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Article

Stereoselective Approach to Hydroxyalkyl-1,2,3-triazoles Containing Cyclooctane Core and Their Use for CuAAC Catalysis

by
Olga V. Ryzhikova
,
Kseniya N. Sedenkova
,
Sergey V. Kositov
,
Victor A. Tafeenko
,
Yuri K. Grishin
and
Elena B. Averina
*
Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Catalysts 2023, 13(5), 835; https://doi.org/10.3390/catal13050835
Submission received: 16 March 2023 / Revised: 27 April 2023 / Accepted: 28 April 2023 / Published: 3 May 2023
(This article belongs to the Special Issue Application of Catalysis-Free and Catalysis in One/Two Dimensional (1D/2D) Nanostructured Materials)
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Abstract

:
1,2,3-Triazoles bearing additional functional groups have found applications as the ligands in catalysis of a broad scope of reactions, synthesis of transition metals complexes for various practicable purposes, and design of metal-based drugs. Triazolyl ligands accelerating CuAAC reactions, such as TBTA and TTTA, are nowadays commonly used in organic synthesis, and the search for novel ligands with a less complicated structure represents an important task. In the present work a series of hydroxyalkyltriazoles, containing a cyclooctane core, were synthesized via cycloaddition of readily available individual diastereomers of azidoalcohols or diazidodiols with phenylacetylene. The obtained hydroxyalkyltriazoles were probed as ligands for CuAAC reactions of benzyl azide with acetylenes, and 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol was demonstrated to act as an effective ligand for these processes. The complex salt of the abovementioned triazole and CuCl2 was readily obtained. According to X-ray diffraction analysis data, the complex contained two molecules of triazole, in which only N1-atoms of the triazole ring acted as coordination centers. Such a molecular structure correlates well with the efficiency of 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol as a ligand in CuAAC reactions: it is able to coordinate copper ions and, at the same time, it forms a sufficiently labile complex to not withdraw copper ions from the catalytic cycle.

1. Introduction

1,2,3-Triazole represents a unique heterocycle that combines availability via straightforward and reliable synthetic approaches, based on copper-catalyzed azide-alkyne cycloaddition (CuAAC) [1,2,3] with tolerance of physiologic conditions and the properties of bioisostere of amide and ester bonds [4]. Altogether, it derives an undiminishing interest to 1,2,3-triazole as valuable scaffold for drug design [5,6,7,8,9,10,11], in particular, as a convenient and stable linker for the connection of pharmacophore fragments [12,13,14,15,16,17] and for the derivatization of natural products [18,19,20,21], as well as for the construction of peptidomimetics [22] and bioorthogonal labeling [23]. Several compounds containing 1,2,3-triazoles were approved as medicinal drugs (see, for example, Figure 1), and a much larger number of molecules with pronounced biological activity have been designed [3,10]. 1,2,3-Triazoles are widely used for the surface functionalization of nanoparticles and triazole-based dendrimers have found applications as ligands for nanoparticles, including nanocatalysts, and as nanoreactors for catalytic processes [24,25,26,27,28,29].
1,2,3-Triazoles bearing a hydroxyalkyl group attract interest as antiadenovirus [30], antimicrobial [31], and anti-inflammatory agents [32], as well as peptidomimetic scaffolds [33]. Nevertheless, the most promising feature of triazoles with additional coordination centers is the ability for ligation [34,35], which is exploited in the design of chelators for metal-based drugs [36], and in catalytic processes (Figure 2), including the catalysis of CuAAC reactions [37]. Polytriazolyl ligands such as TBTA and related compounds [38] have been introduced in the practice of organic synthesis, and novel triazolyl derivatives which may be applied as copper-stabilizing ligands for cycloaddition reactions are being elaborated [39,40]. Another extensive field for the use of triazoles is the catalysis of cross-coupling reactions and construction of ligands containing less or no phosphorous atoms acting as coordination centers [37].
Functionalized eight-membered rings are commonly found in diverse natural and synthetic bioactive compounds [41]. On the other hand, the enhanced conformational flexibility inherent in such medium-ring molecules provides the attached hydroxy and triazolyl functionalities with access to new unusual spatial dispositions that can be useful for applications in medicinal chemistry and catalysis [42,43,44]. In previous work we have elaborated a synthetic approach to a series of azidoalcohols and diazidodiols, containing a cyclooctane core, via nucleophilic ring-opening of oxiranes [45]. The sequence of oxirane ring-opening upon treatment with an azide and following azide-alkyne cycloaddition reactions represents a straightforward approach to β-hydroxytriazoles, as was demonstrated recently [46] by the synthesis of a series of α-hydroxy-β-triazolotetrazoles from α,β-epoxynitriles. In the present work we investigated azidoalcohols, containing a cyclooctane core, in CuAAC protocols aiming to obtain triazoles and bis(triazoles), bearing additional functional groups, and to probe them as the ligands for CuAAC reactions.

2. Results and Discussion

Starting azidoalcohols 2a,b were obtained as a mixture via the reaction of oxirane 1 with NaN3 under reflux and readily separated via the preparative column chromatography (Scheme 1).
Up to today, a number of preparative modifications of CuAAC reactions have been elaborated [1,2,47] and the use of diverse sources of catalytically active Cu(I) was reported, including Cu(I)-complex salt, Cu(I)-containing dendrimers, Cu-nanoparticles, and other molecular frameworks [48]. Nevertheless, Cu(II) salts with the additive of sodium ascorbate (NaAsc) as a reductive agent remain, probably, the most available and easily handled source of Cu(I), which made us chose them for the present work. The optimization of CuAAC conditions was carried out on the example of the model reaction of azidoalcohol 2a and phenylacetylene (Table 1). The catalytic system, amount of the catalyst, the solvent, reaction time, and temperature were varied. Optimal conditions were found to be the use of 0.1 eq CuSO4·5H2O in the presence of sodium ascorbate and triethylamine in DCM at r.t. (entry 7). The change in the solvent led to the decrease in conversion compared to the one in DCM (entries 9, 11, 13, 15, 17), and heating the reaction mixture in most cases resulted in decomposition of the organic material (entries 3, 5, 6, 10, 14, 16). The attempts to perform the reaction without catalyst under conventional heating led to the very slow conversion of azide 2 into triazole 3 (entries 20–22); microwave activation for 1 h did not promoted the cycloaddition (entry 23).
Isomeric azidoalcohol 2b was involved in the cycloaddition with phenylacetylene in the catalytic conditions to yield triazole 4 (Scheme 2). It should be noted that, due to the lower reactivity of tertiary azide, the reaction in the presence of Cu(OAc)2·H2O/NaAsc and Et3N as the ligand was to be performed under reflux in DCM. The attempt to carry out the reaction in the presence of TBTA in the conditions described for tertiary azides [46] resulted in the same yield.
Previously, we elaborated the stereoselective approach to azidoalcohols 5,6 and diazidodiols 7,8 based on the nucleophilic ring-opening of different diastereomers of bis(oxiranes) I,II [45] (Figure 3). Mono- and diazides 5–8 were investigated in the reaction with phenylacetylene (Scheme 3 and Scheme 4).
Epoxide 5 was involved in the reaction with phenylacetylene in presence of CuSO4·5H2O/NaAsc at r.t. in DCM, but the reaction proceeded very slowly: 100% conversion was achieved only after 100 h. On the contrary, reflux with Cu(OAc)2·H2O/NaAsc in DCM overnight afforded triazole 9 in a good yield (Scheme 3). It should be noted that oxirane moiety tolerated the reaction conditions. Oxabicyclononane derivative 6, on the contrary, was found to be extremely labile in the reaction conditions even at room temperature. Nevertheless, performing the reaction in the presence of Cu(OAc)2·H2O/NaAsc for 2 h, we managed to isolate azidoalcohol 10, containing oxabicyclo[3.3.1]nonane moiety (Scheme 3).
In the case of diazidodiols 7,8 the reaction time was increased up to 72 h. Complete conversion of both azido groups of compound 7 was achieved to afford bis(triazole) 11 as the sole product in a good yield. The reaction of compound 8 with phenylacetylene yielded the mixture of products one- or two-fold cycloaddition 12 and 13, correspondingly, which were separated via column chromatography (Scheme 4).
Starting from the work of Fokin [38], there have been a number of reports describing triazolyl and polytriazolyl derivatives as the ligands accelerating CuAAC reactions [39,40,49,50]. Their role in the catalytic process is stabilizing the Cu(I) oxidation state, preventing the formation of unreactive polymeric complexes, and fine tuning the electron density on the metal atoms [51]. In this connection, obtained triazoles 3,9–12 were tested as copper-coordinating ligands using a model cycloaddition reaction between phenylacetylene and benzyl azide (14) in the presence of Cu(OAc)2·H2O and sodium ascorbate (Table 2). It was shown that compound 3 (entry 2), containing one triazole moiety, acted more effectively than triethylamine, affording the complete conversion of the starting compound and preventing the decomposition of the organic material (see Supplementary Materials). Using ligands of a more complicated structure 9–12 led to poorer results than when performing the reaction in the presence of ligand 3 (entries 3–6), that is, presumably, connected to their stronger complexation ability and running the copper ions out of the reaction.
We also tested the use of triazoles 3,9 compared with triethylamine on the example of the cycloaddition reaction of benzyl azide with alkynes, bearing aliphatic and aromatic substituents with different electronic properties, in the same conditions (Table 3). It was demonstrated that in the cases of alkynes, bearing butyl or tert-butylphenyl substituents, the yields were high whether triethylamine or ligand 3 was used (entries 4, 5, 10, 11). In the cases of less-reactive starting alkynes the best yields of triazoles 15d,f were achieved in the presence of compound 3 (entries 8, 14). The addition of compound 9, containing oxirane moiety, generally, resulted in a decrease in the triazoles yields.
The ability of triazole 3 for complexation with copper(II) was demonstrated in the example of its reaction with CuCl2 (Scheme 5). Mixing together saturated solutions of equimolar quantities of compound 3 and CuCl2 in hot acetonitrile after the slow evaporation of solvent at air readily afforded the dark blue crystals of salt 16 in a good yield (62%). The obtained compound was initially characterized with 1H NMR spectrum. The signals corresponding to ligand 3 were observed, and the broadening and low-field shift of the signals of triazolyl and phenyl CH-groups (δ 8.03 and 8.96 ppm, correspondingly) evidenced the formation of the complex with copper.
Compound 16 was characterized via X-ray diffraction analysis (Figure 4, see also Table S1, Figures S1 and S2 in Supplementary Materials). The X-ray structure revealed that complex 16 contains two molecules of triazole 3, in which N1-atoms of the triazole ring act as coordination centers, while hydroxyl groups do not form coordination bonds. Hydroxyl groups participate in the formation of hydrogen bonds O1A-H1A…O1B*4 and O1B-H1B…CL2*3 (see Table 4), thus forming layers of molecules located orthogonally to the b axis.
The interaction between the layers is provided by van der Waals forces. Regarding the coordination of two ligands (A,B) and two chloride ions (Figure 4A), one could note no significant difference of the Cu–N bond lengths forming between the copper and each of two nitrogen (N1A,N1B) atoms—CU1–N1A = 2.204(3) and CU1–N1B = 2.202(3)Å, as well as between copper and chlorine ions CU1-CL1 2.223(1) and CU1-CL2 2.217(1)Å. Two ligands (A,B) and two chloride (CL1, CL2) ions form a slightly distorted square around the copper cation (CU1). Deviations of atoms from the root-mean-square plane drawn through CU1(0.00)/CL1(0.27)/CL2(−0.27)/N1A(−0.32)/N1B(0.32Å) show bends of the lines N1A-CU1-CL2 (angle 162.9) and N1B-CU1-CL1 (angle 163.5) in different directions from this plane. The greatest conformational differences between ligands A and B refer to the eight-membered ring (Figure 4B; the superimposition of ligand A on ligand B was carried out in such a way as to minimize the sum of the standard deviations of the corresponding atoms).
In accordance with above-mentioned results (Table 2), such a complexation mode, lacking strong bonding, is favorable for the use of triazole 3 as the ligand in the CuAAC reaction, as the complex formation may increase the solubility of copper salt, whilst at the same time not preventing copper from participation in the catalytic cycle.

3. Materials and Methods

3.1. General Remarks

1H and 13C NMR spectra were recorded on a 400 MHz spectrometer Agilent 400-MR (400.0 and 100.6 MHz for 1H and 13C, respectively, Agilent Technologies, Santa Clara, CA, USA) at r.t. in CDCl3; chemical shifts δ were measured with reference to the solvent (CDCl3, δH = 7.26 ppm, δC = 77.16 ppm; CD3OD, δH = 3.31 ppm, δC = 49.00 ppm). When necessary, assignments of signals in NMR spectra were made using 2D techniques (see Supplementary Materials). Accurate mass measurements (HRMS) were obtained on the Bruker micrOTOF II (Bruker Daltonik GmbH, Bremen, Gemany) using electrospray ionization (ESI). Analytical thin layer chromatography was carried out with silica gel plates supported on aluminum (Macherey-Nagel, ALUGRAM® Xtra SIL G/UV254, Duren, Germany); the detection was performed using a UV lamp (254 nm). Column chromatography was performed on silica gel (Macherey-Nagel, Silica 60, 0.015–0.04 mm). Oxirane 1 and azides 5–8 were obtained via described methods [45]. All other starting materials were commercially available. All reagents, except commercial products of satisfactory quality, were purified according to the literature procedures prior to use.

3.2. Ring-Opening of Oxirane 1

To the solution of sodium azide (3.64 g, 56.0 mmol) in water (14 mL), oxirane 1 (0.98 g, 7.0 mmol) was added. The reaction mixture was stirred under reflux for 10 h, cooled down to r.t., and extracted using ethyl acetate (3 × 10 mL). The organic layers were combined; the solvent was evaporated under reduced pressure to give the mixture of azido alcohols 2a and 2b in a 1:0.2 mole ratio. The mixture was separated via preparative column chromatography (SiO2) to yield 2a (59%, 606 mg) and 2b (18%, 183 mg).
1-(Azidomethyl)cyclooctanol (2a) [45]
Yield 59% (606 mg), colorless oil, Rf = 0.38 (light petrol:EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.31–1.87 (m, 15H, 7CH2 + OH) and 3.26 (s, 2H, CH2-N3). 13C NMR (400 MHz, CDCl3) δ, ppm: 22.1 (2CH2), 24.9 (CH2), 28.2 (2CH2), 33.8 (2CH2), 60.8 (CH2-N3), and 75.3 (C-OH).
(1-Azidocyclooctyl)methanol (2b)
Yield 18% (183 mg), colorless oil, Rf = 0.28 (light petrol:EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.39–1.92 (m, 15H, 7CH2 + OH) and 3.50 (s, 2H, CH2-OH). 13C NMR (400 MHz, CDCl3) δ, ppm: 22.3 (2CH2), 25.0 (CH2), 28.3 (2CH2), 29.8 (2CH2), 68.5 (CH2-OH), and 68.6 (C-N3). HRMS (ESI+, 70 eV, m/z): calculated for C9H17N3O [M + H]+: 184.1444; found: 184.1427.

3.3. Synthesis of 1,2,3-Triazoles (General Procedure)

Azide (0.1 mmol), Cu(OAc)2∙H2O (2.0 mg, 0.01 mmol) or CuSO4·5H2O (2.5 mg, 0.01 mmol), Et3N (0.003 mL, 0.2 mg, 0.02 mmol), and dry DCM (0.3 mL) were placed into flask under argon. Phenylacetylene (0.013 mL, 12 mg, 0.12 mmol) and sodium ascorbate (7.9 mg, 0.04 mmol) were added under stirring. The reaction mixture was stirred for 2–72 h at r.t. or under reflux and quenched with a saturated aqueous solution of Trilon B (0.5 mL). The organic layer was separated; the water layer was extracted using DCM (3 × 0.5 mL). Combined organic layers were washed with a saturated aqueous solution of Trilon B (3 × 0.5 mL) and water (3 × 0.5 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure. The product was isolated via preparative column chromatography (SiO2).
1-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)cyclooctan-1-ol (3)
The reaction proceeded in the presence of CuSO4·5H2O at r.t. for 20 h. Yield 82% (23 mg), white solid, m.p. 117–118 °C, Rf = 0.32 (light petrol:EtOAc 2:1). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.38–1.74 (m, 14H, 7CH2), 2.54 (br.s, 1H, OH), 4.35 (s, 2H, 2CH2N), 7.28–7.34 (m, 1H, CH, Ph), 7.36–7.44 (m, 2H, 2CH, Ph), 7.78–7.84 (m, 2H, 2CH, Ph), and 7.94 (s, 1H, CH, triazole). 13C NMR (400 MHz, CDCl3) δ, ppm: 22.0 (2CH2), 24.9 (CH2), 28.1 (2CH2), 33.7 (2CH2), 59.0 (CH2N), 74.9 (C-OH), 121.7 (CH, triazole), 125.8 (2CH, Ph), 128.2 (CH, Ph), 128.9 (2CH, Ph), 130.7 (C, Ph), and 147.4 (C, triazole). HRMS (ESI+, 70 eV, m/z): calculated for C17H23N3O [M + H]+: 286.1914; found: 286.1921.
1-((5-Phenyl-1H-1,2,3-triazol-1-yl)methyl)cyclooctan-1-ol (4)
The reaction proceeded in the presence of Cu(OAc)2∙H2O under reflux for 9 h. Yield 26% (7 mg), white solid, m.p. 125–126 °C, Rf = 0.39 (light petrol:EtOAc 1:1). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.50–1.76 (m, 10H, 5CH2), 2.06–2.16 (m, 2H, 2CH2), 2.28–2.42 (m, 2H, 2CH2), 2.79–2.95 (m, 1H, OH), 3.95 (d, 2H, 3J = 6.4, CH2-O), 7.29–7.36 (m, 1H, CH, Ph), 7.38–7.45 (m, 2H, 2CH, Ph), 7.77–7.82 (m, 2H, 2CH, Ph), and 7.87 (s, 1H, CH, triazole). 13C NMR (400 MHz, CDCl3) δ, ppm: 22.4 (2CH2), 25.3 (CH2), 28.4 (2CH2), 30.6 (2CH2), 68.3 (CH2-OH), 69.8 (C-N), 118.8 (CH, triazole), 125.6 (2CH, Ph), 128.1 (CH, Ph), 128.8 (2CH, Ph), 130.6 (C, Ph), and 146.7 (C, triazole). HRMS (ESI+, 70 eV, m/z): calculated for C17H23N3O [M + H]+: 286.1914; found: 286.1916.
(8-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-9-oxabicyclo[6.1.0]nonan-1-yl)methanol (9)
The reaction proceeded in the presence of Cu(OAc)2∙H2O under reflux for 24 h. Yield 77% (24 mg), yellow solid, m.p. 154–156 °C, Rf = 0.71 (MeOH). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.36–1.40 (m, 1H, CH2), 1.43–1.73 (m, 10H, 6CH2), 2.12–2.18 (m, 1H, OH), 2.26–2.38 (m, 1H, CH2), 3.97 (dd, 1H, 2J = 12.1, 4J = 4.1, CH2OH), 4.03 (d, 1H, 2J = 12.1, 4J = 2.1, CH2OH), 4.51 (dd, 1H, 2J = 14.7, 4J = 1.7, CH2N), 5.00 (d, 1H, 2J = 14.7, CH2N), 7.30–7.36 (m, 1H, CH, Ph), 7.39–7.45 (m, 2H, 2CH, Ph), 7.59–7.83 (m, 2H, 2CH, Ph), and 7.96 (s, 1H, CH, triazole).
13C NMR (101 MHz, CDCl3) δ, ppm: 25.0 (CH2), 25.4 (CH2), 26.2 (CH2), 26.7 (CH2), 28.2 (CH2), 30.7 (CH2), 50.5 (CH2N), 63.1 (CH2OH), 65.5 (C), 66.9 (C), 120.4 (CH, triazole), 125.8 (2CH, Ph), 128.3 (CH, Ph), 129.0 (2CH, Ph), 130.6 (C, Ph), and 148.2 (C, triazole). HRMS (ESI+, 70 eV, m/z): calculated for C18H23N3O2 [M + H]+: 314.1863; found: 314.1865.
((1s,5s)-5-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-9-oxabicyclo[3.3.1]nonan-1-yl)methanol (10)
The reaction proceeded in the presence of CuSO4·5H2O at r.t. for 2 h. Yield 12% (4 mg), white solid, m.p. 113–114 °C, Rf = 0.14 (light petrol:EtOAc 1:1). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.32–1.50 (m, 4H, 4CH2), 1.49–1.70 (m, 6H, 6CH2), 1.92–2.05 (m, 3H, 2CH2 + OH), 3.39 (s, 2H, CH2OH), 4.31 (s, 2H, CH2N), 7.29–7.36 (m, 1H, CH, Ph), 7.38–7.47 (m, 2H, 2CH, Ph), 7.80–7.87 (m, 2H, 2CH, Ph), and 7.90 (s, 1H, CH, triazole). 13C NMR (101 MHz, CDCl3) δ, ppm: 18.3 (2CH2), 29.4 (2CH2), 30.7 (2CH2), 60.7 (CH2N), 71.4 (CH2OH), 71.8 (C), 73.1 (C), 121.4 (CH, triazole), 125.8 (2CH, Ph), 128.2 (CH, Ph), 129.0 (2CH, Ph), 130.9 (C, Ph), and 147.7 (C, triazole). HRMS (ESI+, 70 eV, m/z): calculated for C18H23N3O2 [M + H]+: 314.1863; found: 314.1863.
1,2-Bis((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)cyclooctane-1,2-diol (11)
The reaction proceeded in the presence of CuSO4·5H2O at r.t. for 72 h. Double excess of all reagents in relation to azide 7 was used. Yield 64% (29 mg), white solid, m.p. 192–193 °C, Rf = 0.13 (DCM:MeOH = 100:1). 1H NMR (400 MHz, d6-DMSO) δ, ppm: 1.38–1.62 (m, 10H, 6CH2), 1.78–1.91 (m, 2H, 2CH2), 4.57 (d, 2H, 2J = 13.9, 2CH2N), 4.76 (d, 2H, 2J = 13.9, 2CH2N), 4.89 (s, 2H, 2OH), 7.29–7.38 (m, 2H, 2CH, Ph), 7.42–7.50 (m, 4H, 2CH, Ph), 7.82–7.90 (m, 4H, 4CH, Ph), and 8.54 (s, 2H, 2CH, triazole). 13C NMR (101 MHz, CDCl3 + CD3OD) δ, ppm: 22.0 (2CH2), 27.8 (2CH2), 31.3 (2CH2), 55.1 (2CH2N), 77.1 (2C-OH), 122.4 (2CH, triazole), 125.8 (4CH, Ph), 128.5 (2CH, Ph), 129.0 (4CH, Ph), 130.3 (2C, Ph), and 147.7 (2C, triazole). HRMS (ESI+, 70 eV, m/z): calculated for C26H30N6O2 [M + Na]+: 481.2322; found: 481.2322.
(1s,5s)-1-(azidomethyl)-5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)cyclooctane-1,5-diol (12)
The reaction proceeded in the presence of CuSO4·5H2O at r.t. for 72 h. Double excess of all reagents in relation to azide 8 was used. Yield 14% (5 mg), white solid, m.p. 122–123 °C, Rf = 0.20 (DCM:MeOH = 50:1). 1H NMR (400 MHz, CDCl3 + CD3OD) δ, ppm: 1.44–1.64 (m, 6H, 6CH2), 1.70–1.94 (m, 6H, 6CH2), 3.12 (s, 2H, CH2N3), 4.29 (s, 2H, CH2N), 7.26–7.35 (m, 1H, CH, Ph), 7.35–7.42 (m, 2H, 2CH, Ph), 7.71–7.80 (m, 2H, 2CH, Ph), and 8.07 (s, H, CH, triazole). 13C NMR (101 MHz, CDCl3 + CD3OD) δ, ppm: 17.7 (2CH2), 36.0 (2CH2), 36.2 (2CH2), 60.8 (CH2-N), 62.8 (CH2-N3), 73.8 (C-OH), 74.8 (C-OH), 122.4 (CH, triazole), 126.0 (2CH, Ph), 128.6 (CH, Ph), 129.2 (2CH, Ph), 130.6 (C, Ph), and 147.7 (C, triazole). HRMS (ESI+, 70 eV, m/z): calculated for C18H24N6O2 [M + H]+: 357.2034; found: 357.2031.
1,5-Bis((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)cyclooctane-1,5-diol (13)
The reaction proceeded in the presence of CuSO4·5H2O at r.t. for 72 h. Double excess of all reagents in relation to azide 8 was used. Yield 28% (13 mg), white solid, m.p. 242–243 °C, Rf = 0.10 (DCM:MeOH = 50:1). 1H NMR (400 MHz, d6-DMSO) δ, ppm: 1.39–1.56 (m, 6H, 6CH2), 1.64–1.84 (m, 6H, 6CH2), 4.28 (s, 4H, 2CH2N), 4.71 (s, 2H, 2OH), 7.28–7.37 (m, 2H, 2CH, Ph), 7.39–7.49 (m, 4H, 4CH, Ph), 7.81–7.90 (m, 4H, 4CH, Ph), and 8.38 (s, 2H, 2CH, triazole). 13C NMR (101 MHz, d6-DMSO) δ, ppm: 17.1 (2CH2), 35.5 (4CH2), 72.5 (2C-OH), 72.6 (2CH2-N), 122.6 (2CH, triazole), 125.1 (4CH, Ph), 127.7 (2CH, Ph), 128.9 (4CH, Ph), 130.9 (2C, Ph), and 145.7 (2C, triazole). HRMS (ESI+, 70 eV, m/z): calculated for C26H30N6O2 [M + H]+: 459.2503; found: 459.2501.

3.4. Model CuAAC Reactions (General Procedure)

Benzyl azide (0.2 mmol, 26.6 mg), Cu(OAc)2∙H2O (4.0 mg, 0.02 mmol), ligand (0.02 mmol), and dry DCM (1 mL) were placed into a flask under argon. Corresponding acetylene (0.24 mmol) and sodium ascorbate (15.8 mg, 0.08 mmol) were added under stirring. The reaction mixture was stirred for 24 h at r.t. and quenched with a saturated aqueous solution of Trilon B (1 mL). The organic layer was separated; the water layer was extracted using DCM (3 × 1 mL). Combined organic layers were washed with a saturated aqueous solution of Trilon B (3 × 1 mL) and water (3 × 1 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure; crude residue was characterized via 1H NMR spectroscopy with external standard (p-xylene, 10 mol.% in relation to starting azide 14).
1-Benzyl-4-phenyl-1H-1,2,3-triazole (15a) [52]. 1H NMR (400 MHz, CDCl3) δ, ppm: 5.57 (s, 2H, CH2N), 7.27–7.46 (m, 8H, 8CH, Ph), 7.66 (s, 1H, CH, triazole), and 7.75–7.82 (m, 2H, 2CH, Ph).
(1-Benzyl-1H-1,2,3-triazol-4-yl)methanol (15b) [53]. 1H NMR (400 MHz, CDCl3) δ, ppm: 2.70 (br.s, 1H, OH), 4.77 (s, 2H, CH2OH), 5.52 (s, 2H, CH2N), 7.24–7.32 (m, 2H, 2CH, Ph), 7.33–7.41 (m, 3H, 3CH, Ph), and 7.45 (s, 1H, CH, triazole).
1-Benzyl-4-butyl-1H-1,2,3-triazole (15c). [54] 1H NMR (400 MHz, CDCl3) δ, ppm: 0.89 (t, 3H, 3J = 7.3, CH3), 1.28–1.40 (m, 2H, CH2), 1.55–1.66 (m, 2H, CH2), 2.62–2.71 (m, 2H, CH2), 5.46 (s, 2H, CH2N), 7.18 (s, 1H, CH, triazole), 7.20–7.26 (m, 2H, 2CH, Ph), and 7.29–7.37 (m, 3H, 3CH, Ph).
Ethyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate (15d) [49]. 1H NMR (400 MHz, CDCl3) δ, ppm: 1.26 (t, 3H, 3J = 7.2, CH3), 4.27 (q, 2H, 3J = 7.2, CH2O), 5.47 (s, 2H, CH2N), 7.11–7.23 (m, 2H, 2CH, Ph), 7.23–7.31 (m, 3H, 3CH, Ph), and 7.92 (s, 1H, CH, triazole).
1-Benzyl-4-(4-tert-butylphenyl)-1H-1,2,3-triazole (15e) [55]. 1H NMR (400 MHz, CDCl3) δ, ppm: 1.35 (s, 9H, 3CH3), 5.44 (s, 2H, CH2N), 7.25–7.32 (m, 2H, 2CH, Ph), 7.34–7.40 (m, 3H, 3CH, Ph), 7.41–7.47 (m, 2H, 2CH, Ar), 7.69 (s, 1H, CH, triazole), and 7.73–7.80 (m, 2H, 2CH, Ar).
Methyl 4-(1-benzyl-1H-1,2,3-triazol-4-yl)benzoate (15f) [56]. 1H NMR (400 MHz, CDCl3) δ, ppm: 3.92 (s, 3H, CH3), 5.59 (s, 2H, CH2N), 7.29–7.36 (m, 2H, 2CH, Ph), 7.36–7.42 (m, 3H, 3CH, Ph), 7.76 (s, 1H, CH, triazole), 7.82–7.92 (m, 2H, 2CH, Ar), and 8.04–8.10 (m, 2H, 2CH, Ar).

3.5. Synthesis of Salt 16

To the saturated solution of triazole 3 (10.0 mg, 0.036 mmol) in hot acetonitrile, a saturated solution of CuCl2 (4.9 mg, 0.036 mmol) in hot acetonitrile was added. The reaction mixture was cooled down to r.t. to yield salt 16 as dark blue crystals. Yield 62% (8 mg), m.p. 184–185 °C.
1H NMR (400 MHz, CD3OD) δ, ppm: 1.33–1.71 (m, 14H, 7CH2), 4.37 (br.s, 2H, CH2N), 7.24–7.34 (m, 1H, CH, Ph), 7.35–7.47 (m, 2H, 2CH, Ph), 8.03 (br.s, 2H, 2CH, Ph), and 8.96 (br.s, 1H, CH, triazole).

3.6. X-ray Diffraction Analysis of Compound 16

The data of 16 were collected by using a STOE diffractometer Pilatus100K detector (STOE & Cie GmbH, Darmstadt, Germany), focusing mirror collimation Cu Kα (1.54086 Å) radiation, rotation method mode. STOE X-AREA software was used for cells’ refinement and data reduction. Data collection and image processing were performed using X-Area 1.67 (STOE & Cie GmbH, Darmstadt, Germany, 2013). Intensity data were scaled using LANA (part of X-Area) in order to minimize differences of intensities of symmetry-equivalent reflections (multiscan method).
The structures were solved and refined using the SHELX [57] program. The nonhydrogen atoms were refined by using the anisotropic full matrix least-square procedure. Hydrogen atoms were placed in the calculated positions and allowed to ride on their parent atoms [C-H 0.93–0.98; Uiso 1.2 Ueq(parent atom)]. The positions of the hydrogen atoms bound to the oxygen atoms were found from the Fourier syntheses and were freely refined in the isotropic approximation. Molecular geometry calculations were performed using the SHELX program, and the molecular graphics were prepared by using DIAMOND [58] software.
CCDC-2244020 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif accessed on 22 February 2023,

4. Conclusions

In summary, a series of triazoles and bis(triazoles) containing a cyclooctane core bearing hydroxyalkyl groups, were obtained as individual diastereomers starting from corresponding azides. The ability of the synthesized compounds to act as ligands for CuAAC reactions was demonstrated and it was found that 1-(1,2,3-triazol-1-yl)methyl)cyclooctan-1-ol 3, coordinating copper(II) only with the participation of the N1-atom of the triazole ring, is the most effective for this reaction.
In general, copper is an inexpensive and readily available transition metal catalyst which plays an important role in many catalytic processes. Modern organic synthesis widely employs various copper-catalyzed reactions which is known as the renaissance of Ullmann chemistry [59]. Our compounds combining triazole moiety, a hydroxyl group, and a cyclooctane core may find interesting applications as ligands for copper-catalyzed reactions, especially in the field of C-N bond formation. Indeed, these reactions are extremely dependent on the nature of the ligand used. In order to assure good yields of the coupling products meticulous tuning of the catalytic system is needed, and the type of the ligand (N,N-; N,O-; O,O-type) which provides the best reaction outcome is strongly dependent on the nature of the reagents. Moreover, at the present time, more and more efforts are put into the use of heterogeneous or heterogenized copper catalysts, among which copper nanoparticles play a crucial role [60]. It is obvious that the change in the homogeneous to heterogenous catalysis leads to a change in the ligand. Thus, our compounds featuring triazole moiety, a hydroxyl group, and a cyclooctane fragment can be regarded as very promising ligands for the C-N bond forming processes. This will be a focus of our further investigation.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/catal13050835/s1, with details of X-ray diffraction analysis (Table S1. Crystal data and structure refinement for compound 16; Figure S1. Cell unit for compound 16; Figure S2. Molecular layers and hydrogen bonds in the crystal of 16) and copies of NMR spectra.

Author Contributions

Conceptualization, E.B.A. and K.N.S.; methodology, E.B.A. and K.N.S.; investigation, O.V.R., K.N.S., V.A.T., Y.K.G. and S.V.K.; resources, E.B.A. and Y.K.G.; data curation, Y.K.G.; writing—original draft preparation, K.N.S.; writing—review and editing, E.B.A.; supervision, E.B.A.; project administration, K.N.S.; funding acquisition, E.B.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by The Ministry of Science and Higher Education of the Russian Federation (Agreement with Zelinsky Institute of Organic Chemistry RAS No 075-15-2020-803).

Data Availability Statement

Not available.

Acknowledgments

The study was fulfilled using the NMR spectrometer Agilent 400-MR, purchased by the MSU Development Program; the X-ray study was supported by the MSU Development Program.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 13 00835 g001 550
Figure 1. Medicinal drugs containing triazole moiety.
Figure 1. Medicinal drugs containing triazole moiety.
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Figure 2. Examples of triazoles applied in catalysis.
Figure 2. Examples of triazoles applied in catalysis.
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Scheme 1. Ring-opening of oxirane 1.
Scheme 1. Ring-opening of oxirane 1.
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Scheme 2. CuAAC reaction of azidoalcohol 2b and phenylacetylene.
Scheme 2. CuAAC reaction of azidoalcohol 2b and phenylacetylene.
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Figure 3. Stereoselective approach to azidoalcohols 5,6 and diazidodiols 7,8 starting from isomeric bis(oxiranes) [45].
Figure 3. Stereoselective approach to azidoalcohols 5,6 and diazidodiols 7,8 starting from isomeric bis(oxiranes) [45].
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Catalysts 13 00835 sch003 550
Scheme 3. CuAAC reactions of azidoalcohols 5,6 and phenylacetylene.
Scheme 3. CuAAC reactions of azidoalcohols 5,6 and phenylacetylene.
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Scheme 4. CuAAC reactions of azidoalcohols 7,8 and phenylacetylene.
Scheme 4. CuAAC reactions of azidoalcohols 7,8 and phenylacetylene.
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Catalysts 13 00835 sch005 550
Scheme 5. Synthesis of compound 16.
Scheme 5. Synthesis of compound 16.
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Figure 4. (A) Molecular structure of compound 16. Displacement ellipsoids are drawn at 30% probability level. Selected bond length (Å): Cu1-N1A 2.002, Cu1-N1B 2.004. Selected angles (°): N1B-Cu1-N1A 88.99, N1B-Cu1-Cl2 89.51, N1A-Cu1-Cl1 89.74, and Cl2-Cu1-Cl1 96.41. (B) The superimposition of ligand A on ligand B. The largest distance between the corresponding atoms is about 2.21 Å (C13A…C13B; C16A…C16B).
Figure 4. (A) Molecular structure of compound 16. Displacement ellipsoids are drawn at 30% probability level. Selected bond length (Å): Cu1-N1A 2.002, Cu1-N1B 2.004. Selected angles (°): N1B-Cu1-N1A 88.99, N1B-Cu1-Cl2 89.51, N1A-Cu1-Cl1 89.74, and Cl2-Cu1-Cl1 96.41. (B) The superimposition of ligand A on ligand B. The largest distance between the corresponding atoms is about 2.21 Å (C13A…C13B; C16A…C16B).
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Table
Table 1. Optimization of CuAAC conditions.
Table 1. Optimization of CuAAC conditions.
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EntryCatalytic SystemSolventt, °CT, hRatio 2a:3 1
(Yield 3, %) 2
1Cu(OAc)2·H2O (0.1 eq), Et3N, NaAscDCM20200.1:1
2Cu(OAc)2·H2O (0.1 eq), Et3N, NaAscDCM20400:1
3Cu(OAc)2·H2O (0.1 eq), Et3N, NaAscDCM4090:1 3
4Cu(OAc)2·H2O (1 eq), Et3N, NaAscDCM2092:1
5Cu(OAc)2·H2O (1 eq), Et3N, NaAscDCM20960:1 3
6Cu(OAc)2·H2O (1 eq), Et3N, NaAscDCM4090.2:1 3
7CuSO4·5H2O (0.1 eq), Et3N, NaAscDCM20200:1 (82%)
8CuSO4·5H2O (0.1 eq), Et3N, NaAscDCM4090:1 (65%)
9CuSO4·5H2O (0.1 eq), Et3N, NaAscCH3CN20200.5:1
10CuSO4·5H2O (0.1 eq), Et3N, NaAscCH3CN8090:1 3
11CuSO4·5H2O (0.1 eq), Et3N, NaAscDMF20200.7:1
12CuSO4·5H2O (0.1 eq), Et3N, NaAscDMF10090:1 (78%)
13CuSO4·5H2O (0.1 eq), Et3N, NaAscDCE20200.2:1
14CuSO4·5H2O (0.1 eq), Et3N, NaAscDCE8090:1 3
15CuSO4·5H2O (0.1 eq), Et3N, NaAscTHF20201:0.01
16CuSO4·5H2O (0.1 eq), Et3N, NaAscTHF8090.7:1 3
17CuSO4·5H2O (0.1 eq), TBTA, NaAscn-BuOH/H2O20480:1 (28%)
18CuIDCM20201:0.15
19CuIDCM4091:1
20No catalystDCM4091:0
21No catalystDMF10091:0.02
22No catalystDMF1001151:1
23No catalystDMF100 (mw)11:0
1 According to 1H NMR spectra. 2 Isolated yield. 3 Decomposition of organic material.
Table
Table 2. Effect of ligands on model CuAAC reaction between phenylacetylene and benzyl azide.
Table 2. Effect of ligands on model CuAAC reaction between phenylacetylene and benzyl azide.
Catalysts 13 00835 i002
EntryLigandYield 15a, % 1
1Et3N71
2381 (64) 2
3957
4106
5113
6121
1 According to 1H NMR spectra with external standard (p-xylene, 10 mol.% in relation to starting azide 14). 2 Isolated yield.
Table
Table 3. Effect of ligands on model CuAAC reaction between various acetylenes and benzyl azide.
Table 3. Effect of ligands on model CuAAC reaction between various acetylenes and benzyl azide.
Catalysts 13 00835 i003
EntryProductRLigandYield 15b–f, % 1
115bCH2OHEt3N18
2 313
3 921
415cn-BuEt3N71
5 367
6 954
715dCOOEtEt3N39
8 371
9 965
1015e4-tBu-C6H4Et3N75
11 386
12 964
1315f4-MeOOC-C6H4Et3N22
14 348
15 921
1 According to 1H NMR spectra with external standard (p-xylene, 10 mol.% in relation to starting azide 14).
Table
Table 4. Hydrogen bonds for compound 16.
Table 4. Hydrogen bonds for compound 16.
D-H…Ad(D-H), Å d(H…A), Åd(D…A), Å<(DHA), °
C(3A)-H(3A)…Cl(1) 10.932.653.459(4)145.7
C(3B)-H(3B)…O(1A) 20.932.363.161(5)144.6
O(1A)-H(1A)…O(1B) 30.73(6)2.11(6)2.802(5)159(7)
O(1B)-H(1B)…Cl(2) 40.65(4)2.51(4)3.139(4)162(5)
1 xis (Symmetry transformations used to generate equivalent atoms: 1 x + 1/2, −y + 3/2, z + 1/2; 2 x + 1/2, −y + 3/2, z−1/2; 3 x−1/2, −y + 3/2, z + 1/2; 4 x + 1, y, z.
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Ryzhikova, O.V.; Sedenkova, K.N.; Kositov, S.V.; Tafeenko, V.A.; Grishin, Y.K.; Averina, E.B. Stereoselective Approach to Hydroxyalkyl-1,2,3-triazoles Containing Cyclooctane Core and Their Use for CuAAC Catalysis. Catalysts 2023, 13, 835. https://doi.org/10.3390/catal13050835

AMA Style

Ryzhikova OV, Sedenkova KN, Kositov SV, Tafeenko VA, Grishin YK, Averina EB. Stereoselective Approach to Hydroxyalkyl-1,2,3-triazoles Containing Cyclooctane Core and Their Use for CuAAC Catalysis. Catalysts. 2023; 13(5):835. https://doi.org/10.3390/catal13050835

Chicago/Turabian Style

Ryzhikova, Olga V., Kseniya N. Sedenkova, Sergey V. Kositov, Victor A. Tafeenko, Yuri K. Grishin, and Elena B. Averina. 2023. "Stereoselective Approach to Hydroxyalkyl-1,2,3-triazoles Containing Cyclooctane Core and Their Use for CuAAC Catalysis" Catalysts 13, no. 5: 835. https://doi.org/10.3390/catal13050835

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