Synthesis of Pyrazolinyl Heterocycles via Adenine- or Imidazole-Containing Nitrilimine Cycloaddition

Abstract

Pyrazolinyl nucleoside analogues via adenine- or imidazole-containing nitrilimine cycloaddition have been prepared. The key feature of our synthetic strategy is the introduction of the base moiety through the new 1,3-dipole.

modified nucleosides - nitrilimines - pyrazolines - 1,3-dipolar cycloaddition - reduction

References and Notes

For reviews, see:

1a Caramella P. Grunanger P. In 1,3-Dipolar Cycloaddition Chemistry   Padwa A. Wiley; New York: 1984.  Chap. 3.

1b Sharp JT. In The Chemistry of Heterocyclic Compounds   Vol. 59:  Padwa A. Pearson WH. Wiley; New York: 2002.  p.473 

1c Molteni G. Heterocycles  2005,  65:  2513 

2 Foti F. Grassi G. Risitano F. Tetrahedron Lett.  1999,  40:  2605 

3a Foti F. Grassi G. Risitano F. Nicolò F. Rotondo A. Helv. Chim. Acta  2001,  84:  3313 

3b Galati EM. Monforte MT. Miceli N. Ranieri E. Il Farmaco  2001,  56:  459 

3c Foti F. Grassi G. Risitano F. Rotondo E. Zona D. Synlett  2004,  1577 

3d Foti F. Grassi G. Risitano F. Synlett  2005,  125 

4 Merino P. Curr. Med. Chem.  2006,  539 ; and references cited therein

5

Previously reported routes to this kind of synthesis either used the cycloaddition of a 1,3-dipole with a nucleobase-containing dipolarophile [16] or the introduction of the nucleobase into a suitably functionalized preformed cycloadduct. [17]

6 Takamura N. Taga N. Kanno T. Kawazu M. J. Org. Chem.  1973,  38:  2891 

7

Typical Procedure for C -Imidazole Nitrilimine Cyclo-addition
To a stirred solution of 4 (5 mmol) in DMF (10 mL) at r.t. was added methyl acrylate (50 mmol) and then dropwise Et₃N (5 mmol). The reaction mixture was left to stand for 2 h (for 4c) or for 4 h (for 4b), strained to eliminate salt and concentrated. The cycloadducts 6b,c were isolated by flash chromatography on silica gel (eluent: Et₂O-acetone, 1:1).

8

Typical Procedure for C -Adenine Nitrilimine Cyclo-addition
To a stirred suspension of NaH (10 mmol) in DMF (15 mL) under nitrogen at r.t. was added a solution of adenine (10 mmol) in DMF (20 mL). At the same time, bromonitrilimine (10 mmol) was prepared: to a stirred solution of 2 (10 mmol) in DMF (20 mL) at -5 °C was added dropwise Et₃N (10 mmol). After additional stirring (15 min) at r.t., the bromonitrilimine solution was added to the adenine (Na salt) solution. The mixture was left to stir for 15 min, then methyl acrylate (100 mmol) was added. After 2 h stirring at 50 °C, the reaction (monitored by TLC) was complete and the mixture was evaporated in vacuo. The cycloadducts 7a,b were isolated by flash chromatography on silica gel (eluent: Et₂O-acetone, 2:1).

9 Casuscelli F. Chiacchio U. Di Bella M. Rescifina A. Romeo G. Romeo R. Uccella N. Tetrahedron  1995,  51:  8605 

10

Synthesis of 2
To a stirred solution of arylhydrazone 1 (20 mmol) in DMF (40 mL) at r.t. was added dropwise a solution of NBS (40 mmol) in DMF (30 mL). After additional stirring (2 h), the reaction mixture was poured into cold H₂O (200 mL) and extracted three times with Et₂O (100 mL); the organic layer was washed with H₂O and brine, dried over anhyd Na₂SO₄, and concentrated. Column chromatography of the residue on silica gel (PE for 2a; PE-CHCl₃ = 3:1 for 2b; CHCl₃-PE = 2:1 for 2c) gave the indicated products.

11

Synthesis of 4
To a stirred solution of 2 (5 mmol) in DMF (10 mL) at r.t., imidazole (10 mmol) was added. The reaction mixture was stirred for 1 h, poured into cold H₂O (30 mL) and extracted three times with Et₂O (50 mL). For 4b, the organic layer was washed with H₂O and brine, dried over anhyd Na₂SO₄, and the solvent was removed under vacuum. Column chromatography of the residue on silica gel (Et₂O-acetone, 2:1) gave the indicated product. Compound 4c was recovered as a yellow solid from Et₂O solution and was crystallized by slow evaporation of an acetone solution.

12 Brahme NM. Smith WT. J. Heterocycl. Chem.  1985,  22:  109 

13

See ref. 1a, p. 300.

14

Selected Data
Compound 2a: mp 55 °C. IR (Nujol): 3314, 1602 cm^-1. ¹H NMR (DMSO-d ₆): δ = 6.83-7.25 (m, 5 H), 9.62 (s, 1 H). MS (EI): m/z = 276, 278, 280 [M⁺].
Compound 2b: mp 52 °C. IR (Nujol): 3322, 1614 cm^-1. ¹H NMR (DMSO-d ₆): δ = 7.02-7.14 (m, 4 H), 9.67 (s, 1 H). MS (EI): m/z = 294, 296, 298 [M⁺].
Compound 2c: mp 152 °C. IR (Nujol): 3260, 1602 cm^-1. ¹H NMR (DMSO-d ₆): δ = 7.29 (d, 2 H, J = 9 Hz), 8.14 (d, 2 H, J = 9 Hz), 10.53 (s, 1 H). MS (EI): m/z = 321, 323, 325 [M⁺].
Compound 4b: mp 98 °C. IR (Nujol): 3159 cm^-1. ¹H NMR (DMSO-d ₆): δ = 7.04-7.10 (m, 3 H), 7.21-7.27 (m, 2 H), 7.70 (s, 1 H), 8.22 (s, 1 H), 9.52 (s, 1 H). MS (EI): m/z = 282, 284 [M⁺].
Compound 4c: mp 180 °C. IR (Nujol): 3253, 1600 cm^-1. ¹H NMR (DMSO-d ₆): δ = 7.12 (s, 1 H), 7.42 (d, 2 H, J = 9 Hz), 7.80 (s, 1 H), 8.14 (d, 2 H, J = 9 Hz), 8.33 (s, 1 H), 10.40 (s, 1 H). MS (EI): m/z = 309, 311 [M⁺].
Compound 6b: mp 123 °C. IR (Nujol): 1748 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.67 (s, 3 H), 3.71 (dd, 1 H, J = 6, 17 Hz), 3.93 (dd, 1 H, J = 12, 17 Hz), 5.11 (dd, 1 H, J = 6, 12 Hz), 6.93-7.12 (m, 5 H), 7.69 (s, 1 H), 8.16 (s, 1 H). MS (EI): m/z = 288 [M⁺].

Compound 6c: mp 175 °C. IR (Nujol) 1740 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.70 (s, 3 H), 3.85 (dd, 1 H, J = 4.5, 17.0 Hz), 4.14 (dd, 1 H, J = 12, 17 Hz), 5.49 (dd, 1 H, J = 4.5, 12.0 Hz), 7.05 (d, 2 H, J = 9.3 Hz), 7.15 (s, 1 H), 7.76 (s, 1 H), 8.13 (d, 2 H, J = 9.3 Hz), 8.23 (s, 1 H). MS (EI): m/z = 315 [M⁺].
Compound 7a: mp 265 °C. IR (Nujol): 3410, 3305, 3105, 1735, 1635, 1598 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.71 (s, 3 H), 3.96 (dd, 1 H, J = 6, 18 Hz), 4.17 (dd, 1 H, J = 12, 18 Hz), 5.15 (dd, 1 H, J = 6, 12 Hz), 6.78-7.28 (m, 5 H), 7.50 (s, 2 H), 8.20 (s, 1 H), 8.67 (s, 1 H). MS (EI): m/z = 337 [M⁺].
Compound 7b: mp 276 °C. IR (Nujol): 3410, 3311, 3103, 1732, 1653, 1602 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.70 (s, 3 H), 3.97 (dd, 1 H, J = 6.3, 17.7 Hz), 4.16 (dd, 1 H, J = 12.3, 17.7 Hz), 5.14 (dd, 1 H, J = 6.3, 12.3 Hz), 7.02-7.14 (m, 4 H), 7.49 (s, 2 H), 8.21 (s, 1 H), 8.66 (s, 1 H). MS (EI): m/z = 355 [M⁺].
Compound 8b: mp 155 °C. IR (Nujol): 3500-3120 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.34 (m, 2 H), 3.61 (m, 2 H), 4.41 (m, 1 H), 5.04 (t, OH), 7.05-7.14 (m, 5 H), 7.67 (s, 1 H), 8.15 (s, 1 H). MS (EI): m/z = 260 [M⁺].
Compound 8c: mp 210 °C. IR (Nujol): 3450-3120, 1512, 1320 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.49 (m, 2 H), 3.74 (m, 2 H), 4.81 (m, 1 H), 5.14 (t, OH), 7.13 (d, 2 H, J = 9 Hz), 7.13 (s, 1 H), 7.74 (s, 1 H,), 8.10 (d, 2 H, J = 9 Hz), 8.24 (s, 1 H). MS (EI): m/z = 287 [M⁺].
Compound 9a: mp 238 °C. IR (Nujol): 3365, 3309, 1653, 1598 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.61 (m, 2 H), 3.79 (m, 2 H), 4.51 (m, 1 H), 5.07 (t, OH), 6.74-7.38 (m, 5 H), 7.46 (s, 2 H), 8.20 (s, 1 H), 8.62 (s, 1 H). MS (EI): m/z = 309 [M⁺].
Compound 9b: mp 248 °C. IR (Nujol): 3337, 3188, 1663, 1602 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.61 (m, 2 H), 3.79 (m, 2 H), 4.45 (m, 1 H), 5.07 (t, OH), 7.05-7.12 (m, 4 H), 7.47 (s, 2 H), 8.20 (s, 1 H), 8.62 (s, 1 H). MS (EI): m/z = 327 [M⁺].
Compound 10: mp 283-284 °C. IR (Nujol) 3402, 3300, 3165, 1578, 1491 cm^-1. ¹H NMR (DMSO-d ₆): δ = 1.13 (t, 6 H, J = 7 Hz), 3.21 (q, 4 H, J = 7 Hz), 7.22 (d, 2 H, J = 9Hz), 7.54 (s, 2 H), 7.63 (d, 2 H, J = 9Hz), 7.89 (s, 1 H), 8.01 (d, 2 H, J = 9 Hz), 8.26 (d, 2 H, J = 9 Hz), 8.57 (s, 1 H). MS (EI): m/z = 531 [M⁺].

15

X-ray data to be submitted to Acta Crystallogr.

16a Merino P. C. R. Chim.  2005,  8:  775 

16b Procopio A. Alcaro S. De Nino A. Maiuolo L. Ortuso F. Sindona G. Bioorg. Med. Chem. Lett.  2005,  15:  545 

16c Clayton R. Ramsden CA. Synthesis  2005,  2695 ; and references cited therein

17 Coutouli-Argyropoulou E. Pilanidou P. Tetrahedron Lett.  2003,  44:  3755