N-alkyl imides

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). 

A very interesting approach toward solid-supported synthesis under microwave heating was introduced by Chandrasekhar and coworkers [64], The authors developed a synthesis of N-alkyl imides on a solid phase under solvent-free conditions employing tantalum(V) chloride-doped silica gel as a Lewis acid catalyst (Scheme 7.53). 

Scheme 7.53 Solvent-free preparation of N-alkyl imides.

The preparation of N-alkyl imides by exchange reaction of an imide with an alkyl amine was documented [104] well before the application of this chemistry to the preparation of polyimides [105], see Scheme 30. Although no experimental details are provided, the initial reaction of pyromellitimide with p,p-methylene dianiline in NMP takes place at reflux temperatures to apparently yield a poly(amic amide). Subsequent heating of this intermediate at elevated temperatures ( 300 °C) provides the desired polyimide with evolution of ammonia. The final polyimide is quoted to be thermally and chemically stable, however, no mechanical properties are given. 

Chandrasekhar, S., Padmaja, M.B. and Raza, A., Solid phase-solid state synthesis of N alkyl imides from anhydrides, Synlett, 1999, 1597-1599. 

Another approach to improve the tumor affinity of the vfc-dihydroxy-bacteriochlorins is by the introduction of a hydrophobic alkyl ether side chain at position 3 (ring A) of the molecule. Such a modification had proven to be successful in the pyropheophorbide a, BPD and purpurin-18-N-alkyl-imide series. In order to investigate the effect of ether alkyl chain length in this series of compounds, the 3-(l-heptyloxy)ethyl-purpurin-18-N-hexylimide was converted into the corresponding vic-dihydroxy-bacteriochlorin 218 with a long-wavelength absorption at 111 nm. ... 

The hydrolysis of N,N-alkylated imidate salts is also under stereoelectronic control and has been used to understand the mechanism of amide hydrolysis. Two paths are possible ejection of ROH or R2NH. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

C for 6 h afforded the alkylated imides in 60-84% yields. The last approach was extended to unsaturated carboxylic amides. The diene 0,N-acetal 86 was prepared from the amide 85 in high yields and subsequently treated with azoinitiator V-70 to afford the desired products (Scheme 13). ... 

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

Some of the N-alkylated narceine amides and imides were tested for antibacterial effectiveness and showed activity of medium potency against Mycobacterium tuberculosis H37 Rv. Their antimycotic activity was also of medium strength. Coccidiostatic screening showed some effectiveness (100). 

Maleic anhydride derivatives are readily making it possible to perform their transformations into photochromic N-alkyl-substituted dithienylma-leimides with primary amines. This method was used to prepare cyclic imides 187 in anhydrous methanol or ethanol at 20-80°C in 67-90% yields (02ZOR1390) and N-alkyl(aryl) derivatives 188 based on thieno[3,2-b]pyr-role (03IZV1719) in 70-90% yields. 

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide, Ph3P, and diethyl azodicarboxylate (EtOOCN=NCOOEt) at room temperature (the Mitsunobu reaction, see p. 396).925... 

Amination of anhydrides 0-58 N-Alkylation of imides 0-59 N-Acylation of amides or imides 5-7 Addition of imides to olefins... 

In addition to the alkylation with iodoacetate (Eq. 3-24), sulfhydryl groups can react with N-ethylmale-imide (Eq. 3-39).281 This reaction blocks the SH groups irreversibly and has often been used in attempts to establish whether or not a thiol group plays a role in the functioning of a protein. Loss of function in the... 

The success of the Gabriel synthesis depends on N-alkylation being favored over O-alkylation and SN2 being favored over E2. Polar, aprotic solvents such as methylsulfinylmethane, (CH3)2SO, are useful for the Gabriel synthesis. Hydrolysis of the alkylation product often is difficult and amide interchange (analogous to ester interchange, Section 18-7A) with hydrazine can be an effective way to free the amine from the imide. 

Although the foregoing studies are focused on imidations of P, S, Se, and As compounds with [(tosylimino)iodo]benzene, and related reactions, PhI = NTs has also been utilized for conversions of trialkylboranes to N-alkyl-p-toluene -sulfonamides (Scheme 21) [47]. Such reactions presumably occur through N-tosylaminoborane intermediates (i.e., B-N bond formation). 

Cyclic or acyclic imides can be N-alkylated with soft alkylating agents (Scheme 6.24). Cyclic imides generally give better results than acyclic imides. 

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