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From C-O to C-C Through Nickel Coupling

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From C-O to C-C Through Nickel Coupling From C–O to C–C through Nickel Coupling MeO2C CO2Me >99% yield Ph O Homocoupling R = S O OMOM OMe 80% yield Suzuki- Kumada 95% yield O Miyaura O R = RO R = S NEt2 NEt2 R' O O O R = R = P (OEt) Suzuki- Kumada 2 Miyaura n-octyl Kumada R = Me 92% yield NOMe i86% yield Ph N H Nathan Bennett 95% yield Group Meeting May 7, 2011 Title Page Ni Chemistry Timeline Initial Studies 1966 Saito and Yamamoto Et2Ni(bpy) 1960 1970 1980 1990 2000 Saito, T. and Yamamoto, A. N N Et Et2AlOEt vacuum + Ni(acac)2 + Ni + Et O 110 °C N 2 N Et –20 ! –10 °C Et2Ni(bpy) J. Am. Chem. Soc. 1966, 88, 5198. Timeline1 Saito Ni Chemistry Timeline Initial Studies 1966 1971 Saito and Yamamoto Semmelhack Et2Ni(bpy) Ni(COD)2 1960 1970 1980 1990 2000 Semmelhack, M. F. Ni(COD)2 Br DMF 52 °C 82% yield Ullmann Coupling Comparison Cu Bronze Br cymene 180 °C 60% yield Ni: Semmelhack, M. F. J. Am. Chem. Soc. 1971, 93, 5908. Ullmann Coupling: Fanta, P. E. Chem. Res. 1964, 64, 613. Timeline1 Semmelhack Ni Chemistry Timeline Initial Studies 1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4 1960 1970 1980 1990 2000 Semmelhack, M. F. OMe n yield (%) MeO I 2 81 Ni(PPh3)4 3 83 n n DMF, 55 °C 4 76 MeO I 5 85 6 38 OMe J. Am. Chem. Soc. 1975, 97, 3873. J. Am. Chem. Soc. 1981, 103, 646. Timeline1Semmelhack Ni Chemistry Timeline Initial Studies 1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4 1960 1970 1980 1990 2000 1975 Kende NiCl2(PPh3)2 + Zn Kende, A. S. 0 Zn , PPh3 0 II 0 ! Tolman Research: Ni (PPh3)3 active catalyst Ni Cl2(PPh3)2 Ni (PPh3)3 DMF in situ ! Kende formed in situ Tolman, C. A. J. Am. Chem. Soc. 1974, 96, 53. Kende, A. S. Tetrahedron Lett. 1975, 3375. Timeline1 Kende Ni Chemistry Timeline Initial Studies 1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4 1960 1970 1980 1990 2000 1975 1977 Kende Kumada NiCl2(PPh3)2 + Zn Catalytic Ni Kumada, M. NiCl2(PPh3)2 (2.5 mol%) PPh3 (5 mol%) Br Zn (1 equiv) DMF, 50 °C 89% yield Tetrahedron Lett. 1977, 47, 4089. Timeline1 Kumada Why Phenol/Enol Derived Electrophiles? Availability ! 50,000 commercial phenol and aryl polyol ! Enol electrophile from trapping enolates Reactivity ! Directed Ortho Metalation (DoM) Possible with: i. sec-BuLi, TMEDA E THF, –93 °C Sulfamates O NEt2 O NEt2 S S Ethers + Esters O O ii. E , –93 " 23 °C O O Carbamates E = CHO, CONEt2, CH(OH)Ph, SMe, SiMe3, Cl, Br, I, SnBu3, boronate esters ! p-Direction F F F Ph I2, AgOTf O NEt2 O NEt2 S S O O CH2Cl2, 65 °C O O I flurbiprofen 64% yield O OH Garg, N. K. and Percec, V. Chem. Rev. 2011, ASAP, DOI: 10.1021/cr100259t. DoM Review: Snieckus, V. Chem. Rev. 1990, 90, 879. p-Direction Example: Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748. Why Phenol/Enol E+? Ni Chemistry Timeline Sulfonate Highlights 1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4 1960 1970 1980 1986 1990 2000 1975 1977 Yamishito Kende Kumada Homocoupling NiCl2(PPh3)2 + Zn Catalytic Ni Yamishito, J. NiCl2 (8 mol%) PPh3 (60 mol%) Zn (1.5 equiv) MeO OTf MeO OMe NaI (60 mol%) DMF, 60 °C 82% yield ultrasounds Chem. Lett. 1986, 407. Timeline2 Yamishito Ni Chemistry Timeline Sulfonate Highlights 1995 1966 1971 1975 Percec Saito and Yamamoto Semmelhack Semmelhack Homocoupling Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4 1960 1970 1980 1986 1990 2000 1975 1977 Yamishito Kende Kumada Homocoupling NiCl2(PPh3)2 + Zn Catalytic Ni Percec, V. NiCl2(PPh3)2 (10 mol%) O Zn (1.7 equiv) O O OMs MeO Et4NI (1.5 equiv) MeO OMe THF, reflux >99% GC yield J. Org. Chem. 1995, 60, 176. Timeline2 Percec1 Ni Chemistry Timeline Sulfonate Highlights 1995 1995 1966 1971 1975 Percec Percec Saito and Yamamoto Semmelhack Semmelhack Homocoupling Suzuki-Miyaura Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4 1960 1970 1980 1986 1990 2000 1975 1977 Yamishito Kende Kumada Homocoupling NiCl2(PPh3)2 + Zn Catalytic Ni Percec, V. PhB(OH)2 NiCl2(dppf) (10 mol%) O Zn (1.7 equiv) O OMs Ph MeO K3PO4 (3 equiv) MeO dioxane, 95 °C 67% yield J. Org. Chem. 1995, 60, 1060. Timeline2 Percec2 Ni Chemistry Timeline Sulfonate Highlights 1995 1995 1966 1971 1975 Percec Percec Saito and Yamamoto Semmelhack Semmelhack Homocoupling Suzuki-Miyaura Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4 1960 1970 1980 1986 1990 2000 Yamishito 1975 1977 1995 Homocoupling Kende Kumada Percec NiCl2(PPh3)2 + Zn Catalytic Ni Negishi Percec, V. MeO ZnCl NiCl2(PPh3)2 (10 mol%) Zn (1 equiv) OMs OMe THF, 23 °C 31% GC yield J. Org. Chem. 1995, 60, 6895. Timeline2 Percec3 Overview Sulfamates O O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers O Me Esters O O O O Carbamates and Carbonates O O O NEt2 O Ot-Bu Contents Overview Sulfamates O O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers O Me Esters O O O O Carbamates and Carbonates O O O NEt2 O Ot-Bu Contents Sulfamate Ni Cross Coupling Directed Ortho Metalation (DoM) Snieckus, V. (HO)2B i. sec-BuLi, TMEDA I Pd(PPh3)4 (5 mol%) THF, –93 °C Na2CO3 (aq.) O NEt2 O NEt2 S S O O ii. I2, –93 ! 23 °C O O DME, 80 °C, 16 h 78% yield 92% yield BrMg OMe OMe N N Mes Mes (2.5 equiv) NiClCpIMes (3 mol%) Cl Ni O NEt2 S Et2O, reflux, 16 h NiClCpIMes O O 64% yield Org. Lett. 2005, 7, 2519. Sulfamate1 K1 Snieckus1 Sulfamate Ni Cross Coupling Kumada Coupling Du Bois, J. C-H Insertion O O 1. Rh2(OAc)4 (2 mol%) O O S PhI(OAc)2 S i-BuMgCl (2 equiv) O NH O NBn i-Bu NHBn 2 MgO, CH2Cl2 NiCl2(dppp) (5 mol%) 2. BnBr, K2CO3, DMF benzene, 55 °C 78% yield 95% yield Aziridine Formation O O O O S Rh2(OAc)4 (2 mol%) S N O NH2 PhI(OAc)2, MgO O 1. H2O, then TBSCl CH2Cl2 ii. MeI, K2CO3, DMF 83% yield 92% yield O Me O S N i. PhMgCl (2 equiv) Boc O NiCl2(dppp) (5 mol%) Ph N OTBS benzene, 55 °C ii. (Boc) O 2 OH 88% yield Org. Lett. 2005, 7, 4685. Sulfamate3 K3 Du Bois Sulfamate Ni Cross Coupling Suzuki-Miyaura Coupling Garg, N. K. R2 (HO) B R2 O O 2 S (2.5 equiv) O NMe2 NiCl2(PCy3)2 (5 mol%) K3PO4 (4.5 equiv) R1 R1 toluene, 110 °C, 24 h 17 examples R2 = -H, -OMe 63–95% yield Ph Ph t-BuO Ph OMe O !CF3 OMe 81% 80% 85%a 63% Ph N Ph OMe O 95% 75% 75% a 10 mol% NiCl2(PCy3)2, 4 equiv ArB(OH)2, 7.2 equiv K3PO4, toluene, 130 °C J. Am. Chem. Soc. 2009, 131, 17748. Sulfamate SM1 Garg Sulfamate Ni Cross Coupling Total Synthesis of Flurbiprofen Garg, N. K. Cl OMe Me2NO2SO Me NO SO NaOH, MeOH; Me NO SO O 2 2 2 2 F AgOTf, 0 °C I2, AgOTf NiBr2(bpy) (HO)2B F then, MS 3Å, THF CH2Cl2, 65 °C Mn, TFA Selectfluor! DMF, 50 °C 64% yield I 70% yield 70% yield Me2NO2SO Ph Ph F F F PhB(OH)2 NiCl2(PCy3)2 H2SO4 K3PO4 p-dioxane, H2O OMe toluene, 130 °C OMe OH 84% yield O O 2 steps O flurbiprofen 5 steps, 26% yield J. Am. Chem. Soc. 2009, 131, 17748. Sulfamate SM2 Garg Overview Sulfamates O O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers O Me Esters O O O O Carbamates and Carbonates O O O NEt2 O Ot-Bu Contents Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Vinyl Phosphonates Kumada, M. TMS MgCl R TMS OP(O)(OEt) (1.7–3 equiv) 2 R Ni(acac)2 –OR– NiBr2 (3–5 mol%) n n n = 1, 2, 8 Et2O, 23 °C, 15 h 9 examples R = H, Ph 47–92% yield TMS Ph TMS TMS TMS 5 Ph 81%a 48%b 92%b 47%a a b Ni(acac)2. NiBr2 Kumada, M. Synthesis 1981, 1001. Nicolaou, K. C. Chem. Commun. 1998, 1757. Claesson, M. Tetrahedron Lett. 1983, 24, 5137. Backvall, J.-E. J. Org. Chem. 1999, 64, 1745. Phosphonate1a K1 Kumada Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Vinyl Phosphonates Kumada, M. Claesson, A. TMS MgCl R TMS (1.7–3 equiv) 2 OP(O)(OEt)2 R MgX (2.7 equiv) R 2 OP(O)(OEt)2 NiCl2(dppp) (2.5 mol%) R Ni(acac)2 –OR– NiBr2 R1 R1 (3–5 mol%) Et2O, 23 °C n n Et O, 23 °C, 15 h n = 1, 2, 8 2 9 examples R1 = H, Ph R2 = Ph, Bn, n-octyl, Me 4 examples R = H, Ph 47–92% yield 55–78% yield TMS Ph TMS Ph Bn n-octyl Me TMS TMS Ph 5 Ph 81%a 48%b 92%b 47%a 67% 55% 78% 69%a a b a Ni(acac)2. NiBr2 NiCl2(dppe).
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    THE EFFECTS OF NEUROPATHY-INDUCING ORGANOPHOSPHATE ESTERS ON CHICK DORSAL ROOT GANGLIA CELL CULTURES. By Christiane Massicotte Dissertation submitted to the Faculty of the Virginia Polytechnic institute & State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Veterinary Medical Sciences APPROVED ________________________ ______________________ Marion F. Ehrich (Chairman) Bernard S. Jortner ________________________ _____________________ Cornelis Van der Schyf Bradley Klein ________________________ _____________________ Jeffrey Bloomquist Karen D. Inzana September 2001 Blacksburg, Virginia Keywords: Organophosphate, Neuropathy, ATP, mitochondria i. ABSTRACT THE EFFECTS OF NEUROPATHY-INDUCING ORGANOPHOSPHATE ESTERS ON CHICK DORSAL ROOT GANGLIA CELL CULTURES. By: Christiane Massicotte Committee Chairman, Dr. Marion F. Ehrich Veterinary Medical Sciences Cultures of dorsal root ganglia (DRG) can achieve neuronal maturation with axons, making them useful for neurobiological studies. They have not, however, previously been used to investigate subcellular events that occur following exposure to neuropathy-inducing organophosphorus (OP) esters. Recent studies in other systems demonstrated alterations of ATP concentrations and changes in mitochondrial transmembrane potential (∆Ψm) following exposure to neuropathy-inducing OP compounds, suggesting that mitochondrial dysfunction occurs. The present dissertation proposed an investigation using chick embryo DRG cultures to explore early mechanisms associated with exposure to these toxicants. This approach uses an in vitro neuronal system from the species that provides the animal model for OP-induced delayed neuropathy (OPIDN). DRG were obtained from 9-10 day old chick embryos, and grown for 14 days in minimal essential media (MEM) supplemented with bovine and human placental sera and growth factors. Cultures were then treated with 1 µM OP compounds, or the DMSO vehicle control.
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    University of Kentucky UKnowledge Theses and Dissertations--Chemistry Chemistry 2014 Salen Aluminum Compounds in the Dealkylation and Detection of Organophosphates Rahul R. Butala University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Butala, Rahul R., "Salen Aluminum Compounds in the Dealkylation and Detection of Organophosphates" (2014). Theses and Dissertations--Chemistry. 47. https://uknowledge.uky.edu/chemistry_etds/47 This Doctoral Dissertation is brought to you for free and open access by the Chemistry at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Chemistry by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies.
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