Phosgene equivalents

TRICHLOROMETHYL CHLOROFORMATE AS A PHOSGENE EQUIVALENT 3-ISOCYANATOPROPANOYL CHLORIDE... 

Conversion of the amino alcohol 53 to Efavirenz (1) was readily accomplished by reaction with phosgene or phosgene equivalents. The most convenient and economically sound method is to react 53 with phosgene in the absence of base in THF-heptane at 0-25 °C. After aqueous work-up, Efavirenz was crystallized from THF-heptane in excellent yield (93-95%) and purity (>99.5%, >99.5% ee). 

Alternatively, two phosgene equivalents were studied, methyl chloroformate and p-nitrophenyl chloroformate. When methyl chloroformate was used for the end game, N-carbamate 54 was obtained smoothly but subsequent cyclization to ben-zoxazinone 1 was sluggish. Furthermore, removal of the unreacted intermediate methyl carbamate 54 from Efavirenz was not trivial, thus we did not pursue this method. On the other hand, reaction of 53 and p-nitrophenyl chloroformate initially provided the corresponding p-nitrophenyl carbamate 55 under mild basic conditions (KHC03). Carbamate 55 was smoothly cyclized to 1 upon increasing... 

Cyclic carbonates are introduced through the use of phosgene or a phosgene equivalent and a base (pyridine). They are most stable to acid hydrolysis and are removed under rather strongly basic conditions. Interestingly, they can protect both cis- and frani-vicinal diols. 

Merck s HIV-1 reverse transcriptase inhibitor Efavirenz 83 is one of the simplest anti-HIV drugs yet produced. The most straightforward synthesis17 is based on closure of the amino alcohol 84 with some phosgene equivalent and the preparation of 84 by asymmetric addition of cyclopropyl-ethynyl-lithium 86 to the ketone 85. 

Tetronic acids can be constructed using the dianion of an acyloin, this time with the phosgene equivalent, l,l -carbonyldiimidazole. 

A-Acylimidazoles are even more easily hydrolysed than A-acylpyrroles, moist air is sufficient. The ready susceptibility to nucleophilic attack at carbonyl carbon has been capitalised upon commercially available l,l -carbonyldiimidazole (CDI), prepared from imidazole and phosgene, can be used as a safe, phosgene equivalent, i.e. a synthon for O = C, and also in the activation of acids for formation of amides and esters via the A-acylimidazole. ... 

Solid bis(trichloromethyl) carbonate as phosgene equivalent) added under Nj to a stirred soln. of cyclohexanecarboxaldehyde and a little pyridine in carbon tetrachloride at —20 at such a rate that the temp, remained at —10° to —20°, the viscous slurry allowed to warm to room temp, over 90 min, heated to 40° for 1 h, cooled to room temp., and stirred overnight cyclohexyl(chloro)methyl chloroformate. Y 89%. The method is mild, high-yielding, and avoids the use of hazardous phosgene. F.e.s. M.J. Coghlan, B.A. Caley, Tetrahedron Letters 30, 2033-6 (1989). 

The aim of this book is to present the state-of-the-art on phosgenation chemistry, including all its phosgene equivalents and substitutes (some 70 are dealt with in this book), resulting in many novel reactions and processes for improved methods to obtain phosgenation products (see Chapters 4 and 5). 

Carbonyldiimidazole (CDI) is used as a phosgene equivalent for many carbon-ylations, giving yields of 7 comparable of that achieved with phosgene [24] see also Chapter 6. 

Scheme 2.1. Phosgene equivalents and substitutes structures and abbreviations order according to Table 7.2, Section 7.2.

Procedures employing phosgene equivalents can also be applied to the large-scale preparations of those carbamates, ureas, or heterocyclic compounds that are difficult to synthesize efficiently by other and safer methods, mainly compounds bearing different functionalities and incorporating chiral carbons in the side chains. In this regard, a first crucial step towards more environmentally friendly approaches to ureas was taken with the use of bis(4-nitrophenyl)carbonate, S,S-dimethyl-dithiocarbonate, 1,1-carbonyl-bis(imidazole), di-tert-butyl dicarbonate, and phenyl chloroformate [28],... 

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