The Journal of Organic Chemistry
Article
Preparation of N-p-Tosyl-1,5-benzodiazepines (IIa) (1−4). 1-
Methyl-5-(p-toluenesulfonyl)-1,3,4,5-tetrahydro-2H-1,5-benzodia-
zepin-2-one (IIa-1). To a stirred solution of S1 (13.5 mg, 0.078
mmol) in dichloromethane (1 mL) at 0 °C under argon were added
triethylamine (53 mL, 0.077 mmol), DMAP (4.7 mg, 0.038 mmol),
and p-toluenesulfonyl chloride (43.8 mg, 0.23 mmol). After being
stirred at 25 °C for 4 h, the mixture was treated with H2O and
extracted with dichloromethane. The extract was dried and
concentrated. The concentrate was purified by column chromatog-
raphy (silica gel, ethyl acetate/hexane = 1/4) to afford IIa-1 as white
solvent was evaporated. To the residue were added H2O and ethyl
acetate, and the mixture was extracted with ethyl acetate. The extract
was washed with H2O, dried, and concentrated. The concentrate was
purified by column chromatography (silica gel, ethyl acetate/hexane =
1:2) to afford IIb-1 as colorless crystals (16 mg, 0.063 mmol, 54%):
1
mp 119−121 °C; H NMR (400 MHz, CDCl3) δ 2.57 (br, 2H), 2.84
(s, 3H), 3.35 (s, 3H), 4.17 (br, 2H), 7.26−7.32 (m, 2H), 7.45 (dt, J =
1.4, 7.8 Hz, 1H), 7.52 (dd, J = 1.4, 7.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 34.1, 35.0, 39.1, 51.3, 123.0, 127.0, 129.8, 130.7, 132.6,
142.5, 170.8; IR (KBr) 2927, 1663, 1336, 1156 cm−1; HRMS (ESI) m/
z calcd for C11H14N2O3S 255.0798 (M + H)+, found 255.0797.
Compounds IIb-2, IIb-3, and IIb-4 were prepared from the
corresponding 1,5-benzodiazepines (S2, S3, and S4)3f according to a
similar procedure described for the preparation of IIb-1 from S1.
1,6-Dimethyl-5-methanesulfonyl-1,3,4,5-tetrahydro-2H-1,5-ben-
zodiazepin-2-one (IIb-2). Colorless crystals (47%): mp 168−169 °C;
1H NMR (400 MHz, CDCl3) δ 2.46 (ddd, J = 0.9, 5.3, 13.4 Hz, 1H),
1
powder (22.9 mg, 0.069 mmol, 91%): mp 177−179 °C; H NMR
(400 MHz, CDCl3) δ 2.38 (s, 3H), 2.45 (br, 2H), 2.59 (s, 3H), 3.95
(br, 1H), 4.56 (br, 1H), 7.06 (dd, J = 1.4, 7.8 Hz, 1H), 7.24 (d, J = 8.0
Hz, 2H), 7.29 (dt, J = 1.4, 7.8 Hz, 1H), 7.39 (dt, J = 1.4, 7.8 Hz, 1H),
7.47 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 1.4, 7.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.5, 34.0, 34.2, 51.7, 122.6, 126.5, 126.9, 129.4,
129.5, 130.3, 132.9, 137.1, 142.5, 143.3, 170.1; IR (KBr) 2946, 1671,
1341, 1158 cm−1; HRMS (ESI) m/z calcd for C17H18N2O3S 331.1111
(M + H)+, found 331.1115.
2.46 (s, 3H), 2.58 (ddd, J = 7.3, 13.4, 13.4 Hz, 1H), 2.87 (s, 3H), 3.35
(s, 3H), 3.79 (ddd, J = 0.9, 7.3, 13.4 Hz, 1H), 4.41 (ddd, J = 5.3, 13.4,
13.4 Hz, 1H) 7.10 (dd, J = 0.9, 7.8 Hz, 1H), 7.21 (dd, J = 0.9, 7.8 Hz,
1H), 7.33 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.0,
34.3, 34.9, 39.3, 50.3, 120.5, 129.1, 129.4, 130.1, 142.0, 143.2, 170.8; IR
(KBr) 2928, 1654, 1335, 1149 cm−1; HRMS (ESI) m/z calcd for
C12H16N2O3S 269.0954 (M + H)+, found 269.0954.
1,6-Dimethyl-5-(p-toluenesulfonyl)-1,3,4,5-tetrahydro-2H-1,5-
benzodiazepin-2-one (IIa-2). To a stirred solution of 1,6-dimethyl-
1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one (S2) (15 mg, 0.079
mmol) in pyridine (2 mL) at 0 °C under argon were added DMAP
(4.8 mg, 0.039 mmol) and p-toluenesulfonyl chloride (75 mg, 0.39
mmol). After the mixture was stirred at 25 °C for 28 h, the solvent was
evaporated. To the residue were added H2O and ethyl acetate, and the
mixture was extracted with ethyl acetate. The extract was dried and
concentrated. The concentrate was purified by column chromatog-
raphy (silica gel, ethyl acetate/hexane = 1:3) to afford IIa-2 as pale
yellow crystals (25 mg, 0.073 mmol, 92%): mp 186−188 °C; 1H NMR
(400 MHz, CDCl3) δ 2.32 (ddd, J = 0.9, 5.3, 13.4 Hz, 1H), 2.44 (ddd,
J = 7.0, 13.4, 13.6, 1H), 2.41 (s, 3H), 2.52 (s, 3H), 2.58 (s, 3H), 3.84
(ddd, J = 0.9, 7.0, 13.4 Hz, 1H), 4.57 (ddd, J = 5.3, 13.4, 13.6 Hz, 1H),
6.92 (dd, J = 0.9, 7.5 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 7.27−7.31 (m,
3H), 7.56 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 19.3,
21.5, 34.2, 34.3, 50.7, 120.1, 127.1, 128.8, 129.1, 129.6, 129.6, 137.6,
142.4, 143.3, 143.6, 169.7; IR (KBr) 2928, 1667, 1339, 1155 cm−1;
HRMS (ESI) m/z calcd for C18H20N2O3S 345.1267 (M + H)+, found
345.1272.
1-(Methanesulfonyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzo-
1
diazepine (IIb-3). Colorless crystals (91%): mp 112 °C; H NMR
(600 MHz, CDCl3) δ 1.88 (br, 2H), 2.86 (s, 3H), 2.87 (s, 3H), 2.98
(br, 2H), 3.69, (br, 2H), 7.00 (dt, J = 1.8, 8.3 Hz, 2H), 7.29 (dt, J =
1.8, 8.3 Hz, 1H), 7.41 (dd, J = 1.8, 7.8 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 27.5, 39.8, 42.2, 47.7, 54.6, 118.2, 122.3, 129.4, 131.1, 132.1,
149.1; IR (KBr) 1322, 1155 cm−1; HRMS (ESI) m/z calcd for
C11H16N2O2S 241.1005 (M + H)+, found 241.0996.
5,9-Dimethyl-1-(methanesulfonyl)-2,3,4,5-tetrahydro-1H-1,5-
1
benzodiazepine (IIb-4). Colorless crystals (71%): mp 116 °C; H
NMR (600 MHz, CDCl3) δ 1.56−1.63 (m, 1H), 2.02−2.09 (m, 1H),
2.42 (s, 3H), 2.67 (ddd, J = 3.4, 8.3, 11.6 Hz, 1H), 2.82 (s, 3H), 2.95
(s, 3H), 3.16−3.23 (m, 2H), 4.11 (ddd, J = 4.6, 8.1, 13.8 Hz, 1H), 6.86
(d, J = 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 19.2, 26.8, 40.3, 41.8, 46.8, 54.6,
Compounds IIa-3 and IIa-4 were prepared from the corresponding
1,5-benzodiazepines (S3 and S4)3f according to similar procedures
described for the preparation of IIa-1 from S1 and IIa-2 from S2,
respectively.
115.8, 124.9, 129.0, 129.9, 141.2, 149.8; IR (KBr) 1325, 1153 cm−1;
HRMS (ESI) m/z calcd for C12H18N2O2S 255.1162 (M + H)+, found
255.1158.
Separation of the N-Benzoyl- and N-Sulfonyl-1,5-benzodia-
zepines into the Atropisomers using Chiral HPLC. Atropisomers
of 5-Benzoyl-1,6-dimethyl-1,3,4,5-tetrahydro-2H-1,5-benzodiaze-
pin-2-one (aR-I-2 and aS-I-2).3f CHIRALPAK IA (1.0 cm ϕ × 25
cm); eluent, hexane/ethanol (19:1); Flow rate, 3.0 mL/min;
emperature, 25 °C; detection, 254 nm. Former peak (aR-I-2):
retention time = 53.6 min; [α]23D −115.0 (c 0.11, MeOH). Latter peak
5-Methyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1,5-benzo-
1
diazepine (IIa-3). Colorless crystals (81%): mp 80−82 °C; H NMR
(600 MHz, CDCl3) δ 1.74 (br, 2H), 2.36 (s, 3H), 2.37 (s, 3H), 2.71
(br, 2H), 3.72 (br, 2H), 6.78 (dd, J = 0.9, 8.2 Hz, 1H), 6.94 (dt, J =
1.4, 7.8 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.23 (dt, J = 1.9, 7.8 Hz,
1H), 7.41 (dd, J = 1.9, 7.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 21.4, 26.6, 41.2, 47.8, 53.5, 118.0, 121.1,
127.4, 128.7, 129.0, 130.3, 131.7, 137.9, 142.5, 148.5; IR (KBr) 1325,
1142 cm−1; HRMS (ESI) m/z calcd for C17H20N2O2S 317.1318 (M +
H)+, found 317.1337.
(aS-I-2): retention time = 67.2 min; [α]23 +113.1 (c 0.11, MeOH).
D
1H NMR spectra of the enantiomers were the same as that of the
racemate (I-2). The absolute stereochemistry of the separated
atropisomers of I-2 was determined by the single-crystal X-ray analysis
of both enantiomers.
Similarly, atropisomers of I-4, IIa-2, IIa-4, IIb-2, and IIb-4 were
separated using chiral HPLC.
5,9-Dimethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1,5-
1
benzodiazepine (IIa-4). Colorless crystals (96%): mp 96−98 °C; H
NMR (600 MHz, CDCl3) δ 1.42−1.50 (m, 1H), 1.73−1.79 (m, 1H),
2.23 (s, 3H), 2.39 (s, 3H), 2.39−2.44 (m, 1H), 2.47 (s, 3H), 2.59
(ddd, J = 2.7, 9.6, 11.7 Hz, 1H), 3.29 (ddd, J = 5.0, 5.0, 13.3 Hz, 1H),
4.02 (ddd, J = 4.1, 9.3, 13.3 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 6.88 (d,
J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 2H), 7.54
(d, J = 8.3 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 19.2, 21.5, 25.7,
40.8, 46.5, 53.2, 115.5, 123.7, 127.8, 128.6, 128.8, 138.6, 141.3, 142.3,
149.1; IR (KBr) 1336, 1156 cm−1; HRMS (ESI) m/z calcd for
C18H22N2O2S 331.1475 (M + H)+, found 331.1502.
Atropisomers of 5-Benzoyl-1,6-dimethyl-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine (aR-I-4 and aS-I-4).3f CHIRALPAK IA (1.0 cm
ϕ × 25 cm); eluent, hexane/2-propanol (19:1); flow rate, 1.5 mL/min;
temperature, 25 °C; detection, 254 nm. Former peak (aS-I-4):
retention time = 28.6 min; [α]23D +151.0 (c 0.11, MeOH). Latter peak
(aR-I-4): retention time = 35.6 min; [α]23 −146.7 (c 0.11, MeOH).
D
The absolute stereochemistry of the separated atropisomers of I-4 was
determined by the single-crystal X-ray analysis of aS-I-4.
Preparation of N-Methanesulfonyl-1,5-benzodiazepines
(IIb) (1−4). 5-Methanesulfonyl-1-methyl-1,3,4,5-tetrahydro-2H-
1,5-benzodiazepin-2-one (IIb-1). To a stirred solution of S1 (20.4
mg, 0.12 mmol) in pyridine (1.2 mL) at 0 °C under argon were added
DMAP (7.1 mg, 0.058 mmol) and methanesulfonyl chloride (45 mL,
0.58 mmol). After the mixture was stirred at 25 °C for 28 h, the
Atropisomers of 1,6-Dimethyl-5-(p-toluenesulfonyl)-1,3,4,5-tetra-
hydro-2H-1,5-benzodiazepin-2-one (aS-IIa-2 and aR-IIa-2). CHIR-
ALPAK IA (1.0 cm ϕ × 25 cm); eluent, hexane/ethanol (9:1); flow
rate, 2.5 mL/min; temperature, 24 °C; detection, 254 nm. Former
peak (aS-IIa-2): retention time = 27.7 min; [α]22 −155.2 (c 0.295,
D
H
dx.doi.org/10.1021/jo5008509 | J. Org. Chem. XXXX, XXX, XXX−XXX