Glaser-Eglinton-Hay sp-sp coupling and macrocyclization: Construction of a new class of polyether macrocycles having a 1,3-diyne unit

Article abstract of DOI:10.1039/c4ra02174f

Glaser-Eglinton-Hay-type sp-sp coupling, macrocyclization and the construction of skeletally interesting, 18-27 membered, polyether macrocycles having a 1,3-diyne unit-based cylindrical backbone are reported. The utility of polyether macrocycles having th

Full text of DOI:10.1039/c4ra02174f

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Glaser–Eglinton–Hay sp–sp coupling and
macrocyclization: construction of a new class of
Cite this: RSC Adv., 2014, 4, 18904
polyether macrocycles having a 1,3-diyne unit†
*
Naveen, Srinivasarao Arulananda Babu, Gurpreet Kaur, Nayyar Ahmad Aslam
and Maheswararao Karanam
Glaser–Eglinton–Hay-type sp–sp coupling, macrocyclization and the construction of skeletally interesting,
18–27 membered, polyether macrocycles having a 1,3-diyne unit-based cylindrical backbone are reported.
The utility of polyether macrocycles having the 1,3-diyne units is shown by incorporating isoxazole and
thiophene moieties into the macrocycles. The structures of representative crown ether/polyether-type
macrocycles were unambiguously established from single crystal X-ray structure analyses. Investigation
of the X-ray structures of representative macrocycles revealed that the 1,3-diyne unit was not linear and
was found to be bent.
Received 12th March 2014
Accepted 10th April 2014
DOI: 10.1039/c4ra02174f
www.rsc.org/advances
can be considered as important molecular tools to constrain the
molecular conformation and the inherent rigidity and direc-
Introduction
tionally dened precise cylindrical symmetry of diyne units have
been well exploited in different areas of chemical science.6–9
Diverse families of shape persistent unsaturated macrocycles,
especially, having the diyne unit-based rigid backbones, e.g.
annulenes, rotanes, cyclophanes, cage compounds and articial
receptors with novel structures and appreciable physicochem-
ical properties have been constructed using the Glaser–Eglin-
ton–Hay-type coupling strategy.2,7–9
Macrocycles are fascinating molecular frameworks, present as
core units in numerous natural products and biologically active
molecules.1 The construction of macrocycles is one of the
interesting chemical transformations.1,2 Rigidied and strained
macrocycles have found signicant applications in several
scientic elds because of their shape persistent skeletons and
distinctive properties.2 Various methods are available for the
assembly of macrocycles and a large number of macrocycles has
been synthesized by using standard peptide coupling, the
Yamaguchi lactonization, ring closing metathesis and other
techniques.1c,3,4
Along this line, Cu or Pd-based Glaser–Eglinton–Hay-type
reaction is a highly attractive tactic for the synthesis of diyne-
based shape persistent macrocycles and linear conjugated
diynes.5–8 Macrocyclization was also reported with the aid of a
conformational control element, if a normal ring closing
metathesis reaction (RCM) or Glaser–Eglinton–Hay-type reac-
tion is ineffective.8e
Crown ether/polyether-type macrocycles including lariat
crown ethers can be considered as the cornerstones of supra-
molecular chemistry1d,10 and they exhibit unique properties and
numerous applications in chemical and biological sciences,
including anticancer, DNA interaction and other biological
activities.11 Due to the very high importance of crown ether/poly-
ether-type macrocycles in various branches of science, study of
the synthesis and supramolecular chemistry of new crown ether/
polyether macrocycles has become one of the attractive areas of
chemical research.10–12 However, despite the existing develop-
ments in a pivotal research area involving the synthesis of new
polyether macrocycles and the functional derivatization or
periphery modication of crown ethers; the synthesis of crown
ether-type macrocycle having a diyne unit-based cylindrical rigid
backbone has not been well explored. The incorporation of a
diyne unit as a part of crown ether/polyether macrocycles could
provide directionally precise rigidity to polyether macrocycles
and perhaps, new insights on their supramolecular chemistry
including the stereochemical conformations. However, to the
best of our knowledge and a survey of literature revealed that
there exist only two preliminary reports9 dealing on the synthesis
of macrocycles appended with crown ether skeleton, which is
linked via a 1,3-diyne unit-based backbone.
Notably, diyne-based molecules are important building
blocks in industrial and synthetic chemistry and electronic/
optical materials, and exhibit prominent biological activities.7,8
The incorporation of a diyne unit in the molecular frameworks
Department of Chemical Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar, Knowledge City, Mohali, Punjab
140306, India. E-mail: sababu@iisermohali.ac.in; Fax: +91-172-2240266; Tel: +91-
172-2240266
† Electronic supplementary information (ESI) available: Copies of NMR spectra of
all compounds and details of the single crystal X-ray data (CIF) of the compounds
5a, 5f, 5g, 5h, 5i, 5k, 6a, 6c, 6g, 7b, 7d, 8a, 9a and 9c. CCDC 978362, 978447,
970700–970711. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ra02174f
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Motivated by the existing developments related to the
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Successively, we tried the macrocyclization of 4a in DMF
synthesis and applications of macrocyclic materials having the and the Glaser–Eglinton–Hay-type macrocyclization of
diyne units-based backbones7,8 and in line with our objectives substrate 4a in DMF at 110 C afforded the rigidied macro-
ꢀ
directed toward displaying the construction of functionally cycle 5a, possessing a 1,3-diyne unit-based backbone in 38%
modied and rigidied crown ether/polyether macrocyclic yield. Further, the macrocycle 5a was obtained with an
compounds; we herein report our preliminary works on the improved yield (52%) when the reaction was performed in
production of a new class of crown ether/polyether macrocycles reuxing MeCN. Next, the Glaser–Eglinton–Hay-type macro-
having a 1,3-diyne unit-based cylindrical backbone and their cyclization of substrate 4a in the presence of Cu(OAc)2$H2O in
utility for the incorporation of isoxazole and thiophene moieties DMSO at 110 ꢀC under an open-air atmosphere gave the
into the new crown ether/polyether macrocyclic derivatives macrocycle 5a in 70% yield (Scheme 3). Likewise, the macro-
(Scheme 1).
cyclization of the substrates containing two terminal alkynes
4b–f, which were derived from different aliphatic- and benzylic
chain linkers afforded the corresponding macrocycles 5b–f in
43–70% yields (Scheme 3).
Results and discussion
Subsequently, the substrates 4g and 4h, which were derived
from the linkers containing an unsaturated backbone under-
went the intramolecular acetylenic coupling and gave the cor-
responding rigidied macrocycles 5g (43%) and 5h (35%),
connected through a diyne moiety. The Glaser–Eglinton–Hay
coupling reaction of the benzoate derivative 4i, having two
terminal alkyne units gave the macrocycle 5i in 25% yield. The
intramolecular acetylenic coupling of the starting materials 4j
and 4k derived from meta- and para-hydroxy benzaldehydes
furnished the respective macrocycles 5j and 5k in 25% yields
(Scheme 3).
To execute the scope of this protocol, we carried out the
Glaser–Eglinton–Hay coupling reaction using the substrates
4l–p having two terminal alkyne units, which were assembled by
employing various polyether units-based linkers. The intra-
molecular Glaser–Eglinton–Hay coupling reaction of the
substrates 4l–p in the presence of Cu(OAc)2$H2O in DMSO at
110 ꢀC under an open-air atmosphere gave the novel and
structurally interesting crown ether/polyether macrocycles 6a–e
in 30–52% yields, respectively (Fig. 1). The macrocyclization
reaction of the substrates 4q, which was assembled by using a
polythioether unit-based linker afforded an interesting crown-
type macrocycle 6f in 30% yield. Next, in this line the Glaser–
Eglinton–Hay coupling reaction of the benzoate derivative 4r
possessing two terminal alkyne units gave the crown-type
macrocycle 6g in 35% yield (Fig. 1).
At the outset, to prepare crown ether/polyether-based unsatu-
rated macrocycles possessing a 1,3-diyne unit-based rigid
backbone, we prepared the required starting materials pos-
sessing terminal alkyne units with the generalized structure 4,
starting from different o-hydroxy benzaldehydes (Scheme 2).
Various o-hydroxy benzaldehydes (1) were treated with a variety
of linkers (10) using standard procedures, which furnished
several bis-aldehydes with the generalized structure 2. Next,
treatment of the bis-aldehydes (2) with NaBH4 followed by base-
mediated O-propargylation afforded a variety of starting mate-
rials containing the terminal alkyne units with the generalized
structure 4 (Scheme 2).
Then, we began our investigations on the sp–sp carbon–
carbon bond forming macrocyclization of the substrates 4a–r
(Scheme 3 and Fig. 1). Initially, we carried out the Glaser–
Eglinton–Hay-type macrocyclization reaction of substrate 4a in
the presence of Cu(OAc)2$H2O in various solvents to nd out a
suitable reaction condition. The Glaser–Eglinton–Hay-type
macrocyclization reaction of substrate 4a in the presence of
Cu(OAc)2$H2O in toluene at reuxing temperature under an
open-air atmosphere for 24 h did not afford the expected mac-
rocycle 5a (Scheme 3). Similarly, the Glaser–Eglinton–Hay-type
macrocyclization reaction of substrate 4a failed to afford the
expected macrocycle 5a when the reaction was carried out in
1,4-dioxane (Scheme 3).
Scheme 1 Theme of this work.
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Scheme 2 Assembling of the starting materials 4, having the terminal alkyne units.
Further, to elaborate the substrate scope, we aimed to
Taking an impetus from the Gokel's substrate,12f we per-
prepare substrates containing two terminal alkyne units from formed the intramolecular Glaser–Eglinton–Hay coupling
bis-homoallylic alcohol which can be assembled via the Zn- reactions of the substrates 4s–w in the presence of
mediated allylation strategy (Scheme 4). In this line, salicy- Cu(OAc)2$H2O in DMSO at 110 ꢀC under an open-air atmo-
laldehyde was treated with a variety of linkers (10) using stan- sphere. These reactions led to the synthesis of structurally
dard procedures to afford the corresponding bis-aldehydes (2), interesting C-pivot lariat crown ether/polyether-type macro-
which were subsequently treated with allyl bromide and zinc cycles 7a–e having a 1,3-diyne unit in 35–75% yields, respec-
dust. The Zn-mediated allylation of bis-aldehydes gave different tively (Scheme 4). Since the starting substrates 4s–w were
bis-homoallylic alcohols (3s–w) as a mixture of diastereomers isolated as a mixture of diastereomers (dr 50 : 50, Scheme 4) in
(dr 1 : 1). Further, the base-mediated O-propargylation of the the previous step, the Glaser–Eglinton–Hay macrocyclization of
bis-homoallylic alcohols (3s–w) afforded a variety of starting the substrates 4s–w resulted the corresponding macrocycles 7a–
materials comprising of two terminal alkyne units 4s–w incor- e having two remote stereocenters (‘x’ and ‘y’) and as a mixture
porated with the allylic chains as the side-arms (Scheme 4). of diastereomers (dr 60 : 40). Unfortunately, all our attempts to
Before discussing the Glaser–Eglinton–Hay macrocyclization of separate the diastereomers were not successful.
the substrates 4s–w, it is worth to mention here that in some
Subsequently, as a part of our interest in the post ring-
of the crown ethers reported in the literature, the incorporation closure functional derivatization of polyether macrocycles, next
of an allylic chain as a sidearm was found to be important to we focused our attention to execute the utility of the macrocyclic
induce an effective encapsulation of metals.12e,f For example, compounds possessing the 1,3-diyne units, which were
Gokel and co-workers have reported a solid state evidence that obtained in this work. Recently, Yu and Bao reported an effi-
neutral double bonds attached to exible side-arm of a lariat cient method for the synthesis of 3,5-disubstituted isoxazoles
crown ether, serving as the intramolecular p-donors for a ring- via the Cope-type hydroamination of the 1,3-dialkyne units.13d
bound Na+ cation.12f
Along this line, some of the 1,3-diyne units containing
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Scheme 3 Assembling of 18–24-membered, rigidified crown ether/polyether-type macrocycles having a 1,3-diyne unit-based backbone.13c a 1
equiv. of Cu(OAc)2$H2O was used. b The reaction was done in toluene or 1,4-dioxane at refluxing temperature. c The reaction was done in DMF at
110 ꢀC. d The reaction was done in refluxing MeCN. e The reaction was performed using 0.25 mmol of the starting material. f The reaction was
performed using 0.5 mmol of the starting material. g 30 mol% of catalyst was used. h The reaction was performed using 0.12 mmol of starting
material.
macrocycles prepared via the Glaser–Eglinton–Hay macro- condition reported by the Jiang's group,13e we performed the
cyclization were examined for the construction of a variety of reactions of various macrocycles 5c, 6a, 6d and 6f with Na2S$xH2O
ꢀ
new examples of isoxazole appended crown ether-type macro- in the presence of 1,10-phenanthroline and CuI in DMF at 90 C
cycles by using recently procedures.13d,e The reaction of 5a, 5b, under an open-air atmosphere. These reactions afforded the cor-
5e, 5f, 6a, 6c and 7a–c having the 1,3-diyne units with responding thiophene moiety appended 20–26-membered, new
NH2OH$HCl and Et3N gave the corresponding isoxazole moiety crown ether-type macrocycles 9a–d in 17–55% yields (Scheme 6).
appended, a new class of 18–21-membered crown ether-type
The Glaser–Eglinton–Hay-type sp–sp carbon–carbon bond
macrocycles 8a–i in satisfactory yields (Scheme 5). It is note- forming macrocyclization of various substrates with the gener-
worthy to mention that the isoxazole is an important structural alized structure 4 afforded a simple route for the synthesis of
unit, present in several bioactive molecules and natural prod- skeletally interesting, rigidied crown ether/polyether macro-
ucts.14 Further, these crown ether-type macrocycles 8a–i cycles possessing a 1,3-diyne unit-based cylindrical backbone.
appended with the isoxazole moiety can be considered as The structures of all the crown ether/polyether-type macrocycles
crownophane-type molecules.
obtained in this work were characterized by the 1H and 13C NMR
Inspired by an another work reported by the Jiang and co- analysis and mass spectrometry. Further, the structures of
workers, which deals on the Cu(I)-catalyzed synthesis of 2,5- representative crown ether/polyether-type macrocycles were
disubstituted thiophenes from the 1,3-diyne units, we decided to unambiguously established from the preliminary single crystal
examine the construction of thiophene ring appended crown X-ray diffraction studies.13f,g Single crystal data and the results of
ether-type macrocycles from the macrocycles having the 1,3-diyne the structure renement details are listed in the Table 1, which
units, which were prepared in this work. By employing the reaction can be found in the ESI.†
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in the ESI†). No p/p interactions were found in the crystal
structure of these molecules.
The single crystal X-ray structure revealed that the molecule
5f was found to crystallize in the space group P21/c with one
21-membered macrocyclic molecule in the asymmetric unit
(Fig. 3). In contrast to the molecule 5a, with the incorporation of
the benzene ring in to the linker, the distance between the
˚
phenyal rings has increased by ꢁ3 A and the bending angle of
the 1,3-diyne unit was found to be ꢁ11ꢀ. The interplanar angles
between the linker phenyl group (having substitutions at the
1,3-positions) and the two phenyl rings (having substitutions at
the 1,2-positions) was ꢁ21ꢀ and ꢁ77ꢀ, respectively. The two
phenyl rings (having substitutions at the 1,2-positions) have
been found to be inclined at an angle of ꢁ56ꢀ. Whereas, the
torsion angle for the 1,3-diyne unit was ꢁ13ꢀ. C–H/O and
C–H/p hydrogen bonds have been found to pack the mole-
cules in the crystal lattice (Fig. S3 and S4 in the ESI†). Inter-
estingly, the phenyl ring, which act as a linker, has been found
to be involved in p/p stacking (Fig. 3).
The X-ray structure analysis revealed that the molecule 5g
was found to crystallize in the space group P21/c with one
20-membered macrocyclic molecule in the asymmetric unit
(Fig. 4). With reference to the molecule 5a, the incorporation of
Fig.
1 21–27-membered, rigidified crown ether/polyether-type
a
macrocycles having a 1,3-diyne unit-based backbone.13c Reaction an extra trans alkene (ethylene) linkage led the distance between
condition A:13a Cu(OAc)2$H2O (30 mol%), DMSO, 110 ꢀC, 4 h and open-
˚
the phenyl rings to increase by ꢁ2 A. The bending and torsion
air atm. b The reaction was done using 0.3 mmol of the corresponding
angles of the 1,3-diyne linkage were found to be ꢁ14ꢀ and ꢁ11ꢀ,
c
starting material. Reaction condition B:13b Cu(OAc)2$H2O (1 equiv.),
respectively. The interplanar angle between the two phenyl
d
DMSO, 110 ꢀC, 4 h and open-air atm. The reaction was done using
rings was found to be ꢁ53ꢀ. C–H/O and C–H/p hydrogen
e
0.5 mmol of the corresponding starting material. The reaction was
done using 0.2 mmol of the respective starting material.
bonds have been found to pack the molecules in the crystal
lattice (Fig. S5 and S6 in the ESI†). No p/p interactions have
been found in the crystal structure of this molecule.
All the molecules reported in this manuscript contains R3C–
C^C–C^C–CR3 moiety, which is ideally expected to be linear
with all the four :–C^C–C– type angles to be equal to 180ꢀ. It
has been found that all these angles have been deviated from
180ꢀ. Therefore, the bend angle for the R3C–C^C–C^C–CR3
moiety has been calculated by subtracting the sum of all the
four angles from the sum of their ideal values i.e., 720ꢀ – (q1 + q2
+ q3 + q4), where q1–4 are the corresponding observed (from
single crystal X-ray data) bond angles. The bend angles have
been incorporated in the Table 1.
The single crystal X-ray diffraction study revealed that the
molecule 5h was found to crystallize in the space group P21/c
with one 20-membered macrocyclic molecule (Fig. 4). With
reference to the molecule 5a, the incorporation of the alkyne
(acetylenic, (C15 and C16)) group in to the linkage led the
˚
distance between the phenyl rings to increase by ꢁ3 A. The
bending and torsion angles of the 1,3-diyne linkage were found
to be ꢁ8ꢀ and ꢁ115ꢀ, respectively. Two phenyl rings are inclined
at an angle of ꢁ61ꢀ. The bending angle of the (mono) acetylenic
unit was found to be ꢁ11ꢀ. C–H/O and C–H/p hydrogen
bonds have been found to pack the molecules in the crystal
lattice (Fig. S7 and S8 in the ESI†). No p/p interactions have
been found in the crystal structure of this molecule.
Description of the crystal structures of representative crown
ether/polyether macrocycles containing a 1,3-diyne unit
The X-ray structure analysis showed that the molecule 5i
The single crystal X-ray diffraction study revealed that the contains a 20-membered macrocyclic ring and was found to
molecule 5a was found to crystallize in the space group P21/c crystallize in the space group P21/c with one molecule in the
with two independent 18-membered macrocyclic molecules in asymmetric unit. In this molecule, two phenyl groups (having
the asymmetric unit (Fig. 2). In each molecule, the two phenyl substitutions at 1,2-positions such as C8/C13 and C22/C27)
rings have been found to be inclined at an angle of ꢁ90ꢀ to each have been found to be inclined at an angle of ꢁ73ꢀ. The inter-
other and both the conformers majorly differ with respect to the planar angles between the phenyl rings having substitutions at
torsion angles of the 1,3-diyne linkage, which is about <1ꢀ and 1,2-positions and the phenyl group (C15 to C20), which acts as a
ꢁ7ꢀ respectively. The distance between phenyl rings in the both linker were found to be ꢁ86ꢀ and ꢁ47ꢀ (Fig. 4). The torsion
the conformations was same (ꢁ8 A) and in each conformer the angle for the 1,3-diyne unit is ꢁ10ꢀ. The 1,3-diyne unit found to
˚
1,3-diyne linkage has been found to be bent with an angle of be not linear, the bending angle was found to be ꢁ17ꢀ. C–H/O
ꢁ15ꢀ. In the crystal packing of these molecules, majorly C–H/ and C–H/p hydrogen bonds have been found to pack the
O and C–H/p hydrogen bonds have been found (Fig. S1 and S2 molecules in the crystal lattice (Fig. S9 and S10 in the ESI†). No
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a
Scheme 4 18–24-membered rigidified crown ether/polyether-type macrocycles having a 1,3-diyne unit-based backbone.13c Reaction
condition A:13a Cu(OAc)2$H2O (30 mol%), DMSO, 110 ꢀC, 4 h and open-air atm. b Reaction condition B.13b c The reaction was done using 0.4 mmol
of the respective starting material. d The observed dr ¼ 60 : 40. e The reaction was done using 1 mmol of the respective starting material. f The
reaction was done using 0.2 mmol of the respective starting material.
p/p interactions have been found in the crystal structure of found to pack the molecules in the crystal lattice (Fig. S13 in the
this molecule.
ESI†). No p/p interactions have been found in the crystal
The single crystal X-ray diffraction study revealed that the structure of this molecule.
ꢀ
molecule 5k was found to crystallize in the space group P1 with
Preliminary single crystal X-ray diffraction study of the
one 24-membered macrocyclic molecule (Fig. 5) and this 24-membered macrocyclic compound 6c indicated that only half
compound was prepared using 4-hydroxybenzaldehyde. When of the molecule is present in the asymmetric unit due to crys-
compared to the molecule 5a (which was prepared from tallographic imposed two fold symmetry and the structure
2-hydroxybenzaldehyde) in this structure, the distance between having a center of inversion symmetry (Fig. 5). The 1,3-diyne unit
˚
the phenyl rings was found to decrease by ꢁ2 A and the bending between the two phenyl groups was found to be bent and the
and torsion angles of the 1,3-diyne unit were found to be ꢁ16ꢀ bending angle was found to be ꢁ19ꢀ and the angle between the
and ꢁ15ꢀ, respectively. The interplanar angle between the two phenyl rings was found to be ꢁ56ꢀ. The distance between the
phenyl rings has been found to be ꢁ70ꢀ. The C–H/O and C– phenyl rings is ꢁ13 A. The crystal packing doesn't contain any
˚
H/p hydrogen bonds have been found to pack the molecules strong hydrogen bonds other than van der Waals interactions.
in the crystal lattice (Fig. S11 and S12 in the ESI†). No p/p
The compound 6g doesn't have any center of symmetry and
interactions have been found in the crystal structure of this one full molecule was found to be present in the asymmetric
molecule.
unit as a 24-membered macrocyclic ring (Fig. 6). The bending
The single crystal X-ray diffraction study revealed that the angle of the 1,3-diyne unit was found to be ꢁ11ꢀ. The interplanar
molecule 6a was found to crystallize in the space group P21/c angle between two phenyl rings was found to be ꢁ73ꢀ and those
˚
with one 21-membered macrocyclic molecule in the asymmetric rings are ꢁ13 A distance apart from each other, which is similar
unit (Fig. 5). The incorporation of an oxygen atom at the center to the structure 6c. Out of two ester groups, one carbonyl group
of the butyl linkage led the distance between the phenyl rings to (C26/O8) was found to be in-plane to benzene ring whereas the
increase by ꢁ2 A (with respect to 5a). The bending and torsion other group was found to be out of the plane by an angle of ꢁ36ꢀ,
˚
angles of the 1,3-diyne linkage were found to be ꢁ12ꢀ and ꢁ19ꢀ, which has led the molecule to be in an unsymmetrical form. The
respectively. The interplanar angle between two phenyl rings molecules are found to be interconnected by only C–H/O
was found to be ꢁ41ꢀ. C–H/p hydrogen bonds have been hydrogen bonds (Fig. S14 in the ESI†).
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Table 1 Cavity dimensions (in A˚) of the crown ether/polyether mac-
rocycle from their X-ray structures
Approximate cavity
dimensions
Approximate
bend angle
of 1,3-diyne
a
b
˚
(m ꢂ n in A)
Entry Compound Ring size from X-ray structurec,d unit/ꢀ
1
2
3
4
5
6
7
8
5a_1
5a_2
5f*
5g
5h
5i
18
18
21
20
20
20
24
21
24
24
20
21
21
18
20
21
4 ꢂ 7
4 ꢂ 7
4 ꢂ 8
5 ꢂ 7
3 ꢂ 8
4 ꢂ 7
6 ꢂ 8
4 ꢂ 8
4 ꢂ 8
4 ꢂ 8
4 ꢂ 8
4 ꢂ 8
4 ꢂ 8
4 ꢂ 6
6 ꢂ 6
5 ꢂ 8
15
15
11
14
8
17
16
12
18
11
5
12
7
—
—
—
5k
6a
9
6c*
6g*
7b
7d_1
7d_2
8a
10
11
12
13
14
15
16
9a
9c
a
Center to center distance between the 1,3-diyne bridges and the
b
linkers. Center to center distance between two benzylic carbons,
except the compounds 5f, 6c, and 6g. In all the compounds, the
c
Scheme 5 Synthesis of isoxazole ring-appended 18–24-membered,
crown ether-type macrocycles via the Cope-type hydroamination of
cavity dimensions are calculated from the center to center distance
between the 1,3-diyne bridges and the linkers as well as the center to
center distance between two benzylic carbons, except the compounds
the substrates 5/6/7. a The reaction was done using 0.18 mmol of the
b
corresponding starting material.
The reaction was done using
d
5f, 6c, and 6g. In the cases of the compounds 5f, 6c, and 6g, the
0.25 mmol of the corresponding starting material. c Dr ¼ 60 : 40. The
reaction was done using the corresponding mixture of diastereomers
7a–c. d The reaction was done using 0.12 mmol of the corresponding
starting material.
cavity dimensions are calculated from the center to center distance
between the 1,3-diyne bridges and the linkers as well as the distance
between the two oxygen atoms, which are attached to the benzylic
carbons.
diyne unit was found to be ꢁ5ꢀ and the inter-planer angle
between the two phenyl rings was found to be ꢁ57ꢀ. No p/p
interactions have been found in the crystal structure of this
molecule.
The single crystal X-ray diffraction study revealed that the
ꢀ
molecule 7d was found to crystallize in P1 space group and
asymmetric unit was found to contain two independent mole-
cules (Fig. 7). In the molecule 7d_1, the bending angle of the
1,3-diyne unit was found to be ꢁ12ꢀ, however, in the case of
7d_2 the bending angle of the 1,3-diyne unit was found to be
ꢁ7ꢀ. The interplanar angle between two phenyl rings of the
conformers 7d_1 and 7d_2 were found to be ꢁ64ꢀ and ꢁ66ꢀ,
respectively. Two different conformations were found in the
crystal packing and the interplanar angles between phenyl rings
were almost same. The C–H/p hydrogen bonds have been
found to pack the molecules in the crystal lattice (Fig. S15 in
the ESI†).
Scheme
6 Thiophene ring appended 20–26-membered crown
a
ether-type macrocycles. The reactions were done using the corre-
sponding starting materials as given in the parenthesis, (for 9a; 0.25
mmol of 6a) (for 9b; 0.39 mmol of 6d) (for 9c; 0.3 mmol of 5c) (for 9d;
0.06 mmol of 6f).
The single crystal X-ray structure analysis showed that the
18-membered macrocyclic compound 8a was found to crystal-
lize in the P21/c space group and the asymmetric unit contained
The 20-membered macrocyclic compound 7b, doesn't have one full molecule (Fig. 8). The interplanar angle between two
any center of inversion symmetry and one full molecule was phenyl rings was found to be ꢁ76ꢀ and the interplanar angle
found to be present in the asymmetric unit (Fig. 6). This between phenyl and isoxazole rings was found to be ꢁ61ꢀ and
molecule contains a exible sidearm group (allyl chain) at the ꢁ73ꢀ (with respect to each phenyl ring), respectively. The
˚
benzylic carbons (C7 and C24) and the bending angle of the 1,3- distance between the phenyl rings was found to be ꢁ8 A and the
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Fig. 2 (a) Ball and stick model (X-ray structure) of 5a_1 and (b) ball and stick model (X-ray structure) of 5a_2 were drawn at 0.15 times to atomic
van der Waals radius.
Fig. 3 (a) Ball and stick model (X-ray structure) of 5f was drawn at 0.15 times to atomic van der Waals radius. (b) p/p stacking between the
phenyl rings which act as the linker in the compound 5f.
Fig. 4 Ball and stick model (X-ray structures 5g–i) was drawn at 0.15 times to atomic van der Waals radius; (a) 5g (b) 5h (c) 5i.
Fig. 5 Ball and stick model (X-ray structures 5k and 6a, 6c) was drawn at 0.15 times to atomic van der Waals radius; (a) 5k (b) 6a (c) 6c. Only half of
the molecule is present in the asymmetric unit of the X-ray structure of the compound 6c. Therefore, the atoms at the right hand side of X-ray
structure of 6c (shown with a prime (0) label) are at equivalent position (1 ꢃ x, y, 1/2 ꢃ z) with respect to the atoms on the left hand side.
distances between phenyl and isoxazole ring were found to be
Preliminary single crystal X-ray diffraction study revealed
˚
˚
ꢁ6 A and ꢁ7 A (with respect to each phenyl ring), respectively. that the 20-memberd macrocyclic compound 9a was found to
No p/p interactions have been found in the crystal structure of crystallize in the Pnma space group with half the molecule in the
this molecule.
asymmetric unit. The molecule has a crystallographically-
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Fig. 6 Ball and stick model (X-ray structures 6g and 7b) was drawn at 0.15 times to atomic van der Waals radius; (a) 6g (b) 7b.
Fig. 7 (a) Ball and stick model (X-ray structure) of 7d_1 and (b) ball and stick model (X-ray structure) of 7d_2 was drawn at 0.15 times to atomic
van der Waals radius.
Fig. 8 Ball and stick model (X-ray structures 8a, 9a and 9c) was drawn at 0.15 times to atomic van der Waals radius; (a) 8a (b) 9a (c) 9c. Only half of
the molecule is present in the asymmetric unit of the X-ray structure of the compound 9a. Therefore, the atoms at the right hand side of X-ray
structure of 9a (shown with a prime (0) label) are at equivalent position (x, 3/2 ꢃ y, z) with respect to the atoms on the left hand side.
˚
imposed mirror symmetry which leads to the appearance of the rings (centroids) by ꢁ2 A and the interplanar angle between two
half of the molecule in the asymmetric unit (Fig. 8). The both phenyl rings was reduced to ꢁ42ꢀ. This increment has led
the methoxymethyl linkages connecting the thiophene and desymmetrization in the molecule. The crystal packing of 9c
phenyl ring were found to be in the same plane. The interplanar was majorly found to have van der Waals interactions among its
angle between the two phenyl rings was found to be ꢁ77ꢀ and molecules. No p/p interactions have been found in the crystal
the interplanar angle between the phenyl and thiophene rings structure of this molecule.
was found to be ꢁ77ꢀ. The C–H/p hydrogen bonds have been
Subsequently, we calculated the cavity dimensions in the
found to pack the molecules in the crystal lattice (Fig. S16 in X-ray structures of representative crown ether/polyether mac-
the ESI†).
rocycles obtained in this work. The cavities in the X-ray struc-
The single crystal X-ray structure analysis revealed that the ture of representative crown ether/polyether macrocycles can be
21-membered macrocyclic compound 9c was found to pack in approximated to be a rectangular box and the cavity dimensions
P1 space group and one full molecule was found in the asym- are mentioned in Table 1.13f,g From all the above deliberations
ꢀ
metric unit (Fig. 8). While considering that the methoxymethyl about the X-ray structures of representative macrocycles pre-
thiophene linkage between the phenyl rings is same in the sented in this work, it was observed that in these set of mole-
structures 9c and 9a, however, the change of linker from poly- cules the 1,3-diyne unit was not able to hold the linearity.13g It
ether unit-based linker (9a) in to a exible alkyl chain-based seems that the substituents attached to the benzylic carbon,
linker (9c) has led to increase the distance between two phenyl size and nature of the linkers are playing some signicant roles
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to control the conformation including the shape of the 1,3- in the compound 6g, the 1,3-diyne unit is connected via the Ph–
diyne unit of the macrocycles synthesized in this work. In this COO (benzoyl carboxyl) groups (C7 and C24). In the case of the
line, we further scrutinized and compared some of the X-ray compound 6g the carbonyl group has been found to play an
structures to nd out the effect of the substituents attached to important role in controlling the bending of the 1,3-diyne unit;
the benzylic carbon, size and nature of the linkers on the though the ring size is same in the compounds 6g and 6c (entries
conformation of macrocycles having the 1,3-diyne units.
9 and 10, Table 1). However, the incorporation of the –COO
First of all, to see the effect of the substituent on the benzylic (benzoyl carboxyl) group has altered the cavity size of 6g.
carbon and on the bending angle of the 1,3-diyne unit, we have Furthermore, the bending angle of the 1,3-dialkyne unit in the
compared the structures of the compounds 6a and 7d, in which macrocycle 6g (bending angle ꢁ11ꢀ) was found to decrease by ꢁ7ꢀ
the ring size (21-membered) and the linkers are same, while an when compared to the structure of 6c (bending angle ¼ ꢁ18ꢀ).
allyl group has been incorporated at the benzylic carbons
Additionally, to explore the effect of the nature of the linker by
(C7/C24, Fig. 7a) in 7d. In these cases it was observed that the keeping the ring size constant, we have compared the structures
allylic groups at the benzylic carbons have not brought much of 7b, 5g and 5h. In the structure 7b, where the linker is the butyl
change in the cavity size of these molecules (entries 8,12 and 13, group (–CH2–CH2–CH2–CH2– (C14 to C17 unit)), the bending
Table 1) as well as on the bending angles of the 1,3-diyne unit angle of the 1,3-dialkyne unit was found to be ꢁ5ꢀ. Varying the
(bending angle ꢁ11ꢀ in 7d and bending angle ¼ ꢁ11ꢀ in 6a). linker from butyl group (see compound 7b) in to the 2,3-trans
Thus, apparently the allyl group was not playing any role in butenyl group (–CH2–CH]CH–CH2– (C14 to C17 unit), see the
controlling the strain, cavity size or the bending angle of the 1,3- compound 5g), the cavity size of the macrocyclic ring 5g was
diyne unit and the conformation of the molecule 7d.
found to be smaller when compared to the structure of 7b (entries
Then, to study the effect of the size or nature of the linkers on 4 and 11, Table 1), consequently, the ring strain is expected to
the bending angle of the 1,3-diyne unit, the X-ray structures of increase. Hence, the bend angle of the 1,3-dialkyne unit in the
5a and 7b, which have different linkers were compared. In the macrocycle 5g (bend angle ꢁ14ꢀ) was found to increase by ꢁ9ꢀ
compound 5a, the linker is an ethyl group (–CH2–CH2–), while when compared to the structure 7b (bend angle ꢁ5ꢀ).
butyl group acts as a linker in the case of 7b (–CH2–CH2–CH2–
Similarly, varying the linker from the 2,3-trans butenyl group
CH2–). Compound 7b contains the allyl groups at the benzylic (–CH2–CH]CH–CH2– (C14 to C17 unit), see the compound 5g)
carbons, which is not there in the compound 5a. It has already in to the –CH2–C^C–CH2– group (C14 to C17 unit), see the
been discussed that the allyl group was not playing any role in compound 5h, the cavity size of the macrocyclic ring 5h was
altering the cavity size and bending angle of the 1,3-dialkyne found to be smaller when compared to the structure of 5g
unit and hence, we envisaged to compare the structures of both (entries 4 and 5, Table 1). Surprisingly, the bending angle of the
the macrocycles (5a and 7b) on the basis of ring size. It has been 1,3-dialkyne unit in the macrocycle 5h (bending angle ꢁ8ꢀ) did
found that with the increase in the size of the ring from not increase more than the bending angle of the 1,3-dialkyne
18-membered (structure 5a) to 20-membered (structure 7b), the unit of the macrocycle 5g (bending angle ꢁ14ꢀ). On the other
cavity size has increased (entries 1,2 and 11, Table 1). Conse- hand, interestingly, the mono acetylenic unit linker (C14 to C17
quently, there is a decrease in the bending angle of the 1,3- unit) present in the structure 5h was found to be bent and the
dialkyne unit in 7b (bending angle ꢁ5ꢀ) by ꢁ10ꢀ when bending angle of the mono acetylenic unit linker was found to
compared to 5a (bending angle ¼ ꢁ15ꢀ).
be ꢁ11ꢀ, which indicated that in order to accommodate the ring
Increase in the size of the macrocyclic ring from strain, the (mono) acetylenic unit, which act as a linker (C14 to
20-membered (structure 7b) to 21-membered (compound 6a) by C17 unit) is also bending. From the preliminary analysis of the
the incorporation of an oxygen atom in the linker of 6a (–CH2– X-ray structures of representative macrocycles, it has been
CH2–O–CH2–CH2–) has resulted a decrease in the cavity size in found that the ring size and the nature of the linkers have been
the structure of 6a (entries 8 and 11, Table 1) and as a result the found to play vital role to accommodate the ring strain and
bending angle of the 1,3-dialkyne unit has increased by ꢁ7ꢀ in control the conformation including the shape of the 1,3-diyne
the structure of 6a (bending angle ꢁ12ꢀ) when compared to the unit of macrocycles.
structure of 7b (bending angle ꢁ5ꢀ).
When the size of the macrocyclic ring was increased from
21-membered (compound 6a) to 24-membered (compound 6c)
Conclusion
by the incorporation of another –CH2–O–CH2– group in the In summary, we have reported the production of skeletally
linker of 6a, not surprisingly the cavity size has got increased interesting, a new class of rigidied crown ether/polyether mac-
(entries 8 and 9, Table 1) and it is expected that the bending rocycles having a 1,3-diyne unit-based cylindrical backbone via
angle of the 1,3-dialkyne unit in the structure 6c has to decrease the Glaser–Eglinton–Hay macrocyclization route. We have also
when compared to the structure 6a. However, the bending angle shown the utility of polyether macrocycles possessing the 1,3-
of the 1,3-dialkyne unit in the macrocycle 6c (bending angle diyne units by incorporating the isoxazole and thiophene moie-
ꢁ18ꢀ) was found to increase by ꢁ6ꢀ when compared to the ties into the macrocycles. The structures of selected crown ether/
structure of 6a (bending angle ¼ ꢁ12ꢀ).
polyether-type macrocycles were unambiguously conrmed from
In the compounds 6g and 6c the ring size is same (24- the single crystal X-ray analyses of representative compounds. It
membered) and in the compound 6c the 1,3-diyne unit is con- has been found that in the crystal structures of representative
nected via the benzylic carbons (C4 carbon, (Ph-CH2-O unit)) while macrocyclic compounds, the cylindrical backbone comprising a
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1,3-diyne unit is not linear and the 1,3-diyne unit has been found
to be bent. Amongst the X-ray structures which were scrutinized,
in the X-ray structure of the macrocycle 5f, the phenyl ring which
is acting as a linker has been found to be involved in p/p
stacking. Currently, we are working to nd potential applications
and metal binding properties of the crown ether/polyether-type
macrocycles obtained in this work.
Typical procedure for the syntheses of the macrocycles 8a–f.
A mixture of 5a (0.20 mmol), NH2OH$HCl (5 equiv.), Et3N
(6 equiv.) and DMSO (1 mL) was taken in a vial (10 mL capacity).
The ꢀreaction mixture was sealed using a vial cap and stirred at
110 C for 24 h. Aer this period, the vial was cooled to room
temperature. Then, the resulting mixture was diluted with water
(4 mL). The mixture was ltered through a ltration funnel and
the washed with ethyl acetate (4 ꢂ 5 mL). The combined layers
were extracted using ethyl acetate (3 ꢂ 5 mL) and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue was puried by column chromatog-
raphy on silica gel (EtOAc–Hexane) which gave the crown/pol-
yether macrocycles 8a–f. See the corresponding Scheme 5 for
specic examples.
Experimental section
General considerations
Melting points are uncorrected. FT-IR spectra were recorded as
1
thin lms or KBr pellets. H NMR and 13C NMR spectra were
recorded on 400 MHz and 100 MHz spectrometers, respectively
using TMS as an internal standard. Compounds were puried
by column chromatography using silica gel (100–200 mesh).
Reactions were carried out in anhydrous solvent and under a
nitrogen atm, wherever necessary. Solutions were dried using
anhydrous Na2SO4. Thin layer chromatography (TLC) analysis
was performed on silica gel plates and the components were
visualized by observation under iodine. Isolated yields of
products were reported and yields were not optimized.
Typical experimental procedures and characterization data
for representative compounds are given below. The experi-
mental procedures for the synthesis of starting materials and
the characterization data of starting materials and all products
reported in this work can be found in the ESI.†
Typical procedure for the syntheses of the macrocycles 5a–k,
6a–g and 7a–e (ref. 13a–c). A mixture of 4a (0.20 mmol),
Cu(OAc)2$H2O (30 mol% or 1 equiv. as mentioned the respective
Scheme/Table/Figure) and DMSO (2 mL) was taken in a vial (10
mL capacity) or round bottom ask (10 or 20 mL capacity). The
reaction mixture was stirred at 110 ꢀC under an open air
atmosphere for 4 h. Aer this period, the resulting mixture was
cooled to room temperature and diluted with water (4 mL). The
mixture was ltered through a ltration funnel and washed with
ethyl acetate (4 ꢂ 5 mL). The combined layers were extracted
using ethyl acetate (3 ꢂ 5 mL) and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and
the residue was puried by column chromatography on silica
gel (EtOAc–Hexane) which gave the crown/polyether-type mac-
rocycles 5a–k, 6a–g and 7a–7e. See the corresponding Schemes 3
and 4 and Fig. 1 for specic examples.
Typical characterization data for a representative compound
8a. Following the procedure described above, the compound 8a
was obtained aer purication by column chromatography on
silica gel (EtOAc–Hexanes ¼ 50 : 50) as a white solid, mp: 141–
ꢀ
143 C; yield: 0.062 g, 90%; FT-IR (CH2Cl2): 2925, 2875, 1603,
1495 and 752 cmꢃ1 1H NMR (400 MHz, CDCl3): d 7.35–7.33
;
(m, 1H), 7.28–7.21 (m, 3H), 6.95–6.89 (m, 2H), 6.86–6.83
(m, 2H), 6.30 (s, 1H), 4.60 (s, 2H), 4.50 (s, 2H), 4.54 (s, 2H), 4.33–
4.27 (m, 4H), 3.79 (t, J ¼ 5.08 Hz, 2H), 2.92 (t, J ¼ 5.20 Hz, 2H);
13C NMR (100 MHz, CDCl3): d 171.9, 161.9, 156.9, 156.6, 130.9,
129.9, 129.5, 129.2, 126.6, 126.2, 121.2, 120.9, 111.0, 111.8,
101.5, 69.0, 67.6, 67.5, 67.3, 67.2, 63.5, 28.1; HRMS (ESI): m/z [M
+ Na]+ calcd for C22H23NO5Na: 404.1474; found 404.1483. This
compound was crystallized using a mixture of MeOH, DCM and
Hexanes and conrmed by the single crystal X-ray structure
analysis.
Typical procedure for the syntheses of the macrocycles 9a–d.
A mixture of 6f (0.06 mmol), Na2S$xH2O (70 mg), CuI (10 mol%),
1,10-phen (15 mol%) and DMF (0.5 mL) was stirred at 90 ꢀC for 6
h under an open air atmosphere. Aer this period, the vial was
cooled to room temperature. Then, the resulting mixture was
diluted with water (4 mL). The mixture was ltered through a
ltration funnel and the washed with ethyl acetate (4 ꢂ 5 mL).
The combined layers were extracted using ethyl acetate (3 ꢂ 5
mL) and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue was puried
by column chromatography on silica gel (EtOAc–Hexane) which
gave the crown/polyether macrocycles 9a–d. See the corre-
sponding Scheme 6 for specic examples.
Typical characterization data for a representative compound
5a. Following the procedure described above, the compound 5a
was obtained aer purication by column chromatography on
silica gel (EtOAc–Hexanes ¼ 10 : 90) as a white solid, mp: 142–
Typical characterization data for a representative compound
9a. Following the procedure described above, the compound 9a
was obtained aer purication by column chromatography on
silica gel (EtOAc–Hexanes ¼ 50 : 50) as a white solid, mp: 90–92
ꢀC; yield: 0.018 g, 17%; FT-IR (CH2Cl2): 2872, 1602, 1493,1358
and 754 cmꢃ1; 1H NMR (400 MHz, CDCl3): d 7.34 (d, J ¼ 7.5 Hz,
2H), 7.14 (t, J ¼ 7.3 Hz, 2H), 6.90 (t, J ¼ 7.4 Hz, 2H), 6.80 (s, 2H),
6.76 (d, J ¼ 8.2 Hz, 2H), 4.67 (s, 4H), 4.47 (s, 4H), 4.01 (t, J ¼ 4.7
Hz, 4H), 3.82 (t, J ¼ 4.7 Hz, 4H); 13C NMR (100 MHz, CDCl3): d
156.6, 141.6, 129.6, 128.9, 126.8, 126.5, 121.1, 111.9, 70.5, 68.8,
66.6, 65.8; HRMS (ESI): m/z [M + Na]+ calcd for C24H26O5SNa:
449.1399; found 449.1408. This compound was crystallized
ꢀ
144 C; yield: 0.061 g, 70%; FT-IR (CH2Cl2): 3031, 1702, 1599,
1486 and 1027 cmꢃ1; 1H NMR (400 MHz, CDCl3): d 7.37 (d, J ¼
5.8 Hz, 2H), 7.26 (t, J ¼ 6.9 Hz, 2H), 6.98 (t, J ¼ 7.0 Hz, 2H), 6.88
(d, J ¼ 7.6 Hz, 2H), 4.81 (s, 4H), 4.41 (s, 4H), 4.28 (s, 4H); 13C
NMR (100 MHz, CDCl3): d 156.6, 129.3, 128.9, 126.1, 121.1,
111.7, 76.5, 72.1, 67.6, 64.5, 57.3; HRMS (ESI): m/z [M + Na]+
calcd for C20H20O4Na: 371.1259; found 371.1263. This
compound was crystallized using a mixture of EtOAc and
Hexanes and conrmed by the single crystal X-ray structure
analysis.
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using a mixture of EtOAc and Hexanes and conrmed by the
single crystal X-ray structure analysis.
7 (a) F. Diederich and M. B. Nielsen, Synlett, 2002, 544; (b)
F. Diederich, Chem. Commun., 2001, 219; (c) M. M. Haley,
Pure Appl. Chem., 2008, 80, 519; (d) F. Diederich, Pure Appl.
¨
Chem., 2005, 77, 1851; (e) R. Berscheid and F. Vogtle,
Acknowledgements
Synthesis, 1992, 58; (f) R. R. Tykwinski and A. L. K. S. Shun,
Angew. Chem., Int. Ed., 2006, 45, 1034; (g) P. Siemsen,
R. C. Livingston and F. Diederich, Angew. Chem., Int. Ed.,
2000, 39, 2632; (h) F. Diederich, P. J. Stang and
R. R. Tykwinski, Acetylene Chemistry: Chemistry, Biology,
and Materials Science, Wiley-VCH, Weinheim, Germany,
2005; (i) B. J. Whitlock and J. W. Whitlock, in
Comprehensive Supramolecular Chemistry, ed. J. L. Atwood,
This work was funded by IISER-Mohali. We thank the NMR, X-
ray and HRMS facilities of IISER-Mohali. We thank the NIPER-
Mohali, CDRI-Lucknow and IICT-Hyderabad for giving the mass
spectral data. Naveen and N. A. Aslam thank UGC, New Delhi,
for fellowships and Mr V. Rajkumar for the valuable help. We
thank Prof. K. S. Viswanathan and Dr Angshuman R. Choud-
hury for giving useful suggestions and Ms Sadhika K. for
helping in collecting the X-ray diffraction data of few of the X-
ray structures. We sincerely thank the reviewers for giving
valuable suggestions and we are also grateful to the crystallo-
graphic reviewer who willingly carried out the renements of
two structures for us.
¨
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