Fe(II)-mediated fragmentation of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes through competitive single electron transfer pathway and Lewis acid pathway

Article abstract of DOI:10.1016/S0040-4039(01)02201-8

Reactions of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 1a-d (1a: Ar=p-FC₆H₄, 1b: Ar=Ph, 1c: Ar=p-MeC₆H₄, 1d: Ar=p-MeOC₆H₄) with FeBr₂ in THF afforded 1,4-diarylbutan-1,4-diones 2a-d and 1,4-diaryl-7-oxabicyclo[2.2.1]heptanes 3a-d. On the other hand, 4-aryl-3-cyclohexenones 4c-d and p-substituted phenols 5c-d were obtained in the reactions of 1c-d with FeBr₂ in CH₂Cl₂. A new fragmentation mechanism involving an electrophilic oxyl radical 1,5-substitution and a nucleophilic O-1,2-aryl shift is proposed based on the product analysis. In addition, the in vitro antimalarial activities of 1a-d were tested.

Full text of DOI:10.1016/S0040-4039(01)02201-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 617–620
Fe(II)-mediated fragmentation of
1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes through competitive
single electron transfer pathway and Lewis acid pathway
Masaki Kamata,a,* Takashi Kudoh,a Jun-ichi Kaneko,a Hye-Sook Kimb and Yusuke Watayab
aDepartment of Chemistry, Faculty of Education and Human Science, Niigata University, Ikarashi, Niigata 950-2181, Japan
bFaculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan
Received 25 September 2001; accepted 16 November 2001
Abstract—Reactions of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 1a–d (1a: Ar=p-FC6H4, 1b: Ar=Ph, 1c: Ar=p-MeC6H4, 1d:
Ar=p-MeOC6H4) with FeBr2 in THF afforded 1,4-diarylbutan-1,4-diones 2a–d and 1,4-diaryl-7-oxabicyclo[2.2.1]heptanes 3a–d.
On the other hand, 4-aryl-3-cyclohexenones 4c–d and p-substituted phenols 5c–d were obtained in the reactions of 1c–d with FeBr2
in CH2Cl2. A new fragmentation mechanism involving an electrophilic oxyl radical 1,5-substitution and a nucleophilic O-1,2-aryl
shift is proposed based on the product analysis. In addition, the in vitro antimalarial activities of 1a–d were tested. © 2002
Elsevier Science Ltd. All rights reserved.
Much attention has been focused on antimalarial cyclic
peroxides from both synthetic and mechanistic view-
points.1–16 Particularly, mechanistic studies for the frag-
mentation of cyclic peroxides promoted by Fe(II) ions
are important to clarify potent antimalarial intermedi-
Scheme 1.
ates and to develop structurally more simple and easily
prepared antimalarial cyclic peroxides.7–16 In this
regard, Posner and co-workers proposed that struc-
turally simple and inexpensive 1,4-diaryl-2,3-dioxabicy-
clo[2.2.2]octanes 1a–b are potent antimalarial
compounds.11 They also reported that the reaction of
1,4-di(p-fluorophenyl)-substituted cyclic peroxide 1a
with FeBr2 afforded 1,4-di(p-fluorophenyl)butan-1,4-
dione 2a and 1,4-di(p-fluorophenyl)cyclohexan-1,4-
diol 6a as fragmentation products (Scheme 1).11 These
studies strongly prompted us to investigate the reactivi-
ties and the antimalarial activities of other 1,4-diaryl-
ated derivatives 1b–1d, such as Ph, p-MeC6H4,
p-MeOC6H4, since we have been interested in the
effects of aromatic substituents on the reactivities of an
oxyl radical species generated from arylated cyclic per-
oxides.17,18 We wish to report our preliminary but novel
results for the Fe(II)-mediated fragmentation of 1a–d
and their antimalarial activities, which are quite differ-
ent from those reported by Posner.11,19–21
equiv. of FeBr2 in dry THF (10 ml) under nitrogen (4
h), 1,4-diketone 2a (43%) and 1,4-di(p-fluorophenyl)-7-
oxabicyclo[2.2.1]heptane 3a (15%) were obtained
(Scheme 2, run 1 in Table 1).† Likewise, the reactions of
† A typical experimental procedure is as follows: to a solution of 1
(0.2 mmol) in dry THF or dry CH2Cl2 (10 ml) was added FeBr2 (0.2
mmol). The mixture was stirred at 23–25°C under nitrogen atmo-
sphere for 4 h. The mixture was passed through a silica gel short
column and eluted with CH2Cl2 to remove inorganic iron com-
pounds. The eluent was concentrated and the residue was separated
by TLC (n-hexane–CH2Cl2) to afford products. All products were
characterized by their spectral data.
Selected data for 3d: mp 155–157°C; IR (KBr, cm−1) 3040, 2900,
2860, 1612, 1580, 1517; 1H NMR (200 MHz, CDCl3): l 1.94–2.08
(m, 4H), 2.10–2.24 (m, 4H), 3.81 (s, 6H), 6.85–6.94 (m, 4H),
7.38–7.48 (m, 4H); 13C NMR (50 MHz, CDCl3): l 38.67 (t, 4C),
55.26 (q, 2C), 87.00 (s, 2C), 113.54 (d, 4C), 126.49 (d, 4C), 135.06
(s, 2C), 158.57 (s, 2C); MS (EI) 310 (M+, 99%).
Compound 4d: mp 68.5–69.5°C; IR (KBr, cm−1) 3030, 2960, 2930,
2850, 1713 (CꢀO), 1607, 1570, 1505; 1H NMR (200 MHz, CDCl3):
l 2.63 (t, 2H, J=6.7 Hz), 2.80–2.93 (m, 2H), 3.00–3.08 (m, 2H),
3.81 (s, 3H), 5.99 (m, 1H), 6.82–6.95 (m, 2H), 7.28–7.38 (m, 2H);
13C NMR (50 MHz, CDCl3): l 27.85 (t, 1C), 38.65 (t, 1C), 39.83 (t,
1C), 55.24 (q, 1C), 113.70 (d, 2C), 119.12 (d, 1C), 126.22 (d, 2C),
133.13 (s, 1C), 136.92 (s, 1C), 158.89 (s, 1C), 210.43 (s, 1C); MS (EI)
202 (M+, 100%); UV umax (CH3CN) 268.5 (m 20300) nm.
When cyclic peroxide 1a (0.2 mmol) was treated with 1
Keywords: 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes; cyclic peroxides;
FeBr2; fragmentation; reaction mechanism; antimalarial activity; 1,2-
aryl shift.
* Corresponding author. Tel./fax: +81-25-262-7150; e-mail: kamata@
ed.niigata-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02201-8

618
M. Kamata et al. / Tetrahedron Letters 43 (2002) 617–620
Scheme 2.
a
Table 1. Reactions of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 1 with FeBr2
Run
Substrate
Solvent
Additive
Yields (%)b
2
3
4
5
8
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1c
1d
1d
1b
1d
1d
1d
1d
THF
THF
THF
THF
None
None
None
None
None
None
None
None
None
TABDd
TMBd
CHDd
H2Oe
43
55
58
56
47
48
38
0
0
46
0
0
0
15
19
23
18
20
37
21
0
0
36
0
0
0
0
0
0
0
0
0
0
0
0
0
0
9
83
74
0
–
–
–
–
–
–
–
–
–
7
–
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
21
74
83
0
57
95
83
75
9c
10
11
12
13
14
94
97
84
97
TABDd
0
0
B1
a 1=0.2 mmol, FeBr2=0.2 mmol, solvent=10 ml.
b Isolated yield by silica gel TLC.
c FeBr2=0.1 mmol.
d Additive=0.2 mmol.
e H2O=0.6 mmol.
1b–d with FeBr2 exclusively produced 2b–d and 3b–d
(runs 2–4). Similar product distributions were observed
when 1a–b were treated with FeBr2 in dry CH2Cl2 (runs
5 and 6). Interestingly, when 1,4-di(p-methylphenyl)-
substituted peroxide 1c was treated with FeBr2 in dry
CH2Cl2, 4-(p-methylphenyl)cyclohex-3-en-1-one 4c
(21%) and p-methylphenol 5c (9%) were newly obtained
along with 2c (38%) and 3c (21%) (run 7). Unexpect-
edly, cyclohexenone 4d (74%) and p-methoxyphenol 5d
(83%) were exclusively produced in the reaction of
1,4-di(p-methoxyphenyl)-substituted peroxide 1d with
FeBr2 (run 8).
Fe(IV)ꢀO species, which is proposed as a potent anti-
malarial intermediate,19–21,23 afforded only a small
amount of 1,2,4,4-tetra(p-methoxyphenyl)-3-butenone 8
(runs 10 and 14).‡
On the basis of the above results, we propose a plausi-
ble mechanism as shown in Scheme 3. Both in THF
and CH2Cl2, the mono-oxyl radical intermediate A is
generated by single electron transfer (SET) from Fe(II)
to 1.11,24 As for the product formation from the inter-
mediate A, two different pathways are possible. One is
the formation of 1,4-diketone 2 accompanied with elim-
ination of ethylene and Fe(II) through CꢁC bond cleav-
age (path a). The other is the formation of
deoxygenated product 3 through an electrophilic oxyl
radical 1,5-substitution accompanied with elimination
of the Fe(IV)=O species (path b). In CH2Cl2, Fe(II)
also operates as a Lewis acid that generates the com-
plex of 1 with Fe(II) (1-Fe(II)). 1-Fe(II) undergoes a
nucleophilic (Baeyer–Villiger type) O-1,2-aryl shift to
afford the intermediate B (path c), which is promoted
by electron-donating substituents (p-An>p-Tol>Ph=
p-FC6H4: runs 5–9). The intermediate B undergoes
Detailed mechanistic studies further provided the fol-
lowing results: (i) a catalytic amount of FeBr2 (0.5
equiv.) promoted the reaction of 1d (run 9); (ii) addi-
OX
tion of 1,2,4,5-tetramethoxybenzene (TMB, E1/2
=
0.74 V versus SCE) as an effective quencher for single
electron transfer (SET) reactions22 did not significantly
affect the product distribution and the yields (run 11);
(iii) addition of 1,3-cyclohexadiene (CHD, hydrogen
donor) did not afford the expected diol 6d at all (run
12); (iv) addition of water (nucleophile) did not produce
6d either (run 13); (v) addition of 1,1,4,4-tetra(p-
methoxyphenyl)-1,3-butadiene 7 (TABD, E1/2OX=0.86
V versus SCE) to capture the oxygen atom of the
‡ Compound 8 was independently prepared by the reaction of 7
(TABD) with m-chloroperbenzoic acid.

M. Kamata et al. / Tetrahedron Letters 43 (2002) 617–620
619
Scheme 3.
Table 2. Antimalarial activities of 1 against P. falciparum
(FCR-3 strain) and cytotoxicities against FM3A cella
cyclization to produce the intermediate C followed by
Lewis acid (Fe(II))-catalyzed fragmentation to afford 4
and 5. Thus, 2 and 3 are produced through the SET
pathway while 4 and 5 are produced through the Lewis
acid pathway. THF is considered to act as a Lewis base
to interfere with the Lewis acid pathway. Paths a–c
were probably rapid steps because the influences of
TMB, CHD, water, or TABD on the product ratio were
small.
Substrate
EC50 (M)
Selectivityb
P. falciparum
FM3A cell
1a
1b
5.6×10−7
1.8×10−5
(61%)d
\32
\32
(6.3×10−8 c
)
1.0×10−6
3.2×10−5
(60%)d
(2.1×10−7 c
)
1c
1d
5.0×10−7
1.2×10−6
1.7×10−6
1.8×10−5
(88%)d
3.4
\15
The in vitro antimalarial activities of 1 against P.
falciparum were evaluated to clarify the relationship
between the antimalarial activities and the effects of the
aromatic substituents of 1.14 Compounds 1a–d showed
moderate antimalarial activities, and the EC50 values
were 5.6×10−7, 1.0×10−6, 5.0×10−7, 1.2×10−6 M, respec-
tively, for 1a–d (Table 2). Similar antimalarial activities
of 1a–d indicate that there is no pronounced relation-
ship between the antimalarial activities and the effects
of the aromatic substituents of 1a–d.
Artemisinin
Chloroquine
7.8×10−9
1.8×10−8
1.0×10−5
3.2×10−5
1280
1780
a Ref. 14.
b Selectivity=cytotoxicity/antimalarial activity.
c IC50 values against P. falciparum (NF54 strain), Ref. 11.
d Growth percent at the concentration indicated.
Acknowledgements
In conclusion, we have found that competitive SET
pathway and a Lewis acid pathway are responsible for
the Fe(II)-promoted OꢁO bond cleavage of cyclic per-
oxides, and that there is no pronounced relationship
between the antimalarial activities and the effects of the
aromatic substituents of 1a–d. We are conducting fur-
ther studies on the Fe(II)-mediated fragmentation of
other cyclic peroxides to clarify the mechanism and the
relationship between the reaction intermediates and the
antimalarial activities.
We are grateful to Professor Eietsu Hasegawa (Faculty
of Science, Niigata University), Professor Tsutomu
Miyashi and Dr. Hiroshi Ikeda (Faculty of Science,
Tohoku University), Professor Yasutake Takahashi
(Faculty of Engineering, Mie University), and Professor
Akinori Kon-no (Faculty of Engineering, Shizuoka
University) for their helpful comments and assistance.

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M. Kamata et al. / Tetrahedron Letters 43 (2002) 617–620
McCullough, K. J.; Kim, H.-S.; Shibata, Y.; Wataya, Y.
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