cu(i)-catalyzed 1 3 dipolarcatalyzed 1,3 dipolar ...· cu(i)-catalyzed 1 3 dipolarcatalyzed 1,3...

Cu(I)-Catalyzed 1 3 DipolarCu(I) Catalyzed 1,3 Dipolar Cycloadditions

Anne-Marie DechertAnne-Marie DechertFeb. 7, 2008

Outline

Introduction to 1 3 Dipolar Cycloadditions Introduction to 1,3 Dipolar Cycloadditions Cu(I)-catalyzed 1,3 Dipolar Cycloaddition Between Azides and

Alkynes Cascade Reactions Extension of the Original Methodology

S th i f L t Synthesis of Lactams Kinugasa Reaction

1 3 Dipolar Cycloadditions Between Azomethine Ylides and Activated1,3 Dipolar Cycloadditions Between Azomethine Ylides and Activated Alkenes

1, 3 Dipolar Cycloadditions

AB

C

D E

AB

C

D E

Typical 1,3 Dipoles

R2C N O R2C N O R2C O O R2C O ONitrones Carbonyl Oxide2 R2

R

R2C NR

CHR2 R2C NR

CHR2

R2C O O R2C O ONitrones

Azomethine Ylide

Ca bo y O de

R2C N N R2C N N Diazoalkane

RC N O RC N O

RN N N RN N N

Nitrile Oxide

Azide

RC N CHR2 RC N CR2

RC N NR RC N NR

Nitrile Ylide

Nitrile Imine

Typical Dipolarophiles

R2C N R Imine

RC CR

R2C CR2

RN O

Alkyne

Alkene

Nitroso

Padwa, A.; ed., 1,3-Dipolar Cycloaddition Chemistry, John Wiley & Sons, New York, 1984.

RN NR Azo

Stereospecificity

HHPhH

PhC N N PhPh

H

Ph

H

H

Ph

Ph

HN

N PhPh

H Ph

NN PhPh

H H

- Stereospecific syn addition with respect to dipolarophile

Ph H Ph Ph

H CH3HN

NPhH N

NHPh

N NHCPh

3

H3CO2C CO2CH3

N

CO2CH3H3CO2CCH3H

Ph N

CO2CH3H3CO2CCH3H

H

Huisgen, R.; Seidel, G.; Wallibillich, G.; Knupfer, H. Tetrahedron 1962, 17, 3.Huisgen, R.; Eberhard, P. Tetrahedron Lett. 1971, 4743.

Regioselectivity

- Dominated by Frontier Molecular Orbital (FMO) interactions- Sterics can also play a role

C C

E

AB

C

E

AB

D

E

D

E

HOMOdipole - LUMOdipolarophile LUMOdipole - HOMOdipolarophiletypical for an electron def icient dipolarophile typical f or an electron rich dipolarophile

If the energies of the two interactions are similar, both reactions can occur.

Houk, K.; Sims, J.; Due, B.; Strozier, R.; George, J. J. Am. Chem. Soc. 1973, 95, 7287.

g ,

1,3 Dipolar Cycloadditions of Azides and Alkynes

The Cu(I) Catalyzed 1,3 Dipolar Cycloadditions of Azides and Alkynes

C CHR1 N N N R2N

N NR2cat. Cu(I)

R1

NOH NNO

Ph

NPhN N

Ph

NN N

Ph

NN N

HOO

N NPh

NEt2

82% 84%88% 90%

NN N

SO

O

H2N NN NPh

HO NNN

HOOH

NHNH

H2NHO HO

Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.

91% 84% 94%

Generation of The Cu(I) Catalyst

C CHR1 N N N R2N

N NR2

Cu(I) salt1.0 eq. 2,6-lutidine

Formation of Byproducts

RR diacetylenesC CHR N N N R2 N N

R1

Cu(I) salt = CuOTf.C6H6, CuBr, CuI

1.0 eq. 2,6 lutidine

5- hydroxyltriazolesN

N NR1

HO R( ) 6 6

bistriazoles

Cu(II) salt (0 25 2 0 mol %)

NN

N

R1

R

N N

N

R1

R

Cu(II) salt (0.25-2.0 mol %)Na ascorbate and/orascorbic acid (5-10 mol %)C CHR1 N N N R2

NN N

R1

R2

Click Chemistry

NN NR

2

- high yielding- wide in scope- stereospecific- inoffensive byproducts- simple reaction conditions

C CHR1 N N N R2 copper metalN

R1

simple reaction conditions

Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.Kolb, H.; Finn, M.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. J. Am. Chem. Soc. 2005, 127, 210.

A Stepwise Mechanism is Proposed

Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. J. Am Chem. Soc. 2005, 127, 210.

The Unexpected Formation of Trisubstituted Triazoles

OMH

CuI, rt, 1h, air

OOH

N NN

OMeMeO

OOH

N3

OMeH

CuI, rt, 1h, airO

OHN N

N

OMe

OMe

Unexpected Result

OMe

p

Perhaps Glaser Coupling:

OOH

N3CuI, rt, 1h, air

MeO OH

OMeMeO

OH

OMe

MeO

Alternative Pathway:

O N NN

OOH

N NN

OMe

H

CuI, rt, 1h, air

OH

OMeMeO

Gerard, B.; Ryan, J.; Beeler, A.; Porco, J. Tetrahedron 2006, 62, 6405.

NOMe

H O N NN

Mechanistic Rational for the Formation of Trisubstituted Triazoles

N3Cu(CH3CN)4PF6(0.2 eq.)

ligand (0 2 eq )

MeMe

MeN

NH

Me

Me

Me

Me

HMe

ligand (0.2 eq.)DIEA (1 eq.)NMO (0.1 eq.)rt/air

NN

N NN

NN

NMe

Me

MeMe

Ligands

Proposed Mechanism:

Ligands

Proposed Mechanism:

R1LnCu R1L CHR1

HR1DIEA R1L C

R1

II

NNN

R2N

NNR2

RLnCu

B-H

HR DIEA

NNN

R2

RLnCuII

1.[O]2 red elimB H

BwithoutDIEA

R1H

2. red. elim

R1R1

Gerard, B.; Ryan, J.; Beeler, A.; Porco, J. Tetrahedron 2006, 62, 6405.

N NNR2

R1

NNN

R2

R

The Use of N-Sulfonyl Azides as 1,3 Dipoles

Finzi, P.; Grunanger, P. Tetrahedron Lett. 1963, 4, 1839.Yoo, E.; Ahlquist, M.; Kim, S.; Bae, I.; Fokin, V.; Sharpless, K. B.; Chang, S. Angew. Chem. Int. Ed. 2007, 46, 1730.Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.

Proposed Route to Sulfonamides

Cu(I), 2 mol %TBTA, 2 mol %Na ascorbate 4 mol %HC C R1

BnN

NN NNNa ascorbate 4 mol %

NaHCO3, 1 eq

OR1

HN

SO2

R

N N N SO2R

N NBn

BnN NN

TBTA =

HC C R1[Cu]

NN N SO2R

-N2R1 N

[Cu]

SO2R

R1

N N N SO2R-H+

[Cu]R1

N

R1NSO2R

H H2O ONH

O2SR

NSO2R

[Cu]

NN

R1

Cassidy, M.; Raushel, V.; Fokin, V. Angew. Chem. Int. Ed. 2006, 118, 3154.Cho S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16047.

A Cu(I) Catalyzed Cascade to Form Azetidinimines

Ligand t[h] trans-A: cis-A: B

2,6lutidine 3 80:13:7

HC C R1NPh

N N N SO2Tol

Cu(I), 10 mol %ligand (1 eq.)

N

NSO2Tol

R1 NN N SO2Tol

pyridine 3 95:5:0

TBTA

Reaction Scope: the Imine Component

SO2Tol

HC C PhNR2

R1N N N SO2Tol

Cu(I), 10 mol %pyridine, 2 eq.

MeCN, rt N

NSO2Tol

PhPh

R1

R1 R2Yield(%) trans:cis

4-FC6H4 Ph 87 95:5

4-(MeO)C6H4 Ph 79 95:5

Ph SO2Ph 5 NR

CO2Et Ph 53 5:95

CO Et 4 (MeO)C H 63 5:95CO2Et 4-(MeO)C6H4 63 5:95

N N N S NO N N N S MO O O O

Fokin, V.; Whiting, M. Angew. Chem. Int. Ed. 2006, 118, 3157.

N N N S NO2 N N N S Br N N N S IN N N S MeO O O O

Synthesis of N-Sulfonyl-1,2,3-Triazoles

Yoo, E.; Ahlquist, M.; Kim, S.; Bae, I.; Fokin,V.; Sharpless, K. B.; Sukbo, C. Angew. Chem. Int. Ed. 2007, 46, 1730.

Fus Extension to Azomethine Imine Dipoles

Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.

Asymmetric Extension

NN

O

CO2Et

5% CuI0.5 eq. Cy2NMe

NN

O

CO2Et5.5% ligand A

PPh2PPh2

= A

H Ph 1.2 eq. Ph% g

Asymmetric ExtensionO O

NN

O

H PhCO2Et

1 2

5% CuI0.5 eq. Cy2NMe

NN

O

CO2Et

Ph5.5% ligand A = A

PMeMe

MeMeO

NiPrFe

1.2 eq. Ph

98%, 90% ee

MeMe

O5% CuI

N

OP

MeMeO

NtBu

NN

H PhCO2Et

1.2 eq.

0.5 eq. Cy2NMeNN

CO2Et

Ph5.5% ligand B

= BMe

MeMe

MeN

Fe

100%, 58% ee

NN

O

H PhCO2Et

5% CuI0.5 eq. Cy2NMe

NN

O

CO2Et

Ph5.5% ligand C MeMe

P

MeMe

N

O

iPrFe= C

Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.

H Ph1.2 eq. Ph Me

MeMe

100%, 80% ee

Reaction Scope: The Azomethine Imine Component

Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.

Reaction Scope: The Alkyne Component

Me

NN

O

H PhR

5% CuI0.5 eq. Cy2NMe

NN

O

R

Ph5.5% ligand

PMe

Me

Me

MeMeO

NiPrFe

H Ph 1.2 eq. Ph MeMe

Me

O

NN

Ph CO2Et NN

O

NMe

Ph

77%, 88% ee

Ph

100%, 94% ee

O

NN

O

NN

O

Ph

73%, 88% ee

Ph

63%, 74% ee

Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.- erosion of regioselectivity observed for electron rich alkynes

Application to Kinetic ResolutionApplication to Kinetic Resolution

Downey, W.; Fu, G.; Suarez, A. J. Am. Chem. Soc. 2005, 127, 11245.

Limitations to the Kinetic Resolution of Azomethine Imine Dipoles

Downey, W.; Fu, G.; Suarez, A. J. Am. Chem. Soc. 2005, 127, 11245.

Other Cu(I) Catalyzed 1,3 Dipolar Cycloadditions

Synthesis of Pyrazoles: A Direct Approach

i TsNHNH2 NN

2R1

O

HR1

i. TsNHNH2MeCN, rt, 3h

ii. 5M NaOH

N

R1

R2

NNH

R25