Ketene generator

Apparatus Ketene generator (500 ml distillation flask) (see Ref. 20, p. 529) for. the preparation of tetramethylallene 1-1 round-bottomed, three-necked flask, provided with a mechanical stirrer, a thermometer and a vent for the addition of dichlorocarbene 500-ml flask (see Fig. 1) for the dechlorination. 

Whilst the addition of a chiral NHC to a ketene generates a chiral azolium enolate directly, a number of alternative strategies have been developed that allow asymmetric reactions to proceed via an enol or enolate intermediate. For example, Rovis and co-workers have shown that chiral azolium enolate species 225 can be generated from a,a-dihaloaldehydes 222, with enantioselective protonation and subsequent esterification generating a-chloroesters 224 in excellent ee (84-93% ee). Notably, in this process a bulky acidic phenol 223 is used as a buffer alongside an excess of an altemativephenoliccomponentto minimise productepimerisation (Scheme 12.48). An extension of this approach allows the synthesis of enantiomericaUy emiched a-chloro-amides (80% ee) [87]. 

Schultz and Kulkarni have explored the possibilities of using this process in asymmetric synthesis by trapping the ketene generated from these photochemical ring-opening... 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

The most efficient synthetic route to 3-butylcyclobutenone reported previously involves the addition of butylmagnesium bromide or butyllithium to 3-ethoxycyclobutenone followed by acid hydrolysis. 3-Ethoxycyclobutenone is itself available in modest yield via the addition of ketene to ethoxyacetylene. This procedure provides 3-butylcyclobutenone in only 20% overall yield and requires the use of a ketene generator and the rather unstable ethoxyacetylene as starting material. 

The best large-scale preparation of cyclobutanone is the reaction of diazomethane with ketene.2 It requires a ketene generator and implies handling of large quantities of the potentially hazardous diazo compound. A more frequently used method for the preparation of cyclobutanone starts from pentaerythritol, the final step being the oxidative degradation of methylenecyclobutane,3,4 which can also be prepared from other precursors.5 A general survey of all methods used to obtain cyclobutanone has been published.6,7... 

Lastly, Corey has developed B LA species 65, derived from zwitterionic oxazaboro-lidine 64 and tri-n-butyltin trifalte, as a novel catalybc system for the enanboselec-bve synthesis of P-lactones from ketene and aldehydes (Scheme 5.81) [152]. The reaction of B LA 65 with ketene generates intermediate A. The subsequent addition of the ketene acetal unit to the coordinated aldehyde (intermediate B) followed by extrusion of the P-lactone completes the catalybc cycle. 

Esterification of resin-bound alcohols with 3-oxo carboxylic acids (which readily undergo decarboxylation) or with malonic acid is best performed using the corresponding ketenes, which can be generated in situ by thermolysis of dioxinones or other precursors (Entries 6-9, Table 13.12). PEG can also be acetoacetylated with acetyl ketene generated by thermolysis [171]. 

In connection with these results, and as an extension of their studies toward the reactivity of new bicyclic mesoionic compounds and their usefulness in the synthesis of condensed heterocycles, they further reported the stereoselective synthesis of spiro-(3-lactams 153, 154 (Scheme 36) by reactions of imines with mesoionic compounds or ketenes generated from A-acyl-thiozolidine-2-carboxylic acids 152 [110]. 

In 2005, reactions of ketenes generated from a-diazoketones with acyclic and cyclic imines have been investigated under both microwave and photoirradiation conditions [98]. The reported results indicated that the zwitterionic... 

Scheme 1.5 3-Pyridyl ketene generated by laser flash photolysis in acetonitrile, and trapping by n-butylamine investigated by time-resolved IR measurements [14].

A general overview about advances in the catalytic, asymmetric synthesis of -lactams can be found in an article written by Thomas Lectka, whereas a publication by Claudio Palomo discusses reactions of acyl chlorides with imines, including diastereoselectivites and mechanistic insights of the ring closure leading to cis or trans substituted P-lactams and asymmetric induction from the ketene component. The influence of solvents and additives and the pathways of ketene generations and addition modes on the stereoselectivity. 

Another ketene reaction, the enamine ketene reaction, can also be used for ring enlargement. An application of this reaction is shown in Scheme IV/15, in which the enamine of morpholine and cyclotridecanone IV/95 has been transformed to ( )-muscone (IV/99) [53] [54] [55]. Two moles of ketene -generated in situ from acetylchloride and triethylamine or introduced as gaseous ketene - were condensed step-wise with the enamine IV/95 to form the a-pyrone, IV/97. The yield is low (10-28 %). Base catalyzed hydrolysis of IV/97 gave a mixture of the four isomers, IV/98a to IV/98d, yielding, after catalytic hydrogenation, ( )-muscone (IV/99) [53]. 

Okumoto H (2002) Formation and Reactions of Ketenes Generated via Acylpalla-dium Derivatives. In Negishi E, de Meijere A (eds) Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley, New York, p 2655... 

The key reaetion intermediate is an insitu alkyl ketene generated by the dehydrohalo-genation of the aeid chloride and is described (1). 

Mono(lluoroalkyl)-substituted -lactams can also be prepared in good yield by a thermal [2 + 2] cycloaddition of fluoroalkyl aldimines with a ketene generated from 3 -(benzyloxy)acetyl chloride. The reaction is stereoselective only m-azetidinones 3 are obtained,... 

Irradiation of alkoxycarbene complexes in the presence of aUcenes and carbon monoxide produces cyclobutanones. A variety of inter- and intramolecular [2 + 2]cycloadditions have been reported. The regioselectivity is comparable with those obtained in reactions of ketenes generated from carboxylic acid derivatives. Cyclobutanones can be obtained with a high degree of diastereoselectivity upon reaction of alkoxy carbenes with chiral A-vinyloxazolidinones. For example, photolysis of (19) in the presence of (20) gives cyclobutanone (21) (Scheme 31). In addition to aUcoxycarbenes, carbenes having a thioether or pyrrole substituent can also be employed. Related intramolecular cycloadditions of y,5-unsaturated chromimn carbenes afford bicyclo[2.1. IJhexanones (Scheme 32). 

A practical extension of the reaction uses ketenes generated in situ in the presence of a carbonyl compound. Thus the highly reactive dichloroketene generated in situ from the reaction of dichloroacetyl chloride with triethylamine has been trapped by aldehydes (equation 6) or activated ketones (equation 7)... 

A related [4 + 4] annulation strategy relies on the base-promoted l,4-dehydrochlc ination of a,p-un-saturated acid chlorides the transformation outlined in Scheme 29 (reported by Dreiding and cowor-kers) illustrates this approach. In some cases it is possible to effect all three steps — ketene generation, [2 + 2] cycloaddition, and Cope rearrangement — in a single synthetic operation. ... 

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