Cycloaddition of Ketenes and Aldehydes

In the [2 + 2]cycloaddition chemistry, enantioselective carbo[2 + 2]cycloaddition catalyzed by chiral Al(III) Lewis acids has not been reported. On the other hand, catalytic enantioselective [2 + 2]cycloaddition of ketenes and aldehydes is well known. As the pioneering work, Miyano and coworkers reported that substoichiometric amount of chiral Lewis acid (S)-(46a) prepared from (S)-BINOL derivative and Me3Al promotes [2 + 2]cycloaddition of aldehydes and ketene to give P-lactones in moderate optical yield (Scheme 6.106) [125]. The same research group also reported (R,R)-(116a) as a more effective Lewis acid catalyst. 

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 existence of ketenes was established over a hundred years ago, and, in recent years, asymmetric synthesis based on [2 + 2] cycloadditions of ketenes with carbonyl compounds to form chiral p-lactones has been achieved with high yields and high stereoselectivities. In 1994, Miyano et al. reported the use of Ca-symmetric bis(sulfonamides) as ligands of trialkylaluminum complexes to promote the asymmetric [2 + 2] cycloaddition of ketenes with aldehydes. The corresponding oxetanones were obtained in good yields and enantioselectivities... 

It has been long established that Lewis acid-catalysed [2+2] cycloaddition of ketenes and carbonyl compounds provides access to 2-oxetanones. In the development of this reaction prior to 1996, there has been a specific focus on controlling the stereochemistry of the /3-lactone product and cycloadditions have been achieved between trimethyl-silylketene and aldehydes with up to 90% stereoselectivity, as discussed in CHEC-II(1996) <1996CHEC-II(1)721>. CHEC(1984) and CHEC-II(1996) also discuss examples of the Lewis acid-catalyzed, nonphotolytic [2+2] cycloaddition of electron-rich alkenes with aldehydes or ketones <1984CHEC(7)363, 1996GHEC-II(1)721>. While this method can have some advantages over the photolytic reaction in terms of regioselectivity, no examples of this reaction have been reported in recent years. 

The hetero [2+2] cycloaddition reaction is a synthetically important reaction for the construction of 4-membered heterocyclic compounds. As far as the catalytic asymmetric reaction is concerned, however, only the cycloaddition between ketenes and aldehydes has been reported. The thus synthesized chiral oxetan-2-ones are employed as monomer precursors for the biologically degradable co-polyesters and also as chiral building blocks for natural product synthesis. Two types of catalysts. Cinchona alkaloids and a chiral Lewis acid, are known to promote this reaction. 

Cinchona alkaloids are the effective asymmetric catalysts in the [2+2] cycloaddition reaction of ketenes and aldehydes [47]. That is, the reaction between ketenes and chloral proceeds with a catalytic amount (2.5 mol %) of quinidine in toluene at -50 °C to provide the P-propionolactone (-)-18 in quantitative yield with 98% ee (Scheme 17). 

Optically active p-lactones are readily prepared by ketene-aldehyde cycloaddition using 72 as the chirality inducer.The products are excellent precursors of p-amino acids. The [2 + 2]cycloaddition of ketenes and imines in the presence of 0-benzoylqui-nine leads to numerous ciT-2,3-disubstituted p-lactams. ... 

Scheme 37 Asymmetric [2+2] cycloaddition reactions of ketene and aldehydes...

As [2 + 2]cycloaddition, carbo[2 + 2] cycloaddition of a, P-unsaturated carbonyls with vinyl ethers and P-lactone synthesis through [2 + 2]cycloaddition of ketenes with aldehydes were examined. As shown in Scheme 6.99, since under nonpho-tochemical conditions the concerted mechanism for both reactions are disallowed by Woodward-Hoffmann rules, ground-state catalytic reactions must proceed through a stepwise mechanism. 

Scheme 7.28 Formal [2+2] cycloaddition of ketenes with aldehydes and imines.

Romo et al. have used Lewis acids to catalyze the formation of a-silyl-/ -lactones in their synthesis of potential inhibitors of yeast 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) synthase <1998BMC1255>. In addition to various Lewis acid catalysts, a chiral promoter based on the chiral diol (l/ ,2R)-2-[(diphenyl)hydroxymethyl]cyclo-hexan-l-ol was introduced to the reaction in an attempt to improve the stereoselectivity. A variety of chiral 2-oxetanones were formed, with enantioselectivities ranging from 22% to 85%. Dichlorotitanium-TADDOL catalysts 113 and 114 have also been used in an attempt to encourage the stereoselective [2+2] cycloaddition of silyl ketenes and aldehydes (TADDOL = (—)-/ra r-4,5-bis(diphenyl-hydroxymethyl)-2,2-dimethyl-l,3-dioxolane), although this method only afforded 2-oxetanones in moderate yields and optical purity (Equation 41) <1998TL2877>. 

A recent study provides comments on the mechanism and origin of stereoselectivity in the Lewis acid catalyzed [2+2] cycloaddition reaction between ketenes and aldehydes to give P-lactones. The observations made in this study highlight the broad range of factors which must be pondered in order to understand and control stereoselectivity in a multistep reaction <02AG(E)1572>. 

Oxazin-4-ones are obtained by cycloadditions between ketenes and isocyanates (Scheme 167). The benzoylphe-nylketene generated from diazo compound 359 forms [4 + 2] DielsAlder adducts 361 with the C=N group of aldehyde imines 360 (Scheme 168) <2001J(P1)2266, CHEC-III(8.05.9.2)417>. 

Ketene and aldehydes undergo [2+2] cycloaddition in the presence of aluminum catalysts (Scheme 6.56). The reaction involves either isolable or in situ-generated unstable ketenes and is regarded as a variant of the aldol reaction. During the development of the Al(l I l)-calalyzed ketene-aldehyde reaction, the optically active Al(in)-triamine complex 88 was found to catalyze the cyclocondensation of acetyl bromide (AcBr) and benzyloxyacetaldehyde, with di(isopropyl)ethylamine (DIEA)... 

A C2-symmetric N,W-di-3,5-bis(trifluoromethyl)benzenesulfonyl-(ll ,21 )-l,2-diphenylethylenediamine 20-Et3Al complex promotes the [2-1-2] cycloaddition reaction between ketene and aldehydes to afford optically active 4-substituted oxetan-2-ones 21 (Scheme 20) [50]. The catalyst is prepared by mixing the bis-sulfonamide 20 and EtjAl, and the reaction proceeds by the coordination of the aldehyde to the chiral Lewis acid. 

Other titanium complexes derived from tartaric acid have been used as chiral catalysts. The complexes generated from diol 2.50 and TiCl2(0/-Pr)2 are used as catalysts in asymmetric ene-reactions [778, 816], and in Diels-Alder [778, 780] or [2+2] cycloadditions of ketene thioacetals and unsaturated sulfides [778, 817], The best enantiomeric excesses are observed with 2.50 (R = Me, R = Ph) [778, 817] or 2.50 (R = R = Et, Ar = 3,5-Me2CgH3) [45], These catalysts are also efficient in hydrophosphonylation [818] and in asymmetric hydrocyanation of aldehydes with Me3SiCN [778], These titanium complexes may be used in catalytic amounts provided that the reactions are run in the presence of molecular sieves [559,816],... 

Hetero-[2 + 2]-cycloaddition has been extensively investigated since this process provides a variety of /Mactones and /Mactams.178 There are two types of hetero-[2 + 2]-cycloaddition reaction, as illustrated in Scheme 114 one is the reaction of ketenes with aldehydes or imines to give lactones and lactams (Scheme 114, route a) and the other is the reaction of alkynes with nitrones to give lactams (Scheme 114, route b).179... 

Hattori et al. reported the cationic palladium(II)-catalyzed hetero-[2 + 2]-cycloaddition of ketene with the aldehydes 362.180 The reaction of aliphatic and aryl aldehydes 362 gave the /Mactones 363 (Scheme 115), while the reaction of the a,/Tunsaturated aldehydes 364 produced the 3,6-dihydro-z7T-pyran-2-ones 365 in good yields (Scheme 116) the reaction proceeded via the hetero-[2 + 2]-cycloaddition to give 366 first, which underwent a rearrangement to lead to 365. 

Opening of 2-iminooxetanes The easy availability of 2-iminooxetanes from Lewis acid-catalyzed cycloaddition of ketene imines and aldehydes makes it desirable to find some synthetic uses. 3-Iodocarboxamides, which are generated by reaction with HI, are sources of -lactams. Remarkably little hydroxy amides is formed. 

The same class of [2 - - 2] cycloaddition reactions between ketenes and aldehydes has been the subject of subsequent studies, which have enlarged its scope to different substrates. Thus, key contributions by Lectka and coworkers have demonstrated the applicability of zwitterionic enolates from... 

Cycloaddition of diverse types of ketenes and imines leading to the formation of P-lactams is reported. The reactions of chiral ketenes with achiral imines, chiral imines with achiral ketenes, chiral imines with chiral ketenes, and catalytic asymmetrical Staudinger reactions have been investigated. In general, a higher level of asymmetric induction is achieved using either chiral ketenes or chiral imines derived from chiral aldehydes in comparison to the use of a chiral imine derived from an achiral aldehyde with an achiral ketene. Both carboxylic acid chlorides and carboxylic acids themselves have been used as ketene precursors. 

The most general definition of click chemistry is a reaction which proceeds at room temperature, often without a solvent or catalyst, to give the reaction product in close to quantitative yields. The yields in the reactions in this book are by no means optimized, but they often approach quantitative. As an industrial chemist I am well aware that yields can be dramatically increased with modest process development efforts. Sometimes, a change of reaction temperature can have a dramatic effect, as demonstrated by Wilson and Fu who obtained a < 2 % yield of -lactones in their [2+2] cycloaddition reaction of ketenes with aldehydes at room temperature, while at —78 °C a 92 % yield of the cycloadduct is obtained... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The initial reaction between a ketene and an enamine is apparently a 1,2 cycloaddition to form an aminocyclobutanone adduct (58) (68-76a). This reaction probably occurs by way of an ionic zwitterion intermediate (75). The thermal stability of this adduct depends upon the nature of substituents Rj, R2, R3, and R. The enolic forms of 58 can exist only if Rj and/or R4 are hydrogens. If the enamine involved in the reaction is an aldehydic enamine with no 3 hydrogens and the ketene involved is di-substituted (i.e., R, R2, R3, and R4 are not hydrogens), then the cyclo-butanone adduct is thermally stable. For example, the reaction of dimethyl-ketene (61) with N,N-dimethylaminoisobutene (10) in isopropyl acetate... 

Dihydro-2H-pyran-2-ones (e. g., 4-195) are valuable intermediates in the synthesis of several natural products [67]. Hattori, Miyano and coworkers [68] have recently shown that these compounds can be easily obtained in high yield by a Pd2+-catalyzed [2+2] cycloaddition of ct, 3-unsaturated aldehydes 4-192 with ketene 4-193, followed by an allylic rearrangement of the intermediate 4-194 (Scheme 4.42). In this reaction the Pd2+-compound acts as a mild Lewis acid. a,(3-unsaturated ketones can also be used, but the yields are below 20%. 

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