Regioselectivity condensation

There also exists an acidMannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

The reaction of 6-amino-5-(l,2-diethoxycarbonylhydrazino)pyrimidines with enamines represents another convenient method for the preparation of pteridines. Fusion of 5-(l,2-diethoxycarbonylhydrazino)-2,4,6-triaminopyrimidine (281) with an excess of mor-pholinocyclohexene leads to 2,4-diaminotetrahydrobenzo[g]pteridine, and with the morpholinoenamine (282) from 17/3-hydroxy-5a-androstan-3-one regioselective condensation to the fused pteridine (283) takes place in almost quantitative yield (equation 101) (71CC83). 6-Amino-5-nitroso- and 6-amino-5-phenylazo-pyrimidines react similarly, imitating the Timmis-type reaction (72CPB1428). 

Interest continues in the preparation of pyrimido-fused diazepines. In this context, a number of new 6-amino and 6,8-diamino-4-aryl-2,3-dihydropyrimido[4,5- >][l,4]diazepines were synthesised by the highly regioselective condensation of 4,5,6-triaminopyrimidine and 2,4,5,6-tetraaminopyrimidine respectively with 3-dimethylaminopropiophenones <00JHC401>. 

Regioselective condensations of vinylallenones with enamines gave highly substituted arylsilanes 203 after acidic workup [171]. 

The Timmis reaction makes use of the regioselective condensations of 6-amino-5-nitroso-pyrimidines with aldehydes, ketones, esters, and nitriles under base catalysis. An extension of this principle is seen in the condensation reaction of 6-amino-5-nitroso-(320) and 6-amino-5-phenylazo-1,3-dimethyluracils (321) with dimethyl alkenedicarboxylate and propiolamide, respectively, leading by a Michael addition mechanism to 6,7-bis(methoxycarbonyl)- (322) and 6-carbamoyl-l,3-dimethyllumazine (323) (Scheme 52) <82JHC949>. 

A complex multistep synthesis of the 8-CD3 analogue of 5-tocopherol has been described <03EJ02840>. The super Lewis acid, Me3Si[C6FsCTf2], is an effective catalyst for the regioselective condensation between trimethylhydroquinone and isophytol that yields ( )-a-tocopherol <03AG(E)5731>. 

A -methoxy-A -methyl-a-enaminoketoesters were employed as synthetic precursors for the regioselective condensations with hydrazines in a microwave-assisted synthesis of ethyl 1,5-disubstituted-4-pyrazole carboxylate derivatives <06OL3219>. Protected Af(r)-substituted (S)-3-(4-methoxycarbonyl-l//-pyrazol-5-yl)alanines were prepared by acid-catalyzed cyclocondensations of chiral enaminone, available from L-aspartic acid, with hydrazine hydrochlorides <06S2376>. 

As previously mentioned, nitropyrazole 5 is one of the regulatory starting materials for sildenafil citrate, so not surprisingly the compound has attracted the attention of fine chemical companies and within Pfizer. The optimization of the condensation reaction to make intermediate 1 has been previously reported. In the medicinal chemistry synthesis, conversion of 1 to compound 3 was accomplished via reaction with hydrazine followed by a methylation reaction. Clearly a more efficient way of making this transformation is to use a regioselective condensation reaction with methylbydrazine. " " ... 

This catalyst is highly effective for the regioselective condensation of trimethylhydroquinone with isophytol to afford ( )-Q -tocopherol (eq 19). ... 

The synthesis of macrocycles is very important due to their versatile applications in medicinal and naturtil product chemistry [123]. The rhodium-catalyzed one-pot synthesis of functionalized polyether macrocycles, at high concentrations from four components, was achieved under mild conditions by Lacour et aL the synthesis of 16- to 18-membered macrocycles by the regioselective condensation of two a-ditizo-p-ketoesters, and two cyclic ethers, in the presence of RhjlOct) is depicted in Scheme 9.11 [124]. Various diazo esters have been successfully employed as substrates with up to 75% yields. 

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