P.A. Sidhom et al.
Bioorganic Chemistry 114 (2021) 105054
dihydropyridine-3,5-dicarboxylate (9b).
C
6
), 124.75 (1C, Fluorene-C
Fluorene-C ), 126.57 (1C, Fluorene-C
139.80 (1C, Fluorene-C ) ,141.87 (1C, Fluorene-C4b), 142.94 (1C, Flu-
orene-C9a), 143.35 (1C, Fluorene-C8a), 143.76 (1C, Fluorene-C4a),
1
), 124.88 (1C, Fluorene-C
8
), 126.14 (1C,
The general procedure mentioned above was applied using 2,3-
7
3
), 126.82 (1C, Fluorene-C
5
),
(
methylenedioxy)-benzaldehyde (0.250 g, 1.67 mmol), 2c (0.241 g,
2
1
0
.67 mmol) and ethyl 3-aminocrotonate (0.215 g, 1.67 mmol) to give
.459 g, (69.99% yield) as pale-yellow crystals. R
= 0.74 (chloroform
) δ
), 1.28 (t, J = 7.4 Hz, 3H,
), 4.13 (q, J = 7.1 Hz ,2H,
-H), 4.89–5.06 (m, J = 6.5 Hz, 1H, CH(CH ),
O), 6.63 (d, J = 7.9 Hz, 1H, C H),
-H). CNMR
), 19.57 (2C, C -CH and
), 59.71 (1C, CH CH ),
ꢀ 1
f
:
146.82 (2C, C
3331 (N H Str), 2947 (aliphatic C
(aliphatic C
(N
2
and C
6
), 167.73 (2C, 2C ¼ O). IR (KBr disc)
ν
̃(cm ):
◦
1
–
–
H Str), 1658 (C O Str), 1602
isopropanol(90:10)); mp 186–188 C. HNMR (400 MHZ, CDCl
3
–
–
–
–
–
(
ppm): 1.17 (d, J = 6.3 Hz, 6H, CH(CH
3
)
2
C Str), 1453 (aromatic), 1221 (aliphatic C N Str), 735
þ
CH
CH
2
CH
CH
3
), 2.34 (s, 6H, C
), 4.82 (s, 1H, C
2
-CH
3
and C
6
-CH
3
–
H Wag). EI-MS: m/z (% abundance): 417.25 (M , 9.69), 252.20
þ
2
3
4
3
)
2
(M ¡C13
9 4
H ,100.00). Elemental analysis (%) for C26H27NO , calcd.
5
.62 (s, 1H, NH) , 5.90 (s, 2H, OCH
.67 (t, J = 7.9 Hz, 1H, C -H), 6.80 (d, J = 7.9 Hz, 1H, C
) δ (ppm): 14.29 (C, CH CH
), 22.13 (2C, CH(CH ), 39.43 (1C, C
2
′
6 -
(found): C 74.80 (75.04), H 6.52(6.22), N 3.35 (2.98).
1
3
6
6
′
5
′
3,5-Diisopropyl 4-(9H-fluoren-2-yl)-2,6-dimethyl-1,4-dihydropyridine
(
100 MHZ, CDCl
3
2
3
2
3
ꢀ 3,5-dicarboxylate (11c)
C
6
-CH
3
3
)
2
4
2
3
Yield (0.508 g, 88.2%) as pale-yellow crystals. R
f
= 0.95 (chloroform
) δ
), 1.19 (d, J = 6.2 Hz, 6H, CH
), 3.85 (s, 2H, CH ), 4.09 (s, 1H,
), 5.89 (s, 1H, NH), 7.30
-H), 7.39 (t, 2H, J = 7.9 Hz, Flu-
-H), 7.49 (s, 1H, Fluorene C
-H), 7.55 (d, J = 7.5 Hz
-H), 7.66 (dd, 1H, J = 7.8, 1.7 Hz, Fluorene C -H),7.71
) δ(ppm): 19.34 (2C,
), 22.02 (2C, CH(CH ),
), 67.36 (2C, 2 of CH(CH ), 104.67 (2C,
), 119.11 (1C, Fluorene-C ), 119.52 (1C, Fluorene-C ), 124.66
(1C, Fluorene-C ), 124.81 (1C, Fluorene-C ), 126.13 (1C, Fluorene-C ),
126.54 (1C, Fluorene-C ), 126.80 (1C, Fluorene-C ), 139.80 (1C, Fluo-
rene-C ) ,141.85 (1C, Fluorene-C4b), 142.91 (1C, Fluorene-C9a), 143.33
(1C, Fluorene-C8a), 143.72 (1C, Fluorene-C4a), 146.81 (2C, C and C ),
H Str), 2947
:
isopropanol (90:10)); mp 244–247 ◦C. HNMR (400 MHz, CDCl
1
6
7.00 (1C, CH(CH
3
)
2
), 107.46 (1C, C7′), 121.82 (1C, C5′), 122.72 (1C,
3
C
6′), 129.88 (1C, C4′),143.20 (2C, C
2
and C
6
), 145.64 (1C, aromatic C3a
(ppm): 1.12 (d, J = 6.2 Hz, 6H, CH(CH
3
)
2
ꢀ
′
), 147.14 (1C, C7a′), 167.14 (2C, 2C ¼ O). IR (KBr disc):
ν
̃(cm 1): 3331
(CH ), 2.35 (s, 6H, C -CH and C -CH
3
)
2
2
3
6
3
2
–
H Str), 2987 (aliphatic C
–
H Str), 1689 (C
–
O Str), 1649 (aliphatic
C
4
-H), 5.19 (m, J = 6.5 Hz ,2H, 2 of CH(CH
(dd, 1H, J = 7.8, 1.7 Hz, Fluorene C
orene C -H and C
,1H, Fluorene C
(d, J = 7.5 Hz, 1H, Fluorene C
-CH and C -CH ), 21.67 (2C, CH(CH
6.78(1C,CH ), 39.34 (1C, C
and C
3 2
)
(
N
–
–
–
C
–
C Str), 1500 (aromatic), 1219 (aliphatic C N Str), 749 (N H Wag).
4
þ
þ
EI-MS: m/z (% abundance): 386.90 (M ,10.82), 343.85 (M ¡C
3
H
7
,
6
7
1
þ
þ
1
1
7.51), 315.85 (M ¡C
5
H12, 20.34), 265.95 (M ¡C
7
H
5
O
2
, 60.71),
25NO
3
5
þ
13
95.90 (M ¡C12
17
H O
2
, 100). Elemental analysis (%) for C21
H
6
,
8 3
-H). C NMR (CDCl
calcd. (found): C 65.10 (64.80), H 6.50 (6.37), N 3.62 (3.42).
C
2
3
6
3
3
)
2
3 2
)
3
2
4
3 2
)
3
.1.6. General Procedure for Preparation of DHP Derivatives (11a-c).
A mixture of acetoacetate esters 2a-c (2.58 mmol), Fluorene-2-
C
3
5
4
6
1
8
7
carboxaldehyde (0.250 g, 1.29 mmol) and ammonium acetate (0.162
g, 2.10 mmol) was dissolved in isopropanol (10 ml), and then heated
under reflux for 6 h. The reaction mixture was quenched by the addition
of dist. water (20 ml) and then cooled in an ice-bath. The precipitated
solid was filtered and re-crystallized by methanol to afford products
3
5
2
2
6
ꢀ
1
167.74 (2C, 2C ¼ O). IR (KBr disc):
ν
̃(cm ): 3331 (N
–
–
–
H Str), 1658 (C
–
–
O Str), 1602 (aliphatic C
–
C Str), 1453
(aliphatic C
(
11a-c).
,5-Dimethyl
(aromatic), 1221 (aliphatic C
N Str), 735 (N
–
H Wag). EI-MS: m/z (%
þ
þ
3
4-(9H-fluoren-2-yl)-2,6-dimethyl-1,4-dihydropyridine-
abundance): 444.85 (M , 8.65), 279.95 (M ¡C13
9
H , 100.00).
3
,5-dicarboxylate (11a).
Elemental analysis (%) for C28
7.01(7.30), N 3.14 (3.42).
4
H31NO ,calcd. (found): C 75.48 (75.29), H
Yield (0.479 g, 95.4%) as pale-yellow crystals. R
f
= 0.92 (chloroform
) δ
), 3.85 (s,
-H), 5.87 (s, 1H, NH) , 7.28 (dd, 1H, J = 7.8,
-H), 7.35 (t, 2H, J = 7.9 Hz, Fluorene C -H and C
-H), 7.52 (d, J = 7.5 Hz ,1H, Fluorene C -H),
-H), 7.74 (d, J = 7.5 Hz, 1H,
) δ (ppm): 19.65 (2C, C -CH
), 39.50 (1C, C ), 51.03 (2C, COOCH ),
), 119.37 (1C, Fluorene-C ), 119.61 (1C, Fluorene-
), 124.32 (1C, Fluorene-C ), 124.89 (1C, Fluorene-C ), 126.31 (1C,
), 126.43 (1C, Fluorene-C ), 126.59 (1C, Fluorene-C ),
39.99 (1C, Fluorene-C ) ,141.79 (1C, Fluorene-C4b), 143.24 (1C, Flu-
orene-C9a), 143.36 (1C, Fluorene-C8a), 144.15 (1C, Fluorene-C4a),
:
◦
1
isopropanol(90:10)); mp 242–244 C. HNMR (400 MHz, CDCl
ppm): 2.39 (s, 6H, C -CH and C -CH ), 3.69 (s, 6H, COOCH
), 5.13 (s, 1H, C
.7 Hz, Fluorene C
3
(
2
3
6
3
3
3.1.7. General Procedure for Preparation of DHP Derivatives (13a-c)
A mixture of acetoacetate esters 2a-c (3.04 mmol), 1,4-Benzodioxan-
6-carboxaldehyde (0.250 g, 1.52 mmol) and ammonium acetate (0.162
g, 2.10 mmol) was dissolved in isopropanol (10 ml), and then heated
under reflux for 6 h. The reaction mixture was quenched by the addition
of dist. water (20 ml) and then cooled in an ice-bath. The precipitated
solid was filtered and re-crystallized by methanol to afford products
(13a-c).
2
1
H, CH
2
4
4
6
7
-
H), 7.47 (s, 1H, Fluorene C
1
3
7
.65 (dd, 1H, J = 7.8, 1.7 Hz, Fluorene C
5
Fluorene C
8
-H). 13CNMR (100 MHz, CDCl
), 36.87(1C, CH
04.06 (2C, C and C
3
2
3
and C
6
-CH
3
2
4
3
1
3
5
4
C
6
1
8
3,5-Dimethyl 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (13a)
Fluorene-C
7
3
5
1
2
Yield (0.531 g, 90.1%) as pale-yellow crystals. R
f
= 0.69 (chloroform
isopropanol (90:10)); mp 214–216 C. HNMR (400 MHZ, CDCl ) δ
(ppm): 2.35 (s, 6H, C -CH and C -CH ), 3.69 (s, 6H, COOCH ), 4.23 (s,
4H, –CH CH -), 4.93 (s, 1H, C
-H), 6.76–6.79 (m, 2H, C
(ppm): 19.61 (2C, C -CH
COOCH ), 64.29(1C, CH O), 64.37(1C, OCH
:
◦
1
3
ꢀ
1
1
3
46.42 (2C, C
2
and C
6
), 168.16 (2C, 2C ¼ O). IR (KBr disc):
ν
̃(cm ):
2
3
6
3
3
–
–
H Str), 1698 (C
–
–
O Str), 1651
-H), 5.64 (s, 1H, NH), 6.71–6.73 (m, 1H,
349 (N H Str), 2950 (aliphatic C
2
2
4
–
–
–
–
–
′
′
′
13
(
aliphatic C
C Str), 1487 (aromatic C
C), 1221 (aliphatic C N Str),
C
5
7
-H and C
8
-H). CNMR (100 MHz, CDCl
3
) δ
þ
7
38 (N
–
H Wag). EI-MS: m/z (% abundance): 388.90 (M , 4.79), 223.95
2
3
and C
-CH
6 3
), 38.47 (1C, C
4
), 51.00 (2C,
þ
(
M ¡C13
H
9
,100.00). Elemental analysis (%) for C24
H
23NO
4
, calcd.
3
2
2 3 5
), 103.99 (2C, C and C ),
(
found): C 74.02 (74.22), H 5.59(5.86), N 3.60 (3.82).
,5-Diethyl 4-(9H-fluoren-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
116.23 (1C, C5′), 116.60 (1C, C8′), 120.69 (1C, C7′), 140.99 (1C, C6′),
141.97 (1C, C4a′), 143.01 (1C, aromatic C8a′), 143.97 (2C, C and C ),
H Str), 2951
3
2
6
ꢀ
1
dicarboxylate (11b).
168.02 (2C,2C ¼ O). IR (KBr disc):
ν
̃(cm ): 3339 (N
–
–
–
H Str), 1696 (C
–
–
O Str), 1649 (aliphatic C
–
C Str), 1495
Yield (0.465 g, 86.4%) as pale-yellow crystals. R
f
= 0.93 (chloroform
) δ
and C
), 5.09 (s,
-H), 5.81 (s, 1H, NH) , 7.29 (dd, 1H, J = 7.8, 1.7 Hz, Fluorene C
H), 7.35 (t, 2H, J = 7.9 Hz, Fluorene C -H and C -H), 7.47 (s, 1H, Flu-
orene C -H), 7.66 (dd, 1H, J =
-H), 7.53 (d, J = 7.5 Hz ,1H, Fluorene C
.8, 1.7 Hz, Fluorene C -H).
-H), 7.74 (d, J = 7.5 Hz, 1H, Fluorene C
CNMR (100 MHz, CDCl CH ), 19.63 (2C, C
) δ (ppm): 14.29 (2C,CH
CH and C -CH ), 36.90(1C,CH ),39.88 (1C, C ), 59.74 (2C, CH CH
04.33 (2C, C and C ), 119.17 (1C, Fluorene-C ), 119.57 (1C, Fluorene-
:
(aliphatic C
◦
1
isopropanol(90:10)); mp 249–251 C. HNMR (400 MHz, CDCl
ppm): 1.25 (t, J = 7.1 Hz, 6H, 2 of CH CH ), 2.38 (s, 6H, C -CH
CH ),3.85 (s, 2H, CH CH
), 4.10 (m, J = 7.1 Hz ,4H, 2 of CH
H, C
3
(aromatic), 1223 (aliphatic C
N Str), 750 (N
–
H Wag). EI-MS: m/z (%
þ
þ
(
2
3
2
3
6
-
abundance): 358.90 (M , 6.68), 223.95 (M ¡C
8 7 2
H O ,100.00).
3
2
2
3
Elemental analysis (%) for C19
5.89 (5.81), N 3.90 (3.91).
6
H21NO , calcd. (found):C 63.50 (63.29), H
1
4
4
-
6
7
3,5-Diethyl4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,6-dimethyl-1,4-
1
3
dihydropyridine-3,5-dicarboxylate (13b).
7
5
8
Yield (0.509 g, 86.4%) as pale-yellow crystals. R
f
= 0.67 (chloroform
isopropanol(90:10)); mp 195–197 ◦C. HNMR (400 MHz, CDCl
) δ
(ppm): 1.26 (t, J = 7.2 Hz, 6H, 2 of CH CH ), 2.34 (s, 6H, C -CH and C
CH CH ), 4.23(s, 4H, –CH CH -), 4.92 (s,
), 4.11–4.21 (m, 4H, 2 of CH
:
1
3
1
3
2
3
2
-
3
3
6
3
2
4
2
3
),
2
3
2
3
6
-
1
3
5
4
3
2
3
2
2
1
4