Pyridine skeleton formation

In addition to the formation of the pyridine framework by de novo approaches (see section 8.1) or by the cycloaddition/cycloreversion sequence (see section 8.2), one can employ reactions that proceed through a rearrangement pathway. The Boekelheide reaction (see section 8.3.1) involves the rearrangement of an existing pyridine skeleton to a more functionalized scaffold, while the Ciamician-Dennstedt reaction (section 8.3.2) generates the pyridine nucleus by rearrangement of an alternative heterocycle. 

Methods for the construction of the thieno[2,3-c]pyridine skeleton based on the formally simultaneous formation of both the pyridine and thiophene rings were documented. Under the Pummerer rearrangement conditions, ( -s ul liny lain idc 222 underwent a cascade transformation into 223, which was oxidized to fused lactam 224 in low yield (1999JOC2038). Data on the use of cascade transformations, including the Pummerer rearrangement - cycloaddition sequence, in the synthesis of complex heterocyclic systems were summarized in a review (1997S1353). 

Synthesis of anti-malarial reagent enpiroline (17) involved the formation of the pyridine skeleton 206 via the Krdhnke reaction of aroyl acrylic acid 204, acyl pyridinium salt 205, and ammonia acetate. Condensation of the carboxyl group in 206 with 2-lithiopyridine afforded the diaryl ketone 207. The relative higher basicity of the terminal pyridinyl ring allowed selective reduction of this ring via hydrogenation in the presence of an acid and simultaneously reduction of the ketone to the alcohol. The desired isomer was then obtained by fractional crystallization to afford 17. ... 

The reaction with pyridone (167) was interpreted as proceeding by the formation of the pyridone (168), followed by the Smiles rearrangement leading to the spiro compound (169), which by ring opening provides the pyrimidine derivative (170). In a subsequent cyclization step the pyrido-[1,2-aJpyrimidine skeleton (171) is formed, and finally hydrolysis of the imino group leads to the 6-oxo derivative (172). In the homologous imidazo-[l,2-n]pyridine series, the 5-iminoimidazo[l,2-c<]pyridine intermediate of type (171) could be isolated. 

Smiles-type rearrangement followed by cyclization has been described in the formation of thieno[2,3-h][l,6]-naphthryridine skeleton (43) from 2-(3-cyanopropylthio)pyridine-3-carbonitrile (44) (Scheme 31) <95H(41)1307>. 

The formation and intramolecular dipolar cycloaddition of azomethine ylides formed by carbenoid reaction with C=N bonds has recently been studied by the authors group.84 Treatment of 2-(diazoace-tyl)benzaldehyde O-methyl oxime (176) with rhodium(II) octanoate in the presence of dimethyl acetylenedicarboxylate or N-phenylmaleimide produced cycloadducts 178 and 179, respectively. The cycloaddition was also carried out using p-quinone as the dipolarophile. The major product isolated corresponded to cycloadduct 180. The subsequent reaction of this material with excess acetic anhydride in pyridine afforded diacetate 181 in 67% overall yield from 176. The latter compound incorporates the basic dibenzofa, d -cyclohepten-5,10-imine skeleton found in MK-801,85 which is a selective ligand for brain cyclidine (PCP) receptors that has attracted considerable attention as a potent anticonvulsive and neuro-protective agent.86,87... 

Isoinundatine was converted by Jones reagent into the diketone 40 and thus has the same skeleton and substitution pattern as 38 and 29. The presence of the ketone function at 0-2 was established by the uptake of four deuteriums on basic exchange in D2O. The configuration of the hydroxy function at 0-5 was not estabhshed in this study. The authors point out that attempted acetylation of isoinundatine with pyridine-acetic anhydride gave an enol acetate at 0-2 as well as the 0-acetate at 0-5. The formation of the enol acetate is facilitated very likely by the... 

A set of new two-carbon-tethered fused acridine/indoles 62 were synthesized via a AcOH-promoted domino reaction of indoline-2,3-dione 61 and C2-tethered indol-3-yl enaminones 57a (Scheme 12.22) [43]. The reaction was further expanded to prepare C-tethered fused acridine/pyridines pairs, N-substituted amino acids, N-cyclopropyl, and N-aryl-substituted fused acridine derivatives. In these domino processes, a fused acridine skeleton with concomitant formation of two new rings was readily achieved in good yields. 

On the way to further extension of the scope of Cp Co "-catalyzed C-H functionalization, Glorius and coworkers developed a condensation reaction of 2-arylpyridine derivatives and diazoesters to form unique polycyclic heteroaromatics having 6//-pyrido[2,l-a]isoquinolin-6-one skeletons (Scheme 10.15) [38]. The reaction is achieved by the combination of a bench-stable Co precatalyst [Cp Co(CO)l2] [39], a silver salt (AgSbFg), and an acetate source (KOAc) in trifluoroethanol. The in situ-formed Cp Co catalyst is proposed to play a dual role in this condensation reaction. First, it promotes formal carbene insertion into the ortho C-H bond through pyridine-directed C-H metalation, cobalt-carbene formation, carbene insertion into the aryl-Co bond, and protodemetalation. Second, it acts as a Lewis acid to facilitate nucleophilic attack of the pyridine moiety to the ester group, which eventually leads to the product through aromatization and elimination of methanol. The thus-synthesized polycyclic heteroarenes exhibit bright and color-tunable fluorescence in solution and in the solid state. 

Formation of Pyridines, Pyrroles, A -Bipyrrolines, Siloles, and (Z, Z)-Dienylsilanes Remarkable E ect of Substitution Patterns on the Butadienyl Skeletons... 

---