Amino multicomponent reactions

A library of 800 substituted prolines of type 112 was described using a similar synthetic approach. The [3 + 2] cycloaddition occurred via a multicomponent reaction of a-amino esters, aldehydes, and maleimides (Scheme 38). 

Dondoni, A. Massi, A. (2006) Design and Synthesis of New Classes of Heterocyclic C-Glycoconjugates and Carbon-Linked Sugar and Heterocyclic Amino Acids by Asymmetric Multicomponent Reactions (AMCRs). Accounts of Chemical Research, 39, 451M63. 

An interesting observation was made when o-aminophenol (2-411) was employed in the reaction with carbethoxypiperidone 2-410 and acrolein (Scheme 2.98). In this case, the spirocydic scaffold 2-412 was exclusively formed in 67% yield. This result can be explained by invoking a stereoelectronic control due to the presence of the aromatic ring which prevents the formation of the corresponding fused tetracyclic isomer. Moreover, both reactive sites can simultaneously be functionalized using 2-amino-1,3-propanediol (2-413) as partner in the multicomponent reaction. This leads to the formation of three new cycles... 

A series of l/f-pyrrolo[2,l-r][l,4]oxazin-l-ones 196 are also the product of an LJgi multicomponent reaction between proline (and also other a-amino acids that gave the corresponding monocyclic compounds) and several isonitriles in the presence of commercially available glycolaldehyde dimer (Equation 3) <20010L4149>. 

Opatz T, Ferenc D (2005) Facile preparation of 3-amino-4-(arylamino)-l//-isochromen-1-ones by a new multicomponent reaction. Fur J Org Chem 5 817-821... 

Dondoni A, Massi A (2006) Design and synthesis of new classes of Heterocyclic C-glycoconjugates and carbon-linked sugar and heterocyclic amino acids by asymmetric multicomponent reactions (AMCRs). Acc Chem Res 39 451-463... 

Another kind of combinatorial synthesis can be applied to reactions that assemble the product from several components in a single step, a multicomponent reaction. A particularly interesting four-component reaction is the Ugi reaction, which generates dipeptides from an x-amino acid, an isocyanide, an aldehyde, an amine, and a carboxylic acid. Use of 10 different isocyanides and amines, along with 40 different aldehydes and carboxylic acids, has the potential to generate 160,000 different dipeptide products ... 

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>. 

An iron-catalyzed multicomponent reaction of aldehyde 4a, acetophenone, acetyl chloride and acetonitrile, which was used as the solvent, gave P-amino ketones such as 32 (Scheme 8.11) [41]. It was assumed that the sequence starts with an aldol reaction of aldehyde and ketone and then proceeds further with a displacement of a P-acetoxy group by the nucleophilic nitrile-nitrogen. 

The multicomponent reactions of noncyclic ketosulfones with 3-amino-1,2,4-triazole and 2-aminobenzoimidazole were described in [196]. It was found (Scheme 3.65) that the microwave-assisted three-component condensation... 

Scheme 12.32. Multicomponent reactions for amino acid and peptide synthesis.

The Petasis Reaction is a multicomponent reaction (MCR) that enables the preparation of amines and their derivatives such as 01-amino acids. 

The synthesis of novel azetidine derivatives remains the subject of intensive study. New procedures for the preparation of this class of compounds include, e.g., rearrangement of /3,7-aziridino-a-amino esters <2007OL4399>, copper-catalyzed multicomponent reactions of terminal alkynes, sulfonyl azides, and carbodiimides <20070L1585>, regioselective addition of 1,3-dicarbonyl dianions to iV-sulfonyl aldimines <2007T4779>, elaboration of a-amino acids <2007TL2471>, palladium-catalyzed iV-arylation of azetidines <2007S243> and... 

Microwave irradiation has been proven useful in accelerating chemical reactions. A unique approach to multicomponent reactions - the combination of microwave irradiation and microreactors - was developed by Organ and Bremner [25]. The three-component coupling reaction of amino pyrazole with an aldehyde and diketone in a glass capillary tube microflow system (1180 pm i.d.) under microwave irradiation (170 W) proceeded smoothly to give the desired quinolinone in high yield (Scheme 4.16). Without microwave irradiation, the reaction efficiency was very low. 

The Ugi reaction provides another access to a-amino acid derivatives [25]. This important multicomponent reaction will be discussed in Section 4.2.4. 

FIGURE 1.6 Fluorous amino acid-facilitated synthesis of Af-aUcylated dihydropteridinones. 1.3.6.1.7 Fluorous Multicomponent Reactions... 

In combinatorial chemistry, the development of multicomponent reactions leading to product formation is an attractive strategy because relatively complex molecules can be assembled with fewer steps and in shorter periods. For example, the Ugi multicomponent reaction involving the combination of an isocyanide, an aldehyde, an amine, and a carboxylic acid results in the synthesis of a-acyl amino amide derivatives [32]. The scope of this reaction has been explored in solid-phase synthesis and it allows the generation of a large number of compounds with relative ease. This reaction has been employed in the synthesis of a library of C-glycoside conjugated amino amides [33]. Scheme 14.14 shows that, on reaction with carboxylic acids 38, isocyanides 39, and Rink amide resin derivatized with different amino acids 40, the C-fucose aldehyde 37 results in the library synthesis of C-linked fucosyl amino acids 41 as potential mimics of sialyl Lewis. ... 

Banfi, L., Guanti, G., Riva, R. Passerini multicomponent reaction of protected a-amino aldehydes as a tool for combinatorial synthesis of enzyme inhibitors. Chem. Common. 2000, 985-986. 

Dyker, G. Amino acid derivatives by multicomponent reactions. Organic Synthesis Highlights IV2000, 53-57. 

More recently, a novel resin-bound isonitrile has been reported to be suitable for synthesizing libraries of l,4-benzodiazepine-2,5-diones through Ugi multicomponent reactions [25]. The method produces solid-supported Ugi products, which are cleaved by base activation to form N-acyloxazolidone intermediates that can be further elaborated. The flexibility of the approach was demonstrated by an analogous preparation of 2,5-diketopiperazines by simply replacing the 2-aminobenzoyl building blocks with a-amino acids. 

Chen L, Huang XJ, Li YQ, Zhou MY, Zheng WJ (2009) A one-pot multicomponent reaction for the synthesis of 2-amino-2-chromenes promoted by N, N-dimethylamino-functionalized basic ionic liquid catalysis under solvent-free condition. Monatsh fUr Chem 140 45 7... 

Multicomponent reactions, although fashionable these days, have in fact a long history. Indeed, many important reactions such as the Strecker amino acid synthesis (1850)[6], the Hantsch dihydropyridine synthesis (1882) [7], the Biginelli dihydropyrimidine synthesis (1891)[8], the Mannich reaction (1912) [9], and the isocyanide-based Passerini reactions (1921) (Scheme 5.1) [10], among others, are all... 

As many of the classical multicomponent reactions, the Strecker synthesis also takes advantage of the versatile chemistry of the initially formed imine. The formation of the amino nitrile, however, is reversible under the reaction conditions which usually results in lower yields. This problem was elegantly solved in the Bucherer-Bergs variation,3 4-376 where the initially formed aminonitrile is irreversibly trapped by formation of a hydantoin as depicted in Scheme 1.8 (entry b). 

Some of the syntheses of pyrimidines and quinazolines were automated so that combinatorial libraries of compounds could be generated. For instance, 2-thioxo-4-dihydropyrimidinones were prepared in this fashion by reductive alkylation of p-amino acids with aldehydes, addition of isothiocyanates, and then cyclization <97JOC9358>. The use of highly fluorinated substrates in the Ugi and Biginelli multicomponent reactions led to a combinatorially-suitable preparation of dihydropyrimidines 15 <97JOC2917>, and efficient solid phase syntheses of chiral quinazoline-... 

---