Ketenes, cycloaddition with

The limitations of the ketene method for generating cyclobutanoncs is the tendency for ketenes to dimerize as a major competing process. This can be overcome by using excess alkene and by control of reaction temperature in order to minimize dimerization. Another limitation of the ketene route is the inertness of electron-deficient alkcncs to undergo cycloaddition with ketenes. 

Chiral imines derived from D-(+)-glucose have allowed an asymmetric synthesis of p-lactams by the [2+2] cycloaddition with ketenes [85]. c/A-p-Lac tarns were formed with very high diastereoselectivity and the stereochemistry at the C-3 and the C-4 was established as 3S and 4R from the known absolute configuration of the sugar moiety (Scheme 24). 

Other examples concern [2 + 2] cycloadditions with ketenes, giving good access to fluoroal-kyl-substituted propanolactones. Reactions are conducted in the presence of Lewis acids and yields are highly dependent on the Lewis acid and on the fluoroalkyl substituent. 

For thermally induced [2 + 2] cycloadditions, the concerted mechanism is operative only in particular cases, such as in the reactions between an alkene or alkyne and a ketene. The ketene can be generated directly in the reaction mixture from the appropriate acid chloride with triethylamine. The cycloaddition reaction is stereospecific and occurs exclusively in a cis fashion. Although the intermolecular cycloaddition with ketene itself proceeds in poor yields due to the propensity of the unsubstituted ketene to undergo dimerization, it is quite an efficient reaction with ketenes containing electron-withdrawing substituents. Usually, a-chloro ketenes are employed as reagents formed in situ from the corresponding a-chloro acid chlorides. Typical examples are represented in the preparation of cycloadducts such as 378 and 379 (Scheme 2.127). The latter cycloadduct, prepared in modest yield (ca. 20%),... 

The electron-rich character of keten acetals (36) means that they undergo cycloaddition with ketens with judicious choice of reactants, this results in the formation of dihydropyran-2-ones, e.g. (37), which are hydrolysed to the dioxo-derivative (38). /3-Keto-esters are cyclized by their reaction with 3-hydroxy-aldehydes and titanium(rv) chloride to form 5,6-dihydropyran-2-ones. Aroylarylacetylenes condense with either ethyl cyanoacetate or aceto-acetate in the presence of a base to form 4,6-diarylpyran-2-ones (39)." ... 

Benzo[c]cinnoline N-acylimines and JV-alkylimines show interesting reactivities toward dimethyl acetylenedicarboxylate and some ketenes as summarized in Scheme 6.196-199 A multistep mechanism for the formation of 77 has been proposed. In contrast, the JV-(JV-phenylbenzimidoyl)imines undergo [2 + 2]-cycloaddition with ketenes to the C=N bond to give / -lactams, e.g., 78.200 201... 

Three classes of [2 -t- 2] cycloadditions do proceed under thermal conditions. Ketenes (R2C=C=0) undergo concerted cycloadditions to alkenes under thermal conditions because the ketene can react antarafacially with an alkene that reacts suprafacially. The two termini of the C=C tt bond of the ketene react from opposite faces of the tt bond, creating positive overlap between the orbitals at both termini of the two tt systems. The antarafacial nature of the ketene does not have any stereochemical consequences, as there is no cis-trans relationship in the ketene to preserve in the product. The alkene component of the [2 -I- 2] cycloaddition with ketenes, however, reacts suprafacially, and its stereochemistry is preserved in the product. 

An elegant method for the solid-phase synthesis of quinolinone 9 derivatives has been developed by Pei et al. [43]. Using the teabag technology, the synthesis of a 4-amino-3,4-dihydro-2(l//)-quinolinone library was carried out through the rearrangement of /3-lactam intermediates on the solid phase. The condensation of o-nitrobenzaldehyde with a resin-bound amino acid yielded an imine that, following [2-1-2] cycloaddition with ketenes, afforded the -lactams (Fig. 3g). 

Isoindolines and isoquinolines a,co-Diynes in which the connecting chains contain a nitrogen atom undergo [2+2+2]-cycloaddition with ketene equivalents derived from the carbene complexes. After the formation of a benzene ring, the products are isoindoline or isoquinoline derivatives. 

The electron-rich unsaturated ketones 85—87 can be subjected to [4 + 2] cycloaddition with ketenes to give 3,4-dihydro-2-pyranones 88—90 which are readily transformed into the 2-pyranones 91 and 92 in the presence of zinc in moist acetic acid (Scheme 29) (1983JOC5337, 1969AGE312). 

Imines of a-jd-unsaturated carbonyl compounds (1-azadienes) 239 can be subjected to [4 + 2] cycloadditions with ketenes to give rise to dihydropyr-idones 240. When the imine moiety is part of a conjugated system, both 1,2- and 1,4-cycloadducts can be obtained. Although challenging [2 + 2] cycloaddition to the imine moiety of azadienes infrequendy leads to product mixtures containing jd-lactams 241 (Scheme 75), the [4 + 2] cycloaddition commonly proceeds smoothly, giving the products in satisfactory yield at room temperature or sl hdy elevated temperatures via an uncatalyzed reaction (1970TL245). 

A/-Benzoyldiazenes underwent [4 + 2] cycloaddition with ketenes under NHC catalysis (Scheme 163) (2009AGE192). Notably, this reaction is the subject of a computational investigation (2012JOC10729). Reverse enantioselectivities were observed for the NHC-catalyzed reaction of precursors 46a and 46b. The bulky mesityl substituent and the free hydroxy... 

SCHEME 12.20 [2+2] Cycloadditions with ketene silyl acetals. 

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