Indoles 2-cyano- from

Indoles result from o-nitro- and o-amino-phenylacetonitriles by reduction of the cyano group, e.g. (29) — (30) (91T7195, 94SC639). 

The final step can involve introduction of the amino group or of the carbonyl group. o-Nitrobenzyl aldehydes and ketones are useful intermediates which undergo cyclization and aromatization upon reduction. The carbonyl group can also be introduced by oxidation of alcohols or alkenes or by ozonolysis. There are also examples of preparing indoles from o-aminophcnyl-acetonitriles by partial reduction of the cyano group. 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

Beccalli et al. reported a new synthesis of staurosporinone (293) from 3-cyano-3-(lH-indol-3-yl)-2-oxo propionic acid ethyl ester (1464) (790). The reaction of 1464 with ethyl chlorocarbonate and triethylamine afforded the compound 1465, which, on treatment with dimethylamine, led to the corresponding hydroxy derivative 1466. The triflate 1467 was prepared from 1466 by reaction with trifluoromethanesulfonic anhydride (Tf20) in the presence of ethyldiisopropylamine. The palladium(O)-catalyzed cross-coupling of the triflate 1467 with the 3-(tributylstannyl)indole 1468 afforded the vinylindole 1469 in 89% yield. Deprotection of both nitrogen atoms with sodium ethoxide in ethanol to 1470, followed by photocyclization in the presence of iodine as the oxidizing agent provided the indolocarbazole 1471. Finally, reductive cyclization of 1471 with sodium borohydride-cobaltous chloride led to staurosporinone (293) in 40% yield (790) (Scheme 5.248). 

The related cyclization of 2-ethynylanilines 67 also represents one of the usefiil methods for the synthesis of 2-substituted indoles since the precursors are easily prepared from 2-haloanilines 66 by Pd-catalyzed cross-coupling with terminal alkynes. Althou cyclizations of such alkynes are normally effected using Cu(I) or Pd(II) species, Sakamoto showed that in the absence of such metals, base catalysis (e.g., NaOEt) alone can accomplish the same goal. This author now reports that tetrabutylammonium fluoride (TBAF) is capable of inducing cyclization to the indoles 68 without affecting functionalities such as bromo, cyano, ethoxycarbonyl, and ethynyl <99JCS(P1)529>. 

Electron-withdrawing substituents seem to stabilize the benzo[cjfuran system as they do in the analogous benzo[c]thiophene and benzo [c]indole series. l-Cyano-3-phenylbenzo[c]furan (128) was obtained from the aldehyde 127 as stable yellow needles hydrolysis with base yields the carboxylic acid (129). Catalyzed hydrogenation of these cornpounds leads to 1,3-dihydrobenzo[c]furans (130, R = CH2NH2, COOH = Ph). Increased... 

Hydrogen cyanide can also be added to 2-nitrobenzylidine derivatives, such as 299, to give 296, and then cyclization to 298 takes place with ethanolic sodium carbonate. The more basic potassium cyanide or hydroxide, however, converts 2% into the quinolone 300 (72CRV627). Both nitriles 301 and 302 with potassium cyanide give the indole 304 via the common intermediate 303. If piperidine is added, 2-amino-4-cyano-3-phenylquinoline 1-oxide is the main product (60JCS3466). The indole 305 has been obtained similarly from 306 [70JCS(C)1916],... 

The stereochemistry of the cycloaddition has been studied through the reaction with methyl fumarate and maleate. The geometry is preserved and trans- and d.v-adducts are obtained. The di-adduct isomerizes rapidly into the frans-adduct on standing at room temperature. Indications of the regiochemistry were obtained from reaction with acrylonitrile which gives 2,3-dihydro-l-cyano-9-methyl-lH-pyrrolo[l,2a]indole exclusively.407,408... 

Several syntheses are on record which avoid the preparation of 5-benzyloxyindole in these procedures, the indole ring is usually formed after provision is made for the introduction of the ethanamine side chain. The first of these (107, 108) was an adaptation of Ewins original trypt-amine synthesis. A subsequent route (109) started from ethyl a-cyano-2,5-dimethoxycinnamate (VIII), which was prepared by condensation of 2,5-dimethoxybenzaldehyde with ethyl cyanoacetate. When this was boiled with potassium cyanide solution, addition of the elements of hydrogen cyanide was accompanied by hydrolysis of the ester function and decarboxylation, to give 2,5-dimethoxyphenylsuccinonitrile (IX). 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

---