This journal is
©
The Royal Society of Chemistry 2014 Chem.Soc.Rev.,2014, 43, 3229--3243 | 3229
Cite this: Chem. Soc. Rev., 2014,
43, 3229
Functional group directed C–H borylation†
A. Ros,*
a
R. Ferna
´
ndez*
b
and J. M. Lassaletta*
a
The direct borylation of hydrocarbons via C–H activation has reached an impressive level of sophistication
and efficiency, emerging as a fundamental tool in synthesis because of the versatility offered by organo-
boron compounds. As a remarkable particularity, the catalytic systems originally developed for these reac-
tions are relatively insensitive to directing effects, and the regioselectivity of the borylations is typically
governed by steric factors. Likely stimulated by the great synthetic potential of the expected functionalised
organoboranes, however, many groups have recently focused on the development of complementary
strategies for directed, site-selective borylation reactions where a directing group controls the course of
the reaction. In this tutorial review, the different strategies and findings related to the development of
these directed borylation reactions via C(sp
2
)–H or C(sp
3
)–H activation will be summarized and discussed.
Key learning points
(1) Transition-metal catalysis
(2) C–H bond activation
(3) Directing groups
(4) Ligand design
(5) Atom economy
1. Introduction
Direct CH activation/func tionali zation of hydrocarbo ns has
evolved as one of the most fundamental tools in modern synthetic
chemistry, because it enables atom-economic, straightforward
routes to achieve functionalised value-added products and inter-
mediates. One of the most efficient reactions in this field is the
direct borylation of hydrocarbons including arenes, alkenes and
alkanes, which, in combination with cross-coupling methodolo-
gies, represents a powerful methodology for the functionalization
of raw materials (Scheme 1).
1
Until recently, the regioselectivity in most of the catalytic pro-
cesses developed for the borylatio n of alkanes and arenes was mainly
governed by steric factors,
2
and this circumstance has been exploited
by using the direct borylation as a complementary tool to the well
established directed ortho metalation (DoM) methodologies.
3
It is clear, however, that much of the interest in the direct
borylation of hydrocarbons relies on the advantages that
organoboron compounds offer over more basic (or more toxic)
aryl/alkyl metals, not only because of their higher versatility in
cross-coupling applications, but also because of the specific
transformations developed for organoboranes, including oxida-
tion, halogenation, amination, etherification (known as the
Chan–Lam–Evans
4
reaction), etc.
5
In fact, the synthesis of bory-
lated products has been accomplished in an indirect way via a
directed metalation/borylation (transmetalation) sequence.
6
As a consequence, the development of site-selective directed
borylations (Scheme 2) provides a very attractive alternative to the
directed ortho metalation (DoM) methodologies, not in terms of
complementarity but because of the distinct synthetic potential
Scheme 1 Functionalization of hydrocarbons via direct borylation/cross-
coupling strategies.
a
Instituto de Investigaciones Quı
´
micas (C SIC-US), Ame
´
rico V espucio 49,
E-41092 Sevilla, Spain. E-mail: jmlassa@iiq.csic.es; Fax: +34 954460565;
Tel: +34 954489563
b
Departamento de Quı
´
mica Orga
´
nica, Universidad de Sevilla, C/ Prof. Garcı
´
a
Gonza
´
lez, 1, 41012 Sevilla, Spain. E-mail: ffer nan@us.es; Fax: +34 954624960;
Tel: +34 954551518
† Dedicated to Professor Ernesto Carmona on the occasion of his 65th birthday.
Received 18th November 2013
DOI: 10.1039/c3cs60418g
www.rsc.org/csr
Chem Soc Rev
TUTORIAL REVIEW
Published on 20 February 2014. Downloaded by Centro de Investigaciones Cientificas Isla de la Cartuja (CICIC) on 24/06/2014 10:21:16.
View Article Online
View Journal
| View Issue
3230 | Chem.Soc.Rev.,2014, 43, 3229--3243 This journal is
©
The Royal Society of Chemistry 2014
(much broader functional group compatibility, tolerance to oxy-
gen, protic media, etc.) of organoboranes. An additional advant-
age of these methods is that cryogenic cooling can be avoided,
eventually reducing energy costs in large scale reactions. Conse-
quently, the development of methods and strategies toward this
goal h as received considerable attention in the last few years.
The aim of this review is to offer an overview of the recent advances
in this field. Indirect approaches based on transmetalation of
boron will not be discussed herein.
2. Directed borylations via C(sp
2
)–H
activation
As is the case in many other catalytic C–H functionalizations,
the directed borylation via C–H activation was first developed in
Scheme 2 Functionalization of hydrocarbons via direct borylation/cross-
coupling strategies.
Scheme 3 Analysis of regioselectivity in Ir-catalysed borylations.
R. Ferna
´
ndez
Rosario Ferna
´
ndez studied
chemistry at the University of
Seville and received both her BS
degree (1980) and her PhD degree
(1985) under the supervision of
Prof. Antonio Go
´
mez Sa
´
nchez. She
was a NATO postdoctoral fellow at
the University of Paris-Sud (Orsay,
France) in the laboratory of Prof.
Serge David from 1986 to 1987. In
1987 she returned to the University
of Seville, where she was promoted
to Associate Professor. In 2008 she
became a Full Prof. at the same
University. Her current research interests include asymmetric
synthesis and enantioselective catalysis, in both aspects, asymmetric
metal catalysis and organocatalysis.
J. M. Lassaletta
Jose
´
Marı
´
a Lassaletta received his
BS and his PhD in 1990 under the
supervision of Prof. Go
´
mez-Guille
´
n
at the University of Seville. After a
postdoctoral stage in the ‘Instituto
de la Grasa y sus Derivados’ (CSIC,
Seville) he joined the group of
Professor Richard R. Schmidt
(U. Konstanz, Germany). In 1995
he moved to the Instituto de
Investigaciones Quı
´
micas (CSIC,
Seville), where he was promoted
to Tenured Scientist in 1996,
Research Scientist in 2005 and
Research Professor in 2009. He is currently interested in the
development of synthetic methodologies, cross-coupling and C–H
activation strategies, and ligand design, with emphasis on hydrazones
and N-heterocyclic carbenes, and asymmetric organocatalysis.
A. Ros
Abel Ros studied at the University
of Seville obtaining his BS (2001)
and PhD degrees in Chemistry
(2006), under the supervision of
Prof. R. Ferna
´
ndez and Dr J. M.
Lassaletta. After a postdoctoral
period working for Bayer
CropScience (2006–2007), he
joined the group of Prof. Aggar-
wal (U. Bristol, UK) as an IEF-
Marie Curie fellow (2008–2010).
In 2010 he joined the group of Dr
Jose
´
M. Lassaletta at Instituto de
Investigaciones Quı
´
micas as an
ERC-Marie Curie fellow and, since 2012, he has been a JAE-
postdoctoral researcher. He is currently interested in metal-
catalyzed asymmetric methodologies, especially the asymmetric
Suzuki–Miyaura reaction and C–H bond functionalizations.
Tutorial Review Chem Soc Rev
Published on 20 February 2014. Downloaded by Centro de Investigaciones Cientificas Isla de la Cartuja (CICIC) on 24/06/2014 10:21:16.
View Article Online
This journal is
©
The Royal Society of Chemistry 2014 Chem.Soc.Rev.,2014, 43, 3229--3243 | 3231
arenes and heteroarenes. The different approaches have been
classified by the transition metal used.
2.1. Ir-catalysed borylations
It has been demonstrated that direct borylation catalysed by the
1 : 2 [Ir(m-X)(cod)]
2
/dtbpy (X = Cl, OMe) system takes place
through a [Ir(dtbpy)(Bpin)
3
] 16e
catalytically active species
A.
7,8
The lack of sensitivity of this process towards any directing
effects by basic functionalities in the substrate can be arguably
attributed to the lack of additional vacant coordination sites in
the complex B formed upon coordination of directing function-
alities. In this scenario, the reaction can only proceed via
intermediate C, and steric factors represent the main contribu-
tion to regioselectivity (Scheme 3).
In order to enable directing group effects in these reactions,
different strategies based on catalyst or substrate modification
have been recently developed, affording attractive site-selective
borylation methodologies for the synthesis of ortho-substituted
arylboronic esters and related borylated compounds. Three
types of approaches have been designed, with strategies
comprising:
2.1.1. Chelate-directed borylations. The first strategy con-
sists of the development of borylation procedures enabled by
initial coordination of a basic functionality (the more classical
type of directing groups) to the Ir catalyst. In this case,
modification of the ligand is the key to facilitate the generation
of an additional vacant coordination site in the catalyst–
substrate complex. Ishiyama, Miyaura et al. developed a catalytic
system based on the use of [Ir(m-OMe)(cod)]
2
as the iridium source,
and an electron-poor phosphine such as P[3,5-(CF
3
)
2
C
6
H
3
]
3
as the
ligand, which was able to catalyse the site-selective borylation of
several substrates containing oxygen-based directing groups.
This method was first applied to the ortho-regioselective boryla-
tion of benzoates (Scheme 4).
9
Using B
2
pin
2
as the reagent, these
reactions take place in octane at 80 1C for 16 h, leading to the
corresponding products in high yields and with complete regio-
selectivity, although a considerable excess of arene (5 eq.) is
needed to avoid partial ortho,ortho
0
-diborylations. The reactions
tolerate the use of methyl, ethyl, isopropyl and tert-butyl esters
as directing groups, while being suitable for substrates possessing
electron-donating or electron-withdrawing functional groups.
The methodology has also been extended to the borylation of
aryl ketones such as acetophenone, but a modest 56% yield
of the ortho-borylated product was attained in this case.
10
The
substitution of the phosphine ligand by AsPh
3
, however,
increases the catalyst activity, so yields higher than 100% based
on the B
2
pin
2
reagent were observed.‡ The reactions take place
at 120 1C for 16 h, with a broad family of ketones containing
different functional groups, to give the corresponding ortho-
borylated products in high GC yields. A drop in the yield of
ca. 50% was observed after bulb-to-bulb distillation. The catalytic
system 2 : 1 AsPh
3
–[Ir(m-OMe)(cod)]
2
also works for the borylation
of C–H bonds of non-aromatic systems such as the vinylic
b position of a,b-unsaturated esters.
11
Thus, 1-cycloalkene-
carboxylates can be borylated at the sp
2
carbon with total
regioselectivity affording the corresponding borylated products
in moderate to excellent 20–96% yields. This borylation reaction
is compatible with the presence of different groups in the ester
moiety. It is noteworthy that the phenyl group, which should be
borylated under the Ir-catalysed borylation conditions, remains
unmodified after the reaction.
A different approach toward directed, site-selective boryla-
tions was recently reported by Sawamura et al.
12
In this case, a
solid-supported monophosphine–Ir system, Silica-SMAP–Ir,
was used as a suitable catalyst for the directed ortho-borylation
of functionalised arenes in a very efficient manner. This reaction
is successful with a range of functionalised arenes with different
oxygenated directing groups, such as benzoates, benzamides,
arylsulfonates, benzyl acetals, benzyl methoxymethylethers, lead-
ing to the corresponding borylated products with complete
ortho-regioselectivity and good to excellent yields (based on
B
2
pin
2
using a 2 : 1 substrate-B
2
pin
2
ratio) in most cases
(Scheme 5). It is noteworthy that even the chlorine atom of aryl
chlorides can behave as a directing group, though the ortho/para
selectivity (92 : 8 for the unsubstituted chlorobenzene) is not
perfect in this case. Immobilization of the phosphine ligand in
the silica support proved to be essential, as the analogue boryla-
tion performed in homogeneous media using [Ir(m-OMe)(cod)]
2
and monomeric Ph-SMAP (0.5 mol% Ir, 1 : 1 or 1 : 2 Ir/P) afforded
only trace conversion at 25 1C. No reaction was observed with
other phosphines such as 4-CF
3
-Ph-SMAP, PPh
3
,P(tBu)
3
,PCy
3
,
and PMe
3
(using 1 : 1 or 1 : 2 Ir/P ratios) under the same reaction
conditions. Presumably, the supported catalyst assists the for-
mation of 14-electron intermediates necessary for the successive
coordination/CH activation of the substrate. Unfortunately, this
heterogeneous catalyst cannot be recovered for recycling.
Scheme 4 Oxygen-directed Ir-catalysed borylations.
‡ Yields higher than 100% are calculated on B
2
pin
2
(limiting reagent) and
indicate that the catalyst can also use the HBpin generated in the initial reaction
as a boron source after all the B
2
pin
2
is consumed.
Chem Soc Rev Tutorial Review
Published on 20 February 2014. Downloaded by Centro de Investigaciones Cientificas Isla de la Cartuja (CICIC) on 24/06/2014 10:21:16.
View Article Online
3232 | Chem.Soc.Rev.,2014, 43, 3229--3243 This journal is
©
The Royal Society of Chemistry 2014
This methodology was further extended to phenol deriva-
tives bearing oxygenated protecting/directing groups such as
carbamates, carbonates, phosphorodiamides and sulfonates
13
(Scheme 6). All these groups provide complete ortho-regioselectivity
in the borylation reaction with B
2
pin
2
, but moderate to good yields
are achieved only with carbamates. Finally, the method has also
been applied for the site-selective borylation of heteroarenes includ-
ing thiophene, pyrrole, furan, benzothiophene, benzofuran, and
indole derivatives, using in all cases the 2-methoxycarbonyl directing
group. In the case of thiophenes and furans, however, minor
amounts of regioisomers resulting from the borylation at position
5werealsoobserved.
14
With the exception of carbazole, borylation takes place in
the heterocycle at the vicinal position to the directing group.
Interestingly, in the case of 2-methoxycarbonylindoles, the
borylation at position 3 provides a complementary regioselec-
tivity to the previously reported method
15
where the borylation
takes place at the 7-position (vide infra).
The methodologies described above provide satisfactory solu-
tions for the directed borylation of a wide range of arenes,
heteroarenes and alkenes, but are limited to oxygenated directing
groups, and do not work when nitrogen-based directing groups
are used. An early report by Maleczka, Smith and co-workers on
the borylation of 2-substituted indoles, appears to be an excep-
tion.
15
Using the [Ir(m-OMe)(cod) ]
2
/dtbpy catalytic system, these
compounds yield selective borylation at the 7-position, which, as
mentioned above, is complementary to the selectivity achieved
with silica-supported SMAP–Ir.
14
Although the mechanism
remains unclear, control experiments and labelling studies per-
formed so far support a mechanism where N-chelation to the
iridium center (or the boron atom of a boryl ligand) directs the
borylation (Scheme 7). The observed selectivity is also consistent
with an alternative mechanism involving H-bonding of the NH
proton to an O atom of the boryl ligands in the catalyst (vide infra),
but a similar regioselectivity observed for benzofuran suggests
that such an interaction is not a requisite.
As a second exception, Steel, Marder, Sawamura and co-workers
have recently reported on the C(8)-selective borylation of
quinolines using the previ ously mentioned Silica-S MAP–Ir
system (Scheme 8).
16
The development of a more general approach for the nitrogen-
directed Ir-catalyzed arene ortho-borylations was recently reported
by us.
17
We envisaged that replacement of the dtbpy ligand in
complex B (Scheme 2) by a hemilabile N,N ligand should facilitate
the temporary generation of a coordinatively unsaturated inter-
mediate III from the established catalytic species I via complex II.
This complex III is preorganized for the intramolecular activation
of C(ortho)–H bonds (-IV), from which reductive elimination
(-V) and re-coordination of the hemilabile ligand (-VI)leadto
the product and regenerate the catalyst I after reaction with B
2
pin
2
(Scheme 9).
In particular, picolinaldehyde N,N-dibenzylhydrazone L1
combined with [Ir(m-OMe)(cod)]
2
proved to be a very efficient
ligand for the borylation of 1-naphthylisoquinolines and
2-arylpyridines with B
2
pin
2
under mild conditions. Two types
of products were observed, depending on the steric hindrance
around the biaryl axis. Thus, X-ray diffraction and NMR data for
hindered products revealed no internal N–B interactions, and
Scheme 5 Oxygen-directed borylations with Ir-supported catalysts.
Scheme 6 Oxygen-directed borylations with Ir-supported catalysts.
Scheme 7 Selective borylation of 2-substituted indoles.
Scheme 8 Selective borylation of quinolines.
Tutorial Review Chem Soc Rev
Published on 20 February 2014. Downloaded by Centro de Investigaciones Cientificas Isla de la Cartuja (CICIC) on 24/06/2014 10:21:16.
View Article Online
This journal is
©
The Royal Society of Chemistry 2014 Chem.Soc.Rev.,2014, 43, 3229--3243 | 3233
the (hetero)aromatic rings arrange in a perpendicular fashion.
On the other hand, less hindered products present intra-
molecular N–B bonds in planar structures (Scheme 10).
This methodology has been applied to the preparation of BAI
(borylated aryl isoquinolines) dyes as a new class of fluorophores
with potential as ion-triggered molecular switches (Fig. 1).
18
After introduction of an additional 4-methylpiperazin-1-yl group,
these compounds also appear as interesting platforms for the
design of multi-level logic switches as a consequence of the
observed off–on–off ternary and quaternary responses to ortho-
gonal protonation.
19
The reaction has also been extended to the site-selective ortho-
borylation of aromat ic N,N-dimet hylhydrazones (Sche me 11,
method A).
17
The reaction proceeds efficiently for derivatives
carrying electron-withdrawing or donating substituents at any
position of the aromatic ring, and allowed clean monoborylations
of C-6 unsubstituted substrates. In order to increase the activity of
the catalyst, the original picoline dibenzylhydrazone ligand L1 was
modified by the introduction of electron-donating groups
(NMe
2
,
t
Bu) at the 4-position of the pyridine ring. The use of the
best DMAP/hydrazone ligand L2 allowed using cheaper and more
‘atom-economic’ HBpin as the boron source in the same site-
selective borylations (method B).
20
The reaction crudes can be
used in Suzuki–Miyaura couplingswithoutanyfurtherpurifica-
tion, and the resulting biphenyl derivatives can be transformed
into valuable intermediates for the synthesis of modified Sartan-
type drugs upon high yielding, ‘one-pot’ functional group
transformations.
NMR and X-ray data for monoborylated N,N-dimethylhydrazones
indicated the absence of N–B interactions in these products,
17,20
a
fact that can be attributed to the significant NMe
2
/Me(pinacol) steric
repulsion. Therefore, the hydrazone N(sp
2
) atom remains available
to achieve a second directed borylation. Consequently, aromatic N,N-
dimethylhydrazones can be ortho,ortho
0
-diborylated in nearly quan-
titative yields (Scheme 12).
21
These products proved to be useful
synthetic intermediates that can be unsymmetrically function-
alised by introduction of two different electrophiles.
In a related context, Clark et al.
22
have recently reported the
nitrogen-directed ortho-C–H borylation of benzylic amines
using the picolylamine ligand–[Ir(m-OMe)(cod)]
2
(2 : 1) system
as the catalyst (Scheme 13). The original idea was to use
bifunctional ligands containing N–H bonds that could be used
to direct C–H borylation through hydrogen bonding to the
directing group (Lewis base) in the substrate, but during the
study they observed that the N,N-dimethylated ligand (lacking
N–H bonds) afforded the corresponding ortho-borylated pro-
duct with equal regioselectivity and higher yield. In accordance
with this result, the origin of the ortho-regioselectivity seems to
lie in the hemilability of the ligand,
17
instead of a hydrogen
bonding directing effect as it was originally proposed.
2.1.2. Relay-directed borylations. A second strategy devel-
oped by Hartwig and co-workers for the site-selective Ir(
III)-
catalysed borylation of arenes is based on the use of silanes as
traceless directing groups (Scheme 14).
23
Using benzyl
dimethylsilanes as substrates, it was envisaged that an initial
Si–H/Ir–B s-bond metathesis between the above mentioned
catalytically active species I and the substrate would render a
silyl bis-boryl Ir complex II in which the intramolecular activa-
tion of the ortho CH bonds takes place preferentially to afford
intermediate III which after reductive elimination (-IV) and
Scheme 9 Envisaged mechanism using hemilabile N,N-ligands.
Scheme 10 Directed borylation of arylpyridines/isoquinolines.
Fig. 1 Borylated aryl isoquinoline (BAI) dyes.
Chem Soc Rev Tutorial Review
Published on 20 February 2014. Downloaded by Centro de Investigaciones Cientificas Isla de la Cartuja (CICIC) on 24/06/2014 10:21:16.
View Article Online
