Novel ion-binding C3 symmetric tripodal triazoles: Synthesis and characterization

Article abstract of DOI:10.2478/s11532-013-0351-z

Novel C₃ symmetric tripodal molecules were synthesized from cyclohexane 1,3,5-tricarboxylic acid. Utilizing click and Sonogashira reactions, ion-binding triazole and pyridazin-3(2H)-one units were incorporated to form polydentate ligands for ion complexation. The structures of the novel C ₃ symmetric derivatives were extensively characterized by ¹H, ¹³C and 2D NMR techniques along with HRMS and IR. The copper(I)-binding potentials of these ligands were investigated by using them as additives in model copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) reactions. The copper(I) complexation ability of our compound was also proved by different spectroscopic methods, such as mass spectrometry, UV and NMR spectroscopy. Based on the mass spectrometric data all of the C₃ symmetric ligands formed 1:1 complex with copper(I) ion. The specific role of C₃ symmetric polydentate form in the complexation process was also discussed [Figure not available: see fulltext.]

Full text of DOI:10.2478/s11532-013-0351-z

Cent. Eur. J. Chem. • 12(1) • 2014 • 115-125
DOI: 10.2478/s11532-013-0351-z
Central European Journal of Chemistry
Novel ion-binding C3 symmetric tripodal
triazoles: synthesis and characterization
Research Article
Gábor Neumajer, Gergő Tóth*,
Szabolcs Béni, Béla Noszál
Department of Pharmaceutical Chemistry, Semmelweis University,
Hungarian Academy of Sciences, Budapest H-1092, Hungary
and
Research Group of Drugs of Abuse and Doping Agents,
Hungarian Academy of Sciences, Budapest H-1092, Hungary
Received 9 August 2013; Accepted 19 September 2013
Abstract: Novel C symmetric tripodal molecules were synthesized from cyclohexane 1,3,5-tricarboxylic acid. Utilizing click and Sonogashira
3
reactions, ion-binding triazole and pyridazin-3(2H)-one units were incorporated to form polydentate ligands for ion complexation. The
1
13
structures of the novel C symmetric derivatives were extensively characterized by H, C and 2D NMR techniques along with HRMS and
3
IR. The copper(I)-binding potentials of these ligands were investigated by using them as additives in model copper(I)-catalysed azide-
alkyne cycloaddition (CuAAC) reactions. The copper(I) complexation ability of our compound was also proved by different spectroscopic
methods, such as mass spectrometry, UV and NMR spectroscopy. Based on the mass spectrometric data all of the C symmetric
3
ligands formed 1:1 complex with copper(I) ion. The specific role of C symmetric polydentate form in the complexation process was
3
also discussed.
Keywords: Cycloaddition • NMR spectroscopy • CuAAC • RuAAC • Sonogashira reaction
©
Versita Sp. z o.o.
of triazoles became a highly investigated field of organic
chemistry with over a hundred related reports. Several
1
. Introduction
Alarge number of C symmetric tripodal compounds have highly active copper(I)-catalysts have been developed
3
recentlybeensynthesizedwithawidevarietyofstructures since 2002 [16-18]. Because of the high oxidability
for a number of applications such as chelating cations and low solubility of copper(I)-salts, usually additional
[
1-5] and anions [1,6,7], organocatalysts [8], reducing agent or nitrogen base as ligand is used.
chemosensors [2,9,10] or contrast agents [11] etc. The complexation of copper(I) by nitrogen-containing
Symmetric molecules with ion-binding functionalities ligands results in improved solubility and minimized
have great potential in ion-recognition or in catalysis as oxidation.
polydentatecomplexingagents. Oneofthehighlycapable
moieties for metal ion complexation is 1,2,3-triazole.
The
ruthenium(II)-catalysed
azide-alkyne
cycloaddition (RuAAC) was published in 2005 [19], which
Concerning the preparation of triazoles, the raised the possibility to make 1,5-substituted triazoles
well-known limitations of the Huisgen 1,3-dipolar from terminal alkynes and to couple internal alkynes and
cycloadditon (elevated temperature, long reaction time azides to 1,4,5-substituted triazoles as well.
and the lack of regioselectivity) [12,13] were overcome
With these robust methods, triazole could be an easy-
by the introduction of the copper(I)-catalysed azide- to-make building block with a wide variety of substituents.
alkyne cycloaddition (CuAAC) in 2002 [14,15]. Due to In the structures of reported C3 symmetric triazole
its regioselectivity, mild reaction conditions and excellent derivatives, the central elements were benzene [20-23],
yields, CuAAC is the most effective tool to prepare triazine [24], phosphorus [25] or no central element at
1
,4-substituted triazoles from terminal alkynes and all: cyclic pseudohexapeptide [26] and homooxacalix [3]
azides (click reaction). With this process the synthesis arene [10,27] structures. C tripodal triazole derivatives
3
*
E-mail: gergo.toth85@gmail.com
1
15

Novel ion-binding C3 symmetric tripodal triazoles:
synthesis and characterization
with nitrogen core have also been developed especially temperature was maintained at 25°C. The mobile phase
for ligands to enhance CuAAC reactions [16].
consisted of methanol:water 50:50. The flow rate was
-1
Based on all these facts, we aimed at designing 0.2 mL min and the detector wavelength was set to
triazole containing C3 symmetric ion-binding compounds 210 nm for the analysis. Spectra were processed using
with a cyclohexane core (20, 21, 22, 23, 24, 25). The Agilent MassHunter B.02.00 software. The purity of
potential advantage of the cyclohexane scaffold is its the final compounds was determined using the above
flexibility compared to the rigid benzene scaffold. The mentioned HPLC system in conjunction with an Agilent
flexible, conformational motions (often important for 6460 triple-quadrupole mass spectrometer. The mass
ion-binding) can enhance the complexation processes spectrometer was used in positive ion mode with Jet
of many ions. The copper(I) complexation potential Stream electrospray source scanning from 100 to
of these ligands was investigated in a model CuAAC 1500 Da. ESI was carried out at 300°C, with a nebulizer
reaction and by various spectroscopic methods.
pressure of 70 psi and nitrogen dry gas flow rate of
-1
12 L min . The fragmentor voltage was set at 100 V.
2
. Experimental procedure
2.1. General CuAAC procedure for 2, 4, 7
To Cu(OAc) •H O (0.01 equiv.) and PPh (0.02 equiv.)
2
2
3
All solvents and chemicals were obtained commercially in CH Cl (V ) propargyl alcohol (n ) and the appropriate
2
2
1
1
and were used without further purification. Reaction azide (1, 3 or 6; n ) were added. After overnight stirring
1
progress was observed by thin-layer chromatography at room temperature and workup, the title products (2,
on commercial silica gel plates (Merck silica gel F254 4, 7) were obtained.
on aluminum sheets) using different mobile phases.
For column chromatography, Kieselgel 60 (particle
(1-benzyl-1H-1,2,3-triazol-4-yl)methanol (2)
V = 8 mL, n = 4.9 mmol. Workup: evaporated to
1
1
size 0.040–0.063 mm) was employed. High-resolution dryness, then purified by column chromatography
accurate masses were determined with an Agilent (silica gel, EtOAc eluent). Yield: 78%, off-white solid.
1
6230 time-of-flight mass spectrometer. Samples were
H NMR (600 MHz, CDCl ) 7.45(s, 1H, 3-H), 7.35(m,
3
introduced by the Agilent 1260 Infinity LC system, and 2H, 10-H and 12-H), 7.34(m, 1H, 11-H), 7.25(m, 2H, 9-H
the mass spectrometer was operated in conjunction and 13-H), 5.49(s, 2H, 7-H ), 4.74(s, 2H, 1-H ), 3.06(s,
2
2
13
with a Jet Stream electrospray ion source in positive 1H, 1-OH); C NMR (150 MHz, CDCl ) 148.7(C2),
3
ion mode. Reference masses of m/z = 121.050873 and 135.1(C8), 129.8(C10 and C12), 129.5(C11), 128.8(C9
9
22.009798 were used to calibrate the mass axis during and C13), 122.4(C3), 57.0(C1), 55.0(C7); HRMS (ESI)
+
analysis. Mass spectra were processed using Agilent calcd for C H N O [M+H] 190.0975, found 190.0969.
10
12
3
MassHunter B.02.00 software.
Data was consistent with reported analyis [28].
Melting points were taken on a Stuart SMP-3
{1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-1H-
apparatus. IR spectra were recorded in the range of 1,2,3-triazol-4-yl}methanol (4)
−
1
4
000–650cm bymeansofaPerkinElmerSpectrum400
V = 2.5 mL, n = 1.4 mmol. Workup: precipitated from
1
1
FT-IR/FT-NIR spectrometer and Perkin Elmer Spectrum the reaction mixture with Et O, filtered, then extracted
2
Software version 6.3.1. UV spectra were recorded on from H O (15 mL) with CH Cl (3×15 mL), dried over
2
2
2
a Jasco V-550 spectrometer in 1 cm cuvettes at 25°C Na SO , filtered and evaporated to dryness. Yield: 64%,
2
4
1
using diode-array detector. Absorption spectra were off-white solid. H NMR (600 MHz, CDCl ) 7.69(s, 1H,
3
measured in the range of 220-360 nm. NMR spectra 3-H), 7.50(s, 1H, 9-H), 7.37 and 7.38(m, 3H, 16-H, 17-H
were recorded on a VARIAN VNMRS spectrometer and18-H),7.27(m,2H,15-Hand19-H),5.62(s,2H,7-H ),
2
1
13
(
599.9 MHz for H, 150.9 MHz for C) with a dual 5,50(s, 2H, 13- H ), 4.76(d, 2H, J=5.8 Hz, 1- H ), 2.31(t,
5
2
2
13
mm inverse-detection gradient (IDPFG) probehead in 1H, J=5.8 Hz, 1-OH); C NMR (150 MHz, CDCl ) 148.7
3
DMSO-d or chloroform-d solutions. Chemical shifts are (C2), 142.7(C8), 134.6(C14), 130.0 and 129.8(C16, C17
6
1
1
expressed in ppm with TMS as internal standard. H and and C18), 129.0(C15 and C19), 123.6(C9), 122.6(C3),
1
3
C NMR signals were assigned on the basis of one- and 57.3(C1), 55.2(C13), 46.1(C7); HRMS (ESI) calcd for
+
two-dimensional homo- and heteronuclear experiments C H N NaO [M+Na] 293.1121, found 293.1114. Data
13
14
6
(COSY, HMBC and HSQC).
was consistent with reported analysis [29].
Conversion rates of 1 and 28 to 29 in CuAAC
5-{3-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]
reactions were monitored by reversed-phase HPLC propyl}-2-methyl-2,3-dihydropyridazin-3-one (7)
method. HPLC analysis was performed by an Agilent
V =3.0 mL, n =1.4 mmol. Workup: evaporated to
1
1
1
260 Infinity LC system. Agilent Zorbax SB C18, dryness, extracted from brine (15 mL) with CH Cl
2 2
1
.8 μm, 2.1×50 mm column was used; the column (5×15 mL), dried over Na SO , filtered and subsequently
2
4
116

G. Neumajer et al.
evaporated. The residue was precipitated with Et O, H), 6.91(d, 2H, J= 8.6 Hz, 16-H and 18-H), 5.61(s, 2H,
2
filtered and dried. Yield: 67%, off-white solid. TLC: R = 7-H ), 4.65(s, 2H, 1-H ), 3.81(s, 3H, 17-OCH ), 2.72(bs,
f
2
2
3
1
13
0
.03 (eluent: EtOAc); H NMR (600 MHz, CDCl ) 7.60(d, 1H, 1-OH); C NMR (150 MHz, CDCl ) 160.4(C17),
3
3
1H, J= 2.2 Hz, 15-H), 7.57(s, 1H, 3-H), 6.61(m, 1H, 146.9(C3), 135.7(C8), 131.8(C2), 129.73(C10 and
1
1-H), 4.79(s, 2H, 1-H ), 4.43(t, 2H, J= 6.6 Hz, 7-H ), C12), 129.66(C15 and C19), 129.2(C11), 128.2(C9 and
2
2
3
.75(s, 3H, N13-CH ), 2.88(bs, 1H, 1-OH), 2.54(t, 2H, C13), 123.7(C14), 114.9(C16 and C18), 56.0(17-OCH ),
3
3
13
J= 7.6 Hz, 9-H ), 2.26(m, 2H, 8-H ); C NMR (150 MHz, 53.24(C1), 53.20(C7); HRMS (ESI) calcd for C H N O
CDCl ) 161.3(C12), 149.2(C2), 145.4(C10), 138.1(C15), [M+H] 296.1394, found 296.1394.
2
2
17 18
3
2
+
3
126.9(C11), 122.7(C3), 57.3(C1), 49.9(C7), 40.6(N13-
[1-benzyl-5-(4-methylphenyl)-1H-1,2,3-triazol-4-
CH3), 29.7(C9), 29.6(C8); HRMS (ESI) calcd for yl]methanol (15)
+
C H N NaO [M+Na] 272.1118, found 272.1120.
Yield: 18%, pale yellow solid. TLC : R = 0.10
11
15
5
2
f
1
5
-(dimethylamino)-N-{2-[4-(hydroxymethyl)-1H- (eluent: hexane - EtOAc (1:1)); H NMR (600 MHz,
1
,2,3-triazol-1-yl]ethyl}naphthalene-1-sulfonamide CDCl ) 7.26(m, 3H, 10-H, 11-H and 12-H), 7.17(d, 2H,
3
(9)
J= 8.7 Hz, 15-H and 19-H), 7.06(m, 2H, 9-H and 13-
To the solution of 8 (2.0 mmol) in MeCN (5 mL) H), 6.94(d, 2H, J= 8.7 Hz, 16-H and 18-H), 5.44(s, 2H,
and H O (5 mL), propargyl alcohol (1.1 equiv.), Et N 7-H ), 4.66(s, 2H, 1-H ), 3.83(s, 3H, 17-OCH ), 2.59(bs,
2
3
2
2
3
13
(
2.0 equiv.) and CuI (0.1 equiv.) were added. After 1H, 1-OH); C NMR (150 MHz, CDCl ) 161.3(C17),
3
overnight stirring at room temperature, the reaction 145.5(C2), 136.5(C3), 136.1(C8), 131.7(C15 and C19),
mixture was concentrated in vacuo. H O (10 mL) was 129.5(C10 and C12), 128.8(C11), 128.0(C9 and C13),
2
added and extracted with CH Cl (3×15 mL), the organic 118.9(C14), 115.2(C16 and C18), 56.3(C1), 56.1(17-
2
2
layer was dried over Na SO , and evaporated to dryness. OCH ), 52.1(C7). HRMS (ESI) calcd for C H N O
The oily residue was purified by column chromatography [M+H] 296.1394, found 296.1394.
2
4
3
17 18
3
2
+
(
silica gel, EtOAc eluent). Yield: 97%, green solid. TLC
5-[1-benzyl-5-(hydroxymethyl)-1H-1,2,3-triazol-4-
1
R = 0.19 (eluent: EtOAc); H NMR (600 MHz, CDCl ) yl]-2-methyl-2,3-dihydropyridazin-3-one (16)
f
3
8
1
3
.55(dm, 1H, J= 8.5 Hz, 14-H), 8.24(m, 2H, 12-H and
9-H), 7.52(dd, 1H, J= 8.5, 7.3 Hz, 13-H), 7.51(s, 1H, two consecutive column chromatographies using the
-H), 7.49(dd, 1H, J= 8.5, 7.6 Hz, 18-H), 7.16(dm, 1H, mixture of n-hexane, CH Cl2 and acetone (2:5:5) as
V = 20 mL, n = 2.2 mmol. Workup: separation by
2 2
2
J= 7.6 Hz, 17-H), 7.00(t, 1H, J= 6.2 Hz, N9-H), 4.67(d, eluent. Nominal yield: 70%, separated yield: 53%, white
2
1
1
1
1
1
4
H, J= 2.9 Hz, 1-H ), 4.41(m, 2H, 7-H ), 3.49(m, 1H, solid. TLC : R = 0.43 (eluent: hexane - CH Cl - acetone
2
2
f
2
2
1
-OH), 3.45(dd, 2H, J= 10.9, 6.0 Hz, 8-H ), 2.88(s, 6H, (2:5:5)); H NMR (600 MHz, CDCl ) 8.46(d, 1H, J= 2.0
2
3
13
6-N(CH ) ); C NMR (150 MHz, CDCl ) 152.7(C16), Hz, 15-H), 7.36(m, 3H, 10-H, 11-H and 12-H), 7.30(m
3
2
3
47.9(C2), 135.3(C11), 131.4(C14), 130.6(C15), 2H, 9-H and 13-H), 7.27(d, 1H, J= 2.0 Hz, 19-H), 5.73(s,
30.1(C20), 129.9(C12), 129.2(C18), 124.4(C3), 2H, 7-H ), 4.73(s, 2H, 1-H ), 3.78(s, 3H, N17-CH );
2
2
3
13
23.8(C13), 119.5(C19), 116.1(C17), 56.7(C1), 51.4(C7),
C NMR (150 MHz, CDCl ) 161.7(C18), 140.5(C3),
3
6.1(16-N(CH ) ), 43.4(C8); HRMS (ESI) calcd for 137.0(C15), 136.0(C2), 135.8(C14), 135.0(C8), 129.9
3
2
+
C H N O S [M+H] 376.1438, found 376.1421.
and 129.5(C10, C11 and C12), 128.2(C9 and C13),
17
22
5
3
1
24.5(C19), 53.4(C7), 52.8(C1), 40.9(N17-CH ). HRMS
3
+
2
.2. General RuAAC procedure for 14-17
(ESI) calcd for C H N O [M+H] 298.1299, found
15
16
5
2
Cp*RuCl(COD) (0.02 equiv.) was dissolved in CH Cl
298.1299.
5-[1-benzyl-4-(hydroxymethyl)-1H-1,2,3-triazol-5-
The appropriate internal alkyne (11 or 13, n ) and benzyl yl]-2-methyl-2,3-dihydropyridazin-3-one (17)
2
2
(V ) at room temperature under a nitrogen atmosphere.
2
2
azide (1, n ) was added. The reaction mixture was stirred
Nominal yield: 15%, separated yield: 0.5%. TLC :
2
overnight, evaporated to dryness, and the components R = 0.31 (eluent: hexane - CH Cl - acetone (2:5:5));
f
2
2
1
contained (14 and 15, or 16 and 17) was separated by
H NMR (600 MHz, CDCl ) 7.64(d, 1H, J= 2.2 Hz, 15-
3
column chromatography on silica gel.
H), 7.32(m, 3H, 10-H, 11-H and 12-H), 7.09(m, 2H,
[
1-benzyl-4-(4-methylphenyl)-1H-1,2,3-triazol-5- 9-H and 13-H), 6.85(d, 1H, J= 2.2 Hz, 19-H), 5.57(s,
yl]methanol (14)
2H, 7-H ), 4.75(s, 2H, 1-H ), 3.81(s, 3H, N17-CH );
C NMR (150 MHz, CDCl ) 160.0(C18), 147.4(C2)
3
2
2
3
13
V =22mL,n =3.0mmol.Thecolumnchromatography
2
2
eluent was the mixture of n-hexane and EtOAc (1:1). 135.9(C15), 134.8(C8), 132.1(C14), 130.3(C3), 129.9
Yield: 60%, beige solid. TLC: R = 0.32 (eluent: n-hexane- and 129.6(C10, C11 and C12), 129.8(C19), 127.8(C9
f
1
EtOAC (1:1)); H NMR (600 MHz , CDCl ) 7.57(d, 2H, J= and C13), 56.3(C1), 53.7(C7), 41.0(N17-CH ). HRMS
8
3
3
+
.6 Hz, 15-H and 19-H), 7.33(m, 2H, 10-H and 12-H), (ESI) calcd for C H N O [M+H] 298.1299, found
15 16 5 2
7
.31(m, 1H, 11-H), 7.25(d, 2H, J= 7.2 Hz, 9-H and 13- 298.1299.
1
17

Novel ion-binding C3 symmetric tripodal triazoles:
synthesis and characterization
2
.3. General esterification procedure for 124.3(C9), 57.3(C1), 52.9(C13), 44.5(C7), 40.1(C1’, C3’
2
0-25, 27
and C5’), 29.9(C2’, C4’ and C6’); HRMS (ESI) calcd for
+
To cyclohexane 1,3,5-tricarboxylic acid (18, n ) in C H N O [M+H] 973.4077, found 973.4077.
3
48 49 18
6
CH Cl (V ) oxalyl chloride (6 equiv.) and DMF (1 drop)
1 , 3 , 5 - t r i s ( { 1 - [ 3 - ( 1 - m e t h y l - 6 - o x o - 1 , 6 -
2
2
3
were added. The reaction mixture was stirred at reflux dihydropyridazin-4-yl)propyl]-1H-1,2,3-triazol-4-yl}
for 1 hour, then evaporated to dryness. The oily orange methyl) (1R,3S,5S)-cyclohexane-1,3,5-tricarboxylate
residue was dissolved in CH Cl (V ), the appropriate (22)
2
2
4
triazole alcohol (2, 4, 7, 9, 14 or 16, 3 equiv.) and Et N
n = 0.28 mmol, V = 2 mL, V = 7 mL. Workup: brine
3 3 4
3
(
3.3 equiv.) was added. After overnight stirring at room (15 mL) was added, extracted with CH Cl (3×15 mL),
2 2
temperature and workup, the title products (20-25) dried over Na SO , filtered and evaporated. The oily
2
4
were obtained. 27 was prepared according to the same residue was purified by column chromatography (silica
procedure from cyclohexanecarboxylic acid (26, n ) and gel, acetone eluent). Yield: 38%, colourless oil. TLC:
3
1
14.
R = 0.10 (eluent: acetone); H NMR (600 MHz, CDCl )
f
3
1
,3,5-tris(1-benzyl-1H-1,2,3-triazol-4-yl)methyl 7.60(m, 6H, 3-H and 15-H), 6.71(m, 3H, 11-H), 5.20(s,
1R,3S,5S)-cyclohexane-1,3,5-tricarboxylate (20) 6H, 1-H), 4.42(t, 6H, J= 6.9 Hz, 7-H ), 3.75(s, 9H, N13-
n = 0.5 mmol, V = 3 mL, V = 8 mL. Workup: CH ), 2.53(t, 6H, J= 7.4 Hz, 9-H ), 2.38(m, 3H, 1’-H,
(
2
3
3
4
3
2
evaporated to dryness, extracted from H O (20 mL) 3’-H and 5’-H), 2.25(m, 6H, 8-H ), 2.23(m, 3H, 2’-H, 4’-H
2
2
with CH Cl (2×15 mL), dried over Na SO , filtered and and 6’-H), 1.48(ddd, 3H, J= 13.0, 12.9, 12.9 Hz, 2’-H,
2
2
2
4
13
subsequently evaporated. The residue was precipitated 4’-H and 6’-H); C NMR (150 MHz, CDCl ) 174.4(C7’,
3
with EtOAc, filtered and dried. Yield: 54%, off-white C8’ and C9’), 161.3(C12), 145.6(C10), 143.5(C2),
solid. M.p.: 151-153°C; TLC : R = 0.51 (eluent: EtOAc); 138.2(C15), 127.1(C11), 124.6(C3), 58.4(C1), 49.9(C7),
f
-1 1
IR: ν = 1741, 1722, 1240, 1155, 1051, 721 cm ; H 42.2(C1’, C3’ and C5’), 40.6(13-CH ), 30.8(C2’, C4’
3
NMR (600 MHz , CDCl ) 7.49(s, 3H, 3-H), 7.38(m, 6H, and C6’), 29.7(C8), 29.6(C9); HRMS (ESI) calcd for
3
+
1
1
1
1
1
0-H and 12-H), 7.37(m, 3H, 11-H), 7.27(dd, 6H, J= 7.8, C H N O [M+H] 910.4067, found 910.4065.
42
52 15
9
.4 Hz, 9-H and 13-H), 5.52(s, 6H, 7-H ), 5.17(s, 6H,
1,3,5-tris(1-{2-[5-(dimethylamino)naphthalene-
-H ), 2.33(m, 3H, 1’-H, 3’-H and 5’-H), 2.18(d, 3H, J= 1-sulfonamido]ethyl}-1H-1,2,3-triazol-4-yl)methyl
3.0 Hz, 2’-H, 4’-H and 6’-H), 1.44(ddd, 3H, J= 13.0, (1R,3S,5S)-cyclohexane-1,3,5-tricarboxylate (23)
2
2
13
2.8, 12.8 Hz, 2’-H, 4’-H and 6’-H); C NMR (150 MHz,
n = 0.58 mmol, V = 3 mL, V = 8 mL. Workup: washed
3 3 4
CDCl ); 174.3(C7’, C8’ and C9’), 143.6(C2), 135.0(C8), with H O (15 mL), the inorganic layer extracted with
3
2
1
1
3
29.9(C10 and C12), 129.5(C11), 128.8(C9 and C13), CH Cl (2×15 mL), combined organic layers were dried
2 2
24.3(C3), 58.5(C1), 54.9(C7), 42.2(C1’, C3’ and C5’), over Na SO , filtered and evaporated. The green, solid
2
4
0.8(C2’, C4’and C6’); HRMS (ESI) calcd for C H N O
residue was purified by column chromatography (silica
39
40
9
6
+
[
M+H] 730.3102, found 730.3111.
gel, EtOAc eluent), then precipitated with Et O. Yield:
2
1
,3,5-tris({1-[(1-benzyl-1H-1,2,3-triazol-4-yl) 36%, yellow solid. M.p.: 133-136°C; TLC : R = 0.12
f
methyl]-1H-1,2,3-triazol-4-yl}methyl)
cyclohexane-1,3,5-tricarboxylate (21)
(1R,3S,5S)- (eluent: EtoAc); IR: ν = 1733, 1575, 1457, 1323, 1161,
-1 1
1142, 788 cm ; H NMR (600 MHz , CDCl ) 8.50(d, 3H,
3
n = 0.27 mmol, V = 2 mL, V = 7 mL. Workup: J= 8.3 Hz, 14-H), 8.18(m, 3H, 19-H), 8.16(m, 3H, 12-H),
3
3
4
evaporated, precipitated with CH Cl -Et O mixture, 7.57(s, 3H, 3-H), 7.47(t, 3H, J= 8.0 Hz, 13-H), 7.43(t, 3H,
2
2
2
filtered. The precipitate was extracted from H O J= 8.0 Hz, 18-H), 7.11(d, 3H, J= 7.5 Hz, 17-H), 6.51(t, 3H,
2
(
20 mL) with CH Cl (3*20 mL), dried over Na SO , J= 6.0 Hz, N9-H), 5.05(s, 6H, 1-H ), 4.37(s, 6H, 7-H ),
2
2
2
4
2
2
filtered and evaporated to dryness. Yield: 99%, off- 3.39(m, 6H, 8-H ), 2.84(s,18H, 16-N(CH ) ), 2.32(m, 3H,
2
3 2
white solid. M.p.: 168-170°C. TLC : R = 0.05 (eluent: 1’-H, 3’-H and 5’-H), 2.17(d, 3H, J= 12.4 Hz, 2’-H, 4’-H
f
EtOAc); IR: ν = 1728, 1454, 1225, 1160, 1051, and 6’-H), 1.42(ddd, 3H, J= 12.7, 12.7, 12.4 Hz, 2’-H,
-
1
1
13
7
9
7
5
3
6
16 cm ; H NMR (600 MHz, DMSO-d ) 8.23(s, 3H, 4’-H and 6’-H); C NMR (150 MHz , CDCl ) 174.4(C7’,
6
3
-H), 8.16(s, 3H, 3-H), 7.36(m, 6H, 16-H and 18-H), C8’ and C9’), 152.6(C16), 143.0(C2), 135.0(C11),
.31(m, 9H, 15-H, 17-H and 19-H), 5.68(s, 6H, 7-H ), 131.3(C14), 130.5(C15), 130.04 and 130.02(C12 and
.59(s, 6H, 13-H ), 5.11(s, 6H, 1-H ), 2.50(m, 3H, 1’-H, C20), 129.2(C18), 125.8(C3), 123.8(C13), 119.3(C19),
’-H and 5’-H), 2.06(d, 3H, J= 12.7 Hz, 2’-H, 4’-H and 116.0(C17), 58.3(C1), 50.7(C7), 46.0(16-N(CH ) ),
’-H), 1.28(ddd, 3H, J= 12.8, 12.8, 12.7 Hz, 2’-H, 4’-H 43.4(C8), 41.9(C1’, C3’ and C5’), 30.7(C2’, C4’ and
and 6’-H); C NMR (150 MHz, DMSO-d ) 173.4(C7’, C8’ C6’); HRMS (ESI) calcd for C H N O S [M+H]
2
2
2
3
2
13
+
6
60 70 15 12
3
and C9’), 141.9(C2), 141.7(C8), 135.8(C14), 128.7(C16 1288.4491, found 1288.4480.
and C18), 128.2(C17), 128.0(C15 and C19), 124.8(C3),
118

G. Neumajer et al.
1
,3,5-tris[1-benzyl-4-(4-methoxyphenyl)-1H-
[1-benzyl-4-(4-methylphenyl)-1H-1,2,3-triazol-5-
(1R,3S,5S)-cyclohexane- yl]methyl-cyclohexanecarboxylate (27)
n = 0.32 mmol, V = 3 mL, V = 6 mL. Workup:
1
1
,2,3-triazol-5-yl]methyl
,3,5-tricarboxylate (24)
3
3
4
n = 0.23 mmol, V = 2 mL, V = 4 mL. Workup: CH Cl
Workup: H O (15 mL) was added, extracted with
2
3
3
4
2
2
(
10 mL) was added, washed with H O (15 mL), the CH Cl2 (3×15 mL), dried over Na SO , filtered and
2
2
2
4
inorganic layer extracted with CH Cl (15 mL), combined evaporated. The orange solid residue was purified by
2
2
organic layers were dried over Na SO , filtered and column chromatography (silica gel, n-hexane-EtOAC
2
4
evaporated. The orange solid residue was purified by 1:1 mixture as eluent). Yield: 62%, yellow solid. TLC: R =
f
1
column chromatography (silica gel, n-hexane-EtOAC 0.41 (eluent: n-hexane-EtOAC (1:1)); H NMR (600 MHz,
1
:2 mixture as eluent). Yield: 78%, off-white solid. M.p.: CDCl ) 7.64(d, 2H, J= 8.7 Hz, 15-H and 19-H), 7.36(m,
3
1
07-109°C; TLC : R = 0.45 (eluent: hexane – EtoAc 2H, 10-H and 12-H), 7.34(m, 1H, 11-H), 7.30(d, 2H, J=
f
(
1:2)); IR: ν = 1732, 1616, 1508, 1248, 11177, 836, 7.2 Hz, 9-H and 13-H), 6.99(d, 2H, J= 8.7 Hz, 16-H and
-1 1
7
8
7
23 cm ; H NMR (600 MHz , CDCl ) 7.65(d, 6H, J= 18-H), 5.69(s, 2H, 7-H ), 5.09(s, 2H, 1-H ), 3.84(s, 3H,
3
2
2
.8 Hz, 15-H and 19-H), 7.27(m, 6H, 10-H and 12-H), 17-OCH ), 2.39(m, 1H, 1’-H), 1.95(m, 2H, 2’-H and 6’-H
3
.24(m, 3H, 11-H), 7.16(d, 6H, J= 7.2 Hz, 9-H and 13- (equatorial)), 1.77(m, 2H, 3’-H and 5-H’ (eq.)), 1.66(m,
H), 6.97(d, 6H, J= 8.8 Hz, 16-H and 18-H), 5.66(s, 6H, 1H, 4’-H (eq.)), 1.47(m, 2H, 2’-H and 6’-H (axial)),
7
3
4
-H ), 5.15(s, 6H, 1-H ), 3.81(s, 9H, 17-OCH ), 2.02(m, 1.28(m, 2H, 3’-H and 5’-H (ax.)), 1.22(m, 1H, 4’-H (ax.))
2
2
3
13
H, 1’-H, 3’-H and 5’-H), 1.92(d, 3H, J= 12.8 Hz, 2’-H,
C NMR (150 MHz, CDCl ) 175.4 (C7’), 160.1(C17),
3
’-H and 6’-H), 1.23(ddd, 3H, J= 12.8, 12.6, 12.6 Hz, 2’- 146.7(C3), 134.4(C8), 132.0(C2), 129.33(C10 and
13
H, 4’-H and 6’-H); C NMR (150 MHz, CDCl ) 173.5(C7’, C12), 129.10(C15 and C19), 128.8(C11), 127.5(C9
3
C8’ and C9’), 160.6(C17), 148.5(C3), 135.7(C8), and C13), 122.8(C14), 114.6(C16 and C18), 55.5(17-
1
29.6(C10), 129.4(C15), 129.0(C11), 127.7(C9), OCH ), 53.6(C1), 52.8(C7), 42.8 (C1’), 29.0 (C2’ and
3
1
5
27.3(C2), 123.4(C14), 115.0(C16), 56.0(17-OCH ), C6’), 25.8 (C3’ and C5’) 25.4 (C4’); HRMS (ESI) calcd
3
+
4.7(C1), 53.2(C7), 41.7(C1’, C3’ and C5’), 30.4(C2’, for C H N O [M+H] 406.2131, found 406.2141.
24
28
3
3
+
C4’ and C6’); HRMS (ESI) calcd for C H N O [M+H]
60
58
9
9
1
048.4352, found 1048.4335.
,3,5-tris[1-benzyl-4-(1-methyl-6-oxo-1,6-
dihydropyridazin-4-yl)-1H-1,2,3-triazol-5-yl]methyl
3
. Results and discussion
1
3
.1. Synthesis of C tripodal triazoles and their
(
1R,3S,5S)-cyclohexane-1,3,5-tricarboxylate (25)
3
n = 0.18 mmol, V = 2 mL, V = 6 mL. Workup: H O
constituents
3
3
4
2
(
15 mL) was added, extracted with CH Cl2 Several 1,2,3-triazole alcohols (2, 4, 7, 9, 14, 15, 16, 17)
2
(
3×15 mL), dried over Na SO , filtered and evaporated, were prepared by coupling alkynes (propargyl alcohol,
2
4
then precipitated with Et O. The off-white solid residue 11, 13) with azides (1, 3, 6, 8) in an azide-alkyne
2
was purified by column chromatography (silica gel, cycloaddition with copper(I) catalyst [30,31] for terminal
EtOAC-acetone 2:1 mixture as eluent). Yield: 45%, alkynes (propargyl alcohol) and a ruthenium(II) catalyst
white solid. M.p.: 149-151°C; TLC : R = 0.34 (eluent: [32] for internal alkynes (11, 13).
f
EtOAc – acetone (2:1)); IR: ν = 1738, 1655, 1604,
Benzyl azide (1) was prepared from benzyl chloride
248, 1151, 998, 933, 731 cm ; H NMR (600 MHz, by refluxing with 1.1 equivalents of NaN3 and 0.01
CDCl ) 8.46(d, 3H, J= 2.0 Hz, 15-H), 7.33(m, 6H, equivalents of KI in an acetone-water (2:1) mixture.
-
1 1
1
3
1
0-H and 12-H), 7.31(m, 3H, 11-H), 7.21(m, 6H, 9-H Azides 3 and 6 were synthesized from the appropriate
and 13-H), 7.19(d, 3H, J= 2.0 Hz, 19-H), 5.78(s, 6H, alcohol (2, 5) by first treating with mesyl chloride and
7
3
-H ), 5.17(s, 6H, 1-H ), 3.81(s, 9H, N17-CH ), 2.17(m, Et N in CH Cl , followed by stirring with NaN in DMF
2 2 3 3 2 2 3
H, 1’-H, 3’-H and 5’-H), 2.01(d, 3H, J= 13.0 Hz, 2’- at room temperature. 8 was synthesized according to
H, 4’-H and 6’-H), 1.27(ddd, 3H, J= 13.0, 12.8, 12.8 literature procedure [30]. Compound 13 (Scheme 3)
1
3
Hz, 2’-H, 4’-H and 6’-H); C NMR (150 MHz, CDCl3) was reduced to alcohol 5 with catalytic hydrogenation
1
1
1
1
73.3(C7’, C8’ and C9’), 161.1(C18), 142.3(C3), on Pd-charcoal in methanol (Scheme 1).
35.9(C15), 135.1(C8), 134.8(C14), 131.2(C2),
CuAAC reactions to get 2, 4, 7 were carried
29.9(C10 and C12), 129.5(C11), 127.9(C9 and C13), out by coupling of azide and alkyne (1 equiv.) in
24.8(C19), 53.8(C1), 53.6(C7), 41.3(C1’, C3’ and dichloromethane with 0.01 equivalents of Cu(OAc) •H O
2
2
C5’), 40.9(N17-CH ), 30.3(C2’, C4’ and C6’); HRMS and 0.02 equivalent of PPh [31] (Scheme 1), to get 9
3
3
+
(
ESI) calcd for C H N O [M+H] 1054.4067, found 0.1 equivalent of CuI was used with 2 equivalents of
54 52 15 9
1
054.4071.
Et N in acetonitrile-water (1:1) mixture [30] (Scheme 2).
3
1
19

Novel ion-binding C3 symmetric tripodal triazoles:
synthesis and characterization
Internal alkynes (11, 13) were obtained via the Cp*RuCl(COD) catalyst [33] (Scheme 4). In each case
Sonogashira reaction (Scheme 3). Based on the both possible regioisomers (14, 15 and 16, 17) were
literature procedure, [32] iodoanisol (10) or 5-iodo-2- formed. The major product 14 was completely separated
methylpyridazin-3(2H)-one (12) and propargyl alcohol from the minor 15 with a single column chromatography,
were coupled with Pd(PPh ) Cl , CuI and Et N. Besides whereas the minor product 17 co-eluted with a part of
3
2
2
3
DMF, lower boiling point solvents, such as THF and 16 even after several column chromatographic steps.
acetonitrile, were also tested. Acetonitrile proved to be Their yields were therefore determined by HPLC.
the best solvent in these cases (Table 1). Beginning with 14 and the isolated part of 16 were used in further
the Sonogashira reaction of 12 (Scheme 3), pyridazinone reactions.
moiety as another heterocyclic component was
The final step in each case was an esterification
incorporated to two C symmetric molecules (22, 25).
of three equivalents of the appropriate triazole alcohol
3
RuAAC reactions of the internal alkynes (11, 13) were (2, 4, 7, 9, 14, 16) with the acid chloride 19 prepared
performed in dichloromethane with 0.02 equivalents of from cyclohexane 1,3,5-tricarboxylic acid (18)
Scheme 1. Synthesis of mono- (2), bis-triazole (4) and pyridazinone (7) derivatives.
Scheme 2. Synthesis of the fluorescent dansyl derivative (9).
Table 1. Sonogashira reaction with 10 and 12 in different solvents.
Scheme 3. Sonogashira reactions from iodoanisol (10) and
-iodo-2-methylpyridazin-3(2H)-one (12).
5
Iodo derivative Propargyl alcohol
Pd(PPh ) Cl
CuI
Et N
Solvent
Product
Yield (%)
3
2
2
3
10
10
10
10
12
12
1.5 equiv.
3.5 equiv.
3.5 equiv.
3.5 equiv.
1.5 equiv.
1.2 equiv.
0.02 equiv.
0.02 equiv.
0.02 equiv.
0.02 equiv.
0.02 equiv.
0.02 equiv.
0.02 equiv.
0.04 equiv.
0.04 equiv.
0.04 equiv.
0.02 equiv.
0.04 equiv.
2.1 equiv.
3.8 equiv.
3.8 equiv.
3.8 equiv.
2.1 equiv.
1.8 equiv.
THF
THF
11
11
11
11
13
13
10
42
78
99
96
96
DMF
MeCN
DMF
MeCN
120

G. Neumajer et al.
Scheme 4. RuAAC reactions of the internal alkynes 11 and 13.
Scheme 5. Synthesis of C symmetric esters from cyclohexane 1,3,5-tricarboxylic acid (18).
3
different solvent systems (acetonitrile-water 25:2 and
dichloromethane).
Samples were analyzed after 1, 5 and 24 hours
in acetonitrile-water, and after 5 and24 hours in
dichloromethane, conversion rates were determined
by HPLC (Supplementary Fig. 1 in Supplementary
Material). As a reference, the CuAAC reaction was also
Scheme 6. Model CuAAC reaction.
(
Scheme 5). Cyclohexanecarboxylic ester (27) of 14 was performed without any ligands. The reactions did not
also synthesized to investigate a role of ester function in proceed in dichloromethane in the lack of the ligands,
the complexation processes.
but 50% conversion was observed in acetonitrile-
water, due to the much better solubility of CuI in
acetonitrile.
3
.2. II nn vv ee ss tt i igg aa tt i ioo nn of co op fper(I )c- ob pi np de i rn( gI )-binding
pote np t oi at el sn t–i a al sm–o ad eml oC du eA lA CC u Ar eA a Cc tri eo an ction
Best results were found in acetonitrile-water with 21
All final products (20, 21, 22, 23, 24, 25) were tested and 24, in dichloromethane with 20 and 24. To prove
in a CuAAC reaction, in which phenylacetylene (28) the beneficial effect of the C symmetric molecule 24,
3
and benzyl azide (1) 1:1 were reacted (Scheme 6) its constituent (14) and their cyclohexanecarboxylic
in the presence of 0.02 equiv. CuI and 0.02 equiv. of ester (27) was also tested in dichloromethane, and no
the appropriate ligand (20, 21, 22, 23, 24, 25), in two conversion was found for both molecules even after 24
1
21

Novel ion-binding C3 symmetric tripodal triazoles:
synthesis and characterization
Table 2. Conversion rates in MeCN-H O and in CH Cl .
2
2
2
Ligand (0.02 equiv.)
Conversion (%)
MeCN-H O 25:2
CH Cl
2 2
2
1
h
5 h
24 h
5 h
24 h
-
2
7
8
51
55
80
95
-
0
1
0
23
9
2
2
2
0
0
2
2
2
2
0
2
5
9
-
1
22
49
-
0
4
15
0
75
0
.02 equiv. 14
.06 equiv. 14
-
-
-
0
0
7
2
5
3
-
-
-
0
0
4
2
2
13
8
66
60
51
0
4
0
5
7
0
2
Table 3. HRMS data of copper(I)-complexes.
measured mass [M+]
792.2338
calculated mass [M+]
diff. (ppm)
Formula
20
21
22
23
24
25
27
14
7
792.2314
1035.3295
972.3285
-2.41
-3.24
-3.57
-1.64
-0.66
0.79
[C39H39CuN9O6]+
[C48H48CuN18O6]+
[C42H51CuN15O9]+
[C60H69CuN15O12S3]+
[C60H57CuN9O9]+
[C54H51CuN15O9]+
1035.3330
972.3317
1350.3726
1110.3570
1116.3274
1350.3703
1110.3572
1116.3285
No Cu(I) complex was detected
hours. This observation indicates the specific role of 24
as C symmetric polydentate ligand. Conversion rates
3
are summarized in Table 2.
The high conversion rate of 21 containing six
triazole rings was expected, the even higher activity of
the sterically hindered 24 was therefore surprising. The
successful utilization of 24 could be interpreted in terms
of its better solubility and the increased electron density
of its triazole rings attached directly to the electron rich
methoxyphenyl group (Fig. 1).
3
.3. InvI en sv tei gs at i tgi oa nt ion o fo f copper(I)-binding
pote np toi at el sn t–i a sl sp e– c st rpo es cc tor op si cc om p ei ct h mo de st hods
The copper(I) complexation ability of the compounds
was also investigated by different spectroscopic (UV
and NMR) and spectrometric (MS) methods. All of these
methods prove that these ligands form a complex with
copper(I)-ion.
Figure 1. Structure and numbering of the final product 24.
122

G. Neumajer et al.
Table 4. Proton and carbon chemical shifts of free and Cu(I) complexed 24 in ACN-d3.
proton
free
complex
change
carbon
free
complex
change
15-H, 19-H
7.635
7.629
-0.006
C15, C19
129.15
129.03
-0.12
1
1
9
0-H, 12-H
7.249
7.193
7.156
7.250
7.192
7.161
0.001
-0.001
0.005
C10, C12
C11
129.18
128.47
127.88
129.25
128.42
128.01
0.07
-0.05
0.13
1-H
-H, 13-H
C9, C13
1
7
1
1
1
2
2
6-H, 18-H
6.999
5.629
5.196
3.810
1.950
1.725
1.019
6.999
5.644
5.187
3.808
1.941
1.713
1.001
0
C16, C18
C7
114.63
52.19
54.32
55.40
41.07
29.84
173.33
114.69
52.49
53.91
55.44
40.82
29.57
173.02
0.06
0.30
-CH2
0.015
-0.009
-0.002
-0.009
-0.012
-0.018
-CH2
C1
-0.41
0.04
7-O-CH3
C17
’-H, 3’-H, 5’-H
’-H, 4’-H, 6’-H
’-H, 4’-H, 6’-H
C1’, C3’, C5’
C2’, C4’, C6’
C7’, C8’, C9’
-0.25
-0.27
-0.31
Figure 2. HRMS spectrum of 7 with CuI (left) and 20 with CuI (right). Only the C symmetric tripodal ligand (20) show copper(I)-binding.
3
The data in Table 3 clearly show that all of the C3
tripodal ligands form a copper (I) complex with a 1:1
stoichiometry. Moreover, it can be seen - in accordance
with investigation of a model CuAAC reaction –
that the triazole alcohol constituents itself and their
cyclohexanecarboxylic ester cannot bind the copper(I)-
ion (Fig. 2); only the polydentate ligands show copper(I)-
binding.
The UV investigation is a challenge due to the
significant UV absorption of CuI compared to the
triazoles. The UV intensities in the case of the complex
of CuI and the tripodal ligands are lower in the entire UV
rangeexaminedcomparedtothesumoftheabsorbances
of CuI and the ligands recorded separately due to the
reduced absorbtivity of the complex compared to the
Figure 3. The sum of the UV spectra of 24 and CuI (black) and UV
spectra of copper(I) complex of 24 (red).
ligand [5,34]. These changes provide further evidence
In mass spectrometric study the exact, high of complexation as shown in the case of compound 24
resolution mass of the ligand:CuI (1:5) mixture dissolved (see Fig. 3).
in acetonitrile-water was determined. The measured
data are summarized in Table 3.
The molecular interaction of copper(I) and 24
(Fig. 1) was also analysed by NMR spectroscopic
1
23

Novel ion-binding C3 symmetric tripodal triazoles:
synthesis and characterization
method in CDCl and in ACN-d . In the presence of 25). Their structures were fully characterized by NMR
3
3
CuI significant chemical shift changes were observed spectroscopy and HRMS. Investigation of a model
1
13
compared to the H and C NMR spectrum of 24 CuAAC reaction and several spectroscopic examples
alone proving the copper(I)-binding property of 24. The confirmed the copper(I) binding ability of our novel
chemicalshiftchangesatthepositionsnearbythetriazole polydentate triazoles.
ring (1-CH , 15-H, 19-H and C1, C15, C19) prove the
2
role of the triazole moiety in the copper(I)-complexation
(
Table 4, Supplementary Fig. 2) while the chemical shift Acknowledgments
changes of cyclohexane protons and carbons verify the
specific role of 24 as C symmetric polydentate ligand This work was supported by TÁMOP 4.2.1.B-09/1/KMR
3
in the copper(I)-complexation. Moreover the chemical and the National Research Fund of Hungary, OTKA T
shift differences at positions 1’-H, 3’-H, 5’-H and C7’, 73804. This paper was supported by the János Bolyai
C8’, C9’ support the possible interaction between Research Scholarship of the Hungarian Academy of
the ester function and Cu(I), however for detectable Sciences (Sz. B.).
complexation more than one triazole moieties are
needed.
Supplementary Materials
4
. Conclusions
(1) HPLC separation of phenylacetylene (28), benzyl
1
azide (1) and 29; (2) H NMR spectra of 24 and 24 with
1
We have synthesized six novel triazole alcohols (7, 9, CuI in ACN-d ; (3) H NMR spectra of compounds 7,9,
3
13
1
1
4, 15, 16, 17), including three new chemical entities (7, 14-17, 20-25; (4) C NMR spectra of compounds 7,9, 14-
6, 17). We have also prepared six novel C3 symmetric 17, 20-25; (5) HPLC-MS chromatogram of compounds
compounds with cyclohexane core (20, 21, 22, 23, 24, 20-25, (6) IR spectra of compounds 20,21,23,24,25.
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