Tunable regioselective synthesis of pyrazolo[3,4-d]pyrimidine derivatives via aza-Wittig cyclization and dimroth-type rearrangement

Abstract

A novel tunable regioselective synthesis of pyrazolo[3,4-d]pyrimidine derivatives via aza-Wittig/Ag(I) or base-promoted tandem reaction has been developed. This approach provides a simple and efficient way to construct pyrazolo[3,4-d]-pyrimidine derivatives under mild conditions.

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Introduction

Pyrazolo[3,4-d]-pyrimidine and their partially saturated derivatives represent an important class of heterocycles, which are basic constituents in a myriad of natural products, biologically active alkaloids and pharmaceuticals.¹ In particular, functionalization at N-1, C-4 and C-6 positions of these ring systems is extremely important from a drug discovery viewpoint, these key heterocyclic units have been found broad use in synthetic drugs, and drug candidates (Fig. 1).² As a result, numerous synthetic methods have been developed for the construction and modification of the multisubstituted pyrazolo[3,4-d]-pyrimidine structure.³ Although most of these methods suffer from low efficiency and selectivity, in addition, long reaction times, high temperatures and tedious workup procedure are often required in these reactions. Thus, the development of a straightforward and convenient route to multisubstituted pyrazolo[3,4-d]-pyrimidine derivatives under mild reaction conditions is highly attractive in synthetic methodology and pharmaceutical chemistry (Scheme 1).

Fig. 1 Examples of significant pyrazolo[3,4-d]-pyrimidines.

Scheme 1 Tunable regioselective synthesis of pyrazolo[3,4-d]pyrimidine derivatives.

Recently, the aza-Wittig tandem reactions of iminophosphoranes have received much attention for the synthesis of substituted N-containing heterocycles.⁴ Carbodiimides, which were efficiently formed in situ from aza-Wittig reaction of iminophosphoranes with isocyanates under mild neutral conditions, can be used directly as versatile synthetic intermediates. These active carbodiimides can be easily trapped by nucleophiles such as alcohols and amines to form carbamimidates and guanidines which react with ester or nitrile groups in an intramolecular manner to afford N-containing heterocycles. In past decades, a series of tandem processes had been designed based on this principle. Thus far, substituted diaminoimidazoles,^4a dipyrimidinediones,^4d isoquino-line,^4e phen-anthridine,^4f benzoxazole,^4f oxadiazole,^4g amino-oxindole^4h and quinazolin⁴ⁱ had been prepared by using these tandem protocols. In addition, Dimroth-type rearrangement⁵ is an important isomerization process which is assigned to the translocation of hetero atom on heterocycles such as purine, pyrimidine bases of nucleosides and nucleotides.^5d In many cases, Dimroth rearrangement is reversible, so controlling variable reaction condition can remarkably improve the desired product. Here we report a protocol to synthesized two series pyrazolo[3,4-d]pyrimidine derivatives via aza-Wittig tandem process followed by controllable Dimroth-type rearrangement.

Results and discussion

Based on our continued interest on the aza-Wittig tandem protocol to construct heterocycles, we envisioned that the pyrazolo[3,4-d]-pyrimidine frameworks could also be obtained by above protocol. To our delight, the cyclization of carbodiimides compounds 1 (generated from the reactions of iminophosphoranes 5 with isocyanates 6, Scheme 2) indeed proceed as we expected to afford pyrazolo[3,4-d]pyrimidine in the presence of alcohol and various Lewis acids, but not only that, simply changing Lewis acids to base in the reaction, a new product with the functionalization at N-1, C-4 and C-6 positions of pyrazolo[3,4-d]-pyrimidine structure was obtained in good selectivity (Scheme 2). This interesting tunable transformation to the pyrazolo[3,4-d]-pyrimidine heterocycles encouraged us to further examine the feasibility of this cyclization reaction.

Scheme 2 Synthesis of 1.

Our initial efforts focused on the reaction of 5-((((4-chlorophenyl)imino)methylene)amino)-3-(methylthio)-1-phenyl-1H-pyrazole-4-carbonitrile 1a with various Lewis acids as the promoter. We found that in the presence of 10 mol% AgNO₃ in methanol at room temperature in one hour was the best reaction conditions for this cyclization reaction to afford the product 3a (Table 1, entry 4). The reaction could also proceed in other Lewis acids, such as CuI, AgI, AgOAc, Cu(NO₃)₂ and FeCl₃, albeit in reduced yields (Table 1, entries 1–3 and 5–6). A lesser amount of AgNO₃ would reduce the reaction yield (Table 1, entries 7).

Table 1 Optimization of the reaction conditions^a

Entry	Additives	Time (h)	Yield^b (%)
			3a	4a
a The reaction was carried out on the scale of mmol of 1a in the presence of additives in 3 mL CH3OH at 25 °C.b Isolated yield.c With additional 10 mol% AgNO3.
1	0.1 eq. Cul	1	58	—
2	0.1 eq. Agl	1	51	—
3	0.1 eq. AgOAc	1	56	—
4	0.1 eq. AgNO3	1	73	—
5	0.1 eq. Cu(NO3)2	1	5	—
6	0.1 eq. FeCl3	1	Trace	—
7	0.01 eq. AgNO3	1	11	—
8	0.1 eq. AgNO3	0.5	44	—
9	1.0 eq. Et3N	21	—	14
10	1.0 eq. DABCO	21	—	Trace
11	1.0 eq. Na2CO3	21	—	48
12	1.0 eq. CH3ONa	21	—	43
13	1.0 eq. NaOH	21	—	78
14	1.0 eq. NaOH	12	—	59
15	1.0 eq. NaOH	48	—	70
16	0.1 eq. NaOH	15	—	21
17	2.0 eq. NaOH	24	—	74
18^c	1.0 eq. NaOH	21	—	72

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It also turned out to be ineffective to shorten the reaction time to half an hour (Table 1, entries 8). Interestingly, we observed that the product 4a was formed with high selectivity when this reaction was carried out under alkaline reaction conditions. The reaction could proceed in either organic base or inorganic base. Generally, inorganic base offered better results than organic base (Table 1, entries 9–12). In the presence of 1.0 equiv. NaOH in methanol at room temperature was found to be the best reaction condition (Table 1, entries 13). A lesser amount of NaOH would reduce the reaction yield (Table 1, entries 16), but 2.0 equiv. of NaOH did not observably improve the yield (Table 1, entries 17). Albeit stronger base than NaOH, NaOCH₃ is not a better promoter, formation of water may be important to the transformation process (Table 1, entry 12).^5d No improvement of the yield was found while further extending the reaction time (Table 1, entry 15). In addition, the employment with additional AgNO₃ did not improve the yield (Table 1, entry 18).

With the optimized conditions in hand, various carbodiimides compounds 1 were found to be the suitable reaction partners with methanol or ethanol to provide the corresponding products 3 or 4 in moderate to excellent yield (Tables 2 and 3). This transformation showed good functional group tolerance when used the AgNO₃ as the catalyst to afford product 3. Either electron-withdrawing and electron-donating substituted groups or halogen groups at the aromatic ring could be introduced into the desired product under the standard reaction conditions without any difficulties (Table 2, 3a–3n). It was worth noting that the steric effect had no significant effect to the yields, regardless of the substitution pattern of the aryl ring (ortho, meta, or para) of the aryl isocyanates used in the reaction, the corresponding products (3d, 3h and 3i) were obtained in good yields. The reaction between iminophosphoranes and variety of isocyanates to afford product 4 in the presence of NaOH were also carried out to explore the scope of this transformation (Table 3). In most cases, the corresponding product 4 could be obtained in moderate to excellent yields. The steric and electronic properties of the substituents on the phenyl rings had little effect on the yield (Table 3, 4a–4r). Such as the methyl, methoxyl, ethoxyl, fluorine and chlorine at the aromatic ring of aryl isocyanates all reacted smoothly affording the desired products in good to excellent yields. In addition, the structures of compounds 3b and 4j were unambiguously assigned by X-ray crystallography analysis (Fig. 2).⁶

Table 2 Substrate scope^a

Product	Ar	R	Yield^b [%]
a The reactions were carried out with 1 (0.5 mmol), AgNO3 (10 mol%), ROH (3 mL), 25 °C, 1 h.b Isolated yield.
3a	p-Cl-Phenyl	CH3	85
3b	p-F-Phenyl	CH3	83
3c	Phenyl	CH3	91
3d	p-CH3-Phenyl	CH3	64
3e	3,4-DiCl-Phenyl	CH3	66
3f	p-C2H5O-Phenyl	CH3	98
3g	p-CH3O-Phenyl	CH3	90
3h	o-CH3-Phenyl	CH3	85
3i	m-CH3-Phenyl	CH3	73
3j	m-CH3-Phenyl	CH3CH2	83
3k	o-CH3-Phenyl	CH3CH2	94
3l	p-C2H5O-Phenyl	CH3CH2	89
3m	p-CH3O-Phenyl	CH3CH2	74
3n	p-CH3-Phenyl	CH3CH2	97

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Table 3 Substrate scope^a

Product	Ar	R	Yield^b%
a The reactions were carried out with 1 (0.5 mmol), NaOH (1.0 eq.), ROH (3 mL), 25 °C, 21 h.b Isolated yield.
4a	p-Cl-Phenyl	CH3	78
4b	p-F-Phenyl	CH3	75
4c	Phenyl	CH3	89
4d	p-CH3-Phenyl	CH3	60
4e	3,4-DiCl-Phenyl	CH3	57
4f	p-C2H5O-Phenyl	CH3	56
4g	p-CH3O-Phenyl	CH3	56
4h	m-CH3-Phenyl	CH3	71
4i	o-CH3-Phenyl	CH3	64
4j	p-F-Phenyl	CH3CH2	59
4k	p-Cl-Phenyl	CH3CH2	78
4l	3,4-DiCl-Phenyl	CH3CH2	81
4m	p-CH3-Phenyl	CH3CH2	69
4n	o-CH3-Phenyl	CH3CH2	65
4o	Phenyl	CH3CH2	65
4p	p-C2H5O-Phenyl	CH3CH2	85
4q	p-CH3O-Phenyl	CH3CH2	51
4r	m-CH3-Phenyl	CH3CH2	52

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Fig. 2 ORTEP diagram of 3b and 4j.

In order to understand the relationship between the two different products, the product 3a was treated with 1 equiv. NaOH for 24 hours (Scheme 3), we found that the product 3a could further equivalently converted to the product 4a. Based on experiment and literature,⁵ the proposed mechanism was outlined in Scheme 3. The transformation process probably underwent a Dimroth-type rearrangement, and aromatized to thermodynamic stable compound 4a in the presence of base and alcohol as solvent.^5d,e

Scheme 3 Dimroth-type rearrangement.

Conclusions

In summary, we have developed an efficient tunable regioselective synthesis of pyrazolo[3,4-d]pyrimidine derivatives via aza-Wittig/Ag(I) or base-promoted tandem reaction. The regioselectivity of this reaction can be easily controlled by using different reaction conditions. This methodology avoided the using of harsh reaction conditions and had been successfully used for the synthesis various different substituted pyrazolo[3,4-d]pyrimidine derivatives. Further mechanistic studies are still on going in our laboratory and will be reported in due course.

Experiments

General experimental methods

Unless otherwise stated, all commercial reagents and solvents were used without additional purification. FT-IR was recorded on Perkin Elmer-Spectrum One FTIR spectrometer; nuclear magnetic resonance (NMR) spectra are recorded in parts per million from internal tetramethylsilane (TMS) on the δ scale. ¹H NMR spectra, ¹³C NMR spectra were recorded on a Bruker 400 MHz spectrometer in chloroform-d³. All signals are reported in ppm with the internal TMS signal at 0 ppm as a standard. The data is being reported as (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br = broad signal, coupling constant(s) in Hz, integration). High resolution mass spectrometry (HRMS) spectra were obtained on a micro-TOF II Instrument.

General procedure for compound 3

To the solution of iminophos-phorane 1 (0.5 mmol) in dry CH₂Cl₂ (3 mL), ArNCO (0.6 mmol) was added under N₂. The mixture was stirred at 25 °C for 12–24 h, then the solvent was removed under vacuum. The residue was dissolved into ROH (3 mL) and AgNO₃ (0.05 mmol, 10 mol%) was added and the solution was stirred at 25 °C for 0.5–1 h. After the solvent was removed, product 3 was obtained by flash chromatography (PE : EtOAc = 2 : 1).

5-(4-Chlorophenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3a). White solid (yield 85%); mp: 198–199 °C; IR (KBr, ν/cm⁻¹): 3127, 2954, 1664, 1598, 1518, 1490, 1456, 1381, 1352, 1319, 1280, 1240, 1202, 838, 718; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.68 (s, 3H), 3.93 (s, 3H), 7.18 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.45–7.51 (m, 4H), 8.08 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.3, 56.1, 101.0, 121.0, 126.1, 128.9, 130.0, 130.2, 133.7, 135.0, 138.9, 145.0, 148.4, 153.9, 156.1. HRMS (ESI) calcd for C₁₉H₁₇N₅OSCl [M + H]⁺: 398.0842, found: 398.0846.

5-(4-Fluorophenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3b). White solid (yield 83%); mp: 176–177 °C; IR (KBr, ν/cm⁻¹): 3325, 3118, 2953, 1667, 1601, 1525, 1506, 1455, 1378, 1346, 1279, 1244, 1220, 1201, 829, 717; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.67 (s, 3H), 3.91 (s, 3H), 7.21 (d, J = 6.4 Hz, 4H), 7.28–7.29 (m, 1H), 7.46 (t, J = 8.0 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.2, 56.1, 101.0, 116.9 (d, J = 23 Hz), 120.9, 126.1, 128.9, 128.9, 130.6 (d, J = 9 Hz), 130.8 (d, J = 3 Hz), 138.9, 145.0, 148.5, 153.8, 156.2, 162.6 (d, J = 248 Hz). HRMS (ESI) calcd for C₁₉H₁₇N₅OFS [M + H]⁺: 382.1138, found: 382.1135.

6-Methoxy-3-(methylthio)-1,5-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3c). White solid (yield 91%); mp: 204–205 °C; IR (KBr, ν/cm⁻¹): 2956, 1668, 1598, 1523, 1496, 1423, 1350, 1282, 1240, 760; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.68 (s, 3H), 3.92 (s, 3H), 7.24 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.45–7.50 (m, 3H), 7.55 (t, J = 7.6 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.1, 56.0, 101.1, 120.9, 126.0, 128.9, 128.9, 129.1, 129.9, 135.0, 139.0, 145.2, 148.7, 156.3. HRMS (ESI) calcd for C₁₉H₁₈N₅OS [M + H]⁺: 364.1232, found: 364.1240.

6-Methoxy-3-(methylthio)-1-phenyl-5-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3d). White solid (yield 64%); mp: 190–191 °C; (KBr, ν/cm⁻¹): 2924, 2853, 1712, 1671, 1508, 1344, 858, 765; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.43 (s, 3H), 2.67 (s, 3H), 3.92 (s, 3H), 7.10 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.1, 21.2, 55.9, 101.1, 120.9, 125.9, 128.5, 128.8, 130.5, 132.1, 139.1, 139.1, 145.2, 148.8, 153.4, 156.4. HRMS (ESI) calcd for C₂₀H₂₀N₅OS [M + H]⁺: 378.1389, found: 378.1385.

5-(3,4-Dichlorophenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3e). White solid (yield 66%); mp: 202–203 °C; IR (KBr, ν/cm⁻¹): 2920, 1597, 1521, 1469, 1385, 1351, 1257, 1233, 860, 758; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.68 (s, 3H), 3.94 (s, 3H), 7.12 (dd, J = 2.0, 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.4, 56.3, 100.8, 121.0, 126.3, 128.4, 128.9, 131.0, 131.3, 133.4, 133.6, 134.8, 138.8, 144.9, 148.2, 154.2, 155.8. HRMS (ESI) calcd for C₁₉H₁₆N₅OSCl₂ [M + H]⁺: 432.0453, found: 432.0448.

5-(4-Ethoxyphenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3f). White solid (yield 98%); mp: 199–200 °C; IR (KBr, ν/cm⁻¹): 3133, 1676, 1613, 1591, 1513, 1475, 1383, 1349, 1301, 1260, 862, 750; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.38–1.46 (m, 3H), 2.67 (s, 3H), 3.91 (s, 3H), 4.05–4.10 (m, 1H), 7.02 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.0, 14.7, 56.0, 63.7, 101.1, 115.6, 120.9, 125.9, 126.8, 128.8, 129.8, 139.0, 145.2, 148.8, 153.4, 156.5, 159.3. HRMS (ESI) calcd for C₂₁H₂₂N₅O₂S [M + H]⁺: 408.1494, found: 408.1490.

6-Methoxy-5-(4-methoxyphenyl)-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3g). White solid (yield 92%); mp: 182–183 °C; IR (KBr, ν/cm⁻¹): 1672, 1614, 1598, 1510, 1457, 1381, 1343, 1307, 1263, 1230, 1189, 824, 759; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.67 (s, 3H), 3.85 (s, 3H), 3.91 (s, 3H), 5.34 (br, 1H), 7.03 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.25–7.30 (m, 1H), 7.45 (t, J = 8.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.1, 55.5, 56.1, 101.0, 115.2, 120.8, 126.0, 127.0, 128.9, 129.9, 139.0, 145.2, 148.8, 153.5, 156.5, 159.9. HRMS (ESI) calcd for C₂₀H₂₀N₅O₂S [M + H]⁺: 394.1338, found: 394.1337.

6-Methoxy-3-(methylthio)-1-phenyl-5-o-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3h). White solid (yield 85%); mp: 154–155 °C; IR (KBr, ν/cm⁻¹): 3131, 1667, 1519, 1420, 1345, 1261, 761; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.95 (s, 3H), 2.60 (s, 3H), 3.84 (s, 3H), 5.04 (br, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.07–7.21 (m, 1H), 7.26 (m, 3H), 7.29–7.40 (m, 2H), 8.03 (d, J = 8.0 Hz 2H); ¹³C NMR (100 MHz, CDCl₃): 14.1, 17.2, 56.1, 100.9, 120.9, 126.1, 127.5, 128.9, 129.5, 131.4, 133.6, 136.4, 139.0, 145.3, 149.0, 152.4, 156.1. HRMS (ESI) calcd for C₂₀H₂₀N₅OS [M + H]⁺: 378.1389, found: 378.1395.

6-Methoxy-3-(methylthio)-1-phenyl-5-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3i). White solid (yield 73%); mp: 192–193 °C; IR (KBr, ν/cm⁻¹): 2981, 2850, 1709, 1673, 1598, 1552, 1520, 1494, 1457, 1376, 1350, 1314, 1289, 1277, 821, 743; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.41 (s, 3H), 2.68 (s, 3H), 3.92 (s, 3H), 7.03 (d, J = 6.8 Hz, 2H), 7.28 (t, J = 9.2 Hz, 2H), 7.42–7.48 (m, 3H), 8.10 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.1, 21.3, 56.0, 101.1, 120.9, 125.8, 126.0, 128.8, 129.3, 129.6, 130.0, 134.7, 139.0, 140.0, 145.2, 148.8, 153.3, 156.3. HRMS (ESI) calcd for C₂₀H₂₀N₅OS [M + H]⁺: 378.1389, found: 378.1382.

6-Ethoxy-3-(methylthio)-1-phenyl-5-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3j). White solid (yield 83%); mp: 148–149 °C; IR (KBr, ν/cm⁻¹): 1559, 1552, 1516, 1404, 1378, 1335, 1258, 862, 753; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.22–1.25 (t, J = 7.2 Hz, 3H), 2.40 (s, 3H), 2.67 (s, 3H), 4.36–4.42 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 6.4 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 8.09 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.0, 14.1, 21.3, 65.2, 101.0, 120.9, 125.8, 125.9, 128.8, 129.3, 129.6, 129.9, 134.7, 139.0, 139.9, 145.2, 149.0, 153.4, 155.7. HRMS (ESI) calcd for C₂₁H₂₂N₅OS [M + H]⁺: 392.1545, found: 392.1541.

6-Ethoxy-3-(methylthio)-1-phenyl-5-o-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3k). White solid (yield 93%); mp: 120–121 °C; IR (KBr, ν/cm⁻¹): 2959, 1668, 1520, 1495, 1429, 1397, 1381, 1328, 1278, 1241, 762, 741; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.12–1.17 (m, 3H), 2.05 (s, 3H), 2.59 (s, 3H), 4.23–4.37 (m, 2H), 7.04 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.22–7.31 (m, 3H), 7.37 (t, J = 8.4 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.0, 14.1, 17.2, 65.1, 101.0, 120.9, 125.9, 127.4, 128.8, 129.3, 131.3, 133.9, 136.4, 139.1, 145.2, 149.2, 152.4, 155.5. HRMS (ESI) calcd for C₂₁H₂₂N₅OS [M + H]⁺: 392.1545, found: 392.1552.

6-Ethoxy-5-(4-ethoxyphenyl)-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3l). White solid (yield 89%); mp: 200–201 °C; IR (KBr, ν/cm⁻¹): 1664, 1507, 1475, 1402, 1378, 1331, 1300, 1250, 820, 763; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.21–1.25 (t, J = 7.2 Hz, 3H), 1.43–1.46 (t, J = 7.2 Hz, 3H), 2.67 (s, 3H), 4.05–4.10 (m, 2H), 4.36–4.41 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 2H), 8.09 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 13.9, 14.0, 14.7, 63.7, 65.1, 101.0, 115.5, 120.8, 125.9, 126.9, 128.8, 129.8, 139.1, 145.2, 149.0, 153.4, 155.9, 159.2. HRMS (ESI) calcd for C₂₂H₂₄N₅O₂S [M + H]⁺: 422.1651, found: 422.1647.

6-Ethoxy-5-(4-methoxyphenyl)-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3m). White solid (yield 74%); mp: 175–176 °C; IR (KBr, ν/cm⁻¹): 1671, 1611, 1510, 1430, 1398, 1381, 1327, 1303, 1281, 1263, 864, 795; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.22–1.25 (t, J = 7.2 Hz, 3H), 2.67 (s, 3H), 3.86 (s, 3H), 4.36–4.41 (m, 2H), 7.02 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.0, 14.1, 55.4, 65.2, 101.0, 115.0, 120.8, 125.9, 127.2, 128.8, 129.8, 139.0, 145.2, 149.0, 153.5, 155.9, 159.7. HRMS (ESI) calcd for C₂₁H₂₂N₅O₂S [M + H]⁺: 408.1494, found: 408.1488.

6-Ethoxy-3-(methylthio)-1-phenyl-5-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-imine(3n). White solid (yield 96%); mp: 204–205 °C; IR (KBr, ν/cm⁻¹): 1672, 1508, 1472, 1396, 1381, 1324, 1278, 1238, 793, 761; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.22–1.25 (t, J = 7.2 Hz, 3H), 2.43 (s, 3H), 2.67 (s, 3H), 4.38–4.40 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.27 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 13.9, 14.1, 21.3, 65.1, 101.0, 120.9, 125.9, 128.5, 128.8, 130.5, 132.2, 139.0, 139.1, 145.1, 149.0, 153.4, 155.8. HRMS (ESI) calcd for C₂₁H₂₂N₅OS [M + H]⁺: 392.1545, found: 392.1538.

General procedure for compound 4

To the solution of iminophos-phorane 1 (0.5 mmol) in dry CH₂Cl₂ (3 mL), ArNCO (0.6 mmol) was added under N₂. The mixture was stirred at 25 °C for 12–24 h, then the solvent was removed under vacuum. The residue was dissolved in ROH (4 mL) and NaOH (0.5 mmol, 1.0 equiv) was added and the mixture was stirred at 25 °C for 21 h. After the solvent was removed, product 4 was obtained by flash chromatography (PE : EtOAc = 2 : 1).

N-(4-Chlorophenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4a). White solid (yield 78%); mp 174–175 °C; IR (KBr, ν/cm⁻¹): 3129, 2956, 2925, 1624, 1505, 1489, 1446, 1382, 1335, 1327, 1306, 1253, 828, 751; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.76 (s, 3H), 4.06 (s, 3H), 7.29 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 8.0 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H), ¹³C NMR (100 MHz, CDCl₃): 17.1, 55.1, 99.0, 120.5, 121.9, 126.0, 129.0, 129.0, 129.1, 136.5, 138.8, 139.5, 155.56, 156.0, 165.1. HRMS (ESI) calcd for C₁₉H₁₇N₅OSCl [M + H]⁺: 398.0842, found: 398.0838.

N-(4-Fluorophenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4b). White solid (yield 75%); mp 177–179 °C; IR (KBr, ν/cm⁻¹): 3130, 1629, 1591, 1505, 1468, 1410, 1384, 1336, 1307, 1255, 830, 751; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.74 (s, 3H), 4.03 (s, 3H), 7.08 (t, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.68–7.71 (m, 2H), 7.93 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 17.1, 55.0, 98.9, 115.7 (d, J = 22 Hz), 120.6, 122.8, 126.0, 128.5 (d, J = 13 Hz), 129.0, 132.1 (d, J = 10 Hz), 133.8, 138.9, 139.6, 155.8, 156.2, 159.4 (d, J = 243 Hz), 165.2. HRMS (ESI) calcd for C₁₉H₁₇N₅OSF [M + H]⁺: 382.1138, found: 382.1135.

6-Methoxy-3-(methylthio)-N,1-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4c). White solid (yield 89%); mp: 140–141 °C; IR (KBr, ν/cm⁻¹): 3005, 2925, 2852, 1626, 1595, 1498, 1479, 1447, 1397, 1378, 1326, 1259, 1235, 752; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.75 (s, 3H), 4.06 (s, 3H), 7.15 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.48 (t, J = 8.4 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 8.05 (s, 1H), 8.21 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 17.1, 55.1, 99.0, 120.5, 120.7, 124.1, 125.9, 128.9, 129.0, 137.8, 138.5, 139.5, 155.7, 156.1, 165.2. HRMS (ESI) calcd for C₁₉H₁₈N₅OS [M + H]⁺: 364.1232, found: 364.1228.

6-Methoxy-3-(methylthio)-1-phenyl-N-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4d). White solid, (yield 60%); mp 169–170 °C; IR (KBr, ν/cm⁻¹): 3130, 2957, 1626, 1570, 1504, 1473, 1441, 1385, 1337, 1326, 1309, 1254, 862, 753; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.35 (s, 3H), 2.74 (s, 3H), 4.05 (s, 3H), 7.19 (d, J = 8.4 Hz, 2H), 7.27 (m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.98 (s, 1H), 8.21 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 17.0, 20.8, 55.0, 99.0, 120.7, 121.0, 125.9, 128.9, 129.5, 133.9, 135.3, 139.0, 139.6, 155.9, 156.3, 165.3. HRMS (ESI) calcd for C₂₀H₂₀N₅OS [M + H]⁺: 378.1389, found: 378.1395.

N-(3,4-Dichlorophenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4e). White solid (yield 57%); mp 202–203 °C; IR (KBr, ν/cm⁻¹): 3125, 2919, 2850, 1623, 1590, 1504, 1475, 1450, 1380, 1329, 1308, 1262, 1248, 804, 753; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.68 (s, 3H), 3.99 (s, 3H), 7.19 (t, J = 12 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.50–7.51 (m, 1H), 7.92 (t, J = 8.0 Hz, 2H), 8.1 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 17.2, 55.2, 99.1, 120.0, 120.0, 122.3, 126.2, 127.3, 129.0, 130.5, 132.7, 137.4, 138.8, 139.4, 155.4, 156.0, 165.1. HRMS (ESI) calcd for C₁₉H₁₆N₅OSCl₂ [M + H]⁺: 432.0453, found: 432.0459.

N-(4-Ethoxyphenyl)-6-methoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4f). White solid (yield 56%); mp 149–150 °C; IR (KBr, ν/cm⁻¹): 3124, 1628, 1598, 1579, 1505, 1468, 1454, 1380, 1340, 1329, 1307, 1248, 816, 755; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.42 (t, J = 7.2 Hz, 3H), 2.74 (s, 3H), 4.02–4.06 (m, 5H), 6.92 (d, J = 8.8 Hz, 2H), 7.27–7.28 (m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.88 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H), ¹³C NMR (100 MHz, CDCl₃): 14.8, 17.0, 54.9, 63.7, 98.9, 114.9, 120.6, 122.9, 125.9, 128.9, 130.7, 139.1, 139.7, 156.0, 156.0, 156.3, 165.4. HRMS (ESI) calcd for C₂₁H₂₂N₅O₂S [M + H]⁺: 408.1494, found: 408.1491.

6-Methoxy-N-(4-methoxyphenyl)-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4g). White solid (yield 56%); mp 165–166 °C; IR (KBr, ν/cm⁻¹): 3129, 1617, 1595, 1506, 1480, 1451, 1378, 1242, 1324, 1302, 827; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.74 (s, 3H), 3.82 (s, 3H), 4.02 (s, 3H), 6.93 (d, J = 8.8 Hz, 2H), 7.27 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.88 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 17.0, 54.9, 55.5, 98.9, 114.3, 120.6, 123.0, 125.9, 128.9, 130.8, 139.0, 139.7, 156.0, 156.3, 156.6, 165.4 HRMS (ESI) calcd for C₂₀H₂₀N₅O₂S [M + H]⁺: 394.1338 found: 394.1335.

6-Methoxy-3-(methylthio)-1-phenyl-N-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4h). White solid (yield 71%); mp 126–127 °C; IR (KBr, ν/cm⁻¹): 3129, 2956, 1631, 1570, 1507, 1492, 1480, 1455, 1380, 1337, 1306, 1254, 787, 758; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.39 (s, 3H), 2.75 (s, 3H), 4.06 (s, 3H), 6.96 (d, J = 7.6 Hz, 1H), 7.25–7.30 (m, 2H), 7.45–7.51 (m, 3H), 7.64 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 8.21 (t, J = 7.6 Hz 2H); ¹³C NMR (100 MHz, CDCl₃): 17.1, 21.5, 55.0, 99.1, 118.1, 121.4, 125.0, 126.0, 126.8, 128.9, 137.9, 138.9, 139.0, 139.6, 155.8, 156.3, 165.3. HRMS (ESI) calcd for C₂₀H₂₀N₅OS [M + H]⁺: 378.1389, found: 378.1396.

6-Methoxy-3-(methylthio)-1-phenyl-N-o-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4i). White solid (yield 64%); mp 141–142 °C; IR (KBr, ν/cm⁻¹): 1619, 1592, 1507, 1479, 1455, 1376, 1336, 1318, 1308, 1216, 757; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 2.43 (s, 3H), 2.76 (s, 3H), 4.02 (s, 3H), 7.10–7.12 (m, 1H), 7.24–7.29 (m, 3H), 7.48 (t, J = 8.0 Hz, 2H), 7.89 (s, 1H), 8.21–8.27 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): 17.0, 18.3, 55.0, 99.3, 120.6, 122.9, 124.7, 126.0, 126.8, 128.8, 129.0, 130.6, 136.2, 139.0, 139.7, 156.1, 156.4, 165.3. HRMS (ESI) calcd for C₂₀H₂₀N₅OS [M + H]⁺: 378.1389, found: 378.1393.

6-Ethoxy-N-(4-fluorophenyl)-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4j). White solid (yield 59%); mp 157–158 °C; IR (KBr, ν/cm⁻¹): 3129, 1625, 1591, 1575, 1503, 1475, 1445, 1417, 1381, 1357, 1307, 1256, 1209, 862, 748; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.44–1.48 (m, 3H), 2.75 (s, 3H), 4.46–4.49 (m, 2H), 7.09 (t, J = 8.0 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.68–7.71 (m, 2H), 7.94 (s, 1H), 8.20 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.5, 17.1, 63.7, 98.9, 115.7 (d, J = 22 Hz), 120.6, 122.8 (d, J = 8 Hz), 126.0, 128.9, 133.9, 139.0, 139.5, 155.8, 156.3, 159.6 (d, J = 242 Hz), 164.8. HRMS (ESI) calcd for C₂₀H₁₉N₅FOS [M + H]⁺: 396.1294, found: 396.1288.

N-(4-Chlorophenyl)-6-ethoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4k). White solid (yield 78%); mp 169–170 °C; IR (KBr, ν/cm⁻¹): 3132, 1624, 1602, 1503, 1490, 1475, 1456, 1444, 1414, 1381, 1357, 1311, 1290, 1255, 1240, 843, 747; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.47 (t, J = 8.0 Hz, 3H), 2.75 (s, 3H), 4.47–4.50 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.99 (s, 1H), 8.19 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 13.4, 16.1, 62.8, 97.9, 119.5, 120.9, 124.9, 127.9, 127.9, 128.0, 135.5, 137.8, 138.4, 154.5, 155.1, 163.6. HRMS (ESI) calcd for C₂₀H₁₉N₅OSCl [M + H]⁺: 412.0999, found: 412.1005.

N-(3,4-Dichlorophenyl)-6-ethoxy-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4l). White solid (yield 81%); mp: 157–158 °C; IR (KBr, ν/cm⁻¹): 3127, 2957, 2917, 2849, 1633, 1599, 1504, 1473, 1453, 1416, 1382, 1325, 1310, 1260, 862, 754; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.49 (t, J = 8.0, 3H), 2.75 (s, 3H), 4.48–4.50 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.41–7.49 (m, 3H), 7.57 (dd, J = 2.0, 8.0 Hz, 1H), 7.99 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.5, 17.2, 64.0, 99.0, 119.8, 120.6, 122.2, 126.1, 127.1, 129.0, 130.5, 132.7, 137.2, 138.8, 139.4, 155.3, 156.2, 164.6. HRMS (ESI) calcd for C₂₀H₁₈N₅OSCl₂ [M + H]⁺: 446.0609, found: 446.0616.

6-Ethoxy-3-(methylthio)-1-phenyl-N-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4m). White solid (yield 69%); mp 141–142 °C; IR (KBr, ν/cm⁻¹): 3130, 2976, 1623, 1599, 1503, 1473, 1453, 1375, 1361, 1332, 1325, 1305, 1291, 1249, 820, 765; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.46 (t, J = 8.0, 3H), 2.34 (s, 3H), 2.73 (s, 3H), 4.45–4.50 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.27 (m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.96 (s, 1H), 8.20 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 13.4, 16.1, 19.8, 62.7, 97.9, 119.6, 119.8, 124.8, 127.9, 128.4, 132.8, 134.2, 137.9, 138.5, 154.7, 155.2, 163.8. HRMS (ESI) calcd for C₂₁H₂₂N₅OS [M + H]⁺: 392.1545, found: 392.1539.

6-Ethoxy-3-(methylthio)-1-phenyl-N-o-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4n). White solid (yield 65%); mp 134–135 °C; IR (KBr, ν/cm⁻¹): 2928, 1619, 1574, 1505, 1478, 1441, 1379, 1357, 1308, 1259, 1235, 754; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.44 (t, J = 7.2, 3H), 2.43 (s, 3H), 2.75 (s, 3H), 4.43–4.49 (m, 2H), 7.09 (t, J = 7.2 Hz, 1H), 7.24–7.30 (m, 3H), 7.47 (t, J = 8.4 Hz, 2H), 7.88 (s, 1H), 8.21 (t, J = 8.0 Hz, 2H), 8.26 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): 14.5, 17.1, 18.3, 63.7, 99.3, 120.7, 122.9, 124.7, 125.9, 126.7, 128.8, 129.0, 130.6, 136.2, 139.0, 139.7, 156.1, 156.5, 164.9. HRMS (ESI) calcd for C₂₁H₂₂N₅OS [M + H]⁺: 392.1545, found: 392.1552.

6-Ethoxy-3-(methylthio)-N,1-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4o). White solid (yield 65%); mp 147–148 °C; IR (KBr, ν/cm⁻¹): 3131, 1638, 1618, 1573, 1496, 1477, 1455, 1437, 1412, 1381, 1358, 13 210, 1257, 752; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.48 (t, J = 8.0, 3H), 2.75 (s, 3H), 4.49–4.53 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 8.06 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 13.4, 16.1, 62.7, 97.9, 119.6, 119.7, 123.0, 124.8, 127.9, 128.0, 136.9, 137.9, 138.5, 154.6, 155.2, 163.7. HRMS (ESI) calcd for C₂₀H₂₀N₅OS [M + H]⁺: 378.1389, found: 378.1382.

6-Eethoxy-N-(4-ethoxyphenyl)-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4p). White solid (yield 85%); mp 120–121 °C; IR (KBr, ν/cm⁻¹): 3131, 2958, 1629, 1571, 1504, 1476, 1418, 1384, 1359, 1327, 1305, 1257, 1243, 817, 750; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.40–1.46 (m, 6H), 2.73 (s, 3H), 4.04–4.05 (m, 2H), 4.46–4.48 (m, 2H), 6.93 (t, J = 6.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.98 (s, 1H), 8.19 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 13.5, 13.8, 16.0, 62.6, 62.8, 97.9, 113.9, 119.7, 121.9, 124.9, 127.9, 129.8, 138.1, 138.6, 154.9, 155.0, 155.4, 163.9. HRMS (ESI) calcd for C₂₂H₂₄N₅O₂S [M + H]⁺: 422.1651, found: 422.1644.

6-Ethoxy-N-(4-methoxyphenyl)-3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4q). White solid (yield 51%); mp 133–134 °C; IR (KBr, ν/cm⁻¹): 3132, 2931, 1622, 1506, 1446, 1382, 1356, 1327, 1314, 1260, 1246, 818, 755; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.44 (t, J = 6.8, 3H), 2.74 (s, 3H), 3.82 (s, 3H), 4.45–4.49 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.88 (s, 1H), 8.20 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 12.7, 15.2, 53.7, 61.8, 97.1, 112.5, 114.4, 118.9, 121.2, 124.1, 127.1, 129.1, 137.3, 137.8, 154.2, 154.8, 163.1. HRMS (ESI) calcd for C₂₁H₂₂N₅O₂S [M + H]⁺: 408.1494, found: 408.1487.

6-Ethoxy-3-(methylthio)-1-phenyl-N-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(4r). White solid (yield 52%); mp 126–127 °C; IR (KBr, ν/cm⁻¹): 2958, 2927, 2873, 1629, 1589, 1569, 1503, 1382, 1337, 1306, 1254, 789, 751; ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.63 (t, J = 6.4, 3H), 2.32 (s, 3H), 2.67 (s, 3H), 4.41–4.43 (m, 2H), 6.89 (d, J = 6.8 Hz, 1H), 7.20 (t, J = 7.2 Hz, 2H), 7.38–7.44 (m, 3H), 7.55 (d, J = 7.2 Hz, 1H), 7.95 (br, 1H), 8.12 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): 14.5, 17.2, 21.5, 63.8, 99.0, 118.0, 120.7, 121.4, 125.0, 126.0, 128.9, 129.0, 137.9, 138.9, 139.0, 139.6, 155.7, 156.3, 164.8. HRMS (ESI) calcd for C₂₁H₂₂N₅OS [M + H]⁺: 392.1545, found: 392.1552.

Acknowledgements

This project is supported by the National Science Foundation of China (no. 21262018, 20862007), and Natural Science Foundation of Jiangxi Province (20133ACB20008).

Notes and references

1. (a) J. A. Markwalder, M. R. Arnone, P. A. Benfield, M. Boisclair, C. R. Burton, C. H. Chang, S. S. Cox, P. M. Czerniak, C. L. Dean, D. Doleniak, R. Grafstrom, B. A. Harrison, R. F. Kaltenbach, D. A. Nugiel, K. A. Rossi, S. R. Sherk, L. M. Sisk, P. Stouten, G. L. Trainor, P. Worland and S. P. Seitz, J. Med. Chem., 2004, 47, 5894; (b) L. Squarcialupi, V. Colotta, D. Catarzi, F. Varano, G. Filacchioni, K. Varani, C. Corciulo, F. Vincenzi, P. A. Borea, C. Ghelardini, L. Di Cesare Mannelli, A. Ciancetta and S. Moro, J. Med. Chem., 2013, 56, 2256.
2. (a) D. M. Berger, N. Torres, M. Dutia, D. Powell, G. Ciszewski, A. Gopalsamy, J. I. Levin, K.-H. Kim, W. Xu, J. Wilhelm, Y. Hu, K. Collins, L. Feldberg, S. Kim, E. Frommer, D. Wojciechowicz and R. Mallon, Bioorg. Med. Chem. Lett., 2009, 19, 6519; (b) B. J.-Y. Le, A. Pasis, B. Tam, C. Boykin, D. Wang, D. J. Marcotte, G. Claassen, J.-H. Chong, J. Chao, J. Fan, K. Nguyen, L. Silvian, L. Ling, L. Zhang, M. Choi, M. Teng, N. Pathan, S. Zhao, T. Li and A. Taveras, Bioorg. Med. Chem. Lett., 2012, 22, 4033; (c) S. M. Johnson, R. C. Murphy, J. A. Geiger, A. E. DeRocher, Z. Zhang, K. K. Ojo, E. T. Larson, B. G. Perera, E. J. Dale, P. He, M. C. Reid, A. M. Fox, N. R. Mueller, E. A. Merritt, E. Fan, M. Parsons, W. C. Van Voorhis and D. J. Maly, J. Med. Chem., 2012, 55, 2416; (d) P. Bonn, D. M. Brink, J. Faegerhag, U. Jurva, G. R. Robb, V. Schnecke, H. A. Svensson, M. J. Waring and C. Westerlund, Bioorg. Med. Chem. Lett., 2012, 22, 7302; (e) O. M. Ahmed, M. A. Mohamed, R. R. Ahmed and S. A. Ahmed, Eur. J. Med. Chem., 2009, 44, 3519; (f) K. S. Gudmundsson, B. A. Johns and J. Weatherhead, Bioorg. Med. Chem. Lett., 2009, 19, 5689; (g) A. Bendich, P. J. Russell and J. J. Fox, J. Am. Chem. Soc., 1954, 76, 6073; (h) J. Kaplan, J. C. Verheijen, N. Brooijmans, L. Toral-Barza, I. Hollander, K. Yu and A. Zask, Bioorg. Med. Chem. Lett., 2010, 20, 640; (i) A. Zask, J. Kaplan, J. C. Verheijen, D. J. Richard, K. Curran, N. Brooijmans, E. M. Bennett, L. Toral-Barza, I. Hollander, S. Ayral-Kaloustian and K. Yu, J. Med. Chem., 2009, 52, 7942; (j) E. H. M. K. Abd, M. D. Mihovilovic and H. B. El-Nassan, Eur. J. Med. Chem., 2012, 57, 323; (k) M. Bakavoli, G. Bagherzadeh, M. Vaseghifar, A. Shiri, M. Pordel, M. Mashreghi, P. Pordeli and M. Araghi, Eur. J. Med. Chem., 2010, 45, 647; (l) S. Taliani, C. La Motta, L. Mugnaini, F. Simorini, S. Salerno, A. M. Marini, F. Da Settimo, S. Cosconati, B. Cosimelli, G. Greco, V. Limongelli, L. Marinelli, E. Novellino, O. Ciampi, S. Daniele, M. L. Trincavelli and C. Martini, J. Med. Chem., 2010, 53, 3954.
3. (a) V. K. Naganaboina, K. L. Chandra, J. Desper and S. Rayat, Org. Lett., 2011, 13, 3718; (b) O. E. Alawode, V. K. Naganaboina, T. Liyanage, J. Desper and S. Rayat, Org. Lett., 2014, 5, 1494.
4. (a) O. A. Attanasi, S. Bartoccini, G. Favi, P. Filippone, F. R. Perrulli and S. J. Santeusanio, Org. Chem., 2012, 77, 9338; (b) R. Kumar, D. S. Ermolat'ev and E. V. Van der Eycken, J. Org. Chem., 2013, 11, 5737; (c) Y. B. Nie, L. Wang and M. W. Ding, J. Org. Chem., 2012, 77, 696; (d) M. W. Ding, S. Z. Xu and J. F. Zhao, J. Org. Chem., 2004, 69, 8366; (e) Y. Y. Yang, W. G. Shou, Z. B. Chen, D. Hong and Y. G. Wang, J. Org. Chem., 2008, 73, 3928; (f) S. P. Marsden, A. E. McGonagle and B. McKeever-Abbas, Org. Lett., 2008, 10, 2589; (g) A. Ramazani and A. Rezaei, Org. Lett., 2010, 12, 2852; (h) W. Yan, D. Wang, J. Feng, P. Li, D. Zhao and R. Wang, Org. Lett., 2012, 10, 2512; (i) F. Zeng and H. Alper, Org. Lett., 2010, 12, 1188; (j) H. Q. Wang, W. P. Zhou, Y. Y. Wang and C. R. Lin, J. Agric. Food Chem., 2008, 56, 7321; (k) H. Q. Wang, M. W. Ding and Z.-J. Liu, Heteroat. Chem., 2004, 15, 333.
5. (a) R. W. Fischer and M. Misun, Org. Process Res. Dev., 2001, 5, 581; (b) S. I. Mirallai, M. Manoli and P. A. Koutentis, J. Org. Chem., 2013, 78, 8655; (c) L. Sun, Y. Zhu, P. Lu and Y. Wang, Org. Lett., 2013, 15, 5894; (d) N. L. Snyder and T. P. Adams, Named Reactions in Heterocylic Chemistry II, ed. J. J. Li, John-Wiley & Sons, 2011, p. 554; (e) R. N. Lacey, J. Chem. Soc., 1954, 839–844.
6. ESI.†.

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Footnote

† Electronic supplementary information (ESI) available: IR, ¹H and ¹³C NMR of compound 3 and 4. CCDC 850784 and 850785. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra15777j

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