Diethyl phosphoramidate, preparation

In contrast to the anion of diethyl phosphoramidate or trifluoromethanesulfonamide, which cannot be cleanly monoalkylated, - the anion of trifluoroacetamide (100) was monoalkylated by alkyl halides or alkyl methanesulfonate. The resulting A -alkylamides (101) were converted into primary amines by alkaline hydrolysis or reduction (NuBHa Scheme 42). Various primary amines were prepared from (100) with primary alkyl iodides or methanesulfonate, benzyl and allyl halides, a-bromocarbonyl compounds and 2,4-dinitrochlorobenzene. However, competitive elimination is a serious side reaction for less reactive primary alkyl chlorides and secondary halides or methanesulfonate. The synthesis of secondary amines from (100) has also been reported. ... 

The first attempt to prepare dialkyl 1-aIkynyIphosphonates by a Michaelis-Becker reaction was reported in 1965, " Only octyne is produced when 1-bromooctyne is allowed to react with sodium diethyl phosphite in liquid ammonia, the coproduct being diethyl phosphoramidate. It seems likely that reduction of the bromo compound occurs by a halogen-metal exchange, with the resulting diethyl bromophosphate being immediately converted into diethyl phosphoramidate by the hquid anunonia. ... 

Two phosphoramidates newly employed for the preparation of pure amines, are diethyl A -trimethylsilylphosphoramidate and diethyl A -t-butoxycarbonyl-phosphoramidate/ each of which is initially converted into its anion which, in turn, is alkylated in the presence of tetrabutylammonium bromide, deprotected, and acidolysed to give the primary amine. In another modification (Scheme 13) the addition of diethyl phosphoramidate to an alkene occurs in the presence of mercuric nitrate, and acidolysis of the product again gives a pure primary amine. ... 

Together with R. rhodochrous ATCC 21197 [43] and Pseudomonas putida NRRL 18668 [51], also Rhodococcus sp. C3II md Rhodococcus erythropolis MP 50 were used for the enantiospecific preparation of (S)-naproxen [65]. Rhodococcus sp. C3II lacks a nitrilase but exhibits nitrile hydratase and amidase activities, both of which are constitutive and prefer the (5 )-enantiomers of naproxen derivatives. On the other hand, the enzymes from R. erythropolis MP 50 were induced by nitriles and its nitrile hydratase was (R)-specific [44]. Due to the presence of a strictly (5)-specific amidase, both strains finally formed (5)-naproxen with high enantioselectivity (Fig. 18). Evidence for the enantioselectivity of the nitrile hydratases of both strains was obtained by the formation of optically active amides in the presence of the amidase inhibitor diethyl phosphoramidate [63,65]. The nitrile hydratase of Rhodococcus sp. C3II whole cells was used for the sjmthesis of (>S)-naproxen amide with 94% e.e. after 30% conversion in the presence of the amidase inhibitor [63]. In addition, the highly stereoselective amidases of these two strains were used to prepare (5)-ketoprofen (Fig. 28), and the amidase from R. erythropolis MP 50 was used to prepare (5)-2-phenylpropionic acid with more than 99% e.e. and more than 49% conversion [66,67]. 

The reaction of diethyl methylphosphonite (59) with methyl N-chlo-roacetimide has been studied.30 Besides the normal Arbuzov product (60) large amounts of dialkyl methylphosphonates (61) and (62) are formed, presumably as a result of initial halogen attack. Whether (60) is formed directly (N-attack) or via (63) has not yet been clarified. A simple method to prepare N,0,0 -trialkyl phosphoramid-... 

One of the two hydrogen atoms of phosphoramidates can be temporarily blocked with a trimethylsilyl group. The sodium salt of diethyl V-(trimethylsilyl)phosphoramidate (102) reacted with alkyl bromides in benzene in the presence of 10 mol % of tetra-n-butylammonium bromide to afford, after desilylation, the corresponding V-alkyl derivatives (103) in 79-95% yields for primary alkyl halides. Secondary alkyl halides gave poor results (Scheme 43). The addition of the quaternary ammonium salt is essential to promote the alkylation reaction. Hexamethyldisilazane and its cyclic analogs can also be utilized in the preparation of amines under moderate conditions (Scheme 43). ... 

Preparation of the phosphoramidate 37 is outlined.223 Zwierzak also describes the use of diethyl Af-(trimethylsilyl)-phosphoramidate 43 as a Gabriel reagent.24 In a similar method to the above, N-alkylphosphoramidates could be obtained using this reagent in good yields. 

A second total synthesis of ascididemin (323) was achieved by Moody et al. in 1990 in two steps starting from l,10-phenanthroline-5,6-quinone (331) (Scheme 38) (155,156). The quinoneimine 333 was first prepared by reaction between the quinone 331 and the sodium salt of diethyl N-(2-iodophenyl)-phosphoramidate (332). Photocyclization of 333 in cone, sulfuric acid gave ascididemin (323). Because of the low yield of especially the first step, 10%, preparation of 333 was carried out via a different route in two steps. The reaction of epoxide 334 with 2-iodoaniline 335 gave the amino alcohol 336, which was readily oxidized with barium manganate to the desired intermediate 333. 

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