Medium-size cyclophanes. Part 601: Synthesis and conformational studies of 9-substituted [3.3]metacyclophane-2,11-diones and conversion to the corresponding [3.3]metacyclophanes

Article abstract of DOI:10.1139/v02-072

Various syn- and anti-9-substituted [3.3]metacyclophane-2,11-diones are obtained by the coupling reaction of the corresponding 2,6-bis(bromomethyl)benzenes (3) with 2,6-bis[2-cyano-2-(toluenesulfony)ethyl]-4-tert-butyl-1-substituted benzenes (4) in dimeth

Full text of DOI:10.1139/v02-072

510
Medium-size cyclophanes. Part 601: Synthesis
and conformational studies of 9-substituted
[3.3]metacyclophane-2,11-diones and conversion
to the corresponding [3.3]metacyclophanes
Takehiko Yamato, Koji Tsuchihashi, Noriko Nakamura, Mai Hirahara, and
Kan Tanaka
Abstract: Various syn- and anti-9-substituted [3.3]metacyclophane-2,11-diones are obtained by the coupling reaction of
the corresponding 2,6-bis(bromomethyl)benzenes (3) with 2,6-bis[2-cyano-2-(toluenesulfony)ethyl]-4-tert-butyl-1-
substituted benzenes (4) in dimethylformamide (DMF) with an excess of sodium hydride. Depending on the substitu-
ents at positions 1 and 4 on 3, different yields (inversion of selectivity) of anti-5 and syn-5 were achieved.
Key words: metacyclophanes, cyclization, conformation, CH–ꢀ interaction, through-space interaction, charge-transfer-
type interaction.
Résumé : Le couplage des 2,6-bis(bromométhyl)benzènes correspondants (3) et des 2,6-bis[2-cyano-2-toluènesulf-
onyl)éthyl]-4-tert-butylbenzènes substitués en position 1 (4) effectué dans le diméthylformamide (DMF) avec un excès
d’hydrure de sodium permet d’obtenir diverses [3.3]métacyclophane-2,11-diones portant des substituants syn- et anti-
en position 9. Les rendements (avec inversion de sélectivité) en composés anti-5 et syn-5 varient avec la nature des
substituants dans les positions 1 et 4 des divers 2,6-bis(bromométhyl)benzènes (3).
Mots clés : métacyclophanes, cyclisation, conformation, interaction CH–ꢀ, interaction à travers l’espace, interaction de
type transfert de charge.
[Traduit par la Rédaction] Yamato et al. 516
1
Introduction
basis of the H NMR spectrum, in which 1 shows a strong
temperature-dependent phenomenon at low temperatures (5, 6).
Shinmyozu and co-workers (4) prepared [3.3]MCP 1 us-
ing (p-tolylsulfonyl)methyl isocyanide (TosMIC) as the
cyclization reagent, followed by a Wolff–Kishner reduction
(4). They also performed studies on the syn–anti conversions
in other [3.3]MCPs, especially in relation to the size of the
substituents such as halogens (7). Like the parent compound,
9-halo[3.3]MCPs prefer the syn conformation but the corre-
sponding 2,11-diones favour the anti arrangement. Even one
internal halogen substituent is sufficient to allow the isola-
tion of a discrete syn or anti isomer. Although the effect on
the ratio of syn and anti conformers of [3.3]MCPs was re-
ported, it is still not clear what the effects are — including
not only the properties of the internal substituents, but also
the presence of unsymmetrically substituted benzene rings
arising from charge-transfer-type interactions between two
benzene rings, as well as the steric effects of substituents at
the 6 and 15 positions.
The synthesis and stereochemical aspects of conforma-
tionally mobile [3.3]MCPs (MCP= metacyclophane) have
been of interest for the past decade, with particular attention
(2) paid to dithia[3.3]MCPs, which possess an anti-stepped
conformation. The pioneering conformational investigation
of 2,11-dithia[3.3]MCPs was reported by Vögtle and
Schunder (3). While Shinmyozu and co-workers (4) reported
the first preparation and conformational behavior of carbo-
cyclic [3.3]MCPs 1 and their analogues. The [3.3]MCP 1 ex-
ist in the crystal state in a syn geometry with the
trimethylene chains in a chair–chair arrangement (Fig. 1).
The preferred geometry of 1 in solution is also syn on the
Received 7 January 2002. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 10 May 2002.
T. Yamato,2 K. Tsuchihashi, N. Nakamura, and
M. Hirahara. Department of Applied Chemistry, Faculty of
Science and Engineering, Saga University, Honjo-machi 1,
Saga-shi, Saga 840–8502, Japan.
K. Tanaka. Department of Industrial Chemistry, Faculty of
Science and Engineering, Tohwa University, 1–1-1
Chikushigaoka, Minami-ku, Fukuoka-shi, Fukuoka 815–8510,
Japan.
All of the previous compounds are internally unsub-
stituted [3.3]MCP-2,11-diones and it is surprising that there
are very few reports (8) on the preparation of 9-methyl- or
9-methoxy-analogues despite the fact that the chemical shift
of the internal substituents, such as the methyl and the
1
methoxy group, provides a convenient probe for H NMR
studies of any possible conformational changes. We report
here the synthesis and stereochemical assignments of 9-
substituted [3.3]MCP-2,11-diones and conversion to the
1Part 59. See Ref. 1.
2Corresponding author (e-mail: yamatot@cc.saga-u.ac.jp).
Can. J. Chem. 80: 510–516 (2002)
DOI: 10.1139/V02-072
© 2002 NRC Canada

Yamato et al.
511
Fig. 1. syn- and anti-Confomers of [3.3]metacyclophane 1.
Scheme 3.
15
18
9
6
1
syn-conformer
anti-conformer
Scheme 1.
OMe
OMe
Br
i) TosMIC/NaH/
DMF
Br
ii) conc. HCl
O
n
Table 1. Ratios of anti-to-syn in TosMIC cyclization of 3 with 4c.
n = 2: 10%
n = 3: 14%
n = 4: <0.5%
Distribution (%)b
TosMIC =
Me
SO2CH2NC
R1
R2
Product (%)a
anti
syn
0
50
70
72
75
3a
3b
3c
3d
3e
3f
H
Me
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
H
5a (72)
5b (71)
5c (53)
5d (50)
5e (50)
5f (53)
5g (70)
100
50
30
28
25
5
Scheme 2.
R
(HCHO)x/HBr/
H3PO4/HOAc
R
OMe
OEt
OPr
OMe
OMe
Br
Br
90-95°C
for 12h
95
100
3g
Br
0
2a: R = Me
3b: R = Me (82%)
c: R = OMe (78%)
d: R = OEt (72%)
e: R = OPr (70%)
aIsolated yields.
b: R = OMe
c: R = OEt
d: R = OPr
bRatios of anti-to-syn determined by H NMR spectroscopy at 20°C.
1
OMe
Tos
TosMIC (excess)
/NaOH/n-Bu4NI
CH2Cl2/H2O
(78%)
Tos
CN
We therefore have selected the stepwise cyclization of the
TosMIC adduct 4 with 2,6-bis(bromomethyl)-4-tert-butyl-1-
substituted benzenes (3) to prepare the desired cyclic dimer
5. The starting compounds, 2,6-bis(bromomethyl)-4-tert-butyl
substituted benzenes (3), are easily prepared by bromo-
methylation of 4-tert-butyltoluene (2a) and 4-tert-butylalk-
oxybenzenes (12) using the tert-butyl group as a positional
protecting group on the aromatic ring (Scheme 2) (13). Al-
though TosMIC adduct 4c was obtained in 78% yield by the
reaction of 3c with TosMIC as a mixture of two isomers,
i.e., meso and dl, the attempted separation of these isomers
of 4c pure failed.
3c
NC
4c
corresponding [3.3]MCPs by Wolff-Kishner reduction. The
substituent effects on the formation of the syn- and anti-con-
formations are discussed.
Results and discussion
The cyclic diketones (5) were synthesized by coupling 3
with TosMIC adduct 4c under highly diluted conditions in
DMF with an excess of sodium hydride as shown in
Scheme 3. We have improved the addition procedure in
Vögtle’s method (9) — thus, to a suspension of NaH in
DMF was added dropwise a solution of 3 and TosMIC ad-
ducts 4c in DMF at room temperature. This method not only
improves the yield of the desired ketones but also makes the
Vögtle and co-workers reported (9) the preparation of
carbocyclic [3n]MCPs using TosMIC (10) as the cyclization
reagent, which was applied in a new cyclization procedure
without phase-transfer conditions (Scheme 1) (11).
This strategy can be employed for the preparation of
[3.3]MCP containing two benzene rings. The preparation of
[3.3]MCPs using the TosMIC method is, however, difficult
because of its low yield as well as the difficulty of the prod-
uct separation from the other macrocyclic oligoketones, i.e.,
trimer and tetramer. It has, therefore, been very difficult to
obtain sufficient amounts of the above compounds to investi-
gate their chemical behavior.
1
handling of the base (solid NaH) easier (Table 1). The H
NMR spectrum of 5 shows two kinds of methoxy protons,
each as a singlet. By careful column chromatography (silica gel,
Wako C-300), the two conformers, anti-5 and syn-5, are
© 2002 NRC Canada

512
Can. J. Chem. Vol. 80, 2002
1
Table 2. H NMR spectral data for 6,15-di-tert-butyl-9-methoxy[3.3]MCP-2,11-diones 5a.
Methoxy
protons
Benzene
protons
tert-Butyl
protons
Protons of internal substituent (R1)
Compound
anti-5a
anti-5b
anti-5c
anti-5d
anti-5e
syn-5b
syn-5c
syn-5d
syn-5e
3.26
3.15
3.15
3.13
3.12
3.43
3.52
3.54
3.54
H
Me
5.29
0.94
—
0.98, 3.26
0.79, 1.35,a 3.17
2.50
—
1.37
1.18, 1.85,a 3.50
7.08, 7.19
7.19, 7.21
7.14
1.27, 1.36
1.27, 1.35
1.31
1.30, 1.32
1.30, 1.32
1.07, 1.14
1.08
OMe
OEt
OPr
Me
OMe
OEt
OPr
7.15
7.14, 7.15
6.64, 6.70
6.68
6.66, 6.67
6.67
1.07
1.08
Note: Determined in CDCl3 by using SiMe4 as a reference and expressed in ppm given.
aMidpoint value of multiplet.
separated. They are thermally stable and do not interconvert
at 150°C in DMSO solution and at 400°C in the solid state.
Fig. 2. Reaction intermediate for the cyclization to form
[3.3]MCP-2,11-diones.
The structures of 5 have been elucidated by elemental
analyses and spectral data. For instance, the mass spectral
data for anti-5c (M+ = 436) strongly support cyclic dimeric
structure. The IR spectrum of anti-5c shows the absorption
of the carbonyl stretching vibration around 1706 cm–1. The
1H NMR spectrum (in CDCl3) of anti-5c exhibits a set of
doublets at d = 3.22 and 3.73 (J = 14.7 Hz) for the
ArCH2COCH2Ar methylene protons and a singlet for the in-
ternal methoxy group at an upfield shift d = 3.15 from that of
anisole (d = 3.75) due to the ring current of the opposing ar-
omatic ring (13a, b, 14). This observation strongly suggests
that compound anti-5c adopts the anti-conformation.
Tos
R
Tos
NC
Me
NC
Br
O
Br
OMe
OMe
Tos
Tos
NC
through-space interaction
NC
CH–π interaction
These findings suggest that in the case of the 18-methyl ana-
logue the aromatic ꢀ–ꢀ interaction of two opposite benzene
rings and the steric crowdedness at internal positions 9 and
18 may inhibit the formation of the syn-conformer in the
[3.3]MCP-2,11-diones system and in turn the CH–ꢀ interac-
tion (16) between methyl groups, and the opposite aromatic
ꢀ-electrons may favour the formation of anti-conformer in
the cyclization process. The CH–ꢀ interaction involving
aliphatic CH moieties is well documented (16a) as either a
conformation-controlling intramolecular process or a crystal-
structure controlling intermolecular force, especially for in-
clusion complexes of calixarene derivatives (16b–h). In con-
trast, in the case of the 18-alkoxy analogue, the through-
space interaction between the nonbonding electron pairs of
the oxygen atom of the alkoxy groups and the opposite aro-
matic ꢀ-electrons of the anti-conformer may disfavour the
formation of the latter (Fig. 2).
On treatment of 2,6-bis(bromomethyl)anisole (3f) with 4c
a preferential formation of syn-[3.3]MCP-2,11-dione (syn-
5f) in the ratio of 95:5 was observed, which is different from
the result of that of 5c (the syn-to-anti ratio; 70:30). This re-
sult might be attributed to the bulkiness of the tert-butyl
groups, which would inhibit the formation of syn-5c. Ac-
cordingly, the ratio of syn conformer is observed to increase
with decreasing bulkiness of the substituents at the 15-
position, as shown in Fig. 3. Furthermore, the effect on the
In contrast, the methoxy protons of syn-5c are observed at
d 3.52. Furthermore, the aryl hydrogens can clearly be seen
to be shielded (d 6.68) by the adjacent ring, a common con-
sequence of a face-to-face benzene ring (14, 15). Also the
tert-butyl protons were observed at higher field (d 1.09)
compared with that of the anti-5c (d 1.31) due to the strong
shielding effect of the benzene ring. These observations strongly
suggest that compound syn-5c adopts syn-conformation.
Similarly, the assignments of structures for other anti and syn
1
conformers were readily apparent from their H NMR spectra.
The chemical shifts (d) of the internal methoxy protons, the
protons of internal substituents at the 18 position, aromatic
protons, and the tert-butyl protons of anti- and syn-9-meth-
oxy[3.3]MCP-2,11-diones 5a–e are compiled in Table 2.
Dependent on R1 and R2 of 2,6-bis(bromomethyl)-1-
substituted benzenes (3), different yields (inversion of selec-
tivity) of anti-5 and syn-5 were formed. Thus, the 18-
unsubstituted analogue is exclusively formed in the anti-con-
former, but other 18-methyl- and 18-alkoxy-analogues are
formed in a mixture of syn- and anti-conformers. Interest-
ingly, the 18-methyl analogue decreases the ratio of syn-to-
anti conformers of [3.3]MCP-2,11-diones. The effect of the
bulkiness of the alkyl group in alkoxy substituents on the ra-
tio of syn-to-anti conformers was not, however, observed.
© 2002 NRC Canada

Yamato et al.
513
Fig. 3. Steric effect and ꢀ –ꢀ stacking charge-transfer-type inter-
action on the reaction intermediate for the cyclization to form
syn-[3.3]MCP-2,11-diones.
Scheme 5.
tBu
tBu
Me
Me
O
O
-
Tos
-
Tos
NC
O
Br
r
B
NC
O
Me
Me
Tos
NC
Br
R
Scheme 4.
TosMIC (excess)
/NaOH/n-Bu4NI
Tos
NC
Tos
CN
3b
CH2Cl2/H2O
(77%)
Scheme 6.
4b
i) NaH/DMF
ii) conc. HCl
(45%)
Me
Me
O
3b
+
4b
O
anti-5h
ratio of syn-to-anti conformers of MCP-2,11-diones might
be also governed by charge-transfer-type interactions between
the two benzene rings in the case of unsymmetrically substi-
tuted benzene rings. In fact, in the case of syn-6-bromo-15-
tert-butyl-9,18-dimethoxy[3.3]MCP-2,11-dione (5g) the syn-
conformer was exclusively formed due to ꢀ–ꢀ stacking
charge-transfer-type interactions, as shown in Fig. 3.
To study in more detail the effects on the reaction inter-
mediates in the cyclization to form [3.3]MCP-2,11-diones
attributable to through-space interactions, we have attempted
to investigate the cyclization of the TosMIC adduct 4b with
2,6-bis(bromomethyl)-4-tert-butyltoluene (3b). Thus, the cy-
clization of 3b and 4b, carried out under the same conditions
as described above, afforded exclusively the anti-[3.3]MCP-
2,11-dione (anti-5h) in 45% yield (Scheme 4). No formation
of the syn-conformer was observed. This result strongly sug-
gests that the CH–ꢀ interactions play an important role in
the syn–anti conformer distribution during the cyclization re-
action.
In conclusion, we have demonstrated for the first time a
through-space interaction between the nonbonding electron
pairs of the oxygen atom of the methoxy group and the op-
posite aromatic ꢀ-electrons, which may disfavour formation
of the anti-conformer during the coupling reaction of the
corresponding 2,6-bis(bromomethyl)alkoxybenzenes and
TosMIC adduct 4c to preferentially afford syn-9-
methoxy[3.3]MCP-2,11-diones (5).
In contrast, attempted Wolff-Kishner reduction of anti-di-
ketone 5a, carried out under the same reaction conditions as
5c, led to syn-9-9-methoxy[3.3]MCP syn-6a in 80% yield
(Scheme 6). No formation of the corresponding anti con-
former has been observed under the reaction conditions
used. This finding strongly suggests that the ring inversion
to the thermodynamically more stable syn conformation is
possible in the 9-methoxy[3.3]MCP 6a. On the other hand,
as previously mentioned, we have reported that of anti-5a is
thermally stable and does interconvert at 150°C in DMSO
solution and at 400°C in the solid state. Although a detailed
mechanistic conclusion to rationalize the present observation
of anti-to-syn-conversion is not clear, one might assume the
similar behaviour that the [3.3]MCP 1 exists in the syn ge-
ometry with a chair–chair arrangement of the trimethylene
chains. Further studies on the chemical properties of the two
conformers syn- and anti-5 and 6 are now in progress.
The Wolff-Kishner reduction of syn- and anti-diketone 5c
afforded the desired syn- and anti-6,15-di-tert-butyl-9,18-
dimethoxy[3.3]MCP (6c) in 86 and 90% yields, respectively.
Similar results were obtained in the case of reduction of 5f
to afford 6f. No syn–anti isomerization was observed under
the reaction conditions used (Scheme 5).
Experimental
All melting points (Yanagimoto MP-S1) were uncorrected.
1H NMR spectra were recorded on a Nippon Denshi JEOL
FT-270 spectrometer. Chemical shifts are reported as d values
(ppm) relative to internal Me4Si. Mass spectra were obtained
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514
Can. J. Chem. Vol. 80, 2002
on a Nippon Denshi JMS-01SG-2 mass spectrometer at an
ionization energy of 70 eV using a direct-inlet system through
GLC; m/z values reported include the parent ion peak. Infra-
red (IR) spectra were obtained on a Nippon Denshi JIR-
AQ2OM spectrophotometer as KBr disks. Elemental analyses
were performed by Yanaco MT-5. Gas–liquid chromatograph
(GLC) analyses were performed by Shimadzu gas chromato-
graph, GC-14A; silicone OV-1, 2 m; programmed tempera-
ture rise, 12°C min–1; carrier gas nitrogen, 25 mL min–1.
for 30 min, a solution of dibromide 3b (4.0 g, 11 mmol) in
CH2Cl2 (50 mL) was added. The reaction mixture was
stirred at room temperature for 2 h, quenched with water
(100 mL), and extracted with CH2Cl2 (3 × 100 mL). It was
washed with water (100 mL), dried with Na2SO4, and
concentrated in vacuo to leave a residue. To this residue
methanol (100 mL) was added and left overnight in the re-
frigerator to give 2,6-bis[2-cyano-2-(toluenesulfonyl)ethyl]-
4-tert-butyltoluene (4b) (4.90 g, 77%) as pale brown prisms,
mp 176°C (dec.). IR (KBr) ꢁmax (cm–1): 2135 (CN). 1H
NMR (CDCl3) d: 1.26, 1.27 (each s, 9H), 2.26, 2.27 (each s,
3H), 2.50 (s, 6H), 3.00–4.52 (m, 6H), 7.16 (s, 2H), 7.46 (d,
J = 8.3 Hz, 4H), 7.92 (d, J = 8.3 Hz, 4H). MS m/z: 436
(M+). Anal. calcd. for C31H34N2O4S2: C 66.16, H 6.09,
N 4.98; found: C 65.95, H 6.06, N 4.73.
Materials
The preparations of 2,6-bis(bromomethyl)-4-tert-butyl-
benzene (3a), 2,6-bis(bromomethyl)anisole (3f), and 2,6-
bis(bromomethyl)-4-bromoanisole (3g) were previously de-
scribed (17).
Compound 4c was similarly prepared in 78% yield.
Bromomethylation of 4-tert-butyltoluene (2a)
2,6-Bis[2-cyano-2-(toluenesulfony)ethyl]-4-tert-butylanisole
(4c)
A mixture of 2a (37 g, 0.23 mol), paraformaldehyde
(45 g, 1.5 mol), acetic acid (55 mL), H3PO4 (85%, 110 mL),
and concentrated HBr (48%, 164 mL) was heated at
85–90°C with vigorous stirring for 14 h, and then the reac-
tion mixture was extracted with benzene (3 × 200 mL). The
combined extracts were neutralized with a 10% aqueous
Na2CO3 solution, washed with water, dried with Na2SO4,
and the solvent was evaporated in vacuo to leave a residue,
which was chromatographed on silica gel with hexane as the
eluent to give a colorless solid. Recrystallization from hex-
ane afforded 2,6-bis(bromomethyl)-4-tert-butyltoluene (3b)
Pale brown prisms (hexane), mp 150–151°C (dec.). IR
1
(KBr) ꢁmax (cm–1): 2134 (CN). H NMR (CDCl3) d: 1.26,
1.27 (each s, 9H), 2.49, 2.50 (each s, 6H), 2.87, 2.99 (each
dd, J = 11.7 and 13.7 Hz, 2H), 3.66, 3.77 (each dd, J = 2.9
and 13.7 Hz, 2H), 3.76, 3.80 (each s, 3H), 4.73, 4.83 (each
dd, J = 2.9 and 11.7 Hz, 2H), 7.19, 7.20 (each s, 2H), 7.44,
7.46 (each d, J = 8.3 Hz, 4H), 7.87, 7.93 (each d, J = 8.3 Hz,
4H). MS m/z: 578 (M+). Anal. calcd. for C31H34N2O5S2:
C 64.34, H 5.92, N 4.84; found: C 64.56, H 5.87, N 4.73.
1
(63.6 g, 82%) as colorless prisms, mp 89–91°C. H NMR
Stepwise cyclization of TosMIC adduct 4 and dibromide 3
(CDCl3) d: 1.30 (s, 9H), 2.41 (s, 3H), 4.54 (s, 4H), 7.30 (s,
2H). MS m/z: 332, 334, 336 (M+). Anal. calcd. for
C13H18Br2: C 46.73, H 5.43; found: C 46.72, H 5.52.
Compounds 3c, 3d, and 3e were similarly prepared. The
yields are listed in Scheme 2.
Typical procedure
To a suspension of NaH (2.1 g, 51 mmol) in DMF
(150 mL) a solution of 3c (4.7 g, 8.5 mmol) and 4c (5.0 g,
8.5 mmol) in DMF (35 mL) was added dropwise over a pe-
riod of 6 h. After the suspension was stirred for an addi-
tional 5 h at room temperature, it was quenched with ice
water (300 mL). The reaction mixture was extracted with
CH2Cl2 (3 × 100 mL), washed with water (200 mL), dried
with Na2SO4, and concentrated in vacuo to 15 mL. Conc.
HCl (15 mL) was added, and the solution was stirred for
15 min. The organic layer was again extracted with CH2Cl2
(3 × 100 mL), washed with water (2 × 100 mL), dried with
Na2SO4, and concentrated and condensed under reduced
pressure. The residue was chromatographed on silica gel us-
ing CHCl3 as eluents to give crude anti-5c and syn-5c as a
pale yellow solid. Recrystallization from hexane afforded
anti-5c (592 mg, 16%) and syn-5c (1.37 g, 37%).
2,6-Bis(bromomethyl)-4-tert-butylanisole (3c)
Colorless prisms (hexane), mp 88–89°C. 1H NMR
(CDCl3) d: 1.31 (s, 9H), 4.01 (s, 3H), 4.56 (s, 4H), 7.36 (s,
2H). MS m/z: 348, 350, 352 (M+). Anal. calcd. for
C13H18Br2O: C 44.60, H 5.18; found: C 45.30, H 4.99.
2,6-Bis(bromomethyl)-4-tert-butylethoxybenzene (3d)
Colorless prisms (hexane), mp 65–66°C. 1H NMR
(CDCl3) d: 1.31 (s, 9H), 1.51 (t, J = 7.32 Hz, 3H), 4.16 (q,
J = 7.32 Hz, 2H), 4.56 (s, 4H), 7.36 (s, 2H). MS m/z: 362,
364, 366 (M+). Anal. calcd. for C14H20Br2O: C 46.18, H
5.54; found: C 45.95, H 5.39.
2,6-Bis(bromomethyl)-4-tert-butylpropoxybenzene (3e)
Colorless prisms (hexane), mp 108.5–109.5°C. H NMR
(CDCl3) d: 1.13 (t, J = 7.32 Hz, 3H), 1.31 (s, 9H), 1.85–2.00
(m, 2 H), 4.05 (t, J = 6.83 Hz, 2H), 4.56 (s, 4H), 7.36 (s,
2H). MS m/z: 376, 378, 380 (M+). Anal. calcd. for
C15H22Br2O: C 47.64, H 5.86; found: C 47.98, H 5.89.
1
anti-6,15-Di-tert-butyl-9,18-dimethoxy[3.3]metacyclo-
phane-2,11-dione (anti-5c)
Colorless prisms (hexane), mp 210–211°C. IR (KBr) ꢁmax
1
(cm–1): 1706 (C=O). H NMR (CDCl3) d: 1.31 (s, 18H),
3.15 (s, 6H), 3.22 (d, J = 14.7 Hz, 4H), 3.73 (d, J = 14.7 Hz,
4H), 7.14 (s, 4H). MS m/z: 436 (M+). Anal. calcd. for
C28H36O4: C 77.03, H 8.31; found: C 76.66, H 8.37.
Preparation of the TosMIC adduct 4
Typical procedure
syn-6,15-Di-tert-butyl-9,18-dimethoxy[3.3]metacyclophane-
2,11-dione (syn-5c)
To a mixture of 20% aqueous NaOH (40 mL) and CH2Cl2
(50 mL) was added n-Bu4NI (700 mg, 1.9 mmol) followed
by a solution of TosMIC (8 g, 41 mmol) in CH2Cl2 (50 mL).
After the reaction mixture was stirred at room temperature
Colorless prisms (hexane), mp 22–23°C. IR (KBr) ꢁmax
1
(cm–1): 1701 (C=O). H NMR (CDCl3) d: 1.08 (s, 18H),
3.28 (d, J = 12.7 Hz, 4H), 3.52 (s, 6H), 4.24 (d, J = 12.7 Hz,
© 2002 NRC Canada

Yamato et al.
515
4H), 6.68 (s, 4H). MS m/z: 436 (M+). Anal. calcd. for
C28H36O4: C 77.03, H 8.31; found: C 76.83, H 8.34.
Compounds 5a–b and 5d–g were similarly prepared. The
yields are listed in Table 1.
14.16 Hz, 2H), 7.14 (s, 2H), 7.15 (s, 2H). MS m/z: 464 (M+).
Anal. calcd. for C30H40O4: C 77.55, H 8.68; found: C 77.35,
H 8.64.
syn-6,15-Di-tert-butyl-9-methoxy-18-propoxy[3.3]meta-
cyclophane-2,11-dione (syn-5e)
anti-6,15-Di-tert-butyl-9-methoxy[3.3]metacyclophane-
2,11-dione (anti-5a)
Colorless oil. IR (NaCl) ꢁmax (cm–1): 1703 (C=O). 1H
NMR (CDCl3) d: 1.08 (s, 18H), 1.18 (t, J = 7.33 Hz, 3H),
1.80–1.90 (m, 2H), 3.27 (d, J = 12.7 Hz, 2H), 3.30 (d, J =
12.7 Hz, 2H), 3.50 (q, J = 7.33 Hz, 2H), 3.54 (s, 3H), 4.29
(d, J = 12.7 Hz, 2H), 4.33 (d, J = 12.7 Hz, 2H), 6.67 (s, 4H).
MS m/z: 464 (M+). Anal. calcd. for C30H40O4: C 77.55,
H 8.68; found: C 77.41, H 8.47.
Colorless prisms (hexane), mp 142–144°C. IR (KBr) ꢁmax
1
(cm–1): 1688 (C=O). H NMR (CDCl3) d: 1.27 (s, 9H), 1.36
(s, 9H), 3.26 (s, 3H), 3.29 (d, J = 15.6 Hz, 2H), 3.39 (d, J =
13.7 Hz, 2H), 3.51 (d, J = 13.7 Hz, 2H), 3.73 (d, J =
15.6 Hz, 2H), 5.29 (s, 1H), 7.08 (s, 2H), 7.19 (s, 2H). MS
m/z: 406 (M+). Anal. calcd. for C27H34O3: C 79.77, H 8.43;
found: C 79.75, H 8.47.
anti-6-tert-Butyl-9,18-dimethoxy[3.3]metacyclophane-
2,11-dione (anti-5f)
anti-6,15-Di-tert-butyl-9-methoxy-18-methyl[3.3]meta-
cyclophane-2,11-dione (anti-5b)
Colorless prisms (hexane), mp 198–199°C. IR (KBr) ꢁmax
1
(cm–1): 1685 (C=O). H NMR (CDCl3) d: 1.32 (s, 9H), 3.16
Colorless prisms (hexane), mp 252–254°C. IR (KBr) ꢁmax
1
(cm–1): 1699 (C=O). H NMR (CDCl3) d: 0.94 (s, 3H), 1.27
(s, 3H), 3.17 (s, 3H), 3.23 (d, J = 14.6 Hz, 4H), 3.60 (d, J =
14.6 Hz, 2H), 3.63 (d, J = 14.6 Hz, 2H), 6.93–6.99 (m, 1H),
7.16–7.18 (m, 4H). MS m/z: 380 (M+). Anal. calcd. for
C24H28O4: C 75.76, H 7.42; found: C 75.55, H 7.54.
(s, 9H), 1.35 (s, 9H), 3.15 (s, 3H), 3.18 (d, J = 13.2 Hz, 2H),
3.40 (d, J = 15.6 Hz, 2H), 3.63 (d, J = 15.6 Hz, 2H), 3.85 (d,
J = 13.2 Hz, 2H), 7.19 (s, 2H), 7.21 (s, 2H). MS m/z: 420
(M+). Anal. calcd. for C28H36O3: C 79.96, H 8.63; found:
C 79.84, H 8.56.
syn-6-tert-Butyl-9,18-dimethoxy[3.3]metacyclophane-2,11-
dione (syn-5f)
Colorless oil. IR (NaCl) ꢁmax (cm–1): 1688 (C=O). 1H
NMR (CDCl3) d: 1.12 (s, 9H), 3.32 (d, J = 12.7 Hz, 4H),
3.55 (s, 3H), 3.56 (s, 3H), 4.30 (d, J = 12.7 Hz, 4H),
6.48–6.54 (m, 1H), 6.65–6.68 (m, 4H). MS m/z: 380 (M+).
Anal. calcd. for C24H28O4: C 75.76, H 7.42; found: C 75.62,
H 7.35.
syn-6,15-Di-tert-butyl-9-methoxy-18-methyl[3.3]metacyclo-
phane-2,11-dione (syn-5b)
Colorless prisms (hexane), mp 118–120°C. IR (KBr) ꢁmax
1
(cm–1): 1689 (C=O). H NMR (CDCl3) d: 1.07 (s, 9H), 1.14
(s, 9H), 2.50 (s, 3H), 3.30 (d, J = 13.2 Hz, 2H), 3.43 (s, 3H),
3.50 (d, J = 13.7 Hz, 2H), 3.92 (d, J = 13.7 Hz, 2H), 4.14 (d,
J = 13.2 Hz, 2H), 6.64 (s, 2H), 6.70 (s, 2H). MS m/z: 420
(M+). Anal. calcd. for C28H36O3: C 79.96, H 8.63; found:
C 79.78, H 8.53.
syn-6-Bromo-15-tert-butyl-9,18-dimethoxy[3.3]metacyclo-
phane-2,11-dione (syn-5g)
Colorless prisms (hexane), mp 150–153°C. IR (KBr) ꢁmax
1
(cm–1): 1700 (C=O). H NMR (CDCl3) d: 1.18 (s, 9H), 3.27
anti-6,15-Di-tert-butyl-9-ethoxy-18-methoxy[3.3]meta-
cyclophane-2,11-dione (anti-5d)
(d, J = 13.0 Hz, 2H), 3.34 (d, J = 13.0 Hz, 2H), 3.54 (s, 3H),
3.55 (s, 3H), 4.21 (d, J = 13.0 Hz, 2H), 4.27 (d, J = 13.0 Hz,
2H), 6.71 (s, 2H), 6.79 (s, 2H). MS m/z: 458. 460 (M+).
Anal. calcd. for C24H27BrO4: C 62.75, H 5.92; found: C 62.65,
H 5.85.
Colorless prisms (hexane), mp 198–199°C. IR (KBr) ꢁmax
(cm–1): 1702 (C=O). 1H NMR (CDCl3) d: 0.98 (t, J = 7.33 Hz,
3H), 1.30 (s, 9H), 1.32 (s, 9H), 3.13 (s, 3H), 3.14 (d, J =
14.6, 4H), 3.26 (q, J = 7.33 Hz, 2H), 3.63 (d, J = 14.6 Hz,
2H), 3.65 (d, J = 14.6, 2H), 7.15 (s, 4H). MS m/z: 450 (M+).
Anal. calcd. for C29H38O4: C 77.30, H 8.50; found: C 77.54,
H 8.46.
anti-6,15-Di-tert-butyl-9,18-dimethyl[3.3]metacyclophane-
2,11-dione (anti-5h)
Colorless prisms (hexane), mp 282–284°C. IR (KBr) ꢁmax
1
(cm–1): 1698 (C=O). H NMR (CDCl3) d: 0.95 (s, 6H), 1.30
syn-6,15-Di-tert-butyl-9-ethoxy-18-methoxy[3.3]meta-
cyclophane-2,11-dione (syn-5d)
(s, 18H), 3.26 (s, 3H), 3.30 (d, J = 14.7 Hz, 4H), 3.67 (d, J =
14.7 Hz, 4H), 7.25 (s, 4H). MS m/z: 404 (M+). Anal. calcd.
for C28H36O2: C 83.12, H 8.97; found: C 82.98, H 8.88.
Colorless oil. IR (NaCl) ꢁmax (cm–1): 1701 (C=O). 1H
NMR (CDCl3) d: 1.07 (s, 18H), 1.37 (t, J = 7.33 Hz, 3H),
3.28 (d, J = 12.7 Hz, 2H), 3.30 (d, J = 12.7 Hz, 2H), 3.54 (s,
3H), 3.60 (q, J = 7.33 Hz, 2H), 4.27 (d, J = 12.7 Hz, 2H),
4.30 (d, J = 12.7 Hz, 2H), 6.66 (s, 2H), 6.67 (s, 2H). MS
m/z: 450 (M+). Anal. calcd. for C29H38O4: C 77.30, H 8.50;
found: C 77.45, H 8.63.
Wolff-Kishner reduction of 5
Typical procedure
A mixture of anti-5c (1.20 g, 2.75 mmol), KOH (1.28 g,
23.0 mmol), 100% hydrazine hydrate (0.35 mL, 6.2 mmol),
and triethylene glycol (35 mL) was heated at 120°C for 2 h
and then at 220°C for 3 h. The cooled mixture was poured
into water (50 mL), acidified with diluted HCl, and then ex-
tracted with CH2Cl2 (3 × 50 mL), washed with water (2 ×
20 mL), dried with Na2SO4, and concentrated under reduced
pressure. The residue was chromatographed on silica gel
using hexane–benzene (1:1) as eluents to give crude anti-6c
as a colorless solid. Recrystallization from hexane afforded
anti-6,15-Di-tert-butyl-9-methoxy-18-propoxy[3.3]meta-
cyclophane-2,11-dione (anti-5e)
Colorless prisms (hexane), mp 123–124°C. IR (KBr) ꢁmax
(cm–1): 1685 (C=O). 1H NMR (CDCl3) d: 0.79 (t, J =
7.33 Hz, 3H), 1.30 (s, 9H), 1.32 (s, 9H), 1.30–1.40 (m, 2H),
3.12 (s, 3H), 3.17 (t, J = 7.33 Hz, 2H), 3.21 (d, J =
14.16 Hz, 4H), 3.73 (d, J = 14.16 Hz, 2H), 3.74 (d, J =
© 2002 NRC Canada

516
Can. J. Chem. Vol. 80, 2002
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13. (a) M. Tashiro and T. Yamato. J. Org. Chem. 46, 4556 (1981);
(b) M. Tashiro and T. Yamato. J. Org. Chem. 48, 1461 (1983);
(c) M. Tashiro and T. Yamato. J. Org. Chem. 50, 2939 (1985);
(d) T. Yamato, J. Matsumoto, K. Tokuhisa, M. Kajihara, K.
Suehiro, and M. Tashiro. Chem. Ber. 125, 2443 (1992); (e) T.
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anti-6,15-di-tert-butyl-9,18-dimethoxy[3.3]metacyclophane
(anti-6c) (1.02 g, 90%) as colorless prisms, mp 220–222°C.
1H NMR (CDCl3) d: 1.32 (s, 18H), 2.08–2.15 (m, 4H),
2.30–2.39 (m, 4H), 2.57–2.67 (m, 4H), 3.11 (s, 6H), 6.95 (s,
4H). MS m/z: 408 (M+). Anal. calcd. for C28H40O2: C 82.30,
H 9.87; found: C 81.99, H 9.94.
Compounds syn-6c, syn-6a, anti-6f, and syn-6f were simi-
larly prepared. The yields are listed in Scheme 6.
syn-6,15-Di-tert-butyl-9,18-dimethoxy[3.3]metacyclophane
(syn-6c)
Colorless prisms (hexane), mp 116–118°C. 1H NMR
(CDCl3) d: 1.11 (s, 18H), 1.59–1.76 (m, 2H), 2.28–2.52 (m,
5H), 3.00–3.11 (m, 4H), 3.47 (s, 6H), 6.53 (s, 4H). MS m/z:
408 (M+). Anal. calcd. for C28H40O2: C 82.30, H 9.87;
found: C 82.06, H 9.92.
syn-6,15-Di-tert-butyl-9-methoxy[3.3]metacyclophane
(syn-6a)
1
Colorless oil. H NMR (CDCl3) d: 1.06 (s, 9H), 1.14 (s,
9H), 2.25–2.38 (m, 4H), 2.48–2.65 (m, 4H), 2.61–2.73 (m,
4H), 3.66 (s, 3H), 6.57 (s, 2H), 6.58 (s, 1H), 6.69 (s, 1H),
7.10 (s, 1H). MS m/z: 378 (M+). Anal. calcd. for C27H38O:
C 85.66, H 10.12; found: C 85.36, H 9.99.
anti-6-tert-Butyl-9,18-dimethoxy[3.3]metacyclophane
(anti-6f)
Colorless prisms (hexane), mp 220–222°C. 1H NMR
(CDCl3) d: 1.34 (s, 18H), 2.05–2.15 (m, 4H), 2.31–2.42 (m,
4H), 2.57–2.69 (9m, 4H), 3.10 (s, 3H), 3.15 (s, 3H),
6.85–6.88 (m, 1H), 6.95–6.97 (m, 4H). MS m/z: 352 (M+).
Anal. calcd. for C24H32O2: C 81.77, H 9.15; found: C 81.69,
H 9.04.
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(b) C.D. Andreetti, R. Ungaro, and A. Pochini. J. Chem. Soc.
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Andreetti, and O. Domiano. J. Chem. Soc. Perkin Trans. 2,
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syn-6-tert-Butyl-9,18-dimethoxy[3.3]metacyclophane
(syn-6f)
Colorless prisms (hexane), mp 82–84°C. 1H NMR
(CDCl3) d: 1.15 (s, 9H), 1.81–1.89 (m, 2H), 2.45–2.52 (m,
6H), 3.03–3.13 (m, 4H), 3.48 (s, 6H), 6.48–6.56 (m, 5H).
MS m/z: 352 (M+). Anal. calcd. for C24H32O2: C 81.77,
H 9.15; found: C 81.58, H 9.11.
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© 2002 NRC Canada