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Reductive Carbodiazenylationof Nonactivated Olefins via
Aryl Diazonium Salts
Julia VargasJuly, 1, 2006
Markus R. Heinrich, Olga Blank, and Sabrine Wölfel
Org. Lett. ASAP, ol0611393web release date: 6-23-06
Julia Vargas @ Wipf Group 1 7/1/2006
Outline
• Background: - The Meerwein Arylation - Examples of Carboamination and Carbodiazenylation
• Key Reaction and Mechanism: Carbodiazenylation
• Exploring the Scope
•Accessing Potential Synthetic Targets
• Summary and Future Work
Julia Vargas @ Wipf Group 2 7/1/2006
Meerwein ArylationGeneral Reaction
Proposed mechanism
Cu(II)X2
+ e-
- X- Cu(I)X
R1 N N X Cu(I)X
SET
R1 N N - N2
R1
R3
EWG
R2
R1
R2
R3
EWG Cu(II)X2
SET
- Cu(I)X
R1
R2
EWG
R3
+ X-R1
R2
EWG
R3X
-HX
R1
R2
R3
EWG
Kurti L., Czako B. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Academic Press. Burlington, MA 2005
R1 NaNO2
HX (aq.)
R1 N N X EWG
R3
R2
H2O/solventmetal salt (cat.)- N2
R1
R2
X
R3
EWG-HX
R1
R2
R3
EWG
substituted aromatic amine
aryldiazonium halide
!-aryl-"-halo derivative aryl substituted olefin
NH2
Julia Vargas @ Wipf Group 3 7/1/2006
Meerwein ArylationKey Features
Kurti L., Czako B. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Academic Press. Burlington, MA 2005
• Formation of the diazonium salt in situ, no isolation necessary
• Substitution of aromatic ring:
- EWGs leads to higher yields, EDGs are low yielding
• Substitution of olefin:
- Usually contain EWG group
- If disubstituted, aryl radical adds to least substituted carbon
- Potential formation of regioisomers
Draw Backs
- Overall moderate yields obtained due to side reactions(Sandmeyer Reaction, Azo Coupling etc.)
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Carboazidation in Total Synthesis
Polyhydroxylated Pyrrolizidine Alkaloids
• Hyacinthacines isolated from Muscari Armeniacum• New potent inhibitors of glycosidase
• Synthetic strategy based on free-radical carboazidationof a chiral allylsilane as a key step
OL. 2005, 7, 2587
Julia Vargas @ Wipf Group 5 7/1/2006
Carboazidation in Total Synthesis
OL. 2005, 7, 2587
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Methods of CarboaminationOrganometallic Methods
NH2
R
Ar1 Br
cat Pd2(dba)3
cat. 3
NaOt Bu, Tol
HN
R
Ar1
Ar2Br, dppe NR
Ar2
Ar1
P(t-Bu)2
3
Pd-catalyzed tandem N-arylation/ carboamination of pirmary aliphatic amines
R1
NC
O +OCO2Me
1 mol% [Pd(PPh3)4]
4 mol% CuClN
CO2R2
R1
Pd-Cu bimetallic catalyzed Indole Formation
OL. 2005, 7, 2575
ACIE. 2002, 41, 3230ACIE. 2004, 43, 5372
Cp2Zr N
R2R3
R1NR1
R4
Cp2Zr R3
R2R1
R1 R4
R4
NR1
R2R3
Cp2Zr N R1
R2R3
Additions of Imine C=N bonds across Alkynes via imidozirconium complexes
Julia Vargas @ Wipf Group 7 7/1/2006
NH2
R2
R11.) NaNO2
2.) R3
R4
TiCl3
R2
R1
NN
R3
R4
R1
R2
Raney-Ni, H2
Carbodiazenylation
R2
R1
NH2
R3
R4
Carboamination
+
NH2
R2
R1
Recovery of Amine
Key ReactionKey Point: the reduction of aryl diazonium salts in the presence of nonactivated olefins provides rapid entry to carbodiazenylation products, which can undergo transformation to synthetically useful precursors.
Julia Vargas @ Wipf Group 8 7/1/2006
N2+ X
-
R2
R1
Ti 3+ N2
R2
R1
- N2
R2
R1
R3
R4
R2
R1R3
R4
N2+ X
-
R2
R1
R2
R1
NN
R3
R4
R1
R2
Ti 3+
R2
R1
NN
R3
R4
R1
R2
Carbodiazenylation: Mechanism
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NH2
R2
R1
1.) NaNO2
2.) H2SO4
N2+ X-
R2
R1
R3
R4
TiCl3
MeOH-H2O
R2
R1
NN
R3
R4
R1
R2
Carbodiazenylation of Olefins
Exploring the Scope
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Accessing Potential Synthetic Targets
CO2Me
HNN
MeO2C
85%
NH2
+
O
HCl, MeOH !
O
MeO
CO2Me
OAc
HNNH
MeO2C
CO2Me
NNH
MeO2CNH
O
OAc
N
O
OAc
NH
CO2Me
84%
84%
90%
90%
NH2
OMe
O
OAc+
CO2Me
NN
MeO2C
OAc
H2 Pd/CZn powder
HOAc, 80 oC
K2CO3, MeOH Raney-NiMeOH
OH
Julia Vargas @ Wipf Group 11 7/1/2006
Summary and Future Work
Summary
Simple, practical method for diazenylation of non-activated olefins
Can be carried out under non-hazardous conditions
Formation of valuable precursors for polyfunctionalized targetmolecules in high yields
Raney-Ni reductive conditions yielded product and recoveredaniline starting material
Future Work
To continue to apply this methodology toward new synthetic targetsand pathways
Julia Vargas @ Wipf Group 12 7/1/2006