Aryl heteroaryl ketones

The hydrogenation of diaryl ketones or aryl heteroaryl ketones can even be conducted enantioselectively, if the ketones contain different steric or electronic properties. One impressive example of such a hydrogenation is shown in Equation 15.74. In this process, the aryl thazolyl ketone is reduced with the optimized Noyori catalyst with exceptionally high enantioselectivity. This product is then carried forward for the synthesis of an FDE-IV inhibitor. 

Scheme 25 Asymmetric alkylation of aryl heteroaryl ketones by Harutyunyan et al.

Further optimization of the catalytic system for the asymmetric reduction of diaryl- and aryl heteroaryl ketones was disclosed by Chan and Wu [26]. In modification of the blueprint of the successful catalyst introduced by Lipshutz [25] (vide supra), SEGPHOS L3 was replaced with ligand L8, whereas CuH was prepared from hydrated Cu(OAc)2 (5 mol%), f-BuONa (5 mol%), f-BuOH (4 equiv.) and PMHS (4 equiv.) (Scheme 12). With this catalytic system, the time required for... 

Wang, Ji, and coworkers developed a CuI/BF3-Et20/02 system for the synthesis of heteroaromatic imidazo[l,2- ]pyridines from ketones with 2-aminopyridines (Scheme 8.61). The C(sp )-H bonds of ketones are activated under these oxidation conditions. A total of four hydrogen atoms are removed, and two new C-N bonds are formed in one step to construct the imidazo[l,2- ] pyridines [103]. Hajra et al. developed a Cu(0Ac)2-H20-catalyzed direct oxidative cyclization via C-H amination between 2-aminopyridines and methyl aryl/heteroaryl ketones... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Carbonylative cross-coupling of various iodonium salts bearing transferable aryl, heteroaryl, alkenyl, alkynyl residues with phenylboronic acid takes place under mild conditions giving the respective ketones in high yields (Equation (16)). The yields of competing cross-coupling do not exceed 8%. 

The enantioselective addition of organomagnesium compounds to ketones can be most conveniently performed by using a chiral auxiliary in the substrate molecule. Primary aUsyhnagnesium reagents react with aryl and heteroaryl ketones in the presence of magnesium TADDOLate at — 100°C, yielding products with up to 98% ee (equation 143). Chiral a-ketoacetals 214, prepared in two steps from a-substituted cinnamic aldehydes, add organomagnesium species with up to 98% diastereoselectivity (equation 144). 

It is noticeable from the data in Table 1, that the number of examples of reactions involving the enolates of aryl alkyl ketones is limited. Bromo- and iodo-benzene were reported not to react with the enolate of acetophenone112 but the reaction with iodobenzene under more intense and longer irradiation was reported to give a 67% yield of phenacylbenzene.45 Sufficient examples of the ot-arylation of the enolates of aryl (and heteroaryl) alkyl ketones have been cited to indicate that these reactions are worth further investigation. 

Fused pyrazole compounds have been prepared from A -alkyl-substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one pot. A variety of highly substituted six-membered annulated pyrazoles 433 were synthesized in a one-step process in moderate yields from iV-bromoalkyl pyrazoles 431 and aryl iodides 432 (Equation 87) <20060L2043>. An intramolecular cyclization version has also been reported. Exposure of 2equiv of -butyllithium to l//-pyrazole-l-alkanoic acids 434 afforded the cyclic ketones 435 via a Parham-type cyclization process (Equation 88) <1997SL1013>. 

Ketones. Organomangane benzyl, aryl, heteroaryl ) with R halides with lithium naphthalenid ketones. 

Aryl ketones and esters. A Pd-carhene complex is useful for s3mthesis of heteroaryl ketones under CO. The couphng involving ArCHO in the air leads to aryl aroates. ... 

The second method started from derivatives of 6-mercaptopurines and a-halogeno-alkyl or -aryl or -heteroaryl ketones with conversion to the respective 6-[(acylalkyl)thio]- or 6-[(aroylmethyl)thio]- or 6-[(heteroaroylmethyl)thio]-purines 138 and tautomeric 7-hydroxy-7,8-dihydrothiazolo[2,3-r]-purines 139. The final step of this synthesis was cyclodehydratation. 

The Ugated copper hydride-based asymmetric hydrosilylation of electrophilic double bonds developed by Lipshutz (see Section 2.6) can also be applied to the reduction of aryl/alkyl and heteroaryl ketones and high ees in this process have been achieved using very low catalyst loadings. While heteroaryl ketones are reduced... 

Allylation of simple ketone is not possible under usual conditions, but the reaction can be carried out under selected conditions. Asymmetric allylation of the chiral racemic o -methylcyclohexanone 161 with allyl carbonate proceeded in the presence of LDA as a base with or without MesSnCl as a Lewis acid at room temperature to provide the allylated ketone 162 in very high yield with 82 % ee when (5,5)-Trost L-1 was used. The choice of base is crucial, and it was claimed that no reaction took place when Na or K bases were used in this reaction [57]. Asymmetric allylation of a-aryl and heteroaryl ketones has been carried out. Asymmetric allylation of 2-indolylcyclohexanone 163 took place at 0 C to give the the allyl ketone in 82 % yield with 84 % ee. In this reaction, NaHMDS was used as a base and Trost L-2 as chiral ligand [58]. Asymmetric allylation of the tetralone 164 with allyl acetate was carried out using Trost L-6 in the presence of CS2CO3 to provide the allylated ketone with 91 % ee in 90% yield [59]. 

Tin Derivatives. 4-Stannylpyrimidines are highly active in couphng reactions at low temperature and will couple with an acid chloride to form ketones 166 in the absence of a catalyst (Scheme 70). 2-Stannylpyrimidines also react rapidly with acid chlorides to form ketones 167 in the absence of a catalyst.i Alkyl, aryl, and heteroaryl ketones in the benzenoid 5-position 168 are available from 5-stannylpyrimidines and carbonyl chlorides. The trimethylstannyl derivatives gave consistently shghtly higher yields than the tti( -butyl)staimyl pyrimidines. The reaction with pyrroles was run on A-alkylated or A-acylated... 

---