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  • Published: August 03, 2011

    r 2011 American Chemical Society 13337 | J. Am. Chem. Soc. 2011, 133, 1333713348


    Phosphine-Catalyzed Annulations of Azomethine Imines:Allene-Dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] PathwaysRisong Na, Chengfeng Jing, Qihai Xu, Hui Jiang, Xi Wu, Jiayan Shi,

    Jiangchun Zhong, Min Wang, Diego Benitez, Ekaterina Tkatchouk,

    William A. Goddard, III, Hongchao Guo,*, and Ohyun Kwon*,

    Department of Applied Chemistry, China Agricultural University, Beijing 100193, P.R. ChinaMaterials and Process Stimulation Center, California Institute of Technology, Pasadena, California 91125, United StatesDepartment of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States

    bS Supporting Information


    Intermolecular cycloaddition is one of the most powerful toolsfor the convergent synthesis of a variety of carbo- and hetero-cycles from simpler precursors.1 Many metallo- and organocata-lytic systems have been successfully developed for the cyclo-additions of a wide range of starting materials. Among thecatalytic systems, nucleophilic phosphine catalysis has beenestablished as a reliable platform for the efficient assembly of awide array of cyclic products from simple building blocks.2 Inparticular, activated allenes subjected to nucleophilic phosphinecatalysis conditions exhibit superbly diverse reactivity towardelectrophilic reagents. These allenes can function as one-, two-,three-, or four-carbon synthons when reacting with a variety ofelectrophilic coupling partners (including aldehydes, alkenes,imines, and aziridines) undergoing [2 + 1],3 [4 + 1],4 [3 + 2],5

    [2 + 2 + 2],6 [3 + 3],7 [4 + 2],8 [4 + 3],9 or [8 + 2]10 annulations.11

    The particular reactivity of the allene substrate is often inducedby its electrophilic coupling partner. Consequently, the search fornew electrophilic substrates exhibiting suitable reactivity foreffective use in the synthesis of heterocycles with new skeletonsor structural features is a major challenge for the formation ofdiverse cycloaddition products from the nucleophilic phosphinecatalysis of allenes. In this context, we conceived the possibilityof introducing a new type of electrophilic coupling reagent,

    azomethine imines, that might serve as an NNC trio-of-atoms synthon in phosphine-catalyzed annulation processes.

    Scheme 1. Phosphine-Catalyzed [3 + N] Cyclizations ofAzomethine Imines with Allenoates

    Received: January 21, 2011

    ABSTRACT: In this paper we describe the phosphine-cata-lyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations ofazomethine imines and allenoates. These processes mark thefirst use of azomethine imines in nucleophilic phosphinecatalysis, producing dinitrogen-fused heterocycles, includingtetrahydropyrazolo-pyrazolones, -pyridazinones, -diazepinones,and -diazocinones. Counting the two different reaction modesin the [3 + 3] cyclizations, there are five distinct reactionpathwaysthe choice of which depends on the structure andchemical properties of the allenoate. All reactions are operationally simple and proceed smoothly under mild reaction conditions,affording a broad range of 1,2-dinitrogen-containing heterocycles in moderate to excellent yields. A zwitterionic intermediateformed from a phosphine and twomolecules of ethyl 2,3-butadienoate acted as a 1,5-dipole in the annulations of azomethine imines,leading to the [3 + 2 + 3] tetrahydropyrazolo-diazocinone products. The incorporation of two molecules of an allenoate into aneight-membered-ring product represents a new application of this versatile class of molecules in nucleophilic phosphine catalysis.The salient features of this protocolthe facile access to a diverse range of nitrogen-containing heterocycles and the simplepreparation of azomethine imine substratessuggest that it might find extensive applications in heterocycle synthesis.

  • 13338 |J. Am. Chem. Soc. 2011, 133, 1333713348

    Journal of the American Chemical Society ARTICLE

    Herein, we report the phosphine-catalyzed [3 + N] annulationsof allenoates and azomethine imines 1 (Scheme 1).

    Azomethine imines such as 1 are readily accessible, stablecompounds that have been employed recently as efficient 1,3-dipoles in various metal-catalyzed and organocatalytic cycloaddi-tions.1214 In 2003, Fu reported an efficient Cu-catalyzedprotocol for enantioselective [3 + 2] cycloaddition of azo-methine imines with alkynes;14a in 2005, he further extendedthis azomethine imine/alkyne cycloaddition strategy to thekinetic resolution of azomethine imines bearing a stereocenterat the 5-position of the pyrazolidinone core.14b Sibi demon-strated another Cu-catalyzed enantioselective [3 + 2] cycloaddi-tion of azomethine imines with pyrazolidinone acrylates.14i Paleand Sommer presented a heterogeneous Cu(I)-modified zeolite-catalyzed [3 + 2] cycloaddition of azomethine imines withalkynes.14k Hayashi studied Pd-catalyzed [3 + 3] cycloadditionsof azomethine imines with trimethylenemethane to producehexahydropyridazine derivatives under mild conditions,14c andPd-catalyzed [4 + 3] cycloadditions of azomethine imines with-methylidene--valerolactones.14g Toste reported a Au-catalyzed[3 + 3] annulation of azomethine imines with propargylesters.14j Maruoka developed a Ti-catalyzed enantioselective[3 + 2] cycloaddition of azomethine imines with R,-unsatu-rated aldehydes.14m Suga described a Ni-catalyzed enantioselec-tive and diastereoselective [3 + 2] cycloaddition of azomethineimines with 3-acryloyl-2-oxazolidinone.14f Charette also devel-oped a Ni-catalyzed [3 + 3] cycloaddition of aromatic azo-methine imines with 1,1-cyclopropane diesters.14l Morerecently, Scheidt described an N-heterocyclic carbene-catalyzedstereoselective formal [3 + 3] cycloaddition of azomethineimines with enals.14e Chen developed a multifunctional primaryamine (derived from cinchona alkaloids)-catalyzed enantiose-lective [3 + 2] cycloaddition of azomethine imines and cyclicenones,14h and a diarylprolinol salt-catalyzed [3 + 2] cycloaddi-tion of azomethine imines with R,-unsaturated aldehydes.14d

    Despite these extensive efforts at using azomethine imines ascyclization partners in heterocycle synthesis, the application ofazomethine imines in phosphine-catalyzed cycloaddition hasnot been reported previously. This situation prompted us todesign a cycloaddition of azomethine imines and allenoatesusing readily available tertiary phosphines as catalysts. It iswidely accepted that, in the phosphine-promoted reactions of

    activated allenoates, the catalysis cycle is typically initiated by theaddition of the Lewis basic phosphine to the electrophilic-carbon atom of the R-allenic ester, leading to the formationof zwitterionic intermediates. We suspected that exposing theseintermediates to azomethine imines might allow new [3 + N]cycloadditions, with the pathways followed depending on thenumber of carbon atoms that the allenoate contributes to thefinal cyclic products (Scheme 1). Herein, we report the firstexamples of phosphine-catalyzed cycloadditions of variouszwitterionic species to provide functionalized five-, six-, seven-,and eight-membered dinitrogen-containing heterocycles withhigh efficiency.

    The new annulation reactions provide generally applicableroutes toward dinitrogen-fused heterocycles, including tetrahy-dropyrazolo-pyrazolones, -pyridazinones, -diazepinones, and -diazocinones, which are key units in or building blocks of manypharmaceuticals, agrochemicals, biologically active compounds,and other useful chemicals. Among the dinitrogen-containingheterocycles, pyrazolone derivatives are often used as dyes in thefood, textile, photography, and cosmetics industries.15 Severalpyrazolones also exhibit bioactivity. For example, phenazone hasbeen used as a synthetic drug;16 phenylbutazone has anti-inflammatory activity;16 phenidone and BW755C are inhibitorsof lipoxygenase and cyclooxygenase, respectively;17,18 BW357Udisplays anorectic activity (Figure 1).19 Other dinitrogen-fusedheterocycles also exhibit diverse bioactivity and have a variety ofapplications. Tetrahydropyrazolo-pyrazolones have been inves-tigated as antibacterial agents,16 herbicides, pesticides,20 antitu-mor agents,21 calcitonin agonists,22 and potent drugs to relieveAlzheimers disease.23 Pyrazolopyridazinone derivatives havebeen studied extensively as pesticides and, especially, herbicides;more than 60 patents have been filed according to the CASdatabase. Pyrazolodiazepinone and pyrazolodiazocinone deriva-tives have also been explored as herbicides, insecticides,acaricides,24 and acetyl-CoA carboxylase inhibitors.25 In addi-tion, the pyrazolidine derivatives obtained through these annula-tions are readily transformed into 1,3-diamine derivatives viaNN bond cleavage with SmI2;26 this cleavage strategy has beendemonstrated in several reports.14j,27 Such 1,3-diamine deriva-tives serve not only as ligands of metal catalysts but also asbiologically important compounds or building blocks for bioac-tive compounds.28

    Figure 1. Selected examples of biologically active dinitrogen-fused heterocycles.

  • 13339 |J. Am. Chem. Soc. 2011, 133, 1333713348

    Journal of the American Chemical Society ARTICLE


    Although the azomethine imines 1 have received much atten-tion,14 including extensive application in 1,3-diploar cycloadditionsfor the preparation of a plethora of pyrazolidinone derivatives,29

    they have never previously been used in nucleophilic phosphine

    catalysis reactions. Our initial attempts at phosphine-catalyzedannulations of azomethine imines commenced with the reactionsof1-(p-nitrobenzylidene)-3-oxopyrazolidin-1-ium-2-ide(1a).Table1presents the


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