A, 3-unsaturated ketones

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

Another preparative method for the enone 554 is the reaction of the enol acetate 553 with allyl methyl carbonate using a bimetallic catalyst of Pd and Tin methoxide[354,358]. The enone formation is competitive with the allylation reaction (see Section 2.4.1). MeCN as a solvent and a low Pd to ligand ratio favor enone formation. Two regioisomeric steroidal dienones, 558 and 559, are prepared regioselectively from the respective dienol acetates 556 and 557 formed from the steroidal a, /3-unsaturated ketone 555. Enone formation from both silyl enol ethers and enol acetates proceeds via 7r-allylpalladium enolates as common intermediates. 

Ailyl enol carbonates derived from ketones and aldehydes undergo Pd-cat-alyzed decarboxylation-elimination, and are used for the preparation of a, /3-unsaturated ketones and aldehydes. The reaction is regiospecific. The regio-isomenc enol carbonates 724 and 726, prepared from 723, are converted into two isomeric enones, 725 and 727. selectively. The saturated aldehyde 728 can be converted into the a,/3-unsaturated aldehyde 730 via the enol carbonate 729[459]. 

A related ring closure is also successful in the thiazole series. Treatment of a /3-amino-a,/3-unsaturated ketone with thiocyanogen gave the intermediate thiocyano compound (323) which underwent ring closure to the 2-iminothiazoline derivative (324) (83MI40300). Related reactions are described in Chapter 4.19, and for those involving potassium selenocyanate see Chapter 4.20. 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

A number of other syntheses were discussed by Takeuchi and Furusaki and the most common involved reaction of hydroxylamine with selected a,/3-unsaturated ketones to give isoxazolidine-3- or -5-ols, which exist in equilibrium with an open-chain counterpart (77AHC(21)207). A similar equilibrium was observed in the reaction of a,/3-unsaturated ketones with N-hydroxyurea. The geometric orientation of the ring substituents was studied as a dynamic process (Scheme 158) (75TL2337). 

HS(CH2) SH, BF3-Et20, CH2CI2, 25°, 12 h, high yield, n = 2, n = 3. In a,/3-unsaturated ketones the olefin does not isomerize to the /3,7-position as occurs when an ethylene ketal is prepared. Aldehydes are selectively protected in the presence of ketones except when steric factors force the ketone to be protected as in the example below." A TBDMS group is not stable to these conditions. ... 

The results of the reductions of some steroidal a,)3-unsaturated ketones have been summarized by Brown. " The carbonyl group is usually reduced to the hydrocarbon, but the behavior of the double bond depends on the structure of the compound undergoing the reduction. Cholest-4-en-3-one gives chol-est-4-ene. Addition of aluminum chloride to a solution of a 4-ene-3,6-dione followed by treatment with LiAIH4 gives the 4-ene-6-one. Steroid 4,6-dien-3-ones yield mixtures of dienes. When the ketone and double bond are in different rings the results become even more complex dienes as well as mono-enes are obtained. 

The reaction of enamines derived from cyclohexanone with dichlorocarbene to give the 1 1 adducts is now well established (137-139). The morpholine enamine (113) reacted with dichlorocarbene at —10 to —20° in tetrahydrofuran to give the stable crystalline adduct (201). Thermal decomposition followed by an aqueous work-up gave an a,)3-unsaturated ketone identified as 2-chloromethylene-cyclohexan-l-one (202) (139). 

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). 

TsOH, benzene, reflux, 30 min, 76% yield." A t-butyl ester is stable to the conditions needed to convert an a,/3-unsaturated ketone to a dioxolane (HOCH2CH2OH, TsOH, benzene, reflux). ... 

In the case of t-butyl substituted a,/3-unsaturated ketones, however, no reaction with ketones occurred in the presence of triphenylmethyl fluoroborate instead, a 1,2-methyl shift in the unsaturated ketone accompanied by cyclization afforded a crystalline dihydro-furylium salt. ... 

Although deprotonation of simple 1,3-dithiolanes at the 2 position is usually accompanied by cycloreversion to the alkene and dithiocarboxylate, this does not occur for the 2-ethoxycarbonyl compound 55. The anion of this is readily generated with LDA and undergoes conjugate addition to a,(3-unsaturated ketones, esters, and lactones to give, after deprotection, the a,8-diketoester products 56 (73TL2599). In this transformation 55 therefore acts as an equivalent of Et02C-C(0) . 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

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