Alarch 1967
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Anal. Calcd for C13HlixO3: C, citi.93; 11, ti.48; S, 6.01. Found: C, 67.25; H, 6.70; N, 5.81. The infrared spectrum was entirely different from that of ( I bj, authentic ethyl 2,6-dimethyl-5-hydroxyindole-3-carboxylate mp 229-230" (lit., mp 230"): nmr (20rc DMF-d,), 427 and 453 cps (1 H each, singlets, J = ,J = < I cps). orally. Anal. Calcd for C1?Hl2BrNO3:S , 4.69; Br, 26.81. Found: S , 4.66; Br, 27.21. Ethyl 5-acetoxy-2-methylindole-3-carboxylate(I, 0-acetate, Experimental Sectionlo R = H ) was prepared by refluxing I ( R = H j with acetic anEthyl 5-Hydroxy-2-methylindole-3-carboxylate(I, R = H).hydride. It crystallized from benzene-hexane as white plates, The product yield was improved by carrying out the condensation mp 153-154.3'. in acetic acid and using excess quinone." To a stirred solution Anal. Calcd for Cl&s?;O4: C, 64.36: H, 5.79; X, 5.36. of 27 g (0.25 mole) of 1,4-benzoquinone in 450 ml of glacial acetic Found: C, 64.49; H, 5.91; K, 5.19. acid was added 16.2 g (0.126 mole) of ethyl 3-aminocrotonate Ethyl 5-Acetoxy-6-bromo-2-methylindole-3-carboxyIate (IIIb j. during 10 min, the temperature being kept below 45' by exA. By Acetylation of 1IIa.-The bromophenol I I I a was refluxed ternal cooling. St,irring was continued at room temperature for 2 hr with acetic anhydride and the product was isolated as white 5 hr. The precipitated solid was washed with acetic acid and crystals, mp 198.6-20O0, when crystallized from ethyl acetate. water to give 17 g (62yOjof a gray cryst,alline solid, mp 203-205". Anal. Calcd for C14H14BrrV104: C, 49.41; H, 4.14; Br, 23.48; I tecryst allization from pyridine raised the melting point t,o 207K, 4.11. Found: C, 49.63: H, 4.11; Br, 23.48; N, 4.40. 208' (Iit.l1mp 205O j. B. By Bromination of the 0-Acetate of I (R = H).--TIic Ethyl 4-[(dimethylaminojmethyl]-5-hydroxy-2-methylindole- bromination of I 0-acetate ( R = H ) was carried o\lt in the 3-carboxylate (IIa) was prepared and isolated as the hydromanner as the bromination of I ( R = H). The yield was chloride according to the 1it)erature procedure.' The ident,ical of product, mp 195-196", raised to 198-200' by further recrystalprodiict was formed in high yield when the Mannich condensalization. The infrared spectrum was identical with that of the tion was carried out in hot acetic acid. The free base was genproduct obtained by acetylat,ionof IIIa. rrated by shaking a suspension of the hydrochloride in aqueous Ethyl 5-Benzyloxy-6-bromo-2-methylindole-3-carboxylate KYCOpTTith CHZCIZ. Concentration of the dried CHzC1, phase (IIIcj. A. By Bromination of I (0-benzyl ether, R = Hj.-The and recrystallization of the residue from CCli gave a yellow bromination of ethyl 6-benzyloxy-2-methylind01e-3-carboxylate~~ crystalline powder: mp 114.5-116.5"; nmr (DCClpj, 404 and was performed in the same manner as the bromination of I 422 cps (1 H each, doublets, J = 9 cpsj. ( R = H). The product crystallized from ethyl acetate in 74$4 -4naZ. Calcd for C G H ~ ~ N ~SAP,'^ O ~ : 5.07. Found: SAP, 4.9. yield as white needles, mp 204-205". Ethyl 5-Hydroxy-2,4-dimethylindole-3-carboxylate(1Ibj.-A dnal. Calcd for C19HlSBrS03: C, 58.77: H, 4.67; S , 3.60; solution of 13 g of I I a in 1 1. of alcohol was refluxed 20 hr with Br, 20.58. Found: C, 58.66: H, 4.56: ?;, 3.58: Br, 20.86. 150 g of Raney nickel. The catalyst, was removed by filtration, B. By Benzylation of 1IIa.--A stirred suspension of 90 g the filtrate was concentrated to dryness in Z'QCUO, and the crystal(0.302 mole) of ethyl 6-bromo-5-hydroxy-2-methylindole-3line residue was washed (CHzC1,, water) to give 7 g (64%) of a carboxylate ( I I I a ) , 58.3 g (0.460 mole) of benzyl chloride, and tan powder, mp 184-188". The analyt,ical sample melted at 250 g of anhydrous &C03 (dried 6 hr at 600") in 900 ml of re187-189' after recrystallization from ethyl acetate: nmr (207; agent grade acetone was refluxed 28 hr. The solvent was reDMF-d;), 408 and 422 cps (1 H each, doublets, J = 8 cps). moved in ~ r m mand the residlle was dissolved in a hot mixture of 2 1. of water and 2 1. of ethyl acetate. The aqueous phase was ( 8 ) 1:. I t . Snyder and J. €1. B r e w t e r , J . Am. Chem. S o r . , 70, 4230 (19481. extracted with t,hree 75O-ml portions of ethyl acetate. The (Sj R. AI. Reinicke, .J. B i d . Chem., 143, 351 (1942). combined extracts were washed (water, brine), dried (Sa2SO4), (lo) Melting points mere taken in capillary tubes in a n oil b a t h They concentrated to about 1 l., and left at 0' to give 92 g (79%) of are not corrected b u t are within one degree of the melting points of standards. product, mp 202-204'. A recrystallized sample from an earlier .lnalyses x e r e carried o u t under t h e supervision of Mr. K. D. Fleischer. run, mp 206-2O6Oj did not depress the melting point of the prodSpectra were determined under the supervision of Dr. F. C . Piachod. N m r uct, oht,ained by bromination of the benzyl ether of I ( R = H). spectra v e r e determined with a Varian Model .4-60 nmr spectrometer; Ethyl 5-Benzyloxy-6-cyano-2-methylindole-3-carboxylate TXId was used as the internal a t a n d a d unless otherwise indicated. T h e iiltraviolet a n d infrared spectra of most of the compoiinds were determined (IVc).-The method employed was that described by Friedman
_\lannichbase wab degraded by Raiiey nickel in alcohol to the corresponding 6-methylindole Ib. The 4-hydroxypiperidinomethyl derivative IC formed when Ia was heated with 4-hydroxypiperidine, an example of the JIannich base exchange reaction.* Biological Activity.-The effects of these indole derivatives 011 rat blood glucosegmay be been in Table I.
7 -
ani1 are i l l accord with the structiires written. (11) ( a ) (', 1). Neuit/escii, B u l . S o r . C h i m . Runiniiin, 11, 3 7 [ l ! i 2 9 ) ; C I I Y ~ . d i i y t r . . '24, 110 (1930); ( b j G. Uomsclike and €I. E'iirst, Chern. Ber., 9'2, 3244
(1939). (12) X,,l, s t i l n d a f u r p,ercliloric: acid titration in acetic acid for basic nitroXiull.
(13) \Ye are indebted t o I)r. 13. F. Tiillar of o u r Uevelopinent Lalmrators f o r the characterization of the Iiydrochloride. (14) .J. €1. lioehneke ant1 AI. I
