Visible-light-induced [4 + 2] cycloaddition of pentafulvenes by organic photoredox catalysis

Article abstract of DOI:10.1039/d0ob01151g

We have developed thioxanthylium photoredox catalyzed [4 + 2] cycloaddition of pentafulvenes at room temperature under green light irradiation, which affords tetrahydrocyclopenta[b]chromenes with high regioselectivities. The present reaction provides a sustainable approach to carry out the cycloaddition of pentafulvenes without the use of transition metal catalysts or high-temperature conditions. This procedure enables a mild and straightforward access to 1,3a,9,9a-tetrahydrocyclopenta[b]chromenes. The quantum yield of the reaction (Φ = 0.15) indicates that the reaction would mainly proceed via photocatalytic pathways.

Full text of DOI:10.1039/d0ob01151g

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DOI: 10.1039/D0OB01151G
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Visible-light-induced [4+2] Cycloaddition of Pentafulvenes by Or-
ganic Photoredox Catalysis
Kenta Tanaka,*a Yosuke Asada,b Yujiro Hoshino*b and Kiyoshi Honda*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Compared with transition-metal photoredox catalysts, organic
photoredox catalysts have some merit that their use represents
a more cost-effective and sustainable approach.9,10 In 2019, we
reported that thioxanthylium photoredox catalysts efficiently
promoted oxa-[4+2] cycloaddition of ortho-quinone methides
with styrenes to furnish chromanes.10 Based on the
aforementioned background, we assumed that the
photocatalytic systems can be applied to not only styrenes but
also other various dienophiles such as fulvenes. Moreover, only
few hetero-[4+2] cycloaddition reactions of fulvene have so far
been reported.3,11 Therefore, in order to expand to the utility of
the reaction of fulvene, herein, we report thioxanthylium
organic photoredox catalyzed [4+2] cycloaddition of
pentafulvene under green light irradiation at room temperature
(Scheme 1(b)).
We have developed thioxanthylium photoredox catalyzed [4+2]
cycloaddition of pentafulvenes at room temperature under green
light
irradiation,
which
affords
the
tetrahydrocyclopenta[b]chromenes with high regioselectivities.
The present reaction provides a sustainable approach to carry out
cycloaddition of pentafulvenes without the use of transition metal
catalysts or high-temperature condtions. This procedure enables a
mild
and
straightforward
access
to
1,3a,9,9a-
tetrahydrocyclopenta[b]chromenes. The quantum yield of the
reaction (Φ = 0.15) indicates that the reaction would mainly
proceeds via photocatalytic pathways.
Cycloaddition of pentafulvenes potentially have the powerful
approaches to various polycyclic compounds.1 In the past few
decades, a variety of cycloaddition reactions such as [2 + 2], [3
+ 2], [4 + 2], [6 + 2], [6 + 3] and [6 + 4] cycloadditions have been
successfully developed due to their ability to display multiple
cycloaddition profiles.2 More recently, a chiral scandium-
complex-catalyzed asymmetric [4+2] cycloaddition with
fulvenes was also reported.3 However, previously reported
cycloaddition reactions of fulvenes were mainly carried out by
using transition metal catalysts or under high temperature
conditions (Scheme 1 (a)),4 hence, development of more
efficient and milder methods was highly desirable.
Being one such efficient protocol, photochemical reaction is an
attractive method in organic synthetic chemistry, and
especially, visible-light-induced photoredox reaction has
become a powerful tool in organic synthesis over the past
decades.5. However, only few examples of UV light-induced
cycloaddition reactions of pentafulvenes have been
developed.6
In the course of our study on [4+2] cycloaddition reactions,7
we recently synthesized the thioxanthylium organic photoredox
catalysts, which have high excited state reduction potentials
and are able to be used under irradiation with green light.8
Scheme 1 Cycloaddition reaction of pentafulvene.
Initially we screened the reaction of ortho-quinone methide
(
1a) with pentafulvene (2a) in the presence of thioxanthylium
photoredox catalyst using various solvents at room
temperature under green light irradiation (Table 1). When
medium to non-polar solvents such as THF and toluene were
a. Faculty of Pharmaceutical Science, Tokyo University of Science, 2641 Yamazaki,
Noda-city, Chiba, 278-8510, Japan.
b. Graduate School of Environment and Information Sciences, Yokohama National
University, Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan.
†Electronic Supplementary Information (ESI) available: [Experimental details and
supporting characterization]. See DOI: 10.1039/x0xx00000x
used, the reaction did not afford any of the target product (3a
)
(entries 1–2). On the other hand, while polar solvents such as
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DMF and CH3CN were not suitable for the reaction (entries 3– that for the present photoredox catalysis TViXewTArtcicaletOanlylinset
DOI: 10.1039/D0OB01151G
specifically works well.
Table 1 Optimization of the reaction conditionsa
a
All reactions were carried out with 1a (0.250 mmol), 2a (0.125 mmol),
catalyst (1.0 mol%) in solvent (2.0 mL) at room temperature for 4 h under
b
c
irradiation with green light. 1H NMR yield. The ratio is endo/exo. No
catalyst. d No light. e Under Ar. PMP : p-methoxyphenyl
With the optimized conditions in hand, the scope of
pentafulvenes was examined (Table 2). When diarylfulvenes
bearing halogen functionalities such as chloro, bromo and
fluoro groups were used as a dienophile, excellent yields of the
Entry
1
Solvent
THF
Yield (%)
0
drb
/
desired products were obtained (3a-3c). 6,6-Diphenyl fulvene
was well tolerated in the reaction (3d). Diarylfulvene bearing
electron donating groups furnished the corresponding products
2
3
toluene
DMF
0
0
/
/
in moderate to good yields (3e-3g). Next, we investigated
4
5
6
7
8c
9d
10e
CH3CN
CF3CH2OH
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
/
fulvenes bearing aliphatic groups. When 6,6-dipropylfulvene
was used, the reaction smoothly proceeded under the same
reaction conditions leading to the formation of the desired
15
78
98
0
0
6
1:1
1:1
1.4:1
/
cycloadduct in good yield
cyclopentyl, cyclohexyl and cycloheptyl groups were also good
substrates for the formation of the desired cycloadducts (3i 3k).
(3h). Pentafulvenes bearing
/
-
1.4:1
In addition, stereoselectivity of the product was effectively
improved when 5-cyclopentylidenecyclopenta-1,3-diene was
used as a substrate. ortho-Quinone methide bearing dimethoxy
groups furnished the desired product in high yield (3l). When
the reaction was carried out with ortho-quinone methide
bearing p-tolyl group instead of PMP, the corresponding
cycloadduct was also obtained in good yields (3m-3o). Finally,
monosubstituted fulvene at the C-6 position was examined.
When the photocycloaddition reaction of 6-phenylfulvene was
carried out in EtOAc at rt for 24 h in the presence of TXT (5.0
mol%), the corresponding cycloadduct 3p was obtained in 44%
yield. Unfortunately, cis-trans isomers were also produced as a
non-separable mixture along with low diastereoselectivity,
giving the complex mixture of isomers that were hard to
accurately analyze the structure and selectivity of them. These
results indicate that the reaction can be applied to various 6,6-
disubstituted pentafulvenes bearing both aromatic and
aliphatic groups.
4), reactions with CF3CH2OH, CH3NO2 and CH2Cl2 furnished the
desired [4+2] cycloadduct (entries 5–7), whereby especially
CH2Cl2 effectively increased the product yield to 98% (dr =
1.4:1). These solvents were often used for radical cation
cycloadditions, and they would stabilize radical cation
intermediates, suggesting that this reaction system may be
through the radical cation pathway.12 Fortunately, single
crystals of each diastereomer 3a, which are suitable for an X-ray
diffraction analysis, could be obtained by recrystallization.
Therefore, the relative stereochemistry of endo- and exo-
chromanes 3a could be determined by single crystal X-ray
diffraction analysis. From the blank experiments, the reaction
effectively proceeds in the only case of using photocatalyst,
light source, and air (entries 8-10). Finally, the
photocycloaddition reactions using the representative organo-
photocatalysts under otherwise identical reaction conditions
were examined (see Supporting Information, page S5). As a
result, miserable outcomes were obtained, and it was found
2 | J. Name., 2012, 00, 1-3
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Table 2 [4+2] Cycloaddition reaction of ortho-quinone methides with pentafulvenes.
a 8 h. b TXT (5.0 mol%) was used. C Reaction conditions: TXT (5.0 mol%), EtOAc, rt, 24 h.
the photoredox catalyst (PC+) via single-electron transfer to O2.
A
plausible reaction mechanism for the reaction of To support the generation of O2·¯, the control experiment in the
pentafulvene with ortho-quinone methide is represented in presence of benzoquinone, which is known as a trap agent of
Scheme 2. The photoredox catalyst (PC+*; E1/2 (C*/C−) = +1.76 V O2·¯, was carried out under the same reaction conditions (see
vs SCE)10 which can be activated by irradiation with green light Supporting Information, page S4). As expected, no reaction
enables the oxidation of ortho-quinone methide 1a (Ep/2 = +1.19 occurred, suggesting the important role of O2·¯ in the catalytic
V vs SCE). Based on the Stern–Volmer experiments (Figure 1), cycle. Pentafulvene 2a could undergo an [4+2] cycloaddition
the single electron transfer from ortho-quinone methide 1a to with the resulting radical cation
A .
providing radical cation B 13
the photoredox catalyst should occur. Since the reaction seems To confirm the radical chain processes in the catalysis, we
to require oxygen to promote the catalytic cycle (Table 1, entry determined the quantum yield of the reaction (Φ = 0.15),14
10), the reduced photocatalyst (PC·) would be regenerated into which suggests that the reaction mainly proceeds via
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We thank Prof. Mahito Atobe of Yokohama National University
would for cyclic voltammetry measurements. FuDnOdiI:n1g0.f1o0r39th/Dis0rOeBs0e1a15rc1Gh
was provided by Yokohama National University (kyodo kenkyu
suishin program B).
photocatalytic pathways. Thus, single electron transfer from the
superoxide radical (O2 ¯) to radical cation intermediate
occur to afford the cycloadduct 3a
View Article Online
·
B
.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
P. Preethalayam, K. S. Krishnan, S, Thulasitran, S. S. Chand, J.
Joseph, V. Nair, F. Jaroschik and K. V. Radhakrishnan, Chem.
Rev., 2017, 117, 3930.
2
3
4
E. Swan, K. Platts and A. Blencowe, Beilstein J. Org. Chem.,
2019, 15, 2113.
J. Zhang, L. Lin, C. He, Q. Xiong, X. Liu and X. Feng, Chem.
Commun., 2018, 54, 74.
(a) S.-C. Zhang, X.-X. Lei, Y.-J. Yang, Y.-C. Luo, H.-H. Zhanga and
P.-F. Xu, Org. Chem. Front., 2019, 6, 2415; (b) H.-C. Tseng, A.
K. Gupta, B. C. Hong and J.-H. Liao, Tetrahedron, 2006, 62
,
Scheme 2 Proposed reaction mechanism. PMP: p-methoxyphenyl
1425; (c) B.-C. Hong, A. K. Gupta, M.-F. Wu and J.-H. Liao,
Tetrahedron Lett., 2004, 45, 1663; (d) B.-C. Hong, Y.-J. Shr and
J.-H. Liao, Org. Lett., 2002, 4, 663; (e) B.-C. Hong, Y.-F. Jiang
and E. S. Kumar, Bioorg. Med. Chem. Lett., 2001, 11, 1981; (f)
V. Nair, S. Kumar and P. G. Williard, Tetrahedron Lett., 1995,
36, 1605.
5
6
(a) D. A. Nicewicz and D. W. C. MacMillan, Science, 2008, 322,
77; (b) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org.
Chem., 2016, 81, 6898.
(a) A. Padwa and F. Nobs, Tetrahedron Lett., 1978, 2, 93; (b) I.
Erden, J. Basada, D. Poli, G. Cabrera, F. Xu and S. Gronert,
Tetrahedron Lett., 2016, 57, 2190; (c) X. Zhang, F. Lin and C. S.
Foote, J. Org. Chem., 1995, 60, 1333; (d) I. Erden, J.
Drummond, R. Alstad and F. Xu, Tetrahedron Lett., 1993, 34
,
1255; (e) N. Harada, S. Suzuki, H. Uda and H. Ueno, J. Am.
Chem. Soc., 1972, 94, 1777.
7
(a) K. Tanaka, M. Kishimoto, Y. Asada, Y. Tanaka, Y. Hoshino
and K. Honda, J. Org. Chem., 2019, 84, 13858; (b) K. Tanaka,
M. Kishimoto, N. Ohtsuka, Y. Iwama, H. Wada, Y. Hoshino and
K. Honda, Synlett, 2019, 30, 189; (c) K. Tanaka, Y. Hoshino and
K. Honda, J. Synth. Org. Chem., Jpn., 2018, 76, 1341; (d) K.
Tanaka, M. Kishimoto, Y. Hoshino and K. Honda, Tetrahedron
Lett., 2018, 59, 1841; (e) K. Tanaka, M. Sukekawa, Y.
Figure 1 Stern–Volmer plots for ortho-quinone methide 1a (red line) and pentafulvene
2a (blue line).
Shigematsu, Y. Hoshino and K. Honda, Tetrahedron, 2017, 73
,
6456; (f) K. Tanaka, Y. Hoshino and K. Honda, Heterocycles,
2017, 95, 474; (g) K. Tanaka, Y. Shigematsu, M. Sukekawa, Y.
In conclusion, we have developed organic photoredox
catalyzed [4+2] cycloaddition of pentafulvenes under visible
light irradiation. The various pentafulvenes reacted with ortho-
quinone methides in the presence of thioxanthylium organic
photoredox catalyst (TXT) under green light irradiation
furnished the corresponding [4+2] cycloadducts in good yields.
Pentafulvenes bearing aromatic and aliphatic groups could be
successfully applied to the reaction. Based on the quantum yield
of the reaction (Φ = 0.15), the reaction mainly proceeds via
photocatalytic pathways. We hope that the reaction system
provides an efficient and sustainable method for cycloaddition
reaction of fulvenes.
Hoshino and K. Honda, Tetrahedron Lett., 2016, 57
,
5914−5918; (h) K. Tanaka, Y. Hoshino and K. Honda,
Tetrahedron Lett., 2016, 57, 2448.
8
9
(a) K. Tanaka, M. Sukekawa, M. Kishimoto, Y. Hoshino and K.
Honda, Tetrahedron Lett., 2018, 59, 3361; (b) K. Tanaka, Y.
Tanaka, M. Kishimoto, Y. Hoshino and K. Honda, Beilistein J.
Org. Chem., 2019, 15, 2105.
(a) N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116
10075; (b) D. A. Nicewicz and T. M. Nguyen, ACS Catal., 2014,
, 355.
,
4
10 For some recent examples of organo photoredox catalysis
under visible light irradiation, see: (a) L. Mei, J. M. Veleta and
T. L. Gianetti, J. Am. Chem. Soc., 2020, 142, 12056; (b) I. A.
MacKenzie, L. Wang, N. P. R. Onuska, O. F. Williams, K. Begam,
A. M. Moran, B. D. Dunietz and D. A. Nicewicz, Nature, 2020,
580, 76; (c) W. Chen, Z. Huang, N. E. S. Tay, B. Giglio, M. Wang,
H. Wang, Z. Wu, D. A. Nicewicz and Zibo Li, Science, 2019, 364
,
Acknowledgements
1170; (d) J. B. McManus, J. D. Griffin, A. R. White and D. A.
Nicewicz, J. Am. Chem. Soc., 2020, 142, 10325; (e) N. J.
4 | J. Name., 2012, 00, 1-3
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COMMUNICATION
Venditto and D. A. Nicewicz, Org. Lett., 2020, 22, 4817; (f) G.
H. Lovett, S. Chen, X.-S. Xue, K. N. Houk, and D. W. C.
MacMillan, J. Am. Chem. Soc., 2019, 141, 20031; (g) S. Neogi,
A. K. Ghosh, K. Maihi, S. Samanta, G. Kibriya and A. Hajra, Org.
Lett., 2020, 22, 5605; (h) M. Singsardar, S. Mondal, S. Laru and
A. Hajra, Org. Lett., 2019, 21, 5606; (i) M. Shee, S. S. Shah and
N. D. P. Singh, Chem. Commun., 2020, 56, 4240; (j) S.
Shibutani, T. Kondo, M. Takeda, K. Nagao, N. Tokunaga, Y.
Sasaki and H. Ohmiya, J. Am. Chem. Soc., 2020, 142, 1211; (k)
H. Yang, C. Tian, D. Qiu, H. Tian, G. An and G. Li, Org. Chem.
View Article Online
DOI: 10.1039/D0OB01151G
Front., 2019, 6, 2365; (l) C. Tian, Q. Wang, X. Wang, G. An and
G. Li, J. Org. Chem., 2019, 84, 14241; (m) M. Zhang, L. Yang, H.
Yang, G. An and G. Li, ChemCatChem, 2019, 11, 1606; (n) N.
Noto, T. Koike and M. Akita, ACS Catal., 2019, 9, 4382.
11 K. Tanaka, D. Omata, Y. Asada, Y. Hoshino and K. Honda, J.
Org. Chem., 2019, 84, 10669.
12 (a) B.-C. Hong, J.-L. Wu, A. K. Gupta, M. S. Hallur and J.-H. Liao,
Org. Lett., 2004, 6, 3453; (b) V. Nair, B. Mathew, R. S. Menon,
S. Mathew, M. Vairamani and S. Prabgakar, Tetrahedron,
2002, 58, 3235; (c) V. Nair, C. N. Jayan, K. V. Radhakrishnan,
Anilkumar, N. P. G. Rath, Tetrahedron, 2001, 57, 5807; (d) L.
Wei, Q. Zhu, Z.-M. Song, K. Liu and C.-J. Wang, Chem.
Commun., 2018, 54, 2506.
13 (a) S. M. Stevenson, M. P. Shores and E. M. Ferreira, Angew.
Chem. Int. Ed., 2015, 54, 6506; (b) S. Lin, M. A. Ischay, C. G. Fry
and T. P. Yoon, J. Am. Chem. Soc., 2011, 133, 19350; (c) R. F.
Higgins, S. M. Fatur, S. G. Shepard, S. M. Stevenson, D. J.
Boston, E. M. Ferreira, N. H. Damrauer, A. K. Rappꢀ and M. P.
Shores, J. Am. Chem. Soc., 2016, 138, 5451.
14 The stereoselectivity of radical cation [4+2] cycloaddition is
generally low; for details, (a) D. J. Bellville and N. L. Bauld, J.
Am. Chem. Soc., 1982, 104, 2665; (b) D. J. Bellville, D. D. Wirth
and N. L. Bauld, J. Am. Chem. Soc., 1981, 103, 718; (c) N. L,
Bauld, Tetrahedron, 1989, 45, 5307; (d) N. L. Bauld, J. Yang and
D. Gao, J. Chem. Soc., Perkin Trans., 2000, 2, 207.
15 The detailed reaction quantum yield is shown in supporting
Information.
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