Aliphatic amide synthesis

Cefmetazole (78) is a cephamycin-inspired cephalosporin differing from the mainstream compounds in having an aliphatic amide moiety attached to C-7. Its antibacterial spectrum is similar to the second generation agent cefoxitin. The synthesis starts with 7-aminocephalosporan-... 

Irimescu and Kato have recently described an interesting example of enzymatic KR in ionic liquids instead of organic solvents (Scheme 7.4) [12]. The resolution with CALB is based on the fact that the reaction equilibrium was shifted toward the amide synthesis by the removal of water under reduced pressure. Nonsolvent systems have been also employed in this enantioselective amidation processes, reacting racemic amines with aliphatic acids. The best reaction conditions for the conversion of acids to amides was observed using CALB at 90 °C under vacuum. Meanwhile, no... 

Electroreduction of aliphatic amides in the presence of chlorotrimethylsilane gives coupling products and this reaction is useful for the synthesis of a-amino ketones (Scheme 22) [41]. In this reaction, the formation of an Mg salt promotes the coupling of two anion radical centers. 

A Streptomyces enzyme that catalyzes hydrolysis of capsaicin is described by Koreishi et The substrate is an A -vanillyl aliphatic amide, and the authors found that their enzyme also accepted A lauroyl amino acids as substrates. The enzyme was used successfully to catalyze the reaction in the opposite direction, driving the equilibrium toward synthesis by running it in buffer containing 78% glycerol. Yields of 5-40% were obtained for a wide range of natural L-amino acids. In the case of L-lysine the enzyme catalyzed acylation at both amino groups, with a clear preference for the e-NH2. 

The reductive cyclization of 2-nitrobenzyl-A, A -bis(formamide) with zinc in acetic acid to quinazoline was first described by RiedelT ° The reaction is used successfully for the synthesis of larger quantities of quinazoline and its benzene-ring-substituted derivatives 12 from 2-ni-trobenzyl-A, A -bis(formamides) 11. The method is suitable only for the preparation of 4-un-substituted quinazolines, because 2-nitro-substituted phenones do not condense with aliphatic amides to yield bis(amide) derivatives. Zinc in acetic acid is the reducing agent of choice, but iron in hydrochloric acid or Raney nickel can also be used. " Applications of compounds other than bis(formamides) [e.g., bis(acetamides) ] and preparation of 2-substituted quinazolines by Riedel s synthesis are scarce. 

Synthesis of Nitriles from Amides. Aryl carboxamides and other electron-rich amides could be converted to the corresponding nitriles in good yields by treatment with Ag20 and EtI in benzene at reflux (eq 23). This technique is typically compatible with acid-labile moieties or protecting groups (TBDPS, isopropy-lidene). Although this technique was found to be very efficient for the transformation of electron-rich carboxamides, simple aliphatic amides are rarely suitable for this purpose. 

Hofmann s amine synthesis can be applied to both aliphatic and aromatic carboxylic acid amides, benzamide, C HsCONH, thus giving aniline, C4H5NH,. 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

Hydrazides (RCONHNH2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous hydrazine which presents a high thermal hazard. Diacylation products predominate when hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.5... 

An alternative procedure for the synthesis of aliphatic 2-substituted oxazoline hydroxamates was described by Pirrung and colleagues in the context of preparing inhibitors of E. coli LpxC zinc amidase [378], As shown in Scheme 6.210 a, the protocol involved the cyclization of suitable amides, formed in situ by acylation of a serine-derived 0-2,4-dimethoxybenzyl (DMB)-protected hydroxamate. The cyclization... 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

DKR for the Synthesis of Esters, Amides and Acids Using Lipases Table 4.4 DKR of various aliphatic amines... 

---