Butyl trifluoroacetate, hydrolysis

Many carbamates have been used as protective groups. They are arranged in this chapter in order of increasing complexity of stmcture. The most useful compounds do not necessarily have the simplest stmctures, but are /-butyl (BOC), readily cleaved by acidic hydrolysis benzyl (Cbz or Z), cleaved by catalytic hy-drogenolysis 2,4-dichlorobenzyl, stable to the acid-catalyzed hydrolysis of benzyl and /-butyl carbamates 2-(biphenylyl)isopropyl, cleaved more easily than /-butyl carbamate by dilute acetic acid 9-fluorenylmethyl, cleaved by /3-elimination with base isonicotinyl, cleaved by reduction with zinc in acetic acid 1-adamantyl, readily cleaved by trifluoroacetic acid and ally], readily cleaved by Pd-catalyzed isomerisation. 

The hydrolysis of diethyl N-(3-alkoxycarbonyl-2-thienyl)aminomethy-lenemalonates (1439, R = Me, Et) by potassium hydroxide in ethanol yielded diethyl Af-(3-carboxy-2-thienyl)aminomethylenemalonates (1439, R = H) [75GEP2435025, 75JAP(K)77393]. The treatment of the /erf-butyl esters 1439, R = rBu, R1 = R2 = H, Me, (CH2)4] with formic acid or trifluoroacetic acid at room temperature also afforded the carboxylic acid derivatives [1439, R = H, R = R2 = H, Me, (CH2)4] [75JAP(K)77394]. 

Marchand and co-workers reported a synthetic route to TNAZ (18) involving a novel electrophilic addition of NO+ NO2 across the highly strained C(3)-N bond of 3-(bromomethyl)-l-azabicyclo[1.1.0]butane (21), the latter prepared as a nonisolatable intermediate from the reaction of the bromide salt of tris(bromomethyl)methylamine (20) with aqueous sodium hydroxide under reduced pressure. The product of this reaction, A-nitroso-3-bromomethyl-3-nitroazetidine (22), is formed in 10% yield but is also accompanied by A-nitroso-3-bromomethyl-3-hydroxyazetidine as a by-product. Isolation of (22) from this mixture, followed by treatment with a solution of nitric acid in trifluoroacetic anhydride, leads to nitrolysis of the ferf-butyl group and yields (23). Treatment of (23) with sodium bicarbonate and sodium iodide in DMSO leads to hydrolysis of the bromomethyl group and the formation of (24). The synthesis of TNAZ (18) is completed by deformylation of (24), followed by oxidative nitration, both processes achieved in one pot with an alkaline solution of sodium nitrite, potassium ferricyanide and sodium persulfate. This route to TNAZ gives a low overall yield and is not suitable for large scale manufacture. 

The rate constant for the hydrolysis of t-butyl chloride at 298 K decreases as x2 increases in DMSO + water mixtures (Heinonen and Tommila, 1965). A clear-cut contrast between TA and TNAN mixtures is shown by the volumes of activation and related parameters for the solvolysis of benzyl chloride in acetone + water (TA) and DMSO + water mixtures (Fig. 57). Thus, in the latter system, the curves show no marked extrema but there is a shallow minimum in AV near x2 = 0 4. Extrema in Sm AH and T. 5m AS for the hydrolysis of benzyl chloride are also smoothed out when the co-solvent is changed from acetone to DMSO (Tommila, 1966). A similar trend is observed in the kinetic parameters for the hydrolysis of chloromethyl and methyl trifluoroacetates (Cleve, 1972a). For example, in the case of the chloro derivative, 6mACp decreases gradually over the range 0 < x2 < 0-2 for DMSO + water mixtures, whereas a minimum is observed in this range for acetone + water mixtures. 

The /(77-butyl ester groups of the PtBA block can be hydrolyzed under acid conditions by placing them into neat trifhioroacetic acid for 20 min. CAREFUL Trifluoroacetic acid is very corrosive and should be handled by experienced and properly trained personnel according to published safety rules. After hydrolysis the films are rinsed three times using Milli-Q water, and are finally dried in a stream of nitrogen. 

Dichloropyridazine can be successfully alkylated and hydroxyalkylated by free radicals (Scheme 26). 4-t-Butyl-3,6-dichloropyridazine is prepared in high yield <880PP117>, and in a novel radical hydroxyalkylation, hydroxy-t-butyl radicals generated in situ from 2,2-dimethyl-1,3-pro-panediol react to give the 4-hydroxy-t-butyl derivative (76), along with some of the fused dihydro-furopyridazine byproduct the product (76) can be obtained pure in 55-60% yield by recrystallization. In the latter 3,6-dichloropyridazine reaction, trifluoroacetic acid and silver nitrate both catalyse hydrolysis of the dichloropyridazine substrate, but if the acid is omitted, or the quantity... 

More recently Galivan et al. [283] described a synthesis of y-fluoroMTX (VIII.99) involving condensation of di-t-butyl A -[4-(A -methylamino)ben-zoyl]-y-fluoro-L-glutamate with 2,4-diamino-6-bromomethylpteridine, followed by hydrolysis of the ester groups with trifluoroacetic acid. The overall yield was 45 %, and two products with erythro and threo stereochemistry were shown to be present in equal amounts by F-NMR and ion-exchange HPLC. The proton NMR spectrum of the mixture, taken in DjO-DCl solution, showed the /l-CHj protons as a multiplet at b 2.94 and the y-CHF proton as a markedly deshielded multiplet at b 5.42. 

Due to the instability of the feri-butyl ester, and the resistance of the ethyl ester to transesterification, installation of the methyl ester prior to glycosylation was clearly required. Conversion of tert-butyl enol ester 51b to the methyl ester 51a was achieved in 78% yield over two steps, with hydrolysis of the tert-bvAy ester using trifluoroacetic acid at 0 °C, followed by methylation with trimethylsilyl diazomethane (Scheme 21). Gratrfyingly, when methyl enol ester 51a was... 

A second group of analytical methods requires preliminary acid hydrolysis. This is conducted in 7 M HCl at 95 to 9TC for 4 h (73) or in 1 M HCl at 80°C for 3 h (23). The hydrolysis product p-alanine has been analyzed after its conversion to the corresponding Ar-trifluoroacetyl methyl ester or jv-trifluoro-acetyl butyl ester. Derivatization of p-alanine is a two-step procedure. The compound is converted first to its methyl or butyl ester using alcoholic HCl and then to its AT-trifluoroacetate by the use of trifluoroacetic acid anhydride. The resulting derivative is analyzed using a polar stationary phase (23). 

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