Ketenes with imines

Two extreme mechanisms can be envisaged (Scheme 12), concerted [2 + 2] cycloaddition or the more generally accepted formation of a dipolar intermediate (164) which closes to a /3-lactam or which can interact with a second molecule of ketene to give 2 1 adducts (165) and (166) which are sometimes found as side products. In some cases 2 1 adducts result from reaction of the imine with ketene dimer. 

It was first observed that reactions of imines with ketene silyl acetals proceeded smoothly in the presence of 5mol.% Yb(OTf)3 to afford the corresponding /3-amino ester derivatives in moderate yields.50 However, Sc(OTf)3 was found to be a more active catalyst in this reaction. Benzoylhy-drazones also react with ketene silyl acetals in the presence of a catalytic amount of Sc(OTf)3 to afford the corresponding adducts in high yields (Scheme 11).51 In contrast, catalytic activation of benzoylhydrazones by use of a typical Lewis acid such as TiCl4, SnCl4, or BF3-OEt2, etc. is not effective. 

Amberlyst 15 DRY, a sulfonic cation exchange resin with a large surface area, was found to catalyze the imino aldol reaction of imines with ketene silyl acetals to provide racemic y9-amino esters in yields up to 99% [104]. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

The palladium-catalyzed carbonylation reaction of allyl diethyl phosphate, in the presence of imines, gives either cis- or rraws-3-vinyl-/J-lactams, in high yields and in a stereoselective fashion (equation 160)574,575. The reaction is a [2 + 2] cycloaddition process which occurs under simple and mild conditions and has significantly more potential than the reaction of imines with ketenes (due to the more forcing conditions that are usually required to form the ketene intermediates). This reaction, however, only proceeds in low yield if the allyl phosphate is replaced with allyl acetate576. 

Aldol reactions.2 This combination of catalysts is effective for promoting reaction of acetals with silyl enol ethers and ketene silyl acetals. It can also promote reaction of aldehydes or imines with ketene silyl acetals. The reactions occur in high yield at 25° either CH3CN or THF can be used as the solvent. 

Another common method for the synthesis of 2-azetidinones is the cycloaddition of imines with ketenes, which is known as the Staudinger reaction . Although commonly described as a [2 + 2]... 

While cycloadditions of imines with ketenes or their precursors often produce cis P-lactams, the corresponding reactions of keteniminium salts are trans stereoselective (equations 70 and 71). 0 222 It is not clear whether the trans stereoselectivity is kinetic or results from an equilibration of 2-azetidiniminium salts under the basic conditions used in both cycloaddition and hydrolysis steps. 

It was first observed that reactions of imines with ketene silyl acetals proceeded smoothly in the presence of 5 mol % Yb(OTf)3 (a representative lanthanide triflate) to afford the corresponding /3-amino ester derivative in a moderate yield. The yield was improved when Sc(OTf)3, rather than Yb(OTf)3, was used as catalyst (Eq. 3) [10]. Not only silyl enolates derived from esters, but also one derived from a thioester worked well to give the desired /3-amino esters and thioester in high yield. In the reactions of the silyl enolate derived from benzyl propionate, anti adducts were obtained with good selectivity. In addition, the catalyst could be recovered when the reaction was complete, and could be re-used. 

SCHEME 10.7 Mechanism of the formation of p-lactams via the [2+2] cycloaddition of imines with ketenes. 

Scheme 3.3 Mukaiyama type Mannich reaction of imines with ketene silyl acetals.

The synthesis of indolizines by 1,5-dipolar cyclization, the reaction of picolinium salts with ketene dithioacetals, the reaction of 2-pyridyl ketene dithioacetals with halogencarbonyls, and a reaction of A7-imines or S-imines with ketene dithioacetals have been reviewed <85YGK669>. 

Syntheses Based on [2 + 2]Cycloaddition of Sugar-Derived Imines with Ketenes or their Equivalents... 

Reactions of Imines with Ketenes (Staudinger Reaction)... 

Mannich-type Reactions. The reactions of imines with ketene silyl acetals proceed smoothly in the presence of Sc(OTf)3 to afford the corresponding /3-amino ester derivative in moderate yield (eq 6). Sc(OTf)3 shows higher activity than Yb(OTf>3 does in this case. The catalyst can be recovered after the reaction is complete and reused. A Mannich-type reaction of IV-(/3-aminoalkyl)benzotriazoles with sUyl enolates has also been developed. Mannich-type reactions of polymer-supported sUyl enol ethers with imines or of polymer-supported a-iminoaceta-tes with silyl enolates are also catalyzed by Sc(OTf)3. 

Scheme 6.21 [2 + 2] Cycloadditions of A7-/ ara-nosyl imines with ketenes.

A comparison of the reaction products obtained from RCH=NPh (R = MeO, Ph, PhCH=CH) and two heterocyclic imines with ketenes, generated by photolysis of oxazolidine- and oxazolidinone-chromium carbene complexes and from the oxazolidi-none carboxylic acid chlorides, indicated high yields and high diastereoselectivities in some of these reactions... 

The Lectka group has published a catalytic, asymmetric synthesis of /3-lactams using a bifunctional catalyst system consisting of a chiral nucleophile (benzoylquinone) and indium(III) triflate. For the reaction of IV-tosyl imine with ketene precursor pheny-lacetyl chloride, the -lactam product was obtained in excellent yield and high enantioselectivity (eq 18). 

Mannich-type Reactions. Reactions of imines with ketene silyl acetals proceed smoothly in the presence of 5 mol % Y(OTf)3 to give the corresponding /3-amino ester in high yield (eq 2). Yb(OTf)3 and Sc(OTf)3 were both found to be more active for this reaction. 

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