Benzaldehydes multicomponent reactions

Microwave-assisted multicomponent reaction of 6-amino- or hydroxy-aminouracil derivatives with benzaldehyde and malononitrile or ethyl cyanoacetate in the solid state in the absence or presence of Et3N for 5-8 min afforded the pyridopyrimidine derivatives 463 <2003TL8307>. Similarly, 6-aminouracil derivatives or 6-hydroxyamino analogues were reacted with HC(OEt)3 and active methylene compounds [CH2(CN)2 or NCCH2C02Et] in the presence of AcOH under microwave-assisted conditions to give the pyrido[2,3-r7 pyrimidines 464 and their iV-oxides 465 within 2 or 8 min, respectively. The reaction proceeded under thermal conditions in ethanol or without solvent for 1—4h to give 464 and 465 in 45-70% and 35-50% yield, respectively <2004SL283>. 

Tetrahydroisoquinolonic acids were generated in good to excellent yields by the multicomponent reaction of benzaldehydes, amines, and the cyclic anhydride 65 (Equation 197) <2003T1805>. The key element in this example is the use of ionic liquids and in other examples of the same reaction strategy, the high diastereoselectivity achieved <2005JOC350>. 

Some new substituted tetrahydroacridin-8-ones and diverse derivatives were synthesized by uncatalyzed multicomponent reaction of dimedone or cyclohexan-1, 3-dione, a-naphthylamine and various (o, p, w)-substituted benzaldehydes (Scheme 15) [38]. The in vitro antimicrobial activities of the prepared compounds... 

The IL effects can be explained with solvophobic interactions that generate an internal pressure, which promoted the association of the reactants in a solvent cavity during the activation process and showed an acceleration of the multicomponent reactions (MCRs) in comparison to conventional solvents. The reaction proceeded very efficiently with benzaldehyde and electron releasing and electron-withdrawing ortho-, meta-, and para-substituted benzaldehydes. IL was easily separated from the reaction medium by washing with water and distillation of the solvent nnder vacnnm and it can be reused for subsequent reactions and recycled. IL showed no loss of efficiency with regard to reaction time and yield after four successive runs. 

Multicomponent reactions are an increasingly important class of reactions because they combine simplicity, atom economy and efficiency in terms of both yields and the introduction of molecular diversity [52]. These reactions have been described on both solid and soluble supports, as well as giving an easy entry into libraries of compounds. BTSILs are appropriate soluble supports for such reactions. This is illustrated by the tetrahydroquinoline synthesis developed in solution and on solid supports [52]. The reaction of an aniline supported on an ammonium salt in solution of [BuMe3N][NTf2] with benzaldehydes and electron-rich olefins such as styrene, cyclopentadiene and indene in the presence of a trace of TEA, led quantitatively and rapidly (20 to 60 min) to the corresponding tetrahydroquinolines at room temperature according to (Scheme 5.5-36) [21,51]. 

An iron-catalyzed multicomponent reaction forms poly-substituted pyridines in good yields (Scheme 5).The reaction involves a benzaldehyde, malono-nitrile, ethyl acetoacetate, and aniline in a nucleophilic addition followed by intermolecular cyclization. A number of groups are tolerated on the aldehyde including nitro, halogens, methyl, and methoxyls. Methyl and nitro groups were... 

The synthesis of xanthene derivatives using silica-supported add was also investigated by Karimi et al. (2011). They reported a facile procedure for the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[fl]xanthen-ll-one derivatives through a multicomponent reaction using Caro s add-siUca gel (CA-Si02) as a nontoxic, inexpensive, and easily obtained catalyst. Benzaldehyde, P-naphthol 8, and dimedone (12) were allowed to react at different temperatures and with different amounts of catalyst to find the optimal reaction conditions for the preparation of xanthenone (11) (Scheme 1.8). 

When the reaction was run on a 1 mmol scale, 0.1 g of CA-Si02 at 60°C under solvent-free conditions delivered the best result for the synthesis of product 11 (80% yield). When the protocol was applied to other multicomponent reactions employing groups bearing substituted benzaldehydes and electron-donating groups, excellent results were obtained in all cases (yields 75%-90%). 

The roots of the U-4CR lie in research reported long before its discovery in the early 1960s. The first multicomponent reaction (MCR) is credited to Laurent and Gerhardt who, in 1838, isolated an unexpected product from a reaction involving benzaldehyde, ammonia, and hydrogen cyanide. The resulting benzoyl azotide (1) presents the Schiff base of the Strecker adduct and benzaldehyde. Ironically, Strecker described such a reaction more than a decade later. In the years that followed, many variations of MCRs were reported, but it wasn t until 1921 that Passerini first utilized the isocyanide functionality and its unique reactivity in a MCR. It was this work that inspired Ugi and led to focused investigations of this reaction process. 

SCHEME 19 Multicomponent reaction of anilines with benzaldehyde and anise seed anethole in supercritical CO2. 

The synthesis of stabilized phosphorus ylides via multicomponent reactions and their synthetic applications have been reviewed. The Wittig reaction products of keto-stabilized ylides with orf/io-substituted benzaldehydes have been found to show significantly higher than expected Z-alkene content (up to 50%) compared to analogous reactions of the same ylides with benzaldehyde itself. A cooperative effect is seen whereby the unusual Z-content is further augmented if the ylide bears greater steric... 

Multicomponent approaches toward the formation of more complex phthalazine-containing compounds were reported in 2014. A four-component one-pot condensation reaction was employed by Dabiri and coworkers to generate (1,2,3-triazol-4-yl)methyl-3-amino-5,10-dihydro-5,10-dioxo-lH-pyrazolo[l,2-f)]phthalazine-2-carboxylates 26 (Scheme 18) (14SC2037). Catalyzed by Cu(OAc)2 (10mol%) and sodium ascorbate (20mol%), the reaction of benzaldehyde derivatives (1 equivalent), azides (1 equivalent), prop-2-ynyl-2-cyanoacetate (27) (1 equivalent), and phthalhydrazide (28) (1... 

New synthetic methods for benzodiazepine synthesis involving Ugi-type multicomponent/post-Ugi cyclization reactions continue to be of interest. Ugi reactions of indole-2-carboxaldehydes, isocyanides, amines, and 2-iodobenzoic acid derivatives led to intermediates which, with copper(I) catalysis, underwent intramolecular indole N-arylation to produce indolo-fused benzodiazepinones, such as 134 (13CC2894). 2-Azido-benzaldehyde, isocyanides, propargylamines, and nitrophenols underwent Ugi-type reaction, Smiles-type rearrangement, and intramolecular azide-alkyne cyclization to afford triazolo-fused benzodiazepinones such as 135... 

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