Synthesis of Trifluoromethylated Tetrahydrochromeno[2,3-c]pyrazol-5(1H)-ones via a One-Pot Multicomponent Reaction in the Presence of 4-Toluenesulfonic Acid

Abstract

An efficient one-pot multicomponent synthesis of trifluoromethylated tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one derivatives by the reaction of an aromatic aldehyde, a cyclohexane-1,3-dione, and 2-phenyl-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one in the presence of 4-toluenesulfonic acid is described; the reaction has good yields and good functional group tolerance. 4-Toluenesulfonic acid plays a dual role as both catalyst and dehydrating agent in the conversion. In addition, a possible mechanism for the reaction is proposed.

Multicomponent reactions (MCRs), such as the Strecker, Biginelli, and Ugi reactions, have been widely used in the modern drug discovery process, combinatorial chemistry, natural product synthesis, agrochemistry, and polymer chemistry.[1] Multicomponent reactions allow rapid assembly of several simple components into diverse complex structures in one pot by changing the reacting components. Heterocycles containing the pyrazole ring play a considerable role in synthetic and medicinal chemistry because the pyrazole motif is the main substructure in numerous biologically active compounds[2] and prominent drugs, such as celecoxib, celebrex, allopurinol, zaleplon.[3] Therefore, research on the multicomponent synthesis of pyrazole-containing polyfunctionalized heterocyclic compounds is an interesting field to pursue.

The introduction of trifluoromethyl groups into heterocycles can lead to remarkable changes in their physical, chemical, and biological properties.[4] Trifluoromethyl-containing compounds generally play an important role in the pharmaceutical industry due to their lower environmental and mammalian toxicity,[5] as demonstrated in commercial drugs such as Prozac, Difulican, Casodex. In recent years, the synthesis of fluorinated O-heterocyclic and N-heterocyclic compounds has also received much attention due to their potential biological activity.[6]

Tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one derivatives have been efficiently synthesized by the three-component reaction of pyrazolones and activated methylene compounds (e.g., alkylmalonates, malononitrile, cyanoacetic acid esters and their analogues) with aromatic aldehydes or isatins.[7] More recently, simple and efficient synthetic protocols for the construction of compounds containing a pyranopyrazole moiety via four-component reactions have been reported.[8] However, to the best of our knowledge, the preparation of trifluoromethylated tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one derivatives has been considerably less studied. Previously, we successfully demonstrated the feasibility of using ethyl 4,4,4-trifluoroacetoacetate in the synthesis of fluorine-containing heterocyclic compounds via a one-pot multicomponent reaction.[9] As part of our ongoing research program on the development of efficient methodologies to fluorine-containing heterocycles via one-pot multicomponent reactions, we herein report a one-pot multicomponent synthesis of trifluoromethylated tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one derivatives by the reaction of aromatic aldehydes, cyclohexane-1,3-diones, and 2-aryl-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-ones in the presence of 4-toluenesulfonic acid.

Table 1 Optimization of the Reaction Conditions^a,b

Entry	Ratio 1a/2a/3a	Acid or base (equiv)	Solvent	Temp (°C)	Yield (%)
1	1:1:1	–	EtOH	78	–
2	1:1:1	–	CH2Cl2	40	–
3	1:1:1	–	CHCl3	reflux	–
4	1:1:1	Et3N (1)	CHCl3	reflux	4′: 76
5	1:1:1	piperidine (1)	CHCl3	reflux	4′: 72
6	1:1:1	p-TSA (0.5)	CHCl3	reflux	4a: 32
7	1:1:1	p-TSA (1)	CHCl3	reflux	4a: 47
8	1:1:1	p-TSA (2)	CHCl3	reflux	4a: 49
9	2:1:1	p-TSA (1)	CHCl3	reflux	4a: 55
10	1:1:2	p-TSA (1)	CHCl3	reflux	4a: 53
11	2:1:2	p-TSA (1)	CHCl3	reflux	4a: 79
12	1.5:1:1.5	p-TSA (1)	CHCl3	reflux	4a: 62
13	2:1:2	p-TSA (2)	CHCl3	reflux	4a: 78
14	1:1:1	98% H2SO4(1)	CHCl3	reflux	4a: 38

^a Reaction conditions: 1a, 2a, benzaldehyde (3a), solvent (10 mL), reflux.

^b Isolated yield based on 2.

We commenced our studies by exploring the reaction of dimedone (5,5-dimethylcyclohexane-1,3-dione, 1a), 2-phenyl-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one (2a), and benzaldehyde (3a) in commonly used solvents, but no product was detected (Table [1], entries 1–3). When 1.0 equivalents of triethylamine were added to the reaction mixture, a new product was formed though the starting materials were not completely consumed even after refluxing in chloroform for 12 hours. The new product was characterized and shown to be acyclic compound 4′, that is 5,5-dimethyl-2-{[5-oxo-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-4-yl](phenyl)methyl}cyclohexane-1,3-dione (Scheme [1]). In order to obtain the cyclic compound via intramolecular cyclization reaction, it was necessary to treat 4′ with an equimolar amount of 4-toluenesulfonic acid in refluxing chloroform to afford cyclic product 4a in 75% yield. The reaction results indicated that 4-toluenesulfonic acid played a vital role in the intramolecular cyclization, and served as both a dehydrating agent and a catalyst in the second conversion.

We next performed the one-pot, three-component reaction of 1a, 2a, and 3a using chloroform as the solvent in the presence of a catalytic amount of 4-toluenesulfonic acid (entry 6). This was inspired by the following precedents: Firstly, the Knoevenagel condensation reaction between aromatic aldehydes and dimedone could be achieved in the presence of excess of lactic acid;[10] and secondly, a one-pot, multicomponent synthesis of spiro[chromeno[2,3-c]pyrazole-4,3′-indoline]-diones proceeded in the presence of a catalytic amount of 4-toluenesulfonic acid.[7b] The reaction proceeded smoothly (TLC monitoring) and straightforwardly to afford the expected cyclic product 4a in 32% yield. Compared with the stepwise reactions, this one-pot reaction in the presence of 4-toluenesulfonic acid could be a consecutive approach to the cyclic product 4. Further optimization of the reaction conditions showed that the yield of product 4a improved to 47% (entry 7) when the amount of 4-toluenesulfonic acid was increased to one equivalent. But a further increase of the amount of 4-toluenesulfonic acid had no significant effect on the reaction (entry 8). It was noted that the yield of 4a was significantly influenced by the ratios of the reactants. When the loading of 2a was maintained, increasing the ratios of either 1a or 3a to 2a facilitated this conversion (entries 8 and 9). Surprisingly, the best yield was obtained when the ratio of 1a/2a/3a was adjusted to 2:1:2 in the presence of one equivalent of 4-toluenesulfonic acid (entry 11). The reaction could also proceed in the presence of 98% sulfuric acid with a lower yield than that with 4-toluenesulfonic acid (entry 14).

With this optimized procedure in hand, the scope of the one-pot, multicomponent reaction was examined using different aromatic aldehydes 3 and pyrazolones 2. The results are summarized in Table [2]. The reaction proceeded smoothly with functionality substituted aromatic aldehydes to afford the corresponding products in moderate to good yields. The steric effects of the substituents at the ortho-position of the aromatic aldehyde had no observable impact on the yields of the reaction (entries 2 and 9). In addition, the presence of methoxycarbonyl group on the aromatic ring of the aldehyde performed well and afforded the desired product 4l in 78% yield (entry 12). Remarkably, 2-(4-methoxyphenyl)-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one (2b) was also compatible with this reaction and gave the corresponding product 4m in 89% yield (entry 13). Unfortunately, aromatic aldehydes bearing strong electron-withdrawing substituents, such as nitro and cyano, did not give the expected products (entries 14 and 15); TLC of the reaction mixtures showed a mixture of starting materials and numerous products. Moreover, the reaction was found to be complex with aliphatic aldehydes, such as 2-methylpropanal, which failed to give any characterizable product under these reaction conditions (entry 16).

Table 2 Scope of the Reaction of Dimedone (1a), 2, and Aromatic Aldehydes 3 ^a,b

Entry	Ar1	Ar2	Product	Yield (%)
1	Ph	Ph	4a	79
2	Ph	2-ClC6H4	4b	68
3	Ph	3-ClC6H4	4c	66
4	Ph	4-ClC6H4	4d	73
5	Ph	3-BrC6H4	4e	76
6	Ph	4-BrC6H4	4f	68
7	Ph	3-MeC6H4	4g	90
8	Ph	4-MeC6H4	4h	91
9	Ph	2-MeOC6H4	4i	84
10	Ph	3-MeOC6H4	4j	65
11	Ph	4-MeOC6H4	4k	82
12	Ph	4-MeO2CC6H4	4l	78
13	4-MeOC6H4	4-MeC6H4	4m	89
14	Ph	4-O2NC6H4	–	–
15	Ph	4-NCC6H4	–	–
16	Ph	i-Pr	–	–

^a Reaction conditions: 1a (2 mmol), 2 (1 mmol), aldehyde 3 (2 mmol), p-TSA (1 equiv), CHCl₃ (10 mL), reflux, 12 h.

^b Isolated yield based on 2.

Table 3 Scope of the Reaction of Cyclohexane-1,3-dione (1b), 2a, and Aromatic Aldehydes 3 ^a,b

Entry	Ar	Product	Yield (%)
1	Ph	5a	80
2	4-ClC6H4	5b	72
3	4-MeC6H4	5c	86
4	4-MeOC6H4	5d	85

^a Reaction conditions: 1b (2 mmol), 2a (1 mmol), aldehyde 3 (2 mmol), p-TSA (1 equiv), CHCl₃ (10 mL), reflux, 12 h.

^b Isolated yield based on 2.

To further extend the substrate scope, dimedone (1a) was replaced with cyclohexane-1,3-dione (1b). Pleasingly, the reactions were also successful under the same reaction conditions and resulted in similar yields when compared to those with dimedone (Table [3]). The reactions occurred smoothly with benzaldehydes as well as substituted benzaldehydes.

The structures of compounds 4 and 5 were fully confirmed by ¹H, ¹⁹F, and ¹³C NMR, MS, HRMS, and IR spectroscopy. For example, the characteristic features of the ¹H NMR spectra of 4a (CDCl₃) displayed the appearance of a singlet at δ = 5.17 for H4. The chemical shift of the CF₃ group in the ¹⁹F NMR spectra exhibited as a singlet peak at δ = –62.29 (s, Ar-CF₃), indicating that the CF₃ group is bonded to an aromatic ring. Furthermore, the structure of compound 4h was further confirmed by single crystal X-ray analysis to support our speculation on structures of these products (Figure [1]).[11] Regarding the other activated methylene compounds, We further performed the reactions using cyclopentane-1,3-dione as a substrate under the same reaction conditions, but unfortunately the reaction did not proceed and TLC analysis showed that the starting materials remained.

Based on the above results, a possible mechanism for the formation of 4 is illustrated in Scheme [2]. First, an intermediate A or B is formed via an initial Knoevenagel condensation reaction, followed by a Michael addition reaction with the third component to afford the intermediate C catalyzed by 4-toluenesulfonic acid. Subsequent intramolecular cyclization followed by a dehydration reaction in the presence of 4-toluenesulfonic acid affords the compound 4a. The 4-toluenesulfonic acid played a dual role as both catalyst and dehydrating agent in the conversion.

In summary, we report a consecutive approach to tri­fluo­romethylated tetrahydrochromeno[2,3-c]pyrazol-5(1H)-ones via one-pot multicomponent reaction of an aromatic aldehyde, cyclohexane-1,3-dione, and 2-phenyl-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one in the presence of 4-toluenesulfonic acid. Compared with stepwise protocols, 4-toluenesulfonic acid plays a dual role as both catalyst and dehydrating agent in the conversion. In addition, a possible mechanism for the reaction is proposed. These new structures may be considered as useful trifluoromethyl-containing substrates for the synthesis of a variety of heterocyclic compounds with potential biological activity.

Melting points were measured with digital melting point apparatus (WRS-1B, Shanghai Precision & Scientific Instrument Company, Ltd.) and are uncorrected. ¹H, ¹⁹F, and ¹³C NMR spectra were recorded in CDCl₃ on Bruker AM-500 or Varian 400-MR instruments with TMS and CFCl₃ (with upfield negative) as the internal and external standards, respectively. IR spectra were obtained with a Nicolet AV-360 spectrophotometer. LR-MS were determined with Finnigan GC-MS 4021 using the EI ionization technique (70 eV) or Agilent 1100 LC/MSD SL instrument using ESI technique. Elemental analyses were performed using a Vario EL III Analyzer. X-ray crystal structure data were collected on a Bruck SMART CCD area-detector diffractometer using graphite monochromatized MoKα radiation (λ = 0.71073 Å) at 296(2) K.

7,7-Dimethyl-1,4-diphenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4a); Typical Procedure

A mixture of dimedone (1a, 2.0 mmol), 2-phenyl-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one (2a, 1.0 mmol), benzaldehyde (3a, 2.0 mmol), and p-TSA (1.0 mmol) in CHCl₃ (10 mL) was refluxed for 12 h until completion of the reaction (monitored by TLC). The mixture was cooled to r.t., and the mixture was poured into water and extracted with EtOAc; the organic layer was dried (MgSO₄) and filtered. The solvent was evaporated and the residue was purified by column chromatography (silica gel, petroleum ether–EtOAc, 4:1) to afford the pure 4a as a white solid; yield: 346 mg (79%); mp 187–189 °C.

IR (KBr): 2962, 1649, 1518, 1363, 1170, 1133, 1019, 757, 692 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.81–7.80 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.28–7.25 (m, 4 H), 7.20–7.17 (m, 1 H), 5.17 (s, 1 H), 2.69 (d, ² J_gem  = 18.0 Hz, 1 H), 2.64 (d, ² J_gem  = 18.0 Hz, 1 H), 2.31 (d, ² J_gem  = 16.0 Hz, 1 H), 2.26 (d, ² J_gem  = 16.0 Hz, 1 H), 1.15 (s, 3 H), 1.07 (s, 3 H).¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 162.6, 145.4, 143.4, 138.5 (q, ² J _C-F = 39.0 Hz), 137.1, 129.4, 128.3, 128.2, 127.9, 126.8, 121.5, 120.8 (q, ¹ J _C-F = 268.0 Hz), 115.1, 101.8, 50.9, 41.4, 34.7, 32.2, 28.8, 27.4.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.29 (s, Ar-CF₃).

MS (ESI): m/z = 439 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₂F₃N₂O₂: 439.1628; found: 439.1622.

4-(2-Chlorophenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4b)

White solid; yield: 321 mg (68%); mp 227–230 °C.

IR (KBr): 2963, 1648, 1518, 1363, 1172, 1133, 1020, 758, 685 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.79–7.77 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.30–7.28 (m, 2 H), 7.22 (t, J = 7.0 Hz, 1 H), 7.16 (td, J ₁ = 8.0 Hz, J ₂ = 2.0 Hz, 1 H), 5.49 (s, 1 H), 2.68 (d, ² J_gem  = 18.0 Hz, 1 H), 2.64 (d, ² J_gem  = 18.0 Hz, 1 H), 2.31 (d, ² J_gem  = 16.0 Hz, 1 H), 2.26 (d, ² J_gem  = 16.0 Hz, 1 H), 1.16 (s, 3 H), 1.10 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 163.5, 145.7, 139.3, 138.6 (q, ² J _C-F = 39.0 Hz), 137.0, 133.4, 132.1, 130.2, 129.3, 128.3, 127.9, 126.5, 121.8, 120.7 (q, ¹ J _C-F = 268.0 Hz), 113.6, 100.1, 50.8, 41.4, 34.3, 32.1, 28.8, 27.4.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.64 (s, Ar-CF₃).

MS (ESI): m/z = 473 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₁ ³⁵ClF₃N₂O₂: 473.1238; found: 473.1232.

4-(3-Chlorophenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4c)

White solid; yield: 312 mg (66%); mp 179–181 °C.

IR (KBr): 2962, 1645, 1515, 1359, 1191, 1132, 1020, 761, 685 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.79–7.77 (m, 2 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.42–7.39 (m, 1 H), 7.20–7.19 (m, 2 H), 7.18–7.13 (m, 2 H), 5.12 (s, 1 H), 2.68 (d, ² J_gem  = 17.5 Hz, 1 H), 2.62 (d, ² J_gem  = 17.5 Hz, 1 H), 2.29 (d, ² J_gem  = 16.5 Hz, 1 H), 2.25 (d, ² J_gem  = 16.5 Hz, 1 H), 1.13 (s, 3 H), 1.06 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.1, 162.9, 145.4, 145.3, 138.5 (q, ² J _C-F = 39.0 Hz), 137.0, 134.0, 129.4, 128.2, 128.0, 127.1, 126.7, 121.6, 120.7 (q, ¹ J _C-F = 268.5 Hz), 114.5, 101.1, 101.0, 50.8, 41.4, 34.4, 32.3, 28.7, 27.5.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.25 (s, Ar-CF₃).

MS (ESI): m/z = 473 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₁ ³⁵ClF₃N₂O₂: 473.1238; found: 473.1231.

4-(4-Chlorophenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4d)

White solid; yield: 345 mg (73%); mp 230–232 °C.

IR (KBr): 2965, 1653, 1518, 1363, 1171, 1132, 1019, 757, 682 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.81–7.79 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.45–7.42 (m, 1 H), 7.26–7.20 (m, 4 H), 5.15 (s, 1 H), 2.68 (d, ² J_gem  = 18.5 Hz, 1 H), 2.64 (d, ² J_gem  = 18.5 Hz, 1 H), 2.31 (d, ² J_gem  = 16.5 Hz, 1 H), 2.25 (d, ² J_gem  = 16.5 Hz, 1 H), 1.15 (s, 3 H), 1.06 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 162.7, 145.4, 141.9, 138.5 (q, ² J _C-F = 38.0 Hz), 137.0, 132.6, 129.6, 129.4, 128.4, 128.0, 121.7, 120.7 (q, ¹ J _C-F = 268.0 Hz), 114.7, 101.2, 50.8, 41.4, 34.1, 32.2, 28.8, 27.4.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.26 (s, Ar-CF₃).

MS (ESI): m/z = 473 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₁ ³⁵ClF₃N₂O₂: 473.1238; found: 473.1231.

4-(3-Bromophenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4e)

White solid; yield: 393 mg (76%); mp 180–183 °C.

IR (KBr): 2961, 1644, 1514, 1358, 1190, 1311, 1019, 759, 685 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.82–7.80 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.35–7.31 (m, 2 H), 7.29–7.27 (m, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 5.14 (s, 1 H), 2.71 (d, ² J_gem  = 18.0 Hz, 1 H), 2.65 (d, ² J_gem  = 18.0 Hz, 1 H), 2.32 (d, ² J_gem  = 16.5 Hz, 1 H), 2.28 (d, ² J_gem  = 16.5 Hz, 1 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.1, 162.9, 145.5, 145.3, 138.5 (q, ² J _C-F = 38.5 Hz), 137.0, 131.0, 130.1, 129.7, 129.4, 128.0, 127.2, 122.3, 121.7, 120.6 (q, ¹ J _C-F = 268.5 Hz), 114.5, 101.0, 50.8, 41.4, 34.4, 32.3, 28.7, 27.5.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.21 (s, Ar-CF₃).

MS (ESI): m/z = 517 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₁ ⁷⁹BrF₃N₂O₂: 517.0733; found: 517.0724.

4-(4-Bromophenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4f)

White solid; yield: 351 mg (68%); mp 250–252 °C.

IR (KBr): 2965, 1651, 1517, 1361, 1168, 1130, 1012, 756, 682 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.78–7.76 (m, 2 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.42–7.36 (m, 3 H), 7.13 (d, J = 8.5 Hz, 2 H), 5.11 (s, 1 H), 2.66 (d, ² J_gem  = 18.0 Hz, 1 H), 2.61 (d, ² J_gem  = 18.0 Hz, 1 H), 2.28 (d, ² J_gem  = 16.5 Hz, 1 H), 2.23 (d, ² J_gem  = 16.5 Hz, 1 H), 1.13 (s, 3 H), 1.04 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 162.8, 145.4, 142.4, 138.5 (q, ² J _C-F = 38.5 Hz), 137.0, 131.3, 130.0, 129.4, 128.0, 121.6, 120.8, 120.7 (q, ¹ J _C-F = 268.0 Hz), 114.6, 101.1, 50.8, 41.4, 34.2, 32.2, 28.8, 27.4.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.25 (s, Ar-CF₃).

MS (ESI): m/z = 517 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₁ ⁷⁹BrF₃N₂O₂: 517.0733; found: 517.0726.

7,7-Dimethyl-1-phenyl-4-(m-tolyl)-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4g)

White solid; yield: 407 mg (90%); mp 199–201 °C.

IR (KBr): 2960, 1646, 1151, 1360, 1179, 1129, 1020, 763, 688 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.81–7.79 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.44–7.40 (m, 1 H), 7.13 (t, J = 7.5 Hz, 1 H), 7.04–7.02 (m, 2 H), 6.97 (d, J = 7.5 Hz, 1 H), 5.10 (s, 1 H), 2.68 (d, ² J_gem  = 17.5 Hz, 1 H), 2.63 (d, ² J_gem  = 17.5 Hz, 1 H), 2.29 (s, 3 H), 2.28 (d, ² J_gem  = 16.5 Hz, 1 H), 2.24 (d, ² J_gem  = 16.5 Hz, 1 H), 1.13 (s, 3 H), 1.06 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 162.6, 145.4, 143.3, 138.5 (q, ² J _C-F = 38.5 Hz), 137.7, 137.2, 129.4, 128.8, 128.0, 127.8, 127.6, 125.2, 121.5, 120.8 (q, ¹ J _C-F = 268.5 Hz), 115.1, 102.0, 50.9, 41.4, 34.5, 32.3, 28.8, 27.4, 21.4.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.24 (s, Ar-CF₃).

MS (ESI): m/z = 453 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄F₃N₂O₂: 453.1784; found: 453.1780.

7,7-Dimethyl-1-phenyl-4-(p-tolyl)-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4h)

White solid; yield: 411 mg (91%); mp 194–196 °C.

IR (KBr): 2964, 1648, 1517, 1361, 1170, 1131, 1018, 760, 684 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.80 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 7.5 Hz, 2 H), 5.14 (s, 1 H), 2.69 (d, ² J_gem  = 17.5 Hz, 1 H), 2.64 (d, ² J_gem  = 17.5 Hz, 1 H), 2.31 (d, ² J_gem  = 16.5 Hz, 1 H), 2.30 (s, 3 H), 2.26 (d, ² J_gem  = 16.5 Hz, 1 H), 1.15 (s, 3 H), 1.07 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 162.5, 145.4, 140.5, 138.5 (q, ² J _C-F = 38.5 Hz), 137.2, 136.3, 129.4, 128.9, 128.0, 127.9, 121.6, 120.8 (q, ¹ J _C-F = 268.5 Hz), 115.2, 102.0, 50.9, 41.4, 34.2, 32.2, 28.8, 27.4, 21.0.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.22 (s, Ar-CF₃).

MS (ESI): m/z = 453 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄F₃N₂O₂: 453.1784; found: 453.1777.

4-(2-Methoxyphenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4i)

White solid; yield: 393 mg (84%); mp 184–186 °C.

IR (KBr): 2960, 1653, 1518, 1363, 1171, 1131, 1021, 753, 688 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.79–7.78 (m, 2 H), 7.53 (t, J = 8.0 Hz, 2 H), 7.43–7.40 (m, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.19 (t, J = 8.0 Hz, 1 H), 6.91 (td, J = 7.5 Hz, J ₂ = 1.0 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 5.36 (s, 1 H), 3.76 (s, 3 H), 2.71 (d, ² J_gem  = 18.0 Hz, 1 H), 2.65 (d, ² J_gem  = 18.0 Hz, 1 H), 2.32 (d, ² J_gem  = 16.5 Hz, 1 H), 2.28 (d, ² J_gem  = 16.5 Hz, 1 H), 1.15 (s, 3 H), 1.06 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.3, 163.5, 157.3, 146.0, 138.4 (q, ² J _C-F = 38.5 Hz), 137.3, 130.6, 130.5, 129.4, 128.3, 127.7, 121.6, 120.9 (q, ¹ J _C-F = 268.0 Hz), 120.4, 113.8, 111.2, 101.0, 55.4, 50.9, 41.4, 32.2, 31.0, 29.1, 26.9.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.64 (s, Ar-CF₃).

MS (ESI): m/z = 469 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄F₃N₂O₃: 469.1735; found: 469.1729.

4-(3-Methoxyphenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4j)

White solid; yield: 304 mg (65%); mp 189–191 °C.

IR (KBr,): 2962, 1646, 1516, 1360, 1266, 1129, 1019, 757, 687 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.79 (d, J = 7.5 Hz, 2 H), 7.53 (t, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.19 (t, J = 8.0 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.83 (s, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 5.15 (s, 1 H), 3.80 (s, 3 H), 2.69 (d, ² J_gem  = 17.5 Hz, 1 H), 2.63 (d, ² J_gem  = 17.5 Hz, 1 H), 2.31 (d, ² J_gem  = 16.5 Hz, 1 H), 2.28 (d, ² J_gem  = 16.5 Hz, 1 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.2, 162.7, 159.4, 145.3, 145.0, 138.5 (q, ² J _C-F = 38.5 Hz), 137.1, 129.4, 129.1, 127.9, 121.6, 120.8 (q, ¹ J _C-F = 268.0 Hz), 120.6, 115.0, 114.4, 111.9, 101.7, 55.1, 50.9, 41.4, 34.6, 32.2, 28.7, 27.5.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.18 (s, Ar-CF₃).

MS (ESI): m/z = 469 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄F₃N₂O₃: 469.1734; found: 469.1729.

4-(4-Methoxyphenyl)-7,7-dimethyl-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4k)

White solid; yield: 384 mg (82%); mp 193–195 °C.

IR (KBr): 2963, 1651, 1515, 1362, 1172, 1130, 1017, 758, 684 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.79–7.78 (m, 2 H), 7.53 (t, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.19 (d, J = 8.5 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 5.13 (s, 1 H), 3.78 (s, 3 H), 2.68 (d, ² J_gem  = 17.5 Hz, 1 H), 2.63 (d, ² J_gem  = 17.5 Hz, 1 H), 2.31 (d, ² J_gem  = 16.5 Hz, 1 H), 2.26 (d, ² J_gem  = 16.5 Hz, 1 H), 1.15 (s, 3 H), 1.07 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.3, 162.3, 145.4, 143.4, 138.5 (q, ² J _C-F = 39.0 Hz), 137.1, 135.7, 129.4, 129.1, 127.8, 121.5, 120.8 (q, ¹ J _C-F = 268.0 Hz), 115.2, 113.5, 102.0, 55.1, 50.9, 41.4, 33.8, 32.2, 28.8, 27.4.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.29 (s, Ar-CF₃).

MS (ESI): m/z 469 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄F₃N₂O₃: 469.1734; found: 469.1727.

Methyl 4-(7,7-Dimethyl-5-oxo-1-phenyl-3-(trifluoromethyl)-1,4,5,6,7,8-hexahydrochromeno[2,3-c]pyrazol-4-yl)benzoate (4l)

White solid; yield: 387 mg (78%); mp 219–220 °C.

IR (KBr): 2958, 1719, 1653, 1517, 1362, 1279, 1130, 1017, 758 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.96 (d, J = 7.5 Hz, 2 H), 7.80 (d, J = 7.5 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 5.22 (s, 1 H), 3.89 (s, 3 H), 2.70 (d, ² J_gem  = 17.5 Hz, 1 H), 2.65 (d, ² J_gem  = 17.5 Hz, 1 H), 2.31 (d, ² J_gem  = 16.0 Hz, 1 H), 2.25 (d, ² J_gem  = 16.0 Hz, 1 H), 1.15 (s, 3 H), 1.05 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.0, 166.8, 163.0, 148.3, 145.4, 138.5 (q, ² J _C-F = 39.0 Hz), 137.0, 129.6, 129.4, 128.7, 128.3, 128.0, 121.6, 120.6 (q, ¹ J _C-F = 268.0 Hz), 114.5, 101.0, 51.9, 50.8, 41.4, 34.7, 32.2, 28.8, 27.3.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.28 (s, Ar-CF₃).

MS (EI): m/z = 496 [M]^+.

HRMS (EI): m/z [M]⁺ calcd for C₂₇H₂₃F₃N₂O₄: 496.1610; found: 496.1606.

1-(4-Methoxyphenyl)-7,7-dimethyl-4-(p-tolyl)-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (4m)

White solid; yield: 429 mg (89%); mp 232–233 °C.

IR (KBr): 2961, 1643, 1517, 1360, 1252, 1133, 1028, 830, 617 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.67 (d, J = 9.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 7.04 (d, J = 9.0 Hz, 2 H), 5.13 (s, 1 H), 3.89 (s, 3 H), 2.66 (d, ² J_gem  = 17.5 Hz, 1 H), 2.61 (d, ² J_gem  = 17.5 Hz, 1 H), 2.30 (d, ² J_gem  = 16.5 Hz, 1 H), 2.29 (s, 3 H), 2.26 (d, ² J_gem  = 16.5 Hz, 1 H), 1.14 (s, 3 H), 1.06 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 196.3, 162.5, 159.2, 145.1, 140.5, 138.0 (q, ² J _C-F = 38.3 Hz), 136.3, 130.2, 128.9, 127.9, 123.4, 120.8 (q, ¹ J _C-F = 267.8 Hz), 115.2, 114.5, 101.7, 55.5, 50.9, 41.4, 34.3, 32.2, 28.8, 27.4, 21.0.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.09 (s, Ar-CF₃).

MS (EI): m/z = 482 [M] ⁺.

HRMS (EI): m/z [M]⁺ calcd for C₂₇H₂₅F₃N₂O₃: 482.1817; found: 482.1815.

1,4-Diphenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (5a)

White solid; yield: 328 mg (80%); mp 228–230 °C.

IR (KBr): 2951, 1651, 1519, 1363, 1177, 1130, 992, 765, 697 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.81–7.79 (m, 2 H), 7.54 (t, J = 8.0 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.29–7.28 (m, 4 H), 7.21–7.18 (m, 1 H), 5.20 (s, 1 H), 2.87–2.72 (m, 2 H), 2.48–2.36 (m, 2 H), 2.13–2.01 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 196.3, 164.2, 145.3, 143.4, 138.5 (q, ² J _C-F = 38.0 Hz), 137.0, 129.4, 128.2, 128.1, 127.9, 126.8, 121.6, 120.7 (q, ¹ J _C-F = 269.0 Hz), 116.3, 101.8, 37.0, 34.6, 27.8, 20.2.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.31 (s, Ar-CF₃).

MS (ESI): m/z = 411 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₈F₃N₂O₂: 411.1315; found: 411.1312.

4-(4-Chlorophenyl)-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (5b)

White solid; yield: 320 mg (72%); mp 229–230 °C.

IR (KBr): 2966, 1644, 1517, 1361, 1175, 1131, 1006, 762, 682 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.80–7.79 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.43 (t, J = 7.0 Hz, 1 H), 7.24–7.22 (m, 4 H), 5.17 (s, 1 H), 2.86–2.72 (m, 2 H), 2.48–2.37 (m, 2 H), 2.14–2.01 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 196.2, 164.3, 145.2, 141.9, 138.5 (q, ² J _C-F = 39.0 Hz), 137.0, 132.6, 129.6, 129.4, 128.3, 128.0, 121.6, 120.6 (q, ¹ J _C-F = 269.0 Hz), 116.0, 101.2, 37.0, 34.1, 27.8, 20.2.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.29 (s, Ar-CF₃).

MS (ESI): m/z = 445 [M + H]⁺.

HRMS: m/z [M + H]⁺ calcd for C₂₃H₁₇ ³⁵ClF₃N₂O₂: 445.0925; found: 445.0920.

1-Phenyl-4-(p-tolyl)-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (5c)

White solid; yield: 363 mg (86%); mp 193–195 °C.

IR (KBr): 2951, 1661, 1514, 1362, 1171, 1130, 989, 764, 697 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.81–7.79 (m, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 5.17 (s, 1 H), 2.86–2.71 (m, 2 H), 2.47–2.36 (m, 2 H), 2.30 (s, 3 H), 2.13–2.01 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 196.3, 164.1, 145.3, 140.6, 138.0 (q, ² J _C-F = 39.0 Hz), 137.1, 136.3, 129.3, 128.9, 128.0, 127.8, 121.6, 120.7 (q, ¹ J _C-F = 268.0 Hz), 116.5, 101.9, 37.0, 34.1, 27.8, 21.0, 20.2.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.24 (s, Ar-CF₃).

MS (ESI): m/z = 425 [M + H]⁺.

HRMS: m/z [M + H]⁺ calcd for C₂₄H₂₀F₃N₂O₂: 425.1471; found: 425.1466.

4-(4-Methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-4,6,7,8-tetrahydrochromeno[2,3-c]pyrazol-5(1H)-one (5d)

White solid; yield: 374 mg (85%); mp 197–199 °C.

IR (KBr): 2953, 1670, 1514, 1360, 1172, 1131, 1040, 764, 681 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.81–7.79 (m, 2 H), 7.54 (t, J = 8.0 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.20 (d, J = 8.5 Hz, 2 H), 6.81 (d, J = 9.0 Hz, 2 H), 5.15 (s, 1 H), 3.78 (s, 3 H), 2.85–2.71 (m, 2 H), 2.48–2.36 (m, 2 H), 2.14–2.01 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 196.4, 164.0, 158.2, 145.3, 138.4 (q, ² J _C-F = 38.0 Hz), 137.1, 135.8, 129.3, 129.2, 127.8, 121.6, 120.6 (q, ¹ J _C-F = 269.0 Hz), 116.5, 113.5, 102.0, 55.1, 37.1, 33.7, 27.8, 20.2.

¹⁹F NMR (470 MHz, CDCl₃): δ = –62.31 (s, Ar-CF₃).

MS (ESI): m/z = 441 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₀F₃N₂O₃: 441.1421; found: 441.1416.

Acknowledgment

The authors thank the National Natural Science Foundation of China (NNSFC) (Nos. 21272153, 21072128), the Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry for financial support.

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• References

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  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
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• 2b Genin MJ, Biles C, Keiser BJ, Poppe SM, Swaney SM, Tarpley WG, Yagi Y, Romero DL. J. Med. Chem. 2000; 43: 1034
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