Medium-size cyclophanes, 751 synthesis of anti-[2.3] metacyclophan-1ene and conversion to syn-1,2-epoxy[2.3]metacyclophane

Article abstract of DOI:10.3184/030823407X196962

McMurry cyclisation of 1,3-bis(5-formyl-2-methoxyphenyl)propane afforded anti-6,13-dimethoxy[2.3]metacyclophan-1-ene, which was converted to the corresponding syn-1,2-epoxyl[2.3]metacyclophane by treatment of m-chloroperbenzoic acid.

Full text of DOI:10.3184/030823407X196962

JOURNAL OF CHEMICAL RESEARCH 2007
MARCH, 141–143
RESEARCH PAPER 141
1
Medium-size cyclophanes, 75 Synthesis of anti-[2.3]metacyclophan-1-
ene and conversion to syn-1,2-epoxy[2.3]metacyclophane
Tatsunori Saisyo, Mikiko Shiino, Tohru Hironaka and Takehiko Yamato*
Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga 840-8502, Japan
McMurry cyclisation of 1,3-bis(5-formyl-2-methoxyphenyl)propane afforded anti-6,13-dimethoxy[2.3]metacyclophan-
1
-ene, which was converted to the corresponding syn-1,2-epoxyl[2.3]metacyclophane by treatment of
m-chloroperbenzoic acid.
Keywords: cyclophanes, [2.3]metacyclophan-1-ene, McMurry reaction, conformation, strained molecules, epoxidation
Although the parent [2.2]metacyclophane (MCP = meta-
cyclophane) was first reported as early as in 1899 by
2
Pellegrin, the synthesis of syn-[2.2]MCP was not realised
until 85 years later. Mitchell et al.3 have successfully
prepared syn-[2.2]MCP at low temperature by using
[
CH2]n
[CH ]
2 n
(
arene)chromiumcarbonyl
complexation
to
control
4
the stereochemistry. Later, Itô et al. also isolated and
characterised syn-[2.2]MCP without complexation. However,
syn-[2.2]MCP isomerises readily to the anti-isomer
anti-conformation
syn-conformation
Fig. 1
5
6
above 0°C. On the other hand, Boekelheide and Staab
succeeded in synthesising intra-annularly substituted syn-
2.2]MCPs, respectively. However, reports on synthesis and
OMe
OMe
OMe
OMe
OMe
AlCl -MeNO ,
[
3
2
Benzene
reactions of syn-[2.n]MCP have not been published.
On the other hand, A. Merz et al. reported the stereospecific
epoxidation of (E)- and (Z)-stilbene crown ethers with
m-chloroperbenzoic acid to afford the epoxy crown ethers.
Oda et al. also reported the epoxidation of trans-
diethylstilbestrol with m-chloroperbenzoic acid to afford
the racemic trans-diethylstilbestrol oxide.8 Thus there is
substantial interest to synthesise the [2.n]MCP-1-enes and
conversion to 1,2-epoxy[2.n]MCP, which can adopt the syn-
conformation and the flexibility arising from the ring inversion
can be completely restricted.
50°C for 12 h
97%)
2
(
7
1
OMe
2
Cl CHOMe, TiCl4
CH2Cl2
room temp. for 1 h
CHO
CHO
(96%)
3
MeO 13
MeO
OH
Recently, we have reported the preparation of 1,2-
TiCl -Zn-pyridine
in THF
reflux for 60h
H
H
9
4
dimethyl[2.n]MCP-1-enes by using the reductive coupling
1
3
+
of carbonyl compounds by low-valent titanium, the
McMurry reaction10,11 as a key step. We now report on the
2
synthesis of anti-[2.3]MCP-ene using the low-valent titanium
induced McMurry reaction and conversion to syn-1,2-
epoxy[2.3]MCP. The conformational studies of these MCPs
in solution are also described.
OH
MeO
6
MeO
4 (23%)
5 (65%)
Scheme 1
Results and discussion
phenyl)propane, which afforded the corresponding [3.1]MCP
1
,3-Bis(5-tert-butyl-2-methoxyphenyl)propane 1 has been
9b
by the TiCl or acids induced pinacol rearrangements.
9
4
prepared according our previous papers. The AlCl –MeNO -
3
2
The structures of 4 and 5 were elucidated based on their
catalysed trans-tert-butylation of 1 in benzene at 50°C for 12
h afforded 1,3-bis(2-methoxyphenyl)propane 2 in good yield.
elemental analyses and spectral data. Especially, the mass
+
spectral data for 4 and 5 (M = 280 for 4 and 314 for 5) strongly
The TiCl formylation of compound 2 with dichloromethyl
4
support the cyclic structure. The conformation of 4 was
methyl ether at 20°C gave the desired 1,3-bis(5-formyl-2-
methoxyphenyl)propane 3 in good yield. 1,3-Bis(2-formyl-
1
readily apparent from its H NMR spectrum. Thus, the internal
aromatic proton shows an upfield shift (d 5.95 ppm) due to
5
-tert-butyl-3-methoxyl)phenyl)propane (3) was subjected
1
3
1
the ring current of the opposite benzene ring. The H NMR
spectrum of the [2.3]MCP-1-ene 4 prepared in the present
paper shows that its structure corresponds exclusively to the
anti-conformer. In addition, the protons of the trimethylene
bridge give rise to two multiplets centred at d = 2.35 and
1.95 ppm, respectively, providing a fast interconversion of the
two anti conformations of 4 by ring flipping. However, as the
temperature of the solution in CDCl /CS (1:3) is decreased,
to reductive coupling by the McMurry reaction following
the improved Grützmacher’s procedure12 (Scheme 1).
Thus, the reductive coupling reaction of 3 carried out using
TiCl –Zn in the presence of pyridine in refluxing THF under
4
the high dilution conditions afforded the desired compound
6
,13-dimethoxy[2.3]MCP-1-ene (4) in 23% along with 1,2-
dihydroxy-6,13-dimethoxy-[2.3]MCP (5) in 65% yield.
Surprisingly, when the present cyclisation reaction was
carried out in the absence of pyridine, the yield of 4 increased
to 69%. This result was quite different from that of the
similar McMurry cyclisation of 1,3-bis(5-acetyl-2-methoxy-
3
2
a single peak of the benzyl protons splits into two multiplets
at d 1.98 and 2.95 ppm below 10°C. The energy barrier to the
conformational ring flipping estimated from the coalescence
-1
temperature (Tc) is 12.8 kcal mol . We have assigned the
structure of 5 in a similar fashion. Thus, the structure of the
*
Correspondent. E-mail: yamatot@cc.saga-u.ac.jp
PAPER: 06/4443

1
42 JOURNAL OF CHEMICAL RESEARCH 2007
anti-confomer is also readily assigned from the chemical
shift of the internal aromatic protons as a doublet at d 4.99
Conclusions
We have demonstrated a convenient preparation of anti-6,13-
dimethoxy[2.3]MCP-1-ene 4 by McMurry reaction of 1,3-
bis(5-formyl-2-methoxyphenyl)propane 3. The epoxidation
of 4 with m-chloroperbenzoic acid afforded the desired 1,2-
epoxy[2.3]MCP 6, which adopts rigid syn-conformation.
Further studies on the chemical properties of syn-1,2-epoxy-
(
J = 2.4 Hz). The other two aromatic protons were observed
at d 6.80 and 7.21 ppm; the latter protons are in a strongly
deshielding region of oxygen atom of endo-OH on the
ethylene bridge. These observations strongly support that the
two OH groups are endo, endo-arrangement and therefore,
5
is found to be trans-diol.
6
,13-dimethoxy[2.3]MCP 6 are now in progress.
The epoxidation of 4 with m-chloroperbenzoic acid
afforded the desired 1,2-epoxy[2.3]MCP 6 as a colourless oil
in quantitative yield. Compound 6 was labile in solution and
slowly decomposed at room temperature.
Experimental
1
H NMR spectra were recorded at 300 MHz on a Nippon Denshi
JEOL FT-300 NMR spectrometer in deuteriochloroform with Me Si
as an internal reference. IR spectra were measured as KBr pellets
on a Nippon Denshi JIR-AQ2OM spectrometer. Mass spectra were
obtained on a Nippon Denshi JMS-01SA-2 spectrometer at 75 eV
using a direct-inlet system.
4
1
The 300 MHz H NMR spectrum of 6 showed a doublet
of the intra-annular proton H at d 7.01 ppm (J = 2.0 Hz) in
i
addition to the resonances at d 6.28 and 6.65 ppm for the other
two protons of the aromatic rings. These observations strongly
suggest that its structure corresponds exclusively to the syn-
Materials
conformation. The intra-annular proton H was observed
i
Preparation of 1,3-bis(5-tert-butyl-2-methoxylphenyl)propane (1)
was previously described.
Trans-tert-butylation of 1 to give 2: To a solution of 1 (2.21 g, 6.0
mmol) in benzene (16 cm ) was added a solution of anhydrous
at the slightly lower field (d 7.01 ppm) than that of the
corresponding syn-6,13-dimethoxy-1,2-dimethyl[2.3]MCP-
9a
3
1
-ene (d 6.95 ppm)) due to being in a deshielding region of
3
aluminum chloride (1.60 g, 12.0 mmol) in nitromethane (3.2 cm ).
oxygen atom of oxirane. In addition, the oxirane protons of
After the reaction mixture was stirred for 12 h at 50°C, the reaction
was quenched by the addition of 10% hydrochloric acid, and the
solution was washed with water, dried over Na SO , and concentrated.
the ethanobridge were shifted downfield about 0.8 ppm at d
4
(
.68 ppm in comparison with the cis-stilbene oxide
2
4
d 3.88 ppm).14 The oxirane protons might get closer into
The residue was chromatographed over silica gel (Wako C-300,
300 g) with hexane–benzene (1:1) as eluent to give crude 2 as a
colourless solid. Recrystallisation from petroleum ether gave 1,3-
bis(2-methoxyphenyl)propane (2) (1.5 g, 97%) as colourless prisms,
m.p. 63–65°C; d (CDCl ) 1.83–1.95 (2H, m, ArCH CH CH Ar),
the deshielding ring current zone of the benzene rings. These
findings strongly suggest the exo-epoxide structure of 6 and
syn-epoxidation from exo-attack to the double bond of syn-4
formed during the ring inversion of anti-4 might be sterically
favourable.
H
3
2
2
2
2
6
.67 (4H, t, J = 7.8 Hz, ArCH CH CH Ar), 3.77 (6 H, s, Me), 6.79–
.88 (4H, m, Ar–H), 7.12–7.17 (4H, m, Ar–H); m/z 256 (M ) (Found:
2 2 2
+
The protons of the trimethylene bridge gave rise to a
complicated signal pattern as expected for a rigid syn-
C, 79.45; H, 7.58. C H O requires C, 79.65; H, 7.86%).
Preparation of 1,3-bis(5-formyl-2-methoxyphenyl)propane (3):
To a solution of 2 (1.15 g, 4.5 mmol) and Cl CHOCH (1.14 cm ,
1
7
20
2
3
[2.3]MCP. The protons of the benzylic CH2 group were
2
3
3
1
2.6 mmol) in CH Cl (10 cm ) was added a solution of TiCl
observed as two multiplets centred at d 2.58 and 2.90 ppm
which were further split by coupling with the protons of
2
2
4
3
3
(3.0 cm , 27.3 mmol) in CH Cl (10 cm ) at 0°C. After the reaction
2 2
mixture was stirred at room temp. for 1 h, it was poured into a large
amount of ice/water (50 cm ) and extracted with CH Cl (20 cm
the central CH group. This central CH group was also
3
3
2
2
2 2
observed as two multiplets centred at d 1.28 and 2.21 ppm.
The peak pattern ascribed to six chemically distinct protons
of the propano bridge proved the absence of a syn–syn
interconversion which would exchange HA and HB of each
¥ 2). The combined extracts were washed with water, dried with
Na2SO4 and concentrated. The residue was chromatographed over
silica gel (Wako C–300, 200 g) with benzene as eluent to give 3
(
1.35 g, 96%) as a colourless solid. Recrystallisation from hexane
-1
gave 3 as colourless prisms, m.p. 82–84°C; n
(KBr)/cm 1679
max
CH group. These findings suggest the rigid structure of 1,2-
2
(
C=O); d (CDCl ) 1.90–1.96 (2H, m, ArCH CH CH Ar), 2.71 (4H,
H 3 2 2 2
epoxy[2.3]MCP 6 at this temperature. In fact, the signals of the
t, J = 7.8 Hz, ArCH CH CH Ar), 3.91 (6 H, s, OMe), 6.91 (2H, d,
2
2
2
benzyl protons of 6 do not coalesce below 150°C in CDBr ,
J = 7.8 Hz, Ar–H), 7.70 (2H, d, J = 2.0 Hz, Ar–H), 7.72 (2 H, dd,
3
-1
+
and the energy barrier of flipping is above 25 kcal mol . This
result suggests that the introduction of oxirane ring into the
ethano bridge can strongly reduce the flexibility arising from
the ring inversion.
J = 2.0, 7.8 Hz, Ar–H), 9.86 (2H, s, CHO); m/z 312 (M ) (Found C,
7
2.85; H, 6.55. C H O (312.37) requires C, 73.06; H, 6.45%).
19 20 4
McMurry coupling reaction of 3: The McMurry reagent was
3
prepared from TiCl [23.8 g (13.8 cm ), 125 mmol] and Zn powder
4
3
(18 g, 275 mmol) in dry THF (500 cm ) under nitrogen. A solution
of 1,3-bis(5-formyl-2-methoxyphenyl)propane 3 (2.81 g, 9.0 mmol)
3
3
MeO
and pyridine (22.8 cm , 200 mmol) in dry THF (250 cm ) was added
within 60 h to the black mixture of the McMurry reagent by using
a high-dilution technique with continuous refluxing and stirring.
The reaction mixture was refluxed for additional 8 h, cooled to room
H
MCPBA (2equiv.)
Na CO
2
3
4
O
3
temperature, and treated with aqueous 10% K CO (200 cm ) at
2
3
in benzene
room temp. for 40h
3
0
°C. The reaction mixture was extracted with CH Cl (200 cm ¥ 3).
2 2
H
The combined extracts were washed with water, dried with Na SO
2
4
MeO
and concentrated. The residue was chromatographed over silica gel
(
Wako C-300, 300 g) with hexane–benzene (2:1) and CHCl –EtOAc
1:1) as eluents to give 4 (590 mg, 23%) and 5 (1.83 g, 65%) as
3
6
(quant.)
(
colourless solids.
,13-Dimethoxy[2.3]metacyclophan-1-ene
prisms (from methanol), m.p. 133–135°C; n
Scheme 2
6
4
max
was obtained as
(KBr)/cm-1 2936,
H
1
496, 1288; d (CDCl ) 1.93–1.98 (2H, m, ArCH CH CH Ar), 2.35
H 3 2 2 2
(
4H, broad s, ArCH CH CH Ar), 3.82 (6H, s, OMe), 5.95 (2H, d,
O
2 2 2
H
J = 2.4 Hz, Ar–H), 6.58 (2H, s), 6.68 (2H, d, J = 8.2 Hz, Ar–H), 6.93
MeO
MeO
H
+
(2H, dd, J = 2.4, 8.2 Hz, Ar–H); m/z 280 (M ) (Found C, 81.32; H,
7
.15. C H O (280.37) requires C, 81.40; H, 7.19%).
1
9
20
2
H
O
1,2-Dihydroxy-6,13-dimethoxy[2.3]metacyclophane
5
was
MeO
MeO
obtained as prisms (from petroleum ether), m.p. 218–219°C;
(KBr)/cm- 3563, 3327 (OH); d (CDCl ) 1.80–1.95 (2H, m,
1
exo-6
endo-6
n
max
H
3
ArCH CH CH Ar), 1.98–2.12 (2H, m, ArCH CH CH Ar), 2.75
2
2
2
2
2
2
Fig. 2
(2H, s, OH), 2.94–3.05 (2H, m, ArCH CH CH Ar), 3.86 (6H, s,
2 2 2
PAPER: 06/4443

JOURNAL OF CHEMICAL RESEARCH 2007 143
References
OMe), 4.34 (2H, s, CH), 4.99 (2H, d, J = 2.4 Hz, Ar–H), 6.80 (2 H, d,
J = 7.8 Hz, Ar–H), 7.21 (2H, dd, J = 7.8, 2.1 Hz, Ar–H); m/z 314 (M )
+
1
Medium-sized cyclophanes. part 74: T. Saisyo, T. Hironaka, M. Shiino
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(
7
Found C, 72.53; H, 7.06. C H O (314.38) requires C, 72.59; H,
.05%).
19 22 4
2
3
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3
0
.70 mmol) and NaHCO (116 mg, 1.4 mmol) in benzene (35 cm )
3
was added m-CPBA (350 mg, 1.4 mmol) and the mixture was stirred
4
5
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3
for 40 h. The reaction mixture was diluted with water (20 cm ), and
3
extracted with CH Cl (10 cm ¥ 2). The combined extracts were
2
2
3
3
6
7
washed with 10% Na CO (10 cm ¥ 2) and water (10 cm ¥ 2), dried
with Na SO and concentrated to give 207 mg (100%) of syn-1,2-
2
3
2
4
epoxy-6,13-dimethoxy[2.3]metacyclophane (6) as colourless oil.
8
9
1
H NMR (CDCl ) d: 1.28 (1H, m, ArCH CH CH Ar), 2.21 (1H, m,
3
2
2
2
ArCH CH CH Ar), 2.58 (2H, m, ArCH CH CH Ar), 2.90 (2H, m,
2
2
2
2
2
2
ArCH CH CH Ar), 3.61 (6 H, s, OMe), 4.68 (2H, s, CH), 6.28 (2H,
2
2
2
d, J = 8.3 Hz, Ar–H), 6.65 (2H, dd J = 8.3, 2.0 Hz, Ar–H), 7.01 (2H,
+
d, J = 2.0 Hz, Ar–H. MS m/z: M 296. Anal. calcd. for C H O
1
9
20
3
1
0
(a) J.E. McMurry, M.P. Fleming, K.L. Kees and L.R. Krepski, J. Org.
Chem., 1978, 43, 3255; (b) J.E. McMurry, Acc. Chem. Res., 1983, 16,
(
296.37): C 77.00, H 6.80; found: C 77.08, H 6.78.
Estimation of activation energy of ring flipping: The rate constant
kc) of the observed conformational interconversion at the coalescence
4
05; (c) J.E. McMurry, G.J. Haley, J.R. Matz, J.C. Clardy and G.V. Duyne,
J. Am. Chem. Soc., 1984, 106, 5018; (d) J.E. McMurry, Chem. Rev., 1989,
9, 1513.
11 (a) T. Yamato, K. Fujita, K. Okuyama and H. Tsuzuki, New. J. Chem.,
(
(
(
(
T ) can be calculated by using eqn (1). The free energy of activation
c
8
≠
DG ) at coalescence can then be estimated by using Eyring equation
c
15
eqn (2)).
2
2
000, 221; (b) T. Yamato, K. Fujita, T. Abe and H. Tsuzuki, New J. Chem.,
001, 25, 728.
kc = pDu/21⁄
DGc≠ = 2.303RT (10.32 + logT – logk )
(1)
(2)
2
12 H.-F. Grützmacher and E. Neumann, Chem. Ber., 1993, 126, 1495.
1
3
(a) Cyclophanes (Eds.: P.M. Keehn and S.M. Rosenfield), Academic
Press: New York, 1983, vols 1&2; (b) F. Vögtle, Cyclophane chemistry,
Wiley: Chichester, 1993.
c
c
c
1
4
VARIAN NMR spectra catalogue, Varian Associates, 1962 and 1963,
spectra No. 625 and 626.
Received 1 February 2007; accepted 25 February 2007
Paper 07/4443 doi:10.3184/030823407X196962
1
5
M. Oki, Applications of dynamic NMR spectroscopy to organic chemistry;
VCH: Deerfield Beach, FL 1985.
PAPER: 06/4443