One-pot five-component

An interesting one-pot, five-component domino process using an intermolecular Diels-Alder reaction of furans with AT-phenylmaleimide as its final step has been used to construct the central core of indolo[2,3- ]carbazoles (Equation 86) <2002AGE4291>. Thus, aminooxazoles produced from an Ugi three-component reaction undergo acylation/intramolecular Diels-Alder/retro-Diels-Alder cycloreversion with pentafluorophenyl arylprop-2-ynoates to give furan derivatives. Subsequent Diels-Alder cycloaddition at elevated temperatures with A -phenylmaleimide produces carbazoles in good yields (Table 5). 

A one-pot five-component dithiane linchpin coupiing was applied as the key synthetic transformation in A.B. Smith s approach to Schreiber s C16-C28 trisacetonide subtarget for mycoticins A and B. To prevent a premature Brook rearrangement, ether was used instead of THF as a solvent for the initial deprotonation of 2-TBS-1,3-dithiane. The third component in the iinchpin coupiing was (S,S)-diepoxypentane that was added to the reaction mixture along with HMPA in THF. 

Scheme 2 One-pot five-component synthesis of 1,3-dialkylimidazolium tetrafluoroborate ILs.

Lashkari M, Maghsoodlou MT, Hazeri N, Habibi-Khraassani SM, Sajadikhah SS, Doostmohamadi R. Synthesis of highly functionalized piperidines via one-pot, five-component reactions in the presence of acetic acid solvent. Synthetic Comm 2013 43(5) 635. ... 

A one-pot five-component reaction of salicylaldehydes, malononi-trile, hydrazine hydrate, aryl isothiocyanates, and water in a mixture of... 

J. Safaei-Ghomi, A. Ziarati, M. Tamimi, Acta Chim. Slav. 2013, 60, 403 10. A novel method for the one-pot five-component synthesis of highly functionalized pyranopyr-azoles catalyzed by Cul nanoparticles. 

Khan AT, Khan MM, Bannuru KKR (2010) Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines. Tetrahedron 66 7762-7772... 

H. Singh, J. Sindhu, J.M. Khurana, C. Shartna, K.R. Aneja, A facile eco-friendly one-pot five-component synthesis of novel 1,2,3-triazole-linked pentasubstituted 1,4-dihydropyridines and their biological and photophysical studies, Aust. J. Chem. 66 (2013) 1088-1096. 

In particular, the consecutive one-pot four-component reaction of (hetero)aroyl chlorides 7, aUcynes 4, tryptamine derivatives 73 as primary amines and a,p-unsam-rated acid chlorides 71 to form tetrahydro-p-carbolines 74 most clearly demonstrates the potential of this concept and methodology for the rapid construction of highly-substituted, complex heterocycles. Five new CT-bonds and four new stereocenters can be installed in a sequence of consecutive one-pot transformations (Scheme 42). 

A one-pot four-component solution phase procedure has been developed for the synthesis of 2,4,5-trisubstituted thiazoles 25 <05SL79>. The four components, the 3-substituted 3-bromo-2-isocyanoacrylate 18, the ketone or aldehyde 19, the primary amine 20, and the thiocarboxylic acid 21, can vary broadly, thus producing thiazoles with five potential diversity points. Presumably, condensation of 19 with 20 generates imine 22, which reacts regioselectively with 18 and 21 via the Ugi pathway. The intermediate Ugi product 23 is in... 

In 2010, Al-Tel s group described the synthesis of polyfunctional structures using a one-pot five- and six-component sequential process [61]. In this process, firstly the imine 66 was formed in the presence of SclOTOj and then the solution could be directly used in the next [4-i-l]-cycloaddition (Groebke-Blackbum reaction). The cycloaddition product 67 contained an acid moiety, which allowed a subsequent Ugi-4CR. Thus, the final Ugi products 68 were obtained from isocyanides, aldehydes, and amines in good yields (Schane 7.28). 

M. Bararjanian, S. Balalaie, F. Rominger, B. Movassagh, H. R. Bijanzadeh, Mol. Divers. 2011, 15, 583-594. Novel and efficient one-pot five- and six-component reactions for the stereoselective synthesis of highly functionalized enaminones and dithiocarbamates. 

T. H. Al-Tel, R. A. Al-Qawasmeh, W. Voelter, Eur. J. Org. Chem. 2010, 5586-5593. Rapid assembly of polyfnnctional strnctnre using a one-pot five- and six-component sequential Groebke-Blackbnm/Ugi/Passerini process. 

Many versatile approaches to the construction of fused heterocyclic systems (6 5 6) with ring junction heteroatoms have been reported. More general reactions which can be used for synthesis of derivatives of several tricyclic systems, and transformations which have potential for use in the preparation of a series of substituted compounds, are discussed in this section. Formation of the five-membered ring is presented first because it is a conceptually simple approach. It should be noted, however, that the addition of a fused six-membered ring to a bicyclic component offers much more versatility in the construction of a (6 5 6) system. Each subsection below starts with intramolecular cyclization of an isolated intermediate product. Reactions which follow are one-pot intermolecular cyclizations. 

The cyclization of the five-atom component O-acylated amidoximes 204 leads to 1,2,4-oxadiazoles via C-N bond formation as shown in Scheme 30. The requisite O-acylated amidoximes 204 are accessed via the reaction of an amidoxime with an activated carboxylic acid or a carboxylic acid derivative. Often the O-acylated amidoxime 204 is not isolated and the cyclization is either spontaneous or occurs in a one-pot process, and these approaches are dealt with in Section 5.04.9.1.2 as syntheses from a one-atom component and a four-atom component. In this section, only those methods in which the O-acylated amidoxime 204 is isolated and cyclized in a separate step are dealt with. 

Preparation of diketopiperazine as part of a bicyclic system was developed by a one-pot Ugi-4-center-3-component reaction (U-4C-3CR) [50]. A 3-keto or aldo acid 155 was used as bifunctional educt for an intramolecular Ugi reaction forming a five-membered ring. The application of C-protected amino acids 156 as amine components enables an intramolecular cyclization forming 2,6-piperazinediones 158 (Scheme 26). 

C, -polyol chain (47) with five free or protected secondary alcohol functions is formed from five components in a one pot reaction. However, this remarkable efficiency is achieved only if the complete stereochemical information of the polyol chain has already been introduced by the chiral epoxides. 

Another example, also reported by Ugi and co-workers, is the combination of an Ugi five center 4-component reaction (U-5C-4CR) with a Passerini-3CR (Scheme 16) [102]. This one-pot procedure uses an a-amino acid (L-aspartic acid, 168) as a 2-center-1-component input, which explains the origin of the U-5C-4CR. 

A number of unusually fused heterocyclic compounds have been reported by Tu and co-workers [118]. The three-component domino reaction of an aldehyde, an enaminone 72 and malononitrile resulted in the formation of polysubstituted imi-dazo[l,2-a]quinazolines 73 and pyrimido[l,2-a]quinolines 74. (Scheme 56) When enaminone 75 was reacted using the same reaction conditions, this resulted in the formation of quinolino[l,2-a]quinazolines 76 in good yields. In this one-pot reaction, up to five new bonds were formed accompanied by the generation of the lactam group. Interestingly, the volume of ethylene glycol used seems to influence the yield of the product (Scheme 57). 

By using a multicomponent cascade reaction. Parsons et al. [88] achieved one-pot sequential [1+4] and [3+2] cycloadditions to synthesize highly substituted iso-xazolines via nitrile oxides (Scheme 11.28). These five-component reactions proceed by initial formation of isonitriles 109 that react with nitroalkenes 110 to form unstable N-(isoxazolylidene)alkylamines, which in turn fragment to generate the nitrile oxides 111. Cycloaddition then occurs with methyl acrylate, chosen for its expected reactivity with nitrile oxide dipoles, to generate the isoxazolines 112. Reactions using standard thermal conditions and microwave irradiation were com-... 

In a more speculative and intuitive way, 3 and 4 should react in the presence of a base to give intermediates of type 15 (9 compounds), which similarly to entry c should react with 2 to give intermediates 16 (27 compounds) followed by cyclodehydration to yield 17 (27 compounds). Whereas a five component one-pot condensation would maximally yield 243 compounds with one single core structure, the decribed multicomponent cascade approach using reactive building blocks... 

Recently, Cdrdova and co-workers revealed a regiospecific, highly chemo-, diastereo-, and enantioselective one-pot organocatalytic domino reaction of a, 3-unsaturated aldehydes 269, aromatic aldehydes 106, and phenylhydroxyamine 265, providing cycloheptane derivatives 270, Scheme 3.86 [109]. The tandemmulti-component [2+3]/[3 + 2] cycloaddition afforded six new bonds and five new... 

Shaabani, A., Ghadari, R., Ghasemi, S., Pedarpour, M., Rezayan, A.H., Sarvary, A., Ng, S.W. 2009. Novel one-pot three- and pseudo-five-component reactions Synthesis of functionalized benzo[g]- and dihydropyrano[2,3-g]chromene derivatives. Journal of Combinatorial Chemistry ll(6) 956-959. 

SCHEME 4.4 Five-component one-pot reaction via triple-cobalt-catalyzed reaction sequences, py-imine, 2,4,6-trimethylphenyl-A -(pyridin-2-ylmethylene)aniline. 

Khan et al. [131] reported a simple and convenient one-pot multicomponent reaction (MCR) for the synthesis of highly functionalized piperidines 87,88, and 89 using molecular iodine as a catalyst. This strategy demonstrated the five-component reaction of 1,3-dicaiboityl compounds, amines, and aromatic aldehydes in... 

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