Anti-Markovnikov
Olefin Functionalization~Prof. Robert H. Grubbs’ Work~
4th Literature Seminar
July 5, 2014
Soichi Ito (D1)Contents

1. Introduction• Flow of Prof. Grubbs’ Research• Markovnikov’s Rule
• Wacker Oxidation

2. Grubbs’ Work
• Substrate-Controlled Wacker Oxidation• Catalyst-Controlled Wacker-Type Oxidation2

Introduction ~Flow of Research~Anti-Markovnikov
Wacker Oxidationof Terminal Olefin

Olefin Metathesis

Substrate-ControlledWacker Oxidationof Internal Olefin

Z-Selective Metathesis

Hydration
Ethenolysis+ Reduction
Hydroamination

Z-Selective Ethenolysis
Decarbonylative Dehydration

Production of Terminal Olefin

Catalyst-Controlled
Hydrophosphonation

Functionalization of Terminal Olefin
3

Introduction ~Markovnikov’s Rule~

Two-Step

Two-Step(+1C)

4

Robert H. Grubbs et al. Science, 2011, 333, 1609.

Anti-Markovnikov Hydration of Olefins• One-Step

William C. Trogler et al. Science 1986, 233, 1069.

This work was difficult to reproduce.

Inorg. Chem. 1988, 27, 3151.

• One-Step with Activated Olefins
Robert G. Bergman and F. Dean Toste et al.
J. Am. Chem. Soc. 2003, 125, 8696.

• Three-Step

Ben L. Feringa and Gerard Roelfes et al. Nat. Chem. 2010, 2, 991.

5Shannon S. Stahl et al. J. Am. Chem. Soc. 2010, 132, 15116.

Anti-Markovnikov Wacker Oxidation / Reduction StrategyOxidation cycle must be compatible with the reduction cycle.

aldehyde-selective
Wacker Oxidation

6Robert H. Grubbs et al. Science, 2011, 333, 1609.

Introduction ~Wacker-Tsuji Oxidation~• 1894 F. C. Phillips reported stoichiometric reaction.
• 1959 J. Smidt et al. reported the Wacker process.
(oxidation of ethylene to acetaldehyde)
Investigations for convenient laboratory methods• 1976 J. Tsuji et al. reported PdCl2, CuCl / DMF, H2O method.

“Terminal alkenes may be viewed as masked ketones.”

7Jacques Muzart Tetrahedron 2007, 63, 7505.

DMF / H2O System“CuCl2 tends to chlorinate ketones.”
Jiro Tsuji et al.
Tetrahedron Lett. 1976, 2975.

DMSO, acetone, AcOH, THF, dioxane, MeCN were not good.

Charles M. Selwitz et al. J. Org. Chem. 1964, 29, 241.

8

Development: Direct O2-Coupled Wacker Oxidation
Ligand :Roger A. Sheldon et al. Chem. Commun. 1998, 2359.

Kiyotomi Kaneda et al. Angew. Chem. Int. Ed. 2006, 45, 481.

Pd[(-)-sparteine]Cl2
9Matthew S. Sigman et al. Org. Lett. 2006, 8, 4117.

Selectivity of Wacker Oxidation

With directing group

Catalyst-controlled selectivity is required.

10

Robert H. Grubbs et al. J. Am. Chem. Soc. 2014, 136, 890.

Anti-Markovnikov Wacker Oxidation Strategies• with Directing Groups

Ben L. Feringa et al. J. Am. Chem. Soc. 2009, 131, 9473.

• with Stoichiometric Palladium or Excess Heteropolyacidrt

Other Pd(ll) such asPd(OAc)2 and Pd(NO3)2
gave exclusively
the methyl ketone.

Aromatic group was crucial.

11

Jonathan B. Spencer et al. Chem. Eur. J. 2006, 12, 949.

• Catalyst-Controlled (or Solvent-Controlled?)?
Jacques Muzart Tetrahedron 2007, 63, 7505.

12Ben L. Feringa J. Chem. Soc., Chem. Commun. 1986, 909.

Timothy T. Wenzel J. Chem. Soc., Chem. Commun. 1993, 862.

(1 mmol)

Similar Trends
No Isomerization

High Selectivity
Low Yield

The use of LiCl and/or CuCl reduced the regioselectivity.
13

Takahiro Hosokawa et al. Bull. Chem. Soc. Jpn. 2005, 78, 1555.

Ketone-Selective Wacker-Type Oxidation

Catalyst-Controlled!!
Matthew S. Sigman et al. J. Am. Chem. Soc. 2009, 131, 6076.
Matthew S. Sigman et al. J. Am. Chem. Soc. 2011, 133, 8317.
14

Matthew S. Sigman et al. Acc. Chem. Res. 2012, 45, 874.

Contents

1. Introduction• Flow of Prof. Grubbs’ Research• Markovnikov Rule
• Wacker Oxidation

2. Grubbs’ Work
• Substrate-Controlled Wacker Oxidation• Catalyst-Controlled Wacker-Type Oxidation
15

General Reaction Scheme

about Shvo‘s catalyst, see:Chem. Rev. 2010, 110, 2294.

• Control Experiments

16

Substrate ScopeMajor
Byproduct17

Triple Relay Catalysis System• Proposed Mechanism• Initial Mechanistic Study
without H2O, IPA, Shvo’s cat.

enol ether hydrolysis

D2O

Shvo’s cat.

18

Aldehyde Selective Wacker Oxidation
under aerobic condition

19

Robert H. Grubbs et al. Org. Lett. 2012, 14, 3237.

Aldehyde Selective Wacker Oxidation

because of the increase in acidity?
The bulkiness of t-BuOH is important
for aldehyde-selectivity.

Product yield starts decreasing likely due to self-condensation.

20

Catalyst-Controlled Wacker-Type Oxidation• Without t-BuOH (only MeNO2),
no conversion was observed.

• Entry 1• Entry 2

21

Robert H. Grubbs et al. Angew. Chem. Int. Ed. 2013, 52, 11257.

Detailed Yield & Selectivity• Entry 1• Entry 2
22• Substrate ScopeWith styrene…

Intermolecular Markovnikov Attack+Hydrolysis

H• Aldehyde-Selective Wacker Oxidation
on a 10 mmol Scale withReduced Catalyst Loading

23

Comparison of Innate Selectivity

without assistance froma Thorpe-Ingold effect24

Influence of PhO-Proximity

25

Robert H. Grubbs et al. J. Am. Chem. Soc. 2014, 136, 890.

Influence of Oxygen Functionality

aldehyde / ketone

Catalyst-Controlled Regioselectivity

26

Influence of Steric Profile

5h24 h24 h5h24 h27

Applicability of Nitrate-Modified Wacker Oxidation• On a Larger Scale• Synthesis of Atomoxetine

Retention of Stereochemical Information

Drug for the treatment of ADHD

28

about Ir catalyst, see John F. Hartwig et al. J. Am. Chem. Soc. 2003, 125, 3426.

Preliminary Mechanistic Insight· Stoichiometric 18O-Labeling Experiment· Plausible Mode of Oxygen Transfer

 Brief induction period The same catalytic species remains active.

29

Robert H. Grubbs et al. Angew. Chem. Int. Ed. 2013, 52, 11257.

Oxidation of Olefins with Nitro-Nitrosyl Redox Couple• Transition-Metal Nitro-Nitrosyl Redox Couplingcolor:
orange→yellow

detectable
at least 1 hketone selective

Grubbs’ system
30

Mark A. Andrews et al. J. Am. Chem. Soc. 1981, 103, 2894.

Metal Nitro Complexes as Catalysts“we believe far less likely”

Mark A. Andrews et al. Organometallics 1984, 12, 1777.

Nitration of Alkenes by Palladium Nitro Complexes

Path 1: cis

Path 2: transsupporttransMark A. Andrews et al. Organometallics 1984, 3, 1479.

Preliminary Mechanistic Insight• Radical Model to Explain Anti-Markovnikov Selectivity

Robert H. Grubbs et al. Angew. Chem. Int. Ed. 2013, 52, 11257.
• Influence of Electronic Properties

electron-deficient

33

Robert H. Grubbs et al. J. Am. Chem. Soc. 2014, 136, 890.

Compared with Cationic Transition State• Intermolecular Competition Experiments

electron-deficient• Intramolecular Competition Experiments

34

Robert H. Grubbs et al. Angew. Chem. Int. Ed. 2013, 52, 9751

Preliminary Mechanistic Insight Is NO2 generated?

NO2 (gas) flies away?

in a sealed vessel (air)When the reaction is run in an unsealed vessel, significantly lower yield and selectivity is observed.
 What mediates NO2 delivery?
Stoichiometric reaction of CuCl2 and AgNO2 with an alkene (without Pd) gave no conversion of alkene.
Pd may mediate NO2 delivery.
• One-pot Intermolecular Competition Experiments

Robert H. Grubbs et al. J. Am. Chem. Soc. 2014, 136, 890.
 Without metal…

35

William A. Pryor et al. J. Am. Chem. Soc. 1982, 104, 6685.

cf. Plausible Mechanism of Radical Nitration

36Hiroyuki Ishibashi et al. Adv. Synth. Catal. 2011, 353, 2643.

Mechanism?

about hydrolysis of alkyl nitrite,Michael P. Doyle et al. J. Org. Chem. 1983, 48, 3379.

37

Summaryslide 14

Robert H. Grubbs et al. J. Am. Chem. Soc. 2014, 136, 890.
Styrene-type substrate38

Robert H. Grubbs et al. Org. Lett. 2012, 14, 3237.

Appendix

39

Intermediates in the Autoxidation of Nitrogen Monoxide
detected with EPR

40Williem H. Koppenol et al. Chem. Eur. J. 2009, 15, 6161.

cf. Nitration of Olefins with AgNO2 and TEMPOAgNO2 (3 eq)
TEMPO (0.4 eq)
MS4A, DCE

41

Debabrata Maiti et al. J. Am. Chem. Soc. 2013, 135, 3355.

cf. Nitrate as a Redox Co-Catalyt
25 mol% NaNO3

Known Reaction

42Melanie S. Sanford et al. Chem. Sci. 2012, 3, 3192.

Other Olefin Functionalizations• Hydroamination
Wacker Oxidation / Transfer Hydrogenative Reductive Amination
Two-Step, One-Pot Hydroamination Protocol
see: Robert H. Grubbs et al. Chem. Sci. 2014, 5, 101.

• Wacker Oxidation of Internal Olefins

see: Robert. H. Grubbs et al. Angew. Chem. Int. Ed. 2013, 52, 2944.
Robert H. Grubbs et al. Angew. Chem. Int. Ed. 2013, 52, 9751.

• Hydrophosphonation
see: slide 44,45
Robert H. Grubbs et al. Org. Lett. 2011, 13, 6429.

• Pd-Catalyzed Decarbonylative Dehydration of Fatty Acids
see: slide 46~49
Robert H. Grubbs, Brian M. Stoltz et al. Adv. Synth. Catal. 2014, 356, 130.
43

Hydrophosphonation
Precedent : Radical Cyclization – HWE Reactions

James G. T. Rawlinson et al. Org. Lett. 2005, 7, 1597.

Robert H. Grubbs et al. Org. Lett. 2011, 13, 6429.

44Hydrophosphonation

45

Pd-Catalyzed Decarbonylative Dehydration of Fatty Acids· High Temperature Process (Miller, Kraus)

volatile olefins only

· Low Temperature Process (Gooβen, Scott)· Grubbs’ Work

46

Robert H. Grubbs, Brian M. Stoltz et al. Adv. Synth. Catal. 2014, 356, 130.

Effect of Catalyst, Ligand, and Additive47

· Portionwise Addition of Acetic Anhydride· Large-Scale Decarbonylative Dehydration

stearic acid

10-acetoxydecanoic acid48

Substrate Scope49