Efficient synthesis of lower rim α-hydrazino tetrazolocalix[4]arenes via an Ugi-azide multicomponent reaction

Article abstract of DOI:10.1039/c5nj00845j

In this study, we developed an efficient synthesis of α-hydrazino tetrazolocalix[4]arene derivatives in good yields under mild conditions via an Ugi-azide multicomponent reaction. Metal ion binding properties of one of the α-hydrazino tetrazolocalix[4]are

Full text of DOI:10.1039/c5nj00845j

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Efficient synthesis of lower rim a-hydrazino
tetrazolocalix[4]arenes via an Ugi-azide
Cite this:DOI: 10.1039/c5nj00845j
multicomponent reaction†
Nahid S. Alavijeh,a Reza Zadmard,*a Sorour Ramezanpour,b Saeed Balalaie,*b
Mohammad S. Alavijehc and Frank Romingerd
Received (in Montpellier, France)
6th April 2015,
Accepted 18th June 2015
In this study, we developed an efficient synthesis of a-hydrazino tetrazolocalix[4]arene derivatives
in good yields under mild conditions via an Ugi-azide multicomponent reaction. Metal ion binding
properties of one of the a-hydrazino tetrazolocalix[4]arenes (7a) as the model compound were also
investigated, revealing that compound 7a exhibits the highest binding affinity towards Ni(II).
DOI: 10.1039/c5nj00845j
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example in this respect is the synthesis of tetrazoles and para-
substituted phenylazo-coupled calix[4]arenes as highly sensitive
Introduction
Calixarenes, produced by the condensation of p-substituted chromogenic sensors for Ca2+ using the 1,3-dipolar cycloaddition
phenols with aldehydes, have been applied in diverse areas.1 of oxyacetonitrile azocalix[4]arenes activated with trimethylsilyl
Calixarenes are versatile macromolecules, which can be used azide.7 Another fascinating example is the synthesis of the
for the synthesis of multivalent/multifunctional ligands.2 The lower rim 1,3-tetrazole-functionalised calix[4]arene by the reac-
easy accessibility and functionalization at their wide and narrow tion of 5,11,17,23-tetra-tert-butyl-25,27-dicyanomethoxy-26,28-
rims have made them ideal candidates for studying noncovalent dihydroxycalix[4]arene with sodium azide and triethylammonium
interactions involved in many biological processes.3 Calixarenes chloride, which acts as an ionophore for lanthaneid cations, forming
can also be used as metal-selective ionophores by virtue of luminescent complexes.5b
coordinating functional groups at their wide rims.
As part of our interest in the synthesis of functionalized
The presence of nitrogen-rich functional groups such as calixarenes, we reported the synthesis of a number of function-
tetrazole derivatives on the calixarene skeleton has drawn more alized calixarenes using multi-component reactions.8 Multi-
and more attention in the fields of molecular recognition and component reactions (MCRs) are compelling strategies for the
host–guest chemistry.
rapid generation of diverse sets of complex molecules.9 Among
Tetrazoles represent an important class of nitrogen hetero- MCRs, isocyanide-based multicomponent reactions (IMCRs) by
cyclic compounds, and their derivatives possess a broad range of virtue of their synthetic potential, inherent atom efficiency,
biological activities in both medicinal and pharmaceutical fields.4 convergent nature, ease of implementation, and generation of
Besides their well-known applications in medicinal chemistry, molecular diversity have attracted considerable attention of organic
pharmacology, materials chemistry, and organocatalysis, they are chemists, medicinal chemists and pharmacologists worldwide.10
also of interest as ligands in coordination chemistry due to the Despite their undeniable advantages in the field of combinatorial
presence of four nitrogen atoms in the tetrazole ring.5 The ability chemistry, the synthetic utility of IMCRs toward the synthesis of
of two phenolic OH groups to provide more coordination sites functionalized calixarenes is rather under-represented.11
and maintain the cone conformation led to the increasing impor-
In this study, we propose a versatile synthesis of the lower rim
tance of lower rim 1,3-disubstitutedcalix[4]arenes.6 An interesting a-hydrazinotetrazolocalix[4]arenes based on the Ugi-azide multi-
component reaction. The presence of numerous nitrogen atoms
makes a bidentate bonding mode likely for metal ion complexation.
a Chemistry and Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran. E-mail: zadmard@ccerci.ac.ir
b Peptide Chemistry Research Center, K.N. Toosi University of Technology,
P.O. Box 15875-4416, Tehran, Iran. E-mail: balalaie@kntu.ac.ir
c Pharmidex Pharmaceutical Services Ltd, London W1S 1YH, UK
d Organisch-Chemisches Institut der Universitat Heidelberg,
Results and discussion
The basic precursor of our investigation, calixarene dihydrazide
3, was prepared in good yield using the previously reported
synthetic procedure (Scheme 1).12
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
† Electronic supplementary information (ESI) available. CCDC 1025095. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c5nj00845j
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Scheme 1 Synthesis of calixarene dihydrazide 3.
At the outset of this study, our efforts were focused on
Due to the presence of two chiral centers in compounds
finding appropriate reaction conditions to perform the 7g–7j, diastereomeric products are possible. The structure of
proposed reaction. We commenced our study of the Ugi-azide one of the compounds, 7g, has also been established by single
reaction using calixarene dihydrazide 3, cyclohexanone, cyclo- crystal X-ray diffraction analysis (Fig. 1). The crystal structure of
hexyl isocyanide, and trimethylsilyl azide. The results are compound 7g shows the presence of both the diastereomers in
summarized in Table 1. The use of ethanol, acetonitrile, tetra- a 60 : 40 ratio. In 60% of the molecules in this specific crystal,
hydrofuran, and dichloromethane in place of methanol as the the configuration of the asymmetric carbon atom C85 is the
reaction solvent decreased the yield of the desired product same as for the asymmetric carbon C55. In 40% of the mole-
(entries 2–5).
cules it is the opposite one, which means that there are indeed
Furthermore, when TMS-N3 in the reaction was replaced by different stereoisomers.
NaN3, we could isolate only 30% of 7a. To further demonstrate
The strength of this process lies in the simple one-step
the efficiency of the Ugi-azide reaction based on calixarene synthesis of bidentate nitrogen rich calixarene ligands through
dihydrazide 3, the scope of the reaction with various ketones an Ugi-azide multicomponent reaction with easy workup and
and isocyanides was explored and the results obtained are purification procedures. To gain some insights into the intra-
summarized in Table 2.
molecular hydrogen bonding occurring in these compounds,
The products have been characterized using spectroscopic the 1H NMR spectra of 7a as the model compound in CDCl3 and
techniques, and the IR, 1H NMR, 13C NMR, and UHPLC– DMSO-d6 were obtained. Significant downfield shifts of the
TOFMS spectroscopic data confirm the proposed structures. CH proton directly attached to the nitrogen of the tetrazole
All the synthesized compounds exist in the cone conformation (B0.5 ppm) and OH protons (B1.65 ppm) indicate that both
as the signals of all bridging methylene carbons appear at the tetrazole and OH groups participate in significant hydrogen-
about 31 ppm in their 13C NMR spectra.13
bonding interactions in a nonpolar solvent (Fig. 2).
Table 1 Optimization of the reaction conditions
Entry
Solvents
Yield of 7a (%)
1
2
3
4
5
Methanol
Ethanol
Acetonitrile
Tetrahydrofuran
Dichloromethane
80
72
54
40
30
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Table 2 Scope of the Ugi-azide reaction of calixarene dihydrazide 3
Entry
1
Ketones
Isocyanides
Yield of 7 (%)
7a, 80
Entry
6
Ketones
Isocyanides
Yield of 7 (%)
7f, 65
2
3
7b, 72
7c, 68
7
8
7g, 76
7h, 67
4
5
7d, 58
7e, 73
9
7i, 70
7j, 61
10
Ni2+, Cu2+, Zn2+, and Hg2+), and the desired compound demon-
strated the highest binding affinity toward Ni(II) to form a Ni(II)-7a
complex, resulting in prominent fluorescence quenching, as
shown in Fig. 3 and 4.
The fluorescence spectrum of 7a (lex = 280 nm, molar
extinction coefficient e = 9340.66 MÀ1 cmÀ1) in CH3CN exhib-
ited two characteristic emission bands at 309 nm and 612 nm.
The strong band at 390 nm is a characteristic of the aromatic
core of the calixarene.14
As shown, the fluorescence of compound 7a was almost com-
pletely quenched by Ni(ClO4)2. The binding constant of compound
7a with Ni2+ was calculated by non-linear least squares curve fitting
(SigmaPlot Version 10.0), and the corresponding association con-
stant Ka was found to be 1.70 Â 107 MÀ1 (Table 3).15
Job plot analysis and ESI-MS spectra show that 7a and Ni(II)
form a 1 : 1 Ni(II)-7a complex (Fig. 5). Peaks in the 1H NMR
spectra of compound 7a with Ni2+ (1 : 1) decreased in signal
intensities, culminating in a substantial broadening and sub-
sequent disappearance of the resonances ascribable to the
compound 7a. These results provide evidence that 7a and
Ni(II) form a 1 : 1 Ni(II)-7a complex.
Fig. 1 ORTEP view of the major diastereomer of compound 7g.
The metal-binding sites on the synthesized compounds are
To test the highest binding affinity of compound 7a with
the nitrogen and oxygen atoms. Therefore, we further investigated Ni2+, competition experiments were carried out in the presence
the metal cation binding properties of the newly synthesized of Ni2+ at 1 equiv. mixed with Li+, Na+, K+, Ba2+, Mn2+, Co2+,
receptor 7a as the model compound by fluorescence titration Ni2+, Cu2+, Zn2+, and Hg2+ at 1 equiv. and no significant
with cations as metal perchlorates (Li+, Na+, K+, Ba2+, Mn2+, Co2+, variation was found by comparison with and without the other
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Fig. 2 Comparison of 1H NMR spectra of compound 7a in DMSO-d6 (above) and CDCl3 (below).
Table 3 The association constants of 7a with metal cations (1 : 1 binding
model) in CH3CN
Cation
Ka (MÀ1
)
Cation
Ka (MÀ1
)
K+
1560
1640
2480
4290
7767
Hg2+
Cu2+
Co2+
Zn2+
Ni2+
15 100
422 000
599 000
1 430 000
17 000 000
Na+
Li+
Fig. 3 Fluorescence spectra of 7a in response to the presence of Ni2+
ions (0 to 5.45 equiv.) in MeCN; lex = 280 nm.
Ba2+
Mn2+
metal ions besides Ni2+. This means that compound 7a has the
highest binding affinity for Ni2+ ions.
In contrast to many fluorescent sensors used for the detec-
tion of heavy and transition metal ions like Hg2+, Ag+, Cd2+,
Pb2+, and Cr3+, reports concerning fluorescent sensors for Ni2+
detection are scarce.16 Fluorescent sensors for Ni2+ detection
are often based on small molecules and encounter serious
interference problems from other heavy and transition metal
ions.17 This study opens up new opportunities for the design
of an efficient, fast and inexpensive synthesis of fluorescent
sensor libraries based on the calixarene unit.
Conclusion
In summary, an operationally simple Ugi-azide multicompo-
nent reaction protocol was developed for the preparation of
Fig. 4 Fluorescence intensity changes of compound 7a in MeCN upon
addition of 1 equiv. of various metal perchlorates; lex = 280 nm.
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(s, ArH, 4H); 9.49 (d, J = 5.5 Hz, NH, 2H); 13C NMR (75 MHz,
CDCl3) d 21.6, 21.9, 24.8, 24.9, 25.3, 25.5, 30.8, 31.6, 31.8, 33.0,
33.2, 33.4, 33.6, 33.8, 33.9, 57.9, 58.7, 59.4, 74.5, 125.3, 125.9,
127.3, 131.9, 142.9, 147.9, 149.2, 149.6, 155.7, 167.5; UHPLC–
TOFMS (ESI) m/z: calcd for C74H105N12O6: 1257.8275 [M + H]+;
found 1257.8297, calcd for C74H104N12NaO6: 1279.8094 [M + Na]+;
found 1279.8117.
7b. Yield: 72%, mp: 161–163 1C; IR (KBr, n, cmÀ1): 3320, 3056,
2963, 2864, 1685, 1544, 1481, 1427, 1266, 1196, 1120, 1039, 898,
743; 1H NMR (300 MHz, CDCl3) d 0.88 (s, t-Bu, 18H); 1.27 (s, t-Bu,
18H); 1.37–1.41 (m, CH2, 2H); 1.58 (m, CH2, 6H); 1.63 (s, t-Bu, 18H);
1.94–1.98 (m, CH2, 4H); 2.12–2.16 (m, CH2, 4H); 2.34–2.37 (m, CH2,
4H); 3.30 (d, J = 13.4 Hz, ArCH2Ar, 4H); 4.11 (d, J = 13.4 Hz,
ArCH2Ar, 4H); 4.71 (s, OCH2, 4H); 5.55 (d, J = 5.9 Hz, NH, 2H); 6.35
(s, OH, 2H); 6.68 (s, ArH, 4H); 7.00 (s, ArH, 4H); 9.27 (d, J = 5.7 Hz,
NH, 2H); 13C NMR (75 MHz, CDCl3) d 21.9, 25.3, 30.8, 30.9, 31.6,
33.8, 33.7, 34.7, 60.4, 63.5, 74.6, 76.6, 125.2, 125.8, 127.2, 131.9,
142.6, 147.7, 149.4, 149.5, 158.1, 167.7; UHPLC–TOFMS (ESI) m/z:
calcd for C70H100N12NaO6: 1227.7781 [M + Na]+; found 1227.7803.
7c. Yield: 68%, mp: 228–230 1C; IR (KBr, n, cmÀ1): 3394, 3305,
3056, 2961, 2863, 1690, 1549, 1485, 1426, 1359, 1267, 1190, 1102,
Fig. 5 The Job plot for the complexation of 7a with Ni2+ in CH3CN.
lower rim a-hydrazino tetrazolocalix[4]arene derivatives in good
yields under mild conditions. The scope of this reaction was
expanded to include various ketones and isocyanides. A detailed
investigation of the metal ion binding properties of the model
compound 7a is performed mainly by the fluorometric titration
approach, revealing that compound 7a exhibits the highest bind-
ing toward Ni(II). Future efforts in our laboratories are aimed to
develop new and efficient multicomponent reaction protocols for
the rapid synthesis of large libraries of functionalized calixarene
derivatives and will be reported in due course.
1
1039, 894, 743; H NMR (300 MHz, CDCl3) d 0.88 (s, t-Bu, 18H);
1.24–1.27 (m, CH2, 4H); 1.27 (s, t-Bu, 18H), 1.68–1.71 (bs, CH3,
CH2, 14H); 1.78 (m, CH2, 14H); 3.31 (d, J = 13.3 Hz, ArCH2Ar, 4H);
4.11 (d, J = 13.3 Hz, ArCH2Ar, 4H); 4.72 (s, OCH2, 4H); 4.72–4.78
(m, CH, 2H); 5.45 (d, J = 5.1 Hz, NH, 2H); 6.40 (s, OH, 2H); 6.69
(s, ArH, 4H); 7.02 (s, ArH, 4H); 9.50 (d, J = 4.9 Hz, NH, 2H); 13C
NMR (75 MHz, CDCl3) d 18.4, 24.8, 25.4, 30.8, 31.5, 31.6, 33.0,
33.8, 33.9, 56.4, 59.2, 74.4, 76.6, 125.2, 125.8, 127.3, 131.9, 142.7,
147.8, 149.4, 149.5, 157.0, 168.3; UHPLC–TOFMS (ESI) m/z: calcd
for C68H97N12O6: 1177.7649 [M + H]+; found 1177.7665, calcd for
C68H96N12NaO6: 1199.7468 [M + Na]+; found 1199.7488.
Experimental section
All solvents and reagents were commercially sourced. NMR
spectra were obtained on a Bruker DRX-300 AVANCE 300 MHz
spectrometer. All chemical shifts are reported in the standard
d notation of parts per million. UHPLC-TOF mass spectra using
electrospray ionisation were acquired with an Agilent 1290 Infinity
UHPLC and an Agilent 6550 iFunnel Q-TOF. Fluorescence emis-
sion spectra were obtained on an A JASCO FP-6500 spectrofluoro-
meter. UV/Vis spectra were measured on a PerkinElmer LAMBDA
35 UV/Vis spectrophotometer.
7d. Yield: 58%, mp: 162–164 1C; IR (KBr, n, cmÀ1): 3312,
3056, 2968, 2867, 1684, 1546, 1482, 1429, 1357, 1268, 1190,
1123, 1039, 895, 746; 1H NMR (300 MHz, CDCl3) d 0.86 (s, t-Bu,
18H); 1.27 (s, t-Bu, 18H); 1.59 (s, t-Bu, 18H); 1.75 (s, CH3, 12H);
3.27 (d, J = 13.3 Hz, ArCH2Ar, 4H); 4.14 (d, J = 13.3 Hz, ArCH2Ar,
4H); 4.76 (s, OCH2, 4H); 5.51 (bs, NH, 2H); 6.26 (s, OH, 2H); 6.66
(s, ArH, 4H); 7.01 (s, ArH, 4H); 9.45 (s, NH, 2H); 13C NMR
(75 MHz, CDCl3) d 27.1, 27.7, 30.6, 30.8, 31.4, 31.6, 33.8, 58.7,
General procedure for the synthesis of lower rim a-hydrazino
tetrazolocalix[4]arenes
A solution of calixarene dihydrazide 3 (0.2 mmol) and ketone 4 63.3, 74.6, 76.6, 125.1, 125.7, 127.3, 131.7, 142.6, 147.8, 149.4,
(0.5 mmol) in 2 mL MeOH was stirred for 2 h and trimethylsilyl 149.5, 159.0, 168.4; UHPLC–TOFMS (ESI) m/z: calcd for
azide 3 (0.5 mmol) and isocyanide 4 (0.5 mmol) were then
added. The mixture was stirred for 24 h at ambient temperature.
After completion of the reaction, as indicated by TLC (ethyl
C
C
64H93N12O6: 1125.7336 [M + H]+; found 1125.7328, calcd for
64H92N12NaO6: 1147.7155 [M + Na]+; found 1147.717.
7e. Yield: 73%, mp: 220–222 1C; IR (KBr, n, cmÀ1): 3310,
acetate/n-hexane, 1 : 3), the solvent was removed under vacuum, 3051, 2936, 2865, 1702, 1594, 1549, 1480, 1356, 1296, 1269,
and the residue was precipitated by addition of 3 mL of EtOH 1198, 1125, 1098, 1040; 1H NMR (300 MHz, CDCl3) d 0.86
and 1 mL of H2O. The precipitate was filtered off and then (t, CH3, 12H); 0.89 (s, t-Bu, 18H); 1.29 (s, t-Bu, 18H); 1.35–1.39
recrystallized from ethanol.
(m, CH2, 4H); 1.68–1.72 (m, CH2, 4H); 1.72–1.83 (m, CH2, 10H);
7a. Yield: 80%, mp: 223–225 1C; IR (KBr, n, cmÀ1): 3056, 2953, 2.00–2.07 (m, CH2, 6H); 2.14–2.19 (m, CH2, 4H); 3.33 (d, J =
2863, 1673, 1549, 1482, 1425, 1266, 1194, 1104, 1036, 896, 749; 13.4 Hz, ArCH2Ar, 4H); 4.08 (d, J = 13.4 Hz, ArCH2Ar, 4H); 4.65
1H NMR (300 MHz, CDCl3) d 0.90 (s, t-Bu, 18H); 1.27 (s, t-Bu, 18H); (s, OCH2, 4H); 5.02 (m, CH, 2H); 5.53 (d, J = 4.7 Hz, NH, 2H); 6.50
1.44 (m, CH2, 12H); 1.81 (m, CH2, 20H); 2.06 (m, CH2, 4H); 2.24 (s, OH, 2H); 6.72 (s, ArH, 4H); 7.04 (s, ArH, 4H); 9.40 (d, J = 4.7 Hz,
(m, CH2, 4H); 3.32 (d, J = 13.4 Hz, ArCH2Ar, 4H); 4.06 (d, J = NH, 2H); 13C NMR (75 MHz, CDCl3) d 7.7, 25.0, 25.5, 26.3, 30.8,
13.4 Hz, ArCH2Ar, 4H); 4.66 (s, OCH2, 4H); 4.90 (m, CH, 2H); 5.52 31.6, 33.1, 33.8, 33.9, 59.6, 62.9, 74.6, 76.6, 125.3, 125.9, 127.2,
(d, J = 5.7 Hz, NH, 2H); 6.45 (s, OH, 2H); 6.71 (s, ArH, 4H); 7.02 131.8, 142.9, 148.0, 149.3, 155.1, 167.5; UHPLC–TOFMS (ESI)
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m/z: calcd for C72H105N12O6: 1233.8275 [M + H]+; found for observed reflections, final residual values R1(F) = 0.088,
1233.8293, calcd for C72H104N12NaO6: 1255.8094 [M + Na]+; wR(F2) = 0.255 for observed reflections, residual electron density
found 1255.8112.
from À0.37 to 0.78 e ÅÀ3. CCDC 1025095.
7f. Yield: 65%, mp: 161–163 1C; IR (KBr, n, cmÀ1): 3310,
7h. Yield: 67%, mp: 163–165 1C; IR (KBr, n, cmÀ1): 3318, 3050,
3057, 2965, 2865, 1682, 1542, 1480, 1427, 1268, 1268, 1190, 2960, 2860, 1682, 1541, 1479, 1427, 1260, 1190, 898, 743; 1H NMR
1121, 1036, 896, 745; 1H NMR (300 MHz, CDCl3) d 0.84–0.89 (300 MHz, CDCl3, mixture of two diastereomers (52: 48)) d 0.73–
(t, CH3, 12H); 0.87 (s, t-Bu, 18H); 1.29 (s, t-Bu, 18H); 1.64 (s, 0.75 (m, CH3, 6H, mixture); 0.86 (s, t-Bu, 18H, major); 0.87
t-Bu, 18H); 2.21 (q, CH2, 8H); 3.31 (d, J = 13.4 Hz, ArCH2Ar, 4H); (s, t-Bu, 18H, minor); 0.92–0.98 (m, CH2, 4H, mixture); 1.17–
4.12 (d, J = 13.4 Hz, ArCH2Ar, 4H); 4.72 (s, OCH2, 4H); 5.61 (d, J = 1.28 (m, CH3, 6H, mixture); 1.28 (s, t-Bu, 18H, mixture); 1.64
5.4 Hz, NH, 2H); 6.22 (s, OH, 2H); 6.68 (s, ArH, 4H); 7.03 (s, ArH, (s, t-Bu, 18H, major); 1.66 (s, t-Bu, 18H, minor); 1.91–1.99
4H); 9.26 (d, J = 5.2 Hz, NH, 2H); 13C NMR (75 MHz, CDCl3) (m, CH2, 2H, mixture); 2.06–2.19 (m, CH2, 4H, mixture); 2.29–
d 8.1, 27.9, 30.8, 30.9, 31.5, 31.6, 33.8, 64.2, 64.7, 74.6, 76.6, 2.34 (m, CH2, 2H, mixture); 3.28–3.34 (m, ArCH2Ar, 4H, mixture);
125.2, 125.8, 127.4, 131.7, 142.8, 147.8, 149.4, 149.6, 156.8, 4.09–4.31 (m, ArCH2Ar, 4H, mixture); 4.59–4.84 (m, OCH2, 4H,
167.5; UHPLC–TOFMS (ESI) m/z: calcd for C68H100N12NaO6: mixture); 5.56 (s, NH, 2H, major); 5.57 (s, NH, 2H, minor); 6.03
1203.7781 [M + Na]+; found 1203.7803.
(s, OH, 1H, minor); 6.24 (s, OH, 2H, major); 6.30 (s, OH, 1H,
7g. Yield: 76%, mp: 225–227 1C; IR (KBr, n, cmÀ1): 3305, 3054, minor); 6.66 (s, ArH, 4H, minor); 6.72 (s, ArH, 4H, major); 7.01
2981, 2867, 1696, 1546, 1476, 1354, 1267, 1196, 1099, 1038, 897, (s, ArH, 4H, minor); 7.03 (s, ArH, 2H, major); 7.04 (s, ArH, 2H,
819, 744, 560; 1H NMR (300 MHz, CDCl3, mixture of two diastereo- major); 9.30 (m, NH, 2H, mixture); 13C NMR (75 MHz, CDCl3)
mers (60 : 40)) d 0.83–0.96 (m, CH3, 12H, mixture); 0.88 (s, t-Bu, d 8.0, 8.2, 14.1, 17.2, 28.6, 29.7, 30.7, 30.8, 31.4, 31.6, 33.8, 37.9,
18H, major); 0.89 (s, t-Bu, 18H, minor); 1.04–1.09 (m, CH2, 4H, 64.0, 64.5, 74.7, 76.6, 125.1, 125.2, 125.7, 127.0, 127.2, 127.3,
mixture); 1.29 (s, t-Bu, 18H, mixture); 1.34–1.40 (m, CH2, 4H, 127.5, 131.6, 131.6, 131.7, 147.8, 149.3, 149.5, 156.8, 156.9, 167.6;
mixture); 1.67–1.83 (m, CH2, 16H, mixture); 1.91–2.09 (m, CH2, UHPLC–TOFMS (ESI) m/z: calcd for C70H104N12NaO6: 1231.8094
6H, mixture); 2.21–2.25 (m, CH2, 2H, mixture); 3.30–3.35 [M + Na]+; found 1231.8115.
(m, ArCH2Ar, 4H, mixture); 4.07–4.12 (m, ArCH2Ar, 4H, mixture);
7i. Yield: 70%, mp: 221–223 1C; IR (KBr, n, cmÀ1): 3394,
4.56–4.76 (m, OCH2, 4H, mixture); 5.01 (m, CH, 2H, mixture); 5.46 3309, 3056, 2960, 2863, 1689, 1547, 1483, 1426, 1360, 1267,
1
(d, J = 5.0 Hz, NH, 2H, mixture); 6.34 (s, OH, 1H, minor); 6.44 1194, 1099, 1040, 899, 741; H NMR (300 MHz, CDCl3, mixture
(s, OH, 2H, major); 6.49 (s, OH, 1H, minor); 6.71 (s, ArH, 4H, of two diastereomers (54 : 46)) d 0.86 (s, t-Bu, 18H, major); 0.87
mixture); 7.04 (s, ArH, 4H, mixture); 9.30 (d, J = 5.0 Hz, NH, 2H); (s, t-Bu, 18H, minor); 0.87 (s, CH3, 6H, mixture); 1.15–1.4
13C NMR (75 MHz, CDCl3) d 7.6, 7.7, 14.3, 16.8, 16.9, 24.9, 25.4, (m, CH3, CH2, 8H, mixture); 1.27 (s, t-Bu, 18H, minor); 1.28
26.6, 30.8, 31.5, 31.6, 33.0, 33.3, 33.8, 33.9, 36.3, 59.5, 62.6, 62.7, (s, t-Bu, 18H, major); 1.52–1.67 (m, CH2, 4H, mixture); 1.71 (br,
74.5, 76.6, 125.3, 125.8, 125.9, 127.2, 127.3, 131.7, 131.8, 142.7, CH2, 4H, mixture); 1.78–1.87 (m, CH2, 10H, mixture); 1.92–2.07
142.8, 142.9, 147.9, 149.3, 149.4, 155.3, 155.4, 167.6, 167.7; (m, CH2, 4H, mixture); 3.24–3.51 (m, ArCH2Ar, 4H, mixture);
UHPLC–TOFMS (ESI) m/z: calcd for C74H109N12O6: 1261.8588 4.03–4.18 (m, ArCH2Ar, 4H, mixture); 4.32–4.89 (m, CH, OCH2,
[M + H]+; found 1261.8604, calcd for C74H108N12NaO6: 1283.8407 6H, mixture); 5.45 (br, NH, 2H, minor); 5.53 (br, NH, 2H,
[M + Na]+; found 1283.8426.
minor); 6.08 (s, OH, 1H, minor); 6.26 (s, OH, 2H, major); 6.35
(s, OH, 1H, minor); 6.66 (s, ArH, 4H, major); 6.68 (s, ArH, 4H,
Crystallographic analysis. A colourless crystal (polyhedron), minor); 6.98 (s, ArH, 4H, major); 7.02 (s, ArH, 4H, major); 9.38
dimensions 0.110 Â 0.080 Â 0.050 mm3, crystal system triclinic, (br, NH, 2H, major); 9.45 (br, NH, 2H, minor); 13C NMR (75 MHz,
space group P, Z = 2, a = 15.0078(8) Å, b = 15.5458(8) Å, c = CDCl3) d 8.3, 8.4, 21.8, 21.9, 24.8, 25.4, 30.8, 31.6, 32.8, 33.0, 33.8,
18.4958(10) Å, alpha = 99.5345(15) deg, beta = 101.1917(16) deg, 59.2, 59.3, 59.8, 59.9, 74.6, 76.6, 125.0, 125.2, 125.6, 125.7, 125.8,
gamma = 113.0196(14) deg, V = 3754.1(3) Å3, rho = 1.116 g cmÀ3
,
125.9, 127.0, 127.2, 127.4, 127.6, 131.7, 131.9, 142.6, 142.9, 147.7,
T = 200(2) K, Thetamax = 22.464 deg, radiation Mo Kalpha, 147.8, 149.5, 149.5, 149.6, 155.9, 156.2, 168.2, 168.3; UHPLC–
lambda = 0.71073 Å, 0.5 deg omega-scans with CCD area TOFMS (ESI) m/z: calcd for C70H101N12O6: 1205.7962 [M + H]+;
detector, covering the asymmetric unit in reciprocal space with found 1205.7976, calcd for C70H100N12NaO6: 1227.7781 [M + Na]+;
a mean redundancy of 4.95 and a completeness of 99.9% to a found 1227.7795.
resolution of 0.93 Å, 48 309 reflections measured, 9743 unique
7j. Yield: 61%, mp: 160–162 1C; IR (KBr, n, cmÀ1): 3309, 3055,
(R(int) = 0.0512), 6476 observed (I 4 2s(I)), intensities were 2967, 2866, 1687, 1546, 1476, 1357, 1269, 1193, 1121, 1039, 902,
corrected for Lorentz and polarization effects, an empirical 820, 739, 583; 1H NMR (300 MHz, CDCl3, mixture of two
absorption correction was applied using SADABS1 based on diastereomers (52 : 48)) d 0.76–0.85 (m, CH3, 6H, mixture);
the Laue symmetry of the reciprocal space, m = 0.07 mmÀ1
,
0.85 (s, t-Bu, 18H, mixture); 1.28 (m, t-Bu, 18H, mixture);
Tmin = 0.95, Tmax = 1.00, structure refined against F2 with a Full- 1.27–1.30 (m, CH3, 3H, mixture); 1.57 (s, t-Bu, 18H, major)
matrix least-squares algorithm using the SHELXL (Version 1.58 (s, t-Bu, 18H, minor); 1.77–1.84 (m, CH3, 3H, mixture);
2014-3) software 2980 parameters refined, hydrogen atoms 1.98–2.20 (m, CH2, 4H, mixture); 3.20–3.49 (m, ArCH2Ar, 4H,
were treated using appropriate riding models, except those at mixture); 3.96–4.24 (m, ArCH2Ar, 4H, mixture); 4.45–4.94 (m, OCH2,
the hetero atoms, which were refined isotropically (except H54 4H, mixture); 5.07–5.68 (br, NH, 2H, mixture); 5.99 (s, OH,
at N54, that could not be considered at all), goodness of fit 1.06 1H, minor); 6.19 (s, OH, 2H, major); 6.35 (s, OH, 1H, minor);
New J. Chem.
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Paper
(b) R. J. Spandl, A. Bender and D. R. Spring, Diversity-
oriented synthesis; a spectrum of approaches and results,
Org. Biomol. Chem., 2008, 6(7), 1149–1158.
6.64 (s, ArH, 4H, major); 6.65 (s, ArH, 4H, minor); 6.91–7.06
(m, ArH, 4H, mixture); 9.38 (s, NH, 2H, mixture); 13C NMR
(75 MHz, CDCl3) d 8.3, 8.4, 24.1, 24.3, 27.7, 29.8, 30.7, 30.8, 31.3,
31.4, 31.6, 32.1, 32.3, 33.8, 61.7, 63.5, 63.6, 74.6, 76.6, 125.0, 125.1,
125.2, 125.4, 125.7, 125.8, 125.9, 126.9, 127.1, 127.4, 127.6, 131.5,
131.6, 131.8, 142.6, 147.7, 149.2, 149.4, 149.5, 149.6, 157.7, 157.9,
168.1, 168.3; UHPLC–TOFMS (ESI) m/z: calcd for C66H96N12NaO6:
1175.7468 [M + Na]+; found 1175.7486.
¨
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Acknowledgements
We thank the Ministry of Science, Research, and Technology of
Iran for partial financial support of this research.
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