Chemistry of Natural Compounds, Vol. 50, No. 4, September, 2014 [Russian original No. 4, July–August, 2014]
SYNTHESIS OF NEW PINANE-TYPE HETARYLSULFIDES
V. A. Startseva,1 A. V. Bodrov,1 A. V. Arefcev,1 I. V. Kuznetsov,1 O. A. Lodochnikova,2 V. V. Klochkov,3 and L. E. Nikitina1*
New bicyclic thioterpenoids with heterocyclic fragments were prepared via reactions of (–)-E-pinene and its oxide with 1-phenyl-1H-tetrazole-5-thiol, 1-methylimidazole-2-thiol, and 4,6-dimethyl-2pyrimidinesulfenylchloride. Keywords: (–)-E-pinene, E-pinene oxide, 1-phenyl-1H-tetrazole-5-thiol, 1-methylimidazole-2-thiol (methimazole), 4,6-dimethyl-2-pyrimidinesulfenylchloride, hetarylterpenesulfides. Many N-containing heterocyclic compounds, in particular imidazole, tetrazole, and pyrimidine derivatives, are known biologically active compounds that exhibit antihistamine, antibacterial, antiprotozoal, and antithyroid activity [1–3]. On the other hand, terpenes represent one of the most interesting and promising classes of natural products owing to the rich synthetic potential of such hydrocarbons and the broad spectrum of biological activity. We showed previously that thioterpenoids possessed antifungal, anti-inflammatory, anti-aggregation, and other types of activity [4–6]. Therefore, the combination of two pharmacophores, the terpene skeleton and a heterocyclic functional group, through a biogenic element such as S can produce compounds with new and useful properties. We studied the catalyzed reactions of (–)-E-pinene (1) with 1-phenyl-1H-tetrazole-5-thiol, 1-methylimidazole2-thiol, and 4,6-dimethyl-2-pyrimidinesulfenylchloride and of its D-oxide (5) with 1-methylimidazole-2-thiol. The reactions of 1 with various thiols were carried out in the presence of Lewis acids and followed a variety of pathways to afford both thioterpenoids of the starting pinane structure [7] and isomerized bornane or menthane compounds [8, 9]. The reactions of other bicyclic terpenes, e.g., camphene, with thiols are just as varied [10, 11]. Me
Me
Me
Me
8
9 7 4
3
2
CH2
1
Me
a
HS Ar
6
10
S
Ar
5
1
H
Me
3 Me
CH2 Me 2
Ar
Me
N
N
Ar =
S Me H
4
N N Ph
a. ZnCl2, CH2Cl2, 20°C, 5 h
Scheme 1 1) Kazanc State Medical University, Russian Federation, 420012, Kazanc, Ul. Butlerova, 49, e-mail:
[email protected]; 2) A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Russian Federation, 420088, Kazanc, Ul. Arbuzova, 8, e-mail:
[email protected]; 3) Kazan (Volga Region) Federal University, Russian Federation, 420008, Kazanc, Ul. Kremlevskaya, 18, e-mail:
[email protected]. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2014, pp. 566–570. Original article submitted April 21, 2014. 652
0009-3130/14/5004-0652
©2014
Springer Science+Business Media New York
C8
C9 C7 C10
C4 C5
C6
C1 C3
C2 N1 N2
S1 C11
N3
_ SR
N4 C17
C12 C13
C16 C15
C14
Fig. 1. Geometry of crystallographically independent molecule A in the crystal of 3.
_ SR
a
b
Fig. 2. “Nonclassical” pinane (a) and camphane (b) carbonium ions.
We demonstrated earlier that the reaction of (+)-camphene (2) with 1-phenyl-1H-tetrazole-5-thiol in the presence of a Lewis acid involved isomerization of the starting skeleton to form 4 with an exo-sulfide group with respect to the bicyclic molecular framework (Scheme 1) [11]. The reaction of (–)-E-pinene (1) with 1-phenyl-1H-tetrazole-5-thiol in the presence of ZnCl2 also involved isomerization into the bornane structure. However, 3 with not an exo- but an endo-sulfide formed (Scheme 1). The main difference in PMR spectra of the two stereoisomers 3 and 4 was the nature of the S methine proton resonances in the range 2.6–2.7 ppm in endo-isomer 3 and at 4.23 ppm in exo-isomer 4. The resonance of this proton in 4 was a doublet of doublets with SSCC J = 9.54 and 5.56 Hz whereas this resonance for isomeric sulfide 3 was a multiplet. A similar difference in the nature of the methine proton resonance in exo- and endo-isomers was typical for the bornane structure [12]. The structure of 3 was proved using an X-ray crystal structure analysis (XSA), according to which the crystal contained two independent molecules A and B that differed by rotation of the phenyltetrazole fragment relative to the bornane framework (Fig. 1). The structure was solved in chiral space group P21 [Flack parameter 0.04(8)], which indicated that the optical activity of the terpenoid was retained. However, we obtained only racemic adducts in the reaction with enantiomerically pure (+)-camphene because the camphene racemization rate was faster than the formation rate of the adducts [11]. The production of different stereoisomers in the reactions with camphene and E-pinene could be explained by the formation of “nonclassical” carbonium ions a and b, which the sulfide anion attacked from the backside, i.e., from the endo-side with respect to the gem-dimethyl fragment in camphene and from the exo-side in pinane (Fig. 2) [13]. Next, we studied the reactions of (+)-camphene and (–)-E-pinene with 1-methylimidazole-2-thiol in the presence of ZnCl2. Thione–thiol tautomerism is known to be characteristic of 1-methylimidazole-2-thiol. This was studied several times earlier using quantum chemical methods [14, 15]. The calculations indicated that the thione form was preferred. Independent NMR investigations in solution also indicated that the thione form was significantly more stable [16]. It was found that 1-methylimidazole-2-thiol in neutral and acidic solution existed mainly as the NH tautomer whereas in basic solution it was found as the thiolate anion. Unfortunately, the behavior of 1-methylimidazole-2-thiol in the presence of Lewis acids has not been reported. It was suggested that adducts with terpenes would probably form. However, the reaction of (+)-camphene and (–)-E-pinene with 1-methylimidazole-2-thol in the presence of ZnCl2 did not form addition products. Only a crystalline compound that was the thione form of the starting thiol according to an XSA was isolated [17]. Furthermore, we isolated from these reaction mixtures a new polymorphic modification of methimazole that was not described before in the literature. This result was independently significant considering that methimazole is the active principle of several drugs.
653
TABLE 1. Crystallographic Data and X-ray Structure Parameters for 3 and 6 Parameter Formula Molecular weight System Space group a, A° b, A° c, A° E, deg V, A° 3 Z (Zc) Dcalcd, gcm–3 P, cm–1 Scan range Number of measured reflections (Rint) Number of reflections with I t 2 V (I) Number of refined parameters R1 (I t 2 V (I)) wR2 (over all reflections) Flack parameter
3
6
C17H22N4S 314.45 Monoclinic P 21 11.185 (10) 12.616 (12) 12.519 (12) 108.264 (11) 1678 (3) 4 (2) 1.245 1.95 1.92 d T d 27.00 18276 (0.0649) 3951 403 0.0584 0.1312 –0.04 (8)
C14H22N2OS 266.40 Orthorhombic P 212121 8.4859 (6) 10.5951 (8) 15.2697 (11) 90 1372.9 (2) 4 (1) 1.289 2.27 2.34 d T d 28.00 11643 (0.0377) 3086 170 0.0302 0.0755 –0.01 (6)
N15
S1
N15 C11
C10
C3
C2
C14 C13
H1
O1
C1 C7 N12 C16
C4 C5
C8
C6
C9
Fig. 3. Hydrogen-bonded chain of molecules of 6 in the crystal. The reaction of E-pinene (5) with 1-methylimidazole-2-thiol in the presence of NaOMe was carried out in order to prepare a thioterpenoid with a methimazole fragment (Scheme 2). Starting 5 was prepared using the previously developed method [18]. We prepared earlier a series of thioterpenols based on E-pinene D-oxide using various thiols [18–21]. The oxide ring opened according to the Krasusky rule and formed stereochemically pure compounds. Moreover, thiols with N-containing heterocyclic fragments were not studied in these reactions. According to an XSA (Fig. 3), the oxide ring of 5 opened according to the Krasusky rule to form 6. The S-containing substituent on C2 was located in the exo-position relative to the pinane bicycle. A conformation close to trans was observed along the C10–S1 bond (the corresponding torsion angle C2C10S1C11 was 146.8°). Molecules of 6 in the crystal formed infinite chains (Fig. 3) through H-bonds O1–H1…N15 with parameters O1–H1 0.80(2) A° ; H1…N15 1.98(2) A° , 2.776(2) A° ; and O1–H1…N15 178(2)°. 654
Me
Me
Me
Me N
4 5
a
+
HS
O
9
6
8
N Me
3 1
7
2
HO
5
Me N
S N
6
a. MeONa, MeOH, ', 6 h
Scheme 2 The PMR spectrum of 6 showed resonances for –CH2S protons as an AB system at 2.92 and 3.17 ppm with SSCC J = 12.5 Hz. Furthermore, resonances of all protons of the bicyclic framework and the heterocycle occurred in the appropriate regions. (–)-E-Pinene (1) was reacted with 4,6-dimethyl-2-pyrimidinesulfenylchloride in equimolar amounts without a catalyst in order to continue the investigation of its reactions with S-containing reagents. The reaction formed the single addition– elimination product pinenylsulfide (7) (Scheme 3). We showed earlier that sulfenylchlorination of 1 by hetarylsulfenylchlorides was characterized by retention of the pinane structure. However, the reaction occurred differently depending on the nature of the heterocycle [22]. Me
Me
Me 8
Me 6
9 4
+ 1
Cl Ar
S
a
Me
5
- HCl
N
3
Ar = 7
CH2
1
7
2
S
Ar
N Me
a. CH2Cl2, 25°C, 5 days
Scheme 3 The PMR spectrum of 7 exhibited singlets for the C-10 methylene protons at 4.0 ppm and the endo-cyclic doublebond proton at 5.65 ppm in addition to resonances of pinene and heterocyclic protons in the appropriate regions. Formation of a product with the pinene structure was also confirmed by the appearance in the PMR spectrum of two singlets for the gem-dimethyl fragment with chemical shifts characteristic of the pinene structure. The 13C NMR spectrum of 7 had resonances for C atoms of the endocyclic double bond at 122.3 ppm (C-3) and 141.8 (C-2) and the other C atoms in the appropriate regions. Thus, reactions of (–)-E-pinene with 4,6-dimethyl-2-pyrimidinesulfenylchloride occurred without rearrangement of the pinane skeleton and formed an addition–elimination product containing only a sulfide fragment. Apparently, the addition product according to the Markovnikov rule was formed in the first reaction step. Then, it was dehydrohalogenated to form the pinene product. The antifungal activity of several dozen S-containing terpenoids was studied by us earlier [4]. It was hypothesized that the prepared thioterpenoids with N-containing fragments typical of antimycotic drugs would exhibit high antifungal activity. The compounds will be studied for antifungal activity using a broad array of mold and mycelial fungi.
EXPERIMENTAL The course of reactions was monitored by TLC on Sorbfil plates using hexane–Et2O (KMnO4 detector). Preparative chromatography was performed over silica gel (0.06-0.2, Acros). We used (1S)-(–)-E-pinene (98%), 1-phenyl-1H-tetrazole5-thiol (98%), and 1-methylimidazole-2-thiol (98%) (Acros Organics and Aldrich). PMR and 13C NMR spectra were recorded on a Bruker Avance 400 WB spectrometer (operating frequency 400.13 and 100.61 MHz). Chemical shifts are given relative to CDCl3. Melting points were measured on a Kofler bench and are uncorrected. Mass spectra were recorded on a DFS Thermo Electron Corp. instrument (Germany) using electron-impact (EI) ionization 70 eV and source temperature 280°C. Mass spectra data were processed using the Xcalibur program. X-ray crystal structure analyses were performed on a Bruker Smart Apex II diffractometer (graphite monochromator, O Mo KD-radiation of 0.71073 A° , 293 K, Z-scanning). Table 1 presents the crystallographic data and refinement parameters. Absorption was calculated semi-empirically using the SADABS program [23]. The structures were solved by direct methods 655
using the SHELXS program [24]. Non-hydrogen atoms were refined isotropically and then anisotropically using the SHELXL-97 program [25]. H atoms on C atoms were placed in calculated positions and refined using a rider model. The hydroxyl H atom in 6 was found in difference Fourier maps. Its position was refined isotropically in the final refinement cycle. All calculations were performed using the WinGX [26] and APEX2 [27] programs. Figures were drawn using the PLATON program [28]. XSA data were deposited in the Cambridge Crystallographic Data Centre under Nos. 968953 (3) and 968952 (6). 1-Phenyl-5-{[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]sulfanyl}-1H-tetrazole (3). A solution of (–)-E-pinene (2.72 g, 0.02 mol) in anhydrous CH2Cl2 (5 mL) at room temperature was treated with 1-phenyl-1H-tetrazole5-thiol (3.56 g, 0.02 mol) and a catalytic amount of ZnCl2 (0.272 g, 0.002 mol) and left for 5 h. The mixture was treated with H2O (20 mL) and extracted with CH2Cl2. The organic layer was dried over MgSO4. The solvent was evaporated in vacuo. The product was isolated by column chromatography over silica gel (hexane–Et2O eluent, 5:1) to afford sulfide 3, colorless crystals, mp 95°C (hexane–Et2O), yield 3.89 g (62%), C17H22N4S. 1Í NMR spectrum (400 MHz, CDCl , G, ppm): 0.78 (3Í, s, Í-10), 0.91, 1.02 (each 3Í, both s, Í-8, 9), 1.22–1.28, 3 1.49–1.52, 1.71–1.80, 1.92–1.99 (6Í, all m, Í-3, 5, 6), 2.21–2.29 (1Í, m, Í-4), 2.60–2.71 (1Í, m, Í-2), 7.50–7.58 (5Í, m, Ph). Mass spectrum (EI, 70 eV), m/z (Irel, %): 314 (M+, 4), 168 (7), 137 (96), 81 (100), 41 (26). (1R,2S,5S)-6,6-Dimethyl-2-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}bicyclo[3.1.1]heptan-2-ol (6). A solution of NaOMe (0.46 g (0.02 mol) of Na) in anhydrous MeOH (50 mL) was treated with E-pinene D-oxide (2.0 g, 0.013 mol) and 1-methylimidazole-2-thiol (2.4 g, 0.021 mol), refluxed for 6 h, treated with H2O, and extracted with CH2Cl2. The organic layer was washed with saturated NH4Cl solution and H2O until neutral and dried over MgSO4. The solvent was removed. Compound 6 was purified by column chromatography over silica gel (hexane–Et2O eluent, 5:1) to afford colorless crystals, mp 69°C (Et2O), yield 2.71 g (51%), C14H22N2OS. 1Í NMR spectrum (400 ÌÃö, CDCl , G, ppm, J/Hz): 0.98, 1.28 (each 3Í, both s, Í-8, 9), 1.50–2.20 (8Í, m, Í-1, 3, 3 4, 5, 7), 2.92, 3.17 (2Í, AB system, J = 12.5, Í-10), 3.50 (2Í, s, Í-11), 3.90 (1Í, s, OH), 7.00–7.10 (2Í, m, Í-12, 13). 2-[(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methylthio]-4,6-dimethylpyrimidine (7). Freshly prepared 4,6-dimethyl-2-pyrimidinesulfenylchloride (0.348 g, 2 mmol) that was prepared by the literature method [29] in CH2Cl2 (4 mL) at room temperature was stirred, treated with (–)-E-pinene (0.272 g, 2 mmol) in CH2Cl2 (4 mL), and stirred for 5 d. The solvent was evaporated. Compound 7 was isolated by column chromatography over silica gel (hexane–CH2Cl2, 70:30) as a dark-brown odorless oil, yield 0.31 g (57%), C16H22N2S. 1Í NMR spectrum (400 MHz, CDCl , G, ppm): 0.75, 1.22 (each 3Í, both s, H-8, 9), 2.04–2.45 (6H, m, H-1, 4, 5, 6), 3 2.38 (6H, s, 2ÑÍ3-arom), 3.79 (2Í, br.s, -SCH2-), 5.53 (1Í, br.s, Í-3), 6.69 (1Í, br.s, Íàrom), 7.40 (1H, m, Íàrom), 6.74 (1H, d, Íàrom). 13C NMR spectrum (100 MHz, CDCl3, G, ppm): 20.9 (s, Ñ-8), 23.44 (s, C-15, 16), 25.9 (s, Ñ-9), 31.1 (s, Ñ-4), 31.5 (s, Ñ-6), 36.9 (s, Ñ-10), 37.9 (s, Ñ-7), 40.3 (s, Ñ-5), 45.1 (s, Ñ-1), 115.5 (s, Ñ-14), 122.3 (s, C-3), 135.2 (s, Ñ-11), 142.4 (s, Ñ-2), 166.6 (s, Ñ-17, 13), 170.6 (s, C-11).
ACKNOWLEDGMENT The work was performed under the auspices of state support for K(VR)FU for improving its competitiveness as a leading world-wide scientific and educational center.
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