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"1' ‘1 3‘13““ “““éé‘: 1‘1“ “1‘1““ " ‘ AFRIM ‘g leVé, ‘I 9“" “ “1‘11 ““13" ’5‘" ‘. 113335,.“ :1- 4:: iii? a .1 m 1‘: 1%?" 3:11, 35:33:51“ ‘1‘g . :1“. 1‘ '1 M 4“?) ..,,““‘-";;"4‘ ‘ " €151}. .2111.“ ' '1. -‘ ’- ,. 7.“ «551: c. I 1‘ . .. Ig-E‘nz' ' “11‘: '2'. .‘"‘;"I ’1 ’ - I . .. ¢ 4 O- V . y -4 J‘... “3,.-. .. . .. 4‘ ' ' ' ,“l‘ 3‘11 “ ‘1‘“ #IJ’J‘Z“ 213.7 4% ‘|‘ii‘i ‘33:“ L‘Ei“; II mi" 1.013,“ lfJ‘I‘I“ ““ l‘ l" ,,| "“ ““‘l 'F—E; “""‘ """I 1’1"”: ‘1;§’“:¢“‘1I II‘NII‘III I““‘ “‘“III 6““ THESlS This is to certify that the dissertation entitled SYNTHESES OF PYRROLES AND PORPHYRINS presented by Ralph w. Kaesler has been accepted towards fulfillment of the requirements for Ph‘DA degree in (memj stry éémfi/W / Major profess?! V Eugene LeGoff Date Agust 24, 1983 MS U i: an Affirmative Action/Equal Opportunity Institution 0- 12771 MSU RETURNING MATERIALS: Place in book drop to remove this checkout from LIBRARIES . —,—- your record. FINES m'll be charged if book is returned after the date stamped below. Fifi I a?" " 3:1;1' 1"”- F v» :m 1,. . ’ 1.? 15-171 «.11.. J—n- . g _ -1912 1...] 1,}; Sq '5 ”c: SYNTHESES OF PYRROLES AND PORPHYRINS By Ralph w. Kaesler A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1983 ABSTRACT SYNTHESES OF PYRROLES AND PORPHYRINS by Ralph w. Kaesler The syntheses of 2,5-unsubstituted and 2,5-dimethylpyr- roles and their conversion to porphyrins have been investi- gated. Electrophilic substitution in the 3 and 4 positions of 2,5-dimethyl- and N-benzoyl-Z,5-dimethylpyrroles gave 3,4-CH2R-(R=CF3, CFZCFZCF3, N(CH3)2) as well as 3,4-dibromo- and 3,4-dichloropyrroles. Substitution of the dimethylamino group or its quaternary ammonium salt, allowed preparation of more functionalized derivatives (R=C(CH3)2N02, CN, $02¢CH3’ s¢), Hexafluorobut-Z-yne and N-benzoyl-, N-benzoyl-2,5-di- methyl- and N-benzoyl-Z-(l,3-dioxolan-2-yl)pyrroles reacted to form Diels-Alder adducts, which on selective hydrogena- tion of the less substituted double bond and pyrolytic cleavage of ethylene led to the corresponding 3,4-bis(tri- fluoromethyl)pyrroles. A two step synthesis of 3,4-bis- (carbethoxy)pyrrole from diethyl succinate allowed the effi- cient preparation of 2,5-unsubstituted 3,4-bis(N-methyl-, N,N- dimethyl-, N,N-diethyl- and morpholinecarboxamide)pyrroles. The 2,5-dimethyl derivative of 3,4-bis(N,N-dimethylcarbox- amide)pyrrole was obtained from the dimer of N,N-dimethyl- acetylacetamide. The 2,5-dimethylpyrroles were converted to potential porphyrin precursors by oxidation of both methyl substi- tuents. 2,5-bis(Acetoxy- and chloromethyl) derivatives were prepared by oxidation with Pb(OAc)4 and SOZCT2 respectively. Exhaustive chlorination with excess SOZCl2 followed by hydrolysis and iodinative decarboxylation enabled the pre- paration of 2,5-diiodopyrroles. 0ctakis(lH,lH-trifluoroeth-l-yl)- and octakis(lH,lH- heptafluorobut-l-yl)porphyrin were obtained from the acid catalyzed self-condensations of the corresponding 2,5-bis- (acetoxymethyl)pyrroles. Condensations of the 2,5-diiodo- derivatives with formaldehyde in acidified l-propanol gave higher yields of the same porphyrins and also obviated the normally required prolonged air oxidation. 0ctakis(2-methyl- 2-nitroprop-l-yl)- and octakis(N,N-dimethylcarboxamide)por- phyrins were prepared in a similar fashion from the corres- ponding 2,5-diiodo- and 2,5-bis(acetoxymethyl)pyrroles. The latter porphyrin and its N,N-diethyl derivative were also synthesized via the condensations of the 2,5-unsubstituted pyrroles with formaldehyde. 2,5-bis(Acetoxymethyl)-3,4- dibromo-, chloro-, and (p-tolylsulfonylmethyl)pyrroles self- condensed to provide only trace amounts of porphyrin. To My Parents and My Wife Beth ACKNOWLEDGEMENT I am extremely indebted to Dr. Eugene LeGoff for his guidance, enthusiasm and friendship. His insights into chemistry and his willingness to help have made my graduate career both a pleasant and a fruitful one. Financial support in the form of a summer and a one- year fellowship from the Dow Chemical Company and SOHIO are gratefully acknowledged. Also, appreciation is extended to the Department of Chemistry for providing a teaching assis- tantship. ii TABLE OF CONTENTS PAGE LIST OF TABLES. . . . . . . . . . . . . . . . . . . . . . ,viii LIST OF FIGURES. . . . . . . . . . . . . . . . . . . . . . x INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . .1 Scheme l. . . . . . . . . . . . . . . . . . . .4 Scheme 2. . . . . . . . . . . . . . . . . . . . . . . .5 Scheme 3. 7 A. SYNTHESES OF PYRROLES. . . . . . . . . . . . . . . . . 9 Scheme 4. . . . . . . . . . . . . . . . . . . . . . . .9 Scheme 5 Scheme 6. . . . . . . . . . . . . . . . . . . . . . . Scheme 7. . . . . . . . . . . . . . . . . . . . . . . 13 Scheme 8. . . . . . . . . . . . . . . . . . . . . . . Scheme 9. . . . . . . . . . . . . . . . . . . . . . . 15 Scheme 10. . . . . . . . . . . . . . . . . . . . . . .16 Scheme ll. . . . . . . . . . . . . . . . . . . . . . .17 Scheme 12. . . . . . . . . . . . . . . . . . . . . . .18 Scheme 13. . . . . . . . . . . . . . . . . . . . . . .21 Scheme 14. . . . . . . . . . . . . . . . . . . . . . .21 Scheme 15. . . . . . . . . . . . . . . . . . . . . . .22 Scheme 16. . . . . . . . . . . . . . . . . . . . . . .23 Scheme 17. . . . . . . . . . . . . . . . . . . . . . .25 Scheme 18. . . . . . . . . . . . . . . . . . . . . . .26 Scheme 19. . . . . . . . . . . . . . . . . . . . . . .27 Scheme 20. . . . . . . . . . . . . . . . . . . . . . .28 PAGE B. OXIDATION OF 2,5-DIMETHYLPYRROLES. . . . . . . . . . .29 Scheme 21. . . . . . . . . . . . . . . . . . . . . . .30 Scheme 22. . . . . . . . . . . . . . . . . . . . . . .31 Scheme 23. . . . . . . . . . . . . . . . . . . . . . .32 Scheme 24. . . . . . . . . . . . . . . . . . . . . . .39 C. SYNTHESES OF PROPHYRINS. . . . . . . . . . . . . . . .43 Scheme 25. . . . . . . . . . . . . . . . . . . . . . .45 D. CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . .58 EXPERIMENTAL. . . . . . . . . . . . . . . . . . . . . . . 61 General Methods. . . . . . . . . . .61 2, 5- Dimethyl- 3, 4- bis(lH, lH- heptafluorobut- l -y1)- pyrrole (2a). . . . . . . . .62 2, 5- Dimethyl- 3, 4- bis(lH, lH- trifluoroeth- l -y1)- pyrrole (2b). . . . . . 63 3, 4- bis(Dimethylaminomethy)- 2, 5- -dimethylpyrrole (3). .63 3, 4- bis(2- Methyl- 2- nitroprop- l -yl)- 2, 5- dimethyl- pyrrole (4). . . . . . .54 3, 4- bis(Phenylthiomethy1)- 2, 5-dimethy1pyrrole (5). . .64 N- Benzoyl- 3, L bis(dimethylaminomethylL 2, 5- dimethyl- pyrrole (6). . . . .65 3, L bis(Cyanomethyl)- 2, 5- dimethylpyrrole (7).. . . . 66 3, L bis(p- Tolylsulfonylmethyl)- 2, 5- dimethyl- pyrrole (8). . . . . .66 L L bis(Carbethoxymethy1)- 2, 5- dimethylpyrrole (10). . 67 3, 4- Dibromo- 2, 5- -dimethy1pyrrole (Ll). . . . . . . . . 68 L 4-Dichloro- 2, 5- dimethylpyrrole (12). . . . . . . . .68 N- Benzoyl- 2- formylpyrrole (19).. . . . . . . . . 69 N-Benzoyl-Z- (1,3-dioxolan-L y1)pyrrole (16c). . . . . 70 N- Benzoyl- 2, 3- bis(trif1uoromethyl)- 7- azabicyclo-o [2.2.1]-2,5-heptadiene (17a). . . . . . . 70 N-Benzoyl-2,3-bis(trif1uoromethyl)-1,4-dimethy1-7- azabicyclo[2. 2. l]- L 5- heptadiene (119).. . . . . . . 71 N-Benzoyl-2,3-bis(trifluoromethyl)-l-(l,3-dioxolan- 2- y1)- 7- azabicyclo[2. 2. l]- L 5- heptadiene (l7cL . . . 71 N- -Benzoy1- 2, 3- bis(trifluoromethyl)- 7- azabicyclo- [2. 2. l]- -heptane (20).. . . . . . . 72 N- Benzoyl- 2, 3- bis(trif1uoromethy1)- 7- azabicyclo- [2. 2. l]- 2- -heptene (21a). . . . . . . .73 iv N- Benzoy1- 2, 3- bis(trif1uoromethy1)- 1, L dimethy1- 7-azabicyc10[2.2.1]-2-heptene (21b). . . . . N- Benzoy1- 2, 3- bis(trif1uoromethy1)-1- (1, 3- dioxo1an- 2-y1)-7-azabicyc1o[2.2.1]-2-heptene (21c). . N-Benzoy1-3, 4-bis(trif1uoromethy1)pyrro1e (22a). N- Benzoy1- 3, 4- bis(trif1uoromethy1)- 2, 5- dimethyI- pyrro1e (22b). . . N- Benzoy1- 3, 4- bis(trif1uoromethy1)- 2- (1, 3- dioxo1an- 2- y1)- pyrro1e (22c). . . . . . 3, 4- bis(Trif1uoromethy1)pyrroIe (23aL . . . 3, 4- bis(Trif1uoromethy1)- 2, 5- -dimethy1pyrr01e (23b). 3, 4- bis(Trif1uoromethy1)- 2-formy1pyrro1e (24).~ww 3, 4- Dicyanopyrro1e (25a). . . 3, 4- Dicyano- 2, 5- dimethy1pyrro1e (25b). 3, 4- bis(Carbethoxy)- 2, 5- -dimethy1pyrro1e (26b). prepared from 23b. . . 3, 4- bis(Carbethoxy)pyrro1e (26a) prepared from 23a. bis(Dimethy1aminomethy1ene)diethy1succinate (28). 3 ,4-bis(carbethoxy)pyrro1e (263). 3, L Dicarboxypyrro1e (29). . 3, 4- bis(N, N- Diethy1carboxamide)pyrr01e (31a). 3, 4- bis(N, N- Dimethy1carboxamide)pyrro1e (31b). 3,4-bis(N-Morpho1inecarboxamide)pyrro1e (31E). 3 ,4-bis(N-Methy1carboxamide)pyrro1e (31d). 2, 5- Dimethy1- 3, 4- bis(N, N- dimethy1carboxamide)- pyrro1e (37). . . . . 2, 5- bis(Acetoxymethy1)- 3, 4- bzs(1H, 1H- heptaf1uorobut- 1 -y1)pyrro1e (38a). L 5- bis(Bromomethy1)- 3, 4- bis(1H, 1H- heptaf1uorobut- 1 -y1)pyrro1e (38b). . . . 2, 5- bis(Dich10romethy1)- 3, 4- bis(1H, 1H- heptaf1uorobut- 1 -y1)pyrro1e (38dL 3, 4- bis(1H, 1H- Heptaf1uorobut- 1 -y1)- 2, 5- .diformy1- pyrroIe (38e). . . - 2, L bis(Acetoxymethy1)- 3, L bis(1H,1H-trif1uoroeth- 1-y1)pyrro1e (38f). . . . . 2, 5- bis(Carbmethoxy)- 3, 4- (1H, 1H- heptaf1uorobut- 1- y1)pyrro1e (39a). . . . . . 2, 5- bis(Carbethoxy)- 3, 4- (1H, 1H- heptaf1uorobut- 1- y1)pyrro1e (39b). . . . . . . . . PAGE .73 .74 .74 .75 .75 .76 76 .77 78 .78 .79 79 79 80 .81 81 .82 .83 .84 84 86 86 87 .87 88 88 89 2, 5- Dicarboxy- 3, 4- bis(1H, 1H- heptaf1uorobut- 1- y1)- pyrro1e (39c). . . 2, 5- Dicarboxy- 3, 4- bis(1H, 1H- heptaf1uorobut- 1- y1)pyrro1e (39c) prepared from 39a. 2, 5- Dicarboxy- 3, 4- bis(1H, 1H- tr1f1uoroeth- 1 -y1)- pyrro1e (39d). . . . 2, 5- D110do- 3, 4- bis(1H, 1H- .heptaf1uorobut- 1 -y1)- pyrro1e 40a. . . . . 2,5-0110do-3,4-bis(1H,1H-tr1f1uoroeth-1-y1)- pyrro1e (40b). . . 3, 4- bis(1H, 1H- heptaf1uorobut- 1-y1)pyrro1e (41). 3, 4- bis(1H, 1H- Heptaf1uorobut- 1 -y1)pyrro1e 41 prepared from 40a cata1yt1c hydrogenation. 2, 5- bis(Ch1oromethy1)- 3, 4- bis(2- methy1- 2- -n1troprop- 1 -y1)pyrro1e (42). . . . . 3, 4- bis(2- Methy1- 2-n1troprop-1.-y1)- 2, 5- d1carboxypyrro1e (43). . . 3, 4- bis(2- Methy1- 2-n1troprop-1-y1)2, 5- d110dopyrro1e (44). . 2, 5- bis(Acetoxymethy1)- 3, 4- bts(p-to1ysu1fony1- methy1)pyrro1e (45).. . 2, 5- bis(Acetoxymethy1)- 2, 5- d11odopyrro1e (46). 2,5- bis(Acetoxymethy1)- 2,5- -d1bromopyrro1e (41). 2 ,5-bisAcetoxymethy1)- 2, 5- d1ch1oromethy1pyrro1e (4g) 2 ,S-bis{Acetoxymethy1)- 3 ,4—bis(carbethoxy)- pyrro1e (49). . 2 ,5-bis(Acetoxymethy1)- 3, 4- b%S(N, N- dimethy1carbox- am1de)pyrro1e (52). . . . . . . . 2, 5- bis(Ch1oromethy1)3, 4- bas(tr1f1uoromethy1)- pyrro1e (55). . . 3, 4- bis(Tr1f1uoromethy1)- 2, 5- d1formy1pyrro1e (56). 0ctak15(1H, 1H- heptaf1uorobut- 1 -y1)prophyr1n. (57) prepared from 38a. . . 0ctak15(1H,1H-heptaf1uorobut-1 y1)porphyr1n (57) prepared from 38b. . 0ctak15(1H,1H-heptaf1uorobut-1 y1)porphyr1n (57) prepared from 39c. . . 0ctak15(1H,1H-heptaf1uorobut-1 y1)porphyr1n (57) prepared from 40a. . . 0ctak15(1H,1H-heptaf1uorobut-1 y1)porphyr1n (57) prepared from 41. . v1 PAGE 89 9O 91 91 92 92 93 . 94 . 94 95 . 95 . 96 96 . 96 .99 J00 .VJOO 101 .101 PAGE 2,3-bis(Dimethy1amin0methy1)-3,4-bis(1H,1H- heptaf1uorobut-1-y1)pyrro1e (58).. . . . . . .101 0ctak15(1H,1H—tr1f1uoroeth-1.-y1)porphyrin (59) prepared from 38f. . . . . . 102 0ctak1s(1H, 1H- tr1f1uoroeth- 1 -y1)porphyr1n (59) prepared from 40b. . . . . 103 0ctak1s(2-methy1-2-n1troprop-1-y1)porphyr1n (61). . .103 0ctakis(N, N- d1ethy1carboxamide)porphyr1n (62a). . . .103 0ctak15(N, N-d1methy1carboxamide)porphyr1n (62b). . . 104 0ctak1s(N, N- d1methy1carboxam1de)porphyr1n (62b) prepared from 52.. . . .105 3, 4- bis(N, N- d1methy1carboxam1de)- 2- d1methy1am1no- methy1pyrro1e (63L . . . . . . . . . . .105 APPENDIX. . . . . . . . . . . . . . . . . . . . . . . . .107 LIST OF REFERENCES. . . . . . . . . . . . . . . . . . . .137 v11 LIST OF TABLES TABLE PAGE 1 Porphine, 0ctamethy1- and octaethy1porphyrin. . . . . 2 2 Mixed Porphyrins. . . . . . . . . . . . . . . . . . . 8 3 Se1ected 13c NMR Chemica1 Shifts for N-benzoy1-2,3- bis(trif1uoromethy1)-7-azabicyc1o[2.2.1]-2,5-hepta— dienes 17a-c. . . . . . . . . . . . . . . . . . . . .19 4 0x1dat10ns of ha1o-, carbethoxy-, N,N-dimethy1carb- oxamide- and trif1uoromethy1-2,5-dimethy1pyrro1e. . .41 5 Preparations of octakis(1H,1H-heptaf1uorobut-1-y1)- and octakis(1H,1H-trif1uoroeth-1-y1)porphyrins. . . .44 5 Maximum so1ub11it1es of octakis(1H,1H-heptaf1uoro- but-1-y1)- and octakis(1H,1H-trif1uoroeth-1-y1)- porphyrins 1n grams/1iter (mo1es/1iter) at 25°C in se1ected so1vents. . . . . . . . . . . . . . . . . . 49 7 Preparations of octakis(N,N-dia1ky1carboxam1de)- porphyrins. . . . . . . . . . . . . . . . . . . . . .51 1H and 13C NMR chemica1 shifts and UV-vis absorptions of octakis(N,N-diethy1carboxamide)- and octakis (N,N- dimethy1carboxam1de)porphyrins. . . . . . . . . . . .53 9 Maximum so1ub11it1es of octakis(N,N-diethy1carbox- amide)- and octakis(N,N-dimethy1carboxamide)por- phyrins in grams/11ter (mo1es/1iters) at 25°C in se1ected so1vents. . . . . . . . . . . . . . . . . . 54 viii TABLE 10 11 PAGE Reaction conditions for attempted conversions of 3,4-bis(trif1uoromethy1)pyrro1e to porphyrin. . . .56 Reaction conditions for attempted conversions of 2,5-bis(ch1oromethy1)-3,4-bis(trif1uoromethy1)- pyrro1e to porphyrin. 57 ix LIST OF FIGURES FIGURES PAGE 1 13C NMR spectrum of 2,5-diiodo-3,4-bis- (1H.1H-heptaf1uorobut-1-y1)pyrro1e. . . . . . . . . 35 2 Expanded 13C NMR of heptaf1uoropropy1 carbons in 2,5-diiodo-3,4-bis(1H,1H-heptaf1uorobut-1- y1)pyrro1e. . . . . . . . . . . . . .. . . . . . . . 37 3 UV-vis spectrum of octakis(1H.1H-heptaf1uoro- but-1-y1)porphyrin. . . . . . . . . . . . . . . . . 48 A1 60 MHz‘H NMR spectrum of 2,5-dimethy1-3,4-bis- (1H,1H-heptaf1uorobut-1-y1)pyrro1e (£3). . . . . . 107 A2 60 MHz 1H NMR spectrum of 2,5-dimethy1-3,4-bis- (1H,1H-trif1uoroeth-1-y1)pyrro1e (3b). . . . . . . 107 A3 60 MHz 1H NMR spectrum of 3,4-bis(dimethy1amino- methy1)-2,5-dimethy1pyrro1e (3). . . . . . . . . . 108 A4 60 MHz 1H NMR spectrum of 3,4-bis(2-methy1-2- nitroprop-1-y1)-2,5-dimethy1pyrro1e (g). . . . . . 108 A5 so MHz 1H NMR spectrum of 3,4-bis(pheny1thio- methy1)-2,5-dimethy1pyrro1e (5). . . . . . . . . . 109 A6 60 MHz 1H NMR spectrum of N-benzoy1-3,4-bis- (d1methy1am1nomethy1)-2,5-d1methy1pyrro1e (6). . . 109 A7 60 MHz 1H NMR spectrum of 3,4-bis(cyanomethy1)- 2,5-dimethy1pyrro1e (Z). . . . . . . . . . . . . . 110 A8 60 MHz 1H NMR spectrum of 3,4-bis(p-to1y1su1fony1- methy1)-2,5-dimethy1pyrro1e (8). . . . . . . . . . 110 A9 60 MHz 1H NMR spectrum of 3,4-bis(carbethoxy- methy1)-2,5-d1methy1pyrro1e (19). . . . . . . . . .111 FIGURES A10 A11 A12 A13 A14 A15 A16 A17 A18 A19 A20 A21 A22 50 MHz 1H NMR spectrum of 2,5-dibromo-3,4-di- methy1pyrro1e (11). 1 60 MHz H NMR spectrum of N-benzoy1pyrro1e (16a). 60 MHz 1H NMR spectrum of N-benzoy1-2,5-di- methy1pyrro1e (16b). 60 MHz 1H NMR spectrum of N-benzoy1-2-(1,3- dioxo1an-2-y1)pyrro1e (16c). 60 MHz 1H NMR spectrum of N-benzoy1-2,3-bis- (trif1uoromethy1)-7-azabicyc1o[2.2.1]-2,5- heptadiene (17a). . . . . . . . . . . . . . . 60 MHz 1H NMgmspectrum of N-benzoy1-2,3-bis- trif1uoromethy1)-1,4-dimethy1-7-azabicyc1o- [2.2.1]-2.5-heptadiene (112). 60 MHz 1H NMR spectrum of N-benzoy1-2,3-bis- (trif1uoromethy1)-1-(1,3-dioxo1an-2-y1)-7- azabicyc1o[2.2.1]-2,5-heptadiene (17c). 60 MHz 1H NMR spectrum of N-benzoy1-2-formy1- pyrro1e (19). 60 MHZ 1 (trif1uoromethy1)-7-azabicyc1o[2.2.1]-heptane (20). 60 MHz (tr1f1uoromethy1)-7-azabicyc1o[2.2.1]-2-heptene (313). 60 MHz (trif1uoromethy1)-1,4-dimethy1-7-azabicyc1o- [2.2.1]-2-heptene (212). H NMR spectrum of N-benzoy1-2,3-bis- 1H NMR spectrum of N-benzoy1-2,3-bis- 1H NMR spectrum of N-benzoy1-2,3-bis- 60 MHz 1H NMR spectrum of N-benzoy1-2,3-bis- (trif1uoromethy1)-1-(1,3-dioxo1an-2-y1)-7- azabicyc1o[2.2.1]-2-heptene (213). 60 MHz 1 (trif1uoromethy1)pyrro1e (223). H NMR spectrum of N-benzoy1-3,4-bis- xi PAGE 111 112 .112 .113 113 114 114 . 115 0115 .116 .116 .117 FIGURE PAGE A23 60 MHz 1H NMR spectrum of N-benzoy1-3,4-bis- (trif1uoromethy1)-2,5-dimethy1- pyrro1e (222). . . . . . . . . . . . . . . . . . .118 A24 60 MHz 1H NMR spectrum of N-benzdy1-3,4-bis- (trif1uoromethy1)-2-(1,3-dioxo1an-2-y1)- pyrro1e (22c). . . . . . . . . . . . . . . . . . .118 A25 60 MHz 1H NMR spectrum of 3,4-bis(trif1uoro- methy1)pyrro1e (233). . . . . . . . . . . . . . . 119 A26 60 MHz 1H NMR spectrum of 3,4-bis(trif1uoro- methy1)-2,5-dimethy1pyrro1e (23b). . . . . . . . .119 A27 60 MHz 1H NMR spectrum of 3,4~bis(trif1uoro- methy1)-2-formy1pyrro1e (24). . . . . . . . . . . 120 A28 60 MHz 1H NMR spectrum of 3,4-dicyanopyrro1e (25a). . . . . . . . . . . . . . . . . . . . . . .120 A29 60 MHz 1H NMR spectrum of 3,4-bis(carbethoxy)- pyrro1e (2&3). . . . . . . . . . . . . . . . . . .121 A30 60 MHz 1H NMR spectrum of bis(dimethy1amino- methy1ene)diethy1succinate (28). . . . . . . . . .121 A31 60 MHz 1H NMR spectrum of 3,4-bis(N,N-diethy1- carboxamide)pyrro1e (31a). . . . . . . . . . . . .122 A32 60 MHz 1H NMR spectrum of 3,4-bis(N,N-dimethy1- carboxamide)pyrro1e (312). . . . . . . . c . . . .122 A33 60 MHz 1H NMR spectrum of 3,4-bis(N—morpho1ine- carboxamide)pyrro1e (315). . . . . . . . . . . . .123 A34 60 MHz 1H NMR spectrum of 2,5-dimethy1-3,4-bis- (N,N-dimethy1carboxamide)pyrro1e (31). . . . . . .123 A35 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 3,4-bis(1H,1H-heptaf1uorobut-1-y1)pyrro1e (383). .124 A36 60 MHz 1H NMR spectrum of 2,5-bis(dich1orometh- y1)-3,4-bis(1H,1H-heptaf1uorobut-1-y1)pyrro1e (ggg). . . . . . . . . . . . . . . . . . . . . . .124 xii FIGURES A37 A38 A39 A40 A41 A42 A43 A44 A45 A46 A47 A48 A49 A50 A51 PAGE 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 3,4-bis(1H,1H-trif1uoroeth-1-y1)pyrro1e (38:). . . 125 60 MHz 1H NMR spectrum of 2,5-bis(carbmethoxy)- 3,4-bis(1H,1H-heptaf1uorobut-1-y1)pyrrole (39a). . 125 60 MHz 1H NMR spectrum of 2,5-dicarboxy-3,4-bis- (1H,1H-heptaf1uorobut-1-y1)pyrro1e (393). . . . . .126 60 MHz 1H NMR spectrum of 2,5-dicarboxy-3,4-bis- (1H,1H-trif1uoroeth-1-y1)pyrro1e (39d). . . . . . .126 60 MHz 1H NMR spectrum of 2,5-diiodo-3,4-bis- (1H,1H-heptaf1uorobut-1-y1)pyrro1e (423). . . . . .127 60 MHz 1H NMR spectrum of 2,5-diiodo-3,4-bis- (1H,1H-trif1uoroeth-1-y1)pyrro1e (423). . . . . . .127 60 MHz 1H NMR spectrum of 3,4-bis(1H,1H-hepta- f1uorobut-1-y1)pyrro1e (41). . . . . . . . . . . . 128 60 MHz 1H NMR spectrum of 2,5-bis(ch1oromethy1)- 3,4-bis(2-methy1-2-nitroprop-1-y1)pyrro1e (42). . .128 60 MHz 1H NMR spectrum of 3,4-bis(2-methy1-2- nitroprop-1-y1)-2,5-dicarboxypyrro1e (43). . . . . 129 60 MHz 1H NMR spectrum of 3,4-bis(2-methy1-2- nitroprop-1-y1)-2,5-diiodopyrro1e (44). . . . . . .129 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 2,5-diiodopyrro1e (46). . . . . . . . . . . . . . .130 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 3,4-bis(carbethoxy)pyrro1e (49). . . . . . . . . . 130 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 3,4-bis(N,N-dimethy1carboxamide)pyrro1e (52). . . .131 60 MHz 1H NMR spectrum of 3,4-bis(trif1uorometh- y1)-2,5-diformy1pyrro1e (56). . . . . . . . . . . .131 250 MHz 1H NMR spectrum of octakis(1H,1H-hepta- f1uorobut-1-y1)porphyrin (52). . . . . . . . . . . 132 xiii FIGURE PAGE A52 250 MHz 1H NMR spectrum of octakis(1H,1H-tri- f1uoroeth-1-y1)porphyrin (59). . . . . . . . . . .133 A53 250 MHz 1H NMR spectrum of octakis(2-methy1-2- nitroprop-1-y1)porphyrin (61). . . . . . . . . . .134 A54 60 MHz 1H NMR spectrum of 2,3-bis(dimethy1amino- methy1)-3,4-bis(1H,1H-heptaf1uorobut-1-y1)- pyrro1e (58). . . . . . . . . . . . . . . . . . . 135 A55 60 MHz 1H NMR spectrum of octakis(N,N-diethy1- carboxamide)porphyrin (623). . . . . . . . . . . .135 A56 60 MHz 1H NMR spectrum of octakis(N,N-dimethy1- carboxamide)porphyrin (629). . . . . . . . . . . .136 A57 60 MHz 1H NMR spectrum of 3,4-bis(N,N-dimethy1- carboxamide)-2-dimethy1aminomethy1pyrro1e (63). . 136 xiv INTRODUCTION The chemistry of porphyrins and their pyrro1e precur- sors has been examined extensive1y over the past sixty years.“7 A considerab1e amount of this effort is devoted to the syntheses of porphyrins and numerous methods for their preparation are now avai1ab1e. These inc1ude the cyc1ization of pyrro1es, dipyrromethanes, dipyrromethenes, dipyrroketones, (oxy-)bi1anes, bi1enes and bi1adienes.8 The condensation of monopyrro1es bearing identica1 substituents in the 3 and 4 positions constitutes a usefu1 route to symmetrica11y octasubstituted porphyrins. Por- phine, octamethy1porphyrin (0MP) and octaethy1porphyrin (OEP) are the traditiona1 targets of this method. Some of the most faci1e condensations 1eading to these porphyrins are summarized in Tab1e 1. In genera1 two types of a- pyrro1e substitutions are invo1ved: a) 2,5-unsubstituted pyrro1es, which are condensed with forma1dehyde or formic acid and b) a-hydroxymethy1 or aminomethy1pyrro1es, which undergo se1f—condensation on treatment with acid (the 2- carboxy-S-CH R substituted pyrro1es decarboxyiate prior to 2 Table 1 Porphine, 0ctamethy1- and 0ctaethy1porphyrin. R R R R R / X’jz;:§L‘X' ’> H R R R X, X' Method % Yie1da Reference H H, CHO HCOOH, 02 0.026 9 H H HCOH, MeOH 0.021 10 Pyridine H H, CH20H HOAc, ¢0002H 5 11 H H, CHZOH HOAc, 02 5 12 H H, CHZOH ¢Et, 02 8—10 13 CH3 H HCOOH 12 14 CH3 H HCOH, AcOH 77 15 Pyridine CH3 H HCOH, HBr, EtOH 76 16 CH3 CHZOH, COOH HCOOH 47 17 b CH3 CHZNHZ’ COOH MeOH, Cu(0Ac)2 20 18 c CH3 H, CH2N(CH3)2 EtMgBr, Xy1ene 20-36 19 CHZCH3 CHZOH, COOH HOAc, 44 20 K Fe(CN) 3 6 CHZCH3 H, CH2N(CH3)2 HOAc, 02 52 21 d CHZCH3 CH2N(CHZCH3)2, HOAc, 02 52 22 COOK CHZCH3 H HCOH, EtOH, HBr 55 16 aYie1ds of fina1 condensation; ine1d of copper porphyrin; CYie1d of magnesium porphyrin; ine1d based on ethy1ester precursor (Scheme 2). condensation). The mechanistic considerations of these reactions have been discussed e1sewhere.23 The higher yieids of UMP and OEP are attributed to a decrease in side reactions invo1ving the B-positions of the pyrro1e and an increase in reactivity of the a-positions towarde1ectrophi1es. One of the most efficient condensa- tions ever reported invo1ves Treibs and H5ber1e's synthesis of UMP from 3,4—d1methy1pyrroie.15 A yie1d of 77% was obtained for the fina1 condensation, however, iso1ation of the porphyrin proved to be tedious. A more faci1e procedure entai1s heating 3,4-dimethy1pyrro1e and forma1de- hyde in acidified ethano1.16 The porphyrin is co11ected by fi1tering the reaction mixture after air oxidation. 0ctaethy1porphyrin is one of the most wide1y used mode1s in porphyrin chemistry and its synthesis has receiv- ed considerab1e attention. The greatest cha11enges encoun— tered en route to OEP (orany'other porphyrin) are in the preparation of the pyrro1e precursors. 2-Carbethoxy-3,4- diethy1-5-methy1pyrro1e is a common1y emp1oyed intermediate to OEP and three of its most important syntheses are out- 1ined in Scheme 1. Conversion to precursors suitab1e for condensation (Tab1e 1) requires further manipu1ations of the o-pyrro1e substituents. These are i11ustrated in 20 21 Scheme 2 for syntheses by Inhoffen, Whit1ock and Do1phin.22 Except for the recent syntheses of octakis(Z-methyoxy- carbony1ethy1)- and octakis(3-methoxycarbony1propy1)porphy- rin from the corresponding 2-acetoxymethy1~5-carboxypyr- Scheme 1 RE F. 24.25 RE E22 REP. 26 e o NCCHzcozst Rowan M o o 6 MgOEt * I. EtMgl o 2.11303J I.CH,CH,COCI /\g/ \g/\ 1 2.H,o.A l. BF3 W0“ 2.NaOH O 0 H20 l.NaNOz # AcOH 2.2" OH O AcOH \ M O 0 Most 82": Zn NOH AcOl-l cw, (:03 H Scheme 2 2i. CM3 N OzEt H LSOfiM 2 O: aOAc ’0 Br2 3.NaOH V AcOCHiNfiCOZEt HOZCfiCOzH Brc Hificogt H H H 946m) KOH A Et 2NH v 1 4 2’1: 2/ \g / \ HOCH2 N 02H Et 2NC2Hz N OzEt H H H "92"” ° HCI HCOH 1K0" % é / \ MezNC H 2 EtzNCI-i2 N 02K H 35$ 273 other practica1 syntheses of symmetrica11y substi- ro1es, tuted porphyrins from monopyrro1es have been 1imited to dif- ferent a1ky1 and some ary1 substituted cases. 0ctapropy1- porphyrin has been prepared from 2-hydroxymethy1-3,4- dipropy1pyrro1e, but the overa11 procedure was p1agued by 17,27b poor yie1ds and sensitive intermediates. A more efficient synthesis of octapropy1porphyrin as we11 as 1ong- 28 er chain a1ky1 derivatives is out1ined in Scheme 3. The condensation of 3,4-dipheny1pyrro1e and forma1dehyde15 in acetic acid and pyridine as we11 as the se1f-condensations of 2-dimethy1aminomethy1-3,4-dipheny1-and.3,4-bis(p-methoxy- pheny1)pyrro1e529haverservedas routes to octaary1porphyrins. Tab1e 2 summarizes the condensations of monopyrro1es bearing bothan a1ky1 (or ary1) and a strong e1ectron with- 16’30 Remarkab1y high drawing substituent in the B-positions. yie1ds are reported for some cases, however, due to the unsymmetrica1 nature of the pyrro1es, mixtures of por- phyrins cou1d not be avoided. For examp1e the condensation of 3-acety1-4-ethy1pyrr01e with forma1dehyde resu1ted in formation of three of the possib1e four isomers: 2,7,13,18- tetraacety1-3,8,12,17-tetraethy1porphyrin, 2,8,13,18-tetra- acety1-3,7,12,17-tetraethy1porphyrin and 2,8,12,18-tetra- acety1-3,7,13,17-tetraethy1porphyrin in ratios of 1:4:2 respective1y. Exp1ored in this thesis are the app1ications of 2,5- dimethy1pyrro1es and high1y deactivated 2,5-unsubstituted pyrro1es in the syntheses of symmetrica1, non-a1ky1, octa- Scheme 3 R—cw=CH—co—R' R 0 | R H.Et() .. 2+8 DMSO N H cw,—.~so,cw,~c Luurg R R V R e R R FHCOH| HBr U Eton-1,0, R R H R R R % Yie1da Reference CH3(CH2)2 32 28 CH3(CH2)3 33 28 CH3(CH2)4 4o 28 CH3(CH2)5 11 28 CH3(CH2)6 11 28 CH3(CH2)7 22 28 aYie1ds of fina1 condensation. Tab1e 2. Mixed Porphyrins 5" R R RI R R9 2/ \§ N 7’» H . R R R .l R, R' % Yie1d Reference CH3, COZEt 92 16 CH3, C02C8H17 52 16 Ph, COzEt 86 16 CH3, COCH3 64 16 CHZCHB’ COCH3 96 16 CH3(CH2)n, C0(CH2)n_1CH3 n=2 17 30 71:3 57 30 n=4 34 30 n=5 42 30 substituted porphyrins. This work is presented in three sections, describing, a) the syntheses of various 2,5-di- methy1 and 2,5-unsubstituted pyrro1es, b) the preparation of potentia1 porphyrin precursors from 2,5-dimethy1 pyrro1es and c) the uti1ity of the precursors in condensations 1ead- ing to porphyrins. A. SYNTHESES OF PYRROLES Three fundamenta11y different approaches to 2,5-unsub- stituted and 2,5-dimethy1pyrro1es have been investigated and their net transformations are summarized in Scheme 4. The first approach (eq. 1) invo1ves e1ectrophi1ic substitu- tions in the 3 and 4 positions of a 2,5-dimethy1pyrro1e, Scheme 4 Re, R R QCH F A 1' CH5 . a CH, N CH, R H or, or, créEécr ' ' R R kafl‘ H X C) ' ' R1 11 11 R R 2 : ' NH“ > ‘ ing: 3 X=OH orNR, R R ' which proved usefu1 in the preparation of 3,4-CH2R pyrro1es as we11 as ha1opyrro1es. The second approach (eq. 2), 1ead- ing to bis(trif1uoromethy1)pyrro1es, invo1ves the exchange of the two acety1enic carbons in hexaf1uorobut-2-yne for the 10 B-carbons in a series of N-benzoy1pyrro1es. This was accomp1ished using a Die1s-A1der, retro Die1s-A1der reaction sequence. The third approach (eq. 3) provided various ester and amidepyrro1es from the cyc1izations of bisenamine and biseno1 (diketone) precursors. The 2,5-dimethy1-3,4-bis(po1yf1uoroa1ky1)pyrro1es 2a,b were prepared from readi1y avai1ab1e 2,5-dimethy1pyrro1e, 1, by reductive a1ky1ation with heptaf1uorobutyra1dehyde hydrate and trif1uoroaceta1dehyde hydrate (Scheme 5). Scheme 5 R:Cj: U R,CH(0H), 9 f / \ Rf CH, N CH, H1,H0Ac CH, CH, H H,Po, H 1 3a R,=CF,CF,CF, This procedure is an extension of the pyrro1e a1ky1ations described by MacDona1d, which have been usefu1 in the pre- 31,32 paration of severa1 tetrasubstituted pyrro1es. The 1H NMR of 23 inc1udes a distinctive broad trip1et for the po1yf1uorobuty1methy1enes, a resu1t of 1ong-range coup1ing with adjacent f1uorines. Simi1ar1y, a broad quartet is observed for the trif1uoroethy1 substituents in 22. The 13C proton decoup1ed NMR for both pyrro1es show a sing1e 11 resonance for each of the a and B carbons, characteristic of symmetrica11y substituted pyrro1es. The 1H,1H-hepta- f1uorobuty1 substituents give a distinctive 136-19 F coup1ing pattern, which is best seen in the 2,5-diiodo derivative of 23 and is discussed in detai1 on pg 36. Further extension of MacDona1d's method was not rea1iz- ed. Attempts to reductive1y dia1ky1ate 1 with methy1-2,2- dimethoxyacetate under a variety of conditions fai1ed to provide the desired 3,4-disubstituted pyrro1e, despite a simi1ar, reported monoa1ky1ation of 2-carbethoxy-3-(2- methoxycarbony1ethy1)-5-methy1pyrro1e.32 The substitutions of nuc1eophi1es for the dimethy1amino group of dimethy1aminomethy1pyrro1es have been usefu1 in the preparation of a variety of CHZR substituted pyr- 33’34 Investigations into app1ying this method ro1es. toward 2,5-dimethy1-3,4-CH2R pyrroTes revea1ed that heating 2,5-dimethy1-3,4-bis(dimethy1aminomethy1)pyrro1e, 3, (read- i1y avai1ab1e from 1 by a doub1e Mannich reaction35) with 35 affords a 70% yie1d an excess of Z-nitropropane in water of bis(nitroa1ky1)pyrro1e 4 (Scheme 6). Simi1ar1y, the bis(pheny1thiomethy1)pyrro1e 5 was prepared by heating 3 37 The key mecha- with thiopheno1 in the presence of NaOH. nistic steps in these transformations are thought to entai1 formation of an azafu1vene intermediate fo11owed by addi- tion of the nuc1eophi1e. Ana1ogous reactions of 3 with KCN or sodium p-to1uene- su1finate in water fai1ed to provide any bis-substitution 12 Scheme 6 H CH3 N CH3 H .1. HCOH MezNH-HCI Hg) AM2N NNh, ’ Z/ \S CH, CH, H quH "920”"02 NaOH H20 H20 1' Y CH, CH; CH, H; H H .4. products. Heating of the corresponding bis(quaternary am- monium sa1t) with NaCN in DMSO reported1y affords a 40% yie1d of the desired nitri1e.38 The use of DMSO, however, makes iso1ation of the product tedious and attempts to 13 carry out the same reaction with KCN in water proved un- successfu1. An a1ternate so1ution to this prob1em is summarized in Scheme 7. Quaternarization of the N—benzoy1pyrro1e 6 with Scheme 7 Q CH3 CH3 0’ng G e Me,N=CH,Br 9 C1CH,CH,C1 V MeN NMe, ’ Z/ \S CH, CH, o’J‘gf / 6 \ 1.CH,1 1.CH,1 CH,0H CH,0H e e 2.KCN 2.CH,9)so2 Na H20 ¢ H,o NC CN CH,¢o,s so,¢CH, / \ / \ CH, H, CH, N H. H 1 2. 14 methy1 iodide fo11owed by heating at 65°C with excess KCN or sodium p-to1uenesu1finate 1ed direct1y to dinitri1e Z (54%) and disu1fone 8 (47%). None of the N-substituted benzoy1nitri1e or su1fone were observed and are presumab1y hydro1yzed in situ. Pyrro1e 6 was convenient1y prepared from N-benzoy1-2,5-dimethy1pyrro1e and the preformed Mannich reagent 9.39 The difference in reactivity between the N-substituted and N-unsubstituted bis(quaternary ammoni- umsa1t) with KCN has not been exp1ained. Dinitri1e 7 was examined as a possib1e precursor to the corresponding amide and esterpyrro1es, however on1y the 1atter proved synthetica11y usefu1. As shown in Scheme 8 Scheme 8 NC CN m 1. HCI , EtOH Etofifimp C”: H H3 2.H20 CH3 a CH3 7 10 M treatment of an ethano1 so1ution of 7 with HC1 gas over severa1 days, fo11owed by hydro1ysis,40 gave a 98% yie1d of diester 19.41 Scheme 9 summarizes the results of a third approach to 2,5-dimethy1-3,4-disubstituted pyrro1es and invo1ves the preparation of 3,4-diha1opyrr01es 11 and 12 from 2,5-di- 42 methy1pyrr01e. As reported by Treibs 1 is readi1y di- ~ iodinated in the 3 and 4 positions with an aqueous so1ution 15 Scheme 9 l2,Nal I I "0 CH N CH Br Br NBS,DMF Bx m CH, 3 CH, CH, H CH, 1 11 CI Cl NCS,DM1= CH, N CH, H 12 * of KI3. Simi1ar ch1orinations and brominations using ch1orine, su1fury1 ch1oride or bromine are considerab1y 1ess se1ective.43 Recent1y N-bromosuccinimide (N85) and N-ch1orosuccinimide (NCS) have been reported as mi1d and se1ective pyrro1e ha1ogenating reagents in po1ar so1vents 44 such as THF or DMF. App1ying these methods it was found that the reactions of two equiva1ents of NBS or NCS in DMF with 1 give high yie1ds of unstab1e dibromopyrro1e 11 and 13 dich1oropyrro1e 12. The C NMR spectra of 11 and 12 dis- p1ay three resonances at 6 12.35, 96.72, 124.21, and 10.94, 16 107.30. 121.45 respective1y, testifying to their symmetrica1 nature. The introduction of ester substituents into the 8- positions of the pyrro1e ring can be achieved by Die1s-A1der reactions of dia1ky1 acety1enedicarboxy1ates with various N- and C-substituted pyrro1es fo11owed by therma1 c1eavages of acety1ene.45"47 The efficient introduction of trif1uoro- methy1 substituents with hexaf1uorobut-2-yne, 13, however, had not been rea1ized at the onset of this study.48 Wakse1man reported the reaction of N-methy1pyrro1e with 13 to yie1d predominant1y the N-methy1-7-azabicyc1o[2.2.1]- hepta-2,5-diene 14 (30%) and the dihydroindo1e 15 (42%) a1ong with on1y 2% of N-methy1-3,4-bis(trif1uoromethy1)- pyrro1e (Scheme 10).49 Pyrro1e itse1f gave 1ower yie1ds Scheme 10 1%H, K 5 13 CE, /\ _-__> / + l CH, CF: 14 of the N-unsubstituted dihydroindo1e (6%) in addition to 12% of the 1:1 Michae1 adduct of the diene and 13. No pyrro1ic product was observed in the 1atter reaction. Scheme 11 17 M 16 a RzR'zH b R=R'=CH, C R3H0R':CH 100°C 300°C 2 Pd/C EtOH 18 The presence of an e1ectron-withdrawing substituent on the pyrro1e nitrogen faci1itates the Die1s-A1der reaction with dia1ky1 acety1enedicarboxy1ates as we11 as preventing the addition of a second mo1ecu1e of dienophi1e.47 A simi- 1ar outcome was observed with the reactions of N-benzoy1- pyrro1es 16a-c and hexaf1uorobut-2-yne. Quantitative yie1ds of the mono adducts 17a-c were obtained on heating 16a-C with excess 1} inside a c1osed g1ass tube at 100°C (Scheme 11). Un1ike N-methy1pyrro1e, none of the corresponding dihydroindo1e was observed. The reported preparation50 of the N-benzoy1-2-formy1- pyrro1e precursor for 163 was found unsatisfactory. An a1ternate, more efficient procedure entai1s formation of the sodium sa1t of 18 with NaH fo11owed by addition of one equiva1ent of benzoy1 Ch1oride. (Scheme 12). As expected Scheme 12 QCHO I. NaH * QCHO z¢COC1 03K)?! 19 HOCH,CH,OH p-tol SO,H CaSO, ,¢H pr ‘ 19 no Die1s-A1der adduct was observed for the reaction of 19 «M: with 13 and conversion to the 1ess deactivated aceta1 16c 'M W was required. This was accomp1ished by heating of 19 at 55-60°C with ethy1ene g1yco1 in the presence of p-to1uenesu1- fonic acid and anhydrous CaSO4 in benzene. The conventiona1 method of removing water from the reaction by azeotroping with benzene required pro1onged heating at ref1ux and was accompanied by considerab1e destruction of the a1dehyde. The use of CaSO4 was very effective at the 1ower tempera- tures and greater than 95:5 ratios of product to starting 1 materia1 (as determined by H NMR) were consistent1y obtain- ed. Tab1e 3 summarizes the 136 spectra1 data for the Tab1e 3. Se1ected 136 NMR chemica1 shifts for N-benzoy1- 2,3-bis(trif1uoromethy1)-7-azabicyc1o[2.2.1]-2,5- heptadienes 17a-c. 1 4 2 3 5 6 17a R=R'=H 66.59 69.76 140.90 142.65 144.48 "w“ (very broad) 17b R=R'CH3 78.44 150.90 148.00 17c R=H, lo 70.84 83.03 149.47 151.44 140.29 143.28 R'=CH 20 azanorbornene ring systems 17a-c. It is evident from the sing1e absorptions recorded for each pair of carbons in adduct 17b that it possesses greater symmetry than either m 113 or 113. In 113 this can be accounted for by the benz- amide existing in a preferred dipo1ar resonance form. In 112 steric interactions with the methyIS prevent doub1e bond character between the carbony1 carbon and the nitrogen, increasing the overa11 symmetry of the mo1ecu1e. Adduct 11$ is inherent1y 1ess symmetrica1 than 113 or b and is expected to show six absorptions. 1H NMR spectraT data for the adducts support these observations. Attempts to c1eave acety1ene from 113,2 by passing a benzene (or hexane) so1ution of the adduct through a co1umn of g1ass beads at 300°C resu1ted in mixtures of starting materia1, retro Die1s-A1der products 16a,b and on1y trace amounts of the desired pyrro1es 22a,b. Weis reported the conversion of the 5,6-monoreduced Die1s-A1der adduct of furan and 13 to 3,4-bis(trif1uoromethy1)furan by therma1 51 c1eavage of ethy1ene. A simi1ar strategy was investigated here. Cata1ytic hydrogenation of adducts 17a-c with pa1- 1adium on carbon at 70-80 psi resu1ted in the reduction of both C==C in 17a (Scheme 13) and on1y the 5,6 C==C in 17b,c (Scheme 11). The se1ective reduction of the 1ess substitut- ed C==C in 17a was possib1e using one equiva1ent of H2 at atmospheric pressure. NMR spectra1 data for mono-reduced adducts 21a-C show a simi1ar pattern with respect to sym- metry as discussed for 17a-C. The subsequent c1eavage of 21 Scheme 13 o o ¢AN 95AM / F; H, .Pa/C ’ "3 EtOH. CF, 75 ”3' CF, 17a 29 ethy1ene from 21a-c occurred at 300°C affording N-benzoy1- pyrroIes 22a-c in exce11ent yie1ds. Hydro1ysis of the N-benzoy1 protecting groups in 22343 with aqueous KOH provided the desired 3,4-bis(trif1uoro- methy1)pyrro1e, 223, and 2,5-dimethy1-3,4-bis(trif1uoro- methy1)pyrro1e, 222, as vo1ati18, crysta11ine so1ids (Scheme 14). Simu1taneous hydro1ysis of the aceta1 and the N-ben- zoy1 group in 223 was accomp1ished by heating at 60°C in Scheme 14 CF, CF, KOH. H,o > m R R' H CF, CF, 23 a R:R:=H m b R=R=CH, R R 0”»! ' CF, CF, 22 a R=R =H HB'J‘le I l b R=R =CH, ACOH @010 H _ ._ 1° C R-H.R-CH\o:l 24 22 aqueous acetic acid with HBr to give 2-formy1-3,4-bis- (trif1uoromethy1)pyrro1e 24. A recent report of the faci1e conversions of 2-(tri- f1uoromethy1)imidazo1e to the cyanoimidazo1e derivatives pyrro1es 23a,b. It was found 53 pyrro1es 25a,b are obtained methy1pyrroles with aqueous ammonia (Scheme 15). corresponding ester and prompted a simi1ar study with that high yie1ds of dicyano- on reaction of the trif1uoro- The structures of these pyrroles were readi1y confirmed by in- 3 frared and C NMR. Simi1ar1y, heating of 23a,b with NaOH in ethanoi provided the corresponding bis(orthoesters), Scheme 15 NC /CN NH3,H20 > m R R H CF, CF, 2.? : :2” - 3 RLZ;;S;R H 23 a R=H ” Rx”: l. NaOH. EtOH Et02¢\ /c°2lit H 26 a R=H bR:CH, 23 which were hydro1yzed direct1y to give the known diesterpyr— 47,54 ro1es 26a,b in 90% and 89% overa11 yie1ds. A reason- ab1e mechanism for these reactions is out1ined in Scheme 16. Scheme 16. F: H -HF F /F-F 3x "“3 ROH 1:61” “31,1 ‘45 -2HF 'Iio 1136" if” 24 Under the basic conditions 1055 of HF generates an azaf1u- vene intermediate which can add either one equiva1ent of ammonia, fo11owed by further e1imination of HF to provide a nitri1e, or it can add three equiva1ents of a1coho1 (with concurrent e1imination of two more equiva1ents of HF) to provide an orthoester, which may be hydro1yzed to the ester- pyrro1e. Two methods for the preparation of 3,4-bis(carboxamide)- pyrro1es have been investigated. The first is summarized in Scheme 18 and invo1ves the conversion of 3,4-bis(carb- ethoxy)pyrro1e 363 to a series of a-unsubstituted carboxamide pyrro1es 31a—d. The second method (Scheme 20) entai1s the preparation of 2,5-dimethy1-3,4-bis(N,N-dimethy1carboxamide)- pyrro1e 32 from N,N-dimethy1acety1acetamide, 36, a starting materia1 which a1ready incorporates the desired amide functiona1ity. Severa1 syntheses of diester pyrro1e 363 have been reported. Among the most practica1 areinniLeusen's re- action of tosy1methy1isocyanide with dimethy1 fumarate55 and the pyro1yses of the Die1s-A1der adducts of dia1ky1 acety1enedicarboxy1ates and various N-substituted pyrro1es (see page 16). Kornfe1d described the cyc1ization of1-dieth- y1-1-formy1-2-diethyoxymethy1succinate to 3,4-furan, thio- 6 Modest phene and pyrro1e carboxy1ic esters (Scheme 17).5 yie1ds are obtained for the cyc1ization as we11 as the three step preparation of the precursor. A sing1e step 25 Scheme 17 O O ”(DBL How, I. Hco,Et. Na6 HOW, 2. HC(OEt)3 . H O O 5T% HCOZEt Etzo Na V o C CH “02c o,£t¢ "H3'EtOH Wt / \ Et,o 5‘ N 'OHC. O 26a 87% synthesis of bisenamine {g from diethy1succinate by Bredereck57 a110wed a much more direct route to a simi1ar dia1dehyde equiva1ent. (Scheme 18). The bisenamine was prepared in 63% yie1d by heating a mixture of diethy1 succinate and excess amina1 ester £158 at 160°C. Subse- quent reaction with ammonium acetate in 95% ethanoT resu1- ed in near quantitative cyc1ization,and compTeted an effi- cient two-step synthesis of 363. Basic hydro1ysis of £63 to 3,4-dicarboxypyrr01e a2 f011owed by heating with oxa1y1 Ch10ride provided diacid 47 ch10ride 30. The usua1 conversion to amides by addition of the acid Ch10ride to aqueous amines59 was unsatisfactory. 26 Scheme 18 01 HOW: C) O . A ) (CH,)zNj:ost CH, N / OEt /N(CH,)2 ( )2 o t-BuOCQ 23 Iv(CH,)2 LhfliOAC 27 4 “" 2.NaOH 10 3Jfl’n\mr6| #' 10 O 10 O O RR.N)thNRR' RR'NH R R / \ 4 / \ H H Ilia R=R'=CH,(:|--l3 LGa R=OEt b R=R'=CH, 23 R=OH " \ 30 R=C| C RzR: O M. \_/ d R=H,R=CH, Instead exce11ent yie1ds of diamides 31a-d were obtained with the use of the corresponding anhydrous amines. For ease of workup it was essentia1 that excess oxa1y1 Ch10ride was removed prior to aminoTysis. This was accomp1ished most efficientTy by preparation of 30 in toTuene, f011owed by evaporation of the oxa1y1 Ch10ride under reduced pressure. Scheme 19 summarizes the resu1ts of the attempted forma- tion and cyc1ization of other bisenamines. The reaction 27 Scheme 19 o (c H3)2NJ‘\/\Irw(CH,)2 —g—x—> o 27 NC\/\CN -—“'—-X—-> O 27 ¢vn\\,/~\n,¢. ‘“ ¥#,_ 10 10 {1 NR > O1 21:} a R=H b R=CH, (C H,)2N/:l:::N(C H,)2 (CH,)2N / N(C H,)2 (C(43))! \ N (C H3)2NJ:N 28 of 22 with N,N-tetramethy1succinamide, a potentia1 precursor to pyrroTe 312, and succinonitri1e resu1ted in the recovery of starting materia1 and unidentified products. 0n1y furan 32 cou1d be iso1ated from the reaction of dibenzoyTethane and excess 21 and is presumab1y formed from the cyc1ization of a monoenamine precursor. The bisenamines of succini- mides 33a,b were prepared as described by Bredereck,57 but conversion to pyrro1es 34 cou1d not be effected. The second amide synthesis, mode1ed after a preparation of 2,5-dimethy1-3,4-bis(carbethoxy)pyrr01e by Knorr,54 is summarized in Scheme 20. Deprotonation of N,N-dimethyTacetyT- Scheme 20 O (J O O I I |.NaH C”: "“2 CH3)\/\NM€2 2 . V ‘ 2 CH3 M92 35 0* O 36 NHJmNC O 0 F50 [well Nflkh ’ / \ CH, CH, acetamide, 35, with NaH in ether, fo110wed by addition of M iodine gave dimer 36 as a mixture of diasteromers. The 29 mixture was identified on the basis of two sets of four 1H NMR (3 2.13, 2.16; 2.91, 2.95; 3.23, singTets in the 3.33; 4.66, 4.70). Due to the heterogeneous nature of the reaction mixture best resu1ts were obtained with fineTy divided NaH and excess iodine as we11 as vigorous mechanicaT stirring. Heating of purified dimer 36 with ammonium ace- tate in water a110wed near quantitative conversion to pyr- roTe 37. IsoTation of 36, however, was not necessary and a simi1ar treatment of the crude dimer provided a 40% overa11 yie1d of 37 a10ng with a considerab1e amount of starting materia1 35 (65% overa11 yie1d of 37 based on consumption W of 35). B. OXIDATION OF 2,5-DIMETHYLPYRROLES MethyT substituents in the a-position of pyrro1es can be oxidized with a variety of reagents.60'62 Scheme 21 sum- marizes the most common1y used reagents for each oxidation 1eve1. Lead tetraacetate (Pb(0Ac)4) in acetic acid is the 17,63 method of choice for mono-oxidation. It avoids most of the disadvantages associated with bromine and su1fury1 ch10ride (SOZCTZ), which inc1ude ring oxidation of unsubsti- tuted positions, formation of HBr or HC1, and the genera1 instabi1ity of the ha10methy1pyrr01es. The second oxida- . 64 tion 1eve1 is best attained with two equiva1ents of 502C12 65 or excess Pb(0Ac)4. Temperatures near 90°C are norma11y required for a second equiva1ent of Pb(0Ac)4 to react and 30 Scheme 21 Oxidation Leve1 R2 R3 or, or SOzCI2 or } 1m 1 Pb(OAC)‘ R H CH,x X: Br or Cl orOAC R2 R3 R2 R3 , / \ - sozc'z 0" / \ II R CH3 > 1 H PHCAQ, a, H CHx2 X:C| or OAC R R R CCI, H further oxidation is not observed. CompTete oxidation (Leve1 III) is most common1y effected with excess 21,64,66 $02012. It has been observed that B-a1ky1 substituents are inert to oxidation.60 Recent1y however, a high yie1d bromination of the B-methyTs in 2,5-dicarbethoxy-3,4- dimethy1pyrro1e (Brz, CC14, 70°C) was reported67 and side reactions with B-aTkyT substituents can thus not be com- p1ete1y prec1uded. 31 Described be10w are the a-methyT oxidations and subse- quent reactions of the various 2,5-dimethy1pyrr01es prepared in Section A. Attention is focused on the preparation of first and third oxidation 1eve1 products as we11 as the hydroTysis and bisdecarboxyTation of the 1atter in search of synthetica11y usefu1 porphyrin precursors. InitiaT studies were conducted on 2,5-dimethy1-3,4-bis(1H,1H-hepta- f1uorobut-1-y1)pyrr01e, 23. It was found that oxidation of the a-methyTs cou1d be successfu11y contr011ed to give every possib1e oxidation 1eve1, depending on reagents and reaction conditions emp10yed. In no case was oxidation of the B-methy1enes observed. Stirring a so1ution of 23 with an excess of Pb(0Ac)4 in acetic acid at room temperature provided the stab1e bis(acetoxymethy1) derivative 383 in nearly quantitative 1 yie1d (Scheme 22). The H NMR of 38a inc1uded a singIet at Scheme 22 R II II R R f2/ \S f ox. > :2/ \S xf H CH3 H 3 H 2 a Rf=CF2CF2CF3 38 a Rf=CFZCF2CF,,X=CH,OAC b Rf“: b .. x=CH,Br C H X=CH2CI d .. X=CHCh e u X=CHO f Rf=CF,,X=CH,OAC 32 6 5.02, testifying to the presence of an acetoxymethy1ene. The formation of other mono-oxidation derivatives proved to be 1ess practica1. Bis(bromomethy1)pyrr01e 333, prepared by ref1uxing a soTution of 2a and N-bromosuccinimide, rapid- W 1y decomposed during iso1ation attempts. Identification was possibTy on1y by 1 H NMR (CC14) of the crude reaction mix- ture. The spectrum exhibited a broad trip1et at 6 3.20 (J=20 Hz) for the f1uoroa1ky1methy1enesand a singIet at 6 4.40 for the bromomethy1 substituents. Treatment of 33 with two equiva1ents of 502012 in CH2C12 at 0°C a110wed formation of 38c (1H NMR: broad trip1et at 6 3.22 and sing1et at 6 4.53), however contamination with either o-methyT- (at 6 2.30) or dich10romethy1- (at 6 6.13) pyr- ro1es cou1d not be avoided. Dich10ronation of each methy1 in 33 was controTTed se1ective1y with excess SOZCI2 at 0-3°C to provide high yie1ds of the 2,5-bis(dich1oromethy1)- pyrro1e 333 as a stab1e so1id. The structure of 333 was confirmed by hydroTysis in aqueous THF to 2,5-diformy1- pyrroIe 333. At Tow temperatures (0-3°C) trich10rination of 2a was not observed, however in ref1uxing THF68 excess $02C12 readi1y oxidized both a-methyT substituentsto the corres-- ponding trich10romethy15. The best procedure for this oxidation entaiTed rapid addition of SOZCT2 to the dimethy1- pyrroTe, di5501ved in a minimum amount of ref1uxing THF (Scheme 23). Hydro1ysis of the bis(trich10romethy1)pyrroTe was studied in severa1 soIvents and isoTation of the 33 Scheme 23 Rf Z/ \S "f CH, CH, H g a Rf=CF2CF2CF3 b Rf=CF, I. so,cu2 THF 2. ROH Y Rf Z/ \S Rf Rozc H 02R 3? a Rf=CF2CF2CF, . R=CH, b “ R=CH2CH, c " R=H d Rf: CF, ' R=H Na I, I2 CICH2CH2CI NaHCO, H20 Rf: 7:": :Rf waRf ‘ Zn.NH4Cl I / \ I H EtOH ' H20 H «g R,=cr,cr,cr, 19 a Rf:CF2CcmF3 b Rf:CF3 34 the intermediate was found unnecessary in all cases. Direct addition of hot 95% MeOH or Et0H to the reaction mixture gave excellent yields of the corresponding esters 333 (97%) and 322 (87%). Similarly, the 2,5-dicarboxypyr- role 335 was obtained in 80% yield on hydrolysis with hot aqueous THF. In an attempt to increase the overall yield of diacid 325, the conversion of 333 to 335 was examined. The most efficient procedure involved 3N2 dealkylation of the ester with Lil in 0MF,69 but yields never exceeded 50-60%. The final transformation investigated involved conver- sion of 335 to the 2,5-unsubstituted pyrrole 41. Thermal 70 at elevated temperatures (240-250°C) decarboxylation was accompanied by considerable destruction of the pyrrole nucleus. A more practical procedure proved to be iodinative decarboxylation with sodium triiodide in ClCHZCHZCl and water,71 providing near quantitative conversion to diiodo- pyrrole 403. As indicated by Paine72 the two-phase system helps prevent formation of pyrrole-iodine charge-transfer 42 by extraction of the iodopyrrole into the complexes organic phase. Like most iodopyrroles, 40a is sensitive to light and required protection from direct illumination. 1H NMR was of little value in confirming the structure of 40a, but the pyrrole was ideally suited for 13C NMR 13 analysis. Figure l shows the proton decoupled C NMR spectrum of 40a in 00013. It displays a characteristic triplet at 6 29.l for the two methylenes (long range 35 .e_oeesaAF»-P-e=eoeo=_eeeeee-ze.=_veee-e.m-oeeewe-m.N co Esteeeem azz u . mgzmp mp — .m \\ f’rI-hbl II Fir! p 7} D’ Pb {II F D? r: (‘11 1 ‘1‘? is? a Qd—p flan Q§h I _ . cocoa / \ wowowo 36 coupling with adjacent fluorines), as well as singlets at 6 72.3 and 119.0 for the a- and B-PYrrolecarbons. The unusual chemical shift of the a-carbons is not unexpected, since iodine is known to cause large up-field shifts in the 7 13 3). C NMR ("heavy atom effect" Figure 2 shows an expanded and particularly unobstructed view of the heptaf1uoropropyl carbons in 40a. Long-range 130-19 F coupling generates a complex coup1ing pattern, which is recognized as a triplet of triplets assigned to C-2, a triplet ofquartets of trip- lets assigned to C-3, and a quartet of triplets assigned to C-4. Geminal and vicinal coupling constants are on the order of 260 and 40 Hz respectively. All pyrroles bearing heptaf1uorobutyl substituents display a similar coupling pattern. The reduction of diiodopyrrole 423 to the 2,5-unsubstitu- ted pyrrole 41 was readily accomplished by either catalytic hydrogenation with platinum oxide74 or by reduction with zinc dust and ammonium chloride in aqueous ethanol.42 Strong evidence for the structure of 41 was provided by the 1H NMR. appearance of a doublet at 6 6.77 in the The Pb(0Ac)4 oxidation of bis(trifluoroethyl)pyrrole 22 proved to be as efficient as the oxidation of 23, affording a near quantitative yield of the bis(acetoxymethy1) deriva- tive 32: (Scheme 22). Exhaustive oxidation with 502012 followed by hydrolysis to the diacid, however, resulted in low yields (45%), rendering the overall sequence from Eb to 37 -IP.I_Veee-e.m-oeemee-m.m e? meeetee _seoeaoeospeeeaee to «:2 u r if! \at ,..\/\1, BJJ 311k}? . h _ . J J F. . q :tszax J 1.4.2 __. \ pdep a com. uwufu- U \ a a .mpoggxaAFxnpuuznogospmmpam: mp umucmaxm .N mesmwm . £57.... mépwa «.0: u 38 422, despite facile conversion to diiodopyrrole (97%), impractical. The B-substituents of the remaining 3,4-CH2R-2,5-di- methylpyrroles are considerably more reactive toward oxida- tion than the polyfluoroalkyl groups in 2a,b. For cyano- methylpyrrole Z neither selective mono-oxidation with Pb(0Ac)4 nor trichlorination with 502612 proved to be feasi- ble. Although no identifiable products were isolated in these reactions, oxidation 6 to the cyano group is believed to be responsible. Selective oxidation of the a-methyls in carbethoxymethylpyrrole 10 was only possible with Pb(0Ac)4. However, serious contamination with a1dehydes could not be avoided (1H NMR of the crude reaction mixture contained peaks at 6 5.06 for CHZOAc and at 6 9.60 for CHO). The Pb(0Ac)4 oxidation of nitroalkylpyrrole 4 (two equiva- lents or excess Pb(0Ac)4, HOAc, 25°C) gave similar results with 1H NMR indicating products containing aldehyde, acet- oxymethyl and methyl substituents. Aldehydes are normally not observed with Pb(0Ac)4 at ambient temperature60 and further investigation is required to explore the scope of this reaction. The use of 502012 allowed more reliable oxidation of 4. Slow addition of two equivalents of 502012 to 4 in ~ CHZCT2 at 25°C gave a blue solution which on evaporation to dryness and analysis by 1H and 13C NMR revealed surprisingly clean conversion to the bis(chloromethyl) derivative 42 (Scheme 24). Unfortunately 4 proved to be quite labile 39 Scheme 24 no, N0, no, wo2 / \ so,cu2 W H CH > C 3 H 3 CHZCIZIRT CICH2 H HZCI 5. 42 I.so,CI, cu,cw,cw,cu RT 2.cw,cocw, H20. A V N02 NO’ NO, NO, Ho,c /\ CO,H "a'n'z » I /\ l H‘ cucu,cw,cu H 355 Nch03 4;} H20 and decomposition (as indicated by the blue color) occured rapidly. Trichlorination of both methyls was possible with six equivalents of 502012 in ClCHZCHZCl at 25°C. It was found essential to add the oxidant as rapidly as possible to avoid decomposition of the intermediate chloromethylpyrrole (a blue color, which rapidly dissipated, was noticed at the first instant of 502012 addition). Hydrolysis in aqueous acetone, followed by iodinative decarboxylation under the conditions employed for polyfluoroalkylpyrroles 323,3; gave diiodopyrrole 44. The structure of 44 was confirmed 13 by C NMR, which exhibited three peaks for the nitroalkyl 40 substituents (6 26.20, 38.39, 89.74) and single peaks for the the a (6 72.86) and B (6 124.25) pyrrole carbons. Similar to diiodopyrrole 403, the a carbons are shifted upfield due to the "heavy atom effect“ of the iodines. The oxidation of su1fone 8 with six equivalents of $02012 did not provide the desired product. This is most likely a result of the low solubility of 8 in solvents suitable for 802012 oxidation (i.e., Et20, THF, HOAc, ClCHZCH261). Despite the low solubility, theoxidation of 8 with excess Pb(0Ac)4 in acetic acid (25°C, 70 h) allowed efficient conversion to the b£s(acetoxymethyl) derivative 45. The 1H NMR of 45 shows in addition to peaks for the p-tolysulfonylmethyl substituents singlets at 6 2.01 and 4.70 (in the ratio of 3:2), indicative of acetoxymethyl substituents. Table 4 summarizes the oxidations of halo-, carbeth- oxy- N,N-dimethylcarboxamide- and trifluoromethyl-2,5-di- methylpyrroles. Mono-oxidation of both a-methyls with Pb(0Ac)4 was feasible for all cases except the bis(tri- fluoromethyl)pyrrole. Higher than normal reaction tempera- tures, however, were required for 262 and 37. Halopyrroles 11 and 12 are sensitive to excess oxidant and slightly less than two equivalents of Pb(0Ac)4 were used in each case. Under no conditions could the bis(acetoxymethyl) deriv- ative of 232 be prepared. Excess Pb(0Ac)4 at 100°C for 130 h provided only 8% of 2-acetoxymethyl-3,4-bis(tri- fluoromethyl)-5-methylpyrrole. It was isolated from the 41 Table 4. Oxidations of halo-, carbethoxy-, N,N-dimethylcarb- oxamide- and trifluoromethyl-2,5-dimethylpyrroles. )::E;§§ix H R X Pyrrole Method % Yield 1 CHZOAc 39 A 95 Br CHZOAc 51 Aa 96 Cl CHZOAc gg Aa 9o COOEt CH3 26b CHZOAC 42 74 coon so so I g; 90 CONMe2 CH3 8] CHZOAc gg E b coon s3 <15 1 £5 <15 CF3 CH3 gap CHZCl §§ 99 cno §§ H 80 a1.7511 bnot isolated Method A: Pb(0Ac)4 (1.95 equiv), HOAc, 25°C, 4 h. B: Pb(AOC)4, HOAC, 90°C, 48 h. C: Brz, $02C12, HOAC, 60°C, 1 h; H20, 60°C, 1 h. D: NaI, 12, NaHCO3, H20, C1CHZCH201, 85°C, 1 h. E: Pb(0Ac)4, HOAC, 50°C, 26 h. F: $02C12, C1CH2CH2C1, 25°C, 15 h; H20, 60°C, 1 h. G: $02C12, C1CH2CH2C1, 0-3°C, 10 h. H: Brz, $02C1 3-25°C, 2 h; H 0, 90°C, 28 h. 2’ 2 42 tarry reaction mixture by column chromatography (silica: hexane-CH2C1) and identified by mass spectrometry (M+, 289) 1H NMR (broad singlets at 6 5.13 and 2.36 and a sharp and singlet at 6 2.15). $02Cl2 mono-chlorination of 232 proved to be considerably more effective, affording a high yield of the stable bis(chloromethyl)pyrrole 55. The exhaustive chlorination, hydrolysis, and iodinative decarboxylation of pyrroles 269, 32 and 236 were studied under a variety of conditions. The most effective proce- dure for the conversion of carbethoxypyrrole 262 to diacid 59 (M+ at 299; 1H NMR: trip1et at 6 1.35 and quartet at 6 4.38) paralleled the reported oxidation of Knorr's pyrrole 75 The use of bro- with SOzCl2 and bromine in acetic acid. mine in this reaction has not been explained, however poorer results were obtained without it. Iodinative decarboxyla- tion of 59 at 90°C gave a good yield of 51, which displayed a triplet at 6 1.23 (J=7 Hz), quartet at 6 4.31 (J=7 Hz) 1H NMR (M+ at 463). and a broad singlet at 6 10.00 in the Synthetically useful methods for the preparation of amide pyrroles 53 and 54 were not found. Various oxidation and decarboxylation attempts allowed isolation of only small amounts of each pyrrole. Spectral evidence for diiodopyr- role E5 included a singlet in the 1H NMR (DMSO-d6) at 6 2.88 and absorptions at 6 34.32, 38.34, 69.13, 125.97, 164.82 in the 13c NMR (DMSO-dfi). Dichlorination was the highest oxidation level feasible for bis(trifluoromethy1)pyrrole 232. Conditions which 43 normally lead to trichlorination (Brz, SOZClz, HOAc) only gave the bis(dichloromethyl) derivative (broad singlet at 1 6 6.93 in H NMR). Direct hydrolysis provided diformyl- pyrrole 56 in 80% overall yield. C. SYNTHESES OF PORPHYRINS Dipyrromethanes and porphyrins have traditionally been prepared form pyrroles bearing a single a-chloro, bromo or acetoxymethyl substituent.76’77 Initial investigations into the direct synthesis of porphyrins from pyrroles with two such a-substituents involved derivatives of heptaf1uoro- butylpyrrole 23 (Table 5). Pt was found that heating bis (acetoxymethyl) derivative 383 under air in acidified alco- hol allowed self-condensation and oxidation to symmetrically substituted octakis(lH,1H—heptafluorobut-l-y1)porphyrin 78 57. Yields of 20% were obtained when the reaction was conducted at reflux in 1-propanol in the presence of a slow stream of oxygen and subsequently allowed to stand exposed ix>theatmosphere in a large open breaker for 14 days. The porphyrin precipitated slowly from the reaction mixture and was collected by filtration. The mechanism of the condensation is envisioned to be similar to the one proposed for the formation of dipyrro— methanes.79 The key steps are summarized in Scheme 25 and involve the acid catalized solvolysis of the acetoxymethyls followed by self-condensation and elimination of formalde- hyde. 44 Table 5. Preparations<3foctakis(lH,lH-heptafluorobut-l- yl)- and octakis(lH,1H-trif1uoroeth-l-yl)porphy- rins. R R /\ , X N X H R R R . Pyrrole R X Method Porphyrin % Yield 383 CHZCFZCFZCF3 CHZOAc A 51 20 38b CHZBr A 7 38c CH201 A 15 58 CHZNMe2 A 0 41 H B 30 40a I B 35 38: CHZCF3 CHZOAc A 59 31 423 I B 40 Method A: HBr, l-C3H7OH, 02, 98°C. B: HBr, 1-C H OH, 3 7 HCOH, 98°C. An investigation of alternate sources of pyrrylcarbinyl cations revealed 38a to be the most practical porphyrin precursor. Both bromo- and chloromethyl derivatives 38b and 38c are considerably less stable and gave lower yields 45 Scheme 25 R R1 / \ R' H20 R‘ / \ ' ‘L a E”: . HOCHz u 1’ etc. of porphyrin. Dimethylaminomethyl derivative, 58, prepar- ed from 2,5-unsubstituted pyrrole 41 and excess N,N-di- methylmethyleneammonium bromide gave no evidence of por- phyrin formation. Equimolar mixtures of 58 and 41 reacted to form 57, which suggests that self-condensation of 58 is 46 inhibited by deactivation of the pyrrole ring, possibly due to protonation of the second dimethylaminomethyl substi- tuent. Treibs reported the formation of dipyrromethenes from monoiodopyrroles and various a1dehydes.42 An extension of this method to the direct synthesis of porphyrins from a- diiodopyrroles was also investigated. It was found that reaction of 403 with formaldehyde and HBr in refluxing l-propanol provides 51 in 31% yield. The porphyrin preci- pitated during the course of the reaction and was collected by filtration in an essentially pure form. Allowing the filtrate to stand exposed to air for 14 days provided only another 4% of 51. The condensation may entail elimination 42 which ob- of 1+, an efficient internal oxidizing agent, viates the use of oxygen and the normally required pro- longed air oxidation. Although the yield of porphyrin is considerably greater than for 383, a more direct compari- son with the condensation of 41 and formaldehyde (30%) shows no major increase in yield in using the diiodo derivative. Under conditions identical to the ones described above, bis(acetoxymethyl)- anddiiodo(trif1uoromethy1)pyrroles 38f and 40b condensed to form octakis(trifluoroethyl)porphyrin m 59 (Table 5). Yields in both cases were slightly higher than for the corresponding heptaf1uorobuty1pyrroles. 1 The H NMR spectra for porphyrins 52 and 52 display the characteristic triplet (6 5.34, J=18.4 Hz) and quartet 47 (6 5.44, J=10.5 Hz) associated with the heptaf1uorobutyl and trif1uoroethy1 substituents. Singlet absorptions for the the mesa (6 10.62 for 51, 6 10.85 for 55) and NH protons (6 -3.21 for 51, 6 -3.33 for 55) provide strong evidence for the symmetrical nature of the B-substitution pattern. The visible spectra (illustrated for 51 in Figure 3) display a phyllo-type absorption, which is in sharp contrast to the elio-type absorption normally observed for porphyrins of high substitution and symmetry (e.g., octabutyl28 and octaethylporphyringo). Another surprising feature is the low solubility of 51 and 52 in normal organic solvents. This is illustrated in a comparison of solubilities between 51 and octabutyl- porphyrin, 50, summarized in Table 6. Unlike 59, hepta- f1uorobuty1porphyrin 51 is completely insoluble in hexane, benzene, and methylene chloride and demonstrates only moder- ate solubility in acetone and fluorinated solvents. A simi- lar pattern in, although slightly higher overall, solubility is observed for octakis(trifluoroethyl)porphyrin. The acid catalyzed self-condensation of 2,5—bis(acetoxy- methy1)-3,4-bis(p-tolylsu1fonylmethyl)pyrrole, 45, was considerably less efficient than the condensations for the corresponding polyfluoroalkylpyrroles. Optimum condi- tions, involving the heating of 45 (80°C, 60 h) under air in 1-propanol in the presence of HBr, allowed formation of only spectroscopic amounts of what is presumed to be the corresponding octasubstituted porphyrin. Evidence for the structure is provided by the UV-vis spectrum which displays A/—. 48 40- _ R, a, R: 3' 30b R R [0.0- f f x _ a, Rt 7’; Rf-CF2CF2CF3 TU 20" E .5 " o 1E l a '0' l c: .9. 1", r .2 [>5 xe \ O J l l J l 400 500 600 Wavelength (n m) Figure 3. UV-vis spectrum of octakis(lH,1H-heptafluorobut- 1-y1)porphyrin. 49 Table 6. Maximum solubilities of octakis(lH,lH-heptafluoro- but-l-y1)— and octakis(lH,lH—trif1uoroeth-1-y1)- porphyrins in grams/liter (moles/liter) at 25°C in selected solvents. Solvents 57 50 Hexane insoluble 1.4 (1.9X10'4) Benzene insoluble 2.2 (2.9X10'3) CH2612 insoluble 6.5 (8.6x10'3) Acetone 0.18 (1.0x10‘4) 0.054 (7.2x10‘5) c12Fccc1F2 0.064 (3.6x10‘5) 0.097 (1 3x10'4) Hexafluoro- 1.9 (1.1x10‘3) 0.41 (5.4x10“4) benzene a Soret band (large 8) and a visible absorption pattern resembling the phyllo-type observed for polyfluoroalkyl- porphyrins 51 and 55 (xmax in acetone 423.9, 514.0, 547.8, 587.3, 643.3). The unstab1e bis(chloromethyl) derivative of nitroalkyl- pyrrole 4 suffered a similar fate, providing only small amounts of porphyrin when heated with HBr in alcoholic sol- vents. Diiodonitroalkylpyrrole 44 on the other hand served as an efficient precursor to octakis(Z-methyl-2-nitropr0p- l-yl)porphyrin 51. Refluxing of 44 with formaldehyde and HBr in l-propanol gave 25% yield of 51, which precipitated directly from the reaction mixture without the need for prolonged air oxidation. The structure and symmetrical 50 nature of 61 was determined by 1H NMR, which in acetone-d a” 6 gave singlets at 6 -3.50 (NH), 1.93 (nitroalkylmethyls), 4.96 (nitroalkylmethylene) and 10.05 (mesa protons). The UV-vis spectrum shows a Soret band at 407.4 nm and a phyllo- type visible absorption pattern at 501.9, 534.2, 527.9 and 627.0 nm. The aliphatic nature of 51 gives it moderate solubility in chlorinated solvents as well as in acetone. A study of the condensations of the various carboxamide pyrroles prepared in Sections A and B is summarized in Table 7. The reaction of N,N-diethylcarboxamidepyrrole 515 with formaldehyde gave a 25% yield of octakis(N,N-diethy1- carboxamide)porphyrin, 515. It was successfully carried out in alcoholic solvents (ethanol and l-propanol), water, or preferably a mixture of both, which allowed direct crystallization of 555 from the reaction mixture after air oxidation. Previous attempts to prepare a similar type of porphyrin, bearing eight strong electron-withdrawing groups, from 3,4-dibenzoyl- and dicarbethoxypyrroles had failed.81 Success in this case is attributed to the slightly less deactivating nature of the dia1kylcarboxamide substituents. The condensation of N,N-dimethylcarboxyamidepyrrole 515 with formaldehyde proved to be solvent dependent, providing a 14% yield of octakis(N,N-dimethylcarboxamide)porphyrin, 555, when carried out in water, but afforing no porphyrin in alcoholic solvents (methanol, ethanol, 1-propanol). This appears to be a result of the high solubility of pyrrole 515 in aqueous media. Un1ike 62a, porphyrin 62b did not 51 Table 7. Preparations ofoctakis(N,N-dia1kylcarboxamide)- porphyrins. R R R R R R / \ X’an‘x' * H R R R - Pyrrole x x' Method Porphyrin % Yie1d 31a CONEt2 H A 62a 25 32b CONMe2 H 8 62b 14 a E3 CHZOAc C 10 55 H CHZNMez D trace 54 I -— 0 31c CON 0 H E 62c trace 515 CONHMe H —- 0 aPyrrole 52 was not isolated and yield is based on 37. Method A: HBr, H20-Et0H, HCOH, 80°C. B: HBr, H20, HCOH, 100°C. C: HBr, H20, 75°C, N2. 0: HBr, H20, 100°C. E: HBr, EtOH or H20, HCOH reflux. crystallize from the reaction mixture and isolation required extraction with CH2C12 followed by column chromatography (alumina, CHCl3/3% sec-butanol). 52 0f the remaining N,N-dimethylcarboxamide derivatives only bis(acetoxymethyl)pyrrole 52 provided an alternate route to porphyrin 525 and best results were again obtained when water was used as the solvent. Monosubstituted di- methy1aminomethy1pyrrole 55, prepared from 5L5 and dimethyl- aminomethyleneammonium bromide, gave only trace amounts of 555, whereas diiodopyrrole 54 surprisingly provided no evi- dence of porphyrin at all.. The overall yields of por- phyrin in both successful methods are comparable (7.6% from diethyl succinate and 4.0% from N,N-dimethylacetyl- acetamide), however in light of the shorter and more conven- ient preparation of precursor 52 (see page 28) synthesis of 555 via the bis(acetoxymethyl) derivative is more practi- cal. As was observed for the polyfluoroalkylporphyrins the visible spectra of 62a,b in CHCl3 resemble a phyllo-type absorption more so than the expected etio-type82 (Table 8). In water under neutral conditions 62b exhibits a true phyllo-type absorption: 416(264,000), 513 (17,500), Amax(eM) 547 (6,800), 585 (7,400), 636 (2,900). Under basic condi- tions (KOH, H20, 25°C) the Soret band is shifted to longer wavelength with concurrent change in the visible bands: Amax(em) 434 (215,000), 525 (sh, 6,700), 567 (14,200), 603 (sh, 6,100). Since the visible absorption pattern is very similar to the pattern normally observed for metalloporphy- rins, this spectrum is attributed to the dianion of 525. Also, acidification with HC1 regenerates the original spectrum. 53 Table 8. 1H and 13C NMR chemical shifts and UV-vis absorp- tions of octakis(N,N-diethylcarboxamide)- and octakis(N,N-dimethylcarboxamide)porphyrins. 62a 62b xmax, nm (EM)a 416 (249,000) 418 (241,000) 508 (20,000) 510 (17,000) 540 (7,800) 543 (6,000) 581 (3,600) 584 (6,000) 634 (2,900) 636 (2,000) 1H NMR (6)b -3.36 s -3.26 s NH 10.10 s 10.20 s meso 1.16 t 3.27 s NR2 1.65 t 3.59 s 3.61 q 3.96 q 13c NMR (6)b meso 102.85 d 103.68 d o-pyrrolic 142.80 5 142.65 d B-pyrrolic 136.67 s 137.10 5 co 165.74 s 166.60 s NR2 13.38 q 35.73 q 14.32 q 39.92 q 39.79 t 44.45 t arecorded in CHCl3 brecorded in CDCl3 The 1H NMR chemical shifts for the mesa and NH protons as well as the 13C NMR shifts for the mesa and "pyrrolic" carbons in 53355 compare closely with the values observed for other octasubstituted porphyrins.83 Unlike their pyrrole precursors two distinct amide a1ky1 resonances are observed for 628,b in the 1H and 13C NMR. For 54 the pyrroles the single resonance may be the result of de- localization of the amide carbonyl into the aromatic ring allowing rotation about the carbonyl-nitrogen bond. Since similar delocalization is also expected for the porphyrin, steric interactions of the amide alkyls with the mesa pro- tons appear to be the cause of the restricted rotation. The solubilities of porphyrins 62a,b in selected sol- vents are summarized in Table 9. The values indicate a Table 9. Maximum solubilities of octakis(N,N-diethylcarb- oxamide)- and octakis(N,N-dimethylcarboxamide)- porphyrins in grams/liter (moles/liter) at 25°C in selected solvents. Solvent 533 535' H20a 0.013 (1.2 x 10'5) 2.4 (2.7 x 10'3) EtOH 3.5 (3.2 x 10'2) 1.6 (1.8 x 10'3) EtOAc 2.2 (2.0 x 10‘3) 0.097 (1.1 x 10'4) cnzm2 96 (8.7 x 10'2) 65 (7.4 x 10'2) EtZO 0.051 (4.6 x 10'5) 0.004 (4.3 x 10'6) Toluene 7.9 (7.2 x 10'3) 0.05 (5.7 x 10'5) 6Plots of the absorbance of the Soret band vs the concentra- tion of 923 (1.2 x10‘5 to 1.0 x10'7 M) and 939 (7.4 x10'5 to 2.6 X 10'6 M) obey Beer's law, implying a lack of self- aggregation at these low concentrations. a high degree of solubility in a wide range of organic solvents as well as in water. This latter property is 55 usually associated only with porphyrins bearing readily ionized substitutents such as carboxylate,84 sulfonate85 or quaternary ammonium salts.86 Porphyrin 535 demonstrates considerably higher solubility in water, which is attributed to the less aliphatic nature of the carboxamide substitu- ents. Further reduction in the aliphatic character of the por- phyrin could not be effected. Condensation of 3,4-bis- (N-methylcarboxamide)pyrrole 513 with formaldehyde under a variety of conditions failed to give any evidence of porphy- rin formation. The condensation of bis(morpholinecarbox- amide)pyrrole, 5L5,possessing an additional heteroatom capable of hydrogen bonding with water, never proved practi- cal, providing only spectroscopic amounts of the desired porphyrin 535, (A 416.6, 509.7, 543.3, 584.4, 642.3). max’ 0f the remaining oxidized pyrroles prepared in Section B only the self-condensations of the bis(acetoxymethy1)-3,4- dibromo-auuidichloropyrroles were met with at least partial success. Optimum conditions for both condensations involved stirring of the pyrrole in acidified Et0H at 25°C for one week in the presence of air. The resulting residue was fil- tered and washed with EtOH, providing an insoluble black solid, which resisted all attempts of purification. Analysis of the solid was possible only by UV-vis spectrosc0py intri- fluoroacetic acid. The spectra display a Soret band (large a) and absorptions in the visible region and are attributed to the diprotonated octabromo- and chloroporphyrins 5g and 56 55. (Amax at 413.8, 560.5, 604.3 for 53 and 408.2, 554.6, 600.8 for 55). Additional evidence for the existance of 53 and 55 was provided by their conversion to zinc derivatives. This was accomplished by heating of the black solids with zinc acetate in dioxane at 90°C for 7-10 hours. The result- ing crude reaction mixture gave UV-vis spectral data char- acteristic of zinc porphyrins:87 Amax at 420.9, 547.4, Table 10. Reaction conditions for attempted conversions of 3,4-bis(trif1uor0methyl)pyrrole to por- phyrin. CE, CE, ——-x—-—-> PORPHYR IN H Aldehyde Solvent Catalyst Temperature HCOH EtOH HBr 79°C HCOH 1-C3H70H HBr 98°C HCOH 1-C3H70H HBr 170°Ca HCOH H20 HBr 100°C Paraform- o-dichloro- ZnCl2 150°Ca aldehyde benzene ¢COH o-dichloro- 2nc12 150°Ca benzene ¢COH 1-C3H70H HBr 150°Ca ¢COH ——— HBr 170°Ca aReaction conducted inside a sealed heavy-walled glass tube. 57 583.8 for the bromo derivative and 417.0, 545.2, 580.3 for the chloro derivative. Considerable effort was directed toward the preparation of octakis(trifluoromethyl)- and (carbethoxy)porphyrins. Tables 10 and ll summarize the various reaction conditions Table ll. Reaction conditions for attempted conversions of 2,5-bis(chloromethyl)-3,4-bis(trifluoromethyl)- pyrrole to porphyrin. CE, lCfi -——)(-—> PORPHYRIN CICH2 CHZCI H Solvent Catalyst Temperature l-C3H70H HBr 98°C 0 a l-C3H70H HBr l70 C o a l-C3H70H ZnCl2 150 C o-dichloro- 2nc12 150°Ca benzene aReaction conducted inside a sealed heavy-walled glass tube. examined for the condensations of 3,4-bis(trifluoromethyl)- pyrrole, 233, and chloromethyl derivative 22, Neither for these, nor the condensations of 2,5-unsubsituted, 2,5—di- iodo, and 2,5-bis(acetoxymethyl)3,4mbis(carbethoxy)pyrroles (£62, 51 and 49), studied under similar sets of conditions, was any evidence of porphyrin observed. 58 To probe the reactivity of the bis(trifluoromethy1)- pyrrole nucleus two additional reactions of 223 were invest- igated. The Vilsmeier formylation of pyrroles bearing two electron-withdrawing substituents is reportedly a facile reaction,88 however even at higher temperatures (90°C, 6 h and 130°C, 1 h) attempted formylation of 233 re- sulted in recovery of starting material. Treatment of 233 at 90°C for 3 h with excess dimethylmethyleneammonium bro- mide, conditions which successfully a-alkylated diamide pyrrole 319 (page 52), provided only N-dimethylaminomethyl- 3,4-bis(trif1uoromethy1)pyrrole (1H NMR: singlets at 6 3.00, 5.80, 8.20 in ratios of 3:1:1). These results confirm that the a-positions of 3,4-bis(trif1uoromethy1)- pyrroles are highly deactivated toward attack by electro- philes. 0. CONCLUSIONS It has been demonstrated that octasubstituted porphyrins can be efficiently prepared from 2,5-dimethy1pyrroles. The success of this method depends on the availability of the 2,5- dimethylpyrroles, the selective oxidation of the methyl sub- stituents and the feasibility of the final condensation. 2,5-Dimethy1pyrroles and its N-benzoyl derivative served as the preferred starting materials, allowing the faci1e intro- duction of a variety of substituents into the 3 and 4 positions. Selective oxidation of the a-methyls was influenced by the 59 nature of the B-substituents. Unreactive and slightly deacti- vating groups allowed efficient mono- and trioxidation, whereas more reactive substituents (e.g. CHZCN and CHZCOOEt) inter— fered with theoxidation. Highly deactivated pyrroles required more severe reaction conditions, or did not react beyond the second oxidation level (CF3). Condensations leading to porphyrins were also dependent on the nature of the substituents. It was shown that pyrroles bearing electron-withdrawing dialkylamide substituents con- densed to give porphyrins. More deactivated pyrroles, how- ever, bearing esters, trifluoromethyls and monoalkylamides failed to do so. Slightly deactivated pyrroles gave the best results, providing porphyrins via their bis(acetoxy-, chloro- and bromomethy1), 2,5-diiodo and 2,5-unsubstituted derivatives. Where comparisons are possible, the reactivity of the 2,5-bis(CH2X)- and 2,5-diiodopyrroles toward condensations parallels the reactivity of the 2,5-unsubstituted pyrroles. This is consistent with the proposed mechanisms for the three types of condensations in which the key steps are very simi- lar. The condensations of diiodopyrroles are more practical than the condensations of the corresponding bis(acetoxy- and chloromethyl)-pyrroles. They provide considerably higher yields and also avoid the usually required prolonged air ox- idation. Further investigations into the scope of the above por- phyrin syntheses will depend largely on expanding existing and developing new routes to 2,5-dimethylpyrroles. For 60 example the reactions of malonate anions33’34 with quaternary ammonium salts of 3 or 6 could prove useful in the prepara— tion of ester (and eventaully amide) 3,4-bis(CH2CH2R)pyrroles. This may avoid the problems seen with pyrroles Z and 19 and allow the preparation of 2,5-bis(CH2X) derivatives. Another route to a similar pyrrole (and potentially numerous other pyrroles) could involve the use of 2,5-dimethy1-3,4-diformyl- pyrrole, which is readily available in large quantitites by Vilsmeier formylation of 2,5-dimethylpyrrole. Nittig olefina- tion with carbethoxymethylenetriphenylphosphorane, followed by hydrogenation for example could lead to 2,5-dimethyl-3,4- bis(ethoxycarbonylethyl)pyrrole. An alternate strategy to octakis(fluoromethyl)porphyrins may require the syntheses of less deactivated pyrrole deriva- tives. This could entail the preparation of 2,5-dimethyl-3,4- bis(dif1uoromethy1)pyrrole, which may be available by fluor- ination of 2,5-dimethyl-3,5-diformy1pyrrole. Investigations into the application of more reactive pyr- roles could also prove useful. 3,5-Dimethy1-3,4-diethylpyr- role, available from 2,5-dimethylpyrrole by reductive alkyla- tion,32 may serve as an intermediate in what potentially is a three step 0ctaethy1porphyrin synthesis. EXPERIMENTAL General Methods Melting points were taken on a Thomas-Hoover capillary melting point apparatus and are uncorrected. NMR spectra were recorded on a Varian T-60 (1H NMR at 60 MHz) or a Bruker WM-ZSO (1H NMR at 250 MHz and 13 C NMR at 62.9 MHz) instrument in CDC13, or as noted, with Me4Si as an internal standard. Electronic absorption spectra were measured on a Cary 219 spectrophotometer. Mass spectra were obtained on a Finnigan 4000 instrument at 70 eV or using ionized methane (CI). Infrared spectra were measured on a Perkin- Elmer 237 grating spectrophotometer as a Nujol mull for solids or neat for oils. Elemental analyses were performed by Galbraith Laboratories, Incorporated. Solvents were reagent grade and were not usually distilled prior to use. Dry benzene, toluene, and tetrahydrofuran (THF) were obtain- ed by distillation from potassium-benzophenone. Dry methyl- ene chloride (CHZClZ) and 1,2-dichloroethane (ClCHZCHZCl) 61 62 were obtained by passage through a column of alumina (Noelm B, Akt. I). All reactions unless otherwise noted were carried out under an atmosphere of nitrogen. 2,5-Dimethyl-3,4-bis(lH,lH-heptafluorobut-l-yl)pyrrole (23); According to the general procedure of MacDona1d,32 a solution of 189 (8.20 g, 86.3 mmol) and heptaf1uorobutyr- aldehyde hydratego (46.6 g, 2.5 equiv) in acetic acid (100 mL), 47% HI (100 mL), and 58% H3PO2 (20 mL) was magnetical- ly stirred at 100°C for 3.5 h. The dark red solution was diluted with water (100 mL) and CHZCl2 (100 mL) and cooled in an ice bath. NH40H (400 mL) was added slowly with stir- ring and the mixture was extracted with CH2C12. The combin- ed organic fractions were dried over anhydrous Na2504 and concentrated. Distillation (0.08 mm, 68°C) of the result- ing dark red oil gave 25.4 g (64%) of 23 as a colorless oil, which solidified upon standing. An analytical sample was obtained by recrystallization from hexane: mp 32.5- 1 33.0°C; H NMR 6 2.18 (6H, s), 3.15 (4H, t, J=19.9 Hz), 7.69 (1H, br S); 13 C NMR 6 11.28, 26.15 (t, J=23.3 Hz), 106.72, 109.41 (t of q of t, J=261.5, 39.0, 39.1 Hz), 117.22 (t of t, J=251.6, 31.5 Hz), 118.21 (q of t, J=286.2, 33.3 Hz), 125.98; mass spectrum, m/e (relative intensity) 459 (15, M+), 290 (100), 120 (34), 69 (17); IR 3525 (NH), 1230(Cf)cmf. Anal. Calcd for C14H11NF14: C, 36.60; H, 2.40. Found: C, 36.40; H, 2.50. 1 63 2,5-Dimethyl-3,4-bis(1H,lH-trif1uoroeth-1-yl)pyrrole (2b). The above procedure was followed using 1 (7.00 g, 7.37 mmol) and trifluoroacetaldehyde hydratego (21.4 g, 2.5 equiv) inacetic acid (90 mL), 47% H1 (90 mL), and 58% H P02 (18 mL). Distillation (0.10 mm, 57°C) gave 7.6 g 3 (40%) of 23 as a colorless oil which solidified upon stand- ing. An analytical sample was obtained by recrystalliza- . tion from hexane: mp 53.0-53.5°c; 1H NMR 6 2.13 (6H, s), 13 3.18 (4H, q, J=11.0 Hz), 7.58 (1H, br s); C NMR 6 11.03, 29.57 (q. J=30.5 Hz), 107.85, 125.42, 126.91 (q. J=276.5 Hz); mass spectrum, m/e (relative intensity) 259 (35, M+), 258 (12), 190 (100); IR 3460 (NH), 1270, 1135 (CF) cm']. Anal. Calcd for C10“ 11NF6: C, 46.33; H, 4.25. Found: C, 46.46; H, 4.24. 3,4 -bis(Dimethy1aminomethy)-2,5-dimethylpyrrole (3). According to the procedure of Hertz35 a solution of dimethy1amine hydrochloride (17.0 g, 0.210 mol) in 37% formaldehyde (15.8 g, 0.210 mol) was added dropwise to 189 (10.0g, 0.105 mol) at such a rate that the temperature did not exceed 55°C. This was stirred another 111,diluted with water (150 mL) and extracted twice with ether. The aqueous layer was poured into a 25% NaOH solution (40 mL). The white precipitate was filtered, washed with small por- tions of cold water and dried under vacuum, yielding 19.8 g 64 (90%) of 3, which appeared pure by NMR and was used directly in subsequent reactions: 1H NMR 6 2.07 (6H, s), 2.17 (12H, s), 3.20 (4H, s), 7.92 (1H, br s); 13c NMR 6 11.12, 45.20, 53.78, 115.51, 123.47; mass spectrum, m/e (relative intensi- ty) 209 (2, M+), 164 (76), 149 (100), 120 (90), 85 (25), 77 (27), 58 (42), 44 (67). 3,4-bis(2-Methyl-2-nitroprop-l-y1)-2,5-dimethylpyrr01e (4). A solution of 3 (18.0 9, 0.0861 mol) and 2-nitropropane L (31.0 mL, 0.341 mol) in water (500 mL) was stirred at 90°C for 35 h. The yellow precipitate was filtered from the cooled reaction mixture and thoroughly washed with water. Recrystallization from CHCls-hexane gave 17.9 g (70%) of 1H NMR 6 1.51 (12H, s), 2.06 (6H, s), 13 4: mp 127-130°C; 2.95 (4H,s), 7.64 (1H, br S); C NMR 6 11.82, 25.52, 36.55, 89.57, 112.24, 124.27; mass spectrum, m/e (relative intensity) 297 (73, M+), 251 (14), 204 (32), 179 (41), 162 (100), 146 (33), 136 (28), 121 (86); IR 3450 (NH), 1540 (N02) cm']. 3,4-bis(Phenylthiomethyl)-2,5-dimethylpyrrole (5). A solution of 3 (0.588 g, 2.67 mmol) and thiophenol (0.800 mL, 7.80 mmol) in H20 (27 mL) was purged of oxygen 65 by bubbling a rapid stream of nitrogen through the solu- tion at 25°C for 30 min. To this was added NaDH (0.160 g) and then stirred at 95°C for 17 h. The oily precipitate was filtered from the cooled solution and washed with water. Recrystallization from MeOH gave 0.75 g (83%) of 5 as a tan solid: mp 111-112.5°c; 1H NMR 6 2.00 (6H, s), 4.00 (4H, 13 s), 7.16 (10H, m); C NMR 6 10.85, 29.55, 112.77, 124.09, 125.94, 128.68, 129.97, 137.74; mass spectrum, m/e (relative intensity) 339 (5, M+), 230 (100), 121 (50), 120 (45), 108 (11); IR 3400 (NH) cm". N-Benzoyl-3,4-bis(dimethy1aminomethyl)-2,5-dimethylpyrrole (6). -~_ A solution of N-benzoy1-2,5-dimethylpyrroleg] (3.00 g, 15.1 mmol) and N,N-dimethylmethyleneammonium bromide39 (6.00 g, 43.5 mmol) in CHCl3 (50 mL) was stirred at 58°C for 31 h. During the course of the reaction a white preci- pitate formed. The mixture was poured into a saturated, aqueous Na2003 solution (100 mL) and extracted with CH2C12. The organic layer was extracted with aqueous NaZCO3 and dried over Na2504. Evaporation of the solvent gave 4.48 g 1 (95%) of 6 as a yellow oil: H NMR (CDC13) 6 2.00 (6H, s), 2.20 (12H, s), 3.27 (4H, s), 7.50 (5H, m); ‘3 C NMR 6 12.15, 45.35, 53.29, 120.33, 127.25, 128.60, 129.99, 133.07, 135.94, 171.00; mass spectrum, m/e (relative intensity) 66 313 (5, M+), 268 (27), 163 (44), 105 (80), 77 (43), 58 (100); IR 3450 (NH), 2800 (CH), 1710 (cc) cm". 3,4-bis(Cyanomethy1)-2,5-dimethy1pyrrole (7). A solution of pyrrole 6 (3.60 g, 11.5 mmol) and CH3I (33 mL) in MeDH (33 mL) was stirred at 40°C for 2.5 h and then evaporated to complete dryness. The residue was dissolved in a solution of water (125 mL) and KCN (14 g), heated at 65°C for 5 min and suction filtered, removing any undissolved materials. The filtrate was then stirred at 65°C for 25 h. Filtration of the cooled solution gave 1.08 g (54%) of Z as a tan solid, which appeared pure by NMR and was used without further purification in subse- 38 1 quent reactions: mp 166-169°C (lit. mp l71-172°C); H NMR 6 2.17 (6H, s), 3.47 (4H, s), 7.70 (1H, br s); 13c NMR 6 10.62, 12.91, 107.07, 119.15, 124.56; mass spectrum, m/e (relative intensity) 173 (59, M+), 147 (21), 146(100), 145 (50), 133 (23), 85 (13); IR 3300 (NH), 2250 (CN) cm". 3,4-bis(p-Tolylsu1fony1methy1)-2,5-dimethy1pyrrole (8). A solution of pyrrole 6 (0.543 g, 1.74 mmol) and CH3I (5.5 mL) in MeOH (5.5 mL) was stirred at 40°C for 2.5 h and then evaporated to complete dryness. The resinous material was dissolved in water (17 mL) and stirred at 65°C with sodium p-toluenesulfinate (3.00 g, 16.9 mmol) for 12 h. 67 The resulting white solid was filtered from the cooled mixture, washed with water and dried under vacuum, yielding 0.354 g (47.4%) of 8: mp 240-245°c (dec.); 1H NMR 6 1.77 (6H, s), 2.40 ( 6H, s), 4.20 (4H, s), 7.20 (4H, d, J=8 Hz), 7.57 (4H, d, J=8 Hz); mass spectrum, m/e (relative inten- sity) 431 (1, M+), 276 (40), 212 (31), 121 (98), 120 (100), 92 (20), 91 (50), 77 (27), 65 (30); IR 3500 (NH), 1320 and 1170 (s02) cm". 3,4-bis(Carbethoxymethyl)-2,5-dimethy1pyrrole (10), According to the method of Treibs,4O a solution of pyrrole 7 (0.369 g, 2.13 mmol) in absolute EtOH (10 mL) was saturated with gaseous HC1 at 3°C for 4 h and then stored at 25°C for 10 days. The solution was evaporated to dryness and the residue heated on a steam bath for 10 min. Extraction with CH2012 and drying of the combined organic fractions over anhydrous NaZSO4 gave 0.514 g (99%) 1 of 19 as a yellow oil: H NMR 6 1.20 (6H, t, J=7 Hz), 2.07 (6H, s), 3.35 (4H, s), 4.05 (4H, q, J=7 Hz), 7.91 13 (lH, br s); C NMR 6 11.14, 14.22, 30.63, 60.46, 111.09, 123.15, 172.48; mass spectrum, m/e (relative intensity) 267 (29, M+), 221 (25), 194 (75), 122 (100), 120 (56); IR 3350 (NH), 1725 (00) cm". 68 3,4-Dibromo-2,5-dimethy1pyrrole (ll). N-Bromosuccinimide (3.69 g, 1.95 equiv) was added in small portions over 30 min to pyrrole 1 (1.01 g, 10.6 mmol) in DMF (50 mL) at 25°C. The solution was stirred for 2.5 h, diluted with CHCl3 (100 mL) and thoroughly washed with water, removing all of the DMF. The organic layer was dried over anhydrous Na2504 and the solvent evaporated, yielding 1.90 g (71%) of 11 as an unstable, slightly red solid, which appeared pure by NMR and was used directly in the preparation of 64: mp 67-70°C (dec); 1H NMR 6 2.17 (6H, 13 s), 7.63 (1H, br s); C NMR 6 12.35, 96.72, 124.21; mass spectrum,1n/e(re1ative intensity) 255 (8, M+), 254 (8), 253 (17, M+), 252 (14), 251 (10, M+) 172 (21), 93 (20), 73 (19), 65 (27), 51 (70), 42 (100); 1 , 250 (17), 174 (19), IR 3450 (NH) cm- 3,4-Dichloro-2,5-dimethylpyrrole (1 ). M — N-Chlorosuccinimide (2.47 g, 2.00 equiv) was added in small portions over 20 min to pyrrole 1 (0.855 g, 9.00 mmol) in DMF (40 mL) at 2°C. The solution was stirred for 2.5 h, diluted with CHCl3 (100 mL) and thoroughly washed with water, removing all of the DMF. The organic layer was dried over anhydrous Na2S04 and the solvent evaporated, yielding a dark oil. Filtration through a short column of silica gel (CHZCTZ) gave 0.400 g (27%) of 12 as an unstable oily 69 1 solid: H NMR 6 2.13 (6H, s), 7.10 (1H, br s); 13c NMR 6 10.94, 107.30, 121.45; mass spectrum,m/e (relative inten- sity) 167 (5, M+), 166 (12), 165 (38, M+), 164 (66), 163 (65, M+), 162 (100), 128 (53), 85 (16), 65 (12), 51 (38), 50 (27), 42 (75); IR 3500 (NH). N-Benzoyl-Z-formylpyrrole (19). A 50% mineral oil dispersion of NaH (8.82 g, 0.184nufl) was washed thoroughly with dry ether inside a 1000 mL flask, equipped with an efficient condenser and mechanical stirrer. To this was added dry ether (250 mL) followed by 2-formy1pyrrole92 (11.7 g, 0.123 mol) in ether (75 mL) and then heated at gentle reflux for 3 h. The suspension was cooled to 25°C and benzoy1 chloride was added carefully (exothermic reaction) in portions (5.00, 5.00, 3.56 mL). This was then stirred at gentle reflux for 4 h and at 25°C for 15 h. The reaction was monitored by TLC (silica, CH2C12) and additional benzoy1 chloride was added in small amounts as needed. The reaction mixture was rapidly suction filtered and the filtrate evaporated to dryness. Recrystal- lization of the residue from MeDH yielded 12.9 g (53%) 50 mp 90°C); 1H NMR 6 6.30 (1H, m), of 12: mp 89-90°C (lit. 7.17 (2H, m), 7.60 (5H, m), 9.90 (1H, s); 13c NMR 6 111.81, 122.31, 129.06, 128.52, 129.78, 132.37, 135.22, 135.37, 167.88, 180.54; mass spectrum, m/e (relative intensity) 199 (61, M+), 105 (100),77 (54), 51 (16). 70 N-Benzoy1-2-(1,3-dioxolan-2-y1)pyrrole (162); A solution of aldehyde 12 (2.95 g, 14.8 mmol) and ethylene glycol (4.1 mL) in benzene (100 mL) was mechanical- ly stirred with CaSO4 (~4 g) at 55°C for 1 h. To this was added p-toluenesulfonic acid (0.10 g) and stirred at 55°C for 6 h. The cooled mixture was filtered and the filtrate diluted with CH2012 (300 mL) and thoroughly extracted with saturated aqueous NaHC03. Drying of the organic fraction over anhydrous Na2S04 and evaporation of the solvent pro- vided 3.55 g (99%) of a yellow oil, consisting as indicated by TLC (silica, CH2C12) and NMR of a small amount of 19 and 123‘ 1H NMR 6 4.00 (4H, s), 6.10 (1H, m), 6.53 (2H, m), 6.82 (1H, m), 7.55 (5H, m); 13c NMR 6 64.51, 98.01, 110.16, 113.24, 124.51, 128.01, 128.39, 129.44, 132.14, 133.20, 168.01; mass spectrum, m/e (relative intensity) 243 (5, M+), 215 (4), 149 (5), 138 (4), 105 (100), 77 (31), 51 (7); IR 1690 (co) cm']. N-Benzyol-2,3-bis(trif1uoromethy1)-7-azabicyclo[2.2.l]-2,5- heptadiene (17a). m— Hexafluorobut-Z-yne, 13,90 (7.60 g, 46.9 mmol) was condensed at -78°C into a heavy-walled glass tube containing 91 (4.0 g, 23.4 mmol) and THF (15 mL). N-benzoylpyrrole, 16a, The closed tube was heated inside a steam bath for 5 h. The solvent and excess 13 were evaporated on a rotary M 71 evaporator,affording7.79 g (100%) of 178 as a yellow oil. This product appeared pure by NMR and TLC and was used 1 directly in the preparation of 20 and 21a: H NMR 6 5.56 (2H, br s), 7.10 (2H, m), 7.35 (5H, br s); 13C NMR 6 66.59, 69.76, 120.89 (q, J=269.8 Hz), 128.10, 128.86, 132.16, 132.80, 142.65, 144.48, 148.98 (broad), 169.12; mass spec- trum, m/e (relative intensity) 333 (10, M+), 105 (100), 77 (40), 51 (13); IR 3350, 3060, 1675, 1350, 1290, 1180, 1130 cm-1. N-Benzoyl-2,3-bis(trifluoromethy1)-l,4-dimethy1-7-azabi- cyclo[2.2.1]-2,5-heptadiene (119). Pyrrole 119 was prepared as above in 100% yield by 1 heating 16b and 13 for 9 h: H NMR 6 1.67 (6H, s), 6.80 130 NMR 6 16.00, 78.44, 121.76 (q, J= (2H, s), 7.40 (5H, m); 273.0), 128.49, 129.24, 132.39, 137.28,148.00,150.90,174.70; + mass spectrum (CI, CH4), m/e 362 (M + 1); IR 3300, 3000, 1660, 1450, 1325, 1250, 1150, 700 cm-1. N-Benzoy1-2,3-bis(trif1uoromethyl)-1-(1,3-dioxolan-2-y1)- 7-azabicyclo[2;2.1]-2,5-heptadiene (115); Pyrrole 17c was prepared as above in 95% yield by heating 16c and 13 for 23 n in dry benzene: 1H NMR 6 4.05 (4H, m), 5.37 (1H, m), 6.37 (1H, br s), 7.40 (7H, m); 13c NMR 6 65.27, 65.90, 70.84, 83.03, 98.18, 120.31 (9. J = 72 268.6 Hz), 120.61 (0, J=273.6 Hz), 127.92, 128.39, 131.97, 132.57, 140.29, 143.28, 149.47 (br q, J=36 Hz). 151.44 (br q, J=45 Hz), 171.17; mass spectrum (CI, CH4), m/e 406 (M+ + 1); IR 1660 (00) cm". N-Benzoy1-2,3-bis(trifluoromethyl)-7-azabicyclo[2.2.1]- heptane (20). A solution of 113 (0.50 g, 1.5 mmol) in EtOH (20 mL) was hydrogenated in a Parr apparatus at 75 lbs/sq. in. for 2 h in the presence of 10% palladium on activated carbon (10 mg). The solution was filtered and concentrated in vacuo. The resulting solid was recrystallized from hexane, yielding 0.49 g (97%) of 20 as colorless crystals: mp 114- 115°C; 1H NMR 6 2.00 (4H, m), 3.06 (2H, m), 4.60 (2H, m), 7.40 (5H, m); ‘3 C NMR 6 24.05, 44.88, 58.86, 124.65 (q, J=280.5 Hz), 128.13, 128.84, 131.92, 134.08, 169.98; mass spectrum, m/e (relative intensity) 337 (21, M+), 105 (100), 77 (33), 51 (8); IR 3300, 1630, 1410, 1305, 1275, 1230, 725 cm". Anal. Calcd for C15H13N0F6: C, 53.41; H, 3.86. Found: C, 53.42; H, 3.99. 73 N-Benzoy1-2,3-bis(trif1uoromethy1)-7-azabicyclo[2.2.1]- 2-heptene (213). A solution of 113 (2.65 g, 7.96 mmol) in EtOH (20 mL) was hydrogenated atl atm in the presence of 10% palladium on activated carbon (30 mg). The uptake of hydrogen dropped sharply after 1 equiv (180 mL) and the solution was filtered and concentrated in vacuo yielding 2.58 g (97%) of 212 as a yellow oil. The product appeared pure by NMR and TLC and was used directly in the preparation of 223: 1H NMR 6 1.47 (2H, m), 2.13 (2H, m), 5.13 (2H, m), 7.36 (5H, br s); 13C NMR 6 24.15, 61.41, 120.20(q, J=271.3 Hz), 128.86, 128.88, 131.95, 133.30, 139.44, 169.47; mass spectrum (CI, CH4) m/e: 336 (M+ + 1); IR 3250, 3050, 2960, 1670, 1370, 1300, 1180, 1150, 1040, 730, 710 cm“. N-Benzoyl-2,3-bis(trifluoromethyl)-l,4-dimethyl-7-azabi- cyclo[2.2.l]-2-heptene (21b). Hydrogenation of 119 as above gave 21b (95% yield) as 1H NNR 6 1.53 (6H, s), 1.58 (2H, m), 2.03 13 a yellow oil: (2H, m), 7.40 (5H, m); C NMR 6 18.41, 34.39, 72.79, 121.24 (q, J=273.7), 128.43, 129.52, 132.47, 138.00, 140.90 (br), 176.43; mass spectrum (CI, CH4) m/e 364 (M+ + 1); IR 3260, 2950, 1675, 1450, 1335, 1270, 1170, 945, 840, 760, 710 cm". 74 N-Benzoy1-2,3-b£s(trif1uoromethy1)-l-(1,3-dioxolan-2-yl)-7- azabicyclo[2.2.1]-2-heptene (21c). Hydrogenation of 17c as described for 20 gave 21c (95% W m 1 yield) as an oily solid: H NMR 6 1.50 (2H, m), 2.40 (2H, m), 4.02 (4H, s), 4.90 (1H, m), 6.33 (1H, s), 7.47 (5H, m); 130 NMR 6 24.18, 24.68. 65.57, 65.90, 66.03, 76.66, 99.53, 120.10 (q, J=278.6 Hz), 120.29 (q, J=270.5 Hz), 128.22, 128.56, 132.06, 133.92, 139.91 (q, J=37.1 Hz), 141.89 (q, J=37.1 Hz), 172.10; mass spectrum (c1, CH4), m/e 408 (M+ + 1); IR 2950 (CH), 1660 (CO) cm‘]. N-Benzoy1-3,4-bis(trifluoromethyl)pyrrole (22a). A solution of 213 (2.20 g, 6.57 mmol) in benzene (100 mL) was passed dropwise in a slow stream of nitrogen through aitube packed with glass beads and heated to 300°C. The product was collected in a flask, cooled to -78°C. The column was washed with additional benzene (20 mL) and the solution was concentrated in vacuo. Distillation (0.15 mm, 84°C) gave 1.90 g (94%) of 22a as a colorless oil: 1H NMR 13 6 7.56 (7H, m); C NMR 6 115.70 (q, J=37.7 Hz), 121.75 (q, J=270.5 Hz), 123.5, 129.40, 130.00, 130.70, 134.20, 166.50; mass spectrum (c1, CH4), m/e 308 (M+ + 1); IR 3360, 3160, 1730, 1560, 1320, 1250, 1150, 980, 900, 725 cm-1. 75 N-Benzoyl-3,4-bis(trif1uoromethyl)-2,5-dimethy1pyrrole(22b). Pyrolysis of 21b as above gave 22b (95% yield) as colorless crystals from hexane: mp 69.5-70.5°C; 1H NMR 6 13 2.17 (6H, s), 7.60 (5H, m); C NMR 6 12.00, 110.09 (q, J=38.8 Hz), 116.92, 123.35 (q, J=269.1 Hz), 129.78, 130.81, 133.16, 135.85, 169.98; mass spectrum, m/e (relative inten- sity) 335 (1, M+), 105 (100),77 (57), 51 (11); IR 3350, 1725, 1370, 1260, 1200, 1150, 1110, 925, 725 cm-1. Anal. Calcd for C NOF : C, 53.73; H, 3.28. 15”11 6 Found: 0, 53.73; H, 3.31. N-Benzoyl-3,4-bis(trif1uoromethyl)-2-(l,3-dioxolan-2-yl)- pyrrole (22c). Pyrolysis of 210 as above gave 225 (82% yield) as colorless crystals from CHC13-hexane: mp 87.5-89.0°C; 1H NMR 6 3.75 (4H, m), 6.07 (1H, br s), 7.20 (1H, br s), 7.58 (5H, m); 13 C NMR 6 65.48, 96.62, 113.81 (q, J=40.3 Hz), 114.15 (q, J=39.6 Hz), 121.87 (q, J=268.0 Hz), 122.08 (q, J=268.0 Hz), 128.83, 129.15, 130.83, 131.68, 133.03, 135.05, 167.80; mass spectrum, m/e (relative intensity) 379 (9,M+), 105 (100), 77 (42), 51 (11); IR 1725 (00) cm“. 76 3,4-bis(Trifluoromethyl)pyrrole (23a). A solution of 223 (1.30 g, 4.23 mmol) and KOH (0.24 g, 1 equiv) in diethyl ether (60 mL) and water (3 mL) was stir- red at RT for 6 h. The reaction was monitored by TLC (sili- ca, CH2C12) and additional KOH was added in small amounts as needed. Water (200 mL) was added and the solution was extracted with CH2C12. The combined organic fractions were dried over anhydrous Na2504 and concentrated in vacuo. Recrystallization from hexane-CHCl3 (3:1) gave 0.77 g (90%) of 233 as volatile, colorless crystals: mp 36.5-37.5°C; 1 13c NMR 6 H NMR 6 7.16 (2H, d, J=3 Hz), 8.53 (1H, br s); 112.75 (q, J=39.0 Hz), 121.18, 122.96 (q, J=266.7 Hz); mass spectrum, m/e (relative intensity) 203 (38, M+), 184 (100), 153 (8), 134 (3); IR 3475, 3300, 1560, 1450, 1370, 1330, 1230, 1130, 980. Anal. Calcd for CGH3NF6: C, 35.47; H, 1.48. Found: C, 35.00; H, 1.51. 3,4-bis(Trif1uoromethyl)-2,5-dimethy1pyrrole (239). A solution of 229 (2.00 g, 5.97 mmol) and KOH (0.34 g, 1 equiv) in THF (130 mL) and water (7 mL) was stirred at RT for 6 h. The reaction was monitored by TLC (silica, hexane- CH2C12) and additional KOH was added in small amounts as needed. Water (300 mL) was added and the solution was extracted with CH2012. The combined organic fractions were 77 dried over anhydrous Na2S04 and concentrated in vacuo. Recrystallization from hexane gave 1.27 g (92%) of 23b 1 as colorless crystals: mp 95.5-96.5°C; H NMR 6 2.27 13 (6H, s), 7.87 (1H, br s); C NMR 6 12.04, 108.23 (q, J= 39.7 Hz), 123.89 (q, J=267.3 Hz), 128.94; mass spectrum, m/e (relative intensity) 231 (62, M+), 230 (80), 212 (46), 162 (100), 69 (19), 42 (30); IR 3450, 3250, 1330, 1220, 1150, 1110, 1055 cm'1. Anal. Calcd for C H NF : C, 41.56; H, 3.03. 7 6 Found: C, 41.37; H, 3.16. 8 3,4-bis(Trif1uoromethy1)-2-formylpyrrole (24). A solution of 222 (1.00 g, 2.64 mmol) and 48% HBr (0.20 mL) in acetic acid (30 mL) and H20 (4 mL) was stirred at 60°C for 4.5 h. CH2C12 (150 mL) was added and the solu- tion was washed with water followed by saturated aqueous NaHC03. The organic layer was dried over anhydrous Na2S04 and concentrated. Recrystallization from CHCl3 at -10°C gave 0.35 g (58%) of 24 as colorless crystals: mp 108.5- 1 110°C; H NMR (acetone-d6) 6 7.67 (1H, br s), 9.80 (1H, br s); 13 C NMR (acetone-d6) 6 114.72 (q, J=37.1 Hz), 116.9 (q, 0=37.1 Hz), 123.20 (q, J=265.4 Hz), 123.43 (q, J=268.0 Hz), 127.74, 133.15, 180.20; mass spectrum, m/e (relative intensity) 231 (100, M+), 212 (25), 210 (79), 192 (23), 184 (27), 183 (43), 182 (31), 164 (14), 156 (20), 114 (18), 69 (15); IR 3200 (NH), 1675 (c0) cm". 78 3,4-Dicyanopyrrole (258). A suspension of pyrrole 233 (0.339 g, 1.67 mmol) was stirred at 25°C in 7.5% aqueous ammonia (45 mL). After 5 days the solution was filtered yielding 0.074 g of 253 as a white powder. The filtrate was thoroughly extracted with CH2C12 and the combined organic fractions dried over anhydrous Na2504. Evaporation of the solvent gave another 0.090 g of 253 (total yield: 84%) as a white solid: mp 226-228°C; 1 13 H NMR (acetone-d6) 6 7.66 (2H, s), 10.23 (1H, br 5); C NMR (acetone-d6) 6 96.41, 114.13, 129.40; mass spectrum, m/e (relative intensity) 117 (100, M+), 90 (13), 66 (10), 63 (26), 51 (11), 41 (20); IR 3350 (NH), 2250 (CN) cm'1. 3,4+Dicyano-2,5-dimethylpyrrole (253). A heavy-walled glass tube was charged with 23b (0.108 MM~ g, 0.468 mmol) and 7.5% aqueous ammonia (19 mL) and heated inside a steam bath for 20 h. The cooled reaction mixture was filtered and the product washed with water yielding 0.064 g (95%) of 259 as a crystalline solid: mp 238-240°C (1it.53 mp 239°C); 1H NMR (acetone-d6) 6 2.33 (6H, s); 13c NMR (acetone-d6) 6 11.86, 93.20, 114.51, 139.19; mass spec- trum, m/e (relative intensity) 145 (63, M+), 144 (100), 130 (9), 76 (10), 42 (20), 41 (10); IR 3225(NH), 2220 (CN) cm". 79 3,4-bis(Carbethoxy)-2,5-dimethy1pyrrole (26b) prepared from 9.3.2. A solution of pyrrole 232 (0.103 g, 0.446 mmol) and KOH (0.25 g) in Et0H (10 mL) was heated at 55°C for 4 h. The cooled solution was stirred in 5% H01 (50 mL) for 30 min and then extracted with CH2012. The combined organic fractions were washed with saturated aqueous NaHC03 and dried over anhydrous Na2504. Evaporation of the solvent gave 0.095g (89%) of 269 as a crystalline solid which was identical in all respects to an authentic sample.54 3,4-bis(Carbethoxy)pyrrole (263) prepared from 233. Pyrrole 263 was prepared as described for 262 by heat- ing 233 and KOH in EtDH for 20 h. Recrystallization from THF gave 268 (90% yield) as a colorless solid, which was identical in all respects to an authentic sample (see pg 80). bis(Dimethylaminomethylene)diethylsuccinate (28). According to the method of Bredereck,57 a solution of diethyl succinate (2.00 g, 11.5 mmol) and t-butoxybis- (dimethylamino)methane,58 27 (6.00 g, 34.5 mmol), was heat- ed under a nitrogen atmosphere for 5 h at 160°C in a mag- netically stirred flask, equipped with a distilling head and condenser. The flask was cooled to 50°C, evacuated to 0.3 mm pressure and heated at 110°C for another 45 min. 80 During the course of this procedure a clear liquid distilled from the reaction mixture. The remaining dark oil was cool- ed at -10°C overnight and the resulting crystals weretritur- ated with ether (4 mL) and cooled at -10°C for 5 h. The ether was decanted and the process repeated. Recrystalliza- tion from hexane gave 2.05 g (63%) of 28 as yellow needles: 57 mp 70.5°c); 1H NMR (60 MHz) 6 1.16 mp 73.5-74.5°C (lit. (6H, t, 3:7 Hz), 2.90 (12H, s), 4.02 (4H, q, 0:7 Hz), 7.25 (2H, s). 3,4-bis(Carbethoxy)pyrrole (263); A solution of bisenamine 28 (2.00 g, 7.11 mmol) and ammonium acetate (2.74 g, 35.5 mmol) in 95% ethanol (40 mL) was heated under reflux for 24 h. The solution was cooled, poured into water (250 mL) and extracted with CH2012. The combined organic fractions were washed with saturated aque- ous NaHCO3 and dried over anhydrous Na2504. Evaporation of the solvent and recrystallization from THF gave 1.45 g (97%) of 223 as colorless crystals: mp 150-151°C (lit.47 mp 151- 152°C); 1H NMR (250 MHz) 6 1.33 (6H, t, J=7 Hz), 4.29 (4H, q, J=7 Hz), 7.42 (2H, d, J=3 Hz), 10.50 (1H, br s); 13C NMR 6 14.35, 60.24, 115.04, 126.43, 164.41; mass spec- trum,1n/e(re1ative intensity) 211 (12, M+), 166 (34), 138 (100), 94 (16), 66 (20). 81 3,4-Dicarboxypyrrole (29). 47 a solution of According to the procedure of Groves diester 223 (1.50 g, 7.10 mmol) and NaOH (1.40 g) in 50% EtOH (15 mL) was heated under reflux for 2 h. The solu- tion was diluted with water (50 mL), warmed on a steam bath and slowly acidified with 10% HCl. Suction filtration and thorough washing with water gave 1.05 g (95%) of 29 as an insoluble white powder: mp 300°C, dec. (lit.47 300°C, dec.); IR 3160 (NH), 2000-3000 (OH), 1590 (00) cm"; mass spectrum, m/e (relative intensity) 155 (100, M+). 3,4-bis(N,N-Diethylcarboxamide)pyrrole (313). A suspension of diacid 29 (0.960 g, 6.19 mmol) and oxa1y1 chloride (8.0 mL) in dry toluene (100 mL) was mag- netically stirred under an inert atmosphere in a flask equipped with an efficient condenser. Four drops of DMF were added and the suspension was heated to 85°C. After 50 min the yellow, homogeneous solution was cooled to 40°C and evacuated for 30 min (0.5 mm pressure) keeping the temperature at 40-50°C. (This efficiently removed excess oxa1y1 chloride without destruction of the diacid chloride 20.) The warm toluene solution (approximately 60mL) was added slowly via cannula to a flask, equipped with a drying tube and containing a cooled (ice bath) solution of di- ethylamine (40 mL) and toluene (40 mL). This was stirred 82 overnight allowing the temperature to rise to 25°C. The mixture was concentrated on a rotary evaporator, dissolved in water (250 mL) and extracted thoroughly first with ether and then with CHC13. The combined CHCl3 fractions were dried over anhydrous Na2504 and concentrated. The result- ing yellow oil was treated with ether (10 mL) and cooled at -10°C overnight. The solid was suction filtered and washed with ether. Recrystallization from toluene gave 1.46 g (89%) of 213 as colorless crystals: mp 123-124°C; 1H NMR (60 MHz) 6 1.12 (12H, t, 3:7 Hz), 3.42 (8H, q, J= 7H2), 6.66 (2H, d, J=2.5 Hz), 10.96 (1H, br s); 130 NMR 6 13.50, 41.06, 117.94, 118.24, 167.42; mass spectrum, m/e (relative intensity) 265 (12, M+), 193 (67), 192 (62), 122 (41), 72 (100); IR 3170 (NH), 1620 (co) cm". Anal. Calcd for C14N23H302: C, 63.40; H, 8.68. Found: C, 63.44; H, 8.94. 3,4-bis(N,N-Dimethylcarboxamide)pyrrole (31b). Diacid chloride 22 was prepared in toluene as describ- ed above and added slowly via cannula to a flask equipped with a drying tube, dry-ice condenser and magnetic stirrer and containing anhydrous dimethy1amine (approximately 100 mL) at -78°C. This was stirred overnight allowing the reaction to warm slowly to 25°C and the dimethy1amine to evaporate. The mixture was heated on a steam bath for 30 min, removing residual dimethy1amine, and was then 83 cooled in an ice bath. The white, crystalline solid was suction filtered, washed with cold toluene and air dried. This was dissolved in a saturated, aqueous NaHCO3 solution (30 mL) and stirred overnight with an equal volume of CH2C12. (For maximum yield of the water-soluble pyrrole, this extraction was repeated.) The combined organic frac- tions were dried over anhydrous Na2504 and concentrated. Recrystallization from THF-CHZCl2 (15:1) gave 1.2 g (93%) 1 of 312 as colorless needles: mp 206-207°C: H NMR (250 MHZ) 6 3.02 (12H, 5), 6.72 (2H, d, J=2.75 Hz), 11.22 (1H, 13 br s); C NMR 6 37.37, 118.02, 119.81, 167.98; mass spec- trum, m/e (relative intensity) 209 (29, M+), 165 (40), 164 (59), 122 (100), 94 (21), 44 (20); IR 3110 (NH), 1630 and 1610 (C0) cm-]. H Anal. Calcd for C N302: C, 57.42; H, 7.18. 15 Found: C, 57.11; H, 7.35. 10 3,4-bis(N-Morpholinecarboxamide)pyrrole (315). Diacid chloride 30 was prepared in toluene as describ- ed above and added slowly via cannula to a flask equipped with a drying tube and containing morpholine (25 mL) in toluene (75 mL) at 2°C. This was stirred overnight, allow- ing the reaction to warm to 25°C. The mixture was evaporat- ed to dryness and added to water (40 mL). The aqueous solution was acidified with conc. HC1, saturated with NaCl and then thoroughly extracted with CHzClZ. The combined 84 organic fractions were dried over anhydrous N62504 and evap- 95 orated. Purification by flash column chromatography (THF) gave 31c (91%) as a colorless solid: mp 153-157°C; 1H NMR 6 3.61 (16H, br s), 6.71 (2H, d, 0¥2.5 Hz), 10.72 (1H, br 13C NMR 6 45.37, 66.85, 117.19, 120.06, 166.39; mass 5); spectrum, m/e (relative intensity) 293 (8, M+), 207 (50), 122 (100), 94 (30), 86 (71), 70 (24), 56 (23), 42 (20); IR 3375 (NH), 1620 (00) cm'1. 3,4-bis(N-Methy1carboxamide)pyrrole (319); Pyrrole 319 was prepared as described for 312 using anhydrous methylamine. After heating on a steam bath to remove residual methylamine, the mixture was filtered. The white solid was washed with cold acetone followed by cold water. Recrystallization from hot water provided 319 1 as a white solid: mp 228-229.5°C; H NMR (in warm 0 0, 2 acetone-H6 as a reference ) 6 2.33 (6H, s), 7.15 (2H, 5); mass spectrum, m/e (relative intensity) 181 (55, M+), 151 (49), 150 (47), 122 (100), 94 (30); IR 1620 (00) cm". 2,5-Dimethy1-3,4-bis(N,N-dimethylcarboxamide)pyrrole (37); A 2000 mL flask, equipped with a mechanical stirrer and an efficient condenser, was charged under nitrogen with NaH94 (10.0 g, 0.208 mol) and anhydrous Et20 (1200 mL). This was stirred and warmed to a gentle reflux and 85 N,N-dimethylacetylacetamide, 35,95 (20.0 g, 0.155 mol) was added dropwise over 30 min. After 24 h 12, dissolved in a minimum amount of Et20, was added dropwise in portions (20, 10, 5, 5 g) at 1 h intervals to the vigorously stirred suspension. This was stirred at gentle reflux for another 24 h, cooled to RT and a solution of NaHSO3 (10 g), NH4OAc (30 g) in water (300 mL) was added slowly. The ether was removed on a rotary evaporator and the remaining aqueous solution was stirred at 70°C for 15 h, cooled to 25°C, neutralized with NaHCOB, and thoroughly extracted with r ether. The aqueous layer was saturated with NaCl and stir- red overnight with an equal volume of CH2C12. (For a maxi- mum yield of the water-soluble pyrrole, this extraction was repeated.) The CH2C12 layer was dried over anhydrous Na2504 and concentrated, providing 15.5 g of a dark oil. Recry- stallization from a minimum amount of THF gave 8.15 g of crude starting material, 35, and 7.35 g (40%) of 32 as 1H NMR (250 MHz) 6 2.10 (6H, s), 2.97 (12H, s), 9.37 (1H, br s); 130 NMR 6 colorless crystals: mp 183-184.5°C; 11.56, 35.33, 38.65, 114.17, 127.37, 168.82; mass spectrum, m/e (relative intensity) 237 (20, M+), 192 (30), 150 (100), 122 (24), 121 (30), 42 (34); IR 3200 (NH), 1620 (C0) cm']. Anal. Calcd for C12H19N302: C, 60.76; H, 8.02. Found: C, 60.60; H, 8.12. 86 2,5-bis(Acetoxymethyl)-3,4-bis(lH,lH-heptafluorobut-l-yl)- pyrrole (383). A solution of 23 (2.00 g, 4.36 mmol) and Pb(0Ac)496 (4.26 g, 2.2 equiv) in acetic acid (50 mL) and acetic anhy- dride (2.0 mL) was stirred under a nitrogen atmosphere at 25°C for 20 h. CHZCl2 (150 mL) was added and the solution was washed with water followed by saturated aqueous NaHC03. The organic layer was dried over anhydrous Na2504 and con- centrated. Recrystallization from CHZClz-hexane gave 2.40 k g (96%) of 389 as colorless crystals: mp 60-61°C; 1H NMR 5 2.07 (6H, 5), 3.31 (4H, t, J=19.5 HZ), 5.02 (4H, S), 9.37 (1H, br s); 13 0 NMR 6 20.85, 25.85 (t, J=24.l Hz), 56.99, 110.89, 109.40 (t of q of t, J=265.2, 37.9, 38.0 Hz), 116.61 (t of t, 0=252.5, 31.5 Hz), 118.19 (q at t, J=287.6, 34.2 Hz), 127.83, 172.11; mass spectrum, m/e (relative in- tensity) 575 (4, M+), 516 (16), 473 (20), 43 (100); IR 3350 and 3250 (NH), 1750 and 1720 (00), 1220 (CF) cm". Anal. Calcd for C18H15N04F14: c, 37.56; H, 2.61. Found: C, 37.45; H, 2.63. 2,5-bis(Bromomethyl)—3,4-bis(lH,lH-heptafluorobut-l-yl)- pyrrole (386); Pyrrole 2a (0.500 g, 1.09 mmol) and N-bromosuccinimide (0.425 g, 2.1 equiv) in CCl4 (30 mL) were heated at 70°C for 50 min. The dark reaction mixture was cooled to 3°C for 30 min and then suction filtered. The filtrate was 87 'concentrated at 0.2 mm Hg pressure yielding a sensitive dark red oil which was used directly in the preparation of 38a: 1 cww H NMR 6 3.20 (4H, t, J=20 Hz), 4.40 (4H, s). 2,5-bis(0ichloromethyl)-3,4-bis(lH,lH-heptafluorobut-l-yl)- pyrrole (38d). $02012 (0.700 mL, 8.61 mmol) was added to a solution of h pyrrole 2a (0.600 g, 1.31 mmol) in 0Hzc12 (10 mL) at 3°C and fl stirred for 3 h. Water was added and the solution was ex- 1 tracted with CH2C12. The combined organic fractions were dried over anhydrous Na2504 and concentrated yielding 0.720 g (92%) of 38d as a stable yellow oil which appeared pure by NMR and was used directly in the preparation of 38e: 1H NMR MN 6 3.23 (4H, t, J=20 Hz), 6.67 (2H, s), 9.13 (1H, br S). 3,4-bis(lH,lH-Heptafluorobut-l-yl)-2,5-diformylpyrrole(38e). A solution of pyrrole 383 (0.620 g, 1.04 mmol) in THF (30 mL) and water (6 mL) was stirred at 40°C for 6 h. Water (150 mL) was added and the solution extracted with CH2C12. The combined organic fractions were washed with saturated aqueous NaHC03 and dried over anhydrous Na2504. Evapora- tion of the solvent gave 0.40 g (80%) of 383 as a slightly 1 yellow so1id: mp 51-54°C; H NMR 6 3.58 (4H, t, J=18 Hz), 9.73 (2H, 5); mass spectrum, m/e (relative intensity) 487 (33, M+), 468 (18), 348 (100), 318 (58), 69 (34); IR 3500 (NH), 1690 (00), 1220 (CF) cm". 88 2,5-bis(Acetoxymethyl)-3,4-bis(lH,lH-trifluoroeth-l-yl)- pyrrole (38f). The procedure for 383 was followed by using Eb (1.00 g, 3.86 mmol) and Pb(0Ac)4 (3.8 g, 2.2 equiv) in acetic acid (70 mL) and acetic anhydride (2.0 mL). Recrystallization from CH2C12-hexane gave 1.40 g (97%) of 38: as colorless 1 crystals: mp 117.5-118.5°C; H NMR 6 2.05 (6H, s), 3.34 (4H, q, J=10.8 Hz), 5.03 (4H, s), 9.23 (1H, br s); 130 NMR 6 20.79, 29.14 (4. J=31.5 Hz), 56.84, 111.96, 126.08 (q, J=276.51), 127.11, 171.96; mass spectrum, m/e (relative intensity) 375 (7, M+), 316 (27), 274 (47), 273 (61), 43 (100); IR 3330 (NH), 1750 and 1725 (00), 1245 (CF), 1145 -1 cm . Anal. Calcd for C14H15N04F6: C, 44.80; H, 4.00. Found: C, 45.01; H, 4.06. 2,5-bis(Carbmethoxy)-3,4-(lH,lH-heptafluorobut-l-yl)pyrrole 5:222. To a magnetically stirred 500-mL flask equipped with an efficient condenser and containing 23 (2.00 g, 4.36 mmol) in dry THF (10 mL) at 60°C was added SOZCl2 (5 mL) via pipet as rapidly as possible (vigorous reaction!). This was stir— red for 2 min and additional SOZCl2 (2 mL) was added. After 2 min, warm(40°CJ 95% MeOH (40 mL) was added (vigorous re- action) and the solution refluxed for 90 min. This was 89 cooled and extracted with Et20. The combined organic frac- tions were dried over anhydrous Na2504 and concentrated. Recrystallization from hexane (25°C-— -10°C) gave 2.30 g 1 (97%) of 39a as a colorless solid: mp 85-87°C; H NMR 6 W 3.67 (4H, t, J=19 Hz), 3.85 (6H, 5); mass spectrum (CI, CH4), m/e 548 (M++l); IR 3300 (NH), 1750 and 1725 (00) cm". 2,5-bis(Carbethoxy)-3,4-(1H,lH-heptafluorobut-l-y1)pyrrole (39b). Pyrrole 2a was oxidized with $02C12 as described above and hydrolyzed in 95% EtOH under reflux for l h. Water was added and the solution extracted with CHZClz. The combined organic fractions were washed with saturated aqueous NaHC03, dried over anhydrous Na2504 and concentrated, affording 393 1H NMR 6 1.33 (6H, t, J= 7 Hz), as a yellow oil (87%): 3.67 (4H, t, J=19 Hz), 4.27 (4H, q, J=7 Hz); mass spectrum, m/e (relative intensity) 575 (49, M+), 530 (13), 484 (28), 436 (48), 408 (41), 378 (30), 332 (66), 119 (100), 69 (74). 2,5-Dicarboxy-3,4-bis(lH,lH-heptafluorobut-l-yl)pyrrole (39c). To a magnetically stirred 1000-mL flask equipped with an efficient condenser and containing 2a (7.00 g, 15.3 mmol) in dry THF (30 mL) at 60°C was added 50 012 (12 mL) 2 via pipett as rapidly as possible (vigorous reaction!). 90 This was stirred for 3 min and additional $02Cl2 (6 mL) was added. After 3 min hot (60°C) 80% aqueous THF (200 mL) was added (vigorous reaction!) and the solution was refluxed for 3 h. The mixture was poured into water (500 mL) and thoroughly extracted with Et20. The Et20 fractions were combined and extracted with saturated aqueous NaHCO3. The combined NaHCO3 fractions were washed with Et20, heated on a steam bath and slowly acidified with concentrated HC1. Suction filtration and thorough washing with water gave 6.33 g (80%) of 395 as a white powder. An analytical sample was obtained by recrystallization from hexane-Etzo (20:1); mp 270-272°C(dec.); 1H NMR (acetone-d6) 6 3.92 (4H, t, 0= 20.0 Hz); ‘3 C NMR 6 26.38 (t, J=22.6 Hz), 110.09 (t of q of t, J=262.6, 37.1, 37.2 Hz), 117.67 (t of t, J=253.5, 31.5 Hz), 118.98 (q of t, J=286.8, 33.3 Hz), 119.20, 126.05, 161.52; mass Spectrum (CI, CH4), m/e 520 (M+l ion); IR 3420 (NH), 3150-2460 (OH), 1680 (C0), 1220 (CF) cm-l. Ana1. Ca1cd for C14H7N04F14: C, 32.37; H, 1.35. Found: C, 32.46; H, 1.37. 2,5-Dicarboxy-3,4-bis(lH,lH-heptafluorobut-l-yl)pyrrole (392) prepared from 39a. A mixture of 39a (0.300 g, 0.548 mmol) and lithium iodide (1.32 g)ir10MF (20 mL) was refluxed for 3 h. The dark solution was diluted with H20 (100 mL), acidified with 5% HC1 and then extracted with Et20. The organic fractions 91 were combined and extracted with saturated aqueous NaHCO3. The combined NaHCO3 fractions were acidified and then ex- tracted with ether. The organic layer was dried over anhy- drous Na2S04 and concentrated affording 0.160 g (56%) of 39c as a white powder. 2,5-Dicarboxy-3,4-bis(lH,lH-trif1uoroeth-l-yl)pyrrole (39d). W— Pyrrole 39d was prepared from 2b in 45% yield as des- cribed for 39c: mp 294-296°C (dec.); 1H NMR (acetone-d6) 6 3.91 (4H, t, J=ll Hz); mass Spectrum (CI, CH4) 320 (M++l); IR 2700 (OH), 1700 and sh at 1680 (00) cm". 2,5-Diiodo-3,4-bis(lH,1H-heptaf1uorobut-l-yl)pyrrole 40a. Precautions against direct illumination were taken during all the following operations. A solution of 12 (3.0 g) and NaI (3.2 g) in water (14 mL) was added to a flask wrapped in aluminum foil and charged with 392 (1.0 9, CH Cl 2 2 (40 mL). The two-phase mixture was stirred under a nitrogen 1.93 mmol) and NaHCO3 (1.5 g)ir1water (40 mL) and C1CH atmosphere at 25°C for 48 h. NaHSO3 was added slowly until the red color dissipated and the solution was extracted with CH2C12. The combined organic fractions were dried over an- hydrous Na2504 and concentrated on a rotary evaporator yielding 1.27 g (97%) of 423 as a slightly red solid. This product appeared quite pure by NMR and TCL and was used 92 directly in subsequent reactions. An analytical sample was obtained by recrystallization from petroleum ether at -10°c: mp 78-82°C (dec.); 1H NMR 6 3.28 (4H, t, J=l9.0 Hz), 13 8.25 (1H, br s); C NMR 6 29.13 (t, J=23.1 Hz), 72.29, 109.14 (t of q of t, J=264.2, 38.9, 39.0 Hz), 116.90; (t of t, J=253.4, 30.5 HZ), 118.07 (q of t, J=290.8, 34.2 HZ), 119.02; mass spectrum, m/e (relative intensity) 683 (58, M+), 514 (78), 345 (23), 268 (51), 114 (34), 69 (100); IR 3470 (NH), 1230 (CF) cm“. Anal Calcd. for C H N 12 15 1 F14 2: C, 21.08; H, 0.73. Found: C, 21.45; H, 0.80. 2,5-Diiodo-3,4-bis(1H,lH-trifluoroeth-l-y1)pyrrole (40b). Pyrrole 40b was prepared from 39d in 97% yield as des- cribed for 40a: mp 87-88.5°C; 1 H NMR (acetone-d6) 6 3.23 (4H, q, J=11 Hz), 8.80 (1H, br 5); mass spectrum, m/e (rel- ative intensity) 483 (100, M+), 464 (2), 414 (72), 306 (13), 160 (12), 113 (11), 69 (31), 63 (16), 40 (11). 3,4-bis(lH,1H-heptafluorobut-l-yl)pyrrole (41). A suspension of 423 (1.60 g, 2.34 mmol), zinc dust (1.00 g), NH4C1 (1.60 g) and 95% EtOH (40 mL) was stirred under a nitrogen atmosphere at 75°C for 15 h. The excess zinc was filtered and washed with CH2C12 (20 mL). The fil- trate was diluted with water (100 mL) and extracted with 93 CH2012. The combined organic fractions were dried over an- hydrous Na2S04 and concentrated yielding 0.98 g (98%) of 41 as a pale yellow oil. This product appeared quite pure by NMR and TLC and was used directly in the preparation of 57: 1H NMR 6 3.24 (4H, t, J=19.5 Hz), 6.77 (2H, d, 0:2.75 Hz), 8.22 (1H, br s); ‘3 C NMR 6 27.22 (t, J=23.8 HZ), 109.62 (t of q of t, J=263.6, 37.9, 38.0 Hz), 110.76, 116.78 (t of t, J=252.5, 30.5 HZ), 118.37 (q of t, J=287.6, 34.2 Hz), 119.53; mass spectrum, m/e (relative intensity) 431 (14, M+), 412 (8), 262 (100), 142 (15), 93 (31), 69 (39); IR (neat) 3500 (NH), 1220 (CF) cm'1. 3,4-bis(1H,lH-Heptafluorobut-l-yl)pyrrole(41)prepared from 403 by catalytic hydrogenation. Precautions against direct illumination were taken during all the following operations. A solution of 423 (1.00 g, 1.46 mmol) in MeOH (15 mL) was hydrogenated in a Parr apparatus at 75 lbs/in.2 of Hz for 40 h in the presence of 91:02 (10 mg) and NaOAc (0.40 g). CH2C12 (100 mL) was added and the solution was washed with water followed by aqueous NaHC03. The organic layer was dried over anhydrous Na2S04 and concentrated, providing 0.53 g (84%) of 41. 94 2,5-bis(Chloromethyl)-3,4-bis(2-methyl-2-nitroprop-1-yl)- pyrrole (42). $02C12 (0.200 mL, 2.46 mmol) in C1CH2CH2C1 (5 mL) was added dropwise over 30 min to pyrrole 4 (0.367 g, 1.24 mmol) in C1CHZCH2C1 (8 mL) at 25°C and stirred for another 30 min. The dark-blue solution (was evaporated to dryness at 0.2 mmHg to yield 0.45 g (99%) of 42: 1 H NMR 6 1.53 (12H, s), 3.00 (4H, s), 4.43 (4H, s); 130 NMR 6 25.73, 35.70. 37.14, 88.80, 115.77, 127.35. 3,4-bis(2-Methyl-2-nitroprop-l-yl)-2,5-dicarboxypyrrole(43). Toaimagnetically stirred 1000-mL flask equipped with an efficient condenser and containing 4 (2.43 g, 8.18 mmol) CH in C1CH Cl (15 mL) at 25°C was added SOZCl2 (4.00 mL, 2 2 6.00 equiv)via pipett(vigorous reaction!) and then stirred for 4.5 h. To this was added aqueous 80% acetone (200 mL) and then heated under gentle reflux for 5 h. The reaction mixture was evaporated to dryness and the residue dissolved in saturated aqueous NaHCO3 (100 mL). The solution was thoroughly washed with CHZCl2 and then acidified with con- centrated HCl. Suction filtration and washing with water gave 1.46 g (50%) of 43 as a white powder which appeared pure by NMR and was used directly in the preparation of 44: 1H NMR 6 1.55 (12 H, s), 3.45 (4H, s), 8.90 (1H, br s); 95 mass spectrum, m/e (relative intensity) 357 (2, M+), 280 (48), 264 (94), 223 (100), 208 (60), 204 (45), 186 (70), 181 (41); IR 3380 (NH), 1690 (00) cm". 3,4-bis(2-Methy1-2-nitroprop-l-yl)-2,5-diiodopyrrole (44). MN— Pyrrole 44 was prepared from 43 in 96% yield as des- cribed for 40a. The product appeared pure by NMR and was 1H NMR (acetone-d 6 1.60 (12H, s), 3.03 (4H, s), 10.67 (1H, br s); 130 NMR used directly in the preparation of 61: 6) (acetone-d6) 6 26.20, 38.39, 72.86, 89.74, 124.25; mass spectrum, m/e (relative intensity) 521 (29, M+), 428 (32), 345 (47), 317 (33), 259 (46), 207 (38), 164 (79), 132 (100), 118, (64), 91 (35), 77 (40). 2,5-bis(Acetoxymethyl)-3,4-bis(p-tolysu1fonylmethyl)pyrrole (45). -m— The procedure for 38a was followed by using 8 (0.243 g, 0.564 mmol) and Pb(0Ac)4 (0.625 g, 2.5 equiv)ir1acetic acid (15 mL) at 25°C for 70 h. This provided 0.277 g (90%) of 45 as a yellow-orange foam. Due to the sensitive nature MN of 45, it was used directly in subsequent reactions: 1H W NMR 6 2.01 (6H, s), 2.40 (6H, s), 4.30 (4H, s), 4.70 (4H, s), 7.22 (4H, d, J=8 Hz), 7.58 (4H, d, J=8 Hz); 130 NMR 6 20.88, 21.62, 52.56, 56.17, 110.08, 128.29, 128.71, 129.84, 135.82, 144.90,171.64; IR 3300 (NH), 1730 (C0) cm-I. 96 2,5-bis(Acetoxymethyl)-2,5-diiodopyrrole (46). The procedure for 383 was followed by using 2,5-di- methyl-3,4-diiodopyrrole42 (0.4109, 1.18 mmol) and Pb(0Ac)4 (1.04 g, 1.98 equiv) in acetic acid (20 mL) and acetic anhydride (0.25 mL) for 4 h under complete exclusion of light. This gave 0.520 g (95%) of 49 as a brown oil: 1H NMR 6 2.08 (6H, s), 5.08 (4H, s), 9.51 (1H, br s); 130 NMR 6 20.84, 60.12, 78.43, 130.92, 172.01; mass spectrum, m/e (relative intensity) 463 (4, M+), 361 (9), 276 (12), 60 (15), 43 (100); IR 3300 (NH), 1725 (00) cm". 2,5-bis(Acetoxymethyl)-2,5-dibromopyrrole (42); The procedure for 3&3 was followed by using 11 (1.00 g, 3.95 mmol) and Pb(0Ac)4 (3.42 g, 1.95 equiv) in acetic acid (50 mL) and acetic anhydride (1 mL) for 1.75 h, provid- ing 1.40 g (96%) of 42 as a sensitive red oil: 1H NMR 6 2.06 (6H, s), 5.00 (4H, s); ‘3 C NMR 6 20.80, 57.59, 101.17, 125.77, 172.05; mass spectrum m/e (relative intensity) 371 (1, M+), 370 (1), 369 (2, M+), 368 (1), 367 (1, M+), 310 (7), 268 (13), 267 (14), 43 (100). 2,5-bis(Acetoxymethyl)-2,5-dich10romethylpyrrole (48). The above procedure was followed for lg providing 48 1 as a sensitive yellow oil (90%): H NMR 6 2.08 (6H, s), 5.00 (4H, s). 97 2,5-bis(Acetoxymethyl)-3,4-bis(carbethoxy)pyrrole (49). The procedure for 383 was followed by using 349 (0.182 g, 0.761 mmol) and Pb(0Ac)4 (0.90 g, 2.66 equiv) in acetic acid (10 mL) and acetic anhydride (0.25 mL) at 90°C for 48 h. Recrystallization from petroleum ether (30-—60°C)——Et20 gave 0.20 g (74%) of 49 as a white solid: 1 mp 74-75°c; H NMR 6 1.33 (6H, t, J=7 Hz), 2.07 (6H, s), 13 4.27 (4H, q, J=7 Hz), 5.22 (4H, s); C NMR 6 14.25, 20.78, 57.27, 60.72, 115.62, 130.87, 164.10, 171.93; mass spectrum, m/e (relative intensity) 355 (4, M+), 310 (5), 296 (6), 253 (25), 224 (15), 207 (38), 178 (17), 162 (10), 43 (100); IR 3350 (NH), 1720 (00) cm" 2,5-bis(Acet0xymethyl)-3,4-bis(N,N-dimethylcarboxamide)- pyrrole (i2). A solution of 42 (4.00 g, 16.9 mmol) and Pb(0Ac)4 (18.7 g, 2.5 equiv) in acetic acid (70 mL) and acetic anhydride (1.2 mL) was stirred under nitrogen at 50°C for 26 h. This was cooled to 25°C, added to a saturated, aqueous NaCl solution (250 mL), and stirred overnight with an equal volume of CHC13. The CHCl3 layer was dried over Na2504 and concentrated, affording 8.0 g of a yellow oil, consist- ing of §2 and acetic acid. Due to the high solubility of 52 in water and sensitivity to base, this mixture was used directly in the preparation of 839' An analytical sample v. -r! 5-.- "I - 1 98 was obtained by recrystallization from THF-EtZO: mp 117- 118°C; 1H NMR (250 MHz) 6 2.07 (6H, s), 2.99 (12H, 5), 5.08 (4H, s), 9.60 (1H, br s); ‘3 0 NMR 6 20.88, 35.17, 39.08, 57.22, 118.18, 126.88, 166.61, 171.96; mass spectrum, m/e (relative intensity) 309 [1, (M-(CH3)2N)+], 293 [4, (M-CH3C02H)+], 250 (8), 207 (23), 190(9), 147 (11), 60 (43), 45 (72), 43 (100); IR 3140 (NH), 1750 (00), 1625 (co) cm']. Ana1. Calcd for cl6H23N306: C, 54.39; H, 6.52. Found: C, 54.52; H, 6.55. 2,5-bis(Chloromethy1)-3,4-bis(trifluoromethyl)pyrrole (55). 50 C12 (1.0 mL, 12.3 mmol) was added to a solution of 2 pyrrole 23b (0.198 g, 0.857 mmol) in C1CH2CH2C1 (6 mL) at 3°C and stirred for 10 h. The mixture was evaporated to dryness at 0.2 mmHg pressure affording 0.254 g (99%) of l 55 as a slightly red 011: H NMR 6 4.70 (4H, br s), 8.80 (1H, br s); 13 C NMR 6 35.71, 110 (q, J=41.0 Hz), 122.26 (q, J=269.8 Hz), 129.00; mass spectrum (CI, CH4), m/e 300 (M++l). 3,4-bis(Trif1uoromethyl)-2,5-diformylpyrrole (56). Bromine (1.8 mL) was added to a solution of 23b (1.87 g, 8.10 mmol) in HOAc (40 mL) at 25°C and stirred for 3 min. The mixture was rapidly cooled to 3°C and SOZCl2 99 (7.4 mL) added in one portion. After 5 min the reaction mixture was allowed to warm to 25°C and stirred for another 2 h. Water (9 mL) was added carefully to the ice-cooled solution and then heated at 90°C for 28 h. The cooled so- lution was made basic with saturated aqueous NaHCO3 and thoroughly extracted with CH2C12. The combined organic fractions were dried over anhydrous NaHCO3 and concentrated. Recrystallization from CHZCl2 gave 1.68 g (80%) of 59 as colorless crystals: mp 120-121.5°c; 1 13 H NMR (acetone-d6) 6 9.93 (2H, s); C NMR (acetone-d6) 6 117.69 (q, J=45.3 Hz), 122.92 (q, J=268.0 Hz), 134.04, 181.08; mass spectrum, m/e (relative intensity) 259 (100, M+), 240 (16), 238 (67), 211 (18), 210 (16), 182 (27), 114 (35), 69 (59), IR 3150 (NH), 1690 and 1720 (00) cm". 0ctakis(lH,lH-heptafluorobut-l-yl)porphyrin (§Z) prepared from 38a I m - A solution of 243 (0.48 g, 0.835 mmol) and 48% HBr (3.0 mL) in n-propanol (20 mL) was heated at 100°C for 60 h with a slow stream of 02 bubbled through the reaction mixture. The solution was then allowed to stand in a large open beaker for 14 days. Filtration and recrystalli- zation from acetone gave 0.073 g (20%) of 52: mp 282- 1 283°C: H NMR (acetone-d6, 80°C) 6 -3.21 (2H, br s), 5.34 (16H, t, J=18.4 Hz), 10.62 (4H, s); UV-vis (acetone) 100 Amax(€M) 402 (294,000), 499 (17,800), 529 (4900), 574 (5900), 599 (1200), 627 (1400); IR 3275 (NH), 2850 (CH), 1220 (CF) cm". Anal. Calcd for C H N C, 35.33; H, 1.25. 22F56 4‘ Found: c, 35.38; H, 1 16. 52 0ctak1s(lH,1H-heptafluorobut-l-yl)porphyrin (57) prepared from 38b. A solution of crude pyrrole 222 (as prepared above) and 48% HBr (2.5 mL) in 1-propanol (20 mL) was heated at 100°C for 65 h with a slow stream of 02 bubbled through the reaction mixture. The solution was then allowed to stand in a large open beaker for 28 days. Filtration and re- crystallization from acetone gave 0.0337 g (7.0%) of 57. 0ctakis(lH,1H-heptaf1uorobut-1-y1)porphyrin (57) prepared from 39c. SOZCl2 (0.152 mL,1 equiv) was added to pyrrole 23 (0.43 g, 0.937 mmol) in CH2C12 (20 mL) at 3°C and stirred for 1 h. This was followed by evaporation of the solvent at 0.2mmHg pressure. 1-Propanol (20 mL) and 48% HBr (1.5 mL) were added and the solution was heated at 100°C for 70 h with a slow stream of 02 bubbled through the reaction mixture. This was allowed to stand in a large open beaker for 28 days. Filtration and recrystallization from ace- tone gave 0.062 g (15%) of 57. 101 0ctakis(lH,lH-heptafluorobut-1-y1)porphyrin (57) prepared from 40a. m— A solution of 493 (1.19 g, 1.74 mmol), 37% forma1dehyde (8.0 mL) and 48% HBr (2.5 mL) in l-propanol (70 mL) was heated at 100°C for 35 h. The mixture is cooled and suction filtered. Recrystallization from acetone gave 0.238 g (31%) of 32. The filtrate was allowed to stand in a large open beaker for 14 days. Filtration and recrystallization from acetone gave another 0.030 g (4%) of 31. 0ctakis(1H,lH-heptaf1uorobut-1-yl)porphyrin (32) prepared from 41. A solution of 41 (0.78 g, 1.80 mmol), 37% forma1dehyde (7.0 mL) and 48% HBr (1.6 mL) in 1-propanol (60 mL) was heated at 100°C for 48 h. The mixture was allowed to stand in a large open beaker for 21 days. Filtration of the re- action mixture and recrystallization from acetone gave 0.240 g (30%) of 31. 2,3-bis(0imethylaminomethyl)3,4-bis(lH,lH-heptafluorobut- 1-y1)pyrrole (33). Pyrrole 41 (0.20 g, 0.464 mmol) and excess 2 (0.30 9) CH in ClCH C1 (8 mL) were stirred at 80°C for 17 h. CHZCl2 2 2 (50 mL) was added and the solution was thoroughly washed 102 with saturated aqueous NaHC03. The organic layer was dried over anhydrous Na2S04 and concentrated, yielding 0.210 g 1H NMR 6 2.21 (12H, s), 3.20 (4H, t, 0:20 Hz), 3.30 (4H, s), 8.98 (1H, br, s); 13c NMR (83%) of 33 as a yellow oil: 6 25.70 (t, J=23.3 HZ), 45.21, 54.78, 107.55, 109.42 (t of q of t, J=265.0, 37.2, 37.1 HZ), 116.90 (t of t, J=251.4, 30.5 Hz), 118.17 (q of t, J=286.7, 34.2 Hz), 128.69; mass spectrum, m/e (relative intensity) 545 (0.4, M+), 501 (7), 457 (7), 338 (4), 169 (3), 119 (2), 106 (2), 73 (3), 58 (100), 45 (10), 44 (24), 42 (18); IR 3200 (NH), 1230 (CF) -1 cm . 0ctakis(1H,lH-trif1uoroeth-l-y1)porphyrin (59) prepared from 38f. w Porphyrin 33 was prepared from 39f (0.68 g, 1.81 mmol) and 48% HBr (9.0 mL) in 1-propanol (50 mL) as described for the preparation of 57 from 38a. Recrystallization m from 1-propanol/acetone gave 0.135 g (31%) of 59: mp > 1 5w 310°C; H NMR (acetone-d6) 6 -3.33 (2H, br s), 5.44 (16H, q, J=10.5 Hz), 10.85 (4H, s); mass spectrum, m/e (relative intensity) 966 (31, M+), 965 (10), 483 (27), 105 (25), 44 (100), 40 (13), UV-vis(acetone) xmax(sM) 401 (276,000), 498 (17,600), 527 (5100), 572 (6000), 599 (1300), 627 (1500), IR 3325 (NH), 2850, (CH), 1230 (CF), 1170 cm". Anal. Calcd for C F C, 44.72; H, 2,28 24N4‘ Found: C, 44.77; H, 2.55. 36H22 103 Octakis(1H,lH-trifluoroeth-l-yl)porphyrin (59) prepared from 40b. Porphyrin 32 was prepared from 40b (0.500 g, 1.03 mmol), 37% forma1dehyde (4.8 mL) and 48% HBr (1.5 mL) in l-propanol (40 mL) as described for the preparation of 57 from 40a. Recrystallization from l-propanol/acetone gave 0.10 g (40%) of 59. 0ctakis(2-methyl-2-nitroprop-1-yl)porphyrin (31); Porphyrin 61 was prepared from 44 as described for the preparation of 57 from 40a. Recrystallization from l-propanol/acetone gave a 25% yield of 61 as a purple solid: 1 mp 267-268°C: H NMR 6 -3.50 (2H, s), 1.93 (48H, 5), 4.96 (16H, s), 10.05 (4H, s); UV-vis (acetone)Amax(eM) 407 (270,000), 502 (19,000), 534 (8,400), 573 (7,300), 627 (3,300); IR 3450 (NH), 2850 (CH), 1530 (N02) cm']. 0ctakis(N,N-diethylcarboxamide)porphyrin (62a). A solution of 3,4-bis(N,N-diethy1carboxamide)pyrrole, 343 (0.70 g, 2.64 mmol), 37% forma1dehyde (4.0 mL) and 48% HBr (1.4 mL) in water (85 mL) and EtOH (20 mL) was heated under a nitrogen atmosphere at 85°C for 36 h and then allow- ed to stand in a large open beaker for 14 days (slow air oxidation). Filtration of the reaction mixture and recry- 104 stallization of the solid from HZO-MeOH (20:1) gave 0.182 1 g (25%) of 62a as purple crystals: mp > 350°C; H NMR 6 -3.36 (2H, s), 1.16 (24H, br t, J=7 HZ), 1.65 (24H, br t, J=7 HZ), 3.61 (16H, br q, 0:7 HZ): 3-96 (16H: bf Q9 J=7 HZ): 10 10 (4H, s); 130 NMR 6 13.38 (q), 14.32 (q), 39 79 (t), 1 44.45 (t), 102.85 (d), 136.67 (s), 142.80 (s), 165.74 (5); UV-vis (CHC1 )A (EM) 416 (249,000), 508 (20,000), 540 3 max (7,800), 581 (3,600), 634 (2,900); IR 3350 (NH), 2820 (CH), 1630 (00) cm". Anal. Calcd for C60H86N1208: C, 65.34; H, 7.80. Found: C, 65.86; H, 7.53. 0ctakis(N,N-dimethylcarboxamide)porphyrin (62b). A solution of 3,4-bis(N,N-dimethy1carboxamide)pyrrole, 313 (0.70 g, 3.35 mmol), 37% formaldehyde (4.0 mL) and 48% HBr (1.4 mL) in water (105 mL) was refluxed for 36 h and then allowed to stand in a large open beaker for 14 days. This was extracted with CH2C12 and the combined organic fractions were dried over anhydrous Na2504 and concentrated. Chromatography of the residue (activity 1, neutral alumina, I elution with CH013/3% sec-butanol) and recrystallization from CHZClz-EtZOgave 0.10 g (14%) of 323 as purple needles: mp > 350°C; 1H NMR16-3.26(2H, s), 3.27 (24H, s), 3.59 (24H, s), 10.21 (4H, s); 130 NMR 6 35.73 (q), 39.92 (q), 103.68 (d), 137.10 (s), 142 65 (s), 166 60 (s); UV-vis (CHC13) Amax(€M) 418 (241,000), 510 (17,000), 543 (6,000), 584 105 (6,000), 636 (2,000); IR 3350 (NH), 2860 (CH), 1675 (C0) cm-1. Ana1. Calcd for C44H54N1208°H20z C, 58.93; H, 6.25 Found: C, 59.11; H, 6.29. 0ctakis(N,N-dimethylcarboxamide)porphyrin (323) prepared from 32. A solution of crude 32 (8.0 g) in H20 (750 mL) was purged of oxygen by bubbling a strong stream of nitrogen through the solution at 60°C for 3 h. To this was added 48% HBr (29 mL), heated under nitrogen at 75°C for 100 h, and then allowed to stand in a large open beaker for 14 days. This was extracted with CH2C12 and the combined or- ganic fractions were dried over anhydrous Na2504 and concen- trated. Chromatography of the residue (activity 1, basic alumina, elution with CHC13/3% sec-butanol) and recrystal- lization from CH2C12-Et20 gave 0.37 g of 323 (10%, based on 16.9 mmol of 37). 3,4-bis(N,N-dimethylcarboxamide)-2-dimethylaminomethyl- pyrrole (g3). Pyrrole 343 (0.19 g, 0.603 mmol) and 9 (0.126 g, 1 equiv) were stirred in ClCHzCHZCl (10 mL) at relux for 6 h. This was added to saturated aqueous NaHCO3 (20 mL) and thoroughly extracted with CH2C12. The organic layer was 106 dried over anhydrous Na2504 and concentrated, yielding 0.110 g (45.3%) of g; as a colorless oil: 1H NMR 5 2.23 (6H, s), 2.93 (6H, s), 2.96 (6H, s), 3.53 (2H, s), 6.81 (1H, s); 13C NMR 6 35.3-38.7 (four broad absorptions for amide methyls), 44.90, 54.27, 117.39, 118.00, 119.27, 128.96, 167.14, 167.72; mass Spectrum (CI, CH4), m/e 267 (M+-+1); IR 3400 (NH), 1620 (co) cm-]. 1 APPENDIX 107 : W -JJULJ p.224 rrf‘I—Frrrrrvrrrrrffrrffr—rW—v—rrrerf'rrvr'rrrr'v 8 7 6 5 4 3 2 1 O Figure A1. 60 MHz 1H NMR spectrum of 2,5-dimethy1-3,4-bis- (1H,1H-heptafluorobut-1-y1)pyrrole (23). '1/ { 11.31 r—TrrTVrVrTr1rrrTTVrtrfrtrrfitrtrer—Tfir'rr7#1rv 8 7 6 5 4 3 2 1 O Figure A2. 60 MHz 1H NMR spectrum of 2,5-dimethy1-3,4-bis- (lH,1H-trif1uoroeth-l-y1)pyrrole (22). 108 : .. - (178.3 ; J} rrfrfrrrI—frr—rrrrrv‘rrfrfirffrr'rfTYrr—frvTvrtf'v 8 7 6 5 4 3 2 1 0 Figure A3. 60 MHz 1H NMR spectrum of 3,4—bis(dimethylamino- methy1)-2,5-dimethy1pyrrole (3). 1 i ‘1’ i l T—TrrrvvrrfTI’Frvfifrvrrf'rfrvrrrTV—rfrTr'fi'rvt[t 8 7 6 5 4 3 2 l 0 Figure A4. 60 MHz 1H NMR spectrum of 3,4-bis(2-methyl-2- nitroprop-l-yl)-2,5-dimethylpyrrole (4). 109 ] W f—ffrvvvrrfTvrrvrrfrrfrftv'frrrffifv—rv—fi‘rrTTrVTT—r 8 7 6 5 4 3 2 1 LL Figure A5. 60 MHz 1H NMR spectrum of 3,4-bis(pheny1thio- methy1)-2,5-dimethy1pyrrole (5). .21.. LEM..- . J; T—rrfirrrrrvr—rV—V—frrrfrfrrvrvaVij—r 3 2 l 0 rrrrrrtvrfv 8 7 6 5 4 Figure A6. 60 MHz 1H NMR spectrum of N-benzoyl-3,4-bis- (dimethylaminomethyl)-2,5-dimethy1pyrrole (6). 110 (if, / ,1 ,2 M WW4 _+ -J—JWWL rr—‘rrfrrrrrtT—rrer—frfffv—rffrrtrfrTrfrVT—Tft'fr't 8 7 6 5 4 3 2 l 0 Figure A7. 60 MHz 1H NMR spectrum of 3,4-bis(cyanomethyl)- 2,5-dimethy1pyrrole (Z). r—rrrffTv[frrrTrrrfrrfrrrrrr—VrfrVfTrI'TrrfvrvrT 3 7 6 5 4 3 2 1 0 Figure A8. 60 MHz 1H NMR spectrum of 3,4-bis(p-tolylsu1fony1- methyl)-2,5-dimethy1pyrrole (8). lll ..._._ _ - -- - ‘ i . JUMLJJA rrrrrrrrtrerrrrrft'vrTrvV'Trr—‘rv—rrrfTrv 8 7 6 5 4 3 2 1 o 1 Figure A9. 60 MHz 1H NMR spectrum of 3,4-bis(carbethoxy- methy1)-2,5-dimethy1pyrrole (19). A '7 fir—rffrfrrfvrrrrrrrrfir'v rrfv—rrrrrT V rrrt—r'vr‘rrt 8 7 6 5 4 3 2 1 0 Figure A10. 60 MHz 1H NMR spectrum of 2,5-dibromo-3,4-di- methylpyrrole (ll). 112 .1 x , up A M A #2.; LJ 7" v fi'V'v—Vrv vvw V'v—w—v—Y—v—v- I'V'I’V’TrT—Y' rrrv‘ , l ——f T" Y T T V I f' Tfrrr rTrV r7 rrffr 8 7 6 5 4 3 2 1H NMR spectrum of N-benzoylpyrrole (16a). Figure A11. 60 MHz __AL L JL 1 0 rTTr—frfvrfrrrrrfrfrrfvFTffrrI 4 3 2 1 8 7 6 5 I 60 MHz 1H NMR spectrum of N-benzoyl-2,5-dimethyl- Figure A12. pyrrole (16b). ll3 / I! /1 /: T. MM /1 1 1‘ .0 jhwjdt-.. . dig . 22.11 ITTrrrVTIf'r—rft—rrfrerfiffrrrffrrvfiVT—rTTVf'V 8 7 6 S 4 3 2 1 O Figure A13. 60 MHz 1H NMR spectrum of N-benzoyl-Z-(1,3- dioxolan-Z-y1)pyrrole (16$). J 2..) 2.- 2-3- A - we) firrrvvrTrerrrrr‘rrtfrrl'rvVI'TrtT—rrr—fr'rrvv'I 3 7 6 5 4 3 2 1 0 Figure A14. 60 MHz 1H NMR spectrum of N-benzoy1-2,3-bis- (trifluoromethyl)-7-azabicyclo[2.2.1]-2,5- heptadiene (17a). 114 J" L» 1 JJ 1 vrrrrrvvlv'v’rrv—frvrvfi’fvlrrrrrrvvv'rrrrTfrv’Y—‘v 8 7 6 5 4 3 2 1 0 Figure A15. 60 MHz 1H NMR spectrum of N-benzoyl-2,3-bis- (trifluoromethy1)-1,4-dimethy1-7-azabicyclo- [2.2.1]-2,5-heptadiene (112). 13pr4 TV! TTTV’T—V’VV T'Vf TV! 7 TTYT 1 l r r l I r 8 7 6 5 4 3 Figure A16. 60 MHz 1H NMR spectrum of N-benzoy1-2,3-bis- (trif1uoromethy1)-1-(1,3-dioxolan-2-yl)-7- azabicyclo[2.2.1]-2,5-heptadiene (115). 115 fl/f 1 Ute? A c _ so) Trv'rrvtrYrt—‘rrrfrfrff—Y’FrrtrTrfftfrrvarfrTf‘f 8 7 6 5 4 3 2 1 O Figure A17. 60 MHz 1H NMR spectrum of N-benzoyl-Z-formyl- pyrrole (19) MN firrfrrv IrrvvrrvrT'vrrer’vrfTrrfrrfrrvT—V—vvv 8 7 6 5 4 3 2 1 Figure A18. 60 MHz 1H NMR spectrum of N-benzoyl-2,3-bis- (trifluoromethyl)-7-azabicyclo[2.2.1]-heptane (20). .51 f 1 116 J.) J / 22.1032 2th 2* W1 rfirrrrrtfrrvrT—ff‘rrrr—rrirvrrtrTrfrrrrrTrfTr'v 8 7 6 5 4 3 2 1 0 Figure A19. 60 MHz 1H NMR spectrum of N-benzoy1-2,3-bis- (trifluoromethyl)-7-azabicyclo[2.2.1]-2-heptene (21a). rf'[VT'VIVVfr'rvtr.VfirrrT—rrrrrvvrTrrTrT—V'rrvT—r 8 7 6 5 4 3 2 1 0 Figure A20. 60 MHz 1H NMR spectrum of N-benzoyl-2,3-bis- (trifluoromethy1)-1,4-dimethy1-7-azabicyclo- [2.2.l]-2-heptene (21b). F4 117 / * / F / 1 / g 1 j / fL /_ / J)“ j J J J J LJ RJMJ @MUWW) 'fizfifiym *1"r*;””;””1 Figure A21. 60 MHz 1H NMR spectrum of N-benzoy1-2,3-bis- (trifluoromethyl)-1-(l,3-dioxolan-2-yl)-7- azabicyclo[2.2.1]-2-heptene (21c). 27km..- _ 2.2.11 8 7 6 5 4 3 2 1 O Figure A22. 60 MHz 1H NMR spectrum of N-benzoy1-3,4-bis- (trif1uoromethyl)pyrrole (223). 118 f1 J ) rrV'YTVV'TTVI'ffrvT—rrtfirfrrfTrvrf'Tr'T—TTT‘T‘VIV 8 7 6 5 4 3 2 1 0 Figure A23. 60 MHz 1H NMR spectrum of N-benzoy1-3,4-bis- (trifluoromethyl)-2,5-dimethylpyrrole (222). 2.2.31 rvrrrTrvIfrTrerVfrrfrrI—V'vrvrfrrT—rrrTrjfi'VVTT—r 8 7 6 5 4 3 2 1 o Figure A24. 60 MHz 1H NMR spectrum of N-benzoy1-3,4-bis- (trigluoromethy1)-2-(1,3-dioxolan-2-y1)pyrrole 22c . J'L w 3 -1 rrrrfrrtrvvfrrT—V'v—frrfrrrffr—V'rTVVf'ffffirrrfr'v 8 7 6 5 4 3 2 1 O Figure A25. 60 MHz 1H NMR spectrum of 3,4-bis(trif1uoro- methy1)pyrrole (23a) (f / fl ”—4 :— 1 firIerfI—V‘rvv—rrfv—rrrrtfrfrrirfv—rf—rrV—‘rrrfrvrT—V 8 7 6 5 4 3 2 1 0 Figure A26. 60 MHz 1H NMR spectrum of 3,4-bis(trifluoro- methy1)-2,5-dimethylpyrrole (232). 120 j)... - - 21mg) r—TrrrfvvTrV’frIVfffrrfTTvarvarrY—rrv—rv'frvvI—r 8 7 6 5 4 3 2 1 0 Figure A27. 60 MHz 1H NMR spectrum of 3,4-bis(trif1uoro- methyl)-2-formy1pyrrole (24). rr" rT'I'rvrTvrfIFrfirrffrTffrrrrfrf'rrrrjrfv fi'v 8 7 6 5 4 3 2 1 0 Figure A28. 60 MHz 1H NMR spectrum of 3,4-dicyanopyrrole (25a). 121 rvrrfrr—V'rTrV—rerrfrvrfFIT'rrrrfYVfrVfiTv'frvrjfir 8 7 6 5 4 3 2 1 0 Figure A29. 60 MHz 1H NMR spectrum of 3,4-bis(carbethoxy)- pyrrole (263). J J JL 2 e 3,113.31...st errfTTrTrrrrrV'Vf'VTTV'TT—rT—frfrr'rrrjfirrf'rf'I’ 8 7 6 5 4 3 2 1 O Figure A30. 60 MHz 1H NMR spectrum of bis(dimethylamino- methy1ene)diethylsuccinate (28). 122 Lg; l v rvr'vrT—ferT—F' rTffrrf—frrfrrrrrTrf'VfiTTrV—fr—‘Ii 8 7 6 5 4 3 2 1 0 Figure A31. 60 MHz 1H NMR spectrum of 3,4-bis(N,N-diethy1- carboxamide)pyrrole (31a). T—frtrrtvIFerrrrT—V'rvrrfTTrFTrrrTvrrrWrI—V'rrvrT 8 7 6 5 4 3 2 l 0 f 0 J) Figure A32. 60 MHz 1H NMR spectrum of 3,4-bis(N,N-dimethy1- carboxamide)pyrrole (31b). 123 V VYrrtrrfrfFT—frfiffirrrfrTfrrrrrrvrrrrvrrrT—fr—I 1 0 8 7 6 5 4 3 2 Figure A33. 60 MHz 1H NMR spectrum of 3,4-bis(N-morpholine- carboxamide)pyrrole (31c). -: . $ T J .2 32112102221 Figure A34. 60 MHz H NMR spectrum of 2,5-dimethy1-3,4-bis- (N,N-dimethylcarboxamide)pyrrole (37). 124 F‘ V . - 22 Ag I _ -1 ( rrrrrrrv[Trvrrrf—V’rfrrfiirr—rrrr—fovYrerif‘frTY—rfi 8 7 6 5 4 3 2 1 0 Figure A35. 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 3,4-bis(lH,1H-heptaf1uorobut-1-y1)pyrrole (38a). NJ... 34 Q -224 rfrrrrTTrV—rrfirrvrTVfrrrffr—vrrv—rf‘rrrTf'frvVT: 8 7 6 5 4 3 2 1 0 Figure A36. 60 MHz 1H NMR spectrum of 2,5-bis(dichloromethy1)- 3,4-bis(1H,1H-heptaf1uorobut-l-y1)pyrrole (389). 125 1F“ _4~__ A F’ rffrrr“ r' 'frrfirrrrf' ' r *rrrrrfrfrfi'fifrTfiv' 8 7 6 5 4 3 2 1 0 Figure A37. 60 MHz 1H NMR spectrum of 2,5—bis(acetoxymethy1)- 3,4-bis(lH,lH-trifluoroeth-l-yl)pyrrole (38f). WVA WVmWVWflWWwwx—MNW W“ r—frfffrvrffrfrrrrrrfuIrrTTrvrTTvr—Trrrr'rvv—rT—v 8 7 6 5 4 3 2 1 0 Figure A38. 60 MHz 1H NMR spectrum of 2,5-bis(carbmethoxy)- 3,4-bis(1H,1H-heptaf1uorobut-1-y1)pyrrole (323). 126 frirrrrrI—‘rrT—V‘rr—fvr'rrrrrTvrrrt‘fffrrvvtij—ffir 8 7 6 5 4 3 2 1 0 Figure A39. 60 MHz 1H NMR spectrum of 2,5-dicarboxy-3,4—bis- (1H,1H-heptafluorobut-l-yl)pyrrole (323). irrrVTt'vrrvrrrtr'vrvrrrfrfrfffr'rrTr'fvv 8 7 6 s 4 3 2 1 rfi 0 Figure A40. 60 MHz 1H NMR spectrum of 2,5-dicarboxy-3,4-bis- (lH,1H-trifluoroeth-l-y1)pyrrole (323). 127 f 1 frv'rrrv'vrrvrr—frvrfT—rfirfrfT—rrvvrrf—v—rr'vv—Tv—‘v 8 7 6 5 4 3 2 1 0 Figure A41. 60 MHz 1H NMR spectrum of 2,5-diiodo-3,4-bis- (1H,lH-heptafluorobut-l-yl)pyrrole (40a). / M rv fl Vi firrvvvrIfrfrrTYff'TffT—er—fvrrrYrTfr—tfrvfrfiIt 8 7 6 5 4 3 2 1 0 Figure A42. 60 MHz 1H NMR spectrum of 2,5-diiodo-3,4-bis- (1H,lH-trif1uoroeth-1-yl)pyrrole (422). 128 f0 ,// ) fTT"frfrrV—er—rtrrrrft'TrTV'rrr—r—‘irrfrfjr' T 8 7 6 5 4 3 2 1 o rrf Figure A43. 60 MHz 1H NMR spectrum of 3,4-bis(1H,lH-hepta- fluorobut-l-y1)pyrrole (41). ./J . fvrfrvVTrrvfrer—frffrrrfft—rrrfrf—TrrtvIrrVTTI 8 7 6 5 4 3 2 1 O Figure A44. 60 MHz 1H NMR spectrum of 2,5-bis(chloromethyl)- 3,4-bis(2-methyl-2-nitroprop-l-yl)pyrrole (42). 129 1F» ,1 5 1 1 __ __~‘,____ I 1 1 '1 LVJAJ (I T—frl'vrvrrvrvrrrtvf'rfrrti'V—rrrfT—fr—rrt—TV’T—ffVTTI 8 7 6 5 4 3 2 1 0 1 Figure A45. 60 MHz H NMR spectrum of 3,4-bis(2-methy1-2- nitroprop-l-yl)-2,5-dicarboxypyrrole (43). Fr- 14‘]; T'Trrrrrrtfrvr'frrrIrrrrTrrrvTrtrT—rrr—TrT—frvfr! 8 7 6 5 4 3 2 1 0 Figure A46. 60 MHz 1H NMR spectrum of 3,4-bis(2-methyl-2- nitroprop-l-yl)-2,5-diiodopyrrole (44). 130 241 / y 1 .2212 “2223) L~.A3_..-_JL rrY'TrVV'fer'I’VT’frrff'r—TfrrTrrT'rtrrYYrTT'Yr—I‘ 8 7 6 5 4 3 2 1 0 Figure A47. 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 2,5-diiodopyrrole (46). 1f )6 . .311 *2 r—‘TTrttTV'VVYf'VTV—T'TVrf‘rrrrVrVV'rrrrfrrfrfTrI 8 7 6 5 4 3 2 l O K Figure A48. 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 3,4-bis(carbethoxy)pyrrole (49). 1:! 131 1 A I L— 1 { LAJ Ar A___I'L4 A L {L_A A rrTrfrr—rrTrfir rfifrfrrr—rv—Irfr—rrrffr't—rvijVVf'v 8 7 6 5 4 3 2 1 0 Figure A49. 60 MHz 1H NMR spectrum of 2,5-bis(acetoxymethy1)- 3,4-bis(N,N-dimethylcarboxamide)pyrrole (52). 1 i . I) TrTrfrfirl'VVfirrTV—rrerV—I'Tfrrrrffr'V"T'rrTrT‘ 8 7 6 5 4 3 2 1 0 r—‘LA ‘ Figure A50. 60 MHz 1H NMR spectrum of 3,4-bis(trif1uorometh- y1)-2,5-diformylpyrrole (5E). 132 .Ammv ewcseacoafiP»-F-psnoeospeepaee-1_.:va_xepuo co Escpueam mzz I NI: omN .Pm< ecsmwa — I 1- 1- l- h b p y- 133 .Ammv cwsmcqcoaaF»-Picpmogoa—8wcuizF.2vawxmpuo we Echuwam m:z I am: _ ~:z omm .Nm< ecsmwe y- )- h p- F 1- b 134 .Ava cwcxzagoafiFairiaoggocpwcimiFxgameimvmwxmpuo mo Ezgpumam mZZ : F NI: omN .mm< ecsmwu Le 135 #v A '7rT—rrrrT—frfrtV—rffrrrTT—rrrT—fYT—TTffr" 0 rfrrfrvv 8 7 6 5 4 3 2 1 60 MHz 1H NMR spectrum of 2,3-bis(dimethylamino- methyl)-3,4-bis(lH,lH-heptafluorobut-l-yl)pyrrole (53). Figure A54. 1. J ', rvrf‘r’fv—rtvrW—rrr—VrYr—ffrv—rffrrrrf‘rvrrvvr—rfrTf" 8 7 6 5 4 3 2 1 0 w_v_. Figure A55. 60 MHz 1H NMR spectrum of octakis(N,N-diethy1- carboxamide)porphyrin (623). 136 V W“ W ___._V_ s -1 -4 fvtrfrrfT—fVfiffrrr‘rrrffi—vIrfrrrfrffrrrrfrrrfrrv 8 7 6 5 4 3 2 1 0 Figure A56. 60 MHz 1H NMR spectrum of octakis(N,N-dimethyl- carboxamide)porphyrin (629). r” _r— .J k2ss~_3~_-_J1 r—frrfirrfl'vvvrrfrthrfrfrfrrvrrer'TrrTfrfrrTr 8 7 6 5 4 3 2 1 O Figure A57. 60 MHz 1H NMR spectrum of 3,4-bis(N,N-dimethy1- carboxamide)-2-dimethylaminomethylpyrrole (63). 10. 11. 12. 13. LIST OF REFERENCES Ed. "The Porphyrins"; Academic Press: New Dolphin, D., 1978; Vols. I-VII. York, Smith, K. M., Ed. "Porphyrins and Metalloporphyrins"; Elsevier: New York, 1975. Fischer, H.; Orth, H. "Die Chemie des Pyrrols"; Akade- mische Verlagsgesellschaft: Leipzig, 1934; Vol. I. Fischer, H.; Orth, H. "Die Chemie des Pyrrols"; Akade- mische Verlagsgesellschaft: Leipzig, 1937; Vol. IIi. Fischer, H.; Stern, H. "Die Chemie des Pyrrols"; Akade- mische Verlagsgesellschaft: Leipzig, 1940; Vol. IIii. 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