PAPER
Direct Chlorination of Selected Aromatic Compounds Using NCS
1077
13C NMR (75 MHz, CDCl3): d = 51.3, 108.2, 110.4, 121.1, 124.1,
124.9, 125.2, 147.1, 152.7, 162.2.
HRMS (ESI): m/z [M + H]+ calcd for C5H6ClN2: 129.0214; found:
129.0214.
MS (EI, 70 eV): m/z (%) = 210 (33) [M+], 179 (58), 145 (25), 83
(92), 57 (100).
3-Chloro-4-hydroxypyridine (3c)
To a soln of 4-hydroxypyridine (0.95 g, 10 mmol) in MeCN (15
mL) at 25 °C, a soln of NCS (1.34 g, 10 mmol) in MeCN (15 mL)
was added. The solution was heated to 75 °C and stirred for 1 h. The
mixture was concentrated and the reaction was quenched with H2O
(10 mL); the aqueous phase was extracted with EtOAc (3 × 30 mL).
The combined organic phase was washed successively with H2O
(10 mL) and brine (10 mL), dried overnight (Na2SO4), filtered and
concentrated. The residue was recrystallized (EtOH) to afford an
off-white solid; yield: 1.08 g (83%); mp 200–204 °C (Lit.21 204–
205 °C); HPLC purity >99%.
3-Chloro-9H-carbazole (2)
To a soln of 9H-carbazole (0.17 g, 1 mmol) in DMF (5 mL) at
25 °C, a soln of NCS (0.13 g, 1 mmol) in DMF (5 mL) was added.
The solution was heated to 75 °C and stirred for 1 h. The mixture
was concentrated and the reaction was quenched with H2O (10 mL);
the aqueous phase was extracted with EtOAc (3 × 10 mL). The
combined organic phase was washed successively with H2O (10
mL) and brine (10 mL), dried overnight (Na2SO4), filtered and con-
centrated. The residue was recrystallized (petroleum ether–EtOAc)
to afford a white solid; yield: 0.13 g (65%); mp 194–195 °C (Lit.18
191–192 °C); HPLC purity >97%.
IR (KBr): 3012, 2815, 1628, 1520, 1140, 830, 684, 583 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.28 (d, J = 6.4 Hz, 1 H, ArH),
7.70 (d, J = 6.6 Hz, 1 H, ArH), 8.11 (s, 1 H, ArH), 11.87 (br s, 1 H,
OH).
13C NMR (75 MHz, DMSO-d6): d = 115.8, 122.8, 136.8, 137.6,
171.7.
IR (KBr): 3405, 1469, 1271, 1068, 813, 747, 726 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.17–7.20 (m, 1 H, ArH),
7.39–7.44 (m, 2 H, ArH), 7.48 (d, J = 8.4 Hz, 2 H, ArH), 8.15–8.22
(m, 2 H, ArH).
13C NMR (75 MHz, DMSO-d6): d = 111.1, 112.3, 118.8, 119.7,
120.0, 121.5, 122.7, 123.6, 125.4, 126.2, 138.0, 140.2.
HRMS (ESI): m/z [M + H]+ calcd for C5H5ClNO: 130.0054; found:
130.0056.
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN: 202.0418; found:
202.0415.
4-Chloro-3-methoxyaniline Hydrochloride (4a)
To a soln of 3-methoxyaniline (1.23 g, 10 mmol) in MeCN (15 mL)
at 25 °C, a soln of NCS (1.34 g, 10 mmol) in MeCN (15 mL) was
added. The solution was heated to 75 °C and stirred for 1 h. The
mixture was concentrated and the reaction was quenched with H2O
(10 mL); the aqueous phase was extracted with EtOAc (3 × 30 mL).
The combined organic phase was washed successively with H2O
(10 mL) and brine (10 mL), dried overnight (Na2SO4), filtered and
concentrated to about 10 mL. To the solution was added HCl-sat.
EtOAc (25 mL) and the precipitate was collected by filtration, re-
crystallized (EtOH) and dried under reduced pressure to afford a
pink solid; yield: 1.76 g (90%); mp 262–264 °C (Lit.22 265–
266 °C); HPLC purity >97%.
5-Chloro-2-hydroxypyridine (3a)
To a soln of 2-hydroxypyridine (0.95 g, 10 mmol) in MeCN (15
mL) at 25 °C, a soln of NCS (1.34 g, 10 mmol) in MeCN (15 mL)
was added. The solution was heated to 75 °C and stirred for 1 h. The
mixture was concentrated and the reaction was quenched with H2O
(10 mL); the aqueous phase was extracted with EtOAc (3 × 30 mL).
The combined organic phase was washed successively with H2O
(10 mL) and brine (10 mL), dried overnight (Na2SO4), filtered and
concentrated. The residue was recrystallized (MeCN) to afford an
off-white solid; yield: 1.17 g (90%); mp 158–162 °C (Lit.19 159–
161 °C); HPLC purity >97%.
IR (KBr): 2914, 2599, 1523, 1492, 1315, 1286, 1067, 833, 800, 730
cm–1.
1H NMR (300 MHz, CDCl3): d = 3.85 (s, 3 H, OCH3), 6.88–6.92
(dd, J = 8.4, 2.1 Hz, 1 H, ArH), 7.09 (d, J = 2.1 Hz, 1 H, ArH), 7.47
(d, J = 8.4 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 56.2, 107.5, 115.6, 119.7, 130.5,
132.8, 154.8.
IR (KBr): 3028, 2781, 1711, 1678, 1607, 1186, 675, 632 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.40 (d, J = 9.5 Hz, 1 H, ArH),
7.47–7.51 (dd, J = 9.5, 2.8 Hz, 1 H, ArH), 7.63 (d, J = 2.8 Hz, 1 H,
ArH).
13C NMR (75 MHz, DMSO-d6): d = 112.2, 119.4, 135.4, 140.9,
161.2.
HRMS (ESI): m/z [M + H]+ calcd for C5H5ClNO: 130.0054; found:
130.0056.
HRMS (ESI): m/z [M + H]+ calcd for C7H9ClNO: 158.0367; found:
158.0362.
2-Amino-5-chloropyridine (3b)
2-Chloro-3-nitroaniline (4b)
To a soln of 2-aminopyridine (0.94 g, 10 mmol) in MeCN (15 mL)
at 25 °C, a soln of NCS (1.34 g, 10 mmol) in MeCN (15 mL) was
added. The solution was heated to 75 °C and stirred for 1 h. The
mixture was concentrated and the reaction was quenched with H2O
(10 mL); the aqueous phase was extracted with EtOAc (3 × 30 mL).
The combined organic phase was washed successively with H2O
(10 mL) and brine (10 mL), dried overnight (Na2SO4), filtered and
concentrated. The residue was recrystallized (petroleum ether–
EtOAc) to afford an off-white solid; yield: 1.13 g (88%); mp 136–
137 °C (Lit.20 136–138 °C); HPLC purity >99%.
To a soln of 3-nitroaniline (1.38 g, 10 mmol) in DMF (15 mL) at
25 °C, a soln of NCS (1.34 g, 10 mmol) in DMF (15 mL) was added.
The solution was heated to 75 °C and stirred for 1 h. The mixture
was concentrated and the reaction was quenched with H2O (10 mL);
the aqueous phase was extracted with EtOAc (3 × 30 mL). The
combined organic phase was washed successively with H2O (10
mL) and brine (10 mL), dried overnight (Na2SO4), filtered and con-
centrated. The residue was purified by flash chromatography on sil-
ica gel (petroleum ether–EtOAc) to afford a yellow solid; yield:
1.33 g (77%); mp (free base) 94–95 °C (Lit.23 96–97 °C); HPLC
purity >98%.
IR (KBr): 3299, 1626, 1595, 1485, 1111, 827, 669, 517 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.43 (br s, 2 H, NH2), 6.43–6.57
(d, J = 8.2 Hz, 1 H, ArH), 7.35–7.38 (d, J = 8.2 Hz, 1 H, ArH), 8.01
(s, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 108.9, 120.3, 137.0, 145.8, 156.3.
IR (KBr): 3204, 1628, 1526, 1352, 1319, 822, 789, 736 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.40 (br s, 2 H, NH2), 6.77–6.96
(m, 1 H, ArH), 7.13–7.19 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 110.4, 114.1, 118.5, 127.3, 145.0,
149.1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1074–1078