Deprotection with hydrazine

Amino-6-methyl-1,6-naphthyridin-5(6//)-one (17) with (V-(4-iodopentyl) phthalimide gave 6-methyl-8-(l-methyl-4-phthalimidobutyl)amino-l,6-naphthyridin-5(6//)-one (18, R = phthalimido) (substrate, Me2NCHO, 80°C, A, synthon + NEt3 in during 4 h 85°C, 2 h 45%) and thence, by deprotection with hydrazine, 8-(4-amino-l-methylbutyl)amino-6-methyl-l,6-naphthyridin-5(6//)-one (18, R = NH2).1116... 

Certain functionalised esters combine the virtues of acyl protection (ease of introduction, electronic deactivation, lability to base) with the ability to be deprotected under specialised conditions that leave other esters unaffected. Of these, the only example that has seen reasonably widespread application is the levulinate (Lev) derivative which, in chemistry that parallels the cleavage of ClAc derivatives with soft nucleophiles, are cleavable by conversion of the comparitively reactive ketone functionality into a nucleophilic entity that can cyclise onto the ester carbonyl releasing the protected hydroxyl. The example in Figure 2.45 shows that the acetates survive unscathed in Lev deprotection with hydrazine so that only the 2-OH is released [63]. 

The polymer-bound p-nitrobenzophenone oxime (71d) has been found to be a suitable support for stepwise peptide synthesis. Protected peptides can be assembled on 70d by coupling and deprotection steps similar to those employed in the usual Merrifield solid-phase procedures (Scheme 39). Cleavage of peptides from 71d can be accomplished with hydrazine and amino acid esters under mild conditions, which do not affect benzyl ester side-chain protecting groups. 

Phthalimide protection is stable towards acids and bases, but can be cleaved with strong nucleophiles, such as hydrazines or sulfides, or by reduction with sodium boro-hydride [230]. More sensitive towards nucleophilic attack than unsubstituted phthalimide is tetrachlorophthalimide [33]. This group has been successfully used as N(a) protection of amino acids in the solid-phase synthesis of peptides (deprotection N2H4/DMF (15 85), 40 °C, 1 h coupling DIC/HOAt/amino acid (1 1 1), 3 equiv. of each, DMF, 25 °C, 4 h [294]). Typical conditions for the removal of phthaloyl protection on cross-linked polystyrene include treatment of the resin with hydrazine hydrate [295,296], with methyl hydrazine [297], or with primary aliphatic amines [298] in DMF, EtOH, or solvent mixtures for several hours at room temperature or above [296,299,300]. Illustrative examples are sketched in Figure 10.15. It has been claimed that the hydrazinolysis of polystyrene-bound phthalimides proceeds more readily in DCM or DCE than in DMF [301]. 

These may be prepared from a primary amine by reaction with phthalic anhydride. The general procedure described in Section 9.6.21, p. 1276 uses glacial acetic acid reaction conditions using chloroform as the solvent medium have been reported.235 Deprotection using hydrazine is described in Expt 5.198. 

In the synthesis of the glycolipid asialo GMI described by Ogawa and co-workers [107] the trisaccharide derivative (215) (used in the synthesis of asialo GM2) was converted into the 4,6-O-benzylidene derivative (233) and this was condensed with aceto-bromogalactose in the presence of mercury(II) cyanide and molecular sieves to give the P-linked acetylated galactose derivative in 97 % yield. The product was deprotected and acetylated to give the peracetyl derivative (234) of the tetrasaccharide which was converted into the free sugar (235) with hydrazine hydrate. Compound (235) was converted into asialo GMI via the imidate as described above for the synthesis of asialo GM2 from the imidate (219). 

Eschenmoser s pyrone 38 on treatment with cyclopropenone ketal 39 in refluxing benzene afforded lactone 40 (73%). Lactone 40 on hydrolysis with acetic acid at 100°C afforded, after deprotection and decarboxylation, tropone 37 (70%). Introduction of the tropolonic hydroxyl group was achieved with hydrazine hydrate in ethanol, to give a mixture of deacetyl-colchiceinamides 41 (53%) and 42 (37%), followed by reaction with ethano-lic potassium hydroxide, which afforded tropolones 43 and 44, respectively. Tropolone 43 was converted to 44 which, therefore, became the major reaction product. Methylation of 44 gave a mixture of enol ether 18 and 45 which were separated by chromatography. 

We have already seen various syntheses of SMA phthalimides, either through nucleophilic animation of a-chlorosilanes (see Sections III.A.l and III.A.2), hydro-silylation of A-vinyl phthalimide (see Section III.B.5.f) or by reaction of SMA with phthalic anhydride (see Section IV.A.2.h). The deprotection and recovery of free SMA has been conducted in the usual way by reaction with hydrazine.81,88,211... 

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