N-Alkylation amides

Beside amidation, N-alkylation serves to couple aminolactam 81b to a side chain, as by Sn2 displacement of 2-hydroxy-4-phenylbutyric ester triflate, to yield amino acid ester 82a (87M11). 

A series of calpain I inhibitors such as 184 were prepared in a similar fashion from a-chloronitrile 185 in four steps (Scheme 24) <2001JME3488>. The key steps of this synthesis are the aforementioned Friedel-Crafts-type reaction of chloronittile 185 with CISO3H and a one-pot amidation/N-alkylation of dichloride 186 which furnishes the benzosulfonamide core 188 of these inhibitors via intermediate 187. 

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

With cyclic amides, N-alkyl-caprolactams, the tendency was similar, namely no obvious change in the extraction of Th(IV) and U(VI) was observed in the range 102—104 Gy. But if the gamma-ray irradiation dose was higher than 104 Gy, >U(Vi, decreased with the increased dose, as observed for TBP. This effect was stronger when one radical on nitrogen was branched (2-ethylhexyl instead of n-octyl) (201). 

A less common approach to 2,5-diketopiperazine was reported by Marcaccini et al. [79] who used a Ugi-4CR between amines, aldehydes, isocyanides, and chloroacetic acid to get adducts 140. Treatment of 140 with ethanolic potassium hydroxide led to an intramolecular amide N-alkylation reaction, giving 2,5-diketopiperazines 141... 

Amides, N-alkyl amides, lactams, hydantoins have been identified in both Murchison and Yamoto-791198 meteorites [63,65], confirming preliminary results from Cooper and Cronin [66]. The only peptides identified until now are diglycine and diketopiperazine (cyclic diglycine). Since only N1-unsubstituted hydantoins have been detected, this provides a good argument for the involvement of the Biicherer-Bergs reaction in their formation (cf. Sect. 2.1.4). 

In reductive amination, the alkylation is performed under hydrogen in the presence of a catalyst and an aldehyde or ketone as the alkylating agent. The method was developed for anilines and extended to amide N-alkylation [36]. A notable example is the use of nitro derivatives as aniline precursors in a one-pot reduction of the nitro group and subsequent reductive alkylation of the resulting aniline (Fig. 3.12). 

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 ... 

We name compounds of the type RCNHR and RCNR2 as N alkyl and N N dialkyl substituted derivatives of a parent amide... 

The amide group is readily hydrolyzed to acrylic acid, and this reaction is kinetically faster in base than in acid solutions (5,32,33). However, hydrolysis of N-alkyl derivatives proceeds at slower rates. The presence of an electron-with-drawing group on nitrogen not only facilitates hydrolysis but also affects the polymerization behavior of these derivatives (34,35). With concentrated sulfuric acid, acrylamide forms acrylamide sulfate salt, the intermediate of the former sulfuric acid process for producing acrylamide commercially. Further reaction of the salt with alcohols produces acrylate esters (5). In strongly alkaline anhydrous solutions a potassium salt can be formed by reaction with potassium / /-butoxide in tert-huty alcohol at room temperature (36). 

Carbamates are formed from an amine with a wide variety of reagents, the chlo-roformate being the most common amides are formed from the acid chloride. n-Alkyl carbamates are cleaved by acid-catalyzed hydrolysis A-alkylamides are cleaved by acidic or basic hydrolysis at reflux and by ammonolysis, conditions that cleave peptide bonds. 

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). 

Gramstad and coworkers78 studied the formation of association complexes between CHC13 and N, N-disubstituted amides, four alkyl sulphoxides and diethyl sulphite in CC14 by following the JH NMR. The association constants (Afass) were determined by equation ll79,... 

In vielen Fallen erbringt jedoch die Reaktionsfolge ausgehend von einem Carbonsau-re-amid bzw. Lactam bessere Ausbeuten1 4 allerdings muB in diesem Fall das Acyl-amin bereits die gewiinschten N-Alkyl-Gruppen enthalten. 

N-Alkyl-Derivate des 2,2-Dichlor-3-oxo-butansaure-amids lassen sich im kg-MaB-stabe bei niedrigen Potentialen selektiv zu 2-Chlor-3-oxo-butansaure-alkylamiden reduzieren8 ... 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Amides can also be alkylated with diazo compounds, as in 10-49. Salts of sulfonamides (ArS02NH ) can be used to attack alkyl halides to prepare N-alkyl sulfonamides (ArS02NHR) that can be further alkylated to ArS02NRR. Hydrolysis of the latter is a good method for the preparation of secondary amines. Secondary amines can also be made by crown ether assisted alkylation of F3CCONHR (R = alkyl or aryl) and hydrolysis of the resulting F3CCONRR. ... 

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... 

Under certain conditions, amides can add directly to alkenes to form N-alkylated amides. 3-Pentenamide was cyclized to 5-methyl-2-pyrrolidinone by treatment with trifluorosulfonic acid. Acylbydrazine derivatives also cyclized in the presence of hypervalent iodine reagents to give lactams. When a carbamate was treated with Bu3SnH, and AIBN, addition to an alkene led to a bicyclic lactam. 

N-Alkyl-substituted amides can be converted to nitriles and alkyl chlorides by treatment with PCI5. This is called the von Braun reaction (not to be confused with the other von Braun reaction, 10-76). 

A useful method to synthesize ten and fourteen-membered ring imides 346 involved an initial condensation of macrocyclic -ketoestes 343 with alkyl or aryl isocyanates and carbodiimides, respectively, in the presence of a base [68]. After a nucleophilic attack of the enolate on the isocyanate C, the resultant amide N anion 344 induced a ring closure by addition to the keto group. Then, the intermediately formed four-membered ring 345 underwent a fragmentation... 

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