Selectfluor-Mediated Stereoselective [1 + 1 + 4 + 4] Dimerization of Styrylnaphthols

Article abstract of DOI:10.1021/acs.orglett.9b03587

Stereoselective [1 + 1 + 4 + 4] dimerization of 1-styrylnaphthols has been developed by using Selectfluor as the oxidant for the first time. The reaction was compatible with various functional groups, giving a class of ethanodinaphtho[b,f][1,5]dioxocines

Full text of DOI:10.1021/acs.orglett.9b03587

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selectfluor-Mediated Stereoselective [1 + 1 + 4 + 4] Dimerization of
Styrylnaphthols
Hui Yang, Huai-Ri Sun, Rui-Di Xue, Zi-Bo Wu, Bo-Bo Gou, Yibo Lei, Jie Chen,* and Ling Zhou*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, National Demonstration Center for Experimental Chemistry Education, Northwest University, Xi’an 710127,
P.R. China
S
* Supporting Information
ABSTRACT: Stereoselective [1 + 1 + 4 + 4] dimerization of
1-styrylnaphthols has been developed by using Selectfluor as
the oxidant for the first time. The reaction was compatible
with various functional groups, giving a class of
ethanodinaphtho[b,f][1,5]dioxocines with novel 3D skeletons.
DFT calculations indicate that this method merges an
intriguing stereoselective intermolecular 1 + 1 radical coupling
to construct a bridged C−C bond and then an intramolecular
[4 + 4] formal cycloaddition of the in situ generated o-quinone methide intermediate.
imerization reactions represent a synthetically powerful
strategy for the rapid construction of molecular
Scheme 1. 1 + 1 and [4 + 4] Dimerization Reactions
D
complexity in organic chemistry. Many dimerization reactions
have been developed for the synthesis of natural and unnatural
compounds containing symmetric moieties.1 Elegant ap-
proaches including 1 + 1 radical dimerization reactions2 and
[4 + 4] cycloaddition reactions3−5 have emerged as powerful
tools for the construction of C−C and C−X bonds. Various
compounds such as resveratrol,6 oxindoles,1p,2b,i isatins,2l as
well as alkynes1e,k−m,2j,k and other bioactive compounds2n were
employed as substrates for 1 + 1 radical dimerization to
generate one C−C bond by using oxidative or reductive
strategies (Scheme 1, eq 1). The [4 + 4] cycloaddition reaction
is very significant for the construction of annulated eight-
membered rings, including the photocycloaddition of 1,3-
dienes (Scheme 1, eq 2)3 and formal cycloaddition of
unsaturated imines4 or aldehyde/ketone5 with two new
bonds formed (Scheme 1, eq 3). Although the thermal process
is forbidden for the [4 + 4] cycloaddition of 1,3-dienes, it is
allowed for the hetero-[4 + 4] cycloaddition.5 However,
compared with various tandem reaction methods developed
for efficient formation of complex molecules, current
dimerization reactions mostly focuses on one m + m reaction.
Only a few examples of a tandem strategy including
dimerization reactions are available.1n,2n
Tandem dimerization and cyclization of stilbene derived
monomers (e.g., resveratrol) is proposed as biosynthetic route
in nature and also realized in the lab by enzymatic catalysis or
oxidative conditions. A series of resveratrol dimerization
reactions have been developed,6 which appears to proceed
via the coupling of oxidatively generated phenoxyl radicals.
Recently, Stephenson and co-workers developed an efficient
synthetic route to reseveratrol dimers by using oxidative 1 + 1
radical dimerization and Friedel−Crafts reactions.6o Despite
the prominence of dimerization reaction in organic synthesis,
from the synthetic point of view, the combination of m + m
and [n + n] dimerization reactions in a single step may allow
efficient creation of multicyclic ring skeletons.
Stereoselective construction of multiple rings in a single step
is a fascinating and synthetically useful strategy for rapid
assembly of polycyclic molecules. Numerous intramolecular
Diels−Alder reactions and tandem reactions have been
developed for the synthesis of bridged bicyclic ring systems
Received: October 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03587
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
oxidant (equiv)
additive
solvent
t (h)
2a
40
trace
50
3a
55
23
5
1
2
3
4
5
6
7
8
9
DDQ (1.2)
MnO2 (1.2)
Selectfluor (1.2)
NBS (1.2)
THF
THF
THF
THF
8
48
48
48
48
48
48
48
36
36
24
12
12
12
12
12
73
Selectfluor (1.2)
Selectfluor (1.2)
Selectfluor (1.2)
Selectfluor (1.2)
Selectfluor (1.2)
Selectfluor (1.2)
Selectfluor (1.2)
Selectfluor (1.2)
Selectfluor (1.0)
Selectfluor (0.8)
Selectfluor (0.6)
Selectfluor (1.5)
toluene
DCM
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
trace
trace
15
41
10
21
16
18
9
56
34
60
58
77
65
80
85
74
70
Sc(OTf)3
Cu(OTf)2
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
10
11
c
12
13
14
15
16
8
9
8
a
Reactions were carried out with 1a (0.20 mmol), additive (0.04 mmol), and oxidant (0.24 mmol) in solvent (2.0 mL) under N2 at 40 °C.
b
c
Isolated yield. The reaction temperature is 50 °C.
containing the cyclohexene motif.7 Nonetheless, creation of
medium-sized multicyclic rings by other cycloaddition
reactions has lagged far behind, and there are only a few
examples describing the formation of eight-membered ring
systems.8 At the same time, the bridged structure of a
dioxabicyclo[3.3.1] nonane unit commonly occurs in natural
products and drug molecules, such as cyanomaclurin and
cyanomaclurin analogue.8b The design and synthesis of
compounds with novel bridged structures is a significant and
ongoing challenge within molecular science. Therefore,
developing new methods to realize tandem dimerization for
the construction of polycyclic molecules is highly desirable.
Recently, our group has been interested in the chemistry of
vinylphenol by taking advantage of its unique reactivity.9
Motivated by our research program on efficiently accessing
benzofuran9a and benzoindole skeletons9b by [3 + 2]
cycloaddition reactions and previous work on the resveratrol
dimerization, we envisioned that (E)-1-styrylnaphthols bearing
an ortho hydroxyl group could dimerize to generate o-quinone
methide intermediates via a oxidative radical dimerization
strategy. Subsequent intramolecular [4 + 4] cycloaddition
would then generate a bridged bicyclic ring system. Herein, we
report a concise construction of ethanodinaphtho[b,f][1,5]-
dioxocine with novel 3D skeletons from (E)-1-styrylnaphthol
by using Selectfluor as the oxidant in a one-pot fashion for the
first time (Scheme 1). Intriguingly, multiple events occurred in
this reaction: (1) A tandem stereoselective intermolecular 1 +
1 radical coupling and an intramolecular [4 + 4] cyclization
occurred. (2) One bridged C−C single bond and two C−O
single bonds were formed. (3) A bridged bicyclic seven-
membered ring was obtained in one step. (4) The
diastereoselectivity was excellentonly one isomer was
observed.
We commenced our investigations with the model reaction
shown in Table 1. To our delight, the desired product 2a was
obtained in 40% yield when the (E)-1-styrylnaphthol 1a was
treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in
THF at 40 °C for 8 h (Table 1, entry 1). The structure of 2a
was determined unambiguously by X-ray crystallographic
analysis. Meanwhile, the benzofuran 3a was also isolated as a
side product in 55% yield. Encouraged by the result, several
other oxidants were investigated. When MnO2 was used as the
oxidant, almost no desired product was formed (Table 1, entry
2). Compared with DDQ, Selectfluor was found to be more
effective for this transformation (Table 1, entry 3 vs entry 1).
In contrast, the reaction afforded 3a exclusively when N-
bromosuccinimide (NBS) was used as the oxidant (Table 1,
entry 4). Next, various solvents were screened, and EtOAc
gave the best results (Table 1, entries 5−7). To further
improve its synthetic efficiency, a range of additives such as
Sc(OTf)3, Cu(OTf)2, CuBr, and CuCl were evaluated (Table
1, entries 8−11). Fortunately, a significant improvement was
obtained (77% yield) when CuCl (0.2 equiv) was used as an
additive, and it was also found that the starting material 1a was
totally consumed (Table 1, entry 11). In addition, a further
increase of the reaction temperature could not improve the
efficiency of the reaction (Table 1, entry 12 vs entry 11).
Finally, decreasing the amount of Selectfluor to 1.0 equiv or
0.8 equiv has a positive effect on the reaction conversion
(Table 1, entries 13 and 14). However, further reducing the
amount of Selectfluor to 0.6 equiv resulted in a decrease in the
yield of 2a (Table 1, entry 15). On the other hand, an increase
in the Selectfluor loading (from 1.2 equiv to 1.5 equiv) had no
significant influence on the reaction efficiency (Table 1, entry
16).
With the optimized conditions established (Table 1, entry
14), the substrate scope of the reaction was explored. As shown
B
DOI: 10.1021/acs.orglett.9b03587
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of (E)-1-Styrylnaphthols
a
Reactions were carried out with 1 (0.2 mmol), Selectfluor (0.16 mmol), and CuCl (0.04 mmol) in EtOAc (2.0 mL) at 40 °C under N2. The yields
shown are for isolated products.
in Scheme 2, various substituted (E)-1-styrylnaphthols were
surveyed. We were pleased to find that substituents at the
ortho-position of the phenyl ring, such as Cl, Br, and CN, all
could afford the desired products in good yields (Scheme 2,
2b−d). In addition, product 2e with a 3-Br substituent phenyl
was obtained in 72% yield. Furthermore, substrates with
different substituents at the para-position of the phenyl ring
were well tolerated under the identical conditions, all
proceeding in moderate to excellent yields (Scheme 2, 2f−
n). As a result, substrates with electron-donating or -with-
drawing substituents at the para-position of the phenyl ring
could give the corresponding products in good yields.
Nonetheless, strong electron-withdrawing substituents re-
turned measurably lower yields (Scheme 2, 2k−n). The
reason may be that the electron-withdrawing substituents
decreased the electron density of the substrates; thus, the
stability of the corresponding radical intermediates was
reduced. Further investigation demonstrated that disubstituted
substrates could also provide the corresponding products in
good yields (Scheme 2, 2o−p).
In addition, we surveyed the substrate scope with regard to
the naphthol moiety. Substrates with substituents at the 3-
position of the naphthol could be well tolerated, wherein the
corresponding products 2q−2t were delivered in moderate to
excellent yields ranging form 56% to 85%. Additionally,
substrates with different substituents bearing TMS, Et, Br, or
Ph at the 6-position of the naphthol were transformed
effectively (2u−x). Finally, product 2y with an OTf substituent
at the 7-position of the naphthol was obtained in good yield.
Notably, the tolerance of the halogens and OTf provided great
potential to produce more complex structures through cross-
coupling reactions.
C
DOI: 10.1021/acs.orglett.9b03587
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Organic Letters
Letter
Interestingly, the strategy was also applicable for 10-
styrylphenanthren 1z; the corresponding saddle-shaped
product 2z could be readily achieved (Scheme 3). To further
Scheme 5. Plausible Reaction Mechanism
Scheme 3. Reaction of 1z and 1aa with Selectfluor
demonstrate the utility of this method, (E)-2-styrylphenol 1aa
was treated under the standard reaction conditions, and the
desired product 2aa was obtained smoothly in high yield.
To elucidate the reaction mechanism, some control
experiments were conducted. As shown in Scheme 4, it was
Scheme 4. Control Experiments
generate two possible intermediates II or III. The reason why
the diastereoisomer III was produced predominantly may be
due to the π−π stacking interaction between both phenyl and
naphthalene rings in the transition state B-TS. Additionally,
the corresponding tertiary radical coupling product was not
observed probably because of the steric reason. Next, the
substrate-controlled stereoselective intramolecular [4 + 4]
cycloaddition reaction of III would form the desired product
2a. The side-product 3a was formed possibly via an
intramolecular radical cyclization process from intermediate I
or a cationic cyclization process from a carbocation
intermediate generated by further oxidization of intermediate
I.10,12
We next conducted DFT studies to gain insight into the
reaction mechanism and the origin of the high levels of
stereoselectivity observed. All calculations were performed
with Gaussian 09. The geometries of all intermediates and
transition states were optimized at the B3LYP-D3/6-1G(d)
level, and energies were calculated at the M06-2X/6-311G*
level with the solvation effect (Figure 1). Indeed, the potential
energy of the transition state B-TS was found to be lower than
that of the transition state A-TS by 8.7 kcal/mol.11 Further
intramolecular [4 + 4] cycloaddition reaction of III gave the
desired product 2a through a moderate barrier (III-TS, 13.7
kcal/mol), whereas a higher barrier of II-TS (18.9 kcal/mol)
was observed.
found that the desired product could be obtained in only 18%
yield when TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) was
added, indicating that the reaction may proceed via a radical
pathway (Scheme 4, eq 1 vs Table 1, entry 14). At the same
time, the desired product 2a was still obtained when
Selectfluor was absent (eq 2), because compound 1a can be
oxidized by TEMPO directly (eq 3). Moreover, reaction of 1a
with DDQ in the presence of CuCl gave a result similar to that
in the absence of CuCl (Scheme 4, eq 4 vs Table 1, entry 1),
while clear improvement was observed when CuCl was used
together with Selectfluor (Table 1, entry 7 vs entry 11). These
results suggested that CuCl plays a role in the Selectfluor
oxidation process. Indeed, Ritter and co-workers reported an
unusual SET/fluoride transfer/SET mechanism by which a
Pd(IV)-complex captures fluoride and subsequently transfers it
to nucleophiles.10a Lectka and co-workers explored the
supposed SET chemistry between copper and Selectfluor,
including outter-sphere or inner-sphere electron transfer
mechanisms.10b
On the basis of the above results and previous studies, we
propose a plausible reaction mechanism for this transformation
(Scheme 5). First, (E)-1-styrylnaphthol 1a was oxidized by
Selectfluor or a Cu(II) species to form the oxygen radical
intermediate,11 which underwent a radical dearomatization to
generate o-quinone methide radical intermediate I. Next, a
radical−radical coupling reaction of the intermediate I would
In conclusion, we have developed a novel and practical
dimeration of (E)-1-styrylnaphthols by using Selectfluor as the
oxidant under mild reaction conditions, leading efficiently to
interesting bridged ethanodinaphtho[b,f][1,5]dioxocine scaf-
folds. This reaction underwent a formation of bridged C−C
D
DOI: 10.1021/acs.orglett.9b03587
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03587.
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Experimental details and spectroscopic and analytical
data for new compounds (PDF)
Accession Codes
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CCDC 1882505 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chmchenj@nwu.edu.cn (J.C.).
*E-mail: zhoul@nwu.edu.cn (L.Z.).
ORCID
Jie Chen: 0000-0001-6745-5534
Ling Zhou: 0000-0002-6805-2961
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC-21672170), Natural Science Basic Research Plan in
Shaanxi Province of China (2018JC-020, 2018JM2029), and
China Postdoctoral Science Foundation (2018M643705) for
financial support. The calculations were performed at chemical
HPC center of NWU.
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