Phthalimidomethyl derivatives

Phthalimide 233 Ill (i) Hot aniline gives phthal-anil, 205. (ii) Gives the fluorescein and phthalein reactions. (Pages 54, 55.) (iii) Phthalimidomethyl derivative, 144. ... 

The derivatives are indicated as methyl esters (OMe) water-soluble carbodiimide adducts (WSC), etc., where the subscript indicates the established stoichiometry, moles of modifying function per mole of protein. Phth stands for phthalimidomethyl and NR stands for not reported. 

The Mannich reaction is readily applied to isatins. The products of this reaction, the N-aminomethylisatins (Mannich bases), can also be obtained from the A -hydroxymethyl derivatives by reaction with an amine95 or by reaction with acetyl chloride to yield N-chloromethylisatin which can be further treated with potassium phthalimide or alcohols to give the corresponding A-phthalimidomethyl or TV-alkoxymethyl isatins96. The Mannich reaction can also be performed with isatin derivatives, such as isatin-3-hydrazones97 and isatin-3-thiosemicarbazones98. 

The reaction may also be carried out with tertiary phosphines (e.g., triethyl and triphenyl phosphine 265, Fig. 101) on cither the free or the iodomcthylated Mannich base, thus producing the corresponding phosphonium salt. The phthalimidomethyl triphenyl phosphonium salt 266 is a pertinent example of this kind of derivative. 

Phthalimidomethyl-substituted 477-pyrido[4,3-( ]-l-thia-2,4-diazine 1,1-dioxide derivative 125 undergoes hydrazino-lysis to produce the (7-3-aminomethyl-substituted product, which is then acylated to yield the amido adducts 126 (R = H, Ph R =Ar, NHAr) as potential cholecystokinin/gastric receptor ligands (Equation 17) <1997BSB781>. Similar acylation chemistry has been applied to the synthesis of related 5-(methylamides) of 2/7-benzo-l-thia-2,4-diazine 1,1-dioxides (see Section 9.05.9.1.3) <2001CHE237>. 

More recently, 5-phthalimidomethyl xanthates derived from various amino acids have been added to various unactivated alkenes [12]. In particular, ornithine- and phenylalanine-derived xanthates, such as 9, added effectively to 3-cyanoindole and f-butyl 3-indolecarboxylate (8) in the presence of stoichiometric amounts of dOauroyl peroxide (DLP) to give the disubstituted indole 10 in 87% yield. Miranda also utilized this methodology recently to S5mthesize C-2-alkylated tryptamine derivatives en route to azepino[4,5-6]indoles [13]. 

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