Three-Component Oxyarylation of Alkenes Enables Access to C3-Substituted Dihydrobenzofurans

Article abstract of DOI:10.1021/acs.orglett.8b03278

A practical and modular three-component alkene oxyarylation with benzoquinone and H₂O to rapidly access C₃-substituted dihydrobenzofurans has been developed. The (NH₄)₂S₂O₈-mediated redox-r

Full text of DOI:10.1021/acs.orglett.8b03278

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Three-Component Oxyarylation of Alkenes Enables Access to
C3‑Substituted Dihydrobenzofurans
Guidong Feng,†,§ Shutao Sun,†,§ Guoliang Liu,†,§ Huan Long,† and Lei Liu*,†,‡
†School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
‡School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
S
* Supporting Information
ABSTRACT: A practical and modular three-component alkene
oxyarylation with benzoquinone and H2O to rapidly access C3-
substituted dihydrobenzofurans has been developed. The
(NH4)2S2O8-mediated redox-relay process has an excellent
regioselectivity and functional group tolerance and exhibits a
broad scope of simple alkenes, rapidly furnishing a variety of the
substructures that would require multiple steps to prepare with
traditional methods. Mechanistic studies revealed a dual role of
benzoquinone serving as both the arylation agent and the origin of dihydroquinone for the reductive cyclization step.
both of which require multiple steps for substrate prefunction-
alization (Figure 1b).2,3 On the other hand, acid-catalyzed [3 +
2] cycloaddition of alkenes with benzoquinone (BQ)
represents one of the most practical methods for rapid DHB
skeleton construction (Figure 1c).4 Due to the innate alkene
polarization, the biomimetic oxyarylation process follows
Markovnikov’s rule, predominantly giving C2-substituted
DHBs with oxygen bonding to the more substituted olefinic
carbon.5,6 Moreover, the reaction mechanism requires
electron-rich alkenes such as styrenes and enol ethers, with
the widely existing simple olefins intact. Accordingly, direct
access to C3-substituted DHBs by reversing the alkene
polarization in oxyarylation with BQ would be an attractive,
but challenging, project to pursue.7
C3-Substituted dihydrobenzofurans (DHBs) are key motifs in a
number of bioactive natural molecules and have been used for
many pharmaceutical applications (Figure 1a).1 The most
frequently employed approach to access such motifs relies on
intramolecular arylation of an allylic ether of o-halophenol
either through organotin-mediated radical cyclization or
through transition-metal-catalyzed Heck-type cyclization,
Recently, we have disclosed an (NH4)2S2O8-mediated three-
component oxyalkynylation of alkenes using H2O as an
oxygenation agent.8 Notably, the method exhibited reversed
regioselectivity to the existing three-component carbooxyge-
nation of alkenes. Mechanistic studies revealed that the
reversed regioselectivity was dictated by an alkene radical
cation species that underwent hydration to give anti-
Markovnikov β-oxyl radical 1 for the subsequent alkynylation
process. Given the electron-deficient property of BQ toward
radical addition,9 a two-step redox-relay approach for C3-
substituted DHBs was initially designed: (1) alkene 2 proceeds
through regioselective hydroxylation to generate an anti-
Markovnikov β-oxyl radical 1 that participates in oxidative
C−H alkylation of BQ to yield quinone 3, and (2) 3 undergoes
reductive cyclization to furnish the expected C3-substituted
DHB 4 (Figure 1d). Herein, we report an (NH4)2S2O8-
mediated metal-free three-component oxyarylation of alkenes
Figure 1. Overview of the access to C3-substituted DHBs through
alkene arylation reaction.
Received: October 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03278
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with BQ and H2O that furnishes C3-substituted DHBs with
high regio- and diastereoselectivities (Figure 1e).
Scheme 1. Mechanistic Studies
Initially, a three-component reaction of 1-octene (2a), BQ,
and H2O was selected for optimization (Table 1, also see the
a
Table 1. Reaction Condition Optimization
b
yield (%)
entry
oxidant
oxidant
Na2S2O8
Na2S2O8
K2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
additive
3a
4a
c
1
<5
14
<5
<5
<5
<5
<5
<5
<5
<5
<5
8
d
2
e
3
20
15
24
31
28
41
9
4
5
6
7
8
CuSO4
NaI
I2
I2
I2
f
9
g
10
46
a
2a (0.3 mmol), BQ (0.1 mmol), oxidant (0.2 mmol), and additive
(0.02 mmol) in H2O/CH3CN/acetone (2.1 mL, v/v/v = 1:1:1) at 80
b
c
°C for 24 h. Yield of isolated product. (NH4)2Ce(NO3)6,
d
Mn(OAc)3, or TBHP as oxidant. Reaction was analyzed after 6 h.
Reaction without H2O. 2a used as the limiting agent. Reaction at
e
f
g
110 °C for 4 h.
Supporting Information). An exploration of common single-
electron oxidants revealed that Na2S2O8 promoted the
reaction, furnishing the expected alkylated quinone 3a in
14% yield after 6 h (entries 1 and 2). To our surprise, a
considerable amount of C3-substituted DHB 4a was also
observed in 8% yield. Moreover, 3a was found to be converted
to 4a when the reaction ran longer (entry 3). Examination of
the counterion effect of peroxydisulfate as well as the additive
effect identified (NH4)2S2O8 and a catalytic amount of I2 to be
the best candidates (entries 3−8). Reaction with 2a as a
limiting agent afforded an inferior result (entry 9). Variation of
reaction temperature indicated that reaction at 110 °C
provided 4a in optimal 46% yield (entry 10). No regioisomeric
C2-substituted DHB was detected. The commercial availability
of alkenes and BQ combined with the low cost of (NH4)2S2O8
(less than $0.04 per gram) make the three-component
oxyarylation of alkenes more attractive for access to C3-
substituted DHBs than previously reported methods that
require prefunctionalization and expensive reagents.
During the reaction optimization, two interesting observa-
tions merited further elucidation: (1) the proposed two-step
redox-relay sequence in Figure 1d was actualized in a single
step under an oxidative condition, and (2) the optimized
reaction yield was less than 50%. Accordingly, a series of
experiments were conducted to gain a preliminary under-
standing of the reaction mechanism (Scheme 1). First,
subjecting isolated 3a to the standard conditions afforded
DHB 4a in good yield, thus implying the intermediacy of 3a
(eq 1). Second, a considerable amount of dihydroquinone
(DHQ) was detected during the reaction process. Moreover,
the pH value of the reaction solution was less than 7. The
transformation of 3a to 4a proceeded smoothly in the presence
of DHQ and stoichiometric H2SO4, suggesting that DHQ
might be the species in charge of the reductive cyclization step
(eq 2).10 It has been reported that peroxydisulfate ion can
promote the conversion of 2 equiv of BQ to 1 equiv of DHQ
and 1 equiv of highly oxidized dark brown materials.11 Indeed,
(NH4)2S2O8 effected the conversion of BQ to DHQ in 49%
yield together with other unidentified black materials, though
the process required 12 h for complete BQ consumption (eq
3). The reaction with catalytic amount of I2 was completed in 4
h (eq 4). Accordingly, we envisioned that catalytic amount of
I2 might expedite the formation of DHQ, thus harmonizing the
process with the formation of 4a, though the origin of curious
but useful effect has not been elucidated. Third, H218O isotopic
labeling experiments indicated that oxygens in both alkylated
quinone 6 and DHB 4a should originate from H2O (eqs 5 and
6). Finally, intermolecular KIE for BQ is 1.0, suggesting that
C−H cleavage of BQ should be a fast step and might not be
involved in the rate-determining step (eq 7). According to the
above experiments and previous electron paramagnetic
resonance studies, a mechanism is proposed in Scheme 1e.8
1-Octene 2a was oxidized by SO4•− giving alkene radical cation
7, which reacted with H2O, affording a bridged radical cation
complex 8.12 The regiochemistry was dictated by the relative
stabilities of two possible distonic radical cations 9 and 10. The
more stable 10 underwent deprotonation to generate β-
hydroxyl radical 11. Radical 11 was added to BQ to provide
B
DOI: 10.1021/acs.orglett.8b03278
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
radical 12, which underwent hydrogen atom abstraction to
deliver alkylated quinone 3a. Under acidic conditions, a
kinetically favored intramolecular cyclization followed by
dehydration gave oxocarbenium 13, which was reduced by
DHQ, to deliver C3-substituted DHB 4a and regenerate BQ.
The scope of three-component oxyarylation of alkenes was
then explored (Scheme 2). The reaction proved fairly general
evidenced by rapid access to DHB-fused tricyclic 4r and 4s
bearing an all-carbon quaternary center at the C3 position.14
The scope of styrenes was next probed (Scheme 3).
Electronically varied terminal styrenes were competent
Scheme 3. Scope of Styrenes and BQ
Scheme 2. Scope of Aliphatic Alkenes
components, yielding C3-aryl DHBs 15a−c with high
regioselectivity. 1,2-Disubstituted internal styrenes bearing
diverse electronic properties were also tolerated, yielding
trans-2-methyl-3-aryl-DHBs 15d−h related to chrysophyllon
VI-B type natural products shown in Figure 1a with good
regio- and diastereoselectivity. Notably, multiple steps were
previously required to prepare such skeletons.3d
The scopes of the BQs were then examined (Scheme 3).
Symmetric dimethyl-substituted BQ proceeded to give 15i in a
slightly reduced yield, presumably due to the steric factor. The
regioselectivity on unsymmetric BQs appeared to be controlled
by the electronic nature of the substituent. Para and meta
selectivities were observed for monoalkyl-substituted BQs (15j
and 15k), while monophenyl-substituted BQ gave 15l with
meta and ortho selectivities.15
The synthetic utility of the method was further explored
(Scheme 4). C3-Substituted spiro-piperidinyl DHBs such as
DHB-X (Figure 1a), 16a, and 16b have been demonstrated to
possess diverse pharmacological activities.1b−d However, they
were typically prepared via Bu3SnH-mediated intramolecular
cyclization of a highly functionalized piperidine-based allylic
ether of o-bromophenol.16 Under the standard conditions,
piperidine-based exocyclic methylenes 17a and 17b joined in
three-component oxyarylation, directly giving respective spiro-
piperidinyl DHBs 18a and 18b as a single isomer. The free
hydroxyl group could act as a linker for combining diverse
bioactive scaffolds for access to 16a-type compounds. DHBs
18a and 18b can also undergo dehydroxylation or Suzuki
coupling, giving 19a and 19b, respectively, for the synthesis of
16b-type molecules. Together, these applications further
a
Reaction at 1.0 mmol scale.
for a wide range of simple monosubstituted aliphatic alkenes
with varied alkyl chain lengths, providing C3-alkyl-substituted
DHBs 4a−m with excellent regioselectivity. A variety of
commonly encountered functionalities, including benzyl (4e),
silyl moiety (4f), halide (4g and 4h), alcohol (4i and 4j),
acetate (4k), carboxylic acid (4l), and alkene (4m), were
tolerated as additional functional handles. 1,1-Disubstituted
aliphatic alkenes were also found to be amenable to the
reaction, exclusively producing DHBs 4n−q bearing an all-
carbon quaternary center at the C3 position. In particular,
reactions with methylene cycloalkanes bearing different ring
sizes proceeded smoothly, rapidly affording 5-, 6-, and 7-
membered spirocycles 4o−q as a single isomer. Because DHB-
based spirocycles are prominent structural features in bioactive
molecules, and the efficient synthesis of such substructures has
been challenging, three-component oxyarylation starting from
simple alkenes and BQ would provide a complementary
method to the existing spirocyclization approaches.13 Trisub-
stituted aliphatic cyclic alkenes were also suitable substrates, as
C
DOI: 10.1021/acs.orglett.8b03278
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthetic Applications
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Experimental details and spectral data for new
compounds (PDF)
Accession Codes
CCDC 1443601 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: leiliu@sdu.edu.cn.
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Lei Liu: 0000-0002-0839-373X
Author Contributions
§G.F., S.S., and G.L. contributed equally.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Science Foundation of
China (21722204, 21472112) and the Fok Ying Tung
Education Foundation (151035) for their support.
D
DOI: 10.1021/acs.orglett.8b03278
Org. Lett. XXXX, XXX, XXX−XXX