[CONTRrBWTION FROM THE WILLIAM
H.NICHOLS LABORATORY, NEWYORK
UNIVERSITY]
STUDIES I N T H E BEYZINDOLE SERIES’ E. A. GOLDSMITHz AND H. G. LINDWALL Received October 6 , 1962
As a continuation of the many researches in the indole field carried out in this laboratory in recent years, the present work dealing with benzindoles was undertaken. There is a scarcity of information in the literature concerning such derivatives, and the majority of the published work deals with the SH-benz[e]and lH-benz[g]-indoles. At the inception of this work, only two literature references (1, 2) and two patents (3, 4) were found which dealt with the “linear” or 1H-benzjflindole structure. Liebermann (1) described several naphthoquinone derivatives, and Fierz-David and Tobler ( 2 ) recorded the preparation of the “linear” dibenzoindigo. Both of the patents (3, 4) covered the same material, the preparation of a halogenated benzoisatin, and were assigned to the same company. Since the completion of this work, however, several papers (5, 6, 7) have appeared which describe 5,6-benzoisatin, the corresponding oxindole and indoxyl, as well as several of their halogenated derivatives. Hinsberg and co-workers (8, 9, 10) reported the condensation of /3-naphthylamine with the glyoxal-bisulfite adduct to produce 3H-benz[e]indole-2-sodium sulfonate. From this, the oxindole, isatin, and indole analogs were prepared. Schlieper (11) prepared 3H-benz[e]indole, the 2-carboxylic acid, and l-methyl3H-benz[e]indole by cyclization of the /3-naphthylhydrazones of acetaldehyde, pyruvic acid, and acetone respectively. It is of interest to note that the free indole of Schlieper differs markedly from that of Hinsberg. The former author later prepared 1H-benz[g]indole-2-carboxylic acid, and the free indole as well (12). Mayer and Oppenheimer (13) also reported the syntheses of these two compounds, the first by reduction of 0-(l-nitr0-2-naphthyl-)pyruvic acid, followed by ring closure of the resulting amino acid, and the second by decarboxylation of the indole acid. However, the acid prepared by these workers differed from that of Schlieper (12). Hughes and Lions (14) synthesized 2-carboethoxy-3H-benz[e]indoleand the corresponding acid via the Japp-Klingemann reaction (15) and the Fischer synthesis (16), but here too a discrepancy was encountered, for the acid described by Hughes and Lions differed widely from that reported by Schlieper (11). More recently, Findlay and Dougherty (17) recorded the preparation of several more members of this series. Among the compounds reported mere 3H-benz[e]indole-1-acetic acid and 2-carboxy-3H-benz[e]indole-l-acetic acid. Finally, Rydon and Sidappa (18) carried out the syntheses of 4,5- and 6 )7-benzotryptophanes, compounds of interest as possible antibacterial agents. The synthetic approach has been continued in this research, with the purpose Abstracted in part from a dissertation submitted by Edwin A. Goldsmith in partial fulfillment of the requirements for the degree of Doctor of Philosophy, October 1949. 2 Present address : California Research Corporation, Richmond, California. 507
508
E. A. GOLDSMITH AND H. G. LINDWALL
CHART I 3H-BENZ[e]INDOLES
/& 117 9
I
R”
I
R -COOCzHs
R’ -H
-H
I1
-COOH
-H
-H
I11
-COOCzHr
COMPOUND
-H
-CHzN
\
CHa
IV
-COOCzH5
-CHzN
YH5 \
-H
C2H 5
CHzCHi
v
-H
-COOCzHs
/
\
CHzCHz
VI
-COOCzHs
-H
-CHzCH&N
VI1
-COOH
-H
-CHzCHzCOOH
VI11
-COOCzHs
-CHzN
-CH&H&N
\
CHa
IX
-COOC*H5
--CHzN
-CHzCHzCN
\
C2H5
X
-COOCzHs
/cH2CH2
\
\
/
-CHzN CHnCHz
0
-CHzCHzCN
509
STUDIES I N T H E BENZINDOLE S E R I E S
CHART I1 ~H-BENz[f]INDOLES
CHsO
R”
XI11
R -COOC?Hs
R’ -H
R” -H
XIV
-COOH
-H
-H
COWPOUND
CH3
XV
-COOC2H5
-CHzN
/
-H
\ CH3 CHzCHz
XVI
-COOC2Hb
-CHzN
/ \
\
-H
CHzCHz CzHs
XVII
-COOCzHs
-CH2N
/ \
-H
C2HS
XVIII
-COOCzHs
XIX
-COOCzHs
-H
-CHzN
-CHzCHzCN
/cH3 --CHzCH&N
\
CHa
XX
-COOCzH~
-CHzN
/CH2CHz \
\
/”
--CH,CHzCN
CH2CHz
XXI
-COOH
-H
XXII
-COOH
-CH2COOH
-CHzCHzCOOH
-H
of preparing and characterizing additional benzindole derivatives. Charts I and 11 list the compounds synthesized in the course of our work. Entry into the 3H-benz[e]indole series is rather easily accomplished, and 2-carboethoxy-3H-benz[e]indole(I) was prepared following the procedure of Hughes and Lions (14). This compound was used as a starting material for
510
E. A. GOLDSMITH AND H. G. LINDWALL
further work. It was obtained in 43 % yield as an orange crystalline compound, m.p. 164-165". (M.p. 161', ref. 14). It was not possible to obtain a completely colorless product by recrystallization, but a white material could be obtained by saponification, purification of the acid (11),and re-esterification. The acid (11) was obtained as lustrous silvery plates in 85 % yield upon recrystallization from aqueous ethanol, m.p. 224-226' with decomposition. This value is in agreement with the work of Schlieper ( l l ) , but widely divergent from that of Hughes and Lions (14), for the latter authors report the melting point as 160". This large discrepancy might be explained on the basis of the existence of polymorphic forms of the acid, but no evidence for the existence of a lower-melting form was obtained in this work. A number of tertiary amino esters were prepared via the Mannich reaction (19, 20), with the possibility in mind that such basic compounds might possess interesting pharmacological properties. The experimental procedures were based on those of previous investigators (21, 22). The syntheses of 2-carboethoxy-l-dimethylaminomethyl-3H-benz[e]indole (111) and of the corresponding 1-diethylaminomethyl- (IV) and l-morpholinomethyl- (V) derivatives were satisfactory, although the yield of (IV) was lower than those of (111) and (V), thus corroborating the observations of Blicke (20) as to the lower reactivity of diethylamine. illkaline hydrolysis of the amino esters was unsuccessful, no amino acids being isolated. The destructive effects of alkali on compounds of this type have been reported by Bell and Lindwall (22). Attempted acid hydrolysis led to the formation of deep blue decomposition products, and these proved to be insoluble in both acid and alkali. Following the procedures of Blume and Lindwall (23), it was possible to prepare the N-cyanoethyl derivative (VI) of I, and from this, the corresponding di-basic acid (VII) . In addition 3-@-cyanoethyl-2-carboethoxy-l-dimethylaminomethyl-3H-benz[e]indole (VIII), and the analogous 1-diethylaminomethyl- (IX) and 1-morpholinomethyl- (X) derivatives were prepared by cyanoethylation of the Mannich derivatives 111, IV, and V respectively. The yields were quite good in all cases. Entry into the 1H-benz[f]indole series necessitated the synthesis of a l-substituted-:!-naphthylamine as a starting material for the Japp-Klingemann reaction. Since Lellmann and Schmidt (24) had reported cleavage of an a-nitro and an a-chloro group in a quinoline synthesis involving &naphthylamines, such groups were considered too labile for our purposes. The compound selected was 1-methoxy-2-naphthylamine(XII), and it was converted to the desired intermediate 1-methoxy-2-naphthylhydrazoneof ethyl pyruvate upon diazotization and reaction of the diazonium salt with ethyl a-methylacetoacetate. The (XIII) in hydrazone was cyclized to 2-carboethoxy-9-methoxy-1H-benz[flindole 27 % over-all yields. The methoxy amine was prepared via a rather involved synthesis. Orange I1 was prepared from @-naphtholand sulfanilic acid (25), and this was reduced to 1-amino-2-naphthol hydrochloride (25). Oxidation with ferric chloride yielded &naphthoquinone (25), and the technique of Zincke (26,27) was used t o convert
STUDIES I N T H E BENZINDOLE SERIES
511
the quinone to 2-benzeneazo-l-naphthol. Methylation of the azo-naphthol proved to be quite difficult, for the procedures of McPherson (28) and of Noelting, et al. (29) gave yields of about 1% after purification. Methylation with methyl sulfate at temperatures as high as 85" did give an approximately 15 % conversion, but separation of the reaction product from unreacted naphthol was a long and tedious process. The naphthol is but slightly soluble in aqueous alkali, and repeated extractions with hot concentrated base were necessary to separate it from the product. This was decidedly unsatisfactory, and a better method of preparation was needed. It was found that by increasing the reaction temperature to about loo", and by employing a large excess of methyl sulfate, a 96% yield of crude product could be obtained. This was then easily purified by recrystallization from ethanol. The procedure of Noelting, et al. (29) for reduction of the azo compound is quite involved, a number of side reactions cutting the yield down considerably. T o avoid such losses, the much more elegant procedure of Whitmore and Revukas (30), that of catalytic reduction over Raney nickel, was used, and this resulted in almost quantitative yields of the methoxy amine in a high state of purity. The more obvious approach, that of preparation of l-methoxy-2-nitronaphthalene, followed by its reduction, failed of realization. The procedures of Deninger (31) and of Grandmouguin and Michel (32) gave poor yields of 2-nitrol-naphthol, so a synthesis was developed utilizing the hydrogen peroxide oxidation of 2-nitroso-l-naphthol [prepared by the method of Illinski and Henriques (33)], which provided good yields of the nitro compound. However, it proved impossible to methylate this, and after much effort, this method of approach was regretfully abandoned. Amino esters analogous to those reported above in the 3H-benz[e]indole series were prepared, and these too are characterized by their marked instability in both acidic and basic media. '?;-Cyanoethylation was carried out on the parent indole ester (XIII), and on the various Mannich bases prepared. The reaction product from (XIII), 1-6cyanoethyl-2-carboethoxy-9-methoxy-lH-benz[f]indole (XVIII) was hydrolyzed to the corresponding dibasic acid (XXI) in good yield. Because of the remarkable properties of indole-3-acetic acid as a plant hormone, the preparation of a benindole analog was attempted. The procedure of Snyder and Pilgrim (34) was employed, that of reaction of a S-dimethylaminomethyl-derivative with sodium cyanide in boiling aqueous ethanol, and the desired 2-carboxy-9-methoxy-lH-benz[f]indole-3-acetic acid was obtained in 57 % yield. However, this compound proved to be inactive in the avena and pea tests for plant hormonal activity. Acknowledgement. The authors are indebted to Miss Doris Clegg of New York University and Mr. Glenn Swinehart of The California Institute of Technology for the microanalyses reported herein. EXPERIMENTAL
B-Carboethosy-SH-benz[e]indole (I). To a cold (-10") mixture of 50 cc. of 95% ethanol, 7.2 g. of ethyl a-methylacetoacetate, 17 cc. of 50% potassium hydroxide, and 100 g. of ice,
512
E. A. GOLDSMITH AND H. G. LINDWALL
there was added with vigorous stirring a cold (-10') solution of diazotized p-naphthylamine (7.15 g. in 20 cc. of concentrated hydrochloric acid, plus 3.5 g. of sodium nitrite in 20 cc. of water). The mixture turned yellow and then red. After stirring for five minutes, the precipitated 0-naphthylhydrazone of ethyl pyruvate was separated, washed with water, and dried. This was dissolved in 75 cc. of absolute ethanol and gaseous hydrochloric acid was bubbled through the solution until a precipitate of ammonium chloride was noted. The mixture was heated t o boiling and then cooled t o room temperature. The gas flow was stopped, and after standing a t room temperature for two hours, the mixture was poured on to ice with stirring. The crude ester precipitated, and after collection, it was washed free of acid and dried. There resulted 7.5 g. (63%) of an orange solid. Recrystallization from 95% ethanol and acetone produced the purified ester, m.p. 164-165",yield 43%. Anal. Calc'd for CisHiaNOe: C, 75.29; H , 5.48; N, 5.86. Found: C, 75.34,75.29;H, 5.42,5.50;N, 5.97,5.93. 2-Carboxy-SH-benz[e]indole (11). A suspension of 2.4 g. (0.01 mole) of I) in 15 cc. of 20% sodium hydroxide was refluxed until solution was obtained. After cooling and treating with Norit, the solution was acidified with cold dilute hydrochloric acid. The indole acid precipitated in quantitative yield. Recrystallization from aqueous ethanol afforded the purified acid, m.p. 224-226", yield 85%. AnaE. Calc'd for CiaHpNOz: N , 6.64.Found: N , 6.57. 2-Carboethosy-i-dimethylaminomethyl-S"benz[e] indole (111). Compound I (1.8 g., 7.5 mmol.) was added t o a cold mixture of 3.5 cc. of glacial acetic acid and 2.1 cc. of a 33% aqueous solution of dimethylamine. Formaldehyde (1.2cc. of 37% aqueous solution) was added, and the mixture was warmed on the steam-bath for two hours. After standing for two hours further, 15 cc. of water was added, and the precipitated sticky solid was removed by filtration. Addition of excess ice cold ammonium hydroxide t o the filtrate caused precipitation of the amino compound as a cream-orange colored solid. This was dissolved in acetic acid, and the solution was treated with Norit until it was colorless. The amine was then reprecipitated with aqueous ammonia as a white curdy material, crude yield 53%. Recrystallization from 95% ethanol afforded 0.8 g. (36%) of white needles, m.p. 168-169". It is of interest to note that while extension of reaction time t o six hours did not appreciably affect the yield, one run made for eight hours resulted in a crude yield of 75%, and a 59% yield of purified product. Anal. Calc'd for C18HwNzO2: C, 72.95;H, 6.80;N , 9.46. Found: C, 72.88, 72.91;H, 6.71,6.69;N , 9.35,9.39. 2-Carboethosy-1-diethylaminomethyl-SH-benz[e]indoEe (IV). The procedure as described for I11 was followed in this preparation, except for the fact that reaction time was increased to 4% hours. Recrystallization from 95% ethanol afforded the amine, m.p. 175-176",yield 29%. A n d . Calc'd for C Z O H ~ , N ZN, O ~8.63. : Found: N , 8.52. 2-Carboethoxy-1-morphoEinomethyl-SH-benz[e]indole (V) . The procedure as described for I11 was employed in this preparation. Recrystallization from 95% ethanol produced the amine as fine white needles, m.p. 174.5-175.5"'yield 41%. Anal. Calc'd for C ~ H Z Z N ZN, O ~8.28. : Found, N , 8.30. ~-p-CyanoethyZ-2-carboethoxy-SH-benz[e]indoEe (VI). T o a solution of 0.2 cc. of "Triton B" (trimethylbenzylammonium hydroxide) and 0.5 cc. of acrylonitrile in 5 cc. of dioxane, there was added 1.1g. (4.7mmol.) of 2-carboethoxy-3H-benz[e]indole(I). The mixture was warmed to 75" for 30 minutes and then was allowed t o stand a t room temperature overnight. Aqueous acetic acid was added t o neutralize the basic catalyst, and the mixture was filtered. The solid yielded 1.2 g. (88%) of white fluffy material, m.p. 176-177.5"upon recrystallization from 95% ethanol. Anal. Calc'd for C18H18NZOz: N , 9.58.Found: N, 9.81,9.72. ~-(2-Carboxy-SH-benz[e]indole-S)-propionic acid (VII). A suspension of 0.5 g. of V I in 10 cc. of 10% potassium hydroxide was refluxed until the odor of ammonia was no longer detectable. The resulting solution was cooled, filtered, and acidified with cold dilute acetic
STUDIES I N THE BESZINDOLE SERIES
513
acid. The precipitated white solid was collected, washed with water, and dried. Crystallization from aqueous ethanol produced fine white crystals, m.p. 228-229", yield 91%. Anal. Calc'd for ClpH1,NO,: C, 67.84; H, 4.63; N , 4.96. Found: C, 67.71, 67.68; H, 4.39, 4.46; N, 4.97, 4.91. S-~-Cyanoethyl-8-carboethoxy-l-dimethylaminomethyl-S"benz[e]indole (VIII). T o a suspension of 1.33 g. (4.7 mmol.) of I11 in 5 cc. of dioxane, there was added 0.2 cc. of Triton B and 0.5 cc. of acrylonitrile. The orange solution was warmed to 75" for two hours and then allowed to stand a t room temperature overnight. Then 15 cc. of water and several drops of 50% potassium hydroxide solution were added, the mixture was cooled in an ice-bath, and the precipitated tan solid was collected. Crystallization from 95% ethanol resulted in the isolationof0.70g. (43%) of whitecrystals,m.p. 119-120'. Anal. Calc'd for CzlHzaNaOz: N, 12.02. Found: N, 12.11. 9-~-Cyanoethyl-8-carboethoxy-l-diethylaminomethyl-PlH-benz[e]indole (IX). This compound was prepared from IV via the procedure described for VI11 above; m.p. 105-106", yield 60%. Anal. Calc'd for C Z ~ H Z ~ N N,~11.11. O ~ : Found: N , 10.98, 10.91. 3-~-Cyanoethyl-8-carboethoxy-l -morpholinomethyl-3H-benz[e]indole(X) . This was prepared from V via the procedure described for compound VIII; m.p. 149.5-150.5", yield 84%. Anal. Calc'd for Cz3Hz6N3O3:N, 10.74. Found: N, 10.94. I-Methoxy-8-benzeneazonaphthalene(XI). 2-Benzeneazo-1-naphthol (22 g., 0.089 mole) was added with vigorous stirring t o a hot (85') solution of 25 g. of sodium hydroxide in 250 cc. of water. Technical methyl sulfate (40 cc.) was added all a t once (hood!). The temperature rose rapidly t o 100Owith the evolution of foul-smelling vapors. Stirring was continued for 30 minutes before cooling the mixture t o room temperature. The dark red solid material was separated, washed with water, and dried. It weighed 22.3 g. (96%). Recrystallization from 9570 ethanol afforded 17.6 g. (76%) of orange platelets, m.p. 100-101". An additional 1.7 g. of pure material was isolated by working u p the mother liquors, raising the over-all yield t o 84%. I-~~ethoxy-2-naphthylamine (XII) . Approximately 5-6 g. of Raney nickel catalyst was added t o a suspension of 26.2 g. (0.1 mole) of X I in 250 cc. of absolute ethanol in a heavy walled hydrogenation bottle. Hydrogenation was carried out a t 50 p.s.i. using a Parr Instrument Go. apparatus. The orange azo compound went into solution rapidly as reduction proceeded, the color fading at the same time. After one-half hour absorption of hydrogen was complete, and shaking was stopped. The catalyst was removed, and hydrochloric acid was added t o the filtrate. The bulk of the ethanol was removed a t reduced pressure, the last traces being eliminated by steam-distillation. The amine was liberated from its salt by the addition of excess 20% sodium hydroxide and then was rapidly steam-distilled. Cooling of the milky distillate in an ice-bath caused the amine t o crystallize as white shining platelets, m.p. 48-49', yield 15.6 g., (92%). 8-Carboethoxy-9-methoxy-f H-benz[f]indole (XIII). A solution of diazotized l-methoxy2.naphthylamine (17.3 g., 0.1 mole, 40 cc. of concentrated hydrochloric acid, and 6.9 g. os' sodium nitrite) was added with vigorous stirring t o a cold mixture of ethyl a-methylacetoacetate (14.4 g., 0.1 mole), 75 cc. of 95% ethanol, and 34 cc. of 50% potassium hydroxide. Ice (100 g.) was immediately added, the temperature not exceeding 5". Stirring was continued for five minutes, and the deep red oily hydrazone was extracted with ether. The extract was washed with successive 200-cc. portions of cold 5y0 potassium hydroxide, and then with ice-water until i t was neutral. The solvent was removed after drying over magnesium sulfate, and the oily residue was taken up in absolute alcohol. Dry hydrogen chloride was passed into the ethanolic solution until a precipitate of ammonium chloride was noted. The gas flow was stopped, and after standing for two hours, the mixture was poured on t o ice with stirring. The tan precipitate was separated and taken up in chloroform. The solution was washed with water to remove acid, dried, and then concentrated t o a thick purple solution. Cooling and filtration of this afforded a purple-brown solid,
514
E. A. GOLDSMITH A N D H. G . LINDWALL
which on recrystallization from 95% ethanol produced 7.3 g. (27%) of a pink-white fluffy material, m.p. 229-230'. Anal. Calc'd for C16H16X03: C, 71.32; H , 5.62; N, 5.41; OC&, 11.52. Found: C, 71.26,71.31; H, 5.69, 5.65; N, 5.30,5.32; OC&, 11.75. 2-Carboxy-9-methoxy-lH-ben?lf]indole (XIV). A suspension of 500 mg. (1.86 mmol.) of XI11 in 10 cc. of 5y0 aqueous Eodium hydroxide was refluxed until solution was obtained. Cooling and acidification with ice-cold dilute hydrochloric acid precipitated the indole acid as a white gelatinous material which rapidly turned blue in contact with the aqueous medium. It was separated rapidly, washed with water, and then recrystallized from aqueous ethanol as very small white crystals, m.p. 243-245" with decomposition, yield 82%. Anal. Calc'd for C14H11N03: C, 69.70; H, 4.60; N, 5.81. Found: C, 69.76,69.79; H , 4.60,4.65; N, 5.91,5.87. 8-Carboethoxy-3-dimethylamilaomethyl-9-methoxy-1H-benz[f]indole (XV). T o a solution of 2.5 cc. of 33% aqueous dimethylamine, 15 cc. of glacial acetic acid, and 2.0 cc. of 37% aqueous formaldehyde, there vias added 2.01 g. (7.5 mmol.) of X I I I . The mixture was warmed on the steam-bath for !j hours t o effect complete solution. After standing a t room temperature overnight, 15 cc. of water was added, and the precipitated unreacted indole was filtered off. Excess ice-cold ammonium hydroxide was added t o the filtrate t o precipit a t e the amine. This was washed with water and recrystallized from 95% ethanol to produce 900 mg. of white crystals, (45%), m.p. 188-190'. Anal. Calc'd for C ~ ~ H Z Z N C, Z O69.91; ~ : H , 6.80; N, 8.59. Found: C, 69.72, 69.79; H, 6.69, 6.72; N, 8.50,8.53. 2-Carboethoxy-3-morpholinomsthyl-9-methoxy-1H-benzlflindole(XVI). This compound was prepared following the procedure described for XV, yield, a%,m.p. 199-200.5". Anal. Calc'd for C Z ~ H Z ~ NN, Z O7.61. ~ Found: N, 7.55. ~-Carboethoxy-3-diethylaminoinethyl-9-methoxy-1H-ben~lf]indole (XVII). This compound was prepared following the prclcedure described for XV and XVI. Yield, 21y0 of white crystals, m.p. 190-191". Anal. Calc'd for C Z ~ H Z B N ZN, O J7.91. . Found: N , 7.81. l-~-Cyanoethyl-~-carboethoxy-!~-methoxy-1H-benzlf]indole (XVIII). The preparation of this material was essentially that described for VI above. It was obtained as a pure white cottony material upon crystallization from 95% ethanol, m.p. 168.5-169.5', yield 54%. Anal. Calc'd for ClpHlsNzOa: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.71, 70.69; H , 5.59,5,65; N, 8.62,8.64. 1-~-Cyanoethyl-~-carboethoxy-~~-dimethylaminomethyl-9-methoxy-lH-benz~]indoEe (XIX). The procedure as described for the preparation of VI11 was followed here. The material was obtained as white shining needles, m.p. 132-133', yield 41%. Anal. Calc'd for C Z Z H ~ ~ NC,~69.63; O ~ : H , 6.64; N, 11.08. Found: C, 69.60, 69.58; H, 6.60,6.67; N, 10.96,10.91. l-~-Cyanoethyl-d-carboethoxy-d-morpholinomethyl-9-methoxy-lH-benzlf]indole (XX). The procedure for preparation of this material was essentially that described for VIII. It was obtained as white crystals from ethanol, m.p. 194.5-196', yield 39%. Anal. Calc'd for C Z ~ H ~ T NC,68.39; ~ O ~ : H , 6.46; N, 9.97. Found: C, 68.31, 68.34; H, 6.41,6.39; N, 9.94, 9.91. ~-(2-Carboxy-9-methoxy-lH-ber~zLf)indole-1)-propionic acid (XXI). Alkaline hydrolysis of XVIII, followed by recrystallization of the acid from 95% ethanol afforded lustrous silvery plates, m.p. 269-271" with decomposition, yield 54%. Anal. Calc'd for C1,Hl5NOs: Ir?, 4.17. Found: N, 4.29,4.36. 2-Carboxy-9-methoxy-lH-benzIf]indole-3-acetic acid (XXII) . T o a mixture of 10 cc. of water, 60 cc. of 95% ethanol, and 2 g. of sodium cyanide, there was added 1 g. of XV. The mixture was re5uxed for 80 houri , water was added, and the ethanol and some water were removed in vacuo. The resulting suspension was cautiously acidified with dilute hydrochloric acid and then filtered. The residue was refluxed with 10 cc. of 20% sodium hydroxide until solution was obtained. The solution was again acidified, and the di-acid precipitated
STUDIES I N T H E BENZINDOLE SERIES
515
as s white amorphous material. This was dissolved in ammonium hydroxide, and after clarification with Norit, the solution was made acid. There resulted 0.62 g. (57%) of a white amorphous material, m.p. 251.5-253’ with decomposition. Anal. Calc’d for C16H1ZNOL: N, 4.68. Found: N , 4.41, 4.47. SUMMARY
I. A number of 3H-benz[e]indolederivatives have been prepared. 2 . Entry into the “linear” or 1H-benz[f]indoleseries has been accomplished. 3. The benzindole preparations have been shown to undergo the Mannich reaction and cyanoethylation. 4. A 1H-benz[f]indoleanalog of indole-3-acetic acid has been prepared. SEW YORK,N. Y. BIBLIOGRAPHY (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34)
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