Ketones multicomponent reactions

Multicomponent reactions (MCR), in which three or more reactions combine to give a single product, have lately received much attention. The Ugi four-component condensation in which an amine, an aldehyde or ketone, a carboxylic acid, and an isocyanide combine to yield an ot-acylamino amide, is particularly interesting, because... 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

In an extension of traditional Stetter methodology, Miiller and co-workers have used the Stetter reaction in a one-pot multicomponent reaction for the synthesis of furans and pyrroles (Scheme 19) [85,86], The ot,P-unsaturated ketone XXVI is formed in situ and undergoes a Stetter reaction followed by a Paal-Knorr condensation. 

Fan L, Adams AM, Polisar JG, Ganem B (2008) Studies on the chemistry and reactivity of a-substituted ketones in isonitrile-based multicomponent reactions. J Org Chem 73 9720-9726... 

Because of the retained isocyano functionality, the dihydropyridone MCR product 85 can be used in various follow-up (multicomponent) reactions. For example, the Passerini reaction between 85, a carboxylic acid, and an aldehyde or ketone produces a series of dihydropyridone-based conformationally constrained depsipeptides 86 [171]. The subsequent Passerini reaction could also be performed in the same pot, resulting in a novel 6CR toward these complex products containing up to seven points of variation. Reaction of 85 with an aldehyde or ketone and amine component resulted in the isolation of dihydrooxazolopyridines (DHOPs, 87) [172] via a similar approach as the 2,4,5-trisubstituted oxazole variant toward 42 reported by Tron and Zhu (Fig. 15) [155]. The corresponding DHOPs (87), which... 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Acetamido ketones have been prepared in a multicomponent reaction from aromatic aldehydes, enolizable ketones (acetophenone and propiophenone), and acetyl chloride in acetonitrile over Nafion-H1002 [Eq. (5.363)]. High yields are achieved under mild conditions and the catalyst proved to be recyclable. 

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. 

Unlike amidines, the multicomponent reaction of a,(3-unsaturated ketones 96 (aliphatic [94] or aromatic [95, 96]) with carbonyl compounds 97 and ammonia, which are the synthetic precursors of amidines, yielded 1,2,5,6-tetrahydropyrimidines 98 instead of dihydroheterocycles. When R3 is not the same as R4 tetrahydropyrimidines 98 were mixtures of diastereomers A and B, in which the relative configurations of stereogenic centers were also established [95, 96]. In contrast to conventional mechanical shaking requiring about 48 h [95], sonicated reactions were completed within 90 min at room temperature and provided the target heterocycles in high yields and purities [96]. Ultrasonic irradiation also significantly expanded the possibilities of such three-component reactions (Scheme 3.29). 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

The multicomponent reaction of a 1,2-diamine with two moles of ketone resulting in the formation of the dihydrobenzodiazepine system was mentioned for the first time in 1951 [69]. This paper was devoted to the reaction of o-PDA with different aliphatic ketones, in particular, pentane-2-one 57 in boiling benzene forming diazepine 58 (Scheme 4.18). 

Microwave-assisted organic synthesis may also be used for carrying out the multicomponent reactions of ketones and 1,2-diamines [20, 21, 92, 100]. For example, the three-component reaction of o-PDA 1 with acetoacetic acid ethyl ester 83 and a series of aromatic and heteroaromatic aldehydes 84 proceeds under microwave irradiation with very high yields of diazepines 85 (up to 95%) [100]. Reaction of 2 equiv of cyclohexanone 86 with o-PDA 1 was also realized in a microwave field on a basic alumina surface in 4 min [92] (Scheme 4.27). 

Carbon monoxide is able to participate in allyltin-mediated multicomponent reactions. In Scheme 6.19, two examples of three-component coupling reactions giving unsaturated ketones are shown [33], Because of the slow reaction of acyl... 

This simple sketch illustrates clearly that convergent multicomponent reactions performed with a limited set of reactive building blocks (reactophores) in a multigeneration format offer a tremendous potential to produce diverse small-molecule compound collections, depending on the reaction sequence used (the combinatorics of reactive building blocks ). The concept of combinatorics of reactive building blocks should ultimately lead to novel multicomponent reactions. In Section III we will focus on reactophores such as a-alkynyl ketones, which allow the construction of a wide variety of core structures. 

This multigeneration strategy for the synthesis of pyrimidines combines efficiently a novel cyclocondensation reaction using the highly reactive acetylenic ketones 153215,218 to build the pyrimidine skeleton, with a multicomponent reaction, and a multidirectional cleavage procedure. The Ugi four component reaction is especially useful in the context of building peptidomimetic-derived combinatorial libraries as it affords directly dipeptide analogues of type 159. 

Thiazolidin-4-yl-l,3,4-oxadiazoles 59 are prepared through two sequential multicomponent reactions under mild conditions (14S1603). Reaction of a-chloro aldehyde 56 with ketone 57, aqueous ammonia, and sodium hydrosulfide leads to 3-thiazoline 58. Subsequent three-component reaction of 58 with an acid and (isocyanoimino)-triphenylphosphorane provides 1,3,4-oxadiazole derivative 59. 

Phosphonate monomers of type 1 were made from the reaction of allyl glycidyl ether with hydroxy-functionalized phosphonic acid. To obtain azo-phosphonated products (type 2), multicomponent reactions (amine-, aldehyde/ketone-, or phosphorus-containing compounds) such as the Kabachnick-Fields," Mannich," or Moedritzer ° reactions, were used. These reactions generated in a selective way the a-aminoallq lphosphonate products. 

It consists in the condensation of aldehydes or ketones with active methylene compounds in the presence of a base [288]. The first organocatalytic enantiose-lective domino multicomponent reaction, which was developed by Barbas et al. 

As illustrated in Scheme 6.13, a range of other R-X substrates can be coupled with heterocycle formation, as can carbon monoxide insertion to form keto-substituted products (Scheme 6.13b) [22]. These are typically postulated to proceed in an analogous fashion to the reactions above. In addition to these, several mechanistic variants have also been developed. For example, Zhang has reported that allyl-substituted furans can be synthesized in a multicomponent reaction of ketone 11, allylic halides and various nucleophiles (Scheme 6.16) [23]. This reaction utilizes the... 

In the second communication, Passerini also determined that the addition of hydrogen peroxide was unnecessary and, to an extent, deleterious as it mediated the decomposition of /7-isonitrileazobenzene. The formation of a-acyloxyamides from isonitriles, carboxylic acids and ketones or aldehydes subsequently became known as the Passerini reaction or the Passerini multicomponent reaction. The process is sometimes denoted as P-3CR according to Ugi s classification of multicomponent reactions (MCR). ... 

In a series of communications between 1959 and 1962, Ugi described the four-component condensation of an oxo-containing species, amine, isocyanide, and carboxylic acid to give a-acylamino carboxamide products. This discovery introduced the multicomponent reaction to the field of peptide chemistry and, thus, dramatically increased its applicability. Ugi showed that a broad range of nucleophilic components — including hydrogen sulfide, hydrogen selenide, hydrazoic acids, cyanates, thiocyanates, carbonic acid monoesters, salts of secondary amines, and water - were viable partaers in the reaction. In addition, procedures made use of either ketones or aldehydes as the oxo-containing component. Primary or secondary amines, hydroxylamines, ammonia, hydrazides and hydrazines were found to successfully participate as the amine component. 

Q. Ding, J. Wu, Org. Lett. 2007, 9, 4959-4962. Lewis acid-and organocatalyst-cocatalyzed multicomponent reactions of 2-alkynylbenzaldehydes, amines, and ketones. 

Other types of multicomponent reactions have also been successfully developed, such as the first practical three-component imino-Reformatsky reaction, and a pseudo-three-component reaction between allenes and isocyanates, providing excellent levels of enantioselectivity. Finally, excellent results were described for several novel enantioselective tandem sequences. For example, very high enantioselectivities were reached in tandem Michael/ intramolecular cyclisation sequences, as well as in a remarkable multicat-alytic Michael sequence occurring between enones, alkynes, and DIBAL, which stereoselectively afforded a range of chiral p-alkenyl ketones bearing an all-carbon-substituted quaternary stereogenic centre in excellent enantioselectivities. 

Sc(OTf)3 was found to be a versatile catalyst for multicomponent reactions such as Biginelli condensation [55] for the three-component synthesis of a-amino phosphonates [56], and benzothiazoline [57, 58]. A Catalytic amount of Sc(OTf)3 was sufficient for condensation of o-phenylenediamines with ketones to give 2,3-dihydro-IH-1,5-benzodiazepine derivatives in excellent yields under solvent-free conditions (Scheme 12.26) [59]. 

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