Synthesis of 2,2-Disubstituted
Azaindolines by Intramolecular Cyclization in Acidic Media

Thomas-Xavier Métro; Christine Fayet; Florian Arnaud; Nathalie Rameix; Pierre Fraisse; Simon Janody; Mireille Sevrin; Pascal George; Rachel Vogel

doi:10.1055/s-0030-1259678

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Synlett 2011(5): 684-688
DOI: 10.1055/s-0030-1259678

LETTER

Synthesis of 2,2-Disubstituted Azaindolines by Intramolecular Cyclization in Acidic Media

Thomas-Xavier Métro*, Christine Fayet, Florian Arnaud, Nathalie Rameix, Pierre Fraisse, Simon Janody, Mireille Sevrin, Pascal George, Rachel Vogel*
sanofi-aventis, Exploratory Unit, 371, Rue du Professeur Joseph Blayac, 34184 Montpellier, France
Fax: +33(4)99776912; e-Mail: thomasmetro@yahoo.fr; e-Mail: rachel.vogel@sanofi-aventis.com;

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Publication History

Received 10 August 2010
Publication Date:
22 February 2011 (online)

Abstract
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Abstract

The synthesis of a diverse array of 2,2-disubstituted azaindolines is reported. The bicyclic core is built by a simple acidic treatment of conveniently substituted aminopyridines.

Key words

azaindolines - cyclization - nucleophilic addition - spiro compounds - pyridines

References and Notes

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13

Representative Procedures for the Synthesis of 4-(2-Hydroxyethyl)-3-pivaloylaminopyridines of Type 1Compound 1a To a solution of pyridine 5 (960 mg, 4.9 mmol, 1.0 equiv) in anhyd THF (10 mL) at -78 ˚C was added n-BuLi (2.5 M in hexanes, 4.3 mL, 10.8 mmol, 2.2 equiv), and the solution was stirred at 0 ˚C for 1 h. After addition at -78 ˚C of acetone (547 µL, 7.4 mmol, 1.5 equiv), the mixture was stirred for 1 h at -78 ˚C then overnight at r.t. The reaction medium was quenched by addition of H₂O (10 mL), the aqueous phase was extracted with EtOAc, and the combined organic extract was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Flash column chromatography on silica gel (cyclohexane-EtOAc, 20:80) afforded 1a as a yellow solid (430 mg, 35%); mp 159-161 ˚C. IR (neat): 3380, 3278, 2972, 2933, 2870, 1652, 1564, 1521, 1469, 1411, 1379, 1365, 1179, 1113, 914, 779, 722 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 9.87 (s, 1 H), 8.82 (s, 1 H), 8.22 (d, J = 4.9 Hz, 1 H), 7.22 (d, J = 4.9 Hz, 1 H), 5.64 (s, 1 H), 2.71 (s, 2 H), 1.25 (s, 9 H), 1.19 (s, 6 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.3, 145.5, 144.4, 139.3, 134.6, 126.9, 71.5, 44.5, 29.5, 27.5. ESI-MS: m/z = 251 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₄H₂₃N₂O₂ [M + H⁺]: 251.1752; found: 251.1760.
Compound 1b
Off-white powder; mp 179-181 ˚C. IR (neat): 3350, 3060, 2970, 1675, 1566, 1520, 1478, 1416, 1310, 1207, 1064, 751, 698 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 9.91 (s, 1 H), 8.80 (s, 1 H), 8.10 (d, J = 4.9 Hz, 1 H), 7.48 (dd, J = 7.5, 1.4 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.23 (dd, J = 7.5, 1.4 Hz, 1 H), 6.99 (d, J = 4.9 Hz, 1 H), 6.36 (s, 1 H), 2.94 (d, J = 13.3 Hz, 2 H), 1.49 (s, 3 H), 1.29 (s, 9 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.3, 148.3, 145.4, 144.3, 138.6, 134.6, 128.0, 126.9, 126.6, 124.9, 75.5, 45.8, 28.5, 27.5. ESI-MS: m/z = 313 [M + H]⁺. Anal Calcd for C₁₉H₂₄N₂O₂: C, 73.05; H, 7.74; N, 8.97. Found: C, 72.76; H, 8.02; N, 9.05.
Compound 1j
White powder; mp 246-248 ˚C. IR (neat): 3269, 2916, 2862, 1671, 1515, 1417, 1326, 1168, 1055, 928, 699, 667 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 9.77 (s, 1 H), 8.79 (s, 1 H), 8.20 (d, J = 4.9 Hz, 1 H), 7.27 (d, J = 4.9 Hz, 1 H), 5.23 (s, 1 H), 2.93 (s, 2 H), 2.16 (d, J = 12.6 Hz, 2 H), 2.07 (d, J = 12.6 Hz, 2 H), 1.85 (s, 1 H), 1.72 (s, 2 H), 1.69 (s, 1 H), 1.65 (s, 2 H), 1.60 (s, 2 H), 1.45 (d, J = 12.6 Hz, 2 H), 1.25 (s, 9 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.4, 145.6, 144.3, 139.1, 135.0, 126.3, 76.6, 38.1, 36.6, 34.2, 32.3, 27.5, 27.0, 26.8. ESI-MS: m/z = 343 [M + H]⁺. Anal Calcd for C₂₁H₃₀N₂O₂: C, 73.65; H, 8.83; N, 8.18. Found: C, 73.40; H, 9.00; N, 7.99. Representative Procedures for the Synthesis of 2,2-Disubstituted Azaindoline of Type 4Compound 4a
A solution of 1a (215 mg, 0.86 mmol) in 2 M HCl (8.6 mL) was heated at reflux for 96 h. After cooling to r.t., aq NaOH was added until pH 10. The crude was extracted with EtOAc. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Flash column chromatography on silica gel (n-heptane-EtOAc) afforded 4a as a brown solid (90 mg, 71%); mp 49-51 ˚C.
IR (neat): 3199, 2958, 1604, 1496, 1445, 1363, 1258, 1227, 1176, 1038, 817, 725 cm^-¹. ^¹H NMR (250 MHz, DMSO-d ₆): δ = 7.75 (d, J = 4.6 Hz, 1 H), 7.73 (s, 1 H), 7.01 (d, J = 4.6 Hz, 1 H), 5.69 (br s, 1 H), 2.74 (d, J = 0.9 Hz, 2 H), 1.22 (s, 6 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 147.7, 138.2, 136.2, 129.3, 120.0, 60.8, 43.0, 28.6. ESI-MS: m/z = 149
[M + H]⁺. Anal Calcd for C₉H₁₂N₂: C, 72.94; H, 8.16; N, 18.90. Found: C, 72.62; H, 8.19; N, 18.89.
Compound 4b
A solution of 1b (200 mg, 0.64 mmol) in 2 M HCl (6.4 mL) was heated at reflux for 18 h. After cooling to r.t., aq NaOH was added until pH 10. The crude was extracted with Et₂O, and the combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 4b as a white powder (109 mg, 81%); mp >118 ˚C (dec.).
IR (neat): 3164, 2963, 1603, 1491, 1441, 1276, 1170, 1080, 1037, 824, 763, 696 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 7.86 (s, 1H), 7.80 (d, J = 4.5 Hz, 1H), 7.47 (dd, J = 7.5, 1.3 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.22 (dd, J = 7.5, 1.3 Hz, 1H), 7.04 (d, J = 4.5 Hz, 1H), 6.43 (s, 1H), 3.22 (d, J = 16.6 Hz, 1H), 3.05 (d, J = 16.6 Hz, 1H), 1.51 (s, 3H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 148.5, 147.8, 138.6, 136.0, 129.4, 128.3, 126.4, 125.3, 120.2, 66.5, 44.7, 29.4. ESI-MS: m/z = 211 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₄H₁₅N₂ [M + H⁺]: 211.1238; found: 211.1235.
Compound 4j
A solution of 1j (1.0 g, 2.92 mmol) in 2 M HCl (25 mL) was heated at reflux for 18 h. After cooling to r.t., aq NaOH was added until pH = 10. The crude was extracted with EtOAc. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Flash column chromatography on silica gel (CH₂Cl₂-MeOH) afforded 4j as an off-white powder (456 mg, 65%); mp 234-236 ˚C.
IR (neat): 3252, 2885, 2856, 1603, 1498, 1460, 1449, 1254, 1099, 1036, 816, 721 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 7.77 (s, 1 H), 7.71 (d, J = 4.4 Hz, 1 H), 6.98 (d, J = 4.4 Hz, 1 H), 6.27 (s, 1 H), 2.93 (s, 2 H) 2.08 (d, J = 12.6 Hz, 2 H), 1.88-1.80 (4 H), 1.71-1.58 (8 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 147.4, 137.8, 135.8, 128.9, 119.8, 68.2, 37.7, 37.0, 34.1, 32.9, 26.5, 26.4. ESI-MS: m/z = 241 [M + H]⁺. Anal. Calcd for C₁₆H₂₀N₂: C, 79.96; H, 8.39; N, 11.66. Found: C, 79.56; H, 8.62; N, 11.73.