Phthalimides, 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... 

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]. 

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... 

A similar metal-coordination monomer can be prepared as outlined below [4]. In this case, the primary amino groups in diethylenetriamine are first protected as their phthalimides by heating in phthalic anhydride. The secondary amine is subsequently coupled to 4VBC in the presence of potassium carbonate in acetonitrile. After deprotection of the amines with hydrazine, the functional monomer is isolated, which can be further metallated with, e.g., Cu to yield a potent metal coordinating monomer. 

The 5-(aminomethyl)thiophene-2-acetic acid isomer 76 was prepared by chloromethylation in position 2 of thiophene followed by nucleophilic displacement with phthalimide to afford 81, and a second chloromethylation in position 5 to give 82 (Scheme 23). Subsequent reaction with cyanide gave 83, the hydolysis of which afforded the phthalide-protected amino acid 84 which was coupled to H-Ala-Ile-Gly-OMe using propanephosphoric anhydride, followed by hydrazine N-deprotection)110 ... 

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