Indoles 3,4,5-trisubstituted, preparation

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. 

Benzofuranyl)pyrroles, 2-(2-thienyl)pyrroles , 2,2 -dipyrroles, 3-(2-pyr-rolyl)indoles , 2-(2-benzimidazolyl)pyrroles and2-(2-, 3- and4-pyridyl)pyrroles were prepared using this method. Reaction of alkynes (for example, propyne) or allene with ketoximes in a superbase system (MOH/DMSO) leads to 2,5-di- or 2,3,5-trisubstituted pyrroles Pyrroles and dipyrroles were synthesized also from corresponding dioximes and acetylene in a KOH/DMSO system It has also been shown that 1,2-dichloroeth-ane can serve as a source of acetylene in pyrrole synthesis. Oxime 52 in the system acetylene/RbOH/DMSO at 70 °C afforded a mixture of three pyrroles 53-55 in low yields (equation 23). The formation of product 53 occurred through recyclization of pyrrolopy-ridine intermediate. ... 

Hydroamination reactions of alkynes provide an alternate route to arylhydrazones that can be utilized in the Fischer indole synthesis. Treatment of arylhydrazine 99 with alkyne 100 in the presence of catalyst system comprised of titanium tetrachloride and /-butylamine afforded arylhydrazone intermediate 101 which underwent a Fischer cyclization to give 1,2,3-trisubstituted indole 102 as a single regioisomer <04TL9541>. A similar titanium-catalyzed hydroamination reaction was utilized to prepare tryptamine derivatives <04TL3123>. 

A new, water soluble palladium catalyst was used in the Sonogashira reaction (Pd(OAc)2 triphenylphosphine-trisulfonate sodium salt) [131], and several groups adapted the Sonogashira coupling and subsequent cyclization to the solid-phase synthesis of indoles. Bedeschi and coworkers used this method to prepare a series of 2-substituted-5-indolecarboxylic acids [132], CoUini and Ellingboe extended the technique to l,2,3-trisubstituted-6-indolecarboxylic acids [133]. Zhang and... 

A small library of 2,3,5-trisubstituted indoles was obtained by Schultz and coworkers starting from a solid-supported 3-bromo-2-iodoaniline on commercially available PS-TsCl resin (polystyrene sulfonyl chloride Argonaut Technologies). A successive Larock heteroannulation, followed by electrophilic substitution on indole position three and final Suzuki or Sonogashira cross-coupling reactions, gave excellent results for the preparation of an important number of indole derivatives 19 and 20 (Scheme 9 20010L3827). 

Spirotryprostatin A 142 and B 143 are two powerfully bioactive indole alkaloids. Both compounds inhibit the cell cycle in the G2/M phase, and 143 shows cytotoxic activity on the growth of human leukemia cell lines. Meyers and Carreira reported a total synthesis of 143. The Kocienski modified Julia olefmation was used in the formation of trisubstituted olefin without scrambling at Ci8. The alkene 146 was prepared in 78% yield by reacting sulfone 145 with aldehyde 144. The final product 143 was obtained by four-step reaction from the intermediate 146. 

Subsequently, the same group reported a more practical method for preparing indoles by using the azaallylic anion as a synthon (Scheme 8) [36]. They found that imines 25 could couple with o-dihalobenzenes 26 to produce intermediates 27, which underwent an intramolecular aryl amination to afford 1,2,3-trisubstituted indoles 28. Because the azaallylic anion could be prepared by a Pd-catalyzed reaction of alkenyl halides and primary amines, they were able to develop a domino three-component synthesis of indoles. 

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