5- Keto-imine intermediate

As mentioned, the mildness of NaBHaCN (coupled with its effectiveness and stability in aqueous media) has attracted considerable interest for applications in biochemical areas. Examples include the trapping of suspected imine intermediates produced in enzyme (mitochondrial monoamine oxidase) inactivation by amines, the establishment by reduction of the positions of imine-forming amines in 2-keto-3-deoxy-6-phosphogluconate aldolase, and the transfer labeling of methionyl-tRNA synthetase and methionyl-tRNA transformalase by treatment with periodate-treated tRNA. In fact, most biochemical applications of NaBHaCN have utilized in situ imine formation-reduction (i.e. reductive amination) conditions and will be further discussed in Section 1.2.2.3.1. 

The transformation of an active CH compound into the corresponding diazo derivative with -toluenesulfonyl azide has been designated a diazo transfer reaction and possesses a variety of preparative uses. The method has been useful for the syntheses of diazo derivatives of cyclopentadiene, 1,3-dicar-bonyl compounds, 1,3-disulfonyl compounds,1,3-keto-sulfonyl compounds, ketones, " carboxylic acid esters, and /3-keto imines. Further reaction of these diazo intermediates can lead to azo compounds,"- " 1,2,3-triazoles, and pyrazolinones. ... 

An obvious synthetic application of amine addition to the a-keto group in acylphosphonates would be reductive amination. This has been demonstrated [42], and shown to be a useful route to 1-aminoalkylphosphonic acids. Thus, selected acylphosphonates were reacted with benzhydrylamine, giving after reduction of the resulting imine intermediate with triacetoxyborohydride and acid hydrolysis, satisfactory yields of the corresponding aminoalkylphosphonic acids. However, a limitation of this approach is unwanted cleavage of the phos-phonate P-C bond, which was observed with other amines such as benzylamine and a-benzylmethylamine [42]. 

Keto(imine) quinonoid intermediate Aminoacrylate intermediate Figure 25 Mechanism of the /3-elimination catalyzed by tyrosine phenol-lyase. 

The precursor to amidoacrolein 64, 1,3-dioxin 66, was prepared as follows [39] the imine derived from the condensation of 2,2-dimethyl-l,3-dioxan-5-one with aminoacetaldehyde dimethyl acetal was acetylated with acetic anhydride/triethylamine to afford dioxin 66 in 83% yield (Scheme 24). Retro Diels-Alder of dioxin 66 in warm benzonitrile (120 C, 16 h) generated the amidoacrolein 64, which was trapped in situ with the silyloxydiene 65 to afford the desired cycloadduct 63 (64%). An aldol cyclization between the acetamide and neighboring aldehyde functionalities within 63 proceeded smoothly (2 equiv. of KCh-Bu, 10 equiv. of EtOAc, THF, 0 °C, 40 min) and directly afforded the corresponding conjugated lactam. This product was of sufficient purity for the second aldol reaction, which was best accomplished under acidic conditions, presumably proceeding through the achiral keto aldehyde intermediate 62 enroute to the desired, but racemic, (3-hydroxy ketone 61 obtained in 79% yield after the two consecutive ring closures. 

The authors suggest a radical mechanism for the reaction, in which a singleelectron transfer from CAN to the P-keto esters and latter radical adds to the imine intermediate (Scheme 8.32). 

This one-pot protocol had given excellent yields with substituted aromatic aldehydes but the cyclocondensation with aliphatic aldehydes such as n-butanal and -hexanal under the present reaction conditions afforded the corresponding dihy-dropy ritnidin-2( l//)-ones in 76 and 69 % yields, respectively. The reaction proceeds via an acyl imine intermediate formed from the condensation of aldehyde and urea. Subsequent addition of the P-keto ester enolate, followed by cychzation and dehydration afforded the dihydropyrimidinone derivatives. Iodine played a cracial role in accelerating the dehydrative steps and enolization of the P-keto ester. 

One of the biological pathways by which an amine is converted to a ketone involves two steps (1) oxidation of the amine by NAD" " to give an imine, and (2) hydrolysis of the imine to give a ketone plus ammonia. Glutamate, for instance, is converted hy this process into a-keto-glutarate. Show the structure of the imine intermediate, and propose mechanisms for both steps. 

Petrow described the formation of 3-iminoketones from 3-keto-aldehydes and aniline. Cyclization in the presence of aniline hydrochloride and ZnCh smoothly provides the desired quinoline 26. Bis-imine 24 is the proposed intermediate that undergoes cyclization. The aldimine is more reactive than the ketimine toward cyclization thus, cyclization on the aldimine occurs. When the bis-imine is not formed, partial aniline migration can occur which results in mixtures of cyclized products. 

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

Deprotonation of the acidic a carbon of the amino acid gives an intermediate a-keto add imine. .. 

An oxazole substituted with a complex aminohydantoin side chain is described as a muscle relaxant. Imine formation between glyoxylic acid and aminohydantoin (38-1) results in the imino acid (38-2). Use of that intermediate to acylate the amine on 4-chloro-2 -aminoacetophenone (38-3) leads to the amide (38-4), which now includes a 1,4-dicarbonyl array. Treatment of the keto-amide with phosphorus... 

The first step in either direction consists of addition of NaHSO-, to one of the double bonds of the ring, which gives an enol (or enamine) that tautomerizes to the keto (or imine) form. The conversion of 10 to 11 (or vice versa) is an example of 6-14 (or 6-2). Evidence for this mechanism was the isolation of 10 " and the demonstration that for p-naphthol treated with ammonia and HSOj. the rate of the reaction depends only on the substrate and on HSOi. indicating that ammonia is not involved in the rate-determining step.112 If the starting compound is a (i-naphthol, the intermediate is a 2-keto-4-suIfonic acid compound, so the sulfur of the bisulfite in either case attacks meta to the OH or NH2-m... 

Carbacephalosporins The ketene-imine cyclization described above has been extended to a synthesis of a chiral carbacepham (4). This synthesis uses a dihy-droanisole group as the equivalent of a p-keto ester. Thus the azetidinone 1, obtained in 80% yield by the above route, was reduced and acylated in situ to provide 2. Ozonization followed by a rhodium-catalyzed cyclization of an a-diazo-P-keto ester provides 3, which is a useful intermediate to various substituted car-bacephams such as 4. 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

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