B. Long et al. / European Journal of Medicinal Chemistry 44 (2009) 2572–2576
2575
ꢀ
5b: yield: 82.5 %; orange yellow solid; m.p. 102–103 C. Anal.
Table 2
Cytotoxicity of ferrocenyl retinoates 5a–5h against A549, BEL7404 and Tca cancer
cell.
1
calc. for C32
NMR (400 MHz, d
on C ); 1.58 (m, 2H, H on C
on C ); 2.00–2.05 (m, 2H, H on C
H, J ¼ 6.8 Hz, CH CH ); 4.08 (s, 5H, Cp); 4.14 (t, 2H, J ¼ 14.4 Hz,
OCH CH ); 4.19 (s, 2H, C -m); 4.21 (s, 2H, C -o); 5.70 (s, 1H, H
on C14); 6.22 (d, 1H, H
, J ¼ 13.6 Hz); 6.25 (d, 1H, H10, J ¼ 11.2 Hz);
.28 (d, 1H, J ¼ 11.6 Hz,
J ¼ 10.4 Hz); 7.08 (dd, 1H,
J ¼ 15.2 Hz); 7.68 (d, 1H, H12, J ¼ 15.2 Hz). C NMR (400 MHz, d
DMSO) 12.9, 19.3, 21.0, 21.8, 29.0, 33.1, 34.3, 39.7, 62.0, 68.6, 68.7,
69.5, 76.7, 77.0, 77.3, 116.4, 128.5, 129.4, 130.0, 130.4, 132.2, 137.5,
H
40FeO
2
: C, 74.99; H, 7.87, found C, 75.11; H, 7.79. H
: 1.02 (s, 6H, 2CH ); 1.44–1.45 (m, 2H, H
); 1.70 (s, 3H, CH on C ); 1.97 (s, 3H, CH
); 2.08 (s, 3H, CH on C13); 2.62 (t,
6
-DMSO)
d
3
Compound
Cell line/IC50
A549
(
m
M)
2
3
3
5
3
BEL7404
Tca
9
4
3
2
2
2
5
5
5
5
5
5
5
5
a
b
c
d
e
f
20.4
21.5
24.1
26.0
28.8
29.3
30.7
31.2
35.8
22.3
24.9
25.2
27.6
30.5
31.1
33.0
37.2
42.6
18.6
19.7
20.3
21.7
28.0
30.1
31.8
32.5
39.7
2
2
5
H
4
5 4
H
8
6
H ,
7
11
H ,
13
6
-
g
h
d
13-cis-RA
1
4
37.7, 139.8, 151.4, 166.1. IR (KBr) 2930, 1715, 1232, 1140, 974,
ꢁ
1
þ
92 cm . MS: m/z ¼ 513 ([M þ H] )
5
c: yield: 82 %; orange yellow oil. Anal. calc. for C33
H
42FeO
5.28; H, 8.04; found C, 75.36; H, 8.00; H NMR (400 MHz, d
: 1.02 (s, 6H, 2CH ); 1.43–1.46 (m, 2H, H on C ); 1.56–1.61
m, 2H, H on C ); 1.69 (s, 3H, CH on C ); 1.81 (m, 2H, CH ); 2.00 (s,
); 2.01–2.03 (m, 2H, H on C ); 2.08 (s, 3H, CH on C13);
.35 (t, 2H, J ¼ 7.6 Hz, CH ); 4.05 (s, 5H, Cp); 4.08 (t, 2H, J ¼ 6.8 Hz,
CH ); 4.12 (s, 2H, C -m); 4.20 (s, 2H, C -o); 5.72 (s, 1H, H
on C14); 6.22 (d, 1H, H
, J ¼ 16 Hz); 6.28 (d, 1H, H10, J ¼ 11.2 Hz); 6.31
, J ¼ 6.8 Hz); 7.07 (dd, 1H, H11, J ¼ 11.6 Hz, J ¼ 11.6 Hz); 7.68
2
: C,
6
-
1
7
OCH
3
); 4.10 (s, 5H, Cp); 4.44 (s, 2H, C
5
H
4
-m); 4.93 (s, 2H, C
5
H
4
-o);
DMSO)
d
3
2
7
1
.39 (s, 1H, Ar); 7.40 (s, 1H, Ar); 7.65 (d, 1H, Ar, J ¼ 17.6 Hz); 9.95 (s,
(
3
2
3
3
5
2
H, CHO).
H, CH
3
on C
9
4
3
2
5.3. A general synthetic method for compounds 9a and 9b
OCH
2
2
H
5 4
5 4
H
8
Compound 8 (4.0 mmol) was suspended methanol (100 mL) at
room temperature with stirring. NaBH
(
(
2
1
d, 1H, H
d, 1H, H12, J ¼ 15.6 Hz). C NMR (400 MHz, d
1.0, 21.8, 29.0, 33.1, 34.3, 39.7, 62.0, 68.6, 68.7, 69.5, 76.7, 77.0, 77.3,
7
4
(0.15 g, 4 mmol) was added
13
6
-DMSO) d 12.9, 19.3,
with magnetic stirring. The reaction mixture was stirred for an
additional hour at rt and then poured into ice-water (100 mL). The
pH was adjusted to about 6.0–7.0. The mixture was extracted with
ethyl acetate (150 mL ꢂ 3). The combined organic layers were
16.4, 128.5, 129.4, 130.0, 130.4, 132.2, 137.5, 137.7, 139.8, 151.4, 166.1.
ꢁ1
IR (KBr) 2929, 1730, 1242, 1136, 974, 496 cm . MS: m/z ¼ 527
þ
(
[M þ H] )
washed with water (100 mL ꢂ 2), dried with MgSO
4
, and evapo-
ꢀ
5
d: yield: 81 %; orange yellow solid; m.p. 61–62 C. Anal. calc.
rated by vacuum. The residue was isolated by column chromatog-
1
for C34
H
44FeO
400 MHz, d -DMSO)
); 1.56–1.61 (m, 2H, H on C
on C ); 1.81 (m, 2H, CH
.01–2.03 (m, 2H, H on C ); 2.08 (s, 3H, CH
); 4.03 (s, 5H, Cp); 4.05 (t, 2H, J ¼ 6.8 Hz, OCH
-m); 4.14 (s, 2H, C -o); 5.69 (s, 1H, H on C14);
, J ¼ 16.4 Hz); 6.25 (d, 1H, H10, J ¼ 4.8 Hz); 6.29 (d,
, J ¼ 15.6 Hz); 7.06 (dd, 1H, H11, J ¼ 12 Hz, J ¼ 11.2 Hz); 7.67
2
: C, 75.55; H, 8.20; found C, 75.62; H, 8.14; H NMR
: 1.09 (s, 6H, 2CH ); 1.44–1.45 (m, 2H, H on
); 1.45–1.60 (m, 4H, CH CH ); 1.62
); 2.00 (s, 3H, CH on C );
on C13); 2.40 (t, 2H,
CH );
raphy and gave following compounds 9a and 9b.
(
C
(
2
6
d
3
9
a: yield: 91%; yellow oil. IR (KBr): 3094, 1634, 1385, 1107, 1032,
ꢁ
1 1
2
3
2
2
1
005, 820, 764, 490 cm . H NMR (CDCl
Cp); 4.20(t, 2H, J ¼ 1.8); 4.44 (t, 2 H, J ¼ 1.8); 4.60 (s, 2 H); 7.16–7.28
m, 4 H, Ar). 13C NMR (CDCl
): 64.2, 68.8, 69.0, 70.2, 70.5, 127.2,
28.7, 129.3, 129.7, 131.2, 131.6.
b: yield: 90%; yellow solid. m.p. 125 C. 1H NMR (400 MHz,
CDCl : 3.76 (s, 3H, OCH ); 4.44 (s, 5H, C ); 4.52 (s, 2H, C -m);
.90 (s, 2H, C -o); 7.24–7.31(m, 3 H, Ar). IR (KBr) 3096,1641, 1390,
121, 1029, 500 cm . MS: m/z ¼ 322 ([M þ H] ).
3
): 3.0 (bs, OH); 4.05(s, 5 H,
s, 3H, CH
3
5
2
3
9
4
3
(
1
3
J ¼ 7.6 Hz, CH
2
2
2
4
6
1
(
2
4
.10 (s, 2H, C
.21 (d, 1H, H
H, H
5
H
4
5 4
H
ꢀ
9
8
3
)
d
3
5
H
5
5 4
H
7
4
1
5
H
4
13
d, 1H, H12, J ¼ 15.2 Hz). C NMR (400 MHz, d -DMSO)
0.8, 21.8, 27.3, 28.4, 28.8, 29.1, 32.9, 34.1, 39.2, 39.4, 39.6, 39.8,
0.0, 40.2, 40.4, 63.4, 67.1, 68.0, 68.6, 88.8, 116.5, 128.4, 129.3,
6
d 12.9, 19.0,
ꢁ
1
þ
5
.4. General procedure for the synthesis of 5a–5h
129.9, 130.6, 132.9, 137.3, 137.5, 140.3, 151.5, 165.9. IR (KBr) 2929,
ꢁ1
þ
1
730, 1242, 1136, 974, 496 cm . MS: m/z ¼ 541 ([M þ H] )
ꢀ
To a stirred solution of the ferrocenyl alcohol or phenol
5e: yield: 80 %; orange yellow solid; m.p. 128–129 C. Anal.
1
(
3 mmol), PPh
3
(1.18 g, 4.5 mmol), and 13-cis-RA (3 mmol) in dry
calc. for C37
NMR (400 MHz, d
H on C ); 1.56–1.61 (m, 2H, H on C
(s, 3H, CH
H
42FeO
2
: C, 77.34; H, 7.37; found C, 77.41; H, 7.25;
: 1.03 (s, 6H, 2CH
); 1.62 (s, 3H, CH
); 2.01–2.03 (m, 2H, H on C ); 2.08 (s, 3H, CH
); 4.32 (s, 2H, C -m);
-o); 5.70 (s, 1H, H on C14); 6.21 (d, 1H, H
J ¼ 4.8 Hz); 6.29 (d, 1H,
H
THF (20 mL) was added to DIAD (0.8 g, 4.5 mmol) under N
2
atmo-
6
-DMSO)
d
3
); 1.44–1.45 (m, 2H,
on C ); 2.00
on
ꢀ
sphere at 0 C. The reaction mixture was allowed to warm to rt and
was stirred for additional 2 h. The reaction was monitored by TLC.
The yellow reaction mixture was concentrated on a rotary evapo-
rator (30 C) to give a viscous oil. The residue was purified by
column chromatography (ethyl acetate/petroleum ether, v/v) and
2
3
3
5
3
on C
9
4
3
C
13); 4.05 (s, 5H, Cp); 4.06 (s, 2H, OCH
2
5 4
H
ꢀ
4.66 (s, 2H, C
5
H
4
8
,
H ,
7
J ¼ 16.4 Hz); 6.25 (d, 1H,
H
10
,
gave retinoates 5a–5h in various yields.
J ¼ 15.6 Hz); 7.06 (dd, 1H, H11, J ¼ 12 Hz, J ¼ 11.2 Hz); 7.46 (s, 2H,
ꢀ
13
5
a: yield: 83 %; orange yellow solid; m.p. 105–106 C. Anal. calc.
C
6
H
4
); 7.29(s, 2H, C
6
H
d
4
); 7.82 (d, 1H, H12, J ¼ 15.6 Hz). C NMR
1
for C31
H
38FeO
400 MHz, d -DMSO)
); 1.60 (m, 2H, H on C
); 2.00–2.05 (m, 2H, H on C
); 4.30 (s, 2H, C
.62 (s, 1H, H on C14); 6.15 (d, 1H, H
, J ¼ 16.0 Hz); 6.24 (d, 1H, H10
J ¼ 11.2 Hz); 6.27 (d, 1H, H , J ¼ 10.4 Hz); 6.99 (dd, 1H, H11
J ¼ 11.6 Hz, J ¼ 11.6 Hz); 7.79 (d, 1H, H12, J ¼ 15.2 Hz). C NMR
400 MHz, d -DMSO) 12.9, 19.3, 21.0, 21.8, 29.0, 33.1, 34.3, 39.7,
2.0, 68.6, 68.7, 69.5, 76.7, 77.0, 77.3, 116.4, 128.5, 129.4, 130.0, 130.4,
32.2, 137.5, 137.7, 139.8, 151.4, 166.1. IR (KBr) 2924, 1707, 1232, 1140,
2
: C, 74.69; H, 7.68; found C, 74.76; H, 7.58; H NMR
: 1.03 (s, 6H, 2CH ); 1.30–1.50 (m, 2H, H on
); 1.71 (s, 3H, CH on C ); 1.99 (s, 3H, CH on
); 2.06 (s, 3H, CH on C13); 4.17 (s, 5H,
-m); 4.93 (s, 2H, C -o);
(400 MHz, d -DMSO)
6
12.9, 19.2, 21.0, 21.8, 28.9, 29.0, 33.1, 34.3,
(
C
C
6
d
3
39.6, 65.5, 66.8, 69.3, 69.9, 76.71, 77.0, 77.3, 116.2, 126.3, 128.3,
128.6, 129.3, 130.1, 130.3, 132.4, 137.5, 137.7, 139.3, 151.7. IR (KBr)
2
9
3
3
5
3
ꢁ
1
þ
4
3
2929, 1730, 1242, 1136, 974, 496 cm . MS: m/z ¼ 574 ([M þ H] )
ꢀ
Cp); 4.21 (s, 2H, OCH
2
5
H
4
5
H
4
5f: yield: 75 %; orange yellow solid; m.p. 137–138 C. Anal. calc.
1
5
8
,
,
for C36
(400 MHz, d
); 1.60–1.61 (m, 2H, H on C
CH on C ); 2.02–2.03 (m, 2H, H on C
(s, 5H, Cp); 4.31 (s, 2H, C -m); 4.61 (s, 2H, C
on C14); 6.13 (d, 1H, H
, J ¼ 16 Hz); 6.23 (d, 1H, H10, J ¼ 4.8 Hz); 6.28
(d, 1H, H
, J ¼ 15.6 Hz); 7.03 (dd, 1H, H11, J ¼ 12 Hz, J ¼ 11.2 Hz); 7.06
H40FeO
2
: C, 77.14; H, 7.19; found C, 77.26; H, 7.10; H NMR
7
6
-DMSO)
d
: 1.02 (s, 6H, 2CH
); 1.71 (s, 3H, CH
); 2.17 (s, 3H, CH
-o); 5.87 (s, 1H, H
3
); 1.45–1.47 (m, 2H, H on
on C ); 2.01 (s, 3H,
on C13); 4.05
1
3
C
2
3
3
5
(
6
1
9
6
d
3
9
4
3
H
5 4
5 4
H
8
ꢁ
1
þ
74, 833, 488 cm . MS: m/z ¼ 499 ([M þ H] )
7