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Efficient Iron-Catalyzed N-Arylation of ArylHalides with Amines
Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H Org. Lett. ASAP
John MaciejewskiCurrent Literature - 9/27/08
Ar X NR1H
R2
Fe2O3, L-proline, NaOtBu
DMSO
NR1Ar
R2
Recent advances in aromatic carbon-nitrogen bond formation
John Maciejewski @ Wipf Group Page 1 of 15 10/7/2008
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Ullmann Reaction
Ma, D.-W.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.Soc. 1998, 120, 12459.
- Coupling between aromatic halides with either aliphatic and aromatic amines using copper salts and base- Drawbacks: high reaction temperatures (>150 oC) and stoichiometric copper usage- Using ligands that include phosphines, amines, and amino alcohols improve yields and applications- Current methods use readily available ligands, catalytic copper salts at temperatures as low as 40 oC
Ma, D.; Cai, Q. Acc. Chem. Res. ASAP.Yang, M.; Liu, F. J. Org. Chem. 2007, 72, 8969.Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
NHN
O
OH
benzolactam-V8
protien kinase C activator
H2N CO2H
Br
CuI, K2CO3
DMA, 90oC, 48 h
81%
HN CO2H
John Maciejewski @ Wipf Group Page 2 of 15 10/7/2008
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Goldberg Reaction
Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120 (kinetic study)Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311 (ligand studies).Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 16911.
- Amidation of aryl halides using primary and secondary amides (cyclic or acyclic)- Drawbacks similar to Ullmann reaction (high temp., strong base and stoichiometric copper salts)- Efficiency of reaction depends on choice of ligand, temperature and base (similar to Ullmann reaction)- Aryl amidation using copper salts is less expensive on industrial scale compared to palladium catalysis
N
OH
I CuI (5 mol%), K3PO4
glycine, dioxane, 100 oC, 24 h
97%
N
O
representative example
John Maciejewski @ Wipf Group Page 3 of 15 10/7/2008
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Mechanism for Ullmann & Goldberg Couplings
- Two possible mechanisms, but oxidation state of copper intermediates are not known- Radical mechanisms have been ruled out- Ligand choice is critical for reaction efficiency
Kurti, Laszlo, Barbara Czako. Strategic Applications of Named Reactions in Organic Synthesis. San Diego: Elsevier, 2005.
XAr1
Cu(I)X
L2Cu(III)
Ar1
X
L2Cu(III)
Ar1
NHAr2
Cu(I)XL2
2 L -2 LZ Ar1
Cu(II)X2
L2Cu(II)
Ar1
Z
L2Cu(II)X2
2 L -2 L
Cu0 ox.
L2Cu(II)
Ar1
HNAr2
Ar1 NAr2
H
oxidative addition
X-H2N Ar2
transmetallation
X-
H2N Ar2
reductiveelimination
reductiveelimination
+ e-
- e-
X = I, Br, ClY = NH2, HNCOR
Z = B(OH)2, BF3K, Sn(R)3Y = NH2, HNCOR
John Maciejewski @ Wipf Group Page 4 of 15 10/7/2008
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Transition-Metal Free Aryl Amination
Beller, M.; Breindl, C.; Riermeier, T. H.; Eichberger, M.; Trauthwein, H Angew. Chem. Int. Ed.,1998, 37, 3389.Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403 (hydroamination/cyclization studies)
Cl
Ph-NH2
tBuOK, toluene, 135oC
sealed tube, 36 h
N
Ph53%
OMe
OMe
Br KNH2/NH3
C3H7NH2
OMe
OMe
NH
94%
Han, Y. X.; Jovanovic, M. V.; Biehl, E. R.J. Org. Chem. 1985, 50, 1334Biehl, E. R.;Razzuk, A.; Jovanovic, M. V.; Khanapure, S. P.J. Org. Chem. 1986, 51, 5157. (addition of amines, nitriles andmercaptans)
via a benzyne intermediate
John Maciejewski @ Wipf Group Page 5 of 15 10/7/2008
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Mechanism for Benzyne Addition
Shi, L.; Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515 (and references therein).
Br
N
OtBuOK
H
N O
amine attack
proton transferdeprotonation/benzyne formation
tBuOH + KBr
BrN
O
tBuOK H
N O
amine attack
proton transferdeprotonation/benzyne formation
tBuOH + KBr
CH3H3C
H3C
N O
H3C
m:p = 1:1
Br
NO
tBuOK HN O
amine attack
proton transferdeprotonation/benzyne formation
tBuOH + KBr
N O
H3C
m:p = 2:1
H3C CH3
N OH
H3C
or
and
and
(1)
(2)
(3)
H3C
BrtBuOK, DMSO
µW
N
O
H
R
N O
R
John Maciejewski @ Wipf Group Page 6 of 15 10/7/2008
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Buchwald-Hartwig Coupling- Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927 (Stille-type coupling with amino stannanes)- Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1995, 34, 1348.- Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
OMs
t-Bu
NH2Pd(OAc)2 (1 mol%), 1
t-BuOH, 110 oC
99% t-Bu
N
H
OMe
PCy2
i-Pr
i-Pr
i-Pr
MeO
1
Fors, B. P.; Watson, D. A.; Briscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. ASAP
N
O
O
OMOM
CH3
H2N
O
O
OMOM
CH3Br
Br
Pd2(dba)3 (20 mol%)ligand studyt-BuONa (3 equiv)
toluene, 130 oC, 13 h
(sealed tube)
59%
double aryl amination
N O
CH3
murrayazoline1
Ueno, A.; Kitawaki, T.; Chida, N. Org. Lett. 2008, 10, 1999.
John Maciejewski @ Wipf Group Page 7 of 15 10/7/2008
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Buchwald-Hartwig Coupling
Urgaonkar, S.; Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003, 68, 8416.
- Advantage over Ullmann and Goldberg reactions due to the mild reaction conditions- Ligand choice is critical for the stabilization of the active Pd0 species in catalytic cycle- Broadening reaction scope and new ligand design remains a popular research area
Reddy, C. V.; Kingston, J. V.; Verkade, J. G. J. Org. Chem. 2008, 73, 3047 (aryl chloride coupling)Christensen, H.; Kiil, S.; Dam-Johansen, K. Org. Proc. Res. Dev. 2006, 10, 762.
John Maciejewski @ Wipf Group Page 8 of 15 10/7/2008
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Iron/Copper-catalyzed Aryl AminationI N
HN
Entry Iron (mol%) Copper (mol%) Yield (%)
2 equiv. Cs2CO3, DMF
100 oC, 15 h
Fe/Cu catalyst loadings NN
1 Fe(acac)3 (30) Cu0 (10) 100
2 Cu0 (10) 0
3 Fe(acac)3 (30) 0
Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem. Int. Ed. 2007, 46, 934.
- Various iron catylsts were studied, but Fe(acac)3 worked most efficiently with copper metal- First bimetallic catalysis (Fe/Cu) for N-arylation (works for aryl iodides and bromides)- Efficient for heterocyclic amines and 2-pyrrolidinone but not for aliphatic amines
PhI
NH
NH
O
CuO (10 mol%)Fe(acac)3 (30 mol%)
Cs2CO3 (2 equiv)
DMF, 90 oC, 30 h
PhI
CuO (10 mol%)Fe(acac)3 (30 mol%)
Cs2CO3 (2 equiv)
DMF, 90 oC, 30 h
N
Ph
NPh
O
93%
81%
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First Iron only Aryl Amination
- First ligand-assisted iron (only) catalyzed aryl amination process- Scope included pyrazoles, indoles and 2-pyrrolidinone- Aliphatic and aromatic amines failed (gave low yields)- Ligand study showed that catalytic system will work for both electron rich and deficient substrates- No mention of regioselectivity problem using unsymmetrical substrates
Correa, A.; Bolm, C. Angew. Chem. Int. Ed. 2007, 46, 8862.
I N
HN
K3PO4, toluene
135 oC, 24 h
FeCl3 (10 mol%),dmeda (20 mol%) N
N
80%
I N
HN
K3PO4, toluene
135 oC, 24 h
FeCl3 (10 mol%),dmeda (20 mol%) N
N
82%
H3C
H3C
I N
HN
K3PO4, toluene
135 oC, 24 h
FeCl3 (10 mol%),dmeda (20 mol%) N
N
87%
Cl
Cl
N
HN
K3PO4, toluene
135 oC, 24 h
FeCl3 (10 mol%),dmeda (20 mol%) N
N
87%
MeO MeOI
John Maciejewski @ Wipf Group Page 10 of 15 10/7/2008
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Iron-catalyzed Aryl Amidation
Correa, A.; Elmore, S.; Bolm, C. Chem. Eur. J. 2008, 14, 3527
- First ligand-assisted iron catalyzed aryl amidation- Yields complement those of palladium-catalyzed processes
S
O
NH2 I
F
K2CO3, toluene
135 oC, 24 h
FeCl3 (10 mol%),dmeda (20 mol%)
80%
S
O
NH
F
NH2
O
I
CO2Me
H3C K2CO3, toluene
135 oC, 24 h
FeCl3 (10 mol%),dmeda (20 mol%)
86%
NH
O
CO2Me
CH3
K3PO4, toluene
135 oC, 24 h
FeCl3 (10 mol%),dmeda (20 mol%)
79%
NH2
O
I
OMe
NH
O
OMe
John Maciejewski @ Wipf Group Page 11 of 15 10/7/2008
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Efficient Iron-Catalyzed N-Arylation of ArylHalides with Amines
- Coupling observed when using no catalyst or ligand- Entry 3 shows slightly improved yield of product- Entry 4 shows different iron catalyst improves yield- DMSO is superior solvent compared to dioxane, toluene or DMF
Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H Org. Lett. ASAP
Fe, ligand, t-BuONa (2 equiv)
DMSO, 135 oC, 24 h
Entry catalyst (10 mol%) ligand (20 mol%) Yield (%)
1 53
2 L-proline 52
3 77
4 85
FeCl3 L-proline
L-proline
I
HN
ONO
Fe2O3
John Maciejewski @ Wipf Group Page 12 of 15 10/7/2008
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Efficient Iron-Catalyzed N-Arylation of ArylHalides with Amines
- System works well with aromatic and aliphatic amines- Reaction not as efficient with pyrazole (entry 3 - Bolm observed 80% yield)- What role does iron play in this reaction?
Entry amine product Yield (%)
1 72
2 90
3 67
I
N
R1
R2
Fe2O3 (10 mol%)L-proline (20 mol%)t-BuONa (2 equiv)
DMSO, 135 oC, 24 h
NHNH2
N
R2
R1 H
(amine)
NH N
NNH N
N
John Maciejewski @ Wipf Group Page 13 of 15 10/7/2008
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Efficient Iron-Catalyzed N-Arylation of ArylHalides with Amines
- Unsymmetrical aryl iodides affords regioisomeric mixtures - reminiscent of TM free benzyne mechanism(?)- What type of reaction mechanism does this transformation fall under?- Bolm and co-workers do not note any selectivity issues in previous papers using iron catalysis
Fe2O3 (10 mol%)L-proline (20 mol%)t-BuONa (2 equiv)
DMSO, 135 oC, 24 h
I
ONH ON
Fe2O3 (10 mol%)L-proline (20 mol%)t-BuONa (2 equiv)
DMSO, 135 oC, 24 h
I
ONH
ON
Fe2O3 (10 mol%)L-proline (20 mol%)t-BuONa (2 equiv)
DMSO, 135 oC, 24 h
I
ONH
85%
CH3
H3C
ON
H3C
and
m:p - 1:1
66%
H3C
ON
H3C
m:p - 4:1
ONH3C
and
72%
John Maciejewski @ Wipf Group Page 14 of 15 10/7/2008
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Conclusions
- Aryl amination and amidation using iron catalysis is an emerging field with environmental benefits- Scope of process will need to be improved to compete with palladium-based Buchwald-Hartwig systems- Some results in title paper do not agree with those of Bolm and co-workers- Is iron really being used catalytically, or is regioselectivity issue a result of a benzyne intermediate
I
N
R1
R2
Fe2O3 (10 mol%)L-proline (20 mol%)t-BuONa (2 equiv)
DMSO, 135 oC, 24 h
N
R2
R1 H
(amine)
John Maciejewski @ Wipf Group Page 15 of 15 10/7/2008