Literature Meeting March 25, 2008 Buchwald-Hartwig Coupling : Discovery, Buchwald-Hartwig Coupling : Discovery, Optimization, and Applications Optimization, and Applications David Marcoux Charette’s Laboratories X R HNR 2, Base NR 2 R
Dec 16, 2015
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-
Reductive Elimination
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 %)
P(o-tolyl)3 (4 mol %)NaOtBu (1.4 equiv)
Toluene, 100 °C50-95%
BrNPh
Ph
HNMePh (1 equiv)Pd(dba)2 (2 mol %)
P(o-tolyl)3 (4 mol %)NaOtBu (1.4 equiv)
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
Guram, A.S.; Rennels, R.D.; Buchwald, S.L. Angew. Chem. Int. Ed. Engl. 1995, 34, 1348.
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
Guram, A.S.; Rennels, R.D.; Buchwald, S.L. Angew. Chem. Int. Ed. Engl. 1995, 34, 1348.
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 %)
P(o-tolyl)3 (4 mol %)NaOtBu (1.4 equiv)
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
Guram, A.S.; Rennels, R.D.; Buchwald, S.L. Angew. Chem. Int. Ed. Engl. 1995, 34, 1348.
- 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 %)
NaOtBu (1.4 equiv)Toluene, 100 °C
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
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 %)
NaOtBu (1.4 equiv)Toluene, 100 °C
Ph
Me
96% ee
MePh
80%96% ee
H2N Ph
Me
98% ee
PhMe
60%70% ee
46
Bidentate Ligand
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 (1 mol %)BINAP (2 mol %)
NaOtBu (1.4 equiv)Toluene, 100 °C
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
Wagwag, S.; Rennels, R.A.; Buchwald, S.L. J. Am. Chem. Soc. 1997, 119, 8451.
Br Amine
Pd2(dba)3 (1 mol %)BINAP (2 mol %)
NaOtBu (1.4 equiv)Toluene, 100 °C
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
Pd2(dba)3 (1 mol %)BINAP (2 mol %)
NaOtBu (1.4 equiv)Toluene, 100 °C
R R
NR
X = OTf, Cl
Functionnal group tolerance
50
Ligand Screening
Br
Pd2(dba)3 (1 mol %)Ligand (2-4 mol %)
NaOtBu (1.4 equiv)toluene, 80 °C
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)
NaOtBu (1.4 equiv)toluene, 80 °C
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-
Reductive Elimination
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)
NaOtBu (1.4 equiv)toluene, 80 °C
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
Pd2(dba)3 (1 mol %)L (1 mol %)
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
Pd2(dba)3 (0.5 mol %)BINAP (1 mol %)
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
Specific Case: Ammonia
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
ii. HCl/neutralisationNH2
R
X : Cl, Br 1.2 equiv
PCy2L:
Ph3SiNH2
65
Specific Case: Ammonia
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
Specific Case: Ammonia
XR
i. Pd2(dba)3 (2 mol %) P(tBu)3 (2 mol %) toluene, RT, 12-30h
ii. HCl/neutralisationNH2
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
Specific Case: Ammonia
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
Specific Case: Ammonia
Br
i. Pd2(dba)3 (2 mol %) P(tBu)3 (2 mol %) LiCl (0.6 equiv) THF, 50 °C, 2h
ii. HCl/neutralisation
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
ii. HCl/neutralisation
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
Reductive Elimination
(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
Pd2(dba)3 (1 mol %)L (5 mol %)
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
Surry, D.S.; Buchwald, S.L. J. Am. Chem. Soc. 2007, 129, 10354.
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
Surry, D.S.; Buchwald, S.L. J. Am. Chem. Soc. 2007, 129, 10354.
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
Pd2(dba)3 (0.5 mol %)BINAP (1 mol %)
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