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Synlett 2006(11): 1734-1738  
DOI: 10.1055/s-2006-947324
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Alternative Route to Pyrrolotriazoles and other N-Bridgehead Heterocycles

Orazio A. Attanasi, Lucia De Crescentini, Paolino Filippone*, Fabio Mantellini, Francesca R. Perrulli, Stefania Santeusanio*
Istituto di Chimica Organica della Facoltà di Scienze Matematiche, Fisiche e Naturali, Università degli Studi di Urbino ‘Carlo Bo’, Via Sasso 75, 61029 Urbino, Italy
Fax: +39(0722)303441; e-Mail: santeusanio@uniurb.it;
Further Information

Publication History

Received 26 February 2006
Publication Date:
04 July 2006 (online)

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Abstract

1,2-Diaza-1,3-butadienes bearing a Boc moiety at N-1 react with acetonitrile derivatives to afford 1-Boc-protected 1,2-diaminopyrroles that represent, by flexible condensation-deprotection or deprotection-condensation steps, a flexible entry to different N-bridgehead heterocycles.

Key words

1,2-diaza-1,3-butadienes - protecting groups - nitriles - pyrroles - fused-ring systems

    References and Notes

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    Prepared as reported in ref. 5a. Analytical data of 5d: white powder from Et2O; mp 186-188 °C (dec.). IR (nujol): 3439, 3353, 3241, 1751, 1666, 1620, 1563 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 0.94 (t, J = 7.2 Hz, 3 H, OCH2CH 3), 1.47 (s, 9 H, t-BuO), 2.26 (s, 3 H, CH3), 3.90 (q, J = 7.2 Hz, 2 H, OCH 2CH3), 4.28 (s, 2 H, NH2), 7.20-7.35 (m, 2 H, Ar), 7.52 (s, 1 H, Ar), 9.89 (br s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 9.99, 13.69, 27.83, 58.37, 80.66, 95.85, 106.82, 126.45, 127.94, 128.03, 129.53, 130.68, 133.81, 134.07, 135.27, 154.21, 164.39. Anal. Calcd for C19H23N3O4Cl2: C, 53.28; H, 5.41; N, 9.81. Found: C, 53.44; H, 5.29; N, 9.70.
    Analytical data of 5e: white powder from Et2O; mp 215-217 °C (dec.). IR (nujol): 3349, 3264, 1724, 1689, 1680, 1649, 1614, 1593 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.47 (s, 9 H, t-BuO), 2.24 (s, 3 H, CH3), 3.84 (s, 3 H, OCH3), 6.69 (s, 2 H, NH2) 7.34 (d, J = 7.6 Hz, 2 H, Ar), 7.64 (d, J = 7.6 Hz, 2 H, Ar), 10.14 (s, 1 H, NH), 11.73 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 11.33, 27.85, 52.04, 81.14, 88.97, 103.45, 120.08, 125.46, 128.39, 133.62, 138.41, 148.12, 153.61, 163.29, 167.80. Anal. Calcd for C19H23N4O5Cl: C, 53.97; H, 5.48; N, 13.25. Found: C, 53.59; H, 5.37; N, 13.45.
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8

Procedure for the Preparation of Derivatives 7b and 8b. Pyrrole derivative 5a (308 mg, 1 mmol) and 6b (4 mL) were heated at 100 °C in an oil bath under magnetic stirring for 5 h. Then, 6b was removed under reduced pressure and the residue was heated at 180 °C in an oil bath for 30 min. The resulting dark residue was treated with THF and Et2O to afford 8b as a light grey powder that was recrystallised as a white powder from hot EtOH. Analytical data of 8b: mp 221-222 °C. IR (nujol): 3203, 3176, 2220, 1673, 1620, 1562 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.29 (t, J = 6.8 Hz, 3 H, OCH2CH 3), 2.42 (s, 3 H, CH3), 2.53 (s, 3 H, CH3), 4.23 (q, J = 6.8 Hz, 2 H, OCH 2CH3), 13.43 (br s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 10.31, 11.99, 14.21, 59.78, 59.89, 111.88, 115.71, 120.37, 137.98, 153.76, 163.11. MS: m/z (%) = 232 (28) [M+], 203 (100), 187 (20), 159 (9). Anal. Calcd for C11H12N4O2: C, 56.89; H, 5.21; N, 24.12. Found: C, 56.72; H, 5.26; N, 24.43.
Derivative 7b was isolated in a separate experiment by stopping the reaction after heating at 100 °C for 5 h and removing 6b under reduced pressure. The oily residue was treated with Et2O-light PE to obtain 7b as a beige powder.
Analytical data of 7b: mp 160 °C (dec.). IR (nujol): 3260, 2220, 1734, 1677, 1658, 1552 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH 3), 1.41 (s, 9 H, t-BuO), 1.99 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 3.78 (s, 3 H, OCH3), 4.23 (q, J = 7.2 Hz, 2 H, OCH 2CH3), 10.32 (br s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 10.12, 13.99, 17.17, 27.60, 54.25, 59.84, 77.64, 81.28, 106.86, 115.23, 134.89, 146.04, 154.31, 162.36, 168.42. MS: m/z (%) = 364 (38) [M+], 308 (100), 264 (88), 235 (63), 192 (58). Anal. Calcd for C17H24N4O5: C, 56.03; H, 6.64; N, 15.38. Found: C, 55.87; H, 6.68; N, 15.18.

10

Analytical data of 7f: white powder from Et2O-cyclohexane, mp 167 °C (dec.). IR (nujol): 3211, 3178, 1746, 1664, 1645, 1616, 1556 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.40 (s, 9 H, t-BuO), 1.84 (s, 3 H, CH3), 2.28 (s, 3 H, CH3), 3.66 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 7.30 (d, J = 8.8 Hz, 2 H, Ar), 7.63 (d, J = 8.8 Hz, 2 H, Ar), 10.10 (s, 1 H, NH), 10.35 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 10.57, 17.27, 27.71, 51.16, 53.59, 80.74, 102.78, 105.67, 120.60, 126.11, 128.39, 133.43, 138.73, 139.92, 154.50, 162.40, 165.36, 167.74. MS: m/z (%) = 478 (13) [M+], 296 (100), 252 (21), 220 (19). Anal. Calcd for C22H27N4O6Cl: C, 55.17; H, 5.68; N, 11.70. Found: C, 55.03; H, 5.72; N, 11.65.
Analytical data of 8f: white powder from EtOAc-cyclo-hexane, mp 235-239 °C (dec.). IR (nujol): 3393, 3075, 1670, 1635, 1588, 1555 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 2.41 (s, 3 H, CH3), 2.54 (s, 3 H, CH3), 3.87 (s, 3 H, OCH3), 7.36 (d, J = 8.0 Hz, 2 H, Ar), 7.68 (d, J = 8.0 Hz, 2 H, Ar) 11.81 (s, 1 H, NH), 12.95 (br s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 11.48, 11.83, 52.07, 89.38, 107.69, 120.12, 121.85, 125.93, 128.76, 138.61, 154.38, 160.89, 168.71. MS: m/z (%) = 346 (25) [M+], 220 (71), 188 (74), 169 (100). Anal. Calcd for C16H15N4O3Cl: C, 55.42; H, 4.36; N, 16.16. Found: C, 55.46; H, 4.14; N, 16.01.
Analytical data of 9b: beige powder from hot EtOAc, mp 228-229 °C (dec.). IR (nujol): 3326, 3270, 3217, 3054, 1692, 1681, 1615, 1563, 1532 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 2.11 (s, 3 H, CH3), 2.52 (s, 3 H, CH3), 3.66 (s, 3 H, OCH3), 5.87 (s, 2 H, NH2), 7.39 (d, J = 8.4 Hz, 2 H, Ar), 7.61 (d, J = 8.4 Hz, 2 H, Ar). 13C NMR (100 MHz, DMSO-d 6): δ = 10.60, 23.90, 50.76, 100.23, 102.91, 129.45, 130.64, 133.28, 137.48, 139.98, 145.97, 153.79, 156.49, 164.40. MS: m/z (%) = 346 (20) [M+], 314 (58), 299 (40), 271 (13), 152 (100), 111 (70). Anal. Calcd for C16H15N4O3Cl: C, 55.42; H, 4.36; N, 16.16. Found: C, 55.27; H, 4.12; N, 16.22.
Analytical data of 10: beige powder from dioxane, mp 221-222 °C (dec.). IR (nujol): 3464, 3344, 3195, 1661, 1641, 1594, 1546 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 2.42 (s, 3 H, CH3), 3.83 (s, 3 H, OCH3), 5.53 (s, 2 H, NH2), 6.48 (s, 2 H, NH2), 7.33 (d, J = 8.5 Hz, 2 H, Ar), 7.63 (d, J = 8.5 Hz, 2 H, Ar), 11.93 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 12.11, 51.83, 89.12, 101.66, 119.91, 125.24, 128.49, 135.22, 138.69, 148.59, 163.49, 168.18. MS:
m/z (%) = 322 (4) [M+], 290 (13), 196 (12), 168 (28), 153 (56), 127 (100). Anal. Calcd for C14H15N4O3Cl: C, 52.10; H, 4.68; N, 17.36. Found: C, 52.26; H, 4.82; N, 17.09.

12

Representative Procedure for the Preparation of Derivative 11d. Pyrrole derivative 5d (428 mg, 1 mmol) and methyl pyruvate (135 mg, 1.323 mmol) were refluxed in dioxane (4 mL) in the presence of Amberlyst 15H (400 mg) for 2 h. Then the resin was removed by filtration and the solvent evaporated under reduced pressure. The residue, treated with Et2O, gave derivative 11d as a yellow powder.
Analytical data of 11d: mp 226-229 °C. IR (nujol): 3129, 3077, 1706, 1679, 1578 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 0.96 (t, J = 7.2 Hz, 3 H, OCH2CH 3), 2.27 (s, 3 H, CH3), 2.60 (s, 3 H, CH3), 3.97 (q, J = 7.2 Hz, 2 H, OCH 2CH3), 7.29 (d, J = 8.4 Hz, 1 H, Ar), 7.38 (d, J = 8.4 Hz, 1 H, Ar), 7.60 (s, 1 H, Ar), 12.19 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 9.64, 13.61, 17.39, 59.19, 95.53, 110.21, 123.49, 126.36, 126.53, 128.06, 130.84, 132.16, 134.38, 135.70, 150.23, 151.82, 164.02. MS: m/z (%) = 379 (75) [M+], 350 (100), 344 (58), 316 (91). Anal. Calcd for C17H15N3O3Cl2: C, 53.70; H, 3.98; N, 11.05. Found: C, 53.58; H, 3.72; N, 11.18.

13

Preparation of Derivative 13a. Pyrrole derivative 5a (308 mg, 1 mmol) and NaOH (100 mg, 2.5 mmol) were suspended in THF (4 mL) and magnetically stirred for 10 min at r.t. Then 12a (334 mg, 2 mmol) was added to the reaction mixture and the stirring was continued for 30 min; THF was removed under reduced pressure and the residue was dissolved in EtOAc and washed with H2O in a separatory funnel. The organic phase was dried over Na2SO4 and evaporated under reduced pressure; the solid residue was recrystallised from hot EtOAc to give 13a as a white powder.
Analytical data of 13a: mp 155-157 °C (dec.). IR (nujol): 3347, 3321, 3244, 3205, 2214, 1742, 1724, 1699, 1652, 1590 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.15-1.26 (m, 6 H, 2 OCH2CH 3), 1.29 and 1.38 (2 s, 9 H, t-BuO), 2.24 and 2.27 (2 s, 3 H, CH3), 4.11-4.20 (m, 4 H, OCH 2CH3), 4.40-4.60 (m, 2 H, CH2), 6.49 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d 6): δ = 9.95, 14.09, 27.44, 51.51, 52.77, 59.54, 61.46, 65.52, 82.57, 83.07, 105.92, 116.40, 131.40, 148.09, 151.69, 152.06, 162.76, 169.62, 169.86. MS: m/z (%) = 394 (15)[M+], 338 (100), 293 (18), 265 (26), 192 (88). Anal. Calcd for C18H26N4O6: C, 54.81; H, 6.64; N, 14.20. Found: C, 54.67; H, 6.38; N, 14.34.
Analytical data of 14: white powder from hot EtOH, mp 246-250 °C (dec.). IR (nujol): 3250, 3114, 2218, 1699, 1612, 1567 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.26 (t, J = 6.5 Hz, 3 H, OCH2CH 3), 2.35 (s, 3 H, CH3), 3.70 (d, J = 8.0 Hz, 2 H, CH2), 4.20 (q, J = 6.5 Hz, 2 H, OCH 2CH3), 6.79 (t, J = 8.0 Hz, 1 H, NH), 11.68 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 9.93, 14.06, 49.28, 59.66, 71.57, 106.63, 114.08, 132.04, 136.00, 162.57, 165.62. MS:
m/z (%) = 248 (87) [M+], 219 (61), 203 (27), 164 (100). Anal. Calcd for C11H12N4O3: C, 53.22; H, 4.87; N, 22.57. Found: C, 53.34; H, 4.96; N, 22.37.
Preparation of Derivative 13b.
Pyrrole derivative 5a (308 mg, 1 mmol) and NaOH (50 mg, 1.25 mmol) were suspended in THF (4 mL) and magnetically stirred for 10 min at r.t. Then, 12b (229 mg, 1.15 mmol) was added to the reaction mixture and the stirring was maintained for 24 h. The reaction work-up was the same as for 13a. The crude was recrystallised from EtOAc-light PE to obtain 13b as a white powder.
Analytical data of 13b: mp 157 °C (dec.). IR (nujol): 3327, 3243, 3194, 2220, 1726, 1703, 1693, 1650, 1592 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.26 (t, J = 6.8 Hz, 3 H, OCH2CH 3), 1.30 and 1.33 (2 s, 9 H, t-BuO), 2.32 and 2.35 (2 s, 3 H, CH3), 4.19 (q, J = 6.8 Hz, 2 H, OCH 2CH3), 5.13 and 5.15 (2 overlapped d, J = 18.4 Hz, 1 H, COCH aCHb), 5.51 (d, J = 18.4 Hz, 1 H, COCHaCH b), 6.60 and 6.63 (2 s, 2 H, NH2), 7.60 (t, J = 7.6 Hz, 2 H, Ar), 7.72 (t, J = 7.6 Hz, 1 H, Ar), 8.04 (d, J = 7.6 Hz, 2 H, Ar). 13C NMR (100 MHz, DMSO-d 6): δ = 10.70, 14.70, 14.81, 28.13, 28.29, 57.25, 58.29, 60.25, 66.14, 83.09, 83.51, 106.58, 117.15, 128.92, 129.65, 132.09, 134.99, 149.08, 152.64, 152.92, 163.49, 196.03, 196.62. MS: m/z (%) = 426 (7) [M+], 370 (60), 352 (62), 192 (50), 164 (100). Anal. Calcd for C22H26N4O5: C, 61.96; H 6.15; N, 13.14. Found: C, 61.72; H, 6.24; N, 13.26.
Preparation of Derivative 15.
Compound 13b (426 mg, 1 mmol) was refluxed in THF (5 mL) in the presence of Amberlyst 15H (400 mg) for 12 h. The resin was removed by filtration, THF was evaporated under reduced pressure and treated with Et2O to obtain a yellow residue. The crude was recrystallised from MeOH to furnish 15 as light orange crystals.
Analytical data of 15: mp 137-139 °C (dec.). IR (nujol): 3070, 2227, 1751, 1707, 1539 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.20-1.33 (m, 12 H, OCH2CH 3 and t-BuO), 2.45 (2 s, 3 H, CH3), 4.28 (q, J = 7.2 Hz, 2 H, OCH 2CH3), 4.40 (d, J = 17.2 Hz, 1 H, CH aCHb), 5.62 (d, J = 17.2 Hz, 1 H, CHaCH b), 6.60 and 6.63 (2 s, 2 H, NH2), 7.56-7.65 (m, 3 H, Ar), 8.09 (d, J = 8.4 Hz, 2 H, Ar). 13C NMR (100 MHz, DMSO-d 6): δ = 11.20, 14.71, 27.91, 47.32, 60.93, 85.91, 85.98, 109.81, 114.53, 127.98, 129.84, 133.42, 134.86, 135.89, 138.57, 154.98, 162.85, 164.22. MS: m/z (%) = 408 (11) [M+], 352 (100), 323 (19), 307 (13). Anal. Calcd for C22H24N4O4: C, 64.69; H, 5.92; N, 13.71. Found: C, 64.71; H, 5.92; N, 13.69.
Preparation of Derivative 16. Compound 13b (426 mg, 1 mmol) was dissolved at 0 °C in a mixture of CH2Cl2-TFA (1:1, 8 mL) and maintained at the same temperature for 2.75 h. Then the solvent was removed under reduced pressure and the residue was treated with Et2O to obtain a yellow powder that was recrystallised from CHCl3-light PE to give pure derivative 16.
Analytical data of 16: mp 202-203 °C (dec.). IR (nujol): 3258, 2215, 1682, 1550 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.30 (t, J = 6.8 Hz, 3 H, OCH2CH 3), 2.45 (s, 3 H, CH3), 4.25 (q, J = 6.8 Hz, 2 H, OCH 2CH3), 4.31 (d, J = 8.8 Hz, 2 H, CH2), 6.37 (t, J = 8.8 Hz, 1 H, NH), 7.50-7.60 (m, 3 H, Ar), 8.07 (d, J = 8.4 Hz, 2 H, Ar). 13C NMR (100 MHz, DMSO-d 6): δ = 9.91, 14.12, 43.91, 59.89, 84.49, 108.47, 114.60, 127.18, 128.90, 131.99, 133.81, 134.86, 139.16, 162.85. MS: m/z (%) = 308 (82) [M+], 277 (100), 250 (42). Anal. Calcd for C17H16N4O4: C, 66.22; H, 5.23; N, 18.17. Found: C, 66.18; H, 5.26; N, 18.19.
Preparation of Derivative 17.
Compound 13b (426 mg, 1 mmol) was refluxed in dioxane (5 mL) in the presence of Amberlyst 15H (400 mg) for 8 h. The resin was removed by filtration and dioxane was evaporated under reduced pressure. The residue, treated with Et2O, furnished pure derivative 17 as red-orange crystals in a 78% yield, with analytical data as previously reported.