S. Kurhade et al. / Tetrahedron Letters 52 (2011) 1874–1877
1877
42.28, 82.75, 86.56, 114.79 (d, J = 23.1 Hz), 116.83 (d, J = 23.8 Hz), 123.72,
126.42 (d, J = 8.9 Hz), 132.20, 136.06 (d, J = 9.7 Hz), 138.89, 146.08, 148.26,
152.70, 159.30 (d, J = 243.2 Hz), 206.29 (2C). HPLC purity: 100%. LC–MS (m/z):
387.1 [M+1]. HRMS calcd for the [M+1]+: 387.1720, found: 387.1722.
11. Compound 7b: 2-[1-(2-Fluoro-phenoxy)-1-methyl-ethyl]-2-hydroxy-2,3-dihydro-
pyrrolo[2,3-b]pyridine-1-carboxylic acid, tert-butyl ester. Rf-value: 0.35 (30%
ethyl acetate in hexanes). Mp: 52–53 °C. 1H NMR (400 MHz; DMSO-d6;
assignment given for major rotamer): d 1.36 (s, 9H), 1.41 (s, 6H), 4.20 (s,
2H), 7.05–7.15 (aromatics, 3H), 7.21 (dd, J = 7.3, 4.9 Hz, 1H), 7.24–7.30
(aromatics, 1H), 7.61 (d, J = 7.3 Hz, 1H), 8.26 (d, J = 4.9 Hz, 1H), 9.11 (s, 1H).
13C NMR (100 MHz; CD3OD): d 24.18 (2C), 28.63 (3C), 40.24, 81.48, 87.79,
117.53, 117.74, 122.82, 125.56, 125.90 (d, J = 7.0 Hz), 127.95, 142.58, 143.28 (d,
J = 3.8 Hz), 147.79, 151.29, 155.60, 157.17 (d, J = 243.9 Hz), 210.21. HPLC
purity: 99%. LC–MS (m/z): 389.1 [M+1]. HRMS calcd for the [M+1]+: 389.1876,
found: 389.1876.
12. Compound 3d: 7-Azaindolo[2,1-c]-(6,8-difluoro-2,2-dimethyl)-[1,4]benzoxazine.
Rf-value: 0.7 (30% ethyl acetate in hexanes). Mp: 59–60 °C. 1H NMR (400 MHz;
CDCl3): d 1.75 (s, 6H), 6.37 (s, 1H), 6.71 (dt, J = 10.3, 3.0 Hz, 1H), 7.17 (dd, J = 7.7,
4.8 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 3.5 Hz, 1H), 8.74 (app. d,
J = 10 Hz, 1H). 13C NMR (100 MHz; CDCl3): d 27.04 (2C), 75.82, 96.02, 100.38
(dd, J = 27.1, 21.6 Hz), 101.89 (dd, J = 28.6, 3.0 Hz), 118.02, 122.17, 128.12 (dd,
J = 14, 5.4 Hz), 128.30, 129.46 (m, 1C), 139.15, 143.87, 147.84, 152.54 (dd,
J = 244.6, 13.9 Hz), 156.79 (dd, J = 238.5, 12.4 Hz). HPLC purity: 99%. LC–MS (m/
z): 287.2 [M+1]. Structure of 3d was further confirmed using single crystal X-
here:
Supplementary data
A complete list of analytical characterization data of 3a, 3d, 3f–l,
3n, 3o, 4a–i, 6a, 7a and 7b, and single crystal X-ray crystallo-
graphic data of 3d. Supplementary data associated with this article
References and notes
1. For reviews and conceptual articles on heterocycle and drug design, please see:
(a) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887–2893; (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930; (c) Andrews,
P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648–1657; (d) Broughton,
H. B.; Watson, I. A. J. Mol. Graphics Modell. 2005, 23, 51–58.
2. (a) Ilas, J.; Anderluh, P. S.; Dolenc, M. S.; Kikelj, D. Tetrahedron 2005, 61, 7325–
7348; (b) Bromidge, S. M.; Arban, R.; Bertani, B.; Bison, S., et al J. Med. Chem.
2010, 53, 5827–5843.
3. (a) Popowycz, F.; Routier, S.; Joesph, B.; Mérour, J.-Y. Tetrahedron 2007, 63,
1031–1064; (b) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120–1132.
4. Sánchez, I.; Pujol, M. D. Tetrahedron 1999, 55, 5593–5598.
5. (a) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.; Wright, S. H.
B. Synthesis 1996, 877–882; (b) Song, J. J.; Tan, Z.; Reeves, J. T.; Fandrick, D. R.;
Lee, H.; Yee, N. K.; Senanayake, C. H. Tetrahedron Lett. 2009, 50, 3952–3954; (c)
Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.; Yee, N. K.; Senanayake, C. H. J. Org. Chem.
2005, 70, 6512–6514.
6. In a typical synthesis, n-BuLi (1.6 M in hexane, 3.75 mL, 7.21 mmol, 2.5 equiv)
was added dropwise to a solution of (N-Boc)-2-aminopicoline 2a (500 mg,
2.40 mmol, 1 equiv) in 10 mL dry THF at À15 °C to generate the di-anion (dark
red appearance). After stirring for 30 min, 2-(2,4-difluorophenoxy)-N-methoxy-
N-methyl-2-methylpropionamide 1a (560 mg, 2.16 mmol, 0.9 equiv), dissolved
in 5 mL dry THF, was added to the reaction mixture followed by continuation of
stirring for 1.5 h (À15 °C to rt). The reaction mixture was concentrated to
remove THF; the resultant mass was then taken in dry dichloromethane (5 mL)
and was treated with 5 mL TFA at 0 °C. The reaction mixture was stirred at rt
for 30 min to de-protect the N-Boc group and promote cyclization and
elimination process. The resultant reaction mixture was concentrated and
neutralized with aq satd NaHCO3 solution. The organic mass was extracted
with ethyl acetate (20 mL Â 3). The combined organic layer was given a brine
wash (50 mL), dried over anhydrous sodium sulfate, and finally concentrated
on rotavapour to afford the crude product, which was then purified by silica-
gel column chromatography (60–120 mesh, eluents: hexanes to 30% ethyl
acetate in hexanes) to obtain analytically pure 3a (406 mg, 70%) along with
minor amount of 2-(propen-2-yl)-7-azaindole 4a (70 mg, 24%).
7. In addition to Ref. 5, the below literature was consulted to come up with the
typical procedure described here in Ref. 6: Caulkett, P. W. R.; Mckerrecher, D.;
Newcombe, N. J.; Pike, K. G.; Robb, G. R.; Waring, M. J. in PCT Publication No.
WO 2007/031739 A1.
13. Compound 3i: 7-Azaindolo[2,1-c]-(6-fluoro-2,2-spirocyclohexyl)-[1,4]benzoxazine.
Rf-value: 0.7 (30% ethyl acetate in hexanes). Semi-solid mass. 1H NMR
(400 MHz; CDCl3):
d 1.63–1.70 (m, 2H), 1.72–1.86 (m, 6H), 2.12–2.16
8. Compound 3a: 7-Azaindolo[2,1-c]-(6-fluoro-2,2-dimethyl)-1,4]benzoxazine. Rf-
value: 0.7 (30% ethyl acetate in hexanes). Semi-solid mass. 1H NMR (400 MHz;
CDCl3): d 1.70 (s, 6H), 6.34 (s, 1H), 6.80 (dt, J = 8.5, 3.0 Hz, 1H), 6.99 (dd, J = 8.8,
5.0 Hz, 1H), 7.15 (dd, J = 7.8, 4.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 8.39 (dd,
J = 4.8, 1.7 Hz, 1H), 8.89 (dd, J = 10, 3.2 Hz, 1H). 13C NMR (100 MHz; CDCl3): d
26.90 (2C), 74.61, 95.05, 106.23 (d, J = 29.4 Hz), 110.96 (d, J = 23.2 Hz), 117.49,
118.48 (d, J = 8.5 Hz), 122.02, 126.75 (d, J = 11.6 Hz), 128.89, 139.28, 140.30 (d,
J = 3.1 Hz), 143.40, 147.50, 157.78 (d, J = 237.70 Hz). HPLC purity: 99%. LC–MS
(m/z): 269.2 [M+1] base peak. HRMS calcd for the [M+1]+: 269.1090, found:
269.1086.
9. Compound 4a: 2-Isopropenyl-1H-pyrrolo[2,3-b]pyridine. Rf-value: 0.35 (30%
ethyl acetate in hexanes). Mp: 65–66.5 °C. 1H NMR (400 MHz, DMSO-d6): d
2.11 (s, 3H), 5.15 (s, 1H), 5.76 (s, 1H), 6.49 (d, J = 2.0 Hz, 1H) 7.01 (dd, J = 8.0,
5.2 Hz, 1H), 7.88 (dd, J = 7.6, 1.2 Hz, 1H), 8.18 (dd, J = 5.2, 1.6 Hz, 1H), 11.79 (br
s, 1H). 13C NMR (100 MHz; DMSO-d6): d 20.50, 99.03, 113.05, 116.07, 120.92,
128.36, 134.70, 139.69, 143.56, 149.96. HPLC purity: 99%. LC–MS (m/z): 159.1
[M+1] base peak.
(m, 1H), 2.16–2.21 (m, 1H), 6.33 (s, 1H), 6.80 (dt, J = 8.4, 2.9 Hz, 1H), 7.05
(dd, J = 8.8, 5.6 Hz, 1H), 7.15 (dd, J = 7.6, 4.8 Hz, 1H), 7.90 (dd, J = 8.0, 1.6 Hz,
1H), 8.39 (dd, J = 4.8, 1.4 Hz, 1H), 8.86 (dd, J = 10, 2.8 Hz, 1H). 13C NMR
(100 MHz; CDCl3):
d 21.08 (2C), 25.21, 34.28 (2C), 75.31, 94.95, 106.15
(d, J = 29.4 Hz), 110.70 (d, J = 23.0 Hz), 117.24, 118.28 (d, J = 8.6 Hz), 121.95,
127.02 (d, J = 12.4 Hz) 128.67, 139.69, 139.74, 143.17, 147.26, 157.65
(d, J = 236.8 Hz). HPLC purity: 99%. LC–MS (m/z): 309.2 [M+1]. HRMS calcd
for the [M+1]+: 309.1403, found: 309.1417.
14. Compound 4d. 2-Cyclohex-1-enyl-1H-pyrrolo[2,3-b]pyridine. Rf-value: 0.40 (30%
ethyl acetate in hexanes). Mp: 89–91 °C. 1H NMR (400 MHz; CDCl3): d 1.68–
1.76 (m, 2H), 1.78–1.84 (m, 2H), 2.28–2.34 (m, 2H), 2.45–2.52 (m, 2H), 6.37 (s,
1H), 6.37–6.41 (m, 1H), 7.02 (dd, J = 7.8, 4.8 Hz, 1H), 7.84 (dd, J = 7.8, 1.3 Hz,
1H), 8.20 (dd, J = 4.8, 1.3 Hz, 1H), 10.5 (br s, 1H). 13C NMR (100 MHz; CDCl3): d
22.17, 22.56, 25.71, 25.81, 96.25, 115.61, 122.11, 125.06, 128.16, 129.03,
141.12, 141.50, 149.42. HPLC purity: 98%. LC–MS (m/z): 199.0 [M+1]. HRMS
calcd for the [M+1]+: 199.1235, found: 199.1228.
15. Compound 3k. 6-Azaindolo[2,1-c]-(6-fluoro-2,2-dimethyl)-[1,4]benzoxazine. Rf-
value: 0.6 (30% ethyl acetate in hexanes). Mp: 91–92 °C. 1H NMR (400 MHz;
acetone-d6): d 1.72 (s, 6H), 6.68 (s, 1H), 7.00 (dt, J = 8.6, 2.7 Hz, 1H), 7.18 (dd,
J = 8.8, 5.4 Hz, 1H), 7.63 (d, J = 4.9 Hz, 1H), 7.91 (dd, J = 9.3, 2.9 Hz, 1H), 8.33 (d,
J = 4.9 Hz, 1H), 9.42 (s, 1H). 13C NMR (100 MHz; acetone-d6): d 26.01 (2C),
75.26, 97.30, 104.53 (d, J = 28.7 Hz), 111.24 (d, J = 22.4 Hz), 115.48, 119.71 (d,
J = 9.3 Hz), 127.13 (d, J = 10.8 Hz), 131.36, 133.89, 134.74, 140.62, 141.21 (d, J
=3.1 Hz), 143.07, 157.89 (d, J = 236.9 Hz). HPLC purity: 99%. LC–MS (m/z): 269.0
[M+1]. HRMS calcd for the [M+1]+: 269.1090, found: 269.1079.
10. Compound 6a. 11-Fluoro-7,7-dimethyl-6-oxo-6,7-dihydro-5H-8-oxa-1,13-diaza-
dibenzo[a,d]cyclononene-13-carboxylic acid, tert-butyl ester. Mp: 58–60 °C. Rf-
value: 0.4 (30% ethyl acetate in hexanes). 1H NMR (400 MHz; CDCl3): d 1.32 (s,
3H), 1.42 (s, 3H), 1.46 (s, 9H), 3.73 (br s, 1H), 4.25 (br s, 1H), 6.82–6.88
(aromatics, 3H), 7.22 (dd, J = 7.4, 4.9 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 8.35 (d,
J = 4.6 Hz, 1H). 1H NMR (400 MHz; DMSO-d6): d 1.38 (br s, 15H), 3.96 (br s, 1H),
4.10 (br s, 1H), 6.98 (dd, J = 8.8, 5.8 Hz, 1H), 7.05 (dt, J = 9.1, 3.2 Hz, 1H), 7.32
(dd, J = 9.3, 3.0 Hz, 1H), 7.30–7.38 (aromatics, 1H), 7.87 (d, J = 7.4 Hz, 1H), 8.26
(br. d, J = 2.0 Hz, 1H). 13C NMR (100 MHz; CDCl3): d 23.24, 26.49, 28.47 (3C),