Baran Lab Stephen Buchwald Tom Maimone

-This presentation will try to cover the work of professor Buchwald in somewhat chronological order until 2007. -It is fairly comprehensive, with ~ 125 papers referenced.

main topics: I. Zirconium Chemistry (1986-1999) II. Titanium Chemistry (1991-2000) III. Copper Hydride Chemistry (1999-2005) III. Cross-Coupling (Pd, Cu) (1994-present)

Biographical: I. Zirconium Chemistry -Born 1955 in Bloomington, IN The chemistry of Zirconium-alkyne complexes: JACS, 1986, 108, 7441. Bond length 1.295 A -Sc.B Brown University 1977: Li (between double and triple) (Kathlyn Parker and David Cane) PMe3 -Ph.D Harvard 1982: Me Cp2Zr Cp2Zr PMe3 (Jeremy Knowles) Cl ZrCP2 -Postdoc Caltech 1982-1984: PMe3 Cp2Zr air and moisture (Robert Grubbs) Me THF sensitive -hobbies include sports, food, and cats (as of 1988) O N and acylic alkynes: Cp2Zr Professional Appointments: Cp2Zr JACS, 1987, 109, 2544 O CN 1984 assistant professor MIT PMe 1989 associate professor MIT 3 R R 1993 full professor MIT Cp2Zr 1997 Camille Dreyfus Professor O R Cp2Zr PMe3 R Cp2Zr ZrCp2 over 300 publications O and acylic alkenes: over 35 patents R R JACS, 1987, 109, 2544.

Selected Awards: PMe3 Arthur C. Cope Scholar ACS Organometallic Chemistry Award (2000) Cp Zr Cp2Zr 2 Cp2Zr R Siegfried Medal Award (2006) ACS Creative Work in Synthetic Chemistry (2006) an excellent review: National Academy of Science (2008) Chem. Rev. 1988, 88, 1047

1 Baran Lab Stephen Buchwald Tom Maimone

I. Zirconium Chemistry Zirconocene-Thioaldehyde complexes: JACS, 1987, 109, 1591. Cyclopentenone synthesis: JACS, 1989, 111, 9113 JACS, 1988, 110, 3171

Me Me3P Cp O PMe 2 3 ZrCp Zr R SH ZrCp2 Δ 2 R CO Cp2ZrMe2 R S Cp2Zr R S (-CH4) (-CH4) PMe3 R R N C

H also see benzyne complexes: JACS, 1986, 108, 7411. N N ZrCp 2 ZrCp2 benzene PMe3 R S Cp2ZrPh2 Cp2Zr Cp2Zr R S 80 °C PMe3 Butenolide Synthesis: TL, 1988, 29, 3445 O Similar elaboration is possible: TL, 1987, 28, 3245. OH O Cp OH I2 O 2 1. Cp2Zr(H)Cl Cp Zr R C N Zr H O+ 2 Cp Zr 3 O 2 N CO Cl R R Cis Difunctionalization of Cyclic olefins: Organomettalics, 1991, 10, 537. Double complexes can be prepared: JACS, 1987, 109, 4396 O ZrCp Cp2 2 Zr CO Li Me ZrCp2 80 °C MeOH ZrCp2 + Cp2Zr(Me)Cl PMe3 E + other SCl2 THF Δ isomers E S Li Cp2Zr ZrCp2 Me

2 Baran Lab Stephen Buchwald Tom Maimone

I. Zirconium Chemistry Application to Natural Product Synthesis: Pyrrole Synthesis: JACS, 1989, 111, 776. Duocarmycin pharmacophore: JOC, 1992, 57, 6380. SiMe3 SiMe3 SiMe3 I CH R N 3 Li N R N R I I Cp2Zr Br Cp2Zr Cp2Zr Cl THF CH3 N I O t-BuLi 2 1. BBr3

Cp2Zr(Me)Cl 2. NaH O N MeO N R2 R1 R2 R1 R R CO 1 2 OMe

R Cp Zr N 2 R H N

SiMe3 Tetrahydropyrroloquinolines: JACS, 1996, 118, 1028. Me I 1. Pd(PPh ) Benzothiophene Synthesis: JOC, 1989, 54, 2793 as 3 4 Me N MeO Br MeO NHMe K2CO3 R R R before HO Et3N Zr S N 2. BBr3 R SiMe3 SCl2 NH2 Cp2Zr TMS TMS 3. MeI N THF CO2Et H Dehydrobufotenine R R R R R Regioselective, Directed Meta Acylation: JACS, 1998, 120, 9119.

Indole Synthesis: JACS, 1991, 113, 4685., JACS, 1994, 116, 11797 DG Cp2 DG Me Zr Br ZrCp X t-BuLi 2 X = H R X = I Cp2Zr(Me)Cl N N N Bn Bn Bn t-Buli + O 1. H3O or I2 Cp2Zr(Me)Cl + 2. H3O I I I Cp2Zr DG Me DG DG I Cp2 2 ZrCp2 Zr Δ R-CN ZrCp N N N N 2 Bn Bn Bn R 3 Baran Lab Stephen Buchwald Tom Maimone

I. Zirconium Chemistry Interesting Organometallic Structures: Use of Zirconocene in Biaryl Synthesis: JACS, 1999, 121, 9469. cyclic 7-membered cumulene: JACS, 1993, 115, 10394. SiMe R R 3 R ArBr, TMS TMS Cp2 TMS Br Pd (dba) ZrCp2(X) Zr 1. n-BuLi 2 3 TMS Cp2Zr ZrCp ligand Cp Zr ZrCp2 2. Cp2Zr(Me)Cl 2 2 TMS PdAr TMS TMS SiMe TMS 3 desired product product formed R R I Double alkyne Zirconocene Complex: JACS, 1994, 116, 5471 I2 ZrCp2(X)

Ar Ar TMS Interesting Organometallic Structures: TMS Cp ZrCl bimetallic Zirconium complex containing an in-plane briding aromatic ring: 2 2 JACS, 1989, 111, 397-398. ZrCp2 Me Me TMS Br Br TMS t-BuLi Cp2Zr ZrCp2 desired product

Cp2Zr(Me)Cl Cp ZrCl MeO OMe MeO OMe 2 2

TMS TMS TMS 80°C PhH ZrCp 2 ZrCp2 ZrCp2

H3 C TMS TMS Cp2Zr ZrCp2 TMS actually formed

MeO OMe

4 Baran Lab Stephen Buchwald Tom Maimone II. Titanium Chemistry Catalytic Reduction of Esters to Alcohols: JACS, 1991, 113, 5093 O JOC, 1992, 57, 3751 NaOH n-BuLi R OEt Cp TiCl R OSI(OEt) or HCl 2 (10%) 3 R OH (5%) HSi(OEt)3 (2 eq.)

Asymmetric Hydrogenation of imines: JACS, 1992, 114, 7562. JOC, 1993, 58, 7627. JACS, 1994, 116, 8952 (scope and limitations) JACS, 1994, 116, 11703 (Kinetic and mech. analysis)

N R 1) n-BuLi HN R X (2 eq) R R X Ti H R R 2) PhSiH Ti 3 H2 (2000 psi) (2.5 eq) 65 °C thought to (2 - 10 %) stablize active catalyst presumed active catalyst

5 Baran Lab Stephen Buchwald Tom Maimone

II. Titanium Chemistry Kinetic Resolution of Racemic pyrrolines: JACS, 1994, 116, 9373. Asymmetric Hydrogenation of Unfunctionalized trisubstituted usual olefins: JACS, 1993, 115, 12569. suspects R3 Ar Ar R Ar R N 1) n-BuLi 3 R N R N H X (2 eq) R1 R2 X Ti H Ti R R Asymmetric Enamine Hydrogenation: JACS, 1994, 116, 5985 2) PhSiH3 H2 (2000 psi) 1 2 (2.5 eq) 65 °C thought to usual N N (2 - 10 %) stablize active suspects catalyst presumed active catalyst

Enantioselective Ketone Hydrosilylation: JACS, 1994, 116, 11667. O 1) n-BuLi 3) OH X (2 eq) Ar R2 Ti aromatic ketone X Ar R 2) Me 4) TBAF 2 give best ee's or HCl OSiMe3 SiMe3 5% H n (5 eq) polymethyl - hydrosiloxane

Catalytic Reduction of Lactones to Lactols: JACS, 1995, 117, 12641 JOC, 1997, 62, 8522.

Cp2Ti O Cl

O O 2 O OH 2 mol% TBAF/Alumina (1%) PMHS (5 eq)

6 Baran Lab Stephen Buchwald Tom Maimone

Reductive Enyne Cyclizations with a practical Titanocene reaent: JOC, 1992, 57, 5803. JOC, 1996, 61, 2713. II. Titanium Chemistry JACS, 1996, 118, 9450 One-pot conversion of amides to aldehydes: ACIEE, 1996, 35, 1515. JACS, 1999, 121, 5881 O Ti(O-iPr) (1 eq) + O possibly 4 H3O R R via Cp2TiCl2 R NR2 Ph2SiH2 (1.1 eq) NR2 HTi(O-iPr) EtMgBr CO H 3 X X Cp2Ti X O Me Titanocene-based Indole Synthesis: JACS, 1998, 120, 3068. R N C X = O, C(CO2Et)2 N X can be troublesome, Cp2TiCl2 MeMgBr R Cl Me reacts with catalyst MgBr Ti Ti R Use of R3SiCN as the carbon monoxide equivalent: JACS, 1993, 115, 4912. air and Cp2 Cp2 R moisture R R JACS, 1994, 116, 8593.

stable R3Si CN R3Si NC low effective concentration Δ > 95% > 5% of isocyanide R R R Reductive Enone Cyclization: JACS, 1995, 117, 6785. via: Me Br2 JACS, 1996, 118, 3182 Br TiCp2 O Ti HO X Br O 1. Me Cp2Ti Cp2 Cp2Ti(PMe3)2 (10%) R R R PMe (80%) X 3 H Me 1) BnNH2 Ph2SiH2 X Pd(dba)3 Enyne and Dienyne Cycloisomerization: JACS, 1999, 121, 1976. 2. Work up Ph2SiH2 NaOt-Bu R 2) Pd/C γ−Butyrolactone synthesis: JACS, 1996, 118, 5818. Ph2(H)Si Me R JACS, 1997, 119, 4424 CO NH H O 2 4 Cp2Ti(CO)2 Me X X X R O O Cp2Ti PhMe Cp2Ti(PMe3)2 100 °C O CO H N H H Enantioselective Titanium-mediated Pauson-Khand: JACS, 1996, 118, 11688. R JOC, 1999, 64, 5547 JACS, 1999, 121, 7026 - 7033 R CO R OC Ti E CO E O E E typical ee's = 70 - 90

7 Baran Lab Stephen Buchwald Tom Maimone

III. Copper Hydride Chemistry Asymmetric reduction of cyclic enones: JACS, 2000, 122, 6797. O O Asymmetric Ester Conjugate Reduction: JACS, 1999, 121, 9473. CuCl (5%) NaOt-Bu (5%) CuCl (5%) Me Me O NaOt-Bu (5%) Me O (S)-p-tol-BINAP (10%) PMHS (1.05 eq.) Me3Si O Si O SiMe3 R R OEt (S)-p-tol-BINAP (10%) R R OEt H PMHS (4 eq.) n PMHS

(E) and (Z) isomers give opposite enantiomers of similar ee

One-pot Synthesis of 2,3 disubstituted cyclopentanones. OL, 2001, 3, 1129.

O Ph2 Asymm. Si O con. red. O O TBAT Bn Ph2SiH2 BnBr R R R R

TBAT = (Bu4N)Ph3SiF2

8 Baran Lab Stephen Buchwald Tom Maimone

III. Copper Hydride Chemistry Conjugate Reduction by Copper carbene complex: OL, 2003, 5, 2417. Dynamic Kinetic Resolution via conjugate reduction: JACS, 2002, 124, 2892. iPr Me O Me O iPr N A CuCl R OEt NaOt-Bu R OEt N iPr O PHMS O t-BuOH iPr

A R R yields typically ~ 90%

Total synthesis of Eupomatilone -3: ACIEE, 2005, 44, 6177. O B(OH) OMe 2 Br 1) Pd MeO O MeO CO2Me 2) BH3 THF 3) MnO2 MeO OMe 4) MeO O MgCl OEt OMe O Me O MeO O Enantioselective Lactam/lactone conjugate Reduction: JACS, 2003, 125, 11253. O O O O O usual usual CuCl2 2H2O X suspects X X suspects X (R)-MeO-BIPHEP PMHS NaOt-Bu R R R R O Me O X = O, N-PMP OMe OMe Asymmetric Reduction of enamides: PNAS, 2004, 101, 5821. MeO O MeO O Me NaHMDS Me CO R 2 CO2R CO R CO2R MeI 2 MeO MeO Cu(OAc)2 H2O R N R N (S) - BINAP Me N Me N MeO O MeO O PMHS O O O air O 85% ee's 80 - 99 93%ee

9 Baran Lab Stephen Buchwald Tom Maimone

Key Precedent: IV. Cross-Coupling Chemistry Migita: Chem Lett, 1983, 927 Palladium catalyzed Aromatic Amination with in Situ Generated Aminostannanes: PdCl2(P(o-tolyl)3)2 (cat) JACS, 1994, 116, 7901. ArBr + Bu3SnN(Et)2 ArN(Et)2

80°C Br Boger: JOC, 1985, 50, 5782. Bu3Sn-NEt2 HNRR' Bu3Sn-NRR' ArNRR Argon PdCl2(P(o-tolyl)3)2 MeO2C N CO2Me MeO2C N CO2Me purge (1-2%) (-Et2NH) or Pd(dba) H2N Pd(PPh ) (stoich.) 2 3 4 HN P(o-tolyl)3 Br Tin-Free Amination: ACIEE, 1995, 34, 1348. HNRR' (1.2 eq) ArBr ArNRR' t-BuONa (1.4 eq) Pd(dba)2 BINAP TO THE RESCUE: P(o-tolyl)3 Improved catalytic system with bidentate phosphines: JACS, 1996, 118, PhMe 7215. 65 °C primary amines can now be used (β−hydride elim. supressed) for aryl iodides: JOC, 1996, 61, 1133 intramolecular: Tett., 1996, 52, 7525. Pd2(dba)3 (0.5%) ex. ArBr n-HexNH2 ArNHR structure of Pd/amine complexes: OM, BINAP (0.75%) 1996, 15, 2745. OM, 1996, 15, 2755., NaOt-Bu (1.4 eq) OM, 1996, 15, 3534 as low as 0.05% Pd PhMe can be utilized 80 °C

use of pyridyl bromides: JOC,1996, 61, 7240 use of aryl triflates: JOC, 1997, 62, 1264 TL, 1997, 38, 6363 mechanistic study: JACS, 1997, 119, 6787. use of aryl iodides (room temp): JOC, 1997, 60, 6066. use of optically active amines: JACS, 1997, 119, 8451. Amination/Fischer indole synthesis: JACS, 1998, 120, 6621. JACS, 1999, 121, 10251. double amination (2 different ArX): JOC, 1999, 64, 6019. Ammonia equivalent: TL, 1997, 38, 6367 Review: ACR, 1998, 31, 805. JOMC, 1999, 576, 125. aminations With Ni(COD): JACS, 1997, 119, 6054. scope: JOC, 2000, 65, 1144 10 Baran Lab Stephen Buchwald Tom Maimone IV. Cross-Coupling Chemistry (Pd) Intramolecular C-O bond formation: JACS, 1996, 118, 10333. A Highly active Catalyst for Pd-catalyzed cross coupling reactions: JACS, 1998, 120, 9722. mechanistic studies: JACS, 1997, 119, 6787 The Introduction of the biaryl ligands ("Buchwald ligands"), mild conditions now possible for JACS, 1998, 120, 6504 optically active: JACS, 2001, 123, 12202 many reaction types. Pd(OAc) (5%) X NRR' 2 Pd2(dba)3 (0.5 mol%) n Tol-BINAP (6%) HNRR' Cy P L (1.5 %) OH K CO (1.2 eq) O 2 Br 2 3 NaOtBu (1.4 eq) PhMe NMe 2 room temp for X=Br,I 100 °C X = Br, I 80 °C for x =Cl DPPF can -5,6,7 membered rings formed X = Cl also be used -alcohol must normally be 3° L Cl Ph Pd(OAc)2 (0.75%) Intermolecular C-O bond formation: JACS, 1997, 119, 3395. PhB(OH)2 L (1.5%) Pd2(dba)3 (1.5%) CsF (3 eq) Br or OH O R dioxane Pd(OAc) (5%) rt O R R Tol-BINAP (3.5%) R O NaH (2 eq) Pd2(dba)3 (3%) Br L Palladium-Catalyzed α−Arylation of Ketones: JACS, 1997, 119, 11108 NaHMDS JACS, 2000, 1222, 1360 rt Br O Highly active catalyst for the room-temperature Amination and Suzuki Coupling of Aryl Chlorides: Pd2(dba)3 (1.5%) O ACIEE, 1999, 38, 2413. JACS, 1999, 121, 9550. JOC, 2000, 65, 1158. BINAP (3.5 %) -More ligands introduced NaOt-Bu (1.3 eq) - 1 effective for room temp Suzuki rxns of both electron rich THF and poor aryl chlorides. Not good for rt amination of ArCl Cy2P Cy2P 70 °C - 2 better than 1 for C-O bond formation. NMe2 - 3 good for very low cat. loadings, and suzuki of hindered Asymmetric Arylation of Ketone Enolates: JACS, 1998, 120, 1918. substrates. With Ni: JACS, 2002, 124, 3500. 1 3 -4 better than 3 for many room temp applications O ArBr O Pd2(dba)3 (10 - 20%)

(S)-BINAP Ar ligand synthesis: JOC, 2000, 65, 5334. NaOt-Bu (2 eq) (tBu)2P (tBu)2P Adv.Synth.Cat., 2001, 343, 789. PhMe NMe 100°C 2 limited substrate scope 2 4

11 Baran Lab Stephen Buchwald Tom Maimone IV. Cross-Coupling Chemistry (Pd) Diaryl ether formation: JACS, 1999, 121, 4369. Aryl Halide/Amide coupling: OL, 2000, 2, 1101.

X OH O Pd(OAc) (1%) R Pd(OAc) O 2 N R 2 X xantphos (1.5%) L RHN R Cs CO O O NaH 2 3 100 °C PPH2 PPh2 or X = Br, OTf, I K3PO4 Xantphos 100 °C some new ligands: Indole N-arylation: OL, 2000, 2, 1403.

X H N N Pd2(dba)3 NMe2 Ph L P(t-Bu) NaOtBu 2 P(t-Bu)2 P(adamantyl) 2 X = Br, Cl, I PhMe 80 - 100°C

Ester arylation: JACS, 2001, 123, 7996. Asymmetric Biaryl synthesis: JACS, 2000, 122, 12051. Me N Br 2 OtBu OtBu PCy2 Pd(OAc)2 (3%) Br B(OH)2 Me Pd2(dba)3 O L (6%) O P(O)(OEt)2 * L P(O)(OEt) LHMDS (2.5 eq) 2 2.3 eq K3PO4 rt - 80°C 40 - 70°C Intermolecular Aryl ether synthesis: JACS, 2001, 123, 10770 Improved intramolecular C-O Bond Formation: JACS, 2000, 122, 12907. Biaryl Ligands now allow primary alcohols to be used: P(t-Bu)2 X O Pd(OAc) Pd(OAc)2 2 OH OH O X L L Cs CO P(t-Bu)2 Cs2CO3 2 3 X = Br,Cl X = Br, Cl PhMe PhMe 80°C 70 °C NMe2

P(t-Bu)2 L

12 Baran Lab Stephen Buchwald T - $ IV. Cross-Coupling Chemistry (Pd) catalytic Asymmetric Vinylation of Ketone Enolates: OL, 2001, 3, 1897. Good Further reading for ligand design: O O Ligand Design, development, study papers: JACS, 2002, 124, 1162. R Pd (dba) (2.5%) Ph 2 3 Ph Xantphos: JACS, 2002, 124, 6043. N L (6.5%) N overview: ACIEE, 2004, 43, 1871. Me Br Me NaOtBu Insight into high kinetic activity : JACS, 2003, 125, 13978 PhMe Negishi catalyst: JACS, 2004, 126, 13029. Suzuki/sonagashira cat: ACIEE, 2005, 44, 6173. Aryl Trifluoroborate couplings: OL, 2004, 6, 2649. Suzuki catalyst: JACS, 2005, 127, 4685. Ligand effects: ACIEE, 2006, 45, 4321. Ligand Stability: JACS, 2007, 129, 5096. Pd(OAc)2 PCy2 L MeO OMe BF 3 K2CO3 Cl MeOH

C-H Functionalization: oxindole Synthesis: JACS, 2003, 12084.

O Pd(OAc)2 (3%) Cl PtBu2 N N O R R

Et3N, PhMe, 80°C

C-H Functionalization: Carbazole synthesis: JACS, 2005, 127, 14560.

O O

N Me Pd(OAc) (5%) H N Me Cu(OAc)2, O2 PhMe 120 °C

13 Baran Lab Stephen Buchwald Tom Maimone IV. Cross-Coupling Chemistry (Cu) Imidazole aryl halide coupling: TL, 1999, 40, 2657. Aromatic Finkelstein Reaction: JACS, 2002, 124, 14844. N I H Cu(OTf) N Br I dba N CuI (5%) N Cs2CO3 L (10%) xylenes NaI (2 eq) 110 - 125 °C Dioxane MeHN NHMe 110 °C N-Arylation of Nitrogen Heterocycles: JACS, 2001, 123, 7727. indole N-arylation: O JACS, 2002, 124, 7421. JACS, 2002, 124, 11684 JOC, 2004, 69, 5579 Malonate Arylation: OL, 2002, 4, 269. NH2 Ph N O O H I RO RNHR' O O RO OR H I RHN NHR N RHN R key ligand CuI, L ,Cs2CO3 O N RO O H N Copper Amination of aryl Iodides: OL, 2002, 4, 581. HN Copper Coupling of alcoholsL OL, 2002, 4, 973. Copper Coupling of Thiols: OL, 2002, 4, 3517 typically CuI (1%), L (10%), K3PO4 (2 eq), 110 - 130 °C Boronic acid coupling: OL, 2001, 3, 2077. Copper amino alcohol coupling: OL, 2002, 4, 3703 Copper Cyanation of aryl bromides: JACS, 2003, 125, 2890. B(OH)2 NRR' Cu(OAc)2 Copper C-O coupling/claisen: JACS, 2003, 125, 4978. RNHR' 2,6-Lutidine Copper C-P Bond formation: OL, 2003, 5, 2315. air Copper Amide/ vinyl halide: OL, 2003, 5, 3667. rt Room temp Cu C-N: JACS, 2006, 128, 8742. Hydrazide coupling: OL, 2001, 3, 3803. N Vs. O-arylation: JACS, 2007, 129, 3490

O hydroxypyridine Coupling: OL, 2007, 9, 643, CuI Benzimidazole synthesis: OL, 2007, 9, 4749. HN R Cs2CO3 O oxazole synthesis: OL, 2007, 9, 5521. 1,10 C-H Functionalization: ACIEE, 2008, 47, 1932 I NH2 phenanthroline N R

80°C NH2 DMF

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