1760 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 4
Martelli et al.
or CA Index Name. When reactions were performed in
anhydrous conditions, the mixtures were maintained under
nitrogen.
6.34 (d, 1H, CHdCH, J = 16.0 Hz), 6.75 (s, 2H, CH aromatics),
7.60 (d, 1H, CHdCH, J = 16.0 Hz) ppm.
trans-3-(3,4,5-Trimethoxyphenyl)acrylic Acid 3-[3-(3-Anthra-
cen-9-yl-acryloyloxy)propylamino]-propyl Ester (3). Following
the general procedure described above for the general synthesis
of esters, the acyl chloride, obtained from trans-3-(anthracen-
9-yl)acrylic acid37 (375 mg, 1.76 mmol), was allowed to react
with 27 (300 mg, 0.88 mmol). The crude product was then
purified by flash chromatography using CHCl3/CH3OH/
NH4OH (95:5:0.5) as eluting system. By 1H NMR analysis,
the product results a 50/50 mixture of trans/trans (a) and trans/
cis (b) isomers.
The title compound (160 mg, 37% yield) was obtained as an
oil. IR (neat) ν cm-1 1714 (CO). 1H NMR (CDCl3) δ 1.00-1.10
(m, 2H, CH2, b isomer), 1.67-1.76 (m, 4H, 2 CH2N, b isomer),
1.90-2.15 (m, 4H, CH2, a isomer), 2.35 (t, 2H, J = 6.8 Hz, b
isomer); 2.75-2.85 (m, 4H, CH2, a isomer), 3.71 (t, 2H, J = 6.0
Hz, b isomer), 3.80-3.84 (m, 18H, 6 OCH3), 4.17 (t, 2H, CH2O,
J = 6.0 Hz, b isomer), 4.30 (t, 2H, CH2O, J = 6.4 Hz, a isomer),
4.41 (t, 2H, CH2O, J = 6.4 Hz, a isomer), 6.32 (d, 1H, CHdCH,
J = 16.0 Hz, a isomer), 6.35 (d, 1H, CHdCH, J = 16.0 Hz,
b isomer), 6.42 (d, 1H, CHdCH, J = 16.0 Hz, a isomer), 6.61 (d,
1H, CHdCH, J=12.0 Hz, b isomer), 6.71 (s, 2H, CH aromatics,
a isomer), 6.75 (s, 2H, CH aromatics, b isomer), 7.42-7.53 (m,
8H), 7.57 (d, 1H, CHdCH, J = 16.0 Hz, a isomer), 7.60 (d, 1H,
CHdCH, J=16.0 Hz, b isomer), 7.75 (d, 1H, CHdCH, J=12.0
Hz, b isomer), 7.95-8.05 (m, 6H, CH aromatics), 8.22 (d, 2H,
CH aromatics, J=8.4 Hz, a isomer), 8.41 (s, 1H, CH aromatic,
b isomer), 8.44 (s, 1H, CH aromatic, a isomer), 8.64 (d, 1H,
CHdCH, J=16.0 Hz, a isomer) ppm. Compound 3 was tested as
a free base. Anal. (C35H37NO7) C, H, N.
Compound 4 was obtained in the same way by reaction of 32
with trans-3-(anthracen-9-yl)acrylic acid.37 The title compound
(160 mg, 36% yield) was obtained as an oil and resulted in a 50/
50 mixture of trans/trans (a) and trans/cis (b) isomers. IR (neat) ν
cm-1 1710 (CO). 1H NMR (CDCl3) δ 0.93-1.00 (m, 2H, CH2, b
isomer), 1.47 (t, 2H, CH2N, J = 7.2 Hz, b isomer), 1.55-1.63
(m, 2H, CH2, b isomer), 1.87 (s, 3H, NCH3, b isomer),
1.89-1.98 (m, 4H, CH2, a isomer), 2.07 (t, 2H, CH2N, J =
7.2 Hz, b isomer), 2.28 (s, 3H, NCH3, a isomer), 2.49-2.56 (m,
4H, CH2N, a isomer), 3.68 (t, 2H, CH2OCO, J = 6.4 Hz, b
isomer), 3.83-3.88 (m, 18H, 6 OCH3), 4.11 (t, 2H, CH2OCO, J =
6.4 Hz, b isomer), 4.28 (t, 2H, CH2OCO, J = 6.4 Hz, a isomer),
4.39 (t, 2H, CH2OCO, J = 6.4 Hz, a isomer), 6.30 (d, 1H,
CHdCH, J = 16.0 Hz, a isomer), 6.33 (d, 1H, CHdCH, J =
16.0 Hz, b isomer), 6.43 (d, 1H, CHdCH, J = 16.0 Hz, a
isomer), 6.61 (d, 1H, CHdCH, J = 12.0 Hz, b isomer), 6.68 (s,
2H, CH aromatics, a isomer), 6.75 (s, 2H, CH aromatics, b
isomer), 7.43-7.50 (m, 10H), 7.59 (d, 1H, CHdCH, J = 12.0
Hz, b isomer), 7.98-8.04(m, 6H, CHaromatics), 8.22(d, 2H, CH
aromatics, J = 8.4 Hz, a isomer), 8.40 (s, 1H, CH aromatic, b
isomer), 8.42 (s, 1H, CH aromatic, a isomer), 8.63 (d, 1H,
CHdCH, J = 16.0 Hz, a isomer) ppm. Compound 4 was tested
as a free base. Anal. (C36H39NO7) C, H, N.
Compounds 5-12, 15-19, and 21 were obtained in the same
way by reaction of the corresponding alcohol with the suitable
acyl chloride. Compounds 5-12 and 21 were transformed into
the oxalate and recrystallized from ethyl acetate, and com-
pounds 13, 14, and 17-19 were transformed into the hydro-
chloride and recrystallized from the solvent reported in Table S1
(Supporting Information). Compounds 15 and 16 were tested as
free bases. Their chemical and physical characteristics are
reported in Table S1 (Supporting Information), and IR, 1H
NMR, and 13C NMR spectra are reported in Tables S2 and S3
(Supporting Information).
General Procedure for the Synthesis of Haloesters (22-26). A
1 mmol portion of the appropriate carboxylic acid (trans-
3-(3,4,5-trimethoxyphenyl)acrylic acid, anthracene-9-carboxy-
lic acid, trans-3-(3,4-dimethoxyphenyl)acrylic acid) was trans-
formed into the acyl chloride by reaction with SOCl2 (2 mmol), in
5 mL of CHCl3 (free of EtOH), at 60 °C for 4-8 h. 10-Chlo-
roanthracene-9-carbonyl chloride was obtained by reaction of
anthracene-9-carboxylic acid with SOCl2 at 80 °C for 8 h.
The reaction mixture was cooled to room temperature, and
the solvent was removed under reduced pressure. The acyl
chloride obtained was dissolved in CHCl3 (free of EtOH), and
the suitable alcohol (3-bromopropan-1-ol or 5-chloropentan-1-
ol) (1 equiv) was added. The reaction mixture was heated to
60 °C for 4-8 h and then cooled to room temperature, treated
with CH2Cl2, and the organic layer washed with 10% NaOH
solution. After drying with Na2SO4, the solvent was removed
under reduced pressure. The substances obtained were almost
1
pure and used as such for the next reaction. Their IR and H
NMR spectra are consistent with the proposed structures.
The spectra of trans-3-(3,4,5-trimethoxyphenyl)acrylic acid
3-bromopropyl ester 22 are reported as an example. IR (nujol) ν
cm-1 1714 (CO). 1H NMR (CDCl3) δ 2.21-2.23 (m, 2H, CH2),
3.52 (t, 2H, CH2Br, J = 6.8 Hz), 3.88 (s, 3H, OCH3), 3.89 (s, 6H,
2 OCH3), 4.34 (t, 2H, CH2OCO, J = 6.0 Hz), 6.34 (d, 1H,
CHdCH, J = 15.6 Hz), 6.75 (s, 2H, CH aromatics), 7.60 (d, 1H,
CHdCH, J = 15.6 Hz) ppm.
General Procedure for the Synthesis of Hydroxyaminoesters
(27-31). The appropriate haloester (22-26) (1 mmol) and the
suitable aminoalkylalcohol (3-aminopropan-1-ol or 5-amino-
pentan-1-ol) (1.2 mmol) were dissolved in 1 mL of anhydrous
CH3CN and K2CO3 (1 mmol) was added. The mixture was
heated at 60 °C for 5-10 h. The reaction mixture was cooled to
room temperature, treated with CH2Cl2, and the organic layer
was washed with 10% NaOH solution. After drying with
Na2SO4, the solvent was removed under reduced pressure and
the residue purified by flash chromatography using CH2Cl2/abs
EtOH/petroleum ether/NH4OH (340:65:60:8) (compounds 27
and 31), CHCl3/MeOH (95:5) (compounds 28 and 29), or
CH2Cl2/MeOH/NH4OH (98:2:0.2) (compound 30) as eluting
1
system. Yields 50-70%. Their IR and H NMR spectra are
consistent with the proposed structures.
The spectra of trans-3-(3,4,5-trimethoxyphenyl)acrylic acid
3-(3-hydroxypropylamino)propyl ester (27) are reported as an
1
example. IR (neat) ν cm-1 3300 (OH þ NH), 1709 (CO). H
NMR (CDCl3) δ 1.68-1.75 (m, 2H, CH2), 1.84-1.95 (m, 2H,
CH2), 2.40 (bs, NH þ OH), 2.75 (t, 2H, CH2N, J = 7.0 Hz), 2.89
(t, 2H, CH2N, J = 6.0 Hz), 3.81(t, 2H, CH2OH, J = 5.2 Hz),
3.87 (s, 3H, OCH3), 3.89 (s, 6H, 2 OCH3), 4.27 (t, 2H, CH2OCO,
J = 6.4 Hz), 6.34 (d, 1H, CHdCH, J = 16.0 Hz), 6.75 (s, 2H,
CH aromatics), 7.60 (d, 1H, CHdCH, J = 16.0 Hz) ppm.
General Procedure for the Synthesis of Methylhydroxyami-
noesters (32-36). A 1 mmol portion of the appropriate hydro-
xyaminoester (27-31) was dissolved in 15 mL of anhydrous
ethanol and HCOOH (17 mmol) and 37% HCHO solution
(5 mmol) were added. The mixture was heated to 80 °C for 2-9 h
and concentrated in vacuo. The residue was then dissolved in
CH2Cl2, and the organic layer was washed with 10% NaOH
solution. After drying with Na2SO4, the solvent was removed
under reduced pressure. Yields 95-100%. Their IR and 1H
NMR spectra were consistent with the proposed structures.
The spectra of trans-3-(3,4,5-trimethoxyphenyl)acrylic acid
3-[(3-hydroxypropyl)methylamino]-propyl ester (32) are re-
1
ported as an example. IR (neat) ν cm-1 1710 (CO). H NMR
3,4,5-Trimethoxybenzoic Acid 5-({5-[trans-3-(3,4-Dimethoxy-
phenyl)acryloyloxy]pentyl}-methylamino)pentyl ester (20). A so-
lution of compound 36 (50 mg, 0.127 mmol) in 5 mL of CH2Cl2
was cooled at 0 °C, and 38 mg (0.178 mmol) of 3,4,5-trimethox-
ybenzoic acid, 5 mg (0.043 mmol) of 4-dimethylaminopiridine
(CDCl3) δ 1.68-1.74 (m, 2H, CH2), 1.87-1.94 (m, 2H, CH2),
2.23 (s, 3H, NCH3), 2.50 (t, 2H, CH2N, J = 7.2 Hz), 2.61 (t, 2H,
CH2N, J = 6.0 Hz), 3.80 (t, 2H, CH2OH, J = 5.2Hz), 3.87 (s, 3H,
OCH3), 3.88 (s, 6H, 2 OCH3), 4.24 (t, 2H, CH2OCO, J = 6.4 Hz),