Lewis acid—catalyzed carbonyl ene reaction

Ene reactions and carbonyl-ene reactions are synthetically interesting reactions and one of the most direct approaches for aUyl functionalizations. However, the often high activation energy for these reaction requires highly activated substrates and/or high temperatures that is a strongly limitation to these reactions. This also limits the application of in asymmetric catalysis and majority of these reactions developed so far are asymmetric Lewis acid catalyzed carbonyl-ene reactions [84]. 

Sol 3. (i) In case of carbonyl ene reactions, addition of Lewis acids makes the enophiles more electrophilic, so the reaction can be performed at lower temperature. This also improves the yields, regio- and stereoselectivities of the carbonyl ene reactions. For example, in the Lewis acid—catalyzed carbonyl ene reaction between 2-methylhepta-2,6-diene and oxamalonate, a positive charge develops at the ene component due to which the trisubstimted alkene becomes more reactive than the monosubstituted alkene. 

The presence of the silyl substituent at the olefinic carbon provides an important featnre in the regio- and stereochemical control of the Lewis acid-catalyzed carbonyl-ene reactions which gives 230 (equation 188). The changeover of the olefinic stereoselectivity from trans to cis is observed (c/231a) (eqnation 189). when R is a silyl gronp ". Withont a silyl group (R = H) trans product 231b is obtained predominantly. It is noteworthy... 

The Lewis-acid-catalyzed carbonyl-ene reaction represents an important alternative method for the addition of an allyl group to a carbonyl group (Equation 23). The resulting secondary homoallylic alcohols are amenable to a number of structural modifications and constitute useful synthetic building blocks. Because the olefin of the products can be a surrogate for a carbonyl functionality, these homoallylic alcohol are formally the synthetic equivalent of aldol addition products. Powerful asymmetric versions of the carbonyl-ene reaction [196, 197] provide an important alternative to the more traditional allylation methods, which primarily employ silanes, boranes, or stannanes (see Chapter 5). 

As an example of asymmetric intermolecular sigmatropic rearrangement, chiral Lewis acid promoted carbonyl-ene reactions have been utilized as the powerful tool for stereocontrolled carbon-carbon bond formation processes. In 2004, Mamoka et al. demonstrated enantioselective hetero-carbonyl-ene reaction of aldehydes and 2-methoxypropene catalyzed by chiral organoaluminum complex 64, giving enantiomerically enriched (3-hydroxymethylketones (Scheme 45) [78]. 

The use of Lewis acid catalysts greatly expands the synthetic utility of the carbonyl-ene reaction. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3.35 Sc(03SCF3)3 has also been used to catalyze carbonyl-ene reactions.36... 

Reaction of alkenes with carbonyl compounds or carbonyl derivatives in the presence of Lewis acids, the ene reaction, enables the stereoselective preparation of highly functionalized compounds. Copper Lewis acids activate both aldehydes and imines in ene reactions. Evans has reported that Cu(II) Lewis acids catalyze glyoxylates in reactions with alkenes (Sch. 56) [103]. The homoallylic alcohols 257 and 259 are produced in high yield and enantioselectivity. The bis aquo complex 260 is a readily prepared and air-stable catalyst and gave high chemical yield and excellent selectivity in the ene reactions. Another point of note is that catalysts 260 and 261 furnish enantiomeric products even though they differ from each other only by the substituent at the 4-posi-tion of the oxazoline. 

Most carbonyl-ene reactions used in synthesis are intramolecular and can be carried out under either thermal or catalyzed conditions,43 but generally Lewis acids are used. Stannic chloride catalyzes cyclization of the unsaturated aldehyde 5. 

The scheme below depicts the novel use of a carbonyl ene cyclization (A, Lewis acid-catalyzed) and a closely related Prins cyclization (B, Brpnsted acid-catalyzed) to generate predominantly trans (cyclization condition A) or cis (cyclization condition B), di and tri substituted piperidines 160 and 161 <06JOC2460 06OBC51>. Of note, in the formation of di-substituted derivatives, R1 = H and R2 = Ph, no reaction occurs under cyclization condition B and the cis isomer 160 is obtained exclusively under cyclization condition A. In the case of tri-substituted derivatives, when bulky substituents at the 2-position (R1 = f-Bu or Ph) are present the trans diastereomer 161 is obtained almost exclusively under cyclization condition A, while no diastereoselectivity is seen under cyclization condition B. 

The enantiopure BIPHEP-Pt complexes can act as chiral Lewis acids for the enantioselective Diels-Alder and carbonyl-ene reactions. The Diels-Alder products are obtained in 92-94% ee (93 7 = endo exo) and 92-94% ee (94 6 = endo exo) by (R)- and (5)-36, respectively (Scheme 8.3 la)." In the carbonyl-ene reaction catalyzed by the dication species generated from BlPHEP-PtCL 35 and AgSbFs, the (S )- and (/ )-ene products are obtained with 71% ee (99% conversion at room temperature) and 70% ee (90% conversion at room temperature) from (/ )- and (S)-35, respectively (Scheme 8.31b). 

The ene reaction is strongly catalyzed by Lewis acids such as aluminum chloride and diethylaluminum chloride204 Coordination by the aluminum at the carbonyl group increases the electrophihcity of the conjugated system and allows reaction to occur below room temperature, as illustrated in Entry 6. Intramolecular ene reactions can be carried out under either thermal (Entry 3) or catalyzed (Entry 7) conditions 205 Formaldehyde in acidic solution can form allylic alcohols, as in entry 1. Other carbonyl ene reactions are carried out with Lewis acid catalysts. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3 206 Sc(03SCF3)3 has also been used to catalyze ene reactions.207... 

Scheme 8C.X. Carbonyl-ene reaction catalyzed by chiral Lewis acids.

U nder thermal or Lewis acid catalyzed conditions, reactions of fluoroalkyl carbonyl compounds with alkenes usually provide the ene adduct. " One example of a [2 + 2] cycloaddition between hexafluoroacetone and an alkyne has been reported. ... 

ZnCh catalyzed ene reaction of methyl vinyl ketone and acrolein with p-pinene in ether at 25 C gives the expected ene adducts in 62% and 32% yields, respectively. Methyl vinyl ketone is reported to undergo AICI3 catalyzed ene reactions with limonene, carvone and perillaldehyde. Although Lewis acid catalyzed ene reactions of acrolein and methyl vinyl ketone with alkenes are probably general, the initial products often cannot be isolated since the unsaturated carbonyl compound undergoes an intramolecular Lewis acid catalyzed type II ene reaction. ... 

In a clever piece of work, Snider et al. have used a quasi intramolecular carbonyl Diels-Alder cycloaddition to produce a key intermediate for syntheses of pseudomonic acid A (175) (Scheme 20). Thus a Lewis acid catalyzed ene reaction of alkene (170) and formaldehyde afforded (171), which com-plexed with additional formaldehyde to give (172). Intramolecular [4 + 2] cycloaddition of (172) gave adduct (173) which produced dihydropyran (174) upon hydrolysis. 

Ciufolini et al. developed carbonyl-ene reactions catalyzed by the 1 1 complex of Yb(fod)3 and acetic acid [19]. 2-Methoxypropene reacted with a variety of aldehydes under the conditions used, providing the protected alcohols in good yields (Eq. 9). Addition of acetic acid was essential —the reaction did not proceed with Yb(fod)3 alone. Addition of silica gel to the reaction mixture was found to enhance the rate of the reaction and to make the reaction clean, although the use of silica gel was not mandatory. Double activation of the aldehydes as a result of coordination to the Yb Lewis acid and hydrogen-bonding with the acidic hydrogen of the acetic acid was proposed for the reaction (Fig. 2). 

Thermal and Lewis acid catalyzed ene reactions of electron-deficient ketones proceed in good yield. Dialkyl oxomalonate esters " and pyruvate esters have been most extensively studied. 1,2,3-Tri-ketones, methyl phenylglyoxylate, carbonyl sulfide, carbonyl cyanide, hexafluoroacetone, hexafluorocyclobutanone and 1,1,1-trifluoromethyl ketones have also been developed as enophiles. 

Lewis acid are effective catalysts for the ene reaction in many ene-ene or ene-yne reactions, although they are most effective with carbonyl ene reactions (see below). Buchwald and co-workers, for example, reported a titanocene-catalyzed intramolecular ene reaction in which ene-yne 689 was treated with Cp2Ti(CO)2 in hot toluene to give a 97% yield of ene product 690. 

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