transition metal-free cross-coupling reactions
TRANSCRIPT
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Transition-metal-free Cross-coupling Reactions
Presented By
Gurudutt Dubey
M. Tech. (Pharm.)
Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research, Mohali, Punjab (India)
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Flow of Presentation
Introduction of cross-coupling reaction
Classification of transition-metal-free cross-coupling reactions
Transition-metal-catalyzed vs transition-metal-free reaction
Advantages and limitations of transition-metal-free reaction
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Introduction
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Classification of Transition-metal-free Cross-coupling Reactions
1) Radical pathway
2) Aryne pathway
3) Oxidative coupling
4) Nucleophilic aromatic substitution
5) Electrophilic aromatic substitution
6) Photoredox coupling
7) Classical organocatalysis pathway
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Homolytic Aromatic Substitution Reactions (HAS)
1) Radical pathway
RSC Adv. 2014, 4, 44943.
MeO
IMeO
80 oC, 24 h, N2
82%
EtOK/tBuOK (1:3)
Ar-I Ar-IEtOK/tBuOK
SET -IAr
Ar
Ar H
Base
-H
Ar
Ar-IET
Ar
Ar-I
Initiation
Propagation
Mechanism
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Cross-coupling reaction of Grignard ReagentsMgBr I
R1R2
R1
R2
THF (6 equiv)
toluene, 110 oC, 24 h
Ar2-X
Ar2-Ar1
Ar2
X
Ar1_MgBr
MgBr
Ar2_X
Ar2_Ar1
Ar2_X
Ar1_MgBr Ar1_MgBr
initiation propagation
step 1
step 2
step 3
Angew. Chem., Int. Ed. 2012, 51, 218.
Mechanism
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Transition Metal-free Intramolecular Heck-type Cyclization Reaction
Chem. Commun., 2011, 47, 10629.
I
O
Ph
Ph
O
PhPh
KOBut (3 equiv)1,10-phenanthroline (0.4 equiv)
Mesitylene, 160 oC, 90 min
63%
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2) Aryne pathway
OH
O
BrOH
O HO
OKOtBu (2.5 equiv)
dioxane, 140 oC, 16 h
73% 23%
X
Y
Nu
ER R R
Nu-
E+
aryneprecursors
aryneintermediates
I
NH
RR'
O
NR R'
OK2CO3 (2 equiv)
DMSO, 140 oC, 8-48 h
Intramolecular Arylation of Phenols with Aryl Halides via Benzyne Intermediate
Intramolecular C−O Bond Formation for Benzoxazole Derivatives
Org. Lett. 2008, 10, 4625.Org. Biomol. Chem. 2011, 9, 1225.
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OH
O
BrKOtBu
O
O-HOtBu
K O
O
Kortho
para
O
OH
K
HOtBu
-OtBu
O
OH
OHOO
H
K
O
Mechanism
Org. Lett. 2008, 10, 4625.
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3) Oxidative couplingO
R'
NH
ArR
OR'
NH
ArR
TEMPO (2 equiv)KOtBu (2 equiv)
DMSO, 80 oC, 6 h
Org. Lett. 2015, 17,1268.
O
NH
O
NH
H
NO
NO
SET
NOH
NO
KOtBu HOtBuO
N
O
N
O
N
O
NH
O
NH
KOtBu
HOtBu
nucleophilicaddition[O]
Mechanism
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NH
NO2
KOtBu (2 equiv)
DMSO, rt, 3 h, air
NH
NO2
4) Nucleophilic aromatic substitution
NH N N
NO2
N
NO2
H
HKOtBu
N
NO2
H
H
N
NO2
HHO=O
N
NO2
HOHO
N
NO2
H1,3-Hshift
NH
NO2
Org. Lett. 2015, 17, 82.
Mechanism
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RSC. Adv. 2015, 5, 65600.
Metal-free C-N Cross-coupling via Nucleophilic Substitution Reaction
N
O
O
ClBrBr
DBU (1.2 equiv)
DMSO, rt, 2 h
DBU (2.2 equiv)
DMSO, 60 oC, 3 min
N
O
O
Br
N
O
O53%
56%
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N
O
O
Cl N
N
N
NN
O
O
Cl
N
O
O
N
NCl
N
O
O
N
NCl
N
O
O
N
NClR X
N
O
O
R
Mechanism
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5) Electrophilic aromatic substitution
Friedel−Crafts Intramolecular Coupling Reaction of Fluoroarenes
F Me2SiMes2 (1.6 equiv)[ipr3Si]+[CB11H6C16]-
1.2 equiv
PhCl, 110 oC, 8 h, N2
Science 2011, 332, 574.
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F F
SiMe
MesMe2SiF
MesMe2Si+ H
SiH
F
Mes-H
-Mesitylene[Mesitylene-H]+
iPr3Si+
- iPr3SiF
initiation 1
initiation 2
Me2SiMes2
Me2SiMes2
Mechanism
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6) Photoredox coupling reactionsN
Ph O
EtO OEt
ON
Ph
CO2EtEtO2C
92%
Eosin Y (2 mol%)
visible light, rt, air, 10 h
NPh
SET
eosin Y* eosin Y
NPh
NPh
Nu-
NPh
Nu
eosin Yvisible light
[O]
[O]
[OH]
Mechanism
Chem. Eur. J. 2012, 18, 3478.
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Transition-metal-catalyzedvs
Transition-metal-free
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J. Am. Chem. Soc. 2008, 130, 14926.J. Am. Chem. Soc. 2010, 132, 13194.
NR HBr
[RhCl(CO)2]2 (5 mol%)
dioxane, 190 oC, 24 hNR
5-78%
N H
(HO)2B AgNO3 (20-40 mol%)TFA, K2S2O8 (3 equiv)
DCM:H2O (1:1), rt, 3-24 hR1 R2 N
R1
R2
68-92%
Chem. Commun. 2014, 50, 7124.
N
NHNH2
OMeN
OMeHClR1 R1
rt, 24 h
43-76%
Direct arylation of heteroaromatic rings
Metal-catalyzed
Metal-free
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RSC Adv. 2014, 4, 53442.
F
InCl3 (10 mol%)
hexane, reflux, 80 oC, 4 h
75%
Br
O
NaOH (2 equiv)
H2O/PEG (1:1), 170 oC, mW, 5 min
O
67%
Sonogashira reaction
Metal-catalyzed
Metal-free
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1) R3MgCl, H3O+
2) Ph2SiHCl, 5 mol% InCl3, DCM, 80 oC
R1 R2
OR1
R2
HR3
1) TsNHNH2, dioxane, 80 oC, 1.5 h2) R3B(OH)2, K2CO3, 110 oC
70-99%
< 90%
Reduction of ketone followed by C-C coupling
Org. Biomol. Chem. 2014, 12, 10.
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Advantages of transition-metal-free over transition-metal-catalyzed reaction
Limitations
Go Green Reduced Toxicity Reduced Cost
Scope of reactions ????
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