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Research Summary Zhongda Pan

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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 C–O/C–N bonds are formed in conjunction with vicinal C–C or

C–heteroatom 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 C–heteroatom

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 σ-bond activation, an emerging area in

catalysis chemistry (Scheme 1, B).2 Oxidative addition of C–C or “inert” C–heteroatom σ bonds to a transition

metal generates an activated organometallic intermediate, which delivers both fragments onto the C–C π bond of

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

and one C–heteroatom (or C–C) 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 N–CN bond activation; project 3 focuses on oxyacylation reaction by C–O bond

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

2. Summary of results

Project 1: Palladium/Lewis acid-catalyzed aminocyanation reaction via N–CN bond activation.

Cyanamides (R1R

2N–CN) are versatile building blocks for heterocycle synthesis, yet direct, catalytic cleavage

of the N–CN σ 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

N–CN 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 N–CN 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 (2a–2n). A

pyridine ring (2p), different geminal substituents at the 3-position (2r–2v), and various alkene substituents (2w–2z)

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 (2aa–2ad) and sultams (2af–2ao) 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 A–D), 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 N–CN bond activation.4

In attempts to activate the N–CN 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 N–CN 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 (4b–4i) 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 C1–N3 and C2–C4 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 C–O bond activation.7

Catalytic cleavage of the acyl C–O 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 β-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 C–O

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bond activation and stabilizing the resulting acyl–iridium 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, 6a–6g). 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 C–CN 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

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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) Muñiz, K.;

Martínez, 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 97–129. (b) C–C 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

N–CN 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.

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[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 C–O bond activation of esters: (a) Kakino, R.; Shimizu, I. Yamamoto, A. Bull. Chem. Soc. Jpn.

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

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