Gas-Phase Synthesis of Pyrazolo[3,4-b]pyridin-4-ones

Abstract

Flash vacuum pyrolysis (FVP) at 500–600 °C of 1-substituted pyrazolylaminomethylene derivatives of Meldrum’s acid provides 1-substituted pyrazolo[3,4-b]pyridin-4-ones in high yields. If the 1-substituent is a tert-butyl group, FVP at 750–850 °C causes elimination of 2-methyl-1-propene to give the parent pyrazolo[3,4-b]pyridin-4-one.

Key words

gas-phase reactions - pericyclic reactions - heterocycles - Meldrum’s acid - medicinal chemistry

There are very few references to 1-unsubstituted pyrazolo[3,4-b]pyridin-4-ones 1 in the literature[2] and all known derivatives except the parent compound 1 (R = R′ = H) have a substituent in the 6-position. Potential functionalization of the 4-position (e.g., via the triflate or the 4-chloro compound) would provide 4-substituted pyrazolo[3,4-b]pyridines 2 (Figure [1]), which have shown diverse application in medicinal chemistry.[3] On the other hand, substitution at the 1-position generally results in loss of biological activity due to the disruption of the hydrogen bonding regime.[4]

Figure 1 1-Unsubstituted pyrazolo[3,4-b]pyridin-4-ones 1 and 4-substituted pyrazolo[3,4-b]pyridines 2

In earlier work, we explored a potential route to 1 by flash vacuum pyrolysis (FVP) of Meldrum’s acid derivatives [e.g., 3 (R¹ = H)], but cyclization of the imidoylketene intermediate 4 (R¹ = H) occurred exclusively at the adjacent nitrogen atom to provide a useful route to the pyrazolo[1,5-a]pyrimidine system 5 (Scheme [1]).[5] Clearly this route must be blocked to provide pyrazolo[3,4-b]pyridin-4-ones.

Scheme 1

The present work therefore had a range of objectives. First, 3 (R¹ = alkyl or aryl) were synthesized and pyrolyzed to ensure that, in the absence of the pyrazole NH, cyclization onto the adjacent carbon atom to give 1 (R = 1-alkyl or 1-aryl) would take place (Scheme [1]), as observed in many related systems.[6] Second, we explored the design of a thermal N-protecting group, which would remain at low furnace temperatures, but be selectively removed at higher furnace temperatures to provide N-unsubstituted pyrazolopyridinones 1 (R¹ = H). If the previous stages were successful, we aimed finally to functionalize the 4-position of the pyrazolo[3,4-b]pyridin-4-ones to establish that the route has significant potential for the synthesis of pyrazolo[3,4-b]pyridines 2.

The 1-substituted and 1,3-disubstituted 3-aminopyrazoles 6a–f (Figure [2]) were either commercially available or were synthesized by known methods. Compounds 6c,[7] 6e,[8] and 6f [9a] are known only in patents or are formed in poor yield;[9b] their full characterization data are given here. Compound 6c was formed as a 5:1 mixture of 6c and its 1-tert-butyl-3-amino isomer, which was taken on to the next stage without purification. Reaction of 6a–f with methoxymethylene­ Meldrum’s acid in acetonitrile gave the aminomethylene derivatives 3a–f (Figure [2]) in 89–99% yield and (generally) high purity. Compound 3c was purified by recrystallization before pyrolysis.

Figure 2 1,3-Disubstituted 3-aminopyrazoles 6 and aminometh­ylene derivatives 3

FVP of 3a and 3b at 600 °C (0.03 Torr) gave 1-methylpyrazolo[3,4-b]pyridin-4-one (1aa) (92%) and its 3-methyl-1-phenyl analogue 1ba (95%), respectively, as involatile solids that crystallized at the exit point of the furnace. It is clear, therefore, that blocking the 1-position of the pyrazole­ has the effect of diverting the cyclization to the adjacent carbon atom to provide the target pyrazolopyridinones.

In order to access the 1-unsubstituted pyrazolo[3,4-b]pyridines 1 (R¹ = H), a thermally removable N-protecting group was required. If a retro-ene reaction is possible, an N-tert-butyl group is ideal because the only co-product is 2-methyl-1-propene. We have exploited this in the pyridazin-3-one series[10] and it is also known that N-tert-butylpyrazole (7) loses 2-methyl-1-propene at high temperatures (Scheme [2]).[11] A temperature profile of this reaction (Figure [3]) shows that, in our apparatus, at temperatures below 600 °C the N-alkyl product 7 is formed exclusively whereas at temperatures above 850 °C, only the deprotected product 8 was formed. It was therefore anticipated that FVP of 3c–f in the range 500–600 °C should provide the N-tert-butyl products 1 (R¹ = t-Bu) whereas FVP in the range 750–850 °C should provide the deprotected products 1 (R¹ = H).

Scheme 2

Figure 3 Temperature-conversion plot for FVP of 7

These predictions were borne out in practice. FVP of 3c–f at 500 °C gave the pyrazolopyridinones 1ca, 1da, 1ea, and 1fa (Figure [4]) in 83–97% yields and at 750–850 °C gave the deprotected products 1cb and 1db in 67–82% yields whilst the more highly substituted derivatives 1eb and 1fb were obtained as more complex mixtures.[12] N-Unsubstituted pyrazolopyridinones show exceptionally broad peaks in their NMR spectra due to tautomerization, but the two NH resonances at ca. δ_H = 12.8–13.8 and 11.5–11.8 are characteristic, as previously reported.[2a]

Figure 4 Pyrazolopyridinones 1

As an alternative to the one-pass cyclization-deprotection described above, the protecting group can be retained prior to functionalization of the 4-oxo substituent. This strategy is illustrated for the 3-phenyl series 1e, which was chosen as it might prove unreactive owing to peri interactions with the 3-substituent.

Thus, treatment of 1ea with phosphoryl chloride gave the 4-chloro compound 9 (99%), which could either be thermally deprotected to 10 (87%), or reacted further. For example, reaction of 9 with pyrrolidine in the absence of a catalyst provided a low yield of the pyrrolidino compound 11 (37%); alternatively, reaction with aniline under Buchwald–Hartwig conditions gave the anilino compound 12 (87%), which could be thermally deprotected to 13 (72%) (Scheme [3]).

Scheme 3

In conclusion, the work described here has provided a flexible gas-phase route to pyrazolo[3,4-b]pyridin-4-ones and pyrazolo[3,4-b]pyridines. An important feature of the strategy is the use of an N-tert-butyl group, which may be retained at low furnace temperatures (allowing functionalization of the 4-oxo group) or removed at high furnace temperatures to provide a one-pass route to N-unsubstituted analogues.

¹H and ¹³C NMR spectra were recorded at 500 or 250 MHz and 125 or 63 MHz, respectively, unless otherwise stated. Chemical shifts are given in ppm relative to TMS. Mass spectra were recorded under electron impact conditions.

5-Amino-1-tert-butyl-1H-pyrazole (6c)[7]

tert-Butylhydrazine hydrochloride (5.99 g, 48.1 mmol) was added to EtOH (60 mL) to form a slurry. To this was added NaOAc (7.93 g, 96.7 mmol) and 2-chloroacrylonitrile (5 mL, 62.6 mmol). The solution was heated to 80 °C for 18 h, cooled, and the solvent removed in vacuo. The residue was slowly diluted with distilled H₂O (35 mL) and partitioned between sat. aq NaHCO₃ (40 mL) and EtOAc­ (40 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO₄), and the solvent removed in vacuo to afford a red oil; yield: 7.95 g (91%); bp 93–94 °C/0.9 Torr (yellow liquid). The product was a 5:1 mixture of the title compound 6c and its 1-tert-butyl-3-amino isomer. The crude product was used to prepare the Meldrum’s acid derivative 3c, which was purified by recrystallization (see below).

¹H NMR (CDCl₃): δ = 7.21 (d, ³ J = 1.8 Hz, 1 H), 5.57 (d, ³ J = 1.8 Hz, 1 H), 3.60 (br s, 2 H), 1.65 (s, 9 H).

¹³C NMR (CDCl₃): δ = 144.5 (C_q), 136.6 (CH), 94.1 (CH), 58.5 (C_q), 29.3 (3 CH₃).

MS: m/z (%) = 139 (M⁺, 45), 83 (M – C₄H₁₀, 100).

HRMS: m/z calcd for C₇H₁₃N₃ (M⁺): 139.1104; found: 139.1103.

5-Amino-1-tert-butyl-3-phenyl-1H-pyrazole (6e)[8]

A solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) in EtOH (10 mL) was added to a slurry of tert-butylhydrazine hydrochloride (2.6 g, 20.7 mmol) in EtOH (35 mL) and the solution was heated to reflux with stirring for 18 h. The solution was cooled, concentrated and the residue was partitioned between sat. aq NaHCO₃ (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO₄), and the solvent removed in vacuo to give 6e as a pale yellow solid; yield: 2.2 g (97%); mp 100–102 °C.

¹H NMR (DMSO-d ₆): δ = 7.64 (d, ³ J = 7.4 Hz, 2 H), 7.33 (t, ³ J = 7.4 Hz, 2 H), 7.22 (t, ³ J = 7.4 Hz, 1 H), 5.79 (s, 1 H), 4.97 (s, 2 H), 1.58 (s, 9 H).

¹³C NMR (DMSO-d ₆): δ = 148.1 (C_q), 146.1 (C_q), 135.0 (C_q), 128.8 (2 CH), 127.1 (CH), 125.0 (2 CH) 89.2 (CH), 58.3 (C_q), 40.1 (3 CH₃).

MS: m/z (%) = 215 (M⁺, 25), 159 (100).

HRMS: m/z calcd for C₁₃H₁₇N₃ (M⁺): 215.1417; found: 215.1416.

5-Amino-1,3-di-tert-butyl-1H-pyrazole (6f)[9]

A solution of 4,4-dimethyl-3-oxovaleronitrile (1.75 g, 14.0 mmol) in EtOH (10 mL) was added to a slurry of tert-butylhydrazine hydrochloride (3.5 g. 28.1 mmol) in EtOH (35 mL) and the solution was heated to reflux with stirring for 18 h. The solution was cooled, concentrated, and the residue was partitioned between sat. aq NaHCO_3­ (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO₄), and the solvent removed to give 6f as a pale orange solid; yield: 1.8 g (66%); mp 67–69 °C (Lit.[9a] mp 64–66 °C).

¹H NMR (CDCl₃): δ = 5.48 (s, 1 H), 3.46 (s, 2 H), 1.27 (s, 18 H).

¹³C NMR (CDCl₃): δ = 157.8 (C_q), 144.1 (C_q), 90.2 (CH), 58.2 (C_q), 44.7 (C_q), 30.4 (3 CH₃), 29.5 (3 CH₃).

Spectra differ significantly from those reported,[9b] but were recorded in a different solvent.

MS: m/z (%) = 195 (M⁺, 29), 139 (63), 124 (100).

HRMS: m/z calcd for C₁₁H₂₁N₃ (M⁺): 195.1730; found: 175.1728.

Meldrum’s Acid Derivatives; General Procedure

5-(Methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.5 g, 2.9 mmol) was added to a stirred solution of the 5-aminopyrazole 6 (2.9 mmol) in MeCN (10 mL). After stirring for 1 h, the solvent was removed in vacuo to complete the precipitation of the product.

5-(1-Methyl-1H-pyrazol-5-ylaminomethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3a)

Treatment of 6a using the general procedure gave 3a; yield: 0.71 g (98%); yellow solid; mp 144 °C (MeOH).

¹H NMR (CDCl₃): δ = 11.28 (d, ³ J = 13.3 Hz, 1 H), 8.34 (d, ³ J = 13.3 Hz, 1 H), 7.34 (d, ³ J = 2.1 Hz, 1 H), 6.18 (d, ³ J = 2.1 Hz, 1 H), 3.85 (s, 3 H), 1.75 (s, 6 H).

¹³C NMR (CDCl₃): δ = 165.7 (C_q), 162.6 (C_q), 154.7 (CH), 139.1 (CH), 138.0 (C_q), 105.6 (C_q), 95.3 (CH), 88.9 (C_q), 35.4 (CH₃), 27.1 (2 CH₃).

MS: m/z (%) = 251 (M⁺, 16), 193 (100), 149 (14), 122 (40).

Anal. Calcd for C₁₁H₁₃N₃O₄: C, 52.6; H, 5.2; N, 16.75. Found: C, 52.65; H, 5.35; N, 16.8.

5-(3-Methyl-1-phenyl-1H-pyrazol-5-ylaminomethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3b)

Treatment of 6b using the general procedure gave 3b; yield: 0.90 g (95%); yellow solid; mp 167 °C (MeOH).

¹H NMR (CDCl₃): δ = 11.45 (d, ³ J = 13.4 Hz, 1 H), 8.38 (d, ³ J = 13.4 Hz, 1 H), 7.56–7.42 (m, 5 H), 6.17 (s, 1 H), 2.34 (s, 3 H), 1.71 (s, 6 H).

¹³C NMR (CDCl₃): δ = 165.3 (C_q), 162.7 (C_q), 153.1 (CH), 150.1 (C_q), 138.3 (C_q), 136.8 (C_q), 130.0 (2 CH), 128.8 (CH), 124.8 (2 CH), 105.5 (C_q), 94.3 (CH), 88.8 (C_q), 27.1 (2 CH₃), 14.0 (CH₃).

MS: m/z (%) = 327 (M⁺, 23), 269 (100), 225 (22), 184 (74), 156 (22).

Anal. Calcd for C₁₇H₁₇N₃O₄: C, 62.4; H, 5.25; N, 12.85. Found: C, 62.3; H, 5.15; N, 12.75.

5-(1-tert-Butyl-1H-pyrazol-5-ylamino)methylene-2,2-dimethyl-1,3-dioxane-5,6-dione (3c)

Treatment of 6c using the general procedure gave 3c; yield: 0.985 g (97%); yellow solid; mp 84 °C.

¹H NMR (CDCl₃): δ = 11.53 (d, ³ J = 13.4 Hz, 1 H), 8.33 (d, ³ J = 13.4 Hz, 1 H), 7.41 (d, ³ J = 1.9 Hz, 1 H), 6.23 (d, ³ J = 1.9 Hz, 1 H), 1.77 (s, 6 H), 1.70 (s, 9 H).

¹³C NMR (CDCl₃): δ = 165.6 (C_q), 162.9 (C_q), 154.7 (CH), 137.5 (C_q), 137.3 (CH), 105.6 (C_q), 97.8 (CH), 88.4 (C_q), 60.3 (C_q), 29.8 (3 CH₃), 27.3 (2 CH₃).

MS: m/z (%) = 293 (M⁺, 21), 235 (47), 179 (59), 161 (100).

HRMS: m/z calcd for C₁₄H₁₉N₃O₄ (M⁺): 293.1381; found: 293.1384.

5-(1-tert-Butyl-3-methyl-1H-pyrazol-5-ylamine)-2,2-dimethyl-1,3-dioxane-4,6-dione (3d)

Treatment of 6d using the general procedure gave 3d; yield: 0.88 g (99%); yellow solid; mp 82 °C.

¹H NMR (CDCl₃): δ = 11.47 (br d, ³ J = 13.4 Hz, 1 H), 8.29 (d, ³ J = 13.4 Hz, 1 H), 6.00 (s, 1 H), 2.23 (s, 3 H), 1.75 (s, 6 H), 1.66 (s, 9 H).

¹³C NMR (CDCl₃): δ = 165.9 (C_q), 162.9 (C_q), 154.4 (CH), 146.2 (C_q), 137.7 (C_q), 105.5 (C_q), 97.1 (CH), 88.1 (C_q), 59.7 (C_q), 29.8 (3 CH₃), 27.1 (2 CH₃), 13.9 (CH₃).

MS: m/z (%) = 307 (M⁺, 21), 249 (100), 175 (68).

HRMS: m/z calcd for C₁₅H₂₁N₃O₄ (M⁺): 307.1527; found: 307.1533.

5-(1-tert-Butyl-3-phenyl-1H-pyrazol-5-ylamino)methylene-2,2-dimethyl-1,3-dioxane-4,6-dione (3e)

Treatment of 6e using the general procedure gave 3e; yield: 0.97 g (98%); yellow solid; mp 152 °C.

¹H NMR (CDCl₃): δ = 11.59 (d, ³ J = 13.4 Hz, 1 H), 8.43 (d, ³ J = 13.4 Hz, 1 H), 7.80 (d, ³ J = 7.3 Hz, 2 H), 7.44 (t, ³ J = 7.3 Hz, 2 H), 7.35 (t, ³ J = 7.3 Hz, 1 H), 6.75 (s, 1 H), 1.81 (s, 6 H), 1.77 (s, 9 H).

¹³C NMR (CDCl₃): δ = 166.0 (C_q), 162.9 (C_q), 154.4 (CH), 148.5 (C_q), 138.8 (C_q), 132.8 (C_q), 128.7 (2 CH), 128.1 (CH), 125.3 (2 CH), 105.7 (C_q), 94.5 (CH), 88.5 (C_q), 60.6 (C_q), 29.9 (3 CH₃), 27.2 (2 CH₃).

MS: m/z (%) = 369 (M⁺, 33), 311 (100), 237 (58), 211 (57), 183 (44), 108 (45).

HRMS: m/z calcd for C₂₀H₂₃N₃O₄ (M⁺): 369.1683; found: 369.1690.

5-(1,3-Di-tert-butyl-1H-pyrazol-5-ylamino)methylene-2,2-dimethyl-1,3-dioxane-5,6-dione (3f)

Treatment of 6f using the general procedure gave 3f, yield: 0.83 g (89%); yellow solid; mp 105 °C.

¹H NMR (CDCl₃): δ = 11.47 (d, ³ J = 13.1 Hz, 1 H), 8.35 (d, ³ J = 13.1 Hz, 1 H), 6.08 (s, 1 H), 1.78 (s, 6 H), 1.67 (s, 9 H), 1.28 (s, 9 H).

¹³C NMR (CDCl₃): δ = 165.9 (C_q), 163.1 (C_q), 158.9 (C_q), 154.6 (CH), 137.0 (C_q), 105.5 (C_q), 94.0 (CH), 87.8 (C_q), 59.8 (C_q), 32.3 (C_q), 30.3 (3 CH₃), 29.9 (3 CH₃), 27.1 (2 CH₃).

MS: m/z (%) = 349 (M⁺, 24), 291 (100), 217 (27), 202 (45), 176 (56).

HRMS: m/z calcd for C₁₈H₂₇N₃O₄ (M⁺): 349.1996; found: 349.2000.

FVP Reactions

Flash vacuum pyrolysis reactions were carried out by distillation of the substrate in vacuo through an electrically heated silica furnace tube (35 × 2.5 cm). Products were trapped in a U-tube situated at the exit point of the furnace and cooled with liquid N₂. Conditions were first established on a small scale (20 mg) where the product(s) were dissolved in a deuterated solvent and analyzed directly by ¹H NMR spectroscopy. Larger-scale pyrolyses, involving 0.1 g or more of substrate, were usually removed from the trap by solution in CH₂Cl₂ (30 mL). The precursors and pyrolysis conditions [quantity of precursor, inlet temperature (T _i), furnace temperature (T _f), pressure range (P), and pyrolysis time (t)] and yields are stated.

FVP of 1-tert-Butylpyrazole (7)

This compound was too volatile for normal inlet conditions. It was therefore cooled in an acetone-dry ice bath, which was slowly removed to allow sublimation (20 mg, T _i acetone/dry ice bath, T _f 600–850 °C, P 0.03 Torr, t 15 min).

1-Methyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1aa)

FVP of 3a (recrystallized from MeOH, 203 mg, 0.81 mmol, T _i 199 °C, T _f 600 °C, P 0.03 Torr, t 30 min) gave 1aa; yield: 111 mg (92%); off-white solid; mp 164 °C (Lit.[13] mp 165–168 °C).

¹H NMR (DMSO-d ₆): δ = 8.37 (d, ³ J = 4.0 Hz, 1 H), 8.30 (s, 1 H), 6.65 (br s, 1 H), 4.22 (s, 3 H).

¹³C NMR (DMSO-d ₆): δ = 162.4 (br C_q), 150.7 (br C_q), 148.1 (br CH), 130.6 (CH), 107.9 (br C_q), 104.4 (CH), 33.9 (CH₃).

MS: m/z (%) = 149 (M⁺, 100), 95 (12), 78 (14), 63 (13).

HRMS: m/z calcd for C₇H₇N₃O (M⁺): 149.0584; found: 149.0584.

3-Methyl-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-4-one (1ba)

FVP of 3b (recrystallized from MeOH, 195 mg, 0.60 mmol, T _i 170 °C, T _f 600 °C, P 0.03 Torr, t 45 min) gave 1ba; yield: 0.129 mg (95%); off-white solid; mp 195 °C.

¹H NMR (DMSO-d ₆): δ = 11.76 (s, 1 H), 8.31 (br m, 3 H), 7.57 (app t, ³ J = 7.8 Hz, 2 H), 7.32 (d, ³ J = 7.3 Hz, 1 H), 6.66 (br s, 1 H), 2.68 (s, 3 H).

¹³C NMR (DMSO-d ₆): δ = 160.6 (C_q), 153.1 (C_q), 150.9 (CH), 142.0 (C_q), 139.5 (C_q), 128.9 (2 CH), 124.9 (CH), 119.7 (2 CH), 107.4 (C_q), 103.2 (CH), 14.3 (CH₃).

MS: m/z (%) = 226 (M⁺, 30), 225 (100), 79 (15), 78 (39).

HRMS: m/z calcd for C₁₃H₁₁N₃O (M⁺): 225.0897; found: 225.0896.

1-tert-Butyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1ca)

FVP of 3c (recrystallized from cyclohexane, 300 mg, 1.02 mmol, T _i 210 °C, T _f 500 °C, P 0.03 Torr, t 0.5 h) gave 1ca; yield: 185 mg (95%); yellow solid; mp 189–191 °C.

¹H NMR (DMSO-d ₆): δ = 11.40 (s, 1 H), 8.12 (br s, 1 H), 8.02 (s, 1 H), 6.49 (br s, 1 H), 1.74 (s, 9 H). ¹³C NMR (DMSO-d ₆): δ = 159.3 (C_q), 152.9 (C_q), 149.7 (CH), 128.5 (CH), 108.9 (C_q), 102.2 (CH), 59.6 (C_q), 29.2 (3 CH₃).

MS: m/z (%) = 191 (M⁺, 24), 135 (56).

HRMS: m/z calcd for C₁₀H₁₃N₃O (M⁺): 191.1064; found: 191.1060.

1,7-Dihydropyrazolo[3,4-b]pyridin-4-one (1cb)

FVP of 3c (recrystallized from cyclohexane, 50 mg, 0.17 mmol, T _i 210 °C, T _f 750 °C, P 0.03 Torr, t 0.5 h) was followed by distillation of CH₂Cl₂ into the U-tube trap. The solvent was removed in vacuo to afford a yellow solid, which was triturated with Et₂O and filtered under vacuum. The filtrate was further washed with Et₂O to yield 1cb; yield: 24 mg (67%); pale brown solid; mp 327–330 °C (Lit.[2d] mp 328–330 °C).

¹H NMR (DMSO-d ₆): δ (major tautomer) = 13.54 (s, 1 H), 11.71 (s, 1 H), 8.28 (br s, 1 H), 7.62 (br s, 1 H), 5.66 (br s, 1 H).

¹³C NMR (DMSO-d ₆): δ (major tautomer) = 177.1 (C_q), 151.2 (C_q), 139.2 (CH), 125.8 (CH), 113.4 (C_q), 107.3 (CH).

MS: m/z (%) = 135 (M⁺, 100).

1-tert-Butyl-1,7-dihydro-3-methylpyrazolo[3,4-b]pyridin-4-one (1da)

FVP of 3d (125 mg, 0.41 mmol, T _i 160 °C, T _f 500 °C, P 0.03 Torr, t 1 h) gave 1da; yield: 0.70 g (83%); off-white solid; mp 158 °C.

¹H NMR (DMSO-d ₆): δ = 11.17 (br s, 1 H), 8.01 (d, ³ J = 4.7 Hz, 1 H), 6.34 (d, ³ J = 4.7 Hz, 1 H), 2.45 (s, 3 H), 1.63 (s, 9 H).

¹³C NMR (DMSO-d ₆): δ = 160.7 (br C_q), 152.2 (br C_q), 147.5 (CH), 137.4 (br C_q), 107.2 (br C_q), 101.5 (CH), 58.5 (C_q), 28.8 (3 CH₃), 14.3 (CH₃).

MS: m/z (%) = 205 (M⁺, 48), 150, (22), 149 (100), 148 (26).

HRMS: m/z calcd for C₁₁H₁₅N₃O (M⁺): 205.1210; found: 205.1210.

3-Methyl-1,7-dihydropyrazolo[3,4-b]pyridin-3-one (1db)

FVP of 3d (100 mg, 0.33 mmol, T _i 160 °C, T _f 850 °C, P 0.03 Torr, t 45 min) gave 1db; yield: 0.40 g (82%); off-white solid; mp 254 °C.

¹H NMR (DMSO-d ₆): δ (major tautomer) = 13.11 (s, 1 H), 11.51 (s, 1 H), 7.50 (t, ³ J = 6.3 Hz, 1 H), 5.55 (d, ³ J = 6.3 Hz, 1 H), 2.53 (s, 3 H).

¹³C NMR (DMSO-d ₆, 600 MHz): δ (major tautomer) = 178.1 (br C_q), 151.5 (br C_q), 141.5 (br C_q), 138.6 (CH), 110.2 (C_q), 107.1 (CH), 11.0 (CH₃).

MS: m/z (%) = 149 (M⁺, 80), 78 (100).

HRMS: m/z calcd for C₇H₇N₃O (M⁺): 149.0584; found: 149.0583.

1-tert-Butyl-1,7-dihydro-3-phenylpyrazolo[3,4-b]pyridin-4-one (1ea)

FVP of 3e (500 mg, 1.36 mmol, T _i 220 °C, T _f 500 °C, P 0.03 Torr, t 0.5 h) gave 1ea; yield: 358 mg (96%); yellow solid; mp 295–298 °C.
¹H NMR (CDCl₃): δ = 11.51 (s, 1 H), 8.23 (d, ³ J = 5.4 Hz, 1 H), 8.00 (d, ³ J = 7.3 Hz, 2 H), 7.45 (t, ³ J = 7.3 Hz, 2 H), 7.36 (t, ³ J = 7.3 Hz, 1 H), 6.60 (d, ³ J = 5.4 Hz, 1 H), 1.80 (s, 9 H).

¹³C NMR (CDCl₃): δ = 160.0 (C_q), 154.1 (C_q), 149.6 (CH), 140.7 (C_q), 134.1 (C_q), 129.0 (2 CH), 128.4 (2 CH), 128.0 (CH), 105.8 (C_q), 102.6 (CH), 59.9 (C_q), 29.2 (3 CH₃).

MS: m/z (%) = 267 (M⁺, 33), 211 (100).

HRMS: m/z calcd for C₁₆H₁₇N₃O (M⁺): 267.1366; found: 267.1367.

1,7-Dihydro-3-phenylpyrazolo[3,4-b]pyridin-4-one (1eb)

FVP of 3e (500 mg, 1.36 mmol, T _i 220 °C, T _f 750 °C, P 0.03 Torr, t 0.5 h) was followed by distillation of CH₂Cl₂ into the U-tube trap. The solution was removed and the insoluble product filtered under vacuum to give 1eb; yield: 275 mg (96% mix[12]); off-white solid; mp 298 °C.

¹H NMR (DMSO-d ₆): δ (major tautomer) = 13.85 (br s, 1 H), 11.74 (br s, 1 H), 8.29 (br s, 1 H), 8.05 (br d, ³ J = 4.9 Hz, 1 H), 7.63 (m, 2 H), 7.47 (m, 2 H), 5.71 (br s, 1 H).

MS: m/z (%) = 211 (M⁺, 34), 183 (100).

HRMS: m/z calcd for C₁₂H₉N₃O (M⁺): 211.0751; found: 211.0751.

1,3-Di-tert-butyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1fa)

FVP of 3f (500 mg, 1.43 mmol, T _i 200 °C, T _f 500 °C, P 0.03 Torr, t 0.5 h) was followed by distillation of CH₂Cl₂ into the U-tube trap. The solution was removed and solvent removed in vacuo to afford 1fa; yield: 345 mg (97%); yellow solid; mp 264–266 °C.

¹H NMR (CDCl₃): δ = 11.39 (s, 1 H), 8.13 (d, ³ J = 4.7 Hz, 1 H), 6.50 (d, ³ J = 4.7 Hz, 1 H), 1.71 (s, 9 H), 1.43 (s, 9 H).

¹³C NMR (CDCl₃): δ = 159.3 (C_q), 154.4 (C_q), 148.9 (CH), 139.4 (C_q), 105.7 (C_q), 101.9 (CH), 59.0 (C_q), 33.7 (C_q), 29.1 (3 CH₃), 26.1 (3 CH₃).

MS: m/z (%) = 247 (M⁺, 29), 232 (54), 232 (100).

HRMS: m/z calcd for C₁₄H₂₁N₃O (M⁺): 247.1685; found: 247.1690.

3-tert-Butyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1fb)

FVP of 3f (500 mg, 1.43 mmol, T _i 200 °C, T _f 750 °C, P 0.03 Torr, t 0.5 h) was followed by distillation of CH₂Cl₂ into the U-tube trap. The solution was removed and the insoluble product 1fb was filtered under vacuum; yield: 374 mg (95% mix[12]); off-white solid; mp 265–266 °C.

¹H NMR (DMSO-d ₆): δ (major tautomer) = 12.88 (br s, 1 H), 11.56 (br s, 1 H), 7.59 (br s, 1 H), 5.63 (br s, 1 H), 1.44 (s, 9 H).

MS: m/z (%) = 191 (M⁺, 28), 176 (100), 149 (27).

HRMS: m/z calcd for C₁₀H₁₃N₃O (M⁺): 191.1059; found: 191.1063.

1-tert-Butyl-4-chloro-3-phenyl-1H-pyrazolo[3,4-b]pyridine (9)

Compound 1ea (1.00 g, 3.74 mmol) was dissolved in POCl₃ (18 mL, 197 mmol) and heated to reflux for 4 h. The solution was cooled, and the volume reduced in vacuo. H₂O (40 mL) was added slowly to the dark residue followed by sat. aq NaHCO₃ (40 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 30 mL), the combined organic layers were washed with brine (30 mL), dried (MgSO₄­), and the solvent removed in vacuo to afford 9; yield: 1.06 g (99%); brown solid; mp 123–125 °C.

¹H NMR (CDCl₃): δ = 8.41 (d, ³ J = 5.0 Hz, 1 H), 7.77 (m, 2 H), 7.48 (m, 3 H), 7.14 (d, ³ J = 5.0 Hz, 1 H), 1.91 (s, 9 H).

¹³C NMR (CDCl₃): δ = 151.9 (C_q), 147.3 (CH), 141.6 (C_q), 137.7 (C_q), 133.1 (C_q), 130.5 (2 CH), 128.2 (CH), 127.9 (2 CH), 117.2 (CH), 113.5 (C_q), 60.7 (C_q), 29.2 (3 CH₃).

MS: m/z (%) = 287 [M⁺ (³⁷Cl), 10], 285 [M⁺ (³⁵Cl), 31], 231 (32), 229 (100).

HRMS: m/z calcd for C₁₆H₁₆ ³⁵ClN₃ (M⁺): 285.1038; found: 285.1039.

4-Chloro-3-phenyl-1H-pyrazolo[3,4-b]pyridine (10)

FVP of 9 (50 mg, 0.18 mmol, T _i 300 °C, T _f 750 °C, P 0.033 Torr, t 0.5 h) was followed by distillation of CH₂Cl₂ into the U-tube trap. The solvent was removed in vacuo to afford 10; yield: 35 mg (87%); pale brown solid; mp 274–277 °C.

¹H NMR (CDCl₃): δ (major tautomer) = 12.85 (s, 1 H), 8.57 (d, ³ J = 5.2 Hz, 1 H), 7.81 (d, ³ J = 6.2 Hz, 2 H), 7.52 (m, 3 H), 7.26 (d, ³ J = 5.2 Hz, 1 H).

¹³C NMR (CDCl₃): δ (major tautomer) = 153.7 (C_q), 149.1 (CH), 145.8 (C_q), 139.2 (C_q), 132.4 (C_q), 130.3 (2 CH), 128.7 (CH), 128.1 (2 CH), 118.3 (CH), 112.4 (C_q).

MS: m/z (%) = 231 [M⁺ (³⁷Cl), 30], 229 [M⁺(³⁵Cl), 100], 166 (50).

HRMS: m/z calcd for C₁₂H₈ ³⁵ClN₃ (M⁺): 229.0412; found: 229.0414.

1-tert-Butyl-3-phenyl-4-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine (11)

Pyrrolidine (1.0 mL, 11 mmol) was added to a solution of 9 (250 mg, 0.877 mmol) in 1,2-dimethoxyethane (15 mL) and the mixture was heated at reflux with stirring for 18 h. The solvent was removed and the residue was partitioned between sat. aq NaHCO₃ (25 mL) and EtOAc (25 mL). The organic layer was separated and the solvent removed in vacuo to yield an orange residue, which was purified by dry flash chromatography eluting with hexane–EtOAc (20:1). Product containing fractions were combined and solvent removed in vacuo to give 11 as a yellow gum, which crystallized on standing; yield: 87 mg (37%); mp 122–123 °C.

¹H NMR (CDCl₃): δ = 8.18 (d, ³ J = 5.5 Hz, 1 H), 7.66 (d, ³ J = 6.9 Hz, 2 H), 7.42 (t, ³ J = 7.6 Hz, 2 H), 7.35 (t, ³ J = 8.6 Hz, 1 H), 6.28 (d, ³ J = 5.5 Hz, 1 H), 3.06 (t, ³ J = 6.5 Hz, 4 H), 1.89 (s, 9 H), 1.73 (t, ³ J = 6.5 Hz, 4 H).

¹³C NMR (CDCl₃): δ = 153.3 (C_q), 151.5 (C_q), 147.4 (CH), 141.8 (C_q), 136.7 (C_q), 129.2 (2 CH), 128.4 (2 CH), 127.6 (CH), 106.0 (C_q), 99.6 (CH), 59.7 (C_q), 51.5 (2 CH₂), 29.1 (3 CH₃), 25.2 (2 CH₂).

MS: m/z (%) = 320 (M⁺, 54), 264 (100), 263 (M – C₃H₆O, 38).

HRMS: m/z calc for C₂₀H₂₄N₄ (M⁺): 320.2007; found: 320.2005.

4-Anilino-1-tert-butyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine (12)

A solution of 9 (285 mg, 1.00 mmol), aniline (0.1 mL, 1.1 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol), dppp (16 mg, 0.04 mmol), and t-BuONa (134 mg, 1.4 mmol) in toluene (10 mL) contained in an oven-dried flask purged with N₂, was heated to 70 °C for 72 h. The mixture was cooled, taken up in Et₂O (10 mL), washed with brine (3 × 5 mL), and concentrated in vacuo to give the crude product, which was purified by dry flash chromatography eluting with hexane–EtOAc (20:1). Product containing fractions were combined and solvent removed in vacuo to afford 12 as a yellow gum, which crystallized on standing; yield: 280 mg (87%); mp 116–118 °C.

¹H NMR (CDCl₃): δ = 8.23 (d, ³ J = 5.5 Hz, 1 H), 7.68 (d, ³ J = 6.9 Hz, 2 H), 7.77 (t, ³ J = 7.5 Hz, 2 H), 7.55 (t, ³ J = 7.4 Hz, 1 H), 7.38 (dd, ³ J = 8.4, 7.4 Hz, 2 H)Hz,), 7.17 (m, 3 H), 6.72 (d, ³ J = 5.5 Hz, 1 H), 6.62 (br s, 1 H), 1.91 (s, 9 H).

¹³C NMR (CDCl₃): δ = 152.8 (C_q), 148.8 (CH), 145.9 (C_q), 140.5 (C_q), 139.2 (C_q), 134.9 (C_q), 129.5 (2 CH), 129.3 (2 CH), 129.1 (2 CH), 128.6 (CH), 124.5 (CH), 122.3 (2 CH), 104.5 (C_q), 97.7 (CH), 60.0 (C_q), 29.2 (3 CH₃).

MS: m/z (%) = 342 (M⁺, 42), 286 (100).

HRMS: m/z calcd for C₂₂H₂₂N₄ (M⁺): 342.1850; found: 342.1852.

4-Anilino-3-phenyl-1H-pyrazolo[3,4-b]pyridine (13)

FVP of 12 (30 mg, 0.88 mmol, T _i 235 °C, T _f 750 °C, P 0.03 Torr, t 0.5 h) was followed by distillation of CH₂Cl₂ into the U-tube trap. The solvent was removed in vacuo to afford 13; yield: 18 mg (72%); pale yellow solid; mp 216–217 °C.

¹H NMR (CDCl₃): δ (major tautomer) = 12.92 (br s, 1 H), 8.33 (d, ³ J = 5.7 Hz, 1 H), 7.81 (d, ³ J = 7.3 Hz, 2 H), 7.58 (t, ³ J = 7.4 Hz, 2 H), 7.52 (t, ³ J = 7.4 Hz, 1 H), 7.41 (t, ³ J = 7.9 Hz, 2 H), 7.23 (m, 3 H), 6.76 (d, ³ J = 5.7 Hz, 1 H), 6.74 (s, 1 H).

¹³C NMR (CDCl₃): δ (major tautomer) = 154.7 (C_q), 150.3 (C_q), 146.8 (CH), 144.5 (C_q) 138.7 (C_q), 134.4 (C_q), 129.6 (2 CH), 129.3 (2 CH), 129.0 (2 CH), 128.9 (CH), 125.1 (CH), 122.8 (2 CH), 102.8 (C_q), 98.3 (CH).

MS: m/z (%) = 286 (M⁺, 100), 285 (58), 258 (58).

HRMS: m/z calcd for C₁₈H₁₄N₄ (M⁺): 286.1224; found: 286.1218.

Acknowledgment

We thank Cancer Research UK (studentships to AN and MM; Grant Ref C21383/A6950) for financial support and Lorna Murray for assistance with NMR data.

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