Sovember, 1963
ACYLTRYPTAMISES. I1
and 2 g. of ammonium acetate a t 95-loo", diluted with 50-60 ml. of methanol, and cooled, yielding 5.6 g. (80%) of orange-red needles, m.p. 229-230". An analytical sample was sublimed a t 0.5 mm. d n a l . Calcd. for CllH9FKdh: C, Fj9.99; H, 4.12; F, 8.63; S , 12.73. Found: C, 60.23; H, 3.18; F: 8.65; X, 12.90. 6-Fluoro-~methyltryptamine.-A solution of 5.6 g. of 6-fluoro3-(2-methy1-2-nitrovinyl)indole in 100 ml. of tetrahydrofuran was added dropwise to 6..5 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran and refluxed for 2 hr. After the usual procedure, 3.0 g. (61%) of crystals were obtained, m.p. 102-105' (ethyl acetate-petroleum ether). An analytical sample was recrystallized from ethyl acetate, m.p. 104-106". Anal. Calcd. for C1lH1,F"?: C, 68.73; H, 6.82; S , 14..57. Found: C, 68.39; H , 6.83; N , 14.22. The picrate, red crystals from methanol-water, changed to orange-yellow vihen heated above 100-110"; m.p. 232-233" dec. Anal. Calcd. for C17HI,FN,Oi: C, 48.46; H, 3.83; S , 16.63. Found: C,49.03; H,4.28; S , 16.77. 5-Fluoro-3-indolealdehyde.-A solution of 7.7 g. of 5-fluoroindole6 added to 5.8 ml. of phosphorus oxychloride in 20 ml. of dimethylformamide, and processed as described for the 6-fluor0 analog, afforded 7.5 g. ( 8 0 % ) of crystals, m.p. 170-171". Anal. Calcd. for CsH6FNO: C, 66.25; H , 3.71; F, 11.65. Found: C, 66.76; H, 4.22; F, 11.60.
719
5-Fluoro-3-(2-methyl-Z-nitrovinyl)indole.-Reaction between 7.3 g. of 5-fluoro-3-indolealdehyde and 20 ml. of nitroethane in the presence of 2.3 g. of ammonium acetate, carried out as described in preceding sections, gave 6.1 g. (62cz) of orange crystals, m.p. 186-186.5' (from methanol). A-lnal. Calcd. for CllH9FS?02:C, 59.99; H, 4.12; S,12.73. Found: C,60.25; H,3.89; N, 12.45. 5-Fluoro-~t-methyltryptamine.-The foregoing compound (5.8 g.), reduced exactly as described for the 6-fluor0 isomer, was precipitated from an etheral solution as the hydrochloride, m.p. 228-230"; yield 4.9 g. (81:%). An analytical sample was purified from toluene-ethanol; m.p. 233-234'. Anal. Calcd. for CI1H1,C1FXP: C, 57.77; H, 6.17; F, 8.31; S , 12.25. Found: C, 57.79; H,6.48; F, 8.29; ?;, 12.2i. The yellow crystalline picrate, from methanol-water, melted a t 234-235" dec. Anal. Calcd. for CliH18FS607: C, 48.46; H, 3.83; F, 4.51; S , 16.63; Found: C,48.73; H , 3.79; F,3.99; X, 17.07.
Acknowledgment.--We are indebted to Mr. H. G. McCann of the Microanalytical Laboratory, National Institute of Arthritis and Metabolic Diseases, for analyses.
Acyltryptamines. 11. Synthesis of Acyltryptamines, Indazoles, and Azepinoindoles from the Acylphenylhydrazones of 2,S-Piperidinedione'
Warner-Lambert Research Institute, Morris Plains, S e w Jersey Received March 25, 1965' The 3-(0-, m-, and p-acylpheny1)hydrazones of 2,3-piperidinedione ( I )were prepared by the Japp-Klinpemann coupling of the corresponding acylbenzenediazonium salts with 2-oxo-3-piperidinecarboxylic acid. The acyl substituents were o-, m-, and p-acetyl, o-, m-, and p-benzoyl, p-propionyl, p-isonicotinoyl, and p-( 4-chlorobenzoyl). The Fischer-indole cyclization of the p-acylphenylhydrazones gave 6-acyl-1,2,3,4-tetrahydro-l-oxo-p-carbolines (11)which on hydrolysis and decarboxylation yielded 5-acyltryptamines (IV). Cyclizations of the m-acylphenylhydrazones gave a mixture of 5- and 7-acyl-1,2,3,4-tetrahydro-l-oxo-p-carbolines (VI, V) which on hydrolysis and decarboxylation yielded azepino[5,4,3-~d]indoles ( X ) and Gacyltryptamines (T.III),respectively. The o-acylphenylhydrazones on cyclization gave 3-methyl-2-( 1,2,5,6-tetrahydro-2-oxo-3-pyridyl)-2H-indazoleand 3phenyl-2-( 1,2,5,6-tetrahydro-2-oxo-3-pyridyl)-2H-indazole.These were reduced catalytically to the 3-methyl2-( 2-oxo-3-piperidyl)-2H-indazoles and 3-phenyl-2-(2-oxo-3-piperidyl)-2II-indazoles (XIII). Hydrolysis of the indazoles gave the corresponding derivatives of 5-amino-2-indazolylpentanoic acid (XV, XVI ). The 5-acyltryptamines showed antiserotonin and hypotensive properties. The most active compound, 5-acetyltryptamine, which produced marked hypotensive effect in the anesthetized and unanesthetized dog, failed to elicit the same response in man when tested in the clinic.
The synthesis of tryptamines has been extensively pursued because of the biological activities of many naturally occurriiig substances containing this moiety. As a result of our investigations on the chemical modifications of indole alkaloids it became apparent to us that tryptamines, substituted in the benzene ring by acyl groups, had not previously been prepared. During the course of our synthesis in this area we encountered some interesting chemical and pharmacological findings which prompted us to expand our research to include indazoles and azepinoindoles. The most feasible synthetic scheme appeared to be that utilized by hbramovitch and Shapiroz where substituted benzenediazonium salts are coupled with 3carboxy-2-piperidone to give hydrazones which are ( 1 ) Presented in p a r t as a Communication t o the E d i t o r , J . A m . Chem. Soc., 84, 881 (19ii2), a n d before the Division of Medicinal Chemistry a t the
141st National Meeting of the American Chemical Society, Washington, D . C.. March 2 0 , 1902. (2) It. .I. l b r a m o v i t c h a n d D. Shapiro, Chrm. I n d . (London), 1255 il9,55);J . Chem. So?., 4589 (1956).
cyclized to 1,2,3,4-tetrahydro-l-oxo-p-carbolines.Ring opening of the oxocarbolines followed by decarboxylation of the resulting 2-carboxytryptamines yields the tryptamines. Coupling of the 0-, m-,and p-acylbenzenediazonium salts with 3-carboxy-2-piperidone gave the corresponding 3-(0-, m-, and p-acylpheny1)hydrazones of 2,3piperidinedione Ia-i (Table I). Cyclization of the (p-acylpheny1)hydrazones of 2,3-piperidinedione Ia-d in refluxing 88% formic acid gave the B-acyl-1,2,3,4tetrahydro-1-oxo-p-carbolines(IIa-d, Table 11). Hydrazone Ie, which resisted cyclization by formic acid, was successfully cyclized by polyphosphoric acid. Base-catalyzed hydrolysis of IIa- gave the corresponding 5-acyl-2-carboxytryptamines (IIIa-e, Table 111) which were decarboxylated in refluxing hydrochloric acid to the %acyltryptamines (IVa-e, Table IV). (3) S. Keimatsu, S. Sugasawa, and G . Kasuya, J . Pharm SOC.Japan, 48, 762 (1928).
7 21
ACYLTRYPTAMINES. I1
November, 1963
TABLE111 2-CARBETHOXYTRYPTAMIShS
Calcd., % Yield,
Coinpound
R
IIIa
5-CH3C0
%
lI.g., " C .
340-346" 363
IIIb
5-CzHjCO
271.5-275.5 301.5-307.5 287.5-293,5* 270-272
IIId
C
Formula
93 Ci3HiJT203.H20 59.08 (59.04) C I S H ~ ~ ~ ; B O I 55.22 ' HCl (55,51) 93 C14H16S203 64.60 (64.46) CiiHi~N203. 56.66 HC1 (56.74) 90 CiaHi8203 70.11 (70.38) C I ~ H I ~ N ~ O ~62.70 . HCl (62.93) 95 ClSHi5CliY2O3 63.07 (63.33) 80 C17HIjN302' 65.04 0.5C2HSOH (64.83) 90 Ci3H14S208. 58.52 H2O (58.74) 0.5CZHsOH Ci3HirS203. 51.91 HC1 (52.07) 96 C I ~ H I ~ S ~ O ~68.13 . 0.5HzO (68.19) 63.40 93 Ci3H14S203 (63.59)
5{c10c0, \ 268-270
343-353 VIIa
6-CH,CO
242-245
%)--
---(Found,
H
x
6.10 10.60 (6.18) (10.77) 5.35 9.91 (5.62) (!).67) 6.20 10.76 (6.19) (10.76) 5.78 9.44 (5.98) (9.71) 5.23 9.09 (5.28) (0.33) 4.97 8.12 (5.05) (7.97) 4.41 8.17 (4.57) (7.93) 5.46 12.64 (5.80) (12.78) 6.66 9.75 (6.40) ( 9 . 7 3 )
C1
,~:A:
inp
(6)
266 5 (47,000); 303 (8000) 12 54 (12 51)
266 (51,700); 303 (8900) 265 (49,000); 304 (8200)
11 95
266 (51,500); 304 (9100)
(12 08)
10 (10 10 (10
22 24) 34 09)
276 (37,000); 296-305 (10,100) 277 (41,200) 297 5 (37,500) 238 (24,200); 277 (31,000); 311-319 (10,100) 218 (24,000); 308 (21,600)
11 79 5.70 9.31 (5.91) (9.28) (11,89) 8.82 2% (26,000); 249 (19,600); 5.40 210-21 3 T-IIb 6-CsHjCO 313 (18,000) (5.26) (8.58) 216 (30,000):243(sh)(13,500) 11.38 5.73 317-320 IXa 4-CH3C0 260 (15,000); 353 (5,300) (5.99) (11.46) 418 (6,700) 230 (25,600); 267 (15,200) 242-252 88 Ci8H16S203. 68.86 5 78 8 45 362 (5,500); 443 (7,500) 0.5C2Hj9H (69.14) ( 5 80) (8.41) a At 270" softens, puffs up, and resolidifies. * Melts at 240-243' and resolidifies. 272.5-280.5
TABLE IV TRYPT.4MINES
Compound
II'a
1T.b
R
5-CH3C0
hI.p., "C.
Yield,
%
YIIIa
6-CH3CO
S?IIb
G-C,H,CO
Formula
140 557 Ci2HiaSzO 142.5 230-232 CnHi4N20. HC1
5-CzH,C0
264-267
26
251-256
57
14 150.5 249-251 17 148 5-
Calcd., % -(Found, 70)N H
7
C
71.26 (70.99) 60.37 (60.48) 72.19 (71.91) 61.77 (61.96) 67. S8 (67.83) Ci7HijClX20. HC1 60.90 (61.13) CioHijX'3O.2HC1 56.81 (56,88) CizHi*N20 71.26 (71.38) CI~HIGN~O. 66.76 0.5CzHj3H HC1 (66.56)
800-900 em. region whereas the &acetyl isomer showed one band at 870 cm.-'. The 7-acyl-1,2,3,4tetrahydro-1-oxo-P-carbolines (T.'a,b) n-ere hydrolyzed by alkali to the 6-acyl-2-carboxytryptamiiies(VIIa, b, Table 111) which were then decarboxylated in refluxing
6 98 (6.93) 6.33 (6.37) 7.46 (7.46) 6.78 (6.79) 5.70 (L8.5)
4.81 (4.76) 507 (5.36) 6.98 (7.18) 6.23 (6.26)
13.85 (14.09) 11.74 (11.51) 12.95 (12.92) 11.08 (11.12) 9.31 (9.60) 8.36 (8.63) 12.42 (12.18) 33.85 (14.08) 8.65 (8.94)
CI
AI.'oll max
I
m p (e)
254 (34,400); 299 (pl) (7850)
14.87 252 (33,400); 297 (7350) (14.88) 253 (34,400); "97 (7200) 14.03 (14.05) 11.79 (11.53) 21.15 (20,92) 20 97 (20,80)
252 (35,600); 297 (7400)
220 (21,600); 262.5 (25,000) 306 (9600) 219 (23,300); 2 6 (26,700) 308 (30,150) 232 125,400); 266 (18,500) 311 (9500) 237 (sh) (15,300); 253 (21,400) 301 (12,900); 335 (7000) 10.95 219 (27,900); 254 (18,700); (11.06) 306 (12,630)
hydrochloric acid to 6-acyltryptamines (T'IIIa,b, Table IT7). The 5-acyl-l,2,3,4-tetrahydro-1-oxo-P-carbolines (VIa,b) were hydrolyzed to 4-acyl-2-carboxytryptamines(IXa,b, Table III), which on acid decarboxyla-
7%"
tioii gave compomitls lackiiig carhoiiyl ahsorption in thc iiifiwcd.
VI
X
IX :1,
1t = CII,;: I ) , II
= C361!~,
It, \ v u apparent that the pri1iiai.y amiiic of the si& chaiii reacted with the carbonyl group to give dcrivatives of t,hc iiovcl ring struct'ure, 1H-azepiiio [5,4.3-cd Iindole (Xa,b,4Table V). Rast niolecular weight deteriiiiiiatioii confirmed t'he iiioiioiiieric empirical formula. The reactions described proceeded with good yields except for the decarboxylatioii step which was geiierally a slow process goveriied by the clectroii-\~itlidran.ing properties of the substitueiit, K c have observed tli:tl t,he case of dccarhoxylatioii deci.easm n-itli the iiictmsing electroiiegativity of the suhstitueiit p a i n to tlic riiig i i itrogclii, iii agreemelit wit'h .it iraniovitch's5assuinpt ioii t,hat protoiiatioii of the indolt. iiitrogeii is the rate-det,c.i,niiiig step of this reactioii. ( ;ciicrally, the 5-alkaiioyl'-carboxytryptariiiiics ~ v e r edecarboxylated faster t h a i l t,he correspoiidiiig aroyl dcrivatives. The 4- aiitl tihciizoyl-2-carboxytryptamiiics, both of which havr tlw substituent ineta to the indole iiitrogeii, w r c dccarhoxylated more rapidly tliaii .i-t,ei~zoyl-'l-carb~~~yt8i.ypt8aminc. 111 some cases, mtciisivc decomposit'ioii of the product n-as rniiiiinized hy isolatioii of the tryptamine prior t o t'hc conipletioii of' the reactioii aiid wcyclizatioii of the recovercd aniiiio acid hydrochloi,itic.. Ef'fork to improvv this step hy usiiig resorciiiol o r dimethylaniliiie6 as decarhoxylatiiig agciits n.ei~'f i x i t IOSS.7
' l h cyclization of t h e o-acylpliriiylhydrazoiicsof 2,:G pipwidiiiedioiic (Ih,i) ga\.c 1)asic substaiices wliosc~ aiialytical and spectral data irere iircompatiblc with tlic st,ructurc of the desired 8-acyl-l,2,:~,~-tetrahydro-loxo-p-carbolines. The high iiitrogeii content' of t'lic products iiidicated that, cyclizatioii t.o t'he indazolyl,
( I1 ~ ~ , i - ! ) i l ~ ~ ~ ~ r 11-a ~ i - i ~ l I-l ~ ~ l~~ L~ :-~l~ - , d~~tl l l~ d d~< l.X- d l a m l ~~,.4.inu - ~ , l ~ ~ [~5 ;~4 ,~: 3~- dl ]-i ~ i < l u l(
