Benzyl derivatives Carbamates

Benzyl carbamates substituted with one or more halogens are much more stable to acidic hydrolysis than are the unsubstituted benzyl carbamates.For example, the 2,4-dichlorobenzyl carbamate is 80 times more stable to acid than is the simple benzyl derivative. Halobenzyl carbamates can also be cleaved by hydrogenolysis with Pd-C. The following halobeni yl carbamates have been found to be useful when increased acid stability is required. 

Japanese chemists (96) have reported the chemical conversion of kobusine into the chloramine (95). The latter was treated with sodium methoxide in methanol to afford compound 96 in which the bridged C-14-C-20 bond was cleaved. Reduction of kobusine with sodium in n-propanol, followed by acetylation afforded compound 88. Treatment of 88 with excess phenyl chloroformate in refluxing o-dichlorobenzene gave the carbamate 89. The latter was hydrogenated over Pd-C in methanol to obtain compound 90 in 94% yield. Further hydrogenation of 90 in the presence of platinum in acidic solution gave 91. Acidic hydrolysis of 91 afforded compound 92. The carbamate 92 was converted to the benzyl derivative 93 by treating with... 

Aminopyridine is reported to react vigorously with chlorosulfonyl isocyanate at 0°C producing an urea intermediate (12) which in the presence of diisopropylethylamine was shown to yield pyrido[l,2-i][l,2,4,6]thiatriazine-5(6/0 OIte-l l-dioxide (2) (Scheme 3) <79H(6)815>. Its V-benzyl derivative (3) was selectively prepared by the reaction of 2-benzylaminopyridine (13) with either chlorosulfonyl isocyanate via intermediate (15) or pentachlorophenyl chlorosulfonyl carbamate (PCPCSC) in the presence of diisopropylethylamine via intermediate (14) (Scheme 4) <86H(8)2255>. The reaction of 2-alkyl-2-chlorosulfonyl carbamoyl chlorides with 2-aminopyridine resulted in 2-alkylpyrido [l,2-i ][ 1,2,4,6]thiatriazine-3(2/0-one-1,1-dioxides (5) (Equation (2)) <77CR(S)238>. 

The following carbamates have seen little use since the preparation of the first edition of this book they are listed here for completeness. For the most part, they are variations of the BOC and benzyl carbamates, with the exception of the azo derivatives, which are highly colored. The differences between them are largely in the strength of the acid required for their cleavage. 

In 2004, Alterman et al. used a microwave-assisted Ullmann-type protocol for the synthesis of N-(f-butyl)-3-[4-(lH-imidazol-l-yl)benzyl]-5-isobutylthiophene-2-sulfonamide (Scheme 106) [61]. Deprotection of the sulfonamide followed by carbamate formation via reaction with butyl chloro-formate finally gave the target compound for biological evaluation as selective angiotensin II AT2 receptor agonist. The IH-imidazole derivative, however, showed only a low affinity for the AT2 receptor (Ki value > 10 p,M). 

These amino acids were initially synthesized by asymmetric aminomethylation of optically pure (R)- and (S)-N-Acyl-4-phenyhnethyl)oxazolidin-2-ones 52 through TiCVenolates (Evans methodology [135]) with (benzoylamino)methylchloride or benzyl N-(methoxymethyl)carbamate [66, 97-99, 104]. Hydrolytic removal of the auxiliary yielded the N-protected (benzoyl or Z) amino acid 54. Deprotection afforded the free amino acid which was converted to the required Boc- or Fmoc-pro-tected derivatives (Scheme 2.7). 

Okawara et al. reported the photodissociation of several carbamate derivatives on the basis of the product analysis [166]. They demonstrated that the cleavage bonds were different corresponding to the number of the methylene groups in Eq. (43). When n was unity, the reactive benzyl radical and less-reactive thiyl radical were produced. 

The analogous reaction of benzyl and butyl naphthylcarbamates and of benzyl phenylcarbamates has been carried out in good yield under both liquiddiquid and solidrliquid two-phase conditions, using benzyltriethylammonium chloride as the catalyst [16, 17]. A similarly catalysed /V-alkylation of the ethyl carbamic esters derived from 1,2-diaminobenzene is reported [17] to lead to the formation of 1,3-dialkylbenzimidazol-3-ones (Scheme 5.7). 

A versatile activating group for the removal of a-protons that are not benzylic is the carbamate fert-butoxycarbonyl, or t-Boc group, developed for this purpose by Beak and Lee in 1989. Its utility derives from the fact that the Boc group is easy to attach to a secondary amine, and easy to remove after a deprotonation/alkylation sequence. Moreover, stannylation affords a-amino-organostannanes that are themselves useful precursors of a-amino-organolithium compounds (Scheme 29) (see Section II). In a chiral pyrrolidine system, it has been shown that both deprotonation (H Li) and methylation (Li Me) occur with retention of configuration. 

Scheme 37a illustrates a carbamate substrate that has three possible sites for deprotonation the benzylic sites a to either nitrogen or oxygen and the methylene attached to nitrogen. Of these three, the site least likely to deprotonate is the latter. Scheme 37b shows that this organolithinm, inaccessible by deprotonation, can be made readily by tin-lithium exchange. The derived organolithinm compound can be added to electrophiles snch as cyclohexanone in good yields. 

Only few types of benzyUithium compounds being configurationally stable in solution at —78°C are known lithium-TMEDA complexes of secondary 0-benzyl Af,Af-dialkyl carbamates, such as 211 or the 2,4,6-triisopropylbenzoate 212 ° , of secondary N-aryl-Af-Boc-benzylamines (213) and the dUithio-(—)-sparteine derivative 214 . ... 

Initially, the allylation reaction was studied with the /V-benzyloxycarbonylamino sulfone derived from benzaldehyde and benzoyloxycarbonyl (Cbz) carbamate (Scheme 1, R1 = Ph, R = Bn). Various catalysts were screened for the allylation of benzyl phenyl(phenylsulfonyl)methylcarbamate la with allyltrimethylsilane in dichloromethane (Table 1). Among the various Bi catalysts tested, Bi(OTf)3 4H20 was shown to be the most efficient (Table 1, entry 5). BiCl3, BiBr3, Bi(OAc)3, or Bi(OCOCF3)3 did not allow the reaction to proceed and starting material was... 

Optimization of the previously reported Mannich-type reaction of trimethyl (pent-2-en-3-yloxy)silane with the sulfone Is derived from phenyl acetaldehyde (Table 5, entry 11) led to the corresponding (3-amino ketone in a good yield with moderate diastereoselectivity (2 mol% Bi(0Tf)3-4H20, yield = 84%, 24v/24v syn/anti = 72 28) (Scheme 8). Reduction of the major diastereoisomer 24v with lithium tri-ferf-butoxyaluminohydride afforded 25 as the only one diastereoisomer. Further cyclization of the latter with NaH afforded 4-benzyl-6-ethyl-5-methyl-l,3-oxazinan-2-one 26. The relative configuration of the six-membered carbamate was established as cis-cis by NMR analysis. 

The condensation of an aldehyde, benzyl carbamate, and triphenyl phosphite, first described by Oleksyszyn et al., 25,26 affords a direct route to a-aminoalkylphosphonates 4 that are conveniently protected for subsequent reactions (Scheme 4). Since dealkylation of the quaternary phosphonium intermediate 3 is not possible in this case, formation of the pen-tavalent product 4 presumably involves activation of the solvent and formation of phenyl acetate. This method is useful for the synthesis of aliphatic and aromatic amino acid analogues. However, monomers with more elaborate side chains are often incompatible with the reaction conditions. The free amine can be liberated by treatment with HBr/AcOH or by hydrogenolysis after removal of the phenyl esters. The phosphonate moiety can be manipulated by ready exchange of the phenyl esters in alkaline MeOH and activation as described in Section 10.10.2.1.1. Related condensations with other trivalent phosphite derivatives have been reported. 27-30 ... 

The y-amino-p-hydroxy acid derived oxazolidinones 55 are prepared from the corresponding N-unprotected y-amino-p-hydroxy ester derivatives by reaction with phosgene,1119,391 carbonyl diimidazole,[41] or benzyl chloroformate.[86] Alternatively, cyclization is obtained from the N-carbamate protected derivatives, i.e. from the TV-isopropenyloxycarbonyl derivatives under heating,[381 or from the TV-Boc or N-Z derivatives under basic conditions. [68 81 87] By analogy, the p,y-diamino acid analogue is converted into the imidazolidinone 57 by treatment of the unprotected compound with phosgene.[83 88]... 

The rapid microwave-assisted deprotection of N-benzyl carbamate (Cbz) and AT-benzyl (Bn) derivatives in solution as well as on solid support was reported by Daga et al.26 Within this report, amino groups protected as benzyl carbamates or with simple benzyl groups could be deprotected in a few minutes by microwave-assisted catalytic transfer hydrogenation with palladium charcoal in isopropanol, employing ammonium formate as the hydrogen donor (Scheme 7.6). Both MeO-PEG and PS Wang-resin were used as soluble and solid supports, respectively, in these reactions. 

Table 17), but cyclization of -substituted carbamates is highly selective (entries 2,4 and 5), presumably by insuring reversible formation of the intermediate prior to benzyl cleavage and steric interactions between the -substituent and the alkyl substituent favoring the axial orientation (equation 61). Cycliza-tions of this type, where R = H and Y = a-phenethyl, result in little asymmetric induction. However, the diastereomeric products can be separated and used for the synthesis of chiral nonracemic amino alcohol derivatives.164... 

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