Ketene reactions with nucleophiles

In general, vinylketene complexes 221 undergo reaction with nucleophiles at the ketene carbonyl carbon (C-l), yielding /3,y-unsaturated ketones (236).86 It is interesting to note that the analogous vinylketenimine complexes undergo nucleophilic attack at C-2.86 87 89 135 142... 

The only stable 1,3,2-dioxathietanes known are fluorinated sulfate derivatives formed by addition of sulfur trioxide to bis(trifluoromethyl)ketene. These structures are fairly well characterized from spectral data and from reactions with nucleophiles. Hexafluoroisopropy-lidene-l,3,2-dioxathietane 2,2-dioxide acts as a sulfur trioxide transfer agent to alkenes and is in equilibrium with a dimeric form as indicated by 19F NMR (Scheme 138) (71KGS1645, 72KGS306, 73KGS178, 132l). 

DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) conveniently oxidizes ketene silyl acetal (15) to give a-alkoxycarbonyl iminium salt (16)63 Subsequent reaction with nucleophiles gives amino ester derivatives, Nu-CH(NBn2)-C02R. Grignards... 

The phosphorylated ketenes obviously represent the most stable group among ketenes. In reactions with nucleophils having hydrogen atoms they are more reactive than ordinary organic ketenes (diphenylketene). 

Ketenes are normally prepared by the base-catalysed elimination of HC1 from an acid chloride 9 or by elimination of chlorine from a chloroalkyl acid chloride with zinc dust, often assisted by ultrasound. For reactions with nucleophiles, the solution would already contain the nucleophile before the ketene 6 was generated. 

Nowadays, it is an accepted mechanistic model [5, 6] that the photolysis step (which proceeds under thermo-reversible CO insertion) leads to species best described as chromium ketene complexes of type 7 (Scheme 2). Indeed, these intermediates exhibit a ketene-like reactivity they undergo [2 + 2] cycloaddition reactions with olefins, imines and enol ethers, whereas reaction with nucleophiles leads to carboxylic acid derivatives. 

The (dienyl)iron cations of type (248) and (265) are susceptible to reaction with nucleophiles. For the (cyclohexadienyl)iron cations, nucleophilic attack always occurs at a terminal carbon, on the face of the ligand opposite to the metal, to afford / -cyclohexadiene products. Typical nucleophiles used are malonate anions, amines, electron-rich aromatics, silyl ketene acetals, enamines, hydrides, and aUyl silanes intramolecular nucleophilic addition is also possible. The addition of highly basic organometaUic nucleophiles (Grignard reagents, organolithiums) is often problematic this may be overcome by replacing one of the iron carbonyl... 

Further reactions of bis(diethoxyphosphinoyl)ketene dithioacetals with nucleophiles... 

The oxidation of terminal acetylenes, like that of monosubstituted olefins, often results in inactivation of the P450 enzyme involved in the oxidation. In some instances, this inactivation involves reaction of the ketene metabolite with nucleophilic residues on the protein [196, 197], but in other instances it involves alkylation of the prosthetic heme group (Fig. 4.31). Again, as found for heme alkylation in the oxidation of olefins, the terminal carbon of the acetylene binds to a pyrrole nitrogen of the heme and a hydroxyl is attached to the internal carbon of the triple bond. Of course, as one of the two m-bonds of the acetylene remains in the adduct, keto-enol equilibration yields a final adduct structure with a carbonyl on the original internal carbon of the triple bond [182, 198]. It is to be noted that the oxidation of terminal triple bonds that produces ketene metabohtes requires addition of the ferryl oxygen to the imsubstituted, terminal carbon, whereas the oxidation that results in heme alkylation requires its addition to the internal carbon. As a rale, the ratios of metabolite formation to heme alkylation are much smaller for terminal acetylenes than for olefins. 

Ketenes have a very electrophilic r hybridized carbon and are therefore reactive even at low temperature. Most ketenes are so reactive that they must be carefully protected from atmospheric moisture. Nucleophiles add to the carbonyl group to give acyl derivatives. This addition is another reaction that gives students trouble, but shouldn t. The ketene reacts with nucleophiles like any other carbonyl compound to give an addition product (Fig. 18.50). In this case, the addition product is an eno-late (p. 373), and protonation gives the stable carbonyl compound. Figure 18.50 gives some examples. 

Spectroscopic methodologies have provided a wealth of information concerning the amination of ketenes. Scaiano and co-workers have measured rate constants for ketene reactions with various classes of amines in acetonitrile. The reaction rate is influenced by the basicity of the amine as well as by steric factors in both the ketene and the amine. Ketene amination has also been studied by time-resolved infrared (TRIR) spectroscopy. The strong ketene IR band near 2100 cm" makes it an excellent candidate for study by this spectroscopic technique. Scaiano, Wagner, Lusztyk, and co-workers provided evidence for the first nucleophilic attack being rate determining and that the transition state involves an enol amide. They further found that the asymmetric stretching IR band of substituted ketenes... 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

The ketocarbene 4 that is generated by loss of Na from the a-diazo ketone, and that has an electron-sextet, rearranges to the more stable ketene 2 by a nucleophilic 1,2-shift of substituent R. The ketene thus formed corresponds to the isocyanate product of the related Curtius reaction. The ketene can further react with nucleophilic agents, that add to the C=0-double bond. For example by reaction with water a carboxylic acid 3 is formed, while from reaction with an alcohol R -OH an ester 5 is obtained directly. The reaction with ammonia or an amine R -NHa leads to formation of a carboxylic amide 6 or 7 ... 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

Reaction of 4a with TiCl4 was carried out in the presence of siloxyalkene 3 as nucleophile and the results are summarized in Table III. In the reaction with ketene silyl acetals 3a and 3e at -78 °C, y-ketoesters 15a and 15e were obtained instead of chloride product 8 which is a major product in the absence of 3. Formation of product 15 is likely to result from trapping of alkylideneallyl cation 5 with 3 at the sp2 carbon. In contrast, the reactions with silyl enol ethers 3f and 3g gave no acyclic product 15, but gave cyclopentanone derivatives 16-18. The product distribution depends on the mode of addition of TiCl4 (entries 4-7). 

The reaction of (trialkylsilyl)vinylketenes with nucleophilic carbenoid reagents, such as sulfur ylides and diazo compounds, has been used for synthesis of substituted cyclopentenones by stereoselective 4 + 1-annulation (Scheme 12). The strategy relies on the remarkable ability of silyl substituents to stabilize ketenes and suppress their tendency to undergo dimerization and 2 - - 2-cycloaddition. 

The reaction of Cjq with silylated nucleophiles [47] requires compounds such as silyl ketene acetals, silylketene thioacetals or silyl enol ethers. It proceeds smoothly and in good yields in the presence of fluoride ions (KF/18-crown-6) (Scheme 3.10). The advantage of the latter synthesis is the realization of the cyclopropanation under nearly neutral conditions, which complements the basic conditions that are mandatory for Bingel reactions. Reaction with similar silyl ketene acetals under photochemical conditions and without the use of F does not lead to methanofullerenes but to dihydrofullerene acetate [48]. 

In accordance with expectations, the isolable trifluoromethyl substituted ketene imines (186-188) were found to react readily with nucleophilic agents. In the case of 186, the reaction with methanol and aniline led to lactim ether 187a and amidine 187b, respectively (137). 

There are many reactions in which pyridines are used as bases. However in a large number of reactions only pyridine itself is reactive. a-Substituted pyridines behave differently, e.g. in the catalysis of acylation reactions with acyl chlorides or anhydrides [45]. The sterical hinderance of the a-substituents decelerates reactions in which a pyridine reacts as a nucleophile. A reaction which can be base-catalyzed by a-substituted pyridines is the addition of alcohols to hetero-cumulenes such as ketenes and isocyanates. Therefore this reaction was investigated as a model reaction for base catalysis by concave pyridines. 

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