Amides phthalimide

In summary, the direct insertion of zinc dust to organic halides is an excellent method for preparing a broad range of polyfunctional organozinc halides bearing various functional groups like an ester" , an ether, an acetate" , a ketone, cyano", halide" , N,N-bis(trimethylsilyl)amino °, primary and secondary amino, amide, phthalimide , sulfide, sulfoxide and sulfone , boronic ester , enone " or a phosphonate . An alternative method is based on transmetalation reactions. 

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. 

Nitro compounds. Nitromethane Nitrobenzene ni-Dinitrobenzene. Amides and imides. Acetamide re-Caproamide Acetanilide Benz-anilide Phthalimide. 

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). 

Imides (e.g. phthalimide) can be purified by conversion to their potassium salts by reaction in ethanol with ethanolic potassium hydroxide. Hie imides are regenerated when the salts are hydrolysed with dilute acid. Like amides, imides readily crystallise from alcohols and, in some cases (e.g. quinolinic imide), from glacial acetic acid. 

The second proposed mechanism involves initial ring opening of the phthalimide. Alkoxide attack on one of the imide carbonyls furnishes amide anion 26. Proton transfer affords enolate 27, which undergoes Diekmann type condensation followed by aromatization to afford the requisite isoquinoline 23. 

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). 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58... 

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 ... 

Thus amides are found to be only very weakly basic in water [pKa for ethanamide(acetamide) is =0-5], and if two C=0 groups are present the resultant imides, far from being basic, are often sufficiently acidic to form alkali metal salts, e.g. benzene-1,2-dicarboximide (phthalimide, 8) ... 

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. 

The additions of ammonia equivalents, i.e. nitrogen nucleophiles like dibenzylamine (Scheme 27) which are essentially a protected primary amino group, are of special synthetic interest with respect to their possible subsequent chemical transformations. Poorly nucleophilic ammonia equivalents like acetamide or the classical phthalimide, did not add or originally gave low yields of 92a (Scheme 28) [9],but later phthalimide was found to add to 1-Me very well under mild conditions [53]. However, the a-chlorine in 92a could neither be substituted nor could the phthalimido group be cleaved without destroying the cyclopropane ring. The potassium bis(alkoxycarbonyl)amides (Boc)2NK and (Moc)(Boc)NK add to 1-Me in satisfactory yields, but the a-chlorine atom in... 

The UV spectrum [7max 238, 256 (sh), 293 (sh), 314, 362 (sh), and 390 (sh) nm] of rebeccamycin (337) indicated the presence of an indolo[2,3-fl]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. This was also discernible from its IR spectrum. The H-NMR spectrum indicated the presence of an amide NH at 8 11.37 and an indole NH at 6 10.30, in addition to signals for aromatic protons and a sugar moiety. Unlike (+)-staurosporine (295) (see Scheme 2.74), where the lactam function deshielded only the ortho C-4 proton, the C-4 and C-8 aromatic protons in rebeccamycin are both deshielded due to the anisotropic deshielding effect of the phthalimide function. 

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. 

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>. 

Alternatively, lactone 20 could be converted to bromide 23 in the presence of hydro-bromic acid (Scheme 14.4). Subsequent treatment with thionyl chloride generated the doubly functionalized intermediate 24, which was subsequently treated with diethylamine to install the required amide functionality. Nucleophilic attack with potassium phthalimide on the bromide moiety resulted in the generation of intermediate amide 22, at which point this route intersected that already described in Scheme 14.3. Treatment with hydrazine provided milnacipran (2) in 37% overall yield. 

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