Lewis acids, -cycloadditions

Alumina, silica, clays, and zeolites are increasingly used as acidic or basic supports [26], Cycloaddition reactions often require Lewis-acid catalysts if good yields are to be obtained. Clay and doped silica gel catalysts have emerged as useful alternatives to the use of Lewis acids. Cycloaddition offuran (5) under solvent-free conditions, catalyzed by K10 montmorillonite, results in a decrease in the reaction time the endo-exo relationship is no different that obtained by use of classical heating (Scheme 9.2) [27]. 

Like the intermolecular variant, the rate and regioselectivity of intramolecular Diels-Alder reactions may profoundly be affected by the use of Bronsted or Lewis acids. Cycloadditions with these added reagents frequently proceed at significantly lower temperatures, with a corresponding increase in selectivity in cases where the noncatalyzed reactions are only moderately selective. 

AlIylFp reagents [where Fp refers to the Fc(C,H5)(CO)2 residue] are examples of such reagents they are obtained by addition of the appropriate allyl chloride or tosylate to a solution of Fc(C5H5)(CO)2Na in THF at —78 "C. Chromatography on alumina allows isolation of the air-and heat-sensitive product in 80-95 % yield. In the presence of a./1-unsa turated ketones activated by an appropriate Lewis acid, cycloaddition provides stereoselectively the Fp-substituted cyclopenlane8. In the case of cyclohexenone as the acceptor, the two isomers formed in equal amounts both have a a. v-ring fusion. The Lewis acid of choice is freshly sublimed aluminum(III) bromide used in catalytic amounts (5 mol%). 

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

DIELS - ALDER Cyclohexene synthesis A 2 Thermal cycloaddition between a diene and an activated alkene or alkyrte, sometimes catalyzed by Lewis acids. 

Perfluoropolyenes also can rearrange to four-membered ring products upon fluoride ron or Lewis acid catalysis [112, II3, 114] (equations 46 and 47) These intramolecular cycloadditions are multistep processes involving carbanion or carbocation intermediates... 

Covalent fluondes of group 3 and group 5 elements (boron, tin, phosphorus, antimony, etc ) are widely used m organic synthesis as strong Lewis acids Boron trifluoride etherate is one of the most common reagents used to catalyze many organic reactions. A representative example is its recent application as a catalyst in the cycloadditions of 2-aza-l,3-dienes with different dienophiles [14] Boron trifluoride etherate and other fluonnated Lewis acids are effective activators of the... 

Chiral Cu(ll)-complexes ofbis-oxazolines as Lewis acids for catalyzed cycloaddition, carbonyl addition, and conjugate addition reactions 99PAC1407. 

A versatile synthetic route to enantiomeric ally pure Diels-Alder adducts was deduced and found dependent on the application of enantiomerically pure 5-methoxy-174a (R=Me) and 5-(l-menthyloxy)-2(5//)-furanones 174b (R = menthyl), which were expected to undergo tt-face-selective cycloaddition with dienes. The reaction was effected by heating no Lewis acid catalysts were required (Scheme 55) (88JOC1127). 

Catalytic asymmetric Diels-Alder reactions are presented by Hayashi, who takes as the starting point the synthetically useful breakthrough in 1979 by Koga et al. The various chiral Lewis acids which can catalyze the reaction of different dieno-philes are presented. Closely related to the Diels-Alder reaction is the [3-1-2] carbo-cyclic cycloaddition of palladium trimethylenemethane with alkenes, discovered by Trost and Chan. In the second chapter Chan provides some brief background information about this class of cycloaddition reaction, but concentrates primarily on recent advances. The part of the book dealing with carbo-cycloaddition reactions is... 

Gothelf presents in Chapter 6 a comprehensive review of metal-catalyzed 1,3-di-polar cycloaddition reactions, with the focus on the properties of different chiral Lewis-acid complexes. The general properties of a chiral aqua complex are presented in the next chapter by Kanamasa, who focuses on 1,3-dipolar cycloaddition reactions of nitrones, nitronates, and diazo compounds. The use of this complex as a highly efficient catalyst for carbo-Diels-Alder reactions and conjugate additions is also described. 

The main strategy for catalytic enantioselective cycloaddition reactions of carbonyl compounds is the use of a chiral Lewis acid catalyst. This approach is probably the most efficient and economic way to effect an enantioselective reaction, because it allows the direct formation of chiral compounds from achiral substrates under mild conditions and requires a sub-stoichiometric amount of chiral material. 

To achieve catalytic enantioselective cycloaddition reactions of carbonyl compounds, coordination of a chiral Lewis acid to the carbonyl functionality is necessary. This coordination activates the substrate and provides the chiral environment that forces the approach of a diene to the substrate from the less sterically hindered face, introducing enantioselectivity into the reaction. 

The catalytic enantioselective cycloaddition reaction of carbonyl compounds with conjugated dienes has been in intensive development in recent years with the main focus on synthetic aspects the number of mechanistic studies has been limited. This chapter will focus on the development and understanding of cycloaddition reactions of carbonyl compounds with chiral Lewis acid catalysts for the preparation of optically active six-membered ring systems. 

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 reaction course of the cycloaddition reaction can also be dependent on the Lewis acid complex used as the catalyst. When the substrate contains an allylic C-H bond, both a cycloaddition and an ene reaction can occur. In the reaction of glyoxylate 4 with 2,3-dimethyl-l,3-butadiene 5 both the cycloaddition product 6... 

The mechanism of the reaction of ethyl glyoxylate 4 with 2,3-dimethyl-l,3-hutadiene 5 leading to the ene product 7 is shown in Scheme 4.5. This brief introduction to the reaction mechanism for cycloaddition reactions of carhonyl compounds activated hy Lewis acids indicates that many factors influence the course of the reaction. 

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. 

The mechanism of the cycloaddition reaction of benzaldehyde 2a with Danishefsky s diene 3a catalyzed by aluminum complexes has been investigated theoretically using semi-empirical calculations [14]. It was found that the reaction proceeds as a step-wise cycloaddition reaction with the first step being a nucleophilic-like attack of Danishefsky s diene 2a on the coordinated carbonyl compound leading to an aldol-like intermediate which is stabilized by interaction of the cation with the oxygen atom of the Lewis acid. The next step is the ring-closure step, giving the cycloaddition product. 

Chiral boron(III) Lewis acid catalysts have also been used for enantioselective cycloaddition reactions of carbonyl compounds [17]. The chiral acyloxylborane catalysts 9a-9d, which are also efficient catalysts for asymmetric Diels-Alder reactions [17, 18], can also catalyze highly enantioselective cycloaddition reactions of aldehydes with activated dienes. The arylboron catalysts 9b-9c which are air- and moisture-stable have been shown by Yamamoto et al. to induce excellent chiral induction in the cycloaddition reaction between, e.g., benzaldehyde and Danishefsky s dienes such as 2b with up to 95% yield and 97% ee of the cycloaddition product CIS-3b (Scheme 4.9) [17]. 

A simple approach for the formation of 2-substituted 3,4-dihydro-2H-pyrans, which are useful precursors for natural products such as optically active carbohydrates, is the catalytic enantioselective cycloaddition reaction of a,/ -unsaturated carbonyl compounds with electron-rich alkenes. This is an inverse electron-demand cycloaddition reaction which is controlled by a dominant interaction between the LUMO of the 1-oxa-1,3-butadiene and the HOMO of the alkene (Scheme 4.2, right). This is usually a concerted non-synchronous reaction with retention of the configuration of the die-nophile and results in normally high regioselectivity, which in the presence of Lewis acids is improved and, furthermore, also increases the reaction rate. 

The inverse electron-demand catalytic enantioselective cycloaddition reaction has not been investigated to any great extent. Tietze et al. published the first example of this class of reaction in 1992 - an intramolecular cycloaddition of heterodiene 42 catalyzed by a diacetone glucose derived-titanium(IV) Lewis acid 44 to give the cis product 43 in good yield and up to 88% ee (Scheme 4.31) [46]. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Several titanium(IV) complexes are efficient and reliable Lewis acid catalysts and they have been applied to numerous reactions, especially in combination with the so-called TADDOL (a, a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol) (22) ligands [53-55]. In the first study on normal electron-demand 1,3-dipolar cycloaddition reactions between nitrones and alkenes, which appeared in 1994, the catalytic reaction of a series of chiral TiCl2-TADDOLates on the reaction of nitrones 1 with al-kenoyloxazolidinones 19 was developed (Scheme 6.18) [56]. These substrates have turned out be the model system of choice for most studies on metal-catalyzed normal electron-demand 1,3-dipolar cycloaddition reactions of nitrones as it will appear from this chapter. When 10 mol% of the catalyst 23a was applied in the reaction depicted in Scheme 6.18 the reaction proceeded to give a yield of up to 94% ee after 20 h. The reaction led primarily to exo-21 and in the best case an endo/ exo ratio of 10 90 was obtained. The chiral information of the catalyst was transferred with a fair efficiency to the substrates as up to 60% ee of one of the isomers of exo3 was obtained [56]. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

For the activation of a substrate such as 19a via coordination of the two carbonyl oxygen atoms to the metal, one should expect that a hard Lewis acid would be more suitable, since the carbonyl oxygens are hard Lewis bases. Nevertheless, Fu-rukawa et al. succeeded in applying the relative soft metal palladium as catalyst for the 1,3-dipolar cycloaddition reaction between 1 and 19a (Scheme 6.36) [79, 80]. They applied the dicationic Pd-BINAP 54 as the catalyst, and whereas this type of catalytic reactions is often carried out at rt or at 0°C, the reactions catalyzed by 54 required heating at 40 °C in order to proceed. In most cases mixtures of endo-21 and exo-21 were obtained, however, high enantioselectivity of up to 93% were obtained for reactions of some derivatives of 1. 

The author has been involved for quite a long time in the study of Lewis acid catalysis of 1,3-dipolar cycloaddition reactions. From his research group, a series of methodologies directed to the Lewis acid-mediated stereochemical and regiochem-ical control of 1,3-dipolar cycloaddition reactions has been reported this includes ... 

I 7 Aqua Complex Lewis Acid Catalysts for Asymmetric J+2 Cycloaddition Reactions... 

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