Reactions with a,p-Unsaturated Ketones

PdCI2(PPh3)2-catalyzed 1,2-selective acylation (Conditions A). 

The PdCl2(PPh3)2-catalyzed (5 mol%) reaction of n-nonanoylzirconocene chloride with l-phenylhept-2-yn-l-one leads to selective formation of the 1,4-acylation product in 85% yield with a slight preference for the Z-isomer (EjZ = 1/2.4). A trace amount 

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Z)-(3-Silyloxyacrylonitriles 95 undergo cycloaddition reactions with a,P-unsaturated ketones to form a dihydro-pyran intermediate, which eliminates trimethylsilanol to furnish 3-cyano-4//-pyrans (Scheme 31) <1997S628>. 

Reaction with a,p-unsaturated ketones after transmetallation... 

As in hydrogen transfer between alcohols and saturated ketones, the rate-determining step in the reaction with a,p-unsaturated ketones is hydrogen abstraction from the a-carbon atom. It has been suggested that the hydrogen atom is transferred directly to the P-carbon of the enone, yielding an in -oxaallyl complex which following protonation yields the saturated ketone. ... 

In the reaction with a,p-unsaturated ketones (18), 2-lithio-1,3-dithiane (17 R = H) produces 1,2-adduct (20) in THF. By addition of HMPA (1-2 equiv.) to the reaction mixture, 1,4-addition is successfully attained (equation 11). It is noteworthy that the lithio derivative of 2-aryl-1,3-dithiane regiospecifically adds to 2-cyclohexenone in a 1,4-maimer (25 C in THF). °... 

Reaction with a,P-unsaturated ketones and lactones. The reactivity of ot,/ -enones to singlet oxygen depends on the conformation. Systems that exist in s-trans-conformations (e.g., A4-3-ketosteroids) react slowly if at all. However, j-cis-enones react readily. For example, (R)-(+)-pulegone (1) reacts to give the products 2-4. The same products are obtained by oxidation with triphenyl phosphite ozonide (3, 324-325). 

Reactions of organomagnesium compounds with a,(3-unsaturated esters show a somewhat greater tendency to conjugate addition than reactions with a,p-unsaturated ketones (see p. 124). However, copper(i) catalysis may be beneficial even in cases where conjugate addition is the main uncatalysed reaction [30] ... 

Yamamoto et al. have been trying to synthesize limonene by a biomimetic cyclization of nerol (37) derivatives. The principle is to use the chiral derivative 523 and an alkylaluminum. After much experimentation,the best conditions were with the reagent 524 in CCI3F, when 77% ee of (-I-)-limonene (285) was obtained.It is widely believed still that the Wolff-Kishner reduction of optically active carvone (281) will yield optically active limonene (e.g., see Ref. 16, p. 152), a reaction reported by Friedman and Miller." This was already doubtful (Friedman and Miller gave no experimental evidence), since Jeger et al. had shown in 1950 that the Wolff-Kishner reaction with a,p-unsaturated ketones displaces the double bond, but Akhila and Banthorpe have now shown conclusively that (-)-carvone (281) yields ( )-limonene [( -285] by the Wolff-Kishner reaction. ... 

An essential difference between RLnl and RMgX in reactivity has been found in the reactions with a,P-unsaturated ketones [88-90]. Grignard reagents give mainly the products of 1,4-addition, whereas REM derivatives are added exclusively in 1,2-positions. 

Scheme 38,9 Enantioselective Diels-Alder reactions with a,P-unsaturated ketones.

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

A somewhat different result is obtained on reaction of methyleneoxophosphorane 9 (generated thermally from 7) with a,p-unsaturated ketones. Owing to the unusual thermal stability of 713,24> the reaction is carried out in a melt of the trapping reagents at 125 °C. Not surprisingly, the same product spectrum as for photolysis is initially observed, i.e. formation of oxaphosphetanes 22b-d (14-26%) and of... 

Thiazine derivatives have been obtained by reactions of primary thioamides with a,p-unsaturated ketones (Scheme 26).53... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Palladium-catalysed C-C bond formation under Heck reaction conditions, which normally requires anhydrous conditions and the presence of copper(I) salts, is aided by the addition of quaternary ammonium salts. It has been shown that it is frequently possible to dispense with the copper catalyst and use standard two-phase reactions conditions [e.g. 18, 19]. Tetra-/i-butylammonium salts catalyse the palladium-catalysed reaction of iodoarenes with alkynes to yield the arylethynes in high yield [20, 21], whereas the reaction with 3-methylbut-1 -yn-3-ol (Scheme 6.30) provides a route to diarylethynes [22]. Diarylethynes are also formed from the reaction of an iodoarene with trimethylsilylethyne [23], Iodoalkynes react with a,p-unsaturated ketones and esters to produce the conjugated yne-eneones [19],... 

The regio- and diastereo-selectivity of the Michael addition of 2-phenylcyclo-hexanone with a,p-unsaturated ketones are dependent on the reaction conditions. Mixtures of all six diastereoisomers resulting from reaction at either the 2- or 6-position of the cyclohexanone ring can be obtained using solid potassium hydroxide with tetra-n-butylammonium or A-benzylephcdrinium bromide catalysts. At 20°C with tetra-n-butylammonium bromide, the ratio of the 2,2- and 2,6-disubstituted cyclohexanones is ca. 3 2, but at higher temperatures with solid potassium f-butoxide the kinetically formed 2,6-isomer predominates (ca. 5 1) with the (2S,6R, R )-stereoisomer dominant, whereas greater amounts of the thermodynamically preferred 2,2-(2S,lR )-isomer are obtained with the chiral catalyst [61]. 

The catalysed reaction of a,p-unsaturated ketones with dialkylzincs and oxygen leads to the formation of chiral acyloxiranes. The initially formed intermediate complex between the chiral (3-hydroxyamine and the dialkylzine (cf. Scheme 12.9) is oxidized to the peroxyalkylzinc complex prior to the formation of the chiral oxirane (Scheme 12.13) [28]. 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

In 2006, Yamamoto and Nakashima picked np on this and designed a chiral A -triflyl phosphoramide as a stronger Brpnsted acid catalyst than the phosphoric acids based on this concept. In their seminal report, they disclosed the preparation of new chiral BINOL-derived A -triflyl phosphoramides and their application to the asymmetric Diels-Alder (DA) reaction of a,p-unsaturated ketones with sily-loxydienes [83], As depicted in Scheme 59, chiral A-triflyl phosphoramides of the general type 4 are readily synthesized from the corresponding optically active 3,3 -substituted BINOL derivatives 142 through a phosphorylation/amidation route. 

For example, the formation of mixtures of 4,5- and 4,7-dihydroisomers 45 and 46 was observed by Werman and Hartman [79] in the reaction of 3-amino-l,2,4-triazole with two equivalents of methylarylketone in the presence of ZnCl2 as a catalyst (Scheme 20). The ratios between two position isomers were from 50 50 to 74 26. However, Desenko et al. [80] established that treatment of the same starting compounds under acidic catalysis (acetic or mineral acids) yielded only 4,5-dihy-droderivatives 46 and heterocycles 47 [81]. In the latter case, the third component of the multicomponent condensation was the solvent - DMF. It is worth noting that heterocychc compounds 46 were also the products of the reaction between 3-amino-1,2,4-triazole with a,p-unsaturated ketones 48 (Scheme 20). 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

A biphenyl and ct-methylnaphthylamine-derived chiral quaternary ammonium salt 23d, which was shown by Lygo to be effective for the asymmetric alkylation of Schiffs base 20, was also effective in the Michael reaction (Scheme 7.12) [43]. Notably, the enantioselectivity was highly dependent on the reaction conditions and substrates used. The Michael reaction of imine esters such as benzhydryl and benzyl esters with a,p-unsaturated ketones under solid-liquid phase-transfer catalysis conditions afforded the Michael adduct in up to 94% ee and 91% ee, respectively, while the tert-butyl ester showed moderate enantioselectivity (Scheme 7.12). Interestingly, in contrast to earlier reports, acrylate [42] and acrylamides failed to undergo the Michael reaction under these optimized conditions. 

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