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d=8.07 (d, J=7.6 Hz, 2H), 7.44 (t, J=8.4 Hz, 2H), 7.37–7.31 (m,
4H), 7.24 (t, J=8 Hz, 2H), 7.07 (t, J=8 Hz, 2H), 4.45–4.34 (m, 2H),
4.32–4.25 (m, 1H), 3.92 (dd, J=14.4, 7.6 Hz, 1H), 3.76 (dd, J=14.4,
4.8 Hz, 1H), 2.91 ppm (s, 3H); 13C NMR (CDCl3, 100 MHz): d=140.7,
130.4, 130.3, 126.0, 123.1, 120.4, 119.5, 116.9, 116.6, 108.8, 69.1,
55.2, 37.4 ppm; ESI-MS: 413.1 [M+H], 435.1 [M+Na].
NaH (6 mg, 0.24 mmol, 2 equiv) and stirred at 08C for 30 min, fol-
lowed by 2-chloro-N-(2-chloro-6-cyanophenyl)acetamide (27.4 mg,
0.12 mmol) in DMF (1 mL). The reaction mixture was stirred at
808C for 6 h. After reaction completion, the mixture was purified
by preparative HPLC to give KL044 (22.1 mg, 51.4%). 1H NMR
(CD3CN, 400 MHz): d=8.5 (brs, 1H), 8.16 (d, J=7.6 Hz, 2H), 7.74
(dd, J=8, 1.2 Hz, 1H), 7.67 (dd, J=8, 1.6 Hz, 1H), 7.59 (d, J=8 Hz,
2H), 7.52 (t, J=8 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.29 (t, J=7.6 Hz,
2H), 5.25 ppm (s, 2H); 13C NMR (CD3CN, 400 MHz): d=168.3, 144.6,
137.2, 135.2, 133.6, 132.7, 129.8, 126.9, 121.0, 120.6, 116.4, 115.1,
110.0, 47.0 ppm; ESI-MS: 360.0 [M+H].
N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-N-(2-methylbenzyl)me-
thanesulfonamide (KL028). N-(2-Methylbenzyl)-N-(oxiran-2-ylme-
thyl)methanesulfonamide
(120 mg,
0.53 mmol),
carbazole
(133.6 mg, 0.8 mmol), NaH (26.4 mg, 1.1 mmol) were combined in
DMF (8 mL) to give 82 mg (36.4%) of KL028. 1H NMR (CDCl3,
400 MHz): d=8.07 (d, J=8.4 Hz, 2H), 7.47 (td, J=8.4, 1.2 Hz, 2H),
7.24–7.18 (m, 4H), 7.06–6.99 (m, 2H), 6.93 (d, J=7.2 Hz, 1H), 6.87–
6.83 (m, 1H), 4.45 (d, J=13.6 Hz, 1H), 4.19–4.04 (m, 3H), 3.86 (m,
1H), 3.45 (dd, J=15.2, 8.8 Hz, 1H), 3.15 (dd, J=18, 3.2 Hz, 1H), 2.94
(s, 3H), 2.21 ppm (s, 3H); 13C NMR (CDCl3, 100 MHz): d=140.5,
137.2, 132.5, 130.9, 129.5, 128.4, 126.1, 125.8, 123.0, 120.3, 119.3,
108.8, 69.0, 52.1, 51.4, 46.9, 37.1, 19.0 ppm; ESI-MS: 423.1 [M+H],
445.1 [M+Na].
2-(9H-Carbazol-9-yl)-N-(2-cyanophenyl)acetamide (KL046). Same
procedure as described for the synthesis of KL044. 2-Chloro-N-(2-
cyanophenyl)acetamide (20 mg, 0.1 mmol), NaH (10 mg, 0.4 mmol),
and carbazole (16.7 mg, 0.1 mmol) were combined in DMF (3 mL)
to give 22.4 mg (68.9%) of KL046. 1H NMR (CDCl3, 400 MHz): d=
8.21 (d, J=8.4 Hz, 1H), 8.16 (d, J=7.6 Hz, 2H), 7.73 (s, 1H), 7.56–
7.51 (m, 3H), 7.46–7.41 (m, 3H), 7.35 (t, J=8 Hz, 2H), 7.14 (t, J=
7.6 Hz, 1H), 5.13 ppm (s, 2H); 13C NMR (CDCl3, 100 MHz): d=166.9,
140.0, 138.9, 133.9, 132.3, 126.7, 125.8, 123.9, 122.0, 121.0, 120.3,
119.4, 110.6, 108.4, 47.6 ppm; ESI-MS: 326.1 [M+H], 348.1 [M+
Na].
N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-N-(2-(dimethylamino)e-
thyl)methanesulfonamide (KL032). N-(2-(Dimethylamino)ethyl)-N-
(oxiran-2-ylmethyl)methanesulfonamide (103 mg, 0.46 mmol), car-
bazole (153 mg, 0.92 mmol), and 60% NaH (47 mg, 1.15 mmol)
were combined in DMF (7 mL) to give 22 mg (12.3%) of KL032.
1H NMR (CDCl3, 400 MHz): d=8.05 (d, J=7.6 Hz, 2H), 7.50 (d, J=
8.0 Hz, 2H), 7.45 (t, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 2H), 4.45–4.34
(m, 3H), 3.70–3.65 (m, 1H), 3.53–3.46 (m, 1H), 3.42–3.28 (m, 2H),
3.24–3.11 (m, 2H), 2.78 (s, 3H), 2.74 ppm (m, 6H); ESI-MS: 390.2
[M+H].
2-(9H-Carbazol-9-yl)-N-(2-(trifluoromethyl)phenyl)acetamide
(KL048). Same procedure as described for the synthesis of KL044.
2-Chloro-N-(2-(trifluoromethyl)phenyl)acetamide
(40 mg,
0.17 mmol), 95% NaH (10 mg, 0.4 mmol), and carbazole (28.4 mg,
0.17 mmol) were combined in DMF (4 mL) to give 26.8 mg (42.8%)
1
of KL048. H NMR (CDCl3, 400 MHz): d=8.19 (d, J=8 Hz, 1H), 8.15
(d, J=7.6, 2H), 7.58 (s, 1H), 7.52 (t, J=8, 3H), 7.42 (d, J=8 Hz, 3H),
7.34 (t, J=8 Hz, 2H), 7.17 (m, 1H), 5.11 ppm (s, 2H); 13C NMR
(CDCl3, 100 MHz): d=167.0, 140.0, 132.8, 126.6, 125.0, 124.3, 123.7,
120.8, 120.7, 108.4, 47.6 ppm; ESI-MS: 369.1 [M+H], 391.1 [M+
Na].
N-(2-(N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)methylsulfonami-
do)ethyl)acetamide (KL033). N-(2-(N-(Oxiran-2-ylmethyl)methylsul-
fonamido)ethyl)acetamide (80 mg, 0.34 mmol), carbazole (114 mg,
0.68 mmol), and 60% NaH (34 mg, 0.85 mmol) were combined in
DMF (8 mL) to give 24 mg (17.5%) of KL033. 1H NMR (CDCl3,
400 MHz): d=8.06 (d, J=7.6 Hz, 2H), 7.5–7.43 (m, 4H), 7.28–7.20
(m, 2H), 6.33 (s, 1H), 4.48–4.38 (m, 1H), 4.3 (t, J=6 Hz, 2H), 3.45–
3.35 (m, 2H), 3.35–3.20 (m, 3H), 3.18–3.10 (m, 1H), 2.79 (s, 3H),
1.87 ppm (s, 3H); 13C NMR (CDCl3, 100 MHz): d=171.3, 140.8, 126.0,
123.0, 120.3, 119.4, 109.1, 69.6, 54.3, 49.4, 47.3, 38.7, 37.1,
23.1 ppm; ESI-MS: 404.2 [M+H], 426.1 [M+Na].
Acknowledgements
This research was supported by the U.S. National Institutes of
Health (grant R01GM074868 to S.A.K.).
Keywords: 3D-QSAR · circadian clock · cryptochrome · protein
degradation · small molecule
N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-N-(2-methoxyethyl)me-
thanesulfonamide (KL034). N-(2-Methoxyethyl)-N-(oxiran-2-ylme-
thyl)methanesulfonamide (100 mg, 0.48 mmol), carbazole (160 mg,
0.96 mmol), and NaH (43.2 mg, 1.08 mmol) were combined in DMF
1
(10 mL) to give 82 mg (43.2%) of KL034. H NMR (CDCl3, 400 MHz):
[3] a) E. J. Eide, M. F. Woolf, H. Kang, P. Woolf, W. Hurst, F. Camacho, E. L.
Reischl, B. Maier, T. Korte, A. Herrmann, H. Herzel, A. Schlosser, A.
d=8.09 (d, J=7.6 Hz, 2H), 7.49–7.46 (m, 4H), 7.27–7.22 (m, 2H),
4.43–4.32 (m, 3H), 3.83 (d, J=3.6 Hz, 1H), 3.5–3.47 (m, 2H), 3.45–
3.28 (m, 5H), 3.23 (s, 3H), 2.85 ppm (s, 3H); 13C NMR (CDCl3,
100 MHz): d=140.8, 125.9, 123.1, 120.3, 119.3, 109.1, 71.4, 69.8,
58.8, 53.9, 49.5, 37.7 ppm; ESI-MS: 377.1 [M+H], 399.1 [M+Na].
2-(9H-Carbazol-9-yl)-N-(2-chloro-6-cyanophenyl)acetamide
[4] a) L. Busino, F. Bassermann, A. Maiolica, C. Lee, P. M. Nolan, S. I. Godinho,
E. S. Maywood, L. Shaw, V. Tucci, A. R. Barnard, L. Busino, M. Pagano, R.
Kendall, M. M. Quwailid, M. R. Romero, J. O’Neil, J. E. Chesham, D. Brook-
c) S. M. Siepka, S. H. Yoo, J. Park, W. Song, V. Kumar, Y. Hu, C. Lee, J. K.
[5] W. Xing, L. Busino, T. R. Hinds, S. M. Marionni, N. H. Saifee, M. F. Bush, M.
[6] T. Hirota, J. W. Lee, P. C. St. John, M. Sawa, K. Iwaisko, T. Noguchi, P. Y.
Pongsawakul, T. Sonntag, D. Welsh, D. A. Brenner, F. J. Doyle III, P. G.
(KL044).
A solution of 2-amino-3-chlorobenzonitrile (50 mg,
0.33 mmol) in DMF (0.5 mL) was treated with chloroacetyl chloride
(44.8 mg, 0.4 mmol, 1.2 equiv) and TEA (50.5 mL, 0.4 mmol,
1.2 equiv). The reaction mixture was stirred at 408C for 6 h. The re-
action mixture was diluted with CH2Cl2 and washed with H2O. The
organic layer was dried under Na2SO4, filtered, and concentrated
under reduced pressure. The crude compound was purified by
flash column chromatography (EtOAc/hexane 1:3) to give 2-chloro-
N-(2-chloro-6-cyanophenyl)acetamide (54.0 mg, 71.8%). A solution
of carbazole (20 mg, 0.12 mmol) in DMF (1 mL) was treated with
ChemMedChem 2015, 10, 1489 – 1497
1496 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim