Ring-opening 1,3-arylboration of arylcyclopropanes mediated by BCl3

Article abstract of DOI:10.1039/d0ra08151e

Herein, we report a ring-opening 1,3-arylboration of aryl cyclopropanes using BCl3 in the presence of arene nucleophiles. Formal 1,3-oxy arylation and 1,3-amino arylation of the arylcyclopropane via one-pot derivatization of the installed boron group were also achieved.

Full text of DOI:10.1039/d0ra08151e

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Ring-opening 1,3-arylboration of
arylcyclopropanes mediated by BCl3†
Cite this: RSC Adv., 2020, 10, 37797
*
Yuichi Kuboki, Mitsuhiro Arisawa and Kenichi Murai
Received 31st August 2020
Accepted 7th October 2020
Herein, we report a ring-opening 1,3-arylboration of aryl cyclopropanes using BCl3 in the presence of arene
nucleophiles. Formal 1,3-oxy arylation and 1,3-amino arylation of the arylcyclopropane via one-pot
derivatization of the installed boron group were also achieved.
DOI: 10.1039/d0ra08151e
rsc.li/rsc-advances
Cyclopropane derivatives are versatile building blocks in limited to a hydrogen atom. Inspired by these works, we sought
organic synthesis used frequently. Transformations utilizing to develop a new 1,3-functionalization of cyclopropanes.
their ring strain and unique reactivity have been actively Herein, we report a ring-opening 1,3-arylboration of aryl cyclo-
studied.1–3 Among them, the ring-opening reaction is one of the propanes using BCl3 in the presence of arene nucleophiles
important transformations that provide synthetically useful 1,3- (Scheme 1c).
functionalized molecules. The cyclopropane ring-opening
We began our study on the ring-opening 1,3-arylboration of
strategy mainly utilizes donor–acceptor cyclopropanes due to cyclopropanes using cyclopropylbenzene (1a) and toluene (10
their high reactivity.2 The transition metal-mediated process is equiv.) as a model reaction (Table 1). The use of BCl3 in CH2Cl2
also used for cyclopropanes bearing a chelating group that can at room temperature was not effective, and allylbenzene was
coordinate to transition metals.3 On the other hand, the ring- mainly obtained (entry 1). Allylbenzene is considered to be
opening 1,3-functionalization reaction of simply substituted produced through a formation of benzyl cation via C–C bond
cyclopropane, such as aryl-substituted cyclopropane, has not cleavage by BCl3, a formation of homobenzyl cation by 1,2-
been studied so much. Recently, ring-opening of cyclopropane hydride migration, and subsequent dissociation of the boron
by phosphine/borane frustrated Lewis pairs,4 1,3-amino- group.13 On the other hand, when the reaction was carried out at
uorination by N–F reagents,5 1,3-oxyuorination and 1,3- ꢀ30 ꢁC, the formation of allylbenzene was suppressed, and the
diuorination by uoroiodine reagents,6 1,3-dioxygenation by desired 1,3-arylborated product 2a was isolated in 11% yield via
hypervalent iodine reagent,7 oxo-amination by photoredox in situ formations of the pinacol boronate ester by treatment
catalysis,8 and 1,3-hydrosilylation by silylium-ion9 have been with pinacol and triethylamine (entry 2). Encouraged by these
successfully reported. However, the development of new ring- results, we further investigated different borane reagents for the
opening 1,3-functionalization reactions of simply substituted reaction. When BBr3 was used, 2a was not produced. Instead,
cyclopropanes is still signicant due to the limited variety of
functional groups that can be introduced.
Recently, the methods using boron halides as a borane
source has been actively studied and applied to metal-free
electrophilic borylation reaction with arenes, heteroarenes,
alkynes, and alkenes.10 In this context, Shi and Houk have
successfully developed a ring-opening 1,3-hydroboration of
cyclopropanes using BBr3 in the presence of PhSiH3 (Scheme
1a).11 On the other hand, ring-opening 1,3-hydroarylation of
monosubstituted cyclopropanes, including simply substituted
cyclopropanes, was developed by Rowley and Moran. This
reaction has been accomplished using catalytic TfOH in
1,1,1,3,3,3-hexauoro-2-propanol (HFIP) (Scheme 1b).12 Both
methods are useful, but one functional group introduced is
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka, 565-0871, Japan. E-mail: murai@phs.osaka-u.ac.jp
† Electronic supplementary information (ESI) available. See DOI:
Scheme 1 1,3-Functionalization reactions of arylcyclopropanes.
RSC Adv., 2020, 10, 37797–37799 | 37797
10.1039/d0ra08151e
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Table 1 Study of reaction conditions
Table 2 Scope of aryl cyclopropanes
Entry Reagent (equiv.)
Temp. (ꢁC) Time (h) Yield (%)
1b
2
BCl3 (1.1)
BCl3 (1.1)
BBr3 (1.1)
rt
2
5
Trace
11
ꢀ30
3
ꢀ30
10
10
10
48
48
48
48
48
48
N.D.c
N.R.d
N.R.d
45
4b
5b
6
B-Bromocatecholborane (1.1) ꢀ30
BF3$OEt2 (1.1)
BCl3 (1.1)
BCl3 (1.1)
BCl3 (1.1)
BCl3 (3.0)
BCl3 (5.0)
BCl3 (5.0)
ꢀ30
ꢀ30
ꢀ20
ꢀ40
ꢀ30
ꢀ30
ꢀ30
7
8
9
31
Trace
66
81
62
10
11e
a
b
c
p : o ¼ >20 : 1. Pinacol and NEt3 were not treated. Not detected.
d
No reaction. e Toluene (5 equiv.).
allylbenzene was formed even at low temperature (entry 3). The
use of B-bromocatecholborane or BF3$OEt2 was also not effec-
tive (entries 4 and 5). From these results, BCl3 was found to be
an optimal reagent. Then, we investigated the reaction time and
reaction temperature in detail. It was found that extending the
reaction time to 48 hours improves the yield to 45% (entry 6).
On the other hand, further studies on the reaction temperature
did not improve the yield (entries 7 and 8). Finally, it was found
that the amount of BCl3 used is essential for improving the
efficiency of the reaction (entry 9 and 10), and when ve
equivalent of BCl3 was used, compound 2a was obtained in 81%
yield. Regarding the amount of nucleophile, the yield was
decreased when the amount of toluene was reduced to 5
equivalent (entry 11). Therefore, the optimal reaction condi-
tions found for the 1,3-arylboration of arylcyclopropane
involved treatment with BCl3 (5 equiv.) in CH2Cl2 in the pres-
ence of toluene (10 equiv.).
a
Ratio of p : o. b Ratio of b : a.
tBu benzene, and biphenyl provided the corresponding prod-
ucts 2g–2k in good yield. The reaction with 1,2,3,4-tetrahy-
dronaphthalene also proceeded to give 2l regioselectively.
One-pot derivatization using the installed boron group was
also studied in addition to converting it into pinacol boronic
esters for isolation. As shown in Scheme 2, oxidative workup of
the C–B bond using hydrogen peroxide under basic conditions
readily furnished alcohol 4 in excellent yield from 1a. Also, the
treatment of 3 with benzyl azide gave secondary amine 5 in 64%
With optimized conditions in hand, we investigated the
substrate scope of this transformation (Table 2). p-tBu cyclo-
propylbenzene and 2-cyclopropylnaphthalene gave 2b and 2c in
moderate to excellent yields. In contrast, p-PhO cyclo-
propylbenzene gave only a 16% yield, showing that the oxygen
atom in the substrate could not be preferable for the reaction,
probably due to the high affinity of oxygen atom toward BCl3.
On the other hand, bromo or chloro substituted aryl cyclopro-
panes worked well (2e, 2f). We also studied the scope of
nucleophiles with 1a. The reactions using benzene were rst
examined, but it was found that benzene gave a complex
mixture (not shown in table). It is probably because the nucle-
ophilicity of cyclopropylbenzene was relatively higher than that
of benzene. Therefore, we focused on a series of alkyl-
substituted benzenes. p-Xylene, mesitylene, p-Et benzene, p-
Scheme 2 Formal 1,3-oxy arylation and 1,3-amino arylation. Condi-
tions for 4: 1a (0.20 mmol), BCl3 (1.0 mmol), toluene (2.0 mmol),
CH2Cl2 (1.2 mL), ꢀ30 ꢁC, 48 h then 2 M NaOH/30% H2O2 (1.5 mL, 1 : 1
v/v), 0 ꢁC, 3 h; conditions for 5: 1a (0.20 mmol), BCl3 (1.0 mmol),
toluene (2.0 mmol), CH2Cl2 (1.2 mL), ꢀ30 ꢁC, 48 h, then evaporation,
PhCH2N3 (0.4 mmol), CH2Cl2 (1.5 mL), rt, 2 h.
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Scheme 3 Proposed nucleophilic ring-opening of arylcyclopropanes.
yield.14 It should be noted that 3,3-diaryl-propylamine is
a structural motif found in some pharmaceuticals such as fen-
dilline.15 These one-pot transformations can be considered as
a formal 1,3-oxy arylation or 1,3-amino arylation of the arylcy-
clopropane, which has not been reported so far.
A possible reaction mechanism was depicted in Scheme 3.
Given the reported paper,11 this ring-opening 1,3-arylboration is
suggested to proceed in a stepwise manner. That is, the treat-
ment of BCl3 to aryl cyclopropane could generate a zwitterionic
intermediate i. The following nucleophilic addition of an arene
to benzylic cation could give intermediate ii, which is trans-
formed to pinacol borate by the reaction with pinacol and
triethylamine.
In summary, we have developed a method for the 1,3-aryl-
boration of arylcyclopropanes to provide 3,3-diaryl-propyl
boronic esters for the rst time. It was found that BCl3 was
optimal as the boron source in the presence of arene nucleo-
philes. The formal 1,3-oxy arylation and 1,3-amino arylation of
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Chem., Int. Ed., 2020, 59, 1770–1774and references therein.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was nancially supported by a Japan Society for the
Promotion of Science (JSPS) KAKENHI Grant Number
T17K082100 (K. M.) and by a Platform Project for Supporting
Drug Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research (BINDS))
from the AMED under Grant Number JP19am0101084 and
JP20am0101084.
11 D. Wang, X.-S. Xue, K. N. Houk and Z. Shi, Angew. Chem., Int.
Ed., 2018, 57, 16861–16865.
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J. Moran, Chem. Sci., 2018, 9, 6411–6416.
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14 H. C. Brown, A. M. Salunkhe and B. Singaram, J. Org. Chem.,
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