Addition reactions of ketenes

Chemical Properties. The chemistry of ketenes is dominated by the strongly electrophilic j/)-hybridi2ed carbon atom and alow energy lowest unoccupied molecular orbital (LUMO). Therefore, ketenes are especially prone to nucleophilic attack at Cl and to [2 + 2] cycloadditions. Less frequent reactions are the so-called ketene iasertion, a special case of addition to substances with strongly polarized or polarizable single bonds (37), and the addition of electrophiles at C2. For a review of addition reactions of ketenes see Reference 8. 

As discussed in Section 10.4 of Part A, concerted suprafacial [2tt + 2tt] cycloadditions are forbidden by orbital symmetry rules. Two types of [2 + 2] cycloadditions are of synthetic value addition reactions of ketenes and photochemical additions. The latter group includes reactions of alkenes, dienes, enones, and carbonyl compounds, and these additions are discussed in the sections that follow. 

Scheme 6.3 Product range of the addition reactions of ketene silyl acetals to various nitrones activated by thiourea catalyst...

S. Patai, (Ed.), The Chemistry of Ketenes, Allenes, and Related Compounds, Wiley, New York, 1980. H. R. Seikaly, T. T. Tidwell, Addition Reactions of Ketenes, Tetrahedron 1986, 42, 2587. 

Mukaiyama aldol reactions of silylketene acetal and pyruvate ester (eq 14) in the presence of 10 mol % Cu[(5,5)-/-Bu-box] (OTf)2 catalyst furnish the corresponding aldol product in excellent enantiomeric excess (98%). Furthermore, the addition reactions of ketene acetals derived from /-butyl thioacetate and ben-zyloxyacetaldehyde with only 5 mol % catalyst afford the aldol product in 91% ee (eq 15). It is also noteworthy that the addition of both propionate-derived (Z)- and ( )-silylketene acetals stereoselectively forms the jyn-adduct in 97% and 85% ee, respectively. 

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). 

The aromatic primary and secondary stibines are readily oxidized by air, but they are considerably more stable than their aHphatic counterparts. Diphenylstibine is a powerful reducing agent, reacting with many acids to Hberate hydrogen (79). It has also been used for the selective reduction of aldehydes and ketones to the corresponding alcohols (80). At low temperatures, diphenylstibine undergoes an addition reaction with ketene (81) ... 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Catalysis with Pt(Il) Complexes. Fujimura has recently reported the enantioselective addition reaction of isobutyrate-derived dimethyl substituted silyl ketene acetal 125 to aldehydes (Eq. 8B2.29 and Table 8B2.15) [35]. The process utilizes a novel Pt(II) complex first reported by Pregrosin and has several salient features. In this regard, the complex is readily assembled and... 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

The reaction of ketene aminals 240 and methyl propiolate for 2 days gave addition products 241 in near-quantitative yields (Scheme 18). During the heating of addition product 241 (R = H) in methanol for 16 hours, first cis-trans isomerization then ring closure occurred to give tetrahy-dropyrido[l,2-a]pyrimidin-6-one 242 (R = H) (86H2247). When the reac-... 

Table 9 Uncatalyzed aldol addition reactions of silacyclobutyl ketene acetals to aliphatic and aromatic aldehydes...

For a review of reactions of ketene imines, generated from carbene complexes by addition of isocyanides, see Ref. 3q and Aumann, R. In Organometallics in Organic Synthesis Aspects of a Modern Interdisciplinary Field de Meijere, A. tom Dieck, H., Eds. Springer-Verlag Berlin, Heidelberg, 1987, pp. 69-83. 

Irradiation of alkoxycarbene complexes in the presence of aUcenes and carbon monoxide produces cyclobutanones. A variety of inter- and intramolecular [2 + 2]cycloadditions have been reported. The regioselectivity is comparable with those obtained in reactions of ketenes generated from carboxylic acid derivatives. Cyclobutanones can be obtained with a high degree of diastereoselectivity upon reaction of alkoxy carbenes with chiral A-vinyloxazolidinones. For example, photolysis of (19) in the presence of (20) gives cyclobutanone (21) (Scheme 31). In addition to aUcoxycarbenes, carbenes having a thioether or pyrrole substituent can also be employed. Related intramolecular cycloadditions of y,5-unsaturated chromimn carbenes afford bicyclo[2.1. IJhexanones (Scheme 32). 

Ketene Additions. Reaction of the ketene derived from ibuprofen (Ar=p-isobutylphenyl) with (R)-pantolactone in the presence of simple tertiary amine bases in apolar solvents yielded >99% de favoring the (R,R)-ester (eq 9). The reaction is first order in each component and possesses a pronounced deuterium isotope effect knlko 4). The ketene from naproxen (Ar=2-(6-methoxynaphthyl)) affords a de of 80% under similar conditions. 

Enantiopure p-lactones have been obtained from the reaction of acid chlorides or ketene with aldehydes in the presence of optically active tertiary amines. The reaction of ketene with chloral has been studied in considerable detail (Scheme 2). In the presence of 2 mol % of quinidine at -SO C die p-lac-tone is formed in virtually quantitative chemical and optical yield By proper choice of the catalyst, either enantiomer of the -lactone can be obtained. The transition state picture (4) has been propos for the ketene-chloral addition in the presence of quinidine. Hydrolysis converts the -lactone to malic acid with inversion of configuration (Scheme 2). ... 

This section reviews the literature on asymmetric carbonyl additions and reductions mediated by chiral aluminum Lewis acids. This does not include aldol reactions, cycloaddition reactions, and ene reactions, each of which will be covered in separate sections. The earliest such carbonyl addition reaction to be reported was, along with the Muikaiyama aldol reaction of ketene acetal 7 (Sch. 2), the addition of trimethylsi-lyl cyanide to o-valeraldehyde [6]. The catalyst 13 did not result in asymmetric induction as high in this reaction as it did with the Muikaiyama aldol reaction of ketene acetal 7 with wo-valeraldehyde (Sch. 2). The cyanohydrin 45 was isolated in 65 % yield as a 66 34 mixture of enantiomers only. 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

As another example of novel catalysis employing montmorillonite, the clay was found to show excellent catalytic activity for the addition reaction of trimethylsilyl ketene acetal to a, -acetylenic esters (ynoates), which contrasted strikingly with the reactions induced by a homogeneous acid catalyst, trimethylsilyl triflate (TMSOTf), as well as the addition reactions of lithium enolates with ynoates [Eq. (17)] (89). Table XXIII summarizes the results of the reactions of the silicon and lithium enolates of methyl propionate (21) with ynoates (22a-c). Except for the reaction of 22c, ferric ion-exchanged montmorillonite (Fe-Mont), which is more acidic than Al-Mont, catalyzed exclusive 1,2-additions of trimethylsilyl ketene acetal to 22a and 22b to give 23 in... 

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