Recent Developments in Cross-Couplings: … Developments in Cross-Couplings: Coupling Boronates with...

Recent Developments in CrossRecent Developments in Cross--Couplings: Couplings: Coupling Coupling BoronatesBoronates with Inert Cwith Inert C--O Bonds, O Bonds,

and and BoronBoronicic AcidsAcids with Carbonylswith Carbonyls

Wen Yuan12-02-09

2

Cross-Coupling Reaction

The reaction of organometallic reagents with organic electrophiles in the presence of metal catalysts

C-C, C-N, C-O, C-S, C-P, etc.

[M]: Group 8–10 Metal catalystsFe, Co, Ni, Cu, Pd, Ru, Rh…

X: I, Br, Cl, OTf …

m: Mg, B, Si, Sn, Zn, Al …

Miyaura, N. Cross-Coupling Reactions: A Practical Guide. Springer: 2002

Study of Transition Metal Catalyst

Total Synthesis of Natural Product

Synthesis of Macromolecule …

3

Importance in Total Synthesis of Haplophytine

Haplophyton Cimicidum

NOHO

ONMe

MeO NOMe

N

HMe

OO

Suzuki-Miyaura couplingHaplophytine

NOBnO

ONCbz

MeO NOMe CO2Me

N

OI

CO2TMSE

TBSO

+

BPin

Pd(dppf)Cl2TlOEt

Isolated by Snyder, 1952

Total synthesis by Nicolaou, 2009

Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y. Angew. Chem. Int. Ed. 2009, 48, 7616.

4

Suzuki-Miyaura Coupling

Miyaura, N. Cross-Coupling Reactions: A Practical Guide. Springer: 2002Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461

5

Why Non-Halogen Coupling

22

434

1052

6174

16700

0 5000 10000 15000 20000

R-OH

R-OAc

R-Br

R-OTf

R-I

Org

anic

Ele

ctro

phile

Price $/mol

R:

• Cost

• Commercial availability

• Facile preparation

• Environment friendly

http://www.sigmaaldrich.com/sigma-aldrich/home.html

6

[Pd] R-XR-R'

Pd XRPd R'R

B OHOH

OHR'B(OH)3 + X-

path A

R''O-

Pd OR''RR'-B(OH)2(HO)2B

R''O Pd

R'

R path B

path C

1

2

3

45

X=I, Br, Cl, OTf

R-OR''

2

Suzuki-Miyaura Coupling

Miyaura, N. Cross-Coupling Reactions: A Practical Guide. Springer: 2002Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461

7

General Outline

AromaticEther

AromaticEster

TautomerizableHeterocycle

From Ketone toTosylhydrazones

8

General Outline

R1CO

R2

AromaticEther

AromaticEster



9

Oxidative Addition

R-X[M] M

R X

PPh2

PPh2

OCH3RhCl(PPh3)3

P

P

Ph2

Ph2

RhClOCH3

van der Boom, M. E.; Liou, S.-Y.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 1998, 120, 6531.Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.

10

Ru Catalyst for Suzuki Coupling

RuPPh3

PPh3

H

H

PPh3

C O

• How does Ru activate C-O bond?

• What is the selectivity between the C-H and C-O bond?

• What is the reasonable mechanism?

• What is the deficiency in this chemistry and how to improve it?

Kakiuchi, F.; Usui, M.; Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004, 126, 2706

11

Chelating Assistance for C-O Activation

ORu

OR

Ph3P

PPh3

OC

?


run ketone product yield

OMe O

OMe

Ph O

Ph

96%1

OOMe

OMe

OPh

OMe

3 75%

2O

Me Ph0%

12

Crystal Structure of Intermediate

ORu

OAr

Ph3P

PPh3

OC

RuH2(CO)(PPh3)3

O

OAr+

toluenereflux, 20h

Ar=p-C6H4CH3

By Discovery Studio ViewerProUeno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516.

13

Proposed Mechanism

Mechanism :


14

Selectivity of Activation

C-H activation

C-O activation

Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698.


15

C-O Activation vs C-H Activation

• Bond Dissociation Energy

O

+O

BO

PhRuH2(CO)(PPh3)3

toluene, reflux

O

PhOMe

H H O

OMe

Ph

VS

16


• Intermediate Observed by NMR

Ueno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516.

1H NMR 31P NMR

A

B

-5.97

No Ru-H

FAB-MS

35.49; 39.85

33.16

879 (M+-H)

879 (M+-H)


17



• Intermediate Observed by NMR

Ueno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516.

1H NMR 31P NMR

A

B

-5.97

No Ru-H

FAB-MS

35.49; 39.85

33.16

879 (M+-H)

879 (M+-H)

Thermodynamic product Kinetic product

18

Scope of Organoboronates

O

+O

BO

PhRuH2(CO)(PPh3)3

toluene, reflux

O

PhOMe

O

CF3

O

NMe2

O O

CH3

O

86% 89% 84% 83% 81%


19

Deficiency and Improvement1. Ortho Position 2. Price

R=Me 93%

Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem. Int. Ed. 2008, 47, 4866.

0.55

80

334

0 100 200 300 400

Ni

Ru

Pd

Met

al

$/oz

Updated Oct. 2009

Application on Synthesis of Oligoarenes

Symmetric oligoarenes

Asymmetric oligoarenesLittke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.Li, H. Personal communicationGillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.

21

Br

OMe

B(OH)2

cat. [Pd(PPh3)4]Na2CO3

toluene/H2Oreflux, 12h

OMe

77%

BO

O

cat. [Ni(cod)2]/PCy3

toluene, CsF120 oC, 12h 95%

Application on Synthesis of Oligoarenes

Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem. Int. Ed. 2008, 47, 4866.

50g/225$

22

General Outline

R1CO

R2

AromaticEther


AromaticEster


Starting from Trost-Tsuji Reaction

OAcOAc

PdL

L[Pd] PdL

L

OAc-

(II)

PdL

L(II)

allyl

Nu-

PdL

L(II)

Nureductiveelimination

-PdL2

Nu

Trost, B. M.; VanVranken, D. L. Chem. Rev. 1996, 96, 395. Luo, Y.-R.; Holmes, J. L. J. Phys. Chem. 1994, 98, 303.

Allyl C-O bond is weakerthan Acyl C-O bond

24

Allyl Acetate vs Aryl Acetate

Allyl C-O bond is weakerthan Acyl C-O bond

Luo, Y.-R.; Holmes, J. L. J. Phys. Chem. 1994, 98, 303.Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.

25

Acyl C-O Bond Cleavage

NiL2RCOOPh

oxidativeaddition

NiOPh

COR

-COdecarbonylation

L

L

-L

NiOPh

MeOC

L +LNi

OPh

MeL

L

-COdecarbonylation

L2NiOPh

H-C2H4

eliminationL2Ni

OPh

H +CO+L

reductiveelimination

(B)

+CO

disproportionation(A)

L=PPh3

Yamamoto, T.; Ishizu, J.; Kohara, T.; Komiya, S.; Yamamoto, A. J. Am. Chem. Soc. 1980, 102, 3758.

26

Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422.

Guan, B. T.; Wang, Y.; Li, B. J.; Yu, D. G.; Shi, Z. J. J. Am. Chem. Soc. 2008, 130, 14468.

Aryl C-O Bond Cleavage

27

Proposed Mechanism for Shi’s work

Guan, B. T.; Wang, Y.; Li, B. J.; Yu, D. G.; Shi, Z. J. J. Am. Chem. Soc. 2008, 130, 14468.

28

Two Pathways for Oxidative Addition

NiL

L

PhOAc

NiL

LOAc

NiL L

OAcNi

L L

OAcNi

L

L

OAc

-L

+LNiL

PhOAc NiL

OAc

NiL

OAcNi

L

O

OC

IN1

IN2

TS1

IN3 IN4

bis-phosphine mechanism

mono-phosphine mechanism

IN5 IN6 IN7

TS2

L=PPh3IN: IntermediateTS: Transition State

Li, Z.; Zhang, S. L.; Fu, Y.; Guo, Q. X.; Liu, L. J. Am. Chem. Soc. 2009, 131, 8815

29

Energy Comparison between Two Pathways

IN1

IN2

TS1

IN3

IN4

30.3

0.0

17.9

5.3

54.9

IN5

IN6

TS2

IN7

10.5

0.8

22.9

-30.3

NiL

L

OAc

NiL

O

OC

NiL

L

NiL L

OAc

NiL

OAc

Oxidative Addition of PhOAc to Ni(0) prefer the monophosphine mechanism


Unit: kcal/mol

30


NiL

O

OC

IN7

K[PhB(OH)3]Ni

L

O

O BH OH

OH

OK Ni

L OB(OH)2

IN11

H

IN10

KOAc

NiL O

B(OH)2

H

TS4Ni

L OB(OH)2H

IN12

NiL

IN13

B(OH)3

Energy Barrier= 31.2 kcal/mol

Base-assisted Transmetallation:

Transmetallation & Elimination

31

Transmetallation & Elimination

NiL

O

OC

IN7

K[PhB(OH)3]Ni

L

O

O BH OH

OH

OK Ni

L OB(OH)2

IN11

H

IN10

KOAc

NiL O

B(OH)2

H

TS4Ni

L OB(OH)2H

IN12

NiL

IN13

B(OH)3

NiL

IN13

NiL

TS5NiL

NiL

L

+L

IN5IN1

-L

Reductive Elimination:




Base-assisted Transmetallation:

32

Two more Questions Discussed• Why stronger Aryl C-O bond? • Why Ni not Pd in this chemistry?

High reverse barrier is the major reason!

LM

PhX ML

X

MX

L

TS M XL

M=Ni, Pdcomplex

Ph-X Ni(0) barrier Pd(0) barrier

Ph-Br 3.3 3.4

Ph-OAc 26.4 34.0

Ph-NHAc 24.2 31.4

Energy Barrier from η2 complex to TS is the major reason!


Unit: kcal/mol

33

One-Pot Reaction

Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422.

Me

H

H HHO

O1. PivCl, Et3N, CH2Cl22. (4-MePhBO)3, Ni(PCy3)2Cl2K3PO4, H2O, Dioxane

Me

H

H H

O

62% yieldEstrone

Latest Examples of Ester Coupling

OPiv+ PhZnCl

NiCl2(PCy3)2(5 mol%)

THF/DMA70 oC

Ph

84% yield

Li, B. J.; Xu, L.; Wu, Z. H.; Guan, B. T.; Sun, C. L.; Wang, B. Q.; Shi, Z. J. J. Am. Chem. Soc. 2009, 131, 14656.

Yu, J. Y.; Kuwano, R. Angew. Chem. Int. Ed. 2009, 48, 7217.

Li, B. J.; Li, Y. Z.; Lu, X. Y.; Liu, J.; Guan, B. T.; Shi, Z. J. Angew. Chem. Int. Ed. 2008, 47, 10124.

35

Conclusion for Part 1 and 2

• Chelation assistance helps Ru catalyst to activate inert C-O bond in aromatic ethers

• Cheaper Ni catalyst can activate aryl C-O bond in ether or ester for Suzuki coupling

• Computation studies help propose and understand the mechanism

36

General Outline

AromaticEther


AromaticEster


37

Tautomerizable Heterocycles

N

N

NH

N O

O

OH

HOOH

HO

Vitamin B2

38

Synthetic Route for 6-arylpurine Nucleosides

NH

NN

N

O

O

OHOH

HO

NH

NN

N

O

O

OPOP

PO

protection

N

NN

N

X

O

OPOP

PO

N

NN

N

Ar

O

OPOP

PO

activation functionalization

N

NN

N

Ar

O

OHOH

HO

deprotection

traditional multi-step transformation

< 40%

Kang, F. A.; Sui, Z. H.; Murray, W. V. J. Am. Chem. Soc. 2008, 130, 11300.

39

Activation of Carbonyl Group

HN

N

O

N

N POCl3/PhN(Me)2

MeCN/N

N

Cl

N

N

TMSBrButanone

-40 oC

NaIButanone

-40 oC

N

N

Br

N

N N

N

I

N

N

preformation

Reactivity order in transition metal catalyzed couplings:C-I>C-Br,C-OTf,C-OP+>C-Cl

Liu, J.; Robins, M. J. J. Am. Chem. Soc. 2007, 129, 5962.

40

One-step Conversion


41

Castro’s Reagent

Han, S. Y.; Kim, Y. A. Tetrahedron 2004, 60, 2447.


42

N

NN

O P+N

N

N

PF6

PyBOP

N

NN

O Heterocycle

Scope of Phosphonium Salts

EnvironmentalEnvironmentalConsiderationConsideration& Reactivity& Reactivity

Side reactionSide reaction& atom economic& atom economic

Coste, J.; Dufour, M. N.; Pantaloni, A.; Castro, B. Tetrahedron Lett. 1990, 31, 669.

Delarue, S.; Sergheraert, C. Tetrahedron Lett. 1999, 40, 5487.

43

Proposed Catalytic Cycle


44

Intermediates Verified by NMR

31P NMR spectrumWan, Z. K.; Wacharasindhu, S.; Levins, C. G.; Lin, M.; Tabei, K.; Mansour, T. S. J. Org. Chem. 2007, 72, 10194.

hypoxanthine

45

NH

NN

N

O

O

OHOH

HO

NH

NN

N

O

OHOH

HO

O

NH

NN

N

O

OHOH

HO

NH

NH

NN

N

O

OHOH

HO

S

NH

NN

N

O

OHOH

HO

CH2

PyBroP,ArB(OH)2,PdCl2(PPh3)2, 70-72%

PyBroP, ArOH80-84%

PyBroPArSH,82-88%

PyBroPArNH2,70-75%

Kang, F. A.; Sui, Z. H.; Murray, W. V. Eur. J. Org. Chem. 2009, 461.

Single Step Transformation of C6-modified Nucleosides

46

General Outline

AromaticEther


AromaticEster


47

Diazo Compound in Pd Coupling Reaction

Ph

NNHTs+

Br

[Pd], Ligand

Base, Solvent70 oC, 4h

Ph98%

Roglans, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem. Int. Ed. 2007, 46, 5587.

48

Bamford-Stevens Reaction

Base

CH3O2SNN

R1

R2

NN

R1

R2

Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735.

49

Metal Free Coupling by Tosylhydrazones

NNHTs

+

B(OH)2

OMe

K2CO3

Dioxane110 oC

OMe

H

93%

Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Nature Chemistry 2009, 1, 494.

Metal free reaction

One-pot reaction

50

Proposed Mechanism

NNHTs

R1 R2 B-

NNTs

R1 R2

N

R1 R2

-Ts-

Ar-B(OH)2

N

N

R1 B

N

R2

OHOH

Ar

R1 R2Ar-B(OH)2

R1

R2 BOH

OHAr

R1

R2 B(OH)2Ar R2

R1

ArH

1 2 3

4

7 8

56

Mechanism


51

Mechanism Studies


Scope of Tosylhydrazones and Boronic Acids

NNHTs

R1 R2

R2

R1

R3

H

110 oCK2CO3

R3-B(OH)2 Dioxane


NNHTs B(OH)2

MeOH

OMe

H

NNHTs B(OH)2

BrO O

Br

Ph

NNHTs

H

B(OH)2

Br Ph

Br

N

H

NNHTsCH3(CH2)5B(OH)2

N

(CH2)5CH3

Hydrazone Boronic acid Product

Ar1

NNHTs

95%

98%

99%

69%

Ar2 B(OH)2 Ar1 Ar2 Ar1 Ar2

1:2

NNHTs Ar B(OH)2 Ar Ar

1:1

53

[1,3]-borotropic Rearrangement

Ar1

NNHTsAr2 B(OH)2 Ar1 Ar2 Ar1 Ar2

+

110 oC

K2CO3

Dioxane+

Ar2B

HO OH

Ar1

Ar2

Ar1

B

HO OH

1 : 2

NNHTs Ar B(OH)2 Ar Ar+

110 oC

K2CO3

Dioxane+

ArB(OH)2

Ar

(HO)2B

1 : 1

Fang, G. Y.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 359.Henriksen, U.; Snyder, J. P.; Halgren, T. A. J. Org. Chem. 1981, 46, 3767.

54

Conclusion

• Ru and Ni can activate the inert C–O bond in ether or ester group for Suzuki Coupling.

• Castro’s Reagent was used for C–C bond formation and application for one–step modification of nucleosides.

• Metal-free reductive coupling directly via Carbonyl group under Suzuki condition

55

Acknowledgement

• Dr. Baker• Dr. Borhan• Dr. Smith, Dr. Maleczka, Dr. Jackson• Dr. Liu, Dr. Shi

• Baker’s Group: Hui, Gina, Heyi, Quanxuan, Yiding.• Hong, Li, Yong, Hao.• All of you

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