Cyclic /?-diketones, addition

It was reported [59] that temperature in combination with the choice of catalyst is, indeed, the main factor in controlling the direction of this MCR. Under ambient and neutral conditions, the reaction between 5-amino-3-phenylpyrazole, cyclic diketones, and aromatic aldehydes yielded Biginelh-type dihydropyrimidines 54 (Scheme 24). Increase in the reaction temperature with simultaneous addition of triethylamine allowed the reaction to proceed along the thermodynamically controlled pathway with formation of dihydropyrazolopyridines 53. 

The enzyme catalyzing the reduction of ketopantolactone to D-pantolactone was isolated in a crystalline form from the cells of Candida parapsilosis and characterized in some detail [106] (see Tables 4 and 5). It is a novel NADPH-dependent carbonyl reductase with a molecular mass of about 40,000. In addition to the reduction of ketopantolactone, the enzyme catalyzes those of a variety of cyclic diketones, including derivatives of ketopantolactone, isatin, camphorquinone and so on, to give the corresponding (R)-alcohols [106, 107], The enzyme was termed conjugated polyketone reductase , since the enzyme catalyzes only the reduction of conjugated polyketones as follows. 

Conjugate addition followed by Claisen ester cyclization gives cyclic diketones... 

Until recently, the preparation of the bicyclic ene-diones (47a,b), which are important intermediates in steroid total synthesis, has led only to racemic mixtures This deficiency has now been met as follows. Michael addition of the vinyl ketone (44) to the cyclic diketones (45a) and (45b) afforded the triketo-intermediates (46a) and (46b) in high yield, each containing a prochiral centre. Optically active amines and amino-acids were used as chiral reagents to... 

Cyclic diketones showed a greater tendency to undergo 1,2-addition with aliphatic aldehydes. As noted earlier, camphorquinone gave 130> approximately equal amounts of 1,2- and 1,4-adducts with acetaldehyde but only 1,4-adducts with butyraldehyde or pivalaldehyde. Tetramethyl-tetrahydrofurandione gave 15> about 30% of 1,2-adduct and 73 gave 50% with butyraldehyde. 

The quinones are a rather heterogeneous collection of compounds with structures based on an unsaturated system of cyclic diketones. The biologically important plastoquinones, ubiquinones, and vitamin K are included in this group however, as pigments the most widespread and important quinones are the 1,4-naphthaquinones (Fig. 18) and the 9,10-anthraquinones (Fig. 19, Table 10). Methyl, methoxyl, and hydroxyl groups are the most common substituents, and O- and C-glycosides (see Fig. 20) are frequently present in the anthraquinone group. Several structural modifications exist due to reduction, dimerization (Fig. 21), and addition of side chains. 

Bifunctional squaramide-derived chiral catalysts have promoted the addition of cyclic diketones to /0,y-unsaturated a-ketoenols with ee < 99% (Scheme 25). " (S)... 

The bifunctional squaramide (343) has been found to catalyse Michael addition of cyclic -diketones (e.g. dimedone) to / ,y-unsaturated a-keto esters with <99% ee at 2.5 mol% catalyst loading. The reaction model (344) has been proposed to rationalize the enantioselectivity. i... 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

The net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

The Enders method has also been used as a key step in the synthesis of optically active Ar-heterocycles. The use of cyclic 1,3-diketones for the preparation of the SAMP or RAMP lithium azaenolates is shown by the synthesis of substituted 4,6,7,8-tetrahydro-2,5(l//,3//)-quinolinediones 2. Michael addition of 1 with, for example, benzylidene propanedioates followed by removal of the auxiliary and lactamization gives 2 with > 98% ee201. 

A somewhat related approach was followed by Molteni and coworkers, who have described the three-component, one-pot synthesis of fused pyrazoles by reacting cyclic 1,3-diketones with DMFDMA and a suitable bidentate nucleophile, such as a hydrazine derivative (Scheme 6.195) [357]. Again, the reaction proceeds by initial formation of an enamino ketone as the key intermediate from the 1,3-diketone and DMFDMA precursors, followed by a tandem addition-elimination/cydodehydration step. The details of this reaction, carried out in superheated water as solvent, have been described in Section 4.3.3.1. 

These developments are derived from the early work of Ramirez and coworkers16 17, which was concerned with the formation of a type of cyclic oxyphosphorane that is formed by the addition of a trialkyl phosphite to either a diketone (Figure 5.8) or an a, 3-imsaturated carbonyl compound (Figure 5.9). Initially, developments from this effort... 

The scope of Michael additions with catalysts containing cyclohexane-diamine scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst for the addition of phenylthiol to a,p-nnsatnrated imides, the anthors fonnd that thiourea catalyst 170 provided optimal enantioselectivities when compared to Cinchon alkaloids derivatives (Scheme 41). Electrophile scope inclnded both cyclic and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotonation of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based on the observed selectivity, the anthors hypothesized that the snbstrate-catalyst... 

However, further a possibility of the formation of several different reaction products in similar processes was reported [97-99]. With the help of microwave irradiation and ultrasonication, the problem of selectivity was also touched in these communications. It was found that three-component reaction of equimolar mixture of 5-amino-Al-arylpyrazole-4-carboxamides, aldehydes, and cyclic (3-diketones in DMF under conventional thermal heating or under microwave irradiation at 150°C yielded pyrazoloquinazolines 68. The treatment at room temperature under ultrasonication gave the same reaction products, although addition of catalytic amounts of hydrochloric acid changed direction and positional isomeric quinazolines 69 were only isolated in this case. 

On the other hand, unexpectedly it was additionally established that the same MCR at room temperature under ultrasonication or with the help of simple stirring yielded novel type of spirocompounds 80 in 63-98% yields (Scheme 34). BigineUi-type dDiydropyrimidines observed in similar processes involving cyclic 1,3-diketones [59] (Scheme 24) were not isolated. 

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