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    Organocatalytic tandem Michael addition reactions:A powerful access to the enantioselective synthesis

    of functionalized chromenes, thiochromenesand 1,2-dihydroquinolines

    Chittaranjan Bhanja1, Satyaban Jena1, Sabita Nayak2

    and Seetaram Mohapatra*2

    Review Open AccessAddress:1Department of Chemistry, Utkal University, Bhubaneswar-751 004,Odisha, India and 2Department of Chemistry, Ravenshaw University,Cuttack-753 003, Odisha, India, Fax: +91-671-2610304

    Email:Seetaram Mohapatra* - [email protected]

    * Corresponding author

    Keywords:chromenes; 1,2-dihydroquinolines; enantioselective; Michael addition;organocatalytic; thiochromenes

    Beilstein J. Org. Chem. 2012, 8, 16681694.doi:10.3762/bjoc.8.191

    Received: 02 April 2012Accepted: 05 September 2012Published: 04 October 2012

    Associate Editor: D. Dixon

    2012 Bhanja et al; licensee Beilstein-Institut.License and terms: see end of document.

    AbstractEnantioselective organocatalysis has become a field of central importance within asymmetric chemical synthesis and appears to beefficient approach toward the construction of complex chiral molecules from simple achiral materials in one-pot transformationsunder mild conditions with high stereocontrol. This review addresses the most significant synthetic methods reported on chiral-amine-catalyzed tandem Michael conjugate addition of heteroatom-centered nucleophiles to ,-unsaturated compounds followedby cyclization reactions for the enantioselective construction of functionalized chiral chromenes, thiochromenes and 1,2-dihydro-quinolines in optically enriched forms found in a myriad of bioactive natural products and synthetic compounds.


    IntroductionChromenes or benzopyrans and their sulfur and nitrogenanalogues are important classes of structural motifs found innumerous naturally occurring and synthetic compounds. Due toa rich array of functionalities and chiral centers these motifs arewidely recognized as useful building blocks for the synthesis ofa broad and interesting range of biologically active heterocycliccompounds having antiviral, antitumor, antimicrobial, antidia-

    betic, sex-pheromone, diuretic, anticoagulant, anti-anaphylaticand many more activities [1-9]. Some representative moleculesof these structural motifs are shown in Figure 1 [9-21]. There-fore, synthetic methodologies allowing rapid access to theseheterocycles in optically enriched form are highly desirable inorganic synthesis and chemical biology/medicinal chemistry. Inthe past few years very promising progress has been made in[email protected]://

  • Beilstein J. Org. Chem. 2012, 8, 16681694.


    Figure 1: Some representative molecules having chromene, thiochromene or 1,2-dihydroquinolin structural motifs.

    this intriguing area, and among the advances, organocatalyticenantioselective methodologies have gained much attentionfrom many research groups worldwide [22-29]. In the mean-time, organocatalytic tandem Michael conjugate additions ofheteroatom-centered nucleophiles to ,-unsaturated com-pounds appear as one of the most reliable and powerful tools forthe stereocontrolled access to a wide range of biologicallyactive heterocycles in optically enriched form [29-32]. In thisreview we have summarized our efforts to cover various chiral-amine-catalyzed synthetic protocols leading to one-pot enantio-selective synthesis of six membered mono hetero-atom

    containing, biologically active heterocycles, such as functional-ized chromenes (benzopyranes), thiochromenes (thiobenzopy-ranes) and 1,2-dihydroquinolines, by means of tandem/dominohetero Michael addition reactions, or modified versions [33-38],covering the literature up to 2011. Keeping an overview oforganocatalytic modes of activation, and taking the less reac-tive Michael acceptor into account, we discuss here only theiminium/enamine activation or dual activation by iminium andhydrogen-bonding interaction strategies followed by cycliza-tion, for these one-pot enantioselective syntheses. Whereverpossible, working mechanistic models are presented.

  • Beilstein J. Org. Chem. 2012, 8, 16681694.


    Figure 2: Screened chiral proline and its derivatives as organocatalysts. Rb = rubidium.

    This review work is systematized under the headings (1)Organocatalytic oxa-Michael reactions to access functionalizedchromenes; (2) Organocatalytic thio-Michael reactions to accessfunctionalized thiochromenes; and (3) Organocatalytic aza-Michael reactions to access functionalized 1,2-dihydroquino-lines, using chiral proline and its derivatives (Figure 2), chiralbifunctional thioureas, cinchona alkaloids and other organocata-lysts (Figure 3). For each reaction, the initial screening result ofvarious organocatalysts with their percentage of conversion (%yield) and enantiomeric excess (ee) is presented in tabular form,and the best catalyst is used for the given individual scheme.

    Review1 Organocatalytic oxa-Michael additions toaccess functionalized chromenes1.1. Reactions of 2-hydroxybenzaldehydes withacyclic/cyclic ,-unsaturated compoundsThe racemic synthesis of 2H-chromene was reported by Brseet al. in 2005 [39,40]. A strategy based on the organocatalyticenantioselective synthesis of chiral 2H-chromenes throughtandem-oxa-Michaelaldol sequence was first reported byArvidsson et al. [41] in 2006, using diarylprolinolether as aneffective organocatalyst. This method involved an oxa-Michael

  • Beilstein J. Org. Chem. 2012, 8, 16681694.


    Figure 3: Screened chiral bifunctional thiourea, its derivatives, cinchona alkaloids and other organocatalysts.

    attack of salicylaldehydes 1 on the ,-unsaturated aldehydes 2activated through an iminium ion formation with the catalyst Ib,followed by an intramolecular aldol reaction and the subse-quent water elimination to afford the chromene 3 (Scheme 1).The same reaction was also repeated with various catalysts,

    which are presented in Scheme 1. Several base and acid addi-tives were found to affect both the enantioselectivities and theyields of the product. The overall reaction sequence providedchromenes with aromatic substituents at the C-2 position in upto 70% yield and 60% enantioselectivity in dichloromethane at

  • Beilstein J. Org. Chem. 2012, 8, 16681694.


    Scheme 1: Diarylprolinolether-catalyzed tandem oxa-Michaelaldol reaction reported by Arvidsson.

    Scheme 2: Tandem oxa-Michaelaldol reaction developed by Crdova.

    room temperature, while C-2 aliphatic analogues were obtainedin 90% enantiomeric excess, but with only 20% yield, underidentical conditions.

    Taking the advantages of the above methodology, Crdova etal. [42,43] and subsequently Wang et al. [44] independentlyreported similar oxa-Michael/aldol reactions by means of thesame iminium-ion activation strategies but with improved

    yields and enantioselectivities. Crdova et al. reported thetandem reaction of salicylaldehydes 1 and ,-unsaturated alde-hydes 2 catalyzed by diphenylprolinol ether Ib at a slightlyhigher catalyst loading (20 mol %) in toluene and with2-nitrobenzoic acid as cocatalyst, which significantly increasedthe ee of the reaction from 9 to 88%. Further enhancement ofthe yield was achieved by the use of molecular sieves (4 ) inthe reaction (Scheme 2).

  • Beilstein J. Org. Chem. 2012, 8, 16681694.


    Scheme 3: Domino oxa-Michael-aldol reaction developed by Wei and Wang.

    Scheme 4: Chiral amine/chiral acid catalyzed tandem oxa-Michaelaldol reaction developed by Xu et al.

    Wang et al. [44] investigated the same tandem reaction of sali-cylaldehydes 1 and ,-unsaturated aldehydes 2 employingTES-protected diphenylprolinol Ie as organocatalyst with highcatalyst loading (30 mol %). With benzoic acid as cocatalystand dichloroethane as solvent, the test reaction provided thechiral chromenes 3 in good yields (up to 98%) and enantio-selectivities (99%) at room temperature (Scheme 3).

    In 2009, Xu et al. [45] developed an efficient protocol for theasymmetric tandem oxa-Michaelaldol reaction using chiralamine/chiral acid organocatalyst, instead of only organocatalyst,for the enantioselective synthesis of 2H-chromenes. In thereported protocol, the reaction of salicylaldehydes 1 with ,-unsaturated aldehydes 2 catalyzed by (S)-diphenylprolinoltrimethylsilyl ether Ib with (S)-Mosher acid Ib afforded thedesired products 3 with high yield (4590%) and with highenantioselectivity (7799%) (Scheme 4). The reactionproceeded through the iminium intermediate, and the syner-gistic ionic interaction of chiral amine with chiral acid formedin situ in the catalytic system effected an improvement of the

    reaction performance and offered an efficient steric effect in thetransformation. Although the reaction tolerated a broad scope ofsubstrates, the yields as well as enantioselectivities were greatlyaffected by the electronic and steric effect of the substrates.Compound 1 bearing electron-donating groups afforded thedesired product with high yield (up to 90%) and enantio-selectivity (up to 99%), whereas compound 2 having electron-withdrawing groups provided poor results.

    Very recently, Xu et al. [46] reported an improved protocol forthe domino-oxa-Michael reaction of salicylaldehydes 1 with,-unsaturated aldehydes 2 employing tertiary amine-modifieddiarylpyrrolinol-TMS ether III as a water-soluble and re-cyclable organocatalyst with 4-chlorobenzoic acid as cocatalyst(Scheme 5) for the synthesis of 2H-chromene derivatives 3. Theelectronic effect of the tertiary amine group in the modifiedcatalyst was believed to enhance the enantioselectivity of thechiral secondary amine. Since the catalyst is soluble in water,the method provi

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