Regioselective synthesis of polysubstituted

More vigorous oxidation leads directly to quinones. This approach has been employed in a regioselective synthesis of polysubstituted quinones based on benzannulation with trime-thylsilyl allcynes followed by oxidation, iododesilylation, and cross-coupling [66]. 

A palladium-catalysed double C—H activation using sulfoxide as a traceless directing group has been applied to the regioselective synthesis of polysubstituted diben-zothiophenes through a cascade reaction " by the abstraction of four hydrogen atoms (Scheme 136). 

F. Sha, X. Huang, A multicomponent reaction of arynes, isocyanides, and terminal alkynes highly chemo- and regioselective synthesis of polysubstituted pyridines and isoquinolines, Angew. Chem. Int. Ed. 48 (2009) 3458-3461. 

Regioselective synthesis of polysubstituted benzofurans from phenols and alkynes using a Cu(OTf)2 catalyst and ZnClj as Lewis acid in O2 atmosphere in a one-pot procedure has been reported by Jiang et al. (Scheme 8.79). The transformation consists of a sequential nucleophihc addition of phenols to alkynes and oxidative cyclization. A wide variety of phenols and alkynes can be used in this reaction. The reaction might proceed via a Cu-catalyzed intermolecular nucleophilic addition and intramolecular Cu-catalyzed aryl C(sp )-H functionahzation [149]. 

Scheme 8.79 Regioselective synthesis of polysubstituted benzofurans from phenols and alkynes.

Xi, C., Chen, C., Ling, J. and Hong, X. (2005) Pd-catalyzed one-pot multicomponent coupling reaction for the highly regioselective synthesis of polysubstituted benzenes. Organic Letters, 7 2), 347-349. 

Saito, S., Uchiyama, N., Gevorgyan, V. and Yamamoto, Y. (2000) Palladium-catalyzed cross-benzannulation of aminoenynes with diynes. Highly regioselective synthesis of polysubstituted anilines. Journal of Organic Chemistry, 65(14), 4338-4341. 

Chapter 15 described the use of this transformation in the preparation of monosubstituted benzenes. In this chapter we analyze the effect of such a first substituent on the reactivity and regioselectivity (orientation) of a subsequent electrophilic substitution reaction. Specifically, we shall see that substituents on benzene can be grouped into (1) activators (electron donors), which generally direct a second electrophilic attack to the ortho and para positions, and (2) deactivators (electron acceptors), which generally direct electrophiles to the meta positions. We will then devise strategies toward the synthesis of polysubstituted arenes, such as the analgesics depicted on the previous page. 

Polysubstituted benzenes are widely used both in industry and in research laboratories. Regioselective construction of polysubstituted benzenes is usually achieved through the gradual introduction of substituents in the aromatic ring by Friedel-Crafts reaction or similar reactions of electrophilic substitution or through organometallic synthesis. In 1948, Reppe reported the [2+2+2] trimerization of substituted acetylenes in the presence of transition metals to form polysubstituted benzenes (Scheme 1.1) [1]. 

Some time ago, Holliman and co-workers illustrated a method for synthesizing polysubstituted phenazines by reductive cyclization of o-nitrodiphenylamine. However, the yield was poor when competitive cyclizations occurred <70CC1423>. Recently, Kamikawa and co-workers reported a more efficient method to synthesize phenazines using sequential aniline arylation, which was first introduced by Buchwald <97JOC1264>. Regioselective bromination of o-nitrodiphenylamine 226 with bromine in the presence of sodium bicarbonate yielded 227 which was subjected to the Buchwald conditions to provide the desired phenazine 228 and the eliminated product 229 <00TL355>. The former compound is a proposed intermediate for the synthesis of the radical scavenger benthocyanin A. 

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. 

The hydromagnesiation of acetylenes, catalysed by titano- and zirconocenes is well known. A regioselective reaction occurs only if one of the substituents on the triple bond is silicon or an aryl group. Studies on its mechanism were reported by Sato.2 7 Cai has applied this reaction for the synthesis of a number of polysubstituted alkenes (Scheme p).28-28 -2 ... 

Formyl-l//-pyrroles have also been used as synthons for the preparation of polysubstituted 4-(l//-pyrrol-3-yl)-1,4-dihydropyridines 1307-1310 under the conditions of the standard and modified Hantzsch s dihydropyridine synthesis or by regioselective alkylation of the 1,4-dihydropyridine skeleton (Scheme 250) <2005ARK127>. 

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