Phthalimide anion

Electrostatic potential map for phthalimide anion shows most negatively-charged regions (in red) and less negatively-chaiged regions (in blue). 

The two-step procedure includes formation of a N-substituted phthalimide 3, and its subsequent cleavage to the primary amine 5. Phthalimide (which can be obtained from reaction of phthalic acid with ammonia) shows NH-acidity, since the negative charge of the phthalimide anion (the conjugated base) is stabilized... 

Pi peridinobenzimidazole also serves as starting material for the antipsychotic agent halopemide (69). In the absence of a specific reference, one may speculate that the first step involves alkylation with bromochloro-ethane to give halide The chlorine may then be converted to the primary amine by any of several methods such as reaction with phthalimide anion followed by hydrazinolysis. Acylation with j -fluorobenzoyl chloride then gives the desired product. 

The mechanism presumably involves initial oxidative addition of the alkenyl halide to the Cu(I) species and ensuing cyclization analogy for this type of process is provided by the Cu(I)-mediated reaction of phthalimide anions with alkenyl and aryl halides.40 The -isomer of 15 reacts in a different fashion to give an isothiazolidinone derivative, albeit in low yield. 

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. 

V - Phcny I sc Icncn oph th a I i m i dc is an excellent reagent for this process and permits the formation of large-ring lactones.74 75 The advantage of the reagent in this particular application is the low nucleophilicity of the phthalimide anion, which does not compete with the remote internal nucleophile. 

Where there are two carbonyl groups to stabilize the amide anion, as in the l,2-benzenedicarboximide (phthalimide) anion (Section 18-IOC), the acidity increases markedly and imides can be converted to their conjugate bases with concentrated aqueous hydroxide ion. We have seen how imide salts can be used for the synthesis of primary amines (Gabriel synthesis, Section 23-9D and Table 23-6). 

A PET reaction between excess phthalimide (in equilibrium with its conjugate base) and an alkene led to a clean phthalimidation of nonactivated double bonds. Here, the singlet excited state of phthalimide acts as the oxidant and a radical ion pair is formed. The olefin cation radical is trapped by the phthalimide anion, and back electron transfer, followed by protonation, affords the photoaddition products [40], Protected phenethylamines are readily accessible in this way. This reaction has been carried out by using NaOH as the base it has been shown that the amounts (usually equimolar with the alkene) must be carefully chosen in order to avoid the undesired competition with [2 + 2] photocycloaddition. 

In addition, the phthalimide anion undergoes photoaddition with a wide variety of alkenes, providing a preparative method for the synthesis of [2]benzazepine-1,5-diones via a [2 + 2] cycloaddition followed by a thermal ring expansion (Scheme 9.46) [79]. 

Suau, R., Sanchez-Sanchez, C., Garcia-Segura, R., and Perez-Inestrosa, E. (2002) Photocycloaddition of phthalimide anion to alkenes. A highly efficient, convergent method for [2]benzazepme synthesis. European Journal of Organic Chemistry, 1903-1911. 

The second approach for the nucleophilic animation reactions to be considered here will be reactions of allyl halides and allyl acetates leading to allyl amines. Allyl halides are normally very reactive in SN2 reactions, but the direct coupling of allyl halides with nitrogen nucleophiles has been performed with limited success [4], as di- and trialkylated by products often predominate. The application of the Gabriel synthesis can to a certain extent eliminate the problem with polyalkylation of amines using, e.g., the stabilized phthalimide anion 19 as the nucleophile. The allyl amine 20... 

The resulting phthalimide anion is a good nucleophile in the S 2 reaction. 

In 1887, Siegmund Gabriel (at the University of Berlin) developed the Gabriel amine synthesis for making primary amines without danger of over-alkylation. He used the phthalimide anion as a protected form of ammonia that cannot alkylate more than once. Phthalimide has one acidic N—H proton (pKa 8.3) that is abstracted by potassium hydroxide to give the phthalimide anion. 

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. 

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

Also, reaction of an alkyl halide with phthalimide anion, followed by hydrolysis, gives a primary amine (Gabriel amine synthesis). 

Another method of hydroxyselenenation involves trapping the seleniranium ion by water. The use of N-phenyl eleno-succinimide (N-PSS) or -phthalimide (N-PSP) as the selenium electrophile facilitates the reaction, since the sucdnimide or phthalimide anion is not as nucleophilic as water. With dienes, trans-annular cyclizations can occur, forming bis(phenylseleno) ethers in good yields (equation 22). ... 

As an equivalent of ammonia or a primary amine, either the phthalimide anion (crown ether complex or tetrabutylammonium salt) and jV-methyl-4-methylbenzenesulfonamide were used in the addition to allylic tertiary amines40. The addition was unsuccessful for 1,2-disub-stituted double bonds. When two stereogenic centers were formed the relative stereochemistry was not determined, e.g., formation of 1. 

In contrast, nucleophiles react with the cations quite easily. The isomeric halides [HalCgHsFeCsHsJ+BF,- (Ilal is F, or Cl) and [C HeFeC5H4Cl]+ BF4 readily exchanged their halogens for nucleophiles such as AlkO, ArO , AlkS, ArS , NHj", NHR , CN, and phthalimide anion 346-349). 

Attempts at nucleophilic substitution of 20-halogeno-substituents in the halogenohydrins (28) were uniformly unsuccessful, even with ammonia or phthalimide anion. Oxiran ring-closure occurred in all cases. 

The Gabriel synthesis is a classical but still useful procedure for the preparation of primary amines. The method consists of alkylation of phthalimide anion with an appropriate alkylating reagent and subsequent removal of the phthaloyl group to generate primary amines (Scheme 36). ... 

Alkylation of phthalimide anion can be carried out under solid-liquid phase-transfer conditions, using phosphonium salts or ammonium salts. In the reaction systems using hexadecyltributylphosphonium bromide, alkyl bromides and alkyl methanesulfonate are more reactive than alkyl chlorides. Octyl iodide is less reactive than the corresponding bromide and chloride. ( )-2-Octyl methanesulfonate was converted into (S)-2-octylamine with 92.5% inversion. Kinetic resolution of racemic ethyl 2-bromopro-pionate by the use of a chiral quaternary ammonium salt catalyst has been reported. Under liquid-liquid phase-transfer conditions, A -alkylation of phthalimide has been reported to give poor results. ... 

N-Phenylselenophthalimide (N-PSP) is a particularly excellent reagent for the cyclofunctionalization, because the low nucleophilicity of the phthalimide anion results in selective attack by these internal nucleophiles at the seleniranium ion intermediates (Scheme 15.34) [96]. Similarly, phenylselenenyl triflate (PhSeOTf) [97] and sulfate (PhSeOSOs") [98] work as efficient electrophilic reagents toward unsaturated bonds. 

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