Nickel-Catalyzed Boron Insertion into the C2-O Bond of Benzofurans

Article abstract of DOI:10.1021/jacs.6b10255

Treatment of benzofurans with bis(pinacolato)diboron and Cs₂CO₃ under nickel-NHC catalysis resulted in the insertion of a boron atom into the C2-O bond of benzofurans to afford the corresponding oxaborins. The scope of benzofuran substrates is wide, and the reactions proceeded without loss of functional groups such as fluoro, methoxy, and ester that are potentially reactive under nickel catalysis. The boron-inserted products proved to be useful building blocks and subsequently underwent a series of transformations, one of which led to the synthesis of fluorescent π-expanded oxaborins.

Full text of DOI:10.1021/jacs.6b10255

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Communication
Nickel-Catalyzed Boron Insertion into the C2–O Bond of Benzofurans
Hayate Saito, Shinya Otsuka, Keisuke Nogi, and Hideki Yorimitsu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b10255 • Publication Date (Web): 11 Nov 2016
Downloaded from http://pubs.acs.org on November 11, 2016
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NickelꢀCatalyzed Boron Insertion into the C2–O Bond of Benzofuꢀ
rans
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Hayate Saito, Shinya Otsuka, Keisuke Nogi, and Hideki Yorimitsu*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyoꢀku, Kyoto 606ꢀ8502, Japan.
Dedicated to Prof. Takayuki Kawashima on the occasion of his 70th birthday
Supporting Information Placeholder
Despite the everꢀexpanding utility of πꢀconjugated boracycles,
ABSTRACT:
Treatment
of
benzofurans
with
methods to implant a boron atom into a πꢀsystem remain still
limited, undesirably requiring highly Lewis acidic boron halides
and/or reactive organometallic reagents as well as harsh condiꢀ
tions and laborious synthetic procedures.7 New strategies to conꢀ
struct πꢀconjugated boracyclic skeletons have been demanded.
Recently we have been interested in “aromatic metamorphosis”,
which represents a transformation of one aromatic system to anꢀ
other cyclic skeleton through partial disassembly of the starting
aromatic ring.9,10 In this context, here we report nickelꢀcatalyzed
boron insertion into the C2–O bond of benzofurans to construct
benzoxaborin skeletons in one step. This is the first example of a
catalytic introduction of a boron atom into a heteroaromatic ring
through breaking its aromaticity. Such insertion of a boron atom
into a heteroaromatic skeleton would represent an ideally straightꢀ
forward approach to πꢀconjugated boracycles.
bis(pinacolato)diboron and Cs2CO3 under nickelꢀNHC catalysis
resulted in the insertion of a boron atom into the C2–O bond of
benzofurans to afford the corresponding oxaborins. The scope of
benzofuran substrates is wide, and the reactions proceeded withꢀ
out loss of functional groups such as fluoro, methoxy, and ester
that are potentially reactive under nickel catalysis. The boronꢀ
inserted products proved to be useful building blocks and subseꢀ
quently underwent a series of transformations, one of which led to
the synthesis of fluorescent πꢀexpanded oxaborins.
Organoboron compounds are definitely important in modern
organic chemistry due to their various roles such as synthetic
building blocks,1 functional materials,2 and bioꢀrelated agents.3
Especially, πꢀconjugated boracycles have been attracting increasꢀ
ing attention. Some of them can serve as fascinating “boronꢀ
doped” organic materials that utilize the vacant p orbital of boron
for dramatic electronic alteration (Figure 1a).4 Others find medicꢀ
inal or biological applications as exemplified by saccharide senꢀ
sors or antimicrobial agents (Figure 1b).5 From an organometallic
viewpoint, borabenzene derivatives, generally called borins, also
constitute an intriguing class of πꢀconjugated boracycles (Figure
1c).6–8 Among them, 2Hꢀoxaborins7 are emerging as new attracꢀ
tive boracycles also as synthetic intermediates,7h–l and fluorescent
materials.4d,7m–p
Furan derivatives are known to undergo catalytic ringꢀopening
arylation and alkylation with organometallic reagents.11 Although
heteroaromatic cores including benzofuran have never been utiꢀ
lized for ringꢀopening borylation, the recent progress of the
Miyaura ipsoꢀborylation12,13 of inert bonds such as C–F,14 C–O,15
and C–S16 bonds encouraged us to tackle this challenge.17
After optimization of reaction conditions (vide infra), the
borylation of the C2–O bond of benzofuran (1a) was conducted in
the presence of NiCl2(PPh3)IPr18 (IPr
=
1,3ꢀbis(2,6ꢀ
a catalyst,
diisopropylphenyl)imidazolꢀ2ꢀylidene)
as
bis(pinacolato)diboron (B2(pin)2), and Cs2CO3 in toluene at
100 °C (Scheme 1). After acidic workup, a boronꢀinserted prodꢀ
uct, oxaborin 2a, was obtained as the sole identified product. The
Figure 1. Representative πꢀConjugated Boracycles
structure of 2a was confirmed by H and 13C NMR, HRMS, and
1
(a)
O
O
OMe
MeO
B
Xꢀray crystallographic analysis (See Supporting Information).
Importantly, (E)ꢀ2ꢀ[2ꢀ(pinacolatoboryl)ethenyl]phenol, which
would be a possible borylation product according to the previous
alkylation and arylation,11a,e was not observed at all.
IPr was found to be the best ligand and other Nꢀheterocyclic
carbenes and phosphines worked yet with lower efficiencies (Taꢀ
Ar
N
N+
Ar
B–
B
F
F
2,4,6ꢀiꢀPr3C6H2
B
BODIPY
O
O
fluorescent dye
fluoride sensing
ambipolar conductive
H
ble S1 in Supporting Information).
The precoordinated
(c)
(b)
NiCl2(PPh3)IPr complex proved to be superior to mixing Ni(cod)2
and IPr•HCl in situ. Cs2CO3 was the most suitable activator and
other bases served with less efficiencies (Table S2). The choice of
B2(pin)2 was crucial, and other diboron reagents such as
bis(neopentylglycolato)diboron and bis(catecholato)diboron were
totally ineffective (Table S3). Nonpolar toluene is the best solꢀ
vent among tested (Table S4). Ethereal solvents gave marginal
results and polar solvents such as DMF and acetonitrile supꢀ
pressed the reaction.
OH
B
N
1,2ꢀdihydroꢀ
O
O
B
1,2ꢀazaborine
F
H
n
AN2690
O
N+
O
B
B–
antifungal
O
2Hꢀoxaborin
OH
H
H
B
SO2R
N
N
B
B
1,2ꢀdihydroꢀ
1,2ꢀdiborin
fluorescent sensing
for saccharides
S
H
With the optimal conditions in hand, we investigated the scope
of benzofurans 1 (Scheme 1).19,20 Notably, the boron insertion
reactions of 1b, 1e, 1h, and 1j proceeded smoothly without loss of
antibacterial
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their functional groups such as methoxy, ester, and fluoro that are
A plausible reaction mechanism is shown in Scheme 2. As the
1
2
3
4
5
6
7
8
potentially reactive under nickel catalysis. A tꢀbutyldimethylsilyl
ether protection satisfactorily resisted possible C–O bond cleavꢀ
age as well as desilylation to yield 2c. A diethyl acetal unit also
survived under the borylation conditions, and after acidic workup,
the corresponding 4ꢀformylphenylꢀsubstituted oxaborin 2l was
obtained in good yield. Unfortunately, a benzofuran with an unꢀ
protected formyl group did not undergo the reaction. Furthermore,
πꢀextended naphthofurans 1m–1o were also applicable to the
boron insertion to afford tricyclic naphthoxaborin cores. Altꢀ
hough steric hindrance at the 2ꢀposition of the benzofuran ring in
1p lowered reactivity, employing less bulky 1,3ꢀbis(2,4,6ꢀ
trimethylphenyl)imidazolꢀ2ꢀylidene (IMes) as a ligand instead of
IPr improved the yield of 2p. Although a methyl group at the 7ꢀ
position in 1q slightly decreased the yield of 2q, twofold catalyst
loading (10 mol %) gave a favorable result. Attempts to convert
3ꢀsubstituted benzofurans resulted in poor yields.
initial step, B2(pin)2 should reduce the Ni(II) precatalyst to IPrꢀ
Ni(0) species mediated by Cs2CO3. Oxidative addition of the C2–
O bond of benzofuran 1 to IPrꢀNi(0) would give oxanickelacycle
1ꢀNi.21,22 This regioselective pseudovinylic C–O bond cleavage
was in accordance with the known Niꢀcatalyzed arylation reacꢀ
tions of benzofurans.11 Subsequent transmetalation with B2(pin)2
would generate cyclic nickelate intermediate 1ꢀNiꢀB. C–B bondꢀ
forming reductive elimination followed by intramolecular B–O
bond formation would furnish the corresponding spirocyclic boꢀ
rate 2' and regenerate the IPrꢀNi(0). Another possible mechanism
consists of oxidative addition of diboron to nickel,
borylnickelation of the C2–C3 double bond of benzofuran, and βꢀ
oxygen elimination. As oxidative addition of a B–B bond to
Ni(0) is unknown, we are tempted to support the mechanism
shown in Scheme 2. Hydrolysis of 2' upon acidic workup should
give benzoxaborin 2. Ionic borate 2' indeed precipitated out of
the reaction medium and could be collected by filtration before
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1
aqueous workup, which allowed us to characterize 2a' by the H
Scheme 1. Scope of Benzofurans
1.5 equiv B2(pin)2
NMR analysis of 2a' in CD3CN.23
5 mol % NiCl2(PPh3)IPr
3.0 equiv Cs2CO3
The products, oxaborins 2 or spirocyclic borates 2', underwent
a variety of transformations as shown below, which highlights
their synthetic utility.
O
OH
O
B
toluene, 100 °C, 12 h
then acidic workup
R
R
1
2
Scheme 3. Transformations of Oxaborins
(a) protonation
5ꢀsubstituted benzofurans
F
R = H
OMe
2a: 75%
2b: 68%
2c: 72%
2d: 76%
2e: 74%
O
O
2j: 61%a
2k: 68%
OH
H
B–
2g: 76%
O
OSitBuMe2
NPh2
CO2Me
AcOH/toluene
100 °C, 10 h
Ph
OMe
CF3
Ph
2g' (reaction mixture)
3g: 52% from 1g
2h: 75%a
OEt
OEt
(b) iodination
N
O
NMe2
O
2f: 79%
OH
O
B–
1.5 equiv I2
2l: 64%b
O
2i: 84%
THF/toluene/H2O
r.t., 5 h
I
πꢀextended benzofurans
sterically demanding benzofurans
2a' (reaction mixture)
4a: 52% from 1a
O
OH
B
O
OH
Me
B
(c) carbonylation
2m: 62%
CO (balloon)
1.0 equiv Pd(OAc)2
O
OH
O
O
2p: 55%a
B
O
O
OH
2n: 72%a
B
73%c
DMSO/MeOH
r.t., 20 h
5a: 60% from 1a
Me
2a (crude mixture)
O
OH
(d) crossꢀcoupling
B
1) 5 mol % Pd(PPh3)4
2.0 equiv PhI
Ph
OH
OMe
Ph
MeCN/toluene
80 °C, 4 h
O
B–
B
2q: 71%a
O
2o: 81%a
O
b
a10 mol % of catalyst was used. The product 2l was obtained as
R
2) excess MeI
40 °C, 2 h
R
c
6a (R = H)
the corresponding aldehyde after acidic workup. 10 mol % of
2a' or 2e'
(reaction mixture)
69%, E/Z = 1/13
6e (R = CO2Me)
68%, E/Z = 1/6.3
Ni(cod)2 and IMes•HCl were used as a catalyst.
(from 1a or 1e over 3 steps)
Scheme 2. Presumable Reaction Mechanism
II
CsCO3 B(pin)
2
+
+
IPrNi Cl2(PPh3)
Oxaborins 2 are fairly stable under acidic conditions at room
temperature due to their cyclic structure. However, protonolysis
proceeded at 100 °C upon addition of acetic acid, for instance, to
the reaction mixture including 2g' to provide oꢀvinylphenol 3g
(Scheme 3a). This twoꢀstep transformation corresponds to formal
hydrogenolysis of the C2–O bond of benzofuran.
2 B2(pin)2 + 2 Cs2CO3
2 CsCl + B2(pin)2
Ni0ꢀIPr
1
Cs+
O
O
ꢀ
B
O
Iodinolysis24 of the C–B bond of 2a' proceeded in the presence
of I2, affording (E)ꢀoꢀhydroxyꢀβꢀiodostylene (4a) with inversion
of the stereochemistry25 (Scheme 3b).
Cs+
IPr
O
R
R
IPr
2'
H3O+
ꢀ
O
NiII
NiII
B(pin)
R
Palladiumꢀassisted carbonylation reaction of the C–B bond of
2a under a CO atmosphere took place and following intramolecuꢀ
lar cyclization gave coumarin (5a) in 60% yield based on 1a
(Scheme 3c).26,27 The coumarin synthesis via oxaborin 2a is conꢀ
R
1-Ni-B
1-Ni
O
OH
B
CsCO3 B(pin)
B2(pin)2 + Cs2CO3
2
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sidered to be formal carbonyl insertion into benzofuran and is
important as a proofꢀofꢀconcept.
This work was supported by JSPS KAKENHI Grant Numbers
JP23655037, JP24685007, JP25107002, JP16H01019,
1
2
3
4
5
6
7
8
The SuzukiꢀMiyaura coupling of 2a' or 2e' in the reaction mixꢀ
ture with iodobenzene was successful in one pot with retention of
stereochemistry to selectively yield (Z)ꢀ6a or (Z)ꢀ6e after subseꢀ
quent methylation of the reactive hydroxy group (Scheme 3d).
This oneꢀpot transformation proceeded with mild reagents and is
thus advantageous over the known ringꢀopening arylation of benꢀ
zofurans with organolithium or magnesium reagents.11
Interest in πꢀextended oxaborins has been surging due to their
intriguing photophysical properties.4d,7m–p According to Lerner’s
report,7p 9ꢀarylꢀ10,9ꢀoxaboraphenanthrenes bearing an exocyclic
arylꢀboron bond serve as luminescent fluorophores. Thus, we
expected that replacement of the hydroxy group on the boron
atom of 2 with an aryl group would be an attractive method for
the synthesis of oxaborinꢀbased fluorescent molecules. Chlorinaꢀ
tion of the B–OH bond of naphthoxaborin 2o smoothly took place
with BCl3, followed by arylation with arylmagnesium bromide
provided 7 (Scheme 4). Although 2o did not display fluorescence,
7 exhibited strong blue fluorescence with a quantum yield of 40%
(See SI, Figure S1). DFT calculations of 7 (Figure S1) show that
the naphthoxaborin core and the tolyl substituent are coplanar at
the optimized structure and well conjugated. The HOMO and
LUMO of 7 were calculated to be widely delocalized, ranging
from the naphthalene core to the tolyl group through the oxaborin
unit.
JP16H01149, and JP16H04109 as well as by ACTꢀC, JST. H.Y.
thanks Japan Association for Chemical Innovation, Tokuyama
Science Foundation, and The Naito Foundation for financial supꢀ
port. K.N. thanks The Kyoto University Research Fund for
Young Scientists (Startꢀup) FY 2016. S.O. acknowledges JSPS
Predoctoral Fellowship.
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Scheme 4. Exocyclic Arylation of 2o
Me
3.0 equiv BCl
toluene
1)
3
O
O
OH
B
B
100 °C, 4 h
2.0 equiv pꢀTolMgBr
2)
7: 53%
2o
In conclusion, we have developed the first example of catalytic
boron insertion into an aromatic core, taking advantage of a Niꢀ
NHC catalyst. The boron insertion has proved to show reasonable
chemoselectivity while this nickel catalysis breaks the aromaticity
of benzofuran. The resulting organoboron compounds underwent
various transformations such as carbonylation and arylation,
thereby being synthetically useful building blocks. Replacement
of the exocyclic hydroxy group of 2 with an aryl group resulted in
the synthesis of a new blueꢀemitting compound. In light of the
unparalleled importance of organoboron compounds as synthetic
intermediates as well as functional materials and bioactive comꢀ
pounds, this boron insertion strategy will be a powerful means to
create new and/or useful boracycles of importance.28
ASSOCIATED CONTENT
Supporting Information
Optimization of conditions, experimental procedures, characteriꢀ
zation data, and photophysical property and computational details
of 7. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*yori@kuchem.kyotoꢀu.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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(18) Matsubara, K.; Ueno, K.; Shibata, Y. Organometallics 2006, 25,
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(19) Hydroxyoxaborins and their anhydrides are known to be in equiꢀ
librium in organic solvents. For this equilibrium, see reference 7g. Beꢀ
cause of this unavoidable equilibrium, the NMR spectra of 2 always
showed additional signals that originate from the anhydride as "impurity".
For more details, see Supporting Information. The yields of boronꢀ
inserted products were based on the molar weights of 2, without considerꢀ
ing the possible presence of their anhydrides.
(20) Moderate yields, except for 2p (low conversion), resulted from
generations of several unidentified byproducts and from some loss of the
products during purification due to their high affinity to silica gel. Benzoꢀ
furans 1 were almost fully converted.
(21) We performed a stoichiometric reaction of 1g with Ni(cod)2/IPr
without B2(pin)2 and Cs2CO3 followed by acidic workup. The expected oꢀ
vinylphenol 3g was not detected and most of benzofuran 1g was recovered.
(22) The boron insertion reaction of benzofuran (1a) in the presence of
phenyl vinyl ether resulted in recovery of 1a, formation of an only 4%
yield of 2a, and formation of a considerable amount of phenol that implies
the generation of the volatile and somewhat unstable vinylboronate. Pheꢀ
nyl vinyl ether is proved to be more reactive than benzofuran under the
borylation conditions.
(23) The vinylic protons of 2a' moved upfield compared with 2a due to
the increased electron density of the oxaborin core. In addition, the two
singlets corresponding to the methyl groups of the pinacol moiety were
observed (See Supporting Information).
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(25) We assume the inversion of the stereochemistry is due to facile
isomerization of the initially formed (Z)ꢀisomer by the action of I2 or acid.
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(27) Methyl transꢀoꢀhydroxycinnamate was obtained as a byproduct in
11% yield.
(28) Attempts to insert a boron atom into dibenzofuran, 2ꢀbenzylfuran,
2,3ꢀdihydrofuran, and 2,3ꢀdihydrobenzofuran under the nickel catalysis
failed, and no desired products were observed. Attempted boron insertion
into benzothiophene resulted in giving a complex mixture. Development
of such boron insertion reactions is under investigation in our group.
(14) For Rh catalysts, see: (a) Kalläne, S. I.; Teltewskoi, M.; Braun, T.;
Braun, B. Organometallics 2015, 34, 1156. (b) Guo, W.ꢀH.; Min, Q.ꢀQ.;
Gu, J.ꢀW.; Zhang, X. Angew. Chem. Int. Ed. 2015, 54, 9075. For a Ni
catalyst, see: (c) Liu, X.ꢀW.; Echavarren, J.; Zarate, C.; Martin, R. J. Am.
Chem. Soc. 2015, 137, 12470. For Ni/Cu cocatalysts, see: (d) Niwa, T.;
Ochiai, H.; Watanabe, Y.; Hosoya, T. J. Am. Chem. Soc. 2015, 137, 14313.
(15) For a Rh catalyst, see: (a) Kinuta, H.; Tobisu, M.; Chatani, N. J.
Am. Chem. Soc. 2015, 137, 1593. For a Ni catalyst, see: (b) Zarate, C.;
Manzano, R.; Martin, R. J. Am. Chem. Soc. 2015, 137, 6754.
(16) For a Rh catalyst, see: (a) Uetaka, Y.; Niwa, T.; Hosoya, T. Org.
Lett. 2016, 18, 2758. For a Pd catalyst, see: (b) Bhanuchandra, M.; Baralle,
A.; Otsuka, S.; Nogi, K.; Yorimitsu, H.; Osuka, A. Org. Lett. 2016, 18,
2966.
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