Iron(II)-promoted rearrangement of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-enes: A mechanism distinct from that postulated previously

Article abstract of DOI:10.1016/S0040-4039(02)02024-5

Reactions of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-enes 1a-c (1a: Ar=p-FC₆H₄, 1b: Ar=C₆H₅, 1c: Ar=p-MeC₆H₄) with FeBr₂ afforded syn-1,2;3,4-bis(epoxy)-1,4-diarylcyclohexanes 4a-c and cis-3,6-diaryl-2,3-epoxycyclohexanones 5a-c as major products instead of the previously reported 1-aroyl-3-aryl-2,3-epoxycyclopentanes 2a-c.

Full text of DOI:10.1016/S0040-4039(02)02024-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8313–8317
Iron(II)-promoted rearrangement of
1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-enes: a mechanism distinct
from that postulated previously
Masaki Kamata,a,* Chika Satoh,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 12 August 2002; revised 11 September 2002; accepted 13 September 2002
Abstract—Reactions of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-enes 1a–c (1a: Ar=p-FC6H4, 1b: Ar=C6H5, 1c: Ar=p-MeC6H4)
with FeBr2 afforded syn-1,2;3,4-bis(epoxy)-1,4-diarylcyclohexanes 4a–c and cis-3,6-diaryl-2,3-epoxycyclohexanones 5a–c as major
products instead of the previously reported 1-aroyl-3-aryl-2,3-epoxycyclopentanes 2a–c. © 2002 Elsevier Science Ltd. All rights
reserved.
Much attention has been paid to bicyclic peroxides
from both the synthetic and mechanistic viewpoints
because of their antimalarial activity.1 Particularly,
mechanistic studies on the degradation of aryl-substi-
tuted bicyclic peroxides promoted by Fe(II) compounds
are important to disclose potent antimalarial intermedi-
ates and to prepare more effective antimalarial bicyclic
peroxides.1c–g Posner and coworkers reported that
structurally simple and easily prepared 1,4-diaryl-2,3-
dioxabicyclo[2.2.2]oct-5-enes 1a–b (1a: Ar=p-FC6H4,
1b: Ar=C6H5) are potent antimalarials.1e In the reac-
tion of fluorinated cyclic peroxide 1a with FeBr2 in
THF, 1-(p-fluorobenzoyl)-3-(p-fluorophenyl)-2,3-epoxy-
cyclopentane 2a, whose stereochemistry was not deter-
mined, and 1,4-di(p-fluorophenyl)cyclohex-2-ene-1,4-
diol 3a were reported to be produced through a
mono-oxyl radical intermediate (Scheme 1).1e On the
contrary, Suzuki and Noyori reported that the reaction
of 1b with FeCl2(PPh3)2 in CH2Cl2 produced the corre-
sponding diepoxide 4b through a similar mono-oxyl
radical intermediate (Scheme 2).2† These contrasting
results stimulated us to reinvestigate the reaction of 1
with FeBr2 in connection with our ongoing program
studying the degradation mechanism of aryl-substituted
bicyclic peroxides with FeBr2.4 Herein we wish to
report that 1a–c reacted with FeBr2 to produce syn-
1,2;3,4-bis(epoxy)-1,4-diarylcyclohexanes 4a–c and cis-
3,6-diaryl-2,3-epoxycyclohexanones 5a–c as major
Scheme 1.
Keywords: 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-ene; antimalarial cyclic peroxide; malaria; bicyclic peroxide; FeBr2; rearrangement; diepoxide;
epoxyketone; mechanism.
* Corresponding author. Tel./fax: +81-25-262-7150; e-mail: kamata@ed.niigata-u.ac.jp
† Turner and Herz also reported that the reaction of ascaridole with FeSO4 in aqueous THF produced the corresponding diepoxide through a
mono-oxyl radical intermediate.3
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02024-5

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M. Kamata et al. / Tetrahedron Letters 43 (2002) 8313–8317
Scheme 2.
products instead of the previously reported epoxycy-
clopentanes 2a–c.
1,2;3,4-bis(epoxy)-1,4-diphenylcyclohexane 4a (52%)
was obtained along with 3a (<1%), 5a (26%), and 6a
(<1%) in the reaction of 1a with a catalytic amount of
FeBr2 (0.2 equiv.) in THF (run 2). Likewise, syn-
1,2;3,4-bis(epoxy)-1,4-di(p-fluorophenyl)cyclohexane 4b
(52%) was obtained from 1b (run 3). On the other
hand, a similar catalytic reaction of 1c with FeBr2
resulted in the formation of epoxyketone 5c (65%) as a
major product (run 4). In contrast to the reactions in
THF, 4a–c were produced as major products in the
reactions of 1a–c with FeBr2 in CH3CN (runs 6–8).
When bicyclic peroxide 1a (0.2 mmol) was treated with
1 equiv. of FeBr2 (0.2 mmol) in dry THF (10 ml) under
nitrogen (5 min) at 20–23°C,‡ cis-3,6-di(p-
fluorophenyl)-2,3-epoxycyclohexanone 5a (58%)§ was
produced as a major product accompanied with trace
amounts of cis-1,4-di(p-fluorophenyl)cyclohexan-1,4-
diol 3a (<1%) and 4,4%%-difluoro-[1,1%,4%,1%%]terphenyl 6a
(3%) (Scheme 3, run 1 in Table 1). Interestingly, syn-
Scheme 3.
‡ General experimental procedure: To a solution of 1 (0.2 mmol) in dry THF (10 ml) was added FeBr2 (0.04–0.20 mmol, 98%, Aldrich). The
mixture was stirred at 20–23°C under nitrogen atmosphere for 5 min. The mixture was passed through a silica gel short column using CH2Cl2
as a solvent to remove inorganic iron compounds. The eluent was concentrated and the residue was separated by TLC (n-hexane/CH2Cl2). All
products were characterized by their spectral data and 4b was confirmed by the reported spectral data.2,5 Selected data for the representative
products are described below.
Compound 4a: colorless needles; mp 155–156°C; IR (KBr, cm−1); 3020, 2980, 2940, 2890, 1607, 1518, 1509, 1446; 1H NMR (200 MHz, CDCl3)
l 2.17–2.37 (m, 2H), 2.41–2.60 (m, 2H), 3.30 (s, 2H), 6.96–7.17 (m, 4H), 7.28–7.45 (m, 4H); 13C NMR (50 MHz, CDCl3) l 26.30 (t, 2C), 56.76
(s, 2C), 57.80 (d, 2C), 115.39 (d, 4C, JCꢀF=21.5 Hz), 126.76 (d, 4C, JCꢀF=8.2 Hz), 130.03 (s, 2C, JCꢀF=3.1 Hz), 162.22 (s, 2C, JCꢀF=245 Hz).
Anal. calcd for C18H14F2O2; C, 71.99; H, 4.70. Found: C, 71.78; H, 4.86%. MS (EI) 300 (M+, 2.1%), 121 (100%).
Compound 5a: colorless needles; mp 146–149°C; IR (CHCl3, cm−1) 3050, 3020, 2970, 2890, 1711(CꢁO), 1612, 1517; 1H NMR (200 MHz, CDCl3)
l 1.97–2.12 (m, 1H), 2.23–2.70 (m, 3H), 3.29 (dd, 1H, J=12.2 Hz, 6.5 Hz), 3.38 (s, 1H), 6.98–7.27 (m, 6H), 7.30–7.42 (m, 2H); 13C NMR (50
MHz, CDCl3) l 25.11 (t, 1C), 27.29 (t, 1C), 52.68 (d, 1C), 63.25 (s, 1C), 64.26 (d, 1C), 115.63 (d, 2C, JCꢀF=21.4 Hz), 115.68 (d, 2C, JCꢀF=21.5
Hz), 126.99 (d, 2C, JCꢀF=8.3 Hz), 129.96 (d, 2C, JCꢀF=8.1 Hz), 134.12 (s, 1C, JCꢀF=2.9 Hz), 161.88 (s, 1C, JCꢀF=244 Hz), 162.63 (s, 1C,
J
CꢀF=246 Hz), 203.93 (s, 1C). Anal. calcd for C18H14F2O2: C, 71.99; H, 4.70. Found: C, 72.05; H, 4.90%. MS (EI) 300 (M+, 9.9%), 122 (100%).
Compound 6a: colorless prisms; mp 219–222°C; IR (KBr, cm−1) 3070, 1605, 1517, 1491, 1396, 1H NMR (200 MHz, CDCl3) l 7.08–7.22 (m, 4H),
7.52–7.64 (m, 4H), 7.61 (s, 4H); 13C NMR (50 MHz, CDCl3) l 115.68 (d, 4C, JCꢀF=21.2 Hz), 127.36 (d, 4C), 128.52 (d, 4C, JCꢀF=8.2 Hz),
136.65 (s, 2C, JCꢀF=3.3 Hz), 139.09 (s, 2C), 162.46 (s, 2C, JC–F=245 Hz). Anal. calcd for C18H12F2: C, 81.19; H, 4.54. Found: C, 80.80; H,
4.76%. MS (EI) 266 (M+, 100%).
§ The structure of 5a was determined on the basis of the following data (see also Scheme 3). The 13C NMR spectrum exhibited a one-carbon singlet
at 203.93 ppm assigned to the aliphatic carbonyl carbon (C1). The IR spectrum exhibited a carbonyl absorption at 1711 cm−1 assigned to the
cyclohexanone skeleton. In the 1H NMR spectrum was found the one-proton singlet at 3.38 ppm assigned to the hydrogen (Ha) attached to the
epoxy ring. The one-proton doublet of doublets (J=12.2 Hz, 6.5 Hz) at 3.29 ppm was assigned to the hydrogen (Hf) under the aryl a to the
carbonyl group. These data supported the structure of 5a rather than that of 2a. The stereochemistry of 5a was then determined by 1H–1H COSY
and NOE experiments. When the peak at 3.29 ppm (Hf) was irradiated, NOE effects were observed for Hb (3.0%) and Hd (3.9%), but not for
Ha, Hc, and He. Furthermore, no NOE effect was observed for all cyclohexyl ring protons when the peak at 3.38 ppm (Ha) was irradiated. These
data suggest that Ha and Hf are located in equatorial and axial positions, respectively. Thus, the relationship of the two aryl groups in 5a was
concluded to be cis. The structures and stereochemistries of 5b and 5c were similarly determined.

M. Kamata et al. / Tetrahedron Letters 43 (2002) 8313–8317
8315
Table 1. Fe(II)-promoted degradation of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-enes 1 and syn-1,2;3,4-bis(epoxy)-1,4-diarylcy-
clohexanes 4a
Run
Substrate
Solvent
Additive
Conv. (%)
Yield (%)b
3
4
5
6
1c
2
3
1a
1a
1b
1c
1a
1a
1b
1c
THF
THF
THF
THF
None
None
None
None
HMDBd
None
None
None
100
100
100
100
100
95
B1
B1
B1
2
B1
B1
B1
0
0
58
26
20
65
22
B1
B1
22
3
B1
3
3
3
2
2
2
52
52
0
64
69
73
50
4
5c
6
THF
CH3CN
CH3CN
CH3CN
7
8
100
91
9
4a
4b
4c
4a
4b
4c
THF
THF
THF
CH3CN
CH3CN
CH3CN
None
None
None
None
None
None
63
73
100
24
22
65
0
0
0
0
0
0
0
0
0
0
0
0
34
34
76
11
10
48
0
0
0
0
0
0
10
11
12c
13c
14c
a 1 (or 4)=0.20 mmol; FeBr2=0.04 mmol; solvent=10 ml; at 20–23°C; reaction time: runs 1–8=5 min, runs 9–14=30 min.
b Isolated yield by silica gel TLC.
c FeBr2=0.20 mmol.
d Hexamethyl Dewar benzene (0.20 mmol).
Scheme 4.

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M. Kamata et al. / Tetrahedron Letters 43 (2002) 8313–8317
Detailed mechanistic studies further provided the fol-
lowing results: (i) addition of hexamethyl Dewar benz-
ene (HMDB) to capture a high-valent Fe(IV)ꢁO species,
which is proposed as a potent antimalarial inter-
mediate,1e,7–10 did not produce the expected hexa-
methylbenzene (HMB), but changed the product distribu-
tion (compare run 1 with run 5); (ii) when the diepoxides
4a–c¶ were treated with FeBr2 (0.2–1.0 equiv.) for 30
min, the epoxyketones 5a–c were produced in both THF
and CH3CN (runs 9–14); and (iii) the reaction of 1,4-
diol 3a with FeBr2 (2.0 equiv.) produced the terphenyl
6a (31%) at 50% conversion of 3a.
formation from G, two different pathways are possible.
One is the formation of the 1,4-diol 3 presumably
derived from the reaction of G with moisture (path e).
The other is the formation of the terphenyl 6 by
elimination of the Fe(III)OH (path f). Dehydration of 3
by Fe(II) may be an alternative route to give 6 (path g).
Finally, it should be stressed that the high-valent
Fe(IV)ꢁO species was not generated in the reaction
because of the absence of rearrangement from HMDB
to HMB (run 5).1e,7–10
We are conducting further studies on the Fe(II)-pro-
moted degradation of various aryl-substituted cyclic
peroxides to clarify the generality of the reaction and
the relationship between the reaction intermediates and
the antimalarial activity.
On the basis of the above results, we propose a mecha-
nism for the Fe(II)-promoted rearrangement of 1 as
shown in Scheme 4. Both in THF and CH3CN, the
mono-oxyl radical intermediate A is generated by single
electron transfer (SET) from Fe(II) to 1.1e,4,11 As for the
transformation of the intermediate A, two different
pathways are possible. One is the generation of the
carbon radical intermediate B through an intramolecu-
lar oxyl radical addition to the olefin in A (path a). The
other is the generation of the intermediate G by succes-
sive SET from Fe(II) to A which is a minor pathway
(path b). The intermediate B undergoes intramolecular
SET to form the carbocation intermediate C followed
by the formation of the diepoxide 4 with concomitant
elimination of Fe(II). As for the formation of the
epoxyketone 5 from 4, two different pathways are
possible. One is the reductive SET pathway by Fe(II)
(path c) and the other is the Lewis acid-catalyzed
pathway by Fe(III) species (path d). Thus, SET from
Fe(II) to 4 regioselectively generates the carbon radical
intermediate D since the aryl group at C6 stabilizes the
carbon radical (path c). The intermediate D undergoes
intramolecular SET to form the intermediate E followed
by a 1,2-hydride shift. The 1,2-hydride shift stereoselec-
tively occurs in E since the aryl group at C6, which
stabilizes the carbocation, should favor the equatorial
position. As described above, the rearrangement from 4
to 5 required a catalytic amount of Fe(II) as a SET
donor (path c; runs 9–11)** and was also accelerated by
electron-donating aromatic groups (p-MeC6H4>C6H5,
p-FC6H4: runs 4, 8, 11 and 14), while the rearrangement
was significantly inhibited by HMDB and CH3CN (sol-
vent) which may form complexes with Fe(II) to interfere
with the action of Fe(II) (runs 5–8, 12–14). The possibil-
ity that the Fe(III) species, as a Lewis acid, formed in
the reaction should catalyze the rearrangement through
the carbocation intermediate F is considered as an
alternative pathway (path d).†† As for the product
Acknowledgements
We are grateful to Professor Eietsu Hasegawa (Faculty
of Science, Niigata University), Professor Tsutomu
Miyashi and Dr. Hiroshi Ikeda (Graduate School of
Science, Tohoku University) for their helpful discus-
sions and assistance. We also thank Professor Toshio
Suzuki and Mr. Jun-ichi Sakai (Faculty of Engineering,
Niigata University) for the 500-MHz 1H NMR
measurement.
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