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Publicly Available Published by De Gruyter September 22, 2017

Efficient synthesis of novel β-sitosterol scaffolds containing 1,2,3-triazole via copper(I)-catalyzed click reaction under microwave irradiation

  • Jin-Wei Yuan EMAIL logo and Ling-Bo Qu

Abstract

In this work, new derivatives of the β-sitosterol scaffolds containing 1,2,3-triazole are prepared by the reaction of β-sitosterol with aromatic alkynes via copper(I)-catalyzed azide-alkyne cycloaddition reactions under microwave irradiation. The reaction has several advantages including high yields, short reaction times, and a simple work-up procedure.

1 Introduction

Phytosterols, which are derived from vegetable oils, have proved to be natural active substances. β-Sitosterol (24-ethyl-5-cholestene-3-ol) (Fig. 1) is the most abundant plant sterol found in food products, especially in plant oils, nuts, seeds fruits and vegetables [1], [2]. β-Sitosterol has also demonstrated the great potential as steroidal drugs [3], [4], [5], [6], [7], cosmetics with healing effects on damaged skin and anti-inflammatory effects [8], [9], and food ingredients that function as cholesterol-lowering agents [10], [11], [12], [13]. Moreover, β-sitosterol is a particularly potent inhibitor of tumor growth such as human colon cancer, human prostate cancer and breast cancer [14], [15], [16], [17], [18]. However, the free form of β-sitosterol (unesterified) is poorly soluble in fats and various plant oils. Therefore, its widespread application has been prevented by the hydrophobic and lipophobic properties. It can be formulated only as a tablet or capsule, making it difficult and inefficient as a steroidal drug or a food ingredient. To overcome these drawbacks, many studies have focused on the chemical modification of the 3-hydroxy group in β-sitosterol [19], [20], [21], [22], [23], [24]. Despite that many advances have been made, it is still necessary to make efforts for the development of β-sitosterol derivatives with enhanced properties for application in biological systems.

Fig. 1: The structure of β-sitosterol.
Fig. 1:

The structure of β-sitosterol.

1,2,3-Triazole scaffolds are attractive linker units, because they are stable regarding metabolic degradation. Furthermore, these heterocyclic compounds are able to form hydrogen bonds, which are important in binding bimolecular targets and increasing their solubility. 1,4-Disubstituted 1,2,3-triazoles have emerged as an important class of organic compounds, displaying a vast spectrum of properties and are widely used as pharmaceuticals [25], [26], [27], [28]. Many 1,2,3-triazoles have found medicinal applications, such as HIV protease inhibitors, anticancer drugs, antituberculosis drugs, antifungal agents, antibacterial drugs, histone deacetylase inhibitors and bioorthogonal probes. Additionally, 1,2,3-triazoles are used as corrosion inhibitors, lubricants, dyes, and photostabilizers [29], [30], [31], [32]. The regioselective formation of 1,4-disubstituted 1,2,3-triazole can be accomplished by a copper(I)-catalyzed azide-alkyne cycloaddition reaction or click reaction [33], [34], [35], [36], [37]. The click reaction offers a highly efficient technique for connecting two potentially building blocks to other functional groups under mild conditions with high tolerance [38], [39], [40], [41]. It has been widely applied to the synthesis of macromolecules and functionalization of biomolecules [42], [43].

Binding 1,2,3-triazole moieties to other pharmacophores via copper-catalyzed click reactions is important for the synthesis of biologically active compounds [44], [45], [46]. In view of the significance of 1,2,3-triazole moieties and the defect of β-sitosterol, the synthesis of 1,2,3-triazole linked to the β-sitosterol scaffold has gained prominence in the organic synthesis as well as medicinal chemistry. In continuation of our studies directed towards an efficient synthesis of biologically-active molecules with β-sitosterol scaffold [47], herein we decided to synthesize novel derivatives of the 1,2,3-triazole-linked β-sitosterol system via copper(I)-catalyzed click reactions under microwave irradiation.

2 Results and discussion

β-Sitosterol (1) reacted with methylsulfonyl chloride in CH2Cl2 in the presence of triethylamine as a base, and dimethylaminopyridine (DMAP) as a catalyst to afford β-sitosterol-3-yl methanesulfonate (2) in good yield (Scheme 1). Compared with the NMR spectra of β-sitosterol, the 1H NMR spectrum of 2 showed a singlet for CH3 protons at δ=3.00 ppm, which were assigned to protons of the methylsulfonyl group. In the 13C NMR spectrum of 2, the peak at δ=82.0 ppm was assigned to C-3 of the steroidal scaffold. As the inductive effect of the –OSO2CH3 group is much stronger than that of the –OH group, the chemical shift of C-3 shifted from δ=71.8 ppm of 1 to δ=82.0 ppm of 2. These facts verified that β-sitosterol has been coupled successfully with methylsulfonyl chloride.

Scheme 1: Synthesis of β-sitosterol-3-yl azide (3). Reaction conditions: (i) CH3SO2Cl, DMAP, NEt3, CH2Cl2, 0°C, 24 h; (ii) NaN3, DMF, 90°C, N2, 24 h.
Scheme 1:

Synthesis of β-sitosterol-3-yl azide (3). Reaction conditions: (i) CH3SO2Cl, DMAP, NEt3, CH2Cl2, 0°C, 24 h; (ii) NaN3, DMF, 90°C, N2, 24 h.

The reaction of β-sitosterol-3-yl methanesulfonate (2) with sodium azide in dimethyl formamide (DMF) afforded β-sitosterol-3-yl azide (3) under an atmosphere of N2 (Scheme 1). The 1H and 13C NMR signals related to C-3 of 3 were shifted to high field because the methylsulfonyl group of 2 was substituted by the azide group.

The click reaction of β-sitosterol-3-yl azide (3) with phenyl acetylene (4a) in the presence of CuCl (10%) in the t-BuOH-H2O cosolvent under microwave irradiation at 40°C for 30 min yielded 45% of β-sitosterol derivatives containing 1,2,3-triazole (5a) (Scheme 2). Disappointingly, the NMR spectra of 5a verified that it was not a pure product, but MS of 5a showed only one ion peak m/z=542.3 [M+H]+. By adjusting the ratio of eluant, 5a was repurified by silica gel column chromatography. Interestingly, three products were separated from the original product 5a, and their ratio was about 4:4.2:1. The structures of three compounds (5a, 5a′ and 5a″) were elucidated by 1H NMR, 13C NMR, and high-resolution mass spectra (HRMS) (Fig. 2). The H chemical shifts at δ=4.00–6.00 ppm were assigned to protons of a non-conjugated C=C double bond or linked with heteroatom C–X (N, O, S) [1], [48], [49]. In the 1H NMR of 5a, the peaks at δ=4.42 and 5.46 ppm were assigned to H-3 and H-6, respectively. The peaks at δ=4.96 and 5.55 ppm of 5a were assigned to H-3 and H-4, and the signal at δ=5.00 ppm of 5a″ was assigned to H-4. The HRMS values of 5a, 5a and 5a″ were m/z=542.4472, 542.4474, and 542.4477 [M+H]+, respectively. The proposed structures of 5a, 5a′ and 5a″ are in agreement with these data.

Scheme 2: Synthesis of β-sitosterol derivative 5a containing a 1,2,3-triazole substituent.
Scheme 2:

Synthesis of β-sitosterol derivative 5a containing a 1,2,3-triazole substituent.

Fig. 2: The structures and important proton chemical shifts of three isomers of 5a.
Fig. 2:

The structures and important proton chemical shifts of three isomers of 5a.

Compounds of 5a, 5a and 5a″ are isomers. They may be formed by proton transfer. The proton at C4 of 5a was shifted to C6 by 1,3 transfer to form the compound 5a′. Subsequently, the proton at C3 of 5a′ was shifted to C5 by 1,3 transfer to form the compound 5a (Fig. 3).

Fig. 3: The isomerization of 5a by hydrogen transfer.
Fig. 3:

The isomerization of 5a by hydrogen transfer.

We initiated our preliminary optimization of the click reaction of β-sitosterol-3-yl azide (3) with phenylacetylene (4a) (Table 1). The effects of various amounts of catalyst, solvent, temperature, and also the reaction time were studied. Initially, the different catalysts were investigated. The Cu(I) catalysts proved be more efficient than those of Cu(II). CuCl could give the desired products 5a with moderate yield (45%), and Cu(II) was nearly inactive (Table 1, entries 1–4). The direct use of Cu(I) salts requires the strict exclusion of atmospheric oxygen due to the high susceptibility of Cu(I) toward oxidation. Further, this approach usually lacks robustness due to the complicated side reactions in addition to the copper instability [50]. The in situ reduction of Cu(II) salts such as CuSO4·5H2O or Cu(OAc)2·5H2O to Cu(I) with an excess of a reducing agent, such as sodium ascorbate (Vc-Na), proved to be superior. The results show that the click reaction is most effective in the presence of 10 mol% of CuSO4·5H2O and 20 mol% of Vc-Na, which increases the yield of 4a dramatically to 76% (Table 1, entries 5 and 6). The amount of catalyst was also screened. CuSO4·5H2O (10 mol%) and Vc-Na (20 mol%) were found to be ideal (yield of 5a 76%; Table 1, entries 5 and 7–9). The effect of the reaction temperature was investigated. By increasing the reaction temperature from 30°C to 40°C, the yield of 5a increased from 72 to 76%. With continuing to increase the temperature, the yield decreases slightly (Table 1, entries 5 and 10–12). Moreover, in order to avoid 1,5-disubstituted cycloaddition products, the reaction temperature was only increased to 60°C. The reaction time was examined, and 30 min proved to be the ideal time. Longer reaction times increased the formation of the side-products with a concomitant decrease in the yield of 5a (Table 1, entries 5 and 13–15). Subsequently, the effect of solvents such as CH3OH, t-BuOH, THF, dioxane, H2O, and co-solvents was screened. Intriguingly, when H2O was employed as a green reaction solvent, the yield of 5a improved dramatically to 93% (Table 1, entries 5 and 16–23). In the absence of microwave irradiation, the desired product was only obtained in less than 5% yield (Table 1, entry 24), proving that microwave irradiation is essential. Consequently, the optimum reaction conditions were determined to be CuSO4·5H2O (10 mol%) and Vc-Na (20 mol%) as the catalyst, H2O as a green solvent at 40°C for 30 min (Table 1, entry 20).

Table 1:

Optimization of reaction conditions for the preparation of 5.a

EntryCatalyst (eq.)SolventTemperature (°C)Time (min)Yieldb (%)
1CuCl (0.1)t-BuOH–H2O=1:1403045
2CuI (0.1)t-BuOH–H2O=1:1403030
3CuSO4·5H2O (0.1)t-BuOH–H2O=1:14030Trace
4Cu(OAc)2·5H2O (0.1)t-BuOH–H2O=1:14030Trace
5CuSO4·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1403076
6Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1403068
7CuSO4·5H2O (0.05)+Vc-Na (0.1)t-BuOH–H2O=1:1403070
8CuSO4·5H2O (0.15)+Vc-Na (0.3)t-BuOH–H2O=1:1403068
9CuSO4·5H2O (0.2)+Vc-Na (0.4)t-BuOH–H2O=1:1403056
10CuSO4·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1303072
11CuSO4·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1503069
12CuSO4·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1603065
13Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1402060
14Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1404072
15Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)t-BuOH–H2O=1:1405070
16Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)CH3OH403075
17Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)t-BuOH403035
18Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)THF403020
19Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)Dioxane403039
20Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)H2O403093
21Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)CH3OH–H2O=1:1403079
22Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)THF–H2O=1:1403052
23Cu(OAc)2·5H2O (0.1)+Vc-Na (0.2)Dioxane–H2O=1:1403068
24cCu(OAc)2·5H2O (0.1)+Vc-Na (0.2)H2O40120<5
  1. aReaction conditions: β-sitosterol-3-yl azide 3 (0.36 mmol, 158 mg), phenylacetylene 4a (0.3 mmol, 30.6 mg), and catalyst in 5 mL of solvent under microwave irradiation; bisolated yield; cno microwave irradiation.

With the optimized conditions in hand, the scope and generality of CuSO4·5H2O/Vc-Na-catalyzed click reactions were investigated. A variety of functionalized aromatic alkynes 4aj were reacted with β-sitosterol-3-yl azide 3 (Table 2). Interestingly, aromatic alkynes 4bj, which contained functional groups such as alkyl, F, Br and OCH3 at different positions of the aromatic ring, furnished the expected β-sitosterol derivatives 5bj in excellent yields (85–95%) within 0.5 h. Heterocyclic alkynes were also investigated. The results showed that the reaction could proceed smoothly with high yields (90%, 5k and 5l). Moreover, aliphatic alkynes could also be coupled efficiently with 3 to provide the corresponding β-sitosterol derivatives in high yield (5l, 5m and 5n). Furthermore, when a strong electron-withdrawing group was present in the terminal alkyne, the products were obtained in very good yields (97%, 5p, 5p′ and 5p″). Notably, three isomers of the desired product were produced with any of the alkynes. Fortunately, the mixture could be separated by column chromatography, and the ratio of the products was about 4:4.2:1. However, two isomers or one isomer of some products were only obtained because the corresponding isomer 5″ had lower yield, or was inseparable mixture along with starting material. These results demonstrate the broad scope of this methodology covering a structurally diverse group of alkynes. Many of the click reaction products 5 were obtained in very good yields.

Table 2:

Synthesis of β-sitosterol derivatives 5 containing a 1,2,3-triazole substituent from β-sitosterol-3-yl azide 3 and alkynes 4.a,b

EntryRYield (%)EntryRYield (%)
5a
92405i
7736
5a′425i′41
5a″105j
7832
5b
83385j′46
5b′455k
8238
5c
84385k′44
5c′465l
9540
5d
80365l′43
5d′445l″12
5e
78355m
8340
5e′435m′43
5f
74345n′
4242
5f′40
5g′
61345o′n-C7H154545
5g″105p
9738
5h′
65365p′46
5h″135p″13
  1. aReaction conditions: β-sitosterol-3-yl azide 3 (0.36 mmol, 158 mg), phenylacetylene 4a (0.3 mmol, 30.6 mg), CuSO4·5H2O (0.03 mmol, 7.5 mg) and VcNa (0.06 mmol, 12.0 mg) as the catalyst, in 5.0 mL H2O, at 40°C for 30 min under microwave irradiation; bisolated yield.

3 Conclusion

In summary, we have developed a copper(I)-catalyzed click reaction to access β-sitosterol scaffold derivatives containing 1,2,3-triazole. The reaction proceeds under mild conditions with H2O as a green solvent and inexpensive copper as a catalyst. The reaction demonstrates a broad substrate scope and excellent functional-group tolerance.

4 Experimental section

4.1 General

All solvents were used without further purification. All alkynes, β-sitosterol and other substrates were purchased from J & K Scientific Ltd. Nuclear magnetic resonance spectra were recorded on a Bruker Avance 400 MHz spectrometer. 1H NMR spectra were recorded in ppm from tetramethylsilane. Data were reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet and br=broad), coupling constant in Hz and integration. 13C NMR spectra were recorded in ppm from tetramethylsilane. HRMS were obtained on a quadrupole time-of-flight instrument using the electrospray ionization (ESI) technique. Melting points were determined on an XT4A microscopic apparatus and are uncorrected. The microwave reactor was a monomode system (Microwave Synthesis System-Discover Bench Mate from CEM) with focused waves.

4.2 Synthesis of 17-(5-ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate (2)

In a 100 mL Schlenk tube, β-sitosterol 1 (7.0 mmol, 2.9 g), DMAP (1.4 mmol, 0.17 mg), triethylamine (8 mL) in dichloromethane (20 mL) were added, and the solution was stirred until the solid material was dissolved. Methylsulfonyl chloride (14.0 mmol, 1.6 g) was added dropwise to the mixed solution below 0°C. The reaction mixture was stirred at 0°C for 24 h. The solvent was evaporated under reduced pressure. Twenty milliliters of ethyl acetate was added to the mixture. The organic phase was washed once with 10 mL diluted hydrochloric acid (5%), three times with 30 mL sodium bicarbonate (5%) and three times with saturated sodium chloride solution. The resulting solution was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate–petroleum ether (1:30) as eluant to obtain 2 (3.0 g, 90%). White solid; yield: 3.0 g (90%); m.p. 119–120°C. – 1H NMR (400 MHz, CDCl3): δ=5.42 (bs, 1H), 4.54–4.48 (m, 1H), 3.00 (s, 3H), 2.58–2.45 (m, 2H), 2.14–1.95 (m, 3H), 1.93–1.73 (m, 4H), 1.70–1.62 (m, 1H), 1.60–1.43 (m, 7H), 1.33–0.76 (m, 27H), 0.67 (s, 3H). – 13C NMR (100 MHz, CDCl3): δ=138.7, 123.8, 82.0, 56.6, 56.0, 49.9, 45.8, 42.3, 39.6 (CH2), 39.1 (CH2), 36.9 (CH2), 36.3, 36.1, 33.9 (CH2), 31.8 (CH2), 31.7, 29.1, 28.9 (CH2), 28.2 (CH2), 26.0 (CH2), 24.2 (CH2), 23.0 (CH2), 21.0 (CH2), 19.8, 19.1, 19.0, 18.7, 11.9, 11.8. – IR (KBr): ν=3148, 3017, 2927, 1650 cm−1. – HRMS ((+)ESI): m/z=493.3706 (calcd. 493.3710 for C30H53O3S, [M+H]+).

4.3 Synthesis of 3-azido-17-(5-ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene (3)

In a 100 mL Schlenk tube, β-sitosterol-3-yl methanesulfonate 2 (6.0 mmol, 2.95 g) was added to sodium azide (18 mmol, 1.17 g) in DMF (20 mL), and the solution was stirred at 90°C for 24 h under N2. The solvent was evaporated under reduced pressure. Twenty milliliters of ethyl acetate was then added to the mixture, and washed three times with saturated sodium chloride solution. The resulting solution was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate as eluant to obtain 3 (2.24 g, 85%). White solid; yield: 2.24 g (85%); m.p. 39–42°C. – 1H NMR (400 MHz, CDCl3): δ=5.41 (bs, 1H), 3.86 (m, 1H), 2.54 (d, J=14.8 Hz, 1H), 2.21 (d, J=14.8 Hz, 1H), 2.15–1.95 (m, 2H), 1.92–0.80 (m, 40H), 0.71 (s, 3H). – 13C NMR (100 MHz, CDCl3): δ=137.9, 123.1, 58.1, 56.7, 56.1, 49.9, 45.8, 42.3, 39.7 (CH2), 37.0 (CH2), 36.2, 36.0 (CH2), 33.9 (CH2), 33.6 (CH2), 31.8 (CH2), 31.8, 29.2, 28.3 (CH2), 26.1 (CH2), 24.3 (CH2), 23.1 (CH2), 20.7 (CH2), 19.8, 19.1, 18.9, 18.8, 12.0, 11.8. – IR (KBr): ν=3152, 3015, 2925, 2100, 1650, 1626 cm−1. – HRMS ((+)ESI): m/z=440.4002 (calcd. 440.3999 for C29H50N3, [M+H]+).

4.4 General procedure for the synthesis of β-sitosterol scaffolds containing 1,2,3-triazole (5)

β-Sitosterol-3-yl azide 3 (0.36 mmol, 158 mg), phenylacetylene 4 (0.3 mmol), CuSO4·5H2O (0.03 mmol, 7.5 mg), Vc-Na (0.06 mmol, 12.0 mg) and H2O (5.0 mL) were added to a 10 mL microwave reaction tube, and the mixture was irradiated at 40°C for 30 min using a 100 W microwave source. After completion of the reaction, the solvent was evaporated under reduced pressure. Twenty microliters of ethyl acetate was added to the mixture, and the organic phase was washed three times with saturated ammonium chloride solution. The resulting solution was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate–petroleum ether (100:1–10:1) as eluant to obtain the product 5. All the desired compounds were characterized by IR, 1H NMR, 13C NMR and HRMS spectra.

4.4.1 1-(17-(5-Ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-4-phenyl-1H-1,2,3-triazole (5a)

White solid; yield: 64.9 mg (40%); m.p. 186–187°C. – 1H NMR (400 MHz, CDCl3): δ=7.83 (d, J=7.2 Hz, 2H), 7.79 (s, 1H), 7.41 (t, J=7.2 Hz, 2H), 7.32 (t, J=7.2 Hz, 1H), 5.47–5.46 (m, 1H), 4.46–4.40 (m, 1H), 2.84–2.77 (m, 1H), 2.60–2.56 (m, 1H), 2.15–2.02 (m, 5H), 1.90–1.78 (m, 1H), 1.72–1.45 (m, 7H), 1.40–1.10 (m, 14H), 1.09–0.88 (m, 3H), 0.87–0.77 (m, 10H), 0.70 (s, 3H). – 13C NMR (100 MHz, CDCl3): δ=147.3, 139.2, 130.8, 128.8, 128.0, 125.6, 123.3, 117.4, 60.9, 56.6, 56.0, 50.0, 45.8, 42.3, 39.6 (CH2), 37.8 (CH2), 36.7, 36.1 (CH2), 33.9 (CH2), 31.8 (CH2), 29.3 (CH2), 29.1, 28.2 (CH2), 26.0 (CH2), 24.3 (CH2), 23.0 (CH2), 21.0 (CH2), 19.8, 19.4, 19.0, 18.8, 12.0, 11.8. – IR (KBr): ν=3020, 2928, 1650, 1626, 1540, 1377, 1275 cm−1. – HRMS ((+)ESI): m/z=542.4472 (calcd. 542.4469 for C37H56N3 [M+H]+).

4.4.2 1-(17-(5-Ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-4-phenyl-1H-1,2,3-triazole (5a′)

White solid; yield: 68.2 mg (42%); m.p. 189–191°C. – 1H NMR (400 MHz, CDCl3): δ=8.01 (s, 1H), 7.80 (d, J=7.2 Hz, 2H), 7.42 (t, J=7.2 Hz, 2H), 7.32 (t, J=7.2 Hz, 1H), 5.56–5.54 (m, 1H), 4.97–4.96 (m, 1H), 3.02–2.98 (m, 1H), 2.58 (d, J=15.7 Hz, 2H), 2.25–1.95 (m, 4H), 1.92–1.78 (m, 1H), 1.77–0.76 (m, 36H), 0.69 (s, 3H). – 13C NMR (100 MHz, CDCl3): δ=146.7, 138.2, 131.0, 128.7, 127.8, 125.6, 124.4, 119.3, 56.6, 56.0, 50.1, 45.8, 42.3, 39.5 (CH2), 37.1, 36.1, 35.5 (CH2), 33.9 (CH2), 32.7 (CH2), 32.0 (CH2), 31.7, 29.1, 28.2 (CH2), 27.2 (CH2), 26.1 (CH2), 24.2 (CH2), 23.0 (CH2), 20.6 (CH2), 19.8, 19.3, 19.0, 18.7, 11.9, 11.8. – IR (KBr): ν=3022, 2931, 1650, 1626, 1378, 1265 cm−1. – HRMS ((+)ESI): m/z=542.4472 (calcd. 542.4469 for C37H56N3 [M+H]+).

4.4.3 1-(17-(5-Ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-4-phenyl-1H-1,2,3-triazole (5a″)

White solid; yield: 16.2 mg (10%); m.p. 211–212°C. – 1H NMR (400 MHz, CDCl3): δ=7.80 (d, J=7.3 Hz, 2H), 7.65 (s, 1H), 7.40 (t, J=7.3 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 5.04–5.00 (m, 1H), 2.09–2.02 (m, 2H), 1.95–1.75 (m, 2H), 1.75–1.45 (m, 9H), 1.45–1.10 (m, 13H), 1.10–0.89 (m, 9H), 0.86–0.77 (m, 10H), 0.72 (s, 3H). – 13C NMR (100 MHz, CDCl3): δ=146.9, 130.7, 128.7, 128.0, 125.6, 118.5, 58.9, 56.1, 56.0, 47.5, 45.8, 42.8, 40.0 (CH2), 38.8, 37.1 (CH2), 36.1, 35.9, 33.8 (CH2), 32.5 (CH2), 29.7 (CH2), 29.1, 28.2 (CH2), 26.1 (CH2), 24.8 (CH2), 24.1 (CH2), 23.1 (CH2), 23.0 (CH2), 20.8, 19.8, 19.0, 18.7, 12.1, 11.9. – IR (KBr): ν=3027, 2935, 1651, 1628, 1534, 1375, 1243 cm−1. – HRMS ((+)ESI): m/z=542.4477 (calcd. 542.4469 for C37H56N3 [M+H]+).

5. Supplementary information

NMR spectra of compounds 5b5p″ are given as Supplementary Information available online (http://dx.doi.org/10.1515/znb-2017-0074).

Acknowledgments

We gratefully acknowledge the Department of Henan Province Natural Science and Technology Foundation (No. 172102210225), Natural Science Foundation in Henan Province Department of Education (No. 17A150005), the Program for Innovative Research Team from Zhengzhou (No. 131PCXTD605) and Project of Youth Backbone Teachers of Henan University of Technology (No. 2016003).

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Supplemental Material:

The online version of this article offers supplementary material (https://doi.org/10.1515/znb-2017-0074).


Received: 2017-5-11
Accepted: 2017-7-5
Published Online: 2017-9-22
Published in Print: 2017-9-26

©2017 Walter de Gruyter GmbH, Berlin/Boston

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