Photoredox-Catalyzed Cyclopropanation of 1,1-Disubstituted Alkenes via Radical-Polar Crossover Process

Article abstract of DOI:10.1002/adsc.201900708

The photoredox-neutral catalyzed cyclopropanation of 1,1-disubstituted alkenes via radical addition-anionic cyclization cascade has been successfully developed. Another new protocol based on photocatalytic allylation and cyclopropanation cascade was also described between allylic halide and halomethyl radical. In addition to the successful use of bis-catecholato silicates as the alkyl radical precursors, the acyl and alkyl radicals derived from 1,4-dihydropyridines were also engaged in this radical-polar crossover process. The competing experiments displayed that the 3-exo-tet mode of cyclization preferred over 4-exo and 5-exo cyclization modes, allowing for the selective 3-exo-tet cyclization. The superior nucleofuge character of bromide over chloride and tosylate has been demonstrated in the reaction of bromomethyl radical with homoallylic (pseudo)halides. This new protocol is characterized by its redox-neutral process, broad substrate scope, mild conditions, and good functional-group compatibility. (Figure presented.).

Full text of DOI:10.1002/adsc.201900708

Title: Photoredox-Catalyzed Cyclopropanation of 1,1-Disubstituted
Alkenes via Radical-Polar Crossover Process
Authors: Wenping Luo, Yi Yang, Yewen Fang, Xinxin Zhang, Xiaoping
Jin, Guicai Zhao, Li Zhang, Yan Li, Wanli Zhou, Tingting Xia,
and Bin Chen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900708
Link to VoR: http://dx.doi.org/10.1002/adsc.201900708

10.1002/adsc.201900708
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Photoredox-Catalyzed Cyclopropanation of 1,1-Disubstituted Alkenes
via Radical-Polar Crossover Process
Wenping Luo,c Yi Yang,a Yewen Fang,a,* Xinxin Zhang,a Xiaoping Jin,b,* Guicai Zhao,a
Li Zhang,b Yan Li,c,* Wanli Zhou,a Tingting Xia,a and Bin Chena
a
School of Materials and Chemical Engineering, Ningbo University of Technology, No. 201 Fenghua Road, Ningbo
315211, China E-mail: fang@nbut.edu.cn
Department of Pharmaceutical Engineering, Zhejiang Pharmaceutical College, No. 888 Yinxian Avenue East, Ningbo
b
315100, China E-mail: jinxp@mail.zjpc.net.cn
Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials and Ministry-of-Education Key
c
Laboratory for Synthesis and Application of Organic Functional Molecules, Hubei University, No. 368 Youyi Dadao,
Wuhan 430062, China E-mail: liyanok@hubu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
and bench-stable radical precursors involving visible-
cyclopropanation of 1,1-disubstituted alkenes via radical light-mediated SET process is especially attractive. In
Abstract:
The
photoredox-neutral
catalyzed
addition-anionic cyclization cascade has been successfully
developed. Another new protocol based on photocatalytic
allylation and cyclopropanation cascade was also described
between allylic halide and halomethyl radical. In addition
to the successful use of bis-catecholato silicates as the alkyl
radical precursors, the acyl and alkyl radicals derived from
1,4-dihydropyridines were also engaged in this radical-
polar crossover process. The competing experiments
displayed that the 3-exo-tet mode of cyclization preferred
over 4-exo and 5-exo cyclization modes, allowing for the
selective 3-exo-tet cyclization. The superior nucleofuge
character of bromide over chloride and tosylate has been
demonstrated in the reaction of bromomethyl radical with
homoallylic (pseudo)halides. This new protocol is
characterized by its redox-neutral process, broad substrate
scope, mild conditions, and good functional-group
compatibility.
2015, Guo and co-workers reported a visible light
induced generation of carbanion via a double single-
electron reduction and its application in
cyclopropanation of alkenes (Scheme 1a).[6]
A
photocatalytic cyclopropanation reaction of styrene
derivatives and α,β-unsaturated carbonyl compounds
using diiodomethane as methylene transfer reagent
was successfully developed by Sureo and co-workers
(Scheme 1b).[7] Recently, we[8] and other group[9]
a) polar pathway
b) radical process
Keywords: alkene cyclopropanation; photoredox catalysis;
homoallylic (pseudo)halide; radical-polar crossover
c) radical-polar crossover process
Owing to the easy access of highly reactive radical
intermediates via single-electron transfer (SET)
between an excited photoredox catalyst and a radical
precursor,
methodologies have been developed based on visible-
light photoredox Consequently,
catalysis.[1]
a
wide array of novel synthetic
significant efforts using modern photocatalysis were
devoted to the formation of cyclopropanes,[2] which
represent an important structural motif in many
natural products and pharmaceuticals.[3] Compared to
the stepwise formation of cyclopropanes based on
atom transfer radical addition of α-halocarbonyls to
olefins[4] and the radical cation cycloaddition between
alkene and diazo species,[5] cyclopropanation of
alkenes with radicals derived from easily accessible
Scheme 1. Photoredox-catalyzed cyclopropanation of
alkenes.
1
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10.1002/adsc.201900708
Advanced Synthesis & Catalysis
described the successful application of radical-polar
crossover process for the modular synthesis of
functionalized cyclopropanes under visible-light-
mediated photoredox-neutral catalysis (Scheme 1c,
path I). The photoredox-neutral crossover process
proceeded via radical addition and anionic cyclization
cascade in contrast to the previous polar pathway[6]
and radical process.[7]
The
cyclopropylphosphonates
and
cyclopropylphosphonic acids are important cyclic
structural motifs and found in many useful
biologically
active
natural
interesting
products
and
pharmacologically
compounds.[10]
However, compared to the available methods for the
preparation of 1-aryl cyclopropylphosphonates,[8,11]
the general access to 1-alkyl substituted
cyclopropylphosphonates is still limited. We recently
reported a new method for the preparation of 1-aryl
cyclopropylphosphonates via photoredox neutral-
catalyzed cyclopropanation of vinylphosphonates
with chloromethyl silicate as the methylene source
(Scheme 1c, path I).[8] Inspired by our interest in the
application of radical-polar crossover process[8,12]
based on radical addition to vinylphosphonates,[13] we
envisioned that the intermediate of γ-halo-α-
phosphoryl carbanion for the 3-exo-tet cyclization
could be accessible via alkyl radical addition to 1,1-
disubstituted alkenes and the following single-
electron reduction (Scheme 1c, path II).[14] Moreover,
the photoredox-catalyzed allylation/cyclopropanation
cascade reaction would be realized via radical
addition/fragmentation of allylic halides with
halomethyl radical followed by radical addition-polar
cyclization between the excess halomethyl radical
and homoallylic halide generated in situ (Scheme 1c,
path III). Clearly, these new radical-polar crossover
processes would enable the quick modular synthesis
of 1-akyl substituted cyclopropylphosphonates.
Moreover, these new methods would represent a
complementary strategy to our reported procedure,[8]
featuring the readily available alkyl radicals, mild
reaction conditions, and easy preparation of 1-alkyl
Table 1. Optimization of reaction conditions.[a]
Entry
Deviation from standard Yield of 3a
condition[a]
(%)[b]
1
None
In DMF
In DMA
In THF
82
21
33
Trace
Trace
74
18
17
0
2[c]
3[c]
4[c]
5[c]
6
In CH3CN
4CzIPN instead of [Ir]
[Ru] instead of [Ir]
Eosin Y instead of [Ir]
Without light
No [Ir]
7[c]
8[c]
9[d]
10
0
0
11[e]
TEMPO (5 equiv)
[a]
Reaction conditions: a reaction mixture of 1a (0.2
mmol), 2a (0.4 mmol), [Ir] (2 mol %), and DMSO (6 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; [Ru]: [Ru(bpy)3](PF6)2.
[b] Yield of the isolated product 3a.
[c]
NMR yield (500 MHz) was reported by use of p-
nitroacetophenone as an internal standard.
[d] The reaction was run in the dark.
[e] TEMPO (1 mmol) was added.
cyclopropylphosphonates
and
other
various
photocatalyst
1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
dicyanobenzen (4CzIPN)[16] with a long lived excited
state and a high oxidative potential also effective,
albeit in somewhat low yield (Table 1, entry 6).
Control experiments confirmed that both the
photocatalyst and the light are necessary (Table 1,
entries 9-10). Furthermore, the cylclopropanation
process was completely surpressed in the presence of
a radical scavenger (5 equiv of TEMPO) (Table 1,
entry 11).
functionalized cyclopropanes.
In addition to the easy access, high stability, and
low oxidation potential, bis-catecholato silicates are
very reliable radical precursors for the generation of
highly
reactive
primary
radicals.[15]
With
vinylphosphoante 1a and n-octylsilicate 2a as the
model substrates, we first employed the similar
reaction conditions developed in our previous
report[8] (2 mol % Ir[dF(CF3)ppy]2(dtbbpy)PF6, 9 W
blue LEDs irradiation, DMSO, 24 h) (Table 1, entry
1). Delightfully, the expected product 3a was isolated
in 82% yield, validating the hypothesis that radical
addition-polar cyclization cascade would be a nice
strategy for the preparation of the 1-alkyl
cyclopropylphosphonate. Clearly, the influence of
solvent on the reaction efficiency was significant.
The choice of DMSO as the solvent is crucial for the
high yield of 3a (Table 1, entries 1-5). The organic
With the optimized reaction conditions in hand
(Table 1, entry 1), we turned our attention to
investigating the substrate scope of the radical
acceptors and alkyl silicates and the results were
summarized in Table 2. Generally, the primary
radical derived from alkyl silicate 2 could be
successfully engaged as highlighted by the formation
of
product
3.
A
set
of
1-alkyl
cyclopropylphosphonates 3f-j bearing various
functional groups (OAc, Cl, CN, CF3) could be
2
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10.1002/adsc.201900708
Advanced Synthesis & Catalysis
Table 2. Cyclopropanation of Michael acceptors.[a, b]
Table 3. Cyclopropanation of styrene derivatives.[a, b]
[a]
Reaction conditions: a reaction mixture of 1 (0.2
mmol), 2 (0.4 mmol), [Ir] (2 mol %), and DMSO (6 mL)
was irradiated by 9 W blue LEDs for 24 h at room
temperature (cooling with a fan).
[a] Reaction conditions: a reaction mixture of 4 (0.2 mmol),
2 (0.4 mmol), [Ir] (2 mol %), and DMSO (6 mL) was
irradiated by 9 W blue LEDs for 24 h at room temperature
(cooling with a fan).
[b] Yield of the isolated product 3.
[b] Yield of the isolated product 5.
efficiently prepared. Notably, the efficiency of this
radical-polar crossover process is highly dependent
on the employment of the radical precursor. The 4-
cylclohexyl-1,4-dihydropyridine[17] afforded the
expected product 3k with a yield of 35% compared to
the 87% yield from cyclohexyl silicate. The reaction
proved to work perfectly with α-amino-stabilized
primary radical to produce a diverse array of γ-amino
cyclopropylphosphonates 3l-q in high yields. Notably,
in addition to homoallylic halides, the corresponding
sulfonate esters are also ideal substrates for this
crossover process, producing 3n in high yield. The
successful reaction of homoallylic sulfonates could
ensure the cyclization to proceed via intramolecular
nucleophilic substitution, discarding SH2 process.
Additionally, the reaction was found to be amenable
to vinylsulfone, giving 3r in 91% yield. Moreover,
using aminosilicate as the alkyl radical source,
various acrylate olefins were well accommodated
under this photocatalytic cascade reaction, giving 3s-
u in 70-88% yields.
(5j). Satisfyingly, homoallylic (pseudo)halides
bearing five- and six-membered-ring heterocycles
worked
well,
giving
the
corresponding
heteroaromatic substituted cyclopropanes 5k-n in 55-
94% yields. These results revealed that the stabilized
benzylic radical intermediate via Giese-type addition
of alkyl radical to a styrene derivative could undergo
efficient single-electron reduction prior to the ring
closure.
After realizing the successful cyclopropanation of
1,1-disubstituted alkenes, we envisioned that the
employed homoallylic halides could be generated in
situ via radical allylation of allylic halides with
halomethyl radicals. Consequently, the cylclopropane
would be accessible via radical allylation-
cyclopropanation cascade between allylic halide and
excess halomethyl radical. Pleasingly, chloromethyl
radical could nicely engage in the proposed cascade
reaction,
giving
expected
chloro-containing
In addition to various Michael acceptors, styrene
derivatives were also capable substrates. Generally,
this radical-polar crossover process proved to be
relatively insensitive to the electronics of the
aromatic ring. Investigations of aryl substituted
homoallylic (pesudo)halide scope demonstrated that
electron-neutral (5a-c) and electron-rich arenes
containing methyl (5d-e) and methoxy (5f)
functionality may be employed in high yields.
Moreover, electron-deficient groups including
fluoride (5j), chloride (5h), and ester (5i) were also
well tolerated. Notably, the efficiency of the reaction
was not impeded by ortho substituent on the aryl ring
cyclopropanes (3g, 9, and 10) in 60-71% yields
(Scheme 2). In addition to chloromethyl radical, the
corresponding bromomethyl radical derived from 7
and 8 displayed similar reactivity, giving 11 in 65%
and 63% yields, respectively. Of note, with this
allylation-cyclopropanation cascade as the strategy,
the halo substitutents (Cl, Br) could be easily
incorporated into the chain of cyclopropanes, which
are
possible
reactive
sites
for
further
functionalizations via various reliable cross-coupling
reactions. Notably, compared to the various examples
3
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10.1002/adsc.201900708
Advanced Synthesis & Catalysis
be easily accessible via the two different reactions of
homoallylic bromide 1b with chloromethyl radical
and homoallylic chloride 1a with bromomethyl
radical, respectively. As depicted in Scheme 4,
bromide is expectedly a better leaving group
compared to chloride, resulting in 3g as the major
product for both reactions. We also investigated the
difference in leaving group ability between a chloride
and a tosylate via the reaction of the chloromethyl
radical with homoallylic tosylate 14. In contrast to
the superior reactivity of tosylate over halides in
typical bimolecular nucleophilic substitution,[20] the
bulky tosylate displayed inferior reactivity compared
to the much smaller chloride, yielding 3g (38%) and
15 (45%). The steric hindrance and conformational
rigidity could possibly account for the reverse trend
of the above leaving group ability.[21] Expectedly, the
faster reaction was with bromide as leaving group
compared to tosylate in the case of the reaction of
bromomethyl radical with 14, giving the
cyclopropanes 11 and 15 in a ratio of 1 : 3.3 with a
total yield of 78%. Of note, the ratio of tosylate and
halo-containing cyclopropane was decreased with the
Scheme
2.
Photoredox-catalyzed
allylation-
cyclopropanation cascade.
Scheme 3. Application of acyl radical in crossover process.
reaction time extending,
suggesting the
contamination reaction of the substitution of tosylate
with halide ion under this visible-light-mediated
reaction conditions. Based on these results, it is safe
to conclude that the fastest reaction was with bromide,
followed by chloride and tosylate.
Finally, the preference of cyclization modes was
investigated.[22] In the case of the reaction of
chloromethyl radical with 5-chloro vinylphosphonate
16, the cyclopropane 18 arised from 3-exo-tet
cyclization was isolated exclusively (Scheme 5). In
line with the preference of the 3-exo-tet versus 4-exo-
tet modes of cyclizations, 3-exo-tet cyclization was
also preferred over 5-exo-tet cyclization by the
reaction of chloromethyl radical with 6-chloro
vinylphosphonate 17.
with radical allylation as the termination reaction,[18]
the present allylation reaction nicely served as a relay
for this cascade.
Apart from furnishing the application of alkyl
radicals in the crossover process, the reaction has
been briefly demonstrated to be amenable to acyl
radical. Benzoyl radical generated from the precursor
12[19] successfully underwent cyclopropanation
process, producing 13a and 13b in 40% and 60%
yields, respectively (Scheme 3). These results clearly
showcase the generality and robustness of this radical
addition-polar cyclization crossover process.
In order to better understand the reaction pathway
and further the application of this new protocol, some
competition experiments were designed to deal with
the difference in leaving group ability. To address the
intrinsic relative leaving group ability of bromide
versus chloride directly, γ-chloro-γ'-bromo-α-
phosphoryl carbanion with two leaving groups could
Scheme 5. Preference of 3-exo-tet cyclization.
The results of control and radical trapping
experiments demonstrated that the radical species
was involved during this photocatalytic process.
Furthermore, no further reaction was observed in the
dark after 6 h irradiation of the 9 W LEDs, ruling out
the radical-chain propagation mechanism. The
cyclopropanation of homoallylic sulfonates suggests
that the cyclization occurs via anionic 3-exo-tet
manner. Based on these results and the competition
experiments, a plausible mechanism based on polar-
radical crossover process has been postulated in
Scheme 6.[9,14] Single-electron oxidation of bis-
Scheme 4. Experiments for relative leaving group abilities.
4
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10.1002/adsc.201900708
Advanced Synthesis & Catalysis
the corresponding homoallylic (pseudo)halide (0.2
mmol, 1.0 equiv) were added. The tube was
evacuated and filled with nitrogen for 3 times, and
was charged with degassed DMSO (6 mL, 0.033 M).
The tube was irradiated with a 9 W blue LED light
strip spiraled within a bowel for 24 h. After the
reaction was complete, the reaction solution was
diluted with a 1: 1 mixture of saturated Na2CO3
aqueous solution and brine, and was extracted with
EtOAc (4 x 10 mL). The organic layers were washed
with brine, combined and dried over MgSO4,
concentrated in vacuum. Flash chromatography over
silica gel afforded the product.
Scheme 6. Proposed mechanism.
Acknowledgements
This work was supported by the Zhejiang Provincial Natural
Science Foundation of China (No. LY17B020004). The authors
acknowledge Professor Chaozhong Li (SIOC) for valuable
discussions.
catecholate silicate 2 (Eox between +0.34 and +0.87 V
vs. SCE in DMF) by the excited photoredox catalyst
*[Ir] (E [IrIII/IrII = +1.32 V vs. SCE in CH3CN])
produces alkyl radical species 20. This species adds
to the 1,1-disubstituted alkene 1 to generate new
carbon-centered radical intermediate 21. After single-
electron reduction of 21 by the reduced photocatalyst,
the resulting carbanion 22 is subsequently to furnish
the 3-exo-tet cyclization to form the cyclopropane 3.
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10.1002/adsc.201900708
Advanced Synthesis & Catalysis
COMMUNICATION
Photoredox-Catalyzed Cyclopropanation of 1,1-
Disubstituted Alkenes via Radical-Polar Crossover
Process
Adv. Synth. Catal. Year, Volume, Page – Page
Wenping Luo, Yi Yang, Yewen Fang,* Xinxin
Zhang, Xiaoping Jin,* Guicai Zhao, Li Zhang, Yan
Li,* Wanli Zhou, Tingting Xia, and Bin Chen
7
This article is protected by copyright. All rights reserved.