· Benzyl Chloroformate
· (MW 170.60)
(protecting agent for many functional groups, especially for the N-protection of amino acids;7 activates pyridine rings toward nucleophilic attack;53 reagent for the preparation of other benzyloxycarbonylating agents3)
Alternate Name: benzyloxycarbonyl chloride (CbzCl).
Physical Data: colorless oily liquid, bp 103 °C/20 mmHg (with slow decarboxylation to benzyl chloride at this temperature); bp 85-87 °C/7 mmHg; mp 0 °C; d (20 °C) 1.195 g cm-3; n20D 1.5190.
Form Supplied in: widely available.
Preparative Methods: CbzCl can be readily prepared by the reaction of benzyl alcohol and phosgene, either in toluene solution4 or neat.1b,5,6 Purification of such freshly prepared CbzCl is often not necessary; indeed, ca. 25% residual toluene solvent does not interfere with derivatization reactions.4
Purification: commercial CbzCl is typically better than 95% pure and is often contaminated by benzyl chloride, benzyl alcohol, toluene, and HCl.2,3 On storage it can undergo a slow HCl-catalyzed decomposition, even at low temperature.1a,3 It has been recommended1b,2 that CbzCl which has been stored for long periods be purified by flushing with a stream of dry air to remove dissolved CO2 and HCl impurities. Filtration and storage over Na2SO4 may be followed by distillation; it is important that low temperatures (oil bath <=85 °C)1b and high vacuum be used to minimize thermal decomposition.3
Handling, Storage, and Precautions: CbzCl is highly toxic and is a cancer suspect agent; it is a lachrymator with an acrid odor and should be handled with caution in a fume hood.
Protection of Amines.
The most widespread application of CbzCl is in the protection of primary and secondary amines as the corresponding benzyl carbamates. These reactions are usually performed either under Schotten-Baumann conditions,7 by using aq NaHCO3 or aq Na2CO3 as base in an organic solvent (eq 1),8 or in the presence of an organic base (typically Et3N) in CH2Cl2.9 The isolation and/or crystallization of amines is often facilitated by Cbz derivatization of the crude amine generated in another reaction.10 A wide variety of primary and secondary aliphatic amines, including aziridines,11 azetidines,12 and other sensitive7,9 and electron-deficient8c amines, can be selectively protected in the presence
of alcohol,8b,13 phenol,14 and thiol15 functionality; however, the selective protection of hindered secondary amines over secondary alcohols has proved difficult.16
The N-protection of amino acids during peptide synthesis constitutes a major application of this methodology.1,8a References to the N-protection of individual amino acids using CbzCl have been tabulated.1b,e Use of the N-Cbz protecting group generally affords crystalline amino acid derivatives and suppresses racemization at the a-stereocenter during peptide bond formation. The N-Cbz group is stable to conditions used for the formation of peptide bonds. Benzyl carbamates are highly complementary to t-butyl (i.e. Boc) carbamates in peptide synthesis (see t-Butyl Azidoformate). Schotten-Baumann conditions are most commonly employed for the preparation of N-Cbz amino acids (eq 2);1b,4 racemization at the a stereocenter is suppressed
under these basic conditions by the adjacent negatively charged carboxylate group. The use of a lower reaction temperature (-20 °C) has been shown in one case to afford a higher yield of pure N-Cbz derivative.17 One disadvantage of the standard Schotten-Baumann protocol is the need for either the simultaneous addition of CbzCl and aq NaOH, or the sequential addition of small aliquots of these reagents, throughout the course of the reaction. A modified procedure1b using NaHCO3 as the base8d avoids this inconvenience. A recent report indicates that N-Cbz derivatization of a range of a-amino acids can be conveniently achieved, albeit in only moderate yield, by refluxing with CbzCl in ethyl acetate without added base; interestingly, no racemization was observed.18
The selective protection of the o-amine in a,o-diamino acids can be achieved by chelation of the a-amino and a-carboxylate functionality by CuII ion (eq 3).1b,f,18,19 The CuII chelate can be cleaved by H2S,1f by thioacetamide,19 or by use of a chelating ion-exchange resin.17 Selective protection of the ε-amino group in lysine, the imidazole ring nitrogen in histidine, and the a-amino function in serine, can all be accomplished in homogeneous aqueous medium in the absence of added base using Cbz-imidazolium chloride, a water-soluble benzyloxycarbonylating agent which is prepared in situ from CbzCl and N-methylimidazole.20 Benzyl
succinimidyl carbonate, best prepared by reaction of the dicyclohexylammonium salt of N-hydroxysuccinimide with CbzCl,21 is also useful for the N-Cbz protection of a-amino acids without the need for added base.
The N-Cbz group is stable to a variety of weakly acidic and basic conditions.22 Benzyl carbamates are most commonly cleaved to the free amine by catalytic hydrogenolysis (H2/Pd-C)23 although a plethora of alternate reductive (e.g. transfer hydrogenolysis,24 Li/liq NH325), strongly acidic (e.g. HBr/HOAc26), and neutral conditions have been employed.1 The use of transfer hydrogenolysis (cyclohexadiene, 10% Pd-C) allows for the clean deprotection of N-Cbz pyrimidines without concomitant reduction of the 5,6-double bond that is observed under standard catalytic hydrogenolysis conditions.27 The acid stability of the N-Cbz group can be manipulated by the introduction of electron-withdrawing or
electron-donating substituents onto the phenyl ring. Selective deprotection of an N-Cbz group in the presence of an S-Cbz moiety can be achieved using HBr/HOAc at rt.28
Primary and secondary arylamines can also be N-carbamoylated using CbzCl, typically in the presence of aq Na2CO3 (eq 4)29 or pyridine.30 The protection of electron-deficient anilines can be accomplished using MgO in acetone.31 Protection of a pyrrole nitrogen can be achieved by initial deprotonation to the potassium salt.32
N-Benzyl carbamates prepared as outlined above can also serve as useful intermediates in the overall N-methylation of secondary amines, since LiAlH4 reduction of a benzyl carbamate affords the corresponding tertiary N-methylamine (eq 5).33
Other N-Protection Reactions.
The protection of an amide as its N-Cbz derivative can be achieved using CbzCl with Et3N/DMAP,34 or by initial deprotonation of the amide using BuLi or (Me3Si)2NLi.35 The N-protection of nucleosides is usually ineffective with CbzCl but can be selectively and efficiently accomplished using N-Cbz imidazolium salts generated in situ from the reaction of CbzCl with N-alkylimidazoles (eq 6).27,36
Protection of Alcohols and Phenols.
Protection of alcohols and phenols as the corresponding benzyl carbonates is typically achieved using CbzCl in the presence of an organic base (e.g. Et3N,37 pyridine38) in CH2Cl2 or ether at low temperature (-20 °C to rt). The selective protection of one secondary alcohol in the presence of other secondary and tertiary alcohols has been accomplished using DMAP at very low temperatures (-40 to -20 °C) for 3 days (eq 7).39
The use of NaH as base allows for the efficient protection of even hindered electron-deficient alcohols (eq 8).40 A secondary alcohol can be selectively protected over an indole nitrogen.41 1-O-Methylated 2-deoxyribose sugars can be protected at the 3- and 5-hydroxyl groups38 while the hemiacetal function is selectively protected over secondary alcohols in 1-unprotected sugars.42 Both alcohol-38,43 and phenol-derived44 benzyl carbonates are efficiently deprotected by catalytic hydrogenolysis; benzyl carbonates are more readily cleaved under these conditions than benzyl ethers.38 Removal of the O-Cbz group can also be achieved by electrolytic reduction.45
Protection of Thiols.
The protection of thiols using CbzCl can be achieved using Et3N as base.46 The use of aq NaHCO3 as base allows for the selective protection of the SH group in cysteine (eq 9), while N,S-bisprotection is observed under Schotten-Baumann conditions (eq 10).47 Selective protection of the cysteine SH moiety can also be achieved using Cbz-imidazolium chloride, a water-soluble benzyloxycarbonylating agent prepared in situ from CbzCl and N-methylimidazole.20 Both N- and S-Cbz groups are deprotected using refluxing CF3CO2H48 or by electrolytic reduction.45 The use of NaOMe/MeOH at rt for 5-10 min allows for the selective cleavage of S-Cbz over N-Cbz groups.28
Decarboxylative Esterification of Carboxylic Acids.
The preparation of benzyl esters from sterically uncongested carboxylic acids,49 including a-keto acids37,50 and malonic acid half esters,51 can be achieved using CbzCl in the presence of an organic base (Et3N,37,50,51 pyridine,52 or Et3N/DMAP49 in CH2Cl2 or THF). The lack of reactivity of sterically crowded carboxylic acids49 allows for the selective esterification of the less crowded of two acid moieties (eq 11).52 A major attraction of the benzyl ester group is its susceptibility to cleavage to the free carboxylic acid by catalytic hydrogenolysis1d,23 or transfer hydrogenolysis.1d
Activation of Pyridine Ring Towards Nucleophilic Attack.
Pyridine and various 4-substituted pyridines can be activated by CbzCl toward regioselective nucleophilic attack by NaBH453 and by alkyl,54 aryl,55 and alkynyl56 Grignard reagents, affording the corresponding 2-substituted 1,2-dihydropyridines (eq 12). Treatment of a 3-substituted pyridine with CbzCl and NaBH4 can afford a mixture of 1,2- and 1,4-reduction products; however, reaction with CbzCl and Red-Al proceeds via regioselective 1,2-reduction at the less crowded a-carbon (eq 13).57
Generation of Other Benzyloxycarbonylating Agents.
A variety of other benzyloxycarbonylating agents can be prepared from CbzCl.3 For example, reaction of CbzCl with sodium benzyl carbonate affords dibenzyl carbonate, a promising stable crystalline alternative to CbzCl for achieving clean and efficient N-benzyloxycarbonylation.3 N-Cbz-imidazole, prepared from CbzCl and imidazole, has proved a suitable reagent for the selective protection of primary over secondary amines.58
and 2,2,2-Trichloroethyl Chloroformate.
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