N-alkyl phthalimides

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. 

In the Gabriel synthesis, potassium phthalimide is reacted with an alkyl halide to produce an N-alkyl phthalimide. This N-alkyl phthalimide can be hydrolyzed by aqueous acids or bases into the primary amine. 

Potassium phthalimide, CgH CO NK Reacts with alkyl halides to yield N-alkyl-phthalimides, which are hydrolyzed by aqueous sodium hydroxide to yield amines (Gabriel amine synthesis Section 24.6). 

Syntheses of N-alkyl phthalimides and N-alkyl succinimides by alkylation of potassium salts have been performed on silica gel in dry media under MW + PTC conditions with fairly high yields [50]. 

The reaction of halides with phthalimide to generate an N-alkyl phthalimide and the subsequent conversion to an amine is well known. This process is referred to as... 

Our solution to this problem was to use a "protected" nitro-phthalic anhydride. . a nitro-N-alkyl phthalimide. As... 

The negatively charged nitrogen atom of the salt of phthalimide is a good nucleophile. It displaces halides from primary alkyl halides and tosylate groups from primary tosylates to yield an N-alkylated phthalimide. This reaction, with its related workup procedures, is called the Gabriel synthesis. 

The N-alkyl phthalimide product can be hydrolyzed with either aqueous acid or base to form phthalic acid and liberate the amine. However, it is difficult to hydrolyze amides (Section 21.5). A more effective method uses hydrazine to form a phthalyl hydrazide by acyl transfer. 

Dimethoxy-2-(arylimino)-2,3,6,7-tetrahydro-4//-pyrimido[6,1 -n]iso-quinolin-4-ones were N-alkylated with A-(catalytic amount of I2 in boiling 2-butanone in 13-67% yields (00MIP19). 

Phthalimidobutyl)-2,3,4,4u,5,6-hexahydro-l//-pyrazino[l,2-u]quino-line was obtained in the reaction of 2,3,4,4u,5,6-hexahydro-l//-pyrazino[l,2-u]quinoline and A-(4-bromobutyl)phthalimide in boiling MeCN in the presence of K2CO3 (97MIP12). 2,3,4,4u,6,7-He-xahydro-l//-pyrazino[l,2-ujquinolines were N-alkylated with 3-dimethylaminomethyl-l//-pyrrolo[2,3-6]pyridine and a mixture of l//-pyrrolo[2,3-6]pyridine and 37% aqueous H2CO in aqueous AcOH in the presence of NaOAc (96USP5576319). 3-[3-Substituted 2-propen-l-yl]-2,3,4,4u, 5,6-hexahydro-l//-pyrazino[l,2-u]qui-... 

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). 

Phthalimide and N-alkyl-toluenesulfonamide salts are similarly alkylated, and can furthermore be cleaved to polymer-bound secondary and primary amines respectively (57). Potassium pyrrolidonide gives polymer-bound tertiary amide, of interest as a solid cosolvent catalyst ... 

The simplicity of the two-phase modification of the Gabriel synthesis of primary amines, via the N-alkylation of potassium phthalimide, makes the procedure considerably more convenient than the traditional method, which normally requires the use of anhydrous dipolar aprolic solvents. The reaction can be conducted under solid liquid conditions using potassium hydroxide in toluene [25], or with preformed potassium phthalimide [26, 27] (cf ref. 28). As is normal for acylation reactions, relatively mild conditions are required for the preparation of the A-ethoxycarbonyl derivative [29], whereas a reaction temperature of 100°C is generally used for N-alkylation (Table 5.16). The reaction time for the soliddiquid two-phase system can be reduced dramatically with retention of the high yields, when the reaction mixture is subjected to microwave irradiation [30]. 

Selective N-alkylation of potassium phthalimide by ethyl a-bromopropionate"... 

A further alkylation of the nitrogen is not possible. In a second step the N-substituted phthalimide 3 is hydrolyzed to give the desired amine 5 and phthalic acid 4 ... 

Die aus primaren Alkanthiolen sowie aus 2-Mercapto-propan und N-Chlor-succinimid erhaltlichen2 N-Alkylthio-phthalimide reagieren mit Tris-[dimethylamino]-phosphan in Benzol exotherm zu N-Alkyl-phthalimiden, die in ublicher Weise mittels Hydrazin zu den Alkylaminen gespalten werden konnen3. Die Gesamtreaktion stellt also eine Variante der Gabriel-Synthcse dar ... 

Polystyrene-bound amines can be converted into the corresponding phthalimides by heating with other phthalimides (BuOH, 85 °C, 18 h [33]). Support-bound phthalimides have also been prepared by N-alkylation of phthalimide derivatives [295] or by amidomethylation of cross-linked polystyrene with /V-(hydroxymethyl) or /V-(chloro-methyl)phthalimide [296,299]. 

Phase-transfer catalysed N-alkylation of diphenylphosphinic amide (I) is totally unsuitable in the case of easily hydrolysable organic halides, especially those containing additional functional groups (i.e. carbonyl or carboalkoxyl) which decompose readily in strongly alkaline medium. To circumvent the difficulty connected with simultaneous mono- and dialkylation of (I) under anhydrous conditions, N-(t-butyloxycarbonyl) diethyl phosphoroamidate (X), a doubly-protected ammonia derivative, was devised as a useful and superior substitute of phthalimide in the Gabriel-type synthesis of amines. 

Alkyl selenides are most conveniently prepared by the dialkylation of Na2Se or by the monoalkylation of selenolates. Common routes to aryl derivatives include the reaction of a selenolate with a diazonium salt, the SrnI reactions described earlier, and the reaction of aryUithiums with aryl selenocyanates (ArSeCN). A different approach employs the reaction of alcohols with aryl selenocyanates or N-(phenylseleno)phthalimide (see Section 6) in the presence of tri-n-butylphosphine. Similar conditions can also be used to convert carboxylic acids to selenoesters (8). These reactions are illustrated in Scheme 3. 

Under MW irradiation, a number of azaheterocycles (pyrrole, imidazole, pyra-zole, indole, carbazole, phthalimide, etc.) react remarkably fast with alkyl halides to give exclusively N-alkyl derivatives (Table 18). 

Table 18. N-Alkylation of phthalimide using K2CO3, TBAB...

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