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Research Summary Zhongda Pan 1 Synthesis of Oxygen and Nitrogen Heterocycles by Catalytic σ-Bond Activation and Alkene Addition Reactions 1. Introduction Saturated and partially saturated oxygen and nitrogen heterocycles, such as tetrahydrofurans, pyrrolidines, pyrrolidones, and indolines are common motifs in numerous biologically active natural products, pharmaceuticals, and agrochemicals. Thus, developing new strategies for the synthesis of these compounds has been of longstanding importance to the chemical and pharmaceutical community. Scheme 1. Research overview. Metal-catalyzed alkene addition reactions represent an appealing strategy for the construction of saturated oxygen and nitrogen heterocycles because new CO/CN bonds are formed in conjunction with vicinal CC or Cheteroatom bonds in a single process, enabling rapid construction of molecular complexity (Scheme 1, A). 1 Despite significant advances, the established methods typically rely upon an exogenous electrophile (e.g., aryl halides) or nucleophile (e.g., halides, amines, carboxylates) to furnish the subsequent C C or Cheteroatom bonds vicinal to the heteroatom. Therefore, stoichiometric or excess addition of bases, oxidants or metal salts is

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  • Research Summary Zhongda Pan

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    Synthesis of Oxygen and Nitrogen Heterocycles by Catalytic -Bond Activation and

    Alkene Addition Reactions

    1. Introduction

    Saturated and partially saturated oxygen and nitrogen heterocycles, such as tetrahydrofurans, pyrrolidines,

    pyrrolidones, and indolines are common motifs in numerous biologically active natural products, pharmaceuticals,

    and agrochemicals. Thus, developing new strategies for the synthesis of these compounds has been of

    longstanding importance to the chemical and pharmaceutical community.

    Scheme 1. Research overview.

    Metal-catalyzed alkene addition reactions represent an appealing strategy for the construction of saturated

    oxygen and nitrogen heterocycles because new CO/CN bonds are formed in conjunction with vicinal CC or

    Cheteroatom bonds in a single process, enabling rapid construction of molecular complexity (Scheme 1, A).1

    Despite significant advances, the established methods typically rely upon an exogenous electrophile (e.g., aryl

    halides) or nucleophile (e.g., halides, amines, carboxylates) to furnish the subsequent CC or Cheteroatom

    bonds vicinal to the heteroatom. Therefore, stoichiometric or excess addition of bases, oxidants or metal salts is

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    often required, leading inevitable waste formation. In this context, our goal is to develop a direct addition approach

    that simultaneously introduces both the heteroatom group and a synthetically useful functional group (Scheme 1, A,

    FG) onto the alkene double bonds to generate the desired heterocycles in a regioselective manner, thereby

    obviating the need for exogenous reagents.

    To this end, we direct our attention to transition-metal-catalyzed -bond activation, an emerging area in

    catalysis chemistry (Scheme 1, B).2 Oxidative addition of CC or inert Cheteroatom bonds to a transition

    metal generates an activated organometallic intermediate, which delivers both fragments onto the CC bond of

    an alkene/alkyne upon migratory insertion and subsequent reductive elimination. Accordingly, one new CC bond

    and one Cheteroatom (or CC) bond, alongside up to two stereocenters are formed at the expense of breaking

    one bond, thus offering an unconventional yet efficient approach to functionalized carbo- and heterocycles.

    This report summarizes the applicant's four research projects in this area: projects 1 and 2 focus on

    aminocyanation reaction by NCN bond activation; project 3 focuses on oxyacylation reaction by CO bond

    activation; project 4 focuses on cyanoamidation reaction by CCN bond activation (Scheme 1, C).

    2. Summary of results

    Project 1: Palladium/Lewis acid-catalyzed aminocyanation reaction via NCN bond activation.

    Cyanamides (R1R

    2NCN) are versatile building blocks for heterocycle synthesis, yet direct, catalytic cleavage

    of the NCN bond is rare, presumably due to its double bond character.3 We recently discovered that using

    CpPd(1-phenylallyl) as the precatalyst and Xantphos as the ligand, N-aryl, N-acyl cyanamides (1) underwent facile

    NCN bond activation and subsequent alkene addition to form 5,5-disubstituted pyrrolidones (2) bearing a cyano

    group with excellent yields (Scheme 2, A). This transformation, namely aminocyanation reaction, likely involves a

    Pd(II)cyanide intemediate, where a boron Lewis acid (BPh3 or BEt3) binds to the cyano group and assists the

    challenging NCN bond activation process.

    This method demonstrated a broad substrate scope towards synthesizing pyrrolidones (Scheme 2, B).

    Various neutral, electron donating, and electron withdrawing substituents at the para-, meta-, and ortho position of

    aryl groups were well tolerated, affording the corresponded pyrrolidones in good to excellent yields (2a2n). A

    pyridine ring (2p), different geminal substituents at the 3-position (2r2v), and various alkene substituents (2w2z)

    were also effective. Pyrrolidones from a monosubtituted alkene (2o) and a substrate without the geminal

    substitutents (2q), as well as a piperidinone ring (2ae) were obtained in moderate yield. Moreover, this method was

    smoothly extended to benzo-fused lactams (2aa2ad) and sultams (2af2ao) with generally high yields. The

    synthetic utility of aminocyanation reaction was further highlighted by facile transformations of N-aryl isoindolinone

    2aa into various products (Scheme 2, C), including carboxylic acid and its derivatives (products AD), methyl and

    aryl ketones (E and F), tetrazole (I), deprotected isoindolinone (J), and thioamide (K). Chemoselective reductions

    of either the cyano group or the lactam were achieved, affording the corresponding amine (G), carbamate (H), and

    isoindoline (L) in good yields (Scheme 2, C).

    This project is ongoing in our laboratory, focusing on the elucidation of the stereoselectivity of alkene addition

    step and related mechanistic details, and the application in the synthesis of biological active isoindolinones, such

    as PD 172938, pazinaclone, and pagoclone, among others.

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    Scheme 2. Palladium/Lewis acid-catalyzed alkene aminocyanation reaction.

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    Project 2: Metal-free, Lewis acid-promoted aminocyanation reaction via formal NCN bond activation.4

    In attempts to activate the NCN bond of N-tosyl cyanamide 3a, we identified that using a rhodium complex

    [Rh(C2H4)2Cl]2 in conjunction with BPh3 led to the expected indoline 4a in 49% yield (Scheme 3, A). Dramatically, a

    stronger boron Lewis acid, B(C6F5)3 provided the same product in 90% yield in the absence of added metal.5 This

    result challenged our proposed pathway for NCN bond activation (Scheme 1), yet the rather simple and efficient

    conditions alone with the intriguing possibility of an alternative mechanism prompted further investigation.

    Scheme 3. Metal-free, Lewis acid-promoted alkene aminocyanation reaction.

    Substrates bearing various aryl substituents (4b4i) and alkene substituents (4j and 4k) provided the

    corresponding indolines in excellent yields (Scheme 3, B). Tetrahydroquinoline (4l) and a nosyl protecting group

    (4m) were examined. The reaction was scalable using substoichiometric amount of B(C6F5)3 (20 mol%) under air.

    Moreover, an interesting cyanide transfer reaction of cyanamide 3n gave alkenyl nitrile 4n in quantitative yield.

    Double crossover experiments were carried out to probe the reaction mechanism (Scheme 3, C). A mixture of

    3d and the 13

    C-labeled cyanamide (3a-13

    CN) afforded only the non-crossover products 4d and 4a-13

    CN. Similarly,

    no crossover product was observed from reaction using a mixture of 3d and 3m. The lack of crossover indicated

    that aminocyanation proceeded in an intramolecular fashion.

    In an initially proposed, stepwise mechanism, substrate 3a coordinated with B(C6F5)3 to afford the activated

    adduct I-1, which sets stage for an intramolecular nucleophilic attack of alkene and subsequent formation of a

    7-membered intermediate I-2 bearing a tertiary carbocation (Scheme 3, D). I-2 collapsed to the indoline product 4a

    along with the regeneration of B(C6F5)3. Interestingly, a recent computational study suggested a concerted pathway,

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    in which the transition state T-1 accounted for the formation of C1N3 and C2C4 bonds in an asynchronous

    manner.6 This mechanism represents a novel entry to the electrophilic addition reactions of alkenes.

    Project 3: Iridium-catalyzed oxyacylation reaction via CO bond activation.7

    Catalytic cleavage of the acyl CO bond of an ester and subsequent insertion of an alkene, namely

    oxyacylation reaction, is a conceptually new approach to manipulate esters because both an alkoxy and a carbonyl

    group are added across the alkene to generate -alkoxy ketones, which are typically synthesized from aldol

    reactions (Scheme 4, A).8 In addition, it is also rare for an ester to undergo acyl substitution without fragmentation.

    Scheme 4. Iridium-catalyzed alkene oxyacylation reaction.

    Following our previous success in developing a quinoline group-directed oxyacylation reaction,9 we recently

    discovered an oxyacylation reaction with salicylate esters, featuring a more versatile hydroxyl directing group

    (Scheme 4, B). The ester substrates (5) are readily prepared from widely available salicylic acids. Mechanistically,

    the embedding phenol group coordinates to the iridium catalyst upon ligand exchange, thereby directing the CO

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    bond activation and stabilizing the resulting acyliridium complex (I-1). Subsequent alkene insertion and reductive

    elimination regenerates the active catalyst and releases the chromane products (6). Notably, esters either lacking a

    hydroxyl group or substituted with thioether, phosphino, and amino groups failed to produce the oxyacylation

    product, suggesting that the hydroxyl directing group is required.

    Salicylate esters bearing electron neutral, donating, and withdrawing groups para to the carbonyl group

    afforded the corresponding chromanes in synthetically useful yields (Scheme 4, D, 6a6g). Electron-withdrawing

    nitro- and chloro substituents para to the hydroxyl group (6h and 6i), ethyl-substituted alkenes (6j and 6k), and a

    naphthoic ester (6l) were well-tolerated. Dihydrobenzofuran (6m) and dihydrobenzodioxine (6n) were also

    successfully constructed, albeit in modest yields. Additionally, the versatility of hydroxyl directing group was

    demonstrated by facile transformations into ester (6o), methyl ether (6p), triflate (6q), biaryl (6r), and

    deoxygenated product (6s) under straightforward conditions with excellent yields (Scheme 4, E).

    Project 4: Palladium-catalyzed asymmetric cyanoamidation reaction via CCN bond activation.

    Metal-catalyzed intramolecular cyanoamidation reaction allows direct synthesis of functionalized nitrogen

    heterocycles bearing a synthetically useful cyano group (Scheme 5, A).10

    Takemoto group's cyanoamidation

    method for constructing chiral oxindole frameworks is pioneering, yet somewhat limited to the rigid aromatic

    backbones and five-membered ring formation.11

    In this regard, we envision that cyanoamidation reactions of

    readily prepared cyanoformamides with an alkyl-tethered, more flexible alkene (7) would provide pyrrolidinones

    and piperidinones bearing an all-carbon quaternary stereocenter (8). These 3,3-disubstituted lactams are difficult

    to prepare by conventional methods, yet they are found embedded in the core of many indole alkaloids, such as

    ()-quebrachamine, ()-aspidospermidine, and ()-epieburnamonine, among others (Scheme 5, B).

    To create enantioselectivity during the stereocenter-forming, alkene addition step, we identified that the

    combination of a palladium catalyst with a suitable chiral phosphoramidite ligand produced promising results

    (Scheme 5, C). N-Aryl cyanoformamide with a methyl substituted alkene (7a) was quantitatively converted to

    pyrrolidinone 8a in up to 68% ee using BINOL-dervied phosphoramidite ligand L1.12

    Cyanoamidation of styrene

    analogue 7b required slightly higher temperature and the highest 65% ee was obtained using L2. Formation of

    six-membered piperidinones is more challenging, requiring a higher temperature and added Lewis acid to ensure

    completion. The piperidinone bearing an ethyl substituted quaternary stereocenter (8c) was synthesized in up to

    54% ee using L3. Interestingly, the cyanoformamide substituted with a chiral 1-phenylethyl group (7d) underwent a

    diastereoselective cyanoamidation reaction with up to 8.7:1 d.r. The enhanced stereoselectivity is likely owing to a

    synergistic effect between the nitrogen chiral auxiliary and the ligand.

    This project is currently ongoing. More phosphoramidite ligands and other ligand scaffolds (e.g., chiral

    phosphites and N-heterocyclic carbenes) will be examined to further optimize the stereoselectivity, allowing us to

    highlight this method in natural product synthesis.

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    Scheme 5. Palladium-catalyzed asymmetric cyanoamidation reaction.

    3. Summary of applicant's individual contribution

    Projects 1 and 2: The applicant independently proposed and initiated both projects, designed all substrates and

    experiments, completed most synthetic work (> 95%), and crafted the manuscripts as the first author.

    Project 3: The project was initiated by Dr. Giang Hoang (Douglas group). The applicant co-optimized the reactions,

    completed essentially all experiments shown in Scheme 4, and co-drafted the manuscript as the second author.

    Project 4: The applicant performed all studies associated with pyrrolidinones 8a and 8b (Scheme 5). Experiments

    on piperidinones 8c and 8d were independently designed by Dr. Ashley Dreis (Douglas group).

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    References

    [1] Reviews: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe, J. P. Synlett, 2008, 19, 2913. (c) Schultz,

    D. M.; Wolfe, J. P. Synthesis, 2012, 44, 351. (d) Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Lacy, A. R.;

    Rathi, A. H. Chem. Eur. J. 2011, 17, 58. (e) Cardona, F.; Goti, A. Nat. Chem. 2009, 1, 269. (f) Muiz, K.;

    Martnez, C. J. Org. Chem. 2013, 78, 2168. (g) Li, G.; Kotti, S. R. S.; Timmons, C. Eur. J. Org. Chem. 2007,

    2745. (h) Chemler, S. R.; Bovino, M. T. ACS Catal. 2013, 3, 1076. (i) Mueller, T. E.; Hultzsch, K. C.; Yus, M.;

    Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (j) Zi, G. Dalton Trans. 2009, 9101.

    [2] (a) Murakami, M.; Ito, Y. In Activation of Unreactive Bonds and Organic Synthesis; Murai, S., Ed.;

    Springer-Verlag: New York, 1999; pp 97129. (b) CC Bond Activation; Dong, G., Ed.; Topics in Current

    Chemistry 346; Springer: Berlin, 2014.

    [3] Cunningham, I. D.; Light, M. E.; Hursthouse, M. B. Acta Crystallogr. Sect. C 1999, 55, 1833. Examples of

    NCN bond cleavage: (a) Vliet, E. B. Org. Synth. 1925, 5, 43. (b) Fukumoto, K.; Oya, T.; Itazaki, M.;

    Nakazawa, H. J. Am. Chem. Soc. 2009, 131, 38. (c) Wang, R.; Falck. J. R. Chem. Commun. 2013, 49, 6516.

    (d) Bao, B.; Zeng, X. Org. Lett. 2014, 16, 314. (e) Miyazaki, Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem.

    Soc. 2014, 136, 3732.

    [4] Pan, Z.; Pound, S. M.; Rondla, N. R.; Douglas, C. J. Angew. Chem., Int. Ed. 2014, 53, 5170.

    [5] Control experiments confirm neither [Rh(C2H4)2Cl]2 nor BPh3 alone promoted the reaction.

    [6] Zhao, J.; Wang, G.; Li, S. Chem. Commun. 2015, 51, 15450.

    [7] Hoang, G. T.; Pan, Z.; Brethorst, J. T.; Douglas, C. J. J. Org. Chem. 2014, 79, 11383.

    [8] Catalytic acyl CO bond activation of esters: (a) Kakino, R.; Shimizu, I. Yamamoto, A. Bull. Chem. Soc. Jpn.

    2001, 74, 371. (b) Gooen, L.; Paetzold, J.; Angew. Chem., Int. Ed. 2002, 41, 1237. (c) Tatamidani, H.;

    Yokota, K.; Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004, 69, 5615. (d) Tatamidani, H.; Kakiuchi, F.; Chatani,

    J. Org. Lett. 2004, 6, 3597. (e) Murai, M; Miki, K.; Ohe, K. Chem. Commun. 2009, 3466. (f) Ooguri, A.;

    Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2009, 131, 13194. (g) Wang, J.; Zuo, S.; Chen, W.; Zhang,

    X.; Tan, K.; Tian, Y.; Wang, J. J. Org. Chem. 2013, 78, 8217.

    [9] Hoang, G. T.; Reddy, V. J.; Nguyen, H. H. K.; Douglas, C. J. Angew. Chem., Int. Ed. 2011, 50, 1882.

    [10] Nakao, Y. Catalytic CCN Bond Activation, In CC Bond Activation; Dong, G., Ed.; Springer: Berlin, 2014;

    pp 3358.

    [11] (a) Yasui, Y.; Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303. (b) Yasui, Y.; Kinugawa, T.; Takemoto,

    Y. Chem. Commun. 2009, 4275. (c) Yasui, Y.; Kamisaki, H.; Ishida, T.; Takemoto, Y. Tetrahedron 2010, 66,

    1980.

    [12] The absolute stereochemistry of product was not determined.