Copper activation of boronic acids: Factors affecting reactivity

Article abstract of DOI:10.1002/aoc.3144

The generation of nucleophiles from the combination of aryl boronic acids and catalytic amounts of copper salt allows a reactivity distinct from other organometallic species, such as organolithiums or Grignard reagents. Here we examine how the electronic

Full text of DOI:10.1002/aoc.3144

Full Paper
Received: 5 January 2014
Revised: 23 February 2014
Accepted: 24 February 2014
Published online in Wiley Online Library: 20 April 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3144
Copper activation of boronic acids: factors
affecting reactivity
Robin Frauenlob, Carlos García, Susan Butler and Enda Bergin*
The generation of nucleophiles from the combination of aryl boronic acids and catalytic amounts of copper salt allows a
reactivity distinct from other organometallic species, such as organolithiums or Grignard reagents. Here we examine how
the electronic and steric properties of the boronic acid affect the formation of active nucleophiles and their subsequent
reactivity with iminium-type compounds, showing that electron-rich substrates display reduced reactivity. Copyright ©
2014 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: catalysis; copper; C―C bond formation
that the discrepancy could be caused by different rates for
transmetallation, and hence different concentrations of active
Introduction
The generation of nucleophilic species via the activation of bo-
ronic acids and related compounds with copper salts is becoming
a valuable strategy in synthesis.[1–8] The advantages of such a
system are clear: boronic acids are stable, readily available, easy
to prepare, have a low toxicity and tolerate a wide range of
functionalities in reaction partners, while copper salts are again
very inexpensive (especially when compared with the more com-
monly employed noble metals) and relatively air and moisture
stable. In addition, the low reactivity of unactivated boronic acids
makes it possible to use functional groups incompatible with
stronger nucleophiles such as organolithiums or Grignard re-
agents. Finally, the use of a catalytic amount of copper opens
up the possibility of enantio-enriched products by appropriately
chosen chiral ligands.[9–13] These factors make copper/boronic
acid nucleophiles some of the most attractive options available
for carbon–carbon bond formation, and one certain to receive
increasing attention in the future. In this work we examine the
factors affecting the formation of these species and apply them
in a copper-catalysed reaction.
nucleophiles in solution.
To test this, we monitored the rate of transmetallation of elec-
tronically distinct boronic acids (as measured by varying σp
values).[15] The relevant boronic acid and a copper/bipyridyl com-
plex were heated together in DMF, and the reaction was moni-
tored by 11B NMR. First we examined the rate of consumption
of starting material (see Fig. 1). There was a clear trend where
the electron-poor boronic acid was consumed rapidly, while the
methoxy-substituted analogue was consumed at a much slower
rate. After 300min all of compound 1 had been consumed, com-
pared with approximately 50% of 3. The unsubstituted phenyl
boronic acid 2 fell neatly between these two extremes, at least at
longer reaction times. This observation is perhaps not surprising:
electron-withdrawing substituents would be expected to increase
the electrophilicity of the boronic acid and hence accelerate
nucleophilic attack to generate the boronate intermediate (indeed
if formation of the boronate is irreversible, or essentially irreversible,
under these conditions, then the consumption of starting material
is simply a measure of the rate of nucleophilic attack).
This raised the question as to whether the increased reactivity
was simply due to the increased electrophilicity of the boron spe-
cies, or if other factors were involved. To answer this we analysed
the percentage formation of the final product (see Fig. 2). These
results were even more dramatic. Fluorine-substituted boronic
acid (1) quickly reached complete conversion, whereas 4-
methoxyphenyl boronic acid (3) had conversion of approximately
30% even after 6 h at 70 °C. Once again, phenyl boronic acid was
between these two extremes.
Results and Discussion
While a great deal of work has been carried out on new
methodologies utilizing copper catalysts, factors affecting the
reactivity have not been intensively studied. Our group[14]
and the group of Shibasaki[9] have observed activation of
the aryl boronic acids and vinyl boronic esters, respectively,
through the analysis of 11B NMR spectra.
Because of this very significant difference, it was clear that for-
mation of active nucleophile was not faster simply due to
In our previous work[14] we observed that more electron-poor
boronic acids gave yields as good as, or better than, those
obtained with electron-rich boronic acids (see Scheme 1). At
the time we could offer no convincing explanation for this obser-
vation, despite the fact that such information could be useful for
future advances in related processes.
*
Correspondence to: Enda Bergin, School of Chemistry and Chemical Biology,
Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland. E-mail:
ebergin@tcd.ie
Since a simplistic analysis would have suggested that electron-
rich copper nucleophiles should be more reactive, we postulated
School of Chemistry and Chemical Biology, Trinity Biomedical Sciences Institute,
Trinity College, Dublin, Ireland
Appl. Organometal. Chem. 2014, 28, 432–435
Copyright © 2014 John Wiley & Sons, Ltd.

Copper activation of boronic acids: factors affecting reactivity
PhB(OH)2
CuBr, bipy
DMF
N
EtO
O
Ph
EtO
O
90%
B(OH)2
O
+
O
N
CuBr, bipy
DMF
N
H
EtO
O
O
79%
PhB(OH)2
CuBr, bipy
DMF
N
EtO
Ph
51%
O
O
EtO
B(OH)2
O
+
F
N
H
CuBr, bipy
N
DMF
EtO
O
Figure 2. Formation of active nucleophile.
F
57%
Scheme 1. Copper-catalysed Petasis reaction. Yields obtained with elec-
tronically distinct boronic acids.
active nucleophiles. One plausible explanation for this is that,
while the electron-rich nucleophiles are formed in lower
amounts, their reactivity with electrophiles once formed is signif-
icantly higher than the reactivity of electron-poor nucleophiles.
To test the generality of our observations, we tried the same
boronic acid/copper nucleophiles in a new reaction. We examined
the possibility of developing a copper-catalysed addition of bo-
ronic acids to N-acyl quinolinium ions. This is an attractive route
for the synthesis of substituted dihydroquinolines, a commonly
encountered bioactive core.[15–17] A metal-catalysed process has
been developed for this reaction,[15] and in that study it was found
that a Ni(0) catalyst turned electron-deficient aryl boronic acids –
normally unreactive in Petasis-type reactions – into viable nucleo-
philes (although yields were still lower than those observed for
electron-neutral or electron-rich aryl boronic acids).
We examined the possibility of extending our copper catalysis
conditions to reactions of this type (Table 1). To our delight we
obtained the product, albeit in moderate yield (Table 1, entry 1).
Use of tert-butoxide additives gave a small, but reproducible,
improvement (Table 1, entry 3). This effect had been observed
in cross-coupling reaction by Liu and co-workers, who proposed
that the positive effect was due to the tert-butoxide coordinating
to the boron to help transmetallation in addition to the lithium
ion stabilizing the organocuprate intermediate.[5] More interest-
ingly, we once again observed the same trend, with electron-
withdrawing groups improving the yield and electron-donating
groups decreasing it (relative to unsubstituted phenyl boronic
acid derivatives: Table 1 entries 3, 4 and 5). As such, it correlated
well with our previous results and the rate of activation of the
boron species, as shown by 11B NMR.
Figure 1. Consumption of boronic acid starting material.
increased concentrations of boronate, but rather both the
formation of boronate and the transmetallation step were
significantly slower for electron-rich compounds. This has
significant implications for the use of such compounds in
copper-activated procedures.
We had previously observed that ortho substituents on the aryl
boronic acid resulted in low or negligible yields. We re-examined
their use in the current reaction, looking at 2-chlorophenyl
boronic acid. We first monitored the reaction of 2-chlorophenyl
boronic acid with copper bromide by 11B NMR. The fact that this
was rapidly consumed – similar to the results obtained above
with 4-flurophenyl boronic acid – lends support to our hypothesis
It is worth noting, however, that the difference in observed
yields is not as dramatic as the difference in concentrations of
Appl. Organometal. Chem. 2014, 28, 432–435
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

R. Frauenlob et al.
Table 1. A copper-catalysed addition of aryl boronic acids to N-acyl
quinolinium precursors
and at times they can even outperform electron-rich ana-
logues.[7,14,15] To date, however, organocatalytic methods have
proven more successful at enantioselective variants, though re-
cent advances are highlighting the opportunities for metal
catalysed processes.[16]
By analogy with the initially reported Ni-catalysed process,[15–
17]
we tentatively propose the mechanism shown in Fig. 3. The
transmetallation process leads to an aryl copper species,[6] and
this interacts with the iminium (6) to give a Cu(III) intermediate
(7). This oxidative step is consistent with the proposed intermedi-
ary of Cu(III) species for reactions involving Cu(I) nucleophiles.[21]
Intermediate 7 undergoes reductive elimination to give the aryl
substituted product 5 and regenerated Cu(I) salt. We examined
the possibility of rendering the process asymmetric. Unfortu-
nately we obtained 5a in racemic form each time (see supporting
information for ligands screened).
In conclusion, we have examined the factors influencing
reactivity for copper-activated boronic acids, and provided
insight that may help to explain the good performance of
electron-poor variants. In addition, we employed copper/
boronic acid nucleophiles in a separate C―C bond-forming
process and observed a similar trend in reactivity. It is hoped
that this will lead to further study and use of this highly
attractive reagent system.
Entry
Ar
Base
Product
Yield (%)
1
2
3
4
5
6
Ph
Ph
Ph
none
5a
5a
5a
5b
5c
5d
28
30
34
28
49
<5
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
4-MeOC6H4
4-F-C6H4
2-ClC6H4
for a high dependency on electronic factors. We next used this
boronic acid for the addition to 4. We observed only trace
amounts of product formed (Table 1, entry 6). This led us to be-
lieve that in these cases it is the carbon–carbon bond-forming
step (i.e. nucleophilic addition to the iminium) that is prevented
by sterics, whereas the salt formation and transmetallation pro-
ceed as normal.
Furthermore, this highlights the complementarity between
organocatalytic and metal-catalysed boronic acid activations –
organocatalytic methods employing diols and related com-
pounds work best with electron-rich boronic acids, particularly vi-
nyl boronic acids,[18–20] whereas metal-catalysed processes make
electron-poor aryl boronic acids at least viable reaction partners,
Experimental
General Procedure for the Copper-Catalysed Arylation of 4
Dry, degassed DMF (12 ml) was added to a mixture of copper
bromide (0.142 mmol) and 2,2′-bipyridine (26.4 mg, 0.17 mmol)
under N2. The solution was stirred at 60 °C for 1 h. After this time,
starting material 4 (351.2 mg, 1.42 mmol) and aryl boronic acid
(2.84 mmol) were charged to the flask, along with powdered 3 Å
molecular sieves. The solution was stirred at 70 °C under N2 for
24 h and subsequently filtered on a short silica pad. The residue
was then purified by column chromatography on silica gel.
CuX + Ln
X
N
Ar
Acknowledgements
B(OH)2
1-3
EtO
O
5
LnCuX
We thank Trinity College Dublin for funding and Dr John O’Brien
and Dr Manuel Reuther for assistance with NMR analysis.
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OH
LnCu
N
B
X
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