[CONTRIBUTION FROM S I C H O L S
LABORATORY, XEW
YORK UNIVERSITY]
FORMYLATION AND CYANOETHYLATION OF SUBSTITUTED INDOLES R. C. BLUME'
AND
€I. G. LINDWALL
Receiaed March 14, 1945
The preparation of aromatic aldehydes by the use of N-methylformanilide And phosphorus oxychloride was first accomplished by Vilsmeier and Haack (1) who used this method for the synthesis of p-alkylaminobenzaldehydes. In a series of patents, Kalischer, Scheyer, and Keller (2) reported that the reaction is applicable to certain phenolic ethers and aromatic hydrocarbons, and these claims were verified by Wood and Bost (3). Application of the reaction to indole derivatives unsubstituted in the 3-position was made by Wolff and Werner (4) who prepared 2-phenylindole-3-aldehyde,l-methy1-2-phenylindole-3-aldehyde, and others. The preparation of 2-phenylindole-3-aldehyde by the method of Wolff and Werner has been repeated; consistently high yields (90%) were obtained . Io *,!der to establish the structure of 2-phenylindole-3-aldehyde with greater certainty, it was prepared from 2-phenylindole by the use of the Reimer-Tiemann reagents, chloroform and potassium hydroxide. The modification employed by Boyd and Robson (5) in the preparation of other indole-3-aldehydes w m used. Melting point methods showed the aldehyde samples from the two sources to be identical.
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I1
I11
KO attempt was made to prove that the by-product (111) was 2-pheny1-3chloroquinoliie; it was assumed to be that, since in all other similar instances (5, 6, 7) 3-chloroquinolines have been produced. Like indole-3-aldehyde (11), 2-phenylindole-3-aldehyde may be N-alkylated using alkyl sulfates. In this way the 1-methyl and the 1-ethyl derivatives were prepared. Many patents, for example that granted the I. G. Farbenindustrie A.-G. in 1933 (8),have dealt with addition reactions of amines and imines with acrylonitrile. The preparation of 1-(2'-cyanoethy1)-2-phenylindole (IV) by this procedure has been described (9). Since Bruson (10) has shown that active positions other than amino and imino may undergo cyanoethylation, it seemed possible that the structure of IV was open to question. The matter of structure was settled in this way: A sample of the known 2-phenylindole-3-aldehyde, prepared by the method of Wolff and Werner (4),was subjected to cyanoethyb 1
Present address: E. I. duPont de Nemours and Co., Waynesboro, Va. 255
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R . C. BLUME S N D H. G. LINDRALL
tion. Also, a sample of I V was formylated. Each of these procedures should result in the formation of 1-(2’-cyanoethyl)-2-phenylindole-3-aldehyde(V) if the structure of ITr was correctly postulated. The samples of V produced by the two methods were found to be identical; hence, it can be stated that cyanoethylation of 2-phenylindole occurs a t position 1, as had been reported (9).
CHZ CH?C S
V In order t o demonstrate the general applicability of N-cyanoethylatino of indole-3-aldehydes, this reaction was used with 2-methylindole-3-aldehyde and with indole-3-aldehyde; respectively, l-(2’-cyanoethyl)-2-methylindole-3aldehyde and 1-(2’-cyanoethyl)indole-3-aldehydewere produced. Pyrrole was similarly treated with acrylonitrile and the resulting 1-(2’-cyanoethy1)pyrrole was hydrolyzed to yield P-(l-pyrroly1)propionic acid. These products have previously been prepared by Clemo and Ramage (12) by different methods. EXPERIMENTAL
8-Phenylindole-$-aldehyde(iI). A mixture was prepared consisting of 2 g. of 2-phenylindole, 40 cc. of 95% ethyl alcohol, and 15 cc. of chloroform. This mixture was heated under reflux and was vigorously stirred while n solution of 25 g. of potassium hydroxide in 25 cc. of water was added over a period of one and one-half hours. The mixture was heated further under reflux for one hour, cooled, and the potassium chloride was removed by filtration. The alcoholic solution was steam distilled; after removal of the solvent further distillate appeared as a white solid, which presumably Tvas the by-product, 2-phenyl-3-chloroquinoline (111). The dark residue was recrystallized from alcohol and was obtained as small needles, m.p. 253-251’. The melting point of a sample mixed with 2-phenylindole-3-aldehyde prepared by the method of Wolff and Werner (4) was also 353-254”. Yield, 1.21 g. (52%) . Anal. Calc’d for CI6H1,NO:C, 81.4; H, 4.98; Y , G.33. Found: C , 81.2; H, 5.06; S , 6.03. Compound III. The by-product obtained in the preparation of I1 was recrystallized from 70% ethyl alcohol and fron isopropyl alcohol, m.p. 92.5-93”. Anal. Calc’d for CL6HI&lX:N, 5.86. Found: X , 5.78. S-Phsnylindole-3-aldoxime.M .p. 184 .5-185”. Anal. Calc’d for C15Hl,N20:N , 11.9. Found: N, 11.63. Semicarbazone of 8-phenylindole-S-aldehyde. M.p. 238” (decomp.) Anal. Calc’d for ClpHIJJnC): C , 69.1; IT, 5.04. Found: C, 68.8; H, 5.28. p-Nitrophenylhydrazone of IT. S1.p. 281” (decomp.) Anal. Calc’d for CylH,,N,02. S , 15.7. Found S , 15.6. 1-(2’-Cyunoethyl)-$-phenyZindole (9). To 3.6 g. of %phenylindole in 10 cc. of dioxane was added 0.3 cc. of 40% trimethylbenzylammonium hydroxide (“Tryton-R”) . The resulting solution was treated with 1.4 cc. of acrylonitrile and was warmed t o 60’. After standing overnight, gray-green needles had separated. The mixture mas neutralized with phosphoric
FORMYLITIOM AKD CTANOIETHYLATION OF INDOLES
257
acid and 20 cc. of water was further added. The product was recrystallized from 95% ethyl alcohol, and was obtained as colorless needles, m.p. 86.5-89". Yield, 3.6 g. (80%). -4nal. Calc'd for CI,Hl&2:N , 11.4. Found: S ,11.2. 1- (2'-('yanoethyl) -2-phenylzndole-3-aldehyde (1'). Method A: A solution of 2.5 g . of 1-(2'-cyanoethyl)-2-phenylindole in 2 cc. of o-dichlorobenzene and 2.7 g. of methylformanilide was treated with 1.6 cc. of phosphorus oxychloride after being cooled to 15". The solution rapidly became dark red. After remaining for twenty-four hours at 1O-15", a solution of 3 g. of sodium acetate in 5 cc. of water was stirred into the red syrup. The solvents were removed by steam distillation and the residual pink mass was recrystallized from 95% ethyl alcohol yielding crystals which sintered a t 145" and finally melted at 151-153'. Yield, 1.5 g. (60%)). Method B: To 3 2 g. of 2-phenyliiidole-3-aldehydesuspended in 50 cc. of dioxane was added 0.1 cc. of 40% trimethylbenzylammonium hydroxide and 0.68 CC. of acrylonitrile; reaction was complete only after standing a t room temperature for three days. The produrt was obtained by diluting the solution with water. The long colorless needles melted a t 151-153' after sintering at 1.17'. Rec:rystallization from ethyl acetate raised the melting point t o 155-156.5'. Mixed with a similarly purified product obtained by Method A, there was no depression of the melting point. Yield, 2.5 g. (9070). Anal. Calc'd for C18HlaS20: N , 10.2. Found N, 10.2. Oxime of V. M.p. 211" (decomp.) Anal. Calc'd for CleH&aO: S , 14.54. Found K,14.44. l-Methyl-S-phenylindole-3-aldehycle. A suspension of 2.2 g. of 2-phenylindole-3-aldehyde in 30 cr. of 40% potassium hydroxide was warmed t o about 60'. To this mixture was added 6 cc. of dimethyl sulfate in 1-cc. portions a t five minute intervals, with frequent shaking; shaking was continued periodically as the mixture was heated in a water-bath for an hour. Upon cooling, a crystalline mass separated which was washed with water. Recrystallization from dilute alcohol yielded 1.85 g. (80%) of colorless platelets; m.p. 122.5-124°. Anal. Calc'd for CleHlsNO: N , 5.94. Found N , 6.10. 1- M e t hyl-2-phenylindole-3-aldoxime. M.p. 178-178.5'. Baal. Calc'd for C 1 ~ H 1 5 9X, ~ 011.2. : Found: N, 11.2. 1-Ethyl-2-phenylindole-%aldehyde.This compound was prepared by the same method as the I-methyl analog described above, using diethyl sulfate. Prisms from ethyl alcohol, m.p. 104.5-105.5". Yield, 70%. Anal. Calc'd for C17Hlar\'O:S , 5.62. Found: N, 5.68. l-Eth,yl-8-phenylindole-d-aldoxime. M.p. 196197' (decomp.). Anal. Calc'd for Cl,HlsN~0:N , 10.6. Found: N , 10.5. 1-(8'-Cyanoethyl)indole-3-aZdehyde.Indole-3-aldehyde (1.45 g.) and 0.7 cc. of acrylonitrile were added to 10 CC. of dioxane containing 0.5 CC. of 40% of trimethylbenzylammonium hydroxide. After warming to effect solution, the reactants were allowed t o stand at room temperature for twenty-four hours; the product was precipitated by adding 10 CC. of 10% acetic acid. Recrystallized from ethyl acetate, m.p. 127-127.5". Yield, 1.35 g. Anal. Calc'd for CloHloN20: N , 14.1. Found: N, 13.9. 1- (2'-CyaPaoethyl)indole-d-aldoxime. M.p, 180-181' (decomp.) . Anal. Calc'd for CI~H1&;lO:N , 19.7. Found: N , 19.4. 1-(2'-Cyanoeth~l)-8-methylzndole-d-aldehyde. This compound was prepared by the BCtion of acrylonitrile upon 2-methylindole-3-aldehyde following a procedure identical with t h a t described above. Recrystallized from ethyl acetate as colorless needles, m.p. 148149". Anal. Calc'd for C18H12N20:PI;, 13.2. Found: K, 13.2. l-(d'-Cyanoetkyb)-8-methylindole-S-aldoxime. M.p. 181-182" (decomp.). Anal. Calc'd for ClsHtsNaO:N, 18.5. Found: 9, 18.4. p-(1-PyrrolyZ)propConicacid. Acrylonitrile (10 cc.) was added dropwise over a period of thirty minutes to a mixture of 10 g. of pyrrole and 1 cc. of trimethylbenzylammonium hydroxide; the temperature was kept below 40". After one hour at room temperature, the crude nitrile was hydrolyzed (without isolation I by refluxing for one hour with a solution
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R. C. BLUME AND H. G . LINDWALL
of 10 g. of potassium hydroxide in 15 ec. of water. The product was isolated by acidification with hydrochloric acid and extraction with ether; b.p. 125-135”/3 mm.; m.p. 59-60’. Yield, 16.5 g. (80%). Anal. Calc’d for CrHoNO: N, 10.0. Found: K’, 10.2. SUMMARY
1. 2-Phenylindole-3-aldehyde has been prepared from 2-phenylindole using Reimer-Tiemann reagents. 2. 2-Phenylindole-3-aldehyde has been N-alkylated by the use of alkyl sulfates. 3. 1-(2’-Cyanoethyl)-2-phenylindole-3-aldehydehas been prepared by the formylation of 1-(2’-cyanoethyl)-2-phenylindole,and by the cyanoethylation of 2-phenylindole-3-aldehyde. 4. 1-(2’-Cyanoethyl)indole3-aldehydeand 1-(2’-cyanoethyl)-2-methylindole3-aldehyde have been prepared by the cyanoethylation of the respective aldehydes. 5. P-(1-Pyrroly1)propionic acid has been prepared through the use of cyanoethylation procedure. UNIVERSITY HEIGHTS,XER-YORK53, N. E’.
REFERENCES (1) VILSMEIERAND HAACK, Ber., 60, 119 (1927). (2) KALISCHER, SCHEYER, A N D KELLER,(I. G. Farbenind. A.-G.); Chem. Abstr., 23, 3933 (1929), U. S. Pat. 1,717,567;Chem. Abstr., 24, 3800 (1930), U. S. Pat. 1,763,557; Cheni. Abstr., 26, 1536 (1931), German Pat. 514,415; Chem. Abstr., 26,2734 (1931), German Pat. 519,444; Chem. Abstr., 26, 4412 (1931), U. S. Pat. 1,807,693. (3) WOODAND BOST,J . A m . (!hem. Soc., 69, 1721 (1937). (4) WOLFFAND WERNER,Chem. Abstr., 29, 5861 (1935); German Pat. 614,326. (5) BOYDAND ROBSON, Biochem. J . , 29,555 (1935). (6) BLAIKIEAND PERKIN, J . C‘hem.Sac., 126, 296 (19Z4). (7) ELLINGER, Ber., 99,2515 (1908). (8) I, G. FARBENIND. A-G., Chem. Abstr., 27,3483 (1933). French Pat. 742,358. (9) French Pat. 47,563 (1937); Chem. Abstr., a,4608 (1938). (10) BRUSON, J . Am. Chem. SOC.,64, 2457 (1942). (11) WIELAND et al., Ann., 613, 1 (1934). (12) CLEMO AND RAMAGE, J . Chem. Soc., 51 (1936).
