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DOI: 10.1055/s-0030-1259678
Synthesis of 2,2-Disubstituted Azaindolines by Intramolecular Cyclization in Acidic Media
Publication History
Publication Date:
22 February 2011 (online)
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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
- 1
Walter H.Sundermann C. Heterocycles 1998, 48: 1581 - 2
Mérour J.-Y.Gadonneix P.Malapel-Andrieu P.Desarbre E. Tetrahedron 2001, 57: 1995 - 3
Ciganek E. J. Org. Chem. 1992, 57: 4251 - 4
Watanabe T.Oishi S.Fujii N.Ohno H. Org. Lett. 2008, 10: 1759 - 5
Parcerisa J.Romero M.Pujol MD. Tetrahedron 2008, 64: 500 - 6
Hands D.Bishop D.Cameron M.Edwards JS.Cottrell IF.Wright SHB. Synthesis 1996, 877 - 7
Spivey AC.Fekner T.Spey SE.Adams H. J. Org. Chem. 1999, 64: 9430 - 8
Sánchez I.Sobrino M.Pujol MD. Tetrahedron Lett. 2004, 45: 1737 -
9a
Yoshihiko I.Kazuhiro K.Takeo S. Chem. Lett. 1980, 1563 -
9b
Yoshihiko I.Kazuhiro K.Norihiko S.Masayuki M.Takeo S. Heterocycles 1980, 14: 106 - 10
Turner JA. J. Org. Chem. 1990, 55: 4744 - 11
Janiak C.Deblon S.Uehlin L. Synthesis 1999, 959 - 12
Billingsley KL.Anderson KW.Buchwald SL. Angew. Chem. Int. Ed. 2006, 45: 3484
References and Notes
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.