Ketones reactions with dienes

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

These ketones undergo Diels-Alder reactions with dienes to give selenopyrans in good to excellent yields. 

In a study on vitamin D2 synthesis [ 124], a sterically very hindered sulfone 273 (Scheme 90) with the axially oriented sulfonyl group was transformed into an anion (NaHMDS) and subjected to reaction with diene-aldehyde 274 used in excess. After deprotection, vitamin D2 275 and its unstable C7-C8 Z-isomer 276, were obtained in 70% yield, ratio of 72/28, respectively. Some BT-sulfone 277 generated by epimerization of 273 was also isolated. An attempt to carry out the reaction with the reverse allotment of the fimctional groups (sulfone 278 with ketone 279) failed. With regard to the isomer ratio 275 and 276, it is of interest that the classical Julia reaction of phenylsuhbne corresponding to 277 and aldehyde 274 occurs with somewhat lower selectivity towards the -isomer [125]. 

The 2-diazo-4,4-dimethyl-5-ene-3-one (478) is a special case, one of the main products being the l-methyl-19-nor-l(10),5-dien-3-one (480). The same product was formed when boron trifluoride reacted with the l,5-dien-3-one (479), pointing to this being an intermediate in the diazo-ketone reaction. With boron trifluoride. 

Danishefsky and coworkers have used a similar sequence of reactions to synthesize octosyl acid A (144 Scheme 40). Aldehyde (140) readily undergoes a hetero cyclocondensation reaction with diene (8), catalyzed by ZnCb, to give the CF pyrone (141). Reduction of the ketone followed by osmylation, oxidation and introduction of the mesylate gives compound (142). Introduction of the pyrimidine glycoside, followed by an intramolecular displacement of the mesylate through the tin complex (143), gives an intermediate that is converted to octosyl acid A (144) by a series of standard manipulations. 

Disubstituted quinolines of type 21 were obtained from acetylenic ketones 2 as a result of a condensation reaction with 2-amino thiophenol 19 followed by sulfur extrusion (entry f). Acetylenic ketones have also been employed as dienophiles in Carbonyl-Alkyne-Exchange (CAE) reactions with dienes 22 (derived from 2,2-dialkyl-2,3-dihydro-4//-pyran-4-ones )(entry g) or 24 (entry h) to yield aromatic compounds 23 and 25 in a highly regioselective way. 

P-ffeto esters tt-methylene ketones The anhydride (1) undergoes Diels-Alder reactions with dienes at 0-80° to give only endo-adducts usually only one of the two possible cnrfo-adducts is formed. The double bond in the adducts can be reduced without desulfurization with H2 and PdfOH) on carbon. The adducts are convertible by oxidative decarboxylation with NCS (6, 116-117) to the ketal and/or the enol thioether of a j3-keto ester, both of which are hydrolyzable to... 

Cyclobutenylideneammonium salts, and hence cyclobutenones, are formed by the [2 + 2] addition of ketenimmonium salts to acetylenes. The reaction of dimethylketenimmonium tetrafluoroborate with the acetylenes gives the salts (205) in good yield, but the reaction is not highly regioselective. The salts are, themselves, excellent dienophiles, and may be used directly in reactions with dienes. The salt (206) gives the adducts (207) and (208) with butadiene or cyclopentadiene. Dimethyl-cyclobutenone (209) has also been prepared by the adcfition of dimethylketen to methyl vinyl sulphide, followed by methylation at sulphur and elimination of dimethyl sulphide. The ketone itself is a useful dienophile, but is less reactive than its imminium salt. The cyclobutenone (209) is functionally equivalent to terelactone which is an extremely reluctant dienophile. 

The reaction with dienes can be carried out either in benzene at 60-80 °C using a,a -dibromo ketone, diene, and Fe2(CO)g... 

It was claimed that the Z-form of the allylic acetate 430 was retained in homoallylic ketone 431 obtained by reaction with the potassium enolate of 3-vinylcyclopentanone (429), after treatment with triethylborane[282]. Usually this is not possible. The reaction of a (Z)-allylic chloride with an alkenylaluminum reagent to give 1,4-dienes proceeds with retention of the stereochemistry to a considerable extent when it is carried out at -70 C[283]. 

Myrcene with its conjugated diene system readily undergoes Diels-Alder reactions with a number of dienophiles. For example, reaction with 3-meth.5i-3-pentene-2-one with a catalytic amount of AlCl gives an intermediate monocyclic ketone, which when cyclized with 85% phosphoric acid produces the bicycHc ketone known as Iso E Super [54464-57-2] (49). The product is useful in providing sandalwood-like and cedarwood-like fragrance ingredients (91). 

Thioketals are readily formed by acid-catalyzed reaction with ethane-dithiol. Selective thioketal formation is achieved at C-3 in the presence of a 6-ketone by carrying out the boron trifluoride catalyzed reaction in diluted medium. Selective protection of the 3-carbonyl group as a thioketal has been effected in high yield with A" -3,17-diketones, A" -3,20-diketones and A" -3,l 1,17-triones in acetic acid at room temperature in the presence of p-toluenesulfonic acid. In the case of thioketals the double bond remains in the 4,5-position. This result is attributed to the greater nucleophilicity of sulfur as compared to oxygen, which promotes closure of intermediate (66) to the protonated cyclic mercaptal (67) rather than elimination to the 3,5-diene [cf. ketal (70) via intermediates (68) and (69)]." " ... 

Ketals bearing the double bond at the 4,5-position are prepared by reaction with glycol in the presence of weak acids such as adipic acid. In this case ketal formation proceeds via the intermediate 2,4-dien-3-ol ether. Hemithioketals (71) of A -3-ketones are prepared by reaction with mer-... 

A -3-Ketones readily form A -dien-3-ol ethers by acid-catalyzed reaction with orthoformates. Under these conditions A" -3-ketones can be selectively protected in the presence of 17- and 20-ketones (72) (73)]. 

A -Dien-3-ol esters e.g., acetates) have greater utility as reaction intermediates than as protecting groups. They are prepared from A" -3-ketones by reaction with the acetic anhydride"" or by exchange with isopropenyl acetate. 

A"" -3-Ketones are more reactive than cross-conjugated A ""-3-ketones. A"" -3,3-CycIoethylenedioxy compounds can be easily prepared by acid-catalyzed reaction with ethylene glycol or by exchange dioxolanation. 3,3-Cycloethylenedioxy-A -dienes can be prepared from 3,3-cycloethy-lenedioxy-A -enes by allylic bromination and dehydrobromination. Acid hydrolysis yields A"" -3-ketosteroids. ... 

Another example in which A-methyl-l,2-dihydropyridine (41a) behaves as an enamine rather than a diene is its reaction with methyl vinyl ketone (44) (64JCS2165). The product is a pyran 45, which is obtained in 100% yield, rather than an isoquinuclidine derivative (80JOC1657). 

As in the case of the steroids, introduction of additional nuclear substituents yields morphine analogs of increased potency. The more important of these are derived from one of the minor alkaloids that occur in opium. Thebaine (14), present in crude opium in about one-tenth the amount of morphine, exhibits a reactive internal diene system that is well known to undergo various addition reactions in a 1,4 manner (e.g., bromination). Thus, reaction with hydrogen peroxide in acid may be visualized to afford first the 14-hydroxy-6-hemiketal (15). Hydrolysis yields the isolated unsaturated ketone (16). Catalytic reduction... 

Cyclic 1,3-diacetoxy-l,3-dienes can be generated in situ from cyclic 1,3-diketones under the influence of isopropenyl acetate. The dienes then undergo Diels-Alder reactions with maleic anhydride giving as products 1-acetoxybicycloalkane dicarboxylic anhydride derivatives (10). The procedure is also successful with cyclic 1,2- and 1,4-diketones as well as cyclic a,j3-unsaturated ketones. The products, after hydrolysis to... 

Perhaps the most striking difference between conjugated and nonconjugated dienes is that conjugated dienes undergo an addition reaction with alkenes to yield substituted cyclohexene products. For example, 1,3-butadiene and 3-buten-2-one give 3-cycIohexenyl methyl ketone. 

Acetic acid, reaction with bicyclo[2.2,1]-hepta-2,5-diene, 45, 74 reaction with dibenzyl ketone, 47, 54... 

The presence of the catalyst can also favor multiple Diels-Alder reactions of cycloalkenones. Two typical examples are reported in Schemes 3.6 and 3.7. When (E)-l-methoxy-1,3-butadiene (14) interacted with 2-cyclohexenone in the presence of Yb(fod)3 catalyst, a multiple Diels-Alder reaction occurred [21] and afforded a 1 1.5 mixture of the two tricyclic ketones 15 and 16 (Scheme 3.6). The sequence of events leading to the products includes the elimination of methanol from the primary cycloadduct to afford a bicyclic dienone that underwent a second cycloaddition. Similarly, 4-acetoxy-2-cyclopenten-l-one (17) (Scheme 3.7) has been shown to behave as a conjunctive reagent for a one-pot multiple Diels-Alder reaction with a variety of dienes under AICI3 catalysis, providing a mild and convenient methodology to synthesize hydrofluorenones [22]. The role of the Lewis acid is crucial to facilitate the elimination of acetic acid from the cycloadducts. The results of the reaction of 17 with diene... 

Fluoboric acid is also an efficacious promoter of cyclic oxo-carbenium ions (Scheme 4.24) bearing an activated double bond which, in the presence of open-chain and cyclic dienes, rapidly undergo a Diels-Alder reaction [91]. Chiral a, -unsaturated ketones bearing a -hydroxy substituents, protected as acetals, react with various dienes in the presence of HBF4, affording Diels-Alder adducts that were isolated as alcohols by hydrolysis of the acetal group by TsOH. Some examples of reactions with isoprene are reported in Table 4.23. The enantios-electivity of the reaction is dependent on the size of the substituent R on the of-carbon high levels of asymmetric induction were observed with R = z-Pr (90 1) and R = t-Bu (150 1) and low levels with R = Me (2.7 1) and R = Ph (3.0 1). Scheme 4.24 shows the postulated reaction mechanism. 

Indium trichloride [30] and methylrhenium trioxide [31] catalyze the aqueous Diels-Alder reaction of acrolein and acrylates with cyclic and open-chain dienes. Some examples of the cycloaddition of methyl vinyl ketone with 1,3-cyclohexadiene are reported in Scheme 6.18. MeReOs does not give satisfactory yields for acroleins and methyl vinyl ketones with substituents at the jS-position and favors the self-Diels-Alder reaction of diene. 

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