4-Nitrophenyl carbamates

Carbamoyl chlorides, CDI, 4-nitrophenyl carbamates, and the compounds used to prepare them, e.g. phosgene and 4-nitrophenyl chloroformate, are toxic. 

Nitrophenyl carbamates (R R2NC02Np) and related aryl carbamates, e.g. phenyl-, di-nitrophenyl-, trichlorophenyl-, and pentafluorophenyl carbamates, provide an additional route by which an Na-free peptide can be condensed with another amine (peptidic or... 

Scheme 8 Preparation of a 4-Nitrophenyl Carbamate and its Reaction with an N -Free Peptide to Produce a Ureine Peptide1361...

A soln of 4-nitrophenyl carbamate 28 (45 mg, 0.068 mmol), TFA - H-Leu-Leu-OMe (31 mg, 0.083 mmol), and DMAP (13 mg, 0.11 mmol) in CHC13 (5mL) was stirred for 4d under argon. The mixture was washed with 1M HC1, aq NaHC03, brine, and dried (MgS04). The soln was filtered and concentrated to give a residue, which was purified by gel-permeation chromatography to afford the urethane peptide 29 as white crystals yield 31 mg (58%) mp 79-81 °C. UV Xmax (MeOH) 309nm (e 12400). 

In the first approach, an amino acid derived 4-nitrophenyl carbamate is used as the carbamoylating reagent. 4-Nitrophenyl carbamates are generally not very reactive, and carbamoylations with these reagents only proceed smoothly with sufficiently nucleophilic aliphatic amines. 4-Nitrophenyl carbamates [252] and O-succinimidyl carbamates [253] in combination with A-Fmoc protection have also been used for the solid-phase synthesis of oligoureas. 

The use of the Fmoc-protected 4-nitrophenyl carbamate building blocks and resins with acid-labile linkers allows synthesis of the final products with C-terminal carboxylic acid or amide groups (Fig. 6). Unfortunately, Fmoc solid-phase synthesis of oligourea peptidomimetics with C-terminal carboxylic acid also leads to formation of corresponding hydantoin byproducts (53-56) (Fig. 7). In this case hydantoin formation arises as a result of an acid-catalyzed intramolecular cyclizafion reaction. It has been reported that the ratio of desired oligourea pepfidomimetic acid product and hydantoin byproduct is approximately 2 1 (53). However, these two compounds are in principle separable by preparative HPLC. 

Figure 3. 4-Nitrophenyl carbamate content during the reaction of dextran with 4-nitrophenyl chloroformate in DMSO/pyridine (vol. ratio 1/1) at 0°C. [anhydro glucosides]0 = 0.1 M [chloroformate = (X) 90 mM, (A) 50 mM, ( ) 12 mM, (O) 8 mM.

Figure 4. Total carbamate content ( ) and 4-nitrophenyl carbamate content (O) during the activation of dextran with 4-nitrophenyl chloroformate [anhydro glucosides]0 =0.1 M [chlorofor-mate]Q = 50 mM.

Alternatively, Schultz and coworkers [59] have proposed an approach related to that of Burgess which utilizes azido 4-nitrophenyl carbamates 98 as activated monomers. Carbamates 98 were prepared in four steps from alcohol 95. Mesylation of 95 followed by azide displacement afforded the A-Boc-protected azide in high yield (80-90%). Boc deprotection and treatment of the resulting free amine with / -nitrophenyl chloroformate in the presence of pyridine in THF provided 98 (50-90% for the two steps). Solid-phase urea bond formation was performed on a Rink amide resin by coupling 98 (5 equiv.) in CH2CI2 in the presence of DIEA (7 equiv.) for 4 h at room temperature. Support-bound azide 99 was reduced in less than 2 h using... 

Scheme 27 Solid-phase synthesis of oligoureas using azido 4-nitrophenyl carbamates 98 as activated monomers [59].

Typical procedure. N-PhenYl-2-(l-hydroxy-4-nitrophenyl) carbamate 722 (Nu = PhNH). 

To a solution of NPC (0.91 g, 5.0 mmol) in benzene (50 mL), a solution of aniline (0.47 g, 5.0 mmol) in benzene (20 mL) was added dropwise with stirring. After stirring overnight at room temperature, a white precipitate formed, which was collected by filtration and crystallized from benzene to yield 1.07 g (78%) of N-phenyl-2-(l-hydroxy-4-nitrophenyl) carbamate. 

B. Synthesis of m- 4-[o-(2-Chloro-5-fluorosulfonylphenylureido)-phenoxy]butoxy bematnidine (11).To 5.2 mmoles of 3-amino-4-chloro-benzenesulfonylfluoride (18) (Aldrich Chemical Co.) are added 25 ml of benzene (dry reagent grade) and 5.5 mmoles of p-nitrophenylchlorofor-mate (19) (Aldrich Chemical Co.). The mixture is stirred at reflux for 4 hr, at which point hydrochloric acid vapor is no longer detectable. The mixture is cooled, and i T-(2-chloro-5-fluorosulfonyl-0-(4-nitrophenyl) carbamate (W) is collected. Recrystallization is from methylene chloride. To a solution of m-[4-(o-aminophenoxy)butoxy]benzamidine p-toluenesulfonate (21) in 10 ml of DMF are added 10.0 mmoles of pyri-... 

---