Metal-Free sp2-C-H Borylation as a Common Reactivity Pattern of Frustrated 2-Aminophenylboranes

Article abstract of DOI:10.1021/jacs.6b00819

C-H borylation is a powerful and atom-efficient method for converting affordable and abundant chemicals into versatile organic reagents used in the production of fine chemicals and functional materials. Herein we report a facile C-H borylation of aromatic and olefinic C-H bonds with 2-aminophenylboranes. Computational and experimental studies reveal that the metal-free C-H insertion proceeds via a frustrated Lewis pair mechanism involving heterolytic splitting of the C-H bond by cooperative action of the amine and boryl groups. The adapted geometry of the reactive B and N centers results in an unprecedentently low kinetic barrier for both insertion into the sp²-C-H bond and intramolecular protonation of the sp²-C-B bond in 2-ammoniophenyl(aryl)- or -(alkenyl)borates. This common reactivity pattern serves as a platform for various catalytic reactions such as C-H borylation and hydrogenation of alkynes. In particular, we demonstrate that simple 2-aminopyridinium salts efficiently catalyze the C-H borylation of hetarenes with catecholborane. This reaction is presumably mediated by a borenium species isoelectronic to 2-aminophenylboranes.

Full text of DOI:10.1021/jacs.6b00819

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Article
Metal-free sp2-C–H borylation as a common
reactivity pattern of frustrated 2-aminophenylboranes
Konstantin Chernichenko, Markus Lindqvist, Bianka Kótai,
Martin Nieger, Kristina Sorochkina, Imre Pápai, and Timo Repo
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00819 • Publication Date (Web): 22 Mar 2016
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Metal-free sp2-C H borylation as a common reactivity pattern of
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Konstantin Chernichenko,*,† Markus Lindqvist,† Bianka Kótai,‡ Martin Nieger,† Kristina
Sorochkina,†,|| Imre Pápai,*,‡ and Timo Repo*,†
†Department of Chemistry, University of Helsinki, A. I .Virtasen aukio 1, P.O. Box 55, 00014 Helsinki, Finland
‡Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117, Buda-
pest, Hungary
ABSTRACT: C–H borylation is a powerful and atom-efficient method for converting affordable and abundant chemicals
into versatile organic reagents used in the production of fine chemicals and functional materials. Herein we report a facile
C–H borylation of aromatic and olefinic C–H bonds with 2-aminophenylboranes. Computational and experimental studies
reveal that the metal-free C-H insertion proceeds via a frustrated Lewis pair mechanism, a heterolytic splitting of the C–H
bond by a cooperative action of the amine and the boryl groups. Adapted geometry of the reactive B and N centers results
in an unprecedentently low kinetic barrier for both the insertion into sp2-C–H bond and the intramolecular protonation of
sp2-C–B bond in 2-ammoniophenyl(aryl)- or -(alkenyl)borates. This common reactivity pattern serves as a platform for
various catalytic reactions such as C–H borylation and hydrogenation of alkynes. In particular, we demonstrate that simple
2-aminopyridinium salts efficiently catalyze the C–H borylation of hetarenes with catecholborane. This reaction is presum-
ably mediated by a borenium species isoelectronic to 2-aminophenylboranes.
INTRODUCTION
highly symmetric sp-C–H bonds, undergo smooth C–H
bond splitting with FLPs.7 Yet, the splitting of sp2-C–H and
sp3-C–H bonds is still a great challenge for FLP chemistry
since only a few examples of such reactivity have been re-
ported.8
Organoboron compounds, namely boronic acids and
their esters, find wide application in synthetic transfor-
mations such as C-C cross-couplings, reductions, synthesis
of alcohols and phenols, and other reactions. Classical
methods in synthesis of arylboron compounds utilize or-
ganomagnesium or –lithium reagents in stoichiometric
amounts.1 Metal-catalyzed C-H borylation provides an es-
sentially more powerful and atom-efficient method for
converting of affordable and abundant chemicals into ver-
satile organoboron reagents. Until recently, the catalysis of
these reactions was dominated by the complexes of Pd, Pt,
Ru, Ir and other noble metals.2 For economic and toxicity
reasons, there is a significant interest in the development
of C–H borylations catalyzed by abundant transition met-
als3 or metal-free methods.4
Herein we report the results of our comprehensive study
of the reactivity of 2-aminophenylboranes (2-APBs; see A
in Scheme 1). We demonstrate that this particular family of
ansa-aminoboranes (with N and B reactive centers fixed in
a chelating manner), easily undergoes insertion into sp2-C–
H bonds of simple arenes and alkenes, producing zwitteri-
onic FLP adducts B, in a reversible manner (Scheme 1). This
reactivity is of major importance for metal-free catalysis
since these elementary C–H insertion and protonation
steps can be incorporated into various catalytic cycles. For
instance, we have recently reported a 2-APB-catalyzed hy-
drogenation of alkynes into cis-alkenes where facile intra-
molecular protonation of the alkenyl group is crucial for
the successful reaction.9 In continuation of our studies of
2-APBs, we now report facile sp2-C–H borylation of simple
arenes and alkenes, including relatively unreactive ben-
zene and hex-1-ene, with various 2-APBs resulting in for-
mation of novel aminoboranes C.10 Based on our findings
we propose a conceptually new catalytic cycle for sp2-C–H
borylation of various substrates mediated by a borenium
species, isoelectronic to 2-APBs.
A new approach for metal-free activation of various
bonds has recently been proposed. The pairs of Lewis acids
and Lewis bases, so called “frustrated Lewis pairs”(FLPs),
exhibit cooperative reactivity resulting in heterolytic split-
ting of σ- and π-bonds of various substrate molecules pro-
ducing the respective ionic or zwitterionic [Lewis acid]--
substrate-[Lewis base]+ adducts.5 Many of these reactions
were turned into catalytic processes, particularly, H2 acti-
vation into hydrogenation.6 Terminal acetylenes, being rel-
atively acidic compounds with sterically accessible and
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Scheme 1. Common reactivity of 2-aminophenylboranes: facile metal-free sp2-C–H insertion into arenes and al-
kenes forming zwitterions B and their reverse intramolecular sp2-C–B protonolysis
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RESULTS
Preparation of 3 in benzene is accompanied by formation
of up to 40 % of byproduct. Switching to bromobenzene
suppressed byproduct formation to less than 20 %. A side
reaction with aromatic solvents was apparent, since 1 could
be converted into 3 in a high yield in hexane. Accordingly,
aminoborane 3 was shown to furnish the product of C–H
borylation 4 when heated in benzene, while 1 remained in-
tact even upon prolonged heating. The crystalline FLP ad-
duct 5 of 4 and phenyl isocyanate was isolated in 76 % over-
all yield and the structure was determined by the single
crystal X-ray diffraction method (Figure 1).
C–H activation of benzene. We have recently reported
that 2-[bis(pentafluorophenyl)boryl]-N,N-dimethyl-ani-
line (1) reacts with H2 producing the respective adduct 2-
(dimethylammonio)phenylborohydride 2 (Scheme 2).11
This process is reversible at room temperature, whereas at
elevated temperatures an intramolecular protonolysis of
the B–C6F5 bond takes place, forming the aminohydrobo-
rane 3 and pentafluorobenzene.9 This reactivity was sur-
prising since pentafluorophenylborates are known for ex-
treme stability, against protonolysis in particular,12 secur-
ing their application as weakly-coordinating anions in ca-
talysis.13 Further studies revealed that selective sp2-C–B
bond protonative cleavage is a reactivity characteristic for
the 2-dimethylaminophenylboryl core.9
Scheme 2. Preparation of 3 from 1 by hydrogenolysis of
the B–C6F5 bond. C–H borylation of benzene by 3 pro-
ducing aminoborane 4 and isolation of its crystalline
phenyl isocyanate adduct 5
Figure 2. Gibbs free energy diagram computed for the C–H borylation
of benzene with 3. Relative stabilities of involved species are given in
parenthesis (in kcal/mol; with respect to reactants). 3’ and 4’ denote
the open (unquenched) forms of 3 and 4.
The thermodynamic and kinetic requirements of the C–
H borylation of benzene with 3 were then examined com-
putationally. 14 The results pointed to a two-step mecha-
nism involving the C–H bond cleavage (coupled with B–C
bond formation) and the subsequent H2 elimination (see
Figure 2 for the Gibbs free energy diagram and Figure 3 for
corresponding transition states). Of these two steps, the C–
H activation is found to have a higher barrier and the pre-
dicted height is consistent with the elevated temperature
required for this reaction. The zwitterionic reaction inter-
mediate (int) is notably less stable than the reactant state
(3 + C6H6), however, the H2 elimination step is allowed
both kinetically and thermodynamically. The overall
borylation reaction is predicted to be endergonic implying
that the reaction is unfavored in a closed system, but con-
tinuous release of the gaseous H2 from the solution phase
as well as the multiple excess of substrate (i.e. using ben-
zene as a solvent) clearly shifts the equilibrium towards the
borylation product.
Figure 1. Structure of 5 in the solid state based X-ray diffraction stud-
ies.
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Scheme 3. C–H borylation of arenes with 3: isolated aryl-substituted aminoboranes and studies of C–H insertion
regioselectivity by product distribution from the site-selective deuteration. Para- to ortho- and para- to meta-
borylations
ratios
are
reported
as
normalized
to
the
positions
multiplicities
N+
H
N
F
D
N
F
N
F
F
D
+
F
F
CD3OD
neat ArH
F
H
B-
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+
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Ar
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+
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OCD3
B
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H
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120 °C,
10 min
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2, 4a, 6a - 10a
1, 4, 6 - 10
bond strength and electron-donating or -accepting prop-
erties of aryl substituents. In addition to the monosubsti-
tuted compound 8, the product of double borylation of thi-
ophene 13 could be isolated when excess of 3 was used
(Scheme 4). The structure of 13 was established by the sin-
gle crystal X-ray diffraction method (See Supporting Infor-
mation for details).
Scheme 4. Formation of 13, the product of the bis-
borylation of thiophene by 3
Figure 3. Transition states located for the C–H insertion and the H2
elimination steps in the reaction of benzene with 3.
Substrate scope. With these promising preliminary re-
sults in hand, we studied the scope of the C–H borylation
with various substrates using several different 2-APBs,
though focusing on 3 as the most reactive species studied.
This ansa-aminoborane reacts with arenes and hetarenes
at temperatures from -15 (thiophene) to 100 °C (bromoben-
zene), providing the respective triaryl-substituted amino-
boranes and H2. Due to the extreme sensitivity of the prod-
ucts to protic compounds, particularly to moisture, we
were able to characterize only certain compounds (1, 4, 6 –
10 ) that formed selectively under the reaction conditions
used (Scheme 3). These aminoboranes exist as intramolec-
ular N→B adducts, verified by their 11B NMR chemical
shifts appearing in the range 8 – 20 ppm, with 1-methylin-
dole derivative 10 as an exception (42.0 ppm). The shift in
value demonstrates the correlation between the N→B
Regioselectivity of borylation. Reactions between 3
and monosubstituted benzenes produced regioisomeric
mixtures of aminoboranes. The regioselectivity of the C–H
insertion was studied by treating the product mixture with
CD3OD (Scheme 3, right part). The sp2-C–B bond deuterol-
ysis selectively labels the arene carbon atom with deuter-
ium,9 as it is the opposite process to C–H insertion. The
volatile deuterium-labelled arenes 11 were recondensed
under vacuum to a separate vessel and analyzed by 2H, 1H
and, in some cases, 19F and 13C NMR spectroscopy. This al-
lowed reliable determination of the regioselectivity of the
C–H borylation with high precision (see Supporting infor-
mation for details). The increasing preference for para-
over ortho-borylation for fluoro-, chloro-, and bromoben-
zene, and complete suppression of ortho-borylation of t-
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butylbenzene and anisole demonstrated the pronounced
influence of steric effects.
We found that 14 C–H-borylates thiophene smoothly at
room temperature producing bis-thienyl aminoborane 15
(Scheme 5). This reaction is stepwise and the intermediates
can be detected by NMR spectroscopy (see below the
mechanistic studies). These results demonstrate the gen-
erality of the 2-APBs' sp2-C–H borylation reactivity pro-
vided that such 2-APB are powerful FLPs.
When taking the electronic effects into account, the ob-
served regioselectivity positions the arene borylation be-
tween the classical aromatic electrophilic substitution
(SEAr) and a random product distribution that to some ex-
tent reflects the electrophilic character of the attacking bo-
ron species and concerted removal of proton by the amino
group during sp2-C-H insertion step. High regioselectivity
and the rate of the C–H borylation was observed for sub-
strates in which strong positive mesomeric effect was in-
volved. For example, anisole is borylated more rapidly than
benzene with pronounced para-selectivity. Electron-rich
five-membered hetarenes reacted with 3 already at -15 °C
with exclusive borylation of thiophenes into α-positions
and N-methylindole into β-position, similar to classical
SEAr. Furthermore, the rates of C–H borylations of fluoro-,
1,3,5-trifluoro, and pentafluorobenzenes are comparable to
that of benzene. The preference for para- over meta-
borylation dropping from 4.25 to 1.78 in the row of mono-
halogenebenzenes F > Cl > Br, is consistent with increasing
prevalence of inductive over mesomeric effects.15 Eventu-
ally, both tert-butylbenzene and toluene produced almost
statistic distribution of regioisomeric products of boryla-
tion, demonstrating a sharp contrast with classical SEAr
substitution, where such substrates usually result in a pro-
nounced o,p-selectivity. We attributed the exclusive β-
borylation of naphthalene to the combination of electronic
and steric effects. Deuteration experiments also revealed
the self-borylation of 3 at the phenylene bridge connecting
the reactive N and B centers (see Supporting Information
for details).
Interchange of aryl groups. Further exploration of the
2-APBs’ C–H borylation reactivities revealed alternatives to
the dehydrogenative pathway. The -C6F5 and -C6H5 groups
are the sp2-substituents that can easily undergo the proto-
native B–C bond cleavage making the interchange of aryl
groups feasible. The non-fluorinated compound 16 was
prepared analogously to 1 from 2-Me2N-C6H4-Li and
Ph2BCl. Upon heating of aminoboranes 1 or 16 with thio-
phene at 100 °C, a sequential replacement of both pen-
tafluorophenyl or phenyl groups with thienyls was ob-
served (Scheme 6). Similarly to 3, aminoboranes 1 and 16
demonstrated high selectivity for α-borylation of the thio-
phene core. In the course of both reactions, mixed inter-
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mediate aminoboranes 8 and 19 were observed by H, B
and 19F (for 16) NMR, however, no zwitterionic intermedi-
ates 18 or 20 could be detected.
Scheme 6. C–H borylation of thiophene with 1 and 16
with interchange of aryl groups
Borylation with 2-TMP-C6H4-BH2 (14). Motivated by
establishing general requirements for the powerful sp2-C-
H-borylating reactivity featuring 3 among other FLPs, we
explored similar frustrated aminoboranes. First, we rea-
soned that the Lewis acid-base strength of the active B and
N sites has to provide sufficient reactivity for the heteroly-
sis of sp2-C-H bonds. Additionally, we suggested that the
mutual ortho-arrangement of the active sites in 3 facilitates
the C-H insertion. The ansa-aminoborane 14 reported by
us recently is analogous to 3 since this 2-APB is powerful
enough to split H2,16 whereas the BH2 boryl group enables
the dehydrogenative borylation. On the other hand, the
steric surrounding of the reactive centers in 14 with the
bulky tetramethylpiperidino group as a Lewis basic center
and the smallest possible Lewis acidic BH2 group, sharply
contrasts with that in 3.
19F NMR detection of the characteristic pentafluoro-
phenyl pattern provides a convenient tool for monitoring
the conversion of 1 to 17 mediated by 8. Particularly, we
studied the kinetics of the thiophene borylation by 8 (see
the bottom part of Scheme 6). A sample of pure 8 in thio-
phene, prepared through the borylation with 3, was further
heated at 70 – 90 °C, and the consumption of 8 was fol-
lowed online by 19F NMR spectroscopy. The extracted ki-
netic parameters (Ea = 19.9±1.1 kcal/mol; H‡ = 19.9±1.1
Scheme 5. C–H borylation of thiophene by 14 produc-
ing bis-borylation product 15
kcal/mol; S‡ = -30.9±3.1 cal/molK; G‡
= 28.4±2.0
298
kcal/mol) agree well with the results of DFT calculations
for this reaction (G‡298 = 28.8 kcal/mol). As revealed from
the computational analysis, the observed sluggish reaction
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of thiophene with 1 or 8, when compared to 3, can be at-
tributed to the higher steric hindrance of the B center in 1
and 8 (for details see Supporting Information).
complete consumption of 1, the equilibrium establishes be-
tween mono-insertion product 21, alkene, bis-product 22
and C6F5H. For instance, heating of 0.46 M solutions of 1 in
vinylcyclohexane for 36 h at 120 °C resulted in the equilib-
rium mixture of 21b and 22b in the ratio ~ 60:40.
In addition to aryl interchange in 1, we found that the
borylation by 3 can be diverted along this pathway upon
running the reaction in the sealed small volume vessel. At
certain partial pressures of H2, the aryl interchange path-
way becomes thermodynamically more favored. For exam-
ple, when 3 was heated with C6D6 or toluene-d8 in a gas-
tight NMR tube, significant amount of C6F5H was detected
by 19F NMR along with novel B-H species observed in the
1H NMR spectrum (See Supporting Information for de-
tails).17
The C–H borylation of the alkenes is exclusively trans-
selective, which was established by 1H NMR analysis of the
products, by deuteration experiments, and by independent
preparation of aminoboranes 21a and 21b via the respective
hydroborations of hex-1-yne and cyclohexylacetylene with
3. Corresponding DFT calculations carried out for the 1 +
propene model reaction, revealed that trans- borylation is
clearly favored both kinetically and thermodynamically.
The observed regioselectivity can be related to the destabi-
lizing steric effects in the species identified along the cis
reaction pathway (for details, see Supporting Information).
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Scheme 7. C–H borylation of hex-1-ene and vinylcyclo-
hexane with 1 with interchange of aryl groups
Mechanistic studies. Aminoborane 3 inserts smoothly
into the α-C–H bond of the electron rich arene, thiophene,
already at -15 °C. The detailed mechanism and kinetics of
this reaction was investigated by following the reaction
with multinuclear (1H, 2H, 11B, 19F and 13C) 1D and 2D NMR
11
spectroscopy.18 In the B NMR spectrum, we observed a
new doublet resonance at -21.2 ppm that was attributed to
the zwitterionic α-C–H insertion FLP adduct 8a (Figure 4,
Scheme 8). In addition to 8a, a new triplet resonance ob-
served at -28.3 ppm in the 11B NMR was attributed to 24, a
dihydrogen adduct of 3. Also, new signals attributed to in-
termediates 8a and 24 were visible in 1H and 19F NMR spec-
tra.
Borylation of olefins. Olefins represent another major
target for sp2-C–H functionalization. Previously, we re-
ported that facile intramolecular protonation of B–alkenyl
bond within 2-(dimethylammonio)-phenylborohydride
system plays a crucial role in the catalytic hydrogenation
of internal alkynes into cis-alkenes.9 The C–H insertion
into the sp2-C–H bond of an alkene is the opposite reaction
to the protonolysis and should be feasible with 2-APBs, at
least kinetically. At the same time, we demonstrated that
alkenes are hydroborated by 3 producing the correspond-
ing alkylboryl derivatives. Therefore, we attempted the in-
terchange of aryl groups with alkenyls (Scheme 7).
Figure 4. 11B NMR spectra of 3 insertion into thiophene (-10 °C). α-C–
H insertion intermediates 8a is visible as a doublet at -21.2 ppm; a tri-
plet at -28.3 ppm is attributed to 24.
To get deeper insight into the nature of the new reso-
nances in 11B and 1H spectra, and provide additional proofs
for the structures of 8a and 24, we measured a 11B-1H
HMQC spectrum of the reaction between 3 and 2,5-dideu-
teriothiophene. We observed a long-range correlation
Heating 1 with hex-1-ene or vinylcyclohexane at elevated
temperatures (100 – 120 °C) led to the expected C–H boryla-
tion via a sequential replacement of –C6F5 groups with
alkenyls. Interestingly, the fluorine-free aminoborane 16
does not react with hex-1-ene under similar conditions.
Borylation does not stop on monosubstitution, much like
the reaction with thiophene, and competitive formation of
the bis-products 22 was observed. Therefore, isolation of
aminoboranes 21 in pure form was challenging, however,
at a low conversion level (33% after 24 h at 100 °C) it was
possible to isolate 21a as a 92% pure compound contami-
nated with 8% of 1. Yet, the borylation of alkenes, in con-
trast to thiophene, does not result in sole aminoboranes 22
as the ultimate products. After prolonged heating and
11
(through three bonds) between B nuclei and aromatic H
atoms located in positions ortho- to the B atoms, along
with the intense cross-peaks observed for directly bonded
B and H atoms in partially deuterated intermediates 8a-d2
and 24-d (Figure 5). For the tentative intermediate 8a-d2 we
observed two long-range cross-peaks revealing the correla-
tion between the B atom and the aromatic signals of the 2-
(dimethylamino)phenyl and 5-deuterothien-2-yl rings.
The reaction between 3 and thiophene was followed using
11
real time B NMR spectroscopy. The kinetic curves were
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built for the starting 3 consumption, intermediates, and ac-
cumulation of 8 (Figure 6). The concentration of 8a
reached the maximum within 1-2 h and then slowly de-
clined. Interesting, our observations established that 3 ab-
stracted dihydrogen from 8a facilitating conversion into 8
(Scheme 8).
Scheme 8. General scheme of the C–H borylation mechanism of thiophene and 3-methylthiophene by 3 at -15 – 5
°C. Relative stabilities and barriers are given with respect to the reactant state
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When 3 was reacted with 2,5-dideuteriothiophene, we
observed the B NMR signal of 24-d (Figure 5) as a clear
good agreement with the computed barrier of C–H inser-
11
tion in thiophene coreG‡ = 21.5 kcal/mol. Computa-
298
triplet, corresponding to a BH2 species. The latter can form
as results of selective and direct B to B hydride and N to N
proton (deuteron) transfer from 8a-d2 to 3. The site-selec-
tive exchange between 3 and 24 or between 14 and its dihy-
drogen adduct was evidenced by the presence of the corre-
sponding cross-peaks in the 1H NMR EXSY spectra.
tions could also account for the observed regioselectivity,
since the barrier corresponding to the borylation of the -
C–H bond of thiophene is found to be 2.7 kcal/mol higher
as compared to that of the -C–H borylation (for details,
see Supporting Information).
0.14
0.12
8
0.1
3
0.08
8a
[C], M
0.06
24
0.04
0.02
0
0.00
200.00
400.00
600.00
800.00
1000.00
time, min
Figure 5. 11B-1H HMQC spectrum of the reaction between 3 and 2,5-
dideuteriothiophene at -15 °C (with suppression of the β-signals of 2,5-
dideuteriothiophene in F2). The spectrum demonstrates short-range
(through one bond) as well as long-range (through three bonds) 11B-
1H couplings in partially deuterated 8a-d2 and 24-d.
Figure 6. Kinetic curves of the starting material, the product and the
intermediates for the C–H borylation of thiophene with 3 at -10 °C
based on 11B NMR spectroscopy.
The borylation of 3-methylthiophene with 3 provided
the single product of α-insertion 9 at -15 °C, whereas a ~1:1
mixture of two α-insertion products formed at 50 °C
(Scheme 3). To shed light on these selectivity issues we car-
ried out similar mechanistic studies for the reaction be-
tween 3-methylthiophene and 3. Two doublet resonances
The rates of α-C–H insertion of 3 in thiophene were ex-
tracted from the kinetic curves of 3 consumption recorded
at temperatures ranging from -15 to 5 °C and the following
activation parameters were determined: Ea = 11.2±0.4
kcal/mol; H‡ = 10.7±0.4 kcal/mol; S‡ = -34.8±1.6
cal/molK; G‡ = 21.0±0.9 kcal/mol. These values are in
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at -21.6 and -22.4 ppm of nearly similar intensities were ob-
dition to the previously proposed mechanism of the cata-
served by 11B NMR at -5 °C, and they were attributed to iso-
meric α-C–H insertion intermediates 9a and 23 (Scheme 8,
Figure 7). We suggest that the low temperature H2 elimi-
nation process from 9a is assisted by 3 (see above), whereas
H2 transfer from 23 to 3 is hindered due to sterical reasons.
The unassisted dehydrogenation of both 9a and 23 be-
comes rapid at 50 °C and the C–H insertion become the
rate-determining step.
lytic borylation where only diarylboranes like 26, but not
15-like were considered as possible intermediates.10
Further experimental proof for the mechanism of arene
borylation going through an arylborate intermediate was
acquired by isolating of the compound 31 and establishing
its structure by single crystal X-ray diffraction analysis
(Figure 8). Treatment of aminodichloroborane 28 with 2
equivalents of 2-lithiobiphenyl 29 gave compound 31 as a
sole product in a high yield rather than expected bis(2-bi-
phenyl)borylamine 30. Compound 31 containing borafluo-
rene unit formed as result of a spontaneous intramolecular
C–H insertion of one of the ortho-biphenyl substituents at-
tached to the B atom.
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Figure 7. 11B NMR spectra of 3 insertion into 3-methylthiophene at -5
°C. α-C–H insertion intermediates 9a and 23 are visible as doublets at
-21 – -23 ppm; a triplet at -28.9 ppm is attributed to 24.
Scheme 9. Stepwise C–H borylation of thiophene with
14. Formation of zwitterionic intermediates 25 and 27
is observed by 1H and 11B NMR spectroscopies
The reaction between aminoborane 14 and thiophene
(Scheme 9) is interesting due to its relevance to the re-
cently reported catalytic borylation of hetarenes catalyzed
by 14.10 Similar reactivity and regioselectivity, when com-
pared to 3, was observed. We found that in excess of thio-
phene, bis-thienyl derivative 15 is the ultimate product of
the reaction. Besides, by following the reaction with 1H and
11B NMR spectroscopies we could detect the intermediates
25 and 27 but found no evidence of monothienyl borane 26
(See SI for details).19 These findings provide a valuable ad-
Figure 8. Intramolecular C–H insertion into 2-biphenyl group of 30
results in formation of the zwitterionic FLP adduct 31 containing a
borafluorene group. X-ray structure of 31.
Catalysis. With detailed understanding of the scope and
reactivity of 2-APBs we pursued catalytic implementations.
Firstly, we carried out selective α-positions deuteration of
the aromatic core in 3-methylthiophene by heating it with
a catalytic (6.5 mol. %) amount of 3 under 2.2 bar D2 at 55
°C (See Supporting Information for details).
Three-coordinated boranes possessing positively
charged substituents and known as “borenium cations”
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have attracted much interest recently due to their high re-
activity. Strong electron-withdrawing properties of the cat-
ionic substituents bring high Lewis acidity to such species,
and therefore they show reactivities similar to that of the
highly Lewis acidic neutrally charged boranes, as exempli-
fied with H2 splitting by the borenium cation/t-Bu3P FLP,20
by a recent report on the trans-hydroboration of alkynes,21
etc.
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Scheme 10. 2-APBs A and their isoelectronic and
isostructural borenium cationic analogues A'.
Scheme 12. C–H borylation of hetarenes with catechol-
borane (HBcat) catalyzed by 2-dimethlyamino-
pyridinium salt 33 and the proposed mechanism.
As we concluded above, the sp2-C-H-borylation and the
sp2-C-B- protonation is a common reactivity pattern imma-
nent to the frustrated 2-APB core. Isoelectronic or isolobal
analogies are commonly used in developing new catalysts,
particularly, transition-metal-based catalysts. We hypoth-
esized that borenium species A' being isoelectronic and
isostructural to 2-APBs A (Scheme 10), may possess similar
C–H-borylating capabilities significantly extending the
concept reported herein, particularly, paving the way for
the catalytic borylation.22
CONCLUSIONS
2-Aminophenylboranes (2-APBs, A in Scheme 1) easily
insert into sp2-C–H bonds of arenes, hetarenes and alkenes
resulting in the bond heterolysis and formation of zwitter-
ionic intermediates (B in Scheme 1) detected experimen-
tally and supported by DFT calculations. These C–H inser-
tion intermediates can further decompose with formation
of sp2-C–H borylation products (C in Scheme 1) and H2,
C6F5H or C6H6 as byproducts. The C–H borylation reaction
is thermodynamically nearly neutral and, in many cases,
the equilibrium can be shifted by using the excess of the
substrate or discharging H2 from the reaction. Our previ-
ous and present studies demonstrate that the facile sp2-C–
H insertion of 2-APBs and the easy intramolecular proto-
nation of the sp2-C–B bond in the zwitterionic adducts B is
a common reactivity pattern inherent to 2-APBs. We sug-
gest that the primary factor securing such reactivity is the
optimal geometrical arrangement of the amino and the
boryl groups connected by the rigid phenyl bridge in the
ansa-system. Importantly, the reactivity is not sensitive to
any particular substituents attached to the N and the B at-
oms, however, the Lewis acidity/basicity and the steric bal-
ance is crucial. All the studied 2-APBs that demonstrated
borylating reactivity were shown experimentally or com-
putationally to add H2 reversibly. The reaction is signifi-
cantly faster with electron-rich arenes demonstrating
domination of electrophilic character for this reaction,
however, only substituents with mesomeric effect has pro-
nounced influence on the reactivity and regioselectivity.
We also introduced a conceptually new organocatalytic C–
H borylation method that is presumably mediated by bore-
nium species isoelectronic to 2-APBs. Using robust air-sta-
ble and moisture-insensitive substituted 2-dimethyla-
minopyridinium salt as a catalyst, 3-methylthiophene and
N-mehtylindole were borylated with catecholborane.
Scheme 11. Preparation of the borylation catalyst 33
To evaluate this idea, 2-dimethylaminopyridinium salt
33 containing a weakly coordinating anion [B(C6F5)4]- was
prepared in high yield starting from pentafluoropyridine 32
(Scheme 11). Using this robust, air and moisture-stable or-
ganocatalyst, we carried out the borylation of 3-methylthi-
ophene and N-methylindole with catecholborane 34
(Scheme 12) in ~70% yield based on NMR analysis of the
crude reaction mixtures. We suggest that the process is
mediated by the borenium cationic species 35 formed upon
reaction between 34 and 33 accompanied by the release of
H2. No evidence of decomposition of the catalyst was ob-
served in the course of the reaction. The 2-amino-
pyridinium system can be potentially promising for cata-
lytic sp2-C–H borylation of alkenes since the active electro-
philic borenium species does not contain B–H moieties
and is not able to hydroborate the substrate. Although 34
is a reactive hydroborating reagent, other boranes such as
pinacolborane tolerate alkenes. Catalytic studies are un-
derway.
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Int. Ed. 2014, 53, 3552; d) Hounjet, L. J.; Stephan, D. W. Org. Pro-
cess. Res. Dev. 2014, 18, 385. For a selection of most recent achieve-
ments, see: e) Tussing, S.; Greb, L.; Tamke, S.; Schirmer, B.;
Muhle-Goll, C.; Luy, B.; Paradies, J. Chem. - Eur. J. 2015, 21, 8056;
Supporting Information. Procedures, experimental details,
spectra are available in Supporting Information file that is
available free of charge via the Internet at
http://pubs.acs.org.”
CCDC 1434696 (5), 1434697 (13), and 1434698 (31) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
f) Lindqvist, M.; Borre, K.; Axenov, K.; Ko
́tai, B.; Nieger, M.; Les-
kela, M.; Papai, I.; Repo, T. J. Am. Chem. Soc. 2015, 137, 4038; g)
̈
́
Eisenberger, P.; Bestvater, B. P.; Keske, E. C.; Crudden, C. M.
Angew. Chem., Int. Ed. 2015, 54, 2467; (h) Chatterjee, I.; Oestreich,
M. Angew. Chem., Int. Ed. 2015, 54, 1965; i) Zhang, Z.; Du, H.
Angew. Chem., Int. Ed. 2015, 54, 623; j) Gyömöre, Á.; Bakos, M.;
Földes, T.; Pápai, I.; Domján, A.; Soós, T. ACS Catal. 2015, 5, 5366;
k) Scott, D. J.; Simmons, T. R.; Lawrence, E. J.; Wildgoose, G. G.;
Fuchter, M. J.; Ashley, A. E. ACS Catal. 2015, 5, 5540; ; l) Zhang, Z.;
Du, H. Org. Lett. 2015, 17, 6266.
(7) a) Dureen, M. A.; Stephan, D. W. J. Am. Chem. Soc. 2009,
131, 8396; b) Jiang, C.; Blacque, O.; Berke, H. Organometallics 2010,
29, 125; c) Voss, T.; Mahdi, T.; Otten, E.; Fröhlich, R.; Kehr, G.;
Stephan, D. W.; Erker, G. Organometallics 2012, 31, 2367.
(8) Menard, G.; Stephan, D. W. Angew. Chem., Int. Ed. 2012, 51,
4409.; a) Menard, G.; Hatnean, J. A.; Cowley, H. J.; Lough, A. J.;
Rawson, J. M.; Stephan, D. W. J. Am. Chem. Soc. 2013, 135, 6446.
(9) Chernichenko, K.; Madarász, Á.; Pápai, I.; Nieger, M.; Les-
kelä, M.; Repo, T. Nat. Chem. 2013, 5, 718.
(10) When this manuscript was in preparation, a metal-free C–
H borylation of electron-rich hetarenes with pinacolborane was
reported. The key step of the reaction is facile insertion into the
hetarene core utilizing our recently reported aminoborane 14. Lé-
garé, M. A.; Courtemanche, M. A.; Rochette, É.; Fontaine, F. G.
Science 2015, 349, 513.
(11) Chernichenko, K.; Nieger, M.; Leskela, M.; Repo, T. Dalton
Trans. 2012, 41, 9029.
(12) Reed, C. A.; Fackler, N. L. P.; Kim, K.-C.; Stasko, D.; Evans,
D. R.; Boyd, P. D. W.; Rickard, C. E. F. J. Am. Chem. Soc. 1999, 121,
6314.
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AUTHOR INFORMATION
Corresponding Author
*kochern@gmail.com,
*papai.imre@ttk.mta.hu
*timo.repo@helsinki.fi
Present Addresses
|| Division of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
University, 21 Nanyang Link, Singapore
Funding Sources
This work was supported by the Academy of Finland (139550,
276586), and the Hungarian Scientific Research Fund (OTKA,
K-115660).
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kinetic barrier as compared to that of H2 elimination, however,
the former process is thermodynamically more favored (for a de-
tailed analysis, see the SI).
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(18) A sample of 3 was placed in an NMR tube and thiophene
was added via a septum with simultaneous cooling of the tube by
liquid nitrogen. Frozen thiophene was allowed to melt, the con-
tent was homogenized by vigorous shaking and the tube was
placed in the precooled NMR instrument for measurements.
(19) The detection of 26 can be complicated by the overlapping
1
of its H and 11B NMR signals with the signals of other reaction
components and the solvent.
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(20) a) Farrell, J. M.; Hatnean, J. A.; Stephan, D. W. J. Am. Chem.
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4
5
(22) Interestingly, in a recent report, 2-(dimethylamino)pyr-
idium borenium species were shown to react with internal alkynes
to produce products of the triple bond haloborylation. In contrast
to the present work, 2-dimethylamino- group was proposed to
play a role of a pendant ligand stabilizing the borenium species.
Lawson, J. R.; Clark, E. R.; Cade, I. A.; Solomon, S. A.; Ingleson, M.
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