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.)

Julia Vargas @ Wipf Group 4 7/1/2006

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

Julia Vargas @ Wipf Group 6 7/1/2006

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

Julia Vargas @ Wipf Group 9 7/1/2006

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

Julia Vargas @ Wipf Group 10 7/1/2006

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