Synthesis of heterocyclic propellanes using Mn(III)-based oxidative cyclization

Article abstract of DOI:10.1016/j.tetlet.2006.07.090

The manganese(III)-based oxidative cyclization of 1,1-diarylethenes 1 with 3-(2-oxoethyl)piperidine-2,4-diones 2 was carried out in acetic acid at reflux temperature to selectively produce azadioxa[4.3.3]propellanes 3 in high yields. A similar cyclization

Full text of DOI:10.1016/j.tetlet.2006.07.090

Tetrahedron Letters 47 (2006) 7259–7262
Synthesis of heterocyclic propellanes using Mn(III)-based
oxidative cyclization
Kentaro Asahia and Hiroshi Nishinob,*
aDepartment of Materials and Life Sciences, Graduate School of Science and Technology, Kumamoto University,
Kurokami, Kumamoto 860-8555, Japan
bDepartment of Chemistry, Graduate School of Science and Technology, Kumamoto University, Kurokami,
Kumamoto 860-8555, Japan
Received 20 June 2006; revised 17 July 2006; accepted 20 July 2006
Available online 17 August 2006
Abstract—The manganese(III)-based oxidative cyclization of 1,1-diarylethenes 1 with 3-(2-oxoethyl)piperidine-2,4-diones 2 was car-
ried out in acetic acid at reflux temperature to selectively produce azadioxa[4.3.3]propellanes 3 in high yields. A similar cyclization
with the 2-(2-oxoethyl)cycloalkane-1,3-diones 7 and 2-(3-oxopropyl)cycloalkane-1,3-diones 10 also gave the corresponding dioxa-
propellanes 8 and 11 in moderate to good yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Some biologically active furopyridinones are known as
antifungal and antibacterial heterocycles.1 For example,
cladobotryal and an isomeric furopyridinone, which are
metabolites of the fungus Caldobotrium varium, have an
inhibitory effect on the growth of plant pathogens and
moderate activity against some drug-resistant bacteria.1a
Recently, we reported that the reaction of 1,1-disubsti-
tuted ethenes with 2-(2-oxoethyl)malonates in the pres-
ence of a stoichiometric amount of manganese(III)
acetate in boiling acetic acid produced 2,8-dioxabi-
cyclo[3.3.0]oct-3-enes via the cycloaddition-tandem cycli-
zation.2 The 2,8-dioxabicyclo[3.3.0]oct-3-ene skeleton
is found in biologically and pharmacologically active
compounds, such as the insect antifeedant clerodin
isolated from Clerodendrum infortunatum.3 The manga-
nese(III)-based one-pot cycloaddition-tandem cycliza-
tion4 is a useful method for constructing the 2,
8-dioxabicyclo[3.3.0]oct-3-enes. In connection with the
manganese(III)-based cycloaddition-tandem cyclization,
we found the unique synthesis of heterocyclic propell-
anes having both furopyridinone and dioxabicyclo-
[3.3.0]octene frameworks using cyclic 1,3-dicarbonyls.
Although small-ring propellanes are of significant theo-
retical interest,5 [4.3.3]-, [4.4.3]-, [5.3.3]-, or [6.3.3]-pro-
pellanes are also attractive from the standpoint of
their structures and syntheses.6
A mixture of 1,1-disubstituted ethene 1 (R1 = Ph) and 3-
(2-oxoethyl)piperidine-2,4-dione 2 (R2 = Ph, R3 = Bn)7
was oxidized with manganese(III) acetate in acetic acid
at reflux temperature. It was confirmed that the oxida-
tion finished within 1 min since the brown color of the
manganese(III) disappeared. After chromatographic
separation,8 four products were isolated (Scheme 1).
The major product 3 had only one carbonyl carbon (d
170.5 ppm) assigned to an amide, an extremely down-
field shifted quaternary ketal carbon (d 115.9 ppm), a
quaternary carbon of the ring junction (d 63.8 ppm),
two characteristic sp2 carbons due to a dihydrofuran
ring (d 156.3 and 99.0 ppm), and a quaternary carbon
attached to the oxygen of tetrahydrofuran (d
89.8 ppm) in the 13C NMR spectrum. In addition, two
O
Mn(OAc)3
R2
R3
R1
N
R1
AcOH, reflux
O
O
1
2
O
O
O
R3
R3
O
O
O
R2
R1
R1
O
N
N
R2
R1
R3
AcO
R1
R3
R1
N
N
R1
R1
R2
R1
R2
O
O
O
O
O
O
OAc
3
4
5
6
*
Corresponding author. Tel./fax: +81 96 342 3374; e-mail: nishino@
sci.kumamoto-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.090

7260
K. Asahi, H. Nishino / Tetrahedron Letters 47 (2006) 7259–7262
methylenes of the piperidinedione remained unchanged,
ane. A similar reaction of other alkenes (R1 = 4-
MeC6H4, 4-MeOC6H4, 4-ClC6H4, and 4-FC6H4) with
3-(2-oxoethyl)piperidine-2,4-diones 2 (R2 = 4-MeC6H4,
4-ClC6H4, R3 = Me, Et, Pr, i-Pr, and Ph) was carried
out and the desired propellanes 3 were obtained in
moderate to good yields together with the correspond-
ing azatrioxapropellanes 4 and the inseparable acetates
5 and 6 except for entries 2 and 3 in Table 1. The reac-
tion of 1 having an electron-donating aryl group
(R1 = 4-Me–C6H4 and 4-MeO–C6H4) with 2 (R2 = Ph,
R3 = Bn) exclusively gave the corresponding azadioxa-
propellanes 3 (entries 2 and 3). In contrast, when 1 bear-
ing an electron-withdrawing aryl group (R1 = 4-Cl–
C6H4 and 4-F–C6H4) was used, the yield of the propell-
anes 3 decreased, while the yield of the acetates 5 and 6
increased (entries 4 and 5). The substituents R2 and R3
of 2 did not influence the product distribution (entries
6–11).
and an AB geminal quartet (J = 13.4 Hz) newly ap-
1
peared at d 3.59 and 2.97 ppm in the H NMR spec-
trum, one of which shifted to high field because of the
anisotropic effect for the alkenic double bond. There-
fore, the structure was determined to be a 3-aza-7,12-
dioxa[4.3.3]propellane
3
(R1 = R2 = Ph, R3 = Bn)
(Scheme 1).9 The spectroscopic data of the minor prod-
uct 4 were quite similar to those of the propellane 3 ex-
cept for the ketal carbon at C-1, the quaternary carbon
of the ring junction at C-6, and the quaternary carbon
attached to the oxygen at C-4, which were slightly
shifted upfield (4–9 ppm) in the 13C NMR spectrum.
The conclusive difference was the Rf value for the TLC
and an extra oxygen in the FAB mass spectra as well
as the combustion analysis.10 Accordingly, the minor
product 4 (R1 = R2 = Ph, R3 = Bn) was apparently
assigned as 8-aza-2,3,11-trioxa[4.4.3]propellane. The
other minor products 5 and 6 were chromatographically
inseparable, however, the acetate 5 could be isolated
by fractional recrystallization from ethyl acetate–hex-
Since the azadioxapropellanes 3 and the acetates 5, 6
must be formed from the same intermediate, a mixture
Table 1. Reaction of 1,1-diarylethenes 1 with 3-(2-oxoethyl)piperidine-2,4-diones 2 in the presence of manganese(III) acetatea
Product (yield %)c
b
Entry
1
2
1:2:Mn(OAc)3
Time (min)
R1
R2
R3
3
4
5
6
1
2
3
4
5d
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Et
1:1.2:3
1:1.3:3.5
1:1.3:3
1:1.6:4
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1
1.5
1
1
1
1
0.5
1
1
1
53
90
94
28
37
51
51
57
52
51
51
45
9
4
—
10
6
6
6
8
8
13
—
—
39
16
20
23
18
16
15
22
25
13
—
—
19
17
14
18
14
17
8
4-Me–C6H4
4-MeO–C6H4
4-Cl–C6H4
4-F–C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me–C6H4
4-Cl–C6H4
Ph
Ph
Ph
Ph
Ph
9
10
11
12
Pr
i-Pr
Ph
7
6
7
1
1
19
21
a The reaction of a diarylethene 1 (0.5 mmol) was carried out in glacial acetic acid (20 mL) at reflux temperature.
b Molar ratio.
c Isolated yield based on the amount of the alkene 1 used.
d The alkene 1 was recovered in 7%.
Table 2. Result of ten-minute continuous heating after the manganese(III)-based reaction of 1 with 2a
Entry
1
2
1:2:Mnb
Yield (%)c
R1
R2
R3
3
4
1
2
3
4
5
6
7
8
Ph
4-Cl–C6H4
4-F–C6H4
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Me
Et
1:1.2:3
1:1.6:4
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
1:1.2:3
87
73
62
80
93
87
78
93
86
90
98
9
10
4
4
6
6
11
4
4
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me–C6H4
4-Cl–C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Pr
9
10
11d
i-Pr
Ph
Bn
—
a The reaction of 1 (0.5 mmol) was carried out in boiling glacial acetic acid (20 mL). After finishing the oxidation, the mixture was continuously
heated under reflux for 10 min.
b Molar ratio.
c Isolated yield based on the amount of the alkene 1 used.
d Before the oxidation, the mixture was degassed under reduced pressure for 30 min using an ultrasonicator followed by argon displacement, and
freshly prepared manganese(III) acetate was used in the reaction.

K. Asahi, H. Nishino / Tetrahedron Letters 47 (2006) 7259–7262
7261
of acetates 5 and 6 (R1 = 4-Cl–C6H4, R2 = Ph, R3 = Bn)
was heated under reflux in acetic acid for 10 min. As a
result, the acetates 5 and 6 were converted into the cor-
responding propellane 3 in a 92% isolated yield. There-
fore, the continuous heating for 10 min after finishing
the oxidation resulted in the exclusive production of
the azadioxapropellanes (Table 2).
moderate yields and also produced the [4.3.0]nonanes
12 as by-products (Scheme 3 and Table 4). In this case,
the continuous heating after finishing the oxidation did
not effectively increase the yield of 11.
The manganese(III)-based oxidative cycloaddition-
tandem cyclization could be explained by a similar
mechanism for the reaction using the 2-(2-oxoethyl)mal-
onates.2,15 The manganese(III)-piperidinedione enolate
complex A would be formed by the reaction of the pipe-
ridinediones 2 with manganese(III) acetate during the
first stage (Scheme 4). It is known that the manga-
nese(III)-enolate complex formation is the rate-deter-
mining step.4,16 The enolate complex A easily oxidized
the electron-rich alkenes 1 via a weak interaction
between the complex A and the alkene 1 such as an
electron donor–acceptor-like complex,16 giving the
corresponding tertiary carbon radicals B, which were
rapidly oxidized by sufficient amounts of manganese(III)
acetate under the stated conditions. As a result, the
carbocations C would be formed and cyclize at the keto
carbonyl oxygen of the piperidinediones to produce
thermodynamically more stable carbocations D. The
cations D would be allowed to intramolecuarlly cyclize
at the carbonyl oxygen of the most appropriate position
to finally produce the desired propellanes 3 by deproto-
nation. The by-products 5 and 6 were formed by the
attack of the acetate ion on the cations C and D, how-
ever, the reaction should be reversible. The propellanes
3 could be solely obtained when the dissolved molecular
oxygen in the solvent was completely removed by
degassing before the oxidation and the heating of the
reaction mixture was continued for 10 min after the
oxidation.
The formation of the trioxapropellanes 4 deserves com-
ment. In our previous study, we reported the synthesis
of azadioxabicyclo[4.4.0]decanones using the manga-
nese(III)-catalyzed aerobic oxidation of 2,4-piperidine-
diones at ambient temperature.11 The endoperoxide
ring was derived from the molecular oxygen dissolved
in the solvent.12 In fact, when the reaction was carried
out using a sufficient amount of manganese(III) acetate
at elevated temperature under argon, the azadioxabi-
cyclodecanones were not produced, while only azaoxabi-
cyclo[4.3.0]nonanones were obtained.11 Therefore, in
order to avoid the formation of the minor product 4,
the complete degassing under reduced pressure for
30 min using an ultrasonicator followed by argon dis-
placement before the oxidation and also the use of
freshly prepared manganese(III) acetate could control
the formation of 4 (Table 2, entry 11).
In order to examine the applicability of the manga-
nese(III)-based propellane formation, the reaction using
2-(2-oxoethyl)cycloalkane-1,3-diones 713 was carried out
under similar oxidation conditions to give the desired
propellanes 8 (Scheme 2 and Table 3). The ring size of
the cycloalkanedione is bigger, the yield of the propel-
lanes is lower, and the production of spiroalkanes was
promoted (Table 3, entries 3 and 4).
A similar reaction using 3-oxopropyl-substituted cyclo-
In summary, we have accomplished the unique synthesis
of heterocyclic propellanes using the manganese(III)-
alkanediones 1014 gave the desired propellanes 11 in
O
O
O
Mn(OAc)3
Mn(OAc)3
Ph
Ph
Ph
Ph
n
n
AcOH, reflux
Ph
AcOH, reflux
O
Ph
O
R
O
R
R
R
1
10
1
7
Ph
O
O
O
Ph
O
O
O
nR
nR
R
n
R
R
R
Ph
Ph
n
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
R
Ph
Ph PhO
OR'
12
R
8
9
11
Scheme 2.
Scheme 3.
Table 3. Mn(III)-based reaction of 1 with 7a
Table 4. Mn(III)-based reaction of 1 with 10a
Entry
7
n
1:7:Mnb
Time
(min)
Yield (%)c
Entry 10
n
1:10:Mnb Time (min)
Yield (%)c
11 12
R
8
9
R
1
2
3
4
Me
H
H
1
1
2
3
1:1.5:3
1:1.5:4
1:1.2:3
1:1.2:3
10
5
10
2
80
77
66
27
—
—
19
31
1
H
0
1:1.2:3
10
21 37 (R0 = H)
34 (R0 = Ac)
47 27
2
3
Me
H
1
1
1:1.5:3.5
1:1.2:3
10
10
H
49 31
a The reaction of 1 (0.5 mmol) was carried out in boiling glacial acetic
a The reaction of 1 (0.5 mmol) was carried out in boiling glacial acetic
acid (20 mL).
acid (20 mL).
b Molar ratio.
b Molar ratio.
c Isolated yield based on the amount of the alkene 1 used.
c Isolated yield based on the amount of the alkene 1 used.

7262
K. Asahi, H. Nishino / Tetrahedron Letters 47 (2006) 7259–7262
R2
1969, 91, 3372–3373; (c) Gassman, P. G.; Topp, A.; Keller,
O
R2
OIII
Mn O
J. W. Tetrahedron Lett. 1969, 1093–1095; (d) Eaton, P. E.;
Nyi, K. J. Am. Chem. Soc. 1971, 93, 2786–2788; (e)
Chalmers, A. M.; Baker, A. J. Tetrahedron Lett. 1974,
4529–4532; (f) Kurosawa, K.; McOmie, J. F. W. Bull.
Chem. Soc. Jpn. 1981, 54, 3877–3878.
O
R3
1
O
R1
R3
Mn(III)
N
2
N
-Mn(II)
R1
O
A
B
7. (a) Ibenmoussa, S.; Chavignon, O.; Teulade, J.-C.; Viols,
H.; Debouzy, J.-C.; Chapat, J.-P.; Gueiffier, A. Hetero-
cycl. Commun. 1998, 4, 317–324; (b) Kametani, T.; Katoh,
T.; Tsubuki, M.; Honda, T. Chem. Pharm. Bull. 1985, 33,
61–66.
Mn(III)
heat
6
5
AcOH
AcOH
R2
O
R2
O
O
O
N
O
O
R3
R1
R1
R3
8. After the oxidation, the solvent was removed in vacuo,
and the residue was triturated with water followed by
extraction with chloroform (10 mL · 3). The combined
extracts were dried over anhydrous magnesium sulfate,
and then concentrated to dryness. The crude products
were separated by TLC while eluting with chloroform.
9. Compound 3 (R1 = R2 = Ph, R3 = Bn): Rf = 0.22 (chlo-
R1
R1
N
-H
3
D
C
Scheme 4.
1
roform); colorless oil; IR (neat) m 1647 (C@O); H NMR
based cycloaddition-tandem cyclization of 1,1-diaryl-
ethenes with 3-(oxoalkyl)piperidine-2,4-diones. The
selective synthesis of interesting endoperoxide 8-aza-2,3,
11-trioxa[4.4.3]propellanes is currently in progress.
(300 MHz, CDCl3) d 7.57 (2H, m, arom. H), 7.40 (2H, m,
arom. H), 7.39–7.12 (13H, m, arom. H), 7.00 (2H, m,
arom. H), 6.84 (2H, m, arom. H), 5.19 (1H, s, H-9), 4.66
(1H, d, J = 14.9 Hz, Ph–CH2), 4.44 (1H, d, J = 14.9 Hz,
Ph–CH2), 3.59 (1H, d, J = 13.4 Hz, H-10), 3.28 (1H, ddd,
J = 12.9, 10.5, 2.9 Hz, H-4), 3.13 (1H, ddd, J = 12.9, 4.8,
3.9 Hz, H-4), 2.97 (1H, d, J = 13.4 Hz, H-10), 2.49 (1H,
ddd, J = 13.6, 4.8, 2.9 Hz, H-5), 2.14 (1H, ddd, J = 13.6,
10.5, 3.9 Hz, H-5); 13C NMR (75 MHz, CDCl3) d 170.5
(C@O), 156.3 (C-8), 146.1, 144.4, 136.5, 129.2 (arom. C),
128.7, 128.6, 128.2, 127.74, 127.65, 127.5, 127.4, 126.8,
126.3, 125.4, 125.23, 125.16 (arom. CH), 115.9 (C-6), 99.0
and 98.9 (C-9), 89.8 (C-11), 63.8 (C-1), 50.1 (Ph–CH2),
47.5 (C-10), 42.7 (C-4), 33.7 (C-5). FAB HRMS (acetone–
NBA) calcd for C34H30NO3 500.2226 (M+1). Found
500.2229.
Acknowledgements
We gratefully acknowledge Professor Teruo Shinmyozu,
Institute for Materials Chemistry and Engineering, Kyu-
shu University, Japan, for the measurement of the high
resolution FAB mass spectrometry.
Supplementary data
10. Compound 4 (R1 = R2 = Ph, R3 = Bn): Rf = 0.32 (chlo-
roform); colorless microcrystals (from diethyl ether); mp
Experimental details and full characterization of the
1
166.5 ꢁC; IR (neat) m 1639 (C@O); H NMR (300 MHz,
propellanes
3 4
(R1 = R2 = R3 = Ph), (R1 = R2 =
R3 = Ph), 11 (n = 1, R = H) and by-products
5
CDCl3) d 7.55 (1H, m, arom. H), 7.43–7.12 (18H, m,
arom. H), 5.13 (1H, s, H-13), 4.71 (1H, d, J = 14.9 Hz,
Ph–CH2), 4.37 (1H, d, J = 14.9 Hz, Ph–CH2), 3.86 (1H, d,
J = 14.3 Hz, H-5), 3.38 (1H, ddd, J = 12.7, 11.8, 2.8 Hz,
H-9), 3.11 (1H, ddd, J = 12.7, 4.6, 3.5 Hz, H-9), 2.69 (1H,
d, J = 14.3 Hz, H-5), 2.23 (1H, ddd, J = 13.6, 3.5, 2.8 Hz,
H-10), 1.95 (1H, ddd, J = 13.6, 11.8, 4.6 Hz, H-10); 13C
NMR (75 MHz, CDCl3) d 169.3 (C@O), 156.3 (C-12),
146.8, 143.7, 136.3, 129.3 (arom. C), 129.1, 128.7, 128.34,
128.27, 128.0, 127.7, 127.6, 127.1, 127.0, 125.42, 125.35,
125.2 (arom. CH), 111.8 (C-1), 100.5 and 100.4 (C-13),
86.0 (C-4), 54.7 (C-6), 50.6 (Ph–CH2), 41.4 (C-9), 37.1 (C-
5), 27.9 (C-10). Positive FAB MS (acetone–NBA) m/z 516
(M+1). Anal. Calcd for C34H29NO4: C, 79.20; H, 5.67; N,
2.72. Found: C, 79.33; H, 5.60; N, 2.74.
(R1 = R2 = Ph, R3 = Bn), 5 (R1 = R2 = R3 = Ph), 6
(R1 = R2 = R3 = Ph). Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.07.090.
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