Allylic Substitution Reactions

Group Meeting Literature Presentation Alexanian Research Group 15 May 2014 Njamkou N. Noucti “Game Changers”

Born in 1927 in Shiga, Japan Kyoto University (B.S., 1951) Columbia University, Gilbert Stork (Ph.D, 1960) Toray Industries, Inc. (1962–1974)! Tokyo Institute of Technology (1974–1988)! Okayama University (1988–1996)! Jiro Tsuji Kurashiki University of Science and the Arts (1996–1999)!

Born in 1941 in Philadelphia, Pennsylvania Pennsylvania University (B.S. 1962) Massachusetts Institute of Technology, Herbert House (Ph.D, 1965) University of Wisconsin–Madison (1965–1987)! Stanford University (1987–Present)!

Barry M. Trost

2! Introduction “Palladium–catalyzed substitution reactions involving substrates that contain a leaving group in an allylic position”! occur via π–allylmetal intermediates!

Pd LG + Nu Nu

Historically catalyzed by Palladium but now known with Ir, Mo, W, Ru, and Rh! Allyl fragment in allylic substitution reactions is electrophilic ! NOT TO BE CONFUSED WITH! Ÿ Cross–coupling reactions

X MXn + Nucleophilic allyl

M = B, Si, Sn, Mg, Zn M = Cl, Br, I, OTs fragments: not allylic Ÿ Allylations/Crotylations substitution O OH reactions! MXn + R R H M = Li, Mg, Sn, Si, B Cr, Ti, Zn, Zr 3! Why Transition–Metal Catalysis?

R R LG + Nu R Nu + SN2 or SN2' Nu Uncatalyzed allylic substitution reaction!

1) Selectivity (SN2 vs SN2’) is difficult to control without a catalyst 2) Transition–metals allow reaction to proceed at lower temperatures

3) Catalyzed reactions facilitate asymmetric variants

4! Outline

Outline! ! 1. Introduction 2. History and early developments 3. Palladium–catalyzed reactions 4. Iridium–catalyzed reactions 5. Hard nucleophiles 6. Conclusion

Topics not covered! Further reading! ! ! Asymmetric Allylic Alkylations Chem Rev. 1996, 96, 395–422. Reactions not catalyzed by Ir or Pd Chem. Rev. 2003, 103, 2921–2943. Applications in total synthesis

5! History n Wacker–Smidt (1959):! via:

[Pd] PdCl , CuCl R O OH R 2 2 R H2O, HCl H O2 or air n Jiro Tsuji (1965):!

Ÿ Carbon nucleophiles can also attack palladium–olefin complexes!

O O O O Cl O O Na, EtOH Pd + EtO OEt + EtO OEt Pd DMSO Cl EtO OEt

Smidt, J. et. al. Angew. Chem. 1959, 71, 176–182. Smidt, J. et. al. Angew. Chem. 1959, 71, 626. Smidt, J. et. al. Angew. Chem. 1962, 74, 93–102. Tsuji, J. et. al. Tet. Lett. 1965, 4387–4388. 6! History

n Trost (1972):!

CO2Et CO Et CO Et 2 C2H5 C2H5 2 CO2Et CO Et Cl O O Na, PPh3 2 + CO2Et + + nC3H7 Pd Pd nC3H7 THF or DMF Cl EtO OEt

37% yield 23% yield 8% yield

Ÿ 9:1 preference for the less substituted end of π–allyl system ! Ÿ Soft anions favor attack at least substituted end of π–allyl system!

SO Me C2H5 C2H5 2 O O Na, PPh Cl 3 + S CO2Et nC3H7 Pd Pd nC3H7 MeO OEt THF or DMF Cl

80% yield

Trost, B. et. al. J. Am. Chem. Soc. 1973, 95, 292–294. 7! Synthesis of π–Allyl Intermediate n Olefin oxidation:! Ÿ Requires isolation of the PdCl2 Na2CO3 or palladium–allyl intermediate! NaCl, AcOH, NaOAc Cl Pd Ÿ Not amenable to one–pot allylic DCM Pd Cl substitution reaction! Ÿ Stoichiometric in palladium! n Functionalized allylic starting materials:!

Ÿ Atkins (1970)!

Pd(acac)2 (0.5 mol %) PPh3 (0.5 mol %) HNEt2 OH NEt2 50 ºC Pd 95% yield OH Ÿ Hata (1970)!

Pd(PPh3)2 (0.002 mol %) maleic anhydride (0.004 mol %) HNEt2 OPh NEt2 85 ºC Pd OPh quantitative yield Atkins, K. E. et. al. Tetrahedron Lett. 1970, 3821–2824.! Hata, G. et. al. J. Chem. Soc. D, Chem. Comm. 1970, 1932–1933. 8! Reaction Substrates

Pd LG + Nu Nu n Nucleophiles:! Soft, carbon nucleophiles! Heteroatom nucleophiles! Hard, carbon nucleophiles!

pKa < 25 pKa > 25 EWG R 1 2 EWG EWG R1 R2 N R R H HS HO R = H, alkyl, aryl, vinyl EWG = CN, NO , SO R, 2 2 EWG = CN, NO2, SO2R, SOR, CO R, COR 2 SOR, CO2R, COR n Allylic electrophile:!

OCO2Me OP(O)(OEt)2 OAc Cl most common

OSO2Me NO2 NR2 OR less common

9! Substrate Scope

R2 Pd2dba3–CHCl3 (2.5 mol %) R2 PPh3 (8 mol %) 3 3 R OCO2Me + Nu R Nu THF, 30 ºC R1 R1

CO2Et CO Me CO2Me 2 Ph CO2Et O O O 92% yield 91% yield 90% yield

CO2Et CO2Me AcO CO2Et O 86% yield 77% yield

Tsuji, J. et. al. J. Org. Chem. 1985, 1523–1529.! 10! Substrate Scope

Pd2dba3–CHCl3 (2.5 mol %) dppe (10 mol %) OCO2allyl + Nu Nu THF, 65 ºC

NO2 CN CN

Ph 76% yield 91% yield 73% yield

O O CN

THPO 29% yield 0% yield trace yield

Ÿ Simple ketones and unactivated carbon centers are unreactive!

Tsuji, J. et. al. J. Org. Chem. 1985, 1523–1529.! 11! Proposed Mechanism

Nu 0 OCO R Pd Ln 2

nucleophilic attack! oxidative addition!

Pd OCO R Pd 2 Nu deprotonation! decarboxylation! ROH CO2 NuH Pd OR

Ÿ Alkoxide base generated in–situ via decarboxylation of Pd–carbonate intermediate!

Tsuji, J. et. al. J. Org. Chem. 1985, 1523–1529.! 12! Mechanistic Details n Oxidative addition occurs with inversion of configuration:

CO2Me CO2Me [Pd]

OAc [Pd] n Soft nucleophile attacks the allyl fragment with inversion of configuration

CO Me 2 CO2Me CO2Me

NaCH(CO2Me)2 +

[Pd] CH(CO2Me)2 (MeO2C)2HC

Ÿ Hard nucleophiles attack the metal center. Reductive elimination occurs with retention of configuration

Kobayashi, Y. et. al. J. Org. Chem. 1996, 61, 5391–5399.! Tsuji, Y. et. al. Organometallics 1998, 17, 4835–4841.! 13! Iridium–Catalyzed Reactions

n Iridium–catalyzed reactions lead to substitution at the most substituted carbon center.

O O [Ir(COD)Cl]2 (2 mol %) nPr Ligand (16 mol %) CO2Et nPr OAc + EtO OEt + THF, Temperature nPr EtO C CO Et CO2Et Na H 2 2 2 equiv A B

Entry Ligand Temperature Reaction Time % yield A:B

1 PnBu3 reflux 16 h 0 --

2 PPh3 reflux 16 h 6 24:76

3 P(OiPr)3 reflux 9 h 44 53:47

4 P(OEt)3 reflux 3 h 81 59:41

5 P(OPh)3 rt 3 h 89 96:4

Ÿ Electron–poor phosphine ligands give selective reactions!

Takeuchi, R. et. al. Angew. Chem. Int. Ed. Engl. 1997, 263–265.! 14! Regiochemical Explanation n Regioselectivity of allylic substitution reaction controlled by three factors: 1. Steric Interactions between incoming nucleophile and allylic terminus 2. Charge distribution of π–allyl ligand on metal center Most influential 3. Stability of the resulting alkene–metal complex with iridium!

nPr nPr nPr nPr Nu vs. vs. [Ir] [Ir] Nu [Ir] [Ir] A! B! A! B! A is the more stable cation; S 2 attack positions N A is the more stable transition–metal complex! nucleophile on most substituted carbon!

Takeuchi, R. et. al. Angew. Chem. Int. Ed. Engl. 1997, 263–265.! Cramer, R. et. al. J. Am. Chem. Soc. 1967, 89, 4621–4626. Åkermark, B. et. al. Organometallics 1984, 3, 679–682. 15! Substrate Scope

nPr [Ir(COD)Cl]2 (2 mol %) CO2Et P(OPh) (16 mol %) 3 nPr nPr OR + NaCH(CO2Et)2 + CO2Et THF, rt EtO2C CO2Et 2 equiv A B

Entry R Reaction Time % yield A:B

1 Ac 3 h 89 96:4

2 CO2Me 1 h 94 97:3 3 H 2 h 100 96:4

4 C(O)CF3 5 h 70 95:5 n Quaternary centers can also be synthesized:

nBu CO2Et [Ir(COD)Cl]2 (2 mol %) OAc NaCH(CO2Et)2 P(OPh)3 (16 mol %) + Me + CO2Et Me nBu 2 equiv THF, rt EtO2C CO2Et Me nBu A 80 % yield B A:B = 0:100

Takeuchi, R. et. al. Angew. Chem. Int. Ed. Engl. 1997, 263–265.! 16! Nitrogen Nucleophiles

L = [Ir(COD)Cl]2 (1 mol %) L (2 mol %) Ph Ph OCO Me 1 2 Me 2 + NHR R O Ph THF, rt 1 2 NR R P N O Ph Me

OMe

N HN HN HN Ph Ph Ph Ph O 83% yield 84% yield 80% yield 88% yield 97% ee 95% ee 94% ee 96% ee (run at 50 ºC) N N N

Ph Ph Ph 75% yield 91% yield 92% yield 97% ee 96% ee 97% ee

Hartwig, J. et. al. J. Am. Chem. Soc. 2002, 124, 15164–15165. 17! Unactivated Alkene Substrates L1 = O

PhNH2 Pd(OAc)2 (5 mol %) K PO NHPh OBz 3 4 N L1 (5.5 mol %) L2 (5 mol %) N BzO tBu R + 2 R R L2 = Solvent, 65 ºC O O temporary P functional group (COD)Ir N Ph Ph

NHPh NHPh NHPh NHPh O O Cl C7H15 53% yield 68% yield 68% yield 60% yield 89% ee 92% ee 95% ee 88% ee NHPh NHPh NHPh NHPh O TBSO S MeO2C Tol F 65% yield O 53% yield 58% yield 77% yield 97% ee 89% ee a 88% ee 95% ee

a oxidation run at 80 ºC.

Hartwig, J. et. al. J. Am. Chem. Soc. 2013, 135, 17983–17989. 18! Unactivated Alkene Substrates L1 = O

PhNH2 Pd(OAc)2 (5 mol %) K PO NHPh OBz 3 4 N L1 (5.5 mol %) L2 (5 mol %) N BzO tBu R + 2 R R L2 = Solvent, 65 ºC O O temporary P functional group (COD)Ir N Ph Ph

N NHPh NHBn

TBSO N O O C7H15 N TBSO 53% yield 51% yield TBSO 89% ee 89% ee 55% yield O 90% ee 51% yield EtO2C CO2Et 89% ee Tol S O OPh TBSO TBSO TBSO

55% yield 50% yield 50% yield 90% ee 90% ee 88% ee a oxidation carried out at 80 ºC. Hartwig, J. et. al. J. Am. Chem. Soc. 2013, 135, 17983–17989. 19! Oxygen Nucleophiles

L = [Ir(COD)Cl]2 (3 mol %) L (6 mol %) Me 30 % aq. NaOH in MeOH or O Ph TBAF R P N R OCO2tBu + TESOK O Ph 2 equiv DCM, rt OH Me

OH

OH OH R X R = H 88% yield 97% ee X = CF3 78% yield 98% ee X = S 62% yield 99% ee X = S 67% yield 98% ee = OMe 75% yield 95% ee = O 50% yield 97% ee = O 60% yield 99% ee

OH OTES

Ph Me 65% yield 97% ee 65% yield 95% ee

Carreira, E. et. al. Angew. Chem. Int. Ed. 2006, 45, 6204–6207. 20! Oxygen Nucleophiles

OTf

Ph C2 or C3 (1 mol %) O R OCO2Me + KHCO 3 Ir P O DMF/H O 10:1 H C CH 2 OH 3 N 3 H2C Ar Ar C2: diene = dbcot, Ar = Ph C3: diene = dbcot, Ar = 2–MeOC6H4

Ph Ph C7H15 Ph3CO OH OH OH OH OH C3 C2 C3 C3 C3 86% yield 92% yield 90% yield 74% yield 77% yield 95% ee 95% ee 93% ee 89% ee 95% ee

Helmchen, G. et. al. J. Am. Chem. Soc. 2011, 133, 2072–2075. 21! Mechanistic Details

L1 L1 O O O Ir O Ir O Ir O P + Base P – L1 P [(COD)IrCl] 2 + 2 L1 H C CH H C CH H C CH 3 N 3 HBase 2 N 3 + L1 2 N 3 Ph Ph Ph Ph Ph Ph A B C not catalytically active! 18 e–! does not react with allylic reagents! Active species! 16 e–!

CH3COCO2

O O R OCO2Me Ir Ir O Nu P O R P H C CH H2C N CH3 2 N 3 Nu Ph Ph Ph Ph R D E

L1 = Me Ÿ Silver salts lead directly to complex D! O Ph P N Ÿ Nucleophile attacks more substituted carbon atom! O Ph Me Hartwig, J. et. al. J. Am. Chem. Soc. 2003, 125, 14272–14273. Helmchen, G. et. al. Chem. Eur. J. 2009, 15, 11087–11090. 22! Regiochemical Explanation

K4b–K4e: R’ = OMe a: R = C6H5, X = ClO4 b: R = C6H5, X = SbF6 c: R = CH3, X = ClO4 d: R = CH3, X = SbF6 e: R = CH3, X = CF3SO3 ! K4f: R’ = H!

f: R = CH3, X = CF3SO3

Ÿ Ir bond to C1A is longer than Ir bond to C3A! Ÿ Preferred attack of a nucleophile at weaker (longer) Ir–C bond!

Helmchen, G. et. al. Chem. Eur. J. 2010, 16, 6601–6615. 23! Hard Nucleophiles n Few examples of hard nucleophiles in allylic substitution reactions: Ÿ Hard nucleophiles can react with ester functionality of allylic substrate

O R Nu R OH + + Nu O O

unwanted reactivity with hard nucleophiles! n Rare example with vinyl Grignard: ProliNOP: PdCl2(ProliNOP) (5 mol %) + THF, 10 ºC TMS OAc BrMg TMS 85% yield N O

30% ee Ph2P PPh2

Ÿ Poor enantioselectivities typically obtained with hard nucleophiles.

Buono, G. et. al. Tetrahedron Lett. 1990, 31, 77–80. 24! Proposed Mechanism

Nu 0 Pd Ln OAc reductive elimination! oxidative addition!

[Pd] [Pd] OAc Nu

M OAc M Nu

ligand exchange

n Hard nucleophiles attack the metal center and not the allyl fragment

25! “Softening” Hard Nucleophiles n Traditionally hard nucleophiles can be “softened” with activating agents:

Toluene and 2–methyl pyridine (pK > 25) traditionally! X CH a 3 considered hard nucleophiles! X = N pKa = 34 X = C pKa = ~44

Ÿ Trost (2008) OPG n + Catalyst N N H BF3•OEt2 R n R

Ÿ Walsh (2011)

OPG R2 2 CH3 Catalyst R + n [Cr] n R1 R1

Trost, B. et. al. J. Am. Chem. Soc. 2008, 130, 14092–14093. Walsh, P. J. et. al. J. Am. Chem. Soc. 2011, 133, 20552–20560. 26! Boron Activating Agent LiHMDS (3.5 equiv) OPG BF3•OEt2 (1.3 equiv) 3 [(η –C3H5)PdCl]2 (2.5 mol %) O O + L (6.0 mol %) NH HN N N Dioxane, rt H PPh2Ph2P 1.5 equiv R R L

Ph Ph

N N N N

94% yield >99% yield >99% yield 98% yield 92% ee 96% ee 95% ee 98% ee

N H N H

N N H Me Me H Me Br NMeBoc 85% yield, >19:1 d.r. 99% yield, >19:1 d.r. 80% yield, 4:1 d.r. 70% yield, 13:1 d.r. 94% ee a 94% ee a 98% ee a 98% ee a a 3 LiHMDS (3.0 equiv), 1.0 equiv BuLi, BF3ŸOEt2 (1.0 equiv), [(η –C3H5)PdCl]2 (2.5 mol %), L (6 mol %), dioxane, rt. Trost, B. et. al. J. Am. Chem. Soc. 2008, 130, 14092–14093. Trost, B. et. al. J. Am. Chem. Soc. 2009, 131, 12056–12057. 27! Chromium Activating Agent

OPiv Pd(COD)Cl2 (5 mol %) CH3 Xantphos (7.5 mol %) R + LiN(SiMe3)2 (3 equiv) Cr(CO)3 R NEt3 (1 equiv) THF, rt Cr(CO)3

Cl MeO MeO Cr(CO) Cr(CO) 3 Cr(CO)3 3 Cr(CO)3 96% yield 45% yield 80% yield no reaction n Chromium activating agent easily removed with sunlight and air:

OPiv same as CH3 above hν, air + R = H 92% yield Cr(CO) R = OMe 73% yield 3 R R Cr(CO)3

Walsh, P. J. et. al. J. Am. Chem. Soc. 2011, 133, 20552–20560. 28! Conclusion “Palladium–catalyzed substitution reactions involving substrates that contain a leaving group in an allylic position”! occur via π–allylmetal intermediates!

Pd LG + Nu Nu

Ÿ Mild reaction conditions Ÿ Compatible with many leaving groups Ÿ Tolerates a variety of nucleophiles Ÿ Regio–, diastereo–, and enantioselective

Early development: Mechanisc contribuons:

Jiro Tsuji Barry M. Trost John F. Hartwig Günter Helmchen 29!