US EPA

7479603 

Journal Article 

4-Nitrophenyl chloroformate: A versatile coupling reagent 

Sammet, B 

2009 

1 

Synlett
ISSN: 0936-5214
EISSN: 1437-2096 

18 

3050-3051 

English 

10.1055/s-0029-1218291 

(A) In a typical procedure for 4-nitrophenyl carbamate and carbonate synthesis 4-NPC is added to the nucleophile in the presence of an excess amine base at room temperature. In the case of an in situ substitution of the obtained intermediate the second nucleophile is directly added to the system, and stirred at room temperature for usually less than one hour.5 [Chemical equation presented] (B) 4-Nitrophenyl chloroformate is used to block, hydroxyl groups in nucleosides. 4-NPC was applied to synthesize 4-nitrophenyl-5′O-tritylthymidine-3′-carbonate in 89% yield. The obtained compound, is stable enough for phosphorylation reactions and the carbonate can be removed under mild basic conditions using imidazole in aqueous organic solvent.6 [Chemical equation presented] (C) 4-NPC is applicable for the two-step synthesis of even more reactive corresponding isocyanates. The isocyanate is either synthesized in a refluxing solution of triethylamine in toluene7 or via a chlorosilane-induced cleavage of 4-nitrophenol. It was shown, that the latter method selectively activates 4-nitrophenylcarbamates in the presence of 4-methoxyphenyl carbamates. 8 [Chemical equation presented] (D) The conversion of a secondary benzylamine to a corresponding Boc amine in the presence of double bonds is often not trivial. In the example shown, this problem was solved, by cleaving the benzyl group under addition of 4-NPC. The direct substitution of the 4nitrophenyl moiety with potassium, tert-butylate led to the product in 66% yield in a one-pot procedure.9 [Chemical equation presented] (E) In an effort to synthesize deuterated catechols, benzo[d]-l,3dioxoles and their derivatives, an N-methylpiperidine moiety was recently successfully demethylated by the addition, of 4-NPC in a two-step procedure. After the formation of the 4-NP carbamate intermediate, aqueous hydrolysis and subsequent reprotonation gave the piperidinium salt in acceptable yield.10 The reported cleavage of similar methylated secondary amines by phenyl chloroformate was explained by the formation of an N-methylated phenyl carbamate cation, followed by the nucleophilic attack, of the chloride anion at the methyl group. 11 [Chemical equation presented] (F) 4-Nitrophenyl chloroformate can also be used to synthesize thiolactones, thus providing a useful procedure for the synthesis of thiazolidinones in β-lactam chemistry.12,13 The intramolecular substitution of the 4-nitrophenyl moiety by an ester enolate allowed the cyclization in 46% yield.13 [Chemical equation presented] (G) 4-NPC is applicable for the rapid conversion of carboxylic acids into their reactive nitrophenyl esters.14,15 These can be used for Pdcatalyzed decarbonylative olefination reactions with various olefins. High yields were often obtained.15 [Chemical equation presented] (H) Resin activation with 4-NPC is a valuable method for the connection of the first residue in solid phase chemistry. The loading capacity of such a modified PEG-resin can be easily checked by basic cleavage and UV absorption measurement of the liberated 4-nitrophenol. Cleavage from the resin is accomplished by the strong nonnucleophilic base 1,1,3,3-tetramethylguanidine directly leading to a substituted cyclic hydantoin.16 [Chemical equation presented] © Georg Thieme Verlag Stuttgart. 

4 nitrophenyl chloroformate; amine; beta lactam; hydantoin; imidazole; isocyanic acid derivative; nucleoside; reagent; unclassified drug; hydrolysis; olefination; phosphorylation; physical chemistry; reproducibility; short survey; substitution reaction; synthesis