Enone, conjugate carbonyl addition

Whereas, the sulfur ylide 9 undergoes conjugate addition to enones thereby precluding 1,2-cyclopentyl annulation, the organolithium 37a undergoes clean carbonyl addition. Cyclopentenone participates smoothly in this sequence (Eq. 88)81>. 

More recently, using the cyclometallated iridium C,(7-benzoate derived from allyl acetate, 4-methoxy-3-nitrobenzoic acid and BIPHEP, catalytic carbonyl crotylation employing 1,3-butadiene from the aldehyde, or alcohol oxidation was achieved under transfer hydrogenation conditions [274]. Carbonyl addition occurs with roughly equal facility from the alcohol or aldehyde oxidation level. However, products are obtained as diastereomeric mixtures. Stereoselective variants of these processes are under development. It should be noted that under the conditions of ruthenium-catalyzed transfer hydrogenation, conjugated dienes, including butadiene, couple to alcohols or aldehydes to provide either products of carbonyl crotylation or p,y-enones (Scheme 16) [275, 276]. 

Use of proline as a catalyst has become an important methodology in the catalytic asymmetric addition of stabilized carbanions to conjugated carbonyl compounds. Hannessian employed L-proline (S)-l in the addition of nitroalkanes to enones (Scheme 1) [5]. In the presence of 3-7 mol % of (S)-l and an excess of trans-2,5-dimethylpiperazine in chloroform, comparable or higher enantiose-lectivities were attained compared to the Yamaguchi s method using L-proline... 

Aldehydes are susceptible to oxidation to the corresponding carboxylic acid, but ketones are generally not oxidized under pharmaceutically relevant conditions. When ketones are conjugated with one or more double bonds, as in the case of an a,(3-unsaturated ketone (also called an enone ), the carbonyl is less electrophilic but is still susceptible to nucleophilic attack at either the carbonyl carbon (1,2-addition) or at the (3-carbon (1,4-addition, or Michael addition ) (Fig. 22). 

Michael additions to conjugated carbonyls can be catalyzed by gold species. Among them, arene additions are the most studied area but other nucleophiles can attack the gold-coordinated enones as well. In fact, the intermolecular aza-Michael additions of carbamates to enones was reported in 2002 with both Au(I) and Au(III) salts, and in 2007 an intramolecular aUcoxide and amide conjugate addition has been developed and applied to the synthesis of (+)-andrachcinidine (equation 132). In the latter case, the enones are formed as intermediates in a previous gold-catalyzed step that is the hydration of an alkyne and methanol loss. Then the cyclization takes place to give piperidines. 

The tin(IV) enolate can be quenched with a variety of electrophiles to form new carbon-carbon bonds, including carbonyl addition (aldol-type) reactions, alkylations and conjugate additions of tin(IV) enolates. Tin(IV) enolates react readily with aldehydes in both intra- and intermolecular aldol-type reactions [5J]. The best conditions for the intermolecular aldol condensation reaction were to initially generate the tin enolate by reacting the desired enone with tributyltin hydride and then... 

Reaction with Cyclic Enones. Conjugate addition of azide ion to cyclic enones in water using sodium azide in the presence of Lewis base resulted in the formation of 8-azido carbonyl compounds (eq 55). The Schmidt reaction of benzopyranones with sodium azide led to pyrano[3,2-b]azepines in reasonable yields (eq 56). 

DFT calculations have been used to obtain mechanistic insights into the reaction of sulfur ylides PhHC (S+Me2) with dienals and enones by identifying all key transition states and intermediates along the reaction pathway for the 1,2-, 1,4-, and 1,6-nucleophilic attacks at PhCH=CHCH=CHCH=0 and for the 1,2- and 1,4-attacks at MeCH=CHCOMe. The final outcome of the reaction with both substrates has been found to be decided by the interplay between kinetic and thermodynamic factors. Thus, addition of a semi-stabilized ylide to conjugated carbonyl compounds prefers the 1,4-pathway under thermodynamic conditions, in consonance with the experimental reports. However, the formation of epoxides via a 1,2-addition pathway is equally competitive and could be favoured under kinetic conditions. The 2,3-trans cyclo-propanecarbaldehyde is the major product of the 1,4-addition pathway. The enone also prefers the 1,4-addition. ... 

Furthermore, acyclic enones containing an additional non—conjugated carbonyl group were selectively reduced at the double bond under 40 psi with 10% Pd/C in ethyl acetate (Eq. b. Scheme 4)." -" ... 

However, TMEDA unlike HMPA, does not cause flow over from a carbonyl to conjugate addition manifold for many lithiated systems. For example, lithiated allylic sulfides undergo conjugate (or 1,4 ) addition to cyclopent-2-enone in the presence of HMPA (see Allyl Phenyl Sulfide), but in the presence of TMEDA, carbonyl addition only is observed. The perception that TMEDA is unable to form solvent-separated ion pairs required for conjugate addition in this case now requires reevaluation. j In the reaction of lithio a-trimethylsilylmethyl phenyl sulfide with cy-clohexenone, HMPA promotes predominant conjugate addition, whereas TMEDA has little effect on the normal carbonyl addition pathway taken in THF alone (eq 8). ... 

The mechanism of conjugate addition reactions probably involves an initial complex between the cuprate and enone.51 The key intermediate for formation of the new carbon-carbon bond is an adduct formed between the enone and the organocopper reagent. The adduct is formulated as a Cu(III) species, which then undergoes reductive elimination. The lithium ion also plays a key role, presumably by Lewis acid coordination at the carbonyl oxygen.52 Solvent molecules also affect the reactivity of the complex.53 The mechanism can be outlined as occurring in three steps. 

Other bonds that merit attention are those connecting C(7) through C(ll). These could be formed by one of the many methods for the synthesis of ketones. Bond disconnections at carbonyl centers can involve the 0=C-C(a) (acylation, organometallic addition), the C(a)-C((3) bond (enolate alkylation, aldol addition), or C((3)-C(7) bond (conjugate addition to enone). 

In general, aldehydes constitute the more efficient radical acceptors. Surprisingly, when enones were employed as radical acceptors 1,2-addition to the carbonyl group was in some cases preferred over the conjugate 1,4-addition [116]. 

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