Gold-Catalyzed Reactions:Gold-Catalyzed Reactions:A Treasure Trove of A Treasure Trove of

ReactivityReactivity

By: Nathalie GouletBy: Nathalie Goulet

March 9, 2006March 9, 2006

2

Overview- Introduction

- Reactivity of gold with alkynes

- Activation of allenes

- C-H bond activation

- Enantioselectivity

- Synthesis

- Carene terpenoids

- Jungianol

- Conclusions

3

Gold

- Gold used to be thought of as chemically inert

- Oxidation states of gold

• -1 : auride compounds; e.g. CsAu, RbAu

• 1 : aurous compounds; e.g. AuCl

• 3 : auric compounds; e.g. AuCl3

• 5 : e.g. AuF5

- Preconceived notion that gold is expensive

Complex Price for 1 g $/mol Complex Price for 1 g $/mol

AuCl 197$ 45 786 AuCl3 170$ 51 566

PtCl2 260$ 69 160 RhCl3 260$ 54 368

PdCl2 95$ 11 144 RuCl3 97$ 20 108

Prices from Aldrich catalogue

4

Gold

AuAu196.97

79

http://www.molres.org/cgi-bin/pt-request

5

Properties of Au: A Late Transition Metal

Sc

1.3

Ti

1.5

V

1.6

Cr

1.6

Mn

1.6

Fe

1.8

Co

1.9

Ni

1.9

Cu

1.9

Y

1.2

Zr

1.3

Nb

1.6

Mo

2.1

Tc

1.9

Ru

2.2

Rh

2.3

Pd

2.2

Ag

1.9

La

1.1

Hf

1.3

Ta

1.5

W

2.3

Re

1.9

Os

2.2

Ir

2.2

Pt

2.3

Au

2.5

Pauling electronegativities of the transition elements

- More electronegative metals tend to retain their valence electrons

- Low oxidation states for late transition metals are more stable than higher ones

- Back donation in late transition metals is not so marked compared to early transition metals

- Gold is a soft transition metal and thus will prefer soft transition partners

Crabtree, R. H., The 0rganometallic Chemistry of the Transition Metals, John Wiley & Sons, Inc, New York, 2001, p.46

6

Crystal Field Theory- d orbitals of a metal are affected by the presence of ligands where

the ligands act as a negative charge

Mn+ ML6n+

Crabtree, R. H., The 0rganometallic Chemistry of the Transition Metals, John Wiley & Sons, Inc, New York, 2001, p.46

http://science.kennesaw.edu/~mhermes/cisplat/cisplat06.htm

Octahedral geometry

dz2dx2-y2

dyz dxz dxy

7

Why Are d8 Metals Square Planar?

dx2-y2

dxy

dz2

dxz dxz

dxy dyz dxz

dx2-y2 dz2

dx2-y2 dz2

dxy dyz dxz

Square Planar Octahedral Tetrahedral

- The square planar geometry offers the electrons never to be placed in the highest energy orbital

- d10 metals fill all the d orbitals

- Conformation that offers less steric hinderance for the ligands

Crabtree, R. H., The 0rganometallic Chemistry of the Transition Metals, John Wiley & Sons, Inc, New York, 2001, p.46

AuX X

LXAuL X

Au(III): Au(I):

8

Lewis Acid ActivationHard Lewis acids:

- small- high charge states - weakly polarizable- often activate reactions by coordination to the oxygen atom.

- e.g. Ti4+ and Fe3+

Soft Lewis acids: - big- low charge states- strongly polarizable- often activate the reaction through coordination with the π bond

- Cu+ and Pd2+

Au(III) is more oxophilic than Au(I) and so is a harder Lewis acid

Au(I) will have a higher affinity for alkynes

9

Reactivity of Alkynes- The LUMO of alkynes are low in energy and so will eagerly react with

strong nucleophiles

- Unless activated, alkynes will not react with weak nucleophiles

- Using its d orbitals, gold can activate alkynes by interacting with both π orbitals of the alkyne

Toreki, R. http://www.ilpi.com/organomet/alkyne.html, 20/11/2003

Hashmi, A. S. K. Gold Bulletin, 2003, 36, 3-9

σ-type donation:

dx2-y2

dyz

dxz

dxy

Π-type back-donation:

Π-type donation:

δ-type back-donation:

10

Reactivity of Alkynes- Terminal alkynes can interact through a second mode of action

especially with AuI

- Forms a gold(I)-alkynyl complex

- stable

- will not readily react with nucleophiles

Hashmi, A. S. K., Gold Bulletin, 2003, 36, 3

Mingos, D. M. P.; Yau, J.; Menzer, S.; Williams, D. J. Angew Chem. Int. Ed. 1995, 34, 1894

RH

LAuX

base

RAuL

tBu

Au

tBu

η1-Au-η1: tBu

Au tBu

η2-Au-η1:

11

Reactivity of Alkynes

- A broad range of nucleophiles may be used

-Carbon-carbon bond forming reactions:

- Propargyl-Claisen rearrangement

- Carbon-oxygen bond forming reactions:

- Ketone or acetal formation

- Carbon-nitrogen bond forming reactions:

- Acetylenic Schmidt Reaction

Nu [Au] Nu

[Au]

Nu

[Au]

12

Propargyl Claisen Rearrangement- Claisen rearrangement:

O O

- Can be catalyzed by:

- Hard Lewis acids by coordination to the oxygen atom

- Soft Lewis acids by coordination to the π bond

- e.g. Hg(II) and Pd(II)- Propargyl Claisen rearrangement

- Typical soft Lewis acids cannot be used

OO

OLA

X

Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978-15979

13

Propargyl Claisen Rearrangement- Gold is so alkynophilic that it will prefer binding to the alkyne than to the

vinyl ether

Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978-15979

OR1

R2R3

[(Ph3PAu)3O] BF4 (1.0 mol%)CH2Cl2, rt

NaBH4, MeOH, rt

OH

R1

R2

R3

Entry R1 R2 R3 Yield

1 p-MeO-C6H4 H n-C4H9 89%

2 p-CF3-C6H4 H Me 86%

3 PhCH2CH2 Me Me 91%

O

Ph

[(Ph3PAu)3O] BF4 (1.0 mol%)CH2Cl2, 15 min, rt

NaBH4, MeOH, rt80%

OH

Ph

Hard LA or

Ph

O

14

Au

OR1

H

R

OR1

H

RAu

OH

R

R1

O H

R1R

H

[Au]

NaBH4OH

H

R

R1

Interaction of Gold with AlkynesO

R1

R2R3

[(Ph3PAu)3O] BF4 (1.0 mol%)CH2Cl2, rt

NaBH4, MeOH, rt

OH

R1

R2

R3

Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978-15979

15

Active Catalyst: AuI or AuIII

- AuCl3-catalyzed benzannulation by Yamamoto was studied using B3LYP, a DFT calculation method

- Reduction of high oxidation state pre-catalyst to catalyst is mandatory in several late transition state metal catalyzed reactions

- Many reactions can use either AuI or AuIII. Sometimes one is faster than the other, however the active catalyst remains unknown

Straub, B. F. Chem. Commun. 2004, 1726-1728Asao, N.; Tokahashi, K.; Lee, L.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650-12651

H

R

Me

Me

O

R

AuCl3

O

+

16

Active Catalyst: AuI or AuIII

Computational results:

- DFT reveals same predicted Gibbs activation energy of 115 kJ/mol for both AuI and AuIII

- Catalytic activities of AuCl3 and AuCl were indistinguishable within the reliability of the chosen level of theory

Yamamoto’s Proposal:

Straub, B. F. Chem. Commun. 2004, 1726-1728Asao, N.; Tokahashi, K.; Lee, L.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650-12651

AuCl3 O

R

O

RAuCl3

O

R2

R1R

AuCl3

OR2

R1AuCl3

Cl3Au

O R

R1

R2

CHO

R

R2 R1

17

Hydration of Alkynes

Mizushima, E.; Sata, K.; Hayashi, T., Tanaka,M.; Angew. Chem. Int. Ed. 2002,41, 4563

Fukuda, Y., Utimoto, K.; J. Org. Chem. 1991, 56, 3729

- Hydration of alkynes is well-known however only electron-rich acetylenes react satisfactorily

- Simple alkynes need toxic Hg(II) salts to enhance reactivity

- Au has turnover frequencies of at least two orders of magnitude more than other catalysts

- The major product is Markovnikov adduct

R1 R2 + H2O(Ph3P)AuCH3 + acid

MeOH R1

O

R2R1

R2

O+

Entry R1 R2 Adduct Yield

1 n-C4H9 H 1 99%

2 NC(CH2)3 H 1 83%

3 n-C3H7 CH3 1/2 = 1.2:1 76%

1 2

18

Acetylenic Schmidt Reaction

Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260

N3n-Bu

n-Bu

(dppm)Au2Cl2 (2.5 mol %), AgSbF6 (5 mol %)

CH2Cl2

93%

HNn-Bu n-Bu

LAu

N3

R

N

R

N2

AuL

N

RLAu

N2

N

RLAu

N

RH

NH

R

N2

N

RLAu

19

Allene Activation

Entry Catalyst (1-2 mol%)

Solvent (1M)

Temperature (ºC)

Ratio 1:2

1 AuCl3 Toluene 0 88:12

2 AuCl3 Toluene rt 95:5

3 AuCl3 Toluene 70 98:2

4 AuCl3 THF rt 5:95

5 Au(PEt3)Cl Toluene rt <1:99

Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500-10501

Br

OC8H17

catalyst

toluene, rt OC8H17

Br+

OC8H17

Br1 2

20

Proposed Mechanism

Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500-10501

Br

OR

AuCl3Br

OR

AuCl3

Br

H

O

Cl3Au R

OR

Br

Au(PEt3)Cl

Br

OR

Au

OH

Br R

Au

O

Au

Br

H OR

Br

AuIII

AuI

in toluene

21

Carbene-Like Intermediates

Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002-18003

- Gold(I)-catalyzed cyclopropanation reaction tolerated a wide range of olefin substitution

- The cis-cyclopropane is favored

- Concerted carbene transfer from a gold(I) –carbenoid intermediate

ORR1

R2

R3

R4

RO

R1 R2

R4

R3

Ph3PAuCl (5mol%), AgSbF6 (5mol %)

MeNO2, rt+

Entry R R1 R2 R3 R4 Yield (cis:trans)

1 Pivaloate Me Me Me Me 67%

2 Acetate H TMSCH2 H H 62%(1.3:1)

3 Benzoate Cyclohexyl H H 73%

22

Carbene-Like Intermediates

OPiv

Ar

(R)-DTBM-SEGPHOS(AuCl)2 (2.5 mol%)AgSbF6 (5 mol%)

MeNO2, rtAr

OPiv+

Ar = Ph 70 %, 81% ee

= 71%, 94% ee

>20:1 cis:trans

- Identified DTBM-SEGPHOS-gold(I) ligand as the ligand of choice for enantioselective olefin cyclopropanation reaction

PAr'2PAr'2

Ar'= OMe

O

O

O

O

(R)-DTBM-SEGPHOS

Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002-18003

23

Insight Into Mechanism

- Large phosphine ligand increased selectivity for the cis cyclopropane

Path A

Path B

Au

Ph

OAc

L

Ph

L-Au

H

H

Ph

H

Ph

OAc

Au

L

H

H

H

Ph

Ph

OAc

Au

L

+

+

+

+

Ph

Ph

Ph

OAc

Ph

OAc

Ph

PhO

O

Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002-18003

24

C-H Bond Activation

- Not as common as alkyne activation though more examples have been emerging in the last few years

- Activates C-H bonds to create a nucleophile which can interact with electrophiles

- Often there is a dual role of Au in these transformations

- Activates arenes

- Spectroscopic and isotope labelling experiments indicate the presence of the arene gold intermediate

Hoffmann-Roder, A.; Krause, N.; Org. Biomol. Chem. 2005, 3, 387-391

Shi, Z.; He, C.; J. Org. Chem. 2004, 69, 3669

AuCl3 (5 mol%), AgOTf (15 mol%)

ClCH2CH2Cl

O O

R

H

O O

R

Au

O O

R

25

Activation of β-Dicarbonyl Compounds

Yao, X.; Li, C. -J. J. Am. Chem. Soc. 2004, 126, 6884

R

O O

RR1

R2+AuCl3 (5mol%), AgOTf (15mol%)

MeNO2, reflux

R R

R1R2

O O

R

O O

R

R1R2

R R

R1R2

O O [AuI]R

O O

R[AuIII]

H

R

O O

R

[AuIII] H

R2

R1

R

O O

R

[AuIII]

R1R2

26

2,3-Indoline-Fused Cyclobutanes

NR

O

O

R2

R1NR

OO

R1H

R2AuCl(PPh3)/AgSbF6

CH2Cl2, rt

- Tandem cationic Au(I)-catalyzed activations of both propargylic esters and the in situ generated allenylic esters

NR

OH

O

R2

R1

NR

O

OR2

R1

NR

OO

R1

R2

AuL

Product of first catalytic cycle

Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

27

2,3-Indoline-Fused Cyclobutanes

NR

O

O

R2

R1NR

OO

R1H

R2AuCl(PPh3)/AgSbF6

CH2Cl2, rt

- Tandem cationic Au(I)-catalyzed activations of both propargylic esters and the in situ generated allenylic esters

Entry R R1 R2 Yield

1 Me (CH2)4CH3 Me 81%

2 H Ph Bu 98%

3 H Ph (CH2)3Br 95%

4 H Ph Ph 86%

Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

28NR

O

O

R2

R1

NR

O

O

R2

R1

Au(PPh3)

NR

NR

O

OR2

R1

Au(PPh3)

O

OR2

Au(PPh3)

R1

Tandem Sequence

Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

29

Tandem Sequence

NR

OH

O

R2

R1

NR

O

O

R2

R1

Au(PPh3)

NR

O

O

R2

Au(PPh3)

R1

NR

O

OR2

R1

NR

O

OR2

R1

Au(PPh3)

NR

O

OR2

R1Au(PPh3)

NR

O

OR2

LAu R1

NR

OO

R1H

R2

NR

OO

R1

R2

AuL

Au(PPh3)

Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

30

First Enantioselective Example

Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405-6406

Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48, 1999

Aldehyde Ligand R=

Yield

%

Ratio trans/cis

% ee of trans

PhCHO Et 98 89/11 96

Me 91 90/10 94

(E)-n-PrCH=CHCHO Et 83 81/19 84

Me 97 80/20 87

t-BuCHO Et 100 100/0 97

RCHOAu(s-HexNC)2

+BF4-, L

CH2Cl2, rt ON

ON

R RCO2MeCO2Me

Fe PPh2

NMeCH2CH2NR2

MeH

PPh2

L=

R = Me, Et

CN CO2Me

+

31

Control of Chirality- When they created a catalyst with a longer side chain there was a loss of stereoselectivity

- Without the terminal amino group there was a loss of stereoselectivity

- Other chiral phosphines gave racemic products

Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48, 1999

Ito, Y.; Sawamura, M.; Hayashi, T.; J. Am. Chem. Soc. 1986, 108, 6405-6406

AuP

P

FeN

O

OMe

HMe NMe NHR2

O R

HPh Ph

PhPh

- Cu and Ag were much less selective than Au

- Medium size substituent on amino group gave higher trans/cis ratio

32

Enantioselective Hydrogenation

Au Pt Ir

Substrate TOF ee (%) TOF ee (%) TOF ee (%)

R=H 3942 20 10188 3 8088 1

R=Ph 906 80 926 90 1110 26

R=2-Nf 214 95 250 93 325 68

1005 75 1365 15 1118 15

(R,R) Me-Duphos

EtO2C

EtO2C

H

R

M-Duphos catalyst (0.1 mol%)

EtOH, rt, 4 atm of H2

HH

EtO2C RHEtO2C

P

P

Au ClAu Cl

PhN

Ph

Gonzelez-Arrellano C.; Corma, A.; Iglesias, M.; Sanchez, F. Chem. Comm. 2005, 3451

33

Enantioselective hydrogenation- Hydrogen activation by hydrogen splitting promoted by the electron-rich Au-complex bearing heteroatoms (Cl).

Gonzelez-Arrellano C.; Corma, A.; Iglesias, M.; Sanchez, F. Chem. Comm. 2005, 3451

PPh

PhAu Cl

H H

+

PPh

PhAu H

PPh PhAu

H R1 R2

PPh

PhAu

R2R1

*

PPh

PhAu OEt

R1 R2

R1 R2

*H2

HOEt

HOEt

34

Carene Terpenoids Synthesis

2-carene Sesquicarene Isosesquicarene

Furstner, A.; Hannen, P. Chem. Commun. 2004, 2546-2547

H

H

H

H

H

H

- Plant essential oil

- Is a pheromone

- Component of terebentine

- Is a [4.1.0] bicyclo compound that differs at the cyclopropane unit

35

Envisioned Strategy

-This specific type of rearrangement was discovered as a side reaction mediated by ZnCl2

Furstner, A.; Hannen, P. Chem. Commun. 2004, 2546-2547

H

H

R1O

N2

O

R1

R1

OAc

OAc[M]

O

O

O O[M] [M]

OAc

[M]

O

O

- Although PtCl2 is normally the catalyst of choice it resulted in a significant amount of allenyl acetate

36

O

Commercially available geranyl acetone

1) , THF, 0oC rt; 96%

2) Ac2O, DMAP, Et3N 98%

OAcAuCl3 (5 mol%)

1,2-dichloroethane

AuO

O

O OAu

AuOAc

OAc

HC CMgBr

H

H

Sesquicarene Synthesis

Furstner, A.; Hannen, P. Chem. Commun. 2004, 2546-2547

37

Sesquicarene Synthesis

Furstner, A.; Hannen, P. Chem. Commun. 2004, 2546-2547

OAc

H

H

LiAlH4

Et2O, 0°C rt

41% (over 2 steps) O

H

H

L-Selectride

THF, -78°C rt

93%OH

H

H

PPh3, DEAD, THF

70%

H

H

H

Sesquicarene

38

Can Be Applied to the Other Carenes

2-carene

Isosesquicarene

Furstner, A.; Hannen, P. Chem. Commun. 2004, 2546-2547

OAcAuCl3 (5mol%)

1,2-dichloroethane

98%H

H

OAcH

H

AuCl3 (5mol%)

1,2-dichloroethane

87% H

H

OAc H

HOO

39

Jungianol

- Sesquiterpene isolated from Jungia Malvaefolia

- Isolated and characterized by Bohlmann et al. in 1977

- Possesses a trisubstituted phenol substructure and has two side chains on the five membered, benzoannelated ring

Proposed structure of Jungianol

Hashmi, A. S. K.; Ding, L.; Bats, J. W.; Fischer, P.; Frey, W. Chem. Eur. J. 2003, 9, 4339-4345

OH

40

Key Step

Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3, 3769-3771

Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553

OH

O

O

OAuCl3 (2 mol%)

MeCN, 20oC

O

AuO

OHHO

OH

or

O

41

Synthesis

Hashmi, A.S.K.; Ding,L.; Bats, J.W.; Fischer, P.; Frey, W. Chem. Eur. J. 2003, 9, 4339-4345

OH O

BrMgC CH

THF, -60°C 0°C

73%

O H

OH

DMP

CH2Cl2, 0°C rt

77%

OO

AuCl3

CH3CN

75% OH O

1) BrMgCH=C(CH3)2, THF, 0°C

2) silica gel

96% O

LiAlH4, h

Et2O, RT

OH OH

68% 21%

Epi-Jungianol Jungianol (revised structure)

42

Conclusions- Gold can catalyze reactions through Lewis acid activation

- Au is able to activate C-H bonds to open a world of chemistry beyond alkynes

- Aurated species now becomes a nucleophile instead of an electrophile

- Development of ligands for enantioselective reactions

- Synthetically useful

Nu [Au] Nu

[Au]

Nu

[Au]

43

Acknowledgements Dr. Louis Barriault

Patrick Ang Steve Arns Rachel Beingessner Christiane Grisé Mélina Girardin Roch Lavigne Louis Morency Maxime Riou Effie Sauer Guillaume Tessier Jeffrey Warrington