Cacchi indole synthesis

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

The research group of Cacchi made extensive use of these tandem cyclization-Heck reactions to prepare a wide variety of indoles [311-314], For example, vinyl triflates react with o-aminophenylacetylene to afford an array of 2-substituted indoles in excellent yield, e.g., 356 to 357 [312], and a similar reaction of 358 with aryl iodides leads to an excellent synthesis of 3-arylindoles 359 [313],... 

Formation of indole derivative by the reaction of 2-ethynylaniline, aryl halide and CO is known [53]. Cacchi extended the reaction to the synthesis of indolo[3.2-c]quinoline. Reaction of 2-(2 -aminophenylethynyl)trifluoroacetanilide 122, 4-iodoanisole and CO occurred as shown by 123 to provide 124 and then the 3-aroylindole 125. Treatment of 125 with a base gave the indoloquinoline 126 in 70% overall yield [54]. 

S. Cacchi and G. Fabrizi, Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions — Update 1, Chem. Rev., 2011, 111, PR215—PR283. An outstanding review and update of their 2005 paper (cited below). 

Palladium-Catalyzed Indole Ring Synthesis Cacchi... 

During the following twenty years, Cacchi has improved upon and expanded this indole ring synthesis. Some selected examples are shown in Scheme 2 (equations 1 ) [5-8]. 

The Cacchi synthesis and closely related indole syntheses involving the Pd-catalyzed cyclization/trapping of 2-aIkynylanilines have filled the organic literature, and three recent examples are shown in Scheme 3 (equations 1-3) [9-11]. Moreover, this chemistry has been applied to solid-phase synthesis (EUingboe [12]), 3-iodoindoles (Barluenga... 

The Cacchi synthesis of indoles via the Pd-catalyzed cyclization of 2-aIkynylaniUnes and subsequent functionalization has extended enormously the original Yamanaka-Sakamoto-Sonogashira and Larock reactions. For a review of these methods see Beller [41]. 

Catalytic-in-Cu synthesis of indoles was reported by Yamanaka [187], Villemin [188], Yamamoto (Scheme 9.38) [189], and then Cacchi (Scheme 9.39) [190]. In contrast to the previous examples, no loss of the TMS-group was observed under these reaction conditions. 

More recently, Corma reported that this aminomethylation-cydization transformation could be successfidly achieved with a highly active and recoverable heterogeneous catalyst, consisting of nanoparticles of Au supported on a nanocrystalhne Zr02 (212]. Another cascade reaction, involving a domino couphng-cydoisomeriza-tion of terminal o-ethynyl-acetanilides and aryl iodides in the presence of 10 mol% (Cu(phen)(PPh3)2]N03, was developed by Cacchi and Venkataraman for the synthesis of C2-aryl-functionalized indoles [121, 190]. 

Cacchi synthesis (indole) 140 Chichibahin reaction 352 Chichibabin synthesis (indolizine) 153 Claisen synthesis (isoxazole) 188 Combes synthesis (quinoline) 399 Cook-Heilbron synthesis (thiazole) 206 Corey synthesis (oxirane) 22 Cornforth rearrangement 171 imino-Corey reaction 36... 

Ambrogio 1, Arcadi A, Cacchi S, Fabrizi G, Marinelli F (2007) Gold-catalyzed synthesis of 2-substituted, 2,3-disubstituted and 1,2,3-trisubstituted indoles in [bmim]BF4. Synlett 2007 1775-1779. doi 10.1055/s-2007-982572... 

S. Cacchi, G. Fabrizi, Synthesis and functionalization of indoles through paUadium-catalyzed reactions, Chem. Rev. 105 (2005) 2873-2920. 

Cacchi and coworkers developed an efficient Cul-catalyzed synthesis of a mul-tisubstituted indole skeleton from readily available A/ -aryl enaminones with wide functional group tolerance including the whole range of halogen substituents. For... 

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