to avoid the ethyl group transfer from the Lewis acid by using ethylaluminum dichloride (EtAlClz) were not 38 .n~v mo sauuomam «:2 m P n=2 0mm .N dusmwm 1 u u. 39 .nmv ennuomam mzz omP an: m.mo .m enemas ELL ea elem een ee: .eews as? )lqb—l— l1). ). 11)) ‘ fl«_ _—«4qqflqqqq—qqqd—q_qqfl_.qd_qd___q—dq_‘_‘.___«——dqq.fld qqflqqdqfiqqqqfiqq_q_q_fldfl_qd‘_«qdqfldqdfiddd_q#_qwq_qqqd 141.4 l J .111. 40 successful as no cyclization occurred even though the temperature of the reaction was raised to 60°C. This may possibly due to the greater acidity of EtAlCl2 which deactivate the a position through the extended conjugated system of 14c. c1110, [30(3on . 011.131.. 0 o o 12 42: Scheme 29 Finally, it was found that the condensation of benzal- 2 dehyde with a-terfuran 12 in dichloromethane (1x10- M) at room temperature by using POCl as Lewis acid allowed the 3 successful synthesis of the symmetrical macrocyclic polyfuran 42c after 24 hours [Scheme 29]. Evidence supported the cyclic form of 42c comes from its 1H and 13C NMR spectra (see Appendix, Figures A20 and A21). However, the EI mass spectrum of 42c showed the parent peak at m/e 864 which came from the cyclic trimer (n=3) and the field desorption (FD) mass spectrum indicated 42c was actually a mixture of cyclic oligomers (n=2, 3, 4...etc). These mass spectrum results suggested the desired cyclic dimer (n=2) existed but in very small amount. Attempts to separate the mixture of cyclic oligomers using chromatography or recrystallization failed to 41 give any single, pure product. To avoid the formation of higher cyclic oligomers, the reaction was done under more dilute condition. At the concentration of 1x10”3 M, the solution gave back the starting materials after 24 hours. When the solution was allowed to stir for 4 days, in addition to some starting material and cyclized products, two linear, open-chain compounds were detected and identified as 55a and 56a [Scheme 30]. The formation of these linear compounds 55a and 56a from the reaction suggests their cyclization could give the cyclized products and this provides us a practical solution to the desired cyclic dimer (n=2) without the contamination of any odd number of cyclic oligomers by studying the cyclization of 55a. 00033000 C3L42¥l;3+usuuou -..~..m".~.~1m.manasemnd mo ssuuomam mzz 02 was m.~o .o enemas I.‘ I..- ..Ifl I.“ . 0.... 0.8 .I.Ia. 0.00. 0..“— O..P- ..‘a 0.0-N 47 .oNq sundowam mzz omF n=2 m.~6 .e enemas (Ls n. on ..I.. 1.09. 0.04. 0...... 2.05.. . 6....» e o e e. a on 0..» e.... fist—4.3.13 ((1. 1143 (11111111111 48 The disappearance of the free a-carcon's peak and the presence of only 11 peaks in the 13C NMR spectrum [Figure 7] of 42c also demonstrated its centrosymmetrical structure. The EI mass spectrum of 42c showed the parent ion of the desired cyclic dimer (n=2) at m/e 576. But the fast atom bombardment (FAB) mass spectrum showed 42c was still a mixture of cyclic dimer (n=2) and tetramer (n=4). The cyclic tetramer arises from the cyclic dimerization of the linear compound 55a. In a similar manner, the methoxy derivative 55b also underwent cyclization with 4-methoxybenzaldehyde to give 42d after the solution was stirred for 18 days [Scheme 32]. Evidence of cyclization also comes from the comparison of the 1H and 13C NMR spectra of 55b and 426. The 1H NMR spectrum [Figure 8] of 55b looked like that of 55a with two exceptions. The proton from the benzene ring now appears as two doublets (J=8.7 Hz), one at 6.85 ppm while the other at 7.20 ppm. The peak at 3.75 ppm was assigned to the methoxy protons. The linear-open-chain structure of 55b is also indicated by the free a-carbon peak at 141.86 ppm and the presence of 14 peaks due to the aromatic carbons in its 13C NMR spectrum [Figure 10]. However, the disappearance of the free a-hydrogen's and a-carbon's signals as well as the simplicity of the 1H [Figure 9] and 13 C NMR (12 peaks) [Figure 11] spectra of 42d proved it has a cyclic, symmetrical structure. The EI mass spectrum of 42d showed the parent ion of the cyclic dimer (n=2) at m/e 636. Again, the FAB mass .nmm measume.asusoumul..~..mu.~.~-mcm.n 1H>cczd>xozuwelv mo Esuuowom mzz :. n=2 omm .m musmfih thL. 9.9 &.N 84+ .E.m E.m _4lfl441fl4411aA)14J1wHJ)fla)lH441flaA4lflw4A1w4J1wHJ)w44)fi44)fl4#lfi441fifiqjmfifiquw 49 a. i l A. 50 .emv co sauuomcm mzz :. an: omm .m enemas ELL 9.9 E.N 8.: E.w E.m éaélflfljlfiflafiWJlfiflfié J7. 3. . S1 .nmm wcmnume..>usuumus..~..mu.~.~1m.man laxcmco>xocuwelv mo Esuuoomm mzz UmP n=2 m.~m .op munmwm CLL e. be. con new 00.. can a... con. eon. be... eon. no: 1.21.44.72.22—:1:.1_.::::_.::::_..:::._::::._.:..=:_::.::_.23::_..:.::_:.::=_.:. —~««300°C; H NMR: (CDCl3 with CF3C02H) 6 6.48 (d, J=3.8 Hz, 2H), 6.87 (s, 2H), 6.90 (d, J=3.8 Hz, 2H), 7.09 (d, J=3.7 Hz, 2H), 7.57 (d, J=3.9 Hz, 13 2H), 9.43 (s, 2H); C NMR: (CDCl with CF COZH) 6 109.74 3 3 90 109.25, 109.94, 114.48, 131.28, 143.46, 145.69, 148.49, 150.16, 154.31, 179.95; MS (FAB)47: m/e 389 (m*+1); UV-vis: )max ( EM) 300.0 (4.31x103), 430.5 (1.41x104), 456 (1.08x104); IR: cm_1 1668. 5,5'-Dibromo—2,2'-bifuran 34a Asolutionof NBS (2.7 g, 15.1 mmol) in dry DMF (20 mL) was added dropwise to an ice cold solution of cx—bifuran 11 (1.0 g, 7.5 mmol) in dry DMF (30 mL). The solution was then stirred at room temperature for 24h. The solution was poured into water (100 mL) and the aqueous solution was extracted with methylene chloride (3x50 mL). The combined organic layers were washed with water (10x30 mL) and saturated NaCl solution (30 mL). After drying over anhydrous MgSO4, the solvent was removed in vacuo to give the crude product which was flash column chromatographed over silica gel using Et203hexanes (v/v=1/5) as eluent to give 1.23 g (56%) of dibromide 34a as off—white solid: m.p. 73-75°C (lit.44 m.p. 76°C); 1H NMR: 15 6.35 (d, J=3.3 Hz, 2H), 6.50 (d, J=3.3 Hz, 2H); 13C NMR: 5 107.91, 113.20, 121.75, 147.23; MS: m/e (rel. intensity) 294 (M++4, 38), 292 (m*+2, 73), 290 (M+, 36), 213 (100), 211 (99), 185 (51), 183 (49), 157 (28), 155 . 4 (28), 76 (56); UV-Vls: )max ( eM) 300.5 (1.10x10 ), 314.0 (6.67x103). S,5"—Dibromo-2,2':5'2"-terfuran 34b Using the procedure as described for 34a except the 91 solution was stirred at room temperature for 48h, the dibromide 34b (1.29 g, 72%) was obtained from the a-terfuran 12 (1.0 g, 5 mmol) and NBS (2.0 g, 11.2 mmol) as pale yellow solid: m.p. 148-150°C; 1H NMR: 5 6.40 (d, J=3.3 Hz, 2H), 6.58 (d, J=3.3 Hz, 2H), 6.61 (s, 2H); 13C NMR: 5 107.49, 107.81, 113.26, 121.73, 144.72, 147.81; MS: m/e (rel. intensity) 360 (M++4, 44), 358 (M++2, 100), 356 (M+, 46), 279 (24), 277 (24), 170 (54), 142 (75), 125 (53), 114 (65), 76 (43); UV-vis: Xmax ( ‘H’ 348.5 (1.69x1o4), 368.0 (1.15x1o4). 5,5"'-Dibromo-2,2':5',2":5",2"'-quaterfuran 34c Using the procedure as described for 34a except the sol- ution was stirred at room temperature for 48h and using Et20:hexanes (v/v=1/1) as eluent for flash column chromato- graphy, the dibromide 34c (243.9, 77%) was obtained from the a-quaterfuran 13 (200 mg, 0.75 mmol) and NBS (270 mg, 15.2 mmol). Crystallization from the eluent gave yellow solid: m.p. 204-206°c; 1H NMR: 5 6.41 (d, 2H), 6,59 (d, 2H), 6.66 (d, 2H), 6.69 (d, 2H); MS: m/e (rel. intensity) 426 (H*+4, 8), 424 (H*+2, 19), 422 (M+, 8), 345 (10), 343 (10). 317 (12), 315 (13), 208 (17), 152 (27), 104 (68), 76 (100), 50 (50); UV-vis: A ( eM) 295.0 (9.68x103), 375.4 (2.04 max x104), 396 (1.41x104). 5-Acetyl-2,2'-bifuran 17b and 5,5'-diacetyl-2,2'-bifuran 37a To a solution of a-bifuran 11 (1.0 g, 7.5 mmol) in dry ether (40 mL) at -60°C was added n-BuLi (7.5 mmol) in one 92 portion. The solution was stirred at room temperature for further 2h. The solution was cooled at —600C and a solution of N,N-dimethylacetamide (DMAC) (755.2 mg, 10.3 mmol) in dry ether (5 mL) was added dropwise. The solution was stirred at room temperature overnight. The solution was cooled in an ice bath and 10% HCl (40 mL) was added. The mixture was stirred for 4h and the two layers were separated. The aqueous layer was extracted with CHCl (3x50 mL). The combined 3 organic layers were washed with water, saturated NaCl solution and dried over anhydrous M9804. Removal of the solvent in vacuo gave the crude product which was chromatographed over silica gel by flash technique using Et20:hexanes (v/v=1/1) as eluent to give 793.8 mg (60%) of ketone 17b as yellow solid: m.p. 53-55°c; 1H NMR: 5 2.50 (s, 3H), 6.51 (dd, J=3.4, 1.8 Hz, 1H), 6.66 (d, J=3.7 Hz, 1H), 6.84 (d, J=3.5 Hz, 1H), 7.25 (d, J=3.7 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H); 13c NMR: 5 25.84, 107.14, 108.49, 111.82, 119.19, 143.43, 145.22, 149.78, 151.46, 185.98; MS: m/e (rel. intensity) 176 (M+, 100), 161 (55), 105 (69), 43 (36); UV-vis: A IR: cm‘1 1660. 4 . max ( eM) 335.0 (2.29x10 ), The column was flushed by air to dryness. The silica gel from the top of the column was suspended in CHCl (150 mL) 3 and the suspension was stirred for 2h. Filtration and evap- oration of the solvent gave the crude diketone whiCh was purified by recrystallization from methylene chloride and hexanes to give 16.4 mg (1%) of the diketone 37a as pale yellow leaflet: m.p. 201—203OC; 1H NMR: 6 2.50 (s, 6H), 6.95 93 13 (d, J=3.7 Hz, 2H), 7.26 (d, J=3.7 Hz, 2H); C NMR: 5 26.07, 110.10, 118.97, 148.08, 152.52, 186.19; MS: m/e (rel. intensity) 218 (M+, 76), 203 (54), 147 (72), 43 (100); UV-vis: 4 4 4 , Amax ( 6M) 276.5 (4.85X10 ), 344.5 (3.51X10 ), 362 (2.88X1O 1, IR: cm‘1 1668. S-Acetyl-2,2':5',2"-terfuran 17c and 5,5"-diacety1-2,2':5'2"- terfuran 37b Using the procedure described for 17h except using CHC13:EtOAc (v/v=9/1) as eluent for flash column chromato- graphy, the monoketone 17c (282.1 mg, 47%) and the diketone 37b (42.6 mg, 6%) were obtained from the a-terfuran 12 (500 mg, 2.5 mmol) and DMAC (236 mg, 3.33 mmol). Recrystallization of compound 17c from ethanol gave tiny yellow plates: m.p. 142-144°C; 1H NMR: 6 2.51 (s, 3H), 6.50 (d, J=3.3, 1.8 HZ, 1H), 6.65 (d, J=3.6 HZ, 1H), 6.68 (d, J: 3.4 Hz, 1H), 6.72 (d, J=3.6 Hz, 1H), 6.90 (d, J=3.5 Hz, 1H), 13 7.25 (d, J=3.7 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H); C NMR: 6 25.81, 106.44, 107.17, 107.29, 110.41, 111.55, 119.38, 142.46, 144.13, 145.66, 147.28, 149.43, 151.46, 185.86; MS: m/e (rel. intensity) 242 (M*, 100), 227 (10), 171 (78), 143 (16), 115 . -1 (46), 43 (80); uv-v1s: *max ( eM) 372.5 (1.83x104); IR: cm 1664; Exact mass calcd for C14H10 4: 242.0579, found 242.0565. Recrystallization of the diketone 37b from methylene chloride and hexanes gave golden yellow crystal : m.p. 253- 1 255°C; H NMR: 5 2.52 (s, 6H), 6.79 (d, J=3.7 Hz, 2H), 6.94 94 13 (s, 2H), 7.26 (d, J=3.4 Hz, 2H); C NMR: (CDCl3 with CF COZH) 3 5 25.26, 109.29, 112.05, 123.44, 145.89, 150.77, 150.90, 189.64; MS: m/e (rel. intensity) 284 (M+, 63), 269 (4), 213 . 3 (45), 43 (100), UV—VlS. )max ( eM) 283.5 (6.75x10 ), 383.5 1 (4.39x104), 402.5 (3.63x104); IR: cm- 1662. 5-Benzoyl-2,2'-bifuran 36a and 5,5'-dibenzoy1-2,2'-bifuran 37c n-BuLi (3.7 mmol) was added to a solution of a-bifuran 11 (500 mg, 3.7 mmol) in dry ether (15 mL) at -60°C. The solution was stirred at room temperature for additional 2h. The solution was cooled at -60°C and a solution of N,N-dimethylbenzamide (600 mg, 4 mmol) in dry ether (3 mL) was added dropwise. The solution was then stirred at room temp- erature overnight. The solution was cooled in an ice bath and 10% HCl (20 mL) was added. The mixture was stirred for 4h and the layers were separated. The aqueous layer was extracted with CHCl (3x50 mL). The combined organic layers 3 were washed with water, saturated NaCl solution and dried over anhydrous M9804. Removal of the solvent in vacuo gave a dark brown oil which was purified by flash column chromato- graphy over silica gel using Et20:hexanes (v/v=1/1) as eluent to give 525.6 mg (59%) of ketone 36a as yellowish viscous oil. Recrystallization of 36a from methylene chloride and hexanes gave tiny yellowish brown plates: m.p. 62-64OC; 1H NMR: 5 6.52 (dd, J=3.6, 1.8 Hz, 1H), 6.71 (d, J=3.7 Hz, 1H), 6.88 (d, J=3.5 Hz, 1H), 7.26 (d, J=3.8 Hz, 1H), 95 7.47-7.59 (m, 4H), 7.97 (dd, J=8.3’ 1.4 Hz, 1H); 13 c NMR: 6 107.15, 108.97, 111.96, 122.76, 128.39, 129.17, 132.39, 137.52, 143.60, 145.23, 150.56, 150.94, 181.93; MS: m/e (rel. intensity) 238 (M+, 91), 105 (100), 77 (82), 51 (65); UV-vis: )max ( :M) 357.5 (2.27x104); IR: cm‘1 1640. The column was flushed by air to dryness. The silica gel on the top of the column was suspended in CHCl3 (150 mL) and the suspension was stirred for 2h. Filtration and evaporat- ion of the solvent in vacuo gave the crude diketone which was recrystallized from methylene chloride and hexanes to give 37c (81.9 mg, 6%) as small yellow plates: m.p. 185- 187°C; 1H NMR: 5 7.04 (d, J=3.7 Hz, 2H), 7.32 (d, J=3.7 Hz, 2H), 7.49-7.66 (m, 6H), 7.99 (d, J=8.0 Hz, 4H); 13 C NMR: 6 110.36, 122.31, 128.52, 129.23, 132.75, 137.14, 148.73, 152.11, 182.01; MS: m/e (rel. intensity) 342 (M+, 53), 209 (11), 105 . - . 4 (100), 77 (77), UV-VlS. )max ( eM) 367.5 (3.47x10 ), 385.5 1 (3.26x104); IR: cm‘ 1638. 5-Benzoyl-2,2':5',2"—terfuran 36b and S,5"—dibenzoy1- 2,2':5',2"-terfuran 378 Using the procedure described for 36a, the desired ketone 36b (1.27 g, 42%) was obtained from a-terfuran 12 (2.0 g, 10 mmol) and N,N-dimethylbenzamide (2.3 g, 15.4 mmol). Recrystallization of the ketone 36b from methylene chloride and hexanes gave golden yellow needles: m.p. 85-870C; 1H NMR: 6 6.50 (dd, J=3.0, 1.8 Hz, 1H), 6.68 (t, J=4.0 Hz, 2H), 6.68 (d, J=3.7 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 7.28 (d, 96 J=3.6 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.47-7.60 (m, 3H), 7.97 (d, J=7.0 Hz, 2H); 13C NMR: 5 106.52, 107.32, 110.90, 111.61, 122.90, 128.37, 129.10, 132.34, 137.51, 142.52, 144.13, 145.69, 147.42, 150.98, 181.77; MS: m/e (rel. intensity) 304 (M+, 2), 171 (8), 149 (38), 105 (31), 57 (65), 43 (100); . _ 3 4 , , uv-v1s. )max ( eM) 304.0 (4.64x10 ), 395.0 (1.26x10 ), IR. cm’1 1638; Exact mass calcd for C19H1204: 304.0735, found 304.0733. The diketone 37d was obtained similarly from the silica gel on the top of the column. Recrystallization of the crude diketone 37d from methylene chloride and hexanes gave bright 1 yellow fluffy solid (250 mg, 6%) : m.p. 171-172°C; H NMR: 5 6.88 (d, J=3.7 Hz, 2H), 7.02 (s, 2H), 7.33 (d, J=3.7 Hz, 2H), 7.49-7.68 (m, 6H), 8.00 (d, J=7.0 Hz, 4H); ‘3 C NMR: 6 108.31, 111.05, 122.64, 128.42, 129.14, 132.52, 137.80, 145.81, 149.42, 151,37, 181.83; MS: m/e (rel. intensity) 408 (M+, 100), 275 I . O 4 (15), 105 (68), UV-VIS. xmax ( 6M) 404.5 (3.75x10 ), 423.5 (3.43x104); IR: cm71 1536; Exact mass calcd for C26H1605: 408.0998, found 408.1008. S-(4-Methoxybenzoyl)—2,2'-bifuran 36c and 5,5'-Di-(4-methoxyhenzoyl)-2,2'-hifuran 37e To a solution of a-bifuran 11 (500 mg, 3.7 mmol) in dry ether (15 mL) at -60°C was added n-BuLi (3.7 mmol) in one portion. The solution was stirred at room temperature for further 2h. The solution was cooled at -60°C and a solution of N,N-dimethyl-(4-methoxy)-benzamide (700 mg, 3.9 mmol) in 97 dry ether (3 mL) was added dropwise. The solution was stirred at room temperature overnight. The solution was cooled in an ice bath and 10% HCl (20 mL) was added. The mixture was stirred for 2h and the two layers were separated. The aqueous layer was extracted with CHCl (3x50 mL). The combined 3 organic layers were washed with water, saturated NaCl solution and dried over anhydrous MgSO Removal of the solvent in 4. vacuo gave the crude product which was chromatographed over silica gel by flash technique using Et O:hexanes (v/v=1/1) as 2 eluent to give 557.1 mg (56%) of ketone 36c. Recrystallization from methylene chloride and hexanes gave the ketone 36c as pale yellow cubes: m.p. 102-104°C; 1H NMR: 6 3.89 (s, 3H), 6.52 (dd, J=3.6, 1.8 Hz, 1H), 6.71 (d, J=3.7 Hz, 1H), 6.86 (d, J=3.5 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 7.27 (d, J=3.7 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 8.03 (d, J=8.8 Hz, 2H); 13C NMR: 6 55.43, 107.06, 108.58, 111.89, 113.69, 121.74, 130.05, 131.58, 143,42, 145.35, 149.98, 151.34, 163.18, 180.52; MS: m/e (rel. intensity) 268 (M+, 53), 135 (100), 77 (37); UV-vis: 4 , . -1 Amax ( 6“) 356.5 (3.16x10 ), IR. cm 1630. The column was flushed by air to dryness. The silica gel on the top of the column was suspended in CHCl (150 mL) and 3 the suspension was stirred for 2h. Filtration and evaporat- ion of the solvent gave the crude diketone which was recryst- allized from methylene chloride and hexanes to give 37e‘ (89.6 mg, 6%) as pale yellow leaflet: m.p. 182-183OC; 1H NMR: 5 3.90 (s, 6H), 6.99-7.02 (m, 6H), 7.31 (d, J=3.7 Hz, 2H), 13 8.06 (d, J=8.8 Hz, 4H); C NMR: 6 55.47, 109.99, 113.80, 98 121.34, 129.70, 131.69, 148.31, 152.45, 163.43, 180.47; ms: m/e (rel. intensity) 402 (M+, 16), 152 (28), 135 (54), 84 . 4 (55), 49 (100), UV-VlS. Amax ( eM) 372.0 (4.24x10 ), 389.0 (3.98x104); IR: cm‘1 1632. 5-(4-Methoxybenzoyl)-2,2':5',2"-terfuran 36d and 5,5"-Di-(4-methoxybenzoyl)-2,2':5',2"-terfuran 37f Using the procedure described for 36¢ except using Et20:hexanes (v/v=3/1) as eluent for flash column chromato- graphy, the monoketone 36d (1.53 g, 46%) was obtained from a -terfuran 12 (2.0 g, 10 mmol) and N,N,-dimethyl-(4-methoxy)- benzamide (2.0 g, 11.1 mmol). Recrystallization from methylene chloride and hexanes gave 366 as yellowish brown leaflet: m.p. 102-104°C;.1H NMR: 15 3.90 (s, 3H), 6.49 (dd, J=3.6, 1.8 Hz, 1H), 6.68 (t, 2H), 6.78 (d, J=3.7 Hz, 1H), 6.92 (d, J=3.6 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 7.28 (d, J=3.8 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 8.04 (d, J=9.0 Hz, 2H); 13C NMR: 5 55.38, 106.40, 106.61, 107.23, 110.47, 111.58, 113.67, 121.81, 130.05, 131.52, 142.45, 144.29, 145.75, 147.25, 149.61, 151.40, 163.16, 180.35; MS: m/e (rel. intensity) 334 (M*, 100), 135 (34); UV-vis: )max ( 4M) 304.0 (2.81x104), 393.0 (4.61x104); IR: cm"-1 1636; Exact mass calcd for C20H14 5: 334.0841, found 334.0851. The diketone 37f was obtained similarly from the silica gel on the top of the column. Recrystallization of the crude diketone from methylene chloride and hexanes gave 37f (218 mg, 5%) as bright yellow fluffy solid: m.p. 183-185°C; 99 1H NMR: 5 3.91 (s, 6H), 6.48 (d, J=3.7 Hz, 2H), 6.98 (s, 2H), 7.01 (d, J=8.9 Hz, 4H), 7.30 (d, J=3.9 Hz, 2H), 8.05 (d, J: 8.7 Hz, 4H); 13C NMR: 6 55.44, 108.16, 110.67, 113.75, 121.67, 129.90, 131.61, 145.84, 148.98, 151.78, 163.31, 180.42; MS: m/e (rel. intensity) 468 (M+, 100), 135 (58); UV-vis: xmax ( a”) 302.0 (2.41x104), 404.0 (2.47x104), 424.0 (1.35x104); IR: cm-1 1628. Bis(5-2,2'-bifuryl) ketone 39a n-BuLi (3.7 mmol) was added in one portion to a solution of (z-bifuran 11 (500 mg, 3.7 mmol) in dry ether (20 mL) at -60°C. The solution was stirred at room temperature for additional 2h. The solution was cooled at -60°C and a solution of carbamate 38 (200 mg, 1.9 mmol) in dry ether (2 mL) was added dropwise. The solution was stirred at room temperature overnight. The solution was cooled in an ice bath and 10% HCl (20 mL) was added. The mixture was stirred for 2h and the two layers were separated. The aqueous layer was extracted with CHCl3 (3x50 mL). The combined organic layers were washed with water, saturated NaCl solution and dried over anhydrous MgSO Removal of the solvent in vacuo 4. gave a dark brown oil which was chromatographed over silica gel by flash technique using Et20:hexanes (v/v=4/1) as eluent to give 270.9 (49%) of ketone 39a as yellow viscous oil. Recrystallization of the oil from methylene chloride and 1 hexanes gave dark brown needles: m.p. 121-122°C; H NMR: 6 6.53 (dd, J=3.5, 1.8 Hz, 2H), 6.74 (d, J=3.7 Hz, 2H), 6.88 100 (d, J=3.5 Hz, 2H), 7.51 (d, J=1.6 Hz, 2H), 7.62 (d, J=3.7 Hz, 2H); 13C NMR: 5 107.40, 108.76, 111.93, 121.34, 143.54, 145.28, 149.98, 150.37, 167.27; MS: m/e (rel. intensity) 294 (M+, 100), 161 (23), 105 (69); UV-vis: )max ( eM) 274.0 (1.48x104), 394.0 (2.53x104); IR: cm_1 1625; Exact mass calcd for C17H1OOS: 294.0528, found 294.0535. Bis(5-2,2':5',2"-terfuryl) ketone 39b Using the procedure described for 39a, the symmetrical ketone 39b (852 mg, 40%) was obtained from a-terfuran 12 (2.0 g, 10 mmol) and carbamate 38 (515 mg, 5 mmol). Crystall- ization from the eluent gave yellowish orange fluffy solid: m.p. 199-2010C; 1H NMR: (6 6.51 (dd, J=3.4, 1.8 Hz, 2H), 6.69 (t, J=3.6 Hz, 4H), 6.82 (d, J=3.8 Hz, 2H), 6.96 (d, J=3.6 Hz, 2H), 7.46 (d, J=1.4 Hz, 2H), 7.64 (d, J=3.8 Hz, 2H); 13C NMR: 6 106.61, 107.41, 107.70, 110.82, 111.67, 121.50, 142.60, 144.34, 145.84, 147.48, 149.75, 150.66, 167.13; MS: m/e (rel. intensity) 426 (M+, 100), 171 (20); uv-vis: Amax ( eM) 319.5 (2.15x104), 431.5 (3.15x104); IR: cm-1 1630; Exact mass calcd for C25H14O7: 426.0739, found 426.0716. 5,5'-d-2,2'-Bifuran 40a To a solution of a—bifuran 11 (1.0 g, 7.5 mmol) in dry ether (15 mL) at -60°C was added n-BuLi (15 mmol) in one portion. The solution was stirred at room temperature for 2h. The solution was cooled at -70°C and quenched with D O 2 (1 mL) via a syringe. After the solution was stirred at room 101 temperature for 3h, water (10 mL) was added. The two layers were separated and the aqueous solution was extracted with ether (2x10 mL). The combined organic layers were washed with saturated NaCl solution and dried over anhydrous MgSO4. Removal of the solvent in vacuo gave a brown liquid which was vacuum distilled to give the deuteriated 40a (666.6 mg, 65%) as pale yellow liquid: b.p. 60-61OC/10 mmHg; 1H NMR: 6 6.40 (d, J=3.4 Hz, 2H), 6.51 (d, J=3.4 Hz, 2H); 13C NMR; 6 105.02, 111.07, 140.94, 141.43, 141.93, 146.54; MS: m/e (rel. intensi- ty) 137 (M++1, 53), 136 (m*, 100), 106 (30), 80 (66). 5,5"-d-2,2':5',2"-Terfuran 40b Using the procedure described for 40a except the crude product was purified by flash column chromatography over silica gel using Et O:hexanes (v/v=1/5) as eluent. The 2 deuteriated 40b (378.6 mg, 75%) was obtained as a white solid from a-terfuran 12 (500 mg, 2.5 mmol): m.p. 60-61°C; 1H NMR: 5 6.44 (d, J=3.5 Hz, 28), 6.59 (s, 2H), 6.60 (d, J=3.5 Hz, 2H); 13c NMR: 5 105.38, 106.87, 111.22, 141.19, 141.69, V 142.19, 145.69, 146.16; MS: m/e (rel. intensity) 202 (M+, 100), 172 (15), 117 (53); UV-vis: )max ( 4M) 333.0 (2.52x1o4), 351.0 (1.52x104). 5,5'"-d-2,2':5',2":5",2"'-Quaterfuran 40c Using the procedure described for 40a except the aqueous solution was extracted with CHCl (3x30 mL) and the crude 3 product was purified by flash column chromatography over 102 silica gel using Et O:hexanes (v/v=1/5) as eluent. The 2 a-quaterfuran 13 (200 mg, 0.75 mmol) gave the deuteriated derivative 40c (34.8 mg, 17%) as pale yellow solid: m.p. 161- 162°C; 1H NMR: 5 6.47 (d, J=3.4 Hz, 2H), 6.63 (dd, J=3.4, 1.8 HZ, 4H), 6.67 (d, J=3.5 Hz, 2H); 13 C NMR: 5 105.53, 107.03, 107.24, 111.28, 141.28, 141.77, 142.28, 145.36, 145.91, 146.14; ms: m/e (rel. intensity) 269 (M++1, 74), 268 (m*, 100); UV-vis: Amax ( 6M) 274.5 (7.14x103), 366.0 12.93x104), 385.5 (1.88x104). 5,S'-Dimethyl-2,2'—bifuran 41a To a solution of a-bifuran 11 (700 mg, 5.2 mmol) in dry ether (15 mL) at -600C was added n-BuLi (11 mmol) in one portion. The solution was stirred at room temperature for 2h. The solution was cooled at -70°C and quenched with MeI (1 mL) via a syringe. After the solution was stirred at room temperature overnight, water (10 mL) was added. The two layers were separated and the aqueous solution was extracted with ether (2x10 mL). The combined organic layers were washed with saturated NaCl solution and dried over anhydrous M9804. Removal of the solvent in vacuo gave a brown liquid which was vacuum distilled to give 93 mg of (x-bifuran 11. The residue was flash column chromatographed over silica gel using Et20:hexanes (v/v=1/5) as eluent to give the dimethyl derivative 41a (352.5 mg, 48% based on recovered 11) as pale yellow liquid which crystallized upon vaCuum drying: m.p. 45 37-38°C (lit. b.p. 41-43°C/2.8 mmHg); 1H NMR: 5 2.32 (d, 103 J=0.7 Hz, 6H), 5.99 (dd, J=3.1, 0.8 Hz, 2H), 6.34 (d, J=3.1 Hz, 2H); 13C NMR: 5 13.53, 105.05, 107.18, 145.23, 151.22, MS: m/e (rel. intensity) 162 ( M+, 100), 119 (75), 43 (84); . 4 3 UV-VlS. Amax ( 6M) 296.5 (1.33x10 ), 309.0 (8.64x10 ). 5,5"-Dimethyl-2,2':5',2"-terfuran 41b Using the procedure described for 41a, the dimethyl compound 41b (459.8 mg, 81%) was obtained as a white solid fr°m “-terfuran ‘2 (500 mg. 2.5 mmol): m.p. 92-93°c (lit.21f 1 m.p. 91°C); H NMR: 5 2.35 (s, 6H), 6.03 (d, J=3.2 Hz, 2H), 6.47 (d, J=3.2 Hz, 2H), 6.50 (s, 2H); 13C NMR: 6 13.61, 105.90, 106.18, 107.46, 144.78, 145.63, 151.88; MS: m/e (rel. intensity) 228 (m*, 100), 185 (42); UV-vis: Amax ( ‘H’ 342.0 (2.48x104), 360.0 (1.55x104). 5,5"'-Dimethyl-2,2':5',2":5",2"'-quaterfuran 41c Using the procedure described for 41a except the aqueous solution was extracted with CHCl3 (3x30 mL), the a-quaterfuran 13 (200 mg, 0.75 mmol) gave the desired dimethyl derivative 41c (19.2 mg. 9%) as yellow solid: m.p. 178-180°C; 1H NMR: 6 2.36 (s, 6H), 6.04-6.05 (m, 2H), 6.50 (d, J=3.2 Hz, 2H), 6.53 (d, J=3.5 Hz, 2H), 6.63 (d, J=3.5 Hz, 2H); 13c NMR: 5 13.63, 106.06, 106.48, 107.02, 107.55, 144.66, 145.10, 146.12, 152.07; MS: m/e (rel. intensity) 294 (M+, 100), 147 (30), 109 (21); UV-vis: )max ( eM) 281.5 (6.38x103), 373.0 (2.36x104), 393.0 (1.64x104). 104 5,5"-Dibenzoy1-2,2':5',2"—terfuran 37d n-BuLi (20 mmol) was added in one portion to a solution of a-terfuran 12 (2.0 g, 10 mmol) in dry ether (40 mL) at -60°C. The solution was stirred at room temperature for 2h with precipitate formation. The suspension was cooled at -60°C and a solution of N,N—dimethylbenzamide (3.5 g, 23.5 mmol) in dry ether (10 mL) was added dropwise. After the solution was stirred at room temperature overnight, 10% HCl (40 mL) was added and the mixture was stirred for 4h. The two layers were separated and the aqueous layer was extracted with CHCl3 (4x50 mL). The combined organic layers were washed with water, saturated NaCl solution and dried over anhydrous MgSO4. Removal of the solvent in vacuo gave dark brown solid. The crude product was recrystallized from methylene chloride and hexanes with charcoal decolorization to give 376 (1.24 g, 30%) as yellow fluffy solid: spectra data for 37d, see page 96. 2,2-Bis(5-formyl-2—furyl)propane 44 Freshly distilled phosphorous oxychloride (15.3 g, 0.1 mol) was added dropwise to a solution of dry dimethylform- amide (8.0 g, 0.11 mol) in dry 1,2-dichloroethane (25 mL) at 0°C. The mixture was stirred at 0°C for additional 2h with white precipitate formation. A solution of 2,2-difuryl- propane 4630 (8.0 g, 45.5 mmol) in dry 1,2-dichloroethane (75 mL) was added to the cooled reagent slurry over a period of 10 min. After the resulting solution had been stirred at 105 room temperature overnight, the yellowish brown solution was cooled in an ice bath and a solution of sodium acetate (80 g, 0.98 mol) in water (400 mL) was added. The two-phase mixture was stirred at room temperature for 8h. The layers were separated and the aqueous phase was extracted with CHCl3 (5x50 mL). The combined organic layers were washed with water (100 mL), saturated NaHCO3 solution (100 mL), saturated NaCl solution (100 mL), dried over anhydrous MgSO4 and filtered. Removal of the solvent in vacuo gave the crude product which was recrystallizaed from ethanol to give the dialdehyde 44 (9.4 g, 89%) as pale yellow crystal : m.p. 81- 83°C; 1H NMR: 5 1.75 (s, 6H), 6.35 (d, J=3.6 Hz, 2H), 7.20 (d, J=3.6 Hz, 2H), 9.35 (s, 2H); 13C NMR: 6 25.62, 38.33, 108.30, 122.41, 152.01, 164.61, 177.27; MS: m/e (rel. inten- sity) 232 (M+, 23), 217 (100); UV-vis: )max ( 4M) 286.0 (4.00x104); IR: cm"1 1665. 2,2-Bis(5-acety1-2-furyl)propane 47 To a solution of 2,2-difurylpropane 46 (2.0 g, 11.4 mmol) in acetic anhydride (5 mL) at 0°C was added freshly distilled BF3.OEt (0.3 mL) in one portion via a syringe. The solution was stirred at 0°C for 30 min and then at room temperature for another 30 min. The solution was poured into water (50 mL) and neutralized with solid Na CO . The aqueous solution 2 3 was extracted with CH2C12 (3x50 mL). The combined organic layers were washed with water (30 mL), saturated NaCl solution and dried over anhydrous M9804. Filtration and ‘Iir‘xfi. “Bu 1. 106 evaporation of the solvent in vacuo gave an orange oil which was flash column chromatographed over silica gel using Et O:hexanes (v/v=3/1) as eluent to give 1.5 g (49%) of 2 diketone 47 as pale brown viscous oil: 1H NMR: 16 1.78 (s, 6H), 2.45 (s, 6H), 6.26 (d, J=3.7 Hz, 2H), 7.11 (d, J=3.6 Hz, 2H); 13C NMR: 6 25.72, 25.78, 38.16, 107.70, 118.17, 151.81, 163.07, 186.21; ms: m/e (rel. intensity) 260 (M+, 19), 245 (100); UV-vis: Amax ( 6M) 287.5 (2.79x104); IR: cm”1 1675. Bis-Mannich base 45 A mixture of diketone 47 (2.0 g, 7.7 mmol), paraformalde- hyde (550 mg, 18.3 mmol), dimethylamine hydrochloride (1.50 g, 18.3 mmol) and concentrated HCl (0.08 mL) in 95% ethanol (5 mL) was heated under reflux for 16h. After cooling in the freezer for several days, the precipitate was collected and washed with ice—cold ethanol to give the bis-Mannich base hydrochloride (1.39 g, 40%) as white solid: m.p. 179-181°C; 1H NMR: (020, DSS) 5 1.78 (s, 6H), 2.92 (s, 12H), 3.53 (s, 8H), 6.61 (d, J=3.7 Hz, 2H), 7.54 (d, J=3.8 Hz, 2H); MS: m/e (rel. intensity) 450, 448, 446 (M++4, m*+2, M+ (not observed)), 374 (0.4), 329 (23), 269 (53), 58 (100); IR: c111”1 1660. The bis-Mannich base hydrochloride was treated with an aqueous ammonium solution and extracted with ether (3x50 mL). The combined organic extracts were washed with water (10 mL), then saturated NaCl solution (10 mL) and dried over anhydrous M9804. Removal of the solvent in vacuo gave the free bis-Mannich base 45 which was used immediately: 1H NMR: 6' 107 1.75 (s, 6H), 2.25 (s, 12H), 2.74 (t, 4H), 2.97 (t, 4H), 6.28 (d, 2H); 7.18 (d, 2H). 2-Furyl-(5—formyl-2-furyl)-2,2-propane 50 Freshly distilled phosphorous oxychloride (5.2 g, 33.9 mmol) was added dropwise to a solution of dry dimethylform— amide (2.7 g, 36.9 mmol) in dry 1,2-dichloroethane (15 mL) at 0°C. The mixture was stirred at 00C for additional 2b with white precipitate formation. A solution of 2,2-difuryl- propane 46 (5.0 g, 28.4 mmol) in dry 1,2-dichloroethane (35 mL) was added to the cooled reagent slurry over a period of 5 min. After the resulting solution had been stirred at room temperature overnight, the yellowish brown solution was cooled in an ice bath and a solution of sodium acetate (30 g, 0.37 mol) in water (150 mL) was added. The two-phase mixture was stirred at room temperature for 8h. The layers were separated and the aqueous phase was extracted with CHCl3 (3x50 mL). The combined organic layers were washed with water, saturated NaHCO3 solution, saturated NaCl solution and dried over anhydrous MgSO4. Filtration and evaporation of the solvent in vacuo gave a brown oil which was chromatographed over silica gel by flash technique using Et20:hexanes (v/v=1/1) as eluent to give the aldehyde 50 (5.2 g, 90%) as yellow solid: m.p. 50-52°C; 1H NMR: 5 1.75 (s, 6H), 6.14 (d, J=3.2 Hz, 1H), 6.21 (d, J=3.6 Hz, 1H), 6.35 (dd, J=3.2, 1.8 Hz, 1H), 7.15 (d, J=3.6 Hz, 1H), 7.36 (d, J: 1.7 Hz, 1H), 9.56 (s, 1H); 13C NMR: 5 25.87, 37.86, 104.79, 108 107.76, 110.05, ;22.40, 141.58, 151.81, 158.16, 166.81, 177.30, MS: m/e (rel. intensity) 204 (M+, 15), 189 (100); UV-vis: )max ( eM) 289.5 (1.59x104); IR: cnn‘1 1665. 1,4-Bis(2,2-difurylpropane)-1,4-butanedione 51 To a hot stirred solution of thiazolium salt (400 mg, 1.49 mmol) and sodium acetate (240 mg, 2.93 mmol) in absolute ethanol (20 mL) was added the aldehyde 50 (3.0 g, 14.7 mmol) in one portion. The vinyl sulfone (882.8 mg, 7.5 mmol) was added dropwise to the hot solution. The mixture was refluxed overnight and then poured into water. The aqueous solution was extracted with chloroform and the combined organic extracts were suction filtered. The filtrate was washed with saturated NaCl solution and dried over anhydrous M9804. Removal of the solvent in vacuo gave the crude product which was flash column chromatographed over silica gel using Et20:hexanes (v/v=3/5) as eluent to give 2.53 g (79%) of 1,4-diketone 51 as pale yellow viscous oil: 1H NMR: 6 1.70 (s, 12H), 3.20 (s, 4H), 6.11 (d, J=3.2 Hz, 2H), 6.16 (d, J: 3.6 Hz, 2H), 6.30 (dd, J=3.3, 1.8 Hz, 2H), 7.15 (d, J=3.6 Hz, 2H), 7.35 (d, J=1.8 Hz, 2H); 13C NMR: 5 25.98, 31.75, 37.74, 104.62, 107.26, 109.99, 118.11, 141.46, 151.19, 158.51, 164.69, 187.21; MS: m/e (rel. intensity) 434 (M+, 5), 419 (3), 205 (100), 189 (70), 137 (20), 109 (19); UV-vis: A ' ( 4M) max 1 289.5 (3.62x104); IR: cm' 1675. 109 5,5"-Bis(dimethylfurfuryl)-2,2':5',2"-terfuran 52 Tbaulice-cold solution of 1,4-diketone 51 (2.22 g, 5.12 mmol) in acetic anhydride (35 mL) was added concentrated HCl (1.5 mL) in one portion. The solution was stirred at room temperature for 4 days. The solution was poured into water (150 mL) and stirred for 2h. The aqueous solution was extract- ed with CHCl (3x50 mL). The combined organic layers were 3 washed with water, saturated NaHCO3 solution and saturated NaCl solution. After drying over anhydrous M9804, the solvent was removed in vacuo to give an oil which was purified by flash column chromatography over silica gel using Et20:hexanes (v/v=1/3) as eluent to give the furan compound 52 (1.24 g, 58%) as white solid: m.p. 69-71OC; 1H NMR: 6 1.6715, 12H), 6.04 (d, J=3.5 Hz, 2H), 6.06 (d, J=3.3 Hz, 2H), 6.28 (dd, J: 3.3, 1.8 Hz, 2H), 6.47 (d, J=3.3 Hz, 2H), 6.50 (s, 2H), 7.31 (d, J=1.8 Hz, 2H); 13c NMR: 5 26.34, 37.48, 104.20, 105.82, 106.11, 106.29, 109.93, 141.19, 145.04, 145.66, 159.66, 159.72; MS: m/e (rel. intensity) 416 (M+, 100), 410 (85); UV-vis: Amax ( 4M) 344.5 (3.81x104), 363.5 (2.42x104); Exact mass calcd for C H 0 ° 416.1624, found 416.1619. 26 24 5' S, 5 ' ' -Bis( S-formyl-dimethylfurfuryl)-2, 2 ' : 5' , 2 ' ' -terfuran 48 Using the procedure described for 44, the furan compound 52 (3.4 g, 8.17 mmol) gave 2.5 g (65%) of dialdehyde 48. Recrystallization of 48 from ethanol gave yellow solid: m.p. 172-174°C; 1H NMR: 6 1.75 (s, 12H), 6.19 (d, J=3.3 Hz, 2H), 6.24 (d, J=3.6 Hz, 2H), 6.52 (s, 4H), 7.16 (d, J=3.6 Hz, 2H), 110 9.57 (s, 2H); 13C NMR: 5 26.01, 38.10, 105.99, 106.64, 106.93, 107.99, 122.40, 145.40, 145.51, 151.94, 157.86, 166.51, 177.39; MS: m/e (rel. intensity) 472 (M+, 100), 457 (63), 137 (32); UV-vis: A ( 6M) 286.5 (4.13x104), 344.5 (3.78x104), max 1 361.5 (2.47x104); IR: cm- 1680; Exact mass calcd for C28H24O7: 472.1522; found 472.1529. 5,5"—Bis(5-acetyl-dimethylfurfuryl)-2,2':5',2"-terfuran 53 To a solution of furan compound 52 (1.21 g, 2.9 mmol) in acetic anhydride (2 mL) at 0°C was added freshly distilled BF3.OEt (0.07 mL) in one portion via a syringe. The solution was stirred at 00C for 30 min and then at room temperature for another 30 min. The solution was poured into water and neutralized with solid Na2C03. The aqueous solution was extracted with CHC13. The combined organic layers were washed with water, saturated NaCl solution and dried over anhydrous M9804. Filtration and evaporation of the solvent in vacuo gave the crude product which was flash column chromatographed over silica gel using Et20:hexanes (v/v=5/1) as eluent to give the diketone 53 (316 mg, 22%) as white solid: m.p. 109- 110°C; 1H NMR: 5 1.74 (s, 12H), 2.43 (s, 6H), 6.17 (t, J: 3.8 Hz, 4H), 6.51 (d, J=3.7 Hz, 4H), 7.09 (d, J=3.5 Hz, 2H); 13C NMR: 5 25.81, 26.10, 37.95, 105.94, 106.55, 106.70, 107.52, 118.25, 145.34, 145.54, 151.75, 158.19, 164.45, 186.45; MS: m/e (rel. intensity) 500 (M+, 100), 485 (69), 280 (29), 235 (17), 151 (21), 43 (15); IR: cm‘1 1682. Cyclization of 14c to 42b To a solution of aldehyde 14c (100 mg, 0.44 mmol) in dry CH Cl (20 mL) at 0°C was added Et 2 2 2 one portion. The resulting reddish brown solution was stirred AlCl (1.0M, 0.5 mL) in at 00C for 3h and then at room temperature for additional 48h. The solution was passed through a column of silica gel by flash technique using CH2C12 as eluent to give 57.4 mg of 42b as yellowish brown viscous oil: 1H NMR: 6 1.01 (t, 3H), 2.10 (q, 2H), 4.05 (broad m, 1H), 6.18 (d, 2H), 6.50 (m, 4H); 13C NMR: 5 12.02, 25.56, 26.06, 26.33, 26.47, 40.73, 106.05, 106.42, 107.85, 145.19, 145.61, 154.85; MS: m/e (rel. inten- sity) 720 (M+ for n=3, 9), 691 (M+-Et, 11), 40 (100); UV-vis: Amax 346.0, 366.5. Cyclization of (I-terfuran 12 with benzaldehyde to 42¢ Phosphorous oxychloride (329 mg, 2.1 mmol) was added to a solution of a-terfuran 12 (200 mg, 1 mmol) and benzaldehyde (2.0 g, 20 mmol) in methylene chloride (100 mL)., The solution was stirred at room temperature for 24h. Evapor- ation of the solvent to one—fifth volume and flash column chromatography of the reaction mixture over silica gel using CHZCl2 as eluent gave 144.7 mg of 42c as pale greenish solid: 1H NMR: 6 5.55 (broad s, 1H), 6.08 (broad s, 2H), 6.52 (m, 4H), 7.32 (m, 5H); 13 c NMR: 5 45.11, 106.18, 106.83, 109.82, 127.35, 128.43, 128.61, 139.02, 145.54, 145.78, 153.83; MS: m/e (rel. intensity) 864 ()1+ for n=3, 7), 369 (29), 355 (36), 295 (54), 281 (51), 221 (100), 207 (78), 147 (48); 112 MS (FD)46: m/e (rel. intensity) 1440 (H+ for n=5, 14), 1276 (41), 1152 (M+ for n=4, 100), 864 (M+ for n=3, 20), 721 (25), 576 ()4+ for n=2, 34); UV-vis: )max 338.5, 346.0, 369.0. Phenylbis(5-2,2':5',2"-terfuryl)methane 55a and 5,5"-bis(phenyl(5-2,2':5',2"-terfuryl)methyl)-terfuran 56a To a solution of ketone 36b (100 mg, 0.33 mmol) in absolute methanol (15 mL) at 0°C was added sodium borohydride (100 mg, 2.6 mmol) portionwise. The temperature was raised slowly to room temperature and the solution was stirred at room temperature for additional 15 min. The solution was poured into water (30 mL) and then extracted with CH Cl 2 2 (3x30 mL). The combined organic extracts were washed with saturated NaCl solution (20 mL) and dried over anhydrous MgSO4. Removal of the solvent in vacuo gave the alcohol 57a quantitatively as pale yellow oil: 1H NMR: 6 2.42 (bs, 1H), 5.87 (s, 1H), 6.14 (d, J=3.3 Hz, 1H), 6.46 (dd, J=3.3, 1.8 Hz, 1H), 6.50-6.64 (m, 5H), 7.27-7.50 (m, 5H); MS: m/e (rel. intensity) 306 (M+, 26), 289 (27), 115 (40), 105 (100), 95 (54), 77 (82), 51 (56); IR: cm"1 3200-3600 (broad). The alcohol 57a was redissolved in dry CH C12 (20 mL). 2 a -Terfuran 12 (200 mg, 1 mmol) and a catalytic amount of p-TsOH was added and the solution was then stirred at room temperature for 4h. The solution was washed with saturated NaHCO3 solution (10 mL), saturated NaCl solution (10 mL) and dried over anhydrous MgSO4. After filtration, the solvent was removed in vacuo to give a mixture of products which was 113 purified by flash column chromatography over silica gel using Et O:hexanes (v/v=1/5) as eluent to give 55a (83.5 mg, 52% 2 based on ketone 36b) as colorless viscous oil: 1H NMR: 6 5.54 (s, 1H), 6.11 (d, J=3.3 Hz, 2H), 6.44 (dd, J=3.3, 1.8 Hz, 2H), 6.52-6.58 (m, 8H), 7.27-7.37 (m, 5H), 7.39 (d, J=1.7 Hz, 2H); 13c NMR: 5 45.09, 105.37, 106.20, 106.82, 106.91, 109.85, 111.43, 127.34, 128.40, 128.61, 138.02, 141.90, 145.63, 145.75, 146.28, 153.87; MS: m/e (rel. intensity) 488 (M+, 100), 411 (50), 327 (20), 289 (33), 244 (39), 161 (88), 95 (67). Further elution of the column gave 56a (29.3 mg, 11% based on ketone 36b) as pale greenish viscous oil: 1H NMR: 6 5.53 (s, 2H), 6.09 (m, 4H), 6.43 (dd, J=3.3, 1.8 Hz, 2H), 6.50-6.58 (m, 12H), 7.27-7.38 (m, 10H), 7.39 (d, J=1.6 Hz, 2H); 13C NMR: 5 45.09, 105.36, 106.14, 106.20, 106.82, 106.91, 109.82, 111.43, 127.33, 128.40, 128.60, 139.02, 141.90, 145,54, 145.63, 145.77, 146.28, 153.81, 153.89; MS: m/e (rel. intensity) 776 (M+, 100), 699 (4). 4-Methoxyphenylbis(5-2,2':5',2"-terfuryl)methane 55b and 5,5"-bis(4-methoxyphenyl-(5-2,2':5',2"-terfuryl)lethyl)- 'terfuran 56b Using the procedure described for 55a and 56a except using Et20:hexanes (v/v=3/5) as eluting solvent for the flash column chromatography, the ketone 36d (200 mg, 0.60 mmol) gave the alcohol 57b quantitatively which in turn gave the open-chain compound 55b (152 mg, 49% based on ketone 36d) as colorless viscous oil: 1H NMR: 6 3.75 (s, 3H), 5.48 (s, 114 1H), 6.08 (d, J=3.3 Hz, 2H), 6.41 (dd, J=3.3, 1.8 Hz, 2H), 6.51-6.58 (m, 8H), 6.85 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.37 (d, J=1.4 Hz, 2H); 13C NMR: 6 44.30, 55.15, 105.32, 106.17, 106.76, 106.87, 109.64, 111.40, 113.96, 129.37, 131.08, 141.86, 145.64, 146.25, 154.24, 158.84; MS: m/e (rel. inten- sity) 518 (M+, 12), 411 (3), 161 (60), 105 (55), 95 (100). Further elution of the column gave 56b (55.8 mg, 11% FM based on ketone 36d) as pale greenish viscous oil: 1H NMR:6 : 3.78 (5, 5H), 5.47 (5, 2H), 6.09 (m, 4H), 6.45 (dd, 2H), 6.46-6.58 (m, 12H), 6.86 (d, 4H), 7.21 (d, 4H), 7.39 (d, 2H); 13 c NMR: 5 44.33, 55.21, 105.35, 106.14, 106.20, 106.76, i 106.90, 109.62, 111.43, 114.02, 129.40, 131.13, 141.87, 145.57, 145.70, 146.31, 154.19, 154.28, 158.87; MS: m/e (rel. inten- sity) 836 (M+, 100), 295 (26), 221 (29), 105 (45). Spectra data for the alcohol 57b: MS: m/e (rel. intensity) 336 (M+, 55), 319 (77), 135 (100), 95 (48), 77 (46); IR: cm"1 3200-3600 (broad). Cyclization of 55a with benzaldeyde to 42¢ Phosphorous oxychloride (32.9 mg, 0.2 mmol) was added to a solution of linear compound 55a (83.5 mg, 0.17 mmol) and benzaldehyde (177.5 mg, 1.7 mmol) in methylene chloride (50 mL). The solution was stirred at room temperature for 9 days until 55a completely disappeared. Evaporation of the sovent to one—fifth volume and flash column chromatography of the reaction mixture over silica gel using CHZCl2 as eluent gave 53.7 mg of 42c as pale green solid: m.p. 128-131OC; 115 1H NMR: 5 5.52 (broad s, 1H), 6.04-6.08 (m, 2H), 6.48-6.52 (m, 4H), 7.31-7.35 (m, 5H); 13C NMR: 5 45.08, 106.16, 106.81, 109.80, 127.34, 128.41, 128.60, 138.97, 145.52, 145.75, 153.82; MS: m/e (rel. intensity) 576 ()1+ for n=2, 17), 221 (28), 207 (68), 44 (100); ms (FAB)47: m/e (rel. intensity) 1152 ()4+ for n=4, 2), 576 ()4+ for n=2, 3); UV-vis: xmax 337.0, 344.5, 368.0. Cyclization of 55b with 4-methoxybenzaldehyde to 42d Phosphorous oxychloride (49.4 mg, 0.32 mmol) was added to a solution of linear compound 55b (135.6 mg, 0.26 mmol) and 4-methoxybenzaldehyde (335.7 mg, 2.5 mmol) in methylene chloride (60 mL). The solution was stirred at room temperat- ure for 18 days until 55b completely disappeared. Evaporat- ion of the solvent to one-fifth volume and flash column chromatography of the reaction mixture over silica gel using CH2C12 as eluent gave 56.4 mg of 42d as pale green solid: m.p. 149-153°C; 1H NMR: 5 3.84 (s, 3H), 5.50 (broad s, 1H), 6.02-6.10 (m, 2H), 6.44-6.54 (m, 4H), 6.85-6.94 (m, 2H), 7.25-7.35 (m, 2H); 13C NMR: 5 44.30, 55.26, 106.16, 106.77, 109.62, 114.00, 129.47, 131.08, 145.54, 145.70, 154.22, 158.85; ms: m/e (rel. intensity) 636 ()4+ for n=2, 11), 207 (4), 142 (11), 44 (100); MS (FAB)47: m/e (rel. intensity) 1272 ()4+ for n=4, 3), 636 ()4+ for n=2, 5); UV—vis: )max 337.0, 345.0, 368.0. APPENDIX 116 ‘Ul . 1.... 5461.5, .no- macacocco661e.-1.Hsusoan -.N.m-mo-e-lssuoo-mou- no ssuuooou «:2 m- um: omm .-< wusmem 117 .oop oc0wpmcmusn1w.P (flaxuswao1.m.m1mvmfin1v.P mo Esuuomdm ELL so am e... msz I n..m 37 4 P NI: omN .mc cusses 118 .cmp wCprocmusn1v.F1AH>Hsuumu 1..N..m".~.N-m.-e-lesuso1~.1- do asuoooou mzz,=- um: ohm .md ensues rELL %J .5 E. a. Q. 01 e. :- e. (D E. 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Tragizwfi gigjfiJVLE—f 151.11.15.04 3.“ It;§3t¥§231::£.l<~fg(0.4.3.31...s 6 3 N 5 .4 hlfiiifl!ii!lr) . pm ocofiomcmusnlv .P (locnoouo.>uso.o-m.momen-..- no ssuuooou.mzz m. as: omm .NNs ensues ELL @.8 Q.N E...- E.m E.m J5 3 137 IJ .Nm ccus~uou-..~..mu.~.~ 1..>usouso.scoos.oou.o-..m.m no 56060066 «:2 m. um: omN .mmd magmas ELL 8.8 n_.N e... E.m E.m 138 LIST OF REFERENCES 11. 12. 13. 14. 15. LIST OF REFERENCES (a) Kekule, F.A. Bull. Soc. Chim. France 1865, 3, 98; (b) Kekule, F.A. Liebigs. Ann. Chem. 1866, 137, 129; (c) Kekule, F.A. 262d. 1872, 162, 77. (a) Armit, J.w.; Robinson, R. J. Chem. Soc. 1922, 121, 827; (b) Armit, J.W.; Robinson, R. (Kid. 1925, 127, 604; (c) Robinson, R. Tetrahedron 1958, 3, 323. Huckel, E.Z. Physik. 1931, 19, 204. Dewar, M.J.S.; Gleicher, G.J. J. Am. Chem. Soc. 1965, 81, 685. Longuett—Higgins, H.C.; Salem. L. Proc. Roy. Soc. (London) 1959, 251a, 172. Sondheimer, F.; Gaoni, Y. J. Am. Chem. Soc. 1960, 82, 5765. Sondheimer, F.; Amiel, Y.; Wolovsky, R. J. Amer. 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Synthesis 1988, 9, 159; (q) Pecunioso, A.; Menicagli, R. J. Org. Chem. 1988, 99, 2614. (a) Stetter, H. Angew. Chem. Int. Ed. Engl. 1976, 19, 639; (b) Stetter, H.; Rajh, B. Chem. Ber. 1976, 199, 534; (c) Stetter, H.; Schreckenberg, M. Chem. Ber. 1974, 191, 2453; (d) Setter, H.; Schmitz, P.H.; Schreck- enberg, M. Chem. Ber. 1977, 119, 1971; (e) Wynberg, H.; Metselaar, J. §ynthetic Commun. 1984, 19, 1. Luo, T-H. Ph.D Thesis, Michigan State University, 1987, pg. 13. (a) Stetter , H. nder, H-J. Angew. Chem. Int. Ed. Engl. 1978, ll, 1. 3 13 1 Chem. Ber. 1 8 , 1226. Owsley, D.C.; Nelke, .M.; Bloomfield, J.J. J. Org. Chem. 1973, 99,901. (a) Amouroux, R.; Chastrette, F.; Chastrette, M. 9; Heterocyclic Chem. 1981, 19, 565; (b) Stibor, I.; Srogl, J.; Janda, M. J.C.S. Chem. Commun. 1975, 397; (c) Grigg, R.; Roffey, P.; Sargent, M.V. J.Chem. Soc (C). 1966, 2327; (d) Grigg, R.; Knight, J.A.; Sargent, M.V. J. Chem. Soc (C). 1966, 976. Ramanathan, V.; Levine, R. J. Org. Chem. 1962, 21, 1216. Ackman, R.G.; Brown, w.H.; Wright, G.F. J. Org. Chem. 1955, 29, 1147. (a) Snider, B.B.; Rodini, D.J.; Darras, M.; Kirk, T.C.; Deutsch, E.A.; Cordova, R.; Price, R.T. Tetrahedron 1981, 91, 3927; (b) Snider, B.B.; Karras, M.; Price, R.T.; Rodini, D.J. J. Org. Chem. 1982, 91, 4538. Colon, I.; Kelsey, D.R. J. Org. Chem. 1986, 91, 2627. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 142 Still, w.c.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 99, 2923. Gilman, H.; Shirley, D.A. J. Am. Chem. Soc. 1949, 11, 1870. ' Lawson, J.K.; Croom, J.T. J. Org. Chem. 1963, 99, 232. Franchimont, A.P.N.; Klobbie, E.A. Recl. Trav. Chim. Pays-Bas. 1889, 9, 29. Levy, G.A.; Nisbet, H.B. J. Chem. Soc. 1938, 1053. Sawa, Y.; Hashimoto, I.; Ryang, M.; Tsutsumi, S. J. Org. Chem. 1968, 99, 2159. Bailey, P.S.; Lutz, R.E. J. Am. Chem. Soc. 1948, 19, 2412. Kooremen, H.J.; Wynberg, J. Recl. Trav. Chim. Pays-Bas. 1967, 99, 37. Niwa, E.; Miyaka, M. Chem. Ber., 1969, 102, 1443. Mukaiyama, T.; Hata, T. Bull. Chem. Soc. Japan 1961, 99, 99. ' Carpita, A.; Rossi, R.; Veracini, C.A. Tetrahedron 1985, 41, 1919. Reisch.; Mester, I. Chem. Ber. 1979, 112, 1493. Arco. M.J.; Trammell, M.H.; White, J.D. J. Org. Chem. 1976, 91, 2075. Mass spectrum was recorded by JEOX HX110 HF mass spect- rometer using field desorption (FD) technique from the Michigan State University Mass Spectrometer Facility. Fast Atom Bombardment (FAB) mass spectrum was obtained using a Varian-MAT CH5 double-focusing instrument equipped with an Ion Tech fast atom bombardment gun. A matrix of dithioerythreitol:dithiothreitol containing trifluoroacetic acid was used.