Methyl vinyl ketone Robinson annelation with

Similarly, methyl vinyl ketone has been added to enamines derived from aldehydes (3,321,324-327) and ketones (3,328), providing a useful extension of the Robinson annelation reaetion. Condensations of enamines with other a, 3-unsaturated ketones can give a variety of diketones (329). 

The reaction of A2-piperideine (115) with methyl vinyl ketone to give (124) is another example of how initial electrophilic attack on the enamine double bond can be used in heterocyclic synthesis (77ACR193). This overall process is an enamine analog of the Robinson annelation and is a useful approach to the perhydroquinoline ring system. 

Problem 17.49 The Robinson annelation reaction for synthesizing fused rings uses Michael addition followed by intramolecular aldol condensation. Illustrate with cyclohexanone and methyl vinyl ketone, CHj=CHCOCH,. <... 

Phenolannelation. Methyl vinyl ketone (and substituted vinyl ketones) undergo Robinson annelation with the /(-keto sulfoxide (1) to afford the 5,6,7,8-tetrahydro-2-naphthol (2) with loss of hcn/cnesnlfenic acid. Sodium methoxide is used as base, and the reaction proceeds at 0 - 25°. 

This asymmetric phase-transfer method has been applied to enantio-selective Robinson annelation as shown in Scheme 14 (41). First, alkylation of a 1-indanone derivative with the Wichtetie reagent as a methyl vinyl ketone equivalent in the presence of p-CF3BCNB gives the S-alkylation product in 92% ee and 99% yield. With 1 -(p-trifluoro-methylbenzyl)cinchonidinium bromide, a pseudo-enantiomeric diaste-reomer of p-CF3BCNB, as catalyst, the -alkylation product is obtained in 78% ee and 99% yield. These products are readily convertible to the... 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

In preparation for a Robinson annelation, it is often advantageous to increase the reactivity of the position adjacent to the carbonyl group by introduction of a substituent that can later be removed. Thus Turner et al." found direct condensation of 7-methoxy-l-tetralone (1) with methyl vinyl ketone or the corresponding Mannich base to show little promise. They then converted (1) into the 2-hydroxymethylene... 

Robinson annellation reaction. Formation of six-membered-ring ,(i-iinsaturatcd ketones by condensation of cyclohexanones with methyl vinyl ketone or its equivalents, followed by an intramolecular aldol condensation. 

Quinolizidinones can also serve as substrates for Robinson annelation procedures. For example, benzo[c]quinolizidinedione derivative (160) was activated in the position a to the ketone group in C-6 by formylation and then treated with methyl vinyl ketone to yield the pyrido[l,2-/]phenan-thridine (161), which was then functionalized to the CNS active agent (162) <83EUP90526> (Scheme 24). 

In a Robinson-type annelation, benzo[6]quinolizidinones (312) have been obtained by treatment of benzylamino derivatives (311) with methyl vinyl ketone in acid solution (Equation (39)) <83AJC149>. Three quinolizine bonds are also formed in the reaction between 2-silylated pyridines (313) and two equiv. of DMAD (Equation (40)) <83CB2564>. 

An alternative route was also developed for the synthesis of ( )-pisiferic acid (196) as described in "Fig (17)". The starting material for the present synthesis was the already described alcohol (15), which on tetrahydropyranylation yielded the derivative (197). Metal hydride reduction of (197) afforded a mixture of alcohols whose tosyl derivative on heating with lithium bromide and lithium carbonate in dimethylformamide afforded the oily olefin (198). These conditions not only provoked the dehydrosulphonation but also the hydrolysis of the tetrahydropyranyl group, thus shortening the reaction sequence by one step. The oily olefin (198) on oxidation yielded the ketone (199), which was formylated, and subjected to Robinson annelation with methyl vinyl ketone prepared in situ following the procedure of Howell and Taylor [74]. The resulting adduct without purification was heated by boiling with sodium methoxide in methanol to obtain the tricyclic ketone (200). It was treated with... 

Organocopper )V)V-dimethylhydrazone (DMH) derivatives have been used for the synthesis of a variety of 1,5-dicarbonyl compounds. In contrast to the normal Robinson annelation of 2-methylcyclohexanone, which leads to attachment of methyl vinyl ketone analogues at C-(2) and eventual formation of (56), the organocopper DMH derivative of 2-methylcyclohexanone reacts with methyl vinyl ketone to give the 1,5-diketone (57), which undergoes base cyclization to the octalones (58). 

Ziegler, F. E., Hwang, K. J. On the aprotic Robinson annelation of dihydrocarvone and 2-methylcyclohexanone with methyl and ethyl vinyl ketone. J. Org. Chem. 1983,48, 3349-3351. 

An elegant synthesis of Warburganal (12) from the ketone (2) was reported by Kende and Blacklock [8] as depicted in Tig (1)". The ketone (2), prepared [3] by Robinson annelation of the 2-methyl-1,3-cyclohexanedione with ethyl vinyl ketone, on ketalization afforded (3) which was converted to the trans-decalone (4) by the reductive methylation procedure of Stork [9]. Wolff-Kishner reduction of (4) produced the ketal (5), which without purification was hydrolyzed with acid to obtain the trans-decalone (6) [10] in excellent yield. The present method for the synthesis of the decalone (6) appears more efficient and convenient than the methods previously reported [11,12], considering the overall yield and the stereoselectivity. 

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