Vilsmeier reagent-mediated synthesis of 6-[(formyloxy)methyl]-pyrazolopyrimidines via a one-pot multiple tandem reaction

Abstract

A new Vilsmeier reagent-mediated one-pot reaction using 5-(2-chloroacetylamino)pyrazoles as the starting material was developed for the efficient synthesis of 6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine. This new multiple tandem reaction, involving the Vilsmeier–Haack reaction, the Morgan–Walls reaction, sequential elimination, substitution, and final hydrolysis, afforded formyloxymethyl pyrazolo[3,4-d]pyrimidine products in good yields.

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Introduction

For practical synthetic organic chemistry, efficient, rapid and economical strategies are desirable to access valuable compounds.^1,2 One-pot tandem organic reactions have attracted great attention because they can simplify the detection, isolation, and purification of intermediates, and decrease manufacturing costs and pollution.^3,4 Additionally, one-pot multiple processes are also suitable for efficient synthetic methods and designing reactions for developing lead molecules for pharmaceuticals and materials.⁵

The Vilsmeier reaction is a versatile method for constructing many heterocyclic compounds^5,6 and is an important organic synthetic tool for introducing formyl groups.^6–10 Recently, we investigated a new Vilsmeier reaction by studying the reactivity of amide reagents for the preparation of pyrazolone,¹¹ pyrazole,¹² dipyrazolylmethane,¹³ and fused pyrimidine derivatives.¹⁴ The chemoselective products resulted from the different reactivity of the substituted amide Vilsmeier reagents with POCl₃. However, the Morgan–Walls cyclization reaction is widely used for C–C bond formation to build nitrogen ring systems.¹⁵ Herein, we use a Vilsmeier reagent to initiate the Vilsmeier–Haack formylation reaction, the Morgan–Walls cyclization reaction, sequential elimination, substitution, and hydrolysis, to synthesize pyrazole fused pyrimidine derivatives via a tandem multiple reaction.^14,16

Pyrimidines fused with a heterocycle, such as furo-,¹⁷ pyrazolo-,¹⁸ pyrrolo-,¹⁹ pyridopyrazolo-,²⁰ and pyrazolotriazolo-pyrimidine,²¹ are an important class of compounds, and are of interest to the pharmaceutical industry owing to their pharmaceutical properties. Pyrazolopyrimidines can also be accessed via heterocyclization using starting materials such as 5-amino-4-formypyrazoles,²² 5-amino-1H-4-pyrazolcarbonitriles,²³ and 5-amino-1H-4-pyrazolcarboxamides.^23–26 However, the method for preparing pyrazolopyrimidines involves harsh conditions, long reaction times, complex synthetic procedures, and tedious purification steps.²⁷ Therefore, convenient synthetic routes for the synthesis of pyrimidine fused heterocyclic systems have attracted considerable attention. In this work, we describe a direct, convenient one-pot multiple method for the synthesis of a series of pyrazolo[3,4-d]pyrimidine derivatives from 5-(2-chloroacetylamino)pyrazoles with formamide in the presence of PBr₃. This multiple tandem reaction provided formyloxymethyl pyrazolo[3,4-d]pyrimidine products in good yields (73–92%).

Result and discussion

Scheme 1 shows typical reaction conditions for Vilsmeier reagent-mediated synthesis of 1-aryl-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidines 17–32 from 5-(2-chloroacetylamino)pyrazoles 1–16. Starting materials 1–16 were prepared from the reaction of 5-aminopyrazoles and 2-chloroacetyl chloride as previously reported.²⁸ Because 5-(2-chloroacetylamino)pyrazoles 1–16 possessed an activated α-chloro-N-arylacetamide moiety, we introduced the mildly nucleophile iminium group at the C-4 position of the pyrazole ring of 5-(2-chloroacetylamino)pyrazoles 1–16 via the Vilsmeier–Haack reaction, to evaluate the intramolecular cyclization reaction conditions for synthesizing 6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidines.

Scheme 1 One-pot multiple reaction for the synthesis of 1-aryl-6-[(formyloxy)methyl]-1H-parasol[3,4-d]pyrimidines 17–32.

To optimize the reaction conditions, 1,3-diphenyl-5-(2-chloroacetylamino)pyrazole (1) was used as the model and reacted with formamide in the presence of various halogenating agents, including benzoyl chloride (PhCOCl), oxalyl chloride (ClCOCOCl), phosphorous tribromide (PBr₃), phosphorous oxychloride (POCl₃), thionyl chloride (SOCl₂), and p-toluenesulfonic chloride (TsCl), at 50–60 °C for 5.0 h. Without the halogenating agent, virtually no reaction took place (entry 1, Table 1). When 3.0 equiv. of halogenating agent was added, the reaction gave the corresponding 1,3-diphenyl-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine (17) in 26–88% yields (entries 2–7, Table 1). PBr₃ provided the best result with the formation of product 17 in 88% yield (entry 2 in Table 1). POCl₃ also gave a good yield of 17 (73%, entry 2, Table 1).

Table 1 Optimization of halogenating agents

Entry	Halogenating agent (3.0 equiv.)	Yield^a^,^b of 17 (%)
a Based on the weight of starting material 5-(2-chloroacetylamino)pyrazole (1).b Isolated yields.c Not detectable.
1	—	—^c
2	PBr3	88
3	POCl3	73
4	SOCl2	41
5	TsCl	31
6	PhCOCl	26
7	ClCOCOCl	33

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By using PBr₃ as the brominating agent with 5-(2-chloroacetylamino)pyrazoles 1–8 possessing methyl, chloro, and methoxy substituents, the tandem one-pot multiple reaction gave the corresponding 1-aryl-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidines 17–24 in 73–92% yields (Scheme 1 and Table 2). The m- and p-Me-Ph at the N-1 substituents in the pyrazole ring gave 1-aryl-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidines 19 and 20 in better isolated yields (85% and 92%). Employing the same conditions for 5-(2-chloroacetylamino)pyrazoles with methyl, p-NO₂-Ph and p-COOH-Ph substituents at the N-1 position of the pyrazole ring did not give the desired pyrazolo[3,4-d]pyrimidine products. Therefore, we assumed that the electron-donating phenyl group as the N-1 substituent would favor the one-pot multiple reaction.

Table 2 Synthesis of 1-aryl-6[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidines 17–32 via the one-pot tandem multiple reaction

Starting material	X	R	No.	Yield^a (%)
a Isolated yields.
1	H	Ph	17	88
2	o-Me	Ph	18	77
3	m-Me	Ph	19	85
4	p-Me	Ph	20	92
5	o-Cl	Ph	21	83
6	m-Cl	Ph	22	81
7	p-Cl	Ph	23	84
8	p-OMe	Ph	24	73
9	H	Me	25	78
10	H	t-Bu	26	81
11	H	p-Me-Ph	27	74
12	H	p-OMe-Ph	28	75
13	m-Me	p-OMe-Ph	29	74
14	p-Me	p-OMe-Ph	30	84
15	o-Cl	t-Bu	31	72
16	p-Cl	t-Bu	32	77

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To investigate the substitution effect, the same conditions were applied to 5-(2-chloroacetylamino)pyrazoles 9–12 containing methyl, t-butyl, p-Me-Ph, p-Cl-Ph, or p-OMe-Ph groups at the C-3 position and phenyl substituent at the N-1 position. The reaction also gave corresponding compounds 25–28 in 74–81% yields (Scheme 1 and Table 2). In particular, compound 10 with a t-butyl group at the C-3 position showed a better yield (81%). To demonstrate the electronic effects of a meta- or para substituent at the N-1 position of the pyrazole ring, compounds 13 and 14 were synthesized as starting materials. The results in Table 2 indicate that the N-1 para-Me phenyl displayed a better yield than the meta-Me substituent (84% vs. 74%). For compounds 15 and 16 bearing ortho- and para-Cl phenyl substituents, respectively, at the N-1 position, the induction effect of the N-1 para-Cl substituent was stronger than ortho-Cl (77% vs. 72%, Table 2). All 6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidines (17–30) were characterized by spectroscopic methods. The structure of 6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine 24 was also characterized by X-ray crystallography and the ORTEP drawing is shown in Fig. 1.

Fig. 1 ORTEP diagram of 1-(p-methoxyphenyl)-3-phenyl-6-[(formyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine (24).

We investigated the effect of the leaving group at the α position (–(C=O)–CH–X). We prepared the starting materials 5-(2-bromoacetylamino)pyrazole (33), 5-(2-iodoacetylamino)pyrazole (34), and 5-(2-hydroxyacetylamino)pyrazole (35)²⁹ bearing Br, I, and OH at the α-C position (Table 3). Under the same reaction conditions used for compounds 33–35, compounds 33 and 34 were obtained in 86% and 87% yields, respectively (entries 2 and 3, Table 3). Although the hydroxyl group is a poor leaving group, compound 35 was also converted to the corresponding pyrimidine fused product 22 in 73% yield because the hydroxyl group was transformed into the efficient leaving group O(P=O)Br₂ in the presence of PBr₃ (Table 3). Based on these results, the reactivity of leaving group was in the order I > Br > Cl > OH. To consider the cost and commercial availability of reagents, we synthesized a series of 5-(2-hydroxyacetylamino)pyrazoles as starting materials.

Table 3 Optimization of leaving groups

Entry	Starting material	Y	Product	Yield^a (%)
a Isolated yields.
1	6	Cl	22	81
2	33	Br	22	86
3	34	I	22	87
4	35	OH	22	73

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Based on the experimental results, we proposed a mechanism for the one-pot multiple reaction (Scheme 2). Vilsmeier reactive species 36 was generated from the reaction of formamide with PBr₃ in situ.^11–14,30 1,3-Diphenyl-5-(2-chloroacetylamino)pyrazole 1 reacted with 36, undergoing the Vilsmeier–Haack reaction to afford intermediate 37 and introducing an imino group on the C-4 position of pyrazole ring (Scheme 2). Under highly acidic conditions, an excess of PBr₃ would catalyze the Morgan–Walls reaction to provide 38 and subsequently generate 39 via intramolecular cyclization.³¹ Intermediates 37 and 38 containing an electron-withdrawing group, such as NO₂ and COOH, would decrease the nucleophilicity of the imino group through conjugation and favor the heterocyclization reaction. In intermediate 38, the coplanar N-1 aliphatic methyl substituent would interfere with the intra-cyclization reaction. As a result, 5-(2-chloroacetylamino)pyrazoles with methyl, p-NO₂-Ph and p-COOH-Ph substituents in N-1 position of the pyrazole ring did not react. After deprotonation of intermediate 39, 6-(chloromethyl)pyrazolo[3,4-d]pyrimidine intermediate 40 was formed. Formamide possesses two resonance structures (42 and 43).^32,33 Under acidic conditions, formamide favored the C(O–)=N⁺H₂ (42) structure, which displaced the chloro atom in 40 to give substitution product 41. After work-up, intermediate 41 was hydrolyzed to 6-[(formyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine 17 as the major product (88% yield) and (1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol 44 as the minor product (9% yield, Scheme 2).

Scheme 2 Proposed mechanism for synthesis of 1-aryl-6-[(formyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine 17 from 5-(2-chloroacetylamino)pyrazole 1.

During work-up and purification, a small amount of 44 was isolated as the by-product (Scheme 2). This suggested that compound 44 might be in equilibrium toward compound 17 under acidic conditions. Therefore, we isolated compound 44 and treated it with formamide and PBr₃ under the same conditions. Compound 44 was transferred to the corresponding pyrazolo[3,4-d]pyrimidine product 17 in 81% yield (Scheme 3). Based on this result, compound 44 is in hydrolysis equilibrium with compound 17 (Scheme 3). To confirm this, water was added to the reaction mixture and it was kept at room temperature. The mixture was sampled every 30 min and monitored by TLC and ¹H-NMR. The results showed that compound 17 was gradually converted to hydrolysis product 44. Therefore, quenching neutralization must be performed carefully to decrease the amount of hydrolysis product 44.

Scheme 3 Conversion of 1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-)methanol 44 and 6-(chloromethyl)-1H-pyrazolo[3,4-d]pyrimidine intermediate 40 to 6-[(formyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine 17.

To gain insight into the reaction mechanism and the formyloxylation in the reaction, a further study was performed (Scheme 2). We tried to convert compound 44 to the proposed intermediate, 6-(chloromethyl)pyrazolo[3,4-d]pyrimidine (40), by treating it with thionyl chloride in CH₂Cl₂ (80%, Scheme 3).³⁴ Synthesized intermediate 40 reacted with formamide and PBr₃ under the same conditions. Corresponding product 17 was isolated in 74% yield. The results are consistent with our proposed mechanism.

Conclusion

We developed a one-pot multiple reaction for preparing 6-(formyloxymethyl)pyrazolo[3,4-d]pyrimidine by treating 5-(2-chloroacetylamino)pyrazoles with formamide in presence of PBr₃. The reactivity of the leaving group was I > Br > Cl > OH. A mechanistic study showed that key 6-(chloromethyl)pyrazolo[3,4-d]pyrimidine intermediate 40 was synthesized from (1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol 44, and then converted to the desired 6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine 17 under the same conditions, which was consistent with our proposed mechanism.

Experimental section

All chemicals were reagent grade and used as purchased. All reactions were carried out under nitrogen and monitored by TLC. Flash column chromatography was carried out on silica gel (230–400 mesh). Commercially available reagents were used without further purification unless otherwise noted. ¹H NMR spectra were recorded at 200, 400, or 500 MHz, and ¹³C NMR spectra were recorded at 50, 100, or 125 MHz, respectively, in CDCl₃, CH₃OD, and DMSO-d₆. The standard abbreviations, s, d, t, q, and m, refer to singlet, doublet, triplet, quartet, and multiplet, respectively. Coupling constants (J) are reported in hertz. IR spectra were recorded as neat solutions or solids, and mass spectra were recorded using electron impact or electrospray ionization techniques. The wavenumbers reported are referenced to the polystyrene 1601 cm⁻¹ absorption. Flash column chromatography purification of compounds was carried out by gradient elution with hexanes and ethyl acetate (EA), unless otherwise stated. High-resolution mass spectra were obtained with a JEOL JMS-HX110 mass spectrometer.

Standard procedure for synthesis of 5-(2-haloacetylamino)pyrazoles 1–16 and 33–35²⁸

1-Aryl-3-aryl-5-aminopyrazole (1.0 equiv.) was dissolved in CH₂Cl₂ (10 mL) and stirred in an ice-bath. 2-Chloroacetyl chloride, 2-chloroacetyl bromide, or 2-iodoroacetyl chloride (1.2 equiv.) in CH₂Cl₂ or THF (10 mL) was slowly added to the reaction mixture at 0 °C under N₂. The reaction was stirred at 0–10 °C for 3–4 h. The reaction mixture was washed with water (10 mL) and saturated aqueous NaHCO₃ (10 mL × 2). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the corresponding acylation product 5-(2-haloacetylamino)pyrazoles 1–6 and 33–35 in 73–87% yields.

5-(2-Chloroacetylamino)-1-phenyl-3-phenylpyrazole (1). ¹H NMR (CDCl₃, 200 MHz) δ 4.18 (s, 2H, CH₂), 7.10 (s, 1H), 7.23–7.55 (m, 8H, ArH), 7.86 (dd, 2H, J = 8.0, 4.0 Hz), 8.63 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(2-methylphenyl)-3-phenylpyrazole (2). ¹H NMR (CDCl₃, 200 MHz) δ 2.38 (d, J = 7.6 Hz, 3H, CH₃), 4.10 (s, 2H, CH₂), 6.96 (s, 1H), 7.38–7.44 (m, 9H, ArH).

5-(2-Chloroacetylamino)-1-(3-methylphenyl)-3-phenylpyrazole (3). ¹H NMR (CDCl₃, 200 MHz) δ 2.13 (s, 3H, CH₃), 4.04 (s, 2H, CH₂), 7.31–7.47 (m, 8H, ArH), 7.91 (d, J = 3.0 Hz, 2H, ArH), 8.82 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(4-methylphenyl)-3-phenylpyrazole (4). ¹H NMR (CDCl₃, 200 MHz) δ 2.42 (s, 3H, CH₃), 4.18 (s, 2H, CH₂), 7.09 (s, 1H), 7.25–7.43 (m, 7H, ArH), 7.86 (dd, 2H, J = 9.6, 8.0 Hz), 8.61 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(2-chlorophenyl)-3-phenylpyrazole (5). ¹H NMR (CDCl₃, 200 MHz) δ 4.13 (s, 2H, CH₂), 7.04 (s, 1H), 7.25–7.55 (m, 9H, ArH), 8.29 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(3-chlorophenyl)-3-phenylpyrazole (6). Brown solid; mp 101–102 °C; ¹H NMR (CDCl₃, 200 MHz) δ 4.20 (s, 2H, CH₂), 7.08 (s, 1H, ArH), 7.31–7.47 (m, 5H, ArH), 7.61 (s, 2H, ArH), 7.85 (d, J = 7.6 Hz, 2H, ArH), 8.61 (s, 1H, N–H); ¹³C NMR (CDCl₃, 50 MHz) δ 42.64, 96.23, 122.00, 124.88, 125.76 (2 × CH), 128.45, 128.66 (3 × CH), 130.84, 132.42, 135.42, 135.81, 138.64, 152.42, 162.50; IR (KBr) 3046, 2955, 2924, 2853, 1721 (s, C=O), 1201, 764; EIMS m/z: 349 (M⁺ + 4, 2), 347 (M⁺ + 2, 9), 345 (M⁺, 16), 194 (100), 165 (11), 133 (79), 105 (42), 91 (74), 77 (30); HRMS calcd for C₁₇H₁₃Cl₂ON₃: 345.0436, found: 345.0433.

5-(2-Chloroacetylamino)-1-(4-chlorophenyl)-3-phenylpyrazole (7). ¹H NMR (CDCl₃, 200 MHz) δ 4.18 (s, 2H, CH₂), 7.04 (s, 1H), 7.24–7.50 (m, 7H, ArH), 7.79 (dd, 2H, J = 15.7, 7.8 Hz), 7.29 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(3-methoxyphenyl)-3-phenylpyrazole (8). ¹H NMR (CDCl₃, 200 MHz) δ 3.86 (s, 3H, CH₃), 4.17 (s, 2H, CH₂), 7.01–7.07 (m, 3H, ArH), 7.39–7.46 (m, 5H, ArH), 7.83–7.84 (m, 2H, ArH), 8.54 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-phenyl-3-methylpyrazole (9). ¹H NMR (CDCl₃, 200 MHz) δ 2.30 (s, 3H, CH₃), 4.13 (s, 2H, CH₂), 6.55 (s, 1H), 7.36–7.54 (m, 5H, ArH), 8.52 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-phenyl-3-tetrabutanyl pyrazole (10). ¹H NMR (CDCl₃, 200 MHz) δ 1.33 (s, 9H, CH₃), 4.13 (s, 2H, CH₂), 6.63 (s, 1H), 7.46–7.48 (m, 5H, ArH), 8.58 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-phenyl-3-(4-methylphenyl) pyrazole (11). ¹H NMR (CDCl₃, 200 MHz) δ 2.36 (s, 3H, CH₃), 4.15 (s, 2H, CH₂), 6.74 (s, 1H), 7.06–7.54 (m, 7H, ArH), 7.72 (d, J = 6.4 Hz, 2H, ArH), 8.65 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-phenyl-3-(4-methoxyphenyl) pyrazole (12). ¹H NMR (CDCl₃, 200 MHz) δ 3.82 (s, 3H, CH₃), 4.18 (s, 2H, CH₂), 6.93 (d, J = 8.8 Hz, 2H, ArH), 7.04 (s, 1H), 7.43–7.55 (m, 5H, ArH), 7.80 (dd, 2H, J = 8.8, 4.4 Hz), 8.62 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(3-methlyphenyl)-3-(4-methoxyphenyl) pyrazole (13). ¹H NMR (CDCl₃, 200 MHz) δ 2.42 (s, 3H, CH₃), 3.82 (s, 3H, CH₃), 4.17 (s, 2H, CH₂), 6.92 (dd, 2H, J = 8.8, 6.8 Hz), 7.03 (s, 1H), 7.26–7.41 (m, 4H, ArH), 7.80 (dd, 2H, J = 8.8, 6.8 Hz), 8.66 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(4-methlyphenyl)-3-(4-methoxyphenyl) pyrazole (14). ¹H NMR (CDCl₃, 200 MHz) δ 2.39 (s, 3H, CH₃), 3.82 (s, 3H, CH₃), 4.17 (s, 2H, CH₂), 6.92 (dd, 2H, J = 8.8, 4.4 Hz), 7.02 (s, 1H), 7.30–7.42 (m, 4H, ArH), 7.78 (dd, 2H, J = 8.8, 6.8 Hz), 8.60 (br, 1H, N–H).

5-(2-Chloroacetylamino)-1-(2-chlorophenyl)-3-tetrabutanyl pyrazole (15). ¹H NMR (CDCl₃, 200 MHz) δ 1.35 (s, 9H, CH₃), 4.08 (s, 2H, CH₂), 6.56 (s, 1H), 7.38–7.56 (m, 4H, ArH), 8.20 (br, 1H, N–H); ¹³C NMR (CDCl₃, 50 MHz) δ 30.27 (3 × CH), 32.53, 42.49, 94.85, 128.24, 130.26, 130.58, 130.84, 131.61, 135.07, 135.55, 162.53, 163.29.

5-(2-Chloroacetylamino)-1-(4-chlorophenyl)-3-tetrabutanyl pyrazole (16). ¹H NMR (CDCl₃, 200 MHz) δ 1.29 (s, 9H, CH₃), 4.11 (s, 2H, CH₂), 6.56 (s, 1H), 7.39–7.46 (m, 4H, ArH), 8.49 (br, 1H, N–H).

5-(2-Bromoacetylamino)-1-(3-chlorophenyl)-3-phenylpyrazole (33). Yellow solid; mp 106–107 °C; ¹H NMR (CDCl₃, 400 MHz) δ 4.01 (s, 2H, CH₂), 7.05 (s, 1H, ArH), 7.31–7.47 (m, 6H, ArH), 7.61 (s, 1H, ArH), 7.85 (d, J = 7.6 Hz, 2H, ArH), 8.48 (s, 1H, N–H); ¹³C NMR (CDCl₃, 100 MHz) δ 42.63, 96.23, 121.99, 124.87, 125.76 (2 × CH), 127.99, 128.66 (3 × CH), 130.84, 132.40, 135.42, 135.81, 138.61, 152.43, 162.50; IR (KBr) 3046, 2955, 2924, 2853, 1721 (s, C=O), 1201, 764; EIMS m/z: 393 (M⁺ + 4, 25), 391 (M⁺ + 2, 100), 389 (M⁺, 76), 296 (11), 271 (30), 269 (93), 233 (35), 102 (69), 77 (16); HRMS calcd for C₁₇H₁₃BrClON₃: 388.9931, found: 388.9932.

1-(3-Chlorophenyl)-5-(2-iodoacetylamino)-3-phenylpyrazole (34). Yellow solid; mp 103–104 °C; ¹H NMR (CDCl₃, 200 MHz) δ 4.20 (s, 2H, CH₂), 7.08 (s, 1H, ArH), 7.22 (m, 2H, ArH), 7.42 (m, 4H, ArH), 7.61 (s, 1H, ArH), 7.85 (m, 2H, ArH), 8.62 (s, 1H, N–H); ¹³C NMR (CDCl₃, 50 MHz) δ 32.88, 90.21, 126.21, 127.26, 129.94 (2 × CH), 128.45, 132.54 (3 × CH), 134.52, 134.77, 135.69, 139.72, 1345.34, 152.43, 165.23; IR (KBr) 3229, 2920, 1674 (s, C=O), 1593, 1558, 1366, 1076, 763, 1201, 764; EIMS m/z: 439 (M⁺ + 2, 13), 437 (M⁺, 52), 345 (32), 269 (100), 233 (39), 102 (90), 91 (12), 77 (27); HRMS calcd for C₁₇H₁₃ClION₃: 436.9792, found: 436.9793.

Standard procedure for synthesis of 1,3-diphenyl-6-[(formyloxy)methyl]-1H-pyrazolo-[3,4-d]pyrimidine 17 and (1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol 44

5-(2-Chloroacetylamino)pyrazole 1 (203 mg, 0.58 mmol, 1.0 equiv.) was treated with PBr₃ (1.77 mmol, 0.2 mL, 3.0 equiv.) in formamide solution (2 mL) at 50–60 °C within 5 h. When the reaction was complete, the reaction mixture was added to saturate sodium bicarbonate (15 mL) and extracted with dichloromethane (15 mL × 2). The combined organic layer was washed with sodium bicarbonate (15 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel to give the corresponding 6-(formylmethyl)pyrazolo[3,4-d]pyrimidines 17 (168 mg, 0.51 mmol) in 88% yield and the (1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol (44) by-product (17.1 mg, 0.049 mmol) in 9% yield.

1,3-Diphenyl-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine (17). Yellow solid; mp 126–127 °C; ¹H NMR (CDCl₃, 200 MHz) δ 5.55 (s, 2H, CH₂), 7.33–7.37 (m, 1H, ArH), 7.46–7.58 (m, 5H, ArH), 8.01 (dd, J = 1.6, 7.9 Hz, 2H, ArH), 8.28 (dd, J = 1.6, 7.9 Hz, 2H, ArH), 8.33 (s, 1H, CHO), 9.43 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 65.60, 113.14, 121.16 (2 × CH), 126.73, 127.26 (2 × CH), 129.14, 129.63 (4 × CH), 131.29, 138.39, 144.96, 152.97, 153.59, 160.50, 161.48; IR (KBr) 2955, 1721 (s, C=O), 1585, 1497, 1416, 1200, 753; EIMS m/z: 330 (M⁺, 100), 301 (38), 286 (79), 273 (15), 271 (12), 180 (7), 142 (10), 91 (14), 77 (51); HRMS calcd for C₁₉H₁₄O₂N₄: 330.1117, found: 330.1121.

(1,3-Diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol (44). Yellow solid; mp 101–102 °C; ¹H NMR (CDCl₃, 400 MHz) δ 4.99 (s, 2H, CH₂), 7.34–7.38 (m, 1H, ArH), 7.48–7.57 (m, 5H, ArH), 8.04 (d, J = 7.2 Hz, 2H, ArH), 8.26 (d, J = 7.2 Hz, 2H, ArH), 9.44 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 64.85, 113.21, 121.49 (2 × CH), 126.92, 127.36 (2 × CH), 129.22 (4 × CH), 129.70, 131.40, 138.39, 145.25, 152.82, 153.55, 166.22; IR (KBr) 3395 (OH, Br), 2916, 1651, 1543, 748; EIMS m/z: 302 (M⁺, 100), 301 (53), 273 (25), 273 (15), 271 (20), 91 (16), 77 (49); HRMS calcd for C₁₈H₁₄ON₄: 302.1168, found: 302.1161.

Standard procedure for synthesis of 6-(formyloxymethyl)pyrazolo[3,4-d]pyrimidines 18–32

5-(2-Chloroacetylamino)pyrazole (2–16, 1.0 equiv.) was treated with PBr₃ (3.0 equiv.) in formamide solution (2 mL) at 50–60 °C for 5 h. When the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate (15 mL) and extracted with dichloromethane (15 mL × 2). The combined organic layer was washed with sodium bicarbonate (15 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude solution was purified by column chromatography on silica gel to give the corresponding 6-(formylmethyl)pyrazolo[3,4-d]pyrimidines 18–32 in 73–92% yields.

6-[(Formyloxy)methyl]-1-(2-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (18). White solid; mp 133–134 °C; ¹H NMR (CDCl₃, 400 MHz) δ 2.22 (s, 3H, CH₃), 5.47 (s, 2H, CH₂), 7.37–7.57 (m, 7H, ArH), 8.03 (d, J = 7.6 Hz, 2H, ArH), 8.23 (s, 1H, CHO), 9.53 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 18.44, 65.69, 111.90, 126.69, 127.29 (2 × CH), 127.61, 129.24 (2 × CH), 129.41, 129.58, 131.43, 131.63, 135.40, 136.11, 145.16, 153.04, 154.55, 160.47, 161.72; IR (KBr) 2920, 2851, 1721 (s, C=O), 1589, 1458, 1265, 1184, 752; EIMS m/z: 344 (M⁺, 13), 299 (32), 298 (100), 256 (17), 202 (11), 189 (17), 155 (14), 133 (31), 91 (41), 88 (28), 77 (17); HRMS calcd for C₂₀H₁₆O₂N₄: 344.1273, found: 344.1274.

6-[(Formyloxy)methyl]-1-(3-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (19). White solid; mp 127–128 °C; ¹H NMR (CDCl₃, 200 MHz) δ 2.22 (s, 3H, CH₃), 5.47 (s, 2H, CH₂), 7.34–7.59 (m, 5H, ArH), 7.53 (d, J = 7.5 Hz, 2H, ArH), 8.04 (dd, J = 1.4, 7.8 Hz, 2H, ArH), 8.23 (s, 1H, CHO), 9.49 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 18.43, 65.66, 111.88, 126.68, 127.27 (2 × CH), 127.60, 129.23 (2 × CH), 129.39, 129.57, 131.42, 131.60, 135.38, 136.08, 145.14, 153.03, 154.53, 160.46, 161.70; IR (KBr) 3059 (m), 2916, 2847, 1724 (s, C=O), 1589, 1504, 1458, 1184, 1134, 760; EIMS m/z: 344 (M⁺, 15), 298 (100), 256 (19), 163 (20), 146 (47), 134 (35), 120 (55), 115 (58), 99 (84), 77 (30); HRMS calcd for C₂₀H₁₆O₂N₄: 344.1273, found: 344.1268.

6-[(Formyloxy)methyl]-1-(4-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (20). White solid; mp 107–108 °C; ¹H NMR (CDCl₃, 400 MHz) δ 2.42 (s, 3H, CH₃), 5.55 (s, 2H, CH₂), 7.34 (d, J = 8.0 Hz, 2H, ArH), 7.56 (s, 1H, ArH), 8.04 (d, J = 8.0 Hz, 2H, ArH), 8.14 (d, J = 8.0 Hz, 2H, ArH), 8.23 (s, 1H, CHO), 9.46 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 21.10, 65.68, 113.06, 121.35 (2 × CH), 127.34 (2 × CH), 129.22 (2 × CH), 129.71, 129.73 (2 × CH), 131.46, 135.97, 136.79, 144.87, 152.99, 153.45, 160.53, 161.42; IR (KBr) 2922, 1726 (s, C=O), 1514, 1454, 1184, 1172, 957, 816, 766; EIMS m/z: 344 (M⁺, 100), 301 (37), 208 (11), 91 (19), 77 (10); HRMS calcd for C₂₀H₁₆O₂N₄: 344.1273, found: 344.1276.

1-(2-Chlorophenyl)-6-[(formyloxy)methyl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (21). Yellow solid; mp 81–82 °C; ¹H NMR (CDCl₃, 200 MHz) δ 5.47 (s, 2H, CH₂), 7.45–7.64 (m, 7H, ArH), 8.02 (dd, J = 1.4, 7.7 Hz, 2H, ArH), 8.24 (s, 1H, CHO), 9.48 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 65.61, 112.02, 127.37 (2 × CH), 127.59, 129.24 (2 × CH), 129.61, 129.72, 130.69, 130.78, 131.35, 132.09, 134.74, 145.79, 153.03, 154.99, 160.45, 161.92; IR (KBr) 3059, 2922, 2851, 1722 (s, C=O), 1591, 1503, 1410, 1184, 1132, 980, 756; EIMS m/z: 366 (M⁺ + 2, 35), 364 (M⁺, 100), 335 (34), 329 (13), 320 (83), 307 (15), 271 (13), 133 (29), 91 (24), 77 (27); HRMS calcd for C₁₉H₁₃ClO₂N₄: 364.0721, found: 364.0725.

1-(3-Chlorophenyl)-6-[(formyloxy)methyl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (22). Yellow solid; mp 128–129 °C; ¹H NMR (CDCl₃, 400 MHz) δ 5.58 (s, 2H, CH₂), 7.32 (d, J = 7.2 Hz, 1H, ArH), 7.44–7.59 (m, 3H, ArH), 7.57 (s, 1H, ArH), 8.04 (d, J = 8.0, 2H, ArH), 8.31 (d, J = 8.0 Hz, 1H, ArH), 8.34 (s, 1H, ArH), 8.44 (s, 1H, pyrimidine–H), 9.46 (s, 1H, CHO); ¹³C NMR (CDCl₃, 100 MHz) δ 65.46, 113.42, 118.81, 121.05, 126.58, 127.37 (2 × CH), 129.24 (2 × CH), 129.88, 130.15, 131.09, 134.90, 139.52, 145.51, 153.12, 153.97, 160.38, 161.88; IR (KBr) 3059, 2922, 2851, 1722 (s, C=O), 1591, 1503, 1410, 1184, 1132, 980, 756; EIMS m/z: 366 (M⁺ + 2, 34), 364 (M⁺, 100), 355 (16), 335 (53), 320 (77), 307 (22), 281 (18), 221 (18), 111 (12), 77 (18); HRMS calcd for C₁₉H₁₃ClO₂N₄: 364.0721, found: 364.0725.

1-(4-Chlorophenyl)-6-[(formyloxy)methyl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (23). Yellow solid; mp 127–128 °C; ¹H NMR (CDCl₃, 200 MHz) δ 5.56 (s, 2H, CH₂), 7.48–7.57 (m, 5H, ArH), 8.03 (dd, J = 1.5, 8.4, 2H, ArH), 8.31 (d, J = 8.4, 2H, ArH), 8.33 (s, 1H, CHO), 9.46 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 65.61, 113.36, 122.26, 125.75, 127.40, 129.32, 129.90 (2 × CH), 131.18, 132.21, 137.08, 145.41, 153.19, 153.78, 160.50, 161.81; IR (KBr) 3059, 2922, 2851, 1722 (s, C=O), 1591, 1503, 1410, 1184, 1132, 980, 756; EIMS m/z: 366 (M⁺ + 2, 2), 364 (M⁺, 7), 284 (21), 217 (11), 135 (100), 91 (16), 77 (9); HRMS calcd for C₁₉H₁₃ClO₂N₄: 364.0721, found: 364.0718.

6-[(Formyloxy)methyl]-1-(3-methoxyphenyl)-3-phenyl-1H-pyrazolo-[3,4-d]pyrimidine (24). Yellow solid; mp 90–91 °C; ¹H NMR (CDCl₃, 400 MHz) δ 3.87 (s, 3H, CH₃), 5.54 (s, 2H, CH₂), 7.06 (d, J = 8.0 Hz, 2H, ArH), 7.48–7.57 (m, 2H, ArH), 7.55 (s, 1H, ArH), 8.03 (d, J = 8.0 Hz, 2H, ArH), 8.14 (dd, J = 2.0, 8.0 Hz, 2H, ArH), 8.32 (s, 1H, CHO), 9.45 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 55.58, 65.73, 112.91, 114.38 (2 × CH), 123.01 (2 × CH), 127.32 (2 × CH), 129.22 (2 × CH), 129.57, 131.55, 131.72, 144.71, 153.01, 153.29, 158.45, 160.51, 161.46; IR (KBr) 2924, 1728 (s, C=O), 1585, 1512, 1458, 1250, 1173, 1030, 829, 764; EIMS m/z: 360 (M⁺, 100), 331 (13), 316 (12), 77 (10); HRMS calcd for C₂₀H₁₆O₃N₄: 360.1222, found: 360.1224.

6-[(Formyloxy)methyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]-pyrimidine (25). Brown solid; mp 85–86 °C; ¹H NMR (CDCl₃, 400 MHz) δ 2.69 (s, 3H, CH₃), 5.52 (s, 2H, CH₂), 7.29–7.33 (m, 1H, ArH), 7.48–7.52 (m, 1H, ArH), 7.50 (s, 1H, ArH), 8.19 (d, J = 8.0 Hz, 2H, ArH), 8.30 (s, 1H, CHO), 9.12 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 12.58, 65.74, 114.77, 120.87 (2 × CH), 126.41, 129.11 (2 × CH), 138.44, 143.41, 151.95, 153.12, 160.45, 161.58; IR (KBr) 2924, 2854, 1732 (s, C=O), 1589, 1508, 1458, 1161, 752; EIMS m/z: 268 (M⁺, 89), 239 (46), 224 (100), 211 (20), 142 (12), 91 (13), 77 (53); HRMS calcd for C₁₄H₁₂O₂N₄: 268.0960, found: 268.0963.

3-Tetra-butanyl-6-[(formyloxy)methyl]-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (26). Brown solid; mp 91–92 °C; ¹H NMR (CDCl₃, 200 MHz) δ 1.56 (s, 9H, CH₃), 5.51 (s, 2H, CH₂), 7.25–7.33 (m, 1H, ArH), 7.46–7.53 (m, 2H, ArH), 7.50 (s, 1H, ArH), 8.22 (d, J = 8.0 Hz, 2H, ArH), 8.30 (s, 1H, CHO), 9.29 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 30.02 (3 × CH), 65.74, 113.02, 120.99 (2 × CH), 126.28, 129.08 (2 × CH), 138.62, 153.07, 153.53, 154.98, 160.54, 160.90; IR (KBr) 2963, 2924, 1732 (s, C=O), 1582, 1508, 1420, 1366, 1157, 756; EIMS m/z: 310 (M⁺, 21), 295 (30), 265 (12), 159 (15), 113 (12), 98 (13), 91 (100), 77 (20); HRMS calcd for C₁₇H₁₈O₂N₄: 310.1434, found: 310.1430.

6-[(Formyloxy)methyl]-3-(4-methylphenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (27). Yield: 87%; yellow liquid; ¹H NMR (CDCl₃, 200 MHz) δ 2.44 (s, 3H, CH₃), 5.55 (s, 2H, CH₂), 7.36 (d, J = 8.1 Hz, 2H, ArH), 7.53 (dd, J = 8.0, 7.4 Hz, 2H, ArH), 7.94 (d, J = 8.1 Hz, 2H, ArH), 8.30 (d, J = 8.1 Hz, 2H, ArH), 8.32 (s, 1H, CHO), 9.44 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 29.69, 65.70, 113.28, 121.27 (2 × CH), 126.72, 127.24 (2 × CH), 128.58, 129.16 (2 × CH), 129.93 (2 × CH), 138.53, 139.89, 145.19, 153.05, 153.68, 160.51, 160.51, 161.51; IR (KBr) 2920, 2851, 1717 (s, C=O), 1589, 1501, 1411, 1200, 1134, 980, 756 cm⁻¹; EIMS m/z: 344 (M⁺, 100), 315 (36), 300 (51), 287 (11), 91 (13), 77 (17); HRMS calcd for C₂₀H₁₆O₂N₄: 344.1273, found: 344.1275.

6-[(Formyloxy)methyl]-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo-[3,4-d]pyrimidine (28). Yellow solid; mp 165–167 °C; ¹H NMR (CDCl₃, 200 MHz) δ 3.88 (s, 3H, CH₃), 5.55 (s, 2H, CH₂), 7.07 (d, J = 8.8 Hz, 2H, ArH), 7.33–7.37 (m, 1H, ArH), 7.49–7.57 (m, 2H, ArH), 8.29 (dd, J = 1.0, 8.8 Hz, 2H, ArH), 8.32 (s, 1H, CHO), 9.41 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 55.42, 65.69, 113.19, 114.66 (2 × CH), 121.19 (2 × CH), 123.96, 126.24, 128.66 (2 × CH), 129.14 (2 × CH), 138.52, 144.92, 152.97, 153.61, 160.51, 160.83, 161.46; IR (KBr) 2922, 1715 (s, C=O), 1585, 1504, 1412, 1199, 1030, 982, 787 cm⁻¹; EIMS m/z: 360 (M⁺, 100), 331 (24), 316 (29), 77 (15); HRMS calcd for C₂₀H₁₆O₃N₄: 360.1222, found: 360.1217.

6-[(Formyloxy)methyl]-1-(3-methlyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (29). Yellow solid; mp 138–139 °C; ¹H NMR (CDCl₃, 400 MHz) δ 2.47 (s, 3H, CH₃), 3.89 (s, 3H, OCH₃), 5.55 (s, 2H, CH₂), 7.08 (d, J = 8.4 Hz, 2H, ArH), 7.17 (m, 1H, ArH), 7.41 (m, 1H, ArH), 7.99 (d, J = 8.4 Hz, 2H, ArH), 8.08 (m, 2H, ArH), 8.32 (s, 1H, CHO), 9.42 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 21.62, 55.45, 65.73, 113.19, 114.72 (2 × CH), 118.50, 121.94, 124.10, 127.54, 128.72 (2 × CH), 128.97, 138.46, 139.19, 144.89, 152.97, 153.65, 160.49, 160.88, 161.46; IR (KBr) 2953, 1717 (s, C=O), 1585, 1503, 1408, 1175, 1134, 837, 787; EIMS m/z: 374 (M⁺, 100), 345 (19), 330 (24), 91 (8); HRMS calcd for C₂₁H₁₈O₃N₄: 374.1379, found: 374.1383.

6-[(Formyloxy)methyl]-1-(4-methlyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (30). Yellow solid; mp 152–154 °C; ¹H NMR (CDCl₃, 200 MHz) δ 2.42 (s, 3H, CH₃), 3.89 (s, 3H, OCH₃), 5.54 (s, 2H, CH₂), 7.07 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.98 (d, J = 8.0 Hz, 2H, ArH), 8.13 (d, J = 8.0 Hz, 2H, ArH), 8.31 (s, 1H, CHO), 9.41 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 100 MHz) δ 21.62, 55.45, 65.73, 113.19, 114.72 (2 × CH), 118.50, 121.94, 124.10, 127.54, 128.72 (2 × CH), 128.97, 138.46, 139.19, 144.89, 152.97, 153.65, 160.49, 160.88, 161.46; IR (KBr) 2922, 1732 (s, C=O), 1585, 1504, 1412, 1199, 1136, 839, 754; EIMS m/z: 374 (M⁺, 100), 345 (19), 330 (25), 226 (22), 210 (13), 180 (15), 167 (36), 135 (18), 125 (20), 111 (40), 97 (51), 91 (17); HRMS calcd for C₂₁H₁₈O₃N₄: 374.1379, found: 374.1381.

3-Tetra-butyl-1-(2-chlorophenyl)-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine (31). Yellow solid; mp 138–139 °C; ¹H NMR (CDCl₃, 200 MHz) δ 1.56 (s, 9H, CH₃), 5.52 (s, 2H, CH₂), 7.25–7.33 (m, 1H, ArH), 7.46–7.53 (m, 2H, ArH), 8.22 (d, J = 8.0 Hz, 2H, ArH), 8.23 (s, 1H, CHO), 9.46 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 30.01 (3 × CH), 67.54, 112.03, 121.97 (2 × CH), 128.72, 129.08 (2 × CH), 139.63, 153.07, 153.53, 154.98, 156.35, 161.93; IR (KBr) 2916, 1721 (s, C=O), 1578, 1558, 1458, 1261, 1165, 760, 694; EIMS m/z: 346 (M⁺ + 2, 30), 344 (M⁺, 100), 345 (19), 330 (25), 226 (22), 210 (13), 180 (15), 167 (36), 135 (18), 125 (20), 111 (40), 97 (51), 91 (17); HRMS calcd for C₁₇H₁₇ClO₄N₂: 344.1040, found: 344.1044.

3-Tetrabutanyl-1-(4-chlorophenyl)-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine (32). Yellow solid; mp 147–148 °C; ¹H NMR (CDCl₃, 200 MHz) δ 1.55 (s, 9H, CH₃), 5.51 (s, 2H, CH₂), 7.49 (m, 2H, ArH), 8.25 (m, 2H, ArH), 8.30 (s, 1H, CHO), 9.29 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 30.27 (3 × CH), 65.70, 128.24 (2 × CH), 130.26, 130.58, 130.84 (2 × CH), 131.61, 135.07, 135.55, 145.19, 153.05, 162.53, 163.29; IR (KBr) 2922, 1721 (s, C=O), 1585, 1252, 1175, 1026, 781; EIMS m/z: 346 (M⁺ + 2, 37), 344 (M⁺, 94), 345 (19), 330 (25), 226 (22), 210 (13), 180 (15), 167 (36), 135 (18), 125 (20), 111 (40), 97 (51), 91 (17); HRMS calcd for C₁₇H₁₇ClO₄N₂: 344.1040, found: 344.1043 (100), 55 (44); HRMS calcd for C₁₇H₂₂N₄O₃, 330.1692; found 330.1696.

1-(3-Chlorophenyl)-3phenyl-5-(2-hydroxyacetylamino)pyrazole (35)²⁹. A solution of 5-(2-chloroacetylamino)pyrazole (6, 1.0 equiv.) and cesium formate (HCO₂Cs, 3.0 equiv.) in dry MeOH (10 mL) was heated at reflux for >2.0 h. When the reaction was complete, the solution was filtered to remove the excess HCO₂Cs and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel or recrystallization to give the corresponding 5-(2-hydroxyacetylamino)pyrazole (35) in 84% yield. Yellow solid; mp 98–99 °C; ¹H NMR (CDCl₃, 200 MHz) δ 4.15 (s, 2H, CH₂), 7.06 (s, 1H, ArH), 7.32–7.44 (m, 7H, ArH), 7.56 (m, 1H, ArH), 7.83 (dd, J = 4.5, 8.2 Hz, 2H, ArH), 8.79 (s, 1H, NH); ¹³C NMR (CDCl₃, 50 MHz) δ 62.12, 95.94, 122.08, 124.87, 125.78 (2 × CH), 128.46, 128.54, 128.66 (2 × CH), 130.74, 132.44, 135.61, 136.03, 138.75, 152.51, 168.37; IR (KBr) 3429, 2359, 1591, 1184, 966, 756; EIMS m/z: 329 (M⁺ + 2, 33), 327 (M⁺, 73), 329 (33), 270 (32), 235 (20), 220 (39), 207 (25), 195 (58), 180 (97), 162 (24), 135 (94), 121 (100), 102 (36), 91 (56), 81 (77); HRMS calcd for C₁₇H₁₄ClO₂N₃: 327.0775, found: 327.0776.

6-(Chloromethyl)pyrazolo[3,4-d]pyrimidine (40). 1,3-Diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol (44, 1.0 equiv.) was treated with SOCl₂ (∼3.0 equiv.) in formamide solution (2 mL) at 50–60 °C for 3 h. When the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate (15 mL) and extracted with dichloromethane (15 mL × 2). The combined organic layer was washed with sodium bicarbonate (15 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the corresponding 6-(chloromethyl)pyrazolo[3,4-d]pyrimidine (40) in 80% yield. Yellow solid; mp 133–134 °C; ¹H NMR (CDCl₃, 200 MHz) δ 4.89 (s, 2H, CH₂), 7.32–7.40 (m, 1H, ArH), 7.49–7.61 (m, 5H, ArH), 8.05 (dd, J = 7.2, Hz, 2H, ArH), 8.26 (dd, J = 7.2 Hz, 2H, ArH), 9.49 (s, 1H, pyrimidine–H); ¹³C NMR (CDCl₃, 50 MHz) δ 47.33, 112.95, 121.33 (2 × CH), 126.87, 127.37 (2 × CH), 129.24 (3 × CH), 129.73, 131.38, 138.50, 145.07, 153.37, 153.88, 162.99; IR (KBr) 2920, 1581, 1501, 1226, 1134, 976, 756, 691; EIMS m/z: 320 (M⁺, 100), 319 (38), 294 (35), 251 (24), 221 (20), 207 (48), 140 (15), 91 (39), 77 (56); HRMS calcd for C₁₈H₁₃ClN₄: 320.0829; found: 320.0828.

Acknowledgements

We are grateful to the Tsuzuki Institute for Traditional Medicine, and the Ministry of the National Science Council Taiwan (NSC-102-2113-M-039-003) for financial support.

References

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1027455. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra07707a

‡ The contribution equal to first author.

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