English

• 1.   Introduction

  The pyrazole and γ-pyrone scaffolds are frequently-occurring motifs in many biologically active compounds.^[1] In addition, their derivatives have found widespread applications in the fields of medicinal chemistry and synthetic chemistry.^[2] According to the results disclosed in literature, ^[3] the incorporation of γ-pyrone ring motifs into the pyrazole skeleton can contribute to the biological activity of parent molcule. Pyrano[3, 2-c]pyrazol-7(1H)-one represents an unusual example of a γ-pyranone-fused pyrazole ring. However, the pyranopyrazole ring is rarely known, ^[4~6] and practical and effective synthetic protocols and guide-lines for their construction are extremely lack. The general method for preparing the known pyrano[3, 2-c]pyrazole skeleton (A) (Figure 1) relies on a two-step synthetic process, which Gelin et al.^[5] have described. One-pot synthesis of 7H-pyrazolo[5, 1-b]^{[1, 3]}-oxazin-7-one (B) from pyrazolone and 2-propiolic acid has been disclosed.^[4] Recently, we reported an elegant con-struct of pyrano[3, 2-c]pyrazol-7(1H)-one skeleton (C) (Figure 1).^[7] The incorporation of a phosphonyl group on the pyrano[3, 2-c]pyrazol-7(1H)-one moiety at the position 3 of the core structure represents a novel substituted heterocyclic compound. Thus, the investigation on synthesizing them became our objective due to the wide application of phosphonate in pharmaceuticals^[8] and inhibitors.^[9]

  Figure 1

  

  Figure 1.  Structure of g-pyranone-fused pyrazole

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  We proposed a three-step synthetic pathway, involving an aldol condensation-oxidation-cyclization sequence (Scheme 1). Synthesis of intermediates 3 and 1 has been outlined (see Supporting Information). In this protocol, the transformation of compound 1 to target molecular 2 is a key step. We conduct our investigation by optimizing the reaction conditions for this transformation.

  Scheme 1

  

  Scheme 1.  Retrosynthetic approach for the preparation of 3-phosphonyl pyrano[3, 2-c]pyrazol-7(1H)-one (2)

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  2.   Results and discussion

  First, dimethyl 1-diazo-2, 4-dioxo-6-phenylhex-5-ynyl phosphonate (1a) was treated in the presence of different bases in certain solvent at 25 ℃ (Table 1). To our delight, when employing LiOH as base in MeOH, the reaction proceeded smoothly to cleanly afford the expected product 2a in 70% yield (Table 1, Entry 1). This result encouraged us to further attempt the reaction optimization. For other strong bases such as NaOH, KOH, MeONa and t-BuOK, the product 2a was obtained in only 57%~78% yields (Table 1, Entries 2~5). After screening several weak bases such as K₂CO₃, pyridine, i-Pr₂NEt, 1, 8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and Et₃N (TEA) (Table 1, Entries 6~10), we found that 3 equiv. of TEA afforded the best result (up to 99% yield) (Table 1, Entry 10). It was noteworthy that worse result was obtained when this reaction was carried out with a less loading of Et₃N (1 or 2 equiv.) (Table 1, Entries 11~12), while increased loading of Et₃N (up to 4 equiv.) did not perfect the process (Table 1, Entry 13).

  Table 1

  

  Table 1.  Base and solvent screening for dimethyl 7-oxo-5-phenyl-1, 7-dihydropyrano[3, 2-c]pyrazol-3-ylphosphonate (2a) from dimethyl 1-diazo-2, 4-dioxo-6-phenylhex-5-ynylphosphon-ate (1a) ^a

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  Entry	Base (equiv.)	Reaction time/h	Solvent	Yieldb/%
  1	LiOH (3)	12	MeOH	70
  2	NaOH (3)	12	MeOH	61
  3	KOH (3)	10	MeOH	78
  4	MeONa (3)	10	MeOH	70
  5	t-BuOK (3)	10	MeOH	57
  6	K2CO3 (3)	12	MeOH	67
  7	Pyridine (3)	48	MeOH	54c, d
  8	i-Pr2NEt (3)	9	MeOH	78
  9	DBU (3)	8	MeOH	93
  10	Et3N (3)	8	MeOH	99
  11	Et3N (1)	8	MeOH	81
  12	Et3N (2)	8	MeOH	94
  13	Et3N (4)	8	MeOH	99
  14	Et3N (3)	9	1, 4-Dioxane	93
  15	Et3N (3)	10	MeCN	77
  16	Et3N (3)	8	DCM	56c, d
  17	Et3N (3)	12	DCE	53c, d
  18	Et3N (3)	20	DMF	41c, d
  19	Et3N (3)	19	DMSO	50c, d
  20	Et3N (3)	23	Toluene	44c, d
  21	Et3N (3)	19	THF	47c, d
  a Reaction conditions: 1-diazo-2, 4-dioxo-5-ynylphosphonate (1a) (0.2 mmol), solvent (3 mL), 25 ℃. b Isolated yield. c Unknown by-product was formed. d The starting material was recovered.

  Next, the influence of solvent on the reaction was examined at 25 ℃ in the presence of TEA (3 equiv.). For 1, 4-dioxane and MeCN, clean reactions were carried out albeit with lower reactivity (Table 1, Entries 14 and 15). CH₂Cl₂ (DCM), C₂H₄Cl₂ (DCE), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene and tetrahydrofuran (THF) gave the desired product 2a with lower reactivity and/or in low yields due to the formation of unknown by product and recovery of the raw material (Table 1, Entries 16~21). MeOH was found to be the best one among the tested solvents (Table 1, Entry 10). Therefore, the optimized reaction conditions are the following: Et₃N (3 equiv.) in MeOH (Table 1, Entry 10).

  With the optimized conditions, we studied the scope of the new tandem reaction sequence (Table 2). In the case of R＝OMe, the effect of the substituent R¹ appended to the acetylenic moiety on the reaction was first exploited. For phenyl and alkylphenyl groups, the desired product was cleanly afforded in 95%~99% yields (Table 2, Entries 1~3). When R¹ is a substituted aryl bearing a group, such as fluoro, chloro or methoxyl at the 4-position of benzene ring, the reaction was cleanly performed in a slightly higher reactivity (Table 2, Entries 4~6). For vinyl group, slightly lower yield was observed with the comparison of that being obtained in the case of R¹＝aryl group (Table 2, Entry 7). For an aromatic heterocyclic group, the desired product was also obtained not only in a relatively long time but also in very low yield (Table 2, Entry 8), and unreacted material can been recycled. For alkyl and cyclopropyl group, the reaction proceeded in excellent yield (up to 90%) (Table 2, Entries 10 and 11). Next, the effect of R¹ on the reaction was investigated when R was changed from methoxyl group to phenyl group, and similar results were obtained (Table 2, Entries 12~19). However, the substituent Et₃Si (R¹) displayed a distinctly unfavorable effect on the reactivity (Table 2, Entries 9 and 19). Strangely, for substrate 1s, Et₃Si group was present in product 2s, but the removal of Et₃Si group occurred in the transformation of substrate 1i into product. The structure of product 2 was finally established by single-crystal X-ray diffraction analysis of products 2b (CCDC 1573359) (Figure 2).

  Table 2

  

  Table 2.  Scope of the cascade reaction of substrate 1^a

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  Entry	R1/R (1)	Product 2	t/h	Yieldb/%
  1	Ph/OMe (1a)	2a	8	99
  2	p-MeC6H4/OMe (1b)	2b	15	95
  3	p-PrnC6H4/OMe (1c)	2c	14	95
  4	p-FC6H4/OMe (1d)	2d	12	93
  5	p-ClC6H4/OMe (1e)	2e	11	91
  6	p-MeOC6H4/OMe (1f)	2f	10	96
  7	(E)-Cinnamenyl/OMe (1g)	2g	14	81
  8	3-Thienyl/OMe (1h)	2h	16	58 c
  9	Trietylsilyl/OMe (1i)	2i (R 1＝H)	17	60 c
  10	n-Bu/OMe (1j)	2j	12	88
  11	Cyclopropyl/OMe (1k)	2k	10	90
  12	Ph/Ph (1l)	2l	12	85
  13	p-MeC6H4/Ph (1m)	2m	10	86
  14	p-PrnC6H4/Ph (1n)	2n	10	88
  15	p-FC6H4/Ph (1o)	2o	11	82
  16	p-ClC6H4/Ph (1p)	2p	11	84
  17	n-Bu/Ph (1q)	2q	9	80
  18	Cyclopropyl/Ph (1r)	2r	19	77
  19	Et3Si/Ph (1s)	2s	17	48 c
  a Reaction conditions: substrate 1 (0.2 mmol), TEA (3.0 equiv.) in MeOH (3 mL) at 25 ℃. b Isolated yield by column chromatography. c The starting material was recovered.

  Figure 2

  

  Figure 2.  X-ray crystal structure of product 2b

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  On the basis of these results, we conclude that the reaction might be conducted through a cascade 6-p electrocyclic ring closure-intramolecular Michael addition sequence (Scheme 2).^[7] First, carbanion Ⅰ was generated by using TEA as base. The reaction might be initiated by 6-π electrocyclic ring closure^[10] of the intermediate Ⅰ to give an enolate oxygen anion Ⅱ. Subsequent intramolecular Michael addition of the enolate oxygen anion Ⅱ to carbon-carbon triple bond resulted in the formation of carbanion Ⅲ. The protonation of Ⅲ provided the intermediate Ⅳ. Finally, ^{[1, 5]}-hydrogen migration of Ⅳ proceeded to afford product 2.

  Scheme 2

  

  Scheme 2.  Possible mechanism

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  3.   Conclusions

  In summary, a concise construction of novel 3-phosphonyl pyrrolopyrazole skeleton has been presented for the first time. It has several advantages of mild reaction conditions, simple manipulation and 100% atom-economy from 1-diazo-2, 4-dioxo-5-ynylphosphonate 1.

  4.   Experimental section

  4.1   General

  All reagents were purchased from commercial suppliers (Energy Chemical and Tansoole) and they were used without further purification unless otherwise noted. Dry DCM and dry THF were obtained by treatment with CaH₂ and sodium, respectively, and distilled prior to use. The compounds were analyzed by Thermo Science ISQGC-MS and isolated by column chromatography using a hexane-petroleum ether-ethyl acetate eluent. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance-500 Spectrometer in CDCl₃ or DMSO-d₆ solution using tetramethylsilane as an internal standard. X-ray data were taken on a Rigaku Supernova diffractometer equipped with an EOS S2 CCD detector. HRMS were performed on a Thermo Scientific LTQ Qrbitrap XL mass spectrometer (ESI). Melting points were determined by using an Electrothermal Melting Point Apparatus YRT-3. For chromatographic purification, 200~300 mesh silica gel (Qingdao, China) was employed. For thin layer chromatography (TLC) analysis throughout this work, Merck 25 TLC aluminium sheets (silica gel 60 GF254, 0.25 mm) were used. Infrared spectra (IR) were recorded on a Bruker Vector 22 FT-IR spectrophotometer and are reported as wavelength numbers (cm^-1).

  4.2   Typical procedure for oxidation of compound 1 for synthesis of compound 2

  General experimental information: A solution of compound 1a (0.2 mmol, 64 mg) in methanol (3 mL) was syringed into a stirring mixture of trimethylamine (TEA) (0.6 mmol, 61 mg) at 25 ℃. The reaction mixture was stirred for another 12 h and then quenched with saturated aqueous NH₄Cl. The water layer was extracted with chloroform (30 mL×3). Collected organic layers were dried over Na₂SO₄, concentrated in vacuum and then purified by flash chromatography to afford product.

  Dimethyl  (7-oxo-5-phenyl-1, 7-dihydropyrano[3, 2-c]-pyrazol-3-yl)phosphonate (2a): Pale solid (60 mg, yield 94%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]. m.p. 191~192 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.11 (br, 1H), 8.02~8.00 (m, 2H), 7.60~7.59 (m, 3H), 7.08 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.44, 162.99, 148.52, 148.38, 132.11, 131.15, 129.58, 129.36, 126.68, 108.77, 53.84 (d, J_C-P＝5.4 Hz), 53.80 (d, J_C-P＝5.4 Hz); IR (KBr) ν: 3627, 3065, 2957, 1896, 1653, 1546, 1454, 1401, 1331, 1261, 1164, 1032, 908, 842, 767, 675, 628, 563 cm^-1. HRMS (ESI) calcd for C₁₄H₁₄N₂O₅P (M+H)⁺ 321.0634, found 321.0634.

  Dimethyl  (7-oxo-5-(p-tolyl)-1, 7-dihydropyrano[3, 2-c]-pyrazol-3-yl)phosphonate (2b): Pale solid (63 mg, yield 95%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]; m.p. 192~193 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.19 (br, 1H), 7.82 (d, J＝7.5 Hz, 2H), 7.32 (d, J＝7.5 Hz, 2H), 6.92 (s, 1H), 3.82 (d, J＝11.4 Hz, 6H), 2.33 (s, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.87, 163.24, 148.42, 148.28, 142.49, 131.79, 130.20, 128.29, 126.61, 108.03, 53.85, 53.80, 21.38; IR (KBr) ν: 3420, 2957, 2923, 1652, 1557, 1537, 1459, 1264, 1027, 824, 760 cm^-1. HRMS (ESI) calcd for C₁₅H₁₆N₂O₅P (M+H)⁺ 335.0791, found 335.0791.

  Dimethyl(7-oxo-5-(4-propylphenyl)-1, 7-dihydropyrano-[3, 2-c]pyrazol-3-yl)phosphonate (2c): Pale solid (69 mg, yield 95%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]. m.p. 186~187 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 14.36 (br, 1H), 7.84 (d, J＝8.0 Hz, 2H), 7.31 (d, J＝8.0 Hz, 2H), 6.90 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 2.66 (t, J＝7.5 Hz, 2H), 1.69~1.65 (m, 2H), 0.95 (t, J＝7.5 Hz, 3H); ¹³C NMR (125.8 MHz, CDCl₃) δ: 170.42, 164.87, 149.15, 149.01, 147.44, 129.33, 128.79, 128.25, 126.60, 107.78, 53.79 (d, J_C-P＝5.9 Hz), 53.74 (d, J_C-P＝5.9 Hz), 37.87, 24.17, 13.71. IR (KBr) ν: 3620, 3057, 2956, 1896, 1707, 1642, 1547, 1459, 1426, 1329, 1265, 1218, 1160, 1012, 911, 842, 805, 763, 675, 540 cm^-1. HRMS (ESI) calcd for C₁₇H₂₀N₂O₅P (M+H)⁺ 363.1104, found 363.1104.

  Dimthyl(5-(4-fluorophenyl)-7-oxo-1, 7-dihydropyrano[3, 2-c]pyrazol-3-yl)phosphonate (2d): Pale solid (62 mg, yield 91%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]. m.p. 210~212 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.04 (br, 1H), 8.01 (s, 2H), 7.36 (s, 2H), 7.00 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.75, 164.49 (d, J_C-F＝249.2 Hz), 161.98, 148.46, 148.32, 129.33, 129.26, 127.73, 116.70 (d, J_C-F＝21.9 Hz), 108.69, 53.81 (d, J_C-P＝5.2 Hz), 53.76 (d, J_C-P＝5.2 Hz); IR (KBr) ν: 3621, 2954, 1640, 1744, 1532, 1511, 1459, 1423, 1328, 1229, 1159, 999, 906, 838, 798, 752, 668, 570, 533 cm^-1. HRMS (ESI) calcd for C₁₄H₁₃FN₂O₅P (M+H)⁺ 339.0540, found 339.0540.

  Dimthyl(5-(4-chlorophenyl)-7-oxo-1, 7-dihydropyrano-[3, 2-c]pyrazol-3-yl)phosphonate (2e): Pale solid (66 mg, yield 93%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]. m.p. 201~203 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.11 (br, 1H), 8.02 (d, J＝8.7 Hz, 2H), 7.66 (d, J＝8.7 Hz, 2H), 7.12 (s, 1H), 3.82 (s, 3H), 3.79 (s, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.31, 161.80, 148.50, 148.35, 137.04, 130.15, 129.79, 128.53, 126.98, 109.21, 53.84 (d, J_C-P＝5.6 Hz), 53.79 (d, J_C-P＝5.6 Hz); IR (KBr) ν: 3642, 3051, 2951, 2840, 1692, 1639, 1548, 1458, 1410, 1387, 1258, 1218, 1188, 1090, 1046, 1003, 907, 870, 830, 767, 677, 543 cm^-1. HRMS (ESI) calcd for C₁₄H₁₃ClN₂O₅P (M+H)⁺ 355.0245, found 355.0245.

  Dimethyl(5-(4-methoxyphenyl)-7-oxo-1, 7-dihydropy-rano[3, 2-c]pyrazol-3-yl)phosphonate (2f): Pale solid (67 mg, yield 96%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]. m.p. 194~195 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.05 (br, 1H), 7.96 (d, J＝8.8 Hz, 2H), 7.12 (d, J＝8.8 Hz, 2H), 6.96 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 163.14, 162.56, 148.38, 148.24, 128.59, 123.36, 115.17, 107.24, 55.98, 53.81 (d, J_C-P＝5.6 Hz), 53.76 (d, J_C-P＝5.6 Hz); IR (KBr) ν: 3621, 2957, 2846, 1896, 1741, 1633, 1600, 1545, 1506, 1460, 1431, 1298, 1255, 1219, 1175, 1072, 1012, 908, 833, 796, 667, 589, 531 cm^-1. HRMS (ESI) calcd for C₁₅H₁₆N₂O₆P (M+H)⁺ 351.0740, found 351.0740.

  (E)-Dimethyl (7-oxo-5-styryl-1, 7-dihydropyrano[3, 2-c]-pyrazol-3-yl)phosphonate (2g): Pale solid (56 mg, yield 81%). R_f＝0.4 [V(EtOAc):V(MeOH)＝10:1]. m.p. 239~240 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.03 (br, 1H), 7.68 (d, J＝7.2 Hz, 2H), 7.49~7.40 (m, 4H), 7.28 (d, J＝16.2 Hz, 1H), 6.53 (s, 1H), 3.84 (d, J＝11.5 Hz, 6H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.39, 162.12, 148.19, 148.05, 136.53, 135.17, 130.25, 129.97, 129.40, 128.19, 120.69, 111.91, 53.85, 53.80; IR (KBr) ν: 3506, 3447, 3383, 1633, 1559, 1384, 1216, 1189, 1133, 1049, 1015, 690, 565 cm^-1. HRMS (ESI) calcd for C₁₆H₁₆N₂O₅P (M+H)⁺ 347.0791, found 347.0791.

  Dimethyl (7-oxo-5-(thiophen-3-yl)-1, 7-dihydropyrano-[3, 2-c]pyrazol-3-yl)phosphonate (2h): Pale solid (38 mg, yield 58%). R_f＝0.4 [V(EtOAc):V(MeOH)＝10:1]. m.p. 185~186 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.10 (br, 1H), 8.26 (s, 1H), 7.74~7.73 (m, 1H), 7.67 (d, J＝5.0 Hz, 1H), 6.95 (s, 1H), 3.84 (d, J＝11.4 Hz, 6H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.67, 159.59, 148.15, 148.01, 133.52, 129.02, 128.49, 128.39, 125.86, 108.31, 53.85, 53.81; IR (KBr) ν: 3673, 2956, 1651, 1598, 1555, 1457, 1419, 1317, 1253, 1034, 863, 843, 798, 570 cm^-1. HRMS (ESI) calcd for C₁₂H₁₂N₂O₅PS (M+H)⁺ 327.0199, found 327.0198.

  Dimethyl (7-oxo-1, 7-dihydropyrano[3, 2-c]pyrzol-3-yl)-phosphonate (2i): Pale solid (29 mg, yield 60%). R_f＝0.4 [V(EtOAc):V(MeOH)＝10:1]. m.p. 161~162 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.02 (br, 1H), 8.27 (d, J＝5.9 Hz, 1H), 6.38 (d, J＝5.9 Hz, 1H), 3.78 (d, J＝11.4 Hz, 6H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.16, 156.57, 148.59, 148.45, 130.49, 113.70, 53.72, 53.67; IR (KBr) ν: 3650, 2956, 1519, 1459, 1248, 1025, 832, 763, 652 cm^-1. HRMS (ESI) calcd for C₈H₁₀N₂O₅P (M+H)⁺245.0321, found 245.0321.

  Dimethyl (5-butyl-7-oxo-1, 7-dihydropyrano[3, 2-c]pyra-zol-3-yl)phosphonate (2j): Pale solid (53 mg, yield 88%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]. m.p. 175~177 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 14.99 (br, 1H), 6.26 (s, 1H), 3.78 (s, 6H), 2.69 (s, 2H), 1.64 (s, 2H), 1.35 (s, 2H), 0.90 (s, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 170.07, 148.67, 148.53, 129.64, 126.63, 110.73, 53.72, 53.67, 32.97, 29.07, 21.84, 13.88; IR (KBr) ν: 3508, 3447, 3378, 1652, 1384, 1216, 1190, 1133, 1049, 689, 565, 524 cm^-1. HRMS (ESI) calcd for C₁₂H₁₈N₂O₅P (M+H)⁺301.0947, found 301.0947.

  Dimethyl (5-cyclopropyl-7-oxo-1, 7-dihydropyrano[3, 2-c]pyrazol-3-yl)phosphonate (2k): Pale solid (51 mg, yield 90%). R_f＝0.3 [V(CH₂Cl₂):V(EtOAc)＝1:2]. m.p. 172~173 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 14.92 (br, 1H), 6.34 (s, 1H), 3.76 (d, J＝11.4 Hz, 6H), 2.15~2.12 (m, 1H), 1.12~1.05 (m, 4H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 170.46, 168.83, 148.09, 147.95, 129.78, 108.63, 53.70, 53.66, 14.10, 9.23. IR (KBr) ν: 3432, 3000, 2915, 1651, 1599, 1558, 1533, 1437, 1407, 1333, 1252, 1029, 948, 840, 764, 667, 584 cm^-1. HRMS (ESI) calcd for C₁₁H₁₄N₂O₅P (M+H)⁺ 285.0634, found 285.0634.

  3-(Diphenylphosphoryl)-5-phenylpyrano[3, 2-c]pyrazol-7(1H)-one (2l): Yellow solid (70 mg, yield 85%). R_f＝0.5 [V(EtOAc):V(MeOH)＝10:1]. m.p. 219~220 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.13 (br, 1H), 7.90~7.87 (m, 4H), 7.70~7.67 (m, 2H), 7.61~7.59 (m, 4H), 7.51~7.49 (m, 1H), 7.41~7.38 (m, 4H), 7.04 (s, 1H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.51, 162.62, 148.72 (d, J_C-P＝13.5 Hz), 132.83, 132.13, 131.94 (d, J_C-P＝10.0 Hz), 131.70, 131.33, 130.65 (d, J_C-P＝148.2 Hz), 130.84, 129.30 (d, J_C-P＝14.0 Hz), 126.52, 125.95, 108.55. IR (KBr): 3420, 2956, 2926, 2854, 1652, 1491, 1452, 1438, 1328, 1288, 1201, 1164, 1121, 1099, 1027, 997, 908, 757, 704, 661, 626, 551, 528 cm^-1. HRMS (ESI) calcd for C₂₄H₁₈N₂-O₃P (M+H)⁺ 413.1049, found 413.1047.

  3-(Diphenylphosphoryl)-5-(p-tolyl)pyrano[3, 2-c]pyra-zol-7(1H)-one (2m): Yellow solid (73 mg, yield 86%). R_f＝0.5 [V(EtOAc):V(MeOH)＝10:1]. m.p. 234~235 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.05 (br, 1H), 7.89~7.83 (m, 3H), 7.79~7.75 (m, 1H), 7.71~7.68 (m, 2H), 7.62~7.55 (m, 4H), 7.32~7.22 (m, 4H), 6.99 (s, 1H), 2.35 (s, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 162.85, 142.44, 132.26 (d, J_C-P＝121.7 Hz), 132.75, 131.92 (d, J_C-P＝10.0 Hz), 131.70, 131.28 (d, J_C-P＝10.0 Hz), 130.16, 129.97, 129.42, 129.28 (d, J_C-P＝12.0 Hz), 128.06, 126.47, 107.85, 21.41; IR (KBr) ν: 3650, 2956, 2925, 2853, 1651, 1540, 1508, 1458, 1397, 1285, 1165, 1121, 1027, 1002, 827, 762, 634, 548 cm^-1. HRMS (ESI) calcd for C₂₅H₂₀N₂O₃P (M+H)⁺ 427.1206, found 427.1205.

  3-(Diphenylphosphoryl)-5-(4-propylphenyl)pyrano[3, 2-c]pyrazol-7(1H)-one (2n): Yellow solid (80 mg, yield 88%). R_f＝0.5 (EtOAc). m.p. 236~238 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.13 (br, 1H), 7.89~7.85 (m, 4H), 7.70~7.60 (m, 6H), 7.32 (d, J＝7.8 Hz, 2H), 7.21 (d, J＝7.8 Hz, 2H), 6.96 (s, 1H), 2.57 (t, J＝7.2 Hz, 2H), 1.59~1.55 (m, 2H), 0.87 (t, J＝7.2 Hz, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.46, 162.94, 148.77 (d, J_C-P＝13.7 Hz), 146.76, 133.57, 132.78, 131.93 (d, J_C-P＝10.0 Hz), 131.32, 131.24 (d, J_C-P＝139.6 Hz), 130.12, 129.22 (d, J_C-P＝12.9 Hz), 128.25, 126.46, 107.89, 37.38, 24.05, 13.93; IR (KBr) ν: 3510, 3054, 2957, 2928, 2868, 1652, 1555, 1528, 1438, 1292, 1121, 1024, 999, 909, 727, 703, 550, 529 cm^-1. HRMS (ESI) calcd for C₂₇H₂₄N₂O₃P (M+H)⁺ 455.1519, found 455.1518.

  3-(Diphenylphosphoryl)-5-(4-fluorophenyl)pyrano[3, 2-c]pyrazol-7(1H)-one (2o): Yellow solid (71 mg, yield 82%). R_f＝0.5 [V(EtOAc):V(MeOH)＝8:1]. m.p. 248~250 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.11 (br, 1H), 7.89~7.85 (m, 4H), 7.71~7.68 (m, 2H), 7.62~7.59 (m, 4H), 7.47~7.46 (m, 2H), 7.27 (t, J＝8.8 Hz, 2H), 7.03 (s, 1H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.42, 164.48 (d, J_C-F＝249.3 Hz), 161.66, 148.68 (d, J_C-F＝14.6 Hz), 133.69, 132.85, 131.94 (d, J_C-F＝10.0 Hz), 129.96, 129.29 (d, J_C-P＝12.2 Hz), 129.15 (d, J_C-P＝9.0 Hz), 127.43, 116.47 (d, J_C-F＝21.9 Hz), 108.49; IR (KBr) ν: 3650, 2959, 1640, 1594, 1546, 1524, 1485, 1452, 1412, 1282, 1259, 1188, 1120, 1094, 1038, 1013, 909, 860, 835, 728, 703, 691, 670 cm^-1. HRMS (ESI) calcd for C₂₄H₁₇FN₂O₃P (M+H)⁺ 431.0955, found 431.0955.

  5-(4-Chlorophenyl)-3-(diphenylphosphoryl)pyrano[3, 2-c]pyrazol-7(1H)-one (2p): Pale solid (75 mg, yield 84%). R_f＝0.4 [V(EtOAc):V(MeOH)＝10:1]. m.p. 240~242 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.11 (br, 1H), 7.89~7.85 (m, 4H), 7.71~7.69 (m, 2H), 7.62~7.61 (m, 4H), 7.50~7.48 (m, 2H), 7.42~7.40 (m, 2H), 7.06 (s, 1H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.37, 161.42, 148.68 (d, J_C-P＝12.5 Hz), 137.02, 133.77, 132.84, 132.54 (d, J_C-P＝109.0 Hz), 131.94 (d, J_C-P＝10.2 Hz), 129.96, 129.81, 129.48, 129.28 (d, J_C-P＝12.2 Hz), 128.30, 108.97; IR (KBr) ν: 3649, 2957, 1632, 1594, 1546, 1529, 1487, 1452, 1415, 1282, 1259, 1188, 1120, 1094, 1038, 1013, 909, 870, 835, 729, 703, 691, 670 cm^-1. HRMS (ESI) calcd for C₂₄H₁₇ClN₂O₃P (M+H)⁺ 447.0659, found 447.0659.

  5-Butyl-3-(diphenylphosphoryl)pyrano[3, 2-c]pyrazol-7(1H)-one (2q): Yellow solid (63 mg, yield 80%). R_f＝0.5 [V(EtOAc):V(MeOH)＝10:1]. m.p. 173~175 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.02 (br, 1H), 7.81~7.77 (m, 4H), 7.64~7.54 (m, 6H), 6.21 (s, 1H), 2.42 (t, J＝7.5 Hz, 2H), 1.27~1.19 (m, 2H), 1.16~1.09 (m, 2H), 0.76 (t, J＝7.5 Hz, 3H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 169.62, 149.02 (d, J_C-P＝14.0 Hz), 132.40 (d, J_C-P＝109.0 Hz), 132.73, 132.71, 131.81 (d, J_C-P＝10.0 Hz), 129.33, 129.11 (d, J_C-P＝12.2 Hz), 128.81, 110.80, 32.91, 28.76, 21.76, 13.90; IR (KBr) ν: 3055, 2958, 2928, 2869, 1656, 1558, 1526, 1438, 1399, 1330, 1260, 1199, 1169, 1121, 1100, 1025, 941, 756, 727, 704, 562, 527 cm^-1. HRMS (ESI) calcd for C₂₂H₂₂N₂O₃P (M+H)⁺ 393.1362, found 393.1362.

  5-Cyclopropyl-3-(diphenylphosphoryl)pyrano[3, 2-c]pyr-azol-7(1H)-one (2r): Yellow solid (58 mg, yield 77%). R_f＝0.6 [V(EtOAc):V(MeOH)＝10:1]. m.p. 200~201 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 14.94 (br, 1H), 7.80~7.77 (m, 4H), 7.65~7.58 (m, 6H), 6.32 (s, 1H), 1.93 (s, 1H), 0.85 (s, 7.65~7.63 (m, 2H), 7.57~7.54 (m, 4H), 6.44 (s, 1H), 0.79 (t, J＝8.0 Hz, 9H), 0.56 (q, J＝8.0 Hz, 16.0 Hz, 6H); ¹³C NMR (125.8 MHz, DMSO-d₆) δ: 174.83, 167.78, 132.64, 132.47 (d, J_C-P＝109.0 Hz), 131.72 (d, J_C-P＝10.0 Hz), 131.28 (d, J_C-P＝12.0 Hz), 130.27, 129.35 (d, J_C-P＝12.0 Hz), 129.11 (d, J_C-P＝12.2 Hz), 121.77, 7.24, 1.94; IR (KBr) ν: 3418, 2956, 2875, 1655, 1518, 1438, 1271, 1200, 1120, 1052, 1026, 1006, 825, 749, 727, 702, 653, 552, 527 cm^-1. HRMS (ESI) calcd for C₂₄H₂₈N₂O₃PSi (M+H)⁺ 451.1601, found 451.1601.

  Supporting Information   NMR spectra of all compounds and HRMS spectra of compounds 2. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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• 

  Figure 1  Structure of g-pyranone-fused pyrazole

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  Scheme 1  Retrosynthetic approach for the preparation of 3-phosphonyl pyrano[3, 2-c]pyrazol-7(1H)-one (2)

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  Figure 2  X-ray crystal structure of product 2b

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  Scheme 2  Possible mechanism

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  Table 1.  Base and solvent screening for dimethyl 7-oxo-5-phenyl-1, 7-dihydropyrano[3, 2-c]pyrazol-3-ylphosphonate (2a) from dimethyl 1-diazo-2, 4-dioxo-6-phenylhex-5-ynylphosphon-ate (1a) ^a

  Entry	Base (equiv.)	Reaction time/h	Solvent	Yieldb/%
  1	LiOH (3)	12	MeOH	70
  2	NaOH (3)	12	MeOH	61
  3	KOH (3)	10	MeOH	78
  4	MeONa (3)	10	MeOH	70
  5	t-BuOK (3)	10	MeOH	57
  6	K2CO3 (3)	12	MeOH	67
  7	Pyridine (3)	48	MeOH	54c, d
  8	i-Pr2NEt (3)	9	MeOH	78
  9	DBU (3)	8	MeOH	93
  10	Et3N (3)	8	MeOH	99
  11	Et3N (1)	8	MeOH	81
  12	Et3N (2)	8	MeOH	94
  13	Et3N (4)	8	MeOH	99
  14	Et3N (3)	9	1, 4-Dioxane	93
  15	Et3N (3)	10	MeCN	77
  16	Et3N (3)	8	DCM	56c, d
  17	Et3N (3)	12	DCE	53c, d
  18	Et3N (3)	20	DMF	41c, d
  19	Et3N (3)	19	DMSO	50c, d
  20	Et3N (3)	23	Toluene	44c, d
  21	Et3N (3)	19	THF	47c, d
  a Reaction conditions: 1-diazo-2, 4-dioxo-5-ynylphosphonate (1a) (0.2 mmol), solvent (3 mL), 25 ℃. b Isolated yield. c Unknown by-product was formed. d The starting material was recovered.

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  Table 2.  Scope of the cascade reaction of substrate 1^a

  Entry	R1/R (1)	Product 2	t/h	Yieldb/%
  1	Ph/OMe (1a)	2a	8	99
  2	p-MeC6H4/OMe (1b)	2b	15	95
  3	p-PrnC6H4/OMe (1c)	2c	14	95
  4	p-FC6H4/OMe (1d)	2d	12	93
  5	p-ClC6H4/OMe (1e)	2e	11	91
  6	p-MeOC6H4/OMe (1f)	2f	10	96
  7	(E)-Cinnamenyl/OMe (1g)	2g	14	81
  8	3-Thienyl/OMe (1h)	2h	16	58 c
  9	Trietylsilyl/OMe (1i)	2i (R 1＝H)	17	60 c
  10	n-Bu/OMe (1j)	2j	12	88
  11	Cyclopropyl/OMe (1k)	2k	10	90
  12	Ph/Ph (1l)	2l	12	85
  13	p-MeC6H4/Ph (1m)	2m	10	86
  14	p-PrnC6H4/Ph (1n)	2n	10	88
  15	p-FC6H4/Ph (1o)	2o	11	82
  16	p-ClC6H4/Ph (1p)	2p	11	84
  17	n-Bu/Ph (1q)	2q	9	80
  18	Cyclopropyl/Ph (1r)	2r	19	77
  19	Et3Si/Ph (1s)	2s	17	48 c
  a Reaction conditions: substrate 1 (0.2 mmol), TEA (3.0 equiv.) in MeOH (3 mL) at 25 ℃. b Isolated yield by column chromatography. c The starting material was recovered.

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•