Nov. 20, 1954
SYNTHESIS OF @,~-DIPYRRYLPROPIONIC ESTERS
[CONTRIBUTION FROM THE CHEMICAL
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LABORATORIES OF THE JOHNS HOPKINS UNIVERSITY]
The Synthesis of Some p,p-Dipyrrylpropionic Esters1j2 BY GEORGE G. KLEINSPEHN AND ALSOPHH. CORWIN RECEIVED MAY19, 1954 Appropriately substituted B$-dipyrrylpropionic esters are of potential interest as intermediates in a proposed synthetic approach to porphyrins closely related to chlorophyll a. Two condensation methods have proved useful for the preparation of certain P,B-dipyrrylpropionicesters. The structure of the first prepared of these compounds has been confirmed through degradation in order to authenticate both of the condensation methods by which it was synthesized. Three B,B-dipyrrylpropionic esters have been prepared in all. One of these is isomeric with a P,P-dipyrrylpropionicester which is potentially a synthetic precursor of chloroporphyrin e6 and other closely related porphyrins.
The total synthesis of pheoporphyrin a6 by Hans Although numerous dipyrrylmethanes with a Fischer and co-workers still stands as an unique variety of substituent groupings on the methane achievement in its field. The presence in pheopor- bridge have been prepared,I2 in no instance has the phyrin US of both the 9-oxo and 10-carbomethoxy synthesis of a P,P-dipyrrylpropionic ester been regroupings renders its isocyclic ring structurally ported. For this reason the exploration of possible identical with that of chlorophyll a. I n no other synthetic routes to @,B-dipyrrylpropionic esters reported instance has the unequivocal total syn- was undertaken. thesis of a porphyrin or chlorin containing such an A majority of both bridge-substituted and bridgeisocyclic ring been accomplished. The successful unsubstituted dipyrrylmethanes prepared up to the synthetic sequence devised by Fischer consisted in present time have been obtained by the acid-catafirst preparing r - p h y l l ~ p o r p h y r i n an , ~ ~appropri~ lyzed condensation of one mole of an aldehyde or keately substituted y-methylporphyrin with a free 6- tone with two moles of an a-free or @-freepyrrole. position ; then subsequently incorporating the iso- Application of this rather general method to the cyclic ring into this porphyrin through a series of synthesis of a j3,P-dipyrrylpropionic ester would refurther synthetic transformation^.^-' Attempts quire formylacetic ester as the aldehyde moiety. to extend this method to the total synthesis of However, the tendency of this particularly reactive mesopheophorbide a,8-10aof pheophorbide a and intermediate to undergo self-condensation is reits 2-acetyl and 2-hydroxyethyl analogsloband of 2- portedly so greatla that free formylacetic ester itdesvinylpheophorbide ull have been reported, but self has not been isolated. It thus seemed advisin none of these instances has the achievement of a able to conduct exploratory condensation experitotal synthesis been rigorously demonstrated. Up ments with a somewhat less labile, though structurto the present time the method has thus proved ally similar, intermediate, and the ethyl hydrogen inapplicable to the total synthesis of chlorophyll a. oxalacetate (11) of W i ~ l i c e n u s ~ was ~ ~selected ~~~J~~ A proposed alternative synthetic route to por- for this purpose. Fischer and Gademannl' had prephyrins and chlorins of this type is now under inves- viously investigated the condensation of closely retigation in this Laboratory. As a part of the pro- lated pyruvic acid with 3-carbethoxy-2,4-dimethylgram i t has been proposed to explore the possibility pyrrole (111). The a,a-dipyrrylpropionic acid strucof synthesizing porphyrins of the type of pheopor- ture which they assigned to the product is in all phyrin a6 or chloroporphyrin ee directly from two probability correct, although no proof of structure dipyrryl intermediates, one of which already con- was undertaken. tains all of the structural features essential for the I t was anticipated that reaction of ethyl hydrofacile production of the isocyclic ring. A P,P-dipyr- gen oxalacetate(I1) with pyrrole I11 would afford rylpropionic ester of the type of I is just such an in- an ethyl hydrogen gem-dipyrrylsuccinate which termediate and is therefore of potential interest might, it was hoped, be made to undergo subsequent from the synthetic standpoint. decarboxylation to yield 0,p-dipyrrylpropionic ester IV. Actually the condensation of one mole of I1 COOR with two moles of pyrrole I11 in refluxing glacial I acetic acid has been found to proceed smoothly with attendant decarboxylation to afford I V directly. The successful preparation of I V from I1 and .. .. H H I11 prompted us to examine a closely related alterI native synthetic approach to IV. The key intermediate for our investigation was the already (1) Studies in the Pyrrole Series. XXV. Paper XXIV, G . G . Kleinspehn and A. H. Corwin, THIS JOURNAL, 7 6 , 5295 (1953). known 4, a-dicarbethoxy-3, 5-dimethyl-2-pyrrole(2) This work was carried out under a research grant from the acrylic acid (VI).IBb Kiister and co-workers had National Science Foundation. (3) H. Fischer and H. Helberger, Ann., 480, 255 (1930). (4) H. Fischer, W. Siedel and L. le T. d'Ennequin, ibid., 600, 167 (1933). (5) H. Fischer and H. Kellermann, ibid., 694, 25 (1936). (6) H.Fischer and E. Stier, ibid., 649, 224 (1939). (7) H. Fischer, E. Stier and W. Kanngiesser. ibid., 648,258(1940). ( 8 ) H. Fischer and I?. Gerner, ibid., 663, 67 (1942). (9) H.Fischer and M . Strell, ibid., 666, 224 (1944). (10) H.Fischer and F. Gerner, ibid., 669, (a) 77,(b) 84 (1948). (11) M. Strell and A. Kalojanoff, ibid.. 677, 97 (1952).
(12) H. Fischer and € Orth, I. "Die Chemie des Pyrrols," Vol. I, Akademische Verlagsgesellschaft m.b.H., Leipzig, 1934,pp. 361-359. (13) M.Cogan, Bull. SOC. chim., 8, 125 (1941). (14) W. Wislicenus, Ber., 19, 3226 (1886). (15) W. Wislicenus, Ann., 946 (a) 318; (b) 323 (1888). (16) W. Wislicenus and A. Endres, i b i d . , 391, (a) 373, (b) 381 (1902). (17) H. Fischer and H. Gademann, ibid., 660, 196 (1942). (18) W. Kltster, E. Brudi and G. Koppenhtifer, B e . , 68, (a) 1018, (b) 1019 (1026).
5642
Vol. 76
GEORGEG. KLEINSPEHN AND ALSOPH H. CORWIN COOCiHs I CHz
H ~ C Z O O C ~ C+ H IT=o I
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COOCzHj CHz I CHsmCOOCzH.
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COOCzHs THs I
CHj
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a
this instance the potential methane bridge with its IV substituent grouping is already bonded to one of obtained a-carbethoxyacrylic acid VI from the al- the pyrrole units prior to the condensation. Thus dehyde VII'9,20via the a-carboxyacrylic acid VIII, with respect to the production of P,P-dipyrrylpropiwhose monosilver salt afforded VI upon reaction onic esters in which the two pyrrole units are difwith ethyl iodide. We have found that VI may be ferent, the method is inherently less ambiguous than prepared from the aldehyde by either of two other the ethyl hydrogen oxalacetate method. Since our methods : (A) alkaline monohydrolysis of the projected synthetic approach either to chlorophyll n known triester I X , l S a v 2 l which is obtained by con- or to closely related porphyrins requires just such densation of VI1 with diethyl malonate; (B) con- unsymmetrical dipyrrylpropionic ester intermedidensation of VI1 with ethyl hydrogen malonate to ates, this is an important consideration. afford VI directly. In order to establish the structure of IV and thereby definitely preclude the rather HbCzOOCCHs unlikely possibility that both condensa--+ C H ~ [ ~ ~ C H = C tions ( ~ might ~ ~ ~ have ~ ~ afforded ~ the isomeric H H COOCJL a$-dipyrrylpropionic ester (X), the degradation of 1V to the known 1,l-dipyrrylethane (XII)22 was undertaken. Saponification of IV with one mole of base HsCzOOC-CH3 H~CIOOC-CH~ effected a selective hydrolysis of the proiiCH;=C
