Palladium-Catalyzed Asymmetric [3+2] Cycloaddition of Vinylethylene Carbonates with 2-Arylidene-1,3-Indandiones: Synthesis of Tetrahydrofuran-Fused Spirocyclic 1,3-Indandiones

Article abstract of DOI:10.1002/ejoc.202000762

An asymmetric [3+2] cycloaddition of 2-arylidene-1,3-indandiones with vinylethylene carbonates (VECs) had been achieved in the presence of Pd₂dba₃·CHCl₃ and axially chiral phosphoramidite ligand. The reaction of various su

Full text of DOI:10.1002/ejoc.202000762

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Palladium-Catalyzed Asymmetric [3+2] Cycloaddition of
Vinylethylene Carbonates with 2-Arylidene-1,3-Indandiones:
Synthesis of Tetrahydrofuran-Fused Spirocyclic 1,3-Indandiones
Authors: Huihui Zhang, Xing Gao, Feng Jiang, Wangyu Shi, Wei
Wang, Yongjun Wu, Cheng Zhang, Xueyan Shi, and
Hongchao Guo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000762
Link to VoR: https://doi.org/10.1002/ejoc.202000762
01/2020

10.1002/ejoc.202000762
European Journal of Organic Chemistry
COMMUNICATION
Palladium-Catalyzed Asymmetric [3+2] Cycloaddition of
Vinylethylene Carbonates with 2-Arylidene-1,3-Indandiones:
Synthesis of Tetrahydrofuran-Fused Spirocyclic 1,3-Indandiones
Huihui Zhang,[a] Xing Gao,[b] Feng Jiang,[b] Wangyu Shi,[b] Wei Wang,[c] Yongjun Wu,[c] Cheng Zhang,[b]
Xueyan Shi,*,[a] and Hongchao Guo*[b]
[a]
[b]
[c]
H. Zhang, Prof. Dr. X. Shi
College of Plant Protection
China Agricultural University
Beijing 100193, P. R. China
Homepage: http://cpp.cau.edu.cn/art/2012/5/30/art_21989_458020.html
E-mail: shixueyan@cau.edu.cn
X. Gao, F. Jiang, W. Shi, Prof. Dr. C. Zhang, Prof. Dr. H. Guo
Department of Chemistry
China Agricultural University
Beijing 100193, P. R. China
Homepage: http://sci.cau.edu.cn/art/2018/3/23/art_30085_39.html
E-mail: hchguo@cau.edu.cn
W. Wang, Y. Wu
College of Public Health
Zhengzhou University
Zhengzhou 450001, P. R. China
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: An asymmetric [3+2] cycloaddition of 2-arylidene-1,3-
indandiones with vinylethylene carbonates (VECs) had been
achieved in the presence of Pd2dba3•CHCl3 and axially chiral
phosphoramidite ligand. The reaction of various substituted VECs and
2-arylidene-1,3-indandiones proceeded smoothly under mild
conditions, giving the highly functionalized spirocyclic 1,3-
indanedione derivatives in good to excellent yield with moderate
diastereoselectivity and high enantioselectivity. The reaction on the
gram scale had also been demonstrated.
containing heterocycles. Pd-catalyzed [3+2] cycloaddition
reactions of VECs with electron-deficient alkenes such as
methylenemalononitriles,[5b]
β-nitroolefins[5h]
and
cyanochromones[5i] have been developed to construct
3-
Multi-functionalized spirocyclic compounds are highly attracting
molecules because they have promising biological utilization and
can be further converted to more complex spirocyclic molecules.[1]
The 1,3-indandione-derived spiro rings are an important class of
such scaffolds and synthetic methods accessing to them have
been extensively studied.[2] To date, cycloadditions of 1,3-
arylidene-1,3-indandiones with dipolar species are prevalent
strategies to construct these molecules. Within these
achievements, the method that generating reactive zwitterionic
species in situ by the interaction of one substrate with the catalyst
followed by cycloaddition with 1,3-arylidene-1,3-indandiones is
one of the most attractive strategies.[3] Vinylethylene carbonates
(VECs) had been intensively explored as precursors for
generation of dipoles in situ in the past five years and are a
privileged reaction partner for cycloaddition reactions.[4] In the
presence of a palladium catalyst, they can effectively form
zwitterionic allylpalladium intermediates which act as 1,3 or 1,5-
dipoles that undergo cycloadditions with dipolarphiles[5] or act as
nucleophiles via umpolung inversion.[6] Among those
dipolarphiles, alkenes are often used in the cycloaddition
reactions of vinylethylene carbonates for synthesis of oxygen-
Scheme 1. Pd-catalyzed cycloaddition reactions for synthesis of oxygen-
containing heterocycles.
1
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10.1002/ejoc.202000762
European Journal of Organic Chemistry
COMMUNICATION
tetrahydrofuran derivatives (Scheme 1a). In 2019, we achieved a
Pd-catalyzed [5+4] annulation of VECs with coumalates or
pyrones via tandem [3+2] cycloaddition/Cope rearrangement to
synthesize nine-membered cyclic compounds[5l] (Scheme 1c).
Most recently, Peng and Han reported [5+2] and [5+4] annulations
of VECs and allylidenemalononitriles to assemble seven and
nine-membered rings[7] (Scheme 1b and 1c). With respect to our
work on application of 1,3-arylidene-1,3-indandiones in
cycloaddition reactions, we recently reported a palladium-
tetrahydropyran-fused spirocyclic scaffolds in good to excellent
yield and with high enantioselectivity (up to 99% ee)[8] (Scheme
1d). We also successfully developed a phosphine-catalyzed
cascade Michael addition/[4+2] cycloaddition reaction of
indandione-derived alkenes with tetrahydrobenzofuranone-
derived allenoates, giving spirocyclic 1,3-indanedione derivatives
in moderate to high yield and with good to excellent
diastereoselectivity.[9] On the basis of these works,[4–10] we herein
report a palladium-catalyzed enantioselective [3+2] cycloaddition
of vinylethylene carbonates with 2-arylidene-1,3-indandiones to
synthesize spirocyclic 1,3-indanedione compounds (Scheme 1e).
catalyzed
asymmetric
[4+2]
cycloaddition
of
2-
methylidenetrimethylene carbonate with alkenes derived from
indandione, affording pharmacologically interesting chiral
Table 1. Optimization of the reaction conditions for asymmetric [3+2] cycloaddition of VEC 1a with 2-benzylidene-1,3-indandione 2a.[a]
Entry
1
Lx
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
T [°C ]
25
25
25
25
25
25
25
25
25
25
25
25
0
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
t [h]
19
19
25
43
48
48
48
48
48
48
48
48
48
48
48
Yield[b] [%]
99
dr (3aa:4aa)[c]
78:22
54:46
51:49
54:46
54: 46
57:43
56:44
81:19
65:35
76:24
74:26
57:43
53:47
51:49
57:43
ee[d] of 3aa, 4aa [%]
85, 53
2
99
95, 95
3
99
75, 91
4
99
94, 91
5
99
10, -52
92, 92
6
90
7
CHCl3
toluene
PhCF3
THF
93
95, 93
8
88
99, 65
9
98
92, 81
10
11
12
13
14
15
69
98, 79
EtOAc
MeCN
CHCl3
CHCl3
CHCl3
87
96, 82
89
91, 83
99
99, 98
-20
40
92
98, 98
44
96, 93
[a] Unless noted otherwise, the reaction of 1a (0.15 mmol), 2a (0.10 mmol), Pd2dba3•CHCl3 (5.0 mol%) and ligand (20 mol%) was stirred in 1.0 mL of solvent under
indicated reaction conditions. [b] Isolated yield. [c] dr was determined by 1H NMR analysis of the product. [d] Determined by chiral HPLC analysis.
We started our investigation by selecting the reaction of VEC
1a and 2-benzylidene-1,3-indandione 2a as the model substrates,
and probed the optimal reaction conditions by screening various
chiral ligands, solvents, and temperatures, etc (Table 1). To our
2
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10.1002/ejoc.202000762
European Journal of Organic Chemistry
COMMUNICATION
delight, under catalysis of a complex of Pd2(dba)3•CHCl3 (5.0
mol %) and axially chiral phosphoramidite ligand L1 (20 mol%),
almost quantitative yield of the desired annulation product
3aa/4aa with 85, 53% ee and 78:22 dr was obtained after workup
(entry 1). Then, several axially chiral phosphoramidite ligands
were examined (entries 2–5). The results showed that L2 was the
best ligand while two spirocyclic diastereoisomers were obtained
in almost quantitative yield along with 54:46 dr and 95% ee for
both of them. Solvents screening showed that CHCl3 was the best
solvent in which the reaction exhibited the best
diastereoselectivity and the yield and enantioselectivity were
almost retained as that in DCM (entries 6–12). Lowering the
temperature resulted in higher enantioselectivity but lower
diastereoselectivity, and increasing the reaction temperature
impaired the reaction by greatly decreasing its yield albeit with
high enantioselectivity (entries 13–15).
excellent enantioselectivity. Phenyl (1a), methylphenyl (1b and
1c), and methoxyphenyl-substituted VECs (1d–1f) were all
welltolerated to the reaction, in spite of lower yield for 2 and 3-
methoxyphenyl-substituted VECs (1d and 1e) and lower
enantioselectivity for 4-methoxyphenyl-substituted VEC (1f). With
respect to halogenphenyl-subsituted VECs (1g–1m), results
showed that the 4-chlorophenyl (1k) and bromophenyl- (1l and
1m) substituted substrates afforded corresponding products in
much lower yield compared to other halogenphenyl-substituted
VECs, although the excellent enantioslelectivities were retained.
The 4-phenylphenyl-substitued VEC (1n) furnished product
3na/4na with much lower yield compared to the phenyl
substituted VEC (1a), but enantioselectivity for both
diastereoisomers are retained. As indicated in Scheme 2, the
gram-scale cycloaddition of VEC 1a and olefin 2a proceeded
smoothly, furnishing the cycloaddition product 3aa and 4aa in
good yield with high enantioselectivity.
Table 2. The scope of VECs.[a]
Entry
1
R
Yield[b] [%]
dr (3:4)[c]
53:47
52:48
51:49
54:46
53:47
54:46
53:47
56:44
52:48
52:48
51:49
52:48
50:50
53:47
ee[d] of 3, 4 [%]
99, 98
99, 95
96, 95
99, 95
99, 98
96, 89
93, 92
97, 94
94, 92
93, 95
96, 95
93, 89
95, 95
93, 94
Scheme 2. Gram-scale synthesis
Ph (1a)
99
99
97
82
84
93
96
86
96
94
76
77
68
71
2
3-MeC6H4 (1b)
4-MeC6H4 (1c)
2-MeOC6H4 (1d)
3-MeOC6H4 (1e)
4-MeOC6H4 (1f)
2-FC6H4 (1g)
3-FC6H4 (1h)
4-FC6H4 (1i)
3-ClC6H4 (1j)
4-ClC6H4 (1k)
3-BrC6H4 (1l)
4-BrC6H4 (1m)
4-PhC6H4 (1n)
Table 3. The scope of 2-arylidene-1,3-diones.[a]
3
4
5
6
7
Entry
1
R
Yield[b] [%]
dr (3:4)[c]
56:44
64:36
62:38
59:41
81:19
68:32
68:32
53:47
73:27
59:41
63:37
76:24
ee[d] of 3, 4 [%]
96, 97
8
3-MeC6H4 (2b)
2-MeOC6H4 (2c)
3-MeOC6H4 (2d)
4-MeOC6H4 (2e)
3,4-MeO2C6H4 (2f)
2-FC6H4 (2g)
3-FC6H4 (2h)
4-FC6H4 (2i)
94
73
99
93
79
89
91
89
90
99
97
99
9
2
84, 88
10
11
12
13
14
3
96, 96
4
98, 97
5
99, 95
6
91, 90
7
96, 90
[a] Unless noted otherwise, the reaction of 1 (0.15 mmol), 2a (0.10 mmol),
Pd2dba3•CHCl3 (5.0 mol%) and ligand L2 (20 mol%) was stirred in 1.0 mL of
CHCl3 at 0 °C for 48 h. [b] Isolated yield. [c] dr was determined by 1H NMR
analysis of the product. [d] Determined by chiral HPLC analysis.
8
94, 92
9
3-CF3C6H4 (2j)
4-CF3C6H4 (2k)
2-furyl (2l)
93, 91
10
11
12
97, 81
After the determination of the optimal reaction conditions, we
then evaluated its effectiveness to produce diverse spirocyclic
compounds by expanding the scope of VECs to various aryl-
substituted ones (Table 2). Generally, all of the VECs, regardless
of their substitution patterns or electronic properties of the aryl
substituents, were suitable substrates and afforded
corresponding spirocyclic products in good to high yield with
99, 99
4-Br-2-thienyl (2m)
99, 96
[a] Unless noted otherwise, the reaction of 1a (0.15 mmol), 2 (0.10 mmol),
Pd2dba3•CHCl3 (5.0 mol%) and ligand L2 (20 mol%) was stirred in 1.0 mL of
CHCl3 at 0 °C for 48 h. [b] Isolated yield. [c] dr was determined by 1H NMR
analysis of the product. [d] Determined by chiral HPLC analysis.
3
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10.1002/ejoc.202000762
European Journal of Organic Chemistry
COMMUNICATION
4859–4863; l) X. Gao, M. Xia, C. Yuan, L. Zhou, W. Sun, C. Li, B. Wu, D.
Zhu, C. Zhang, B. Zheng, D. Wang, H. Guo, ACS Catal. 2019, 9, 1645–
1654.
After the probing of diverse VEC substrates, we further
expanded the scope of 2-arylidene-1,3-diones (Table 3). An array
of 2-arylidene-1,3-diones derived from the condensation of 1,3-
indanedione and various aromatic aldehydes containing electron-
neutral, electron-rich or electron-deficient phenyl rings all proved
to be viable substances in this protocol, producing a series of
spirocyclic products 3ab/4ab–3am/4am in good to high yield with
excellent enantioselectivity (entries 1–10). Furthermore, 2-furyl
and 4-Br-2-thienyl aldehyde derived olefins 2l and 2m were also
tested, and the corresponding product 3al/4al and 3am/4am
could be obtained in 97 and 99% yield with high enantioselectivity
(entries 11 and 12). The absolute configuration of 3am and 4ab
was unambiguously confirmed by single crystal X-ray diffraction
analysis.[11]
[6]
For selected examples, see: a) Y. J. Zhang, J. H. Yang, S. H. Kim, M. J.
Krische, J. Am. Chem. Soc. 2010, 132, 4562–4563; b) S.-S. Zhang, J.-
Q. Wu, X. Liu, H. Wang, ACS Catal. 2014, 5, 210–214; c) W. Guo, L.
Martinez-Rodriguez, E. Martin, E. C. Escudero-Adan, A. W. Kleij, Angew.
Chem. Int. Ed. 2016, 55, 11037–11040; d) A. Khan, S. Khan, I. Khan, C.
Zhao, Y. Mao, Y. Chen, Y. J. Zhang, J. Am. Chem. Soc. 2017, 139,
10733–10741; e) L. Deng, A. W. Kleij, W. Yang, Chem. Eur. J. 2018, 24,
19156–19161; f) A. Khan, H. Zhao, M. Zhang, S. Khan, D. Zhao, Angew.
Chem. Int. Ed. 2020, 59, 1340–1345.
[7]
[8]
[9]
X. Zhang, X. Li, J.-L. Li, Q.-W. Wang, W.-L. Zou, Y.-Q. Liu, Z.-Q. Jia, F.
Peng, B. Han, Chem. Sci. 2020, 11, 2888–2894.
B. Mao, H. Liu, Z. Yan, Y. Xu, J. Xu, W. Wang, Y. Wu, H. Guo, Angew.
Chem. Int. Ed. 2020, DOI: 10.1002/anie.202002765.
W. Shi, B. Mao, J. Xu, Q. Wang, W. Wang, Y. Wu, X. Li, H. Guo, Org Lett
2020, 22, 2675–2680.
In conclusion, we have developed an enantioselective [3+2]
annulation of VECs and 2-arylidene-1,3-diones. A broad range of
VECs and olefins were compatible in this procedure and were
effectively converted into the corresponding spirocyclic products
in high yield with moderate diastereoselectivity and high
enantioselectivity. Furthermore, this practical protocol features
simple reaction conditions and readily available starting materials.
[10] a) B. Mao, J. Zhang, Y. Xu, Z. Yan, W. Wang, Y. Wu, C. Sun, B. Zheng,
H. Guo, Chem. Commun. 2019, 55, 12841–12844; b) L. Zhou, C. Yuan,
Y. Zeng, Q. Wang, C. Wang, M. Liu, W. Wang, Y. Wu, B. Zheng, H. Guo,
Org. Lett. 2019, 21, 4882–4886; c) L. Zhou, Y. Zeng, X. Gao, Q. Wang,
C. Wang, B. Wang, W. Wang, Y. Wu, B. Zheng, H. Guo, Chem. Commun.
2019, 55, 10464–10467.
[11] CCDC 1946684 and 1946851 for the compounds 3am and 4ab contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
This work is supported by the Natural Science Foundation of
China (No. 21871293) and Chinese Universities Scientific Fund
(Nos. 2018TC052, 2018TC055 and 2019TC085).
Keywords: asymmetric catalysis • cycloaddition • palladium
catalysis • spirocyclic compounds
[1]
a) Y.-J. Zheng, C. M. Tice, Expert Opin. Drug Dis. 2016, 11, 831–834; b)
A. Ding, M. Meazza, H. Guo, J. W. Yang, R. Rios, Chem. Soc. Rev. 2018,
47, 5946–5996; c) E. Chupakhin, O. Babich, A. Prosekov, L. Asyakina,
M. Krasavin, Molecules 2019, 24, 4165.
[2]
a) S. Turroni, M. Tolomeo, G. Mamone, G. Picariello, E. Giacomini, P.
Brigidi, M. Roberti, S. Grimaudo, R. M. Pipitone, A. Di Cristina, M.
Recanatini, PLOS ONE 2013, 8, e57650; b) N. Sudhapriya, P. T.
Perumal, C. Balachandran, S. Ignacimuthu, M. Sangeetha, M. Doble, Eur.
J. Med. Chem. 2014, 83, 190–207.
[3]
[4]
For selected example, see: E. Li, Y. Huang, L. Liang, P. Xie, Org. Lett.
2013, 15, 3138–3141.
For recent reviews of VECs, see: a) W. Guo, J. E. Gómez, À. Cristòfol,
J. Xie, A. W. Kleij, Angew. Chem. Int. Ed. 2018, 57, 13735–13747; b) J.
E. Gómez, A. W. Kleij, in Adv. Organomet. Chem., Vol. 71 (Ed.: P. J.
Pérez), Academic Press, 2019, pp. 175–226.
[5]
For selected examples, see: a) A. Khan, R. Zheng, Y. Kan, J. Ye, J. Xing,
Y. J. Zhang, Angew. Chem. Int. Ed. 2014, 53, 6439–6442; b) A. Khan, L.
Yang, J. Xu, L. Y. Jin, Y. J. Zhang, Angew. Chem. Int. Ed. 2014, 53,
11257–11260; c) A. Khan, J. Xing, J. Zhao, Y. Kan, W. Zhang, Y. J.
Zhang, Chem. Eur. J. 2015, 21, 120–124; d) L. C. Yang, Z. Q. Rong, Y.
N. Wang, Z. Y. Tan, M. Wang, Y. Zhao, Angew. Chem. Int. Ed. 2017, 56,
2927–2931; e) Y. Wu, C. Yuan, C. Wang, B. Mao, H. Jia, X. Gao, J. Liao,
F. Jiang, L. Zhou, Q. Wang, H. Guo, Org. Lett. 2017, 19, 6268–6271; f)
C. Yuan, Y. Wu, D. Wang, Z. Zhang, C. Wang, L. Zhou, C. Zhang, B.
Song, H. Guo, Adv. Synth. Catal. 2018, 360, 652–658; g) P. Das, S.
Gondo, P. Nagender, H. Uno, E. Tokunaga, N. Shibata, Chem. Sci. 2018,
9, 3276–3281; h) K. Liu, I. Khan, J. Cheng, Y. J. Hsueh, Y. J. Zhang,
ACS Catal. 2018, 8, 11600–11604; i) I. Khan, C. Zhao, Y. J. Zhang,
Chem. Commun. 2018, 54, 4708–4711; j) L. C. Yang, Z. Y. Tan, Z. Q.
Rong, R. Liu, Y. N. Wang, Y. Zhao, Angew. Chem. Int. Ed. 2018, 57,
7860–7864; k) B. Niu, X. Y. Wu, Y. Wei, M. Shi, Org. Lett. 2019, 21,
4
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European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
An asymmetric [3+2] cycloaddition of 2-arylidene-1,3-indandiones with vinylethylene carbonates in the presence of Pd2dba3•CHCl3
and axially chiral phosphoramidite ligand was developed.
5
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