Synthesis and Structures of [2.n]Metacyclophan-1-enes and their Conversion to Highly Strained [2.n]Metacyclophane-1-ynes

Article abstract of DOI:10.1002/ejoc.202000548

The syntheses of syn-[2.n]metacyclophan-1-enes (n = 5, 6, 8) in good yields using the McMurry cyclization of 1,n-bis(3-formyl-4-methoxyphenyl)alkanes are reported. Conversion of syn-[2.6]- and [2.8]metacyclophan-1-enes to the corresponding highly strained syn-type [2.6]- and [2.8]metacyclophane-1-ynes was achieved by successive bromination and dehydrobromination reactions. An attempted trapping reaction of the putative corresponding [2.5]metacyclophane-1-yne by Diels–Alder reaction with 1,3-diphenylisobenzofuran failed due to its smaller ring size and strained structure. X-ray crystallographic analyses show that the triple bonds in syn-[2.6]- and [2.8]metacyclophane-1-ynes are distorted from linearity with bond angles of 156.7° and 161.4°, respectively. A DFT (Density Functional Theory) computational study was conducted to determine the stabilities of different conformations of the target compounds.

Full text of DOI:10.1002/ejoc.202000548

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis and Structures of [2.n]Metacyclophan-1-enes and their
Conversion to Highly Strained [2.n]Metacyclophane-1-ynes
Authors: Thamina Akther, Md. Monarul Islam, Zannatul Kowser,
Taisuke Matsumoto, Junji Tanaka, Shofiur Rahman, Abdullah
Alodhayb, Paris E. Georghiou, Carl Redshaw, and Takehiko
Yamato
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000548
Link to VoR: https://doi.org/10.1002/ejoc.202000548
01/2020

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
Synthesis and Structures of [2.n]Metacyclophan-1-enes and their
Conversion to Highly Strained [2.n]Metacyclophane-1-ynes
Thamina Akther,[a] Md. Monarul Islam,[a],[b] Zannatul Kowser,[a],[c] Taisuke Matsumoto,[d] Junji Tanaka,[d]
Shofiur Rahman,[e],[f] Abdullah Alodhayb,[f],[g] Paris E. Georghiou,[e] Carl Redshaw,[h] and Takehiko
Yamato*[a]
trifoliaphane.2 Meijere3a,b and Wong3c,d and their respective
Abstract: The syntheses of syn-[2.n]metacyclophan-1-enes (n = 5,
6, 8) in good yields using the McMurry cyclization of 1,n-bis(3-
formyl-4-methoxyphenyl)alkanes are reported. Conversion of syn-
[2.6]- and [2.8]metacyclophan-1-enes to the corresponding highly
strained syn-type [2.6]- and [2.8]metacyclophane-1-ynes was
achieved by successive bromination and dehydrobromination
reactions. An attempted trapping reaction of the putative
corresponding [2.5]metacyclophane-1-yne by Diels-Alder reaction
with 1,3-diphenylisobenzofuran failed due to its smaller ring size and
strained structure. X-ray crystallographic analyses show that the
triple bonds in syn-[2.6]- and [2.8]metacyclophane-1-ynes are
distorted from linearity with bond angles of 156.7° and 161.4°,
respectively. A DFT (Density Functional Theory) computational
study was conducted to determine the stabilities of different
conformations of the target compounds.
coworkers used reactive trapping reagents such as furan,
to confirm the formation of other strained cyclophynes as
transient intermediates leading to the observed formed
cycloaddition products.
Figure 1. Left: Paracyclophyne; middle: [4.4]metacyclophyne and right:
[2.2.2]metacyclophyne
The
syntheses
of
several
medium-sized
[n.n]metacyclophane-diynes such as [4.n]metacyclophyne,
were reported by Ramming and Gleiter.4a Under different
reaction conditions the triple bonds of some of these diynes
could be isomerized into the corresponding cis double
bonds and in others into allenic moieties. Kawase and co-
workers reported the syntheses of [2n]metacyclophane-n-
ynes such as [2.2.2]metacyclophyne (Fig. 1) which are
considerably strained and have bent triple bonds, via
sequential bromination-dehydrobromination reactions of
the corresponding metacyclophan-n-enes.4b–d
Introduction
Cyclophanes are an important class of compounds that have
been shown to possess unique properties. This has attracted
the interest of many research groups. These properties include
having highly strained and unusual conformers with distorted
aromatic ring components and this has resulted in much on-
going research into the fundamental aspects of aromaticity 1
.
Among the cyclophanes, the highly strained cyclophynes
containing at least one ethyne bridging group have proven
to be elusive. The formation of a paracyclophyne (Fig.1)
was inferred by Psiorz and Hopf as the transient
intermediate that led, via its cyclotrimerization reaction, to
the formation of the novel C3-symmetrical hydrocarbon
Previously, we reported our own attempts to produce
the shorter chain-length [2.3]- and [2.4]metacyclophane-1-ynes
by the dehydrobromination of the corresponding 1,2-dibromo-
[2.n]metacyclophanes, but only 1-bromo[2.n]metacyclophan-1-
enes
together
with
[2.n]metacyclophan-1-ones
were
obtained.5a,b Later, we reported the successful preparation of
syn- and anti-[2.8]metacyclophan-1-enes using the low-valent
titanium-induced McMurry coupling reaction and their
conversion to syn- and anti-[2.8]metacyclophane-1-ynes, in a
ratio of 35:65.6 The bromine adduct of [2.10]metacyclophan-1-
ene on the other hand, gave the [2.10]metacyclophane-1-yne as
[a]
Dr. T. Akther, Dr. M. M. Islam, Dr. Prof. T. Yamato
Department of Applied Chemistry, Faculty of Science and Engineering, Saga
University, Honjo-machi 1, Saga 840-8502 Japan
E-mail: yamatot@cc.saga-u.ac.jp
[b]
[c]
[d]
[e]
[f]
Dr. M. M. Islam
Chemical Research Division, Bangladesh Council of Scientific and Industrial
Research (BCSIR), Dhanmondi, Dhaka-1205, Bangladesh
Dr. Z. Kowser
Department of Chemistry, Jessore University of Science and Technology, 1
Churamonkathi-Chaugachha Road, 7408, Bangladesh
Dr. T. Matsumoto, Dr. J. Tanaka
Institute of Materials Chemistry and Engineering, Kyushu University,
6-1, Kasugakoen, Kasuga 816-8580, Japan
Dr. S. Rahman, Dr. Prof. P. E. Georghiou
Department of Chemistry, Memorial University of Newfoundland, St. John’s,
Newfoundland and Labrador A1B 3X7, Canada
Dr. S. Rahman, Dr. A. Alodhayb
Aramco Laboratory for Applied Sensing Research, King Abdullah Institute for
Nanotechnology, King Saudi University, Riyadh, 11451, Saudi Arabia
Dr. A. Alodhayb
Research Chair for Tribology, Surface, and Interface Sciences, Department of
Physics and Astronomy, College of Science, King Saud University, Riyadh
11451, Saudi Arabia
the major product, along with
a monodehydrobrominated
product 1-bromo[2.10]metacyclo-phan-1-ene as a by-product.6
We also recently reported the synthesis, structures and DFT
(Density Functional Theory) computational studies of
several
[2.n]metacyclophanes7a–g
and
[3.3]metacyclophanes8 as well as ring-expanded
metacyclophanes containing three aromatic rings.9
In this paper, in continuation of our previous work
related to the synthesis of [2.n]metacyclophane-1-ynes,6 we
now report the first synthesis of highly strained
[g]
[2.n]metacyclophane-1-ynes (n
=
5,
6
and 8) using the
of their
[h]
Dr. Prof. C. Redshaw
Department of Chemistry and Biochemistry, The University of Hull
Cottingham Road, Hull, Yorkshire HU6 7RX, UK
bromination-dehydrobromination
reactions
corresponding [2.n]metacyclophan-1-ene precursors
.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
Results and Discussions
[2.n]metacyclophan-1-enes (n = 3–6) were shifted upfield at
d 6.05–6.77 ppm, due to the shielding effect of the ring current
of the opposite benzene ring.20 Thus, the observed chemical
shift for the intra-annular protons of 3a strongly suggests that the
molecule adopts a syn-conformation. Previous work has shown
the chemical shifts of olefinic protons for (E)- and (Z)-olefins to
be at d >7.4 ppm and d <6.9 ppm repectively.21 In the case of 3a
the olefinic bridge protons were observed as a singlet at d 6.79
ppm indicating that the structure of 3a is a (Z)-syn-isomer.
Similarly, the spectra of [2.6]metacyclophan-1-ene (3b) and
[2.8]metacyclophan-1-ene (3c), indicate that they exisist as (Z)-
syn-isomers.
The starting compounds for the target [2.n]metacyclophane-1-
ynes, i.e. 1,5-bis(4-methoxyphenyl)pentane 1a, 1,6-bis(4-
methoxyphenyl)hexane 1b and 1,8-bis(4-methoxyphenyl)-
octane 1c were readily prepared in good yields via one-step
cross-coupling reactions of 4-methoxyphenylmagnesium
bromide with 1,n-dibromoalkanes (n = 5, 6 and 8) respectively,
in the presence of CuBr, in a mixture of HMPA and THF, heated
at reflux.10–12 Dichloromethyl methyl ether-TiCl4, regioselective
Friedel-Crafts
formylation
reactions
of
1,n-bis(4-
methoxyphenyl)alkanes 1 (n = 5, 6 and 8) afforded the required
1,n-bis(3-formyl-4-methoxyphenyl)alkanes 2a (n = 5), 2b (n = 6)
and 2c (n = 8) in 80–86 % yields, respectively (Scheme 1).
Cl2CHOMe
(CH2)n
MeO
OMe
TiCl4 in CH2Cl2
rt, 1 h
(CH2)n
(CH2)n
1 a; n = 5
b; n = 6
c; n = 8
d; n =10
OHC
CHO
OMe
anti-conformation
syn-conformation
(CH2)n
MeO
Figure 2. (E)-Anti- and (Z)-syn-conformations of [2.n]metacyclophan-1-enes.
2 a; n = 5 (80%)
b; n = 6 (85%)
c; n = 8 (86%)
d; n= 10 (82%)
Fast interconversion on the NMR timescale between the two
conformations of 3a can be observed since the three multiplets
centered at d 1.03, 1.28 and 2.32 ppm, which are due to the
protons of the pentane bridge, do not change upon decreasing
the temperature to –100°C in a 1:3 mixed CDCl3-CS2 solvent.
Thus the larger cyclophane ring size and the smaller intra-
annular protons in 3a allow for a more flexible structure
(CH2)n
)
n
H
(C
2
TiCl4-Zn
+
THF
reflux, 24 h
OMe
MeO
(Z)-3
OMe
MeO
(78%)
(62%)
(65%)
(E)-3a; n= 5 ( 0%)
b; n= 6 ( 0%)
a; n= 5
b; n= 6
c; n= 8
c; n= 8 ( 0%)
d; n= 10 (52%)
d; n= 10 (42%)
compared
to,
for
example,
anti-6,14-dimethoxy-1,2-
dimethyl[2.4]metacyclophan-1-ene.20a
Scheme 1. Synthesis of syn-dimethoxyl[2.n]metacyclophan-1-enes 3a–d.
OMe
Br
The McMurry TiCl4/Zn reductive coupling reaction of
carbonyl compounds catalyzed by low-valent titanium13 has
been extensively used to synthesize cyclophanes.14,15 In the
present work, using the reductive coupling reaction,
intramolecular cyclization of 1,5-bis(3-formyl-4-methoxy-
phenyl)pentane 2a successfully afforded 4,17-dimethoxy[2.5]
metacyclophan-1-ene 3a in 78% yield. Similarly, 4,18-
BTMA-Br3
(Z)-3
(CH2)n
CH2Cl2
rt, 5 min.
Br
OMe
4a; n = 5
(96%)
b; n = 6 (98%)
c; n = 8 (98%)
d; n = 10 (94%)
dimethoxy[2.6]-metacyclophan-1-ene
3b
and
4,20-di-
methoxy[2.8]metacyclophan-1-ene 3c were obtained in 62%
and 65% yields, respectively. No formation of any of the
corresponding (E)-isomers were observed with 2a–c but with
1,10-bis(3-formyl-4-methoxyphenyl)decane 2d as previously
reported, a mixture of the corresponding (E)- and (Z)-4,22-
dimethoxy[2.10]metacyclo-phan-1-enes (E)-3d and (Z)-3d was
obtained (Scheme 1).16
Scheme 2. Synthesis of dibromo-dimethoxyl[n.2]metacyclophanes 4a–d.
Conversion of the double bonds to the corresponding triple
bonds was accomplished by the bromination-dehydro-
bromination sequence of reactions. First, using equimolar
amounts of benzyltrimethylammonium tribromide (BTMA-Br3)22
in dichloromethane solution at room temperature, syn-3a and
syn-3b afforded quantitatively the racemic trans-dibromo
adducts syn-4a (endo-exo-Br) and endo-exo syn-4b (endo-exo-
Br), respectively in which the bromine atoms are endo or exo to
the macrocycle with R,R and/or S,S configurations (Scheme 2).
However, with syn-3c a mixture of dibromo meso-syn-4c (endo-
endo-Br) with the bromine atoms in R,S configurations and syn-
4c (endo-exo-Br) was formed quantitatively in a 53:47 ratio.
Interestingly, the bromination reactions of the syn-3a–c
compounds afforded the corresponding syn-4a–c dibromo
products, without any of the corresponding anti-conformers. In
these bromination reactions no syn- to anti-ring inversion occurs.
[2.n]Metacyclophan-1-enes can adopt either a “staircase”
anti-conformation or a syn-conformation by overlapping of their
aromatic rings (Fig. 2).17 Syn-anti interconversion can occur by
ring flipping, and is dependent upon both the length of the
bridges18 and also on the nature of the intra-annular
substituents.19
1
The H-NMR spectrum of 3a clearly showed the doublet of
the intra-annular protons at d 7.05 ppm (d, J = 2.2 Hz) separated
from the other protons of the aromatic rings at d 6.80 (d, J =8.4
Hz) and 6.91 (dd, J = 2.2, 8.4 Hz) ppm. Previously, we had
reported that the intra-annular aromatic potons in the anti-
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
The structures of these products were determined from their
1
elemental analyses and spectral data. The H-NMR signals of
4a–d in CDCl3, were assigned based upon the trans-addition of
bromine to the double bonds with endo-exo- and endo-endo-
arrangements of the two bromine atoms with respect to the
macrocycle. The two intra-annular aromatic protons which are
located ortho to the two bridging aromatic carbon atoms in 4a
now appeared as two distinct doublets at d = 6.93 (J = 2.2 Hz)
and 7.00 (J = 2.2 Hz) ppm, which is supportive for 4a being in a
syn-conformation. Furthermore, the methine protons at the
dibromoethano bridge also appear as a pair of doublets (J = 10.4
Hz) at d = 5.57 and 6.62 ppm. The lower field signal is attributed
to one of the exo-methine protons which is in a strongly shielding
region of the oxygen atom of the methoxy group on the aromatic
ring. The data are strong evidence that the two methine protons
at the ethano bridge are in an exo-endo arrangement with
respect to the macrocycle (Figure S18). Thus, 4a is assigned as
being a racemic pair i.e. rac- or dl-syn-12-endo-bromo-13-exo-
bromo-9,15-dimethoxy[5.2]metacyclophane, or dl-syn-4a as
shown in Fig. 3 (where n = 5). None of the corresponding anti-
isomer was observed under the conditions used here.
Figure 4. ORTEP figures of 4b with top (left) and side (right) views. Thermal
ellipsoids are drawn at the 50% probability level. Only hydrogen atoms at the
ethano bridge are shown. Other hydrogen atoms are omitted for clarity.
The single crystal X-ray structure of syn-4b is illustrated in
Fig. 4. The compound crystallized in the monoclinic space group
P21/a (CCDC 1547285 and SI Table S1) and clearly reveals that
the conformation is syn in which two aromatic rings are face-to-
face and mostly cause distortion in a boat-like shape and deviate
from planarity to some extent as can be seen from the side view
of the ORTEP drawing. Further, the X-ray analysis shows an
unsymmetrical structure with a staggered orientation of the two
methine protons on the ethano bridge and located distally from
the bridging methylene groups. These results suggest that the
introduction of the two bromine atoms at the ethano bridge might
dominate the potential for interconversion of the two syn
conformations of 4 by ring flipping.
(CH2)n
(CH2)n
H
H
H
Br
OMe
H
Br
Br
Br
MeO MeO
MeO
Interestingly, the 1H-NMR spectrum of 4c showed it to be a
mixture of meso-syn-4c (endo-endo-Br) and dl-syn-4c (endo-
exo-Br) in the ratio of 53:47. The presence of the diastereomeric
meso-syn-4c can be inferred by the presence of singlet signals
for the its methoxy protons at d = 3.54 ppm and for the ethylene
bridge methine protons at d = 6.12 ppm. The intra-annular
protons appear as a broad singlet signal at d = 7.30 ppm due to
their being in the strongly deshielding region of the endo-Br
atoms on the ethylene bridge. This data strongly supports the
assignment of having the two Br atoms in an endo-arrangement.
In contrast, dl-syn-4c showed a similar 1H-NMR spectrum to
those of 4a and 4c, which suggests an unsymmetrical syn-endo-
exo-dibromo-structure.
meso-4
dl-4
Figure 3. Possible structure of bromine adducts 4a–d.
The protons of the –(CH2)5– bridge generated a complicated
signal pattern, as to be expected for a rigid structure. The
bridged methylene protons in syn-4a are clearly located in
different spaces with one of them folded into the p-cavity formed
by the two benzene rings and high-field signals at d = –0.13–
and d = –0.03 ppm are observed. The individual signals of the
methylene protons for the middle CH2 group in the pentane
bridge do not coalescence below 130°C in CDBr3 and the energy
barrier to conformational wobbling is above 25 kcal mol–1.
The structure of 4b was similarly confirmed by elemental
analysis, 1H-NMR spectroscopic data and additionally, with a
single crystal X-ray crystallographic analysis. The 1H-NMR
spectrum of 4b exhibits two singlets at d 3.71 and 3.82 ppm for
the methoxy protons. The two intra-annular aromatic protons at
d = 6.96 and 6.99 ppm are at lower fields than those seen for
the corresponding anti-[2.n]metacyclophan-1-enes.20 The data
is supportive for 4b being in a syn-conformation. Furthermore,
similar to syn-4a the two methine protons at the ethano bridge
appear as a pair of doublets (J = 10.2 Hz) at d = 5.66 and 6.67
ppm. The lower field absorption is attributed to the exo-methine
proton in a strongly shielding region of the oxygen atom of the
methoxy group on the aromatic ring (Figure S20). Thus, the two
methine protons at the ethano bridge are similarly in an exo-
endo arrangement and thus 4b is assigned as being a racemic
pair i.e. rac- or dl-syn-13-endo-bromo-14-exo-bromo-10,16-
dimethoxy[6.2]metacyclophane dl-syn-4b. As in the case of
4a the protons of the –(CH2)6– bridge generated a similarly
complicated signal pattern.
(CH2)n
KOtBu
4b–4d
tBuOH
80°C, 24 h
MeO
OMe
(95%)
(98%)
(90%)
6 b; n = 6
c; n = 8
d; n = 10
Scheme 3. Synthetic route of [2.n]metacyclophane-1-ynes 6b–d.
Treatment of 4b and 4c with t-BuOK in t-BuOH at 80°C for
24
h
gave the doubly dehydrobrominated products,
[2.n]metacyclophane-1-yne 6b and 6c in 95% and 98% yields,
respectively (Scheme 3). Similar treatment of 4a however,
afforded only the t-butoxide product 5a in 83% yield and none of
the desired [2.5]metacyclophane-1-yne 6a (Scheme 4). In this
case, it could be supposed that when the highly strained
acetylenic moiety in 6a formed in the dehydrobromination
reaction, that it immediately reacts with the solvent t-BuOH to
produce the addition product 5a. Other attempts to
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
dehydrobrominate this shorter chain cross-linked compound 4a
using different t-BuOK/t-BuOH reaction conditions however
failed. Attempts to trap putative 6a as its Diels-Alder adduct 7a
with 3-diphenylisobenzofuran in t-BuOH were unsuccessful
affording only 5a again. However attempts to form the
corresponding Diels-Alder adducts from the reaction of the
isolated [2.n]metacyclophane-1-ynes 6b and 6c with 1,3-
diphenylisobenzofuran under the same reaction conditions
shown in Scheme 4 also failed and only the unreacted starting
comounds were recovered. Presumably the sterically crowded
bridged acetylene moiety having the methoxy groups on the
benzene rings likely suppress the approach of the 1,3-
diphenylisobenzofuran (Scheme 4).
linear structure than reference compound 11 shown below in
Scheme 5. The C11–C13–C14 and C15–C14–C13 bond angles
of 156.74° and 156.74° are unusual. This clearly shows that 6b
is a moderately bent molecule and is consistent with the lower
field chemical shifts of the signals of the acetylenic carbons in
its solution state 13C NMR spectrum (see below).
OMe
OMe
OtBu
tBuOH
KOtBu
4a
(CH2)5
(CH2)5
tBuOH / THF
H
80°C, 24 h
OMe
OMe
Figure 5. ORTEP figures of 6b with top (left) and side (right) views. Thermal
ellipsoids are drawn at the 50% probability level. All hydrogen atoms are
omitted for clarity and the carbon numbering system is shown.
6a
5a
Ph
O
OMe
Ph
The structure of the syn-confomer for [2.8]metacyclophane-
1-yne 6c is also readily assigned from its NMR spectra and the
chemical shift of the intra-annular aromatic protons at d 7.50
Ph
O
(CH2)5
Ph
ppm.
The perspectives of the structure of the syn-6c are
OMe
illustrated in Fig. 6. This compound crystallized in the same
monoclinic space group P21/a (SI Table S3). The X-ray
crystallography (CCDC 1547284) clearly reveals that the
conformation of 6c is also syn. The bond distance of C14–C15
is 1.203 Å and the bond angles of C13–C14–C15 and C16–
C15–C14 are unusual values, 161.91° and 161.43°. The two
aromatic rings diverge similarly from planarity to some extent, to
avoid p-electron repulsion.
7a
Scheme 4. Trapping reaction of [2.5]metacyclophane-1-yne 6a with 1,3-
diphenylisobenzofuran.
The structure of 5a was determined by elemental analyses
and spectral data. The mass spectra showed the predicted
molecular ion for 5a at m/z = 380.19. The 1H-NMR spectrum of
shows the two methoxy protons as singlets at d = 3.79 and 3.87
ppm. The tert-butoxy protons and the olefinic proton appear at d
= 1.31 ppm (9H) and 6.52 ppm (1H) as nine- and one-proton
singlets, respectively.
The structures of 6b and 6c were also determined by
elemental analyses and spectral data. The intra-annular
aromatic protons of 6b appear as a doublet at d 7.52 (H8,20, J =
2.4 Hz) ppm and the other aromatic protons appear at d 6.82
(H5,17, d, J = 8.5 Hz) and 7.06 (H6,16, dd, J = 2.4, 8.5 Hz) ppm.
As with the previous examples, the syn-conformer structure is
assigned to 6b. The lower-field signal of the intra-annular
protons in comparison with the other aromatic protons indicate
that are situated within the deshielding region owing to the p-
electrons of the triple bond.
The X-ray structure of a single-crystal 6b obtained from slow
evaporation of a saturated dichloromethane solution clearly
indicates that it is also the syn-conformer in the solid state (Fig.
5). This compound crystallized in the same monoclinic space
group P21/a (CCDC 1547283; SI Table S2). The side view
shown in Fig. 5 shows that the two methoxy groups are situated
away from the direction of macrocyclic ring to constrain steric
repulsion with the bridge chain. The C13–C14 bond distance is
1.203 Å, which is almost equal to the normal distance between
the carbon atoms in acetylene. The C11–C13 and C14–C15
bond distances are both 1.440 Å, and are much shorter than
those of C6–C7 (1.521 Å) and C1–C19 (1.521 Å). Interestingly,
the acetylenic moiety in the bridge does not adopt a different
Figure 6. ORTEP figures of 6c with top (left) and side (right) views. Thermal
ellipsoids are drawn at the 50% probability level. All hydrogen atoms are
omitted for clarity.
The chemical shifts of the 1H- and 13C-NMR signals arising
from the benzene rings of 6b, 6c and 6d (n = 10)16 are
comparable to those of the acyclic compound 11, which was
prepared from 2-formyl-6-methylanisole in 3 steps using the
same procedure as for the [2.n]metacyclophane-1-ynes 6b–d by
following our previous report (Scheme 5).16 The signals of the
acetylenic carbons (Table 1) in 6b–d are located at lower fields
than those of 11 (d 89.7 ppm). This reflects the appreciable strain
in the triple bonds due to bending. In particular, the chemical
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
shift of the sp carbons in 6b is at considerably lower field than
that of 11 and has almost the same value as that of
[23]metacyclophane-1,9,17-triyne (d 99.86 ppm),23 but is at
lower field than that of [24]metacyclophane-1,9,17,25-tetrayne (d
92.20 ppm) or 1,5-cyclooctadiyne (d 95.8 ppm).24
The individual geometry-optimized structures and their
energies are summarized in Fig. 7 and Table 2. The energies of
the less energetically-favoured conformers for each compound
are presented as ΔE values relative to the most energetically-
favoured conformer for that compound.As can be seen, the syn
conformers are the lower energy ones in each case.
Me
Table2. B3LYP/6-31G(d) gas phase calculated optimized relative energies
(ΔE kJ mol–1), HOMO/LUMO energies (E; eV); and HOMO–LUMO energy
gaps (ΔE; eV), of the conformers of 3a–c and 6b–c.
OMe
Me
CHO
BTMA-Br3
TiCl4-Zn
CH2Cl2
rt, 24 h
(84%)
THF
reflux, 24 h
(70%)
MeO
(E)-9
HOMO-
LUMO
gap
(ΔEg)
Relative
Energy
(ΔE)
Me
Optimized
energy (E)
HOMO
energy
LUMO
energy
OMe
8
Conformer
Me
Br
(kcal
(kcal mol–1
)
(eV)
-5.15
-5.08
-5.22
-5.06
-5.07
-4.97
-5.32
-5.11
-5.10
-5.04
-5.08
(eV)
-0.84
-0.75
-0.77
-0.76
-0.93
-0.91
-0.56
-1.07
-0.92
-0.93
-0.95
(eV)
4.31
4.33
4.45
4.30
4.14
4.06
4.76
4.05
4.19
4.11
4.12
Me
Me
mol–1
0.00
)
Me
KOtBu
tBuOH
-605609.54
-605580.77
-630276.41
-630260.41
-679616.44
-679610.77
-728954.95
-728950.72
-629484.59
-678829.10
-728174.55
syn-3a
anti-3a
syn-3b
anti-3b
syn-3c
anti-3c
syn-3d
anti-3d
syn-6b
syn-6c
syn-6d
MeO
MeO
80°C, 24 h
(53%)
OMe
28.78
0.00
16.00
0.00
5.67
0.00
4.22
-
Br
OMe
10
11
Scheme 5. Synthetic route of the reference compound 11.
Table 1. 13C NMR data and dihedral angle of [2.n]metacyclophane-1-ynes 6b–
d and reference compound 11.
13C NMR, d ppm; (CDCl3)
Compounds
-(CH2)n-
angle
156.7
161.4
169.6
180.0
CºC
101.6
95.6
91.5
89.7
6b
6c
6d
11
6
8
-
10
-
-
Computational Details
Conclusions
Computational studies were conducted to explore the
conformational properties of the conformers of 3a–c and 6b–6c.
All computations were carried out with the Gaussian 09.e01
package.25 The molecular geometries of the conformers shown
were fully optimized in the gas phase, at the DFT level of theory
using the B3LYP (Becke, three-parameter, Lee-Yang-Parr),26
exchange–correlation with the 6-31G(d) basis set.
We have synthesized, for the first time, the highly strained syn-
[2.6]metacyclophane-1-yne 6b and [2.8] metacyclophane-1-yne
syn-6c, of the metacyclophane-1-yne systems. Single-crystal X-
ray structures of the dibromo precursors 4b and 4c adducts
were determined and their NMR spectra analysed. The
subsequent double-dehydrobromination of the bromine adducts
of [2.n]metacyclophan-1-enes with base will also open up new
mechanistic aspects for cyclophane chemistry. The
conformations were also determined by DFT studies and were
cosistent with the experimental results. Further studies on the
chemical properties of [2.n]metacyclophane-1-ynes are now in
progress.
Experimental Section
General procedures
All melting points (Yanagimoto MP-S1) are uncorrected. NMR
spectra were determined at 300 MHz with a Nippon Denshi
JEOL FT-300 spectrometer with Me4Si as an internal reference:
J values are given in Hz. IR spectra were measured for samples
as KBr pellets or as liquid films on NaCl plates in a Nippon
Denshi JIR-AQ2OM spectrophotometer. UV spectra were
measured by a Shimadzu 240 spectrophotometer. Mass spectra
were obtained on
a Nippon Denshi JMS-01SG-2 mass
Figure 7. The B3LYP molecular geometry optimized structures of the various
conformers of 3 and 6 MCPs in gas phase. Colour code: carbon = green;
hydrogen = white; oxygen atom = red.
spectrometer at an ionization energy of 70 eV using a direct inlet
system through GLC. Elemental analyses were performed by
Yanaco MT-5. G.L.C. analyses were performed with
a
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
Shimadzu gas chromatograph, GC-14A; silicone O V-1, 2 m;
programmed temperature rise, 12°C min–1; carrier gas nitrogen,
25 mL min–1.
After the reaction mixture was stirred at room temperature for 1
h, it was poured into a large amount of ice/water (50 mL) and
extracted with CH2Cl2 (20 mL × 2). The combined extracts were
washed with water, dried with Na2SO4 and concentrated. The
residue was chromatographed over silica gel (Wako C–300, 200
g) with benzene as eluent to give 2a (1.22 g, 80%) as a
colourless solid. Recrystallization from hexane gave 2a as
colourless prisms. M.p. 64–65 °C. IR: nmax (KBr): 2925, 2841,
1676 (C=O), 1596, 1500, 1439, 1280, 1260, 1207, 1121, 1019,
811 cm–1. 1H-NMR (400 MHz, CDCl3): d = 1.31–1.37 (2H, m,
CH2), 1.58–1.70 (4H, m, CH2), 2.55 (4H, t, J = 7.9 Hz, CH2), 3.90
(6H, s, OMe), 6.90 (2H, d, J = 8.5 Hz, Ar-H), 7.34 (2H, dd, J =
2.4, 8.5 Hz, Ar-H), 7.61 (2H, d, J = 2.4 Hz, Ar-H) and 10.40 (2H,
s, CHO) ppm. MS: m/z 340 [M+]. C21H24O4 (340.42): calcd C
74.09, H 7.11; found: C 74.37, H 7.29.
Materials
4,22-Dimethoxy[2.10]metacyclophane-1-yne
prepared following previous reports.16,27
(
6d
)
was
Preparation of 1,5-bis(4-methoxyphenyl)pentane (1a)
To a solution of magnesium (2.19 g, 90 mmol) and a small
amount of iodine in THF (5 mL) was added a solution of 4-
bromoanisole (14.3 g, 75 mmol) in THF (20 mL) and the mixture
was refluxed for 12 h. To a solution of 1,5-dibromopentane (5.75
g, 25 mmol) and CuBr (750 mg, 5.2 mmol) in HMPA (3.5 mL)
was added dropwise a solution of 4-methoxyphenylmagnesium
bromide with gentle refluxing. After the reaction mixture was
refluxed for an additional 24 h, it was quenched with a 10%
aqueous ammonium chloride solution and extracted with CH2Cl2
(50 mL × 3). After the combined CH2Cl2 extracts were dried over
Na2SO4 and concentrated. The residue was chromatographed
over silica gel (Wako C–300, 200 g) with hexane–ethylacetate
(5:1) as eluent to give 1a (6.4 g, 90%) as a colourless solid.
Recrystallization from hexane gave 1a (5.7 g, 80%) as
colourless oil. 1H-NMR (400 MHz, CDCl3): d = 1.37–1.43 (2H, m,
CH2), 1.60–1.68 (4H, m, CH2), 2.57 (4H, t, J = 7.8 Hz, CH2),
3.81 (6H, s, OMe), 6.84 (4H, d, J = 8.6 Hz, Ar-H) and 7.12 (4H,
d, J = 8.6 Hz, Ar-H) ppm. 13C-NMR (100 MHz, CDCl3): d = 28.96,
31.75, 35.08, 55.36, 113.79, 129.36, 135.01 and 157.75 ppm.
MS: m/z 284 [M+]. C19H24O2 (284.39): calcd C 80.24, H 8.51;
found: C 80.21, H 8.31.
Similarly, compounds 2b and 2c were prepared in the same
manner as described above.
1,6-Bis(3-formyl-4-methoxyphenyl)hexane (2b)
This compound was obtained as pale-yellow prisms (from
hexane). Yield 85%. M.p. 61–63 °C. IR: nmax (KBr): 2924, 2841,
1682 (C=O), 1600, 1495, 1257, 1192, 1100, 1017, 812 and 641
cm–1. 1H-NMR (300 MHz, CDCl3): d = 1.30–1.33 (4H, m, CH2),
1.54–1.61 (4H, m, CH2), 2.56 (4H, t, J = 7.9 Hz, CH2), 3.91 (6H,
s, OMe), 6.91 (2H, d, J = 8.5 Hz, Ar-H), 7.35 (2H, dd, J = 2.4,
8.5 Hz, Ar-H), 7.62 (4H, d, J = 2.4 Hz, Ar-H) and 10.45 (2H, s,
CHO) ppm. 13C-NMR (100 MHz CDCl3): d = 29.00, 31.36, 34.79,
55.80, 111.70, 124.55, 127.99, 135.09, 136.17, 160.26 and
190.21 ppm. MS: m/z 354.25 [M+]. C22H26O4 (354.45): calcd C
74.55, H 7.39; found: C 74.54, H 7.42.
1,8-Bis(3-formyl-4-methoxyphenyl)octane (2c)
1,6-Bis(4-methoxyphenyl)hexane (1b)
This compound was obtained as pale-yellow prisms (from
hexane). Yield 86%. M.p. 62–64 °C. IR: nmax (KBr): 2935,
2851, 1682 (C=O), 1598, 1495, 1258, 1131, 1022, 823 and
This compound was obtained as colourless prisms (from
hexane). Yield 77%. M.p. 56–57 °C. 1H-NMR (300 MHz, CDCl3):
d = 1.38–1.38 (4H, m, CH2), 1.58–1.62 (4H, m, CH2), 2.53 (4H,
t, J = 7.8 Hz, CH2), 3.80 (6H, s, OMe), 6.84 (4H, d, J = 8.6 Hz,
Ar-H) and 7.10 (4H, d, J = 8.6 Hz, Ar-H) ppm. 13C-NMR (100
MHz CDCl3): d = 29.21, 31.78, 35.12, 55.35, 113.77, 129.35,
135.05 and 157.73 ppm. MS: m/z 298 [M+]. C20H26O2 (298.42):
calcd C 80.50, H 8.78; found: C 80.54, H 8.62.
641 cm–1. 1H-NMR (300 MHz, CDCl3):
d = 1.28 (8H, broad
s, CH2), 1.55–1.59 (4H, m, CH2), 2.56 (4H, t, J = 7.9 Hz, CH2)
,
3.91 (6H, s, OMe), 6.91 (2H, d, J = 8.5 Hz, Ar-H), 7.36 (2H,
dd, J = 2.4, 8.5 Hz, Ar-H), 7.63 (2H, d, J = 2.4Hz, Ar-H) and
10.45 (2H, s, CHO) ppm. 13
C-NMR (100 MHz, CDCl3): d =
29.22, 29.47, 31.51, 34.86, 55.82, 111.69, 124.57, 128.05,
135.26, 136.19, 160.26 and 190.26 ppm. MS: m/z 382.47
[M+]. C24H30O4 (382.49): calcd C 75.36, H 7.91; found: C
75.52, H 8.00.
1,8-Bis(4-methoxyphenyl)octane (1c)
This compound was obtained as colourless prisms (from
hexane). Yield 83%. M.p. 62–63 °C. 1H-NMR (300 MHz, CDCl3):
d = 1.32 (8H, broad s, CH2), 1.56–1.60 (4H, m, CH2), 2.55 (4H,
t, J = 7.9 Hz, CH2), 3.80 (6H, s, OMe), 6.84 (4H, d, J = 8.6 Hz,
Ar-H) and 7.10 (4H, d, J = 8.6 Hz, Ar-H) ppm. 13C-NMR (100
MHz CDCl3): d = 29.38, 29.58, 31.87, 35.15, 55.37, 113.77,
129.36, 135.15 and 157.72 ppm. MS: m/z 326 [M+]. C22H30O2
(326.47): calcd C 80.94, H 9.26; found: C 80.67, H 9.32.
McMurry coupling reaction of 2 –Typical Procedure
The McMurry reagent was prepared from TiCl4 [23.8 g (13.8 mL),
125 mmol] and Zn powder (18 g, 275 mmol) in dry THF (500 mL)
under
nitrogen.
A
solution
of
1,5-bis(3-formyl-2-
methoxyphenyl)pentane (2a) (2.81 g, 9.0 mmol) and pyridine
(22.8 mL, 200 mmol) in dry THF (250 mL) was added within 60
h to the black mixture of the McMurry reagent by using a high-
dilution technique with continuous refluxing and stirring. The
reaction mixture was refluxed for additional 24 h, cooled to room
temperature, and hydrolyzed with aqueous 10% K2CO3 (200 mL)
at 0 °C. The reaction mixture was extracted with CH2Cl2 (200 mL
Preparation of 1,5-bis(3-formyl-4-methoxyphenyl)pentane
(2a)
To a solution of 1a (1.15 g, 4.5 mmol) and dichloromethyl methyl
ether (1.14 mL, 12.6 mmol) in CH2Cl2 (10 mL) was added a
solution of TiCl4 (3.0 mL, 27.3 mmol) in CH2Cl2 (10 mL) at 0 °C.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
× 3). The combined extracts were washed with water, dried with
Na2SO4 and concentrated. The residue was chromatographed
over silica gel (Wako C-300, 300 g) with hexane–toluene (2:1)
and CHCl3–EtOAc (1:1) as eluents to give 3a (2.17 g, 78%) as a
colourless solid. Recrystallization of crude 3a from methanol
1.40–1.54 (2H, m, CH2), 1.57–1.68 (2H, m, CH2), 2.28–2.43 (2H,
m, CH2), 2.49–2.69 (4H, m, CH2), 3.75 (3H, s, OMe), 3.78 (3H,
s, OMe), 5.58 (1H, d, J = 10.4 Hz, CH), 6.62 (1H, d, J = 10.4 Hz,
CH), 6.52 (1H, d, J = 8.4 Hz, Ar-H), 6.55 (1H, d, J = 8.4 Hz, Ar-
H), 6.73 (1H, dd, J = 2.2, 8.4 Hz, Ar-H), 6.80 (1H, dd, J = 2.2,
8.4 Hz, Ar-H), 6.93 (1H, d, J = 2.2 Hz, Ar-H) and 7.00 (1H, d, J
= 2.2 Hz, Ar-H) ppm. 13C-NMR (100 MHz, CDCl3): d = 22.69,
27.51, 28.29, 31.93, 33.15, 50.91, 55.36, 55.73, 59.05, 110.54,
111.43, 126.20, 127.17, 129.46, 129.71, 129.86, 132.22, 132.84,
133.42, 153.58 and 155.72 ppm. MS: m/z: 468.03 [M+].
C21H24O2Br2 (468.23): calcd C 53.87, H 5.17. found: C 54.08, H
5.39.
gave
4,17-dimethoxy[2.5]metacyclophan-1-ene
(3a)
as
colourless prisms. M.p. 147–149 °C. IR: nmax (KBr): 2919, 2858,
1608, 1498, 1249, 1121, 1035 and 828 cm–1. 1H-NMR (300 MHz,
CDCl3): d =1.00–1.07 (2H, m, CH2), 1.25–1.34 (4H, m, CH2),
2.30–2.34 (4H, m, CH2), 3.87 (6H, s, OMe), 6.79 (2H, s, CH),
6.80 (2H, d, J =8.3 Hz, Ar-H), 6.91 (2H, dd, J = 2.2, 8.3 Hz, Ar-
H) and 7.05 (2H, d, J = 2.2 Hz, Ar-H) ppm. 13C-NMR (100 MHz,
CDCl3): d = 26.23, 30.32, 35.22, 55.72, 110.63, 125.24, 125.55,
128.91, 131.02, 133.60 and 155.52 ppm. MS: m/z 308.2 [M+].
C21H24O2 (308.42): calcd C 81.90, H 7.84; found: C 81.78, H 7.84.
Similarly, compound 4b and 4c were prepared in the same
manner as described above.
13,14-Dibromo-10,16-dimethoxy[6.2]metacyclophane
Similarly, compound 3b and 3c were prepared in the same
(4b)
manner as described above.
This compound was obtained as colourless prisms (from
hexane) in 98% yield. M.p. 116–117 °C. IR: nmax (KBr): 2963,
2921, 2855, 1605, 1503, 1447, 1258, 1117, 1030, 810 and 775
cm–1. H-NMR (300 MHz, CDCl3): d = 0.41–0.52 (1H, m, CH2),
4,18-Dimethoxy[2.6]metacyclophan-1-ene (3b)
This compound was obtained as prisms (from methanol). Yield
62%. M.p. 193–194 °C. IR: nmax (KBr): 2925, 1604, 1498, 1254,
1160, 1117, 1034, 912 and 822 cm–1. 1H-NMR (300 MHz,
CDCl3): d = 1.01 (4H, broad s, CH2), 1.60 (4H, broad s, CH2),
2.33–2.37 (4H, m, CH2), 3.81 (6H, s, OMe), 6.75 (2H, s, CH),
6.81 (2H, d, J = 8.4 Hz, Ar-H), 6.96 (2H, dd, J = 2.1, 8.4 Hz, Ar-
H) and 7.24 (2H, d, J = 2.1 Hz, Ar-H) ppm. 13C-NMR (100 MHz,
CDCl3): d = 24.36, 30.72, 31.99, 55.81, 111.31, 123.98, 124.76,
128.20, 130.40, 133.15 and 155.40 ppm. MS: m/z 322.2 [M+].
C22H26O2 (322.45): calcd C 81.95, H 8.13; found: C 81.90, H 7.84.
1
0.68–0.79 (1H, m, CH2),1.10–1.24 (2H, m, CH2), 1.28–1.44 (2H,
m, CH2), 1.60–1.70 (1H, m, CH2), 1.79–1.89 (1H, m, CH2), 2.40
–2.61 (4H, m, CH2), 3.71 (3H, s, OMe), 3.82 (3H, s, OMe), 5.66
(1H, d, J = 10.2 Hz, CH), 6.54 (1H, d, J = 8.4 Hz, Ar-H), 6.62
(1H, d, J = 8.4 Hz, Ar-H), 6.67 (1H, d, J = 10.2 Hz, CH), 6.82
(1H, dd, J = 2.2, 8.4 Hz, Ar-H), 6.87 (1H, dd, J = 2.2, 8.4 Hz, Ar-
H), 6.96 (1H, d, J = 2.2 Hz, Ar-H) and 6.99 (1H, d, J = 2.2 Hz,
Ar-H) ppm. 13C-NMR (100 MHz, CDCl3): d = 27.76, 28.36, 28.89,
28.92, 33.68, 35.14, 51.92, 55.14, 55.71, 59.96, 110.77, 111.43,
126.47, 127.34, 128.40, 129.59, 130.14, 130.72, 133.48, 134.21,
153.46 and 155.49 ppm. MS: m/z: 480, 482, 484 [M+].
C22H26O2Br2 (482.26): calcd C 54.79, H 5.43; found: C 54.87, H
5.49.
4,20-Dimethoxy[2.8]metacyclophan-1-ene (3c)
This compound was obtained as colourless prisms (from
methanol). Yield 65%. M.p. 131 °C. IR: nmax (KBr): 2963, 2855,
1605, 1503, 1466, 1239, 1119, 1030 and 813 cm–1. 1H-NMR
(300 MHz, CDCl3): d = 1.05–1.09 (4H, m, CH2), 1.19 (4H, broad
s, CH2), 1.37–1.46 (4H, m, CH2), 2.36–2.40 (4H, m, CH2), 3.83
(6H, s, OMe), 6.73 (2H, s, CH), 6.80 (2H, d, J = 8.4 Hz, CH),
6.97 (2H, dd, J = 2.4, 8.4 Hz, Ar-H) and 6.99 (2H, s, Ar-H) ppm.
13C-NMR (100 MHz, CDCl3): d = 25.38, 27.02, 29.84, 34.20,
110.13, 126.84, 129.85, 131.71, and 155.92 ppm. MS: m/z
350.23 [M+]. C24H30O2 (350.49): calcd C 82.24, H 8.63; found: C
82.33, H 8.62.
15,16-Dibromo-12,18-dimethoxy[8.2]metacyclophane
(4c)
To a solution of 3c (200 mg, 0.57 mmol) in CH2Cl2 (20 mL) was
added BTMA-Br3 (244 mg, 0.63 mmol) at room temperature.
After the reaction mixture was stirred at room temperature for 5
min, it was poured into a large amount of ice/water (50 mL) and
extracted with CH2Cl2 (50 mL × 2). The combined extracts were
washed with water, dried with Na2SO4 and concentrated to
afford 4c (285 mg, 98%) as a colorless solid. Recrystallization
from hexane gave 226 mg (78%) of a mixture of meso-syn-15-
endo-bromo-16-endo-bromo-12,18-dimethoxy[8.2]metacyclo-
phane (meso-4c) and dl-syn-15-endo-bromo-16-exo-bromo-
12,18-dimethoxy[8.2]metacyclophane (dl-4c) in the ratio of
53:47 as colourless prisms. M.p. 122–123 °C. IR: nmax (KBr):
2922, 1603, 1501, 1254, 1134, 1032 and 659 cm–1. 1H-NMR
(300 MHz, CDCl3): (meso-4c) d = 0.86–1.83 (12H, m, CH2),
2.36–2.61 (4H, m, CH2), 3.54 (6H, s, OMe), 6.12 (2H, s, CH),
6.58 (2H, d, J = 8.4 Hz, H11,1 9, Ar-H), 6.95 (2H, dd J = 2.4, 8.4
Hz, H10, 20, Ar-H) and 7.31 (2H, broad s, H14, 22, Ar-H) ppm. (dl-
4c) d = 0.86–1.83 (12H, m, CH2), 2.36–2.61 (4H, m, CH2), 3.77
(3H, s, OMe), 3.81 (3H, s, OMe), 5.65 (1H, d, J = 10.4 Hz, CH),
Bromination of 3 with BTMA-Br3 –Typical Procedure
To a solution of 3a (200 mg, 0.71 mmol) in CH2Cl2 (20 mL) was
added BTMA-Br3 (300mg, 0.78 mmol) at room temperature.
After the reaction mixture was stirred at room temperature for 5
min, it was poured into a large amount of ice/water (50 mL) and
extracted with CH2Cl2 (50 mL × 2) The combined extracts were
washed with water, dried with Na2SO4 and concentrated to
afford 4a (300 mg, 96%) as a colourless solid. Recrystallization
from hexane gave 134 mg (43%) of 12,13-dibromo-9,15-
dimethoxy[5.2]metacyclophane (4a) as colourless prisms. M.p.
116–117 °C. IR: nmax (KBr): 2963, 2921, 2855, 1605, 1503, 1447,
1258, 1117, 1030, 810 and 775 cm–1. 1H-NMR (300 MHz,
CDCl3): d = –0.13– –0.03 (1H, m, CH2), 0.78–0.89 (1H, m, CH2),
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
6.62 (1H, d, J = 8.4 Hz, Ar-H), 6.63 (1H, d, J = 8.4 Hz, Ar-H),
6.81 (1H, d, J = 10.4 Hz, CH), 6.87 (1H, dd, J = 2.2, 8.4 Hz, Ar-
H), 6.90 (1H, d, J = 2.2 Hz, Ar-H), 6.92 (1H, dd, J = 2.2, 8.4 Hz,
Ar-H) and 7.12 (1H, d, J = 2.2 Hz, Ar-H) ppm.MS: m/z 508, 510,
512 [M+]. C24H30O2Br2 (510.31): calcd C 56.49, H 5.93; found: C
56.53, H 5.93.
(6H, s, OMe), 6.78 (2H, d, J = 8.4 Hz, Ar-H), 7.03 (2H, dd, J =
2.4, 8.4 Hz, Ar-H) and 7.50 (2H, d, J = 2.4 Hz, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): d = 28.02, 29.19, 29.48, 32.17, 55.81,
95.68, 111.13, 112.63, 130.00, 134.05, 136.61 and 155.38 ppm.
MS: m/z: 348.27 [M+]. C24H28O2 (348.49): calcd C 82.72, H 8.1;
found: C 83.60, H 10.14.
Electronic Supplementary Information (ESI): 1H, 13C NMR
and MS spectra of 2 to 6. Details of single-crystal X-ray
crystallographic data and DFT calculation.
Dehydrobromination of 4a with t-BuOK – Typical
Procedure
To a solution of 4a (100 mg, 0.214 mmol) in t-BuOH (20
mL) was added t-BuOK (995 mg, 8.51 mmol) at room
temperature. After the reaction mixture was heated at 80 °C
for 24 h, it was poured into a large amount of ice/water (50
mL) and extracted with CH2Cl2 (100 mL × 2). The combined
extracts were washed with water, dried with Na2SO4 and
concentrated. The residue was chromatographed over
silica gel (Wako C-300, 300 g) with toluene as eluents to
give 1-tert-butoxy-4,17-dimethoxy[2.5]metacyclophan-1-
ene 5a (68 mg, 83%) as a colourless oil. 1H-NMR (300 MHz,
Acknowledgements
We would like to thank the OTEC at Saga University for financial
support. This work was performed under the Cooperative
Research Program of “Network Joint Research Center for
Materials and Devices (Institute for Materials Chemistry and
Engineering, Kyushu University)”. CR thanks the EPSRC for an
Overseas Travel Grant (EP/R023816/1).
Keywords: [2.n]Metacyclophane-1-ynes• Structures• Strained
molecule• Diels-Alder reaction • Conformational studies.
CDCl3):
d = 0.83–0.92 (2H, broad s, CH2), 1.12–1.21 (4H,
m
, CH2), 1.31 (9H, s, tBu), 2.35–2.45 (4H, m, CH2), 3.79 (3H,
s, OMe), 3.87 (3H, s, OMe), 6.52 (1H, s, CH), 6.62 (1H, d,
J = 2.2 Hz, Ar-H), 6.65 (1H, d, J = 8.4 Hz, Ar-H), 6.74 (1H,
dd, J = 2.2, 8.4 Hz, Ar-H), 6.85 (1H, d, J = 8.4 Hz, Ar-H),
6.92 (1H, d, J = 2.2 Hz, Ar-H) and 7.02 (1H, dd, J = 2.2, 8.4
[1] (a) T. Ohno, M. Sakai, Y. Ishino, H. Haekawa and I. Nishiguchi, Org. Lett.,
2001, 3, 3439; (b) M.S. Collins, M. E. Carnes. B. P. Nell, L. N. Zakharov
and D. W. Johnson, Nat. Com., 2016, 7, 11052.
[2] M. Psiorz and H. Hopf, Angew. Chem., 1982, 94, 647; M. Psiorz and H.
Hopf, Angew. Chem. Int. Ed. Engl., 1982, 21, 623.
Hz, Ar-H) ppm. 13C
-NMR (100 MHz, CDCl3): d = 23.14,
[3] (a) O. Reiser, S. Reichow and A. de Meijere, Angew. Chem. Int. Ed. Engl.,
1987, 26, 1301; (b) B. König, J. Prinzbach, K. Meerholz and A. de Meijere,
Angew. Chem., Int. Ed. Engl., 1991, 30, 1361(c) T. Wong, S. S. Cheung
and H. N. C. Wong, Angew. Chem. Int. Ed. Engl., 1988, 27, 705; (d) C. W.
Chan and H. C. Wong, J. Am. Chem. Soc.,1988, 110, 462.
25.37, 29.12, 29.72, 32.86, 34.13, 35.08, 55.40, 55.76,
110.05, 111.14, 112.01, 113.13, 127.27, 129.81, 131.42,
132.85, 133.76, 151.37, 154.99 and 154.74 ppm. MS: m/z:
380.19 [M+]. C25H32O3 (380.53): calcd C 78.91, H 8.48;
found: C 78.83, H 8.55.
[4] (a) M. Ramming and R. Gleiter, J. Org. Chem., 1997, 62, 5821; (b) T.
Kawase, H. R. Darabi and M. Oda, Angew. Chem., 1996, 108, 2803; T.
Kawase, H. R. Darabi and M. Oda, Angew. Chem., Int. Ed. Engl., 1996,
35, 2664; (c) T. Kawase, N. Ueda, H. R. Darabi and M. Oda, Tetrahedron
Lett., 1996, 37, 1558; (d) Y. Tobe and M. Sonoda, Cyclophynes, 2004, 1–
40 (Chapter 1), R. Gleiter and H. Hopf (Editors), Modern Cyclophane
Chemistry, Wiley-VCH Verlag GmbH&Co. KGaA.
Dehydrobromination of 4b with KOBut
To a solution of 4b (100 mg, 0.21 mmol) in t-BuOH (20 mL)
was added t-BuOK (970 mg, 7.8 mmol) at room temperature.
After the reaction mixture was heated at 80 °C for 24 h, it was
poured into a large amount of ice/water (50 mL) and extracted
with CH2Cl2 (100 mL × 2). The combined extracts were washed
with water, dried with Na2SO4 and concentrated. The residue
was recrystallized from methanol gave 64 mg (95%) of 4,18-
dimethoxy[2.6]metacyclophane-1-yne (6b) as colourless prisms.
M.p. 175–179°C. IR: nmax (KBr): 2935, 2153, 1497, 1290, 1240,
1119, 1028 and 810 cm–1. 1H-NMR (300 MHz, CDCl3): d = 1.61–
1.65 (4H, m, CH2), 1.76–1.79 (4H, m, CH2), 2.71 (4H, m, CH2),
3.89 (6H, s, OMe), 6.82 (2H, d, J = 8.5 Hz, Ar-H), 7.06 (2H, dd,
J = 2.4, 8.5 Hz, Ar-H) and 7.52 (2H, d, J = 2.4 Hz, Ar-H) ppm.
13C-NMR (100 MHz, CDCl3): d = 26.53, 29.19, 30.76, 56.08,
101.60, 112.30, 113.15, 130.49, 133.22, 134.99 and 154.07
ppm. MS: m/z: 320.21 [M+]. C22H24O2 (320.42): calcd C 82.46,
H,7.55; found: C 82.13, H 7.55.
[5] (a) T. Yamato, J. Matsumoto, S. Ide, K. Suehiro, K. Kobayashi and M.
Tashiro, Chem. Ber., 1993, 126, 447; (b) T. Yamato, M. Sato, K. Noda, J.
Matsumoto and M. Tashiro, J. Chem. Res., 1993, (S) 394; (M)2601.
[6] T. Yamato, K. Fujita, T. Abe and H. Tsuzuki, New J. Chem., 2001, 25, 728-
736
[7] (a) T. Akther, M. M. Islam, T. Matsumoto, J. Tanaka, P. Thuery, C.
Redshaw and T. Yamato, Tetrahedron, 2018, 74, 329–325; (b) T. Akther,
M. M. Islam, S. Rahman, P. E. Georghiou, T. Matsumoto, J. Tanaka, C.
Redshaw and T. Yamato, Org. Biomol. Chem., 2017, 15, 3519–3527; (c)
T. Akther, M. M. Islam, S. Rahman, P. E Georghiou, T. Matsumoto, J.
Tanaka, P. Thuéry, C. Redshaw and T. Yamato, ChemistrySelect, 2016,
1, 3594–3600; (d) T. Akther, M. M. Islam, T. Matsumoto, J. Tanaka, X.
Feng, C. Redshaw and T. Yamato, J. Mol. Struct. 2016, 1122, 247–255;
(e) T. Akther, M. M. Islam, T. Matsumoto, J. Tanaka, P. Thuery, C.
Redshaw and T. Yamato, Eur. J. Org. Chem. 2017, 1721–1726; (f) M. M.
Islam, X. Feng, S. Rahman, P. E. Georghiou, T. Matsumoto, J. Tanaka,
A. Alodhayb, C. Redshaw and T. Yamato, ChemistrySelect 2019, 4(13),
3630–3635. (g) M. M. Islam, X. Feng, C.-Zeng Wang, S. Rahman, A.
Alodhayb, P. E. Georghiou, T. Matsumoto, J. Tanaka, C. Redshaw and
T. Yamato, ChemistrySelect, 2020, 5, 1269–1274.
Similarly, compound 4c was treated with t-BuOK in t-BuOH at
80°C for 24 h to afford 4,20-dimethoxy[2.8]- metacyclophane-1-
yne, 6c in 98% yield as colourless prisms (methanol). M.p.
137 °C. IR: nmax (KBr): 2925, 1504, 1228, 1240, 1100, 1030 and
811 cm–1. 1H-NMR (300 MHz, CDCl3): d = 1.47–1.51 (8H, broad
s, CH2), 1.65 (4H, broad s, CH2), 2.63–2.66 (4H, m, CH2), 3.88
[8] (a) M. M. Islam, T. Hirotsugu, T. Matsumoto, J. Tanaka and T. Yamato,
Can. J. Chem., 2015, 93, 1161–1168; (b) M. M. Islam, T. Akther, S.
Rahman, P. E. Georghiou, T. Matsumoto, J. Tanaka, C. Redshaw and T.
Yamato, ChemistrySelect, 2017, 2, 7255–7262.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
(b) Y. Okada and J. Nishimura, J. lncl. Phenom. Mol. Recognit. Chem.,
1994, 19, 41–53.
[27] T. Yamato, K. Fujita and H. Tsuzuki, Can J. Chem., 2000, 78, 1089–1099.
[9] (a) M. M. Islam, T. Hirotsugu, P.Thuery. T. Matsumoto, J. Tanaka, M. R. J.
Elsegood, C. Redshaw and T. Yamato, J. Mol. Struct., 2015, 1098, 47–
54; (b) M. M. Islam, T. Hirotsugu, T. Matsumoto, J. Tanaka, S. Rahman, P.
E. Georghiou, C. Redshaw and T. Yamato, Org. Biomol. Chem., 2015, 13,
9055–9064; (c) M. M. Islam, T. Akther, Y. Ikejiri, T. Matsumoto, J. Tanaka,
S. Rahman, P. E. Georghiou, D. L. Hughes, C. Redshaw and T. Yamato,
RSC Adv., 2016, 6, 50808–50817; (f) M. M. Islam, C.-Z. Wang, X. Feng,
S. Rahman, P. E. Georghiou, A. Alodhayb and T. Yamato,
ChemistrySelect, 2018, 3, 13542–13547
[10] T. Yamato, J. Matsumoto, M. Sato, K. Noda and M. Tashiro, J. Chem.
Soc., Perkin Trans. 1, 1995, 1,1299.
[11] (a) M. Tashiro and T. Yamato, Synthesis, 1981, 435; (b) T. Yamato, J.
Matsumoto, K. Tokuhisa, K. Tsuji, K. Suehiro and M. Tashiro, J. Chem.
Soc., Perkin Trans. 1, 1992, 2675; (c) T. Yamato, A. Miyazawa and M.
Tashiro, J. Chem. Soc., Perkin Trans. 1, 1993, 3127; (d) T. Yamato, Y.
Saruwatari, L. K. Doamekpor, K. Hasegawa and M. Koike, Chem. Ber.,
1993, 126, 2501.
[12] (a) T. Yamato, J. Matsumoto, S. Ide, K. Tokuhisa, K. Suehiro and M.
Tashiro, J. Org. Chem., 1992, 57, 5243; (b) T. Yamato, J. Matsumoto, K.
Tokuhisa, M. Kajihara, K. Suehiro and M. Tashiro, Chem. Ber., 1992,
125, 2443.
[13] (a) J. E. McMurry, M. P. Fleming, K. L. Kees and L. R. Krepski, J. Org.
Chem. 1978, 43, 3255; (b) J. E. McMurry, Acc. Chem. Res. 1983, 16,
405; (c) J. E. McMurry, G. J. Haley, J. R. Matz, J. C. Clardy and G. V.
Duyne, J. Am. Chem. Soc. 1984, 106, 5018; (d) J. E. McMurry, Chem.
Rev., 1989, 89, 1513; (e) R. H. Mitchell and S. A. Weerawana,
Tetrahedron Lett., 1986, 27, 453.
[14] (a) D. Tanner and O. Wennerström, Acta Chem. Scand. Ser. B, 1983,
37, 693; (b) H. Hopf and C. Mlynek, J. Org. Chem. 1990, 55, 1361.
[15] (a) H.-F. Grützmacher, E. Neumann, F. Ebmeyer, K. Albrecht and P.
Schelenz, Chem. Ber., 1989, 122, 2291–2297; (b) H.-F. Grützmacher
and E. Neumann, Chem. Ber., 1993, 126, 1495–1497; (c) H.-F.
Grützmacher and G. Nolte, Chem. Ber., 1994, 127, 1157–1162; (d) H.-
F. Grützmacher, A. Mehdizadeh and A. Mülverstedt, Chem. Ber., 1994,
127, 1163–1166.
[16] Y. Uchikawa, K. Tazoe, S. Tanaka, X. Feng, T. Matsumoto, J. Tanaka
and T. Yamato, Can. J. Chem., 2012, 90, 441–449.
[17] (a) Cyclophanes. Vol. 1. P. M. Keehn and S. M. Rosenfield (Editors).
Academic Press. New York, 1983. Chap. 6 p. 428; (b) F. Vögtle,
Cyclophane-Chemistry, Wiley, Chichester, 1993.
[18] D. Krois and H. Lehner, Tetrahedron, 1982, 38, 3319.
[19] (a) H. Förster and F. Vögtle, Angew. Chem., 1977, 89, 443; Angew.
Chem. Int. Ed. Engl., 1977, 16, 429; (b) R. H. Mitchell, K. S. Weerawana
and G. W. Bushnell, Tetrahedron Lett., 1984, 25, 907; (c) K. Böckman
and F. Vögtle, Chem. Ber., 1981, 114, 1065; (d) M. F. Semmelhack, J. J.
Harrisson, D. C. Young, Y. Guitierrez, S. Rafii and J. Clardy, J. Am. Chem.
Soc., 1985, 107, 7508.
[20] (a) T. Yamato, K. Fujita and H. Tsuzuki, J. Chem. Soc., Perkin Trans. 1,
2001, 2089–2097; (b) T. Saisyo, M. Shiino, T. Hironaka and T. Yamato,
J. Chem. Res., 2007, (S) 141–143; (c) T. Saisyo, M. Shiino, T. Shimizu,
A. Paudel and T. Yamato, J. Chem. Res., 2008, (S)479–483.
[21] A. Merz, A. Karl, T. Futterer, N. Stacherdinger, O. Schneider, J. Lex, E.
Luboch and J. F. Biernat, Liebigs Ann. Chem., 1994, 1994, 1119.
[22] S. Kajigaeshi, T. Kakinami, H. Tokiyama, T. Hirakawa and T. Okamoto,
Chem. Lett. 1987, 627.
[23] T. Kawase, N. Ueda and M. Oda, Tetrahedron Lett., 1997, 38, 6681.
[24] E. Kloster-Jenzsen and J. Wurz, Angew. Chem., 1973, 85, 723; E.
Kloster-Jenzsen and J. Wurz, Angew. Chem. Int. Ed. Engl., 1973, 12,
671.
[25] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A.
Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F.
Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, Jr. J. A. Montgomery, J. E. Peralta, F.
Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N.
Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A.
Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A.
D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J.
Fox, Gaussian 09, Revision D.01; Gaussian, Inc., Wallingford CT, 2013.
[26] (a) K. K. Catlin and F. J. Heldrich, Syn. Commun., 1990, 20, 439-446;
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000548
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Synthesis and structures of
[2.n]metacyclophan-1-enes
Metacyclophanes
T. Akther,[a] M. M. Islam,[a],[b] J. Kowser,[a],[c] T.
Matsumoto,[d] J. Tanaka,[d] S. Rahman,[e],[f] A.
Alodhayb,[f],[g] P. E. Georghiou,[e] C. Redshaw[h]
and T. Yamato*[a]
and their conversion to highly
strained [2.n]metacyclophane-
1-ynes, in which the triple
bonds are distorted from
linearity with bond angles of
156.7°–161.4°, are discussed.
Page No. – Page No.
Synthesis
[2.n]Metacyclophan-1-enes
Conversion to
[2.n]Metacyclophane-1-ynes
and
Structures
and
Highly
of
their
Strained
Keywords: [2.n]Metacyclophane-1-ynes•
Structures• Strained molecule• Diels-Alder
reaction • DFT Calculation.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.