Ketones, heteroaryl synthesis

Kwak SH, Lee D-M, Lee K-I. Enantioselective Rh-catalyzed transfer hydrogenation of a-suKonyloxy heteroaryl ketones asymmetric synthesis of (.S)-bufuralol. Tetrahedron Asymm. 2009 20(22) 2639-2645. 

Vinylpyrroles and vinylindoles are extremely sensitive to acid-catalyzed dimerization and polymerization and it is significant that much of the early research was conducted on systems which were produced in situ. Even by this approach, the dimerization of, for example, 2-(3-indolyl)propene and l-(3-indolyl)-l-phenylethylene was difficult to prevent (see the formation of 110 and 120, Section 3.05.1.2.8). Similarly, although it is possible to isolate ethyl 2-(2- and 3-indolyl)propenoates, they appear to be extremely unstable at room temperature even in the absence of acid (81UP30500) to give [ 4 + 2] cycloadducts of the type (348) (cf. 77JCS(P1)1204>. For many years simple vinylpyrroles also eluded isolation, on account of their facile acid-catalyzed polymerization. Application of the Wittig reaction, however, permits the synthesis of vinyl-pyrroles and -indoles under relatively mild and neutral conditions (see Section 3.05.2.5). In contrast, heteroarylvinyl ketones, esters, nitriles and nitro compounds, obtained by condensation of the appropriate activated methylene compound with the heteroaryl aldehydes (see Section 3.05.2.5), are thermally stable and... 

A useful synthesis of heteroaryl ketones uses the photostimulated a-cyanoalkylation reaction followed by oxidation (Scheme 4). The oxidation of products formed from phenylacetonitrile (R = Ph in Scheme 4) proceeded in over 90%.110... 

Unfortunately, several important classes of a-diazo ketones cannot be prepared in good yield via these standard methods. a -Diazo derivatives of a.p-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.1113 12 The acylation of diazomethane with a.p-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain a,p-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones. 

In the traditional benzoin condensahon, aromatic and heteroaryl aldehydes are converted to a-hydroxy ketones in the presence of a catalytic amount of cyanide ion. Since the discovery of this reaction in the early 20th century, improvements have made, including the use of quaternary thiazolium salts as the catalyst. This improvement has broadened the scope of this reaction to include aliphatic aldehydes to deliver acyloins. Review Hassner, A. Lokanatha Rai, K. M. In Comprehensive Organic Synthesis, Trost, B. M. Fleming, 1. Eds. Pergamon Press Oxford, 1991 Vol. 1, Chapter 2.4 The Benzoin and Related Acyl Anion Equivalent Reactions, pp. 541-577. 

Addition of hydrazines to 1,3-difunctional compounds is one of the most common methods employed for the preparation of pyrazoles. For example, several synthesis of pyrazoles have been reported where azide reagents are added to a,P-unsaturated systems. Reactions of trifluoroacetyl enol ether (thiophene) 1 with hydrazines afforded 3-(2-furyl) or 3-(2-thienyl)pyrazoles 2 <05S2744>. A regiospecific one-pot synthesis of trifluoromethyl-substituted heteroaryl pyrazolyl ketones has also been disclosed <05JHC631, 05JHC1055>. 1,3,5-... 

L-Proline is an efficient catalyst for the reaction between 2 -hydroxyacetophenones and aryl and heteroaryl carboxaldehydes which yields a mixture of chalcone and chroman-4-one cyclic ketones afford only the 2-spiro-linked chromanone <05TL6991> and a lipase-catalysed reaction introduces asymmetry in a multistep synthesis of 3-benzylchromanones <05H(65)761>. 

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. 

Kanai and colleagues developed an enantioselective synthesis of various 2-(2-hydroxyethyl)indole scaffolds via the amido-cupration of allenes followed by the asymmetric addition of carbonyl compounds. Treatment of allene 88 with a copper catalyst forms a stable and highly nucleophilic allyl-copper species, which then adds into benzaldehyde (89) to furnish indole 90. A range of carbonyl compounds are competent in the sequence, including aryl- and heteroaryl aldehydes, alkyl aldehydes, and aryl ketones. This is reported to be the first example of a combined catalytic indole generation and subsequent enantioselective addition of carbonyl compormds (14CS1585). 

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. 

High-throu put, multi-dimensional substrate-catalyst screening was described by Adolfsson et al. for the ATH of heteroaryl alkyl ketones. The evaluated mthenium and rhodium precatalysts were derived from a library of modular amino acid-based ligands. The results of screening were used as a key step in the formal synthesis of the antidepressant drugs, (/f)-Huoxetine and (5)-Duloxetine. The ATH... 

---