32
N. Primas et al. / European Journal of Medicinal Chemistry 83 (2014) 26e35
6), 7.36 (dd, J ¼ 5.6; 8.8 Hz, 1H, H-3), 6.98 (td, J ¼ 2.9; 7.8 Hz, 1H, H-
4), 6.78 (t, J ¼ 2.0 Hz, 2H, H-2 pyrrole), 6.43 (t, J ¼ 2.0 Hz, 2H, H-3
6.45 (t, J ¼ 2.1 Hz, 2H, H-3 pyrrole), 3.96 (s, 3H, CH3). 13C NMR
(50 MHz, CDCl3)
d
¼ 165.9, 159.4, 135.5, 131.8, 130.7, 127.5, 127.0,
pyrrole). 13C NMR (100 MHz, CDCl3)
d
¼ 162.4 (d, J ¼ 266.8 Hz),
112.5, 121.8, 111.8, 92.4, 52.7. HRMS (ESI): m/z [M þ H]þ calcd for
159.3, 134.1 (d, J ¼ 12.3 Hz), 128.6 (d, J ¼ 9.9 Hz), 127.5, 122.3, 112.5
(d, J ¼ 23.0 Hz), 111.5, 108. 1 (d, J ¼ 29.6 Hz), 92.3. HRMS (ESI): m/z
[M þ H]þ calcd for [C12H9N2OFCl3]þ: 320.9759; found: 320.9762.
[C14H12N2O3Cl3]þ: 360.9908; found: 360.9904.
4.1.8. Representative procedure for the preparation of 7-
substituted-4-(trichloromethyl)pyrrolo[1,2-a]quinoxaline (10aei)
A 100-mL round-bottomed flask equipped with a condenser, an
Ar inlet and a magnetic stir bar was charged with appropriated
2,2,2-trichloro-N-[5-substituted-2-(1H-pyrrol-1-yl)phenyl]acet-
amide (5.0 mmol), 15 mL of freshly distilled POCl3 and anhydrous
pyridine (1 mL). The mixture was refluxed until disappearance of
starting material (ca. 4 h). After the reaction mixture was cooled
with an ice bath, it was carefully poured over 200 mL of ice. The
mixture was made alkaline with concentrated ammonia to pH 10.
The alkaline aqueous phase was extracted three times with CH2Cl2.
The combined organic layers were washed with 10% hydrochloric
acid and then by water. Then the organic layer was dried with
anhydrous sodium sulphate and was concentrated under vacuum.
Purification by chromatography on silica gel (Petroleum Ether/
EtOAc) gave the expected 7-substituted-4-(trichloromethyl)pyrrolo
[1,2-a]quinoxaline.
4.1.7.3. 2,2,2-Trichloro-N-[5-chloro-2-(1H-pyrrol-1-yl)phenyl]acet-
amide (9c). Yield 63%. Yellow powder. Mp 98 ꢃC. 1H NMR (400 MHz,
CDCl3)
d
¼ 8.43 (d, J ¼ 2.2 Hz, 1H, H-6), 8.29 (bs, NH), 7.26 (d,
J ¼ 8.6 Hz, 1H, H-3), 7.20 (dd, J ¼ 2.2; 8.6 Hz, 1H, H-4), 6.73 (t,
J ¼ 1.7 Hz, 2H, H-2 pyrrole), 6.38 (t, J ¼ 1.7 Hz, 2H, H-3 pyrrole). 13
C
NMR (100 MHz, CDCl3)
d
¼ 159.3, 135.1, 133.4, 130.0, 128.2, 125.9,
122.1, 120.8, 111.6, 92.3. HRMS (ESI): m/z [MꢀH]ꢀ calcd for
[C12H7N2OCl4]ꢀ: 336.9289; found: 336.9288.
4.1.7.4. N-[5-bromo-2-(1H-pyrrol-1-yl)phenyl]-2,2,2-
trichloroacetamide (9d). Yield 63%. Beige powder. Mp 90 ꢃC. 1H
NMR (400 MHz, CDCl3)
d
¼ 8.57 (d, J ¼ 2.0 Hz, 1H, H-6), 8.29 (bs,
NH), 7.37 (dd, J ¼ 2.2; 8.6 Hz, 1H, H-3), 7.20 (d, J ¼ 8.6 Hz, 1H, H-4),
6.73 (t, J ¼ 1.7 Hz, 2H, H-2 pyrrole), 6.38 (t, J ¼ 1.7 Hz, 2H, H-3
pyrrole). 13C NMR (100 MHz, CDCl3)
d
¼ 159.3, 133.5, 130.6, 128.9,
128.5, 123.7, 122.8, 122.0, 111.7, 92.3. HRMS (ESI): m/z [M þ H]þ
calcd for [C12H9N2OBrCl3]þ: 382.8934; found: 382.8933.
4.1.8.1. 4-(Trichloromethyl)pyrrolo[1,2-a]quinoxaline
(10a).
Yield 57%. Beige powder. Mp 202 ꢃC. 1H NMR (400 MHz, CDCl3)
4.1.7.5. 2,2,2-Trichloro-N-[5-iodo-2-(1H-pyrrol-1-yl)phenyl]acet-
d
¼ 8.10 (dd, J ¼ 1.4; 8.3 Hz, 1H, H-6), 8.02 (dd, J ¼ 1.0; 2.7 Hz, 1H, H-
amide (9e). Yield 69%. Brown powder. Mp 90 ꢃC. 1H NMR (400 MHz,
1), 7.90 (dd, J ¼ 1.2; 8.3 Hz, 1H, H-9), 7.63 (dt, J ¼ 1.2; 8.3 Hz, 1H, H-
8), 7.50 (dt, J ¼ 0.7; 7.3 Hz, 1H, H-7), 7.40 (dd, J ¼ 0.7; 4.2 Hz, 1H, H-
3), 6.98 (dd, J ¼ 2.7; 4.2 Hz, 1H, H-2). 13C NMR (100 MHz, CDCl3)
CDCl3)
d
¼ 8.79 (d, J ¼ 1.7 Hz, 1H, H-6), 8.32 (bs, NH), 7.63 (dd,
J ¼ 1.9; 8.3 Hz, 1H, H-4), 7.10 (d, J ¼ 8.3 Hz, 1H, H-3), 6.79 (t,
J ¼ 1.9 Hz, 2H, H-2 pyrrole), 6.43 (t, J ¼ 1.9 Hz, 2H, H-3 pyrrole). 13
C
d
¼ 150.1, 133.5, 131.5, 130.0, 127.8, 125.8, 120.6, 115.2, 114.2, 113.8,
NMR (100 MHz, CDCl3)
d
¼ 159.3, 135.1, 133.3, 131.3, 129.5, 128.6,
110.4, 96.3. Anal. Calcd for C12H7Cl3N2: C, 50.47; H, 2.47; N, 9.81.
Found: C, 50.35; H, 2.37; N, 9.67.
122.0, 111.6, 93.8, 82.3. HRMS (ESI): m/z [M þ H]þ calcd for
[C12H9N2OICl3]þ: 428.8820; found: 428.8818.
4.1.8.2. 7-Fluoro-4-(trichloromethyl)pyrrolo[1,2-a]quinoxaline (10b).
4.1.7.6. 2,2,2-Trichloro-N-(5-methyl-2-(1H-pyrrol-1-yl)phenyl)acet-
Yield 56%. Yellow powder. Mp 192 ꢃC. 1H NMR (400 MHz, CDCl3)
amide (9f). Yield 46%. Amber oil. 1H NMR (200 MHz, CDCl3)
d
¼ 8.31
d
¼ 7.97 (dd, J ¼ 1.2; 2.7 Hz, 1H, H-1), 7.85 (dd, J ¼ 4.9; 9.0 Hz, 1H, H-
(bs, NH), 8.23 (s, 1H, H-6), 7.26 (d, J ¼ 8.0 Hz, 1H, H-3), 7.09 (d,
J ¼ 8.0 Hz, 1H, H-4), 6.79 (t, J ¼ 2.1 Hz, 2H, H-2 pyrrole), 6.41 (t,
J ¼ 2.1 Hz, 2H, H-3 pyrrole), 2.46 (s, 3H, CH3). 13C NMR (50 MHz,
6), 7.77 (dd, J ¼ 2.9; 9.0 Hz,1H, H-9), 7.41e7.34 (m, 2H, H-3 and H-8),
6.97 (dd, J ¼ 2.7; 4.1 Hz, 1H, H-2). 13C NMR (100 MHz, CDCl3)
d
¼ 160.0 (d, J ¼ 244.3 Hz), 151.1, 134.6 (d, J ¼ 11.5 Hz), 124.4, 120.4,
CDCl3)
d
¼ 159.2, 139.5, 132.0, 129.3, 126.9, 126.5, 122.2, 121.2, 110.9,
117.9 (d, J ¼ 23.9 Hz), 116.6 (d, J ¼ 23.0 Hz), 115.4, 115.0 (d,
J ¼ 9.1 Hz), 114.4, 110.7, 96.2. Anal. Calcd for C12H6Cl3FN2: C, 47.48;
H, 1.99; N, 9.23. Found: C, 47.81; H, 1.76; N, 9.10.
92.6, 21.6. HRMS (ESI): m/z [M þ H]þ calcd for [C13H11N2OCl3]þ:
317.0010; found: 317.0013.
4.1.7.7. 2,2,2-Trichloro-N-(5-methoxy-2-(1H-pyrrol-1-yl)phenyl)
4.1.8.3. 7-Chloro-4-(trichloromethyl)pyrrolo[1,2-a]quinoxaline (10c).
acetamide (9g). Yield 88%. Yellow powder. Mp 67 ꢃC. 1H NMR
Yield 52%. Yellow-green powder. Mp 132 ꢃC. 1H NMR (400 MHz,
(200 MHz, CDCl3)
d
¼ 8.29 (bs, NH), 8.04 (d, J ¼ 2.8 Hz,1H, H-6), 7.28
CDCl3)
d
¼ 8.09 (d, J ¼ 2.2 Hz, 1H, H-6), 7.97 (dd, J ¼ 1.2; 2.9 Hz, 1H,
(d, J ¼ 9.3 Hz, 1H, H-3), 6.79 (dd, J ¼ 2.2; 8.2 Hz, 1H, H-4), 6.76 (t,
H-1), 7.81 (d, J ¼ 8.8 Hz, 1H, H-9), 7.57 (dd, J ¼ 2.4; 8.8 Hz, 1H, H-8),
J ¼ 2.1 Hz, 2H, H-2 pyrrole), 6.40 (t, J ¼ 2.1 Hz, 2H, H-3 pyrrole), 3.88
7.41 (dd, J ¼ 1.0; 4.2 Hz, 1H, H-3), 6.98 (dd, J ¼ 2.7; 4.2 Hz, 1H, H-2).
(s, 3H, OCH3). 13C NMR (50 MHz, CDCl3)
d
¼ 159.9, 159.2, 133.5,
13C NMR (100 MHz, CDCl3)
d
¼ 151.1, 134.4, 131.0, 130.8, 130.0, 126.4,
128.0, 124.3, 122.4, 111.6, 110.8, 105.1, 92.4, 55.8. HRMS (ESI): m/z
[M þ H]þ calcd for [C13H12N2O2Cl3]þ: 332.9959; found: 332.9958.
120.5, 115.5, 115.0, 114.6, 110.9, 95.9. Anal. Calcd for C12H6Cl4N2: C,
45.04; H, 1.89; N, 8.75. Found: C, 45.44; H, 1.89; N, 8.75.
4.1.7.8. 2,2,2-Trichloro-N-(5-cyano-2-(1H-pyrrol-1-yl)phenyl)acet-
4.1.8.4. 7-Bromo-4-(trichloromethyl)pyrrolo[1,2-a]quinoxaline (10d).
amide (9h). Yield 77%. Yellow powder. Mp 129 ꢃC. 1H NMR
Yield 59%. Yellow-green powder. Mp 156 ꢃC. 1H NMR (400 MHz,
(200 MHz, CDCl3)
d
¼ 8.75 (d, J ¼ 1.6 Hz,1H, H-6), 8.54 (bs, NH), 7.59
CDCl3)
d
¼ 8.27 (d, J ¼ 2.2 Hz, 1H, H-6), 7.99 (dd, J ¼ 1.0; 2.7 Hz, 1H,
(dd, J ¼ 1.7; 8.2 Hz, 1H, H-4), 7.48 (d, J ¼ 8.1 Hz, 1H, H-3), 6.84 (t,
H-1), 7.77 (d, J ¼ 8.8 Hz, 1H, H-9), 7.72 (dd, J ¼ 2.2; 8.8 Hz, 1H, H-8),
7.41 (dd, J ¼ 1.0; 4.2 Hz, 1H, H-3), 6.99 (dd, J ¼ 2.7; 4.2 Hz, 1H, H-2).
J ¼ 2.1 Hz, 2H, H-2 pyrrole), 6.48 (t, J ¼ 2.1 Hz, 2H, H-3 pyrrole). 13
C
NMR (50 MHz, CDCl3)
d
¼ 159.5, 135.1, 132.8, 129.6, 127.9, 124.5,
13C NMR (100 MHz, CDCl3)
d
¼ 151.0,134.7,133.9,132.9,126.8,120.6,
121.7, 117.6, 112.8, 112.4, 92.1. HRMS (ESI): m/z [M þ H]þ calcd for
118.3, 115.5, 115.2, 114.7, 111.0, 95.9. Anal. Calcd for C12H6BrCl3N2: C,
39.55; H, 1.66; N, 7.69. Found: C, 39.39; H, 1.74; N, 7.61.
[C13H9N3OCl3]þ: 327.9806; found: 327.9802.
4.1.7.9. Methyl 4-(1H-pyrrol-1-yl)-3-(2,2,2-trichloroacetamido)ben-
4.1.8.5. 7-Iodo-4-(trichloromethyl)pyrrolo[1,2-a]quinoxaline (10e).
zoate (9i). Yield 77%. Amber oil. 1H NMR (200 MHz, CDCl3)
d
¼ 9.00
Yield 56%. Brown powder. Mp 170 ꢃC. 1H NMR (400 MHz, CDCl3)
(d, J ¼ 1.8 Hz, 1H, H-6), 8.46 (bs, NH), 7.98 (dd, J ¼ 1.8; 8.2 Hz, 1H, H-
d
¼ 8.45 (d, J ¼ 2.0 Hz, 1H, H-6), 7.97e7.95 (m, 1H, H-1), 7.87 (dd,
4), 7.44 (d, J ¼ 8.2 Hz, 1H, H-3), 6.85 (t, J ¼ 2.1 Hz, 2H, H-2 pyrrole),
J ¼ 1.7; 8.6 Hz, 1H, H-8), 7.62 (d, J ¼ 8.8 Hz, 1H, H-9), 7.40 (d,