Ketones multicomponent

An adequate prediction of multicomponent vapor-liquid equilibria requires an accurate description of the phase equilibria for the binary systems. We have reduced a large body of binary data including a variety of systems containing, for example, alcohols, ethers, ketones, organic acids, water, and hydrocarbons with the UNIQUAC equation. Experience has shown it to do as well as any of the other common models. V7hen all types of mixtures are considered, including partially miscible systems, the... 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

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... 

For example, the formation of mixtures of 4,5- and 4,7-dihydroisomers 45 and 46 was observed by Werman and Hartman [79] in the reaction of 3-amino-l,2,4-triazole with two equivalents of methylarylketone in the presence of ZnCl2 as a catalyst (Scheme 20). The ratios between two position isomers were from 50 50 to 74 26. However, Desenko et al. [80] established that treatment of the same starting compounds under acidic catalysis (acetic or mineral acids) yielded only 4,5-dihy-droderivatives 46 and heterocycles 47 [81]. In the latter case, the third component of the multicomponent condensation was the solvent - DMF. It is worth noting that heterocychc compounds 46 were also the products of the reaction between 3-amino-1,2,4-triazole with a,p-unsaturated ketones 48 (Scheme 20). 

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... 

The same research group has further performed radical carbonylation reactions on the same microreactor system [36]. First, alkyl halides were initiated and effectively reacted with pressurized carbon monoxide to form carbonyl compounds. The principle was subsequently successfully extrapolated to the multicomponent coupling reactions. 1-Iodooctane, carbon monoxide and methyl vinyl ketone were reacted in the presence of 2,2 -azobis(2,4-dimethylvaleronitrile) (V-65) as an initiator and tributyltin hydride or tris(trimethylsilyl)silane (TTMSS) as catalyst (Scheme 15). 

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. 

These multicomponent catalyst systems have been employed in a variety of aerobic oxidation reactions [27]. For example, use of the Co(salophen) cocatalyst, 1, enables selective allylic acetoxylation of cyclic alkenes (Eq. 6). Cyclo-hexadiene undergoes diacetoxylation under mild conditions with Co(TPP), 2 (Eq. 7), and terminal alkenes are oxidized to the corresponding methyl ketones with Fe(Pc), 3, as the cocatalyst (Eq. 8). 

Fleming and coworkers have developed a number of such multicomponent assembling reactions using alkyl halides, aldehydes, ketones and acid chlorides as electrophiles for post-functionalization of carbomagnesiation . The stereoselectivity of the reaction with electrophiles is not only generally high but also highly dependent on the nature of electrophiles. 

An analogous non-electrochemical Ni(0)-catalysed process, exploited in a Mannich/ Reformatsky multicomponent process58, will be discussed in Section III (equation 41). In the third study, the a-bromoester Id is simply electrolysed in the presence of a carbonyl compound in DMF/THF in a 1 2 ratio using both indium and zinc rods as sacrificial anodes. While aldehydes afford the expected 3-hydroxyesters in high yield, aliphatic, aromatic and cyclic ketones, with the exception of acetone, directly afford /3-lactones,... 

Because of our interest in one-pot, multicomponent annulations,7 we envisioned a flexible and efficient protocol which would link the four different components via the formation of four new bonds (a-d, eq. 1) in one reaction vessel. The intermediate 7-hydroxystannanes thus formed in eq. 1 could be oxidatively fragmented8 to produce both ring enlargement and regiospecific formation of an alkenyl unit. This 4-atom ring expansion methodology of common sized a,p-unsaturated ketones has led to the syntheses of many mono- and disubstituted 9-, 10-, and 11-membered unsaturated macrolides (Table ). 

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. 

This chapter will be divided into sections according to the electrophiles aldehydes and ketones, imines and iminium salts, carboxylic acid derivatives and finally a,P-unsaturated carbonyl compounds, which undergo conjugate additions. Further subdivision will be made according to the nature of the nucleophile, i.e. 0-, N-, S-, P- or C-nucleophiles. Finally, multicomponent heterocyclic syntheses will be mentioned, if they consist at least of one iron-catalyzed addition step to a carbonyl compound. 

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. 

A possibility of formation of 5,7-diaryl-4,7-dihydro-1,2,4-triazolo[l,5-a]pyr-imidines 182 in reactions of 3-amino-l,2.4-triazole 147 with synthetic precursors of unsaturated ketones—aldehydes 179 and ketones 180—or in condensation of acetophenones 180 and azomethynes 183 was established in [176, 177]. It was shown that in the first case the multicomponent procedure was not an independent method but resulted in the initial formation of unsaturated ketones 181 themselves and their further reaction with aminoazol (Scheme 3.53). 

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. 

Examples of the synthesis of thieno[2,3-Z>]pyridines according to method C are scarce. In this case, the synthesis of the starting 3-cyanopyridine-2(l //)-thione, its -alkylation, and cyclization of an intermediate occur as a multicomponent one-pot process. For example, the reaction of thioamides 28 with l-(4-morpho-lino)cyclohexene (29) in anhydrous ethanol followed by treatment with a twofold excess of KOH and then with a-bromo ketones produced thienoquinolines 30 (1997KGS1384). 

Multicomponent one-pot reactions continue to be the focus of heterocyclic synthesis when multi-bonds are formed. Malononitrile condenses with 3-pyridinecarbaldehyde and a ketone to form a substituted bipyridine (Equation 179) <1995JCM146>. In another condensation, with aniline being the ultimate source of the tetrahydroquinoline nitrogen atom, iodine is used as a catalyst in a reaction that was optimized for yield and diastereoselectivity (Equation 180) <2005SL2357>. 

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