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DOI: 10.1055/s-0035-1562473
Diastereoselective Synthesis of Spiro[pyrazolone-4,3′-tetrahydrothiophenes] via a Sulfa-Michael/Aldol Domino Reaction
Publication History
Received: 14 June 2016
Accepted: 14 June 2016
Publication Date:
12 August 2016 (online)
Abstract
A new approach for the diastereoselective synthesis of spiro[pyrazolone-4,3′-tetrahydrothiophenes] was developed. The N,N-diisopropylethylamine-catalyzed reaction of arylidenepyrazolones with in situ generated 2-sulfanylacetaldehyde provides the corresponding spiro-heterocycles via a domino sulfa-Michael/aldol reaction in 42–98% yield and 3:2:1 to 20:1 d.r. under mild reaction conditions.
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Key words
spiro compounds - domino reaction - tetrahydrothiophene - pyrazolone - sulfa-Michael additionThe development of new and efficient synthetic routes to access bioactive heterocyclic compounds is fundamental for the synthesis of valuable natural products, pharmaceuticals and agrochemicals. Tetrahydrothiophenes are present in many natural products and pharmaceuticals,[1] such as the essential coenzyme biotin[2] or analogues of penicillin.[3] In addition, bioactive compounds bearing a pyrazolone moiety display a wide range of biological and pharmaceutical properties, and especially spiro-pyrazolones,[4] such as the spiro compounds A,[5] with antimicrobial activity, B, a phosphodiesterase inhibitor,[6] C, with antitumor activity,[7] and D, with antibacterial activity,[8] have attracted much interest in medicinal chemistry (Figure [1]).
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Recently, arylidenepyrazolones have been recognized as very good substrates to provide new pyrazole and pyrazolone derivatives.[9] 1,4-Dithiane-2,5-diol, the dimer of 2-sulfanylacetaldehyde, emerged as an excellent precursor for the development of domino sulfa-Michael/aldol reactions to provide tetrahydrothiophene rings (Scheme [1]).[10] Similar domino transformations of 1,4-dithiane-2,5-diol resulted in the construction of spiro-tetrahydrothiophenes containing oxindole,[11a] [c] 1,3-indanedione,[11e] and chromanone cores.[11b,d] However, to the best of our knowledge, there is no report in the literature on the formation of spiro-tetrahydrothiophenes bearing a pyrazolone moiety.
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Herein we report a diastereoselective sulfa-Michael/ aldol domino reaction of arylidenepyrazolones 1 and 1,4-dithiane-2,5-diol (2) to provide spiro[pyrazolone-4,3′-tetrahydrothiophenes] 3 (Scheme [1]). In our initial investigations, different organic and inorganic bases were tested (Table [1]). The first attempt using DMAP (10 mol%) in CH2Cl2 at room temperature afforded the spirocyclic product 3a in 83% yield and 12:2:1 d.r (entry 1). The product was acetylated in situ to ease the analysis of the NMR spectra. The screening of other organic bases such as Et3N, DABCO, or DBU provided 3a in moderate to very good yields and good diastereomeric ratios, but the reaction time extended to 19 hours when the base DABCO was used (entries 2–4). The sulfa-Michael/aldol domino reaction proceeded well when the inorganic base K2CO3 was used, to afford 3a in 97% yield and 9:2:1 d.r., but in a longer reaction time (entry 5).
a Reaction conditions: 1a (0.25 mmol), 2 (0.15 mmol), cat. (10 mol%), solvent (2.5 mL, 0.1 M).
b Yield of 3a after flash chromatography.
c The diastereomeric ratio was determined by 1H NMR.
d HMTA = hexamethylenetetramine.
e The reaction was carried out at 0 °C.
f The reaction was carried out with DIPEA (30 mol%) at 0 °C.
g The reaction was carried out with DIPEA (1 mol%).
h The reaction was carried out with DIPEA (5 mol%).
After further screening of organic bases, DIPEA was found to be the best catalyst, providing the spirocyclic product 3a in 98% yield and 12:2:1 d.r. within 15 minutes (Table [1], entry 9). The reaction was further optimized by conducting the reaction in different solvents and varying the catalyst loading to determine the optimal reaction conditions. We found that DIPEA (5 mol%) in CH2Cl2 at room temperature provided 3a in the best yield of 98% and a d.r. of 15:2:1 within 15 minutes (entry 16).
The optimized reaction conditions were then used to probe the general applicability of the domino sequence (Scheme [2]). The sulfa-Michael/aldol reaction of arylidenepyrazolones bearing electron-donating (1a–f) and electron-withdrawing groups (1g–j) provided the spirocyclic compounds 3a–j in good to excellent yields and moderate to excellent diastereomeric ratios. Good results in terms of yield and d.r. were also obtained by using a thionyl substituent at the arylidenepyrazolone, showing the presence of heterocyclic substituents in this reaction. The substrate scope was extended by varying the substituents at the N-1 and C-3 positions of the alkylidenepyrazolone. The reaction with different aryl substituents at the N-1 position provided good yields and moderate to very good diastereomeric ratios (3l–n). Moderate to good yields and moderate to excellent diastereomeric ratios were achieved by varying the alkyl substituent at C-3 (3o–q). It was observed that an increase in the steric hindrance at C-3 resulted in a lower yield (3n–p).
Furthermore, an enantioselective sulfa-Michael/aldol domino sequence was investigated, catalyzed by different chiral bifunctional organocatalysts such as squaramides[12] and thioureas.[13] Initially different squaramide and thiourea catalysts (Table [2,] I–IV) were tested to provide the product 3a. In all approaches good to excellent yields could be achieved with good diastereomeric ratios, but the best enantioselectivity of only 19% ee was obtained with catalyst I. The reaction was then conducted in different solvents and at low temperature employing catalyst I, but so far the ee value could not be increased beyond 23% (entry 6).
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The relative cis-configuration of the spiro[pyrazolone-4,3′-tetrahydrothiophenes] was determined by X-ray crystal structure analysis of compound 3i (Figure [2]).[14]
a Reaction conditions: 1a (0.25 mmol), 2 (0.15 mmol), cat. (5 mol%), solvent (2.5 mL, 0.1 M).
b Yield of 3a after flash chromatography.
c The enantiomeric excess was determined by HPLC on a chiral stationary phase.
d The diastereomeric ratio was determined by 1H NMR.
e The reaction was carried out at –65 °C.
In conclusion, we have developed a diastereoselective sulfa-Michael/aldol domino reaction of arylidenepyrazolones with 1,4-dithiane-2,5-diol to afford spiro[pyrazolone-4,3′-tetrahydrothiophenes] in moderate to excellent yields and diastereomeric ratios. An attempt to develop an enantioselective variant of this protocol has also been carried out, but so far only 23% ee could be reached.
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Unless otherwise noted, all commercially available chemicals were used without purification. All solvents were distilled and purified according to standard procedures. Analytical TLC was performed using SIL G-25 UV254 from Macherey & Nagel (particle size 0.040–0.063 nm; 230–240 mesh flash) and visualized with UV radiation at 254 nm. 1H, 13C, and 19F NMR spectra were recorded at ambient temperature on a Varian Innova 400 or Innova 600 instrument. Chemical shifts of the major diastereomer for the 1H NMR and 13C NMR spectra are reported in ppm with coupling constants given in Hz. Melting points were measured on a LLG MPM-H2 melting point instrument. Mass spectra were acquired on a Finnigan SSQ7000 (EI, 70 eV) spectrometer and on a ThermoFinnigan LCQ Deca XP plus (ESI) spectrometer, and high resolution ESI spectra were obtained on a ThermoFisher Scientific LTQ Orbitrap XL. Analytical HPLC was performed on a Agilent 1260 instrument by using chiral stationary phases (Daicel Chiralpak IA column). The alkylidenepyrazolones 1 were prepared according to known procedures.[15]
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Compounds rac-3a–q; General Procedure
1,4-Dithiane-2,5-diol (2; 0.15 mmol) and DIPEA (5 mol%) were added to a solution of 1 (0.25 mmol) in CH2Cl2 (2.5 mL). The reaction mixture was stirred at r.t. until 1 was completely consumed as indicated by TLC. The solution of the crude product was cooled to 0 °C and treated with Ac2O (0.30 mmol), DMAP (0.05 mmol), and pyridine (0.30 mmol). The crude product was then subjected to flash chromatography (silica gel, n-pentane–Et2O, 20:1 to 6:1); this afforded the spiro product 3.
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1-Methyl-4-oxo-3,6-diphenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3a)
Yield: 93 mg (98%); colorless solid; mp 78–80 °C; Rf = 0.60 (n-pentane–Et2O, 1:1).
IR (ATR): 1750, 1709, 1595, 1495, 1452, 1401, 1364, 1323, 1292, 1216, 1148, 1053, 918, 839, 798, 758, 696 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.70 (m, 2 H, Ar-H), 7.39–7.33 (m, 4 H, Ar-H), 7.25–7.15 (m, 4 H, Ar-H), 5.75 (t, J = 8.5 Hz, 1 H, CHOAc), 5.14 (s, 1 H, CHAr), 3.81 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.19 (dd, J = 11.1, 8.8 Hz, 1 H, SCHH), 2.38 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 170.9 (C=O), 169.3 (C=O), 157.5 (Cq), 137.4 (Cq), 133.1 (Cq), 128.9 (2 C, Ar-C), 128.8 (Ar-C), 128.6 (2 C, Ar-C), 127.2 (2 C, Ar-C), 125.5 (Ar-C), 119.2 (2 C, Ar-C), 79.3 (CHOAc), 69.2 (Cq), 54.3 (CHAr), 33.0 (SCH2), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 381.3 (7) [M + H]+, 380.1 (33) [M]+, 320.1 (55) [M – OAc]+, 263.1 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H21N2O3S: 381.1267; found: 381.1268.
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6-(4-Methoxyphenyl)-1-methyl-4-oxo-3-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3b)
Yield: 83 mg (81%); yellow solid; mp 38–40 °C; Rf = 0.47 (n-pentane–Et2O, 1:1).
IR (ATR): 2944, 1719, 1596, 1493, 1363, 1216, 1044, 918, 829, 753, 692 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.72 (d, J = 8.6 Hz, 2 H, Ar-H), 7.36 (m, 2 H, Ar-H), 7.29–7.23 (m, 2 H, Ar-H), 7.17 (m, 1 H, Ar-H), 6.74 (t, J = 7.7 Hz, 2 H, Ar-H), 5.72 (t, J = 8.5 Hz, 1 H, CHOAc), 5.09 (s, 1 H, CHAr), 3.80 (dd, J = 11.0, 8.5 Hz, 1 H, SCHH), 3.72 (s, 3 H, OCH3), 3.17 (m, 1 H, SCHH), 2.40 (s, 3 H, CH3), 1.97 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 171.0 (C=O), 169.3 (C=O), 159.7 (Cq), 157.6 (Cq), 137.4 (Cq), 129.6 (Cq), 128.8 (2 C, Ar-C), 128.4 (2 C, Ar-C), 125.4 (Ar-C), 119.1 (2 C, Ar-C), 113.9 (2 C, Ar-C), 79.2 (CHOAc), 69.2 (Cq), 55.2 (OCH3), 53.9 (CHAr), 33.0 (SCH2), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 411.1 (16) [M + H]+, 410.1 (62) [M]+, 350.1 (50) [M – HOAc]+, 293.1 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H22N2O4SNa: 433.1193; found: 433.1192.
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1-Methyl-4-oxo-3-phenyl-6-p-tolyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3c)
Yield: 91 mg (92%); colorless solid; mp 35–37 °C; Rf = 0.68 (n-pentane–Et2O, 1:1).
IR (ATR): 2951, 1750, 1709, 1596, 1497, 1434, 1402, 1364, 1291, 1216, 1146, 1052, 920, 821, 798, 757, 727, 689 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.72 (m, 2 H, Ar-H), 7.36 (m, 2 H, Ar-H), 7.22 (d, J = 8.1 Hz, 2 H, Ar-H), 7.18 (m, 1 H, Ar-H), 7.01 (d, J = 7.9 Hz, 2 H, Ar-H), 5.73 (t, J = 8.5 Hz, 1 H, CHOAc), 5.11 (s, 1 H, CHAr), 3.80 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.17 (dd, J = 11.1, 8.8 Hz, 1 H, SCHH), 2.39 (s, 3 H, CH3), 2.25 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 171.0 (C=O), 169.3 (C=O), 157.6 (Cq), 138.6 (Cq), 137.5 (Cq), 129.9 (Cq), 129.3 (2 C, Ar-C), 128.8 (2 C, Ar-C), 127.0 (2 C, Ar-C), 125.4 (Ar-C), 119.1 (2 C, Ar-C), 79.4 (CHOAc), 69.2 (Cq), 54.1 (CHAr), 33.0 (SCH2), 21.1 (CH3), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 395.2 (11) [M + H]+, 394.2 (31) [M]+, 334.1 (64) [M – HOAc]+, 277.1 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H22N2O3SNa: 417.1243; found: 417.1240.
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6-(3-Methoxyphenyl)-1-methyl-4-oxo-3-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3d)
Yield: 92 mg (90%); brown oil; Rf = 0.55 (n-pentane–Et2O, 1:1).
IR (ATR): 2951, 1751, 1709, 1595, 1493, 1458, 1433, 1402, 1366, 1270, 1216, 1153, 1045, 923, 872, 756, 713, 692 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 7.8 Hz, 2 H, Ar-H), 7.34 (t, J = 7.9 Hz, 2 H, Ar-H), 7.19–7.08 (m, 2 H, Ar-H), 6.93 (d, J = 7.5 Hz, 1 H, Ar-H), 6.84 (s, 1 H, Ar-H), 6.75 (d, J = 8.4 Hz, 1 H, Ar-H), 5.72 (t, J = 8.6 Hz, 1 H, CHOAc), 5.09 (s, 1 H, CHAr), 3.78 (dd, J = 11.0, 8.3 Hz, 1 H, SCHH), 3.56 (s, 3 H,OCH3), 3.16 (dd, J = 10.9, 9.0 Hz, 1 H, SCHH), 2.36 (s, 3 H, CH3), 1.96 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 171.0 (C=O), 169.2 (C=O), 159.6 (Cq), 157.5 (Cq), 137.4 (Cq), 134.6 (Cq), 129.6 (Ar-C), 128.8 (2 C, Ar-C), 125.4 (Ar-C), 119.3 (Ar-C), 119.0 (2 C, Ar-C), 114.8 (Ar-C), 112.2 (Ar-C), 79.3 (CHOAc), 69.1 (Cq), 55.0 (OCH3), 54.1 (CHAr), 33.0 (SCH2), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 411.0 (9) [M + H]+, 410.0 (21) [M]+, 350.0 (38) [M – HOAc]+, 292.9 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H22N2O4SNa: 433.1193; found: 433.1193.
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1-Methyl-4-oxo-3-phenyl-6-o-tolyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3e)
Yield: 69 mg (70%); colorless solid; mp 127–129 °C; Rf = 0.59 (n-pentane–Et2O, 1:1).
IR (ATR): 2958, 2312, 2093, 1724, 1476, 1361, 1212, 1025, 737 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75–7.65 (m, 3 H, Ar-H), 7.35–7.28 (m, 2 H, Ar-H), 7.17–7.09 (m, 3 H, Ar-H), 7.02 (m, 1 H, Ar-H), 5.73 (t, J = 8.3 Hz, 1 H, CHOAc), 5.41 (s, 1 H, CHAr), 3.82 (dd, J = 11.2, 8.1 Hz, 1 H, SCHH), 3.21 (dd, J = 11.2, 8.5 Hz, 1 H, SCHH), 2.53 (s, 3 H, CH3), 2.26 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 170.9 (C=O), 169.2 (C=O), 157.8 (Cq), 137.5 (Cq), 137.3 (Cq), 131.6 (Cq), 131.0 (Ar-C), 128.8 (2 C, Ar-C), 128.5 (Ar-C), 128.1 (Ar-C), 125.9 (Ar-C), 125.3 (Ar-C), 118.8 (2 C, Ar-C), 79.6 (CHOAc), 68.2 (Cq), 50.3 (CHAr), 33.4 (SCH2), 20.7 (CH3), 19.6 (CH3), 18.6 (CH3).
MS (EI, 70 eV): m/z (%) = 395.2 (1) [M + H]+, 335.0 (1) [M – OAc]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H22N2O3SNa: 417.1243; found: 417.1226.
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6-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-4-oxo-3-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3f)
Yield: 69 mg (65%); orange solid; mp 42–44 °C; Rf = 0.63 (n-pentane–Et2O, 1:1).
IR (ATR): 2902, 1717, 1598, 1488, 1362, 1221, 1037, 922, 758 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.73 (m, 2 H, Ar-H), 7.40–7.34 (m, 2 H, Ar-H), 7.18 (m, 1 H, Ar-H), 6.91 (d, J = 1.8 Hz, 1 H, Ar-C), 6.80 (dd, J = 8.2, 1.9 Hz, 1 H, Ar-H), 6.62 (d, J = 8.1 Hz, 1 H, Ar-H), 5.90 (dd, J = 12.0, 1.5 Hz, 2 H, -OCH2O-), 5.70 (t, J = 8.6 Hz, 1 H, CHOAc), 5.05 (s, 1 H, CHAr), 3.79 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.17 (dd, J = 11.1, 8.9 Hz, 1 H, SCHH), 2.42 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 170.8 (C=O), 169.2 (C=O), 157.5 (Cq), 147.9 (Cq), 147.8 (Cq), 137.4 (Cq), 128.9 (2 C, Ar-C), 126.6 (Cq), 125.5 (Ar-C), 121.0 (Ar-C), 119.2 (2 C, Ar-C), 108.2 (Ar-C), 107.5 (Ar-C), 101.3 (-OCH2O-), 79.1 (CHOAc), 69.2 (Cq), 54.2 (CHAr), 33.0 (SCH2), 20.6 (CH3), 17.9 (CH3).
MS (EI, 70 eV): m/z (%) = 425.3 (2) [M + H]+, 424.2 (7) [M]+, 364.2 (16) [M – HOAc]+, 307.1 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H20N2O5SNa: 447.0985; found: 447.0984.
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6-(4-Chlorophenyl)-1-methyl-4-oxo-3-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3g)
Yield: 81 mg (78%); colorless solid; mp 37–39 °C; Rf = 0.50 (n-pentane–Et2O, 1:1).
IR (ATR): 2939, 2291, 2083, 1715, 1596, 1491, 1361, 1213, 1043, 917, 828, 751, 691 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.74–7.70 (m, 2 H, Ar-H), 7.37 (m, 2 H, Ar-H), 7.31–7.27 (m, 2 H, Ar-H), 7.22–7.18 (m, 3 H, Ar-H), 5.73 (t, J = 8.6 Hz, 1 H, CHOAc), 5.09 (s, 1 H, CHAr), 3.81 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.19 (dd, J = 11.1, 8.9 Hz, 1 H, SCHH), 2.37 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 170.7 (C=O), 169.2 (C=O), 157.2 (Cq), 137.3 (Cq), 134.6 (Cq), 131.8 (Cq), 128.9 (2 C, Ar-C), 128.8 (2 C, Ar-C), 128.6 (2 C, Ar-C), 125.6 (Ar-C), 119.1 (2 C, Ar-C), 79.2 (CHOAc), 69.1 (Cq), 53.5 (CHAr), 33.1 (SCH2), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 416.1 (16) [M, 37Cl]+, 414.1 (39) [M, 35Cl]+, 356.0 (17) [M – HOAc, 37Cl]+, 354.0 (65) [M – HOAc, 35Cl]+, 299.1 (31) [M – C4H5O2S, 37Cl]+, 297.0 (100) [M – C4H5O2S, 35Cl]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19ClN2O3SNa: 437.0697; found: 437.0698.
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6-(4-Bromophenyl)-1-methyl-4-oxo-3-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3h)
Yield: 90 mg (78%); colorless solid; mp 38–40 °C; Rf = 0.53 (n-pentane–Et2O, 1:1).
IR (ATR): 1750, 1708, 1595, 1492, 1430, 1398, 1365, 1279, 1214, 1147, 1105, 1054, 1009, 955, 920, 881, 827, 793, 757, 725, 691 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.74–7.70 (m, 2 H, Ar-H), 7.40–7.33 (m, 4 H, Ar-H), 7.24–7.17 (m, 3 H, Ar-H), 5.73 (t, J = 8.6 Hz, 1 H, CHOAc), 5.07 (s, 1 H, CHAr), 3.80 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.19 (dd, J = 11.1, 8.9 Hz, 1 H, SCHH), 2.37 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 170.7 (C=O), 169.2 (C=O), 157.1 (Cq), 137.3 (Cq), 132.3 (Cq), 131.8 (2 C, Ar-C), 128.9 (2 C, Ar-C), 128.9 (2 C, Ar-C), 125.6 (Ar-C), 122.8 (Cq), 119.1 (2 C, Ar-C), 79.2 (CHOAc), 68.98 (Cq), 53.5 (CHAr), 33.1 (SCH2), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 460.1 (34) [M, 81Br]+, 458.0 (33) [M, 79Br]+, 400.0 (62) [M – OAc, 81Br]+, 398.0 (60) [M – OAc, 79Br]+, 343.1 (94) [M – C4H6O2S, 81Br]+, 341.0 (100) [M – C4H6O2S, 79Br]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19N2O3S79BrNa: 481.0192; found: 481.0193.
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6-(3-Chlorophenyl)-1-methyl-4-oxo-3-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3i)
Yield: 87 mg (84%); colorless solid; mp 119–121 °C; Rf = 0.59 (n-pentane–Et2O, 1:1).
IR (ATR): 2950, 1728, 1589, 1489, 1361, 1219, 1041, 913, 768, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.72–7.66 (m, 2 H, Ar-H), 7.43 (m, 1 H, Ar-H), 7.39–7.32 (m, 2 H, Ar-H), 7.23–7.10 (m, 4 H, Ar-H), 5.71 (t, J = 8.6 Hz, 1 H, CHOAc), 5.07 (s, 1 H, CHAr), 3.79 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.18 (dd, J = 11.1, 8.9 Hz, 1 H, SCHH), 2.36 (s, 3 H, CH3), 1.97 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 170.7 (C=O), 169.2 (C=O), 157.1 (Cq), 137.2 (Cq), 135.4 (Cq), 134.6 (Cq), 129.9 (Ar-C), 129.0 (Ar-C), 128.9 (2 C, Ar-C), 127.3 (Ar-C), 125.7 (Ar-C), 125.5 (Ar-C), 119.3 (2 C, Ar-C), 79.1 (CHOAc), 69.0 (Cq), 53.5 (CHAr), 33.1 (SCH2), 20.6 (CH3), 17.7 (CH3).
MS (EI, 70 eV): m/z (%) = 415.9 (14) [M, 37Cl]+, 414.0 (35) [M, 35Cl]+, 356.0 (19) [M – HOAc, 37Cl]+, 354.0 (48) [M – HOAc, 35Cl]+, 298.9 (29) [M – C4H5O2S, 37Cl]+, 297.0 (100) [M – C4H5O2S, 35Cl]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19N2O3SClNa: 437.0697; found: 437.0696.
#
1-Methyl-4-oxo-3-phenyl-6-[4-(trifluoromethyl)phenyl]-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3j)
Yield: 107 mg (95%); colorless solid; mp 40–42 °C; Rf = 0.53 (n-pentane–Et2O, 1:1).
IR (ATR): 2101, 1712, 1600, 1497, 1322, 1219, 1119, 1053, 921, 846, 755, 688 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.70 (m, 2 H, Ar-H), 7.48 (m, 4 H, Ar-H), 7.37 (m, 2 H, Ar-H), 7.20 (t, J = 7.4 Hz, 1 H, Ar-H), 5.75 (t, J = 8.6 Hz, 1 H, CHOAc), 5.16 (s, 1 H, CHAr), 3.83 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.21 (dd, J = 11.1, 8.9 Hz, 1 H, SCHH), 2.37 (s, 3 H, CH3), 1.99 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 170.6 (C=O), 169.2 (C=O), 157.0 (Cq), 137.46 (Cq), 137.2 (Cq), 130.9 (q, J = 32.7 Hz, Cq), 128.9 (2 C, Ar-C), 127.7 (2 C, Ar-C), 125.7 (Ar-C), 125.6 (2 C, Ar-C), 123.7 (q, J = 272.3 Hz, CF3), 119.1 (2 C, Ar-C), 79.3 (CHOAc), 69.0 (Cq), 53.5 (CHAr), 33.1 (SCH2), 20.6 (CH3), 17.7 (CH3).
19F NMR (376 MHz, CDCl3): δ = –62.78 (s).
MS (EI, 70 eV): m/z (%) = 449.0 (7) [M + H]+, 447.9 (31) [M]+, 387.9 (33) [M – HOAc]+, 330.6 (100) [M – C4H6O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H19N2O3S F3Na: 471.0961; found: 471.0961.
#
1-Methyl-4-oxo-3-phenyl-6-(2-thienyl)-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3k)
Yield: 82 mg (85%); orange solid; mp 39–41 °C; Rf = 0.46 (n-pentane–Et2O, 1:1).
IR (ATR): 3073, 2953, 1750, 1708, 1595, 1495, 1431, 1363, 1274, 1215, 1141, 1050, 919, 849, 800, 757, 697 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.81–7.77 (m, 2 H, Ar-H), 7.40–7.35 (m, 2 H, Ar-H), 7.19 (m, 1 H, Ar-H), 7.16 (m, 1 H, Ar-H2-Thienyl), 6.97 (m, 1 H, Ar-H2-Thienyl), 6.85 (m, 1 H, Ar-H2-Thienyl), 5.69 (t, J = 8.6 Hz, 1 H, CHOAc), 5.32 (s, 1 H, CHAr), 3.80 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.21 (dd, J = 11.0, 9.0 Hz, 1 H, SCHH), 2.47 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 170.4 (C=O), 169.2 (C=O), 157.4 (Cq), 137.5 (Cq), 136.6 (Cq), 128.9 (2 C, Ar-C), 127.1 (Ar-C), 126.4 (Ar-C), 125.8 (Ar-C), 125.5 (Ar-C), 119.1 (2 C, Ar-C), 78.8 (CHOAc), 69.0 (Cq), 49.3 (CHAr), 33.3 (SCH2), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 387.0 (10) [M + H]+, 385.9 (36) [M]+, 325.8 (38) [M – HOAc]+, 268.7 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O3S2Na: 409.0651; found: 409.0651.
#
3-(2-Chlorophenyl)-1-methyl-4-oxo-6-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3l)
Yield: 78 mg (75%); colorless solid; mp 153–155 °C; Rf = 0.50 (n-pentane–Et2O, 1:1).
IR (ATR): 3016, 2969, 2040, 1740, 1592, 1486, 1443, 1366, 1218, 1052, 919, 763, 701 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43 (m, 3 H, Ar-H), 7.31–7.25 (m, 5 H, Ar-H), 7.08–7.04 (m, 1 H, Ar-H), 5.76 (t, J = 8.6 Hz, 1 H, CHOAc), 5.14 (s, 1 H, CHAr), 3.78 (dd, J = 11.0, 8.3 Hz, 1 H, SCHH), 3.20 (dd, J = 11.0, 8.9 Hz, 1 H, SCHH), 2.39 (s, 3 H, CH3), 2.02 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 169.7 (C=O), 168.9 (C=O), 156.5 (Cq), 133.9 (Cq), 133.8 (Cq), 131.9 (Cq), 130.3 (Ar-C), 129.8 (Ar-C), 128.7 (4 C, Ar-C), 128.5 (2 C, Ar-C), 127.3 (Ar-C), 75.8 (CHOAc), 66.5 (Cq), 49.6 (CHAr), 30.9 (SCH2), 20.7 (CH3), 13.7 (CH3).
MS (EI, 70 eV): m/z (%) = 356.1 (11) [M – HOAc, 37Cl]+, 354.1 (27) [M – HOAc, 35Cl]+, 299.1 (35) [M – C4H5O2S, 37Cl]+, 297.1 (100) [M – C4H5O2S, 35Cl]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19N2O3SClNa: 437.0697; found: 437.0685.
#
3-(4-Chlorophenyl)-1-methyl-4-oxo-6-phenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3m)
Yield: 92 mg (89%); yellow oil; Rf = 0.61 (n-pentane–Et2O, 1:1).
IR (ATR): 2951, 1723, 1595, 1490, 1357, 1215, 1143, 1044, 929, 825, 769, 697 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.70–7.64 (m, 2 H, Ar-H), 7.29 (m, 4 H, Ar-H), 7.23–7.17 (m, 3 H, Ar-H), 5.72 (t, J = 8.5 Hz, 1 H, CHOAc), 5.10 (s, 1 H, CHAr), 3.79 (dd, J = 11.2, 8.3 Hz, 1 H, SCHH), 3.17 (dd, J = 11.2, 8.7 Hz, 1 H, SCHH), 2.36 (s, 3 H, CH3), 1.96 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 170.9 (C=O), 169.2 (C=O), 157.8 (Cq), 135.9 (Cq), 132.9 (Cq), 130.5 (Cq), 128.8 (3 C, Ar-C), 128.6 (2 C, Ar-C), 127.1 (2 C, Ar-C), 120.1 (2 C, Ar-C), 79.3 (CHOAc), 69.3 (Cq), 54.5 (CHAr), 33.1 (SCH2), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 416.0 (14) [M, 37Cl]+, 414.0 (36) [M, 35Cl]+, 356.0 (18) [M – HOAc, 37Cl]+, 354.0 (47) [M – HOAc, 35Cl]+, 299.0 (31) [M – C4H5O2S, 37Cl]+, 297.0 (100) [M – C4H5O2S, 35Cl]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19N2O3SClNa: 437.0697; found: 437.0697.
#
1-Methyl-4-oxo-6-phenyl-3-p-tolyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3n)
Yield: 85 mg (86%); brown solid; mp 37–39 °C; Rf = 0.56 (n-pentane–Et2O, 1:1).
IR (ATR): 3479, 2940, 2655, 2333, 2099, 1719, 1613, 1510, 1362, 1215, 1044, 919, 814, 698 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.59–7.54 (m, 2 H, Ar-H), 7.36–7.33 (m, 2 H, Ar-H), 7.24–7.20 (m, 3 H, Ar-H), 7.17–7.14 (m, 2 H, Ar-H), 5.74 (t, J = 8.5 Hz, 1 H, CHOAc), 5.13 (s, 1 H, CHAr), 3.81 (dd, J = 11.1, 8.3 Hz, 1 H, SCHH), 3.18 (dd, J = 11.1, 8.8 Hz, 1 H, SCHH), 2.37 (s, 3 H, CH3), 2.33 (s, 3 H, ArCH3), 1.98 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 170.7 (C=O), 169.3 (C=O), 157.3 (Cq), 135.3 (Cq), 135.0 (Cq), 133.1 (Cq), 129.3 (2 C, Ar-C), 128.7 (Ar-C), 128.6 (2 C, Ar-C), 127.2 (2 C, Ar-C), 119.2 (2 C, Ar-C), 79.3 (CHOAc), 69.1 (Cq), 54.2 (CHAr), 33.0 (SCH2), 21.0 (CH3), 20.6 (CH3), 17.8 (CH3).
MS (EI, 70 eV): m/z (%) = 395.2 (10) [M + H]+, 394.2 (26) [M]+, 334.1 (21) [M – HOAc]+, 277.1 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H22N2O3SNa: 395.1424; found: 395.1423.
#
1-Isopropyl-4-oxo-3,6-diphenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3o)
Yield: 55 mg (54%); yellow solid; mp 101–103 °C; Rf = 0.63 (n-pentane–Et2O, 1:1).
IR (ATR): 2973, 1749, 1710, 1596, 1495, 1452, 1355, 1217, 1148, 1051, 979, 921, 883, 753, 693 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.79 (m, 2 H, Ar-HDiast), 7.52 (m, 2 H, Ar-H), 7.47–7.43 (m, 2 H, Ar-H, Ar-H), 7.39 (m, 2 H, Ar-HDiast), 7.33 (m, 2 H, Ar-H, Ar-HDiast), 7.30–7.25 (m, 4 H, Ar-H, Ar-HDiast), 7.24–7.19 (m, 4 H, Ar-H, Ar-HDiast), 7.17 (m, 1 H, Ar-HDiast), 7.11 (m, 1 H, Ar-H), 5.75 (dd, J = 10.1, 7.8 Hz, 1 H, CHOAcDiast), 5.68 (dd, J = 9.9, 7.1 Hz, 1 H, CHOAc), 5.19 (s, 1 H, CHArDiast), 4.95 (s, 1 H, CHAr), 3.99 (t, J = 9.7 Hz, 1 H, SCHH), 3.75 (dd, J = 10.6, 7.8 Hz, 1 H, SCHHDiast), 3.44 (dd, J = 9.5, 7.1 Hz, 1 H, SCHH), 3.23 (t, J = 10.3 Hz, 1 H, SCHH Diast), 3.12 (m, 1 H, CH(CH3)2Diast), 2.91 (m, 1 H, CH(CH3)2), 1.98 (s, 3 H, CH3), 1.96 (s, 3 H, CH3Diast), 1.43 (d, J = 6.8 Hz, 3 H, CH3 ( i Pr)), 1.31 (d, J = 6.8 Hz, 3 H, CH3 ( i Pr)Diast), 1.21 (d, J = 6.8 Hz, 3 H, CH3 ( i Pr)), 0.80 (d, J = 6.7 Hz, 3 H, CH3 ( i Pr)Diast).
13C NMR (151 MHz, CDCl3): δ = 171.0 (C=ODiast), 169.9 (C=O), 169.1 (C=O), 168.7 (C=ODiast), 165.4 (Cq Diast), 163.6 (Cq), 137.7 (Cq Diast), 137.3 (Cq), 134.0 (Cq Diast), 133.8 (Cq), 128.8 (2 C, Ar-CDiast), 128.7 (2 C, Ar-C), 128.6 (2 C, Ar-CDiast), 128.5 (2 C, Ar-C), 128.3 (2 C, Ar-C), 127.3 (2 C, Ar-CDiast), 125.4 (2 C, Ar-CDiast), 125.2 (2 C, Ar-C), 119.3 (2 C, Ar-C), 119.1 (2 C, Ar-CDiast), 79.8 (CHOAcDiast), 76.5 (CHOAc), 69.5 (Cq Diast), 67.7 (Cq), 53.0 (CHArDiast), 49.7 (CHAr), 32.3 (SCH2 Diast), 30.7 (SCH2), 29.7 (CH(CH3)2 Diast), 27.2 (CH(CH3)2), 22.8 (CH3 Diast), 22.3 (CH3), 20.8 (2 C, CH(CH3)2 Diast), 20.6 (2 C, CH(CH3)2).
MS (EI, 70 eV): m/z (%) = 408.1 (3) [M]+, 348.1 (13) [M – HOAc]+, 291.2 (67) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H24N2O3SNa: 409.1580; found: 409.1573.
#
1-tert-Butyl-4-oxo-3,6-diphenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3p)
Yield: 44 mg (42%); orange solid; mp 155–157 °C; Rf = 0.70 (n-pentane–Et2O, 1:1).
IR (ATR): 2965, 1721, 1596, 1490, 1373, 1218, 1044, 967, 849, 748 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.45 (m, 4 H, Ar-H), 7.28–7.24 (m, 2 H, Ar-H), 7.21 (m, 2 H, Ar-H), 7.17–7.12 (m, 1 H, Ar-H), 7.09 (m, 1 H, Ar-H), 5.91 (dd, J = 9.7, 7.2 Hz, 1 H, CHOAc), 5.32 (s, 1 H, CHAr), 4.01 (t, J = 9.6 Hz, 1 H, SCHH), 3.43 (dd, J = 9.5, 7.2 Hz, 1 H, SCHH), 1.98 (s, 3 H, CH3), 1.47 (s, 9 H, t Bu).
13C NMR (151 MHz, CDCl3): δ = 170.0 (C=O), 168.9 (C=O), 163.6 (Cq), 137.1 (Cq), 134.3 (Cq), 128.5 (Ar-C), 128.5 (2 C, Ar-C), 128.4 (2 C, Ar-C), 128.1 (2 C, Ar-C), 125.2 (Ar-C), 119.2 (2 C, Ar-C), 77.0 (CHOAc), 68.4 (Cq), 48.5 (CHAr), 37.1 (C(CH3)3), 30.5 (SCH2), 29.8 (3 C, t Bu), 20.7 (CH3).
MS (EI, 70 eV): m/z (%) = 423.2 (36) [M + H]+, 422.2 (18) [M]+, 362.1 (89) [M – HOAc]+, 305.0 (100) [M – C4H5O2S]+.
HRMS (ESI): m/z [M + H]+ calcd for C24H27N2O3S: 423.1737; found: 423.1736.
#
1-Ethyl-4-oxo-3,6-diphenyl-7-thia-2,3-diazaspiro[4.4]non-1-en-9-yl Acetate (3q)
Yield: 74 mg (76%); colorless oil; Rf = 0.65 (n-pentane–Et2O, 1:1).
IR (ATR): 2978, 2940, 2106, 1751, 1708, 1596, 1495, 1453, 1353, 1218, 1142, 1049, 957, 913, 837, 800, 757, 728, 696 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.74 (m, 2 H, Ar-H), 7.39–7.31 (m, 5 H, Ar-H), 7.24–7.20 (m, 3 H, Ar-H), 5.73 (t, J = 8.6 Hz, 1 H, CHOAc), 5.13 (s, 1 H, CHAr), 3.79 (dd, J = 11.0, 8.2 Hz, 1 H, SCHH), 3.17 (dd, J = 10.9, 9.1 Hz, 1 H, SCHH), 2.68–2.58 (m, 2 H, CH 2CH3), 1.97 (s, 3 H, CH3), 1.12 (t, J = 7.2 Hz, 3 H, CH2CH 3).
13C NMR (151 MHz, CDCl3): δ = 171.0 (C=O), 169.3 (C=O), 161.3 (Cq), 137.6 (Cq), 133.3 (Cq), 128.8 (2 C, Ar-C), 128.7 (Ar-C), 128.5 (2 C, Ar-C), 127.2 (Ar-C), 125.4 (2 C, Ar-C), 119.1 (2 C, Ar-C), 79.3 (CHOAc), 69.2 (Cq), 54.2 (CHAr), 33.1 (SCH2), 24.5 (CH2), 20.7 (CH3), 9.0 (CH2 CH3).
MS (EI, 70 eV): m/z (%) = 394.0 (3) [M]+, 333.9 (12) [M – HOAc]+, 77.2 (100) [C6H5]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H22N2O3SNa: 417.1243; found: 417.1242.
#
#
Acknowledgment
Financial support from the European Research Council (ERC Advanced Grant 320493 ‘DOMINOCAT’) is gratefully acknowledged.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1562473.
- Supporting Information
-
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For selected examples, see:
For a recent review, see:
For selected examples, see:
-
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- 1b Yoshimura Y, Watanabe M, Satoh H, Ashida N, Ijichi K, Sakata S, Machida H, Matsuda A. J. Med. Chem. 1997; 40: 2177
- 1c Yoshikawa M, Murakami T, Yashiro K, Matsuda H. Chem. Pharm. Bull. 1998; 46: 1339
- 1d Wirsching J, Voss J, Adiwidjaja G, Giesler A, Kopf J. Eur. J. Org. Chem. 2001; 1077
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For selected examples, see:
For a recent review, see:
For selected examples, see:
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