The Journal of Organic Chemistry
Note
(CH), 117.8 (CH), 119.5 (CH), 121.6 (CH), 127.4 (C), 132.5 (C),
136.2 (C); HRMS (ESI−, m/z) calcd for (C12H11N4)− (M − H)−
211.0989, found 211.0947; Analytical separation (HPLC) Chiralpak
OD n-hexane/2-propanol (80:20), 0.8 mL/min, 30 °C, tR (S) = 15.9
min, tR (R) = 18.9 min.
Enzymatic Kinetic Resolution of 2,3,4,9-Tetrahydro-1H-
carbazol-3-amine (11). To a suspension of racemic amine (11, 19
mg, 0.19 mmol) and CAL-B (19 mg) in dry THF (1.9 mL), the
corresponding methoxyacetyl ester (0.50 mmol) was added under a
nitrogen atmosphere. The reaction was shaken at the corresponding
temperature and 250 rpm, and regular aliquots (15 μL) were regularly
taken. The aliquots were dissolved in CH2Cl2 (0.5 mL), and K2CO3
(20 mg) and benzyl chloroformate (1 drop) were successively added.
The suspension was shaken at rt for 5 min and dried over Na2SO4, and
the solvent removed with a nitrogen flow. The crude was redissolved
in hexane/2-propanol 90:10 (1 mL), filtered, and injected in the
HPLC for ee measurement.
Synthesis of (R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine
(11). A solution of PPh3 (440 mg, 1.68 mmol) in dry THF (4.6
mL) was cooled to −15 °C under a nitrogen atmosphere.
Diethylazodicarboxylate (DEAD, 134 μL, 0.84 mmol) was added to
the reaction dropwise, and the reaction was stirred at −15 °C for 30
min. Then, the reaction was cooled to −20 °C, and the alcohol (S)-6
(110 mg, 0.60 mmol) was added to the reaction mixture, which was
stirred for additional 30 min. After this time, the reaction was cooled
to −25 °C, and DPPA (196 μL, 0.90 mmol) added dropwise. The
mixture was stirred between −25 °C and −15 °C until complete
disappearance of the starting material (10 h). Next, additional PPh3
(221 mg, 0.90 mmol) and H2O (16 μL, 0.90 mmol) were added, and
the reaction stirred at 65 °C for 15 h. The solvent was removed under
reduced pressure, and the crude purified by flash chromatography
(100% MeOH−3% NH3/MeOH) affording 73 mg of (R)-11 as a
white solid (67%): Rf (1% NH3/MeOH) 0.20; mp 174−176 °C (lit.
176−177).24 IR (KBr) ν 3396, 2920, 1640, 1595, 1153 cm−1; 1H NMR
(CD3OD, 300.13 MHz) δ 1.68−1.81 (m, 1H), 2.07−2.11 (m, 1H),
2.37−2.45 (m, 1H), 2.77−2.83 (m, 2H), 2.95−3.05 (m, 1H), 3.12−
Synthesis of (R)-4-Fluoro-N-(2,3,4,9-tetrahydro-1H-carbazol-
3-yl)benzenesulfonamide (16). To a solution of (R)-11 (73 mg,
0.40 mmol) in CH2Cl2 (4 mL), Et3N (65 μL, 0.48 mmol) and 4-
fluorobenzenesulfonyl chloride (15, 91 mg, 0.48 mmol) were
successively added. The solution was stirred at rt for 1 h, and then
the solvent removed by distillation at reduced pressure. The reaction
crude was purified by flash chromatography (30% EtOAc/hexane),
affording 126 mg of (R)-16 as a white solid (91%): Rf (30% EtOAc/
hexane) 0.15; mp 138−140 °C; IR (KBr) ν 3396, 3286, 2931, 1735,
1
1592, 1494, 1241, 1154 cm−1; H NMR (CDCl3, 300.13 MHz) δ
1.96−2.03 (m, 2H), 2.49−2.54 (m, 1H), 2.72−2.92 (m, 3H), 3.75−
3
3.83 (m, 1H), 4.96 (d, JHH = 6.1 Hz, 1H), 7.06−7.18 (m, 4H), 7.27
3
3
3
(d, JHH = 6.1 Hz, 1H), 7.32 (d, JHH = 5.9 Hz, 1H), 7.79 (br s, 1H),
7.87−7.90 (m, 2H); 13C NMR (CDCl3, 75.5 MHz) 20.2 (CH2), 28.5
(CH2), 29.1 (CH2), 49.5 (CH), 106.5 (C), 110.6 (CH), 116.3 (d,
2JCF= 16.6 Hz, 2CH), 117.6 (CH), 119.5 (CH), 121.7 (CH), 127.3
3.20 (m, 1H), 6.94−7.05 (m, 2H), 7.24 (d, JHH = 7.9 Hz, 1H), 7.35
(d, 3JHH = 7.9 Hz, 1H); 13C NMR (CD3OD, 75.5 MHz) δ 22.6 (CH2),
31.3 (CH2), 33.1 (CH2), 49.3 (CH), 108.2 (C), 111.5 (CH), 118.1
(CH), 119.3 (CH), 121.5 (CH), 129.0 (C), 134.4 (C), 138.1 (C);
HRMS (ESI+, m/z) calcd for (C12H15N2)+ (M + H)+ 187.1230, found
187.1221; [α]D20= +62.8 (c 2.0, MeOH) for 99% ee.
3
(C), 129.7 (d, JCF= 6.8 Hz, 2CH), 132.5 (C), 136.1 (C), 137.1 (C),
1
165.0 (d, JCF= 191.0 Hz, C); HRMS (ESI−, m/z) calcd for
20
(C18H16FN2O2S)− (M − H)− 343.0922, found 343.0911; [α]D
=
Synthesis of ( )-2-Methoxy-N-(2,3,4,9-tetrahydro-1H-carba-
zol-3-yl)acetamide (13). To a solution of the racemic amine 11 (25
mg, 0.13 mmol) in dry CH2Cl2 (1 mL), Et3N (22 μL, 0.16 mmol), and
methoxyacetyl chloride (15 μL, 0.16 mmol) were successively added
under a nitrogen atmosphere, and the solution stirred for 1 h. After
this time, the solvent was removed under reduced pressure, and the
crude purified under flash chromatography (100% EtOAc), affording
23 mg of the racemic amide 13 as a white solid (68%): Rf (100%
EtOAc) 0.24; mp 168−170 °C; IR (KBr) ν 3384, 2948, 2840, 1647,
+43.3 (c 0.25, CHCl3) for 99% ee [lit. [α]D20= −35.2 (c 0.25, CHCl3)
for (S)-16 in 86% ee];12 Analytical separation (HPLC) Chiralpak IC n-
hexane/2-propanol (80:20), 0.8 mL/min, 20 °C, tR (S) = 12.5 min, tR
(R) = 13.6 min.
Synthesis of (R)-N-[9-(2-Cyanoethyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-4-fluorobenzenesulfonamide (17). To a solution
of (R)-16 (58 mg, 0.17 mmol) in dry DMF (2 mL) was added dry
NaH (4.5 mg, 0.19 mmol), and the solution was stirred for 5 min at rt.
After this time, acrylonitrile (22 μL, 0.34 mmol) was added to the
reaction vessel, and the reaction stirred until disappearance of the
starting material (1 h). Then, the reaction was quenched with EtOAc
(10 mL) and extracted with H2O (3 × 10 mL). The organic phase was
dried over Na2SO4, the solvent removed under reduced pressure, and
the crude purified by flash chromatography (40% EtOAc/hexane)
affording 45 mg of (R)-17 as a colorless viscous oil (67%): Rf (40%
EtOAc/hexane) 0.26; IR (NaCl) ν 3277, 2926, 2251, 1592, 1494,
1466, 1359, 1153 cm−1; 1H NMR (CDCl3, 300.13 MHz) δ 1.96−2.10
(m, 2H), 2.52−2.59 (m, 1H), 2.72−2.90 (m, 5H), 3.75−3.91 (m, 1H),
1
1423, 1103 cm−1; H NMR (CDCl3, 300.13 MHz) δ 1.96−2.17 (m,
2H), 2.63−2.71 (m, 1H), 2.82−2.92 (m, 2H), 3.10−3.17 (m, 1H),
3.41 (s, 3H), 3.93 (s, 2H), 4.43−4.54 (m, 1H), 6.69 (br s, 1H), 7.09−
3
3
7.19 (m, 2H), 7.31 (d, JHH = 7.4 Hz, 1H), 7.50 (d, JHH = 7.0 Hz,
1H), 8.00 (br s, 1H); 13C NMR (CDCl3, 75.5 MHz) 21.1 (CH2), 28.1
(CH2), 28.7 (CH2), 45.1 (CH3), 59.5 (CH), 72.5 (CH2), 107.7 (C),
111.0 (CH), 118.1 (CH), 119.7 (CH), 121.8 (CH), 128.0 (C), 133.2
(C), 136.6 (C), 169.6 (C); HRMS (ESI+, m/z) calcd for
(C15H18N2NaO2)+ (M + Na)+ 281.1260, found 281.1265; Analytical
separation (HPLC) Chiralpak IA n-hexane/2-propanol (80:20), 0.8
mL/min, 40 °C, tR (S) = 9.4 min, tR (R) = 18.7 min.
3
3
4.32 (t, JHH = 6.6 Hz, 2H), 5.10 (d, JHH = 8.3 Hz, 1H), 7.09−7.22
(m, 5H), 7.33 (d, 3JHH = 7.7 Hz, 1H), 7.86−7.89 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz) δ 19.0 (CH2), 19.4 (CH2), 28.8 (CH2), 29.2
(CH2), 39.1 (CH2), 49.5 (CH), 107.6 (C), 108.8 (CH), 116.8 (d,
2JCF= 21.9 Hz, 2CH), 117.8 (C), 118.6 (CH), 120.3 (CH), 122.3
(CH), 127.9 (C), 130.0 (d, 3JCF= 9.1 Hz, 2CH), 133.6 (C), 136.3 (C),
Synthesis of ( )-Benzyl 2,3,4,9-tetrahydro-1H-carbazol-3-
ylcarbamate (14). To a solution of the racemic amine (11, 25 mg,
0.13 mmol) in dry CH2Cl2 (1 mL), Et3N (22 μL, 0.16 mmol) and
benzyl chloroformate (23 μL, 0.16 mmol) were successively added
under a nitrogen atmosphere. The solution was stirred for 2 h at rt,
then the solvent removed by distillation under reduced pressure, and
the crude purified by flash chromatography (30% EtOAc/hexane),
affording 28 mg of the carbamate 14 as a white solid (67%): Rf (30%
EtOAc/hexane) 0.20; mp 157−159 °C; IR (KBr) ν 3357, 3307, 3051,
137.6 (C), 165,4 (d, 1JCF= 255.1 Hz, C); HRMS (ESI+, m/z) calcd for
20
(C21H21FN3O2S)+ (M + H)+ 398.1333, found 398.1314; [α]D
=
+38.0 (c 1.7, CH2Cl2) for 99% ee; Analytical separation (HPLC)
Chiralcel OJ-H n-hexane/2-propanol (65:35), 0.8 mL/min, 40 °C, tR
(S) = 32.6 min, tR (R) = 37.9 min.
1
1666, 1545, 1453, 1265 cm−1; H NMR (DMSO-d6, 300.13 MHz) δ
1.71−1.84 (m, 1H), 1.99−2.07 (m, 1H), 2.51−2.72 (m, 1H), 2.75−
2.85 (m, 2H), 2.91−2.98 (m, 1H), 3.72−3.91 (m, 1H), 5.06 (s, 2H),
6.89−7.01 (m, 2H), 7.22−7.46 (m, 7H), 10.60 (s, 1H); 13C NMR
(DMSO-d6, 75.5 MHz) 22.3 (CH2), 28.4 (CH2), 30.0 (CH2), 48.3
(CH), 66.0 (CH2), 107.3 (C), 111.4 (CH), 117.9 (CH), 118.9 (CH),
121.1 (CH), 128.0 (C), 128.6 (2CH), 129.2 (3CH), 134.3 (C), 137.0
(C), 138.1 (C), 156.5 (C); HRMS (ESI+, m/z) calcd for
(C20H20N2NaO2)+ (M + Na)+ 343.1417, found 343.1420; Analytical
separation (HPLC) Chiralpak IA n-hexane/2-propanol (80:20), 0.8
mL/min, 40 °C, tR (S) = 11.1 min, tR (R) = 20.1 min.
Synthesis of (R)-3-[3-(4-Fluorophenylsulfonamido)-3,4-dihy-
dro-1H-carbazol-9(2H)-yl Propanoic Acid, Ramatroban (1). To
a solution of (R)-17 (40 mg, 0.10 mmol) in 2-propanol (0.50 mL) was
added a 10% aqueous NaOH solution (1 mL), and the solution was
stirred at 100 °C for 24 h. After this time, the solution was cooled,
diluted with water (5 mL), and extracted with CH2Cl2 (2× 5 mL) to
remove neutral impurities. Then, the aqueous phase was acidified with
HCl 1 N (5 mL) and extracted with CH2Cl2 (5 × 5 mL). Organic
layers were collected, dried over Na2SO4, and filtered, and the solvent
was evaporated under reduced pressure affording 33 mg of (R)-1
4847
dx.doi.org/10.1021/jo300552v | J. Org. Chem. 2012, 77, 4842−4848