Displacement phthalimide

Azide ions are by far the most common nucleophilic species employed in substitution reactions for the preparation of amino sugars. An azido moiety is stable under many reaction conditions but can be reduced to an amino group by a variety of reagents. The nucleophilicity of azido ions can be increased by the addition of a suitable crown ether to complex the counterion.36c,63b In the past, ammonia and hydrazine were used as nucleophiles to overcome unfavourable dipolar interactions that arise when charged nucleophiles were used. However, a drawback of the use of these nucleophiles is that the product is still nucleophilic and can perform a second displacement. Phthalimide ions have successfully been applied in displacement reactions to yield a protected amino sugar derivative.58 63f... 

I itro-DisplacementPolymerization. The facile nucleophilic displacement of a nitro group on a phthalimide by an oxyanion has been used to prepare polyetherimides by heating bisphenoxides with bisnitrophthalimides (91). For example with 4,4 -dinitro monomers, a polymer with the Ultem backbone is prepared as follows (92). Because of the high reactivity of the nitro phthalimides, the polymerkation can be carried out at temperatures below 75°C. Relative reactivities are nitro compounds over halogens, Ai-aryl imides over A/-alkyl imides, and 3-substituents over 4-substituents. Solvents are usually dipolar aprotic Hquids such as dimethyl sulfoxide, and sometimes an aromatic Hquid is used, in addition. 

Propenylphenoxy compounds have attracted much research. BMI—propenylphenoxy copolymer properties can be tailored through modification of the backbone chemistry of the propenylphenoxy comonomer. Epoxy resins may react with propenylphenol (47,48) to provide functionalized epoxies that may be low or high molecular weight, Hquid or soHd, depending on the epoxy resin employed. Bis[3-(2-propenylphenoxy)phthalimides] have been synthesized from bis(3-rutrophthalimides) and o-propenylphenol sodium involving a nucleophilic nitro displacement reaction (49). They copolymerize with bismaleimide via Diels-Alder and provide temperature-resistant networks. 

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

A similar sequence that takes place under milder conditions uses 4-nitrophthalimides as the protecting group and /V-melhylhydrazine for deprotection.234 Reduction by NaBH4 in aqueous ethanol is an alternative method for deprotection of phthalimides. This reaction involves formation of an o-hydroxybenzamide in the reduction step. Intramolecular displacement of the amino group follows.235... 

The most successful approach to producing an aminomethyl derivative was the Gabriel synthesis. A phthalimide substituent can be introduced by Sn2 displacement of the chloride on 17 with potassium phthalimide under homogeneous conditions in DMF. The reaction is quantitative in all D.F. ranges and the phthalimldo-methyl intermediates, 18, are quite soluble in organic solvents. 

There are examples of nucleophilic displacement of halide from halo-1,2,5-thiadiazoles by ammonia, primary alkylamines, secondary alkylamines, arylamines, sulfonamides, and phthalimide <1984CHEC(6)513, 1996CHEC-II(4)355>, but the reactions often require high temperatures and excess of the nucleophile. 

Of particular interest was the reaction of two equivalents of potassium phthalimide with PFB using 18-crown-6 in refluxing acetonitrile. This reaction with either small molecules or the polymeric analogs represents a novel approach to arylimide synthesis via PTC. After 4 hr. under nonoptimized PTC reaction conditions, disubstitution afforded the bisimide 6 in ca. 50% yield. This shows that phthalimide anion, a considerably poorer nucleophile than either the phenoxide or thiophenoxide, is a strong enough nucleophile in the presence of 18-crown-6 to displace aryl fluoride with facility, and demonstrates that the synthesis of polyimides, an important class of thermally stable polymers, is feasible by this PTC polycondensation route. 

By selection of an appropriate derivative the hydroxyl group can become activated towards displacement (via an 8 2 exchange process) with a suitably chosen nucleophile. Conversion to the sulfonate ester (SO2R) [115] promotes displacement by either an acetate ( OAc) (sequence Dl) or phthalimide nucleophile (Sequence D2), whilst the trimethylsilyl derivative facilitates introduction of fluorine (Sequence E) [116]. 

A detailed study of the conversion of 3,4-dichloro-l,2,5-thiadiazole into 3,4-diamino-l,2,5-thia-diazole has been carried out <76JHC13>. Reaction with lithium or sodium amide produces only 4% of the diamine together with cyano-containing by-products, a consequence of direct attack on sulfur. Use of a less powerful nucleophile, ammonia or potassium phthalimide, resulted in an increased attack on carbon and produced the diamine in 24% and 66% yields, respectively. Secondary amines, e.g. morpholine <76JOC3l2l> and dimethylamine <72JMC315>, produce the normal displacement products. The reaction of dichlorothiadiazole with potassium fluoride in sulfolane gives a mixture of 3-chloro-4-fluoro and 3,4-difluoro-l,2,5-thiadiazole <82CB2135>. 

The synthesis of the benzazepinone portion of benazepril began with monobromination of 1-tetralone (35), followed by oxime formation to give 36 (Scheme 10.9). A Beckmann rearrangement mediated by polyphosphoric acid provided the ring-expanded lactam 37. Displacement of the a-bromine with potassium phthalimide installed the necessary... 

The preparation of a trisulfide bridge between two different linear peptides is outlined in Scheme 3. In a first step, the free thiol of one peptide forms an activated mixed disulfide by reaction with TV,A1 -1hiobisphthalimide, and upon the subsequent addition of the second cysteine peptide, nucleophilic displacement of the phthalimide moiety by the free thiol yields the desired interchain trisulfide bridged peptide 3.1 3 Homodimeric analogues, e.g. 4, are prepared similarly.[13]... 

The majority of transformations carried out at ring substituents of bicyclic azetidinones were described in Section 5.12.3.3.2 for azetidinones related to cephalosporins and penicillins. Nucleophilic displacement reactions of 7-halo-l-azabicyclo[4.2.0]octan-8-ones with thallium phthalimide and hydrazine have been reported (76ACS(B)318). 

Various nucleophilic attacks at C(3) and C(4) of -lactams have been employed to introduce desired functionalities. Nucleophilic displacement of a halogen at C(3) by nucleophiles, for example, potassium phthalimide, has been performed (93JCS(Pl)2357). The a-azidation of l-hydroxy-2-azetidi-nones, for example (37), with arenesulfonyl azides in the presence of triethylamine affords 3-azido-2-azetidinones (38) via Otosylation and SN2 -type of displacement of the tosyloxy group (92JA2741, 93JA548, 93BMC2429). 

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 ... 

Carbon-Nitrogen Bonds. Several groups have studied the synthesis of optically active a-amino acids from inexpensive and readily available a-haloesters by displacement with phthalimide in the presence of chiral cinchona catalysts [1 le,24h,24i,47e,60d,77]. Early studies, with chiral, non-racemic starting material, showed that this reaction occurs with partial... 

The phthalimide anion is a strong nucleophile, displacing a halide or tosylate ion from a good Sn2 substrate. Heating the /V-alkyl phthalimide with hydrazine displaces the primary amine, giving the very stable hydrazide of phthalimide. 

Synthesis of primary amines by alkylation of the potassium salt of phthalimide, followed by displacement of the amine by hydrazine, (p. 922)... 

Table 8. Phthalimide Anion Displacement Reactions with 2-(2-Bromoacyl)-2-ethyl-1,3-dithiane 1-Oxide Substrates...

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