Mechanistic studies into amine-mediated electrophilic arene borylation and its application in MIDA boronate synthesis

Article abstract of DOI:10.1021/ja3100963

Direct electrophilic borylation using Y₂BCl (Y₂ = Cl₂ or o-catecholato) with equimolar AlCl₃ and a tertiary amine has been applied to a wide range of arenes and heteroarenes. In situ functionalization of the ArBCl₂ products is possible with TMS ₂MIDA, to afford bench-stable and easily isolable MIDA-boronates in moderate to good yields. According to a combined experimental and computational study, the borylation of activated arenes at 20 C proceeds through an S _EAr mechanism with borenium cations, [Y₂B(amine)] ⁺, the key electrophiles. For catecholato-borocations, two amine dependent reaction pathways were identified: (i) With [CatB(NEt ₃)]⁺, an additional base is necessary to accomplish rapid borylation by deprotonation of the borylated arenium cation (σ complex), which otherwise would rather decompose to the starting materials than liberate the free amine to effect deprotonation. Apart from amines, the additional base may also be the arene itself when it is sufficiently basic (e.g., N-Me-indole). (ii) When the amine component of the borocation is less nucleophilic (e.g., 2,6-lutidine), no additional base is required due to more facile amine dissociation from the boron center in the borylated arenium cation intermediate. Borenium cations do not borylate poorly activated arenes (e.g., toluene) even at high temperatures; instead, the key electrophile in this case involves the product from interaction of AlCl₃ with Y₂BCl. When an extremely bulky amine is used, borylation again does not proceed via a borenium cation; instead, a number of mechanisms are feasible including via a boron electrophile generated by coordination of AlCl₃ to Y₂BCl, or by initial (heteroarene)AlCl₃ adduct formation followed by deprotonation and transmetalation.

Full text of DOI:10.1021/ja3100963

Article
pubs.acs.org/JACS
Mechanistic Studies into Amine-Mediated Electrophilic Arene
Borylation and Its Application in MIDA Boronate Synthesis
Viktor Bagutski,†,§,⊥ Alessandro Del Grosso,†,§ Josue Ayuso Carrillo,† Ian A. Cade,† Matthew D. Helm,†
James R. Lawson,† Paul J. Singleton,†,∥ Sophia A. Solomon,†,⊗ Tommaso Marcelli,*,‡
and Michael J. Ingleson*,†
†Department of Chemistry, University of Manchester, Manchester, M13 9PL, United Kingdom
‡Dipartimento di Chimica, “Giulio Natta”, Politecnico di Milano, Via Mancinelli, 7, 20131 Milano, Italy
S
* Supporting Information
ABSTRACT: Direct electrophilic borylation using Y2BCl (Y2 = Cl2
or o-catecholato) with equimolar AlCl3 and a tertiary amine has been
applied to a wide range of arenes and heteroarenes. In situ
functionalization of the ArBCl2 products is possible with TMS2MIDA,
to afford bench-stable and easily isolable MIDA-boronates in
moderate to good yields. According to a combined experimental
and computational study, the borylation of activated arenes at 20 °C
proceeds through an SEAr mechanism with borenium cations,
[Y2B(amine)]+, the key electrophiles. For catecholato-borocations,
two amine dependent reaction pathways were identified: (i) With
[CatB(NEt3)]+, an additional base is necessary to accomplish rapid borylation by deprotonation of the borylated arenium cation
(σ complex), which otherwise would rather decompose to the starting materials than liberate the free amine to effect
deprotonation. Apart from amines, the additional base may also be the arene itself when it is sufficiently basic (e.g., N-Me-
indole). (ii) When the amine component of the borocation is less nucleophilic (e.g., 2,6-lutidine), no additional base is required
due to more facile amine dissociation from the boron center in the borylated arenium cation intermediate. Borenium cations do
not borylate poorly activated arenes (e.g., toluene) even at high temperatures; instead, the key electrophile in this case involves
the product from interaction of AlCl3 with Y2BCl. When an extremely bulky amine is used, borylation again does not proceed via
a borenium cation; instead, a number of mechanisms are feasible including via a boron electrophile generated by coordination of
AlCl3 to Y2BCl, or by initial (heteroarene)AlCl3 adduct formation followed by deprotonation and transmetalation.
exact mechanistic sequence leading to formation of ArB(OR)2
still remain to be addressed.
INTRODUCTION
■
Aryl and heteroaryl boronates (ArB(OR)2) are ubiquitous
synthetic building blocks. This is due to their versatility
(especially in Suzuki-Miyaura cross-coupling), low toxicity, and
enhanced stability relative to hard organometallic carbon
nucleophiles.1,2 Numerous effective routes to aryl boronates
exist; however, these generally require aryl halide or
pseudohalide intermediates.2,3 Direct borylation, the conversion
of Aryl-H to Aryl-B(OR)2, represents a more efficient approach,
and considerable progress has been made in this area using
iridium catalysts.4−8 The amine-mediated intermolecular boron
analogue of Friedel−Crafts chemistry represents a new
approach for the direct borylation of arenes and hetero-
arenes.9−11 The excellent regioselectivity observed in electro-
philic borylation is controlled by arene electronic effects in
synergy with steric effects and thus is complementary to
directed lithiation (ortho-directed or C−H acidity con-
trolled)12−14 and iridium catalysis (sterically controlled).4−8
Electrophilic borylation, particularly with BCl3-derived electro-
philes, is already established as a useful addition to the synthetic
toolbox for ArB(OR)2 production. However, questions
concerning substrate scope, the reaction limitations, and the
Recent developments in amine-mediated electrophilic
borylation are built upon the pioneering work of Lappert and
Muetterties. They reported the borylation of alkyl-arenes using
highly electrophilic mixtures of BCl3 and AlCl3 with activated
Al to sequester the protic byproduct.15−18 The mechanism and
the active electrophile were not identified in these systems.
Muetterties proposed that explicit solvation was important,
implicating [Cl2B(solvent)][AlCl4] (solvent = arene),16 where-
as Olah favored a Cl2B(μ-Cl)AlCl3 electrophile.19 Irrespec-
tively, the aggressive conditions used in these reports limited
applications due to incompatibility with many functional groups
and heteroarenes.16,20−22 A key advantage of amine-mediated
electrophilic borylation is that a strong boron Lewis acid
releases a Brønsted base during the borylation process. This
Brønsted base ultimately captures the proton from electrophilic
aromatic substitution (SEAr), thus preventing protodeborona-
tion.13,23 In preliminary communications, we demonstrated that
Received: October 12, 2012
Published: December 3, 2012
© 2012 American Chemical Society
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amine-mediated electrophilic borylation produced high yields
of ArB(OR)2 even for an acid-sensitive heteroarene containing
a methoxy group (eq 1).9
iminodiacetic acid (MIDA) as a boron protecting group post
borylation. The factors controlling isomerization and deboro-
nation have also been elucidated, enabling the production of a
single regioisomer in most cases. Combined experimental and
computational studies indicate that a range of borylation
pathways are feasible depending on conditions and reagents.
The most viable borylation method (from cost and scope
perspectives), using Y2BCl, AlCl3, and an inexpensive amine at
20 °C, proceeds by SEAr with a borenium cation (a three-
coordinate boron cation)33,34 as the key electrophile. However,
for less activated arenes (e.g., toluene) amine-mediated
borylation requires temperatures >70 °C and borenium cations
are not the active electrophile.
Overall, electrophilic borylation represents the heterolytic
cleavage of an arene C−H bond by a boron Lewis acid and an
amine base. This is reminiscent of the activation of alkynes by
frustrated Lewis pairs (FLPs)24 and the stepwise reaction of N-
Me-pyrrole with B(C6F5)3/NEt3. The latter reaction proceeds
via a zwitterionic borylated arenium cation which is
deprotonated by subsequent addition of Et3N to generate the
heteroarylborate (eq 2).25,26 A related mechanism is feasible for
intermolecular electrophilic borylation, but to date, the key
electrophiles are not definitively known. Three- or four-
coordinate (at boron) transition states and C−H insertion or
SEAr mechanisms are feasible, with both mechanisms finding
precedence in intramolecular electrophilic borylation.27−29
Identification of the active electrophile in direct borylation is
complicated by multiple equilibria (Figure 1). [Y2B(amine)]-
RESULTS AND DISCUSSION
■
B-halo-1,3,2-benzodioxaborole (CatBX) is insufficiently electro-
philic for the borylation of even strongly activated arenes (e.g.,
indoles). While BCl3 and N-Me-indole slowly produced a
mixture of borylated and protonated indole (4 days, Figure 3),
Figure 3. Reaction of N-Me-indole with BCl3.
BCl3 does not borylate 2-Me-thiophene (with or without a
base). Enhancement of electrophilicity at boron relative to
Y2BCl is therefore essential. This can be achieved by forming
either a borenium cation (type IV) or a neutral electrophile
(type II/III, Figure 2), with each a feasible strong boron
electrophile.29,34,35
Figure 1. Key equilibria present in formation of [Y2BL][AlCl4].
[AlCl4] (Y2 = Cl2 or o-catecholato) undergoes reversible halide
transfer from aluminum to boron resulting in the concomitant
presence of Lewis acidic “AlCl3” species and Y2B(amine)Cl.30
The latter can react further, reversibly forming free amine and
Y2BCl. A range of electrophilic species can therefore be present
in solution, each one potentially viable for the borylation of
arenes (Figure 2, type I to V). Importantly, the key electrophile
Substrate Scope. Borenium cations, or electrophiles
derived from them, are more reactive than the Y2BCl precursors
enabling the borylation of a wide range of activated arenes.
BCl3/AlCl3/amine derived electrophiles are more reactive than
catechol analogues, e.g., [CatB(NEt3)][AlCl4], 1[AlCl4] (or the
electrophile derived from it). 1[AlCl4] borylates only the most
highly activated arenes such as indoles, pyrroles, anilines, and
azulene (Table 1). Borylation with 1[AlCl4] proceeds in high
yield and with excellent regioselectivity from electronic control
(azulene is borylated exclusively at C1, entry 13; iridium
catalysis produces both the C1 and C2 isomers).36 Borylation
using BCl3/AlCl3/amine derived electrophiles not only has a
wider arene scope than with [1]+, but produces ArylBCl2, a
more versatile intermediate than ArylBCat (produced using
[1]+). MIDA protected boronate esters are readily synthesized
in situ from ArylBCl2 post borylation. Optimum conditions for
MIDA esterification of ArylBCl2 use the bis-trimethylsilyl ester
of MIDA (TMS2MIDA). While it is necessary to use ≥2 equiv
of pinacol and Et3N in the esterification to ArylBPin (due to a
competitive reaction with [AlCl4 ] producing
[Et3NH]2[{(PinH)AlCl2}2Cl2]),37 only 1 equiv of TMS2MIDA
is required. This new route to aryl MIDA-boronates does not
require the synthesis and isolation of heteroaryl boronic acid
intermediates. This is particularly important for heterocycles, as
heterocyclic boronic acids are often sensitive to protodeboro-
nation. Furthermore, our combined electrophilic borylation/
MIDA protection protocol for heteroarenes proceeds at
temperatures ≥0 °C and <30 °C. This is in contrast to current
methods which require cryogenics for boronic acid synthesis
Figure 2. Top: possible boron electrophiles for direct borylation, X =
Cl, Br, or H; E = Lewis acid; [anion] = weakly coordinating anion; L =
neutral ligand. Bottom: transmetalation mechanism.
is not limited to boron. Borylation may proceed by initial
interaction of “AlCl3” with an activated arene.31,32 Subsequent
deprotonation to [ArylAlCl3] and transmetalation with Y2BCl
would then yield ArBY2 (Figure 2, bottom).
Herein is presented an extensive substrate exploration for
amine-mediated electrophilic borylation. This is coupled with
the development of a simple route to install N-methyl-
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Table 1. Substrate Scope for Electrophilic Arene Borylation
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Table 1. continued
a,b
c
d
For exact borylation and workup procedures, see Supporting Information. Time before esterification. Reactions at 20 °C were performed in
e
f
g
CH2Cl2; those at elevated temperatures in o-C6H4Cl2. Isolated yields unless otherwise stated. In situ yields by 1H NMR spectroscopy. Isolated as a
h,i
93:7 mix of the 2,4:2,3-regioisomers. C1:C2 ratios are 1.5:1 and 1:1, respectively. Only the C2 isomer observed. 2:1 mixture of the 2,4:3,5
l−n
j
k
o
1
1
borylated isomers.
All in situ yields by H NMR spectroscopy, p:m ratios are 5.1:1, 5.4:1, 2.1:1, respectively. In situ yield by H NMR
p
spectroscopy, p:m ratio 5.2:1. Prior to esterification, p:m ratio = 4.0:1; after esterification and isolation, p:m ratio = 4.2:1.
and temperatures >110 °C for efficient MIDA installa-
tion.23,38,39 Thus, this new approach to MIDA boronates has
advantages over established routes to these increasingly popular
cross coupling precursors.
Borylation scope with Y2BCl/AlCl3/amine derived electro-
philes was found to be highly dependent on the basicity of the
amine. The greatest arene substrate scope is observed when
using Me2NPh ≈ Me2NTol > 2,6-lutidine > Et3N. It is
noteworthy that no borylation of 3-X-N,N-dimethylaniline (X =
H, Br, or Cl) was observed when these anilines were combined
with BCl3/AlCl3 at 20 °C. In contrast, mixtures of CatBCl, 3-X-
N,N-dimethylaniline, and AlCl3 rapidly produced [4-(CatB)-3-
X-C6H3(NMe2H)][AlCl4] at 20 °C (Figure 5).37 The disparity
is attributed to different equilibrium positions (Figure 1) which
with CatBCl/AlCl3 allow free (thus not deactivated by Lewis
acid coordination) 3-X-N,N-dimethylaniline and the active
boron electrophile to be present concomitantly. At temper-
atures ≥70 °C, borylation of 3-X-N,N-dimethylaniline is
observed with BCl3/AlCl3 indicating free aniline is present at
raised temperatures. As weakly activated arene substrates
required high temperatures (≥70 °C) for borylation, the
widest arene scope is achieved using BCl3, Me2NTol, and AlCl3.
Figure 4. Electrophilic borylation with protection steps.
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sequential electrophilic borylation/MIDA protection/bromina-
tion process is amenable to larger-scale synthesis. When applied
to 3-hexyl thiophene on a 25 mmol scale, this affords 6.6 g of
the bifunctional heteroarene in an overall 69% yield.
At raised temperatures, less activated arenes can also be
monoborylated using stoichiometric BCl3, Me2NTol, and AlCl3
provided that the arene is more nucleophilic than benzene. The
borylation of benzene itself was extremely slow even at 130 °C,
establishing a lower nucleophilicity limit below which
borylation does not proceed. This is exemplified by the
complete absence of borylation of o-dichlorobenzene even after
7 days at 130 °C. A range of weakly activated arenes undergo
electrophilic borylation with the sterically least hindered isomer
generally the only product observed (entries 43−50). For
example, naphthalene and anthracene (entries 43−46) are
monoborylated, with boron exclusively at the C2 position in the
products despite C1 and C9, respectively, being the kinetically
preferred sites.43 Diborylation is not observed due to the
reduction in the nucleophilicity of these weakly activated arenes
post installation of -BCl2.41 The selective monoborylation of
these polyaromatic hydrocarbons (PAHs) is in contrast to
other direct borylation routes which provide a mixture of
mono- and bis-borylated products.44,45 Benzothiophene also
afforded the thermodynamic borylated product exclusively
(entry 47) with no C3 regioisomer observed (C2 and C3 have
similar reactivity in SEAr, but C2 is the thermodynamic
product).46,47 In contrast, pyrene was borylated (entries 51−
53) to give a mixture of C1 and C2 regioisomers at 80 and 120
°C. Meta-xylene (entry 54) and toluene (entry 55−57) also
reacted to give mixtures of kinetic and thermodynamic
regioisomers (boron at C4 and C5 for m-xylene and C3 and
C4 for toluene). The relative regioisomer ratios did not change
significantly during borylation (relative ratio range of 5.3:1 to
6:1 para to meta for toluene during borylation at 110 °C over 7
days).
Factors Controlling Isomerization during Borylation.
The regioisomer ratios of borylated products formed using the
BCl3/AlCl3/aluminum system were previously studied and
found to be complicated by the formation of the Brønsted
superacid, HCl-AlCl3.16,17 This superacid induced extensive
intramolecular isomerization and intermolecular trans-alkyla-
tion (e.g., borylated toluene and mesitylenes produced during
xylene borylation).48 In contrast, amine mediated electrophilic
borylation occurs with no trans alkylation (by NMR and GC-
MS) and relatively less positional isomerization (for toluene
and m-xylene). This suggested more effective sequestering of
the Brønsted acid byproduct, preventing HCl-AlCl3 induced
trans-alkylation. Isobutyl benzene is a useful probe for
superacids, as in the presence of HCl-AlCl3, it undergoes
rapid isomerization to sec-butyl benzene.49 Borylation of
isobutyl benzene with BCl3/Me2NTol/AlCl3 produced only
meta and para regioisomers of borylated isobutyl benzene with
no sec-butyl products observed (entries 58−59, by NMR
spectroscopy and GC-MS). The absence of any isobutyl to sec-
butyl isomerization during borylation precludes formation of
HCl-AlCl3. It is also consistent with a mechanism where the
amine is deprotonating the borylated arenium intermediate.
Deboronation of (C6alkylxH5‑x)BCl2 is known to only occur
with HCl-AlCl3.17 Therefore, the regioisomer ratios in amine
mediated electrophilic borylation of alkyl arenes/PAHs are
controlled by the rate of intramolecular migration relative to
the rate of deprotonation of the borylated arenium complex
(Figure 6). The regioisomer ratio was strongly temperature
Figure 5. Reactivity of BCl3 and CatBCl electrophiles with AlCl3 and
3-X-N,N-dimethylaniline (X = H, Cl, or Br).
Heteroarene borylation using BCl3, amine, and AlCl3
proceeds in moderate to high yield to provide the regioisomers
expected from SEAr.40 For N-R-indoles (R = Me, Benzyl,
TIPS), borylation occurs only at C3 (entries 3−5, 7, and 11)
complementary to iridium catalyzed8 and deprotonation
approaches (both C2 selective).13 For thiophenes, borylation
occurs exclusively at the α position (entries 18−31). Post
borylation MIDA and pinacol installation is facile for both
thiophenes and indoles. Pinacol can be replaced in the
esterification step with the less expensive diol neopentylglycol
(neop, entry 21), with no loss in isolated yield. The good
regioselectivity afforded by synergic steric and electronic
control is demonstrated by 3-hexyl-thiophene undergoing
1
borylation predominantly at C5 (entry 28 ca. 93% by H
NMR spectroscopy with 7% the C2 borylated product,). When
both thiophene α positions are substituted, borylation proceeds
at the β position (entries 32−33). Thiophenes and indoles
containing electron withdrawing and donating groups, e.g.,
alkyl, halide, dialkylamino, methoxy, and cyano, are all
amenable to electrophilic borylation. The compatibility of the
latter two functional groups to a strong boron Lewis acid is
notable. This is presumably due to a more rapid reaction of the
boron Lewis acid at the nucleophilic C3 position of indole.
Indeed, attempts to borylate the less activated arene anisole
(Mayr nucleophilicity of 1.18)41 led instead to ether cleavage.
NO2, CF3, and CO containing groups were also not
compatible with electrophilic borylation, presumably due to
the high fluoro- and oxophilicity of the strong B/Al-based
electrophiles present.
While borylation of 1,2-disubstituted arenes under iridium
catalysis produces regioisomers,8 the sensitivity to electronic
effects ensures excellent regioselectivity in electrophilic
borylation. N-Methyl-phenothiazine and N-alkyl-carbazole
both produce a single regioisomer, with borylation always
proceeding para to NR2 (entries 34−36). Electrophilic di-
(entries 37−39) and triborylation (entry 42) of di- and tri-
arylamines is also facile. The additional borylations proceed
despite the installation of the mesomerically deactivating -BY2
group (electronically comparable to cyano).42 Protection of
boron is limited to pinacol in the absence of long alkyl chain
substituents as the di-MIDA functionalized aryl boronates are
extremely poorly soluble. Direct, regioselective diborylation and
the monoborylation of halo-arenes (entries 22−24 and 41) is of
particular importance as it represents a simple one-step route to
polymerization precursors used in organic-electronics. Bifunc-
tional heteroarenes can also be accessed through subsequent
bromination of (thienyl)B(MIDA) with NBS (e.g., eq 3). The
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Table 2. Stoichiometry Dependent Product Distribution
a
a
BCl3
(equiv)
AlCl3
(equiv)
base
(equiv)
time
(h)
mono
(%)
bis
entry
(%)
Figure 6. Isomerization during electrophilic arene borylation (L =
1
2
1
1
1.1
1.1
1.05
1.3
1
60
76
11
<1
amine or AlCl4 or nothing).
14
a
Isolated yields post chromatography.
dependent. At 20 °C, the borylation of pyrene and toluene with
BCl3/AlCl3/Me2NTol was significantly slower but produced
considerably more of the thermodynamic borylated products
(C2- and meta, respectively, entries 51−53, 55−57).50
Therefore, at lower temperatures the deprotonation of the σ
complex is slower relative to intramolecular migration enabling
a greater degree of positional isomerization. This effect will be
exacerbated by the extremely low concentration of free amine
at 20 °C (as indicated by the absence of borylation of Me2NPh
by BCl3/AlCl3 with effectively all amine coordinated to Lewis
acids at 20 °C).
of amine. For example, the selective monoborylation of N-Me-
carbazole proceeds with either exact equimolar stoichiometry or
an excess of amine (Table 2, entry 2).
N-Me-pyrrole was chosen to investigate the factors affecting
regioisomer distribution. Borylation with 1[AlCl4] produced
mixtures of C2/C3 monoborylation and the 2,4-diborylated
product in ratios that were sensitive to the stoichiometry of
CatBCl:AlCl3:NEt3. The addition of 1.3 equiv of AlCl3 and 1
equiv of 2,6-di-tert-butylpyridine (termed dTBP and used to
sequester adventitious “H+”) to a mixture of 2- and 3-
catecholboryl-N-methylpyrrole, 2 and 3, respectively (ratio
76:24) did not change the relative ratio of 2:3. However, slow
formation of 2,4-diborylated N-Me-pyrrole, 4, was observed.
The formation of 4 during deboronation proceeds as the
combination of CatBCl/AlCl3/dTBP is itself a highly effective
borylating agent (discussed in more detail in a later section)
able to borylate 2 (or 3). In contrast, in the absence of dTBP
the addition of AlCl3 (0.1 equiv) to the mixture of 2 and 3
(ratio 76:24) resulted in rapid isomerization with 3 dominating
after 1 h. For borylated five-membered heterocycles, proto-
deboronation occurs with the C2 isomer in preference to the
C3 regiosiomer.53,54 Compound 2 is thus more susceptible to
protodeboronation than 3, consistent with the relative increase
in 3 over time. This indicates that a strong Brønsted acid (at
adventitious levels from partially hydrolyzed AlCl3) can induce
C2 to C3 isomerization. Therefore, with the more nucleophilic
heteroarenes there are two separate deboronation processes: (i)
Brønsted acid catalyzed (via an arenium cation intermediate,
Figure 7 left); (ii) Lewis acid initiated deboronation (Figure 7,
right). The latter does not occur with (C6alkylxH5‑x)BCl2 where
deboronation only occurs with HCl−AlCl3.48
In contrast to PAHs and alkyl-arenes, where isomerization to
the thermodynamic favored arenium cation occurs at 20 °C, the
borylation of N-Me-pyrrole at 20 °C using equimolar BCl3/
Me2NTol/AlCl3 was highly selective for the kinetic C3 position
1
(ca. 95% by in situ H NMR spectroscopy). The isolation of
the C3 borylated regioisomer in good yield (entries 60 and 61)
is a unique example of pyrrole C3 selective direct borylation
that does not require deactivation of C2 by a bulky protecting
group at nitrogen.51 While SEAr of N-Me-pyrrole generally
gives products from C2 functionalization, the C3 position is the
kinetically favored site with hard electrophiles.52 When
isomerization is occurring rapidly in the pyrrolenium cation
the thermodynamic C2 product dominates. When there is no
isomerization and the electrophile is “hard”, as in the silylation
of N-Me-pyrrole with TMSOTf/NEt3, the C3 product
dominates (≥90%). The C2 isomer is only present as a
minor product (≤10%) from direct silylation at C2.52 With 3-
(BCl2)-N-Me-pyrrole the observed major product, the electro-
phile derived from BCl3/Me2NTol and AlCl3 also reacts at C3
and does not undergo intramolecular isomerization. The
disparity to the extensive isomerization observed with alkyl-
arene borylation at 20 °C we attribute to more rapid
deprotonation of the borylated arenium complex of N-Me-
pyrrole. Rapid deprotonation may be facilitated by another
equivalent of N-Me-pyrrole acting as the Brønsted base. In
contrast, toluene is an extremely poor base and deprotonation
of the borylated toluenium cation will require free Me2NTol,
which at 20 °C is present at extremely low concentration.
During a number of borylations, the product distribution
(mono vs bis borylation, relative regioisomer ratios) was found
to be sensitive to reagent stoichiometry. During the attempted
monoborylation of N-Me-carbazole when even a slight excess
of AlCl3 was used the 3,6-diborylated carbazole was observed as
a minor product (Table 2), which increased over time
concomitantly with N-Me-carbazole. This indicated that the
initial monoborylated product was undergoing deboronation.
Accurate stoichiometric control is challenging to realize with
commercial BCl3 solutions due to variations in molarity. Exact
stoichiometric control can be achieved by preforming (amine)-
BCl3, which precipitates analytically pure on addition of 1
equivalent of amine to a heptane solution of BCl3. An
alternative to preforming (amine)BCl3 is using a slight excess
Figure 7. Deboronation/isomerization of N-Me-(CatB)-pyrrole.
Further evidence for deboronation of heteroaryl boronate
esters by AlCl3 came from the addition of AlCl3 to pure 3. This
led to the rapid (<10 min) formation of CatBCl as the only
boron containing product along with a broad 27Al NMR
resonance at 103 ppm, attributed to oligomers of {(heteroaryl)-
AlCl2}n (Figure 7, right).55 Interestingly, addition of Et3N to
this mixture led to the regeneration of 3 with Et3N-AlCl3
produced as the major byproduct. Presumably, coordination of
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Et3N to Al in {(heteroaryl)AlCl2}n generates a better aluminum
leaving group post halide transfer from CatBCl to Al.
Importantly, there was no formation of 2 during this process
precluding interconversion of 2 and 3 mediated by AlCl3.
Deboronation was also observed on addition of AlCl3 to 3-
(CatB)-N-Me-indole producing CatBCl and a broad 27Al
resonance at 104 ppm. No intermediates were observed during
this rapid deboronation with AlCl3. Deboronation of 3-(CatB)-
1
N-Me-indole was slower with GaCl3. The H NMR spectrum
showing that all the proton resonances of 3-catecholboryl-N-
methylindole were shifted downfield. The indole C2 proton, in
particular, was shifted downfield by 0.94 ppm, consistent with
the coordination of GaCl3 to C3 of 3-catecholboryl-N-
methylindole.
Figure 8. ORTEP representations of left, 5, and right, the cationic
portion of 1[CbBr6]. Hydrogens are omitted for clarity and thermal
ellipsoids are at 50% probability. Selected bond lengths (Å) and angles
(°) for 5: B1−O5 = 1.481(10), B1−N1 = 1.618(9), B1−O1 =
1.428(9), B1−O2 = 1.435(9), O1−B1−O2 = 108.4(6). For 1[CbBr6]:
B1−N1 = 1.515(16), B1−O1 = 1.339 (15) B1−O2 = 1.377(15), O1−
B1−O2 = 113.9(3).
While direct borylation is highly effective for the generation
of ArB(OR)2, are borenium cations the active electrophile and
what is the exact mechanistic sequence? There is evidence that
is consistent with [Y2B(amine)]+ cations being active electro-
philes. For example, the arene substrate scope is dependent on
amine nucleophilicity (e.g., entries 30−31) which could be
attributed to different borenium cation electrophilicities.
However, the equilibria present using [AlCl4] allow more
than one electrophile/mechanism to be feasible. Furthermore,
it is noteworthy that after heating equimolar BCl3/AlCl3/
Me2NTol in o-C6H4Cl2 to 100 °C for 10 min (common
borylation conditions) the 11B NMR spectrum showed no
borenium cation. The only boron containing products were
BCl3 and (amine)BCl3. To reduce mechanistic complexity, the
anion was changed from [AlCl4] to more robust weakly
coordinating anions to preclude halide transfer equilibria.
Electrophiles derived from Lewis acid coordination to Y2BX
(types II and III in Figure 2) and a transmetalation mechanism
involving initial “AlCl3” attack on an arene are thus excluded.
Catechol borenium cations partnered with weakly coordinating
anions were predominantly used in this section due to their
reduced sensitivity relative to dichloro analogues. [Cl2B-
(amine)]+ partnered with weakly coordinating anions are
accessible but only in situ. These salts proved extremely
challenging to isolate in analytically pure form due to their
extreme electro- and oxophilicity.
does borylate activated arenes in the presence of a non-
coordinating amine to scavenge the protic byproduct.11
The synthesis of borenium cations using the more weakly
coordinating anions [closo-1-H-CB11H5Br6]− and [B(3,5-
C6H3Cl2)4]− (termed CbBr6 and BArCl, respectively) was
facile. Combination of Ag[CbBr6]57 and CatBCl(Et3N) formed
1[CbBr6]. 1[CbBr6] displayed an 11B NMR resonance (in
CD2Cl2) for the cation comparable to 1[AlCl4]. The
formulation as 1[CbBr6] was structurally confirmed (Figure
8, right) with the angles at B1 summing to 360° and the
shortest (Cat)B···Br contact being >5 Å. [BArCl] congeners
were accessed by stoichiometric combination of CatBCl,
Na[BArCl],58 and amine. 1[CbBr6] and 1[BArCl] cannot
form type II or III electrophiles (Figure 2), while anion
coordination (type V) is highly unlikely in the presence of
superior nucleophiles (such as amines) due to the extremely
weakly coordinating nature of these anions.59 Borenium
systems containing either anions react analogously in
borylations supporting their robust and weakly coordinating
nature.
Using Robust Weakly Coordinating Anions. CatB-
(Me2NPh)(OTf), 5, was readily synthesized from TMSOTf
and equimolar CatBCl/Me2NPh. A four-coordinate neutral
formulation was indicated by the 11B NMR chemical shift of 9.7
ppm (in CD2Cl2) and further confirmed by X-ray diffraction
studies (Figure 8, left). Compound 5 has structural metrics
comparable to CatBCl(NEt3).56 The short B−OTf bond length
(1.481(10) Å) is only marginally longer than the catechol B−O
distances consistent with a strong B−OTf interaction. 5 was
stable at 20 °C with no Me2NPh borylation observed with or
without addition of excess Me2NPh (in CH2Cl2 or C6D6). The
absence of Me2NPh borylation with 5 is in contrast to the
reactivity of CatBCl/AlCl3/Me2NPh which undergoes rapid
borylation at 25 °C. The absence of borylation suggests no
dissociation of amine or triflate from 5 at 20 °C. This is also
consistent with the lack of reaction between 5 and Et3N at 20
°C. Borylation of Me2NPh was observed on heating 5 to 90 °C
in the presence of excess Me2NPh, indicating that an
electrophilic three-coordinate boron species is accessible at
raised temperature. However, with the observed strong
coordination of triflate to boron this does not discriminate
between [CatB(Me2NPh)]+ or CatB(OTf) being the active
borylating agent. A related neutral electrophile, 9-BBNNTf2,
The addition of 1 equivalent of Me2NPh, or N-Me-indole, to
1[CbBr6] led to complete arene borylation in 2 and 5 h,
respectively (in CD2Cl2), closely comparable to the reactivity of
1[AlCl4]. The borenium cation [1]+ is therefore an active
borylating species, as no other electrophiles can be feasibly
formed from 1[CbBr6]. It is noteworthy that no additional base
was required for the borylation of Me2NPh and N-Me-indole
with recrystallized (thus strictly stoichiometric) 1[CbBr6]. This
indicates that either these arenes act as Brønsted bases (Figure
9, left pathway) or that Et3N is released sufficiently early in the
borylation process to act as the base in a concerted or stepwise
process (Figure 9 center and right pathways). The involvement
of the anion in the deprotonation step is precluded as the anion
is an extremely weak base (H[CbBr6] is a Brønsted superacid
able to protonate benzene).60 Precedence for N-Me-indole
acting as a base during borylation was previously observed in
the reaction of BCl3 with N-Me-indole (Figure 3). As the
product CatB(heteroaryl) does not bind Et3N to any significant
extent (by 11B NMR spectroscopy), Et3N will rapidly dissociate
from arylBCat(amine). The released Et3N will then rapidly
deprotonate [H(heteroarene)]+; thus, all mechanisms in Figure
9 are consistent with [Et3NH]+ being the only protonated
species observed during borylation with 1[CbBr6].
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145°, respectively),61 it precludes deprotonation proceeding by
dissociation of Et3N from the arenium cation and deprotona-
tion via a concerted intramolecular proton transfer to Et3N.
Consequentially, N-Me-indole must be acting as the Brønsted
base during borylation of N-Me-indole with [1][CbBr6]. It is
presumably the combination of significantly greater sterics and
the lower basicity of N-TIPS-pyrrole relative to N-Me-indole62
that prevents N-TIPS-pyrrole acting as a Brønsted base during
borylation. The successful, though slow, borylation of N-TIPS-
pyrrole with 1[AlCl4] is therefore attributed to a low
concentration of free Et3N generated by the various equilibria.
When borenium cations are partnered with [AlCl4] FLP
formation is often precluded by competitive halide transfer.
Thus, addition of Me2NTol to 1[AlCl4] rapidly formed
CatBCl(Me2NTol) and Et3N-AlCl3.30 Pleasingly, the combina-
tion of PPh3 and 1[AlCl4] leads to a stable FLP. The lack of
halide transfer is attributed to the lower nucleophilicity of PPh3
(relative to Me2NTol) toward aluminum.63 The use of the FLP
1[AlCl4]/PPh3 in borylation reactions that previously took days
with just 1[AlCl4] reduced reaction times to <1 h for complete
borylation. Furthermore, the use of the FLP 1[AlCl4]/PPh3
prevented decomposition of highly Lewis acid sensitive
heteroarenes enabling the regioselective C5 borylation of 2-
methylfuran and 2-methoxyfuran (Figure 11). Furans are not
amenable to borylation using only the borenium cation [1]+
due to competitive heteroarene decomposition reactions.
Figure 9. Borylation pathways using 1[CbBr6] or 1[BArCl] (base = an
activated arene, e.g., Me2NPh or N-Me-indole).
Surprisingly, 1[CbBr6] (or 1[BArCl]) borylated N-TIPS-
pyrrole only extremely slowly (<5% in 72 h by NMR
spectroscopy). In contrast, the complete borylation of N-
TIPS-pyrrole with 1[AlCl4] took place in 72 h. The anion
dependency must be an effect of the halide transfer equilibria
(Figure 1) present when using 1[AlCl4]. Presumably, the
equilibria result in another compound vital for borylation being
present in solution at a low (unobservable by NMR
spectroscopy) concentration. We surmised that this was either
(i) free Et3N to deprotonate the borylated arenium cation or
(ii) another more reactive electrophile (e.g., of type II or III).
To probe the effect of a free Lewis base on borylation, dTBP
(dTBP = 2,6-di-tert-butyl-pyridine) and PPh3 were added to
[1]+ partnered with [CbBr6] or [BArCl]. In all cases, there is no
Lewis adduct formation; thus, these combinations represent
borocation frustrated Lewis pairs (FLPs).24 The FLP 1-
[CbBr6]/dTBP did not accelerate the borylation of N-TIPS-
pyrrole with minimal borylation observed (<5%, 24 h, Figure
10). In contrast, the FLP 1[BArCl]/PPh3 resulted in the
complete borylation of N-TIPS-pyrrole in <1 h. The presence
of a free Brønsted base that has sufficient basicity and is below a
certain steric threshold is therefore essential for the borylation
of N-TIPS-pyrrole using [1]+. As Et3N is a stronger base than
PPh3 and has a similar steric profile (cone angles 150° and
Figure 11. Borylation of 2-R-furan with 1[AlCl4]/PPh3.
The primary product, if an SEAr mechanism commencing
from a borenium cation is operating, is a borylated arenium
cation. Unfortunately, no intermediates were observed during
the borylation of a wide range of arenes and heteroarenes with
[1]+. Arenium cations are, however, observable on addition of
the more electrophilic cations [Cl2B(amine)][AlCl4] (amine =
Et3N or Me2NTol) to N-TIPS-pyrrole at 20 °C. The borylated
arenium cations, 6(amine) (Figure 12 center), have 11B NMR
Figure 12. Reactivity of N-TIPS pyrrole toward [Y2B(amine)]+.
resonances (δB 6.1 and 6.6 ppm) indicative of a four-coordinate
boron center and comparable to (η1-C5Me5)BCl2(NMe3) (δB
5.1 ppm).64 In contrast, with [Cl2B(2,6-lutidine)]+ the expected
intermediate 6(2,6-lut) is not observable; instead, N-TIPS-
pyrrole is extremely rapidly borylated to ArylBCl2 (complete in
<30 min with [AlCl4] or [BArCl] anions). Presumably, the
combination of the lower nucleophilicity (relative to Et3N) and
Figure 10. Borylation of N-TIPS pyrrole with [1]+ cations.
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greater steric bulk of lutidine (relative to Me2NTol) favors
faster dissociation of 2,6-lut from the four-coordinate boron
center in 6(2,6-lut). This generates an equivalent of Brønsted
base enabling subsequent rapid deprotonation. The rapid (<1
h) borylation of N-TIPS-pyrrole by [CatB(Me2NTol)][BArCl]
also indicates that dissociation of amines from borylated
arenium cations can be facile with catechol-based borenium
cations provided the amine is more weakly nucleophilic than
Et3N. There are thus two distinct deprotonation mechanisms
(Figure 12): (i) when amine dissociation from the borylated
arenium cation is extremely slow (e.g., with [1]+), deprotona-
tion requires an additional base and occurs at a 4 coordinate, at
boron, intermediate; (ii) with less nucleophilic amines,
dissociation from the borylated arenium cation is faster,
presumably forming a three coordinate (at boron) cationic
intermediate, and an equivalent of free base for deprotonation.
Although a concerted deprotonation mechanism cannot be
excluded in the second case. This mechanistic divergence can
be utilized to selectively produce the kinetic or thermodynamic
borylated isomer. Equimolar BCl3/AlCl3/Me2NTol predom-
inantly borylates N-Me-pyrrole to provide the kinetic C3
borylated product (in a 5:95 C2:C3 regioisomer ratio) due to
rapid deprotonation of the arenium cation intermediate. In
contrast, the borylation of N-Me-pyrrole using 1[AlCl4]
produces the thermodynamic C2 borylated regioisomer as the
major product (4:1 C2:C3) at reaction times <1 h or in the
presence of a proton sponge.37
borylated isomer formed using tTBP as base compared to
borylation with Me2NTol (both at 120 °C for 75 h; Figure 13).
Figure 13. Borylation using equimolar Y2BCl, AlCl3, and TBP.
The increase in formation of the kinetic regioisomer is
consistent with a rapid deprotonation of the borylated arenium
cation intermediate by tTBP minimizing intramolecular
migration. Equimolar CatBCl/AlCl3/dTBP also generated an
effective borylation agent which was more reactive than [1]+.
For example, CatBCl/AlCl3/dTBP rapidly diborylated N-Me-
carbazole, whereas 1[AlCl4] does not borylate this substrate.
Importantly, CatBCl/AlCl3/dTBP does not borylate toluene
(24 h, 110 °C). This confirms that CatBCl is not
disproportionating to produce BCl3, which does borylate
toluene with TBP and AlCl3. The more activated arenes,
pyrene and fluorene, are borylated at 100 °C with CatBCl/
AlCl3/dTBP. Formation of the thermodynamic product is also
minimized using hindered TBP bases with CatBCl (Figure 13).
The hindered TBP pyridines will be more weakly bound to
the Lewis acids (compared to Me2NTol) due to steric
destabilization. This enables a higher concentration of free
base to be present and consequentially a more rapid
deprotonation step. Weak coordination of TBP to BCl3 is
indicated by the 11B NMR spectrum of equimolar Cl3B/dTBP
(δ 11B 44.9 ppm at 20 °C, CD2Cl2) revealing only a small
upfield shift. On addition of AlCl3, this forms BCl3 (δ 11B 46.0
ppm) and dTBP-AlCl3 (δ 27Al broad at 103.5 ppm). In
contrast, coordinating amines (Me2NTol) form stronger
adducts with ECl3 (e.g., equimolar BCl3 and Me2NTol has an
11B NMR resonance at 10.4 ppm). Thus, there will be an
extremely low amount of free Me2NTol present in solution,
resulting in slower deprotonation and more isomerization.
With no boron electrophile other than BCl3 (or CatBCl)
observed by NMR spectroscopy during borylation with Y2BCl/
TBP/AlCl3, a number of mechanisms are feasible. These
include (i) borylation via a type II or III electrophile (Figure 14
top) or (ii) an organometallic transmetalation route (Figure 14
bottom). The inability of BCl3/AlCl3/tTBP to borylate toluene
to any significant degree at 20 °C is in contrast to Muetterties
system, precluding formation of BCl2(μ-Cl)AlCl3 (or
[(areneH)BCl2][AlCl4]) at this temperature. The borylation
of toluene with BCl3/AlCl3/TBP does occur at raised
temperatures (≥70 °C) suggesting that under more energetic
conditions a type II or III electrophile (or [(areneH)BCl2]-
[AlCl4]) is accessible. With BCl3/AlCl3/TBP, the active
electrophile in the borylation of less activated arenes is
presumably identical to that operating in the original report
by Muetterties. The presence of the TBP amine prevents
heteroarene decomposition and trans-alkylation (intermolecular
Brønsted superacid induced alkyl scrambling) due to more
effective proton trapping.
The use of [CbBr6] and [BArCl] has demonstrated
definitively that borenium cations are active borylating
electrophiles. However, attempts to borylate toluene with
[(Me2NTol)BCl2][CbBr6] (formed by hydride abstraction
from (Me2NTol)BHCl2 with Ph3C[CbBr6]65) in o-C6H4Cl2
failed, with no borylation observed at 110 °C without (after 3
days) or with (after 24 h) the hindered base 2,4,6-tritBu-
pyridine (tTBP). Therefore, another, non-borenium cation,
borylating electrophile must be present in Y2BCl/amine/AlCl3
systems at the raised temperatures used to borylate toluene and
other weakly activated arenes. To prevent the formation of a
borenium cation, the combination of an extremely bulky amine
with Y2BCl and AlCl3 was investigated.
Borylation without Borenium Cations. The 2,6 and
2,4,6-tert-butyl-substituted pyridines (dTBP and tTBP, respec-
tively) were selected as suitable “noncoordinating” bulky bases.
Equimolar BCl3/AlCl3/tTBP gave no evidence for borenium
cation formation (by NMR spectroscopy). However, this
mixture did react rapidly with 2-Me-thiophene, with complete
borylation within 10 min (20 °C in CH2Cl2). In contrast, BCl3/
AlCl3/tTBP did not borylate toluene at ambient temperatures
(<5% in 6 h by 11B NMR spectroscopy). This is in contrast to
the rapid (1 h) borylation of toluene reported with BCl3/
AlCl3/activated aluminum (at 35 °C).15−17 At raised temper-
atures, BCl3/AlCl3/tTBP does borylate toluene (at 110 °C >
95% conversion by 11B NMR spectroscopy after 21 h).
Successful borylation indicates that a more reactive electrophile
is present relative to the borenium cation [Cl2B(Me2NTol)]-
[CbBr6]. It is also noteworthy that using BCl3/AlCl3/tTBP
para-borylated toluene was the predominant product (ca. only
7% of meta isomer is observed, compared to 5:1 para:meta ratio
with BCl3/AlCl3/Me2NTol). This is remarkable selectivity for
the Friedel−Crafts functionalization of toluene, and is superior
when compared to direct borylation under iridium catalysis
(para:meta borylation 31:69 ratio).66 The borylation of pyrene
proceeded analogously with significantly more of the kinetic 1-
With more nucleophilic arenes (e.g., indoles/thiophenes),
borylation is extremely rapid at 20 °C; thus, a transmetalation
mechanism is also feasible. While neutral AlX3 Lewis acids
interact weakly with benzene,67,68 the greater nucleophilicity of
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short (Al1−C3 = 2.083(8) and Ga1−C3 = 2.105(3) Å)
consistent with a strong interaction and are considerably
shorter than (toluene)Al(C6F5)3 (Al−C = 2.366(2) Å).69 This
emphasizes the effect of high arene nucleophilicity on
increasing adduct strength. The E-C distances in 9 and 10, in
fact, more closely approach that of [ArylECl3] species (e.g.,
70
i
Ga−C = 1.944(8)Å in ([(Et2O)Li][Cl3Ga(C6H2 Pr3)])2).
Compounds 9 and 10 represent a step on the proposed
transmetalation pathway, with coordination of ECl3 lowering
the pKa of N-Me-indole. However, attempts to deprotonate 9
and 10 with dTBP predominantly formed insoluble and
intractable material (in CH2Cl2 and in o-C6H4Cl2).
[HdTBP]+ was observed in these reactions suggesting that
deprotonation of 9 and 10 is taking place. In contrast, the
addition of the slightly less bulky base, PCy3, did not
deprotonate 9 and 10; instead, this produced Cl3E-PCy3 and
N-Me-indole. Furthermore, a combination of N-Me-indole and
Me2NTol-AlCl3 (a significant AlCl3 containing species present
from combining Y2BCl/Me2NTol/AlCl3) in o-C6H4Cl2 re-
sulted in no reaction.
Combined, the studies with weakly coordinating anions and
TBP bases indicate the following: (i) a transmetalation
mechanism is not possible when the base is less bulky than
TBP; (ii) in borylation reactions using coordinating amines,
more activated arenes are borylated at 20 °C by borenium
cations; (iii) less activated arenes (e.g., pyrene, toluene) are
only borylated by Type II/III electrophiles; (iv) when the
amine is Me2NTol or TBP, less activated arenes only undergo
significant borylation at high temperatures precluding for-
mation and borylation by Olah’s proposed Cl2B(μ-Cl)AlCl3
electrophile at 20 °C. Thus, at ambient temperatures with
coordinating amines the borenium cation, [Y2B(amine)]+, is
the most important borylating electrophile. To seek further
support for these conclusions and elucidate borylation
mechanistic details, each of the key proposed mechanisms
were probed computationally for the CatBCl system.
Computational Studies. The theoretical study of the
borylation reaction was carried out at the M06−2X/6-
311+G(2d,2p)//M06−2X/6-31G(d,p) level using a computa-
tional model composed of CatBCl, AlCl3, trimethylamine, and
N-Me-indole. In the following discussion, all energies are
relative to the four reactants at infinite distance and have been
corrected to account for solvation effects.
Figure 14. Proposed non-borenium borylation pathways.
activated heteroarenes will result in a stronger interaction with
AlCl3 to form zwitterionic arenium-ECl3 species (Figure 14
bottom left). Deprotonation by TBP to form [(heteroaryl)-
AlCl3] (a carbanion equivalent) and transmetalation with
Y2BCl would then afford ArylBY2. To probe this mechanism,
N-Me-Indole was added to equimolar CatBH/AlCl3 mixtures at
20 °C in o-C6H4Cl2. As expected, N-Me-indole has a greater
nucleophilicity toward AlCl3 relative to CatBX species, with a
new 27Al NMR resonance centered at 110 ppm observed
consistent with {N-Me-indole)·AlCl3. Confirmation of this
product as {N-Me-indole)·AlCl3, 9, was provided by single
crystal X-ray diffraction analysis (Figure 15). The gallium
analogue, {N-Me-indole)·GaCl3, 10, was also structurally
characterized. The structural metrics for 9 and 10 are similar,
including shortened N1−C2 bonds and elongated C2−C3
bonds relative to free N-Me-indole. The E-C3 distances are
Figure 16 summarizes the three products possible from a
combination of CatBCl, AlCl3, and trimethylamine. The
Figure 16. Relative E(G298) in CH2Cl2 (kcal/mol) for different species
prior to addition of N-Me-indole.
borenium cation optimizes as CatBNMe3(μ-Cl)(AlCl3) (A1)
in contrast to the experimentally synthesized [CatB(NEt3)]-
[AlCl4]. CatBNMe3(μ-Cl)(AlCl3) has a significantly longer
bridging Al−Cl bond (2.33 Å compared to 2.11 Å for the
remaining three Al−Cl distances) and a short B−Cl contact
(2.06 Å). This is consistent with the facile chloride transfer
Figure 15. Schematic and ORTEP representations of 9 and 10 with
thermal ellipsoids at 50% probability. Selected bond lengths (Å) for 9:
N1−C1 = 1.448(11), N1−C2 = 1.332(10), C2−C3 = 1.404(12), C3−
Al1 = 2.083(8). For 10: N1−C1 = 1.463(4), N1−C2 = 1.322(4), C2−
C3 = 1.421(5), C3−Ga1 = 2.105(5).
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observed with [CatB(amine)][AlCl4], which presumably
proceeds by attack of an external base on CatB(amine)(μ-
Cl)(AlCl3).30 The lowest energy structure using this computa-
tional model was found to involve oxygen coordination to AlCl3
(A2).71 Coordination of the amine to the aluminum center
(A3) with no interaction between the boron atom and the
Lewis base is predicted to have similar stability to the borenium
cation.
mol−1, respectively.37 The energetically favored formation of
the aryl boronate ester should therefore be rapid with both
PPh3 and Et3N. Experimentally, the borylation of highly
activated arenes with the [1]+/PPh3 FLP is indeed fast (<10
min). However, borylation with 1[AlCl4] and no additional
base, where the base is presumably Et3N generated through
equilibrium processes, is slower. The slower borylation with
1[AlCl4] is attributed to the equilibrium positions effectively
suppressing the amount of free Et3N present in solution. In the
borylation of N-Me-indole with 1[CbBr6], the presence of free
Et3N is precluded; thus, N-Me-indole was proposed to be the
base. The borylation of N-Me-Indole with 1[CbBr6] proceeded
to >95% within 5 h, in contrast with <10 min using the FLP
[1][AlCl4]/PPh3. This disparity suggests a considerably higher
barrier to deprotonation when N-Me-indole is the Brønsted
base. Computationally, ΔG‡ for deprotonation using another
molecule of N-Me-indole (instead of Me3N or PPh3) was 23
kcal/mol above the σ complex, consistent with the observed
rate of reaction. The deprotonation is actually endothermic
when N-Me-indole is the base, but subsequent rapid amine
dissociation from neutral 3-(CatB(NMe3))-N-Me-indole will
result in deprotonation of the protonated indole and formation
of [Me3NH][AlCl4] generating an overall exothermic reaction.
Thus, the computational results support a SEAr mechanism
with the borenium cation [1]+ viable as the active electrophile,
provided a secondary base is present to deprotonate the σ
complex.
The sequence of elementary steps for borylation of N-
methyl-indole starting from the borenium cation is depicted in
Figure 17. Addition of N-Me-indole to the borenium cation
We also considered the direct borylation of N-Me-indole
using CatBCl(AlCl3) as the electrophile, with NMe3 only acting
as a Brønsted base abstracting the proton on the C3 position to
liberate the product. Due to the high nucleophilicity of N-Me-
indole, geometry optimization of the complex between
nucleophile and electrophile spontaneously converges to a σ-
complex, F. Despite repeated attempts, no transition state for
B−C formation could be found. Proton abstraction (TSFG) was
extremely facile (Figure 18), as testified by the negative barrier
Figure 17. Relative E (G298) in CH2Cl2 (kcal/mol) for the borenium
pathway including a second molecule of Me3N as Brønsted base.
[CatB(NMe3)][AlCl4] is calculated to be weakly exothermic
with a very low barrier to formation of the σ complex between
the boron electrophile and N-Me-indole (TSBC). The σ
complex, C, is the key intermediate en route to the aryl
boronate ester. Borylation is calculated to proceed by an SEAr
mechanism, in line with the experimentally observed borylated
arenium cations. There was no evidence for a competing C−H
insertion mechanism as found during intramolecular borylation
with electrophilic borocations containing a B−H moiety.27
Likewise, intramolecular proton transfer from the C3−H to
NMe3 through a four-membered transition state was not found
computationally.28 The [AlCl4]− anion was also found to be
insufficiently basic to deprotonate the arenium cation. This is
consistent with the superacid HCl−AlCl3 being orders of
magnitude more acidic than protonated N-Me-indole. No
transition state could be optimized for the dissociation of NMe3
from the σ complex C. The barrier for B−N bond breaking was
thus estimated as roughly 25 kcal/mol by gradually stepping the
B−N distance and applying a solvation correction to the
electronic energy of each point.37 A 25 kcal/mol barrier is
consistent with borylation with 1[CbBr6] requiring a second
equivalent of base due to slow B-NEt3 cleavage in the σ
complex at 298 K.
Figure 18. Relative E (G298) in CH2Cl2 (kcal/mol).
obtained after adding vibrational corrections to the calculated
energies. However, the ease of the process does not render this
pathway favored with respect to the borenium mechanism, as
all the stationary points lie significantly higher in energy than
those depicted in Figure 17.
An alternative pathway involving transmetalation is depicted
in Figure 19. Optimization of N-Me-indole and AlCl3 resulted
in a barrierless formation of a σ-complex, H. This can be easily
deprotonated by Me3N (TSHI) to form adduct I. Upon
addition of one molecule of CatBCl, the resulting adduct
undergoes a stepwise transmetalation, beginning with the attack
of the boron electrophile on C3 (TSJK). The final step of the
pathway involves a concerted 1,3-halide shift/Al−C bond
breaking (TSKL), liberating the borylation product. While the
reaction barriers in this pathway are also very low, the
optimized stationary points again lie significantly higher in
The only deprotonation process with a sufficiently low
barrier to be consistent with the observed reactivity at 20 °C
involved the addition of a further equivalent of base to the σ-
complex. When the base is a second equivalent of Me3N
(TSDE) or an equivalent of PPh3, the calculated Gibbs energy
barriers of the deprotonation step are low, 9.6 and 16.5 kcal
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Article
significantly lower the overall barrier, with a calculated Gibbs
energy value (25.8 kcal mol−1) still not consistent with a fast
process taking place at 20 °C. The direct attack pathway has a
barrier of only 19.1 kcal/mol (Figure 21), which is compatible
Figure 21. Relative E (G298) in CH2Cl2 (kcal/mol) for the direct
attack pathway with dTBP as Brønsted base.
Figure 19. Relative E (G298) in CH2Cl2 (kcal/mol) for the
transmetalation pathway.
with rapid borylation at 20 °C. Thus, the direct borylation
pathway is feasible with dTBP-provided transfer of AlCl3 from
compound 9 to CatBCl is sufficiently rapid at 20 °C, as
experimentally N-Me-indole is more nucleophilic toward AlCl3
than CatBX.
energy than those found in the borenium pathway, thus also
rendering this mechanistic hypothesis less favored. The
optimized geometries of the lowest-energy transition states
for the three pathways considered are represented in Figure 20.
Alternative mechanisms must be operating at 20 °C when the
hindered TBP bases are used as borylation cannot proceed via
synthetically inaccessible [Y2B(TBP)]+ cations. With the dTBP
base, we theoretically scrutinized the transmetalation and direct
borylation (with CatBCl(AlCl3)) pathways for the borylation of
N-Me-indole. The overall Gibbs energy barrier for the
transmetalation pathway was calculated to be 29.6 kcal/mol.37
This is inconsistent with the experimentally observed rapid
(<10 min at 20 °C) borylation of N-Me-indole with CatBCl/
AlCl3/dTBP. Specifically, we found the direct proton transfer
step to dTBP to be very energetically demanding due to steric
crowding around the nitrogen atom. Addition of a second
equivalent of N-Me-indole to act as the Brønsted base did not
SUMMARY
■
Amine-mediated electrophilic direct borylation has been
demonstrated for a range of activated arenes and heteroarenes.
The subsequent installation of the MIDA protecting group
provides an alternative synthetic route to these increasingly
popular Suzuki-Miyaura cross-coupling precursors. Electro-
philic borylation is particularly well suited for preparing
precursors for Suzuki-Miyaura polymerization and iterative
cross coupling39 due to its compatibility with halo functional
groups and the ability to di- and triborylate activated arenes.
Regioselectivity at 20 °C is high, operating under synergic steric
and electronic control. Good yields are obtainable provided the
correct borane/AlCl3/amine ratios are used to prevent
Figure 20. Optimized geometries of the transition states (distances in Å).
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Journal of the American Chemical Society
Article
deboronation and acid induced heterocycle decomposition. At
raised temperatures, less activated arenes are also amenable to
borylation. Regioselectivity under these more forcing con-
ditions is dependent on the rate of positional isomerization in
the borylated arenium cation (σ complex) relative to the rate of
deprotonation. By using “noncoordinating” TBP bases, kinetic
products can be selectively formed due to more rapid
deprotonation of the σ complex.
AUTHOR INFORMATION
■
Corresponding Author
michael.ingleson@manchester.ac.uk; tommaso.marcelli@chem.
polimi.it
Present Addresses
⊥Clemens Schopf Institute of Organic Chemistry and
̈
Biochemistry, Technische Universitat Darmstadt, Germany
̈
∥Apollo Scientific, Cheshire, United Kingdom
⊗Department of Chemistry, University of Cambridge, United
Kingdom
Mechanistically, a range of amine and temperature depend-
ent borylation pathways are viable (Figure 22). Using
Author Contributions
§V.B. and A.D. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Royal Society (M.J.I. for the
award of a University Research Fellowship), the University of
Manchester (A.D., S.A.S., and V.B.), the EPSRC (J.R.L., I.A.C.
Grant Number EPJ000973/1 and M.D.H. for a KTA award),
Cambridge Display Technologies (S.A.S.), CONACYT
(J.A.C.), MIUR and Politecnico di Milano (T.M.) for financial
support, and CILEA for computing time. Dr. Chris Muryn and
Mr. Daniel Woodruff are thanked for assistance with
crystallography.
Figure 22. Viable direct borylation pathways.
inexpensive coordinating amines, the dominant mechanism at
20 °C involves a borenium cation as the key electrophile.
Computational and experimental studies indicate that bor-
ylation proceeds by a SEAr pathway. The deprotonation step
was found to be highly amine dependent. With [CatB(NEt3)]+,
an additional Brønsted base is required; thus, borylation is only
rapid when FLP containing [CatB(NEt3)]+ and PPh3 are used.
The use of a FLP also enabled borylation of highly sensitive
substrates (e.g., furans). Borylation with [Y2B(Me2NTol)]+ and
[Cl2B(2,6-lutidine)]+ borenium cations was rapid relative to
[CatB(NEt3)]+. This is due to the higher electrophilicity of
these cations and the ability of the more weakly nucleophilic
amines to dissociate more rapidly from the borylated arenium
cations. Surprisingly, despite its high electrophilicity [Cl2B-
(Me2NTol)]+ is not an active electrophile for the borylation of
less activated arenes (e.g., toluene). Instead, this requires the
formation of more activated species, presumably Cl2B(μ-
Cl)AlCl3 (solvated or nonsolvated by the arene). In the
presence of a noncoordinating amine base borylation by
borenium cations is also not energetically viable. In this case, at
least two different mechanisms are feasible: (i) coordination of
AlCl3 to Y2BCl to generate a highly reactive electrophile; (ii)
transmetalation, involving initial attack of aluminum Lewis
acids on the activated arene nucleophile. The latter mechanism
would proceed via unusual (heteroarene)AlCl3 adducts, an
example of which has been structurally characterized.
Irrespective of the significant mechanistic complexity, this
new direct method to produce MIDA boronate esters
complements the established route of organometallic deproto-
nation.
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Full experimental, crystallographic, and computational details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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