Phthalimides, preparation

The 4-nitro-A -phthalimide, prepared by heating the amine with the anhydride to 130° for 30 min, is cleaved with MeNHCH2CH2NH2 (71-92% yield). These cleavage conditions were compatible with cephalosporins, where the phthalim-ide was removed in 92% yield at —50° in 30 min. ... 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

Template reactions are those in which formation of a complex places the ligands in the correct geometry for reaction. One of the earliest was for the formation of phthalocyanines (Figure 12.17). The study of this chanistry began in 1928, after discovery of a blue impurity in phthalimide prepared by reaction of phthalic anhydride with ammonia in an enameled vessel. This impurity was later discovered to be an iron phthalocyanine complex, created from iron released into the mixture via a scratch in the enamel surface. A similar reaction takes place with copper intermediates isolated from this reaction are shown in Hgure 12.17. Phthalic acid and ammonia first form phthalimide, then l-keto-3-iminoisoindoline, and then l-amino-3-iminoisoindolenine. The cyclization reaction then occurs, probably with the assistance of the metal ion, which holds the chelated reactants in position. This is confirmed by the lack of cyclization in the absence of the metals. The essential feature of these reactions is the formation of the cyclic compound by coordination to a metal ion. 

A method that achieves the same end result as that of alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis. Alkyl halides are converted to primary alkylamines without contamination by secondary or tertiary amines. The key reagent is the potassium salt of phthalimide, prepared by the reaction... 

In 2011, Bhanage and co-workers reported a carbon monoxide-free one-step synthesis of phthalimides by using formamides as an amine and CO source. With POCI3 as the activator, various phthalimides were produced in moderate to excellent yields (Scheme 2.2). In addition to 1,2-dihalobenzenes, 2-iodobenzoic acid and methyl 2-iodobenzoate can be applied as substrates for phthalimide preparation with formamides as an amine and CO source as well. This methodology was extended and applied in the synthesis of isobenzofuran-l(3/f)-one (70% yield) by using o-iodoben l alcohol as the substrate. 

P = phthalimide prepared from urethan or urea and cleaved by hydrazine. 

It is prepared by the action of sodium hydroxide and sodium hypochlorite on phthalimide (Hofmann reaction). When heated with soda lime it gives aniline. 

Prepared by stirring phthalimide with cold concentrated ammonia solution. Hydrolysed to phlhalic acid with dilute acids. Dehydration with ethanoic anhydride gives first n-cyano-benzamide and then phthalonitrile. 

The independent preparation of potassium phthabmide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75 per cent, ethanol) may be avoided in many cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The N-substituted phthalimide (I) is frequently cleav with difficulty this is often facilitated by reaction with hydrazine hydrate to give an intermediate product, which is easily decomposed by hydrochloric acid to 3deld the insoluble hydrazide of phthaUc acid (II) and the primary amine (III) ... 

P-Phenylethylamine. Prepare p-phenylethyl phthalimide as above by substituting P phenylethyl bromide (Section 111,37) for benzyl... 

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) ... 

Phthalonitrile may be prepared by the following series of reactions from phthalimide —... 

The carbonyiation of o-diiodobenzene with a primary amine affords the phthalimide 501 [355,356]. Carbonyiation of iodobenzene in the presence of (9-diaminobenzene (502) and DBU or 2,6-lutidine affords 2-phenylbenzimida-zole (503)[357, The carbonyiation of aryl iodides in the presence of pentaflnor-oaniline affords 2-arylbenzoxazoles directly, 2-Arylbenzoxazole is prepared indirectly by the carbonyiation of (9-aminophenol[358j. The optically active aryl or alkenyl oxazolinc 505 is prepared by the carbonyiation of the aryl or enol triflates in the presence of the opticaly active amino alcohol 504, followed by treatment with thionyl chloride[359]. 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Carboxyhc acids react with aryl isocyanates, at elevated temperatures to yield anhydrides. The anhydrides subsequently evolve carbon dioxide to yield amines at elevated temperatures (70—72). The aromatic amines are further converted into amides by reaction with excess anhydride. Ortho diacids, such as phthahc acid [88-99-3J, react with aryl isocyanates to yield the corresponding A/-aryl phthalimides (73). Reactions with carboxyhc acids are irreversible and commercially used to prepare polyamides and polyimides, two classes of high performance polymers for high temperature appHcations where chemical resistance is important. Base catalysis is recommended to reduce the formation of substituted urea by-products (74). 

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. 

In a typical experiment, triethylene glycol was treated with two equivalents of sodium toluenesulfonamide in dry DMF solution. After 6 h at reflux, the solution was distilled and product obtained by a standard work-up procedure. By this procedure, 9 was obtained in about 10% yield. The transformation is illustrated below as Eq. (4.10). Note also that Vogtle and his coworkers have also utilized phthalimide as a source of nitrogen in the preparation of such azacrown precursors as H2N(CH2CH2 0)2CH2CH2NH2 In such reactions, a standard hydrazine cleavage was used to remove the phthaloyl residue. 

Primaty amines may be prepared from alkyl halides using phthalimide. This is called the Gabriel amine synthesis. 

The Gabriel-Colman reaction has been used to prepare 3-alkyl isoquinoline 1,4-diols. Phthalimides 8 and 9 rearrange as expected when treated with alkoxides. Further treatment with sodium ethoxide results in decarboxylation and the expected isoquinolinone 1,4-diols 12 and 13. 

The Gabriel-Colman reaction can be used to prepare isoquinoline-1,4-diols regioselectively by the use of unsymmetrically substituted phthalimides. Reaction of phthalimide 32 with sodium ethoxide in ethanol provides a 1 7 mixture of 33 34. It was rationalized that attack at carbon b is preferred because of its greater steric accessibility and diminished electron density compared to carbon a. In spite of the reasonable regioselectivity observed m this reaction, the Gabriel-Colman reaction has not been substantially investigated in the preparation of non-symmetrically substituted isoquinolines. 

The reaction of potassium phthalimide 1 with an alkyl halide 2 leads to formation of a N-alkyl phthalimide 3/ which can be cleaved hydrolytically or by reaction with hydrazine (Ing-Manske variant) to yield a primary amine 5. This route owes its importance as a synthetic method to the fact that primary amines are prepared selectively, not contaminated with secondary or tertiary amines. 

It was found that a high-impact strength is obtained in PP-EPDM blends by slow curing with sulfur. Thiuram disulfide N-(cyclohexylthio)phthalimide was used as an inhibitor of curing, and its effect on the impact strength of dynamically cured PP-EPDM blends was studied (Table 6). It was also found that the one-step method of blend preparation also has a favorable effect on the impact strength of the resultant blend system. 

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). 

The polymeric resin used for Merrifield solid-phase peptide synthesis (Section 26.8) is prepared by treating polystyrene with iV-(hydroxymethyl) phthalimide and trifluoromethanesulfonic acid, followed by reaction with hydrazine. Propose a mechanism for both steps. 

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. 

Palladiumphthalocyanine (PcPd) can be synthesized from phthalimide, ammonium molyb-date(VI), urea and palladium(II) chloride in nitrobenzene.285 Peripherally substituted palladium phthalocyanine is prepared by the reaction of phthalonitrile286 or isoindolinediimine114,117 and palladium(II) acetate in 2-(dimethylamino)ethanol. Also a metal insertion into metal-free phthalocyanine in dimethylfonnamide starting from bis(triphenylphos-phane)palladium(II) chloride has been performed.141,287... 

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... 

BromoaUylamine has been prepared by heating N-(2-bromo-allyl)-phthalimide with hydrazine in methanol 1 by treatment of 2,3-dibromopropylamine hydrochloride with excess alcoholic potassium hydroxide 6 by treatment of 1,2,3-tribromopropane with alcoholic ammonia at 100° and by the present procedure.7... 

M-Aminophthalimide is available from Fluka AG or may be prepared from phthalimide and hydrazine.2 The quality is important the m.p. should be 199-202° with subsequent resolidification of the melt due to thermal reaction. Reerystallization, if necessary, can be carried out in ethanol. The checkers observed that with one batch of recrystallized material, the solid never really did melt, but seemed to sinter at 200°. 

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