Catalytic Intramolecular Cycloaddition Reactions by Using a Discrete Molecular Architecture

Article abstract of DOI:10.1002/chem.201702507

A discrete tetragonal tube-shaped complex (MT-1) has been synthesised by coordination-driven self-assembly of a carbazole-based tetraimidazole donor L and a Pd(II) 90° acceptor, that is, [cis-(dppf)Pd(OTf)₂] (dppf=diphenylphosphinoferrocene, OTf=CF₃SO₃^?). Complex MT-1 was characterised by multinuclear NMR, ESI-MS and single-crystal X-ray diffraction analysis (SCXRD), which showed its symmetrical tetrafacial tube-shaped architecture possessing a large cavity described by four aromatic walls. This coordination cage was successfully utilised as a molecular vessel to perform intramolecular cycloaddition reactions of O-allylated benzylidinebarbituric acid derivatives inside its confined nanospace. The presence of a catalytic amount of MT-1 promoted [4+2] cycloaddition reactions in a regio- and stereoselective manner, yielding the corresponding penta/tetracyclouracil derivatives in good yields under mild reaction conditions. This protocol is interesting compared with the literature reports for the synthesis of similar chromenopyran pyrimidinedione derivatives under high-temperature reflux conditions or solid-state melt reactions (SSMRs).

Full text of DOI:10.1002/chem.201702507

A Journal of
Accepted Article
Title: Catalytic Intramolecular Cycloaddition Reactions Using a Discrete
Molecular Architecture
Authors: Partha Sarathi Mukherjee, Bijan Roy, Anthonisamy Devaraj,
Rupak Saha, Suprita Jharimune, and Ki-Whan Chi
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To be cited as: Chem. Eur. J. 10.1002/chem.201702507
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Catalytic Intramolecular Cycloaddition Reactions Using a Discrete
Molecular Architecture
Bijan Roya, Anthonisamy Devaraj a, Rupak Saha a, Suprita Jharimune a, Ki-Whan Chi b and Partha
Sarathi Mukherjeea*
Dedication ((optional))
Abstract: A discrete tetragonal tube-shaped complex (MT-1) has
been synthesized by coordination-driven self-assembly of
Synthetic chemists are constantly involved in designing molecular
system which can efficiently emulate the enzymatic activity.[4]
a
A
carbazole-based tetraimidazole donor L and a Pd(II) 90° acceptor, viz.
[cis-(dppf)Pd(OTf)2] (dppf = diphenylphosphino ferrocene, OTf =
number of different types of container molecules with well-defined
cavity have been reported so far including- crown ethers,
cyclodextrins, cucurbituril, hydrogen bonded capsules, discrete
metal-organic cages etc., which are proved to be efficient
supramolecular catalysts.[5]
-
CF3SO3 ). Complex MT-1 was characterized by multinuclear NMR,
ESI-MS and single crystal X-ray diffraction analysis (SCXRD), which
showed its symmetrical tetrafacial tube-shaped architecture
possessing a large cavity described by four aromatic walls. This
coordination cage was successfully utilized as a molecular vessel to
perform intramolecular cycloaddition reactions of O-allylated
benzylidinebarbituric acid derivatives inside its confined nanospace.
The presence of catalytic amount of MT-1 promoted the [4+2]
cycloaddition reactions in regio- and stereo-selective manner yielding
the corresponding penta-/tetra-cyclouracil derivatives in good yields
under mild reaction condition. This protocol is interesting compared to
the literature reports for the synthesis of similar chromenopyran
pyrimidinedione derivatives under high temperature reflux conditions
or solid-state melt reaction (SSMR).
Coordination-driven self-assembly has been evolved as one of
the most successful methods to construct discrete molecular
architectures with predesigned shapes, sizes and functionality
owing to the strong directional nature of metal-ligand coordination
and availability of plenty of organic donors of versatile
geometries.[6] In addition, the reversibility of certain metal-ligand
bonds gives thermodynamic control over the self-assembly
process which allows ‘self-error correction’ in order to form a
desired architecture in high yield. Such architectures have been
extensively explored for guest encapsulation, drug delivery,
sensing, supramolecular catalysis etc.[7] Coordination-driven self-
assembly also provides opportunity to fine-tune the shape and
property of the final architecture as well as the environment of the
cavity by imparting changes in the building blocks in a way that
does not alter the metal-ligand composition.
Introduction
Nature extensively exploits weak non-covalent interactions to
modulate complex biochemical processes, which always
remained a constant source of inspirations for the synthetic
chemists.[1] For example- enzymes, which are biological catalysts,
generally contain a substrate binding site inside a hydrophobic
cavity surrounded by the walls of protein molecules.[2] An enzyme
can specifically recognize and bind substrates, that get stabilized
or activated by several weak non-covalent interactions that
promote selective product formation and thus, creates ideal
example of supramolecular catalysis. A supramolecular catalyst
can modulate chemical reactions in several ways such as by (1)
reducing entropy of the substrate(s); (2) stabilizing the transition
state; (3) increasing effective concentration of the substrates; (4)
spatial control over the specific product formation etc.[3]
Scheme 1. Synthesis of the ‘symmetrized’ molecular tube MT-1.
In this article, we report the synthesis of a ‘symmetrized’
tetrafacial tube-shaped molecular architecture viz., MT-1 by the
self-assembly of a tetraimidazole donor L with a bulky Pd(II) 90
acceptor,
i.e.,
cis-[(dppf)Pd(OTf)2]
(dppf
=
1,1-
diphenylphosphino ferrocene). MT-1 was characterized by
multinuclear (1H and 31P) NMR spectroscopy, ESI-MS
spectrometry and SCXRD analysis which showed MT-1 to have
tetrafacial tube-shaped architecture with symmetrical cavity,
unlike our analogous water-soluble complex with less-
symmetrical cavity, synthesized by using the same donor.[8] The
newly synthesized MT-1 is soluble only in non-aqueous media.
Most interestingly, MT-1 is found to catalyze intramolecular hetero
[4+2] cycloaddition reactions (IMHDA) of Benzylidenebarbituric
acid derivatives (1a-1f) containing 1-Oxa-1,3-butadiene where
the corresponding cyclized products (2a-2f) were obtained in
good yields under relatively milder reaction condition in a stereo-
and regio-controlled manner. The restriction of conformational
[a]
[b]
Bijan Roy, Anthonisamy Devaraj , Rupak Saha , Suprita Jharimune
and Prof. Partha Sarathi Mukherjee
Inorganic and Physical Chemistry Department
Indian Institute of Science
Bangalore-560012, India
E-mail: psm@ipc.iisc.ernet.in
FAX: 91-80-23601552
Prof. Ki-Whan Chi
Department of Chemistry, University of Ulsan
Indian Institute of Science
Ulsan 680-749, Republic of Korea
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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flexibility of the substrates in the confined cavity of the cage leads
to the product formation with increased selectivity, while similar
kind of reactions need high temperature in absence of the cage
and mostly yield mixture of isomers.[9] While intermolecular [4+2]
cycloaddition reactions in closed molecular cage are known, most
of such reactions are stoichiometric and the products are trapped
inside the cage. Larger windows in MT-1 allow the products to
come out and enabling the cycloaddition reactions in catalytic
fashion.
1733.50 and 1419.77 with clear isotopic distribution patterns
corresponding to the 4+, 5+ and 6+ charged fragments
Results and Discussion
The self-assembly was carried out in freshly distilled nitromethane
under nitrogen atmosphere. When a colourless clear solution of L
was added drop wise to a deep purple solution of the acceptor at
room temperature, the sharp colour change into wine red
indicated the product formation. The solution was heated at 50 ºC
for 3h, which was then completely dried and the residue was
washed with chloroform and diethyl ether to obtain the desired
product (MT-1) as brown powder. The 31P NMR spectrum of the
compound in CD3NO2 showed the presence of two peaks of equal
intensities at  = 35.5 and 34.2 ppm, which are significantly upfield
shifted compared to the acceptor ( = 46.2 ppm) due to the
enhanced Pd(II)-P back donation as a result of Pd(II)-L
coordination (Figure 1).[10] Such NMR pattern is expected for a
molecular architecture bearing all the donor units in identical
environment and considering the palladium ions are coordinated
to two different sets of imidazole moieties in L.
Figure 2: ESI-MS isotopic distribution patterns corresponding to the [MT-1∙PF6
- 4PF6 ]4+ (calcd. m/z = 2200.84) (a) and [MT-1∙PF6 - 5PF6 ]5+ (calcd. m/z =
1733.47) (b) charged species confirmed the formation of M8L4 assembly. (c) and
(d) are the calculated isotopic distribution patterns for the 4+ and 5+ charged
fragments, respectively.
-
-
of a M8L4 assembly are assigned for [MT-1∙PF6 - 4PF6-]4+ (calcd.
m/z = 2200.83), [MT-1∙PF6 - 5PF6-]5+ (calcd. m/z = 1733.47) and
- 6+
[MT-1∙PF6 - 6PF6 ] (calcd. m/z = 1419.73) charged fragments,
respectively (Figure 2).
Figure 1: Comparison of 31P NMR spectra of MT-1 recorded in CD3NO2 (up)
and cis-[(dppf)Pd(OTf)2] recorded in CDCl3 (down).
Although the 1H NMR spectra of the compound was very complex
to interpret, the appearance of the sharp singlets of equal
intensities corresponding to the cyclopentadienyl protons at  =
5.30-4.50 ppm region further suggested the formation of a pure
product. Finally, the exact composition of the product was
successfully determined from high resolution ESI-MS spectra
obtained for the hexafluorophosphate analogue of MT-1 (MT-
1PF6), which was prepared by treating the compound with excess
KPF6 in methanol.[11] The peaks obtained at m/z = 2200.88,
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Figure 3: Ball and stick model representation of the crystal structure of MT-1
showing distances between the opposite walls. Colour codes: Grey = C, blue=
N, brown = Pd, red = Fe, and violet = P. H atoms are omitted for clarity.[15]
barbituric acid provides a beautiful way to synthesize tetracyclic
uracil compounds pertaining potential biological applications.[13]
Such reactions are usually performed at significantly higher
temperatures (~150-200 ºC) or in presence of toxic solvents like
toluene, xylene etc. or via solid-state melt reaction (SSMR)
technique, as mentioned in literature.[13] Intramolecular hetero
Diels-Alder reaction on benzylidene derivative (compound 1b)
was initially reported by Tietze[13b] and co-workers employing
xylene as solvent medium under reflux condition for 92 h which
led to the formation of anticipated tetracyclic compound 2b in
good yield along with other isomer. Following this pioneering
research Bhuyan[14] and coworkers demonstrated an interesting
protocol for accessing similar compound (2b) using benzylidene
derivative (compound 1b) in toluene under reflux condition for a
period of 12 h which also led to the formation of 2b along with
other isomer which necessitates the development of new protocol
for the stereo selective synthesis of such compound/s under mild
reaction condition, while such stereo control can potentially be
enabled by supramolecular catalysis using confined space.
Finally, the solid state structure of MT-1 was unambiguously
confirmed by SCXRD analysis. [15] Suitable single crystals were
grown by slow vapor diffusion of diisopropyl ether into a
nitromethane solution of the complex. Brown rectangular crystals
were very weakly diffracting and thus synchrotron radiation
source was used for collecting X-ray data. The compound
crystallized in monoclinic C2/c space group. Structure solution
clearly showed MT-1 to have a hollow tetrafacial tube architecture
where the four donor moieties describe the walls of the tube and
the Pd(II) ions are occupying the eight vertices. Moreover, the
eight dppf groups are anchored outside the cavity (Figure 3).
Interestingly, unlike the dissimilar spacing between the opposite
donor walls in analogous water soluble tube,[8] the gaps are equal
in MT-1 which measured to be ~12.4 Å. The adjacent Pd(II)-Pd(II)
distances at the rhombus-shaped apertures are within 11.5-12.0
Å. Moreover, the tilt angle of all four N-Me groups are also
identical (~29º), which again reflected the highly symmetric nature
of the architecture. This further unveiled that, although the
Table 1: Optimization of Hetero Diels-Alder Reaction of 1a Using MT-1 as
Molecular Vessel.
Entry
Loading
Temperature
(ºC)
Solvent
Yield (%)*
Pd1/Pd4 (similarly Pd2/Pd3, Figure 3) atoms form
a
(Mole
%)
crystallographically distinguishable pair, due to the overall
symmetrical nature of the assembly their magnetic environments
are same. Hence, the coordination of Pd1 and Pd4 with one set
of imidazole moiety is responsible for a single peak in 31P NMR
spectra. Similarly, the second peak is arising due to the
coordination of Pd2 and Pd3 with the other set of imidazole in L
(SI, Figure S3).
with
without
cage
cage
1
2
2.5
5
80
80
80
80
Rt
50
60
70
80
80
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3CN
20
-------
-------
--------
--------
None
None
None
-----
34
3
Formation of the symmetrical architecture of MT-1 can be
explained by the steric hindrance possessed by the bulky dppf
10
20
10
10
10
10
None
10
78
groups. For
a hypothetical non-symmetric tetrafacial tube
4
81
structure of MT-1, the steric repulsion between the externally
anchored phenyl groups of dppf moiety would be severe along the
shorter walls of the tube, which is energetically not favorable. As
a result, complex MT-1 acquires symmetrical topology to
distribute the steric strain ‘homogenously’ throughout the
molecule. The versatile tunability of the donor angle in L as a
result of the twisting of the imidazole moieties assisted the
formation of symmetrical architecture.
5
None
None
24
6
7
8
46
Scheme 2: Intramolecular Hetero Diels-Alder Reaction of 1a.
9
-----
32
11
10
8
*Isolated by preparatory TLC. All the reactions were carried out for 48 h.
In order to check the suitability of the newly synthesized MT-1 as
Hetero Diels-Alder reactions found prime significance in the
synthesis of fused poly-heterocyclic compounds, which show
promising bioactivity and are also used as intermediates in natural
product synthesis.[12] The intramolecular [4+2] cycloaddition of
benzylidene derivatives obtained by the acid catalyzed
Knoevenagel condensation of O-allylated salicylaldehydes and
molecular vessel for hetero Diels-Alder reaction,
a few
benzylidenebarbituric acid derivatives (1a-1f) were selected as
substrates which consist of an 1-Oxa-1,3-butadiene as a
heterodiene and a terminal alkene moiety as dienophile (Scheme
2 and Table 1). It was envisioned that upon encapsulation inside
the large cavity of MT-1, the flexibility of the diene part of the
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Figure 4: Ball and stick model of the crystal structure of 2a. Colour code: Grey=
substrates will be restricted, which also may bring the diene closer
to the dienophile to eventually facilitate the formation of [4+2]
adduct in a regio- as well as stereo- controlled manner. The
optimization of MT-1 catalyzed IMHDA was performed using the
naphthylidenebarbituric acid derivative (1a) as substrate (Scheme
2).
The requisite precursor i.e., naphthylidenebarbituric acid
derivative (1a) was prepared from 2-hydroxy-1-naphthaldehyde,
allyl bromide and N,N-dimethylbarbituric acid through
Williamson’s ether synthesis followed by Knoevenagel
condensation according to the procedure reported by Bhuyan and
coworker.[14] The condition for the MT-1 catalytic cycloaddition
reaction was optimized for 1a at 80 ºC for 48 h by using 10 mole
percent catalyst loading which gave best result in nitromethane
with an isolated yield of 2a by 78% (Table 1). Interestingly, only
11% product was isolated when the same reaction was carried
out in the absence of MT-1. The pentacyclic product (2a) was
isolated by complete evaporation of the solvent followed by
extraction with chloroform. The crude product was subsequently
purified by preparative TLC and unambiguously characterized by
1H, 13C NMR spectroscopy, ESI-MS spectrometry and elemental
analysis.
C, blue= N, red= O and cyan= H.[15
Table 2. Substrates and corresponding [4+2] cycloaddition products obtained
by supramolecular catalysis with MT-1.*
Entr
y
Substrate
Product
Yield
(%)
Yield(%
)
With
catalys
t
Without
catalyst
The oxygen atom of the 1-Oxa-1,3-butadiene moiety of 1a can
attack either C1 or C2 atom of the terminal alkene group during the
course of the cycloaddition (Scheme 2). While C2 attack leads to
the annulated product (cis-fused 2a and trans-fused 2aꞌ), C1
attack forms bridged heterocycle (2aꞌꞌ). We have observed
predominantly the cis-fused product 2a (based on the analysis of
crude 1H NMR spectra, SI, Figure S36) in good yield presumably
due to the conformational restriction of the substrate by MT-1
during cycloaddition whereas literature report is available for the
significant formation of a mixture of products during IMHDA
reaction which demonstrates the efficacy of the cage promoted
cycloaddition. [13b, 13c] In this direction we have also investigated
the Diels-Alder reaction profile of 1a in xylene under reflux
condition over a period of 48 h which leads to the formation of
mixture of isomers (SI, Figure S37) in accordance with the
literature method.[13b, 13c] The comparison of 1H NMR spectrum of
crude samples obtained by MT-1 promoted cycloaddition (SI,
Figure S36) as well as by the reported procedure without MT-1
(SI, Figure S37) clearly demonstrates the stereo- as well as regio-
selectivity of the cage promoted Diels-Alder reaction which is
interesting in view of stereoselective organic transformations.
One of the compounds in Table 2 (2b, entry 1) was reported
earlier by Bhuyan[14] in high yield (75%) along with other isomer
under reflux condition in toluene. However, selectivity in stereo
control by the confined cavity of MT-1 (formation of cis-product),
mild reaction condition and reusability of cage make the present
protocol interesting. Moreover, the presence of the individual
building blocks of MT-1 [i.e. cis-(dppf)Pd(OTf)2 and L] could not
promote the cycloaddition reaction significantly, which indicates
that the tetrafacial tube architecture plays key role in the stereo-
and regio-selective product formation at relatively low
temperature.
61
None
1
2
3
4
1b
1c
1d
2b
2c
2d
65
71
68
9
6
None
1e
2e
The regioselectivity and relative stereochemistry of the product
are unambiguously confirmed by single crystal X-ray diffraction
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f) in good yields and the results are summarized in Table 2.
The plausible mechanism for the tube catalysed intramolecular
hetero Diels-Alder reaction is depicted in Figure 5. In
homogeneous solution, the substrate molecule enters in to empty
MT-1 by collision and possibly gets stabilised via -stacking
interaction with the aromatic walls of the cavity. The confined
space restricts the conformational flexibility of the substrate
molecule and helps to orient the reacting functionalities, i.e. the
diene and the dienophile in close proximity (S2 in Figure 5). At
higher temperature, the substrate undergoes [4+2] cycloaddition
to form the corresponding product (S3 in Figure 5). As the product
has rigid non-planar tetra/pentacyclic structure (Figure 4), it hardly
fits in to the cavity and eventually comes out to the bulk medium
leaving the empty cage for further substrate encapsulation. The
guest release is much easier from MT-1 due to its wide
rectangular aperture and good solubility of the products in organic
medium. In contrast, the analogous water soluble architecture
(PSMBR-1) could not catalyse the same cycloaddition reaction as
the product does not come out in the aqueous medium due to the
hydrophobicity. However, the kinetic study by 1H NMR
spectroscopy revealed that there is minute product inhibition
taking place, which was evident from the decrease in the amount
of the substrate conversion in presence of 10 mol% of the product
at the beginning of the reaction (SI, Figure S41). This may be due
to competition between the substrate and the product to get
encapsulated inside the cavity of MT-1.
54
None
5
1f
2f
*Products were isolated by preparatory TLC. All the reactions were carried
out for 48 h.
analysis[15] (CCDC-1545091) which clearly shows that the product
is 2a which exhibited relative stereochemistry corresponding to
the thermodynamically favorable cis-fused adduct (Figure 4).
Interestingly, traditional intramolecular Diels- Alder reaction of the
same substrate under high temperature in absence of the tube
(MT-1) mostly yields a mixture of regio- and stereo-isomers. Thus
the selective formation of 2a promoted by the ‘symmetrized’
molecular tube (MT-1) is interesting in view of supramolecular
catalysis as well as a molecular vessel for stereoselective organic
transformation.
Unfortunately, the exact interaction between MT-1 and the
substrate 1a could not be proved due to the fast equilibrium
between the substrate in encapsulated and free forms in non-
aqueous medium. Moreover, the strong absorption of the
molecular tube in the visible wavelength region restricts the
identification of the host-guest complex via UV-Vis spectroscopy.
However, the successful encapsulation of 1a by an analogues
[8]
water soluble architecture
in aqueous media was studied by
To judge the reusability of the molecular tube, the substrate 1a
was subjected to cycloaddition by using recovered MT-1 from the
reaction of the same substrate, which showed minute loss of
efficiency in each step up to fifth cycle measured (SI, Figure S40).
In addition, 31P NMR spectra of MT-1 recovered after the fifth
cycle of catalysis of 1a showed no sign of disintegration (SI,
Figure S36). This advocates the potency of MT-1 as a
supramolecular catalyst for such intramolecular reactions.
UV-Vis (SI, Figure S32) and NMR (SI, Figure S33) spectroscopic
techniques, which suggests that the cavity of MT-1 is large
enough to accommodate the substrates under investigation.
Furthermore, MT-1 showed no sign of deformation upon heating
up to 90 ºC in presence of the substrate 1a as observed from the
variable temperature 31P NMR spectroscopy, confirming its
thermal stability during the reaction (SI, Figure S34). A series of
benzylidenebarbituric acid derivatives containing functionalized
phenyl backbones (1b-1f) has been prepared and subsequently
allowed to form Diels–Alder addition products under the similar
reaction condition. In all the cases, the reactions smoothly led to
the anticipated tetracyclic chromenopyran pyrimidinediones (2b-
Scheme 3: Domino Reaction Catalyzed by Complex MT-1.
Product Yield (%)**
With 1 Without 1
Time
(h)
.
H (1g)
2g
73
71
None
None
22
22
Br (1h) 2h
**Isolation done by preparatory TLC
Figure 5: Pictorial representation showing the plausible mechanism of
intramolecular hetero Diels-Alder reaction catalysed by MT-1. S1 represents the
empty molecular architecture MT-1.
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Domino reactions are very important in terms of atom economy,
which involve consecutive steps where the functionality
generated in the previous step undergoes reaction in the next step.
Among various reactions, the domino Knoevenagel hetero Diels–
Alder reaction is an efficient as well as convenient tool for
accessing polyheterocyclic compounds and ranges of natural
products. Construction of library of fused polyheterocyclic
scaffolds has been performed using the domino Knoevenagel
hetero Diels–Alder reaction as a key protocol.[13d] In this aspect it
occurs to us that the MT-1 can be utilized as an efficient catalyst
in domino reaction which will be very interesting in supramolecular
catalysis using confined nanospace. In order to check the efficacy
of the molecular tube (MT-1) to catalyze domino type synthesis of
the tetracyclo uracil derivatives by starting from O-allylated
salicylaldehydes, we prepared substrates (1g-h) containing
dimethyl substituted terminal alkenes (activated). When treated
with N,N-dimethylbarbituric acid in presence of 10 mol% of MT-1
in nitromethane at room temperature for a period of 22 h, they
successfully afforded the corresponding tetracyclic uracil
derivatives in good yields, whereas, the same reactions in
absence of the cage produced no detectable amount of products
(Scheme 3) which successfully demonstrates the catalytic role of
MT-1 in domino Knoevenagel hetero Diels–Alder reaction
representing the utility of supramolecular catalysis in domino
reaction.
Experimental Section
Materials and Methods:
All the reagents and solvents were purchased from various commercial
suppliers and used without further purification. NMR spectra were
recorded in a Bruker 400 MHz spectrometer. UV-Visible and fluorescence
spectra were recorded in Perkin Elmer Lambda-750 and Horiba Jobin
fluoromax4 spectrophotometers, respectively. ESI-MS experiments were
done in Agilent 6538 Ultra-High Definition (UHD) Accurate Mass Q-TOF
spectrometer. Single crystal X-ray diffraction data for complex MT-1
(CCDC-1545089) was collected in synchrotron beam line facility while the
SCXRD data for 2a was collected in a Bruker D8 QUEST CMOS
diffractometer. The structures were solved by direct methods using
SHELX-2013 incorporated in WinGX. Empirical absorption corrections
were applied with SADABS. The non-hydrogen atoms of the main
fragments were refined with anisotropic displacement coefficients.
Hydrogen atoms were assigned with isotropic displacement coefficients,
U(H) = 1.2U(C) or 1.5U (C-methyl), and their coordinates were allowed to
ride on their respective carbons. Proper restrains were used to the
minimum extent while solving the structure of MT-1. To further improve the
structure solutions, final refinement was performed with the modification of
the structure factors of the solvent molecules and counter anions using
SQUEEZE option of PLATON.
Synthesis of MT-1. A 50 mL Schlenk flask was degassed and purged with
nitrogen and then charged with 100 mg (0.10 mmol) of cis-[(dppf)Pd(OTf)2]
and 20 mL freshly distilled nitromethane. To the purple solution, a
colourless solution of L (23.2 mg, 0.05 mmol) in 10 mL nitromethane was
added very slowly by a syringe for 30 min with stirring. The solution finally
became wine red which was then heated at 50 °C for 3 h. The solvent was
evaporated completely under vacuum and the solid was washed with
chloroform and diethyl ether and dried to obtain the product as dark red
powder. Isolated yield: 110 mg (89%). 1H NMR (400 MHz, CD3NO2):  =
8.43, 8.26, 7.87, 7.83, 7.72, 7.54, 7.44, 7.37, 7.30, 7.23, 7.02, 6.29, 5.29,
5.13, 5.02, 4.89, 4.71, 4.65, 4.55, 2.11, 2.10. 31P NMR (CD3NO2):  = 35.5,
34.2; Anal. Calcd. (%) for C388H300F48Fe8N36O48P16S16: C, 49.30; H, 3.20;
N, 5.33. Found: C, 48.83; H, 3.55; N, 5.73. ESI-MS: m/z calcd for
hexafluorophosphate analogue of MT-1 (MT-1∙PF6) are 2200.84 for [MT-
Conclusions
In conclusion, we have synthesized a new discrete tetrafacial
molecular architecture (MT-1) by employing coordination-driven
self-assembly of a cis-blocked Pd(II) 90° acceptor and the
tetraimidazole donor L. The presence of large cavity with wide
apertures makes complex MT-1 a very potent molecular vessel
for performing organic transformations. A series of O-allylated
benzylidenebarbituric acid derivatives has been transformed in to
the corresponding tetra/pentacyclo uracil products in presence of
10 mole% of MT-1 under mild reaction condition. Interestingly, the
similar reactions in absence of the tube resulted very less or no
product formation, which successfully demonstrates the potency
of the molecular vessel MT-1 for enhanced conversion. While
intermolecular [4+2] cycloaddition reactions in confined
coordination cages are known, majority of such reactions are
stoichiometric and products are generally trapped inside the cage.
Catalytic nature of the reactions in the present case due to having
larger open windows in our molecular tube makes our result
important. The newly synthesized nanotube is quite efficient in
controlling the regio- as well as stereo-selective pathways in the
intramolecular hetero [4+2] cycloaddition reaction through the
restriction of conformational flexibility of diene and tethered olefin.
While literature reports mostly exemplify the formation of isomeric
mixtures in such reactions, stereoselective transformation using
MT-1 as a molecular vessel is noteworthy. In addition, complex
MT-1 also promoted the Domino type synthesis of the tetracyclo
product directly starting from the dimethyl substituted O-allylated
salicylaldehyde derivatives at room temperature.
1∙PF6 - 4PF6-]4+, 1733.48 for [MT-1∙PF6 - 5PF6 ] and 1419.73 for [MT-
1∙PF6 - 6PF6-]6+. Found: 2200.88, 1733.50 and 1419.77.
- 5+
Synthesis of 1a: 1a was synthesized in two steps following reported
procedure.[14] To a solution of 2-hydroxy-1-naphthaldehyde (344 mg, 2
mmol) in N,N′-dimethylformamide (10 mL) was taken in a 50 mL round
bottom flask and added with potassium carbonate (552 mg, 4 mmol). To
this mixture, allyl bromide (0.9 mL, 10 mmol) was added slowly with
constant stirring and the resultant solution was heated at 70 °C for 2 h. The
reaction mixture was cooled down to room temperature and added with 80
mL of water. The solution was then extracted with chloroform. The organic
layer was treated with sodium sulphate and the solvent was evaporated to
get crude product which was purified by silica gel column chromatography
(eluted with 20% diethyl ether in hexane) to get the intermediate 2-
(allyloxy)-1-naphthaldehyde (1aꞌ) as white solid. Yield: 400 mg (94%).
In the next step, 1aꞌ (400 mg, 1.88 mmol) was added slowly to a mixture
of N,N-dimethyl barbituric acid (312 mg, 2 mmol) and aqueous HCl (25 mL,
13%), with constant stirring. After 3 h stirring at room temperature the
precipitate was collected by filtration and washed with hot water and
ethanol and dried under vacuum to get yellow coloured solid product in
89% overall yield (624 mg). 1H NMR (400 MHz, CDCl3):  = 8.95 (s, 1H),
7.91-7.24 (m, 6H), 5.97 (d, 1H, J = 8 Hz), 5.38-5.23 (m, 2H), 4.69 (s, 2H),
3.46 (s, 3H), 3.25 (s, 3H). 13C NMR (100 MHz, CDCl3):  = 162.41, 160.11,
This article is protected by copyright. All rights reserved.

10.1002/chem.201702507
Chemistry - A European Journal
FULL PAPER
155.16, 153.47, 151.98, 133.37, 133.25, 132.19, 129.12, 128.94, 128.03,
124.75, 124.35, 121.82, 118.10, 118.06, 114.14, 70.30, 29.33, 28.73; ESI-
MS m/z: Calculated [M+H]+ = 351.1266; Found: 351.1356; Melting Point:
148 °C. Elemental analysis calcd (%) for (vacuum-dried) C20H18N2O4: C
68.56, H 5.18, N 8.00; found: C 68.59, H 4.98, N, 8.30.
Procedure for the Catalytic Intramolecular Diels-Alder Reaction: To a
clear solution of MT-1 (37.7 mg, 0.004 mmol) in 4 mL nitromethane, the
substrate (1a-1f, 0.04 mmol) was added and the solution was then heated
at 80 °C for 48 h. After the completion of reaction as evidenced by TLC,
the solvent was evaporated completely and the residue was extracted with
chloroform. The crude products obtained after evaporation of chloroform
were purified using preparative thin layer chromatography to afford pure
samples.
Synthesis of 1b: 1b was synthesized in a similar procedure as described
for 1a by using salicylaldehyde (244 mg, 2 mmol) as the starting material
instead of 2-hydroxy-1-naphthaldehyde.[14] The pure product was obtained
as yellow solid in 92% overall yield (552 mg). 1H NMR (400 MHz, CDCl3):
 = 8.91 (s, 1H), 8.02 (d, 1H, J = 8Hz), 7.45 (t, 1H, J = 12Hz), 6.99 (t, 1H,
J = 8Hz), 6.91 (d, 1H, J = 8Hz), 6.03-5.99 (m, 1H), 5.43-5.39 (m, 1H), 5.31-
5.28 (m, 1H), 4.62 (d, 2H, J = 4Hz), 3.40 (s, 3H), 3.33 (s, 3H). 13C NMR
(100 MHz, CDCl3):  = 163.0, 160.9, 159.1, 155.5, 152.0, 134.8, 133.2,
132.9, 122.9, 120.4, 118.4, 117.9, 112.2, 69.7, 29.4, 28.8; ESI-MS m/z:
Calculated [M+H]+ = 301.1110; Found: 301.1172; Melting Point: 150 °C.
Elemental analysis calcd (%) for (vacuum-dried) C16H16N2O4: C 63.99, H
5.37, N 9.33; found: C 63.67, H 5.15, N 9.55.
Synthesis of 2a: By starting with 1a (14 mg, 0.04 mmol), 2a was obtained
as off-white coloured solid in 78% yield (11 mg). 1H NMR (400 MHz,
CDCl3):  = 8.20 (d, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 7.49 (t, 1H), 7.35 (t,
1H), 7.03 (d, 1H), 4.73 (d, 1H), 4.54 (s, 2H), 4.33 (s, 2H), 3.34 (s, 3H), 3.22
(s, 3H), 2.55 (m, 1H); 13C NMR (100 MHz, CDCl3):  = 162.8, 156.2, 151.7,
151.2, 134.8, 129.7, 129.6, 128.7, 126.2, 124.8, 123.7, 119.0, 116.8, 99.1,
69.6, 64. 9, 31.8, 29.4, 28.7, 27.9; ESI-MS m/z: Calculated [M+H]+
=
351.38; Found: 351.13. Elemental analysis calcd (%) for (vacuum-dried)
C20H18N2O4: C 68.56, H 5.18, N 8.00; found: C 68.40, H 4.83, N 8.37.
Synthesis of 1c: The similar procedure was followed for the synthesis of
1c by using 5-fluoro-2-hydroxybenzaldehyde (280 mg, 2 mmol) as the
starting material. The pure product was obtained as yellow solid in 89%
overall yield (566 mg). 1H NMR (400 MHz, CDCl3):  = 8.82 (s, 1H), 7.84-
7.80 (m, 1H), 7.15 (d, 1H, J = 4Hz), 6.86-6.83 (m, 1H), 6.02-6.00 (m, 1H),
5.42-5.28 (m, 2H), 4.59 (d, 2H, J = 4Hz), 3.40 (s, 3H), 3.33 (s, 3H); 13C
NMR (100 MHz, CDCl3):  = 162.6, 160.7, 157.4, 155.3, 155.0, 153.7,
151.7, 132.7, 123.7, 121.1, 119.4, 119.1, 118.7, 118.5, 113.2, 113.1, 70.4,
29.4, 28.8; ESI-MS m/z: Calculated [M+H]+ = 319.1015; Found: 319.1099;
Melting Point: 109 °C.
Synthesis of 2b: 2b was obtained as colourless solid in 61% yield (7.3
mg) by the Diels-Alder reaction of 2a (12 mg, 0.04 mmol). 1H NMR (400
MHz, CDCl3):  = 7.45-6.75 (m, 4H), 4.59-4.56 (m, 1H), 4.55-4.33 (m, 4H),
3.44 (s, 3H), 3.32 (s, 3H), 2.37-2.33 (m, 1H); 13C NMR (100 MHz, CDCl3):
 = 164.6, 156.6, 152.2, 151.3, 131.0, 128.5, 124.1, 122.2, 117.2, 90.8,
68.3, 66.0, 30.1, 29.3, 29.1, 28.8; ESI-MS m/z: Calculated [M+H]+
=
301.1110; Found: 301.1226; Melting point: 193 C. Elemental analysis
calcd (%) for (vacuum-dried) C16H16N2O4: C 63.99, H 5.37, N 9.33; found:
C 63.65, H 5.12, N 9.09.
Synthesis of 2c: 2c was obtained from 1c (12.7 mg, 0.04 mmol) as off-
white solid in 65% yield (8.3 mg). 1H NMR (400 MHz, CDCl3):  = 7.23-
7.20 (m, 1H), 6.81-6.78 (m, 1H), 6.72-6.69 (m, 1H), 4.58-4.55 (m, 1H),
4.36-4.25 (m, 4H), 3.43 (s, 3H), 3.33 (s, 3H), 2.35-2.32 (m, 1H); 13C NMR
(100 MHz, CDCl3):  = 164.4, 159.2, 156.8, 151.2, 148.3, 125.3, 125.2,
118.1, 117.1, 116.9, 115.6, 115.4, 90.3, 68.3, 66.0, 29.9, 29.4, 29.3, 28.8;
ESI-MS m/z: Calculated [M+H]+ = 319.1015; Found: 319.1080; Melting
point: 200 C.
Synthesis of 1d: 1d was synthesised in similar manner as described
above by using 5-bromo-2-hydroxybenzaldehyde (402 mg, 2 mmol). The
product was obtained as yellow solid in 90% overall yield (682 mg).1H NMR
(400 MHz, CDCl3):  = 8.75 (s, 1H), 8.12 (d, 1H, J = 4Hz), 7.54-7.51 (m,
1H), 6.80 (d, 1H, J = 8Hz), 5.99 (m, 1H), 5.42-5.29 (m, 1H), 4.60 (d, 2H, J
= 4Hz), 3.41 (s, 3H), 3.34 (s, 3H); 13C NMR (100 MHz, CDCl3):  = 162.5,
160.5, 157.7, 153.4, 151.7, 136.7, 135.1, 132.5, 124.6, 119.0, 118.6,
113.8, 112.6, 70.0, 29.4, 28.9; ESI-MS m/z: Calculated [M+H]+ = 379.0215;
Found: 379.0296; Melting Point: 119 C. Elemental analysis calcd (%) for
(vacuum-dried) C16H15BrN2O4: C 50.68; H 3.99, N 7.39; found: C 50.49, H
4.02, N 7.55.
Synthesis of 2d: 2d was formed as off-white solid in 71% yield (10.8 mg)
by the Diels-Alder reaction of 1d (15.2 mg, 0.04 mmol). 1H NMR (400 MHz,
CDCl3):  = 7.55-7.54 (m, 1H), 7.20 (d, 1H, J = 8Hz), 6.65 (d, 1H, J = 8Hz),
4.55-4.54 (m, 1H), 4.34-4.25 (m, 4H), 3.44 (s, 3H), 3.33 (s, 3H), 2.34 (t,
1H, J = 8Hz); 13C NMR (100 MHz, CDCl3):  = 164.3, 156.7, 151.4, 151.2,
133.5, 131.5, 126.2, 119.0, 114.2, 90.2, 68.2, 66.0, 29.8, 29.3, 29.1, 28.9;
ESI-MS m/z: Calculated [M+H]+ = 379.0215; Found: 379.0308; Melting
point: 236 C. Elemental analysis calcd (%) for (vacuum-dried)
C16H15BrN2O4: C 50.68; H 3.99, N 7.39; found: C 51.00, H 3.79, N 7.46.
Synthesis of 1e: Same synthetic procedure was applied for the
synthesise of 1e using 2-hydroxy-3,5-diiodobenzaldehyde (748 mg, 2
mmol). Pure product was obtained as yellow solid in 94% overall yield
(1038 mg). 1H NMR (400 MHz, CDCl3):  = 8.58 (s, 1H), 8.19 (s, 1H), 8.07
(s, 1H), 6.05 (s, 1H), 5.39-5.28 (m, 2H), 4.38 (s, 2H), 3.42 (s, 3H), 3.35 (s,
3H); 13C NMR (100 MHz, CDCl3):  = 161.7, 160.1, 158.6, 152.8, 151.5,
150.2, 140.5, 132.6, 130.5, 120.5, 119.9, 93.5, 88.03, 29.5, 29.0; ESI-MS
m/z: Calculated [M+H]+ = 552.9042; Found: 552.9168; Melting Point: 160
C. Elemental analysis calcd (%) for (vacuum-dried) C16H14I2N2O4: C
34.81, H 2.56, N 5.07; found: C 34.79, H 2.61, N 4.92.
Synthesis of 2e: Similarly 2e was obtained from 1e (22.1 mg, 0.04 mmol)
as off-white solid in 68% yield (15 mg). 1H NMR (400 MHz, CDCl3):  =
7.88 (s, 1H), 7.68 (s, 1H), 4.58 (d, 1H, J = 8Hz), 4.47-4.16 (m, 5H), 3.42
(s, 3H), 3.33 (s, 3H), 2.36-2.33 (m, 1H); 13C NMR (100 MHz, CDCl3):  =
164.3, 156.8, 151.1, 145.8, 139.9, 127.0, 89.7, 86.5, 84.9, 68.0, 66.9, 29.8,
29.4, 29.3, 28.9; ESI-MS m/z: Calculated [M+H]+ = 552.9042; Found:
552.9146; Melting point: 257 C. Elemental analysis calcd (%) for
(vacuum-dried) C16H14I2N2O4: C 34.81, H 2.56, N 5.07; found: C 34.50, H
2.53, N 5.15.
Synthesis of 1f: Similar synthetic protocol starting with 2-hydroxy-4-
methoxybenzaldehyde (304 mg, 2 mmol) provided 1f as yellow solid in 85
% yield (561 mg). 1H NMR (400 MHz, CDCl3):  = 9.02 (s, 1H), 8.54 (d,
1H, J = 8Hz), 6.58-6.55 (m, 1H), 6.41 (s, 1H), 6.08-6.01 (m, 1H), 5.48-5.31
(m, 2H), 4.62 (d, 2H, J = 8Hz), 3.87 (s, 3H), 3.40 (s, 3H), 3.30 (s, 3H); 13
C
NMR (100 MHz, CDCl3):  163.76, 162.31, 161.54, 154.36, 136.43,
132.62, 118.62, 116.09, 114.39, 105.71, 99.05, 69.95, 56.16, 29.37, 28.79;
ESI-MS m/z: Calculated [M+H]+ = 331.1215; Found: 331.1294; Melting
Point: 170 C. Elemental analysis calcd (%) for (vacuum-dried)
C17H18N2O5: C 61.81, H 5.49, N 8.48; found: C 61.43, H 5.33, N8.49.
Synthesis of 2f: Diels-Alder reaction of 1f (13.2 mg, 0.04 mmol) formed
2f in 54% yield (7.1 mg). 1H NMR (400 MHz, CDCl3):  = 7.08 (d, 1H, J =
8Hz), 6.86-6.82 (m, 1H), 6.74 (d, 1H, J = 8Hz), 4.59 (d, 1H, J = 4Hz), 4.56-
4.32 (m, 4H), 3.85 (s, 3H), 3.43 (s, 3H), 3.32 (s, 3H), 2.38-2.35 (m, 1H);
13C NMR (100 MHz, CDCl3):  = 164.5, 156.7, 151.3, 148.4, 141.7, 124.8,
This article is protected by copyright. All rights reserved.

10.1002/chem.201702507
Chemistry - A European Journal
FULL PAPER
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122.47, 121.6, 110.0, 90.7, 68.3, 66.47, 56.3, 29.9, 29.3, 29.0, 28.8; ESI-
MS m/z: Calculated [M+H]+ = 331.1215; Found: 331.1300; Melting point:
238 C. Elemental analysis calcd (%) for (vacuum-dried) C17H18N2O5: C
61.81, H 5.49, N 8.48; found: C 61.68, N 5.32, N 8.57.
Synthesis of 2g: 2-(3-methylbut-2-enyloxy)benzaldehyde (7.6 mg, 0.04
mmol) and N,N’-dimethyl barbutaric acid (6.24 mg, 0.04 mmol) were added
with a solution of MT-1 (37.7 mg, 0.004 mmol) in nitromethane and the
mixture was stirred at room temperature for 22 h. After the completion of
reaction the solvent was evaporated completely and the residue was
extracted with chloroform. The crude product obtained upon evaporation
of the solvent was purified by preparative thin layer chromatography to
provide 2g in 73% yield (9.59 mg). 1H NMR (400 MHz, CDCl3):  = 7.42 (d,
1H, J = 8Hz), 7.10-6.69 (m, 3H), 4.48-4.34 (m, 3H), 3.42 (s, 3H), 3.34 (s,
3H), 2.15-2.14 (m, 1H), 1.63, (s, 3H), 1.23 (s, 3H); 13C NMR (100 MHz,
CDCl3):  = 155.9, 153.9, 151.6, 130.2, 128.3, 123.3, 121.6, 116.2, 89.0,
84.4, 65.2, 39.2, 29.4, 29.3, 28.6, 24.3; ESI-MS m/z: Calculated [M+H]+ =
329.1423; Found: 329.1494; Melting point: 205 C. Elemental analysis
calcd (%) for (vacuum-dried) C18H20N2O4: C 65.84, H 6.14, N 8.53; found:
C 65.91, H 6.05, N 8.71.
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Synthesis of 2h: 2h was obtained by following the same protocol as
applied for 2g starting with 5-bromo-2-(3-methylbut-2-enyloxy)
benzaldehyde (8.04 mg, 0.04 mmol) and N,N’-dimethyl barbutaric acid
(6.24 mg, 0.04 mmol) and the product was obtained in 71% yield (11.6
mg). 1H NMR (400 MHz, CDCl3):  = 7.55 (d, 1H, J = 4Hz), 7.19-7.16 (m,
1H), 6.69 (d, 1H, J = 8Hz), 4.42-4.40 (m, 2H), 4.31 (d, 1H, J = 8Hz), 3.43
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(s, 3H), 3.34 (s, 3H), 2.13 (d, 1H, J = 4Hz), 1.61 (s, 3H), 1.21 (s, 3H); 13
C
NMR (100 MHz, CDCl3):  = 164.3, 156.0, 153.1, 151.5, 132. 79, 131.3,
125.6, 118.1, 113.8, 88.4, 84.3, 65.3, 38.9, 29.4, 29.3, 28.6, 24.2; ESI-MS
m/z: Calculated [M+H]+ = 407.0528; Found: 407.0618; Melting point: 200
C. Elemental analysis calcd (%) for (vacuum-dried) C18H19BrN2O4: C
53.08; H 4.70, N 6.88; found: C 53.28, H 4.77, N 7.03.
Acknowledgements
[6](a)S. M. Jansze, M. D. Wise, A. V. Vologzhanina, R. Scopelliti, K. Severin,
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P.S.M. thanks the Science and Engineering Research Board
(New Delhi) for research grant [Grant No. EMR/2015/002353].
A.D. is grateful to UGC (New Delhi) for the Dr. D. S. Kothari
postdoctoral fellowship. X-ray diffraction experiments using the
synchrotron radiation for complex MT-1 were performed at the
Pohang Accelerator Laboratory in Korea.
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Keywords: Supramolecular chemistry • self-assembly • cage
compounds • catalysis • coordination chemistry
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A
discrete tetragonal tube-shaped
Bijan Roy a, Anthonisamy Devaraj a,
Rupak Saha a, Suprita Jharimune a, Ki-
Whan Chi b and Partha Sarathi
Mukherjeea*
molecular architecture (MT-1) has
been synthesized by self-assembly of
a tetraimidazole donor L and a Pd(II)
90° acceptor. Complex MT-1 was
utilized as a molecular vessel to
perform intramolecular hetero Diels-
Page No. – Page No.
Catalytic Intramolecular
Alder
reactions
of
O-allylated
Cycloaddition Reactions Using a
Discrete Molecular Architecture
benzylidinebarbuturic acid derivatives
inside its confined nanospace. The
presence of catalytic amount of the
molecular tube promoted the [4+2]
cycloaddition reactions in highly regio-
and stereo-selective manner yielding
the
corresponding
penta
/
tetracyclouracil derivatives in good
yields under mild reaction condition.
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Title
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