Chemistry 206 Advanced Organic Chemistry Handout-35A The Use of Fischer Carbenes in Organic Synthe esI every synthetic chemist is well advised to follow this fascinating field with appropriate attention Schmalz, H.-G, ACIEE, 1994, 303 Brian Connell Evans group seminar, February 1999 Matthew d. shair Monday December 16. 2002
Chemistry 206 Advanced Organic Chemistry Handout–35A The Use of Fischer Carbenes in Organic Synthesis Matthew D. Shair Monday , December 16, 2002 Brian Connell Evans Group Seminar, February, 1999 "...every synthetic chemist is well advised to follow this fascinating field with appropriate attention." - Schmalz, H.-G., ACIEE, 1994, 303
B. Connell Fischer carbenes Chem 206 The Use of Fischer Carbenes in Organic Synthesis every synthetic chemist is well advised to fowlow this fascina Schmalz, H.-G, ACIEE, 1994 Brian Connell Evans Group Seminar 2/1299 Outline Introduction and Fundamentals Reactions Cyclopropanation Diels-Alder Cycloaddition Other Cycloadditions Dotz Reaction and Analogs otner Reactons cs,1998,3116 hensive Organic Synthesis, Vol 5, Chap 9. 2: Metal Carbene Cycloadditions, Pergamon Press, 1991 and Vinyl Ketene che or emistry l Vol 12, Chap 5.3: Transition Metal Carbene Complexes. Alkyne Chemistry l, Vol. 12, Chap 5.4: Transition Metal Carbene Complexes Photochemical Reactions of Carbene Complexes, Pergamon Press, 1994 Introduction bilized complexes having formal metal-to-carbon double bonds Group 6 metals(Cr, Mo, W are the most common metals used First prepared by Fischer(ACIEE, 1964, 580) Cr(cO)6 下c cale and stored (CO)5Cr hard"alkylating reag (CH3)3OBF4, CH3C cellent yields for all steps cheap starting materials(20-50c/mr ·air, silica stable crystalline, easy to handle 01/0212/20993:49PM
The Use of Fischer Carbenes in Organic Synthesis Brian Connell Evans Group Seminar 2/12/99 • Introduction and Fundamentals • Reactions Outline • Cyclopropanation • Diels-Alder Cycloaddition • Other Cycloadditions • Dotz Reaction and Analogs • Photochemistry • Conjugate Additions • Other Reactions "...every synthetic chemist is well advised to follow this fascinating field with appropriate attention." - Schmalz, H.-G., ACIEE, 1994, 303. General References: Wulff,Organometallics, 1998, 3116. Wulff,Comprehensive Organic Synthesis, Vol. 5, Chap 9.2: Metal Carbene Cycloadditions, Pergamon Press, 1991. Wulff, Comprehensive Organometallic Chemistry II, Vol. 12, Chap 5.3: Transition Metal Carbene Complexes: Alkyne and Vinyl Ketene Chemistry, Pergamon Press, 1994. Hegedus, Comprehensive Organometallic Chemistry II, Vol. 12, Chap 5.4: Transition Metal Carbene Complexes: Photochemical Reactions of Carbene Complexes, Pergamon Press, 1994. Introduction • Definition: electrophilic, heteroatom stabilized complexes having formal metal-to-carbon double bonds • Group 6 metals (Cr, Mo, W) are the most common metals used. • First prepared by Fischer (ACIEE, 1964, 580): Cr(CO)6 RLi O (CO)5Cr R Li O (CO)5Cr R (CH3)4NBr N(CH3)4 "hard" alkylating reagents (CH3)3OBF4, CH3COBr OCH3 (CO)5Cr R can be prepared on large scale and stored for long periods • excellent yields for all steps • air, silica stable • crystalline, easy to handle • colored (yellow to red) • cheap starting materials (20-50¢/mmol) B. Connell Fischer Carbenes Chem 206 01/02 12/20/99 3:49 PM
B. Connell Fischer carbenes Chem 206 N(CH3)4 HC (CO)5C (CO)sCI OTMS K2 cr(CO)5 MSCI 2 Selected Physical Data H3C CH Bond Lengths Bond Lengt Bond Lengths Ccarbene -O=1.33 A Ccarbene -N=1.31A N=129A Ccarbene -Cr=2.04 A Ccarbene-Cr=2.16A Cr-COs=1.86-191A Cr- cOcks=1.90A carbonyl-O=1.23 A 1.87A Cr-CO,rans =1.85 A IR Frequencies IR Frequencies VCO~2070,1992,1953cm co=-2060.1970.1940c vco = -1650 cm 1 TH NMR 1H NMR H NMR CH3=~21 3C NMR Ccarbene 320-360 ppm 13C NMR Ccarbene= 250-290 ppn =~165ppm 03/041220/994:21PM
B. Connell Fischer Carbenes Chem 206 Dotz, Synlett, 1991, 381. Nitrogen Analogs O (CO)5Cr R N(CH3)4 H3C Br O O (CO)5Cr R CH3 O NR2 (CO)5Cr R NHR2 K2Cr(CO)5 O R1 NR2 O NR2 R1 (CO)5Cr TMSCl OTMS NR2 R1 (CO)5Cr NR2 (CO)5Cr R1 (CO)5Cr OCH3 CH3 (CO)5Cr N CH3 H3C CH3 O N CH3 H3C CH3 Bond Lengths Ccarbene - O = 1.33 Å Ccarbene - Cr = 2.04 Å Cr - COcis = 1.86 - 1.91 Å Cr - COtrans = 1.87 Å IR Frequencies vCO ~2070, 1992, 1953 cm-1 1H NMR Ccarbene - CH3 = ~5 13C NMR Ccarbene 320-360 ppm Bond Lengths Ccarbene - N = 1.31 Å Ccarbene - Cr = 2.16 Å Cr - COcis = 1.90 Å Cr - COtrans = 1.85 Å IR Frequencies vCO = ~2060, 1970, 1940 cm-1 1H NMR Ccarbene - CH3 = ~3.2 13C NMR Ccarbene = 250-290 ppm Bond Lengths Ccarbonyl - N = 1.29 Å Ccarbonyl - O = 1.23 Å IR Frequencies vCO = ~1650 cm-1 1H NMR Ccarbonyl - CH3 = ~2.1 13C NMR Ccarbonyl = ~165 ppm Selected Physical Data 03/04 12/20/99 4:21 PM
Major Contributors Ernst Otto Fischer 929, from which I gr Sthey sf Che mistry n munich after he reopening of the technical colee n, 1948. r gradated th e949n ook up a pasn ano- college in igss ved ly of Munich. After turming down an offer of the Chair of Inorganic Ch Professor at the univ of munich in 195 k Memorial pri ry Prize by the Gottingen Academ Inorganic Chemistry at the University of Marburg. In 1964 I took the Chair of Inorganic Chemistry at the Technical Coll of the German Academy of Scientists Leopoldina I was given an and oligo-olefins and most recently metalcarbonyl carbene and carbyne complexes, led me on l venezuela, Brazil, Israel and Lebanon, as well as numerous European countries, including the he University of Wiscons son, Wisconsin, USA; in 19 organic Chemistry Pacific West Coast Lecturer. In the spring of 1973 I held lectures as the Arth Institute of Technology, Cambridge, Massachusetts, USA, and that was followed by a period when I was Visiting Disting Nobel lecture: On the way to carbene and carbyne complexes. Angew. Chem.(1974),86(18),65 Karl Heinz dotz Kekule-lnstitut fur Organische Chemie und Biochemie der Universitat Bonn Born1943 Ph. D. Technical University of Munich(EO. Fischer)1971 Habilitation Technical University of Munich 1980 Professor of Organometallic Chemistry University of Marburg 1986-1992, Dean of the Faculty 1990-1 Professor of Organic Chemistry University of Bonn since Karl's research is focused on the following areas Synthetic Organometallic Chemistry( metal carbenes and planar-chiral arene complexes) Physical Organic and Organometallic Chemistry (distorted fused arenes and cyclophanes: synthesis and structure-chiroptics correlation, transition met nitio-calculations on organometallic complexes and intermediates) Metal-Mediated Organic Synthesis(stereoselective C-C formation via metal carbenes Organometallic Catalysis(chromium-catalyzed cyclopropanation, axial-chiral and redox-active biaryl Transition Metal Modified Sugars(metal glycosylcarbenes and glycosylidenes: synthesis and appli disaccharide mimetics, conformation of acyclic metal modified sugars) 01a contributors 1 2/13/99 8: 42 AM
Major Contributors Kekule-Institut fur Organische Chemie und Biochemie der Universitat Bonn Born1943 Ph.D. Technical University of Munich (E.O. Fischer) 1971. Habilitation Technical University of Munich 1980. Professor of Organometallic Chemistry University of Marburg 1986-1992, Dean of the Faculty 1990-1 Professor of Organic Chemistry University of Bonn since 1992. Karl's research is focused on the following areas: • Synthetic Organometallic Chemistry (metal carbenes and planar-chiral arene complexes) • Physical Organic and Organometallic Chemistry (distorted fused arenes and cyclophanes: synthesis and structure-chiroptics correlation,transition met initio-calculations on organometallic complexes and intermediates) • Metal-Mediated Organic Synthesis (stereoselective C-C formation via metal carbenes, diastereosele cyclopentannulation) • Organometallic Catalysis (chromium-catalyzed cyclopropanation, axial-chiral and redox-active biaryl • Transition Metal Modified Sugars (metal glycosylcarbenes and glycosylidenes: synthesis and applica disaccharide mimetics,conformation of acyclic metal modified sugars) Ernst Otto Fischer Nobel lecture: On the way to carbene and carbyne complexes. Angew. Chem. (1974), 86(18), 651 I was born in Solln, near Munich, on 10 November 1918 as the third child of the Professor of Physics at the Technical C Fischer (died 1953), and his wife, Valentine, née Danzer (died 1935). After completing four years at elementary school 1929, from which I graduated in 1937 with my Abitur. Following a subsequent period of "work service" and shortly befor compulsory military service, the Second World War broke out. I served in Poland, France and Russia. In the winter of 1 Chemistry at the Technical College in Munich during a period of study leave. I was released by the Americans in the au study of Chemistry in Munich after the reopening of the Technical College in 1946. I graduated in 1949. I took up a posi Professor Walter Hieber in the Inorganic Chemistry Department, and under his guidance I dedicated myself to working o Mechanisms of Carbon Monoxide Reactions of Nickel II Salts in the Presence of Dithionites and Sulfoxylates". After rec was invited by Professor Hieber to continue my activities at the college and consequently chose to specialise in the stud organo-metallic chemistry. I wrote my university teaching thesis on "The Metal Complexes of Cyclopentadienes and Ind lecturer at the Technical College in 1955 and in 1956 I completed a scientific sojourn of many months in the United Stat Professor at the University of Munich. After turning down an offer of the Chair of Inorganic Chemistry at the University o Professor at the University of Munich in 1959 . In 1957 I was awarded the Chemistry Prize by the Göttingen Academy o German Chemists awarded me the Alfred Stock Memorial Prize in 1959. In 1960 I refused an appointment as Senior Pr Inorganic Chemistry at the University of Marburg. In 1964 I took the Chair of Inorganic Chemistry at the Technical Colle vacated by Professor Hieber. In the same year I was elected a member of the Mathematics/Natural Science section of t Sciences; in 1969 I was appointed a member of the German Academy of Scientists Leopoldina. In 1972 I was given an Faculty of Chemistry and Pharmacy of the University of Munich. Lectures on my fields, particularly those on metallic complexes of cyclopentadienes and indenes, metal-pie-complex s o di- and oligo-olefins and most recently metalcarbonyl carbene and carbyne complexes, led me on lecture tours of the U Venezuela, Brazil, Israel and Lebanon, as well as numerous European countries, including the former Soviet Union. In 1 the University of Wisconsin, Madison,Wisconsin, USA; in 1971 Visiting Professor at the University of Florida, Gainesville Inorganic Chemistry Pacific West Coast Lecturer. In the spring of 1973 I held lectures as the Arthur D. Little Visiting Pro Institute of Technology, Cambridge, Massachusetts, USA; and that was followed by a period when I was Visiting Disting University of Rochester, Rochester, New York, USA. Karl Heinz Dotz 01a contributors1 2/13/99 8:42 AM
Major Contributors Claude F Bernasconi Charles P.Casey D.Wulff Jose Barluenga University of California at Santa University of Chicago University of Oviedo Cruz Born eau cla orn 1942. St Louis. Mo Wisco Jose Barluenga obtained his Louis S S 1971, University of . D degree(solvomercuration Colorad Wisconsin-Eau claire of dienes )at the University of the Swiss Federal Ph.D.1968. MIT Ph. D. 1979. lowa State B S. 196 titute of Technology(ETH) irection of Professor v Chuck received a Ph. D in University Gomez-Aranda. He spent 3.5 Ph. D ollowing a postdoctoral year with Manfred Eigen at the Max in 1968. where he studied professor Wulf received years as a postdoctoral fellow at Max Planck Institut fur Kohlenforschung, Mulheim, in the Clevelar faculty at 1979 with Professor studying aluminum chemistry. In temptati ornia at Whitesides. After spending Thomas Barton. After NIH 1970 he took a position as a under Santa Cruz in 1967. where has been a professor of Martin Semmelhack at artlett he joined the faculty Princeton University, he University of Zaragoza, where he where s esearch interests are in terested in studying the accepted a position at the professor in 1972. In 1975 he Albert h 980. Professor Wulff's moved to the University o at harva esearch interests are in Oviedo as Professor of Organi the applications of Chemistry in the Department of chemist Organometallic Chemistry. His Stanfor synth major research interest focused on the development of nts for synthesis and hods in th moved t nucleophilic vinylic substitution area of heterocyclic chemistry Universi and reactions of Fischer today as carbene complexes His res∈ the organIc 01b contributors 2/13/99 8: 40 AM
University of Wisconsin-Madison Born 1942, St. Louis, MO B.S. 1963, St. Louis University Ph.D. 1968, MIT Chuck received a Ph.D. in organic chemistry from MIT in 1968, where he studied organocopper chemistry under the direction of Professor George M. Whitesides. After spending 6 months at Harvard as an NSF postdoc with Paul D. Bartlett he joined the faculty at Wisconsin. Chuck is interested in studying the mechanisms of organometallic reactions and in developing an understanding of homogeneous catalysis. In addition, he is trying to design new organometallic reagents for synthesis and new heterobimetallic catalysts. University of California at Santa Cruz Claude was born in Zurich, Switzerland. He received his undergraduate and Ph.D. degrees from the Swiss Federal Institute of Technology (ETH) with Heinrich Zollinger. Following a postdoctoral year with Manfred Eigen at the Max Planck Institute for Biophysical Chemistry in Gottingen, he joined the chemistry faculty at the University of California at Santa Cruz in 1967, where he has been a professor of chemistry since 1977. His main research interests are in physical organic chemistry and center on problems of mechanism, structure-reactivity relationships, intrinsic barriers of reactions, and catalysis in organic and organometallic reactions, particularly proton transfer reactions, nucleophilic addition to electrophilic alkenes, nucleophilic vinylic substitution and reactions of Fischer carbene complexes. University of Chicago Born Eau Claire, Wisconsin, 1949 B. S. 1971, University of Wisconsin-Eau Claire Ph.D. 1979, Iowa State University Professor Wulff received his Ph.D. degree from Iowa State University in 1979 with Professor Thomas Barton. After NIH postdoctoral work with Martin Semmelhack at Princeton University, he accepted a position at the University of Chicago in 1980. Professor Wulff's research interests are in the applications of organometallics in organic synthesis as both reagents and catalysts. Colorad Born Cle B.S, 196 M.A. 196 Ph.D., 1 Lou was Clevelan rural Oh temptati undergra Pennsyl where s redox ch Albert H at Harva chemistr and a N Stanford studying homoge moved t Universi today as His rese the use organic Major Contributors University of Oviedo Jose Barluenga obtained his Ph.D. degree (solvomercuration of dienes) at the University of Zaragoza in 1966 under the direction of Professor V. Gomez-Aranda. He spent 3.5 years as a postdoctoral fellow at Max Planck Institut Fur Kohlenforschung, Mulheim, in the group of Professor Hoberg studying aluminum chemistry. In 1970 he took a position as a research associate at the University of Zaragoza, where he was promoted to Associate Professor in 1972. In 1975 he moved to the University of Oviedo as Professor of Organic Chemistry in the Department of Organometallic Chemistry. His major research interest is focused on the development of new synthetic methods in the area of heterocyclic chemistry and functionalized systems. Claude F. Bernasconi Charles P. Casey William D. Wulff Jose Barluenga Louis S 01b contributors2 2/13/99 8:40 AM
B. Connell Fischer carbenes Chem 206 Recurring Themes The Wall of co Res O OCH3 OCH CO)5Cr (cO5Cr一 rotation about heteroatom carbene bond is restricted by 14-25 kcal'mol 53 Cr NMR is consistent with strong (CO)5Cr is sterically very larg resonance contribution Hegedus and Dotz JACS, 1988, 8413 Kinetic Electrophilicity HOCH (CO)5CI H .Formation of tetrahedral intermediate is 109 faster than CH3o- addition to BnO,C( enascon Chem. Soc. Rev., 1997. 299 JACs,1998,8632 pKa Data Thermodynamic Acidity 3C C (CO)sCr= (CO)cCra O= pKa(THF)=8 pKa(H2O)=12.3 quivalent to p-cyanophenol Casey, JACS, 1974, 1230 05/0612/20994:22PM
B. Connell Fischer Carbenes Chem 206 Recurring Themes OCH3 R CO CO OC OC CO Cr The Wall of CO • (CO)5Cr is sterically very large Resonance (CO)5Cr OCH3 R (CO)5Cr OCH3 R •Rotation about heteroatom carbene bond is restricted by 14-25 kcal/mol • 53Cr NMR is consistent with strong resonance contribution Hegedus and Dotz JACS, 1988, 8413. Bernasconi Chem. Soc. Rev., 1997, 299. JACS, 1998, 8632. Kinetic Electrophilicity (CO)5Cr OCH3 CH3 (CO)5Cr OCH3 CH3 •Formation of tetrahedral intermediate is 109 faster than CH3O– addition to BnO2CCH3. OCH3 H HOCH3 pKa Data (CO)5Cr OCH3 CH3 (CO)5Cr N CH3 H3C CH3 O N CH3 H3C CH3 • pKa = 20.4 (DMSO) • pKa = 35 (DMSO) Thermodynamic Acidity • pKa(THF) = 8 • pKa(H2O) = 12.3 equivalent to p-cyanophenol Casey, JACS, 1974, 1230. 05/06 12/20/99 4:22 PM
B. Connell Fischer carbenes Chem 206 ivity to Acid OCH3 pyridine (CO)5C (CO)5.pyr reductive el ⊙ pyridinium (CO)5CI (CO CH2 See Hegedus, JACS, 1990, 6255 Meta/ Removal and Functionalization CH3Li, CICH2l Barluenga, TL, 1994, 9471 80-90% CH2N2 OCH- Casey,TL,1973,1421 Ph3 PCH2 Casey, JACS, 1972, 65 (CO) Via similar intermediates OCH3 (CO)5Cr-y-Ar (CO)5Cl 070812/20/994:22PM
B. Connell Fischer Carbenes Chem 206 (CO)5Cr OCH3 CH3 pyridine H3CO + (CO)5Cr•pyr Sensitivity to Acid (CO)5Cr OCH3 CH2 (CO)5Cr OCH3 CH2 pyridinium pyridine H reductive elimination See Hegedus, JACS, 1990, 6255. (CO)5Cr OCH3 Ar CH3Li, ClCH2I O Ar CH3 80-90% Metal Removal and Functionalization Barluenga, TL, 1994, 9471. (CO)5Cr OCH3 R CH2N2 R OCH3 (CO)5Cr OCH3 Ar Ph3PCH2 H2C OCH3 Ar Casey, TL, 1973, 1421. Casey, JACS, 1972, 6543. Via similar intermediates: (CO)5Cr OCH3 Ar Cl (CO)5Cr OCH3 R N2 (CO)5Cr OCH3 Ar Ph3P 07/08 12/20/99 4:22 PM
Connell Fischer carbenes Chem 206 Selected Reactions of Unsaturated Fischer Carbene Complexes (CO)5CI (CO)5CI Nu H CH3 R2 R3 OCH3 OCH3 Selected Reactions of saturated Fischer Carbene Complexes H3 R6 (CO)5M RI OCHR R3 HR2R3 RCHO (CO)5M CH3 OCH3 XR6=OCH3, N(R5)2 R3 SnCI R2 091012/20993:51PM
B. Connell Fischer Carbenes Chem 206 (CO)5M OCH3 R3 R2 R1 R1 R3 R2 (CO)5Cr OCH3 R4 R4 Nu (CO)5Cr OCH3 R3 R2 R1 Nu R R2 = H OH OCH3 R1 R3 R R R2, R3 ≠ H O OCH3 R1 R3 R R2 R4 R1 R2 R4 OCH3 R3 Bu3SnH Bu3Sn OCH3 R3 R2 R1 R R2 = NR2 O R R OCH3 R3 N H3CO R4 R5 R2 R3 HN R4 R5 Selected Reactions of Unsaturated Fischer Carbene Complexes Selected Reactions of Saturated Fischer Carbene Complexes (CO)5M XR6 CH3 XR6 = OCH3, N(R5)2 (CO)5M XR6 R OH RCHO CH3 OCH3 R1 R1 O R1 OCH3 CH3 O O H3C R2 R3 OCHR2R3 OCHR2R3 R O O OCH3 CH3 R O N R2 R1 N R O 2 R1 CH3 XR6 R3SnCl R3Sn XR6 RX (CO)5M XR6 R R O (CO)5M XR6 O R 09/10 12/20/99 3:51 PM
B. Connell Fischer carbenes Chem 206 n-Bu (CO)5Mo THF,65°C 78% OCH Harvey, TL, 1990, 2529 OCH Wulff Chem,1988,137 OCH OCH 81% Harvey, JACS, 1992, 8424 (CO)5Cr Hoye, JACS, 1988, 2676 11/1212/20993:54PM
B. Connell Fischer Carbenes Chem 206 Cyclopropanation OCH3 (CO)5Mo n-Bu CO2CH3 THF, 65 °C 78% CO2CH3 n-Bu OCH3 E:Z 1.9:1 Harvey, TL, 1990, 2529. OCH3 (CO)5Mo CH3 OTBS 25 °C, 49% TBSO OCH3 CH3 >95% cis Wulff Pure Appl. Chem., 1988, 137. JACS, 1988, 2653. Cyclopropanation R OCH3 1 (CO)5Cr R2 M(CO)4 R2 OCH3 Reaction with Alkynes R1 M(CO)4 R2 OCH3 (CO)5Cr OCH3 PhH reflux 97% OCH3 Hoye, JACS, 1988, 2676. O OCH3 (CO)5Cr n-Bu PhH, 100 °C 81% O OCH3 n-Bu Harvey, JACS, 1992, 8424. R1 11/12 12/20/99 3:54 PM
B. Connell Fischer carbenes Chem 206 Selective Cyclopropanation Ph,OCH3 THF,80°C,3h t-B (CO)5Cr n-Bu △NcH n-Bu, DMF,152°C.4%BHT 30 min 88%,97%de mun,1995,665 997,7591 Cyclopropanation Reaction with Alkynes Phh CO2Et CO2E Harvey, JOC, 1992, 5559 13/1412/20993:55PM
B. Connell Fischer Carbenes Chem 206 Selective Cyclopropanation Barluenga Chem. Commun., 1995, 665. JACS, 1997, 7591. n-Bu Fe (CO)5Cr OCH3 88%, 97% de Fe OCH3 H n-Bu DMF, 152 °C, 4% BHT 30 min N Ph H t-Bu OCH3 (CO)5Cr Ph THF, 80 °C, 3 h Ph OCH3 Ph H H N t-Bu SiO2 Ph OCH3 Ph H H O H H O OCH3 H n-Bu H O3 Cyclopropanation Reaction with Alkynes Harvey, JOC, 1992, 5559. O CH3 Mo(CO)5 O CO2Et PhH 65 °C, 55% O CH3 O H CO2Et O O CH3 CO2Et H 13/14 12/20/99 3:55 PM