Dimethyl ketene, 1,2-cycloaddition with

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... 

It is interesting to note that the dimethyl-substituted derivative with the identical chiral auxiliary gives the opposite configuration in the cycloadduct compared to that obtained for the parent derivative. This has been ascribed to the nature of the [2 + 2] transition state in these cycloadditions. The enantioselectivities of these reactions exceed that for a ketene cycloaddition with a chiral auxiliary group (menthyloxy) attached to the a-carbon of the ketene in which a 45-50% ee was reported.12... 

Dihydropyrans have been produced by the 1,3 cycloaddition of methyl vinyl ketone (77) or acrolein (29-J7) with enamines (see Section II.A.2). S-Lactones have been formed as a side product in the reaction of dimethyl ketene with enamines (77), and as the primary products in the reaction of excess ketene with enamines derived from ketones (75) (see Section II.A.4). 

The use of chiral catalysts can result in asymmetric induction in [2 + 2] cycloadditions. The cycloaddition of ketene dimethyl thioacetal (44) with various enamides (43) in the presence of a chiral titanium(IV) catalyst, generated in situ, gives good yields of cyclobutanes 45 with high enantioselectivity.18... 

Until recently, the reaction of a,p-unsatuiated esters with electron-rich alkenes has been reported to provide cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate, and the first documented example of the 4ir participation of an a,3-unsaturated ester in a Diels-Alder reaction appears to be the report of Snider and coworkers in their description of the reversible, intramolecular [4 + 2] cycloaddition reaction of l-allylic-2,2-dimethyl ethylenetricarboxylates. Subsequent efforts have demonstrated that substitution of an a, -unsaturated ester with a C-3 electron-withdrawing substituent may permit their well-behaved 4ir participation in LUMOdiene-controlled Diels-Alder reactions (equation 3). ... 

Cyclopropylidene-l,3-dioxanes or -1,3-dioxolanes are ketene acetals and examples of bis-donor-substituted methylenecyclopropanes which undergo facile cycloaddition with electron-deficient alkenes 12. Thus, spiro[2.3]pentanone acetals 13 were obtained after reaction in an aromatic solvent either at room temperature or 40 C. Upon subsequent aqueous workup, hydrolytic cleavage of a C-C bond of the cyclobutane ring took place rather than the expected acetal hydrolysis (Table 7). This cycloaddition was found to proceed in a stepwise fashion as reaction of the dimethyl ( )-but-2-enedioate gave a cisj tram mixture of cycloadducts on further heating, this ratio changed. 

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... 

Ketenes are usually prepared in situ by elimination from acid chlorides with a tertiary amine. Thus (6) gives dimethyl ketene. If no other reagent is present, dimer (5) is formed. If a nucleophile is present, product (3) is formed, whilst thermal 2 + 2 cycloadditions take place with alkenes to give cyclobutanones (7). ... 

Treatment of the pyrido-pyrimidines (346) with pyrrolidine gives the 1,8-naph-thyridines (347) (Scheme 133). The meso-ionic oxazines (349) that are formed by the reaction of chloroformyl-ketens with 2-pyridone undergo cycloaddition reactions with dimethyl acetylenedicarboxylate or with phenyl isocyanate, followed by loss of carbon dioxide, to yield quinolizines (350) and pyrido-pyrimidines (348), respectively (Scheme 134). Pyrido-pyrimidines (352) also result from the cycloaddition of anils of type (351) to ethyl vinyl ether (Scheme 135)."""... 

The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A, O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. 

Cycloaddition of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with EWG-substituted primary ketene N,0-acetals provides a tetrasubstituted pyridazine, methyl 4-amino-5,7-dioxo-6,7-dihydro-5/7-pyrrolo[3,4-4pyridazine-3-carboxylate <200681513>. 

Ketene acetals and thioacetals can be used as ketene equivalents in cyclobutanone synthesis in situations where ketene to alkene cycloadditions are inefficient such as in the case of electron-deficient alkenes.14 Although thermal cycloadditions of ketene acetals and thioacetals with electron-deficient alkenes have been observed (see Section 1,3.2.1.), such cycloadditions proceed more efficiently and under milder conditions with metal catalysts. Efficient cycloadditions between ketene dimethyl acetal and alkenes substituted by a single electron-withdrawing group have been reported.15... 

Ketene thioacetals can also be used as ketene equivalents in the preparation of cyclobutanones and cyclobutanes. Boron trifluoride catalyzes the [2 + 2] cycloaddition of 2-[(l-pyrro-lidinyl)mcthylene]-1,3-dithiane (39) with dimethyl maleate (40).17 Although the cycloadduct is obtained in good yield, stereochemical integrity is not maintained and the thermodynamically most stable isomer predominates. 

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>. 

Thus, [2-1-2] cycloaddition of 2-methylpropene with chloro(2,2,2-trichloroethyl)ketene (prepared in situ from 2,4,4,4-tetrachlorobutanoyl chloride and triethylamine) in cyclohexane yielded 2-chloro-3,3-dimethyl-2-(2,2,2-trichloroethyl)cyclobutanone (70%). This a-chloro-cyclobutanone undergoes a stereoselective cine rearrangement in the presence of triethylamine in refluxing toluene for 20 hours to give cw-(2a,4a)-2-chloro-3,3-dimethyl-4-(2,2,2-tri-chloroethyl)cyclobutanone in 94% yield,which was resolved by means of the diastereomeric salts of their sodium hydrogen sulfite adducts with ( —)- or (- -)-l-phenylethylamine. ... 

Generally, 1,3,5-triazines react with a number of dienophiles by a [4 + 2] cycloaddition to form pyrimidines. Electron-rich dienophiles, such as ynamines, enamines and ketene /V,<9-acetals, as well as the electron-deficient dimethyl acetylenedicarboxylate react in this manner.1... 

The final reaction of the sequence was the [4 + 2] cycloaddition of the thioacyl ketene aminal 14 with dimethyl acetylenedicarboxylate. 

Di-0-methyltartaric acid [(/ ,/ )-33] was the starting material for the synthesis of chiral ketenes, e.g., 34, used in diastereoselective [2 + 2] cycloadditions (Section D. 1.6.1.3.). The acid (R.R)-33 can be obtained by O-methylation of dimethyl or diethyl tartrate, either with diazomethane37 or, more conveniently, with sodium hydride/dimethyl sulfate28, followed by base hydrolysis. 

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