Pyridines, phosphorylation

Phosphoryl chloride Carbon disulflde, A,A-dimethylformamide, 2,5-dimethylpyrrole, 2,6-dimethyl-pyridine 1-oxide, dimethylsulfoxide, water, zinc... 

The most useful general method for the C-acylation of pyrroles is the Vilsmeier-Haack procedure in which pyrrole is treated with the phosphoryl chloride complex (55a, b) of an AiA-dialkylamide (54). The intermediate imine salt (56) is hydrolyzed subsequently under mildly alkaline conditions to give the acylated pyrrole (57). On treatment of the imminium salt (56 R =H) with hydroxylamine hydrochloride and one equivalent of pyridine and heating in DMF, 2-cyanopyrrole (58) is formed (80CJC409). 

One of the most widely used systems for dehydration is the combination of phosphorous oxychloride and pyridine. This reagent is apparently incompatible with the A" -3-keto system/ probably due to formation of a phosphorylated enol. It is, however, more selective than thionyl chloride-pyridine since 17a-alcohols are not dehydrated ... 

Chloro-l//-l-benzazepines 2 are obtained as unstable red oils in excellent yields by heating 1 //-l-benzazepin-2(3//)-ones 1 with phosphoryl chloride in pyridine.208 Reaction conditions are important since in the absence of pyridine, or in dichloromethane solution, only poor yields of dimers, e.g. 3, are produced. The chlorobcnzazepines are stable for only short periods (24 hours in anhydrous pyridine) and rapidly polymerize. Isolation of the pure chloro compounds is difficult since they undergo very rapid hydrolysis to the benzazepinones. 

Methoxy-5//-pyrido[2,3-c]azepin-9(8//)-one (4) on chlorodehydroxylation with phosphoryl chloride in A,A, -dimethylaniline yields a mixture (20 %) of the chlorc)-6-methoxypyrido[2,3-c -azepines5and6.192 An unseparablemixture (3 7) of 5H- and 7ff-pyrido[2,3-c]azcpine-9-thione 7 and 8 is obtained on treating the pyridoazepinone 4 with phosphorus pentasulfide in warm pyridine. 

Phosphoryl chloride converted imidazo[4,5-c]pyridin-4(5//)-one into the 4-chloro derivative (65JMC708), and there are other examples of hydroxy displacement in the [4,5-b] series (58AP368 70CHE1073). 

Note As in related series, the addition of pyridine or (better) A,A-dimethylani-line (free of A-methylaniline, a common contaminant in some grades of this reagent) to phosphoryl chloride, appears to improve the yield of chloroqui-noxaline, especially if electron-withdrawing passenger groups are present. 

Reactivators of phosphorylated ChE. Pyridine aldoxime methiodide (PAM) and related compounds are the best known. They reactivate the phosphorylated enzyme so long as aging has not occurred. They do not, however, reactivate the aged enzyme. ChE which has been phosphorylated by certain nerve gases ages rapidly ... 

The addition products of MesSiCN 18 to carbonyl groups eliminate trimethylsilanol 4, in the presence of phosphoryl chloride in pyridine or of AICI3 in benzene, to give unsaturated nitriles. Thus ketone 1635 adds 18 and is subsequently converted, in a one-pot procedure, in 82% overall yield, into the olefin 1636 [27], whereas the adduct 1637 gives a mixture of the unsaturated nitriles 1638 [28] and ketone 1639 adds MesSiCN 18 and eliminates MesSiOH 4 or HMDSO 7, in one step, to give the a,y9-unsaturated nitrile 1640 [29] (Scheme 10.12). 

Several of these steroid derivatives underwent elimination of phosphorodichloridate anion, giving hydrocarbon products, rather than ester formation when treated with methanolic pyridine. Pyrophosphoric acid itself has been used to phosphorylate (2-hydroxymethyl)pyridine. ... 

The factors affecting the preparation of the cyclic chlorophosphazenes from phosphorus pentachloride and ammonium chloride continue to receive attention. For example, the yields and reaction times for the preparation of the series, (NPCla) ( — 3—7), varied with the fineness of the ammonium chloride, the nature and volume of the solvent, and added catalysts such as phosphoryl chloride. A procedure, giving due consideration to these factors, was described for the preparation of N3P3CI6 in good yield (88% of cyclic products) and in a relatively short time (2J h). The cyclic chlorophosphazenes can be obtained in even shorter times ca. 10 min) by addition of four moles of pyridine to remove the hydrogen chloride formed ... 

Although pyridines and quinolines were first produced during the carbonization of coal, they are now available by synthesis in quantities that far exceed those by the former. Phosphorylated ribosides of hydroxylated and aminated pyrimidines and purines make up the basic structure of ribonucleic and deoxyribonucleic acids. The polycyclic oxaarenes are plant metabolites, while thiaarenes are primarily important components of high-sulfur petroleum that must be removed. 

The strategies used in the synthesis of polymethine dyes are illustrated for a series of indoline derivatives in Scheme 6.1. There is an even wider range of synthetic routes to polymethine dyes than is described here, but they are based for the most part on a similar set of principles. The starting material for the synthesis of this group of polymethine dyes is invariably 2-methylene-1,3,3-trimethylindolenine (121), known universally as Fischer s base. As illustrated in the scheme, compound 121 may be converted by formylation using phosphoryl chloride and dimethylformamide into compound 122, referred to as Fischer s aldehyde, which is also a useful starting material for this series of polymethine dyes. When compound 121 (2 mol) is heated with triethylorthoformate (1 mol) in the presence of a base such as pyridine, the symmetrical cyanine dye, C. I. Basic Red 12 109 is formed. The synthesis of some hemicyanines may be achieved by... 

The condensation reactions are preferentially carried out in pyridine. As reactive species for phosphorylation of the nucleoside R OH (synthesis of a phosphortriester), the phosphoric acid azolide has been assumed. The mixed phosphoric sulfonic anhydride and a pyrophosphate tetraester have been suggested as intermediates leading to the phosphoric acid azolide. 

This shows that the combination of diphenylphosphate and arylsulfonyl-3-nitro-triazole is a powerful phosphorylating agent in pyridine solution. 

The extent to which 151 phosphorylates the aromatic amine in the phenyl ring is highly dependent upon the solvent. For instance, aromatic substitution of N-methylaniline is largely suppressed in the presence of dioxane or acetonitrile while pho.sphoramidate formation shows a pronounced concomitant increase. The presence of a fourfold excess (v/v) or pyridine, acetonitrile, dioxane, or 1,2-di-methoxyethane likewise suppresses aromatic substitution of N,N-diethylaniline below the detection limit. It appears reasonable to assume that 151 forms complexes of type 173 and 174 with these solvents — resembling the stable dioxane-S03 adduct 175 — which in turn represent phosphorylating reagents. They are, however, weaker than monomeric metaphosphate 151 and can only react with strong nucleophiles. 

The fact that the 3,P-NMR signal of 183a can only be observed in pyridine-containing solution provides food for thought124). Viewed in conjugation with the idea that alkyl metaphosphates could form adducts such as 173 and 174 U9,120) as discussed above, formulation as a zwitterionic pyridine/metaphosphate adduct (188) seems reasonable. Similar adducts have also been found in the reaction of TPS with dinucleotides and trinucleoside diphosphate 126). In any case, the reactions of 183 or 188 are in full accord with the expected properties of a monomeric metaphosphate and its reactivity towards alcohols is far greater than that of all other reactive phosphorylation intermediates which can arise on reaction of TPS with oligonucleotides 126). 

Steric reasons for differences between singly and doubly substituted amino derivatives can presumably be ruled out since it has been shown that nucleophiles other than OHe, such as Fe, N , and pyridine, react comparably fast with 192c and bis(dimethylamino)phosphoryl chloride131). 

Pyridine A-oxides were converted to tetrazolo[l,5-a]pyridines 172 by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent <06JOC9540>. 3-R-5-Trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-ones 173 have been prepared from the alkylation of 5-trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-one silver salt with different alkylation agents <06CHE417>. The use of 2-fluorophenylisocyanide in the combinatorial Ugi-tetrazole reaction followed by a nucleophilic aromatic substitution afforded tricylic tetrazolo[l,5-a]quinoxaline 174 in good yields and with high diversity <06TL2041>. 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

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