E. Rack et al. / Bioorg. Med. Chem. 19 (2011) 3141–3151
3149
0.32 mmol), acetic acid (16
l
L, 0.287 mmol) and NaBH(OAc)3 (95%,
the residue was purified by FC (2 cm, cyclohexane + 1% N,N-
dimethylethanamine, 20 cm, 5 mL, Rf = 0.10). Colorless solid, mp
85 mg, 381 mmol) were added and the mixture was stirred for
2.5 h at rt. Then, 1 M NaOH (5 mL) was added and the mixture
was extracted with CH2Cl2 (4 ꢃ 5 mL), the combined organic layers
were dried (K2CO3), concentrated in vacuo and the residue was
purified by FC (2 cm, cyclohexane/ethyl acetate 9/1 + 2% N,N-
dimethylethanamine, 20 cm, 5 mL).
91 °C, yield 47 mg (84%).
(%) = 352 [MH, 100]. FT-IR:
C
~
m
23H29NO2 (351.5). MS (ESI): m/z
(cmꢀ1) = 3024 (m, v, C–H, arom),
2928 (s, v, C–H, alkyl), 2839 (s, v, OCH3), 2788 (m, v, N-CH3)
1603, 1492 (w, v, C@C, arom), 754 (s, d, C–H, o-disubst. arom),
732, 698 (s, d, C–H, mono-subst. arom). 1H NMR (CDCl3): d
(ppm) = 1.64 (‘td’, J = 14.0/3.9 Hz, 1H, 20-Ha), 1.75–1.84 (m, 2H,
(CH2CH2)2CHN), 1.84–1.95 (m, 2H, (CH2CH2)2CHN), 1.96 - 2.09
(m, 2H, (CH2CH2)2CHN), 2.11 (ddd, J = 14.1/6.4/3.2 Hz, 1H, 20-He),
2.28 (s, 3H, NCH3), 2.67 (‘tt’, J = 11.6/3.6 Hz, 1H, 40-Ha), 2.90 (dd,
J = 15.3/6.7 Hz, 1H, ArCH2CHOCH3), 2.95 (dd, J = 15.4/3.5 Hz, 1H,
ArCH2CHOCH3), 3.59 (s, 3H, OCH3), 3.65 (s, 2H, NHCH2Ar), 4.88
(dd, J = 6.9/3.9 Hz, 1H, Ar-CH2-CH–OCH3), 7.07–7.12 (m, 2H, Ar-
H), 7.13–7.22 (m, 2H, Ar-H), 7.22–7.29 (m, 1H, Ar-H), 7.30–7.39
(m, 4H, Ar-H). Purity (HPLC): 99.8%, tR = 17.68 min.
trans-10 (Rf = 0.38): Colorless solid, mp 67 °C, yield 13.8 mg
(18%). C17H25 NO2 (275.4). MS (ESI): m/z (%) = 276 [MH, 100]. IR:
~
m
(cmꢀ1) = 2959, 2926 (s, v, C–H, alkyl), 2854 (s, v, OCH3), 2805,
2760 (m, v, N-CH3), 1449 (s, d, C–H, alkyl), 759 (s, d, C–H, o-disubst.
arom).1H NMR (CDCl3): d (ppm) = 1.57–1.65 (m, 1H, 20-He), 1.76
(ddd, J = 13.4/5.8/2.9 Hz, 1H, 60-He), 1.84–1.92 (m, 3H, 30-He, 50-
Ha, 50-He), 1.92–2.05 (m, 2H, 30-Ha, 60-Ha), 2.10 (‘quint’, J = 2.8 Hz,
1H, 40-He), 2.15 (‘td’, J = 13.3/3.7 Hz, 1H, 20-Ha), 2.28 (s, 6H,
N(CH3)2), 2.89 (dd, J = 15.6/6.9 Hz, 1H, ArCH2CHOCH3), 2.94 (dd,
J = 15.6/3.9 Hz, 1H, ArCH2CHOCH3), 3.57 (s, 3H, OCH3), 4.86 (dd,
J = 6.8/4.1 Hz, 1H, ArCH2CHOCH3), 7.05–7.09 (m, 1H, Ar-H), 7.15
(‘td’, J = 7.3/1.6 Hz, 1H, Ar-H), 7.20 (‘td’, J = 7.4/1.6 Hz, 1H, Ar-H),
7.26–7.29 (m, 1H, Ar-H). Purity (HPLC): 99.6%, tR = 15.09 min.
cis-10 (Rf = 0.07): Colorless solid, mp 83 °C, yield 51.9 mg (66%).
~
7.2.9. cis-N-Benzyl-N-ethyl-3-methoxy-3,4-dihydrospiro-
[[2]benzopyran-1,10-cyclohexan]-40-amine (cis-12)
Benzylamine cis-8 (54 mg, 0.16 mmol), 1-iodoethane (18 lL,
0.226 mmol) and K2CO3 were dissolved and suspended in acetoni-
trile (3 mL) in a microwave tube (10 mL) and irradiated with
microwaves. Reaction parameter: Program: Standard, power:
max. 220 W, pressure: max. 4 bar, temperature: 100 °C, reaction
time: 5 min ramp time, 40 min hold time, 5 min cool off time.
The reaction mixture was filtered and concentrated in vacuo.
H2O (4 mL) was added and the mixture was extracted with CH2Cl2.
The organic layers were dried (K2CO3) concentrated in vacuo and
the residue was purified by FC (2 cm, cyclohexane/ethyl acetate
9:1 + 2% N,N-dimethylethanamine, 15 cm, 5 mL, Rf = 0.55). Color-
less solid, mp 74 °C, yield 26.1 mg (45%). C24H31NO2 (365.6). MS
~
C17H25 NO2 (275.4). MS (ESI): m/z (%) = 276 [MH, 100]. IR: m
(cmꢀ1) = 2979, 2946, 2921, 2857 (s, v, C–H, alkyl), 2824, (m, v,
OCH3), 2774 (m, v, N-CH3), 1446 (s, d, C–H, alkyl), 767 (s, d, C–H,
o-disubst. arom). 1H NMR (CDCl3): d (ppm) = 1.61–1.67 (m, 1H,
(CH2CH2)2CHN), 1.74–1.96 (m, 5H, (CH2CH2)2CHN), 1.96–2.02 (m,
1H, (CH2CH2)2CHN), 2.14 (ddd, J = 13.9/6.2/3.1 Hz, 1H,
(CH2CH2)2CHN), 2.35 (s, 6H, N(CH3)2), 2.32–2.40 (m, 1H, 40-Ha),
2.90 (dd, J = 15.3/6.5 Hz, 1H, ArCH2CHOCH3), 2.94 (dd, J = 15.7/
3.5 Hz, 1H, ArCH2CHOCH3), 3.58 (s, 3H, OCH3), 4.85 (dd, J = 6.9/
3.9 Hz, 1H, ArCH2CHOCH3), 7.07–7.12 (m, 2H, Ar-H), 7.14–7.22
(m, 2H, Ar-H). Purity (HPLC): 95.4%, tR = 15.35 min.
(ESI): m/z (%) = 366 [MH,100]. FT-IR:
m
(cmꢀ1) = 3021 (m, v, C–H,
arom), 2946, 2919 2860 (s, v, C–H, alkyl), 2807 (–H2C–N–), 1602,
1491 (w, v, C@C, arom), 768 (s, d, C–H, o-disubst. arom), 732, 696
(s, d, C–H, mono-subst. arom). 1H NMR (CDCl3): d (ppm) = 1.05 (t,
J = 7.1 Hz, 3H, NCH2CH3), 1.60 (‘td’, J = 13.7/4.0 Hz, 1H, 20-Ha),
1.69–1.79 (m, 2H, (CH2CH2)2CHN), 1.81–1.89 (m, 2H,
(CH2CH2)2CHN), 1.91–2.05 (m, 2H, (CH2CH2)2CHN), 2.13 (ddd,
J = 14.1/6.1/3.1 Hz, 1H, 20He), 2.57–2.66 (m, 2H, N-CH2CH3), 2.74
(‘tt’, J = 11.7/3.7 Hz, 1H, 40-Ha), 2.88 (dd, J = 15.5/6.5 Hz, 1H, Ar-
CH2CHOCH3), 2.94 (dd, J = 15.5/3.6 Hz, 1H, Ar-CH2CHOCH3), 3.58
(s, 3H, OCH3), 3.68 (d, J = 14.6 Hz, 1H, N–CH2–Ar), 3.72 (d,
J = 14.7 Hz, 1H, N-CH2-Ar), 4.86 (dd, J = 6.9/3.9 Hz, 1H, ArCH2-
CHOCH3), 7.06–7.11 (m, 2H, Ar-H), 7.13–7.19 (m, 2H, Ar-H),
7.19–7.25 (m, 1H, Ar-H), 7.29–7.34 (m, 2H, Ar-H), 7.37–7.43 (m,
2H, Ar-H). Purity (HPLC): 97.2%, tR = 19.43 min.
7.2.7. trans-N-Benzyl-3-methoxy-N-methyl-3,4-dihydrospiro-
[[2]benzopyran-1,10-cyclohexan]-40-amine (trans-11)
Under N2 benzylamine trans-8 (56.6 mg, 0.168 mmol) was dis-
solved in CH2Cl2 (2.5 mL) and formalin 37% (250
lL, 3.36 mmol)
and NaBH(OAc)3 (95%, 57 mg, 0.256 mmol) were added. The reac-
tion mixture was stirred for 23 h at rt. Subsequently H2O (10 mL)
was added and the mixture was extracted with CH2Cl2
(4x20 mL). The combined organic layers were dried (K2CO3), con-
centrated in vacuo and the residue was purified by FC (2 cm, cyclo-
hexane + 1% N,N-dimethylethanamine, 20 cm, 10 mL, Rf = 0.25).
Colorless solid, mp 62 °C, yield 51.8 mg (88%).
C
23H29 NO2
~
(351.5). MS (ESI): m/z (%) = 352 [MH, 100]. FT-IR:
m
(cmꢀ1) = 3024
(m, v, C–H, arom), 2952 (s, v, C–H, alkyl), 2834 (s, v, OCH3), 2784
(m, v, N–CH3), 1604, 1494 (w, v, C@C, arom), 1494 (s, d, C–H, alkyl),
752 (s, d, C–H, o-disubst. arom), 732, 697 (s, d, C–H, mono-subst.
arom). 1H NMR (CDCl3): d (ppm) = 1.66 (ddd, J = 13.5/5.8/3.0 Hz,
1H, 20-He), 1.81 (ddd, J = 13.6/5.8/3.0 Hz, 1H, 60-He), 1.94–2.22 (m,
5H, 30-He, 30-Ha, 50-Ha, 50-He, 60-Ha), 2.17 (s, 3H, NCH3), 2.39 (‘td’,
J = 13.2/4.1 Hz, 1H, 20-Ha), 2.46 (‘quint’, J = 3.0 Hz, 1H, 40-He), 2.91
(dd, J = 15.6/6.9 Hz, 1H, ArCH2CHOCH3), 2.96 (dd, J = 15.7/4.1 Hz,
1H, ArCH2CHOCH3), 3.59 (s, 3H, OCH3), 3.60 (s, 2H,NHCH2Ar),
4.89 (dd, J = 6.7/4.2 Hz, 1H, Ar-CH2-CH-OCH3), 7.07–7.11 (m, 1H,
Ar-H), 7.16–7.20 (m, 1H, Ar-H), 7.22–7.30 (m, 3H, Ar-H), 7.33–
7.42 (m, 4H, Ar-H). Purity (HPLC) 98.6%, tR = 18.88 min.
7.2.10. cis-N-Benzyl-3-methoxy-N-pentyl-3,4-dihydrospiro-
[[2]benzopyran-1,10-cyclohexan]-40-amine (cis-13)
Under N2 benzylamine cis-8 (46.5 mg, 0.138 mmol) was dis-
solved in CH2Cl2 (5 mL). Valeraldehyde (18 lL, 0.169 mmol) and
NaBH(OAc)3 (95%, 45 mg, 0.213 mmol) were added and the reac-
tion mixture was stirred for 23 h at rt. Then H2O (10 mL) was
added and the mixture was extracted with CH2Cl2 (4 ꢃ 20 mL)
the combined organic layers were dried (K2CO3), concentrated in
vacuo and the residue was purified by FC (2 cm, cyclohexane + 2%
N,N-dimethylethanamine, 20 cm, 10 mL, Rf = 0.37). Colorless oil,
yield 50.3 mg (90%). C27H37NO2 (407.6). MS (ESI): m/z (%) = 408
~
7.2.8. cis-N-Benzyl-3-methoxy-N-methyl-3,4-dihydrospiro-
[[2]benzopyran-1,10-cyclohexan]-40-amine (cis-11)
Under N2 benzylamine cis-8 (54 mg, 0.16 mmol) was dissolved
in CH2Cl2 (2.5 mL) and formalin 37% (238 lL, 3.2 mmol) and NaB-
H(OAc)3 (95%, 57 mg, 0.256 mmol) were added. The reaction mix-
ture was stirred for 3 h at rt. Subsequently H2O (10 mL) was added
and the mixture was extracted with CH2Cl2 (4 ꢃ 20 mL). The com-
bined organic layers were dried (K2CO3), concentrated in vacuo and
[MH,100]. IR: m
(cmꢀ1) = 3062, 3022 (m, v, C–H, arom), 2926,
2858 (s, v, C–H, alkyl), 1603, 1492 (w, v, C@C, arom), 1451 (m, d,
C–H, alkyl), 754 (s, d, C–H, o-disubst. arom), 731, 697 (s, d, C–H,
monosubst. arom). 1H NMR (CDCl3): d (ppm) = 0.86 (t, J = 7.0 Hz,
3H, NCH2CH2CH2CH2CH3), 1.24–1.27 (m, 4H, NCH2CH2CH2CH2CH3),
1.39–1.46 (m, 2H, NCH2CH2CH2CH2CH3), 1.57 (‘td’, J = 13.7/3.9 Hz,
1H, 20-Ha), 1.67–1.77 (m, 2H, (CH2CH2)2CHN), 1.78–1.91 (m, 2H,
(CH2CH2)2CHN), 1.92–2.04 (m, 2H, (CH2CH2)2CHN), 2.09 (ddd,