An Overview ofHomogeneous Gold Catalysis

Matthew CampbellMarch 23, 2006

Gold Catalysis

•Gold rarely performs some common transition metal catalyzed processes

•A process gold does commonly perform

–Migratory Insertion–Oxidative Addition–Reductive Elimination–β-Hydride Elimination

–Proto-demetalation

O

[M]

M = Pd

M = Au

!-H elimination

O

O

H

Proto-demetalation

Catalysis

1. C-H bond activation

2. Alkyne activation toward nucleophilic attack

R

H [Au]

R

[Au] E

R

E

RRAu

R

Au

RAu R

NuR

-H+R

Nu

proto-demetalation

Au-

+H+ RNuH

NuH

H

Catalysis

O

H

OO

H

O

[Au]

H

OO

[Au]

O

O

H

[Au]

[Au]

•Generation of Au carbenes from propargylic carboxylates

•1,2-Hydride shift of Au carbenes

H

[Au]

Me

MeMe

H

[Au]

Me

MeMe

[Au]

Me

Me

Me

H Me

MeH

Me-[Au]

[Au]

O

O

H

O

O

H±

O

O

H

•Cyclopropanation of alkenes

3. Carbene Chemistry

Relativistic Effects on the Chemistry of Gold

AuPt

IrHg

[!(R)-!(NR)]/!(NR) [in %]

Relativistic stabilization of the 6s shell for elements Cs to Rn (Period 6)

•Contraction of 6s orbital

•Expansion of 5d orbitals due to increased shielding

Schwerdtfeger, P. Heteroatom Chemistry 2002, 13, 578.

6s6s

5d5d

Gold Catalysts

N

N N

N

Au

Cl

N

AuCl

Cl

Cl

N

AuCl

Cl

O

O

OHO

N

AuCl

Cl

O

•Au(I)

•Au(III)

-PPh3AuX X = Cl-, Br-, OTf-, NTf2-, SbF6-, BF4

-

-PPh3AuMe with acids (BF3·OEt2, heteropolyacids - H3PW12O40, TfOH)

-AuCl, AuBr

-AuCl3, AuBr3

-Na[AuCl4], K[AuCl4]

-[(PPh3Au)3O]BF4

Catalytic Species in Solution

Generally, it is unknown what the catalytically active species is

AuCl3 + AgOTfMeNO2, r.t.

Au9Ag11Cl28 + ?

4 AuCl3 + 5 AuCl + 11 AgCl

AuCl3 + 3 AgOTf Au(OTf)3 + 3 AgCl

3 Au(I) Au(III) + 2 Au(0)

Au(III)unsat. compounds

Au(I)

Reetz, M.T.; Sommer, K. Eur. J. Org. Chem. 2003, 68, 3385.

It is possible for Au cations to change oxidation state in solution

Aryl C-H Bond Activation

Ar-H AuCl3 ArAuCl2 HCl+ +

•Gold can activate aryl C-H bonds stoichiometrically

•Aryl gold species is dimeric [ArAuCl2]2 - typically unstable

•Can isolate ligand stabilized structures, ArAuCl2(L)L = PPh3, pyridine, SPr2, or 2,6-lutidine

•Stoichiometric aryl gold - alkyne coupling

Kharasch, M.S.; Isbell, H.S. J. Am. Chem. Soc. 1931, 53, 443. Liddle, K.S.; Parkin, C. J. Chem. Soc., Chem. Commun. 1972, 26.

De Graaf, P.W.J.; Boerasma, J.; van der Kerk. J. Organometallic Chem. 1976, 105, 399.Fuchita, Y.; Utsunomiya, Y.; Yasutake, M. J. Chem. Soc., Dalton Trans. 2001, 2330.

Me

Me

Au

Cl

Cl

N

Me

Me

+THF, 50 °C

Me

Me

94%

Me

Me

AuLn

ReductiveElimination

+ Au(I)

Reactivity of Aryl Gold Species

•Intermolecular hydroarylation of alkynes

Reetz, M.T.; Sommer, K. Eur. J. Org. Chem. 2003, 68, 3385.

Ph

+

1.5 mol % AuCl32.0 mol % AgSbF6

MeNO2, 50 °C

+

1.5 mol % AuCl35.0 mol % BF3•OEt2

MeNO2, 50 °CCO2Et

CO2Et

70%

90%

H

H

Hydroarylation Mechanism Unclear

Reetz, M.T.; Sommer, K. Eur. J. Org. Chem. 2003, 68 3385.

H

Au

R HR

Au

Deprotonation, thenProto-demetalation

AuR

R

H

Au

Au

RR

Au

Protonation

Proto-demetalation

R

Mechanism of Hydroarylation

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

Me

Me

Me

Me

Me

H stoich. Au(III) Solution darkens

Loss of Ar-H signal in 1H NMR

stoich. Au(III)Alkene orAlkyne

No change

O5.0 mol % AuCl315.0 mol % AgOTf

ClCH2CH2Cl, 50 °C

O O

R

H

O

R

R = H, 84% Me, 99% Ph, 73%

Reaction of Aryl Gold Species with Epoxides

Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964.

OO

R2

R1

2.5 mol % AuCl37.5 mol % AgOTf

ClCH2CH2Cl, 50 - 83 °C

OOH

R2

R1

O 2.5 mol % AuCl37.5 mol % AgOTf

ClCH2CH2Cl, 50 °C

OOH

82%, ring opening with inversion

O

65%

OOH

OOH

OOH

OOH

OOH

OOH

t-Bu OMe

Br

68% 58% 65%

85%

69%

Exclusively 6-endo cyclization product

Activation of Alkynes (Alkenes) towards Nucleophiles

R2R1Au

R2

Au

R1Au R2

NuR1

-H+R2

Nu

+ regioisomer

proto-demetalation

Au-

+H+ R1NuH

NuH

Au

Me H

Me3P

OMe

H

RR

bond length

RR

Au R

R

1.19 Å 1.26 Å 1.33 ÅC C

Formation of Ketones and Ketals

•Terminal alkynes give complete regioselectivity in favor of the Markovnikov addition product

•Use of cationic Au catalyst from (PPh3)AuMe and acid increased TON from 50 to 100000

Fukaka, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729.Teles, J.H.; Brode, S.; Chabanas, M. Angew. Chem. Int. Ed. 1998, 37, 1415.

R2R1O

R1

R2

R2R1

+5 mol % Na[AuCl4]

MeOH/H2O, reflux, 1-10 h(typically >90% yield)

R2R1

MeOR1

R2

R1

R2

OMe+5 mol % Na[AuCl4]

MeOH, reflux, 1-10 h(typically >80% yield)

OMe

MeO

RR

HO [Au]

O

Cycloisomerization of Bis-homopropargylic Diols

Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J. J. Am. Chem. Soc. 2005, 127, 9976.

HO

OH

R

n

2 mol % AuCl or AuCl3

MeOH, rt, <1h

AuO

H

R

HO

O

O

R n

n = 1, 2

No ketals derived from methanol addition were detected

Bn

Ph

n-Bu

cinnamyl

3-methylbut-2-enyl

AuCl

AuCl3

AuCl3

AuCl3

AuCl

AuCl

AuCl

AuCl3

1

2

1

1

1

1

1

1

allyl AuCl

AuCl3

2

1

99

99

99

99

80

82

82

91

74

77

R = Catalyst n Yield (%)

Formation of Imines

•Intermolecular

•Again, preference for Markovnikov addition product

•Intramolecular

Fukaka, Y.; Utimoto, K. Nozaki, H. Heterocycles. 1987, 25, 297.Fukaka, Y.; Utimoto, K. Synthesis 1991, 975.

R2

NH2N

R1

R2

5 mol % Na[AuCl4]

MeCN, rt, 12 h

quantitative yield

R1

N

R1

R2

R1

R2

H2NR1

R2H2N

5 mol % Na[AuCl4]

MeCN, rt, 12 h

"

"

>98% yield

Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349.

R2R1N

R1

R2 R1R2

N

+

0.01 - 0.2 mol % (PPh3)AuMe0.05 - 1.0 mol % H3PW12O40

ArNH2, Solvent free, 70 °C, 2 h(59-99%)

ArArHN

RR

Ar

Rearrangement of Alkynones

Hashmi, A.S.K.; Schwarz, L.; Choi, J.; Frost, T.M. Angew. Chem. Int. Ed. 2000, 39, 2285.

Et

O

1 mol % AuCl3

MeCN, rt

OEt

Au

OEt

Me OH R

Carboauration

Proto-demetallationO

OEt

OH

61%

Et

O Et 0.1 mol % AuCl3

MeCN, rt, minutes

OEt Et

Au

OEt Etquantitative yield

Et

O Et

[Au]

Deprotonation OEt Et

Au

Proto-demetalation

Rearrangement of 2-(1-alkynyl)-2-alkenones

Yao, T.; Zhang, X.; Larock, R.C. J. Am. Chem. Soc. 2004, 126, 11164.

O

O

1 mol % AuCl3CH2Cl2, rt, 1 h

MeOH

O

O

MeO

MeO

R1

O

R2

R3

R1

O

R2

R3

Au

O

R3

R1

R2

AuNuH

-H+

O

R3

R1

R2

Au

Proto-demetalation

Nu

O

R3

R1

R2Nu

52-90% yield

Nu = MeOH,

NH

H

H NMe2

Ph OH

1 mol % AuCl3CH2Cl2, rt, 1 h

O

R3

R1

R2

Au

Rearrangement of Alkynyl Epoxides

Hashmi, A.S.K; Sinha, P. Adv. Synth. Catal. 2004, 346, 432.

R2

-H+

OR2

Proto-demetallation

O R2

5 mol % AuCl3CH2Cl2, rt

O

R1R1

R1 Au

OR2

R1 Au

HH

H

R2

O

R1

Au

O

Me

OH

O

Me

OH

O Ph

HO

O

HO

O

O

H

OH

O

MeO

HOH

OMe

from

80%, 17 h 84%, 17 h 56%, 27 h 25%, 9 h 69%, 1 h

Cyclization of Allenyl Alcohols and Thiols

Hoffmann-Röder, A.; Krause, N. Org. Lett. 2001, 3, 2537.Hoffmann-Röder, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387.

•Complete axis to center chirality transfer

SH

Me

H

i-Pr

OBn

5 mol % AuCl3CH2Cl2, rt

S H

Me

i-Pr

H OBn (53%)

-H+

Proto-demetalation

5-10 mol % AuCl3CH2Cl2, rt

OH

R4

Au R3

R2

R1

OH

H

R4

R3

R1

R2

OH

H

R4

R3

R1

R2

AuH

O R4

Au R3

R2

R1 H

O R4

R3

R2

R1 H

R1 R2 R3 R4 Yield (%)

t-Bu

t-Bu

t-Bu

t-Bu

t-Bu

t-Bu

H

H

Me

Me

n-Bu

Me

H

Me

Me

n-Hex

H

Me

H

H

Me

Me

Me

Me

CO2Et

CO2Et

CO2Et

CH2OH

CH2OTBS

CH2OMe

CH2OTBS

CH2OTBS

74

94

quant

24

95

90

77

65

Cyclization of Allenyl Amines

Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.

2 mol % AuCl3

NHPG

Me

H

i-Pr N

Me

i-Pr

HCH2Cl2, rt

PG

OBn OBn

(dr > 99:1)

PG time Yield (%)

H

Ms

Ts

Ac

Boc

5 days

30 min

30 min

30 min

30 min

74

77

93

80

69

dr

>99:1

94:6

95:5

70:30

46:54

•Chirality transfer dependent on N-protecting group

HN

OBn

H i-Pr

Me

Au

HN

OBn

i-Pr H

Me

Au

PG PG

Cyclization of Allenones

Hashmi, A.S.K.; Schwarz, L.; Choi, J.; Frost, T.M. Angew. Chem. Int. Ed. 2000, 39, 2285.

2 mol % AuCl3

OCH2Cl2, rtO

R

R ORO

R O

R

O

R

O

R

++

R 1 2

4-MeOBn

3-MeOPh

4-(NO2)Ph

Me

4-(TBSO)Bn

60%

34%

88%

35%

47%

31%

38%

4%

47%

5%

3

-

-

-

-

42%

1 2 3

Rationalization of Byproduct Formation

Hashmi, A.S.K.; Schwarz, L.; Choi, J.; Frost, T.M. Angew. Chem. Int. Ed. 2000, 39, 2285.

O

R Au

OR

C-H Activation

OR Au-H+

O

RConjugateAddition

OR R

O

AuProto-demetalation

OR R

O

OR

O

R

O

R

O

R

Isomerization

Gold(III) Porphyrin Catalysts

Zhou, C.; Chan, P.W.H; Che, C. Org. Lett. 2006, 8, 325.

N

N N

N

Au

Cl

[Au(TPP)]Cl

1 mol % [Au(TPP)]Cl

OAcetone, 60 °CO

R1

R110 mol % CF3CO2H

R2

R3

R2

R3

73 - 97% Yield

•No products from C-H activation of furans detected (when R1 or R3 = H)

•Recovered/reused 10 times with small loss of activity

•Also used for hydration/hydroamination of alkynes

Divergent Catalysis of Haloallenones

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

•Changing the oxidation state of Au changes reaction pathway

•Also able to use other halogens (Cl, I)

Br

R

O

H

1-2 mol % AuCl3

C7H8, rt5 min to 1 day

1-2 mol % (PEt3)AuCl C7H8, rt

OR1-2 mol % AuCl3 THF, rt

Br

R

O

H

[Au]

BrRO

H

[Au]

BrRO

H

[Au] 1,2 Hydride Shift

RO

H

Br

Br

R

O

H

[Au]

R

O

H

[Au]

Br

RO

Br

H

61-88% yieldHigh Selectivity

1,2 Bromide shift?

Addition of Heteroatom Nucleophiles to Alkenes

Yang, C-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966.Zhang, J.; Yang, C-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798.

2 mol % PPh3AuCl2 mol % AgOTf

C7H8, 85 °C

MeO4 eq

1 eq nucleophile

MeO

NHTs

MeO

O

MeO

O

Me

Me

Me

Ph(4-MeO)

Nu = H2NTs

Nu =

Nu = Phenylacetic acid w/ 5 mol % cat

Bn

O

95%

58%

OMe

HO

95%

Nu

Nu

>7:1

Absence of nucleophile, 75% conv. E:Z = 2.2:1

•Migration of terminal alkenes

Conia-Ene Reaction of β-Ketoesters

Kennedy-Smith, J.J.; Staben, S.T.; Toste, F.D. J. Am. Chem. Soc. 2004, 126, 4526.

Me

O

OMe

O

Me

OMeO

O

OH

Me

AuMeO2C Me

OMeO

OAu1 mol % (PPh3)AuCl

1 mol % AgOTf

CH2Cl2, rt

•Deuterium labeling studies support mechanism

•Only terminal alkynes can be employed

R1

O

R2O OO

MeO O

X

H

Me

O

MeO O

Ph

Me

O

MeO O

n-Pr

R1 R2 Yield (%)

Me

Et

t-Bu

CH2CCH

Me

Ph

Me

Me

94

93

81

79

90% 95%, 4.2:1 dr 97%, 2.9:1 dr

OH

Me

AuMeO2C

PhOH

Me

AuMeO2C

n-Pr

Carbocyclization of Acetylenic Dicarbonyl Compounds

Staben, S.T.; Kennedy-Smith, J.J.; Toste, F.D. Angew. Chem. Int. Ed. 2004, 43, 5350.

Me

O

O O

MeO O

90% 94% 99% 90%

Me

Ph

O

EtO OMe

PhO

H

Me

CO2Me

O

BnO

MeO O

IO

H

96%

Me

O

OMe

O

Me

OMeO

O

OH

Me

CO2Me Me

OMeO

O1 mol % (PPh3)AuOTf

CH2Cl2, rt

AuEt

Et

Au

Et

Et

One-Pot Method to Pyridines

Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959.

MeO

Me

Me

O

MeO

Me

Me

N

" "

68%

O

Me

N2.5 mol % Na[AuCl4] • 2 H2O

N HN

H2N

[Au]

HN

H [Au]

H2N

2 eq 100 °C, 12 h

78%

Oxidation (?)

Gold Catalyzed Propargylic Claisen Rearrangement

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

[Au]

O

n-Bu

OTIPS

Ph

95% ee

O

Ph

OTIPS

n-Bu

H

OPh

OTIPS

n-BuH

H

n-Bu

H

Ph

OTIPS

OH

(after reduction)81%, 94% ee, >20:1 dr

R1

R3R2

OH

[1,3]-rearrangement product

•Effective transfer of chirality

•Selective for propargylic Claisen over allylic Claisen

O

Ph

OH

Ph

H

80%

O

R1

R3R2

0.1-1 mol % [(Ph3PAu)3O]BF4

CH2Cl2, rt, 0.5-25 hthen, NaBH4, MeOH, rt

OH

R3

R2

R1

Broad scope76-96% yield

Domino Claisen/Allene Cycloisomerization

Suhre, M.H.; Reif, M.; Kirsch, S.F. Org. Lett. 2005, 7, 3925.Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.

•Starting materials readily available

R1

O

OR3

OH

R2

cat PMe3O

R2

R1

OR3

O

61-98% yield

O

R2

2 mol % (Ph3P)AuCl2 mol % AgBF4

CH2Cl2, rt, 2-48 h

R2

R1

OR3

OR1O

O

OR3

5-endo-dig OR5-exo-dig

then isomerization

OMe

R2

R1

O

OR3

72-99% yield

Addition of Activated Methylenes to Alkenes

Yao, X.; Li, C-J. J. Am. Chem. Soc. 2004, 126, 6884.Nguyen, R-V.; Yao, X.; Bohle, D.S.; Li, C-J. Org. Lett. 2005, 7, 673.

R

O

R

O

R = alkyl, arylO

O

R

O

R

O

R

O

R

OR

O

R

O

R

OO

R

all using 5 mol % AuCl315 mol % AgOTf

39-98%

42%, R = Ph

38-54%58%, R = Ph

Overview of Gold Carbene Chemistry

O

H

OO

H

O

[Au]

H

OO

[Au]

O

O

H

[Au]

[Au]

•Generation of Au carbenes

–Alkynes and alkenes

–Propargylic carboxylates

[Au][Au]

[Au]

[Au]

CH

Overview of Gold Carbene Chemistry

•General reactions of Au carbenes

–1,2-Hydride Shift of Au Carbenes

H

[Au]

Me

MeMe

H

[Au]

Me

MeMe

[Au]

Me

Me

Me

H Me

MeH

Me-[Au]

[Au]

O

O

H

O

O

H±

O

O

H

–Cyclopropanation of alkenes

Cycloisomerization of 1,5-Enynes

Luzung, M.R.; Markham, J.; Toste, F.D. J. Am. Chem. Soc. 2004, 126, 10858.

Ar

H

HAr

H

PhPh

HPh

Ph

Ph

Ph

OAc OAc

H

HBn

Bn Me

Me

H

H

Me

Me

OMe

OMeOMe

OMe

OTIPSOTIPS

substrate product substrate product

substrate product

yieldyield

yield

99%Ar = Ph

99%Ar = 2,3-MeOPh

94%

96%

96%(97:3 dr)

99%(91% ee, >99:1 dr)

(97% ee, 98:2 dr)

1-3 mol % (PPh3)AuPF6

CH2Cl2, rtRcis

Rtrans

R

AuL

R

Rcis

Rtrans

AuL

R

Rcis

Rtrans

H

H

H

H Rtrans

Rcis

R1,2-hydride shift

Nucleophilic Trapping of Gold Carbene

Luzung, M.R.; Markham, J.; Toste, F.D. J. Am. Chem. Soc. 2004, 126, 10858.

5 mol % (PPh3)AuPF6

MeOH, rt

Me

[Au]

Me

Me

Me

PhMe

Me

Me

OH

[Au]

Me

Me

OMe

Me

HO

85%

Intramolecular Trapping of Gold Carbene

Zhang, L.; Kozmin, S. J. Am. Chem. Soc. 2005, 127, 6962.

R2 R1

Ph

HO

R2

R1

HO

[Au]Ph Ph

OR2 R1

R1 = H, Me, Ar

R2 = Me, Ph

89-92% yield5 mol % AuCl3 or (PPh3)AuClO4

MeCN or CH2Cl2 rt, 1 h

MeMe

Me

Ph

MeMe

Me

PhHOOH

Me

[Au]Ph

MeMe

HH

HO

H

Me

[Au]Ph

MeMeHO

H

O

Ph

Me

Me

Me

H

O

Me

MeMe

Ph

98%

90%

•Bicyclo[3.2.1]octene

•6-endo-dig or 5-endo-dig?

Formation of 1,4-Cyclohexadienes

Zhang, L.; Kozmin, S.A. J. Am. Chem. Soc. 2004, 126, 11806.

•1,3 dienes sometimes formed even without blocking group (>3:1)

•Can be deprotected to form 1,2 or 1,3-cyclohexenones

[Au]

1 mol % AuCl

CH2Cl2, rt, 30 min

Me

OTIPS

MeMeMe

TIPSO

93%

Me

OTIPS

Me

TIPSO

MeMe

[Au]TIPSO

MeMe

[Au]

TIPSO

Me Me

[Au]

Me

TIPSO [Au]

MeMe

TIPSO

MeMe

88%

Dienes from Enynes

Nieto-Oberhuber, C.; Paz Muñoz, M.; Buñuel, E.; Nevado, C.; Cárdenas, D.J.; Echavarren, A.M. Angew. Chem. Int. Ed. 2004, 43, 2402.

•Typically, 5-exo-dig for enynes with electron poor bridging carbons

•However, small effect can change course to 6-endo-dig

2 mol % PPh3AuCl2 mol % AgSbF6

CH2Cl2, rt, 5 min

PhO2S

PhO2S

PhO2S

PhO2S

PhO2S

PhO2S

[Au] [Au]

PhO2S

PhO2S

[Au]

PhO2S

PhO2S

5-exo-dig

100%

1,3-alkyl shift

2 mol % PPh3AuCl2 mol % AgBF4

CH2Cl2, rt, 10-20 min

MeO2C

MeO2C

MeO2C

MeO2C96%

Me

Me

MeO2C

MeO2CMeO2C

MeO2C

7 : 1

77%

MeO2C

MeO2C

H

" "

H

H

Cyclization of Nitrogen Tethered Enynes

Nieto-Oberhuber, C.; Paz Muñoz, M.; Buñuel, E.; Nevado, C.; Cárdenas, D.J.; Echavarren, A.M. Angew. Chem. Int. Ed. 2004, 43, 2402.

2 mol % PPh3AuCl2 mol % AgSbF6

CH2Cl2, rt, 10 min TsNMe

TsN Me

TsN

Me

93%

1 : 2.4

2 mol % PPh3AuCl2 mol % AgSbF6

CH2Cl2, rt, 15 min

TsN

TsN

[Au]

6-endo-dig

96%

TsN

Me

Me

Me

Me

TsN

[Au]

TsN

[Au]

Me

Me

Me

Me

MeMe

1,3-alkyl shift

Cyclization of Dienynes

Nieto-Oberhuber, C.; López, S.; Echavarren, A.M. J. Am. Chem. Soc. 2005, 127, 6178.

•Use of aromatic ring as nucleophilic alkene allows exclusive control of elimination

P Au Cl

CyCy

Au cat =

MeO2C

MeO2C

Me

Me

[Au]

MeO2C

MeO2C

MeMe

MeO2C

MeO2C

Me MeH

[Au]

MeO2C

MeO2C

Me Me

86%

2 mol % Au cat2 mol % AgSbF6

CH2Cl2, rt, 1 h

MeO2C

MeO2C

MeO2C

MeO2C

[Au] [Au]

MeO2C

MeO2C

[Au]

MeO2C

MeO2C

5-exo-dig

Me

Me

R

R

Me

Me

R

MeMe

H

HMe Me

B:

B:

path a

path b

MeO2C

MeO2C

Me Me

RMeO2C

MeO2C

Me Me

R

R = H 72%

R = Me 53% + 5%

R

Divergent Cycloisomerization Pathways of Enynes

Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8054.

Ph

OH

OHLAu

OHLAu

Ph

Ph

H

O

Ph

2 mol % (PPh3)AuCl2 mol % AgSbF6

CH2Cl2, rt

75%

•Hydroxylated enyne performs a 1,2-hydride shift to complete reaction

•Acyl protected analog engages in acetate migration prior to cyclopropanation

Ph

OAc

AuL

AcO

Ph

O2 mol % (PPh3)AuCl2 mol % AgSbF6

CH2Cl2, rt Ph Ph

AcO K2CO3

MeOH

74%

Gold Catalyzed Rautenstrauch Rearrangement

Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802.

R1

R2

OPiv

O R1

R2

5% Ph3AuSbF6

CH3CN, -20 °C, 12h

(79-98% ee) (77-96% ee)

AuL

PivO R1

R2

LAu

Me

OPiv

Me

Me

OMe

MeAuL

O

t-Bu

HMe

MeO

Ot-Bu

AuLH

Me

MeLAu

O

Ot-Bu

PivO MeHydrolysis

Me

O Me

Me

MeLAu

O

Ot-Bu

H

H

Nazarov Cyclization of Enynyl Acetates

Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442.

R1

OAc

R3

R2R3

R2

O

R1

1-5 mol % (PPh3)AuCl/AgSbF6

wet CH2Cl2, rt, 0.5 - 2hr

(57 - 95%)

Catalytic Cycle:

LAu

O R4

O

R3

R2R1

R3

R2

AuL

O

O

R4

R1 R3

R2

R3

R2

O

R1

LAu

O

R4

R3

R2

O

R1

LAu

O

R4

AuL

LAu

R3

R2

O

R1

R3

R2

O

R1

O

R4

Hydrolysis

[3,3]-sigmatropic

4! electrocyclicring closure

O

R4 O

R1

R3

R2

O

R4 O

R1

Acetylenic Schmidt Reaction

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

R1 N3

R3

HNR1 R32.5% (dppm)Au2Cl2

5% AgSbF6 , CH2Cl2, 35 °C

41-93% Yield

R2

R2

LAu N3

R

N

R

N2

LAu

N

LAu R

N2

N

LAu R

N

R

NH

R

Generation and Cycloaddition of Au-ContainingAzomethine Ylides

Kusama, H.; Miyashita, Y.; Takaya, J.; Iwasawa, N. Org. Lett. 2006, 8, 289.

N

R2

1-10 mol % AuBr3

C7H8, rt, 4Å MS, 0.5 to 42 h

60-89% yieldusually 1:1 dr

R1

Ot-Bu N

R2

R1

Ot-Bu

N

R2

R1

[Au]

N

R1

R2

[Au]

N

R1

R2

[Au]

Ot-Bu

N

[Au]

R1

Ot-BuR2

R1 = Ph or Oi-PrR2 = alkyl or aryl

Benzannulation of Enynals with Alkynes

Asao, N.; Nogami, T.; Lee, L.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921.

•Catalytic Cycle

CHO

Ph

H

Ph

3 mol % AuCl3 or AuBr3

ClCH2CH2Cl, 80 °C Ph

O Ph

AuCl3 96% 2.5 h

AuBr3 100% 0.7 h

LAu

H

O

R

H

O

R[Au]

O

[Au]

R

EWG

O

[Au]

R

EWG

[Au]

Me

Me

OR

EWG

O R

Benzannulation of Enynals with Enols

Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458.

•Can change dienophile to favor the opposite regioisomer

MeO

MeO

CHO

Ph

O

O

O

O Ph

MeO

MeO52%

•Also able to use acetals

CHO

Ph

10 mol % AuBr3

1,4-Dioxane, 100 °C, 3 h

O Ph

MeH

O

Me

87%

OHMeO

[Au]

R

[4+2]

[Au]

Me

OR

HH

OH

[Au]

Me

OR

H

Phenol Synthesis

Hashmi, A.S.K.; Frost, T.M.; Bats, J.W. J. Am. Chem. Soc. 2000, 122, 11553.Hashmi, A.S.K.; Weyrauch, J.P.; Rudolph, M.; Kurpejović. Angew. Chem. Int. Ed. 2004, 43, 6545.

X R1R2 Yield (%)

H

H

H

Me

H

H

H

H

65

69

97

94

93

96

88

81

CH2

O

NTs

NTs

NTs

NNs

C(CO2Me)2

H

H

H

H

Me

H

H

HN(Ts)CH2

5 mol % AuCl3

MeCN, rtO X

R2

Me

Me

OH

X

R1

R2

R1

Me

X

R1

R2

HO

no other isomers detected

4 mol % AuCl3

MeCN, rtO NTs

NTs NTs

OH

HO

51% 31%

Mechanism of Phenol Synthesis

Hashmi, A.S.K.; Rudolph, M.; Weyrauch, J.P.; Wölfle, M.; Frey, W.; Bats, J.W. Angew. Chem. Int. Ed. 2005, 44, 2798.

O NTsR

Au assisted Diels-Alder [4+2]

Au carbene stabilizedcyclopropanation

Insertion intofuran C-O bond

O

R

NTs

RNTs

O

ONTs

[Au]

R

O[Au]

NTs

R

[Au]O

R

NTs

Insertion intoalkyne

O[Au]

R

NTs

NTs

O

R

H

O

NTsR

HObserved by NMR at -20 °C(H,H-COSY, HMQC)

Warm to rt

NTs

R

OH

N N

NO O

NTs

O

R

H

NN

NO

OPh

Ph

[4+2]

N

AuCl

Cl

Ousing

6! electrocyclization

Conclusions

–Gold can activate aryl C-H bonds stoichiometrically, but the mechanism is vague for catalytic systems used for hydroarylations and other reactions.

–Alkynes, allenes and alkenes are activated by gold salts towards attack by a variety of heteroatom and carbon nucleophiles.

–Gold carbene chemistry is similar to that of other late transition metals, but it often possesses greater catalytic acitivity and allows higher selectivities to be achieved.

Acknowledgements

Jeff Johnson

and the Johnson Group