One-pot multicomponent coupling

Keywords Acid chlorides, (V-Boc-protected propargylamine, PdCl2(PPh3)2, copper(l) iodide, triethylamine, p-toluenesulfonic acid, THF, BuOH, one-pot multicomponent, coupling-addition-cyclocondensation reactions, (V-Boc-iodopyrroles... 

Scheme 10.10 Synthesis of benzo[b]phospholes through one-pot multicomponent coupling.

Xi, C., Chen, C., Ling, J. and Hong, X. (2005) Pd-catalyzed one-pot multicomponent coupling reaction for the highly regioselective synthesis of polysubstituted benzenes. Organic Letters, 7 2), 347-349. 

Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described <06JOC3494>. The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed coupling-isomerization reaction of aryl halides (e.g., 18) with propargyl V-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with V.S -ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17). 

A similar-type copper-catalyzed C-N coupling reaction for the one-pot multicomponent synthesis of substituted indulines was reported by Wang and his group. 

Synthetic strategy One-pot multicomponent synthesis involving coupling-addition-cyclocondensation reactions... 

IL-supported one-pot multicomponent reaction for the construction of bi-heterocyclic-fused pyrrolo[l,2-a]benz-imidazoles 114 under microwave irradiation were reported by Sxm and coworkers (Scheme 12) [47]. The IL-anchored diamines 97 were coupled with cyanoacetic acid followed by cyclodehydration to generate key intermediate 2-sub-stituted benzimidazoles 113. IL-supported 113 reacted with aldehyde and isocyanide through Knoevenagel condensation followed by [4 +1] cycloaddition in one-pot affording pyrrolo[l,2-fl]benzimidazole 114. Remarkably, this is the first time applied IL support and isocyanide-based multicomponent react for the synthesis of fused tricyclic heterocycles under microwave irradiation. 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

Quite recently, Grigg and co-workers have based several of their ingenious multicomponent reactions on the combination of the above-mentioned palladium-catalyzed coupling reactions of allenes with a subsequent reaction in a one-pot operation. For example, the catalytic re-allylpalladium species generated from the carbopalladation of the allene with iodobenzene was captured by a phenolic nucle-... 

The utility of Ru-catalyzed cross-metathesis in multicomponent coupling strategies has also been demonstrated. For instance, one-pot cross-metathesis/allylboration sequences have been reported by Miyaura [170] and by Goldberg and Grubbs [171]. Pinacol allyl boronate 174 was reacted with a series of functionalized olefins, which include symmetrically 1,2-disubstituted olefins as well as hindered olefins and styrenes, in the presence of catalyst 175 to produce intermediate allyl boro-nates (e.g. 176). The latter may then be reacted in situ with aldehydes to produce functionalized homoallylic alcohols with high levels of anti-selectivity (Scheme 8.80). 

Andreana and co-workers [188] developed a one-pot method for generating molecular diversity via a multicomponent coupling reaction under microwave irradiation. The initially formed Ugi four-component coupling products gave rise to three structurally distinct scaffolds depending on the solvent effects and sterics the 2,5-diketopiperazines 137, the 2-azaspiro[4.5]deca-6,9-diene-3,8-diones 138, and the thiophene-derived Diels-Alder tricyclic lactams 139 (Scheme 107). 

Multicomponent Coupling Reactions. Tandem one-pot Pd-catalyzed processes have been developed that permit the coupling of three (or more) reactants in a single step. For example, allenes, aryl halides, and aryl boronic acids react in the presence of Pd(dba)2 and CsF to afford functionalized olefins (eq 25). In related transformations, in situ-generated benzynes have been... 

Dihydropyridines can be prepared via the three-eomponent coupling of cinnamaldehyde, aniline and p-keto esters under solvent-free conditions by means again of L-Pro as catalyst in the transformation. The three-component reaction of 1,3-indanedione, isatins and enamines as the nucleophiles is also possible in the presence of L-Pro for the one-pot synthesis of highly functionalised spirooxindoles derivatives. While only some examples are highlighted here, ° ° the possibilities of L-Pro in multicomponent reactions are tremendous. It has also shown good catalytie activity in classic multicomponent reactions such as Biginelli reactions and Hantzsch dihydropyridine synthesis. 

Based on the aforementioned amination process, Xi developed a one-pot synthesis of 2-alkynylindoles 36 involving the multicomponent coupling of o-bromo-(2,2-dibromovinyl)ben-zenes 35, arylamines, and terminal alkynes. The reaction is proposed to proceed through a Pd-catalyzed Sonogashira coupling leading to a monoalkynylated product XIV, followed by an intermolecular Buchwald-Hartwig amination to XV and a... 

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