Indole Methyl-substituted

Investigation of a related indole template, however, yielded potent compounds, as exemplified by the sulphonamide derivative (33). Activity was improved further by introducing steric constraints to the sidechain and introduction of a 7-methyl substituent on the indole ring, leading to compound (34) [82]. Derivatives generally possessed only moderate pharmacokinetic properties however (clearance 25-45 ml/min/kg in dog), which was attributed to metabolic vulnerability of the indole (C2-C3) double bond. Attempts to block metabolism by C2, C3 di-methyl substitution resulted in the loss of oxytocin activity. 

Methyl-substituted indole has been the subject of an investigation and the degradation metabolites were identified [346], An indole-degrading methanogenic consortium induced a two-step reaction on 3-methylindole, through a hydroxylation pathway that... 

A reinvestigation of the experiments on the UV irradiation of l-acetyl-l,2-dihydroquinoline-2-carbonitriles (Reissert compounds) 561 unequivocally demonstrated that the rearrangement via the diradical intermediate 562 gave 4//-3,l-benzoxazines 563 and 565 rather than the benzazete derivatives described earlier. The yields and the type of products were strongly influenced by the substituent R at position 4 while irradiation of the unsubstituted quinoline 561 (R=H) gave 3,1-benzoxazine 563 in nearly quantitative yield, the amount of the corresponding methyl-substituted analog 565 that could be isolated was considerable lower, due to its irreversible isomerization via 562 to the stable cycloprop[/ ]indole derivative 564 (Scheme 107) <199811(49)121 >. 

A related scheme can be applied to indole synthesis, with the aromatization being the result of elimination of Pd(0) and a proton (equation 27) (76JA2674). This scheme has been put into practice for AT-alkyl-o-allylanilines, a few aryl-substituted analogs and methyl-substituted allyl groups. The requisite o-allylanilines were obtained from o-bromoanilines and allylnickel. Provided the requisite starting materials can be constructed, the mild conditions of this cyclization would seem to recommend it for sensitive molecules. 

Methylpyridazin-3 (2H)-one 1-oxides unsubstituted at position 6 afford photochemi-cally a mixture of the corresponding 6-hydroxypyridazin-3(2H)-one, lactone (46) and isomaleimide (47). 4-Methylcinnoline 1-oxide gives a mixture of the methyl substituted benzofuran (48), the indazole (49) and the indole (50), while 4-methylcinnoline 2-oxide gives a mixture of the deoxygenated starting compound, benzisoxazole (51) and o-aminoacetophenone (Scheme 16). 

For the indole, methyl sustitution at the 2-position (i.e. 71) appears to sterically block C—C annulation vs C—N annulation (Scheme 46)126a. Note also that electrochemical methods are only useful for the substituted vinylindoles, as unsubstituted indoles passivate the working electrode. The results of cycloadditions of substituted enamines 66 and 69 to vinylindoles 65 and 71 are summarized in Tables 7 and 8. 

Jouannetaud and co-workers229 have explored electrophilic trifluoromethylation under superacidic conditions of aniline derivatives229 and /V-heterocycles. Methyl-substituted anilines and substituted acetanilides [Eq. (5.85)] react with the CC13+ cation generated from CC14 in HF-SbF5 followed by fluorination to yield the corresponding trifluoromethyl derivatives. Under similar conditions, indolines are transformed to the 6-triluoromethyl derivatives, whereas substituted indoles yield 5-triluoromethyl derivatives.230... 

A conducting, polymeric film of poly(indole-5-carboxylic acid) has been employed for covalent immobilization of tyrosinase, which retains catalytic activity and catalyzes oxidation of catechol to the quinone <2006MI41>. Poly(l-vinylpyrrole), polyfl-vinylindole), and some methyl-substituted compounds of poly(l-vinylindole) are of potential interest as photorefractive materials with a relatively low glass-transition temperature and requiring a lower quantity of plasticizer in the final photorefractive blend <2001MI253>. Polymers of 5,6-dihydroxyindoles fall within the peculiar class of pigments known as eumelanins and their chemistry has been reviewed <2005AHC(89)1>. 

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]. 

Murraya exotica has yielded5 3-formylindole it would be intriguing to know if the biogenesis of this simple indole is related to that of the Murraya carbazoles, for which it has been postulated that the methyl-substituted c or a rings are derived from an indole by interaction with an isoprene unit. 

The synthesis of pyrrolo[l,2-a]indoles (113) has been successfully accomplished in 85% yield through a 1,3-dipolar cycloaddition reaction using A-(trimethylsilyl)methyl substituted indoles (112) (Equation (6)) <89JOC644>. 

In a beautiful synthesis of (+ )-vindorosine (64b) (Scheme 22), c and E rings are made in a one-step process which depends on the fact that indoles, even / -substituted indoles, react more rapidly with electrophiles at the jS-position than at the a-position. In the present context the elegant step which makes use of this concept is the formation of (74), together with some (76), from (73). The electrophilic species is generated by interaction of the enamide at the future C-20 with an acid. The success of this step depends on the possibility of trapping a rapidly formed 3,3-disubstituted-3H-indolium salt intermediate, (75) in the present case, by an intramolecular nucleophilic addition to the indole a-carbon here the nucleophile is the enol of the methyl ketone. 

The photocycloaddition chemistry of pyridines substituted with electron-donor and electron-acceptor groups at the 2- and 3- positions continues to be exploited. The results of irradiation of such pyridines in the presence of 2-cyanofuran have now been described. The yields of the (47r+47r) cycloadducts (29) and (30), the pyridine dimer (31) and the transposition isomer (32) are dependent on the level of methyl substitution on the heteroarene and are given in Scheme 2. Other photocycloadditions to heteroarenes reported within the year include the reactions of benzodithiophene (33) with butadiyne derivatives and dimethyl acetylene dicarboxylate, giving low yields of (34) and (35) respectively, the latter from photorearrangement of the primary adduct (36). The (271+471) photocycloaddition of indoles (37) to cyclohexa-1,3-dienes (38) is sensitized by the aromatic ketones (39), and yields (14-46%) of the exo and endo isomers of the adduct (40) in ratios which are dependent on the substituents on the addends. 

Radical bromination of pyrrole and indole methyl substituents continues to be investigated, as does the substitution of the resulting bromo compound. Selective bromination of the 2-methyl group in 1-acetyl-2,3-dimethylindole can be achieved and the bromide ion displaced by malonate <85TL5253>. A recent example of an effective sequence of bromination and substitution is shown in Scheme 116 <928743, 930PP249,93TL3215>. 

---