Medium-Sized Cyclophanes. 43. First Evidence for anti-syn-Ring Inversion under the Nitration of 5,13-Di-tert-butyl-8,16-dimethoxy[2.2]metacyclophane

Article abstract of DOI:10.1021/jo970192p

Nitration of 5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP (metacyclophane = MCP) (1) with various nitrating reagents led to ipso-nitration at the tert-butyl group to give 5-tert-butyl-8,16-dimethoxy-13-nitro[2.2]MCP (2), as well as the corresponding 8,16-epo

Full text of DOI:10.1021/jo970192p

7560
J . Org. Chem. 1997, 62, 7560-7564
Med iu m -Sized Cyclop h a n es. 43.1 F ir st Evid en ce for
a n ti-syn -Rin g In ver sion u n d er th e Nitr a tion of
5,13-Di-ter t-bu tyl-8,16-d im eth oxy[2.2]m eta cyclop h a n e
Takehiko Yamato,* Hideo Kamimura and Tsuyoshi Furukawa
Department of Applied Chemistry, Faculty of Science and Engineering, Saga University,
Honjo-machi 1, Saga-shi, Saga 840, J apan
Received February 3, 1997 (Revised Manuscript Received J uly 22, 1997X
)
Nitration of 5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP (metacyclophane ) MCP) (1) with various
nitrating reagents led to ipso-nitration at the tert-butyl group to give 5-tert-butyl-8,16-dimethoxy-
13-nitro[2.2]MCP (2), as well as the corresponding 8,16-epoxy[2.2]MCP (4) arising from intramo-
lecular condensation reaction via anti-syn-ring inversion of the nitration intermediate. This novel
intramolecular condensation reaction to afford 8,16-epoxy[2.2]MCP (4) was also observed in the
presence of Nafion-H under chlorobenzene reflux. The mechanism of the ipso-nitration as well as
the present novel intramolecular condensation reaction is also discussed.
In tr od u ction
sannular reaction products5 under the electrophilic,8
radical,9 and photolytic10 reaction conditions together
with other transformation products derived from tet-
rahydropyrene. These have usually been rationalized as
involving initial dehydrogenation to 4,5,9,10-tetrahydro-
pyrene. Allinger and his co-workers have reported11 that
the nitration of 8,16-unsubstituted [2.2]MCP with fuming
HNO3 affords 2-nitro-4,5,9,10-tetrahydropyrene via the
addition-elimination mechanism.
For many years various research groups have been
attracted by the chemistry and spectral properties of the
[2.2]metacyclophane ([2.2]MCP) skeleton.2,3 Its confor-
mation, which was elucidated by X-ray measurements,4
is apparently frozen into a chair-like nonplanar form. The
two halves of the molecule form a stepped system. The
benzene rings are not planar but have a boat conforma-
tion, with the result that the molecule 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) dis-
tance is 2.689 Å. The increased strain in the molecule
8,16-dimethyl[2.2]MCP as compared with that in the
parent hydrocarbon 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)-C(16) distances are increased from
2.689 Å in [2.2]MCP to 2.819 Å in 8,16-dimethyl-
[2.2]MCP.5 On the basis of the temperature-indepen-
dence of the methylene resonances of [2.2]MCP between
-80 and 190 °C,6 the molecule is rigid in solution; in
agreement with molecular model considerations, ring
inversion can be ruled out. The [2.2]MCPs described so
far, according to the spectroscopic findings, have the anti
conformation with staggered benzene rings, but the
existence of a syn form for a [2.2]MCP has also been
detected.7
Subsequently, we reported that12 nitration of 8,16-
dimethyl[2.2]MCP with fuming HNO3 afforded only 5-ni-
tro-8,16-dimethyl[2.2]MCP but not 5,13-dinitro-8,16-
dimethyl[2.2]MCP and that similar reaction of 5,13-di-
tert-butyl-8,16-dimethyl[2.2]MCP gave a different type
of product, 2,7-di-tert-butyl-4,9-dinitro-trans-10b,10c-dim-
ethyl-10b,10c-dihydropyrene.
Although the replacement of a tert-butyl group by a
nitro group in electrophilic aromatic substitutions has
frequently been described in the literature,13,14 generally
the yields are modest because of the accompanying side
reactions.15 Only in activated compounds are better
yields obtained. More recently, Reinhoudt et al. re-
ported16 the high-yield 4-fold ipso-nitration of p-tert-
butylcalix[4]arenes.
However, the mechanistic aspects for ipso-attack in
electrophilic aromatic substitutions having more than
(8) (a) Allinger, N. L.; Gordon, B. J .; Hu, H.-E.; Ford, R. A. J . Org.
Chem. 1967, 32, 2272. (b) Sato, T.; Yamada, E.; Okamura, Y.; Amada,
T.; Hata, K. Bull. Chem. Soc. J pn. 1965, 38, 1049. (c) Fujimoto, M.;
Sato, T.; Hata, K. Bull. Chem. Soc. J pn. 1967, 40, 600. (d) Sato, T.;
Wakabayashi, M.; Okamura, Y.; Amada, T.; Hata, K. Bull. Chem. Soc.
J pn. 1967, 40, 2363.
(9) Sato, T.; Nishiyama, K. J . Chem. Soc., Chem. Comm., 1973, 220.
(10) (a) Sato, T.; Nishiyama, K.; Shimada, S.; Hata, K. Bull. Chem.
Soc. J pn. 1971, 44, 2858. (b) Hayashi, S.; Sato, T. Bull. Chem. Soc.
J pn. 1972, 45, 2360.
Due to electronic interaction between the two benzene
rings, the proximity of the 8,16-positions, and the con-
siderable strain energy, [2.2]MCP is prone to give tran-
(11) (a) Alliger, N. L.; DaRooge, M. A.; Hermann, R. B. J . Am. Chem.
Soc. 1961, 83, 1974. (b) Griffin, R. W.; Coburn, R. A. J . Org. Chem.
1967, 32, 3956.
(12) Tashiro, M.; Mataka, S.; Takezaki, T.; Takeshita, M.;Arimura,
T.; Tsuge, A.; Yamato, T. J . Org. Chem. 1989, 54, 451.
(13) Moodie, R. B.; Schofield, K. Acc. Chem. Res. 1976, 9, 297.
(14) (a) Fischer, A.; Ro¨derer, R. Can. J . Chem. 1976, 54, 3978. (b)
Fischer, A.; Teo, K. C. Can. J . Chem. 1978, 56, 258. (c) Fischer, A.;
Teo, K. C. Can. J . Chem. 1978, 56, 1758.
(15) (a) Suzuki, H. Synthesis 1977, 217. (b) Myhre, P. C.; Beug, M.
J . Am. Chem. Soc. 1966, 88, 1568. (c) Myhre, P. C.; Beug, M.; J ames,
L. L. J . Am. Chem. Soc. 1968, 90, 2105. (d) Myhre, P. C.; Beug, M.;
Brown, K. S.; O¨ stman, B. J . Am. Chem. Soc. 1971, 93, 3452.
(16) Verboom, W.; Durie, A.; Egberink, R. J .; Asfari M. Z.; Reinhoudt,
D. N. J . Org. Chem. 1992, 57, 1313.
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) Medium-Sized Cyclophanes. 42: Yamato, T.; Fujita, K.; Ide, S.;
Nagano, Y. J . Chem. Res. (S) 1997, 190, (M) 1301.
(2) Griffin, J r. R. W. Chem. Rev. 1963, 63, 45.
(3) Cram, D. J . Acc. Chem. Res. 1971, 4, 204.
(4) Brown, C. J . J . Chem. Soc. 1953, 3278.
(5) (a) Smith, B. H. Bridged Aromatic Compounds; Academic Press
Inc.: New York, NY, 1964. (b) Cyclophanes (Eds.: Keehn, P. M.,
Rosenfield, S. M., Eds.; Academic Press: New York, 1983.
(6) Sato, T.; Akabori, S.; Kainosho, M.; Hata, K. Bull. Chem. Soc.
J pn. 1966, 39, 856.
(7) (a) Mitchell, R. H.; Vinod, T. K.; Bushnell, G. W. J . Am. Chem.
Soc. 1985, 107, 3340. (b) Fujise, Y.; Nakasato, Y.; Itoˆ, S. Tetrahedron
Lett. 1986, 27, 2907.
S0022-3263(97)00192-8 CCC: $14.00 © 1997 American Chemical Society

Medium-Sized Cyclophanes
Ta ble 1. Nitr a tion of
J . Org. Chem., Vol. 62, No. 22, 1997 7561
Sch em e 1
5,13-Di-ter t-bu tyl-8,16-d im eth oxy[2.2]MCP (1) a t Room
Tem p er a tu r ea
1/reagent reaction
run
reagent
[mol/mol] time [h] products [% yield]b
1
2
3
4
Cu(NO3)2
Cu(NO3)2
63% NHO3
Fuming HNO3
2.2
4.2
excess
excess
24
24
1
2 (50), 3 (25), 4 (12)
2 (40), 3 (41), 4 (5)
2 (22), 3 (57), 4 (5)
2 (74), 3 (9) 4 (0)
1
a
The detailed reaction conditions are shown in the Experimen-
b
tal Section. Yields determined by GLC analysis.
two aromatic rings are still not clear in spite of the
possibility of through-space electronic interactions among
the other benzene rings.17 Thus there is substantial
interest in investigating the nitration of the internally
methoxy-substituted [2.2]MCPs, which might afford single
mono- and dinitrated products because conformational
ring rotation of the meta-bridged benzene ring is impos-
sible at room temperature, in contrast to the case of
tetramethoxy-p-tert-butylcalix[4]arene. We report here
on the through-space electronic interaction among the
two benzene rings and evidence for anti-syn-ring inver-
sion under the nitration of 5,13-di-tert-butyl-8,16-di-
methoxy[2.2]MCP (1).
Sch em e 2
Resu lts a n d Discu ssion
Nitration of 5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP
(1)18 with 2.2 equiv. of copper(II) nitrate in acetic
anhydride led to ipso-nitration at just one tert-butyl group
to give 2 in 50% yield along with 9-endo-nitro[2.2]MCP
(3) and 8,16-epoxy[2.2]MCP (4) in 25 and 12% yields,
respectively (eq 1, Table 1). Increasing the amount of
has been explained, in addition to steric reasons, by
activation of the concerned tert-butyl group by the
electron-releasing amino group (Scheme 1).19
Attempted further nitration of 2 with copper(II) nitrate
failed. No formation of dinitro compound 3 or 6 was
observed; starting compound 2 was recovered quantita-
tively. These results demonstrate that 2 is not an
intermediate leading to 3. Rather, competition between
ipso-nitration at the tert-butyl group and substitution on
the ethylene bridge could occur in the nitration of 1.
Similarly, 4-tert-butyl-2,6-dimethylanisole (7) with ex-
cess copper(II) nitrate in an acetic anhydride solution or
with 70% HNO3 in acetic acid at room temperature only
gave a quantitative recovery of starting compound.
Raising the reaction temperature to 50 °C afforded the
product 8 from ipso-nitration at the tert-butyl group in
40% yield, along with recovered 7. When nitration of 7
with fuming HNO3 in an acetic acid solution was carried
out at room temperature for 30 min, 2,6-dimethyl-4-
nitroanisole (8) was obtained in quantitative yield
(Scheme 2).
In contrast with 7, nitration of [2.2]MCP 1 with excess
copper(II) nitrate in an acetic anhydride solution or with
70% HNO3 led to ipso-nitration only at one of the tert-
butyl groups to give 2 and 3 in moderate yields. We
previously reported12 that nitration of 5,13-di-tert-butyl-
8,16-dimethyl[2.2]MCP with copper(II) nitrate afforded
only 2,7-di-tert-butyl-4,9-dinitro-trans-10b,10c-dimeth-
yldihydropyrene. No products arising from ipso-nitration
were observed. This result seems to indicate that the
methoxy group in 1 plays an important role in the present
ipso-nitration reaction. The ipso-nitration of 1 is at-
tributed to the highly activated character of the aryl ring
and the increased stabilization arising from dienone
character made possible by the methoxy substituent.
copper(II) nitrate ratio to 4.2 equiv increased the yield
of 1-endo-nitro[2.2]MCP (3).
Similar treatment of 5-tert-butyl-8,16-dimethoxy[2.2]-
MCP (5) with 2.2 equiv of copper(II) nitrate in acetic
anhydride under the same conditions afforded 2 in 70%
yield and recovered 5.
Apparently the ipso-nitration of 1 at the tert-butyl
group is much faster than the normal nitration of 5 at
the 13 position. This might be explained by the higher
π-density on the benzene rings of 1 (cf. 5) due to the two
electron-releasing tert-butyl groups. This is precedented
in the ipso-nitration of 2,4,6-tri-tert-butylaniline, which
(17) Yamato, T.; Kamimura, H.; Noda, K.; Tashiro, M. J . Chem. Res.
(S) 1994, 424, (M) 2401.
(18) Tashiro, M.; Yamato, T. J . Org. Chem. 1981, 46, 1543.
(19) Watari, W. Bull. Chem. Soc. J pn. 1964, 37, 204.

7562 J . Org. Chem., Vol. 62, No. 22, 1997
Yamato et al.
Ta ble 2. Na fion -H ca ta lyzed in tr a m olecu la r
Ch a r t 1
con d en sa tion r ea ction of
5,13-d i-ter t-bu tyl-8,16-d im eth oxy[2.2]MCP 1a
product yields (%)
run
solvent
benzene
toluene
chlorobenzene
4
5
10
recovd 1
1
2
3
3
9
34
12
23
15
4
9
4
70
10
14
a
The detailed reaction conditions are shown in the Experimen-
b
tal Section. Yields determined by GLC analysis.
Ch a r t 2
increased the yields of 2 and 3. Thus, the positional
selectivity for the nitration of 1 was strongly affected by
the reactivity of the nitration reagents (as reported in
normal aromatic systems24). However, the formation of
the 2-fold ipso-nitration product, 8,16-dimethyl-5,13-
dinitro[2.2]MCP (6) was not observed under these reac-
tion conditions. This result strongly suggests that in the
first step ipso-nitration at the tert-butyl group competes
with the substitution reaction at the benzylic position.
Nitration with mixed acid, however, led only to an
intractable mixture. No di-ipso-nitration was detected.
Nitration of 5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP
(1) with various nitrating agents led to an intramolecular
condensation reaction at the intraannular 8,16-positions
to give 5,13-di-tert-butyl-8,16-epoxy[2.2]MCP (4) in 5-12%
yield along with ipso-nitration products 2 and 3. The
present novel intramolecular condensation reaction of
two methoxy groups might be similar to the protic-acid
catalyzed condensation of 2,2′-dihydroxybiphenyls to
afford dibenzofurans at high temperatures (above 200
°C).25 Thus, attempted condensation of 1 to afford 4 in
the presence of protic acids, such as sulfuric acid,
trifluoroacetic acid, trifluoromethanesulfonic acid, and
Lewis acids, such as titanium tetrachloride and alumi-
num chloride-nitromethane, under various conditions
failed. No formation of the desired 4 was observed under
the conditions used.
Quite recently, Cacace et al. reported20 the intramolecular
proton shift, namely, ring-to-ring proton migration in (â-
phenylethyl)arenium ions from the higher cationic alky-
lation rate of 1,2-diphenylethane than that of toluene in
the gas phase. Thus in the present system, σ-complex
intermediate A would be stabilized by a through-space
electronic interaction through intraannular 8,16-positions
with the opposing benzene ring, therefore accelerating
the reaction (like the formylation of tert-butyl[n.2]-
MCPs21). However, only one tert-butyl group is ipso-
nitrated because of deactivation of the second aromatic
ring by the nitro group introduced (structure B)
(Chart 1).
The structures of 2 and 3 were assigned on the basis
of elemental analyses and spectral data. Thus, we
1
previously assigned22 the H-NMR signals of 1-exo-1,5,-
13-trichloro-8,16-dimethyl[2.2]MCP (9). We have as-
signed the 1H-NMR signals of 3 in a similar fashion
(Chart 2). For example, the 1H-NMR spectrum of 3
shows two internal methoxy resonances as singlets at δ
2.88 and 2.96, a bridge methine signal as a doublet at δ
5.56 (J ) 1.95 Hz), and two aromatic protons as two sets
of doublets at δ 7.11, 7.42 (J ) 2.44 Hz) and 8.05, 8.14
(J ) 2.45 Hz); the latter protons are strongly deshielded
by the nitro group. We observed one methoxy signal not
to be deshielded by the endo-nitro group on the ethylene
bridge, resulting in a downfield shift (δ 0.08) considerably
less than the δ 0.42 shift observed in 1-exo-1,5,13-
trichloro-8,16-dimethyl[2.2]MCP (9) (Chart 2). These
data strongly support the endo-arrangement for the nitro
Recently, we have found Nafion-H, a perfluorinated
resin sulfonic acid,26 catalyzed condensation of 2,2′-
dihydroxybiphenyl to afford dibenzofurans under rela-
tively mild conditions (Table 2).27
Condensation reaction of 1 in the presence of Nafion-H
as a catalyst was carried out in boiling benzene or toluene
to afford the desired 8,16-epoxy[2.2]MCP (4) in 3-9%
yield along with the trans-tert-butylated products 5 and
10 (eq 2). Benzene or toluene could be an acceptor for
1
group. An aromatic proton in the H NMR spectrum of
3 at δ 7.42 was observed which is similar to one in the
endo-Br analog (δ 7.69).23 Thus 3 is assigned the
structure 9-endo-5-tert-butyl-8,16-dimethoxy-9,13-dinitro-
[2.2]MCP.
The ratio of (2 + 3)/4 varied with the reactivity of the
nitrating reagents. Increasing the reactivity of the
nitration reagents (from 61% HNO3 to fuming HNO3)
(24) Olah, G. A. Acc. Chem. Res. 1971, 4, 240.
(25) (a) Kruber, O. Ber. 1932, 65, 1413. (b) Gilman, H.; Swiss, J .;
Cheney, L. C. J . Am. Chem. Soc. 1940, 62, 1963. (c) Gray, A. P.; Dipinto,
V. M.; Solomon, I. J . J . Org. Chem. 1976, 41, 2428.
(26) (a) Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis 1986,
513. (b) Yamato, T. J . Synth. Org. Chem. J pn. 1995, 53, 487 and
references therein.
(27) (a) Yamato, T.; Hideshima, C.; Prakash, G. K. S.; Olah, G. A.
J . Org. Chem. 1991, 56, 3192. (b) Yamato, T.; Hideshima, C.; Suehiro,
K.; Tashiro, M.; Prakash, G. K. S.; Olah, G. A. J . Org. Chem. 1991,
56, 6248. (c) Yamato, T.; Hideshima, C.; Tashiro, M.; Prakash, G. K.
S.; Olah, G. A. Catalysis Lett. 1990, 6, 341. (d) Yamato, T.; Hideshima,
C.; Nagano, Y.; Tashiro, M. J . Chem. Res.(S) 1996, 266 (M), 1457.
(20) Cacace, F.; Crestoni, M. E.; Fornarini, S.; Kuck, D. J . Am. Chem.
Soc. 1993, 115, 1024.
(21) (a) Yamato, T.; Matsumoto, J .; Kabu, S.; Takezaki, Y.; Tashiro,
M. J . Chem. Res.(S) 1993, 44. (b) Yamato, T.; Maeda, K.; Kamimura,
H.; Noda, K.; Tashiro, M. J . Chem. Res.(S) 1995, 310 (M), 1865.
(22) (a) Tashiro, M.; Yamato, T.; Kobayashi, K. J . Org. Chem. 1984,
49, 3380. (b) Yamato, T.; Matsumoto, J .; Ando, T.; Tokuhisa, K.;
Tashiro, M. J . Chem. Res. (S) 1991, 276.
(23) Yamato, T.; Matsumoto, J .; Ide, S.; Suehiro, K.; Kobayashi, K.;
Tashiro, M. Chem. Ber. 1993, 126, 447.

Medium-Sized Cyclophanes
J . Org. Chem., Vol. 62, No. 22, 1997 7563
Sch em e 3
the tert-butyl group under the reaction used. In contrast,
the reaction carried out in boiling chlorobenzene for 12
h afforded 8,16-epoxy[2.2]MCP (4) in 34% yield.
The synthesis and stereochemical aspects of confor-
mationally mobile [m.n]MCPs have been of interest for
the past decade, particular attention being paid to [2.2]-
MCPs, which possess an anti-stepped conformation.
Although the parent [2.2]MCP was first reported as early
as 1899 by Pellegrin,28 the synthesis of syn-[2.2]MCP was
not realized until 85 year later. Mitchell et al.7a have
successfully prepared syn-[2.2]MCP at low temperature
by using (arene)chromiumcarbonyl complexation to con-
trol the stereochemistry. However, syn-[2.2]MCP isomer-
izes readily to the anti-isomer above 0 °C. More recently,
Itoˆ et al.7b have isolated and characterized syn-[2.2]MCP
without complexation. However, a ring inversion of anti-
[2.2]MCPs to the corresponding syn-[2.2]MCPs has not
yet been published. The meta-bridged benzene ring has
not been shown to undergo conformational flipping above
200 °C (eq 3). A great part of this high-energy barrier is
Sch em e 4
believed to arise from steric destabilization of the transi-
tion 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.
On the other hand, we have reported29 that the novel
intramolecular dehydration of hydroxyl groups in the syn-
intraannular positions of syn-6,14-di-tert-butyl-9,17-
dihydroxy[3.2]MCP (11) occurred easily under AlCl3-
MeNO2-catalyzed trans-tert-butylation reaction conditions
to afford 9,17-epoxy[3.2]MCP (12) in 76% yield, attribut-
able to the release of strain in 11 leading to the more
strainless 9,17-epoxy[3.2]MCP (12) containing an ether
linkage.
The structure of 4 was assigned on the basis of
elemental analysis and spectral data. The 1H NMR
spectrum of 4 in CDCl3 shows the disappearance of two
internal methoxy protons and tert-butyl protons as a
singlet at δ 1.21, a bridged methylene protons as a
multiplet at δ 2.64-3.66, and aromatic protons as a
singlet at δ 6.85.
This result strongly suggests that the formation of 8,-
16-epoxy[2.2]MCP (4) might have arisen from syn-8,16-
dimethoxy[2.2]MCP.
The AlCl3-MeNO2-catalyzed trans-tert-butylation of 4
was carried out in benzene at 50 °C to afford 8-epoxy-
[2.2]MCP (13) in 75% yield (Scheme 4). The physical
properties and spectral data were identical with those
of the sample which was already prepared by Boekelheide
et al.30 Attempted nitration of 4 with copper(II) nitrate
under the conditions mentioned above resulted only in
the recovery of starting compound; with fuming HNO3
the intractable mixture only was afforded. No formation
of ipso-nitrated product was observed. In contrast,
acetylation of 4 with acetyl chloride carried out in the
presence of AlCl3-MeNO2 afforded the desired ipso-
acetylated product, 5,13-diacetyl-8,16-epoxy[2.2]MCP (15),
in 72% yield. These results strongly support the 8,16-
epoxy[2.2]MCP structure of 4.
Although the detailed mechanism of formation of 8,-
16-epoxy[2.2]MCP (4) is not clear from the available
results, one might assume the reaction pathway shown
in Scheme 3.
Although it is well-recognized that the anti-syn-ring
inversion is inhibited, that of the intermediate C arising
from ipso-attack by nitro group at the ethylene bridge
might be possible. This phenomenon is strongly sup-
ported by the molecular models. Subsequently the in-
tramolecular nucleophilic aromatic substitution might
proceed to form the intermediate D. Elimination of
methanol would afford 8-epoxy[2.2]MCP 4 via the inter-
mediate E.
The present novel intraannular condensation reaction
is the first evidence for anti-syn-ring inversion under the
nitration of 5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP
(1).
We conclude that the ipso-nitration reactions of 1 lead
to the first-reported direct introduction of one nitro group.
The selective ipso-nitration of 1 is attributed to the highly
activated character of the aryl ring and the increased
(28) Pelligrin, M. Recl. Trav. Chim. Pays-Bas Belg. 1889, 18, 458.
(29) Yamato, T.; Matsumoto, J .; Tokuhisa, K.; Kajihara, M.; Suehiro,
K.; Tashiro, M. Chem. Ber. 1992, 125, 2443.
(30) Hess, B. A., J r.; Bailey, A. S.; Bartusek, B.; Boekelheide, V. J .
Am. Chem. Soc. 1969, 91, 1665.

7564 J . Org. Chem., Vol. 62, No. 22, 1997
Yamato et al.
Nitr a tion of 5-ter t-Bu tyl-8,16-d im eth oxy[2.2]MCP (5)
w ith Cu (NO3)2 in Acetic An h yd r id e. Copper(II) nitrate
(250 mg, 0.492 mmol) was added at 0 °C to a solution of 5
(149.0 mg, 0.461 mmol) in a mixture of CH2Cl2 (2.5 mL) and
acetic anhydride (50 mL). The mixture was stirred at room
temperture for 24 h, poured into ice-water, and extracted with
CH2Cl2. The extracts were washed with water and then 10%
sodium bicarbonate, dried over anhydrous sodium sulfate, and
concentrated in vacuo. Chromatography on silica gel (Wako,
C-300; 100 g) eluting with hexane and hexane-benzene (1:1)
and benzene afforded 5 (32 mg, 30%) and 2 (61 mg, 70%),
respectively.
stabilization of the σ-complex intermediate arising from
dienone character made possible by the methoxy sub-
stituent. And we have observed that the first σ-complex
intermediate, (â-phenylethyl)arenium ion, would be sta-
bilized by the through-space electronic interaction with
the other benzene ring in nitration reactions like the
electrophilic aromatic substitution of MCPs. The pres-
ently developed novel intramolecular condensation reac-
tion to afford 8,16-epoxy[2.2]MCP will open up new
mechanistic aspects for cyclophane chemistry. Further
studies on ipso-nitration are currently in progress in our
laboratory.
Nit r a t ion of 7 w it h F u m in g Nit r ic Acid . Typ ica l
P r oced u r e. Fuming HNO3 (0.83 mL) was added at 0 °C to a
solution of 4-tert-butyl-2,6-dimethylanisole (7) (55.6 mg, 0.289
mmol) in a mixture of CH2Cl2 (2.5 mL) and acetic acid (2.5
mL). The mixture was stirred at room temperture for 0.5 h,
poured into ice-water, and extracted with CH2Cl2. The
extracts were washed with water and then 10% sodium
bicarbonate, dried over anhydrous sodium sulfate, and con-
centrated in vacuo to give 2,6-dimethyl-4-nitroanisole (8) (53.3
Exp er im en ta l P r oced u r e
All melting points are uncorrected. 1H NMR spectra were
recorded at 270 MHz in CDCl3. Mass spectra were obtained
at 75 eV using a direct-inlet system.
Ma ter ia ls. The preparations of anti-5,13-di-tert-butyl-8,-
16-dimethoxy[2.2]MCP (1) and anti-5-tert-butyl-8,16-dimethoxy-
[2.2]MCP (5) were previously described.18
1
mg, 97%) as pale yellow prisms (hexane): mp 91-92 °C; H
Nitr ation of 5,13-Di-ter t-bu tyl-8,16-dim eth oxy[2.2]MCP
(1) w ith Cu (NO3)2 in Acetic An h yd r id e. Copper(II) nitrate
trihydrate (150 mg, 0.62 mmol) was added at 0 °C to a solution
of 5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP (1) (110.6 mg,
0.289 mmol) in a mixture of CH2Cl2 (2.5 mL) and acetic
anhydride (50 mL). The mixture was stirred at room temper-
ture for 24 h, poured into ice-water, and extracted with CH2-
Cl2. The extracts were washed with water and then 10%
sodium bicarbonate, dried over anhydrous sodium sulfate, and
concentrated in vacuo. Chromatography on silica gel (Wako,
C-300; 100 g) eluting with hexane, hexane-benzene (1:1), and
benzene afforded 4 (11 mg, 12%), 2 (53 mg, 50%), and 3 (30
mg, 25%), respectively.
5-ter t-Bu t yl-8,16-d im et h oxy-13-n it r o[2.2]m et a cyclo-
p h a n e (2): pale yellow prisms (hexane); mp 241-243 °C; 1H
NMR (CDCl3) δ 1.32 (9 H, s), 2.61-2.89 (8 H, m), 2.93 (3 H,
s), 3.02 (3 H, s), 7.06 (2 H, s), 7.97 (2 H, s); MS (m/e) 369 (M+).
Anal. Calcd for C22H27O4N: C, 71.52; H, 7.37; N, 3.79.
Found: C, 71.52; H, 7.37; N, 3.79.
NMR (CDCl3) δ 2.36 (6 H, s), 3.79 (3 H, s), 7.91 (2 H, s).
Tr a n s-ter t-bu tyla tion of 4. To a solution of 4 (30.0 mg,
0.09 mmol) in benzene (3 mL) was added a solution of AlCl3
(200 mg, 1.50 mmol) in nitromethane (1.0 mL) at 0 °C. The
mixture was stirred at room temperature for 24 h, poured into
ice-water, and extracted with CH2Cl2. The extracts were
washed with water and then 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 8,16-epoxy[2.2]metacyclophane (13) (15
mg, 75%) as colorless prisms (methanol): mp 91-94 °C (lit.30
1
mp 94-95 °C); H NMR (CDCl3) δ 2.52-2.69 (4 H, m), 3.52-
3.65 (4 H, m), 6.79 (6 H, s); MS (m/e) 222 (M+). Anal. Calcd
for C16H14O: C, 86.45; H, 6.35. Found: C, 86.39; H, 6.54.
ipso-Acetyla tion of 4. To a solution of 4 (40.0 mg, 0.12
mmol) and acetyl chloride (0.034 mL, 0.48 mmol) in CH2Cl2
(2 mL) was added a solution of AlCl3 (96.0 mg, 0.72 mmol) in
nitromethane (0.2 mL) at 0 °C. The mixture was stirred at
room temperature for 5 h, poured into ice-water, and extracted
with CH2Cl2. The extracts were washed with water and then
10% sodium bicarbonate, dried over anhydrous sodium sulfate,
and concentrated in vacuo. Chromatography on silica gel
(Wako, C-300; 100 g) eluting with benzene afforded 5,13-
diacetyl-8,16-epoxy[2.2]metacyclophane (15) (24 mg, 72%) as
colorless prisms (chloroform): mp 177-179 °C; IR (KBr) 1683
(CdO) cm-1; 1H NMR (CDCl3) δ 2.48 (6 H, s), 2.75-2.83 (4 H,
m), 3.69-3.78 (4 H, m), 7.79 (4 H, s); MS (m/e) 306 (M+). Anal.
Calcd for C20H18O3: C, 78.41; H, 5.92. Found: C, 78.39; H,
5.84.
9-en d o-5-ter t-Bu t yl-8,16-d im et h oxy-9,13-d in it r o[2.2]-
m eta cyclop h a n e (3): pale yellow prisms (hexane:benzene
1
5:1); mp 110-113 °C; H NMR (CDCl3) δ 1.31 (9 H, s), 2.42-
2.64 (2 H, m), 2.81-3.33 (3 H, m), 2.88 (3 H, s), 2.96 (3 H, s),
3.85 (1 H, d, J ) 1.95 Hz), 5.56 (1 H, d, J ) 1.95 Hz), 7.11 (1
H, d, J ) 2.44 Hz), 7.42 (1 H, d, J ) 2.44 Hz), 8.05 (1 H, d, J
) 2.45 Hz), 8.14 (1 H, d, J ) 2.45 Hz); MS (m/e) 414 (M+).
Anal. Calcd for C22H26O6N2: C, 63.75; H, 6.32; N, 6.76.
Found: C, 64.18; H, 6.53; N, 6.57.
5,13-Di-ter t-bu tyl-8,16-ep oxy[2.2]m eta cyclop h a n e (4):
colorless prisms (methanol); mp 207-209 °C; 1H NMR (CDCl3)
δ 1.21 (18 H, s), 2.64-3.66 (8 H, m), 6.85 (4 H, s); MS (m/e)
334 (M+). Anal. Calcd for C24H30O: C, 86.17; H, 9.04.
Found: C, 86.05; H, 8.89.
The formation of tert-butylbenzene (14) was confirmed by
GLC. GLC analyses were performed by a Shimadzu gas
chromatograph (GC-14A) with Silicone OV-1 (2 m), a pro-
grammed temperature rise of 12 °C/min, and nitrogen carrier
gas as (25 cm3/min).
Nitr a tion of 1 w ith 63% Nitr ic Acid . HNO3 (63%, 1.8
mL) was added at 0 °C to a solution of 1 (110.6 mg, 0.289
mmol) in a mixture of CH2Cl2 (2.5 mL) and acetic acid (4 mL).
The mixture was stirred at room temperture for 1 h, poured
into ice-water, and extracted with CH2Cl2. The extracts were
washed with water and then 10% sodium bicarbonate, dried
over anhydrous sodium sulfate, and concentrated in vacuo.
Chromatography on silica gel (Wako, C-300; 100 g) eluting
with hexane, hexane-benzene (1:1) and benzene afforded 4
(5 mg, 5%), 2 (26 mg, 22%), and 3 (61 mg, 57%), respectively.
Nitr a tion of 1 w ith F u m in g Nitr ic Acid . Fuming HNO3
(1.8 mL) was added at 0 °C to a solution of 1 (110.6 mg, 0.289
mmol) in a mixture of CH2Cl2 (2.5 mL) and acetic acid (4 mL).
The mixture was stirred at room temperture for 1 h, poured
into ice-water, and extracted with CH2Cl2. The extracts were
washed with water and then 10% sodium bicarbonate, dried
over anhydrous sodium sulfate, and concentrated in vacuo.
Chromatography on silica gel (Wako, C-300; 100 g) eluting
with hexane-benzene (1:1) and benzene afforded 2 (79 mg,
74%) and 3 (10 mg, 9%), respectively.
Na fion -H-Ca ta lyzed In tr a m olecu la r Con d en sa tion Re-
a ction of 1. Typ ica l P r oced u r e. To a solution of 1 (110.4
mg, 0.289 mmol) in chlorobenzene (4 mL) was added Nafion-H
(110 mg, 100 wt %) at room temperature. After stirring the
reaction mixture had been refluxed for 12 h, it was cooled to
room temperature. The solid resinsulfonic acid was then
filtered off and the filtrate analyzed by GLC.
The results are compiled in Table 2. The formation of 10
was confirmed by the comparison of the retention time in GLC
with that of an authentic sample.31
J O970192P
(31) Yamato, T.; Matsumoto, J .; Shinoda, N.; Ide,S.; Shigekuni, M.;
Tashiro, M. J . Chem. Res. (S) 1994, 178.