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TECHNISCHE UNIVERSITÄT MÜNCHEN

Professur für Molekulare Katalyse

Intramolecular α-alkylation and α-alkenylation of coumarin and quinolinone derivatives

Dawen Xu

Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität München

zur Erlangung des akademischen Grades eines

Doktors der Naturwissenschaften

genehmigten Dissertation. Vorsitzender: Prof. Dr. Klaus Köhler Prüfer der Dissertation: 1. Prof. Dr. Fritz. E. Kühn

2. Prof. Dr. Lukas Hintermann Die Dissertation wurde am 16.07.2019 bei der Technischen Universität München eingereicht

und durch die Fakultät für Chemie am 25.07.2019 angenommen.

For my beloved parents

The road ahead is long and has no ending; yet high and low I will search with my will unbending.

---Qu Yuan

I

Acknowledgements Foremost, I would like to express my sincere gratitude to my academic supervisor Prof. Dr. Fritz E. Kühn for giving me the opportunity to work in his research group as a Ph.D candidate. Thank you for providing an excellent environment for me to succeed in my Ph. D project. Your kind and gentle personality are greatly appreciated. I would like to thank Prof. Hao Guo for his patient guidance, suggestions, and frequent discussions on the time of my Ph. D project. Your ideas and suggestions about my project are highly valuable. I would like to thank Dr. Robert M. Reich for his patient guidance, suggestions in my research. Your proofreading for my manuscript and thesis is appreciated. Dr. Felix Kaiser and Oberkofler, Jens are appreciated for their work in the X-ray crystallographic measurements and contribution to my manuscripts. Acknowledgments also go to secretary staff Ulla Hifinger in our group, for her help with organization and office matters. I give my thanks to all my colleagues at the chair of molecular catalysis, for the peaceful environment and great working atmosphere during the last three years. Here, special thanks go to Han Li for his support during my time in Germany, and Pan Huang, Yuanhui Li for their accompany in the lab CRC 2005. The China Scholarship Council (CSC) and TUM Graduate School are acknowledged for the grant and the financial support in this work. I give my heartily thanks to my family for their endless love. I could not have finished this Ph. D project without their support.

II

Abstract α-Functionalization of α,β-unsaturated carbonyl compounds has long been a hot research field in organic chemistry as this α,β-unsaturated structure motifs widely exist in organic or inorganic compounds. This work focuses on developing an efficient and regioselective way of functionalizing α-position of α,β-unsaturated systems. In the course of this thesis an intramolecular AlCl3 initiated α-alkylation of α,β-unsaturated lactams and lactones has been reported. The reaction needs more than one equivalent of aluminum chloride and trace of water to initiate. The first equivalent of AlCl3 coordinates to carbonyl and the second one reacts with water to generate the necessary hydrogen ions. The reaction products are exclusively six-membered rings with high regioselectivity. The mechanism investigations show that a carbon cation rearrangement and six-membered ring intermediate formation are essential in this transformation. This reaction protocol unearths a new reactivity of quinolinone and coumarins. More importantly, it also generates a new stereo center, which may find its application in further bioactive coumarin and quinolinone derivative synthesis. Visible-light-promoted thioxanthone sensitized intramolecular α-alkenylation of quinolinones and coumarins is developed. This photoreaction proceeds in an unprecedented transition-metal-free cross-coupling manner. By adding an appropriate base, the seven-membered ring product can be selectively generated from an alkyl chain tethered coumarins or quinolinones and terminal brominated olefins. A triplet sensitization and bromine radical oxidation mechanism have been proposed for this transformation, hydrogen bonding may also play a role in accelerating this reaction. This reaction protocol tolerates electron-withdrawing and electron-donating groups, as well as a broad range of functional groups, being feasible for seven, or even eight-membered synthesis, providing a unique opportunity for the synthesis of α-alkenylated coumarins and quinolinones.

III

Zusammenfassung Die α-Funktionalisierung von α,β-ungesättigten Verbindungen ist seit langem einen Forschungsschwerpunkt in der organischen Chemie, da diese α,β-ungesättigten Strukturmotive in organischen oder anorganischen Verbindungen weit verbreitet sind. Diese Arbeit konzentriert sich auf die Entwicklung einer effizienten und regioselektiven Methode zur Funktionalisierung der α-Position von α,β-ungesättigten Systemen. Im Rahmen dieser Arbeit wurde über eine intramolekulare AlCl3-initiierte α-Alkylierung von α,β-ungesättigten Lactamen und Lactonen berichtet. Die Reaktion benötigt mehr als ein Äquivalent Aluminiumchlorid und Spuren von Wasser. Das erste Äquivalent AlCl3 koordiniert mit Carbonyl, das zweite Äquivalent reagiert mit Wasser, um die erforderlichen Protonen zu erzeugen. Die Reaktionsprodukte sind ausschließlich Sechsringe mit hoher Regioselektivität. Mechanismusuntersuchungen zeigen, dass eine Umlagerung von Kohlenstoffkationen und die Bildung von Sechsringen für diese Umwandlung von wesentlicher Bedeutung sind. Dieses Reaktionsprotokoll zeigt eine neue Reaktivität von Chinolinon und Cumarinen. Dabei wird ein neues Stereozentrum, das möglicherweise für die weitere Synthese von bioaktiven Cumarin- und Chinolinonderivaten verwendet wird. Eine, durch sichtbares Licht aktivierte Thioxanthon-sensibilisierte intramolekulare α-Alkenylierung von Chinolinonen und Cumarinen wurde entwickelt. Diese Photoreaktion verläuft in bisher nicht gekannter Weise metallfrei. Durch Zugabe einer geeigneten Base kann das siebengliedrige Ringprodukt selektiv aus an eine Alkylkette gebundenen Cumarinen oder Chinolinonen und endständigen bromierten Olefinen erzeugt werden. Für diese Umwandlung wurden eine Triplettsensibilisierung und ein Bromradikaloxidationsmechanismus vorgeschlagen, wobei die Wasserstoffbindung ebenfalls eine Rolle bei der Beschleunigung dieser Reaktion spielen kann. Diese Vorgehensweise erlaubt die Toleranz Lewis-sauren und Lewis-basischen Gruppen sowie einen breiten Bereich an funktionellen Gruppen, die für eine 7- oder sogar 8-gliedrige Synthese geeignet sind, und bietet eine einzigartige Möglichkeit zur die

IV

Synthese von α-alkenylierten Cumarinen und Chinolinone.

Table Of Contents

V

Table Of Contents

Acknowledgements ........................................................................................................ I Abstract ......................................................................................................................... II Zusammenfassung........................................................................................................ III Introduction .................................................................................................................... 1

General introduction .............................................................................................. 1 1.1 α-Alkylation of α,β-unsaturated carbonyl derivatives ..................................... 1

1.1.1 Baylis-Hillman reaction based α-alkylation ......................................... 1 1.1.2 Rauhut-Currier reaction based α-alkylation .......................................... 3 1.1.3 Transition metal catalyzed coupling based α-alkylation ....................... 6 1.1.4 Multiple-steps reaction based α-alkylation ........................................... 8 1.1.5 Visible-light-induced α-alkylation ........................................................ 9

1.2 α-Alkenylation of α,β-unsaturated carbonyl compounds............................... 10 1.2.1 Cross-coupling based α-alkenylation .................................................. 10 1.2.2 Photo-irradiation based α-alkenylation ............................................... 13 1.2.3 Radical based α-alkenylation .............................................................. 14

1.3 α-Alkynylation of α,β-unsaturated carbonyl compounds .............................. 16 1.4 Other α-functionalizations of α,β-unsaturated carbonyl compounds ............. 17 1.5 Objective ........................................................................................................ 18 1.6 References ...................................................................................................... 19

α-Alkylation of quinolinones and coumarins ............................................................... 22 2.1 Introduction .................................................................................................... 22 2.2 Optimization of reaction conditions ............................................................... 23 2.3 Substrate scope investigations ....................................................................... 26 2.4 Mechanism investigations .............................................................................. 28 2.5 Experimental Section ..................................................................................... 31

2.5.1 General experimental methods ........................................................... 31 2.5.2 General Procedure I for the synthesis of substrates ............................ 32 2.5.3 Synthesis of 1-methyl-4-(pent-4-en-1-yl)quinolin-2(1H)-one (2a) .... 35

Table Of Contents

VI

2.5.4 Synthesis of 6-acetoxy -4-(pent-4-en-1-yl)quinolin-2(1H)-one (4a) .. 36 2.5.5 Synthesis of 6-((tert-butyldimethylsilyl)oxy)-4-methylquinolin-2(1H)-one ................................................................................................................ 37 2.5.6 General procedure II for the α-alkylation reaction ............................. 37

2.6 Reproduction acknowledgement .................................................................... 44 2.7 References ...................................................................................................... 44

α-Alkenylation of quinolinones and coumarins ........................................................... 48 3.1 Introduction .................................................................................................... 48 3.2 Optimization of reaction conditions ............................................................... 50 3.3 Substrate scope investigations ....................................................................... 51 3.4 Proposed reaction mechanism ........................................................................ 53 3.5 Experimental Section ..................................................................................... 55

3.5.1 General experimental methods ........................................................... 55 3.5.2 Synthesis of 4-(((3-bromoallyl)oxy)methyl)quinolin-2(1H)-one ....... 56 3.5.3 General Procedure I for the synthesis of substrates ............................ 56 3.5.4 General Procedure II for the synthesis of substrates ........................... 58 3.5.5 General procedure III for the synthesis of substrates .......................... 60 3.5.6 Synthesis of 4-(5-bromopent-4-en-1-yl)-6-((tert-butyldimethylsilyl)oxy)-1-methylquinolin-2(1H)-one (1f) ......................... 62 3.5.7 Synthesis of 4-(5-bromopent-4-en-1-yl)-6-hydroxy-1-methylquinolin-2(1H)-one (1h) ............................................................................................. 63 3.5.8 General procedure IV for the synthesis of substrates ......................... 64 3.5.9 Synthesis of 4-(4-bromo-5-methylhex-4-en-1-yl)-1-methylquinolin-2(1H)-one (1o) ............................................................................................. 65 3.5.10 General procedure V for the photoreaction ....................................... 66

3.6 References ...................................................................................................... 74 Summary and Outlook ................................................................................................. 78 Appendix ...................................................................................................................... 81

4.1 Supporting information for α-alkylation of quinolinones and coumarins ..... 81 4.1.1 Crystal data of compound 2b .............................................................. 81

Table Of Contents

VII

4.1.2 Intermediate trapping experiment data ............................................... 86 4.1.3 NMR spectrums .................................................................................. 87

4.2 Supporting information for α-alkenylation of quinolinones and coumarins 109 4.2.1 Crystal data of compound 2h ............................................................ 109 4.2.2 Crystal data of compound 2n ............................................................ 114 4.2.3 NMR spectrums ................................................................................ 119

List of publications .................................................................................................... 155

Introduction

1

Introduction General introduction α-Functionalization of α,β-unsaturated carbonyl compounds α,β-Unsaturated carbonyl compounds are important substrates in organic synthesis. α-Functionalization enables the synthesis of a series of compounds that are applicable in both bioorganic chemistry and applied chemistry. α-Functionalization of α,β-unsaturated carbonyl compounds allows a direct C-C bond forming in organic synthesis. According to different types of substituents on the product, α-functionalization can be classified as α-alkylation, α-alkenylation, α-alkynylation and α-heterofunctionalization, which includes aza-functionalization, oxa-functionalization, sulfa-functionalization, phospha-functionalization and so on.

1.1 α-Alkylation of α,β-unsaturated carbonyl derivatives The α-alkylation of α,β-unsaturated carbonyl compounds builds a new C(sp2)-C(sp3) between the α-position of the above compounds and an electrophile. Generally, there are five strategies to approach α-alkylation: the Baylis-Hillman reaction, the Rauhut-Currier reaction, Michael addition reaction, cross-coupling reaction, and -ketovinyl cation based multiple-steps reaction.

1.1.1 Baylis-Hillman reaction based α-alkylation The Baylis-Hillman reaction[1] is an atom-economic carbon-carbon bond forming reaction. As the double bond of an alkene is activated by electron-withdrawing groups, theα-position of the alkene is therefore activated. In the classical Baylis-Hillman reaction, aldehydes can be attacked at the α-position of the alkene in the presence of a nucleophile as catalyst; this is referred as the Baylis-Hillman reaction. Most the Baylis-Hillman reactions are catalyzed by nucleophiles, such as amines,[2] phosphines.[3]

Introduction

2

Besides. Lewis acids also serve as the catalysts in non-typical Baylis-Hillman reaction.[4] For the general type of the Baylis-Hillman reaction, the mechanism proceeds as below, amine reacts with α,β-unsaturated ester to form an enol intermediate, which then attacks aldehyde to build a new C-C bond, elimination of amine affords Baylis-Hillman product. (Scheme 1).

Scheme 1: General types of the Baylis-Hillman reaction

Aldehyde is frequently used as an electrophile in the Baylis-Hillman reaction, Li and coworkers reported a Lewis acid Et2AlI as catalyzed intermolecular α-alkylation.[5] For Lewis acid catalyzed non-typical Baylis-Hillman reaction, the following mechanism was proposed. AlEt2I coordinated to both aldehyde and enone, iodine anion was then released after AlEt2I coordination to attack the β-position of enone to form iodinated enone. This enone intermediate then underwent intermolecular electrophilic attack to build a new C-C bond. Elimination of Lewis acid adducts took place subsequently to afford the α-alkylated product (Scheme 2).

Scheme 2: Lewis acid catalyzed aldehyde as substrate in the non-typical Baylis-

Hillman reaction

Introduction

3

Apart from aldehyde, orthoester also serves as an electrophile in the non-typical Baylis-Hillman reaction.[6] Osamu Muraoka and coworkers reported a Lewis acid BF3•Et2O catalyzed intermolecular α-alkylation of enone using Baylis-Hillman method. Trimethyl orthoformate was used as a precursor in this transformation to generate α-alkoxy carbocations, which underwent nucleophilic attack to enone to afford α-alkylation product. Notably, this reaction protocol built its own advantage by enabling a much faster reaction rate than traditional Baylis-Hillman reaction (Scheme 3).

Scheme 3: Orthoester as substrate in the non-typical Baylis-Hillman reaction

α-Alkylation can take place intramolecularly to afford polyfunctionalized rings. Michael Miesch and coworkers reported an example of synthesizing tricyclo-ring in 2018 (Scheme 4).[7] The crucial step in this transformation was an intramolecular Baylis-Hillman reaction, in which the catalyst was phosphine nucleophile. As there were two reaction sites in the substrate, the Baylis-Hillman reaction therefore afforded two polyfunctionalized ring systems. By decreasing the reaction time and temperature, the quadrane core product ratio could be improved.

Scheme 4: Intramolecular Baylis-Hillman reaction for tricycle-ring synthesis

1.1.2 Rauhut-Currier reaction based α-alkylation The Baylis-Hillman reaction mainly involves the coupling of the activated alkene/latent

Introduction

4

enolate with an aldehyde. The Rauhut-Currier reaction involves the coupling of one activated alkene/latent to a second Michael acceptor, which is normally olefins. Therefore, the Rauhut-Currier reaction can be two olefins dimerization or two olefins cross coupling. Compared to the Baylis-Hillman reaction, the Rauhut-Currier reaction lacks substrate reactivity and selectivity. (Scheme 5).

Scheme 5: Distinction between the Baylis-Hillman and the Rauhut-Currier reaction

The origin reaction of Rauhut-Currier reaction was reported by Rauhut Currier in 1963 catalyzed by an organic phosphine.[8] The reaction mechanism was believed as follows. Conjugate addition took place between an activated alkene and phosphine to afford zwitterionic species, the zwitterionic species thus generated underwent a second conjugate addition to another portion of activated alkene to afford zwitterionic α-alkylated intermediate. Elimination of the above intermediate regenerated the phosphine catalyst and gave the α-alkylation product (Scheme 6).

Introduction

5

EWGEWG

EWGEWG P(alkyl)3 or P(aryl)3EWG = CO2RCN

EWGEWG R3P

V

EWGEWG

R3PIV

EWGEWG

R3PIII

H

EWGR3PII

EWGI

Scheme 6: The Rauhut-Currier reaction catalyzed by phosphine nucleophile

The Rauhut-Currier α-alkylation takes place between not only two identical activated alkenes, but also two different activated alkenes. The first cross-coupling Rauhut-Currier α-alkylation was reported by Morita and Kobayashi in 1969 (Scheme 7).[9] The reaction took place between methyl acrylate and diethyl fumarate, the yields were not satisfying, with the cross-coupling product being the major product. However, dimerization still existed, which made this reaction less applicable. The catalyst of cross-coupling Rauhut-Currier reaction in this case was still phosphine, however, 15 years later, the trend of using phosphine-based catalyst has shifted to amine-based catalyst, since amine-based catalyst is more efficient and easy to handle.[10]

Scheme 7: The cross-coupling Rauhut-Currier reaction catalyzed by phosphine

nucleophile Generally, electron-withdrawing groups are essential in activating the alkene. In the year of 2018, Wei Wang and his coworkers reported a novel example of electron-poor system for the synthesis of asymmetric cross-coupling Rauhut-Currier reaction.[11] The

Introduction

6

reaction utilized chiral phosphines as catalyst to chemo- and enantioselectively activate 2-vinylpyridines, affording a series of structurally diverse, highly valued chiral pyridine building blocks. Further mechanistic study revealed that the N-H bond in the phosphine catalyst was crucial since it formed a hydrogen bond with 2-vinylpyridines to govern the stereoselectivity of this reaction (Scheme 8).

Scheme 8: Enantioselective cross-coupling Rauhut-Currier reaction catalyzed by

phosphine nucleophile

1.1.3 Transition metal catalyzed coupling based α-alkylation Last century, chemists have seen the power of transition metal catalyzed cross-coupling reaction. Transition metal catalyzed cross-coupling reaction has been widely used to build C(sp2)-C(sp2) bond, or even C(sp2)-C(sp3) bond. Carl R. Johnson reported in 1993 an example of Suzuki type Pd-catalyzed ɑ-alkylation of 2-iodo-4-(t-butyldimethylsiloxy)-2-cyclopentenone with B-(6-methoxycarbonyl)hexyl-9-BBN (9-BBN = 9-borabicylo[3.3.1]nonane).[12] The synthesized was further used to synthesize prostaglandins.

Scheme 9: Cl2Pd(dppf) catalyzed Suzuki type cross-coupling for α-alkylation reaction Negeshi reaction is widely used to build C(sp2)-C(sp3) bond. Georg and coworkers reported an Pd(PPh3)4 catalyzed intermolecular cross-coupling between alkyl zinc reagent and α-substituted enone.[13] The reaction mechanism involved an oxidative addition of palladium into sp2 C-I bond, followed by nucleophilic attack by zinc reagent.

Introduction

7

Subsequently, a reductive elimination of palladium species afforded the α-alkylation product (Scheme 10).

Scheme 10: Pd(PPh3)4 catalyzed Negishi type cross-coupling for α-alkylation reaction There are also other transition metal catalyzed α-alkylation. Recently, Yunfei Du and coworkers reported a cobalt-catalyzed regioselective α-alkylation of coumarins under mild conditions.[14] The reaction tolerated many functional groups with good yields. Reaction mechanism involved a t-BuOOH assisted cobalt catalyzed dehydrogenative-coupling process. The decomposition of t-BuOOH generated t-BuO• and OH•, the t-BuO• oxidized ether substrate to form species B, which underwent radical addition to 1 to form species E. Deprotonation of E afforded product 3, the Co(III) catalyst was regenerated by OH• oxidation (Scheme 11). Similar reactions have also been reported by other chemists using Fe,[15] Cu.[16] The common characteristic of these metal catalyzed oxidative cross coupling is the application of stoichiometric amounts of oxidant to regenerate the catalyst.

Introduction

8

O OO O OO

1 2 3

CoCl2. 6 H2O (10 mol%)t-BuOOH (5 equiv.)DBU (3 equiv.)ether (20 equiv.)sealed tube, 75 oC

O OO O OO

1C (more favored)

Bcross-coupling or

O O

O

D (less favored)

O OO

Co(III)

Co(II)t-BuOOH

t-BuOA

HBE

O O-

OO O

O

3 F

O

2t-BuOH OH-

Scheme 11: CoCl2 catalyzed dehydrogenative coupling for α-alkylation of coumarin

1.1.4 Multiple-steps reaction based α-alkylation Multiple-steps reaction methodology allows generation of α-alkylated product from α,β-unsaturated ketones. The key step of the reaction is the formation of α-ketovinyl anion or cation,[17] which can be attacked by either electrophile or nucleophile in the following step. Based on this, chemists like Corey,[18] Hs,[19] and Stork[20] have all independently developed several ways to alkylate the α,β-unsaturated ketones. These strategies have now become very useful methods to synthesize versatile α-alkylated enone derivatives. The following scheme shows an example of using multiple-steps reaction method to synthesize α-alkylated enones (Scheme 12).

Introduction

9

Scheme 12: Multiple-steps reaction for the synthesis of α-alkylated enones.

1.1.5 Visible-light-induced α-alkylation Very recently in 2019, Jin Yang and coworkers reported a visible light irradiated regioselective α-alkylation of coumarins via oxidative coupling with N-hydroxyphthalimide esters.[21] Compared to previous oxidative coupling of coumarin, visible light and Ir(ppy)3 are used to avoid using excess amounts of oxidants and harsh reaction conditions. Meanwhile, this reaction also represents a very rare example of α-alkylating coumarin.[22] Similar to transition metal catalyzed thermo α-alkylation, the crucial step of this reaction was the generation of alkyl radical. The generated radical underwent radical addition to α-position of coumarin, which was then oxidized by excited state of iridium. A deprotonation process happened to give the α-alkylated product (Scheme 13).

Introduction

10

Scheme 13: Visible-light-promoted intermolecular α-alkylation of coumarin.

1.2 α-Alkenylation of α,β-unsaturated carbonyl compounds The α-alkenylation of α,β-unsaturated carbonyl compounds generates new C(sp2)-C(sp2) between α,β-unsaturated carbonyl compounds and electrophiles. This reaction protocol is very useful in building a conjugated system. Since breaking sp2 C-H or C-X (X = halogen) bond needs more energy, direct nucleophilic or electrophilic attack is not a feasible solution. Currently, there are three approaches to access this reaction: the transition metal catalyzed cross-coupling, the photo-irradiated alkenyl radical or cation substitution, and the radical initiator mediated radical substitution.

1.2.1 Cross-coupling based α-alkenylation α-Alkenylation of α,β-unsaturated carbonyl compounds builds a new C(sp2)-C(sp2) bond between the α-position of a α,β-unsaturated carbonyl compounds. In most cases, transition metal catalyst is required in this cross-coupling reaction. In the year of 1991, Hauck and coworkers reported a new coupling procedure between 5-iodouracil and unsaturated tributylstannanes, the product was an alkene substituted uracil (Scheme

Introduction

11

14a).[23] This reaction protocol was a typical Stille cross-coupling reaction. Compared to traditional Stille cross-coupling, this methodology tolerated different blocking groups on the sugar moiety, as well as an unprotected hydroxyl group. The broad substrate scope made this reaction more versatile than the traditional one. Later on, Brian C. Froehler and coworkers developed this method to successfully synthesize a series of bioactive compounds (Scheme 14b).[24] Stanislaw F. Wnuk also developed this method to catalyze α-arylation.[25]

Scheme 14: Palladium catalyzed cross-coupling for α-alkenylation of α,β-unsaturated

carbonyl compounds The α-position of quinone is active in cross-coupling reaction. S. Hong and coworkers reported in 2012 an example of intermolecular cross-coupling of chromones with various quinones (Scheme 15a).[26] Compared to traditional functionalization of quinones that needed pre-functionalizaton, this method was straightforward and produced quinone motifs rapidly. The crucial point in this reaction was the application of AgOAc as an oxidant. AgOAc was assumed to oxidize the α-position of quinones, thus activating quinones and starting the catalysis. David R. Williams reported a similar method of intermolecular α-alkylation between two conjugated enones (Scheme 16b).[27] Bases were required for this transformation instead of oxidants, however, pre-functionalized quinones and enones were still necessary (Scheme 15b).

Introduction

12

Scheme 15: Palladium catalyzed cross-coupling for α-alkenylation of quinones

α-Arylation of quinoxalin-2(1H)-ones provides nitrogen heterocycles which is very useful in natural and non-natural product synthesis.[28] Coupling reactions in electron rich heteroarenes or those already acidic C-H bond is well developed, however, for those electron-withdrawing heteroarenes, similar reactions are rare.[13,29] Mouad Alami and coworkers reported a straightforward α-arylation of quinoxalin-2(1H)-ones with arylboronic acids.[30] This reaction protocol provided a practical way of synthesizing 3-arylquinoxalin-2(1H)-ones of biological interest (Scheme 16). It was also worth noting that the α-arylated product in this reaction could be further functionalized. The generated quinoxalin-2(1H)-ones could be used in a regioselective palladium catalyzed chelation-assisted C-H functionalization. Similar reactions were also reported by Abbas Shafiee,[31] where coumarins were used as substrate.

Scheme 16: Palladium catalyzed cross-coupling reaction for α-arylation of

quinoxalinone In 2016, Alexandros L. Zografos and coworkers reported the first alkenylation of N-substituted-4-hydroxy-2-pyridones with non-activated alkenes (Scheme 17).[32] This

Introduction

13

reaction protocol allowed efficient production of α-alkenylated pyridines. Although the reaction was mild and easy to handle, it generated byproducts, which made this reaction less applicable in synthetic chemistry.

Scheme 17: Palladium catalyzed cross-coupling reaction for α-alkenylation of

pyridines with non-activated alkenes

1.2.2 Photo-irradiation based α-alkenylation In 1985, S. Tai reported the first example of intermolecular α-alkenylation of 1,4-naphthoquinones.[33] The reaction proceeded via photoinduced-electron-transfer (PET) mechanism (Scheme 18). The starting material brominated naphthoquinone reacted with diphenylethylene under high-pressure Hg lamp irradiation to afford ethylene adduct, which underwent a consecutive trans β-elimination to yield benz[a]anthracene-7,12-dione derivative. For the photo-irradiated α-alkenylation of 1 and 2a to 3, the author proposed two possible reaction pathways. These two pathways proceeded via the generation of ion radical pair or exciplex. Pathway I generated an alkenyl radical and diphenylethylene radical cation, a following radical coupling and deprotonation took place to afford 3. Pathway II generated diradical or zwitterion intermediate, elimination of HBr yielded 3. In this report, the author supported pathway II, since leaving of halogen anion from ion radical pair was difficult.

Introduction

14

Scheme 18: Photoinduced-electron-transfer for α-alkenylation of 1,4-

naphthoquinones Recently, S. Hong and coworkers reported a visible light irradiated intramolecular α-alkenylation of quinolinones.[34] The mechanism was supposed to be photoinduced single-electron-transfer (SET) radical addition. The substrate directly reached an excited state upon light irradiation to trigger radical-based bond-forming process. In terms of the substrate scope, application of S- and P-centered radicals would lead to different α-alkenylated products (Scheme 19). This reaction represented the first example of photoinduced α-alkenylation of α,β-unsaturated carbonyl compounds from an alkyne substrate.

Scheme 19: Photoinduced single-electron-transfer for α-alkenylation of quinolinone

1.2.3 Radical based α-alkenylation Radical based α-alkenylation of α,β-unsaturated carbonyl compounds usually require

Introduction

15

aryldiazonium salts, which are usually difficult to synthesize and preserve. Compared to transition metal catalyzed cross-coupling based α-alkenylation, the radical-based α-alkenylation or α-arylation avoided using heavy metals and expensive arylating counterparts such as boronic acid and stannanes. Krishnacharya G. Akamanchi reported an example of oxidative arylation of naphthoquinones.[35] The reaction did not require prefunctionalization of naphthoquinone moiety and its reaction conditions were quite mild. The oxidant IBX (2-Iodoxybenzoic acid) oxidized the phenylhydrazine to generate phenyl radical, which underwent radical addition to quinones to yield α-arylated product (Scheme 20).

Scheme 20: IBX initiated radical addition for α-arylation of quinone

In 2017, Prem. P. Yadav reported a similar reaction using arylhydrazines as aryl radical source and air as oxidant (Scheme 21).[36] The reaction did not require any prefunctionalization. High regioselectivity was achieved even for nonsubstituted quinolinones. Broad substrate scope was obtained in this transformation and good yields were reported.

Scheme 21: Air initiated radical addition for α-arylation of quinolinone

Recently, coumarin as substrate was also tested by Prashant Prajapati.[37] The reaction yields were good, as well as its substrate scope. In this research, the author

Introduction

16

demonstrated the practicality by applying optimized reaction conditions to both coumarins and quinlinones. The results indicated that both substrates were applicable and the nitrogen-protected quinolinone was tolerated. (Scheme 22).

Scheme 22: Air initiated radical addition for α-arylation of quinolinone and coumarin

1.3 α-Alkynylation of α,β-unsaturated carbonyl compounds The coupling between sp2 carbon and sp3 carbon normally requires Sonogashira reaction. For Sonogashira reaction based α-alkynylation, the α-position of the respective α,β-unsaturated carbonyl compounds needs prefunctionalization. A feasible prefunctionalization way is iodination or bromination. For alkynes involved in Sonogashira reaction based α-alkynylation, functionalization of the terminal is necessary when external CuI is not present (Scheme 23).[38]

Scheme 23: Sonogashira coupling for α-alkynylation of enone

Introduction

17

1.4 Other α-functionalizations of α,β-unsaturated carbonyl compounds Recently, Masoumeh Abbasnia reported an intermolecular α-acylation of coumarins.[39] This reaction method was suitable for benzyl alcohols and styrenes. The mechanism was supposed to be radical based addition. Upon heated, the tert-butyl hydro peroxide (TBHP) underwent homolytic cleavage to generate alkoxy radical, which then oxidize aldehyde carbonyl to form carbonyl radical. This radical then selectively attacked the α-position of coumarin, producing a radical intermediate, another hydroxyl radical from TBHP abstracted a hydrogen radical then α-acylation product was generated (Scheme 24).

Scheme 24: α-Acylation of coumarin catalyzed by TBHP as an oxidant

α-Bromination provides useful synthon for other reactions like cross-coupling. W. Massefski reported in 2007 a facile and mild reaction protocol for selectively α-bromination of α,β-unsaturated carbonyl compounds.[40] This was a two-steps reaction, firstly, alkenes of α,β-unsaturated carbonyl compounds reacted with bromine to yield dibrominated alkenes, which then underwent base-free elimination to give exclusively α-brominated product. DMSO served as a reagent in this reaction, as well as a solvent

Introduction

18

(Scheme 25).

Scheme 25: Multiple-steps α-Bromination of α,β-unsaturated aldehyde

1.5 Objective In summary, functionalization of α,β-unsaturated carbonyl compounds generates a lot of useful synthons being widely applied in organic synthesis. Compared to β and γ functionalization, α-functionalization is more profoundly investigated. Especially for the α-functionalization of quinolinones and coumarins, generating bioactive quinolinones and coumarins derivatives that have great potential in synthetic chemistry and biochemistry. The α-alkylation of quinolinones and coumarins requires activated alkenes as substrates, however, α-alkylation of quinolinones and coumarins with non-activated alkenes as substrates have yet been developed. The α-alkenylation of quinolinones and coumarins has the potential to build seven-, eight-membered rings, however, the designated field has not been deeply studied. The first study of this thesis will focus on intramolecular α-alkylation of quinolinones and coumarins.

a) The reactivity of quinolinones and coumarins tethered with terminal alkene at β-position will be studied by using Lewis acids as initiators.

b) The synthetic applicability will be exemplified by applying this method to a lot of intramolecular quinolinones and coumarins dienes.

c) The mechanism of this reaction protocol will be studied. d) Conclusions of this study.

In a second study, the intramolecular α-alkenylation of quinolinones and coumarins will be examined.

a) This reaction will be evaluated by applying base as additive and thioxanthone as the triplet sensitizer, terminal brominated alkene tethered quinolinones will be applied as standard substrates.

Introduction

19

b) The synthetic applicability will be exemplified by applying this method to many functionalized quinolinones and coumarins brominated dienes. In addition, the synthesis of seven-, eight-membered rings will be tested.

c) The mechanism of this reaction will be studied. d) Conclusions of this study.

1.6 References [1](a) D. Basavaiah, A. J. Rao, T. Satyanarayana, Chem. Rev., 2003, 103, 811-892; (b)

D. Basavaiah, B. S. Reddy, S. S. Badsara, Chem. Rev., 2010, 110, 5447-5674. [2](a) A. Baylis, M. Hillman, in Chem. Abstr, 1972, p. 34174q; (b) N. E. Leadbeater, C.

van der Pol, J. Chem. Soc., Perkin Trans. 1, 2001, 2831-2835; (c) M. Mantel, M. Guder, J. Pietruszka, Tetrahedron, 2018, 74, 5442-5450; (d) S. K. Chittimalla, M. Koodalingam, C. Bandi, S. Putturu, R. Kuppusamy, RSC Adv., 2016, 6, 1460-1465.

[3](a) Y. Wei, M. Shi, Acc. Chem. Res., 2010, 43, 1005-1018; (b) Y.-Q. Jiang, Y.-L. Shi, M. Shi, J. Am. Chem. Soc., 2008, 130, 7202-7203.

[4](a) D. Basavaiah, B. Sreenivasulu, R. M. Reddy, K. Muthukumaran, Synth. Commun., 2001, 31, 2987-2995; (b) G. Li, H.-X. Wei, J. J. Gao, T. D. Caputo, Tetrahedron Lett., 2000, 41, 1-5.

[5]S. Karur, J. Hardin, A. Headley, G. Li, Tetrahedron Lett., 2003, 44, 2991-2994. [6]H. Kinoshita, T. Osamura, S. Kinoshita, T. Iwamura, S. Watanabe, T. Kataoka, G.

Tanabe, O. Muraoka, J. Org. Chem., 2003, 68, 7532-7534. [7]C. Peter, P. Geoffroy, M. Miesch, Org. Biomol. Chem., 2018, 16, 1381-1389. [8]M. Rauhut, H. Currier, in Chem. Abstr, 1963, p. 11224a. [9]K.-i. Morita, T. Kobayashi, Bull. Chem. Soc. Jpn., 1969, 42, 2732-2732. [10] (a) H. Amri, J. Villieras, Tetrahedron Lett., 1986, 27, 4307-4308; (b) D. Basavaiah,

V. Gowriswari, T. Bharathi, Tetrahedron Lett., 1987, 28, 4591-4592; (c) S. E. Drewes, N. D. Emslie, N. Karodia, Synth. Commun., 1990, 20, 1915-1921.

[11] C. Qin, Y. Liu, Y. Yu, Y. Fu, H. Li, W. Wang, Org. Lett., 2018, 20, 1304-1307. [12] C. R. Johnson, M. P. Braun, J. Am. Chem. Soc., 1993, 115, 11014-11015.

Introduction

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[13] H. Ge, M. J. Niphakis, G. I. Georg, J. Am. Chem. Soc., 2008, 130, 3708-3709. [14] L. Dian, H. Zhao, D. Zhang-Negrerie, Y. Du, Adv. Synth. Catal., 2016, 358, 2422-

2426. [15] (a) S. H. Doan, V. H. H. Nguyen, T. H. Nguyen, P. H. Pham, N. N. Nguyen, A. N.

Q. Phan, T. N. Tu, N. T. S. Phan, RSC Adv., 2018, 8, 10736-10745; (b) A. Banerjee, S. K. Santra, N. Khatun, W. Ali, B. K. Patel, Chem Commun (Camb), 2015, 51, 15422-15425; (c) B. Niu, W. Zhao, Y. Ding, Z. Bian, C. U. Pittman, Jr., A. Zhou, H. Ge, J. Org. Chem., 2015, 80, 7251-7257.

[16] (a) H. Zhuang, R. Zeng, J. Zou, Chin. J. Chem., 2016, 34, 368-372; (b) C. Wang, X. Mi, Q. Li, Y. Li, M. Huang, J. Zhang, Y. Wu, Y. Wu, Tetrahedron, 2015, 71, 6689-6693; (c) S. L. Zhou, L. N. Guo, X. H. Duan, Eur. J. Org. Chem., 2014, 2014, 8094-8100.

[17] (a) J. Ficini, J.-C. Depezay, Tetrahedron Lett., 1969, 4797-&; (b) H. O. House, W. C. McDaniel, J. Org. Chem., 1977, 42, 2155-2160.

[18] E. Corey, L. S. Melvin Jr, M. F. Haslanger, Tetrahedron Lett., 1975, 16, 3117-3120. [19] P. L. Fuchs, J. Org. Chem., 1976, 41, 2935-2937. [20] G. Stork, A. Ponaras, J. Org. Chem., 1976, 41, 2937-2939. [21] C. Jin, Z. Yan, B. Sun, J. Yang, Org. Lett., 2019, 21, 2064-2068. [22] H. Zhuang, R. Zeng, J. Zou, Chin. J. Chem., 2016, 34, 368-372. [23] V. Farina, S. I. Hauck, Synlett, 1991, 1991, 157-159. [24] A. J. Gutierrez, T. J. Terhorst, M. D. Matteucci, B. C. Froehler, J. Am. Chem. Soc.,

1994, 116, 5540-5544. [25] Y. Liang, J. Gloudeman, S. F. Wnuk, J. Org. Chem., 2014, 79, 4094-4103. [26] Y. Moon, S. Hong, Chem. Commun (Camb)., 2012, 48, 7191-7193. [27] D. R. Williams, S. A. Bawel, Org. Lett., 2017, 19, 1730-1733. [28] J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. Int. Ed., 2012, 51, 8960-

9009. [29] (a) J. Wang, S. Wang, G. Wang, J. Zhang, X.-Q. Yu, Chem. Commun., 2012, 48,

11769-11771; (b) Y. Li, Z. Qi, H. Wang, X. Fu, C. Duan, J. Org. Chem., 2012, 77, 2053-2057; (c) M. T. Molina, C. Navarro, A. Moreno, A. G. Csaky, Org. Lett., 2009,

Introduction

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11, 4938-4941. [30] A. Carrer, J. D. Brion, S. Messaoudi, M. Alami, Org. Lett., 2013, 15, 5606-5609. [31] F. Jafarpour, H. Hazrati, N. Mohasselyazdi, M. Khoobi, A. Shafiee, Chem.

Commun (Camb)., 2013, 49, 10935-10937. [32] T. Katsina, E. E. Anagnostaki, F. Mitsa, V. Sarli, A. L. Zografos, RSC Adv., 2016,

6, 6978-6982. [33] K. Maruyama, T. Otsuki, S. Tai, J. Org. Chem., 1985, 50, 52-60. [34] K. Kim, H. Choi, D. Kang, S. Hong, Org. Lett., 2019, 21, 3417-3421. [35] P. Patil, A. Nimonkar, K. G. Akamanchi, J. Org. Chem., 2014, 79, 2331-2336. [36] M. Ravi, P. Chauhan, R. Kant, S. K. Shukla, P. P. Yadav, J. Org. Chem., 2015, 80,

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(b) M. W. Miller, C. R. Johnson, J. Org. Chem., 1997, 62, 1582-1583; (c) E.-i. Negishi, Z. Tan, S.-Y. Liou, B. Liao, Tetrahedron, 2000, 56, 10197-10207.

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α-Alkylation of quinolinones and coumarins

22

α-Alkylation of quinolinones and coumarins A highly selective way to produce six-membered rings

This chapter is based on the following paper published in Organic & Biomolecular Chemistry. Dawen Xu, Felix Kaiser, Han Li, Robert M. Reich, Hao Guo,* Fritz E. Kühn* "Highly selective AlCl3 initiated intramolecular α-alkylation of α,β-unsaturated lactams and lactones."Organic & Biomolecular Chemistry 17.1 (2019): 49-52.

2.1 Introduction Lactams and Lactones are very useful organic molecule that are widely used in pharmaceutical, biological and medicinal area,[1] the derivatives of those compounds are therefore intensely studied by chemists.[2] The reactive structure in lactams and lactones are α,β-unsaturated carbonyl motifs. These motifs bear carbonyl and alkene units, they exhibit the reactivity of both carbonyl and alkene, such as addition to carbonyl and alkene,[3] [2+2] cycloadditions.[4],[5] Since the carbonyl and alkene form a conjugated system, new reactivity also emerges such as [4+2] thermocycloadditions[6],[7] and Michael additions.[8] Besides those reactions that take place in β-position, the α-position of a α,β-unsaturated carbonyl compounds are also active.[9] As stated in previous chapter, α-alkylation,[10] α-alkenylation,[11] α-alkynylation[12] and α-halogenation[13] take place at α-position of a unsaturated carbonyl compounds in proper conditions. For the α-alkylation, there are several protocols that allow this process, such as the Baylis–Hillman reaction,[14],[15] the Rauhut-Currier reaction[14a],[16],[17] and cross-coupling reactions.[18] Although numerous reaction protocols have been found to access the α-alkylation, drawbacks exist in those transformations. For the Lewis-base catalyzed Baylis-Hillman and Rauhut-Currier reaction, electron-deficient olefins are always required. While the cross-coupling reactions need noble metal and halogenated alkene as precursors. In this end, to develop a reaction protocol that enables direct α-alkylation of α,β-unsaturated carbonyl compounds from non-activated alkenes is of great significance, either for synthetic chemistry or for biological chemistry.


23

Lewis acids, upon coordination with carbonyl, will change the characteristic of carbonyl and the α-position of a α,β-unsaturated carbonyl system,[19] making the α-position easily attacked by an electrophile, such as an alkene, which can be a good electrophile after protonation. It is therefore anticipated that, by deliberately adding trace of water and equivalents of Lewis acid to a tethered olefin and α,β-unsaturated carbonyl compound, α-alkylation of this α,β-unsaturated carbonyl compound will take place. Based on the above concept, 4-(pent-4-en-1-yl) quinolinone was chosen as the standard substrate containing olefin and α,β-unsaturated carbonyl. With more than one equivalent of Lewis acid catalysis, a six-membered ring product was detected. This α-alkylation proceeded in a highly selective way. As far as we understand, this example represents the first α-alkylation between α,β-unsaturated carbonyl and non-activated olefin.

2.2 Optimization of reaction conditions A set of optimizations had been carried out to screen the reaction conditions to get the optimized one. The initial experiment was conducted with two equivalents of Cu(OTf)2 as initiator, dichloromethane as solvent at room temperature under argon atmosphere for 2 hours, no reaction took place and 98% of starting material was recycled (Table 1, entry 1). A similar Lewis acid Zn(OTf)2 was subsequently tested, no product except starting material was detected again (Table 1, entry 2). Later on, similar but stronger Lewis acid Fe(OTf)3 was applied, still no trace of six-membered ring product was yielded. The result was identical when Sc(OTf)3 was applied (Table 1, entries 3,4). Application of lanthanide Lewis acid Nd(OTf)3 in this alkylation reaction resulted in no reaction (Table 1, entry 5). Subsequently, attentions turned to Lewis acids with halogen as counter anion. Firstly, FeCl3 was tested. However, no trace of six-membered ring product was detected. However, the recycled yield was lower compared to previous one, presumably because that FeCl3 decomposed the substrate (Table 1, entry 6). Other halogen countered Lewis acids, such as CuCl2, ZnCl2 and TiCl4, gave no products at all, their recycled yields were almost quantitative (Table 1, entries 7-9). Boron Lewis acids are very strong Lewis acids, therefore, in a next step, boron Lewis acids were examined. BF3●OEt2 yielded no product


24

(Table 1, entry 10). Other boron Lewis acids like BCl3, BBr3 were not capable of initiating this reaction, although BBr3 was one of the strongest Lewis acids (Table 1, entries 11,12). After examining boron Lewis acids, aluminum Lewis acids were subsequently tested (Table 1, entries 13-19). Alkyl anion countered Lewis acids like AlMe3, AlEt3 gave no desired product except starting material. Same results were obtained when mono-chloro substituted aluminum acids, such as AlMe2Cl, and AlEt2Cl were used (Table 1, entries 13-16). However, when dichloro-substituted aluminum Lewis acid AlEtCl2 was applied, target molecule was detected, albeit with low yield (Table 1, entry 17). This result might indicate that aluminum Lewis was capable of initializing this reaction. Encouraged by this trial, AlCl3 was subsequently examined, a full conversion and almost quantitative yield were achieved (Table 1, entry 18). The application of AlBr3 resulted in lower yield than AlCl3, the reason of which was that the excessive Lewis acidity of AlBr3 decomposed part of the substrate.[20] Protic acid as initiator was evaluated by using excess amounts of HBr aqueous solution, no target molecule was yielded, which meant that Lewis acid was necessary for this transformation. The amount of AlCl3 loading was studied by setting gradient experiments (Table 1, entries 21-24). The results indicated that lower loading of AlCl3 did not affect the reaction yield, although lower catalyst loading meant longer reaction time. As the reaction needed at least more than one equivalent of AlCl3 to initiate, it was therefore reasonable to deduce that the first equivalent of AlCl3 coordinated to the substrate, while the second portion of AlCl3 initiated the reaction. Since AlCl3 was cheap and only 2 hours were required for this transformation, two equivalents of AlCl3 as initiator was chosen as the optimized loading for this transformation and all other following reactions. Finally, solvent effects were examined by using several reaction mediums (Table1, entries 25-29). The reaction in CH3CN yielded no desired product after 24 hours. In addition, no target product was detected in MeOH, THF, and Et2O. Considering the coordinating nature of AlCl3, it was assumed that MeOH, THF, Et2O coordinated to AlCl3, weakening its ability to activate the substrate, leading to no reaction. Non-coordinating solvent like CHCl3 still afforded the six-membered rings with an excellent yield. However, dichloromethane was chosen as the best


25

available solvent for this ɑ-alkylation as it had relatively low toxicity compared to chloroform. Table 1 Optimization of reaction conditionsa[21]

Entry Initiator Solvent Equiv. T (h) Yield (100%)b

1 Cu(OTf)2 CH2Cl2 2 2 0 (98)c 2 Zn(OTf)2 CH2Cl2 2 2 0 (99)c 3 Fe(OTf)3 CH2Cl2 2 2 0 (98)c 4 Sc(OTf)3 CH2Cl2 2 2 0 (98)c 5 Nd(OTf)3 CH2Cl2 2 2 0 (98)c 6 FeCl3 CH2Cl2 2 2 0 (93)c 7 CuCl2 CH2Cl2 2 2 0 (98)c 8 ZnCl2 CH2Cl2 2 2 0 (99)c 9 TiCl4 CH2Cl2 2 2 0 (99)c

10 BF3•OEt2 CH2Cl2 2 2 0 (93)c 11 BCl3 CH2Cl2 2 2 0 (99)c 12 BBr3 CH2Cl2 2 2 0 (99)c 13 AlMe3 CH2Cl2 2 2 0 (99)c 14 AlEt3 CH2Cl2 2 2 0 (99)c 15 AlMe2Cl CH2Cl2 2 2 0 (99)c 16 AlEt2Cl CH2Cl2 2 2 0 (99)c 17 AlEtCl2 CH2Cl2 2 2 15 18 AlCl3 CH2Cl2 2 2 99 19 AlBr3 CH2Cl2 2 2 86 20 HBr (48% in H2O) CH2Cl2 2 2 0 (99)c 21 AlCl3 CH2Cl2 1.5 4 96 22 AlCl3 CH2Cl2 1.3 8 97


26

23 AlCl3 CH2Cl2 1.1 24 96 24 AlCl3 CH2Cl2 0.8 24 0 (99)c 25 AlCl3 MeCN 2 24 0 (98)c 26 AlCl3 MeOH 2 24 0 (99)c 27 AlCl3 THF 2 24 0 (98)c 28 AlCl3 Et2O 2 24 0 (98)c 29 AlCl3 CHCl3 2 2 95

a All reactions were carried out using 1a (0.2 mmol) and a Lewis acid (0.4 mmol) in anhydrous solvents (10 mL) at room temperature under an argon atmosphere. b Isolated yields were reported. c Recovered yield of 1a.

2.3 Substrate scope investigations With the optimized reaction conditions in hand, the substrate scope investigations were subsequently carried out (Table 2). Firstly, amide N-methylated substrate 2a was tested; the alkylation went smoothly to give 2b in 98% after 2 h (2b). The exact structure of 2b was determined by single crystal X-ray diffraction analysis.[22] Lactones were then tested, the yield experienced a slight decrease compared to lactam 1b (88%, 3b). The tolerance of electron-donating and electron-withdrawing groups on the aromatic ring of lactones were examined by introducing acetoxy, fluorine, methyl, hydroxyl, and dimethoxyl (4b-8b). A moderate yield of 63% was achieved when acetoxy moiety was installed on the aromatic ring (4b). Electron withdrawing fluorine substituted Substrate 5a furnished the six-membered ring product in a good yield of 78% (5b). Electron-donating group, methyl substituted substrate, afforded desired products in good yield (6b). Other electron-donating groups, such as hydroxyl, and dimethoxyl substituted substrates afforded the target products in 83% and 95%, respectively. (6b-8b). The combined results from 4b to 8b indicated that electron-donating and electron-withdrawing groups were all tolerated, the functional groups tolerance of this reaction was very good. Later on, the effects of substituent on the terminal alkene were studied (9b-11b). Terminal methyl substituted substrate 9a yielded the desired product in 80% yield, while ethyl substituted


27

substrate 10a lead only to 52% yield. Subjecting iso-methylated substrate 11a to the reaction resulted in a significantly decreased in reaction yield (24%). It was assumed that this lower yield was due to the hindrance caused by a quaternary carbon center in the product (11b). At last, the influence of the length of the alkyl tether chain on the α-alkylation reaction results were investigated. However, 12a, with methyl substituted to terminal alkene of 11a, afforded again a six-membered ring product, in a yield of 65% (12a→1b). The combined results of 11a and 12a might indicated that a six-membered ring transition state existed in the reaction process. In order to explore the significance of the proposed six-membered ring transition state in the process of this transformation, an even longer alkyl chain tethered substrate 13a was synthesized. Interestingly, desired six-membered ring product 9b was again formed, in a yield of 49% (13a→9b); without even forming seven- or eight-membered rings product. Subsequently, two CH2- longer in the alkyl tether chain 14a was synthesized and subjected to the alkylation. Surprisingly, six-membered ring product 10b was again detected, although the yield was only 33% (14a→10b). In addition, only six-membered ring product was observed, no traces of eight- or night-membered ring product could be detected. The combined results of 12a to 14a indicated that this alkylation could only take place through a six-membered ring transition state, it also demonstrated that there existed hydride shifts during the cyclization (vide infra). Table 2. Substrate scope of this α-alkylationa[21]

1b, 2 h, 95%

N O 2b, 2 h, 98%

3b, 2 h, 88%


28

4b, 2 h, 63%b

5b, 2 h, 78%

6b, 2 h, 89%

7b, 5 h, 83%

8b, 2 h, 95%

9b, 2 h, 80%

10b, 2 h, 52%

11b, 2 h, 24%

1b, 2 h, 65%

9b, 3 h, 49%

10b, 4 h, 33%

a A solution of a (0.2 mmol) and AlCl3 (0.4 mmol) in anhydrous CH2Cl2 (10 mmol) was stirred at room temperature under an argon atmosphere. b 3 equiv. AlCl3 have been applied.

2.4 Mechanism investigations A set of experiments was conducted in order to get more information about the reaction mechanism, (Scheme 1). Finely sublimated AlCl3 was prepared to rule out the impact of trace of water. The results showed that traces of product was detected with sublimated AlCl3 as initiator. Deuterated water was then added to see the influence of water on this transformation. The alkylation result indicated that deuterated product was only 7%, compared to 93% of normal product (Figure S1). Hence, these two mechanistic investigations demonstrated that trace amounts of water in the medium were necessary for this alkylation and there existed


29

hydronium ions propagation in this transformation, as it was shown that the rate of deuterated product did not match its loading.

Scheme 1: Reaction with (water-free) sublimated AlCl3[21]

A possible reaction mechanism for this reaction is proposed based on above proofs, (Scheme 2). For the general product, the mechanism starts with the coordination of the first equivalent of AlCl3 to the carbonyl of the lactam starting material A, the coordination forms resonance structure B.[23] Subsequently, trace water in the medium reacts with AlCl3 to generate hydronium ions, a carbocation in species C is hence generated by this hydronium ion protonation. A conventional Friedel-Craft alkylation then takes place between the carbocation in terminal alkene and the α-position of the lactam ring to afford the desired α-alkylation product D.[24] Possibly, the hydronium ions will be regenerated to propagate the reaction via a deprotonation process from D.

Scheme 2: Proposed mechanism of this α-alkylation reaction[21]

To explain the uncommon results for the reaction of 12a, 13a, and 14a, a preceding hydride


30

shifts mechanism was proposed as illustrated in Scheme 3. These hydride shifts proceed between B’ and C’, irrespective of the length of the tether chain, respectively. With the coordination of AlCl3 to the lactam carbonyl of the starting material, species B’ was then formed. Subsequently, a carbon cation was generated as hydronium ion protonated the remote alkene. The hydride shifts then took place in this carbon cation species,[25] respectively. It was assumed that these shifts were reversible, proceeding in both directions of the alkyl chain. The six-membered ring species can only be generated when 5-position of the alkyl chain born carbon cation (C’). Subsequently the six-membered ring species followed the general pathway to afford desired molecule E’ (see Scheme 3). Since the yields of 12a, 13a, and 14a were relatively low, it therefore indicated that there might be a possible decomposition process during these shifts, the longer the alkyl tether chain, the more the decomposition rate.

n

Scheme 3: Proposed preceding hydride shifts equilibrium for the reactions of 12a, 13a and

14a[21] In summary, an unprecedented AlCl3 initiated intramolecular α-alkylation has been studied. The reaction took place between coumarins or quinolinones and β-alkyl tethered olefins. The functional groups tolerance of this reaction was very good. The selectively of this transformation was great with exclusively six-membered ring products being formed. A possible mechanism for the reaction was proposed including a preceding hydride shifts and a six-membered ring species. This reaction will find its application in quinolinone and coumarin derivatives synthesis. In addition, this reaction forms a stereo centre, which makes it applicable for bioactive drug design.


31

2.5 Experimental Section 2.5.1 General experimental methods 1H (400 MHz) and 13C (100 MHz) NMR spectra were acquired on a Bruker Avance Ultrashield 400 MHz and a Bruker DPX 400 MHz spectrometer. Mass Spectroscopy (MS) and High Resolution Mass Spectroscopy (HR-MS) was performed on a Thermo Scientific LTQ-FT Ultra (ESI). IR spectra were recorded on a Varian FTIR-670 spectrometer using a GladiATR accessory with a diamond ATR element. Melting points were determined on a MPM-H2 apparatus. Anhydrous CH2Cl2, THF was obtained from a M. Braun SPS purification system. The following compounds were synthesized according to literature procedures. Pent-4-en-1-ylzinc(II) bromide,[5a] 1-methyl-2-oxo-1,2-dihydroquinolin-4-yl trifluoromethane sulfonate,[5a] (E)-5-bromopent-2-ene,[26] 5,7-dimethoxy-4-methylquinolin-2(1H)-one,[27] 1a,[28] 3a,[5a] 5a,[29] 6a,[29] 10a,[29] 11a.[29] Crystal structure determination details for compound 2b: A clear, colorless fragment-like specimen of C15H17NO, approximate dimensions 0.186 mm x 0.209 mm x 0.317 mm, was used for the X-ray crystallographic analysis. The crystal was mounted on a microsampler with perfluorinated ether and transferred to the diffractometer. The X-ray intensity data were measured on a Bruker D8 Kappa Apex II system equipped with a Triumph monochromator and a Mo fine-focus sealed tube (λ = 0.71073 Å). A total of 1199 frames were collected. The total exposure time was 19.98 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 14663 reflections to a maximum θ angle of 25.02° (0.84 Å resolution), of which 2068 were independent (average redundancy 7.090, completeness = 99.9%, Rint = 4.52%, Rsig = 2.82%) and 2002 (96.81%) were greater than 2σ(F2). The final cell constants of a = 7.1064(12) Å, b = 10.3163(18) Å, c = 15.973(2) Å, volume = 1171.0(3) Å3, are based upon the refinement of the XYZ-centroids of 122 reflections above 20 σ(I) with 13.10° < 2θ < 50.61°. Data were corrected for absorption effects using the multi-scan method (SADABS). The calculated minimum and maximum transmission


32

coefficients (based on crystal size) are 0.9750 and 0.9850. The final anisotropic full-matrix least-squares refinement on F2 with 205 variables converged at R1 = 2.79%, for the observed data and wR2 = 7.36% for all data. The goodness-of-fit was 1.083. The largest peak in the final difference electron density synthesis was 0.120 e-/Å3 and the largest hole was -0.157 e-/Å3 with an RMS deviation of 0.032 e-/Å3. On the basis of the final model, the calculated density was 1.289 g/cm3 and F(000), 488 e-.

2.5.2 General Procedure I for the synthesis of substrates Synthesis of 5,7-dimethoxy-4-(pent-4-en-1-yl)quinolin-2(1H)-one (8a)

To a 100 mL Schlenk flask is added 5,7-dimethoxy-4-methylquinolin-2(1H)-one[27] (765 mg, 3.5 mmol), and dry THF (20 mL). The reaction mixture is cooled to 0 °C under argon atmosphere and treated dropwise with n-butyl lithium (2.5 M in n-hexane, 2.8 mL, 7.0 mmol). The dark red solution is stirred at room temperature for 3 h, cooled to -78 °C and treated with tetrabutylammonium iodide (nBu4NI) (970 mg, 2.6 mmol) and 4-bromobut-1-ene (0.7 mL, 7.0 mmol) is added subsequently. The yellow solution is stirred at room temperature overnight and then cooled to 0 °C, treated with 10 mL 1 N HCl. The solvent is evaporated and the residue is extracted with ethyl acetate (3 × 30 mL). The combined organic layers are washed with brine (15 mL), dried over MgSO4, filtered, and evaporated. The crude product is purified by column chromatography (n-hexane/ethyl acetate = 1:1) to give the product 8a as a solid (191 mg, 20%); mp 156.1-156.8 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 11.89 (s, 1 H), 6.44 (d, J = 1.6 Hz, 1 H), 6.28 (s, 1 H), 6.24 (d, J = 2.0 Hz, 1 H), 5.95-5.75 (m, 1 H), 5.10-4.90 (m, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 2.98 (t, J = 7.6 Hz, 3 H), 2.22-2.10 (m, 2 H), 1.80-1.60 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 164.1, 161.8, 158.9, 154.7, 142.3, 138.6, 117.4, 114.8, 105.6, 94.6, 91.4, 55.7, 55.5, 36.6, 33.8, 29.8; IR (neat) 1591, 1500, 1477, 1463, 1452, 1442,


33

1428 cm-1; HRMS (ESI): calcd for C16H20NO3+: 274.1438, found: 274.1437. The following compounds were prepared according to General Procedure I (1) 6-((tert-Butyldimethylsilyl)oxy)-4-(pent-4-en-1-yl)quinolin-2(1H)-one (7a)

The reaction of 6-((tert-butyldimethylsilyl)oxy)-4-methylquinolin-2(1H)-one (1.096 g, 3.8 mmol), n-butyl lithium (2.5 M in n-hexane, 3 mL, 7.6 mmol), nBu4NI (1.054 g, 2.9 mmol), and 4-bromobut-1-ene (1 mL, 7.6 mmol) in THF (20 mL) affords 7a as a solid (182 mg, 21%); mp 238.8-239.3 oC (methanol); 1H NMR(400 MHz, DMSO) δ 11.40 (s, 1 H), 9.37 (s, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 7.06-6.94 (m, 2 H), 6.30 (s, 1 H), 5.93-5.80 (m, 1 H), 5.11-4.95 (m, 2 H), 2.70 (t, J = 7.8 Hz, 2 H), 2.18-2.08 (m, 2 H), 1.75-1.63 (m, 2 H); 13C NMR (100 MHz, MeOD) δ 164.5, 154.6, 154.4, 139.1, 133.2, 122.0, 121.4, 119.9, 118.6, 115.9, 109.3, 34.5, 32.7, 29.3; IR (neat) 2942, 1638, 1624, 1576, 1502, 1453 cm-1; HRMS m/z (ESI): m/z calcd for C14H16NO2+: 230.1176, found: 230.1175. (2) (E)-4-(Hex-4-en-1-yl)quinolin-2(1H)-one (9a)

The reaction of 4-methylquinolin-2(1H)-one (2.387 g, 15.0 mmol), n-butyl lithium (2.5 M in n-hexane, 12.0 mL, 12 mmol), nBu4NI (4.155 g, 11.3 mmol), and (E)-5-bromopent-2-ene[26] (4.478 g, 30 mmol) in THF (50 mL) affords 9a as a solid (2.351 g, 69%); mp 145.7-146.4 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.43 (s, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.55-7.39 (m, 2 H), 7.23 (t, J = 8.0 Hz, 1 H), 6.60 (s, 1 H), 5.59-5.38 (m, 2 H), 2.86 (t, J = 7.6 Hz, 2 H), 2.20-2.07 (m, 2 H), 1.87-1.74 (m, 2 H), 1.68 (d, J = 5.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 164.4, 153.2, 138.6, 130.31, 130.26, 126.0, 124.2, 122.4, 119.8, 119.5, 116.8,


34

32.2, 31.6, 28.6, 17.9; IR (neat) 1647, 1611, 1554, 1508, 1439 cm-1; HRMS (ESI): calcd for C15H18NO+: 228.1383, found: 228.1382. (3) 4-(Hex-4-en-1-yl)quinolin-2(1H)-one (12a)

The reaction of 4-methylquinolin-2(1H)-one (1.592 g, 10.0 mmol), n-butyl lithium (2.5 M in n-hexane, 8.0 mL, 20.0 mmol), nBu4NI (2.772 g, 7.5 mmol), and 1-bromobut-2-ene (2.700 g, 20.0 mmol) in THF (60 mL) affords 12a as a solid (1.408 g, 66%); mp 167.9-170.3 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.76 (s, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.53-7.46 (m, 2 H), 7.26-7.19 (m, 1 H), 6.60 (s, 1 H), 5.60-5.44 (m, 2 H), 2.92 (t, J = 7.6 Hz, 2 H), 2.46-2.33 (m, 2 H), 1.72-1.60 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ 164.5, 152.6, 138.6, 130.3, 129.5, 126.4, 124.1, 122.4, 119.8, 119.5, 116.9, 32.3, 31.6, 17.9; IR (neat) 1648, 1611, 1557, 1506, 1438, 1401 cm-1; HRMS (ESI): calcd for C14H16NO+: 214.1226, found: 214.1226. (4) 4-(Hex-5-en-1-yl)quinolin-2(1H)-one (13a)

The reaction of 4-methylquinolin-2(1H)-one (1.593 g, 10.0 mmol), n-butyl lithium (2.5 M in n-hexane, 8 mL, 20 mmol), nBu4NI (2.775 g, 7.5 mmol), and 5-bromobut-1-ene (2.4 mL, 20.0 mmol) in THF (40 mL) affords 13a as a solid (1.800 g, 74%); mp 115.7-116.3 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.91 (s, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.55-7.44 (m, 2 H), 7.29-7.15 (m, 1 H), 6.60 (s, 1 H), 5.90-5.70 (m, 1 H), 5.10-4.90 (m, 2 H), 2.86 (t, J = 7.6 Hz, 2 H), 2.20-2.05 (m, 2 H), 1.85-1.65 (m, 2 H), 1.61-1.45 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 164.6, 153.2, 138.6, 138.3, 130.3, 124.0, 122.4, 119.8, 119.3, 116.9, 114.8,


35

33.5, 32.0, 28.7, 28.2; IR (neat) 1651, 1555, 1466, 1434, 1396 cm-1; HRMS (ESI): calcd for C15H18NO+: 228.1383, found: 228.1382. (6) 4-(Hept-6-en-1-yl)quinolin-2(1H)-one (14a)

The reaction of 4-methylquinolin-2(1H)-one (955 mg, 6.0 mmol), n-butyl lithium (2.5 M in n-hexane, 4.8 mL, 12.0 mmol), nBu4NI (1.848 g, 5.0 mmol), and 6-bromobut-1-ene (1.5 mL, 11.0 mmol) in THF (30 mL) affords 14a as a solid (738 mg, 51%); mp 105.1-105.9 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.80 (s, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.52-7.46 (m, 2 H), 7.25-7.18 (m, 1 H), 6.60 (s, 1 H), 5.89-5.71 (m, 1 H), 5.07-4.87 (m, 2 H), 2.86 (t, J = 7.8 Hz, 2 H), 2.13-2.00 (m, 2 H), 1.80-1.66 (m, 2 H), 1.53-1.40 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 164.4, 153.4, 138.7, 138.5, 130.3, 124.1, 122.5, 119.9, 119.3, 116.9, 114.5, 33.6, 32.2, 29.0, 28.7; IR (neat) 1650, 1553 1471, 1431, 1394 cm-1; HRMS (ESI): calcd for C16H20NO+: 242.1539, found: 242.1539.

2.5.3 Synthesis of 1-methyl-4-(pent-4-en-1-yl)quinolin-2(1H)-one (2a)

Under argon atmosphere, pent-4-en-1-ylzinc(II) bromide[5a] (8.6 mL, 13 mmol, 1.5 M in DMAC), 1-methyl-2-oxo-1,2-dihydroquinolin-4-yl trifluoromethanesulfonate[5a] (2.000 g, 6.51 mmol), and Pd(PPh3)4 (690 mg, 0.65 mmol) are added to dry THF (10 mL) at rt. The resulting mixture is stirred at 50 oC under argon atmosphere. The coupling reaction is completed after 4 h as monitored by TLC (n-hexane/ethyl acetate = 5:1). The reaction is quenched with 1 N HCl (10 mL) and extracted with ethyl acetate (20 mL x 4). The combined organic layers are washed


36

with brine (30 mL x 3), dried over Na2SO4, filtered, and evaporated. The residue is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 5:1) to afford product 2a as a solid (991 mg, 67%); mp 44.8-45.4 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 7.71 (dd, J = 8.0, 1.2 Hz, 1 H), 7.53 (td, J = 7.2, 1.2 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.22 (t, J = 8.4 Hz, 1 H), 6.57 (s, 1 H), 5.90-5.75 (m, 1 H), 5.10-4.95 (m, 2 H), 3.68 (s, 3 H), 2.79 (t, J = 7.8 Hz, 2 H), 2.25-2.10 (m, 2 H), 1.85-1.73 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 162.0, 149.9, 140.0, 137.7, 130.2, 124.8, 121.7, 120.5, 120.0, 115.4, 114.5, 33.3, 31.2, 29.1, 27.8; IR (neat) 1655, 1643, 1588, 1453, 1417 cm-1; HRMS (ESI): calcd for C15H18NO+: 228.1383, found: 228.1382.

2.5.4 Synthesis of 6-acetoxy -4-(pent-4-en-1-yl)quinolin-2(1H)-one (4a)

To a three necked bottle 7a (138 mg, 0.6 mmol), acetic anhydride (1 mL), and acetic acid (4 mL) are added. The mixture is then refluxed overnight. The mixture is diluted with 10 mL water and extracted with ethyl acetate (10 mL x 3). The combined organic layers are washed with brine and dried over MgSO4, filtered, evaporated. The residue is purified by column chromatography (n-hexane/ethyl acetate = 1:1) to give the product 4a as a solid (150 mg, 92%); mp 154.2-155.0 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.51 (s, 1 H), 7.49-7.40 (m, 2 H), 7.28-7.23 (m, 1 H), 6.62 (s, 1 H), 5.92-5.76 (m, 1 H), 5.16-5.00 (m, 2 H), 2.82 (t, J = 7.8 Hz, 2 H), 2.34 (s, 3 H), 2.26-2.16 (m, 2 H), 1.89-1.78 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 169.7, 164.1, 152.5, 145.6, 137.6, 136.3, 124.5, 120.3, 120.1, 117.7, 116.4, 115.6, 33.2, 31.4, 27.5, 21.1; IR (neat) 1760, 1663, 1504, 1426 cm-1; HRMS (ESI): calcd for C16H18NO3+: 272.1281, found: 272.1282.


37

2.5.5 Synthesis of 6-((tert-butyldimethylsilyl)oxy)-4-methylquinolin-2(1H)-one

To a 10 mL Schlenk flask 6-hydroxy-4-methylquinolin-2(1H)-one (175 mg, 1.0 mmol), tert-butylchlorodimethylsilane (TBDMSCl) (181 mg, 1.2 mmol), imidazole (171 mg, 2.5 mmol), and DMF (2 ml) are added. The mixture is stirred at 35 oC for 24 h. The mixture is washed with 15 mL water and extracted with ethyl acetate (10 mL x 3). The combined organic layers are washed with brine and dried over MgSO4, filtered, evaporated. The residue is purified by column chromatography (ethyl acetate) to give the product 6-((tert-butyldimethylsilyl)oxy)-4-methylquinolin-2(1H)-one as a solid (266 mg, 92%); mp 173.7-175.0 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.57 (s, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.10-7.01 (m, 2 H), 6.58 (s, 1 H), 2.46 (s, 3 H), 1.00 (s, 9 H), 0.21 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 163.9, 150.8, 148.4, 133.2, 124.0, 121.3, 120.7, 117.6, 113.7, 25.7, 19.2, 18.2, -4.4; IR (neat) 1656, 1619, 1473, 1424 cm-1; HRMS (ESI): calcd for C16H23NO2Si+: 289.1498, found: 289.1498.

2.5.6 General procedure II for the α-alkylation reaction Synthesis of 7-methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (1b)

To a 25 mL Schlenk flask 1a (43 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) are added. The mixture is stirred at room temperature under argon atmosphere. The reaction is completed after 2 h as monitored by TLC (n-hexane/ethyl acetate = 1:1). The reaction mixture is quenched with saturated NH4Cl (10 mL), washed with water and extracted with ethyl acetate


38

(10 mL x 3). The combined organic solvent is evaporated and the residue is purified by column chromatography (n-hexane/ethyl acetate = 3:1) to give the product 1b as a solid (41 mg, 95%); mp 207.5-208.5 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 11.79 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 3.37-3.20 (m, 1 H), 3.10-2.96 (m, 1 H), 2.82-2.65 (m, 1 H), 2.05-1.73 (m, 4 H), 1.33 (d, J = 6.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 163.4, 143.6, 136.6, 133.0, 129.0, 123.2, 122.0, 120.5, 115.9, 29.1, 27.3, 25.7, 19.7, 17.1; IR (neat) 1644, 1609, 1561, 1505, 1433 cm-1; HRMS (ESI): calcd for C14H16NO+: 214.1226, found: 214.1226. The following reactions were conducted according to general procedure IV. (1) 5,7-Dimethyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (2b)

The reaction of 2a (45 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 2b as a solid (44 mg, 98%); mp 88.8-89.8 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 7.71 (d, J = 9.2 Hz, 1 H), 7.49 (t, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.22 (t, J = 8.2 Hz, 1 H), 3.73 (s, 3 H), 3.28-3.15 (m, 1 H), 3.03-2.90 (m, 1 H), 2.80-2.63 (m, 1 H), 1.96-1.83 (m, 2 H), 1.81-1.66 (m, 2 H), 1.26 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.7, 141.3, 138.2, 133.2, 129.0, 123.8, 121.6, 121.2, 114.0, 29.5, 29.2, 27.9, 25.5, 19.6, 17.1; IR (neat) 1626, 1592, 1571, 1453, 1411 cm-1; HRMS (ESI): calcd for C15H18NO+: 228.1383, found: 228.1382. (2) 7-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (3b)

The reaction of 3a (43 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords


39

3b as a solid (38 mg, 88%); mp 89.0-91.0 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1 H), 7.45 (t, J = 8.4 Hz, 1 H), 7.33-7.24 (m, 2 H), 3.15-3.01 (m, 1 H), 2.97-2.84 (m, 1 H), 2.73-2.60 (m, 1 H), 1.96-1.68 (m, 4 H), 1.27 (d, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.2, 152.1, 146.7, 130.3, 128.5, 123.9, 123.3, 120.2, 116.7, 28.9, 27.8, 25.4, 19.4, 16.8; IR (neat) 1705, 1621, 1606, 1572, 1448 cm-1; HRMS (ESI): calcd for C14H15O2+: 215.1067, found: 215.1067. (3) 2-Acetoxy-7-methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (4b)

The reaction of 4a (54 mg, 0.2 mmol), AlCl3 (81 mg, 0.6 mmol), and CH2Cl2 (10 mL) affords 4b as a solid (34 mg, 63%); mp 203.0-203.9 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.26 (s, 1 H), 7.45-7.31 (m, 2 H), 7.17 (dd, J = 8.4, 2.2 Hz, 1 H), 3.31-3.18 (m, 1 H), 3.00-2.85 (m, 1 H), 2.78-2.62 (m, 1 H), 2.33 (s, 3 H), 1.99-1.68 (m, 4 H), 1.31 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 169.8, 163.5, 145.3, 143.1, 134.5, 133.8, 122.9, 121.1, 116.9, 115.6, 29.0, 27.3, 25.7, 21.1, 19.7, 17.0; IR (neat) 1753, 1643, 1624, 1501, 1428, 1415 cm-1; HRMS (ESI): calcd for C16H18NO3+: 272.1281, found: 272.1282. (4) 2-Fluoro-7-methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (5b)

The reaction of 5a (46 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 5b as a solid (36 mg, 78%); mp 116.2-116.9 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 7.30-7.10 (m, 3 H), 3.12-3.00 (m, 1 H), 2.89-2.75 (m, 1 H), 2.69-2.53 (m, 1 H), 1.98-1.68 (m, 4 H), 1.27 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 160.8, 160.0, 157.6, 148.2, 145.9, 129.6, 121.2, 121.1, 118.1, 118.0, 117.6, 117.4, 109.3, 109.1, 28.8, 27.9, 25.4, 19.3, 16.6; IR (neat) 1711, 1579, 1493, 1434 cm-1; HRMS (ESI): calcd for C14H14FO2+:


40

233.0972, found: 233.0971. (5) 2,7-Dimethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (6b)

The reaction of 6a (45 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 6b as a solid (40 mg, 89%); mp 119.6-120.3 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 7.34 (s, 1 H), 7.25 (dd, J = 8.0, 2.0 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 3.12-3.00 (m, 1 H), 2.94-2.82 (m, 1 H), 2.72-2.58 (m, 1 H), 2.41 (s, 3 H), 1.95-1.69 (m, 4 H), 1.26 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.4, 150.1, 146.7, 133.4, 131.2, 128.3, 123.3, 119.9, 116.4, 28.9, 27.8, 25.4, 21.1, 19.4, 16.8; IR (neat) 1705, 1618, 1577, 1457, 1431, 1413 cm-1; HRMS (ESI): calcd for C15H17O2+: 229.1223, found: 229.1223. (6) 2-Hydroxy-7-methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (7b)

The reaction of 7a (46 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 7b as a solid (38 mg, 83%); mp 268.0-268.9 oC (ethanol/ethyl acetate); 1H NMR(400 MHz, DMSO) δ 11.34 (s, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 6.92 (dd, J = 8.8, 2.4 Hz, 1 H), 3.03-2.91 (m, 1 H), 2.86-2.73 (m, 1 H), 2.63-2.52 (m, 1 H), 1.86-1.58 (m, 4 H), 1.14 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, MeOD) δ 163.6, 154.1, 145.1, 133.6, 131.3, 122.8, 119.8, 117.7, 108.6, 30.1, 28.5, 26.7, 20.1, 18.0; IR (neat) 2930, 1650, 1619, 1502, 1429, 1417 cm-1; HRMS (ESI): calcd for C14H16NO2+: 230.1176, found: 230.1175. (7) 1,3-Dimethoxy-7-methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (8b)


41

The reaction of 8a (55 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 8b as a solid (52 mg, 95%); mp 214.6-215.5 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 12.19 (s, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 6.20 (d, J = 2.4 Hz, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.41-3.29 (m, 1 H), 3.26-3.16 (m, 1 H), 3.04-2.89 (m, 1 H), 1.86-1.61 (m, 4 H), 1.30 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 163.6, 160.6, 159.3, 146.8, 140.1, 128.7, 106.4, 94.4, 90.9, 55.4, 30.2, 28.9, 27.7, 20.2, 18.3; IR (neat) 1653, 1602, 1551, 1460, 1439, 1407 cm-1; HRMS (ESI): calcd for C16H20NO3+: 274.1438, found: 274.1437. (8) 7-Ethyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (9b)

The reaction of 9a (45 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 9b as a solid (36 mg, 80%); mp 193.2-193.8 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 11.79 (s, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.44 (t, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.19 (t, J = 8.2 Hz, 1 H), 3.09-2.92 (m, 2 H), 2.85-2.66 (m, 1 H), 2.07-1.80 (m, 4 H), 1.70-1.56 (m, 1 H), 1.43-1.28 (m, 1 H), 1.08 (t, J = 7.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 163.4, 143.5, 136.6, 132.8, 128.9, 123.2, 122.0, 120.5, 115.8, 33.9, 25.6, 25.5, 24.1, 17.1, 12.6; IR (neat) 1644, 1610, 1561, 1433, 1397 cm-1; HRMS (ESI): calcd for C15H18NO+: 228.1383, found: 228.1382. (9) 7-Propyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (10b)


42

The reaction of 10a (48 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 10b as a solid (25 mg, 52%); mp 180.0-180.9 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 11.15 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 1 H), 3.14-3.06 (m, 1 H), 3.03-2.94 (m, 1 H), 2.81 -2.68 (m, 1 H), 2.00-1.77 (m, 4 H), 1.67-1.41 (m, 3 H), 1.40-1.27 (m, 1 H), 1.00 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 163.1, 143.4, 136.5, 133.0, 128.9, 123.2, 122.0, 120.6, 115.6, 35.0, 32.1, 25.5, 24.7, 21.2, 17.1, 14.3; IR (neat) 1645, 1609, 1563, 1505, 1456, 1433 cm-1; HRMS (ESI): calcd for C16H20NO+: 242.1539, found: 242.1539. (10) 7,7-Dimethyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (11b)

The reaction of 11a (45 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 11b as a solid (11 mg, 24%); mp 179.2-180.0 oC (n-hexane/ethyl acetate); 1H NMR(400 MHz, CDCl3) δ 10.63 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.42 (t, J = 8.2 Hz, 1 H), 7.23-7.13 (m, 2 H), 2.89 (t, J = 6.2 Hz, 2 H), 1.93-1.80 (m, 2 H), 1.72-1.62 (m, 2 H), 1.52 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 162.7, 144.5, 136.7, 135.5, 129.1, 123.8, 121.9, 120.6, 115.0, 40.9, 34.1, 27.5, 27.4, 18.5; IR (neat) 1639, 1604, 1553, 1503, 1432 cm-1; HRMS (ESI): calcd for C15H18NO+: 228.1383, found: 228.1382. (11) 7-Methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (1b)


43

The reaction of 12a (43 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 1b as a solid (28 mg, 65%); 1H NMR(400 MHz, CDCl3) δ 11.58 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.20 (t, J = 8.2 Hz, 1 H), 3.37-3.20 (m, 1 H), 3.09-2.95 (m, 1 H), 2.83-2.67 (m, 1 H), 2.02-1.86 (m, 2 H), 1.84-1.74 (m, 2 H), 1.33 (d, J = 6.8 Hz, 3 H). (12) 7-Ethyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (9b)

The reaction of 13a (45 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 9b as a solid (22 mg, 49%); 1H NMR(400 MHz, CDCl3) δ 11.64 (s, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.44 (t, J = 8.2 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.19 (t, J = 8.2 Hz, 1 H), 3.05-2.91 (m, 2 H), 2.84-2.68 (m, 1 H), 2.08-1.81 (m, 4 H), 1.70-1.54 (m, 1 H), 1.43-1.28 (m, 1 H), 1.08 (t, J = 7.2 Hz, 3 H). (13) 7-Propyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (10b)

The reaction of 14a (48 mg, 0.2 mmol), AlCl3 (53 mg, 0.4 mmol), and CH2Cl2 (10 mL) affords 10b as a solid (16 mg, 33%); 1H NMR(400 MHz, CDCl3) δ 11.07 (s, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.43 (t, J = 8.2 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 7.19 (t, J = 8.2 Hz, 1 H), 3.14-2.93 (m, 2 H), 2.83-2.68 (m, 1 H), 2.01-1.70 (m, 4 H), 1.65-1.41 (m, 3 H), 1.39-1.25 (m, 1 H), 1.00


44

(t, J = 7.4 Hz, 3 H).

2.6 Reproduction acknowledgement Reproduced from Ref. Organic & Biomolecular Chemistry, 2019, 17, 49-52. With permission from the Royal Society of Chemistry.

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Chem., 1968, 80, 27-37; (c) A. Svendsen, P. Boll, Tetrahedron, 1973, 29, 4251-4258; (d) J.-P. Alazard, C. Millet-Paillusson, D. Guénard, C. Thal, Bull. Soc. Chim. Fr., 1996, 3, 251-266; (e) D. Bertin, D. Gigmes, S. R. Marque, P. Tordo, Tetrahedron, 2005, 61, 8752-8761; (f) T. Xiong, Q. Zhang, Z. Zhang, Q. Liu, J. Org. Chem., 2007, 72, 8005-8009.

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[17] (a) X. Dong, L. Liang, E. Li, Y. Huang, Angew. Chem. Int. Ed. Engl., 2015, 54, 1621-1624; (b) M. Frias, R. Mas-Balleste, S. Arias, C. Alvarado, J. Aleman, J. Am. Chem. Soc., 2017, 139, 672-679; (c) S. Jeon, S. Han, J. Am. Chem. Soc., 2017, 139, 6302-6305; (d) S. Li, Y. Liu, B. Huang, T. Zhou, H. Tao, Y. Xiao, L. Liu, J. Zhang, ACS Catal., 2017, 7, 2805-2809; (e) H. Wang, K. Wang, Y. Man, X. Gao, L. Yang, Y. Ren, N. Li, B. Tang, G. Zhao, Adv. Synth. Catal., 2017, 359, 3934-3939; (f) S. Maity, S. Sar, P. Ghorai, Org. Lett., 2018, 20, 1707-1711.

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[28] R. Alonso, T. Bach, Angew. Chem. Int. Ed. Engl., 2014, 53, 4368-4371. [29] N. Vallavoju, S. Selvakumar, S. Jockusch, M. P. Sibi, J. Sivaguru, Angew. Chem. Int. Ed.

Engl., 2014, 53, 5604-5608.

α-Alkenylation of quinolinones and coumarins

48


Visible-light promoted transition metal-free cross-coupling: Highly selective intramolecular α-alkenylation for seven-membered ring synthesis

This Chapter is based on: Dawen Xu,a Han Li,a Pan Huang,a Oberkofler Jens,a Robert M. Reich,a Hao Guo,b,* Fritz E. Kühna,* “Visible-light promoted transition metal-free cross-coupling: Highly selective intramolecular α-alkenylation of quinolinones and coumarins for seven-membered ring synthesis” manuscript in preparation

3.1 Introduction The last decade has witnessed the rapid development of photochemistry. Thanks to the pioneering work of excellent organic chemists,[1] a broad range of photoinitiated transformations have been brought to light involving C-C,[2] C-N,[3] C-O,[4] C-F[5] and other formations.[6] Among those formations, the coupling of carbon and carbon is most frequently studied. According to the characteristics of the reacting carbon, the visible-light-promoted C-C coupling can be classified as C(sp3)-C(sp3),[7] C(sp3)-C(sp2),[8] C(sp3)-C(sp),[9] C(sp2)-C(sp2)[10] and C(sp2)-C(sp)[11] coupling. Of those couplings, the C(sp2)-C(sp2) coupling allows straightforward building of complex conjugated molecules from simple and affordable raw starting material, which has great potential in synthetic chemistry. However, photoinitiated C(sp2)-C(sp2) couplings are only feasible between electron-withdrawing group activated olefins and arenes with the assistance from transition metal catalysis, or with UV irradiated cyclization between 1,4-naphthoquinone and olefins.[12] The visible light promoted C(sp2)-C(sp2) coupling


49

between two olefins remains a great challenge. Considering the necessity of the methodology and the practicality of the coupling product of two olefins, to realize this transformation is then of great significance. Quinolinones and coumarins are widely used in medical and biochemical area.[13] One important reaction is the [2+2]-photocycloaddition of these compounds with β-tethered olefins.[14],[15] However, for the coupling of quinolinones and coumarins with β-tethered olefins, similar reaction protocols have not been developed. As reported by K. Maruyama,[16] 1,4-naphthoquinones 1 reacted with 1,1-diarylethylene 2a under UV irradiation to give ethylene adduct 3 as an intermediate. The reaction mechanism was proven to involve an encounter complex and ion radical pair/exciplex formation. Since the high electron-accepting carbonyl will abstract an electron from electron-donating olefin, it is reasonable to deduce a structural similar compound quinolinone with β-tethered terminal brominated olefin will undergo similar process to yield intermolecular cyclized product.

Scheme 1: Proposed C(sp2)-C(sp2) coupling mechanism for quinolinones with β-tethered olefins As part of our ongoing studies investigating the coupling of two olefins, in this manuscript, a visible-light promoted transition metal free intramolecular Heck-type


50

cross coupling of β-tethered alkene and quinolinones (or coumarins) is presented based on above-mentioned concept. This photoreaction yielded seven-, and eight-membered ring products with high regioselectivity and good functional groups tolerance. The designated reaction protocol directly built a double bond at the α-position of quinolinones and coumarins, which was not possible with previous photoreactions.

3.2 Optimization of reaction conditions β-Brominated alkene tethered quinolinone 1a was chosen as the model substrate for initial investigation, thioxanthone was applied as photosensitizer and violet LED strip (5W) was employed as source of visible light. The photoreaction was carried out at room temperature under argon atmosphere (Table 1). Initially, 5 mol % of thioxanthone was applied in acetonitrile as solvent. Seven-membered ring 2a was detected with a yield of 52% (Table 1, entry 1). The control experiment without light or thioxanthone resulted in no reaction, 99% of starting material was recycled (Table 1, entries 2-3). These results indicate that visible light and sensitizer are necessary for this transformation. Showing that seven-membered ring 2a is indeed generated as expected, it thus confirmed the general design concept. Later on, base as additive was added to the reaction mixture to neutralize the byproduct HBr, as it was known that protonic acid accelerates [2+2]-photocycloaddition.[17] The use of different bases like Na2CO3, K2CO3, and NaOH only leads to no improvements in yield (Table 1, entries 4-6). However, addition of MeONa significantly improved the reaction yield to an acceptable isolated yield of 80% (Table 1, entry 7). Further screening of additives lead to no better results (Table 1, entry 8). The change of the solvent in the reaction to dichloromethane, THF, acetone and MeOH did not lead to an improvement of the reaction either, compared to acetonitrile (Table 1, entries 9-12). Table 1. Optimization of reaction conditions


51

Entry Thioxanthone

(100%) Additive

(1.2 equiv.) Solvent Yield of 2ab

(100%) 1 5 none CH3CN 35 2c 5 none CH3CN 0 (99)d 3 0 none CH3CN 0 (99)d 4 5 Na2CO3 CH3CN 44 5 5 K2CO3 CH3CN 43 6 5 NaOH CH3CN 57 7 5 MeONa CH3CN 84 (80)e 8 5 nBu4NOH (1M in

methanol) CH3CN 0f

9 5 MeONa CH2Cl2 62 10 5 MeONa THF 70 11 5 MeONa Aceton --- 12 5 MeONa MeOH 0f

a A solution of 1a (0.1 mmol), additive (1.2 equiv.) in tested solvent (10 mL) was irradiated by violet LED strips (5 W) at room temperature under an atmosphere of argon. b Yields were determined by 1H NMR spectroscopy using CH2Br2 as internal standard. c Reaction was carried out under exclusion of light. d Recovered yield of 1a. e Isolated yield of 2a. f Unknown products were detected.

3.3 Substrate scope investigations With the optimized reaction conditions in hand, several substrates with differing functional groups were evaluated. (Table 2, 2b,2c,2d). Electron donating or electron withdrawing groups have no influence on the reaction activity in terms of the time,


52

yield and selectivity. The investigated (phenyl and fluorophenyl) substrates are all well tolerated. Inner alkene methylated 1e afforded product 2e in an excellent yield and selectivity. The functional group tolerance of the phenyl ring of quinolinones was studied. Tert-butyldimethylsilyl, methoxy, hydroxyl are tolerated with good to excellent yields and selectivity (Table 2, 2f-2h). The exact structure of 2h was determined by X-ray single crystal diffraction analysis.[18] Subsequently, coumarin skeleton substrates with oxygen near β-position were applied and show a relatively slow reaction speed (Table 2, 2i-2k). The structure of coumarin skeleton product is determined by analyzing 2D NMR of 2j (see supporting information, spectrum 2j). However, electron-donating and electron-withdrawing groups do not influence the reaction yield. Notably, halogenated arenes have no impact on reaction products even though the sp2-hybrid nature of carbon-halogen bond. The β-chlorinated and iodinated alkene tether quinolinones were also evaluated. The result indicates that the chlorinated alkene has a lower reaction efficiency, while the iodinated alkene shows similar reactivity with the brominated alkene (Table 2, 2l,2m). Considering the necessity of building even bigger rings, this reaction protocol was subsequently applied to create eight-membered ring (Table 2, 2n), the exact structure of 2n is determined by Xray single crystal diffraction analysis.[19] Table 2 Substrate scope investigationsa


53

a A solution of 1a (0.1 mmol), MeONa (1.2 equiv.), and thioxanthone (5 mol %) in CH3CN (10 mL) was irradiated by violet LED strips (5 W) at room temperature under argon atmosphere. b An extended reaction time of 24 h was applied.

3.4 Proposed reaction mechanism Two reaction pathways have been proposed for this transformation, Upon irradiation by violet LED, the triplet sensitizer thioxanthone transfers its triplet energy to 1a to render the generation of excited triplet state of 1a. The triplet excited of 1a forms a chair conformation to shorten the distance between the 1,4-unsaturaed carbonyl moiety and the brominated olefin moiety to favor the formation of an encounter complex. Pathway A proceeds via [2+2]-photocycloaddition mechanism. Elimination of possible intermediate 3 affords seven-membered ring product 2a. Path B proceeds via photo-


54

induced-electron-transfer mechanism similar to the work of K. Maruyama.[16] The excited 1,4-unsaturaed carbonyl moiety abstracts an electron from π electron of brominated olefin to form ion radical pair/exciplex. Intramolecular coupling of this ion radical pair generates 3, which undergoes elimination to afford the desired product 2a (Scheme 2).

Scheme 2: Proposed mechanism for this α-alkenylation reaction

To prove the reaction mechanism, intermediate 3 has been isolated. Elimination of 3 with sodium methoxyoxide in acetonitrile affords 2a in 95%, the yield of which is determined by NMR internal standard technique. This result proves the possibility of path A and path B, which proceeds via elimination of intermediate 3. In addition, substrate 1o, which does not favor elimination after [2+2]-photocycloaddition has been prepared. The only product of 1o under standard reaction condition is [2+2]-photo cycloaddition product 3o, which is as expected since elimination of 3o is rather difficult (Scheme 3).


55

N O

O Br

CH3CN1.2 eq. MeONa

N O

O

95%3 2a

N O

Br

S

O

5%

CH3CN, RT, 4 h

violet LED

1.2 eq. MeONaN O

Br

93%1o 3o Scheme 3: Proofs for the proposed reaction mechanism

In summary, an intramolecular visible-light-promoted thioxanthone sensitized diene coupling has been developed. Compared to the existing photoirradiated coupling reaction, the visible light-irradiated coupling between two olefins is realized for the first time. It also provides an applicable solution for transition metal catalyzed olefin-cross coupling that requires electron-withdrawing groups to activate. The transformation generates exclusively seven, or even eight-membered rings with good to excellent yields. Electron-donating and electron-withdrawing groups are all well-tolerated. It is expected that the current strategy will find potential applications for future olefin-olefin coupling and ring synthesis, also allowing the access to quinolinones and coumarins derivatives.

3.5 Experimental Section 3.5.1 General experimental methods 1H (400 MHz) and 13C (100 MHz) NMR spectra were acquired on a Bruker Avance Ultrashield 400 MHz and a Bruker DPX 400 MHz spectrometer. Anhydrous CH2Cl2, THF, CH3CN were obtained from a M. Braun SPS purification system. Anhydrous MeOH was prepared using CaH2 as drying agent. Anhydrous acetone was prepared using CaCl2 as drying agent.


56

3.5.2 Synthesis of 4-(((3-bromoallyl)oxy)methyl)quinolin-2(1H)-one

To a Schlenk flask is added 3-bromoprop-2-en-1-ol (164 mg, 1.2 mmol), and anhydrous THF (10 mL). The mixture is stirred under 0 oC for 10 min and then NaH (48 mg, 2 mmol) is added dropwise. The mixture is stirred under 0 oC for 2 h and 4-(bromomethyl)quinolin-2(1H)-one (238 mg, 1 mmol) is add subsequently. The mixture is stirred at room temperature overnight, and then cooled to 0 oC, treated with 10 mL 1 N HCl. The solvent is evaporated and the residue is filtered, washed with water (10 mL ×3), dried under vacuum to afford 4-(((3-bromoallyl)oxy)methyl)quinolin-2(1H)-one without further purification (234 mg, 80%). 1H NMR(400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 13.6 Hz, 1H), 6.54-6.36 (m, 2H), 4.75 (s, 2H), 4.09 (dd, J = 6.1, 1.3 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.0, 139.3, 134.8, 130.8, 124.6, 122.2, 119.5, 117.8, 116.0, 109.7, 70.1, 68.4. HRMS (ESI): calcd for C13H13BrNO2+: 294.0124, found: 294.0214.

3.5.3 General Procedure I for the synthesis of substrates Synthesis of 4-(((3-bromoallyl)oxy)methyl)quinolin-2(1H)-one (1a)

To a Schlenk flask is added 3-bromoprop-2-en-1-ol (329 mg, 2.4 mmol), and anhydrous THF (20 mL). The mixture is stirred under 0 oC for 10 min and then NaH (96 mg, 2 mmol) is added dropwisely. The mixture is stirred under 0 oC for 2 h and 4-


57

(bromomethyl)-1-methylquinolin-2(1H)-one (504 mg, 2 mmol) is add subsequently. The mixture is stirred at room temperature overnight, and then cooled to 0 oC, treated with 10 mL 1 N HCl. The solvent is evaporated and the residue is extracted with ethyl acetate (3 × 30 mL). The combined organic layers are washed with brine (15 mL), dried over MgSO4, filtered, and evaporated. The crude product is purified by column chromatography (n-hexane/ethyl acetate = 3:1) to give the product 1a as a solid (553 mg, 90%). 1H NMR(400 MHz, Chloroform-d) δ 7.71 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.33-7.21 (m, 1H), 6.80 (s, 1H), 6.56-6.21 (m, 2H), 4.73 (s, 2H), 4.07 (d, J = 5.7 Hz, 2H), 3.73 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 161.9, 144.9, 140.0, 133.4, 130.6, 124.5, 122.1, 119.9, 119.1, 114.6, 109.1, 70.2, 68.7, 29.3. HRMS (ESI): calcd for C14H15BrNO2+: 308.0281, found: 308.0281. The following compounds are synthesized according to general procedure I. (1) 4-(((3-Chloroallyl)oxy)methyl)-1-methylquinolin-2(1H)-one (1l)

The reaction of 4-(bromomethyl)-1-methylquinolin-2(1H)-one (252 mg, 1 mmol), 3-chloroprop-2-en-1-ol (112 mg, 1.2 mmol), NaH (48 mg, 2 mmol), and THF (10 mL) affords 1l as a solid (229 mg, 87%). 1H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 8.8 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.29 – 7.22 (m, 2H), 6.80 (s, 1H), 6.30 (d, J = 13.4 Hz, 1H), 6.06 (dt, J = 12.5, 6.1 Hz, 1H), 4.72 (s, 2H), 4.10 (dd, J = 6.1, 1.5 Hz, 2H), 3.72 (s, 3H).13C NMR (101 MHz, Chloroform-d) δ 161.9, 144.9, 140.0, 130.6, 129.2, 124.6, 122.7, 122.1, 121.8, 120.0, 119.1, 114.6, 100.0, 68.7, 29.4, 14.2. HRMS (ESI): calcd for C14H14BrNO2+: 264.0786, found: 264.0786. (2) 4-((2-(Iodomethylene)butoxy)methyl)-1-methylquinolin-2(1H)-one (1m)


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The reaction of 4-(bromomethyl)-1-methylquinolin-2(1H)-one (180 mg, 0.7 mmol), 2-(iodomethylene)butan-1-ol (148 mg, 0.7 mmol), NaH (34 mg, 1.4 mmol), and THF (10 mL) affords 1m as a solid (228 mg, 85%). 1H NMR(400 MHz, Chloroform-d) δ 7.70 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.30-7.20 (m, 1H), 6.85 (s, 1H), 6.15 (s, 1H), 4.71 (s, 2H), 4.28 (s, 2H), 3.72 (s, 3H), 2.39-2.25 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.0, 149.0, 145.3, 140.0, 130.5, 124.6, 122.0, 119.8, 119.1, 114.5, 77.1, 74.4, 68.6, 29.3, 28.8, 12.3. HRMS (ESI): calcd for C16H19INO2+: 384.0455, found: 384.0455. (3) 4-(((4-Bromopent-3-en-1-yl)oxy)methyl)-1-methylquinolin-2(1H)-one (1n)

The reaction of 4-(bromomethyl)-1-methylquinolin-2(1H)-one (252 mg, 1 mmol), 4-bromo-3-methylbut-3-en-1-ol (198 mg, 1.2 mmol), NaH (48 mg, 2 mmol), and THF (10 mL) affords 1n as a solid (238 mg, 71%). 1H NMR(400 MHz, Chloroform-d) δ 7.72 (dd, J = 8.0, 1.2 Hz, 1H), 7.62-7.53 (m, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.31-7.21 (m, 1H), 6.78 (s, 1H), 5.98 (s, 1H), 4.71 (s, 2H), 3.72 (s, 3H), 3.64 (t, J = 6.5 Hz, 2H), 2.44 (t, J = 6.3 Hz, 2H), 1.79 (d, J = 1.1 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.0, 145.3, 140.0, 138.5, 130.6, 124.8, 122.1, 120.0, 119.2, 114.5, 103.1, 69.8, 68.7, 38.2, 29.3, 19.3. HRMS (ESI): calcd for C16H19BrNO2+: 336.0594, found: 336.0595.

3.5.4 General Procedure II for the synthesis of substrates Synthesis of 1-benzyl-4-(((3-bromoallyl)oxy)methyl)quinolin-2(1H)-one (1b)


59

To a Schlenk Flask is added 4-(((3-bromoallyl)oxy)methyl)quinolin-2(1H)-one (294 mg, 1 mmol), benzyl bromide (342 mg, 2 mmol), K2CO3 (414 mg, 3 mmol), and DMF (15 mL). The mixture is stirred under 70 oC for 4 h as monitored by TLC (eluent: n-hexane/ethyl acetate = 3:1). The solvent is evaporated and the residue is purified by column chromatography (eluent: n-hexane/ethyl acetate = 3:1) to afford 1b as a solid (352 mg, 92%). 1H NMR(400 MHz, Chloroform-d) δ 7.69 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.33-7.27 (m, 3H), 7.25-7.17 (m, 4H), 6.90 (s, 1H), 6.55-6.29 (m, 2H), 5.56 (s, 2H), 4.76 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 162.1, 145.5, 139.4, 136.3, 133.4, 130.6, 128.8, 127.2, 126.5, 124.5, 122.2, 119.8, 119.3, 115.5, 109.2, 70.3, 68.8, 45.8. HRMS (ESI): calcd for C20H19BrNO2+: 384.0594, found: 384.0595. The following compounds are synthesized according to general procedure II. (1) 4-(((3-Bromoallyl)oxy)methyl)-1-((perfluorophenyl)methyl)quinolin-2(1H)-one (1c)

The reaction of 4-(((3-bromoallyl)oxy)methyl)quinolin-2(1H)-one (294 mg, 1 mmol), 2,3,4,5,6-Pentafluorobenzyl bromide (521 mg, 2 mmol), K2CO3 (414 mg, 3 mmol), and DMF (15 mL) affords 1c as a solid (449 mg, 95%).1H NMR(400 MHz, Chloroform-d) δ 7.70 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.26-7.21 (m, 3H), 6.84 (s, 1H), 6.48-6.22 (m, 2H), 5.69 (s, 2H), 4.74 (s, 2H), 4.09 (d, J = 6.8 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 161.7, 146.0, 138.7, 133.3, 130.9, 125.0, 122.6, 119.4 (d, J =


60

13.1 Hz), 113.9, 109.3, 70.4, 68.6, 35.0. HRMS (ESI): calcd for C20H14BrF5NO2+: 474.0123, found: 474.0125.

3.5.5 General procedure III for the synthesis of substrates Synthesis of 4-(5-bromopent-4-en-1-yl)-1-methylquinolin-2(1H)-one (1d)

To a flame dried flask is added 1,4-dimethylquinolin-2(1H)-one (1.731g, 10 mmol), THF (50 mL). The mixture is cooled to -78 oC under argon atmosphere and treated dropwise with n-butyl lithium (2.5 M in n-hexane, 8.0 mL, 20 mmol). The solution is stirred at room temperature for 3 h, cooled to -78 °C and treated with 1,4-dibromobut-1-ene (4.24 g, 20 mmol). The solution is stirred at room temperature overnight and then cooled to 0 °C, treated with 20 mL 1 N HCl. The solvent is evaporated and the residue is extracted with ethyl acetate (3 × 40 mL). The combined organic layers are washed with brine (50 mL), dried over MgSO4, filtered, and evaporated. The crude product is purified by column chromatography (n-hexane/ethyl acetate = 1:1) to give the product 1d as a solid (1.07 g, 35%). 1H NMR(400 MHz, Chloroform-d) δ 7.71 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31-7.23 (m, 1H), 6.59 (s, 1H), 6.28-6.04 (m, 2H), 3.72 (s, 3H), 2.83 (t, J = 7.7 Hz, 2H), 2.19 (q, J = 7.2 Hz, 2H), 1.91-1.77 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 162.1, 149.9, 140.0, 136.9, 130.6, 124.8, 122.2, 120.6, 119.9, 114.8, 105.4, 32.5, 31.2, 29.5, 27.6. HRMS (ESI): calcd for C15H17BrNO+: 306.0488, found: 306.0490. The following compounds are synthesized according to general procedure III (1) 4-(5-Bromo-4-methylpent-4-en-1-yl)-1-methylquinolin-2(1H)-one (1e)


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The reaction of 1,4-dimethylquinolin-2(1H)-one (346 mg, 2 mmol), 1,4-dibromo-2-methylbut-1-ene (915 mg, 4 mmol), nBuLi (1.6 mL, 4 mmol), and THF (10 mmol) affords 1e as a solid (256 mg, 40%). 1H NMR(400 MHz, Chloroform-d) δ 7.80-7.67 (m, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.30-7.23 (m, 1H), 6.61 (d, J = 11.3 Hz, 1H), 5.95 (s, 1H), 3.72 (s, 3H), 2.91-2.74 (m, 2H), 2.46-2.35 (m, 1H), 2.25 (t, J = 7.5 Hz, 1H), 1.91-1.84 (m, 2H), 1.81 (s, 3H). HRMS (ESI): calcd for C16H19BrNO+: 320.0645, found: 320.0646. (2) 4-(5-Bromopent-4-en-1-yl)-6-methoxy-1-methylquinolin-2(1H)-one (1g)

The reaction of 6-methoxy-1,4-dimethylquinolin-2(1H)-one (406 mg, 2 mmol), 1,4-dibromobut-1-ene (857 mg, 4 mmol), nBuLi (1.6 mL, 4 mmol), and THF (20 mL) affords 1g as a solid (281 mg, 42%). 1H NMR(400 MHz, Chloroform-d) δ 7.32 (d, J = 9.2 Hz, 1H), 7.18 (dd, J = 9.2, 2.8 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 6.58 (s, 1H), 6.27-6.03 (m, 2H), 3.88 (s, 3H), 3.69 (s, 3H), 2.78 (t, 2H), 2.18 (q, J = 7.2 Hz, 2H), 1.88-1.76 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 161.6, 154.6, 148.6, 136.9, 134.6, 121.2, 120.9, 118.0, 115.8, 107.8, 105.4, 55.7, 32.4, 31.1, 29.4, 27.3. HRMS (ESI): calcd for C16H19BrNO2+: 336.0594, found: 336.0595.


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3.5.6 Synthesis of 4-(5-bromopent-4-en-1-yl)-6-((tert-butyldimethylsilyl)oxy)-1-methylquinolin-2(1H)-one (1f)

To a flame dried flask is added 1,4-dimethylquinolin-2(1H)-one (920 mg, 3.18 mmol), THF (20 mL). The mixture is cooled to -78 oC under argon atmosphere and treated dropwise with n-butyl lithium (2.5 M in n-hexane, 2.5 mL, 6.25 mmol). The solution is stirred at room temperature for 3 h, cooled to -78 °C and treated with 1,4-dibromobut-1-ene (1.36 g, 6.35 mmol). The solution is stirred at room temperature overnight and then cooled to 0 °C, treated with 20 mL 1 N HCl. The solvent is evaporated and the residue is extracted with ethyl acetate (3 × 40 mL). The combined organic layers are washed with brine (50 mL), dried over MgSO4, filtered, and evaporated. The crude product is purified by column chromatography (n-hexane/ethyl acetate = 1:1) to give the product 4-(5-bromopent-4-en-1-yl)-6-((tert-butyldimethylsilyl)oxy)quinolin-2(1H)-one as a solid ( 402 mg, 35%). 1H NMR(400 MHz, Chloroform-d) δ 12.58 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.13-6.99 (m, 2H), 6.56 (s, 1H), 6.33-6.05 (m, 2H), 2.87-2.72 (m, 2H), 2.20 (q, J = 7.2 Hz, 2H), 1.95-1.77 (m, 2H), 1.01 (s, 9H), 0.22 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 163.7, 151.6, 150.9, 136.9, 133.5, 124.2, 120.4, 119.9, 117.8, 113.4, 105.4, 32.5, 31.4, 27.5, 25.7, 18.3, -4.4. HRMS (ESI): calcd for C20H29BrNO2Si+: 422.1145, found: 422.1145.

To a sealed tube is added 4-(5-bromopent-4-en-1-yl)-6-((tert-butyldimethylsilyl)oxy)quinolin-2(1H)-one (421 mg, 1 mmol), CH3I (426 mg, 3 mmol), K2CO3 (827 mg, 6 mmol), and anhydrous DMF (10 mL). The mixture is stirred at 70


63

oC for 4 h as monitored by TLC (eluent: n-hexane/ethyl acetate = 3:1). The reaction is quenched with 1 N HCl (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers are washed with brine (30 mL x 3), dried over Na2SO4, filtered, and evaporated. The residue is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 5:1) to afford product 1f as an oil (414 mg, 95%); 1H NMR(400 MHz, Chloroform-d) δ 7.23 (d, J = 9.5 Hz, 1H), 7.13-7.02 (m, 2H), 6.53 (s, 1H), 6.25-6.01 (m, 2H), 3.65 (s, 3H), 2.72 (t, 2H), 2.15 (q, J = 7.2 Hz, 2H), 1.89-1.67 (m, 2H), 0.98 (s, 9H), 0.20 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 161.5, 150.3, 148.5, 136.8, 134.9, 123.3, 121.2, 120.6, 115.6, 114.4, 105.2, 32.4, 31.1, 29.2, 27.4, 25.6, 18.2, -4.4. HRMS (ESI): calcd for C21H31BrNO2Si+: 436.1302, found: 436.1303.

3.5.7 Synthesis of 4-(5-bromopent-4-en-1-yl)-6-hydroxy-1-methylquinolin-2(1H)-one (1h)

To a flask is added 1f (436 mg, 1 mmol), tetra-n-butylammonium fluoride (TBAF) (522 mg, 2 mmol), and anhydrous THF (10 mL). The mixture is stirred at room temperature for 1 h as monitored by TLC (eluent: n-hexane/ethyl acetate = 1:1). The crude product is washed with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers are washed with brine (30 mL x 3), dried over Na2SO4, filtered, and evaporated. The residue is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1:1) to afford product 1h as a solid (321 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.15-7.05 (m, 4H), 6.45 (s, 1H), 6.40-6.21 (m, 2H), 2.77-2.69 (m, 2H), 2.15 (q, J = 7.1 Hz, 2H), 1.72 (p, J = 7.5 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 171.1, 160.7, 152.6, 149.2, 138.1, 121.1, 120.3, 119.7, 116.7, 109.7, 105.9, 32.4, 31.1, 29.3, 27.5. HRMS (ESI): calcd for C15H17BrNO2+: 322.0437, found: 322.0437.


64

3.5.8 General procedure IV for the synthesis of substrates Synthesis of 4-((4-bromobut-3-en-1-yl)oxy)-6-methyl-2H-chromen-2-one (1i)

To a flask is added 4-hydroxy-6-methyl-2H-chromen-2-one (880 mg, 5 mmol), 1,4-dibromobut-1-ene (1.065 g, 5 mmol), K2CO3 (1.656 g, 12 mmol), and anhydrous aceton (15 mL). The mixture is refluxed for 24 h as monitored by TLC (n-hexane/ethyl acetate = 3:1). The solvent is evaporated and the residue is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 5:1) to afford product 1i as solid (1.078 g, 70%). 1H NMR(400 MHz, Chloroform-d) δ 7.59-7.50 (m, 1H), 7.34 (dd, J = 8.4, 1.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.40-6.22 (m, 2H), 5.62 (s, 1H), 4.14 (t, J = 6.3 Hz, 2H), 2.70-2.63 (m, 2H), 2.41 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 165.2, 162.9, 151.4, 133.6, 133.4, 132.6, 122.5, 116.5, 115.1, 107.8, 90.5, 67.3, 32.1, 20.9. HRMS (ESI): calcd for C14H14BrO3+: 309.0121, found: 309.0121. The following compounds are synthesized according to general procedure IV (1) 6-Bromo-4-((4-bromobut-3-en-1-yl)oxy)-2H-chromen-2-one (1j)

The reaction of 4-bromo-6-methyl-2H-chromen-2-one (964 mg, 4 mmol), 1,4-dibromobut-1-ene (1.026 g, 4.8 mmol), K2CO3 (1.656 g, 12 mmol), and anhydrous aceton (15 mL) affords 1j as a solid (967 mg, 68%).1H NMR(400 MHz, Chloroform-d) δ 7.89 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 8.8, 2.3 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.46-6.22 (m, 2H), 5.67 (s, 1H), 4.16 (t, J = 6.3 Hz, 2H), 2.68 (q, J = 6.2 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 164.0, 161.9, 152.1, 135.3, 132.2, 125.6, 118.6, 117.1,


65

116.8, 108.2, 91.4, 67.7, 32.1. HRMS (ESI): calcd for C13H11Br2O3+: 372.9070, found: 372.9069. (2) 4-((4-Bromobut-3-en-1-yl)oxy)-6-fluoro-2H-chromen-2-one (1k)

The reaction of 6-fluoro-4-hydroxy-2H-chromen-2-one (180 mg, 1 mmol), 1,4-dibromobut-1-ene (257 mg, 1.2 mmol), K2CO3 (414 mg, 3 mmol), and anhydrous aceton (10 mL) affords 1k as a solid (235 mg, 68%). 1H NMR (400 MHz, Chloroform-d) δ 7.44 (dd, J = 8.3, 2.7 Hz, 1H), 7.33-7.26 (m, 2H), 6.45-6.22 (m, 2H), 5.69 (s, 1H), 4.17 (t, J = 6.3 Hz, 2H), 2.67 (q, J = 6.1 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 164.40, 164.37, 162.3, 159.9, 157.4, 149.45, 149.43, 132.3, 120.1, 119.9, 118.5, 118.4, 116.5, 116.4, 108.9, 108.6, 108.1, 91.4, 67.6, 32.1. HRMS (ESI): calcd for C13H11BrFO3+: 312.9870, found: 312.9870.

3.5.9 Synthesis of 4-(4-bromo-5-methylhex-4-en-1-yl)-1-methylquinolin-2(1H)-one (1o)

To a sealed tube is added 4-(5-methylhex-4-en-1-yl)quinolin-2(1H)-one (241 mg, 1 mmol), CH3I (426 mg, 3 mmol), K2CO3 (827 mg, 6 mmol), and anhydrous DMF (10 mL). The mixture is stirred at 70 oC for 4 h as monitored by TLC (eluent: n-hexane/ethyl acetate = 3:1). The reaction is quenched with 1 N HCl (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers are washed with brine (10 mL x 3), dried over Na2SO4, filtered, and evaporated. The residue is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 5:1) to afford product 1-


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methyl-4-(5-methylhex-4-en-1-yl)quinolin-2(1H)-one as an oil (209 mg, 82%); 1H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26-7.20 (m, 1H), 6.59 (s, 1H), 5.15 (t, J = 7.1 Hz, 1H), 3.71 (s, 3H), 2.80 (s, 2H), 2.12 (q, J = 7.2 Hz, 2H), 1.90-1.66 (m, 5H), 1.62 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.3, 150.3, 140.0, 132.6, 130.3, 124.9, 123.6, 121.8, 120.7, 120.0, 114.6, 31.5, 29.2, 28.9, 27.7, 25.7, 17.8. HRMS (ESI): calcd for C17H22NO+: 256.1696, found: 256.1696.

To a flask is added 1-methyl-4-(5-methylhex-4-en-1-yl)quinolin-2(1H)-one (255 mg, 1 mmol), CuBr2 (447 mg, 2 mmol) and CH2Cl2 (10 mmol). The reaction is stirred under room temperature for 48h. The mixture is filtered, tBuONa (384 mg, 4 mmol) is added to the filtered solvent. The reaction is stirred under room temperature for 24h. The reaction is quenched with 1 N HCl (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers are washed with brine (10 mL x 3), dried over Na2SO4, filtered, and evaporated. The residue is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 5:1) to afford product 1o as a solid (250 mg, 75%).1H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 9.0 Hz, 1H), 7.57 (t, J = 8.5 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.29-7.26 (m, 1H), 6.62 (s, 1H), 3.72 (s, 3H), 2.89-2.75 (m, 2H), 2.64 (t, J = 7.1 Hz, 2H), 1.98 (dt, J = 14.9, 7.4 Hz, 2H), 1.90 (s, 3H), 1.77 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.2, 149.9, 140.1, 131.3, 130.4, 124.9, 121.9, 120.7, 120.6, 120.1, 114.6, 36.9, 30.8, 29.3, 27.5, 25.4, 20.6. HRMS (ESI): calcd for C17H2BrNO+: 334.0810, found: 334.0810.

3.5.10 General procedure V for the photoreaction (1) Synthesis of 7-methyl-3,7-dihydrooxepino[4,3-c]quinolin-6(1H)-one (2a)


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To a flame dried Schlenk tube is added 1a (31 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL). The reaction is irradiated by a violet LED strips (5 w) under argon atmosphere at room temperature. The reaction is completed after 4 h as monitored by TLC (eluent:n-hexane/ethylacetate = 3:1). The solvent is removed and the residue was purified by flash chromatography on silica gel (eluent: n-hexane/ethylacetate = 5:1) to afford 2a as a solid (19 mg, 84%). 1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.28-7.22 (m, 1H), 7.13 (dt, J = 12.6, 2.2 Hz, 1H), 6.20 (dt, J = 12.5, 3.2 Hz, 1H), 4.93 (s, 2H), 4.59 (t, J = 2.7 Hz, 2H), 3.76 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 161.9, 144.9, 140.0, 133.4, 130.6, 124.5, 122.1, 119.9, 119.1, 114.6, 109.1, 70.2, 68.7, 29.3. HRMS (ESI): calcd for C14H14NO2+: 228.1091, found: 228.1091. (2) 7-Benzyl-3,7-dihydrooxepino[4,3-c]quinolin-6(1H)-one (2b)

The reaction of 1b (38 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2b as a solid (28 mg, 92%). 1H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.32-7.27 (m, 3H), 7.25-7.17 (m, 5H), 6.23 (dt, J = 12.5, 3.1 Hz, 1H), 5.61 (s, 2H), 4.98 (s,


68

2H), 4.63 (t, J = 2.5 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 161.5, 145.1, 138.4, 136.3, 136.1, 130.2, 128.8, 127.3, 127.2, 126.5, 124.2, 124.2, 122.4, 119.4, 115.5, 73.5, 65.7, 46.6. HRMS (ESI): calcd for C20H18NO2+: 304.1332, found: 304.1333. (3) 7-((Perfluorophenyl)methyl)-3,7-dihydrooxepino[4,3-c]quinolin-6(1H)-one (2c)

The reaction of 1c (48 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2c as a solid (37 mg, 94%).1H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.29-7.22 (m, 2H), 7.12 (dt, J = 12.5, 2.0 Hz, 1H), 6.23 (dt, J = 12.5, 3.1 Hz, 1H), 5.72 (s, 2H), 4.95 (s, 2H), 4.61 (t, J = 2.5 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 161.3, 145.3, 137.6, 136.6, 130.4, 127.0, 124.8, 123.8, 122.8, 119.7, 113.9, 73.5, 65.7, 35.9. 19F NMR (376 MHz, Chloroform-d) δ -141.9--142.8 (m), -154.5 (t, J = 22.4 Hz), -161.4--163.7 (m), HRMS (ESI): calcd for C20H13F5NO2+: 394.0861, found: 394.0860. (4) 5-Methyl-5,9,10,11-tetrahydro-6H-cyclohepta[c]quinolin-6-one (2d)

The reaction of 1d (31 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2d as a solid (21 mg, 91%). 1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 9.3 Hz, 1H), 7.53 (t, J = 8.5 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.28-7.23 (m, 2H), 6.95 (d, J = 11.8 Hz, 1H), 6.38-6.24 (m, 1H), 3.76


69

(s, 3H), 3.04-2.94 (m, 2H), 2.32 (q, J = 6.1, 5.7 Hz, 2H), 2.26-2.12 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 147.4, 138.9, 135.4, 129.6, 127.4, 125.9, 124.9, 122.0, 121.6, 120.7, 114.4, 31.6, 30.0, 29.8, 27.5. HRMS (ESI): calcd for C15H16NO+: 226.1226, found: 226.1227. (5) 5,8-Dimethyl-5,9,10,11-tetrahydro-6H-cyclohepta[c]quinolin-6-one (2e)

The reaction of 1e (32 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2e as a solid (22 mg, 91%). 1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 9.3 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.27-7.22 (m, 1H), 6.69 (s, 1H), 3.75 (s, 3H), 2.98-2.86 (m, 2H), 2.32-2.15 (m, 4H), 2.06 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 161.4, 146.4, 144.8, 138.6, 129.2, 128.4, 124.7, 121.9, 121.5, 120.9, 114.4, 33.8, 32.5, 29.8, 27.1, 26.3. HRMS (ESI): calcd for C16H18NO+: 240.1383, found: 240.1383. (6) 2-((tert-Butyldimethylsilyl)oxy)-5-methyl-5,9,10,11-tetrahydro-6H-cyclohepta [c] quinolin-6-one (2f)

The reaction of 1f (44 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2f as a solid (27 mg, 76%). 1H NMR (400 MHz, Chloroform-d) δ 7.29 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 7.05 (dd, J = 9.0, 2.6 Hz, 1H), 6.94 (d, J = 11.7 Hz, 1H), 6.37-6.25 (m, 1H), 3.72 (s, 3H), 2.94-


70

2.86 (m, 2H), 2.31 (q, J = 6.1, 5.7 Hz, 2H), 2.25-2.13 (m, 2H), 1.02 (s, 9H), 0.23 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 161.1, 150.6, 146.7, 135.4, 133.9, 127.7, 126.1, 122.4, 121.6, 115.4, 114.8, 31.6, 29.9, 29.9, 27.7, 25.7, 18.3, -4.4. HRMS (ESI): calcd for C21H30NO2Si+: 356.2040, found: 356.2041. (7) 2-Methoxy-5-methyl-5,9,10,11-tetrahydro-6H-cyclohepta[c]quinolin-6-one (2g)

The reaction of 1g (34 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2g as a solid (24 mg, 94%). 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.28 (m, 2H), 7.15 (dd, J = 9.1, 2.7 Hz, 1H), 6.95 (d, J = 11.8 Hz, 1H), 6.36-6.26 (m, 1H), 3.90 (s, 3H), 3.74 (s, 3H), 2.99-2.90 (m, 2H), 2.32 (q, J = 6.2 Hz, 2H), 2.25-2.13 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 161.0, 154.7, 146.8, 135.4, 133.6, 128.0, 126.1, 121.5, 117.2, 115.6, 108.1, 77.0, 55.8, 31.6, 30.0, 29.9, 27.7. HRMS (ESI): calcd for C16H18NO+: 256.1332, found: 256.1333. (8) 2-Hydroxy-5-methyl-5,9,10,11-tetrahydro-6H-cyclohepta[c]quinolin-6-one (2h)

The reaction of 1h (32 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (12 mg, 0.22 mmol), and CH3CN (10 mL) affords 2h as a solid (22 mg, 93%). 1H NMR (400 MHz, Methanol-d4) δ 7.43 (d, J = 9.1 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 9.1, 2.7 Hz, 1H), 6.82 (dd, J = 11.7, 1.7 Hz, 1H), 6.37-6.26 (m, 1H), 3.73 (s, 3H), 2.99-2.91 (m, 2H), 2.36-2.15 (m, 4H). 13C NMR (101 MHz, Methanol-d4) δ 162.5,


71

154.4, 149.6, 136.4, 133.5, 128.0, 126.9, 123.0, 120.3, 117.4, 110.4, 33.0, 30.6, 30.5, 28.6. HRMS (ESI): calcd for C15H16NO2+: 242.1176, found: 242.1176. (9) 10-Methyl-2,3-dihydro-6H-oxepino[3,2-c]chromen-6-one (2i)

The reaction of 1i (31 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2i as a solid (19 mg, 84%). 1H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.32-7.25 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 11.8 Hz, 1H), 6.18-6.08 (m, 1H), 4.54 (t, J = 4.4 Hz, 2H), 2.77 (q, J = 4.6 Hz, 2H), 2.40 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 163.8, 162.9, 149.6, 133.7, 132.6, 131.6, 123.4, 122.3, 116.8, 116.0, 105.3, 71.4, 33.7, 20.9. HRMS (ESI): calcd for C14H13O3+: 229.0859, found: 229.0860. (10) 10-Bromo-2,3-dihydro-6H-oxepino[3,2-c]chromen-6-one (2j)

The reaction of 1j (37 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2j as a solid (26 mg, 86%). 1H NMR (400 MHz, Chloroform-d) δ 8.01-7.95 (m, 1H), 7.56 (dd, J = 8.7, 2.3 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 11.8 Hz, 1H), 6.24-6.14 (m, 1H), 4.54 (t, J = 4.4 Hz, 2H), 2.83-2.74 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 163.0, 161.3, 150.2, 134.3, 132.8, 126.3, 122.0, 118.7, 117.9, 116.8, 106.0, 71.6, 33.6. HRMS (ESI): calcd for C13H10BrO3+: 292.9808, found: 292.9808. (11) 10-Fluoro-2,3-dihydro-6H-oxepino[3,2-c]chromen-6-one (2k)


72

O O

O Br

O O

OS

OViolet LED (5 w)

5 mol%MeONa (1.2 eq)CH3CN, rt, 24 h

1k 2k80%

F F

The reaction of 1k (31 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2k as a solid (19 mg, 80%). 1H NMR (400 MHz, Chloroform-d) δ 7.52 (dd, J = 8.8, 2.9 Hz, 1H), 7.27-7.17 (m, 2H), 6.81 (d, J = 11.8 Hz, 1H), 6.26-6.15 (m, 1H), 4.55 (t, J = 4.4 Hz, 2H), 2.84-2.73 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 163.3, 161.73, 161.70, 160.0, 157.6, 147.5, 132.7, 122.0, 119.1, 118.9, 118.2, 118.1, 117.8, 117.7, 109.5, 109.3, 106.0, 71.5, 33.6. HRMS (ESI): calcd for C13H10FO3+: 233.0609, found: 233.0609. (12) 7-Methyl-3,7-dihydrooxepino[4,3-c]quinolin-6(1H)-one (2a)

The reaction of 1l (26 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2a as a solid (7 mg, 25%).1H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.29-7.23 (m, 1H), 7.13 (dt, J = 12.6, 2.2 Hz, 1H), 6.20 (dt, J = 12.5, 3.2 Hz, 1H), 4.94 (s, 2H), 4.59 (t, J = 2.7 Hz, 2H), 3.77 (s, 3H). (13) 4-Ethyl-7-methyl-3,7-dihydrooxepino[4,3-c]quinolin-6(1H)-one (2m)


73

The reaction of 1m (38 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2m as a solid (23 mg, 90%). 1H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.26-7.19 (m, 1H), 6.98 (s, 1H), 4.88 (s, 2H), 4.45 (s, 2H), 3.76 (s, 3H), 2.25 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 161.4, 150.2, 143.0, 138.6, 129.7, 127.6, 123.9, 122.2, 120.0, 119.3, 114.5, 74.7, 65.5, 30.1, 28.8, 13.5. HRMS (ESI): calcd for C16H18NO2+: 256.1332, found: 256.1332. (14) 5,8-Dimethyl-4,8-dihydro-1H-oxocino[4,3-c]quinolin-7(3H)-one (2n)

The reaction of 1n (34 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), MeONa (6.5 mg, 0.12 mmol), and CH3CN (10 mL) affords 2n as a solid (23 mg, 89%). 1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 6.67 (s, 1H), 4.93-4.28 (m, 2H), 3.76 (s, 3H), 3.72-3.43 (m, 2H), 2.23-2.10 (m, 2H), 2.06 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.0, 142.7, 139.2, 139.0, 129.7, 129.6, 125.8, 122.5, 122.0, 120.9, 114.2, 66.6, 63.8, 36.9, 29.7, 25.6. HRMS (ESI): calcd for C16H18NO2+: 256.1332, found: 256.1332.


74

Photoreaction of 1a under standard condition without MeONa

To a flame dried Schlenk tube is added 1a (31 mg, 0.1 mmol), thioxanthone (1.1 mg, 0.005 mmol), and CH3CN (10 mL). The reaction is irradiated by a violet LED strips (5 w) under argon atmosphere at room temperature. The reaction is completed after 4 h as monitored by TLC (eluent:n-hexane/ethylacetate = 3:1). The solvent is removed and the residue was purified by flash chromatography on silica gel (eluent: n-hexane/ethylacetate = 5:1) to afford 3 as an oil (10 mg, 33%). 1H NMR (400 MHz, Chloroform-d) δ 7.32 (t, J = 8.6 Hz, 1H), 7.26-7.23 (m, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.77 (t, J = 8.3 Hz, 1H), 4.57 (d, J = 10.4 Hz, 1H), 4.16-4.07 (m, 1H), 4.03 (d, J = 9.4 Hz, 1H), 3.68 (d, J = 9.4 Hz, 1H), 3.59 (d, J = 8.6 Hz, 1H), 3.39 (s, 3H), 3.17 (t, J = 7.4 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 165.8, 139.4, 128.9, 127.1, 123.5, 121.7, 115.4, 78.6, 71.8, 57.0, 50.4, 49.2, 44.3 , 29.1. HRMS (ESI): calcd for C14H15BrNO+: 308.0281, found: 308.0281.

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4341; (b) C. Brenninger, T. Bach, Top. Catal., 2018, 61, 623-629. [18] For crystal data of 2b, see EXPERIMENTAL SECTION. CCDC:. [19] For crystal data of 2n, see EXPERIMENTAL SECTION. CCDC:.

Summary and Outlook

78

Summary and Outlook The aim of this thesis is to develop a facile and novel reaction protocol for the α-alkylation and α-alkenylation of quinolinone and coumarin derivatives. The following results have been achieved throughout the present research project. 1. The intramolecular α-alkylation of quinolinone and coumarin derivatives has been realized for the first time, allowing 100% atom economy. Fifteen substrates have been evaluated for this transformation, with a good functional groups and electronic tolerance. Since this reaction selectively generates six-membered rings with stereo centers, it may be of high interest for the derivation of bioactive quinolinone and coumarin related drugs (Scheme 1).

Scheme 1: AlCl3 initiated intramolecular α-alkylation of quinolinones and coumarins 2. The intramolecular α-alkenylation of quinolinone and coumarin derivatives has been realized for the first time in which visible-light is applied as the energy source and thioxanthone as the energy transferor. This reaction protocol provides a solution to transition metal catalyzed olefin-cross coupling, since electron-withdrawing groups activated olefins are always required. Electronic effect tolerance in this reaction is excellent, as well as the functional groups tolerance. A possible triplet sensitization mechanism has also been provided to explain the reaction mechanism (Scheme 2).

Summary and Outlook

79

Scheme 2: Visible-light-promoted intramolecular α-alkenylation of quinolinones and

coumarins 3. The mechanism of visible-light promoted photocatalysis has been proposed as below based on photoinduced electron transfer mechanism. An encounter complex and ion radical pair formation are proposed as part of the reaction mechanism.

Scheme 3: Proposed mechanism for visible-light-promoted intramolecular α-

alkenylation of quinolinones and coumarins In our design, the synthetic applicability can be further demonstrated by derivation of the α-alkenylation product. By utilizing the α-alkenylation product as starting material, a head-head selectivity in [2+2]-photocycloaddition reaction may be achieved, which

Summary and Outlook

80

is difficult with a one-step [2+2]-photocycloaddition. The Diels-Alder reaction between the α-alkenylation product and olefins may take place to afford structural diverse compounds (Scheme 4).

Scheme 4: Possible application of the α-alkenylation product

Meanwhile, we would like to subject this reaction to other substrates, such as alkyne tethered quinolinone, α-brominated quinolinone, or allene tethered quinolinone. Highly functionalized α,β-unsatured carbonyl compounds might be generated, which would be very helpful for further bioactive molecules synthesis (Scheme 5).

Scheme 5: Possible applications for visible-light-promoted cross-coupling

Appendix

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Appendix 4.1 Supporting information for α-alkylation of quinolinones and coumarins This section contains NMR spectrums and X-ray crystal structure to chapter 2: α-Alkylation of lactams and lactones, a highly selective way to produce six-membered rings

4.1.1 Crystal data of compound 2b

Figure 1. ORTEP-style representation of the X-ray crystal structure of 2b. Ellipsoids are depicted at 50% probability level, hydrogen atoms with an arbitrary radius. Disorder in the alkyl part of the structure (C11-C15) omitted for clarity. Table 1. Sample and crystal data for 2b

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Identification code 2b Chemical formula C15H17NO Formula weight 227.29 Temperature 110(2) K Wavelength 0.71073 Å Crystal size 0.186 x 0.209 x 0.317

mm

Crystal system orthorhombic Space group P 21 21 21 Unit cell dimensions a = 7.1064(12) Å

b = 10.3163(18) Å c = 15.973(2) Å

α = 90° β = 90° γ = 90°

Volume 1171.0(3) Å3 Z 4 Density (calculated) 1.289 g/cm3 Absorption coefficient 0.080 mm-1 F(000) 488

Table 2. Data collection and structure refinement for 2b. Diffractometer BrukerD8 Kappa Apex II Radiation source fine-focus sealed tube Mo Theta range for data collection 2.35 to 25.02° Index ranges -8<=h<=8, -12<=k<=12, -19<=l<=19 Reflections collected 14663 Independent reflections 2068 [R(int) = 0.0452] Coverage of independent reflections 99.9%

Absorption correction multi-scan

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83

Max. and min. transmission 0.9850 and 0.9750 Refinement method Full-matrix least-squares on F2 Refinement program SHELXL-2016/6 (Sheldrick 2016) Function minimized Σ w(Fo2 - Fc2)2 Data / restraints / parameters 2068 / 116 / 205 Goodness-of-fit on F2 1.083

Final R indices 2002 data; I>2σ(I) R1 = 0.0279 wR2 = 0.0731 all data R1 = 0.0291 wR2 = 0.0736

Weighting scheme w=1/[σ2(Fo2)+(0.0387P)2+0.1643P] where P=(Fo2+2Fc2)/3

Absolute structure parameter 1.7(19) Largest diff. peak and hole 0.120 and -0.157 eÅ-3 R.M.S. deviation from mean 0.032 eÅ-3

Table 3. Bond lengths (Å) for 2b. O1-C9 1.242(3) O1A-C9 1.24(3) N1-C9 1.390(2) N1-C1 1.392(2) N1-C10 1.463(2) C1-C2 1.404(2) C1-C6 1.414(2) C2-C3 1.374(3) C2-H2 0.95 C3-C4 1.387(3) C3-H3 0.95 C4-C5 1.378(3) C4-H4 0.95 C5-C6 1.401(3) C5-H5 0.95 C6-C7 1.457(2) C7-C8 1.352(3) C7-C15 1.511(2) C8-C9 1.467(3) C8-C11 1.528(3) C8-C11A 1.62(2) C10-H10A 0.98 C10-H10B 0.98 C10-H10C 0.98

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C15-C14A 1.52(2) C15-C14 1.528(3) C15-H15A 0.99 C15-H15B 0.99 C11-C13 1.531(3) C11-C12 1.537(3) C11-H11 1.0 C12-H12A 0.98 C12-H12B 0.98 C12-H12C 0.98 C13-C14 1.532(4) C13-H13A 0.99 C13-H13B 0.99 C14-H14A 0.99 C14-H14B 0.99 C11A-C12A 1.52(3) C11A-C13A 1.57(3) C11A-H11A 1.0 C12A-H12D 0.98 C12A-H12E 0.98 C12A-H12F 0.98 C13A-C14A 1.50(3) C13A-H13C 0.99 C13A-H13D 0.99 C14A-H14C 0.99 C14A-H14D 0.99

Table 4. Bond angles (°) for 2b. C9-N1-C1 123.28(15) C9-N1-C10 117.91(15) C1-N1-C10 118.80(15) N1-C1-C2 121.06(16) N1-C1-C6 119.06(15) C2-C1-C6 119.87(16) C3-C2-C1 120.11(17) C3-C2-H2 119.9 C1-C2-H2 119.9 C2-C3-C4 120.78(16) C2-C3-H3 119.6 C4-C3-H3 119.6 C5-C4-C3 119.60(17) C5-C4-H4 120.2 C3-C4-H4 120.2 C4-C5-C6 121.63(17) C4-C5-H5 119.2 C6-C5-H5 119.2 C5-C6-C1 118.00(16) C5-C6-C7 122.81(15) C1-C6-C7 119.18(15) C8-C7-C6 120.08(16) C8-C7-C15 121.81(16) C6-C7-C15 118.11(15) C7-C8-C9 121.23(17) C7-C8-C11 123.90(16)

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C9-C8-C11 114.86(16) C7-C8-C11A 118.7(8) C9-C8-C11A 113.2(7) O1-C9-N1 120.61(19) O1A-C9-N1 116.1(17) O1-C9-C8 122.36(19) O1A-C9-C8 120.0(16) N1-C9-C8 117.01(16) N1-C10-H10A 109.5 N1-C10-H10B 109.5 H10A-C10-H10B 109.5 N1-C10-H10C 109.5 H10A-C10-H10C 109.5 H10B-C10-H10C 109.5 C7-C15-C14A 109.4(17) C7-C15-C14 113.6(2) C7-C15-H15A 108.9 C14-C15-H15A 108.9 C7-C15-H15B 108.9 C14-C15-H15B 108.9 H15A-C15-H15B 107.7 C8-C11-C13 110.89(17) C8-C11-C12 110.85(19) C13-C11-C12 111.19(18) C8-C11-H11 107.9 C13-C11-H11 107.9 C12-C11-H11 107.9 C11-C12-H12A 109.5 C11-C12-H12B 109.5 H12A-C12-H12B 109.5 C11-C12-H12C 109.5 H12A-C12-H12C 109.5 H12B-C12-H12C 109.5 C11-C13-C14 111.1(2) C11-C13-H13A 109.4 C14-C13-H13A 109.4 C11-C13-H13B 109.4 C14-C13-H13B 109.4 H13A-C13-H13B 108.0 C15-C14-C13 110.0(2) C15-C14-H14A 109.7 C13-C14-H14A 109.7 C15-C14-H14B 109.7 C13-C14-H14B 109.7 H14A-C14-H14B 108.2 C12A-C11A-C13A 112.0(17) C12A-C11A-C8 98.9(17) C13A-C11A-C8 113.1(15) C12A-C11A-H11A 110.8 C13A-C11A-H11A 110.8 C8-C11A-H11A 110.8 C11A-C12A-H12D 109.5 C11A-C12A-H12E 109.5 H12D-C12A-H12E 109.5 C11A-C12A-H12F 109.5 H12D-C12A-H12F 109.5

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H12E-C12A-H12F 109.5 C14A-C13A-C11A 104.(2) C14A-C13A-H13C 110.9 C11A-C13A-H13C 110.9 C14A-C13A-H13D 110.9 C11A-C13A-H13D 110.9 H13C-C13A-H13D 108.9 C13A-C14A-C15 113.(2) C13A-C14A-H14C 109.0 C15-C14A-H14C 109.0 C13A-C14A-H14D 109.0 C15-C14A-H14D 109.0 H14C-C14A-H14D 107.8

4.1.2 Intermediate trapping experiment data

Figure S1. Deuterium labeling experiment

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87

Figure S2. Intermediate trapping experiment

4.1.3 NMR spectrums

5 min

15 min

25 min

35 min

55 min

120 min

overnight

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88

Appendix

89

NH O7a

HO

Appendix

90

NH O7a

HO

9aNH O

Appendix

91

9aNH O

Appendix

92

Appendix

93

NH O14a

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94

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95

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109

4.2 Supporting information for α-alkenylation of quinolinones and coumarins This section contains NMR spectrums and X-ray crystal sturcture to chapter 3: Visible-Light Promoted Transition Metal-Free Cross-Coupling: Highly Selective Intramolecular α-Alkenylation of quinolinones and coumarins for seven-membered ring synthesis

4.2.1 Crystal data of compound 2h

Figure S1. ORTEP-style representation of the X-ray crystal structure of 2h. Ellipsoids are depicted at 50% probability level, hydrogen atoms with an arbitrary radius. Disorder in the alkyl part of the structure (C11-C17) omitted for clarity.

Table S1. Sample and crystal data for 2h Identification code 2h Chemical formula C15H15NO2 Formula weight 241.28 Temperature 100(2) K

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110

Wavelength 0.71073 Å Crystal size 0.110 x 0.249 x 0.479 mm Crystal habit clear yellow fragment Crystal system monoclinic Space group P 1 21/c 1

Unit cell dimensions a = 8.4227(3) Å α = 90o b = 16.6533(6) Å β= 95.7590(10)° c = 8.2953(3) Å γ= 90°

Volume 1157.67(7) Å3 Z 4 Density (calculated) 1.384 g/cm3 Absorption coefficient 0.092 mm-1

Table S2. Data collection and structure refinement for 2h. Diffractometer Bruker D8 Venture Duo IMS Radiation source IMS microsource, Mo Theta range for data collection 2.43 to 26.39° Index ranges -10<=h< = 10, -20<=k<=20, -10<=l< = 10 Reflections collected 18989 Independent reflections 2375 [R(int) = 0.0289] Coverage of independent reflections

100.0%

Absorption correction Multi-Scan Max. and min. transmission 0.9900 and 0.9570 Structure solution technique direct methods Structure solution program SHELXT 2014/5 (Sheldrick, 2014) Refinement method Full-matrix least-squares on F2 Refinement program SHELXL-2014/7 (Sheldrick, 2014)

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111

Function minimized Z w(Fo2 - Fc2)2 Data / restraints / parameters 2375 / 0 / 166 Goodness-of-fit on F2 1.100 Final R indices 2176 data; I>2σ(I) Rl = 0.0400, wR2 = 0.1072

all data Rl = 0.0432, wR2 = 0.1094

Weighting scheme w=1/[σ2(Fo2)+(0.0516P)2+0.5563P] where P=(Fo2+2Fc2)/3

Largest diff. peak and hole 0.286 and -0.219 eÅ3 R.M.S. deviation from mean 0.044 eÅ3

Table S3. Bond lengths (Å) for 2h. Ol-Cl 1.2444(16) Cl-Nl 1.3761(16) C1-C2 1.4632(18) C2-C8 1.3680(18) C2-C3 1.4721(17) 02-C11 1.3641(16) 02-H2 0.91(2) N1-C14 1.3998(16) N1-C15 1.4651(16) C3-C4 1.3363(19) C3-H3 0.95 C4-C5 1.497(2) C4-H4 0.95 C5-C6 1.5175(19) C5-H5A 0.99 C5-H5B 0.99 C6-C7 1.5369(19) C6-H6A 0.99 C6-H6B 0.99 C7-C8 1.5049(17) C7-H7A 0.99 C7-H7B 0.99 C8-C9 1.4475(17) C9-C14 1.4077(17) C9-C10 1.4089(17) C10-C11 1.3797(18) C10-H10 0.95 C14-C13 1.4032(18) C15-H15A 0.98 C15-H15B 0.98 C15-H15C 0.98 C13-C12 1.3794(18)

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112

C13-H13 0.95 C12-C11 1.3962(18) C12-H12 0.95

Table S4. Bond angles (°) for 2h. Ol-Cl-Nl 119.50(11) 01-C1-C2 123.02(12) N1-C1-C2 117.47(11) C8-C2-C1 120.91(11) C8-C2-C3 125.02(12) C1-C2-C3 113.88(11) C11-02-H2 109.5 C1-N1-C14 122.77(11) C1-N1-C15 118.14(10) C14-N1-C15 119.08(10) C4-C3-C2 131.70(13) C4-C3-H3 114.1 C2-C3-H3 114.1 C3-C4-C5 131.29(13) C3-C4-H4 114.4 C5-C4-H4 114.4 C4-C5-C6 114.98(11) C4-C5-H5A 108.5 C6-C5-H5A 108.5 C4-C5-H5B 108.5 C6-C5-H5B 108.5 H5A-C5-H5B 107.5 C5-C6-C7 110.89(12) C5-C6-H6A 109.5 C7-C6-H6A 109.5 C5-C6-H6B 109.5 C7-C6-H6B 109.5 H6A-C6-H6B 108.0 C8-C7-C6 112.29(11) C8-C7-H7A 109.1 C6-C7-H7A 109.1 C8-C7-H7B 109.1 C6-C7-H7B 109.1 H7A-C7-H7B 107.9 C2-C8-C9 119.90(11) C2-C8-C7 119.34(11) C9-C8-C7 120.75(11) C14-C9-C10 118.15(11) C14-C9-C8 119.05(11) C10-C9-C8 122.79(11) C11-C10-C9 121.60(12) C11-C10-H10 119.2 C9-C10-H10 119.2 N1-C14-C13 120.72(11) N1-C14-C9 119.57(11) C13-C14-C9 119.70(12) N1-C15-H15A 109.5 N1-C15-H15B 109.5

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H15A-C15-H15B 109.5 N1-C15-H15C 109.5 H15A-C15-H15C 109.5 H15B-C15-H15C 109.5 C12-C13-C14 120.90(12) C12-C13-H13 119.5 C14-C13-H13 119.5 C13-C12-C11 119.94(12) C13-C12-H12 120.0 C11-C12-H12 120.0 O2-C11-C10 122.33(12) 02-C11-C12 117.99(11) C10-C11-C12 119.67(12)

Table S5. Torsion angles (°) for 2h. 01-C1-C2-C8 -178.17(12) N1-C1-C2-C8 3.17(18) 01-C1-C2-C3 6.63(18) N1-C1-C2-C3 -172.03(11) 01-C1-N1-C14 174.89(11) C2-C1-N1-C14 -6.40(18) 01-C1-N1-C15 -3.85(18) C2-C1-N1-C15 174.87(11) C8-C2-C3-C4 21.9(2) C1-C2-C3-C4 -163.10(14) C2-C3-C4-C5 5.0(3) C3-C4-C5-C6 0.3(2) C4-C5-C6-C7 -51.08(17) C5-C6-C7-C8 92.62(14) C1-C2-C8-C9 2.00(19) C3-C2-C8-C9 176.64(12) C1-C2-C8-C7 -177.25(12) C3-C2-C8-C7 -2.6(2) C6-C7-C8-C2 -58.42(16) C6-C7-C8-C9 122.33(13) C2-C8-C9-C14 -4.17(18) C7-C8-C9-C14 175.07(12) C2-C8-C9-C10 177.13(12) C7-C8-C9-C10 -3.63(19) C14-C9-C10-C11 -1.31(19) C8-C9-C10-C11 177.40(12) C1-N1-C14-C13 -175.57(11) C15-N1-C14-C13 3.15(18) C1-N1-C14-C9 4.31(18) C15-N1-C14-C9 -176.97(11) C10-C9-C14-N1 179.90(11) C8-C9-C14-N1 1.14(18) C10-C9-C14-C13 -0.22(18) C8-C9-C14-C13 -178.98(11) N1-C14-C13-C12 -179.03(12) C9-C14-C13-C12 1.09(19) C14-C13-C12-C11 -0.5(2) C9-C10-C11-O2 -177.94(12)

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C9-C10-C11-C12 2.0(2) C13-C12-C11-02 178.85(12) C13-C12-C11-C10 -1.1(2)

4.2.2 Crystal data of compound 2n

Figure S2. ORTEP-style representation of the X-ray crystal structure of 2n. Ellipsoids are depicted at 50% probability level, hydrogen atoms with an arbitrary radius. Disorder in the alkyl part of the structure (C11-C17) omitted for clarity. Table S6. Sample and crystal data for 2n. Identification code 2n Chemical formula C48H51N3O6 Formula weight 765.91 Temperature 100(2) K Wavelength 0.71073 )1 Crystal size 0.122 x 0.292 x 0.377 mm Crystal habit clear colourless fragment

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Crystal system trigonal Space group R -3 Unit cell dimensions a = 27.772(12)Å ɑ = 90°,

b = 27.772(12) Å β = 90°, c = 9.413(4) Å γ = 120°

Volume 6287.(6) Å3 Z 6 Density (calculated) 1.214 g/cm3 Absorption coefficient 0.080 mm-1 F(000) 2448

Table S7. Data collection and structure refinement for 2n. Diffractometer Bruker D8 Venture Duo IMS Radiation source IMS microsource, Mo Theta range for data collection 2.32 to 25.34 Index ranges -33<=h<=33, -33<=k<=33, -11<=I<=11 Reflections collected 61427 Independent reflections 2568 [R(int) = 0.0574] Coverage of independent reflections

99.7%

Absorption correction Multi-Scan Structure solution technique direct methods Structure solution program SHELXT 2014/5 (Sheldrick, 2014) Refinement method Full-matrix least-squares on F2 Refinement program SHELXL-2017/1 (Sheldrick, 2017) Function minimized Z w(Fo2 - Fc2)2 Data / restraints / parameters 2568 / 0 / 174 Goodness-of-fit on F2 1.162

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116

A/omax 0.002 Final R indices 2388 data; I>20(I) R1 = 0.0494, wR2 = 0.0984

all data R1 = 0.0540, wR2 = 0.1003 Weighting scheme w=1/[σ2(Fo2)+(0.0216P)2+12.6854P]

where P=(Fo2+2Fc2)/3 Largest diff. peak and hole 0.202 and -0.208 eÅ3 R.M.S. deviation from mean 0.036 eÅ3

Table S8. Bond lengths (A) for 2n. O1-C1 1.233(2) N1-C1 1.382(2) N1-C14 1.394(2) N1-C16 1.470(2) C1-C2 1.468(2) C2-C8 1.364(2) C2-C3 1.465(2) O2-C6 1.432(2) O2-C7 1.4362(19) C3-C4 1.334(2) C3-H3 0.95 C4-C15 1.496(3) C4-C5 1.520(2) C5-C6 1.525(3) C5-H5A 0.99 C5-H5AB 0.99 C9-C10 1.408(3) C9-C14 1.414(2) C9-C8 1.447(2) C8-C7 1.511(2) C7-H7A 0.99 C7-H7AB 0.99 C6-H6A 0.99 C6-H6AB 0.99 C10-C11 1.375(3) C10-H10 0.95 C11-C12 1.391(3) C11-H11 0.95 C16-H16A 0.98 C16-H16B 0.98 C16-H16C 0.98 C15-H15A 0.98 C15-H15B 0.98 C15-H15C 0.98 C14-C13 1.403(3) C13-C12 1.376(3) C13-H13 0.95 C12-H12 0.95

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Table S9. Bond angles (°) for 2n. C1-N1-C14 123.09(14) C1-N1-C16 117.44(14) C14-N1-C16 119.47(15) O1-C1-N1 121.11(15) O1-C1-C2 121.85(16) N1-C1-C2 117.04(15) C8-C2-C3 123.48(15) C8-C2-C1 121.22(15) C3-C2-C1 115.25(14) C6-O2-C7 113.64(13) C4-C3-C2 124.84(15) C4-C3-H3 117.6 C2-C3-H3 117.6 C3-C4-C15 120.92(16) C3-C4-C5 123.15(16) C15-C4-C5 115.91(15) C4-C5-C6 116.07(14) C4-C5-H5A 108.3 C6-C5-H5A 108.3 C4-C5-H5AB 108.3 C6-C5-H5AB 108.3 H5A-C5-H5AB 107.4 C10-C9-C14 118.11(16) C10-C9-C8 122.76(15) C14-C9-C8 119.11(15) C2-C8-C9 119.81(15) C2-C8-C7 120.77(15) C9-C8-C7 119.41(15) O2-C7-C8 111.77(13) O2-C7-H7A 109.3 C8-C7-H7A 109.3 O2-C7-H7AB 109.3 C8-C7-H7AB 109.3 H7A-C7-H7AB 107.9 O2-C6-C5 114.86(14) O2-C6-H6A 108.6 C5-C6-H6A 108.6 O2-C6-H6AB 108.6 C5-C6-H6AB 108.6 H6A-C6-H6AB 107.5 C11-C10-C9 121.34(18) C11-C10-H10 119.3 C9-C10-H10 119.3 C10-C11-C12 119.70(18) C10-C11-H11 120.2 C12-C11-H11 120.2 N1-C16-H16A 109.5 N1-C16-H163 109.5 H16A-C16-H16B 109.5 N1-C16-H16C 109.5 H16A-C16-H16C 109.5 H16B-C16-H16C 109.5 C4-C15-H15A 109.5 C4-C15-H15B 109.5

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H15A-C15-H15B 109.5 C4-C15-H15C 109.5 H15A-C15-H15C 109.5 H15B-C15-H15C 109.5 N1-C14-C13 120.42(16) N1-C14-C9 119.54(15) C13-C14-C9 120.03(17) C12-C13-C14 119.86(18) C12-C13-H13 120.1 C14-C13-H13 120.1 C13-C12-C11 120.96(18) C13-C12-H12 119.5 C11-C12-H12 119.5

Table S10. Torsion angles (°) for 2n. C14-N1-C1-Ol 178.63(14) C16-N1-C1-01 -2.1(2) C14-N1-C1-C2 -2.2(2) C16-N1-C1-C2 177.11(13) O1-C1-C2-C8 -175.77(15) N1-C1-C2-C8 5.1(2) Ol-Cl-C2-C3 1.7(2) N1-C1-C2-C3 -177.51(13) C8-C2-C3-C4 -51.2(2) C1-C2-C3-C4 131.38(17) C2-C3-C4-C15 173.40(16) C2-C3-C4-C5 -8.2(3) C3-C4-C5-C6 91.8(2) C15-C4-C5-C6 -89.8(2) C3-C2-C8-C9 178.15(14) C1-C2-C8-C9 -4.6(2) C3-C2-C8-C7 -3.1(2) C1-C2-C8-C7 174.08(13) C10-C9-C8-C2 -177.30(15) C14-C9-C8-C2 1.3(2) C10-C9-C8-C7 4.0(2) C14-C9-C8-C7 -177.40(13) C6-02-C7-C8 -95.54(16) C2-C8-C7-02 98.09(17) C9-C8-C7-02 -83.20(17) C7-O2-C6-C5 59.65(18) C4-C5-C6-02 -81.2(2) C14-C9-C10-C11 0.4(2) C8-C9-C10-C11 179.07(15) C9-C10-C11-C12 -0.5(3) C1-N1-C14-C13 179.34(15) C16-N1-C14-C13 0.1(2) C1-N1-C14-C9 -1.0(2) C16-N1-C14-C9 179.75(14) C10-C9-C14-N1 -179.81(14) C8-C9-C14-N1 1.5(2) C10-C9-C14-C13 -0.1(2) C8-C9-C14-C13 -178.81(15) N1-C14-C13-C12 179.54(16) C9-C14-C13-C12 -0.1(3)

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C14-C13-C12-C11 0.1(3) C10-C11-C12-C13 0.2(3)

4.2.3 NMR spectrums

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N O

Br

1o

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Br

1o

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N O

O

2a

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139

N O

O

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N O

O

2cC6F5

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N O2d

N O

O

2cC6F5

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N O2d

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Appendix

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Appendix

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Appendix

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Appendix

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Figure S3. COSY spectrum of 2j

Appendix

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Figure S4. HSQC spectrum of 2j

Appendix

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Figure S5. HMBC spectrum of 2j

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N O

O

2a1l

Appendix

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Appendix

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Appendix

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List of publications

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List of publications 1. Dawen Xu, Felix Kaiser, Han Li, Robert M. Reich, Hao Guo,* Fritz E. Kühn,*.

“Highly selective AlCl3 initiated intramolecular α-alkylation of α,β-unsaturated lactams and lactones.” Organic & Biomolecular Chemistry, 2019, 17, 49-52.

2. Pan Huang, Dawen Xu, Robert M. Reich, Felix Kaiser, Boping Liu, Fritz E. Kühn,* “Et2Zn-mediated Stoichiometric C(sp)-H Silylation of 1-Alkynes and Chlorosilanes” Tetrahedron Letters, 2019, 69, 1574-1577.

3. Dawen Xu, Han Li, Pan Huang, Oberkofler Jens, Robert M. Reich, Hao Guo,* Fritz E. Kühn,* “Visible-Light Promoted Transition Metal-Free Cross-Coupling: Highly Selective Intramolecular α-Alkenylation of quinolinones and coumarins for seven-membered ring synthesis” manuscript in preparation

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