Electrophilic C-H borylation and related reactions of B-H boron cations

Article abstract of DOI:10.1021/om400651p

Catalytic procedures are described for the amine-directed borylation of aliphatic and aromatic tertiary amine-boranes. Sequential double borylation is observed in cases where two or more C-H bonds are available that allow 5-center or 6-center intramolecular borylation. The HNTf₂-catalyzed borylation of benzylamine-boranes provides a practical means for the synthesis of ortho-substituted arylboronic acid derivatives, suitable for Suzuki-Miyaura cross-coupling applications.

Full text of DOI:10.1021/om400651p

Article
pubs.acs.org/Organometallics
Electrophilic C−H Borylation and Related Reactions of B−H Boron
Cations
Aleksandrs Prokofjevs, Janis Jermaks, Alina Borovika, Jeff W. Kampf, and Edwin Vedejs*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: Catalytic procedures are described for the amine-
directed borylation of aliphatic and aromatic tertiary amine−
boranes. Sequential double borylation is observed in cases where
two or more C−H bonds are available that allow 5-center or 6-
center intramolecular borylation. The HNTf2-catalyzed boryla-
tion of benzylamine−boranes provides a practical means for the
synthesis of ortho-substituted arylboronic acid derivatives,
suitable for Suzuki−Miyaura cross-coupling applications.
to the intermediate 8 and hydrogen gas. Subsequent borylation
affords a mixture of the hydrolytically labile 9 and the cyclic
amine−borane 10 resulting from intermolecular hydride transfer
from 7 to 9, and reductive quenching with Bu4NBH4 completes
the conversion to the stable product 10. We now describe a more
extensive investigation of catalytic and stoichiometric boryla-
tions involving aliphatic substrates and also show that a similar
catalytic borylation gives much-improved yields with represen-
tative aromatic substrates. In some examples, the stoichiometric
and catalytic methods give distinctly different product mixtures.
INTRODUCTION
■
Recent reports from our laboratory have described the
intramolecular borylation of aromatic C−H bonds via hydride
abstraction from amine−borane 1 with Ph3C+B(C6F5)4¯ (2; eq
1).1−4 Near-stoichiometric activation procedures gave the best
RESULTS AND DISCUSSION
■
The first stage of our investigation was designed to clarify the
nature of activated intermediates derived from amine−boranes
and Tf2NH. Thus, treatment of a range of amine−borane
complexes 11 with 1 equiv of Tf2NH in CD2Cl2 or d8-PhMe
generally produced mixtures of two isomeric species (eq 3; Table
results using 90 mol % of the trityl salt 2 at room temperature,
and borylation was attributed to transient borenium inter-
mediates 3 or equivalent species, although the only observable
borocations were the relatively stable hydride-bridged “dimers” 4
(at 50% loading of 2) and the product borenium salts 6 (using
90% of 2).3 Although the mechanistic details remain uncertain,
conversion to 64 requires a dehydrogenation step that may
correspond to the transition state 5.
We have also disclosed related chemistry for the borylation of
aliphatic C−H bonds in a preliminary account.5,6 In this case, the
stoichiometric process using trityl salt 2 also occurs at room
temperature, but cleaner reactions are observed in several
examples using the strong acid Tf2NH as catalyst at 160 °C (eq
2), apparently via the initial conversion of the amine−borane 7
1). The reactions proceeded vigorously, and gas liberation
ceased within seconds at room temperature, indicating complete
consumption of Tf2NH. The products were identified as N- and
O-bound covalent boron bis(triflimides) 12 and 13 on the basis
of multinuclear NMR spectroscopy. Thus, both species could be
reliably assigned as tetracoordinate boron complexes on the
basis of 11B NMR data. From 19F and 13C NMR data it is also
apparent that in one of the isomers both CF3 groups are
magnetically equivalent, as expected in the N-bound isomer 12,
but they are distinctly different in the O-bound isomer 13.
Special Issue: Applications of Electrophilic Main Group Organo-
metallic Molecules
Received: July 3, 2013
© XXXX American Chemical Society
A
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Table 1. 11B and 19F NMR Data for R3N·BH2NTf2 Complexes
and 13b in the same 1:4.7 ratio as in the stoichiometric Tf2NH
activation experiment (Table 1), the third product was assigned
as the unusual H-bridged borocation 14 on the basis of the
similarity of the multinuclear NMR spectra to data reported
previously for the corresponding [B(C6F5)4]− salt.1 Structurally,
the central 3c-2e B−H−B bond of borocation 14 can be viewed
as being derived from the σ-basic B−H bond of Et3N·BH3 and
the formally empty p orbital of the hypothetical primary
borenium cation 15b. The observed equilibrium ratio among
Et3N·BH3, 12b, 13b, and 14 (ca. 7.2:1.1:5.0:1.0 mol) thus
suggests that B−H σ bonds of Et3N·BH3 are sufficiently
nucleophilic to compete with Tf2N− for binding to 15b in the
thermodynamic sense.
a
12 and 13
Despite the structural description of cation 14 as a complex
between Et3N·BH3 and 15b, the free primary borenium cation
(15b) is not necessarily present at any stage of the reaction
shown in eq 4, since both the forward and the reverse processes
can also be envisioned as proceeding by SN2-type displacements
at boron for 12b or 13b (forward process) or 14 (reverse
process). Presumably, such displacements would involve the
weakly nucleophilic Tf2N− anion that is inevitably present as a
contaminant in all Tf2NH activations, as suggested by 19F NMR
data. On the other hand, reversible dissociation of 12b/13b to
15b and of 14 to Et3N·BH3 and 15b provides a sufficient
explanation for our observations in the absence of evidence to
the contrary. In terms of reactivity as well as structure, H-bridged
cations analogous to 14b occupy an intermediate position
between tricoordinate borenium and tetracoordinate boronium
species.3 Furthermore, eq 4 represents the borderline case for
the formation of covalent counterion adducts 12/13 in the
presence of 14. Any further decrease in the coordinating ability
of the anion can be expected to favor conversion of 12/13 to
hydride-bridged species such as 14 when excess borane complex
a
Conditions: 1:1 R3N·BH3:Tf2NH, CD2Cl2, room temperature.
Monitored up to 2−14 days at room temperature. In d8-PhMe.
b
c
Bis(triflimide) connectivity isomerism has not previously been
observed in boron compounds (very few boron sulfonylimides
have been reported so far),7 although similar isomerism is a
known phenomenon in Si bis(triflimides).8
In most cases the ratio of 12 to 13 measured immediately
following mixing of 11 and Tf2NH was different from that
observed after a few hours at room temperature, suggesting a
kinetic preference for the formation of one of the isomers. Such
kinetic product mixtures initially contained larger amounts of the
O-bound isomer 13, which partially turned into 12 over time.
Activation of Me3N·BH3 with Tf2NH in d8-PhMe serves as a
representative example where equilibration to the thermody-
namic product ratio was observed to be particularly slow (hours
at room temperature). To avoid discrepancies caused by slow
kinetics, ratios of N- vs O-bound products (12 vs 13)
summarized in Table 1 were confirmed to remain unchanged
for days following the initial equilibration period. The product
ratio (12 vs 13) measured at equilibrium correlates reasonably
well with steric properties of the amine fragment. Thus, while 12
is the thermodynamically preferred isomer in the relatively
unhindered Me3N series (7:1 12a:13a), the O-bound isomer is
clearly the dominant species in the far more hindered i-Pr2NEt
derivatives (<1:25 12c:13c). Similar observations in Si bis-
(triflimides) have been rationalized on the basis of lower steric
demands of the bis(triflimide) fragment in the O-bound isomer,8
and the same considerations apparently can be extended to
boron compounds. The observed equilibration suggests facile
interconversion of 12 and 13, although the exact mechanism of
this process is unclear.
−
is present, as observed when the anion is B(C6F5)4 .
Having developed a better understanding of the activation
process, we turned our attention to broadening the substrate
scope for the aliphatic borylations reported in the preliminary
study.5 Several amine−borane substrates were selected for
evaluation under optimum stoichiometric and/or catalytic
activation conditions (Scheme 1). In most cases the substrates
were chosen such that multiple C−H bonds would be in
proximity to the cationic boron center in activated intermediates
so that issues of regioselectivity or multiple borylation could be
addressed.
a
Scheme 1.
When activations of amine−boranes were performed using
only a substoichiometric amount of Tf2NH, formation of an
additional product was observed by NMR spectroscopy. Thus,
when Et3N·BH3 was treated with 0.5 equiv of Tf2NH in CD2Cl2,
NMR assay after 30 min at room temperature indicated the
presence of three new compounds aside from unreacted amine−
borane (eq 4). While two of the products were found to be 12b
a
Legend: (a) catalytic borylation conditions, 5 mol % of Tf2NH,
PhMe, sealed tube, 160 °C, 14 h, quenched with ca. 10 mol % of n-
Bu4NBH4; (b) stoichiometric borylation conditions, 0.9 equiv of
Ph3C+[B(C6F5)4]−, PhF, room temperature, 4 h, quenched with ca. 1.1
equiv of n-Bu4NBH4.
B
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a
First, the substrate 16 was investigated to allow 6 assessment
of the potential for competition between intramolecular
borylation pathways leading to 5- vs six-membered rings.
Under both catalytic and stoichiometric reaction conditions,
borylation of the N-neopentyl group was preferred, resulting in
17 as the dominant product after reductive quenching to convert
intermediate B-NTf2 species to B−H. The isomeric six-
membered borylation product 18 or doubly borylated products
were not detected in either the catalytic or stoichiometric
experiments. In the case of the catalytic reaction using 5 mol % of
Tf2NH in toluene at 160 °C (sealed tube), the material balance
consisted of 17 (72% isolated) together with recovered starting
material 16 due to incomplete reaction. The corresponding
Scheme 2.
stoichiometric experiment using 0.90 mol % of Ph3C+B(C6F5)4
−
(2) in fluorobenzene at room temperature gave an 81% yield of
17, but isolation of the product was complicated by substantial
amounts of the Ph3CH byproduct.
The modified substrate 19 (Scheme 1) was designed to have
two reactive C−H’s within a 5-atom distance from the boron
atom, and formation of the doubly borylated 20 was the result
(catalytic conditions; structure of 20 confirmed by a single-
crystal X-ray diffraction study, Figure 1). Similar to the
a
Legend: (a) catalytic borylation conditions, 5 mol % of Tf2NH,
PhMe, sealed tube, 160 °C, 14 h, quenched with ca. 10 mol % of n-
Bu4NBH4; (b) stoichiometric borylation conditions, 0.9 equiv of
Ph3C+[B(C6F5)4]−, PhF, room temperature, 4 h, quenched with ca. 1.1
equiv of n-Bu4NBH4.
Table 2. Borylations of 27
yield, %
Figure 1. X-ray structure of amine−borane 20 (50% probability
ellipsoids, H atoms omitted for clarity except at B). Selected bond
lengths (Å) and angles (deg): B1−N1, 1.66; B1−C7, 1.61; B1−C8,
1.63; N1−B1−C7, 97; N1−B1−C8, 101.
entry
conditions
28
29
30
a
a
1
2
3
5 mol % Tf2NH, 160 °C, 14 h
30
48
38
4
0
b
b
b
b
b
0.9 equiv Ph3C+[B(C6F5)4]−, room temp, 4 h 29
25
70
b
0.9 equiv Ph3C+[B(C6F5)4]−, 60 °C, 20 h
17
a
b
Isolated yields. NMR yields vs internal reference.
experiment starting from 16, no substantial amount of the
isomeric product 21 resulting from a 6-center intramolecular
borylation was observed. Although the timing of sequential
borylation events was not established, formation of 20 indicates
that both the aliphatic and aromatic C−H bonds have
comparable reactivity in this example.
with HNTf2, 27 was converted exclusively to monoborylated
products 28 and 29 in a 1:1.7 ratio after the usual reductive
quench with n-Bu4NBH4 (1H NMR assay of the crude reaction
mixture). Products 28 and 29 were isolated in 30% and 48%
yields, respectively. No products of a second borylation event
were observed, not even with extended reaction times at 160 °C!
A partial explanation for these observations is shown in Scheme
2 by considering a pathway from 27 to the activated intermediate
31 followed by the expected borylation to give 33. Subsequent
reductive quenching would then afford the major product 29.
On the other hand, stoichiometric activation of 27 with
Ph3C+B(C6F5)4¯ (2) at room temperature (4 h) followed by
reductive quenching did afford a doubly borylated product (30)
in addition to 28 and 29 (Table 2). As established by X-ray
crystallography (Figure 2), structure 30 is noteworthy because it
contains a bicyclo[4.2.1] subunit involving the borylated azacene
ring. Surprisingly, 30 becomes the dominant product and
accumulates at the expense of the symmetrical bicyclo[3.3.1]
product 29, as evidenced by the borylation outcome under more
forcing stoichiometric conditions at 60 °C (Table 2, entry 3). A
convincing explanation for these findings would require a more
detailed knowledge of the timing of initial C−H insertion events
under stoichiometric conditions, but analogy suggests that a
hypothetical 3c-2e structure 32 is generated first and that it
undergoes borylation to give 34 or, more likely, the
The next step was to evaluate the reactivity of C−H bonds in a
transannular position, accomplished using 11- and 8-membered-
ring substrates 22, 24, and 27 (Scheme 2). No borylation of the
aliphatic ring was observed in 22, and the spirocyclic structure 23
was the only product isolated under standard catalytic or
stoichiometric activation conditions. However, transannular
borylation was observed in the 8-membered cyclic amine−
borane 24 to give the symmetrical bicyclo[3.3.1] product 25. In
contrast to the other borylations discussed so far, 25 is the result
of a 6-center borylation process. The modest isolated yield
(52%) of 25 in the high-temperature catalytic protocol is largely
the result of incomplete consumption of the starting material 24,
although traces of a second product were detected by NMR
spectroscopy. This substance could not be purified, but the
limited NMR data are consistent with the tentative assignment
of structure 26, having the isomeric bicyclo[4.2.1] skeleton.
We also explored the 8-membered amine borane 27, an
analogue of 24 having an N-benzyl subunit in place of N-ethyl.
The modified substrate 27 showed remarkably rich behavior due
to the presence of three reactive C−H bonds (Scheme 2; Table
2). When it was subjected to the standard catalytic conditions
C
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Scheme 3
Figure 2. X-ray structure of amine−borane 30 (50% probability
ellipsoids, H atoms omitted for clarity except at B). Selected bond
lengths (Å) and angles (deg): B1−N1, 1.65; B1−C7, 1.61; B1−C8,
1.62; N1−B1−C7, 97; N1−B1−C8, 101.
that the key activated intermediate 38 can be regenerated from
the initial borylation product 39 or its corresponding ion pair 40
as required for catalyst turnover. The cycle includes the hydride-
bridged cation 4 because its presence is predicted from eq 4 and
Table 1. While we have no direct evidence that 4 is the
immediate precursor of 39 or 40, our preliminary investigation
of internal borylation using stoichiometric activation had found a
correlation between effective electrophiles (Ph3C+ salts, Tf2NH,
B(C6F5)3, or AlCl3) and the generation of hydride-bridged
“dimers” similar to 4. Weaker electrophiles such as TfOH
converted 1 to a tetracoordinate analogue of 38, gave no 4, and
did not induce borylation. Intriguingly, while catalytic amounts
of Tf2NH efficiently promoted the borylation of 1 at >120 °C,
essentially no cyclization was observed using a 1:1 ratio of
Tf2NH and 1. This observation suggests that the crucial
borylating agent can be formed from 4 but not by spontaneous
BNTf2 heterolysis from 38 (BnMe2N·BH2NTf2). So far, the
observation remains unexplained and is particularly surprising in
view of the comparable affinity of [R3N−BH2]+ for R3N·BH3
and Tf2N− (eq 4).
precedented5,6 monoalkyl borenium cation 35. Either 34 or 35
might serve as the precursor of 29 when the entire stoichiometric
reaction sequence, including reductive quenching, is conducted
at room temperature. However, if the borylation is conducted at
60 °C, then the activated intermediates apparently can undergo a
competing retrohydroboration process. For the sake of
simplicity, we assume that the borenium cation 35 undergoes
retrohydroboration to generate 36, which rapidly recloses to
afford the bicyclo[4.2.1] skeleton followed by borylation of the
aromatic ring (not shown). However, it is conceivable that 36
would borylate the aromatic ring faster than it hydroborates the
alkene. In either case, reductive quenching would ultimately
afford the doubly borylated product 30. Precedents for facile
retrohydroboration under similar thermal conditions are well-
known,9 including reported cases involving borenium equiv-
alents generated from N-heterocyclic carbene−boranes with
HNTf2.9e
It is important to note that 30 was obtained when the
borylation of 27 was performed under stoichiometric conditions
at room temperature or at 60 °C but was not detected under
catalytic conditions at 160 °C. This observation argues against
the involvement of identical activated intermediates in both the
catalytic and the stoichiometric experiments. Stated more
explicitly, if the borenium cation 35 was responsible for the
formation of 30, then it either was not formed or was not viable
in the catalytic process at 160 °C.
With a catalytic cycle established for the simple substrate 1
under HNTf2 catalysis, the regioselectivity of aromatic
borylations with several meta-substituted N,N-dimethylbenzyl-
amine−boranes was investigated using similar catalytic con-
ditions (eq 5; Table 3).10
As discussed in the preceding sections, the catalytic activation
method using HNTf2 allows efficient borylation with optimal
substrates such as 22. In other, less hindered aliphatic examples,
the catalytic process does not go to completion, suggesting some
form of product inhibition of the catalytic cycle or a dead end
decomposition pathway perhaps involving the product bore-
nium cations. The reasons for this behavior remain unexplained
in the aliphatic borylations, and the potential for retrohydrobo-
ration may be partially responsible for unknown decomposition
or disproportionation events that interfere with catalyst
turnover. On the other hand, aromatic borylations should be
less prone to complications under catalytic conditions. The
product borenium cations are somewhat more stabilized due to
their “bora-benzylic” nature, involving delocalization between
the aromatic π system and the planar tricoordinate boron.
Furthermore, the aromatic borylation products are incapable of
undergoing retrohydroboration. On the basis of these
considerations, we tested the catalytic activation method with
the simple N,N-dimethylbenzylamine−borane 1 (Scheme 3)
and were pleased to find that >90% of the known borylation
product 37 was formed after reductive quenching. Evidently, an
efficient catalytic cycle is possible.
Table 3. Aromatic C−H Borylation in Meta-Substituted
Benzylamine−Boranes
para:ortho
borylation
combined
a
entry substrate
X
R
yield, %
1
2
1
H
Me
37
94
a
c
41
Cl
Me
42:43, 25:1
(1:1.2)
93
b
a
c
3
44
I
Me
45:46, 40:1
(1:2.4)
91
b
a
a
4
5
47
50
Cl
F
(CH2)4 48:49, 10:1
95
c
Me
51:52, 13:1
(4:1)
95
b
a
6
53
PhO
Me
54:55, 10:1
96
a
Catalytic borylation conditions: 5 mol % of Tf2NH, PhMe, sealed
tube, 160 °C, 14 h, quenched with ca. 10 mol % of n-Bu4NBH4.
b
Stoichiometric borylation conditions: 0.9 equiv of Ph3C+[B(C6F5)4]−,
A hypothetical catalytic cycle is illustrated in Scheme 3 so that
plausible intermediates can be mentioned. Although several
important details are not addressed in this cycle, it does show
PhBr, room temperature, 4 h, quenched with ca. 1.1 equiv of n-
c
Bu4NBH4. 24 h.
D
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The most striking difference between the catalytic and
stoichiometric borylation processes is in the opposite trends in
regioselectivity for the halogenated amine−boranes 41, 44, and
50. While in the catalytic process the para:ortho selectivity
increases from F or Cl to I, the changes are not systematic in
view of the two contrasting chlorine examples (entries 2 and 4).
In the stoichiometric trityl-activated borylations at room
temperature for the meta halides, the selectivity is much lower
and decreases from fluoride (4:1, entry 5) to chloride (1:1.2,
entry 2) but inverts for iodide (1:2.4, entry 3). It is tempting to
assume that the differences in catalytic vs stoichiometric product
ratios arise from thermodynamic equilibration under the high-
temperature conditions, but so far all indications suggest that the
catalytic borylations are kinetically controlled. Thus, the product
regioisomer ratios do not change with percent conversion, and
the isolated borylation products do not undergo equilibration
under the reaction conditions. To support this assertion, each of
the purified isomers 42 and 43 was activated with 5 mol % of
Tf2NH in d8-PhMe, and the resulting solutions were heated at
120 °C.11 No equilibration of pure 42 or 43 to the isomer
mixture was observed, although the catalytic activation of 41
under the same conditions gave a ca. 25:1 mixture of 42:43.
Since it can be argued that catalytic activation of the products
42 or 43 did not exactly mimic the borylation conditions because
the starting amine−borane was not present, a modified set of
experiments was also performed. Thus, mixtures of 0.1 equiv of
either 42 or 43 with 1 equiv of 1 in toluene were activated with 5
mol % of Tf2NH and then heated in sealed tubes at 160 °C.
Under the reaction conditions, full conversion of 1 to 37 was
observed after 10 mol % borohydride quench, but 42 and 43
were recovered unchanged. In a second control experiment
under similar conditions, 0.1 equiv of 41 and 1 equiv of 1 were
used along with 5% HNTf2. This time, a mixture of the cyclized
products 37, 42, and 43 was formed, and the ratio of 42 and 43
was found to be the same as in the cyclization of 41 with no 1
present (ca. 25:1 42:43). This suggests that the starting amine−
borane 41 cyclizes to form a mixture of 42 and 43 under the
indicated conditions, while the interconversion of the two
isomers does not occur. In this series of experiments, the
cyclization of 1 to 37 serves not only to mimic the actual
cyclization conditions but also to act as a probe confirming that
the catalytic cycle is viable.
Scheme 4. Benzylic Amine−Borane Hydrodeamination
give ethyltoluene and, to a lesser extent, for 1-
(dimethylaminomethyl)naphthalene−borane (61). In the latter
case, the expected borylation product 62 was obtained in 52%
yield, while 1-methylnaphthalene 63 and (Me2N−BH2)2
constituted the rest of the crude reaction mixture according to
NMR and GC-MS assay. Overall, it appears that C−N
fragmentation predominates in those cases where a reasonably
stable carbocation can be formed.
While a substantial degree of C−N cleavage (ca. 70%) was
observed in the catalytic borylation of ortho,ortho′-disubstituted
amine−borane 64, this substrate also presented an unusual case
of C−C bond reactivity (eq 6). Thus, aside from the 1,2,3-
The rates of the catalytic borylation are qualitatively
insensitive to the electronic effects in the substrate. In an
attempt to estimate the rate effect caused by a phenoxy group
positioned para with respect to the C−H bond that undergoes
borylation (i.e., the m-PhO-benzylamine substrate), a 1:1
mixture of 1 and 53 (Table 3) activated with 10% HNTf2 in
d8-PhMe was heated at 120 °C. The relative rates of
consumption of both amine−boranes were monitored in situ
using NMR spectroscopy and were found to be similar (equal,
within experimental uncertainty).
In sharp contrast to the high-yielding cyclization of the m-PhO
substrate 53 (96% isolated yield of 54 + 55), the cyclization of
the corresponding para isomer 56 delivered only 10% of the
expected 57, while the major product was found to be p-
phenoxytoluene (77% isolated; the only other product detected
in the crude mixture was the dimer of Me2NBH2) (Scheme 4).
To explain the net hydrodeamination from 56, we suggest that
activation produces 58 as usual, followed by fragmentation to the
stabilized benzylic cation 59 that abstracts hydride from the
starting 56. Similar hydrodeamination was observed during
attempted borylation of α-methylbenzylamine derivative 60 to
trimethylbenzene and the expected aliphatic borylation product
65, a small amount of the C-demethylation product 66 (ca. 6.3:1
65:66) was isolated and identified by comparison with an
authentic sample.2 The mechanism of this process was not
investigated, but the observed demethylation can be understood
as an insertion of electrophilic tricoordinate boron into a C−C
bond, forming CH4 as the byproduct.12,13
The success of small-scale catalytic aromatic borylations in the
substituted benzylamine−borane series prompted experiments
to develop a larger scale (3−4 g) reaction protocol featuring a
more scalable isolation procedure. Performing the reaction with
5% HNTf2 in dry tetralin at 180 °C obviated the need for sealed
glass tubes, and removal of tetralin was accomplished by
precipitating the crude product with hexane. Subsequent
extraction of the crude solid with either toluene (37) or THF/
Et2O (45) separated the products from insoluble Tf2N
derivatives, affording pure products 37 (77% after crystalliza-
tion) and 45 (95%).14
Having demonstrated gram-scale access to representative
aromatic borylation products, we briefly tested their conversion
to arylboronic acid derivatives that are potentially useful
E
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substrates for transition-metal-catalyzed cross-coupling reac-
tions. Thus, refluxing amine−boranes 37 and 45 in aqueous
MeOH for 4 h followed by concentration and azeotropic
removal of water furnished cyclic boroxines 67 and 68,
respectively, in nearly quantitative yields (Scheme 5). Alter-
natively, refluxing 37 with catechol in xylenes afforded the
catechol ester 69 in 93% yield after crystallization.
The same catalytic conditions are especially effective for
amine-directed aromatic borylation and generally give yields well
above 90%. The catalytic method is more practical than an earlier
variation using stoichiometric Ph3C+B(C6F5)4¯ (2) for hydride
abstraction from the amine−borane.1,2 The catalytic reactions
also give considerably higher regioselectivity with meta-
substituted benzylamine−boranes. Conversion of the borylation
products into arylboronic acid derivatives is possible and is
illustrated in selective Suzuki−Miyaura cross-coupling reactions.
Scheme 5. Cross-Couplings of 67 and 68
EXPERIMENTAL SECTION
■
General Remarks. All reactions were performed at room
temperature (unless otherwise stated), under an atmosphere of dry
nitrogen, either in a glovebox or using standard Schlenk techniques.
Nuclear magnetic resonance experiments were performed on Varian
Inova 700, Varian Inova 500, and Inova 400 spectrometers at the
following frequencies: 1H, 700, 500, or 400 MHz; 11B and 11B{1H}, 225,
160, or 128 MHz; 13C{1H}, 176, 126, or 101 MHz; 19F, 471 MHz. All
spectra were recorded in CDCl3, d5-PhBr, or CD2Cl2 and referenced to
1
the H signal of internal Me4Si according to IUPAC recommenda-
tions,17 using a Ξ (referencing parameter) value of 32.083974 for BF3·
OEt2 (11B), a Ξ value of 25.145020 for Me4Si (13C), and a Ξ value of
94.094011 for CCl3F (19F). When the internal Me4Si reference could
not be used, residual solvent peaks in 1H NMR spectra were referenced
instead. Hexanes, CH2Cl2, and THF were dried by passing through a
column of activated alumina. Hexanes and CH2Cl2 were further dried
by storing over activated 3 Å molecular sieves in the glovebox.
Commercially available NMR grade deuterated solvents (Cambridge
Isotope Laboratories) as well as benzene and fluorobenzene were not
distilled; instead, they were simply dried over a large amount of
activated 3 Å molecular sieves in the glovebox. All other reagents were
used as received from commercial suppliers or prepared according to
published procedures.
Amine−Borane Activations with Tf2NH. In Situ NMR Study.
Every possible effort was made to protect the reaction mixtures from
exposure to air and moisture. The reactions were set up in dry J. Young
NMR tubes under an N2 atmosphere in a glovebox. The NMR tubes
were dried in a heating oven at ca. 200 °C overnight, and the fitted
Teflon valves were dried in a desiccator over Drierite. Commercial
grade Tf2NH and amine−boranes (Me3N·BH3 (11a), Et3N·BH3 (11b),
and (iPr)2EtN·BH3 (11c)) were used without further purification. The
benzylic amine−borane p-MeC6H4CH2NMe2·BH3 (11d)2 and 1-
neopentylpyrrolidine−borane (11e)5 were prepared as reported
previously. Commercial grade CD2Cl2 and d8-PhMe (Cambridge
Isotope Laboratories) were not distilled but simply dried with freshly
activated molecular sieves in the glovebox.
When solid amine−boranes were used (Me3N·BH3 (11a), p-
MeC6H4CH2NMe2·BH3 (11d), 1-neopentylpyrrolidine−borane
(11e)), the reaction tube was charged with a mixture of solid Tf2NH
and the corresponding amine−borane. The solid mixture was dissolved
by adding the solvent (either 0.6 mL of CD2Cl2 or 0.8 mL of d8-PhMe)
to the tube in one portion at room temperature. Gas liberation was
observed, although no substantial exotherm was noted, potentially due
to the small scale of the reaction. The tube was sealed with a fitted
Teflon valve and then shaken vigorously for ca. 1 min. The amounts of
the reagents used in each particular case are listed below.
When liquid amine−boranes were used (Et3N·BH3 (11b) and
(iPr)2EtN·BH3 (11c)), the reaction tube was charged with a solution of
Tf2NH in 0.6 mL of CD2Cl2. Neat amine−borane was then added to the
solution via a microsyringe at room temperature, causing intense gas
liberation, although no substantial exotherm was noted, potentially due
to the small scale of the reaction. The tube was sealed with a fitted
Teflon valve and then shaken vigorously for ca. 1 min. The amounts of
the reagents used in each particular case are listed below.
Attempts to use boronic anhydride 67 in Suzuki−Miyaura
cross coupling indicated that its reactivity is somewhat lower in
comparison to that of arylboronic acids (Scheme 5). Thus, 67
could be efficiently coupled with PhI/Pd(PPh3)4 in DME/H2O
using Ba(OH)2·8H2O as base (82% of 70 isolated), but no
coupling was observed using K3PO4/Pd(OAc)2/SPhos in THF,
conditions that are known to effect the cross-coupling of aryl
iodides with PhB(OH)2.15 This suggested the possibility of using
68 in a sequence of two distinct Suzuki−Miyaura coupling
events. The added base was identified as the crucial variable
determining the reactivity of the C−B bond of 67, and a protocol
for a selective two-stage cross coupling of 68 with PhB(OH)2
was developed. First, 68 was reacted with PhB(OH)2 using
K3PO4/Pd(OAc)2/SPhos in THF, the same conditions that gave
no coupling with 67. Selective coupling was evident from the 1H
NMR spectrum of the crude reaction mixture, suggesting that
only a single benzylamine derivative (71) was present. In the
second stage, Ba(OH)2·8H2O was used to activate the boroxine
moiety of 71, and this enabled cross-coupling with added 4-
iodoacetophenone. While the unoptimized isolated yield of 72 is
modest (40%), the goal of this sequence was to illustrate the
potential of the bifunctional coupling partner 68 for selective
sequential attachment of two distinct aromatic substituents. The
analogy between these results and selective coupling reactions of
MIDA-protected boronates16 suggests that the pendant
(dimethylamino)methyl moiety is responsible for the decreased
boroxine reactivity in 68.
SUMMARY
■
Catalytic borylation conditions (5% HNTf2, 160 °C) have been
developed that allow intramolecular borylation starting from
tertiary amine−boranes. The reactions of aliphatic amine−
boranes are shown to have a preference for 5-membered-ring
formation, although 6-membered rings can be formed with
biased substrates. Retrohydroboration appears to be possible
under the reaction conditions and is responsible for skeletal
isomerization during the borylation step from 29 to 30. Two
sequential borylations are demonstrated starting from amine−
boranes 19 and 27.
The ratios of N- to O-bound isomers of the products were measured
by NMR after the initial equilibration had completed and were
confirmed to remain stable for 2−14 days at room temperature.
F
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12a:13a, 7:1 ratio after equilibration. The following reagents were
used: trimethylamine−borane (11a; 8.0 mg, 0.109 mmol), Tf2NH (30.7
mg, 0.109 mmol), CD2Cl2 (0.6 mL). 12a: 1H NMR (500 MHz,
CD2Cl2) δ 3.2−1.9 (br m, 2H), 2.65 ppm (s, 9H); 11B NMR (160 MHz,
CD2Cl2) δ −3.7 ppm (t, J = 115 Hz); 13C NMR (126 MHz, CD2Cl2) δ
119.6 (q, JC−F = 326 Hz), 51.8 ppm; 19F NMR (471 MHz, CD2Cl2) δ
twice with saturated NaHCO3 solution and then dried over MgSO4,
filtered, and concentrated under reduced pressure. The resulting amide
(2.49 g, 68%) was used in subsequent transformations without further
purification. The expected structure was confirmed by 1H NMR
spectroscopy. 1H NMR (500 MHz, CDCl3): δ 5.52 (s, 1H), 3.30−3.18
(m, 2H), 1.43−1.37 (m, 2H), 1.18 (s, 9H), 0.93 ppm (s, 9H).
1
−69.2 ppm (s). 13a: H NMR (500 MHz, CD2Cl2) δ 3.2−1.9 (br m,
Amine−Borane 16. The commercially available KH suspension in
mineral oil (30 wt %, 0.78 g, 5.82 mmol) was shaken vigorously, and the
resulting slurry was quickly transferred to a flask with a pipet and
weighed; the flask was then immediately sealed with a septum and
purged with dry nitrogen. Anhydrous THF (10.0 mL) was added to the
flask, and a solution of N-(3,3-dimethylbutyl)pivalamide (980 mg, 5.29
mmol) in 10.0 mL of THF was then added dropwise. The reaction
mixture was stirred for 1 h at room temperature. Ethyl iodide (0.47 mL,
907 mg, 5.82 mmol) was added dropwise, and the reaction mixture was
stirred for an additional 5 h at room temperature, following which it was
carefully quenched with isopropyl alcohol and diluted with water. The
reaction mixture was extracted three times with EtOAc, and the
combined organic extracts were washed with brine and then dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting yellow oil was dissolved in 10.0 mL of anhydrous THF and
treated with Me2S·BH3 (0.95 mL, 9.52 mmol). The addition of the
borane complex resulted in an exothermic reaction after a short
induction period. After the exothermic reaction had ceased, the reaction
mixture was refluxed for 1 h, following which it was filtered through a
short (2−3 cm) plug of silica, while eluting with CH2Cl2, to decompose
the residual Me2S·BH3. Crystallization from hexanes afforded 0.691 g
(61%) of 16 as a white crystalline solid, mp 49 °C (hexanes). 1H NMR
(500 MHz, CDCl3): δ 3.02−2.90 (m, 2H), 2.89−2.79 (m, 2H), 2.70
(AB q, J = 14.3 Hz, 2H), 1.9−1.1 (br m, 3H), 1.71−1.55 (m, 2H), 1.24
(t, J = 7.2 Hz, 3H), 1.15 (s, 9H), 0.93 ppm (s, 9H). 13C NMR (126
MHz, CDCl3): δ 69.4, 57.0, 55.0, 36.2, 33.6, 31.0, 29.9, 29.4, 9.4 ppm.
11B NMR (128 MHz, CDCl3): δ −11.79 ppm (q, J = 90 Hz). HRMS
(EI): m/z calcd for C13H30N [M − BH3 + H]+ 200.2373, found
200.2376 (+1 ppm). IR (CDCl3, NaCl): 3258, 2954, 2865, 1465, 1364,
1311, 1215, 1027 cm−1.
Preparation of 19. This compound was prepared following the
procedure given above for the preparation of 16, using BnBr (0.549 mL,
789 mg, 4.61 mmol) instead of EtI. Yield: 0.685 g (59%) of a white
crystalline solid, mp 107 °C (hexanes). 1H NMR (500 MHz, CDCl3): δ
7.48−7.43 (m, 2H), 7.38−7.33 (m, 3H), 4.11 (d, J = 12.9 Hz, 1H), 3.96
(d, J = 12.9 Hz, 1H), 2.98−2.88 (m, 1H), 2.79 (d, J = 13.9 Hz, 1H), 2.73
(td, J = 12.1, 5.7 Hz, 1H), 2.61 (d, J = 13.9 Hz, 1H), 2.0−1.3 (br m, 3H),
1.84−1.72 (m, 2H), 1.19 (s, 9H), 0.90 ppm (s, 9H). 13C NMR (126
MHz, CDCl3): δ 132.8, 132.1, 128.7, 127.9, 70.6, 66.0, 56.4, 36.6, 33.7,
31.2, 30.1, 29.5 ppm. 11B NMR (128 MHz, CDCl3): δ −11.23 ppm (q, J
= 70 Hz). HRMS (EI): m/z calcd for C18H32N [M − BH3 + H]+
262.2529, found 262.2534 (+2 ppm). IR (CDCl3, NaCl): 2958, 2867,
2383, 2335, 2283, 2242, 1455, 1364, 1172 cm−1.
2H), 2.69 ppm (s, 9H); 11B NMR (160 MHz, CD2Cl2) δ 4.0 ppm (t, J =
120 Hz); 13C NMR (126 MHz, CD2Cl2) δ 119.1 (q, JC−F = 320 Hz),
118.7 (q, JC−F = 321 Hz), 49.7 ppm; 19F NMR (471 MHz, CD2Cl2) δ
−76.6 (s), −79.1 ppm (s).
12b:13b, 1:4.7 ratio after equilibration. The following reagents were
used: triethylamine−orane (12b; 13.3 μL, 90.7 μmol), Tf2NH (25.5
mg, 90.7 μmol), CD2Cl2 (0.6 mL). 12b: 1H NMR (500 MHz, CD2Cl2)
δ 3.4−1.9 (br m, 2H), 2.88 (q, J = 7.2 Hz, 6H), 1.21 ppm (t, J = 7.2 Hz,
9H); 11B NMR (160 MHz, CD2Cl2) δ −7.4 ppm (unres t); 13C NMR
(126 MHz, CD2Cl2) δ 119.6 (q, JC−F = 327 Hz), 49.8, 8.2 ppm; 19F
NMR (471 MHz, CD2Cl2) δ −68.9 ppm (s). 13b: 1H NMR (500 MHz,
CD2Cl2) δ 3.4−1.9 (br m, 2H), 2.90 (q, J = 7.2 Hz, 6H), 1.21 ppm (t, J =
7.2 Hz, 9H); 11B NMR (160 MHz, CD2Cl2) δ 0.7 ppm (unres t); 13
NMR (126 MHz, CD2Cl2) δ 119.2 (q, JC−F = 320 Hz), 118.7 (q, JC−F
C
=
321 Hz), 49.2, 7.5 ppm; 19F NMR (471 MHz, CD2Cl2) δ −76.7 (s),
−79.1 ppm (s).
12c:13c, <1:25 ratio after equilibration. The following reagents were
used: (iPr)2EtN·BH3 (11c; 26.7 μL, 0.153 mmol), Tf2NH (43.0 mg,
0.153 mmol), CD2Cl2 (0.6 mL). Due to the low concentration of the N-
bound isomer 12c in solution, only 19F signals were assigned. 12c: 19
F
NMR (471 MHz, CD2Cl2) δ −68.4 ppm (s). 13c: 1H NMR (500 MHz,
CD2Cl2) δ 3.70−3.60 (m, 2H), 3.4−2.1 (br m, 2H), 3.01 (q, J = 7.3 Hz,
2H), 1.37−1.33 (m, 12H), 1.26 ppm (t, J = 7.3 Hz, 3H); 11B NMR (160
MHz, CD2Cl2) δ 1.2 ppm (unres t); 13C NMR (126 MHz, CD2Cl2) δ
119.2 (q, JC−F = 321 Hz), 118.7 (q, JC−F = 321 Hz), 56.7, 56.6, 45.3, 18.3
(overlapping s), 9.5 ppm; 19F NMR (471 MHz, CD2Cl2) δ −77.0 (s),
−79.1 ppm (s).
12d:13d, 4.2:1 ratio after equilibration. The following reagents were
used: p-MeC6H4CH2NMe2·BH3 (11d; 23.0 mg, 0.141 mmol), Tf2NH
(39.6 mg, 0.141 mmol), CD2Cl2 (0.6 mL). 12d: 1H NMR (500 MHz,
CD2Cl2) δ 7.30−7.17 (m, 4H), 3.96 (s, 2H), 3.3−2.0 (br m, 2H), 2.48
(s, 6H), 2.39 ppm (s, 3H); 11B NMR (160 MHz, CD2Cl2) δ −3.2 ppm
(unres t); 13C NMR (126 MHz, CD2Cl2) δ 140.0, 132.5, 129.4, 125.5,
119.7 (q, JC−F = 326 Hz), 64.9, 46.8, 20.9 ppm; 19F NMR (471 MHz,
CD2Cl2) δ −69.0 ppm (s). 13d: 1H NMR (500 MHz, CD2Cl2) δ 7.30−
7.17 (m, 4H), 3.99−3.97 (m, 2H), 3.3−2.0 (br m, 2H), 2.54 (s, 3H),
2.53 (s, 3H), 2.39 ppm (s, 3H); 11B NMR (160 MHz, CD2Cl2) δ 4.0
ppm (unres t); 13C NMR (126 MHz, CD2Cl2) δ 140.3, 132.3, 129.5,
125.1, 119.2 (q, JC−F = 321 Hz), 118.8 (q, JC−F = 321 Hz), 63.5, 45.5,
45.4, 20.9 ppm; 19F NMR (471 MHz, CD2Cl2) δ −76.6 (s), −79.1 ppm
(s).
12e:13e, 1:2.6 ratio after equilibration. The following reagents were
used: 1-neopentylpyrrolidine−borane (11e; 10.9 mg, 70.3 μmol),
Tf2NH (19.8 mg, 70.3 μmol), d8-PhMe (0.8 mL). 12e: 1H NMR (700
MHz, d8-PhMe) δ 3.2−2.3 (br m, 2H), 3.01−2.94 (m, 2H), 2.60−2.55
(m, 2H), 2.44 (s, 2H), 1.57−1.42 (m, 2H), 1.22−1.11 (m, 2H), 0.73
ppm (s, 9H); 11B NMR (225 MHz, d8-PhMe) δ −4.6 ppm (unres t);
13C NMR (176 MHz, d8-PhMe) δ 120.5 (q, JC−F = 327 Hz), 68.8, 57.8,
33.0, 30.3, 22.0 ppm; 19F NMR (471 MHz, d8-PhMe) δ −69.2 ppm (s).
13e: 1H NMR (700 MHz, d8-PhMe) δ 3.2−2.3 (br m, 2H), 3.01−2.94
(m, 1H), 2.79−2.74 (m, 1H), 2.33 (d, J = 13.7 Hz, 1H), 2.08 (d, J = 13.7
Hz, 1H), 1.98−1.93 (m, 1H), 1.93−1.86 (m, 1H), 1.57−1.42 (m, 2H),
1.22−1.11 (m, 2H), 0.78 ppm (s, 9H); 11B NMR (225 MHz, d8-PhMe)
Preparation of 22. 1-Benzylazacycloundecan-2-one. The com-
mercially available KH suspension in mineral oil (30 wt %, 1.54 g, 11.5
mmol) was shaken vigorously, and the resulting slurry was quickly
transferred to a flask with a pipet and weighed and then immediately
sealed with a septum and purged with dry nitrogen. Anhydrous THF
(10.0 mL) was added to the flask, and a solution of undecan-2-one (1.77
g, 10.5 mmol) in 20.0 mL of THF was then added dropwise. The
reaction mixture was stirred for 1 h at room temperature. Benzyl
bromide (1.50 mL, 2.15 g, 12.6 mmol) was then added dropwise, and
the reaction mixture was stirred for an additional 8 h at room
temperature and then carefully quenched with isopropyl alcohol and
diluted with water. The reaction mixture was extracted three times with
EtOAc, and the combined organic extracts were washed with brine and
then dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification by column chromatography (10/1 hexanes/
EtOAc) afforded 2.45 g (90%) of the amide as a white powder. The
product was obtained as a mixture of E/Z amide isomers at room
temperature, which prevented accurate assignment of the peaks and
δ 0.6 ppm (unres t); 13C NMR (176 MHz, d8-PhMe) δ 120.2 (q, JC−F
=
320 Hz), 119.6 (q, JC−F = 320 Hz), 72.2, 60.4, 59.4, 33.1, 29.7, 22.6, 22.1
ppm; 19F NMR (471 MHz, d8-PhMe) δ −76.7 (s), −78.7 ppm (s).
Preparation of Borylation Substrates. Preparation of 16. N-
(3,3-Dimethylbutyl)pivalamide. Pivaloyl chloride (2.68 mL, 2.62 g,
21.7 mmol) in 20.0 mL of CH2Cl2 was slowly added to a stirred solution
of 3,3-dimethylbutan-1-amine (2.00 g, 19.8 mmol) and Et3N (3.0 mL,
2.20 g, 21.7 mmol) in 20.0 mL of CH2Cl2. The reaction mixture was
stirred at room temperature for 6 h, following which it was acidified with
1 N HCl and extracted with CH2Cl2. The organic extracts were washed
1
their integral values. H NMR (500 MHz, CDCl3): δ 7.36−7.22 (m),
7.16 (d, J = 7.3 Hz), 5.00 (d, J = 16.7 Hz), 4.63 (s), 4.46−4.39 (m), 4.36
(d, J = 16.7 Hz), 3.43 (s), 2.65−2.45 (m), 2.22−2.11 (m), 1.94−1.63
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(m), 1.64−1.19 ppm (m). 13C NMR (126 MHz, CDCl3): δ 175.5,
173.8, 137.8, 137.2, 128.8, 128.5, 128.3, 127.5, 127.2, 126.4, 51.7, 46.5,
46.3, 44.9, 34.0, 29.3, 27.3, 26.3, 25.7, 25.14, 25.07, 25.0, 24.9, 24.7, 24.3,
24.1, 23.8, 23.6, 22.6 ppm. HRMS (ES+): m/z calcd for C17H26NO [M
+ H]+ 260.2009, found 260.2011 (+1 ppm).
204.1747, found 204.1751 (+2 ppm). IR (CDCl3, NaCl): 2993, 2952,
2916, 2871, 2860, 2398, 2334, 2275, 1482, 1454, 1177, 1168, 748, 695
cm−1.
N,N-Dimethyl-3-iodobenzylamine−Borane (44). This compound
was prepared according to the previously published procedure for
substituted N,N-dimethylbenzylamine−borane complexes from m-
iodobenzyl bromide.2 1H NMR (500 MHz, CDCl3): δ 7.76 (dt, J =
8.0, 1.5 Hz, 1H), 7.69 (t, J = 1.5 Hz, 1H), 7.34−7.31 (m, 1H), 7.15 (t, J =
8.0 Hz, 1H), 3.91 (s, 2H), 2.52 (s, 6H), 2.2−1.4 ppm (br m, 3H). 13C
NMR (101 MHz, CDCl3): δ 140.9, 138.2, 133.5, 131.5, 130.1, 94.1,
66.8, 49.9 ppm. 11B NMR (128 MHz, CDCl3): δ −8.2 ppm (q, J = 90
Hz). HRMS (EI): m/z calcd for [M − 3H]+ 272.0108, found 272.0108
(0 ppm).
N,N-Dimethyl-3-chlorobenzylamine−Borane (47). Neat pyrroli-
dine (20 mL, 17.4 g, 0.245 mol) was added slowly to a stirred solution of
3-chlorobenzyl bromide (1.96 g, 9.54 mmol) in MeOH (10 mL) at 0
°C. Upon full consumption of the bromide the reaction mixture was
concentrated under vacuum, and the residue was dissolved in 10 mL of
6 M HCl. The solution was washed with 3 × 10 mL of Et2O (washes
discarded) and then carefully made strongly basic by adding NaOH.
The reaction mixture was then extracted with Et2O, and the combined
extracts were dried with MgSO4, filtered, and concentrated under
reduced pressure. Treatment of the resulting oil with Me2S·BH3 (0.96
mL, 9.5 mmol) in CH2Cl2 afforded a clear solution, which was
concentrated under reduced pressure. Dissolution of the crude product
in CHCl3 followed by filtration through a fine frit afforded a white solid
after concentration. Crystallization of the solid from cyclohexane/
CHCl3 produced 1.57 g (79%) of the desired amine−borane. 1H NMR
(500 MHz, CDCl3): δ 7.41−7.39 (m, 1H), 7.39−7.35 (m, 1H), 7.34−
7.29 (m, 2H), 3.99 (s, 2H), 3.16−3.05 (m, 2H), 2.88−2.78 (m, 2H),
2.28−2.12 (m, 2H), 2.1−1.2 (br m, 3H), 1.89−1.74 ppm (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 134.1, 133.9, 132.4, 130.8, 129.4, 129.1,
64.9, 59.2, 22.5 ppm. 11B NMR (128 MHz, CDCl3): δ −11.1 ppm (q, J
= 95 Hz). HRMS (ES+): m/z calcd for [M + Na]+ 232.1040, found
232.1042 (+1 ppm).
Amine−Borane 22. Dry 1-benzylazacycloundecan-2-one (2.41 g, 9.3
mmol) was dissolved in 9.3 mL of anhydrous THF and then treated
with Me2S·BH3 (1.7 mL, 17 mmol). The addition of the borane
complex resulted in an exothermic reaction after a short induction
period. After the exothermic reaction had ceased, the reaction mixture
was refluxed for 1 h, following which it was filtered through a short (2−3
cm) plug of silica, while eluting with CH2Cl2, to decompose the residual
Me2S·BH3. Crystallization of the crude product from hexanes afforded
1.71 g (71%) of pure 22 as a white crystalline solid, mp 103 °C
(hexanes). 1H NMR (500 MHz, CDCl3): δ 7.54−7.46 (m, 2H), 7.36−
7.31 (m, 3H), 3.81 (s, 2H), 3.03−2.91 (m, 2H), 2.89−2.75 (m, 2H),
1.9−1.1 (br m, 3H), 1.79−1.66 (m, 4H), 1.56−1.33 ppm (m, 12H). 13C
NMR (126 MHz, CDCl3): δ 133.0, 131.9, 128.7, 127.7, 65.8, 56.5, 25.3,
24.9, 24.5, 20.3 ppm. 11B NMR (128 MHz, CDCl3): δ −12.0 ppm (q, J
= 75 Hz). HRMS (EI): m/z calcd for C17H28N [M − BH3 + H]+
246.2216, found 246.2221 (+2 ppm). IR (CDCl3, NaCl): 2927, 2894,
2845, 2408, 2343, 2287, 1481, 1453, 1172, 742, 696 cm−1.
N-Ethylheptamethyleneimine−Borane (24). Acetic anhydride
(0.86 mL, 0.93 g, 9.14 mmol) was added dropwise to a solution of
heptamethyleneimine (0.941 g, 8.31 mmol) in 5 mL of anhydrous
CH2Cl2. Triethylamine (2 mL) was added to the mixture, and the
resulting solution was stirred overnight at room temperature. Following
concentration under reduced pressure the residue was partitioned
between CH2Cl2 and 10% NaOH solution (10 mL), and the aqueous
layer was additionally extracted with 2 × 10 mL of CH2Cl2. The
combined organic extracts were dried with MgSO4, filtered, and
concentrated. The residual oil was dissolved in anhydrous THF (10
mL), and Me2S·BH3 (1.4 mL, 14 mmol) was then added. The addition
of the borane complex resulted in an exothermic reaction after a short
induction period. After the exothermic reaction had ceased, the reaction
mixture was refluxed for 1 h, following which it was quenched with
water (frothing!) and extracted with CH2Cl2. The combined extracts
were dried with MgSO4, filtered, and concentrated under reduced
pressure. Column chromatography (∼150 mL silica gel, PhMe)
afforded 0.591 g (49%) of a colorless oil. 1H NMR (700 MHz,
CDCl3): δ 3.14−3.09 (m, 2H), 2.82−2.78 (m, 2H), 2.78 (q, J = 7.2 Hz,
2H), 1.91−1.83 (m, 2H), 1.8−1.2(br m, 3H), 1.78−1.65 (m, 5H,
integral intensity somewhat uncertain due to overlap with B−H signal),
1.59−1.45 (m, 3H, integral intensity uncertain due to overlap with B−H
signal), 1.29 ppm (t, J = 7.2 Hz). 13C NMR (101 MHz, CDCl3): δ 56.0,
55.3, 27.4, 25.2, 22.9, 9.6 ppm. 11B NMR (128 MHz, CDCl3): δ −12.3
ppm (q, J = 100 Hz). IR (CDCl3, NaCl): 2926, 2378, 2278, 1482, 1448,
1175, 1038 cm−1.
N-Benzylheptamethyleneimine−Borane (27). Benzoyl chloride
(1.44 mL, 1.73 g, 12.3 mmol) in 12.0 mL of CH2Cl2 was slowly
added to a solution of heptamethyleneimine (1.27 g, 11.2 mmol) and
Et3N (2.35 mL, 1.70 g, 16.8 mmol) in 12.0 mL of CH2Cl2 at room
temperature. After 18 h at room temperature the reaction mixture was
acidified with 1 N HCl and extracted with CH2Cl2. The organic phase
was washed with saturated NaHCO3 solution and then dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting dark yellow oil was dissolved in 11 mL of anhydrous THF
and then treated with Me2S·BH3 (2.1 mL, 21 mmol). The addition of
the borane complex resulted in an exothermic reaction after a short
induction period. After the exothermic reaction had ceased, the reaction
mixture was refluxed for 1 h, following which it was filtered through a
short (2−3 cm) plug of silica, while eluting with CH2Cl2, to decompose
the residual Me2S·BH3. Crystallization of the crude product from
hexanes afforded 2.20 g (90%) of the pure product as a white crystalline
solid, mp 76 °C (hexanes). 1H NMR (500 MHz, CDCl3): δ 7.51−7.42
(m, 2H), 7.40−7.31 (m, 3H), 3.87 (s, 2H), 3.10−2.92 (m, 4H), 2.01
(m, 2H), 1.9−1.2 (br m, 3H), 1.77−1.65 (m, 1H), 1.66−1.43 ppm (m,
7H). 13C NMR (126 MHz, CDCl3): δ 132.8, 132.0, 128.7, 127.8, 67.0,
55.5, 27.2, 25.3, 23.5 ppm. 11B NMR (128 MHz, CDCl3): δ −11.7 ppm
(q, J = 93 Hz). HRMS (EI): m/z calcd for C14H22N [M − BH3 + H]+
N,N-Dimethyl-3-phenoxybenzylamine−Borane (53). A solution of
3-phenoxybenzoic acid (2.14 g, 10 mmol) in 20 mL of SOCl2 was
refluxed for 3.5 h. Unreacted SOCl2 was distilled off, and the residual oil
was dissolved in 20 mL of CH2Cl2. The acid chloride solution was then
added dropwise to 40% aqueous Me2NH (40 mL) at 0 °C, and the
resulting mixture was stirred at room temperature for several hours. The
reaction mixture was then carefully acidified with 10% aqueous HCl and
extracted with 3 × 40 mL of CH2Cl2. The combined extracts were
washed with 10% NaOH, dried with MgSO4, concentrated, and dried
under vacuum. The crude amide was dissolved in 25 mL of THF and
then treated with BH3·SMe2 (3.0 mL). After a brief induction period an
exothermic reaction followed. The reaction mixture was then refluxed
for 1 h, diluted with hexanes (∼20 mL), and left in the freezer overnight.
The slurry was filtered through a glass frit, and the clear solution was
then passed through a short plug of silica, while eluting with CH2Cl2.
Concentration of the solution afforded a clear oil, which was crystallized
1
from CHCl3/hexanes, affording 1.90 g (79%) of a colorless solid. H
NMR (500 MHz, CDCl3): δ 7.39−7.32 (m, 3H), 7.16−7.11 (t, J = 7.3
Hz, 1H), 7.08−6.99 (m, 4H), 6.97 (s, 1H), 3.94 (s, 2H), 2.51 (s, 6H),
2.2−1.2 ppm (br m, 3H). 13C NMR (101 MHz, CDCl3): δ 157.4, 156.7,
133.1, 129.9, 129.7, 126.9, 123.8, 122.4, 119.2, 119.0, 67.2, 49.8 ppm.
11B NMR (128 MHz, CDCl3): δ −8.2 ppm (q, J = 80 Hz). HRMS (ES):
m/z calcd for C15H20BNONa [M + Na]+ 264.1530, found 264.1532.
Mp: 68 °C (CHCl3/hexanes).
N,N-Dimethyl-4-phenoxybenzylamine−Borane (56). This com-
pound was prepared following the procedure given above for the
preparation of 53, using 4-phenoxybenzoic acid (2.14 g, 10 mmol)
instead of 3-phenoxybenzoic acid. It was crystallized by dissolving the
crude product oil in cyclohexane and allowing the solution to stand at
room temperature overnight. Yield: 1.36 g (56%) of 56, mp 144 °C
1
(hexanes). H NMR (500 MHz, CDCl3): δ 7.40−7.33 (m, 2H), 7.27
(m, 2H), 7.18−7.13 (m, 1H), 7.06−7.02 (m, 2H), 7.02−6.97 (m, 2H),
3.95 (s, 2H), 2.51 (s, 6H), 2.1−1.5 ppm (br m, 3H). 13C NMR (126
MHz, CDCl3): δ 158.4, 156.3, 133.7, 129.9, 125.7, 124.0, 119.5, 118.0,
66.9, 49.7 ppm. 11B NMR (128 MHz, CDCl3): δ −8.5 ppm (q, J = 70
H
dx.doi.org/10.1021/om400651p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Hz). HRMS (EI): m/z calcd for C15H18NO [M − BH3 + H]+ 228.1383,
found 228.1382. IR (CDCl3, NaCl): 3003, 2949, 2373, 2324, 2272,
2248, 1589, 1508, 1489, 1243, 1168, 1017 cm−1.
37.6, 36.6, 32.5, 32.4, 30.3, 29.7, 29.3, 9.2 ppm; 11B NMR (128 MHz,
CDCl3) δ −4.4 ppm (t, J = 80 Hz); HRMS (ESI+) m/z calcd for
C13H29BN [M − H]+ 210.2388, found 210.2388; IR (CDCl3, NaCl)
2955, 2864, 2348, 1467, 1366, 1235, 1197, 1171, 1133 cm−1.
N,N-Dimethyl-1-naphthylmethylamine−Borane (61). This com-
pound was prepared according to the previously published procedure
for substituted N,N-dimethylbenzylamine−borane complexes from 1-
(chloromethyl)naphthalene.2 1H NMR (500 MHz, CDCl3): 8.31 (d, J =
8.5 Hz, 1H), 7.95−7.88 (m, 2H), 7.59 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H),
7.55−7.48 (m, 3H), 4.55 (s, 2H), 2.53 (s, 6H), 2.6−1.6 ppm (br m,
3H). 11B NMR (128 MHz, CDCl3): δ −7.7 ppm (q, J = 95 Hz).
N,N-Dimethyl-2,6-dimethylbenzylamine−Borane (64). This com-
pound was prepared according to the previously published procedure
for substituted N,N-dimethylbenzylamine−borane complexes from 2,6-
dimethylbenzyl chloride.2 1H NMR (500 MHz, CDCl3): δ 7.19 (dd, J =
8.2, 6.9 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H), 4.26 (s, 2H), 2.52 (s, 6H),
2.44 (s, 6H), 2.3−1.5 ppm (br m, 3H). 13C NMR (101 MHz, CDCl3): δ
139.8, 129.2, 128.9, 128.7, 59.4, 50.1, 21.6 ppm. 11B NMR (128 MHz,
CDCl3): δ −7.7 ppm (q, J = 95 Hz). HRMS (ES+): m/z calcd for
C11H18N [M − BH3 + H]+ 164.1434, found 164.1431 (−2 ppm).
Intramolecular C−H Borylation. General Procedures. Small-
Scale Activation. Stoichiometric borylations using 0.9 equiv of
Ph3C[B(C6F5)4] were performed as described in the previously
published procedure.2 Catalytic activation used the previously
published procedure as follows.5 A dry 12 mL thick-walled Schlenk
tube fitted with a Teflon stopper was charged with a mixture of solid
amine−borane (1.32 mmol) and Tf2NH (18.6 mg, 66.2 μmol). Solvent
(3 mL) was then added, and some minor frothing due to gas formation
was observed. The gas which formed during the initial activation stage
was identified as H2 in an in situ NMR study. After H2 liberation ceased,
and the gas was allowed to escape the reaction vessel, the tube was
sealed and heated at 160 °C (bath) for the indicated time. When liquid
amine−borane complexes were used, the substrate was first dissolved in
1 mL of the solvent, and then Tf2NH and the additional solvent were
added. The reaction mixture was quenched by adding solid n-Bu4NBH4
(∼30 mg) under an N2 atmosphere. The mixture was then diluted with
CH2Cl2 and filtered through a short plug of silica, with CH2Cl2 or
CHCl3 as eluent. The products were isolated by concentration of the
solution, followed by crystallization or chromatography to isolate pure
isomers.
20: white crystalline solid, mp 78 °C (hexanes); 1H NMR (400 MHz,
CDCl3) δ 7.34 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.07 (t, J =
7.2 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 4.21 (d, J = 14.6 Hz, 1H), 4.08 (d,
J = 14.6 Hz, 1H), 3.57−2.60 (br m, 1H), 3.09 (ddt, J = 17.2, 13.5, 8.3
Hz, 2H), 2.88 (d, J = 12.4 Hz, 1H), 2.68 (d, J = 12.4 Hz, 1H), 1.56 (dd, J
= 17.2, 9.1 Hz, 2H), 1.11 (d, J = 9.9 Hz, 3H), 1.05 (dd, J = 13.4, 7.1 Hz,
1H), 0.94 (s, 9H), 0.83−0.78 ppm (m, 4H); 13C NMR (126 MHz,
CDCl3) δ 157.0−155.7 (br m), 138.1, 128.9, 127.1, 124.8, 121.3, 72.1,
13
66.2, 58.1, 39.6, 37.5, 32.9, 31.3, 29.8, 29.3 ppm (the additional
C
−
aliph
B signal is likely to be located between 33.6 and 32.0 ppm, as suggested
by peak shape analysis, but precise assignment is complicated by the
overlapping sharp signal at 32.9 ppm); 11B NMR (128 MHz, CDCl3) δ
6.0 ppm (unres d); HRMS (ESI+) m/z calcd for C18H29BN [M − H]+
270.2388, found 270.2396 (+3 ppm); IR (CDCl3, NaCl) 3056, 3000,
2956, 2898, 2863, 2833, 2351, 2330, 1456, 1446, 1365, 1172, 1070,
1018, 844 cm−1.
23: white crystalline solid, mp 73 °C (hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.41 (d, J = 7.1 Hz, 1H), 7.17 (td, J = 7.1, 1.8 Hz, 1H), 7.10 −
7.03 (m, 2H), 3.97 (s, 2H), 3.11 − 2.97 (m, 4H), 2.96 − 2.34 (br m,
2H), 1.91 − 1.78 (m, 2H), 1.78 − 1.66 (m, 2H), 1.53 (m, 4H), 1.49 −
1.35 ppm (m, 8H); 13C NMR (126 MHz, CDCl3) δ 154.0−152.2 (br
m), 138.5, 129.6, 127.0, 124.7, 121.5, 65.0, 54.7, 25.7, 25.3, 24.8, 21.4
ppm; 11B NMR (128 MHz, CDCl3) δ −2.9 ppm (t, J = 90 Hz); HRMS
(ESI+) m/z calcd for C17H27BN [M − H]+ 256.2231, found 256.2233
(+1 ppm); IR (CDCl3, NaCl) 2999, 2960, 2915, 2859, 2386, 2343,
2299, 1480, 1448, 1173, 1072 cm−1.
25: white crystalline solid, mp 56 °C (hexanes); 1H NMR (500 MHz,
CDCl3) δ 2.94−2.87 (m, J = 11.7 Hz, 2H), 2.87−2.74 (m, 2H), 2.78 (q,
J = 7.4 Hz, 2H), 2.22−2.07 (m, 2H), 2.07−1.36 (br m, 2H), 1.89 (ddd, J
= 17.7, 12.1, 5.6 Hz, 2H), 1.76−1.64 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H),
0.93 ppm (br s, 1H); 13C NMR (126 MHz, CDCl3) δ 61.5, 57.4, 30.8,
24.8, 21.1−20.0 (br m), 7.1 ppm; 11B NMR (128 MHz, CDCl3) δ −4.8
ppm (t, J = 95 Hz); HRMS (ESI+) m/z calcd for C9H19BN [M − H]+
152.1605, found 152.1604 (−1 ppm); IR (CDCl3, NaCl) 2989, 2893,
2834, 2315, 1468, 1450, 1184, 1150, 794 cm−1.
Large-Scale Catalytic Borylation of 1. A dry 50 mL flask was
charged with a mixture of solid BnNMe2·BH3 (1; 4.00 g, 26.8 mmol)
and Tf2NH (0.377 g, 1.34 mmol). To the solid mixture was added 10
mL of dry tetralin, and the resulting suspension was heated to 180 °C
for 17 h. When the reaction mixture was cooled to room temperature,
20 mL of hexanes was added, and the resulting suspension was left in the
freezer overnight. The solid was filtered out and thoroughly washed
with 2 × 10 mL of cold hexanes. The crude product was extracted on the
filter with 20 mL + 2 × 10 mL of PhMe, and the combined toluene
extracts were concentrated under vacuum. Recrystallization from 10 mL
of cyclohexane, followed by washing the product with 2 × 4 mL of
cyclohexane and drying under vacuum, afforded 3.05 g (77%) of 37 as a
white solid, identical by NMR assay with material prepared on a small
scale using the stoichiometric method.5
Formation of Isomers 28−30 by Borylation of 27. The isomer
mixture was separated by preparative TLC on silica gel (1:1
CH2Cl2:hexanes). 28: white crystalline solid, mp 85 °C (hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.40 (d, J = 7.2 Hz, 1H), 7.17 (td, J = 7.1,
1.9 Hz, 1H), 7.09−7.03 (m, 2H), 4.03 (s, 2H), 3.24 (tt, J = 30.6, 12.0
Hz, 2H), 3.08 (ddd, J = 14.0, 8.3, 2.0 Hz, 2H), 2.94−2.41 (br m, 2H),
1.97−1.87 (m, 2H), 1.86−1.75 (m, 2H), 1.74−1.59 ppm (m, 8H); 13C
NMR (126 MHz, CDCl3) δ 138.5, 129. 6, 127.0, 124.7, 121.6, 66.1,
55.0, 27.4, 24.7, 23.5 ppm, aromatic 13C−B signal not detected; 11B
NMR (128 MHz, CDCl3) δ −2.3 ppm (t, J = 91 Hz); HRMS (ESI+) m/
z calcd for C14H21BN [M − H]+ 214.1762, found 214.1764 (+1 ppm);
IR (CDCl3, NaCl) 2920, 2855, 2342, 2283, 1476, 1446, 1340, 1177,
1068, 1021 cm−1. 29: white crystalline solid, mp 105 °C (hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.39−7.35 (m, 3H), 7.31 (dt, J = 7.8, 3.8
Hz, 2H), 3.89 (s, 2H), 3.04−2.90 (m, 2H), 2.85 (dd, J = 11.9, 6.3 Hz,
2H), 2.04 (dtd, J = 19.3, 13.0, 6.2 Hz, 2H), 1.97−1.86 (m, 2H), 1.84−
1.59 (br m, 2H), 1.75−1.64 (m, 4H), 0.96 ppm (s, 1H); 13C NMR (126
MHz, CDCl3) δ 132.6, 130.4, 128.8, 128.2, 71.4, 57.7, 30.7, 25.0, 21.9−
20.2 ppm (br m); 11B NMR (128 MHz, CDCl3) δ −3.3 ppm (t, J = 85
Hz); HRMS (ESI+) m/z calcd for C14H21BN [M − H]+ 214.1762,
found 214.1763; IR (CDCl3, NaCl) 2895, 2839, 2319, 1452, 1150,
1097, 1021 cm−1. 30: white crystalline solid, mp 94 °C (hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.32 (d, J = 7.1 Hz, 1H), 7.19−7.15 (m,
1H), 7.10−7.04 (m, 2H), 4.26 (d, J = 13.2 Hz, 1H), 4.07 (d, J = 13.2 Hz,
1H), 3.46−2.79 (br m, 1H), 3.12 (dd, J = 9.3, 3.6 Hz, 2H), 2.99 (td, J =
12.4, 6.1 Hz, 1H), 2.87 (ddd, J = 12.4, 9.3, 5.5 Hz, 1H), 2.16−2.06 (m,
1H), 2.05−1.93 (m, 2H), 1.91−1.83 (m, 1H), 1.82−1.72 (m, 2H),
1.71−1.61 (m, 1H), 1.36 ppm (ddd, J = 14.3, 12.1, 5.1 Hz, 2H); 13C
NMR (126 MHz, CDCl3) δ 138.8, 128.6, 126.9, 124.7, 121.7, 68.4, 61.9,
59.2, 37.1, 35.8, 29.5−27.4 (br m), 26.3, 25.6 ppm, aromatic 13C−B
signal not detected; 11B NMR (128 MHz, CDCl3) δ 2.25 ppm (d, J = 95
Large-Scale Catalytic Borylation of 44. A dry 50 mL flask was
charged with a mixture of solid 44 (4.00 g, 14.5 mmol) and Tf2NH (204
mg, 0.727 mmol). To the solid mixture was added 10.0 mL of dry
tetralin, and the resulting suspension was heated to 180 °C for 17 h.
When the reaction mixture was cooled to room temperature, 20 mL of
hexanes was added, and the resulting suspension was left in the freezer
overnight. The solid was collected by filtration and thoroughly washed
with 2 × 10 mL of cold hexanes. The crude product was extracted on the
filter with 20 mL + 2 × 15 mL of a 2:1 mixture of THF and Et2O, the
organic extracts were combined, and solvents were evaporated under
reduced pressure. The product 45 (3.77 g, 95%) was found to be
sufficiently pure to be used further without recrystallization.
Intramolecular C−H Borylation Products. 17: clear oil; 1H NMR
(400 MHz, CDCl3) δ 2.99−2.67 (m, 4H), 2.64−2.51 (unres AB q, J =
12.6 Hz, 2H), 2.3−1.7 (br m, 2H), 1.58 (td, J = 12.6, 4.3 Hz, 1H), 1.30
(ddd, J = 12.9, 10.5, 4.1 Hz, 1H), 1.13 (m, 9H), 0.93 (s, 9H), 0.68 ppm
(t, J = 5.5 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 73.0, 53.7, 52.1,
I
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Article
Hz); HRMS (ESI+) m/z calcd for C14H19BN [M − H]+ 212.1605,
found 212.1610 (+2 ppm); IR (CDCl3, NaCl) 3057, 2999, 2923, 2833,
2325, 1459, 1448, 1334, 1177, 1177, 1117, 1055, 990 cm−1.
boroxine 68 as a pale yellow powder after drying under vacuum,
sufficiently pure for use in the next stage. Under an N2 atmosphere, in a
preheated 20 mL vial Pd(OAc)2 (13 mg, 58 μmol) and SPhos (48 mg,
116 μmol) were dissolved in 10.0 mL of degassed, anhydrous THF, and
the resulting solution was stirred at room temperature for 20 min. A
preheated 100 mL round-bottom flask was charged with a portion of the
boroxine 68 from above (0.50 g, 0.58 mmol), phenylboronic acid (425
mg, 3.49 mmol), dry K3PO4 (740 mg, 3.49 mmol), and 20.0 mL of
degassed, anhydrous THF. Under an N2 atmosphere, the catalyst
solution was then added to this mixture, which was then stirred for 22 h
at 65 °C. A solution of p-iodoacetophenone (1.14 g, 4.63 mmol) in 5.0
mL of degassed, anhydrous THF and solid Ba(OH)2·8H2O (1.10 g,
3.49 mmol) were then added under an N2 atmosphere, and the reaction
mixture was stirred for additional 20 h at 65 °C. The reaction was
filtered through Celite, concentrated under reduced pressure, and
purified by column chromatography (95/5/2 CH2Cl2/MeOH/
NH4OH). The purified compound still contained minor impurities;
therefore, it was acidified with 1 N HCl and washed with Et2O (×3).
The aqueous layer was then made basic by adding 10% NaOH solution
and extracted with Et2O (×3). Organic layers were combined, dried
over MgSO4, and concentrated to afford 228 mg (40%) of 72 as a pale
yellow powder. 72: 1H NMR (500 MHz, CDCl3) δ 8.06−7.99 (m, 2H),
7.81 (t, J = 7.4 Hz, 1H), 7.69−7.63 (m, 2H), 7.58−7.52 (m, 3H), 7.45
(dd, J = 10.6, 4.7 Hz, 2H), 7.38 − 7.35 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H),
3.38 (s, 2H), 2.68−2.60 (m, 3H), 2.18 ppm (s, 6H); 13C NMR (126
MHz, CDCl3) δ 197.9, 146.3, 140.69, 140.63, 140.3, 136.8, 135.7, 130.3,
129.9, 128.82, 128.77, 128.1, 127.4, 127.2, 125.6, 61.2, 45.3, 26.7 ppm;
HRMS (ES+): m/z calcd [M + H]+ 330.1852, found 330.1854 (+1
ppm).
Borylation of 47 To Give 48 and 49. The major product 48 was
isolated by crystallizing the crude isomer mixture from hexanes. The
minor product 49 was recovered from the concentrated mother liquor
by preparative TLC on silica gel (4:1 hexanes:EtOAc). 48: white
1
crystalline solid; H NMR (500 MHz, CDCl3) δ 7.31 (d, J = 7.8 Hz,
1H), 7.14 (dd, J = 7.8, 1.9 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 4.07 (s,
2H), 3.36−3.25 (m, 2H), 3.1−2.3 (br m, 2H), 2.29−2.82 (m, 2H),
2.23−2.11 (m, 2H), 2.05−1.94 ppm (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 153.0−150.3 (br m), 140.9, 130.7, 130.4, 127.0, 121.5, 66.3,
60.3, 22.6 ppm; 11B NMR (128 MHz, CDCl3) δ −3.3 ppm (t, J = 95
Hz); HRMS (EI) m/z calcd [M − H]+ 206.0908, found 206.0916 (+4
ppm). 49: colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 7.9
Hz, 1H), 7.02 (t, J = 7.7, 1H), 6.95 (d, J = 7.5 Hz, 1H), 4.15 (s, 2H),
3.41−3.32 (m, 2H), 3.2−2.3 (br m, 2H), 2.94−2.83 (m, 2H), 2.27−
2.15 (m, 2H), 2.06−1.95 ppm (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 152.7−150.5 (br m), 140.7, 136.1, 127.3, 126.7, 119.5, 66.9, 60.7, 22.5
ppm; 11B NMR (128 MHz, CDCl3) δ −3.6 ppm (t, J = 95 Hz); HRMS
(EI) m/z calcd [M − H]+ 206.0908, found 206.0899 (−4 ppm).
Borylation of 53 To Form 54 and 55. The major product 54 was
isolated by crystallizing the crude isomer mixture from hexanes/CHCl3.
The minor product 55 was recovered from the concentrated mother
liquor by preparative TLC on silica gel (eluted with 2:1 hexanes:EtOAc
to collect the fraction with Rf = 0.38, which was then additionally
purified by preparative TLC using PhMe eluent). 54: white solid, mp
1
109 °C (hexanes); Rf = 0.53 (2:1 hexanes:EtOAc); H NMR (700
MHz, CDCl3) δ 7.37 (d, J = 7.8, 1H), 7.31−7.28 (m, 2H), 7.04 (tt, J =
7.4, 0.9 Hz, 1H), 6.99−6.96 (m, 2H), 6.89 (dd, J = 7.8, 2.2 Hz, 1H), 6.77
(d, J = 1.7 Hz, 1H), 4.00 (s, 2H), 3.1−2.4 (br m, 2H), 2.77 (s, 6H); 13C
NMR (176 MHz, CDCl3) δ 158.3, 154.8, 148.4−147.3 (br m), 140.2,
130.7, 129.5, 122.4, 118.6, 118.1, 113.2, 69.4, 51.0 ppm; 11B NMR (128
MHz, CDCl3) δ −1.5 ppm (unres t); HRMS (EI) m/z calcd for
C15H17BNO [M − H]+ 238.1403, found 238.1412 (+4 ppm). 55: white
solid; 1H NMR (700 MHz, CDCl3) δ 7.27−7.24 (m, 2H), 7.10 (t, J =
7.6 Hz, 1H), 6.99 (tt, J = 7.4, 1.1 Hz, 1H), 6.96−6.93 (m, 2H), 6.90 (d, J
= 7.4 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 4.05 (s, 2H), 3.0−2.3 (br m,
2H), 2.73 (s, 6H); 13C NMR (176 MHz, CDCl3) δ 158.4, 157.3, 144.4−
143.0 (br m), 141.4, 129.1, 127.0, 121.7, 118.7, 118.0, 117.8, 69.4, 50.9
ppm; 11B NMR (225 MHz, CDCl3) δ −2.6 ppm (unres t); HRMS (ES
+) m/z calcd for C15H17BNO [M − H]+ 238.1398, found 238.1401 (+1
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, and CIF files giving X-ray crystallography data and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for E.V.: edved@umich.edu.
Notes
1
ppm). 57: white colorless solid, mp 88 °C (hexanes); H NMR (700
The authors declare no competing financial interest.
MHz, CDCl3) δ 7.30 (dt, J = 8.3, 4.8 Hz, 2H), 7.07−6.99 (m, 5H), 6.74
(dd, J = 8.0, 2.3 Hz, 1H), 4.02 (s, 2H), 3.0−2.4 (br m, 2H), 2.76 (s, 6H);
13C NMR (176 MHz, CDCl3) δ 157.9, 156.6, 156.4−155.5 (br m),
133.6, 129.5, 122.7, 122.5, 120.1, 118.6, 115.7, 69.2, 50.9 ppm; 11B
NMR (225 MHz, CDCl3) δ −1.5 ppm (unres t); HRMS (ESI+) m/z
calcd for C15H17BNO [M − H]+ 238.1398, found 238.1400 (+1 ppm).
62: 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.61 (d, J =
8.0 Hz, 1H), 7.50 (d, J = 6.6 Hz, 1H), 7.45 (dd, J = 8.0, 6.8 Hz, 1H), 7.32
(dd, J = 8.2, 6.9 Hz, 1H), 7.12 (m, 1H), 4.22 (s, 2H), 3.3−2.4 (br m,
2H), 2.72 ppm (s, 6H); 11B NMR (128 MHz, CDCl3) δ −4.0 ppm (t, J
= 95 Hz).
ACKNOWLEDGMENTS
■
This work was supported by the National Institute of General
Medical Sciences of the NIH (GM067146).
REFERENCES
■
(1) De Vries, T. S.; Vedejs, E. Organometallics 2007, 26, 3079.
(2) De Vries, T. S.; Prokofjevs, A.; Harvey, J. N.; Vedejs, E. J. Am.
Chem. Soc. 2009, 131, 14679.
(3) (a) De Vries, T. S.; Prokofjevs, A.; Vedejs, E. Chem. Rev. 2012, 112,
4246. (b) Piers, W. E.; Bourke, S. C.; Conroy, K. D. Angew. Chem., Int.
Borylation of 64: Isolation of 65. Isolation of 64 and 65 was
accomplished by repeated preparative TLC on silica gel (4:1
hexanes:EtOAc). The identity of C−C bond insertion product 64
Ed. 2005, 44, 5016. (c) Kolle, P.; Noth, H. Chem. Rev. 1985, 85, 399.
̈
̈
2
1
1
was established by H and 13C NMR analysis. 65: colorless oil; H
NMR (500 MHz, CDCl3) δ 7.13 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz,
1H), 6.91 (d, J = 7.3 Hz, 1H), 3.82 (s, 2H), 2.67 (s, 6H), 2.4−1.6 (br m,
2H), 2.19 (s, 3H), 1.97 ppm (unres t, 2H); 13C NMR (101 MHz,
CDCl3) δ 140.9, 134.4, 130.1, 129.6, 126.8, 126.3, 62.4, 51.2, 20.1−18.4
(br m), 19.5 ppm; 11B NMR (128 MHz, CDCl3) δ −6.0 ppm (t, J = 90
Hz); HRMS (EI) m/z calcd [M]+ 175.1532, found 175.1525 (−4 ppm).
Hydrolysis of 45 and Preparation of 72. A 250 mL round-bottom
flask was charged with 45 (3.50 g, 12.8 mmol), 90 mL of MeOH, and 18
mL of H2O, and the resulting mixture was refluxed for 4 h, following
which the contents were concentrated under reduced pressure. The
residue was then azeotropically dried by evaporating with toluene (five
to seven times) under reduced pressure, affording 3.60 g (98%) of the
(4) Recent examples of electrophilic C−H borylation by amine-based
borenium cations (also see refs 2 and 5): (a) Bagutski, V.; Del Grosso,
A.; Carrillo, J. A.; Cade, I. A.; Helm, M. D.; Lawson, J. R.; Singleton, P.
J.; Solomon, S. A.; Marcelli, T.; Ingleson, M. J. J. Am. Chem. Soc. 2013,
135, 474. (b) Solomon, S. A.; Del Grosso, A.; Clark, E. R.; Bagutski, V.;
McDouall, J. J. W.; Ingleson, M. J. Organometallics 2012, 31, 1908.
(c) Del Grosso, A.; Singleton, P. J.; Muryn, C. A.; Ingleson, M. J. Angew.
Chem., Int. Ed. 2011, 50, 2102. (d) Del Grosso, A.; Helm, M. D.;
Solomon, S. A.; Caras-Quinteroa, D.; Ingleson, M. J. Chem. Commun.
2011, 47, 12459. (e) Prokofjevs, A.; Kampf, J. W.; Vedejs, E. Angew.
Chem., Int. Ed. 2011, 50, 2098. (f) Ishida, N.; Moriya, T.; Goya, T.;
Murakami, M. J. Org. Chem. 2010, 75, 8709.
(5) Prokofjevs, A.; Vedejs, E. J. Am. Chem. Soc. 2011, 133, 20056.
J
dx.doi.org/10.1021/om400651p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(6) To strengthen the structural assignment of the product cation 6
previously deduced on the basis of NMR data, X-ray-quality crystals of
the [HCB11Cl11]− salt were obtained from CH2Cl2/hexanes. The
structure is fully consistent with the proposed connectivity, but
extraction of the exact structural parameters was prevented by disorder;
the X-ray structure is shown for the borenium salt corresponding to 6
with anion = [HCB11Cl11]− (50% probability ellipsoids; the counterion
is omitted for clarity).
(7) Wirth, A.; Moers, O.; Blaschette, A.; Jones, P. G. Z. Anorg. Allg.
Chem. 1998, 624, 991.
(8) Simchen, G.; Jonas, S. J. Prakt. Chem. 1998, 340, 506.
(9) (a) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am. Chem. Soc.
1974, 96, 7765. (b) Brown, H. C.; Bhatt, M. V. J. Am. Chem. Soc. 1966,
88, 1440. (c) Rickborn, B.; Wood, S. E. J. Am. Chem. Soc. 1971, 93, 3940.
(d) Parks, D. J.; Piers, W. E.; Yap, G. P. A. Organometallics 1998, 17,
5492. (e) Prokofjevs, A.; Boussonnier
Curran, D. P.; Vedejs, E. J. Am. Chem. Soc. 2012, 134, 12281.
̀ ̂
e, A.; Li, L.; Bonin, H.; Lacote, E.;
(10) Preliminary results on the catalytic borylations of 1 and 41 were
reported in refs 2 and 5, respectively.
(11) The NMR study to probe 42/43 interconversion was performed
at 120 °C for reasons of experimental convenience. The temperature
decrease from 160 to 120 °C was confirmed to have no effect on the
ratio of 42/43 (ca. 25:1) formed in the cyclization of 41.
(12) Electrophilic borane insertions in C−C bonds are rare. For
selected examples, see: (a) Xu, B.-H.; Kehr, G.; Frohlich, R.; Erker, G.
̈
Chem. Eur. J. 2010, 16, 12538. (b) Xu, B.-H.; Kehr, G.; Frohlich, R.;
̈
Grimme, S.; Erker, G. J. Am. Chem. Soc. 2011, 133, 3480.
(13) The reductive C−N bond cleavage is made possible by the
combination of strongly electrophilic and reducing conditions and is
somewhat reminiscent of the recently studied silylium ion promoted
hydrodefluorination: Douvris, C.; Ozerov, O. Science 2008, 321, 1188 In
view of this analogy, the reactivity of PhCF3 with 1 equiv of Me3N·BH3
activated by 5 mol % of Tf2NH was briefly explored. Indeed, after 18 h at
120 °C ca. 30% conversion to PhCH3 was observed, although neither
Tf2N− nor n-C12F26 were affected..
(14) Due to differences in solubility among benzylamine−boranes
with different substituents, the solvent mixture used for product
extraction from the crude mixture needs to be optimized in each
individual case.
(15) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685.
(16) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.
(17) Harris, R. K.; Becker, E. D.; Cabral de Menezes, S. M.;
Goodfellow, R.; Granger, P. Pure Appl. Chem. 2001, 73, 1795.
K
dx.doi.org/10.1021/om400651p | Organometallics XXXX, XXX, XXX−XXX