B. Wittel et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
4.9. (2,3-Dimethylphenyl)-naphthalen-1-yl-amine (32)
4H), 4.02 (t, J = 4.4 Hz, 4H), 7.13 (d, J = 7.4 Hz, 1H), 7.46 (t,
J = 7.8 Hz, 1H), 7.54 (m, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.88 (d,
J = 2.2 Hz, 1H), 8.28 (d, J = 7.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz):
δ = 53.55 (t, 2C), 67.49 (t, 2C), 114.74 (d, 1C), 123.46 (d, 1C), 123.90
(d, 1C), 125.54 (d, 1C), 125.91 (d, 1C), 125.96 (d, 1C), 128.54 (d, 1C),
128.82 (s, 1C), 134.86 (s, 1C), 149.40 (s, 1C). MS (EI+, 70 eV): m/
z = 213 (96) [M+], 155 (1 0 0), 127 (37). HRMS (EI+, 70 eV): m/
z = C14H15NO calcd. 213.1154; found 213.1158.
NaOtBu (18.3 g, 190 mmol), ligand 3b (424 mg, 0.95 mmol) and Pd
(OAc)2 (213 mg, 0.95 mmol) were added to a dry, round-bottom flask
under Ar. Diglyme (290 mL) was added and after 15 min, the resulting
suspension was sequentially treated with 2,3-dimethylanilin (13.2 g,
109 mmol) and 1-bromonaphthalene (19.7 g, 95 mmol). After being
stirred at 120 °C for 14 h, the reaction mixture was cooled to rt,
750 mLof H2O was added and the resulting solution was extracted with
toluene (3 × 250 mL). The combined organic phases were dried
(Na2SO4), subjected to filtration and the filtrate was concentrated to
dryness in vacuo. The resulting brown residue was fractionally distilled
using a Kugelrohr apparatus to yield the crude product as red crystals.
Recrystallization from hexane gave 18.7 g (80%) of compound 32 as
pale red crystals, mp. 58–60 °C (hexane), mp.45 68–69 °C (ethanol). 1H
NMR (CDCl3, 400 MHz): δ = 2.32 (s, 3H), 2.44 (s, 3H), 5.86 (s, 1H),
6.95 (m, 3H), 7.12 (m, 1H), 7.41 (m, 1H), 7.56 (m, 3H), 7.92 (1H), 8.08
(m, 1H). 13C NMR (CDCl3, 100 MHz): δ = 13.75 (q, 1C), 20.78 (q, 1C),
113. 40 (d, 1C), 118.72 (d, 1C), 121.37 (d, 1C), 124.45 (d, 1C), 125. 28
(d, 1C), 125.50 (d, 1C), 126.05 (d, 1C), 126.21 (d, 1C), 126.29 (d, 1C),
126.46 (s, 1C), 127.97 (s, 1C), 128.67 (d, 1C), 134.71 (s, 1C), 137.88 (s,
1C), 140.59 (s, 1C), 142.11 (s, 1C). MS (EI+, 70 eV): m/z = 247 (1 0 0)
[M+], 232 (29), 217 (11). HRMS (EI+, 70 eV): m/z = C18H17N calcd.
247.1361; found 247.1373. Pd-content: 3.20 ppm.
4.12. Methylnaphthalen-2-yl-phenyl-amine (38)
NaOtBu (577 mg, 6.0 mmol) was added to a dry round-bottom flask
and the solid stirred for 12 h at 120 °C under Ar. Diglyme (7mL) was
added and after 60 min, the resulting suspension was sequentially
treated with N-methylaniline (306 μl, 3.0 mmol), 2-bromonaphthalene
(621 mg, 3.0 mmol) and, after an additional 30 min, a suspension of Pd
(OAc)2 (14 mg, 0.06 mmol) and ligand 4b (28 mg, 0.06 mmol) in di-
glyme (2 mL). After being stirred at 120 °C for 1 d, the reaction mixture
was passed through silica gel and the residue was washed with MeOH.
The filtrate was evaporated to dryness in vacuo and the residue was
subjected to flash column chromatography on silica gel (hexane) to give
547 mg (78%) of compound 38 as a yellow-orange oil. IR (neat):
υ = 3056, 2876, 2811, 1712, 1627, 1592, 1493, 1388, 1365, 1321,
1228, 1192, 1135, 1120, 1086, 1060, 1025, 951, 836, 748, 700 cm−1
.
1H NMR (CDCl3, 400 MHz): δ = 3.33 (s, 3H), 6.92 (t, J = 7.3 Hz, 1H),
7.02 (d, J = 8.0 Hz, 2H), 7.12 (dd, J = 2.2 Hz, J = 9.0 Hz, 1H), 7.23
(m, 4H), 7.32 (m, 1H), 7.61 (m, 3H). 13C NMR (CDCl3, 100 MHz):
δ = 40.68 (q, 1C), 114.65 (d, 1C), 121.44 (d, 1C), 121.83 (d, 1C),
122.04 (d, 1C), 122.04 (d, 1C), 123.78 (d, 1C), 126.31 (d, 1C), 126.78
(d, 1C), 127.58 (d, 1C), 128.62 (d, 1C), 129.18 (s, 1C), 129.34 (d, 2C),
134.71 (s, 1C), 146.60 (s, 1C), 149.08 (s, 1C). MS (EI+, 70 eV): m/
4.10. Methylnaphthalen-1-yl-phenyl-amine (33)
NaOtBu (577 mg, 6.0 mmol) was added to a dry round-bottom flask
and the solid stirred for 12 h at 120 °C under Ar. Diglyme (7 mL) was
added and after 60 min, the resulting suspension was sequentially
treated with N-methylaniline (306 μl, 3.0 mmol), 1-bromonaphthalene
(420 μl, 3.0 mmol) and, after an additional 30 min, a suspension of Pd
(OAc)2 (14 mg, 0.06 mmol) and ligand 4 (28 mg, 0.06 mmol) in diglyme
(2 mL). After being stirred at 120 °C for 1 d, the reaction mixture was
filtered over silica gel and the residue was washed with MeOH. The
filtrate was evaporated to dryness in vacuo and the residue was sub-
jected to flash column chromatography on silica gel (hexane) to give
506 mg (72%) of compound 33 as a yellow oil. IR (neat): υ = 3088,
3057, 3004, 2935, 2881, 2810, 1712, 1599, 1574, 1498, 1476, 1393,
z = 233 (1 0 0) [M+], 217 (35). HRMS (EI+, 70 eV): m/z = C17H15
N
calcd. 233.1204; found 233.1196.
4.13. 4-Naphthalen-2-yl-morpholine (39)
NaOtBu (577 mg, 6.0 mmol) was added to a dry round-bottom flask
and the solid stirred for 12 h at 120 °C under Ar. Diglyme (8 mL) was
added and after 30 min, the resulting suspension was sequentially
treated with morpholine (288 µl, 3.0 mmol), 2-bromonaphthalene
(621 mg, 3.0 mmol) and,after stirring for an additional 30 min, a sus-
pension of Pd(OAc)2 (14 mg, 0.06 mmol) and ligand 4b (28 mg,
0.06 mmol) in diglyme (3 mL). After being stirred at 120 °C for 1 d, the
reaction mixture was passed through a bed of silica gel and the residue
was washed with MeOH. The filtrate was evaporated to dryness in
vacuo and the residue was subjected to flash column chromatography
on silica gel (hexane/acetone, 20:1) to give 482 mg (75%) of compound
39 as colourless solid, mp. 75 °C (hexane/acetone), mp.46 90 °C
(ethanol). IR (neat): υ = 3051, 2961, 1893, 1712, 1628, 1598, 1446,
1364, 1266, 1255, 1220, 1122, 1067, 931, 878, 836, 807, 747 cm−1. 1H
NMR (CDCl3, 400 MHz): δ = 3.19 (t, J = 4.6 Hz, 4H), 3.84 (t,
J = 4.6 Hz, 4H), 7.04 (s, 1H), 7.20 (m, 2H), 7.34 (t, J = 7.5 Hz, 1H),
7.64 (m, 3H). 13C NMR (CDCl3, 100 MHz): δ = 49.84 (t, 2C), 66.97 (t,
2C), 110.12 (d, 1C), 118.93 (d, 1C), 123.58 (d, 1C), 126.38 (d, 1C),
126.79 (d, 1C), 127.47 (d, 1C), 128.70 (s, 1C), 128.86 (d, 1C), 134.56
(s, 1C), 149.12 (s, 1C). MS (EI+, 70 eV): m/z = 213 (88) [M+], 155
1339, 1297, 1186, 1139, 1009, 775, 693 cm−1 1H NMR (CDCl3,
.
400 MHz): δ = 3.61 (s, 3H), 6.89 (d, J = 8.1 Hz, 2H), 7.00 (t,
J = 7.2 Hz, 1H), 7.41 (m, 2H), 7.23 (m, 2H), 7.59–7.72 (m, 2H), 8.00
(d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H).
13C NMR (CDCl3, 100 MHz): δ =40.47 (q, 1C), 113.89 (d, 2C), 117.58
(d, 1C), 124.13 (d, 1C), 125.50 (d, 1C), 126.53 (d, 1C), 126.66 (d, 1C),
126.76 (d, 1C), 126.92 (d, 1C), 128.77 (d, 1C), 128.94 (d, 2C), 131.62
(s, 1C), 135.43 (s, 1C), 145.68 (s, 1C), 150.39 (s, 1C).. MS (EI+, 70 eV):
m/z = 233 (1 0 0)[M+], 217 (40).
. , 70 eV): m/
HRMS (EI+
z = C17H15N calcd. 233.1204; found 233.1203.
4.11. 4-Naphthalen-1-yl-morpholine (35)
NaOtBu (577 mg, 6.0 mmol) was added to a dry round-bottom flask
and the solid stirred for 12 h at 120 °C under Ar. Diglyme (7mL) was
added and after 30 min, the resulting suspension was sequentially
treated with morpholine (262 µl, 3.0 mmol), 1-bromonaphthalene
(621 mg, 3.0 mmol) and, after an additional 30 min, a suspension of Pd
(OAc)2 (14 mg, 0.06 mmol) and ligand 4b (28 mg, 0.06 mmol) in di-
glyme (2 mL). After being stirred at 120 °C for 1 d, the reaction mixture
was passed through silica gel and the residue was washed with MeOH.
The filtrate was evaporated to dryness in vacuo and the residue was
subjected to flash column chromatography on silica gel (hexane/
acetone, 400:1, 300:1, 200:1, 40:1) to give 546 mg (85%) of compound
35 as a yellow solid, mp. 64 °C (hexane/acetone), mp.46 83 °C (ethanol).
IR (neat): υ = 3049, 2954, 2885, 2820, 1592, 1577, 1452, 1398, 1262,
(1 0 0), 127 (46). HRMS (EI+
213.1154; found 213.1155.
, 70 eV): m/z = C14H15NO calcd.
Alternative procedure: NaOtBu (577 mg, 6.0 mmol) was added to a
dry round-bottom flask and the solid stirred for 12 h at 120 °C under Ar.
Diglyme (8 mL) was added and after 60 min, the resulting suspension
was sequentially treated with morpholine (288 µl, 3.0 mmol), 2-bro-
monaphthalene (621 mg, 3.0 mmol) and, after an additional 30 min, a
suspension of Pd(OAc)2 (14 mg, 0.06 mmol) and ligand 3 (27 mg,
0.06 mmol) in diglyme (3 mL). After being stirred at 120 °C for 2 d, the
reaction mixture was passed through silica gel and the residue was
1257, 1113, 1103, 776 cm−1 1H NMR (CDCl3, 400 MHz): δ = 3.16 (s,
.
10