Transition-Metal-Catalyzed：过渡金属催化

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Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis Elsevier 2005
Ugi, I. Angew. Chem. Int. Ed. 1962, 1, 8-21. McFarland, J.W. J. Org. Chem. 1963, 28, 2179-2181
• Double allylation • Ring opening/Ring closing metathesis
• opens a 5-membered ring • closes two 7-membered rings
• 4 new C-C bonds
Lee, D.; Sello, J.K., Schreiber, S.L. Org. Lett. 2000, 2, 709-712.
19
Synthesis or Pyrroles
Arndtsen, B.A; St. Cyr, D.J; Martin, N. J. Am. Chem. Soc. 2004, 126, 468-469.
Yoshimur, H.; et. al. J. Med. Chem. 1995, 38, 3163.
Transition-Metal-Catalyzed Multicomponent Reactions
Emily Blamer April 3, 2008
What is a Multicomponent Reaction?
1-CR
2-CR
6-CR
A reaction in which three or more compounds react to form one product
[Pd]
H
O N R1 R3
H R2 [Pd]
R1
N R3
O
CO coordination
CO
H R2 CO
Pd Cl
R1 N
R3
O
CO insertion
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Dhawan, R.; Dghaym, R.D.; Arndtsen, B.A. J. Am. Chem. Soc. 2003, 125, 1474-1475.
Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis Elsevier 2005
Ugi, I. Angew. Chem. Int. Ed. 1962, 1, 8-21
Carofigilo, T.; Floriani, C. Organometallics 1991, 10, 1659-1660
Advantages
• Mild conditions
– 1 atm CO – 55°C – Catalytic in Pd
• Scope
• Slight reagent changes lead to other useful compounds
Disadvantages • Both nitrogens are substituted •Cannot us C-alkyl imines
Efaroxan
pyrrolnitrin
H N O2N
Cl Cl
histidine/histamine
Pyrroles
porphyrin
tolmetin
NH N
N HN
Jonas, J.C.; Garcia-Barrado, M.J.; Angel, I.; Henquin, J-C. Eur. J. Pharm. 1994, 264, 81-84
3
Synthesis Methods
Divergent Synthesis
90% 90%
90%
Convergent Synthesis
90% 90%
90 %
90%
90%
90% Overall yield: 59%
90%
•Higher yield 73% •Time reduction
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Passerini 3-Component Reaction: 1921
Rondu, F.; Godfroid, J.J.; et. al. J. Med. Chem. 1997, 40, 3793-3803 Brown, E.G. Ring Nitrogen and Key Biomolecules Kluwer Academic Publishers, Boston, 1998.
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Easy as addition of an alkyne?
• Rate limiting step: oxidative addition
• Solution: add labile donor ligand to stabilize Pd complex
Arndtsen, B.A; St. Cyr, D.J; Martin, N. J. Am. Chem. Soc. 2004, 126, 468-469
Cl O R2
[Pd]
H
O N R1 R3
H R2 CO
Pd Cl
R1 N
R3
O
CO insertion
Dghaym, R.D.; Dhawan, R., Arndtsen, B.A. Angew. Chem. Int. Ed. 2001, 40, 3228-3230.
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Addition of Base
• Removal of acid allows isolation of Münchnone intermediate
• Removal of dba ligand and addition of anion leads to higher yield
Dghaym, R.D.; Dhawan, R.; Arndtsen, B.A. Angew. Chem. Int. Ed. 2001, 40, 3228-3230 Dhawan, R.; Dghaym, R.D.; Arndtsen, B.A. J. Am. Chem. Soc. 2003, 125, 1474-1475
Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005 Oro, J. Biochem. Biophys. Res. Commun. 1960, 2, 407-417.
2
Advantages of Multicomponent Reactions
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Münchnones
• Traditional Synthesis
R2
R1 N H
OH O
OO R3 O R3
heat
R1
R2
N O
R3 O
• Isolable unless C-alkylated
• Typically generated in situ
• Undergo [3 + 2] cycloadditions with alkenes and alkynes
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Ugi 4-Component Reaction: 1960
R3
N H
R1 R2 R4 N
N NN
HNNN
CO2, R5OH
R5
O
R1 R2 NHR4
ON
R3 O
Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis Elsevier 2005
Ar HO
1) KHMDS allylbromide (89%) 2) Grubbs II (69%) 3) HF-pyridine (95%)
OO H
Ar
N
N
H
O
H
O
N
H
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Nitrogen Heterocycles Imidiazolines
Imidazoles
antiprotozoal (metronidazole)
8
L = linker
NH2 O CHO
O L
O
Ugi 4CR/Diel's Alder HN
H
O
67%
ON
NC Ar N H
CO2H
O H
O L
O HN
• Ugi-4CR of simple, available starting materials • 5 new bonds
• Diels-Alder • two C-C bonds • three rings
R1
N R3
O
H
Pd(0)
R2
OO R3
R2 N R1
O
CO [Pd]
R2 N R5 R1
HCl
R3 R1
O N Cl R2 H
oxidative addition
O R3 Cl
R1 N R2 H
H R2 Cl [Pd]
R1 N
R3 O
CO coordination CO
-hydride elimination
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O R1
MeO
N R3
R2 O
MeOH
OO R3
R2 N R1
Pd(0)
R3 R1
O N Cl
R2 H oxidative addtion
O R3 Cl
R1 N R2 H
O
CO [Pd]
R2 N R3 R1
-hydride elimination
Cl HNEtiPr2 NEtiPr2
Cl O R2
Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis Elsevier 2005
Ugi, I. Angew. Chem. Int. Ed. 1962, 1, 8-21
Carofigilo, T.; Floriani, C. Organometallics 1991, 10, 1659-1660
• High atom economy • Operationally simple: in one-pot • Highly Modular • Functional group tolerant • Resource efficient (time & cost)
Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem., 2003, 4101-4111 Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005; pxiii.
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O R2 R3
H O
O R1
-R1CO2
H O R2 R3
C N R4
O H
R3 R2
R1
O
N
O
R4
O R1
O
R2 R3 NHR4
O
H
PT
R2 O R1
R3
O
O
R4 N
R2 H R3 O R1 R4 NO O
Reaction is faster in non-polar solvents that facilitate hydrogen bonding of polar substrates
Huisgen, R.; Gotthardt, H.; Bayer, H.O.; Schaefer, F.C. Angew. Chem. Int. Ed. 1964, 3, 135-137.
Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765-2809.
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Review of [3 + 2] Cycloaddition
1,3-dipole
b ac
dipolarophile
de
b ac
de
Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, 565, 633
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Some Common 1,3-dipoles
Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, 565, 633
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Steep 70-92 %
Gilbert, I.H,; Ress, D.C.; Crockett, A.K.; Jones, R.C.F. Tetrahedron, 1995, 51, 6315-6336.
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Imidazolines
.
70-92 %
Dghaym, R.D.; Dhawan, R., Arndtsen, B.A., Angew. Chem. Int. Ed. 2001, 40, 3228-3230
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R3 R1 N N R1
R2 R2 COO
R1 [3 + 2] cycloaddition Cl N
H
R1
R2
N R2 O