Alkoxycarbonylation reactions pyridines

Another example of a carbonylation of chloropyridines is the synthesis of alkyl 3-chloropicolinates and dialkyl pyridine-2,3-dicarboxylates by Bessard and Roduit at Lonza Starting from 2,3-dichloro-5-(methoxymethyl)pyridine, both the mono- and the dicarbonylated pyridine derivatives can be obtained at low CO pressure (15 atm) with high selectivities and yields (Scheme 15). Utilizing PdCl2(PPh3)2 and dppb at 145 °C, 94% of methyl 3-chloropicolinate has been isolated, whereas palladium(II) acetate and dppf at 160 C leads to a double alkoxycarbonylation reaction. 

Alternatively, the desethylcatharanthine can be obtained from the adduct 21 in the reaction of 2-(indol-2-yl)acrylate 20 and A-alkoxycarbonyl-1,2-dihydro-pyridine 8f(81CC37). 

JV-Alkoxycarbonyl- and iV-arenesulfonyl-imines can be prepared by the reaction between pyridines and nitrenes, the latter being generated from the corresponding azides (72JOC2022, 64TL1733). Thermolysis of pyridinium iV-acylimines gives isocyanates and the parent heterocycle <79JCS(P1)446). 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

In connection with these catalytic cyclopropanation reactions, it should be mentioned that the isolable ruthenium-carbene complex 162, which is obtained from 19, [RuCMp-cymene)]2 and 2,6-bis(4-isopropyl-l,3-oxazolin-2-yl)pyridine, reacts with styrene at elevated temperature in a carbene transfer reaction83 (equation 41). Since complex 162 is also catalytically active for (alkoxycarbonyl)carbene transfer to olefins, this reaction represents one of the few connecting links between catalytic and stoichiometric carbene transfer reactions of metal-carbene complexes. 

Approach G involves the successive formation of the N(3)-C(4) and C(2)-N(3) bonds of the pyrimidine ring during cascade heterocyclization. Such transformations can be exemplified by condensation of substituted 2-alkoxycarbonyl-3-(R2-car-bonyl)aminothieno[2,3-6]pyridines 95 with primary amines or hydrazine giving rise to fused pyrimidin-4(3A)-ones 96 (1993PH26, 1997KGS847). In the case of R4 = EtO, the reaction gives pyrimidine-2,4-dione derivatives 97 as the final products (1993PH95). 

Representative examples of Pd-catalyzed heterocycle carbonylation reactions are shown below. Alkoxycarbonylation of 2,3-dichloro-5-(methoxymethyl)pyridine (79) took place regioselectively at C(2) to give ester 80 [79]. Aminocarbonylation of 2,5-dibromo-3-methylpyridine also proceeded preferentially at C(2) to give amide 81 despite the steric hindrance of the 3-methyl group [80]. 

Using functionalized 3,4-dialkyl pyridines, Shiao and co-workers have described an alternative synthesis of actinidine (183) based on mixed metal reactions with l-(alkoxycarbonyl)pyridinium salts. Thus, ethyl 3-iodopropi-onate was successively treated with zinc and cuprous cyanide, and after being cooled to —78°C the resulting solution was reacted with 5-methyl-methylnicotinoate (158) and the mixture warmed to room temperature to afford 159. Cyclization and decarboxylation was effected with sodium hydride followed by heating in aqueous solution to afford 160. A Wittig reaction on 160 gave the olefin 161, and catalytic hydrogenation (Pd-C) afforded ( )-actinidine (134) (Scheme 5) (183). 

The great significance of the later discovery that exactly comparable additions to A-acylpyridinium cations, generated and reacted in situ, is that the dihydropyridines which result can be further manipulated if required and that during rearomatisation the iV-substituent can be easily removed to give a substituted pyridine. It is worth noting the contrast to the use of iV-acylpyridinium salts for reaction with alcohol, amine nucleophiles (section 5.1.1.7) when attack is at the carbonyl carbon the use of an alkoxycarbonyl substituent in the present context aids this discrimination. 

Useful precursors for agrochemicals were obtained by either single or double alkoxycarbonylation of a dichloropyridine 4.65 (Scheme 4.27). Either product, 4.66 or 4.67, could be obtained by the choice of the reaction temperature, on a 120 g scale. For single carbonylation, the expected selectivity (see Chapter 2, Section 2.1.4) for greater reactivity a to the pyridine nitrogen giving ester 4.67 was found. 

Gabriele, B., Salerno, G. and Cassoni, S. (2005) Heteroqfdic derivative syntheses by palladium-catalyzed oxidative cyclization-alkoxycarbonylation of substituted y-oxoalkynes. The Journal of Organic Chemistry, 70, 4971 979. no Gabriele, B., Salerno, G., Fazio, A. and Campana, F.B. (2002) Unprecedented carbon dioxide effect on a Pd-catalysed oxidative carbonylation reaction a new synthesis of pyrrole-2-acetic esters. Journal of the Chemical Society, Chemical Communications, 1408-1409. m Gabriele, B., Salerno, G., Fazio, A. and Veltri, L (2006) Versatile synthesis of pyrrole-2-acetic esters and (pyridine-... 

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