A Convenient and Practical Synthesis of Aminopyrazoles

This manuscript is dedicated to Dr. John A. Myers on the occasion of his retirement from NCCU Chemistry.

Abstract

A selective methodology for preparing highly substituted aminopyrazoles has been demonstrated. Starting with an acetophenol core, the corresponding substituted isoxazole is prepared in two steps. The isoxazole is transformed into a benzopyran. Alkylation of the aminobenzopyranone gives N-substituted aminobenzopyranone derivatives that react with substituted hydrazine to give aminopyrazoles. This versatile synthesis enables the preparation of highly substituted aminopyrazoles for use as key synthetic building blocks for biologically active molecules. In addition, this process represents the first amine alkylation of aminobenzopyranones.

The agrochemical and pharmaceutical industries make use of the pyrazole heterocycle unit in many biologically active molecules. Because of its importance, the study and synthesis of such compounds has generated renewed interest.[2a] For example, the pyrazole ring is present in important marketed pharmaceuticals such as Celecoxib.[2b] Furthermore, aminopyrazoles are increasingly found in many biologically relevant compounds.[2c] Additional interest in the transformation of pyrazoles is due to their use as scaffolds for the preparation of other heterocycles.[2d]

Until recently, the primary means of preparing 3(5)-amino-1H-aminopyrazole has followed traditional routes from β-ketonitriles or similar derivatives.[3] Heterocycles have been reported as precursors to pyrazoles and 3(5)-amino-1H-pyrazoles. Isoxazoles have been used as substrates for the synthesis of pyrazoles,[4] although the use of isoxazoles as precursors to 3(5)-aminopyrazoles is less common.[5] Both isothiazoles[6] and pyrazolones[7] have been used as starting materials in the preparation of aminopyrazoles, although reports of this have been limited. There is a precedent for the generation of 3(5)-aminopyrazoles from 2-aminochromen-4-ones, although a full-scale examination of the reaction has not been undertaken.[8]

Control of regiochemistry in the reactions of unprotected 3-amino-1H-pyrazoles can be difficult. Selectivity varies depending on the electrophile added, with reaction occurring at four possible locations on the ring.[2] Thus, methods for the regioselective synthesis of 3(5)-aminopyrazoles are desirable.[9] This paper outlines the modular preparation of 3(5)-aminopyrazoles 4 from 2-aminochromones 3 and 3-arylisoxazoles 2 that allows the desired substitution pattern to be incorporated (Scheme [1]). The methodology allows selective control of all seven possible substitution patterns of an aminoarylpyrazole if an arylacetophenol is used as the starting material 1 (Scheme [1]).

Substituted 2-(isoxazol-5-yl)phenol derivatives 2a–d (Table [1]) were prepared by using reported methods[10] utilizing commercially available acetophenone derivatives. Condensation­ of acetophenones 1a,b with N,N-dimethylformamide dimethylacetal followed by addition of hydroxylamine provided the desired isoxazoles. Substituents on the aromatic ring were well tolerated, but the change to ethyl ketone (entry 4) resulted in incomplete reaction after 48 hours and a reduction in yield.

Table 1Conversion of Acetophenones into Isoxazoles 2

Entry	R1	R2	Time (h)a	2	Yield (%)b
1	H	H	0.6/1	2a	88
2	4-Br	H	0.5/1	2b	95
3	3-OMe	H	2/1.5	2c	85
4	H	Me	3/48	2d	69

^a Time for reaction 1 then reaction 2

^b Isolated yield after purification by recrystallization (H₂O).

With isoxazoles 2a–d in hand, their conversion into 2-aminodihydropyran-2-ones 3a–d was accomplished by heating to reflux with K₂CO₃ in a mixture of ethanol and water (2:1).[11] The yields of the pyranone were good to excellent. Substitution on the aromatic ring resulted in a slight decrease in isolated yield (Table [2]).

Table 2 Synthesis of 2-Aminochromen-4-ones 3

Entry	R1	R2	Time (h)	3	Yield (%)a
1	H	H	19	3a	87
2	5-Br	H	22	3b	69
3	4-OMe	H	21	3c	69
4	H	Me	20	3d	80

^a Isolated yield after purification by recrystallization (EtOH).

To expand the scope of the reaction to 3(5)-aminopyrazole formation via 2-aminochromen-4-one, derivatization of the amino group was explored. Representative transformations are shown in Scheme [2], which demonstrates the ability to generate monosubstituted amino derivatives 3e–g.

Our goal at this stage was to substitute a primary or secondary amine for the aminobenzopyranone amino group. Amino group substitution with primary amines proved challenging. Literature precedent for addition–ammonia elimination of these substrates is limited to a few examples of Michael addition reactions with the amine as nucleo­phile.[12] Given such problems, we investigated other transformations. Alkylation by S_N2 reaction did not lead to monoalkylation but did provide the dimethylated product 3f (Scheme [2], equation ii). The S_NAr reaction led to bis-arylation­, as did Buchwald–Hartwig amination[13] with Pd(dppf)Cl₂ and K₂CO₃. Buchwald–Hartwig amination with Pd₂(dba)₃ and t-BuPhos in the presence of Cs_sCO₃ provided a 30% yield in situ of the monoarylated product 3e (Scheme [2], equation i). Reductive amination was unsuccessful. Alkylation­ with the Chan–Lam reaction[14] afforded a 27% yield in situ of the monoethylamine 3g (Scheme [2,]Equation iii), but the analogous reaction with methylboronic acid gave a complex mixture. Since compounds 3e–g were obtained in low yields, the unpurified products were utilized directly in the next step.

Having established access to a range of 2-aminobenzopyran-4-ones, the next step for the methodology was their conversion into aminopyrazoles (Table [3]). The aminobenzopyranones were reacted with both unsubstituted and substituted hydrazines in dimethyl sulfoxide (DMSO) at 100–125 °C for 2–48 hours to provide the corresponding substituted aminopyrazoles (Table [3], entries 1–13). The reaction was sensitive to steric influences. The highest yields were obtained with the use of hydrazine hydrate. For example, aminopyrazole 4c was formed in 83% yield, but the methyl analogue 4k was isolated in 58% yield and the tert-butyl derivative 4m was obtained in only 43% yield. A similar trend was observed for aminopyrazoles 4b, 4i, and 4j. In the case of the addition of tert-butylhydrazine, a byproduct was formed in which the tert-butylhydrazine moiety was incorporated twice, 4j' �and 4m' (Equation 1).

Table 3 Synthesis of Aminopyrazoles 4

Entry	R1	R2	R3	R4	4	Yield (%)a
1	H	H	H	H	4a	81
2	4-Br	H	H	H	4b	78
3	3-OMe	H	H	H	4c	83
4	H	Me	H	H	4d	66
5	3-OMe	H	4-CF3C6H4	H	4e	45
6	3-OMe	H	Me (Me)	H	4f	54
7	H	Me	Et	H	4g	45b
8	H	H	H	Me	4h	45b
9	4-Br	H	H	Me	4i	39b
10	4-Br	H	H	t-Bu	4j	24b
11	3-OMe	H	H	Me	4k	58b
12	H	Me	H	Me	4l	40
13	3-OMe	H	H	t-Bu	4m	43b

^a Isolated yield after purification by recrystallization (petroleum ether–EtOAc­) unless otherwise stated.

^b Purified by column chromatography (silica; petroleum ether–EtOAc).

When 5-hydrazinylpyrazine-2-carbonitrile was used as the hydrazine source, the pyrazine-2-carbonitrile was not incorporated into the product. Instead, the product contained a hydrazine at the 5-position in place of the amino group, similar to the reaction with tert-butylhydrazine (Equation 1).

Steric influence was also observed when the isoxazole was substituted with a methyl group, as shown in the comparison of 4a and 4d. The presence of alkyl or aryl groups on the 2-amino substituent also led to decreased yields relative to the unsubstituted amino group as with 4e and 4g. The reactions proceeded faster at 125 than at 100 °C; however, additional hydrazine was needed at the higher temperature. The presence of additional substituents on the aromatic ring did not impact the yield of the reaction. For example, 4a, 4b, and 4c were formed in similar yields.

In situ NMR[15] [16] spectroscopic analysis was employed to characterize and monitor the transformation of chromen­one into aminopyrazole. A proposed reaction mechanism is provided in Scheme [3]. The NMR data supported the presence of intermediates 5, 6a, and 6b. Kinetic profiles for the formation and consumption of the reaction species support the interconversions as shown. A future publication will provide a detailed characterization of the formation of aminopyrazoles from isoxazole precursors that further supports the mechanism depicted in Scheme [3].

In conclusion, a modular approach to the synthesis of aminopyrazoles has been demonstrated. The reported method provides control of substitution on the aryl ring, the pyrazole ring, and the exocyclic amino group.

All commercial reagents were used as received without further purification. Known compounds were prepared according to reported procedures or were purchased from commercial sources. Reaction mixtures were stirred magnetically and monitored by LC-MS with an Agilent 1200 series fitted with a Waters SunFire C18 (30 × 4.6 mm, 2.5 μm) and Zorbax SB-C8 (75 × 4.6 mm, 3.5 μm) column; UV analysis at 214 nm (API-ES). Column chromatography was performed by using 200–300 mesh silica gel (petroleum ether–EtOAc, 5:1 to 1:1, or CH₂Cl_2­–MeOH, 50:1 to 30:1); UV detection at 254 nm and iodine staining. Melting points were determined by TGA (Q500 V6.5 Build 196) and DSC (Q2000 V24.4 Build 116). IR spectra were recorded with a Shimadzu Irprestige-21. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded with a Bruker ASENDTM (DMSO-d ₆, CDCl_3­, and CD₃OD; TMS). HRMS analyses were performed with a Bruker Daltonics, Inc. APEXIII 7.0 TESLA FTMS.

2-(5-Amino-1H-pyrazol-3-yl)phenol (4a); Typical Procedure[16]

A similar procedure for H₂NNH₂·H₂O addition was used to prepare 4b, 4c, 4d, and 4f.

To a 100 mL flask was added 2-amino-4H-chromen-4-one (3.0 g, 18.62 mmol), DMSO (30 mL) and hydrazine hydrate (50% in H₂O, 3.73 g, 37.26 mmol). The solution was stirred and heated to 100 °C for 23 h, then the mixture was cooled to 25 °C and H₂O (100 mL) was added. The solution was extracted with CH₂Cl₂ (3 × 50 mL) until there was almost no product remaining in the aqueous layer (TLC: CH₂Cl₂–MeOH, 20:1 v/v). The combined organic layer was washed with brine (100 mL), and dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was slurried with a mixture of petroleum ether and EtOAc (1:1 v/v, 10 mL) at 25 °C for 20 min. The solid was filtered and dried to afford 4a.

Yield: 2.66 g (81.6%); off-white solid; mp 148.7 °C.

IR (KBr): 3431.4, 3346.5, 3145.9, 3064.9, 2729.3, 2683.0, 1950.0, 1911.5, 1784.2, 1595.1, 1562.3, 1508.3, 1477.5, 1446.6, 1411.9, 1375.3, 1288.5, 1257.6, 1236.4, 1195.9, 1103.3, 1004.9, 972.1, 850.6, 825.5, 787.0, 766.0, 673.2, 644.2, 576.7, 536.2 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 5.38 (s, 2 H), 5.76 (s, 1 H), 6.83 (t, J = 7.6 Hz, 2 H), 7.12 (m, 1 H), 7.51 (d, J = 7.2 Hz, 1 H), 11.53 (s, 1 H), 11.85 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 84.24, 116.61, 117.82, 119.31, 126.75, 128.66, 149.63, 151.48, 156.29.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₀N₃O: 176.0824; found: 176.0818.

2-(5-Amino-1H-pyrazol-3-yl)-4-bromophenol (4b)

Purified by trituration (petroleum ether–EtOAc, 2:1).

Yield: 1.6 g (78%); off-white solid; mp 167.4 °C.

IR (KBr): 3425.6, 3298.3, 3205.7, 1859.4, 1637.6, 1591.3, 1570.1, 1510.3, 1454.3, 1413.8, 1359.8, 1251.8, 1143.8, 1124.5, 1080.1, 1020.3, 970.2, 877.6, 833.3, 800.5, 761.9, 731.0, 673.2, 597.9, 553.6, 526.6, 472.6 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 5.43 (s, 2 H), 5.86 (s, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 7.26 (dd, J = 2.4, 8.4 Hz, 1 H), 7.69 (d, J = 2.8 Hz, 1 H), 11.69 (s, 1 H), 11.96 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 84.45, 110.57, 118.88, 119.93, 128.78, 131.07, 149.58, 150.06, 155.50.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₉BrN₃O: 253.9929; found: 253.9924.

2-(5-Amino-1H-pyrazol-3-yl)-3-methoxyphenol (4c)

Compound 4c was isolated after trituration (petroleum ether–EtOAc, 1:1) of the crude reaction residue.

Yield: 2.23 g (83%); white solid; mp 162.9 °C.

IR (KBr): 3361.9, 3298.3, 3211.5, 3176.8, 3126.6, 2833.4, 1907.6, 1620.2, 1597.1, 157738, 1460.1, 1379.1, 1325.1, 1300.0, 1244.1, 1178.5, 1082.1, 1024.2, 945.1, 846.8, 790.8, 733.0, 632.7, 532.4 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 3.82 (s, 3 H), 5.29 (s, 2 H), 5.99 (s, 1 H), 6.50 (m, 2 H), 7.06 (t, J = 8.4 Hz, 1 H), 11.88 (s, 1 H), 12.67 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 55.99, 89.57, 102.31, 107.12, 109.83, 128.49, 148.63, 158.03, 158.36.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₂N₃O₂: 206.0930; found: 206.0924.

2-(5-Amino-4-methyl-1H-pyrazol-3-yl)phenol (4d)

Compound 4d was isolated after trituration (petroleum ether–EtOAc, 1:1) of the crude reaction mixture.

Yield: 0.36 g (66%); white solid; mp 132.6 °C.

IR (KBr): 3439.1, 3373.5, 3140.1, 2953.0, 2862.4, 2586.5, 1934.6, 1899.9, 1593.2, 1496.8, 1452.4, 1421.5, 1375.3, 1317.4, 1253.7, 1230.6, 1193.9, 1165.0, 1114.9, 1080.1, 1047.4, 933.6, 823.6, 754.2, 740.7, 678.9, 623.0, 590.2, 580.6, 526.6 cm^–1.

¹H NMR (400 MHz, CD₃OD): δ = 2.03 (s, 3 H), 6.90 (m, 2 H), 7.20 (s, 1 H), 7.40 (d, J = 7.2 Hz, 1 H).

¹³C NMR (100 MHz, CD₃OD): δ = 7.04, 115.64, 118.05, 118.93, 128.70, 128.84, 155.11.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₃N₃O: 190.0980; found: 190.0975.

2-[5-(N,N-Dimethylamino)-1H-pyrazol-3-yl]-3-methoxyphenol (4f)

Yield: 0.32 g (54%); white solid; mp 198.9 °C.

IR (KBr): 3454.5, 3178.7, 2868.2, 2841.2, 2798.7, 2586.5, 1892.2, 1595.1, 1556.6, 1473.6, 1425.4, 1383.0, 1365.6, 1309.7, 1292.3, 1238.3, 1153.4, 1082.1, 1016.5, 945.1, 927.8, 787.0, 765.7, 727.2, 657.7, 609.5, 547.8, 522.7, 489.9 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.83 (s, 6 H), 3.83 (s, 3 H), 6.06 (s, 1 H), 6.52 (t, J = 8.4 Hz, 2 H), 7.09 (m, 1 H), 12.31 (s, 1 H), 12.56 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 49.07, 55.90, 89.25, 102.38, 106.83, 109.81, 128.80, 148.98, 152.82, 158.13, 159.52.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₅N₃NaO₂: 256.1062; found: 256.1056.

2-(5-Amino-1,4-dimethyl-1H-pyrazol-3-yl)phenol (4l); Typical Procedure

A similar procedure for MeNHNH₂ addition was used to prepare 4k, 4h, and 4i.

To a 100 mL three-necked flask was added 2-amino-3-methyl-4H-chromen-4-one (2.0 g, 11.42 mmol), DMSO (20 mL), and methylhydrazine (40% in H₂O, 6.59 g, 57.24 mmol). The solution was heated to 125 °C, stirred for 25 h, then an additional batch of methylhydrazine (40% in H₂O, 6.6 g, 5.0 equiv) was added. After an additional 24 h, another batch of methylhydrazine was added (40% in H₂O, 6.6 g). After a total of 75 h at 125 °C, the reaction mixture was cooled to r.t., and H₂O (80 mL) was added. The solution was extracted with EtOAc (3 × 80 mL), then the combined organic layer was washed with H₂O (2 × 100 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (petroleum ether–EtOAc, 3:1 v/v) to give 4l.

Yield: 860 mg (39.8%); white solid; mp 124.6 °C.

IR (KBr): 3387.0, 3331.1, 3242.3, 2929.9, 2586.5, 1909.5, 1637.6, 1587.4, 1568.1, 1504.5, 1460.1, 1423.5, 1410.0, 1313.5, 1280.7, 1267.2, 1251.8, 1172.1, 1157.3, 1041.6, 1014.6, 937.4, 842.9, 794.7, 758.0, 644.2, 551.6, 497.6, 452.6 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 2.14 (s, 3 H), 3.35 (s, 2 H), 3.68 (s, 3 H), 6.89 (t, J = 7.2 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.57 (d, J = 6.8 Hz, 1 H), 11.22 (s, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 9.90, 34.53, 97.74, 116.77, 118.29, 118.72, 126.88, 128.27, 142.90, 147.07, 152.21.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₄N₃O: 204.1137; found: 204.1131.

2-(5-Amino-1-methyl-1H-pyrazol-3-yl)-3-methoxyphenol (4k)

The product was isolated by column chromatography (petroleum ether–EtOAc, 3:1).

Yield: 115 mg (58%); white solid; mp 130.3 °C.

IR (KBr): 3388.9, 3329.1, 3232.7, 3169.0, 2997.4, 2937.6, 2590.4, 1898.0, 1624.1, 1591.3, 1560.4, 1469.8, 1377.2, 1311.6, 1284.6, 1242.2, 1186.2, 1091.7, 1078.2, 1041.6, 941.3, 788.9, 769.6, 729.1, 630.7, 532.4 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 3.61 (s, 3 H), 3.82 (s, 3 H), 5.49 (s, 2 H), 6.02 (s, 1 H), 6.50 (m, 2 H), 7.06 (t, J = 8.4 Hz, 1 H), 12.31 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 34.58, 56.00, 90.32, 102.39, 106.87, 109.87, 128.49, 146.64, 147.76, 158.04, 158.09.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₄N₃O₂: 220.1086; found: 220.1081.

2-(5-Amino-1-methyl-1H-pyrazol-3-yl)phenol (4h)

The product was isolated by column chromatography (petroleum ether–EtOAc, 3:1).

Yield: 590 mg (45.4%); yellow solid; mp 109 °C.

IR (KBr): 3398.6, 3329.1, 3238.5, 2943.4, 1942.3, 1907.6, 1871.0, 1830.5, 1793.8, 1637.6, 1591.3, 1560.4, 1525.7, 1508.3, 1460.1, 1294.2, 1280.7, 1244.1, 1192.0, 1159.2, 1120.6, 1037.7, 962.5, 935.5, 864.1, 837.1, 790.8, 752.2, 719.5, 638.4, 567.1, 534.3 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 3.61 (s, 3 H), 5.57 (s, 2 H), 5.79 (s, 1 H), 6.83 (m, 2 H), 7.11 (m, 1 H), 7.50 (dd, J = 2.0, 8.0 Hz, 1 H), 11.19 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 34.09, 85.04, 116.67, 117.61, 119.39, 126.62, 128.73, 148.73, 149.34, 156.02.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₂N₃O: 190.0980; found: 190.0975.

2-(5-Amino-1-methyl-1H-pyrazol-3-yl)-4-bromophenol (4i)

Yield: 1.33 g (39%); white solid; mp 165.9 °C.

IR (KBr): 3458.4, 3371.6, 3063.0, 2937.6, 2891.3, 2848.9, 2802.6, 2700.3, 1888.3, 1730.2, 1612.5, 1556.6, 1519.9, 1456.3, 1415.8, 1386.8, 1356.0, 1275.0, 1190.1, 1138.0, 1087.9, 1033.9, 972.1, 866.0, 831.3, 817.8, 790.8, 758.0, 719.5, 686.7, 628.8, 553.6 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 3.61 (s, 3 H), 5.62 (s, 2 H), 5.88 (s, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J = 2.4, 8.4 Hz, 1 H), 7.69 (d, J = 2.8 Hz, 1 H), 11.31 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 34.77, 85.62, 110.65, 118.97, 120.00, 128.63, 131.08, 147.82, 148.82, 155.23.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₁BrN₃O: 268.0085; found: 268.0080.

3-Methoxy-2-{5-[4-(trifluoromethyl)phenylamino]-1H-pyrazol-3-yl}phenol (4e)

To a 25 mL Schleck tube was added 5-methoxy-2-[4-(trifluoromethyl)phenylamino]-4H-chromen-4-one (500 mg, 1.49 mmol), DMSO (10 mL), and hydrazine hydrate (50% in H₂O, 500 mg, 4.99 mmol,). The solution was heated to 125 °C, then stirred at 125 °C for 3 h before additional hydrazine hydrate (50% in H₂O, 500 mg, 4.99 mmol) was added. The reaction mixture was stirred for an additional 3 h at 125 °C, then cooled to 25 °C, H₂O (30 mL) was added, and the solution was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with H₂O (2 × 50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (petroleum ether–EtOAc, 3:1) to afford 4e.

Yield: 250 mg (45.0%); white solid; mp 172.3 °C.

IR (KBr): 3396.6, 3192.2, 3088.3, 3020.5, 2966.5, 2939.5, 2843.1, 2617.4, 2563.4, 1923.0, 1903.7, 1622.1, 1597.1, 1556.6, 1516.1, 1491.0, 1465.9, 1342.5, 1311.6, 1282.7, 1246.0, 1192.0, 1168.9, 1153.4, 1111.0, 1095.6, 1087.9, 1072.4, 1026.1, 962.5, 945.1, 839.0, 823.6, 783.1, 690.5, 648.1, 628.8, 570.9, 518.9, 505.4 cm^–1.

¹H NMR (400 MHz, CD₃OD): δ = 3.91 (s, 3 H), 6.61 (t, J = 8.0 Hz, 3 H), 7.15 (t, J = 8.4 Hz, 3 H), 7.29 (s, 2 H), 7.46 (d, J = 7.6 Hz, 2 H).

¹³C NMR (100 MHz, CD₃OD): δ = 56.22, 98.63, 103.70, 110.09, 115.18, 127.28, 130.30, 149.31, 159.55.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₅F₃N₃O₂: 350.3116; found: 350.3111.

2-[5-(Ethylamino)-4-methyl-1H-pyrazol-3-yl]phenol (4g)

To a 25 mL Schlenk tube was added 2-amino-3-methyl-4H-chromen-4-one (600 mg, 2.95 mmol), DMSO (6 mL) and hydrazine (700 mg, 98%, 21.9 mmol). The reaction mixture was stirred and heated to 125 °C for 18 h, then cooled to 25 °C and H₂O (20 mL) was added. The solution was extracted with EtOAc (3 × 20 mL) and the combined organic layer was washed with H₂O (2 × 30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (petroleum ether–EtOAc, 3:1) to give 4g.

Yield: 300 mg (45.0%); white solid; mp 145.0 °C.

IR (KBr): 3406.3, 3352.3, 2968.5, 2926.0, 2864.3, 2694.6, 2569.2, 2250.9, 1597.1, 1581.6, 1535.3, 1444.7, 1373.3, 1352.1, 1292.3, 1265.3, 1213.2, 1170.8, 1109.1, 1062.8, 1041.6, 1008.8, 947.1, 920.1, 752.2, 713.7, 690.5, 628.8, 561.3, 509.2 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 1.24 (t, J = 7.2 Hz, 3 H), 2.07 (s, 3 H), 3.20 (q, J = 7.2 Hz, 2 H), 6.91 (t, J = 7.6 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 7.20 (m, 1 H), 7.51 (d, J = 7.6 Hz, 1 H).

¹³C NMR (100 MHz, CD₃OD): δ = 7.02, 13.53, 38.19, 94.25, 114.82, 116.19, 117.33, 126.00, 127.02, 144.89, 147.42, 153.80.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₆N₃O: 218.1293; found: 218.1288.

2-(5-Amino-1-tert-butyl-1H-pyrazol-3-yl)-3-methoxyphenol (4m)

Prepared as described for 4j. To a 250 mL flask was added tert-butylhydrazine hydrochloride (3.9 g, 31.30 mmol), DMSO (45 mL), and Et₃N (4.8 g, 47.44 mmol) at 25 °C. The reaction mixture was stirred for 10 min, then 2-amino-5-methoxy-4H-chromen-4-one (3.08 g, 16.11 mmol) was added, and the mixture was heated to 100 °C. The reaction mixture was stirred at 100 °C for 48 h then cooled to 25 °C and H₂O (100 mL) was added. The solution was extracted with EtOAc (3 × 50 mL) and the combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether–EtOAc, 5:1 to 3:1 v/v) to provide 4m.

Yield: 1.8 g (43.0%); white solid; mp 163.9 °C.

IR (KBr): 3468.0, 3385.1, 3163.3, 2978.1, 2933.7, 2835.4, 1901.8, 1801.5, 1741.7, 1626.0, 1593.2, 1552.7, 1496.8, 1469.8, 1373.3, 1305.8, 1247.9, 1191.8, 1182.4, 1089.8, 1072.4, 968.3, 941.3, 814.0, 788.9, 733.0, 630.7, 532.4 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.55 (s, 9 H), 3.82 (s, 3 H), 5.23 (s, 2 H), 6.12 (s, 1 H), 6.50 (m, 2 H), 7.06 (t, J = 8.4 Hz, 1 H), 12.62 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 28.89, 56.01, 58.43, 93.57, 102.33, 106.92, 109.86, 128.41, 144.83, 147.30, 158.06, 158.12.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₂₀N₃O₂: 262.1556; found: 262.1550.

2-(1-tert-Butyl-5-(2-tert-butylhydrazinyl)-1H-pyrazol-3-yl)-3-methoxyphenol (4m′)

Obtained from chromatography of compound 4m.

Yield: 0.6 g (11%); yellow solid; mp 170.3 °C.

IR (KBr): 3313.7, 3271.3, 3178.7, 2970.4, 2958.8, 2868.2, 2497.8, 1917.2, 1815.0, 1710.9, 1618.3, 1587.4, 1556.6, 1502.6, 1452.4, 1357.9, 1344.4, 1236.4, 1180.4, 1085.9, 1026.1, 964.4, 943.2, 877.6, 831.3, 796.6, 723.3, 700.2, 628.8, 613.4, 574.8, 532.4 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.06 (s, 9 H), 1.56 (s, 9 H), 3.82 (s, 3 H), 4.14 (d, J = 4.4 Hz, 1 H), 6.25 (d, J = 4.8 Hz, 1 H), 6.49 (m, 3 H), 7.06 (t, J = 8.2 Hz, 1 H), 12.51 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 27.38, 28.57, 53.63, 55.61, 58.32, 94.04, 101.94, 106.51, 109.34, 127.99, 144.15, 151.78, 157.52, 157.60.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₉N₄O₂: 333.2291; found: 333.2285.

2-(5-Amino-1-tert-butyl-1H-pyrazol-3-yl)-4-bromophenol (4j)

Yield: 0.92 g (23%); yellow solid.

IR (KBr): 3437.2, 3358.1, 2980.0, 2933.7, 2806.4, 2708.1, 1872.9, 1737.9, 1620.2, 1579.7, 1552.7, 1514.1, 1458.2, 1369.5, 1275.0, 1253.7, 1240.2, 1195.9, 1168.9, 1087.9, 974.1, 875.7, 844.8, 817.8, 763.8, 727.2, 671.2, 628.8, 603.7, 567.1, 553.6, 484.1 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.59 (s, 9 H), 5.38 (s, 2 H), 5.95 (s, 1 H), 6.81 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J = 2.4, 8.8 Hz, 1 H), 7.63 (d, J = 2.4 Hz, 1 H), 11.65 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 28.34, 58.21, 87.95, 110.05, 118.43, 119.41, 127.91, 130.54, 145.55, 147.93, 154.81.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₆BrN₃NaO: 332.0374; found: 332.0369.

4-Bromo-2-[1-tert-butyl-5-(2-tert-butylhydrazinyl)-1H-pyrazol-3-yl]phenol (4j′)

Obtained from compound 4j reaction mixture.

Yield: 1.20 g (26%); yellow solid; mp 134.7 °C.

IR (KBr): 3352.3, 3331.1, 3250.1, 2953.0, 2866.2, 2700.3, 1867.1, 1747.5, 1616.4, 1566.2, 1518.0, 1460.1, 1371.4, 1357.9, 1342.5, 1276.9, 1261.5, 1226.7, 1161.2, 1082.1, 1026.1, 974.1, 875.7, 817.8, 769.6, 729.1, 688.6, 628.8, 601.8, 574.8, 526.6, 495.7 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.07 (s, 9 H), 1.60 (s, 9 H), 4.14 (s, 1 H), 6.39 (s, 2 H), 6.82 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J = 2.4, 8.8 Hz, 1 H), 7.72 (d, J = 2.4 Hz, 1 H), 11.55 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 27.27, 28.49, 53.75, 58.58, 89.00, 110.13, 118.42, 119.41, 128.05, 130.56, 145.42, 153.12, 154.77.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₆BrN₄O: 381.1290; found: 381.1285.

Acknowledgment

We thank Shanghai Pharmexplorer’s staff for optimizing reaction conditions. Discussions with Professors Marvin J. Miller and William R. Roush during this work are also appreciated.

• References

• 1a Shanghai Pharmexplorer, Shanghai, 201210, P. R. of China.
• 1b Current address: Butler University, Department of Chemistry, 4600 Sunset Avenue, Indianapolis, IN 46208, USA.
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• References

• 1a Shanghai Pharmexplorer, Shanghai, 201210, P. R. of China.
• 1b Current address: Butler University, Department of Chemistry, 4600 Sunset Avenue, Indianapolis, IN 46208, USA.
• 2a Kim I, Song JH. Park C. M, Jeong JW, Kim GR, Ha JR, No Z, Hyun Y.-s, Kang NS, Jeon DJ. Bioorg. Med. Chem. Lett. 2010; 20: 922
  CrossrefSearch in Google Scholar
• 2b Dakshanamurthy S, Issa NT, Assefnia S, Seshasayee A, Peters OJ, Madhavan S, Uren A, Brown ML, Byers SW. J. Med. Chem. 2012; 55: 6832
  CrossrefSearch in Google Scholar
• 2c Estrada AA, Chan BK, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, Chen H, Dominguez SL, Dotson J, Drummond J, Flagella M, Fuji R, Gill A, Halladay J, Harris SF, Heffron TP, Kleinheinz T, Lee DW, Le Pichon CE, Liu X, Lyssikatos JP, Medhurst AD, Moffat JG, Nash K, Scearce-Levie K, Sheng Z, Shore DG, Wong S, Zhang S, Zhang X, Zhu H, Sweeney ZK. J. Med. Chem. 2014; 57: 921
  CrossrefPubMedSearch in Google Scholar
• 2d Farouz FS, Holcomb RC, Kasar R, Myers SS. US Patent 20110144126 A, 2011 ; Chem. Abstr. 2011, 155, 30770.
• 2e Kim H, Kim M, Lee J, Yu H, Hah J.-M. Bioorg. Med. Chem. 2011; 19: 6760
  CrossrefSearch in Google Scholar
• 3a Aggarwal R, Kumar V, Kumar R, Singh SP. Beilstein J. Org. Chem. 2011; 7: 179
  CrossrefPubMedSearch in Google Scholar
• 3b Anwar HF, Elnagdi MH. ARKIVOC 2009; (i): 198
  Search in Google Scholar
• 4a Gardner TS, Smith FA, Wenis E, Lee J. J. Org. Chem. 1956; 21: 530
  CrossrefSearch in Google Scholar
• 4b Lemke TL, Sawhney KN, Lemke BK. J. Heterocycl. Chem. 1982; 19: 363
  Search in Google Scholar
• 4c Sviridov SI, Vasil’ev AA, Shorsnev SV. Tetrahedron 2007; 63: 12195
  CrossrefSearch in Google Scholar
• 4d Musante C. Gazz. Chim. Ital. 1942; 72: 537
  Search in Google Scholar
• 4e Musante C. Gazz. Chim. Ital. 1943; 73: 355
  Search in Google Scholar
• 4f Musante C, Stener A. Gazz. Chim. Ital. 1959; 89: 1579
  Search in Google Scholar
• 4g Fusco R, Zumin S. Gazz. Chim. Ital. 1946; 76: 223
  Search in Google Scholar
• 4h Cusmano C. Gazz. Chim. Ital. 1940; 70: 227
  Search in Google Scholar
• 4i Cusmano C. Gazz. Chim. Ital. 1940; 70: 237
  Search in Google Scholar
• 4j Cusmano C. Gazz. Chim. Ital. 1940; 70: 240
  Search in Google Scholar
• 4k d’Alcontres GS. Gazz. Chim. Ital. 1950; 80: 441
  Search in Google Scholar
• 4l Quilico A. Five- and Six-Membered Compounds with Nitrogen and Oxygen. In The Chemistry of Heterocyclic Compounds. Vol. 17. Wiley RH. Interscience; New York/London: 1962: 48-49
  CrossrefSearch in Google Scholar
• 5a Bell F. J. Chem. Soc. 1941; 285
  Crossref
• 5b Donati D, Fusi S, Ponticelli F. J. Heterocycl. Chem. 1998; 35: 109
  CrossrefSearch in Google Scholar
• 6 Ioannidou HA, Koutentis PA. Tetrahedron 2009; 65: 7023
  CrossrefSearch in Google Scholar
• 7a Bernhammer JC, Huynh HV. Dalton Trans. 2012; 41: 8600
  CrossrefSearch in Google Scholar
• 7b Huang y.-Y. Tetrahedron Lett. 2011; 52: 3786
  CrossrefSearch in Google Scholar
• 8a Shokol TV, Turov VA, Semeniuchenko VV, Krivokhizha NV, Khilya VP. Chem. Heterocycl. Compd. 2006; 42: 500
  CrossrefSearch in Google Scholar
• 8b Sosnovskikh VY. Tetrahedron Lett. 2008; 49: 6856
  CrossrefSearch in Google Scholar
• 8c Sosnovskikh VY, Kodess MI, Moshkin VS. Russ. Chem. Bull. 2009; 58: 1253
  CrossrefSearch in Google Scholar
• 9a Braibante ME. F, Braibante HT. S, Tavares Ld C, Rohte SR, Costa CC, Morel AF, Stüker CZ, Burrow RA. Synthesis 2007; 2485
  Thieme Connect
• 9b Dodd DS, Martinez RL. Tetrahedron Lett. 2004; 45: 4265
  CrossrefSearch in Google Scholar
• 10 Levchenko KS, Semenova IS, Yarovenko VN, Shmelin PS, Krayushkin MM. Tetrahedron Lett. 2012; 53: 3630
  CrossrefSearch in Google Scholar
• 11 Ghosh T, Saha S, Bandyopadhyay C. Synthesis 2005; 1845
  Thieme Connect
• 12a Nohara A, Ishiguro T, Ukawa K, Sugihara H, Maki Y, Sanno Y. J. Med. Chem. 1985; 28: 559
  CrossrefSearch in Google Scholar
• 12b Connor DT, Young PA, Von Strandtmann M. J. Heterocycl. Chem. 1981; 18: 697
  CrossrefSearch in Google Scholar
• 12c Ishiguro T, Ukawa K, Sugihara H, Nohara A. Heterocycles 1981; 16: 733
  CrossrefSearch in Google Scholar
• 13a Guram AS, Buchwald SL. J. Am. Chem. Soc. 1994; 116: 7901
  CrossrefSearch in Google Scholar
• 13b Paul F, Patt J, Hartwig JF. J. Am. Chem. Soc. 1994; 116: 5969
  CrossrefSearch in Google Scholar
• 14 Lam PY. S, Clark CG, Saubern S, Adams J, Winters MP, Chan DM. T, Combs A. Tetrahedron Lett. 1998; 39: 2941
  CrossrefSearch in Google Scholar
• 15a Foley DA, Doecke CW, Buser JY, Merritt JM, Murphy L, Kissane M, Collins SG, Maguire AR, Kaerner A. J. Org. Chem. 2011; 76: 9630
  CrossrefSearch in Google Scholar
• 15b Magnus NA, Astleford BA, Laird DL. T, Maloney TD, McFarland AD, Rizzo JR, Ruble JC, Stephenson GA, Wepsiec JP. J. Org. Chem. 2013; 78: 5768
  CrossrefSearch in Google Scholar
• 15c Buser JY, McFarland AD. Chem. Commun. 2014; 50: 4234
  CrossrefPubMedSearch in Google Scholar
• 16 Checchi S, Pecori Vettori L, Vincieri F. Gazz. Chim. Ital. 1968; 98: 1488
  Search in Google Scholar

• Supplementary Material