MAY
1961
1651
NOTES
structure I11 to the product of the action of iodine and sodium hydroxide a t room temperature on the semicarbazone of phenyl glyoxylic acid (VI) ana Girard3s4 in 1941 reported that this material was changed to 1-11 by hot alkali. More recently Gehlens proposed a cyanohydrazide structure, CsH5CONHNHCK, instead of structure I11 for the Bougault-Popovici compound, on the basis of its independent synthesis from cyanogen bromide and 1-benzoylhydrazine (VII). He also reported the synthesis of a compound considered to be 1-11 from 1-bcnzoylsemicarbazide (VIII) and alkali. Gehlen's proposal was criticized by Mautner and Kumber6 who showed that the cyanohydrazide structure was inconsistent with the physical and chemical properties of the Bougault-Popovici product, which Mautner and Kumber regarded as 111. They considered Young and Wit,ham's JOHN HARRISON LABORATORY OF CHEMISTRY product to be best represented by the tautomer IV, OF PENNSYLVANIA UNIVERSITY a view with which we agree. We thought, however, PHILADELPHIA, PA. that the physical and chemical dissimilarities of the (6) A petroleum hydrocarbon fraction (b.p. range 70two isomers might well be the result of skeletal, 74'). Sold by Skelly Oil Company, Kansas City, Mo. rather than tautomeric differences. For example, we considered it unlikely that tautomers I11 and IV would be so slowly interconTransformation of 2-Amino-5-phenyl-1,3,4verted that their individual Katsand Kb's could be oxadiazole to 3-Phenyl-1,2,4-triazolin-5-one determined ; however, the Bougault-Popovici product was found to be a weak base and IV a weak acid.6 As an alternative for I11 we were considering JOHN C. HOWARD A N D HOMER A. BURCH 2-amin0-5-phenyl-1,3,4-oxadiazole7~~ (IX) as the Received August l?4, 1960 structure for the Bougault-Popovici product when we discovered that Gehlen's cyanogen bromide reA survey of the literature pertaining to 3- action had been recently patented by Swaing as substituted 1,2,4-triazolin-5-ones reveals a state a method of synthesis for IX. We have now comof disorder caused by the contradict,ory claims of pared Swain's product with an authentic sample various workers. The 3-phenyl member, which may be considered YOOH typical of the series, can be described in part by CeH5C'NNHCONH2 the tautomeric structures I to IV. Argument as to whkh best represents the properties of the compound has created much confusion. I N-N BrCN
became cloudy. The precipitate obtained was removed by filtration and recrystallized from benzene-Skellysolve H ; yield, 2175, m.p. 144-145'. 4 (7)-Iodobenzimidaaole. Several attempts were made to prepare this compound by methods similar to those used for the preparation of 5(6)-iodobenzirnidazole. The only method which yielded the desired product started from the 4(7)-henzimidazolediazonium fluoborate prepared by the procedure described by Fisher and JoulliB.6 4(7)-Benzimidazolediazonium fluohornte (5 g., 0.0216 mole) was dissolved in 300 ml. of water and the resulting solution was added slowly with stirring to a solution of 3.57 g. (0.0216 mole) of potassium iodide in 10 ml. of water. Gas was evolved and the solution turned dark red. It was heated on a steam bath for 6 hr., cooled and neutralized with ammonium hydroxide. The precipitate formed was extracted with benzene in a Soshlet apparatus. It was recrystallized from benzene-Skellysolve H; yield, lo%, m.p. 188-189'. Anal. Calcd. for C7HhN21:C, 34.45; H, 2.07; N, 11.48; I, 52.01. Found: C, 34.33; H, 2.18: N, 11.38; I, 51.83.
C~H~CONHN-CC-NH~ C- CSHSCONHNH2 v C6ZAOANH2 VI1 A
HN-N
r-
IX
" N
HN-YH r
u/N+o H IV
3-Phenyl-1,2,4-triazolin-5-one was first prepared
by Young and Witham' by the oxidation of benzaldehyde semicarbazone (V) with ferric chloride. They pictured the product as either I or 11. Nearly thirty years later Bougault and Popovici* assigned (1) 0.Young and E . Withani, J . Chem. SOC.,77, 224 1900). ' (2)'J. Bougault and L. Popovici, Compt. rend., 189, 188 (1929).
"";/ 1
L
p-
C6H5CONHNCONH2 VI11
C6H5CH=NNHCONH2
v
(3) M. Girard, Ann. Chim. (Paris),16, 383 (1941). (4) M. Girard, Compt. rend., 2 1 2 , 547 (1941). (5) H. Gehlen, Ann., 563, 185 (1949). (6) H. G. Mautner and W. I>. Kumber, J . A m . Chem. Soc., 77,4076 (1955). (7) R. StollB and K. Fehrenbach, J. Prakt. Chem., 122, 289 (1929). (8) E. Hoggarth, J . Chem. Soc., 1918 (1949). (9) A. P. Swain, U. S. Patent 2,883,391 (1959).
1652
VOL.
NOTES
of I X prepared by the thermal elimination of methyl mercaptan from 1-benzoyl-3-methyl-3-thioisosemicarbazide (X).* The compounds were identical with respect to melting point, mixed melting point and infrared spectrum. Thus it now is clear that the reaction of phenylglyoxylic acid semicarbazone (VI) with iodine and base actually yields 2-amino-5-phenyl-1,3,4oxadiazole (IX). The reaction of I X with hot sodium hydroxide solution to yield IV (whose properties in solution may of course resemble I, 11, and 111) can be pictured as the base-catalyzed ring cleavage of I X and subsequent ring closure on the nitrogen. It is interesting that the intermediate in this reaction is probably the same as in the reaction of 1-bensoylsemicarbazide (VTII) with base. THENORWICH PHARMACAL COMPANY NORWICH, N. Y.
N,N-Disubstituted Carboxamides as Agents for t,he Acylation of Pyrroles' GEORGEG. KLEINSPEHN* A N D ANDRBE. B R I O D ~
Received August 26,1960
Several pyrrolecarboxaldehydes and other acylpyrroles were prepared in this laboratory as intermediates for the synthesis of potential anticancer agentsla and for the prosecution of certain synthetic studieslb in the porphyrin area. The use of N,N-dimethylformamide and phosphoryl chloride for the formylation of pyrroles has been reported by a number of investigator^.^-" The utility and convenience of this formylation (1) This work was supported in part by ( a ) the Cancer Chemotherapy National Service Center, National Cancer Institute, National Institutes of Health, Contract Nos. SA-43-ph-1747 and SA-43-ph-1914 and in part by (b) Research Grant CY-3216 from the National Cancer Institute of the National Institutes of Health. (2) Present address: Ballistic Research Laboratories, Aberdeen Proving Ground, Md. (3) Present address: Sterling-Winthrop Research Inetitute, RenRselaer, N. Y. (4) E. J.-H. Chu and T. C. Chu, J. Org. Chem., 19, 266 (1954). (5) G. F. Smith, J. Chem. SOC.,3842 (1954). (6) R. M. Silverstein, E. E. Ryskiewicz, and S. W. Chaikin, J. Am. Chem. Soc., 76, 4485 (1954). (7) E. E. Ryskiewicz and R. M. Silverstein, J. Am. Chem. SOC.,76, 5802 (1954). (8) R. A. Nicolaus and L. Mangoni, Ann. chim. (Rome), 46, 865 (1956); Chem. Abstr., 51, 6600i (1957). (9) E. Ghigi and A. Drusiani, Atti accad. sci. ist. Bologna, CZusse sci. fis., 11, No. 3, 1 (1956); Chem. Ahstr., 51, 6602d (1957). (10) E. Ghigi and A. Drusiani, Atti accad. sci. ist. Bologna, Chem. Abstr.., 52.. Classe sei. fis.. 11. No. 4. 14 (1957): . 118188 (19&).' ' (11) R. Rips and N. P. Buu-Hoi, J. Org. Chem., 24, 372 (19591. I ,
26
method prompted us to examine N,N-disubstituted carboxamides of homologous cafboxylic acids as potential agents for the introduction of ot,her acyl groups into pyrroles under relatively mild conditions. Vilsmeier and Haack12 were t,he first to demonstrate the utility of N,N-disubstituted formamides for the formylation of aromat,ic systems. The formation of a quinaldine derivative from N-methylacetanilide and phosphoryl chloride had been observed earlier by Fischer, Muller, and Vilsmeier,13 and it was suggested12that this condensation might, have proceeded via the o-acetylation of the anilide. Despite this observation, the use of N,N-disubstituted carboxamides and phosphoryl chloride by subsequent investigators for the acylation of aromatic nuclei appears to have been lirnitedl3" to formylation with formamide derivatives. In an effort to extend the scope of the acylation method, we first attempted acetylation of the pyrrole ring with N,N-dimethylacetamide. This reagent with phosphoryl chloride was found to convert ethyl 2,4-dimethyl-3-pyrrolecarboxylate (I) to its 5-acetyl derivative (11). Similarly 2,5-dimethylpyrrole afforded 3-a~etyl-2~6-dimethylpyrrole(V). In ord.er to test further the generality of the reaction, acylation with the more complex carboxamide; N - (p carbomethoxypropionyl)piperidine (VI),14 was attempted. Amide VI, prepared from methyl p-(chloroformyl) propionate and piperidine,
-
3 I. R = H 11. R=C-CH,
V
6
111. R = C-CHz-CHz-COOCH3
b
IV. R = C-CBHS
a
H3COOC-CHz-CHz-C-N
/CHz-cHz
8
\CHz \CH~-CH~ /
VI /CH~-CHZ CeHsC-N
A
\o
\ C H ~ - C H ~/ VI1
(12) A. Vilsmeier.and AlHaack, Ber., 60, 119 (1927). (13) 0. Fischer, A. Miiller, and A. Vilsmeier, J . prakt.. Chem., 109, 69 (1925). (13a) NOTEADDEDIN PROOF.Following the completion of this"work and its acceptance for publication, the acylation of certain indoles and of pyrrole usingvvarious N,N-disubstituted carboxamides and phosphoryl chloride:was*recently reported. See W. C. Anthony, J. Org. C h . , 25, - a 4 9 (igso). (14) M. SemonskO and A. Cern?, Chem. &sty, 47, 281 (lj53); Chem. Abstr.; 49, 233a (1955).
