Enaminoketones hydrolysis

Pyrazolooxazepine 153 was synthesized starting from the condensation of hydrazinol 151 with enaminoketone 150. When the isolated ester intermediate 152 (R = OMe) was saponified, ester hydrolysis afforded acid 152 (R = H), which cyclized on subsequent treatment with l-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) to form oxazepine 153 (Scheme 22) <2003TL5867>. 

And finally, acylating agents can also be used as electrophiles to react with enamines. Following the hydrolysis of the enaminoketones (i.e., compounds with the substructure R2N-C=C-C(=0)-R ) or enaminoesters (i.e., compounds with the substructure R2N-C=C-C(=0)-0R ) the acylation products of the corresponding ketones are obtained. Figure 12.21 gives the mechanistic details of the acylation with an acid chloride, and Figure 12.22 shows the acylation with ethyl chloroformate. The first acylation yields /1-diketones, the second furnishes a /1-ketoester. 

In accord with MO calculations (67BCJ1580), benzo[Z>]furans are attacked by a variety of nucleophiles at the 2-position. Hydroxide under drastic conditions affords (59) and (60), which are presumably formed by Cannizzaro reaction of the aldehyde (58 Scheme 31). Methylsulfinyl anion in DMSO at 70 °C followed by aqueous work up affords 2-ethy-nylphenol (66JOC248). With a -M group at the 3-position, nucleophilic attack at the 2-position is facilitated. 3 -Benzoyl-2-ethylbenzo[Z> ]furan with hydroxide affords products which can be rationalized by / - diketonic fission of the intermediate (61), further transformations of which produce (62) and (63) (Scheme 32). With a nitrile at the 3-position a similar degradation takes place but an ester is not sufficiently electron withdrawing and hydrolysis ensues. Ammonia will attack the ketone (64) at the 2-position, producing the unstable / - enaminoketone (65 Scheme 33). Other nucleophiles attack in a similar manner thus hydroxylamine under certain conditions will afford oxazoles (66BSF1587). 

Conversion of an isoxazole to a 1,3-diketone simply requires reductive cleavage of the N-O bond followed by hydrolysis of the resulting enaminoketone. 

For the conversion of 9 to 3 (Scheme 1), catalytic hydrogenation (or NaBH iC MF) had achieved the first half of fhe sequence (9 - 10), and aqueous NaOn had effected the hydrolysis of 10 (in this case an iminoenol instead of an enaminoketone) (If)). The transformation 16 11 proceeded differently in each Step reduction of the carbonyl of 16 tended to conq>ete with reduction of die N-O bond, and the reduction product 17 was stable to aqueous base. 

The next stage of the synthesis called for conversion of the terminal olefin to an aldehyde. This was accomplished using a Johnson-Lemieux oxidation. The resulting ketoaldehyde was then converted to fr-ketal 15. Basic hydrolysis of the formamide provided 16 and hydrolysis of the acetals afforded a mixture of diastereometic enaminoketones 17. An acid-promoted intramolecular Mannich reaction gave 2. Presumably epimerization of the ketone allowed both diastereomers of 17 to follow the path to 2. Reduction of ketone 2 with sodium borohydride provided an alcohol, which underwent formal dehydration upon treatment with thionyl chloride and pyridine, to give porantherine (1) as a racemic mixture. 

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