Aryl-substituted enals

Bode and co-workers have used NHCs to form y-butyrolactams 34 from enals 27 and saccharin-derived cyclic sulfonylimines 32. A range of [3-alkyl and [3-aryl substituted enals, and a variety of substituted imines, are tolerated in this reaction,... 

Bode and co-workers rendered this transformation asymmetric allowing access to a>cyclopentenes 244 with high enantioselectivity (Table 19) [128], Optimized reaction conditions include the use of A-mesityl substituted aminoindanol derived triazo-lium catalyst 214. When chalcone and derivatives we re subjected to the reaction conditions, ax-cyclopentenes were formed selectively. Although the substrate scope is also limited to P-aryl substituted enals, cis. trans ratios of up to >20 1 are observed. 

The Michael-type addition of thiols to a,p-unsaturated aldehydes has been reported to proceed very efficiently using O-TMS protected diarylprolinol 31c as catalyst (Scheme 3.32). The low configurational stability of the adducts at r.t. led the authors to modify the reaction conditions, which finally involved carrying out the reaction at -24 °C and reducing the adducts in situ, furnishing the corresponding y-thio alcohols in excellent yields and enantioselectivities. Both alkyl- and aryl-substituted enals could be used as suitable Michael... 

Vicario reported that cyclopropanation also works well in water.Using typical Cl catalyst, the reaction worked well with p-aryl substituted enals, however, it failed with alkyl enals. Therefore, they used a 4-hydro3gr>roliii derived catalyst with a long aliphatic chain C2b (Figure 8.3). Later, this laboratory introduced a dialkylamino group in the 4 position of the... 

The Scheidt group reported a highly enantioselective NHC-catalyzed addition of a,p-unsaturated aldehydes to isatins activated by lithium cations (up to 93% yield, >20 1 dr, 97% ee). The addition of lithium chloride as a Lewis acid with p-aryl substituted enals generates lactone products with high enantioselectivity (up to 93% ee) which result from an organized transition... 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

An alternate approach, pioneered by Kunz and MacMillan, proceeds by reaction of sulfur ylides with a,(3-unsaturated iminium ions, formed by reaction of a,p-enals with enantiomerically pure amines. In this approach the sulfur ylide (9.87) reacts with a range of (3-aryl- and P-alkyl-substituted enals, including (9.88), in the presence of the dihydroindole (9.89) to give the cyclopropane with ees ranging from 89 to 96%. More recently, it has been shown that replacement of the carboxylate functional group in (9.89) with an isosteric tetrazolic acid gives an improved catalyst that effects cyclopropanation with 99% ees in all cases studied. 

Synthesis of y-Lactams. The Lewis acidic properties of Mg(OrBu)2 and Lewis basic properties of carbenes have been exploited in a cooperative catalytic cycle leading to the elegant synthesis of y-lactams. The reaction is a formal [3+2] cycloaddition, and the Mg alkoxide base is presumed to be involved in chelation to the hydrazone species 7. Thus, in the presence of 5 mol % Mg(OrBu)2,5 mol % L, and 15 mol % TBD as the base, 9 is obtained in 78% yield with 7 1 dr and 97% ee (eq 3). The reaction tolerates a wide variety of aryl-substituted hydrazones and a. -unsaturated aldehydes, while alkyl-substituted enals furnish moderate yields. 

In the same context, the addition of 2-bromoketoesters to enals was developed by Rios et al. in the presence of TEA as a base in toluene at 4°C producing, upon catalysis with amine 8, the corresponding formal [2+1] cycloadducts in high yields of up to 95% and diastereoselectivities >92% de combined with enantioselectivities of up to 99% ee [135]. To make this type of reaction even more interesting from an environmental point of view, Vicario et al. have recently demonstrated that it was possible to react diethyl bromomalonate and enals in water at room temperature (rt) without using an external base [136]. The reaction, catalyzed by a chiral diarylprohnol trimethylsilyl ether, proceeded efficiently when (i-aryl-substituted a,P-unsaturated aldehydes were employed as substrates, while it failed when ahphatic enals were used. The corresponding formal cycloadducts were formed with enantioselectivities of up to >99% ee combined with good yields of up to 84%. In addition, amine 8 was apphed as catalyst to the enantioselective cyclopropana-tion of a-substituted a,P-unsaturated aldehydes with diethyl bromomalonate. 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

Cacchi, S. Fabrizi, G. Gasparrini, F. Pace, P. Villani, C. The utilization of supercritical C02 in the Pd-catalyzed hydroarylation of /i-substi-tuted-a,/i-enones. Synlett 2000, 650-652. Amorese, A. Arcadi, A. Bemocchi, E. Cacchi, S. Cerrini, S. Fedeli, W. Ortar, G. Conjugate addition vs vinylic substitution in Pd-catalyzed reaction of aryl halides with /i-substituted-a, /i-enones and -enals. Tetrahedron 1989, 45, 813-828. 

Another type of intramolecular electrophilic substitution is shown in Equation (1).25 In this case, the reaction sites are located in different substituents on silicon. This reaction mode is useful for highly diastereoselective alkenylation and phenylation of aminoacetals and hemiaminals.26 Intramolecular conjugative arylation of a-enals bearing an aryldimethylsilyl group is effectively promoted by tetrabutylammonium fluoride (TBAF) (Equation (2)).27,27a... 

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