Pyridine derivatives rearrangement

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

On the basis of previously published data (235), concerning thermal rearrangement of 68 (R = Ph and mesityl) to furo[3,2-c]pyridine derivatives, reactions of mesitonitrile oxide and triphenylacetonitrile oxides were carried out (o-ChCehU, 170°C, 5 days) leading to compounds 72 (R = 2,4,6-Me3C6H2, PI13C) in 7% and 21% yields, respectively (Scheme 1.20) (234). 

In a rearrangement reaction, 2-hydroxy-2-phenyl-2-(3-pyridinyl)acetic hydrazide, 102, reacts with methanesulfonyl chloride to generate a mixture of pyrrolo[2,3-. ]pyridine derivatives (Equation 42) <1998JHG145>. The proposed mechanism for the rearrangement involves intramolecular attack of compound 102 on a reactive pyridinium intermediate formed during the reaction. 

Tetrahydroquinolones can be transformed also by (diacetoxyiodo)benzene 3 to the aromatic arylquinolines, a structure found in various alkaloids [101]. Depending on the reagent, it is possible to oxidize flavanones 50 either into flavones 51 or into rearranged isoflavones 52 [102, 103]. (Diacetoxyiodo)-benzene 3 or the polymer-supported reagent 18 were also efficient reagents for the oxidation of 1,4-dihydropyridines 53 to the corresponding pyridine derivatives 54, Scheme 23 [104]. 

In 1998 Fu and Ruble reported that the planar chiral 4-(diakylamino)pyridine derivatives 79a and 79b (Scheme 13.42) induce high enantiomeric excesses in the catalytic O-acyl azlactone rearrangement [85, 86]. In particular with the PPY-derivative 79b, O-acyl azlactones 80 were smoothly rearranged to the products 81 in almost quantitative yields and enantiomeric excesses up to 92% (Scheme 13.42) [85]. 

Heterocyclic nitrogen-derived ylids behaviors have been studied.373 For instance, pyridine derivatives lead exclusively to [2,3]-sigmatropic rearrangement (Sommelet-Hauser) products. 

In an interesting reaction, furo- and thieno[2,3-A]pyridine derivatives have been synthesized via a facile Smiles rearrangement under basic conditions followed by a cyclization forming the pyridine ring in modest yields (Scheme 3) <2001H(55)741>. 

However, studies on the scope of this sequence revealed that the substrate has to be an N-tosyl sulfonamide and that certain boronic acids are not trans-metallated but rather give rise to the formation of the pyrrole 21 or a pyridine derivative 22 (Scheme 7). The peculiar outcome as a carbopalladation-Suzuki sequence is rationalized by co or dinative stabilization of the insertion intermediate 18 by the sulfonyl oxygen atom, as represented in structure 19, now suppressing the usual /3-hydride elimination. If the transmetallation is rapid the Suzuki pathway is entered leading to product 17. However, if the transmetallation is slow, as for furyl or ferrocenyl boronic acid, either /i-hydride elimination or a subsequent cyclic carbopalladation occurs. The former leads to the formation of the diene 20 that is isomerized to the pyrrole 21. The latter furnishes the cyclopropylmethyl Pd species 23, which rearranges with concomitant ring expansion to furnish piperidyl-Pd intermediate 24 that suffers a -hydride elimination to give the methylene tetrahydro pyridine 22. 

Amino-Claisen rearrangement of propargylamino-cyclohexenone and cyclopentenone is reported to proceed with ring closure to quinoline and pyridine derivatives (equation 82). The isomeric 2-propynylenaminone gave an indolone in good yield118 (equation 83). 

Cycloaddition of nitriles with dipropargyl ethers. A new synthesis of pyridoxine (4, vitamin BJ is based on the (2 + 2 + 2 cyclo.iddition of acetonitrile with dipropargyl ethers catalyzed by Cp,Co or Cp(CO),Co to torn the pyridine derivative I. Subsequent steps involve rearrangement of the N-oxide of 1 to the 3-hydroxypyridine 2 with acetic anhydride. The final step involves the known cleavage of the dihydrofuranc ring. 

The titanocene vinylidene intermediate Cp2Ti(=C=CH2) formed by ethane or methane elimination from titanacyclobutane (4) or Cp2Ti(CH=CH2)Me, respectively, reacts with isothiocyanates, RNCS (R = CeHn, Ph or r-Bu), by a [2 + 2] cycloaddition, to give the titanathietane complexes (8). In all cases, the regioisomer in which the S atom is bonded to Ti is found as the primary product. Upon heating in the presence of pyridine, a rearrangement of (8) to the regioisomeric titanacyclobutane derivative (9) was observed (equation 12)." ... 

Extensive work by Smiles and his collaborators and by other groups clarified the main features of the rearrangement involving nitro-, sulfonyl- and halo-substituted aromatic rings. Rearrangement of 2-amino-pyridine derivatives has also been extensively studied. Reactions involved the replacement of hetero-substituents, a C - O bond by a C - N bond (N - 0), C - S by C - N (N - S) and C - S by C - O (O - S), etc. Early work has been reviewed by Bun-nett [3] (1951) and Truce [4] (1970). 

Hydroxy-2-(trifluoromethyl)pyridine derivatives 80 (Scheme 31) were linked [53] to the acetamide moiety in the usual way. Pyridyloxy-acetamides 81 smoothly rearranged into the respective 4-aminopyridines 82 when heated with potassium carbonate in DMF at 150 °C. Acid hydrolysis provided amines 83. In a similar way, hydroxy-quinolines and hydroxy-acridines were transformed into the respective amines [50,54]. 

Direct cyclization products were obtained mainly or exclusively when X was a halogen atom. Only small differences in the product composition were recorded upon changing the halogen atom. The nitro-derivative gave the rearranged product in excess (Table 36, entry 3). Inactivated pyridine derivative (X = H) remained unchanged under the reaction conditions. Some other... 

The same authors [166] used 2-chloropyridine derivatives 415 and 416 as precursors in the synthesis of 417 and 418 (Scheme 132), respectively. Rearrangement-cyclization of 415 (n = 2) was effected with NaH in DMF at 80 °C to give 417 (n = 2) in 44% yield (no direct cyclization product was detected). Rearrangement-cyclization of 416 leads to the product 418 in 57% yield contaminated by some 419. Chloro-pyridine derivative 416, when treated with sodium hydride in THF at 55 °C, afforded mainly the respective direct cyclization product 419. Several other base-solvent combinations were also examined. Another 0-0 rearrangement has been recently recorded [167]. 

The formation of the pyridinol is prevented if, in the step 19 to 20, no anion can be eliminated from C-3 this is the case with 5-amino-3,5-dideoxy-l,2-0-isopropylidene-a-D-er /thro-pentofuranose, which, on acid hydrolysis, afFords only the Amadori rearrangement product and no pyridine derivative. The reaction then proceeds, according to the above mechanism, in only one direction from 19. The 3-deoxypentose is prepared, in a manner analogous to the formation of 15, from 3-deoxy-l,2-0-isopropylidene-a-D-riho-hexofuranose through catalytic reduction of the phenylhydrazone of its periodate-oxidation product. ... 

If, in an attempt to obtain free 6-amino-6-deoxy-L-xt/Io-hexulose, the isopropylidene compound 80 is hydrolyzed at 65° with 2 M hydrochloric acid, an almost quantitative yield of 3-hydroxy-2-pyrldinemeth-anol (86) hydrochloride is obtained instead. The formation of 86 can result only through the intermediate 6-amino-6-deoxy-L-xyfo-hexulo-pyranose (83). The furanose (81) first formed is in equilibrium with the pyranose (83). The latter is dehydrated in acid solution to 82 which, under acid catalysis, rearranges to the intermediate 84. In the following steps, the allylic hydroxyl groups on C-4 and C-5 are readily removed, and aromatization to the pyridine derivative (86) ensues. 

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