Contribution of heterobifunctional ligands to transition metal-catalysed C-C coupling reactions

Article abstract of DOI:10.3906/kim-1507-73

In this account the authors' latest results in C-C coupling catalysis are reviewed. First, an efficient catalytic system for the Kumada-Tamao-Corriu coupling reaction based on NHC-phosphine (NHC = N-heterocyclic carbene) nickel complexes is presented. Then the use of palladium complexes of chiral ferrocenyl NHC-phosphines in the asymmetric Suzuki-Miyaura coupling reaction is reported. High catalytic activities and moderate enantioselectivities (ee up to 46%) were obtained. Chiral ferrocenyl phosphine-ethers were also tested in the asymmetric Suzuki-Miyaura reaction yielding good activities and moderate enantioselectivities (ee up to 37%). Finally, the original synthesis of a ferrocenyl rhodium(III) complex and its successful use as catalyst for a C-C coupling reaction via C-H activation of 2-phenylpyridine is presented.

Full text of DOI:10.3906/kim-1507-73

Turk J Chem
Turkish Journal of Chemistry
(2015) 39: 1158 – 1170
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1507-73
Review Article
Contribution of heterobifunctional ligands to transition metal-catalysed C–C
coupling reactions
Agn`es LABANDE1,2,∗, Eric DEYDIER1,2,3,∗, Eric MANOURY1,2,∗
Jean-Claude DARAN1,2, Catherine AUDIN3, Rinaldo POLI1,2,4
1CNRS, LCC (Laboratoire de Chimie de Coordination), Toulouse, France
2University of Toulouse, Toulouse, France
,
3IUT A Paul Sabatier, Department of Chemistry, Castres, France
4Institut Universitaire de France, Paris, France
Received: 24.07.2015
•
Accepted/Published Online: 10.09.2015
•
Printed: 25.12.2015
Abstract: In this account the authors’ latest results in C–C coupling catalysis are reviewed. First, an efficient
catalytic system for the Kumada–Tamao–Corriu coupling reaction based on NHC-phosphine (NHC = N-heterocyclic
carbene) nickel complexes is presented. Then the use of palladium complexes of chiral ferrocenyl NHC-phosphines in the
asymmetric Suzuki–Miyaura coupling reaction is reported. High catalytic activities and moderate enantioselectivities
(ee up to 46%) were obtained. Chiral ferrocenyl phosphine–ethers were also tested in the asymmetric Suzuki–Miyaura
reaction yielding good activities and moderate enantioselectivities (ee up to 37%). Finally, the original synthesis of a
ferrocenyl rhodium(III) complex and its successful use as catalyst for a C–C coupling reaction via C–H activation of
2-phenylpyridine is presented.
Key words: Chiral ferrocenyl ligands, NHC ligands, P,O ligands, palladium, Kumada–Tamao–Corriu reaction, Suzuki–
Miyaura cross-coupling, asymmetric catalysis
1. Introduction
Cross-coupling reactions have become one of the most powerful reactions to access functionalised aromatics and
are involved in key steps in the synthesis of molecules for pharmaceutical and agrochemical applications.1−4
Many transition metals have been used to catalyse these reactions, aided by a great variety of ligands ranging
from simple, commercial phosphines to complex custom-made molecules. It is known that the nature of
the ligand strongly determines the activity and the selectivity of the catalyst. Therefore, its design is of
prime importance for a given application, particularly when asymmetric catalysis is involved. Ligand design
directed toward catalytic applications has been a major focus in our group for many years, particularly
concerning heterobifunctional ligands that can produce robust yet very active catalysts by the careful choice
of their coordinating units and that can be prepared easily in enantiopure form when asymmetric induction is
required.5−9 In this area, chiral phosphines have played a significant role and, among the numerous phosphine
ligands reported to date, ferrocenyl phosphines constitute a distinct class of ligands attracting increasing
interest.10−12 More recently, N-heterocyclic carbene (NHC) ligands have also emerged as powerful ligands
for catalysis and asymmetric catalysis.13,14
∗Correspondence: agnes.labande@lcc-toulouse.fr, eric.deydier@iut-tlse3.fr, eric.manoury@ lcc-toulouse.fr
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LABANDE et al./Turk J Chem
We have recently developed promising ferrocenyl and NHC ligands as racemic mixtures or in enantiomer-
ically pure forms when chiral and started investigating their efficiency in catalysis. Cross-coupling reactions
naturally came to us as interesting targets, as room for improvement was available in terms of catalyst de-
sign, particularly for challenging reactions such as the asymmetric Suzuki–Miyaura cross-coupling of hindered
aromatics15−17 or the direct C–H functionalisation of aryl substrates.18 Our first objective, however, was the
study of the nickel-catalysed Kumada–Tamao–Corriu (KTC) reaction for the coupling of less reactive but more
available aryl chlorides with arylmagnesium halides.
2. Kumada–Tamao–Corriu with NHC-phosphine ligands
When our investigations started in 2004, most catalysts were based on phosphine ligands, which are air-sensitive
and often gave poorly stable catalysts.19,20 In 1994, Herrmann first showed the efficiency of N-heterocyclic
carbene ligands in catalysis, and more particularly in palladium-catalysed cross-coupling reactions.21,22 Later,
the same authors described catalytic systems based on Ni(acac)2 and imidazolium salts, precursors of N-
heterocyclic carbenes (A, Figure 1), for the KTC reaction.23 The NHC/Ni catalysts, generated in situ by
deprotonation of the imidazolium salts, proved very active for the coupling of more demanding (hetero)aryl
chlorides with arylmagnesium halides at room temperature and more selective than palladium-based NHC or
phosphine catalysts for similar substrates.
Cl
Ar
Ar
=
or
Ar
2,4,6-trimethylphenyl
2,6-diisopropylphenyl
N
N
(Mes)
(Dipp)
+
/
Ni(acac)2
A
Figure 1. First NHC ligands used in the nickel-catalysed Kumada–Tamao–Corriu reaction.23
On these premises, we developed heterobifunctional ligands bearing one N-heterocyclic carbene donor,
capable of creating a very strong bond with the metal centre, and one phosphine donor that possesses different
stereoelectronic properties.24,25 We envisaged that the association of these two donors in a chelating ligand could
give robust yet active catalysts, and that the different stereoelectronic environment would enforce a different
trans influence on the incoming substrates, thus bringing interesting selectivity issues.
The synthesis of several phosphine-imidazolium salts, differing by the tether length as well as the
imidazolium N-substituent, was thus developed and 1a–d (Figure 2) were obtained in good yields in 3 steps
from substituted imidazoles. We envisioned that the phosphine-imidazolium salts 1a–b, with a tether length of
two carbons, would give the most active catalysts since they would form 6-membered metallacycles with nickel,
similar to the efficient Ni/dppp system. The reaction of these salts with nickel(II) precursors gave air-stable
zwitterionic complexes 2a–d, with coordination of the phosphine only. All complexes are paramagnetic and
possess a distorted tetrahedral geometry. Upon deprotonation of the imidazolium moiety and generation of
the N-heterocyclic carbene, however, the resulting complexes are diamagnetic and likely adopt a square-planar
geometry around the metal. An NMR monitoring of the deprotonation of 2a by methyl lithium confirmed the
presence of two different nickel NHC-phosphine complexes, attributed to a monomeric and a dimeric species.
1159

LABANDE et al./Turk J Chem
n
N
+
Br
N
Ph2P
Br
NiBr2(DME) or NiBr2(MeCN)2
THF, rt, 30 min to 1h
Ar
Ar
N
N
Ph2P
+
Ni
n
Br
Br
1a-c
2a: Ar = 2,4,6-Me3C6H2
n = 1 (95%)
2b: Ar = 2,6-i-Pr2C6H3
n = 1 (92%)
2c: Ar = 2,4,6-Me3C6H2
n = 2 (79%)
N
+
BF4
N
Ph2P
NiCl2, NaCl
Ar
N
N
Ph2P
+
Ni
THF, 60°C, 18h
Cl
Cl
Cl
2d (63s%)
1d
Figure 2. Synthesis of the phosphine-NHC nickel complexes used in the Kumada–Tamao–Corriu reaction.24,25
The activity of all zwitterionic complexes in the KTC coupling was evaluated in the presence of a range of
(hetero)aryl chlorides and a sterically demanding aryl bromide (Table 1). The reactions were run in the presence
of 3 mol% catalyst at room temperature in THF and were stopped after 18 h to allow for a direct comparison
of activities with the different substrates. The N-heterocyclic carbene complexes were presumably generated at
the start of the reaction, as the colour of the reaction mixture changed from blue-green to brown-orange upon
addition of the Grignard reagent.
Table 1. KTC reaction of aryl chlorides with arylmagnesium halides catalysed by complexes 2a–c.
Entry R1
E
N
C
C
C
C
C
N
C
C
C
C
R2
H
H
H
H
H
H
X
Cat. 2a[b] Cat. 2b[b] Cat. 2c[b] IPr/Ni(acac)[2c]
1
H
Cl > 99
Cl 37
Cl 86
Cl 95
Cl 78
> 99
53
> 99
29
> 99
96
2
3
4
5
6
7
4-CF3
4-CH3
4-OCH3
2-CH3
bromomesitylene
H
96
92
63
80
81
71
82
3
23
7
73
5
Cl
4
4-OCH3 Br > 99
4-OCH3 Br 36
4-OCH3 Br 99
4-OCH3 Br 92
4-OCH3 Br 48
> 99
33
98
87
> 99
42
76
89
> 99
> 99
93
88
77
8
9
4-CF3
H
10
11
4-CH3
2-CH3
87
12
[a] Conditions: 1.0 eq aryl halide, 1.5 eq aryl Grignard, 3 mol% 1a–c, THF, 25 ◦ C, t = 18 h. [b] GC yield using
[c]
diethyleneglycol-di-n-butylether as the internal standard.
Reference 23.
The nature of the halogen on the nickel centre did not prove important as similar yields of 4-methoxybip-
henyl were obtained with complexes 2a and 2d (not detailed in Table 1). No noticeable influence of the aryl
substituent borne by the NHC was observed since complexes 2a (Ar = Mes) and 2b (Ar = Dipp) showed
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LABANDE et al./Turk J Chem
similar activities. However, complex 2b was slightly more selective than 2a in many cases. The presence
of the phosphine did not prove detrimental as both complexes showed an equal or slightly better activity
than the Ni(acac)2 /IPr system described by Herrmann, and they even showed an improved selectivity for
the heterocoupling product in most cases. Two exceptions were observed with bulky bromomesitylene (entry
6) and with p-chloro(trifluoromethyl)benzene (entries 2 and 8), where conversions were low. In the latter
cases, the problem appeared closely related to the simultaneous presence of a CF3 group on the substrate
and a phosphine in the ligand system, showing one limitation of our heterobifunctional ligand compared to
Herrmann’s monodentate NHC. Finally, as expected, the presence of a seven-membered cycle in the case of
complex 2c slowed the reaction down in most cases but not all (entries 6, 8, and 10).
One major drawback of our systems, as with all in situ generated catalysts, is the uncertain nature of the
species that truly catalyses the reaction. However, we can assume that the two nickel NHC-phosphine complexes
observed by NMR after deprotonation with methyllithium (vide supra) correspond to the species generated after
addition of the Grignard reagent, although we do not know the relative activity of the monomeric versus the
dimeric species.
Due to the high activity and high selectivity of these complexes for the cross-coupling of aryl chlorides with
arylmagnesium halides, we can assert that the choice of a bidentate NHC-phosphine ligand was well adapted
and their potential for the coupling of other, more challenging substrates should be investigated further.26,27
3. Asymmetric Suzuki–Miyaura reaction for the synthesis of axially chiral biaryls
The asymmetric version of the palladium-catalysed Suzuki–Miyaura cross-coupling reaction has only been
developed in the last 15 years because of the difficulty of finding efficient catalysts enabling the coupling of
very hindered substrates. Indeed, the axial chirality of the biaryl products is induced by the restricted rotation
around the aryl–aryl bond (so-called atropisomerism) and to exhibit such chirality there must be at least three
ortho substituents about the biaryl axis. Atropisomerism is encountered for instance in a class of chiral ligands
frequently used in asymmetric catalysis, such as BINAP, in chiral organocatalysts like the TRIP-type chiral
Brønsted acids, but also in natural products like Vancomycin (Figure 3), underlining the need to develop efficient
strategies toward their synthesis in optically pure form.
OH
O
NH
2 HO
O
O
OH
OH
OAc
O
PPh2
PPh2
O
MeO
MeO
O
O
O
O
Cl
O
OMe
H
BINAP
Steganacin
OH
OMe
OH
OH
HO
Cl
H
O
O
H
N
O
R
O
N
NHMe
N
N
N
H
O
H
H
O
O
HN
O H2N
O
HO
P
OH
HO2C
NH
O
R
OH
OH
TRIP-type chiral acids
HO
Korupensamine A
Vancomycin
Figure 3. Examples of products containing a chiral biaryl unit.
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LABANDE et al./Turk J Chem
Buchwald28,29 and Cammidge30,31 almost simultaneously reported the first examples of the enantiose-
lective Suzuki–Miyaura cross-coupling reaction in 2000 and a wide range of catalytic systems has been reported
since. However, as underlined in recent reviews, even if excellent activities and enantioselectivities (>98%) have
been reported for some systems, no ligand or catalyst has allowed reaching high levels of enantioselectivities
for a large range of substrates.10−12 Some trends emerged nonetheless in terms of ligand design, as it was
shown that bulky, electron-rich ligands allowed stabilising very reactive 14e- palladium species. Two classes of
chiral ligands were consistently used and proved their efficiency, i.e. ligands based on an atropisomeric biaryl
backbone and planar chiral ferrocenyl ligands. In this last category, various P,P, P,N, P,O, or P chiral ferrocenyl
ligands (Figure 4) have been synthesised by different groups and used with different levels of success for this
reaction.30−37
PCy2
PPh2
PPh2
NMe2
Fe
Fe
PPh2
Ph
NMe2
PPh2
NMe2
NMe2
PAr2
PCy2
NMe2
NMe2
PPh2
PPh2
Fe
Fe
Fe
Fe
Fe
Ar = 4-OMe-3,5MePh
Ar = 4-CF3Ph
O
PPh2
O
OMe
PCy2
PPh2
Fe
Fe
Fe
Ph
PCy2
PCy2
PPh2
PCy2
Fe
Fe
Fe
Fe
Figure 4. Examples of P,P, P,N, P,O, and P chiral ferrocenyl ligands used for asymmetric Suzuki–Miyaura reaction.
Our group has expertise in the synthesis of planar chiral ferrocenyl ligands for various catalytic applicat-
ions5−9 and we thus envisioned that we could build on this to design new ligands for the asymmetric Suzuki–
Miyaura reaction. We considered two different approaches for the synthesis of the chiral ligands: our experience
in the synthesis of functionalised N-heterocyclic carbenes prompted us to develop a chiral version of the strongly
σ-donating NHC-phosphine ligand;38,39 on the other hand, bulky monodentate or bidentate hemilabile ligands
are efficient for this reaction, and therefore ferrocenyl P,O ligands were also evaluated.40 Both types of ligands
are based on the relatively inexpensive, commercial reagent N,N-dimethylaminomethylferrocene, whereas most
other chiral ligands based on the ferrocene backbone are accessible starting from Ugi’s amine. They were
1162

LABANDE et al./Turk J Chem
prepared in a two-step synthesis from 2-thiodiphenylphosphino(hydroxymethyl) ferrocene, 3 (Figure 5). This
precursor can be prepared in multigram quantities and isolated either as a racemic mixture or in each one of the
two enantiomerically pure forms, giving direct access to planar chiral ligands of either absolute configuration.41
Its functionalisation is performed in a one-pot process by successive additions of a strong acid (HBF4) and the
appropriate imidazole (Im), benzimidazole (BIm) or alcohol reagent.
N
N
N
N
1. HBF4, CH2Cl2, rt
PPh2
R
PPh2
R
Raney Ni
MeCN, rt
-
-
S
Fe
BF4
Fe
BF4
2. N-R imidazole, rt
or
N-R benzimidazole, rt
4a Im, R=Me
4b Im, R=Mes
5a Im, R=Me
5b Im, R=Mes
4c Im, R=CH2Mes
4d BIm, R=Me
5c Im, R=CH2Mes
5d BIm, R=Me
5e BIm, R=CH2Mes
OH
PPh2
4e BIm, R=CH2Mes
S
Fe
R'OH
EtOH
R'
O
R'
a
O
3
1. HBF4, CH2Cl2, rt
2. R'OH, rt
PPh2
PPh2
P(NMe2)3
toluene
b
HO
S
Fe
Fe
7a-c
(reflux)
c
6a-c
HO
Figure 5. Synthesis of chiral phosphine-imidazolium proligands 5a–5e and chiral phosphine-ether ligands 7a–7c.
3.1. Catalytic application of P,NHC bidendate ligands
The use of these ligands necessitates first to synthesise and isolate the palladium catalyst as the in situ formation
of the latter is not well controlled. The complexes were prepared in moderate to good yields (31%–75%) from two
palladium precursors: PdCl2 (MeCN)2 or PdCl2 (PhCN)2 led to the neutral complexes 8 while [Pd(allyl)Cl]2
gave the cationic complexes 9 (Figure 6). They have been fully characterised by NMR, mass spectrometry, and
X-ray diffraction.
PdCl2(MeCN)2
or
PdCl2(PhCN)2
N
N
R
8a Im, R=Me
8c Im, R=CH2Mes
8d BIm, R=Me
P
Pd Cl
Cl
Ph2
Fe
8e BIm, R=CH2Mes
tBuONa, MeCN
50°C
N
N
PPh2
-R
Fe
BF4
5a Im, R=Me
5b Im, R=Mes
R
N
N
9a Im, R=Me
9b Im, R=Mes
5c Im, R=CH2Mes
5d BIm, R=Me
5e BIm, R=CH2Mes
[PdCl(allyl)]2
P
Pd
Ph2
Fe
tBuONa, MeCN
-
BF4
50°C
Figure 6. Synthesis of chiral phosphine-NHC palladium complexes 8a, 8c–8e, and 9a–9b.
1163

LABANDE et al./Turk J Chem
Preliminary catalytic tests were carried out for the coupling between aryl bromide and phenylboronic
acid with the racemic complexes in order to assess the catalyst activity and to optimise the reaction conditions.
Toluene, K2 CO3 , and 0.1–0.5 mol% catalyst were chosen respectively as solvent, base, and catalyst loading for
the subsequent asymmetric coupling of binaphthalene compounds (Figure 7; Table 2). The reaction time was
B(OH)2
Pd cat.
8a, 8c-e or 9a-b
R2
R1
R2
+
R1
toluene, Base
Br
Figure 7. Asymmetric Suzuki–Miyaura coupling reaction of naphthalene derivatives.
Table 2. Asymmetric Suzuki–Miyaura reaction between naphthyl bromides and naphthylboronic acids using P-NHC
ligands.a
Entry Pd cat. (mol%) R1
R2 T (◦C) Reaction time (h) % Yieldb % eec
1
2
3
4
5
6
7
8
8a-(S) (0.5)
8a-(R) (0.1)
8a-(R) (0.5)
8a-(S) (0.5)
8a-(R) (0.5)
8c-(S) (0.5)
8d-(S) (0.5)
8e-(S) (0.5)
9a-(S) (0.5)
9b-(S) (0.5)
8a-(R) (0.1)
8a-(S) (0.5)
8a-(R) (0.5)
8c-(S) (0.5)
8d-(S) (0.5)
8e-(S) (0.5)
9a-(S) (0.5)
9b-(S) (0.5)
8a-(R) (0.1)
8a-(S) (0.5)
8a-(R) (0.5)
8c-(S) (0.5)
8d-(S) (0.5)
8e-(S) (0.5)
8e-(S) (2.0)
9a-(S) (0.5)
9b-(S) (0.5)
8a-(S) (0.5)
8c-(S) (0.5)
8d-(S) (0.5)
8e-(S) (0.5)
H
Me
Me
Me
Me
Me
Me
Me
Me 40
24
24
8
0
-
38
39
40 (S)
42 (R)
46 (S)
9 (S)
37 (S)
-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
70
40
40
40
40
40
40
40
40
70
40
40
40
40
40
40
40
70
40
40
40
40
40
40
40
40
40
40
40
40
89
57
88
88
58
48
47
0
86
86
95
93
65
54
57
30
82
89
95
92
22
65
62
54
14
0
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
9
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
19
33
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
35 (R)
33 (S)
31 (R)
17 (S)
22 (R)
28
< 2
30
23 (R)
24 (S)
26 (R)
13 (S)
23 (R)
28 (R)
10
-
-
-
-
0
0
0
0
-
a Reagents and conditions: naphthyl bromide (1.0 equiv), boronic acid (1.2 equiv), Pd cat., K2 CO3 (2.4 equiv), toluene.
b Isolated yield. c Determined by HPLC with a Chiracel-OJ column. d The commercial 1-bromo-2-methylnaphthalene
contains ca. 6% of 2-methylnaphthalene.
1164

LABANDE et al./Turk J Chem
fixed at 24 h in order to maximise conversions even if complex 8a (0.1 mol%) was found to give 83% yield of
biaryl after only 1 h at 70 ◦ C.
As observed by numerous research groups, the reaction is very sensitive to the nature of R1 and R2
substituents as no reaction was observed when R1 = P(O)(OEt)2 (entries 28–31) or R2 = Me (entry 1).
Moderate to good yields were obtained with neutral complexes (8a–e) whereas cationic allyl complexes (9a–
b) appeared to be less active and selective under the same conditions. These complexes (9a–b) seemed to
decompose during the reaction as a black precipitate, probably nanoparticles,42−44 was observed in the reaction
media. This decomposition may explain the lower activity and selectivity observed for the 9a–b catalysts.
Another relevant observation is that increasing the catalyst steric hindrance led to decreased activity. This
is expected, as steric hindrance lowers the reagents accessibility to the catalytic centre. However, we did not
observe any ee improvement upon lowering the temperature from 70 ◦ C to 40 ◦ C (entries 2 and 5, 11, and 12, or
19 and 20). The enantioselectivity seemed unaffected by catalyst concentration and reaction time (entries 2 and
3), suggesting that the active species remains unchanged throughout the reaction. Finally, as expected, similar
enantioselectivity was observed with the two enantiomers of opposite configuration (entries 4 and 5, 12 and 13,
20 and 21). One reason for the moderate levels of enantioselectivity may be the strongly coordinating nature
of the ligands. Indeed, Buchwald et al. already observed that the use of diphosphine BINAP furnished the
expected binaphthyls with lower ees than the corresponding P,N ligand KenPhos.28 Similarly, the P,N ferrocenyl
ligand PPFA used by Cammidge et al. showed a high selectivity whereas JosiPhos was totally inefficient.31 The
use of a mixed NHC,N ligand may therefore be an interesting alternative to consider.
3.2. Catalytic application of P,O bidendate ligands
According to a previously optimised protocol on the coupling between aryl bromides and phenylboronic acid,
the reactions were carried out with caesium carbonate as base, Pd2 (dba)3 (1.1 mol%) as metal precursor,
and 1.2 mol% of ligand (7a–c). Contrary to the catalytic reactions with P-NHC ligands, the catalysts were
generated in situ in the present case. All reactions were carried out in a low polarity solvent (toluene) to favour
the coordination of both phosphorus and oxygen atoms (bidendate coordination) of the ligand for a better
chirality transfer. As the temperature may be also crucial for high enantioselectivity, activity and selectivity
were monitored (kinetics) for each ligand (7a–c) at three different temperatures (40, 50, and 60 ◦ C).
As expected, the reaction rate increased with temperature whatever ligand was used. One can also
note the influence of ligand steric hindrance on catalytic activity. The reaction rates are lower with the
more sterically hindered benzyl- and “menthol”-substituted ligands 7b-(R) and 7c-(R) than with the less
hindered ethyl-substituted 7a (Table 3). However, the activity remains good, as almost 90% conversions are
still observed after only 1 h at 60 ◦ C with 7b-(R) and 7c-(R) (vs. 30 min for 7a). The ee of the cross-coupling
product increased, as expected, when the reaction temperature was decreased for ligand 7c but no significant
temperature effect was observed with ligand 7b. The addition of chiral centres (menthol) to the planar chirality
of the ferrocenyl moiety led to a selectivity improvement, but we cannot exclude that this is a simple steric
crowding effect. The 37% ee obtained at 40 ◦ C with 7c is, to our knowledge, one of the best results obtained
with a (P,O) ferrocenyl ligand.30−32,35,36
3.3. Conclusion
Since the pioneering work by Cammidge and Buchwald on enantiomeric Suzuki–Miyaura coupling, many
contributions on chiral ligand design have appeared but no ligand really emerges as universal. Despite the high
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LABANDE et al./Turk J Chem
Table 3. Asymmetric Suzuki–Miyaura reaction between 1-bromo-2-methylnaphthalene and naphthylboronic acids using
P-O ligands.a
Entry Ligand R1 R2 T (◦C) Reaction time (h) Conversionb (%) % eec TOF (h)d
1
2
3
4
5
6
7
8
9
7a-rac
7a-rac
7a-rac
7b-(R) Me
7b-(R) Me
7b-(R) Me
7c-(R) Me
7c-(R) Me
7c-(R) Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
40
50
60
40
50
60
40
50
60
24
24
24
24
24
24
24
24
24
89
-
-
-
10
11
12
37
27
26
245
403
474
223
376
430
125
289
338
100
100
81
88
100
75
87
99
a Reagents and conditions: 1-bromo-2-methylnaphthalene (1.0 equiv), 1-naphthaleneboronic acid (1.2 equiv), Pd2 (dba)3
(1.1 mol %), ligands 7a–c (1.2 mol %), Cs2 CO3 (2.3 equiv), toluene. b Determined by integration of characteristic 1 H
d
NMR signals in the crude mixture. c Determined by HPLC with a Chiracel-OJ column.
reaction.
evaluation after 10 min
steric hindrance of both substrates and reagents, the use of sterically hindered ligands (binaphthyl phosphines,
ferrocenyl phosphines, etc., or more recently NHCs), which can stabilise very reactive 14e- palladium species,
has led to increased catalytic activity, allowing running reactions under relatively mild conditions. However,
increasing the steric crowding at the metal centre may also reduce the reagent’s accessibility to the metal, thus
decreasing the reaction rate. Indeed P,O ferrocenyl ligands (7a–c), which may be considered hemilabile ligands,
gave higher catalytic activity than the strongly coordinating P,NHC bidentate ligands.
A literature survey shows that the best selectivities are generally obtained with reagents and substrates
bearing polar moieties (phosphonates, amides, or aldehydes) at the ortho position relative to the reactive groups
(halide or boronic acid), which is not observed with our phosphine-carbene ligands. Another observation to
be made is that P,NHC ligands gave slightly higher ee’s compared to P,O ferrocenyl ligands. This may be
consistent with the hypothesis that bidendate ligand coordination (more strongly favoured for P,NHC ligands)
leads to better chirality transfer. However, the role of the substituents and the ligands in enantioselectivity
control is far from being fully understood, underlying the remaining challenges for the near future.
4. Rhodium(III) complex with a NHC-phosphine ligand for the direct functionalisation of C(sp2 )-
H bonds
The direct C–H functionalisation of aryl substrates has emerged in the last 10 years as a very powerful synthetic
methodology and a good alternative to more classical C–C coupling reactions, as it avoids the preparation of
halogenated substrates and Grignard reagents or boronic acids, such as those involved in the KTC or Suzuki–
Miyaura reactions, respectively. Although very important advances have been made using palladium-based
catalysts,45−50 rhodium also proved a valuable option as the simple RhIII salt [RhCp*Cl2 ]2 is capable of
activating aromatic C(sp2)-H bonds. Since the pioneering work by Fagnou,51 Satoh and Miura,52 and Jones,53
many reviews have related the most important aspects of these reactions.54−56 One limitation of this type of
reaction, however, is the very poor variety of rhodium(III) catalysts reported. Apart from the ubiquitous
[RhCp*Cl2 ]2 and [RhCp*(MeCN)3 ][X]2 complexes, the few others are also based on the Cp ligand,57−62 the
functionalisation of which is not trivial. This could be explained by the difficulty in finding rhodium(III)
1166

LABANDE et al./Turk J Chem
complexes that possess three available coordination sites, which are necessary for the functionalisation of C–H
bonds. There is therefore a need for new catalysts in this domain.
We have recently described an original strategy to access a new rhodium(III) complex by simple oxidation
of rhodium(I) complexes bearing a redox-active ferrocenyl NHC-phosphine ligand (Figure 8).63,64 The reaction
is initiated by ferrocene oxidation, either by thianthrenium tetrafluoroborate (for complex 10) or AgBF4 (for
complex 11). In the presence of acetonitrile as solvent and as coordinating ligand, the oxidation products
rearrange to give an intermediate tricationic rhodium(III) complex (observed spectroscopically) in which the
ferrocene is back in its reduced state. The rhodium centre in this intermediate is very electrophilic and inserts
into a ferrocene C–H bond to give the stable dicationic rhodium(III) complex 12. The structure of this new, air-
stable complex appeared very interesting to us as it is isoelectronic to the well-known [RhCp*(MeCN)3 ][BF4 ]2 ,
which is commonly used as catalyst in C–H functionalisation reactions, and possesses three available coordination
sites. It also stands out since it is not based on the Cp motif and, though obtained in a racemic form,
possesses planar chirality. This prompted us to evaluate its performances in the Grignard-type arylation of 4-
nitrobenzaldehyde via the C–H activation of 2-phenylpyridine (Figure 9).65 Preliminary catalytic tests showed
33% conversion into the expected alcohol after 24 h at 65 ◦ C in THF (1 H NMR measurement, nonoptimised
conditions). The reaction was also carried out in 1,2-dichloroethane at 60 ◦ C and gave 24% conversion after
24 h.
-
BF4
Ph2
P
Rh
Fe
2+
2 [Th][BF4]
-
N
N
Fe
N
2BF4
PPh2
MeCN, rt
- HBF4
N
10
Rh
N
N
Ph2
P
-
N
CO
Rh CO
BF4
2 AgBF4
Fe
12 (75%)
N
N
11
Figure 8. Synthesis of rhodium(III) complex 12 from rhodium(I) complexes 10 or 11.
O
N
N
5 mol% [Rh]
OH
H
+
THF, 65°C,
24h
NO2
NO2
33% conversion (1H NMR)
Figure 9. Grignard-type arylation of 4-nitrobenzaldehyde catalysed by RhIII complex 12.
One of the main challenges associated with the emerging asymmetric C–H functionalisation reaction is
the development of adapted chiral ligands; therefore our future efforts will be devoted to the synthesis and
optimisation of our rhodium(III) complexes, possibly in enantiopure form, in order to find the best possible
C–H functionalisation catalyst.
1167

LABANDE et al./Turk J Chem
5. Conclusion
We have reported here some recent results obtained in C–C coupling catalysis (Kumada–Tamao–Corriu, asym-
metric Suzuki–Miyaura, C–H activation) using nonchiral P,NHC or chiral P,O and P,NHC ferrocenyl ligands
synthesised by our group. These preliminary studies allowed us to achieve good catalytic activities albeit
with only moderate enantiomeric excesses (up to 46% in the asymmetric Suzuki–Miyaura cross-coupling re-
action using P,NHC ferrocenyl ligands). Future work will aim at designing new NHC, ferrocenyl phosphines
or NHC ferrocenyl ligands, to improve both catalytic activity and enantioselectivity, and to better understand
the relationships between ligands’ structure and activity and selectivity, especially enantioselectivity in C–C
coupling reactions through experimental and computational work, as we already started to carry out for other
reactions.66,67
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