Research Article
RSC Medicinal Chemistry
cis-N-Benzyl-3,4-dihydrospiro[[2]benzopyran-1,1′-cyclo-
hexan]-3′-amine (cis-4a). Ketone 9 (100 mg, 0.46 mmol) was
dissolved in THF (5 mL). Benzylamine (79 μL, 0.70 mmol),
acetic acid (27 μL, 0.46 mmol) and NaBH(OAc)3 (95%, 186
mg, 0.83 mmol) were added and the mixture was stirred for
24 h under a N2 atmosphere at rt. NaOH (1 M, 10 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 20 mL)
and with Et2O (3 × 20 mL). The combined organic layers were
dried (K2CO3), concentrated in vacuo and the residue was pu-
rified by FC (ϕ 2 cm, 20 cm, cyclohexane + 2% N,N-dimethyl-
ethanamine, 10 mL). Rf (cyclohexane + 2% N,N-dimethyl-
ethanamine = 0.17). Colorless oil, yield 128 mg (90%).
NCH2(cyclohexyl-H) (1H), 4′-H, 5′-H or 6′-H (2H)), 1.62 – 1.90
(m, 8H, NCH2(cyclohexyl-H) (5H), 2′-H, 5′-H, 6′-H, (3H)), 1.92–
1.99 (m, 1H, 6′-H or 5′-H), 1.99–2.08 (m, 1H, 4′-H), 2.26 (ddd,
J = 14.8/4.4/2.1 Hz, 1H, 2′-H), 2.36 (dd, J = 11.1/6.5 Hz, 1H,
NCH2(cyclohexyl-H), 2.40 (dd, J = 11.1/7.0 Hz, 1H, NCH2(cyclo-
hexyl-H), 2.75–2.88 (m, 2H, ArCH2CH2O), 2.92–2.97 (m, 1H,
3′-H), 3.88 (“dt”, J = 11.6/5.2 Hz, 1H, ArCH2CH2O), 3.94 (ddd,
J = 11.5/7.0/4.7 Hz, 1H, ArCH2CH2O), 7.06–7.19 (m, 4H, Ar–
H). A signal for the NH-proton is not seen in the spectrum.
Purity (HPLC): 99.5%, tR = 17.4 min.
cis-N-Benzyl-N-methyl-3,4-dihydrospiro[[2]benzopyran-1,1′-
cyclohexan]-3′-amine (cis-5a). Benzylamine cis-4a (56.6 mg,
0.18 mmol) was dissolved in CH2Cl2 (3.5 mL) and formalin
(37%, stab. with 10–15% MeOH, 274 μL, 3.68 mmol) and
NaBH(OAc)3 (95%, 66 mg, 0.29 mmol) were added. The reaction
mixture was stirred under a N2 atmosphere at rt for 3 h. Subse-
quently, H2O (10 mL) was added and the mixture was extracted
with CH2Cl2 (4 × 20 mL) and once with Et2O (20 mL). The com-
bined organic layers were dried (K2CO3), concentrated in vacuo
and the residue was purified by FC (ϕ 2 cm, 30 cm, cyclohexane
+ 2% N,N-dimethylethanamine, 10 mL). Rf (cyclohexane + 2% N,
N-dimethylethanamine = 0.31, cyclohexane + 1% N,N-dimethyl-
˜
C21H25NO (307.5). MS (ESI): m/z (%) = 308 [MH,100]. FT-IR: v
(cm−1) = 3341 (w, v, N–H), 3060, 3025 (w, C–H, arom), 2929,
2865 (s, v, C–H, alkyl), 1604, 1490 (w, CC, arom), 1451 (m,
δ, C–H, alkyl), 1089 (s, v, C–O), 751 (s, δ, C–H, o-disubst.
arom), 729, 696 (s, δ, C–H, mono-subst. arom). 1H NMR
(CDCl3): δ (ppm) = 1.45–1.54 (m, 2H, 4′-H, 5′-H or 6′-H), 1.70
(“td”, J = 13.2/3.6 Hz, 1H, 6′-H or 5′-H), 1.79 (dd, J = 14.6/4.6
Hz, 1H, 2′-H), 1.85–1.94 (m, 1H, 5′-H or 6′-H), 1.97 – 2.03 (m,
1H, 6′-H or 5′-H), 2.06 – 2.13 (m, 1H, 4′-H), 2.32 (ddd, J =
14.6/4.4/2.2 Hz, 1H, 2′-H), 2.76 – 2.88 (m, 2H, ArCH2CH2O),
2.98–3.04 (m, 1H, 3′-H), 3.79 (d, J = 13.2 Hz, 1H, ArCH2NH),
3.83 (d, J = 13.2 Hz, 1H, ArCH2NH), 3.88 (ddd, J = 11.2/5.6/5.1
Hz, 1H, ArCH2CH2O), 3.97 (ddd, J = 11.5/6.2/5.1 Hz, 1H,
ArCH2CH2O), 7.06–7.12 (m, 2H, Ar–H), 7.13–7.18 (m, 2H, Ar–
H), 7.20–7.25 (m, 1H, Ar–H), 7.28–7.34 (m, 2H, Ar–H), 7.35–
7.39 (m, 2H, Ar–H). A signal for the NH-proton is not seen in
the spectrum. 13C NMR (CDCl3): δ (ppm) = 16.6 (1C, C-5′),
29.3 (1C, 4′-C), 29.9 (1C, ArCH2CH2O), 37.9 (1C, 6′-C), 38.8
(1C, 2′-C), 51.3 (1C, NHCH2Ar), 52.0 (1C, 3′-C), 59.3 (1C,
ArCH2CH2O), 77.1 (1C, 1′-C), 125.8 (1C, arom), 126.3 (1C,
arom), 126.4 (1C, arom), 126.9 (1C, arom), 128.4 (2C, arom),
128.6 (2C, arom), 129.2 (1C, arom), 133.9 (1C, arom), 141.5
(1C, arom), 143.1 (1C, arom). Purity (HPLC): 99.1%, tR = 15.9
min.
ethanamine = 0.13). Colorless oil, yield 55 mg (92%). C22H27NO
−1
˜
(321.5). MS (ESI): m/z (%) = 322 [MH, 100]. FT-IR: v (cm ) =
3060, 3023 (w, v, C–H, arom), 2932, 2858 (s, v, C–H, alkyl), 2782
(m, v, N–CH3), 1603, 1490 (w, v, CC, arom), 1450 (m, δ, C–H,
alkyl), 1092 (s, v, C–O), 754 (s, δ, C–H, o-disubst. arom), 733, 698
(s, δ, C–H, mono-subst. arom). 1H NMR (CDCl3): δ (ppm) = 1.61–
1.81 (m, 3H, 4′-H, 5′-H or 6′-H), 1.83–2.02 (m, 4H, 2′-H (1H), 4′-
H, 5′-H or 6′-H (3H)), 2.17–2.21 (m, 1H, 2′-H), 2.21 (s, 3H,
NCH3), 2.86 (t, J = 5.7 Hz, 2H, ArCH2CH2O), 3.01 (“tt”, J = 9.9/4.4
Hz, 1H, 3′-H), 3.54 (d, J = 13.5 Hz, 1H, NCH2Ar), 3.65 (d, J = 13.5
Hz, 1H, NCH2Ar), 3.94–4.03 (m, 2H, ArCH2CH2O), 7.08–7.18 (m,
3H, Ar–H), 7.20–7.33 (m, 6H, Ar–H). Purity (HPLC): 98.5%, tR
15.9 min.
=
cis-N-(Cyclohexylmethyl)-N-methyl-3,4-dihydrospiro[[2]
cis-N-(Cyclohexylmethyl)-3,4-dihydrospiro[[2]benzopyran-
1,1′-cyclohexan]-3′-amine (cis-4b). Ketone 9 (37 mg, 0.17
mmol) was dissolved in THF (5 mL). Cyclohexylmethylamine
(98%, 30 mg, 0.26 mmol in THF (2 mL)), acetic acid (10 μL,
0.17 mmol), and NaBH(OAc)3 (95%, 69 mg, 0.31 mmol) were
added and the mixture was stirred for 24 h under a N2 atmo-
sphere at rt. Subsequently, NaOH (1 M, 10 mL) was added
and the mixture was extracted with Et2O (3 × 20 mL) and
once with CH2Cl2 (3 × 20 mL). The combined organic layers
were dried (K2CO3), concentrated in vacuo and the residue
was purified by FC (ϕ 2 cm, 0 cm, cyclohexane: ethyl acetate +
1% N,N-dimethylethanamine, 10 mL). Rf (cyclohexane : ethyl
acetate 9 : 1 + 1% N,N-dimethylethanamine = 0.11). Colorless
benzopyran-1,1′-cyclohexan]-3′-amine
(cis-5b).
Cyclo-
hexylmethylamine cis-4b (19 mg, 0.06 mmol) was dissolved in
CH2Cl2 (3.5 mL) and formalin (37%, stab. with 10–15%
MeOH, 90 μL, 1.20 mmol) and NaBH(OAc)3 (95%, 22 mg,
0.10 mmol) were added. The reaction mixture was stirred for
3 h under a N2 atmosphere at rt. H2O (10 mL) was added and
the mixture was extracted with CH2Cl2 (4 × 20 mL). The com-
bined organic layers were dried (K2CO3), concentrated in
vacuo and the residue was purified by FC (ϕ 1.5 cm, cyclohex-
ane + 1% N,N-dimethylethanamine, 20 cm, 10 mL). Rf (cyclo-
hexane + 2% N,N-dimethylethanamine = 0.31, (cyclohexane +
1% N,N-dimethylethanamine = 0.15). Colorless oil, yield 18
mg (88%). C22H33NO (327.6). MS (ESI): m/z (%) = 328 [MH,
−1
˜
oil, yield 43 mg (80%). C21H31NO (313.5). MS (ESI): m/z (%) =
100]. IR: v (cm ) = 3067, 3021 (w, C–H, arom), 2920, 2848 (s,
−1
˜
314 [MH, 100]. FT-IR: v (cm ) = 3357 (w, v, N–H), 3059, 3019
v, C–H, alkyl), 2786 (m, v, N–CH3), 1488 (w, CC, arom),
1448 (m, δ, C–H, alkyl), 755 (s, δ, C–H, o-disubst. arom), 733
(m, δ, C–H, mono-subst. arom). 1H NMR (CDCl3): δ (ppm) =
0.75–0.89 (m, 2H, NCH2(cyclohexyl-H)), 1.08–1.28 (m, 3H,
NCH2(cyclohexyl-H)), 1.30–1.40 (m, 1H, NCH2(cyclohexyl-H)),
1.46–1.56 (m, 1H, 4′-H), 1.60–1.76 (m, 8H,(cyclohexyl-H) (4H),
(w, C–H, arom), 2919, 2848 (s, v, C–H, alkyl), 1489 (w, CC,
arom), 1448 (m, δ, C–H, alkyl), 1090 (s, v, C–O), 751 (s, δ, C–
H, o-disubst. arom), 731, 668 (m, δ, monosubst. arom). 1H
NMR (CDCl3): δ (ppm) = 0.86–0.97 (m, 2H, NCH2(cyclohexyl-
H)), 1.10–1.32 (m, 3H, NCH2(cyclohexyl-H)), 1.42–1.52 (m, 3H,
242 | RSC Med. Chem., 2021, 12, 237–244
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