One-Flask Synthesis of Pyrazolo[3,4-d]pyrimidines from 5-Aminopyrazoles and Mechanistic Study

Abstract

A novel one-flask synthetic method was developed in which 5-aminopyrazoles were reacted with N,N-substituted amides in the presence of PBr3. Hexamethyldisilazane was then added to perform heterocyclization to produce the corresponding pyrazolo[3,4-d]pyrimidines in suitable yields. These one-flask reactions thus involved Vilsmeier amidination, imination reactions, and the sequential intermolecular heterocyclization. To study the reaction mechanism, a series of 4-formyl-1,3-diphenyl-1H-pyrazol-5-yl-N,N-disubstituted formamidines, which were conceived as the chemical equivalent of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl-formamidine, were prepared and successfully converted into pyrazolo[3,4-d]pyrimidines. The experiments demonstrated that the reaction intermediates were the chemical equivalents of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl)formamidines. The rate of the reaction could be described as being proportional to the reactivity of amine reactants during intermolecular heterocyclization, especially when hexamethyldisilazane was used.

One‐pot Microwave‐assisted Synthesis of Pyrazolopyrimidines from 5‐Amino‐4‐thiocyanato‐pyrazoles with Vilsmeier Reagent

“…For example, compound 3 i presented three singlet peaks at δ 3.87 ppm for À OMe group and at δ 9.09 ppm and 9.49 ppm for pyrimidine ring in 1 H NMR. [17][18][19][20] In 13 C NMR spectrum, compound 3 i possessed characteristic absorptions at δ 155.5 ppm for pyrmidine carbon N = 13 CHÀ N=C. [17][18][19][20] Furthermore, the structure of compound 3 i was also characterized by the single-crystal X-ray diffraction study (ORTEP) presented in Figure 1.…”

“…[17][18][19][20] In 13 C NMR spectrum, compound 3 i possessed characteristic absorptions at δ 155.5 ppm for pyrmidine carbon N = 13 CHÀ N=C. [17][18][19][20] Furthermore, the structure of compound 3 i was also characterized by the single-crystal X-ray diffraction study (ORTEP) presented in Figure 1. By product pyrazolothiazoles 4 a-o were also fully characterized by spectroscopic methods.…”

“…96-97 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 2.39 (s, 3H, CH 3 ), 4.50 (br, 2H, NH 2 ), 7.28 (d, J = 8.36 Hz, 2H, ArH), 7.39-7.47 (m, 5H, ArH), 7.86 (d, J = 6.88, Hz, 2H, ArH); 13 (30), 214 (10), 188 (46), 187 (10), 161 (17), 153 (81), 129 (24), 128 (100), 127 (13), 126 (22), 118 (11), 113 (29), 104 (13), 103 (24), 102 (17), 90 (29), 89 (17), 77 (67), 76 (13), 75 (39), 51 (16); HRMS (EI) calcd for C 16 H 11 ClN 4 S 326.0393, found 326.0388. (21), 188 (21), 187 (11), 156 (25), 154 (25), 128 (20), 103 (10), 77 (16), 76 (18), 75 (14) ; HRMS (EI) calcd for C 16 H 11 BrN 4 369.9888, found 369.9897. (13), 187 (13), 172 (11), 150 (12), 149 (100), 134 (15), 133 (23), 129 (12), 128 (46), 122 (12), 121 (40), 118 (16), 107 (29), 106 (15), 105 (10), 104 (16), 103 (20), 92 (56), 78 (15), 77 (98), 64 (16); HRMS (EI) calcd for C 17 H 14 N 4 OS 322.0888, found 322.0898.…”

“…[10][11][12][13][14] One-pot reaction (Route A and B in Scheme 1) [15] and microwave-assisted/solvent free synthesis (Route C in Scheme 1) [16] possess significant advantages and are widely considered as powerful tools in synthetic chemistry and reaction design approaches. Previously, we have developed efficient one-pot reaction and/or microwave-assisted synthesis method of pyrazolo [3,4-d]pyrimidines by treating 5-aminopyrazoles or 1H-pyrazol-5-yl-N,N-dimethyl-formamidines with formamide or DMF as well as, PBr 3 or POCl 3 as a coupling agent (Route A [17,18] and B [19,20] in Scheme 1).…”

Synthesis of various pyrazole-fused heterocyclic systems using pyrazole-4-carbaldehydes as versatile precursors

“…On the other hand, the reaction of triphenylphosphanimines 38 with acyl chlorides 50 gave the corresponding pyrazolo [3,4-d]pyrimidinium salts 51 (Scheme 15). 66 The intermolecular heterocyclization from N'-(4-formylpyrazol-5-yl)formimidamide 52 with various amines 67 or cyanamide (NH2CN) in acidic solution at reflux 68 Cyclization of 5-aminopyrazole-4-carbaldehyde 11 with formamide 69,70 or benzamide 70 and phosphorus tribromide (PBr3) 69 afforded pyrazolo [3,4-d] Gondek et al 83 [4,3-c]pyrazole. Under a Cu(0)/Selectfluor catalyzed system, a range of 3-methyl-1,5diphenyl-1H-pyrazole-4-carbaldehydes 116 could be intramolecularly lactonized to chromeno [4,3-c]pyrazoles 117 in moderate to good yields (55-72%, 117a-e, Scheme 40, Table 1).…”