J. R. Cashman, S. Ghirmai / Bioorg. Med. Chem. 17 (2009) 6890–6897
6895
1H), 4.95 (m, 1H), 3.93 (m, J = 4.5 Hz, 2H), 2.2 (m, 2H); HRMS calcd
for C15H13NNaO3S, 310.0514, found 310.0512.
for another 2 h, 3-chloro-1-thiophene-2-yl-propan-1-ol (0.25 g,
1.4 mmol) in THF (1.5 ml) was added. The reaction mixture was
stirred at room temperature for 36 h. The solvent was evaporated
and diethyl ether was added to the residue. After a few minutes
of stirring, the solution formed a white precipitate. The precipitate
was filtered through filter paper. The ether was evaporated and the
crude product was purified by flash chromatography (hexane/
ether, 30/1, v/v) giving 60 mg, 14% yield of the product as a thick
oil. Rf = 0.43; 1H NMR (CDCl3) d 8.3 (m, 1H), 7.75 (m, 1H), 7.55–
7.28 (m, 5H), 7.17 (m, 1H), 6.93 (m, 1H), 6.86 (m, 1H), 5.92 (m,
1H), 3.84 (m, 1H), 3.63 (m, 1H), 2.78 (m, 1H), 2.44 (m, 1H).
4.1.1.6. 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-1,3-dione,
(R)- 5. Compound (R)-5 was synthesized according to the procedure
described for compound (S)-5. Analytical data were in accord with
compound (R)-5. Rf = 0.23; mp = 128 °C; ½a D25
ꢀ3.55 (c 4.5, MeOH),
ꢅ
1H NMR (CDCl3) d 7.87 (m, 2H), 7.74 (m, 2H), 7.19 (m, 1H), 6.96 (m,
1H), 6.9 (m, 1H), 4.95 (m, 1H), 3.93 (m, J = 4.5 Hz, 2H), 2.2 (m, 2H);
HRMS calcd for C15H13NNaO3S, 310.0514, found 310.0509.
4.1.1.7. 3-Amino-1-thiophen-2-yl-propan-1-ol, (S)-6. The phtha-
lamide (S)-5 (170 mg, 0.59 mmol) was dissolved in methanol (5 mL)
and hydrazine monohydrate (0.14 mL, 2.96 mmol) was added. The
mixture was stirred at room temperature overnight. The precipitate
was filtered off, washed with methanol and the solvent was re-
moved to give a white solid. The white crude product was purified
by a small plug of C18 silica gel (100% methanol) to afford 59 mg,
64% yield of compound (S)-6 as a white solid. 1H NMR (CDCl3) d
7.18 (m, 1H), 6.96–6.85 (m, 2H), 6.05 (br s, 1H), 5.16 (m, 1H), 3.3
(m, 2H), 2.1 (m, 2H).
4.1.1.12. 2-[3-Chloro-1-(naphthalen-1-yloxy)-propyl]-thiophene,
(S)-8. Compound (S)-8 was prepared according to the procedure
described for compound (R)-8 giving 51 mg, 12% yield of (S)-5 as
a thick oil. 1H NMR (CDCl3) d 8.3 (m, 1H), 7.75 (m, 1H), 7.55–7.28
(m, 5H), 7.17 (m, 1H), 6.93 (m, 1H), 6.86 (m, 1H), 5.92 (m, 1H),
3.84 (m, 1H), 3.63 (m, 1H), 2.78 (m, 1H), 2.44 (m, 1H).
4.1.1.13. 2-[3-(Naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-iso-
indole-1,3-dione, (R)-9. 2-[3-Chloro-1-(naphthalene-1-yloxy)-
propyl]-thiophene (17 mg, 0.06 mmol) was dissolved in dry
DMF (0.5 ml). To this solution, sodium iodide (1 mg, 0.006 mmol)
and potassium phthalimide (31 mg, 0.17 mmol) were added and
the reaction mixture was stirred at 85 °C for 48 h. The progress
of the reaction was monitored by TLC (3:1, hexane/ethyl acetate).
The solvent was evaporated and the crude product was purified
by flash chromatography (hexane/ethyl acetate, 3/1, v/v) to give
15 mg, 65% yield of the desired product as a white powder.
Rf = 0.32; 1H NMR (CDCl3) d 8.28 (m, 1H), 7.87 (m, 1H), 7.77–
7.71 (m, 3H), 7.63 (m, 2H), 7.42–7.35 (m, 4H), 7.18 (m, 1H),
7.12 (m, 1H), 6.81 (m, 1H), 5.78 (m, 1H), 4.08 (m, 1H), 3.95 (m,
1H), 2.73 (m, 1H), 2.43 (m, 1H); HRMS calcd for C25H20NO3S
436.0984, found 436.0985.
4.1.1.8. 3-Amino-1-thiophen-2-yl-propan-1-ol, (R)-6. The phtha-
lamide (R)-5 (250 mg, 0.87 mmol) was dissolved in methanol
(20 mL) and hydrazine monohydrate (0.21 mL, 4.35 mmol) was
added and the mixture was stirred at room temperature overnight.
The precipitate was filtered off, the solid was washed with methanol
and the solvent was removed to give a white solid. The white crude
product was purified by a small plug of C18 silica gel (100% metha-
nol) to afford 122 mg, 89% yield of compound (R)-6 as a white solid.
1H NMR (CDCl3) d 7.18 (m, 1H), 6.96–6.85 (m, 2H), 6.05 (br s, 1H),
5.16 (m, 1H), 3.3 (m, 2H), 2.1 (m, 2H).
4.1.1.9. 1-((S)-3-Hydroxy-3-(thiophen-2-yl)propyl)-3-((R)-1-(naph-
thalen-1-yl)ethyl)urea, (S,R)-7. 3-Amino-1-thiophen-2-yl-propan-
1-ol, (S)-6 (10 mg, 0.06 mmol) was dissolved in toluene (0.2 mL).
(R)-(ꢀ)-1-(1-naphthyl)ethyl isocyanate (11 mg, 0.06 mmol) was
slowly added and the mixture was stirred at room temperature over-
night. Solvent was removed and the resulting material was purified
by PTLC (MeOH/DCM, 1/20, v/v) to give 20 mg of the product.
Rf = 0.34, ESI/MS: m/z = 377 (MNa+). 1H NMR d 8.31 (m, 1H), 8.15
(m, 1H), 7.85 (m, 2H), 7.56 (m, 3H), 7.18 (m, 1H), 6.9 (m, 2H), 5.96
(m, 1H), 4.75 (m, 2H), 4.5 (m, 1H), 3.66 (m, 1H), 3.08 (m, 1H), 1.78
(d, J = 6.6 Hz, 2.3H), 1.65 (d, J = 6.6 Hz, 0.7H).
4.1.1.14. 2-[3-(Naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-iso-
indole-1,3-dione, (S)-9. Compound (S)-9 was prepared according
to the procedure described for compound (R)-9 and afforded
40 mg, 75% yield of (S)-9 as a white powder. (hexane/ethyl acetate,
3/1, v/v). Rf = 0.32; 1H NMR (CDCl3) d 8.28 (m, 1H), 7.87 (m, 1H),
7.77–7.71 (m, 3H), 7.63 (m, 2H), 7.42–7.35 (m, 4H), 7.18 (m, 1H),
7.12 (m, 1H), 6.81 (m, 1H), 5.78 (m, 1H), 4.08 (m, 1H), 3.95 (m,
1H), 2.73 (m, 1H), 2.43 (m, 1H). HRMS calcd for C25H20NO3S
436.0984, found 436.0984.
4.1.1.10. 1-((R)-3-Hydroxy-3-(thiophen-2-yl)propyl)-3-((R)-1-
(naphthalen-1-yl)ethyl)urea, (R,R)-7. 3-Amino-1-thiophen-2-yl-
propan-1-ol, (R)-6 (10 mg, 0.06 mmol) was dissolved in toluene
(0.2 mL). (R)-(ꢀ)-1-(1-naphthyl)ethyl isocyanate (11 mg, 0.06 mmol)
was slowly added and the mixture was stirred at room tempera-
ture overnight. Solvent was removed and the resulting material
was purified by PTLC (MeOH/DCM, 1/20, v/v) to give 21 mg of
the product. Rf = 0.34, ESI/MS: m/z = 377 (MNa+). 1H NMR d 8.14
(t, J = 6.9 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H),
7.46 (m, 4H), 7.2 (m, 1H), 6.88 (m, 2H), 5.63 (m, 1H), 4.75 (m,
2H), 4.5 (m, 1H), 3.66 (m, 1H), 3.08 (m, 1H), 1.85 (m, 1H), 1.65
(m, 3H).
4.1.1.15. 3-(Naphthalen-1-yloxy)-3-thiophen-2-yl-propylamine,
(R)-10b. To a solution of 2-[3-(naphthalen-1-yloxy)-3-thiophen-
2-yl-propyl]-isoindole-1,3-dione, (R)-9 (52 mg, 0.13 mmol) in
anhydrous methanol (2.5 ml) was added hydrazine monohydrate
(0.06 ml, 1.3 mmol). The reaction mixture was stirred at room tem-
perature overnight. The white precipitate was filtered through fil-
ter paper and the filtrate was concentrated. The crude product was
subjected to flash chromatography (CH2Cl2/MeOH/0.1%NH4OH, 8/
1, v/v) to give 29 mg, 79% yield of compound (R)-10b as a thick
light yellow oil. ESI/MS: m/z = 284 (MH+); 1H NMR (CDCl3) d 8.28
(m, 1H), 7.87 (m, 2H), 7.5 (m, 2H), 7.38 (m, 1H), 7.23 (m, 1H),
7.19 (m, 2H), 6.9 (m, 1H), 5.92 (m, 1H), 3.2 (m, 2H), 2.75 (m, 1H),
2. 54 (m, 1H).
4.1.1.11. 2-[3-Chloro-1-(naphthalen-1-yloxy)-propyl]-thiophene,
(R)-8. Diisopropyl azodicarboxylate (0.33 ml, 1.7 mmol) was
added to a solution of triphenylphosphine (0.45 g, 3.4 mmol) in
freshly dried THF (1.4 ml) under Argon gas. The solution formed
a yellow precipitate after 10 min stirring at room temperature. 1-
Naphthol (0.51 g, 3.6 mmol) in THF (1.4 ml) was added to the mix-
ture. The reaction turned into a clear solution and started forming a
precipitate after 15 min stirring at room temperature. After stirring
4.1.1.16. 3-(Naphthalen-1-yloxy)-3-thiophen-2-yl-propylamine,
(S)-10b. Compound (S)-10b was prepared according to the proce-
dure described for compound (R)-10b providing 25 mg, 68% yield
of (S)-10b as a thick light yellow oil. ESI/MS: m/z = 284 (MH+); 1H
NMR (CDCl3) d 8.28 (m, 1H), 7.87 (m, 2H), 7.5 (m, 2H), 7.38 (m,