3- (2-PYRROLIDINYL)INDOLES
July, 1964
dry ether, and reacted with lithium aluminum hydride (20 g.) in dry ether to give the pyrrolidine as a colorless oil, b.p. 130-132' (0.8 mm.), n Z o1.5216; ~ yield 20 g., 297,. Anal. Calcd. for ClsHpsNO: C, 77.7; H, 10.2; S, 5.7. Found: C, 77.7; H, 10.1; N, 5.8. m- [I '-( l-Methyl-3-pyrrolidinyl)butyl] phenol.-This was prepared following method C and isolated as a hygroscopic (+)-tartrate, m.p. 70" (sealed tube). C, U 59.5; ~ : H, 7.6; S, 3.7. Found: Anal. Calcd. for C ~ S H ~ ~ N C, 59.5; H, 7.9; N, 4.0. m- [ 1 '-( 1-Methyl-3-pyrrolidinyl)butyl]phenyl Acetate.-This
415
waa prepared from the above following method D and isolated as a colorless oil, b.p. 134-136" (0.8 mm.), n 2 0 1.5158. ~ Anal. Calcd. for C ~ ~ N ~ S NC,O ~74.1; : H, 9.2; N, 5.1. Found: C, 74.3; H, 9.0; N, 5.3.
Acknowledgment.-The authors thank Dr. R . E. Bowman for helpful discussions, N r . F. H. Oliver for the microanalyses, and Miss Sue Ketchuni, U s . S. Stanat, and A h . J. Grant for help in the pharmacological work.
Synthesis and Pharmacological Activity of 3-(2-Pyrrolidinyl)indoles GILBERTA. YOUNGDALE, DOUGLAS G. ANGER, WILLIAM c. -h-THOKY, JOHSP. DAVANZO, ~\IARGARET E. GREIG,RICHARD T.'. HEINZELMBK, HUGHH. I > l l ~ ' :Id (54) aiid illethyl fol.liiat(1 (Ilicthod (i). (l,~~,.i-tri~~i~tliyl-~-pyriolidiii~~l)iiidole (59) i t a s prvpared in Ion- yield by alkylation of 54 \ritli iii~thyl iodide. -1cetylatioii of 54 a t rooin teiiiperature with acetic anhydride afforded the iiiorioacetyl derivative Ii' (infrared C=O band, 1612 c111.-l) which lcd to :3-(1ethyl->,5-diiiiethyl-2-pyrrolidinyl)iiidole (60) on lithiim I aluiiiiiiiiiii liydridt. 1 rductioii (inethod ( i ) . hcc~tylatioii of 54 at ieflux teiiiperature gave the diacetyl deriT-ati\ (' \ * wliic*lielion-cd ('4') lmids in thc iiifrarcd a t l(iNand 1710 (3111. '
July, 1964
419
3-(2-PYRROLIDIXYL)IXDOLES
H
2-pyrrolidinylidene)-XH-indoles (products of method A) is based on analytical and spectral data, and on independent syntheses as shown for conipounds 29 and 31. 3-(2-I’yrrolidinyl)iiidole (29) was prepared by catalytic hydrogenolysis of 3-(1-benzyl-2-pyrrolidiny1)indole (48), aiid also by catalytic hydrogenation of 3-(l-pyrroliii-2-y1)indole (24). This structure (29) was assigned by Fuhlhage and T’anderWerfj to the coiiipound obtained from indole and 1-pyrroline. The melting point of our product is siiiiilar to that reported by these authors. Compound 29 was iiiade to react with inethyl forinate and the resulting formyl intermediate T’II
H
54
IV
l-Jlethyl-3-( 1-inethyl-2-pyrrolidiiiy1)iridole(43) was prepared by reaction of 31 with sodaniide followed by iiiethyl iodide, and also by treatment of 1 with methyl iodide followed by the reduction of the iiiterniediate VI with sodium borohydride. The same interinediate (VI) resulted from the reaction of 28 with methyl iodide. The fact that the identical product 43 was obtained from these three sequences established unequi\rocally the position of inethylatiori in the processes 1 to TI and 28 to VI.
-
n
2%
Y C
1
H 3 *-
I
I
H
VI1
24
I
CK VI
28
r
A 31
Treatment of 1 with 2-diethylaminoethyl chloride followed by sodium hydroxide, sodium borohydride, and then hydrogen chloride produced 1-(2-diethylaminoethyl)-3-(l-niethyl-2-pyrrolidinyl)indole dihydrochloride (45). 3-(1-~lethyl-2-pyrrolidinyl)i1idol-~5-ol (35) and 3-(1niethyl-2-pyrrolidinyl)indol-6-ol (41) were prepared from 9 and 10, respectively, by catalytic debenzylatioii employing palladium-on-charcoal as the catalyst. Xlthough the reduction of 9 could be stopped before hydrogenolysis of the pyrrolidine ring occurred, it was necessary to use the hydrochloride of 10 to enable the isolation of the desired product 41. Troxler, et aZ.,1° previously had employed the hydrochlorides of benzyloxygraniines to prevent hydrogenolysis of the dimethylamine moiety. Proof of the structure of &(l-substituted 2-pyrrolidiny1)indoles produced by reduction of %(l-substituted (10) 1- Troxler I (19a .
beenian. and \ Hoflndnn H e i r
Ch?m S c f n 42, 2073
was reduced with lithium aluininuni hydride to produce 31 identical with the material prepared via method A. Xlkylation and acetylation experiments were conducted with 3-(l-pyrrolin-2-yl)indole(24). Xlkylation of 24 with methyl iodide led to the hydriodide of 1 which on being made basic afforded 3H-indole (1) identical with the coiiipound prepared by method A. Thus, the position of methylation in the sequence 24 to 1 was established unequivocally. Acetylation of 24 with one equiralent of acetic anhydride in benzene afforded the inonoacetyl derivative VIII. It showed a C=O band at 1712 c1n-l and A, 305 nip and was converted to 24 on attempted crystallization from methanol. Treatment of VI11 with methyl iodide afforded niethiodide I X (C=O a t 1723 cin-‘; XI,,,, 299 nip) which on heating with mater gave the hydriodide of 1, thus confirming the assigiinient of the position of the acetyl group in YIII. Xcetylation of 24 with excess acetic anhydride in hot pyridinell gave the diacetyl derivative X (C=O a t 1637, 1708 cni.-’; A,, 301 mp) which resisted alkylation upon refluxing for 21 hr. with methyl iodide. The possibility of utilizing VI as an enamine precursor was investigated. Treatment of 1-1 with base afforded an oil which showed A,, 293 nip ( E 6500) in (11) Cf. .\, Brossi, Ii. Besendorf, B. Pellniont, AI. Walter, and 0. Selinider, ibid., 43, 1459 (1960).
July, 19G4
3-(2-PYRROLIDINYL)IKDOLES
shock (an escape response) stopped both the shock and the noise immediately. A bar press during the noise before the shock (an avoidance response) stopped the noise and prevented the occurrence of any shock on that trial. The electric shock was 260 volts, 60 cycles a.c. delivered to the rat through a 150,000 ohm series resistor and through a grid scrambler (type 45 Automatic Electric stepping switch). Animals were teated every fourth day. For drug testing, animals were required to avoid on 9Sc? or more of the trials. RIost animals developed such avoidance in four 10-hr. training periods. Subsequent test periods lasted 5.75 hr., and i.p. injections ($1-ith a blunt no. 18 needle to prevent acridental injection into the gastrointestinal tract) were given after the first 45 min. Before testing drugs, rats were tested with 5.9 or 6.9 mg./kg. of chlorpromazine hydrochloride and saline. Aninials were used only when chlorpromazine produced a t least 120 escape responses, ix.,when on at least 120 of the 200 trials the avoidance response to noise was eliminated, but the escape response to shock occurred. Most animals shoxed this reac*tion, though a few, especially when the loiver dose was used, required a second injection. This chlorpromazine control was run after every 10 test runs or less, as was a saline control where 95% avoidance was required for continuation. Data w x e not used if the following saline control run showed less than 90c7, avoidance or less than 100 escape responses with chlorpromazine. Vi'istar rats over 100 days old were used. The number of escape responses that could be produred by a drug was the measure of primary interest since this measure reveals the selective actiop of the drug eliminating the avoidance response to the noise while allowing the escape response t o the shock. The major tranquilizing drugs (such as the phenothiazines and reserpine) are distinguished by a consistent selective actlion which lasts for several hours and occurs over a moderate doee range. Under the conditions employed here, t,his e:'fect is rarely seen outside the major tranquilizing drugs; even morphine is less consistent than chlorpromazine. The test conipound was first tested a t 2897 of the rat LDa in 2 rats. If less than 30 escape responses occurred and the animal avoided for a t least 100 trials then the compound was not tested further and was recorded as negative in Table \'I. If more than 30 escape responses occurred or if all behavior was eliminated for more than 100 trials, then the compound was tested further and the dose was found for each anirnal that produred the largest number of escape responses. The average for a t least 3 rats of the escape responses at the niost effective dose was represented in Table \'I as folloivs: - = 0-30: k = 31-60; = 61-90; = above 90. When tested in this way, chlorpromazine averages tthout 150 escape responses. Ordinarily testing was only (wried up to 28C: of the LDj, but a few compounds that showed some activity a t 2gC& were tested at 40% or 56% of the LI>ao. I n those rases, if a larger selective effect was seen a t either of those doses, its magnitude is indicated in Table T I in parentheses. K. Pseudocholinesterase (Pseudo-ChE).-Inhibition of this enzyme is determined manometrically using human serum as the enzyme source and acetylcholine c*hlorideHS the substrate. Test rompounds %re dissolved or suspended in water. Compounds producing less than 5Oc/, inhibition a t c-oncentration of 10-3 .If are considered of no interest. The I;, was estimated graphically using various concentrations. L. Monamine Oxidase (MAO).-Inhibition of this enzyme is determined manometrically using guinea pig liver as the enzyme source and serotonin creatinine sulfate as the substrate. Test compounds are dissolved in water (using HC1 if needed). Compounds producing less than 50y0 inhibition a t .If are considered of no interest. The Is, was estimated graphically using various concentrations.
+
++
Results The results of these test procedures are detailed in Table VI. Loss of righting reflex, antagonism of the running convulsion induced by nicotine salicylate, and tryptamine potentiation are not tabulated since no compound was active in these tests. Structure-Activity Relations. Mpuse Behavior.I n general our findings indicate that while overt depression was noted with these materials they produce
42 1
little neurological deficit. Of the four end points used, the compounds were most active in dish (D) and chimney (Ch) and occasionally in pedestal (P), but little effect on traction (Tr) was noted. Indole nitrogen substitution reduced activity (31 us. 43, 44, 45), whereas pyrrolidine nitrogen substitution with small groups enhanced it (29 us. 31, 46; 52 us. 57; 53 us. 58 ; 54 us. 59). Benzyl groups on pyrrolidine nitrogen eliminated activity (36 us. 50; 38 us. 49; 39 us. 51). Benzene ring substitution in an active compound had little effect (31 us. 32-42). Pyrrolidine ring substitution on carbon often reduced activity (46 us. 60; 31 us. 55-59). 1ntroduc.tion of a 2-methyl substituent into the indole ring of one of the niost active conipounds (31 us. 61) eliiiiiriated niouse behavior along with tryptamine antagonisni, classical avoidance, and JIAO inhibition activities, while leaving fighting niouse and pseudoChE effects unchanged and imparting nicotine antagonism to the molecule. Correlation with classical avoidance showed that all compounds significantly active in mouse behavior also possessed smie activity in classical ayoidance and further, that all but two of the 12 coinpounds showing any activity in classical avoidance had significant activity in niouse behavior (31, 33, 36, 39, 42, 46, 59), five were significantly active in inhibiting monamine oxidase ( X 4 0 ) , while of the 11 best MA0 inhibitors seven were significantly active in mouse behavior. Tryptamine Antagonism.-Substitution on the indoleS (31 us. 43) and especially o n a pyrrolidine ring carbon (46 us. 60; 31 us. 55-59) reduced activity while pyrrolidirie-K substitution by small groups (29 us. 31, 46) e ihaiiced and by large groups (36 us. 50 ; 38 us 49 ; 33 is. 51) eliniiriated activity. Benzene ring substitution in an already active niolecule usually had 110 effect 011 activity (31 tis. 32-39). I n the majority of cases, antagonisin was considerably greater against AH and PAW than against HLS and HW. The inost active coinpound here seeins to he 39. The antagonisni of AB by these agents is in iiiarked coiitrast to chlorproiiiaziiie which is not able to antagonize this effect of tryptaiiiiiie. These differential antagonisins caniiot be correlated clearly with clinical efficacy a t this time. Nicotine Antagonism.-This test seemed to rorrelat c very poorly with either structure or other tests. AIorr often than not, rompounds with this activity seemed to have little activity in the mouse behavior or tryptamine antagonism tests and were the most highly substituted compounds, especially in the pyrrolidine ring ( e . g . , 54, 56, 58, 59, 60). If nicotine acts within the central nervous system as it does in the peripheral nervous system these data u7ould indicate that these indoles have little central anticholinergic activity. Fighting Mouse.-To be active in this test a compound must have a small alkyl group on one or both nitrogens (29 us. 30, 31-43, 46, 56-59, 61). Larger groups on nitrogen either reduced or eliminated activity (43 us. 44, 45; 46 us. 47, 48; 36 us. 50; 38 us. 49; 39 us. 51). Introduction of a benzene ring substituent retained activity except for the case of OH (35) where penetration into the brain may be poor. Introduction of alkyl groups on a pyrrolidine carbon enhanred (29 us. 52) or retained activity (31 us. 55-59) except in one case (46 us. 60). The most active compounds in this test were 30, 37,
July, 1964
423
3-(8-PYRROLIDISYL)ISDOI~ES
39, 42, and 43, although several others were almost as active as these Of the five best only two were potent in classical alroidance and two in mouse behavior. Little correlation with other tests was apparent. Classical Avoidance.-There appears to be greater structural specificity for activity here than in any of the other tests. The most critical substituent was a small pyrrolidine-S-alkyl group. All compounds possessing a pyrrolidine-SH group (29, 30, 52, 53, 54) mere inactive, while introduc*tionof a small alkyl group on the pyrrolidine nitrogen resulted in active compounds (29 us. 31, 46; 52 cs. 57; 53 vs. 58; 54 us. 59). Larger groups such as butyl or benzyl, and sometimes even ethyl, gave inactive compounds (47, 48, 60). On the other hand, substitution on the indole nitrogen resulted in inactive compounds (31 z's. 43, 44, 45). Introduction of a benzene ring substituent into an active compound eliiiiinated activity if it mas an oxygen function (31 us. 32, 34, 35) and either reduced or retained activity if it was an alkyl or halogen function (31 us. 33, 39; 31 is. 36, 37, 38, 42). Introduction of an alkyl group onto a pyrrolidine ring carbon of an active coinpound eliminated (31 US. 55; 46 us. 60), reduced (31 us. 56, 58, 59), or retained activity (31 us. 57). The most active compounds in this test were 31, 37, 39, and 57. .ill of these were also very active in the fighting mouse assay and exhibited moderately good JIXO inhibition. Several of these were also actire in either D and Ch or BB and PAW or both. S o correlation with other tests was apparent. Pseudocholinesterase Inhibition.-The substituent which was most important for activity was that on the pyrrolidine nitrogen. Activity increased as this substituent became larger (31 us. 46, 47, 48). I n all cases, replacement of a pyrrolidine-S-methyl group by a pyrrolidine-?;-benzyl group enhanced activity (36 L'S. 50; 38 us. 49; 39 is. 51). Although an indole-Salkyl group was desirable (31 cs. 43, 44, 45), it was not necessary for good activity (c,f. 34,35, 46-53,55,58,59, 60). Benzene ring substitution either had no effect (31 1's. 33, 36, 37, 38; 48 us. 49, 50, 51) or enhanced activity (31 us. 34, 35). Pyrrolidiiie ring substitution on carbon always enhanced activity (29 2's. 52, 53, 54 ; 31 us. 55,56,57,58,59 ; 46 us. 60). The most active compounds in this test were 44, 45, 58, and 60. It is interesting that only one of these (58) had even slight activity in fighting mice or classical avoidance. Two of them (58, 60) possess fair nicotine antagonism. There was a notable tendency for the more active conipounds to be more consistently inactive in the remaining tests (e.g. 34, 35, 44, 45, 47-51, 60). Monamine Oxidase Inhibition.-&\ free indole-?;H (31 11s. 43, 44, 45) and a small pyrrolidine-S-alkyl group (29 us. 31, 46; 31 tis. 47, 48; 39 L I S . 51) were needed for good activity. h benzene ring substituent was not necessary and may eliininate activity (31 us. 32-36, 38), but the best compound (39) contained a 7methyl substituent. A pyrrolidine ring substituent on carbon either did not change activity significantly (46 vs. 60; 31 25s. 55-58) or enhanced it (31 us 59, in which case both pseudo-ChE and MA0 inhibition were increased more than tenfold by introduction of 5,5-dimethyl groups). The two most active compounds were 39 and 59, with
Iso values close to Ai. It is interesting that these conipounds did not demonstrate overt stimulation in the mouse or rat. Compounds 31, 37, 39, and 57, the four most potent in classical avoidance, all possess significant MA0 inhibition, but one of the most potent 1L4O inhibitors (59) had only slight activity in the classical avoidance assay. General Comments.-The data presented show that these materials share many of the actions of chlorpromazine although they are less active on a mg. basis. In particular, they are quite active in the classical avoidance assay and protect against the isolationinduced aggressive behavior in mice. On the other hand, there are a number of other tests in which these compounds are clearly different from chlorpromazine. The significance of these similarities and differences for therapeutic effertiveness can only be assessed in man. The compounds showing activity in the greatest nuniber of assays are 31,39,58, and 59. Of these conipound 31 has been studied in considerably more detail preparatory to clinical trial iii the niental disease area. The complete pharinacology of this compound will be reported elsewhere. Most of the intermediates described in this paper have not been screened as widely as the final products. However, representatixre members of the unsaturated intermediates of Tables I and T' as well as their quaternary salts have consistently shown lack of classical avoidance activity, fair to poor activity in the fighting mouse test, and good to excellent inhibition of the two enzyme systems. The Ibovalues ranged from to JI for -11 for 3IXO inhibition and lop4and pseudo-ChE inhibition. Experimen tal1* Method A. Example : 3-(l-MethyI-2-pyrrolidinylidene)-3Hindole (I).-To 40 ml. (0.4 mole) of 1-methyl-2-pyrrolidinone cooled in an ice bath was added 40.8 g. (0.26 mole) of phosphorus oxychloride with stirring during 30 min. The temperature did not exceed 15'. The mixture was stirred an additional 10 min. and then a solution of 28 g. (0.24 mole) of indole in 40 ml. (0.4 mole) of 1-methyl-2-pyrrolidinone was added slowly during 1 hr. The temperature rose to 45" and a solid separated. The mixture was heated a t 80" for 2 hr. and then mixed with 1 1. of water. The clear solution was made basic by the addition of 60 g. of sodium hydroxide in 300 ml. of water causing a solid to separat'e. The solid was filtered and washed with water. Crystallization from ethanol-water afforded 41.6 g. (89y0) of product, m.p. 229-231' dec.; umax 3020, 1600, 1560, 1500, 1315, 1300, sh 244 mp ( e i400), 2ril (8850), 1208, 767, and 736 cm.-': A, 271 (11,700), sh 2 i 6 (9050),and 339 (15,300). l-Benzyl-3-(l-methyl-2-pyrrolidinyl)indoleCyclohexanesulfof 49.7 g. of 1-benzylindole19 according amate (44).-Reaction to method A produced 58.7 g. of oil isolated by ether extraction; umax 3460, 3320, 3120, 3070, 3040, 2810, 1645, 1615, 1575, 1530, 1500, 1485, 1180, 1080, 1050, 745, and 695 mi.-': A,, 209 mp ( e 8750), 2.52 (12,600), sh 269 (7500), and 333 (12,750). A solution of 14.5 g. of the oil in 150 ml. of ethanol containing 0.2 g. of platinum oxide was shaken on a Parr apparatus a t an init,ial pressure of 3 atm. iifter 3.5 hr. 1 equiv. of hydrogen was absorbed (based on structure 111). The catalyst was removed by filtration and the solvent under reduced pressure on a steam bath. The remaining material was distilled giving 7 g. of oil, b.p. 171-181" (0.03 mm). A 6.3-g. (0.0216 mole) portion of the oil was dissolved in a minimum volume of 2-propanol and added (18) Melting points nere taken in a capillary tube and are corrected. Infrared spectra a c r e recorded on a Perkin-Elmer Model 21 spectropliotoineter from Nujol mulls unless otherwise noted. U t r a v i o l e t spertra a e r e determined i n 95% ethanolic solution unless otherwise noted, usinrr a Car? Model 14 spectrophotometer. (19) H. Plieninger, Chem. Be?., 87, 127 (1961).
to a solution of 3.88 g. (0.0216 rnolej of cyclo1iexanesulf:~nii~~ w i d in 2-propanol. F:t,her was :iddetl until :t solid hegari to sep:irate. Tlie solid w:is c~rystallized frrrni 2-priii)ariirl--~,ther giving 0..5 g., m p . 127--l20.3, nritl a secwntl c.rcrp of 2 . 1 p., in.p. 123--129..5. A portion of tile first i'rop ~ v t i 2-propanol~etlier fijr : i n ati:tlyticd s a i i i ~ ~ l vlrlilT 321i0, 27.40, 2W0, 1fjl4, 1 (i04, 13S3, 13 1113, 1075, 1034, 1005, 765, 7 3 5 , 720, :inti ~ n p( c 41,7WI, sh 260 (4900), sh 2% (ti73 280 (7350), and sh 291 (5850). Method B. Example : 5-Methyl-3-( 1-methyl-2-pyrrolidinyliindole (33).-A mixture of 12.7 g. of 5-methyl-3-( 1-methyl-2j)yrrolidinylidene)-3H-indole, 150 nil. o f methanol, and 0.2 g. of platinum oxide w t s shaken on :I Parr apparatus a t ziti initi;il pressure of 3 atni. In 10 min. 1 equiv. of hydrngeri \ v w ahsorhrd. The catalyst ivas removed hy filtration and the solvent wider reduc,ed pressure on the steam bath. The remaining yellniv i d wts crystallized froni Skellgsolve I%giving 11.5 g. (91 tl,) ~ r f yellow prisms. in.]). 116-1 17.5". The nnzilytical s:tmple \\'as recarystallized from ether-Skellysolv~~ T3 :tf'l'crrtlingcolorless prisms : n i . 1 ) . 116..i- l l i . 3 " ; Y , , ~ , , 3130, XO:lO, 27;00, Iti25, 1300. 1545, 1235, ), 875, a l l d 790 ~ l i l , - ' :, , ,A 21s 111p ( c (S700), anti ?!I3 14100;. e : 5-Chloro-3-( 1-methyl-2-pyrrolidiny1~indole (36).--A niixturr of 23 g. o f 5-1-hl11ro-3-( 1-methyl-2-pyrrolidinylideri~~)-3T-I-i1rd1~le, 12 g. of sritliiiiii l)orohydride, :ind 250 1111. of :ihsoiiitR ethanol is a l l i ~ n c dt o stand overnight a t rooni teinperntiirth. The solvent \v:is renrovecl under redured pressure o n a s t e m Ixith. The residue \vas trr:Ltetl with 300 n i l , (Jf w t t r r :tnd extr:icted with two 300-ml.portioiis of ether. The extr:trts were washeti ivith two 100-nil. pitrtions of iv:Lter :ind dried over :tnhydr~riisniayriesiuni sillfate. The ether \v:is evapor;ited :and the residue was crystallized froni e -Skellysolve I%giving 18.3 g. (79l.i;) of ivory prisms, m.p. ,.j-111'. The analytird smrple wtis recryst,allized twice e?lle,.-Skell\-sl~lvr n :iffording cwioriess prisnis: ni,p. 14:1-14-t.~o:Y , , ~ . ~ , 3180, 3125, 3023, 2815, 1615, In70, l.5.50, 1490, 1255. 1227, 1210. 1154, 1117, 1075, :ind 102s c l l l . - l ; A,,,,,, 226 nifi ( e 35.150): dl "3 i Z O O ) , 38:) (5550'),:tnd sh 2117 (4230). Method D. Example : 3 4 I-Methyl-2-pyrrolidiny1)indole(31 I. A 9.X-g. (0.05 n i o l r ) jiortioii of solid 3-( I-inethyl-2-pyrrnl i 1 ~ i 1 ~ y l i ~ l ~ ~ r 1 ~ is ~ ~:idtied - ~ 1 Ht-ni t:I i ~ rrfhiuing ~ ~ i l ~ ~niisturc of 4.Ti g. 10.12 i i i o l r ) of l i i l i i i i r i i :ilurninuiri Iiytlride :ind 150 nil. o f tc,tr:ihydrirfiirmi. Tht, niiiture WE rrflusetl for t i hr., ~ ~ o o l r:inti d , (It)c~oni~~osecl ivith n : i t e r follo\vetl Iiy :ip]irosiniately 10 n i l . nf 50Yl sodiiini hydroxitlr. Tho inixturc, i v m filterrd :tiid tlit' solid ~v:is \v:isIi~d \vitli rt1ic.r. The roinl)inc:d fi1tr:itc.s \vrrfs dried I J V P ~ i i i n i*:trl)ibn:it(, : i n t i rvapor t i . Tlicl oily resithie \vas lizetl fritni Skellysolve 13 :tH'i) m.p. ! ) . 5 - 9 i o ; P , ~ : , 3100, ~ :1020, 27 1.550, 150.5, 1235, 1213, 113.l 11:10 A,,,;,, 21!) nip ( c 3(j,750): SII 274 i ( 5400 ) . Method E. Example : l-Indol-3-yl-4-nitro-l-butanone(19'~. --.A mixture of 129.6 g. (0.6 mole) of 3-diiiietliy1:tiiiirio-l-illd(iI:I-yl-l-pro~~aiione,? 600 nil. of riitrcrineth:ine, :ind 3.1S g. (0.059 inole) of sodium nietlioside KRY stirred and refluxed for 7 hr. n.hile a slirvi s t r e m i of nitrogen as passed through the suspeiisioii. The reaction mixture wts allowed to crystallize overnight, arid filt,ered. The solid was dissolved in 900 nil. of nc9etoiie (filtered from some insoluble material), 300 nil. of ethyl acetate IY:M :idtled, and the solution was evaporat,ed to cn. 500 nil. Cooling prodrired 31 g. of solid and 14.9 g. wts oht.ained froin the filtrate giving :L total of 68.0 g. (.ioc; ) of product, 1n.p. 178-180". The :tn:tlytical mniple was recrystallizer1 frrirn nirthanol: m.p. 17slsoO: umzix 3180, 3060, 1625, 1 I . I I I . - ~ ; A,,,;,, 209 n ~ pi c 32,100 ,630), sh Z i T (94,50,, :ind 208 (13,200). 3-(l-Pyrrolin-%-yl)indole (24).- A solution of 12.3 g . i r f 1iiitlol-3-yl-4-nitro-l-liiit:~n~i~ie i r i 300 ml. of :tl)solute eth:inol 1-ontaining 2 t,e:ispoons of Raney nic.kel \v:is sh;ikrn o n :t P:trr :ipp:iratus :tt :in initial pressure of 3 atin. Three equivalents of 11) clrogen were nbsorbed in IS Iir. Three runs were ciinihinetl, flt>tvwi,arid twipora ted. The imide prodiic-t I ~ R Rcrystnllixetl f r o i n ethyl w e t a t e affording 16 g. ( 5 5 C ; ) , ni.1). 178-18I'. Tlity cmitie p r o d i i v t from some runs w w (.iintarninnted ~ v i ? htlic s:ctiir:itrd coinpound. Sepitration \Y:LS :ic*liievecl re:idily liy :in :icetone solution of the prodiict tlirough a cwlunin of n e u t r d duniina whereby the inipurity was retained [ i n the i ~ r l uriiri. The analytical sample was recrystallized from ethyl
n ~ p ( B 23,-100), 2.i; :3;32[ 1200).
-lSS.T,o: Y , , , ~ :31%0, 3080, 3060, 3040, 3020. 620, 1375, 1.530, and 1500 cm.-'; A,;, 217 1 1,7001, sll 271 ( W ~ O ~2% i , [ 1 1 ,O:iO), atid R t i
3-!5-Ethyl-l-pyrrolin-2-gl)indole Hydrochloride 126). ~ ' I I i f ~ filtrnti. froiii thrs hytlrugenation of foiir riins r r f 1 3 g. tw.h of 1i i i ~ l ~ ~ l - ~ ~ - ~ l - ~ - i i i t ~ ~ ~ - l - \vas l i f ~ u:tcitlifird : ~ i i i J i i enit11 rtlir~rrnlhydrogt'ii c~hloritl
