Indoles, 3,4-disubstituted, precursors

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

Phosphorinanones have been utilized as substrates for the preparation of alkenes,11 amines,12 indoles,5,13 and in the synthesis of a series of secondary and tertiary alcohols via reduction,10 and by reaction with Grignard6,11 and Refor-matsky11,14 reagents. Phosphorinanones have also been used as precursors to a series of 1,4-disubstituted phosphorins.15 The use of 4-amino-l,2,5,6-tetrahydro-l-phenylphosphorin-3-carbonitrile for the direct formation of phosphorino-[4,3-d] pyrimidines has been reported.16... 

P.B. Alper and co-workers developed a practical approach for the synthesis of 4,7-disubstituted indoles based on the Sommeiet-Hauser rearrangement of aryl sulfilimines. The multihundred-gram preparation of methyl 7-chloroindole-4-carboxylate was achieved. The synthesis commenced with the activation of a sulfide precursor with SOCI2 and coupling the intermediate with 3-amino-4-chlorobenzoate to afford an aromatic sulfilimine. This sulfilimine was exposed to excess triethylamine and heated to generate the sulfonium ylide that underwent the rearrangement. 

Two type Ib approaches to indoles were reported involving tin-mediated radical cyclization reactions. Treatment of either 2-alkenylthioanilides <05H(66)241> or 2-(l-alkenyl) imidoyltellurides <05SL1893> provided 2,3-disubstituted indoles. The former precursor was also utilized in a synthesis of tetrahydro- 3-carbolines. 

Ethyl 3-bromomethy1-4-iodoindo1e-1-carboxylate, which can be prepared from the zirconocene intermediate 87 has been shown to be a versatile precursor for preparation of several 3,4-disubstituted indoles. <94J0C7164> The bromide can be readily displaced by such nucleophiles as cyanide, carbanions and amines. 

Biologically important heteroarenes are readily prepared by the reaction of ketone, ester or amide enolates with ortho-substituted aryl halides [11]. The ortho-substituent can subsequently be used for further synthetic manipulations. For example, the reaction of o-iodo or o-bromoaniline with enolates generated from aliphatic or aromatic ketones under SrnI conditions provides 2,3-disubstituted indoles in moderate to excellent yields (Equation 13.2) [12, 13]. 2,3-Disubstituted isoquinolin-l-ones (Equation 13.3) and isoquinolines are readily prepared using o-iodobenzamide and o-iodobenzylamine as radical precursors by the same approach [14]. 

Afterwards, several parameters, such as ligand and palladium precursor, were optimized. In 2008, phenylurea was found to be an effective ligand for the palladium-catalyzed annulation of 2-bromoanilines with internal allenes.Good yields of 2,3-disubstituted indoles were prepared by this catalyst system [Pd(OAc)2 (1 mol%), phenylurea (4 mol%), K2CO3, DMF, 130 °C]. 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

The synthesis of indoles from 2,6-xylylisocyanides involving sp C-H bond activation has been reported as early as 1986. The catalyst precursor was the ruthenium (II) complex RuH2(dmpe)2 (dmpe=l,2-dimethylphosphinoethane) and the reaction was performed at 140°C in a sealed tube in the presence of 20 mol% of the catalyst (Scheme 60) [63]. The catalytic reaction could also be carried out in the presence of RuH(2-naphthyl)(dmpe)2 but required the presence of hydrogen to complete the catalytic cycle, which is proposed in Scheme 61 [65, 66]. The catalytic preparation of indoles was only possible starting from 2,6-disubstituted isocyanides (2,6-dimethyl, 2-ethyl-6-methyl, 2,6-diethyl), whereas less substituted isocyanides only led to stoichiometric formation of indole ruthenium species [66]. 

Guella, G., Mancini, I., N Diaye, I., and Pietra, F. (1994) Almazole C, a new indole alkaloid bearing an unusually 2,5-disubstituted oxazole moiety, and its putative biogenetic peptidic precursors, from a Senegalese Delesseriacean seaweed. Hdv. Chim. Acta, 77, 1999-2006. 

---