Synthesis and structures of 8- tolylmethyl)[2.2]metacyclophanes and 8,8'-(ethane-1,2 diyl)bis(16-methoxy[2.2]metacyclophane)

Article abstract of DOI:10.3184/030823409X12508764525015

A convenient preparation of 8-(tolylmethyl)[2.2]metacyclophanes and 8,8'-(ethane-1,2-diyl)bis(16-methoxy[2.2]metacyclophane) using a cross-coupling reaction of 8-bromomethyl[2.2]metacyclophanes with tolylmagnesium bromides is described. The structures of

Full text of DOI:10.3184/030823409X12508764525015

570 RESEARCH PAPER
SEPTEMBER, 570–573
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis and structures of 8-(tolylmethyl)[2.2]metacyclophanes and
8,8'-(ethane-1,2-diyl)bis(16-methoxy[2.2]metacyclophane)
Tomoe Shimizu, Kan Tanaka, Arjun Paudel and Takehiko Yamato*
Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga 840-8502, Japan
A convenient preparation of 8-(tolylmethyl)[2.2]metacyclophanes and 8,8'-(ethane-1,2-diyl)bis(16-methoxy[2.2]meta-
cyclophane) using a cross-coupling reaction of 8-bromomethyl[2.2]metacyclophanes with tolylmagnesium bromides
is described. The structures of these novel [2.2]metacyclophanes in solution are also discussed.
Keywords: cyclophanes, Grignard cross coupling reaction, strain, ring current effect
The geometry of the [2.2]MCP ([2.2]MCP
= [2.2]
Results and discussion
metacyclophane) skeleton is known in detail from an X-ray
structural analysis.1 The crystal consists of discrete molecules
each of which has a centre of symmetry. The two halves of the
molecule form a stepped system. It is interesting to note that
the benzene rings are not planar, but have a boat conformation,
with the result that the molecule evidently avoids the steric
interaction of the central carbon atoms C-8 and C-16 and of the
attached hydrogen atoms. The C(8)– C(16) distance is 2.689
Å. The average length of the aromatic C–C bond was found
to be 1.386 Å, and that of the aliphatic bond 1.543 Å. It is
remarkable that the normally hexagonal, planar benzene ring
suffers such a pronounced deformation with no appreciable
change in the interatomic distances.2
The X-ray structural analysis of 8,16-dimethyl[2.2]MCP 2
confirms the results obtained for the parent compound.3 The
increased strain in the molecule 2 as compared with that in the
parent hydrocarbon 1 can be seen in particular in the distance
between C-1 and C-2 (1.573 Å). It is also remarkable that
the two methyl carbon atoms lie in one plane together with
the carbon atoms 8, 7 and 3 and 16, 11 and 15. The C(8)–
(16) distance is increased from 2.689 Å in 1 to 2.819 Å in 2.
The rotation of the methyl groups (which are fixed above the
aromatic rings) about their axes appears to be hindered, if not
blocked. However, proton resonance measurements down to –
20°C show no rotation barrier for the molecule in solution.4–15
Thus introduction of methyl substituted benzyl groups to
the 8-position of [2.2]MCP might increase the rotation barrier
around the [2.2]MCP-CH2–Ar for the molecule in solution.
It is surprising that there are no reports on the preparation of
8-(tolylmethyl)[2.2]MCPs despite the fact that the chemical
shift of the 2, 3, and 4-methyl substituent provides a
convenient probe for 1H NMR studies of any possible
conformational changes. Therefore, there is substantial interest
to investigate the structures of 8-(tolylmethyl)[2.2]MCPs.
We report here the convenient preparation of 8-(tolylmethyl)
[2.2]MCPs and 8,8'-(ethane-1,2-diyl)bis(16-methoxy[2.2]
MCP) using cross coupling reaction of 8-bromomethyl
[2.2]MCPs with tolylmagnesium bromides.
We have prepared 8-bromomethyl[2.2]MCPs
3
by
bromination of the corresponding 8-methy[2.2]MCPs with
N-bromosucccinimide (NBS) in the presence of benzoyl
peroxide under CCl4 reflux for 3 h in 80 and 70% yields,
respectively, as following our previous reported procedure.16–18
The Grignard coupling reaction of 8-bromomethyl[2.2]MCP
3 with tolylmagnesium bromides 4 was carried out under the
various conditions and the results are compiled in Table 1.
The Grignard coupling reaction of 3a with a large excess of
(2-methylphenyl)magnesium bromide 4a under THF reflux
for 90 min afforded a desired 8-(2-methylbenzyl)[2.2]MCP
5a in 52% yield. Similar results were obtained in the case
of the coupling reaction of 3a with (3-methylphenyl) (4b)
and (4-methylphenyl)magnesium bromide (4c) to afford
the corresponding coupling products 5b and 5c in 46 and
40% yields, respectively. On the other hand, the coupling
reaction of 3b with 4a under the same reaction conditions
described above afforded the coupling product 5d in 42%
yield along with the reduction product 6b and 8,8'-(ethane-
1,2-diyl)bis(16-methoxy[2.2]MCP) 7 in 14 and 2% yields,
respectively. Interestingly, the present coupling reaction
was carried out in the presence of almost 2 equivalents of
(2-methylphenyl)magnesium bromide 4a to increase the yield
of bis[2.2]MCP 7 to 43%. In contrast, compounds 5e and 5f
were obtained only in 5 and 10% yields in spite of using a
2
3
8
8
Me
1
7
15
16
16
Me
11
2
1
Fig. 1 Structure and numbering of [2.2]MCP and 8,16-
dimethyl[2.2]MCP.
Table 1 Grignard coupling reaction of 8-bromomethyl[2.2]metacyclophanes (3) with tolylmagnesium bromides (4)a
Run
Substrate
Grignard reagent
Products yield/%b
1
2
3
4c
5
6
7
3a
3a
3a
3b
3b
3b
3b
4a
4b
4c
4a
4a
4b
4c
5a (52)
5b (46)
5c (40)
5d (0)
5d (42)
5e (5)
5f (10)
6a (0)
6a (0)
6a (0)
6b (0)
6b (14)
6b (5)
6b (17)
7 (43)
7 (2)
7 (4)
aReaction conditions: [substrate]: [bromotoluene]:[ Mg] = 1:10:20 (mol mol-1); reaction time was 90 min otherwise indicate.
bIsolated yields are shown. c[substrate]: [bromotoluene]:[ Mg] = 1:5:2.4 (mol/mol); reaction time was 6 h.
* Correspondent. E-mail: yamatot@cc.saga-u.ac.jp

JOURNAL OF CHEMICAL RESEARCH 2009 571
Me
MgBr
tBu
tBu
CH2Br
THF
+
Me
reflux for 90 min.
R
tBu
R
tBu
4 a; 2-Me
b; 3-Me
c; 4-Me
3
a; R = H
a; R= H; 2-Me
5
b; R = OMe
b; R= H; 3-Me
c; R= H; 4-Me
d; R= OMe; 2-Me
e; R= OMe; 3-Me
f; R= OMe; 4-Me
OMe
tBu
tBu
Me
tBu
+
+
tBu
R
tBu
MeO
tBu
6 a; R = H
b; R = OMe
7
Scheme 1
large excess of (3-methylphenyl)magnesium bromide 4b
and (4-methylphenyl)magnesium bromide 4c, respectively.
Quite different results from the coupling reaction of 3a with
tolylmagnesium bromides 4 were observed by the introduction
of methoxy group at the 18-position.
The formation of 6b in the reaction of 3b with 4 suggests
the occurrence of an exchange reaction between 3b and 4 to
generate the intermediate [2.2]MCP-8-methylmagnesium
bromide A, which could react with 3b to afford bis[2.2]MCP
7. The exchange reaction would occur competitively with the
C–C-coupling reaction of 3b with 4a–c, which would give the
product 5d–f. The intermediate A is so stable in the reaction
mixture that compound 6 might be formed when the reaction
mixture is quenched with water. Thus the methoxy group at
16-position could contribute the stability of the intermediate
A by through-space electronic interaction between two
benzene rings.
methylene protons of benzyl group at the 8-position which is in
a strongly shielding region of opposite meta-bridged benzene
ring and d 3.68 ppm for the internal aromatic proton at the
16-position, respectively. Similar findings were observed in
compounds 5b–f. The mass spectral data for 7 (M + = 726)
strongly support bis[2.2]-MCP structure. The 1H NMR
spectrum of bis[2.2]MCP 7 shows the protons of the central
ethano-bridge at d 0.34 ppm, indicating that it is shielded by
the ring current of the both opposing aromatic rings. It was
also found that the one of the tert-butyl groups appeared at
higher field d 0.92 ppm due to the ring current effect of the
other MCP benzene ring.
The benzyl protons of the above-prepared 8-(tolylmethyl)
1
[2.2]MCPs 5 are observed as a singlet in H NMR spectra at
25°C. The conformation of 5 has been evaluated by dynamic
1H NMR spectroscopy. However, for instance, the methylene
protons of the 8-(2-methylbenzyl)[2.2]MCP 5a appear each
as a singlet even below –60°C (CDCl3/CS2 1/3), and the rate
of the rotation around the [2.2]MCP-CH2–Ar of 5a is faster
than the NMR time scale above this temperature. Similar
findings were obtained in other 8-(tolylmethyl)[2.2]MCPs
5b–f. These results indicate that the rotation barrier around
the [2.2]MCP-CH2–Ar 5a and 5d are still quite low in spite of
the introduction of the methyl group at the ortho position of
the 8-benzyl group.
The structures of 5a–f and 7 were determined on the basis
1
of their elemental analyses and spectral data. The H NMR
spectrum of 5a in CDCl3 shows a singlet at d 2.08 ppm for
ArMgBr (4)
5d–f
The values of the chemical shifts of the methylene protons,
methyl protons and aromatic protons of the 8-benzyl group
in [2.2]MCPs 5 are summarised in Table 2.18–20 As shown in
Table 2, the chemical shifts of the methylene protons in 5a–c
(d 2.08–2.11 ppm) are upper field than those (d 2.29–2.31
ppm) in 16-methoxy analogues 5d–f.
Considering the molecular model, it is concluded that
the conformation of the 8-(tolylmethyl)[2.2]MCPs should
be strongly affected by the size of the substituents at the
position 16. The interaction between the methylene protons
and opposite benzene ring might be much more favourable
for unsubstituted [2.2]MCP 5a–5c than the 16-methoxy one
5d–f. Thus, the steric repulsion of 16-substituent for the
opposite benzene ring could make the distance between the
methylene protons and the opposite benzene ring longer,
whereas the H–p interaction at the 16-position could shorten
3b
tBu
CH2MgBr
ArMgBr (4)
3b
7
MeO
tBu
A
H2O
6b
Scheme 2

572ꢀ JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2009
Me
H
tBu
tBu
H
tBu
tBu
R
R
B
C
Fig. 2 Structure of 8-(2-methylbenzyl)[2.2]MCPs.
Grignard coupling reaction of 3ꢀwith (tolyl)magnesium bromide 4;
typical procedure
Table 2 Chemical shifts of the methylene protons, methyl
protons and aromatic protons of 8-benzyl group in 8-(tolyl-
methyl)[2.2]MCPs 5a
Aꢀsolutionꢀofꢀ3b (100 mg, 0.23 mmol) in THF (2 mL) was added
to a solution of (2-methylphenyl)magnesium bromide [prepared fromꢀ
2-bromotoluene (400 mg, 2.3 mmol) and magnesium (112 mg, 4.6 mg-ꢀ
atom)] in refluxing THF (3 mL) was added. After the reactionꢀ
mixture had been refluxed for 90 min, it was quenched with
10% aqueous ammonium chloride and extracted with methylene
dichloride; the extract was dried (Na2SO4) and concentrated under
reduced pressure. The residue was subjected to silica-gel (Wako,ꢀ
C-300; 100 g) column chromatography using as eluent hexane to give
6 (12 mg, 14%) and 5d (44 mg, 42%), respectively.
Substrate
dCH2
dMe
dArH
5a
2-Me
3-Me
4-Me
2-Me
3-Me
4-Me
2.08
2.11
2.10
2.29
2.31
2.31
1.94
2.16
2.19
1.95
2.13
2.16
6.39, 6.87b
6.42, 6.87b
6.51
5b
5c
5d
5e
5f
6.23, 6.84b
6.32, 6.94b
6.62
aDetermined in CDCl3 using SiMe4 as a reference.
bThe midpoint value of multiplets
8-Methoxy-16-methyl-5,13-di-tert-buyl[2.2]metacyclophane(6):Prismsꢀ
(hexane); m.p. 215–216°C (lit.17 215–216°C).
5,13-Di-tert-butyl-8-(2-methylbenzyl)-16-methoxy[2.2]metacyclo-
phane (5d): Prisms (from hexane); m.p. 136°C; nmax(KBr)/cm-1 2960,
2864, 1601, 1478, 1461, 1361, 1242, 1027 and 742; dH (CDCl3) 1.32
(9H, s, tBu), 1.34 (9H, s, tBu), 1.95 (3H, s, Me), 2.29 (2H, s, CH2),
2.64–2.82 (8H, m, CH2), 2.89 (3H, s, OMe), 6.21–6.24 (1H, m, ArH),
6.80–6.90 (3H, m, ArH), 7.06 (2H, s, ArH) and 7.17 (2H, s, ArH);ꢀ
m/z 454 (M+) (Found: C, 87.18; H, 9.93. C33H42O (454.7) requires C,
87.17; H, 9.31%).
thisꢀdistance.ꢀInterestingly,ꢀtheꢀchemicalꢀshiftsꢀofꢀtheꢀmethylꢀ
protonsꢀ andꢀ orthoꢀ aromaticꢀ protonsꢀ benzylꢀ groupꢀ inꢀ 5a–fꢀ
shifted upper field in order of 2-methyl-, 3-methyl- andꢀ
4-methylbenzyl group. From these findings, it is concluded
that 8-(tolylmethyl)[2.2]MCPs 5ꢀ haveꢀ theꢀ conformersꢀ Bꢀ
andꢀ C and that 8-(2-methylbenzyl) analogues 5aꢀ andꢀ 5dꢀ
mightꢀ existꢀ inꢀ conformerꢀ Bꢀ becauseꢀ ofꢀ stericꢀ repulsionꢀ
between the 2-methyl group and the bridged ethylene bonds.
Accordingly, the 2-methyl protons of the benzene rings of 5aꢀ
andꢀ5dꢀmightꢀbeꢀslightlyꢀaffectedꢀbyꢀtheꢀringꢀcurrentꢀofꢀtheꢀ
aromaticꢀringsꢀonꢀtheꢀsameꢀsideꢀratherꢀthanꢀthatꢀofꢀtheꢀoppositeꢀ
aromaticꢀrings.
Reactionꢀofꢀ3ꢀwithꢀvariousꢀGrignardꢀreagentsꢀwasꢀcarriedꢀoutꢀusingꢀ
theꢀsameꢀprocedureꢀasꢀdescribedꢀaboveꢀandꢀdetailsꢀofꢀtheꢀproductsꢀ
and yields are compiled in Table 1.
5,13-Di-tert-butyl-8-(2-methylbenzyl)[2.2]metacyclophane
(5a):
Prisms (from hexane); m.p. 136–137°C; nmax(KBr)/cm-1 2959, 2864,
1502, 1460, 1358, 1178 and 870; dH (CDCl3) 1.34 (9H, s, tBu), 1.38
(9H, s, tBu), 1.94 (3H, s, Me), 2.08 (2H, s, CH2), 2.20–3.05 (8H, m,
CH2), 3.68 (1H, s, ArH), 6.38–6.40 (1H, m, ArH), 6.80–6.95 (3H, m,
ArH), 7.09 (2H, s, ArH) and 7.18 (2H, s, ArH); m/z 424 (M+) (Found:
C, 90.66; H, 9.51. C32H40 (424.68) requires C, 90.51; H, 9.49%).
5,13-Di-tert-butyl-8-(3-methylbenzyl)[2.2]metacyclophane (5b):
Prisms (from hexane); m.p. 136–138°C; nmax(KBr)/cm-1 2960, 2860,
1502, 1358, 1380 and 840; dH (CDCl3) 1.36 (18H, s, tBu), 2.11 (2H,
s,ꢀCH2), 2.16 (3H, s, Me), 2.69–3.00 (8H, m, CH2), 3.70 (1H, s, ArH),
6.41–6.43 (1H, m, ArH), 6.80–6.95 (3H, m, ArH), 7.07 (2H, s, ArH)
and 7.18 (2H, s, ArH); m/z 424 (M + ) (Found: C, 90.73; H, 9.41.
C32H40 (424.68) requires C, 90.51; H, 9.49%).
Conclusions
We have developed a convenient preparation of 8-(tolyl-
methyl)[2.2]MCPs and 8,8'-(ethane-1,2-diyl)bis-(16-methoxyꢀ
[2.2]MCP) using a cross-coupling reaction of 8-bromomethylꢀ
[2.2]MCPs with tolylmagnesium bromides. The rotation
barrier around the 8-(2-methylbenzyl)[2.2]MCPs 5aꢀ andꢀ 5dꢀ
areꢀstillꢀquiteꢀlowꢀinꢀspiteꢀofꢀtheꢀintroductionꢀofꢀmethylꢀgroupꢀ
atꢀtheꢀortho position of the 8-benzyl group. Interestingly, the
2-methyl protons of the benzene rings of 5aꢀ andꢀ 5dꢀ mightꢀ
beꢀslightlyꢀaffectedꢀbyꢀtheꢀringꢀcurrentꢀofꢀtheꢀaromaticꢀringsꢀ
onꢀ theꢀ sameꢀ sideꢀ ratherꢀ thanꢀ thatꢀ ofꢀ theꢀ oppositeꢀ aromaticꢀ
rings.ꢀ Furtherꢀ studiesꢀ onꢀ theꢀ chemicalꢀ propertiesꢀ ofꢀ theꢀ
8-(tolylmethyl)[2.2]MCPs 5ꢀareꢀnowꢀinꢀprogress.
5,13-Di-tert-butyl-8-(4-methylbenzyl)[2.2]metacyclophane
(5c):
Prisms (from hexane); m.p. 140–141°C; nmax(KBr)/cm-1 2961, 2860,
1504, 1450, 1360, 1180 and 860; dH (CDCl3) 1.35 (18H, s, tBu), 2.10
(2H, s, CH2), 2.19 (3H, s, Me), 2.64–3.05 (8H, m, CH2), 3.70 (1H, s,
ArH), 6.51 (2H, d, Jꢀ=ꢀ7.8ꢀHz,ꢀArH), 6.87 (2H, d, Jꢀ=ꢀ7.8ꢀHz,ꢀArH), 7.06
(2H, s, ArH) and 7.18 (2H, s, ArH); m/z 424 (M+) (Found: C, 90.67; H,
9.45.ꢀC32H40 (424.68) requires C, 90.51; H, 9.49%).
5,13-Di-tert-butyl-8-(3-methylbenzyl)-16-methoxy[2.2]metacyclo-
phane (5e): Prisms (from hexane); m.p. 145–147°C; nmax(KBr)/cm-1ꢀ
2956, 2860, 1478, 1459, 1360, 1276, 1027, 1185, 885, 796 and 479;
dH (CDCl3) 1.31 (9H, s, tBu), 1.36 (9H, s, tBu), 2.13 (3H, s, Me),
2.31 (2H, s, CH2), 2.65–2.84 (8H, m, CH2), 2.89 (3H, s, OMe), 6.31–
6.33 (1H, m, ArH), 6.85–6.98 (3H, m, ArH), 7.04 (2H, s, ArH) and
7.16 (2H, s, ArH); m/z 454 (M+) (Found: C, 87.07; H, 9.83. C33H42Oꢀ
(454.7) requires C, 87.17; H, 9.31%).
5,13-Di-tert-butyl-8-(4-methylbenzyl)-16-methoxy[2.2]metacyclo-
phane (5f): Prisms (from hexane); m.p. 144–145°C; nmax(KBr)/cm-1ꢀ
2960, 2864, 1597, 1483, 1455, 1290 and 980; dH (CDCl3) 1.31 (9H, s,
tBu), 1.36 (9H, s, tBu), 2.16 (3H, s, Me), 2.31 (2H, s, CH2), 2.64–2.88
(8H, m, CH2), 2.89 (3H, s, OMe), 6.62 (2H, d, Jꢀ=ꢀ7.8ꢀHz,ꢀArH), 6.83
(2H, d, Jꢀ=ꢀ7.8ꢀHz,ꢀArH), 7.04 (2H, s, ArH) and 7.16 (2H, s, ArH);
m/z 454 (M+) (Found: C, 87.26; H, 9.81. C33H42O (454.7) requires C,
87.17; H, 9.31%).
Experiment
Allꢀ meltingꢀ pointsꢀ areꢀ uncorrected.ꢀ 1Hꢀ NMRꢀ spectraꢀ wereꢀ recordedꢀ
at 300 MHz on a Nippon Denshi JEOL FT-300 NMR spectrometer
inꢀdeuteriochloroformꢀwithꢀMe4Siꢀasꢀanꢀinternalꢀreference.ꢀIRꢀspectraꢀ
were measured as KBr pellets on a Nippon Denshi JIR-AQ2OM
spectrometer. Mass spectra were obtained on a Nippon Denshiꢀ
JMS-HX110A Ultrahigh Performance Mass Spectrometer at 75 eV
using a direct-inlet system. Elemental analyses were performed by
Yanaco MT-5.
Materials
Preparations of 5,13-di-tert-butyl-8-bromomethyl[2.2]metacyclophaneꢀ
3aand5,13-di-tert-butyl-8-bromomethyl-16-methoxy[2.2]metacyclo-
phaneꢀ3b17,18ꢀwereꢀpreviouslyꢀdescribed.

JOURNAL OF CHEMICAL RESEARCH 2009 573
6
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8,8'-(Ethane-1,2-diyl)bis(5,13-di-tert-butyl-16-methoxy[2.2]
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n
max(KBr)/cm-1 2954, 2864, 1478, 1460, 1360, 1291, 1278, 1207,
7
8
1020 and 864; dH (CDCl3) 0.34 (4H, s, CH2), 0.92 (18H, s, tBu), 1.27
(18H, s, tBu), 2.46–2.84 (16H, m, CH2), 2.77 (6H, s, OMe), 6.80 (4H,
s, ArH) and 6.87 (4H, s, ArH); m/z 726 (M+) (Found: C, 86.23; H,
9.85. C52H70O2 (727.14) requires C, 85.90; H, 9.70%).
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Received 5 May 2009; accepted 8 July 2009
Paper 09/0567 doi: 10.3184/030823409X12508764525015
Published online: 8 September 2009
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