Dealkenylative Alkenylation: Formal σ-Bond Metathesis of Olefins

Article abstract of DOI:10.1002/anie.202005267

The dealkenylative alkenylation of alkene C(sp³)?C(sp²) bonds has been an unexplored area for C?C bond formation. Herein 64 examples of β-alkylated styrene derivatives, synthesized through the reactions of readily accessible feedstock olefins with β-nitrostyrenes by ozone/Fe^II-mediated radical substitutions, are reported. These reactions proceed with good efficiencies and high stereoselectivities under mild reaction conditions and tolerate an array of functional groups. Also demonstrated is the applicability of the strategy through several synthetic transformations of the products, as well as the syntheses of the natural product iso-moracin and the drug (E)-metanicotine.

Full text of DOI:10.1002/anie.202005267

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Dealkenylative Alkenylation: Formal σ-Bond Metathesis of Olefins
Authors: Ohyun Kwon, Manisha Swain, Gusein Sadykhov, and Ruoxi
Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202005267
Link to VoR: https://doi.org/10.1002/anie.202005267

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
Dealkenylative Alkenylation: Formal σ-Bond Metathesis of Olefins
Manisha Swain,[a] Gusein Sadykhov,[a] Ruoxi Wang,[a] and Ohyun Kwon*[a]
Abstract: Dealkenylative alkenylation of alkene C(sp3)–C(sp2)
bonds has been an unexplored area for C–C bond formation. Herein,
we report 64 examples of β-alkylated styrene derivatives
synthesized through the reactions of readily accessible feedstock
olefins with β-nitrostyrenes through ozone/Fe(II)-mediated radical
substitution. These reactions proceed with good efficiency and high
stereoselectivity under mild conditions and tolerate an array of
functional groups. We demonstrate the applicability of the strategy
through several synthetic transformations of the products, as well as
the syntheses of the natural product iso-moracin and the drug (E)-
metanicotine.
Alkenes are seemingly ubiquitous functionalities in the library of
organic molecules, and they play hugely important roles in
chemical science, organic synthesis,[1] the functionalization of
bio-active molecules, and materials synthesis.[2] Furthermore,
olefins are the second most frequently encountered functional
group in natural products (39.85%) and are also readily available
from petroleum,[3] so the development of new modalities for
synthesizing alkenes directly from feedstock alkenes would
presumably benefit the scientific community. Seminal examples
of alkene-to-alkene conversions, including olefin metathesis[4]
and the Heck reaction,[5] complement the more traditional Wittig
reaction[6] and alkyne semi-reduction.[7] In addition, Heck-type
alkenylations[8] and carbonyl–olefin metathesis[9] have emerged
as alternative platforms for olefin synthesis in recent years
(Scheme 1A).
Radicals
play
significant
roles
in
many
chemical
transformations.[10] One of the important methods for accessing
olefin-derived alkyl radicals[11] relies upon pioneering studies on
iron-mediated decomposition of α-alkoxy hydroperoxides.[12,13]
Continuing our interest in the dealkenylative functionalization of
alkenes through ozone/Fe(II)-mediated C(sp3)–C(sp2) bond
fragmentation,[14] we envisioned trapping their alkyl radical
intermediates through addition–elimination onto olefins. When
Scheme 1. (A) Known transformations of olefins into functionalized olefins, (B)
the dealkenylative alkenylation presented herein, and (C) the structures of
three examples of styrene-containing drugs.
implemented, this dealkenylative alkenylation could, for example, The process we propose herein involves Criegee ozonolysis[15]
of an alkene
I
in MeOH followed by Fe(II)-mediated
employ feedstock alkenes (e.g., terpenes, terpenoids) in
conjunction with alkenes containing an open-shell leaving group.
This approach could also be an attractive option for the
synthesis and functionalization of a new class of terpenoid-
tethered alkenes. To the best of our knowledge, there are no
previous examples of dealkenylative approaches for generating
alkyl radical intermediates for the synthesis of functionalized
olefins.
fragmentation of the resulting α-methoxy hydroperoxide II, β-
scission of the alkoxy radical to generate the alkyl radical III,
radical addition with an alkenylating agent to give the
intermediate IV, and β-elimination giving the (E)-alkenylated
product V (Scheme 1B). Most notably, this method is a
complementary procedure for the synthesis of β-alkylated
styrenes—important structural units in many natural products,
bioactive
molecules,
and
pharmaceuticals,
including
metanicotine, vorapaxar, and tamoxifen (Scheme 1C).[16,17]
[a]
Dr. M. Swain, G. Sadykhov, R. Wang, and Prof. Dr. O. Kwon.
Department of Chemistry and Biochemistry
University of California – Los Angeles
We commenced our investigation by reacting (–)-isopulegol (1a)
as a model alkene with a range of structurally diverse vinylation
agents: (E)-(2-bromovinyl)benzene (2),[18] cinnamic acid (3),[19]
two β-nitrostyrenes 4,[20] (E)-[2-(benzenesulfonyl)vinyl]benzene
(5),[21] (E)-1-styryl-1,2-benziodoxol-3(1H)-one (6)[22] (entries 1–6,
Table 1). Among them, 4-methyl-β-nitrostyrene (4b) performed
Los Angeles CA 90095-1569, United States
E-mail: ohyun@chem.ucla.edu
Homepage: https://www.thekwonlab.net
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
d.r.) was obtained when performing the reaction with 2.2
equivalents of the alkene and 1.5 equivalents of FeSO4·7H2O at
0 °C (entry 11). Further lowering the reaction temperature to –
20 °C diminished the yield of 7ab, presumably because of the
poor solubility of 4b in MeOH at this temperature (entry 12).
We applied the conditions optimized for deisopropenylative
styrylation of (–)-isopulegol (1a) to other terpenoids and their
derivatives (Scheme 2). The dealkenylative alkenylations of 1a
in conjunction with 4-methoxy-β-nitrostyrene (4e) and 4-bromo-
β-nitrostyrene (4i) provided their expected products 7ae and 7ai
in yields of 78 and 68%, respectively. The (–)-isopulegol–derived
methyl ether 1b afforded the product 7bb in 72% yield. Other
monoterpenoids, including trans-(+)-dihydrocarvone (1c) and (–
)-dihydrocarveol (1d), were also viable substrates, producing
their corresponding products 7cb and 7db in yields of 72 and
69%, respectively. cis-(–)-Limonene oxide (1e) underwent
opening of the epoxide, through methanolysis, to afford the (E)-
alkenylated product 7eb in 55% yield, consistent with our
previous finding.[14b] The diterpenoid (+)-nootkatone (1f) also
underwent fragmentation cleanly to give the alkenylated product
Table 1. Optimization of conditions for the reaction of 1a with selected
olefins[a]
1a
2–6
metal salt
(equiv)
conc. temp yield (%)[b,c]
entry
(equiv) (equiv)
(M)
(°C) 7aa/7ab (d.r.)
1
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.2
2.2
2.2
2 (1.5)
3 (1.5)
FeSO4·7H2O (1.2)
FeSO4·7H2O (1.2)
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.025
0.025
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
13 (7:1)
10 (13:1)
41 (10:1)
47 (10:1)
18 (8:1)
22 (10:1)
–
7fb in 50% yield. Betulin (1g),
a
biologically active
3
4a (1.5) FeSO4·7H2O (1.2)
4b (1.5) FeSO4·7H2O (1.2)
triterpenoid,[24] afforded the desired product 7ga in a relatively
low yield of 32%, while the protected dehydroleucine 1h
delivered the stryrylated α-amino acid derivative 7ha in 38%
yield. The carvone-derived cyclopentanol 1i also gave the ester
7ib in 57% yield. Two other terpenoid-derived substrates, the
dihydrocarvone-derived hydroxy ketone 1j and the enone 1k,
provided their respective products 7jb (70%) and 7kb (62%).
The stereoselectivity of the radical addition was dictated by a
combination of torsional and steric strain induced by the
substituents at the -, -, and -positions of the alkene
substrate.[25] To expand the scope of olefin coupling partner, we
tested other readily accessible alkenes. Expectedly, both
isopropenyl- and -styrylcyclohexane provided the desired
product 7lb in 76 and 74% yield, respectively. We found that all
degrees of alkyl radicals (1°, 2°, and 3°) engaged efficiently in
the dealkenylative alkenylation, generating their corresponding
products in moderate to good yields (7lb–7zb, 30–76%). In
contrast, the benzylic radical precursor 1aa failed to deliver the
desired product 7aab under our standard reaction conditions
(see the Supporting Information for other incompatible
4
5
5 (1.5)
6 (1.5)
FeSO4·7H2O (1.2)
FeSO4·7H2O (1.2)
6
7
4a (1.5) MnSO4·xH2O (1.2)
4a (1.5) CoSO4·7H2O (1.2)
8
–
9
4a (1.5)
TiCl3 (1.2)
–
10
11[d]
12
4b (1.0) FeSO4·7H2O (1.5)
4b (1.0) FeSO4·7H2O (1.5)
4b (1.0) FeSO4·7H2O (1.5)
65 (10:1)
71 (10:1)
42 (8:1)
0.025 –20
[a] Reaction performed on 0.05-mmol scale, [b] Yield determined using 1H
NMR spectroscopy with 1-chloro-2,4-dinitrobenzene as internal standard (d.r.
in parentheses) [c] Unless stated otherwise, E/Z ratio was >20:1, calculated
from 1H NMR spectrum of crude product. [d] Isolated yield was 62%. See the
Supporting Information for detailed procedures.
substrates). Notably,
a variety of commonly encountered
the best, providing the desired styrylated cyclohexanol 7ab in
47% yield (entry 4, Table 1). The byproducts associated with the
reaction were the alkene 7a´ and the ketone 7a´´, as well as a
trace amount of the radical homocoupling product 7a´΄΄, which
was detected using liquid chromatography mass spectrometry
(LCMS) (see the Supporting Information for further discussion).
Among various iron salts tested, FeSO4·7H2O proved to be the
most efficient in promoting the desired alkenylation. Other
transition metal salts known to facilitate the decomposition of
hydroperoxides,[23] including MnSO4·xH2O, CoSO4·7H2O,
VOSO4, and TiCl3, were ineffective at delivering the desired
product 7aa (entries 7–9). Screening of solvents revealed that
MeOH was crucial for the reaction. Additional efforts at
optimizing the reaction conditions using co-solvents, excess of
radical acceptor, and additives failed to offer better results. A
promising yield of 7ab (71%) with high diastereoselectivity (10:1
functionalities, including hydroxyl, ketone, ester, amide, enone,
carbamate, and phthalimide units, were compatible with the
reaction conditions.
Next, we examined the scope of the nitroolefin coupling partner
for reactions with the alkene 1l (Scheme 3). Nitrostyrenes
bearing a variety of substituents on the benzene ring (4c–4n),
thiophene (4o), naphthalene (4p), and benzodioxole (4q) were
compatible, giving their corresponding alkenylated products 7lc–
7lq in yields of 42–78%. Several functional groups, including
hydroxyl (4h), halide (4i–4l), nitro (4m), and trifluoromethyl (4n)
units, were tolerated. Notably, the β,β-disubstituted nitroolefins
4r and 4s generated the trisubstituted olefins 7lr and 7ls in 64
and 70% yield, respectively. In contrast, when the α-methylated
nitroolefin 4t was used as substrate, the desired product 7lt was
not observed, presumably because its steric bulk hindered
This article is protected by copyright. All rights reserved.

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
Scheme 2. Scope of alkene coupling partner in reactions with nitroolefins 4. [a] Nitroolefin (0.46 mmol), alkene (1.0 mmol), FeSO4·7H2O (1.50 mmol), MeOH
(0.025 M), 0 °C, 5 min. [b] Unless otherwise stated, the E/Z ratio was >20:1 and the d.r. ratio was calculated from the 1H NMR spectrum of the crude product or
the isolated yields of the major and minor isomers. [c] Isolated yield. [d] The reaction was performed on a 5.00-mmol scale. [e] The reaction was performed at
room temperature.
addition of the cyclohexyl radical at the α-carbon atom. The -
alkyl–substituted nitroolefins (4u and 4v), as well as -
dimethylamino– (4w) and -styryl–nitroolefins (4x) failed to
afford their desired products 7lu–7lx, under these reaction
conditions. Notably, this dealkenylative alkenylation proceeded
with excellent stereoselectivity, producing only E-isomers in
most cases.
styrylated aldehydes in yields of 51 and 60%, respectively.
Remarkably, we could access the aldehyde 11ab—an
intermediate for the synthesis of cyclopenta[b]quinoline and
taxol-like tricyclic derivatives that has previously been made
over five steps in 41% yield[26]—in a single step in 51% yield.
(+)-p-1-Menthene (9c) also reacted to generate the desired
aldehyde 11cb in 56% yield. The disubstituted olefins
norbornene (9d) and cis-cyclooctadiene (9e) produced their
respective aldehydes 11db (53%) and 11eb (41%).
Dealkenylative cleavage of (+)-2-carene (9f) produced the
aldehyde 11fb in 51% yield. Finally, the reaction of (1S)-(+)-3-
carene (9g) gave the dienyl-aldehyde product 11ge, isolated in
45% yield, through a radical-induced ring opening process of the
transient cyclopropylcarbinyl radical.
We broadened the substrate scope by converting the
exomethylene cycloalkanes 8 and cycloalkenes 9 into their
corresponding alkenyl methyl esters 10 and aldehydes 11,
respectively (Scheme 4). The simple exomethylene
cycloalkanes 8a–8c gave their styrylated esters 10ab–10cb in
yields of 58–67%. 1-Methylene indane (8d) afforded 41% of its
styrylated product 10db, while 1-methylene tetralin (8e) gave the
product 10eb in 21% yield. Camphene (8f) and sabinene (8g)
fragmented to give their corresponding esters 10fb and 10gb in
moderate yields (32 and 45%, respectively). The cycloalkenes
9a and 9b also underwent the reaction smoothly, affording their
In addition to the radical ring opening test, we conducted several
control experiments to support the involvement of radical
intermediates (Scheme 5). The addition of 1.5 equivalents of
TEMPO, under our standard conditions, inhibited the
This article is protected by copyright. All rights reserved.

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
Scheme 3. Substrate scope of the reactions of 1l with various nitroolefins 4.
[a] Standard conditions: nitroolefin 4 (0.46 mmol), alkene 1l (1.00 mmol),
FeSO4·7H2O (1.50 mmol), MeOH (0.025 M with respect to 1l), 0 °C, 5 min. [b]
Isolated yield.
alkenylation of 1j with 4b, yielding only 12% of the desired
product along with the TEMPO-alkyl adduct in 74% yield with 4:1
d.r. The alkenylation was stereoconvergent, with both trans-
and cis-β-nitrostyrenes yielding the trans-(E)-alkenylated product
7aa exclusively with the same E/Z ratio.
To validate the practicality and generality of this transformation,
we performed a gram-scale reaction employing 20 mmol of (–)-
isopulegol (1a) and obtained the desired styrylated cyclohexanol
7ab in a yield of 57% (1.12 g) and with 10:1 d.r. (Scheme 6A).
Furthermore, the operational simplicity of this ozone/Fe(II)-
mediated process encouraged us to explore its synthetic utility
by performing various post-alkenylation transformations and by
synthesizing a natural product and a known pharmaceutical drug
(Schemes 6B–D). Ozonolysis and reductive workup of the
dealkenylative product 7ab gave the chiral cyclohexanediol 13 in
59% yield. Hydrogenation of the product 7ab furnished the
enantiopure cyclohexanol 14 in almost quantitative yield (95%).
β-Chlorotetrahydrofuran derivatives are important motifs in
several natural products.[27] We converted the alkene 7ab to the
enantiopure tetrahydrofuran 15 in 82% yield. This reaction,
proceeding via a 5-endo-chlorocycloetherification, could serve
Scheme 4. Substrate scope for the reactions of exocyclic and endocyclic
olefins. [a] Nitroolefin (0.33 mmol), alkene (1.00 mmol), FeSO4·7H2O (1.50
mmol), MeOH (0.025 M with respect to the alkene), 0 °C, 5 min. Unless
otherwise stated, the E/Z ratio was >20:1 and the d.r. ratio was calculated
from the 1H NMR spectrum of the crude product. [b] Isolated yield.
functionalized products containing multiple stereocenters,
obtained from readily accessible starting materials, could find
potential applications in organic synthesis.
as
a convenient strategy for the synthesis of various
tetrahydrofuran derivatives.[28] A cascade reaction generating the
octahydroindenobenzofuran 16 was achieved in an excellent
yield of 75% through selective Prins cyclization followed by
Friedel–Craft cyclization when reacting the stryrenylated
cyclohexanol 7ai and 3,4,5-trimethoxybenzaldehyde with
BF3·OEt2 in CH2Cl2 at room temperature.[29] These post
We have also completed a formal synthesis of iso-moracin C
(17),[30] a 2-arylbenzo[b]furan from the Artocarpus family that has
potent 5-lipooxygenase inhibitory activity [IC50 (5LOX) = 1.67
µM]. The known precursor 7ry was obtained in 56% yield from
the dealkenylative alkenylation of the commercially available
This article is protected by copyright. All rights reserved.

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
Scheme 5. Reactions conducted to examine mechanistic features of the
dealkenylative alkenylation. See the Supporting Information for details.
alkene 1r with the nitroolefin 4y; the synthesis of 7ry was
achieved previously in 23% yield in three steps staring from 3,5-
dimethoxybromobenzene.[31] Finally, we have achieved the
synthesis of the drug (E)-metanicotine (19), commonly known as
rivanicline, developed originally as a potential treatment for
Alzheimer’s disease.[32,33] The dealkenylative alkenylation of the
alkene 18
with the nitroolefin 4z proceeded smoothly to afford the
intermediate 18z, which, upon work-up and direct subjection to
deprotection with 6 N HCl, afforded the drug 19 in an overall
yield of 37% with excellent selectivity (E/Z > 20:1, Scheme 6D).
In summary, we describe
a simple and straightforward
ozone/Fe(II)-mediated dealkenylative alkenylation that proceeds
under mild reaction conditions in less than 10 min. This
transformation is stereoselective and tolerant of a broad range of
functionalities. Several natural products and readily accessible
alkenes react with an array of nitroolefins to give
pharmaceutically relevant and synthetically important alkylated
styrenes. This protocol also provides a useful synthetic route
toward styrenes presenting tethered aldehydes and esters. We
have also demonstrated the utility of the products through
various post-alkenylation transformations, synthetic applications,
and the diversification of natural products. In view of the mild
experimental conditions and the ready availability of both the
reaction partners and the inexpensive earth-abundant reagents,
this convenient and site-specific alkenylation should find
practical applications in chemical science.
Scheme 6. Synthetic utility and applications of the dealkenylative alkenylation.
[a] Unless otherwise noted, yields are isolated yields. See the Supporting
Information for experimental details. [b] E/Z ratios were determined from 1H
NMR spectra. [c] Conditions: a) O3, CH2Cl2, –78 °C, NaBH4 (excess), 1 h. b)
Pd/C, H2, EtOH, rt, 8 h. c) SO2Cl2, CH2Cl2, 0 °C, 15 min. d) 3,4,5-Trimethoxy
benzaldehyde, BF3·OEt2, CH2Cl2, 45 min.
Acknowledgments
Financial support for this study was provided by the NIH
(R01GM071779). We thank the UCLA Molecular Instrumentation
Center for the NMR spectroscopy and mass spectrometry
instrumentation and the X-ray diffraction studies (S. I. Khan). We
thank Andrew J. Smaligo for his assistance with the preparation
of the figures and the recording of 2D NMR spectra.
[1] Selected reviews: a) S. R. Chemler, D. Trauner, S. J. Danishefsky,
Angew. Chem. Int. Ed. 2001, 40, 4544–4568; Angew. Chem. 2001, 113,
4676–4701; b) S. E. Denmark, C. R. Butler, Chem. Commun. 2009,
20–33; c) N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem.
Educ. 2010, 87, 1348–1249; d) C. C. C. J. Seechurn, M. O. Kitching, T.
J. Colacot, V. Snieck, Angew. Chem. Int. Ed. 2012, 51, 5062–5085;
Angew. Chem. 2012, 124, 5150–5174; e) M. B. Smith, J. March,
March’s Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 7th ed., John Wiley & Sons, Hoboken, NJ, 2013; f) R.
Álvarez, B. Vaz, H. Gronemeyer, A. R. de Lera, Chem. Rev. 2014, 114,
Keywords: alkenylation • ozonolysis • redox chemistry • ferrous
• radical • nitroolefin • terpene
This article is protected by copyright. All rights reserved.

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
1–125; g) M. Hassam, A. Taher, G. E. Arnott, I. R. Green, W. A. L. Van
Otterlo, Chem. Rev. 2015, 115, 5462–5569.
[15] R. Criegee, G. Wenner, Justus Liebig Ann. Chem. 1949, 564, 9–15.
[16]
a) B. M. Fox, X. S. Xiao, S. Antony, G. Kohlhagen, Y. Pommier, B. L.
Staker, L. Stewart, M. Cushman, J. Med. Chem. 2003, 46, 3275–3282;
b) J. Cheel, C. Theoduloz, J. Rodríguez, G. Saud, P. D. S. Caligari, G.
Schmeda-Hirschmann, J. Agric. Food Chem. 2005, 53, 8512–8518; c)
B. S. Siddiqui, H. Aslam, S. Begum, S. T. Ali, Nat. Prod. Res. 2007, 21,
736–741; d) Y. Lee, B. Park, W. Lyoo, Synthesis 2009, 2146–2154; e)
P.-H. Nguyen, J.-L. Yang, M. N. Uddin, S.-L. Park, S.-I. Lim, D.-W.
Jung, D. R. Williams, W.-K. Oh, J. Nat. Prod. 2013, 76, 2080–2087.
a) K. Patel, C. Karthikeyan, N. S. H. N. Moorthy, G. S. Deora, V. R.
Solomon, H. Lee, P. Trivedi, Med. Chem. Res. 2011, 21, 1780–1784; b)
N. Sharma, D. Mohanakrishnan, A. Shard, A. Sharma, A. K. Sinha, D.
Sahal, J. Med. Chem. 2012, 55, 297–311; c) R. S. P. Singh, D. Michel,
U. Das, J. R. Dimmock, J. Alcorn, Bioorg. Med. Chem. Lett. 2014, 24,
5199–5202.
[2]
[3]
[4]
D. C. S. Costa, Arabian J. Chem. 2020, 13, 799–834.
P. Ertl, T. Schuhmann, J. Nat. Prod. 2019, 82, 1258–1263.
For reviews, see: a) M. Schuster, S. Blechert, Angew. Chem. Int. Ed.
1997, 36, 2036–2056; Angew. Chem. 1997, 109, 2124–2144; b) O. M.
Ogba, N. C. Warner, D. J. O’Leary, R. H. Grubbs, Chem. Soc. Rev.
2018, 47, 4510–4544. For an article describing the synthesis of
styrenes, see: c) W. E. Crowe, Z. J. Zhang, J. Am. Chem. Soc. 1993,
115, 10998–10999.
[17]
[5]
For seminal work, see: a) M. Tsutomu, M. Kunio, O. Atsumu, Bull. Chem.
Soc. Jpn. 1971, 44, 581–581; b) R. F. Heck, J. P. Nolley, J. Org. Chem.
1972, 37, 2320–2322; c) R. F. Heck, Acc. Chem. Res. 1979, 12, 146–
151; for selected reviews on Heck reaction, see: d) I. P. Beletskaya, A.
V. Cheprakov, Chem. Rev. 2000, 100, 3009–3066; e) J. Ruan, J. Xiao,
Acc. Chem. Res. 2011, 44, 614–626; f) J. Le Bras, J. Muzart, Chem.
Rev. 2011, 111, 1170–1214; g) D. McCartney, P. J. Guiry, Chem. Soc.
Rev. 2011, 40, 5122–5150.
[18] A. Noble, S. J. McCarver, D. W. C. MacMillan, J. Am. Chem. Soc. 2015,
137, 624–627.
[19] a) Z. Cui, X. Shang, X.-F. Shao, Z.-Q. Liu, Chem. Sci. 2012, 3, 2853–
2858; b) J. Zhao, H. Fang, J. Han, Y. Pan, Beilstein J. Org. Chem. 2013,
9, 1718–1723; c) W.-P. Mai, G. Song, G.-C. Sun, L.-R. Yang, J.-W.
Yuan, Y.-M. Xiao, P. Mao, L.-B. Qu, RSC Adv. 2013, 3, 19264–19267;
d) J. Ji, P. Liu, P. Sun, Chem. Commun. 2015, 51, 7546–7549; e) Z.
Fang, C. Wei, J. Lin, Z. Liu, W. Wang, C. Xu, X. Wang, Y. Wang, Org.
Biomol. Chem. 2017, 15, 9974–9977; f) C. Wang, Y. Lei, M. Guo, Q.
Shang, H. Liu, Z. Xu, R. Wang, Org. Lett. 2017, 19, 6412–6415; g) R.
Kancherla, K. Muralirajan, B. Maity, C. Zhu, P. E. Krach, L. Cavallo, M.
Rueping, Angew. Chem. Int. Ed. 2019, 58, 3412–3416; Angew. Chem.
2019, 131, 3450–3454.
[6]
[7]
For reviews, see: a) B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89,
863–927; b) P. R. Blakemore, J. Chem. Soc. Perkin Trans. 1, 2002,
2563–2585; c) P. A. Byrne, D. G. Gilheany, Chem. Soc. Rev. 2013, 42,
6670–6696.
a) R. Shen, T. Chen, Y. Zhao, R. Qiu, Y. Zhou, S. Yin, X. Wang, M.
Goto, L.-B. Han, J. Am. Chem. Soc. 2011, 133, 17037–17044; b) S. Fu,
N.-Y. Chen, X. Liu, Z. Shao, S.-P. Luo, Q. Liu, J. Am. Chem.
Soc. 2016, 138, 8588–8594; c) K. Tokmic, A. R. Fout, J. Am. Chem.
Soc. 2016, 138, 13700–13705.
[8]
For reviews on Heck-type alkenylations, see: a) S. Tang, K. Liu, C. Liu,
A. Lei, Chem. Soc. Rev. 2015, 44, 1070–1082; b) W. Ma, P.
Gandeepan, J. Li, L. Ackermann, Org. Chem. Front. 2017, 4, 1435–
1467; c) D. Kurandina, P. Chuentragool, V. Gevorgyan, Synthesis 2019,
51, 985–1005.
[20] a) J.-Y. Liu, J.-T. Liu, C.-F. Yao, Tetrahedron Lett. 2001, 42, 3613–
3615; b) J.-T. Liu, Y.-J. Jang, Y.-K. Shih, S.-R. Hu, C.-M. Chu, C.-F.
Yao, J. Org. Chem. 2001, 66, 6021–6028; c) Y.-J. Jang, Y.-K. Shih, J.-
Y. Liu, W.-Y. Kuo, C.-F. Yao, Chem. Eur. J. 2003, 9, 2123–2128; d) Y.-
J. Jang, M.-C. Yan, Y.-F. Lin, C.-F. Yao, J. Org. Chem. 2004, 69, 3961–
3963; e) S.-r. Guo, Y.-q. Yuan, Synlett 2015, 26, 1961–1968; f) J.
Zheng, D. Wang, S. Cui, Org. Lett. 2015, 17, 4572–4575; g) S. Zhang,
Y. Li, J. Wang, X. Hao, K. Jin, R. Zhang, C. Duan, Tetrahedron Lett.
2020, 61, 151721.
[9]
For reviews on carbonyl–olefination, see: a) L. Ravindar, R. Lekkala,
K. P. Rakesh, A. M. Asiri, H. M. Marwani, H.-L. Qin, Org. Chem. Front.
2018, 5, 1381–1391; b) P. S. Riehl, C. S. Schindler, Trends in
Chemistry 2019, 1, 272–273.
[10]
Recent reviews on radical chemistry, see: a) A. Studer, D. P. Curran,
Angew. Chem. Int. Ed. 2016, 55, 58–102; Angew. Chem. 2016, 128,
58–102; b) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh,
A. Lei, Chem. Rev. 2017, 117, 9016–9085; c) A. Kaga, S. Chiba, ACS
Catal. 2017, 7, 4697–4706; d) K. J. Romero, M. S. Galliher, D. A. Pratt,
C. R. J. Stephenson, Chem. Soc. Rev. 2018, 47, 7851–7866. For more
articles on radicals, see: e) M. Yan, J. C. Lo, J. T. Edwards, P. S. Baran,
J. Am. Chem. Soc. 2016, 138, 12692–12714; f) S. Z. Zard, Org. Lett.
2017, 19, 1257–1269.
[21] a) A. Noble, D. W. C. MacMillan, J. Am. Chem. Soc. 2014, 136, 11602–
11605; b) S. Sumino, M. Uno, H.-J. Huang, Y.-K. Wu, I. Ryu, Org. Lett.
2018, 20, 1078−1081; (c) Q.-Q. Zhou, S. J. S. Düsel, L.-Q. Lu, B.
König, W.-J. Xiao, Chem. Commun. 2019, 55, 107–110.
[22] A. Boelke, L. D. Caspers, B. J. Nachtsheim, Org. Lett. 2017, 19, 5344–
5347.
[23] a) J. K. Kochi, J. Am. Chem. Soc. 1962, 847, 1193–1197; b) W. H.
Richardson, J. Org. Chem. 1965, 30, 2804–2808; c) R. R. Hiatt, K. C.
Irwin, C. W. Gould, J. Org. Chem. 1968, 33, 1430–1435.
[11] For review on radical from olefins via HAT, see: a) S. W. M. Crossley, C.
Obradors, R. M. Martinez, R. A. Shenvi, Chem. Rev. 2016, 116, 8912–
9000; For article, see: b) J. C. Lo, D. Kim, C.-M. Pan, J. T. Edwards, Y.
Yabe, J. Gui, T. Qin, S. Gutiérrez, J. Giacoboni, M. W. Smith, P. L.
Holland, P. S. Baran J. Am. Chem. Soc. 2017, 139, 6, 2484–2503.
[12] a) E. G. E. Hawkins, J. Chem. Soc. 1955, 3463–3467; b) J. Kumamoto,
H. E. De La Mare, F. F. Rust, J. Am. Chem. Soc. 1960, 82, 1935–1939;
c) H. E. De Le Mare, J. K. Kochi, F. F. Rust, J. Am. Chem. Soc. 1961,
83, 2013; d) S. Murai, N. Sonoda, S. Tsutsumi, Bull. Chem. Soc. Jpn.
1964, 37, 1187–1190; e) S. L. Schreiber, J. Am. Chem. Soc. 1980, 102,
6163–6165.
[24] a) S. Alakurtti, T. Mäkelä, S. Koskimies, J. Yli-Kauhaluoma, Eur. J.
Pharm. Sci. 2006, 29, 1–13; b) M. Grymel, M. Zayozak, J. Adamek, J.
Nat. Prod. 2019, 82, 1719–1730.
[25] a) B. Giese, Angew. Chem. Int. Ed. 1989, 28, 969–1146; Angew. Chem.
1989, 28, 969–980; b) G. Bar, A. F. Parsons, Chem. Soc. Rev. 2003,
33, 251–263.
[26] a) K. L. Jensen, G. Dickmeiss, B. S. Donslund, P. H. Poulsen, K. A
Jørgensen, Org. Lett. 2011, 13, 3678–3681; b) J. Petrignet, A. Boudhar,
G. Blond, J. Suffer, Angew. Chem. Int. Ed. 2011, 50, 3285–3289;
Angew. Chem. 2011, 123, 3343–3347.
[13] a) D. Huang, A. W. Schuppe, M. Z. Liang, T. R. Newhouse, Org. Biomol.
Chem. 2016, 14, 6197–6200; b) J. Bao, H. Tian, P. Yang, J. Deng, J.
Gui, Eur. J. Org. Chem. 2020, 339–347.
[27] For reviews on the halogenation of olefins, see: a) G. Chen, S. Ma,
Angew. Chem. Int. Ed. 2010, 49, 8306–8308; Angew. Chem. 2010, 122,
8484–8486; b) A. Castellanos, S. P. Fletcher, Chem. Eur. J. 2011, 17,
5766–5776; c) S. C. Snyder, D. S. Treitler, A. P. Brucks, Aldrichimica
Acta 2011, 44, 27–40; d) U. Hennecke, Chem. Asian J. 2012, 7, 456–
465; e) S. E. Denmark, W. E. Kuester, M. T. Burk, Angew. Chem. Int.
Ed. 2012, 51, 10938–10953; Angew. Chem. 2012, 124, 11098–11113.
[28] X. Zeng, C. Miao, S. Wang, C. Xia, W. Sun, Synthesis 2013, 45, 2391–
2396.
[14] a) A. J. Smaligo, S. Vardhineedi, O. Kwon, ACS Catal. 2018, 8, 5188–
5192; b) A. J. Smaligo, M. Swain, J. C. Quintana, M. F. Tan, D. A. Kim,
O. Kwon, Science 2019, 364, 681–685; c) A. J. Smaligo, O. Kwon, Org.
Lett. 2019, 21, 8592–8597; d) A. J. Smaligo, J. Wu, N. R. Burton, A. S.
Hacker, A. C. Shaikh, J. C. Quintana, R. Wang, C. Xie, O. Kwon,
Angew. Chem. Int. Ed. 2020, 59, 1211–1215; Angew. Chem. 2020, 132,
1227–1231.
This article is protected by copyright. All rights reserved.

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
[29] Y. Sakata, E. Yasui, K. Takatori, Y. Suzuki, M. Mizukami, S. Nagumo, J.
Org. Chem. 2018, 83, 9103−9118.
[30] a) Y. M. Syah, E. H. Hakim, L. Makmur, V. A. Kurdi, E. L. Ghisalberti, N.
Aimi, S. A. Achmad, Nat. Prod. Commun. 2006, 1, 549–552; b) X. Li, H.
Xie, R. Zhan, D. Chen, Molecules 2018, 23, 754–764.
[31] D. Wu, H. Mei, P. Tan, W. Lu, J. Zhu, W. Wang, J. Huan, J. Li,
Tetrahedron Lett. 2015, 56, 4383–4387.
[32] J. Jang, K. S. Sin, H. Park, Arch. Pharm. Res. 2001, 24, 503–507.
[33] a) M. Bencherif, M. E. Lovette, K. W. Fowler, S. Arrington, L.
Reeves, W. S. Caldwell, P. M. Lippiello, J. Pharmacol. Exp. Ther. 1996,
279, 1413–21; b) N. S. Sapronov, Y. O. Fedotova, N. N. Kuznetsova,
Bull. Exp. Biol. Med. 2006, 142, 700–702.
This article is protected by copyright. All rights reserved.

10.1002/anie.202005267
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Manisha Swain, Gusein Sadykhov,
Ruoxi Wang, and Ohyun Kwon *
Page No.0000 – Page No.0000
Dealkenylative Alkenylation: Formal
σ-Bond Metathesis of Olefins
Dealkenylative alkenylation of alkene C(sp3)–C(sp2) bonds has been an unexplored area
for C–C bond formation. Herein, we report 64 examples of β-alkylated styrene
derivatives synthesized through the reactions of readily accessible feedstock olefins with
β-nitrostyrenes through ozone/Fe(II)-mediated radical substitution. These reactions
proceed with good efficiency and high stereoselectivity under mild conditions and
tolerate an array of functional groups. We demonstrate the applicability of the strategy
through several synthetic transformations of the products, as well as the syntheses of
the natural product iso-moracin and the drug (E)-metanicotine.
.
This article is protected by copyright. All rights reserved.