Palladium-Catalyzed Peripheral Arylation of 5-Pyrazolones via Enolizable Bond Protection

Abstract

Peripheral cross-coupling of the enol form of the 5-pyrazolone scaffold with arylboronic acids promoted by [PdCl₂(dppf)] afforded the arylated products in good yields. In this coupling, the protection of the enolizable hydroxyl group of pyrazolone is a prerequisite for ensuring the Suzuki-Miyaura cross-coupling. A particular feature of this process is that it enables the synthesis of 5-hydroxy-3-biphenyl and -terphenylpyrazole derivatives with structural diversity.

Pyrazoles are structural units that are frequently found in natural products and pharmaceuticals, and there has been a growing interest in new synthetic methods for their preparation. Such heterocyclic frameworks serve as important core structures that are required for a wide range of biological activities, such as antibacterial/antitumor, anti-inflammatory, analgesic, and anti-hyperglycemic activity­, [¹] and are interesting templates that can be used to access­ highly functionalized pyrazole derivatives. In particular, many arylated pyrazoles have been synthesized and have proven to be effective inhibitors of COX-2, p38 MAP kinase, and CDK2/Cyclin A. [²] As part of pyrazole diversity-oriented syntheses, [³] we were interested in an efficient method for incorporating an aryl group onto a peripheral site on enolizable pyrazolone derivatives.

Decades of progress in transition-metal-catalyzed arylation of pyrazoles has provided an indispensable method for the construction of a number of diversely arylated pyrazoles. [4] Substantial effort has focused on the use of pyrazole halides or triflates derived from pyrazolones through enolizable bond activation (Scheme  [¹] , route I). [5] These approaches are rather limited to the use of tautomerizable heterocycles as synthetic precursors for halides or pseudohalides. However, palladium-catalyzed peripheral arylation of the pyrazolone fragment keeping the structure intact has not been widely explored to date (Scheme  [¹] , route II). [6] Herein, we wish to report Suzuki-Miyaura cross-coupling of the peripheral haloaryl group of enolizable 1-(2-pyridinyl)pyrazolone derivatives with arylboronic acids promoted by [PdCl₂(dppf)] [dppf = 1,1"-bis(diphenylphosphino)ferrocene], resulting in good yields of arylated products.

To examine the feasibility of peripheral arylation of the tautomeric pyrazolone scaffold, we initiated Suzuki-Miyaura cross-coupling of 1-(2-pyridinyl)-5-hydroxypyrazole (1a) and 1-phenyl-5-pyrazolone (1b) as substrates. Based on NMR analysis (CDCl₃, r.t.), it was noted that 1a exists exclusively in enol form, whereas 1b remains as it stands. [7] Despite employing various conditions reported in literature, we failed to accomplish the Suzuki coupling of 1a with phenylboronic acid (Table  [¹] , entries 1-3). It is assumed that the palladium catalyst is stabilized and inactivated through chelation with the substrate bearing a bidentate ligand. [8] On the other hand, the Suzuki cross-coupling of 1b furnished the corresponding 3-(3-biphenyl)pyrazolone 1c in 71% yield within one hour (entry 4). The observed difference indicates that initial oxidative addition of palladium(0) to bromide 1a may hamper or compete with substantial complexation, with the substrate leading to the formation of inactive species 1a′ (Figure  [¹] ). [8a-c] We rule out a plausible alternative Pd complex with the two nitrogen atoms of the pyridine-pyrazole ligand, [8d] [e] because 1-(2-pyridinyl)pyrazole 1d also exists in the enol form, and the X-ray crystal structure clearly shows that the carbonyl oxygen and pyridine nitrogen adopt an almost syn-periplanar arrangement that is capable of accommodating intramolecular hydrogen bonding (Figure  [²] ).

Table 1 Suzuki Cross-Coupling of 5-Pyrazolone/5-Hydroxypyrazole Derivatives with Phenylboronic Acid^a

Entry	Bromide	Reagents	Solvent	Time (h)	Product [yield (%)b]
1	1a	[Pd(PPh3)4], Na2CO3	DME	72	-c
2	1a	[Pd(PPh3)4], CsCO3	DME	72	-c
3	1a	[PdCl2(dppf)], dppf, K3PO4	1,4-dioxane	20	-c,d
4	1b	[PdCl2(dppf)], dppf, K3PO4	1,4-dioxane	0.5	1c (71)
5	2a	[Pd(PPh3)4], Na2CO3	DME	30	1a (23)
6	3a	[PdCl2(dppf)], dppf, K3PO4	1,4-dioxane	1	3b (5), 6a (24)
7	4a	[PdCl2(dppf)], dppf, K3PO4	1,4-dioxane	0.5	5a (90)
a Reaction conditions: phenylboronic acid (2-3 equiv), Pd (5-8 mol%), dppf (4 mol%), base (2-3 equiv), 85-100 ˚C. b Isolated yield. c No reaction observed; the starting material decomposed. d Trace amounts of two unidentified byproducts were isolated.

These results led to further investigations into whether protection of the enolizable ketone could influence the outcome of the Suzuki reaction. Suzuki coupling with acetate­ 2a was unsuccessful, [4b] and only led to liberation of the parent molecule (entry 5). Protection of 1a with TIPS-Cl and imidazole in N,N-dimethylformamide (DMF) smoothly afforded the corresponding silyl enol ether 3a. However, even when the TIPS group was used, the Suzuki coupling gave the two arylated pyrazoles 3b and 6a in poor yields (entry 6). We reasoned that a pentacoordinated silicon species, which was brought about by coordination with the adjacent pyridine nitrogen, was presumably responsible for the unusual basic hydrolysis of the TIPS group. [9] The hydrolytic susceptibility of this moiety eventually forced us to find protecting groups that were more stable towards base-mediated hydrolysis. A survey of protecting groups revealed that the tert-butoxycarbonyl (Boc) group allows facile Suzuki coupling to take place within one hour in excellent yield (entry 7). Thus, this strategy was subsequently employed for all substrates.

The 5-hydroxypyrazole derivatives 1e-k were conveniently prepared by treatment of the corresponding benzoylacetates with 2-hydrazinopyridines, respectively, in refluxing acetic acid. [7] Benzoylacetates were available from commercial sources and α-alkylated derivatives were prepared according to a previous procedure. [¹0] Consequently, the 5-hydroxypyrazole derivatives were readily protected to provide their Boc-derivatives 4b-h using di-tert-butyldicarbonate (Boc₂O) in the presence of catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP) in dichloromethane. [¹¹] The Boc-protected pyrazoles were sufficiently stable to allow chromatographic separation and isolation in excellent yields, as shown in Table  [²] .

Table 2 Boc-Protection of 5-Hydroxypyrazole Derivatives

Entry	1	A	X	Y	4	Yield (%)
1	1a	CH	4-Br	H	4a	97
2	1e	CH	4-I	H	4b	99
3	1f	CH	3-I	H	4c	99
4	1g	CH	2-I	H	4d	98
5	1h	CH	4-Br	n-Pr	4e	89
6	1i	CH	4-Br	Bn	4f	94
7	1j	CCl	3-I	H	4g	95
8	1k	N	4-I	H	4h	97

With substrates in hand, we wished to demonstrate the scope of this protocol for the palladium-catalyzed peripheral arylation of 3-haloarylpyrazole derivatives with electronic and steric variations on both coupling partners, and to secure synthesis of biphenyl and terphenylpyrazole analogues with structural diversity. Coupling of the Boc-protected pyrazoles with arylboronic acids was accomplished with [PdCl₂(dppf)] in 1,4-dioxane, with K₃PO₄ as the base, to provide the coupling products within one hour. The reaction with electron-rich arylboronic acids generally tolerates differing substitution patterns on the peripheral aryl group, as shown in Table  [³] . In addition, reaction of sterically hindered 2-phenoxyphenylboronic acid with either p- or m-iodide-substituted starting materials 4b and 4c, respectively, provided the corresponding products in moderate yields (entries 6 and 8). However, the reaction failed with electron-poor arylboronic acids. Although the coupling of o-isomers showed a decreased reactivity compared to those of the corresponding m-congeners, the yields were still acceptable (Table  [³] , entries 9 and 10 vs. entries 13 and 14).

A higher degree of substitution, for example in 4e and 4f, ultimately led to a drop in yields although the reactions proceeded smoothly (Table  [³] , entries 15 and 16). Variation at the pyridine moiety did not affect the yield or reaction times (entries 17 and 18). Therefore, the Boc group protecting strategy was suitable for the Suzuki cross-coupling­ of 3-haloarylpyrazoles and prevented problems caused by the pyridine nitrogen.

The Boc group is widely used in organic synthesis as both an amine and a phenol protecting group, and cleavage is usually achieved by treatment with an acid such as tri­fluoroacetic acid (TFA) or HCl. In a typical procedure, Boc-protected 3-biphenylpyrazole 5a was thus treated with TFA at ambient temperature in dichloromethane to release the desired product 6a in 93% yield. [¹¹] All the Boc-protected derivatives were deprotected within five hours, to produce 5-hydroxy-3-biphenyl and -terphenylpyrazole analogues 6b-s in good yields (Table  [³] ). Again, all the products existed exclusively in the enol form.

Table 3 Pd-Catalyzed Arylation of 5-(tert-Butoxycarbonyl­oxy)pyrazole Derivatives 4 and TFA-Mediated Boc-Deprotection
(continued)

Entry	4	ArB(OH)2	5 (% yield)	6 (% yield)
1	4a		5b (70)	6b (70)
2	4a		5c (95)	6c (58)
3	4a		5d (98)	6d (71)
4	4a		5e (81)	6e (99)
5	4b		5f (98)	6f (85)
6	4b		5g (63)	6g (86)
7	4c		5h (66)	6h (84)
8	4c		5i (56)	6i (80)
9	4c		5j (99)	6j (98)
10	4c		5k (90)	6k (85)
11	4c		5l (84)	6l (97)
12	4c		5m (90)	6m (99)
13	4d		5n (84)	6n (84)
14	4d		6o (82)a
15	4e		5p (74)	6p (91)
16	4f		5q (87)	6q (96)
17	4g		5r (95)	6r (90)
18	4h		5s (90)	6s (93)
a The deprotected product 6o was obtained in 82% yield.

In summary, transition-metal-catalyzed arylation of pyrazoles provides a powerful method for the construction of a number of diversely arylated pyrazoles. However, approaches have mainly been based on the use of pyrazole halides and triflates derived from pyrazolones through enolizable bond activation. In this study, we revealed that the peripheral cross-coupling of the enol form of the 5-pyrazolone scaffold with arylboronic acids promoted by [PdCl₂(dppf)] afforded the arylated products in good yields. To ensure the Suzuki-Miyaura cross-coupling, protection of the enolizable hydroxyl group of pyrazolone is crucial. The advantage of this process is the ability to secure the synthesis of 5-hydroxy-3-biphenyl and -terphenylpyrazole derivatives with structural diversity.

The reactions were monitored by TLC with Merck silica gel 60 F₂₅₄ TLC glass plates, and the products were purified by flash chromatography with Merck Kiesel 60 silica gel (particles size 0.040-0.063 mm) using a glass column. ^¹H (300 MHz) and ^¹³C (75 MHz) NMR spectra were recorded with a Jeol Eclipse FT 300 MHz spectrometer. Mass spectra were recorded with an Agilent 1100 Series VLL or a JEOL the MStation JMS 700 mass Spectrometer.

Preparation of 5-Pyrazolone/5-Hydroxypyrazole; General Procedure

The starting 5-pyrazolone (keto form) and 5-hydroxypyrazole (enol form) were obtained in 65-88% yields after chromatographic separation, by the treatment of the appropriate hydrazines with β-keto ­esters in refluxing acetic acid according to the procedure described by Huang et al. [7]

1-(2-Pyridinyl)-3-(4-bromophenyl)-5-hydroxypyrazole (1a)

Yield: 81%.

^¹H NMR (300 MHz, CDCl₃): δ = 12.86-12.84 (br s, 1 H), 8.30-8.28 (m, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.94-7.88 (m, 1 H), 7.74 (d, J = 8.5 Hz, 2 H), 7.54 (d, J = 8.4 Hz, 2 H), 7.21-7.16 (m, 1 H), 5.91 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 154.6, 151.6, 145.3, 140.1, 132.1, 131.8, 127.5, 122.6, 120.2, 112.4, 85.7.

HRMS (EI): m/z calcd for C₁₄H₁₀BrN₃O: 315.0007; found: 314.9998.

1-Phenyl-3-(3-bromophenyl)-5-pyrazolone (1b)

Yield: 88%.

^¹H NMR (300 MHz, CDCl₃): δ = 7.97-7.93 (m, 3 H), 7.67-7.56 (m, 2 H), 7.46-7.40 (m, 2 H), 7.33 (t, J = 7.9 Hz, 1 H), 7.25-7.20 (m, 1 H), 3.81 (s, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 170.0, 153.2, 138.0, 133.6, 132.9, 130.5, 129.0, 128.9, 125.6, 124.7, 123.3, 119.2, 39.5.

HRMS (EI): m/z calcd for C₁₅H₁₁BrN₂O: 314.0055; found: 314.0056.

1-(2-Pyridinyl)-3-(phenyl)-5-hydroxypyrazole (1d)

Yield: 87%.

^¹H NMR (300 MHz, CDCl₃): δ = 12.83 (br s, 1 H), 8.28-8.27 (m, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.92-7.85 (m, 3 H), 7.48-7.32 (m, 3 H), 7.19-7.14 (m, 1 H), 5.94 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.3, 154.7, 152.7, 145.2, 140.0, 133.2, 128.7, 128.6, 125.9, 120.0, 112.4, 85.8.

EIMS (70 eV): m/z (%) = 237 (100) [M]⁺, 209 (28), 196 (77), 180 (17), 160 (28), 102 (31), 79 (65).

X-ray Crystallographic Data (1d)

Empirical formula: C₁₄H₁₁N₃O; Formula weight: 237.26; Crystal system: monoclinic; Space group: P2(1)/c; Unit cell dimensions: a = 9.8059(4) Å, α = 90˚, b = 10.6374(5) Å, β = 104.000(2)˚, c = 11.4730(5) Å, γ = 90˚; Density (calculated): 1.357 Mg/m^³; Reflections collected: 11635; Final R indices [I > 2σ(I)], R1 = 0.0451, wR2 = 0.1206; R indices (all data), R1 = 0.0594, wR2 = 0.1316. Atomic coordinates and crystallographic parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC 805262). These data can be obtained free of charge from the Cambridge­ Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Pd-Catalyzed Direct Arylation of 5-Pyrazolone: Preparation of 1-Phenyl-3-(3-biphenyl)-5-pyrazolone (1c)

To a stirred solution of 1b (120 mg, 0.38 mmol), phenylboronic acid (139 mg, 1.14 mmol), K₃PO₄ (242 mg, 1.14 mmol), [PdCl₂(dppf)] (25 mg, 0.03 mmol), and dppf (8.4 mg, 0.015 mmol) in 1,4-dioxane (6 mL) was heated at 100 ˚C for 1 h. The reaction mixture was cooled to r.t., filtered through Celite, and the filtrate was concentrated to dryness. The residue was taken up with EtOAc (20 mL), and the organic layer was washed with H₂O (3 × 10 mL), dried over anhydrous MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane-EtOAc, 10:1) to afford 1c.

Yield: 85 mg (72%).

^¹H NMR (300 MHz, CDCl₃): δ = 8.00-7.97 (m, 3 H), 7.73-7.62 (m, 4 H), 7.55-7.40 (m, 6 H), 7.25-7.20 (m, 1 H), 3.89 (s, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 170.3, 154.7, 142.2, 140.4, 138.2, 131.5, 129.6, 129.5, 129.1, 129.0, 127.3, 127.3, 125.5, 125.0, 124.7, 119.2, 39.8.

HRMS (EI): m/z calcd for C₂₁H₁₆N₂O: 312.1263; found: 312.1263.

Boc-Protection of 5-Hydroxypyrazoles: tert -Butyl 1-(2-Pyridinyl)-3-(4-bromophenyl)-5-pyrazolyl Carbonate (4a); Typical Procedure

To a solution of 1a (272 mg, 0.86 mmol) and di-tert-butyldicarbonate (0.24 mL, 1.03 mmol) in CH₂Cl₂ (7 mL), DMAP (5 mg, 0.04 mmol) was added. When the reaction was complete (1 h as judged by TLC), the mixture was washed with H₂O (3 × 5 mL), dried over anhydrous MgSO₄, and concentrated to dryness. The crude material was purified by column chromatography on silica gel (hexane-EtOAc, 10:1) to afford 4a.

Yield: 347 mg (97%).

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.41 (m, 1 H), 7.99-7.96 (m, 1 H), 7.85-7.80 (m, 1 H), 7.75 (d, J = 8.5 Hz, 2 H), 7.55 (d, J = 8.5 Hz, 2 H), 7.22-7.18 (m, 1 H), 6.49 (s, 1 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.2, 150.1, 149.6, 147.8, 146.6, 138.6, 131.9, 131.8, 127.3, 122.6, 121.7, 115.2, 96.0, 85.0, 27.7.

MS (CI⁺): m/z (%) = 418 (3) [M]⁺, 416 (2) [M]⁺, 358 (26), 356 (17), 317 (100), 315 (87), 79 (16).

tert -Butyl 1-(2-Pyridinyl)-3-(4-iodophenyl)-5-pyrazolyl Carbonate (4b)

^¹H NMR (300 MHz, CDCl₃): δ = 8.42-8.40 (m, 1 H), 7.99-7.96 (m, 1 H), 7.85-7.80 (m, 1 H), 7.76 (d, J = 8.5 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 2 H), 7.22-7.18 (m, 1 H), 6.50 (s, 1 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.1, 150.2, 149.6, 147.8, 146.6, 138.6, 137.8, 132.4, 127.5, 121.7, 115.2, 96.0, 94.3, 85.0, 27.7.

MS (CI⁺): m/z (%) = 465 (1) [M]⁺, 464 (43) [M]⁺, 420 (12), 406 (12), 365 (15), 364 (100), 363 (29), 238 (2), 237 (1).

tert -Butyl 1-(2-Pyridinyl)-3-(3-iodophenyl)-5-pyrazolyl Carbonate (4c)

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.41 (m, 1 H), 8.26-8.25 (m, 1 H), 8.01-7.98 (m, 1 H), 7.86-7.78 (m, 2 H), 7.70-7.66 (m, 1 H), 7.23-7.18 (m, 1 H), 7.15-7.13 (m, 1 H), 6.50 (s, 1 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.1, 149.6, 149.5, 147.8, 146.5, 138.6, 137.5, 134.9, 134.6, 130.4, 125.0, 121.7, 115.2, 96.1, 94.7, 85.0, 27.7.

MS (CI⁺): m/z (%) = 465 (5) [M]⁺, 464 (25) [M]⁺, 420 (9), 406 (10), 365 (15), 364 (100), 363 (26), 238 (3), 237 (1).

tert -Butyl 1-(2-Pyridinyl)-3-(2-iodophenyl)-5-pyrazolyl Carbonate (4d)

^¹H NMR (300 MHz, CDCl₃): δ = 8.42-8.41 (m, 1 H), 7.97 (d, J = 8.1 Hz, 2 H), 7.83-7.78 (m, 1 H), 7.63-7.61 (m, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.21-7.17 (m, 1 H), 7.08-7.02 (m, 1 H), 6.58 (m, 1 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 153.0, 152.2, 149.7, 147.8, 145.3, 140.3, 138.6, 138.0, 130.8, 130.0, 128.2, 121.7, 115.3, 99.6, 96.8, 84.9, 27.7.

MS (CI⁺): m/z (%) = 465 (12) [M]⁺, 464 (54) [M]⁺, 420 (8), 419 (6), 406 (11), 404 (6), 365 (15), 364 (100), 363 (26), 238 (3), 237 (1).

tert -Butyl 1-(2-Pyridinyl)-3-(4-bromophenyl)-4-propyl-5-pyrazolyl Carbonate (4e)

^¹H NMR (300 MHz, CDCl₃): δ = 8.39-8.37 (m, 1 H), 7.96 (d, J = 8.3 Hz, 1 H), 7.81-7.15 (m, 1 H), 7.59 (dd, J = 14.8, 8.8 Hz, 4 H), 7.18-7.14 (m, 1 H), 2.56 (t, J = 7.7 Hz, 2 H), 1.59-1.54 (m, 2 H), 1.52 (s, 9 H), 0.92 (t, J = 7.4 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 149.9, 149.4, 147.7, 143.6, 138.5, 132.8, 131.7, 129.3, 122.4, 121.3, 114.6, 110.6, 84.7, 27.7, 24.6, 22.8, 14.0.

MS (CI⁺): m/z (%) = 460 (50) [M]⁺, 458 (49) [M]⁺, 402 (14), 400 (20), 398 (9), 361 (17), 360 (96), 359 (57), 358 (100), 357 (40), 328 (13).

tert -Butyl 1-(2-Pyridinyl)-3-(4-bromophenyl)-4-benzyl-5-pyrazolyl Carbonate (4f)

^¹H NMR (300 MHz, CDCl₃): δ = 8.40-8.38 (m, 1 H), 8.01-7.98 (m, 1 H), 7.83-7.77 (m, 1 H), 7.48 (s, 4 H), 7.24-7.15 (m, 6 H), 3.94 (s, 2 H), 1.48 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 149.9, 149.6, 147.7, 144.5, 139.3, 138.6, 132.2, 131.7, 129.4, 128.6, 128.3, 126.3, 122.6, 121.4, 114.6, 108.8, 84.9, 28.5, 27.6.

MS (CI⁺): m/z (%) = 508 (40) [M]⁺, 506 (38) [M]⁺, 450 (17), 448 (22), 446 (9), 409 (21), 408 (98), 407 (62), 406 (100), 405 (40), 328 (4), 318 (1).

tert -Butyl 1-[2-(3-Chloro)pyridinyl]-3-(3-iodophenyl)-5-pyrazolyl Carbonate (4g)

^¹H NMR (300 MHz, CDCl₃): δ = 8.57-8.55 (m, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 7.7 Hz, 1 H), 7.66-7.63 (m, 2 H), 7.58-7.56 (m, 1 H), 7.50-7.34 (m, 1 H), 6.71 (s, 1 H), 1.52 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 150.7, 148.3, 147.3, 147.0, 146.9, 139.8, 137.4, 134.9, 134.7, 130.3, 128.9, 125.4, 125.1, 94.6, 92.4, 85.6, 27.5.

MS (CI⁺): m/z (%) = 500 (25) [M]⁺, 499 (16) [M]⁺, 498 (74) [M]⁺, 454 (7), 440 (14), 400 (32), 399 (22), 398 (100), 397 (21), 364 (6), 363 (2), 362 (1), 306 (1), 272 (1).

tert -Butyl 1-(2-Pyrimidinyl)-3-(4-iodophenyl)-5-pyrazolyl Carbonate (4h)

^¹H NMR (300 MHz, CDCl₃): δ = 8.79 (d, J = 4.8 Hz, 2 H), 7.76 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.26-7.22 (m, 1 H), 6.55 (s, 1 H), 1.58 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.7, 156.2, 151.7, 149.5, 147.5, 137.7, 131.7, 127.9, 118.9, 97.2, 94.9, 85.2, 27.7.

MS (CI⁺): m/z (%) = 465 (15) [M⁺ + 1], 421 (6), 407 (7), 405 (5), 366 (15), 365 (100), 364 (25), 273 (5), 239 (2).

Pd-Catalyzed Arylation of Boc-Protected 5-Hydroxypyrazoles: tert -Butyl 1-(2-Pyridinyl)-3-[4-(3′,4′-methylenedioxy)biphenyl]-5-pyrazolyl Carbonate (5b); Typical Procedure

A stirred solution of 4a (624 mg, 1.50 mmol), 3,4-(methylenedioxy)phenylboronic acid (747 mg, 4.50 mmol), K₃PO₄ (955 mg, 4.49 mmol), [PdCl₂(dppf)] (98 mg, 0.12 mmol), and dppf (33 mg, 0.06 mmol) in 1,4-dioxane (20 mL) was heated at 100 ˚C for 1 h. The reaction mixture was cooled to r.t., filtered through Celite, and the filtrate was concentrated to dryness. The residue was taken up with EtOAc (50 mL), and the organic layer was washed with H₂O (3 × 10 mL), dried over anhydrous MgSO₄, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (hexane-EtOAc, 8:1) to afford 5b.

Yield: 481 mg (70%).

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.40 (m, 1 H), 8.03-8.00 (m, 1 H), 7.92-7.89 (m, 2 H), 7.85-7.80 (m, 1 H), 7.59-7.56 (m, 2 H), 7.21-7.17 (m, 1 H), 7.13-7.10 (m, 2 H), 6.91-6.88 (m, 1 H), 6.54 (s, 1 H), 6.01 (s, 1 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 150.9, 149.7, 148.3, 147.8, 147.3, 146.5, 141.1, 138.5, 135.2, 131.4, 127.1, 126.2, 121.1, 120.7, 115.2, 108.7, 108.2, 106.7, 101.3, 98.4, 96.1, 84.9, 27.7.

MS (CI⁺): m/z (%) = 458 (4) [M]⁺, 415 (2), 414 (12), 400 (12), 364 (4), 358 (100), 69 (1).

tert -Butyl 1-(2-Pyridinyl)-3-(4-biphenyl)-5-pyrazolyl Carbonate (5a)

^¹H NMR (300 MHz, CDCl₃): δ = 8.44-8.41 (m, 1 H), 8.05-8.02 (m, 1 H), 7.97-7.93 (m, 2 H), 7.87-7.81 (m, 1 H), 7.69-7.64 (m, 4 H), 7.49-7.44 (m, 2 H), 7.39-7.34 (m, 1 H), 7.22-7.18 (m, 1 H), 6.56 (s, 1 H), 1.58 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 150.9, 149.7, 147.8, 146.5, 141.3, 140.8, 138.5, 131.8, 128.9, 127.5, 127.4, 127.1, 126.2, 121.5, 115.1, 96.1, 84.9, 27.7.

MS (CI⁺): m/z (%) = 414 (19) [M]⁺, 371 (2), 370 (8), 356 (13), 354 (5), 315 (21), 314 (100), 313 (38).

tert -Butyl 1-(2-Pyridinyl)-3-[4-(3′-phenyl)biphenyl]-5-pyrazolyl Carbonate (5c)

^¹H NMR (300 MHz, CDCl₃): δ = 8.44-8.41 (m, 1 H), 8.04-7.95 (m, 3 H), 7.86-7.80 (m, 2 H), 7.73-7.27 (m, 11 H), 7.22-7.17 (m, 1 H), 6.57 (s, 1 H), 1.58 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 156.1, 152.3, 150.9, 149.7, 147.8, 146.5, 142.0, 141.4, 140.9, 138.6, 131.9, 130.0, 129.3, 128.9, 128.8, 127.5, 127.4, 127.2, 126.4, 126.3, 126.1, 121.5, 119.8, 115.2, 114.3, 114.2, 96.2, 85.0, 27.7.

MS (CI⁺): m/z (%) = 446 (8), 432 (12), 392 (4), 390 (100), 358 (8).

tert -Butyl 1-(2-Pyridinyl)-3-[4-(1-naphthyl)phenyl]-5-pyrazolyl Carbonate (5d)

^¹H NMR (300 MHz, CDCl₃): δ = 8.44-8.42 (m, 1 H), 8.06-7.81 (m, 7 H), 7.58-7.42 (m, 6 H), 7.22-7.18 (m, 1 H), 6.59 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 151.0, 149.7, 147.8, 146.5, 141.1, 140.0, 138.6, 133.9, 131.8, 131.7, 130.5, 128.4, 127.9, 127.0, 126.2, 126.1, 125.9, 125.7, 125.5, 121.5, 115.1, 96.2, 84.9, 27.8.

MS (CI⁺): m/z (%) = 464 (4) [M]⁺, 420 (10), 406 (13), 390 (6), 364 (100), 363 (29), 283 (13), 69 (7).

tert -Butyl 1-(2-Pyridinyl)-3-[4-(3′-dimethylamino)biphenyl]-5-pyrazolyl Carbonate (5e)

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.41 (m, 1 H), 8.04-8.01 (m, 1 H), 7.93 (d, J = 8.2 Hz, 2 H), 7.86-7.80 (m, 1 H), 7.66 (d, J = 8.2 Hz, 2 H), 7.35-7.30 (m, 1 H), 7.21-7.17 (m, 1 H), 7.00-6.98 (m, 2 H), 6.78-6.75 (m, 1 H), 6.55 (s, 1 H), 3.02 (s, 6 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 151.1, 151.0, 149.7, 147.8, 146.5, 142.4, 141.8, 138.5, 131.6, 129.6, 127.6, 126.1, 121.5, 116.0, 115.1, 112.0, 111.5, 96.1, 84.9, 40.9, 27.7.

MS (CI⁺): m/z (%) = 457 (5) [M]⁺, 456 (2), 413 (10), 399 (9), 364 (8), 357 (100), 356 (36), 283 (11), 69 (7).

tert -Butyl 1-(2-Pyridinyl)-3-[4-(4′-benzyloxy)biphenyl]-5-pyrazolyl Carbonate (5f)

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.41 (m, 1 H), 8.03-8.01 (m, 1 H), 7.92 (d, J = 8.3 Hz, 2 H), 7.86-7.80 (m, 1 H), 7.63-7.56 (m, 4 H), 7.48-7.33 (m, 5 H), 7.21-7.17 (m, 1 H), 7.09-7.05 (m, 2 H), 6.54 (s, 1 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.6, 152.3, 150.9, 149.7, 147.8, 146.5, 140.9, 138.5, 137.1, 133.6, 131.2, 128.7, 128.2, 127.6, 126.9, 126.2, 121.5, 116.1, 115.3, 115.1, 96.1, 84.9, 70.2, 27.7.

MS (EI, 70 eV): m/z (%) = 519 (1) [M]⁺, 460 (2), 329 (24), 328 (100), 300 (5), 91 (48).

tert -Butyl 1-(2-Pyridinyl)-3-[4-(2′-phenoxy)biphenyl]-5-pyrazolyl Carbonate (5g)

^¹H NMR (300 MHz, CDCl₃): δ = 8.41-8.39 (m, 1 H), 8.00 (d, J = 8.28 Hz, 1 H), 7.87-7.78 (m, 3 H), 7.62 (d, J = 8.1 Hz, 2 H), 7.52-7.49 (m, 1 H), 7.34-7.15 (m, 5 H), 7.04-6.91 (m, 4 H), 6.51 (s, 1 H), 1.56 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.1, 156.2, 151.0, 149.8, 147.7, 138.5, 138.0, 131.8, 131.3, 129.7, 129.6, 129.0, 128.5, 126.1, 125.6, 125.0, 124.3, 122.7, 121.5, 120.5, 118.1, 115.1, 84.9, 27.7.

MS (CI⁺): m/z (%) = 462 (5), 448 (13), 446 (3), 407 (27), 406 (100), 405 (30).

tert -Butyl 1-(2-Pyridinyl)-3-[3-(4′-bromo)biphenyl]-5-pyrazolyl Carbonate (5h)

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.42 (m, 1 H), 8.06-8.00 (m, 2 H), 7.86-7.81 (m, 2 H), 7.60-7.49 (m, 6 H), 7.22-7.18 (m, 1 H), 6.57 (s, 1 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.2, 150.9, 149.7, 147.8, 146.5, 140.6, 140.1, 138.6, 133.5, 132.0, 129.3, 129.0, 127.2, 125.2, 124.4, 121.8, 121.6, 115.2, 96.2, 85.0, 27.7.

MS (CI⁺): m/z (%) = 494 (5) [M]⁺, 492 (6) [M]⁺, 450 (10), 448 (11), 434 (16), 432 (7), 394 (100), 392 (98), 314 (6).

tert -Butyl 1-(2-Pyridinyl)-3-[3-(2′-phenoxy)biphenyl]-5-pyrazolyl Carbonate (5i)

^¹H NMR (300 MHz, CDCl₃): δ = 8.40-8.39 (m, 1 H), 8.03 (s, 1 H), 7.95-7.92 (m, 2 H), 7.82-7.77 (m, 2 H), 7.56-7.52 (m, 2 H), 7.42-7.15 (m, 6 H), 7.05-6.93 (m, 3 H), 6.44 (s, 1 H), 1.56 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.1, 153.6, 152.3, 151.1, 149.7, 147.7, 146.4, 138.5, 138.2, 133.7, 132.7, 131.4, 129.7, 129.5, 128.9, 128.5, 126.7, 124.7, 124.3, 122.6, 121.4, 120.6, 118.1, 115.1, 96.1, 84.8, 27.7.

MS (CI⁺): m/z (%) = 506 (3) [M]⁺, 462 (12), 448 (14), 407 (28), 406 (100), 405 (32), 69 (1).

tert -Butyl 1-(2-Pyridinyl)-3-[3-(3′,4′-methylenedioxy)biphenyl]-5-pyrazolyl Carbonate (5j)

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.41 (m, 1 H), 8.04-8.01 (m, 2 H), 7.86-7.78 (m, 2 H), 7.52-7.43 (m, 2 H), 7.21-7.11 (m, 3 H), 6.91-6.89 (m, 1 H), 6.56 (s, 1 H), 6.01 (s, 2 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 151.1, 149.7, 148.2, 147.8, 147.3, 146.5, 141.4, 138.5, 135.5, 133.3, 129.1, 127.2, 124.5, 124.3, 121.5, 120.9, 115.2, 108.7, 107.9, 101.3, 96.2, 84.9, 27.7.

MS (CI⁺): m/z (%) = 456 (1) [M]⁺, 415 (3), 414 (11), 400 (13), 359 (23), 358 (100), 357 (35), 299 (6), 145 (2), 69 (2).

tert -Butyl 1-(2-Pyridinyl)-3-[3-(3′-phenyl)biphenyl]-5-pyrazolyl Carbonate (5k)

^¹H NMR (300 MHz, CDCl₃): δ = 8.43-8.41 (m, 1 H), 8.15 (s, 1 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.88-7.80 (m, 3 H), 7.69-7.45 (m, 9 H), 7.40-7.35 (m, 1 H), 7.22-7.17 (m, 1 H), 6.59 (s, 1 H), 1.58 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 151.1, 149.7, 147.8, 146.5, 141.9, 141.8, 141.3, 138.5, 133.4, 129.3, 129.2, 128.9, 127.6, 127.5, 127.4, 126.4, 124.9, 124.7, 121.5, 115.2, 96.3, 84.9, 27.7.

MS (CI⁺): m/z (%) = 446 (5), 433 (4), 432 (12), 430 (4), 392 (4), 391 (28), 390 (100), 389 (33), 215 (7).

tert -Butyl 1-(2-Pyridinyl)-3-[3-(1-naphthyl)phenyl]-5-pyrazolyl Carbonate (5l)

^¹H NMR (300 MHz, CDCl₃): δ = 8.41-8.39 (m, 1 H), 8.01-7.87 (m, 6 H), 7.82-7.76 (m, 1 H), 7.57-7.41 (m, 6 H), 7.19-7.15 (m, 1 H), 6.55 (s, 1 H), 1.56 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 151.0, 149.7, 147.7, 146.5, 141.3, 140.1, 138.5, 133.9, 132.9, 131.8, 130.3, 128.7, 128.3, 127.9, 127.5, 127.0, 126.2, 126.2, 125.9, 125.5, 124.7, 121.5, 115.1, 96.3, 84.9, 27.7.

MS (CI⁺): m/z (%) = 464 (2) [M]⁺, 420 (9), 406 (12), 390 (10), 364 (100), 363 (33), 272 (3), 144 (1), 69 (6).

tert -Butyl 1-(2-Pyridinyl)-3-[3-(3′-dimethylamino)biphenyl]-5-pyrazolyl carbonate (5m)

^¹H NMR (300 MHz, CDCl₃): δ = 8.42-8.40 (m, 1 H), 8.07-8.01 (m, 2 H), 7.86-7.79 (m, 2 H), 7.59-7.56 (m, 1 H), 7.50-7.45 (m, 1 H), 7.36-7.30 (m, 1 H), 7.20-7.16 (m, 1 H), 7.01-6.97 (m, 2 H), 6.78-6.75 (m, 1 H), 6.56 (s, 1 H), 3.02 (s, 6 H), 1.57 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 151.2, 151.0, 149.7, 147.7, 146.5, 142.8, 142.3, 138.5, 133.1, 129.5, 129.5, 127.7, 124.9, 124.6, 121.5, 116.2, 115.1, 112.0, 111.9, 96.3, 84.9, 40.9, 27.7.

MS (CI⁺): m/z (%) = 457 (4) [M]⁺, 456 (2) [M]⁺, 413 (9), 399 (10), 397 (3), 364 (5), 358 (23), 357 (100), 356 (43), 138 (4), 69 (2).

tert -Butyl 1-(2-Pyridinyl)-3-[2-(3′,4′-methylenedioxy)biphenyl]-5-pyrazolyl Carbonate (5n)

^¹H NMR (300 MHz, CDCl₃): δ = 8.38-8.36 (m, 1 H), 7.94-7.88 (m, 2 H), 7.82-7.76 (m, 1 H), 7.41-7.31 (m, 3 H), 7.17-7.13 (m, 1 H), 6.78 (m, 3 H), 5.96 (s, 2 H), 5.55 (s, 1 H), 1.51 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 151.4, 149.5, 147.6, 147.4, 146.9, 145.1, 140.8, 138.5, 135.4, 131.8, 130.5, 129.2, 128.5, 127.5, 123.1, 121.3, 114.9, 110.3, 108.2, 101.1, 99.8, 84.7, 27.6.

MS (CI⁺): m/z (%) = 459 (18), 458 (62) [M]⁺, 457 (6), 419 (3), 415 (5), 414 (20), 400 (13), 359 (22), 358 (100), 357 (32), 183 (4), 138 (3), 123 (1).

1-(2-Pyridinyl)-3-[2-(3′-phenyl)biphenyl]-5-hydroxypyrazole (6o)

^¹H NMR (300 MHz, CDCl₃): δ = 8.10-8.06 (m, 2 H), 7.67 (s, 1 H), 7.56-7.47 (m, 5 H), 7.40-7.26 (m, 9 H), 6.04 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 159.4, 155.7, 147.1, 143.3, 142.3, 142.2, 140.4, 140.4, 138.0, 132.4, 131.9, 130.6, 128.8, 128.1, 127.4, 126.9, 126.3, 119.8, 113.7, 96.6, 90.5.

HRMS (EI): m/z calcd for C₂₆H₁₉N₃O: 389.1528; found: 389.1523.

tert -Butyl 1-(2-Pyridinyl)-3-(4-biphenyl)-4-propyl-5-pyrazolyl Carbonate (5p)

^¹H NMR (300 MHz, CDCl₃): δ = 8.40-8.37 (m, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 7.84-7.75 (m, 3 H), 7.70-7.63 (m, 4 H), 7.48-7.43 (m, 2 H), 7.38-7.33 (m, 1 H), 7.17-7.12 (m, 1 H), 2.63 (t, J = 7.7 Hz, 2 H), 1.65-1.60 (m, 2 H), 1.57 (s, 9 H), 0.95 (t, J = 7.4 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.4, 150.2, 150.0, 147.6, 146.8, 143.6, 140.9, 140.8, 138.4, 132.8, 131.7, 129.3, 128.9, 128.1, 127.4, 127.3, 127.1, 121.1, 114.5, 110.7, 85.2, 27.7.

MS (CI⁺): m/z (%) = 457 (10), 456 (33) [M]⁺, 412 (9), 398 (13), 396 (3), 357 (24), 356 (100), 355 (40), 326 (16).

tert -Butyl 1-(2-Pyridinyl)-3-(4-biphenyl)-4-benzyl-5-pyrazolyl Carbonate (5q)

^¹H NMR (300 MHz, CDCl₃): δ = 8.40-8.38 (m, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.84-7.78 (m, 1 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.62-7.58 (m, 4 H), 7.46-7.41 (m, 2 H), 7.36-7.31 (m, 1 H), 7.27-7.25 (m, 4 H), 7.20-7.15 (m, 2 H), 4.01 (s, 2 H), 1.48 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 150.5, 149.5, 147.6, 146.6, 144.3, 141.0, 140.7, 139.5, 138.4, 132.1, 128.8, 128.5, 128.3, 128.1, 127.4, 127.2, 127.0, 126.2, 121.2, 114.5, 108.8, 85.2, 27.4.

MS (CI⁺): m/z (%) = 504 (5) [M]⁺, 447 (5), 446 (16), 405 (28), 404 (100), 403 (38), 356 (9), 326 (4).

tert -Butyl 1-[2-(3-Chloro)pyridinyl]-3-[3-(3′,4′-methylenedioxy)biphenyl]-5-pyrazolyl Carbonate (5r)

^¹H NMR (300 MHz, CDCl₃): δ = 8.55-8.53 (m, 1 H), 8.02 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.82 (d, J = 7.2 Hz, 1 H), 7.48-7.37 (m, 3 H), 7.13-7.10 (m, 2 H), 6.88 (d, J = 7.8 Hz, 1 H), 6.70 (s, 1 H), 5.99 (s, 2 H), 1.52 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.2, 148.4, 148.1, 147.3, 137.2, 146.8, 141.3, 139.8, 135.5, 133.4, 129.0, 128.9, 127.0, 125.3, 124.6, 124.5, 120.9, 108.6, 107.9, 101.2, 92.5, 85.5, 27.6.

MS (CI⁺): m/z (%) = 492 (1) [M]⁺, 463 (1), 447 (4), 419 (27), 392 (26), 391 (100), 279 (36), 205 (69), 111 (24), 69 (13).

tert -Butyl 1-(2-Pyrimidinyl)-3-[4-(3′-phenyl)biphenyl]-5-pyrazolyl Carbonate (5s)

^¹H NMR (300 MHz, CDCl₃): δ = 8.80 (d, J = 4.8 Hz, 2 H), 8.03 (d, J = 8.5 Hz, 2 H), 7.85-7.84 (m, 1 H), 7.73-7.44 (m, 9 H), 7.40-7.35 (m, 1 H), 7.25-7.21 (m, 1 H), 6.62 (s, 1 H), 1.59 (s, 9 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.7, 156.3, 152.5, 149.6, 147.5, 142.0, 141.8, 141.3, 131.4, 129.3, 128.9, 127.5, 127.4, 126.8, 126.5, 126.1, 118.8, 97.4, 85.2, 27.8.

MS (CI⁺): m/z (%) = 447 (1), 419 (2), 391 (6), 373 (20), 329 (4), 275 (32), 274 (19), 273 (100), 272 (13), 239 (16), 111 (2), 69 (7).

Boc-Deprotection: 1-(2-Pyridinyl)-3-[4-(3′,4′-methylenedioxy)biphenyl]-5-hydroxypyrazole (6b); Typical Procedure

To a solution of 5b (286 mg, 0.62 mmol) in CH₂Cl₂ (10 mL), TFA (707 mg, 6.2 mmol) was added. When the reaction was complete (3 h as judged by TLC), the mixture was washed with H₂O (3 × 5 mL), dried over anhydrous MgSO₄, and concentrated to dryness. The crude material was purified by column chromatography on silica gel (hexane-EtOAc, 10:1) to afford 6b.

Yield: 155 mg (70%).

^¹H NMR (300 MHz, CDCl₃): δ = 8.29-8.27 (m, 1 H), 8.08-8.05 (m, 1 H), 7.93-7.87 (m, 3 H), 7.59-7.55 (m, 2 H), 7.19-7.14 (m, 1 H), 7.12-7.09 (m, 2 H), 6.90-6.88 (m, 1 H), 6.00 (s, 2 H), 5.96 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 152.4, 148.3, 147.3, 145.2, 141.1, 140.0, 135.2, 131.7, 127.1, 126.3, 120.7, 120.0, 112.4, 108.7, 108.2, 107.6, 106.7, 101.3, 101.2, 85.9.

HRMS (EI): m/z calcd for C₂₁H₁₅N₃O₃: 357.1113; found: 357.1121.

1-(2-Pyridinyl)-3-(4-biphenyl)-5-hydroxypyrazole (6a)

^¹H NMR (300 MHz, CDCl₃): δ = 8.31-8.28 (m, 1 H), 8.10-8.07 (m, 1 H), 7.96-7.89 (m, 3 H), 7.69-7.63 (m, 4 H), 7.49-7.44 (m, 2 H), 7.39-7.33 (m, 1 H), 7.20-7.16 (m, 1 H), 5.99 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 154.6, 152.4, 145.2, 141.4, 140.8, 140.0, 132.1, 129.7, 128.9, 127.5, 127.4, 127.1, 126.3, 120.0, 112.4, 86.07.

HRMS (EI): m/z calcd for C₂₀H₁₅N₃O: 313.1215; found: 313.1218.

1-(2-Pyridinyl)-3-[4-(3′-phenyl)biphenyl]-5-hydroxypyrazole (6c)

^¹H NMR (300 MHz, CDCl₃): δ = 12.84-12.83 (br s, 1 H), 8.30-8.28 (m, 1 H), 8.09-8.06 (m, 1 H), 7.97-7.85 (m, 4 H), 7.73-7.45 (m, 9 H), 7.40-7.36 (m, 1 H), 7.20-7.16 (m, 1 H), 6.00 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.4, 154.7, 152.4, 145.2, 142.0, 141.4, 141.3, 140.1, 132.3, 129.3, 128.9, 127.5, 127.5, 127.4, 126.4, 126.1, 120.1, 112.4, 85.9.

HRMS (EI): m/z calcd for C₂₆H₁₉N₃O: 389.1528; found: 389.1533.

1-(2-Pyridinyl)-3-[4-(1-naphthyl)phenyl]-5-hydroxypyrazole (6d)

^¹H NMR (300 MHz, CDCl₃): δ = 12.89 (br s, 1 H), 8.31-8.29 (m, 1 H), 8.10-8.08 (m, 1 H), 8.00-7.86 (m, 6 H), 7.58-7.41 (m, 6 H), 7.21-7.17 (m, 1 H), 6.03 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 154.7, 152.6, 145.2, 141.1, 140.1, 140.0, 133.9, 132.2, 131.7, 130.4, 128.4, 127.8, 127.7, 127.0, 126.5, 126.2, 126.1, 125.9, 125.5, 125.2, 120.0, 112.4, 108.7, 85.9.

HRMS (EI): m/z calcd for C₂₄H₁₇N₃O: 363.1372; found: 363.1372.

1-(2-Pyridinyl)-3-[4-(3′-dimethylamino)biphenyl]-5-hydroxypyrazole (6e)

^¹H NMR (300 MHz, CDCl₃): δ = 10.26 (br s, 1 H), 8.31-8.30 (m, 1 H), 8.10-8.07 (m, 1 H), 7.98-7.90 (m, 3 H), 7.75-7.50 (m, 5 H), 7.50-7.49 (m, 1 H), 7.22-7.18 (m, 1 H), 5.99 (s, 1 H), 3.27 (s, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.6, 154.4, 151.9, 145.3, 144.4, 143.6, 140.2, 139.1, 133.2, 131.0, 127.8, 127.4, 126.7, 120.2, 118.7, 118.5, 112.5, 86.1, 46.2.

HRMS (EI): m/z calcd for C₂₂H₂₀N₄O: 356.1637; found: 356.1644.

1-(2-Pyridinyl)-3-[4-(4′-benzyloxy)biphenyl]-5-hydroxypyrazole (6f)

^¹H NMR (300 MHz, CDCl₃): δ = 12.85-12.83 (br s, 1 H), 8.30-8.28 (m, 1 H), 8.08-8.05 (m, 1 H), 7.93-7.89 (m, 3 H), 7.63-7.56 (m, 4 H), 7.50-7.29 (m, 5 H), 7.19-7.15 (m, 1 H), 7.08-7.05 (m, 2 H), 5.97 (s, 1 H), 5.12 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.6, 157.5, 155.8, 152.5, 145.2, 140.0, 137.1, 133.7, 131.9, 128.7, 128.2, 128.1, 127.6, 126.9, 126.3, 120.0, 116.2, 115.3, 112.4, 84.2, 70.2.

HRMS (EI): m/z calcd for C₂₇H₂₁N₃O₂: 419.1634; found: 419.1635.

1-(2-Pyridinyl)-3-[4-(2′-phenoxy)biphenyl]-5-hydroxypyrazole (6g)

^¹H NMR (300 MHz, CDCl₃): δ = 12.78 (br s, 1 H), 8.26-8.25 (m, 1 H), 8.04-7.83 (m, 4 H), 7.62-7.48 (m, 3 H), 7.33-6.92 (m, 9 H), 5.93 (m, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.9, 157.4, 154.9, 153.7, 152.5, 145.2, 140.0, 138.0, 133.6, 132.0, 131.2, 129.7, 129.5, 128.9, 125.7, 124.2, 122.7, 120.4, 120.0, 118.1, 112.4, 85.8.

HRMS (EI): m/z calcd for C₂₆H₁₉N₃O₂: 405.1477; found: 405.1476.

1-(2-Pyridinyl)-3-[3-(4′-bromo)biphenyl]-5-hydroxypyrazole (6h)

^¹H NMR (300 MHz, CDCl₃): δ = 12.85-12.83 (br s, 1 H), 8.30-8.28 (m, 1 H), 8.08-8.06 (m, 2 H), 7.94-7.88 (m, 1 H), 7.84-7.81 (m, 1 H), 7.60-7.46 (m, 6 H), 7.20-7.16 (m, 1 H), 5.99 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 154.7, 152.4, 145.3, 140.5, 140.2, 140.1, 133.9, 132.0, 129.2, 129.0, 127.2, 125.3, 124.5, 121.8, 120.1, 112.5, 85.9.

HRMS (EI): m/z calcd for C₂₀H₁₄BrN₃O: 391.0320; found: 391.0294.

1-(2-Pyridinyl)-3-[3-(2′-phenoxy)biphenyl]-5-hydroxypyrazole (6i)

^¹H NMR (300 MHz, CDCl₃): δ = 12.76 (br s, 1 H), 8.27-8.25 (m, 1 H), 8.03-7.77 (m, 4 H), 7.55-6.93 (m, 12 H), 5.86 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.1, 157.3, 154.7, 153.6, 152.6, 145.2, 140.0, 138.1, 133.8, 133.0, 131.4, 129.7, 129.5, 128.9, 128.4, 126.9, 124.8, 124.3, 122.6, 120.5, 119.9, 118.1, 112.4, 85.8.

HRMS (EI): m/z calcd for C₂₆H₁₉N₃O₂: 405.1477; found: 405.1475.

1-(2-Pyridinyl)-3-[3-(3′,4′-methylenedioxy)biphenyl]-5-hydroxy­pyrazole (6j)

^¹H NMR (300 MHz, CDCl₃): δ = 8.30-8.28 (m, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 8.03-8.02 (m, 1 H), 7.94-7.88 (m, 1 H), 7.80-7.76 (m, 1 H), 7.52-7.46 (m, 2 H), 7.20-7.12 (m, 3 H), 6.92-6.89 (m, 1 H), 6.02 (s, 2 H), 5.99 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 154.6, 152.6, 148.2, 147.3, 145.2, 141.4, 140.1, 135.6, 133.6, 129.1, 127.2, 124.7, 124.5, 120.9, 120.1, 112.5, 108.7, 107.9, 101.3, 86.0.

HRMS (EI): m/z calcd for C₂₁H₁₅N₃O₃: 357.1113; found: 357.1107.

1-(2-Pyridinyl)-3-[3-(3′-phenyl)biphenyl]-5-hydroxypyrazole (6k)

^¹H NMR (300 MHz, CDCl₃): δ = 8.31-8.28 (m, 1 H), 8.6-8.15 (m, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.94-7.84 (m, 3 H), 7.70-7.45 (m, 9 H), 7.41-7.36 (m, 1 H), 7.20-7.16 (m, 1 H), 6.02 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 154.6, 152.6, 145.2, 141.9, 141.8, 141.7, 141.3, 140.1, 133.7, 129.3, 129.1, 128.9, 127.6, 127.5, 127.4, 127.2, 126.4, 125.1, 124.8, 120.1, 112.5, 86.0, 29.8.

HRMS (EI): m/z calcd for C₂₆H₁₉N₃O: 389.1528; found: 389.1525.

1-(2-Pyridinyl)-3-[3-(1-naphthyl)phenyl]-5-hydroxypyrazole (6l)

^¹H NMR (300 MHz, CDCl₃): δ = 12.81 (s, 1 H), 8.27-8.25 (m, 1 H), 8.03-8.00 (m, 2 H), 7.95-7.83 (m, 5 H), 7.57-7.40 (m, 6 H), 7.17-7.12 (m, 1 H), 5.97 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.4, 154.7, 152.6, 145.2, 141.2, 140.2, 140.0, 133.9, 133.3, 131.8, 130.3, 128.6, 128.3, 127.8, 127.6, 127.0, 126.2, 125.9, 125.5, 124.9, 120.0, 112.4, 85.9.

HRMS (EI): m/z calcd for C₂₄H₁₇N₃O: 363.1372; found: 363.1367.

1-(2-Pyridinyl)-3-[3-(3′-dimethylamino)biphenyl]-5-hydroxypyrazole (6m)

^¹H NMR (300 MHz, CDCl₃): δ = 13.09 (s, 1 H), 8.31-8.29 (m, 1 H), 8.10-8.07 (m, 2 H), 7.95-7.84 (m, 2 H), 7.69-7.44 (m, 6 H), 7.22-7.17 (m, 1 H), 6.00 (s, 1 H), 3.23 (s, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.6, 154.5, 152.2, 145.4, 145.3, 143.7, 140.2, 140.1, 133.9, 130.8, 129.4, 127.5, 126.5, 126.0, 124.6, 120.2, 118.1, 117.9, 112.5, 45.4, 86.1.

HRMS (EI): m/z calcd for C₂₂H₂₀N₄O: 356.1637; found: 356.1629.

1-(2-Pyridinyl)-3-[2-(3′,4′-methylenedioxy)biphenyl]-5-hydroxy­pyrazole (6n)

^¹H NMR (300 MHz, CDCl₃): δ = 12.58 (s, 1 H), 8.26-8.24 (m, 1 H), 7.98-7.95 (m, 1 H), 7.90-7.84 (m, 2 H), 7.42-7.30 (m, 3 H), 7.16-7.12 (m, 1 H), 6.78 (s, 3 H), 5.97 (s, 2 H), 5.05 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 156.0, 154.7, 153.2, 147.3, 146.8, 145.2, 140.9, 140.0, 135.7, 132.3, 130.7, 129.3, 128.4, 127.4, 123.0, 119.9, 112.4, 110.3, 108.1, 101.1, 89.6.

HRMS (EI): m/z calcd for C₂₁H₁₅N₃O₃: 357.1113; found: 357.1105.

1-(2-Pyridinyl)-3-(4-biphenyl)-4-propyl-5-hydroxypyrazole (6p)

^¹H NMR (300 MHz, CDCl₃): δ = 12.55 (s, 1 H), 8.28-8.27 (m, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.89-7.79 (m, 3 H), 7.69-7.64 (m, 4 H), 7.46 (m, 2 H), 7.38-7.36 (m, 1 H), 7.16-7.12 (m, 1 H), 2.61-2.55 (m, 2 H), 1.68-1.60 (m, 2 H), 0.97 (t, J = 7.1 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 154.6, 154.2, 152.1, 145.3, 140.9, 139.9, 133.2, 128.9, 128.2, 127.4, 127.3, 127.2, 119.8, 112.3, 100.4, 24.4, 23.1, 14.1.

HRMS (EI): m/z calcd for C₂₃H₂₁N₃O: 355.1685; found: 355.1686.

1-(2-Pyridinyl)-3-(4-biphenyl)-4-benzyl-5-hydroxypyrazole (6q)

^¹H NMR (300 MHz, CDCl₃): δ = 12.61 (br s, 1 H), 8.29-8.27 (m, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.92-7.86 (m, 1 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.62-7.60 (m, 4 H), 7.46-7.41 (m, 2 H), 7.36-7.25 (m, 5 H), 7.20-7.14 (m, 2 H), 3.97 (s, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 154.7, 154.6, 152.4, 145.3, 141.0, 141.0, 140.8, 140.0, 132.6, 128.9, 128.5, 128.3, 127.5, 127.2, 127.1, 126.0, 120.0, 112.3, 98.6, 29.8, 22.83.

HRMS (EI): m/z calcd for C₂₇H₂₁N₃O: 403.1685; found: 403.1676.

1-[2-(3-Chloro)pyridinyl]-3-[3-(3′,4′-methylenedioxy)biphenyl]-5-hydroxypyrazole (6r)

^¹H NMR (300 MHz, CDCl₃): δ = 8.57-8.54 (m, 1 H), 7.93-7.90 (m, 2 H), 7.67-7.57 (m, 2 H), 7.49-7.44 (m, 1 H), 7.38-7.34 (m, 1 H), 7.09-7.05 (m, 2 H), 6.89 (d, J = 8.5 Hz, 1 H), 6.00 (s, 2 H), 3.90 (s, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 170.4, 156.0, 148.3, 147.5, 147.0, 141.8, 139.7, 134.6, 131.2, 131.0, 129.4, 128.9, 128.8, 124.9, 124.8, 124.5, 120.9, 108.7, 107.8, 101.4, 38.4.

HRMS (EI): m/z calcd for C₂₁H₁₄ClN₃O₃: 391.0724; found: 391.0720.

1-(2-Pyrimidinyl)-3-[4-(3′-phenyl)biphenyl]-5-hydroxypyrazole (6s)

^¹H NMR (300 MHz, CDCl₃): δ = 8.78 (d, J = 4.9 Hz, 2 H), 8.01 (d, J = 8.3 Hz, 2 H), 7.85-7.83 (m, 1 H), 7.73-7.44 (m, 9 H), 7.39-7.34 (m, 1 H), 7.23-7.22 (m, 1 H), 6.06 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 158.3, 157.4, 157.4, 154.2, 141.9, 141.7, 141.2, 131.5, 129.3, 128.9, 127.5, 127.3, 126.9, 126.4, 126.1, 117.6, 86.7.

HRMS (EI): m/z calcd for C₂₅H₁₈N₄O: 390.1481; found: 390.1488.

Acknowledgment

This work was supported by the Seoul R&BD program (10527) from the Seoul Development Institute, Seoul, Korea.

References

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References

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  Search in Google Scholar
• 1b Terrett NK. Bell AS. Brown D. Ellis P. Bioorg. Med. Chem. Lett.  1996,  6:  1819 
  Search in Google Scholar
• 1c Lv P.-C. Li H.-Q. Sun J. Zhou Y. Zhu H.-L. Bioorg. Med. Chem.  2010,  18:  4606 ; and many references cited therein
  Search in Google Scholar
• 2a Patel MV. Bell R. Majest S. Henry R. Kolasa T. J. Org. Chem.  2004,  69:  7058 
  Search in Google Scholar
• 2b Walker JK. Selness SR. Devraj RV. Hepperle ME. Naing W. Shieh H. Kurambail R. Yang S. Flynn DL. Benson AG. Messing DM. Dice T. Kim T. Lindmark RJ. Monahan JB. Portanova J. Bioorg. Med. Chem. Lett.  2010,  20:  2634 
  Search in Google Scholar
• 2c Berta D. Villa M. Vulpetti A. Felder ER. Tetrahedron  2005,  61:  10801 
  Search in Google Scholar
• 3a Park M.-S. Park H.-J. Park KH. Lee K.-I. Synth. Commun.  2004,  34:  1541 
  Search in Google Scholar
• 3b Park H.-J. Lee K. Park S.-J. Ahn B. Lee J.-C. Cho HY. Lee K.-I. Bioorg. Med. Chem. Lett.  2005,  15:  3307 
  Search in Google Scholar
• 4a Fall Y. Doucet H. Santelli M. Synthesis  2010,  127 
• 4b Arbačiauskiené E. Vilkauskaité G. Eller GA. Holzer W. Šačkus A. Tetrahedron  2009,  65:  7817 
  Search in Google Scholar
• 4c Goikhman R. Jacques TL. Sames D. J. Am. Chem. Soc.  2009,  131:  3042 
  Search in Google Scholar
• 4d Clapham KM. Batsanov AS. Bryce MR. Tarbit B. Org. Biomol. Chem.  2009,  7:  2155 
  Search in Google Scholar
• 4e Khera RA. Ali A. Hussain M. Tatar J. Villinger A. Langer P. Synlett  2010,  1923 
• 5a Dragovich PS. Bertolini TM. Ayida BK. Li L.-S. Murphy DE. Ruebsam F. Sun Z. Zhou Y. Tetrahedron  2007,  63:  1154 
  Search in Google Scholar
• 5b Wang X.-j. Tan J. Grozinger K. Tetrahedron Lett.  2000,  41:  4713 
  Search in Google Scholar
• 5c Dvorak CA. Rudolph DA. Ma S. Carruthers NI. J. Org. Chem.  2005,  70:  4188 
  Search in Google Scholar
• 5d Bourrain S. Ridgill M. Collins I. Synlett  2004,  795 
• For peripheral arylation of 2-pyridone derivatives, see:
• 6a Heo J.-N. Song YS. Kim BT. Tetrahedron Lett.  2005,  46:  4621 
  Search in Google Scholar
• 6b Siddle JS. Batsanov AS. Caldwell ST. Cooke G. Bryce MR. Tetrahedron  2010,  66:  6138 
  Search in Google Scholar
• 7 Huang Y.-Y. Lin H.-C. Cheng K.-M. Su W.-N. Sung K.-C. Lin T.-P. Huang J.-J. Lin S.-K. Wong FF. Tetrahedron  2009,  65:  9592 
  CrossrefSearch in Google Scholar
• 8a Patil SA. Weng C.-M. Huang P.-C. Hong F.-E. Tetrahedron  2009,  65:  2889 
  Search in Google Scholar
• 8b Lai Y.-C. Chen H.-Y. Hung W.-C. Lin C.-C. Hong F.-E. Tetrahedron  2005,  61:  9484 
  Search in Google Scholar
• 8c Kealey S. Long NJ. Miller PW. White AJP. Hitchcock PB. Gee A. J. Chem. Soc., Dalton Trans.  2007,  2823 
• 8d Ojwach SO. Darkwa J. Inorg. Chim. Acta  2010,  369:  1947 
  Search in Google Scholar
• 8e Budzisz E. Miernicka M. Lorenz I.-P. Mayer P. Krajewska U. Polyhedron  2009,  28:  637 
  Search in Google Scholar
• 9 Maryanoff BE. Greco MN. Zhang HC. Andrade-Gordon P. Kauffman JA. Nicolaou KC. Liu A. Brungs PH. J. Am. Chem. Soc.  1995,  117:  1225 
  CrossrefSearch in Google Scholar
• 10 Best WM. Cook APF. Russell JJ. Widdowson DA. J. Chem. Soc., Perkin Trans. 1  1984,  1139 
• 11 Hansen MM. Riggs JR. Tetrahedron Lett.  1998,  39:  2705 
  CrossrefSearch in Google Scholar