Asymmetric Chlorination of β-Keto Esters Using Diaminomethylenemalononitrile Organocatalyst

Abstract

Diaminomethylenemalononitrile organocatalysts promote the asymmetric chlorination of simple cyclic β-keto esters such as methyl, ethyl, and benzyl esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid. This affords the corresponding chiral α-chlorinated carbonyl products in excellent yields with high enantioselectivities.Key words organocatalyst; asymmetric chlorination; β-keto ester Chiral α-chlorinated carbonyl compounds are valuable building blocks in the production of various biologically active compounds. [1][2][3][4][5] To synthesize enantiomerically enriched α-chlorinated carbonyl compounds, direct chlorination of carbonyl compounds using a chlorine source, such as N-chlorosuccinimide (NCS), is a reliable method. Several research groups have reported on the asymmetric chlorination of β-keto esters using metal catalysts.6-17) Organocatalysis, meanwhile, has received considerable attention in the area of organic synthesis because, in comparison to reactions involving metal catalysts, it is an environmentally benign method. Synthetic methods for producing α-chlorinated compounds from β-keto esters using organocatalysts have also been developed. [18][19][20][21][22][23][24] Although chiral α-chlorinated β-keto esters are valuable synthetic intermediates, their preparation using organocatalysts and NCS with high enantioselectivity (>80% enantiomeric excess (ee)) has rarely been reported upon.19-21) Several methods for the synthesis of chiral α-chlorinated β-keto esters require high catalyst loading (>5 mol%), a complex chlorine source, and bulky ester units such as the t-butyl and adamantyl groups. The highly stereoselective (>80% ee) α-chlorination of simple esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid, such as methyl, ethyl, and benzyl esters (6a-c), is very rare.12,18) Among the various chlorine sources, NCS is one of the best reagents because of its simple structure and low cost. The α-chlorination of a simple cyclic β-keto ester with NCS, in the presence of an organocatalyst (ca. 1 mol%), is therefore highly desirable, and it is one of the most challenging research topics.Recently, we reported on some asymmetric reactions using organocatalysts bearing diaminomethylenemalononitrile (DMM) or diaminomethyleneindenedione (DMI) motifs. [25][26][27][28][29][30][31][32] In order to further demonstrate the value of DMM organocatalysts, we attempted to apply them to the asymmetric α-chlorination of simple cyclic β-keto esters. Results and DiscussionWe examined organocatalysts 1-5 (Fig. 1) for an enantioselective α-chlorination of β-keto ester 6a, as shown in Table 1. DMM organocatalysts 1-3 with tertiary or secondary amine groups provided the desired product 7a in excellent yields with low enantioselectivities (entries 1-3). Organocatalyst 4, which bears a chiral primary amine group, accelerates the α-chlorination of 6a and gives 7a with good enantioselectivity

Stereoselective α-Chlorination of β-Keto Esters in the Presence of Hybrid Amide-Based Cinchona Alkaloids as Catalysts

“…To our knowledge, only Miura group’s presented organocatalytic synthesis of these products with moderate enentioselectivities (78% for methyl ester). 9 Likewise, the use of bulky esters such as i -propyl, t -butyl, or adamanthyl in the chlorination reaction gave chlorinated products 14c–14e and 14e′ with very high enantiomeric excess (up to 97%). For 14g–14i derivatives based on tetralone, a decrease in the asymmetric induction is observed; however, it is still a satisfactory value (up to 86% ee), which is not always achievable with the use of known organocatalysts.…”

“…Since Hintermann and Togni reported the first example of α-halogenation of β-keto esters with a Ti­(IV)/TADDOL complexes, extensive studies have been undertaken. Most such procedures are based on metal catalysis, including a Lewis acid transition metal species accompanied by a chiral ligand. , Organocatalytic approaches for asymmetric halogenation have also been developed, including enamine catalysis, diaminomethylenemalononitrile, Cinchona-mediated processes, and indirect approaches using halogenated substrates in enantioselective C–C bond forming reactions . There are also reports related to chiral quaternary ammonium catalysts …”

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

“…The main interest in these compounds comes from their versatility for further functionalizations by stereospecific nucleophilic S N 2-type displacement reactions with different nucleophiles [ 66 , 85 – 87 ]. Accordingly, it comes as no surprise that their asymmetric synthesis has been intensively investigated in the past, either relying on asymmetric (transition)-metal- or organo-catalysis [ 76 , 85 – 94 ]. In sharp contrast to the numerous reports describing the use of asymmetric phase-transfer catalysis for α-fluorination reactions (as stated above), the use of chiral PTCs for enantioselective α-chlorinations of prochiral nucleophiles has been much less systematically investigated so far [ 76 , 90 , 92 ].…”

Catalytic Asymmetric Chlorination of β-Ketoesters Using N-PFB-PyBidine-Zn(OAc)2

“…The use of Cu and Zn salts for a single chiral ligand allows a switch in enantioselectivity [10]. Organocatalyzed reactions also have been reported [18][19][20][21][22][23][24][25][26][27][28][29]. In these reports, formation of enolates from the β-ketoesters has been proposed.…”