Download Cross-coupling: Catalytic C

Cross-coupling:
Catalytic C-C bond formation
Carbon-carbon bond formation is fundamental to all of
organic chemistry. Over the past thirty years,
organometallic coupling has been brought to a level of
practical importance.
1
Cross-coupling
Generalized cross-coupling (R1 and R2 = alkyl, aryl, alkenyl):
catalyst
R1-X + R2-M
Typically:
→ R1-R2 + M-X
catalyst = PdLn (sometimes NiLn)
X = halide
M = MgX
(Kumda coupling)
M = ZnX
(Negishi coupling)
M = SnR3
(Stille reaction)
M = BX2
(Suzuki reaction)
2
General mechanism of cross-coupling
LnPd(II)
R1 R2
reduction with R2-M
LnPd(0)
reductive
elimination
R1 X
oxidative
addition
LnPd
R1
LnPd
R2
X M
transmetalation
R1
X
R2 M
R = alkyl, vinyl, aryl
3
Kumada coupling
Kumada coupling was the first Ni or Pd-catalyzed cross-coupling reaction (1972).
X
+
MgBr
R2
P
Cl
Ni
P
Cl
R2
0.7 mol%
1-butylbenzene
"Grignard reagent"
The advantage of this reaction is the direct coupling of Grignard reagents with organohalides. The coupling of Grignard reagents with alkyl, vinyl or aryl halides provides an
economic transformation; only the limited functional group tolerance can be a problem.
4
Kumada coupling
Phosphines (arsines or NHC) are necessary in cross-coupling reactions to prevent
catalyst decomposition to metal.
X
R2
P
Cl
Ni
P
Cl
R2
+
0.7 mol%
MgBr
1-butylbenzene
"Grignard reagent"
Effect of the phosphine, X = Cl
Effect of the halide, L = dppp
L=
% Yield
X=
% Yield
dppp
100
F
31 (2h)
2 PPh3
dppe
84
79
Cl
95 (3h)
dmpe
47
Br
54 (4.5)
dppb
28
I
80 (3 h)
1,3-Bis(diphenyphosphino)propane, dppp, is the optimal ligand for a wide range of aryl
and vinyl halides. Unlike other cross-coupling methods, aryl and vinyl chlorides exhibit
higher reactivity than their Br and I analogs.
Kumada, Bull. Chem. Soc. Jpn. 1976, 49, 1958.
5
Applications of Kumada coupling
Industrial production of styrene derivatives (Hokka Chemical Industry, Japan):
MgCl
Ph2
P
Cl
Ni
P
Cl
Ph2
t-BuO
+
t-BuO
0.1 mol%
1-tert-butoxy-4-vinylbenzene
Cl
Banno, JOMC 2002, 653, 288.
Functionalization of heterocyclic halides:
N
Br
+
R MgCl
Ph2
P
Cl
Ni
P
Cl
Ph2
N
0.5 - 1 mol%
S
2-(thiophen-2-yl)pyridine
Kumada, Tetrahedron 1982, 38, 3347.
N
SiMe3
2-((TMS)methyl)pyridine
N
C4H9
2-butylpyridine
6
Application of Kumada coupling
Kumada coupling is the method of choice for low-cost synthesis of unsymmetrical sterically
hindered biaryls:
Cl
O
O
R
Ni
O
O
R
3 mol%
+
BF4
i
Pr
N
Pri
N
BrMg
Pri Pri
R = CF3 (91%)
H (99%)
CH3 (95%)
OCH3 (98%)
3 mol%
NHC bind strongly to
transition metals
Hermann, ACIEE 2000, 39, 1602.
7
Stereoselective Kumada coupling
The Ni-catalyzed Kumada coupling is stereoselective for vinyl halides but nonstereospecific for alkenyl Grignards:
Ph
Br
P
P
Ni
Cl
Cl
(Z)-β-bromostyrene
+
MeMgBr
Ph
Me
1-((Z)-propenyl)benzene
(E)-β-bromostyrene
P
Ph
P
Br
Ni
Cl
Cl
Ph
Me
+
1-((E)-propenyl)benzene
MeMgBr
BrMg
Me
(Z)
+
Br
P
P
Ni
Cl
Cl
Ph
Me
(Z) 27% + (E) 73%
Palladium (0) catalysts, e.g. Pd(PPh3)4, have been shown to be stereospecific for
alkenyl Grignard reagents. (Linstrumelle, TL 1978, 191).
8
Negishi coupling
Negishi Coupling, published in 1977, was the first reaction that allowed the preparation of
unsymmetrical biaryls in good yields. The versatile nickel- or palladium-catalyzed coupling of
organozinc compounds with various halides (aryl, vinyl, benzyl, or allyl) has a broad scope,
and is not restricted to the formation of biaryls.
catalyst
R1-X + R2-ZnX
→ R1-R2 + ZnX2
R1 = alkenyl, aryl, allyl, benzyl, propargyl
R2 = alkenyl, aryl, alkynyl, alkyl, benzyl, allyl
Cataysts:
NiCl2(PPh3)2 + 2(i-Bu)2AlH →
(PPh3)2Ni(0)
Pd(PPh3)4 → (PPh3)2Pd (0) + 2PPh3
Negishi, Acc. Chem. Res., 1982, 15, 340
9
Application of Negishi coupling
Alkylzinc bromides can be efficiently prepared by insertion of iodine- activated zinc metal
into alkyl bromides in N,N-dimetylacetamide (DMA). The in situ Ni- or Pd-catalyzed Negishi
cross-coupling gives alkylarenes in excellent yields.
1.5 eq Zn (dust)
5 mol% I2
R ZnBr
R Br
DMA, 80 °C, ca. 3 h
R = n-Oct, > 90%
R - alkyl or functionalized alkyl groups
(-CN, -COOR, -Cl, -CH=CH2)
R ZnBr
0.8 eq ArX
Cat: 2 mol% NiCl2(PPh3)2
or 2 mol% Pd(PPh3)4
R Ar
r.t. ca. 1 h
71 - 90%
S. Huo, Org. Lett. 2003, 5, 423.
10
Stille coupling
Stille coupling is a versatile C-C bond forming reaction between stannanes and halides or
pseudohalides, with very few limitations on the R-groups. Advantages:
-Highly functional group tolerant
-Stannanes are readily synthesized and are air and moisture stable (often distillable).
Pd-catalyst
R1-X + R2-SnBu3
→ R1-R2 + XSnBu3
Catalysts: (commercially available) Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3 + PR3 or AsR3
The easy of transfer from Sn: alkynyl > alkenyl > aryl > benzyl = allyl > alkyl.
The main drawback is the toxicity of stannanes and their low polarity, which makes them
poorly soluble in some solvents. Boronic acids and their derivatives undergo much the same
chemistry in what is known as Suzuki coupling. Improvements in the Suzuki coupling may
soon lead to the same versatility without the drawbacks of using tin compounds.
11
Stille coupling
Well-elaborated methods allow the preparation of different products from all of the
combinations of halides and stannanes depicted below.
O
R
R3Sn Alk(H)
Cl
R
R
R3Sn
X
R'
X = Cl, Br
R"
R"
R
R
R'
X
+
ArylH2C X
Aryl
X
CO2R
H
X
R'
R3Sn
X = I, OTf
R"
R'
R'
R"
X = Cl, Br
R3Sn CH2Aryl
X = Br, I
R3Sn Aryl
X = Br, I
R3Sn
CR'
12
Stille coupling: extraordinary functional group tolerance
The successful cross-coupling in the presence of an epoxide, alcohol, carboxylic acid and
several olefin groups illustrates compatibility of the Stille reaction with common functional
groups. This example is a step in the total synthesis of (+)-Amphidinolide. Note retention of
configuration for the sp2 carbon, which is typical for Stille coupling.
O
O
Bu3Sn
OR
Pd2(dba)3 (0.2 eq)
AsPh3 (0.8 eq.)
Cu(I) tiophene-2-carboxylate
NMP, 35 °C
HO
+
O
O
OR
HO
I
OH
Williams, JACS 2001, 123, 765.
OH
O
50 %
O
O
Ph
O
Ph
Ph
Pd O
Ph
Ph
Pd
Ph
Pd2(dba)3
13
Stille coupling: ligand effect.
Large rate enhancements (102–103) occur with ligands which are poor σ-donors:
AsPh3 > P(2-furyl)3 > PPh3
No correlation exists between the cone angle of L and observed rates, indicating that the
effect is not of steric origin.
Pd2(dba)3 + L (1 : 2)
THF, 50 °C
I
O
O
P
O
+
Bu3Sn
tri(2-furyl)phosphine
Farina, JACS 1991, 113, 9585.
Kinetic studies support a mechanism involving rapid oxidative addition followed by the ratedetermining transmetalation which may involve solvent/ligand exchange. The dissociation of
L is more favorable for poor σ-donors such as AsPh3.
Pd2(dba)3 + L
THF, 50 °C
I
L
S = solv
Pd I
L
S
Bu3Sn
Pd I + L
L
Bu3Sn
Espinet, JACS 1998, 120, 8978; JACS 2000, 122, 11771.
I
14
Mechanism of Pd/Sn transmetalation
The mechanism of transmetalation is highly dependent on reaction conditions, and is a
subject of ongoing debate in the literature.
δ−
X
R' Pd
L
H
H
C
R"
δ+
Electrophilic substitution, SE2
δ+
SnR3
X
X
δ+
SnR3
R' Pd δ+
L
C
H
R' Pd
δ−
H
H
SnR3
C (sp2)
L
R"
Stille, JACS 1983, 105, 669.
Espinet, JACS 1998, 120, 8978; JACS 2000, 122, 11771.
15
Stille coupling: copper effect
Addition of CuI can increase the reaction rate by > 102
Pd2(dba)3 (5 mol%)
PPh3 (20 mol %)
I
+
mol% CuI
dioxane, 50 °C
Bu3Sn
Farina& Liebeskind J.Org.Chem. 1994, 59, 5905
relative rate
0
1
10
114
The rate increase is attributed to the free ligand scavenging ability of CuI; strong ligands in
solution are known to inhibit the rate-limiting transmetalation step. When a weakly coordinating
ligand AsPh3 is used, addition of CuI has a less dramatic effect and the rate increases only by
34%. Transmetalation of Bu3Sn with CuCl may also contribute to the increase of the rate:
+ CuX
Bu3Sn
[Cu]
+ Bu3SnX
Stoichiometric Cu itself can mediate cross-coupling reactions under mild conditions, without
O
Pd:
CuO
SnBu3
CH3 O
+
Cl
I
CH3
S
CH3 O
1.5 equiv
CH3
NMP, 23 °C, 15 min
Allred & Liebeskind J. Am. Chem. Soc. 1996, 118, 2748.
Cl
16
Stille coupling for aryl chlorides
Yields are low for conventional Stille coupling of aryl chlorides. This can be due to the strength
of the Ar-Cl bond (Ph-X: Cl (96) Br (81)> I (65 kcal/mol)). The low cost of aryl chlorides,
however, makes them very attractive substrates. An improved method was developed with the
use of L = P-t-Bu3 and CsF.
Additive (1.1 eq)
Pd2(dba)3 (1.5 %)
6% P-t-Bu3
Cl
+
dioxane, 100 °C
1-methyl-4-vinylbenzene
Bu3Sn
Example: synthesis of sterically hindered biaryls.
Cl
2-chloro-m-xylene
+ Bu3Sn
mesityl stannane
none
12%
NEt3
16%
CsCO3
40%
NaOH
42%
KF
28%
CsF
50%
CsF (2.2 eq)
59%
3% Pd(PBut3)2
2.2 eq CsF
dioxane, 100 °C
Fu, JACS 2002, 124, 6343; Angewandte 1999, 38, 2411..
89 %
17
Suzuki coupling
The original Suzuki reaction was coupling of an aryl boronic acid with an aryl halide using a
palladium catalyst. Recent developments have broadened the possible applications
enormously so that the scope of the reaction partners now includes alkyls, alkenyls, and
alkynyls.
B(OH)2
CHO
Pd(OAc)2 (0.3 mol%)
PPh3 (0.9 mol%)
Na2CO3 (1.2 equiv)
CHO
+
Br
i-PrOH, H2O, reflux
86%
Due to the stability, ease of preparation and low toxicity of the boronic acid compounds, there
is currently widespread interest in applications of the Suzuki coupling, with new developments
and refinements being reported constantly.
A variety of organoboron reagents can be used:
O
O
R B
O
diisopropyl alkylboronate
O
2-alkyl-1,3,2dioxaborinane
O
O
R B
R B
R B
O
catecholborane
R B
O
pinacolborane
9-BBN
9-borabicyclo[3.3.1]nonane
Miyaura & Suzuki, Chem. Rev. 1995, 95, 2457; Suzuki A. J. Organomet. Chem. 1999, 576, 147.
18
General features of Suzuki coupling
• Relative reactivity of leaving groups:
I – > OTf – > Br – >> Cl –
• Relative rates of reductive elimination from palladium(II) complexes:
aryl–aryl > alkyl–aryl > n-propyl–n-propyl > ethyl–ethyl > methyl–methyl
Catalyst and ligands: The most commonly used system is Pd(PPh3)4.
Certain reactions need more specialized combinations (e.g. the successful coupling of
alkylboranes requires PdCl2(dppf) as a catalyst).
PPh2
Ph2
P
Fe 99°
Fe
PPh2
P
Ph2
Cl
Pd
88°
Cl
dppf
Dppf favors reductive elimination vs. competitive β-H elimination for two reasons: (1) the
bidentate ligand enforces a cis geometry between the alkyl and vinyl/aryl substituents; (2) the
large bite angle of dppf results in a smaller angle between the alkyl and vinyl/aryl substituents.
This is thought to promote reductive elimination event by increasing orbital overlap.
19
Mechanism of Suzuki coupling
The mechanism is related to other palladium-catalyzed coupling reactions involving oxidative
addition, transmetalation, and reductive elimination steps. The details of the transmetalation
step are unresolved; boron "ate" complexes are frequently invoked.
LnPd(0)
R1 R 2
R1 X
reductive
elimination
R1
LnPd(II)
LnPd(II)
2
R
LnPd
2
R
(II)
R
OR
R1
R'
X
Base:
MOR (M = Na, K,Tl)
1
BY2OR
transmetalation
Transmetalation – an
“ate” compound. Note
retention of configuration
oxidative
addition
MX
LnPd
O
C
B
Tl - most effective!
BY2
Soderquist, J. Org. Chem. 1998, 63, 461
Boron-carbon bonds are covalent/non-ionic. As a result, organoboron compounds are
generally insensitive to water and are compatible with most organic functionality. For the same
reason, these intermediates do not readily undergo transmetalation and must be activated with
a base.
20
Coupling of aryl chlorides
Aryl chlorides are unreactive towards Suzuki cross couplings. Fu was the first to discover that
bulky, electron rich ligands could overcome this reactivity issue.
Cl
B(OH)2
1.5% Pd2(dba)3
3.6% Phosphine
2 equiv CsCO3
+
dioxane, 80 °C
Fu, Angewandte 1998, 37, 3387
Bidentate ligands are ineffective. The optimal phosphine to ligand ratio is between 1 and 1.5.
This suggests that the active catalyst has a single phosphine attached. Two examples of such
14-e species have been crystallographycally characterized:
21
Hartwig, JACS 2002, 124, 9346; 2004, 126, 1184
Coupling of aryl chlorides
Conditions for Suzuki coupling of aryl chlorides at 23 °C have been developed.
Ac
Cl
2 mol%
(HO)2B
methyl 4-chlorobenzoate
Ac
PBut2
+
MeO2C
Pd(OAc)2 (1 mol%)
KF (3 equiv)
3-acetylphenylboronic acid
MeO2C
91 %
THF, rt, 2 h
Sp2-sp3 coupling:
Pd(OAc)2 (0.5 mol%)
KF (3.3 equiv)
Cl
PBut2
+
MeO2C
methyl 4-chlorobenzoate
n-C6H13 B
1 mol%
THF, 65 °C, 2 h
C6H13
MeO2C
83 %
Buchwald, Angew. Chem.1999, 38, 2413; JACS 1999, 121, 9550
22
Buchwald ligands
PBut2
PBut2
Me2N
PCy2
PCy2
Me2N
The electron rich nature of the phosphines promotes oxidative addition and tight binding to the
metal (prevents Pd black formation). The steric bulk of the ligand promotes reductive
elimination. The phenyl group may be oriented such that π-interaction with the metal occurs.
Alternatively, the NMe2 group can coordinate, when present.
Buchwald, Angew. Chem.1999, 38, 2413
23
NHC in Suzuki coupling
Nucleophilic N-heterocyclic carbenes (imidazol-2-ylidenes): these so called "phosphine
mimics" do not dissociate from the metal center, and thus an excess of ligand is not required
to prevent aggregation of the catalyst to yield the bulk metal.
PdCl(η3-C3H5)(NHC)
Nolan, J. Org. Chem. 1999, 64, 3804.
24
Stereospecific Suzuki coupling
• Oxidative addition is known to proceed with retention of stereochemistry with vinyl halides
and with inversion with allylic or benzylic halides.
• Reductive elimination proceeds with retention of stereochemistry:
O
HB
OR
D
OR
BBN-H
D
OR
H
D
H
O
D
H
I
D
B
H
Pd(dppf)Cl2
NaOH
D
H
Representative stereospecific Suzuki coupling: the configurations of the vinylborane and vinyl
halide are retained. Excellent method for the construction of conjugated dienes.
O
HB
C4H9
H
O
catecholborane
syn hydroboration
Br
C4H9
H
Ph
H
C4H9
O
B
O
Pd(PPh3)4 (1 mol%)
NaOEt, benzene
reflux
H
H
Ph
86 %
25
Comparison of Suzuki and Stille coupling
phenylboronic acid
26