Heterocyclic ketone moiety

A series of compounds identified during our HTS featured small dipeptides with the C-terminus replaced by a heterocyclic ketone moiety as exemplified by compound 6. We were pleased to see the high activity of 6 (59 nM) and assumed that the activated ketone residue might act as a covalent-reversible inhibitor of CatA. 

A palladium-catalyzed three-component assembly process of an aryl iodide, carbon monoxide and allene offers a facile synthesis of heterocycles bearing an a-exo-methylene ketone moiety (Scheme 16.10) [15, 16]. 

The chromenes and benzofurans are rather simple compounds built from acetate and Isoprene metabolites. Heterocyclic ring formation gives rise to 2,2-dlmethyl chromene or 2-isoprophenyl benzofurans. The majority of known chromenes and benzofurans exhibit a methyl ketone moiety at a position para to the oxygen of the heterocyclic ring. Constituents esterified with phenolic acids or lacking methyl ketones are rare. 

Any heterocycle containing the OCH=CH moiety can in principle extrude the superfluous fragment and form oxirene, as illustrated for a five-membered ring in Scheme 105. Probably the most propitious AB fragment would be nitrogen, but the required 1,2,3-oxadiazole (123) is unknown (see Chapter 4.21), probably because of ready valence tautomerization to diazoethanal (Scheme 106) (this approach has been spectacularly successful with the sulfur analogue of (2) (8UA486)). The use of (123) as an oxirene precursor is thus closely linked to the important diazo ketone decompositions discussed in Section 5.05.6.3.4(f). 

Poly(arylene ether ketone)s can also be modified by introducing the functional groups using similar approaches to polysulfones. For example, poly(arylene ether ketone)s were sulfonated.189 In addition, o-dibenzoylbenzene moieties in the poly(arylene ether)s can be transformed to heterocycles by cyclization with small molecules. These polymers can react with hydrazine monohydrate in the presence of a mild acid in chlorobenzene or with benzylamine in a basic medium.190 Another example of the use of the o-benzyl cyclization strategy is the intramolecular ring closure of poly(arylene ketone)s containing 2,2/-dibenzoylbiphenyl units to form poly(arylene ether phenanthrenes).191... 

Synthesis of 2-heterocyclic thiosemicarbazones can be summarized in three reaction sequences following the lead of Klayman et al. [5]. Condensation of equimolar quantities of a thiosemicarbazide and a 2-heterocyclic aldehyde or ketone in an alcoholic solvent is represented by Eq. (1). The product s superscripts refer to positions of substitution in the thiosemicarbazone moiety in accord with lUPAC. 

S-methyldithiocarbazate. The reaction sequence (2) starts with the ketone and hydrazine carbodithioate. A third synthetic method, Eq. (3), which has proven most useful for attaching a heterocyclic ring at on the thiosemiearbazone moiety [111], is shown below ... 

To select between these two alternative structures it was necessary to synthesize a labeled analog. Three hydrogen atoms of the methyl moiety of the ester group were substituted for deuterium. One of the principal pathways of fragmentation of [M N2]+ ions involves the loss of CH3 radical. Since all R substitutes in diazo ketones 4-1 were also methyls it was important to detect what group exactly is eliminated from the [M N2]+ ion. The spectrum of deuterated sample has confirmed that the methyl radical of the ester moiety leaves the parent ion. As a result the cyclic structure 4-2 was selected as the most probable. The ketene structure 4-3 is hardly able to trigger this process, while for heterocyclic ion 4-2 it is highly favorable (Scheme 5.22). 

Symmetrical and unsymmetrical thenoines, diketones, and chloro ketones 213-225 containing substituted thienyl, benzothiophene, and other moieties are versatile precursors of structures containing various heterocycles as bridges. Chloro ketones were used, for example, in the synthesis of photochromic thiazoles 226 (01IZV113) and tetrathiafulva-lenes 227 (99CL1071) (Scheme 65). 

Most of the conformational properties of the acyl derivatives originate in the high polarity of the C=0 bond. Comparative studies have been reported between several chemical functionalities containing the C=0 moiety, i.e., besides heterocyclic aldehydes and ketones, acyl halides, esters, amides, and urethanes, which have different electronic character. Furthermore, the behavior of the C=0 group has been compared, with regard to its conformational properties, to C=C and C=N double bonds in vinyl derivatives, oximes, and azomethines. Most of the results relative to five-membered aromatic heterocycles have been discussed previously (81RCR336 84KGS579). 

The biosynthesis of the polyketide moiety is thought to involve the condensation of coenzyme A esters of acetic acid with malonyl coenzyme A to give thiol esters of 3-keto acids. Further Claisen condensations with malonyl coenzyme A add further ketone units, leading to 3,5-diketo, 3,5,7-triketo acids and so on as their thiol esters. Intramolecular condensations subsequently afford heterocyclic or aromatic structures (Scheme 275). 

Particularly in [32] it was shown that cycloaddition of the chalcones 10 and diazomethane is a regioselective process providing 3-aroyl-4-aryl-2-pyrazolines 12, most likely via heterocycles 11. These are the sole products irrespective of the bulkiness and/or the electronic influence of the two aryl moieties of the starting a,(3-unsaturated ketones 10 (Scheme 2.4). 

Sucheta and Rao [36] investigated the reaction of o-PDA with heterocyclic a,(3-unsaturated ketone 17, based on the A-methylquinolin-2-one moiety (Scheme 4.5). The reaction proceeds rapidly (40 s) in solvent-free conditions on acidic alumina under microwave irradiation. 

The latter example (reaction 36) already indicates that the Yang cydization can also be used to synthesize four-membered heterocycles. After light absorption, the a,(3-unsaturated carbonyl compound 84 undergoes intramolecular hydrogen abstraction at the a-position of the carbonyl moiety (reaction 37), leading to the 1,4-biradical intermediate XXX [87]. A radical combination then efficiently yields the spirocyclic P-lactam derivative 85, and only one stereoisomer is formed in this case. In this transformation, the a,P-unsaturated carbonyl function can be considered as being vinylogous to a simple ketone. 

The treatment of 4,6-dichloro-5-aminopyrimidine 1198 with indoline 1197 gave 4-chloro-6-(2,3-dihydro-l//-indol-l-yl)-5-pyrimidinamine 1199 in 79% yield (Scheme 230) <2005JC0813>. Subsequent oxidation of the indoline moiety to the corresponding indole was achieved with DDQ in refluxing benzene to yield the indole-substituted pyrimidine 1200, the key compound in the cyclization reactions with various aldehydes and ketones leading to a novel heterocyclic scaffold consisting of indole-fused pteridines. 

Heterocyclic compounds originated by the involvement of the amine moiety of the base (group B) can be prepared from several different classes of Mannich derivatives P-aminoketones in particular, are largely employed. Thus, 4-hydroxypipcridines 322 are obtained from bis-ketones 321 (Fig. 124), prepared by Mannich synthesis with primary alkylaminc. Both the mechanism and the stereochemistry - of the reaction have been investigated it has been demonstrated that cyclization proceeds -stereo.specif-ically, and the resulting product has the configuration depicted in 322. 

Scheme 3-54). This transformation constitutes a cascade of an intramolecular Heck insertion and subsequent heterocyclization. The initially formed arylpalladium species attacks the bridgehead position of the diene functionality in 238 to foim a JT-allylpalladium complex which is trapped by the internal nucleophilic phenol moiety (cf. Scheme 3-26). Since the starting diene 238 can be prepared in both enantiomeric forms by asymmetric reduction of a ketone, this sequence allows the preparation of both the natural morphine and its unnatural enantiomer. 

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