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:10.3184/030823409X401105

Various anfti-9-substituted [3.3]MCP-2,11-diones are exclusively obtained by the coupling reaction of the corresponding 1,3-bis(bromomethyl)benzenes and 2,6-bis[2-isocyano-2-(tolylsulfonyl)ethyl]-4-tert-butylbenzenes in dimethylformamide (DMF) with an exc

Full text of DOI:10.3184/030823409X401105

60 RESEARCH PAPER
JANUARY, 60–64
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis and conformational studies of 9-substituted
[3.3]metacyclophane-2,11-diones and conversion to the
corresponding [3.3]metacyclophanes
Tomoe Shimizu, Ryuji Ueno, Masa'odi Ziewandy and Takehiko Yamato*
Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga 840-8502, Japan
Various anti-9-substituted [3.3]MCP-2,11-diones are exclusively obtained by the coupling reaction of the
corresponding 1,3-bis(bromomethyl)benzenes and 2,6-bis[2-isocyano-2-(tolylsulfonyl)ethyl]-4-tert-butylbenzenes
in dimethylformamide (DMF) with an excess of sodium hydride, from which the corresponding syn-[3.3]MCP are
synthesised via anti-syn-isomerisation during the Wolff–Kishner reduction.
Keywords: metacyclophanes, cyclisation, conformation, CH–S–interaction, Wolff–Kishner reduction, anti-syn-isomerisation
The synthesis and stereochemical aspects of conformationally
mobile [3.3]MCPs (MCP = metacyclophane) have been
of interest for the past decade, with particular attention1-3
paid to dithia[3.3]MCPs, which possess an anti-stepped
conformation. The pioneering work of the conformational
investigation of 2,11-dithia[3.3]MCPs was reported by Vögtle
et al.4 Shinmyozu and his co-workers5ꢀKDYHꢀUHSRUWHGꢀWKHꢀ¿UVWꢀ
preparation and conformational behaviour in the carbocyclic
[3.3]MCPs and their analogues. [3.3]MCP exists in the syn
geometry with a chair–chair arrangement of the trimethylene
chains in the crystal state. The preferred geometry of
2,11-diones and conversion to the corresponding [3.3]MCPs
by Wolff–Kishner reduction. The substituent effects on the
formation of the syn- and anti-conformations are discussed.
Results and discussion
Vögtle reported14–17 the preparation of carbocyclic [3n]MCPs
using TosMIC18,19 as the cyclisation reagent, which was
applied in a new cyclisation procedure without phase-transfer
conditions.20-24
This strategy can be employed for the preparation of
[3.3]MCP containing two benzene rings. However, the
preparation of [3.3]MCPs using the TosMIC method is
GLI¿FXOWꢀEHFDXVHꢀRIꢀLWVꢀORZꢀ\LHOGꢀDVꢀZHOOꢀDVꢀWKHꢀGLI¿FXOW\ꢀRIꢀWKHꢀ
product separation from the other macrocyclic oligoketones,
i.e.ꢀWULPHUꢀDQGꢀWHWUDPHUꢁꢀ7KHUHIRUHꢂꢀLWꢀKDVꢀEHHQꢀYHU\ꢀGLI¿FXOWꢀ
WRꢀ REWDLQꢀ VXI¿FLHQWꢀ DPRXQWVꢀ RIꢀ WKHꢀ DERYHꢀ FRPSRXQGVꢀ WRꢀ
investigate their chemical behaviour.
Therefore, we have selected the stepwise cyclisation of
TosMIC adduct 2 with 1,3-bis(bromomethyl)-5-substituted
benzenes 3 to prepare the desired cyclic dimer 4. The starting
compounds, 2,6-bis(bromomethyl)-4-tert-butyl-1-substituted
benzenes 1, are easily prepared by bromomethylation of 4-
tert-butyltoluene and 4-tert-butylanisole25 using the tert-
butyl group as a positional protecting group on the aromatic
ring.26–32 Although TosMIC adduct 2a and 2b were obtained
in 77 and 78% yields by the reaction of 1a and 1b with
TosMIC as a mixture of two isomers, i.e. meso and dl, the
attempted separation of these isomers of 2 pure failed. The
preparation of 1,3-bis(bromomethyl)-5-substituted benzenes 3
are carried out by the treatment of 1,3-dimethyl-5-substituted
benzenes with N-bromosuccinimide as following the reported
procedure.28,30 The cyclic diketones 4 were synthesised by
coupling the 1,3-bis(bromomethyl)-5-substituted benzenes 3
with TosMIC adduct 2 under highly diluted conditions in
DMF with an excess of sodium hydride as shown in Scheme 2.
We have improved the addition procedure in Vögtle's
1
[3.3]MCP in solutionis also a syn on the basis of H NMR
spectrum, in which [3.3]MCP shows strong temperature-
dependent phenomenon at low temperature.6–10
Shinmyozu and co-workers5 prepared [3.3]MCP using
(p-tolylsulfonyl)methylisocyanide (TosMIC) as the cyclisation
reagent, followed by Wolff–Kishner reduction. They have
studied syn-anti conversions in other [3.3]MCPs, especially
in relation to the size of the substituents such as halogens.11
Like the parent compound 9-halo[3.3]MCPs prefer the syn
conformation but the corresponding 2,11-diones favour the
anti arrangement. Even one internal halogen substituent is
VXI¿FLHQWꢀWRꢀDOORZꢀWKHꢀLVRODWLRQꢀRIꢀDꢀGLVFUHWHꢀsyn or anti isomer.
Although the effect on the ratio of syn and anti conformers of
[3.3]MCPs was reported, it is still not clear what the effects
are, not only properties of the internal substituents, but also
having unsymmetrically substituted benzene rings arising from
charge-transfer-type interactions between two benzene rings as
well as steric effects of substituents at the 6 and 15-positions.
All of the previous compounds are internally unsubstituted
[3.3]MCP-2,11-diones and it is surprising that there are
very few reports12,13 on the preparation of 9-methyl- or 9-
methoxy-analogues despite the fact that the chemical shift of
the internal substituents, such as methyl and methoxy group
provides a convenient probe for 1H NMR studies of any
possible conformational changes. We report here the synthesis
and stereochemical assignments of 9-substituted [3.3]MCP-
OMe
OMe
i) TosMIC/NaH/
DMF
Br
Br
ii) conc. HCl
O
n
n = 2; 10%
n = 3; 14%
n = 4; <0.5%
TosMIC =
Me
SO2CH2NC
Scheme 1
* Correspondent. E-mail: yamatot@cc.saga-u.ac.jp

JOURNAL OF CHEMICAL RESEARCH 2009 61
method.14–17 Thus, to a suspension of NaH in DMF a solution
of 3 and TosMIC adducts 2 was added dropwise in DMF at
room temperature. This not only improves the yield of the
desired ketones but also makes the handling of the base (solid
NaH) easier. The 1H NMR spectrum of 4 shows methoxy
protons as a singlet except diketone 4d, which shows two
kinds of methoxy protons, each as a singlet. By careful column
chromatography (silica gel, Wako C-300), two isomers, anti-
4d and syn-4d, are separated. They are thermally stable and
do not interconvert at 150°C in DMSO solution and at 400°C
in the solid state.
The structures of 4 have been elucidated by elemental
analyses and spectral data. For instance, the mass spectral
data for anti-4d (M+ = 364) strongly supports a cyclic dimeric
structure. The IR spectrum of anti-4d shows the absorption
of the carbonyl stretching vibration around 1697 cm-1. The
1H NMR spectrum (in CDCl3) of anti-4d exhibits two sets of
doublets at G = 3.28, 3.76 ppm (J = 15.0 Hz) and G = 3.40,
3.45 ppm (J = 13.2 Hz) for the ArCH2COCH2Ar methylene
protons and a singlet for the internal methoxy group at an
XS¿HOGꢀVKLIWꢀG = 3.36 ppm from anisole (G = 3.75 ppm) due
to the ring current of the opposing aromatic ring.26-28,33-38
Similarly, the internal aromatic proton at 18-position was
REVHUYHGꢀDWꢀDꢀKLJKHUꢀ¿HOGꢂꢀG 5.39 ppm compared to that of the
3b at G 7.28 ppm. These observations strongly suggest that
compound anti-4d adopts the anti-conformation.
syn-conformation. Similarly, the assignments of structures
for other anti conformers were readily apparent from their 1H
NMR spectra. The chemical shifts (G) of the internal methoxy
protons, the internal protons at the 18-position, the protons of
substituent at 15 position, aromatic protons and the tert-butyl
protons of anti-9-substituted [3.3]MCP-2,11-diones anti-
4a–f and syn-6-tert-butyl-9-methoxy-15-methyl[3.3]MCP-2,
11-dione syn-4d are compiled in Table 2.
Thus 9-substituted analogue is exclusively formed in the
anti-conformer independent on R1 of 2,6-bis[2-isocyano-2-
(tolylsulfonyl)ethyl]-4-tert-butyl-1-substituted benzenes
2
and R2 of 1,3-bis(bromomethyl)-5-substituted benzenes 3, but
only 9-methoxy-15-methyl analogue 4d is formed in a mixture
of syn- and antiꢃFRQIRUPHUVꢁꢀ7KHVHꢀ¿QGLQJVꢀVXJJHVWꢀWKDWꢀLQꢀWKHꢀ
case of 9-methyl analogue the aromatic S–S interaction of
two opposite benzene rings and the steric crowdness by the
bulky tert-butyl group at the external positions 6 and 15 may
inhibit the formation of the syn-conformer in the [3.3]MCP-
2,11-diones system, Furthermore, the CH–S interaction44-51
between 9-methyl group and the opposite aromatic S-electrons
Table 1 Anti-to-syn ratios in TosMIC cyclisation of 2 with 3
Substrate
Product
yield/%a
Isomer
distribution/%b
2(R1)
3(R2)
anti
syn
In contrast, the methoxy proton of syn-4d is observed at G
3.63 ppm. Furthermore, the aryl hydrogens at 5,7-positions can
clearly be seen to be shielded at G 6.61 ppm by the adjacent
ring, a common consequence of a face-to-face benzene
ring.33–43 Also the tert-butyl protons was observed at higher
¿HOGꢂꢀG 0.89 ppm compared to that of the anti-4d at G 1.34 ppm
due to the strong shielding effect of the benzene ring. These
observations strongly suggest that compound syn-4d adopts
Me
Me
tBu
H
Me
tBu
Br
4a (48)
4b (53)
4c (72)
4d (71)
4e (72)
4f (50)
100
100
100
60
100
100
0
0
Me
OMe
OMe
OMe
OMe
0
40
0
0
aIsolated yields. banti-to-syn ratios determined by 1H NMR
spectroscopy at 20°C
R1
R1
TosMIC (excess)
Tos
NC
Tos
CN
/NaOH/n-Bu4NI
Br
Br
CH2Cl2/H2O
tBu
tBu
1 a; R1 = Me
a; R1 = Me (77%)
2
b; R1 = OMe
b; R1 = OMe (78%)
Br
Br
i) NaH/DMF
ii) conc. HCl
+
2
R2
tBu6
6
tBu
2
3
9
a; R = H
R1
b; R2 = Me
c; R2 = tBu
d; R2 = Br
9
R1
2
2 O
O
+
O11
11
18
O
18
R2
15
R2
15
anti-4
syn-4
a; R1 = Me, R2= Me
b; R1 = Me, R2= tBu
c; R1 = OMe, R2= H
d; R1 = OMe, R2= Me
e; R1 = OMe, R2= tBu
f; R1 = OMe, R2= Br
Scheme 2

62 JOURNAL OF CHEMICAL RESEARCH 2009
Table 2 1H NMR spectral data of 6-tert-butyl-9-substituted [3.3]MCP-2,11-diones 4a
Compound
R1 protons
H18
R2 protons
Benzene protons tert-Butyl protons
anti-4a
anti-4b
anti-4c
anti-4d
anti-4e
anti-4f
syn-4d
Me
Me
OMe 3.34
OMe 3.36
OMe 3.26
OMe 3.40
OMe 3.63
0.94
0.97
4.80
4.94
5.54
5.39
5.29
5.58
7.22
Me 2.14
6.86, 7.29
7.15, 7..5
7.10, 7.20
6.84, 7.36
7.08, 7.19
7.18, 7.19
6.61, 6.97
1.37
1.24
1.35
1.34
1.36
1.34
0.89
tBu 1.24
H
7.06b
Me 2.22
tBu 2.27
Br
–
Me 1.91
aDetermined in CDCl3 by using SiMe4 as a reference and expressed in ppm given.
bMidpoint value of multiplet.
may also favour the formation of anti-conformer in the
process of the cyclisation reaction. The CH–Sꢀ interaction
involving aliphatic CH moieties is well documented44 as
either a conformation-controlling intramolecular process or a
crystal-structure controlling intermolecular force, especially
for inclusion complexes of calixarene derivatives.45-51
Although in the case of 9-methoxy analogue the detailed
reaction pathway of the formation of syn-4d is still not
clear from the present results, one might propose the CH–S
interaction between the methyl group at 15 position and
the opposite aromatic S-electrons, which may increase the
formation of the syn-conformer during the present coupling
reaction in spite of being the through-space interaction
between the non-bonding electron pairs of the oxygen atom
of the methoxy group and the opposite aromatic S-electrons
of the anti-conformer, which may disfavour the formation of
the latter.
observed under the reaction conditions used (Scheme 3).
7KHVHꢀ¿QGLQJVꢀVWURQJO\ꢀVXJJHVWꢀWKDWꢀWKHꢀULQJꢀLQYHUVLRQꢀWRꢀWKHꢀ
thermodynamically more stable syn-conformation is possible
in the 9-methoxy[3.3]MCPs 5c–e.
On the other hand, as mentioned previously we have
reported that syn-4d and anti-4d are thermally stable and do
not interconvert at 150°C in DMSO solution and at 400°C in
the solid state. Although the detailed mechanistic conclusion
to rationalise the present observation of anti-to-syn-conversion
is not clear, one might assume the similar behaviour that
the [3.3]MCP exists in the syn geometry with a chair–chair
arrangement of the trimethylene chains.5
Conclusions
Various anti-9-substituted [3.3]MCP-2,11-diones are
exclusively obtained by the coupling reaction of the
corresponding 2,6-bis[2-isocyano-2-(tolylsulfonyl)ethyl]-4-
tert-butylbenzenes 2 and 1,3-bis(bromomethyl)-5-substituted
benzenes 3 in dimethylformamide (DMF) with an excess of
sodium hydride. In the case of the coupling reaction of 2,6-
bis[2-isocyano-2-(tolylsulfonyl)ethyl]-4-tert-butylanisole 2b
with 1,3-bis(bromomethyl)-5-methylbenzene 3b a mixture of
anti-4d and syn-4d was obtained due to the CH–S interaction
between the methyl group at 15-position and the opposite
aromatic S-electrons, which may favour the formation of
syn-4d. Further studies on the chemical properties of the two
conformers syn- and anti-4 and 5 are now in progress.
The Wolff–Kishner reduction of syn-diketone syn-
4d afforded the desired syn-6,15-di-tert-butyl-9,18-
dimethoxy[3.3]MCP (syn-5d) in 85% yield. No formation of
the corresponding anti-conformer has been observed under
the reaction conditions used.
The structure of syn-5d has been elucidated by elemental
analyses and spectral data. The 1H NMR spectrum (in CDCl3)
of syn-5d exhibits a singlet at G 3.63 ppm for the methoxy
protons. Furthermore, a singlet of the intra-annular proton H18
at G 6.94 ppm in addition to the resonances at G 6.26 and 6.48
ppm for the other two protons of the aromatic rings which can
clearly be seen to be shielded by the adjacent ring, a common
consequence of a face-to-face benzene ring.33-38 Also the tert-
butyl protons and methyl protons were observed at higher
¿HOGꢂꢀG 1.03 and 1.96 ppm compared to those of the anti-4d
at G 1.34 and 2.22 ppm due to the strong shielding effect of
the benzene ring. These observations strongly suggest that
compound syn-5d adopts syn-conformation.
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.
Interestingly, similar results were obtained in the case of
reduction of anti-4c–e to afford syn-5c–e carried out under
the same reaction conditions. anti-syn-Isomerisation was
tBu
tBu
i) NH2NH2
120°C for 2 h
OMe
OMe
anti-4
ii) KOH
c; R= H
220°C for 3 h
d: R= Me
R
e; R= tBu
R
syn-5
anti-5
c; R= H (70%)
d: R= Me (80%)
e; R= tBu (80%)
i) NH2NH2
120°C for 2 h
syn-5d
syn-4d
ii) KOH
220°C for 3 h
(85%)
Scheme 3

JOURNAL OF CHEMICAL RESEARCH 2009 63
Materials
anti-6,15-Di-tert-butyl-9-methyl[3.3]metacyclophane-2,11-dione
(anti-4b): Colourless prisms (hexane), m.p. 144–147°C; Qmax (KBr)/
cm-1 1699 (C=O); GH (CDCl3) 0.97 (3H, s, Me), 1.24 (18H, s, tBu),
3.39 (2H, d, J = 11.6 Hz, CH2), 3.50 (2H, d, J = 16.5 Hz, CH2), 3.61
(2H, d, J = 11.6 Hz, CH2), 3.67 (2H, d, J = 16.5 Hz, CH2), 4.94 (1H, s,
ArH), 7.15 (2H, s, ArH) and 7.35 (2H, s, ArH); m/z 390 (M+) (Found:
C, 83.28; H, 8.65. C27H34O2 (390.57) requires C, 83.03; H, 8.77%).
anti-6-tert-Butyl-9-methoxy[3.3]metacyclophane-2,11-dione (anti-
4c): Colourless prisms (MeOH), m.p. 110–111°C; Qmax (KBr)/cm-1
1698 (C=O); GH (CDCl3) 1.35 (9H, s, tBu), 3.32 (2H, d, J = 14.2 Hz,
CH2), 3.33 (3H, s, OMe), 3.33 (2H, d, J = 12.2 Hz, CH2), 3.48 (2H, d,
J = 12.2 Hz, CH2), 3.74 (2H, d, J = 14.2 Hz, CH2), 5.55 (1H, s, ArH),
7.05–7.10 (3H, m, ArH) and 7.25 (2H, s, ArH); m/z 350 (M+) (Found:
C, 78.71; H, 7.48. C23H26O3 (350.46) requires C, 78.83; H, 7.48%).
anti-6,15-Di-tert-butyl-9-methoxy[3.3]metacyclophane-2,11-
dione (anti-4e): Colourless prisms (hexane), m.p. 142–144°C; Qmax
(KBr)/cm-1 1688 (C=O); GH (CDCl3) 1.27 (9H, s, tBu), 1.36 (9H, s,
tBu), 3.26 (3H, s, OMe), 3.29 (2H, d, J = 15.6 Hz, CH2), 3.39 (2H,
d, J = 13.7 Hz, CH2), 3.51 (2H, d, J = 13.7 Hz, CH2), 3.73 (2H, d,
J = 15.6 Hz, CH2), 5.29 (1H, s, ArH), 7.08 (2H, s, ArH) and 7.19 (2H,
s, ArH); m/z 406 (M+) (Found: C, 79.75; H, 8.47. C27H34O3 (406.57)
requires C, 79.77; H, 8.43%).
2,6-Bis(bromomethyl)-4-tert-butyltoluene (1a) and 2,6-bis(bromo-
methyl)-4-tert-butylanisole (1b) were prepared by the reported
procedure.25,52The preparationsof 1,3-bis(bromomethyl)-5-substituted
benzenes (3a–d) were previously described.28,30
Preparation of the TosMIC adduct 2; typical procedure
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 for 30 min, a solution of dibromide
1a (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 was extracted with CH2Cl2 (3 u 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 refrigerator to give 2,6-bis
[2-isocyano-2-(tolylsulfonyl)ethyl]-4-tert-butyltoluene (2a) (4.90 g,
77%) as pale brown prisms, m.p. 176°C (dec.); Qmax (KBr)/cm-1 2135
(CN); GH (CDCl3) 1.26, 1.27 (9H, s, tBu), 2.26, 2.27 (3H, s, Me), 2.50
(6H, s, Me), 3.00–4.52 (6H, m, CH2, CH), 7.16 (2H, s, ArH), 7.46
(4H, d, J = 8.3 Hz, ArH) and 7.92 (4H, d, J = 8.3 Hz, ArH); m/z
562 (M+) (Found: C, 65.95; H, 6.06; N, 4.73. C31H34N2O4S2 (562.75)
requires C, 66.17; H, 6.09; N, 4.98%).
anti-6-tert-Butyl-15-bromo-9-methyl[3.3]metacyclophane-2,11-
dione (anti-4f): Colourless prisms (hexane), m.p. 137–139°C; Qmax
(KBr)/cm-1 1699 (C=O); GH (CDCl3) 1.34 (9H, s, tBu), 3.34 (2H, d,
J = 15.1 Hz, CH2), 3.40 (3H, s, OMe), 3.45 (2H, d, J = 13.2 Hz,
CH2), 3.65 (2H, d, J = 13.2 Hz, CH2), 3.81 (2H, d, J = 15.1 Hz, CH2),
5.58 (1H, s, ArH), 7.18 (2H, s, ArH) and 7.19 (2H, s, ArH); m/z 428,
430 (M+) (Found: C, 64.48; H, 5.65. C23H25BrO3 (429.36) requires
C, 64.34; H, 5.87%).
Compound 2b was similarly prepared in 78% yield.
2,6-Bis[2-isocyano-2-(tolylsulfonyl)ethyl]-4-tert-butylanisole (2b):
Pale brown prisms (hexane), m.p. 150–151°C (dec.); Qmax (KBr)/cm-1
2134 (CN); GH (CDCl3) 1.26, 1.27 (9H, each s, tBu), 2.49, 2.50 (6H,
each s, Me), 2.87, 2.99 (2H, each dd, J = 11.7/13.7 Hz, CH2), 3.66,
3.77 (2H, each dd, J = 2.9/13.7 Hz, CH2), 3.76, 3.80 (3H, each s,
OMe), 4.73, 4.83 (2H, each dd, J = 2.9/11.7 Hz, CH), 7.19, 7.20 (2H,
each s, ArH), 7.44, 7.46 (4H, d, J = 8.3 Hz, ArH) and 7.87, 7.93 (4H,
d, J = 8.3 Hz, ArH); m/z 578 (M+) (Found: C, 64.56; H, 5.87; N, 4.73.
C31H34N2O5S2 (578.75) requires C, 64.34; H, 5.92; N, 4.84%).
Wolff–Kishner reduction of 5; typical procedure
A mixture of anti-4d (1.20 g, 3.3 mmol), KOH (1.28 g, 23.0 mmol),
100% hydrazine hydrate (0.35 mL, 6.2 mmol), and triethylene glycol
(3 u 50 mL) was heated at 120°C for 2 h and then at 220°C for 3 h.
7KHꢀFRROHGꢀPL[WXUHꢀZDVꢀSRXUHGꢀLQWRꢀZDWHUꢀꢄꢅꢆꢀP/ꢇꢂꢀDFLGL¿HGꢀZLWKꢀ
diluted HCl, and extracted with CH2Cl2 (3 u 50 mL), washed with
water (2 u 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 syn-5d as a
colourless solid. Recrystallisation from hexane afforded syn-6-tert-
butyl-9-methoxy-18-methyl[3.3]metacyclophane (syn-5d) (886 mg,
80%) as colourless prisms, m.p. 90–92°C; GH (CDCl3) 1.03 (9H, s,
tBu), 1.63–1.68 (2H, m, CH2), 1.96 (3H, s, Me), 2.21–2.29 (2H, m,
CH2), 2.39–2.66 (4H, m, CH2), 2.90–3.02 (2H, m, CH2), 3.55–2.68
(2H, m, CH2), 3.60 (3H, s, OMe), 6.26 (2H, s, ArH), 6.48 (2H, s,
ArH) and 6.94 (1H, s, ArH); m/z 336 (M+) (Found: C, 85.79; H, 9.52.
C24H32O (336.52) requires C, 85.66; H, 9.58%).
Stepwise cyclisation of TosMIC adduct 2 and dibromide 3; typical
procedure
To a suspension of NaH (2.1 g, 51 mmol) in DMF (150 mL) a solution
of 2b (4.7 g, 8.5 mmol) and 3b (5.0 g, 8.5 mmol) in DMF (35 mL)
was added dropwise over a period of 6 h. After the suspension was
stirred for an additional 5 h at room temperature, it was quenched with
ice-water (300 mL). The reaction mixture was extracted with CH2Cl2
(3 u 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 u 100 mL), washed with water (2 u 100 mL),
dried with Na2SO4, and concentrated and condensed under reduced
pressure. The anti-to-syn ratio was determined as 60:40 by 1H NMR
spectrum. The residue was chromatographed on silica gel using
CHCl3 as eluents to give crude anti-4d and syn-4d as a pale yellow
solid, respectively. Recrystallisation from hexane afforded anti-4d
(965 mg, 31%) and syn-4d (712 mg, 23%), respectively.
Compounds syn-5c and syn-5e were similarly prepared in 70 and
80% yields, respectively.
syn-6-tert-Butyl-9-methoxy[3.3]metacyclophane (syn-5c): Colourless
prisms (MeOH), m.p. 112–114°C; GH (CDCl3) 1.09 (9H, s,
tBu), 1.70–1.82 (2H, m, CH2), 2.30–2.37 (2H, m, CH2), 2.47–2.76
(6H, m, CH2), 3.00–3.09 (2H, m, CH2), 3.67 (3H, s, OMe), 6.54
(2H, d, J = 7.0 Hz, ArH), 6.55 (2H, s, ArH), 6.73 (1H, t, J = 7.0 Hz,
ArH) and 7.18 (1H, s, ArH); m/z 322 (M+) (Found: C, 85.65; H, 9.39.
C23H30O (322.49) requires C, 85.66; H, 9.38%).
anti-6-tert-Butyl-9-methoxy-15-methyl[3.3]metacyclophane-2,11-
dione (anti-4d): Colourless prisms (hexane), m.p. 98–100°C.; Qmax
(KBr)/cm-1 1697 (C=O); GH (CDCl3) 1.34 (9H, s, tBu), 2.22 (3H, s,
Me), 3.28 (2H, d, J = 15.0 Hz, CH2), 3.36 (3H, s, OMe), 3.40 (2H,
d, J = 13.2 Hz, CH2), 3.45 (2H, d, J = 13.2 Hz, CH2), 3.76 (2H, d,
J = 15.0 Hz, CH2), 5.39 (1H, s, ArH), 6.84 (2H, s, ArH) and 7.36
(2H, s, ArH); m/z 364 (M+) (Found: C, 78.86; H, 7.68. C24H28O3
(364.49) requires C, 79.09; H, 7.74%).
syn-6,15-Di-tert-butyl-9-methoxy[3.3]metacyclophane (syn-5e):
Colourless oil; GH (CDCl3) 1.06 (9H, s, tBu), 1.14 (9H, s, tBu),
2.25–2.38 (4H, m, CH2), 2.48–2.65 (4H, m, CH2), 2.61–2.73 (4H,
m, CH2), 3.66 (3H, s, OMe), 6.57 (2H, s, ArH), 6.58 (2H, s, ArH) and
syn-6-tert-Butyl-9-methoxy-15-methyl[3.3]metacyclophane-2,11-
dione (syn-4d): Colourless prisms (hexane), m.p. 172–174°C; Qmax
(KBr)/cm-1 1706 (C=O); GH (CDCl3) 0.89 (9H, s, tBu), 1.91 (3H,
s, Me), 3.02 (2H, d, J = 13.7 Hz, CH2), 3.21 (2H, d, J = 13.6 Hz,
CH2), 3.55 (2H, d, J = 13.7 Hz, CH2), 3.63 (3H, s, OMe), 3.74 (2H, d,
J = 13.6 Hz, CH2), 6.61 (2H, s, ArH), 6.97 (2H, s, ArH) and 7.22 (1H,
s, ArH); m/z 364 (M+) (Found: C, 78.96; H, 7.63. C24H28O3 (364.49)
requires C, 79.09; H, 7.74%).
7.10 (1H, s, ArH); m/z 378 (M+) (Found: C, 85.36; H, 9.99. C27H38
(378.6) requires C, 85.66; H, 10.12%).
O
Received 14 October 2008; accepted 2 December 2008
Paper 08/0226 doi: 10.3184/030823409X401105
Published online: 23 January 2009
Compounds anti-4a–c and anti-4e–f were similarly prepared.
The yields are listed in Table 1.
References
anti-6-tert-Butyl-9,15-dimethyl[3.3]metacyclophane-2,11-dione
(anti-4a): Colourless prisms (hexane), m.p.148–151°C; Qmax (KBr)/
cm-1 1699 (C=O); GH (CDCl3) 0.94 (3H, s, Me), 1.37 (9H, s, tBu),
2.14 (3H, s, Me), 3.25 (2H, d, J = 11.3 Hz, CH2), 3.46 (2H, d,
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(2H, s, ArH); m/z 348 (M+) (Found: C, 82.84; H, 8.06. C24H28O2
(348.49) requires C, 82.72; H, 8.1%).
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