Phthalimide hydrolysis

Two diphenylaminophthalides have been synthesized The 3,3-diphenyl-6-aminophthalide [24] was synthesized in 20% yield by the following sequence of reactions which was patterned after early work °. This series involved nitration of phthalimide, hydrolysis and dehydration to 4-nitrophthalic anhydride, Friedel-Crafts reaction with benzene to 2-benzoyl-5-nitrobenzoic acid, cyclization with thionyl chloride to the pseudoacid chloride, Friedel-Crafts reactions with benzene, and, finally reduction of the nitro group to the amino function with Adams catalyst. 

They are formed by heating dibasic acids or their anhydrides with ammonia. The hydrogen atom of the NH group is acidic and can be replaced by a metal. Mild hydrolysis breaks the ring to give the half amide of the acid. See succinimide and phthalimide. 

Anthranilic acid. This substance, the ortho amino derivative of benzoic acid, may be conveniently prepared by the action of sodium hypobromite (or sodium hypochlorite) solution upon phthalimide in alkaline solution at 80°. The ring in phthalimide is opened by hydrolysis to phthalamidic acid and the latter undergoes the Hofmann reaction (compare Section 111,116) ... 

Alkylation of phthalimide The Gabriel synthesis (Section 22 8) The potassium salt of phthalimide reacts with alkyl hal ides to give N alkylphthalimide deriva fives Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine... 

A less obvious scheme that can lead to a bell-shaped curve has been recognized by Zemer and Bender. The substrate is a weak acid or base, but possesses only one ionizable group, and no other ionizable reactant is involved (other than water). The second inflection in the curve is ascribed to an ionizable group created in an intermediate. An example has been discovered in the hydrolysis of o-carboxy-phthalimide ... 

Analogous, but slightly different, is the treatment of the acid-base equilibria and the basic hydrolysis rates of the phthalimids (19). In both of these cases, the two paths to the reaction site are equivalent, hence pi and po of Eq. (3) are equal, and the equation reduces to ... 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Gabriel amine synthesis (Section 24.6) A method for preparing an amine by SN2 reaction of an alkyl halide with potassium phthalimide. followed by hydrolysis. 

Bromoethylamine hydrobromide has been prepared by the reaction of potassium phthalimide with ethylene bromide, followed by hydrolysis,1 by the addition of hydrogen bromide to ethyleneimine,2 and by the present method.3... 

It is obvious that the primary amines formed in this reaction will be uncontaminated by secondary or tertiary amines (unlike 10-44). The reaction is usually rather slow but can be conveniently speeded by the use of a dipolar aprotic solvent such as DMF or with a crown ether. Hydrolysis of the phthalimide, whether acid or base catalyzed (acid catalysis is used far more frequently), is also usually very slow, and better procedures are generally used. A common one is the Ing-Manske procedure,in which the phthalimide is heated with hydrazine in an exchange... 

On the other hand, the reaction of 3-,sec-aminophenols (71) with phthalic anhydride does not give the corresponding keto acids (72). The keto acids (72) having a secondary amino group at 4-position are prepared by the reaction of 3-sec-aminophenols (71) with phthalimide at 150-220°C in the presence of boric acid, followed by hydrolysis of the intermediate carboxamide with aqueous sodium hydroxide (Eq. 3). 

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

Indeed, the choice of a nitrogen compound to be used as carrier in such O-alkyl prodrugs is not restricted to benzamides. Other amides were examined, e.g., phthalimide, succinimide, and saccharin. Thus, the saccharin prodrug of estradiol (11.50, R = 17/J-estradiol) underwent rapid nonenzymatic hydrolysis in rat and human plasma [85]. Administration of the prodrug to rats led to an impressive fivefold increase in the oral bioavailability of estradiol, and it was approximately nine times more potent orally, based on the 50% effective dose. 

In addition, desulfonation generally has to be taken into account with benzamides and phthalimides that are sulfonated at the amine subunit. The sulfonamide linkage proved to be stable with sulfonated and nonsul-fonated sulfonamides. Compounds with electron-withdrawing substituents at the sulfonic acid-bearing ring were more stable with respect to the hydrolysis of sulfonic acid groups. 

Gabriel s synthesis org chem A synthesis of primary amines by the hydrolysis of n-alkylphthallmldes the latter are obtained from potassium phthalimide and alkyl halides. ga-bre-alz, sin-tha-sas ... 

Soil. In soils, phosmet is rapidly hydrolyzed to phthalimide (Camazano and Martin, 1980 S nchez-Camazano and S nchez-Martin, 1983). The rate of hydrolysis is greater in the presence of various montmorillonite clays and chloride salts. The calculated hydrolysis half-lives of phosmet in the presence of calcium, barium, copper, magnesium, and nickel montmorillonite clays were 0.084, 0.665, 10.025, 16.926, and 28.738 d, respectively. Similarly, the half-lives of phosmet in the presence of copper, calcium, magnesium, and barium chlorides were <0.020, 5.731, 10.680, and 12.242 d, respectively. In comparison, the hydrolysis of phosmet in a neutral water solution was 46.210 d (Sanchez-Camazano and S nchez-Martin, 1983). 

Gabriel synthesis is used for the preparation of primary amines. Phthalimide on treatment with ethanolic potassium hydroxide forms potassium salt of phthalimide which on heating with allqrl halide followed by alkaline hydrolysis produces the corresponding primary amine. Aromatic primary amines cannot be prepared by this method because aryl halides do not undergo nucleophilic substitution with the anion formed by phthalimide. 

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

It was also synthesised by E. Fischer in 1901 from 7-phthalimido-propylmalonic ester which he employed in the preparation of ornithine. The bromine derivative of this compound when treated with ammonia gave a complex mixture of products which after hydrolysis by hydrochloric acid at 100° C. gave phthalimide and a-pyrrolidine carboxylic acid —... 

Arylene ether/imide copolymers were prepared by the reaction of various amounts 4,4 -carbonylbis[Ar-(4 -hydroxyphenyl)phthalimide] and 4,4 -biphenoi with a stoichiometric portion of 4,4 -dichlorodiphenyl sulfone in the presence of potassium carbonate in NMP/CHP [55]. To obtain high molecular weight polymer, the temperature of the reaction was kept below 155 °C for several hours before heating to >155°C in an attempt to avoid undesirable side reactions such as opening of the imide ring. The imide ring is not stable to conditions of normal aromatic nucleophilic polymerizations unless extreme care is exercised to remove water. Special conditions must be used to avoid hydrolysis of the imide as previously mentioned in the section on Other PAE Containing Heterocyclic Units and as practiced in the synthesis of Ultem mentioned in the Historical Perspective section. 

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