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CationRadical[3+2]CycloadditionofChalcone
Epoxides:AFacileSynthesisofHighly
SubstitutedTetrahydrofurans
ArticleinSynlett·February2004
ImpactFactor:2.42·DOI:10.1055/s-2003-44966
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LETTER
251
Cation Radical [3+2] Cycloaddition of Chalcone Epoxides: A Facile Synthesis
of Highly Substituted Tetrahydrofurans
CationRadical[3+2]Cycload iton
Congde
Huo, Xiaodong Jia, Wei Zhang, Li Yang, Jianming Lü, Zhong-Li Liu*
National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China
Fax +86(931)8625657; E-mail: [email protected]
Received 11 November 2003
Abstract: Cycloaddition of electron-rich chalcone epoxides with
electron-rich olefins was efficiently catalyzed by tris(4-bromophenyl)aminium hexachloroantimonate producing poly-substituted
tetrahydrofuran derivatives in high yield.
Key words: cation radical, cycloaddition, epoxides, tetrahydrofurans
Substituted tetrahydrofurans are important synthetic targets due to their presence in a variety of natural products1
with wide range of biological activities.2 Therefore, new
synthetic approaches have continuously emerged for construction of the tetrahydrofuran subunit.3,4 Shim and
Yamamoto5 have reported a palladium-catalyzed [3+2]
cycloaddition of vinyl oxiranes with olefins, but the olefin
must be activated by substitution of two electron-withdrawing groups with at least one cyano group, i.e., the
olefin must be highly electron deficient. Electronwithdrawing substituents on olefins are also essential for
the free radical mediated [3+2] cycloaddition of vinyl
oxiranes with olefins.6 As a part of our ongoing research
program on the synthetic potential of cation radical
induced reactions7 we found recently that tris(4-bromophenyl)aminium hexachloroantimonate (TBPA+·SbCl6–),
which has been widely used to initiate cation radical cycloaddtion reactions,8 could efficiently catalyze the cross
cycloaddition of aromatic imines and electron-rich olefines to form tetrahydroquinolines.9 Since cation radical
initiation can carry out polarity umpolung,8 it is expected
that [3+2] cycloaddition between oxiranes and electronrich olefins may be able to take place by cation radical initiation. We report herein a cation radical induced [3+2]
cycloaddition of electron-rich chalcone epoxides with
electron-rich olefins that produces multi-substituted
tetrahydrofuran derivatives in high yield.
An anhydrous CH2Cl2 solution (20 mL) of the activated
trans-chalcone epoxide (1, 0.55 mmol) and the electronrich olefin (2, 0.5 mmol) was added dropwise a catalytic
amount of tris-(4-bromophenyl)aminium hexacholoantimonate (TBPA+, 0.025 mmol) suspended in anhydrous
CH2Cl2 (20 mL) at ambient temperature under stirring.
The reaction completed within 30 minutes as monitored
by TLC, producing tetrahydrofuran derivatives 3 in high
SYNLETT 2004, No. 2, pp 0251–025402.0 204
Advanced online publication: 08.12.2003
DOI: 10.1055/s-2003-44966; Art ID: U24003ST.pdf
© Georg Thieme Verlag Stuttgart · New York
yield as a mixture of four stereoisomers (Scheme 1). Careful column chromatographic separation (silica gel, PE/
EtOAc 10:1 to 40:1) gave the four pure stereoisomers, i.e.,
2,3-cis-3,5-cis-3 (3-A), 2,3-trans-3,5-cis-3 (3-B), 2,3-cis3,5-trans-3 (3-C), and 2,3-trans-3,5-trans-3 (3-D) in most
cases. Their structures were fully identified by HRMS, 1H
NMR, 13C NMR and 2D NMR spectroscopy10 and the stereochemistry evaluated by chemical shift considerations
and NOESY as exemplified in Figure 1. It is seen from the
scheme that when the 2-benzoyl and the 3-aryl groups are
in cis-configuration the chemical shifts of the aromatic
protons are significantly up-field shifted in comparison
with those of the corresponding trans-isomers due to the
mutual shielding of the two phenyl rings. In the case of
furan (entry 6) substituted product 4 was obtained in lieu
of the cycloaddition product 3 because the intermediate
cation radical 6 is prone to aromatize (vide infra). The
results are listed in Table 1 together with the oxidation
potentials of the substrates for discussing the substituent
tolerance of the reaction (vide infra).
O
O
R3
Ph
O
1
+
Ar R2
TBPA+
.
Ar
Ph
O
R1
2
R3
R2
R
1
3
Scheme 1
It is seen from Table 1 that this reaction could only take
place between electron-rich chalcone epoxides and electron-rich olefins. Unsubstituted chalcone epoxide 1e and
nitro-substituted chalcone epoxide 1f showed no cross reaction with 2a under the same experimental conditions
(entries 10 and 11). Steckhan and co-workers11 have
pointed out that in the case of cation radical [4+2] cycloadditions the oxidation potentials of the diene and the
dienophile should not differ by more than 500 mV to ensure a good match of their HOMO energies, hence an efficient reaction. Similar criterion seems also applicable to
the present reaction. The differences of the oxidation potentials between 1 and 2 are 120, 100, 130, 200, 110, 100,
330, 360 and 360 mV for entries 1–9 respectively, while
the differences for entries 10 and 11 are 400 and over 680
mV respectively. This implies that the HOMO energies of
1 and 2 are close for entries 1–9 to accomplish efficient
cross reactions, while they are far apart in the case of
entries 10 and 11 for the cross reaction to take place.
252
C. Huo et al.
Figure 1
Selected chemical shifts and NOESY correlations for the four stereoisomers of 3a
Table 1
LETTER
TBPA+·SbCl6– initiated Cycloaddition of Chalcone Epoxides 1 with Olefins 2
Entry 1
Ar
Eox (V)a
2
Eox (V)a
Products and yields (%)b
1
1a
4-MeOC6H4
1.60
2a
1.72
3a
82
(32/33/19/16)
2
1a
4-MeOC6H4
1.60
2b
1.70
3b
74
(38/36/0/26)
3
1a
4-MeOC6H4
1.60
2c
1.47
3c
70
(39/37/0/24)
4
1a
4-MeOC6H4
1.60
2d
1.40
3d
72
(22/47/13/18)
Synlett 2004, No. 2, 251–254
© Thieme Stuttgart · New York
LETTER
Table 1
Cation Radical [3+2] Cycloaddition
253
TBPA+·SbCl6– initiated Cycloaddition of Chalcone Epoxides 1 with Olefins 2 (continued)
Entry 1
Ar
Eox (V)a
2
Eox (V)a
Products and yields (%)b
5
1a
4-MeOC6H4
1.60
2e
1.71
3e
61
(26/33/20/21)
6
1a
4-MeOC6H4
1.60
2f
1.70
4
70
7
1b
3,4-(CH2O2)C6H3
1.39
2a
1.72
3f
76
(26/37/17/20)
8
1c
2,4-(MeO)2C6H3
1.36
2a
1.72
3g
80
(34/31/15/20)
9
1d
3,4,5-(MeO)3C6H2
1.36
2a
1.72
3h
78
(24/33/12/31)
10
1e
C 6 H5
2.12
2a
1.72
N.r.
11
1f
4-NO2-C6H4
2a
1.72
N.r.
a
b
>2.4
Oxidation peak potential determined vs SCE by cyclic voltammetry in MeCN using a platinum electrode.
Isolated yields based on 2. The diastereomeric ratios of 3-A, 3-B, 3-C and 3-D are shown in parenthesis.
It was found that no reaction took place in the absence of
the aminium radical TBPA+·, hence the reaction might be
rationalized as a cation radical initiated [3+2] chain
cycloaddition8 as depicted in Figure 2. Single electron
transfer between 1 and TBPA+· produces the cation radical
of the chalcone epoxide 1+· which subjects selective Cb-O
bond cleavage affording a new cation radical 5. Addition
of 5 to the electron-rich olefin 2 forms the cation radical
adduct 6, which undergoes the second electron transfer
from 1 and/or TBPA followed by ring closure to produce
the tetrahydrofuran 3.
It is well known that a,b-epoxy ketones can subject various ring-opening processes leading to different products,
depending on the substitution and the nature of the reactive intermediate.12 Photoinduced reductive electron
transfer via anion radical intermediates gave predominantly b-hydroxy ketones as the result of selective Ca-O
bond cleavage,7e,12a–d while oxidative electron transfer via
cation radical intermediate gave b-ketone aldehydes and
solvent molecule substituted products as the result of selective Cb-O bond cleavage.12e Tin-hydride mediated free
radical reactions could proceed via either Ca-O or Ca-Cb
bond cleavage depending on the substituents.12a Direct
1
TBPA+.
O
ET
TBPA
1
+.
O.
1
O
3
+
5
ET
ET
Ar
Ph
Ar
2
Ph
O
. +
R
2
R3
R
1
6
Figure 2
photolysis of a,b-epoxy ketones produced a-diketones, bdiketones and/or aldehydes attributed to the intermediacy
of excited triplet state and/or carbonyl ylid, and the later
could be trapped by dipolarophiles to give cycloaddition
products.12f–h The present work provides a new cycloaddition reaction of epoxides for construction of multisubstituted tetrahydrofurans that is complementary to
the palladium catalyzed5 and free radical mediated6
Synlett 2004, No. 2, 251–254
© Thieme Stuttgart · New York
254
LETTER
C. Huo et al.
approaches which request electron-deficient olefins. Extension to other substrates and studies on the mechanistic
details of this reaction are underway in this laboratory.
Acknowledgment
We thank the National Natural Science Foundation of China
(20372030) for financial support.
References
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(10) Representative spectral data for the products: (±)-cic,cis-2Benzoyl-3-(4-methoxyphenyl)-5-phenyl-5-methyl
tetrahydrofuran (3a-A): colorless oil. HR-ESI-MS: m/z
calcd for C25H24O3 + Na+: 395.1618). Found: 395.1614. 1H
NMR (400 MHz, CDCl3): d = 1.73 (s, 3 H, Me), 2.62 (dd,
J = 12.4, 12.0 Hz, 1 H, H-4a), 2.67 (dd, J = 12.4, 8.4 Hz, 1
H, H-4e), 3.63 (s, 3 H, MeO), 4.15 (m, 1 H, H-3a), 5.91 (d,
J = 8.8 Hz, 1 H, H-2e), 6.51 (d, J = 8.8 Hz, 2 H, Ar), 6.86 (d,
J = 8.8 Hz, 2 H, Ar), 7.26 (dd, J = 8.0, 7.6 Hz, 2 H, Bz), 7.32
(t, J = 8.0 Hz, 1 H, Ph), 7.40 (t, J = 8.0 Hz, 1 H, Bz), 7.42
(dd, J = 8.0, 8.0 Hz, 2 H, Ph), 7.57 (d, J = 8.0 Hz, 2 H, Bz),
Synlett 2004, No. 2, 251–254
© Thieme Stuttgart · New York
7.68 (d, J = 8.0 Hz, 2 H, Ph). 13C NMR (100.08 MHz,
CDCl3): d = 29.3 (Me), 46.2 (C-4), 48.5 (C-3), 55.1 (MeO),
82.6 (C-2), 85.2 (C-5), 113.4 (Ar), 124.8 (Ph), 126.5 (Ph),
127.9 (Bz), 128.1 (Ph), 128.4 (Bz), 129.3 (Ar), 130.3 (Ar),
132.4 (Bz), 136.8 (Bz), 147.7 (Ph), 158.2 (Ar), 198.5 (C=O).
(±)-trans,cis-2-Benzoyl-3-(4-methoxyphenyl)-5-phenyl-5methyl tetrahydrofuran (3a-B): colorless oil, HR-ESI-MS:
m/z calcd for C25H24O3 + H+: 373.1798. Found: 373.1794. 1H
NMR (400 MHz, CDCl3): d = 1.67 (s, 3 H, Me), 2.61 (dd,
J = 12.4, 7.6 Hz, 1 H, H-4a), 2.79 (dd, J = 12.4, 7.6 Hz, 1 H,
H-4e), 3.77 (s, 3 H, MeO), 4.12 (m, 1 H, H-3a), 5.25 (d,
J = 8.0 Hz, 1 H, H-2a), 6.80 (d, J = 8.8 Hz, 2 H, Ar), 7.15 (d,
J = 8.8 Hz, 2 H, Ar), 7.42 (dd, J = 8.0, 8.0 Hz, 2 H, Bz), 7.33
(t, J = 7.6 Hz, 1 H, Ph), 7.55 (t, J = 8.0 Hz, 1 H, Bz), 7.44
(dd, J = 7.6, 7.6 Hz, 2 H, Ph), 7.99 (d, J = 8.0 Hz, 2 H, Bz),
7.57 (d, J = 7.6 Hz, 2 H, Ph). 13C NMR (100.08 MHz,
CDCl3): d = 30.5 (Me), 48.2 (C-4), 46.8 (C-3), 55.2 (MeO),
86.3 (C-2), 86.3 (C-5), 114,0 (Ar), 124.5 (Ph), 126.7 (Ph),
127.8 (Bz), 128.3 (Bz), 128.8 (Ph), 129.2 (Ar), 131.8 (Ar),
133.1 (Bz), 135.9 (Bz), 148.2 (Ph), 158.4 (Ar), 197.4 (C=O).
(±)-cis,trans-2-Benzoyl-3-(4-methoxyphenyl)-5-phenyl-5methyl tetrahydrofuran (3a-C): colorless oil. HR-ESI-MS:
m/z calcd for C25H24O3 + Na+: 395.1618. Found: 395.1608.
1
H NMR (400 MHz, CDCl3: d = 1.90 (s, 3 H, Me), 2.58 (dd,
J = 12.0, 11.5 Hz, 1 H, H-4a), 2.81 (dd, J = 12.4, 7.2 Hz, 1
H, H-4e), 3.63 (s, 3 H, MeO), 3.70 (m, 1 H, H-3a), 5.72 (d,
J = 9.1 Hz, 1 H, H-2e), 6.53 (d, J = 8.8 Hz, 2 H, Ar), 6.91 (d,
J = 8.8 Hz, 2 H, Ar), 7.20 (dd, J = 8.0, 7.6 Hz, 2 H, Bz), 7.32
(t, J = 7.5 Hz, 1 H, Ph), 7.35 (t, J = 8.0 Hz, 1 H, Bz), 7.42
(dd, J = 7.5, 7.5 Hz, 2 H, Ph), 7.49 (d, J = 7.6 Hz, 2 H, Bz),
7.56 (d, J = 7.5 Hz, 2 H, Ph). 13C NMR (100.08 MHz,
CDCl3): d = 30.2 (Me), 45.4 (C-4), 48.1 (C-3), 55.0 (MeO),
82.4 (C-2), 85.6 (C-5), 113.3 (Ar), 124.7 (Ph), 126.7 (Ph),
127.3 (Bz), 127.8 (Bz), 128.3 (Ph), 129.2 (Ar), 130.0 (Ar),
132.3 (Bz), 136.5 (Bz), 147.0 (Ph), 158.2 (Ar), 198.9 (C=O).
(±)-trans,trans-2-Benzoyl-3-(4-methoxyphenyl)-5-phenyl5-methyl tetrahydrofuran (3a-D): colorless oil. HR-ESI-MS:
m/z calcd for C25H24O3 + H+: 373.1798. Found: 373.1797. 1H
NMR (400 MHz, CDCl3): d = 1.75 (s, 3 H, Me), 2.53 (dd,
J = 12.4, 12.4 Hz, 1 H, H-4a), 2.85 (dd, J = 12.4, 6.0 Hz, 1
H, H-4e), 3.77 (s, 3 H, MeO), 3.80 (m, 1 H, H-3a), 5.25 (d,
J = 9.2 Hz, 1 H, H-2a), 6.82 (d, J = 8.8 Hz, 2 H, Ar), 7.23 (d,
J = 8.8 Hz, 2 H, Ar), 7.43 (dd, J = 8.0, 8.0 Hz, 2 H, Bz), 7.29
(t, J = 7.6 Hz, 1 H, Ph), 7.37 (d, J = 7.6 Hz, 2 H, Ph), 7.39
(dd, J = 7.6, 7.6 Hz, 2 H, Ph), 7.55 (t, J = 8.0 Hz, 1 H, Bz),
8.01 (d, J = 8.0 Hz, 2 H, Bz). 13C NMR (100.08 MHz,
CDCl3): d = 30.9 (Me), 45.2 (C-3), 48.3 (C-4), 55.2 (MeO),
86.0 (C-2), 86.3 (C-5), 114.0 (Ar), 124.8 (Ph), 126.7 (Ph),
128.0 (Bz), 128.3 (Bz), 128.8 (Ph), 129.3 (Ar), 131.6 (Ar),
133.0 (Bz), 136.2 (Bz), 147.1 (Ph), 158.4 (Ar), 196.6 (C=O).
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