Desulfonylation-Initiated Distal Alkenyl Migration in Copper-Catalyzed Alkenylation of Unactivated Alkenes

Article abstract of DOI:10.1021/acs.orglett.8b02840

A novel and efficient protocol for desulfonylation-initiated distal alkenyl migration and its application to the elusive alkenylation of unactivated alkenes have been presented. This radical cascade process has successfully achieved the vicinal difluoroal

Full text of DOI:10.1021/acs.orglett.8b02840

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Desulfonylation-Initiated Distal Alkenyl Migration in Copper-
Catalyzed Alkenylation of Unactivated Alkenes
Xiaoyang Wang,† Jing Liu,† Ze Yu,† Minjie Guo,‡ Xiangyang Tang,† and Guangwei Wang*,†
†Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University,
Tianjin 300072, P. R. China
‡Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin
300072, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient protocol for desulfonyla-
tion-initiated distal alkenyl migration and its application to the
elusive alkenylation of unactivated alkenes have been
presented. This radical cascade process has successfully
achieved the vicinal difluoroalkylalkenylation of unactivated
alkenes with excellent chemo-, regio-, and stereoselectivity in
high efficiency under mild conditions. The reactions afford
previously unknown 3,3-difluoro-5-styrylpiperidin-2-one deriv-
atives or β-styryl-γ-difluoroalkyl amines bearing a quaternary stereocenter. This is the first report of difunctionalization of
unactivated alkenes through desulfonylation-initiated distal alkenyl migration.
Scheme 1. Vicinal Difunctionalization of Unactiviated
Olefins via Remote Radical Functional Migration
he remote radical migration strategy has attracted much
Tattention recently since it not only offers new synthetic
protocols to reconstruct the molecular structures through a
modular approach in organic synthesis but also provides an
excellent alternative pathway to existing ionic-type rearrange-
ment reactions.1 During the past several years, a great number
of examples of the radical-mediated distal functional group
migration have been documented. Vicinal difunctionalization
of alkenes through intramolecular functional group migration
has been established as a promising synthetic method, in
particular, for the unactivated alkenes, and the migration of
diverse functional groups, including hydrogen,2 formyl,3
(hetero)aryl,4 cyano,5 alkynyl,6 and oximino7 has been
achieved. Although energetically unfavorable compared with
other functional groups based on density functional theory
calculations,8 the efficient radical-mediated alkenyl migration
has been developed recently and subjected to vicinal
fluoroalkylalkenylation of unactivated alkenes by Liu’s and
Studer’s groups, respectively.9 These excellent works take
advantage of the delicate incorporation of hydroxyl moieties
that tend to form a low energy neutral ketyl radical, thus
facilitating the intramolecular migration of adjacent vinyl
group. However, the requirement of a hydroxyl moiety
seriously limits the substrate scope to alcohols (Scheme
1A).10 Therefore, it is highly desirable to develop a novel and
efficient strategy to expand the substrate scope of radical-
initiated migration into manifold substrates.
recent progress of the radical reaction of alkenes with ethyl
bromodifluoroacetate (BrCF2CO2Et),12 the substrate 1 was
designed which might undergo vinyl migration to afford
skeletal reorganization products. In this scenario, the radical B
might be formed by difluoroalkylation of terminal alkene
followed by 5-exo cyclization in the substrate 1. Subsequent
Sulfur dioxide extrusion has been successfully applied to
Smiles rearrangement to promote transfer of the aryl group.11
Enlightened by this, we hypothesized that incorporating a
sulfonyl group into the substrates bearing two alkenyl groups
could trigger alternative reaction pathways. Based on our
Received: September 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
kinetically favored β-scission of the sulfonyl group followed by
desulfonylation could afford the intramolecular 1,4-alkenyl
migration product C. (E)-3,3-Difluoro-5-styrylpiperidin-2-one
2 would then be obtained upon annulation of the N-centered
radical C (Scheme 1B). Herein, we present a novel and
efficient protocol for desulfonylation-initiated distal alkenyl
migration and its application to the elusive alkenylation of
unactivated alkenes.
We initiated this study with (E)-N-allyl-N-methyl-2-phenyl-
ethenesulfonamide 1a as a model substrate and commercially
available ethyl bromodifluoroacetate (BrCF2CO2Et) as a CF2
radical source13 for the optimization of reaction conditions
(Table 1). To our delight, the desired product 3,3-difluoro-1-
the dosage of PMDETA was decreased to 30 mol % (entry
14), the yield of 2a decreased dramatically to 32%, so
PMDETA is not only a ligand but also a base in the catalytic
system.14
With the optimal reaction conditions established, the scope
of the reaction was next investigated. First, the migrating styryl
group was systematically investigated (Scheme 2). A variety of
substrates bearing electron-donating or electron-withdrawing
groups at the para position in the aryl afforded the desired
products 2a−f in 63−72% yields, so the electronic effects of
the para position of the aryl moiety are not pronounced. The
Scheme 2. Copper-Catalyzed Difluoroalkylation/5-Exo
a
Cyclization/Desulfonylation and Annulation
a
Table 1. Optimization of Reaction Conditions
b
entry
[Cu]
solvent
additive
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
CuI
CuI
CuI
CuI
CuCl
CH3CN
DMF
31
27
50
61
33
43
31
36
59
72
58
53
63
32
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
c
CuCN
Cu(OTf)2
Cu(MeCN)4PF6
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Na2S2O5
Na2S2O3
quinol
Cu
Na2S2O5
d
14
a
Reaction conditions: Unless otherwise noted, all reactions were
performed with 1a (0.4 mmol), BrCF2CO2Et (0.6 mmol), PMDETA
(0.6 mmol), and [Cu] (10 mol %) in solvent (1 mL) at 80 °C under
b
c
d
Ar for 12 h. Isolated yield. CuI (1.1 equiv) was used. PMDETA
(0.12 mmol, 30 mol %).
methyl-5-styrylpiperidin-2-one 2a was obtained in 31% yield
with excellent E/Z selectivity via a vinyl migration and
desulfonylation process in the presence of CuI (10 mol %) and
PMDETA (pentamethyldiethylenetriamine, 1.5 equiv) at 80
°C for 12 h (entry 1). The yield decreased to 27% when N,N-
dimethylformamide (DMF) was used as the solvent (entry 2)
but increased to 50% when dimethyl sulfoxide (DMSO) was
used (entry 3). When the amount of CuI was increased to 1.1
equiv, the desired product 2a can be obtained in 61% yield
(entry 4). Then different copper salts were screened, including
CuCl, CuCN, Cu(OTf)2, Cu(MeCN)4PF6, and Cu2O (entries
5−9). For this cascade difluoroalkylation/5-exo cyclization/
desulfonylation and annulation reaction, Cu2O proved to be
the optimized catalyst and provided the desired product 2a in
59% yield (entry 9). Encouraged by this result, we used
sodium pyrosulfite (Na2S2O5) as the reducing reagent for the
regeneration of Cu(I) catalyst, and the yield of the desired
product 2a was improved to 72% with 10 mol % of Cu2O
(entry 10). Replacing Na2S2O5 with other reducing reagents,
such as sodium thiosulfate (Na2S2O3), hydroquinone, and
copper powder, led to inferior results (entries 11−13). When
a
Reaction conditions: 1 (0.4 mmol, 1.0 equiv), BrCF2CO2Et (0.6
mmol, 1.5 equiv), PMDETA (0.6 mmol, 1.5 equiv), Cu2O (10 mol
%), DMSO (1.0 mL), under Ar at 80 °C for 12 h. Isolated yield was
based on 1. 50 °C. 5 mmol scale.
b
c
B
DOI: 10.1021/acs.orglett.8b02840
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Organic Letters
Letter
ortho-substituted substrates generated the targeted products
2g−i in 65−73% yields; the meta-substituted substrates also
worked well, and both 2j and 2k were isolated in 69% yields.
Substrates bearing a disubstituted styryl group afforded the
corresponding product 2v in 61% yield. Next, we focused on
the substrates bearing different substituents at the N atom.
Isopropyl, cyclohexyl, benzyl, and phenyl were tolerated,
affording the desired products 2l−o in good yields. Notably,
the geminal-disubstituted alkenes also underwent this trans-
formation and furnished the desired products 2p−u bearing a
quaternary carbon center on the ring of piperidin-2-ones in
excellent yields even under lower reaction temperature (50
°C), indicating that alkenyl migration also works for tertiary
alkyl radical. The substituents both on the benzene ring of the
migrating styryl and at the N atom do not play a major role. An
aromatic group could also be incorporated at the 2-position of
the terminal alkene, and the corresponding product 2w was
obtained in moderate yield. However, when the more sterically
demanding adamantyl directly bound to N atom was used, the
annulation was hindered and the noncyclic product 3 was
isolated in 63% yield.
corresponding products 4b and 4c. Both electron-donating and
electron-withdrawing substituents at the para position had no
effect and the corresponding products 4d to 4f were formed in
good yields. We then investigated a variety of other
bromodifluoroacetamides, and the corresponding products 4g
to 4i were obtained in good yields, respectively. However,
when β-bromodifluoroacetamides derived from pyrrole or
alkyl/benzyl amine were subjected to above condition, the
reaction became messy and no desired products can be isolated
(see the Supporting Information).
Base on the above results and the previous works about the
radical-mediated difunctionalization of alkenes through distal
migration of functional groups, a plausible mechanism is
suggested in Scheme 4. The initiation of the catalytic cycle
Scheme 4. Proposed Mechanism
In order to afford the noncyclized product, the ethyl
bromodifluoroacetate with labile ester group was replaced by
β-bromodifluoroacetamides with robust amide group, thus the
annulation through ester exchange would be hindered
(Scheme 3). As expected, the desired product β-styryl-γ-
difluoroalkyl amine 4a bearing a quaternary carbon center was
isolated in 86% yield. The influence of the substituents on the
aryl group directly bonded to the N atom was investigated first,
and p- and m-methyl were efficiently transformed into the
occurs with oxidation of Cu(I) species by BrCF2R3 through a
single-electron transfer process, and an electrophilic fluoroalkyl
radical I and Cu(II) species are generated concomitantly.
Subsequently, fluoroalkyl radical I selectively attacks the less
sterically hindered terminal alkene to give the transient alkyl
radical II. The alkyl radical II then adds to the internal double
bond to furnish a 5-exo cyclization and generate the cyclized
radical III, which will undergo rapid desulfonylation to form
the key N-centered radical IV, delivering the radical alkenyl
migration and the formation of a new C(sp2)−C(sp3) bond.
Then, hydrogen abstraction of the N-centered radical IV from
solvent gives the desired products 4 (path a) (see the
Supporting Information for the deuterated labeling experi-
ment). An annulation will proceed rapidly if R3 is CO2Et and
generates the products 3,3-difluoro-5-styrylpiperidin-2-ones
(2) (path b). Finally, recycling Cu(I) species is completed
after the reduction of Cu(II) species by solvent or Na2S2O5.
Although the reaction can occur without Na2S2O5, the yield
decreased obviously. Therefore, the major role of Na2S2O5
might be accelerating the reduction of Cu(II) species, thus
facilitating the regeneration of Cu(I) species. These results are
consistent with the results in our previous work.12e
Scheme 3. Copper-Catalyzed Difluoroalkylation/5-Exo
Cyclization/Desulfonylation
a
In conclusion, a novel and efficient protocol for
desulfonylation-initiated formal distal alkenyl migration and
its application to the elusive alkenylation of unactivated alkenes
has been presented. The vicinal difluoroalkylalkenylation of
unactivated alkenes has been successfully achieved with
excellent chemo-, regio-, and stereoslectivity under mild
conditions. In particular, this transformation offers a unique
and broadly applicable platform to directly access to previous
unknown 3,3-difluoro-5-styrylpiperidin-2-ones derivatives. Al-
ternatively, β-styryl-γ-difluoroalkyl amine bearing a quaternary
a
Reaction conditions: 1 (0.4 mmol, 1.0 equiv), BrCF2R3 (0.6 mmol,
1.5 equiv), PMDETA (0.6 mmol, 1.5 equiv), Cu2O (10 mol %),
DMSO (1.0 mL), under Ar at 50 °C for 12 h. Isolated yield was based
on 1.
C
DOI: 10.1021/acs.orglett.8b02840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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This is the first report of difunctionalization of unactivated
alkenes with desulfonylation-initiated distal alkenyl migration,
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02840.
Experimental procedures, spectral and analytical data,
and 1H and 13C NMR spectra for new compounds
(PDF)
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6741−6748. (b) Wang, K.; Villano, S. M.; Dean, A. M. J. Phys. Chem.
A 2015, 119, 7205−7221. (c) Bian, H.; Wang, Z.; Zhang, F.; Wang,
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wanggw@tju.edu.cn.
ORCID
(9) (a) Li, L.; Li, Z.-L.; Gu, Q.-S.; Wang, N.; Liu, X.-Y. Sci. Adv.
2017, 3, No. e1701487, DOI: 10.1126/sciadv.1701487. (b) Tang, X.;
Studer, A. Angew. Chem., Int. Ed. 2018, 57, 814−817.
Guangwei Wang: 0000-0003-4466-9809
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of Tianjin (No.
16JCYBJC20100) and Tianjin University for support of this
research.
́
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