Superelectrophilic intermediates in nitrogen-directed aromatic borylation

Article abstract of DOI:10.1021/ja905369n

The first examples of borylation under conditions of borenium ion generation from hydrogen-bridged boron cations are described. The observable H-bridged cations are generated by hydride abstraction from N,N-dimethylamine boranes Ar(CH₂)_nNMe₂BH₃ using Ph₃C⁺ (C₆F₅)₄B ^- (TrTPFPB) as the hydride acceptor. In the presence of excess TrTPFPB, the hydrogen-bridged cations undergo internal borylation to afford cyclic amine borane derivatives with n = 1-3. The products are formed as the corresponding cyclic borenium ions according to reductive quenching experiments and ¹¹B and ¹H NMR spectroscopy in the case with Ar = C₆H₅ and n = 1. The same cyclic borenium cation is also formed from the substrate with Ar = o-C₆H₄SiMe₃ via desilylation, but the analogous system with Ar = o-C₆H ₄CMe₃ affords a unique cyclization product that retains the tert-butyl substituent. An ortho-deuterated substrate undergoes cyclization with a product-determining isotope effect of k_H/k_D 2.8. Potential cationic intermediates have been evaluated using B3LYP/6-31G* methods. The computations indicate that internal borylation from 14a occurs via a C-H insertion transition state that is accessible from either the borenium π complex or from a Wheland intermediate having nearly identical energy. The Ar = o-C₆H₄SiMe₃ example strongly favors formation of the Wheland intermediate, and desilylation occurs via internal SiMe₃ migration from carbon to one of the hydrides attached to boron.

Full text of DOI:10.1021/ja905369n

Published on Web 09/28/2009
Superelectrophilic Intermediates in Nitrogen-Directed
Aromatic Borylation
Timothy S. De Vries,† Aleksandrs Prokofjevs,† Jeremy N. Harvey,*,‡ and
Edwin Vedejs*,†
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109, and School of
Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
Received November 13, 2008; E-mail: jeremy.harvey@bristol.ac.uk; edved@umich.edu
Abstract: The first examples of borylation under conditions of borenium ion generation from hydrogen-
bridged boron cations are described. The observable H-bridged cations are generated by hydride abstraction
from N,N-dimethylamine boranes Ar(CH2)nNMe2BH3 using Ph3C+ (C6F5)4B- (TrTPFPB) as the hydride
acceptor. In the presence of excess TrTPFPB, the hydrogen-bridged cations undergo internal borylation to
afford cyclic amine borane derivatives with n ) 1-3. The products are formed as the corresponding cyclic
1
borenium ions according to reductive quenching experiments and 11B and H NMR spectroscopy in the
case with Ar ) C6H5 and n ) 1. The same cyclic borenium cation is also formed from the substrate with
Ar ) o-C6H4SiMe3 via desilylation, but the analogous system with Ar ) o-C6H4CMe3 affords a unique
cyclization product that retains the tert-butyl substituent. An ortho-deuterated substrate undergoes cyclization
with a product-determining isotope effect of kH/kD 2.8. Potential cationic intermediates have been evaluated
using B3LYP/6-31G* methods. The computations indicate that internal borylation from 14a occurs via a
C-H insertion transition state that is accessible from either the borenium π complex or from a Wheland
intermediate having nearly identical energy. The Ar ) o-C6H4SiMe3 example strongly favors formation of
the Wheland intermediate, and desilylation occurs via internal SiMe3 migration from carbon to one of the
hydrides attached to boron.
Introduction
The structural chemistry of cationic, trivalent boron environ-
ments (“borenium” ions according to the No¨th terminology)1
has attracted interest over many years because of the similarity
with the isoelectronic carbenium ions in terms of orbital
occupancy, electron count, and net charge. In an early investiga-
tion, Ryschkewitsch and Miller reported NMR evidence that
the cation 2 is in equilibrium with the picoline-BCl3 complex
1 in the presence of excess aluminum chloride (Figure 1).2a
Morerecently,Fujioetal.foundthatthepyridine-diphenylchloro-
borane adduct 3 is converted into 4 using SbCl5 as the chloride
abstracting agent.2b According to the analogies initially recog-
nized by Olah et al.3 and also noted by No¨th in his excellent
review,1 salt 4 is isoelectronic with trityl cation, while 2 is
Figure 1. Generation of borenium ions in solution.
analogous to dichlorobenzyl cation. By the same analogy,
borenium ions have been included in Olah’s classification of
superelectrophiles, along with several other monocationic spe-
cies that have a positively charged heteroatom adjacent to an
unoccupied p-orbital.3 Several O- and/or N-substituted borenium
species have been detected in structural studies using spectro-
scopic1,2,4 and crystallographic techniques,5,6 as summarized in
the review literature.1,7
† University of Michigan.
‡ University of Bristol.
(1) Ko¨lle, P.; No¨th, H. Chem. ReV. 1985, 85, 399.
(2) (a) Ryschkewitsch, G. E.; Miller, V. R. J. Am. Chem. Soc. 1973, 95,
2836. (b) Uddin, M. K.; Nagano, Y.; Fujiyama, R.; Kiyooka, S.; Fujio,
M.; Tsuno, Y. Tetrahedron Lett. 2005, 46, 627.
According to prior work, borenium ions are potent electro-
philes that may approach the more familiar carbenium8 or
(3) (a) Olah, G. A. Angew. Chem., Int. Ed. 1993, 32, 767. (b) The definition
of “superelectrophile” stated in the Olah review specifies that dicationic
species are superelectrophiles, but the discussion also identifies several
factors that enhance the electrophilicity of neutral or monocationic
species. Explicit examples in Olah’s review include Lewis acid
complexes of boric acid, trimethyl borate, and boron trichloride. In
this usage, “superelectrophilicity” may be understood more broadly
as a qualitative comparison between an exceptionally enhanced
electrophile and the unenhanced parent electrophile. (c) Superelec-
trophiles and Their Chemistry; Olah, G. A., Klumpp, D. A., Eds.;
John Wiley & Sons, Inc.: Hoboken, NJ, 2008.
(4) (a) No¨th, H.; Wrackmeyer, B. Chem. Ber. 1981, 114, 1150. (b) Narula,
C.; No¨th, H. Inorg. Chem. 1984, 23, 4147. (c) Kuhn, N.; Kuhn, A.;
Lewandowski, J.; Speis, M. Chem. Ber. 1991, 124, 2197.
(5) Cowley, A. H.; Lu, Z.; Jones, J. N.; Moore, J. A. J. Organomet. Chem.
2004, 689, 2562.
(6) Chiu, C.-W.; Gabbai, F. P. Organometallics 2008, 27, 1657.
(7) Piers, W. E.; Bourke, S. C.; Conroy, K. D. Angew. Chem., Int. Ed.
2005, 44, 5016.
(8) Review: Olah, G. A. J. Org. Chem. 2001, 66, 5943.
9
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A R T I C L E S
De Vries et al.
In the absence of stabilizing heteroatom electron pairs or
hindered aryl substituents at boron, borenium ions should be
exceptionally reactive electrophiles. Furthermore, the structural
analogy with carbenium ions resulting from the net positive
charge and vacant p-orbital at boron suggests potentially
important applications for the formation of C-B bonds. Isolated
examples of relevant electrophilic borylation chemistry have
been encountered over the years, usually under relatively drastic
conditions (boron halide/aluminum trichloride),16 but the pos-
sible involvement of borenium species has been largely over-
looked.17
Given the intensive current interest in transition metal
catalyzed applications of aryl and alkyl boranes and boronic
acids,18,19 it is time to revisit mechanistic options available to
electrophilic boron for C-B bond formation. Little is known
regarding the reactivity of borenium cations with carbon
nucleophiles. We were especially interested to learn whether
the tendency of trivalent boron to form three-center two-electron
(3c2e) bonds would enable or impede the Friedel-Crafts
electrophilic substitution pathway in an intramolecular context,
but the mechanistic analogy with carbenium ion chemistry was
a larger consideration. Therefore, our work began with the
investigation of a borenium ion analogy for the classical
Friedel-Crafts cyclization using benzylic amine boranes as the
substrates. The study detailed below has demonstrated a series
of relevant cyclizations and has encountered evidence for a
mechanism that has implications for electrophilic borylation
chemistry beyond the nitrogen-directed examples described
herein.
Figure 2. Oxazaborolidines as borenium ion precursors.
silylium9 cations in terms of reactivity. Indeed, the challenge
of obtaining X-ray quality crystals of a structure related to 4
was met only recently6 and required highly hindered B-aryl
groups to prevent boron coordination by external electron
donors. Borenium species containing nitrogen or oxygen electron
pair donors are more stable because delocalization partially
satisfies electron demand at boron, but they retain substantial
Lewis acidity and act as catalysts in several important applica-
tions. The best known example is the enantioselective Corey-
Bakshi-Shibata reduction of ketones via the intermediate 5,
generated in situ from an oxazaborolidine and a borane source
(Figure 2).10 Although 5 does not carry a net positive charge,
a borenium subunit can be recognized along the N-B-O
segment due to the formally positive nitrogen. Structurally
similar but far more potent borenium electrophiles 9 can be
generated from neutral precursors 7 by protonation at nitrogen.11
In this case, 9 does carry a net positive charge and serves as a
highly reactive Lewis acid catalyst despite the moderating
influence of oxygen electron pairs and the tendency of triflate
to form a covalent adduct at boron (8). In other applications,
related O- or N-substituted (stabilized) borenium ion intermedi-
ates may be involved in the epimerization at boron in several
families of chiral heterocycles,12 while nonstabilized borenium
species may play a role in C-F bond cleavage reactions,13 the
abstraction of hydride from amine boranes using trityl or
diarylmethyl cations,14 and perhaps also some of the hydrobo-
ration chemistry of iodoborane complexes.15 Given the com-
plexity and debatable information content of formal charges in
structures related to species such as 5, 6, or 9, we omit the
charges at individual atoms in most of the subsequent drawings
to allow focus on the far more important net charge.
Methods and Results
A prior study in our laboratory generated the nonstabilized
borenium ion 11 from triethylamine borane 10 by hydride abstrac-
tion with trityl cation and found that 11 is trapped efficiently by
the starting complex 10 to form the hydride-bridged cation 12
(Figure 3).20 The 3c2e bond in 12 increases the electron density at
boron compared to the borenium ion 11, but 12 is a capable
electrophile nevertheless and undergoes bonding interactions with
weak nucleophiles including triflate and bistriflimidate anions,
trialkylsilanes, and dichloromethane.
The above observations indicate that 12 acts as an in situ source
of borenium species equivalent to 11. We therefore performed the
analogous activation of N,N-dimethylbenzylamine borane 13a while
monitoring intermediates by NMR spectroscopy (Scheme 1).
(16) Muetterties, E. L.; Tebbe, F. N. Inorg. Chem. 1968, 7, 2663.
(17) An intramolecular borylation has been rationalized by proposing a
catalytic effect by adventitious acid, a process that may be interpreted
as invoking a borenium ion intermediate: Genaev, A. M.; Nagy, S. M.;
Salnikov, G. E.; Shubin, V. G. Chem. Commun. 2000, 1587.
(18) (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (b)
Yin, L. Liebscher, J. Chem. ReV. 2007, 107, 133. (c) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. (d)
Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2458.
(9) Reviews: (a) Lambert, J. B.; Zhao, Y.; Zhang, S. M. J. Phys. Org.
Chem. 2001, 14, 370. (b) Reed, C. A. Acc. Chem. Res. 1998, 31, 325.
(10) Review: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1987.
(11) Review: (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (b)
Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388. (c)
Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9536.
(12) (a) Mancilla, T.; Contreras, R. J. Organomet. Chem. 1987, 321, 191.
(b) Gyori, B.; Emri, J. J. Organomet. Chem. 1982, 238, 159. (c) Vedejs,
E.; Fields, S. C.; Schrimpf, M. R. J. Am. Chem. Soc. 1993, 115, 11612.
(d) Vedejs, E.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem.
1995, 60, 3028. (e) Vedejs, E.; Fields, S. C.; Hayashi, R.; Hitchcock,
S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc. 1999, 121,
2460.
(19) (a) General review of boronic acid preparation: Hall, D. G. Boronic
Acids 2005, 1. (b) Directed lithiation routes to arylboronic acids: Anctil,
Eric J.-G.; Snieckus, V. Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; Wiley-VCH: Weinheim, 2004; Vol. 2, p 761. (c) Arylboronate
esters from diboron alkoxide coupling with aryl halides: Ishiyama,
T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813. Ishiyama,
T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (d)
transition metal catalyzed borylation: Cho, J.-Y.; Iverson, C. N.; Smith,
M. R., III. J. Am. Chem. Soc. 2000, 122, 12868. Paul, S.; Chotana,
G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E., Jr.; Smith, M. R.,
III. J. Am. Chem. Soc. 2006, 128, 15552. Murphy, J. M.; Tzschucke,
C. C.; Hartwig, J. F. Orglett. 2007, 9, 757. (e) directed transition metal
catalyzed intramolecular borylation: Boebel, T. A.; Hartwig, J. A.
J. Am. Chem. Soc. 2008, 130, 7534.
(13) Vedejs, E.; Nguyen, T.; Powell, D. R.; Schrimpf, M. R. Chem.
Commun. 1996, 2721.
(14) (a) Benjamin, L. E.; Carvalho, D. A.; Stafiej, S. F.; Takacs, E. A.
Inorg. Chem. 1970, 9, 1844. (b) Funke, M.-A.; Mayr, H. Chem.sEur.
J. 1997, 3, 1214.
(15) Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766.
(20) De Vries, T. S.; Vedejs, E. Organometallics 2007, 26, 3079.
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Intermediates in Nitrogen-Directed Aromatic Borylation
A R T I C L E S
that is coupled to boron and integrates to 1H and can, therefore, be
assigned as the B-H proton.
An earlier encounter with cation 16a has been reported from
our laboratory, starting from the benzazaborolidine 17a.13 Hydride
abstraction using trityl tetrafluoroborate in the presence of pyri-
dine readily afforded the pyridine adduct 18 (as the tetrafluoroborate
salt), but attempts to detect intermediates by NMR initially gave
complex results. Using TrTPFPB as the hydride acceptor at -78
°C converted 17a into species having unidentified broad NMR
signals, including a transient signal at δ 11B ) 38.7 ppm that
disappeared upon adding pyridine at -50 °C or warming to room
temperature. The δ 38.7 ppm signal was tentatively attributed to
16a, but anomalies were noted that could not be explained, including
partial recovery of 17a after the pyridine quench. In the current
study, the δ 38.7 ppm signal was detected at δ 39 ppm as a minor
peak in experiments starting from either 13a or 17a (conditions
designed to minimize contamination by water) while the major
signal was observed at δ 11B ) 59 ppm. However, the δ 39 ppm
signal (broad singlet; no proton coupling) became major if 1 equiv
of water was added to the solution obtained from 17a with TrTPFPB
in CD2Cl2 at room temperature and was, therefore, assigned as the
hydroxyborenium ion 19. In support of this assignment, addition
of a second equivalent of water produced the protonated boronic
Figure 3. Hydride-bridged borenium species.
Scheme 1
1
acid 20 (δ 11B ) 29 ppm; δ H ) 5.29 (2H, br s, OH), 4.28 (2H,
d, benzylic CH2), 2.89 (6H, d, NMe2) ppm), identical to the salt
formed by protonation of known boronic acid 21 followed by anion
metathesis and extraction into CD2Cl2.
Having clarified the identity of the signal at δ 11B ) 39 ppm,
we returned briefly to the NMR experiment from 17a using
TrTPFPB activation, but under conditions expected to favor the
formation of hydride-bridged cations (50 mol % TrTPFPB). The
dominant species formed in C6D5Br was assigned as the hydride-
bridged structure 22, based on δ 11B ) 11 ppm. This signal is
downfield compared to neutral 17a but far upfield from the signals
of B-hydroxyborenium cation 19 or the borenium ion 16a. In the
cleanest experiments, the only other 11B NMR signal detected was
that due to the TPFPB anion. However, distinct maxima for 16a
or 17a were present in addition to the 11 ppm signal of 22 if the
amount of TrTPFPB used for activation of 17a was adjusted to 83
mol % or 33 mol %, respectively. The proton chemical shifts were
less characteristic, but the shift values varied as the mol % of
TrTPFPB used for cation generation was changed. This behavior
is consistent with an equilibrium between 22 and 17a + 16a that
is fast on the H NMR time scale but slow on the 11B NMR time
1
Treatment of 13a with trityl tetrakis(pentafluorophenyl)borate
(TrTPFPB) at -78 °C in CD2Cl2 and assay by 1H NMR at -20 °C
showed the expected conversion of 13a to 15a, according to an
upfield peak at δ 1H ) -1.9 ppm and a 11B chemical shift at δ 0.0
ppm. No signals for trivalent boron species such as 14a were
detected. However, a highly deshielded peak did appear in the range
expected for trivalent boron (δ 11B ) 59 ppm) when a similar
experiment was performed in the more robust solvent C6D5Br at
room temperature. The new boron signal was not consistent with
the 1:2:1 triplet expected for 14a but could be interpreted as a barely
resolved, broad doublet (J ca. 150 Hz) by comparing proton-coupled
and -decoupled spectra. This magnitude of B-H splitting would
be consistent with the sp2 environment in a free borenium ion, but
the multiplicity requires a single proton at boron. Capture of 14a
by an external or an internal nucleophile followed by a second
hydride abstraction would satisfy the multiplicity requirement and
suggested several possible structures, but the question of cation
identity was quickly resolved when addition of Bu4NBH4 to quench
the reaction mixture produced the known benzazaborolidine 17a21
(72% isolated). The δ 11B ) 59 ppm signal must therefore be due
to the trivalent boron cation 16a, stabilized by “bora-benzylic”
delocalization between the formally unoccupied boron p-orbital and
the aromatic π-electrons. Structure 16a also helps to understand
an unusually broad, strongly deshielded signal at δ 1H ) 5.9 ppm
scale. Quenching cation 22 with pyridine generates the adduct 18
previously isolated as well as recovered 17a. Thus, the hydride
bridged cation 22 apparently was present as a latent source of 16a
in the original experiment starting from 17a,13 while a different
species (the hydroxyborenium ion 19) was responsible for the
trivalent boron chemical shift observed (δ 11B 39 ppm) in the
complex NMR spectra resulting from water contamination. We note
that structure 16a as redefined in the current study remains as
the only borenium ion detected to date that contains a B-H bond,
but it is now clear that 16a has the δ 11B ) 59 ppm chemical shift.
To establish the scope of conversion from substituted benzyl-
amine boranes into cyclic amine boranes, several experiments were
conducted with modified substrates (Table 1). A comparison of
solvents for the cyclizations showed that bromobenzene (or other
halobenzenes) gives higher conversion and better isolated yield of
17a (72%) compared to toluene (48%) or dichloromethane (27%),
so the conditions developed for the bromobenzene NMR experi-
ments were used for the other entries of Table 1 without optimiza-
tion of individual examples,22 followed by Bu4NBH4 reductive
workup. A slurry of NaBH4 in diglyme also gave an acceptable
(22) The bromobenzene experiments are also more convenient because
activation with TrTPFPB can be performed at room temperature, in
contrast to dichloromethane. In the latter solvent, solvent-assisted
degradation of triphenylmethane occurs via Friedel-Crafts alkylation
as discussed in ref 20.
(21) For characterization of 17a, see ref 13.
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A R T I C L E S
De Vries et al.
Table 1. Nitrogen-Directed Borylationa
product 17b (41% obtained after Bu4NBH4 quench) was assayed
using 1H NMR. Based on the ratio of deuterium-free vs deuterated
products, the magnitude of the kinetic isotope effect (KIE) was
found to be kH/kD ) 2.8. This result indicates that the C-H(D)
bond at which boron substitution occurs is broken during or before
the regioselectivity-determining step (see Discussion).
entry
substrate
R
n
time (h)
product (%)b
1
2
3
4
5
6
7
8
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
23
H
1
1
1
1
1
1
1
1
1
1
1
1
2
3
4
4
4
4
8
17a (72%)
17b (41%)
17c (79%)c
17d (76%)
17e (53%)
17f (73%)
17g (67%)d
17h (59%)
17i (67%)e
17j (55%)
17k (55%)
17l (39%)
24 (74%)
26f
p-Me
m-Me
o-Me
p-Br
p-Cl
m-Cl
p-F
m-F
o-Br
o-Cl
o-F
8
4
16
4
16
16
16
4
9
10
11
12
13
14
Given that proton removal plays a unique role in conversion to
products, we investigated additional substrates designed to provide
insight regarding mechanistic details of the electrophilic borylations.
In the first series, the aryllithium reagent 27a was trapped with
TMSCl, followed by conversion into the amine borane 28 as usual.
Treatment of 28 with TrTPFPB at room temperature resulted in
efficient conversion to desilylated cyclization products, and reduc-
tive quenching with Bu4NBH4 gave 17a in 96% isolated yield
(Scheme 2). Even 10 mol % of the trityl salt was sufficient for
91% conversion of 28 to cyclization products within 1 h at room
temperature, in striking contrast to the behavior of 13a. In the latter
case, the only product observed under similar conditions was the
hydrogen-bridged dimer 15a, and no cyclization occurred at room
temperature unless >50 mol % of TrTPFPB was used for the
activation as in Table 1 (ca. 40 mol % TrTPFPB is present in
addition to the amount needed to generate 15). Evidently, the
TrTPFPB activates 15a for cyclization by promoting the release
of the more reactive borenium ion 14a. However, no hydrogen-
bridged intermediate analogous to 15a could be detected starting
from 28 and TrTPFPB, and additional TrTPFPB was not required
to effect the cyclization. According to this evidence, the hydrogen-
bridged structure 29 would have to be considerably more reactive
than 15 due to the presence of silicon, sufficient to undergo
spontaneous cyclization via 30.
H
H
25
16
a Reactions at room temperature in C6H5Br, 90 mol % TrTPFPB,
followed by quench with Bu4NBH4. b Yields based on TrTPFPB as
limiting reagent. c 3:1 mixture of inseparable regioisomers. d 1:1.3
mixture of regioisomers. e 4:1 mixture of regioisomers. f ca. 30% (major
product) + ca. 10% contaminants
yield in the case of 17a (63%). Reductively quenched reaction
mixtures were loaded directly onto silica gel for FC purification
even though the borohydride caused cracking of the silica column.
This resulted in poor separation for some cases, but the simple
technique allowed convenient solvent removal and reasonable
recoveries of 17 in addition to 10-20% unreacted 13 in typical
experiments. Overall, the conversions were modest for some
examples, but cyclized products were easily obtained over a range
of aromatic substitutuents. Halogen substituents required longer
reaction times for conversion to 17 (entries 5, 6, 8), especially in
the case of the ortho-halogen derivatives (entries 10-12) by
comparison with the para-isomers, suggesting the possibility of
nonproductive formation of a B-X bond between electrophilic
boron and the ortho-halogen. Longer tethers were also tolerated
(entries 13, 14), although activation of 25 resulted in slower
cyclization (30-40% 25 recovered after 16 h) and formed 26 along
with degradation products that could not be separated from 26.
Scheme 2
To gain further insight into events leading to 16, the product-
determining step was probed by a deuterium labeling study. The
monodeuterated substrates 13a-D1 and 13b-D1 were prepared by
D2O quench of the corresponding ortho-lithiated N,N-dimethyl-
benzylamines 2723 and borane complexation, giving 95% deuterium
incorporation (eq 1). The directed borylation of these substrates
can occur with either loss or retention of deuterium in the product,
so the ratio of 17-D1 to 17 corresponds to kH/kD. Substrate 13b-D1
proved more suitable for this study compared to 13a-D1 because
When an experiment from 28 and equimolar TrTPFPB was
monitored by 11B NMR spectroscopy, we were surprised to find
that the chemical shift for the cationic cyclization product does
not match the δ 59 ppm value found for 16a. Instead, the observed
value was δ 11B ) 42 ppm. We attribute the chemical shift
difference to an equilibrium involving the 3c2e hydrogen-bridged
silane adduct 31, formally corresponding to the interaction of 16a
with Me3SiH formed during the electrophilic borylation. Control
experiments in bromobenzene-D5 support this premise and indicate
that the chemical shift of the equilibrating mixture of 16a + 31
moves upfield as the proportion of added silane increases.24 Both
1
the H NMR signal for the ortho-C-H of 17a-D1 overlaps with
another aromatic proton signal while all aromatic proton signals
1
for 13b-D1 are fully resolved in the 500 MHz H NMR spectrum.
Accordingly, 13b-D1 was treated with TrTPFPB as usual, and the
(24) Borenium cation 16a was generated in bromobenzene and was treated
with progressively increasing amounts of iPr3SiH. The following
relationship between mol % of added iPr3SiH vs 11B chemical shift
was observed: 0 mol %, 59 ppm; 10 mol %, 57 ppm; 50 mol %, 48
ppm; 300 mol %, 45 ppm.
(23) (a) Slocum, D. W.; Book, G.; Jennings, C. A. Tetrahedron Lett. 1970,
11, 3443. (b) Mu¨ller, P.; Bernardinelli, G.; Jacquier, Y. HelV. Chim.
Acta 1992, 75, 1995.
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Intermediates in Nitrogen-Directed Aromatic Borylation
A R T I C L E S
Scheme 3
Scheme 4
Scheme 5
16a and 31 are converted into 17a by the borohydride quench
according to this interpretation.
The last series of experiments compared the above cyclizations
with the analogous reaction starting from the o-tert-butyl substrate
34, available from the benzyne-derived o-tert-butylbenzaldehyde
32 via reductive amination as shown in Scheme 3. The standard
activation procedure from 34 was performed in bromobenzene at
room temperature, and reductive workup provided the cyclization
product 35 in 66% yield. Loss of the tert-butyl group had been
anticipated as a possible outcome in this reaction given the behavior
of the silicon analogue 28, but no such products were detected (<2%
of 17a).
Discussion; Evaluation of Potential Reactive
Intermediates
exceptionally nonbasic conditions because the conjugate acid
of the TPFPB anion would correspond to a superacid that is
known only as the etherate complex.28 In this situation, the
bromobenzene solvent is one candidate for the “strongest”
external base, while various boron bonds, internal as well as
external, constitute the alternative choices. Hydridic B-H bonds
in amine boranes do have basic properties, although direct
protonation of the B-N σ-bond is competitive under some
conditions.29 In any event, C-H bond breaking could well be
rate limiting in the absence of adequate external base, resulting
in k2[B] , k-1 in Scheme 4. The sequence of events might then
proceed from the observable H-bridged 15a via transient
intermediates including the borenium ion 14a and the Wheland
intermediate 36, followed by slow proton transfer and aroma-
tization.30
If no external base “B” is capable of removing the proton
from 36, then k2[B] will be too small to account for facile
product formation at room temperature. In this scenario,
conversion from 36 directly to the observed intermediate 16a
may occur by evolution of hydrogen as the slow step and
without the intermediacy of 17a (Scheme 5; eq 3). Another
Most electrophilic aromatic substitution reactions proceed
with no KIE,25,26 although many exceptions are known.25c,27
Negligible KIE has been taken as evidence not only that a
σ-bonded cationic (Wheland) intermediate is involved in the
reaction but also that its formation is rate-limiting. On the other
hand, the interpretation of a significant KIE can be more
challenging. In a recent example, the acylation of toluene using
the mixed anhydride PhCO2Tf was characterized by kH/kD
)
1.14 in the presence of the hindered base 2,4,6-tri-tert-
butylpyridine, but a substantially larger value of 1.85 was
observed in the presence of TfOH.27h Under the conditions with
base added, k2[B] is much greater than k-1 and k1 is the rate-
determining step (eq 2). However, with TfOH added, k2[B]
decreases relative to k-1 and deprotonation becomes rate
limiting.
(27) (a) Zollinger, H. HelV. Chim. Acta 1955, 38, 1617. (b) Grovenstein,
E.; Kilby, D. C. J. Am. Chem. Soc. 1957, 79, 2972. (c) Berliner, E.
J. Am. Chem. Soc. 1960, 82, 5435. (d) Olah, G. A.; Kuhn, S. J.; Flood,
S. H.; Hardie, B. A. J. Am. Chem. Soc. 1964, 86, 2203. (e) Kresge,
A. J.; Brennan, J. F. J. Org. Chem. 1967, 32, 752. (f) Reich, H. J.;
Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3505. (g) Perrin, C. L. J.
Org. Chem. 1971, 36, 420. (h) Effenberger, F.; Maier, A. H. J. Am.
Chem. Soc. 2001, 123, 3429. (i) Dzudza, A.; Marks, T. J. J. Org.
Chem. 2008, 73, 4004.
For the electrophilic borylations, a small modification of the
above argument would explain the value of KIE ) 2.8 observed
for conversion from 13a to 17a. In contrast to typical electro-
philic aromatic substitutions, this process is conducted under
(25) (a) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper and Row: New York, 1987; pp 623-640.
(b) March, J. AdVanced Organic Chemistry, 5th ed.; John Wiley &
Sons: New York, 2001; pp 675-758. (c) Melander, L. C. S. Isotope
Effects on Reaction Rates; Roland Press: New York, 1960; pp 107-
122.
(26) (a) Melander, L. Ark. Kemi 1950, 2, 211. (b) Lauer, W. M.; Noland,
W. E. J. Am. Chem. Soc. 1953, 75, 3689. (c) Olah, G. A.; Kuhn, S. J.;
Flood, S. H. J. Am. Chem. Soc. 1961, 83, 4571. (d) Ehrlich, A.;
Berliner, E. J. Org. Chem. 1972, 37, 4186. (e) Zhang, B.-L.; Pionnier,
S. J. Phys. Org. Chem. 2001, 14, 239.
(28) Jutzi, P.; Mu¨ller, C.; Stammler, A.; Stammler, H.-G. Organometallics
2000, 19, 1442.
(29) (a) Kelly, H. C.; Marchello, F. R.; Giusto, M. B. Inorg. Chem. 1964,
3, 431. (b) Kelly, H. C.; Marriott, V. B. Inorg. Chem. 1979, 18, 2875.
(c) Kelly, H. C.; Giusto, M. B.; Marchello, F. R. J. Am. Chem. Soc.
1964, 86, 3882.
(30) (a) Hubig, S. M.; Kochi, J. K. J. Org. Chem. 2000, 65, 6807. (b)
Reed, C. A.; Kim, K.-C.; Stoyanov, E. S.; Stasko, D.; Tham, F. S.;
Mueller, F. J.; Boyd, P. D. W. J. Am. Chem. Soc. 2003, 125, 1796.
9
J. AM. CHEM. SOC. VOL. 131, NO. 41, 2009 14683

A R T I C L E S
De Vries et al.
Scheme 6
possible explanation for the observed KIE is that 36 is not on
the pathway leading to products (i.e., negligible contributions
from k2[B], Scheme 4, and eq 3, Scheme 5). Instead, conversion
from 14a to the initial product 16a might take place by a C-H
insertion process involving the 3c2e interactions represented by
structures 37 and 38 (eq 3b). In some respects, this sequence is
reminiscent of mechanisms proposed for transition metal C-H
insertions involving aromatic substrates,31 but the 3c2e bonding
interaction between the mostly vacant borenium p-orbital of 14a
and the arene C-H σ bond leads to a cationic borenium-
hydrogen complex 38. Related hypervalent species may be
involved in high temperature hydrogen transfer reactions
catalyzed by trialkyl boranes,32 the recent hydrogen activation
experiments of Stephan et al. and related studies,33 and gas phase
equilibria involving BH2(+), H2, and BH4(+).34 The relationship
between 38 and 16a has a close parallel in the cationic ammonia
borane derivatives [H3N•BH4]+ (borenium ion hydrogen adduct)
and [H3N•BH2]+ (borenium ion), structures that have been
evaluated computationally.35
The contrasting behavior of the trimethylsilyl (28) and tert-
butyl (34) substrates is especially interesting in the mechanistic
context. The simplest interpretation in the silicon case invokes
formation of a transient hydrogen-bridged cation 29 followed
by spontaneous cyclization to the Wheland intermediate 30 and
desilylation (Scheme 6). Facile conversion to 30 is due to
stabilization by the well-known beta effect of silicon in the ipso
substitution.36 According to the extensive studies of Lambert
et al. and Reed et al.,9a,b the naked cation Me3Si(+) cannot
simply “fall off”, but the solvents used in our study (bromoben-
zene, toluene) would be sufficiently nucleophilic to assist in
the desilylation step from 30 by coordination at silicon.27g
Alternatively, desilylation from 30 might occur via bonding
between silicon and an adjacent (nucleophilic) H-B bond to
give 31 followed by formation of 16a upon loss of Me3SiH.
This alternative pathway reverses the order of events after
generation of the Wheland intermediate 30 but does not change
the overall result, namely the facile conversion to 16a using
stoichiometric trityl activation or to 17a using 10 mol % of
TrTPFPB. No silicon-containing products were detected that
might have been formed via proton removal from the isomeric
Wheland intermediate 39. This observation is consistent with
exclusive formation of the more stabilized 30 in the cyclization
step or reversible formation of both 30 and 39, followed by
product determining desilylation.
(31) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754. (b) Lafrance, M.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 16496. (c) Garcia-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
(d) Harvey, J. N.; Aggarwal, V. K.; Bathelt, C. M.; Carreo´n-Macedo,
J.-L.; Gallagher, T.; Holzmann, N.; Mulholland, A. J.; Robiette, R. J.
Phys. Org. Chem. 2006, 19, 608. (e) Chiong, H. A.; Pham, Q.-N.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879.
(32) (a) DeWitt, E. J.; Ramp, F. L.; Trapasso, L. E. J. Am. Chem. Soc.
1961, 83, 4672. (b) Ramp, F. L.; DeWitt, E. J.; Trapasso, L. E. J.
Org. Chem. 1962, 27, 4368. (c) Ko¨ster, R.; Bruno, G.; Binger, P. Ann.
1961, 644, 1.
For somewhat different reasons, an equally simple scenario
might have been expected in the tert-butyl case. Activation of
34 with TrTPFPB would generate 40 as usual, and conversion
to Wheland intermediates 41 and 42 is feasible in principle.
However, in contrast to the silicon analogy, loss of the cation
Me3C(+) from 41 should not require nucleophilic assistance
by solvent. Protonated tert-butylbenzene 43 is known to
fragment to benzene and Me3C(+) in superacid solution at
temperatures well below -30 °C.37 These conditions rule out
assistance by nucleophiles or by base, and the analogy argues
that 41 would undergo unassisted fragmentation to the amine
borane 17a and Me3C(+). Because this was not observed, we
conclude that 41 was never formed. Without the stabilizing beta
effect of silicon, it is easy to believe that 41 would not be
formed, but similar logic suggests that 42 may also not be
formed if an alternative, lower energy pathway is available to
explain the conversion from 34 into 35. We have therefore
explored the possibility that a C-H insertion pathway may be
(33) (a) Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W.
Science 2006, 314, 1124. Geier, S. J.; Gilbert, T. M.; Stephan, D. W.
J. Am. Chem. Soc. 2008, 130, 12632. Chase, P. A.; Stephan, D. W.
Angew. Chem., Int. Ed. 2008, 47, 7433. Geier, S. J.; Stephan, D. W.
J. Am. Chem. Soc. 2009, 131, 3476. (b) Review: Stephan, D. W. Dalton
Trans. 2009, 3129, and references therein. (c) Sumerin, V.; Schulz,
F.; Atsumi, M.; Wang, C.; Nieger, M.; Leskela¨, M.; Repo, T.; Pyykko¨,
P.; Rieger, B. J. Am. Chem. Soc. 2008, 130, 14117. Rendler, S.;
Oestreich, M. Angew. Chem., Int. Ed. 2008, 47, 5997. Sumerin, V.;
Schulz, F.; Nieger, M.; Leskela¨, M.; Repo, T.; Rieger, B Angew.
Chem., Int. Ed. 2008, 47, 6001. Spies, P.; Schwendemann, S.; Lange,
S.; Kehr, G.; Fro¨hlich, R.; Erker, G. Angew. Chem., Int. Ed. 2008,
47, 7543. Axenov, K. V.; Kehr, G.; Frohlich, R.; Erker, G. J. Am.
Chem. Soc. 2009, 3454. Rokob, T. A.; Hamza, A.; Stirling, A.; Pa´pai,
I. J. Am. Chem. Soc. 2009, 131, 2029. (d) Privalov, T. Chem.sEur.
J. 2009, 15, 1825. (e) The current view of hydrogen activation invokes
simultaneous action by an amine or phosphine in addition to B(C6F5)3
as the electrophile. No such additives are present in our deuterium
exchange experiment, although assistance by internal B-H bonds in
deuterium activation may play a similar role.
(34) (a) DePuy, C. H.; Gareyev, R.; Hankin, J.; Davico, G. E.; Damrauer,
R. J. Am. Chem. Soc. 1997, 199, 427. (b) DePuy, C. H.; Gareyev, R.;
Hankin, J.; Davico, G. E.; Krempp, M.; Damrauer, R. J. Am. Chem.
Soc. 1998, 120, 5086.
(35) (a) Protonated ammonia borane [H3N•BH4]+ is more stable than
[H3N•BH2]+ + H2 by 5.7 kcal/mol (ref 35b). However, the analogous
comparison between 38 and 16a plus hydrogen would have to take
into account the effect of borabenzylic delocalization that would help
stabilize 16a. (b) Rasul, G.; Prakash, G. K.; Olah, G. A. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 13387. (c) Zeng, X.; Davico, G. E. J.
Phys. Chem. 2003, 107, 11565.
(36) (a) Bennetau, B.; Dunogues, J. Synlett. 1993, 171. (b) Kaufmann, D.
Chem. Ber. 1987, 120, 853. (c) For a general review of the silicon
ꢀ-effect, see: Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador,
L. A.; Liu, X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res. 1999, 32,
183.
(37) Olah, G. A.; Schlosberg, R. H.; Porter, R. D.; Mo, Y. K.; Kelly, D. P.;
Mateescu, G. D. J. Am. Chem. Soc. 1972, 94, 2034.
9
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Intermediates in Nitrogen-Directed Aromatic Borylation
A R T I C L E S
Figure 4. B3LYP/6-31G* energies for cationic structures from 14a to 16a.
a viable alternative for this conversion as well as for the related
events shown in Scheme 5.
4; ca. 20%) as one component of precipitated material that could
not be dispersed reproducibly during the deuterium incorporation
attempts. Formation of 46 was confirmed in control experiments
in the absence of deuterium (46% isolated after 24 h reflux in
benzene; 10% after 12 d at rt). Faster decomposition was
observed in bromobenzene (>90% conversion within 24 h at
rt), but other significant decomposition products were formed
in addition to 46. In the best deuterium experiment, ca. 40%
D1 incorporation was measured in both 46 and recovered 17a.
These results exceed reaction rate expectations based on the
calculated value of TSBC, depending on the precision of the
computations, but cautious interpretation is appropriate in any
event, given the uncertainties regarding mechanism under the
highly dilute, heterogeneous reaction conditions used for the
deuterium incorporation studies. Among other concerns, de-
composition from 16a to 46 presumably also generates (C6F5)3B,
a potent electrophile that may play a role in the deuterium
exchange in view of its known interaction with molecular
hydrogen.33
The geometry and energy of potential cationic intermediates,
starting with the presumed borenium ion 14a, was evaluated
using B3LYP/6-31G* calculations performed using the Gaussian
03 program package.38 An energy minimum (Erel ) 0.0 kcal/
mol) was found for a π-complex (MinA, Figure 4), showing
interaction between the benzene ring and the empty p orbital at
boron with two short rCB contacts at 2.38 Å for C(1) and 2.55
Å for C(2), respectively. A second local minimum (Erel ) 0.43
kcal, corrected for zero-point energy) was assigned as the
Wheland intermediate 36 ) MinB based on the shorter rCB
contacts compared to MinA, 2.31 Å for C(1) and 2.01 Å for
C(2). The transition structure TSAB (Erel ) 0.27 kcal/mol) was
also identified along the relatively flat energy surface from MinA
to MinB, similar structures that lead to TSBC (Erel ) 18 kcal/
mol; Figure 4). Subsequent exchange between products and H2
can occur through an isomeric transition state TSCexch (Erel
)
22 kcal/mol). MP2 calculations with the cc-pVTZ basis confirm
the results obtained with B3LYP to within a few kcal/mol,
suggesting that the broad features of the potential energy
surfaces are correct.39
In the context of Scheme 5, TSBC corresponds to the 3c2e
transition structure 37 for the C-H insertion pathway and the
energy barrier relative to the π-complex (MinA) is consistent
with cyclization at room temperature. For the reverse reaction
from 16a + H2, the relatively high enthalpic barrier (ca. 27 kcal/
mol, corresponding to somewhat higher ∆G‡) suggests that the
exchange reaction between 16a and molecular hydrogen should
be too slow to be detected, but the possibility was explored
experimentally (eq 4). Thus, 16a was generated independently
by reaction of 17a with TrTPFPB, and the suspension in benzene
was stirred under D2 (ca. 2-3 atm). After 15-30 days, the
heterogeneous mixture was quenched with Bu4NBH4 and ca.
20% of 17a was recovered with variable deuterium incorporation
(MS assay). However, extensive decomposition of 16a was
evident and resulted in the formation of borane complex 46 (eq
Byproduct 46 was not formed in substantial amounts in the
stoichiometric cyclization experiments from 13a and TrTPFPB
under the usual conditions (4 h, rt), although traces of 46 were
observed by NMR assay after 9 h. On the other hand, no sign
of 46 or other decomposition products was detected when 13a
was activated using 5% TrTPFPB in early attempts to achieve
catalytic conversion to 17a, even at toluene reflux temperatures.
These experiments encouraged the investigation of more forcing
conditions. Remarkably, heating 13a with 5% TrTPFPB in
toluene (160 °C bath, sealed tube) followed by quenching with
Bu4NBH4 resulted in efficient conversion to 17a (90% isolated).
Evidently, the presence of excess amine borane ensures hydride
transfer to the cation 16a and suppresses formation of the
byproduct 46 in the catalytic procedure.
(38) Frisch, M. J. Gaussian 03, rev. C.02; Gaussian, Inc: Wallingford, CT,
2004; see Supporting Information for details.
(39) Details of these calculations, carried out using the MOLPRO software
(MOLPRO, version 2008.1, Werner H.-J. et al.), are in the Supporting
Information.
Attention was now turned to the cationic trimethylsilyl-
containing structures generated starting from 28 (Figure 5).
9
J. AM. CHEM. SOC. VOL. 131, NO. 41, 2009 14685

A R T I C L E S
De Vries et al.
Figure 5. B3LYP/6-31G* energies for cationic structures from 28 to 16a.
Attempted optimization of a presumed π-complex analogous
to MinA (Figure 4) having the BH2 subunit placed near the
Me3SiC(2)-C(1) segment resulted instead in the Wheland
intermediate MinD ) 30 (Erel ) 0.0 kcal/mol, Figure 5). The
structure is clear from the almost fully formed B-C(2) bond
(1.67 Å) with boron nearly in the plane of the aromatic ring
and a somewhat elongated C(2)-Si bond (2.19 Å) at an angle
of 105° relative to the ring. A low-lying TSDE was found just
5.9 kcal/mol above MinD that leads to formal migration of
Me3Si(+) from carbon to the adjacent boron-bound hydride.
The result is conversion to MinE ) 31 (Erel ) -14.2 kcal/mol)
with a hydride bridge linking boron (rBH ) 1.41 Å) and silicon
(rSiH ) 1.61 Å), followed by B-H-Si dissociation (MinF). On
the other hand, when the initial optimization was performed
with the BH2 subunit rotated to be near the benzene C(1)-C(6)
segment, a local minimum corresponding to a π-complex MinG
was found (Erel ) 6.3 kcal/mol). The higher energy path for
loss of hydrogen from MinG via TSGH (Erel ) 23.5 kcal/mol) is
analogous to the sequence of Figure 4, but it does not compete
with the more facile Si migration pathway from MinD to MinE.
These results reflect substantial cation stabilization by the ꢀ-silyl
group in MinD compared to the regioisomeric Wheland inter-
mediate derived from borylation at benzene C(6). Furthermore,
the computations reveal a low-energy mechanism for aromati-
zation from MinD via TSDE that does not require participation
by an external nucleophile or base.
The remaining stages of the conversion from MinE to 16a
(stoichiometric) or 17a (catalytic) are not fully depicted in Figure
5 because dissociation of a B-H bond into Me3SiH and 16a
(MinF, Erel ) -6.0 kcal/mol) or dissociation of a Si-H bond
into Me3Si(+) and 17a (Erel ) +32 kcal/mol) would be followed
by adduct formation involving the high energy borenium or
silylium cations and various external electron donors. The
specific details would include interactions between 16a and
solvent (stoichiometric conditions via MinF) or between
Me3Si(+) and potentially bridging B-H bonds from unreacted
28 or with solvent (catalytic conditions). No attempt was made
to evaluate the relevant energy profiles, but the latter pathway
formally involving Si-H dissociation followed by intermolecu-
lar hydride transfer from 28 to Me3Si(+) would nicely explain
the facile catalytic conversion from 28 to 17a using 10%
TrTPFPB. For similar reasons, the details of the reverse reaction
from Me3SiH and 16a (MinF) were also not evaluated in detail.
However, a transition state was found (Erel ) -2.3 kcal/mol;
TSEentE, not illustrated) for the reversible migration of Me3Si
between the two B-H hydrogens in MinE (31). The activation
barrier from MinE is quite small (11.9 kcal/mol) and meets one
of the requirements for facile isotopic exchange with an external
Si-D bond. Accordingly, independently generated 16a was
stirred with excess Et3SiD in benzene at room temperature. After
10 min, 16a was isolated by precipitation with hexane and was
1
assayed by H NMR spectroscopy. Only 8% of residual B-H
signal intensity was found in recovered 16a, as expected for
the reverse reaction from MinF (16a + R3SiH) followed by fast
H/D exchange20 at the stage of MinE. This decisive experiment
provides qualitative confirmation for the relative energies
deduced by the computational method. It is also consistent with
the observed change in the 11B chemical shift of 16a upon
addition of R3SiH as mentioned earlier.
Finally, the computations were used to evaluate cationic
intermediates in the tert-butyl series starting from 34. Most
features of the pathway leading to 35 were found to be analogous
to those shown in Figure 4 from cation 14a to 16a. However,
attempted optimization of a π-complex with boron interacting
with C(2) resulted in a local energy minimum corresponding
to the less hindered π-complex rotamer where boron interacts
with the unsubstituted C(6). Constrained optimization indicates
that the more hindered rotamer would be ca. 10 kcal/mol less
stable, suggesting that simple steric repulsions are the reason
why intermediate 41 is never formed. Subsequent events from
the π-complex to structures 44 and 45 resemble those of Figure
4, but the local minimum corresponding to the Wheland
intermediate 42 was not found (see Supporting Information for
details).
Summary
Our findings support the involvement of borenium species
or hydrogen-bridged cations such as 15 and 29 in the boryla-
tions, and they raise the intriguing prospect of C-H insertion
mechanisms via borenium ion intermediates at room tempera-
ture.40,41 According to the B3LYP/6-31G* computations, the
rate-determining step can be described as a C-H insertion at
the stage of the intermediate borenium π-complex or the
corresponding Wheland intermediate. In the case of 14a, the
9
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Intermediates in Nitrogen-Directed Aromatic Borylation
A R T I C L E S
two cations (π-complex or Wheland) have essentially identical
energies and similar geometries. We did not attempt to evaluate
transition states for potentially competing intermolecular proton
removal at the stage of the Wheland intermediates, partly
because external bases were not added in these experiments,
and partly because simpler benzenium ions are remarkably stable
if the counterion is noninteractive (neither basic nor
nucleophilic).30b In the present study, the tetrakis(pentafluo-
rophenyl)borate (TPFPB) anion is sufficiently nucleophilic to
react with sextet boron in the dearylation process shown in eq
4,42 but there is no evidence to suggest that TPFPB functions
as a base.
The detection of hydrogen bridged cationic intermediates
related to 15a with representative substrates not containing
ortho-silicon indicates that hydrogen bridging is a stabilizing
factor that somewhat impedes intramolecular borylation. Al-
though we have not revisited intermolecular or intramolecular
electrophilic borylations described in earlier literature reports,17,43
we note that borenium intermediates would explain the isolated
reports of surprisingly facile oxygen-directed aromatic boryla-
tions of biaryl phenols and related structures because these
reactions are conducted in the presence of the oxophilic Lewis
acid AlCl3.44 It may be rewarding to re-examine this chemistry
under reaction conditions chosen to promote more specific
generation of borenium intermediates.45 If borenium electro-
philes can be accessed in the absence of potentially bridging
(and, therefore, stabilizing) ligands at boron, reactions should
be faster and it may be possible to develop new methodology
for low temperature borylation and C-H insertion chemistry.
Acknowledgment. This work was supported by the National
Institute of General Medical Sciences, NIH (GM067146).
Supporting Information Available: Experimental procedures
and characterization data. Full computational details including
optimized Cartesian coordinates. Complete refs 38 and 39. This
material is available free of charge via the Internet at at http://
pubs.acs.org.
JA905369N
(40) At higher temperatures, intramolecular aryl borylation is also known
in the case of neutral, trivalent borane intermediates: (a) Ko¨ster, R.;
Reinert, K. Angew. Chem. 1959, 71, 521. (b) Laaziri, H.; Bromm,
L. O.; Lhermitte, F.; Gschwind, R. M.; Knochel, P. J. Am. Chem.
Soc. 1999, 121, 6940. Varela, J. A.; Pen˜a, D.; Goldfuss, B.; Denisenko,
D.; Polborn, K.; Knochel, P. Chem.sEur. J. 2004, 10, 4252, and
references therein.
(43) (a) Dewar, M. J. S.; Kubba, V. P.; Pettit, R. J. Chem. Soc. 1958, 3073.
(b) Davis, F. A.; Dewar, M. J. S. J. Am. Chem. Soc. 1968, 90, 3511.
(c) Grassberger, M. A.; Turnowsky, F.; Hildebrandt, J. J. Med. Chem.
1984, 27, 947. (d) Boldyreva, O. G.; Dorokhov, V. A.; Mikhailov,
B. M. IzV. Akad. Nauk, Ser. Khim. 1985, 2, 428. (e) Allaoud, S.;
Frange, B. Inorg. Chem. 1985, 24, 2520. (f) Arcus, V. L.; Main, L.;
Nicholson, B. K. J. Organomet. Chem. 1993, 460, 139. (g) Lee, G. T.;
Prasad, K.; Repie`, O. Tetrahedron Lett. 2002, 43, 3255.
(41) Similar transition state geometries have been identified for the
thermal cyclizations of neutral boranes (ref 40) and have been
discussed using the terminology of C-H activation and 4-center
dehydrogenation: Goldfuss, B.; Knochel, P.; Bromm, L. O.; Knapp,
K. Angew. Chem., Int. Ed. 2000, 39, 4136. Varela, J. A.; Pen˜a, D.;
Goldfuss, B.; Polborn, K.; Knochel, P. Org. Lett. 2001, 2395.
(42) (a) The dearylation of TPFPB by 16a reflects exceptional electrophi-
licity at boron despite “borabenzylic” stabilization. By comparison,
borenium ion 14a is stabilized only to the extent that π-complexation
compensates for sextet character at boron. According to the test of
extraordinary reactivity, we regard 14a as a monocationic superelec-
trophile. (b) For prior examples of TPFPB anion dearylation involving
cationic non-octet electrophiles, see: Go´mez, R.; Green, M. L. H.;
Haggitt, J. L. J. Chem. Soc., Dalton Trans. 1996, 939. Bochmann,
M.; Sarsfield, M. J. Organometallics 1998, 17, 5908. Korolev, A. V.;
Ihara, E.; Guzei, I. A.; Young, V. G., Jr.; Jordan, R. F. J. Am. Chem.
Soc. 2001, 123, 8291.
(44) In principle, the oxophilic Lewis acid can promote borylation of
phenols HOAr by reversibly forming intermediates Cl3AlO(Ar)BX2
that contain a borenium subunit. This chemistry warrants re-investiga-
tion under reaction conditions designed to promote more specific
generation of borenium species.
(45) In a qualitative comparison of relative electrophilicities, the B3LYP/
6-31G* bond energies were calculated for the hypothetical gas phase
reactions of H3B, Me3C+, Me3N+BH2, and H3C+ with the representa-
tive nucleophiles H3N and H3P. The sum of the bond energies (B-N
+ B-P) for each electrophile provides a rough measure of electro-
philicity: H3B (54 kcal/mol), Me3C+ (79 kcal/mol), Me3N+BH2 (87
kcal/mol), and H3C+ (224 kcal/mol); these data indicate that the
borenium ion is much more electrophilic than borane but does not
approach the most electrophilic cation H3C+ in this series.
9
J. AM. CHEM. SOC. VOL. 131, NO. 41, 2009 14687