The triple role of fluoride ions in palladium-catalyzed Suzuki-Miyaura reactions: Unprecedented transmetalation from [ArPdFL2] complexes

Article abstract of DOI:10.1002/anie.201107202

Fluoride ions play three roles in the Suzuki-Miyaura reaction. They favor the reaction by formation of trans-[ArPdF(PPh₃)₂], which reacts with Ar B(OH)₂ in an unprecedented rate-determining transmetalation, and by promoting the reductive elimination from the trans-[ArPdAr (PPh₃)₂] intermediate. Conversely, F ^- disfavors the reaction by formation of unreactive anionic Ar B(OH)_n-3F_n^- (n=1-3), leading to two antagonistic effects of F^- in the transmetalation. Copyright

Full text of DOI:10.1002/anie.201107202

Angewandte
Chemie
DOI: 10.1002/anie.201107202
Suzuki–Miyaura Reactions
The Triple Role of Fluoride Ions in Palladium-Catalyzed Suzuki–
Miyaura Reactions: Unprecedented Transmetalation from [ArPdFL2]
Complexes**
Christian Amatore,* Anny Jutand,* and Gaꢀtan Le Duc
Palladium-catalyzed Suzuki–Miyaura reactions between aryl
boronic acids (Ar’B(OH)2) and aryl halides (ArX) to
generate ArAr’ require a base,[1] such as hydroxide,[2]
carbonate, or fluoride. The mechanism of the reaction has
been thoroughly established for cases in which the base
employed is OHÀ associated with nBu4N+, an innocent
counter cation (Scheme 1).[2] The hydroxide ions play three
roles. Two are antagonistic in the rate-determining trans-
Fluoride ions have a strong affinity for aryl boron moieties
À
[1,5]
owing to the stability of Ar’BF3
.
Batey and Quach have
hypothesized that anionic Ar’BF2(OH)À or Ar’BF(OH)2
À
must be formed from Ar’BF3 in the presence of a base.[5a]
À
À
The successive basic hydrolysis of Ar’BF3
into
À
Ar’B(OH)3ÀnFn (n = 1–3) and, ultimately, Ar’B(OH)2 was
established by Molander et al.[5b–d] Hutton et al.,[5e] and
Lloyd-Jones et al,[5f] who also demonstrated that fluoride
ions react reversibly with aryl boronic acids to eventually
generate Ar’BF3À[5f] [Eq. (1)].
We have tested the effect of fluoride ions introduced as
nBu4NF (3 equiv) on p-FC6H4B(OH)2 in DMF. As reported
for KF in THF/H2O,[5f] in the 19F NMR spectrum, the singlet
of p-FC6H4B(OH)2 at À112.11 ppm disappeared and led to a
complex mixture of signals. In the presence of excess nBu4NF
À
(> 3 equiv), p-FC6H4BF3 was detected at À136.31 ppm
Scheme 1. Catalytic cycle of the Suzuki–Miyaura reaction performed in
the presence of hydroxide (nBu4NOH) as a base.
À
(BF3 ) and À116.89 ppm (p-F), in agreement with literature
values.[5f]
Consequently, in the presence of a large amount of FÀ, the
major reagent must be Ar’BF3À [Eq. (2)]. Batey and Quach[5a]
metalation: 1) formation of trans-[ArPd(OH)L2] (L = PPh3),
which reacts with Ar’B(OH)2; and 2) formation of unreactive
Ar’B(OH)3À. The third role is positive: fast promotion of
reductive elimination from the trans-[ArPdAr’L2] intermedi-
ate (Scheme 1). The overall reaction rate is thus controlled by
the ratio [OHÀ]/[Ar’B(OH)2].[2] The higher reactivity of
observed that no reaction took place between PhBF3 Cs+ and
À
À
Ar’B(OH)2 with [ArPd(OH)(PPh3)2] versus Ar’B(OH)3
with [ArPdX(PPh3)2] shown in our previous work[2] was
later confirmed by Hartwig and Carrow.[3]
p-CHOC6H4Br in the presence of [Pd0(PPh3)4] (3 mol%) in
DMF and in the absence of a base, whereas the same reaction
involving PhB(OH)2 and CsF (3 equiv) proceeded, establish-
Herein we present kinetic and mechanistic data on the
role of fluoride anions in Suzuki–Miyaura reactions.[1,4] Three
roles for FÀ were determined, including an unprecedented
transmetalation from [ArPdFL2] complexes.
ing that PhBF3 was not the reactive species.[6] Lloyd-Jones
À
À
et al. have also established that Ar’BF3 ions are quite
unreactive in the absence of a base. However, in the presence
À
of OHÀ (generated from Cs2CO3 in THF/H2O), Ar’BF3 is
[*] Dr. C. Amatore, Dr. A. Jutand, G. Le Duc
Dꢀpartement de Chimie, Ecole normale Supꢀrieure,
UMR CNRS-ENS-UPMC 8640
partly converted to Ar’B(OH)2, which reacts with an [Ar-
Pd(OH)L] species in a transmetalation step.[5f] We have also
observed that no p-NCC6H4Ph was formed after two hours
when p-[NCC6H4PdI(PPh3)2] (1.9 mm) was combined with
PhBF3À (20 equiv) in DMF at RT, once more confirming that
aryltrifluoroborates are not reactive.[5] This suggests another
role for fluoride ions that could promote the formation of
[ArPdFL2] as the reactive species.
24 Rue Lhomond, 75231 Paris Cedex 5 (France)
E-mail: christian.amatore@ens.fr
anny.jutand@ens.fr
[**] CNRS, ENS, and UPMC are thanked for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107202.
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The substitution of other halides by fluorides in trans-
[ArPdX(PPh3)2] was also investigated. Grushin et al. have
reported the synthesis of one fluorinated aryl complex, trans-
[PhPdF(PPh3)2], by reacting trans-[PhPdI(PPh3)2] with AgF
in benzene.[7] We first synthesized an authentic sample of
trans-p-[NCC6H4PdF(PPh3)2] by reacting excess AgF with
[{p-NCC6H4Pd(m-I)(PPh3)}2] in the presence of PPh3 (2 equiv)
in toluene. trans-[p-NCC6H4PdF(PPh3)2] was isolated in 66%
yield and characterized by NMR (Supporting Information,
Figure S1). In the 31P NMR spectrum, a doublet was observed
at 19.38 ppm (d, JFP = 12 Hz; Figure S1a) and the 19F NMR
spectrum revealed a broad, poorly defined signal. Gratify-
ingly, a more defined 19F signal structure was observed at
À281.67 ppm (tt, JFP = 12 Hz, JFH = 2 Hz; Figure S1b) in the
presence of excess PPh3 (4 equiv). This improvement was
most likely due to a trans/cis equilibrium that lies in favor of
the trans complex in the presence of excess PPh3. When
nBu4NF (1 equiv) was added to trans-[p-NCC6H4PdI(PPh3)2]
(5.8 mmol) in 0.5 mL of DMF/[D7]DMF containing PPh3
(2 equiv),[8] the doublet of [p-NCC6H4PdF(PPh3)2] was
observed in the 31P NMR spectrum together with the singlet
of the starting complex in a ratio of 61:39, respectively. The
ratio was 94:6 in the presence of nBu4NF (2 equiv). Con-
sequently, fluoride ions exchanged with the original halide of
trans-[ArPdX(PPh3)2] to generate trans-[ArPdF(PPh3)2]
through the equilibrium given in Equation (3). The equilib-
rium constant was estimated from the 31P NMR data: KX =
5 Æ 1 (X = I, Ar= p-NCC6H4, DMF, 278C).
Scheme 2. Mechanistic pathways in the Suzuki–Miyaura reaction per-
formed in the presence of fluoride anions.
reductive elimination from the trans-complex (path A in
Scheme 2). Indeed, it is reported that a fifth ligand on square-
planar four-coordinate trans d10 complexes favors reductive
elimination.[12] In the case of FÀ, the lifetime of the five-
coordinate species is too short to be observed.
However, as indicated above, FÀ reacted with PhB(OH)2
to release OHÀ [Eq. (2)], which also favors the reductive
elimination in path A (Scheme 1).[2] In actual catalytic
reactions involving Ar’B(OH)2 and FÀ, FÀ and OHÀ (released
from Ar’B(OH)2) are always present in large amounts.
Whatever the anion, FÀ or OHÀ, that promotes the reductive
elimination, the key point is that the resulting process is
always faster than the transmetalation in the presence of
those anions.
The kinetics of the reaction of trans-[p-NCC6H4PdI-
(PPh3)2] (1) with PhB(OH)2 (2) were then investigated in
DMF at 258C in the presence of PPh3 (2 equiv) and nBu4NF
(a equiv) introduced from a 1m stock solution in THF
[Eq. (4)].
Having the isolated trans-[p-NCC6H4PdF(PPh3)2] in hand,
its reactivity with PhB(OH)2 could be directly tested in DMF.
The reaction was followed by cyclic voltammetry (see the
Supporting Information). Gratifyingly, the known complex
trans-[p-NCC6H4PdPh(PPh3)2][2,9] was formed and detected
by its reduction peak in cyclic voltammetry (see the Support-
ing Information) upon reacting [p-NCC6H4PdF(PPh3)2]
(1.9 mm) with PhB(OH)2 (5 equiv) in the presence of PPh3
(2 equiv) in DMF at room temperature. Also, as observed in
our previous work, trans-[p-NCC6H4PdPh(PPh3)2] was quite
stable.[2] It is only after the addition of CsF (8 equiv) that
[Pd0(PPh3)3] and p-NCC6H4Ph (characterized by their oxida-
tion and reduction peak respectively,[2] see the Supporting
The kinetics of the formation of [Pd0(PPh3)3] were
followed by chronoamperometry using a rotating disk elec-
trode polarized at + 0.05 V (oxidation potential of [Pd0-
(PPh3)3]). The increase in its oxidation current (proportional
to its concentration) was then recorded with time (Figure 1a)
after addition of nBu4NF (20 equiv) to a solution containing 1
(C0 = 1.9 mm), 2 (20 equiv), and PPh3 (2 equiv). The plot of
lnx with time was linear (Figure 1b). The value of kobs
=
Information) were generated together in a fast reaction (t1/2
=
0.032 sÀ1 was determined from the slope of the linear
correlation (Figure 1b).
ca. 2 min). It is thus shown for the first time that [ArPdFL2]
undergoes transmetalation with Ar’B(OH)2, as a consequence
of the fluorophilicity of the boron center (Scheme 2).[10]
Furthermore, FÀ promotes the reductive elimination from
stable trans-[ArPdAr’L2] complexes (path A in Scheme 2),
bypassing the classical path B in which the rate of the
reductive elimination from the related cis-complex is retarded
by slow trans/cis isomerization (Scheme 2). By analogy to the
proposed formation of an anionic five-coordinate species
involving OHÀ as the fifth ligand (Scheme 1),[2] the formation
of an anionic five-coordinate[11] species involving FÀ as the
fifth ligand is now proposed to explain the promotion of the
The variation of kobs versus the amount of fluoride (a
equiv) exhibited a bell-shaped maximum (Figure 2a), as
previously observed for hydroxides,[2] although the phenom-
enon was less accurate than for OHÀ. The same behavior was
observed in the reaction of trans-[PhPdBr(PPh3)2] (1.9 mm)
with PhB(OH)2 (20 equiv) performed in the presence of
nBu4NF (a equiv; Figure 2b). The dependence on the FÀ
concentration reveals that kobs describes the kinetics of the
rate-determining transmetalation.
Therefore, as with hydroxides, fluorides are involved in
two kinetic antagonist effects: FÀ ions are required to
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the reductive elimination from trans-[ArPdAr’L2], making
this reaction faster than the transmetalation, which becomes
rate-determining (Scheme 2). The rate of the overall reaction
is thus controlled by the ratio [FÀ]/[Ar’B(OH)2].
Therefore, we have established that FÀ plays the very
same three roles already identified for OHÀ in the trans-
metalation and reductive elimination processes (Scheme 3).
However, the reaction of FÀ with Ar’B(OH)2 is more complex
than that of OHÀ. Indeed, at least three fluorinated species
À
Ar’B(OH)3ÀnFn (n = 1–3) may be formed [Eq. (2)] with
progressive release of OHÀ, which may participate in a
catalytic cycle involving OHÀ as the base, as in Scheme 1 (see
the variation of kobs vs. OHÀ concentration in Figure 2). A
competitive substitution of IÀ in complex 1 by FÀ or OHÀ was
indeed observed (ꢀ 2.5 in favor of FÀ) when the two anions
were added together at the same concentration (14 mm) to 1
(14 mm). As observed in Figure 2, the reaction was less
inhibited by high FÀ concentrations than by OHÀ, suggesting
that OHÀ ions were more easily trapped by Ar’B(OH)2 than
FÀ ions (the oxophilicity of boron is higher than its
fluorophilicity). Whereas the ratio [OHÀ]/[Ar’B(OH)2] must
be lower than 1 to have an efficient reaction, the ratio
[FÀ]/[Ar’B(OH)2] may be higher than 1 (Figure 2). Interest-
ingly, the range of the FÀ concentrations which led to an
efficient reaction appears to be larger than that for OHÀ
(Figure 2). In other words, the control of the fluoride
concentration is not so crucial for an efficient reaction.
In conclusion, the mechanism of the reaction of trans-
[ArPdX(PPh3)2] with Ar’B(OH)2, a key step in Suzuki–
Miyaura reactions, has been established in DMF in the
presence of fluoride anions (Scheme 3) and compared to that
reported in our previous work with hydroxide anions
(Scheme 1).[2] The formation of [Pd0(PPh3)3] and the cross-
coupling product ArAr’ was followed using electrochemical
techniques that provide kinetic data. As with hydroxide ions,
fluoride ions play three roles. FÀ favors the reaction by:
1) forming trans-[ArPdF(PPh3)2], a key complex that reacts
with Ar’B(OH)2 (an unprecedented rate-determining trans-
metalation) and 2) promoting the reductive elimination from
intermediate trans-[ArPdAr’(PPh3)2], which generates ArAr’
and active Pd0. Conversely, FÀ disfavors the reaction by the
Figure 1. Kinetics of the reaction of trans-[p-NCC6H4PdI(PPh3)2]
(1.9 mm) with PhB(OH)2 (20 equiv) in the presence of PPh3 (2 equiv)
and nBu4NF (20 equiv) in DMF at 258C. a) Evolution of the oxidation
current of [Pd0(PPh3)3] (proportional to its concentration) measured by
chronoamperometry using a rotating gold disk electrode (d=2 mm)
polarized at 0.05 V. b) Variation of lnx versus time (x=(ilimÀit)/ilim
where ilim =final value of the oxidation current of [Pd(PPh3)3] and
it =oxidation current at t). y=À0.032367x R=0.99788.
,
Figure 2. Variation of the pseudo first-order rate constant kobs with
À
[2]
aequiv of FÀ ( ) or OH ( ) for the reaction of PhB(OH)2 (20 equiv)
with a) trans-[p-NCC6H4PdI(PPh3)2] (1.9 mm) and b) trans-[PhPdBr-
(PPh3)2] (1.9 mm). All of the reactions were performed in the presence
of PPh3 (2 equiv) in DMF at 258C.
*
*
generate the active trans-[ArPdFL2], which reacts with
Ar’B(OH)2, as shown above (Scheme 2). However, at suffi-
ciently high concentrations, FÀ inhibits the reaction by
À
competitive formation of unreactive Ar’B(OH)3ÀnFn (n =
1–3) [Eq. (2), Scheme 3]. This confirms the results reported
À
À
in the literature, which established that Ar’BF3 is not
formation of unreactive anionic Ar’B(OH)3ÀnFn (n = 1–3),
reactive in the absence of OHÀ.[4d,5] As for OHÀ, FÀ promotes
leading to the two antagonistic effects of FÀ in the trans-
metalation. Consequently, the overall reactivity is finely
tuned by the concentration of FÀ and passes through a
maximum as FÀ concentration increases. Therefore, the rate
of the overall reaction is controlled by the ratio [base]/
[Ar’B(OH)2] when the base is either FÀ (this work) or OHÀ,[2]
both associated with the counter cation nBu4N+. Work is in
progress to expand the scope of the transmetalation of
[ArPdFL2] complexes.
Received: October 11, 2011
Published online: December 23, 2011
Keywords: aryl boronic acid · fluoride ions · palladium ·
reaction mechanism · Suzuki–Miyaura reactions
Scheme 3. Catalytic cycle of the Suzuki–Miyaura reaction performed in
the presence of fluoride anions (nBu4NF).
.
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[ArPd(OH)L2] through Ar’B(OH)2 (Scheme 1). However, the
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