Ugi Three-Component Reactions

Staudinger reduction/aza-Wittig/Ugi three component reaction... 

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). 

In another example of combinatorial parallel chemistry, we have recently used the Ugi three-component reactions (Ugi 3-CR) to construct a library of 16,840 protease inhibitors (25). It has been demonstrated previously that the Ugi-3CR reaction provides a useful chemical scaffold for the design of serine protease inhibitors N-substituted 2-substituted-glycine /V-ary 1/alky 1 -amidcs have been identified that are potent factor Xa, factor Vila, or thrombin inhibitors. The three variable substituents of this scaffold, provided by the amine, aldehyde, and isonitrile starting materials, span a favorable pyramidal pharma-cophoric scaffold that can fill the S1, S2, and S3 pockets of the respective protease. This library was screened against five proteases (factor Xa, trypsin, uro-... 

Staudinger reduction/aza-Wittig/Ugi three component reaction 2 -trimethyls ilylethoxymethoxy single-electron transfer Shell Higher Olefin Process... 

The discovery synthesis of Almorexant starts with an Ugi three-component reaction (Ugi-3CR) between benzaldehyde (4), 2-(3,4-dimethoxyphenyl)ethanamine (5), and methyl isocyanide (6) affording product 7, which in a post-Pictet-Spengler reaction with 3-(4-(trifluoromethyl)phenyl)propanal (8) in the presence of strongly acidic conditions gives the end product Almorexant (9). Clearly, the synthesis is not stereoselective and yields four different stereoisomers, of which only one is biologically highly active (Scheme 15.3). 

Indolinone (—)-154 was transformed into the key imine intermediate (- -)-155 smoothly in just a few step reactions. Treatment of (- -)-155 with A-Boc-L-phenylalanine and p-methoxyphenyl (PMP)-isonitrile at room temperature provided 78% yield of ipeptide (- -)-156 via the stereoselective Ugi three-component reaction. Noteworthily, the isonitrile attacks predominantly on the side opposite the bulky 1,1-dimethylallyl group of imine (+)-155 in the Ugi reaction, which was then transformed into (—)-fmctigenine A 157 in just a few steps. Alternatively, the Ugi reaction of (- -)-155 with A-Boc-D-alanine and isonitrile 158 stereoselectively provided 71% yield of tripeptide (- -)-159, which was then transformed into (—)-5-A-acetylardeemin 160 in just a few steps. 

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]. 

Ugi five-center three-component reaction of pipecolinic acid and glycol aldehyde dimer with isocyanides gave a 1 1.7-2.1 diastereomeric mixture of l-oxoperhydropyrido[2,Tc][l,4]oxazine-9-carboxamides 397 (Scheme 35) <20010L4149>. Using CF3CH2OH as solvent is critical for the reaction. When 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was employed, 1,3,4,6,11,11 a-hexahydro-[ l,4]oxazino[4,3+]isoquinoline-4-carboxarnide was formed. 

Practically irreversible multicomponent reactions (MCRs), like the Ugi 4-component reaction (U-4CR), can usually fulfill aU essential aspects of green chemistry. Their products can be formed directly, requiring minimal work by just mixing three to nine educts. Often minimal amounts of solvents are needed, and almost quantitative yields of pure products are frequently formed. 

In 1998, three different research groups discovered a novel multi-component reaction almost simultaneously40. They found (partly by serendipity ) that when using 2-aminopyridines as the amine component in the Ugi four-component reaction (4CR), the formation of imidazo-pyridines was observed. The imidazo-pyridine is the product... 

Ley and Taylor17 reported a polymer-supported oxazaphospholidine to convert isothiocyanides to isonitriles for subsequent application in Ugi three-component coupling reactions (entry 13). This method affords clean isonitriles and facilitates the handling of a toxic and unstable reactant. 

The time consuming chromatographical purification of heterocycles 28 and 29 slowed down the rate of library production. A phase separation using fluorous chemistry was employed by Zhang and Lu to address the workup and purification of fused 3-aminoimidazo[ l,2-a]pyridines (such as 30) [54]. Thus, attachment of a perfluorooctanesulfonyl tag to aldehydes and subsequent Ugi three-component microwave-assisted condensations with 2-aminopyridines and isocyanides furnished the desired heterocycles 30, which were conveniently isolated by fluorous solid-phase extraction. The fluorous tag could be subsequently used as an activating group in the post-condensation modifications, such as Suzuki-Miyaura cross-coupling reactions. 

Alicyclic P-lactams 28 were successfully synthesized via a parallel liquid-phase Ugi four-center three-component reaction, starting from alicyclic P-amino acids such as cis-2-aminocyclohexanecarboxylic acid, c/.s-2-aminocyclopentanecarboxylic acid, 2,3-diexo-3-aminobicyclo-[2.2.1]heptane-2-carboxylic acid and some of their partially unsaturated analogues <02OL1967>. 

HX=H20, HiSe, H2S2O3, HN3, H2NCN, HOCN, HSCN, RCO2H, RCOSH, ROCO2H, etc.) form the ions 8 and 9, which subsequently undergo an a-addition onto the unique divalent carbon of the isocyanide 10 (Scheme 2). The a-substituted adduct 13 then rearranges into its final product.t 1 Since 1962 this reaction has been called the Ugi four-component reaction (U-4CR).P 1 The U-4CR can formally be considered as the union of the HO-3CR and the P-3CR. Both of these three-component reactions have in common that they use carbonyl compounds and acids as reactants. 

In an elegant and different approach, an array of C-linked, glycopeptide-like mimics of SLex were synthesized in parallel by an Ugi four-component reaction. Reaction of different anomeric two- or three-carbon extended C-glycosyl aldehydes or acids with resin-bound amine, isonitriles and with other acids or aldehydes, respectively, yielded an array of C-linked analogues. The method is easy to perform in good yield on solid phase. How-... 

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