High-Selective One-Pot Synthesis of Spirocyclopropane Pyrazolones Promoted by 4-Dimethylaminopyridine

Jie Liang Huifang Ma Keyume Ablajan

Citation:  Liang Jie, Ma Huifang, Ablajan Keyume. High-Selective One-Pot Synthesis of Spirocyclopropane Pyrazolones Promoted by 4-Dimethylaminopyridine[J]. Chinese Journal of Organic Chemistry, 2019, 39(11): 3169-3175. doi: 10.6023/cjoc201904028 shu

4-二甲氨基吡啶促进的一锅法合成高选择性螺环丙烷吡唑啉酮衍生物

    通讯作者: 阿布拉江·克依木, ablajan209@hotmail.com
  • 基金项目:

    国家自然科学基金 21462041

    国家自然科学基金 21961038

    国家自然科学基金(Nos.21961038,21462041)资助项目

摘要: 发展了一种4-二甲氨基吡啶(DMAP)促进的高立体选择性合成多取代螺环丙烷吡唑啉酮的方法.该反应以吡唑啉酮、芳醛和溴乙酸酯为原料,DMAP作为碱,经三组分一锅反应,合成一系列收率高且非对映选择性好的目标化合物.该反应具有操作简单、产率高以及非对映选择性好等优点.该合成方法对于螺环丙烷的研究具有重要的价值.

English

  • The syntheses of multi-substituted spirocyclopropane ring systems have aroused much attention due to their various biological and pharmacological activities, [1] such as anticancer, antifungal, antitumor, insecticidal, etc. This oxindole derivative A exhibits PLK4 inhibitors activity, [2] and the cyclopropane compound B has high anti-HIV-1 activity.[3] The structure occurs widely as a basic skeleton in natural products, [4] and they are often used as versatile starting materials for the production of natural and synthetic compounds.[5] Spirocyclopropane derivatives feature intrinsic ring strain, and those are attractive for using in organic synthesis.[6]

    In recent decades, many asymmetric cyclopropanation reactions have been reported, such as Simmons-Smith cyclopropanation, [7] Michael-initiated ring-closure of ylides with electron-deficient olefins, [8] transition-metal-catalyzed decomposition of diazoalkanes, [9] base-catalyzed α-halo-genation with olefins[10] and miscellaneous reactions.[11] Electron-deficient olefins and ylides were used to prepare enantioenriched cyclopropanes, using sulfonium, [12] sulfoximines, [13] chloroallyl amides, [14] phosphonates, [15] phosphorus ylides[16] and pyridinium ylide.[17] Asymmetric organocatalytic reaction of unsaturated 1, 4-diketones and 3-chlorooxindoles generated a series of spiro-oxindoles with higher enantioselectivities (Scheme 1a).[18] Triphenylarsine has been used as a catalyst for the synthesis of cyclopropane-indan-diones using the cyclopropanation of alkene with phenacyl bromide (Scheme 1b).[19] Furthermore, the reaction of 4-arylidene-3-methyl- 1-phenyl-pyrazolin-5-one with arsonium salt was resulted in spiro-cyclopropane-pyrazoles in the presence of KF· 2H2O (Scheme 1c).[20] The stereoselective construction of spiro-pyrazolone-cyclopropane-oxindoles derivertives from the reaction of arylidenepyrazolones with 3-chloroo- xindoles was reported using DIPEA as catalyst.[21] However, those methods have yet to be improved for preparing highly stereoselective cyclopropanes or mixtures of cis-trans isomers. Indeed, the catalysts used in those reactions are expensive and poisonous, and the product obtained by multi-step process does not meet the requirements of green chemistry.

    Scheme 1

    Scheme 1.  Synthesis of spirocyclopropanes.

    Multicomponent reactions (MCRs) effectively combine more reactants to form a new molecule with several chemical bonds in a single route, and it has received much attention due to its environmental safety, economy steps and simple work-up.[22] Based on the importance of spirocyclopropane rings containing heterocycle moiety, it is very challenging to develop an efficient and simple method for the synthesis of spirocyclopropane linked to pyrazole. Herein we described a simple one-pot synthesis of multisubstituted spirocyclopropane pyrazolones using 4-dimethylaminopyridine oxide (DMAP) as a base (Scheme 1d).

    Our study on the one-pot reaction of pyrazolone 1b, aromatic aldehyde 2c, and bromoacetic ester 3a with different bases was commenced. On the basis of other work, [23] the product was also anticipated to be trans- 4, 5-dihydro-1H-furo[2, 3-c]pyrazole-5-carboxylate. However, the reaction product was further confirmed and verified as a trans-spirocyclopropane 4h by NMR, HRMS and IR spectra. In addition, single crystal structure of product 4c was carried out, which further confirmed the structure of the product (Figure 1).

    Figure 1

    Figure 1.  Bioactive compounds containing cyclopropane unit

    Initially, the model reaction to optimize the reaction conditions was examined (Table 1). At first, several bases were selected and screened using acetonitrile as solvent (Entries 1~8). Obviously, the model reaction did not proceed well in the absence of base (Entry 1). As shown in Table 1, the corresponding product 4h was generated with lower yields and diastereoselectivities in presence of inorganic base NaOH and Cs2CO3 (Entries 2 and 3). Then, various organic bases (Entries 4~8) were investigated. When using organic base, the yield and diastereoselectivity of compound 4h got improved. Compound 4h was obtained in the highest yield of 86% with excellent diastereoselectivity (94:6) using DMAP as base (Entry 8). Subsequently, the reaction conditions were optimized by screening different solvents. The yield was 65% in CH2Cl2 (Entry 9), and the worst result was obtained in H2O (Entry 10). Compound 4h was obtained with 78% yield and good diastereoselectivity (88:12) in solvents of CH3CO2C2H5 (Entry 11). Further comparisons considered reaction time and temperature (Entries 12~14). No significant change was found when running the reaction for 15 h or longer (Entry 12). Decreasing the reaction temperature from 81 ℃ to 25 ℃ and 60 ℃ resulted in incomplete reaction with 68% and 36% yields (Entries 13 and 14). These results further indicated that the reaction was completed at the boiling point of CH3CN. Furthermore, the impact of base loading was examined. The result showed that reducing the base loading from 100 mol% to 50 mol% significantly decreased the reaction yield (Entry 15).

    Table 1

    Table 1.  Optimization of the reaction conditionsa
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    Entry Base Solvent Temp./℃ Yieldb/% transc/cis
    1 No base CH3CN 81 NR NR
    2 NaOH CH3CN 81 41 45:55
    3 Cs2CO3 CH3CN 81 48 48:52
    4 Pyridine CH3CN 81 82c 72:28
    5 TEBA CH3CN 81 56 80:20
    6 CTAB CH3CN 81 60 85:15
    7 DABCO CH3CN 81 70 72:28
    8 DMAP CH3CN 81 86 94:6
    9 DMAP CH2Cl2 81 65 40:60
    10 DMAP H2O 100 Trace NR
    11 DMAP CH3CO2Et 81 78 88:12
    12 DMAP CH3CN 81 86d 94:6
    13 DMAP CH3CN 25 36 46:54
    14 DMAP CH3CN 60 68 79:21
    15 DMAP CH3CN 81 50e 90:10
    a Reaction conditions: 1b (0.5 mmol), 2c (0.5 mmol), 3a (0.5 mmol), solvent (5 mL), and base (0.5 mmol), reflux for 10 h. b Isolated yield. c Determined by 1H NMR.d Reflux for 15 h. e 50 mol% DMAP

    Once the reaction conditions had been optimized (Table 1, Entry 8), the scope of this tandem reaction was explored with a wide array of pyrazolone 1 (0.5 mmol), aryl aldehyde 2 (0.5 mmol), and bromoacetic ester 3 (0.5 mmol). The results summarized in Table 2 show that all the reactions proceeded well to afford the desired products in goodtoexcellent yields (58%~89%) with excellent diastereoselectivities (6:1 to > 25:1 dr).

    Table 2

    Table 2.  Substrate scopea
    下载: 导出CSV
    Entry R1 R2 R3 4 Yieldb/% trans/cisc
    1 Ph 4-ClC6H4 Me 4a 62 6:1
    2 Ph 4-BrC6H4 Me 4b 67 8:1
    3 Ph 2-O2NC6H4 Me 4c 84 11:1
    4 Ph 2-ClC6H4 Me 4d 85 12:1
    5 Ph 2, 4-Cl2C6H4 Me 4e 79 10:1
    6 4-CH3C6H4 4-ClC6H4 Me 4f 62 15:1
    7 4-CH3C6H4 4-BrC6H4 Me 4g 65 11:1
    8 4-CH3C6H4 2-O2NC6H4 Me 4h 86 18:1
    9 4-CH3C6H4 2-ClC6H4 Me 4i 86 17:1
    10 4-CH3C6H4 2, 4-Cl2C6H4 Me 4j 80 15:1
    11 4-CH3C6H4 Ph Me 4k 65 6:1
    12 4-ClC6H4 4-ClC6H4 Me 4l 62 9:1
    13 4-ClC6H4 4-BrC6H4 Me 4m 66 8:1
    14 4-ClC6H4 2-O2NC6H4 Me 4n 58 > 25:1
    15 4-ClC6H4 2, 4-Cl2C6H4 Me 4o 82 15:1
    16 2-ClC6H4 4-ClC6H4 Me 4p 77 11:1
    17 2-ClC6H4 4-BrC6H4 Me 4q 78 12:1
    18 2-ClC6H4 2-O2NC6H4 Me 4r 83 18:1
    19 2-ClC6H4 2, 4-Cl2C6H4 Me 4s 80 13:1
    20 Ph 2, 4-Cl2C6H4 C(Me)3 4t 89 > 25:1
    21 4-CH3C6H4 2-O2NC6H4 C(Me)3 4u 87 > 25:1
    22 2-ClC6H4 2-O2NC6H4 C(Me)3 4v 87 > 25:1
    23 4-ClC6H4 2, 4-Cl2C6H4 C(Me)3 4w 85 > 25:1
    a Reaction conditions: pyrazolone 1 (0.5 mmol), aryl aldehyde 2 (0.5 mmol), bromoacetic esters 3 (0.5 mmol), and DMAP (0.5 mmol) in 5 mL of CH3CN, and refluxing for 10 h. b Isolated yield. c Determined by 1H NMR.

    The effect of substituent in different positions on the aromatic aldehyde was first explored, and the corresponding products were obtained in moderate yield for compounds 4a~4e. As shown in Table 2, aromatic aldehydes with adjacent substituents showed higher yields and diastereoselectivity than para-position substituents. 4-Cl and 2-Cl groups gave 4a and 4d in 62% and 85% yields, respectively. 4d had the higher dr (12:1) than 4a (6:1). When an electron donating group as CH3 or OCH3 is linked to aromatic aldehyde, the reaction is not ideal, so we can not get the pure product. Pyrazolones with 4-Me, 4-Cl, and the same aromatic aldehyde as above proceeded with 4-Cl and 4-Br (4f~4g, 4l~4m) generated much lower yields than those of products containing 2-NO2, 2-Cl and 2, 4-Cl2 (4h~4i, 4o). As for the diastereoselectivity, 4h~4i and 4o were obtained with excellent diastereoselectivity (> 15:1). However, compounds 4k and 4n were obtained in 65% and 58% yields, and the structure of 4n product converted to trans-isomers totally (> 25:1). Furthermore, the influence of pyrazolone on the reaction was further explored. Using pyrazolone bearing 2-Cl under standard conditions with different aromatic aldehydes, 4p~4s were obtained in 77%~83% yields. tert-Butyl bromoacetate was then used to prepare compounds 4t, 4u, 4v, and 4w in 85%~89% yield with excellent diastereoselectivities (> 25:1 dr), giving slightly better yields and dr than the methyl bromoacetate. To summarize, multi-substituted spirocyclopropanes have been obtained easily via one-pot reaction route in high yield and with excellent diastereoselectivities.

    Compound 4 was analyzed using NMR, HRMS, and IR spectroscopies. Single-crystal X-ray diffraction (Figure 2) was used to confirm the structure of compound 4c.

    Figure 2

    Figure 2.  X-ray crystal structures of compound 4c

    A plausible reaction mechanism for the synthesis of compound 4 by the one-pot multicomponent tandem reaction is shown in Scheme 2. At first, N-alkyl pyridinium A was obtained by the reaction of bromoacetic esters with DMAP. Intermediate C was smoothly formed by Knoevenagel condensation of the pyrazolones and aromatic aldehydes. The second step is Michael addition between intermediates A and C to generate the zwitterion D. An intramolecular cyclization finally results the ultimate compound 4. The reaction mechanism further explains that the stereoselectivity at the spirocyclic carbon is affected by the structure of the reac tants and reaction intermediates.

    Scheme 2

    Scheme 2.  Plausible reaction mechanism for the formation of spiropyrazolone cyclopropanes

    In summary, a simple and efficient approach for the synthesis of multi-substituted spirocyclo-propanepyra- zolones has been developed. Those derivatives were obtained in good yields and excellent diastereoselectivities via one-pot three-component cascade spirocyclopropanation reactions of bromoacetic esters, pyrazolones and aromatic aldehydes using DMAP as base. DMAP plays a significance role in forming a stabilized intermediate and in acquiring a good leaving group for the Micheal-initiated ring-closure reaction. This methodology has the advantages of easy operation, high isolated yields, and convenient work-up. This novel and effective methodology for the synthesis of spirocyclopropanes containing pyrazole in a stereoselective fashion will lead to works assessing and researching the biological and pharmacological activities of these fused nitrogen-containing heterocyclic compounds.

    Reagents and solvents were from Aladdin, TCI or Acros, and used without further purification. The progress of the reaction was examined by TLC using analytical-grade silica gel plates (GF-254). Column chromatography was carried out using silica gel (300~400 mesh). Infrared (IR) spectra were recorded on a Bruker Equinox 55 spectrophotometer using samples as KBr pellets. NMR spectra (1H NMR at 400 MHz, 13C NMR at 100 MHz) were obtained on a Bruker Inova-400 instrument using CDCl3 as solvent. Chemical shifts were relative to TMS as an internal standard. High-resolution mass spectrometry (HRMS) were obtained using a Micromass Q-TOF Global Tandem Mass Spectrometer.

    A mixture of bromoacetic esters (0.5 mmol), pyrazolone (0.5 mmol), aromatic aldehyde (0.5 mmol) and DMAP (0.5 mmol) in acetonitrile (5 mL) was refluxed for 10 h. After completion of the reaction, as monitored by thin-layer chromatography (TLC), the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. Finally, compounds 4a~4w were separated by purification through column chromatography (silica gel 300-400 mesh) using CH2Cl2 and petroleum ether (V:V=2:1~5:1) as the eluent.

    Methyl 2-(4-chlorophenyl)-4-methyl-7-oxo-6-phenyl-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4a): Light yellow solid, m.p. 190~192 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.81 (dd, J=8.8, 1.1 Hz, 2H), 7.39~7.27 (m, 4H), 7.24 (d, J=8.3 Hz, 2H), 7.15 (dd, J=10.6, 4.3 Hz, 1H), 3.96~3.76 (m, 4H), 3.35 (d, J=8.7 Hz, 1H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.08, 167.04, 156.09, 138.06, 134.20, 130.57, 129.29, 128.78, 128.53, 125.06, 118.55, 52.93, 44.85, 38.72, 37.43, 15.15; IR (film) v: 3083, 3024, 2958, 2843, 1721, 1721, 1592, 1524, 1452, 1381, 1352, 1262, 1163, 865, 771, 735, 699, 534, 508 cm-1; HRMS (TOF MS ES+) calcd for C20H18ClN2O3 [M+H]+ 369.1006, found 369.1002.

    Methyl 2-(4-bromophenyl)-4-methyl-7-oxo-6-phenyl-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4b): Light yellow solid, m.p. 188~190 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88~7.75 (m, 2H), 7.49~7.41 (m, 2H), 7.38~7.30 (m, 2H), 7.21~7.11 (m, 3H), 3.87 (d, J=8.7 Hz, 1H), 3.83 (s, 3H), 3.35 (d, J=8.7 Hz, 1H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.02, 166.99, 156.02, 138.03, 131.43, 130.85, 129.81, 128.74, 125.02, 122.37, 118.52, 52.89, 44.76, 38.73, 37.34, 15.10; IR (film) v: 3084, 3021, 2957, 2840, 1734, 1704, 1575, 1520, 1453, 1376, 1342, 1272, 1174, 871, 766, 734, 695, 534, 502 cm-1; HRMS (TOF MS ES+) calcd for C20H18BrN2O3 [M+H]+ 413.0500, found 413.0504.

    Methyl 4-methyl-2-(2-nitrophenyl)-7-oxo-6-phenyl-5, 6- diazaspiro[2.4]hept-4-ene-1-carboxylate (4c): yellow solid, m.p. 183~185 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.05 (dd, J=8.2, 1.2 Hz, 1H), 7.78~7.71 (m, 2H), 7.65 (td, J=7.6, 1.3 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.49 (m, 1H), 7.35~7.28 (m, 2H), 7.13 (m, 1H), 4.22 (d, J=8.6 Hz, 1H), 3.84 (s, 3H), 3.33 (d, J=8.7 Hz, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.77, 167.18, 156.69, 148.77, 137.92, 133.28, 132.06, 129.38, 128.68, 127.59, 125.14, 118.82, 52.95, 44.59, 37.83, 36.62, 14.94; IR (film) v: 3064, 3030, 2965, 2824, 1755, 1710, 1581, 1532, 1464, 1387, 1339, 1259, 1166, 880, 726, 731, 691, 535, 509 cm~1; HRMS (TOF MS ES+) calcd for C20H18N3O5 [M+H]+ 380.1241, found 380.1236.

    Methyl 2-(2-chlorophenyl)-4-methyl-7-oxo-6-phenyl-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4d): yellow solid, m.p. 172~174 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.91~7.74 (m, 2H), 7.43~7.26 (m, 6H), 7.15 (t, J=7.4 Hz, 1H), 3.98~3.80 (m, 4H), 3.35 (d, J=8.6 Hz, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.00, 167.04, 156.16, 138.14, 135.11, 130.74, 129.55, 129.17, 128.64, 126.51, 124.86, 118.62, 52.80, 44.33, 37.42, 15.02; IR (film) v: 3080, 3020, 2950, 2842, 1736, 1704, 1595, 1501, 1443, 1373, 1332, 1270, 1172, 873, 756, 736, 691, 538, 507 cm-1; HRMS (TOF MS ES+) calcd for C20H18ClN2O3 [M+H]+ 369.1000, found 369.0996.

    Methyl 2-(2, 4-dichlorophenyl)-4-methyl-7-oxo-6-phen- yl-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4e): Light yellow solid, m.p. 158~160 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.02~7.64 (m, 2H), 7.39~7.23 (m, 5H), 7.18~7.10 (m, 1H), 3.90~3.75 (m, 4H), 3.29 (d, J=8.6 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.84, 166.99, 156.10, 138.13, 135.83, 134.83, 131.65, 129.23, 128.79, 128.44, 127.02, 125.10, 118.71, 52.97, 44.29, 37.34, 36.77, 15.10; IR (film) v: 3085, 3017, 2957, 2839, 1731, 11697, 1601, 1510, 1442, 1374, 1342, 1275, 1162, 773, 762, 741, 694, 543, 508 cm-1; HRMS (TOF MS ES+) calcd for C20H17Cl2N2O3 [M+H]+ 403.0616, found 403.0614.

    Methyl 2-(4-chlorophenyl)-4-methyl-7-oxo-6-(p-tolyl)- 5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4f): Light yellow solid, m.p. 175~177 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.68 (d, J=8.6 Hz, 2H), 7.31~7.27 (m, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.3 Hz, 2H), 3.87 (d, J=8.6 Hz, 1H), 3.83 (s, 3H), 3.34 (d, J=8.7 Hz, 1H), 2.31 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.12, 166.84, 155.92, 135.64, 134.72, 134.13, 130.56, 129.31, 128.50, 118.56, 52.91, 44.80, 38.62, 37.36, 20.90, 15.13; IR (film) v: 3085, 3013, 2954, 2824, 1754, 1715, 1588, 1563, 1464, 1399, 1343, 1235, 1162, 884, 722, 735, 693, 534, 502 cm-1; HRMS (TOF MS ES+) calcd for C21H20ClN2O3 [M+H]+ 383.1157, found 383.1151.

    Methyl 2-(4-bromophenyl)-4-methyl-7-oxo-6-(p-tolyl)- 5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4g): Light yellow solid, m.p. 169~170 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.70~7.65 (m, 2H), 7.47~7.42 (m, 2H), 7.15 (m, 4H), 3.87~3.82 (m, 4H), 3.34 (d, J=8.6 Hz, 1H), 2.31 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.12, 166.85, 155.89, 135.67, 134.74, 131.45, 130.89, 129.92, 129.28, 122.37, 118.59, 52.90, 44.76, 38.68, 37.33, 20.91, 15.13; IR (film) v: 3065, 3028, 3036, 2954, 2935, 1752, 1688, 1575, 1506, 1445, 1378, 1333, 1293, 1166, 964, 856, 745, 684, 506 cm~1; HRMS (TOF MS ES+) calcd for C21H20BrN2O3 [M+H]+ 427.0651, found 427.0647.

    Methyl 4-methyl-2-(2-nitrophenyl)-7-oxo-6-(p-tolyl)- 5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4h): yellow solid, m.p. 180~183 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.05 (dd, J=8.2, 1.2 Hz, 1H), 7.69~7.58 (m, 3H), 7.55 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.12 (d, J=8.2 Hz, 2H), 4.22 (d, J=8.7 Hz, 1H), 3.85 (s, 3H), 3.32 (d, J=8.7 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.84, 167.01, 156.57, 148.78, 135.53, 134.82, 133.31, 132.10, 129.29, 127.68, 125.18, 118.89, 52.97, 44.56, 37.79, 36.58, 20.89, 14.96; IR (film) v: 3032, 3013, 2952, 2855, 1734, 1708, 1577, 1516, 1452, 1345, 1272, 1200, 1174, 821, 790, 729, 506 cm-1; HRMS (TOF MS ES+) calcd for C21H20N3O5 [M+H]+ 394.1397, found 394.1394.

    Methyl 2-(2-chlorophenyl)-4-methyl-7-oxo-6-(p-tolyl)- 5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4i): Light yellow solid, m.p. 165~168 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.82~7.63 (m, 2H), 7.44~7.24 (m, 4H), 7.16 (dd, J=8.8, 0.6 Hz, 2H), 4.00~3.74 (m, 4H), 3.35 (d, J=8.6 Hz, 1H), 2.32 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.10, 166.93, 156.05, 135.86, 135.17, 134.54, 130.83, 129.75, 129.55, 129.22, 126.57, 118.69, 52.84, 44.37, 37.42, 20.90, 15.08; IR (film) v: 3017, 2998, 2948, 2864, 1739, 1701, 1597, 1512, 1449, 1332, 1270, 1203, 1161, 821, 740, 696, 509 cm-1; HRMS (TOF MS ES+) calcd for C21H20ClN2O3 [M+H]+ 383.1157, found 383.1153.

    Methyl 2-(2, 4-dichlorophenyl)-4-methyl-7-oxo-6-(p- tolyl)-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4j): yellow solid, m.p. 158~160 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.75~7.63 (m, 2H), 7.35~7.23 (m, 3H), 7.20~7.12 (m, 2H), 3.82 (d, J=8.5 Hz, 4H), 3.29 (d, J=8.5 Hz, 1H), 2.32 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.76, 166.71, 155.79, 135.72, 134.62, 131.59, 129.14, 128.46, 126.89, 118.61, 52.81, 44.15, 37.16, 36.60, 20.82, 14.97; IR (film) v: 3019, 2955, 2925, 2861, 1738, 1695, 1592, 1511, 1450, 1329, 1277, 1103, 971, 871, 813, 649, 505 cm-1; HRMS (TOF MS ES+) calcd for C21H19Cl2N2O3 [M+H]+ 417.0767, found 417.0763.

    Methyl 4-methyl-7-oxo-2-phenyl-6-(p-tolyl)-5, 6-diaz- aspiro[2.4]hept-4-ene-1-carboxylate (4k): yellow solid, m.p. 118~120 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.80 (d, J=8.5 Hz, 2H), 7.47~7.26 (m, 5H), 7.20 (d, J=8.3 Hz, 2H), 3.96 (d, J=8.6 Hz, 1H), 3.82 (s, 3H), 3.32 (d, J=8.6 Hz, 1H), 2.35 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.55, 166.16, 156.05, 135.99, 134.60, 132.66, 129.33, 129.00, 128.52, 118.59, 52.82, 43.23, 40.15, 35.26, 20.93, 14.77; IR (film) v: 3029, 2956, 2924, 2851, 1745, 1685, 1588, 1521, 1454, 1323, 1267, 1110, 971, 873, 811, 644, 506 cm-1; HRMS (TOF MS ES+) calcd for C21H21N2O3 [M+H]+ 349.1552, found 349.1550.

    Methyl 2, 6-bis(4-chlorophenyl)-4-methyl-7-oxo-5, 6- diazaspiro[2.4]hept-4-ene-1- carboxylate (4l): Light yellow solid, m.p. 178~180 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.95~7.61 (m, 2H), 7.43~7.27 (m, 4H), 7.23 (d, J=8.3 Hz, 2H), 3.92~3.87 (m, 1H), 3.83 (s, 3H), 3.35 (d, J=8.7 Hz, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.94, 167.01, 156.43, 136.65, 134.30, 130.55, 130.08, 129.12, 128.80, 128.57, 119.60, 52.97, 44.84, 38.89, 37.53, 15.16; IR (film) v: 3101, 3012, 2953, 2924, 2853, 1754, 1698, 1583, 1493, 1455, 1337, 1275, 1173, 1087, 835, 732, 695, 503 cm-1; HRMS (TOF MS ES+) calcd for C20H17- Cl2N2O3 [M+H]+ 403.0616, found 403.0614.

    Methyl 2-(4-bromophenyl)-6-(4-chlorophenyl)-4-methyl- 7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4m): Light yellow solid, m.p. 170~172 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.87~7.70 (m, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.38~7.27 (m, 2H), 7.17 (d, J=8.3 Hz, 2H), 3.87 (d, J=8.7 Hz, 1H), 3.83 (s, 3H), 3.35 (d, J=8.7 Hz, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.92, 166.99, 156.42, 136.64, 131.50, 130.86, 130.10, 129.65, 128.81, 122.51, 119.60, 52.98, 44.78, 38.93, 37.47, 15.16; IR (film) v: 3100, 3022, 2913, 2954 2832, 1755, 1687, 1598, 1483, 1445, 1335, 1254, 1177, 1083, 830, 730, 693, 504 cm-1; HRMS (TOF MS ES+) calcd for C20H17BrClN2O3 [M+H]+ 447.0105, found 447.0101.

    Methyl 6-(4-chlorophenyl)-4-methyl-2-(2-nitrophenyl)- 7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4n): yellow solid, m.p. 185~187 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.06 (dd, J=8.2, 1.3 Hz, 1H), 7.75~7.60 (m, 3H), 7.58~7.49 (m, 2H), 7.20~7.04 (m, 2H), 4.22 (d, J=8.6 Hz, 1H), 3.86 (s, 3H), 3.32 (d, J=8.6 Hz, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.87, 167.01, 156.56, 148.81, 135.52, 134.85, 133.30, 132.09, 129.30, 128.76, 127.70, 125.22, 119.87, 118.92, 52.98, 44.57, 37.79, 36.58, 20.91, 14.97; IR (film) v: 3110, 3032, 2920, 2955, 2838, 1752, 1682, 1579, 1486, 1455, 1340, 1239, 1169, 1079, 832, 732, 691, 507 cm-1; HRMS (TOF MS ES+) calcd for C20H17ClN3O5 [M+H]+ 414.0856, found 414.0853.

    Methyl 6-(4-chlorophenyl)-2-(2, 4-dichlorophenyl)-4- methyl-7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4o): Light yellow solid, m.p. 165~167 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.87~7.67 (m, 2H), 7.39~7.19 (m, 5H), 3.83 (d, J=8.2 Hz, 4H), 3.27 (d, J=8.6 Hz, 1H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.58, 166.85, 156.32, 136.61, 135.69, 134.83, 131.50, 129.99, 129.14, 128.68, 128.18, 126.94, 119.62, 52.89, 44.16, 37.34, 36.81, 14.97; IR (film) v: 3113, 3001, 2952, 2923, 2851, 1744, 1697, 1593, 1491, 1451, 1330, 1275, 1171, 1090, 836, 738, 693, 509 cm-1; HRMS (TOF MS ES+) calcd for C20H16Cl3N2O3 [M+H]+ 437.0227, found 437.0223.

    Methyl 6-(2-chlorophenyl)-2-(4-chlorophenyl)-4-methyl- 7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4p): Light yellow solid, m.p. 159~161 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.45~7.41 (m, 1H), 7.37~7.33 (m, 1H), 7.30~7.25 (m, 6H), 3.95~3.81 (m, 4H), 3.37 (d, J=8.6 Hz, 1H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.10, 167.57, 156.19, 134.44, 134.20, 131.67, 130.50, 129.73, 129.58, 129.37, 129.16, 128.75, 128.44, 127.39, 52.95, 43.71, 38.76, 37.04, 15.19; IR (film) v: 3103, 3024, 2955, 2923, 2864, 1744, 1716, 1594, 1523, 1482, 1452, 1343, 1334, 1268, 1198, 1087, 865, 766, 733, 545 cm-1; HRMS (TOF MS ES+) calcd for C20H17Cl2N2O3 [M+H]+ 403.0610, found 403.0605.

    Methyl 2-(4-bromophenyl)-6-(2-chlorophenyl)-4-methyl- 7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4q): Light yellow solid, m.p. 169~170 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.43 (dt, J=4.5, 2.0 Hz, 3H), 7.37~7.33 (m, 1H), 7.33~7.26 (m, 2H), 7.19 (d, J=8.6 Hz, 2H), 3.95~3.80 (m, 4H), 3.37 (d, J=8.6 Hz, 1H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.08, 167.56, 156.18, 134.44, 131.66, 131.38, 130.92, 130.40, 129.78, 128.75, 127.40, 122.41, 52.96, 43.65, 38.80, 36.98, 15.19; IR (film) v: 3105, 3026, 2965, 2923, 2865, 1724, 1723, 1593, 1525, 1485, 1489, 1323, 1332, 1263, 1198, 1085, 866, 767, 736, 543 cm-1; HRMS (TOF MS ES+) calcd for C20H17Br- ClN2O3 [M+H]+ 447.0105, found 447.0099.

    Methyl 6-(2-chlorophenyl)-4-methyl-2-(2-nitrophenyl)- 7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4r): yellow solid, m.p. 182~184 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.06 (dd, J=8.2, 1.3 Hz, 1H), 7.60 (td, J=7.7, 1.3 Hz, 1H), 7.54 (s, 1H), 7.49~7.42 (m, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.31 (s, 1H), 7.29~7.23 (m, 2H), 4.28 (d, J=8.6 Hz, 1H), 3.92~3.80 (m, 3H), 3.35 (d, J=8.6 Hz, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.78, 156.97, 148.65, 134.40, 133.38, 132.30, 131.68, 130.28, 129.73, 129.44, 128.68, 127.74, 127.42, 125.22, 53.04, 43.35, 37.61, 36.80, 15.05; IR (film) v: 3101, 3023, 2952, 2926, 2860, 1737, 1711, 1596, 1525, 1487, 1450, 1348, 1330, 1270, 1183, 1092, 852, 764, 738, 549 cm-1; HRMS (TOF MS ES+) calcd for C20H17ClN3O5 [M+H]+ 414.0851, found 414.0847.

    Methyl 6-(2-chlorophenyl)-2-(2, 4-dichlorophenyl)-4- methyl-7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4s): Light yellow solid, m.p. 160~161 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.43 (dd, J=5.0, 4.4 Hz, 1H), 7.40~7.31 (m, 2H), 7.32~7.19 (m, 4H), 3.86 (s, 4H), 3.32 (d, J=8.5 Hz, 1H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.74, 167.38, 156.07, 135.73, 134.77, 134.38, 131.55, 130.34, 129.51, 129.06, 128.43, 128.22, 127.25, 126.81, 77.26, 76.94, 76.62, 52.89, 43.01, 36.80, 15.00; IR (film) v: 3095, 3032, 2894, 2952, 2862, 1738, 1721, 1585, 1555, 1459, 1457, 1343, 1334, 1286, 1175, 1089, 856, 765, 732, 541 cm-1; HRMS (TOF MS ES+) calcd for C20H16Cl3N2O3 [M+H]+ 437.0226, found 437.0221.

    tert-Butyl 2-(2, 4-dichlorophenyl)-4-methyl-7-oxo-6- phenyl-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4t): Light yellow solid, m.p. 151~153 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.94~7.81 (m, 2H), 7.39~7.22 (m, 5H), 7.19~7.10 (m, 1H), 3.81 (d, J=8.8 Hz, 1H), 3.25 (d, J=8.6 Hz, 1H), 2.29 (s, 3H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 167.11, 166.08, 156.24, 138.20, 135.81, 134.55, 131.68, 129.04, 128.66, 126.82, 124.86, 118.45, 83.13, 44.24, 38.67, 36.57, 27.94, 15.08; IR (film) v: 3077, 3002, 2979, 2933, 1734, 1707, 1594, 1502, 1486, 1438, 1372, 1333, 1206, 1148, 1051, 833, 752, 691, 498 cm-1; HRMS (TOF MS ES+) calcd for C23H23Cl2N2O3 [M+H]+ 445.1080, found 445.1075.

    tert-Butyl 4-methyl-2-(2-nitrophenyl)-7-oxo-6-(p-tolyl)- 5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4u): yellow solid, m.p. 177~179 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.64~7.48 (m, 2H), 7.42 (t, J=7.7 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 4.16 (d, J=8.7 Hz, 1H), 3.27 (d, J=8.7 Hz, 1H), 2.30 (d, J=6.2 Hz, 6H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 167.16, 166.10, 156.74, 148.83, 135.68, 134.49, 133.09, 132.10, 129.12, 127.80, 124.94, 118.61, 83.15, 44.54, 39.15, 36.35, 27.91, 20.80, 14.96; IR (film) v: 3081, 3031, 2969, 2925, 2859, 1732, 1706, 1577, 1518, 1448, 1371, 1342, 1212, 1152, 960, 816, 731, 507 cm-1; HRMS (TOF MS ES+) calcd for C24H26N3O5 [M+H]+ 436.1867, found 436.1863.

    tert-Butyl 6-(2-chlorophenyl)-4-methyl-2-(2-nitro phenyl)-7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4v): yellow solid, m.p. 165~167 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.04 (dd, J=8.2, 1.2 Hz, 1H), 7.57 (m, 2H), 7.47–7.14 (m, 5H), 4.23 (d, J=8.7 Hz, 1H), 3.28 (d, J=8.7 Hz, 1H), 2.27 (s, 3H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 167.88, 166.06, 157.12, 148.65, 134.42, 133.15, 132.25, 131.57, 130.17, 129.57, 129.21, 128.60, 127.83, 127.28, 125.01, 83.21, 43.27, 38.96, 36.58, 27.93, 15.00; IR (film) v: 3078, 3018, 2982, 2932, 2863, 1715, 1579, 1529, 1485, 1438, 1369, 1341, 1207, 1153, 1061, 838, 737, 542 cm~1; HRMS (TOF MS ES+) calcd for C23H23ClN3O5 [M+H]+ 456.1326, found 456.1322.

    tert-Butyl 6-(4-chlorophenyl)-2-(2, 4-dichlorophenyl)- 4-methyl-7-oxo-5, 6-diazaspiro[2.4]hept-4-ene-1-carboxylate (4w): Light yellow solid, m.p. 158~160 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~7.75 (m, 2H), 7.41 (d, J=1.9 Hz, 1H), 7.32 (m, 4H), 3.69 (d, J=8.7 Hz, 1H), 3.20 (d, J=8.7 Hz, 1H), 1.49 (s, 9H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.08, 163.89, 155.57, 136.9, 135.21, 130.60, 130.19, 129.76, 129.53, 128.72, 127.27, 119.50, 83.10, 42.86, 38.00, 36.71, 27.92, 14.34; IR (film) v: 3034, 3004, 2974, 2928, 1740, 1701, 1594, 1495, 1450, 1370, 1308, 1220, 1148, 1090, 828, 798, 540, 490 cm-1; HRMS (TOF MS ES+) calcd for C23H22Cl3N2O3 [M+H]+ 479.0690, found 479.0687.

    辅助材料(Supporting Information)  化合物4a~4w的核磁共振氢谱、碳谱.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.


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  • Scheme 1  Synthesis of spirocyclopropanes.

    Figure 1  Bioactive compounds containing cyclopropane unit

    Figure 2  X-ray crystal structures of compound 4c

    Scheme 2  Plausible reaction mechanism for the formation of spiropyrazolone cyclopropanes

    Table 1.  Optimization of the reaction conditionsa

    Entry Base Solvent Temp./℃ Yieldb/% transc/cis
    1 No base CH3CN 81 NR NR
    2 NaOH CH3CN 81 41 45:55
    3 Cs2CO3 CH3CN 81 48 48:52
    4 Pyridine CH3CN 81 82c 72:28
    5 TEBA CH3CN 81 56 80:20
    6 CTAB CH3CN 81 60 85:15
    7 DABCO CH3CN 81 70 72:28
    8 DMAP CH3CN 81 86 94:6
    9 DMAP CH2Cl2 81 65 40:60
    10 DMAP H2O 100 Trace NR
    11 DMAP CH3CO2Et 81 78 88:12
    12 DMAP CH3CN 81 86d 94:6
    13 DMAP CH3CN 25 36 46:54
    14 DMAP CH3CN 60 68 79:21
    15 DMAP CH3CN 81 50e 90:10
    a Reaction conditions: 1b (0.5 mmol), 2c (0.5 mmol), 3a (0.5 mmol), solvent (5 mL), and base (0.5 mmol), reflux for 10 h. b Isolated yield. c Determined by 1H NMR.d Reflux for 15 h. e 50 mol% DMAP
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    Table 2.  Substrate scopea

    Entry R1 R2 R3 4 Yieldb/% trans/cisc
    1 Ph 4-ClC6H4 Me 4a 62 6:1
    2 Ph 4-BrC6H4 Me 4b 67 8:1
    3 Ph 2-O2NC6H4 Me 4c 84 11:1
    4 Ph 2-ClC6H4 Me 4d 85 12:1
    5 Ph 2, 4-Cl2C6H4 Me 4e 79 10:1
    6 4-CH3C6H4 4-ClC6H4 Me 4f 62 15:1
    7 4-CH3C6H4 4-BrC6H4 Me 4g 65 11:1
    8 4-CH3C6H4 2-O2NC6H4 Me 4h 86 18:1
    9 4-CH3C6H4 2-ClC6H4 Me 4i 86 17:1
    10 4-CH3C6H4 2, 4-Cl2C6H4 Me 4j 80 15:1
    11 4-CH3C6H4 Ph Me 4k 65 6:1
    12 4-ClC6H4 4-ClC6H4 Me 4l 62 9:1
    13 4-ClC6H4 4-BrC6H4 Me 4m 66 8:1
    14 4-ClC6H4 2-O2NC6H4 Me 4n 58 > 25:1
    15 4-ClC6H4 2, 4-Cl2C6H4 Me 4o 82 15:1
    16 2-ClC6H4 4-ClC6H4 Me 4p 77 11:1
    17 2-ClC6H4 4-BrC6H4 Me 4q 78 12:1
    18 2-ClC6H4 2-O2NC6H4 Me 4r 83 18:1
    19 2-ClC6H4 2, 4-Cl2C6H4 Me 4s 80 13:1
    20 Ph 2, 4-Cl2C6H4 C(Me)3 4t 89 > 25:1
    21 4-CH3C6H4 2-O2NC6H4 C(Me)3 4u 87 > 25:1
    22 2-ClC6H4 2-O2NC6H4 C(Me)3 4v 87 > 25:1
    23 4-ClC6H4 2, 4-Cl2C6H4 C(Me)3 4w 85 > 25:1
    a Reaction conditions: pyrazolone 1 (0.5 mmol), aryl aldehyde 2 (0.5 mmol), bromoacetic esters 3 (0.5 mmol), and DMAP (0.5 mmol) in 5 mL of CH3CN, and refluxing for 10 h. b Isolated yield. c Determined by 1H NMR.
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  • 收稿日期:  2019-04-10
  • 修回日期:  2019-06-11
  • 网络出版日期:  2019-11-25
通讯作者: 陈斌, bchen63@163.com
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