4-Component condensation

The CO-transfer reaction onto o-aminophenol or o-phenylenediamine by GDI has been used as a method for converting /Mactam carbanilides, obtained by a 4-component condensation, into the corresponding carboxylic acids without damaging the sensitive fi-lactam moiety. The method has its basis in the production of easily cleavable compounds from o-hydroxy- and o-aminoanilides and CDI [76]... 

Keating, T. A. Armstrong, R. W. Postcondensation Modifications of Ugi 4-Component Condensation Products—1-Isocyanocyclohexane as a Convertible lsocyanide—Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture, J. Am. Chem. Soc. 1996, 118, 2574-2583. 

CC-IMDA 4-component condensation/intramolecular Diels-Alder reaction sequence... 

These various reactions should be minimized to avoid plugging the catalyst and to prevent fouling of the downstream air preheaters, when these components condense from the gas at the lower temperatures. 

Pressure drop on the condensing side may be estimated by judicious application of the methods suggested for pure-component condensation, taking into account the generally nonlinear decrease of vapor-gas flow rate with heat removah... 

Peptide synthesis via a three or tour component condensation (amino acid, imine and bocyanide)... 

It should be clear from the description of LTX units in Chapter 5 that the lower pressure separator in an LTX unit is a simple form of cold-feed condensate stabilizer. In the cold, upper portion of the separator some of the intermediate hydrocarbon components condense. In the hot, lower portion some of the lighter components flash. 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

This method is especially useful as part of a three-component condensation of optically active y-alkoxycyclopentenones leading to prostaglandin and compactin precursors268. 

The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels-Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels-Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

Scheme 24 Synthesis of tetrahydrocarbazoles by four-component condensation...

If ammonia or an amine is also added to the mixture (in which case the reaction is known as the Ugi reaction, or the Ugi four-component condensation, abbreviated 4... 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

P., Warrington, B., Wong, S., A microreactor device for the Ugi four component condensation (4CC) reaction, in Ramsey,... 

N-Hydro-2/C-(a-AcyloxyallFour component Condensation (4CC)... 

Armstrong, R.W., Combs, A.R, Tempest, P.A., Brown, S.D., Keating, T.A. (1996) Multiple-Component Condensation Strategies for Combinatorial Library Synthesis. Accounts of Chemical Research, 29, 123-131. 

The condensation will not be isothermal. As the heavy component condenses out the composition of the vapour, and therefore its dew point, change. 

Such a strategy follows the philosophy of resin capture, as introduced by Armstrong and Keating Keating TA, Armstrong RW. Postcondensation modifications of Ugi four-component condensation products 1-isocyano-cyclohexane as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 1996 118 2574-2583. See also Brown SD, Armstrong RW. Synthesis of tetrasubstituted ethylenes on solid support via resin capture. J Am Chem Soc 1996 118 6331-6332. 

Perhaps the best-known MCR is the Ugi four-(or higher) component condensation (U-4CR) [29]. First reported in 1959, the Ugi-4CR describes the conversion of carbonyl compounds 9-16, amines 9-17, various types of acids 9-19 and isocyanides 9-21, the final product being peptide-like structures 9-24. A rather simplified mechanism of the Ugi-4CR is depicted in Scheme 9.4. 

The l-chloro-2,2-dibromocyclopropanes 164 similarly undergo the nickel-carbonyl-induced ring-opening carbonylation with an amine or an alcohol to give the / ,y-unsaturated carboxylic acid derivatives 165 and the dicarboxylic acid ones 166 [84]. The mechanism described above appears to be operating this is supported by the four-component condensation to 167. (Scheme 61 and 62)... 

Another method for preparing pyrrole rings is by Ugi-type three-component condensation (Scheme 6.184). In the protocol published by Tye and Whittaker [345], levulinic acid was reacted with two different isonitriles and four amine building blocks (1.5 equivalents) to provide a set of eight pyrrole derivatives. While the previously published protocol at room temperature required a reaction time of up to 48 h and provided only moderate product yields, the microwave method (100 °C, 30 min) optimized by a Design of Experiments (DoE) approach (see Section 5.3.4), led to high yields of the desired lactams for most of the examples studied. 

Scheme 6.184 Ugi-type three-component condensation reactions.

Scheme 6.195 Three-component condensation leading to fused pyrazoles.

A different multicomponent route to imidazoles has been described by the group of O Shea, involving the diversity-tolerant three-component condensation of an aldehyde, a 2-oxo-thioacetamide, and an alkyl bromide (5 equivalents) in the presence of ammonium acetate (Scheme 6.201) [364]. This allowed the preparation of a 24-membered 4(5)-alkylthio-lH-imidazole demonstration library from 21 different aldehydes, 12 alkyl bromides, and two 2-oxo-thioacetamides. The library was synthesized in a parallel format using a custom-built reaction vessel. Alkylthioimidazoles... 

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