Ketene dimethyl acetal

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... 

Unlike coumarin, chromone (206) undergoes efficient unsensitized photoaddition to tetramethylethylene, cyclopentene, ketene dimethyl acetal, and but-2-yne.180 The major product of such an addition to tetramethylene is the cis-fused cyclobutane derivative (207) the formation of the two minor products (208 and 209) is easily rationalized. Added benzophenone has no visible effect on this cycloaddition, which is therefore believed to involve the attack of triplet chromone on the ground-state alkene. Photoaddition to furo-chromones has also been studied,179 and the photosensitized cyclo-... 

Ketene dimethyl acetals react with phenyl azide to give a-anilido esters after acid hydrolysis of the intermediate triazolines, but yields are low.291 The reaction of ketene acetals with arenesulfonyl azides does not appear to have been investigated. 

A combination of known reactions has been used for the a -alkoxycarbonylmethyl-ation of a/3-unsaturated ketones, (146), by photochemical [2 + 2] addition of ketene dimethyl acetal and subsequent Baeyer-Villiger oxidation to give a mixture of the expected lactone and the derived unsaturated acid, arising from hydrolysis of the lactone and dehydration. A final alkylation step serves to convert both compounds into the desired ester (147). The enol acetate of acetaldehyde can be used in place of the ketene, although here of course, an extra oxidation step is required. ... 

It took another 35 years until the first (and still the only known) enantioselective total synthesis of (/ )-ochratoxin a (326), and therefore of ochratoxins A and B, was published by Gill et al. in 2002 (264, 265). Scheme 6.1 shows six steps of the nine-step synthesis, which was achieved with 10% overall yield. The first three steps of the procedure are not shown and comprise the preparation of 327 from (/ )-2-methyloxirane according to ref. (266). Ketene dimethyl acetal and acetylenic ester 327 react in an intermolecular cycloaddition to give 328. This diene undergoes a Diels-Alder reaction with methyl propiolate to yield 329. Lactonization ( 330), demethylation ( 331), chlorination ( 332), and methyl ester cleavage finally furnished enantiomerically pure ochratoxin a (326) (267). 

Scheme 6.1 Total synthesis of (/f)-ochratoxin a (326) as well as ochratoxins A-C (323-325). Reagents and conditions a) ketene dimethyl acetal, sealed tube, 165°C, 23 h b) methyl propiolate, sealed tube, 145 C, 22 h, 69% over two steps c) p-TsOH, CH2CI2, rt, 72 h, 82% d) BCI3, CH2CI2, 0°C, 10 min, 92% e) SO2CI2, CH2CI2, rt, 48 h f) MeOH, LiOH H20, reflux, 5 h, 68% over two steps g) L-phenylalanine t-butyl ester, EEDQ, THF, rt, 15 h h) EtOH...

Synthesis of the first authentic case of a non-annulated silepin (318) utilizes the addition of keten dimethyl acetal to (317) followed by a series of routine transformations (Scheme 25). ... 

A. Claisen Rerrangements of Ketene Aminats and Imidates. A reaction that is related to the orthoester Claisen rearrangement utilizes an amide acetal, such as dimethylacetamide dimethyl acetal, in the exchange reaction with allylic alcohols.257 The products are y, 8-unsaturated amides. The stereochemistry of the reaction is analogous to the other variants of the Claisen rearrangement.258... 

Scheme 54 Photoreaction of aromatic carbonyl compounds with p,p-dimethyl ketene silyl acetals.

Similar experiments were also carried out with dichloroketene diethyl and dimethyl acetals but no intermediate could be detected. This is readily explained since the cyclic ketene acetals undergo acid-catalysed hydration about 30 times more rapidly than the corresponding acyclic ones (Straub, 1970 Chiang et al., 1974 Kresge and Straub, 1983) whereas cyclic hemi-orthoesters undergo acid-catalysed breakdown 50-60 times more slowly than the corresponding acyclic ones do (see p. 70). Therefore the ratio of rate constants favourable for the detection of the cyclic hemiorthoesters becomes unfavourable with the acyclic hemiorthoesters. 

Silyl enol ethers can be dimerized to symmetrical 1,4-diketones by treatment with Ag20 in dimethyl sulfoxide or certain other polar aprotic solvents.465 The reaction has been performed with R2, R-1 = hydrogen or alkyl, though best yields are obtained when R2 = R1 = H. In certain cases, unsymmetrical 1,4-diketones have been prepared by using a mixture of two silyl enol ethers. Other reagents that have been used to achieve either symmetrical or cross-coupled products are iodosobenzene-BFy-EtiO.466 ceric ammonium nitrate,467 and lead tetraacetate.m If R1 = OR (in which case the substrate is a ketene silyl acetal), dimerization with TiCL, leads to a dialkyl succinate (32, R1 = OR).4 9... 

One method for the synthesis of hydroxyalkyl-substituted P-lactams is by the Staudinger reaction, the most frequently used method for the synthesis of P-lactams.86 This method for the preparation of 4-acetoxy- and 4-formyl-substituted P-lactams involves the use of diazoketones prepared from amino acids. These diazoketones are precursors for ketenes, in a diastereoselective, photochemically induced reaction to produce exclusively tram-substituted P-lactams. The use of cinnamaldimines 96, considered as vinylogous benzaldimines, resulted in the formation of styryl-substituted P-lactams. Ozonolysis, followed by reductive workup with dimethyl sulfide, led to the formation of the aldehyde 97, whereas addition of trimethyl orthoformate permitted the production of the dimethyl acetal 98 (Scheme 11.26). 

The procedure is successful with ketene silyl acetals prepared from the enolate anions of methyl 2-methylpropanoate and methylpropanoate, and provides good yields of the propionic esters 7 in a single step (Scheme 10.20). The latter are known to be intermediates in the preparation of analgesic compounds. No significant difference in the yields is observed when 4-chloroaniline is used as the starting material in place of its dimethylated analogue [31]. 

The authors apphed this new concept to chemoselective functionalization of carbonyls rather than acetals [194], which is usually quite difficult to achieve because of the high reactivity of the acetal counterparts with Lewis acids. Reaction of a mixture of 1 equiv. each of acetophenone and its dimethyl acetal with ketene silyl acetal 191 under the influence of bidentate aluminum Lewis acid 188 in CH2CI2 at -78 °C for 3 h afforded aldol products 195 exclusively (88 % yield). It is worth noting that employment of dibutyltin bis(triflate) (DBTT) (10 mol%) as catalyst [195], which is quite useful for activation of aldehyde carbonyls rather than acetals, gave unsatisfactory results, producing the y3-methoxy ester preferentially (Sch. 147). 

Several examples of Sc(OTf)3-catalyzed aldol reactions of silyl enolates with aldehydes were been examined. Silyl enolates derived from ketones, thioesters, and esters reacted smoothly with different types of aldehyde in the presence of 5 mol % Sc(OTf)3 to afford the aldol adducts in high yields. Sc(OTf)3 was also found to be an effective catalyst in aldol-type reactions of silyl enolates with acetals. The reactions proceeded smoothly at -78 °C or room temperature to give the corresponding aldol-typc adducts in high )delds without side-reaction products. It should be noted that aldehydes were more reactive than acetals. For example, while 3-phenylpropionalde-hyde reacted with the ketene silyl acetal of methyl isobutyrate at -78 °C to give the aldol adduct in 80 % yield, no aldol-type adduct was obtained at -78 °C in the reaction of the same ketene silyl acetal with 3-phenylpropionaldehyde dimethyl acetal. The acetal reacted with the ketene silyl acetal at 0 °C to room temperature to give the... 

It is important to emphasize that three different types of reactions, i.e., electron transfer from (TPP)Co to Q (Eq. 13), Diels-Alder reaction of anthracenes with Q (Scheme 12) and hydride transfer from BNAH to Q (Scheme 14), have the common rate-determining step of Mg +-catalyzed electron transfer from these electron donors to Q. In each case, the relative catalytic dependence of A obs on [Mg ] is the same as indicated by Eq. 14, irrespective of different electron donors. The nucleophilic addition of a / ,/ -dimethyl-substituted ketene silyl acetal such as Me2C= C(OMe)OSiMe3 is also catalyzed by Mg + in MeCN [227, 228]. No reaction takes... 

The reaction outlined in O Scheme 59 is an example of a variant of the Claisen rearrangement of allyl ketene aminal (so-called Eschenmoser-Claisen rearrangement) [87], The reaction dose not require an acid catalyst glycal was just heated with dimethylacetamide dimethyl acetal to form ketene aminal, which underwent the sigmatropic rearrangement to form the corresponding )/,5-unsaturated amide. 

Related to the orrAo-ester rearrangement is the Eschenmoser variation, which involves exchange of A, A -dimethylacetamide dimethyl acetal with an allylic alcohol and in situ rearrangement of the intermediate ketene 0-acetal to furnish the corresponding unsaturated amides. Again, transfer of stereochemistry from the allylic alcohol to the product is observed. ... 

CYCLOADDITION Alumina chloride. l,2-Bis(trimethylsilyloxy)cyclo-butene. 2,2-Dimethyl-3(2/T)-furanone. Ethylaluminum dichloride. Ketene diethyl acetaL Methyl cyclobutene-carboxylate. Trimethyl-1,3-diox olen-one. Zinc chloride. 

To the ketene silyl acetal (1 equiv.) was added, at room temperature, neat ethyl propynoate, dimethyl acetylenedicarboxylate (DMAD) or ethynyl methyl ketone (1 equiv.). The mixture was stirred for 5 h at room temperature in vacuo (0.1 Torr) for 30 min. Purification of the crude reaction mixture by silica gel column chromatography (ethyl acetate/hexane, 5 95) afforded the cycloadducts. 

Molecular oxygen can add to the double bonds of olefins such as styrene, 1,1-diphenylethylene, dimethyl- and diethyl-ketene, vinyl acetate, cyclopentadiene and cyclohexadiene with formation of polymeric peroxy compounds. The course of the reaction corresponds to that of a mixed polymerization 1 r>2 3 4b d... 

Electron-donating silyl ethers such as ketene silyl acetals and cyclopropanone silyl acetals also can be used as latent carbon-functional groups. The photoreactions of 1,2,4,5-tetracyanobenzene with dimethyl ketene silyl acetal and 2,2-dimethylcyclopropanone silyl methyl acetal afford substituted products in good yields, respectively. 

Sc(OTf)3 also catalyzes aldol-type reactions of silyl enolates with acetals. For example, the reaction of 3-phenylpropionaldehyde dimethyl acetal with the ketene silyl acetal of methyl isobutyrate proceeds at 0°C to room temperature to give the desired adduct in 97% yield (eq 2) ... 

BF3-etherate added to 2-bromopropanal dimethyl acetal at ca. 5°, and ketene (generated by the pyrolysis of acetic anhydride) bubbled into the mixture for 30 min intermediate ester (Y 85%), added dropwise to a stirred dispersion of KOH in DMF at 0°, stirring continued for 2 h, treated with further powdered KOH at 1 hourly intervals (for a further 4 h), and acidified with 1 M HCl product (Y 84%). F.e.s. P.B. Rasmussen, S. Bowadt, Synthesis 1989, 114-7. 

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