10.1002/cmdc.201900284
ChemMedChem
FULL PAPER
NMR (400 MHz, CD3OD): δ (ppm) = 1.66 (dq, J = 12.7/3.2 Hz, 1H, 2’-
Hequ), 1.83 – 1.97 (m, 3H, 3’-H, 5’-H, 6’-Hequ), 2.03 (td, J = 13.6/3.2 Hz,
1H, 6’-Hax), 2.09 – 2.20 (m, 1H, 5’-H), 2.20 – 2.37 (m, 2H, 2’-Hax, 3’-H),
2.48 (s, 3H, ArCH3), 2.67 (dd, J = 16.3/7.4 Hz, 1H, 4-H), 2.99 (ddd, J =
16.3/3.3/1.4 Hz, 1H, 4-H), 3.17 – 3.22 (m, 1H, 4’-Hequ), 3.58 (s, 3H,
OCH3), 3.98 (s, 2H, ArCH2NH), 4.95 (dd, J = 7.5/3.3 Hz, 1H, 3-H), 5.36
(d, J = 48.0 Hz, 2H, ArCH2F), 6.94 (ddd, J = 9.3/7.6/1.7 Hz, 1H, 6-H), 7.17
– 7.25 (m, 2H, 7-H, 8-H), 7.25 – 7.31 (m, 2H, 3-Hbenzyl, 5-Hbenzyl), 7.47
(d, J = 7.6 Hz, 1H, 6-Hbenzyl). A signal for the NH proton is not observed
in the spectrum. 13C NMR (101 MHz, CD3OD): δ (ppm) = 19.3 (1C,
ArCH3), 25.95 (1C, C-3’), 26.00 (1C, C-5’), 29.0 (d, J = 4.2 Hz, 1C, C-4),
31.4 (1C, C-6’), 34.1 (1C, C-2’), 49.7 (1C, ArCH2NH), 53.1 (1C, C-4’), 56.5
(1C, OCH3), 77.7 (1C, C-1), 85.3 (d, J = 164.5 Hz, 1C, ArCH2F), 97.2 (d,
J = 1.1 Hz, 1C, C-3), 113.6 (d, J = 21.7 Hz, 1C, C-6), 120.3 (d, J = 18.4
Hz, 1C, C-4a), 121.7 (1C, C-8), 126.4 (d, J = 5.6 Hz, 1C, C-5benzyl), 128.4
(d, J = 8.7 Hz, 1C, C-7), 130.6 (1C, C-6benzyl), 130.8 (d, J = 5.6 Hz, 1C,
C-3benzyl), 137.5 (d, J = 14.9 Hz, 1C, C-4benzyl), 138.0 (1C, C-1benzyl),
138.4 (1C, C-2benzyl), 145.7 (d, J = 4.1 Hz, 1C, C-8a), 161.5 (d, J = 243.3
Hz, 1C, C-5). FT-IR (neat): ν [cm-1] = 3306 (N-H), 2920, 2839 (C-Halkyl),
1458, 1447 (C=Carom). Purity (HPLC, method 1): 96.3 %, tR = 19.4 min.
organic layers were dried (Na2SO4), filtered, concentrated in vacuo and
the residue was purified by fc (d = 1 cm, l = 20 cm, V = 3 mL,
cyclohexane/ethyl acetate 80:20 + 1 % N,N-dimethylethanamine). Pale
yellow oil, yield 12 mg (50 %). C24H30FNO2 (383.5 g/mol). Rf = 0.41
(cyclohexane/ethyl acetate 80:20 + 1 % N,N-dimethylethanamine). HR-
MS (APCI, method 1): m/z = 384.2344 (calcd. 384.2333 for C24H31FNO2
[MH+]). 1H NMR (600 MHz, CD3OD): δ (ppm) = 1.58 (dq, J = 13.6/3.1 Hz,
1H, 2’-Hequ), 1.75 – 1.81 (m, 2H, 3’-H, 5’-H), 1.83 (dq, J = 13.2/2.6 Hz,
1H, 6’-Hequ), 2.00 – 2.08 (m, 2H, 5’-H, 6’-Hax), 2.08 – 2.17 (m, 1H, 3’-H),
2.32 (td, J = 13.6/3.9 Hz, 1H, 2’-Hax), 2.45 (s, 3H, ArCH3), 2.80 (dd, J =
15.6/7.6 Hz, 1H, 4-H), 2.91 (dd, J = 15.6/3.1 Hz, 1H, 4-H), 3.02 (quint, J =
2.9 Hz, 1H, 4’-Hequ), 3.55 (s, 3H, OCH3), 3.84 (s, 2H, ArCH2NH), 4.90
(dd, J = 7.7/3.1 Hz, 1H, 3-H), 5.33 (d, J = 48.2 Hz, 2H, ArCH2F), 7.07 (d,
J = 7.5 Hz, 1H, 5-H), 7.14 (td, J = 7.4/1.3 Hz, 1H, 6-H), 7.16 – 7.20 (m, 1H,
7-H), 7.21 – 7.26 (m, 2H, 3-Hbenzyl, 5-Hbenzyl), 7.32 (dd, J = 7.8/1.2 Hz,
1H, 8-H), 7.42 (d, J = 7.5 Hz, 1H, 6-Hbenzyl). A signal for the NH proton is
not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ (ppm) =
19.2 (1C, ArCH3), 26.7 (1C, C-3’), 26.8 (1C, C-5’), 31.6 (1C, C-6’), 34.3
(1C, C-2’), 36.3 (1C, C-4), 50.2 (1C, ArCH2NH), 52.5 (1C, C-4’), 56.3 (1C,
OCH3), 78.3 (1C, C-1), 85.4 (d, J = 164.2 Hz, 1C, ArCH2F), 97.8 (1C, C-
3), 126.1 (1C, C-8), 126.4 (d, J = 5.7 Hz, 1C, C-5benzyl), 127.5 (1C, C-7),
127.5 (1C, C-6), 130.0 (1C, C-5), 130.2 (d, J = 1.7 Hz, 1C; C-6benzyl),
130.7 (d, J = 5.2 Hz, 1C, C-3benzyl), 132.4 (1C, C-4a), 136.7 (d, J = 16.8
Hz, 1C; C-4benzyl), 138.1 (d, J = 1.7 Hz, 1C; C-2benzyl), 140.1 (1C; C-
1benzyl), 143.5 (1C, C-8a). FT-IR (neat): ν [cm-1] = 3318 (N-H), 2924,
2835 (C-Halkyl), 1443, 1381 (C=Carom). Purity (HPLC, method 1): 93.5 %,
tR = 18.6 min.
cis-N-[4-(Fluoromethyl)-2-methylbenzyl]-5-fluoro-3-methoxy-3,4-
dihydrospiro[[2]benzopyran-1,1’-cyclohexan]-4’-amine (cis-28c)
A solution of alcohol cis-27c (60 mg, 0.15 mmol) in CH2Cl2 (3 mL) was
added dropwise to a solution of DAST (0.05 mL, 0.38 mmol, 2.5 eq) in
CH2Cl2 (8 mL) under N2 atmosphere at -78 °C. After 45 min, the mixture
was warmed to rt and stirred for 2 h. H2O (20 mL) was added and the
aqueous layer was extracted with CH2Cl2 (4 x 10 mL). The combined
organic layers were dried (Na2SO4), filtered, concentrated in vacuo and
the residue was purified by fc (d = 2 cm, l = 21 cm, V = 10 mL,
cyclohexane/ethyl acetate 50:50 + 1 % N,N-dimethylethanamine). Pale
yellow solid, mp 140 °C, yield 36 mg (60 %). C24H29F2NO2 (401.5 g/mol).
cis-N-[4-(Fluoromethyl)-2-methylbenzyl]-3-methoxy-3,4-
dihydrospiro[[2]benzopyran-1,1’-cyclohexan]-4’-amine (cis-28e)
A solution of alcohol cis-27e (60 mg, 0.16 mmol) in CH2Cl2 (4 mL) was
added dropwise to a solution of DAST (0.04 mL, 0.30 mmol, 1.9 eq) in
CH2Cl2 (5 mL) under N2 atmosphere at -78 °C. After 1 h, the mixture was
warmed to rt and stirred for 2 h. H2O (10 mL) was added and the aqueous
layer was extracted with CH2Cl2 (4 x 8 mL). The combined organic layers
were dried (Na2SO4), filtered, concentrated in vacuo and the residue was
purified twice by fc (d = 2 cm, l = 21 cm, V = 5 mL, cyclohexane/ethyl
acetate 80:20 + 1 % N,N-dimethylethanamine → 67:33 + 1 % N,N-
dimethylethanamine; d = 2 cm, l = 24 cm, V = 10 mL, CH2Cl2/CH3OH 98:2
+ 1 % N,N-dimethylethanamine). Colorless solid, mp 99 °C, yield 21 mg
(35 %). C24H30FNO2 (383.5 g/mol). Rf = 0.31 (CH2Cl2/CH3OH 95:5 +
1 % N,N-dimethylethanamine). HR-MS (APCI, method 1): m/z = 384.2330
(calcd. 384.2333 for C24H31FNO2 [MH+]). 1H NMR (600 MHz, CD3OD):
δ (ppm) = 1.72 (td, J = 13.7/3.5 Hz, 1H, 2’-Hax), 1.76 – 1.84 (m, 1H, 3’-H),
1.84 – 1.90 (m, 2H, 5’-H, 6’-H), 1.91 – 1.96 (m, 2H, 3’-H, 5’-H), 2.00 (td, J
= 13.4/3.0 Hz, 1H, 6’-H), 2.12 (dq, J = 14.0/3.1 Hz, 1H, 2’-Hequ), 2.41 (s,
3H, ArCH3), 2.74 – 2.78 (m, 1H, 4’-Hax), 2.80 (dd, J = 15.7/7.4 Hz, 1H, 4-
H), 2.92 (dd, J = 15.6/3.2 Hz, 1H, 4-H), 3.58 (s, 3H, OCH3), 3.88 (s, 2H,
ArCH2NH), 4.92 (dd, J = 7.5/3.1 Hz, 1H, 3-H), 5.33 (d, J = 48.1 Hz, 2H,
ArCH2F), 7.07 – 7.10 (m, 1H, 5-H), 7.13 – 7.19 (m, 3H, 6-H, 7-H, 8-H),
7.21 – 7.25 (m, 2H, 3-Hbenzyl, 5-Hbenzyl), 7.39 (d, J = 7.7 Hz, 1H, 6-
Hbenzyl). A signal for the NH proton is not observed in the spectrum. 13C
NMR (151 MHz, CD3OD): δ (ppm) = 19.1 (1C, ArCH3), 29.0 (1C, C-5’),
29.1 (1C, C-3’), 36.2 (1C, C-4), 36.6 (1C, C-2’), 39.1 (1C, C-6’), 48.7 (1C,
ArCH2NH), 56.5 (1C, OCH3), 57.3 (1C, C-4’), 77.5 (1C, C-1), 85.4 (d, J =
164.1 Hz, 1C, ArCH2F), 97.8 (1C, C-3), 125.7 (1C, C-8), 126.5 (d, J = 5.8
Hz, 1C, C-5benzyl), 127.5 (1C, C-7), 127.6 (1C, C-6), 130.0 (d, J = 1.5 Hz,
1C, C-6benzyl), 130.1 (1C, C-5), 130.7 (d, J = 5.3 Hz, 1C, C-3benzyl),
132.6 (1C, C-4a), 136.8 (d, J = 16.4 Hz, 1C, C-4benzyl), 137.8 (d, J = 1.7
Hz, 1C, C-2benzyl), 139.5 (d, J = 3.2 Hz, 1C, C-1benzyl), 142.7 (1C, C-
8a). FT-IR (neat): ν [cm-1] = 3298 (N-H), 2940, 2859 (C-Halkyl), 1443,
1373 (C=Carom). Purity (HPLC, method 1): 96.8 %, tR = 18.7 min.
Rf
=
0.19 (cyclohexane/ethyl acetate 50:50
+
1 % N,N-
dimethylethanamine). HR-MS (ESI): m/z = 402.2245 (calcd. 402.2239 for
C24H30F2NO2 [MH+]). 1H NMR (400 MHz, CD3OD): δ (ppm) = 1.68 –
1.79 (m, 2H, 2’-H, 3’-H), 1.80 – 1.98 (m, 4H, 3’-H, 5’-H, 6’-H), 2.03 (td, J =
13.6/3.6 Hz, 1H, 6’-H), 2.13 – 2.20 (m, 1H, 2’-H), 2.42 (s, 3H, ArCH3), 2.67
(dd, J = 16.3/7.4 Hz, 1H, 4-H), 2.79 (tt, J = 10.9/3.8 Hz, 1H, 4’-Hax), 2.99
(ddd, J = 16.3/3.4/1.3 Hz, 1H, 4-H), 3.61 (s, 3H, OCH3), 3.89 (s, 2H,
ArCH2NH), 4.95 (dd, J = 7.4/3.2 Hz, 1H, 3-H), 5.34 (d, J = 48.1 Hz, 2H,
ArCH2F), 6.94 (ddd, J = 9.2/8.1/1.0 Hz, 1H, 6-H), 7.04 (d, J = 7.7 Hz, 1H,
8-H), 7.19 – 7.27 (m, 3H, 7-H, 3-Hbenzyl, 5-Hbenzyl), 7.38 – 7.42 (m, 1H,
6-Hbenzyl). A signal for the NH proton is not observed in the spectrum.
13C NMR (101 MHz, CD3OD): δ (ppm) = 19.1 (1C, ArCH3), 28.9 – 29.1
(m, 3C, C-4, C-3’, C-5’), 36.3 (1C, C-2’), 38.9 (1C, C-6’), 48.7 (1C,
ArCH2NH), 56.6 (1C, OCH3), 57.1 (1C, C-4’), 77.4 (d, J = 1.9 Hz, 1C, C-
1), 85.4 (d, J = 164.2 Hz, 1C, ArCH2F), 97.1 (1C, C-3), 113.6 (d, J = 22.0
Hz, 1C, C-6), 120.5 (d, J = 18.5 Hz, 1C, C-4a), 121.5 (d, J = 3.3 Hz, 1C,
C-8), 126.5 (d, J = 5.7 Hz, 1C, C-5benzyl), 128.4 (d, J = 8.5 Hz, 1C, C-7),
130.0 (d, J = 1.6 H, 1C, C-6benzyl), 130.7 (d, J = 5.4 Hz, 1C, C-3benzyl),
136.8 (d, J = 16.9 Hz, 1C, C-4benzyl), 137.8 (1C, C-2benzyl), 139.5 (1C,
C-1benzyl), 145.3 (d, J = 4.3 Hz, 1C, C-8a), 161.6 (d, J = 243.4 Hz, 1C, C-
5). FT-IR (neat): ν [cm-1] = 3260 (N-H), 2924, 2855 (C-Halkyl), 1462, 1443
(C=Carom). Purity (HPLC, method 1): 95.1 %, tR = 19.2 min.
trans-N-[4-(Fluoromethyl)-2-methylbenzyl]-3-methoxy-3,4-
dihydrospiro[[2]benzopyran-1,1’-cyclohexan]-4’-amine (trans-28e)
A solution of alcohol trans-27e (24 mg, 0.06 mmol) in CH2Cl2 (3 mL) was
added dropwise to a solution of DAST (0.02 mL, 0.15 mmol, 2.5 eq) in
CH2Cl2 (4 mL) under N2 atmosphere at -78 °C. After 45 min, the mixture
was warmed to rt and stirred for 2 h. H2O (10 mL) was added and the
aqueous layer was extracted with CH2Cl2 (4 x 5 mL). The combined
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