United States Patent (19) 11) 3,976,639 Batcho Et Al

United States Patent (19) 11) 3,976,639 Batcho et al. (45) Aug. 24, 1976

54 INTERMEDIATES FOR INDOLES OTHER PUBLICATIONS (75) Inventors: Andrew David Batcho, Belleville; Robert Wahl, Doctoral Dissertation, Univ. of Stutt Willy Leimgruber, Montclair, both gart, frontispage and pp. 26-39, available to public of N.J. Sept. 15, 1967 copies of correspondence from Stug gart, Radtke-Directress of Library and Prof. John E. (73) Assignee: Hoffmann-La Roche Inc., Nutley, Hiller showing proof of date Wahl Doctor Thesis N. available to public. 22 Filed: Mar. 31, 1975 Meerwein et al., Annalen Der Chemie, vol. 641, pp. 1-39 (1961). (21) Appl. No.: 563,557 Chardonnens et al., Helv. Chim. Acta vol. 22, pp. Related U.S. Application Data 1471-1482 (1939). 60) Continuation of Ser. No. 260,021, May 31, 1972, Brederick et al. I, Chem. Ber. vol. 97, pp. 3397-3406 abandoned, which is a division of Ser. No. 86,953, (1964). Nov. 4, 1970, Pat. No. 3,732,245, which is a Brederick et al. II, Chem. Ber. vol. 101, pp. continuation-in-part of Ser. No. 879,619, Nov. 24, 4048-4056 (1968). 1969, abandoned. Primary Examiner-John D. Randolph (52) U.S. Cl...... 260/240 D; 260/240 R: 260/319.1; 260/570.8 R Attorney, Agent, or Firm-Samuel L. Welt; Bernard S. (51) Int. Cl.’...... C07D 21 1/26 Leon; William G. Isgro . 58) Field of Search...... 260/570.8 R, 240 R, 260/240 D 57) ABSTRACT Ortho-nitrotoluenes are condensed with formamide acetals to yield the corresponding otho-nitro-g- 56 References Cited aminestyrenes which undergo cyclization upon reduc UNITED STATES PATENTS tion to yield indoles. 3,530,120 9/1970 Von Hirsch...... 260/240 R 3,732,245 5/1973 Batcho et al...... 260/230 D X 14 Claims, No Drawings 3,976,639 1. 2 INTERMEDIATES FOR INDOLES example, formyl, acetyl, propionyl, and the like; and an aroyl group derived from an aromatic carboxylic acid, CROSS-REFERENCE TO RELATED such as benzoyl and the like. The term acyloxy denotes APPLICATIONS an alkanoyloxy group derived from an aliphatic carbox This is a continuation, of application Ser. No. 5 ylic acid of 1 to 7 carbon atoms, for example, for 260,021 filed May 31, 1972, now abandoned, which is myloxy, acetoxy, propionyloxy, and the like; and an a division of U.S. Pat. application Ser. No. 86,953 filed aroyloxy group derived from an aromatic carboxylic Nov. 4, 1970, now U.S. Pat. Nos. 3,732,245 issued May acid, such as benzoyloxy and the like. The term lower 8, 1973, which in turn is a continuation-in-part of U.S. alkylenedioxy denotes an alkylene diether group hav Pat. application Ser. No. 879,619 filed Nov. 24, 1969, 10 ing from 1 to 7 carbon atoms such as methylenedioxy, now abandoned. ethylenedioxy, propylenedioxy, and the like. The term BRIEF SUMMARY OF THE INVENTION lower alkylene denotes a hydrocarbon radical of 2 to 5 carbon atoms, such as ethylene, propylene, butylene, The invention relates to a process for preparing in and pentylene; preferred are those of 2 to 3 carbon doles which comprises condensing an ortho-nitrotol 15 atoms. The term ar-alkyl denotes a lower alkyl group in uene with a formamide acetal and subsequently reduc which one or more of the hydrogen atoms have been ing the resulting ortho-nitro-g-aminostyrene to yield replaced by an aryl group. Exemplary is benzyl. The the corresponding indole. term cyclo-alkyl denotes a cyclic hydrocarbon of 3-6 In another aspect, the invention relates to the inter carbon atoms, for example, cyclopentyl and the like. mediate ortho-nitro-S-aminostyrenes. 20 Exemplary of aryl-lower alkoxy groups are ben DETAILED DESCRIPTION OF THE INVENTION zyloxy, l-phenylethyloxy, 2-chlorobenzyloxy, and the The invention comprises a process and intermediates like. Exemplary of aryl-hydroxymethyl groups are phe for preparing indole and substituted indoles. nylhydroxymethyl, p-chlorophenylhydroxymethyl, and More particularly, the invention comprises condens 25 the like. Exemplary of lower alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, and the like. Exem ing a formamide acetal with an ortho-nitrotoluene to plary of mono-lower alkylamino groups are me yield as an intermediate the corresponding ortho-nitro thylamino, ethylamino, propylamino, isopropylamino, (3-aminostyrene and reducing said intermediate to yield butylamino, pentylamino, and the like. Exemplary of the corresponding indole. di-lower alkylamino groups are dimethylamino, dieth As used herein, the term “lower alkyl' denotes a 30 ylamine, ethylmethylamino, dipropylamino, and the straight or branched chain saturated hydrocarbon con like. Exemplary of lower alkoxycarbonylamino groups taining 1 to 7 carbon atoms, for example, methyl, ethyl, are methoxycarbonylamino, ethoxycarbonylamino, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, and the like. Exemplary of aryl-lower alkoxycar heptyl, and the like. The term “lower alkoxy' denotes bonylamino groups are benzyloxycarbonylamino, p an alkyl ether group in which the lower alkyl group is as 35 chlorobenzyloxycarbonylamino, and the like. Exem described above, for example, methoxy, ethoxy, plary of acylamino groups are formamino, acetamino, propoxy, pentoxy, and the like. The term "halogen' propionylamino, benzoylamino, and the like. Exem denotes the four halogens, i.e., bromine, chlorine, fluo plary of N-lower alkylacylamino groups are N rine, and iodine. The term “aryl' denotes phenyl or methylacetamino, N-methylformamino, N phenyl bearing one or more substituents selected from 40 the group consisting of halogen, trifluoromethyl, lower ethylacetamino, and the like. Exemplary of di-lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, alkylformamidino groups are dimethylformamidino, and di-lower alkylamino. The term "aryloxy' denotes diethylformamidino, and the like. an aryl ether group in which the aryl group is as de In a preferred embodiment, the process of the inven scribed above, for example, phenoxy and the like. The 45 tion is characterized by reaction scheme I: term “acyl' denotes an alkanoyl group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for REACTION SCHEME I 9Rs

CH R2 Fis

I 3,976,639 3. 4 wherein R, R2, Ra and Rindependently, are selected hydroxy, aryl-lower alkoxy, aryloxy, acyloxy, hydroxy from the group consisting of hydrogen, lower alkyl, methyl, aryl-hydroxymethyl, carboxy, lower alkoxy aryl, hydroxy, lower alkoxy, aryl-lower alkoxy, aryloxy, carbonyl, carbamoyl, halogen, cyano, amino, mono acyloxy, formyl, aroyl, hydroxymethyl, aryl-hydrox lower alkylamino, di-lower alkylamino, lower alkox ymethyl, carboxy, lower alkoxycarbonyl, carbamoyl, ycarbonylamino, aryl-lower alkoxycarbonylamino, ac halogen, cyano, amino, mono-lower alkylamino, di ylamino, N-lower. alkylacylamino, di-lower alkylfor lower alkylamino, lower alkoxycarbonylamino, aryl mamidino, or di-lower alkoxymethyl; R1 and R2, R2' lower alkoxycarbonylamino, acylamino, N-lower al and R,R and R', when taken together, are lower kylacylamino, di-lower alkylformamidino, di-lower O alkylenedioxy; and R and Rs are as previously de alkoxymethyl, or nitro; R and R2, or R2 and Ra, or Ra scribed. and R4, when taken together, are lower alkylenedioxy; In a further aspect, the invention relates to the inter R5 and Rs, independently, are lower alkyl, and when mediates characterized by the formula taken together, are lower alkylene; and R and R8, independently, are lower alkyl and when taken to 15 gether, are lower alkylene. -R7 . In a more preferred embodiment, the process of the R N NR invention is characterized by reaction scheme II: R2" REACTION SCHEME II 20 O2 IVa

R2R DEDICN NO2CH -- II a

NOe Wa. reduction

V R

Re n N H I a. wherein R, R2, Rs, Re, R, and Rs are as previously wherein R and R2, independently, are hydrogen, described. Preferably, R and R, independently, are lower alkyl, lower alkoxy, aryl, formyl, aroyl, hydroxy, hydrogen, lower alkyl, hydroxy, lower alkoxy, aryl 45 aryl-lower alkoxy, aryloxy, acyloxy, hydroxymethyl, lower alkoxy, acyloxy, formyl, aroyl, halogen, cyano, aryl-hydroxymethyl, carboxy, lower alkoxy-carbonyl, nitro, amino, or acylamino, and when taken together carbamoyl, halogen, cyano, amino, mono-lower alkyl are lower alkylenedioxy; and Rs, R, R and Rs, inde amino, di-lower alkylamino, lower alkoxycar pendently, are lower alkyl, and Rs and Rs or R and Rs. bonylamino, aryl-lower alkoxycarbonylamino, acyl when taken together, are lower alkylene. 50 amino, N-lower alkylacylamino, di-lower alkylfor In a most preferred embodiment of the invention, mamidino, or di-lower alkoxymethyl; R' and R', when o-nitrotoluene is condensed with N,N-dimethylforma taken together, are lower alkylenedioxy; and R and Rs mide dimethyl acetal to yield trans-g-dimethylamino-2- are as previously described. nitrostyrene. The latter is hydrogenated to yield indole. Preferably, in formula IVa', Ri' and R', indepen 55 dently, are hydrogen, hydroxy, lower alkyl, lower alk In a further aspect, the invention relates to intermedi oxy, formyl, aroyl, cyano, acyloxy, aryl-lower alkoxy, ates characterized by the formula halogen, amino, or acylamino, and when taken to gether, are lower alkylenedioxy; and R and Rs, inde pendently, are lower alkyl. 60 It will be appreciated that the ortho-nitro-g-aminos tyrenes of formulas IV, IVa, IVa' and Va' have the trans-configuration. As is evident from the above, the present invention relates to a novel preparative route to indoles. It pro 65 vides to the art a new and significant reaction route to many compounds of commercial value. The process is particularly salient in providing such compounds with greater efficiency than heretofore known in the prior. art. wherein R', R.', Ra' and R.", independently, are hy Broadly stated, the novel preparative path herein drogen, lower alkyl, lower alkoxy, aryl, formyl, aroyl, disclosed involves condensing the methyl function of 3,976,639 S 6 an ortho-nitrotoluene with the formyl group of a form about 10 atmospheres. Any suitable hydrogenation amide acetal, whereby a nitrobenzene derivative is catalyst may be employed, for example, a metal Se obtained which bears a N,N-di-substituted aminovinyl lected from the group consisting of chromium, molyb function ortho to the nitro group, and thereafter by denum, tungsten, platinum, palladium, rhodium, co reducing the nitro group to an amino group which balt, nickel, and ruthenium, their oxides, and combina concurrently displaces the N,N-di-substituted amino tions thereof, for instance, the oxides of cobalt or no function effecting cyclization to a compound having an lybdenum in admixture and including cobalt molyb indole nucleus. date. The preferred hydrogenating component is palla The ortho-nitrotoluenes are known compounds or dium, as well as other platinum group metals, or Raney can be prepared by known procedures. Such com 10 nickel. Conveniently, the catalyst may be supported on pounds have monocyclic or bicyclic structures which charcoal, carbon or the like. may contain hetero atoms. Further, they may be unsub Advantageously, the catalyst may be utilized in the stituted or substituted independently with up to 4 moi eties such as lower alkyl, aryl, hydroxy, lower alkoxy, presence of an inert solvent, for example, an alkanol aryl-lower alkoxy, aryloxy, acyloxy, formyl, aroyl, hy 15 such as methanol, ethanol, and the like, a hydrocarbon droxymethyl, arylhydroxymethyl, carboxy, lower alk such as benzene, toluene and the like; ethyl acetate; oxycarbonyl, carbamoyl, halogen, cyano, nitro, amino, and DMF. Most preferably, benzene is utilized. mono-lower alkylamino, di-lower alkylamino, lower The chemical reduction may be effected in a conven alkoxycarbonylamino, aryl-lower alkoxycar tional manner, for example, with a metal such as iron, bonylamino, acylamino, N-lower alkylacylamino, di zinc, tin, and the like, in an organic or inorganic acid lower alkylformamidino or di-lower alkoxymethyl; or such as acetic acid, hydrochloric acid, and the like; with up to 2 moieties of lower alkylenedioxy. Examples stannous chloride in hydrochloric acid, ferrous sulfate; of such compounds are 3-methyl-4-nitrobiphenyl, 2 sodium dithionite; sodium or ammonium sulfide or methyl-3-nitrobenzyl alcohol, 3-nitro-p-toluamide, 4 hydrosulfide; and the like. The reaction conditions for methyl-3-nitrobenzophenone, 3-nitro-p-toluic acid 25 the chemical reduction are not critical. Preferably, it is methyl ester, N,N-dimethyl-3-nitro-p-toluidine, 3 effected at a temperature in the range of between about nitro-p-toluic acid, 4-methyl-3-nitrobenzophenone, room temperature and reflux temperature of the reac N-methyl-3-nitro-p-toluidine, 3-nitro-p-toluidine, and tion mixture, in the presence of a solvent such as water, the like. or water miscible solvents, for example, alkanols such The formamide acetals are known compounds or can as methanol, ethanol or the like, or tetrahydrofuran. be prepared by known procedures. Preferred form While the substituents represented by R, R2, Ra, and amide acetals are, for example, N,N-dimethylforma R4 generally do not undergo a change during the con mide diethyl acetal, N-N-dimethylformamide dimethyl densation and subsequent reduction, in certain cases acetal, N-formylpyrrolidine dimethyl acetal, 2-dime changes may occur. For instance, during the condensa thylamino-1,3-dioxolane, N-formylpiperidine dimethyl 35 tion, a carboxyl group may be converted to an ester acetal, N,N-dimethylformamide dibenzyl acetal, N,N- group and a phenolic hydroxyl group may be converted dimethylformamide dicyclohexyl acetal, N,N-dimethyl to a phenolic ether. A dialkoxymethyl group can be formamide dineopenty acetal, N,N-dimethylforma retained or hydrolyzed depending on the work up. mide di-isopropyl acetal, N,N-dimethylformamide di-n- Thus, in the presence of acid, the dialkoxymethyl group heptyl acetal, and the like. 40 is cleaved, and if no acid is present, it is retained. The condensation of the ortho-nitrotoluene, e.g., of Upon completion of the reaction, if desired, the end formula II or IIa, with the formamide acetal, e.g., of products, for example, indole, may be recovered utiliz formula III, can be effected in the presence or absence ing conventional means such as crystallization, distilla of an inert organic solvent. Preferably, the condensa tion or steam distillation and the like. The class of tion is conducted in the presence of a polar aprotic 45 products resulting from the process of the invention, solvent, such as, for example, N,N-dimethylformamide i.e., indole and the substituted indoles exemplified by (DMF), diethyleneglycol dimethyl ether (Diglyme), formula I are well documented in the literature and are hexamethylphosphortriamide (HMPT), and the like. useful for many purposes, for example, as intermedi The reaction conditions for the condensation are not ates in the preparation of amino acids, alkaloids, trypt - narrowly critical. Thus, the condensation can be con SO amines, and the like. Thus, for example, indole, 6 ducted at a temperature in the range of between about methoxyindole, and 5-benzyloxyindole can be utilized room temperature and the reflux temperature of the as intermediates in the preparation of tryptophan, re reaction mixture. Preferably, the reaction is conducted serpine, and serotonin, respectively, etc. at a temperature in the range of 100-160. Most con The following examples further illustrate the inven veniently, the reaction is conducted at the reflux tem 55 perature of the reaction mixture. The condensation tion. All temperatures are in Centigrade degrees unless may be effected at atmospheric or super-atmospheric otherwise indicated. pressures. Conveniently, it is effected at atmospheric EXAMPLE 1. pressure. The compounds of formulas IVa' and Va'are novel 60 Preparation of trans-6-dimethylamino-2-nitrostyrene compounds. In accordance with the invention, the or A one-liter three-necked flask fitted with a thermom tho-nitro-g-aminostyrene intermediates, e.g., of for- . eter, a 15-cm. Vigreux column connected to a descend mula IV or IVa, hereinafter referred to as aminosty ing condenser and a receiver with a nitrogen inlet was renes, are reduced chemically or catalytically to yield charged with 137 g of o-nitrotoluene, 191 g of N,N- the corresponding indoles, e.g., of formula 1 or a. The 65 dimethylformamide diethyl acetal, and 235 ml. of N,N- catalytic reduction may be effected in any conventional dimethylformamide. The flask was immersed in a pre manner; preferably, it is effected at about room tem heated oil bath which was maintained at 165 for 24 perature with a hydrogen pressure of from about 1 to hours. The pot temperature was maintained at 3,976,639 7 8 145-150 by continuous distillation of the formed then extracted with 3 x 600 ml. of 1N sulfuric acid and ethanol. 2 X 500 ml. of water. The aqueous phases were back The volatile components were removed by vacuum washed in a counter-current manner with 500 ml. of distillation under an atmosphere of nitrogen. The re benzene. The combined benzene phases were dried maining dark red liquid was then transferred to a flask over a mixture of anhydrous sodium sulfate and potas and distilled to yield 186 g. (97%) of trans-g-dime sium carbonate, filtered, and evaporated to give 96.0g. thylamino-2-nitrostyrene as a dark red liquid having a of greyish solid, which on rapid distillation under nitro boiling point of 125/ 0.03 mm. gen gave 91.3 g of a slightly yellowish solid having a Anal. Calcd. for CHNO: C, 62.48; H, 6.29; N, melting point of 51-53. The distillate, on fraction 14.58 Found: C, 62.66; H, 6.63; N, 14.50. O ation, gave a total of 87.4 g (80%) of indole as a white EXAMPLE 2 solid having a melting point of 52.5-53.5. Preparation of trans-f6-dimethylamino-2-nitrostyrene EXAMPLE 6 Preparation of indole by reduction of In a one-liter three-necked flask fitted with a ther 5 mometer, a vacuum-jacketed, silvered column with trans-g-dimethylamino-2-nitrostyrene with iron and Goodloe packing, distillation head and a receiver with acetic acid. a nitrogen inlet were placed 137.1 g of o-nitrotoluene, In a 500-ml. three-necked flask fitted with a ther 121.6 g. of 98% N,N-dimethylformamide dimethyl mometer and mechanical stirrer were placed 19.2g.of acetal, and 200.0 g of N,N-dimethylformamide 20 trans-g-dimethylamino-2-nitrostyrene, 100 ml. of 2B (DMF). The reaction mixture was heated at reflux for ethanol, and 100 ml. of glacial acetic acid followed by 24 hours. The reaction temperature was maintained at 41.9 g, of iron powder over a 5-min. period. The sus 135-155 by continuous distillation of the methanol as pension was stirred for 2 hours during which time the formed. A total of 56.0 g. of distillate was collected. temperature rose to 45 (the temperature was con By careful distillation 206.3 g of DMF, b.p. 25 trolled by a water bath); then 30 ml. of in hydrochloric 51-55/20 mm., and 13.0 g. (10%) of o-nitrotoluene, acid was added. The red color discharged and the tem b.p. 109/23 mm., were removed from the reaction perature rose to about 45°. The reaction was allowed to mixture to give a residual dark liquid which after distil stand for 18 hours and then was poured onto 1 1. of lation yielded 167.0 g. (87%) of trans-3-dime ice-water. To the resulting slurry was added 250 ml. of thylamino-2-nitrostyrene as a dark red liquid having a benzene; then both phases were filtered through a dia boiling point of 128/0.05 mm. tomaceous silica bed. The benzene layer was separated and the aqueous layer extracted once more with 200 EXAMPLE 3 ml. of benzene. The combined benzene extracts were Preparation of trans-g-dimethylamino-2-nitrostyrene washed successively with 2 X 200 ml. of 0.5N HSO A solution of 27.4 g. of o-nitrotoluene and 31.2g. of 35 and 100 ml. of 10% K2CO. The aqueous phases were 95% N,N-dimethylformamide diethyl acetal was heated backwashed in a counter-current manner with 100 ml. under a nitrogen atmosphere in a 165 oil bath for 22 of benzene. The combined organic phases were dried hours with continuous distillation of the ethanol (Na2SO4), filtered, and evaporated to give 4.2 g of a formed in the reaction through a distillation head and brown solid which was dissolved in a minimum amount descending condenser. 40 of benzene and was chromatographed on 50 g. of alu The volatile components were removed by vacuum mina (Woelm, activity III). Eluted fractions containing distillation and then 20.2 g. (52%) of trans-(3-dime indole (pet. ether-benzene, 9:1) were pooled according thylamino-2-nitrostyrene was collected at boiling point to thin layer chromatography. Evaporation of the sol 12729/0.08 mm. vents and sublimation of the residue (40-50 oil 45 bath/0.03 mm.) yielded 2.02 g. (17%) of indole, as EXAMPLE 4 white plates having a melting point of 51.5-52.5. Preparation of trans-g-dimethylamino-2-nitrostyrene EXAMPLE 7. A 50-ml. glass liner containing 15.6 g. of 95% di Preparation of indole by reduction of W methylformamide diethyl acetal and 13.7 g. of o 50 trans-g-dimethylamino-2-nitrostyrene with sodium nitrotoluene was pressurized with nitrogen in an auto dithionite clave to 35 atm. and then heated to 155 for 24 hours. To a stirred solution of 19.2 g of trans-g-dime The resulting red solution was distilled from a 50-ml. thylamino-2-nitrostyrene in 500 ml. of water and 200 Claisen flask. The forerun (b.p. up to 60/0.2 mm.) was ml. of methanol was added portionwise over 5 min. a discarded. The red liquid distilling at 134-136/0.25 55 mixture of 55.0 g. of sodium dithionite and 28.0 g. mm. amounted to 13.4 g (70%) of trans-g-dime potassium carbonate while maintaining the tempera thylamino-2-nitrostyrene. ture at 60-65 by a water bath. A suspension formed; EXAMPLE.5 So 300 ml. of methanol was added and stirring was continued for 0.75 hour. To this were added 20 ml. of Preparation of indole from 60 30% ammonium hydroxide and, after removal of the trans-g-dimethylamino-2-nitrostyrene methanol with a rotary evaporator, an additional 60 ml. A solution containing 178.6 g. of trans-(3-dime of 30% ammonium hydroxide. The solution was then thylamino-2-nitrostyrene in 2.5 liters of benzene con extracted with 3 X 400 ml. of benzene. The organic taining 2.0 g. of 10% palladium on carbon was shaken phases were backwashed in a counter-current manner. in a 4-liter autoclave under an initial hydrogen pressure 65 with 100 ml. of water. The combined organic phases of 4.5 atm. until the absorption of hydrogen ceased. were dried (Na2SO4), filtered, and evaporated to give The catalyst was removed by filtration and was washed 3.5 g. of a dark brown solid which was dissolved in a several times with benzene. The benzene solution was minimum amount of benzene and chromatographed on 3,976,639 9 10 60 g. of alumina (Woelm, activity III). Eluted fractions ml. of N,N-dimethylformamide. The flask was im (pet. ether) containing indole were pooled according mersed in a 150 oil bath for 7 hours during which time to thin layer chromatography. Evaporation of the sol 4 ml. of methanol distilled. Vacuum distillation from a vents and sublimation of the residue (2.4 g) yielded Claisen flask afforded, after removal of the volatile 2.14 g. (18%) of indole having a melting point of 5 components, three fractions: 2.86 g. (b.p. 50°-52. 144° 145°/0.06 mm.), 0.73 g. (b. p. 145-14610.06 mm.), and 5.35 g. (b.p. i46-147/0.07 mm.). The last EXAMPLE 8 fraction was pure trans-2-nitro-g-piperidinostyrene. Preparation of trans-2-nitro-g-pyrrolidinostyrene Anal. Calcd. for CHNO: C, 67.22; H, 6.94, N, 10 In a 100-ml. three-necked flask fitted with a ther 12.06 Found: C, 67.03; H, 7.08; N, 12.06. mometer and 8-cm. Vigreux distillation head con EXAMPLE 1 nected to a descending condenser and receiver with a Preparation of indole via nitrogen inlet were placed 6.85 g. of o-nitrotoluene, trans-2-nitro-g-piperidinostyrene 7.25 g. of N-formylpyrrolidine dimethyl acetal, and 25 15 ml. of N,N-dimethylformamide. The flask was im In a 100 ml, three-necked flask fitted with a ther mersed in 160 oil bath for 1 hour during which time mometer and 8-cm. Vigreux distillation head con 2.8 mi. of methanol distilled. Volatile components were nected to a descending condenser and receiver with a removed by vacuum distillation from a Claisen flask. A nitrogen inlet were placed 13.40 g. of o-nitrotoluene, portion of the residue was distilled with partial decom 20 13.40 g. of N-formylpiperidine dimethyl acetal, and 25 position in a short path distillation flask (bath 150/0.1 ml. of N,N-dimethylformamide. The solution was then mm.). The distillate was then vaporized twice in a mo heated to 130-50 for 3 hours allowing the methanol lecular still (bath 10/0.04 mm.), discarding a small to distill as it formed. Removal of the volatile compo amount of fore-run each time. In this way, 560 mg. of nents by vacuum distillation (water bath at 60/0.5 trans-2-nitro-f6-pyrrolidinostyrene was obtained as a 25 mm.) gave trans-2-nitro-g-piperidinostyrene as a red red liquid. liquid. Anal. Calcd. for CHNO: C, 66.03; H, 6.47; N, The trans-2-nitro-g-piperidinostyrene was dissolved 12.84 Found: C, 65.89; H, 6.45; N, 12.79. in 250 ml. of benzene, 0.460 g. of 5% palladium on EXAMPLE 9 charcoal was added, and the suspension was shaken 30 under an initial hydrogen pressure of 3.5 atm. until the Preparation of indole via absorption of hydrogen ceased (3 equivalents). The trans-2-nitro-g-pyrrolidinostyrene catalyst was removed by filtration and was washed To a 100-m. three-necked flask fitted with a ther several times with benzene. The filtrate was extracted mometer and 8-cm. Vigreux column connected to a with 3 X 100 mi. of 1M sulfuric acid, 100 ml. of water, descending condenser and receiver with a nitrogen 35 2 X 100 ml. of 1N sodium hydroxide, and 100 ml. of inlet was added 13.7 g. of o-nitrotoluene, 16.0 g. of water. The aqueous phases were back-washed in a N-formylpyrrolidine dimethyl acetal, and 50 ml. of counter-current manner with 100 ml. of benzene. The N,N-dimethylformamide. The solution was then heated combined organic phases were dried (Na2SO4), fil to 130-150 for 1.5 hours, maintaining the tempera tered, and evaporated to give 9.06 g. of a brown solid. ture by continuous distillation of the methanol which 40 Distillation in a Claisen flask gave 7.66 g. (70%) of formed in the reaction. indole, boiling point 60-65/0.06 mm., melting point Removal of the volatile components by vacuum dis 44' 49. tillation (bath 50/1 mm.) gave trans-2-nitro-g-pyr EXAMPLE 12 rolidinostyrene as a red liquid. The product was dissolved in 100 ml. of benzene and 45 Preparation of was shaken in a hydrogen atmosphere with 440 mg. of trans-g-dimethylamino-2,4-dinitrostyrene 10% palladium on charcoal at an initial pressure of 3.5 A 250 ml. three-necked flask fitted with a thermome atm. until hydrogen absorption ceased (3 equivalents). ter and condenser with nitrogen inlet was charged with The catalyst was removed by filtration through a bed of 50 18.21 g of 2,4-dinitrotoluene and 18.00 g. of N,N- diatomaceous silica and was washed with 3 X 50 ml. of dimethylformamide diethyl acetal. The reaction vessel benzene. The filtrate was then extracted consecutively was then immersed in a 165 oil bath for 2 hours. The with 2 X 200 m. of M sulfuric acid, 2 X 200 ml. of precipitate was triturated with ether and filtered. The water, and 100 ml. of 1M sodium carbonate. The aque resulting solid was crystallized from chloroform hexane ous phases were backwashed in a counter-current man 55 (200 ml.) to yield 19.54 g. (82%) of trans-G-dime ner with 2 X 200 mi. of benzene. The combined organic thylamino-2,4-dinitrostyrene as dark violet crystals phases were dried (Na2SO4), filtered, and evaporated having a melting point of 172.5-174. (rotary evaporator) to give 1 1.0 g of greenish solid, which on distillation gave 9.6 g. (82%) of indole, EXAMPLE 3 boiling point 78/0.3 mm., melting point 50-51.5°. 60 Preparation of 6-aminoindole EXAMPLE 10 A solution containing 4.75 g. of trans-G-dime thylamino-2,4-dinitrostyrene in 250 ml. of ethanol Preparation of trans-2-nitro-f3-piperidinostyrene N,N-dimethylformamide (4:1) was shaken with a tea In a 100 ml. three-necked flask fitted with a ther Spoonful of Raney nickel in a Parr apparatus under an mometer and 8-cm. Vigreux distillation head con 65 initial hydrogen atmosphere of 3.5 atm. until hydrogen nected to a descending condenser and receiver with a absorption ceased. The catalyst was removed by filtra nitrogen inlet were placed 6.85 g. of o-nitrotoluene, tion through a bed of Celite and washed with ethanol. 8.76 g. of N-formylpiperidine dimethyl acetal, and 25 The filtrate and washings were dried on a rotary evapo 3,976,639 11 2 rator. The residue was filtered in benzene through a dry Raney nickel were shaken under a hydrogen atmo column of 25 g. of Florisil and the fractions contain sphere in a Parr apparatus until hydrogen absorption ing the product were combined. The material was sub ceased. The catalyst was removed by filtration. The limed at 60/0.05 mm. to give 600 mg. (23%) of 6 solvents were removed under vacuum. The residue was aminoindole as a white solid having a melting point of 5 sublimed and the sublimate was crystallized from ether 77.5°-78.5°. petroleum ether to yield 5.1 g. (45%) of 5-benzyloxyin Anal. Calcd. for CHN: C, 72.71; H, 6.10; N, 21.19 dole as white needles having a melting point of Found: C, 72.50; H, 6.24; N, 21.28. 103-105. * diatomaceous silica ** magnesia - silica gel EXAMPLE 1.7 EXAMPLE 14 10 Preparation of Preparation of 5-benzyloxy-2-nitrotoluene trans-3-(A-dimethylaminovinyl)-4-nitrobenzoic acid To a solution containing 15.3 g of 3-methyl-4-nitro ethyl ester phenol in 200 ml. absolute ethanol stirred under nitro 15 A 100-ml. three-necked flask fitted with a thermome gen, 5.40 g. of sodium methoxide were added over a ter and a 15-cm. Vigreux column connected to a de period of 15 minutes. The solution was then stirred at scending condenser and a receiver with a nitrogen inlet reflux for 1.5 hours. Thereafter, 12.66 g. of benzyl was charged with 18. 1 g of 3-methyl-4-nitrobenzoic chloride were added dropwise, and the reaction was acid, 37.6 g. of N,N-dimethylformamide diethyl acetal, maintained at reflux for 20 hours. The ethanol was 20 and 25 ml. of N,N-dimethylformamide. The reaction evaporated from the reaction mixture. To the residue vessel was then immersed in a 100 oil bath for 4.5 were added 200 ml. of ether and 100 ml. 1N sodium hours. The pottemperature was maintained above 135° hydroxide. The ether solution was washed with an addi by continuous distillation of the ethanol formed in the tional 100 ml. of lN sodium hydroxide solution and reaction. then with 100 ml. of water. The aqueous phases were 25 The volatile components were removed by vacuum washed with ether (3 X 300 ml.) in a counter-current distillation. After trituration with petroleum ether, the manner. The combined aqueous phases were acidified residue crystallized to give 18.5 g. (70%) of trans-3-((3- with phosphoric acid and extracted with methylene dimethylaminovinyl)-4-nitrobenzoic acid ethyl ester as chloride (3 x 200 ml.). The combined methylene a red solid having a melting point of 55-56.5. chloride layers were dried (Na2SO4) and evaporated to dryness to give 2.8 g. (18%) of recovered 3-methyl-4- 30 Anal. Calcd. for CHNO: C, 59.08; H, 6.10; N, nitro-phenol. The ether extracts were dried (Na2SO) 10.60 Found: C, 59.02; H, 6.00; N, 10.63. and evaporated to dryness. The aqueous phases were EXAMPLE: 8 discarded and the organic phases dried (Na2SO4) and evaporated to dryness. The product was crystallized Preparation of 5-indolecarboxylic acid ethyl ester from methanol (75 m.), yielding 15.1 g. (62%) of 5 35 A solution containing 7.5 g. of trans-3-((3-dime benzyloxy-2-nitrotoluene as white needles having a thylaminovinyl)-4-nitrobenzoic acid ethyl ester in 250 melting point of 70.5-71.5°. ml. of absolute ethanol and 715 mg. of 10% palladium Anal. Calcd. for CHNO: C, 69.13; H, 5.39;N, on carbon were shaken under 3.5 atm. of hydrogen in 5.76 Found: C, 69.34; H, 5.44; N, 5.69. a Parr apparatus until hydrogen absorption ceased. The 40 catalyst was removed by filtration, and the filtrate was EXAMPLE 1.5 dried. The residue was applied to a Florisil column Preparation of (100 g.). The fractions containing the product (eluted trans-5-benzyloxy-6-dimethylamino-2-nitrostyrene with benzene) were combined. Crystallization from ether-petroleum ether yielded 2.1 g (39%) of 5 A 100-ml. three-necked flask fitted with a thermome 45 indolecarboxylic acid ethyl ester as white crystals hav ter and a 15-cm. Vigreux column connected to a de ing a melting point of 95-96. scending condenser and a receiver with a nitrogen inlet Anal. Calcd. for CHNO: C, 69.82; H, 5.86; N, was charged with 24.32 g. of 5-benzyloxy-2-nitrotol 7.40 Found: C, 70.14; H, 5.87; N, 7.45. uene, 23.0 g. of N,N-dimethylformamide diethyl acetal, * magnesia - silica gel and 25 ml. of N,N-dimethylformamide. The reaction 50 vessel was then immersed in a 160 oil bath for 40 EXAMPLE 19 hours. The pottemperature was maintained above 140 Preparation of by continuous distillation of the ethanol as it was trans-6-chloro-3-dimethylamino-2-nitrostyrene formed. A 250 ml. three-necked flask fitted with a thermome The volatile components were removed under re 55 ter and a 15-cm. Vigreux column connected to a de duced pressure on a rotary evaporator. The red solid scending condenser and receiver with a nitrogen inlet residue, crystallized from 300 ml. of ether and 25 ml. of was charged with 17.16 g. of 2-chloro-6-nitrotoluene, benzene, yielded 23.3 g (78%) of trans-5-benzyloxy-6- 24 g. of N,N-dimethylformamide diethyl acetal, and dimethylamino-2-nitrostyrene as red needles having a 100 ml. of N,N-dimethylformamide. The reaction ves melting point of 97.5-99. 60 sel was immersed in an oil bath, preheated to 160, for Anal. Calcd. for CHNO: C, 68.44; H, 6.08; N, 6 hours. The pot temperature was maintained about 9.39 Found: C, 68.73; H, 6.13; N, 9.46. 140 by continuous distillation of the ethanol formed in EXAMPLE 16 the reaction. The volatile components were removed by vacuum Preparation of 5-benzyloxyindole 65 distillation at 25/3 mm. and the product was distilled A solution containing 15.0 g. of trans-5-benzyloxy-g- to give 20.2 g (89%) of trans-6-chloro-g-dime dimethylamino-2-nitrostyrene in 250 ml. of 80% thylamino-2-nitrostyrene as a dark red liquid having a ethanol-N,N-dimethylformamide and 1 teaspoonful of boiling point of 1 1 1/0.03 mm. 3,976,639 13 14 Anal. Calcd. for CoH,ClNO,: C, 52.99; H, 4.89; Cl, percolated through about a gram of alumina. After 15.67; N, 12.36 Found C, 53.18; H, 4.57; C1, 15.75 N, removal of the ether, the residue was crystallized from 12.23. 30 ml. of petroleum ether to give 6.0 g. (78%) of 5 magnesia - silica gel chloroindole as white plates having a melting point of EXAMPLE 20 71-729. Preparation of 4-chloroindole EXAMPLE 23 To a solution containing 10.40 g. of trans-6-chloro-g- Preparation of dimethylamino-2-nitrostyrene in 250 ml. of benzene in trans-4-chloro-g-dimethylamino-2-nitrostyrene a 500-ml. Parr, bottle was addded a half teaspoon of 10 In a 100 ml. three-necked round-bottom flask fitted Raney nickel. The suspension was shaken under an with a thermometer and a condenser with a nitrogen initial hydrogen pressure of 3.5 atm. Until the absorp inlet were placed 17.15 g. of 4-chloro-2-nitrotoluene tion of hydrogen, ceased. The catalyst was removed by and 18.00 g. of N,N-dimethylformamide diethyl acetal. filtration and was washed several times with benzene. The flask was immersed in a 145 oil bath for 58 hours. The benzene filtrate was then extracted with 3 x 75 ml. 15 After 24 hours an additional 3 g. of acetal was added. of 1M sulfuric acid and 2 X 100 ml. of water. The The volatile components were removed by vacuum aqueous phases were back-washed with 125 ml. of distillation under nitrogen until the head temperature benzene in a counter-current manner. The combined began to rise to 158/0.09 mm. Subsequent distillation benzene phases were dried (KCOs), filtered, and evap gave 12.0 g. (57%) of trans-4-chloro-g-dimethylamino orated to give 5.4g. of dark green oil which, on distilla 20 2-nitrostyrene as a red liquid having a boiling point of tion, yielded 4.75 g. of a yellow liquid having a boiling 158/0.09 mm., which crystallized on standing to a point of 1 16/2 mm. After redistillation there was ob solid having a melting point of 44-46. tained 4.41 g. (63%) of 4-chloroindole as a slightly Anal. Calcd. for CHClNO: C, 52.99; H, 4.89, Cl, yellow liquid having a boiling point of 900.04 mm. 25 15.63; N, 12.36 Found: C, 52.96; H, 4.89; Cl, 15.63; EXAMPLE 21 N, 12.30. Preparation of EXAMPLE 24 trans-5-chloro-3-dimethylamino-2-nitrostyrene Preparation of 6-chloroindole A 250-m. three-necked flask fitted with a thermome 30 A solution of 4.50 g of trans-4-chloro-g-dime ter and a 15-cm. Vigreux column connected to a de thylamino-2-nitrostyrene in 250 ml. of absolute ethanol scending condenser and receiver with a nitrogen inlet and 1 teaspoonful of Raney nickel were shaken under a was charged with 34.3 g of 5-chloro-2-nitrotoluene, hydrogen atmosphere until hydrogen absorption 55.0 g of 85% N,N-dimethylformamide diethyl acetal, ceased. The catalyst was removed by filtration, and the and 200 ml. of N,N-dimethylformamide. The reaction 35 filtrate was evaporated. The residue was applied to a vessel was immersed in an oil bath, preheated to 160, Florisil column (25 g.). The fractions containing the for 7 hours. The pottemperature was maintained above product (eluted with 5% benzene-hexane) were com 146 by continuous distillation of the formed ethanol. bined. Crystallization from benzenehexane yielded The volatile components were removed by vacuum 1.59 g. (52%) of 6-chloroindole as white crystals hav distillation (70° bath/0.5 mm.). The resulting dark red 40 ing a melting point of 89-89.5. residue was crystallized from ether-petroleum ether . (275 ml.) to give. 33.2 g of red crystals having a melt EXAMPLE 25 ing point of 81.5-82.5°. From the mother liquor an Preparation of additional 6.6 g. of crystals having a melting point of trans-4-cyano-6-dimethylamino-2-nitrostyrene 78-81 was obtained. Thus, the total yield of trans-5- 45 chloro-g-dimethylamino-2-nitrostyrene was 39.8 g. A 500-ml. three-necked flask fitted with a thermome (88%). ter and a 15-cm. Vigreux column connected to a de Anal. Calcd. for CHCNO: C, 52.99; H, 4.89; Cl, scending condenser and receiver with a nitrogen inlet 15.64; N, 12.36 Found: C, 52.65; H, 5.20; C1, 15.69; was charged with 24.3 g of 3-nitrop-tolunitrile, 33.9 g. of N,N-dimethylformamide diethyl acetal, and 150 ml. N, 11.89. 50 of N,N-dimethylformamide. The reaction vessel was EXAMPLE 22 immersed in an oil bath, preheated to 160, for 2.5 hours. The pottemperature was maintained above 140 Preparation of 5-chloroindole by continuous distillation of the formed ethanol. To a solution of 11.6 g. of trans-5-chloro-3-dime The volatile components were removed by vacuum thylamino-2-nitrostyrene in 250 ml. of benzene in a 55 distillation at 25/0.5 mm. The resulting dark red solid 500-ml. Parr bottle was added a half teaspoon of Raney residue was crystallized from 600 ml. of methanol, to nickel. The suspension was shaken under an initial yield 27.9 g of trans 4-cyano-g-dimethylamino-2- hydrogen pressure of 3.5 atm. until the absorption of nitrostyrene as red crystals having a melting point of hydrogen had ceased. The catalyst was removed by 134°-137.5°. filtration and was washed several times with benzene. 60 The benzene filtrate was then extracted with 2 X 100 Anal. Calcd. for CHNO: C, 60.82; H, 5.10; N, ml. of 1N sulfuric acid, 2 X 100 ml. of water, and 100 19.55 Found: C, 60.89; H, 5.10; N, 19.09. ... ml. of 10% sodium bicarbonate solution. The aqueous EXAMPLE 26 phases were back washed with 100 ml. of benzene in a Preparation of 6-cyanoindole counter-current manner. The combined benzene 65 phases were dried (Na2SO4), filtered and evaporated to A solution containing 10.85g. of trans-4-cyano-g- give 6.8 g. of greenish solid; Distillation yielded 6.26 g. dimethylamino-2-nitrostyrene in 500 ml. of benzene of almost white solid which was dissolved in ether and was separated into two equal portions and to each was 3,976,639 15 16 added 215 mg. of 10% palladium on carbon. The sus tal, and 100 ml. of N,N-dimethylformamide. The reac pensions were shaken under an initial hydrogen pres tion vessel was immersed in an oil bath, preheated to sure of 3.5 atm. until the absorption of hydrogen 160, for 3.5 hours. The pot temperature was main ceased. The reaction was exothermic and was exter tained above 140 by continuous distillation of the nally cooled with a stream of air. The catalyst was formed ethanol...... removed by filtration and washed several times with The volatile components were remoyed by vacuum benzene. The benzene filtrates were combined and distillation at 25/0.5 mm., and the residual dark red then extracted with 2 x 100 ml. of 1M sulfuric acid, 2 solid was crystallized from 70 ml. of ether-petroleum X 150 ml. of water, and 150 ml. of 10% sodium bicar ether to give 20.55g of red needles having a melting bonate solution. The aqueous phases were back O point of 52°-55°. The mother liquor, after removal of washed with 100 ml. of benzene in a counter-current the solvents and distillation at 138-140/0.1 mm. manner. The combined benzene phases were dried yielded an additional 4.24 g. of red solid having a melt (Na2SO4), filtered, and evaporated to give 5.79 g. of ing point of 56-58. Total yield was 24.79g. (92%). A solid which was dissolved in 150 ml. of benzene and portion of the material was recrystallized to give trans filtered through 20 g. of alumina. After removal of the 5 fe-dimethylamino-5-fluoro-2-nitrostyrene as red crys solvent, the residue was sublimed (1 10/0.05 mm.) to tals having a melting point of 56-58. give 5.39 g of white crystalline material which, after Anal. Calcd. for CHFNO: C, 57.14; H, 5.28; F, crystallization from 30 ml. of benzene-petroleum ether, 9.03; N, 13.32 Found: C, 57.05; H, 5.36; F, 8.72; N, yielded 4.57 g. (65%) of 6-cyanoindole having a melt 13.39. ing point of 128-129. s 20 EXAMPLE 29 EXAMPLE 27 Preparation of 5-fluoroindole Preparation of 5,6-dimethylindole To a solution of 10.51 g of trans-g-dimethylamino-5- A 500-ml. three-necked flask fitted with a thermome 25 fluoro-2-nitrostyrene in 250 ml. of benzene in a 500 ter and i5-cm. Vigreux column connected to a de ml. Parr bottle was added a half teaspoon of Raney scending condenser with a receiver and nitrogen inlet nickel. The suspension was shaken under an initial was charged with 33.0 g. of 5-nitropseudocumene, 48.3 hydrogen pressure of 3.5 atm. until the absorption of g. of N,N-dimethylformamide diethyl acetal, and 200 hydrogen ceased. The catalyst was removed by filtra ml. of N,N-dimethylformamide. The reaction vessel 30 tion and washed several times with benzene. The ben was immersed in an oil bath, preheated to 165, for 31 zene filtrate was then extracted with 2 X 100 ml. of 1M hours. The pot temperature was maintained above 140 sulfuric acid, 2 X 150 ml. of water, and 150 ml. of 10% by continuous distillation of the formed ethanol. sodium bicarbonate solution. The aqueous phases were The volatile components were removed by vacuum back-washed with 100 ml. of benzene in a counter-cur. distillation at 25/0.5 mm. The residue was triturated 35 rent manner. The combined benzene phases were dried with methanol and the insoluble material crystallized (Na2SO4), filtered, and evaporated to give 5.23 g. of from 600 ml. methanol to give 25.5 g. (58%) of trans brown solid. Distillation (b.p. 85/0.5 mm.) yielded As-dimethylamino-2,5-dimethyl-4-nitrostyrene as dark 5.01 g of yellowish solid, which upon crystallization red needles having a melting point of 130-131. . from pentane yielded 2.36 g. of 5-fluoroindole as white Anal. Calcd. for CHNO: C, 65.43; H, 7.32; N, 40 leaflets having a melting point of 46.5-47. The 12.72 Found: C, 65.17; H, 7.29; N, 12.88. mother liquor was percolated through 10 g. of alumina The methanol triturate was evaporated and the resi and the product eluted with ether. Sublimation of this due digested with petroleum ether (20 x 100 ml.). The material gave an additional 1.07 g. of product having a petroleum ether extracts yielded 14.5 g. of red solid melting point of 46-47. Thus, the total yield was 3.44 which after dissolution in 50 ml. of ethanol was added 45 g. (51%). to a solution of 140 g. of ferrous sulfate heptahydrate, 500 ml. of water, and 85 ml. of concentrated ammonia. EXAMPLE 30 The resulting mixture was heated at reflux for 15 min Preparation of utes, and the precipitate which formed was removed by trans-4-(A-dimethylaminovinyl)-3-nitrobenzaldehyde filtration. The filtrate was concentrated by evaporation 50 dimethyl acetal and then extracted with carbon tetrachloride (3 x 200 A 250-ml. three-necked flask fitted with a thermome ml.). The combined organic phases were dried (Na2 ter and a 15-cm. Vigreux column connected to a de SO), filtered, and evaporated. The residue was perco scending condenser and receiver with a nitrogen inlet lated through a dry column of alumina with 5% ben was charged with 1 1.18 g. of 4-methyl-3-nitrobenzalde zene-hexane. The fractions were combined and the 55 hyde dimethyl acetal, 11.8 g. of N,Ndimethylforma solvents removed to give 450 mg. of a white solid. The mide diethyl acetal, and 50 ml. of N,N-dimethylformia material was crystallized from 8 ml. of petroleum ether mide. The reaction vessel was immersed in an oil bath, to give 277 mg. of 5,6-dimethylindole as white needles preheated to 160, for 8 hours. The pot temperature having a melting point of 64.5-65.5. was maintained above 140 by continuous distillation EXAMPLE 28, 60 of the formed ethanol. The volatile components were removed by vacuum Preparation of distillation at 25/0.5 mm. The dark red solid residue trans-g-dimethylamino-5-fluoro-2-nitrostyrene was triturated with cold methanol. The remaining solid A 250-ml. three-necked flask fitted with a thermome was crystallized from 30 ml of ether-pentane to obtain ter and a 15-cm. Vigreux column connected to a de 65 7.22 g of trans-4-(g-dimethylaminovinyl)-3-nitroben scending condenser and receiver with a nitrogen inlet zaldehyde dimethyl acetal having a melting point of was charged with 20.00 g. of 5-fluoro-2-nitrotoluene, 67-68.5. The residue, obtained after evaporation of

56.0 g of 85% of N,N-dimethylformamide diethylace the mother liquor, was crystallized from 5 ml. of ether 3,976,639 8 pentane to give an additional 0.57 g. of product having ml. of ethyl acetate to give an additional 2.21 g of a melting point of 66.5°-68.0. Thus, the total yield was product having a melting point of 134-136. Thus, the 7.79 g (55%). total yield was 6.81 g. (62%). Anal. Calcd. for CHNO: C, 58.63; H, 6.81; N, Anal. Calcd. for CHNO: C, 59.99; H, 5.49; N, 10.52 Found: C, 58.69; H, 6.75, N, 10.40. 12.72 Found: C, 60.23; H, 5.22; N, 12.66. EXAMPLE 3 EXAMPLE 34 Preparation of 6-formylindole Preparation of trans-g-dimethylamino-4-isopropyl-2-nitrostyrene To a solution containing a 5.31 g. of trans-4-(£3-dime 10 thylaminovinyl)-3-nitrobenzaldehyde dimethyl acetal In a 100-ml. three-necked flask fitted with a ther in 250 ml of benzene in a 500-ml. Parr bottle was mometer and 8-cm. Vigreux distillation head con added a half teaspoon of Raney nickel. The suspension nected to a descending condenser and receiver with a was shaken under an initial hydrogen pressure of 3.5 nitrogen inlet were placed 17.9 g of 2-nitro-p-cymene, atm. until the absorption of hydrogen ceased. The cata 5 17.9 g of N,N-dimethylformamide dimethyl acetal, lyst was removed by filtration and was washed several and 25 ml. of N,N-dimethylformamide. The flask was times with benzene. The residue, obtained by the evap immersed in a 150 oil bath for 42 hours, during which oration of the benzene filtrate, was chromatographed time 8 ml. of methanol distilled. The contents of the on 150 g. alumina. The fractions eluted with 20% ben reaction vessel were transferred to a Claisen flask. zene-hexane followed by ether were combined and Vacuum distillation, after removal of the more volatile rechromatographed on 300 g. of alumina. The fractions components up to 130/0.06 mm., afforded 19.6 g. eluted with ether were combined (1.33 g.) and crystal (84%) of trans-g-dimethylamino-4-isopropyl-2-nitros lized from ether-pentane to give 0.76 g. (26%) of 6for tyrene as a red liquid (b.p. 138-140/0.06 mm.). An mylindole having a melting point of 127-128.5. analytical sample obtained from a previous experiment 25 gave: EXAMPLE 32 Anal. Calcd. for CHINO: C, 66.64; H, 7.74; N, Preparation of 6-formylindole dimethyl acetal 11.95 Found: C, 66.69; H, 7.89; N, 11.95. To a solution containing 6.65 g. of trans-4-(g-dime EXAMPLE 35 thylaminovinyl)-3-nitrobenzaldehyde dimethyl acetal in 125 ml. of benzene were added 1.0 g. potassium Preparation of 6-isopropylindole carbonate and 0.332 g. of 10% palladium on carbon. A solution containing 1 1.7l g. of trans-g-dime The suspension was stirred under an atmosphere of thylamino-4-isopropyl-2-nitrostyrene in 125 ml. of ben hydrogen. After the hydrogen absorption ceased, the zene and 0.234 g. of 10% palladium on carbon were catalyst was removed by filtration and was washed stirred under a hydrogen atmosphere. After hydrogen several times with benzene. Evaporation of the filtrate 35 absorption ceased, the catalyst was removed by filtra gave 4.95 g. of residue which on short-path distillation tion and was washed several times with benzene. The yielded 1.74 g. of purplish oil, which crystallized on benzene filtrate was then extracted with 2 X 50 m. of cooling. Crystallization of this solid from 10 ml. of 1N sulfuric acid, 100 ml. of water, and 50 ml. of 10% ether-petroleum ether yielded 1.18 g. of white solid sodium bicarbonate solution. The aqueous phases were having a melting point of 62-63.5. The mother liquor 40 back-washed with 100 ml. of benzene in a counter-cur was applied to 10 g of alumina and an additional 0.52 rent manner. The combined benzene phases were dried g. of the same product was eluted with 1:1 ether (Na2SO4), filtered, and evaporated to give 7.47 g. of a petroleum ether. Recrystallization from ether green semi-solid. Trituration of this material with 3 X petroleum ether yielded 1.34 g. (27%) of 6-formylin 20 ml. of ether gave 6.8 g. of ether-soluble green liquid dole dimethyl acetal having a melting point of 45 which was distilled (b.p. 79-87/0.05 mm.). Crystalli 62-63.5°. zation of the yellow distillate from pentane yielded 4.04 Anal. Calcd. for CHNO: C, 69.09; H, 6.35; N, g. (51%) of 6-isopropylindole having a melting point of 7.33 Found: C, 69.22; H, 6.76; N, 7.34. 404. 50 Anal. Calcd. for CHN: C, 82.97; H, 8.23; N, 8.80 EXAMPLE 33 Found: C, 83.20; H, 8.23; N, 8.91. Preparation of trans-4-(6-dimethylaminovinyl)-3-nitrobenzaldehyde EXAMPLE 36 A 100-ml. three-necked flask fitted with a reflux Preparation of condenser with a nitrogen inlet was charged with 8.25 55 trans-6-dimethylamino-4-methoxy-2-nitrostyrene g. of 4-methyl-3-nitrobenzaldehyde, 11.1 g of N,N- In a 250-ml. three-necked flask fitted with a ther dimethylformamide diethyl acetal, and 50 ml. of N,N- mometer, a 15-cm. Vigreux column connected to a dimethylformamide. The reaction vessel was immersed descending condenser and a receiver with a nitrogen in an oil bath, preheated to 145, for 45 minutes. inlet were placed 25.1 g of 4-methyl-3-nitroanisole, The volatile components were removed by vacuum 60 42.0 g of 88% N,N-dimethylformamide diethyl acetal distillation at 25/0.5 mm. The dark red residue was and 150 ml. of N,N-dimethylformamide. The flask was triturated three times with 10 ml. of petroleum ether. immersed in an oil bath, preheated to 165, for 70 - The solid residue gave, on crystallization from metha hours. The pottemperature was maintained above 140 nol, 5.47 g. and on recrystallization from 100 ml. of by continuous distillation of the formed ethanol. methylene chloride-ether, 4.61 g. of trans-4-(6dime 65 The volatile components were removed by vacuum thylaminovinyl)-3-nitrobenzaldehyde as red crystals distillation under nitrogen until the head temperature having a melting point of 134°-136. The residue ob rose above 95/0.05 mm. The remaining dark liquid tained from the mother liquors was crystallized from 12 was then transferred to a Claisen flask and distilled to 3,976,639 19 20 yield 21.2 g (64%) of trans-g-dimethylamino-4- dimethylamino-5-methoxy-2-nitrostyrene having a methoxy-2-nitrostyrene as a dark red liquid having a melting point of 68.5°-69.5°. boiling point of 152/0.06 mm. - Anal. Calcd. for CHNO: C, 59.45; H, 6.35; N, EXAMPLE 40 Preparation of 12.60. Found: C, 59.68; H, 6.53; N, 12.64. . . trans-(3-dimethylamino-5-methoxy-2-nitrostyrene EXAMPLE 37 A solution of 3.0 g of 3-methyl-4-nitroanisole, 5.1 g. Preparation of 6-methoxyindole of N,N-dimethylformaide dicyclohexyl acetal, and 25 To a solution of 13.478 g. of trans-g-dimethylamino 0 ml. of N,N-dimethylformamide was heated at reflux 4-methoxy-2-nitrostyrene in 250 ml. of benzene in a under a nitrogen atmosphere for 40 hours and then was 500-ml. Parrbottle was added a half teaspoon of Raney transferred to a Claisen flask. Vacuum distillation gave, nickel. The suspension was shaken under an initial after removal of the volatile components, 1.89 g. of a hydrogen pressure of 3.5 atm. until hydrogen absorp red liquid (b.p. 158/0.04 mm.) which crystallized on tion ceased. The catalyst was removed by filtration and 15 scratching to give a solid, having a melting point of was washed several times with benzene. The benzene 61–64. Recrystallization from 10 ml. of ether and 7 filtrate was then extracted with 2 X 100 ml. of 1M ml. of petroleum ether gave 1.46 g (36%) of trans-g- sulfuric acid, 2 X 100 ml. of water, and 100 ml. of 10% dimethylamino-5-methoxy-2-nitrostyrene having a sodium bicarbonate solution. The aqueous phases were melting point of 67.5°-69. back-washed with 100 ml. of benzene in a counter-cur 20 rent manner. The combined benzene phases were dried EXAMPLE 41 (Na2SO4), filtered, and evaporated to give 6.7 g of Preparation of yellowish solid which, on distillation, yielded 5.64 g. trans-(3-dimethylamino-5-methoxy-2-nitrostyrene (63%) of 6-methoxy-indole as an almost white solid A solution of 16.71 g of 3-methyl-4-nitroanisole, having a melting point of 88–90. 25 30.00 g. of N,N-dimethylformamide dibenzyl acetal, EXAMPLE 38 and 50 ml. of N,N-dimethylformamide was heated at Preparation of reflux under a nitrogen atmosphere for 17 hours and trans-g-dimethylamino-5-methoxy-2-nitrostyrene then was transferred to a Claisen flask. Vacuum distil 30 lation gave, after removal of the volatile components, A 250-ml. three-necked flask fitted with a thermome 9.42 g. of a red liquid (b.p. 158/0.10 mm.) which gave ter and a 15-cm. Vigreux column connected to a de a tacky solid upon scratching. Recrystallization from scending condenser and receiver with a nitrogen inlet was charged with 16.7 g. of 5-methoxy-2-nitrotoluene, 150 ml. of etherpetroleum ether gave 7.15g. (32%) of 32.3 g. of N,N-dimethylformamide diethyl acetal, and trans-(3-dimethylamino-5-methoxy-2-nitrostyrene hav 100 ml. of N,N-dimethylformadide. The reaction vessel 35 ing a melting point of 68.0°-69.5°. was then immersed in an oil bath, preheated to 165, EXAMPLE 42 for 22 hours. The pot temperature was maintained Preparation of above 140 by continuous distillation of the formed trans-g-dimethylamino-5-methoxy-2-nitrostyrene ethanol. The volatile components were removed by vacuum 40 A solution of 8.35g. of 3-methyl-4-nitroanisole, 8.76 distillation at 25/0.5 mm. The resulting dark red solid g. of N,N-dimethylformamide ethylene acetal (2-dime residue was crystallized from 100 ml. of ether and 75 thylamino-1,3-dioxolane), and 25 ml. of N,N-dimethyl ml. of petroleum ether, and yielded 17.0 g of trans-g- formamide was heated at 150 under a nitrogen atmo dimethylamino-5-methoxy-2-nitrostyrene as red crys sphere for 53 hours and then was transferred to a tals having a melting point of 67.5°-69.5°. The residue, 45 Claisen flask. Vacuum distillation gave, after removal obtained after evaporation of the mother liquor, was of the volatile components, 4.00 g. of a red liquid (b.p. triturated with 10 ml. of ice-cold methanol. Recrystalli 149/0.07 mm.) which formed a gummy solid on zation of the resulting solid (2.8 g.) from 10 ml. of scratching. Crystallization from 15 ml. of methanol methanol gave an additional 2.7 g of product having a 50 gave 1.57 g. (14%) of trans-g-dimethylamino-5- melting point of 68-69. Thus, the total yield was 19.7 methoxy-2-nitrostyrene having a melting point of g. (89%). 68-69. S. Anal Calcd. for CHNO: C, 59.45; H, 6.35; N, 12.60 Found: C, 59.53; H, 6.39; N, 12.65. EXAMPLE 43 55 Preparation of trans-5-methoxy-2-nitro-g-pyr EXAMPLE 39 rolidinostyrene . Preparation of To a 100-ml. three-necked flask fitted with a ther trans-g-dimethylamino-5-methoxy-2-nitrostyrene mometer and 8-cm. Vigreux column connected to a A solution of 8.35 g. of 3-methyl-4-nitroanisole, descending condenser and receiver with a nitrogen 14.58 g. of N,N-dimethylformamide dineopentyl ace 60 inlet was added 8.35 g of 3-methyl-4-nitroanisole, 8.0 tal, and 50 ml. of N,N-dimethylformamide was heated g. of N-formylpyrrolidine dimethyl acetal, and 25 ml. of at reflux under a nitrogen atmosphere for 41 hours and N,N-dimethylformamide. The solution was heated at then was transferred to a Claisen flask. Vacuum distill 135 for two hours with continuous distillation of the lation gave, after removal of the volatile components methanol which formed in the reaction. 4.75 g. of a red liquid (b.p. 152/0.04 mm.) which 65 - Removal of the volatile components under vacuum crystallized on scratching to give a solid having a melt (40 bath/1 mm.) and recrystallization of the red resi ing point of 61-65. Recrystallization from 70 ml. of due from 75 ml. of methanol gave, in two crops, 11.7 g. ether-petroleum ether gave 3.70 g. (33%) of trans-(3- (94%) of red needles, melting point 71-72. 3,976,639 21 22 Recrystallization of a portion of the first crop from hours. The pottemperature was maintained above 140 methanol gave an analytical sample of trans-5- by continuous distillation of the formed ethanol. methoxy-2-nitro-g-pyrrollidinostyrene, melting point The volatile components were removed by vacuum 7 10.729. distillation at 25/0.05 mm. The reside was crystallized Anal. Calcd. for CHNO: C, 62.89; H, 6.50; N, from 300 ml. of ethanol to give 17.0 g. (72%) of trans 1 1.28 Found: C, 62.87; H, 6.58; N, 11.24. g-dimethylamino-4,5-methylenedioxy-2-nitrostyrene as red-brown crystals having a melting point of EXAMPLE 44 14-1 6. Anal. Calcd. for CHNO: C, 55.93; H, 5.12; N, Preparation of 5-methoxyindole 10 To a solution containing 11.1 g. of trans-g-dime 11.86 Found: C, 56.09; H, 5.17; N, 11.56. thylamino-5-methoxy-2-nitrostyrene in 250 ml. of ben EXAMPLE 47 zene in a 500-ml. Parr bottle was added 230 mg. of 10% Preparation of 5,6-methylenedioxyindole palladium on carbon. The suspension was shaken under an initial hydrogen pressure of 3.5 atm. until the ab 15 A solution containing 11.83 g of trans-g-dime sorption of hydrogen had ceased. The catalyst was thylamino-4,5-methylenedioxy-2-nitrostyrene in 250 removed by filtration and was washed several times ml. of benzene was shaken with 1 teaspoonful of Raney with benzene. The benzene filtrate was then extracted nickel under an initial hydrogen pressure of 3.5 atm. with 2 X 100 ml. of 1M sulfuric acid, 2 X 100 ml. of until hydrogen absorption ceased. The catalyst was water, and 100 ml. of 10% sodium bicarbonate solu 20 removed by filtration and washed several times with tion. The aqueous phases were back-washed with 100 benzene. The filtrate and washings were washed with ml. of benzene in a counter-current manner. The com 1M sulfuric acid (2 X 100 ml.), 100 ml. of water, and bined benzene phases were dried (Na2SO4), filtered 100 ml. of 10% sodium bicarbonate. The combined and evaporated to give 5.45 g. of a brown solid. Distill organic phases were dried (Na2SO4), filtered and evap 25 orated to give 5.52g. of a brown solid. A solution of the lation yielded 5.26 g. (72%) of 5-methoxyindole as a residue in benzene was percolated through a column of slightly yellowish liquid, having a boiling point of alumina. The eluate, after evaporation of the solvent, 108/0.3 mm., which crystallized on cooling to an off was sublimed at 110/0.2 mm. to give 5.2 g of a white white solid having a melting point of 56-57. solid which, upon crystallization from methylene chlo EXAMPLE 45 30 ride-hexane, yielded 4.50 g (50%) of 5,6-methylenedi oxyindole as white needles having a melting point of Preparation of 4,5-methylenedioxy-2-nitrotoluene 109.5-1 1 0.5°. A solution containing 75.0 g of piperonal, 200 ml. of glacial acetic acid, and 1 ml. of cone. hydrochloric acid EXAMPLE 48 was shaken with 4 g. of 10% palladium on carbon in an 35 Preparation of autoclave under an initial hydrogen pressure of 35 atm. trans-(3-dimethylamino-6-methyl-2-nitrostyrene until hydrogen absorption ceased. The catalyst was A 250-ml. three-necked flask fitted with a thermome removed by filtration. ter and a 15-cm. Vigreux column connected to a de The filtrate was transferred to a three-neck flask scending condenser and receiver with a nitrogen inlet fitted with a thermometer, mechanical stirrer, and a 40 was charged with 15.22 g of 3-nitro-o-xylene, 20.00 g. dropping funnel. A solution containing 80.0 ml. of of N,N-dimethylformamide diethyl acetal, and 100 ml. conc. nitric acid in 200 ml. of glacial acetic acid was of N,N-dimethylformamide. The reaction vessel was added to the reaction vessel with stirring over a period immersed in an oil bath, preheated to 160, for 24 of 1 hour. The reaction vessel was maintained below. hours. The pottemperature was maintained above 140 10 by means of an ice-acetone bath. After the addition 45 by continuous distillation of the formed ethanol. was complete, the reaction mixture was allowed to The volatile components were removed by vacuum reach room temperature and was then poured over a distillation until the head temperature began to rise mixture of sodium hydroxide and ice. The resulting above 90/0.1 mm. Further distillation yielded 14.54 g. suspension was extracted with (chloride 94 X 1000 (70%) of trans-g-dimethylamino-6-methyl-2-nitrosty ml.). The combined organic phases were dried (Na2 50 rene as a dark red liquid having a boiling point of SO), filtered, and evaporated to give a yellow solid, 108.10.05 mm. which after crystallization from 300 ml. of ethanol, Anal. Calcd. for CHNO: C, 64.06; H, 6.84; N, gave 76.5 g. (84%) 0f 4,5-methylenedioxy-2-nitrotol 13.58 Found: C, 63.79; H, 7.28; N, 13.71. uene as yellow needles having a melting point of 55 85-86.5°. EXAMPLE 49 Preparation of 4-methylindole EXAMPLE 46 To a solution containing 9.327 g. of trans-9-dime Preparation of thylamino-6-methyl-2-nitrostyrene in 250 ml. of ben trans-g-dimethylamino-4,5-methylenedioxy-2-nitrosty 60 Zene in a 500-ml. Parr bottle was added a half teaspoon rene of Raney nickel. The suspension was shaken under an A 250-ml. three-necked flask fitted with a thermome initial hydrogen pressure of 3.5 atm. until the absorp ter and a 15-cm. Vigreux column connected to a de tion of hydrogen had ceased. The catalyst was removed scending condenser with a receiver and a nitrogen inlet by filtration and washed several times with benzene. was charged with 18.1 g of 4,5-methylenedioxy-2- 65 The benzene filtrate was then extracted with 2 X 100 nitrotoluene, 20 g. of N,N-dimethylformamide diethyl ml. of 1M sulfuric acid, 2 X 100 ml. of water, and 100 acetal, and 100 ml. of N,N-dimethylformamide. The ml. of 10% sodium bicarbonate soltuion. The aqueous reaction vessel was immersed in a 165 oil bath for 17.5 phases were back-washed with 150 ml. of benzene in a 3,976,639 23 24 counter-current manner. The combined benzene From a previous experiment, an analytical sample of phases were dried (Na2SO4), filtered, and evaporated trans-g-dimethylamino-4,5-dimethoxy-2-nitrostyrene, to give 3.89 g. of a brown oil which after two distilla a red solid, m.p. 125-126, was obtained by crystalliza tions yielded 3.37 g. (57%) of 4-methylindole as a tion from methanol. yellow liquid having a boiling point of 82/0.4 mm. 5 Anal. Calcd. for CHNO: C, 57.13; H, 6.39; N, 11.1 Found: C, 57.47; H, 6.65; N, 11.35. EXAMPLE 50 Preparation of EXAMPLE 53 trans-G-dimethylamino-3-methyl-2-nitrostyrene Preparation of 5,6-dimethoxyindole O A 500-ml. three-necked flask fitted with a thermome To a solution of the crude trans-3-dimethylamino ter, a 15-cm. Vigreux column connected to a descend 4,5-dimethoxy-2-nitrostyrene obtained in Example 52 ing condenser and receiver with a nitrogen inlet was in 2.0 . of benzene was added 10 g. of 10% palladium charged with 30.23g of 2-nitro-m-xylene, 64.77 g. of on carbon and the suspension was shaken under an N,N-domethylformamide diethyl acetal, and 200 ml. of 5 initial hydrogen pressure of 7 atm. After hydrogen N,N-dimethylformamide. The reaction vessel was then absorption ceased (3 equivalents), the catalyst was immersed in an oil bath, preheated to 165, for 46 filtered and washed with 2 l. of benzene. The combined hours. The pottemperature was maintained above 140 filtrate and washings were concentrated to 2 l. in vacuo by continuous distillation of the formed ethanol. and the organic phase washed with 3 X 300 ml of IN The volatile components were removed by vacuum 20 sulfuric acid, 200 ml. of 1N sodium hydroxide and 200 distillation at 25/0.5 mm. The resulting dark red liquid ml. of water. The aqueous phases were back-washed in residue was distilled under vacuum, the forerun (15.32 a counter-current manner with 500 ml. of benzene. The g., b.p. 93-99/0.2 mm.) was a mixture of trans-g- combined organic phases were dried (Na2SO4) and dimethylamino-3-methyl-2-nitrostyrene and 2-mitro-m- filtered through 280 g. of silica gel. The filtrate was xylene (ratio of 3:5 resp.). Subsequent fractions 25 evaporated and the residue triturated with ether. The yielded 16.60 g. (40%) of trans-g-dimethylamino-3- residual white solid was crystallized from 700 ml. of methyl-2-nitrostyrene as a red liquid (b.p. benzene to give (in two crops) 24.5 g. (28%) of 5,6- 1 16-17/0.04 mm.) which crystallized on cooling and dimethoxyindole as white crystals, m.p. 154-155. had a melting point of 75-77. Anal. Calcd. for CHNO: C, 64.06; H, 6.84; N, EXAMPLE 54 13.58 Found: C, 63.95; H, 6.70; N, 13.37. Preparation of trans-4,5-dibenzyloxy-6-dimethylamino-2-nitrostyrene EXAMPLE 51 In a 1-l. three-necked flask fitted with a thermometer Preparation of 7-methylindole and 8-cm. Vigreux distillation head connected to a To a solution containing 10.31 g of trans-g-dime 35 descending condenser and receiver with a nitrogen thylamino-3-methyl-2-nitrostyrene in 250 ml. of ben inlet were placed 87.3 g of 4,5-dibenzyloxy-2-nitrotol zene was added 103 mg. of 10% palladium on carbon. uene, 38.0 g of N,N-dimethylformamide dimethyl ace The suspension was shaken under an initial hydrogen tal, and 250 ml. of N,N-dimethylformamide. The solu pressure of 3.5 atm. until the absorption of hydrogen tion was heated at 140 for 48 hours with continuous had ceased. The catalyst was removed by filtration and removal of the methanol as it formed. The volatile was washed several times with benzene. The benzene components were removed by vacuum distillation filtrate was then extracted with 2 X 100 ml. of 1M (bath temperature 65/0.1 mm.). Crystallization of the sulfuric acid, 100 ml. of water, and 100 ml. of 10% residue from methanol (2.5 l.) yielded (two crops) 86.8 sodium bicarbonate solution. The aqueous phases were 45 g. (86%) of red solid, m.p. 99-100. back-washed with 100 ml. of benzene in a counter-cur An analytical sample, obtained from a previous ex rent manner. The combined benzene phases were dried periment, was characterized as trans-4,5-dibenzyloxy (NaSO), filtered and evaporated to give 4.628 g. of £8-dimethylamino-2-nitrostyrene, m.p. 99.5-101. residue which, on distillation under vacuum, gave Anal. Calcd. for CHNO: C, 71.27; H, 5.98; H, 4.203 g. (b.p. 109/0.9 mm.) of light tan solid. Filtra 6.93 Found: C, 71.09; H, 6.30; N, 6.83. tion of the distillate through 50 g. of alumina and crys 50 tallization from 30 ml. of ether-petroleum ether gave EXAMPLE 55 3.15 g. (48%) of 7-methylindole as white crystals hav Preparation of 5,6-dibenzyloxyindole ing a melting point of 83-84. To a solution of 10.1 1 g of trans-4,5-dibenzyloxy-3- EXAMPLE 52 55 dimethylamino-2-nitrostyrene in 250 ml. of benzene in a 500-ml. Parr bottle was added a teaspoon of Raney Preparation of nickel. The suspension was shaken under an initial trans-g-dimethylamino-4,5-dimethoxy-2-nitrostyrene hydrogen pressure of 3.5 atm. until the absorption of A 1-1. three-necked flask fitted with a thermometer hydrogen ceased. The catalyst was removed by filtra and a 15-cm. Vigreux column connected to a descend 60 tion and washed several times with benzene. The ben ing condenser with a receiver and nitrogen inlet was zene filtrate was extracted. with 3 X 100 ml. of N charged with 98.6 g. of 4,5-dimethoxy-2-nitrotoluene, sulfuric acid, 250 ml. of water, 3 x 100 ml. of 1N so 500 ml. of N,N-dimethylformamide, and 120 g. of N,N- dium hydroxide and 250 ml. of water. The aqueous dimethylformamide dimethyl acetal. The reaction tem phases were back-washed in a counter-current manner perature was maintained at 140 for 42 hours. The 65 with 100 ml. of benzene. : volatile compounds were removed by vacuum distilla The combined organic phases were dried (Na2SO4), tion at 25/0.1 mm. to give a solid residue of crude filtered and evaporated to give 7.67 g. of a brown solid trans-(3-dimethylamino-4,5-dimethoxy-2-nitrostyrene. which was dissolved in a minimum amount of benzene 3,976,639 25 26 and was chromatographed on 40 g. of silica gel pre 2. A compound in accordance with claim 1, wherein R" is hydrogen and R2 is lower alkoxy. pared in hexane. Eluted fractions benzene-hexane 3. A compound in accordance with claim 2, trans-6- (1:1) were pooled according to thin layer chromatog dimethylamino-4-methoxy-2-nitrostyrene. raphy. Evaporation of the solvents and recrystallization 4. A compound in accordance with claim 1, wherein of the residue (5.8 g.) from benzene-hexane yielded R" is hydrogen and R." is phenyl-lower alkoxy. 4.34 g. (54% of 5,6-dibenzyloxyindole as white nee 5. A compound in accordance with claim 4, trans-5- dles, m.p. 1 12-113. benzyloxy-6-dimethylamino-2-nitrostyrene. We claim: 6. A compound in accordance with claim 1, wherein 1. A compound of the formula 10 R" is hydrogen and R2 is halogen. 7. A compound in accordance with claim 6, trans-5- chloro-G-dimethylamino-2-nitrostyrene.

8. A compound in accordance with claim i, trans-2- nitro-G-piperidinostyrene. 15 9. A compound in accordance with claim 1, trans-2- nitro-6-pyrrolidinostyrene. 10. A compound in accordance with claim 1, trans-g- dimethylamino-4,5-dimethoxy-2-nitrostyrene. 11. A compound in accordance with claim 1, trans 20 4,5-dibenzyloxy-6-dimethylamino-2-nitrostyrene. 12. A compound in accordance with claim 1, trans-fé wherein Ru' is hydrogen, lower alkoxy, formyl, phenyl dimethylamino-4,5-methylenedioxy-2-nitrostyrene. lower alkoxy, halogen or di-lower alkoxymethyl, R' is 13. A compound in accordance with claim 1, trans-4- lower alkoxy, formyl, phenyl-lower alkoxy, halogen or (A-dimethylamino-vinyl)-3-nitrobenzaldehyde. di-lower alkoxymethyl, and when taken together, R.' 14. A compound in accordance with claim 1, trans-4- and R2 are methylenedioxy; R and Rs, independently, 25 (A-dimethylamino-vinyl)-3-nitrobenzaldehyde dimeth are lower alkyl, and when taken together, are piperi ylacetal. dino or pyrrolidino. sk k -k -k sk