Base free aryl coupling of diazonium compounds and boronic esters: Self-activation allowing an overall highly practical process

Article abstract of DOI:10.1039/b926547n

Boronic esters have long been considered as poor partners in cross-coupling reactions with arene diazoniums. Here is reported an unprecedented application of self-activated boronic esters in a base-free cross-coupling reaction with diazonium salts under mild and user friendly conditions.

Full text of DOI:10.1039/b926547n

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Base free aryl coupling of diazonium compounds and boronic esters:
self-activation allowing an overall highly practical processw
a
b
b
acd
´
Helene Bonin, Dominique Delbrayelle, Patrice Demonchaux and Emmanuel Gras*
Received (in Cambridge, UK) 9th December 2009, Accepted 12th January 2010
First published as an Advance Article on the web 8th February 2010
DOI: 10.1039/b926547n
Boronic esters have long been considered as poor partners in
cross-coupling reactions with arene diazoniums. Here is reported
an unprecedented application of self-activated boronic esters in a
base-free cross-coupling reaction with diazonium salts under
mild and user friendly conditions.
and cyclic triolborates.19 Interestingly, deactivation by
pyramidalisation of boron has also been nicely exemplified
by Burke,20 allowing orthogonal cross-coupling.21 On the
other hand boronic esters have represented the ‘‘historical’’
alternative, but significantly these esters have been proven to
be unable to couple with diazonium salts as reported in the
seminal work of Genet et al.22 Indeed, only one coupling
reaction of boronic esters with diazonium salts has been
successfully achieved, but required the assistance of basic
fluoride ions.23 In preliminary studies we have established by
simple 11B NMR studies that the fluoride assistance involves a
pyramidalisation of boron (see ESIw).
The Suzuki–Miyaura Reaction (SMR) is the most developed
metal-catalysed cross-coupling reaction, proving unrivaled in
terms of its scope and efficiency.1 It has been applied in a wide
variety of applications including organic synthesis, materials,
and medicinal chemistry, etc.2–6 Nevertheless, there is still an
intense research effort directed towards further enhancing the
SMR; numerous ligands have been developed and there are
now systems of high efficiency and tolerating bulk and various
organic functions.7–9 In contrast not much attention has been
paid to the organic partners involved in these cross-couplings,
with easily purified and isolated substrates being of major
importance from a synthetic point of view. The electrophilic
partners involved in SMRs are generally halogens or triflates.
Oppositely bench-stable diazonium tetrafluoroborates that
exhibit excellent leaving group ability have been barely
involved in these reactions.10,11 Nevertheless, being both easily
prepared from cheap, readily available anilines and highly
reactive they represent an excellent alternative to halogenated
compounds and related substrates.
Herein we report the first base-free coupling of boronic
esters self-activated by way of an intramolecular N - B
interaction (i.e. using dioxazaborocanes) in cross-coupling
reactions with diazonium salts.
Indeed a boronic ester being self-activated by a pendant
coordinating site should be the substrate of choice for
cross-coupling reactions involving diazonium salts eliminating
the necessity for additional base. This indicated that dioxaza-
borocanes, whose pyramidalised structure at boron has clearly
been established by X-ray crystallography in the solid state, were
likely candidates.24 To facilitate purification and handling, it was
of interest to introduce a polar bond (such as an N–H) to
possibly increase the crystaline character of the target compound.
Dioxazaborocanes derived from addition of diethanolamine to
boronic acids were therefore the target of choice.
In contrast, the nature of the nucleophilic coupling partner
has only very recently received serious investigation. Indeed, for
decades boronic acids have been extensively used despite their
contamination by hard to separate boroxines and/or boric acid
necessitate their use in greater than stoichiometric quantities.
The use of tetravalent boron substrates in SMR represents a
relevant approach currently thoroughly explored. It is well
known that boron tends to transfer one substituent when its
number of valence electrons is increased from 6 to 8.12 This
electronic change is associated with a switch from a trigonal to a
pyramidal geometry at boron. Computational investigations
describing the role of the base in the SM cross-coupling have
also brought further evidence for this electronic effect.13 Despite
their limited use, these recently developed tetravalent boronic
derivatives couple very efficiently with halogenated counterparts
as exemplified with trifluoroborate salts,14,15 un-isolated
trialkylborates,16 sodium trihydroxyborates,17 tetraarylborates,18
As shown in Table
1 dioxazaborocanes were readily
prepared by simple addition of diethanolamine to 2-fluoro-3-
methoxy-phenylboronic acid. This led to the corresponding
dioxazaborocane in quantitative yield and high purity following
simple filtration (entry 1). The ease and efficiency of this
methodology prompted us to establish a simple one-pot
procedure for the synthesis of dioxazaborocanes from aryl
bromide compounds. Initial lithium-halogen exchange was
carried out employing aryl bromide starting materials, which
was followed by addition of triisopropylborate and finally by
washing of the organic phase with saturated NH4Cl to yield the
crude boronic acids in solution. Treatment of the latter with a
3 M solution of diethanolamine in isopropanol then afforded
the desired dioxazaborocane in a highly pure form as crystalline
solids after a simple filtration.25 As shown in Table 1 entries 2
and 3, isolated yields of dioxazaborocanes were similar to the
isolated yields reported for the corresponding boronic
acids.26–28 Unprotected phenol could be efficiently employed
(entry 4) yielding the dioxazaborocane of this unusual, barely
described boronic acid.29 Benzaldehyde derivatives were
also obtained in excellent yields either unprotected (entries 5
and 7) or protected (entry 6).30,31 Finally, benzonitrile-derived
a
´
CNRS, Universite Paul Sabatier, LSPCMIB, 118,
route de Narbonne, F-31062 Toulouse Cedex 9, France
b Minakem, 145, Chemin des Lilas, F-59310 Beuvry-La-Foreˆt, France
c CNRS, LCC, 205 route de Narbonne, F-31077 Toulouse, France
d
´
Universite de Toulouse, UPS, INPT, LCC, F31077 Toulouse,
France. E-mail: emmanuel.gras@lcc-toulouse.fr
w Electronic supplementary information (ESI) available: Experimental
details and analytical data. See DOI: 10.1039/b926547n
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2677–2679 | 2677

View Online
Table 1 Synthesis of dioxazaborocanes
Typically the reaction of a diazonium salt 1 with a dioxaza-
borocane 2 yields the cross-coupling product 3 with various
amounts of homocoupling of the boronic ester 4. We have more
specifically investigated the effect of the relative ratio of the two
coupling partners, the nature of the palladium source and
copper cocatalyst, the influence of the solvent, the temperature
and the reaction time on the outcome of the reaction (yield and
4/3 ratio).
Entry
R=
Yield (%)a
1
2
3
4
5
6
7
8
2-F, 3-OMe
H
4-OMe
4-OH
4-CHO
3-(OCH2)2
3-CHO
4-CN
98b
73
Although no direct correlations can be made, the following
general trends are apparent: (i) copper(I) iodide exhibits a
detrimental effect on the 3/4 ratio (entries 1 and 2); (ii) a slight
excess (or slow addition) of the diazonium component gave
enhanced 3/4 ratios (entries 2 and 3); (iii) a strong solvent
effect was observed; isopropanol only afforded rather sluggish
reactions (entries 1–3), but methanol had a huge accelerating
effect with reaction completion achieved in less than 10 min
(entries 4, 6–8); (iv) palladium is essential for the reaction to
proceed (entry 5) and the nature of the palladium source
exhibits a major role on the fate of the reaction. Pd(OAc)2
was only moderately efficient (entry 4), whereas palladium on
charcoal or Herrmann’s catalyst gave significantly enhanced
catalytic performance yielding only the desired cross-coupling
product with the former requiring heating (entries 6 and 8).40
The use of Pd2dba3 resulted in a slight but significant drop in
yield (entry 7).
77
63c
73d
63
63d
71e
a
b
Unoptimised yields. Obtained from the boronic acid. 3 eq. of
c
d
t-BuLi used instead of 1 eq. of n-BuLi. Starting from the corresponding
e
dioxolane and using 1 M HCl instead of ammonium chloride. During
the first 2 steps the temperature was maintained below À100 1C.
dioxazaborocanes was also prepared with high efficiency.32,33 It is
also noteworthy that transesterification from pinacol boronate to
the dioxazaborocane was also performed.34 Dioxazaborocanes
might therefore be accessed under very mild conditions after
C–H or C–X borylation with bis-pinacoldiboron.35–37
The pyramidalisation of boron has been unambiguously
confirmed in solution by 11B NMR spectroscopy and in the
solid state by X-ray structural studies on 4-methoxyphenyl
dioxazaborocane as a model structure. The 11B chemical shift
is decreased from around 30 ppm for boronic acids and esters
to 10 ppm for dioxazaborocanes clearly accounting for the
B–N interaction in CD3OD and DMSO solution. In the solid
state the B–N distance of 1.675 A is significantly lower
than the sum of the Van der Waals radii (2.91 A) therefore
establishing the B–N interaction.38
Having established these optimised conditions, the cross-
coupling of an array of diazonium salts 5 with a range
of dioxazaborocanes
6 was examined (Table 3). The
4-nitrodiazonium salt has been shown to couple efficiently
with dioxazaborocanes bearing an electron donating group or
an electron withdrawing group in the meta or para positions
(entries 1–4). Only the cyanodioxazaborocane unexpectedly
and repeatedly proved to be a poor partner with this electron
poor aryldiazonium (entry 5).
The most efficient cross-coupling conditions were
established using a non-linear optimisation (Table 2).39
Moving to an electron rich diazonium partner proved to
be detrimental with the simplest dioxazaborocane, but
Table 2 Reaction condition optimisation
Entry
1 (eq.)
2 (eq.)
Time/min
Catalyst 5% mol
Solvent
T/1C
3d
4d
b
1
2
3
4
5
6
7
8
1
1,2
1
1
1
1
1
1
1
2880
2880
720
10
1440
10
10
Pd(OAc)2
Pd(OAc)2
Pd/C
i-PrOH
i-PrOH
i-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
25
25
50
25
50
50
25
25
26
49
24
44
0
83
63
78
34
22
6
15
0
4
9
4
1a
1.2a
1
1.5
1.5
1.5
1.5
Pd(OAc)2
None
Pd/C
Pd2dba3
HCc
5
a
b
c
d
Slow addition rate. 10% mol CuI. Hermann’s catalyst [trans-di(m-acetato)bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium(II)]. Isolated
yields.
ꢀc
This journal is The Royal Society of Chemistry 2010
2678 | Chem. Commun., 2010, 46, 2677–2679

View Online
Table 3 Cross-coupling of arene diazonium salts with dioxaza-
borocanes
4 T. S. Jo, S. H. Kim, J. Shin and C. Bae, J. Am. Chem. Soc., 2009,
131, 1656–1657.
5 Y. L. Zhong, K. P. Loh, A. Midya and Z.-K. Chen, Chem. Mater.,
2008, 20, 3137–3144.
6 Q. Yang, H. Jin, Y. Xu, P. Wang, X. Liang, Z. Shen, X. Chen,
D. Zou, X. Fan and Q. Zhou, Macromolecules, 2009, 42, 1037–1046.
7 R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461–1473.
8 N. Marion and S. Nolan, Acc. Chem. Res., 2008, 41, 1440–1449.
´
9 M. Blug, C. Guibert, X. Le Goff, N. Mezailles and P. Le Floch,
Chem. Commun., 2009, 201–203.
10 S. Sengupta and S. Bhattacharyya, J. Org. Chem., 1997, 62,
3405–3406.
11 S. Darses, G. Michaud and J.-P. Genet, Tetrahedron Lett., 1998,
39, 5045–5048.
Entry R1
R2
Reaction time/min Isolated yield
12 Bottoni, M. Lombardo, A. Neri and C. Trombini, J. Org. Chem.,
2003, 68, 3397–3405.
13 A. Braga, G. Ujaque and F. Maseras, Organometallics, 2006, 25,
3647–3658.
14 S. Darses and J. P. Genet, Chem. Rev., 2008, 108, 288–325.
15 G. A. Molander and B. Canturk, Angew. Chem., Int. Ed., 2009, 48,
9240–9261.
16 K. L. Billingsley and S. L. Buchwald, Angew. Chem., Int. Ed., 2008,
47, 4695–4698.
17 A. N. Cammidge, V. H. M. Goddard, H. Gopee, N. L. Harrison,
D. L. Hughes, C. J. Schubert, B. M. Sutton, G. L. Watts and
A. J. Whitehead, Org. Lett., 2006, 8, 4071–4074.
18 G. Lu, R. Franzen, Q. Zhang and Y. Xu, Tetrahedron Lett., 2005,
46, 4255–4259.
19 Y. Yamamoto, M. Takizawa, X.-Q. Yu and N. Miyaura, Angew.
Chem., Int. Ed., 2008, 47, 928–931.
20 E. P. Gillis and M. D. Burke, J. Am. Chem. Soc., 2007, 129,
6716–6717.
1
4-NO2
H
10
5
88
83
92
96
15
10
49
20
86
80
72
78
88
82
90
77
80
80
43
58
2
3
4
5
4-NO2
4-NO2
4-NO2
4-NO2
4-OMe
4-OMe
4-CHO
3-CHO
4-CN
H
10
30
30
30
30
30
30
15
30
30
30
30
30
6
7
4-OMe 4-OH
8
9
2-Ac
4-Br
4-Br
4-Br
4-Br
4-I
4-CHO
H
4-OMe
4-CHO
3-CHO
H
4-OMe
H
2-F-3-OMe 30
4-OMe
3-CHO
4-OMe
4-OMe
10
11
12
13
14
15
16
17
18
19
20
4-I
3-Br
3-Br
3-Br
3-Br
2-Br
2-CF3
30
30
20
20
21 M. Tobisu and N. Chatani, Angew. Chem., Int. Ed., 2009, 48,
3565–3568.
22 S. Darses, T. Jeffery, J.-P. Genet, J.-L. Brayer and J.-P. Demoute,
Tetrahedron Lett., 1996, 37, 3857–3860.
23 D. M. Willis and R. M. Strongin, Tetrahedron Lett., 2000, 41,
6271–6274.
readily afforded the unsymmetrical dioxygenated biphenyl
(entries 6 & 7). A biscarbonylated biphenyl was prepared
using this methodology, but only in poor yields (entry 8). As
expected, complete chemoselectivity is achieved when para-,
meta- and ortho-halogenated diazonium salts are involved,
potentially opening the possibility to undertake further
functionalisation via the halogen (entries 9–19).41 Noticeably
the presence of a fluorine ortho to the boron moiety does not
inhibit the coupling as exemplified by the preparation of the
polyhalogenated biphenyl in good yield (entry 16). Finally,
bulky ortho-trifluoromethylated diazonium was also success-
fully employed as a substrate (entry 20). It should be noted,
however, that ortho substitution tends to lower the reaction
efficiency (entries 19–20). In summary, this work represents
the first example of base-free cross-coupling of boronic
esters with diazonium salts. We have established that simple
dioxazaborocanes are useful and commonly high yielding
substrates for SMR chemistry. Moreover, they are easy to
prepare and handle and only require the use of a single
equivalent for the cross-coupling reaction. These features are
of high interest for preparative purposes and should be
attractive to both the academic and industrial communities.
Minakem (PhD grant for H.B.), the CNRS and the
University Paul Sabatier are acknowledged for their support.
24 H. Hopfl, J. Organomet. Chem., 1999, 581, 129–149.
¨
25 According to a reaction search on CAS, yields claimed for boronic
acids using a similar process vary from 20% to quantitative,
testifying the reproducibility issue.
26 S. S. Moleele, J. P. Michael and C. B. De Koning, Tetrahedron,
2006, 62, 2831–2844.
27 Y. Iwai, K. M. Gligorich and M. S. Sigman, Angew. Chem., Int.
Ed., 2008, 47, 3219–3222.
28 T. Fukuda, E.-i. Sudo, K. Shimokawa and M. Iwao, Tetrahedron,
2008, 64, 328–338.
29 J.-P. Chao, W.-Q. Wu, X.-D. Luo and Y.-Z. Ling, Youji Huaxue,
2006, 26, 1004–1007.
30 D. Cousin, J. Mann, M. Nieuwenhuyzen and H. Van den Berg,
Org. Biomol. Chem., 2006, 4, 54–62.
31 L. Vandromme, H.-U. ReiBig, S. Groper and J. P. Rabe, Eur. J.
Org. Chem., 2008, 2049–2055.
32 A. Littke, M. Soumeillant, R. F. Kaltenbach, III, R. J. Cherney,
C. M. Tarby and S. Kiau, Org. Lett., 2007, 9, 1711–1714.
33 M. Nishimura, M. Ueda and N. Miyaura, Tetrahedron, 2002, 58,
5779–5787.
34 A similar exemple has been reported very recently: D. Fandrick,
J. Reeves, Z. Tan, H. Lee and J. Song, Org. Lett., 2009, 11,
5458–5461.
35 I. A. I. Mkhalid, D. N. Coventry, D. Albesa-Jove, A. S. Batsanov,
J. A. K. Howard, R. N. Perutz and T. B. Marder, Angew. Chem.,
Int. Ed., 2006, 45, 489–491.
36 J. M. Murphy, J. D. Lawrence, K. Kawamura, C. Incarvito and
J. F. Hartwig, J. Am. Chem. Soc., 2006, 128, 13684–13685.
37 J. Takagi, K. Takahashi, T. Ishiyama and N. Miyaura, J. Am.
Chem. Soc., 2002, 124, 8001–8006.
38 According to a Cambridge Database search, the average B–N
distance within this class of compound is 1.66 A.
39 W. Spendley, G. R. Hext and F. R. Himsworth, Technometrics,
1962, 4, 441–461.
Notes and references
1 A. Suzuki, Chem. Commun., 2005, 4759–4763.
2 S. Ishikawa and K. Manabe, Chem. Commun., 2006, 2589–2591.
3 A. Collier and G. Wagner, Chem. Commun., 2008, 178–180.
40 M. Beller, H. Fischer, W. Herrmann, K. Ofele and C. Brossmer,
Angew. Chem., Int. Ed. Engl., 1995, 34, 1848–1849.
41 R. H. Taylor and F. X. Felpin, Org. Lett., 2007, 9, 2911–2914.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2677–2679 | 2679