Multi-substituted

Olefinic iodoethers 52 undergo the Cp2TiCl2-catalyzed reductive cycli-zation in the presence of Mn and Mc3SiCl (Scheme 32) [72]. This protocol provides a versatile method for the selective formation of multi-substituted tetrahydrofurans 53. 

As can be seen in the scheme below, the catalytic activity of gold species was also shown in a multi-substituted furan synthesis. Cyclization of allenones in the presence of Au(III)-porphyrin gave rise to the corresponding substituted furan in good to high yields. The catalyst can be recycled several times and still maintain the same catalytic activity <06OL325>. 

Trisubstituted carbon-centred radicals chemically appear planar as depicted in the TT-type structure 1. However, spectroscopic studies have shown that planarity holds only for methyl, which has a very shallow well for inversion with a planar energy minimum, and for delocalized radical centres like allyl or benzyl. Ethyl, isopropyl, tert-butyl and all the like have double minima for inversion but the barrier is only about 300-500 cal, so that inversion is very fast even at low temperatures. Moreover, carbon-centred radicals with electronegative substituents like alkoxyl or fluorine reinforce the non-planarity, the effect being accumulative for multi-substitutions. This is ascribed to no bonds between n electrons on the heteroatom and the bond to another substituent. The degree of bending is also increased by ring strain like in cyclopropyl and oxiranyl radicals, whereas the disubstituted carbon-centred species like vinyl or acyl are bent a radicals [21]. 

Arimitsu, S. Jacobsen, J. M. Hammond, G. B. Synthesis of Multi Substituted 3-Fluoro Furans and 3,3-Difluoro Hydrofurans. Proceedings of the 233rd American Chemical Society National Meeting, Chicago, IL, March 25-29, 2007. 

The double N-arylation of primary amines or ammonia equivalents 592 with 2,2 -biphenylylene ditriflate (591) under Buchwald-Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various... 

Lee, J.C., Choi, H.J. and Lee, Y.C., Efficient synthesis of multi-substituted oxazoles under solvent-free microwave irradiation, Tetrahedron Lett., 2003, 44, 123-125. 

Scandium triflate catalyses a highly diastereoselective addition of imines to 1,1-cyclopropane diesters to give multi-substituted pyrrolidines.77... 

The varied biological activity of coumarins fused with a benzopyrano pyrimidines ring system [1-6] has continued to stimulate a great deal of interest in the development of new methodologies for the synthesis of multi-substituted [ 1 ]benzopyranopyrimidines. 

Radical cyclization is also an efficient method for the formation of tetrahydrofuran rings. Thus, treatment of the seleno radical precursor with n-Bu3SnH in hot toluene gave the multi-substituted tetrahydrofuran in high yield <02T2605>. 

The second catalytic method involves reaction of pyridine with alkyl alcohols at both atmospheric (65) and elevated pressures (66-68) over alumina or alumino-silicate catalysts. The atmospheric pressure reaction afforded a mixture of all three picoline Isomers in approximately equal amounts with multi-substitution also reported. At elevated pressures, the substitution is claimed to be primarily in the 3- position with low conversions. 

The multi-substituted oxazoles (vii) have been synthesized by Lee et al. [20]. The carbonyl compounds were used as the starting materials and the synthesis was carried out under solvent free microwave conditions. 

Rule III chiefly applies to multi-substituted benzene derivatives. If we assume that the six carbon atoms in benzene are arranged so as to form a regular hexagon, the angle between the directions of the substituents is 6o° in the or Ao-position, 120° in the mp -position, and 180° in the /> m-position. If the two substituents have the group moments fx and /xg he moment of the di-substituted molecule is given by... 

This notation is useful when representing a structure in type, especially an aliphatic compound that has only a few substituents. However, multi substituted alicyclic or aromatic compounds can rapidly become a little unclear, because of the number of parentheses that must be employed in order to resolve any ambiguity. 

Chambers, R. D., Hoskin, P. R., Sandford, G., et al. (2001) Synthesis of multi-substituted pyridine derivatives from pentafluoropyridine. J. Chem. Soc., Perkin Trans 1, 2788-2795. 

EC>12-EC16 fraction includes a few longer-chain and multi-substituted alkyl benzenes, biphenyls,... 

The choice of substituents in the aromatic ring is limited to halogen with chlorine being the most effective. The position of this substituent is also important in that it must be on the two-position of the ring. A similar situation exists in multi-substituted analogs. The 2,5-dichloro and 2,4-dichloroisoxazolidinedione were active but neither substitution pattern was as effective as a single chlorine at the two-position. 

Zhong et al. also developed a domino double Michael reaction to access multi-substituted cyclopetanes 20 with excellent enantioselectivities (90-99% ee) and high diastereoselectivities (95 5->99 1) catalyzed by 9-amino-9-deoxyepiquinine lo (Scheme 10.24). A similar concerted activation mode was proposed [32],... 

The In(OTf)3-catalyzed (3,5) oxonium-ene type cyclization affords various multi-substituted tetrahydrofurans and tetrahydropyrans (Tab. 8.30). For tetrahydrofuran syntheses the reaction is temperature-dependent - increasing the reaction temperature converts the kinetic product 11 to the thermodynamic isomer 10 via a 1,3-shift (Scheme 8.124) [167]. 

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