1546
GEORGEG. KLEINSPEIIN
was recrystallized from benzene to give an additional 11.5 Total yield was 35.5 g. (80%). Annl. Calcd. for ClrHlzN204: C , 61.8; H, 4.42; N, 10.30. Found: C, 61.93; H, 4.60; N,10.37. 2,2'-p-Phenylenebis-[4-isobutyl-5(4H)-oxazolone] .-Fifty grams of N,N'-terephthaloylbis-(dl-leucine) (0.128 mole) was treated with 250 ml. of acetic anhydride as above to yield 30 g. (65% yield) of large white crystalline flakes after recrystallization from benzene, m.p. 167'. Anal. Calcd. for C ~ O H Z ~ N ZC, O ~67.4; : H, 6.7; N, 7.87. Found: C, 67.6; H,6.92; N,8.00. 2,2'-p-Phenylenebis-[4,4-dimethyl-5(4H)-oxazolone] Fifty grams of S,N'-terephthaloylbis-(a-arninoisobutyric acid) (0.149 mole) was heated in 500 ml. of acetic anhydride a t 120" for one-half hour. During this time, the solid failed to dissolve but became more crystalline in appearance. After recrystallization from chloroform, there was obtained 32 g. (72% yield) of small white crystals, m.p. 260' (sublimes). Anal. Calcd. for CleHlaN204: N, 9.34. Found: N, 9.12. 2,2'-p-Phenylenebis-[5(4H)-oxazolone].-Two grams of S,N'-terephthaloylbis-(glycine) (0.071 mole) was heated in 40 ml. of refluxing acetic anhydride for 15 minutes. The solid failed to dissolve but became more crystalline in appearance. After recrystallization from a large volume of dioxane, there was obtained essentially a quantitative yield of white crystals, m.p. 245' dec. Anal. Calcd. for C I Z H ~ N Z OC, ~ : 59.0; H , 3.28; PIJ, 11.49. Found: C , 58.9; H , 3.43; N, 11.53. 2,2'-Tetramethylenebis- [4,4-dimethyl-5(4H)-oxazolone]. -Ten grams of N,N'-adipoylbis-(a-aminoisobutyric acid) g. of colorless crystals.
.-
[CONTRIBUTION FROM
THE
Vol. 77
(0.0316 mole) was warmed with 25 ml. of acetic anhydride on a steam-bath for 20 minutes. After cooling and recrystallization from benzene, there was obtained 8 g. (8241, yield) of crystals, m.p. 108-109". Anal. Calcd. for CllHzoN2O4: C, 60.00; H, 7.15; S, 10.00. Found: C, 59.29; H, 7.07; N, 10.04. 2,2'-Dimethylenebis- [4,4-dimethyl-5(4H)-oxazolone].Two grams of N,N'-succinoylbis-(a-aminoisobutyric acid) (0.07 mole) was treated as above with 20 ml. of acetic anhydride and the product recrystallized from a benzenepetroleum ether mixture to yield about 0.5 g. or white crystals (ca. 25% yield), m.p. 102-103'. Anal. Calcd. for C1~HlsN~04: C, 57.2; H, 6.35; N, 11.10. Found: C,57.3; H, 6.40; N, 11.5. 2,2 '-Tetramethylenebis-( spiro-[cyclohexane- 1,4'-oxazol]J'(4'H)-one).-Five grams of N,N'-adipoylbis-( l-aminocyclohexanecarboxylic acid) (0.013 mole) was treated as above with 20 ml. of acetic anhydride and the product recrystallized from a benzene-petroleum ether mixture to yield ca. 2.5 g. of white crystals (ca. 60% yield), m.p. 109-111'. Anal. Calcd. for CgoH28NzO4: C, 66.66; H, 7.78; N, 7.78. Found: C, 66.76; H, 7.88; N, 7.85. Evidence was also obtained for the synthesis of 2,2'tetramethylenebis-[4-isobutyl-5(4H)-oxazolone]and 2,2'tetramethylenebis-[5(4H)-oxazolone]. These products were liquids which decomposed during distillation, and complete purification was not effected.
Acknowledgment.-The authors wish to thank Dr. W. A. Gregory of the Grasselli Chemicals Department for suggesting this route to cliazlactones. WILMIVGTON, DEIAWARE
CHEMICAL LABORATORIES OF THE
JOHNS
HOPKINSUNIVERSITY]
A Novel Route to Certain 2-Pyrrolecarboxylic Esters and Nitriles',' BY GEORGE G. KLEINSPEHN RECEIVED SEPTEMBER 7, 1984 Diethyl oximinomalonate undergoes reduction and condensation with certain p-diketones and a @-ketoaldehyde t o give 2-pyrrolecarboxylic esters. Similarly, ethyl oximinocyanoacetate and certain @-diketones afford 2-pyrrolecarbonitriles. The method has been applied to the synthesis of five previously known pyrroles: 2-carbethoxy-3,5-dimethylpyrrole,2carbethoxy-4-ethyl-3,5-dimethylpyrrole, 5-carbethoxy-2,4-dimethyl-3-pyrrolepropionicacid, 2-carbethoxy-3,4-dimethylpyrrole and 4-ethyl-3,5-dimethy1-2-pyrrolecarbonitrile.This synthetic approach constitutes the most direct route to four 3,5-dimethyl-2-pyrrolecarbonitrile, also has been prepared of these five Dvrroles. A sixth and Dreviouslv unreDorted Dvrrole, .. by this met&d.
A little more than a decade ago Fischer and Fink,3 pyrrole, in good yield. From the mother liquor, while attempting a Knorr-type reductive condensa- however, Fischer and Finka were able to isolate 2tion4 of ethyl a-oximinoacetoacetate with the di- carbethoxy-3,5-dimethylpyrrole(V), the product ethyl acetal of 3-oxobutyraldehyde, observed the arising from the new-type condensation, in a yield unexpected formation of 2-carbethoxy-5-methyl- amounting to a few tenths of 1%. A subsequent pyrrole. Thus it became apparent that in this publication5 by these investigators reports t h a t instance a new type of pyrrole ring-synthesis involv- two more p-ketoaldehydes have been found to uning the cleavage of the acetyl group of ethyl a-oxim- dergo the new-type condensation, and CooksonBreinoacetoacetate was occurring in preference to the cently has elucidated a further example of a cyclizaanticipated Knorr condensation. Reinvestigation tion of this same general type. I n the interest of achieving a more direct synof the reductive condensation of ethyl a-oximinoacetoacetate with 2,4-pentanedione (11)by these same thetic route to certain 2-pyrrolecarboxylic esters workers3revealed that in the case of this P-diketone which are important intermediates in the preparathe new condensation does in fact compete, though tion of porphyrins and other polypyrryl comvery unsuccessfully, with the Knorr cyclization. pounds, it was decided to attempt a series of conAs has long been known, this reaction affords the densations closely related to those reported by Knorr product, 4-acetyl-3,5-dimethyl-2-carbethoxy-Fischer and Fink, but employing diethyl oximinomalonate (I) rather than ethyl a-oximinoacetoace(1) Studies in the Pyrrole Series, XXVII. Paper XXVI, A. H. tate. It was anticipated that the use of I by preCorwin and K. W. Doak, THIS J O U R N A L , 77, 464 (1955). (2) This work was carried out under a research grant from the Nacluding the possibility of competing Knorr-type tional Science Foundation. cyclizations would both widen the scope of the con(3) H.Fischer and E. Fink, Z. physioi. Chem., 280, 123 (1944). (4) H. Fischer and H. Orth, "Die Chemie des Pyrrols," i'ol, I, Akademische Verlagsgesellschaft m. b. H., Leipzig, 1934, pp. 3-5.
(5) H. Fischer and E . Fink, Z phrsiol Ciiem , 283, 152 (1048) (6) G. H. Cookson, J . Chrm. SOL..2789 (1953).
March 20, 1955
2-PYRROLECARBOXYLIC
ESTERS AND NITRILES
1347
densation and afford more satisfactory yields of the this impurity could give rise to either or both of two additional pyrroles, it was necessary t o establish desired products. A reductive condensation of diethyl oximinomal- the structure of our condensation product b y cononate (I) with 2,4-pentanedione (11) was first car- verting it to a derivative, an authentic sample of ried out, and 2-carbethoxy-3,5-dimethylpyrrole which was available for mixed melting point deter(V) was obtained in a yield of 60%. Some 3-sub- minations. Thus our pyrrole was condensed with stituied 2,4-pentanediones were next employed in formaldehyde to give the corresponding pyrromeththe reaction. Thus, as is shown below, I under- ane, and this pyrromethane indeed proved identiwent reductive cyclization with 3-ethyl-2,4-pen- cal with 5,5'-methylenebis-(2-carbethoxy-3,4-ditanedione (111) and with y-acetyl-6-oxohexanoic methylpyrrole) (X). acid (IV)' to afford 2-carbethoxy-4-ethyl-3,5-di- The encouraging results obtained with diethylmethylpyrrole (VI) and 5-carbethoxy-2,4-dimethyl- oximinomalonate prompted us t o examine the pos3-pyrrolepropionic acid (VII), respectively, in good sibility of preparing 2-pyrrolecarbonitriles by reyield. Each of the pyrroles V, VI and VI1 was ductive condensation of ethyl oximinocyanoacetate (XI) with 0-diketones. While attempting such a CHI-C-CI-I-R condensation of 2,4-pentanedione (11) with XI, i t I/ I Zn was observed that the order of addition of the reH5cz00C>C=NOH + 0 C-CHIHsCzOOC Ii CHaCOOH actants affects the course of the reaction. Thus 0 when a solution of ethyl oximinocyanoacetate is I 11, R = H added slowly t o a stirred suspension of zinc dust 111, R = CHzCHs in a hot solution of 2,4-pentanedione, there results a IV, R = CH~CHZCOOH mixture of 2-carbethoxy-3,5-dimethylpyrrole(V) CH3-R with what is probably the corresponding nitrile I 1 V,R=H XII. From this mixture ester V may be isolated H,C,OOCSNj~cHI VI, R = CHzCH3 H VII, R = CHzCHgCOOH readily. If, however, zinc dust is slowly introduced with stirring into a hot solution of both XI identified by analysis and by mixed melting point and the /3-diketone 11, 3,5-dimethyl-2-pyrrolecarwith the authentic material. The novel synthesis bonitrile (XII) is formed in about 35% yield. of VI1 is of particular interest, for since the acid IV Under the latter reaction conditions, ethyl oximinomay be prepared from commercially available @- cyanoacetate and 3-ethyl-2,4-pentanedione(111) propiolactone and 2,4-pentanedinne by a one-step afford a 45% . yield of 4-ethyl-3,5-dimethyl-2pyrrolepropionic acid VI1 now becomes pyrrolecarbonitrile (XIII).1zs13 for the first time a rather directly accessible interCHI-C-CH-R mediate. NSC\ I1 I Zn I n order to investigate further the applicability -)C=NOH 0 e-CH3Ii CHICOOH of the cyclization reaction, a reductive condensa- HsC200C 0 tion of diethyl oximinomalonate (I) with the @-keXI 11, R = H toaldehyde, 2-methyl-3-oxobutyraldehyde (VIII), 111, R = CHICHI was next carried out. Curiously enough, melting CHI-R point data indicated the product to be 2-carbethoxy-3,4-dimethylpyrrole (IX)s,9 rather than the iY=d[$CH, XII, R = H isomeric 2-carbethoxy-4,5-dimethylpyrrolewhich H XIII, R = C H ~ C H I Fischer and Fink5 had obtained previously from Acknowledgment.-The author wishes to acthe analogous reductive cyclization of ethyl CYoximinoacetoacetate with VIII. knowledge the helpful consultation and continuing interest of Dr. Alsoph H. Corwin. CHs-C-CH-CH3
+
H5c200c)C=~~H HbCzOOC
il
+
I
0
I
Zn
II
CHICOOH
C-H
VI11 0
CHa-CH3
I1 II
1
L--
IX HCHO r lA 77
+
HjCzOOC H
X
H
It has been demonstrated recently by Royals and Brannock'O that VIII, as usually prepared, contains some isomeric 3-oxovaleraldehyde. Since
__
I
Experimental l4# 2-Carbethoxy-3,5-dimethylpyrrole (V).-The
diethyl oximinomalonate employed in this and subsequent preparations was obtained by the procedure of Cerchez.16 The crude product was not purified by distillation, but was heated on the steam-bath at 1-2 mm. for 1.5 hr. in order to remove some of the unchanged diethyl malonate. The following condensation procedure is based upon that described by Corwin and Quattlebauml' for the preparation of 2,4-dicarbethoxy-3,5-dirnethylpyrrole. A solution of 5.00 g. of 2,4-pentanedione (Carbide and Carbon) in 26 ml. of glacial acetic acid was placed in a 100-ml. three-neck flask equipped with a mechanical stirrer, dropping funnel, thermometer and gas exit. The solution was heated, and (11) H . Fischer and B. Walach, Ann., 460, 127 (1926). (12) H.Fischer, P.Halhig and B. Walach, i b i d . , 462, 296 (1927). (13) H.Fischer and Z. Csukas, ibid., 608, 183 (1933). (14) All melting points were determined on t h e Fisher-Johns melting
(7) T . L.Gresham, J. E. Jansen, F. W. Shaver, M. R. Frederick and W. L. Beesrs, THIS JOURNAL, 73, 2346 (1951). ( 8 ) H. Fischer and H . Hofelmann, A n n . , 533, 223 (1938). (9) W. Siedel, i b i d . , 664, 158 (1943). (10) E. E. Royals and K. C. Brannock, THIS JOURNAL, 76, 1180
point block. (15) Carbon s n d hydrogen microanalyses were performed b y Mr. Joseph A. Walter. (16) V. Cerchez, Bull. SOL. chirn. France, [ 4 ] 47, 1280 (1930). 68, (17) A. H.Corwin and W. M. Quattlebaum, Jr., THISJOURNAL,
(1954).
1083 (1936).
1548
GEORGEG.KLEINSPEIIX
Vol. 77
at 80" a mixture of 13 g. of anhydrous sodium acetate and was then added with stirring. Next 7.00 g. of the sodium saltz5 of 2-methyl-3-oxobutyraldehyde, 9.48 g. of diethyl 11 g. of zinc dust was added with vigorous stirring. At 95" the dropwise addition of a solution of 9.47 g. of diethyl oxi- oximinomalonate and a solution of 12 ml. of glacial acetic minomalonate in 12 ml. of acetic acid and 5 ml. of water was acid in 5 ml. of water mere consecutively introduced, and begun. T h e addition was completed in 30 t o 40 min. be- the mixture was heated to 95". Eleven grams of zinc dust tween 95 and 105", vigorous stirring being maintained con- was then added during several minutes between the limits stantly throughout. After heating t o 100-105" for a n addi- of 95 and 1 0 5 O , after which the reaction mixture was heated tional 20 min., the reaction mixture was poured with stirring and stirred for an additional 20 minutes. Pouring into 170 into 170 ml. of ice-water mixture, then refrigerated. The ml. of ice-water mixture caused the separation of a pale crude product was filtered off, washed with water, pressed yellow oil which soon solidified. After refrigeration of the on the filter then taken up in 50 ml. of boiling 95% ethanol. mixture, the product was filtered off, taken up in 10 ml. of After filtration of the hot mixture to remove the zinc dust, boiling ethanol and filtered t o remove the zinc dust. The the filtrate was concentrated to 30 ml., poured into 85 ml. pyrrole was then precipitated by pouring the filtrate into 20 of ice-water mixture and refrigerated. Filtration then nil. of ice-water mixture; yield 2.49 g. or 30% yield of crude afforded a product which after drying in vacuo weighed 5.03 product melting over a wide range. After one recrystallizag. (60% yield), m.p. 120-124'. Two recrystallizations tion from 957, ethanol followed by two more from isooctane from 95% ethanol afforded the analytically pure material the analytically pure product of m.p. 94-95' was obtained; of 1n.p. 124124.5"; mixed melting points with authentic lit.8,9m.p. 95-96". Y (m.p. 124.5-125O) prepared by the method of Fischer and Anal. Calcd. for CgH1302N: C, 64.65; H, 7.84; CzHsO, Walachl* showed no depression. 26.95. Found: C, 64.54; H, 7.85; CzH50,26.80. Anal. Calcd. for C ~ H I ~ O ~ TC,\ ' 64.65; : H, 7.84; C Z H ~ O , 5,5'-Methylenebis-(2-carbethoxy-3,4-dimethylpyrrole) 26.95. Found: C, 64.46; H, 7.86; C2Hb0,26.95. (X).ll-This methane was prepared from pyrrole I X by 2-Carbethoxy-4-ethyl-3,5-dimethylpyrrole(VI).ig-Fifty heating briefly in ethanolic solution with excess 40% formalmillimoles each of I and of 3-ethyl-2,4-pentanedi0ne~O?~~ dehyde and a few drops of concentrated hydrochloric acid. (b.p. 79-83.5" a t 23-23.5 mm.) were used. The procedure The product melted a t 202-203' and did not depress the was that employed for the preparation of V except that the melting point of a sampl; of the authentic methane SI1 crude product containing zinc dust was taken up in only 30 which melted at 200-202.5 ; lit." m.p. 198". ml. of boiling 95% ethanol. A65%yield or 6.36 g. of crude Anal. Calcd. for C19HZ604N2:C2Hs0, 26.01. Found: product (m.p. 81-89') mas obtained. Two recrystallizaC Z H ~ O26.01. , tions from 95% ethanol afforded the analytically pure prod2-Carbethoxy-3,5-dimethylpyrrole (V) from XI and 11.uct of m.p. 90-91'. Authentic VI prepared by hydrogenaThe procedure was t h a t employed for preparation of V from tion22 of the corresponding 4-acetylpyrrole in the presence I and 11. Fifty millimoles each of X I and I1 were used, of a palladium catalyst melted at 89.5-92'; admixture of and the crude product containing zinc dust was taken up in these two products caused no melting point depression. Anal. Calcd. for C11H1702N: C, 67.66; H , 8.78; CZHSO, 25 ml. of boiling 95% ethanol. The filtrate was then poured into 75 ml. of ice-water mixture t o precipitate the product, 23.08. Found: C, 67.60; H, 8.76; C2H50, 23.19. yield 2.48 g. of product melting in the range 63-110'. 5-Carbethoxy-2,4-dimethyl-3-pyrrolepropionicAcid (VII).lQ Three crystallizations from ethanol and subsequent sublima-7-Acetyl-6-oxohexanoic acid prepared by t h e method of tion i n vacuo afforded analytically pure V melting at 124Gresham, et al.,? was employed in this instance. However, 125". !io depression of the melting point was observed because the crystallization of this diketo acid I Y from the upon admixture with authentic V. rather viscous distillates proved slow and tedious,. purificaAnal. Calcd. for CgHI302N: C 2 H 5 0 , 26.95. Found: tion was achieved instead by repeated fractional distillation C2Hs0, 27.01. of the product, and t h e appropriate liquid fraction boiling 3,5-Dimethyl-2-pyrrolecarbonitrile(XII) from XI and 11.at 155-165" at 1.5 mm. was utilized directly in the syntheThe preparative procedure for obtaining XI1 is as follows. sis of VII. Fifty millimoles each of I and IV were employed in the Twenty-six milliliters of glacial acet: acid and 5.00 g. of condensation. The procedure was that described for the 2,4-pentanedione were heated t o 80 . Thirteen grams of preparation of V except for the following alteration. I n anhydrous sodium acetate, 7.11 g. of ethyl oximinocyanoorder t o effect complete solution of the pyrrole prior to re- acetate26 and a solution of 12 ml. of acetic acid in 5 ml. of moval of the zinc dust by filtration i t was necessary to add water were then ~onsecutivelyintroduced, and the mixture was heated to 95 . Zinc dust (11 g.) was then added during 5 ml. of concentrated hydrochloric acid to the 35 ml. of boiling ethanol. T h e hydrochloric acid presumably con- 20-25 min. between the limits of 95 and 105", and the inixverts some salt of the pyrrole acid which is present to free turc was heated and stirred for a n additional 20 min. Pouring the reaction mixture into 170 ml. of ice-water mixture 1.11. The crude product (7.08 g. or 59% yield) melted caused the separation of an oil which solidified upon refrigeraover a wide range, but was readily purified by recrystallization from boiling benzene. An analytical sample was ob- tion. The product was filtered off, taken up in 15 ml. of tained after three recrystallizations from benzene and sub- boiling ethanol and filtered to remove the zinc dust. The nitrile was precipitated by stirring the filtrate into 30 ml. of icesequent drying in vacuo a t 80-90" for one hour; m.p. 154water mixture and refrigerating. The crude nitrile weighed 156". Mixed melting points with authentic VI1 of m.p. 155-156' showed no depression. T h e authentic VI1 was 2.10 g. ( 3 5 7 , yield) and melted a t 60-73". Two recrystalliprepared by hydrogenationZ3 of the corresponding 3-pyr- zations from isooctane with centrifugation of the darkroleacrylic acid in glacial acetic acid in the presence of 5% colored, tarry impurities afforded the analytically pure material of m.p. 7576.5'. palladium-on-carbon . Anal. Calcd. for C1zHli04X: C, 60.24; H , 7.16; C?HsO: .4naZ. Calcd. for C i H 8 N 2 : C, 69.97; H, 6.71. Found: 18.83. Found: C, 59.96; H, 7.30; C2Hs0, 18.66. C, C9.82; H , 6.86. 2-Carbethoxyd ,4-dimethylpyrrole ( IX).24-Twenty-nine 4-Ethyl-3,5-dimethyl-2-pyrrolecarbonitrfie(XIII).-The milliliters of glacial acetic acid was heated to 85' in a 100- immediately preceding procedure was utilized in the prepa; ml. three-neck flask and 7.9 g. of anhydrous sodium acetate ration of XIII, 3-ethyl-2,4-pentanedi0ne20,~~ (b.p.79-83.5 a t 23-23.5 mm.) being substituted for 2,4-pentanedione; (18) H. Fischer and B. Walach, B e y . , 66, 2821 (1925). yield 3.35 g. of crude product or 4570. A single recrystalli(19) T h e author wishes t o acknowledge t h e collaboration of Dr. zation from ethanol-xvater afforded a product melting a t Anna Leone who first carried o u t this condensation employing a n elec135-136". A subsequent recrystallization from benzenetrolytic rather t h a n a zinc dust reduction. isooctane gave the analytically pure substance with un(20) N. P. Buu-Hol and D . Guettier. Rec. Ij.at8. hi^;;,, 6 5 , 505 changed melting point; lit.12313 m.p. 134'. (1946). Anal. Calcd. for C9H121--.:C, 72.94: H , 8.16. Found: (21) T h e author wishes t o thank M r . Peter M'ei for the preparation C , 72.91; H , 8.31. of this intermediate. (22) S. R. Buc, Dissertation, T h e Johns Hopkins University, 1938, BALTIMORE, MARYLASD pp. 56-58. (23) C . S . Vestling, J . Bioi. Chem., 156, 624 (1940). (21) T h e author wishes t o thank hlr. George T . McGrew who first carried out this preparation.
(25) A. H. Tracy a n d R. C. Elderfield, J . Orp. Chcm., 6, 66 (1941). (26) hl. Fields, D . E. Walz and S. Rothschild, THISJOI:RNAL, 73, 1001 (1931)
