Copper-Catalyzed Electrochemical Selective B-H Oxygenation of o-Carboranes at Room Temperature

Article abstract of DOI:10.1021/jacs.0c02490

Copper-catalyzed electrochemical selective cage B-H oxygenation of o-carboranes has been achieved for the first time. Under a constant electric current (4.0 mA) at room temperature, copper-catalyzed cross-coupling of carboranyl amides with lithium phenolates results in the formation of B(4,5)-diphenolated o-carboranes via direct B-H activation, whereas the use of lithium tert-butoxide affords B(4)-monooxygenated products. This reaction does not require any additional chemical oxidants and generates H₂ and a lithium salt as byproducts. Control experiments indicated that a high-valent Cu(III) species is likely involved in the reaction process.

Full text of DOI:10.1021/jacs.0c02490

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Communication
Copper-Catalyzed Electrochemical Selective B-
H Oxygenation of o-Carboranes at Room Temperature
Yik Ki Au, Hairong Lyu, Yangjian Quan, and Zuowei Xie
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02490 • Publication Date (Web): 31 Mar 2020
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Copper-Catalyzed Electrochemical Selective B-H Oxygenation of o-
Carboranes at Room Temperature
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Yik Ki Au,† Hairong Lyu,† Yangjian Quan,* and Zuowei Xie*
Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong,
Shatin, N. T., Hong Kong, China
ABSTRACT: Copper-catalyzed electrochemical selective cage B-H oxygenation of o-carboranes has been achieved for the
first time. Under constant electric current (4.0 mA) at room temperature, copper-catalyzed cross-coupling of carboranyl
amides with lithium phenolates results in the formation of B(4,5)-diphenolated-o-carboranes via direct B-H activation,
whereas the use of lithium tert-butoxide affords B(4)-monooxygenated products. This reaction does not require any addi-
tional chemical oxidants and generates H2 and lithium salt as by-products. The control experiments indicate that a high
valent Cu(III) species is likely involved in the reaction process.
Carboranes, polyhedral boron-carbon molecular clus-
ters, possess unique properties including icosahedron ge-
ometry, three-dimensional aromaticity conjugated by σ-
bonds, and inherent robustness.1 These endowments en-
able carboranes as valuable building blocks for applica-
tions ranging from functional materials to pharmaceuti-
cals.2 Moreover, recent research indicates that the func-
tionalization of bioactive molecules with carboranes will
bring in strengthened potencies and new properties.3
However, the progress of this research realm is encum-
bered by the shortage of efficient synthetic methods for
carborane-functionalized molecules. For example, alt-
hough phenol and its derivatives exist extensively in
pharmaceutical drugs, the syntheses of o-carborane-
functionalized phenol derivatives remain challenging,
because of alcohol-induced deboronation of o-car-
boranes under basic conditions.4 Attributing to the re-
cent development in transition metal catalyzed cage B-H
activation, vertex-specific functionalization of car-
boranes has been realized at different BH vertices.5 In
spite of this, most of the established protocols require no-
ble transition metal catalysts6 and an excess amount of
chemical oxidants (e.g. silver salts),7 which compromises
the atom-economy and generality. In this connection, the
exploration of synthetic methodologies with great con-
sideration of atom-economy, sustainability and environ-
mentally friendliness is eagerly desired for the function-
alization of carboranes.
reductants. Taking these points into consideration and
on the basis of our previous study on Cu-promoted cage
B-H activation of carboranes,9 we initiated a proof-of-
principle study using a combination of base metal catal-
ysis and electrochemistry10,11 for the functionalization of
carboranes. We disclose herein the first example of cop-
per-catalyzed electrochemical regioselective cage B-H
oxygenation of o-carboranes with alkoxide or phenoxide
(Scheme 1). The key features of current strategy include
(a) replacement of chemical oxidants (e.g. silver salts)
with electricity, (b) employment of earth abundant cop-
per salt as catalyst, (c) room-temperature B-H oxygena-
tion, and (d) use of removable directing group.
Scheme 1. Transition Metal Catalyzed B-H Function-
alization of o-Carborane
The past several years have witnessed a renaissance of
electrochemistry in organic synthesis.8 Due to the merits
of stability, storability and readily availability, electricity
is an important alternative form of energy to facilitate
chemical transformations. Furthermore, in comparison
with thermal energy and solar energy, electricity can
serve as infinite electron pool and electron hole, and thus
enable redox reactions without any external oxidants or
To evaluate the feasibility of the strategy of electro-
chemical copper catalysis, carboranyl amide 1aa was cho-
sen as the model compound. Under constant electric cur-
rent (4.0 mA), treatment of 1aa with LiOtBu in the pres-
ence of 30 mol% Cu(OTf)2 at room temperature for 12 h
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afforded the target cage B(4)-oxygenated product 3aa in
Scheme 2. Evaluation of Bidentate Directing Groups
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2
3
4
5
6
7
8
60% isolated yield (entry 1, Table 1). To our delight,
switching the cell membrane from AMI-7001 to P4 sin-
tered glass led to a dramatically increased yield of 86%
for 3aa (entry 2, Table 1). Reducing the loading of copper
catalyst resulted in decreased yields for 3aa (entries 2-4,
Table 1). Only trace amount of target product was ob-
served, when Pt electrode was used as the anode instead
of RVC one (RVC = reticulated vitreous carbon) (entry 6,
Table 1). Other coupling partners such as NaOtBu and
KOtBu gave no desired products, as they induced the de-
boronation,4 suggestive of the crucial role of Li+ ion (en-
tries 7 and 8, Table 1). In addition, both copper catalyst
and electricity were proved to be essential for this cross-
coupling (entries 9 and 10, Table 1). In view of the yield of
3aa and the reaction efficiency, entry 3 in Table 1 was cho-
sen as the optimal reaction conditions (see Table S1 in the
SI for more screening tests).
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a
Reactions were conducted in divided cell separated by
P4 sintered glass membrane with a RVC anode and a Pt cath-
ode at 25 oC and 4.0 mA for 12 h. Anode: 1 (0.2 mmol), 2a (5.0
equiv, 1.0 mmol), Cu(OTf)2 (20 mol%, 0.04 mmol),
nBu4NOTf (0.5 mmol, 2.5 equiv) and THF (2 mL). Cathode:
nBu4NOTf (0.5 mmol, 2.5 equiv) and THF (2 mL).
The substrate scope was subsequently explored under
the optimal reaction conditions using 8-aminoquinoline
(AQ) as the directing group. A variety of substituents on
cage C(2) including alkyls and phenyl worked well to af-
ford the desired products 3 in 83%-96% isolated yields
(Table 2). Sterically bulky group such as iPr also gave the
corresponding product 3ac in 84% yield. It was noted
that primary and secondary alkoxides were not compati-
ble with this reaction because of deboronation of the
cage.4
Table 1. Optimization of reaction conditionsa
entry cat. (mol %)
MOtBu (equiv)
LiOtBu (5)
LiOtBu (5)
LiOtBu (5)
LiOtBu (5)
LiOtBu (3)
LiOtBu (5)
NaOtBu (5)
KOtBu (5)
LiOtBu (5)
LiOtBu (5)
3aab (%)
60
1c
30
30
20
10
Table 2. Electrochemical Cage B-H Oxygenation with
2
86
Lithium tert-Butoxidea
3
84
4
68
5
6d
20
20
20
20
-
18
<5
7
N.R.
N.R.
N.R.
8
8
9
10e
20
a Reactions were conducted at 0.2 mmol scale in divided cell
separated by P4 sintered glass membrane, 1 and 2 in anode
cell, 2 mL of THF and 0.5 mmol nBu4NOTf in each cell. b Iso-
lated yield. c AMI-7001 membrane was employed to separate
anode and cathode. d Pt anode was employed. e No electric
current.
a
Reactions were conducted in divided cell separated by
P4 sintered glass membrane with a RVC anode and a Pt cath-
ode at 25 oC and 4.0 mA for 12 h. Anode: 1 (0.2 mmol), 2 (5.0
equiv, 1.0 mmol), Cu(OTf)2 (20 mol%, 0.04 mmol),
nBu4NOTf (0.5 mmol, 2.5 equiv) and THF (2 mL). Cathode:
nBu4NOTf (0.5 mmol, 2.5 equiv) and THF (2 mL).
With the optimized conditions in hand, other biden-
tate directing groups were examined for such electro-
chemical copper-catalyzed B-H oxygenation (Scheme 2).
Interestingly, the use of (pyridin-2-yl)isopropyl (PIP) am-
ide auxiliary produced B(4,5)-dioxygenated carboranes
(4da) in 74% isolated yield (Scheme 2), which may be as-
cribed to the Thorpe-Ingold effect of PIP.12 This result il-
lustrates an important role of the directing groups in
mono-/di-selectivity of the reaction.
Under the same reaction conditions aforementioned,
treatment of carboranyl amide 1aa with lithium pheno-
late gave, however, a mixture of mono- and di-pheno-
lated products. After extensive screening (see Table S2 in
the SI for detail), the optimal reaction conditions were
able to be identified (Table 3). Accordingly, a new class of
B(4,5)-diphenolated o-carboranes 6 were synthesized,
and the results were compiled in Table 3. No obvious
electronic effects were observed. Lithium phenolates
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with either electron-donating or electron-withdrawing
substitutes served as competent coupling partners, giving
6 in 57%-79% isolated yields (6aa to 6ap, Table 3). It was
noteworthy that this cross-coupling was tolerant of many
functional groups including –F, –Cl, –Br, –I, –SMe, –OMe
and –COOMe. Substrates bearing naphthalene, tetrahy-
dronaphtnelene, indane and benzodioxole rings per-
formed well to deliver the corresponding 6aq to 6au in
very good isolated yields. Estrone, one of three major en-
dogenous estrogens, was also compatible with this reac-
tion to give its carborane derivative 6av in 58% yield, fur-
ther illustrating the generality of this protocol. The rea-
son why the reaction stopped at di-substitution may be
attributable to steric reasons. The planar structure of AQ
could accommodate two phenoxy units, but only one
OtBu.
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Table 3. Electrochemical Cage B-H Oxygenation with Lithium Phenoxides a
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a Reactions were conducted in divided cell separated by P4 sintered glass membrane with a RVC anode and a Pt cathode at 25
oC and 4.0 mA for 12 h. Anode: 1ac (0.20 mmol), 5 (8.0 equiv, 1.6 mmol), LiOtBu (2 equiv, 0.4 mmol), Cu(OTf)2 (50 mol%, 0.1 mmol),
nBu4NOTf (0.75 mmol, 3.75 equiv) and THF (2 mL). Cathode: nBu4NOTf (0.75 mmol,3.75 equiv) and THF (2 mL).
The transformations of the products (3aa, 4da, 3af
and 6aa) were also studied. Treatment of 3aa or 4da with
HCl (conc.) at 120 oC for 12 h gave the B(4)-hydroxylated
o-carborane 7 or B(4,5)-dihydroxylated o-carborane 8 in
quantitative yields (Scheme 3a,b). Furthermore, the 8-
aminoquinoline (AQ) bidentate directing group was eas-
ily removed by heating 3af or 6aa with K2CO3 in THF,
generating 9af or 10aa in 81% or 88% isolated yield
(Scheme 3c,d).12c In this regard, -CONH-AQ can serve as
a traceless directing group for the functionalization of o-
carboranes.
Compounds 3, 4, 6, 7, 8, 9 and 10 were fully character-
ized by 1H, 13C, and 11B NMR spectroscopy as well as high-
resolution mass spectrometry (see the Supporting Infor-
mation for detail). The molecular structures of 3aa, 3af,
4da, 6ac, 6ae, 6an, 9af and 10aa were further confirmed
by single-crystal X-ray analyses.
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Scheme 3. Transformations of 3aa,4da, 3af and 6aa
sence of electric current, the employment of O2 as the ox-
1
2
3
4
5
6
7
8
idant offered a yield of 35% for 3aa (Scheme 4a). Without
electric current and O2, 20% Cu(OTf)2 led to the for-
mation of 3aa in 8% yield (entry 10, Table 1). These results
indicated that a high valent Cu(III) species, generated by
the oxidation of O2 or via disproportionation of cop-
per(II) salt, [2Cu(II)  Cu(I) + Cu(III)],13 may be involved
in the reaction. On the other hand, the addition of radical
scavengers such as TEMPO (2,2,6,6-tetramethyl-1-piperi-
dinyloxy) or Ph2C=CH2 to the reaction mixture brought
in negligible influences on the formation of the product
(Scheme 4b), suggesting that the radical process might
not be involved in the reaction pathway.
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Scheme 4. Control Experiments
To gain some insights into the reaction mechanism,
several control experiments were performed. In the ab-
Scheme 5. Plausible Reaction Mechanism
On the basis of the aforementioned experimental re-
sults and literature reports,9,13 a plausible reaction mech-
anism is proposed in Scheme 5. Bidentate chelation of 1
with Cu(OTf)2 followed by salt metathesis reaction gives
an intermediate A.9 Anodic oxidation occurs to generate
an active Cu(III) species B.13 Electrophilic attack of the
Cu(III) center at the relatively electron rich B(4)-H af-
fords the intermediate C, which undergoes reductive
elimination and protonation to give the B(4)-monooxy-
genated product 3. Anodic oxidation of Cu(I) in D to
Cu(II) finishes the catalytic cycle. Such a cycle repeats to
generate the B(4,5)-dioxygenated product 4 or 6. It is
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In summary, the first example of Cu-catalyzed elec-
trochemical selective B-H oxygenation of o-carboranes
has been realized under constant electric current at room
temperature, resulting in the facile synthesis of a series of
B(4)-monooxygenated and B(4,5)-diphenolated car-
borane derivatives in an economy, sustainable and green
manner. The strategy of merging base metal catalysis
with electrochemistry in this research opens up new ave-
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boron clusters. This work will also provide useful refer-
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synthesis.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization of the products
(PDF)
Crystal structures (CIF)
AUTHOR INFORMATION
Corresponding Author
* yjquan@cuhk.edu.hk
* zxie@cuhk.edu.hk
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by grants from the Research Grants
Council of HKSAR (Project No. 14305918) and NSFC/RGC
Joint Research Scheme (Project No. N_CUHK402/18). We are
thankful for the financial support from Innovation and
Technology Commission (HKSAR) to the State Key Labora-
tory of Synthetic Chemistry.
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