Synthesis of (Camphor-3-yl)acetic Acid-Derived Pyrazoles

Abstract

Two pyrazole derivatives were prepared in three steps from (camphor-3-yl)acetic acid. The pyrazole derivatives were fully characterized. The stereochemistry at the newly formed stereogenic center was confirmed by NOESY measurements and single crystal X-ray analysis.

1. Introduction

Pyrazole is a five-membered heterocycle with two adjacent nitrogen atoms that occurs in numerous molecules with different biological activities, e.g., compounds of agricultural and pharmaceutical importance [1,2,3,4,5,6,7]. On the other hand, there are numerous methods for the synthesis of pyrazoles and their functionalization [8,9,10,11,12]. As a result, interest in pyrazole chemistry is constantly increasing. One of the established methods for the synthesis of pyrazoles is the enaminone methodology, as the reactants are readily available and the chemistry is reliable and repeatable [13]. Camphor is one of nature’s privileged scaffolds, present in both enantiomeric forms. More importantly, its rich chemistry enables the preparation of structurally and functionally diverse products [14,15]. (Camphor-3-yl)acetic acid was prepared by simple alkylation of camphor with alkyl haloacetate [16,17]. It was used in the synthesis of tricyclic lactones [16,18], synthesis of cyclopentadienyl metal complexes [17], synthesis of fused thiophenes [19] and the study of kinetic and thermodynamic effects in acetal formation [20]. Herein, (camphor-3-yl)acetic acid was used to prepare the corresponding enaminone in two steps, which was converted to functionalized pyrazole derivatives with substituted hydrazines.

2. Results and Discussion

Enaminone 5 was prepared in four steps from (1R)-(+)-camphor (1) (Scheme 1). Following a modified literature procedure [16], (1R)-(+)-camphor (1) was alkylated with methyl bromoacetate to give the γ-keto ester 2 [17], which was hydrolyzed under basic conditions to give the acid 3 (dr = 65:35) in 50% yield in two steps. Masamune-Claisen homologation of acid 3 gave the β-keto ester 4 (dr = 64:36) in 60% yield, while subsequent treatment with DMFDMA gave the enaminone 5 (dr = 64:36) in 55% yield.

Heterocyclization of enaminone 5 with phenylhydrazine and 3-chloro-6-hydrazinopyridazine in acetic acid at elevated temperature gave the expected pyrazoles 6a (dr = 62:38) and 6b (dr = 64:36) in yields of 57% and 47%, respectively, as two inseparable diastereomers. Under the same conditions, the reaction of 5 with 1-hydrazinophthalazine hydrochloride gave a complex mixture of products. Repeating the reaction in methanol at room temperature gave the enehydrazine 7 in 53% yield as an inseparable mixture of endo- and exo-diastereomers in a ratio of 60:40. Subsequent attempts to cyclize enehydrazine 7 in acetic acid at elevated temperature did not give the desired pyrazole 6c, which is probably due to steric reasons. All attempts to oxidatively cyclize [21,22,23] enehydrazine 7 to triazoloazine 8 led to complex product mixtures (Scheme 2).

The structures of compounds 5, 6a, 6b and 7 were confirmed by spectroscopic methods (¹H- and ¹³C-NMR, DEPT 135, 2D-NMR, IR and high-resolution mass spectrometry, for details see Supplementary Materials), while compounds 2–4 were used as crude products for further transformations. The diastereomeric ratio of compounds 3–7 was determined by proton spectra in which the signals of the singlets of the methyl groups were integrated. The structure of the endo-isomer 6a was confirmed by single-crystal X-ray diffraction analysis (Figure 1). In addition, the (S)-absolute configuration at the chiral C(3) center of the major endo-isomer 6a was confirmed from the NOE signal in the NOESY spectra between H-C(3) and H₃-C(8). Similarly, the NOE signal between Ha-C(3′) and H₃-C(8) was detrimental to confirm the (R)-absolute configuration of the minor exo-isomer 6a′ (Figure 2). On this basis, we assigned the endo-isomer of compounds 3–7 as the major diastereomer. The (Z) configuration around the C=C bonds of compounds 5 and 7 was tentatively assigned based on steric considerations. The enehydrazine tautomer of compound 7 (opposite the hydrazone form) was assigned based on the vicinal H-C(3′)-NH coupling constant (³J = 10 Hz).

3. Materials and Methods

Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical grade anhydrous Na₂SO₄. Melting points were determined on a Kofler micro hot stage and on SRS OptiMelt MPA100—Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA, USA). The NMR spectra were obtained on a Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) at 500 MHz for 1H and 126 MHz for 13C nucleus, using CDCl₃ with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA), IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035–0.070 mm (Sigma-Aldrich, St. Louis, MO, USA)). All the commercially available chemicals used were purchased from Sigma-Aldrich (St. Louis, MO, USA).

3.1. Synthesis of 2-((1R,2S,4S)-4,7,7-Trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)acetic Acid (3) and 2-((1R,2R,4S)-4,7,7-Trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)acetic Acid (3′)

The methyl ester of (camphor-3-yl)acetic acid 2 was prepared according to a modified literature procedure [17]. To a lithium diisopropylamide solution (LDA, 2 M in THF/n-hexane/ethylbenzene, 44 mmol, 22 mL) in anhydrous THF (50 mL) cooled to −78 °C, (1R)-(+)-camphor (1) (40 mmol, 6.089 g) in anhydrous THF (8 mL) was added via syringe over the course of 30 min. After 15 min, hexamethylphosphoramide (HMPA, 44 mmol, 7.655 mL) was added, and after a further 30 min, methyl bromoacetate (80 mmol, ω = 0.97, 7.81 mL) was added as quickly as possible (approx. 30 s), both via syringe. The solution turned yellow while it was stirred for 1 h at −78 °C. After the reaction mixture was warmed to room temperature over 1 h, it was stirred for another 12 h at room temperature. The reaction mixture was carefully acidified with HCl (aqueous, 1 M) to pH = 1 and extracted with EtOAc (2 × 50 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The crude ester 2 was used in the following hydrolysis without further purification.

The crude ester 2 was dissolved in a mixture of H₂O (20 mL), MeOH (10 mL) and THF (20 mL), and then KOH (240 mmol, ω = 0.97, 15.84 g) was added. After stirring at room temperature for 4 h, the reaction mixture was diluted with H₂O (40 mL) and washed with Et₂O (2 × 20 mL). The aqueous phase was carefully acidified with HCl (aqueous, 6 M) to pH = 1 and extracted with EtOAc (4 × 50 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The crude acid 3/3′ [16] (3/3′ = 65:35) was used in the following Masamune-Claisen homologation without further purification. Yield: 4.205 g (20 mmol, 50%) of yellowish oil.

3.2. Synthesis of Methyl 3-Oxo-4-((1R,2S,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)butanoate (4) and Methyl 3-Oxo-4-((1R,2R,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)butanoate (4′)

Acid 3/3′ (3/3′ = 65:35, 20 mmol, 4.205 g) was azeotropically evaporated with anhydrous toluene (3 × 40 mL) and dissolved under argon in anhydrous THF (40 mL), followed by the addition of 1,1′-carbonyldiimidazole (CDI, 24 mmol, ω = 0.97, 4.01 g). The resulting reaction mixture was stirred under argon at room temperature for 2 h, then a solid mixture of MgCl₂ (19 mmol, 1.81 g) and methyl potassium malonate (30 mmol, 4.69 g) was added. The reaction mixture was stirred for a further 24 h at room temperature. The volatiles were evaporated in vacuo, and the residue was dissolved in EtOAc (150 mL) and washed with NaHSO₄ (aq., 1 M, 4 × 30 mL), NaHCO₃ (aq. sat., 2 × 20 mL) and NaCl (aq. sat., 2 × 40 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The crude β-keto ester 4/4′ (4/4′ = 64:36) was used in the following reaction without further purification. Yield: 3.196 g (12 mmol, 60%) of yellowish oil. EI-HRMS: m/z = 267.1588 (MH⁺); C₁₅H₂₃O₄ requires: m/z = 267.1591 (MH⁺).

3.3. Synthesis of Methyl (Z)-2-((Dimethylamino)methylene)-3-oxo-4-((1R,2S,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)butanoate (5) and Methyl (Z)-2-((Dimethylamino)methylene)-3-oxo-4-((1R,2R,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)butanoate (5′)

To a solution of β-keto ester 4/4′ (4/4′ = 64:36, 4 mmol, 1.07 g) in anhydrous toluene (10 mL), N,N-dimethylformamide dimethylacetal (DMFDMA, 20 mmol, ω = 0.94, 2.83 mL) was added under argon, and the resulting reaction mixture was heated at 70 °C for 3 h. The volatiles were evaporated in vacuo, and the residue was purified by column chromatography (Silica gel 60; 1) EtOAc/petroleum ether = 1:1 for elution of non-polar impurities, 2) EtOAc for elution of 5/5′). The fractions containing the pure product 5/5′ were combined and the volatiles were evaporated in vacuo. The product was stored under argon. Yield: 707 mg (5/5′ = 64:36, 2.2 mmol, 55%) of yellow oil. EI-HRMS: m/z = 322.2010 (MH⁺); C₁₈H₂₈NO₄ requires: m/z = 322.2013 (MH⁺). ¹H-NMR (600 MHz, CDCl₃) for 5: δ 0.89 (s, 3H), 0.92 (s, 3H), 0.98 (s, 3H), 1.22–1.29 (m 1H), 1.48–1.58 (m, 2H), 1.70–1.79 (m, 2H), 2.15 (t, J = 4.4 Hz, 1H), 2.70–3.33 (m, 8H), 3.74 (s, 3H), 7.69 (s, 1H). ¹H-NMR (600 MHz, CDCl₃) for 5′: δ 0.84 (s, 3H), 0.90 (s, 3H), 1.59–1.69 (m, 3H), 1.94 (d, J = 4.0 Hz, 1H), 1.96–2.02 (m, 1H), 2.63 (dd, J = 3.9, 9.1 Hz, 1H), 3.73 (s, 3H), 7.70 (s, 1H). ¹³C-NMR (151 MHz, CDCl₃) for 5/5′: δ 9.60, 9.67, 19.42, 19.78, 20.52, 20.71, 21.61, 29.15, 29.44, 31.24, 46.14, 46.75, 46.86, 47.10, 48.22, 50.27, 51.29, 57.46, 58.66, 157.26, 168.54, 168.59, 221.80, 222.09 (10 signals missing and/or overlapping).

3.4. Synthesis of Methyl 1-Phenyl-5-(((1R,2S,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)methyl)-1H-pyrazole-4-carboxylate (6a) and Methyl 1-Phenyl-5-(((1R,2R,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)methyl)-1H-pyrazole-4-carboxylate (6a′)

To a solution of enaminone 5/5′ (5/5′ = 64:36, 0.5 mmol, 161 mg) in anhydrous AcOH (3 mL) at room temperature was added phenylhydrazine (0.5 mmol, ω = 0.97, 51 μL), and the resulting reaction mixture was heated at 90 °C for 20 h. The volatiles were evaporated in vacuo, and the residue was dissolved in EtOAc (30 mL) and washed with NaHCO₃ (aq. sat, 2 × 5 mL) and NaCl (aq. sat., 2 × 5 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60, EtOAc/petroleum ether = 1:2). The fractions containing the pure product 6a/6a′ were combined and the volatiles were evaporated in vacuo. Yield: 104 mg (6a/6a′ = 62:38, 0.285 mmol, 57%) of yellowish solid; m.p. = 111–113 °C. EI-HRMS: m/z = 367.2012 (MH⁺); C₂₂H₂₇N₂O₃ requires: m/z = 367.2016 (MH⁺); ν_max 2948, 2928, 2868, 1737, 1706, 1597, 1553, 1500, 1446, 1416, 1394, 1372, 1344, 1316, 1255, 1201, 1175, 1098, 1076, 1044, 1018, 985, 944, 922, 876, 844, 807, 781, 772, 744, 699, 668 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) for 6a: δ 0.64 (s, 3H), 0.81 (s, 3H), 0.88 (s, 3H), 1.04–1.15 (m, 1H), 1.20–1.28 (m, 1H), 1.47–1.58 (m, 2H), 1.66–1.70 (m, 1H), 2.56–2.63 (m, 1H), 3.18 (dd, J = 10.0, 14.9 Hz, 1H), 3.37 (dd, J = 5.6, 14.9 Hz, 1H), 3.85 (s, 3H), 7.39–7.54 (m, 5H), 8.04 (s, 1H). ¹H-NMR (600 MHz, CDCl₃) for 6a′: δ 0.51 (s, 3H), 0.79 (s, 3H), 0.81 (s, 3H), 1.32–1.38 (m, 1H), 1.79–1.88 (m, 1H), 2.12 (dd, J = 5.1, 10.1 Hz, 1H), 3.20 (dd, J = 10.1, 14.5 Hz, 1H), 3.45 (dd, J = 5.1, 14.5 Hz, 1H), 3.86 (s, 3H), 8.05 (s, 1H). ¹³C-NMR (151 MHz, CDCl₃) for 6a/6a′: δ 9.47, 9.49, 19.20, 19.46, 20.05, 20.43, 20.98, 22.17, 26.05, 28.99, 29.22, 30.97, 45.69, 46.25, 46.34, 46.61, 48.84, 51.38, 53.09, 57.47, 58.60, 112.42, 112.53, 126.24, 126.57, 129.29, 129.49, 129.52, 139.04, 139.24, 142.23, 146.30, 146.80, 163.96, 164.04, 218.87, 218.93 (3 signals missing and/or overlapping).

3.5. Synthesis of Methyl 1-(6-Oxo-1,6-dihydropyridazin-3-yl)-5-(((1R,2S,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)methyl)-1H-pyrazole-4-carboxylate (6b) and Methyl 1-(6-Oxo-1,6-dihydropyridazin-3-yl)-5-(((1R,2R,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)methyl)-1H-pyrazole-4-carboxylate (6b’)

To a solution of enaminone 5/5′ (5/5′ = 64:36, 0.5 mmol, 161 mg) in anhydrous AcOH (3 mL) at room temperature was added 3-chloro-6-hydrazinopyridazine (0.5 mmol, ω = 0.97, 75 mg), and the resulting reaction mixture was heated at 90 °C for 16 h. The volatiles were evaporated in vacuo, and the residue was dissolved in EtOAc (40 mL) and washed with NaHCO₃ (aq. sat, 2 × 5 mL) and NaCl (aq. sat., 2 × 5 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60; 1) EtOAc/petroleum ether = 1:2 for elution of non-polar impurities, 2) EtOAc for elution of 6b/6b′). The fractions containing the pure product 6b/6b′ were combined and the volatiles were evaporated in vacuo. Yield: 67 mg (6b/6b′ = 64:36, 0.235 mmol, 47%) of yellowish solid; m.p. = 182–184 °C. EI-HRMS: m/z = 385.1871 (MH⁺); C₂₀H₂₅N₄O₄ requires: m/z = 385.1870 (MH⁺); ν_max 2957, 2870, 1736, 1712, 1682, 1667, 1604, 1543, 1475, 1435, 1391, 1371, 1311, 1261, 1238, 1194, 1167, 1140, 1081, 1009, 984, 971, 921, 858, 804, 784, 746, 685, 655, 626 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) for 6b: δ 0.79 (s, 3H), 0.83 (s, 3H), 0.97 (s, 3H), 1.26–1.31 (m, 1H), 1.65–1.72 (m, 1H), 1.78–1.85 (m, 1H), 1.91–1.98 (m, 1H), 2.04 (t, J = 4.2 Hz, 1H), 2.76–2.84 (m, 1H), 3.38 (dd, J = 6.8, 14.0 Hz, 1H), 3.71 (dd, J = 7.9, 14.1 Hz, 1H), 3.85 (s, 3H), 7.13 (d, J = 10.0 Hz, 1H), 7.95 (d, J = 10.0 Hz, 1H), 8.04 (s, 1H), 12.02 (br s, 1H). ¹H-NMR (600 MHz, CDCl₃) for 6b’: δ 0.87 (s, 3H), 0.94 (s, 6H), 1.20–1.26 (m, 1H), 1.40–1.46 (m, 1H), 1.58–1.63 (m, 1H), 1.71–1.76 (m, 1H), 2.07 (d, J = 4.0 Hz, 1H), 2.26 (dd, J = 5.5, 8.5 Hz, 1H), 3.57 (dd, J = 8.5, 14.0 Hz, 1H), 3.73 (dd, J = 5.5, 14.0 Hz, 1H), 3.87 (s, 3H), 7.13 (d, J = 10.0 Hz, 1H), 7.94 (d, J = 10.0 Hz, 1H). ¹³C-NMR (151 MHz, CDCl₃) for 6b/6b’: δ 9.59, 9.61, 19.33, 19.72, 20.51, 20.74, 21.43, 22.89, 26.61, 29.15, 29.31, 31.07, 45.91, 46.98, 47.00, 47.40, 49.40, 51.59, 51.62, 53.79, 57.74, 58.92, 114.26, 114.28, 130.77, 131.22, 132.32, 132.47, 142.83, 142.93, 143.01, 143.31, 148.24, 148.33, 160.91, 161.12, 163.54, 163.58, 219.73, 219.97.

3.6. Synthesis of Methyl (Z)-3-Oxo-2-((2-(phthalazin-1-yl)hydrazineyl)methylene)-4-((1R,2S,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)butanoate (7) and Methyl (Z)-3-Oxo-2-((2-(phthalazin-1-yl)hydrazineyl)methylene)-4-((1R,2R,4S)-4,7,7-trimethyl-3-oxobicyclo [2.2.1]heptan-2-yl)butanoate (7′)

To a solution of enaminone 5/5′ (5/5′ = 64:36, 1.0 mmol, 322 mg) in MeOH (6 mL) at room temperature was added 1-hydrazinophthalazine hydrochloride (1.0 mmol, 197 mg), and the resulting reaction mixture was stirred for 7 h at room temperature. The precipitate (product 7/7′) was collected by filtration and washed with cooled MeOH (0 °C, 6 mL). Yield: 231 mg (7/7′ = 60:40, 0.530 mmol, 53%) of yellow solid; m.p. = 154–157 °C. EI-HRMS: m/z = 437.2180 (MH⁺); C₂₄H₂₉N₄O₄ requires: m/z = 437.2183 (MH⁺); ν_max 2957, 2929, 2870, 1733, 1697, 1616, 1568, 1557, 1492, 1440, 1414, 1383, 1330, 1307, 1276, 1258, 1229, 1191, 1139, 1125, 1113, 1075, 1058, 1006, 982, 905, 763, 736, 707, 671, 647 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) for 7: δ 0.92 (s, 3H), 0.94 (s, 3H), 1.00 (s, 3H), 1.30–1.38 (m, 1H), 1.48–1.71 (m, 2H), 1.73–1.81 (m, 1H), 2.15 (t, J = 4.1 Hz, 1H), 3.10–3.17 (m, 2H), 3.27–3.34 (m, 1H), 3.75 (s, 3H), 7.49–7.56 (m, 1H), 7.63–7.71 (m, 2H), 7.94 (s, 1H), 8.24–8.31 (m, 1H), 8.51 (d, J = 10.2 Hz, 1H), 9.89 (s, 1H), 13.80 (d, J = 10.2 Hz, 1H). ¹H-NMR (600 MHz, CDCl₃) for 7′: δ 0.92 (s, 3H), 1.92–1.96 (m, 1H), 1.97–2.05 (m, 1H), 2.69 (dd, J = 4.2, 8.6 Hz, 1H), 3.19 (dd, J = 8.6, 17.6 Hz, 1H), 3.41 (dd, J = 4.2, 17.6 Hz, 1H), 3.74 (s, 3H), 8.51 (d, J = 10.3 Hz, 1H), 9.88 (s, 1H), 13.74 (d, J = 10.2 Hz, 1H). ¹³C-NMR (151 MHz, CDCl₃) for 7/7′: δ 9.68, 9.74, 19.47, 19.83, 20.55, 20.91, 21.76, 29.25, 29.54, 31.19, 38.60, 43.35, 46.21, 46.96, 47.29, 48.50, 49.65, 51.14, 57.54, 58.71, 99.06, 99.16, 124.25, 126.20, 126.42, 126.61, 132.40, 139.72, 139.73, 143.33, 143.37, 156.13, 167.07, 167.14, 198.74, 198.84, 221.46, 221.95 (10 signals missing and/or overlapping).

3.7. X-Ray Crystallography

Crystal Data for C₂₂H₂₆N₂O₃ (M = 366.46 g/mol): orthorombic, space group P2₁2₁2₁, a = 8.24173(13) Å, b = 11.73800(19) Å, c = 20.3598(3) Å, α = β = γ = 90°, V = 1969.64(6) Å3, Z = 4, T = 150(2) K, μ(CuKα) = 1.54184 mm⁻¹, Dcalc = 1.236 g/cm³, 33,413 reflections measured (8.68° ≤ 2Θ ≤ 145.84°), 3912 unique (Rint = 0.0918, Rsigma = 0.0319) which were used in all calculations. The final R1 was 0.0450 (I > 2σ(I)) and wR2 was 0.1185 (all data). The data was processed using CrysAlis PRO [24]. Using Olex2.1.2. [25], the structure was solved by direct methods implemented in SHELXS [26] or SHELXT [27] and refined by a full-matrix least-squares procedure based on F² with SHELXT-2014/7 [28]. All nonhydrogen atoms were refined anisotropicallly. Hydrogen atoms were placed in geometrically calculated positions and were refined using a riding model. The drawing and the analysis of bond lengths, angles and intermolecular interactions were carried out using Mercury [29] and Platon [30]. CCDC 2,479,111 for compound 6a contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).

4. Conclusions

Enaminone 5 was prepared in four steps from (1R)-(+)-camphor (1). The pyrazoles 6a,b were prepared by heterocyclization of enaminone 5 with substituted hydrazine derivatives. The pyrazole products were formed as mixtures of inseparable diastereomers. The absolute configuration at the chiral C(3) center of compound 6a was determined by NOESY measurement and single-crystal X-ray analysis.