Intramolecular a-alkylation

Very recently, the first catalytic asymmetric intramolecular a-alkylation of an aldehyde has been achieved by the List group [70]. In the presence of a-methyl-substituted L-proline, (S)-61, as organocatalyst, ring-forming reactions leading to chiral cyclopentanes, cyclopropanes, and pyrrolidines proceed with high enantioselectivity - in the range 86-96% ee. Selected examples are shown in Scheme... 

The addition of halomethyl metal reagents provides another Darzens-like route to aziridines <06JOC9373>. Reaction of ICHjCl with MeLi generates a chloromethyllithium reagent, which then adds to the imine 74. A subsequent intramolecular A -alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene. 

Vignola, N., List, B. Catalytic asymmetric intramolecular a-alkylation of aldehydes. J. Am. Chem. Soc. 2004,126, 450-451. 

Although the reaction failed with cyclopent-2-enone itself, methylations of kinetic lithium dienolates of 3-alkylcyclopent-2-enones have been carried out in acceptable yields.Intramolecular a -alkylations... 

An interesting application in this field is the work reported by Habermann et al. a bicychc 7-aza[2.2.1]heptane system, which has a mother skeleton of epibatidine, was efficiently constructed via PS-BEMP promoted intramolecular A-alkylation [59] (Scheme 6.13). 

Japanese chemists have reported a stereoselective synthesis of humulene (9), an 11-membered cyclic sesquiterpene, by intramolecular a-alkylation of a keto group by a jr-allylpalladium complex. The starting material (7) was derived from geranyl acetate. In this case, the efficiency of the cyclization was markedly improved by addition of a diphosphine ligand such as l,3-bis(diphenylphosphino)-... 

Most classes of reduced and benzodiazocines are accessible through moderately flexible synthetic routes, although the 1,4-benzodiazocines remain exceedingly scarce and apparently no dibenzo[6,e][l,4]diazocines are known. Intramolecular A-alkylation or acylation appears to represent a reasonably effective route, from comparatively readily available precursors, of monocyclic-and benzodiazocines in their polyhydro forms, while routes involving C—C bond formation, to... 

Reported syntheses of the 1,5-thiazocine ring system from acychc precursors invariably employ unimolecular cyclization reactions. Intramolecular A-alkylation affords dibenzothiazocine (94) in ca. 80% yield (Equation (32)) <85BCJ1946>, while lactamization reactions afford phthalimide (91) (31 %) (Equation (33)) <88TL181 > and benzo derivatives (103 X = Br, Ar = 2-pyridyl X = Cl, Ar = 2-CIC6H4, 2-FC6H4 X = NO2, Ar = 2-CIC6H4) (Equation (34)) <83EUP72029>. 

Scheme 11.6 Asymmetric intramolecular a-alkylation of aliphatic aldehydes catalysed by (S)-proline (1) and (S)-a-2-methyl-proline (7a).

Subsequently, they were the first to demonstrate that saturated alkyl halides 279 as sp hybridized electrophiles never before used in an organo-mediated MBH reaction facilitated the intramolecular a-alkylation of enones to afford five- and six-membered enone products 280 (Scheme 1.101). ... 

In 2004, Vignola and List [111] demonstrated the ability of proline-derived catalysts to overcome drawbacks associated with the stoichiometric alkylation of preformed aldehyde enolates when they described an elegant amino acid catalyzed intramolecular a-alkylation reaction of haloaldehydes. The reaction furnished substituted cyclopentanes, cyclopropanes, and pyrrolidines in good yields and good enantio-selectivities (Scheme 8.23), when commercially available (5)-a-methyl proline (LV) as catalyst was used. The presence of a stoichiometric amount of additional base (tertiary amine) was required, not only to trap the hydrogen halide produced in the reaction but also because it has also significant effect on the stereoselectivity of the C—C bond-formation process by stabilizing the ant/ -TS of the /ra 5-enamine intermediate. Nevertheless, an intermolecular version of the reaction remains still elusive, mainly because of the deactivation of the amine catalyst by A -alkylation with the alkyl halide [112]. 

During the following several years, many examples of organocatalytic tandem reactions such as the intramolecular a-alkylation step were developed, but they are not subjected in this chapter [113]. Unlike any yet published example of intermolecular a-alkylation of aldehydes and ketones via an Sat2 mechanism, several works via the SAr2 -type addition-elimination pathway were disclosed to date. 

SCHEME 8.23. Enantioselective intramolecular a-alkylation of haloaldehydes 65 reported by Vignola and List [111]. 

In 2007 two independent contributions made by Cordova and co-workers [14] and by W. Wang and co-workers [15] reported a simple and highly stereoselective cyclopropanation via the reaction of enals (15) and 2-bromomalonates (18). Catalyst VII allowed, based on a Michael addition and subsequent intramolecular a-alkylation (i.e., a Bingel-Hirsch reaction) of the enamine intermediate, the production of the cyclopropane motif 17 (Scheme 10.9, B). 

Scheme 32 Intramolecular a-alkylation of C(2)-linked pyrrolidine by catalytic ruthenium carbene...

Interestingly, when the reaction of A -benzyl-/3-aminoketones with TMSC(Li)N2 is carried out at low temperature, intramolecular A -alkylation via initially formed diazoalkoxides preferentially occurs to give 3-substituted-3-(trimethylsiloxy)pyrrolidines as the major products (eq 25). ... 

The a-alkylation of carbonyl compounds is a key carbon-carbon bond forming reaction in organic chemistry. Despite the widespread apphcations of this method, a general asymmetric intramolecular a-alkylation via enamine catalysis has proven to be extremely challenging because of catalyst alkylation, or racemization of products in the reaction. List and coworkers developed an intramolecular a-alkylation of aldehydes by using (S)-a-methylproline (15) as the catalyst [10]. To eliminate the influence of the by-product HX, a stoichiometric amount of NEts was added. A diversity of chiral cyclopentanes and pyrrolidines 17, or cyclopropanes 19, could be obtained in high yields and ees (Scheme 36.5). 

Brpnsted acids 814 intramolecular alkylation 1107 intramolecular a-alkylation 1072... 

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