One- and two-component domino reactions

Tetrasubstituted pyrroles could be obtained by skeletal rearrangement of 1,3-oxazolidines, a reaction that is substantially accelerated by microwave irradiation. Dielectric heating of a 1,3-oxazolidine 7, absorbed on silica gel (1 g silica gel/mmol) for 5 min in a household MW oven (900 W power) cleanly afforded the 1,2,3,4-tetrasubstituted pyrrole 8 in 78% yield, thus reducing the reaction time from hours to minutes (Scheme 5) [24], 1,3-Oxazolidines are accessible in one-pot, two-step, solvent-free domino processes (see also Sect. 2.6). The first domino process, a multi-component reaction (MCR) between 2 equivalents of alkyl propiolate and 1 equivalent of aldehyde furnished enol ethers 9 (Scheme 5). Subsequent microwave-accelerated solvent-free reactions of enol ethers 9 with primary amines on silica support afforded intermediate 1,3-oxazolidines, which in situ rearranged to the tetrasubstituted pyrroles (2nd domino process). Performed in a one-pot format, these... 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

Tsuchii et al. reported a very interesting four-component domino process where an alkyne, two olefins and diphenyl diselenide sequentially react to form a highly functionalized cyclopentane derivative, after a linear addition sequence and 5-exo-trig cyclization [136]. This reaction can be seen as an interrupted polymerization process initiated by the addition of selenyl radical to an electron-deficient alkyne in the presence of a large excess of a Michael acceptor. The identity of each reaction partner is important for the outcome of the reaction. For instance, use of (PhS)2 instead of (PhSe)2 leads to the polymerization product rather than to the cyclization one, while (PhTe)2 did... 

Multicomponent reactions have been described for several syntheses of imidazoles. Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted three-component one-pot sequential reactions or one-pot domino reactions have been described <06JOC3137>. Multicomponent reactions between 2-aminopyrimidine, aldehydes and isonitriles afforded imidazo[l,2-a]pyrimidines <06TL947>. Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[l,2-a]pyridines and imidazo[l,2-a]pyridyn-3-ylamino-2-acetonitriles were synthesized by multicomponent reactions under microwave condition in methanol by simply mixing a-aminopyridines, aldehydes, and trimethylsilylcyanide catalyzed by polymer-bound scandium triflate <06TL2989>. 3-Aminoimidazo[l,2-a]pyridines have been synthesized via the multicomponent reaction of aldehydes, isocyanides and 2-aminopyridines in the presence of the ionic liquid l-butyl-3-methylimidazolium bromide [bmim]Br<06TL3031>. 

The cyclic a,/ -unsattirated ketone cyclohex-2-en-l-one (50) was used as building block in the one-pot domino cycloaddition of enol ether 14 and nitrostyrene 15a. At 15 kbar and 50 "C, nitroso acetal 51 was formed in 67 % yield, whereas nitroso acetal 54a was formed as a side product (Scheme 9.18). This result indicated that the 1,3-dipolar cycloaddition is still faster with the electron-poor substituted cyclohexenone 50 than with the electron-rich mono-substituted enol ether 14. The one-pot reaction of 52 with enol ether 14 and nitrostyrene 15a merely resulted in formation of nitroso acetal 54a instead of nitroso acetal 53. The unwanted side reaction was not observed in the one-pot three-component reaction with 14 and methyl-substituted nitrostyrene 15b and 52 (Scheme 9.19). The large difference in reactivity between the three components in both the Diels-Alder and the [3 + 2] cycloaddition resulted in the formation of 55 as the main product. The side reaction of 16b with 14 to form 54b was prevented, since 14 was completely consumed in the reaction with 15b to give nitronate 16b (15 kbar, 50 °C, 16 h). However, heating (50 °C) the reaction mixture for 76 h at 15 kbar was necessary to produce nitroso acetal 55, which was formed as a mixture of two major diastereomers (ratio 3 1) in 69 % yield. 

Tandem domino and tandem consecutive reactions do not necessarily involve more than one reactant and can be unimolecular, as is exemplified by such processes as polyolefin cyclization [13]. Tandem sequential reactions cannot be unimolecular processes and involve two reactants at least. Both, tandem sequential and higher-order tandem domino reactions are of foremost interest in this text, because they enable the concept of multicomponent reactions (MCRs) to be introduced [4, 7-9]. Depending on the reaction conditions, MCRs can be regarded as a subclass of either tandem sequential (Scheme 17.1a) or higher order tandem domino reactions (Scheme 17.1b). In the former, formation of intermediate AB is followed by addition of a third component C to the reaction mixture to enable formation of reaction product ABC. In the latter, components A, B, and C are simply... 

Later, Tu and coworkers [57] reported domino synthesis of furo[3,4-h][l, Sjnaphthyridines 93 through three-component reactions of aldehydes 69, 2-aminoprop-l-ene-l,l,3-tricarbonitrile 29, and N-substituted 4-aminofuran-2(5H)-ones 57 in EtOH using EtONa as a base (Scheme 12.36). N-substituted 3-aminocyclohex-2-enones were also suitable for this domino reaction, affording 21 examples of benzo[h][l,8]naphthyridines in 69-84% chemical yield, with the concomitant formation of two new pyridine rings. 

A catalytic asymmetric isatin-involved Povarov reaction was utilized by Shi and colleagues to prepare 251 in a diastereo- and enantioselective manner. During the three-component coupling, two chiral quaternary centers are formed in >99 1 dr and up to 97% ee (130L128). Complex polyhet-erocyclics 252 and 253 were prepared by a highly selective four-component domino multicyclization with an isatin, an enamineone, and two acetylenes. Four new rings and four stereocenters are created in a one-pot operation, with the reactions complete within 30 min in up to 64% yield (13OL1540). 

In the particular case of acrolein, which can be used both as a donor and acceptor component (3 equiv to nitrosobenzene), a novel domino amidation-redox amination took place under similar conditions (triazolium XII/DBU, CH Clj, rt), yielding A-propionyloxy-A-phenylacrylamide 54 as the major product (75%) [42]. In this reaction, as depicted in Scheme 5.36, two catalytic cycles seem to operate, one forming the Af-phenylhy-droxamic acid 53 by reaction of nucleophilic intermediate 135 (as d ) with nitrosobenzene. The second one operates through P-protonation of 135 (as d ) forming the activated ester 136, which then reacts with the hydroxamate of 53 yielding 54 along with NHC catalyst. 

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