Buchwald-Hartwig Coupling : Discovery, Optimization, and Applications

Literature MeetingMarch 25, 2008

Buchwald-Hartwig Coupling : Discovery, Buchwald-Hartwig Coupling : Discovery, Optimization, and ApplicationsOptimization, and Applications

David MarcouxCharette’s Laboratories

XR Pd, Ligand

HNR2, BaseNR2

R

2

Importance (Natural Products)

N

NH

MeMe

HO

Dehydrobofotenine

N

NH

N

NH

O

O

Me

Damirone B

Me

O

H2N

Makaluvamine C

NH

HN

NH

S

BrO

ODiscorhakdin A

OH

HO

NH

OH

Carbazomadurin A

N

HHO

O

NH O

N

O

(-)-Aspectrine

3

Importance (Drugs)

Buchwald, S.L.; Mauger, C.; Mignani, G.; Sholz, U. Adv. Synth. Catal. 2006, 348, 23.

4

Importance (Drugs)

Aripiprazole®Otsuka

NN

ClCl

O

NHO

Ciprofloxacin®Bayer

N

OO

HOF

N

NH

Cl

N

N N

NN

O

Etoperidone®Angelini

N

N

HO

OH

Levodropropizin®J & J

5

Importance (Materials)

They formed stable aminium radical cations that can be building blocks for high-spin polyradicals that shown ferromagnetic coupling, as well as for conductive polymers.They have been used as hole-transport layer in electroluminescent devices. They can initiatepericyclic reactions, act as electrocatalyst, or act as mild and selective oxidizing agent.

Theu found many uses in pharmaceuticals, agrochemicals, photography, xeroxography, pigments and electronic materials.

6

Common C(aryl)-N Bond Formation (Reductive Amination and Alkylation)

N

NH2

O

NaBH3CN

N

N

NH2

O

M.S.

NaBH3CNNH

NH

NH2 NH

O

NH N

NH2

Br

NNHCs2CO3

7

Common C(aryl)-N Bond Formation (SNAr)

X

EWG

EWG

EWG : NO2, CO2H, CN, COR ....X : F > Cl > Br >> INu : OR, NR2 ...

EWG

EWGNu

XNu

EWG

EWG

Carey, F.A.; Sundberg, R.J. Advanced Organic Chemistry, Part B: Reaction and Synthesis; Plenum Publishers; New-York, 2001; pp 714-731.

8

Common C(aryl)-N Bond Formation (Nitration)

EDGHNO3, H2SO4

EDG

NO2

EDGO2NRed

EDG

NH2

EDGH2N

EWGHNO3, H2SO4

EWGRed

O2N

EWG

H2N

Carey, F.A.; Sundberg, R.J. Advanced Organic Chemistry, Part B: Reaction and Synthesis; Plenum Publishers; New-York, 2001; pp 693-695.

9

Common C(aryl)-N Bond Formation (Ullman Reaction)

X

CuX (0.5-1.5 equiv)base (1-2 equiv)

NuH (1.5-2.0 equiv)Heat (180-250 °C)

Nu

Nu :

R R

NHRR

OHR

Kürti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Inc.: Amsterdam, 2005; pp 464-465.

10

Common C(aryl)-N Bond Formation(Larock Indole Synthesis)

I

NH2

R' R

Pd(OAc)2Base

R'' R''

NH

R'

R

R larger than R'

I

NH2

R'' Pd(0) PdI

NH2

R'' R' R

NH2

R''R'

R

PdI

Base

NH

R''

Pd

R'

RR''

NH

R'

RPd(0)

Kürti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Inc.: Amsterdam, 2005; pp 260-261.

11

Common C(aryl)-N Bond Formation (Aryne Chemistry)

R

X

X : Cl, Br, I, OTf

RNHNaR

+

RRNH2

R R RNHR

NHR

NHR

12

Common C(aryl)-N Bond Formation (Pd-Mediated)

N CO2Me

MeH2N

Br

MeO2CPd(PPh3)4 (1.5 equiv)

THF, 80 °C, 21 h

84%

N CO2Me

Me

MeO2C

HN

Boger, D.L.; Panek, J.S. Tetrahedron Lett. 1984, 25, 3175.Boger, D.L.; Duff, S.R.; Panek, J.S.; Yasuda, M. J. Org. Chem. 1985, 50, 5782.

13

Hartwig-Buchwald Pd-Catalyzed C(Aryl)-X Coupling

XMLn

RYHYR

X : Cl, Br, I, OTf, ONf, OTs, H Y : N, O, S, -carbonyl

Buchwald :- Over 90 publications on this subject- Aborded the problematic as a synthetic organic chemist

Hartwig :

- Over 70 publications on this subject- Aborded the problematic as an organometalic chemist

M : Cu, Pd, Ni

14

Pd-Catalyzed C-C Coupling

XR

R'SnBu3

PdL2, CsF, CuX'R'

RXSnBu3

XR O

OR

PdL2, Base R

OR

O

XR

R' BOH

OH

PdL2, Base

R'R

NaX, B(OH)2OR

XR

R' ZnXPdL2

R'R

ZnX2

Stille :

Heck :

Suzuki :

Negishi :

Kürti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Inc.: Amsterdam, 2005.

15

Catalytic Cycle

L2X2Pd(II)

L4Pd(0)

Reduction

+ R-X18 e-

- 2 L

X Pd R

L

L16 e-

+ R'-M, - M-X

Oxidative Addition

Transmetallation

R' Pd R

L

L16 e-

R' Pd L

R

L16 e-

Isomerisation

Reductive Elimination

R-R

16

Generation of the Active Catalyst

Pd(L)4

PdCl2L2

DIBAL-H, 2 LNH2NH2, 2 LEt3N, 2 L2 R-M, 2 L

Pd(OAc)2

PR3, 4 LCO, ROH, NR3 or RM, 4LK2PdCl4

NaBH4, 4 L

Pd(dba)2

PdCl2 + dba + NaOAc

CHCl3Pd2(dba)3·CHCl3

4 L 8 L

L2X2Pd(II)

L4Pd(0)

Reduction

18 e-

17

Oxidative Addition

L4Pd(0)+ R-X18 e-

- 2 L

X Pd R

L

L16 e-

Oxidative Addition

- The metal is oxidized from 0 to +2- The substrate is reduced- Reaction can be done at RT- Shown to be reversible in some cases- The 14 e- complexe is beleived to be involved- As a general guideline: - -donating L accelerates this step - L helps oxidative addition in ArBr but slows down the rate for ArI - EWG on the activated arene accelerate this step - I > OTF > Br >> Cl

PdL4 PdL3 PdL2

XR

X Pd

L

L18 e- 16 e- 14 e- 16 e-

XPd

18

Transmetallation

X Pd R

L

L16 e-

+ R'-M, - M-XTransmetallation

R' Pd R

L

L16 e-

- Many nucleophile have been studied - Zn, Zr, B, Al, Sn, Si, Bi, Cu, Mg, Li- Is the rate limiting step of most couplings- Importantly, both M need a benefit in energie- Additive often required - Base, Cu, F-

- Beleived to be an equilibrium- EDG on the Nu facilitate the transmetallation- Mechanism is believed to be an associative process (SN2)

X Pd

L

L

X Pd LL

R

RM - MXR Pd

L

L

19

Isomerisation

R' Pd R

L

L16 e-

R' Pd L

R

L16 e-

Isomerisation

Ph2P PPh2Pd

Me

Me

Heat, light ...N.R.

- Not well understood- Beleived to be required for reductive elemination- Mechanism not well known- Probably reversible

R Pd

L

L

L Pd

R

L

20

Reductive EliminationL4Pd(0)

18 e-

R' Pd L

R

L16 e-


R-R

L4Pd(0)

18 e-

16 e-

- Reverse of the oxidative addition- The metal is reduced from +2 to 0- Can be done at RT in some cases- Irreversible- Electron-poor substituant favor the elimination (or acceptor L)- Dissociation of a L favor the elimination- Oxidants favor the elimination- Heat and light can also promote it

R' Pd L

R

L+ L

R'-R

21

-H Elimination

- Requires a M-Alkyl bearing a-H- It is usually in equilibrium with the insertion- Electron-poor L or Ar accelerate the elimination- Bulky alkyl favor the elimination- More importantly it requires an empty site on an electron-poor M

Pd

L

R

Pd

L

R

L Pd

H

LR

16 e- 14 e- 16 e-

22

Migita First Results in Pd-Catalyzed C(Aryl)-N Bond Formation

Br

1.5 equiv

R PdCl2(o-tolyl3P)2 (1 mol %)PhMe, 100 °C, 3h NEt2

Rn-Bu3SnNEt2

NEt2

Me

NEt2

Me

NEt2Me NEt2

NEt2Cl NEt2Br NEt2O2N NEt2Me2N

33% 61% 79% 81%

55% 30% 24% 36%

- Proposition of an oxidative-addition, transmetallation, reductive-elimination- Reaction does not work with ArCl and ArI

Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.

23

Prof. John F. Hartwig

1964 Born1986 A.B. Princeton University Professor Maitland Jones Jr. 1990 Ph.D. University of California, Berkeley Professor Richard A. Anderson and Professor Robert G. Bergman 1992 American Cancer Society Postdoctoral Fellow, MIT Professor Stephen J. Lippard1993 Professor at Yale University2006 Moved to University of Illinois

24

Hartwig First Look

L2Pd

Br

PdBr

PdBr

LL

X-Ray

i. Toluene RTii. Ether

Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969.

BrPdCl2(o-tolyl3P)2 (1 mol %)

PhMe, 90-110 °C NR2n-Bu3SnNR275-85%

L = (o-tolyl)3PL2PdCl2

n-Bu3SnNEt2 LPd

Black precipitateElem. Anal.

LPd(NHEt2)Cl2NHEt2 (excess)

LPd(NHEt2)Cl2

X-Ray

+ L, the complex catalyze the reaction

Pd(dba)2 + 2 L L2Pd

X-Ray

Catalyzed the reactionFaster than Pd(II) pre-catalyst10 TON after 18h at RT

L2Pd n-Bu3SnNR2 N.R.

25

Hartwig First Look

Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969.Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030.

L = (o-tolyl)3P

- Irreversible oxidative addition- More L diminished the rates of oxidative addition- 3 L on Pd have never been observed- They beleive that the oxidative addition is occuring after L dissociation

PdBr

PdBr

LL

X-Ray

LiNEt2NEt2 2 L2Pd2

RT

PdBr

PdBr

L

L

X-Ray

BrBu

No exchange

PdBr

PdBr

LL

X-Ray

BrBu

Bu3SnNMe2

NEt2

RT

NEt2Bu

Both observed

All these experiments prove that C-N bond is formed by reductive elimination !

26

Catalytic Cycle with Tin Amide

L2X2Pd(II)

PdL2 + Ar-X

- L

X Pd Ar

L

+ R2NSnBu3Ar Pd X

L

Ar-NR2

L : P(o-tolyl)3

X Pd Ar

L

2

- XSnBu3N

SnBu3RR

Ar Pd

L

NR

R

27

Prof. Stephen L. Buchwald

1955 born,1977 B.Sc., in chemistry, from Brown University. Professors Kathlyn A. Parker and David E. Cane at Brown University Professor Gilbert Stork at Columbia University.1982 Ph.D. Harvard University Professor Jeremy R. Knowles1984 Post-doc California Institute of Technology Professor Robert H. Grubbs1984 Assistant professor MIT1989 Associate professor MIT1997 Camille Dreyfus Professor of Chemistry MIT

28

Buchwald First Look

BrR

PdCl2(o-tolyl3P)2 (1-2.5 mol %)PhMe, 105 °C, 4h

AmineR

n-Bu3SnNEt2

N N NN

N NH NHNMe

88% 55% 79% 83%

84% 66% 64% 73%

Guram, A.S.; Buchwald, S.L. J. Am. Chem. Soc. 1994, 116, 7901.

AmineAr purge

- Et2NHn-Bu3SnAmine

Only way to generate it

EtO2CBn

Me

MeC18H38N

81%

Me2NBn

N

79%

MeO Ph MeO Ar MePh

MePMP

Ph

PhEtO2C

29

First Coupling Using Free Amine

Br NMe2PhPh

B(NMe2)3 (1 equiv)Pd(dba)2 (2 mol %)

P(o-tolyl)3 (4 mol %)NaOtBu (1.4 equiv)

Toluene, 100 °C 85%

Br NR2PhPh

B(NR2)3 (1 equiv)Pd(dba)2 (2 mol %)


Toluene, 100 °C50-95%

BrNPh

Ph

HNMePh (1 equiv)Pd(dba)2 (2 mol %)


Toluene, 65 °C88%

PdCl2(P(o-tolyl)3)2 can be used but requires 100 °C

Guram, A.S.; Rennels, R.D.; Buchwald, S.L. Angew. Chem. Int. Ed. Engl. 1995, 34, 1348.

30

First Coupling Using Free Amine

Br Amine

Amine (1 equiv)Pd(dba)2 (2 mol %)

P(o-tolyl)3 (4 mol %)NaOtBu (1.4 equiv)Toluene, 65-100 °C


R R

NPhPh

88%

N

Ph

78%

NPh O

86%

NPhOCPh

89%

NMe2NBn

71%

N N

79%

N

67%

F3C

O

ON

67%

MeO

O

O N

67%

Me

O

O

Me

NPhOCC6H13

72%

31

Intramolecular Version


NHBn

I

- PPh3 is the optimal ligand- ArI are better partners than ArBr- Coupling performed at RT

Pd(PPh3)4 (5 mol %)NaOtBu (1.4 equiv)

Et3N, RT, 15hNBn

83-87%

BrNPh

Ph

HNMePh (1 equiv)Pd(dba)2 (2 mol %)


Toluene, 65 °C88%

HPh

8%

32

Side Product

LnPd(0)+ R-X

- 2 L

X Pd

R

L

+ R'2NH, NaOtBu

R'2N Pd

R

L

R-NR'2


- tBuOH

If R has a H

R'

NR'

H Pd

R

L

LnPd(0)

RH

33

Real Problem

Wagwag, S.; Rennels, R.A.; Buchwald, S.L. J. Am. Chem. Soc. 1997, 119, 8451.

HN

Br

Pd(dba)2 (2 mol %)P(o-tolyl)3 (4 mol %)

NaOtBu (1.4 equiv)Toluene, 100 °C

N

BrNHPh

Ph

Pd2(dba)3 (2 mol %)P(o-tolyl)3 (8 mol %)


Ph

Me

96% ee

MePh

80%96% ee

H2N Ph

Me

98% ee

PhMe

60%70% ee

34

2 Weeks Later

LnPd(0)+ R-X

X Pd R

L

+ R'2NHR'2NH Pd R

L

R'2N Pd

R

L

R-NR'2

2

X

NaBase

BaseH+ NaX

Louie, J.; Hartwig, J.F. Tetrahedron Lett. 1995, 36, 3609.

X Pd R

L

35

Hartwig’s Conditions

Louie, J.; Hartwig, J.F. Tetrahedron Lett. 1995, 36, 3609.

BrR

L2Pd or L2PdCl2 (5 mol %)LiHMDS (1.2 equiv)

Amine (1.5 equiv)toluene, 100 °C, 2h

L = P(o-tolyl)3

AmineR

NBu

89-94%

NMeO

94%

NF3C

72%

NBu

55 °C26%

Reduced ArBr : Major Product

NHBu

Bu

90% for the reduced arene

NHCy

Bu

88% for the reduced arene

36

Unsolved Problems- Primary amines do not react well- Aniline reacts sluggishly- Reduced Aryl halide still obtained in important amount

Br

Me

Me

HexNH2

Pd2(dba)3 (1 mol %)Ligand (2-4 mol %)

NaOtBu (1.4 equiv)toluene, 80 °C

NHHex

Me

Me

H

Me

Me

NHHex

Me

Me

N

Me

Me

Hex

Me

Me

PPh2

PPh2Ph2P

PPh2 P(o-tolyl)3

Ph2P PPh2Ph2PPPh2

FePPh2

PPh2

40/139/1

100% conv. (2h)

1/5.4--

7% conv. (6h)

1.5/17.6/1

88% conv. (22h)

1/1.16--

18% conv. (3h)

13.2/12.2/1

100% conv. (3h)N.R.

Wolfe, J.P.; Wagaw, S.; Buchwald, S.L. J. Am. Chem. Soc. 1996, 118, 7215.

37

BINAP Scope

Br

Pd2(dba)3 (0.5 mol %)BINAP (1 mol %)

Amine (1.1 equiv)NaOtBu (1.4 equiv)

toluene, 80 °C

Wolfe, J.P.; Wagaw, S.; Buchwald, S.L. J. Am. Chem. Soc. 1996, 118, 7215.

RAmine

R

NH

Me

Me

Bn

NH

Me

Me

Hex

NH

Me

Me

CyNHNC

HexNHMeO

HexMe

79%79% with 0.05 mol % 88% (35%) 84% 96% 95%

N

Me

Me N

98% (47%)

N

Me

MePh

94% (5%)

* Yields in parentheses are those obtained using P(o-tolyl)3 as ligand.

N

OMePh

75% (0%)

N

NMe2Ph

65% (0%)

38

Back-to-Back

FePPh2

PPh2Ph Pd N(tolyl)2

PPh3

PPh3

FePPh2

PPh2

Pd Ph

N(tolyl)2

85 °C

xs PPh3

PhN(tolyl)2Pd(DPPF)2Pd(PPh3)4

XR

X : Br, I

(DPPF)

Pd(DPPF)Cl2 (5 mol %)RNH2 (1.2 equiv)

NaOtBu (1.4 equiv)THF, 100 °C, 3 h

If a primary amine is used, red. el. occurs ar RT

NHR

R

NHPh

NHPh

NHPh NH

Bu

NHNH

NHBu

NHPh

Me

92%

MeO OMe

92% 96%

PhOC

96%

PhOCEt2NOC

84% 82%

NC

93%

Ph

94%

Driver, M.S.; Hartwig, J.F. J. Am. Chem. Soc. 1996, 118, 7217.

39

Mechanism

Pd(0)+ R-X

+ tBuONa

R-NR'2

R'2NH

tBuOH+ NaX

L Pd R

X

L

L Pd R

OtBu

L

L Pd R

NR'2

L

Driver, M. ; Hartwig, J. J. Am. Chem. Soc. 1997, 119, 8232.Wolfe, J.; Wagaw, S.; Buchwald, S. J. Am. Chem. Soc. 1996 , 118, 7215.Driver, M. ; Hartwig, J. J. Am. Chem. Soc. 1996, 118, 7217.

40

Why ArI are Less Reactive

PdI

PdI

LAr

L Ar

LnPd(0)+ R-X

X Pd R

L

+ R'2NHR'2NH Pd R

L

R'2N Pd

R

L

R-NR'2

2

X

NaBase

BaseH+ NaX

X Pd R

L

41

Etheral Solvents

I

Pd2(dba)3 (0.5 mol %)P(o-tolyl)3 (2 mol %)

Amine (1.1-2.4 equiv)NaOtBu (1.4 equiv)dioxane 65-100 °C

Wolfe, J.P.; Buchwald, S.L. J. Org. Chem. 1996, 61, 1133.

RAmine

R

NBn

Me NPh

Me NMe NBu

BuMe NMeO

O

O

NHBu

Me NO

OMeO

NPh

Bu2NOC NHHex

Me

Me

79% 74% 73% 68% 66%

18% 58% 59% 69%

42

Lower Temperature

IR

Pd2(dba)3 (0.5 mol %)BINAP or tol-BINAP (1 mol %)

Amine (1.2 equiv)

18-C-6 (3 mol %)NaOtBu (1.4 equiv)THF, RT, 17-30h

AmineR

Wolfe, J.P.; Buchwald, S.L. J. Org. Chem. 1997, 62, 6066.

NHHex

Et2N

O Me

Me

NMe N Me NH

Ph

88% 78% 85% 78%

MeO N Br N

91% 90%

N O

Br

78%

43

Why 18-C-6 ?

LnPd(0)+ R-X

X Pd R

L

+ tBuONa

BuO Pd R

L

R'2N Pd

R

L

R-NR'2

2

R'2NH

tBuOH+ NaX

X Pd R

L

44

Pyridine Containing Substrates

Br

Pd2(dba)3 (1 mol %)BINAP or DPPP (2 mol %)

Amine (1.2 equiv)NaOtBu (1.4 equiv)

toluene, 70 °C

Wagaw, S.; Buchwald, S.L. J. Org. Chem. 1996, 61, 7240.

RAmine

R

ArX2 PdL2

+ 4 LL = P(o-tolyl)3

PdX

PdX

Ar

L

L

Ar

Pyr.2 Ar Pd X

Pyr

Pyr

NN Bn

NHN Cy

NN

NHN Cy

NHN Pyr

NN NHNHex

NN Ph

O

O

86% 73% 87% 82%

87% 91% 67% 86%

45

Chiral Amine


HN

Br



N

BrNHPh

Ph

Pd2(dba)3 (2 mol %)P(o-tolyl)3 (8 mol %)


Ph

Me

96% ee

MePh

80%96% ee

H2N Ph

Me

98% ee

PhMe

60%70% ee

46

Bidentate Ligand


HN

Br



N

BrNHPh

Ph

Pd2(dba)3 (1 mol %)BINAP (2 mol %)


Ph

Me

96% ee

MePh

80%96% ee

H2N Ph

Me

98% ee

PhMe

86%98% ee

PdN

Me

Ph

P(o-tolyl)3less prone to elimination

McDermott, J.X.; Withe, J.F.; Whitesides, G.M. J. Am. Chem. Soc. 1976, 98, 6521.

47

Mechanism

LnPd(0)+ R-X18 e-

- 2 L

X Pd R

L

L16 e-

+ R'2NH, NaOtBuR'2N Pd R

L

L16 e-

R'2N Pd L

R

L16 e-

R-NR'2

- tBuOH

If R has a H

R'

NR'

H Pd L

R

L

LnPd(0)

RH

R'

NR'

H Pd L

R

NR'

R'

-L

+LR'2N Pd L

R

L

48

Scope


Br Amine



R R

NH N NH

N

NH

NH

Ph

PhMe

F3CMe

Ph

PhOC

CyMe Cl

Ph

Me PhOC

Ph

Ot-BuN

OO

Ot-Bu

86% 43% 89% 82%

71% 98% 72%

49

Limitation

X Amine



R R

NR

X = OTf, Cl

Functionnal group tolerance

50

Ligand Screening

Br

Pd2(dba)3 (1 mol %)Ligand (2-4 mol %)


PPh2

PPh2 P(o-tolyl)3

FePPh2

PPh2

1/5.28%

12.6/183%

1/4.99%

Marcoux, J.-F.; Wagaw, S.; Buchwald, S.L. J. Org. Chem. 1997, 62, 1568.

Bu2NHtBu NBu2tBu HtBu

FePPh2

PPh2

1.7/118%

MeNMe2

FePPh2

12.5/189%

MeNMe2

FePPh2

39/193%

MeOMe

51

Scope

Br

Pd2(dba)3 (0.25 mol %)PPF-OMe (0.75 mol %)

Amine (1.1 equiv)


Marcoux, J.-F.; Wagaw, S.; Buchwald, S.L. J. Org. Chem. 1997, 62, 1568.

AmineR R

NtBuEt

PhNtBu

Et

BnNtBu

Bu

BuNMeOC

Et

Ph

NEt

PhN

Cy

EtN

N

Bu

BuNN

Bu

Bu

91% 81% 93% 92%

Me

Me91%

Me

Me89% 60%52%

52

Why? L4Pd(0)

18 e-

R' Pd L

R

L16 e-


R-R

L4Pd(0)

18 e-

16 e-

- Reverse of the oxidative addition- The metal is reduced from +2 to 0- Can be done at RT in some cases- Irreversible- Electron-poor substituant favor the elimination (or acceptor L)- Dissociation of a L favor the elimination- Oxidant favor the elimination- Heat and light can also promote it

R' Pd L

R

L+ L

R'-RFe

PPh2

MeOMe

53

From ArylOTf

OTfR

Pd2(dba)3 (1 mol %)L (2 mol %)

Amine (1.1 equiv)


OHR

OTfR

Pd(OAc)2 (3 mol %)BINAP (5 mol %)Amine (1.1 equiv)

Cs2CO3 (1.4 equiv)toluene, 65-100 °C

AmineR

N N NHHex

NHPMP

NN

Bn

NHPMP

N

MeOC MeOC O MeOC MeOC

MeO2C

MeO2C

CO2Me Me

MeO

54% 86% 46% 90%

91% 85% 78% 83%

Ahman, J.; Buchwald, S.L. Tetrahedron Lett. 1997, 38, 6363.

54

Functionnal Groups Tolerance

BrR

Pd(OAc)2 (3 mol %)BINAP or PPF-OMe (5 mol %)

Amine (1.2 equiv)

Cs2CO3 (1.4 equiv)toluene, 65-100 °C

AmineR

Wolfe, J.P.; Buchwald, S.L. Tetrahedron Lett. 1997, 38, 6359.

Ester, methyl ketone, aldehyde, Nitro, Cyano

NH

Cl

O2N N

O

NH

Cl

NCBn

Me

NHPh

ON

Bn

O

75% 84% 73% 54%

55

Lower Temperature

BrR

Pd(dba)2 (1-2 mol %)P(t-Bu)3 (0.8-1.6 mol %)

Amine (1.2 equiv)

NaOtBu (1.4 equiv)toluene, RT, 1-6h

AmineR

Hartwig, J.F.; Kawatsura, M.; Hauck, S.I.; Shaughnessy, K.H.; Alcazar-Roman, L.M. J. Org. Chem. 1999, 64, 5575.

NPMP

PMP

NPh

NBu

Bu

N

NBu

BuN

Ph

Ph

NPh

NPh

Ph

MeO MeO

Me Me

Me NPh

Ph

94% 99% 81%

90% 85%

O

96%

NC

87%95%

56

Lower Temperature and ArCl

Wolfe, J.P.; Buchwald, S.L. Angew. Chem. Int. Ed. 1999, 38, 2413.

PCy2

Me2N

P(tBu)2

Me2N

PCy2 P(tBu)2

L

ClR

Pd(OAc)2 (1 mol %)L (2 mol %)

Amine (1.2 equiv)

NaOtBu (1.4 equiv)toluene, RT, 15-26h

AmineR

NPh

N NBu

BuN

NHBn

N NNH

Bn

Me Me

98%95% with 0.005 mol %

O

94%

Me

Me

Me

81% 98%

Me

Me

99%

MeO O ONC

OMe

90% 86% 99%

57

Lower Temperature and ArCl

N N

iPr

iPr iPr

iPrBF4L :

ClR


Amine (1.2 equiv)

NaOtBu (1.5 equiv)DME, RT-100 °C, 3-20h

AmineR

NBu

BuNH

HexNH

Ph NH

NPh

NPh

N NN

Me

86%

Me

40%

Me

82%

Me

Me

Me

88%

Me

97%

NC MeO

97%

O

96%

O

98%

Stauffer, S.R.; Lee, S.; Stambuli, J.P.; Hauck, S.I.; Hartwig, J.F. Org. Lett. 2000, 2, 1423.

58

Chloropyridines

NCl

Pd(OAc)2 (0.001-1 mol %)L (0.001-1 mol %)RNH2 (1.2 equiv)

NaOtBu (1.4 equiv)DME, RT-80 °C, 5-48 h

FePCy2

MePtBu2

L :

NNHR

N N

Ph

Ph

92%

N NH

99%

N Ph

Ph

N NH

96% using 0.005 mol %

Oct

N

HN

Cy

79%

N

NHOct

93% (1 mol % 8h)83% (0.01 mol % 24h)

N NH

Oct

94%

N

HNOct

91%

N NH

Cy

94%

59

Functionalized Arylclorides

Pd(OAc)2 (0.05-2 mol %)L (0.05-2 mol %)RNH2 (1.2 equiv)

LiHMDS (1.4 equiv)DME, 70-100 °C, 18-20 h

FePCy2

MePtBu2

L :

ClR

NHRR

NHHO

90%

NHCy

86%

HO

NHHOOct

72%

NH

87%

O

NH

67%

H2N

O

NHOct

81%

HO

O

NHCy

74%

NHOct

98%

NH

NHO

O

60

Enlarging the Scope

XR

X : Cl, Br, I, OTf, Nf, Ts ... H

R : Become more and more functionalized

R2NH, RNH2, NH3

NH3 : Getting thereRNH2 : Many catalyst are doing the jobR2NH : Many catalyst are doing the job

R can be Aryl or AlkylPyrrole and other aromatic N-H can arylated

Other N :

H2N O

O

tBu H2NS

R

O

O

H2N

O

R RHN

O

R

61

C-H Functionalization

R

NH

O

R'

Pd(OAc)2 (5 mol %)Cu(OAc)2 (1 equiv)

O2 (1 atm)toluene, 120 °C, 12-24 h

R

R'

NO

HN

OPd

OAcOAc

- AcOHPd

HN

O

OAc

- AcOHPd

N

O

NO

Pd(0)

Cu(OAc)2, O2

Tsang, W.C.P.; Zheng, N.; Buchwald, S.L. J. Am. Chem. Soc. 2005, 127, 14560.

62

But Why NH3 Can’t Be Used ?

H2N

Pd

NH2

PdH3N

NH3

1. NH3 can displace L to afford an unreactive complex

2. No known Ar-Pd-NH2 reductive elimination

3. The newly formed arylamine can react also

63

Specific Case: Ammonia

XR


NaOtBu (1.4 equiv)toluene, 65-80 °C, 17-30h

NH2

R

Wolfe, J.P.; Ahman, J.; Sadighi, J.P.; Singer, R.A.; Buchwald, S.L. Tetrahedron Lett. 1997, 38, 6367.

Br, I, OTf

HNR

N

HCl, wet THF, RTor

NH4HCO2, Pd/C

orNH2OH·HCl, AcOH

BrBr

Br

I

I OTf OTf OTf

OMeMe

Me

OO

Br

MeO NC MeOC MeO2C

87%

* Pd(OAc)2 and Cs2CO3 in THF is used for ArOTf** 18-C-6 in THF is used as an additive in the case of ArI

77% 89% 91%

88% 84% 83% 89%

64


XR

i. Pd2(dba)3 (0.5 mol %) L (1.2 mol %) toluene, 65-85 °C, 12-30h

ii. HCl/neutralisationNH2

R

Huang, X.; Buchwald, S.L.Org. Lett. 2001, 3, 3417.

X : Cl, Br

Li NTMS

TMS1.2 equiv

PCy2L:

XR

i. Pd2(dba)3 (0.5 mol %) L (1.2 mol %) LiHMDS (1.2 equiv) toluene, 65-85 °C, 12-30h


R

X : Cl, Br 1.2 equiv

PCy2L:

Ph3SiNH2

65


XR

Pd2(dba)3 (1 mol %)L (2.4 mol %)

LiNH2 (5 equiv)

NaOtBu (1.2 equiv)toluene, 65-80 °C, 12-30h

Huang, X.; Buchwald, S.L.Org. Lett. 2001, 3, 3417.

X : Cl, Br

PtBu2L:

NR

3

NH

2

R

66


XR

i. Pd2(dba)3 (2 mol %) P(tBu)3 (2 mol %) toluene, RT, 12-30h


R

Sunwoo, L.; Jorgensen, M.; Hartwig, J.F. Org. Lett. 2001, 3, 2729.

Cl, Br

Br Cl

Br

Br

Br Cl Br Br

OO

Me2N

MeO MeO F3C F

92%

* More than 20 ligands screened** Loading : 2-5 mol % RT 12-20h or 0.2-0.5 mol % 70 °C 12-30h*** More than 20 substrates

97% 99% 87%

85% 90% at 50 °C 75% 85%

Li NTMS

TMS1.2 equiv

MeO2C MeO2C

67


XR

i. Pd2(dba)3 (1 mol %) P(tBu)3 (1 mol %) LiCl (0.6 equiv) THF, 50 °C, 1-24h

ii. HCl/neutralisation

NH2

R

Lee, D.-Y.; Hartwig, J.F. Org. Lett. 2005, 7, 1169.

Cl, Br

Br Cl Br Br

Br Cl Br Br

NC

MeO MeO F3C

91% 85% 95% 97%

87% 88% 92% 90%

ZnN(TMS)2

N(TMS)20.6 equiv

MeO2C MeO2C O2N

O

68


Br

i. Pd2(dba)3 (2 mol %) P(tBu)3 (2 mol %) LiCl (0.6 equiv) THF, 50 °C, 2h


NH2

Lee, D.-Y.; Hartwig, J.F. Org. Lett. 2005, 7, 1169.

ZnN(TMS)2

N(TMS)2

0.6 equiv

OMe

OMeO

99% ee 85%

OMe

OMeO

98% ee

Br

i. Pd2(dba)3 (2 mol %) P(tBu)3 (2 mol %) PhNH2 (1.2 equiv) THF, 85 °C, 2h


NHOMe

OMeO

99% ee

OMe

OMeO

% ee

BasePh

yield

ZnN(TMS)2

N(TMS)2

0.6 equiv

K3PO4

2.5 equiv

CsCO3

2.5 equiv

NaOtBu

1.2 equiv

91%99% ee

91%97% ee

92%25% ee

32%2% ee

69

First Coupling with NH3(g)

FePCy2

MePtBu2

XR

PdCl2L (1 mol %) NaOtBu (2 equiv)

NH3(g) (80 psi)

DME (0.05 M), 90 °C, 20-24h

NH2

R

Shen, Q.; Hartwig, J.F. J. Am. Chem. Soc. 2006, 128, 10028.

X : Cl, Br, I, OTf, OTs

Br OTfCl I

Br Br

BrN

Br

86%17:1

N.R. 69%23:1

79%>50:1

94%31:1

89%>50:1

80%>50:1

70%>50:1

tBu tBu

L =

Me Me

Ph iPr

N

* Ratio of ArNH2:Ar2NH

70

More Convenient NH3 Source

FePCy2

MePtBu2

XR

PdCl2L (1 mol %) LiNH2 (10 equiv)

DME (0.05-0.50 M), 90 °C

20-24h

NH2

R

Shen, Q.; Hartwig, J.F. J. Am. Chem. Soc. 2006, 128, 10028.

X : Cl, Br, I, OTf, OTs

Br OTfCl I

Br Br

BrN

Br

72%9.5:1

N.R. 75%11.1:1

81%>50:1

76%12:1

82%>50:1

82%>50:1

79%>50:1

tBu tBu

L =

Me Me

Ph iPr

N

* Ratio of ArNH2:Ar2NH

Br

68%10.9:1

Cl

BrBr

64%

71


(CyPFtBu)PdNH2

Ar

Ar : C6H4-4-OMe

d15-PPh3

C6D6, 90 °C, 1h(CyPFtBu)Pd d15-PPh3 ArNH2 Ar2NH

45% 45%

72

With Ammonia

Br


NaOtBu (1.4 equiv)

NH3 (5 equiv)dioxane (0.042 M), 80 °C

NH2

NH2

tBu

tBu

85%>30:1

* Ratio of monoarylated : diarylated

NH2

BnO

78%18:1

NH2

64%>30:1

Ph

Br

Pd2(dba)3 (1 mol %)L' (5 mol %)

NaOtBu (1.4 equiv)

NH3 (3 equiv)dioxane (0.625 M), 80 °C

NH

NH

Me

Me

71%

NH

F3C

80%

NH

88%

2

2 2 2

Surry, D.S.; Buchwald, S.L. J. Am. Chem. Soc. 2007, 129, 10354.

L : PtBu2

Me2N

L' :

PCy2

iPr iPr

iPr

73

Triarylamine

Br

Pd2(dba)3 (1 mol %)L' (5 mol %)

NaOtBu (1.4 equiv)

NH3 (0.75 equiv)dioxane (0.66 M), 100 °C

N

N

Me

Me

82%

N

81%

N

66%

2

3 3 3


FTHPO

L : PtBu2

Me2N

L' :

PCy2

iPr iPr

iPr

74

Sequential AdditionPd2(dba)3 (1 mol %)

L (5 mol %)NaOtBu (4.2 equiv)

NH3 (0.75 equiv)dioxane, 80 °C, 3 h


ArX

i. -NH3ii. Concentration

iii. Ar'X (0.9 equiv) L' (5 mol %) 80 °C, 3 h

Ar''X (0.9 equiv)100 °C, 16 h N

ArAr'

Ar''

N

N

N

N NN

N

N

tBu

Me

Me

tBu

OTHP

N

tBu

OTHP

Me

Me

tBu N OBn tBu

tBu

61% 55% 75%

61% 77% 64%

75

Total Synthesis

I

Br

CO2Et

NHAc

Pd(OAc)2Et3N

100 °C, 2.5 h74%

BrNHAc

CO2Et[(COD)2Rh]OTf

(S,S)-Et-DuPHOS

H2 (30 psi)MeOH, RT

90%, 99% ee

BrNHAc

CO2Et

Pd2(dba)3 (2.5 mol %)P(o-tolyl)3 (10 mol %)

Cs2CO3 (2 equiv)toluene

100 °C, 4 h93%, 99% ee

NAc

CO2EtN

CO2H

OCO2Et

Wagaw, S.; Rennels, R.A.; Buchwald, S.L. J. Am. Chem. Soc. 1997, 119, 8451.

76

Total Synthesis

Dehydrobofotenine

I

MeO

N

NMe2

CO2Et

NH2

Br

OMe

3 steps52%

1)

DCE, reflux

2) EtOH, DCE, reflux 83%

Cl O

O Cl

I

MeO

N

NHMe

CO2Et

Pd(PPh3)4 (10 mol %)K2CO3, Et3Ntoluene, 200 °C81%

MeO

NCO2Et

NMe

HO

NH

NMe

Me

1) BBr3

2) MeI 50%

Peat, A.J.; Buchwald, S.L. J. Am. Chem. Soc. 1996, 118, 1028.

77

Total Synthesis

NH2

MeO

OMe

NH2

MeO

OMe

BrBu4NBr3MeOH

DCM65%

HN

MeO

OMe

Br

K2CO3NaI74%

IK2CO3

MeI

96%

N

MeO

OMe

Br

i. Cp2Zr(Me)Cl t-Buli THF

ii. I2

N

I

OMe

MeO

I

N

I

OMe

MeO

Pd2(dba)3 (2.5 mol %)P(o-tolyl)3 (10 mol %)NaOtBu (1.4 equiv)

toluene, 80 °C72%

Pd/C (10 mol %)NH4CO2H

MeOH, reflux80% N

NMe

BnMeO

OMe

NH

NMe

MeO

OMe

Peat, A.J.; Buchwald, S.L. J. Am. Chem. Soc. 1996, 118, 1028.

BnNH2

NHBn

N

NH

O

O

Me

Damirone B

78

Synthesis of Analogs

N

ClCl

O O

R

NH2

R'Pd2(dba)3 (0.5 mol %)

XPhos (1.1 mol %)

K3PO4 (2.8 equiv)toluene, 110 °C

N

HNNH

O O

R

R' R'

HN

HNNH

O O N

HNNH

O ON

HNNH

O O N

HNNH

O O

N

HNNH

O O N

HNNH

O O N

HNNH

O O

TIPSTIPS

TIPS

PMPPMPTIPS

Cl Cl

F F

NO2O2N

Henneessy, E.J.; Buchwald, S.L. J. Org. Chem. 2005, 70, 7371.

79

Aryl Piperazine (large scale)

ClF3C NHHN

1.5 equiv

Pd2(dba)3 (0.1 mol %)L (0.4 mol %)

NaOtBu (1.4 equiv)

toluene, 90 °C, 2h

NF3C NH

93%

Buchwald, S.L.; Mauger, C.; Mignani, G.; Sholz, U. Adv. Synth. Catal. 2006, 348, 23.

80

Merck

N

BocHN

N Br Pd(OAc)2DPPF, NaOtBu

toluene, 80 °CHN Ph

Ph N

BocHN

N N Ph

Ph

Citric acid

N

BocHN

N NH2

86%3.6 kg

81

Wyeth

Br

R

R


NaOtBu (1.4 equiv)

toluene (0.7 M), 80 °C, 4 h

NHHN

1.2 equiv

N

R

R

NH

80% conv18 kg

82

Conclusion

XR

X : Cl, Br, I, OTf, Nf, Ts ... H

R : Becomes more and more functionalized

R2NH, RNH2, NH3

NH3 : Getting thereRNH2 : Many catalyst are doing the jobR2NH : Many catalyst are doing the job

R can be Aryl or AlkylPyrrole and other aromatic N-H can arylated

Other N :

H2N O

O

tBu H2NS

R

O

O

H2N

O

R RHN

O

R

Other than N :

OHR

-OH SHR

-SH R

O

R

O

R

O

Buchwald-Hartwig Coupling : Discovery, Optimization, and Applications

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