Synthesis of tri-substituted biaryl based trianglimines: Formation of C3-symmetrical and non-symmetrical regioisomers

Article abstract of DOI:10.1039/c0ob00944j

2-Functionalised aromatic monoaldehydes were synthesised in good to excellent yields by reacting 4-bromo-2-fluorobenzaldehyde with different secondary amines and phenol. The Suzuki-coupling reaction of the newly functionalised aromatic monoaldehydes with

Full text of DOI:10.1039/c0ob00944j

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PAPER
Synthesis of tri-substituted biaryl based trianglimines: formation of
C3-symmetrical and non-symmetrical regioisomers†
Hany F. Nour, Marius F. Matei, Bassem S. Bassil, Ulrich Kortz and Nikolai Kuhnert*
Received 27th October 2010, Accepted 6th January 2011
DOI: 10.1039/c0ob00944j
2-Functionalised aromatic monoaldehydes were synthesised in good to excellent yields by reacting
4-bromo-2-fluorobenzaldehyde with different secondary amines and phenol. The Suzuki-coupling
reaction of the newly functionalised aromatic monoaldehydes with 4-formylphenylboronic acid
afforded the corresponding 2-functionalised-4,4¢-biphenyldialdehydes in good yields (47–85%). The
[3+3]-cyclocondensation reactions of the 2-functionalised-4,4¢-biphenyldialdehydes with
(1R,2R)-1,2-diaminocyclohexane afforded a mixture of regioisomeric C3-symmetrical and
non-symmetrical trianglimines. Reduction of the C3-symmetrical and the non-symmetrical
trianglimines with NaBH4 in a mixture of THF and MeOH afforded the corresponding trianglamines
in high yields.
functionalities and complementary size to be included in the
macrocyclic host by well-designed building blocks.
Introduction
Trianglimines form a class of chiral non-racemic macrocycles
that are formed in a [3+3]-cyclocondensation reaction between
a chiral non-racemic diamine and an aromatic dicarboxalde-
hyde, in which six new imine bonds are formed in a single
reaction. The first member of this class of macrocycles has
been introduced by Gawron´ski a decade ago; more recently the
compounds were named trianglimines by our group due to their
unique triangular geometry.1–3 Hexa-amine macrocycles, which
constitute reduced versions of their hexa-imine analogues are
referred to as trianglamines.4 Trianglimines combine a series of
features and characteristics that make them promising compounds
for molecular recognition applications including sensing, chiral
recognition, etc., in many cases their potential is much superior
if compared to their macrocyclic competitors such as calix-
[n]-arenes,5–8 cyclodextrins,9 cucurbiturils10,11 or crown ethers.12
Trianglimines are chiral, and unlike in cyclodextrin chemistry
both enantiomers of any derivative are readily available in a
pure form and have been reported.4 Trianglimines are obtained
using a modular approach, in which two building blocks are
reacted to form macrocyclic compounds with complete control
over the size of the macrocycle,13 electronic properties of the
macrocycle and functional groups included.14 These features make
trianglimines in particular attractive for the molecular recognition
of small and medium sized organic molecules with complementary
The [3+3]-cyclocondensation reaction is usually high yielding,
with quantitative conversions not uncommon, at relatively high
concentrations of the two building blocks. The formation of
trianglimines is based on conformational bias rather than on a
template effect or high dilution conditions, frequently used in
other macrocyclic chemistry.1 Despite these obviously attractive
features of trianglimines, only few applications of trianglimines
and their amine analogues in supramolecular chemistry have
been reported. Gawron´ski and others have used trianglimines as
organo-catalysts for asymmetric catalysis and they also reported
the inclusion of solvent molecules into the trianglimine cavity.1,15,16
Hodacova17 reported on the binding of simple aromatic guests
in the trianglimine cavity and finally we have reported on
chiral recognition of trianglimines binding chiral carboxylic acids
and amino acid derivatives.18 In most of these cases, binding
constants were reported with the best values in the region of
104 M-1. A second currently existing obstacle in trianglimine
and trianglamine chemistry is the poor water solubility. For any
attractive application in supramolecular chemistry, host molecules
should have satisfactory solubilities in aqueous solution. The
imines themselves are of course sensitive to hydrolysis and water
stable trianglamines obtained so far, possess water solubilities
at neutral pH in low mM region only. In order to overcome
these obstacles, in particular unsatisfactory binding constants
and water solubilities, novel trianglamine derivatives are urgently
required, in which these properties are improved. The strategy to
achieve this must include the incorporation of further substituents
in one of the trianglimine building blocks that due to their
polar nature enhance water solubility and that at the same
time offer suitable complementary binding motifs, including salt
bridges, hydrogen bond donors and acceptors or further aromatic
School of Engineering and Science, Jacobs University Bremen, P.O. Box
750 561, 28725 Bremen, Germany. E-mail: n.kuhnert@jacobs-university.de;
Fax: +49 421 200 3229; Tel: +49 421 200 3120
† Electronic supplementary information (ESI) available: 1H, 13C NMR
and ESI-MS spectra. CCDC reference number 779417. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00944j
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Table 1 Theoretical and experimental molecular weights for both the newly synthesised compounds and the assigned intermediates (ESI-MS, micrOTOF)
Compound / intermediate (Int.) Molecular formula Molecular weight (Calcd.) Molecular weight (m/z) (Exp.)
Error [ppm] Yield (%)
6
C14H17BrN2O3
C15H15BrN2O
C12H16BrNO3
C21H22N2O4
C20H14O3
C22H20N2O2
C19H21NO4
C81H96N12O6
C75H93N9O6
C78H72N6O3
C81H96N12O6
C75H93N9O6
C78H72N6O3
C84H90N12
C28H32N4O
C50H50N6O2
C56H60N8
C78H84N6O3
C81H108N12O6
C78H84N6O3
C75H105N9O6
340.0423
318.0368
301.0314
366.1580
302.0943
344.1525
327.1471
1332.7576
1215.7249
1140.5666
1332.7576
1216.7322
1140.5666
1267.7482
440.2576
766.3995
844.4941
1152.6605
1344.8515
1152.6605
1227.8188
363.0400
341.0367
324.0326
389.1554
325.0820
367.1598
350.1356
1333.7668
1216.7305
1163.5534
1333.4865
1216.7292
1163.5545
1267.7439
441.2758
767.4107
845.5072
1153.6665
1345.8617
1153.6658
1228.8261
M + Na+
M + Na+
M + Na+
M + Na+
M + Na+
M + Na+
M + Na+
M + H+
M + H+
M + Na+
M + H+
M+
2.6
1.7
4.2
1.0
4.8
2.0
2.0
0.3
0.1
4.0
0.3
2.4
1.8
3.4
5.0
4.9
2.8
1.8
2.2
1.7
0.4
90
66
94
75
47
85
79
10
4
22
35
31
37
11
(Int.)
(Int.)
(Int.)
>98
>98
>98
>98
8
9
11
12
13
14
16
17
18
19
20
21
22
23
24
25
26
27
28
29
M + Na+
M+
M + H+
M + H+
M + H+
M + H+
M + H+
M + H+
M + H+
groups for the binding of functionalised organic molecules.
Within this contribution we present a new synthetic strategy
for the introduction of a series of such substituents into novel
trianglimines and trianglamines. As core building blocks we have
chosen substituted biaryl dicarboxaldehydes. We present a novel
functionalisation approach, in which starting from a fluorinated
aromatic aldehyde a nucleophilic aromatic substitution reaction
introduces a suitable heteroatom substituent. Subsequent Suzuki-
coupling methodology,19 based on our previous work, furnishes a
substituted biaryl dialdehyde that serves as a building block for
trianglimine synthesis.
Fig. 1 Molecular structure of substituted monoaldehyde (6); thermal
Results and discussion
˚
ellipsoids are drawn at 50% probability level. Selected bond lengths (A)
and angles (◦) are given in the supplementary information.† Hydrogen
Aromatic nucleophilic substitution reactions of 4-bromo-2-
fluorobenzaldehyde (1) with secondary amines in DMF have
been reported by Nielsen et al.20 We modified this method using
alternative nucleophiles such as ethyl piperazine-1-carboxylate
(2), phenol (3), N-methyl-2-(pyridin-2-yl)-ethanamine (4) and 2,2-
dimethoxy-N-methylethanamine (5) in acetonitrile to afford the
corresponding 2-functionalised monoaldehydes (6–9) (Scheme 1)
in good to excellent yields (62–94%, Table 1). Compound (7) has
already been reported in the literature.21–23
The solid state structure of compound (6) based on single
crystal X-ray diffraction is shown in Fig. 1. The Suzuki-coupling
reaction19 of the 4-functionalised monoaldehydes (6–9) with 4-
formylphenylboronic acid (10) afforded the newly functionalised
4,4¢-biphenyldialdehydes (11–14) (Scheme 1) in good yields (47–
85%). Compound (12) was isolated in low yield (26%) in the case
where 0.9 mol% of tetrakis-(triphenylphosphine)-palladium-(0)
was used as a catalyst. The yield for compound (12) was dramati-
cally improved to (47%) by using 3.0 mol% of the catalyst. With the
2-substituted-4,4¢-biphenyldialdehydes (11–14) in hand we investi-
gated their behaviour in the [3+3]-cyclocondensation reaction. It is
worth noting that compounds (11–14) constitute non-symmetric
dialdehyde building blocks leading potentially to regioisomeric
macrocycles where the reactivity of such non-symmetrical building
atoms are shown as small grey balls.
blocks has never been investigated in trianglimine chemistry and
forms an interesting topic. We have previously investigated non-
symmetric 2,5-aryl substituted dialdehydes, where no issue of
regiochemistry arose, however, diastereomeric compounds with
the aromatic ring acting as a stereogenic plane were formed.
Furthermore we have reported on the use of non-symmetric
biaryl dialdehydes, in which the [O C–CAr–CAr–C O] angle was
smaller than 180◦ resulting in [2+2]-cyclocondensation products
that form in excellent regioselectivities. Hence compounds (11–
14) were reacted with (1R,2R)-1,2-diaminocyclohexane24 (15) in
dichloromethane to afford crude macrocyclic products in almost
quantitative yields (16–22, Fig. 3) each containing mixtures of C3-
symmetrical trianglimines, non-symmetrical regioisomers along
with some oligomers (Fig. 2 and 3). An accurate estimation of
the regioselectivity was not possible due to signals overlapping in
the1H-NMR spectra. However, a ratio of 1 : 1 for the formation of
the C3-symmetrical and the non-symmetrical regioisomers can be
established from the crude integrals. C3-symmetrical trianglimines
(16–18) and their non-symmetrical regioisomers (19–22) could be
separated using column chromatography on pretreated silica gel
to give the individual regioisomers in high purity, although low
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Scheme 1 Reagents, solvents and conditions: (i) acetonitrile, K2CO3, reflux. (ii) 3.0 mol% of Pd(PPh3)4, toluene, EtOH, Na2CO3, reflux.
Fig. 2 Reagents, solvents and conditions: 1.5 mmol of (1R,2R)-1,2-diaminocyclohexane (15), 1.0 mmol of dialdehydes (11–14), DCM (0.1 M).
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Fig. 3 C3-symmetrical (16–18) and the non-symmetrical (19–22) macrocyclisation products from the [3 + 3]-cyclocondensation reaction of
(1R,2R)-1,2-diaminocyclohexane (15) with dialdehydes (11–14).
isolated yield. It is worth noting that in previous work due to
their water sensitivity trianglimines were always purified using
crystallisation methods, whereas we give here for the first time
in trianglimine chemistry an experimental procedure allowing
purification by column chromatography. ESI mass spectrum for
trianglimine (20) showed two peaks at m/z 1216 and 1238
corresponding to [M+H+]and [M+Na+], respectively (Fig. 4).
1
Fig. 5a represents the H-NMR spectrum for a crude mixture
of trianglimines (17) and (20) before being purified by column
chromatography (CC). The number of signals corresponding to
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(20) and its C3-symmetrical regioisomer (17), respectively. The
1H-NMR spectrum for the non-symmetrical trianglimine (20)
showed four singlets at d 8.94, 8.93, 8.89 and 8.18 ppm. Each
signal had an integration of one. It also showed a broad signal
at d 8.14 ppm with an integration of two corresponding to the
six non-equivalent azomethine protons (Fig. 5b). On the other
hand the 1H-NMR spectrum for the C3-symmetrical trianglimine
(17) showed two set of singlets at d 8.90 and 8.19 ppm. Each
signal had an integration of three corresponding to the six
azometine protons (Fig. 5c). Furthermore, the IR spectra for
regioisomers (17) and (20) showed an intense absorption band
at nmax 1637 cm-1 corresponding to the imine functional groups.
In addition, all the protons and carbons could be unambiguously
1
1
assigned by H-1H-COSY, H-1H-ROESY, HMBC and HMQC
2D-experiments.
Monitoring the [3+3]-cyclocondensation reactions by direct
infusion ESI-MS
Fig. 4 ESI-MS spectrum for trianglimine (20) (micrOTOF, CH2Cl2 and
Here, we report the use of the high resolution ESI-mass
spectrometry as an efficient technique for monitoring the
progress of the [3+3]-macrocyclisation reactions. (1R,2R)-1,2-
Diaminocyclohexane (15) reacted with dialdehyde (13) in
dichloromethane at 0.1 M concentration. The mixture was stirred
at room temperature for 43 h. Aliquots were taken at different
time intervals, diluted and methanol added to the solution before
being directly infused to the ESI-TOF-MS. Fascinatingly a total of
15 different reaction intermediates could be detected at different
intensities and their appearance and disappearance monitored
over the cause of the reaction. This represents to our knowledge
the largest number of reaction intermediates ever observed in
a single chemical reaction. All intermediates could be assigned
on the basis of their high resolution m/z values. This method
does not only allow monitoring of the progress of the reaction,
previously not possible by TLC due to the acidic nature of
silica plates,25 but provides an intriguing insight into mechanistic
aspects of this unusual reaction. Intermediates (23) and (24) were
for example detected along with both the [2+2]-macrocyclisation
product (25) and the starting material (13) after 3 h from the
start of the experiment (Fig. 6). Most of these intermediates
were completely consumed in the construction of trianglimine
(22) after 43 h (Fig. 7). A peak at m/z 845, corresponding to the
[2+2]-cyclocondensation intermediate (25) was still observed after
that time. We assumed that intermediates (24), (25) and the final
product (22) are non-symmetric, but in fact the peaks appearing
at m/z 767, 845 and 1267 can also be related to their symmetrical
counterparts. Although the [3+3]-macrocyclisation reaction of
dialdehyde (13) with (1R,2R)-1,2-diaminocyclohexane (15) had
resulted in the formation of the non-symmetrical trianglimine (22)
along with its C3-symmetrical regioisomer, we could not succeed
in separating the C3-symmetrical regioisomer because its Rf value
was very close to that of the non-symmetrical trianglimine (22).
The chirality of the newly synthesised trianglimines was confirmed
by circular dichromism (CD) spectra (Fig. 8). Trianglimines (18)
and (21) have very similar UV absorption spectra with a slightly
increased absorption for the non-symmetrical trianglimine (21).
Large negative amplitudes were observed for the two regioisomers
(18) and (21) at l ª 300 nm indicating negative Cotton effects.
MeOH).
Fig. 5 Expanded 1H-NMR spectra for (a) a crude mixture of trianglim-
ines (17) and (20) before purification with CC, (b) the non-symmetrical
trianglimine (20) after purification and (c) the C3-symmetrical trianglimine
(17) after purification with CC (C6D6, 400 MHz).
the azomethine protons for the C3-symmetrical trianglimine (17)
should be two singlets and each signal should have an integration
of three. For the non-symmetrical trianglimine (20), six different
azomethine protons should be recognised. The presence of many
signals in the region from d 8.8 to 9 ppm indicates that the crude
mixture contains more than one isomer. Fig. 5b and 5c represent
1
the H-NMR spectra for both the non-symmetrical trianglimine
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Fig. 6 ESI-MS spectrum for following up the [3+3]-macrocyclisation reaction of diamine (15) with dialdehyde (13) (micrOTOF, measured after 3 h from
the start of the experiment in CH2Cl2 and MeOH).
Fig. 7 ESI-MS spectrum for following up the [3+3]-macrocyclisation reaction of diamine (15) with dialdehyde (13) (micrOTOF, measured after 43 h
from the start of the experiment in CH2Cl2 and MeOH).
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Fig. 11 Conformation structure of trianglimine (20).
Fig. 8 CD spectra for (a) the C3-symmetrical trianglimine (18) and (b)
the non-symmetrical regioisomer (21) in CHCl3.
Fig. 9 2D-ROESY spectrum for trianglimine (20) showing through space
interactions between the aromatic protons (CDCl3, 400 MHz).
Fig. 12 Computed structures of trianglimines (17) and (20) using the
Polak–Ribiere conjugate gradient with rms 0.007 Kcal/mol.
Equilibration of the C3-symmetrical trianglimine (16) with its
non-symmetrical regioisomer (19)
Fig. 10 2D-ROESY spectrum for trianglimine (20) showing through
space interactions between aromatic and aliphatic protons (CDCl3,
400 MHz).
CDCl
3
ꢀꢀꢀꢀꢁ
C3-symmetrical TA −16
Non-symmetrical TA-19
ꢂꢀꢀꢀ
58%
42%
Regioisomers (18) and (21) can be distinguishable by their spectral
fine structure between 250 and 280 nm.
Surprisingly, trianglimine (16) equilibrated with its non-
symmetrical regioisomer (19) in the NMR tubes during the
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Fig. 13 Reduced trianglamines (26–29).
NMR measurements in the case where CDCl3 was the sol-
vent used. On attempts to elucidate the reason behind this
equilibration, the H-NMR measurements were carried out in
(ArH). It also showed many aldehydic signals in the region from
d 10.02 to 10.07 ppm and d 10.32 to 10.36 ppm. The singlet
signals appearing at d 10.07 and 10.36 ppm are related to the two
aldehydic protons of dialdehyde (11). In addition, all the assigned
signals corresponding to the azomethine protons for both the
C3-symmetrical trianglimine (16) and its non-symmetrical regio-
isomer (19) were observed at d 8.18, 8.20, 8.23, 8.43, 8.44, 8.50
and 8.53 ppm indicating clearly an equilibration between the two
isomers.
1
different deuterated solvents, such as acetone-d6, CDCl3 and C6D6.
Only C3-symmetrical trianglimines equilibrated with their non-
symmetrical regioisomers in CDCl3. This can be attributed to the
slight acidity of CDCl3 which facilitates the acid catalysed imine
exchange reaction in addition to the fact that the non-symmetrical
trianglimine (19) is statistically favoured since the arrangements of
the building blocks are three times more probable than that with
trianglimine (16). The ratio of the C3-symmetrical trianglimine
(16) to its non-symmetrical regioisomer (19) after six days of
standing in CDCl3 was estimated from the 1H-NMR integrals and
was found to be 58 to 42%, respectively. The 1H-NMR spectrum
for the non-symmetrical trianglimine (19) showed a doublet signal
at d 6.93 ppm (ArH) and six different signals at d 8.19, 8.20,
8.23, 8.43, 8.44 and 8.53 ppm corresponding to the imine protons
Conformational analysis for the non-symmetrical trianglimine (20)
The two-dimensional 1H-1H-ROESY experiments confirmed both
the regiochemistry and the stereochemistry for all of the newly syn-
thesised trianglimines (e.g., trianglimine 20). The 1H-1H-ROESY
spectrum for compound (20) showed through space interactions
between the methylene protons (q) and the azomethine proton (d)
(Fig. 9–11). It can be concluded from the observed nOe effects that
trianglimine (20) adopts a conformation in solution in which the
2-biaryl substituent is placed syn- to the imine (HC N) group
and anti- to the nitrogen lone pairs. Structures of trianglimines
(17) and (20) were optimised with Hyperchem26 software (Release
8.0) using MM+ molecular mechanics along with the semi-
empirical molecular orbital PM3 method (Parametic Method 3,
1
(see supplementary information†). The H-NMR spectrum for
the C3-symmetrical trianglimine (16) showed a set of two singlet
signals at d 8.23 and 8.50 ppm corresponding to the azomethine
protons.
1
After six days of standing in CDCl3, the H-NMR spectrum
for the C3-symmetrical trianglimine (16) showed a doublet signal
at d 6.93 ppm related to the non-symmetrical trianglimine (19)
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Fig. 12).27 The structures were minimised using the Polak–Ribiere
conjugate gradient with rms 0.007 Kcal/mol. Reaching a gradient
of 0.007 Kcal/mol took 28 h of calculations for the C3-symmetrical
trianglimine (17) and 30 h for its non-symmetrical regioisomer
(20). The total energies for trianglimines (17) and (20) were found
to be exactly identical with a value of -497.56 a.u.
The results from the computational calculations were found
to be in accordance with both the conformational structures
suggested by the 2D-ROESY experiments and the previously
reported X-ray data.28
Experimental
Ethyl 4-(5-bromo-2-formylphenyl)-piperazine-1-carboxylate (6)
To a stirred solution of 4-bromo-2-fluorobenzaldehyde (1) (2.02 g,
10 mmol) in acetonitrile (20 mL), K2CO3 (4.07 g, 29.5 mmol)
and ethyl N-piperazinecarboxylate (2) (2.2 mL, 14.79 mmol)
was added. The mixture was stirred at 100 ◦C for 48 h. The
solvent was evaporated under vacuum. Water was added to the
crude product and the aqueous phase was extracted with Et2O
(3 ¥ 100 mL). The combined organic phases were washed with
H2O, dried with Na2SO4 and evaporated under vacuum. The
crude mixture was purified by column chromatography (petroleum
ether : ethylacetate, 9 : 1, the polarity was increased gradually to
7 : 3 after receiving the first fraction of impurities) to give the title
Reduction of trianglimines (18–21)
NaBH
Trianglimines (18 - 21) ⎯⎯⎯4⎯⎯→ Trianglamines(26 - 29)
◦
THF / MeOH
compound (6) as a yellow solid (3.06 g, 90%); mp 95–96 C; Rf
(0.6, petroleum ether : ethylacetate, 7 : 3); IR nmax/cm-1 1686 (br,
N(C O)O and H(C O)); 1H-NMR (400 MHz, CDCl3) dH 10.20
(1H, s, CHO), 7.62 (1H, dd, J = 8.2, ArH), 7.24 (1H, d, J = 8.2,
ArH), 7.19 (1H, s, ArH), 4.14 (2H, q, CH2CH3), 3.64 (4H, t, J =
4.5, CH2N-), 3.01 (4H, t, J = 4.1, CH2N-), 1.25 (3H, m, CH2CH3);
13C-NMR (100 MHz, CDCl3) dC 189.91, 155.78, 155.48, 132.00,
130.08, 127.46, 126.38, 122.76, 61.70, 53.57, 43,72, 14.74; MS (ESI-
MS, micrOTOF) m/z (Calcd. 340.0423; exp. 363.0400, M + Na+,
100%). A crystal structure was obtained and solved.19
Trianglimines (18–21) were reduced by sodium borohydride
(NaBH4) in a mixture of THF and MeOH to the corresponding
trianglamines (26–29) in excellent yields without needing further
1
purification (Fig. 13). The H-NMR spectrum for trianglamine
(27) showed multiplet signals at d 3.94–4.00 and 3.63–3.72
(J = 13.2) ppm corresponding to -CHACHBN and -CHACHBN
in the AB spin system. It also showed a broad multiplet at d 2.08–
2.31 ppm with an integration of 18 corresponding to the twelve
methylene protons (-CH2-) of the cyclohexyl group and the six
(-NH-) protons. On the other hand, the IR spectrum showed a
broad absorption band at n = 3286 cm-1 corresponding to the
(-NH-) groups.
4-Bromo-2-phenoxybenzaldehyde (7)
To a stirred solution of 4-bromo-2-fluorobenzaldehyde (1) (4.0 g,
19.7 mmol) in acetonitrile (20 mL), K2CO3 (8.18 g, 59.3 mmol) and
phenol (3) (2.32 g, 24.7 mmol) was added. The mixture was stirred
at 100 ◦C for 48 h. The solvent was evaporated under vacuum.
Water was added to the crude product and the aqueous phase
was extracted with Et2O (3 ¥ 100 mL). The combined organic
phases were washed with H2O, dried with Na2SO4 and evaporated
under vacuum. The crude compound was purified by column
chromatography (petroleum ether : ether, 9.7 : 0.3 mL) to give the
title compound (7) as a pale yellow solid (3.68 g, 62%); mp 86–
Conclusion
In conclusion, we have shown an efficient procedure for syn-
thesising functionalised aromatic dialdehydes in excellent yields
using nucleophilic aromatic substitution reactions along with the
Suzuki-coupling methodology. The newly functionalised dialde-
hydes successfully underwent [3+3]-cyclocondensation reactions
to give C3-symmetrical trianglimines along their non-symmetrical
regioisomers, which were separated and purified efficiently using
column chromatography. Computational calculations at the PM3
level showed great flexibility of the newly synthesised trianglimines
due to the free rotations around the C9–C10, C23–C24 and C37–C38
single bonds. The C3-symmetrical trianglimines showed dynamic
interchange to the non-symmetrical regioisomers in CDCl3 during
the NMR measurements. All the synthesised trianglimine and tri-
anglamine regioisomers are enantiomerically pure and can serve as
good receptors for different guests. Although the water solubility
for the newly synthesised trianglamines was not enhanced in a
satisfactory way by the introduction of the substituents chosen in
this work, we still believe that a careful choice of the substituents
which possess functional groups capable of forming hydrogen
bonds or salt bridges can lead to a dramatic improvement in
the solubility of this class of macrocycle, leading to potential
applications. We showed that the ESI-MS instrument can be used
as an efficient technique for monitoring the progress of the [3+3]-
macrocyclisation reaction providing vital information about the
reactive intermediates participating in the formation of the final
product.
◦
87 C; Rf (0.9, petroleum ether : ethylacetate, 7 : 3); IR nmax/cm-1
1676 (C O); 1H-NMR (400 MHz, CDCl3) dH 10.46 (1H, s, CHO),
7.77 (1H, d, J = 8.4, ArH), 7.41 (2H, t, J = 8.4, ArH), 7.21–7.29
(2H, m, ArH), 7.08 (2H, d, J = 8.4, ArH), 6.99 (1H, s, ArH);
13C-NMR (100 MHz, CDCl3) dC 188.39, 160.51, 155.44, 130.46,
130.27, 129.69, 126.66, 125.44, 125.22, 121.09, 119.95; MS (APCI-
MS, HCTultra) m/z (Calcd. 275.9; exp. 276.9, M + H+, 100%).
4-Bromo-2-[methyl-(2-pyridin-2-yl)-ethylamino]-benzaldehyde(8)
To a stirred solution of 4-bromo-2-fluorobenzaldehyde (1) (4.0 g,
19.7 mmol) in acetonitrile (20 mL), K2CO3 (8.14 g, 59 mmol) and
N-methyl-2-(pyridin-2-yl)-ethanamine (4) (2.7 mL, 19.8 mmol)
was added. The mixture was stirred at 100 ◦C for 48 h. The
solvent was evaporated under vacuum. Water was added to the
crude product and the aqueous phase was extracted with Et2O
(3 ¥ 100 mL). The combined organic phases were washed with
H2O, dried with Na2SO4 and evaporated under vacuum. The
crude mixture was purified by column chromatography (petroleum
ether : ethylacetate, 8 : 2) to give the title compound (8) as a yellow
oil (4.43 g, 66%); Rf (0.17, petroleum ether : ethylacetate, 7 : 3);
1
IR nmax/cm-1 1682 (C O), 1580 (C N); H-NMR (400 MHz,
3266 | Org. Biomol. Chem., 2011, 9, 3258–3271
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CDCl3) dH 9.92 (1H, s, CHO), 8.41 (1H, m, ArH), 7.44–7.51 (2H,
m, ArH), 7.12 (1H, s, ArH), 6.99–7.05 (3H, m, ArH), 3.51 (2H,
m, CH2N-), 2.99 (2H, m, CH2CH2), 2.86 (3H, s, CH3); 13C-NMR
(100 MHz, CDCl3) dC 190.16, 158.98, 155.99, 149.45, 136.41,
131.66, 129.56, 126.76, 124.56, 123.30, 122.77, 121.58, 57.58,
42.40, 36.03; MS (ESI-MS, micrOTOF) m/z (Calcd. 318.0368;
exp. 341.0367, M + Na+, 100%).
3-Phenoxybiphenyl-4,4¢-dicarbaldehyde (12)
To a stirred solution of 4-bromo-2-phenoxybenzaldehyde (7) (3.0
g, 10.9 mmol) in toluene (20 mL) under nitrogen atmosphere,
Pd(PPh3)4 (0.32 g, 0.28 mmol, 3.0 mol%) and an aqueous solution
of Na2CO3 (10 mL, 2mol L-1) was added. The mixture was
stirred vigorously and then 4-formylphenylboronic acid (10) (1.62
g, 10.8 mmol) in 15 mL ethanol was added. The mixture was
refluxed overnight under vigorous stirring. The organic phase was
extracted with Na2CO3 solution (2 ¥ 50 mL) and 10 mL brine.
The organic phase was dried over MgSO4, filtered, and the solvent
was removed under vacuum. The crude product was purified by
column chromatography (petroleum ether : ethylacetate, 8 : 2 mL)
to give the title compound (12) as a pale yellow solid (1.54 g, 47%);
4-Bromo-2-[(2,2-dimethoxyethyl)-methylamino]-benzaldehyde (9)
To a stirred solution of 4-bromo-2-fluorobenzaldehyde (1) (4.0 g,
19.7 mmol) in acetonitrile (20 mL), K2CO3 (8.14 g, 59 mmol) and
1,1-dimethoxy-N-methylethanamine (5) (2.5 mL, 19.78 mmol)
was added. The mixture was stirred at 100 ◦C for 48 h. The
solvent was evaporated under vacuum. Water was added to the
crude product and the aqueous phase was extracted with Et2O
(3 ¥ 100 mL). The combined organic phases were washed with
H2O, dried with Na2SO4 and evaporated under vacuum. The crude
mixture was purified by column chromatography (petroleum ether
was used as an eluent for the first fraction of impurities and then
a mixture of petroleum ether and ethylacetate was used to get the
target product, 7 : 3 mL) to give the title compound (9) as a yellow
mp 100–101 ◦C; Rf (0.74, petroleum ether : ethylacetate, 7 : 3); IR
1
n
max/cm-1 1733 (C O); H-NMR (400 MHz, CDCl3) dH 10.52
(1H, s, CHO), 10.01 (1H, s, CHO), 8.01 (1H, d, J = 7.7, ArH), 7.90
(2H, d, J = 7.7, ArH), 7.63 (2H, d, J = 7.7, ArH), 7.38–7.44 (3H,
m, ArH), 7.10–7.21 (4H, m, ArH);13C-NMR (100 MHz, CDCl3)
dC 191.66, 188.88, 160.35, 156.33, 147.21, 145.09, 136.19, 130.37,
130.09, 129.28, 127.97, 126.47, 124.68, 122.50, 119.44, 117.32; MS
(ESI-MS, micrOTOF) m/z (Calcd. 302.0943; exp. 325.0820, M +
Na+, 100%).
oil (5.66 g, 94%); Rf (0.67, petroleum ether : ethylacetate, 7 : 3); IR
n
3-[Methyl-(2-pyridin-2-yl)-ethylamino]-1,1¢-biphenyl-4,4¢-di-
carbaldehyde (13)
1
max/cm-1 1738 (C O); H-NMR (400 MHz, CDCl3) dH 10.12
(1H, s, CHO), 7.54 (1H, d, J = 8.2, ArH), 7.21 (1H, s, ArH), 7.10
(1H, d, J = 8.2, ArH), 4.51 (1H, m, CH2CH), 3.23–3.25 (8H, m,
2 -OCH3, CH2CH), 2.92 (3H, s,-NCH3); 13C-NMR (100 MHz,
CDCl3) dC 190.25, 156.02, 132.04, 129.60, 126.67, 124.72, 122.98,
102.41, 59.16, 53.72, 42.96; MS (ESI-MS, micrOTOF) m/z (Calcd.
301.0314; exp. 324.0326, M + Na+, 100%).
To a stirred solution of 4-bromo-2-[methyl-(2-pyridin-2-yl)-eth-
ylamino]-benzaldehyde (8) (3.02 g, 9.49 mmol) in toluene (20 mL)
under nitrogen atmosphere, Pd(PPh3)4 (0.33 g, 0.28 mmol,
3.0 mol%) and an aqueous solution of Na2CO3 (10 mL, 2mol
L-1) was added. The mixture was stirred vigorously and then
4-formylphenylboronic acid (10) (1.56 g, 10.4 mmol) in 15 mL
ethanol was added. The mixture was refluxed overnight under
vigorous stirring. The organic phase was extracted with Na2CO3
solution (2 ¥ 50 mL) and 10 mL brine. The organic phase was dried
over MgSO4, filtered and the solvent was removed under vacuum.
The crude product was purified by column chromatography
(petroleum ether : ethylacetate, 7 : 3 then the polarity was increased
to 6 : 4) to give the title compound (13) as a yellow oil (2.8 g, 85%);
Rf (0.28, petroleum ether : ethylacetate, 7 : 3); IR nmax/cm-1 1697
and 1676 (C O), 1596 (C N); 1H-NMR (400 MHz, CDCl3) dH
10.12 (1H, s, CHO), 10.05 (1H, s, CHO), 8.48 (1H, m, ArH), 7.95
(2H, d, J = 8.2, ArH), 7.83 (1H, d, J = 8.2,ArH), 7.74 (2H, d, J =
8.2, ArH), 7.53 (1H, ddd,, J = 7.7, ArH), 7.30 (1H, s, ArH), 7.24–
7.26 (1H, m, ArH), 7.06–7.10 (2H, m, ArH), 3.64 (2H, m, CH2N-),
3.10 (2H, m, CH2CH2), 3.01 (3H, s, CH3N); 13C-NMR (100 MHz,
CDCl3) dC 191.83, 190.91, 159.27, 155.83, 149.46, 146.27, 145.76,
136.50, 135.95, 131.05, 130.33, 128.05, 123.37, 121.58, 120.65,
118.68, 57.60,42.97, 36.19; MS (ESI-MS, micrOTOF) m/z (Calcd.
344.1525; exp. 367.1598, M + Na+, 100%).
Ethyl 4-[4,4¢-diformyl-(1,1¢-biphenyl)-3-yl]-piperazine-1-
carboxylate (11)
To a stirred solution of ethyl 4-(5-bromo-2-formylphenyl)-pip-
erazine-1-carboxylate (6) (3.0 g, 8.82 mmol) in toluene (20 mL) un-
der nitrogen atmosphere, Pd(PPh3)4 (0.4 g, 0.35 mmol, 3.0 mol%)
and an aqueous solution of Na2CO3 (10 mL, 2mol L-1) was
added. The mixture was stirred vigorously and then 4-formyl-
phenylboronic acid (10) (1.32 g, 8.8 mmol) in 15 mL of ethanol
was added. The mixture was refluxed overnight under vigorous
stirring. The organic phase was extracted with Na2CO3 solution
(2 ¥ 50 mL) and 10 mL brine. The organic phase was dried over
MgSO4, filtered and the solvent was removed under vacuum. The
crude product was purified by column chromatography (petroleum
ether : ethylacetate, 8 : 2 mL) to give the title compound (11) as a
yellow solid (2.43 g, 75%); mp 139–140 ◦C; Rf (0.28, petroleum
ether : ethyl-acetate, 7 : 3); IR nmax/cm-1 1684 (br, N(C O)O,
H(C O)); 1H-NMR (400 MHz, CDCl3) dH 10.36 (1H, s, CHO),
10.07 (1H, s, CHO), 7.97 (2H, d, J = 8.2, ArH), 7.92 (1H, d, J = 7.7,
ArH), 7.74 (2H, d, J = 7.7, ArH), 7.40 (1H, dd, J = 7.7, ArH), 7.30
(1H, s, ArH), 4.17 (2H, q, CH2CH3), 3.71 (4H, m, CH2N-), 3.12
(4H, m, CH2N-), 1.28 (3H, m, CH2CH3); 13C-NMR (100 MHz,
CDCl3) dC 191.76, 190.55, 155.63, 146.42, 145.91, 136.10, 131.35,
130.40, 128.37, 128.05, 122.23, 118.29, 61.72, 53.77, 43.88, 14.76;
MS (ESI-MS, micrOTOF) m/z (Calcd. 366.1580; exp. 389.1554,
M + Na+, 100%).
3-[(2,2-Dimethoxyethyl)-methylamino]-1,1¢-biphenyl-4,4¢-dic-
arbaldehyde (14)
To a stirred solution of 4-bromo-2-[(2,2-dimethoxyethyl)-methyl-
amino]-benzaldehyde (9) (3.0 g, 9.9 mmol) in toluene (20 mL)
under nitrogen atmosphere, Pd(PPh3)4 (0.35 g, 0.3 mmol,
3.0 mol%) and an aqueous solution of Na2CO3 (10 mL, 2 mol
L-1) was added. The mixture was stirred vigorously and then
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4-formylphenylboronic acid (10) (1.49 g, 9.9 mmol) in 15 mL
ethanol was added. The mixture was refluxed overnight under
vigorous stirring. The organic phase was extracted with Na2CO3
solution (2 ¥ 50 mL) and 10 mL brine. The organic phase was
dried over MgSO4, filtered, and the solvent was removed under
vacuum. The crude product was purified by column chromatog-
raphy (petroleum ether : ethylacetate, 9 : 1 mL) to give the title
compound (14) as a yellow oil (2.58 g, 79%); Rf (0.37, petroleum
m, ArH overlapping with C6D6 signals), 4.38 (3H, m, CH2CH),
3.52–3.65 (6H, m, HCN), 2.91–3.10 (24, m, CH3, -NCH2), 2.48
(9H, s, CH3), 1.83–2.00 (16H, br, m, CH2), 1.66–1.69 (8H, br,
m, CH2); 13C-NMR (100 MHz, C6D6) dC 159.65, 158.34, 153.74,
142.47, 142.21, 135.97, 129.94, 128.79, 128.69, 126.87, 121.50,
119.07, 102.66, (75.31, 77.21) 58.00, (52.65, 52.61), 43.79, (33.38,
33.18), 24.74; MS (ESI-MS, micrOTOF) m/z (Calcd. 1215.7249;
exp. 1216.7305, M + H+, 100%).
1
ether : ethylacetate, 7 : 3); IR nmax/cm-1 1697, 1678 (C O), H-
NMR (400 MHz, CDCl3) dH 10.31 (1H, s, CHO), 10.06 (1H, s,
CHO), 7.96 (2H, d, J = 8.2, ArH), 7.86 (1H, d, J = 7.7, ArH),
7.75 (2H, d, J = 7.7, ArH), 7.34 (1H, s, ArH), 7.29 (1H, d, J = 8.2,
ArH); 13C-NMR (100 MHz, CDCl3) dC 191.80, 190.96, 155.93,
146.21, 145.84, 135.99, 131.35, 130.35, 128.04, 127.79, 120.80,
118.90, 102.58, 59.20, 53.72, 43.46; MS (ESI-MS, micrOTOF)
m/z (Calcd. 327.1471; exp. 350.1356, M + Na+, 100%).
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,35)-triphenoxy-
(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-etheno-
(2H,3H,16H,17H,30H,31H)-hexahydro-[42]-annulene (18)
Dialdehyde (12) (1.2 g, 3.97 mmol) in dichloromethane (19.9 mL)
was added to a solution of (1R,2R)-1,2-diaminocyclohexane (15)
(679 mg, 5.96 mmol) in dichloromethane (19.9 mL). The mixture
was stirred at room temperature for 8 h. The solvent was evapo-
rated under vacuum. The crude mixture was purified by column
chromatography (petroleum ether : diethylether : triethylamine,
5 : 4: 1 mL) to give the title compound (18) as a pale yellow solid
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,35)-tri-N-
piprazinocarboxylate-(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-
hexa-etheno-(2H,3H,16H,17H, 30H,31H)-
hexahydro-[42]-annulene (16)
(344 mg, 22%); mp > 250 ◦C; IR nmax/cm-1 1637 (C N); H-
1
NMR (400 MHz, CDCl3) dH 8.51 (3H, s, -N CH), 8.14 (3H, s,
-N CH), 7.93 (3H, d, J = 8.2, ArH), 7.52 (6H, d, J = 8.2, ArH),
7.35 (6H, d, J = 8.2, ArH), 7.20–7.28 (5H, m, ArH), 6.94–6.99 (8H,
m, ArH), 6.66–6.80 (8H, m, ArH), 3.35 (6H, br, m, HCN), 1.83
(18H, br, m, CH2), 1.46 (6H, br, m, CH2); 13C-NMR (100 MHz,
CDCl3) dC 170.03, 160.59, 157.57, 156.49, 143.58, 141.12, 135.83,
129.80, 128.47, 127.88, 126.97, 126.83, 123.23, 122.35, 118.05,
117.61, (74.40, 74.13), 32.72, 24.52; MS (ESI-MS, micrOTOF)
m/z (Calcd. 1140.5666; exp. 1140.5534, M+, 100%).
Dialdehyde (11) (1.15 g, 3.14 mmol) in dichloromethane (16 mL)
was added to a solution of (1R,2R)-1,2-diaminocyclohexane (15)
(540 mg, 4.74 mmol) in dichloromethane (16 mL). The mixture
was stirred at room temperature for 72 h. The solvent was
removed under vacuum. The crude mixture was purified by
column chromatography (petroleum ether : ethylacetate : triethyl-
amine, 7 : 2: 1 mL) to give the title compound (16) as a yellow solid
(140 mg, 10%); mp > 150 ◦C; IR nmax/cm-1 1687 (N(C O)O), 1638
1
(C N); H-NMR (400 MHz, CDCl3) dH 8.49 (3H, s, N CH),
8.22 (3H, s, -N CH), 7.80–7.85 (1H, m, ArH), 7.70 (2H, d, J =
8.2, ArH), 7.60 (6H, d, J = 8.2, ArH), 7.44 (6H, d, J = 8.2, ArH),
7.14–7.21 (4H, m, ArH), 7.05 (2H, s, ArH), 4.08–4.17 (6H, m,
CH2CH3), 3.35–3.62 (18H, m, -NCH2, HCN), 2.75–2.98 (12H,
br, m, -NCH2), 1.86 (18H, br, m, CH2), 1.49 (6H, br, m, CH2),
1.21–1.32 (9H, m, CH3CH2); 13C-NMR (100 MHz, CDCl3) dC
160.35, 158.57, 155.54, 152.73, 142.82, 142.32, 135.56, 129.09,
128.54, 126.99, 121.93, 117.70, (74.83, 74.76), 61.49, 45.95, 44.95,
44.00, 32.76, 24.57, (14.94, 14.79); MS (ESI-MS, micrOTOF) m/z
(Calcd. 1332.7576; exp. 1333.7668, M+H+, 100%).
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,40)-tri-N-
piprazinocarboxylate-(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-
hexa-etheno-(2H,3H,16H,17H,30H,31H)-hexahydro-[42]-
annulene (19)
Dialdehyde (11) (1.15 g, 3.14 mmol) in dichloromethane (16 mL)
was added to a solution of (1R,2R)-1,2-diaminocyclohexane (15)
(537 mg, 4.71 mmol) in dichloromethane (16 mL). The mixture
was stirred at room temperature for 72 h. The solvent was
removed under vacuum. The crude mixture was purified by
column chromatography (petroleum ether : ethylacetate : triethyl-
amine, 7 : 2: 1 mL) to give the title compound (19) as a pale
yellow solid (430 mg, 35%); mp > 200 ◦C; IR nmax/cm-1 1691
(N(C O)O), 1638 (C N); 1H-NMR (400 MHz, CDCl3) dH 8.53
(1H, s, -N CH), 8.43 (1H, s, -N CH), 8.42 (1H, s, -N CH),
8.22 (1H, s, -N CH), 8.19 (1H, s, -N CH), 8.18 (1H, s,
-N CH), 7.83–7.86 (2H, m, ArH), 7.75 (1H, d, J = 8.2, ArH),
7.57–7.60 (6H, m, ArH), 7.42–7.45 (6H, m, ArH), 7.17–7.25 (3H,
m, ArH), 7.06 (1H, s, ArH), 6.90–6.93 (2H, m, ArH), 4.12–4.18
(6H, m, CH2CH3), 3.72 (2H, br, m, CH2N-), 3.50 (6H, br, m,
HCN), 3.36–3.41 (10H, m, CH2N-), 2.76 (4H, br, m, CH2N-),
2.53 (4H, br, m, CH2N-), 2.43 (4H, br, m, CH2N-), 1.85 (18H,
br, m, CH2), 1.48 (6H, br, m, CH2), 1.23–1.28 (9H, m, CH2CH3);
13C-NMR (100 MHz, CDCl3) dC (160.59, 160.48, 160.27), (158.36,
157.86, 157.76), (155.54, 155.48, 155.42), (152.84, 153.68), (143.44,
143.22, 142.84), (142.38, 142.12), (135.63, 135.57, 135.46), (129.10,
(2R,3R,16R,17R,30R,31R)-(1,4, 15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,35)-tri-(2,2-dimethoxy-N-
methylethanamino)-(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-
etheno-(2H,3H,16H,17H,30H,31H)-hexahydro-[42]-
annulene (17)
Dialdehyde (14)(1.73 g, 5.29 mmol) in dichloromethane (26 mL)
was added to a solution of (1R,2R)-1,2-diaminocyclohexane
(15) (906 mg, 7.95 mmol) in dichloromethane (26 mL). The
mixture was stirred at room temperature for 50 h. The crude
product was purified by column chromatography (petroleum
ether : ethylacetate : triethylamine, 8 : 1 : 1) to give the title com-
pound (17) as a yellow solid (90 mg, 4%); mp > 115 ◦C; IR
n
max/cm-1 1637 (C N); 1H-NMR (400 MHz, C6D6) dH 8.90 (3H,
s, -N CH), 8.27 (3H, d, J = 7.7, ArH), 8.19 (3H, s, -N CH), 7.61
(6H, d, J = 8.7, ArH), 7.27 (6H, d, J = 8.2, ArH), 7.60–7.09 (6H,
3268 | Org. Biomol. Chem., 2011, 9, 3258–3271
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128.98), (128.60, 128.51, 128.44), (128.41, 128.33, 128.27), (127.26,
127.14, 126.96), (122.11, 121.97), (118.18, 118.03, 117.82), (75.25,
75.14, 75.01, 74.82, 74.66, 74.38), (61.53, 61.50, 61.45), (52.53),
(43.98), (32.98, 32.83, 32.73, 32.61), (24.60), (14.87, 14.82); MS
(ESI-MS, micrOTOF) m/z (Calcd. 1332.7576; exp. 1333.4865,
M + H+, 100%).
diaminocyclohexane (15) (1.14 g, 10.03 mmol) in dichloromethane
(33.4 mL). The mixture was stirred at room temperature for 96
h. The crude product was purified by column chromatography
(petroleum ether : ethylacetate : triethylamine, 7 : 2 : 1) to give the
title compound (22) as a yellow solid (310 mg, 11%); mp >
125 ◦C; IR nmax/cm-1 1637; 1H-NMR (400 MHz, C6D6) dH 8.66–
8.69 (3H, br, m, -N CH), 8.41–8.43 (3H, br, m, -N CH), 8.14–
8.26 (6H, m, ArH), 7.62–7.68 (6H, m, ArH), 7.24–7.28 (6H, m,
ArH), 6.95–7.04 (9H, m, ArH), 6.58–6.71 (6H, m, ArH), 3.48–
3.55 (6H, m, CH2), 3.13–3.23 (6H, m, -NCH2), 2.77–2.84 (6H, m,
CH2CH2), 2.34–2.41 (9H, m, CH3), 1.86–1.95 (12H, br, m, CH2),
1.68 (6H, br, m, CH2), 1.37 (6H, br, m, CH2); 13C-NMR (100 MHz,
C6D6) dC (160.25), (159.83, 159.76, 159.67), (158.34, 158.20,
158.18), (153.65, 153.58, 153.50), (149.42), (142.49, 142.42),
(135.87, 135.82, 135.79), (135.54, 135.50, 135.47), (130.16, 130.13,
130.09), (128.68, 128.63, 128.53), (127.06, 127.04, 126.96), (123.08,
122.97), (121.34),(120.85), (119.26, 119.18, 119.10), (75.61, 75.53),
(75.34, 75.27), (74.80), (56.09), (43.27, 43.22, 43.19), (36.65, 36.63,
36.53), (33.36, 33.21, 33.16), (24.84, 24.78, 24.70); MS (ESI-MS,
micrOTOF) m/z (Calcd. 1267.7482; exp. 1267.7439, M +, 100%).
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,40)-tri-(2,2-dimethoxy-N-
methylethanamino)-(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-
etheno-(2H,3H,16H,17H,30H,31H)-hexahydro-[42]-
annulene (20)
Yellow solid (680 mg, 31%); mp > 125 ◦C; IR nmax/cm-1 1637
1
(C N); H-NMR (400 MHz, C6D6) dH 8.94 (1H, s, -N CH),
8.93 (1H, s, -N CH), 8.89 (1H, s, -N CH), 8.21–8.27 (3H, m,
ArH), 8.18 (1H, s, -N CH), 8.14 (2H, br, s, -N CH), 7.62–7.66
(6H, m, ArH), 7.31 (2H, d, J = 8.2, ArH), 7.26 (2H, d, J = 8.2,
ArH), (2H, d, J = 8.2, ArH), 7.00–7.13 (6H, m, ArH), 4.36–4.42
(3H, m, CH2CH), 3.46–3.68 (6H, m, CH2), 3.00–3.03 (24H, m,
CH3, -NCH2) 2.51 (3H, s, CH3), 2.47 (3H, s, CH3), 2.43 (3H,
s, CH3), 1.82–1.99 (12H, br, m, CH2), 1.67 (6H, br, m, CH2),
1.36 (6H, br, m, CH2); 13C-NMR (100 MHz, C6D6) dC (159.78,
159.69, 159.60), (158.42, 158.22, 158.17), (153.87, 153.82, 153.77),
(142.43, 142.36, 142.31), (136.01, 135.88, 135.84), (130.00, 129.91),
(128.88, 128.73, 128.58), (126.97, 126.86), (121.45), (119.25,
119.21, 119.11), (102.78, 102.69), (75.62, 75.57), (75.24), (74.76),
(58.08, 58.04, 57.94), (52.77, 52.70, 52.61), (44.01, 43.95, 43.87),
(33.34, 33.14), (24.74); MS (ESI-MS, micrOTOF) m/z (Calcd.
1215.7322; exp. 1216.7292, M+H+, 100%).
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,35)-triphenoxy-
(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-etheno-(1H,2H,
3H,4H,5H,14H,15H,16H, 17H,18H,19H,28H,29H,30H,
31H,32H,33H,42H)-octadecahydro-[42]-annulene (26)
To a stirred solution of trianglimine (18) (125 mg, 0.11 mmol) in
THF–MeOH (1 : 1, 20 mL) solid NaBH4 (36.5 mg, 0.96 mmol)
was gradually added and the solution was stirred for 5 h at room
temperature. After removal of solvents the residue was extracted
with CH2Cl2 and water. The organic extracts were dried over
MgSO4, filtered and evaporated under reduced pressure to give the
title compound (26) as a pale yellow solid (>98%) which required
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,40)-triphenoxy-
(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-etheno-
(2H,3H,16H,17H,30H,31H)-hexahydro-[42]-annulene (21)
◦
no further purification; mp > 180 C; IR nmax/cm-1 3289 (NH);
1H-NMR (400 MHz, CDCl3) dH 7.48 (8H, t, J = 7.7, ArH), 7.38
(8H, d, J = 8.2, ArH), 7.20–7.25 (8H, m, ArH), 7.14 (3H, s, ArH),
6.99 (3H, m, ArH), 6.92 (6H, d, J = 7.7, ArH), 3.94–3.98 (6H,
m, AB system, -CHACHBN), 3.63–3.74 (6H, m, AB system, J =
12.8, CHACHBN-), 2.18–2.34 (18H, m, CH2, -NH), 1.73 (6H,
br, s, CHN-), 1.18–1.27 (6H, br, m, CH2), 1.03–1.08 (6H, br, m,
CH2); 13C-NMR (100 MHz, CDCl3) dC 157.70, 155.18, 141.34,
140.42, 138.79, (130.97, 130.64), 129.87, 128.63, 126.98, 122.91,
122.44, (118.02, 117.78), (61.02, 60.97), 50.50, (31.52, 31.37),
(25.22, 25.10); MS (ESI-MS, micrOTOF) m/z (Calcd. 1152.6605;
exp. 1153.6665, M + H+, 100%).
Yellow solid (564 g, 37%); mp > 135 ◦C (decomposition); IR
n
max/cm-1 1637 (C N); 1H-NMR (400 MHz, CDCl3) dH 8.57 (1H,
s,-N CH), 8.55 (1H, s, -N CH), 8.54 (1H, s, -N CH), 8.18
(1H, s, -N CH), 8.15 (1H, s, -N CH), 8.14 (1H, s, -N CH),
7.94–7.97 (3H, m, ArH), 7.53–7.57 (6H, m, ArH), 7.34–7.42 (6H,
m, ArH), 7.22–7.31 (6H, m, ArH), 6.99–7.11 (7H, m, ArH), 6.91
(1H, s, ArH), 6.75–6.86 (5H, m, ArH), 6.69 (2H, d, J = 8.2, ArH),
3.37 (6H, m, br, HCN), 1.85 (18H, m, br, CH2), 1.47 (6H, m, br,
CH2); 13C-NMR (100 MHz, CDCl3) dC (160.62, 160.53), (157.78,
157.65, 157.45), (156.49), (143.63, 143.58), (141.23, 141.18),
(135.93, 135.85, 135.78), (130.00, 129.95, 129.80), (128.54, 128.47),
(128.23), (127.92), (127.17, 127.06), (126.86), (123.28, 123.19,
123.13), (122.51, 122.37, 122.26), (118.18), (117.70, 117.60),
(74.45, 74.36, 74.32, 74.26, 74.20, 74.05), (32.78, 32.71), (24.57);
MS (ESI-MS, micrOTOF) m/z (Calcd. 1140.5666; exp. 1163.5545,
M+Na+, 100%).
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,40)-triphenoxy-
(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-etheno-
(1H,2H,3H,4H,5H,14H,15H,16H,
17H,18H,19H,28H,29H,30H,31H,32H,33H,42H)-
octadecahydro-[42]-annulene (27)
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-(2,3 : 16,17 :
30,31)-tributano-(7,21,40)-tri-[N-methyl-2-(pyridin-2-yl)-eth-
anamino]-(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-etheno-
(2 H,3H,16H,17H,30H,31H)-hexahydro-[42]-annulene (22)
To a stirred solution of trianglimine (21) (125 mg, 0.11 mmol) in
THF–MeOH (1 : 1, 10 mL) solid NaBH4 (36.5 mg, 0.96 mmol)
was gradually added and the solution was stirred for 5 h at room
temperature. After removal of solvents the residue was extracted
with CH2Cl2 and water. The organic extracts were dried over
Dicarbaldehyde (13) (2.3 g, 6.69 mmol) in dichloromethane
(33.4 mL) was added to
a
solution of (1R,2R)-1,2-
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MgSO4, filtered and evaporated under reduced pressure to give the
temperature. After removal of solvents the residue was extracted
with CH2Cl2 and water, the organic extracts were dried over
MgSO4, filtered and evaporated under reduced pressure to give
the title compound (29) as a yellow oil (>98%) which required
no further purification, 1H-NMR (400 MHz, C6D6) dH 7.49–
7.54 (8H, m, ArH), 7.37–7.40 (9H, m, ArH), 7.23–7.28 (1H, m,
ArH), 7.09 (2H, s, ArH), 4.45–4.47 (3H, m, CH2CH), 4.11–4.19
(3H, m, AB system, J = 12.82,-CHACHBN), 3.76–3.87 (6H, m,
HCN), 3.53–3.58 (3H, m, AB system, -CHACHBN), 3.13–3.21
(6H, m, CH2CH), 3.03 (18H, s, OCH3), 2.64 (9H, s, NCH3),
2.01–2.37 (18H, m, CH2, NH), 1.56–1.62 (6H, m, CH2), 1.24
(6H, br, s, CH2); 13C-NMR (100 MHz, C6D6) dC (152.47), (140.59,
140.56, 140.50, 140.41), (140.08, 140.04, 140.00), (135.47), (130.57,
130.49), (128.65, 128.52), (127.15, 127.06), (125.55), (122.65,
122.53), (119.99, 119.92), (102.71), (77.65), (61.74), (60.97, 60.90),
(58.04), (52.45), (43.53), (31.52, 31.36), (25.35, 25.17); MS (ESI-
MS, micrOTOF) m/z(Calcd. 1227.8188; exp. 1228.8261, M++H+,
100%).
title compound (27) as a pale yellow solid (>98%) which required
◦
no further purification; mp > 110 C; IR nmax/cm-1 3286 (NH);
1H-NMR (400 MHz, CDCl3) dH 7.53 (2H, dd, J = 7.7, ArH), 7.46–
7.49 (6H, m, ArH), 7.29–7.38 (12H, m, ArH), 7.20–7.25 (8H, m,
ArH), 7.12–7.15 (3H, m, ArH), 6.97–7.02 (4H, m, ArH), 6.91–6.92
(6H, d, J = 7.3, ArH),3.94–4.00 (6H, m, AB system, -CHACHBN),
3.63–3.72 (6H, m, AB system, J = 13.2, -CHACHBN), 2.08–2.31
(18H, m, CH2, NH), 1.96–1.74 (6H, br, s, CHN), 1.26 (6H, br,
m, CH2), 1.05–1.07 (6H, br, m, CH2); 13C-NMR (100 MHz,
CDCl3) dC (157.57, 157.54), (155.23, 155.20, 155.16), (141.49,
141.45, 141.39), (140.25), (138.81), (135.87), (130.96), (130.69),
(129.87), (128.66, 128.49), (127.00, 127.03), (125.62), (122.96),
(122.53, 122.47), (118.04, 118.02, 117.98), (117.72, 117.69, 117.61),
(60.99, 60.92, 60.86, 60.81), (50.45), (31.43, 31.14, 31.02), (25.14,
25.02); MS (ESI-MS, micrOTOF) m/z (Calcd. 1152.6605; exp.
1153.6658, M+H+, 100%).
(2R,3R,16R,17R,30R,31R)-(1,4,15,18,29,32)-Hexaza-
(2,3 : 16,17 : 30,31)-tributano-(7,21,40)-tri-N-
piprazinocarboxylate-(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-
hexa-etheno-(1H,2H,3H,4H,5 H,14H,15H,16H,17H,
18H,19H,28H,29H,30H,31H,32H,33H,42H)-octadecahydro-
[42]-annulene (28)
Acknowledgements
Hany Nour deeply thanks the German Academic Exchange
Service (DAAD) for giving him the opportunity to carry out his
PhD project in Germany by granting him a full PhD scholarship
in 2008. He also thanks Jacobs University Bremen for hosting
the project. We thank Mrs Anja Mu¨ller for carrying out the MS
measurements.
To a stirred solution of trianglimine (19) (111 mg, 0.083 mmol)
in THF–MeOH (1 : 1, 10 mL) solid NaBH4 (32 mg, 0.83 mmol)
was gradually added and the solution was stirred for 5 h at room
temperature. After removal of solvents the residue was extracted
with CH2Cl2 and water. The organic extracts were dried over
MgSO4, filtered and evaporated under reduced pressure to give the
title compound (28) as a pale yellow solid (>98%) which required
Notes and references
1 J. Gawron´ski, H. Kolbon, M. Kwit and A. Katrusiak, J. Org. Chem.,
2000, 65, 5768.
◦
no further purification; mp > 110 C; IR nmax/cm-1 3293 (NH),
1686 (N(C O)O);1H-NMR (400 MHz, CDCl3) dH 7.50–7.56 (6H,
m, ArH), 7.45 (2H, d, J = 7.79, ArH), 7.41 (3H, d, J = 7.79, ArH),
7.29–7.38 (7H, m, ArH), 7.27 (1H, s, ArH), 7.25 (3H, s, ArH),
3.96–4.71 (12H, m, AB system, J = 13.28, -CHACHBN), 3.49–3.69
(18H, m, CH2N, HCN), 2.90–2.95 (12H, br, m, CH2N), 2.24–2.33
(12H, br, m, CH2), 2.02 (6H, br, s, CH2NH), 1.78 (6H, br, s, CH2),
1.17–1.25 (15H, m, CH3CH2, CH3CH2); 13C-NMR (100 MHz,
CDCl3) dC (155.68, 155.65), (151.76, 151.72), (140.72), (140.19,
140.15, 140.07), (139.55, 139.53, 139.50), (134.79, 134.74), (130.61,
130.58, 130.48), (128.55), (127.09, 127.05, 127.02), (123.02),
(121.39), (122.93), (118.84), (61.60, 61.53, 61.42), (61.14, 61.01,
60.94), (52.76), (50.66, 50.61, 50.58), (44.30), (31.53), (25.18),
(14.77); MS (ESI-MS, micrOTOF) m/z (Calcd. 1344.8515; exp.
1345.8617, (ESI-MS, micrOTOF) m/z (Calcd. 1344.8515; exp.
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methylethanamino)-(6,9 : 10,13 : 20,23 : 24,27 : 34,37 : 38,41)-hexa-
etheno-(1 H, 2H,3H,4H,5H,14H,15H,16H,17H,
18H,19H,28H,29H,30H,31H,32H,33H,42H)-octadecahydro-
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To a stirred solution of trianglimine (20) (207 mg, 0.17 mmol)
in THF–MeOH (1 : 1, 10 mL) solid NaBH4 (65 mg, 1.7 mmol)
was gradually added and the solution was stirred for 5 h at room
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This journal is
The Royal Society of Chemistry 2011
©

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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3258–3271 | 3271
©