Isocyanates 2- pyridones

The 4-hydroxy-THISs react with electron-deficient alkynes to give cycloadducts (3) that spontaneously eliminate sulfur, producing 2-pyridones (3). Bulky 5-substituents lead to a decrease in the addition rate, and elimination of isocyanate with formation of thiophenes becomes favored (3, 12, 13). Benzyne yields an isolable adduct that exclusively extrudes isocyanate on thermolysis, but sulfur on irradiation (Scheme 7)... 

Electron-deficient alkenes add stereospecifically to 4-hydroxy-THISs with formation of endo-cycloadducts. Only with methylvinyl-ketone considerable amounts of the exo isomer are produced (Scheme 8) (16). The adducts (6) may extrude hydrogen sulfide on heating with methoxide producing 2-pyridones. The base is unnecessary with fumaronitrile adducts. The alternative elimination of isocyanate Or sulfur may be controlled using 7 as the dipolarenOphile. The cycloaddition produces two products, 8a (R = H, R = COOMe) and 8b (R = COOMe, R =H) (Scheme 9) (17). Pyrolysis of 8b leads to extrusion of furan and isocyanate to give a thiophene. The alternative S-elimi-nation can be effected by oxidation of the adduct and subsequent pyrolysis. 

Hydroxy-THISs add to the C-C bond of diphenylcyclopropenethione (181. Inner salts without substituents in 5-posnion react similarly with diphenylcyclopropenone (Scheme 10) (4, 18). Pwolysis of the stable adducts (9) leads to rupture of the R-C-CY bond. Subsequent ring closure yields 10. When Y = O. 10 eliminates COS. producing 2-pyridone. When Y = S. 10 is isolated together with its isocyanate extrusion product, a thiopyran-2-thione (18). 

It is worth noting that the 2-pyridone 42 (99MI1) and thione 43 (88H(27)733), which could react in either of the two ways as shown, with an isocyanate or isothiocyanate and with a nitrile respectively, actually give a one-carbon insertion. There is a case of formation of 2,3 and 3,4 bonds in the preparation of 8-hydroxy-triazolopyridine 44 (83MI1). 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

The NHC-nickel catalytic system is also useful in the synthesis of pyridones 48. The [2h-2h-2] cycloaddition of diynes 44 and isocyanates 47 affords a wide range of pyridones 48 in excellent yields in presence of [Ni(COD)2]/SIPr catalytic system (Scheme 5.14) [18]. 

The reaction described above can also be performed in a fully intermolecular fashion. When monoyne 49 is used in presence of isocyanate 47 and catalytic amount of [Ni(COD)j]/SlPr, pyridone 50 is formed in 90% yield (Scheme 5.15) [18], However, when an excess of isocyanate 47 is used in the same reaction... 

The nickel-catalysed co-trimerisation of acetylenes with isocyanates gave good yields of uracils 46, depending on the isocyanate substituents, pyridones being unwanted by-products... 

Itoh and co-workers reported the ruthenium(n)-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes with isocyanates to afford the corresponding bicyclic pyridones 163 (Scheme 72).356 357 For previously reported ruthenium-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes see Refs 358 and 358a, and for theoretical calculations of the cyclocotrimer-ization of alkynes with isocyanates, isothiocyanates, and carbon disulfide see Refs 359 and 359a. 

Mesoionic oxadiazoles are available from 2(l//)-pyridones and methyl isocyanate via carbodiimide (88CB1495). 

Reactions involving the [4 + 1 + 1] principle, an example of which is shown in equation (136), are rather uncommon and of strictly limited utility [3 + 2 + 1] and [2 + 2 + 2] processes, on th,e other hand, are well known. Representative [3 + 2+1] three-bond formation processes are given in equations (137)—(141), from which it can be seen that the common situation is where ammonia, a substituted amine or formamide constitutes the one-atom fragment. Many [2 + 2 + 2] atom fragment syntheses are known and some are familiar reactions. Thus, the cobalt(I)-catalyzed condensation of nitriles and isocyanates with alkynes gives pyridines and 2-pyridones, often in excellent yield (e.g. equation 142), while the cyclotrimerizations of nitriles, imidates, isocyanates, etc., are well established procedures for the synthesis of 1,3,5-triazine derivatives (e.g. equation 143). Further representative examples are given in equations (144)-(147), and the reader is referred to the monograph chapters for full discussion of these and other [2 + 2 + 2] processes. Examination of the... 

Vinyl isocyanates, readily available from the corresponding a,/3-unsaturated acids by a Curtius procedure, have been by far the systems studied in more detail, mainly by the Rigby group, e.g., in the construction of the pyridone ring (Scheme 53). Thus, heteropolycyclic compounds having 2-pyridone structure 233 were shown to be formed in moderate to... 

In an extension of this reaction, the same group prepared functionalized 4-hydroxy-2(l//)-pyridones by reacting vinyl isocyanates with ester eno-lates (Scheme 54). The reaction of 2-azadienes 232 with enolates derived... 

Heteroaromatic vinyl isocyanates have been used as a source of bicyclic pyridones. In the preparation of the l-methylpyrazolo[4,3-c]pyridone 153 the isocyanate 152b, obtained by Curtius rearrangement of the corresponding acid azide 152a, was heated at 220°C in diphenyl ether to furnish the product in good yield.143,144 Several 2-alkyl derivatives were also prepared.144... 

The cobalt(I)-catalyzed condensation of nitriles (1 mole) or isocyanates (1 mole) with alkynes (2 moles) gives pyridines and 2-pyridones, often in excellent yield (Scheme 72). 

The cycloaddition chemistry of pyridones (695) is quite analogous to that of the a-pyrones (79CC1091). Pyridones will react under high pressure conditions with acetylenedicarboxylic acid esters to furnish cycloadducts (696) which when heated expel a molecule of an isocyanate to yield substituted aromatics (697 Scheme 163). 

A synthesis of the monoterpene alkaloid ( )-actinidine has been accomplished through the intramolecular cycloaddition of a substituted pyrimidine (81JCS(P1)1909). Condensation of the diester (756) with formamidine provided the pyrimidine precursor (757) which when heated at its melting point (203 °C) underwent cycloaddition with elimination of isocyanic acid to produce the pyridone (758). Conversion of the pyridone into the chloropyridine was effected with phosphoryl chloride. The chlorine atom was then removed by hydrogenoly-sis over palladium on charcoal to afford the racemic alkaloid (759 Scheme 175). 

Substituted 2-pyridones were obtained from enamines with appropriate functional groups. Phenyl isocyanates and phenyl isothiocyanates... 

Recently, it has been shown that 2-pyridones with the nitrogen atom substituted by alkyl,262 aryl, or methoxyl265 do undergo Diels-Alder reactions. Heating l-methyl-2-pyridone with DMAD to 195°, the first successful example studied,262 gave 51, which was thought to be formed via 49 as shown. Under milder conditions,265 Diels-Alder adducts (cf. 49) can be isolated and, on further heating, yield phthalic esters and isocyanates. 

Cava and Saris591 refluxed the mesoionic selenazole 5 for a week with DM AD in benzene, and obtained 65% of the pyridone 6. This may be compared with the analogous mesoionic thiazole 49 (Section X,E). The easy loss of selenium from 6 contrasts with the loss of phenyl isocyanate from 49. 

Moreover, sorboyl chloride (466) was transformed into the corresponding isocyanate (467) and via subsequent cyclization, 3-methyl-2-pyridone (468) could be isolated241. ... 

Pyridones are prepared by insertion at the N=C bond of isocyanate using cobaltacyclopentadiene as a catalyst [74], The reaction was applied to the synthesis of the intermediate 182 of camptotecin from the isocyanate 180 and the alkyne 181 [75], Insertion at the C=0 bond of aldehydes also occurs. The Ni(0)-catalysed reaction of 3,9-dodecadiyne (183) with butanal affords the a-pyran 184 [76],... 

Irradiation of a tert-butyl alcohol solution of 6-ethoxy-4,5-dihydro-2(3H> pyridone (14) under conditions similar to those described for 12 gives two products, tert-butyl N-(ethoxyethylidene)carbamate (27) in 15% yield and glutarimide in 23% yield18. There is no indication of formation of the cyclobutyl analogue of 13. In aprotic solvent, ethoxyvinyl isocyanate (28) and glutarimide (29) are the major photoproducts formed. The gaseous byproducts from the irradiation of 6-propoxy-... 

Strategies to pyridines include a ruthenium-mediated [2+2+2] cycloaddition to produce annulated products <20010L2117>. Reaction of 1,6-heptadiynes with electron-deficient nitriles yields the pyridine (Equation 175), whereas the same strategy using isocyanates leads to the 2-pyridone (Equation 176). 

Analogously, aromatic high molecular weight poly(pyridone)s have been obtained using terminal and internal aromatic diynes, e.g. 1,4-diethynylbenzene [98] and l,4-bis(phenylethynyl)benzene [99] respectively, for 1 1 cycloaddition copolymerisation with isocyanates. 

---