P-nitrobenzyl chloroformate

The formal total synthesis of the novel /3-lactam antibiotic thienamycin has been accomplished from an isoxazoline derivative generated by [3 + 2] dipolar cycloaddition <79H(l2)l 183). Reaction of the nitrile oxide derived from 3-nitropropanal dimethyl acetal with methyl crotonate gave the isoxazoline (477) regio- and stereo-selectively. The isoxazoline was converted to amino ester (478) by hydrogenation and then to /3-lactam (479) by ester saponification and ring closure with DCC. Treatment of (479) with p-nitrobenzyl chloroformate and reaction of the derived acetal (480) with excess N-p-nitrobenzyloxycar-bonylcysteamine gave thioacetal (481), a compound which has previously been converted into ( )-(8S )-thienamycin (Scheme 106). 

The nitrobenzyl caibonates were prepared to protect a secondary hydroxyl group in a thienamycin precursor. The o-nitrobenzyl carbonate was prepared from the chloroformate (DMAP, CH2CI2, 0° - 20°, 3 h) and cleaved by irradiation, pH 7. The p-nitrobenzyl carbonate was prepared from the chloroformate (—78°, n-BuLi, THE, 85% yield) and cleaved by hydrogenolysis (H2/Pd-C, dioxane, H2O, EtOH, K2HP04). It is also cleaved by electrolytic reduction. ... 

Kinetics and Mechanism of Reactions of Bis (methyl-2,2 -dimercaptodiethyl-amine) dinickel(II) with Alkyl Halides. The rates of reaction of [Ni2 CH3N-(CH2CH2S)2 2], structure III, with methyl iodide, benzyl bromide, benzyl chloride, p-chlorobenzyl chloride, and p-nitrobenzyl chloride have been studied as functions of temperature and concentration in chloroform (3). Absorbance measurements were utilized to determine the rates. All experiments were conducted with excess alkyl halide (20 to 1000 times the initial concentration of complex). Jicha and Busch (18) were able to isolate alkylated complexes of the composition... 

On the other hand, the dilute solution of poly(p-benzyl-L-aspartate) in chloroform or dichloromethane gives a weak but existant CD band centered at 252 nm. A large positive CD band at 222 nm means that poly(p-benzyl-L-aspartate) (PBLA) exists in the left-handed a-helical form. Poly(y-p-nitrobenzyl-L-glutamate) also shows a definite negative CD band around 275 nm, even if the concentration of the polymer... 

Dibenzyl diselenide crystallises from alcohol in yellow needles, which are slightly deeper in colour than those of the p-nitrobenzyl compound, and melt at 92° to 93° C. Exposure to light for an hour or so causes the crystals to turn red. The selenide readily dissolves in hot alcohol, but is only sparingly soluble in ether, insoluble in water. Oxidation with fuming nitric acid converts it into benzyl seleninic acid, and boiling with copper or mercury in suspension precipitates selenium. Boiling with iodine in chloroform solution gives the tetra-iodide, M.pt. 98° C. the tetrabromide melts at 137° C.5... 

Cognate preparations. p-Nitrobenzaldehyde. This preparation is an example of the Sommelet reaction in which the hexaminium salt is isolated. Dissolve llg (0.13mol) of hexamethylenetetramine in 70ml of chloroform (CAUTION) and add 11.4 g (0.067 mol) of p-nitrobenzyl chloride or 14.4 g of p-nitrobenzyl bromide (Expt 6.28). Heat the mixture under reflux on a steam bath for 4 hours a precipitate gradually separates. Replace the reflux condenser by a condenser set for distillation and distil off about 35 ml of solvent. Add 35 ml of acetone, cool in ice, collect the precipitate by suction filtration and dry it in the air. Heat the hexaminium salt thus obtained under reflux for 1 hour with 100 ml of 50 per cent acetic acid then add 100 ml of water and 25 ml of concentrated hydrochloric acid and continue the refluxing for 5-10 minutes. Cool the solution in ice, collect the crystals of p-nitrobenzaldehyde and dry them in a vacuum desiccator. The yield is 6.4 g (63%), m.p. 106 °C. The p.m.r. spectrum is noted in Expt 6.117. 

To a 1 liter flask containing dimethylformamide at 0°C, was added 24.8 g sodium N-(2-methoxycarbonyl-l-methylvinyl)-D-a-phenylglycine (prepared from sodium D-a-phenylglycine and methyl acetoacetate). The mixture was cooled to -40°C and methyl chloroformate (7.5 ml) and dimethylbenzylamine (0.26 ml) added. After stirring for 25 minutes, p-nitrobenzyl 7-aminodesacetoxycephalosporanate (32.8 g) in the form of its hydrochloride salt was added, followed by triethylamine (12.1 ml) and dimethylformamide (140 ml) over a period of 20 minutes. The reaction mixture was stirred for 2 hours at -25°C to -35°C, then warmed to 0°C and water (32 ml) added. To the resultant solution, hydrochloric acid (54 ml) was added followed by zinc (21.8 g) in portions over a period of 5 minutes, the temperature being maintained at 5°C to 10°C. Further hydrochloric acid (35 ml) was added and the solution stirred at 15°C to 20°C for 7 hours. 

Reductions. Reports of rather simple reductions by indium keep appearing of tx-halocarbonyl compounds in water with ultrasound assistance, of p-nitrobenzyl ethers and esters, disulfides, amine IV-oxides, and organic azides in alcoholic solvents in the presence of NH4CI. When the azide reduction is carried out in DMF the products can be directly converted to carbamates by having a chloroformate ester in the reaction vessel. ... 

Procedure C [147] Add d- 10-camphorsulphonyl chloride (2 mM, 30 ml) in anhydrous ether dropwise to the amino acid (1 mM in diethyl ether, 10 ml), add sodium hydroxide solution (IM 20 ml) and stir at 0°C. Allow to each room temperature and stir for 3h. Separate the phases and wash the aqueous phase with diethyl ether, acidify with hydrochloric acid and re-extract with diethyl ether. Dry the ether phase over anhydrous sodium sulphate and evaporate to dryness. Dissolve the residue in N,N-dimethylformamide (10 ml), triethylamine (1 drop) and p-nitrobenzyl bromide (1.1 mM). Heat at 55 °C for 2 h and dilute with chloroform. Wash the organic phase with water and dry over anhydrous sodium sulphate. Analyse HPLC. 

Monofunctionalization of diamines has been reported (Leznoff and Dixit, 1977). Symmetrical diamines were bound to a benzyl chloride support that had been first reacted with p-nitrobenzyl carbonate. The aminocarbonates thus obtained were benzoylated and then treated with trifluoroacetic acid-trifluoroacetic anhydride in chloroform to yield the A -benzoyl-A -trifluoroacetyI-l-ft)-diaminoalkanes (50-80% yields). 

Vinyl chloroformate can be used for the protection of hydroxyl and amino groups as well as for N-dealkylation. Sec. alcohol groups have been conveniently tritylated with triphenylcarbonium perchlorate in the presence of 2,4,6-tri- err-butylpyridine as acid acceptor . Wet silica gel has been recommended as a convenient reagent for deacetali-zation . p-Nitrobenzyl carboxyl-protective groups can be rapidly re-... 

Methyl, ethyl, benzyl, benzhydryl, p-nitrobenzyl, p-methoxy-benzyl, 4-picolyl, j3j -trichloroethyl, j3-methylthioethyl, /J-p-toluenesulphonylethyl, and -p-nitrophenylthioethyl esters may be prepared directly from the acid and alcohol. TTie most usual method [4, 5] consists of heating the acid and an excess of the alcohol with an acid catalyst (e.g., Fischer-Speier, hydrochloric or sulphuric acid). The extent of reaction is improved if the water formed is removed by azeotropic distillation with an inert solvent (benzene, carbon tetrachloride, or chloroform). Considerable variation is possible in the natvire of the acid catalyst thus phosphoric acid [6], aryl sulphonic acids [7, 8, 9], alkyl sulphates [10], and acidic ion-exchange resins [11] may be employed. Removal of the water by azeotropic distillation during the formation of methyl esters is difficult and Brown and Lovette [12] introduced the novel reagent acetone dimethyl acetal (7) for the direct formation of methyl esters. In the presence of a trace of methanol and an acid catalyst the reagent acts as a scavenger of water formed by esterification and liberates further methanol for reaction. 

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