Phosphoryl chloride reaction with alcohols

Phosphorylation. Alcohols may be phosphorylated in good yield by the reaction of phosphorous acid, mercury(II) chloride and A-methylimidazole (eq 1). An intermediate salt 1 is formed. This method has been used to prepare nucleoside 5 -phosphates in yields of 60-70%. Similarly, amines may be phosphorylated by reaction with phosphorus oxychloride andiV-methylimidazole (eq 2). ... 

No details are given for scheme A. Presumably one could use the phosphoryl chloride instead of the fluoride. Scheme B, in which ethyl chloride is formed, was run in boiling xylene using equimolar quantities of the reactants. Michaelis (33) has partially described the preparation of starting materials from secondary amines with phosphorus oxychloride and also ethyl dichlorophosphate. Schrader (38) obtained alkyl and amido fluophosphates by reaction of the corresponding chlorophosphates with sodium fluoride in aqueous or alcoholic solution. 

The ring closure of 2-pyridylaminomethylenemalonates (1023, both 6-substituted and 6-unsubstituted) took place readily in phosphoryl chloride in the presence of a catalytic amount of polyphosphoric acid ( 1-10%) at reflux temperature. When hydrogen chloride gas evolution ceased, the reaction mixtures were treated with the appropriate alcohol, and hydrochloride salts of pyrido[l,2-a]pyrimidine-3-carboxylates (1024) were ob-... 

Rosoxacin was obtained in 16% yield by the cyclization of isopropylidene N-ethyl-N-[3-(4-pyridinyl)phenyl]aminomethylenemalonate in pol-yphosphoric acid at 125-137°C for 30 min [77JAP(K)116460], Isopropylidene 2-pyridyl- and 2-quinolinylaminomethylenemalonates (1195) were cyclized in boiling phosphoryl chloride by the action of poly-phosphoric acid at I35-140°C. When the formation of hydrogen chloride gas ceased, the reaction mixtures were treated with an alcohol or water to afford the corresponding alkyl 4-oxopyrido[ 1,2-a]pyrimidine-3-carbox-ylates or alkyl 1 -oxopyrimido[ 1,2- ]quinoline-2-carboxylates (1196, R2 = alkyl) in 51-96% yields or to afford carboxylic acids (1196, R2 = H) in 64-84% yields (79MIP2 80MIP3 84S152). 

Thermal cyclization of the isopropylidene ester of the malonates (70) was accompanied by decarboxylation at position 3, whereby 4-oxo-4H-pyrido-[l,2-fl]pyrimidines (74 R1 = H) were obtained.79,142,143 When the cyclization was performed in phosphoryl chloride-polyphosphoric acid and the reaction mixture was treated with alcohol, 4-oxo-4H-pyrido[l,2-a]pyri-midine-3-carboxylic acid esters were isolated.151 Treatment of the reaction mixture with water gave carboxylic acids. 

The cyclization of isopropylidene 2-pyridylaminomethylenemalonates 147 in a mixture of phosphoryl chloride-polyphosphoric acid gave 4-oxo-4ff-pyrido[l,2-a]pyrimidine-3-carboxylic acids 131 (R1 = COOH) or their esters 131 (R1 = COOalkyl), depending upon whether the excess of phosphoryl chloride was reacted with water or an alcohol. In this way a mixed ester or a half-ester (e.g., 131 R = COOEt, R1 = COOR2, R2 = H, Me) was obtained from an ester derivative of isopropylidene aminomethyl-enemalonate 147 (R = COOEt) (84S152). The 6-ethoxycarbonyl derivative of isopropylidene 2-pyridylaminomethylenemalonate 147 (R = 6-COOEt) afforded triester 138 when the reaction mixture was treated with ethanol. 

The reaction of 0,jV,-dimethyllythranidine (77) with phosphoryl chloride in pyridine followed by catalytic hydrogenation gave a crystalline chloro compound (83) as a major product and an amorphous dichloroderivative (84). Both products underwent hydrogenolysis of the chlorine atom with sodium in iso- and //-propyl alcohol, respectively, to yield bisdcoxy-CUV-dimethyllythranidine (85). 

An important method for the preparation of lactim ethers is the transformation of lactams to imidochlorides followed by treatment with alcohols. Thus, the reaction of caprolactam with phosphoryl chloride followed by methanol resulted in O-methylcaprolactim (2, R = Me)43 (Scheme 2). 

Phosphate esters are produced by reaction of phosphoryl chloride with phenols or alcohols, or, less commonly, sodium phenoxides/alkoxides, as Reaction (2.12) ... 

The vast majority of modern phosphate esters are synthetic , using materials derived from petrochemical sources. For example, alcohols are from a-olefins by the 0X0 process and iso-propylated or t-butylated phenols are produced from phenols by reaction with propylene or butylene. Reaction of alcohol or phenol with phosphoryl chloride yields the crude product, which is washed, distilled, dried and decolourised to yield the finished product. Low molecular weight trialkyl esters are water soluble and require non-aqueous techniques. For mixed alkylaryl ester production the reactant phenol and alcohol are added separately, the reaction being conducted in a stepwise fashion. Reaction temperatures are kept as low as possible to avoid transesterification reactions. 

An alternative approach to the synthesis of benzodiazepines involves the reaction of /3-chlorovinyl carbonyl compounds with o-phenylenedi-amine. In the first example methyl /3-chlorovinyl ketone was used to obtain 5-methylbenzodiazepinium chloride.31 An extensive investigation has been made of the use of /3-chlorovinylaldehydes for the preparation of 2,3-substituted benzodiazepines.3233 The preferred conditions for reaction were in alcoholic hydrogen chloride. By this means a variety of 2-aryl-, 2,3-cycloalkeno-, and 2,3-diarylbenzodiazepines was prepared. If no acid is present an uncyclized anil results, formed by condensation of one amino group with the aldehyde. Since the /3-chlorovinylaldehydes are themselves readily obtained by reaction of a-methylene ketones with phosphoryl chloride and N, JV-dimethylformamide or jV-methylformani-lide,34 this provides an attractive route to 2,3-disubstituted benzodiazepines. 

PHOSPHORYL CHLORIDE (10025-87-3) Fumes in moist air. Contact with water, steam, or alcohols produces hydrochloric acid, phosphoric acid, and phosphine gas, which is pyrophoric, with possible ignition or explosion (may be a delayed reaction). Contact with air produces corrosive fumes. Violent reaction with carbon disulfide, 2,6-dimethylpyridine-N-oxide, dimethyl sulfoxide, ferrocene-1,1 -dicarboxylic acid, pyridine, zinc powder. Reacts, possibly violently, with acids, alkali metals, alkalis, combustible materials, dimethyl for-mamide, organic matter, zinc powder. Incompatible with acetic anhydride, V,V-dimethyl formamide, 2,5-dimethylpyrrole, sodium. Rapid corrosion of steel and most metals, except lead, occurs in the presence of moisture. 

Various reactions of the 7-substitutent have been carried out, all of which have their counterparts in indole chemistry." Reduction of the imino compound 13, obtained from DMF-phosphoryl chloride treatment of 11 (R = Me), with potassium borohydride gave the Mannich base 14 (R = Me). Reduction of the aldehyde 12 (R = H) with sodium borohydride in the presence of aqueous dimethylamine gave the amine 14 (R = H), whereas the analogous aldehyde 12 (R = Me) gave only the alcohol 15 (R = Me)." The related alcohol 15 (R = H) was obtained on reducing the aldehyde with sodium borohydride in the absence of dimethylamine. ... 

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