Visible-Light-Mediated [4+2] Cycloaddition of Styrenes: Synthesis of Tetralin Derivatives

Article abstract of DOI:10.1002/anie.201702940

We report a formal [4+2] cycloaddition reaction of styrenes under visible-light catalysis. Two styrene molecules with different electronic or steric properties were found to react with each other in good yield and excellent chemo- and regioselectivity. This reaction provides direct access to polysubstituted tetralin scaffolds from readily available styrenes. Sophisticated tricyclic and tetracyclic tetralin analogues were prepared in high yield and up to 20/1 diasteroselectivity from cyclic substrates.

Full text of DOI:10.1002/anie.201702940

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702940
German Edition: DOI: 10.1002/ange.201702940
Photochemistry
Visible-Light-Mediated [4+2] Cycloaddition of Styrenes: Synthesis of
Tetralin Derivatives
Leifeng Wang, Fengjin Wu, Jiean Chen, David A. Nicewicz,* and Yong Huang*
Abstract: We report a formal [4+2] cycloaddition reaction of
styrenes under visible-light catalysis. Two styrene molecules
with different electronic or steric properties were found to react
with each other in good yield and excellent chemo- and
regioselectivity. This reaction provides direct access to poly-
substituted tetralin scaffolds from readily available styrenes.
Sophisticated tricyclic and tetracyclic tetralin analogues were
prepared in high yield and up to 20/1 diasteroselectivity from
cyclic substrates.
T
etralin and its derivatives are prevalent structural motifs
among natural products, pharmaceuticals, and agrochemi-
cals.[1,2] Substituents along the tetrahydronaphthalene frame-
work play a central role in controlling the biochemical
properties of tetralins. As a result, considerable efforts[3] have
been made to access this class of structures. Typically, tetralin
systems are synthesized through metal-catalyzed cyclization
reactions of aryl derivatives (Scheme 1a).[4] A major draw-
back of this strategy is the need for pre-functionalization of
the starting materials, which is often non-trivial. An alter-
native approach is the hydrogenation of naphthalene deriv-
atives using H2/transitional-metal catalysts[5] or Birch con-
ditions[6] (Scheme 1a). Step economy and differentiation
between two fused benzene rings remain significant chal-
lenges. A strong demand remains for a mild, efficient, and
atom-economic synthetic method for tetralins and their
derivatives.
Scheme 1. Synthetic approaches to tetralins.
ing this class of catalysts allows the photooxidation of styrenes
to highly electrophilic cation radical species that can be
captured by various nucleophiles.[12] Considering that the
photooxidant is used in catalytic amounts, the remaining
unoxidized styrene could also serve as an internal nucleophile
to react with the cation radical intermediate. The resulting
dimeric cation radical has two cyclization pathways: [2+2] to
form cyclobutanes and [4+2] to form tetralin derivatives. We
recently reported a [2+2] homodimerization of styrenes using
an acridinium/naphthelene catalyst system.[13] Herein, we
disclose our findings on the [4+2] cycloaddition of two
different styrenes using a hydrogen atom transfer (HAT)
cocatalyst to access tetralin derivatives (Scheme 1b).
We made our initial discovery of the [4+2] cycloaddition
of 4-methoxystyrene (product 3, Table 1) by using PhSSPh as
a HAT cocatalyst. In the absence of phenyl disulfide, the
[2+2] cycloaddition (2, Table 1) was the only reaction
observed. Although 2 remained the major product in
acetonitrile, the chemoselectivity was reversed in dichloro-
ethane. We hypothesized that the use of a nonpolar solvent
would yield a shorter-lived cation radical that immediately
undergoes electrophilic cyclization before reduction of the
radical. The identity of the acridinium counterion had a minor
effect on the yield. Mes-Acr-PhBF4 (PS-B) delivered 3 in
77% yield of isolated product (Table 1, entry 3). Similar
yields were obtained for the corresponding perchlorate and
chloride salts, both of which produced 2 as side product in
approximately 10% yield (Table 1, entries 2 and 4). No
reaction occurred in the absence of blue light.
Over the past decade, photoredox catalysis using photo-
sensitizers (PS) has introduced a new paradigm for olefin
activation.[7,8] We recently established a number of trans-
formations by means of styrene activation using the Fuku-
zumi acridinium as a single-electron photooxidation cata-
lyst.[9,10] This family of organic photosensitizers are powerful
oxidants in their singlet excited state under blue-LED
radiation [E*red(Acr-Me+/Acr-MeC) =+ 2.18 V].[7a,11] Employ-
[*] L. Wang, F. Wu, Dr. J. Chen, Prof. Dr. D. A. Nicewicz,
Prof. Dr. Y. Huang
Key Laboratory of Chemical Genomics
School of Chemical Biology and Biotechnology
Peking University, Shenzhen Graduate School
Shenzhen, 518055 (China)
E-mail: huangyong@pkusz.edu.cn
Homepage: http://web.pkusz.edu.cn/huang
Prof. Dr. D. A. Nicewicz
Department of Chemistry, University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
E-mail: nicewicz@unc.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702940.
We next examined the feasibility of employing two
different styrenes to obtain structurally more diverse [4+2]
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Table 1: Diverting the dimerization pathway from [2+2] to [4+2].[a]
Ru(bpy)3Cl2, Ir(ppy)3, [Ru(bpz)3][PF6], and [Ru(bpm)3]Cl2 all
afforded very little product formation.
With optimized reaction conditions in hand, we next
examined the substrate scope with respect to the a-substi-
tuted styrenes as the 4p component (Table 2). Various alkyl
Table 2: Substrate scope with respect to the diene and dienophile.[a]
Entry
Photosensitizer (PS)
Solvent
2 [%][b]
3 [%][b]
1
2
3
4
PS-A
PS-A
PS-B
PS-C
ACN
DCE
DCE
DCE
64
10
<5
8
14
52
77[c]
56
[a] Reaction conditions: 1 (0.2 mmol), PS (5 mol%), PhSSPh
(20 mol%), solvent (2.0 mL), 20 hrs (two 15 W blue LEDs). [b] NMR
yield. [c] Yield of isolated product.
cross cycloaddition products. Statistically, two different styr-
enes would yield three possible dimers. We envisioned that
chemoselectivity might be accomplished by introducing
electronic/steric bias. We decided to use a less oxidizable
but more nucleophilic styrene to trap the cation radical from
4-methoxystyrene (1). a-Methylstyrene (4) has both a high
redox potential (+ 1.91 V)[10b] and high nucleophilicity (N =
2.35–2.39, Mayr scale)[14] and is well-suited to test our
proposal. We were pleased to find that 1 reacted smoothly
with 4 to give the desired hybrid cycloadduct 5 in 29% yield
and 1:1 d.r. (Scheme 2), along with a large amount of
[a] Reactions were run on a 0.2 mmol scale. Yields of isolated product are
shown.
groups were well tolerated. Polysubstituted tetralins were
prepared in good to moderate yields. Little diastereoselec-
tivity was observed for a-alkyl styrenes, thus indicating
a stepwise cyclization process. 1,1-Diphenylethylene reacted
more slowly with decreased yield, likely as a result of the
attenuated nucleophilicity of this substrate. A moderate d.r.
favoring the trans product was obtained for the reaction
involving 1,1-diphenylethylene, likely due to steric influence
during the HAT process (Table 2, products 8 and 10). The
scope with respect to the dienophile was also investigated.
Styrenes with either electron-rich (e.g., MeO) or electron-
poor (e.g., F) aryl substituents reacted with similar efficiency,
however, a strong electron-withdrawing nitro substituent was
not tolerated. In addition to styrenes, ethyl vinyl ether could
also function as a 2p component for this reaction, giving the
oxygenated tetralin product 15 in moderate yield.
The [4+2] cycloaddition of two styrenes lacking an a-
substituent would be significantly more challenging since both
diene and dienophile are very similar sterically. In order to
address the chemoselectivity issue, we choose styrene pairs
that are electronically distinguishable. As exemplified in
Table 3, a number of styrene pairs can be implemented in
chemo- and regioselective tetralin formation reactions. p-
Methoxystyrene (1) serves as an excellent cation radical
precusor (diene) to react with a number of less electron-rich
styrenes (dienophile). Unlike in cases involving a-substituted
styrenes (Table 2), 1 always functions as the diene when
reacting with other non-a-substituted styrenes (Table 3).
Both electron-neutral and deficient styrenes are good reac-
tion partners (dienophile) for 1. When o-methylstyrene was
Scheme 2. A cross-cycloaddition reaction between 4-methoxystyrene
and a-methylstyrene.
homodimer 3 (52% yield) as the major side product. Styrene
1 serves as dienophile in this transformation, thus suggesting
a radical cyclization as opposed to Friedel–Crafts-type
electrophilic ring closure. In order to minimize the homo-
dimerization, we added 1 slowly into a stirring solution of 4
and catalysts. We expected that the transient radical cation of
1 would react with abundant 4 in the reaction vessel faster
than with 1, which would be present in very low concen-
trations. We were delighted to find that increasing the
concentration of 4 from 0.1m to 1.0m and adding 1 slowly
over 10 hours significantly improved the selectivity for cross
cycloadduction over homodimerization. The yield of 5 was
improved to 60% (d.r. = 1:1), with very little of homodimer 3
produced. Expanding the addition time of 1 to 20 hours
further improved the yield of 5 (71%, d.r. = 1:1), while the use
of PS-A and PS-C afforded slightly lower yields (42% and
48% respectively). Nevertheless, acrimidiniums proved crit-
ical for this reaction. Other photooxidants, such as Eosin-Y,
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Table 3: Reactivity screening of terminal styrenes.
Scheme 3. Synthesis of fused polycyclic tetralins by using the [4+2]
cycloaddition reaction.
6/6/7-fused tricyclic scaffolds. In this case, a 1:1 mixture of cis
and trans isomers is generally obtained.
Preliminary isotope-labeling experiments were carried
out. Partial deuterium incorporation was observed at one of
the benzylic carbon atoms of the product when using fully
deuterated a-methylstyrene (Scheme 4a). The incomplete
used as the dienophile, a mixture of two isomers (27 and 28)
was isolated owing to competing cationic and radical cycliza-
tion pathways (see below). b-Methylstyrenes were good
dienophiles for this transformation despite their low nucleo-
philicity, delivering trisubstituted tetralin products with
excellent chemo-, regio-, and diastereoselectivity. It is worth
noting that both trans- and cis-b-methylstyrenes yielded the
same diastereomeric product 29, with the cis alkene substrate
delivering higher yields (65% vs. 42% yield). This result also
confirms that the cyclization is stepwise and that bond
rotation occurs during ring closure. Other electron-rich
styrenes, such as o-methoxystyrene, are also competent
dienes for this transformation. Strongly electron-deficient
styrenes, such as p-nitrostyrene, failed to undergo the [4+2]
cycloaddition reaction.
The synthetic application of this visible-light-promoted
photoredox [4+2] cycloaddition of styrenes was further
demonstrated in the one-step synthesis of several tetralin
scaffolds with additional fused rings (Scheme 3). When
indene was used as dienophile, a fused 6/6/5/6 ring system
was obtained by using either p- or o-methoxystyrene as the 4p
component. The structure and relative stereochemistry was
confirmed by X-ray crystallography of product 30. The
corresponding 6/6/6/6 framework was accessed by using
tetrahydronaphthalene as the dienophile. These reactions
can be conveniently performed on a gram scale without
compromising the yield, and the products were always
isolated as single diastereomers. Additionally, exocyclic
olefins also react with p-methoxystyrene to yield 6/6/6- and
Scheme 4. Isotope-labeling experiments.
deuterium labeling suggests that the HAT process is not
entirely intramolecular. In order to confirm this, D2O was
introduced to the reaction and the product was found to
possess 14% deuterium at the same carbon atom (Sche-
me 4b). This result indicates that intramolecular hydrogen
transfer might be slow and a compensating process from other
hydrogen sources in the reaction system is also operative.
Based on these results and our previous studies on the
hydrofunctionalization of styrenes, we propose a polar radical
crossover cycloaddition (PRCC) reaction mechanism
(Scheme 5). Under blue-light irradiation, the acridinium
catalyst oxidizes the more electron-rich styrene through
photoinduced electron transfer (PET) to give the acridine
radical (Mes-AcrC) and cation radical A. Reoxidation of Mes-
AcrC by a phenylthiyl radical, generated by homolytic
cleavage of the cocatalyst PhSSPh, completes the photoredox
catalytic cycle. Intermediate A reacts with another styrene to
yield radical cation B. In the presence of an electron-relay
catalyst, B preferentially undergoes four-membered-ring
formation to give the formal [2+2] product. In the presence
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Conflict of interest
The authors declare no conflict of interest.
Keywords: cycloaddition · organocatalysis ·
photoredox chemistry · radical reactions · tetralin
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accelerated. Depending on the relative reactivity of its radical
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cyclization pathway becomes predominant. Nevertheless,
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styrenes using visible-light-promoted organocatalysis.
A
formal Diels–Alder cycloaddition between two styrenes is
catalyzed by acridinium salts under irradiation by blue LED
light. A disulfide cocatalyst was found to be essential to divert
the chemoselectivity of the styrene/styrene cycloaddition
from [2+2] to [4+2]. This method exhibits remarkable
chemo-, regio-, and stereoselectivity between the several
possible cyclization pathways between two styrenes. Multi-
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Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21572004, 21372013), Guang-
dong Province Special Branch Program (2014TX01R111),
Guangdong Natural Science Foundation (2014A030312004)
and
Shenzhen
Basic
Research
Program
(JCYJ20160226105602871, JSGG20140717102922014).
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Manuscript received: March 21, 2017
Revised: April 9, 2017
Final Article published: && &&, &&&&
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Communications
Photochemistry
L. Wang, F. Wu, J. Chen, D. A. Nicewicz,*
Y. Huang*
&&&& — &&&&
Visible-Light-Mediated [4+2]
Cycloaddition of Styrenes: Synthesis of
Tetralin Derivatives
Circle of light: A formal [4+2] cycloaddi-
tion reaction of styrenes under visible-
light catalysis was developed. Two styrene
molecules with different electronic or
steric properties were found to react with
each other in good yield and excellent
chemo- and regioselectivity. This reaction
provides direct access to polysubstituted
tetralin scaffolds from readily available
styrenes.
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!