Three-component one-pot reaction

In analogy, Ugi et al. reported on a lactam formation by running a one-pot three components reaction the condensation of L-lysine 7, isobutyraldehyde and methyl isocyanide led to the corresponding a-amino-c-caprolactam 9, but the yield was not given. The authors presumed either a nucleophilic substitution of the ester 8 as the primary Ugi product by the amino function of the side chain or, alternatively, the nucleophilic attack of the NH2-group on an intermediately formed 0-acylamide and a subsequent rearrangement (Scheme 1) [4]. 

Oxidation of the tetrahydroindolizine 338 with sodium chlorite gives the lactam 339, which rapidly lactonizes to give the pyranoindolizine 340 (Equation 122) <2001T8647>, and the one-pot , three-component reaction between the keto ester 235, acrolein, and o-aminophenol (formally analogous to that of Equation 63) gives the benzoxazolo-naphthyridine 341 (Equation 123) <20010L2145>. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Murai K, Nakatani R, Kita Y, Fujioka H (2008) One-pot three-component reaction providing 1,5-henzodiazepine derivatives. Tetrahedron 64 11034—11040... 

The stereoselective synthesis of c/.v-fused pyrano and furanobenzopyran can be achieved through the one-pot three-component reaction of o-hydroxy benzaldehyde, aromatic amines, and cyclic enolethers in the presence of catalytic amounts of Bi(OTf)3 (10 mol%) in air and the moisture-stable ionic liquid [bmim]PF6 [116]. The reaction of salicilaldehyde, aniline and 2,3-dihydrofuran furnishes the c/.v-fused furanochroman. In a similar fashion, various substituted salicilaldehydes and... 

A facile one-pot synthesis of furopyrans takes place with aromatic aldehydes, cyclohexyl isocyanide, and 4-hydroxy-6-methyl-2-pyrone in the presence of a solid support such as Montmorillonite K-10 (Equation 62) <2005SC535>. The solvent-free reaction, which is enhanced by microwave irradiation, proceeds much more rapidly under these conditions than by conventional methods <2002TL2293>. The one-pot, three-component reaction is also reported to take place rapidly using water as solvent <2004M589>. 

This one-pot, three-component reaction has been successfully applied to the total synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide 131 (Scheme 9.23). 

Based on the previous work of this group on the three-component aza[4+2]/ allylboration strategy to construct polysubstituted piperidines [62], Gao and Hall developed a catalytic enantioselective version [63] of the corresponding oxygeneous process to construct a-hydroxyalkylated pyrans from 3-boronoacrolein [64], This recent variant of a Vaultier-Lallemand one-pot three-component reaction (see Scheme 12.14) was successfully applied to a concise total synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide 128 (Scheme 12.20), the oviposition attractant pheromone of the female Culex mosquito [65] capable of transmitting the West Nile virus. 

Aminoquinolines 62 have been prepared in a two-step, one-pot, three-component reaction of 2-azidobenzophenones, secondary amines and arylac-etaldehydes [110]. The microwave-assisted reaction proceeded via the initial formation of enamines 59. Subsequent addition of 2-azidobenzophenones 60 afforded the triazoline intermediates 61, which underwent thermal rearrangement and cyclocondensation to furnish 2-aminoquinolines 62 (Scheme 41). Direct comparison with conventional thermal conditions demonstrated the superiority of microwave dielectric heating in terms of yields (73% vs. 31% of heterocycle 63 after 10 min at 180 °C). Furthermore, the formation of by-products due to decomposition of azide 60 was diminished in the microwave-assisted synthesis. Purification of the products was achieved using solid-phase extraction techniques. 

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

In a one-pot three-component reaction, aromatic aldehydes, malononitrile and 1,3-dicarbonyl compounds react to form 2-amino-5-carboxy-4-aryl-47/-pyran-3-carbonitriles 87. The reaction proceeds by an initial Knoevenagel condensation of malononitrile with the aromatic aldehyde to afford the 2-benzylidenemalononitrile intermediate 88. Michael addition of the activated methylene group forms the 1,5-dicarbonyl equivalent 89, which upon ring closure affords 477-pyrans (Scheme 29) <2004SL871, 1999H(51)1101 >. 

A novel type of heteroannulation reaction has been reported by Wamhoff, Schmidt et al. <91TL4473, 93JOC6976). Uracil-iminophosphoranes (108) are converted into pyrimido[4,5-rf]pyrimidine betaines (109) in a one-pot three-component reaction with isocyanates and hetarenes (double bonds) (Equation (14)). 

A one-pot, three-component reaction of isocyanides 45, dialkyl acetylenedicarboxylates 46 and ethyl 2-oxo-2-(l,3-thiazol-2-ylamino)acetates 44 provides easy access to 5H-[1,3]thiazolo[3,2- pyrimidinc derivatives 52 <07SL2703>. Presumably, addition of... 

Shaabani et al. described a novel water-promoted one-pot three-component reaction of aldehydes, 2-aminobenzothiazole and 6-hydroxyquinoline to synthesize a series of 5-(2 ... 

A one-pot three component reaction in which benzaldehyde, dimedone and an activated methylene compound are boiled together in water gives fused 4/7-pyrans in almost quantitative yield and in a high state of purity (Scheme 5) <07AJC305>. 

Ji and co-workers [73] have elaborated a simple and efficient approach for the synthesis of highly functionalized pyridines 24 via a one-pot, three-component reaction under microwave irradiation. This method enables the incorporation of a pyrazolo[3,4-h]pyridine and an indole moiety into the same molecule. The synthesis was achieved by reaction of a suitable aldehyde and 3-cyanoacetyl indole with 5-aminopyrazol. Particularly valuable features of this method include high yields, broad substrate scope, and short reaction times. It has been observed that when there are electron-withdrawing groups on the aryl aldehyde this results in a faster and higher yielding reaction (Scheme 21). 

A microwave-assisted one-pot three-component reaction of a (un)substituted anthranilic acid, ribosylamine and an (un)substituted benzoic acid has been... 

Tu S-J, Jiang B, Zhang J-Y et al (2006) Efficient and direct synthesis of poly-substituted indeno[l, 2-b]quinolines assisted by p-toluene sulfonic acid using high-temperature water and microwave heating via one-pot, three-component reaction. Org Biomol Chem 4 3980-3985... 

The one-pot three-component reaction of polyethylene glycol-supported acrylate 623 with aldehydes 621 and hydrazines 622 in the presence of chloramine-T followed by methanolysis afforded pyrazolines 624 in good yields and high purities (Scheme 77) <2003SL1467>. 1,3-Dipolar cycloaddition of resin-supported acrylic acid 625 with the nitrilimines generated in situ by oxidation of the aldehyde phenylhydrazones with (diacetoxy)iodobenzene under microwave irradiation gave 626, which was converted into l-phenyl-3-substituted-2-pyrazolinyl-5-carboxylates 627 (Scheme 78) <2004SC3521>. 

One pot, three component reactions of a variety of arylaldehydes, dip-henylphosphinamide and methyl vinyl ketone catalysed by TiCU, PPhs and Et3N have been found to give the aza-Baylis-Hillman adducts (230) (Scheme 63). ... 

Muller reported an intriguing one-pot three-component reaction for the preparation of... 

Shaabani A, Maleki A (2007) Ionic liquid promoted one-pot three-component reaction synthesis of annulatedimidazo[l,2-a]azines using trimethylsUylcyanide. Monatsh fiirChemie 138 51-56... 

A one-pot three-component reaction of 2-aminobenzimidazoles, aldehydes 71 and P-ketoesters 72 has been developed for the synthesis of 4//-pyrimido[2,l-6]benzothiazoles 75 <05BMCL5553>. The reaction presumably proceeds in two steps Knoevenagel condensation of 71 with 72 produces 3-benzylidene-2,4-pentanedione 73 Michael addition of 73 with 2-aminobenzothiazole then generates 74, which cyclizes to 75. 

A novel one-pot, three-component reaction using an aminopentanoate, aldehydes and isocyanoacetamide as starting materials gave tetrahydrofuro[2,3-c]pyridines in high yields <04OL115>. 

Remarkably N-phenyl maleic imide (34) reacted completely stereoselectively in the one-pot three-component reaction with 14 and 31a resulting in the formation of nitroso acetal (35) as one single diastereomer in 90 % yield (Scheme 9.12). This diastereomer arose from a completely endo-selective [4 + 2] and a completely endo-selective [3 + 2] cycloaddition following an anti approach with respect to the pyr-idyl group. 

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. 

Vinylbenzo[l)]furans were synthesized via copper-catalyzed one-pot, three-component reactions of o-iodophenols, in situ generated aUenes, and dichloromethane (14OL5160). 

A one-pot three-component reaction of malononitrile, ethyl aceto-acetate, and various aromatic aldehydes using a few drops of piperidine and deionized water as solvent led to 2-amino-4-aryl-3-cyano-4ff-pyrans in good-to-excellent yields (14JHC106). Similar derivatives arise from the condensation of 3-[l,4-dioxo-3,4-dihydrophthalazin-(lfi)-yl]-... 

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