Lewis acid carbonyl compound reactions

There have been few mechanistic studies of Lewis acid-catalyzed cycloaddition reactions with carbonyl compounds. Danishefsky et ah, for example, concluded that the reaction of benzaldehyde 1 with trans-l-methoxy-3-(trimethylsilyloxy)-l,3-di-methyl-1,3-butadiene (Danishefsky s diene) 2 in the presence of BF3 as the catalyst proceeds via a stepwise mechanism, whereas a concerted reaction occurs when ZnCl2 or lanthanides are used as catalysts (Scheme 4.3) [7]. The evidence of a change in the diastereochemistry of the reaction is that trans-3 is the major cycloaddition product in the Bp3-catalyzed reaction, whereas cis-3 is the major product in, for example, the ZnCl2-catalyzed reaction - the latter resulting from exo addition (Scheme 4.3). 

The best carbonyl components for these reactions are highly electrophilic compounds such as glyocylate, pyruvate, and oxomalonate esters, as well as chlorinated and fluorinated aldehydes. Most synthetic applications of the carbonyl-ene reaction utilize Lewis acids. Although such reactions may be stepwise in character, the stereochemical outcome is often consistent with a cyclic TS. It was found, for example, that steric effects of trimethylsilyl groups provide a strong stereochemical influence.28... 

Another example of the use of Lewis acids in organic reactions in water is the lan-thanide(III) triflate catalysed aza-Diels-Alder reaction, exemplified in Scheme 14. In this reaction the hetero-dienophile is formed in situ from a primary ammonium hydrochloride and a carbonyl compound followed by the actual Diels-Alder reaction288,289. This type of reaction proceeds readily in aqueous media290-296, and a dramatic increase in the yield upon addition of lanthanide triflates was observed288,289. The exact role of the catalyst, however, is not entirely clear. Although it was suggested that the catalyst binds to the dienophile, other mechanisms, such as simple proton catalysis, are also plausible. Moreover, these reactions are further complicated since they are often heterogeneous. 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

Lewis acids catalyze electrophilic reactions of carbonyl compounds with phenols. Reaction of ethyl pyruvate and 1-naphthol in the presence of a dibomacyclopentadienyl Zr(IV) complex affords the ortho-hy-dtoxyalkylated product in up to 87% ee (Scheme 121). Intervention of a Zr naphthoxide intermediate has been proposed, and addition of a small amount of water increases the enantioselectivity (293). 

Zulfiqar, F. and Kitazume, T. (2000) Lewis acid-catalysed sequential reaction in ionic liquids. Green Chem., 2, 296-297. Kamal, A. and Chouhan, G. (2004) Investigations towards the chemoselective thioacetalization of carbonyl compounds by using ionic liquid [bmim]Br as a recyclable catalytic medium. Adv. Synth. Catal., 346 (5), 579-582. 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

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. ... 

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. 

Titanium compounds are frequently investigated as Lewis acids in radical reactions [677-680]. When addition of an alkyl radical to a chiral vinylsulfoxide was conducted in the absence or presence of Ti(0-/-Pr)2Cl2, the stereochemistry of the product was reversed, very high diastereoselectivity being observed in the presence of the titanium salt (Eq. 302) [681,682]. The stereochemistry and high selectivity in the presence of the titanium salt were readily rationalized on the basis of a chelation intermediate between the titanium metal and the carbonyl and sulfoxide oxygens, as shown in Eq. (302). 

Lewis acid-catalysed decompositions. Reactions in which the azide (derived from an alcohol or carbonyl compound) is not isolated, but reacts further to give various products (Schmidt reaction), are included. 

Lewis acid-promoted allylation reactions of carbonyl compounds with allyltrialkyltin were reported, (a) Yamamoto, Y Yatagai, H. Naruta, Y Maruyama, K. J. Am. Chem. Soc. 1980, 102, 7107. (b) Pereyre, M. Quintard, J.-R Rahm, A. Tin in Organic Synthesis, Butterworths, London, 1987, p 216. 

Enolates are undoubtedly the most versatile intermediates for C-C, C-N, C-O bond-forming reactions [36]. Continuous progress has been made not only in fundamental operations involving these anionic species but also during the synthesis of complex natural products. Compared with metal enolates with counter cations of, e.g., B, Si, Li, Na, K, Mg, Ti, Sn, Cu, etc., aluminum enolates have found fewer apphcations, probably because no particular advantages over the other metals have been perceptible. There are, however, still intriguing aspects of novel reactivity and selectivity in the formation and reaction of aluminum enolates. Specifically, very recent development have highhghted pre-formation of Lewis acid-carbonyl complexes by use of bulky aluminum compounds as precursors of aluminum enolates the behavior of these complexes is unprecedented. 

As described in the sections above, it is well established that reactions of Lewis acid-activated aldehydes and ketones with silyl enolates afford -hydroxy or /7-sil-oxy carbonyl compounds (Mukaiyama aldol reactions). Occasionally, however, ene-type adducts, that is /-siloxy homoallyl alcohols, are the main products. The first example of the carbonyl-ene reaction of silyl enolates was reported by Snider et al. in 1983 [176]. They found that the formaldehyde-MesAl complex reacted smoothly with ketone TMS enolates to give y-trimethylsiloxy homoallyl alcohols in good yield. Yamamoto et al. reported a similar reaction of formaldehyde complexed with methylaluminum bis(2,6-diphenylphenoxide) [177]. After these early reports, Kuwajima et al. have demonstrated that the aluminum Lewis acid-promoted system is valuable for the ene reactions of several aldehydes [178] and for-maldimine [179] with silyl enolates bearing a bulky silyl group. A stepwise mechanism including nucleophihc addition via an acyclic transition structure has been proposed for the Lewis acid-promoted ene reactions. 

Under high-pressure (0.8 GPa) the alkenylation of carbonyl compounds 196 with phosphonate 197 [Horner-Wadsworth-Emmons (HWE) reaction] is accomplished efficiently (50-90% yields) at room temperature in the presence of triethylamine without further activation by Lewis acid. In contrast, reactions carried out at atmospheric pressure give negligible yields (0—8%) (Scheme 7.50). 

Ene reactions involve the addition of a compound bearing a double bond (enophile) to an olefin possessing an allylic hydrogen atom (ene). They can be thermally activated, but, as the enophile, like the dienophile in the Diels-Alder reaction, should be electron deficient, complexation with a Lewis acid increases the reaction rate thus allowing to carry out the reaction under milder conditions. On the other hand Bronsted acids can also catalyze the reaction through protonation of the carbonyl group and rearrangement to form a more stable carbonium ion. 

Under Lewis add catalysis, the reaction of allylsilanes takes place easily with a-enones but not with a,P-unsaturated esters [162]. Because disappointing results were obtained in reactions of allylmetals with a,P-unsaturated carbonyl compounds, reactions of allylsilanes with electrophiles bearing chiral auxiliaries have been examined. Schultz and Lee [1435] performed the T1CI4 catalyzed addition of trimethylallylsilane to compound 7.67 at -78°C. After treatment with methylhy-droxylamine in acidic media, the 1,4-adduct 7.80 was obtained with high ee (Figure 7.56). Under similar conditions, N-enoyloxazolidinone 7.68 (R = Ph) or sultam... 

---