K. Wang et al.
Bioorganic Chemistry 112 (2021) 104879
CH), 1.74 (d, J = 13.6 Hz, 2H, CH2), 1.23–1.21 (m, 2H, CH2). HR-ESI-
MS: Calcd. for C21H23NO [M + H]+: 306.1852, found: 306.1859.
4.1.1.23. 1-(4-benzylpiperidin-1-yl)-2-methylprop-2-en-1-one (5 g). Yel-
low oil, 81.5% yield, 98.1% HPLC purity. 1H NMR (400 MHz, CDCl3) δ
7.24 (t, J = 7.3 Hz, 2H, 2 × Ar-H), 7.15 (t, J = 7.3 Hz, 1H, Ar-H), 7.10 (d,
J = 7.2 Hz, 2H, 2 × Ar-H), 5.09 (s, 1H, 1/2 CH2), 4.97 (s, 1H, 1/2 CH2),
4.52 (s, 1H, 1/2 NCH2), 3.90 (s, 1H, 1/2 NCH2), 2.72 (m, 2H, NCH2),
2.50 (d, J = 7.0 Hz, 2H, CH2), 1.91 (s, 3H, CH3), 1.72 (m, 1H, CH), 1.63
(d, J = 12.4 Hz, 2H, CH2), 1.10 (d, J = 7.2 Hz, 2H, CH2). HR-ESI-MS:
Calcd. for C16H21NO [M + H]+: 244.1696, found: 244.1712.
4.1.1.18. (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxyphenyl)prop-2-en-1-
one (5b). Yellow oil, 56.5% yield, 98.2% HPLC purity. 1H NMR (400
MHz, CDCl3) δ 7.57 (d, J = 15.2 Hz, 1H, CH = CH), 7.35–7.12 (m, 7H, 7
× Ar-H), 6.86 (d, J = 8.0 Hz, 2H, 2 × Ar-H), 6.71 (d, J = 15.2 Hz, 1H, CH
= CH), 4.69 (d, J = 9.2 Hz, 1H, 1/2 phCH2), 4.08 (d, J = 10.8 Hz, 1H, 1/
2 phCH2), 3.04 (t, J = 11.2 Hz, 1H, 1/2 NCH2), 2.64 (t, J = 11.2 Hz, 1H,
1/2 NCH2), 2.60–2.53 (m, 2H, NCH2), 1.80–1.71 (m, 3H, CH + CH2),
1.26–1.20 (m, 2H, CH2). HR-ESI-MS: Calcd. for C21H23NO2 [M + H]+:
322.1802, found: 322.1815.
4.1.1.24. 1-(4-benzylpiperidin-1-yl)-3-phenylprop-2-yn-1-one (5 h). Yel-
low oil, 79.3% yield, 98.0% HPLC purity. 1H NMR (400 MHz, CDCl3) δ
7.51 (d, J = 7.1 Hz, 2H, 2 × Ar-H), 7.31 (m, 5H, 5 × Ar-H), 7.18 (t, J =
7.0 Hz, 1H, Ar-H), 7.12 (d, J = 7.4 Hz, 2H, 2 × Ar-H), 4.57 (d, J = 13.3
Hz, 1H, 1/2 NCH2), 4.41 (d, J = 13.2 Hz, 1H, 1/2 NCH2), 3.04 (t, J =
12.6 Hz, 1H, 1/2 NCH2), 2.57 (m, 3H, 1/2 NCH2, CH2), 1.74 (dt, J =
4.1.1.19. (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-3-methoxyphenyl)
prop-2-en-1-one (5c). Yield 61.3%, 98.2% HPLC purity. 1H NMR (400
MHz, CDCl3) δ 7.58 (d, J = 15.2 Hz, 1H, C = CH), 7.29 (t, J = 6.8 Hz, 2H,
2 × Ar-H), 7.21 (t, J = 7.2 Hz, 1H, Ar-H), 7.14 (dd, J1 = 5.8 Hz, J2 = 1.2
Hz, 2H, 2 × Ar-H), 7.09 (dd, J1 = 6.4 Hz, J2 = 1.6 Hz, 1H, Ar-H), 6.98 (d,
J = 1.6 Hz, 1H, Ar-H), 6.91 (d, J = 8.4 Hz, 1H, Ar-H), 6.73 (d, J = 15.2
Hz, 1H, C = CH), 6.16 (s, 1H, OH), 4.71 (d, J = 11.2 Hz, 1H, 1/2 phCH2),
4.00 (d, J = 11.6 Hz, 1H, 1/2 phCH2), 3.91 (s, 3H, OCH3), 3.04 (d, J =
12.0 Hz, 1H, 1/2 NCH2), 2.61 (d, J = 12.0 Hz, 1H, 1/2 NCH2), 2.58–2.53
(m, 2H, NCH2), 1.84–1.77 (m, 1H, CH), 1.76–1.71 (d, J = 13.2 Hz, 2H,
CH2), 1.22 (d, J = 13.2 Hz, 2H, CH2). 13C NMR (100 MHz, CDCl3) 165.9,
147.6, 147.0, 143.1, 140.0, 129.1 (2C), 128.3 (2C), 127.5, 126.1, 121.9,
115.1, 114.3, 110.1, 56.0, 46.3, 43.0, 42.8, 38.3, 32.8, 31.9. HR-ESI-MS:
Calcd. for C22H25NO3 [M + H]+: 352.1907, found: 352.1913.
23.1, 7.7 Hz, 3H, CH, CH2), 1.19 (dd, J = 25.4, 12.6 Hz, 2H, CH2). 13
C
NMR (100 MHz, CDCl3) δ 152.7, 139.6, 132.1 (2C), 129.8, 128.9 (2C),
128.4 (2C), 128.2 (2C), 125.9, 120.5, 90.1, 81.4, 47.3, 42.7, 41.5, 38.0,
32.3, 31.4. HR-ESI-MS: Calcd. for C21H21NO [M + H]+: 304.1696,
found: 304.1702.
4.1.1.25. (E)-1-(4-benzylpiperidin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-
one (5i). Yellow oil, 66.7% yield, 98.2% HPLC purity. 1H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 15.4 Hz, 1H, Ar-H), 7.46 (dd, J = 8.4, 5.5 Hz,
2H, 2 × Ar-H), 7.27 (t, J = 7.3 Hz, 2H, 2 × Ar-H), 7.18 (t, J = 7.3 Hz, 1H,
Ar-H), 7.12 (d, J = 7.7 Hz, 2H, 2 × Ar-H), 7.01 (t, J = 8.6 Hz, 2H, 2 × Ar-
H), 6.82 (d, J = 15.4 Hz, 1H, Ar-H), 4.68 (d, J = 10.1 Hz, 1H, 1/2 NCH2),
4.05 (d, J = 10.4 Hz, 1H, 1/2 NCH2), 3.00 (s, 1H, 1/2 NCH2), 2.55 (m,
3H, 1/2 NCH2, CH2), 1.76 (m, 3H, CH, CH2), 1.19 (d, J = 11.2 Hz, 2H,
CH2). HR-ESI-MS: Calcd. for C21H22FNO [M + H]+: 324.1758, found:
324.1765.
4.1.1.20. (E)-1-(4-benzylpiperidin-1-yl)-3-(thiophen-2-yl)prop-2-en-1-one
(5d). Light yellow oil, 58.2% yield, 98.1% HPLC purity. 1H NMR (400
MHz, CDCl3) δ 7.75 (d, J = 15.1 Hz, 1H, C = CH), 7.25 (m, 3H, 3 ×
Ar–H), 7.17 (dd, J = 8.9, 5.5 Hz, 2H, 2 × Ar–H), 7.11 (d, J = 7.0 Hz, 2H,
2 × Ar–H), 6.99 (dd, J = 5.0, 3.7 Hz, 1H, Ar-H), 6.66 (d, J = 15.1 Hz, 1H,
C = CH), 4.65 (s, 1H, 1/2 NCH2), 4.00 (d, J = 9.4 Hz, 1H, 1/2 NCH2),
2.99 (s, 1H, 1/2 NCH2), 2.53 (d, J = 5.4 Hz, 3H, 1/2 NCH2, CH2), 1.76
(m, 1H, CH), 1.70 (d, J = 13.3 Hz, 2H, CH2), 1.20 (m, 2H, CH2). 13C NMR
(100 MHz, CDCl3) δ 165.0, 140.7, 140.0, 135.2, 130.0, 129.2 (2C), 128.4
(2C), 128.0, 127.0, 126.1, 116.4, 43.0 (3C), 38.4 (3C). HR-ESI-MS:
Calcd. for C19H21NOS [M + H]+: 312.1417, found: 312.1425.
4.1.1.26. 1-(4-benzylpiperidin-1-yl)-3-phenylpropan-1-one (5j). Yellow
oil, 73.2% yield, 98.0% HPLC purity. 1H NMR (400 MHz, CDCl3) δ 7.22
(t, J = 7.3 Hz, 4H, 4 × Ar-H), 7.14 (dd, J = 16.8, 7.8 Hz, 4H, 4 × Ar-H),
7.06 (d, J = 7.4 Hz, 2H, 2 × Ar-H), 4.57 (d, J = 13.1 Hz, 1H, 1/2 NCH2),
3.62 (d, J = 13.3 Hz, 1H, 1/2 NCH2), 2.93 (dd, J = 11.1, 4.8 Hz, 2H,
NCH2), 2.73 (dd, J = 18.7, 7.0 Hz, 1H, 1/2 CH2), 2.52 (dt, J = 12.8, 6.3
Hz, 2H, CH2), 2.40 (m, 3H, 3/2 NCH2), 1.63 (m, 1H, CH), 1.55 (m, 1H,
1/2 CH2), 1.49 (d, J = 12.9 Hz, 1H, 1/2 CH2), 1.03 (qd, J = 12.5, 3.9 Hz,
1H, 1/2 CH2), 0.86 (qd, J = 12.6, 3.7 Hz, 1H, 1/2 CH2). 13C NMR (100
MHz, CDCl3) δ 170.6, 141.6, 140.1, 129.2 (2C), 128.6 (2C), 128.6 (2C),
128.4 (2C), 126.2, 126.2, 46.0, 43.1, 42.2, 38.3, 35.3, 32.6, 31.9, 31.8.
HR-ESI-MS: Calcd. for C21H25NO [M + H]+: 308.2009, found: 308.2015.
4.1.1.21. (E)-1-(4-benzylpiperidin-1-yl)-3-(naphthalen-2-yl)prop-2-en-1-
one(5e). Yellow oil, 60.9% yield, 98.0% HPLC purity. 1H NMR (400
MHz, CDCl3) δ 8.48 (d, J = 15.1 Hz, 1H, C = CH), 8.21 (d, J = 8.1 Hz, 1H,
Ar-H), 7.81 (d, J = 7.7 Hz, 2H, 2 × Ar-H), 7.67 (d, J = 7.1 Hz, 1H, Ar-H),
7.45 (dt, J = 15.5, 8.1 Hz, 3H, 3 × Ar-H), 7.25 (d, J = 7.4 Hz, 2H, 2 × Ar-
H), 7.19 (d, J = 7.3 Hz, 1H, Ar-H), 7.10 (d, J = 7.2 Hz, 2H, 2 × Ar-H),
6.92 (d, J = 15.2 Hz, 1H, C = CH), 4.73 (d, J = 12.3 Hz, 1H, 1/2 NCH2),
4.04 (d, J = 12.8 Hz, 1H, 1/2 NCH2), 2.97 (t, J = 12.5 Hz, 1H, 1/2
NCH2), 2.59 (t, J = 12.7 Hz, 1H, 1/2 NCH2), 2.50 (t, J = 6.3 Hz, 2H,
CH2), 1.71 (s, 1H, CH), 1.66 (d, J = 12.6 Hz, 2H, CH2), 1.24 – 1.13 (m,
2H, CH2). 13C NMR (100 MHz, CDCl3) δ 165.2, 140.0, 139.6, 133.7,
133.2, 131.5, 129.8, 129.2 (2C), 128.7, 128.4 (2C), 126.7, 126.2, 126.1,
125.5, 124.6, 123.8, 120.8, 46.3, 43.0, 42.7, 38.3, 32.9, 31.9. HR-ESI-
MS: Calcd. for C25H25NO [M + H]+: 356.2009, found: 356.2014
4.1.1.27. 1-(4-benzylpiperidin-1-yl)-3-(4-hydroxyphenyl)propan-1-one
(5 k). Yellow oil, 68.6% yield, 98.1% HPLC purity. 1H NMR (400 MHz,
CDCl3) δ 7.27 (t, J = 7.2 Hz, 2H, 2 × Ar-H), 7.18 (t, J = 7.2 Hz, 1H, Ar-
H), 7.10 (d, J = 7.2 Hz, 2H, 2 × Ar-H), 7.00 (d, J = 8.0 Hz, 2H, 2 × Ar-H),
6.79 (d, J = 8.0 Hz, 2H, 2 × Ar-H), 4.60 (d, J = 13.2 Hz, 1H, 1/2 phCH2),
3.73 (d, J = 13.2 Hz, 1H, 1/2 phCH2), 2.87–2.79 (m, 2H, phCH2),
2.60–2.54 (m, 2H, NCH2), 2.52–2.42 (m, 2H, NCH2), 1.71–1.55 (m, 3H,
CH + CH2), 1.14–1.04 (m, 2H, CH2). HR-ESI-MS: Calcd. for C21H25NO2
[M + H]+: 324.1958, found: 324.1969.
4.1.1.22. (E)-1-(4-benzylpiperidin-1-yl)-2-methyl-3-phenylprop-2-en-1-
one (5f). Yellow oil, 71.9% yield, 97.6% HPLC purity. 1H NMR (400
MHz, CDCl3) δ 7.38 – 7.22 (m, 8H, 7 × Ar–H, C = CH), 7.20 (d, J = 7.2
Hz, 1H, Ar–H), 7.13 (d, J = 7.4 Hz, 2H, 2 × Ar–H), 4.58 (s, 1H, 1/
2NCH2), 3.91 (d, J = 59.4 Hz, 1H, 1/2NCH2), 3.14 – 2.83 (m, 1H, 1/
2NCH2), 2.60 (d, J = 5.6 Hz, 1H, 1/2NCH2), 2.55 (d, J = 6.6 Hz, 2H,
CH2), 2.09 (s, 3H, CH3), 1.84 – 1.75 (m, 1H, CH), 1.70 (d, J = 10.3 Hz,
2H, CH2), 1.28 – 1.11 (m, 2H, CH2). HR-ESI-MS: Calcd. for C22H25NO
[M + H]+: 320.2009, found: 320.2020.
4.1.1.28. (4-benzylpiperidin-1-yl)-3-(4-hydroxy-3-methoxyphenyl)
propan-1-one (5 l). Yellow oil, 70.3% yield, 98.1% HPLC purity. 1H
NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.6 Hz, 2H, 2 × Ar-H), 7.19 (t, J =
7.2 Hz, 1H, Ar-H), 7.11 (d, J = 7.2 Hz, 2H, 2 × Ar-H), 6.83 (d, J = 8.0 Hz,
1H, Ar-H), 6.72 (s, 1H, Ar-H), 6.68 (dd, J1 = 6.4 Hz, J2 = 1.6 Hz, 1H, Ar-
H), 6.85–5.80 (brs, 1H, OH), 4.62 (d, J = 13.2 Hz, 1H, 1/2 phCH2), 3.86
(s, 3H, OCH3), 3.74 (d, J = 13.6 Hz, 1H, 1/2 phCH2), 2.88 (t, J = 7.2 Hz,
2H, phCH2), 2.84 (t, J = 13.2 Hz, 1H, 1/2 NCH2), 2.60–2.55 (m, 2H,
COCH2), 2.53–2.48 (m, 2H, NCH2), 2.47 (t, J = 13.2 Hz, 1H, 1/2 NCH2),
1.75–1.70 (m, 1H, CH), 1.66 (d, J = 14.4 Hz, 1H, 1/2 CH2), 1.58 (d, J =
14