Chloroformate, benzyl, reaction with amines

Alkyl esters are efficiently dealkylated to trimethylsilyl esters with high concentrations of iodotrimethylsilane either in chloroform or sulfolane solutions at 25-80° or without solvent at 100-110°.Hydrolysis of the trimethylsilyl esters serves to release the carboxylic acid. Amines may be recovered from O-methyl, O-ethyl, and O-benzyl carbamates after reaction with iodotrimethylsilane in chloroform or sulfolane at 50—60° and subsequent methanolysis. The conversion of dimethyl, diethyl, and ethylene acetals and ketals to the parent aldehydes and ketones under aprotic conditions has been accomplished with this reagent. The reactions of alcohols (or the corresponding trimethylsilyl ethers) and aldehydes with iodotrimethylsilane give alkyl iodides and a-iodosilyl ethers,respectively. lodomethyl methyl ether is obtained from cleavage of dimethoxymethane with iodotrimethylsilane. 

A,r-Benzyl groups can be removed by reaction of amines with chloroformates. This can be a useful method for protecting-group manipulation if the resulting carbamate is also easily cleaved. A particularly effective reagent is a-chloroethyl chloroformate, which can be removed by subsequent solvolysis.78... 

The synthesis of this scaffold requires a set of diverse anthranilic acids 71, of which only a few are commercially available. A variety of these was prepared by nucleophilic substitution of 2-chlorobenzoic acid 70 with a range of primary amines (alkyl, benzyl, phenyl). These anthranilic acids 71 were bound to a polysty-rene/triethyleneglycol chloroformate resin through the amine group (72). Amidation of the carboxylic acid function gave 73 and reaction at 125 °C in DMF gave the cyclized product 74 (Scheme 20) [33]. 

BENZYL CHLOROFORMATE (501-53-1) Combustible liquid (flash point 176°F/80°C oc). Vigorous decomposition occurs at these temperatures thus, these values are anomalous due to the effect of the decomposition products (benzyl chloride and carbon dioxide). Reacts with water, producing hydrochloric acid. Violent reaction with strong oxidizers, bases. Incompatible with strong acids, nitrates. The aqueous solution is incompatible with sulfuric acid, alkalis, ammonia, aliphatic amines, alkanolamines, alkylene oxides, amides, epichlorohydrin, organic anhydrides, isocyanates, nitromethane, vinyl acetate. Attacks metals in the presence of moisture. 

Amino groups can be blocked by converting them into carbamates through simple addition-elimination reactions (p. 901).Two popular methods involve the transformation of the free amine into a carbamate by reaction with either di- -butyl dicarbonate or benzyl chloroformate. Biochemists are even more addicted to acronyms than are organic chemists, and these protecting groups are called tBoc and Cbz, respectively (Fig. 23.45). 

Amino Acids. Chloroformates play a most important role for the protection of the amino group of amino acids (qv) during peptide synthesis (32). The protective carbamate formed by the reaction of benzyl chloroformate and amino acid (33) can be cleaved by hydrogenolysis to free the amine after the carboxyl group has reacted further. The selectivity of the amino groups toward chloroformates results in amino-protected amino acids with the other reactive groups unprotected (34,35). Methods for the preparation of protected amino acids on an industrial scale have been developed (36,37). A wide variety of chloroformates have been used that give various carbamates that are stable or cleaved under different conditions. 

Williams and coworkers used a [G4]-PAMAM dendrimer as a scavenger in the reactions of an arylpiperazine with slight excesses of three different electrophiles (an isocyanate, a sulfonyl chloride, and a benzyl halide) [62]. After TLC had indicated that all amine substrate had reacted the dendritic scavenger was added. Solvent removal, adding of chloroform, and filtration of the unsoluble dendrimer afforded the products in high yields (87-99%) and purities (>95%, HPLC). 

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... 

The triethylamine salt of 2,2-dimethyl-3-(3,4-methylenedioxyphenyl)-propionic acid (5.4 g amine, 11.4 g acid) was dissolved in 10 mL 11,0 and diluted with sufficient acetone to maintain a clear solution at ice-bath temperature. A solution of 6.4 g ethyl chloroformate in 40 mL acetone was added to the 0 °C solution over the course of 30 min, followed by the addition of a solution of 4.1 g sodium azide in 30 mL H20. Stirring was continued for 45 min while the reaction returned to room temperature. The aqueous phase was extracted with 100 mL toluene which was washed once with H20 and then dried with anhy drou s Mg S04. Thi s org ani c sol uti on of the azide was heated on a steam bath until nitrogen evolution had ceased, which required about 30 min. The solvent was removed under vacuum and the residue was dissolved in 30 mL benzyl alcohol. This solution was heated on the steam bath overnight. Removal of the excess benzyl alcohol under vacuum left a residue 13.5 g of l-(N-(benzyloxycarbonyl)amino)-1,1 -dimethyl-2-(3,4-methylenedioxyphenyl)ethane as an amber oil. The dimethyl group showed, in the NMR, a sharp singlet at 1.30 ppm in CDCH,. Anal. (C19H2lN04) C,H. This carbamate was reduced to the primary amine (below) or to the methylamine (see under MDMP). 

The interaction of alkyl halides, preferably iodides or bromides, with hexamine in chloroform or alcohol solution forms quaternary ammonium salts which on heating with hydrochloric acid are readily converted to primary amines. The procedure has been employed successfully in the reaction of primary, but not secondary or tertiary, aliphatic halides, certain benzyl halides, halo ketones, halo acids, and halo esters. The yields range from 40% to 85%. 

Try to anticipate the formation of azeotropes when distillation and concentration occur. Unexpected azeotropes may cause unsafe operations. For instance, distillative removal of water from the reaction of an amine with benzyl chloroformate (PhCH2COCl) resulted in formation of an azeotrope of water and benzyl chloride, a common impurity in benzyl chloroformate [40]. 

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