Protection Allyl chloroformate

Allyl carbonate esters are also useful hydroxy-protecting groups and are introduced using allyl chloroformate. A number of Pd-based catalysts for allylic deprotection have been developed.209 They are based on a catalytic cycle in which Pd° reacts by oxidative addition and activates the allylic bond to nucleophilic substitution. Various nucleophiles are effective, including dimedone,210 pentane-2,4-dione,211 and amines.212... 

Scheme 1. Synthesis of the protected scaffold, (a) Boc-ON, dioxane water (1 1), pH 11 (b) Allyl chloroformate, pH 9.5 (c) 50% TFA-DCM (d) Fmoc-Cl, Na2C03, dioxane water.

Alcohols are protected as allyl ethers, which are difficult to cleave with the Pd catalyst and deprotected by other methods [149]. Alcohols are conveniently converted to allyl carbonates 334 by treatment with allyl chloroformate (333). The allyl carbonates are deprotected using HCO2H [150], and HSnBu3 [151]. This method is called the AOC (allyloxycarbonyl) method. Phenols are protected as allyl phenyl ethers, which can be cleaved with HSnBu3 [152]. 

The protection of a-amino groups is usually effected with allyl chloroformate under Schotten-Baumann conditions,P but diallyl dicarbonate (AI0C2O) can also be used.P As with other chloroformates, a severe side reaction is the formation of A -Aloc-protected dipeptides. Since most A -Aloc amino adds are not crystalline compounds, they are preferentially isolated as the corresponding DCHA salts (for A -Aloc amino acids and their analytical characterization, see reff l). 

A fourth urethane protecting group, the TV-allyloxycarbonyl group (Alloc) is introduced in the usual way using allyl chloroformate or diallyl dicarbonate. Its main interest concerns its removal by a Pd-catalysed hydrostannolysis with tri-butyltin hydride (Scheme 7.4). It thus provides orthogonal protection without the need to expose the peptide to acid, conditions that would cleave, for example, O-gly-coside derivatives of peptides. 

Allyl chloroformate was used to protect both the phenolic hydroxyl and the amine of a series of amino acids (85-98% yield) with the aim of using a single protective group that was readily cleaved from the phenol (20% piperidine/DMF) but retained on the amine. Many of the Pd based methods discussed in the alcohol section should be applicable. 

Allyl Chloroformate Vapor-proof protective goggles and face shield, plastic or rubber gloves, shoes, and clothing, gas mask or self-contained breathing apparatus. Remove from exposure, support respiratory if necessary, call physician. Wash with large amounts of water for at least 15 minutes. If irritated by either vapor or liquid, flush with water for at least 15 minutes. 

A benzyl carbonate was prepared in 83% yield from the sodium alkoxide of glycerol and benzyl chloroformate (20°, 24 h). It was also prepared by a lipase-catalyzed ester exchange with allyl benzyl carbonate. It is cleaved by hydrogenolysis (H2/Pd-C, EtOH, 20°, 2 h, 2 atm, 76% yield) and electrolytic reduction (—2.7 V, R4N X, DMF, 70% yield). A benzyl carbonate was used to protect the hydroxyl group in lactic acid during a peptide synthesis." ... 

The thermal rearrangement of O-allyl trichloroacetimidates 1 affords the corresponding 7V-allyl amides 31 2, which have been cyclized with the aim of obtaining amino diols or amino alcohols different to those from the cyclization of the trichloroacetimidates. Cyclization of these latter substrates 1 leads to 4,5-dihydro-4-(l-iodoalkyl)oxazoles 2, while treatment of unsaturated trichloroacetamides 3 with /V-iodosuccinimide3 in chloroform affords the corresponding 4,5-dihydro-5-(l-iodoalkyl)oxazoles 4 in high yield. These heterocyclic products are protected forms of the corresponding amino alcohols. 

Acid-catalyzed addition of aliphatic, aromatic or heteroaromatic cyanohydrins to ethyl vinyl ether, n-butyl vinyl ether or dihydro-4//-pyran provides base stable, protected cyanohydrin derivatives. Phase transfer catalyzed alkylation of aliphatic cyanohydrins with allylic bromides gave a-substituted a-allyl-oxyacetonitrile. Carbonyl compounds react wiA cyanide under phase transfer catalysis to give cyanohydrin anions, which are trapped by an acyl chloride or ethyl chloroformate to give acyl- or alkoxycarbonyl-protected cyanohydrins respectively. The reduction of the carbonyl group of an acyl cyanide by NaBH4 under phase transfer conditions followed by esterification serves as an alternative route to aldehyde-derived cyanohydrin esters. ... 

The doubly protected substrates are readily prepared by addition of ally) chloroformate on the amino function, followed by esterification of the carboxylic acid with the appropriate substituted allylic bromide in the presence of DBU. 

The 0-protection of A -protected amino acids 55 was achieved by decarboxylative esterification in solvent-free conditions by Colacino et al. (Scheme 4.13). It was found that the use of planetary ball mill was more effective than vibratory mill [8], Commonly used 0-activation reagents (diaUcyl dicarbonate (B0C2O), carbonate (A, A -disuccinimidyl carbonate, DSC), and alkyl chloroformates (ROCOCl, R=Bn, Et, allyl)) were employed in combination with DMAP as base. Reaction parameters had to be optimized for each individual reagent to achieve acceptable yields (selection of results. Table 4.3). Due to high reactivity of benzyloxy chloroformate (Z-Cl), the two-step cycled milling was executed by addition of Z-Cl in 2equiv. portions, so as to consume the chloroformate and reduce the formation of the undesired byproducts. Acidic workup with 10% aqueous citric acid of ether extracts eliminates DMAP and affords the A-protected amino ester derivatives 56 in good yields. 

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