Straightforward Synthesis of Functionalized 4,5,6,7‐Tetrahydro‐pyrazolo[1,5‐a]pyrazines – Important Building Blocks for Medicinal Chemistry

Abstract

A set of building blocks based on the 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazine scaffold is synthesized in a multigram scale in a cost‐efficient manner. The possibility of the introduction of different substituents, neutral or functionalized in different positions of pyrazole and/or piperazine rings, is shown. The efficacy of using NH‐pyrazole carbonic acids as a key intermediate of the process is demonstrated. The regioselectivity for direct insertion of the substituent to the 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazine core is discussed. The synthetic perspectives for using the functionalized 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazine as a bifunctional scaffold is discussed. The utilizing of building blocks obtained for the different region‐ and/or stereoselective synthesis, including sole transformations or modifications of functional groups, is demonstrated. The advantages of the proposed approach are proven compared with the other known methodologies.

Palladium-Catalyzed C7–H (Hetero)arylation of Pyrazolo[1,5-a]pyrazines with Heteroarenes and Aryl Iodides with the Assistance of Silver Salts

“…2b Synthetically, pyrazolo[1,5- a ]pyrazines can be constructed from either pyrazine or pyrazole fragments using different cyclization strategies, with substituents introduced to the molecules early in the synthetic sequences. 1 2a 3 On the other hand, further diversification of the cores using C–H bond functionalization is still not available, even though it would be promising for the expedient exploration of the new chemical space.…”

New synthetic approach to pyrazolo[1,5‐a]pyrazine derivatives from 2,2‐dichlorovinylacetophenones

“…The solvent was evaporated and water (10 mL) was added and the product was extracted with diethyl ether (2 Â 10 mL), which was dried over anhydrous magnesium sulfate, filtered, and removed under reduced pressure, leaving a residue which was purified by silica gel chromatography (ethyl acetate/pet ether 1:3 as eluent). , J = 8.9 Hz), 7.59 (d, 2H, J = 8.9 Hz), 13 (m, 4H), 7.99 (d, 1H, J = 8.9 Hz), 13 13 To a solution of compound 5 (1.0 mmol) in methanol (15 mL) containing hydrochloric acid (36%, 1 mL), Pd/C catalyst (5%, 0,05 g) was added. The reaction mixture was stirred under a hydrogen atmosphere (4.05 bar) at room temperature for 5 h. The solvent was then filtered, removed in vacuo and the residue was washed with EtOAc/pet ether 1:1 mixture.…”

“…The ring fusion of pyrazoles with some heterocyclic systems has been shown of great interest in bringing out biologically active compounds, several of which possess pharmacological significance [1][2][3][4][5][6][7][8][9][10][11][12]. Recent studies have pointed out that molecules containing an aromatic heterocycle fused either with a saturated cyclic hydrocarbon or a non-aromatic heterocycle-in other words, when the fraction of sp 3 centers increases-can have substantial clinical effects [13][14][15][16][17]. Thus, certain tetrahydropyrazolo [1,5-a]pyrazine derivatives, which contain an aromatic pyrazole nucleus condensed with a hydrogenated pyrazine moiety, exhibit an important range of therapeutic utilities, such as ATR inhibitors [18], metabotropic glutamate receptors [19], antivirals [20,21], ROS1 inhibitors [22], GLP-1 agonists [23], protein G inhibitors [24], dopamine D4 receptor agonists [25], etc.…”

“…(2-Azidoethyl)-5-dichloromethyl-3-phenyl-2-pyrazoline (4a) Yellow oil, IR (ATR): 2100, 1363, 1268, 756, 692 cm À1 , 1 H NMR (CDCl 3 , 600 MHz) δ: 3.32 (m, 2H), 3.45 (m, 2H), 3.56 (dt, 1H, J = 6.5 Hz, J = 13.1 Hz), 3.77 (m, 1H), 4.05 (ddd, 1H, J = 4.5 Hz, J = 9.6 Hz, J = 11.8 Hz), 5.88 (d, 1H, J = 4.5 Hz), 7.36 (m, 3H), 7.21 (m, 2H), 13 C NMR (CDCl 3 , 150 MHz) δ: 37.61 (CH 2 ), 50.67 (CH 2 ), 55.28 (CH 2 ), 73.36 (CH), 74.42 (CH), 127.09 (CH), 129.62 (CH), 130.27 (CH), 132.92 (C), 151.06 (C), HRMS (ESI): m/z [M + H] + calcd for C 12 H 14 Cl 2 N 5 : 298.0621, found 298.0616. 6.2 | 1-(2-Azidoethyl)-5-dichloromethyl-3-(4-fluorophenyl)-2-pyrazoline (4b) Yellow oil, IR (ATR): 2104, 1514, 1230, 906, 838, 726, 651 cm À1 , 1 H NMR (CDCl 3 , 400 MHz) δ: 3.42 (m, 2H), 3.44 (m, 2H), 3.55 (dt, 1H, J = 5.3 Hz, J = 11.9 Hz), 3.77 (m, 1H), 4.05 (ddd, 1H, J = 4.4 Hz, J = 10.0 Hz, J = 11.2 Hz), 5.86 (d, 1H, J = 4.4 Hz), 7.07 (t, 2H, J = 8.9 Hz), 7.59 (dd, 2H, J = 5.5 Hz, J = 8.9 Hz),13 C NMR (CDCl 3 , 100.8 MHz) δ: 37.48 (CH 2 ), 50.51 (CH 2 ), 55.13 (CH 2 ), 73.32 (CH), 74.13 (CH), 116.50 (d, CH, J = 21.7 Hz), 128.62 (d, CH, J = 8.3 Hz), 129.09 (C), 149.96 (C), 163.50 (d, C, J = 250 Hz), HRMS (ESI): m/z [M + H] + calcd for C 12 H 13 Cl 2 FN 5 : 316.0527, found 316.0537.6.3 | 1-(2-Azidoethyl)-3-(4-chlorophenyl)-5-dichloromethyl-2-pyrazoline (4c) Yellow oil, IR (ATR): 2099, 1591, 1494, 1362, 1090, 829, 763 cm À1 , 1 H NMR (CDCl 3 , 300 MHz) δ: 3.32 (m, 4H), 3.53 (dt, 1H, J = 5.4 Hz, J = 12.6 Hz), 3.73 (m, 1H), 4.05 (m, 1H), 5.88 (d, 1H, J = 4.5 Hz), 7.30(d, 2H, J = 8.9 Hz), 7.54 (d, 2H, J = 8.9 Hz),13 C NMR (CDCl 3 , 75.4 MHz) δ: 37.38 (CH 2 ), 50.64 (CH 2 ), 55.03 (CH 2 ), 73.38 (CH), 74.19 (CH), 128.22 (CH), 129.75 (CH), 131.44 (C), 135.91 (C), 149.69 (C), HRMS (ESI): m/z [M + H] + calcd for C 12 H 13 Cl 3 N 5 : 332.0231, found 332.0226.6.4 | 1-(2-Azidoethyl)-3-(4-bromophenyl)-5-dichloromethyl-2-pyrazoline (4d) Yellow oil, IR (ATR): 2963, 2879, 1473, 1445, 1358, 1292, 760, 690 cm À1 , 1 H NMR (CDCl 3 , 200 MHz) δ: 3.45 (m, 4H), 3.52 (dd, 1H, J = 6.8 Hz, J = 16.8 Hz), 3.73 (m, 1H), 4.04 (ddd, 1H, J = 4.3 Hz, J = 6.8 Hz, J = 14.8 Hz), 5.84 (d, 1H, J = 4.3 Hz), 7.47 (s, 4H), 13 C NMR (CDCl 3 , 50.4 MHz) δ: 37.31 (CH 2 ), 50.64 (CH 2 ), 55.01 (CH 2 ), 73.37 (CH), 74.13 (CH), 124.25 (C), 128.47 (CH), 131.82 (C), 132.71 (CH), 149.80 (C), HRMS (ESI): m/z [M + H] + calcd for C 12 H 13 BrCl 2 N 5 : 375.9726, found 375.9728. 6.5 | 1-(2-Azidoethyl)-5-dichloromethyl-3-(4-methoxyphenyl)-2-pyrazoline (4e) Yellow oil, IR (ATR): 2100, 1612, 1435, 1251, 1173, 838 cm À1 , 1 H NMR (CDCl 3 , 400 MHz) δ: 3.28 (m, 2H), 3.42 (m, 2H), 3.56 (dt, 1H, J = 5.3 Hz, J = 12.8 Hz), 3.77 (m, 1H), 3.83 (s, 3H), 4.00 (ddd, 1H, J = 4.6 Hz, J = 9.5 Hz, J = 11.0 Hz), 5.84 (d, 1H, J = 4.6 Hz), 6.90 (d, 2H…”