應用多種策略和成具有生物活性的含氮及氧雜環化合物

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(1)MULTIFACETED APPROACH TOWARDS THE SYNTHESIS OF BIOLOGICALLY ACTIVE O, N - HETEROCYCLES. A Dissertation Submitted to the NationalTaiwanNormalUniversity for the Degree of Doctor of Philosophy in Chemistry. Submitted by. R.R. RAJAWINSLIN 80042008S. Advisor. Prof. Dr. Ching-Fa Yao. Department of Chemistry NationalTaiwanNormalUniversity Taipei – 116 Taiwan, R.O.C. September 2015.

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(3) Prof. Dr. Ching-Fa Yao Department of Chemistry NationalTaiwanNormalUniversity. E-mail:. 88, Sec. 4, Ting-Chow Rd. cheyaocf@ntnu.edu.tw. Taipei, Taiwan 11677. TEL +886-2-29309092. R. O. C.. FAX +886-2-29324249. CERTIFICATE This is to certify that the work incorporated in the thesis entitled “Multifaceted approach towards the synthesis of biologically active O,N- heterocycles” submitted by R.R.Rajawinslin was carried out by him under my supervision at the Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.. Prof. Dr. Ching-Fa Yao Department of Chemistry NationalTaiwanNormalUniversity Taipei – 116 TAIWAN R.O.C..

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(5) CANDIDATE’S DECLARATION I hereby declare that the work presented in the dissertation entitled “Multifaceted approach towards the synthesis of biologically active O,N- heterocycles” submitted for Ph.D. degree to NationalTaiwanNormalUniversity, Taipei, Taiwan. The work has been carried out by myself at the Department of Chemistry, NationalTaiwanNormalUniversity, Taipei, Taiwan, R.O.C., under the supervision of Prof. Dr. Ching-Fa Yao. The work is original and any of the part of this work was not submitted by me for another degree or diploma to this or any other university. Any inadvertent omissions that might have occurred, due to oversight or error in judgment are regretted.. R.R.Rajawinslin Date: September 2015 Department of Chemistry, NationalTaiwanNormalUniversity, Taipei -116, TAIWAN R.O.C..

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(7) Acknowledgement I would like to express my sincere and humble gratitude to my supervisor Prof. Dr. Ching-Fa Yao, for his valuable advice and financial support during my Ph.D study at National Taiwan Normal University. He provided continuous encouragement, good teaching and lots of troubleshooting ideas during my Ph.D career. He helped me a lot during tough situation in my Ph.D study. I also like to extend my thanks to all the professors of the Department of Chemistry, National Taiwan Normal University. Especially, I would like to thank Prof. Dr. Kwunmin Chen, Prof. Dr. Wenwei Lin, Prof. Dr. Ming-Chang P. Yeh, Prof. Dr. Tun-Cheng Chien, Prof. Dr. Jenghan Wang, Prof. Dr. Cheng-Huang Lin, Prof. Dr. Wen-Chang Huang, Prof. Dr. Way-Zen Lee, for their excellent guidance during my course work. I am particularly thankful to Dr. Mustafa Jahir Raihan, Dr. VeerababuraoKavala, Dr. ChunWei Kuo and Dr. Ju-Tsung Liu for their kind help and co-operation during my research. I wish to thank all the past and present members of the Prof. Yao group, like Dr. PateliyaMujjamil Habib, Dr. Chintakunta Ramesh, Dr. Deepak Kumar Barange, Dr. BalrajGopula,. Dr.. DonalaJanreddy,. Dr.SachinDadajiGawande,. Dr.ManojZanwar,. TrimurtuluKotipalli,Sachin S. Ichake,Bharath Kumar Villuri, VijayalaksnmiBandi, and all the labmatesfor their friendly interaction and help during my research. I would like to thank NMR operator Ms. Chiu-Hui and X-ray crystallographer Mr. Ting-Shen Kuo, Mei-Ling Chen and Chiu-Hui He for providing me analytical support during my Ph.D study. I wish to thank all the office staff members of Department of Chemistry and Office of International Affairs, for their kind help during my Ph.D study at NTNU..

(8) I would like to thank Primary and High School Teachers, Degree College Lecturers and P. G. College professors. They taught me discipline and good education to reach here. I am thankful to all the Well-Wishers for their constant support and encouragement. My final, and most heartfelt, acknowledgment must go to my beloved wife Dr. T.A. Jose Priya (Post-doctoral Researcher, Department of Life Science, National Taiwan University, Taipei, Taiwan). She is the best part of my life. She supported me, encouraged me and loved me during my Ph.D life. Each and every moment I remember her and this thesis is indeed a realization of her dream.. R.R. Rajawinslin.

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(10) Dedicated to my family.

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(12) TABLE OF CONTENTS Page Abbreviations Abstract. Part – I Part – I, Section-A: Overview on Selectfluor mediated fluorination reactions I.A.1. Introduction. 1-2. I.A.2. Common electrophilic fluorinating agents. 2-3. I.A.3. Electrophilic fluorination reactions. 3-4. I.A.4. Recent advances in Selectfluor mediated fluorination reactions. 4-5. I.A.5.Selectfluor mediated decarboxylative fluorination reactions. 5-6. I.A.6.Selectfluor as oxidizing agent. 5-7. I.A.7.Selectfluor- a reagent forcyclization. 7-8. I.A.8.An introduction to cyclohexene-fused isoxazoline N-oxides. 8-10. I.A.9. References. 12-14. Section-B:Selectfluor-mediated fluorination and C–C bond cleavage of cyclohexenefused isoxazoline N-oxides I.B.1. Introduction. 15-16. I.B.2. Result and discussions. 16-24. I.B.3. Conclusion. 24. I.B.4. Experimental section. 24-31. I.B.5. References. 32-34. Section-C: Selectfluor mediatedone pot synthesis of cyclohexanone ring fused isoxazole derivatives I.C.1. Introduction. 35-36. I.C.2. Result and discussions. 36-43. I.C.3. Conclusion. 43. I.C.4. Experimental section. 43-49.

(13) I.C.5. References. 49-51. Part – II Part – II, Section-A: Overview on iron/acetic acid mediated reactions II.A.1. Introduction. 53. II.A.2.Recent advances in iron/acetic acid mediated reactions. 54-55. II.A.3. Iron/acetic acid mediated protocols from our group. 55-57. II.A.4. References. 58-61. Section-B: Iron/Acetic acid mediated intermolecular tandem C-C and C-N bond formation: An easy access to acridinone and quinoline derivatives II.B.1. Introduction. 63-64. II.B.2. Review of literature. 64-65. II.B.3. Result and discussions. 65-75. II.B.4. Conclusion. 75. II.B.5. Experimental section. 75-86. II.B.6. References. 87-89. Section-C: Iron/acetic acid mediated synthesis of 6,7-dihydrodibenzo [b,j] [1,7] phenanthroline derivativesvia intramolecular reductive cylization II.C.1. Introduction. 91-92. II.C.2. Review of literature. 92-93. II.C.3. Result and discussions. 94-105. II.C.4. Conclusion. 105. II.C.5. Experimental section. 106-123. II.C.6. References. 124-129. X-ray crystallographic data. 131-148. 1. 149-275. H and 13C NMR spectral copies. List of publications. 277-278.

(14) Abbreviations Å. Angstrom. Ac2O. Acetic anhydride. AcOH. Acetic acid. AlCl3. Aluminium chloride. Ar. Aryl. aq.. Aqueous. BHA. Baylis-Hillman adduct. Bn. Benzyl. Boc. Butyloxycarbonyl. Bu. Butyl. t-Bu. tert-Butyl. t-BuOH. tert-Butanol. br. Broad (IR). brs. Broad singlet (NMR). Bz. Benzoyl. o. C. Degree Celsius. Cat.. Catalyst. CDCl3. Chloroform (Deuterated). Cm. Centimeter. d. Doublet (NMR). d. Day(s). dd. Doublet of doublet(NMR).

(15) DABCO. 1,4-Diazabicyclo[2.2.2]octane. DBU. 1,8-Diazabicyclo[5.4.0]undec-7-ene. DEAD. Diethyl azodicarboxylate. DIEPA. N,N-Diisopropylethyl amine. DIB. (Diacetoxyiodo)benzene. EI. Electron impact. Et. Ethyl. Et3N. Triethylamine. EtOAc. Ethyl acetate. Et2O. Diethyl ether. EtOH. Ethanol. equiv.. Equivalent(s). FAB. Fast atom bombardment. Fe. Iron powder. FT. Fourier transform(NMR). h. Hour (s). hν. Irradiation with light. HBr. Hydrogen bromide. HCl. Hydrochloric acid. H2O. Water. HRMS. High resolution mass spectrometry. HTIB. [Hydroxy(tosyloxy)iodo]benzene. Hz. Hertz. IBX. o-Iodoxybenzoic acid.

(16) IR. Infrared spectrometry. KBr. Potassium bromide (IR). LRMS. Low resolution mass spectrometry. M. Moles per liter. Me. Methyl. Me2NH. Dimethylamine. MgSO4. Magnesium sulfate. MHz. Mega hertz(NMR). Min. Minute(s). mL. Milliliter(s). mmol. Millimole(s). MnO2. Manganese dioxide. mol. Mole(s). m.p.. Melting point. MS. Mass spectrometry. MVK. Methyl vinyl ketone. MW. Microwave. μL. Microliter(s). N. Equivalents per liter (Normality). NaHCO3. Sodium bicarbonate. NBS. N-Bromosuccinimide. NCS. N-Chlorosuccinimide. NIS. N-Iodosuccinimide. NMR. Nuclear magnetic resonance.

(17) NH2NH2. Hydrazine. Nu. Nucleophile. OAc. Acetate. OsO4. Osmium tetroxide. Pd/C. Palladium over charcoal. Pd(PPh3)2Cl2. Bis(triphenylphosphine)palladium(II)dichloride. Pd(PPh3)4. Tetrakis(triphenylphosphine)palladium(0). Pd(OAc)2. Palladium(II)acetate. PdCl2. Palladium(II)chloride. Ph2CO. Benzophenone. Ph. Phenyl. ppm. Parts per million(NMR). q. Quartet (NMR). Rf. Retention factor. r.t.. Room temperature. s. Singlet (NMR). SiO2. Silicon dioxide. SN2. Substitution nucleophilic bimolecular. t. Triplet (NMR). TBAF. Tetrabutylammonium fluoride. TCCA. Trichloroisocyanuric acid. TEA. Triethylamine. TFA. Trifluoroacetic acid. TFAA. Trifluoroacetic anhydride.

(18) THF. Tetrahydrofuran. TLC. Thin layer chromatography. TMSN3. Trimethylsilylazide. UV. Ultraviolet. Zn. Zinc powder.

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(20) ABSTRACT OF THE THESIS MULTIFACETED APPROACH TOWARDS THE SYNTHESIS OF BIOLOGICALLY ACTIVE O, N - HETEROCYCLES The content of this dissertation is divided into two parts. Part I is subdivided into three sections. Section A describes the overview on Selectfluor mediated fluorination reactions. Section B describes the “Selectfluor-mediated fluorination and C–C bond cleavage of cyclohexene-fused isoxazoline N-oxides”. In this section, a rapid method for the synthesis of long chain fluoro compounds using C-C bond cleavage and the synthetic utility of these compounds are described. Section C describes the “Selectfluor mediatedone-pot synthesis of cyclohexanone ring fused isoxazole derivatives”. Part II also subdivided into three sections. Section A describes the overview of iron/acetic acid mediated reactions, importance of reductive cyclization reactions in organic synthesis and the recently reported iron/acetic acid mediated protocols from our group. Section B describes the “Iron/Acetic acid mediated intermolecular tandem C-C and C-N bond formation: An easy access to acridinone and quinoline derivatives”. In this section, a rapid method for the synthesis of biologically active compounds by using iron/acetic acid is described. Section C describes the “Iron/acetic acid mediated synthesis of. 6,7-dihydrodibenzo [b,j] [1,7] phenanthroline derivativesvia. intramolecular reductive cylization”. In this section, an easy method for the synthesis of polycyclic compounds by using iron/acetic acid and the synthetic utility of these newly synthesized compounds are described. Key words: Selectfluor/ Fluorination/ Ring cleavage/Isoxazoline N-Oxide/ C-C bond cleavage Synthetic methods/ Defluorination/N-O Coupling/Heterocycles..

(21) Part – I Part – I, Section-A: Overview on Selectfluor mediated fluorination reactions This section describes about electrophilic fluorination reactions, previous reports of Selectfluor mediated fluorination reactions, advantages of Selectfluor over other electrophilic fluorinating agents and the different roles of Selectfluor in organic synthesis. Part-I, Section-B:Selectfluor-mediated fluorination and C–C bond cleavage of cyclohexene-fused isoxazoline N-oxides This section discusses about the synthesis of long chain fluoro compounds by using Selectfluor along with the plausible mechanism. When cyclohexene-fused isoxazoline Noxides were treated with Selectfluor in acetonitrile at room temperature produced a long chain diketofluoro nitrile in excellent yield. This rapid C–C bond cleavage reaction proceeded via the formation of nitroso intermediate.. N. O O. Cl. N. N F. F. O 2 BF4. R CH3CN rt. -. R. N. O. R = NO2, F, Br, Cl, CN, CH3, OCH3. Scheme 1:Selectfluor-mediated synthesis of diketofluoro nitriles Part-I, Section-C: Selectfluor mediatedone-pot synthesis of cyclohexanone ring fused isoxazole derivatives This section discusses about the one pot synthesis of cyclohexanone ring fused isoxazole derivatives from cyclohexene-fused isoxazoline N-oxides by using Selectfluor. This rapid, one-pot, two-step transformation is achieved in acetonitrile, through nitroso intermediate followed by hydration, defluorination and N-O coupling in the presence oftriethylamine. The scope and plausible mechanism of this protocol also demonstrated..

(22) Scheme 2:Selectfluor-mediated synthesis of cyclohexanone ring fused isoxazoles. Part – II Part – II, Section-A: Overview on iron/acetic acid mediated reactions This section discusses about theoverview on iron/acetic acid mediated reactions, importance of reductive cyclization reactions in organic synthesis and recently reported iron/acetic acid mediated protocols from our group. Part- II, Section-B: Iron/Acetic acid mediated intermolecular tandem C-C and C-N bond formation: An easy access to acridinone and quinoline derivatives This section describes an efficient iron/acetic acid mediated one-potreductive cyclization protocol for the synthesis ofacridinone and quinoline derivatives. This highly efficient process proceeds under mild conditions, tolerates different functional groups, and provides various substituted. acridinone. and. quinoline. derivatives. in. good. to. excellent. addition,biologically active compounds accessed from this method also described..    . Simple operation Broad substrate scope No need of work up No need of expensive reagents. Scheme 3:Iron/Acetic acid mediated synthesis of acridinone and quinoline derivatives. yields.In.

(23) Figure 1: Iron/Acetic acid mediated one pot synthesis of biologically active compounds Part-II: Section-C: Iron/Acetic acid mediated synthesis of 6,7-dihydrodibenzo [b,j] [1,7] phenanthroline derivativesvia intramolecular reductive cylization This section demonstrates an efficient iron/acetic acid mediated intramolecular reductive cyclization protocol for the synthesis of novel 6,7-dihydrodibenzo[b,j][1,7] phenanthroline derivatives. In this two-step procedure, aldol addition and reductive cyclization methods are effectively utilized for the construction of C-C and C-N bonds. This highly efficient process proceeds under mild conditions, tolerates different functional groups, and provides various substituted 6,7-dihydrodibenzo [b,j] [1,7]phenanthroline derivatives in good to excellent yields.In addition, various synthetic utilities of these derivatives are also described.. Scheme. 4:Iron/Acetic. phenanthroline derivatives. acid. mediated. synthesis. of. 6,7-dihydrodibenzo. [b,j]. [1,7].

(24) Figure 2: Synthetic utilities of 6,7-dihydrodibenzo [b,j] [1,7] phenanthroline derivatives.

(25) Part – I, Section-A Overview on Selectfluor mediated fluorination reactions I.A.1. Introduction The synthesis of organo-fluorine compounds is an important area of research in modern pharmaceutical chemistry. Introduction of fluorine into bio-active compounds has been shown to be very effective in biological systems in regulating metabolism and also in drug discovery by improving the delivery and binding of pharmaceutically active agents to their specific targets.Most of the drugs for human use, approved by FDA in the United States, containing one or more than one fluorine atoms.. Figure I.A.1.1 Fluorine containing biologically active compounds. Xtandi1is an effective medicine used to treat men with prostate cancer that no longer responds to a medical or surgical treatment that lowers testosterone and that has spread to other parts of the body.Stivarga (Regorafenib)2 is used to treat patients with colorectal cancer. Stivarga is a multi-kinase inhibitor that blocks several enzymes that promote cancer growth. Lipitor3 is used 1.

(26) to treat high cholesterol, and to lower the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors.Prevacid4 is used to treat and prevent stomach and intestinal ulcers, erosive esophagitis(damage to the esophagus from stomach acid), and other conditions involving excessive stomach acid such as Zollinger-Ellison syndrome. Lexapro5 (Escitalopram) is an antidepressant belonging to a group of drugs called selective serotonin reuptake inhibitors (SSRIs). Escitalopram affects chemicals in the brain that may become unbalanced and cause depression or anxiety.. I.A.2. Common electrophilic fluorinating agents Classically, the source of electrophilic fluorine has been fluorine gas, which is highly toxic and a strong oxidizer. In this context, mild, safe and highly stable alternative for electrophilic fluorination is highly desirable. These reagents have shown excellent utility in several applications, ranging from electrophilic aromatic substitution to formation of α-fluoro-keto species.. Selectfluor,. Selectfluor. II,N-fluorobenzenesulfonimide,. 1-fluoropyridinium. tetrafluoroborate and 2,6-Dichloro-1-fluoropyridinium tetrafluoroborate are the most commonly used. fluorinating agents. Among these electrophilic fluorinating agents,. Selectfluor is a well known, stable, non-volatile, user-friendly reagent, used widely in one-step reactions to introduce fluorine into organic compounds electrophilically.6. Figure I.A.2.1. Common electrophilic fluorinating agents. 2.

(27) I.A.3. Electrophilic fluorination reactions In 2012, Zhang et al. developed a catalyst-free and highly selective electrophilic monofluorination of acetoacetamides. A series of α-mono-fluorinated acetoacetamides were synthesized under mild condition with industrialized Selectfluor as the F+ source in PEG-400. This approach avoided the use of base or metal catalyst, and most of cases proceeded in nearly quantitative conversions regardless of the electronic nature of the diversity substituent.7. Scheme I.A.3.1 In 2014, You and co-workers developed a highly efficient cyclization/fluorination reaction of 2-alkynylanilines with electrophilic fluorinating reagents in a single operation by employing inexpensive and air-stable silver salts as the catalyst. The current protocol conveniently affords structurally diverse fluorinated indole derivatives including 3-fluoroindoles, 3,3-difluoro-3Hindoles, 2-hydroxy-3,3-difluoroindolines and 2-alkoxy-3,3-difluoroindolines.8. Scheme I.A.3.2. I.A.4. Recent advances in Selectfluor mediated fluorination reactions In 2015, Sun and co-workers developed an efficient protocol to access 3-fluoro-2-hydroxy-2substituted benzo[b]furans with Selectfluor as the fluorinating reagent in MeCN and water. By utilizing SOCl2/Py as the dehydrating agent, the compounds prepared were readily converted to 3-fluorinated, 2-substituted benzo[b]furans in high yields.9. 3.

(28) Scheme I.A.4.1 In 2015, Cai and co-workers developed an operationally simple and selective method for the direct conversion of benzylic C–H to C–F to obtain mono- and difluoro-methylated arenes using Selectfluor as a fluorine source. In this protocol Persulfate can be used to selectively activate benzylic hydrogen atoms toward C–F bond formation without the aid of transition metal catalysts.10. Scheme I.A.4.2 In 2013, Zhang and co-workers reported a novel one-pot fluorination and asymmetric Michael addition reaction sequence promoted by recyclable fluorous bi-functional cinchona alkaloid– thioureaorganocatalysts for the synthesis of α-fluoro-β-ketoesters bearing two chiral centers. The new bi-functional cinchona alkaloid-thioureaorganocatalysts can be readily applied to other asymmetric transformations such a Henry, Friedel–Crafts,Diels–Alderand Morita– Baylis–Hillman reactions.11. Scheme I.A.4.3. 4.

(29) In 2014, Yang and co-workers developed a metal-free, efficient acylfluorination method to access α-fluoroketones. Inexpensive and easily available unsaturated olefins, wide functionalgroup tolerance, and atom economical conditions are key features of this reaction. Moveover, this method produced not only important building blocks of ketones but also a wide range of applications in medicinal and agrochemical research of the Csp3−F bond that will be applied to other organic syntheses.12. Scheme I.A.4.4 In 2013, Lectka and co-workers developed a mild, one-pot synthesis of mono-fluorinated benzylic substrates with commercially available iron (II) acetylacetonate and Selectfluor in good to excellent yields and selectivity. A convenient route to β-fluorinated products of 3-aryl ketones is also highlighted, providing a synthetic equivalent to the difficult to accomplish conjugate addition of fluoride to β-unsaturated ketones.13. Scheme I.A.4.5. I.A.5.Selectfluor mediated decarboxylative fluorination reactions In 2012, Li and co-workers reported an efficient method for decarboxylative fluorination of various aliphatic carboxylic acids. Various aliphatic carboxylic acids underwent efficient decarboxylative fluorination with Selectfluor/ AgNO3 reagent system in aqueous solution, leading to the synthesis of the corresponding alkylfluorides in satisfactory yields. This radical fluorination method is not only efficient and general but also chemo-selective and functionalgroup-compatible, thus making it highly practical in the synthesis of fluorinated molecules.14 5.

(30) Scheme I.A.5.1 In 2014, Duan and co-workers reported a mild catalytic decarboxylativeacylfluorination of styrenes with α-oxocarboxylic acids and Selectfluor. This operationally simple and efficient method provides a fundamentally novel approach towards the synthesis of β-fluorinated 3-aryl ketones with a wide range of substrate scope. This method provides ready access to benzylic fluorides with high selectivities through tandem C–C and C–F bond formation in one step.15. Scheme I.A.5.2 In 2013, Gouverneur and co workers reported a catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethylarenes. The treatment of readily available α, α-difluoro and α-fluoroaryl acetic acids with Selectfluor under Ag (I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy.16. Scheme I.A.5.3 In 2015, Flower and co-workers reported a silver-catalyzed fluorination of aliphatic carboxylic acids by Selectfluor in acetone/water system which provides access to fluorinated compounds 6.

(31) under mild and straight forward reaction conditions. Although this reaction provides efficient access to fluorinated alkanes from a pool of starting materials that are ubiquitous in nature, little is known about the details of the reaction mechanism. They reported spectroscopic and kinetic studies on the role of the individual reaction components in decarboxylative fluorination. The studies presented here provide evidence that Ag (II) is the intermediate oxidant in the reaction. In the rate-limiting step of the reaction, Ag (I)-carboxylate is oxidized to Ag (II) by Selectfluor. Substrate inhibition of the process occurs through the formation of a silver-carboxylate. Water is critical for solubilizing reaction components and ligates to Ag (I) under the reaction conditions. The use of donor ligands on Ag (I) provides evidence ofoxidation to Ag (II) by Selectfluor. 17. Scheme I.A.5.4. I.A.6. Selectfluor as oxidizing agent In 2013, Zhang and co-workers reported an unprecedented oxidant-mediated reductive amination of tertiary anilines and aldehydes without external reducing agents via the nucleophilic attack of the oxygen atom of the carbonyl group to in situ generated iminium ions, in which tertiary anilines were used as both nitrogen source and reducing agent. For the first time a novel oxidant-mediated direct reductive amination of tertiary anilines and aldehydes was reported, in which simple N,N-dialkylanilides acted as both nitrogen sources and reducing agents. The nucleophilic addition of carbonyl group to the in situ generated iminium ion intermediate was realized for the first time, which initiated the next intramolecular sequential amination and reduction. This protocol might open a new window for the construction of C–N bonds through reductive amination. 18. Scheme I.A.6.1. 7.

(32) In 2015, Su and co-workers reported an effective copper-catalyzed esterification of unactivated (non-benzylic and allylic) C(sp3)–H bonds of hydrocarbons with Selectfluor as an oxidant. This reaction could provide a direct, new and useful strategy for the synthesis of esters and alkyl alcohols by ester hydrolysis.19. Scheme I.A.6.2. I.A.7. Selectfluor- a reagent for Cyclization In 2012, Zhang et al. developed a novel Selectfluor-mediated copper-catalyzed highly selective benzylic C-O cyclization for the synthesis 4H-3,1-benzoxazines. The predominant selectivity for a benzylic C(sp3)-H over an aromatic C(sp2)-H bond in N-o-tolylbenzamides was achieved by using this protocol. 20. Scheme I.A.7.1 In 2013, Michelet and co-workers developed an unprecedented gold-catalyzed amino fluorination of unprotected 2-alkynylanilines. This is an alternative approach to 3,3difluoroindole derivatives with better flexibility over the previously described procedures. This two-step, one-pot gold (III)-catalyzed cyclization/electrophilic fluorination was achieved in green ethanol and allowed the synthesis of 3,3-difluoro-2-substituted-3H-indoles in good yield under mild conditions. Extension of the procedure to the synthesis of 2-aryl-3-fluoro-1Hindoles was also explored. This methodology is simple to perform and requires use of neither bases, acids, nor N-protective groups.21 8.

(33) Scheme I.A.7.2 In 2014, Ryu and co-workers developed a protocol for the synthesis of fluorinated isoxazoles via catalytic intramolecular cyclizations of 2-alkynone o-methyl oximes and ensuing fluorination. The reactions proceed smoothly at room temperature in the presence of 5 mol % of (IPr)AuCl, 5 mol % of AgOTs, 2.5 equiv of Selectfluor and 2 equiv of NaHCO3. This process features an efficient one-pot cascade route to fluoroisoxazoles with high yields and high selectivity under mild reaction conditions. This is the first report of construction of fluoro-isoxazoles using one-pot gold (I)-catalyzed tandem cyclization−fluorination. This methodology may be useful in medicinal chemistry, and its application to the synthesis of bioactive fluorinated isoxazoles.22. Scheme I.A.7.3 In 2014, Xu and co-workers reported a Cu (0)/Selectfluor system-mediated oxidative cyclization of 1,5-enynes with concomitant C−C bond cleavage to access 3-formyl-1-indenone derivatives. Preliminary mechanistic investigations disclosed that the C−C bond cleavage involved novel water-participated oxygen-insertion β-carbon elimination through double oxycuprations. The present procedure enabled simultaneous formation of one C−C, one C−F, and two C-O bonds as well as cleavage of one C−C bond merely in a single synthetic step by a single copper catalyst. This is the first example of water-participated oxygen-insertion βcarbon elimination and the oxidative cleavage of a single C−C bond into a C-O and a C−F bond.23 9.

(34) Scheme I.A.7.4 In 2015, Yang and co-workers developed a novel and practical reaction for the direct intramolecular oxidative coupling of butenylatedarenes .With the catalysis of Pd(OAc)2, reactions of various butenylatedarenes and carboxylic acids with Selectfluor reagent in CH3CN solution afforded the corresponding monocarboxylation/cyclization products in good yields under mild conditions. This research demonstrated an economic method with the synthesis of 2-tetralyl carboxylic esters, a valuable class of bioactive compounds.24. Scheme I.A.7.5 In 2015, Liu and co-workers reported a novel and facile method for the mild construction of fluorinated fluorenones from non-aromatic precursors (1,6-enynes) mediated by a Cu(0)/Selectfluor system. Preliminary mechanistic investigations indicate that the reaction may proceed via an unprecedented annulation/C−C single bond cleavage/fluorination sequence. The present method for the synthesis of fluoroarenes features (1) the use of nonaromatic precursors, (2) mild reaction conditions, and (3) the use of inexpensive copper species as the catalyst. Furthermore, the resulting fluorinated arenes containing both fluorenone and fluorinated aryl moieties potentially may have biological and pharmaceutical activities as well as optical and electronic properties. 25. 10.

(35) Scheme I.A.7.6. I.A.8.An Introduction to Cyclohexene-Fused Isoxazoline N-Oxides In 2011, M. J. Raihan et al, developed a HTIB mediated oxidative N-O coupling strategy for the synthesis of some isoxazoline N-oxide derivatives from β-hydroxyketoximes. This protocol describes a novel route to the synthesis of isoxazoline N-oxides via oxidative intramolecular N-O coupling and verified that this methodology is also applicable to the synthesis of benzoisoxazole N-oxide derivatives. This is the first report of an “on water” protocol for the synthesis of the five-membered cyclic nitronates. This protocol is mild and efficient, and the substrates are easily accessible. In most cases, the product is insoluble in both water and methanol and hence is precipitated at the bottom of the reaction vessel. A simple filtration is sufficient to isolate the pure product in such cases. A plausible mechanism for the oxidative N-O coupling, which is supported by experimental evidence aswell as literature reports, is also described.26. Scheme I.A.8.1. Figure I.A.6.1 Structure of Hydroxy(tosyloxy)iodobenzene (HTIB), Koser's Reagent. In 2012, M. J. Raihan et al, developed a protocol for the N-bromosuccinimide (NBS) and trichloroisocyanuric acid (TCCA) mediated cleavage of the C-C bond of isoxazolineN-oxides,. 11.

(36) fused with a cyclohexene ring, leading to the production of a long-chain diketo-halo-nitrile skeleton. This conversion occurs via the formation of a nitric oxide intermediate.27. Scheme I.A.8.2 In 2013, M. J. Raihan et al, developed a protocol for the N–bromosuccinimide (NBS)- and trichloroisocyanuricacid. (TCCA)-. mediated. synthesis. of. novel. 2-halomethylene-3-. oxoketoximes via one- pot halogenation/oxidation of isoxazoline N-oxide derivatives. The keto functionality of 3-ketoximes was selectively reduced by lithiumaluminum hydride to synthesize an unprecedented type of Baylis− Hillman oxime, which underwent N−O coupling to produce new isoxazoline N-oxide derivative.28. Scheme I.A.8.3. I.A.9. References 1. (a) Ilardi, E. A.; Vitaku, E.; Njardarson , J. T. J.Med.Chem. 2014, 57, 2832. (b) Njar, V.C. O.; Brodie, A. M. H. J.Med.Chem. 2015, 58, 2077 2. (a) Smith, B. R.; Eastman, C. M.; Njardarson, J. T. J. Med. Chem. 2014, 57 9764. (b) Gharbia, M. A.; Childers, W. E. J. Med. Chem. 2014, 57, 5525. 3. (a) Gharbia, M. A. ; Childers, W. E. J. Med. Chem. 2013, 56, 5659. (b) Zhou, H.; Chen, J.; Meagher, J. L.; Yang, C.-Y.; Aguilar, A.; Liu, L.; Bai, L.; Cong, X.; Cai, Q.; Fang, X.; Stuckey, J. A.; Wang S. J. Med. Chem., 2012, 55, 5987. (c) Cong, X.; Cai, Q.; Fang, X.; 12.

(37) Stuckey, J. A.; Wang, S. X.; Cai, Q.; Fang, X.; Stuckey, J. A.; Wang S. J. Med. Chem. 2012, 55, 4664. (d) Noel, A.; Powell J. Med. Chem. 2007, 50, 1720. 4. (a) Branch , S. K.; Agranat, I. J. Med. Chem. 2014, 57, 8729. (b) Gharbia, M.A.; Childers, W. E. J. Med. Chem. 2014, 57, 5525. (c) Bruns, R. F.; Watson, I. A. J. Med. Chem. 2012, 55, 9763. 5. (a) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T.; J.Med.Chem. 2014, 57, 2832. (b) Gharbia, M.A.; Childers, W. E. J. Med. Chem. 2014, 57, 5525. 6. (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. H. Angew.Chem. Int. Ed. 2005, 44, 192. (b) Khazaei, A.; Rahmati, S.; Nezhad, A. K; Saednia, S. J. Fluorine Chem. 2012, 137, 123. (c) Krow, G. R.; Gandla, D.; Guo,W.; Centafont, R. A.; Lin, G.; Brosse, C. D.; Sonnet, P. E; Ross, C. W.; Ramjit, H. G.; Cannon, K. C. J. Org. Chem. 2008, 73, 2122. 7. Bi, J.; Zhang, Z.; Liu, Q.; Zhang, G. Green Chem.2012, 14, 1159. 8. Yang, L.; Ma, Y.; Song, F.; You , J. Chem.commun, 2014, 50, 3024. 9. Wang, M.; Liu, X.; Zhou, L.; Zhu. J. Sun, X. Org.Biomol.Chem. 2015, 13,3190 10. Ma, J.-J.; Yi, W.-B.; Lu, G.-P.; Cai, C. Org.Biomol.Chem. 2015, 13, 2890. 11. Yi, W.-B.; Zhang, Z.; Huang, X.; Tanner, A.; Cai, C.; Zhang, W. RSC.Adv. 2013, 3, 18267. 12. Yang, Q.; Mao, L.-L.; Yang, B.; Yang, S.-D. Org. Lett. 2014, 16, 3460. 13. Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.; Lectka, T. Org. Lett. 2013, 15, 1722. 14. Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134, 10401. 15. Wang, H.; Guo, L.-N.; Duan, X.-H. Chem.Commun. 2014, 50, 7382. 13.

(38) 16. Mizuta, S.; Stenhagen, I. S. R.; Duill, M.O.; Wolstenhulme, J.; Kirjavainen, A. K.; Forsback, S.J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur, V. Org. Lett. 2013, 15, 2648. 17. Patel, N. R.; Flowers, R.A. J. Org. Chem 2015, 80, 5834. 18. Zheng, Y.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. Chem.Commun. 2013, 49, 8866. 19. Zhou, J.; Jin, C.; Li, X.; Su, W. RSC.Adv, 2015, 5, 7232. 20. Li, Y.; Li, Z.; Xiong, T.; Zhang, Q.; Zhang, X. Org. Lett. 2012, 14, 3522. 21. Arcadi, A.; Pietropaolo, E.; Alvino, A.; Michelet, V. Org. Lett. 2013, 15, 2766. 22. Jeong, Y.; Kim, B.-I.; Lee, J. K.; Ryu, J.-S. J. Org. Chem. 2014, 79, 6444. 23. Zhang, J.; Wu, D.; Chen, X.; Liu, Y.; Xu, Z. J. Org. Chem. 2014, 79, 4799. 24. Liu, R.; Lu, Z.-H.; Hu, X.-H.; Li, J.-L.; Yang, X. J.Org. Lett. 2015, 17, 1489. 25. Zhang, J.; Wang, H.; Ren, S.; Zhang, W.; Liu, Y. Org. Lett. 2015, 17, 2920. 26. Raihan, M. J.; Kavala, V.; Habib, P.M.; Guan, Q-Z.; Kuo, C.-W.; Yao, C.-F J. Org. Chem. 2011, 76 , 424. 27. Raihan, M. J.; Kavala, V.; Guan, Q. Z.; Kuo, C.-W.; Kataria, S.; Shishodia, S.; Janreddy, D.; Habib, P. M.; Yao, C.-F. Adv.Synth.Catal. 2012, 354, 2251. 28. Raihan, M. J.; Rajawinslin, R. R.; Kavala,V.; Kuo, C.-W.; Kuo, T.-S.; He, C.-H.; Huang, H. N.; Yao, C.-F. J. Org. Chem. 2013, 78, 8872.. 14.

(39) Part – II, Section-B Selectfluor-mediated fluorination and C–C bond cleavage of cyclohexene-fused isoxazoline N-oxides I.B.1. Introduction The synthesis of fluoro-organic compounds is an important topic in modern pharmaceutical chemistry.1The replacement of hydrogen by small, highly electronegative fluorine atom can greatly change the physical and biological properties of an organic molecule. A variety of methodologies for the synthesis of fluoro-organic compounds have been developed.2 Because of the reactivity and hazards of elemental fluorine and hydrogen fluoride, the task of introducing fluorine into organic molecules is a particular challenge to synthetic chemists.3Undoubtedly, electrophilic fluorination is one of the direct methods for selective introduction of fluorine into organic compounds. C-C bond cleavage reactions are as important as C-C bond formation reactions. In particular, C-C bond cleavage of cyclohexene ring is an efficient tool in the synthesis of many complex organic molecules. Dudley and co-workers established the C-C bond cleavage of cyclohexenone rings via nucleophilic addition.4 Although numerous methods are used for the cleavage of cyclohexene rings,5 the use of electrophilic source in cleavage of cyclohexene ring is not known in literature. Recently, we reported the selective bromination and chlorination of isoxazoline N-oxides by C-C bond cleavage using N-bromosuccinimide (NBS) and trichloroisocyanuric acid (TCCA), respectively.6 However, Selectfluor mediated fluorination and ring cleavage of isoxazolineN-oxides is not reported up till now. Thus, we intended to proceed this reaction by using different fluorinating agents.7 Recently, much attention has been given to the fluoro-nitrogen compounds such as Nfluorobenzenesulfonimide(A),Selectfluor. (B),. Selectfluor. II. (C),. 1-fluoropyridinium. tetrafluoroborate (D), etc. N-fluorobenzenesulfonimide is one of the most common fluorinating agents which is readily available and cost effective.8 On the other hand, the application of Selectfluor is remarkably broad, because it is a stable, nonvolatile, user-friendly reagent, used widely in one-step reactions to introduce fluorine into organic compounds electrophilically.9,10. 15.

(40) Figure I.B.1.1 Fluorinating reagents. I.B.2. Result and discussions The newly reported chemical approach to the synthesis of long chain diketo halo nitrile from cyclohexene fused isoxazoline N-oxide derivatives by C-C bond cleavage encouraged us to apply this electrophilic method for introducing fluorine into a large variety of organic compounds.6 In order to achieve this objective, we used cyclohexene fused isoxazoline Noxide (1a) as model substrate as it is easy to prepare. Firstly, N-fluorobenzenesulfonimide (A) was used as the fluorinating agent and a long chain diketo fluoro nitrile was formed from isoxazoline N-oxide for 30 hours of reaction, but the product yield was only 46 % (Table 1 entry 1). In order to increase the product yield as well as to decrease the reaction time, we tested the reaction with various other fluorinating reagents such as Selectfluor (B), Selectfluor II (C), and 1-fluoropyridinium tetrafluoroborate (D) (Table 1, entries 12 and 13). Interestingly, when Selectfluor (B) was used as the fluorinating agent, the starting material was completely consumed in 5 minutes and the desired product 1awas formed in excellent yield (99%) at room temperature (Table 1, entry 11). The structure of the product was confirmed by 1H NMR, 13C NMR,19F NMR, LRMS, HRMS and Single crystal X-ray analysis (Figure I.B.2.1).. Figure I.B.2.1 Crystal structure of compound 1a12 16.

(41) Table I.B.2.1.Optimization of the reaction with various solvents and reagents. entrya 1. reagent N-Fluorobenzene. solvent. time. yield (%)b. CH3CN. 30 h. 46. sulfonimide (A) 2. Selectfluor (B). CH2Cl2. 96 h. 53. 3. Selectfluor (B). THF. 96 h. 44. 4. Selectfluor (B). MeOH. 96 h. 16. 5. Selectfluor (B). H2O. 96 h. 27. 6. Selectfluor (B). Toluene. 96 h. 30. 7. Selectfluor (B). DMSO. 96 h. 14. 8. Selectfluor (B). CHCl3. 96 h. 17. 9. Selectfluor (B). Dioxane. 96 h. 18. 10. Selectfluor (B). DMF. 30 min. 66. 11. Selectfluor (B). CH3CN. 5 min. 99. 12. Selectfluor II (C). CH3CN. 2h. 84. 13. 1-Fluoropyridinium. CH3CN. 96 h. No reaction. tetrafluoroborate(D) a. All the reactions were performed on 0.5mmol scale by using 1.1 equiv of reagent.bNMR. yields (CH2Br2 as internal standard).. 17.

(42) With this preliminary observation in hand, we conducted this reaction in various solvents as shown in Table 1. While using acetonitrile as solvent at room temperature, the reaction proceeded fast and the desired product 1awas formed in excellent yields. With other solvents, the reaction time was longer and the yields were less. Thus, we selected acetonitrile as a suitable solvent for this reaction (Table 1, entry 11). Selectfluor (B) is F+ active fluorinating agent. In acetonitrile, it releases F+ ion which aids for fluorination and C–C bond cleavage. We assume, in this reaction a fluorocarbocationic intermediate (I) was generated upon the electrophillic addition of selectfluor to the cyclohexene ring.11 It leads to loss of proton(Ha) to produce the nitric oxide intermediate (II) in the presence of base that was formed from the selectfluor. This intermediate (II) was isolated and confirmed by 1H NMR and 13C NMR spectra. The intermediate (II) undergoes1,4 addition of water to afford Eschenmoser-Tanabe type of intermediate (III) and the final product (10a) was formed via C-C cleavage of the resulting cyclohexane ring.. Scheme I.B.2.1. Plausible mechanism for the Selectfluor mediated fluorination and ring cleavage of cyclohexene fused isoxazoline N-oxide. 18.

(43) Table I.B.2.2.Selectfluor mediatedfluorinationand ring cleavage of sterically hindered isoxazoline N-oxides. a. All the reactions were performed on 0.5mmol scale by using 1.1 equiv of reagent.bIsolated. yields. 19.

(44) After the optimization of reaction condition, we aimed to explore the scope of our methodology. We primarily focused on the study of the effects of steric and electronic factors of the phenyl substituent towards Selectfluor mediated ring cleavage. Accordingly, the isoxazoline N-oxide derivative containing aphenyl ring with o-substitution was first examined; the treatment of Selectflour with o-derivative produced the desired product in excellent yield (Table 2, entry 1). In the same way, the product yields were significantly high in case of 2nitro-5-fluoro, 2-chloro, 2-bromo and 2,4-dichloro derivatives (Table 2, entries 2, 4, 5 and 6). Furthermore, 2-fluoro and 2-nitro- 4, 5-dimethoxy derivatives conferred moderate to good yields of the desired product (Table 2, entries 3 and 7).. Subsequently, we tested a number of m- and p-substituted, un-substituted phenyl derivatives with Selectfluor at room temperature (Table 3 When isoxazoline N-oxide with p-NO2 substitution at the phenyl ring (10) treated with Selectfluor, nitric oxide intermediate (II) was formed immediately. This intermediate was isolated as green solid and confirmed by 1H NMR and. 13. C NMR spectra. The 1H NMR spectra showed a doublet of tripletat 5.97 ppm with J. values of 46.4, 4.9 Hz. This doublet of tripletis due to the Hb proton of the intermediate.. Figure I.B.2.2 .The doublet of tripletof Hb proton of the nitroso intermediate. This intermediate was stable at room temperature and produced its corresponding ring cleaved product (10a) little longer time compared to other substrates. Hence, 1H NMR experiments 20.

(45) were done to observe the product formation from the intermediate. After isolation by column chromatography, the intermediate was placed in NMR tube with CDCl3 and continuously observed the spectra with an interval of one hour. The half life for the conversion of intermediate into product was found to be 6 hours and 35 minutes at room temperature (Supporting information). But at 50oC, the intermediate was converted into product in 30 minutes. In order to confirm the rapid formation of intermediate (II), anotherexperiment was conducted in CD3CN. The substrate and reagent were placed in a NMR tube and observed the 1. H NMR spectra in every 2 minutes. From this experiment it is confirmed that the formation of. intermediate is very fast (5 min.) in CD3CN.. Figure I.B.2.3.1H NMR experiments for half-life study. 21.

(46) Table I.B.2.3..Selectfluor mediated. fluorinationand. ring cleavage of isoxazoline N-oxides with m-. or p-substituted and un-substituted phenyl ring. a. All the reactions were performed on 0.5 mmol scale by using 1.1 equiv of reagent. bIsolated. yields. 22.

(47) While m-substituted substrates such as 3-bromo and 3-nitro isoxazoline N-oxides were tested, the yield was excellent for the former one (Table 3, entry 1) and moderate for the later one (Table 3, entry 2). Subsequently, the p-substituted substrates (4-nitro and 4-cyano isoxazoline N-oxides) furnished only moderate yields (Table 3, entries 3 and 4). Next, our study focused on the synthesis of isoxazoline N-oxides with electron donating groups (methyl and methoxy), which are unreported perhaps due to the setback in preparation and isolation. Interestingly, we successfully synthesized 4-methyl and 4-methoxy isoxazoline N-oxides. When these substrates were then treated with Selectfluor, the desired product was formed in moderate to good yields(Table 3, entries 5 and 6). Finally, the un-substituted isoxazoline N-oxide was experimented and the yield was moderate (Table 3, entry 7).. Scheme I.B.2.2.Selectfluor mediated fluorination and. ring cleavage of 4,4-dimethyl. cyclohexene derivative This methodology was applied to test the effect of Selectfluor treatment in isoxazoline Noxides having substitution on cyclohexene ring. When 4,4-dimethyl cyclohexene derivative of isoxazoline N-oxide was treated with Selectfluor, the desired product was formed in moderate yield (Scheme I.B.2.2.). To implement the utility of long chain fluoro compounds, we synthesized quinoxaline derivatives from 1a (Scheme 3). Quinoxaline derivatives are pharmacologically active compounds with a broad spectrum of biological activity. With this application in hand, we speculate that long chain fluoro compounds are an essential resource for the synthesis of large number of clinically effective compounds. Moreover, due to the presence of different functional groups (fluoro, nitro, cyano and carbonyl), our products (1a-15a) could be structurally modified into valuable compounds. In this way, it would be useful for the development of new therapeutic agents in future.. 23.

(48) Scheme I.B.2.3.. Synthetic applications of our methodology. I.B.3. Conclusion In conclusion, we have extended our concept of fluorination followed by ring cleavage in cyclohexene fused isoxazoline N-oxide derivatives via the formation of nitric oxide intermediate. The scope of this transformation is broad and we have demonstrated the effect of fluorination and ring cleavage in substrates having both electron-donating and electronwithdrawing groups on phenyl and cyclohexene ring. Our future work will focus on expanding different reagents and conditions for effective halogenation and ring cleavage in cyclohexene fused isoxazoline N-oxides.. I.B.4. Experimental section Reagents and solvents were purchased from various commercial sources and used directly without any further purification unless otherwise stated. Column chromatography was performed on 63-200 mesh silica gel. 1H,proton decoupled 19F NMR and. 13. C NMR spectra. were recorded at 400 and 100 MHz, respectively. Chemical shifts are reported in parts per million (δ) using CDCl3 as an internal standard and coupling constants are expressed in hertz. IR spectra were recorded on an FT-IR spectrometer and are reported in cm-1. Melting points were recorded using an Electro Thermal capillary melting point apparatus and are uncorrected. 24.

(49) I.B.4.1.Procedure for Selectfluor mediated fluorination and ring cleavage of isoxazoline N-oxides (for 1a, 2a and 7a) Selectfluor (0.55mmol) was added to a stirred solution of isoxazoline N-oxide derivative (0.5 mmol) in acetonitrile (2 mL) at room temperature. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was added to 15 mL of brine solution and the organic layer was extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over magnesium sulfate and filtered. The solvent was evaporated at reduced pressure. The resulting residue was further purified by column chromatography. I.B.4.2.Procedure for Selectfluor mediated fluorination and ring cleavage of isoxazoline N-oxides (for 3a-6a and 8a-15a) Selectfluor (0.55mmol) was added to a stirred solution of isoxazoline N-oxide derivative (0.5 mmol) in acetonitrile (2 mL) at room temperature. The reaction was monitored by TLC. After the formation of intermediate, the reaction mixture was added to 15 mL of brine solution and the organic layer was extracted with chloroform (15 mL × 3). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was heated to 50°C for 30 minutes. The solvent was evaporated at reduced pressure. The resulting residue was further purified by column chromatography. I.B.4.3.Preparation of 5-fluoro-5-(3-(2-nitrophenyl) quinoxalin-2-yl) pentanenitrile (16a) To a stirred solution of 1a (0.5 mmol) in methanol (2 mL) in a 25 mL round bottom flask, was added o-phenylenediamine at room temperature. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was added to 15 mL of water and the organic layer was extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over magnesium sulfate and the solvent was evaporated at reduced pressure. The resulting residue was further purified by column chromatography. I.B.4.4.Preparation. of. 5-fluoro-5-(6-fluoro-3-(2-nitrophenyl). quinoxalin-2-. yl)pentanenitrile (17a) To a stirred solution of 1a (0.5 mmol) in methanol (2 mL) in a 25 mL round bottom flask, was added 4-fluorobenzene-1,2-diamine at room temperature. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was added to 15 mL of water and the 25.

(50) organic layer was extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over magnesium sulfate and the solvent was evaporated at reduced pressure. The resulting residue was further purified by column chromatography. I.B.4.5. Spectral data of compounds. 5-fluoro-7-(2-nitrophenyl)-6,7 dioxoheptanenitrile (1a) Yellow solid; mp 82-84°C, IR [KBr, cm-1] 2940, 2249, 1738, 1710, 1529; 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.1 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 5.78 (ddd, J = 48.6, 8.4, 3.5 Hz, 1H), 2.49 – 2.43 (m, 2H), 2.40 – 2.27 (m, 1H), 2.22 – 2.07 (m, 1H), 2.02 – 1.91 (m, 2H); 13C NMR (100 MHz, CDCl3); δ192.1 (d, J = 19.0 Hz), 188.2, 147.3, 135.4, 133.2, 131.3, 130.6, 124.4, 119.1, 91.4 (d, J = 185.0 Hz), 30.5 (d, J = 21.0 Hz), 21.3 (d, J = 3.0 Hz), 17.1; 19. F NMR (376 MHz, CDCl3) δ -200.29 (s, 1F); MS m/z (relative intensity): 301 (100), 296. (10), 182 (23); HRMS (ESI) calcd for C13H11N2O4FNa ([M+Na]+): 301.0601, found 301.0601. 5-fluoro-7-(5-fluoro-2-nitrophenyl)-6,7-dioxoheptanenitrile(2a) Yellow solid; mp 67-69°C, IR [KBr, cm-1] 2946, 2250, 1722, 1619, 1588; 1H NMR (400 MHz, CDCl3): δ 8.26 (dd, J = 9.1, 4.5 Hz, 1H), 7.41 (ddd, J = 9.7, 7.2, 2.7 Hz, 1H), 7.27 (dd, J = 7.2, 2.5 Hz, 1H), 5.74 (ddd, J =48.4, 8.5, 3.5 Hz,1H), 2.50 – 2.44 (m, 2H), 2.38– 2.24 (m, 1H), 2.18 – 2.07(m,1H), 1.99 – 1.90 (m, 2H);. 13. C NMR (100 MHz, CDCl3); δ191.7 (d, J = 19.0 Hz), 186.4, 166.1 (d, J =. 261.0 Hz), 143.2, 134.4 (d, J = 8.0 Hz), 127.5 (d, J =10.0 Hz), 119.8 (d, J =23.0 Hz), 119.1, 117.9 (d, J = 26.0 Hz), 91.4 (d, J = 185.0 Hz), 30.4 (d, J = 21.0 Hz),21.2 (d, J = 3.0 Hz), 16.9; 19. F NMR (376 MHz, CDCl3) δ -99.70 (s, 1F), -200.28 (s, 1F); MS m/z (relative intensity): 319. (100), 314 (10), 288 (3); HRMS (ESI) calcd for C13H10N2O4F2Na ([M+Na]+): 319.0506, found 319.0500.. 26.

(51) 5-fluoro-7-(2-fluorophenyl)-6,7-dioxoheptanenitrile (3a) Yellow liquid; IR [KBr, cm-1] 2947, 2248, 1735, 1678, 1610; 1H NMR (400 MHz, CDCl3): δ 7.94 – 7.92 (m, 1H), 7.70 – 7.65 (m, 1H), 7.36-7.32 (m, 1H), 7.18 (dd, J =10.3, 8.6 Hz, 1H), 5.49 (ddd, J = 48.1, 7.8, 4.2 Hz, 1H), 2.49– 2.45 (m, 2H), 2.29 – 2.14 (m, 2H), 2.02 – 1.89 (m, 2H); 13C NMR (100 MHz, CDCl3); δ 198.7 (d, J = 32.0 Hz), 190.9, 163.1 (d, J = 254.0 Hz), 137.5 (d, J = 9.0 Hz), 130.3 (d, J = 1.0 Hz), 125.3 (d, J = 4.0 Hz), 121.1 (d, J = 11.0 Hz), 119.0, 116.6 (d, J = 21.0 Hz), 93.2 (dd, J = 2.0, 180.0 Hz), 30.4 (d, J = 20.0 Hz), 20.9 (d, J = 3.0 Hz), 16.8; 19F NMR (376 MHz, CDCl3) δ 110.20 (d, J = 0,1F), -199.56 (d, J = 3.7Hz,1F); MS m/z (relative intensity): 274 (100), 252 (3); HRMS (ESI) calcd for C13H11NO2F2Na ([M+Na]+): 274.0656, found 274.0653. 7-(2-chlorophenyl)-5-fluoro-6,7-dioxoheptanenitrile (4a) Yellow liquid; IR [KBr, cm-1] 2929, 2249, 1953, 1730, 1692, 1588; 1H NMR (400 MHz, CDCl3): δ 7.80 (dd, J = 7.6, 1.4 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.46 – 7.41 (m, 2H), 5.55 (ddd, J = 48.2, 8.4, 3.8 Hz, 1H), 2.48 (t, J = 7.0 Hz, 2H), 2.33 – 2.17 (m, 2H), 2.03 – 1.90 (m, 2H); 13C NMR (100 MHz, CDCl3);δ197.5(d, J = 29.0Hz), 192.6, 135.3, 134.4, 132.5, 131.9, 130.7, 127.7, 119.0, 93.1 (d, J = 182.0Hz), 31.1(d, J = 21.0 Hz), 21.3(d, J = 3.0 Hz), 17.1; 19F NMR (376 MHz, CDCl3) δ -198.30 (s, 1F);MS m/z (relative intensity): 290 (100), 274 (43), 257 (17), 240 (30), 234 (3); HRMS (ESI) calcd for C13H11NO2FNaCl ([M+Na]+): 290.0360, found 290.0354. 7-(2-bromophenyl)-5-fluoro-6,7-dioxoheptanenitrile (5a) Brown liquid; IR [KBr, cm-1] 2948, 2248, 1727, 1693, 1585; 1H NMR (400 MHz, CDCl3): δ 7.71 – 7.70 (m, 1H), 7.66 – 7.63 (m, 1H), 7.50 – 7.47 (m, 2H), 5.58 (ddd, J = 48.2, 8.5, 3.8 Hz, 1H), 2.49 (t, J = 7.1 Hz, 2H), 2.30 – 2.19 (m, 2H), 2.03 – 1.93 (m, 2H);. 13. C NMR (100 MHz, CDCl3); δ.196.7(d, J = 27.0 Hz), 192.9,. 135.0, 134.7, 133.9, 132.3, 128.2, 122.3, 119.0, 93.0(d, J = 183.0 Hz), 31.3 (d, J = 21.0 Hz), 21.4 (d, J = 3.0 Hz), 17.1; 19F NMR (376 MHz, CDCl3) δ -197.72 (s, 1F); MS m/z (relative 27.

(52) intensity): 333 (70), 329 (3), 240 (3), 200 (3); HRMS (ESI) calcd for C 13H11NO2NaBrF ([M+Na]+): 333.9855, found 333.9846. 7-(2,4-dichlorophenyl)-5-fluoro-6,7-dioxoheptanenitrile(6a) Yellow liquid; IR [KBr, cm-1] 2954, 2249, 1729, 1681, 1582; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.4Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.4, 1.7 Hz, 1H), 5.53 (ddd, J = 48.2, 8.5, 3.9 Hz, 1H), 2.48 (t, J = 7.1 Hz, 2H), 2.31 – 2.15 (m, 2H), 2.02 – 1.89 (m, 2H); 13C NMR (100 MHz, CDCl3); δ197.2 (d, J = 30.0 Hz), 191.6, 141.5, 135.3, 132.9, 130.8( d, J = 15.0 Hz), 128.4, 118.9, 93.0 (d, J = 182.0 Hz), 31.1 (d, J =20.0 Hz),21.3(d, J =3.0 Hz), 17.1; 19F NMR (376 MHz, CDCl3) δ -198.34 (s, 1F); MS m/z (relative intensity): 323 (87), 316 (7), 268 (3), 231 (3); HRMS (ESI) calcd for C13H10NO2FNaCl2 ([M+Na]+): 323.9970, found 323.9968. 7-(4,5-dimethoxy-2-nitrophenyl)-5-fluoro-6,7-dioxoheptanenitrile (7a) Brown liquid; IR [KBr, cm-1] 2944, 2249, 1737, 1702, 1574; 1H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.01 (s, 1H), 5.72 (ddd, J = 48.4, 8.4, 3.4 Hz, 1H), 4.02 (d, J = 5.3 Hz, 6H), 2.54 – 2.45 (m, 2H), 2.39 – 2.26 (m, 1H), 2.23 – 2.19 (m, 1H), 2.18 – 2.13 (m, 2H);. 13. C NMR (100 MHz,. CDCl3); δ192.6 (d, J = 20.0 Hz), 188.3, 154.7, 151.9, 141.0, 125.1, 119.1, 111.6, 106.9, 91.7 (d, J = 185.0 Hz), 57.1, 57.0, 30.6 (d, J = 21.0 Hz), 21.4 (d, J = 3.0 Hz), 17.1; 19F NMR (376 MHz, CDCl3) δ -199.74 (s, 1F); MS m/z (relative intensity): 361 (100), 339 (3), 240 (3), 182 (3); HRMS (ESI) calcd for C15H15N2O6FNa([M+Na]+): 361.0812, found 361.0807. 7-(3-bromophenyl)-5-fluoro-6,7-dioxoheptanenitrile (8a) Brown liquid; IR [KBr, cm-1] 2944, 2250, 1730, 1683, 1565; 1. H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.89 (d, J =. 7.72 Hz, 1H), 7.82 (dd, J = 8.0, 1.0 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 5.56 (ddd, J = 48.4, 8.2, 4.0 Hz, 1H), 2.47 (t, J = 7.1 Hz, 2H), 2.26– 2.10 (m, 2H), 2.00 – 1.90 (m, 2H);. 13. C. NMR (100 MHz, CDCl3); δ 197.5 (d, J = 27.0 Hz), 189.8, 138.2, 133.4, 132.6, 130.8, 128.7, 28.

(53) 123.4, 118.9, 92,7 (d, J =181.0 Hz), 30.3 (d, J = 21.0 Hz), 20.9 (d, J = 3.0 Hz), 16.9; 19F NMR (376 MHz, CDCl3) δ -198.82 (s, 1F); MS m/z (relative intensity): 312 (50), 311 (27), 235 (20), 218 (47); HRMS (ESI) calcd for C13H12NO2FBr([M+H]+): 312.0035, found 312.0031. 5-fluoro-7-(3-nitrophenyl)-6,7-dioxoheptanenitrile (9a) Yellow liquid; IR [KBr, cm-1] 3091, 2251, 1727, 1695, 1614; 1. H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 8.49 (d, J = 8.1. Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 5.62 (ddd, J = 48.3, 8.4, 3.8 Hz, 1H), 2.48 (t, J = 7.0 Hz, 2H), 2.25– 2.09 (m, 2H), 1.97 – 1.89 (m, 2H); 13C NMR (100 MHz, CDCl3); δ196.7(d, J =26.0 Hz), 188.6, 148.7, 135.5, 133.1, 130.6, 129.3, 124.8, 118.9, 92.6 (d, J = 181.0 Hz), 30.3 (d, J = 21.0 Hz), 21.0 (d, J =3.0 Hz),16.9; 19F NMR (376 MHz, CDCl3) δ 198.81 (s, 1F); MS m/z (relative intensity): 277 (100), 166 (27), 148 (17); HRMS (ESI) calcd for C13H10N2O4F([M-H]-): 277.0625, found 277.0620. 5-fluoro-7-(4-nitrophenyl)-6,7-dioxoheptanenitrile (10a) Yellow solid; mp 74-76°C IR [KBr, cm-1] 2250, 1645, 1526, 1348; 1H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.9 Hz, 2H), 5.61 (ddd, J = 48.4, 8.4, 3.9 Hz, 1H), 2.49 (t, J = 7.0 Hz, 2H), 2.28 – 2.11 (m, 2H), 2.01 – 1.90 (m, 2H); 13C NMR (100 MHz, CDCl3); δ196.9 (d, J = 27.0 Hz), 189.3, 151.6, 136.2, 131.3, 124.4, 118.8, 92.6 (d, J = 181.0 Hz), 30.4 (d, J = 21.0 Hz), 21.1 (d, J = 3.0 Hz),17.1; 19F NMR (376 MHz, CDCl3) δ -198.82 (s, 1F); MS m/z (relative intensity): 277 (100), 244 (13), 194 (7), 166 (23), 148 (100); HRMS (ESI) calcd for C 13H10N2O4F([M-H]-): 277.0625, found 277.0618. 4-(6-cyano-3-fluoro-2-oxohexanoyl)benzonitrile (11a) Yellow liquid; IR [KBr, cm-1] 2942, 2234, 1731, 1691; 1. H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.4 Hz, 2H),. 7.83 (d, J = 8.4 Hz, 2H), 5.58 (ddd, J = 48.4, 8.4, 3.9 Hz, 1H), 2.48 (t, J = 7.0 Hz, 2H), 2.27 – 2.10 (m, 2H), 2.03 – 13. 1.90 (m, 2H); C NMR (100 MHz, CDCl3); δ197.0(d, J = 27.0 Hz), 189.6, 134.8, 133.0, 130.5, 29.

(54) 118.8, 118.6, 117.6, 92.6 (d, J =181.0 Hz), 30.4 (d, J = 21.0 Hz), 21.1 (d, J = 3.0 Hz), 17.1; 19F NMR (376 MHz, CDCl3) δ -198.85 (s, 1F); MS m/z (relative intensity): 257 (100), 237 (3), 211 (7), 178 (7); HRMS (ESI) calcd for C14H10N2O2F([M-H]-): 257.0726, found 257.0732. 5-fluoro-6,7-dioxo-7-p-tolylheptanenitrile (12a) Yellow liquid; IR [KBr, cm-1] 2927, 2428, 1729, 1669,1H NMR (400 MHz, CDCl3):δ7.86 (d, J = 8.2Hz, 2H), 7.33(d, J = 8.0Hz, 2H), 5.55(ddd, J = 48.6, 8.2, 4.0 Hz, 1H), 2.47 2.44 (m, 5H), 2.24- 2.09 (m, 2H);. 13. C NMR (100 MHz,. CDCl3); δ198.7 (d, J = 27.0 Hz), 191.3, 147.1, 130.3, 130.1, 129.5, 118.5, 92.9 (d, J = 182.0 Hz), 30.5 (d, J = 21.0 Hz), 22.2, 21.2 (d, J = 3.0 Hz), 17.1;19F NMR (376 MHz, CDCl3) δ 198.95 (s, 1F); MS m/z (relative intensity): 246 (100), 245 (7), 199 (17), 195 (3); HRMS (ESI) calcd for C14H13NO2F([M-H]-): 246.0930, found 246.0936. 5-fluoro-7-(4-methoxyphenyl)-6,7-dioxoheptanenitrile (13a) Yellow liquid;. IR [KBr, cm-1] 2937, 2248, 1727,. 1662, 15971H NMR (400 MHz, CDCl3):δ7.96 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 5.57 (ddd, J = 48.6, 8.1, 3.9 Hz, 1H), 2.45 (t, J = 7.1 Hz, 2H), 2.23 – 13. 2.07(m, 2H),1.96 – 1.88 (m, 2H); C NMR (100 MHz, CDCl3); δ198.7 (d, J = 25.0 Hz), 189.8, 165.7, 132.8, 124.9, 118.9, 114.8, 92.8 (d, J = 182.0 Hz), 55.9, 30.5 (d, J = 20.0 Hz), 21.2 (d, J = 3.0 Hz),17.1; 19F NMR (376 MHz, CDCl3) δ -198.90 (s, 1F); MS m/z (relative intensity): 262 (100), 245 (7), 195 (7), 144 (13); HRMS (ESI) calcd for C14H13NO3F([M-H]-): 262.0879, found 262.0882. 5-fluoro-6,7-dioxo-7-phenylheptanenitrile (14a) Yellow liquid; IR [KBr, cm-1] 2945, 2249, 1730, 1679; 1. H NMR (400 MHz, CDCl3): δ 7.96 (dd, J = 8.2, 1.0 Hz,. 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 5.56 (ddd, J = 48.6, 4.2, 4.0 Hz, 1H), 2.47 (t, J = 7.1 Hz, 2H), 2.26 – 2.10 (m, 2H), 1.98 – 1.90 (m, 2H); 13C NMR (100 MHz, CDCl3); δ198.6 (d, J = 26.0 Hz), 191.7, 135.6, 131.8, 130.1, 129.3, 118.9, 92.9 (d, 30.

(55) J = 181.0 Hz), 30.4 (d, J = 21.0 Hz), 21.1 (d, J = 3.0 Hz),17.0; 19F NMR (376 MHz, CDCl3) δ -198.95 (s, 1F); MS m/z (relative intensity): 234 (70), 230 (3), 185 (2); HRMS (ESI) calcd for C13H13NO2F([M+H]+): 234.0930, found 234.0923. 5-fluoro-4,4-dimethyl-7-(4-nitrophenyl)-6,7-dioxoheptanenitrile (15a) Yellow liquid; IR [KBr, cm-1] 2976, 2251, 1830, 1696; 1. H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 8.8 Hz, 2H),. 8.14 (d, J = 8.8 Hz, 2H), 5.30 (d, J = 47.3 Hz, 1H), 2.47 – 2.42 (m, 2H), 2.01 – 1.94 (m, 1H) , 1.88 – 1.80 (m, 1H), 1.15 (d, J = 3.2 Hz, 6H);13C NMR (100 MHz, CDCl3); δ198.8 (d, J = 30.0 Hz), 189.6, 151.6, 136.0, 131.2, 124.4, 119.7, 97.7 (d, J = 185.0 Hz), 38.4 (d, J = 18.0 Hz), 34.3 (d, J = 3.0 Hz), 23.0 (d, J= 5.0 Hz), 22.6 (d, J= 5.0 Hz), 12.7 (d, J= 3.0 Hz); 19F NMR (376 MHz, CDCl3) δ -200.11 (s, 1F); MS m/z (relative intensity): 305 (53), 281 (17), 233 (3), 208 (3), 199 (6); HRMS (ESI) calcd for C15H14N2O4F([M-H]-): 305.0938, found 305.0940. 5-fluoro-5-(3-(2-nitrophenyl)quinoxalin-2-yl)pentanenitrile (16a) Yellow liquid; IR [KBr, cm-1] 2957, 2247, 1610, 1528, 2348; 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.2 Hz, 1H), 8.21 - 8.18 (m, 1H), 8.07 - 8.04 (m, 1H), 7.85 – 7.78 (m, 3H), 7.69 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 5.58 (ddd, J = 47.8, 8.3, 4.8 Hz, 1H), 2.45 – 2.20 (m, 4H), 1.89 – 1.70 (m, 2H);. 13. C NMR (100. MHz, CDCl3); δ 152.0, 149.8 (d, J = 19.0 Hz), 147.9, 141.4 (d, J = 1.0 Hz), 140.9, 133.9, 133.7, 131.9, 131.3, 130.8, 130.4, 129.6, 129.2, 125.0, 119.3, 91.5 (d, J = 172.0 Hz), 31.8 (d, J = 22.0 Hz), 21.4 (d, J = 5.0 Hz), 17.2; MS m/z (relative intensity):351(100), 331(10), 317(5), 263(5), 235(10); HRMS (ESI) calcd forC19H16N4O2F([M+H]+): 351.1253, found 351.1257. 5-fluoro-5-(6-fluoro-3-(2-nitrophenyl)quinoxalin-2-yl)pentanenitrile (17a) Yellow liquid; IR [KBr, cm-1] 2962, 2247, 1623, 1570; 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 19.2 Hz, 1H), 8.20 – 8.18 (m, 1H), 7.82 (t, J = 3.8 Hz, 1H), 7.80 – 7.66 (m, 2H), 7.64 – 7.26 (m, 2H) , 5.56 (ddd, J = 47.9, 8.2, 4.8 Hz, 1H), 2.45 – 2.21 (m, 4H), 1.91 – 1.70 (m, 2H); 13CNMR (100MHz,CDCl3); δ 164.9, 162.4, 153.0, 149.3 (dd, 31.

(56) J = 3.0, 19.0 Hz), 147.9, 142.3 (d, J= 14.0 Hz), 138.2, 134.0, 133.5, 131.9 (d, J= 10.0 Hz), 130.6, 125.1, 121.4 (d, J= 26.0 Hz), 119.3, 112.9 (d, J =21.0 Hz), 91.4 (d, J = 172.0 Hz), 31.8 (d, J = 22.0 Hz), 21.4 (d, J= 5.0 Hz), 17.2; MS m/z (relative intensity):369(100), 349(25), 337(10), 263(15), 249(20) HRMS (ESI) calcd forC19H15N4O2F2([M+H]+): 369.1161, found 369.1163.. I.B.5. References 1. (a) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (b) Kirk, K. L. Organic Process Research & Development. 2008, 12, 305. (c) Hagan, D. O. J. Fluorine Chem. 2010, 131, 1071. (d) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (e) Filler, R.; Sha, R. Future Med. Chem. 2009, 1, 777. (f) Isanbor, C.; Hagan, D.; J. Fluorine Chem. 2006, 127, 303. (g) Muller, K.; Faeh, C.; Diederich, F. Science, 2007, 317, 1881. 2. (a) Becerril, M. R.; Sazepin, C. C.; Leun, J. C. T; Okbinoglu, T.; Kennepohl, P.; Paquin, J. F.; Sammis, G. M. J. Am. Chem. Soc. 2012, 134, 4026. (b) Kuehnel, M. F.; Lentz, D.; Braun, T. Angew.Chem.Int. Ed. 2013, 52, 3328. (c) Troegel, B.; Lindel, T. Org. Lett. 2012, 14, 468. (d) Barker, T. J.; Boger, D. L J. Am. Chem. Soc 2012, 134, 13588. (e) Tian, T.; Zhong, W.H.; Meng, S.; Meng, B.; Li, J.Z J. Org. Chem. 2013, 78, 728. (f) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Nakamura, S.; Toru, T. J. Fluorine Chem. 2006, 127, 548. 3.(a) Chambers, R. D.; Okazoe, T.; Sandford, G.; Thomas, E.; Trmcic, J. J. Fluorine Chem. 2010, 131, 933. (b) Struble, M. D.; Scerba, M. T.; Siegler, M.; Lectka, T. Science, 2013, 340, 57. (c) Hennecke, U. Science, 2013, 340, 41. (d) Zhang, X.; Liao, Y.; Qian, R.; Wang, H.; Guo, Y. Org. Lett. 2005, 7, 3877. (e) Zhou, C.; Zhichao, M.; Zhenhua, G.; Chunling, F.; Shengming, M. J. Org. Chem. 2008, 73, 772. (f) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 1268. (g) Li, Z.; Song, L.; Li, C. J. Am. Chem.Soc. 2013, 135, 4640.. 32.

(57) 4. (a) Jones, D. M.; Lisboa, M. P.; Kamijo, S.; Dudley, G. B. J. Org. Chem. 2010, 75, 3260. (b) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028. (c) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499. 5. Selected references for cyclohexene ring cleavage (a) Nicolau, K. C.; Ding, H.; Richard, J.A.; Chen, D. Y.-K. J. Am. Chem. Soc. 2010, 132, 3815. (b) Miyamoto, K.; Sei, Y.; Yamaguchi, K.; Ochiai, M. J. Am. Chem. Soc. 2009, 131, 1382. (c) Menger, F. M.; Lu, H.; Chem. Commun. 2006, 3235. d) Ho, C.-M.; Yu, W.-Y.; Che, C.- M. Angew. Chem. Int. Ed. 2004, 43, 3303. (e) Kuhn, F. E.; Fischer, R. W.; Herrmann, W. A.; Weskamp,T. in Transition Metals for OrganicSynthesis, Vol. 2 (Eds: M. Beller, C. Bolm), WILEY-VCH: Weinheim, Germany, 2004, pp. 427-428; (f) Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824. (g) Sato, K.; Aoki, M.; Noyori, R. Science 1998, 281, 1646. 6. (a) Raihan, M. J.; Kavala, V.; Guan, Q. Z.; Kuo, C.-W.; Kataria, S.; Shishodia, S.; Janreddy, D.; Habib, P. M.; Yao, C.-F. Adv.Synth.Catal. 2012, 354, 2251. (b) Raihan, M. J.; Kavala, V.; Habib, P. M.; Guan, Q. Z.; Kuo, C.- W.; Yao, C.- F. J. Org. Chem. 2011, 76, 424. 7. (a) Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Arkhipov, D. E.; Korlyukov, A. Tartakovsky, V. A. J. Org. Chem. 2010, 75, 5367. (b) Junan, M.; Cahard, D. Chem. Rev. 2008, 108, 1. (c)Yasui, H.; Yamamoto, T.; Ishimaru, T.; Fukuzumi, T.; Tokunaga, E.; Akikazu, K.; Shiro, M.; Shibata, N. J. Fluorine Chem. 2011, 132, 222. (d) Lin, R.; Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2011, 13, 4498. 8.(a) Weijun, F.; Zou, G.; Zhu, M.; Hong, D.; Deng, D.; Xun, C.; Baoming, J. J. Fluorine Chem.2009, 130, 996. (b) Verniest, G.; Hende, E. V.; Surmont, R.; Kimpe, N. D. Org. Lett. 2006, 8, 4767. (c) Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W.C. J. Am.. 33.

(58) Chem. Soc. 2011, 133, 1738. (d) Lubin, H.; Dupuis, C.; Pytkowicz, J.; Brigaud, T J. Org. Chem. 2013, 78, 3487. 9. (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. H. Angew.Chem. Int. Ed. 2005, 44, 192. (b) Khazaei, A.; Rahmati, S.; Nezhad, A. K.; Saednia, S. J. Fluorine Chem. 2012, 137, 123. (c) Krow, G. R.; Gandla, D.; Guo, W.; Centafont, R. A.; Lin, G.; Brosse, C. D.; Sonnet, P. E.; Ross, C. W.; Ramjit, H. G.; Cannon, K. C.J. Org. Chem. 2008, 73, 2122. (d) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science, 2011, 334, 1681. 10.(a) Olszewska, K. R.; Palacios, F.; Kafarski, P. J. Org. Chem. 2011, 76, 1170. (b) Xiao, J. C.; Shreeve, J. M. J. Fluorine Chem.2005, 126, 475. (c) Peng, W.; Shreeve, J. M. J. Org. Chem. 2005, 70, 5760. (d) Ye, C.; Twamley, B.; Shreeve, J. M. Org. Lett. 2005, 7, 3961. (e) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133, 5802. 11. Luo, H.-Q.; Loh, T.-P. Tetrahedron Lett. 2009, 50, 1554. 12. CCDC number of 1a is 895146. This data can be obtained free of charge from Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/datarequest/cif.. 34.

(59) Part – I, Section-C Selectfluor mediated one-pot synthesis of cyclohexanone ring fused isoxazole derivatives I.C.1. Introduction Isoxazoles are valuable heterocyclic compounds of natural and synthetic origin with varied applications in industrial and medicinal agents and they have been demonstrated to be very versatile building blocks in organic synthesis.1 Structurally, isoxazole rings are the core component in different drug categories and natural products.2The construction of the isoxazole ring can be achieved by several synthetic approaches,3,4 including the two major routes such as 1,3-dipolar cycloadditon of alkenes and alkynes with nitrile oxides and the reaction of hydroxylamine with a three-carbon atom component, such as 1,3-diketone or an α,βunsaturated ketone. Since, isoxazolederivatives has been a much attentive focus in recent agricultural and medicinal industries, synthesis of these compounds by alternative and optimized routes are required.. The carbon-fluorine bond is the strongest covalent bond in organic chemistry. Selective C-F bond activation and transformation have become an interesting challenge in organic synthesis.5In this context, base mediated C-F bond cleavage is a useful tool for the synthesis of heterocycles which are difficult to obtain through classical methodologies. Recently, we reported the selective fluorination of isoxazoline N-oxides by C–C bond cleavage by using Selectfluor.6This reaction proceeds through nitroso intermediate and produced the corresponding ring-cleaved products in the absence of base. But in the presence of base, the above nitroso intermediate undergoes a simultaneoushydration, defluorination and N-O coupling to form cyclohexanone ring fused isoxazoles (Scheme I.C.1). This rapid, multifaceted reaction without ring cleavage of isoxazoline N-oxides has not been reported till now. Thus, we intended to develop this reaction using different fluorinating agents.. 35.

(60) Scheme I.C.1. Selectfluor and base mediated formation of cyclohexanone ring fused isoxazoles Selectfluor (A), Selectfluor II (B), N-fluorobenzenesulfonimide (C) and 1-fluoropyridinium tetrafluoroborate (D) are among the important N-fluorinated compounds used in electrophilic fluorination (Figure 1). Of these, Selectfluor (A) is a stable, nonvolatile, user-friendly reagent, widely used in one-step fluorination reaction.7Earlier, we have reported the synthesis of longchain halodioxo nitriles from isoxazoline N-oxides via nitroso intermediates by using Selectfluor,6N-bromosuccinimide. (NBS). and. trichloroisocyanuric. acid. (TCCA).8In. continuation of our research work on isoxazoline N-oxides and in order to utilize the nitroso intermediate for its wide application in various fields,we have developed a new route for the synthesis of cyclohexanone ring fused isoxazoles.. Figure I.C.1.Reagents used in this study.. I.C.2. Result and discussions To achieve this objective, we used cyclohexene-fused isoxazoline N-oxide 1 as a model substrate. When Selectfluor (A) was used, the starting material was completely consumed 36.

(61) after 8 min, and the nitroso intermediate was formed, which on treatment with NaHCO 3,a cyclohexanone ring fused isoxazole was formed after 12 h, but the yield of the product was only 22% (Table 1, entry 1). Aiming to increase the yield of the product and also to decrease the reaction time, we tested the reaction with various other inorganic and organic bases, such as K2CO3, pyridine, diethylamine, triethylamine etc (Table 1, entries 2- 4). The reaction with K2CO3 provided 26% of the desired product, while pyridine and diethylamine gave a mixture of products. Interestingly, when triethylamine was used as base, the nitroso intermediate was completely converted into the desired product (i.e., 1a) in good yield (84%) at room temperature (Table 1, entry 5). The structure of the product was confirmed by 1H,. 13. C NMR. spectroscopy, MS, HRMS, and single-crystal X-ray analysis (Figure 2).. Figure I.C.2.1. Crystal structure of compound 1a10 Having achieved this result, we conducted the same reaction in different solvents, as shown in Table 1. Whilst acetonitrile was used as solvent at room temperature, the nitroso intermediate was formed quickly, and the desired product (i.e., 1a) was formed in good yields by the addition of triethylamine. With other solvents, the reaction times were longer, and the yields were lower. The reason might be explained by the assumption that the solubility of selectfluor is higher in acetonitrile than other solvents.Thus, we selected acetonitrile as a suitable solvent for this reaction (Table 1, entry 5).As shown in Table 1, we tested the reaction with various other fluorinating reagents, such as Selectfluor II (B), N-fluorobenzenesulfonimide (C) and 1fluoropyridinium tetrafluoroborate (D) (Table 1, entries 11 - 13). The desired product was formed. in. moderate. yield. for. Selectfluor. II. (B),. and. poor. yield. fluorobenzenesulfonimide (C), however, no reaction was progressed for the latter.. 37. for. N-.

(62) Table I.C.2.1.Optimization of reaction conditions with various solvents, bases and reagents.. Entrya. Reagent. Solvent. Base. Time. Yield (%)b. 1. Selectfluor (A). CH3CN. NaHCO3. 12 h. 22. 2. Selectfluor (A). CH3CN. K2CO3. 4h. 26. 3. Selectfluor (A). CH3CN. Pyridine. 15 min. -c. 4. Selectfluor (A). CH3CN. Et2NH. 20 min. -c. 5. Selectfluor (A). CH3CN. Et3N. 10 min. 84. 6. Selectfluor (A). CHCl3. Et3N. 12 h. 15. 7. Selectfluor (A). THF. Et3N. 2h. 28. 8. Selectfluor (A). CH2Cl2. Et3N. 12 h. 18. 9. Selectfluor (A). MeOH. Et3N. 12 h. 12. 10. Selectfluor (A). H2O. Et3N. 12 h. 10. 11. Selectfluor (B). CH3CN. Et3N. 30 min. 56. 12. N-fluorobenzene. CH3CN. Et3N. 10 h. 38. CH3CN. Et3N. 12 h. no. sulfonimide (C) 13. 1- fluoropyridinium. reaction. terafluoroborate(D) a. All the reactions were performed on 0.5mmol scale by using 1.1 equiv of reagent.bNMR. yields (CH2Br2 as an internal standard).cMixture of products. 38.

(63) A plausible mechanism for the formation of cyclohexanone ring fused isoxazoles is shown in scheme 2. We assume that, in this reaction a fluorocarbocationic intermediate (I) was generated upon the electrophillic addition of Selectfluor to the cyclohexene ring.6,9 It leads to the loss of a proton (Ha) to produce the nitroso intermediate (II) in the presence of base that was formed from the Selectfluor. This intermediate (II) was isolated and confirmed by 1H NMR and. 13. C NMR spectra (see Supporting Information). When triethylamine was added,. intermediate (II) might undergo a rapid multifaceted set of reactions, starting with a baseinduced ketoxime formation, followed by a sequential nucleophilic addition of hydroxide (– OH) / elimination of floride (F-), which afforded intermediate (III), and a subsequent N-O coupling which produced the final product (1a).. Scheme I.C.2.1.Plausible mechanism for the formation of cyclohexanone ring fused isoxazoles. 39.

(64) Table I.C.2.2. Selectfluor and base mediated synthesis of cyclohexanone ring fused isoxazoles from o- or m- or p- and un-sbstituted isoxazoline N-oxides.. 40.

(65) a. All the reactions were performed on 0.5 mmol scale by using 1.1 equiv of reagent. bIsolated. yields. The time mentioned in the parentheses corresponds the time for addition of triethylamine. 41.

(66) Having obtained the optimized conditions, we turned our attention to examine the substrate scope of this method. As shown in Table 2, various p-substituted isoxazoles were successfully synthesized from isoxazoline N-oxides. For the substrates bearing either an electron withdrawing group (nitro, cyano and chloro) or an electron donating group (methyl) on the aromatic ring, the reaction proceeded smoothly and furnished the corresponding isoxazoles in good yields (Table 2, entries 1-4). Subsequently, we tested a number of o- or m-substituted and unsubstituted phenyl derivatives, with the optimized conditions. o-substituted derivatives such as 2-nitro, 2-bromo, 2-fluoro and 2-chloro produced the desired products in moderate to good yields (Table 2, entries 5-8). Similarly, the disubstituted derivatives such as 2,4-dichloro, 2-nitro-5-fluoro, 2-nitro-5-chloro, 2-nitro-5-bromo, 2,5-dimethoxy also gave moderate to good yields of desired products (Table 2, entries 9-13). Finally, the m-substituted derivative (3-nitro) and unsubstituted derivatives were tested and the yield was moderate for the former (entry 14) and good for the latter (entry 15).. Scheme I.C.2.2..Base mediated synthesis of 3-methyl-4-methylene-5-(4-nitrophenyl)-4,5dihydroisoxazol-5-ol. Scheme I.C.2.3.. Plausible reaction pathway for the formation of 16b 42.

(67) Finally,inorder to enhance the substrate scope, we tested the reaction of isoxazoline N-oxide (16) generated from acyclic Baylis-Hillman oxime, in the present reaction conditions. Under these conditions, the reaction provided a different product 16b rather than 16a. On the other hand, the treatment of triethylamine with compound 16 in acetonitrile also produced the same product(Scheme I.C.2.2).The structure of this new product was confirmed by 1H,. 13. C NMR. spectroscopy, MS, HRMS, and single-crystal X-ray analysis (Figure 3).The plausible base mediated reaction pathway for the formation of 16b is described in scheme 4. From these two experiments, it is quite clear that the formation of nitroso intermediate did not occur with Selectfluor in the case of acyclic isoxazoline N-oxide.. Figure I.C.2.2. Crystal structure of compound 16b10. I.C.3. Conclusion In conclusion, we have demonstrated a Selectfluor and base mediated protocol for the synthesis of cyclohexanone ring fused isoxazole derivatives from isoxazoline N-oxides via nitroso intermediates. The scope of this transformation is broad, and we have reported the synthesis of a series of isoxazole derivativesfrom substrates bearing electron-donating or electron-withdrawing groups on the phenyl ring.. I.C.4. Experimental section General Remarks: Reagents and solvents were purchased from commercial suppliers and were used directly without any further purification unless otherwise stated. Column chromatography was performed on 63–200 mesh silica gel. 1H and 13C NMR spectrawere recorded at 400 and 100 MHz, respectively. Chemical shifts are reported in parts per million (ppm) on the δ scale. 43.