H.B.
2172
LfACPHILLAMY,
[CONTRIBUTION FROM THE
K. L.
DZIEMIAN,
R.A. LUC,ZS AND h l . E.KUEHNB
RESEARCH DEPARTMEST OF
r01. 80
C I B A PHARMACEUTICAL PRODUCTS, I h C . ]
The Alkaloids of Tabernanthe iboga. Part V1.l The Synthesis of the Selenium Dehydrogenation Products from Ibogamine BY H. B. MAC~HILLARIY, R. L. DZIEMIrlN, R. A. LUCASAND 11. E. KUEHNE RECEIVED DECEMBER 26, 1957
4-Ethyl-2,6-dimethyl-11H-indolo[3,2-c]quinoline ( I b ) and 4-eth~~1-5,6,7,12-tetrahydro-2-methyliri~olo[3,2-d][l]betiz azepine ( I I b ) have been synthesized. A comparison of the physical properties of these substances with those of the two selenium dehydrogenation products from ibogamine showed their identity and thus established the structure of these ibog'i alkaloid degradation products.
Paper IV of this series2 described the selenium dehydrogenation of the iboga alkaloids ibogaine and ibogamine, and gave a discussion of the reasoning which led to the proposed structures (Ia and IIa) for the two products derived from ibogaine. Proof also was presented that, as had been considered previously, ibogamine was desmethoxybogaine. Hence, its degradation products would in all probability be the desmethoxy analogs Ib and I I b of those from ibogaine. As such they CHB
I
CHj Ia, R = OCHB Ib,R = H
CHI
repeated attempts with known iiiodel compoutids and a wide variety of reagents. These same authors further showed that the dcsired compound could be made by a Dieckmann cyclization of the appropriately N-substituted methyl anthranilate. Accordingly, the anthranilic acid V was prepared from I11 via the isatin IY. However, all attempts to synthesize the N-7carboethoxypropyl substituted ester by either direct alkylation or from the corresponding tolylsulfonamide were unsuccessful. A similar alkylation ol methyl K-p-tolylsulfonylanthranilate and its cyclization has since been reported.6 In another series of experiments with model substances it was shown that ethyl anthranilate reacted with ethyl succinate in the presence of sodium hydride to yield a product of the structure shown
IIa, R = 0 C H 3 IIb, R = H
would be simpler to synthesize and we were, therefore, requested to devise a method of preparation for these compounds. The ultimately successful route is given in Chart I. The most logical starting point for the synthesis of the desired substances appeared to be 2-ethyl-4methylaniline (111) which was prepared by Willgerodt and Brandt3 by the direct alkylation of p-toluidine. These authors also presented a convincing proof of structure for their product, an essential point for the starting material of a synthetic project such as this. The substance also had been prepared by Hill and Graf4 by the reduction of 2'-acetamido-2-chloroacetophenone.Although me obtained the same material by both methods, we found the direct alkylation method more adaptable to larger scale preparation. Synthesis of the Indolobenzazepine In reviewing the literature on benzazepiiie derivatives it was found that =Istill and Boekelheide" had reported that they were unable to cyclize 4(N-p-tolylsulfonylani1ino)-butyric acid by the application of the usual conditions for the FriedelCrafts reaction. UTe also were unsuccessful in applying this procedure to our synthesis in spite of ( I ) P a r t V ,W .I . T a y l o r , E x p e r i e i i l i i i , 13, 454 (1958). ( 2 ) 31. F. Bartlett, 11. F. Dickel a n d X', I. T a y l o r , THISJ O I J R N A I . , 8 0 , 126 (1958). ( 3 ) C . Willgerodt a n d 1.. B r a n t i t , . I . p v n k f C h c u . , [i'] 69,-138 (I!lOlJ (4) .4. J Hill a n d I. 1%:.Graf, Tms J O T . R N A L , 37, 1839 (1915) ( 5 ) € 3 D . Xstill and V . Boekelheide, ibid., 77, 4079 (19.55); .-PC also G . R Proctor a n d I
