Bromomethyl Silicate: A Robust Methylene Transfer Reagent for Radical-Polar Crossover Cyclopropanation of Alkenes

Article abstract of DOI:10.1002/ejoc.202000134

A general protocol for visible-light-induced cyclopropanation of alkenes was developed with bromomethyl silicate as a methylene transfer reagent, offering a robust tool for accessing highly valuable cyclopropanes. In addition to α-aryl or methyl-substituted Michael acceptors and styrene derivatives, the unactivated 1,1-dialkyl ethylenes were also shown to be viable substrates. Apart from realizing the cyclopropanation of terminal alkenes, the methyl transfer reaction has been further demonstrated to be amenable to the internal olefins. The photocatalytic cyclopropanation of 1,3-bis(1-arylethenyl)benzenes was also achieved, giving polycyclopropane derivatives in excellent yields. With late-stage cyclopropanation as the key strategy, the synthetic utility of this transformation was also demonstrated by the total synthesis of LG100268.

Full text of DOI:10.1002/ejoc.202000134

A Journal of
Accepted Article
Title: Bromomethyl Silicate: A Robust Methylene Transfer Reagent for
Radical-Polar Crossover Cyclopropanation of Alkenes
Authors: Wenping Luo, Yewen Fang, Li Zhang, Tianhang Xu, Yongjun
Liu, Yan Li, Xiaoping Jin, Jiakan Bao, Xiaodong Wu, and
Zongyong Zhang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000134
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000134
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10.1002/ejoc.202000134
European Journal of Organic Chemistry
COMMUNICATION
Bromomethyl Silicate: A Robust Methylene Transfer Reagent
for Radical-Polar Crossover Cyclopropanation of Alkenes
Wenping Luo,a Yewen Fang,b,* Li Zhang,c Tianhang Xu,b Yongjun Liu,a Yan Li,a,* Xiaoping Jin,c,* Jiakan
Bao,b Xiaodong Wu,b and Zongyong Zhangb
[a]
W. Luo, Y. Liu, Prof. Dr. Y. Li
Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials and Ministry-of-Education Key Laboratory for Synthesis and Application of
Organic Functional Molecules
Hubei University
No. 368 Youyi Dadao, Wuhan 430062, China
Email: liyanok@hubu.edu.cn
[b]
[c]
Prof. Dr. Y. Fang, T. Xu, J. Bao, X. Wu, Z. Zhang
School of Materials and Chemical Engineering
Ningbo University of Technology
No. 201 Fenghua Road, Ningbo 315211, China
E-mail: fang@nbut.edu.cn
Dr. L. Zhang, Prof. Dr. X. Jin
Department of Pharmaceutical Engineering
Zhejiang Pharmaceutical College
No. 888 Yinxian Avenue East, Ningbo 315100, China
E-mail: jinxp@mail.zjpc.net.cn
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
general
protocol
for
visible-light-induced
(Scheme 1a).[11] In contrast to the above reductive generation of
iodomethyl radical, the general access of halomethyl radical was
realized via oxidative SET process with halosilicate as the
methylene source (Scheme 1b).[12,13] Of note, these
cyclopropanation reactions based on photooxidative generation
of halomethyl radical proceed efficiently via redox-neutral
radical-polar crossover[14] without any aid of external additives.
Due to the superior leaving group ability of iodide over bromide
and chloride, the use of high reactive iodomethyl radical has
more opportunities to prevent the formation of the undesired
noncyclized Giese-type addition product.[13] During our recent
investigation of nucleofuge character of halides, at least 10-
times higher reactivity of bromide compared with chloride was
observed in the 3-exo-tet cyclization.[12b] Furthermore, compared
to chloromethyl and iodomethyl radicals, a good balance
between atom economy and cyclization efficiency could be
expected employing the less investigated bromomethyl radical
as a bifunctional C1 reagent. With this idea in hand, we set out
to explore the application of bromomethyl silicate as the CH2
source in photoredox-catalyzed cyclopropanation of alkenes.
cyclopropanation of alkenes was developed with bromomethyl
silicate as a methylene transfer reagent, offering a robust tool for
accessing highly valuable cyclopropanes. In addition to α-aryl or
methyl substituted Michael acceptors and styrene derivatives, the
unactivated 1,1-dialkyl ethylenes were also shown to be viable
substrates. Apart from realizing the cyclopropanation of terminal
alkenes, the methyl transfer reaction has been furtherly
demonstrated to be amenable to the internal olefines. The
photocatalytic cyclopropanation of 1,3-bis(1-arylethenyl)benzenes
was also achieved, giving polycyclopropane derivatives in excellent
yields. With late-stage cyclopropanation as the key strategy, the
synthetic utility of this transformation was also demonstrated by the
total synthesis of LG100268.
Due to the facile generation and termination of radicals in
sustainable way during photoredox catalysis process,
photocatalytic single electron transfer (SET) reactions are
becoming increasingly prevalent over the past decade.[1]
Consequently, spectacular progress dealing with SET process
has been achieved in the development of versatile radical
precursors,[2] new photocatalysts,[3] asymmetric photoredox
catalysis,[4] merging photoredox with other catalysis,[5]
application of new technology,[6] and mechanism investigations.[7]
Among these numerous efforts devoting to the visible-light-
driven photoredox catalysis, development and application of
practical and efficient organic transformations are always in high
demand.[8]
Efficient strategy that allows for
a rapid and selective
construction of strained pharmacophores represents valuable
tools for drug discovery and high throughput screenings (Figure
1).[9] Recently, we and other groups devoted significant efforts to
the cyclopropanation of alkenes by means of photoredox
catalysis.[10] Surprisingly, only a few general and successful
methods were described concerning alkene cyclopropanation
with a methylene transfer reagent. In 2017, Suero and co-
Figure 1. Examples of biologically active cyclopropane-containing molecules.
workers reported
a
photocatalytic methodology for the
stereoconvergent cyclopropanation of styrene derivatives and
Michael acceptors using diiodomethane as a methylene source
1
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10.1002/ejoc.202000134
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Cyclopropanation of Michael acceptors and styrene
derivatives.[a,b]
Scheme 1. Generation of halomethyl radical and the applications in
cyclopropanation reactions.
Bis-catecholato bromomethyl silicate 3 was easily obtained
from
the
reaction
of
the
readily
prepared
in the
bromomethyltrimethoxysilane 1[13] with catechol
2
presence of 18-crown-6 and potassium methoxide in methanol
(eq 1).[15] Bromomethyl silicate 3 was isolated in 88% yield
without any chromatography as free-flowing and bench-stable
powder.
[a] Reaction conditions: a reaction mixture of 4 (0.2 mmol), 3 (0.4 mmol), [Ir] (2
mol %), and DMSO (6.0 mL) was irradiated by 9 W blue LEDs for 24 h at room
temperature (cooling with a fan). [Ir]: Ir[dF(CF3)ppy]2(dtbbpy)PF6.
[b] Isolated yield.
With bis-catecholato bromomethyl silicate
3
in hand,
[c] bis-catecholato chloromethyl silicate (2.0 equiv) was used instead of 3.
photocatalytic cyclopropanation of vinylphosphonates[16] with 3
as the methylene source was initially explored for modular
synthesis of cyclopropylphosphonates (Table 1). Gratifyingly, 1-
aryl substituted cyclopropylphosphonates 5a-e were cleanly
prepared under our previous reported reaction conditions (2
mol % Ir[dF(CF3)ppy]2(dtbbpy)PF6, 9 W blue LEDs irradiation,
yields. α,β-Unsaturated amides were converted to their
cyclopropanes 5p-q in high efficiency. Of note, compared to the
formation of 1-phenylcyclopropylnitrile 5r, higher efficiency for
the preparation of 5s containing ortho-bromo substituted arene
was observed. Interestingly, this methylene transfer reaction
could be further extended to the cyclopropanation of α-
phenylacrolein, giving 5t in 69% yield. Vinylsulfone also reacted
with 3 to produce 5u in 78% yield. In addition to the above α-aryl
substituted Michael acceptors, 2-methyl-1-phenyl-2-propenone
and benzyl 2-methylacrylate were also shown to be viable
substrates, giving 5v and 5w in 71% and 60% yields,
respectively. In the case of the reaction of 4-chlorostyrene
derivatives, low yield of the cyclopropane product 5x was
DMSO, 24 h). Regardless of the electron-donating or
-
withdrawing characters of the substituents on the aromatic ring,
no contamination of the undesired noncyclized Giese-type
addition product was observed.[12a] Furthermore, the protocol
was extended to the access of cyclopropylketones which can be
found in a number of bioactive substances by exalting crucial
hydrophobic interactions.[17] In addition to the efficient formation
of 5f from 2-phenyl-1-buten-3-one, 2-methoxyphenyl substituted
methyl vinyl ketone was nicely cyclopropanated to
cyclopropylketone 5g in 66% yield. Moreover, the
cyclopropanaiton was also suitable for 2-aryl-1-buten-3-one
containing halogens on aryl group, producing 5h-j in 63-65%
yields. 2-Naphtyl acetylcyclopropane 5k could be efficiently
accessed in 75% yield. In addition, cyclopropylketones 5l and
5m were prepared from 2-phenyl substituted vinyl isopropyl
ketone and vinyl phenyl ketone, respectively. After realizing
obtained,
plauged
by
the
possible
formation
of
polymers/oligomers. Clearly, incorporation of an alkyl or aryl
substituent at the α-position of 4-chlorostyrene has a positive
effect for the efficiency of cyclopropanation. 1,1-Diarylethylenes
exceptionally worked well, affording 1,1-diaryl cyclopropanes 5z
and 5aa' in high yields. Interestingly, chloromethyl silicate[12a]
was a suitable methylene source for the cyclorpropanation of
1,1-diaryethylenes, giving 5z and 5aa' in 91% and 90% yields,
respectively. Of note, no cyclopropanation of 1,1-
diphenylethylene could be observed with CH2I2 as the CH2
source via radical addition-SH2 cyclization process.[11a]
cyclopropanation
of
α,β-unsaturated
ketones,
the
cyclopropanation of 2-phenyl substituted acrylates was also
successful, delivering cyclopropylcarboxylates 5n-o in 55-65%
2
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10.1002/ejoc.202000134
European Journal of Organic Chemistry
COMMUNICATION
In light of the exceptional mildness of the photocatalytic
conditions, we embarked on the cyclopropanation of polyalkenes.
Notably, the cyclopropanation of 1,3-bis(1-arylethenyl)benzenes
10 produced bis(cyclopropane) derivatives 11 in 88-95% yields
in the presence of 3 mol% iridium catalyst with 4.0 equivalent
bromomethyl silicate 3 (eq 2). These results showcase the
promising application of the present protocol in the preparation
of polycyclopropanes.[18]
Scheme 2. Cyclopropanation of 1,1-dialkyl ethylenes. a) Isolated yield. b) The
conversions given in parentheses were determined by 1H NMR analysis of the
crude reaction mixture. c) NMR yield (500 MHz) was reported by use of p-
nitroacetophenone as an internal standard.
Synthetic utility of this methylene transfer reaction has been
demonstrated by the total synthesis of LG100268, being a high
affinity, selective retinoid X receptor (RXR) agonist (Scheme
3).[19] The requisite N-tosylhydrazone 14[20] was prepared in 2
steps with commercially available 1,1,4,4,6-pentamethyl-1,2,3,4-
tetrahydronaphthalene 12 as the starting material. Fortunately,
the coupling of hydrazone 14 with ethyl 6-bromoronicotinate
furnished the expected 1,1-diarylethylene 15 in 78% yield in the
presence of a catalytic amount of both PdCl2(CH3CN)2 and t-
Bu2(Me)PHBF4. Nicely, 15 underwent smooth cyclopropanation
to give 16 in 86% yield under the standard reaction conditions.
Meanwhile, chloromethyl silicate was aslo demonstrated to be
viable methylene source, producing 16 in 74% yield. The
LG100268 17 was obtained in 93% yield by simple hydrolysis of
the resulting diarylcyclopropane 16.
After achieving the cyclopropanation of Michael acceptors and
styrene derivatives, the unactivated 1,1-dialkyl ethylenes were
subjected to the present methylene transfer reaction conditions.
To the best of our knowledge, there is no literature precedent for
CH2 transfer reaction of 1,1-dialkyl ethylenes by means of
photoredox
catalysis.
Impressively,
the
expected
spirocyclopropanes 7a and 7b were accessed in good yields
(Scheme 2). Unfortunately, their full conversions were not
achieved by varying the reaction parameters (catalyst loading,
reaction time, and equivalent of bromomethyl silicate). It is worth
noting that no 7a could be observed with chloromethyl silicate as
the methylene source under similar conditions.
Apart from realizing the cyclopropanation of terminal alkenes 4
and 6, the methyl transfer reaction has been furtherly
demonstrated to be amenable to the internal olefines 8 (Table 2).
Generally, the double bond geometry of 8 was retained during
cyclopropanation. With (E)-β-phenyl substituted Michael
acceptors as the substrate, trans-cyclopropanes 9a-c were
isolated in 26-72% yields. Furtherly, efficient cyclopropanation
could be realized employing trisubstituted alkenes, delivering
diphenyl substituted 9d-g in 53-70% yields. As a further
extension, assembling polycyclic structures bearing cyclopropyl
motif was also successful, giving 9h-j in moderate to high yields.
Interestingly, spirocyclopropane 9k was easily prepared in 70%
yield. As a limitation, the tetrasubstituted 1,1-dimethyl-2,2-
diphenylethene was not suitable for this cyclopropanation
protocol.
Scheme 3. Synthesis of LG100268. Reagent and conditions: a) CH3COCl,
AlCl3, CH2Cl2, 5 h, reflux, 96%; b) TsNHNH2, CH3OH, 2 h, reflux, 82%; c) ethyl
6-bromonicotinate, Pd(CH3CN)2Cl2, t-Bu2(Me)PHBF4, t-BuOLi, dioxane, 90 oC,
3 h, 78%; d) 3, [Ir], 9 W blue LEDs, DMSO, 24 h, rt, 86%; e) NaOH, MeOH, 12
h, reflux, 93%.
Table 2. Methylene transfer reaction of internal alkenes.[a]
In conclusion, with easily accessible bromomethyl silicate as
the methylene transfer reagent, cyclopropanation of an array of
alkenes has been reported by means of photoredox-neutral
catalysis. With radical-polar crossover process as the strategy
for the cyclopropanation of alkenes, various Michael acceptors
and styrene derivatives were demonstrated to be viable
substrates. The unactivated electron-rich 1,1-dialkyl ethylenes
were also successfully transformed into the corresponding
cyclopropanes. We have also realized that this methylene
transfer reaction was efficient to construct bis(cyclopropane)
derivative in one pot with diene as the substrate. The reactions
are operationally simple and tolerate a diversity of functional
groups under photoredox-catalyzed mild conditions. New
applications of bromomethyl silicate as a bifunctional C1
feedstock will be reported in due course.
[a] Isolated yield.
[b]
The reaction was run with 3 (3.0 equiv) in the presence of [Ir] (3 mol %) for
72 h.
[c]
Yield of 9j was determined by 1H NMR integration against p-
nitroacetophenone as an internal standard.
3
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10.1002/ejoc.202000134
European Journal of Organic Chemistry
COMMUNICATION
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Experimental Section
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To an oven dried transparent 10 mL Schlenk tube equipped with
stirring bar, Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (4.5 mg, 0.004 mmol,
0.02
equiv),
potassium
[18-C-6]
bis(catecholato)bromomethylsilicate (3) (256.6 mg, 0.4 mmol, 2
equiv), and the corresponding alkene (0.2 mmol, 1.0 equiv) were
added. The tube was evacuated and filled with nitrogen for 3
times. The tube was then charged with degassed DMSO (6.0
mL, 0.033 M) via a syringe. The tube was irradiated with a 9 W
blue LED light strip spiraled within a bowel for 24 h (cooling with
a fan). After the reaction was complete, the reaction solution
was diluted with saturated Na2CO3 aqueous solution (10.0 mL),
and was extracted with EtOAc (4 x 10 mL). The organic layers
were combined and dried over MgSO4, concentrated in vacuo.
Flash chromatography over silica gel afforded the product.
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This work was supported by the Zhejiang Provincial Natural
Science Foundation of China (No. LY20B020008), the Ningbo
Natural Science Foundation (Nos. 2019A610130 and
2019A610203), Science and Technology Innovation 2025 Major
Project of Ningbo (No. 2019B10112), and the National Training
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Programs
Undergraduates.
Chaozhong Li (SIOC) for valuable discussions.
for
Innovation
The authors
and
Entrepreneurship
acknowledge Professor
for
Keywords: photoredox • bromomethyl radical • redox-neutral •
radical-polar crossover • cyclopropanation
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4
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10.1002/ejoc.202000134
European Journal of Organic Chemistry
COMMUNICATION
Cyclopropanation
A new bifunctional C1 synthon: With bromomethyl silicate as a CH2 source, visible-light-induced cyclopropanation has been
demonstrated to be amenable to the alkenes including Michael acceptors, styrene derivatives, and unactivated 1,1-dialkyl ethylenes.
In addition to the broad substrate scope, this radical-polar crossover process is also characterized by its redox-neutral process , mild
conditions, and good functional-group compatibility.
5
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