Pyrolysis of dimethoxy[n.2]metacyclophanes: An intramolecular condensation reaction to give oxa[n.2.1](1,3,2)cyclophanes

Article abstract of DOI:10.3184/174751912X13296759770106

Pyrolysis of anti-8,16-dimethoxy[2.2]metacyclophane at 500 °C gave 17-oxa[2.2.1](1,3,2)cyclophane in 35% yield arising from intramolecular condensation reaction of syn-8,16-dimethoxy[2.2]metacyclophane; similar results were also obtained in the pyrolysis

Full text of DOI:10.3184/174751912X13296759770106

134 RESEARCH PAPER
MARCH, 134–137
JOURNAL OF CHEMICAL RESEARCH 2012
Pyrolysis of dimethoxy[n.2]metacyclophanes: an intramolecular
condensation reaction to give oxa[n.2.1](1,3,2)cyclophanes
Jung-Hee Do, Yuta Yamada, Bigyan Sharma and Takehiko Yamato*
Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga 840-8502, Japan
Pyrolysis of anti-8,16-dimethoxy[2.2]metacyclophane at 500 °C gave 17-oxa[2.2.1](1,3,2)cyclophane in 35% yield
arising from intramolecular condensation reaction of syn-8,16-dimethoxy[2.2]metacyclophane; similar results were
also obtained in the pyrolysis of the higher anti- and syn-dimethoxy[3.2] metacyclophane to afford the corresponding
18-oxa[3.2.1](1,3,2)cyclophane. The mechanism of this novel intramolecular condensation reaction is discussed.
Keywords: cyclophanes, strained molecules, pyrolysis, intramolecular condensation reaction
The synthesis and stereochemical aspects of conformationally
mobile [m.n]metacyclophanes (MCPs) have been of interest
for the past two decades,1,2 particular attention being paid to
[2.2]MCPs, which possess an anti-stepped conformation.3–7
Although the parent [2.2]MCP was first reported as early as in
1899 by Pellegrin,8 the synthesis of syn-[2.2]MCP was not
realised until 85 year later. Mitchel et al.9 have successfully
prepared syn-[2.2]MCP at low temperature by using
(arene)chromium–carbonyl complexation to control the ste-
reochemistry. However, syn-[2.2]MCP isomerises readily to
the anti-isomer above 0 °C.10 In contrast, a ring inversion of
anti-[2.2]MCPs to the corresponding syn-[2.2]MCPs has not
yet been reported. The meta-bridged benzene ring has not been
shown to undergo conformational flipping above 200 °C. A
large part of this high energy barrier is believed to arise from
steric destabilisation of the transition state in which the 8 or
16 hydrogen to each meta-bridged ring impinges into the
π-electron cloud of the opposing benzene ring. Therefore, the
cleavage of the ethylene bridge must be necessary for the ring
inversion. Whereas according to the spectroscopic findings,
the [2.2]MCPs have the anti conformation with staggered
benzene rings, the existence of a syn form for a [n.2]MCP has
also been detected.11–18
Results and discussion
Preparation of anti-5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP
(anti-1a),21 syn- and anti-6,14-di-tert-butyl-9,17-dimethoxy[3.2]
MCP (1b)22 has been described elsewhere. Attempted pyroly-
sis of anti-8,16-dimethoxy[2.2]MCP anti-1a was carried out
in triglyme at 216 °C to recover the starting compound. No
formation of the intramolecular condensation product, 17-oxa
[2.2.1](1,3,2)cyclophane 2a19 has been observed under the
reaction conditions used. Only the recovery of the starting
compound was obtained. Interestingly, the present pyrolysis
was carried out at 400 °C, the expected intramolecular conden-
sation product 2a was obtained in 2% yield along with the
recovery of the starting compound anti-1a in 96% yield.
Pyrolysis of anti-1a at 500 °C led to the intramolecular
condensation reaction to give 17-oxa[2.2.1](1,3,2)cyclophane
2a in 35% yield along with the transannular cyclisation prod-
uct 3 in 37% yield. However, the increasing the temperature at
560 °C the yield of the transannular cyclisation product 3
increased to 65%. The present novel intra-annular condensa-
tion reaction is the first evidence for anti–syn-ring inversion
under the pyrolysis of anti-8,16-dimethoxy[2.2]MCP anti-1a.
It was also found that the pyrolysis reaction of anti-8,16-
dihydroxy[2.2]MCP anti-45,6 at 550 °C, which was prepared
by demethylation of anti-1a with BBr3 in CH2Cl2 in 80% yield,
also led to the present intramolecular condensation reaction to
afford 2a in 13% yield along with the transannular cyclisation
reaction product 3 in 23% yield.
On the other hand, we have reported19 that nitration of anti-
5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP anti-1a led to
ipso-nitration at the tert-butyl group to give 5-tert-butyl-8,16-
dimethoxy-13-nitro[2.2]MCP, as well as the corresponding
17-oxa[2.2.1](1,3,2)cyclophane arising from intramolecular
condensation reaction via anti–syn-ring inversion of the nitra-
tion intermediate. Recently, Hopf et al. reported20 the pyrolysis
of 5,13-dibromo[2.2]paracyclophane in triglyme at 216 °C
to afford 7,13-dibrom[2.2]paracyclophane through the ring
clevage of ethylene bridge. Thus there is substantial interest
in studying the pyrolysis of anti-8,16-disubstituted [2.2]MCPs
to give the corresponding syn-[2.2]MCPs. We report here the
first evidence for anti–syn-ring inversion under the pyrolysis
of di-tert-butyl-dimethoxy[n.2]MCPs 1. The mechanism of
the present novel intramolecular condensation reaction is also
discussed.
Although the detailed mechanism of formation of 17-oxa
[2.2.1](1,3,2)cyclophane 2a is not clear from the available
results, one might assume that the reaction pathway is similar
to the radical mechanism proposed for the racemisation of
4-methoxycarbonyl[2.2]paracyclophanes at 200 °C.23 as shown
in Scheme 4. Although it is recognised that the anti–syn ring
inversion is inhibited, that of the intermediate A generated
arising from the high temperature at the ethylene bridge might
be possible. Subsequently the anti–syn-ring inversion to form
Fig. 1 Possible conformations of [n.2]MCPs.
* Correspondent. E-mail: yamatot@cc.saga-u.ac.jp
Scheme 1

JOURNAL OF CHEMICAL RESEARCH 2012 135
Table 1 Pyrolysis of anti-5,13-di-tert-butyl-8.16-dimethoxy
[2.2]MCP anti-1a
the present novel intraannular condensation reaction does
occur through anti–syn-ring inversion followed by the dehy-
drogenation reaction at the 11, 12 bridged ethylene protons
under the pyrolysis of anti-9,17-dimethoxy[3.2]MCP anti-1b.
In contrast, attempted pyrolysis of syn- and anti-7,15-di-
tert-butyl-10,18-dihydroxy[4.2]MCP 1c22 at 560 °C resulted
in the recovery of the starting compound. No formation of the
intramolecular condensation product 2c has been observed
under the reaction conditions used. These findings suggest that
the novel intramolecular condensation of internal methoxy
groups in the syn-intra-annular positions is attributed to the
release of strain in syn-9,17-dimethoxy[3.2]MCP syn-1b lead-
ing to the more strainless 18-oxa[3.2.1](1,3,2)cyclophane 2b
containing an ether linkage.
Run
Temp./°C
Products yield/%a,b
Recovd.
1a
2a
3
1
2
3
400
500
560
2
2
37
65
96 [90]
28
8
35 [25]
27 [15]
a Yields were determined by GLC analysis.
b Isolated yields are shown in square bracket.
the intermediate B might proceed to form the syn-8,16-
dimethoxy[2.2]MCP syn-1a, from which the intramolecular
condensation reaction of the two methoxy groups afford 17-ox
a[2.2.1](1,3,2)cyclophane 2a. The present novel intraannular
condensation reaction is the first evidence for anti–syn-ring
inversion under the pyrolysis of anti-5,13-di-tert-butyl-8,16-
dimethoxy[2.2]MCP anti-1a.
The structure assigned to 2b is supported by its elemental
analysis and spectral data. The 1H NMR (CDCl3) spectrum of
2b shows the disappearance of methoxy protons (δ 3.02 ppm
for anti-1a and δ 3.51 ppm for syn-1b22, and exhibits a pattern
quite different from those of syn- and anti-6,14-di-tert-butyl-
9,17-dimethoxy[3.2]MCP 1b. The structure 5b was deduced
from the 1H NMR spectrum of a mixture of 2b and 5b. Thus,
The structure of 2a was assigned on the basis of elemental
1
analysis and spectral data. The H NMR spectrum of 2a in
1
the H NMR (CDCl3) spectrum of a mixture of 2b and 5b
CDCl3 shows the disappearance of two internal methoxy
protons and tert-butyl protons as a singlet at δ 1.21 ppm, a
bridged methylene protons as a multiplet at δ 2.64–3.66 ppm,
and aromatic protons as a singlet at δ 6.85 ppm.
shows the bridged olefinic protons for 5b as a singlet at δ 6.91
ppm.
Several attempted separations of 2b and 18-oxa[2.3.1](1,3,2)
cyclophane-1-ene 5b failed. However, a mixture of 2b and 5b
(ratio of 70:30) was treated with hydrogen in the presence of
10% Pd–C in ethylacetate at room temperature to afford 2b in
quantitative yield.
The AlCl3–MeNO2-catalysed trans-tert-butylation of 2a
wascarriedoutinbenzeneat50°Ctoafford17-oxa[2.2.1](1,3,2)
cyclophane 6a in 75% yield along with tert-butyl-benzene 7.
The physical properties and spectral data were identical with
those of the sample which has already been prepared by
Boekelheide et al.24 Similarly, 18-oxa[3.2.1](1,3,2) cyclophane
6b was obtained in 80% yield.
Similar results were also obtained in the pyrolysis of the
higher anti- and syn-dimethoxy[3.2]MCPs anti-1b and syn-1b
to afford the corresponding 18-oxa[3.2.1](1,3,2)cyclophane
2b. In fact, pyrolysis of anti-1b was carried out under the same
conditions as anti-1a at 500 °C only resulted the recovery
of the starting compound anti-1b. However, increasing the
temperature at 560 °C led to the intramolecular condensation
reaction at the 9, 17 positions to afford 2b in 46% yield along
with 18-oxa[2.3.1](1,3,2)cyclophane-1-ene 5b in 10% yield.
The formation of the latter product 5b strongly suggests that
Conclusions
In conclusion, we have demonstrated that pyrolysis of anti-
8,16-dimethoxy[2.2]MCP anti-1 at 500 °C afforded 17-oxa
[2.2.1](1,3,2)cyclophane 2a in 35% yield arising from
anti–syn-ring inversion and then intramolecular condensation
reaction of syn-8,16-dimethoxy[2.2]MCP syn-1a. Similar
results were also obtained in the pyrolysis of the higher anti-
and syn-dimethoxy[3.2]MCPs anti-1b and syn-1b to afford the
Scheme 2
Scheme 3

136 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 4
pressure at 1 mmHg using the same procedure as reported previ-
ously.25,26
The sublimed product was collected and
chromatographed on silica gel with hexane as an eluent to give a
colourless solid. Recrystallisation from hexane afforded 33 mg (25%)
of 5,13-di-tert-butyl-17-oxa[2.2.1](1,3,2)cyclophane, 2a as colourless
prisms (methanol), m.p. 207–209 °C; δH (CDCl3) 1.21 (18H, s, tBu),
2.64–3.66 (8H, m, CH2) and 6.85 (4 H, s, ArH); MS m/z: 334 (M+)
(Found: C, 86.05; H, 8.89%. C24H30O (334.5) requires C, 86.18; H,
9.04%).
The formation of 2,7-di-tert-butyl-4,5,9,10-tetrahydropyrene, 327
was confirmed by GLC analyses.
Scheme 5
Pyrolysis of 6,14-di-tert-butyl-9,17-dimethoxy[3.2]metacyclophane
(1b); general procedure
corresponding 18-oxa[3.2.1](1,3,2)cyclophane 2b along
with 18-oxa[2.3.1](1,3,2)cyclophane-1-ene 5b. The presently
developed novel intramolecular condensation reaction to afford
oxa[n.2.1](1,3,2)cyclophanes will open up new mechanistic
aspects for cyclophane chemistry. Further studies on chemical
properties of oxa[n.2.1](1,3,2)cyclophanes 6a and 6b are in
progress in our laboratory.
The anti-6,14-di-tert-butyl-9,17-dimethoxy[3.2]metacyclophane
anti-1b (150 mg, 0.381 mmol) was pyrolysed at 550 °C under reduced
pressure at 1 mmHg using the same procedure as reported previously.
The sublimed product was collected and chromatographed on silica
gel with hexane as an eluent to give a colourless oil. The residue
was chromatographed on a silica gel with hexane:benzene (1:1)
as an eluent to give a colourless oil (80 mg, 60%) as a mixture of 6,14-
di-tert-butyl-18-oxa[3.2.1](1,3,2)cyclophane 2b and 5,14-di-tert-
butyl-18-oxa[2.3.1](1,3,2)cyclophane-1-ene 5b in a ratio of 70:30.
However, the attempted isolation of the pure product failed.
Reduction of a mixture of 2b and with H2 in the presence of Pd–C:
To a solution of a mixture of 2b and 5b (54 mg, 0.16 mmol) in ethyl
acetate (30 mL) was added Pd-C (10%, 15 mg) and stirred for 12 h
under the hydrogen atomosphere at room temperature. The reaction
mixture was concentrated. The residue was chromatographed over
silica gel (Wako C-300, 100 g) with hexane:benzene (1:1) as eluents
to give 6,14-di-tert-butyl-18-oxa[3.2.1](1,3,2)cyclophane, 2b (54 mg,
100%) as a colourless oil; νmax (NaCl)/cm−1 2922, 2899, 2851, 1468,
1460, 1433, 1424, 1265, 1207, 1184, 885 and 877; δH (CDCl3) 1.24
(18H, s, tBu), 1.30–1.40 (1H, m, CH2), 2.29–2.40 (1H, m, CH2), 2.66–
2.79 (4H, m, CH2), 3.24–3.33 (2H, m, CH2), 3.53–3.61 (2H, m, CH2),
6.91 (2H, d, J = 2.4, ArH) and 6.97 (2H, d, J = 2.4, ArH); MS m/z: 348
(M+) (Found: C, 86.39; H, 9.52%. C25H32O (348.53) requires C, 86.15;
H, 9.25%).
Experimental
All melting points are uncorrected. 1H NMR spectra were recorded at
300 MHz on a Nippon Denshi JEOL FT-300 NMR spectrometer in
deuteriochloroform with Me4Si 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-HX110A Ultrahigh Performance Mass Spectrometer at 75 eV
using a direct-inlet system. Elemental analyses were performed by
Yanaco MT-5. GLC analyses were performed by Shimadzu gas chro-
matograph, GC-14A; Silicone OV-1, 2 m; programmed temperature
rise, 12 °C min−1; carrier gas nitrogen, 25 mL min−1.
Preparations of anti-5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP (anti-
1a),21 syn- and anti-6,14-di-tert-butyl-9,17-dimethoxy[3.2]MCP (1b),
syn- and anti-7,15-di-tert-butyl-10,18-dimethoxy[4.2]MCP (1c)22
have been described elsewhere.
5,14-Di-tert-butyl-18-oxa[3.2.1](1,3,2)cyclophan-1-ene (5b): δH
(CDCl3) 1.27 (18H, s, tBu), 1.30–1.40 (1H, m, CH2), 2.55–2.47 (1H,
m, CH2), 2.73–2.83 (2H, m, CH2), 3.35–3.48 (2H, m, CH2), 6.91 (2H,
s, CH), 7.09 (2H, d, J = 2.4, ArH) and 7.14 (2H, d, J = 2.4, ArH).
Trans-tert-butylation of 2a: To a solution of 2a (30 mg, 0.09 mmol)
in benzene (3 mL) was added a solution of aluminum chloride
(200 mg, 1.50 mmol) and nitromethane (1 mL) at 0 °C. The mixture
was stirred at 50 °C for 24 h, poured into ice-water, and extracted with
CH2Cl2. The extracts were washed with water, then 10% sodium
bicarbonate, dried over anhydrous sodium sulfate, and concentrated
Pyrolysis of anti-5,13-di-tert-butyl-8,16-dimethoxy-[2.2]metacyclo-
phane (anti-1a); general procedure
Pyrolysis of anti-5,13-di-tert-butyl-8,16-dimethoxy[2.2]metacycloph
ane anti-1a was carried out in an apparatus consisting of a horizontal
tube (15 mm in diameter) passing through two adjacent tube furnaces,
each of which was 20 cm long. The first furnace provided a tempera-
ture that would induce sublimation of the metacyclophane; the second
was used at a higher temperature (500 °C) that would assure pyrolysis.
A vacuum pump was connected to the exit from the second furnace.
The (150 mg, 0.395 mmol) was pyrolysed at 500 °C under reduced

JOURNAL OF CHEMICAL RESEARCH 2012 137
5
6
7
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in vacuo. Chromatography on silica gel (Wako, C-300; 100 g) eluting
with hexane afforded a colourless solid. Recrystallisation from hexane
afforded 15 mg (75%) of 18-oxa[2.2.1](1,3,2)cyclophane, 6a as
colourless prisms (hexane), m.p. 91–94 °C (lit.24 m.p. 94–95 °C); δH
(CDCl3) 2.52–2.69 (4H, m, CH2), 3.52–3.65 (4H, m, CH2) and 6.79–
6.99 (6H, s, ArH); MS m/z: 222 (M+) (Found: C, 86.39; H, 6.54%.
C16H14O (222.3) requires C, 86.45; H, 6.35%).
Trans-tert-butylation of 2b: To a solution of 2b (64 mg, 0.212
mmol) in benzene (6 mL) was added a solution of aluminum chloride
(975 mg, 7.32 mmol) and nitromethane (1 mL) at 0 °C. The mixture
was stirred at 50 °C for 24 h, poured into ice-water, and extracted with
CH2Cl2. The extracts were washed with water, then with 10% sodium
bicarbonate, dried over anhydrous sodium sulfate, and concentrated
in vacuo. Chromatography on silica gel (Wako, C-300; 100 g) eluting
with hexane afforded a colourless solid. Recrystallisation from hexane
afforded 40 mg (80%) of 18-oxa[3.2.1](1,3,2)cyclophane, 6b as
colourless prisms (methanol), m.p. 96–98 °C; δH (CDCl3) 1.30–1.40
(1 H, m, CH2), 2.33–2.42 (1H, m, CH2), 2.68–2.81 (4H, m, CH2),
3.24–3.33 (2H, m, CH2), 3.55–3.63 (2H, m, CH2) and 6.90–6.99 (6H,
m, ArH); MS m/z: 236 (M+) (Found: C, 86.61; H, 6.85%. C17H16O
(236.3) requires C, 86.41; H, 6.82%).
8
9
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Received 27 December 2011; accepted 1 February 2012
Paper 1101064 doi: 10.3184/174751912X13296759770106
Published online: 22 March 2012
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