2.3.4.6- Tetrasubstituted pyridine derivatives

The enantioselective intramolecular formal 2+4-cycloaddition of acrylates and a, -unsaturated imines (99) catalysed by chiral phosphines (100), derived from amino acids, produced A-heterocycles (101) (Scheme 31). Chiral dirhodium(II) carboxamidates (102) catalysed the hetero-Diels-Alder reactions between 2-aza-3-silyloxy-l,3-butadienes and aldehydes to yield all cw-substituted l,3-oxazinan-4-ones in high yields and high enantioselectivity (98% ee)P The nickel-catalysed 4 + 2-cycloaddition of a, -unsaturated oximes with alkynes yielded 2,3,4,6-tetrasubstituted pyridine derivatives. The reaction of isoquinoline, an activated alkyne, and 4-oxo-4//-l-benzopyran-3-carboxaldehyde (103), in ionic solvents, produced 9a//,15//-benzo[a][l]benzopyrano[2,3-/t]quinolizine derivatives (105) via the zwitterion (104) selectively and in good yields (Scheme 32).The Diels-Alder cycloaddition of ethyl 3-(tetrazol-5-yl)-l,2-diaza-l,3-butadiene-l-carboxylates with -rich heterocycles, nucleophilic olefins, and cumulenes formed 3-tetrazolyl-l,4,5,6-tetrahydropyridazines regioselectively. The silver-catalysed formal inverse-electron-demand Diels-Alder... 

In marked contrast to the above results, double nitrile insertion into both the titanium-alkyl and titanium—vinyl bonds occurs to form the diazatitanacycles 74. Treatment of these titanacycles with dry hydrogen chloride affords the tetrasubstituted pyridine derivatives 75 (Scheme 14.32) [74], On the other hand, 2,3-diphenyltitanacyclobutene reacts with various nitriles to afford the products of mono-insertion, which afford the corresponding unsaturated ketones upon hydrolysis [73,74]. 

Tri-substituted pyridine derivatives 201 were prepared by Katritzky et al. using a-benzotriazolyl ketones 199 and a,P-unsaturated ketones 200 in the presence of ammonitun acetate in refluxing acetic acid in good yields.Fused 2,3,4,6-tetrasubstituted pyridines 203 were also formed from the appropriate fused bicyclic ketone substrates 202. ... 

T. Lee et. al. [167] reported a series of 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivatives (168) from solid-phase s)mthesis. Thorpe-Ziegler type cyclization of solid supported cyanocarbonimidodithioate with a-halo ketones gave thiazole resin, which were transformed to the preferred thiazolop5rridine resin by the Friedlander procedure under microwave irradiation conditions. After oxidation of sulfides to sulfones, nucleophilic desulfonative substitution with amines 4elded the target thiazolo[4,5-b]pyridine derivatives. 

In 1999, Katritzky reported a novel [3+2+1] synthesis of 2,4,6-trisubstituted pyridine derivatives that used the Michael addition of a-benzotriazolyl ketones to a,P-unsaturated carbonyl compounds. This reaction resembles the Krohnke pyridine synthesis and is an extension of Katritzky s earlier studies with benzotriazolyl derivatives that provided access to pyridones, 2-thiopyridones, 5-alkyl-2,4-diphenylpyridines and 2-aminopyridines. This approach is attractive as both components are readily synthesized or commercially available. The availability of these starting materials allows for an efficient access to structurally diverse 2,4,6-triaryl pyridines when combined with ammonium acetate in acetic acid at reflux. In addition, it is possible to access fused 2,3,4,6-tetrasubstituted pyridines from the requisite fused bicyclic ketone starting material. The preparation of the pyridine ring via benzotriazole methodology has resulted in improved yields for many compounds and the opportunity to synthesize molecules with a substitution pattern that would be difficult to prepare by other methods. 

Recently, alkynyl oximes have attracted attention as an intriguing substrate in catalytic skeletal rearrangements. Nakamura et al. reported that 0-propargylic oximes 88 derived from a,(3-unsaturated aldehydes in the presence of eopper catalysts afforded 2,3,4,5-tetrasubstituted pyridine oxides 89 (Scheme 27.32) [41]. The reaction proceeds via tandem copper-catalyzed 2,3-rearrangement and b-ir-electrocyclization of the resulting N-allenylnitrone intermediate 90. 

Recently, a ternary complex for a signal transmission system has been constructed by Aida and his co-workers [36], It involved three movable components a biaryl derivative bearing four zinc porphyrins (2), a pyridine-appended dithienylethene derivative (1), and a chiral tetrasubstituted ferrocene (3 ), as illustrated by its structure (Scheme 8). The three components were interconnected with bidentate coordination bonds. Component 2 was the bridge between 1 and 3. The well-designed triad was built up by multi-step reactions through routine methods. 

---