Carbamates derived from secondary alcohols

The chemoselectivity of the reaction favors insertion in the most electron-rich C—H bond available to produce an oxazolidinone (Eqs. (5.6) and (5.7)) [33, 49, 50). When a bicyclic system is formed, the C—H amination reaction leans toward the formation of the cis-isomer. The scope of the reaction is large and many examples of carbamates derived from primary and tertiary alcohols are known. The use of carbamates derived from secondary alcohols is, however, more limited to substrates having conformational bias and/or very reactive C—H bonds (benzylic and allyl-ic) [51, 52]. Otherwise the formation of the corresponding ketone is observed, probably via a hydride shift process, similar to what is observed in C—H bond insertion with metal carbene [53, 54). 

Allylsilanes are available by treatment of allyl acetates and allyl carbonates with silyl cuprates17-18, with antarafacial stereochemistry being observed for displacement of tertiary allyl acetates19. This reaction provides a useful asymmetric synthesis of allylsilanes using esters and carbamates derived from optically active secondary alcohols antarafacial stereochemistry is observed for the esters, and suprafacial stereochemistry for the carbamates20,21. 

Alkyl carbamates, derived from 2,2,4,4-tetramethyl-1,3-oxazo-lidine (R-CH2-OCby), are deprotonated by s-Butyllithium- —)-sparteine with differentiation between the enantiotopic protons (eq 5). The pro-S proton is removed with high stereoselectivity and reliability, and, subsequently, stereospecifically substituted by electrophiles with stereoretention to give enantiomerically enriched secondary alcohols (>95% ee) after deprotection, ... 

Fig. 9.8 presents another, more complex type of phosphate prodrugs, namely (phosphoryloxy)methyl carbonates and carbamates (9-26, X = O or NH, resp.) [84], Here, the [(phosphoryloxy)methyl]carbonyl carrier appears quite versatile and of potential interest to prepare prodrugs of alcohols, phenols, and amines. The cascade of reactions leading from prodrug to drug as shown in Fig. 9.8 involves three steps, namely ester hydrolysis, release of formaldehyde, and a final step of carbonate hydrolysis (X = O) or A-decar-boxylation (X = NH). Three model compounds, a secondary alcohol, a primary aliphatic amine, and a primary aromatic amine, were derivatized with the carrier moiety and examined for their rates of breakdown [84], The alcohol, indan-2-ol, yielded a carrier-linked derivative that proved relatively... 

The original discovery synthesis of the P2 domain of telaprevir utilized bicycloproline derivative 56 (Scheme 10),"° which was prepared in racemic form using a four-step, two-pot protocol starting from 2-cyclopentenone, as described by Monn and Valli." In this approach, enantiomerically pure 56 was obtained via chiral HPLC separation." Reduction of the ketone of 56 produced secondary alcohol 57, which was further reduced to 58 under Barton-McCombie deoxygenation conditions. The synthesis of P2 fragment 59 was completed by hydrogenolysis of the benzyl carbamate. 

The intramolecular C(sp )—H amination of carbamates developed by Du Bois and coworkers can be performed from substrates derived from primary, secondary, and tertiary alcohols. The reaction allows the efficient functionahzation of benzyhc, aUyHc," and tertiary C(sp )—H bonds, as well as that of secondary unactivated positions, but, to a lesser extent. Its efficiency, in specific cases, can be improved by replacing Rh2(OAc)4 with Rh2(tpa)4." An important feature is the stereospecificity of the nitrene C—H insertion that was unambiguously demonstrated to proceed with retention of configuration using a stereochemical probe prepared from (S)-2-methyl-l-butanol (Scheme 6A). 

The reactions of HN3 with cyclic alcohols to yield mixtures of ketones, amines, and products with an enlarged ring are catalyzed by H2SO4 [1]. Tertiary alcohols are converted to azides in the presence of acid [12] or TiCU [13]. Aldehydes and ketones with HN3 undergo a Schmidt-type reaction by liberating N2 and inserting NH In the presence of H or Lewis acids [14]. Ketones yield secondary amides and, in the case of cyclic ketones, lactames. Aldehydes are converted to nitriles or N-formylamines. Tetrazole derivatives result with excess HN3 [1, 15]. However, a-azido ethers are obtained from aldehydes and HN3 in the presence of alcohols by catalysis of TiC [16]. Carboxylic acids and anhydrides form amines, N2, and CO2 in Schmidt reactions with HN3. Intermediates are carbamic acids which form by insertion of NH into the R-COOH bond [1, 14]. High yields result for acids of arenes [17]. 

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