homogeneous gold catalysis michelle monnens rogers stahl group 3/31/05 michelle monnens rogers stahl...
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Homogeneous Gold CatalysisHomogeneous Gold Catalysis
Michelle Monnens RogersStahl Group
3/31/05
Michelle Monnens RogersStahl Group
3/31/05
22
History of GoldHistory of Gold
http://www.goldinstitute.org/history/
Robert and William Forrest and John S. MacArthur patent the process for extracting gold from ore using cyanide
4000 BC
Gold was known in central Europe
1350 BC
1887 AD
1903 AD
1927 AD
1960 AD
1968 AD
1971 AD
33
Why Gold?Why Gold?
Precious Metal Prices / Gram. Silver - $0.19 Ruthenium - $1.96 Iridium - $4.66 Palladium - $6.17 Osmium - $12.86 Gold - $13.66 Platinum - $27.62 Rhenium - $39.38 Rhodium - $50.15
Precious Metal Prices / Gram. Silver - $0.19 Ruthenium - $1.96 Iridium - $4.66 Palladium - $6.17 Osmium - $12.86 Gold - $13.66 Platinum - $27.62 Rhenium - $39.38 Rhodium - $50.15
http://www.taxfreegold.co.uk/preciousmetalpricesusdollars.html
Gold complexes are air and water stable
Gold selectively binds to alkynes
Gold complexes are air and water stable
Gold selectively binds to alkynes
44
Early Catalysis ExamplesEarly Catalysis Examples
Schwemberger, W.; Gordon, W. Chem. Zentralbl. 1935, 106, 514.
Gassman, P. G.; Mayer, G. R.; Williams, F. J. J. Am. Chem. Soc. 1972, 94, 7741.
2 mol% AuI3
CHCl3, 0 oC+ + +
15% 15% 6% 6%
Cat. AuCl or AuCl3
Cl2
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
55
C-N Bond FormationC-N Bond Formation
N C9H19
HO
PhNH
N
AcO OHMeO
Preussin AnisomycinMeO
HO OH
Codonopsinine
NH
N
OHH
H
MeOO
Ajalicine
N
NN
NH2
OH
BrO
N
HH
H HOHimbacine
Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.Gompel, M.; Leost, M.; Bal De Kier Joffe, E.; Puricelli, L.; Franco, L. H.; Palermo, J.; Meijer, L.; Bioorg. Med. Chem. Lett. 2004, 1, 1703.Franco, L. H.; Joffe, Bal de Kier, E.; Puriceli, L.; Tatian, M.; Seldes, A. M.; Palermo, J. J. Nat. Prod. 1998, 61, 1130.Takadoi, M.; Katoh, T. Ishiwata, A.; Terashima, S. Tetrahedron 2002, 58, 9903.
66
Intermolecular Hydroamination of AlkynesIntermolecular Hydroamination of Alkynes
Internal alkynes are less reactive. Aliphatic amines do not react.
Internal alkynes are less reactive. Aliphatic amines do not react.
Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349.
R1 R2 H2N R3
(Ph3P)AuClH3PW12O40
Solvent Free+
R1
NR3
R2
1 2 3
R1= R2= Amine R3 Au (mol%) H3PW12O40 (mol%) time (h) yield 3 (%)
C6H5 H C6H5 0.2 1.0 2 98
C6H5 H 4-NO2C6H4 0.1 0.5 1 86
4-CH4OC6H4 H 4-BrC6H4 0.1 0.5 0.25 90
C6H5
C6H5
0.2
0.2
1.0
1.0
3
5
96
59
nHexyl H
nPr nPr
77
Synthesis of 2,3,4,5-Tetrahydropyridines from 5-Alkynylamines
Synthesis of 2,3,4,5-Tetrahydropyridines from 5-Alkynylamines
Fukuda, Y.; Utimoto, K. Synthesis, 1991, 975.
R1
R2
NH2 NR1R2
5% NaAuCl4MeCN, reflux, 1h
1 2
R1 R2 [] mmol % Conversion 2 (% Yield)
H 100 63
H 50 82
H 25 100 80
H 1 100
n-C6H13
n-C6H13
n-C6H13
n-C6H13
Ph H 25 0
25 90
H
H n-C6H13
25 92
88
Proposed Mechanism for Cyclization of 5-Alkynylamines
Proposed Mechanism for Cyclization of 5-Alkynylamines
Fukuda, Y.; Utimoto, K. Synthesis, 1991, 975.
R1
R2
NH2
NR1R2
R1
R2
NH2
[Cl3Au]
NH2
R2R1
[Cl3Au]
AuCl3
NH
R1R2
Tautomerization
Protonolysis
Nucleophilic Attack
Coordination
99
Synthesis of IndolesSynthesis of Indoles
Au(I), Pt(IV), Pd(II) and Cu(II) were less effective catalysts. Yields were maintained in solvent mixtures up to 50% water.
Au(I), Pt(IV), Pd(II) and Cu(II) were less effective catalysts. Yields were maintained in solvent mixtures up to 50% water.
Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis, 2004, 610.
4 mol% NaAuCl4Ethanol, rt
NH2
R HN
R
Substrate Product % Yield
NH2
nBu
NH2
Ph
NH2
NH2
HN
Ph
HN
nBu
HN
HN
Time (h)
S
5 83
4 70
20 90
4 80S
1010
Proposed Mechanism of Tandem Cyclization / Conjugate AdditionProposed Mechanism of Tandem Cyclization / Conjugate Addition
Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265.
NH2
R1
NH2
R1Cl3Au
H2N
R1
[AuCl3]
H2N
R1
R2
[AuCl3]
OR3
HN
R1
R2
OR3
1
2
R2 R3
O
R2 R3
O AuCl3
AuCl3
3
5
6
7
8 HN
R1
4
7
1111
2-Alkynylaniline Cyclization Coupled with Conjugate Addition
2-Alkynylaniline Cyclization Coupled with Conjugate Addition
Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265.
NH2
R1
HN
R1
R2
OR3
R2 R3
O+
5% NaAuCl4Ethanol, 30 oC
Alkynyl-phenylamine ,-Enone 2,3-Disubstituted-indole Time (h) % Yield
NH2
PhPh CH3
O
HN
Ph
PhO
CH3
5 74
NH2
S CH3
O
HN
OCH3
S
1.5 88
NH2
Ph
CH3
O
HN
OCH3
Ph23 95
1212
Cycloisomerization of -Aminoallenes to 3-Pyrrolines
Cycloisomerization of -Aminoallenes to 3-Pyrrolines
Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
PG Time 2 (% yield) dr
H
Ms
Ts
Ac
Boc
5 days
30 min
30 min
30 min
30 min
74
77
93
80
69
99:1
94:6
95:5
70:30
46:54
2 mol% AuCl3CH2Cl2, RT N
PGR
OR'
21
•R
H NHPGOR'
R R' dr
99:1
99:1
99:1
99:1
99:1
Bn
Bn
Bn
Bn
Bn
iPr
iPr
iPr
iPr
iPr
Bn
TBS
TBS
Me
nhexyl
Ph
90:10
85:15
99:1
71
82
79
90:10
85:15
99:1
H
H
H
5 days
5 days
5 days
1
1313
Proposed Mechanism for -Aminoallene CyclizationProposed Mechanism for -Aminoallene Cyclization
Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
AuCl3N
[Cl3Au]
OR'RHH PG
H+ Shift- AuCl3 N
PGR
OR'
ONH
OR'
R"RH
[Cl3Au]
ONH
OR'
R"HR
[Cl3Au]
N
[Cl3Au]
OR'HRH PG
H+ Shift- AuCl3 N
PGR
OR'
•R
H NHPGOR' •
RH NHPG
OR'Cl3Au
1414
C-O Bond FormationC-O Bond Formation
N
O
N
O
MeO
OMe
OMe
Annuloline
NOH
OH
O
OO
O
OMe
O
Verrucosidine
OOAc
OH
OH
O
O
OO O
HOO
Krause, N.; Laux, M.; Hoffmann-Roder, A. Tetrahedron Lett. 2000, 9613.Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389.Liu, Y.; Bae, B. H.; Alam, N.; Hong, J.; Sim, C. J.; Lee, C.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2001, 64, 1301.Fisch, K. M.; Bohm, V.; Wright, A. D.; Konig, G. M. J. Nat. Prod. 2003, 66, 968.
1515
Alkynyl Epoxide Rearrangement to FuransAlkynyl Epoxide Rearrangement to Furans
Base, Ru and Mo catalyzed conditions suffer substrate limitations.
Hg(II) catalysis presents environmental issues.
Base, Ru and Mo catalyzed conditions suffer substrate limitations.
Hg(II) catalysis presents environmental issues.
Hashmi, A. S. K.; Sinah, P. Adv. Synth. Catal. 2004, 346, 432.
R'R
O
5% AuCl3MeCN, rt
O
O
O
O
Substrate Product Yield (%)
HO
HO
OEtEtO
OH
OH OOH
O
O
O
OMe
O
HO
HO
O
OH
OMe
O
84
56
25
69
O R'
R
1616
Proposed Mechanism of Alkynyl Epoxide Rearrangement to Furans
Proposed Mechanism of Alkynyl Epoxide Rearrangement to Furans
Hashmi, A. S. K.; Sinah, P. Adv. Synth. Catal. 2004, 346, 432.
O R'
R [AuCl3]
AuCl3
H
H
1
3
4 2
5
H
R
H
[AuCl3]
R'O
OR'
R
O R'
RR'
O
AuCl3
R
1717
Cyclization to FuransCyclization to Furans
Yao, T.; Whang, X.; Larock, R. J. Am. Chem. Soc. 2004, 126, 11164.
1% AuCl3CH2Cl2, rt, 1h
R1
O
R2
R3
OR3 R1
R2
Nu
Alkenynone Nucleophile Product Yield (%)
O Ph
O Ph
Me
Ph
O Ph
O
O
Ph
O
OMe
Ph
OPh
MeOH 88
O O
N
O81
90N
OPh Me
PhOMe
O Ph
MeOH 60
+ Nuc
1818
Proposed Rearrangement Mechanism for 2-(Alkynyl)-2-alken-1-one
Proposed Rearrangement Mechanism for 2-(Alkynyl)-2-alken-1-one
AuCl3 fails to catalyze the 1,4-addition of methanol to methyl vinyl ketone or 2-cyclohexenone under the reaction conditions.
AuCl3 fails to catalyze the 1,4-addition of methanol to methyl vinyl ketone or 2-cyclohexenone under the reaction conditions.
Yao, T.; Whang, X.; Larock, R. J. Am. Chem. Soc. 2004, 126, 11164.
O R
AuCl3
O R
AuCl3
OR
O
Nu
R
AuCl2
AuCl2
HCl
NuH
H
O
Nu
R
Cl
1919
Cyclization of Allenyl Ketones to FuransCyclization of Allenyl Ketones to Furans
Pd(II) catalysis leads to different products. Ag(I) leads to lower yields.
Pd(II) catalysis leads to different products. Ag(I) leads to lower yields.
Hashmi, A. S. K.; Schwarz, L.; Choi, J.; Frost, T. J. Angew. Chem. Int. Ed. 2000, 39, 2285.
•R
O
1% AuCl3MeCN, rt OR OR
O1 2 3
+
R = 2 (% Yield) 3 (% Yield)
O
NO
O
S
Me
60 31
88 4
48 51
47 47
1
2020
Allenyl Ketone Rearrangement to Furans Coupled with Michael Addition
Allenyl Ketone Rearrangement to Furans Coupled with Michael Addition
Hashmi, A. S. K.; Schwarz, L.; Choi, J.; Frost, T. J. Angew. Chem. Int. Ed. 2000, 39, 2285.
•R
O
1% AuCl3MeCN, rt OR
R2
R1
O1 3
O74
64
46
62
R2 R1
O2
O
1 R 2 R1 R2 3 (% Yield)
O
OO
O O
O
Me H
Et Me
Me H
Me H
+
2121
-Hydroxyallene Cyclization to 2,5-Dihydrofurans
-Hydroxyallene Cyclization to 2,5-Dihydrofurans
Yield increases from 67 to 94% with AuCl3. Yield increases from 67 to 94% with AuCl3.
Hoffmann-Roder, A.; Krause, N. Org. Lett. 2001, 3, 2537.Krause, N.; Hoffmann-Roder, A.; Canisius, J. Synthesis 2002, 1759.Krause, N.; Laux, M.; Hoffmann-Roder, A. Tetrahedron Lett. 2000, 41, 9613.
OR2
R1
R4
H
R35-10% AuCl3CH2Cl2, rt
R1 R2 R3 R4 2 (% Yield)
tBu Me Me CO2Et 94
tBu nBu H CO2Et 100
tBu Me H CH2OH 24
tBu H Me CH2OTBS 95
H2C=CH(CH2)2 Me Me CH2OMe 86
•
R2
R1
R3
OH
R4H
1 2
2 dr
60:40
65:35
70:30
85:15
95:5
1
60:40
65:35
70:30
85:15
95:5
dr
AuCl3 increases the rate of the reaction compared with HCl gas in CHCl3.
AuCl3 increases the rate of the reaction compared with HCl gas in CHCl3.
2222
Synthesis of Oxazoles from N-Propargylcarboxamides
Synthesis of Oxazoles from N-Propargylcarboxamides
No conversion is observed with internal alkynes. H2SO4 and Hg(OAc) cyclization require elevated temperatures.
No conversion is observed with internal alkynes. H2SO4 and Hg(OAc) cyclization require elevated temperatures.
Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
NH
O R1
N
O R
2
5% AuCl3CH2Cl2
1 R T (oC) t (h) 2 Yield (%)
20 12 95
20 12 95
20 48 88
20 12 98
20 12 73
50 2 86
Me
Ph
O
OMe
O
2323
Reaction Profile of Oxazole FormationReaction Profile of Oxazole Formation
Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
NH
O Ph1b
N
O Ph
2b
5% AuCl3CH2Cl2
N
O Ph
3
12 hours for complete conversion of 1b to 2b
2424
NMR Analysis of Reaction IntermediateNMR Analysis of Reaction Intermediate
Cyclization and proto-demetalation are stereospecific. Cyclization and proto-demetalation are stereospecific.
Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
NH
O Ph1b
N
O Ph
2b
5% AuCl3CH2Cl2
N
O Ph
3
Ha
Hb
NH
O Ph5
N
O Ph
6
5% AuCl3CH2Cl2
N
O Ph
4
DHa
D D
Proton NMRN
O Ph
3
Hb
Ha
Hc
Hc
4
N
O PhHb
D
Hc
Hc
2525
C-C Bond FormationC-C Bond FormationH
O(-)-Thujone
H
OHDebromolaurinterol
O
O
OMe
O
Crispatene
OH
OH
OHO
HO
O
Gossypol
N
O
O
MeO
H2NN
NH2
OMeOMe
OMe
CO2H
Rufocrpmomycin
NPH
NHN NH nC13H27
OH
NH2OH
D-threo-sphingosine
O
O OH
OMe
CO2H
Mycophenolic Acid
Kdebati, M. B.; Schmitz, F. J. J. Org. Chem. 1985, 50, 5637.Selover, S. J.; Crews, P. J. Org. Chem. 1980, 45, 69.Ali, s.; Singh, P.; Thomson, R. H. J. Chem. Soc. Perkin Trans. 1 1980, 257.Rees, J. C.; Whittaker, D. J. Chem. Soc. Perkin Trans. 2 1981, 953.Tilford, C. H.; Hudak, W. J.; Lewis, R. E. J. Med. Chem. 1971, 14, 328.Tennant, S.; Richards, R. W. Tetrahedron 1997, 53, 15101.
2626
Isomerization of 1,5-Enynes to Bicyclo[3.1.0]hexenes
Isomerization of 1,5-Enynes to Bicyclo[3.1.0]hexenes
Only a trace yield in the presence of silver alone. Only a trace yield in the presence of silver alone.
Luzuing, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858.
1-3% (PPh3)AuCl1-3% AgXCH2Cl2, rt
Substrate Catalyst Product Yield (%)
Ph X= PF6Ph
H
H 99
PhPh
X= SbF6
Ph
H
Ph94
Ph
X= SbF6
PhH
96
OAc OAc
Substrate Catalyst Product Yield (%)
X= SbF6H
H
6199:1 dr
X= SbF6
H
H
8210:1 dr
X= SbF6
H
H
9697:3 dr
OTIPS OTIPS
PhPh
H
PhPh
No AgX 0
2727
Cyclization of Enynes in MethanolCyclization of Enynes in Methanol
Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Chem. Eur. J. 2003, 9, 2627.D. J. Echavarren. A. M., et al. Angew. Chem. Int. Ed. 2004, 43, 2402.Munoz, M. P.; Adrio, J.; Carrentro, J. C.; Echavarren, A. M. Organometallics 2005, 46, 1293.
Au(III) and Au(I) are effective catalysts for the cyclization. A series of chiral AuI complexes gave high yields but low ee’s.
Au(III) and Au(I) are effective catalysts for the cyclization. A series of chiral AuI complexes gave high yields but low ee’s.
TsNOMe
TsNOMe
MeO
OMeOMe
MeO
MeO2C
MeO2C
MeO2C
MeO2C
OMeOMe
MeO
TIPSO
TIPSO
TIPSO
TIPSO MeO2C
MeO2COMe
MeO2C
MeO2C OMe
OMe
ZR
ZR
MeO
5% AuCl3MeOH, Reflux(Acid w/ alkenes)
Substrate Product Yield (%)
97
95
90 94
MeO2C
MeO2C
MeO2C
MeO2C
Substrate Product Yield (%)
97OMe
Acid
HBF4
TsNTsN
85H3PW12O40
---
OMe
2828
Conia-Ene Reaction of -Ketoesters with Alkynes
Conia-Ene Reaction of -Ketoesters with Alkynes
Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526.
Ag(OTf) alone does not catalyze the reactions. Ag(OTf) alone does not catalyze the reactions.
R1 OR2
O O O
O
R2OR1
1% (PPh3)AuCl1% AgOTfCH2Cl2, rt
1 2
Substrate Time Product Yield (%)
Me OMe
O O O
O
MeOMe
15 min 94
OOMe
O CO2MeO
H
1h 90
O
OEt
O
Me
OCO2Et
Me
O O
OMe
H H
OCO2Me
2.5 h
5 min
90
99
Substrate Time Product Yield (%)
Me OMe
O O O
O
MeOMe
24 h86
(4.2:1)
Me OMe
O O O
O
MeOMe
1h96
4.0:1
Ph
Ph
Ph
Ph
2929
Mechanistic Studies on Conia-Ene ReactionMechanistic Studies on Conia-Ene Reaction
Deuterium labeling experiments support enol addition to a gold-alkene complex.
Deuterium labeling experiments support enol addition to a gold-alkene complex.
Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526.
Me2OC
Me OMe
O OO
O
MeOMe(Ph3P)AuOTf OH
Me
AuAu
AcMeO2C
123 4
Me OMe
O O
5a
D
H
Me OMe
O O
5a
H
D
O
O
MeOMe
H D O
O
MeOMe
D H
90%48%
6b6a
3030
Carbocyclization of Internal AlkynesCarbocyclization of Internal Alkynes
Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem. Int. Ed. 2004, 43, 5350.
R1 OR2
O O
1
R3
OR1
OR2O
2
Substrate Time Product Yield (%)
R3
Me O
O O
Me
Me
OMe
OO10 min 90
OEt
O O
Me
Me
O
OEtO5 h 90
Me O
O O
Me10 min 88
MeO2C
Substrate Time Product Yield (%)
10 min 94
5 h 99
10 min 99
OO
O
Ph
O Ph
H
CO2Me
BnO
O
OMe
O OCO2Me
BnO
NCO2Me
OH
ON
OCO2Me
1% (PPh3)AuCl1% AgOTfCH2Cl2, rt
3131
Addition of -Diketones to OlefinsAddition of -Diketones to Olefins
Yao, X.; Li. C. J. Am. Chem. Soc. 2004, 126, 6884.Nguyen, R.; Yao, X.; Bohle, S.; Li. C. Org. Lett. 2005, 7, 673.
R1
O
R2
OR3+ R1
O
R2
O
R3
5% AuCl315% AgOTfCH2Cl2, rt
Me
O
Me
O
R
Me
O
Me
O
RR = H
R = OMe
R = Cl
Substrate Alkene Product Yield %
89
62
97
OOOO
70(1:1)
Ph
O
Ph
OPh
O
Ph
O
H
81
R4
Substrate Alkene Product Yield %
R4
Ph
O
Ph
O Ph
O
Ph
O
65
Ph
O
Ph
O
42
O Ph
O
Ph
O
O68
3232
Benzannulation: Synthesis of Naphthyl Ketone Derivatives
Benzannulation: Synthesis of Naphthyl Ketone Derivatives
Electron withdrawing groups on the alkyne favor product 4. Electron withdrawing groups on the alkyne favor product 4.
Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yanamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650.Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921.
O
H
R1
R2 R3
O R1
R2
R3
O R1
R3
R23% AuCl3DCE, 80 oC
+ +
1 2 3 4
R1 = 2 R2 = R3 = Time (h) Ratio 3:4 Yield %
Ph nPr H 1.5 92:8 91
Ph Ph H 2.5 99:1 96
Ph CO2Et H 3 18:82 72
Ph COCH3 H 3.5 1:99 75
Ph Ph Me3Si 2 99:1 92
C6H13 Ph H 1.5 92:8 91
1
3333
Proposed Mechanism for BenzannulationProposed Mechanism for Benzannulation
Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yanamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650.Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921.
H
O
R1AuCl3
H
O
R1Cl3Au
O
H
RAuCl3
O
H
RAuCl3
R3
R2
R2
R3
OR1
O
Cl3Au
R
R2
R3
3434
Synthesis of Functionalized PyridinesSynthesis of Functionalized Pyridines
Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959.
H2N R
OR'
NR
R'2.5% NaAuCl4EtOH
+
1 2 3
Ketone 2 T (oC) Time (h) Yield (%)
Ph PhO
75 12 98
Pyridine 3
NPh
Ph
Ph O 78 5 74N
Ph
O 78 7 77N
O78 12 96
N
Ph
3535
Proposed Mechanism for Pyridine Synthesis
Proposed Mechanism for Pyridine Synthesis
Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959.
R
OR'
H2N
R
OR'
AuCl3
R
HN
R'
AuCl3
NH
R
R' [AuCl3]
NR
R'
NR
R'Aromatization
AuCl3
H2O
3636
Synthesis of QuinolinesSynthesis of Quinolines
Acradi, A.; Chiarini, M.; Di Giuseppe, S.; Marinelli, F. Synlett. 2003, 203.
R1
OR2
NH2
R3
O
+2.5% NaAuCl4EtOH, 40-60 oC, 6h
N R1
R2R3
1 2 3
Ketone 1 Aniline 2 Product 3 Yield (%)
OEt
O O
NH2
Ph
O
N Me
Ph
OEt
O
93
O
O NH2
Ph
O
N
Ph O
78
O O
NH2
Ph
O
N Me
Ph O
87
NH2
Ph
O
N
Ph
73O
Acid or T (oC) Yield (%)
H2SO4
HOAc Reflux85
100-120 80
150 70
100-120 47
3737
Synthesis of PyrrolesSynthesis of Pyrroles
Acradi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Adv. Synth. Catal. 2001, 343, 443.Acradi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Tetrahedron Asymm. 2001, 2715.
R1 R2
OO
R3NH2+5% NaAuCl4EtOH, 40 oC
NR3
OR2
CH3R1
1 2 3
Diketone 1 Amine 2 Pyrrole 3 Yield (%)
Me Me
OONH2
NBn
OMe
CH3Me100
Me Me
OO
NPh
OMe
CH3Me
NH278
Me OEt
OO
S NH
O ONH2
NNTs
OEtO
CH3Me100
Me Me
OONH2
HMePh
N
OMe
CH3Me
HMePh
98%, 99% ee
3838
Propargyl Claisen RearrangementPropargyl Claisen Rearrangement
Sherry, B. J.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
O
R1
H R2
1. 1% [(Ph3PAu)3O]BF4
CH2Cl2, rt2. NaBH4, MeOH, rt R1 •
H
R2
OH
1 2
R1 = R2 = Time (h) Yield (%)
Ph H 0.5 78
Ph 0.5 89
Ph 25 81
p-MeO-C6H4nBu 12 89
p-F3C-C6H4 Me 19 86
iPr Ph 6 87
nBu 23 76
nC5H11 6 90
OTBS
OPiv
OTBS
3939
Chiral Propargyl Claisen Rearrangement and Proposed Mechanism
Chiral Propargyl Claisen Rearrangement and Proposed Mechanism
Sherry, B. J.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
O
R2
1. 1% [(Ph3PAu)3O]BF4
CH2Cl2, rt2. NaBH4, MeOH, rt •
H
R1
R2
OHR1
O
n-C4H9
•
H
Ph
n-C4H9
OH
1 Substrate ee 2 Product Yield (%) ee
O
H
•
H
Ph
H
OH
O
SiMe3
•
H
Ph
SiMe3
OH
Ph
Ph
Ph
95% 91 90%
92% 78 88%
92% 98 92%
1 2
•
R1
HO
R3
R2R1
R2
O R3
R1
R2
O R3
[Au]
OH
R3
R2
[Au]R1
H
[Au]
4040
Phenol Synthesis from FuransPhenol Synthesis from Furans
Hashmi, A. S. K.; Frost, T.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553.Hashmi, A. S. K.; Frost, T.; Bats, J. W. Catalysis Today 2002, 72, 19.
O Z Z
OH
2% AuCl3MeCN, rt
1 2
1 Z = 2 Yield
CH2 65 %
O 69 %
NTs 97 %NNs 96 %
C(CO2Me)2 88 %
N(Ts)CH2 81 %
O ZO Z
AuCl3
O
Z
Z
O
Z
O H
AuCl3 Z
OH
Aromatization
4141
Ligand Development for Furan Rearrangement
Ligand Development for Furan Rearrangement
Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejovic, E. Angew. Chem. Int. Ed. 2004, 43, 6454.
O NTsNTs
OH1
2
Catalyst 3
N
AuCl Cl
Cl
N
AuCl O
Cl
O N
AuCl O
Cl
O N
AuCl O
Cl
O
OHCO2H
3 4 5 6
4242
Comparison with Other CatalystsComparison with Other Catalysts
Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
O NTsNTs
OH1
2
4343
Total Synthesis Application of the Furan Cyclization to Phenols
Total Synthesis Application of the Furan Cyclization to Phenols
Hashmi, A. S. K.; Ding, L.; Bats, J. W.; Fischer, P.; Frey, W. Chem. Eur. J. 2003, 9, 4339.
OH
O
ONa H
THF, 0 oCOH
O
O
"Dess-Martin"CH2Cl20 oC rt
AuCl3MeCN, rt
OOH
BrMg
THF, 0 oC
Silica GelCH2Cl2, rt O
LAH, hEt2O, rt
OH
73% 77% 53%
96%21%
OH
68%
Jungianol epi-J ungianol
4444
Hayashi-Ito Aldol with Isocyanoacetates and Aldehydes
Hayashi-Ito Aldol with Isocyanoacetates and Aldehydes
Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405.
RCHO
Au(CNCy)2BF4 (1 mol%)1 (1 mol%)
NO
OC
CH2Cl2, 25 oC
+O N O N
CO2MeR R CO2Me+
trans-3 cis-3
Aldehyde Ligand Yield 3 (%) Ratio trans/cis % ee, trans
O
O
O
O
O
1a
1b
1a
1a
1a
98
97
100
95
100
89 / 11
80 / 20
84 / 16
97 / 3
100 / 0
96
87
72
90
97
Fe
PPh2
PPh2
NMe
NR2
1a R= Et1b R= Me
First example of a catalytic asymmetric aldol. First example of a catalytic asymmetric aldol.
4545
Asymmetric Aldol - Stereochemical Control and Conversion to the Amino Acid
Asymmetric Aldol - Stereochemical Control and Conversion to the Amino Acid
Ligand stereochemistry controls product formation. Ligand stereochemistry controls product formation.
Ito, Y.; Sayamura, M.; Hayashi, T. Tetrahedron Lett. 1998, 29, 239.
Fe
PPh2
PPh2MeN N
O
Au(CNCy)2BF4 (1 mol%)2 (1 mol%)
NO
OC
CH2Cl2, 25 oC
+O N O N
+
trans-3 cis-3
CO2Me CO2Me
OnC13H27
2
nC13H27nC13H27
Conc HClMeOH, 55 oC, 2h100%
89%, 93% ee 11%, 20% ee
nC13H27 CO2MeOH
NH3ClLiAlH4
THFnC13H27
OH
NH2OH
D-threo-sphingosine
4646
Importance of Central ChiralityImportance of Central Chirality
Pastor, S.D.; Togni, A. J. Am. Chem. Soc. 1989, 111, 2333.
FePPh2
PPh2
NMe
FePPh2
PPh2MeN NMe2
NMe2
(R)-(S)-1 (S)-(R)-1
FePPh2
PPh2
NMe
NMe2
(S)-(S)-1
O N O
OC+
Au(CNCy)2BF4 (1 mol%)1 (1 mol%)
CH2Cl2, 25 oCO N
CO2Me
O N
CO2MePhPh+
trans cis
Ligand % trans, % ee % cis, % ee
(R)-(S)-1
(S)-(S)-1
(S)-(R)-1
89, 91, (4S,5R)
83, 41, (4R,5S)
89, 90, (4R, 5S)
10, 7, (4S,5S)
16, 20, (4S,5S)
10, 12, (4R,5R)
4747
Proposed Transition StateProposed Transition State
Sawamura, M.; Ito, Y. Tetrahedron Lett. 1990, 31, 2723.
P
AuI
P
O
Ph
Ph
Ph
Ph
Fe
N
N
H
OMe
O
NHR2
H
R
BF4
4848
NOE Evidence for Interaction with Distant Dimethyl Amine
NOE Evidence for Interaction with Distant Dimethyl Amine
31P NMR spectrum indicated a tridentate gold complex as the major species.
1H NMR spectra of the silver and gold complexes are analogous.
31P NMR spectrum indicated a tridentate gold complex as the major species.
1H NMR spectra of the silver and gold complexes are analogous.
Sawamura, M.; and Ito, Y. Tetrahedron Lett. 1990, 31, 2723.
Fe
PHPh2
Ph2P
Ag
H H
HH
H
1.8%
2.3%
1.0%
NMe
HNMe2
CNCH2CO2Me
CNCH2CO2Me
8.6%
OTf
P
AuI
P
O
Ph
Ph
Ph
Ph
Fe
N
N
H
OMe
O
NHR2
H
R
4949
Crystal Structure of Ferrocenylphosphine Ligand Bound to Gold
Crystal Structure of Ferrocenylphosphine Ligand Bound to Gold
Crystal structure shows expected linear Au(I) binding mode. Each phosphorus atom is binding a separate gold atom.
Crystal structure shows expected linear Au(I) binding mode. Each phosphorus atom is binding a separate gold atom.
Togni, A.; Pastor, S.D.; Rihs, G. J. Organomet. Chem. 1990, 381, C21.
5050
Ligand Modification Effects on Enantiomeric Excess
Ligand Modification Effects on Enantiomeric Excess
Togni, A.; Pastor, S.D. J. Org. Chem. 1990, 55, 1649.
FePPh2
PPh2
NMe
FePPh2
PPh2MeN NMe2
NMe2
(R)-(S)-4 (S)-(R)-4
FePPh2
PPh2
NMe
NMe2
(S)-(S)-4
FeSePh
SePh
NMe
NMe2
(R)-(S)-5a
FeSPh
SPh
NMe
NMe2
(R)-(S)-5b
O N O
OC+
Au(CNCy)2BF4 (1 mol%)Ligand (1 mol%)
CH2Cl2, 25 oCO N
CO2Me
O N
CO2MePhPh+
trans-2a- (4S,5R)b- (4R,5S)
cis-3a- (4S,5S)b- (4R,5R)
FePPh2
NMe
NMe2
(R)-(S)-6
Fe
PPh2MeN NMe2
(S)-(R)-6
2a - 90%, 91% ee3a - 10%, 7% ee
2 - 68%, 0% ee3 - 31%, 0% ee
2 - 72%, 0% ee3 - 28%, 0% ee
2b - 84%, 41% ee3a - 16%, 29% ee
2b - 90%, 90% ee3b - 10%, 12% ee
2 - 77%, 16% ee3 - 23%, 1% ee
2b - 74%, 21% ee3b - 26%, 4% ee
5151
Determination of the Rate Limiting Step in the Asymmetric Aldol
Determination of the Rate Limiting Step in the Asymmetric Aldol
Electron density on the aldehyde carbon increases in the transition state.
Rate determining step involves electrophilic attack of the aldehyde on the -isocyanoacetate ester.
Electron density on the aldehyde carbon increases in the transition state.
Rate determining step involves electrophilic attack of the aldehyde on the -isocyanoacetate ester.
Togni, A.; Pastor, S.D. J. Org. Chem. 1990, 55, 1649.
NOEt
OC+
O N O N
CO2MeR R CO2Me
+
R
O
R = NO2, CH3, Cl, H, CH3, OCH3, N(CH3)2
= 1.4
5252
Refined Transition State ModelRefined Transition State Model
Internal cooperativity controls the orientation of the -isocyano ester enolate and the approach of the attacking electrophile.
The steric approach control model explains the stereochemistry observed in the product.
Internal cooperativity controls the orientation of the -isocyano ester enolate and the approach of the attacking electrophile.
The steric approach control model explains the stereochemistry observed in the product.
Togni, A.; Pastor, S.D. J. Org. Chem. 1990, 55, 1649.
Fe
Ph2P
PPh2
NMe
N
AuI N H
OMeO
H
O H
Fe
Ph2P
PPh2
NMe N
AuI NH
OMeO
H
O H
si
re
O N
CO2Me
O N
CO2MePhPh
5353
Related Aldol ReactionsRelated Aldol Reactions
Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashiizaki, K.; Hayashi, T. Tetrahedron Lett. 1988, 29, 235.Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaka, K.; Hayashi, T. Tetrahedron 1988, 44, 5253.Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247.Ito, Y.; Sawamura, M.; Kobayashi, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 6321. Ito, Y.; Sawamura, M.; Hamashima, H.; Emura, T.; Hayashi, T. Tetrahedron Lett. 1989, 30, 4681.
Au(CNCy)2BF4 (1 mol%)1 (1 mol%)
CH2Cl2, 25 oC
R2 ONNR1
2
OC +
O N
PR2
R2 ON P(OR1)2
OC (OR1)2
O
+
+O N O N
CO2MeR2 R2 CO2Me+R1 R1R2 O
+NO
OC
O N
RCO2Me
H H
O" "
R
O NR2
O
R3
ON
R1
OC +
O N
R2 R2O
R1O
R1
R3OCR3OC+
O N
R2 NR12
O
O N
R2 NR12
O
+
NO
OC
R1
5454
ConclusionsConclusions
Gold(I) and gold (III) are becoming important reagents for organic synthesis.
Gold catalyzed reactions can replace some more traditional synthetic transformations with milder conditions.
Significant ligand development and mechanistic understanding of these transformations is needed.
Gold(I) and gold (III) are becoming important reagents for organic synthesis.
Gold catalyzed reactions can replace some more traditional synthetic transformations with milder conditions.
Significant ligand development and mechanistic understanding of these transformations is needed.
5555
AcknowledgementsAcknowledgements Prof. Shannon S. Stahl The Stahl Group
Practice Talk AttendeesJodie Brice, Sharon Beetner, Sarah Eldred, Emily English, Justin Hoerter, Jenna Harang, Lauren Huffman, Amanda King, Brian Popp, and Chris Scarborough.
Prof. Shannon S. Stahl The Stahl Group
Practice Talk AttendeesJodie Brice, Sharon Beetner, Sarah Eldred, Emily English, Justin Hoerter, Jenna Harang, Lauren Huffman, Amanda King, Brian Popp, and Chris Scarborough.
5656
History of GoldHistory of Gold
4000 BC - Gold was known in Central Europe 1350 BC - Babylonians began to use fire to test the purity of
Gold 1887 AD - Doctors, Robert and William Forrest, and chemist
John S. MacArthur patent the process for extracting gold from ore using cyanide.
1903 AD - The Engelhard Corporation introduces an organic medium to print gold on surfaces.
1927 AD - A Medical study proves gold to be valuable in treatment of Rheumatoid arthritis.
1960 AD - The laser is invented using gold-coated mirrors to maximize infrared reflection.
1968 AD - Intel introduces a microchip with 1,024 transistors connected by gold circuits.
1971 AD - The colloidal gold marker system is introduced to mark or tag specific proteins to reveal their function in the human body for the treatment of disease.
4000 BC - Gold was known in Central Europe 1350 BC - Babylonians began to use fire to test the purity of
Gold 1887 AD - Doctors, Robert and William Forrest, and chemist
John S. MacArthur patent the process for extracting gold from ore using cyanide.
1903 AD - The Engelhard Corporation introduces an organic medium to print gold on surfaces.
1927 AD - A Medical study proves gold to be valuable in treatment of Rheumatoid arthritis.
1960 AD - The laser is invented using gold-coated mirrors to maximize infrared reflection.
1968 AD - Intel introduces a microchip with 1,024 transistors connected by gold circuits.
1971 AD - The colloidal gold marker system is introduced to mark or tag specific proteins to reveal their function in the human body for the treatment of disease.
http://www.goldinstitute.org/history/
5757
Proposed Mechanism of 1,5-Enyne Isomerization
Proposed Mechanism of 1,5-Enyne Isomerization
Luzuing, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858.
Ph
Rtrans
Rcis
Ph
Rtrans
Rcis
LAu+
HPh
AuL
Rcis
Rtrans
Rcis
Rtrans
AuL
Ph
H
Ph3PAu+
Ph
H
H
Rcis
Rtrans
PhPh
H
HD
1% (Ph3P)AuPF6
CH2Cl2, rt
D
99% Yield
5858
Proposed Mechanism for CarbocyclizationProposed Mechanism for Carbocyclization
The 5-endo-dig cyclization is possible because no allylic 1,3 strain.
The 5-endo-dig cyclization is possible because no allylic 1,3 strain.
Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem. Int. Ed. 2004, 43, 5350.
CO2Me
Me OMe
O O
R
OMe
OMeO
R
Me
OH
Au Au
R
OMe
OMeO
5-endo-digR
5959
Asymmetric Aldol - Synthesis of -Alkylserines
Asymmetric Aldol - Synthesis of -Alkylserines
Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashiizaki, K.; Hayashi, T. Tetrahedron Lett. 1988, 29, 235.
Fe
PPh2
PPh2N NR2
2a NR2 = NMe2
2b NR2 = N
+
Au(CNCy)2BF4 (1 mol%)2 (1 mol%)N
O
OC
CH2Cl2, 25 oCO N
RCO2Me
H H
O" "
R1
-I socyanocarboxylate Ligand 2 Yield % ee (config)
R= H
R= Me
R= Et
R= iPr
2a
2a
2a
2b
99%
100%
89%
96%
52 (S)
64 (S)
70 (S)
81 (S)
2
6060
Asymmetric Aldol- Synthesis of -Hydroxy--Alkylamino Acids
Asymmetric Aldol- Synthesis of -Hydroxy--Alkylamino Acids
Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaka, K.; Hayashi, T. Tetrahedron 1988, 44, 5253.
Fe
PPh2
PPh2
NMe
NR2
1 NR2 = N O
RCHO
Au(CNCy)2BF4 (1 mol%)1 (1 mol%)
NO
OC
CH2Cl2, 25 oC
+O N O N
CO2MeR R CO2Me+
trans-2(4S,5R)
cis-2(4S,5S)
R'
Aldehyde Isocyano-carboxylate
Ligand Reactiontime (h)
% Yield
R' R'
% eetrans
Ratiotrans/cis
O R' = H
R' = Me
R' = iPr
O R' = H
R' = Me
R' = iPr
1
1
1
16
% eecis
93 95/5 95 12
67 97 93/7 94 53
1 330 86 62/38 88 17
70 99 89/11 89 10
1 41 86 56/44 86 54
1 260 100 24/76 26 51
6161
Asymmetric Aldol - Synthesis of (1-Aminoalkyl)phosphoric AcidsAsymmetric Aldol - Synthesis of (1-Aminoalkyl)phosphoric Acids
Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247.
Fe
PPh2
PPh2
NMe
Au(CNCy)2BF4 (1 mol%)1 (1 mol%)
CH2Cl2, 25 oCO N
PR2
trans-3
Fe
PPh2
PPh2MeN N
N
(R)-(S)-1a
(S)-(R)-1b
R2 ON P
(OR1)2
OC (OR1)2
O
+
Aldehyde
2
(Isocyanomethyl)-phosphonates
TempoC
Time(h)
Yield%
% ee(Config)
Ligand
N P(OEt)2
O O 1a
1b
60
60
60
60
89
85
90 (4R,5R)
90 (4S,5S)
O 1a 60 99 85 88 (4R,5R)
N P(OPh)2
O O 1a 60 39 94 93 (4R,5R)
O 1a 40 75 88 95 (4R,5R)
6262
Asymmetric Aldol - Reactions of -Isocyanoacetamides with Aldehydes
Asymmetric Aldol - Reactions of -Isocyanoacetamides with Aldehydes
Ito, Y.; Sawamura, M.; Kobayashi, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 6321.
FePPh2
PPh2
NMe
N
(R)-(S)-1
Au(CNCy)2BF4 (1 mol%)1 (1 mol%)
CH2Cl2, 25 oC
Isonitrile Aldehyde Time(h)
% Yieldtrans
Ratiotrans/cis
% eetrans
R2 ONNR1
2
OC +
NNMe2
O
NN
O
O
O
O
O
40
40
6
74
85
84
92
74
91 / 9
95 / 5
94 / 6
94 / 6
98.6
96.3
94.1
94.5
O
O
20
50
84
73
94 / 6
95 / 5
96.1
93.9
O N
R2O
NR12
O N
R2O
NR12
trans cis
+
6363
Asymmetric Aldol - Reactions of -Ketoesters with Isonitriles
Asymmetric Aldol - Reactions of -Ketoesters with Isonitriles
Ito, Y.; Sawamura, M.; Hamashima, H.; Emura, T.; Hayashi, T. Tetrahedron Lett. 1989, 30, 4681.
FePPh2
PPh2
NMe
O N
cis-4
N
(R)-(S)-1
R
O
R'
ON
R"
OC
+O N
R RO
R"O
R"R'OCR'OC
1. conc HCl in MeOH 50 oC, 1h2. N-benzoylation
trans-4
HO HN HO HN
R R
OR"
OR"
R'OCR'OC O
Ph
O
Ph
2 3
-Ketoester2
I sonitrile3
Time(h)
Yield of 4
Ratiocis/trans
Yield and % eeof Benzamide
Erythro-5e-5
Threo-5t-5
R"= OMe 12 90% 73 / 27R= MeR'= OMe
e-5= 82% eet-5= 33% ee
e-5= 67%, 90% eet-5= 11%, 36% ee
e-5= 71%, 76% eet-5= 11%, 84% ee
e-5= 42%, 42% eet-5= 17%, 74% ee
e-5= 37%, 75% eet-5= 28%, 74% ee
R= iBuR'= OMe
R= PhR'= OMe
R= MeR'= Me
R= MeR'= OMe
R"= NMe2
R"= NMe2
R"= NMe2
R"= NMe2
20
68
108
39 92%
88 / 12
79 / 21
80 / 20
51 / 49
Au(CNCy)2BF4 (1 mol%)2 (1 mol%)
CH2Cl2, 25 oC
6464
Energy Profile for Enyne Cyclization Thought Cyclopropane
Energy Profile for Enyne Cyclization Thought Cyclopropane
Nevado, C.; Cardenas, D. J. and Echavarren, A. M. Chem. Eur. J. 2003, 9, 2627.
6565
Synthesis of 3-HaloindolesSynthesis of 3-Haloindoles
Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis, 2004, 610.
4 mol% NaAuCl4Ethanol, rt
NH2
RN
R
Substrate Product % Yield
NH2
NH2
Ph
HN
Ph
HN
X= Br 74
X= Br 70
Br2 or I2
KOH
X
XCl
Cl Cl
Cl
NH2
nBu
HN
nBu
X
X= Br 81
X
X= I 66
X= I 64
6666
Aza-Michael Reaction of Enones with Carbamates
Aza-Michael Reaction of Enones with Carbamates
A number of additional metal complexes were also effective catalysts for this transformation.
Gold acts as a Lewis Acid to activate the enone.
A number of additional metal complexes were also effective catalysts for this transformation.
Gold acts as a Lewis Acid to activate the enone.
Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319.
Ph
O
H2N O
O
Ph
Enone Nucleophile Adduct Catalyst Time(h) % Yield
Ph
O
O
O
H2N O
O
Ph
H2N O
O
Ph
HN O
O
Ph
O NHCbz
Ph
O N
OO
O NHCbz
O NHCbz
AuCl
AuCl
6
48
20
20
quant.
54
65
78
AuCl
AuCl3