Aryl bromide/triflate selectivities reveal mechanistic divergence in palladium-catalysed couplings; the Suzuki-Miyaura anomaly

Article abstract of DOI:10.1039/b701517h

In palladium-catalysed cross-coupling reactions, the outcome of competition between aryl bromides and aryl triflates depends on the nucleophilic partner; Suzuki couplings with R-B generally follow a different pattern from other R-M species. The Royal Society of Chemistry.

Full text of DOI:10.1039/b701517h

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Aryl bromide/triflate selectivities reveal mechanistic divergence in
palladium-catalysed couplings; the Suzuki–Miyaura anomaly{
Gustavo Espino, Almira Kurbangalieva and John M. Brown*
Received (in Cambridge, UK) 31st January 2007, Accepted 26th March 2007
First published as an Advance Article on the web 5th April 2007
DOI: 10.1039/b701517h
In palladium-catalysed cross-coupling reactions, the outcome
of competition between aryl bromides and aryl triflates depends
on the nucleophilic partner; Suzuki couplings with R–B
generally follow a different pattern from other R–M species.
Scheme 1 Some previous results obtained for intramolecular bromide/
triflate competition in Kumada coupling; (i) Cl2Pd(monophosphine)2, (ii)
The original nickel-catalysed cross-coupling reactions reported by
Cl2Pd(diphosphine), added LiBr.
Kumada1 and Corriu2 involved the reaction of vinyl- and
arylmagnesium halides with unsaturated halides; palladium
with the appropriate Pd[0] precatalysts afforded the same trends,
catalysts followed rapidly thereafter.3 A high level of generality
with dppp preferring insertion into C–OTf and (PPh3)2 preferring
has been achieved through extension in scope of both the
C–Br. The favouring of C–Br over C-OTf cleavage with catalysts
electrophilic and nucleophilic components. In particular, organo-
that operate by a monophosphine mechanism has been more
boron, organozinc and organotin reagents are all regularly
generally observed.9 It is worth noting that the effect of added
employed as nucleophiles.4 Heck-type reactions involve an alkene
halide on chemoselectivity was noted in Hayashi’s work, and the
as the nucleophilic component.5 All such palladium-catalysed
effect on reactivity10 has been a consistent feature of coupling
reactions are considered to involve a stepwise process from a low-
chemistry.
valent metal complex that first activates the electrophile in a formal
This protocol seemed to have general value in distinguishing
oxidative addition step A. The resulting complex then undergoes
between mechanistic pathways for the addition step. In particular,
nucleophilic attack in step B. This permits C–C bond formation in
questions about the generality of coupling mechanisms can be
step C, and direct or indirect return to the original state with
addressed, comparing the variation of either the electrophile RX or
product liberation. It is widely assumed that the addition of the
the nucleophile R9M. With this in mind a preliminary screen of
electrophile to Pd[0] is commonly the turnover-limiting step.6
several palladium-catalysed coupling reactions was carried out,
employing the bromotriflate 2 and varying the nucleophile; the
results are shown in Scheme 2.
This set of data immediately confirms the main conclusion of
Hayashi’s work and extends it to both Negishi (Zn) and Stille (Sn)
coupling; in all these cases the nucleophile reacts preferentially to
In studies of SN reactions at sp3 carbon, the relative reactivity of
halide and tosylate as leaving groups has been widely used as a
mechanistic tool.7 Since both triflate and halide are commonly
employed as electrophilic leaving groups in palladium catalysis, the
opportunity for related studies exists. The only systematic work
along these lines is due to Hayashi and co-workers,8 involving an
internal competition as recorded in Scheme 1. For Kumada
(RMgX) coupling, a bulky monophosphine induces preferential
displacement of bromide over triflate in compound 1; a chelating
aryldiphosphine does the reverse, and PPh3 as ligand is unselective.
The selectivity shown in Scheme 1 (ii) was demonstrated to occur
for a wide range of bromoaryl triflates. Stoichiometric reactions
Scheme 2 Triflate/bromide selectivity in coupling reactions; preliminary
results: (i) PhMgBr, LiBr, 5 mol% Cl2Pd(dppp), Et2O, 0 uC, 2 h, 60%, ca.
20% m-terphenyl; (ii) PhZnBr, 4 mol% Cl2Pd(dppp), thf, 60 uC, 11 h, 90%;
(iii) CH2LCHSnBu3, 3 eq. LiCl, 2 mol% Cl2Pd(dppp), DMF, 25 uC, 39 h,
25%; (iv) 4-MeOC6H4B(OH)2, 3 eq. KF, 0.5 mol% Pd(dba)2, 1.2 mol%
PBut3, thf, 25 uC, 3 h, 76%; (v) as (iv) with 5 mol% Cl2Pd(dppp) as
catalyst, 4 h, 52%; (vi) PhB(OH)2, 3 eq. KF, 1.5 mol% Pd(dba)2, 3.6 mol%
PBut3, thf, 25 uC, 4 h, 80%.
Chemistry Research Laboratory, Mansfield Rd., Oxford, UK OX1 3TA.
E-mail: john.brown@chem.ox.ac.uk; Fax: 44 1865 285002;
Tel: 44 1865 275642
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b701517h
1742 | Chem. Commun., 2007, 1742–1744
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displace triflate rather than bromide when a palladium chelate or
diphosphine complex is employed. The reverse result was observed
in Suzuki coupling, where Br-displacement was observed irrespec-
tive of whether the ligand was dppp, or P(But)3 under Fu’s
conditions – see entries (iv), (v), Scheme 2.9 Indeed, no evidence for
competing electrophilic reactivity of the triflate group was
observed in these cases.
The unusual nature of these results encouraged us to extend
them with a different reactant 7,11 designed to provide rapid 19F
NMR screening of the reaction course in diverse Pd couplings.
Under a variety of conditions, Suzuki coupling of compound 7
using either 2 6 PPh3 or dppp as ligand led predominantly to the
product of Br-displacement (Table 1). At lower temperatures, the
reaction was slow and unspecific with these ligands and both
possible monosubstituted products were formed, with bromide
replacement dominant; entry 1 is typical. At higher temperatures,
and in the non-polar solvent toluene following literature precedent,
the reaction course was more selective. With either catalyst, the
triflate-bearing monosubstitution product was formed near-
exclusively at high conversion.
Scheme 3 Amination and Heck reactions with reactant 7; (i) 10 mol%
catalyst ex. Pd2(dba)3/dppp, NaOBut, C7H8, 80 uC, 22 h, 50% as only
amination product; (ii) same catalyst, Na2CO3, C7H8, 80 uC, 22 h, 25%
with 15% disubstitution product.
amination and a Pd-catalysed Mizoroki–Heck reaction (Scheme 3)
under typical conditions, without optimisation. In both cases it is
triflate that functions preferentially as the electrophilic leaving
group, although the latter reaction gives a significant proportion of
disubstituted product even at low conversion. In addition, the
preference for triflate displacement in Kumada coupling with
reactant 7 using 5 mol% Cl2Pd(dppp)2 was confirmed (PhMgBr,
dioxane, 90 uC, 22 h; 100% conversion 2 : 1 12 : 13).
In keeping with these results, the complex 14 isolated in high
yield from the reaction of bromotriflate 7 with Pd(PPh3)4 in hot
toluene involves only C–Br insertion.{ Employing this complex as
the catalyst (5 mol%) in reaction of further reactant 7 with
PhB(OH)2 afforded complete conversion with biaryl 11 as the
major product accompanied by traces of compound 13, but with
no detectable 12.
Hence triflate is reluctantly displaced by boronate nucleophiles
under the conditions of palladium coupling, but is otherwise the
reactive partner. This puts Suzuki coupling out of line with all
other common cross-coupling reactions in the present survey. In a
more general sense, the activity of aryl triflates is ligand dependent,
supporting Hayashi’s observations. Hence lower reactivity has
been observed here for monophosphine catalysts by Fu and co-
workers. They demonstrate that when PBut3 is employed as ligand,
even aryl chlorides are more reactive than aryl triflates.9 What is
the explanation of the anomalous behaviour of the aryl triflate
bond in Suzuki couplings? Differences as profound and general as
the ones observed here require a radical explanation. Two of the
three original papers on the Suzuki coupling of triflates comment
on the lowered reactivity of –OTf relative to –Br, based on
qualitative comparisons.12 The oxidative addition step between
various Ar–OTf and in situ generated Pd(PPh3)2 in DMF has a
Hammett r value of 2.55, in line with an earlier value of r = 2.0 for
aryl iodides.13 A reactivity order of PhI & PhOTf . PhBr was
established for DMF. Since the aryl triflate oxidative addition
generates a cationic product directly, it must be irreversible under
the conditions of Suzuki coupling where more powerful oxygen
nucleophiles (e.g. PO432) are present. Hence the oxidative addition
step appears to be perfectly normal for Ar–OTf, in line with aryl
halides. This must indeed be the case, given the large number of
successful Suzuki reactions that have been performed with aryl
triflates.14 It is preferable to consider ways in which Suzuki
couplings of aryl bromides might be subject to enhanced reactivity.
Although data are limited, and confined to two particular
palladacyclic catalysts, it appears that the activity of m-,
p-substituted aryl bromides towards coupling with PhB(OH)2 is
insensitive to electronic effects, with recorded r-values of 0.48 for
catalyst 17 and ca. 1.0 for catalyst 18.15 The authors suggest that
under their conditions oxidative addition is not the turnover-
limiting step in catalysis, but alternative suggestions are lacking
and this one requires reversibility of the Ar–Br addition to
In order to check further the generality of this anomalous set of
observations, reactant 7 was also subjected to a Pd-catalysed
Table 1 Suzuki reactions with triflate 7, 5 mol% catalyst. Reactions I
involve boronic acid (X = OMe); reactions II (X = H). A refers to L2 =
dppp in Cl2PdL2, B refers to L2 = 2 PPh3
% Conversion (8 : 9 : 10)
or (11 : 12 : 13)
Entry Reaction Conditions
1
2
3
4
5
6
7
IA
IA
IB
IIA
IIA
IIB
IIB
KF–thf; 23 uC, 4 h
28 (65 : 35 : –)
K3PO4–C7H8; reflux 22 h 54 (90 : – : 10)
As entry 2
As entry 2
As entry 2/added LiBr
As entry 2
As entry 5
88 (. 95 : – : , 5)
57 (60 : 25 : 15)
78 (. 90 : – : , 10)
66 (100 : – : –)
89 (. 95 : – : , 5)
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We suggest possible explanations with direct involvement of the
boronic acid, compatible with the observed facts and not requiring
a change in turnover-limiting step. ArB(OH)2 could feasibly be
involved in one of two ways. It is known that boranes have an
affinity for Br2,17 and possible that the association of trigonal
boron with the halide could facilitate its departure, providing a
pathway of lowered energy that is not available to the triflate. If
correct, electrophilic assistance of this type could provide a novel
feature of catalyst design capable of enhancing chemoselectivity.18
For the second and more plausible alternative, we consider recent
DFT calculations on the ArX addition step to Pd, studied in detail
by several authors.19 These reinforce the viability of the Amatore–
Jutand pathway, where the oxidative addition step is facilitated by
pre-coordination of an anion (Cl2, OAc2) to the palladium
catalyst, either PdL or PdL2.19a,b Specific coordination of a 3- or
4-coordinate boronate anion is thus feasible as an activation
pathway, and one which permits the b-transfer of the aryl group to
Pd. A similar pathway has been demonstrated for the Rh-catalysed
conjugate addition of ArB(OH)2 to electrophilic alkenes, which the
authors indicate may have relevance to Suzuki coupling.20 Further
experimental work is required to distinguish between a modified
oxidative addition step and a turnover-limiting boronate transme-
tallation.
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We thank the Royal Society for the award of a NATO
Exchange Fellowship (to AK) and the University of Burgos for
support of a visit to Oxford by GE. We thank Prof. T. Hiyama
(Kyoto) for a related suggestion of B–Br activation. We thank
Johnson-Matthey plc for the loan of palladium salts.
Notes and references
{ The X-ray structure of complex 14 has been obtained and will be
described in detail elsewhere because of the interesting dual p-stacking
involved; G. Espino, A. R. Cowley and J. M. Brown, in preparation.
20 P. Zhao, C. D. Incarvito and J. F. Hartwig, J. Am. Chem. Soc., 2007,
129, 1876–7.
1744 | Chem. Commun., 2007, 1742–1744
This journal is ß The Royal Society of Chemistry 2007