Synthesis of functionalized cyclopropylboronic esters based on a 1,2-metallate rearrangement of cyclopropenylboronate

Article abstract of DOI:10.1039/d0cc07134j

A procedure converting tribromocyclopropane to densely functionalized β-selenocyclopropylboronic ester using the 1,2-metallate rearrangement of a boron ate-complex has been developed. Treatment of an in situ-generated cyclopropenylboronic ester ate-complex with phenylselenenyl chloride triggered stereospecific rearrangement to produce functionalized cyclopropanes. DFT calculations for 1,2-metallate rearrangement suggested that the reaction proceeds through a seleniranium intermediate. This journal is

Full text of DOI:10.1039/d0cc07134j

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Synthesis of functionalized cyclopropylboronic
esters based on a 1,2-metallate rearrangement
of cyclopropenylboronate†
Cite this:DOI: 10.1039/d0cc07134j
Received 28th October 2020,
Accepted 17th November 2020
Haruki Mizoguchi, * Masaya Seriu and Akira Sakakura
*
DOI: 10.1039/d0cc07134j
rsc.li/chemcomm
A procedure converting tribromocyclopropane to densely functio- multiple functional groups and substituents in a simple operation,
nalized b-selenocyclopropylboronic ester using the 1,2-metallate we envisioned the use of 1,2-metallate rearrangement of a boron ate-
rearrangement of a boron ate-complex has been developed. Treat- complex7 in the context of transition metal-free cyclopropene func-
ment of an in situ-generated cyclopropenylboronic ester ate-complex tionalization. Treatment of a vinylboronic ester ate-complex, gener-
with phenylselenenyl chloride triggered stereospecific rearrangement ated from a vinylboronic ester and an organometallic nucleophile,
to produce functionalized cyclopropanes. DFT calculations for 1,2- with an electrophile is known to promote the reaction with p-bonds,
metallate rearrangement suggested that the reaction proceeds through concomitant with migration of a group on the boron atom to a
a seleniranium intermediate.
positively charged adjacent carbon atom (1,2-metallate rearrange-
ment). Although the 1,2-metallate rearrangement of a vinyl-boronic
Cyclopropanes, the smallest of the cycloalkanes, are a ubiqui- ester ate-complex has been actively studied,8 to the best of our
tous structural motif in biologically active molecules.1 Due to knowledge, there have been no reports on the use of strained double
their rigid planer carbocyclic system, the three-dimensional bonds such as in cyclopropene.9
arrangements of their substituents are highly defined and
Our synthetic plan is depicted in Scheme 1B. The one-
programmable. Therefore, cyclopropanes are an important pot three-step process would be initiated by the treatment of
class of compounds for the design of functional materials such
as pharmaceuticals.2
Their utility, as well as their unique physical and chemical
properties derived from the strained ring system, have inspired
chemists to develop methods for the synthesis of highly functiona-
lized cyclopropanes.3 A straightforward method for introducing
multiple substituents to a cyclopropane would be the functionaliza-
tion of cyclopropene.4 The double bond of cyclopropene is highly
strained and reactive. Therefore, transition metal-mediated carbo-
metallation- and hydrometallation-based approaches have been
developed. Considering the high utility of organoboronic esters as
a basis for a variety of bond-forming events, we sought to develop
a novel synthetic method to access cyclopropylboronic esters.5
Although the transition metal-catalyzed stereoselective hydrobora-
tion of cyclopropenes is a known method for preparing cyclopro-
pylboronic esters, their products are limited to relatively simple
compounds (Scheme 1A).6 To develop a method for introducing
Graduate School of Natural Science and Technology, Okayama University,
3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
E-mail: h_mizoguchi@okayama-u.ac.jp, sakakura@okayama-u.ac.jp
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for all new compounds (PDF). CCDC 2025164. For ESI
Scheme 1 Synthesis of cyclopropylboronic esters exploiting the 1,2-metallate
rearrangement of the boron ate-complex.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0cc07134j
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tri-bromocyclopropane 1 with butyllithium (n-BuLi) to generate
cyclopropenyllithium 3.10 3 would then be trapped in situ by an
organoboronic ester (R2–B(pin)) to give cyclopropenylboronic
ester ate-complex 4.11 Activation of the double bond of cyclo-
propene with a soft electrophile would induce 1,2-metallate
rearrangement to give a cyclopropylboronic ester 2. In this
study, we chose phenylselenenyl chloride (PhSeCl) as an elec-
trophile, which has been reported to be a good electrophile to
trigger the 1,2-metallate rearrangement of a vinylboronic ester
ate-complex.12 With the selenium electrophile, the reaction
would proceed through a seleniranium ion 5. Therefore, the
rearrangement was expected to proceed in a stereospecific
manner. During this process, three carbon–bromine bonds
would be converted to a carbon–carbon bond, a carbon–boron
bond, and a carbon–selenium bond in a one-pot process. The
organoselenium groups and organoboronic acids can not only
be converted to other groups, but are also key components of
some bioactive molecules13,14 and organocatalysts.15,16
According to the plan, we started our investigation using
tribromocyclopropane 1a and 4-methoxyphenyl boronic ester as
a substrate (Scheme 2). To our delight, the three-step process
was effective, and, after the cyclopropenylboronate ate-complex
was treated with PhSeCl at À78 1C, b-selenocyclopropylboronic
ester 2a was obtained in 79% yield as a single isomer. The
structure was unambiguously confirmed using X-ray crystallo-
graphic analysis, and the stereochemistry was found to be cis.17
This result suggests that the metallate rearrangement is a
stereospecific process in which a migrating group (4-(MeO)C6H4)
is delivered from the backside of an approaching phenylselenyl
group through a seleniranium ion intermediate, as we expected
in Scheme 1B.
Scheme 3 Synthesis of cyclopropylboronic esters using various boronic
esters.
With the conditions to synthesize cyclopropylboronic esters
in hand, we investigated the scope and limitations of the up to gram scale and 2b was obtained in 84% yield. The position of
substrates. First, we explored a variety of boronic esters the substituents did not affect the effectiveness of the process, and
(Scheme 3). In addition to an electron-rich aromatic group meta- and ortho-substituted arenes were introduced to the cyclo-
(2a), electron-neutral and electron-deficient aryl groups were propanes (2e, 2f). Boronic esters with more complex aromatics such
also tolerated to give the corresponding cyclopropylboronic as a 2-naphthyl group and an amide-substituted arene also afforded
esters in good yield (2b–2d). The reaction could be easily scaled the corresponding cyclopropanes in good yields (2g, 2h). In addi-
tion to aryl boronic esters, alkyl boronic esters were also effective
substrates, and cyclopropanes possessing silyl ether (2i) and cyclo-
pentane (2j) were obtained. Furthermore, even in the presence of
reactive olefins such as furyl- and isopropenyl-groups, the reaction
with PhSeCl predominantly occurred at the strained cyclopropene
to induce metallate rearrangement, and cyclopropanes 2k and 2l
were obtained, albeit in lower yield.18
The scope of tribromocyclopropane was also explored
(Scheme 4). The substrate possessing silyl ether afforded 2m in
67% yield. In addition, an adamantyl group adjacent to the
cyclopropane ring as a bulky substituent was also tolerated and
the corresponding cyclopropylboronic ester 2n was obtained,
although the yield was moderate. Tribromocyclopropane with
an aryl substituent was also applicable, however, the yield was
not satisfactory. In addition to the monocyclic substrate, the
reaction of tribromocyclopropane fused to a cycloheptane ring
proceeded in a stereoselective fashion to afford compound 2p
X-ray structure (grey: carbon, red: oxygen, pink: boron, orange: selenium). bearing a bicyclo[5.1.0]octane skeleton as a single diastereomer.
Scheme 2 Optimized reaction conditions for the synthesis of 2a, and its
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Scheme 6 Oxidation of cyclopropylboronic ester 2b.
(19.8 kcal molÀ1), which might be driven by the release of ring-
strain of the cyclopropene. The lithium ion initially coordinates
to a pinacol moiety and a selenium atom, apparently directing
the electrophile close to the ate-complex. During the course of
the reaction, lithium begins to interact with a chloride atom,
and ultimately, lithium chloride would be formed. From
IM-3, 1,2-metallate rearrangement occurs to afford IM-4, a
b-seleno-cyclopropylboronic ester complexed with lithium
chloride via TS-2. This rearrangement is also highly exothermic
(62.6 kcal molÀ1), with an activation barrier of 5.1 kcal molÀ1
,
and again releases ring strain. The calculated results strongly
suggest that the selenium-induced 1,2-metallate rearrangement
proceeds through a seleniranium intermediate, as we expected.
Also, opening of the seleniranium ring and 1,2-migration seem to
proceed in a concerted manner. This observation is consistent
Scheme 4 Synthesis of cyclopropylboronic esters using various tribromo-
cyclopropanes.
The electrophile for this type of metallate rearrangement
was not limited only to the selenium electrophile (Scheme 5).
A sulfur electrophile, N-(phenylthio)phthalimide,19 could also
induce the rearrangement and b-selenocyclopropylboronic
ester 6a was obtained in 36% yield (unoptimized).
Derivatization of the obtained cyclopropylboronic ester was also
examined (Scheme 6). Treatment of boronic ester 2b with sodium
perborate resulted in a selective oxidation of carbon–boron bonds
in the presence of the oxidation sensitive selenoether group to
afford cyclopropylalcohol 7 in good yield.
To obtain further insight into the reaction mechanism, 1,2-
metallate rearrangement was analyzed by density functional
theory (DFT) calculations for a simplified ate-complex and
methylselenenyl chloride as a starting point (IM-1, Fig. 1).20
According to the calculations, the reaction would be initiated by
the formation of complex IM-2 followed by the generation of
seleniranium intermediate IM-3 via TS-1 with an activation
barrier of 1.3 kcal molÀ1. This step is an exothermic process
Fig. 1 Calculated reaction coordinates for selenenyl chloride-induced
1,2-metallate rearrangement. Optimized geometry was calculated using
DFT (B3LYP-D3BJ/6-31G(d)). DG values are in kcal molÀ1, calculated using
DFT (B3LYP-D3BJ/6-311+G(d,p); SMD solvation model with Et2O). Calcu-
lated structures are shown with the following color code: grey: carbon,
red: oxygen, pink: boron, orange: selenium, purple: lithium, green:
chloride.
Scheme 5 The metallate rearrangement induced by N-(phenylthio)
phthalimide.
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as single diastereomers.
In conclusion, we developed a concise protocol for the synthesis
of densely functionalized cyclopropylboronic esters from simple
tribromocyclopropanes. PhSeCl-induced 1,2-metallate rearrange-
ment of the cyclopropenylboronic ester ate-complex proceeded
smoothly at À78 1C in a stereospecific manner to produce
b-selenocyclopropylboronic esters in good yield. Over the course
of the reaction, three carbon–bromide bonds were converted to a
carbon–carbon bond, a carbon–borane bond, and a carbon–sele-
nium bond. DFT calculations for the 1,2-metallate rearrangement
step suggested that the reaction proceeds through the formation of
a seleniranium intermediate. The process was highly exothermic
through a transition state with low activation barrier, probably due
to the high ring strain of cyclopropene and the corresponding
seleniranium species. Application of this strain release 1,2-
metallate rearrangement to other electrophiles is currently being
investigated in our laboratory.
This work was supported by a Grant-in-Aid from JSPS
KAKENHI (19K21128, 20K15282), and a grant from the Uehara
Memorial Foundation. The authors gratefully thank the Divi-
sion of Instrumental Analysis, Department of Instrumental
Analysis & Cryogenics, Advanced Science Research Center,
Okayama University, for the NMR and HRMS measurements.
The authors are grateful to Dr Hiromi Ota at the Division of
Instrumental Analysis for the X-ray single-crystal structural
analyses. The authors are grateful to Dr Koichi Mitsudo
(Okayama University) for useful discussions regarding DFT
calculations.
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17 CCDC 2025164 contains the supplementary crystallographic data for
this paper†.
There are no conflicts to declare.
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20 See the Supporting Information for details†.
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