Pyridines from cycloadditions

IPr)Ni(NCR)]2 complexes, obtained in high yields from [Ni(COD)2], IPr and nitrile, are also competent in the formation of pyridines from cycloaddition of diynes and nitrile (Scheme 10.7). The mechanism pathway could involve a partial dissociation of a dimer in which nitriles are Tj - and T -coordinated, allowing exogenous nitrile coordination before cycloaddition. 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

Van der Eycken and coworkers have presented a study describing the microwave-assisted solid-phase Diels-Alder cycloaddition reaction of 2(lH)-pyrazinones with dienophiles [69]. After fragmentation of the resin-bound primary cydoadduct formed by Diels-Alder reaction of the 2(lH)-pyrazinone with an acetylenic dieno-phile, separation of the resulting pyridines from the pyridinone by-products was achieved by applying a traceless linking concept, whereby the pyridinones remained on the solid support with concomitant release of the pyridine products into solution (Scheme 7.58). 

Ring synthesis of such molecules can proceed from diazines nsing methods analogous to those described for the synthesis of azolo-pyridines from pyridines, for example the dipolar cycloaddition of an A-imide to an alkyne, or the bromine-promoted ring closure of hydrazones of 2-hydrazino-pyridines, -pyridazines (shown) or -pyrimidines. ... 

The full scope of the acid-catalyzed one-step conversion of N-tert-bu-tylmethanimine, generated in situ from 1,3,5-tri-tm-butylhexahydro-1,3,5-triazine, to symmetrical 3,5-disubstituted pyridines employing enamines has been detailed.290 The generation of 2,3,5,6-tetrasubstituted pyridines from the thermal reaction of enolizable ketones with hex-amethylphosphoric triamide has been proposed to proceed by in situ generation and subsequent [4 + 2] cycloaddition of /V-methyl-1 -aza-1,3-butadienes with intermediate dimethylamino enamines.30... 

Pyridines from nitriles. 2-Subsot I-2-F2]-cycloaddition of nitriles vnth... 

One of the main problems with this approach is synthesis of the starting bis(halomethyl) helerocycles. Two main routes have been used free radical halogenation of the appropriate bis(methyl) compound (usually using iV-bromosuccinimide) or transformation of the bis(hydroxymethyl) derivative which in turn can be obtained from the corresponding diacid or diester as, for example, in Scheme 13. Lack of selectivity in the formation of the desired dihalo compound can be a problem in the former case. A different approach to bis(halomethyl)pyridines involves cycloaddition of chloroalkylacetylenes to oxazinones (Scheme 15) <96T11889>. 

Seitz et al. prepared various l,2,4-triazine-C -nucleosides 340 via cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 to monosaccharide-derived imido esters 339 as intermediates in their quest for new pyridine C-nucleosides <1999ZNB549, 1997ZNB851, 1995AP175>. Similarly, the same group reported the preparation of novel 2-(2 -pyrrolidinyl)pyridines from (3 )- and (R)-proline via cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 to heterodienophilic imidates or hydrazones derived from (3)- and (R)-proline <1999TA573>. Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 150 with either 0-methylisourea or cyanamide gave... 

Treatment of acyl chlorides with pyridine and trifluoroacetic anhydride (TFAA) was assumed to involve generation of ketenes which can be subjected to electrophiUc attack by TFAA to afford jd-trifluoroacetylacetic acid derivatives 484. Quenching of the reactions with dienophiles resulted in construction of heterocycles 485 that clearly result from cycloaddition reactions of intermediate acylketenes generated by ehmination from 484 (Scheme 155) (1992TL1285, 1995T2573, 1995T2585). 

Additionally, several nickel-catalyzed systems for pyridines synthesis have also been developed by Louie and coworkers. In 2005, they reported that with Ni(COD)2 as the catalyst and carbene as the ligand, the cyclization can be carried out at room temperature (Scheme 3.23a) [51]. Both intramolecular and intermolecular reactions were proceeded well and the cycloaddition of an asymmetrical diyne afforded a single pyridine regioisomer. This catalytic system was extended to cyanamides as well [52], In their systematic studies, they found the in situ formed dimeric [Ni(IPr)RCN]2 from the reaction of Ni(COD)2, IPr, and nitrile are catalytically competent in the formation of pyridines from the cycloaddition of diynes and nitriles. X-ray analysis revealed that these species display simultaneous f- and 17 -nitrile binding modes. Kinetic... 

A novel strategy for the synthesis of pyridines from aldehyde, enam-ide, and isonitrile was described by Wang and coworkers in 2013 [122], The reaction works under mild reaction conditions and good to excellent yields can be achieved. Mechanistically, this cascade reaction consisted by Zn(OTf)2-promoted [1 + 5] cycloaddition of isonitrile with A-formylmethyl-substituted enamide, facile aerobic oxidative aromatization and intermolecular acyl transfer from the pyridinium nitrogen to the 5-hydroxy oxygen, and finally acylation of the 4-amino group by an external acyl chloride efficiently afforded 2-substituted 4-acylamino-5-acyloxypyridines. 

From Diazo Compounds via 1,3-Dipolar Cycloaddition. This method has been utilized widely in heterocychc chemistry. Pyrazohne (57) has been synthesized by reaction of ethyl diazoacetate (58) with a,P-unsaturated ester in the presence of pyridine (eq. 12) (42). 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

An example of this methodology was its use in the synthesis of vitamin Be, pyridoxine 12. Cycloaddition of oxazole 9, prepared from ethyl A-acetylalanate and P2O5, with maleic anhydride initially gave 10. Upon exposure to acidic ethanol, the oxabicyclooctane system fragments to afford pyridine 11. Reduction of the ester substituents with LiAlIU generated the desired product 12. 

The adduct derived from (a-benzyloxyacetaldehyde (97 % ee) is an important intermediate en route to compactin and mevinolin [76]. In contrast, modest enantioselectivity was attained when the cycloadditions were catalyzed by a chiral BINOL-ytterbium-derived catalyst [77]. Pyridines were used as additives, and the best enantioselection (93% ee) was attained only in the case of p-methoxybenzaldehyde using 2,6-lutidine. 

Hoomaert has studied Diels-Alder reactions of pyridine oquinodimethane analogs generated from functionalized o-bis(chloromethyl)pyridines <96T(52)11889>. The photochemical cycloaddition of 2-alkoxy-3-cyano-4,6-dimethylpyridine with methacrylonitrile gives a bicyclic azetine, 6-alkoxy-3,5-dicyano-2,5,8-trimethyl-7-azabicyclo[4.2.0]octa-2,7-diene, in moderate yield <96CC1349>. Regiospecific hydroxylation of 3-(methylaminomethyl)pyridine to 5-(methylaminomethyl)-2-(17/)-pyridone by Arthrobacter ureafaciens has been reported <96MI173>. 

Pyridine compounds 45 can also be produced by the NHC-Ni catalysed cycloaddition between nitriles 43 and diynes 44 (Scheme 5.13) [16]. The SIPr carbene was found to be the best ligand for the nickel complex in this reaction. The reaction required mild reaction conditions and low catalyst loadings, as in the case of cycloaddition of carbon dioxide. In addition to tethered aUcynes (i.e. diynes), pyridines were prepared from a 3-component coupling reaction with 43 and 3-hexyne 23 (Scheme 5.13). The reaction of diynes 44 and nitriles 43 was also catalysed by a combination of [Ni(COD)J, NHC salts and "BuLi, which generates the NHC-Ni catalyst in situ. The pyridines 45 were obtained with comparable... 

Diaz-Ortiz and co-workers carried out microwave cycloadditions to synthesize pyrazolo[3,4-A]pyridines, including tricyclic derivative 149 obtained from pyrrole 147 using A-methylmaleimide 148 as the dienophile (Equation 34)... 

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