Indole cyclization product

Similarly, reaction of Grignard reagent 112 with 2-methoxyallyl bromide [75] leads to compound 113 that leads after acidic deprotection of the formamidine moiety and the enol ether to the indole cyclization product 114 in 90% yield (Scheme 4.25). 

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

Gassman and co-workers developed a synthetic route from anilines to indoles and oxindoles which involves [2.3]-sigmatropic rearrangement of anilinosul-fonium ylides. These can be prepared from Ai-chloroanilines and ot-thiomcthyl-ketones or from an aniline and a chlorosulfonium salt[l]. The latter sequence is preferable for anilines with ER substituents. Rearrangement and cyclizalion occurs on treatment of the anilinosulfonium salts with EtjN. The initial cyclization product is a 3-(methylthio)indole and these can be desulfurized with Raney nickel. Use of 2-(methylthio)acetaldehyde generates 2,3-unsubstituled indoles after desulfurization[2]. Treatment of 3-methylthioindoles with tri-fiuoroacetic acid/thiosalieylie acid is a possible alternative to Raney nickel for desulfurization[3]. 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

Many aryhydrazones provide two or more isomers when subjected to the conditions of the Fischer indole cyclization. The product ratio and the direction of indolization can also be affected by different reaction conditions (i.e. catalysts and solvents), which is attributed, at least in part, to the relative stabilities of the two possible tautomeric ene-hydrazine intermediates. Generally, strongly acidic conditions favor formation of the least substituted ene-hydrazine, while cyclization carried out in weak acids favors the most substituted ene-hydrazine. Eaton s acid (10% P2O5 in MeSOsH) has been demonstrated to be an effective catalyst for the preparation of 3-unsubstituted indoles from methyl ketones under strongly acidic conditions. Many comprehensive reviews on this topic have appeared. ... 

Radical cyclization of the indole thioesters 107 and 110 with tributyltin hydride and 2,2 -azobisisobutyronitrile (AIBN) gives a mixture of products in each case the 6-< Wo-cyclization product (the indolonaphthyridine, 109 or 112) and the 5-f vv-cyclisation product (the spiro compound 108 or 111) are obtained in approximately equal yield (Equations 22 and 23) <20040L759>. 

Pd(Ph3P)4 and Et3N in refluxing acetonitrile to form the intramolecular Heck cyclization product 152 [125]. The mechanism is akin to that of the Mori-Ban indole synthesis (see page 24). In another case, the intramolecular Heck cyclization of enamidone 153 with a pendant thienylbromide moiety furnished the 6-trig-endo product, indolizine 154, in 63% yield, along with the debrominated enamidone 155 in 37% yield [126],... 

Carboxy-2-pyridylthio)propionic acids, prepared by the reaction of 2-mercatopyridin-3-carboxylic acid with 3-bromopropionic acid in aqueous KOH, undergo cyclization upon treatment with anhydrous sodium acetate and acetic anhydride to afford 2,3-dihydrothiopyrano[2,3-3]pyridin-4(4//)-ones. These products undergo further reaction with phenylhydrazine to give the phenylhydrazone (isolated) and then Fischer indole cyclization to give novel 5/7,1177-pyrido[2, 3 2,3]thiopyrano[4,3-3]indoles <2000JHC379>. 

Another version of the o-aminobenzyl anion synthon is obtained by dilithi-ation of A-t-Boc-protected n-alkylanilines. These intermediates are C-acylated by DMF or JV-methoxy-lV-methyl carboxamides, leading to either 3- or 2,3-disubstituted indoles. In this procedure dehydration is not spontaneous but occurs on brief exposure of the cyclization product to acidf4]. Use of C02 as the electrophile generates oxindoles. 

All of these processes are of limited synthetic utility because of the requirement of the use of stoi chiometric amounts of palladium complexes. However, by judicious choice of reactants and condition the above-mentioned impediments to catalysis can be overcome. For example, an efficient palladium(II) catalyzed cyclization of o-allyl- and o-vinyl-anilines to indoles has been developed (equation 14).28 Be cause arylamines are -106 less basic than aliphatic amines, and because the cyclized product in thi system gave an enamine (indole) stabilized by aromatization, the problems of catalyst poisoning by sub strate or product were circumvented, and catalysis was successfully achieved. The system was quit tolerant of a variety of functional groups and was used to prepare indoloquinones in excellent yieli... 

The usefulness of Pd-catalysed reactions is demonstrated amply in the total synthesis of clavicipitic acid [76]. The first step is intramolecular aminopalladation of the 2-vinyltosylamide 92 with Pd(II) to give the indole 93. Then stepwise Heck reactions of the iodide and bromide of 94 with two different alkenes 95 and 96 in the absence and presence of a phosphine ligand give 97. In the last step of the synthesis, the intramolecular aminopalladation of 97 with a catalytic amount of Pd(II) gives the cyclized product 99. It should be noted that the aminopalladation is a stoichiometric... 

Ring closure reactions taking place by intramolecular addition of an aromatic radical to a double bond have been widely studied on both their regio- and stereochemical aspects [93]. Aryl halides and diazonium salts substituted at ortho- position with a 0-allyl or TV-allyl chain were used for the preparation of 2,3-dihydrobenzofuranes and 2,3-dihydro-1/7-indoles under different reaction conditions. The reaction pattern involves the generation of an aryl radical 20, which reacts with the double bond in a 5-exo trig fashion to afford the exocyclic radical 21, plausible of reduction by a hydrogen donor to obtain the reduced-cyclized product 22 (Sch. 23) [93d,94]. 

A fascinating cyclization product of this nor-compound is a cyclic dehydrogenation product where there is a direct coupling of the tryptamine nitrogen to the 4-position of the indole ring. This tricyclic material, O-methyl-nordehydrobufotenine, proved to be of comparable activity to DMT in rat studies, but has not apparently been studied in man. 

Indolo-steroids have been obtained by -coupling of steroid dienamines with dia-zonium salts in dimethylformamide followed by Fischer-indole cyclization of the resulting hydrazone39 (Scheme 37). In methylene chloride the /Fcoupled product 75 was obtained, cyclization of which gave indazoles 74 and 762a. The oxidative role of dimethyl sulphoxide in the formation of 76 was attributed to nucleophilic attack by the solvent on 75 leading to intermediates 77 and 78, with elimination of dimethyl sulphide (Scheme 38). 

Indolylacyl radicals participate in a productive cascade reaction featuring an intermolecular alkene addition-indole cyclization sequence to give the cyclopenta[ >]indole... 

More satisfactorily, the regioisomeric selenoester 17, incorporating the tetrahydropyridine moiety at the 3-position of the indole ring, upon exposure to the above standard reductive conditions underwent a regioselective 6-endo cyclization to give the pyrido[4,3- >]carbazole 18 as a 2 1 mixture of trans-cis stereoisomers in 75% yield. No 5-exo cyclization product was detected <06JOC1746>. 

Cyclization of aryl radicals on to either 2- or 3-carbonyl substituted pyrroles occurs preferentially at the 2-position. In the case of the former cyclizations, the yields are poor but this could represent a rapid approach to a range of indole alkaloids. Thus, cyclization of 2-substituted pyrroles 929 by treatment with Bu3SnH (0.02 M) and AIBN (catalytic amounts) as initiator in refluxing toluene for 12 h gave the -exo cyclization products 931 and 932 as the major products judging by H NMR of the crude product (Scheme 181) <1995TL6743>. 

Alkyl radicals 968, generated on the 1-A -alkyl group of 2-(phenylsulfanyl)indole from the corresponding A -alkyl bromides 965 by the action of Ph3SnH/AIBN (reflux 6h in benzene under Ar), triphenyltincobaloxime (Ar, DMF, 130 °C, 24 h) or by the photolysis (350 nm, benzene, 24 h, Ar) of the corresponding A -alkylcobaloxime, transform into a reduction product 966 and a cyclization product 969 (Scheme 187) <1997J(P1)3591>. Reaction modes differ little... 

Quinolizinium ions fused with indole are related to yohimbine alkaloids flavopereirine, sempervirine, reserpine, alstoniline, ajmaline, and so on. Parent indolo[2,3-a]quinolizinium salt (272) has been reported (87TL5259). l-Phenylsulfonyl-2-(2-pyridyl)indole 271 was treated with H-butyllithium to afford the 3-lithio species, which was quenched with bromoacetalde-hyde to give the cyclization product (48%). It was dehydrated with aq. NaOH to afford 272 (89%). Using this method, sempervirine (273) was obtained (88T3195). 

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