Pyridine ring construction/formation

Pyridine ring construction according to strategy P is based on the one-step formation of the C(4)-N(5) and C(7)-C(7a) bonds. For example, this approach provides the basis for the synthesis of the simplest isomeric dithienopyridines (1988CS281). The Stille cross-coupling reaction of 2-tributylstannyl-3-thiophene-carbaldehyde (256) with thienylcarbamates 115, 257, and 258 affords the target compounds 259-261, respectively, in different yields. 

Method U (pyridine ring construction through N(5)-C(4) and C(6)-C(7) bond formation) can be exemplified by the synthesis of 6,7-dihydrothieno[3,2-c]pyridines... 

Extension of this work by studying the reaction of 3-methyl-5-nitro-pyrimidin-4(3//)-one with -X-arylketones in the presence of ammonium acetate surprisingly revealed the formation of a mixture of 4-arylpyrimidines and 6-arylpyridin-2(l//)-ones (00JCS(P1)27). The ratio between pyridine and pyrimidine formation is dependent on the substituent X. With electron-donating substituents the formation of the pyridin-2(l//)-ones is favored, with electron-attracting substituents the formation of the pyrimidine derivatives (Scheme 21) In the formation of the 6-arylpyridin-2(l//)-ones the C-4- C-5-C-6 part of the pyrimidone-4 is the building block in the construction of the pyridine ring. Therefore, the pyrimidone can be considered as an activated o -nitroformylacetic acid (Scheme 21). 

The Balz-Schiemann reaction continues to attract attention, with much of it generated by the interest in fluoroquinolones, e.g., (7), which is a potential antibacterial. Two approaches to its synthesis are possible—introduction of fluorine prior to or post ring construction. Decomposition of the tetrafluoroborate salt was unsuccessful, whereas the PF6 salt (8) gave only a poor yield (84JMC292). A more successful approach was the introduction of F into the pyridine nucleus prior to formation of the 1,8-naphthyridine ring (84JHC673). A comparison of decomposition media showed that cyclohexane was the best with regard to yield and time. 

The H mode of the pyrimidine ring construction assuming the stepwise formation of the N(l)-C(2) and C(2)-N(3) bonds as a result of the insertion of a component serving as the source of the C(2) atom is more often used in practice. The simplest modification involves intramolecular condensation of 3-(acylamino)thienopyri-dines produced by acylation of 3-amino-2-carbamoylthieno[2,3-Z>]pyridines or their structural analogs (1995PS83). An example is the synthesis of pyrimidothienobenzo-quinoline 98 from chloroacetamide 99. 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

Synthetic approaches to thienopyridines are conveniently considered under two headings, according to which heterocyclic ring is constructed. Generally syntheses involving formation of the pyridine ring have been adaptations of classical quinoline and isoquinoline syntheses. 

The great majority of quinolines and isoquinolines have been prepared by ring construction, instead of transformation of preexisting derivatives. They are obtained by variants of two main routes. The first route involves the cyclization of mono-substituted benzene rings, usually A-substituted anilines (Skraup, Doebner-von Miller, Knorr, Conrad-Limpach), and the second route involves the intramolecular condensation of o-disubstituted benzenes for the formation of the requisite pyridine ring (Friedlander, Pfitzinger reaction, etc.). 

The reaction of 2,4,6-trihydroxyacetophenone with the acetal also yields a mixture of products, but is of interest in that the addition of pyridine hydrochloride has a beneficial effect on the formation of the major product (69). This compound arises by the construction of two pyran rings and involves cyclization on to a hydroxy group adjacent to the acyl side-chain (72JCS(Pl)25), although it is recognized that both the 2- and 6-hydroxy groups cannot be simultaneously chelated with the acyl group. 

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). 

The [l,2,4]triazolo[l,5- ]pyridine system is usually constructed by the closure of the triazole ring either by oxidative formation of the NN bond or by condensation of the N-aminopyridine derivatives . Various compounds 78 were obtained by the oxidation of the amidine 77 with Mn02 (Scheme 47) <2003IJB2901, 2005ARK(xiii)21>. A dehydrative cyclization by treatment of formamidoximes 79 with trifluoroacetic anhydride (TFAA) has been used in the synthesis of 80 (Scheme 48), which are key building blocks in the preparation of DPP (IV) inhibitors <2005EJ03761, 2006JME3614>. 

While the existence of such molecules would clarify the formation and the observed mutarotation of the pyridine compound, it would also seem that in the usual acetylation and methylation reactions an acidic orthoester would behave as though it posse.ssed a normal structure. This would make impo.ssible the exact proof of the structure of the acidic orthoesters by means of chemical transformations. The situation concerning this problem was not further clarified by Helferich and Muller s contention that, contrary to the opinion of Haworth and coworkers, it is possible to construct a strainless orthoacid ring between positions 4 and 6 in the pyranose ring. 

Bromobenzamides couple with arylboronic acids thermal deprotection of the amino group is followed by the formation of a fused pyridin-2-one in good yield. The 4-one ring may be constructed in low yield by stirring at a low temperature (—S °C) a 2-fluorobenzoyl chloride with the lithium derivative of ethyl pyridine-2-acetate. 

As described previously, thiazolines are versatile intermediates to thiazoles. In addition, thiazoline rings are structural motifs found in numerous natural products. Among a variety of methods for the construction of thiazolines, the cyclodehydration protocol is perhaps most popular. Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is used as the cyclo-dehydrating agent for the conversion of 3-hydroxy thioamide 60 to the bis(thiazoline) 15 <04H(63)773>. A more recent protocol for the cyclodehydration of P-hydroxy thioamides to thiazolines involves pyridine-buffered phosphorus oxychloride as exemplified by the formation of 62 from 61 <04JA12897>. 

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