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 β L t• Synthesis of β−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 Oxide2R

2R

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 CH3H NNPh

H NNH

Ph

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 - HOMOdipolarophile

typical 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 CHR1N N N R2

NN NR2cat. Cu(I)

R1

NOHNN

O

Ph

NPhN N

Ph

NN N

Ph

NN N

HOO

N NPh

NEt2

82% 84%88% 90%

NN N

SO

O

H2NN

N NPhHO N

NN

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 CHR1N N N R2

NN 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 R2N

N N

R1

R2

Click Chemistry

NN NR2

- 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:

R1LnCuR1L CHR1

HR1

DIEA R1L C

R1

II

NNN

R2

NNN

R2

RLnCu

B-H

HR DIEA

NNN

R2

RLnCu II

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]N

N N SO2R-N2

R1 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 <2 42:58:0

Ph MeCN, rt NPhPh HR1

NSO2R• N

Ph

Ph

A B

R1H Ph

via [2+2]BnN

NN

N NBnNN

TBTA =

Alkyne Scope

PhCu(I), 10 mol %

idi 2 NSO2Tol

R1

N

BnN NN

HC C R1NPh

PhN N N SO2Tol

pyridine, 2 eq.

MeCN, rt N

N

PhPh

N

NSO2Tol

PhPh

Ph

N

NSO2Tol

PhPh

Me Me

Cl

N

NSO2Tol

PhPh

TMS

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

yield = 90%trans: cis = 95:5



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 R2 Yield(%) 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.

Fu’s 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

PPh2

PPh2= A

H Ph 1.2 eq. Ph% g

<2%

N

O5% CuI0 5 eq Cy2NMe N

O

O

Me Me

O = BN

N

H PhCO2Et

1.2 eq.

0.5 eq. Cy2NMeNN

CO2Et

Ph5.5% ligand B

N N

iPr iPr

= B

O O

98%, 19% ee

MeO

NN

O

H PhCO2Et

1 2 eq


NN

O

CO2Et

Ph5.5% ligand C

= C

PMe

MeMe

Me

MeNiPr

Fe


1.2 eq.

98%, 90% ee

Asymmetric ExtensionO O

NN

O

H PhCO2Et

1 2


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


NN

O

CO2Et

Ph5.5% ligand C MeMe

P

MeMe

N

O

iPrFe= C


H Ph1.2 eq. Ph

MeMe

Me100%, 80% ee

Reaction Scope: The Azomethine Imine Component


Reaction Scope: The Alkyne Component

Me

NN

O

H PhR


NN

O

R

Ph5.5% ligand

PMe

Me

Me

MeMeO

NiPrFe

H Ph 1.2 eq. Ph Me

MeMe

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

R250 oC

1

20 mol % InCl

R1 = EDGR2 = EWG

OR1

O

R1

N2

R2

20 mol % InCl3H2O, rt

NNH

R2

R1 OE

R

O

R1 = OEtR2 = EWG

OR1

O

R1

N2

R2

R1 = OEt

NNH

R2

Aggarwal, V.; Bonnert, R.; Vicente, J. J. Org. Chem. 2003, 68, 5381.Jiang, N.; Li, C. Chem. Commun. 2004, 394.Ready, J.; Qi, X. Angew. Chem. Int. Ed. 2007, 46, 3242.

R2 = aryl, alkyl

Initial Attempts to Form Pyrazoles Using

Cu(I) as a PromoterCu(I) as a Promoter

Ready, J.; Qi, X. Angew. Chem. Int. Ed. 2007, 46, 3242.

Reaction Scope: The Alkyne Component

R H i) nBuLi -78 oC

ii) Cu (I), -17 oC

O

BnON2

NNH

R

O

BnO BnOH

) ( ), O

F3CCH3

NNBnO

CF3

NNBnO O

Diazocarbonyl Compounds

ONH

O

75% yield

NH

O

72% yield

BnON2

EtON2

O

Cl

O

t-BuON2

O

NN2Me

MeON

NNH

O

BnO NNH

O

BnO NNH

O

BnO


60% yield 74% yield 74% yield

A Concerted Mechanism

R CuLn

OR1

N NN R1

O

H

HN

N R1

ON

O

R1

N2

[3+2] R CuLn R

- EWGs slow reaction

R CuLn

EWGs slow reaction

- Similar rates in THF, ether, and toluene

- Observed regioselectivity

consistent witha concerted mechanism

- Observed regioselectivity

L b li St diLabeling Studies

HN OBn

O

Ph LiCuCN.6LiCl

O

BnON2

D

NN

Ph D

73 % D

BnOH Ph H/D

16% D


N2

An Unexplained Side Product

O

BnON2

DHN

NOBn

O

BnOH Ph H/DPh Li

CuCN.6LiCl Ph D

73 % D

BnOH Ph H/D

16% D

n 2 n 4 9 2

major product:BnOH

Non-deuterated 6.0:1deuterated

Deuterated 6.2:1


Outline

I d i 1 3 Di l C l ddi i• Introduction to 1,3 Dipolar Cycloadditions• Cu(I)-catalyzed 1,3 Dipolar Cycloaddition Between Azides and

Alkynesy– Cascade Reactions– Extension of the Original Methodology

• Synthesis of β−Lactams– Kinugasa Reaction

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

Synthesis of β−Lactams

NO

S

COOH

R

OO• N

X NX O

The Staudinger Synthesis

COOH•

RR HR R RR

Staudinger, H. Liebigs. Ann. Chem. 1908, 356, 51.

Penicillin Core

Ullmann Type Coupling

Cl

Ph

NHTs CuIDMEDA

Cs2CO2

NTs

Ph

O3 NTsO

Ph

Lu H ; Li C Org Lett 2006 8 5365Lu, H.; Li, C. Org. Lett. 2006, 8, 5365.

Intramolecular C-H insertion

Rh2(S-PTA)4(5 mol %)ON

M O C

N2

ON

HHMeO2C

OMeO2C ON

O

Ananda, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 9063.

The Kinugasa Reaction

CHN

R1

N

O

R1

Ph

R2

R2

CC CuLnPh pyridine

O OPhR2

H OH

O

CC CuLnPh

[3+2]Ph CuLn

OH

H

CuLnPh

H OPh

H

CH

NR1 OR2

[3+2]

NO

R1

HR2

N OPh

R1

H R2N

Ph

R1

H R2

OPh

OPhOPh

H

NR1

H R2

NR1

H R2NR1

H R2

Kinugasa, M.; Hashimoto, S. J. Chem. Soc. Chem. Commun. 1972, 466-467.Ding, L.; Irwin, W. J. Chem. Soc. Perkin Trans. 1. 1976, 2382.Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.

Pioneering Efforts by Miura

Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.

Attempts at Asymmetric Induction in the Kinugasa Reaction

OPh CuI (10 mol %)N

OPhHPh N

O

Ph

Ph

H

ligand A (1 eq.) N

Ph PhK2CO3/DMF

O

N N

OMe Me

iP

Ligand A =

45% yield40% ee

iPr iPr

HPh NO

Ph

Ph

H

CuI (1 eq.)ligand A (1 eq.) N

OPh

K2CO3/DMFPhHPh Ph

K2CO3/DMF

54% yield68% ee68% ee

Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.

A Chiral Auxiliary Based Approach

PhRH

R1 Ph R1R H33

O

N

O

Ph

ON

[Cu]

R1

O

N

O

Ph

ON

[Cu]

R134

34

lower in energy:substituents on opposite faces

higher in energy:substituents on the same face

B Bn BnOMeOMeMeO

NO

O

Bn

NPhO

HNO

O

Bn

NO Ph

NO

O NO Ph

CuI, Et3N

O Ph Ph

5:3

Basak, A.; Ghoh, S.; Bhowmick, T.; Das, A.; Bertolasi, V. Tetrahedron Lett. 2002, 43, 5501.

5:3

70% combined yield

Fu’s Use of a Chiral Ligand to Induce Asymmetry

R1 NO R3

R2 H

1-2.5%CuCl, ligand A

Cy2NMe2 NO

R2R1

R3 NFe MeM

Me NMe

FeMeMe

MeMeMe

= AMeMe

MeMeMe

up to 93% ee

Alkyne Scope

R1NO 1-2.5%CuCl, ligand A

CyR1OMe

RN

Cy H

g

Cy2NMe2N

O

OMe

R1 cis:trans %ee,cis

isolatedyield %(cisisomer)

4 CF C H 95 5 92 654-CF3C6H4 >95:5 92 65

4-OMeC6H4 >95:5 93 57

CH2Ph 71:29 73 43

Lo, M.; Fu, G. J. Am. Chem. Soc. 2002, 124, 4572.

2

1-cyclohexenyl 90:10 91 45

Variation of the Nitrone Component

Lo, M.; Fu, G. J. Am. Chem. Soc. 2002, 124, 4572.

Intramolecular Attempts With the Kinugasa Reaction

MMe

O

CuBr (5%)ligand A (5.5%)

Cy2NMe (0.5 eq) NAr NMe N

Me

FeMeMe

MeMeMe

= A

NO

ArO Fe Me

MeMe

MeMeMe Me

30% yield6% ee

NO

CuBr (5%)ligand B (5.5%)

Cy2NMe (0.5 eq)N

Ar PPh N

OMe

Me

= BAr OAr

74% yield

PFe Me

MeMe

MeMePh N iPr = B

Shintani, R.; Fu, G. Angew. Chem. Int. Ed. 2003, 42, 4082.

74% yield88% ee

Intercepted Intermediate

Shintani, R.; Fu, G. Angew. Chem. Int. Ed. 2003, 42, 4082.

Other Attempts to Induce Asymmetry in the Kinugasa Reaction

Coyne, A.; Muller-Bunz, H.; Guiry, P. Tetrahedron: Asymmetry. 2007, 18, 199.

Outline

I d i 1 3 Di l C l ddi i• Introduction to 1,3 Dipolar Cycloadditions• Cu(I)-catalyzed 1,3 Dipolar Cycloaddition Between Azides and

Alkynesy– Cascade Reactions– Extension of the Original Methodology

• Synthesis of β−Lactams– Kinugasa Reaction

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

1,3 Dipolar Cycloadditions of Azomethine Ylides Catalyzed by Chiral Metal Complexes

Highly Endo Selective Cycloadditions of Azomethine Ylides

1O

Cu(CH3CN)4ClO4(3 mol %)ligand A (3 mol %)

PhN OO

F

StBuPPh2 = AN CO2MeR1

R2 R3NPh

O

ligand A (3 mol %)Et3N, -10 oC

NH

CO2MeR1

R3R2

Fe 2 = A

endo

Ph

N

O

OPh

OMeO

N[Cu]

PhN OO

CO MeF

PhN OO

CO MeMeO

PhN OO

CO Me

PhN OO

CO MeNH

CO2MeHH N

H

CO2MeHH N

H

CO2MeHMeN

H

CO2MeMeH

Cabrera, S.; Arrayas, R.; Carretero, J. J. Am. Chem. Soc. 2005, 127, 16394.

endo:exo = >98:2yield(%) = 82ee(%) = >99

endo:exo = >98:2yield(%) = 81ee(%) = >99

endo:exo = >98:2yield(%) = 78ee(%) = 94

endo:exo = >98:2yield(%) = 50ee(%) = 80

Endo Selectivity Scope Continued

N CO2MePh

CO2Me

CO2Me

Cu(CH3CN)4ClO4(3 mol %)ligand (3 mol %)Et3N, -10 oC N

HCO2Me

PhFe

S-t-BuPPh2CO2MeMeO2C

= Ligand

CO2Me H 2

endo

47% yield94% eeendo/exo = 67:33

N CO2MePh CO2Me

Cu(CH3CN)4ClO4(3 mol %)ligand (3 mol %)

Ph

CO2MeMeO2C

Et3N, -10 oC NH

CO2MePh

endo

MeO2C

89% yield>99% ee

d / 90 10endo/exo = 90:10

Cu(CH3CN)4ClO4(3 mol %) OHC

N CO2MePhCHO (3 mol %)

ligand (3 mol %)Et3N, -10 oC N

HCO2Me

Ph

endo

Me Me

Cabrera, S.; Arrayas, R.; Carretero, J. J. Am. Chem. Soc. 2005, 127, 16394.

48% yield69% eeendo/exo = >98:<2

Highly Exo-selective and Enantioselective Cycloadditions of Azomethine Ylides

Ot BCuI (5 mol %) Ht B O C Ht B O C

Fe PAr2N t-Bu

N CO2MeAr

H

CO2t-BuCuI (5 mol %)ligand (5.5 mol %)

base (10 mol%)-25 oC N

HCO2MeAr

Ht-BuO2C

NH

CO2MeAr

d

Ht-BuO2C

exo endo

Ar base exo/endo yield (exo, %) ee ofexo

o-ClPh Et3N 76/24 76 98

p-MePh DBU 97/3 61 89

OM Ph 97/3 82 91p-OMePh DBU 97/3 82 91

Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241.

Mechanism

NOMe

OAr

LnCuX

NOMe

OAr

CuLL

X Base

OMe

L

Ar

CO2R2

R1HH

NOMe

OAr

CuLL

CO2R2R1

OMeO

N[Cu]18 electron

tetrahedralcomplex

NOMe

R1R2O2C

ArBase.HX

NOMe

R1R2O2C

Ar

Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241.

OCuLL

NH O

Varying the Electronic Nature of the Ligand to Change Stereoselectivityy

Yan, X.; Peng, Z.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.; Wu, Y. Angew. Chem. Int. Ed. 2006, 45, 1979.

Proposed Mechanism

RMLn, Et3N

OMLn OMLn

N

CO2Me

R

Et3NH

NRO

OMe

n

NRO

OMe

n

R2NO2

CO2Me 3

MLR2O2N

NRO

OMe

MLn

R2 NO2

NRO

OMe

R2 NO2

H+

NH

R CO2Me

RO2N

R R2


Summary of Cu(I)-Catalyzed Processes

Regioselective formation of 1,4 disubstituted triazoles

R1 N N N R2 NN N

R1

R2 1

4

cat. Cu(I)

1, 4 regioisomer obtained exclusively

Cascade reactions

HC C R1

N N N SO R

CuI (0.1 eq), base

R1HNR2R H O

NSO2R

NR1 R3

R1

HN

SR N

SO2TolR1

N N N SO2RN

R2

R1

R3

HNR2R, H2O, or NR2 O

R1 SO2 N

PhPh

amidines sulfonamides azetidinimines

Summary of Cu(I)-Catalyzed ProcessesReactions of other 1,3 dipoles

OO

Ph Cu

BnON2

HN

NOBn

O

Ph H

Kinugasa reaction

C NR1

N

O

R1

Ph

R2

O

CC CuLnPh

CH

NR OR2

Lewis acid activation

O LnCuX CuLL

X CO2R2R1 R1R2O2C

NOMe

ArN

OMe

OAr N

H O

OMeArBase

Acknowledgements

Dr Michael T CrimminsDr. Michael T. Crimmins

The Crimmins’ GroupDr. Anita Mattson Dr. Christie StaufferDee Jacobs Lizzie O’BryanMariam Shamszad Colin HughesMatt Haley Mark MansJay Stevens Tim MartinAdam Azman Philip WilliamsAdam Azman Philip WilliamsDr. Luke Zuccarello Dr. Michael EllisDr. Yan Zhang

Byproduct FormationByproduct Formation

Azide-Acetylide MechanismR2 H

CuLn (CuLn)2 R2 HCumLn

B BH

R2 Cu2Ln R2 Cu2Ln

2

R1N3

CuLL

Cu

R2

NN

R1

N

N

• CuL L

Cu

R2

NNR1

NN

NR1

R2LnCu2

NN

NR1

R2LnCu2

RR2

B BHN

NNR1

R2H

Kinetic Studies:Process is 2nd Order in Cu when process is catalytic in Cu.

- Increasing [Cu] causes less reactive metal aggregates to form ->Increasing [Cu] causes less reactive metal aggregates to form >indicate that Cu1 acetylide species is changing in solution.

- complexation may play a role.- 2nd Cu atom is likely is to activate the azide functionality, or complex with the acetylide

(causing a reduction in alkyne electron density, favoring cyclization)

Overall, little is known about the copper acetylide complex.

Bock, V.; Hiemsra, H.; van Maarseveen, J. Eur. J. Org. Chem. 2007, 51.

An Explanation for the Stereochemical Outcome

LnCu

NPhO

OMe

LnCu

CC


C1C4

Stereochemical Explanation Continued


Mechanism Support

Cu(I)-Catalyzed 1 3 DipolarCatalyzed 1,3 Dipolar ... · Cu(I)-Catalyzed 1 3 DipolarCatalyzed 1,3...

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