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. 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) 5 Cr R Li O (CO) 5 Cr R N(CH 3 ) 4(CH 3 ) 4 NBr "hard" alkylating reagents (CH 3 ) 3 OBF 4 , CH 3 COBr OCH 3 (CO) 5 Cr 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 Dotz, Synlett, 1991, 381. Nitrogen Analogs O (CO) 5 Cr R N(CH 3 ) 4 H 3 CBr O O (CO) 5 Cr R CH 3 O NR 2 (CO) 5 Cr R NHR 2 K 2 Cr(CO) 5 O R 1 NR 2 O NR 2 R 1 (CO) 5 Cr TMSCl OTMS NR 2 R 1 (CO) 5 Cr NR 2 (CO) 5 Cr R 1 (CO) 5 Cr OCH 3 CH 3 (CO) 5 Cr N CH 3 H 3 C CH 3 O N CH 3 H 3 C CH 3 Bond Lengths C carbene - O = 1.33 ? C carbene - Cr = 2.04 ? Cr - CO cis = 1.86 - 1.91 ? Cr - CO trans = 1.87 ? IR Frequencies vCO ~2070, 1992, 1953 cm -1 1 H NMR C carbene - CH 3 = ~5 13 C NMR C carbene 320-360 ppm Bond Lengths C carbene - N = 1.31 ? C carbene - Cr = 2.16 ? Cr - CO cis = 1.90 ? Cr - CO trans = 1.85 ? IR Frequencies vCO = ~2060, 1970, 1940 cm -1 1 H NMR C carbene - CH 3 = ~3.2 13 C NMR C carbene = 250-290 ppm Bond Lengths C carbonyl - N = 1.29 ? C carbonyl - O = 1.23 ? IR Frequencies vCO = ~1650 cm -1 1 H NMR C carbonyl - CH 3 = ~2.1 13 C NMR C carbonyl = ~165 ppm Selected Physical Data 03/04 12/20/99 4:21 PM 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 G?ttingen 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 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. Charles P. Casey Claude F. Bernasconi William D. Wulff Jose Barluenga Louis S 01b contributors2 2/13/99 8:40 AM B. Connell Fischer Carbenes Chem 206 Recurring Themes OCH 3 R CO CO OC OC CO Cr The Wall of CO ? (CO) 5 Cr is sterically very large Resonance (CO) 5 Cr OCH 3 R (CO) 5 Cr OCH 3 R ?Rotation about heteroatom carbene bond is restricted by 14-25 kcal/mol ? 53 Cr 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) 5 Cr OCH 3 CH 3 (CO) 5 Cr OCH 3 CH 3 ?Formation of tetrahedral intermediate is 10 9 faster than CH 3 O – addition to BnO 2 CCH 3 . OCH 3 H HOCH 3 pKa Data (CO) 5 Cr OCH 3 CH 3 (CO) 5 Cr N CH 3 H 3 C CH 3 O N CH 3 H 3 C CH 3 ? pK a = 20.4 (DMSO) ? pK a = 35 (DMSO) Thermodynamic Acidity ? pK a (THF) = 8 ? pK a (H 2 O) = 12.3 equivalent to p-cyanophenol Casey, JACS, 1974, 1230. 05/06 12/20/99 4:22 PM B. Connell Fischer Carbenes Chem 206 (CO) 5 Cr OCH 3 CH 3 pyridine H 3 CO + (CO) 5 Cr?pyr Sensitivity to Acid (CO) 5 Cr OCH 3 CH 2 (CO) 5 Cr OCH 3 CH 2 pyridinium pyridine H reductive elimination See Hegedus, JACS, 1990, 6255. (CO) 5 Cr OCH 3 Ar CH 3 Li, ClCH 2 I O Ar CH 3 80-90% Metal Removal and Functionalization Barluenga, TL, 1994, 9471. (CO) 5 Cr OCH 3 R CH 2 N 2 R OCH 3 (CO) 5 Cr OCH 3 Ar Ph 3 PCH 2 H 2 C OCH 3 Ar Casey, TL, 1973, 1421. Casey, JACS, 1972, 6543. Via similar intermediates: (CO) 5 Cr OCH 3 Ar Cl (CO) 5 Cr OCH 3 R N 2 (CO) 5 Cr OCH 3 Ar Ph 3 P 07/08 12/20/99 4:22 PM B. Connell Fischer Carbenes Chem 206 (CO) 5 M OCH 3 R 3 R 2 R 1 R 1 R 3 R 2 (CO) 5 Cr OCH 3 R 4 R 4 Nu (CO) 5 Cr OCH 3 R 3 R 2 R 1 Nu R R 2 = H OH OCH 3 R 1 R 3 R R R 2 , R 3 ≠ H O OCH 3 R 1 R 3 R R 2 R 4 R 1 R 2 R 4 OCH 3 R 3 Bu 3 SnH Bu 3 Sn OCH 3 R 3 R 2 R 1 R R 2 = NR 2 O R R OCH 3 R 3 N H 3 CO R 4 R 5 R 2 R 3 HN R 4 R 5 Selected Reactions of Unsaturated Fischer Carbene Complexes Selected Reactions of Saturated Fischer Carbene Complexes (CO) 5 M XR 6 CH 3 XR 6 = OCH 3 , N(R 5 ) 2 (CO) 5 M XR 6 R OH RCHO CH 3 OCH 3 R 1 R 1 O R 1 OCH 3 CH 3 O O H 3 C R 2 R 3 OCHR 2 R 3 OCHR 2 R 3 R O O OCH 3 CH 3 R O N R 2 R 1 N O R 2 R 1 CH 3 XR 6 R 3 SnCl R 3 Sn XR 6 RX (CO) 5 M XR 6 R R O (CO) 5 MXR 6 O R 09/10 12/20/99 3:51 PM B. Connell Fischer Carbenes Chem 206 Cyclopropanation OCH 3 (CO) 5 Mo n-Bu CO 2 CH 3 THF, 65 °C 78% CO 2 CH 3 n-Bu OCH 3 E:Z 1.9:1 Harvey, TL, 1990, 2529. OCH 3 (CO) 5 Mo CH 3 OTBS 25 °C, 49% TBSO OCH 3 CH 3 >95% cis Wulff Pure Appl. Chem., 1988, 137. JACS, 1988, 2653. Cyclopropanation R 1 OCH 3 (CO) 5 Cr R 2 M(CO) 4 R 2 OCH 3 Reaction with Alkynes R 1 M(CO) 4 R 2 OCH 3 (CO) 5 Cr OCH 3 PhH reflux 97% OCH 3 Hoye, JACS, 1988, 2676. O OCH 3 (CO) 5 Cr n-Bu PhH, 100 °C 81% O OCH 3 n-Bu Harvey, JACS, 1992, 8424. R 1 11/12 12/20/99 3:54 PM B. Connell Fischer Carbenes Chem 206 Selective Cyclopropanation Barluenga Chem. Commun., 1995, 665. JACS, 1997, 7591. n-Bu Fe (CO) 5 Cr OCH 3 88%, 97% de Fe OCH 3 H n-Bu DMF, 152 °C, 4% BHT 30 min N Ph t-Bu H OCH 3 (CO) 5 Cr Ph THF, 80 °C, 3 h OCH 3 Ph Ph H H N t-Bu SiO 2 OCH 3 Ph Ph H H O H H O OCH 3 H n-Bu H O 3 Cyclopropanation Reaction with Alkynes Harvey, JOC, 1992, 5559. O CH 3 Mo(CO) 5 O CO 2 Et PhH 65 °C, 55% OCH 3 O H CO 2 Et O O CH 3 CO 2 Et H 13/14 12/20/99 3:55 PM B. Connell Fischer Carbenes Chem 206 [4 + 3] Annulation N H NHt-Bu Cr(CO) 5 OCH 3Ph N H 3 CO Et Ph NHt-Bu Et [2 + 1] HN OCH 3 Et Ph NHt-Bu [3,3] N H H 3 CO Et Ph NHt-Bu Barluenga Chem. Commun., 1994, 321. JACS, 1995, 9419. JACS, 1996, 695. Chem. Eur. J., 1996, 88. -78 °C to -40 °C 91% (CO) 5 Cr OCH 3 H 3 CO (CO) 5 Cr 10 4 times faster than methyl acrylate Wulff, JACS, 1990, 4550. Diels-Alder Cycloaddition CH 3 H 3 C 25 °C, 3 h 70% O OCH 3 H 3 CO O CH 3 H 3 C 25 °C, 7 mo 54% 92:8 regioselectivity 70:30 regioselectivity 15/16 12/20/99 3:56 PM B. Connell Fischer Carbenes Chem 206 O Si(CH 3 ) 2 O H 3 CO W(CO) 5 H 3 CO 120 °C, 48 h 25 °C, 2 h Si(CH 3 ) 2 O H 3 CO W(CO) 5 H Si(CH 3 ) 2 O H 3 CO O H Wulff JACS 1983, 6726. JACS 1990, 3642. Diels-Alder Cycloadditions CH 3 (OC) 5 Cr H 3 CO CH 3 O H 3 CO 25 °C, 2 h 85% 170 °C, 1 h 22% Me H 3 CO Cr(CO) 5 Me H 3 CO O 100% addition of LA causes decomp Diels-Alder Cycloadditions Wulff, JACS, 1990, 3642. Cr(CO) 5 H 3 CO CH 3 (CO) 5 CrH 3 CO H 3 C 25 °C, 2 h 87% 25 °C, 2 h 88% Me H 3 CO Cr(CO) 5 9:1 + Me OCH 3 Cr(CO) 5 Me H 3 CO Cr(CO) 5 Me OCH 3 Cr(CO) 5 + 8.5:1.5 17/18 12/20/99 3:57 PM B. Connell Fischer Carbenes Chem 206 Asymmetric Exo-Selective Diels-Alder Reaction Wulff, JACS, 1997, 6438. CH 3 N N O CH 3 Ph (CO) 4 Cr CH 3 OCH 3 TBSO 25 °C, 12 h, 80% CH 3 N N O CH 3 Ph (CO) 4 Cr CH 3 OTBS H 3 CO >96:4 exo:endo non-oxygenated dienes give ~85:15 exo:endo NCH 3 O Ph H 3 C M H 3 C C O C O HC O C O N OCH 3 TBSO Proposed Transition State [2 + 2] Cycloaddition O CH 3 W(CO) 5 H 3 CO 25 °C, 6 h 97% O CH 3 W(CO) 5 H 3 C corresponding ester does not react O CH 3 O H 3 C DMSO 10 min 95% O 180 °C, 16 h OH 3 CO O OCH 3 O O H 3 C O H 3 CO + 36% 24% O CO 2 CH 3 CO 2 CH 3 Wulff, JACS, 1988, 8727. 19/20 12/20/99 3:58 PM B. Connell Fischer Carbenes Chem 206 [3 + 2] Cycloaddition CH 3 M(CO) 5 H 3 CO OH 3 CO CH 3 TMSCHN 2 25 °C, 2 h TMSCHN 2 70 °C, 5 d HN N CH 3 OCH 3 (OC) 5 M 76 - 87% CAN 97% HN N CH 3 OCH 3 O HN N CH 3 OCH 3 O HN N H 3 C H 3 CO O + 30 min 25% 48% Wulff, JACS, 1986, 6726. Barluenga TL, 1998, 4887. Barluenga JCS Perkin I, 1997, 2267. >300:1 regioselection Dotz Reaction (CO) 5 Cr OCH 3 R S R L ? –CO OH OCH 3 R L R S (CO) 3 Cr Dotz ACIEE, 1975, 644. New J. Chem., 1990, 433. ACIEE, 1984, 587. R L R S H 3 CO (CO) 5 Cr O Observed Connectivity: Thermal Reaction of Unsaturated Carbene Complexes "...one of the most utilized reactions in natural product synthesis involving an organometallic process." 21/22 12/20/99 3:59 PM B. Connell Fischer Carbenes Chem 206 Dotz Proposed Reaction Mechanism (CO) 5 Cr OCH 3 –CO ?S ? = +6.2 e.u. ?H ? = +26 kcal/mol (CO) 4 Cr OCH 3 R S R L (CO) 4 Cr OCH 3 R S R L (CO) 4 Cr OCH 3 R L R S rate-limiting CO dissociation (CO) 4 Cr OCH 3 R L R S (CO) 3 Cr OCH 3 R L R S O O R L R S OCH 3 Cr(CO) 3 HO R L R S OCH 3 Cr(CO) 3 Barluenga, JACS, 1994, 11191. 800 psi CO HO R L R S OCH 3 Cr(CO) 6 + Dotz Alternative Workup Procedures HO R L R S OCH 3 Cr(CO) 3 air or FeCl 3 H 2 O (NH 4 ) 2 Ce(NO 3 ) 6 (NH 4 ) 2 Ce(NO 3 ) 6 CH 3 OH HO R L R S OCH 3 O R L R S O O R L R S OCH 3 OCH 3 See Wulff, JOC, 1984, 2293. 23/24 12/20/99 4:00 PM B. Connell Fischer Carbenes Chem 206 Dotz: Large Scale Applicability (CO) 5 Cr OCH 3 Ph 1.5 equiv. n-Bu THF, reflux, 45-60 min 1.1 equiv. Ac 2 O 1.1 equiv. NEt 3 0.16 equiv. DMAP OAc OCH 3 n-Bu 400 g scale 68% Timko TL, 1988, 2513. Org. Synth., 1992, 72. Dotz: Nitrogen Analog (CO) 5 Cr N CO 2 Et Barluenga, JOC, 1998, 7588. PhH THF, 60 °C 95% N Ph OH CO 2 Etthen SiO 2 U-66,858 lipoxygenase inhibitor Wulff, JOC, 1995, 4566. Biaryl Synthesis OCH 3 (CO) 5 Cr R 3 H R 2 R 1 R 1 R 2 R 1 HO R 3 R 1 OCH 3 R 3 R 2 OH OCH 3 + Wulff, JACS, 1996, 2166. 2 equiv. The concept works, in moderate to low yield, but the reactions must be run stepwise. Occasionally CO insertion is suppressed and five-membered rings are formed. 25/26 12/20/99 4:00 PM B. Connell Fischer Carbenes Chem 206 Synthetic Uses OCH 3 TMS OCH 3 OCH 3 Cr(CO) 5 OCH 3 CH 3 H 3 CO 2 C CH 3 CN, 45 °C, 24 h 66% OCH 3 TMS OCH 3 OCH 3 OH OCH 3 CH 3 CO 2 CH 3 O OH O O OCH 3 CH 3 OCH 3 menogaril antitumor antibiotic Wulff, JOC, 1998, 840. Intercepted Intermediates H 3 C CH 3 H 3 CO (CO) 6 Cr OH EtEt O H 3 C O CH 3 Et Et OCH 3 37% O Et Et OCH 3 Cr(CO) 3 HO Et Et OCH 3 Cr(CO) 3 via CH 3 CH 3 HO O H 3 C O CH 3 Et Et OCH 3 H Wulff, Chem. Commun., 1996, 1863. 27/28 12/20/99 4:05 PM B. Connell Fischer Carbenes Chem 206 AcO H 3 CO OCH 3 Cr(CO) 4 Synthetic Uses Wulff, Synthesis, 1999, 80. Ot-Bu O CH 2 Cl 2 , 45 °C, 24 h 1) 2) Tf 2 O, pyr O Ot-Bu OTf OCH 3 CH 3 O AcO 67% OHOH O O OH OCH 3 OH CH 3 O disaccaride H O trisaccaride R R = CH 3 Chromomycin R = H, Olivomycin antitumor antibiotics O O OH OH OHOCH 3 OH O CH 3 Application to Synthesis Daunomycinone OTMS H 3 CO (CO) 5 Cr TMS H 3 CO (CO) 5 Cr OTMSTMS O O OCH 3 TMS OTMS O O O OCH 3 OTMS OTMS O O Wulff, JACS, 1984, 434 & 7565. 8 equiv. 1.5 equiv. 50 °C, THF, 3 d ~25% 29/30 12/20/99 4:05 PM B. Connell Fischer Carbenes Chem 206 N H 3 C O Ph W(CO) 5 H 3 CO Dihydrofluorene Synthesis N O OCH 3 H 3 C Barluenga, Chem Commun., 1995, 1973. + N O H 3 C W(CO) 5 OCH 3 N O H 3 C W(CO) 5 OCH 3 N O OCH 3 H 3 C -20 °C to rt 12 h >95% Wulff, JOC, 1993, 5571. Alkyne-Alkene Reactions (OC) 5 Cr OCH 3 CH 3 H 3 C CH 3 CH 3 CN, 70 °C, 3 h 83% 1) 2) H + O H 3 C CH 3 O (OC) 5 Cr OCH 3 H 3 C CH 3 H 3 C H 3 CO OCH 3 Cr(CO) 3 CH 3 H 3 C O H 3 C CH 3 H 3 C OCH 3 H + 31/32 12/20/99 4:06 PM B. Connell Fischer Carbenes Chem 206 Merlic, JACS, 1992, 5602. Ketene Cyclizations Cr(CO) 5 OCH 3 hν OCH 3 OH 60 - 90% Via: CH 3 O O Cr(CO) 4 "Asymmetric" Benzopentaannulation CH 3 O H 3 C CH 3 (CO) 5 WPh LiPh MeOTf quench then H 3 C R * O Ph Barluenga, JACS, 1998, 12129. OR * (CO) 5 W Ph Ph [1,3] R * O Ph Ph (CO) 5 W R * O Ph W(CO) 5 MeOTf H 3 C W(CO) 5 Ph H 3 C R * O 90%, 2:1 diastereoselectivity 33/34 12/20/99 4:07 PM B. Connell Fischer Carbenes Chem 206 "A Versatile [4 + 2 + 1 - 2] Cycloaddition" Herndon JACS, 1988, 3334. TL, 1989, 295. JOC, 1990, 786. JACS, 1991, 7808. JACS, 1992, 8394. O OCH 3 R L R S R S R L 99:1 dioxane:H 2 O 8 h, ? (CO) 5 Cr OCH 3 Cr 0 , H 2 O (CO) 4 Cr R L R S OCH 3 (CO) 3 Cr O R S R L OCH 3 (CO) 3 Cr O OCH 3 R L R S Cr (CO) 3 O CH 3 O R S R L O OCH 3 R L R S H 2 CCH 2 loss of O OCH 3 R L R S (CO) 5 W OCH 3 same conditions O R L R S OCH 3 65% 40 - 90% Furan Synthesis Herndon, JOC, 1998, 4564. R 3 R 1 R 2 R 4 O (CO) 5 Cr OCH 3 CH 3 1) 2) H 3 O + 66 - 84% O R 4 R 2 R 1 R 3 CH 3 O R 1 R 2 R 4 O (CO) 4 Cr R 3 OCH 3 H 3 C R 1 R 2 R 4 O (CO) 4 Cr R 3 OCH 3 H 3 C O R 4 R 2 R 1 R 3 H 3 C OCH 3 H 3 O + 35/36 12/20/99 4:08 PM B. Connell Fischer Carbenes Chem 206 Photochemistry ? Electronic absorption consists of three low-lying bands: ? ~500 nm: spin-forbidden M → carbene π* charge transfer transition ? 360-450 nm: spin allowed M → carbene π* charge transfer transition (visible) ? 300-350 nm: ligand field transition ? In addition, all carbene complexes absorb strongly below 300 nm. Geoffroy, JACS, 1983, 3064. (CO) 4 Cr OCH 3 CH 3 hν OC (CO) 4 Cr O OCH 3 CH 3 (CO) 4 Cr H 3 CO CH 3 O ? Exposure to light leads to a reversible CO insertion: Molecular Orbital Diagram (CO) 5 Cr OCH 3 CH 3 (CO) 5 Cr OCH 3 CH 3 Geoffroy, JACS, 1983, 3064. ? Photolysis results in a formal, reversible, one electron oxidation of the metal. HOMO is metal-d-orbital centered LUMO is carbene carbon p-orbital centered 37/38 12/20/99 4:09 PM B. Connell Fischer Carbenes Chem 206 Ketene [2 + 2] OCH 3 (CO) 5 Cr CH 3 N S hν N S H 3 C H 3 CO H 81% Hegedus Tetrahedron, 1985, 5833. JOC, 1997, 3586. Hegedus JOC, 1995, 3787. JOC, 1996, 6121. Organometallics, 1997, 2313. JOC, 1998, 4691 & 8012. OCH 3 (CO) 5 Cr C 8 H 17 NO O Ph hν NO O Ph C 8 H 17 H 3 CO O MCPBA NO O Ph O O C 8 H 17H 3 CO TBAF O O C 8 H 17H 3 CO 84%, ≥97% de 1) NaOCl 2) NH 3 O O H 2 N O C 8 H 17 (+)-Cerulenin 92% 90% 30% 100% O NO O Ph Ene Carbamate Synthesis (CO) 5 Cr HN CH 3 OH Ph 2 equiv. NaH O PhO OPh O N O Ph (CO) 4 Cr CH 3 PhONa O N O Ph (CO) 4 Cr CH 2 PhOH O N O Ph (CO) 4 Cr CH 2 H Hegedus, JACS, 1990, 6255. 88% 39/40 12/20/99 4:10 PM B. Connell Fischer Carbenes Chem 206 Amino Acid Synthesis Hegedus JACS, 1990, 2264. JACS, 1992, 5602. JACS, 1993, 87. Acc. Chem. Res., 1995, 299. JOC 1995, 5831. JACS, 1995, 3697. JOC 1997, 7704. N (CO) 5 Cr CH 2 R H 3 C H 3 C Ph hν, t-BuOH 60-80% ≥97% de O Ot-Bu R N CH 3 CH 3 Ph ? Mutiply-labeled amino acids are readily prepared from ( 13 CO) 6 CO and CH 3 OD: O 13 C 13 C Ot-Bu R N CH 3 CH 3 Ph D Peptide Synthesis N (CO) 5 Cr CH 3 H 3 C H 3 C Ph hν NH 2 H 3 CCO 2 t-Bu N CH 3 CH 3 Ph O N H CO 2 t-Bu CH 3 H 3 C 68 - 88% yield 80-96% de Solid Support ? Reactions have been performed and do work, but are not as practical because the failure to achieve 100% yields and high diastereoselectivity limit this method. ? hard to work with because the polymer "sticks to everything, making quantitative transfer difficult". Acc. Chem. Res., 1995, 299. Merrifield Resin: Acc. Chem. Res., 1995, 299. PEG: JOC 1995, 5831; JOC 1997, 7704. 41/42 12/20/99 4:10 PM B. Connell Fischer Carbenes Chem 206 Aryl Glycines (CO) 5 Cr HN Ar OH Ph Ph hν O H N HO Ar Ph Ph (CO) 5 Cr H N O Ph Ph O Ar H 2 , PdCl 2 Ar H 3 NCO 40 - 95% yield 56 - 98% ee Aryl glycines cannot be made via the previous route due to instability of the required carbenes: N (CO) 5 Cr Ar H 3 C H 3 C Ph Hegedus, JOC, 1992, 6914. Tertiary Amino Acids Hegedus, JOC, 1993, 5918. N (CO) 5 Cr H O H 3 C H 3 C Ph N O hν N O O N O H 3 C H 3 C Ph 1) 0.2 M HCl 2) phosgene N O O N O Ph O 1) KHMDS 2) RX, DMF N O O N O Ph O R HCl, CH 3 OH O CH 3 O 2 C N O Ph O R tertiary amino acids H 43/44 12/20/99 4:11 PM B. Connell Fischer Carbenes Chem 206 Zwitterionic Aza Cope Rearrangement Hegedus, JOC, 1996, 2871. OCH 3 (CO) 5 Cr CH 3 N Bn hν 71% Bn N O OCH 3 CH 3 91:8 81:19 (CO) 4 Cr H 3 CO CH 3 ON Bn [3,3] H 3 CO CH 3 ON Bn Michael Reaction NCH 3 N O(CO) 4 Cr R OLi -40 °C NCH 3 N O (CO) 4 Cr RO R Ph CH 3 Yield 81% 92% syn:anti 99.5:0.5 98.3:1.7 Wulff, JACS, 1993, 4602. N(CH 3 ) 2 (CO) 5 Cr CH 3 Ob) a) n-BuLi O (CH 3 ) 2 N (CO) 5 Cr DMSO O (CH 3 ) 2 N O 71% 85% -78 °C, 20 min Heathcock, JOC, 1986, 279. 45/46 12/20/99 4:12 PM B. Connell Fischer Carbenes Chem 206 NCH 3 N O CH 3 Ph (CO) 4 Cr H 3 C Asymmetric Michael Addition NCH 3 N O CH 3 Ph (CO) 4 Cr H 3 C OLi Ph -20 °C CH 3 O Wulff, Chem. Commun., 1996, 2601. 3:1diastereoselection NCH 3 N O CH 3 Ph H 3 C (CO) 4 Cr a) n-BuLi b) O R 1 R 2 NCH 3 N O CH 3 Ph (CO) 4 Cr R 1 R 2 O >96:4 diastereoselection NCH 3 N O CH 3 Ph (CO) 4 Cr R 1 CH 3 O 1) CAN 2) NaOCH 3 R 1 CH 3 O OCH 3 O 90% 80% Asymmetric Michael Reaction CH 3 O H 3 C CH 3 (CO) 5 Cr Ph OLi OCH 3 CH 3 OR * (CO) 5 Cr Ph CH 3 OCH 3 O 74%, 84% de OR * (CO) 5 Cr Ph O 89%, 99% de Ph OLi Ph H 3 C Barluenga, Chem. Eur. J., 1995, 236. Ph CH 3 47/48 12/20/99 4:12 PM B. Connell Fischer Carbenes Chem 206 Michael Reactions: Selectivity NCH 3 N O CH 3 Ph C Cr CO CO OC OC H H O R 1 H R 2 Open Transition States are Postulated O CO CO OC OC CO Cr R CH 3 H 3 CCH 3 Ph W(CO) 5 EtO H 3 CCH 3 OHN H Pyridine Synthesis then HBF 4 N CH 3 O CH 3 Ph 75% Ph (CO) 5 W EtO O CH 3 H N CH 3 H Aumann, Synlett, 1993, 669. HN CH 3 O CH 3 Ph (CO) 5 W HBF 4 H W(OC) 5 EtO CH 3 NH H 3 C O W(OC) 5 EtO CH 3 HN H 3 C O W(OC) 5 EtO CH 3 HN H 3 C O H H 49/50 12/20/99 4:13 PM B. Connell Fischer Carbenes Chem 206 Alkylation OCH 3 (CO) 5 Cr CH 3 a) n-BuLi b) MeI OCH 3 (CO) 5 Cr CH 2 CH 3 22% OCH 3 (CO) 4 Cr CH 3Bu 3 P a) n-BuLi b) EtI 65% OCH 3 (CO) 4 Cr Bu 3 P + CH 3 OCH 3 (CO) 4 Cr Bu 3 P CH 3 CH 3 7:3 OCH 3 (CO) 5 Cr CH 3 a) n-BuLi b) OCH 3 (CO) 5 Cr 80% OTf Wulff, JOC, 1987, 3263. Hegedus Org. Synth., 1987, 140. Wulff, TL, 1989, 4061. N (CO) 5 Cr CH 3 a) n-BuLi b) EtI 87% N (CO) 5 Cr Bu 3 P substitution often leads to different reactivity: TL, 1995, 8159. CH 3 "Aldol" Reaction (CO) 5 Cr OCH 3 CH 3 a) n-BuLi b) 10 equiv. PhCHO/BF 3 ?OEt 2 (CO) 5 Cr OCH 3 Ph OH 81% (CO) 5 Cr N CH 3 a) n-BuLi b) 1.1 equiv. PhCHO/BF 3 ?OEt 2 96% (CO) 5 Cr N Ph OH Wulff, JACS, 1985, 503. Wulff, JACS, 1989, 5485. Wulff, JOC, 1994, 6882. oxazolidinone complexes were unstable: Hegedus, JACS, 1990, 6255. NCH 3 N O CH 3 Ph H 3 C (CO) 4 Cr a)n-BuLi b) Bu 3 B c) i-PrCHO then CAN NCH 3 N O CH 3 Ph O CH 3 H 3 C OH 74% ds: 98.6: 1.4 in absense of Bu 3 B, ds: 91:9 Ketones work as well. 51/52 12/20/99 4:13 PM B. Connell Fischer Carbenes Chem 206 Ene Reaction CH 3 W(CO) 5 H 3 CO OR + 25 °C, 4 h R = CH 3 90% R = TBS 96% RO CH 3 (CO) 5 W OCH 3 RO CH 3(CO) 5 W OCH 3 R = CH 3 23: 77 R = TBS 90:10 + Wulff, JACS, 1990, 6419. Reaction of Ketene Acetals Wulff, JACS, 1992, 10665. (CO) 5 Cr O CH 3 CH 3 H 3 C 1) OCH 3 OCH 3 2) aq. HCl O O H 3 C CH 3 H 3 C (±)-eldanolide sex pheromone 50% 24:1 trans:cis 80 °C, 3 d (CO) 5 Cr O CH 3 CH 3 H 3 C OCH 3 OCH 3 (CO) 5 Cr CH 3 CH 3 H 3 C OCH 3 OCH 3 O H O OCH 3 OCH 3 H 3 C CH 3 H 3 C 53/54 12/20/99 4:14 PM B. Connell Fischer Carbenes Chem 206 Vinylsilane Synthesis Iwasawa, Chem. Lett., 1994, 231. (CO) 5 Mo OCH 3 SiPh 2 CH 3 RCH 2 Li or RCH 2 MgX CeCl 3 H 3 CPh 2 Si R R = i-Pr, 94%, 96:4 E:Z R = Bu, 86%, 96:4 E:Z R = i-Bu, 85%, 97:3 E:Z -78 °C, cold quench H 3 CPh 2 Si R RCH 2 Li or RCH 2 MgX CeCl 3 , HMPA -78 °C to rt R = i-Pr, 76%, 92:8 Z:E R = Bu, 79%, 97:3 Z:E R = i-Bu, 61%, 97:3 Z:E (CO) 5 Mo OCH 3 SiPh 2 CH 3 Vinylsilane Synthesis Proposed Mechanism n-BuLi (CO) 5 Mo OCH 3 SiPh 2 CH 3 n-Bu Li warm (CO) 5 Mo n-Bu SiPh 2 CH 3 CH 3 OLi (CO) 5 Mo SiPh 2 CH 3 Li SiPh 2 CH 3 H 2 O -78 °C (CO) 5 Mo OCH 3 SiPh 2 CH 3 n-Bu H – LiOCH 3 – HOCH 3 (CO) 5 Mo n-Bu SiPh 2 CH 3 hydrogen migration (CO) 5 Mo SiPh 2 CH 3 H SiPh 2 CH 3 55/56 12/20/99 4:14 PM B. Connell Fischer Carbenes Chem 206 Allyl Stannane Synthesis Merlic, TL, 1995, 1007. W(CO) 5 OCH 3 H 3 C Bu 3 SnH, pyr SnBu 3 OCH 3 H 3 C 73% Cr(CO) 5 OCH 3 H 3 CO Ph Bu 3 SnH, pyr 69% SnBu 3 OCH 3 H 3 CO Ph W(CO) 5 OCH 3 1,1 addition is usually observed, however 1,3 addition is possible: TMS Bu 3 SnH, pyr 88% OCH 3 TMS Bu 3 Sn E:Z 1:1 W(CO) 5 MOM Me OMOM Me Bu 3 Sn Bu 3 SnH, pyr 66% Wulff JACS, 1990, 1645. JACS, 1991, 5459. Halban-White Cyclizations Ph O O Ph COPhPhCO hν Ph OPh O COPhPhCO Ph OPh O O Ph Ph O O O Ph PhO Ph OPh Andres, A. Dissertation, Strasbourg, 1911. van Halban, Helv. Chim. Acta, 1948, 1899. (CO) 5 M OCH 3 R 5 R 6 R 4 R 1 R 2 O yields 30-70% Dotz byproduct R 4 O R 1 OR 2 H 3 CO R 6 R 5 O O R 2 R 6 R 5 R 3 R 4 R 1 57/58 12/20/99 4:15 PM