Pyridine polysubstituted

A useful synthesis of polysubstituted pyridines (i.e., 11) is based on the legioselective addition of Uthiated -enaminophosphonates to unsaturated carbonyl compounds. These pyridines can also be obtained via a one-pot reaction from metalated phosphonates and sequential addition of nitriles and unsaturated caibonyl compounds <96TL(37)4577>. 

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. 

Lieby-Muller F, Allais C, Constantieux T, Rodriguez J (2008) Metal-free Michael addition initiated multicomponent oxidative cyclodehydration route to polysubstituted pyridines from 1,3-dicarbonyls. Chem Commun 4207-4209... 

The reaction of a,-unsaturated oximes with ethyl acetoacetate and related / -dicarbonyl compounds in the presence of FeCls or InCls leads to polysubstituted pyridines. Thus, oxime 295 in the system ethyl acetoacetate/FeCls (5 mol%) at 150-160 °C formed the pyridines 296 in 41-81% yield (equation 127). 

Polysubstituted pyridines 312 can be prepared by a sequence involving an intramolecular thermal or high-pressure Diels-Alder cycloaddition of oximino dienophile 310,... 

Synthesis of Polysubstituted Pyridines via Directed Metalation AT THE 3-POSITION... 

Certain polysubstituted pyridines yield isolable Dewar pyridines, as illustrated in equation (2) (see CHEC 2.05). 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

Polysubstituted pyridines can be generated by the regioselective addition of lithiated /3-enaminophosphonates to unsaturated carbonyl compounds. This variation on the classic condensation reaction can also be obtained using a one-pot reaction of metallated phosphonates and sequential addition of nitriles and unsaturated carbonyl compounds (Equation (169) Table 8) <1996TL4977>. 

The alkyllithium reagents to be used in tandem reactions can be prepared by direct alkylation or by an aldol reaction involving nucleophilic addition of the alkyllithium as the first step. Several complex heteroaromatic compounds, which can serve as pivotal intermediates in synthetic strategy of biologically active species, could be synthesized by this procedure. The preparation of polysubstituted pyridines has been an active research area for many years181. The synthesis of 2-alkyl- or 2-aryl-5-hydrazinopyridines 327 has never been performed directly from pyridine. The reported methods involve several steps... 

Directed ortho lithiation of 2-, 3-, and 4-pyridyl diethylcarbamates provides a route to a variety of polysubstituted pyridines. The 2- and 4-pyridyl carbamates are metallated at C-3, whereas the 3-pyridyl carbamate is lithiated at C-4. For example, 3-pyridyl diethylcarbamate (118) on treatment with sec-BuLi/TMEDA/THF (TMEDA = N,N,A, Af -tetramethylethylenediamine) at — 78°C followed by McjSnCI gives 3,4-disubstituted pyridine 120 in 83% yield via lithiated intermediate 119. On warming, the metallated pyridyl... 

The Rh complex also catalyzes the [4+2]cycloaddition of conjugated oximes with aUcynes that results in polysubstituted pyridines. ... 

When the trimer was used as a precursor of the CF3S anion, compound 136 reacted further at 20°C to give a mixture of polysubstituted pyridines 137-139 (Scheme 6.41). 

The protonation of polysubstituted pyridines (from di- to penta-) was also investigated for halogen (Cl or Br) derivatives (2007JMGM(26)740). The obtained acidity constants (plexperimental values. Additionally, the experimental pX values... 

A slight modification to a traditional three-component synthesis of polysubstituted pyridines allows access to 4-substituted pyridines and... 

Scheme 15 A cyclization of enynes to form polysubstituted pyridines.

A simple, modular synthesis of polysubstituted pyridines of type 180 involves Cu-catalyzed cross-coupling of alkenylboronic acids with a,P-unsaturated ketoxime-N-pentafluorobenzoates 179 followed by cyclization and air oxidation [128] ... 

Tetrafluoro-4-trifluoromethylthiopyridine (240) was prepared in high yield by the reaction of pentafluoropyridine (144) with the CF3S anion, generated from F2C=S or its trimer, and cesium fluoride at -15 °C [139] (Scheme 71). When the trimer was used as a precursor of the CF3S anion compound 240 reacted further at 20 °C to give a mixture of polysubstituted pyridines 241-243 in the ratio of 4.5 2 1, respectively. When the reaction mixture was then heated at 100 °C both compounds 241 and 243 were fully converted into compound 242. Compound 242 was the only product (65 %) of the reaction which was carried out at 100-110 °C [141] (Scheme 71). 

SCHEME 46 Mechanism of the formation of isoquinolines and polysubstituted pyridines [69]. 

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. 

Feng et al. [104] developed an efficient method combining the advantages of ultrasonication with microwave radiation for the synthesis of polysubstituted pyridines (137) (Scheme 35). The reaction was carried out via a K2CO3-promoted tandem addition/cyclization/hydrogen shift process. The proposed reaction mechanism consists of a Michael addition. 

H. Feng, Y. Li, E.V. van der Eycken, Y. Peng, G. Song, Synthesis of polysubstituted pyridines under combined microwave and ultrasound irradiation K2C03-promoted tandem addition/cycBzation/hydrogen shift process. Tetrahedron Lett. 53 (2012) 1160-1162. 

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