Fischer Carbene Complexes in Organic Synthesis Ke Chen 1/31/2007

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Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen 1/31/2007

Ernst Otto Fischer (1918 - ) Other Types of Stabilized Carbenes: German inorganic chemist. Born in Munich Schrock carbene, named after Richard R. Schrock, is nucleophilic on November 10, 1918. Studied at Munich at the carbene carbon atom in an unpaired triplet state. Technical University and spent his career there. Became director of the inorganic Comparision of Fisher Carbene and Schrock carbene: chemistry institute in 1964. In the 1960s, discovered a metal alkylidene and alkylidyne complexes, referred to as Fischer carbenes and Fischer carbynes. Shared the Nobel Prize in Chemistry with Geoffery Wilkinson in 1973, for the pioneering work on the chemistry of organometallic compounds. Schrock carbenes are found with: Representatives:

Isolation of first transition-metal carbene complex: high oxidation states early transition metals Ti(IV), Ta(V) CH2 non pi-acceptor ligands Cp2Ta CH N Me LiMe Me 2 2 non pi-donor substituents CH3 (CO) W CO (CO)5W 5 (CO)5W A.B. Charette J. Am. Chem. Soc. 2001, 123, 11829. OMe O

E. O. Fischer, A. Maasbol, Angew. Chem. Int. Ed., 1964, 3, 580. Persistent carbenes, isolated as a crystalline solid by Anthony J. Arduengo in 1991, can exist in the singlet state or the triplet state.

Representative Fischer Carbenes:

W(CO) Cr(CO) 5 5 Fe(CO)4 Mn(CO)2(MeCp) Co(CO)3SnPh3

Me OMe Ph Ph Ph NEt2 Ph OTiCp2Cl Me OMe Foiled carbenes were defined as "systems where stabilization is Fischer carbenes are found with : obtained by the inception of the facile reaction which is foiled by the impossibility of attaining the final product geometry". They only low oxidation state metals; exist in the singlet state. middle and late transition metals Fe(0), Mo(0), Cr(0), W(0); pi-electron acceptor metal ligands; Rolf Gleiter, Ronald Hoffman J. Am. Chem. Soc. 1968, 90, 5457 - 5460. pi-donor substituents on methylene group such as alkoxy and Jean-Luc Mieusset and Udo H. Brinker J. Am. Chem. Soc. 2006, 128, amino groups. 15843 - 15850.

1 Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen 1/31/2007

Advantages over regular carbenes 2. Excellent functional group compatibility - serving as blocking groups - From fleeting intermediates to powerful reagents in organic synthesis.

1. Improved stability OTMS OMe Ph O H OMe o Typical carbenes such as diphenyl carbene have lifetimes in the BuLi, THF, -78 C [Cr] nanosecond regime. [Cr] Ph Et 75 % Et

3 equiv of CH2CHCH2Li, THF [Cr] O Most Fischer carbene complexes are stable to air and water and to -78 oC to RT, then SiO dilute acids and bases. Despite the high dipole moment of these 2 complexes (~ 4 - 5 Debye), most complexes can be purified by 71 % H chromatography on silica gel with hexane as eluent and are usually Ph Et the first compounds to elute. Identification of the fractions from the column containing the carbene complex can simply be done by eye on the basis of their color. The colors of complexes bearing alkoxy J. Barluenga. J. Am. Chem. Soc. 2002, 124, 9056 -9057. groups as the heteroatom-stabilizing group tend to correlate with the hybridzation of the carbon substituent of the carbene carbon. Those 3. Improved reactivity and selectivity with sp3 carbons usually are yellow, those with sp2 carbons are normally red and those with sp hybridized carbon substituents are Cr(CO)5 Cr(CO)5 invariably an intense purple/black color. Cr(CO)5 RT, 3 h MeO MeO MeO 70 %

92 : 8 O O O

MeO MeO MeO

thermal conditions: RT, 7 months, 54 % 70 : 30

AlCl3, 0.5 h , 50 % 95 : 5

W. Wulff. J. Am. Chem. Soc. 1990, 112, 3642. http://www.chemistry.msu.edu/faculty/wulff/myweb26/research/carbenes.htm

2 Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen 1/31/2007

Synthesis of Fischer carbene complexes: 2. Hegedus-Semmelhack approach 1. Standard Fischer route O

OK OR2 OLi OR C8K R1 Cl R X R Li RX 2 K [M(CO) ] (OC) M 2 M(CO) 1 M(CO)6 2 5 5 (OC)5M 6 (OC)5M (OC)5M R1 R1 R1 R1 O M = Cr, Mo, W R3 R1 = alkyl, aryl, vinyl HN R1 NR3R4 2 + - HS R3 RX = R 3O BF4 , R2OSO3F R4 R3, R4 = H, alkyl - O NR3R4 SR3 NR3R4 TMSCl (OC)5M NR3R4 (OC)5M (OC)5M (OC)5M R1 R1 R1 R1

This is the most direct and general approach to Fischer carbene M = Cr, W complexes; R1 = alkyl, aryl, vinyl Limitations are the availability of organolithium compound R X = R2 O+BF -, R OSO F and the alkylation reagent. 2 3 4 2 3 R3, R4 = H, alkyl

O R2 This strategy combining an organoelectrophile and a metal nucleophile - + OLi + - O NMe4 O can be extended to the synthesis of aminocarbene complexes. Me4N Br X R2 (OC)5M (OC)5M O

R1 R1 (OC)5M R1 Recent reviews: M = Cr, W R1 = alkyl, aryl, vinyl W. D. Wulff, in Comprehensive Organometallic Chemistry II, ed. R3OH R2 = Me, tBu A. W. Abel, F. G. A. Stone and G. Wilkinson, pergamon Press, Oxford, 1995, vol. 12, p. 469 X = Br, Cl L. S. Hegedus, ibid., vol. 12, p. 549. R = terpene, sugar skeletons 3 OR3

(OC)5M

This is the standard approach to optically active Fischer carbene complexes bearing alkoxy substituents.

3 Baran Group Meeting Fischer Carbene Complexes in Organic Synthesis Ke Chen 1/31/2007

Reaction pattern of carbene complexes: Pattern B: Bond formation via metal carbene anions

Part I: Ligand-centered OR OR OMe OMe (OC)5M (OC)5M (OC)5Cr O R R pKa = 12 pKa = 25 C

H3C OH O O OC CO O R A E CH3 N 1. nBuLi OC Cr O 2. PhCHO Ph N CH OC CO N 3 CR2 Nu N 3. HOAc / Ce(IV) Ph H B (OC)4Cr Ph B 60 %, > 96 % de CH3 CH3 W. Wulff, J. Org. Chem., 1994, 6882.

Pattern A: Addition of nucleophiles OMe OMe 1. nBuLi O OMe (OC)5Cr (OC)5Cr (OC)5Cr OMe NHR H - MeOH 2. O (OC)5Cr NH2R (OC) Cr 5 NHR (OC)5Cr Ph OLi Ph Ph

B. A. Anderson, J. Am. Chem. Soc., 1993, 115, 4602. OMe O (OC) Cr OLi 5 THF, -80 oC to RT Ph Li Pattern C: Transformation of metal carbenes to metal carbynes Ph O O 50 %

Cr(CO)5 J. Barluengal, J. Chem. Soc., Chem. Commun. 1993, 1068

Ph OMe ? (OC)5Cr N N MeO For reviews on reaction pattern of carbene complexes, see "Carbene Chemistry : From Fleeting Ph Intermediates to Powerful Reagents", chapter 8. Cr(CO)5

H. Fischer, Chem. Ber. 1980, 113, 193

4 Baran Group Meeting Ke Chen 1/31/2007 Fischer Carbene Complexes in Organic Synthesis

Reaction pattern of carbene complexes: Diels-Alder reaction of boroxycarbene complexes: Part I: Ligand-centered 1. t-BuLi, Et2O F Cycloaddition reactions: (OC)5Cr O Ph OMe Br 2. Cr(CO)6, Et2O B F OMe N [2 + 2] CH3 N OMe (OC)5W . N Me RT, 12 h 3. BF3 Et2O, RT (OC)5W H3CO 87 % 1.THF, -78 oC to RT 85%

CH3 K. L. Faron, J. Am. Chem. Soc. 1988, 110, 8727 -8729. 2. 3N HCl, THF, RT 95 % [3 + 2] TMSCHN2 F OMe OMe (OC)5Cr O hexanes, RT CHO B F (OC)5W (OC)5W HBr, DCM, RT N 4.5 h, 87 % NH N 85 % N H3C O O CH3 W. D. Wulff, J. Am. Chem. Soc. 1986, 108, 5229 -5236. [4 + 2] J. Barluenga. J. Am. Chem. Soc. 1998, 120, 2514 -2522. H3C H3C CH TBSO CH N 3 N 3 Miscellaneous cases O O Ipc N OCH3 N Ph OLi O B Ph (-) -Ipc2BCl, Et2O Ph H (OC)4Cr (OC)4Cr CH3 DCM, RT, 12 h (OC)5W 80 %,single isomer -78 oC to RT CH O 3 Ph CH3 OTBS

W. D. Wulff, J. Am. Chem. Soc. 1997, 119, 6438 -6439. J. Barluenga, J. Am. Chem. Soc,, 1996, 118, 6090 -6091. H2O2, NaOH Intramolecular Pauson -Khand reaction: 83 %, > 99 % de

NH (OC) W Ph (OC) W 5 OH OH 5 [Co2(CO)8] Ph 75 % O Ph J. M. Moreto. Angew. Chem. Int. Engl. 1991, 11,1470.

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Reaction pattern of carbene complexes: OMe OMe Part II: Metal-centered DMF, 152 oC (OC)5Cr H 1. Reaction with olefins Fe 88 %, 97 % de Fe OR 1 OR1 OR1 (OC)5Cr (OC)4Cr (OC)4Cr R2 R 2 R2 "The functionalized Ru Fischer-type complexes are active in a variety of Cr(CO) H 5 THF, 100oC Me olefin metathesis reactions, although Et with significantly lower rates than the Olefin Metathesis Me OMe 55 % MeO corresponding carbon analogues." Cyclopropanation Et favored R, H. Grubbs, Organometallics. 2002, 21, 2153 -2164. H H General carbene complexes used in cyclopropanation reactions: Et Et Cr R R MeO MeO Cp Cp (CO)4 Cr(CO) Cr(CO) Cr(CO)5 Cr(CO)4 R*Ph2P OC 5 5 Fe H Fe H H OC OC CH 2 Me OMe Ph OMe OMe Me H Me MeO Cr R MeO R Et MeO (CO) Et W(CO)5 W(CO) Mo(CO) 4 Et 5 5 Cr(CO)4 disfavored

Ph OMe Ph H Bu OMe J. Am. Chem. Soc. , 113, 23, 1991, 8916-8921 (leads to olefin (less stable ) metathesis product) O O Cr(CO)5 Suitable olefins: O Cl 85oC,12 h Alkyl R1 OMe intermediate A O Alkyl R 85 % EWG EWG 1 O EWG R2 R2

R1 R1, R2 = akyl, aryl R1, R2 and R3 = alkyl R3 Chemtracts - Organic Chemistry. 17, 67 -71, 2004 R requires stronger 2 electrophilic metal carbenes

6 Baran Group Meeting Ke Chen 1/31/2007 Fischer Carbene Complexes in Organic Synthesis

Reaction pattern of carbene complexes: Part II: Metal-centered OMe O O OMe O O OH ether, reflux 2. Benzannulation (Dotz reaction) Cr(CO) nPr 5 51 % Cr(CO)5 Cr(CO)4

- CO O OMe OMe M. F. Semmelhack, Tetrahedron, 1985, 5803. + CO

RS RL OTBS OCPh3 OMe OCPh3 RS TBSCl, hunig base (OC)5Cr RL Cr(CO) > 92 % d. e. 3 RS OMe RL Cr(CO)4 O Cr(CO)3 W. D. Wulff, J. Am. Chem. Soc,, 1994, 116, 6449. OMe

OMe RS OMe RL OC Cr CO OTBS O O OMe OC CO minimization of interaction MeO Cr(CO)5 35 % RL RL O RS TBSO HO RS O O Cr(CO)3 BnO OMe Cr(CO)3 OMe EtO N O O OMe OTBS MeO

Suitable metal: Compatible substitution pattern: fredericamycin A Cr (metal of choice) Aryl carbenes with various substituents O O OH OTBS Mo ( furan formation occasionally) Naphthyl and heteroaryl carbenes W (favor 3 + 2 cycloaddtion) BnO Vinyl carbenes bearing alkyl substituents N Mg (low yields) EtO Electron - neutral alkynes with various substituents D. L. Boger, J. Am. Chem. Soc,, 1995, 11839.

7 Baran Group Meeting Ke Chen 1/31/2007 Fischer Carbene Complexes in Organic Synthesis

Reaction pattern of carbene complexes: Me OMe O Part II: Metal-centered MeO Me OMe (OC)5Cr O 3. General Annulation of Fischer carbenes with alkynes and alkenes: CH3

Organometallics, 1990, 9, 3014 - 3015 13 % 10 %

OMe H (OC)5Cr CO2Et CH3 CO2Et 66 % OMe J. Am. Chem. Soc. 1994, 116, 6719 - 6732 Bu

OMe O THF, 70 oC, 24 h O (OC)5Cr O OMe Ph O CO, 73 %, d. r. = 3 :1 H O O CH3 O CH3 J. Am. Chem. Soc. 1992, 114, 10665 - 10666 OMe Ph C3H7 Ph (OC)5Cr O O O CH OMe Ph O 3 CH3 THF, 105 oC, 15h OMe O CH CH3 CH 3 Ph 3 Ph OMe OMe (OC)5Mo 48 % 18 % THF, 70 oC, 14 h, 40 % Ph Me J. Am. Chem. Soc. 1991, 113, 5459 - 5461 CH3

J. Am. Chem. Soc. 1990, 112, 1645 - 1647 Ph OMe Ph Ph THF, 90 oC O O OEt Me Me EtO Ph EtO Ph (OC)5Cr Ph Me (OC)5Cr NMe2 3 71 % TMSO OTMS MeO Me THF Ph NMe NMe SiMe3 2 2 Ph Ph Ph J. Barluenga, Org. Lett., 2006, 8, 2703 -2706. Angew. Chem. 1999, 111, 1369 64 : 36

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State of art: Group 6 metal carbenes in catalytic carbene transfer reactions

OMe OMe (OC)5M L M multi-faced n chemistry R R M = Cr, W M = Pd, Cu, Rh stable, storable, less reactive reactive, unstable

NMe2 O CO2Me (OC)5Cr 2 mol %Pd(OAc)2, Et3N CO2Me

Jose Barluenga THF, reflux, 8 h, 80 % Br Daniel F. Harvey

Br M. A. Sierra, J. Am. Chem. Soc., 2001, 123, 851 -861.

1. [Cu(MeCN) ][PF ], DCM O 4 6 2. DCM, Et2O (OC)5Cr

MeCN O J. Barluenga, Angew. Chem. Int. Ed., 2001, 40, 3392. Cu PF6 Et2O O William D. Wulff Louis S. Hegedus