Radical-Triggered Tandem Cyclization of 1,6-Enynes with H2O: A Way to Access Strained 1 H-Cyclopropa[ b]naph thalene-2,7-diones

Article abstract of DOI:10.1021/acs.orglett.8b03007

A radical-triggered tandem cyclization of 1,6-enynes has been developed herein. Strained 1H-cyclopropa[b]naphthalene-2,7-diones are successfully obtained in moderate to good yields with excellent stereoselectivity. Mechanistic studies reveal a key role of water in generating a hydroxyl radical that initiates a sequential Michael addition/ring closure pathway. Importantly, the formed hydroxyl is proposed to be a good leaving group during the cyclopropane ring formation.

Full text of DOI:10.1021/acs.orglett.8b03007

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical-Triggered Tandem Cyclization of 1,6-Enynes with H2O: A
Way to Access Strained 1H‑Cyclopropa[b]naph thalene-2,7-diones
Limeng Zheng,† Bingwei Zhou,† Hongwei Jin,† Ting Li,*,‡ and Yunkui Liu*,†
†State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou,
310014, P. R. China
‡College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nangyang, Henan 473061, P. R. China
S
* Supporting Information
ABSTRACT: A radical-triggered tandem cyclization of 1,6-
enynes has been developed herein. Strained 1H-cyclopropa-
[b]naphthalene-2,7-diones are successfully obtained in mod-
erate to good yields with excellent stereoselectivity. Mecha-
nistic studies reveal a key role of water in generating a hydroxyl
radical that initiates a sequential Michael addition/ring closure
pathway. Importantly, the formed hydroxyl is proposed to be a
good leaving group during the cyclopropane ring formation.
Scheme 1. Construction of the Cyclopropane Ring via an
Anionic/Cationic Pathway
yclopropanes are known as biologically and medicinally
Cactive structures that are widely found in natural
products, medicines, and agrochemicals.1 Synthetically, they
are versatile building blocks enabling a ring-opening reaction
to access functionalized acyclic compounds due to the unique
structure of the three-membered ring.2 Additionally, cyclo-
propanes have practical utilities in mechanistic studies of
various organic transformations associating with a radical
pathway.3 Consequently, the construction of the cyclopropane
subunit is of synthetic interest, and various methodologies have
been developed over the past several decades.4 Among them,
the sequential Michael addition-ring closure pathway has
gained considerable attention since the pioneering work by
Corey in 1958.5 A variety of heteroatom-derived ylides and
electron-withdrawing group (EWG)-stabilized carbanions are
proven to be versatile methylene precursors (Scheme 1a).
Other anionic cyclizations of 1,2-electrophiles such as
epichlorohydrins, epoxyolefins, and cyclic 1,2-sulfates are also
demonstrated (Scheme 1b).6 Relatively, the cationic cycliza-
tions of O-protected allylic alcohols are less reported (Scheme
1c).7 It should be mentioned that a good leaving group such as
sulfide, OTf, or bromide is indispensable to facilitate the
formation of the cyclopropane ring in those reactions, whereas
the free hydroxyl has never been disclosed as a leaving group in
the ring closure step. Thus, the development of facile
cyclopropane ring formation by using small leaving groups
(such as a hydroxyl group) in a more atom-economic manner
is highly desirable.
group has also reported a Cu(0)/Selectfluor system-catalyzed
annulation of 1,6-enynes affording benzo[b]fluorenones under
mild conditions.13 To further extend the reaction scope of 1,6-
enynes, we herein disclose a radical-triggered tandem
Transition metal-catalyzed or radical-mediated cascade
cyclization of 1,n-enynes has emerged as a powerful strategy
to achieve cyclic compounds with operational simplicity and
high efficiency.8,9 Specifically, (E)-3-phenyl-1-(2-(2-phenyl-
ethynyl) phenyl)prop-2-en-1-one represents one of the typical
1,6-enynes and has been explored in several reactions
independently by Li,10 Hu,11 and others.12 Recently, our
Received: September 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03007
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclization for the synthesis of strained 1H-cyclopropa[b]-
naphthalene-2,7-diones with an exclusive cis stereoselectivity
(Scheme 1d). The strained cyclopropane ring can be
constructed with an in situ-generated hydroxyl as a suitable
leaving group, thus featuring an excellent step and atom
economy.
With the optimized reaction conditions in hand, we set out
to investigate the scope of 1,6-enynes (Scheme 2). The
Scheme 2. Substrate Scope for 1,6-Enynes
Initially, we chose (E)-3-phenyl-1-(2-(phenylethynyl) phe-
nyl) prop-2-en-1-one 1a as a model substrate to optimize the
reaction conditions. The reaction was performed in the
presence of I2O5 and water in dioxane at 100 °C.
Unexpectedly, 1H-cyclopropa[b]naphthalene-2,7-dione 2a
was obtained in 50% LC yield (Table 1, entry 1). We then
a
Table 1. Optimization of the Reaction Conditions
I2O5
(equiv)
temp
(°C)
b
entry
additive (mol %)
solvent
yield (%)
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
1.5
1.0
d
c
dioxane
dioxane
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
110
90
50
59
62
57
61
50
72
36
35
21
trace
trace
0
FeCl3/20
CuSO4·5H2O/20 dioxane
Cu/20
CuCl/20
Cu(OAc)2/20
FeCl3·6H2O/20
AgNO3/20
AlCl3/20
BF3·Et2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/20
FeCl3·6H2O/10
FeCl3·6H2O/30
FeCl3·6H2O/40
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
PhCF3
MeCN
DMSO
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
substitutes R1 on phenyl ring A were first examined. It was
found that electron-donating groups had a positive effect on
the outcome of the reaction, whereas electron-withdrawing
groups had a negative effect (2a, 2b vs 2c−e). A substrate with
fluorine at the 2- or 5-position of phenyl ring A provided a
comparable yield (2d, 2e). Next, the R2 group on the chalcone
moiety of 1 was screened. When R2 equals an aryl group, it was
found that a range of electron-varied functional groups such as
halogen, cyano, or free hydroxyl on the phenyl ring were all
tolerated in this reaction (2f−n). Of note, the structure of 2j
and the cis configuration of the two aryl rings on the
cyclopropane were unambiguously confirmed by the X-ray
crystallographic analysis (see Supporting Information). In
addition, substrates with R2 as 1-naphthalenyl and 2-
thiophenyl were also workable for the reaction, and the
desired products were obtained in 51 and 81% yields,
respectively (2o, 2p). Substrate 1y with R2 as an n-propyl
group failed to give the desired product. Surprisingly, 1z with
R2 as a cyclopropyl group delivered diketonized product 2z′ in
67% yield instead of the formation of 2z. Furthermore, we
evaluated the scope of the R3 group connecting to the alkyne
moiety. Again, the reaction could proceed very well when R3
equals an aryl ring (either electron-rich or -deficient) as well as
a heteroaromatic ring (2q−x). When 1aa with R3 as a tert-butyl
group was used, the reaction failed to give desired product 2aa,
whereas carbon−carbon bond-cleaved product 2aa′ was
obtained in 55% yield. Finally, a gram-scale (5 mmol of 1a
used) synthesis of 2a was also carried out, and 2a could be
obtained in 67% yield (see Supporting Information).
0
66
65
69
0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
69
70
77
70
50
80
70
80
80
e
87 (83 )
80
78
a
Reaction conditions: 1a (0.2 mmol), H2O (0.4 mmol), oxidant,
b
additive in dry solvent (4 mL) under air for 0.5 h. Yields determined
by LC analysis. No additive. No oxidant. Isolated yield shown in
parentheses.
c
d
e
screened a series of Lewis acids where FeCl3·6H2O promoted
this transformation efficiently (entries 2−10). Different
solvents were examined, and dioxane was proven to be the
best one (entries 11−14). Two equivalents of I2O5 were
enough to obtain a satisfactory yield of 2a, as either increasing
or decreasing the amount of I2O5 could not improve the yield
of 2a (entry 7 vs 15−18). Finally, the optimal reaction
conditions were obtained by tuning the reaction temperature
to 80 °C and using 30 mol % of FeCl3·6H2O (entry 24).
B
DOI: 10.1021/acs.orglett.8b03007
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Organic Letters
Letter
To ascertain the possible reaction mechanism, we conducted
several mechanistic experiments (Scheme 3). At the beginning,
under thermal conditions might generate a hydroxyl radical
and I2.14,16 The sequential Michael addition of the hydroxyl
radical to 1a followed by an intramolecular cyclization
produced intermediate B. Active B was then captured by I2
to form intermediate C.14a An oxidation of C by HIO3
provided an vinyl-λ3-iodane intermediate D that underwent
substitution by H2O to deliver intermediate E.14a The
cyclopropane moiety was constructed via a ring closure
process where the hydroxyl acted as a leaving group under
the assistance of a proton (or FeCl3·6H2O if added).17
Eventually, the deprotonation of resulting intermediate F
released desired product 2a. In addition, mechanism II
involved in a high-valent iron(IV or V)18 species-triggered
water addition to chalcone10,19 followed by the formation of
intermediate E under oxidative conditions16,20 is also possible.
In summary, we have developed a tandem cyclization of 1,6-
enynes via a cascade Michael addition/ring closure pathway.
During the cyclopropane ring formation, the hydroxyl is
viewed as a good leaving group under the assistance of a Lewis
acid. Various substituted 1H-cyclopropa[b]naphthalene-2,7-
diones were obtained in moderate to good yields with excellent
cis stereoselectivity. The characteristic features of this reaction
are as follows: (1) low toxicity and inexpensive iron catalyst,
(2) water as a source for C=O bond formation, and (3) the
reaction exhibiting step and atom economy due to the in situ-
generated hydroxyl group as the leaving group. Further studies
on cyclizations of other 1,n-enynes via a radical process are
underway in our laboratory.
Scheme 3. Mechanistic Studies Based on 1a
TEMPO was used as a radical scavenger and subjected to the
standard conditions. We found that the reaction was almost
suppressed, which indicated that a radical pathway might be
involved in this reaction. Next, we performed an isotope
labeling experiment by utilizing H218O to clarify the oxygen
source and possible radical species. The result shows that 18O
was incorporated into product 2a and the oxygen in air was
excluded to be an oxygen precursor. Thus, a hydroxyl radical
was proposed to be generated from the reaction of H2O and
I2O5.14 Furthermore, we performed a control experiment by
removing the H2O and using anhydrous FeCl3. As expected, no
product was detected, and this result further supported our
previous hypothesis. At last, an attempt to run the reaction
under dark conditions was also investigated, and 2a could still
be obtained in 85% yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03007.
Experimental details, full characterization data, mecha-
nistic experiments, X-ray crystallographic structure of 2j,
and copies of NMR spectra for compound 2 (PDF)
Accession Codes
CCDC 1856715 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
On the basis of our preliminary results and previous
literature,14−20 we proposed two possible mechanisms of this
reaction, as depicted in Scheme 4. Mechanism I involves a
radical process: First, the hydrolysis of I2O5 by water gave
HIO3.15 Then, the oxidation reaction between HIO3 and water
Scheme 4. Proposed Mechanism
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: ykuiliu@zjut.edu.cn.
*E-mail: chemlt2015@nynu.edu.cn.
ORCID
Ting Li: 0000-0002-2186-6992
Yunkui Liu: 0000-0001-8614-458X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Natural Science Foundation of China
(Nos. 21772176 and 21372201) for financial support.
C
DOI: 10.1021/acs.orglett.8b03007
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