IIARY LU.“ .‘ligcln State University This is to certify that the thesis entitled Part I: The Synthesis Of Porphyrins Part II: The Synthesis And Reactions Of Pyrroles presented by Dah-Chieh Otto Cheng has been accepted towards fulfillment of the requirements for Ph . D . degree in Chemis try Major professor Date 2'22’77 0-7639 ABSTRACT PART I THE SYNTHESIS OF PORPHYRINS PART II THE SYNTHESIS AND REACTIONS OF PYRROLES BY Dah-chieh Otto Cheng PART I In the synthesis of the porphyrin macrocycles from pyrrole or a substituted pyrrole yields are usually poor. Thus, a new synthetic route was developed by condensing formaldehyde with 3,4-disubstituted pyrroles (1) in the presence of hydrobromic or hydrochloric acid in a large volume of ethanol to give octa-substituted porphyrins (2) in high yields. R R’ 4R U H’, cuzo _> N 4 R’ H 1 2 In the case of R,R'= C H or CH CO, diborane reduction 2 5 3 of 2 gave octaethylporphyrin (3) in almost quantitative yield. Dah-chieh Otto Cheng / 4C2H5 Bsz THF 4CH3CO 2 3 In the case of R,R'= CH or COZCZHS’ base hydrolysis 3 and reesterification with a long chain alkyl iodide yielded an oily porphyrin. PART I I Various 3,4-disubstituted pyrroles (1) were prepared by the reaction of p-toluenesulfonyl methyl isocyanide (4) with 0,8—unsaturated carbonyl or nitro compounds (5). n n R—CH=CH— R’ + CH3@SOZCH2NC -——-> i N :| H 5 4 ‘ Two pyrrole molecules were connected by one (6), three (7) and five (8) carbon bridges. The synthesis of their derivatives will also be discussed. C c ' 8 6 7 PART I THE SYNTHESIS OF PORPHYRINS PART II THE SYNTHESIS AND REACTIONS OF PYRROLES BY Dah—chieh Otto Cheng A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1977 To my wife who has been a continuing source of encouragement; To my parents who have given me so much. ii ACKNOWLEDGEMENTS I would like to thank the Department of Chemistry at Michigan State University for providing financial support in the form of teaching assistantship for the past four years. I would also like to express my appreciation to Professor Eugene LeGoff for his patient guidance, his care- ful and constructive evalution of my ideas, and for arranging financial support. Thanks also goes to Mr. and Mrs. y. M. Chen, who gave me encouragement during hard times. iii TABLE OF CONTENTS PART I INTRODUCTION ...................................... RESULTS AND DISCUSSION ............................ EXPERIMENTAL.. .................................... General procedure ...... ........ ............. Tetracarbethoxytetraphenylporphyrin (12), tetracarbethoxytetramethylporphyrin (Ia), tetraacetyltetraethylporphyrin (I4), tetraacetyltetramethylporphyrin (15), tetracarbobctoxytetramethylporphyrin (16) and tetratrimethylenecarbonylporphyrin (l7). ..... Octamethylporphyrin (II).............. ....... Tetramethylporphyrin tetracarboxylic acid (34)........................ ......... Tetraphenylporphyrin tetracarboxylic acid (37)........................ ..... .... Tetracarbododecoxytetramethylporphyrin (36). Octaethylporphyrin (38)...................... 3—Methylpyrrole-4-carboxylic acid (4|)....... APPENDIX.... ............. . ....... .. ....... ........ Nomenclature of porphyrins ............ . ...... PART II INTRODUCTION ...................................... RESULTS AND DISCUSSION ............................ EXPERIMENTAL ...................................... General ...................................... p-Toluenesulfonyl methyl isocyanide (27) ..... 3-Hexen-2-one (73) ........................... iv Page 11 25 25 28 29 29 30 31 31 33 33 47 50 58 58 58 58 TABLE OF CONTENTS--Continued Page n-Octyl crotonate (76) ...................... 59 1,3-Dicinnamoyl propane (28) ................ 59 3-Carbethoxy-4-phenylpyrrole (1), 3-carbethoxy-4-methylpyrrole (2), 3-acetyl-4-ethylpyrrole (3), 3-acetyl-4-methylpyrrole (4), 3-carboBctoxy-4-methylpyrrole (5), 3,4-trimethylenecarbonylpyrrole (6), 3,4-dibenzoylpyrrole (8), 3-nitro-4-phenylpyrrole (9), 3-benzoyl-4-phenylpyrrole (10) 3,4-dicarbethoxypyrrole (11) and l,3-bis-(4-pheny1pyrrole-3-carboxy)-propane (26)..... ...... ............ ...... ........ 6O 3,4-Dimethylpyrrole (7) ........... . ......... 63 3-Amino-4-phenylpyrrole (39).. ....... . ...... 63 3—Acetylamino-4-phenylpyrrole (40).......... 64 2,2'-Dipyrromethane (44).............. ...... 64 Reactions of 1 and 2 with dimethoxymethane in an acidic methanolic solution, dipyrromethanes (688) and (68b)... ....... 65 5,5'-Diformyl-2,2'-dipyrromethane (51) ...... 65 5,5'-Diacetyl-2,2'-dipyrromethane (52) ...... 66 3,3:5,5'-Tetramethyl-4,4'-diethyl-2,2'- dipyrromethene-HBr (45)...... ........ .... 67 5,5'-Dibromomethyl-4,4'-diethyl-3,3'- dimethyl-Z,2'-dipyrromethene-HBr (60).... 67 5,S'-Di-dibromomethyl-4,4'-diethyl-3,3'- dimethyl-Z,2'-dipyrromethene-HBr (61).... 68 5,5'-Diformyl-4,4'-diethyl-3,3'-dimethyl- 2,2'-dipyrromethene-HBr (53)............. 68 1,3-Bis-(3,5-dicarbethoxy-4-methylpyrr-2- yl)-propan—2-one (46).................... 69 1,3-Bis-(2-pyrryl)-l-propen-3-one (47)...... 70 1,3-Bis-(2-pyrry1)-propan-3-one (88)... ..... 70 1,3-Bis-(pyrr-2-yl)-l,3-propanedione (46)... 71 l,3-Di-pyrr-2-ylmethylene-2-cyclopentanone (49) and l,S-di-Z-pyrryl-l,4-pentadien- 3-One (5°) 0 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o 71 APPENDIX ............. . ............ . ............. . 73 BIBLIOGRAPHY ..................................... 107 TABLE LIST OF TABLES PART I Porphyrins... ......... . ................. Nmr chemical shifts of tetraacetyltetraethylporphyrin (14) ..... PART II 3,4—Disubstituted pyrroles.............. vi Page 12 14 51 FIGURE 10. ll. 12. 13. LIST OF FIGURES PART I Reaction monitoring of porphyrin formationOOOOOO......OOOOOOO. 0000000000000 Visible spectra of porphyrin aggregation.... ...... Infrared spectrum of tetraphenylporphyrin Infrared spectrum of tetramethylporphyrin Infrared spectrum of tetracarbethoxy- (12) ...... . .......... tetracarbethoxy- (‘3)00000000 ooooo o... tetraacetyl- tetraethylporphyrin (14) .................. Infrared spectrum of tetramethylporphyrin Infrared spectrum of tetramethylporphyrin Infrared spectrum of tetramethylporphyrin tetraacetyl- ('5)ooooooooooooooooo tetracarboactoxy- ('6)Ooooooooooooooooo tetracarbododecoxy- (36)....o ..... o ...... Nmr spectrum of tetracarbethoxy- tetraphenylpopphyrin (12)......... ..... ... Nmr spectrum of tetracarbethoxy- tetramethylporphyrin (13).... ............. Nmr spectrum of tetraacetyl- tetraethylporphyrin (14)......... ......... Nmr spectrum of tetraacetyl- tetramethylporphyrin (15).. ............... Nmr spectrum of tetracarbooctoxy- tetramethylporphyrin vii (16).... ...... . ...... Page 17 21 34 35 36 37 38 39 40 41 42 43 44 LIST OF FIGURES--Continued FIGURE 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. Nmr spectrum of tetracarbododecoxy- tetramethylporphyrin (36) ................. PART II Infrared spectrum of 3-carbethoxy— 4—phenylpyrrole (1).. .......... . .......... Infrared Spectrum of 3-carbethoxy- 4-methylpyrrole (2) ....................... Infrared spectrum of 3-acetyl- 4-ethylpyrrole (3). ....... . ............... Infrared Spectrum of 3-carb06ctoxy- 4-methylpyrrole (5)....................... Infrared spectrum of 3,3:5,5'-tetramethyl- 4,4'-diethyl-2,2'-dipyrromethene-HBr (45). Infrared spectrum of 5,5'-dibromomethyl- 4,4'-diethyl-3,3'-dimethyl-2,2'- dipyrromethene-HBr (60)... ................ Infrared spectrum of 5,5'-di-dibromo- methyl-4,4'-diethyl-3,3'-dimethyl- 2,2'-dipyrromethene-HBr (61).............. Infrared spectrum of 5,5'-diformyl- 4,4'-diethyl-3,3'-dimethyl-2,2'- dipyrromethene-HBr (53)........ ........... Infrared spectrum of l,3-bis-(3,5- dicarbethoxy-4-methylpyrr-2-yl)- propan-Z-one (46).................. ....... Infrared spectrum of l,3-bis-(2-pyrryl)— 1-propen-3-one (47)..... ..... ............. Nmr Spectrum of 3-carbethoxy- 4-phenylpyrrole (1)........ ......... ...... Nmr spectrum of 3—carbethoxy- 4-methylpyrrole (2)........... ............ viii Page 45 73 74 75 76 77 78 79 80 81 82 83 84 LIST OF FIGURES--Continued FIGURE 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. Page Nmr spectrum of 3-acetyl-4-ethyl— pyrrole (3) ....... . ................ . ...... 85 Nmr spectrum of 3-acetyl-4-methyl- pyrrole (4)......................... ...... 86 Nmr Spectrum of 3-carboBctoxy— 4-methylpyrrole (5)....................... 87 Nmr Spectrum of 3,4-trimethylenecarbonyl- pyrrole (6)... ...... ...................... 88 Nmr Spectrum of 3—nitro-4-phenyl- pyrrole (9) .......... . .................... 89 Nmr Spectrum of 1,3-bis-(4-phenylpyrrole- 3-carboxy)-propane (26)..... ...... ... ..... 90 Nmr Spectrum of 3-amino-4-phenyl- pyrrole (39).. ..... ................ ....... 91 Nmr spectrum of 3-acetylamino-4—phenyl- pyrrole (40)....... ...... ...... ..... ...... 92 Nmr spectrum of 3,3',4,4'-dicarbethoxydi- phenyl-Z,2'-dipyrromethane (638).......... 93 Nmr spectrum of 3,3',4,4'-dicarbethoxydi- methyl-2,2'-dipyrromethane (63b).......... 94 Nmr spectrum of 5,5'-diformyl- 2,2'-dipyrromethane (51).................. 95 Nmr spectrum of S,5'-diacetyl- 2,2'-dipyrromethane (52).................. 96 Nmr Spectrum of 3,3',5,5'-tetramethyl- 4,4'-diethyl-2,2‘-dipyrromethene-HBr (45). 97 Nmr spectrum of S,5'-dibromomethyl-4,4'- diethyl-3,3'-dimethyl-2,2'- dipyrromethene-HBr (60)............ ..... .. 98 Nmr Spectrum of 5,5'-di-dibromomethyl- 4,4’-diethyl-3,3'-dimethyl-2,2'- dipyrromethene-HBr (61)... ................ 99 ix LIST OF FIGURES--Continued FIGURE Page 42. Nmr spectrum of 5,5'-diformy1-4,4'- diethy1-3,3'-dimethy1-2,2'- dipyrromethene-HBr (53). .................. 100 43. Nmr Spectrum of 1,3-bis-(3,5-di- carbethoxy-4-methy1-pyrr-2-y1)- propan-Z-one (46).............. ........... 101 44. Nmr Spectrum of l,3-bis-(2-pyrry1)- 1-propen-3—one (47)........... ....... ..... 102 45. Nmr spectrum of 1,3-bis-2-pyrryl- propan-3-one (33)................ ...... ... 103 46. Nmr spectrum of 1,3-bis-(PYrr-2—y1)- 1,3-propanedione (43)....... ....... . ...... 104 47. Nmr Spectrum of 1,3-di-pyrr-2-y1methy1ene- 2-cyclopentanone (49) .......... ........... 105 48. Nmr spectrum of 1,5-di-2-pyrry1-1,4- pentadien-3-one (50)................. ..... 106 PART I THE SYNTHESIS OF PORPHYRINS INTRODUCTION Heme and chlorophylls a and b10 are the most widespread natural pigments and perform a complementary role in nature, being associated with the oxidative and energy—liberating processes of plant and animal metabolism on the one hand and the reduction and energy-trapping processes of photosynthesis on the other. Massive contributions u)our knowledge of the structure and chemistry of porphyrins were accumulated in 1-3 this century since the classic work of Hans Fischer for the synthesis of porphyrins and related compounds. Various methods3’5-9 are available for the syntheses of porphyrins from pyrroles (a), dipyrromethanes (b), di- pyrromethenes (c and d), dipyrroketones (e), (oxy-)bilanes (f), bilenes (g) or biladienes (h), Scheme 1. Scheme 1 CHO R3 \ \ \ \NH ~— 39 c '3': x 2HBr "2x B Br 0'0 ' H —N HN\ C) o \ \ '5’: W The first synthesis of a porphyrin directly from a pyrrole (route a) was the formation of aetioporphyrin from 3-methy1- 4-ethylpyrrole (opsopyrrole)45. In 1935, Rothemund46 found that the reaction of pyrrole with aldehyde in the presence of pyridine under pressure and at elevated temperature gave rise to small yields of meso-substituted porphyrins. Thus, acetal- dehyde gave rise to meso-tetramethylporphyrin while formaldehyde gave a small yield of parent porphin itself. The best result was found when benzaldehyde was used to give meso-tetraphenyl- 11 in about 20% yield. porphyrin Dipyrromethanes were considered as unsuitable intermediates for the synthesis of porphyrins due to their acid lability unless substituted with electron-withdrawing groups. Under the acidic conditions of the reaction (route b), the unsymmetrically sub- stituted dipyrromethanes sometimes resulted in mixtures of porphyrins because cleavage and recombination reactions47 may occur at the methane bridges, presumably by the mechanism out- lined in Scheme 2 on page 5. A more versatile method introduced by MacDonald and his 48 is the mild acid-catalyzed condensation of 5,5’- colleagues diformyl-dipyrromethane with 5,5'-unsubstituted dipyrromethane or dipyrromethane-5,5'-dicarboxylic acid (route b in Scheme 1). However, MacDonald's method still suffers from the limitation that one of the two dipyrromethanes must be symmetrical , otherwise, two porphyrins could be formed. Scheme 2 \\ /, \\ r’ \\ z’ x’ A \ \ NH HNB/ \‘NH HNA/ \BNH HNB/ The most widely used porphyrin synthesis to date has been the fusion of two dipyrromethene units2 in a melt of succinic or tartaric acid at temperature in the range of 160-2000. When different dipyrromethenes are employed in route d, three porphyrins can be formed; one by cross-condensation and two by self-condensation. A logical variation of this method was developed49 to overcome this shortcoming, a 5,5'-dimethy1 or 5,5'-dibromomethyl-dipyrromethene was condensed under Similar condition with a 5,5'-dibromodipyrromethene as shown in route c. In this variation one dipyrromethene component supplies both bridge carbon atoms. Unfortunately, this method is also limited in that a single porphyrin can be obtained only if both of the dipyrromethenes are symmetrically substituted. Apart from symmetry considerations, other limitations to the usefulness of this fusion method are that labile substituents may not survive the drastic experimental conditions, and, more- over, yields may be extremely low. The same symmetry limitations apply to route e as for the syntheses from dipyrromethanes and from dipyrromethenes. An added constraint is that the formyl groups which form the bridging carbon atoms between the two dipyrrolic halves must be sited on the dipyrroketone moiety because the oxo-function in a dipyrroketone deactivates the 5- and 5'-positions toward electrophilic attackso. Redistribution reactions during coupling reactions of dipyrromethenes and dipyrromethanes, as well as limitations with regard to symmetry, led to the development of alternatives, particularly designed for the preparations of porphyrins con- taining unsymmetrically arrangedWB-substituents. In 1952, Corwin and Coolidge51 reported the first attempt to synthesize a porphyrin using a discrete open-chain tetrapyrrole as an inter- mediate (route f). It should be noted that the conditions em- ployed for the final ring closure have been known47 to cause methane bridge cleavage with the resultant production of more than one porphyrin isomer. A more sophisticated approach52v53 is to use a- or b- oxobilanes (Scheme 3a and b) which are considerably more stable 7 to acid—catalyzed redistribution of the pyrrole rings by virtue of the electron—withdrawing ester functions and the oxo- function. Scheme 3 Scheme 3 (cont'd) I ,xzfiMoé R=OCH2 n, X=O ; R: OCHZ m, x = O ; R: H ... 14/0le C(OM013 PM. M9 . 0 MG Me PM. M9 Fin. / Hz/ Pd __ O hfle IW9 ““8 '“e PMe PMe PMG PMG H is. . Aczo/p, lo, \V 0 Mo p Mo 1 Hz/ Pd 7 2, non M9 M0 PMs PMO h53 is essentially a two-stage Fischer dipyrro- Route methene condensation in which orientation difficulties of the coupling have been overcome by the isolation of the intermediates. The final cyclization is ususlly achieved by a template method by the use of a copper salt in pyridine or dimethylformamide. However, the dematallation of strongly bound copper from the porphyrin complex requires strong acid such as sulfuric acid in trifluoroacetic acid which sometimes causes difficulties. Clearly, these methods of using tetrapyrrolic inter- mediates are limited to the synthesis of porphyrins bearing substituents which are capable of withstanding the conditions of the intermediate Steps. In certain case554'55, the tetra- pyrroles can not be prepared in the laboratory in a completely stepwise fashion; moreover, when prepared in other ways they are not very susceptible to oxidation but readily undergo acid-catalyzed rearrangements, so that attempts at cyclization lead to mixtures of porphyrins. The major drawback of these approaches is after all the complexity of the reaction sequence. In 1968, Treib and Haberle11 reported a synthesis of porphyrins unsubstituted in the meso-positions by using the Rothemund reaction conditions which are a 2:1 mixture of acetic acid and pyridine. The yields are from 77% for the preparation of octamethylporphyrin from 3,4-dimethy1pyrrole and formaldehyde to 20% for the synthesis of octaphenyl- porphyrin. However, the work-up procedure was rather tedious; starting from vacuum drying the acetic acid-pyridine solvent, extracting with tetrahydrofuran then boiling o-dichlorobenzene 10 (bp. 180.40) to vacuum drying o-dichlorobenzene extracts. To date, the most satisfactory preparation of octaethylporphyrin12 from 4-acetyl-3-ethyl-S-methylpyrrole-2-carboxylic ethyl ester was reported to give a 40% yield for a multi—step reaction sequence as shown in Scheme 4. Scheme 4 O i i 82H6 I l N COzEt N 02IEt H H \éflsg N 025: “car; " '\ I " c 02 ‘c02\:/’°|3C H02C MQZNH CHZO W HOAc \ II N Ii N/ H \ RESULTS AND DISCUSSION In order to overcome the difficulties as stated in the introduction and provide a general synthetic route to meso— free porphyrins, Simplified procedures have been devised to give high yields of substituted porphyrins. The 3,4-disub- stituted pyrroles (preparation in Part II) were chosen mainly because they posses only reactive a—positions, thus preventing reactions at B-positions. In addition the porphyrins formed from them would have a substitution pattern Which resembles those which occur naturally. The study of reaction conditions of porphyrin formation from 3,4-disubstituted pyrrole with formaldehyde was carried out with 3-carbethoxy-4-pheny1pyrrole since the starting ethyl cinnamate was readily available. The combination of ethanol and hydrobromic (or hydrochloric) acid was used due to the fact that all the following reaction conditions failed to give porphyrin: (l) Methanol-hydrobromic (or hydrochloric) acid (2) Tetrahydrofuran-hydrobromic (or hydrochloric) acid (3) P—dioxane-hydrobromic (or hydrochloric) acid (4) Acetic acid (5) Propionic acid (6) Acetic acid-pyridine 11 12 Thus, the reactions were carried out by refluxing for several hours an ethanolic solution of a 3,4-disubstituted pyrrole with an excess of formaldehyde and a strong acid such as hydrobromic or hydrochloric acid. The reaction mixtures were allowed to stand in a large beaker exposed to the air for periods of a few days to several weeks. Slow air oxida- tion in this way gave somewhat better yields than procedures involving bubbling air through the reaction mixture. The following pyrroles were put through the reaction and results are tabulated in Table l: R, R R R' R R' Ii H ”CH “8' e N II Ethanol H 0 R’ R n =1: R‘ . R R Table l R R' Yield 1 Ph cozczas 86% 12 2 CH3 COZCZHS 92% 13 3 (3sz COCH3 96% 14 4 CH3 mag 64% 15 5 CH3 COzn-C8H17 57% 16 6 -CH2CH2CH2CO- 27% 17 7 CH3 CH 65-75% 18 8 PhCO Ph 0 0% 9 Ph N02 0% 10 Ph PhCO 0% 11 C02C2H5 C02C2H5 0% For reactions where R=R'= alkyl, symmetrical porphyrins are obtained in comparative yields using this Simplified procedure which circumvents the need to prepare aldehyde, aminomethyl or hydroxymethyl pyrrole precursors. Thus, l3 condensing formaldehyde with 3,4—dimethylpyrrole (7) gives 2,3,7,8,12,13,17,lB-octamethyl-Zl,23-2H-porphyrin (18) in 76% while 3,4—diethylpyrrole gives 2,3,7,8,12,13,17,18-octa— ethyl-21,23-2H-porphyrinS6 in 65% yields (Nomenclature of porphyrins in Appendix). For reactions where RxR', four isomeric porphyrins are possible. In the case of tetraacetyltetraethylporphyrin.(14), Scheme 5, separation was achieved by High Pressure Liquid Chromatography to give three different bands. Their structures were identified by nmr Spectroscopy.The results are summarized in Table 2: Scheme 5 '0 140 (type I) O 14¢ (type III) 0 14d(type IV) 14 Table 2, nmr* Chemical Shifts of 14 (6 values) CH3 ------- CH2 CH3CO meso-H N-H 1.70 4.30 3.23 9.03 -4.97 (m, 12H) (m, 8H) (s, 6H) (s, 1H) (s, 2H) First Band 3.30 9.93 (14.6%) (s, 6H) (s, 2H) 10.30 (s, 1H) 1.80 4.13 3.21 9.43 -4.45 (m, 12H) (m, 8H) (S, 3H) (s, 1H) (s, 2H) 3.24 10.22 Second (5, 3H) (s, 2H) Band (57.1%) 3.31 10.58 (S! 3H) (Sr 1H) 3.34 (s, 3H) 1.86 4.18 3.33 9.76 -4.37 Third (t, 12H) (q, 8H) (s, 12H) (3, 2H) (s, 2H) Band (28.3%) 10.76 (s, 2H) * nmr was taken in CDCl3 Thus, the first band is type IV; 2,8,13,17-tetraacety1- 3,7,12,lB-tetraethyl-Zl,23-2H-porphyrin or l,4,6,7-tetra- acetyl-2,3,5,8-tetraethylporphyrin (14d). The second band is type III; 2,7,12,18-tetraacetyl- 3,8,13,17-tetraethyl-21,23-2H-porphyrin or l,3,5,8-tetra- acetyl-2,4,6,7-tetraethylporphyrin (14c). 15 The third band is type II; 2,8,12,18-tetraacety1-3,7,13, l7-tetraethyl-12,23-2H-porphyrin or 1,4,5,8-tetraacety1-2,3, 6,7-tetraethylporphyrin (14b). It is interesting that the major isomer is the type III which has the substitution pattern of the naturally occuring porphyrins, but not surprising since the statistical calculation of random formation of porphyrins bearing two sets of different substituents would give the distribution of l/8type I : 1/8type II : l/2type III : l/4type IV. The absence of type I isomer, 2,7,12,17-tetraacetyl-3,8, 13,lB-tetraethyl-Zl,23-2H-porphyrin or l,3,5,7-tetraacetyl- 2,4,6,8-tetraethylporphyrin.(14a), seems to suggest the possible mechanism of this porphyrin formation reaction as shown in Scheme 6. Scheme 6 0:: 0:: i i + HCHO —"——-> n. . N N CH20H H H 3 O: o: o: l i , <""_=°_ l i 41L “‘" H ii CH, N + \N. 3m H OH! H OH 16 Scheme 6 (cont'd) 3 3m-———-> 17 Another piece of evidence in support of the porphyrino- gensl6 (20), (21) and (22) as intermediates is that a reaction sample after Sitting in an UV cell with chloroform showed the following spectral changes (Figure 1). l l l i i I I I I \\ ______ 400 500 600 700 800 nm Figure l, ( ) is taken immediately after sampling; ( ——————— ) is the sample after 10 minutes. The band at 525 nm is consistant with the formation of porphodimethenel7 (23) and the greatly increased Soret band is a strong indication of oxidation of porphyrinogen to porphyrin, Scheme 7. Scheme 7 H' a n n’ ... H 914 + a: H’ R, R R, 3:51 or CHacO n H’ 23 20, 21, 22 18 No porphyrin was obtained when pyrroles 8, 9,1() and 11 were used. This appears to be due to the low nucleophilicity of pyrrole as a result of the lone pair electrons on the pyrrole nitrogen conjugated to a strong electron-withdrawing substituent, i.e., nitro group in 9(and benzoyl group in 10, and, to two benzoyl groups in 8 and carbethoxy groups in 11. Aldehydes (24) other than formaldehyde and 3,4-dimethyl- pyrrole (7) were used in an attempt to prepare dodecasubsti- tuted porphyrin (25) as shown in Scheme 8. Scheme 8 R Ii “ + RCHO > R n N 24 ii 7 R 25 When 24 is acetaldehyde, propionaldehyde, butyraldehyde, 3-cyanopropionaldehyde-diethyl acetal, N,N-dimethylamino- acetaldehyde-dimethyl acetal, bromoaceta1dehyde-diethyl acetal or 1,1,3-trimethoxyethane, no 25 was detected. In most cases the reaction stopped at the formation of dipyrromethene salts. The total failure of the preparation of 251did not come as a surprise since the introduction of R groups into the meso-positions causes a great deal of strain (see I) wheras in the octasubstituted porphyrin system (II) there is nonezz. 19 I . II In an attempt to limit the porphyrin formation to one isomer, 1,3-bis-(4-pheny1pyrrole-3-carboxy)-pr0pane (26) was prepared and subjected to the same reaction condition. Only a trace amount of porphyrin (31) was obtained with dipyrro- methenes (32) and (33) as the major products (Scheme 9). This is best explained by steric interactions that prevent the approach of the protonated formaldehyde to form the carbon bridge between the two pyrrole units of 26. Scheme 9 20 When 3-carb06ctoxy-4-methylpyrrole (5) was converted to tetracarbofictoxytetramethylporphyrin (16), transesterification between the octyl ester and solvent ethanol appeared likely. n-Octanol was employed as the solvent, but after two weeks there was no detectable porphyrin formation. Fortunately, the transesterification was not observed in ethanolic solvent and the resulting porphyrin (16) was very soluble in hexanes whereas tetracarbethoxytetramethylporphyrin (13) has no solubility in hexanes. Modification of the porphyrin substituents was carried out on porphyrin esters using a hydrolysis-reesterification sequence. Thus, the long hydrocarbon chain can be put onto the ester functional groups after the formation of porphyrin. One example is to hydrolyze tetracarbethoxytetramethyl- porphyrin (13) to tetramethylporphyrin tetracarboxylic acid (34), then to esterify with n-iodododecane (35) to give tetracarbododecoxytetramethylporphyrin (36)19 as shown in Scheme 10. Scheme 10 R’ R R” R R R, R R 9 KC"! \‘ 'THF' " R, R R R R R’ R Ru , R: R” n =2 R "_ R. R‘ = CHzor 60,51 R. n_3c:130, coou 13 R’ R. = 0 ”00251 R: R": O or 0001-1 ‘12 :37 21 Scheme 10 (cont'd) R. R R R’ E13N 34 + C12H25| > 35 , R R R R' R: R’ R, 8': Mo 01002012325 36 The combination of lithium iodide and dimethylformamide20 gave better results than aqueous potassium hydroxide and tetrahydrofuran18 in the hydrolysis of tetracarbethoxytetra- phenylporphyrin (12) to tetraphenylporphyrin tetracarboxylic acid (37). Both tetracarboactoxytetramethyl (16) and tetracarbo- dodecoxytetramethyl (36) porphyrins showed aggregation in non-polar solvent and their visible spectra are shown in Figure 2. C20“ «6.) ‘ 3 : 4. : ; f1 2 400 500 600 700 800 nm Figure 2, compounds 16 and 36 in hexanes (1) and methylene chloride (4), CH2C12 concentration increases from (1) —--—->(4) . 22 When the solvent polarity was increased by adding methy- lene chloride to hexanes, the peak at ~420 nm increased at the expense of the peak at ~4lO nm and finally collapsed to one peak as (4). Presumably, the absorption at shorter wave- length is caused by the aggregation of porphyrins 16 and 36 through the four long hydrocarbon chains on the peripheral positions. While switching solvent to more polar methylene chloride resulted in the dissociation of the aggregates and consequently gave only one Soret band. Another transformation of the peripheral substituents involving isomeric mixtures proved wholly satisfactory. Thus, diborane reduction of the carbonyl groups of tetraacetyl- tetraethylporphyrin (14) affords octaethylporphyrin (38) in 97-lOO% yield (Scheme 11). Scheme 11 R’ R R R’ 32% \ THF ’ R’ R R R’ R a: R‘ R, R’ =MoCO or Et 33 14 23 Therefore, this method is particularly attractive in the syntheses of symmetrical porphyrins as shown in Scheme 12. Scheme 12 CORn_1 Rn Rn con,“ RWET__]WKDRn4 H+ k¥) N HCHO ’ H a..9° “n Rn 003.14 ‘Ke/ + Rn Rn y three other isomers R R“ R" Rn Rn Rn Since 3-nitro-4-phenylpyrrole (9) is not reactive toward the reaction conditions of porphyrin formation, 9 was converted to 3-amino-4-phenylpyrrole (39) and 3-acetylamino-4-phenyl- pyrrole (40) (transformation of 9—539 and 40 in Part II). However, when 39 and 40 were subjected to porphyrin formation conditions respectively, still no porphyrin formation could be detected. A reaction condition was devised to simulate the prebiotic enviroment of porphyrin formation by nature. 3-Carbethoxy-4- methylpyrrole (2) was hydrolyzed with sodium hydroxide then carefully neutralized with hydrochloric acid. Upon the addition 24 of formaldehyde and heating, tetramethylporphyrin tetracar- boxylic acid (34) was obtained (4.5%) in essentially a "salt" solution (Scheme 13). Scheme 13 C023 " u (I NaOH N ”20 H 2 ._ R’ R R R' R’ R R R’ R: R’ RJfi=CWhowCOOH 34 EXPERIMENTAL General Procedure The melting points were determined on a Thomas Hoover Uni-melt melting point apparatus and are uncorrected. The infrared spectra were recorded on a Perkin-Elmer Model 237 B spectrophotometer. The NMR spectra were obtained on a Varian T-6O spectrometer with.chemical shifts reported‘ in é-units measured from tetramethylsilane as the internal standard. The UV and visible spectra were recorded on a Unicam SP-800 spectrophotometer using 1 cm quartz cells. A Hitachi Perkin-Elmer RMU-6 mass spectrometer was used to ob- tain the mass spectra. Microanalyses were performed by Spang Microanalysis Laboratory, Ann Arbor, Michigan. A Waters Associates Prep-HPLC Model 500 was used to se- parate porphyrin isomers. Tetracarbethoxytetraphenylporphyrin (12), tetracarbethoxyte- tramethylporphyrin (13), tetraacetyltetraethylporphyrin (14), tetraacetyltetramethylporphyrin (15), tetracarbooctoxytetra- methylporphyrin (16) and tetratrimethylenecarbonylporphyrin (11) General procedure: 25 26 In a flask equipped with a side arm so that a slow stream of air was passing through the flask over the solution through- out the reaction, a solution of 15 mmoles of pyrrole, 60 m1 of 40% formaldehyde and 24 ml of 48% hydrobromic acid in 600 ml of ethanol was stirred and refluxed for n hours. Best results were obtained when n=10, in the preparation of 14 and 17; n=12, in the preparation of 12; n=15, in the preparation of 15; n=l8, in the preparation of 16; n=24, in the preparation of 13. The reaction mixture was then allowed to stand at room temperature for one week, except in the case of 16 where one month standing was necessary. The precipitate was collected by filtration. The filtrate was diluted with water and ex- tracted with methylene chloride. The extracts were evaporated to dryness and the residue was chromatographed on a neutral alumina column with 1% methanol in methylene chloride to give another portion of the product. The combined yields are listed in Table l on page 12. Spectral characteristics of 12, 13, 14 , 15, 16 and 17 are summarized as below. Tetracarbethoxytetraphenylporphyrin (12) nmr (CDCl3) 51.33 (m, 12H, -c02cnzcg3), 4.60 (m, 8H, COzCflzCH3), 7.67 (m, 20H, phenyl H), 10.67 (s, 1H, meso-fl ), 11.64 (s, 2H, meso-g ), 12.54 (s, 1H, meso-fl ) and -3.1 (brd s, 2H, N-g); Amax (CH2C12), 433 nm (e 3.0x105), 525 nm (e 1.9x1o4), 560 nm.h:7.5x1o3), 595 nm (e 7.3x1o3) and 654 nm (e 3.0x1o3) 27 5231. Calcd for C56H46N4O : c, 74.48; H, 5.15; N, 6.20 Foun ; c, 74.35; 8, 5.09; N, 5.92 Tetracarbethoxytetramethylporphyrin (13) nmr (c0013) 61.77 (m, 128, -C02CH2C§3); 2.87 (m, 128, -c83), 4.66 (m, 88, -C02CH2CH3), 6.83,7.25,7.52,8.07,8.45,8.69, 9.49,9.78 and 9.94 (9 singlets, 4H, meso-H); Amax (CH2C12) 425 nm (e 3.2x105), 521 nm (e 1.6x104), 556 nm (e 7.6x103), 595 nm (e 5.9x103) and 651 nm (e 2.2x103). Anal. Calcd for C36H38N4O : C, 66.24; H, 5.67; N, 8.58 Foun : C, 66.32; H, 5.99; N, 7.57 Tetraacetyltetraethylporphyrin (14) nmr (c0c13) 61.75 (m, 128, -CH2c83), 3.30 (s, 68, -coc83), 3.23 (s, 68, -c0c83), 4.08 (m, 88, -c82CH3), 9.20 (s, 18, meso-H), 10.10 (s, 2H, meso-H), 10.40 (s, 1H, meso-H) and -4.75 (s, 28, N-fl); Amax (C82c12) in nm, 428 (e 3.2x105), 524 (e 2.5x104), 560 (a 1.1x104), 596 (e 1.0x104) and 652 (a 4.5x103). Anal. Calcd for C36H38N4O4 : C, 73.18; H, 6.50; N, 9.49 Found : c, 72.98; H, 6.76; N, 8.15 Tetraacetyltetramethylporphyrin (15) nmr (c0c13) 62.90 (m, 248, -c83 and -coc83), 7.37,7.55, 8.89,8.90,9.09,9.47,9.56,9.60 (8 singlets, 4H, meso-H) and -8.33 (s, 28, N-g); Amax (CH2C12) in nm, 429 (e 3.1x105), 524 (e 2.0x104), 561 (e 9.6x103), 599 (e 8.1x103) and 654 (e 3.7x103). 28 Tetracarbooctoxytetramethylporphyrin (16) nmr (CDC13) 60.70-1.85 (3 brd peaks, ~CH2C7H15), 2.07 (s, -CH3), 3.47,4.10,4.80 (3 brd peaks, -CH2C7H15), 7.42,8.52, 9.42,9.68,9.85,10.75,10.88 (6 singlets, meso-H) and -7.33 (brd s, N-g); Amax (CH2C12) in mm, 425 (e 3.1x105), 521 (e 1.6X104), 556 (E 7.4X103), 595 (E 6.0x103) and 652 (E 2.2 x103). Anal. Calcd for C76H118N408°H20 : C, 71.40; H, 8.79; Found : C, 71.68; H, 8.91; N, 5.17 Tetratrimethylenecarbonylporphyrin (17) Due to the purification difficulties, only the visible spectrum was taken, Amax (CH2C12) in nm, 436 (e 1.8x105), 530 (e 1.7x104), 570 (e 1.2x104), 610 (e 7.0x103) and 665 (e 3.5x103). Octamethylporphyrin (18)11 To a refluxed solution of 3 ml of 40% formaldehyde and 1 ml of l N HCl in 250 ml of ethanol was added a solution of 1.9 g (0.02 mol) of 3,4-dimethy1pyrrole (7) in 200 ml of ethanol. Upon completion of addition oxygen was bubbled through the reaction mixture for two hours. The resulting solution was cooled and allowed to stand for 10 days. The precipitate was collected by filtration, and the filtrate was deposited on neutral alumina and dried in an oven (110°) for 24 hours. Soxhlet extraction of the alumina with chloro- form afforded another portion of 18. The combined yield was 1.3 g (65%). lmax (CH2C12):398 (Soret), 491,530,567 and 620. 29 Tetramethylporphyrin tetracarboxylic acid (34) A mixture of 653 mg (1 mmol) of tetracarbethoxytetra- methylporphyrin (19) and 45 ml of l N KOH solution in 200 m1 of oxygen-purged tetrahydrofuran was refluxed in a nitrogen atomsphere for 150 hours. The solvents were removed under reduced pressure. The residue was dissolved in 50 m1 of water and acidified with concentrated hydrochloric acid until pre- cipitation occurred (PH=1). The precipitate was centrifuged and repeatly washed with water to free it from traces of acid. The yield was 503 mg (93%). nmr (5% Na2C03 in D20) showed total disappearance of ethyl esters. CO lmax (5% Na in H20), 403 nm (e 2.2x105), 507 nm 2 3 (a 1.7x104), 542 nm (e 1.0x104), 568 nm (e 8.5x103) and 620 nm (e 4.2x1o3). C, 61.99; H, 4.09; N, 10.33 Anal. Calcd for C23H2%N4O C 62 24, H 4 98 N 9 02 —— ' o I I . ' . Gun ‘0 Tetraphenylporphyrin tetracarboxylic acid (37) Lithium iodide was finely grounded and vacuum dried at 150 for two days prior to use. A mixture of 90 mg (0.1 mmol) of tetracarbethoxytetra- phenylporphyrin (15) and 697 mg (5.2 mmol) of lithium iodide in 25 m1 of dimethylformamide (dried over calcium hydride) was stirred and refluxed for 7 days under nitrogen. The reaction mixture was poured into 125 m1 of water, acidified with 1 N hydrochloric acid to slightly acidic and extracted with methylene chloride. After the solvent was removed, the 30 residue was extracted with 10% sodium carbonate solution until no more color in the extract. The combined extracts were then acidified with concentrated hydrochloric acid to PH 1. The fine purple precipitate was filtered and washed with plenty of water to give 67 mg of 37 (The yield was 85%). nmr (5% Na2CO3 in D20) showed no ethyl esters. Amax (in 5% aqueous Na2C03), 414 nm (E 2.0x105), 514 nm (e 1.0x104), 550 nm (E 7.2x103), 565 nm (E 5.7x103) and 626 nm (e 2.7x103). Anal. Calcd for C48H30N408°H20 : C, 71.28; H, 3.99; N, 6.93 Found : C, 70.71; H, 4.08; N, 7.08 Tetracarbododecoxytetramethylporphyrin (36) A mixture of 54 mg (0.1 mmol) of tetramethylporphyrin tetracarboxylic acid (32) and 150 mg (0.5 mmol) of n-iodo-do- decane in 2 m1 of triethylamine was heated in a sealed tube at 140-1500 for 20 hours. The reaction mixture was cooled to room temperature and extracted with hexanes. The extracts were then washed with 1% hydrochloric acid, 5% sodium car- bonate solution and water. The solvents were removed. The residue (dissolved in hexanes) was chromatographed on a neutral alumina column until 100 ml of hexane were collected then eluted with chloroform. The first purple band was dried to yield 38 mg of 36 (32.3%): nmr (CDC13), 50.70-2.50 (3 brd peaks, -C02CH2C11H23), 3.58 (brd m, -CH3), 4.83 (brd m, -c02c82c11823), 8.62, 9.55,9.78,9.95,10.62,10.82 (6 singlets, 31 meso-H), and -7.03 (brd s, N-H); Amax (CH2C12), 422 nm (e 2.8x105), 520 nm (e 1.7x104), 555 nm (a 7.2x103), 594 nm (e 5.7x103) and 651 nm (a 2.2x103). Anal. Calcd for C76H118N408-H20 : C, 73.98; H, 9.80 Found : C, 74.06; H, 10.18 Octaethylporphyrin (38) Toaniice cooled solution of 175 mg (0.3 mmol) of tetra- acetyltetraethylporphyrin (17) in 60 m1 of freshly distilled tetra- hydrofuran was added 4 m1 (4 mmol) of 1 N borane-tetrahydro- furan solution under nitrogen. Upon completion of addition, the reaction mixture was further stirred for one hour at ice temperature and two hours at room temperature, then cooled to ice temperature. A solution of 5% hydrochloric acid (45 ml) was introduced dropwise to the solution so that the pot tem- perature remained below 35°. The resulting solution was added to a separatory funnel containing 50 m1 of water and 40 m1 of 2 M sodium carbonate solution, and extracted with methylene chloride. Removal of the solvent and chromatographycnla neutral a1umina 1:-_ ’ ' .... uni. . . y.._—L.—. 1.- t. .. 1 . ‘ g . i TRANSMITTANCE (1.) 01_ -.- .. - ’ 2000 I800 1600 1400 1200 1000 800 0 NGUINC' C» Figure 5, Infrared spectrum of tetraacetyl- tetraethylporphyrin (l4). 37 2.5 ‘ 3.0 3.5 4.0 “00““ 5.0 6.0 8.0 - 1 k41-1-1 lvafiJrfLL 7111111171111; 111' .111111 1myI' * *” gmo E . f; . 80: :80 E . 3601- ‘60 z 4 . < p— .— : . . 5. R 1 1 \ \ . 4 ~— R . ‘ 1 \ R <40 3 or. \ ~11 144 v— :— 1‘ j 7:1_W . ‘ R \ /= / R 20:- R “\R/ .20 - n ‘ J _ R_:FI'n-_-Ic or M000 0 1 i i A: i ' 1 1 '-l ' 3 l ' ' 1 o 4000 3500 3000 2500 2000 1500 ’I'OUINC' ICH' 5.0 M'CR‘ENS 10.0 111.0 121. 16.0 1 1 1 1 11 1 1 l 100»---' j 1 :1: {11.1 ’6 f "~ '11“ ‘ 4+.“ 7%."? -: :-‘ 80 .1- . _‘ . __ 198" E 360 z < .— : E 340 < E 20 01____._ ....-__ -.- --_._._ 1 I" I’ 0 2000 1800 1600 1400 1200 1000 800 "tOUINC' \“. Figure 6, Infrared spectrum of tetraacetyl- tetramethy1porphyrin (15). TRANSMITTANCE (76) 38 TRANSMITIANCE (x1 2.5 ‘ 3.0 3.5 _. 4.0 mcaous 5.0 6.0 8.0 - . . . . 1 -4 -1 1%: 1.1.}: 3.11 L LIL. 1.1.1.11 11111115111191.3—31 ‘JIH * a‘EJ 00 “ "“' ' 100 80 80 60 60 40: 40 20: 20 ~ 11: l' .. R.R'=IcorCO;CJ1n 0 - .15'1;§;§il.§!L‘i.l~.ijélliz- '1; 4000 3 500 3000 2500 2000 1500 MOWV 1C0" 50 60 70 80““JUN>100 80120 no 1 1 1% 111.11%11;111_1:11.1.1 ‘. 111 1...11 100 "331‘““1‘7' I .1 '1 fi‘ 1 TV .. 1 1 41‘ "1‘ ' ‘ j. 100 1 ' ‘ I ' . f . ‘ l 1 . . . . . . 4 . . . . . . . ‘ _ L“ ... 1 e .-...11-_'.._11--._..__;-;--1--.- - 4 - - ... ......f . 1 : ' 1 Z - 1 31* 1L"; ""77“"- - 80 R .; , . . 1 R. — -.. . .. .‘ 4L .. 1 1 . 1 2 60 . 1 _. n I R. 40 n.n'=noor 00,121.; 20 01———-— - ~- - o 200 1800 1600 1400 1200 1000 800 "1000'“ v (M Figure 7, Infrared spectrum of tetracarbofictoxy- tetramethy1porphyrin (16). 39 2.5 3.0 i.e-L. - 1 - L' r 1 1 100 30 80 E 500 6° 2 < E 3, a ' RCMR' " NH NH 20 §~ “"JR 20 E R \/"\%~/. R R a: 3' R R": u. 0100,0113” O - 0 4000 3500 3000 2500 2000 1500 MOVING 300' 5.0 , 610 710 . 810 11110101115 10.0 11.0 12.0 16.0 - A . Lrwrr .. . ..lr.r‘.f .1.1 1T. Ioo—-— 4T1 'l1L »—1—:%: % ~1°° 2 : 1 1 . 1 1 1 _. . 1 . . '. ._. .-.: ”..- +__.1-... _. ....._.. . 1 . i..- -..... ....L.. .1-. .. 1____. 80 I ‘ " ‘ ‘ ' ‘ “1"_;""“"‘“. 1 ‘ i ' '80 '1 . A .. - _ . ., r g :00 . 60 L . . 4 1 : ~ —~ ~ 1 1. 3 1 : (I) 240 40 4 2‘. 2O Figure 8, 1600 1400 1200 800 Infrared spectrum of tetracarbo- dodecoxytetramethylporphyrin (36). 4O ..«_. caumnmuomaxcmnmmnumumxocumnumomuumu mo Eduuommm HEz .m musmwm o o. 2 on o. it 3 9.1 - 2 o. 1 41. <111H11+4.11J1_ 11. H1111%111 1 w M q 1 1 11 4 1 _ . _ r . D . . , i 3‘ . .. .mdUB 9 ".c .m .1 .muuz . :20 . . r . . . . m1» . ... L F 1 1 _ L _ p p p 1 .11 .p111rH.111H1111. 1H H 1r—.11 41 ..n—. cfiumzmhomaAcumemuumuaxonumnumomuumu mo Eduuowmm HEz .OH munmflm o 3 on on o. . it on o. 2 o. q. 11.411. 1Jr11.1fl11qh.1140.11 .11 ... . 4 01 1 4 a 1 q 1 1 1 _ 1 1 . . M II . E603 :01... c .cuuc .m a m .m _ m .m a m a .m «.03 § 3. ..2 3.. ...q ...: _ _ . 1 1. . _ r 1 1 b 1 . F . 1 1 _ F H1? P P M b r ? p1~ fi .1—1 P h P W P 11— L P — b 1? _ b .- H1» 1L 42 .A1_V cfiHanmuomamcummuumpHmumommugmu mo Eduuommm H52 .HH musmfim _n U U o o.— 3 3 3 .... at 9.. od 3 o.- 1 _ q 4 1 q 1 11 1 fi F + 1 ‘ J1 1H 1‘1 1 d1 11 H 1 1 1 * fly 1 1 1 I d A 1 1 1 4 H 1 1 1 1H 1 4 4 4 1 1 11 1 1 fl 11 q 1 1 — ? 43 1NH musmflm . An: c.“umzmuomaanumpfiuumuahumomwuumu no 5730QO H82 9 9.. 3 3" 3 2. at o.- 3 3 a. H ._1 .1_414._.141_411._ ~1411M1‘11111 _ 1 A 1 1 J 1 _ 1 1 1 395 m p — 1 r r L n > — > r [Fflblrll .L_r ..ul 1 1 1M > W > b 1? h H 1_11 1 m H 1 1r 1 44 .Ao—v cfiumnmuomamcumEmuumuwxouowonumumuum» mo Esugowmm H82 .MH musmflm 4 4 o. 4 4 a” o... o. . at on oo 3 o. {—— fl 1 M 1 1 111-1 H + 1 1 1 L 1 1 q a 1 1 1 1 H 1 1 1 d 1 4 1 1 _ — 1 fi 1 J 1‘ 1 q fl 1 21.6100 3 o: H a .m tuna 45 . 32 cwumnmuomawnumannamumxoomwononnmomnumu mo Esuuommm HEz .va musmflm o q. 3 3 3 3 at ... o.- 4 3 o.- _44 H4444_4414~4444H111.H1-4.41H4444_14‘4T11 d 4 a . _ 4 A 4 q 4 4 1 :25 mNINwQ «00.0 I: ".1 .C .ch m L 11 _ 1 _ 1 _ . P 1 mvp P 1 H 1* b1 17 H + 51 F 1H P P } b H b P 1? > H 5 P P 1 11—1 h 11F 1P 1— 1> F > P — P 51- PART II THE SYNTHESIS AND REACTIONS OF PYRROLES 46 INTRODUCTION The synthesis of 3,4-disubstituted pyrroles has been . . 1,35,57,58 known as a multi-step reaction sequence usually involving decarboxylation at N and/or a-carbons in the final stage of the reaction. In 1972, van Leusen, Siederius and 13, . . Hoogenboom introduced a new synthetic approach from Michael acceptors and p-toluenesulfonyl methyl isocyanide (TosMIC), Scheme 1. R C" Scheme 1 R" CH=CH'CN II II N H 3 "‘U°°"’ CH3@SOZCH2NC + R1’CH=CH’C32 ‘P—as—o'9 N H R NCb R—CH=CH-N02 I] I] N H In this manner eleven pyrroles were prepared according to the needs in the porphyrin synthesis (Part I) and trans- formation of pyrrole functional groups. In the investigation of ring-expanded porphyrin (43) synthesis3l, several potentially useful dipyrrolic inter- mediates were synthesized: 47 48 n,m = 2k + l (k can be any integer) n n when k = 0 n = m = l; a porphyrin H1 43 1) Two pyrrole units are connected by one carbon bridge to form dipyrromethane (44) and dipyrromethene (45). \‘ ” \\ \\ \\ \NHHN/ \NH N__ HBr 44 45 2) Two pyrrole units are connected by three carbon bridge to form dipyrropropanone (46), dipyrropropenone (47) and dipyrropropanedione (48). M NH O 46 £=COZEt i ‘8 3) Two pyrrole units are connected by five carbon bridge to form dipyrropentadienones (49, 50). 49 5° 49 Carbonyl functional groups were successfully introduced into compounds 44»and 45 by the processes shown in Schemes 2 and 3 to give dipyrromethane-dialdehyde (51), dipyrromethane- diketone (52) and dipyrromethene-dialdehyde (53). Scheme 2 m @°°°' \ NH nu / HCONM.2’ 44 EtMgBr HOAc 7 NH H33— Br ' 3,. 50 RESULTS AND DISCUSSION Synthesis of pyrroles It is fortunate that a variety of a,B-unsaturated carbonyl compounds were readily available, thus the synthesis of pyrroles could be carried out rapidly. However, in special cases the preparation of starting unsaturated carbonyls are necessary such as, in the synthesis of 3-acetyl-4-ethylpyrrole (3), 3- hexen-Z-one (73) was prepared by reacting propionaldehyde (74) with acetylmethylene triphenylphosphorane (75)1u as shown in Scheme 4. Scheme 4 CH3CH20H0 + 03P=CHCOCH3———> EtCH=CHCOCH3 74 75 73 1,3—Bis-(4-phenylpyrrole-3-carboxy)-propane (26) and n—octyl crotonate (76) were prepared by esterification of acyl chlorides and alcohols as shown in Scheme 5. Scheme 5 //§§v//C“DJ1 .lLEEEEEL___9//Q§>/JL\O’”\\//~\v//\\¢/A\\ 77 2' "-08H‘7OH 76 0’ 0 II II c, ‘\\ \ E 29 30 d) // 28 'c', 50 51 Various 3,4-disubstituted pyrroles were therefore synthe- sized by reacting TosMIC under basic conditions with a,B- unsaturated ketones, esters or nitro compounds to give, by concomitant loss of p-toluenesulfinic acid, 3-acylpyrroles, pyrrole-B-carboxylates and 3-nitropyrroles respectively, as shown in Scheme 1. The actual experimental results and the purification methods are summarized in Table l. Table 1, RD IR I! P! R R' Yield Purification method 2 C02C2H5 CH3 65% 100 /0.05 mm 3 COCH3 C2H5 91.3% alumina/ether 4 COCH3 CH3 84% boiling pet. ether 5 COzn-C8H17 CH3 91.4% alumina/MeClz 6 -COCH2CH2CH2- 80% alumina/MeClz 8 COPh COPh 71% 95% ethanol 9 N02 Ph 42% EtOH/HZO 1O COPh Ph 70% CHCl3/MeOH 11 C02C2H5 coz c 56% Eton/H20 26 2 Ph -C02(CH2?3HC5-02 100% Eton/H20 This synthesis provides a simple method for preparing a variety of 2,5-unsubstituted pyrroles which are otherwise relatively inaccessable. This unique approach took a rather convergent pathway by constructing C2, C5 and nitrogen atoms of the pyrrole ring in the TosMIC moiety while the vinylic carbon atoms of the Michael acceptors become C3 and C4 in the pyrrole ring formation. 52 Reactions of pyrroles 1) Transformation of functional groups: When 3-carbethoxy-4-methylpyrrole (2) was treated with sodium dihydro—bis-(2-methoxyethoxy)-a1uminate (78) in benzene, moderate (44%) yield of 3,4-dimethylpyrrole (7) was obtained15 ,uu 1. (Scheme 6). Several other methods3 all involving a multiple step sequence suffered from low overall yields. Scheme 6 coats: I) N u + Na H2A|(O\/\o/)2 ———-> [I N I] H 73 H 2 7 The nitro group of 3-nitro-4-phenylpyrrole (9) was converted to amino and acetylamino groups upon hydrogenation 25 and acylation as shown in Scheme 7. Scheme 7 o NH2 Pd/c “ 'I II II 2 H :39 N A o o NHCOM. 9 EM] H ‘40 3-Amino-4-phenylpyrrole (39) is very air-sensitive (decomposition took place in 10 minutes) and should be protected by acylation immediately to form 3-acetylamino- 4-phenylpyrrole (40). 53 2) Preparation and derivatization of dipyrrolic intermediates: Much of the synthetic effort in this part of research was directed toward the preparation of dipyrrolic inter- mediates 44-53 and their derivatives. They are divided into three catagories. (i) Single carbon bridge: Dipyrromethane (44) was prepared according to the pro- cedure of Clezy32 (Scheme 8). The bridging carbon was intro- duced by condensing pyrrole (54) with thiophosgene (55) to form 2,2'-dipyrrothione (56) which upon treatment with hydro- gen peroxide in a basic ethanolic solution was converted to 2,2'-dipyrroketone (57). Reduction of 57 with sodium boro- hydride afforded dipyrromethane (44)33 in almost quantitative yield. Scheme 8 In an attempt to differentiate the reactivities between the two a-positions of 3,4-disubstituted pyrroles,‘land 2 were reacted with dimethoxymethane (69) and a catalytic amount of toluenesulfonic acid in methanol, Scheme 9. 54 Scheme 9 n’ R + (MOO)2CH2—I£gfl—* \ "”88”" / Yield 69 83‘8'; I) R,R’=¢ or £ 76% b) R,R’=Mo or g 63% 2 Good yields of dipyrromethanes (Saaand 68b) were obtained, but their nmr spectra (in Appendix) showed that the products were mixtures. Therefore, the two a-positions showed no pre- ference toward electrophiles under these reaction conditions. When pyrrole (54) was used, only a 5% yield of 44 was obtained. Conversion of 44 to 5,5'-diformyl-2,2'-dipyrromethane (51)3u was done under Vilsmeier-Haack formylation condition, i.e., benzoyl chloride-dimethylformamide, as shown in Scheme 2. Pyrrole magnesium halides have been frequently used as intermediates in the synthesis of substituted pyrrolesss, therefore the potential is there to make the same use of 44. Schemelfl illustrates that S,5'-diacety1-2,2'-dipyrromethane (57) was prepared in 35-40% yield by reacting two moles of acetyl chloride with one mole of 2,2'-dipyrromethane magnesium salt (58) . The salt 58 was first prepared from one mole of 44 and two moles of ethyl magnesium bromide (59). Scheme 10 2 Mo CO Cl 58 V 55 Another way to link two pyrroles together is to unite them with a -CH- to form dipyrromethene such as 3,3'5,5'- as tetramethyl-4,4'-diethyl-2,2'-dipyrromethene-HBr (45) from 3-ethyl-2,4-dimethylpyrrole (kryptopyrrole) (59), Scheme 11. Scheme ll l I HCOzH \ \\ \ \ N H87 7 NH "5*,— H Successfulnmmobromination of S- and 5'-methyl groups with stoichimetric amount of bromine in acetic acid was reported by Fischer37 in 1927. Upon repeating his procedure, the yield was found to be very low. However, a simplier procedure was found to give better than 85% yield by adding bromine dropwise to a heated acetic acid solution of ‘45 until the red 5,5'-dibromomethyl-4,4'-diethyl-3,3'-dimethyl- 2,2'-dipyrromethene-HBr (60) precipitated out of solution. The nmr spectrum of this precipitate showed no contamination of di- or multi-bromination. Further bromination was carried out in liquid bromine according to the procedure of MacDonald38 and tetrabrominated product, 5,5'-di-dibromomethyl-4,4'- diethyl-B,3'-dimethyl-2,2'-dipyrromethene-HBr (61), was converted to 5,5'-diformyl-4,4'-diethyl-3,3'-dimethyl-2,2'- dipyrromethene-HBr (53) by stirring 61 in 95% ethanol over- night (Scheme 3 on page 49). (ii) Three carbon bridge: The first route of bringing two pyrrole molecules 56 together with a three carbon bridge is shown in Scheme 12. 2-Bromomethyl-4-methyl-3,5-dicarbethoxypyrrole (62)39 was first prepared by bromination of 2,4-dimethyl-3,S-dicarb- ethoxypyrrole (Knorr's pyrrole) (63) and then converted to 1,3-bis-(3,S-dicarbethoxy—4-methy1pyrr-2-yl)-propan-2-one 0 u (46) upon carbonylation with disodium tetracarbonylferrate (Collman's reagent). Scheme 12 E i ll—9'2—>l| HOAc {N E" H H8 63 62' The second method was to condense l—acetylpyrrole (63) and 1-formylpyrrole (64) to give 1,3-bis—(2-pyrryl)-l-propen- 3-one (47)u1, Scheme 13. Scheme 13 0 II II N 'l ,H "' u N '1 , NaOH A \ \ / H 3 H g / \ "H "" / 64 63 ‘7 Catalytic hydrogenationuz with palladium on charcoal in a Paar hydrogenator brought about the reduction of ‘97 to 1,3-bis-(2-pyrryl)-propan-3-one (88). 47 ___.>Pdv "2 HOAc 57 The third method (Scheme 14) was first making the pyrrole magnesium bromide (65) then reacting it with malonyl dichloride (66) to yield 1,3—bis-(pyrr-Z-yl)-1,3-propane- dione (48)21. Scheme 14 [—3 M a a I | EtMgBr I ‘ Cl CI> \ / [N] ”1:13 \ NH HN / H 9 ' 54 65 48 (iii) Five carbon bridge: Both l,3-di-pyrr-2-ylmethylene-2-cyclopentanone (49) and l,5-di-2-pyrryl-l,4-pentadien-3-one (50) were synthesized by reacting 64 under Aldol condensation conditions with cyclopentanone (67) and acetone (68) respectively, Scheme 15. Scheme 15 LN'H H3 EXPERIMENTAL General Instruments used are described in Part I. p-Toluenesulfonyl methyl isocyanide (27) a light brown solid, mp. 111-1140; prepared according to the procedure of van Leusen, Tetrahedron Letters, 5337 (1972). 3-Hexen-2-one (73) Acetylmethylene triphenylphosphorane (75) was prepared according to the procedure of Ramirez and Dershowitzza. A solution of 31.6 g (0.10 mol) of acetylmethylene triphenylphosphorane (75) and 11.0 g (0.19 mol) of propion- aldehyde (74) in 100 ml of methylene chloride was stirred and refluxed for six hours then allowed to stand overnight under nitrogen. The resulting mixture was condensed to 10- 20 m1 on a rotatory evaporator and diluted with 500 ml of pentane to precipitate triphenylphosphine oxide. After removal of the precipitate by filtration, the filtrate was again concentrated and distilled under water aspirator pressure. The fraction boiling at 55-560 at 30 mm (lit.29 64—700 (57 mm)) was collected as a colorless liquid to give 6.8 g (70%) of 73. Compound 73 was also identified by nmr. 58 59 n-Octyl crotonate (76) A mixture of 86 g (1 mol) of crotonic acid (77) and 119 g (72 ml, 1 mol) of thionyl chloride was placed in a two-neck round bottom flask (500 ml) which was fitted with a condensor and a addition funnel. The mixture was heated and stirred on a steam bath until no further evolution of gas was noted 0v1.5 hours) and then allowed to cool, and 130 g (1 mol) of n-octanol was added through the addition funnel. The mixture was again heated on the steam bath until the evolution of hydrogen chloride gas ceased (2 hours). This reaction mixture after cooling to room temperature was diluted with 200 m1 of ether and washed with 10% sodium carbonate solution (3x100 ml) then water (4x100 ml). The ether layer was condensed on a rotatory evaporator and stirred overnight with 20 g of anhydrous calcium chloride and 3 g of charcoal. Filtration of the solids gave 191 g (96%) of 76 as a light brown transparent oil. Compound 76‘was identified by nmr. 1,3-Dicinnamoyl propane (28) A mixture of 16.7 g (0.1 mol) of cinnamyl chloride (27) and 3.4 g (>0.05 mol) of 1,3-propanediol was heated to 130- 1400 under nitrogen until no more hydrochloric gas evolved. Upon cooling the solidified solution was crushed and washed with water and 5% sodium carbonate solution, then chromato- graphed on a neutral alumina column with benzene to give 60 14.2 g (85%) of white crystalline diester 26; mp. 79.5-810; nmr (CDC13), 52.07 (p, 2H, -OCH2C§2CH20-), 4.27 (t, 4H, -OCH2CH2CH20-), 6.13 to 7.67 (ABq, J=16Hz, 4H, vinylic H) and 7.25 (m, 10H, aromatic H); mass (m/e): 336 (parent). 3-Carbethoxy-4-pheny1pyrrole (1), 3-carbethoxy-4-methy1- pyrrole (2), 3-acety1-4-ethy1pyrrole (3), 3-acetyl-4- methylpyrrole (4). 3-carboBctoxye4-methy1pyrrole (5), 3,4-trimethylenecarbonylpyrrole (6). 3,4-dibenzoyl- pyrrole (8), 3-nitro-4epheny1pyrrole (9), 3-benzoyl- 4-pheny1pyrrole (10), 3,4-dicarbethoxypyrrole (11) and 1,3-bis-(4-phenylpyrrole-3-carboxy)-propane (26) General procedure: A solution of 5 mmoles of p-toluenesulfonyl methyl isocyanide (TosMIC) and 5 mmoles of 0,8-unsaturated carbonyl (or nitro compound) in 25 ml of ether-dimethylsulfoxide (2:1) was added dropwise to a stirred suspension of ca. 1.2 equi- valents of sodium hydride in ether (10 ml). The mixture was diluted with water after 15-30 minute further stirring and extracted with ether (3x50 ml). Purification methods and yields are given in Table l on page 51.Spectral characteristics for 1, 2, 3, 4, 5, 6, 8, 9, 1o, 11 and 26 are given below: 3-Carbethoxy—4-phenylpyrrole (1) mp. 121-1230; ir (CHC13), 3460 and 3230 cm”1 (N-H), l 1 1700 cm“ (c=0), 1525 cm‘ (C=C) and 1230 cm" (C-O); nmr 650 (m, 1H, pyrrolic proton), 7.25 (m, 6H, phenyl and pyrrolic 61 protons) and 8.83 (brd s, 1H, N-H); mass (m/e): 215 (parent). Anal. Calcd for C13H13N02 : C, 72.54; H, 6.09; N, 6.51 Found : C, 72.58; H, 6.07; N, 6.53 3-Carbethoxy-4-methy1pyrrole (2) mp. 67-710 (lit.28 73°); ir (CHC13), 3450 and 3290 cm‘1 (N-H), 1650 cm‘1 (0:0), 1510 cm“1 (C=C) and 1270 cm'1 (C-O); nmr (c0c13), 61.30 (t, 3H, -0cn2cg3), 2.26 (s, 3H, -cg3), 4.18 (q, 2H, -OC§2CH3), 6.38 (m, 1H, pyrrolic proton) and 7.20 (m, 1H, pyrrolic proton). 3—Acetyl-4-ethy1pyrrole ( 3 ) mp. 60.5-62.50; ir (cuc13), 3450 and 3290 cm“1 (N-H), 1650 cm’1 (0:0) and 1510 cm“l (C=C); nmr (c0c13), 61.13 (t, 3H, -CH2cg3), 2.38 (s, 3H, -cocg3), 2.75 (q, 23, -cg2 CH3), 6.47 (m, 1H, pyrrolic proton) and 7.27 (m, 1H, pyrr- olic proton); mass (m/e) : 137 (parent). Anal. Calcd for CnglNO : C, 70.04; H, 8.08; N, 10.21 Found : C, 70.08; H, 8.12; N, 10.16 3-Acety1-4-methy1pyrrole (4) mp. 113-1140 (11tf3112-1140); nmr (c0013), 62.33 (s, 3H, -C§3), 2.42 (s, 3H, -COC§3), 6.46 (m, 1H, pyrrolic proton), 7.25 (m, 1H, pyrrolic proton) and 9.58 (brd s, 1H, N-H). 3-Carbofictoxy-4-methylpyrrole (5) a yellow oil freezes at 0-50; ir (CHC13), 3455 and 3300 cm‘1 (N-H), 2900 and 2840 cm‘1 (C-H), 1680 cm'1 (c=0), 1540 cm”! (C=C), 1250 and 1145 cm-1 (c-0); nmr (cnc13), 60.7-1.8 (3 brd peaks, 15H, -OCH2C7H15), 2.25 (s, 3H, -C§3), 4.15 (t, 62 2H, -OC§2C7H15), 6.40 (m, 1H, pyrrolic proton) and 7.23 (m, 1H, pyrrolic proton); mass (m/e) : 237 (parent). Anal. Calcd for C14H23NO : C, 70.85; H, 9.77; N, 5.90 Foun : C, 70.12; H, 9.90; N, 5.32 3,4-Trimethy1enecarbonylpyrrole (6) a yellow oil freezes around -10° and turns brown very rapidly at room temperature; its nmr (CDC13) was taken immediately and showed, 61.83-2.83 (m, 6H, -(C§2)3CO-), 6.43 (m, 1H, pyrrolic proton), 7.20 (m, 1H, pyrrolic proton) and 9.80 (brd s, 1H, N—A); mass (m/e) : 135 (parent). 3,4-Dibenzoylpyrrole (8) mp. 221-2230 (lit.13 221-2220); nmr (D6MSO), 67.20-7.72 (m, aromatic and pyrrolic protons). 3-Nitro-4-phenylpyrrole (9) mp. 152-153°; nmr (D6MSO), 66.62 (m, 1H, pyrrolic A), 7.27 (brd s, 5H, phenyl A), 7.60 (m, 1H, pyrrolic A) and 11.27 (brd s, 1H, N-H); mass (m/e) : 188 (parent). Anal. Calcd for C10H N202 : C, 63.82; H, 4.29; N, 14.89 ound : C, 64.83; H, 4.38; N, 14.49 3-Benzoy1-4ephenylpyrrole (10) mp. 228-2310 (1it.13 229-231 (dec.)); nmr (D6MSO), 66.90 (m, 1H, pyrrolic proton), 7.00-7.50 (m, 10H, aromatic protons), 7.73 (m, 1H, pyrrolic proton) and 11.40 (brd s, 1H, N-H). 3,4-Dicarbethoxypyrrole (11) 26 mp. 153-1550 (lit. 153-1550); ir (CHC13), 3450 and 63 3300 cm"1 (N-H), 1725 cm-1 (c=0), 1525 cm-1 (C=C), 1280 and 1150 cm“ (C-O); nmr (CDC13), 51.32 (t, 6H, -OCH2C_I'l3), 4.23 (q, 4H, -OCA2CH3) and 7.27 (d, 2H, pyrrolic protons). l,3-Bis-(4-phenylpyrrole-3-carboxy)-propane (26) mp. 154-1560; nmr (D6MSO), 61.88 (p, 2H, -OCH2cnzcnzo-), 4.08 (t, 4H, -OCA2CH2CA20-), 6.62 (m, 2H, pyrrolic protons), 7.27 (m, 12H, aromatic and pyrrolic protons) and 10.59 (brd s, 2H, N-A); mass (m/e) : 414 (parent). Anal. Calcd for C25H22N204 : C, 72.45; H, 5.35; N, 6.76 Found : C, 73.36; H, 5.57; N, 6.39 3,4-Dimethylpyrrole (7) A solution of 5 g (34 mmol) of 3-carbethoxy-4-methy1- pyrrole (2) in 50 m1 of benzene was added dropwise to a benzene solution of 23 g 0~80 mmol) of sodium dihydro-bis- (2-methoxyethoxy) aluminate (78) at 250 under an atomsphere of nitrogen. After the reaction mixture was stirred for 18 hours, 100 ml of water was added. The benzene layer was separated, washed with 2x200 m1 of water and dried over anhydrous sodium sulfate. The solvent was removed and the residual Oil distilled to give 1.4 g (44%) of 72? bp. 69-700 (10 torr); nmr (CD013), 62.00 (s, 6H, -CA3) and 6.38 (d, 2H, pyrrolic protons). 3-Amino-4-phenylpyrrole (39) A mixture of 188 mg (1 mmol) of 3-nitro-4—phenylpyrrole (9) and one-third of a Spatula of 10% palladium on charcoal 64 in 15 m1 of 95% ethanol was shaken under 45 psi of hydrogen for 10 minutes. The catalysts were filtered and the filtrate was evaporated under reduced pressure. Since 39 is very air- sensitive, its nmr was taken immediately without further purification; nmr (CC14), 62.87 (brd s, 2H, amino-A), 6.47 (m, 1H, pyrrolic A), 6.82 (m, 1H, pyrrolic A), 7.55 (m, SH, phenyl H) and 8.10 (brd s, 1H, N-A). 3-Acetylamino-4-pheny1pyrrole (40) A mixture of 188 mg (1 mmol) of 9, 0.1 g of calcium chloride and 3.0 g of zinc dust in 16.4 ml of 95% ethanol and 3.6 ml of water was stirred and refluxed for two hours under nitrogen. The reaction mixture was condensed to 5 ml by distillation under nitrogen. A solution of 102 mg (1 mmol) of acetic anhydride in 5 m1 of acetic acid was added and further stirred for 30 minutes. The reaction mixture was then decanted into 50 m1 of ether and washed with 5% sodium carbonate solution three times and water twice. Removal of solvent gave 150 mg (75%) of 40 as a grey powder. Its nmr (CDC13) showed: 61.93 (s, 3H, -COCA3), 3.92 (s, 1H, amide E), 6.55 (m, 1H, pyrrolic A), 7.10 (brd s, 6H, phenyl and pyrrolic A) and 11.35 (brd s, 1H, N-H). 2:2'-Dipyrromethane (44) 32 The procedure of Clezy was used and the product was purified by crystallization from petroleum ether, mp. 72-730, Compound 44 is air-sensitive and stored in a refrigerator. 65 Reactions of 1 and 2 with dimethoxymethane (69) in an acidic methanolic solution, dipyrromethanes (688) and (68b) General procedure: A solution of 1 mmole of pyrrole, 1 m1 of dimethoxy- methane and 40 mg of toluenesulfonic acid monohydrate in 10 m1 of methanol was stirred and refluxed for 24 hours in an atomsphere of nitrogen. The reaction mixture was diluted with water and extracted with methylene chloride. The extracts was evaporated to dryness and extracted with boiling petroleum ether (bp. 60-1100) until only a small amount of residue remained. Removal of petroleum ether gave a white powder and the yields are given on page 54. nmr of 688 (CDC13), 61.23 (t, 6H, -OCH2C§3), 3.68 (s, 2H, methane-protons), 4.15 (q, 4H, -OC§2CH3), 6.50 (m, 2H, pyrrolic protons) and 7.25 (m, 12H, phenyl and pyrrolic protons). nmr of 68b1(CDC13), 61.30 (t, 6H, -OCH2C§3), 2.26 (38, 6H, -CH3), 3.73 (s, 2H, methane-protons), 4.18 (q, 4H, -0CAZCH3), 6.38 (m, 2H, pyrrolic protons) and 7.20 (m, 2H, pyrrolic protons). Therefore, both 68a and 68b are mixtures of possibly three isomers. ;§,5'-Diformyl-2,2'-dipyrromethane (51) Three ml of benzoyl chloride was added dropwise over a period of 10 minutes to a stirred solution of 0.7 g 66 (4.8 mmol) of 2,2'-dipyrromethane (44) in 5 m1 of N,N'- dimethylformamide at 0-5° under nitrogen. This solution was further stirred at ice bath temperature for two hours then at room temperature for two hours. Benzene (10 ml) was added and after 30 minutes the crystalline pale yellow imine salt precipitated. The salt was collected by fil- tration and washed well with benzene but not allowed to dry. The solid was immediately dissolved in 10 m1 of 10% sodium acetate solution and slowly warmed to 35-400, then cooled and allowed to stand overnight. The product 51 precipitated as a pale yellow powder which was collected by filtration to yield 0.8 g (80%); mp. 218-2230 (lit.3~ 219-2220); nmr (DSMSO), 63.90 (s, 2H, methane-protons), 5.97 (d, 2H, pyrrolic protons), 6.73 (d, 2H, pyrrolic protons) and 9.23 (s, 2H, -C§Q). 5,5'-Diacety1-2,2'-dipyrromethane (52) A solution of 4 m1 (4 mmol) of 1 M ethyl magnesium bromide in ether and 292 mg (2 mmol) of 2,2'-dipyrro- methane (44) in 20 m1 of anhydrous ether was stirred and refluxed for two hours under nitrogen. This solution was then added dropwise to an ice chilled solution of 314 mg (4 mmol) of acetyl chloride in 20 m1 of ether. After stirring at ice bath temperature for two hours then at room temperature for another two hours, the resulting yellow solution was poured into 130 m1 of ice water and 40 m1 of saturated aqueous ammonium chloride then 67 extracted with chloroform. Evaporation of the extracts and crystallization from CHC13/ether gave 180 mg (39.1%) of 52 as fine white powders; mp. (sealed tube) 234-236O (decomp.); nmr (CDC13/trace D5MSO), 62.33 (s, 6H, -COCH3), 3.90 (s, 2H, methane-protons), 5.93 (m, 2H, pyrrolic A) and 6.67 (m, 2H, pyrrolic protons); mass (m/e) : 230 (parent) Anal. Calcd for C13H14N202 : C, 67.81; H, 6.13; N, 12.17 Found : C, 66.48; H, 5.91 N, 12.76 3,3',5,5'-Tetramethy1-4,4'-diethy1-2,2'- dipyrromethene-HBr (45) A mixture of 5.0 g (40.3 mmol) of kryptopyrrole (59), 10 ml of 88% formic acid and 8 m1 of 48% hydrobromic acid was heated on a steam bath for two hours, then allowed to stand overnight. The shining purple precipitate was filtered and air dried to give 5.8 g (85.4%) of 45; nmr (CDC13/ CF3C02H), 61.10 (t, J=6.5 Hz, 6H, -CH2CA3), 2.30 (s, 6H, -CH3), 2.46 (q, J=6.5 Hz, 4H, -C§2CH3), 2.53 (s, 6H, -CH3) and 7.08 (s, 1H, methene-A); Amax (CHC13), 486 nm. 5,5'-Dibromomethyl-4,4'-diethy1-3,3'-dimethy1- 2,2'-dipyrromethene-HBr (60) A solution of 0.92 g (27.3 mmol) of 3,3'5,5'-tetra- methyl-4,4'-diethyl-2,2'-dipyrromethene-HBr (45) in 35 m1 of acetic acid was heated on a steam bath with occasional swirling. Liquid bromine was added dropwise until 68 precipitation occurred, then two more drops of bromine were introduced. The mixture was cooled to room temper- ature and filtered. The deep red precipitate after air drying, gave 1.15 g (85.2%) of 60; nmr (CDC13/CF3C02H), 61.17 (t, J=6.5 Hz, 6H, -CH2CA3), 2.32 (s, 6H, -CH3), 2.52 (q, J=6.5 Hz, 4H, -CH2CH3), 4.68 (s, 4H, Br-CA2-) and 7.20 (s, 1H, methene-A); Xmax (CHC13), 509 nm. 5,5'-Di-dibromomethy1-4,4'-diethyl-3,3'-dimethyl- 2,2'-dipyrromethene-HBr (61) A solution of 4.50 g (9.1 mmol) of 5,5'-dibromo- methyl-4,4'-diethy1-3,3'-dimethyl-2,2'-dipyrromethene- HBr (60) in 30 m1 of liquid bromine was stirred at room temperature for one hour. Bromine was removed under re- duced pressure and 60 m1 of acetone was introduced. The acetone solution was refluxed for 30 minutes then cooled to room temperature and refrigerated overnight. The red precipitate was filtered, washed with cold acetone and dried to give 5.28 g (90%) of 61 as a red powder; nmr (CDC13/CF3C02H), 61.27 (t, J=7 Hz, 6H, -CH2ca3), 2.37 ( s, 6H, -C§3), 2.80 (q, J=7 Hz, 4H, -CH2CH3), 7.13 (s, 2H, Br2C§-) and 7.42 ( s, 1H, methene-H); Amax (CHC13), 514 nm (111:.38 519 nm). 5,5'-Diformyl-4,4'-diethyl-3,3'-dimethyl- 2,2'-dipyrromethene-HBr (53) A solution of 1.0 g (1.53 mmol) of 5,5'-di-dibromo- methyl-4,4'-diethyl-3,3'-dimethyl-2,2'-dipyrromethene-HBr 69 (61) in 50 ml of 95% ethanol was stirred at room temperature for 17 hours. The resulting solution was diluted with 170 m1 of water and refrigerated. A dark precipitate was collected and dried to give 0.4 g (72%) of 53; mp. 220-2220 (decomp.); nmr (CDC13), 61.15 (t, J=6.5 Hz, 6H, -CH2CA3), 3.28 (s, 6H, -CA3), 2.58 (q, J=6.5 Hz, 4H, -CHZCH3), 5.53 (s, 1H, methene- A) and 9.46 (s, 2H, -C§Q); Amax (CHC13), 507 nm, 575 nm and 615 nm. 1,3-Bis-(3,S-dicarbethoxy-4-methy1pyrr-2—y1)- propan-Z-one (46) A solution of 3.27 g (10.3 mmol) of 2-bromomethyl-4- methyl-3,S-dicarbethoxypyrrole (62) in 5 m1 of N-methyl- 2-pyrrolidone was added to a stirred solution of 3.84 g (11.1 mmol) of NaZFe(CO)4°3/2dioxane in 30 ml of N-methyl- 2-pyrrolidone in a nitrogen atomsphere. Bubbling occurred immediately. After the reaction mixture was stirred for one hour, 9.81 g (30.9 mmol) of 62 in 15 ml of N-methyl- 2-pyrrolidone was added and stirred for an additional 24 hours. Ether (150 ml) was added and the diluted solution was washed with saturated sodium chloride solution three times. During the third washing white solids precipitated, 50 m1 of methylene chloride was introduced to dissolve the precipitate. The combined ether-methylene chloride layer was evaporated to dryness and crystallization from ethanol— water gave 4.30 g (41.75%) of 46 as a fluffy white solid; mp. 185-1870; nmr (CDC13), 61.35 (2 overlapping triplets, 70 J=7 Hz, 12H, -C02CH2CA3), 2.58 (s, 6H, -CA3), 4.18 (s, 4H, CH2 0 to -CO-) and 4.27 (2 overlapping quartets, J=7 Hz, 8H, -C02CA2CH3); mass (m/e) : 504 (parent). Anal. Calcd for C25H32N209 : C, 59.50; H, 6.41; N, 5.55 Found : C, 59.56; H, 6.34; N, 5.44 1,3-Bis-(2-pyrryl)-1-propen-3-one (47) A solution of 1.09 g (0.01 mol) of 2-acetylpyrrole (63), 0.95 g (0.01 mol) of 2-formy1pyrrole (64), 7 ml of ethanol, 5 m1 of water and 2 m1 of 15% NaOH was stirred for 5 hours then allowed to stand for 12 hours. Dilution with water and refrigeration resulted in a golden flaky precipitate. This product after recrystallization from ethanol and water gave 0.60 g (32%) of 47; mp. 157-1600 (decomp. at 120°, 11):."1 174°); lmax (CHC13), 382 nm; nmr (CDC13/DGMSO), 66.13 (m, 2H, pyrrolic protons), 6.42 (m, 1H, pyrrolic proton), 6.78 (m, 1H, pyrrolic proton), 6.92 (m, 2H, pyrrolic protons), 6.93-7.68 (ABq, J=15 Hz, 2H, vinylic protons) and 10.72 (s, 2H, N-n). 1,3-Bis-(2-pyrryl):propan—3-one (66) A solution of 93 mg (0.5 mmol) of 1,3-bis-(2-pyrryl)- l-prOpen-3-one (47) in 5 m1 of acetic acid was hydrogenated at 30 psi over a small amount of 10% palladium on charcoal for 45 minutes. The catalyst was filtered immediately, and the filtrate was diluted with 5% sodium carbonate solution and extracted with chloroform. Evaporation of the extracts and crystallization from chloroform/cyclohexane gave 80 mg 71 (89%) of 66 as a pale yellow solid which is acid and air sensitive; nmr (CDC13), 63.00 (t, J=3 Hz, 4H, -COCA2CA2-), 5.83 (m, 1H, pyrrolic proton), 5.97 (m, 1H, pyrrolic A), 6.13 (m, 1H, pyrrolic A), 6.50 (m, 1H, pyrrolic proton), 6.83 (m, 2H, pyrrolic protons), 8.40 (brd s, 1H, N-A) and 9.80 (brd s, 1H, N-A). 1,3-Bis-(pyrr-2-y1)-1,3-propanedione (46) A solution of 10.0 ml (10 mmol) of 1 M ethyl magnesium bromide in ether and 670 mg (10 mmol) of pyrrole in 50 m1 of ether was stirred and refluxed for two hours under N2. This solution was then added to a stirred solution of 705 mg (5 mmol) of malonyl dichloride in 50 ml of ether at dry ice and ethanol temperature. The resulting yellow solution after two hour stirring at dry ice temperature was poured into 200 m1 of water and 50 ml of saturated ammonium chloride, extracted with ether then the ether extracts was evaporated to dryness. The residue after crystallizing from ethanol and water gave 354 mg (35%) of 46 as a pale yellow powder; nmr (CDC13/D6MSO), 64.13 (s, 2H, ~COCA2CO-), 6.13 (m, 2H, pyrrolic protons), 6.93 (m, 4H, pyrrolic protons) and 11.01 (brd s, 214, N-A). ‘lLB-Di-pyrr-2-y1methy1ene-2-cyclopentanone (49) and l,5-di-2-pyrryl-1,4-pentadien-3-one (50) To a stirred mixture of 480 mg (0.5 mmol) of 2-formyl- pyrrole (64), 4 m1 of 15% NaOH, 10 ml of water and 14 ml of 72 ethanol was added 210 mg (0.25 mmol) of cyclopentanone (or 120 mg of acetone) at room temperature under nitrogen. After completion of addition, the mixture was stirred for two hours then allowed to stand overnight. The orange precipitate was collected by filtration to yield 526 mg (90%) of149 (or after crystallizing from ethanol/water to give 32 mg (15%) of 50). Compound 49 showed nmr (D6MSO) absorptions at : 62.83 i (s, 4H, cyclopentanone-protons),’6.20 (m, 2H, pyrrolic protons), 6.43 (m, 2H, pyrrolic protons), 6.96 (m, 2H, pyrrolic protons), 7.27 (s, 2H, vinylic protons) and 11.20 (brd s, 2H, N-A). Anal. Calcd for C15H14N20 Found C, 75.60; H, 5.92; N, 11.76 C, 74.22; H, 5.86; N, 11.31 Compound 50 showed nmr (DGMSO) absorptions at : 66.10 (m, 2H, pyrrolic protons), 6.43 (m, 2H, pyrrolic protons), 6.80 (m, 2H, pyrrolic protons), 6.57-7.60 (ABq, J=15 Hz, 4H, vinylic protons) and 10.77 (brd s, 2H, N-A). APPENDIX 2.5 0 O Imwwwnmwth o. O TRANSMITTANCE (96) b O '20 Figure 15, 8 b O 3.0 3500 6.0 1 73 3.5 70 46 “‘m" 30 MICRONS A A A I L4 - u 810 J | f 1500 10.0 ".0 '2. 16.0 . .1 .. 1 .1 - A T . - ——- ..- A . . o .. I l I I I . 1T: .4 -4 o I D 1-1+. "L I?) l 100 20 ; 9 § ‘ . f i i i g - -_ é ;- - -— -- ' 1 4 - - 5 ‘ 4O . - :- . i .. .3 - . E... .. .... - : .l"']°q"-.: : -3 u ' 1 3 i H 1 ; [-4 ~( -§ ‘ : ' ‘ ~1800 1600 1400 1200 1000 800 "teat“? CM Infrared spectrum of 3-carbethoxy- 4-pheny1pyrrole (1). 74 2'5 L 1 3101 1 1 131511 13011111111910 610 8'0 A l n A A _‘ 1 1w ‘4 -I f :0 -‘ . L‘ J T —‘-r-""‘ I’ ' r V ' v ' ' ''''''' i ‘m 80 33 360' 60 g L E '; 95 ’ N H 20E 20 o 1 ' 1 ' 1 1 ' l :4 - L' I -n - - z - 1 - U H o 4000 3500 3000 2500 2000 1500 ”QUINCV -CI' so 80‘W0mms m0 "6120 . Iw o l u‘ #b‘.‘ “ 9A -A A. , 1 . - ‘00 80 3 360 Z < E E 240 < P.‘ 20 01...... 2000 Figure 16, Infrared spectrum of 3-carbethoxy- 4-methylpyrrole (2). 75 E 360‘ 60 z , < E )- 24 - < O, 40 :5 5 20: 2O o'3‘3!;j;-Li:|3;§)'i-J:!!.o1:.U.o 4000 3500 3000 2500 2000 1.500 M00040 'CM‘ 5.0 6.0 .o 8.0 M'CRONS 10.0 ".0 12.0 16.0 worm-- ”11T-I.J'#J - 1 24, 53 ‘ ‘. i 3 232' a a: ..z-‘ 5.4. * ‘L‘ '00 . ' , . . - . .. *"“’—".’ _ L . -.-..--.l.-'.- E ‘ - 80 - -g -80 I 4 JS . 660 60 z < t: 3 2,40 40 < 95 ocn, [I H ' N 20 ” ‘ § 20 0' - ‘ ' 0 2000 I800 1200 1000 800 Figure 17, Infrared Spectrum of 3-acety1- 4-ethylpyrrole (3). 76 so 80 .5 n P) "8“” °° < E < I 9.‘ N H . 20 “20 J o 4 1 - 1 - r ' - -j - - 1 J ‘ U | _L 4000 3500 3000 2500 2000 1500 "(QUINCY (Can . 6.0 710 8.0 W 10.0 111.0 12.0 16.0 1 A A I .A . J a 1 .‘ Ar 3‘ A 14 A . A c A A u. u a I. - f ‘ a ‘ l 4 m0 ‘7' j ‘1 I '1 f . : ab ‘1‘ -'00 . . . .. 7 ..a g... . .L. 1.14:1 .. z ; ..+_._'..L.. ..--1—4 .--1...L.._JL_'. f ‘ ‘ L... ’ ..1 7 ' . O O IRANSMIUANCI: (1;) A O 20 3.. 2000 Figure 18, “16m‘ 7 . .... ......mg.” 11 I400 1200 NIGUINC' CM ' I600 1000 800 Infrared spectrum of 3-carb06ctoxy- 4-methylpyrrole (5). 77 23 3.0 3.5 40 mcm 50 6.0 60 ‘w{;.: i I I‘fi: -‘. I- ~ ~' _‘I: .1. ' » 0 ~ I an no . -. ... . - 1m 5 80 80 g 86° ‘°° z < E 540 40 s 20 20 0 ~— 0 4000 3500 3000 2500 2000 1500 MOWNCV (6“ 5.0 6.0 7.0 8.0 ”CRONS 10.0 11.0 12.0 16.0 4 .‘ . 1 1 - 1 . . 1 . . . J . I I . 1 A 100 W-—-+— pi i)‘ ' ' 'g .1 T100 : 3 . --21. .— .1. .1 - +~r+e+4«.-- 7 4 ‘ ' ? I t 3 3' 50 60 Z < E .‘ 2 . ‘2 40’ I 5 , 40 '— \\ \ \_ NH "a“ 20 20 0 ... - --.._.___.,_ --. ‘ - ' o 3009 1800 1600 1400 1200 1000 800 Figure 19, than \f‘ (M Infrared spectrum of 3,3:5,5'- tetramethy1-4,4'-diethyl-2,2'- dipyrromethene-HBr (45). 78 '60 40 20 60 40 20 4.0 MICRONS 5. . m .. 1 .1-1.!.1.3..l;:1.:a--.1. was“ .;f _. ;._ 553128;; 915.53».- 2 is... p 80; 5 ~ 1 9“: < I E 240} < 3 . \ \ \ . \ - ‘ H67 20: m u _» . . ' ' ' ; i . ' * i 2 ' ._1._ ‘3_-"—- "- -. —-'—" n" r “‘i '44“! ;‘j. :._!._1..) +3-3 i.7"T: 5 - I '1 ' 0'44; ,,;i;: .2'21:..e!;'72: IL; 4000 3500 3000 2500 2000 1500 WHO cm 5.0 7.0 8.0 ““0” 10.0 ".0 12.0 16.0 ‘00 L 1 11:11 ng. 1 41'. 11%”11'. ... f' . '1 l. '13:; ..1 ..1 2.21;; . .. ...£ ' .{......f... .11. u 80‘ - ...... . - ‘ ‘ 1 - . 1- 5 i 360 ... Z . i ' < 3 . E 2 --) ‘ ' l 340 - < '. E . 20 i . . . . . 4 4 0'. 2000 I800 1600 1400 1200 1000 800 momma Cu Infrared Spectrum of 5,5'-dibromo- methyl-4,4'-diethy1-3,3'-dimethy1- 2,2'-dipyrromethene-HBr (60). Figure 20, 79 80 30 E “160 \ ‘° 1: < 40 E , m 20 20 o 1 1 1 ' 1 1 - J 1 - : . o 4000 3500 3000 2500 2000 1500 MMNC' (an 5.0 6.0 7.0 8.0 MICRONS 10.0 ".0 12.0 16.0 loo -. 1+ - -. -1.._‘;*_..A......:.:__ :4;— AT 1 LIL 1 “‘1‘ J . 1 t J l .. [-1 31141;.1“ m (Uri-IT'S" f-F‘ ‘ s " I i 13 ' 3 1 . I 3 1 . . . .... 1 . 80 z ; l _ I g ' : A ...... -11 . 1 . . 1 . 3 . 1 I . : . E. ;. ' é . . Z a I . . i i H m . £40 i v - :2-) --f 40 t - 2.2 '1 . U ? 20 0 _ _ , 2000 Jo 18:10 Figure 21, 1400 I200 ’IIOt-ENC' .0 Infrared Spectrum of 5,5'-di-dibromo- methyl-4,4'-diethy1-3,3'-dimethy1- 2,2'-dipyrromethene-HBr (61). 80 IRANSMITTANCE (96) TRANSMITTANCE (75) 7. so -00 1 60: ‘60 40% 40 F 2°? 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AV 104 .Aavv mcoflomcmmoumlm.HIAHMINIHH>QVumflnum.a mo Eduuommm H82 .mv musmflm o O. on on 0. 1*On 00 Os 0. 7~ 41¢H4‘4‘H11.~. .4 1 ..L+ F“1‘H“_ H. p fiprrL~L_ .Aoev wcocmucmmoHomo umnmcwamnumEHmumunummuflonm.H mo Eduuommm H52 .nv musmflm o 3 a.” 2" 3 1. at o.- 3 3. o.- .H. .H.«¢«F+‘+._“J._‘..‘_+‘Hilfi<¢4+w1 -4f‘* 1 4 _ . 4 ‘ . _ . _ ‘ a J 105 106 . 33 wcoum acmflomucmmlv.Hlaxuummumlflolm.H mo Eduuommm HEz ~mv musmflm BIBLIOGRAPHY 10. ll. 12. l3. 14. 15. 16. BIBLIOGRAPHY H. Fischer and H. Orth, "Die Chemie des Pyrrols", Vol. I, Akademische Verlag, Liepzig, 1934. H. Fischer and H. Orth, "Die Chemie des Pyrrols", Vol. IIi, Akademische Verlag, Liepzig, 1937. H. Fischer and H. Stern, "Die Chemie des Pyrrols", Vol. IIii, Akademische Verlag, Liepzig, 1940. I. U. P. A. C. Rules for Nomenclature, J. Amer. Chem. Soc., 82, 5582 (1960). R. L. Harris, A. W. Johnson and I. T. Kay, Quart. Rev., 2Q, 211 (1966). K. M. Smith, Quart. Rev., 2%, 31 (1971). A. H. Jackson and K. M. Smith in "Toatl Synthesis of Natural Products", Vol. 1, Ed. J. W. ApSimon, Wiley, New York, 1973, P. 143. H. H. Inhoffen, J. W. Buchler and P. Jager, Fortsch. Chem. Org. Naturst., 26, 284 (1968). K. M. Smith in "Porphyrins and Metalloporphyrins", Elsevier Scientific Publishing Company, 1975, pp. 29-58. G. S. Marks, "Heme and Chlorophyll", Van Nostrand, London, 1969. A. Treibs and N. Haberle, Liebigs Ann., 718, 183 (1968). H. W. Whitlock and R. Hanner, J. Org. Chem., 33, 2169 (1968). A. M. van Leusen, H. Siederius, B. E. Hoogenboom and D. van Leusen, Tetrahedron Lett., 5337 (1972). H. 0. House, W. L. Respass and G. W. Whitesides, J. Org. Chem., 31, 3128 (1966) D. 0. Cheng, T. L. Bowman and E. LeGoff, J. Heterocyclic Chem., 13, 1145 (1976). A. R. Batteraby and E. McDonald in "Porphyrins and Metallo- porphyrins", Elsevier Scientific Publishing Company, 1975, p. 61. 107 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 108 D. Dolphin, J. Heterocyclic Chem.,,g, 275 (1970). N. Datta- Gupta and T. J. Bardos, J. Heterocyclic Chem. , 1, 495 (1966) R. H. Mills, M. W. Farrar and O. J. Weinkauff, Chem. Ind., 2144 (1962). P. D. G. Dean, J. Chem. Soc., 6655 (1965). B. Oddo and C. Dainotti, Gazzetta Chimica Italiana, 421, 716 (1912) . "’ R. B. Woodward, Angew. Chem., 1%, 651 (1960). A. Ramirez and S. Dershowitz, J. Org. Chem., 22, 41 (1957). M. Farnier and P. Fournari, Bull. Soc. Chim. France, 2335 (1975). R. Adams and F. L. Cohen, Org. Syn. Coll. Vol. I, p. 240; W. E. Kahn, ibid., C011. Vol. II, p. 448. E. C. Kornfeld and R. G. Jones, J. Org. Chem., 19, 1671 (1954). H. Fischer, E. Sturm and H. Friedrich, Liebigs Ann., 4Q1, 259 (1928); O. Pilotz and A. Blomer, Chem. Ber., 45, 3752 (1912) H. Fischer and O. Wiedemann, Hoppe-Seylers Zeitschrift fur Physiologische Chemie, 155, 58 (1926). E. R. Alexander and G. R. Coraor, J. Amer. Chem. Soc., 1%, 2721 (1951). H. Fischer and L. Nussler, Liebigs Ann., 491, 168 (1931). Thomas L. Bowman, PH. D. thesis, Michigan State University, 1973. P. S. Clezy and G. A. Smythe, Austr. J. Chem., 22, 239 (1969). R. Chong, P. S. Clezy, A. J. Liepa and A. W. Nichol, ibid., 22, 229 (1969). —‘——— A. W. Johnson and W. R. Overend, J. Chem. Soc., Perkin I, 268 (1972). A. Gossauer, "Die Chemie der Pyrrole", Springer-Verlag, Berlin, 1974. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 109 H. Fischer, P. Halbig and B. Walach, Liebigs Ann., 452, 297 (1927). H. Fischer and R. Baumler, ibid., agg, 83 (1929). A. Markovac and S. F. MacDonald, Can. J. Chem., 43, 3364 (1965). H. Fischer and H. Scheyer, Liebigs Ann., 434, 245 (1923). J. P. Collman, S. R. Winter and D. R. Clark, J. Amer. Chem. Soc., 94, 1788 (1972). A. Corvaisier, Bull. Soc. Chim. France, 528 (1962). E. C. Horning, J. Koo, M. S. Fish and G. N. Walker, Org. Syn., Coll. Vol. IV, p. 408. M. Farnier and P. Fournari, Bull. Soc. Chim. France, 2335 (1975). H. Fischer and B. Walach, Liebigs Ann., 450, 128 (1926). H. Fischer and A. Treibs, ibid., 450, 146 (1926). P. Rothemund, J. Amer. Chem. Soc., 51, 2010 (1935). D. Mauzerall, ibid., 82, 2601 (1960). G. P. Arsenault, E. Bullock and S. F. MacDonald, ibid., 82, 4384 (1960). H. Fischer and G. Stangler, Liebigs Ann., 459, 53 (1927). J. A. Ballantine, A. H. Jackson, G. W. Kenner and G. Mc Gillivary, Tetrahedron, Suppl. 7, 241 (1966). A. H. Corwin and E. C. Coolidge, J. Amer. Chem. Soc., 14, 5196 (1952). A. H. Jackson, G. W. Kenner, G. McGillivary and G. S. Sach, ibid., 81, 676 (1965). R. L. N. Harris, A. W. Johnson and I. T. Kay, J. Chem. Soc., (C), 22 (1966). J. Ellis, A. H. Jackson, A. C. Jain and G. W. Kenner, ibid., 1935 (1964). J. L. Davis, J. Chem. Soc., (C), 1392 (1968). Private communication to my groupmate, Mr. Fred Batzer. 110 57. J. M. Patterson, Synthesis, 281 (1963). 58. E. Baltazzi and L. I. Krimen, Chem. Rev., 511 (1963). LB mm)) 19 WY“) 1111111115