Aliphatic amide cyclization

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. 

Scheme 7.14 Proposed mechanism for ruthenium-catalyzed carbonylation and cyclization of aliphatic amides.

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... 

Similarly, solid cyclic imides are attacked by gaseous aliphatic amines and lead to open-chain diamides. For example, 269a-c react with ethylamine gas to give a 100% yield of the diamide 270, which can be quantitatively cyclized to the JV-ethylimide 271 by the action of gaseous HCl [12]. As expected, the solid alicyclic imides 272 behave correspondingly and yield the bis-amides 273 in an easy waste-free procedure [12] (Scheme 39). 

Muratake et al. reported the intramolecular a-arylation of ketones [55,56]. Thus, polycyclic compounds are readily obtained from aromatic keto-bromides and keto-triflates (Eq. 16). Bromo-amides can give the corresponding cycliza-tion products (Eq. 17) [52]. Related intramolecular vinylation reactions to give aliphatic polycyclic compounds have also been reported (Eq. 18) [57,581. The intramolecular cyclization of aromatic halo-ketones under carbon monoxide, which proceeds by mechanism C, gives the corresponding a-acylated products (Eq.l9) [321. 

Schiff bases (14), which are formed by reaction between DAMN and appropriate carbonyl reagents, are oxidatively cyclized to give a variety of 2-substituted 4,5-dicyanoimidazoles (15) (Scheme 2.1.5). Although dichlorodicyanoquinone (DDQ) or diaminosuccinonitrilc (DISN) have been used frequently to achieve the oxidative cyclization, long reaction times (17 h to 4 days under reflux) are a disadvantage, and N-chlorosuccinimide (NCS) under basic conditions is more convenient in many cases. The Schiff bases are best formed from aromatic aldehydes, but aliphatic aldehydes and ketones, ketoesters, orthoesters, amides, imidates and cyanogen chloride have all been used [15, 41-49J. 

Another way to form a-aminoketones from a-amino acids is via the Dakin-West reaction, in which amino acids are treated with aliphatic acid anhydrides to give ketone amides. Thus, reaction of ( )-phenylalanine with the appropriate aliphatic acid anhydrides followed by acidic hydrolysis afforded keto-amide 1271. Cyclization of 1272 with potassium cyanate gave 5-alkyl-4-benzyl-l,3-dihydroimidazol-2-ones 1273 (Scheme 322) <2002JHC375>. 

Compounds of structure 10 react readily with nucleophiles. Thus moisture causes rapid hydrolysis to the pyrazine amino acid, and aliphatic amines give the amides (11), which may be cyclized to pteridinones (12) by dissolving in phosphoryl chloride. Ammonia, hydroxylamine, and aniline give the pteridinones (13) directly. ... 

The method works well for both aliphatic and aromatic primary amines. An asymmetric synthesis of the cis-5-alkylproline derivatives (149) has been described by Ho et al., which involves, as the key step, reductive cyclization of the protected keto-amides (148). The cis products are formed generally with high... 

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