Transient imine as a directing group for the metal-free o-C-H borylation of benzaldehydes

Article abstract of DOI:10.1021/jacs.0c13013

Organoboron reagents are important synthetic intermediates and have wide applications in synthetic organic chemistry. The selective borylation strategies that are currently in use largely rely on the use of transition-metal catalysts. Hence, identifying much milder conditions for transition-metal-free borylation would be highly desirable. We herein present a unified strategy for the selective C-H borylation of electron-deficient benzaldehyde derivatives using a simple metal-free approach, utilizing an imine transient directing group. The strategy covers a wide spectrum of reactions and (i) even highly sterically hindered C-H bonds can be borylated smoothly, (ii) despite the presence of other potential directing groups, the reaction selectively occurs at the o-C-H bond of the benzaldehyde moiety, and (iii) natural products appended to benzaldehyde derivatives can also give the appropriate borylated products. Moreover, the efficacy of the protocol was confirmed by the fact that the reaction proceeds even in the presence of a series of external impurities.

Full text of DOI:10.1021/jacs.0c13013

pubs.acs.org/JACS
Article
Transient Imine as a Directing Group for the Metal-Free o‑C−H
Borylation of Benzaldehydes
Supriya Rej and Naoto Chatani*
Cite This: J. Am. Chem. Soc. 2021, 143, 2920−2929
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Organoboron reagents are important synthetic intermediates and have wide applications in synthetic organic
chemistry. The selective borylation strategies that are currently in use largely rely on the use of transition-metal catalysts. Hence,
identifying much milder conditions for transition-metal-free borylation would be highly desirable. We herein present a unified
strategy for the selective C−H borylation of electron-deficient benzaldehyde derivatives using a simple metal-free approach, utilizing
an imine transient directing group. The strategy covers a wide spectrum of reactions and (i) even highly sterically hindered C−H
bonds can be borylated smoothly, (ii) despite the presence of other potential directing groups, the reaction selectively occurs at the
o-C−H bond of the benzaldehyde moiety, and (iii) natural products appended to benzaldehyde derivatives can also give the
appropriate borylated products. Moreover, the efficacy of the protocol was confirmed by the fact that the reaction proceeds even in
the presence of a series of external impurities.
strategy clearly reduces the step-economical issue because
the installation and removal of the transient directing group
can proceed in a one-pot reaction (Figure 1C). Although these
metal-catalyzed, directed C−H functionalizations are reliable
in terms of regioselectivity, the major concern involves the
requirement of a precious metal and the production of metal-
containing residues in the final product, which clearly limit the
application of this process. Therefore, recent trends involve
metal-free directed approaches. In this regard, the early studies
of metal-free C−H borylation were achieved using various
nitrogen-containing heterocycles such as benzimidazoles,15 2-
mercaptobiphenyl,16 pyridines,17−19 benzothiadiazole,20−22
quinoline,23 benzoselenadiazole, and benzotriazole24 as direct-
ing groups. However, such examples require harsh reaction
conditions, which decrease the substrate scope for the reaction.
Notably, most of the research studies have focused on
materials chemistry, i.e. studies of the physical properties of
boron-containing nitrogen-heterocycles, and the synthetic
utility of this reaction has not flourished much at all. Another
drawback involves the use of a rigid heterocyclic directing
INTRODUCTION
■
During the past two decades, remarkable progress has been
made in transition-metal-catalyzed directed C−H bond
functionalization reactions.1−4 One of the important trans-
formations is borylation to produce organoboron reagents,5,6
which potentially have wide applications in many research
areas, including natural product synthesis, drug discovery, and
advanced material synthesis.7 Among various C−H borylation
strategies,8−11 one of the commonly known strategies is a
metal-catalyzed directed approach, which has been widely
explored due to its reliability and for the high regioselectivity of
such reactions (Figure 1A−C).12,13 Initial explorations in this
area focused on the use of either an in-built directing group, in
which the functional group itself acts as a directing group
(Figure 1A), or a directing group that has been preinstalled on
a functional group (Figure 1B). Although this preinstalled
auxiliary-directed, metal-catalyzed C−H borylation approach
has enjoyed considerable success, one of the major issues is
that this strategy is not step economical because the directing
group needs to be first installed and then removed after the
borylation. Due to the high reactivity of borylated compounds,
the removal of a directing group sometimes results in the
decomposition of the borylated compound. Hence, the further
transformation of the borylated compound is required before
the removal of the directing group. To overcome this issue, a
new concept involving the use of transient directing group
assisted C−H bond functionalization has arisen.14 This
Received: December 16, 2020
Published: February 15, 2021
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929
© 2021 American Chemical Society
2920

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 1. Strategies for directed C−H borylation: (A−C) strategies for transition-metal-catalyzed directed C−H borylation; (D) pathways for
metal-free directed C−H borylation using a preinstalled directing group; (E) metal-free directed C−H borylation of an electron-rich arene system;
(F) Lewis acid promoted transition-metal-free C−H borylation of an electron-rich arene system; (G) our approach for the directed metal-free
borylation of electron-deficient benzaldehyde derivatives using a transient directing group.
group, thus making the removal of the directing group
impossible. Consequently, the borylation was nearly exclusively
limited to heterocyclic compounds.
deficient molecules and generally unreactive in SEAr reactions
(Figure 1G). Using such derivatives would emphasize the
efficacy of a directing group over an electronic effect in this
rection.
Some reports have recently appeared on metal-free C−H
borylation reactions in which a removable or modifiable
directing auxiliary is used.25 For example, the metal-free
directed o-C−H borylation of phenol derivatives using either a
pyridine26 or a phophinite directing group,27 an acyl-group-
directed o-C−H borylation of anilines, the C7−H borylation of
indoles,28−30 and the o-C−H borylation of diphenylamine
were also achieved.31 In these reports, the directing groups
were installed prior to the borylation step. In some cases,
further functionalization of the borylated product was carried
out before the removal of the directing group, due to the low
stability of the boron moiety (Figure 1D). Thus, a unified
directed strategy continues to be needed for metal-free C−H
borylation, in which the installation and removal of a directing
auxiliary can proceed with ease. It should be noted that
previously reported metal-free directed C−H borylation
systems have been applicable to only electron-rich arene
systems, such as phenol, aniline, and indole derivatives, due to
the favorable electrophilic aromatic substitution (SEAr) step
(Figure 1E),26−31 which originated from the previous concept
of the nondirected Lewis acid mediated p-C−H borylation of
an electronically rich system via an SEAr reaction (Figure
1F).32−38 We chose benzaldehyde derivatives for metal-free
directed C−H borylation, since they are highly electron
RESULTS AND DISCUSSION
■
Reaction Development. On consideration of the
coordinating ability of an oxygen atom toward a Lewis acidic
boron atom, an initial coordination of an O atom and B atom
was realized, but no C−H borylation was detected (Scheme
1A). The directing group was then manipulated so as to alter
the electronic effect of an arene system. Imines have been used
as auxiliaries for the transition-metal-catalyzed o-C−H
borylation of aldimines.14,39−44 Hydrazones 1b-NHPh, 1b-
NHSO2Ph, and 1b-NMe2 were examined as directing groups
in an attempt to increase the nucleophilicity of the aromatic
ring. However, the expected products were not formed.
Likewise, an electron-donating oxygen substituent on the
imine 1b-OH also failed to allow the desired electrophilic
borylation reaction to proceed. We next screened aromatic or
aliphatic group substituted imine derivatives. When N-arylated
imines (1b-Ph and 1b-PhOH) were used, the unreacted
starting material was recovered. The breakthrough came when
a N-cyclohexyl substituent (1b-Cy) was used, as 41% of the
expected product was formed. Further tuning of the aliphatic
substituents indicated that a tert-butyl-substituted imine (1b-
tBu) was the superior substituent for producing the desired
2921
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Hence, the product yield for the reaction could not exceed
50%. Considering this fact, we anticipated that a stoichiometric
amount of a base could be used to suppress salt formation.
Another significant advantage of using a base additive would be
that it would react with BBr3 to form an electrophilic boron
species which would be a much more electrophilic species
(vide infra).45 A screening of bases indicated that 2,6-lutidine
was the superior additive, giving the desired product in 90%
yield (Scheme 1B). With the optimized conditions in hand, we
applied this metal-free directed C−H borylation strategy to the
reaction of benzaldehyde 1a by converting it into an imine in a
one-pot reaction. Remarkably, the imine was readily trans-
formed into an aldehyde upon workup with water and the final
product 1d was obtained in 82% isolated yield (Scheme 1C).
Scope. The substrate scope for this metal-free directed C−
H borylation of benzaldehyde derivatives was examined, and
the results are summarized in Scheme 2. All of the ortho-,
meta-, or para-substituted benzaldehydes that were examined
were reactive in this system and afforded the desired products
in good to excellent yields. In the case of meta-substituted
benzaldehydes, a mixture of regioisomers was formed (4d and
16d). Benzaldehyde derivatives bearing methyl (2d−5d), tert-
butyl (6d), phenyl (7d and 8d), thiomethyl (9d), ethoxy
(10d), methoxy (11d), hexyloxy (13d), OTBS (14d, TBS =
tert-butyldimethylsilyl), hydroxy (15d), F (16d and 17d), Cl
(18d−20d), Br (21d and 22d), I (23d), CHO (24d), CF3
(25d), and alkene (26d) substituents were borylated smoothly
and afforded the borylated products in 41−93% yield.
Additionally, aldehydes with an N,N-dimethylamine (27d),
carbazole (28d), or N,N-diphenylamine (29d) moiety also
underwent the borylation reaction selectively at the desired
position despite the presence of another coordinating moiety.
Heterocyclic carboxaldehyde compounds, such as 2-thiophe-
necarboxaldehyde (30a) and N-methylindole-2-carboxalde-
hyde (31a), reacted to give the desired products 30d and
31d in high yields. Notably, in the presence of a slight excess of
BBr3, a substrate bearing a m-methoxy group can undergo
successive directed o-C−H borylation and O-demethylation to
give the corresponding product 12d in 72% yield. Aldimines
that contained an additional highly electron withdrawing
group, 32d and 33d, were unreactive. It was found that other
boronate esters can be conveniently accessed when different
diols are used instead of pinacol (1e,f).
Scheme 1. Development of Metal-Free Directed C−H
a
Borylation
Most significantly, this transient imine directed o-C−H
borylation reaction was even applicable to a sterically hindered
C−H bond, which certainly enriches the utility of this method
(34d−45d, Scheme 3). It should also be noted here that it is
difficult to prepare all of 34d−45d in the majority of the metal-
catalyzed C−H bond functionalization reactions reported thus
far, because of the steric effect caused by the substituents.
Hence, this protocol represents a complementary strategy that
will allow the selective functionalization in sterically hindered
arene systems to proceed and can provide diversified
substituted arene cores that are widespread in pharmaceuticals.
This metal-free imine directed borylation approach can be
utilized for the synthesis of even a hexasubstituted (45d) arene
system in excellent yield.
The superior directing ability of an imine moiety was
realized because the selective C−H borylation occurred even
in the presence of other coordinating groups. Unlike the metal-
catalyzed C−H borylation methods,14,40−45 this metal-free C−
H borylation approach can override the directing effect of a
nitro group (46d and 47d), an ester (48d), and a ketimine
a
Legend: (A) The aldehyde oxygen atom directed C−H borylation.
Reaction conditions: 1a (0.2 mmol) and BBr3 (0.4 mmol) in DCE
(0.5 mL) at rt for 4 h, then pinacol (0.4 mmol) and NEt3 (2.0 mmol)
in DCE (0.5 mL) for 2 h at rt. (B) The imine-directed C−H
borylation. Reaction conditions: 1 (0.2 mmol), base (0.4 mmol) and
BBr3 (0.4 mmol) in DCE (0.5 mL) at rt for 4 h, then pinacol (0.4
mmol) and NEt3 (2.0 mmol) in DCE (0.5 mL) for 2 h at rt. (C) The
transient imine directed C−H borylation. Reaction conditions: 1a
(0.4 mmol) and tBuNH2 (1.6 mmol) in DCE (1.0 mL) at 70 °C for 4
h, then evaporation under reduced pressure, 2,6-lutidine (0.8 mmol)
and BBr3 (0.8 mmol) in DCE (1.0 mL) at rt for 4 h, then pinacol (0.8
mmol) and NEt3 (4.0 mmol) in DCE (1.0 mL) for 2 h at rt.
borylated product 1d in 49% yield. In this reaction, an equal
amount of an insoluble compound was also formed, which
could be attributed to the formation of an imine-BBr3 salt.
2922
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
h
Scheme 2. Substrate Scope for the Metal-Free Directed C−H Borylation
a
b
c
d
3-Methoxybenzaldehyde was used as a substrate. 3.0 equiv of BBr3 and 2,6-lutidine were used. 5.0 equiv of BBr3 and 2,6-lutidine were used. 1.5
e
f
equiv of BBr3 and 2,6-lutidine were used. Yields of the products were determined by 1H NMR spectroscopy. 2-Methylpentane-2,4-diol was used
g
h
in the final step instead of pinacol. 2,2-Dimethylpropane-1,3-diol was used in the final step instead of pinacol. Reaction conditions unless
specified otherwise: 1a−33a (0.4 mmol) and tBuNH2 (1.6 mmol) in DCE (1.0 mL) at 70 °C for 4 h, then evaporation under reduced pressure, 2,6-
lutidine (0.8 mmol) and BBr3 (0.8 mmol) in DCE (1.0 mL) at rt for 4 h, then pinacol (0.8 mmol) and NEt3 (4.0 mmol) in DCE (1.0 mL) for 2 h
at rt. Isolated yields are given.
(49d) to provide the desired functionalization with complete
site selectivity. Notably, for the convenient diversification of
this protocol, natural product appended benzaldehyde
derivatives which include oleyl alcohol (50d) and menthol
2923
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
d
Scheme 3. Scope of Complex Molecules
a
b
c
5.0 equiv of BBr3 and 2,6-lutidine were used. 4.0 equiv of BBr3 and 2,6-lutidine were used. 3.0 equiv of BBr3 and 2,6-lutidine were used.
d
Reaction conditions unless specified otherwise: 34a−51a (0.4 mmol) and tBuNH2 (1.6 mmol) in DCE (1.0 mL) at 70 °C for 4 h, then
evaporation under reduced pressure, 2,6-lutidine (0.8 mmol) and BBr3 (0.8 mmol) in DCE (1.0 mL) at rt for 4 h, then pinacol (0.8 mmol) and
NEt3 (4.0 mmol) in DCE (1.0 mL) for 2 h at rt. Isolated yields are given.
(51d) were also tested and were found to react smoothly with
BBr3 with the assistance of an imine substituent to afford the
desired borylated products.
Impurity Compatibility. C−H borylation reactions are
frequently used in the synthesis of complex molecules. Most of
the available reports on C−H borylation reactions have mainly
used a metal catalyst. Because of this, a pure starting material is
needed for the C−H borylation reaction. On the other hand,
an in situ borylation strategy would be much appreciated, since
the isolation of the pure starting material would not be
necessary. Therefore, a mild, practical, environmentally benign
selective C−H borylation protocol that can efficiently function
even in the presence of external impurities would be highly
desirable.
2924
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
To examine the interference caused by external impurities
for this metal-free directed C−H borylation strategy, the effect
of 41 different compounds was examined (Scheme 4). From
these series of experiments, we were able to obtain some
valuable insights regarding the interference caused by various
additives. Among the 41 additives examined, only a few, such
as DMF (56), N-Boc proline (63), 1,2-dimethyl-1H-indole
(76), and methyl acrylate (79), had a negative effect on the
product yield. It is worth noting that this metal-free borylation
protocol tolerates a variety of coordinating and reactive
functional groups and salts of inorganic bases well, which
clearly increases the synthetic importance of this protocol.
Although Maleczka and Smith carried out an in-depth
screening of solvent tolerance for the Ir-catalyzed nondirected
C−H borylation of arene,46 it would be anticipated that, due to
the high reactivity of Ir complexes toward many organic
compounds and inorganic salts, that this could lead to
unprecedented side reactions. In fact, the Ir-catalyzed ortho-
borylation of 1b-tBu was carried out in the presence of some
external additives by following a literature method14 to
compare with our protocol. Notably, it was observed that
this metal-free borylation protocol showed a much greater
efficiency in comparison to the Ir catalytic system (see the
Supporting Information for details).
Scheme 4. Effect of External Additives on Metal-Free
a
Directed C−H Borylation
Diversification of Products. Importantly, this convenient,
easily handled, synthetically useful, highly impurity tolerant
metal-free directed C−H borylation protocol can be performed
on a large scale without any difficulties. As an example, the
desired ortho-borylated benzaldehyde 1d could be produced in
81% yield (Scheme 5). The borylated benzaldehyde 1d can be
transformed into a number of important compounds via a
deborylative iodination (93)47 and Suzuki−Miyaura coupling
Scheme 5. Application for Metal-Free Directed C−H
a
Borylation
a
Condition A: tBu-NH2 (1.2 equiv), DCE, 70 °C, 4 h, then
evaporation under reduced pressure, BBr3 (2 equiv), 2,6-lutidine (2
equiv), DCE, rt, 4 h, and then pinacol (2 equiv), NEt3 (10 equiv),
DCE, rt, 2 h. Condition B: Cu2O (5 mol %), 1,10-phenanthroline (20
mol %), KI (1.1 equiv), MeOH/H2O (4:1), 80 °C, 1 h, in air.
Condition C: Pd(dba)2 (5 mol %), PPh3 (20 mol %), K3PO4 (3
equiv), PhBr (1.2 equiv), DMF, 90 °C, 24 h. Condition D: Pd(dba)2
(5 mol %), PPh3 (20 mol %), K3PO4 (3 equiv), 2-bromo-4-
methylaniline (1.2 equiv), DMF, 90 °C, 24 h. Condition E:
Ph2PMeBr (1.5 equiv), K2CO3 (2 equiv), 1,4-dioxane, 80 °C, 16 h.
Condition F: MeMgBr (1.25 equiv), THF 0 °C to rt, 12 h, then H3O+
workup.
a
Reaction conditions: 1b-tBu (0.2 mmol), external additive 52−92
(0.2 mmol), 2,6-lutidine (0.4 mmol), and BBr3 (0.4 mmol) in DCE
(0.5 mL) at rt for 4 h, then pinacol (0.4 mmol) and NEt3 (2.0 mmol)
in DCE (0.5 mL) for 2 h at rt. H NMR yields of borylated product
1
1d are given in parentheses.
2925
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
with phenyl iodide (94) without the decomposition of the
aldehyde moiety. A one-step synthesis of phenanthrene (95)
can also be achieved by the reaction of 1d and 2-bromo-4-
methylaniline via an imine condensation followed by Suzuki−
Miyaura coupling. Notably, the benzaldehyde moiety can easily
be converted to a styrene derivative (96) via a Wittig reaction
without the C−B bond undergoing decomposition. An
oxaborole compound (97) can be obtained in high yield
when 1d is reacted with MeMgBr followed by acidic workup.
Mechanistic Considerations. To gain insights into the
reaction mechanism, a number of control experiments were
carried out. The possibility of a radical-based mechanism was
ruled out by control experiments that involved the presence of
radical quenchers, such as 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and butylated hydroxytoluene (BHT). In both
cases, the yields of the desired compound 1d remained
unaffected (see the Supporting Information). A slight decrease
in the product yield in the presence of TEMPO can be
attributed to the direct reaction of BBr3 and TEMPO.48
Some important information regarding the reaction
mechanism was obtained when a series of control experiments
in which the amounts of BBr3 and a base were varied: (i) when
1 equiv of BBr3 was used in the absence or the presence of a
base, the reaction only reached half-completion (entries 2, 4,
and 5 in Figure 2A); (ii) when 2 equiv of BBr3 was used with a
combination of 1 equiv of a base, the reaction nearly reached
completion (entry 3), suggesting that 2 equiv of BBr3 is
essential for the reaction to reach completion; (iii) even when
2 equiv of BBr3 was used in the absence of a base, the reaction
stopped in the middle of the reaction (entry 6), suggesting that
a base plays a crucial role in this present reaction. To
determine the reaction profile for this metal-free borylation,
time versus yields were plotted, and the results show that the
reaction proceeds very rapidly and more than 70% of the
desired product is formed within 2 min under the optimized
conditions (Figure 2B). Consistent with the previous
observation, when 2 equiv of BBr3 was used in the absence
of any 2,6-lutidine, the reaction stopped in the middle.
Gratifyingly, we were able to isolate and confirm the structure
of the dibromo borane intermediate 1′ by a single-crystal X-ray
crystallographic analysis (Figure 2C).49 To gain further
information regarding the reaction mechanism, we carried
out 11B NMR experiments (Figure 2D). A 1:1 mixture of BBr3
and 2,6-lutidine in CDCl3 gave several signals in the negative
chemical shift region, which are similar to those previously
assigned to the tetracoordinated borate complex generated
from a disproportionation reaction of BBr3 in the presence of
2,5-dichloropyridine (Figure 2D-II).45 11B and 1H NMR
spectroscopic characterization suggested that two compounds
are predominantly generated from the reaction of BBr3 and
2,6-lutidine, one being the acid−base adduct complex Br3B·L
(L = 2,6-lutidine) and the other being the borenium
intermediate [BBr2(L)2]+[BBr4]−.50,51 A ESI-MS measurement
of this reaction mixture in DCE/MeOH (5/1) provided a peak
at m/z 367.1183, which is consistent with the formation of he
cationic complex [BL2Br(OMe)]+ and is further indicative of
the formation of borenium intermediate (see the Supporting
Information for details). Hence, the requirement of 2 equiv of
BBr3 for the reaction to reach completion is reasonable. This
result is consistent with our previous observation in control
experiments (entries 1 and 3, Figure 2A). Notably, when a
similar experiment was performed using the 2,6-dimethyl-
substituted imine 98 in combination with BBr3, a similar 11B
Figure 2. Control experiments and mechanistic studies of the metal-
free directed C−H borylation reaction: (A) control reaction in which
the amounts of BBr3 and 2,6-lutidine used were varied; (B) yield vs
time graph of the reaction; (C) isolation of an intermediate dibromo
boron complex; (D) 11B NMR studies.
NMR pattern was obtained (Figure 2D-III), suggesting that a
similar borenium species is formed during the reaction. This
result suggests that even the imine substrate functioned as a
2926
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
base in the absence of 2,6-lutidine to result in an acid−base
interaction with BBr3 to facilitate the disproportionation
reaction. Therefore, the reaction reached only half-completion
when the reaction was carried out in the absence of a base.
On the basis of all of the information obtained in control
experiments, we propose a plausible mechanism for this
rection, as shown in Scheme 6. In the presence of a base
Scheme 7. Competition of Directing Groups in a Directed
Metal-Free C−H Borylation
a
Scheme 6. Proposed Mechanism for the Metal-Free
Directed Borylation of Benzaldehyde Derivatives
a
Reaction conditions: 1b-tBu (0.2 mmol), XX or XX (0.2 mmol),
2,6-lutidine (0.4 mmol) and BBr3 (0.4 mmol) in DCE (0.5 mL) at rt
for 4 h, then pinacol (0.4 mmol) and NEt3 (2.0 mmol) in DCE (0.5
mL) for 2 h at rt. 1H NMR yields of borylated product 1d are given in
parentheses. Unreacted starting materials are given in parentheses.
(either 2,6-lutidine or the imine starting material), BBr3
undergoes disproportionation to provide the highly electro-
philic borenium species A. Due to the nitrogen-philic nature of
boron, an interaction between 1b-tBu and A gives the
borenium species B. The high electrophilic character of the
borenium species B directs the electrophilic aromatic
substitution to the ortho position of an aromatic ring despite
the fact that this is an electron-deficient system. A free base
abstracts a proton from the aromatic ring in C to generate the
dibromo boron complex 1′. Due to the rapidity of the reaction,
it is difficult to perfectly assign the exact structure of the
borenium species.
To check whether the imine directing group can compete
with the existing directing group (anilide29 and phenoxypyr-
idine26) in metal-free C−H borylation, two sets of control
experiments were performed (Scheme 7). Notably, in both
cases, the use of an imine directing group was more successful
over the others despite being an electron-deficient system in
comparison to the others. Surprisingly, no reaction occurred in
the case of N-phenylbenzamide (99) and 2-phenoxypyridine
(101). This observation further emphasizes the high ability of
the imine directing group for a metal-free electrophilic C−H
borylation reaction. A possible reason for this high reactivity
could be attributed to the geometrical orientation via
formation of a five-membered boracycle. The lack of reactivity
of 99 and 101 is also indicative of their incompatibility toward
external impurities.
high functional group compatibility and a high chemo-
selectivity. The borylation proceeds selectively at the ortho
position of benzaldehyde even in the presence of another
potential directing group. The most significant application for
this transformation will be to functionalize a highly sterically
hindered C−H bond via this metal-free borylation protocol,
because the C−H functionalization of highly sterically
hindered C−H bonds is a longstanding challenge. The further
importance of this directed borylation approach was
emphasized by the finding that this transformation can
function even in a presence of external impurities that are
carried over from the last step of the synthetic route.
Moreover, being a highly useful synthetic intermediate, the
obtained borylated product can be utilized in a number of
useful transformations. A series of control experiments was
carried out, in attempts to rationalize the mechanism
responsible for this reaction, and the results indicate that the
formation of a highly reactive borenium species is the key to
achieving a directed electrophilic aromatic substitution
reaction, even in a highly electron deficient system. Overall,
we anticipate that this reaction meets all the criteria needed for
it to become a widely used transformation in organic syntheses.
CONCLUSION
■
ASSOCIATED CONTENT
We have reported herein on a metal-free borylation strategy for
an ortho-directed C−H borylation of electron-deficient
benzaldehyde derivatives by overriding the directing ability
of a transient imine directing group over the electronic effect of
the aromatic ring. The protocol is convenient, easily handle-
able, and synthetically highly useful. Notably, this process
displayed a wide range of substrate applicability, including a
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13013.
Experimental procedure, synthesis of starting materials,
and characterization of compounds (PDF)
2927
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(9) Cook, A. K.; Schimler, S. D.; Matzger, A. J.; Sanford, M. S.
Catalyst-Controlled Selectivity in the C−H Borylation of Methane
and Ethane. Science 2016, 351, 1421−1424.
Accession Codes
CCDC 2046399 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
(10) Smith, K. T.; Berritt, S.; Gonzalez-Moreiras, M.; Ahn, S.; Smith
III, M. R.; Baik, M.-H.; Mindiola, D. J. Catalytic Borylation of
Methane. Science 2016, 351, 1424−1427.
(11) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peters, D. S.;
Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; et al.
Decarboxylative Borylation. Science 2017, 356, No. eaam7355.
AUTHOR INFORMATION
́
(12) Ros, A.; Fernandez, R.; Lassaletta, J. M. Functional Group
■
Directed C−H Borylation. Chem. Soc. Rev. 2014, 43, 3229−3243.
(13) Li, Y.; Wu, X.-F. Direct C−H Bond Borylation of (Hetero)-
Arenes: Evolution from Noble Metal to Metal Free. Angew. Chem., Int.
Ed. 2020, 59, 1770−1774.
Corresponding Author
Naoto Chatani − Department of Applied Chemistry, Faculty of
Engineering, Osaka University, Suita, Osaka 565-0871,
Japan; orcid.org/0000-0001-8330-7478;
Email: chatani@chem.eng.osaka-u.ac.jp
(14) Bisht, R.; Chattopadhyay, B. Formal Ir-Catalyzed Ligand-
Enabled Ortho and Meta Borylation of Aromatic Aldehydes via in
Situ-Generated Imines. J. Am. Chem. Soc. 2016, 138, 84−87.
(15) Letsinger, R. L.; MacLean, D. B. Organoboron Compounds.
Author
Supriya Rej − Department of Applied Chemistry, Faculty of
Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
̈
XVI. Cooperative Functional Group Effects in Reactions of
Boronoarylbenzimidazoles. J. Am. Chem. Soc. 1963, 85, 2230−2236.
(16) Davis, F. A.; Dewar, M. J. S. New Heteroaromatic Compounds.
XXX. A Derivative of 10,9-Borathiarophenanthrene. J. Am. Chem. Soc.
1968, 90, 3511−3515.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13013
̈
(17) Liu, K.; Lalancette, R. A.; Jakle, F. B-N Lewis Pair
Functionalization of Anthracene: Structural Dynamics, Optoelec-
tronic Properties, and O2 Sensitization. J. Am. Chem. Soc. 2017, 139,
18170−18173.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
̈
(18) Yusuf, M.; Liu, K.; Guo, F.; Lalancette, R. A.; Jakle, F.
Luminescent Organoboron Ladder Compounds via Directed Electro-
philic Aromatic C−H Borylation. Dalt. Trans. 2016, 45, 4580−4587.
(19) Ishida, N.; Moriya, T.; Goya, T.; Murakami, M. Synthesis of
Pyridine-Borane Complexes via Electrophilic Aromatic Borylation. J.
Org. Chem. 2010, 75, 8709−8712.
(20) Crossley, D. L.; Urbano, L.; Neumann, R.; Bourke, S.; Jones, J.;
Dailey, L. A.; Green, M.; Humphries, M. J.; King, S. M.; Turner, M.
L.; et al. Post-Polymerization C−H Borylation of Donor-Acceptor
Materials Gives Highly Efficient Solid State Near-Infrared Emitters for
Near-IR-OLEDs and Effective Biological Imaging. ACS Appl. Mater.
Interfaces 2017, 9, 28243−28249.
(21) Crossley, D. L.; Cade, I. A.; Clark, E. R.; Escande, A.;
Humphries, M. J.; King, S. M.; Vitorica-Yrezabal, I.; Ingleson, M. J.;
Turner, M. L. Enhancing Electron Affinity and Tuning Band Gap in
Donor-Acceptor Organic Semiconductors by Benzothiadiazole
Directed C−H Borylation. Chem. Sci. 2015, 6, 5144−5151.
(22) Crossley, D. L.; Vitorica-Yrezabal, I.; Humphries, M. J.; Turner,
M. L.; Ingleson, M. J. Highly Emissive Far Red/Near-IR Fluorophores
Based on Borylated Fluorene−Benzothiadiazole Donor−Acceptor
Materials. Chem. - Eur. J. 2016, 22, 12439−12448.
(23) Shaikh, A. C.; Ranade, D. S.; Thorat, S.; Maity, A.; Kulkarni, P.
P.; Gonnade, R. G.; Munshi, P.; Patil, N. T. Highly Emissive Organic
Solids with Remarkably Broad Color Tunability Based on N,C-
Chelate, Four-Coordinate Organoborons. Chem. Commun. 2015, 51,
16115−16118.
Funding
This work was supported by a Grant in Aid for Specially
Promoted Research by MEXT (17H06091) and The Naito
Foundation.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.R. wishes to expresses his special thanks for a JSPS
Postdoctoral Research Fellowship.
REFERENCES
■
(1) Murai, S.; Kakiuchl, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Efficient Catalytic Addition of Aromatic
Carbon-Hydrogen Bonds to Olefins. Nature 1993, 366, 529−531.
(2) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J.
Mild Metal-Catalyzed C−H Activation: Examples and Concepts.
Chem. Soc. Rev. 2016, 45, 2900−2936.
̈
(3) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-Huy, T.;
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord,
J.; Besset, T.; et al. A Comprehensive Overview of Directing Groups
Applied in Metal-Catalysed C−H Functionalisation Chemistry. Chem.
Soc. Rev. 2018, 47, 6603−6743.
(4) Rej, S.; Das, A.; Chatani, N. Strategic Evolution in Transition
Metal-Catalyzed Directed C−H Bond Activation and Future
Directions. Coord. Chem. Rev. 2020, 213683.
(24) Dash, B. P.; Hamilton, I.; Tate, D. J.; Crossley, D. L.; Kim, J. S.;
Ingleson, M. J.; Turner, M. L. Benzoselenadiazole and Benzotriazole
Directed Electrophilic C−H Borylation of Conjugated Donor-
Acceptor Materials. J. Mater. Chem. C 2019, 7, 718−724.
(25) Iqbal, S. A.; Pahl, J.; Yuan, K.; Ingleson, M. J. Intramolecular
(Directed) Electrophilic C−H Borylation. Chem. Soc. Rev. 2020, 49,
4564−4591.
(5) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. C−H Activation for the Construction of C-B Bonds.
Chem. Rev. 2010, 110, 890−931.
(26) Niu, L.; Yang, H.; Wang, R.; Fu, H. Metal-Free Ortho C−H
Borylation of 2-Phenoxypyridines under Mild Conditions. Org. Lett.
2012, 14, 2618−2621.
(6) Hartwig, J. F. Regioselectivity of the Borylation of Alkanes and
Arenes. Chem. Soc. Rev. 2011, 40, 1992−2002.
(7) Suzuki, A. Cross-Coupling Reactions of Organoboranes: An Easy
Way to Construct C-C Bonds (Nobel Lecture). Angew. Chem., Int. Ed.
2011, 50, 6722−6737.
(27) Cazorla, C.; De Vries, T. S.; Vedejs, E. P-Directed Borylation of
Phenols. Org. Lett. 2013, 15, 984−987.
(28) Lv, J.; Chen, X.; Xue, X.-S.; Zhao, B.; Liang, Y.; Wang, M.; Jin,
L.; Yuan, Y.; Han, Y.; Zhao, Y.; et al. Metal-Free Directed Sp2-C−H
Borylation. Nature 2019, 575, 336−340.
(8) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith
III, M. R. Remarkably Selective Iridium Catalysts for the Elaboration
of Aromatic C−H Bonds. Science 2002, 295, 305−308.
2928
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(29) Iqbal, S. A.; Cid, J.; Procter, R. J.; Uzelac, M.; Yuan, K.;
Ingleson, M. J. Acyl-Directed Ortho-Borylation of Anilines and C7
Borylation of Indoles Using Just BBr3. Angew. Chem., Int. Ed. 2019, 58,
15381−15385.
(48) Li, J.; Wang, H.; Qiu, Z.; Huang, C.-Y.; Li, C.-J. Metal-Free
Direct Deoxygenative Borylation of Aldehydes and Ketones. J. Am.
Chem. Soc. 2020, 142, 13011−13020.
(49) A similar dichloro borane intermediate was previously isolated
by the reaction between the corresponding organolithium precursor
(30) Lv, J.; Zhao, B.; Yuan, Y.; Han, Y.; Shi, Z. Boron-Mediated
Directed Aromatic C−H Hydroxylation. Nat. Commun. 2020, 11,
1316.
̌
̊
̌
̌
́
and BCl3: Hejda, M.; Lycka, A.; Jambor, R.; Ruzicka, A.; Dostal, L.
Reactivity of C,N-chelated organoboron compounds with lithium
anilides − formation of unexpected 1,2,3-trisubstituted 1H-2,1-
benzazaboroles. Dalton Trans. 2013, 42, 6417−6428.
(31) Wu, G.; Fu, X.; Wang, Y.; Deng, K.; Zhang, L.; Ma, T.; Ji, Y.
C−H Borylation of Diphenylamines through Adamantane-1-Carbonyl
Auxiliary by BBr3. Org. Lett. 2020, 22, 7003−7007.
(50) Farquharson, M. J.; Hartman, J. S. Bis(pyridine)difluoroboron,
tris(pyridine)fluoroboron, and other (pyridine)haloboron cations. A
systematic NMR study. Can. J. Chem. 1996, 74, 1309−1320.
(51) Burt, J.; Emsley, J. W.; Levason, W.; Reid, G.; Tinkler, I. S.
(32) Del Grosso, A.; Singleton, P. J.; Muryn, C. A.; Ingleson, M. J.
Pinacol Boronates by Direct Arene Borylation with Borenium
Cations. Angew. Chem., Int. Ed. 2011, 50, 2102−2106.
(33) Del Grosso, A.; Helm, M. D.; Solomon, S. A.; Caras-Quintero,
D.; Ingleson, M. J. Simple Inexpensive Boron Electrophiles for Direct
Arene Borylation. Chem. Commun. 2011, 47, 12459−12461.
(34) Prokofjevs, A.; Kampf, J. W.; Vedejs, E. A Boronium Ion with
Exceptional Electrophilicity. Angew. Chem., Int. Ed. 2011, 50, 2098−
2101.
+
Systematics of BX3 and BX2 Complexes (X = F, Cl, Br, I) with
Neutral Diphosphine and Diarsine Ligands. Inorg. Chem. 2016, 55,
8852−8864.
(35) Stahl, T.; Muther, K.; Ohki, Y.; Tatsumi, K.; Oestreich, M.
̈
Catalytic Generation of Borenium Ions by Cooperative B-H Bond
Activation: The Elusive Direct Electrophilic Borylation of Nitrogen
Heterocycles with Pinacolborane. J. Am. Chem. Soc. 2013, 135,
10978−10981.
(36) Bagutski, V.; Del Grosso, A.; Carrillo, J. A.; Cade, I. A.; Helm,
M. D.; Lawson, J. R.; Singleton, P. J.; Solomon, S. A.; Marcelli, T.;
Ingleson, M. J. Mechanistic Studies into Amine-Mediated Electro-
philic Arene Borylation and Its Application in MIDA Boronate
Synthesis. J. Am. Chem. Soc. 2013, 135, 474−487.
(37) Del Grosso, A.; Ayuso Carrillo, J.; Ingleson, M. J. Regioselective
Electrophilic Borylation of Haloarenes. Chem. Commun. 2015, 51,
2878−2881.
(38) Yin, Q.; Klare, H. F. T.; Oestreich, M. Catalytic Friedel−Crafts
C−H Borylation of Electron-Rich Arenes: Dramatic Rate Acceleration
by Added Alkenes. Angew. Chem., Int. Ed. 2017, 56, 3712−3717.
(39) Kawamorita, S.; Miyazaki, T.; Ohmiya, H.; Iwai, T.; Sawamura,
M. Rh-Catalyzed Ortho-Selective C−H Borylation of N-Function-
alized Arenes with Silica-Supported Bridgehead Monophosphine
Ligands. J. Am. Chem. Soc. 2011, 133, 19310−19313.
́
(40) Ros, A.; Estepa, B.; López-Rodríguez, R.; Alvarez, E.;
́
Fernandez, R.; Lassaletta, J. M. Use of Hemilabile N,N Ligands in
Nitrogen-Directed Iridium-Catalyzed Borylations of Arenes. Angew.
Chem., Int. Ed. 2011, 50, 11724−11728.
́
(41) López-Rodríguez, R.; Ros, A.; Fernandez, R.; Lassaletta, J. M.
Pinacolborane as the Boron Source in Nitrogen-Directed Borylations
of Aromatic N,N-Dimethylhydrazones. J. Org. Chem. 2012, 77, 9915−
9920.
́
(42) Ros, A.; López-Rodríguez, R.; Estepa, B.; Alvarez, E.;
́
Fernandez, R.; Lassaletta, J. M. Hydrazone as the Directing Group
for Ir-Catalyzed Arene Diborylations and Sequential Functionaliza-
tions. J. Am. Chem. Soc. 2012, 134, 4573−4576.
(43) Sasaki, I.; Amou, T.; Ito, H.; Ishiyama, T. Iridium-Catalyzed
Ortho-C−H Borylation of Aromatic Aldimines Derived from
Pentafluoroaniline with Bis(Pinacolate)Diboron. Org. Biomol. Chem.
2014, 12, 2041−2044.
(44) Maeda, Y.; Sato, M.; Okada, S.; Murata, M. Ruthenium-
Catalyzed Nitrogen-Directed Ortho C−H Borylation of Aromatic
Imines with Pinacolborane. Tetrahedron Lett. 2018, 59, 2537−2540.
(45) Tanaka, S.; Saito, Y.; Yamamoto, T.; Hattori, T. Electrophilic
Borylation of Terminal Alkenes with BBr3/2,6-Disubstituted
Pyridines. Org. Lett. 2018, 20, 1828−1831.
(46) Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.;
Maleczka, R. E., Jr.; Smith, M. R. III High-Throughput Optimization
of Ir-Catalyzed C−H Borylation: A Tutorial for Practical Applications.
J. Am. Chem. Soc. 2013, 135, 7572−7582.
(47) Partridge, B. M.; Hartwig, J. F. Sterically Controlled Iodination
of Arenes via Iridium-Catalyzed C−H Borylation. Org. Lett. 2013, 15,
140−143.
2929
https://dx.doi.org/10.1021/jacs.0c13013
J. Am. Chem. Soc. 2021, 143, 2920−2929