Haloenol Lactones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3289
benzene (2h ) (3.4 g, 20 mmol) in 37.7% yield: 1H NMR (CDCl3)
δ 7.28-7.19 (m, 5H), 4.19 (q, J ) 6.96 Hz, 4H), 3.31 (t, J )
7.50 Hz, 1H), 2.61 (t, J ) 7.69 Hz, 2H), 1.94 (m, 2H), 1.64 (m,
2H), 1.37 (m, 2H), 1.25 (t, J ) 6.96 Hz, 6H).
Hz, 1H), 3.00 (d, J ) 7.69 Hz, 2H), 2.88 (d, J ) 2.56 Hz, 2H),
2.08 (t, J ) 2.56 Hz, 1H).
2-Bu t-2-yn yl-2-cin n a m ylm a lon ic Acid (5c). Compound
5c was synthesized as for 5a from 4c (1.30 g, 4.0 mmol) in
82.6% yield as a yellow oil: 1H NMR (CDCl3) δ 10.60 (broad s,
2H), 7.34-7.19 (m, 5H), 6.55 (d, J ) 15.75 Hz, 1H), 6.07 (dt,
J 1 ) 7.69 Hz, J 2 ) 15.75 Hz, 1H), 2.95 (d, J ) 7.69 Hz, 2H),
2.82 (q, J ) 2.20 Hz, 2H), 1.77 (t, J ) 2.20 Hz, 3H).
2-(3-P h en ylpr opyl)-2-pr opar gylm alon ic Acid (5d). Com-
pound 5d was prepared as for 5a from 4d (6.08 g, 19.2 mmol)
in 97.0% yield as a yellow oil: 1H NMR (CDCl3) δ 10.87 (broad
s, 2H), 7.39-7.22 (m, 5H), 2.94 (d, J ) 2.40 Hz, 2H), 2.74 (m,
2H), 2.23 (m, 2H), 2.08 (t, J ) 2.40 Hz, 1H), 1.70 (m, 2H).
2-Naph th alen -1-ylm eth yl-2-pr opar gylm alon ic Acid (5e).
Compound 5e was synthesized as for 5a from 4e (1.40 g, 4.1
mmol) in 90.7% yield as a yellow oil: 1H NMR (CDCl3) δ 9.27
(broad s, 2H), 8.27-7.36 (m, 7H), 3.94 (s, 2H), 2.76 (d, J )
2.44 Hz, 2H), 2.27 (t, J ) 2.44 Hz, 1H).
2-Ben zyl-2-p r op a r gylm a lon ic Acid (5f). Compound 5f
was prepared as for 5a from 4f (1.03 g, 3.6 mmol) in 98.8%
yield as a yellow oil: 1H NMR (CDCl3) δ 7.85 (broad s, 2H),
7.31-7.19 (m, 5H), 3.40 (s, 2H), 2.73 (d, J ) 2.37 Hz, 2H),
2.20 (t, J ) 2.37 Hz, 1H).
2-P h en eth yl-2-p r op a r gylm a lon ic Acid (5g). Compound
5g was synthesized as for 5a from 4g (3.35 g, 11 mmol) in
89.4% yield as a yellow oil: 1H NMR (CDCl3) δ 7.28-7.15 (m,
5H), 6.12 (broad s, 2H), 2.94 (d, J ) 2.56 Hz, 2H), 2.61 (t, J )
8.42 Hz, 2H), 2.39 (t, J ) 8.42 Hz, 2H), 2.08 (t, J ) 2.56 Hz,
1H); EIMS m/z 246 (M+), 91 (100).
2-(4-P h en ylbu tyl)-2-p r op a r gylm a lon ic Acid (5h ). Com-
pound 5h was prepared as for 5a from 4h (1.80 g, 5.5 mmol)
in 94.0% yield as a yellow oil: 1H NMR (CDCl3) δ 9.76 (broad
s, 2H), 7.30-7.16 (m, 5H), 2.86 (d, J ) 2.56 Hz, 2H), 2.64 (t,
J ) 7.68 Hz, 2H), 2.15 (m, 2H), 2.06 (t, J ) 2.56 Hz, 1H), 1.68
(m, 2H), 1.36 (m, 2H).
Meth od C. 2-Cin n a m yl-2-p r op a r gylm a lon ic Acid Di-
eth yl Ester (4a ). Sodium (334 mg, 14.5 mmol) was dissolved
in 40 mL of absolute EtOH. To the EtONa solution 2.7 g (9.6
mmol) of compound 3a was added, followed by addition of 1.3
g (10 mmol) of propargyl bromide in 20 mL of absolute EtOH.
The resulting mixture was stirred at 40 °C overnight. The
solvent and remaining propargyl bromide were removed by
evaporation in a vacuum, followed by addition of 20 mL of H2O.
The resulting aqueous was extracted with chloroform, and the
combined organic layers were dried over anhydrous Na2SO4
and concentrated in a vacuum to provide 2.6 g (87.2%) of 4a
as a yellow oil: 1H NMR (CDCl3) δ 7.34-7.22 (m, 5H), 6.52
(d, J ) 15.75 Hz, 1H), 6.04 (dt, J 1 ) 7.69 Hz, J 2 ) 15.75 Hz,
1H), 4.23 (q, J ) 7.32 Hz, 4H), 2.97 (dd, J 1 ) 1.1 Hz, J 2 ) 7.69
Hz, 2H), 2.84 (d, J ) 2.57 Hz, 2H), 2.06 (t, J ) 2.57 Hz, 1H),
1.26 (t, J ) 7.32 Hz, 6H).
2-Bu t -2-yn yl-2-cin n a m ylm a lon ic Acid Diet h yl E st er
(4c). Compound 4c was synthesized as for 4a from 3a (1.3 g,
4.8 mmol) and 0.7 g (5.2 mmol) of 1-bromo-2-butyne in 88.8%
yield as a yellow oil: 1H NMR (CDCl3) δ 7.31-7.19 (m, 5H),
6.49 (d, J ) 15.74 Hz, 1H), 6.06 (dt, J 1 ) 7.69 Hz, J 2 ) 15.74
Hz, 1H), 4.20 (q, J ) 7.33 Hz, 4H), 2.93 (d, J ) 7.69 Hz, 2H),
2.78 (q, J ) 2.20 Hz, 2H), 1.78 (t, J ) 2.20 Hz, 3H), 1.26 (t, J
) 7.33 Hz, 6H).
2-(3-P h en ylp r op yl)-2-p r op a r gylm a lon ic Acid Dieth yl
Ester (4d ). Compound 4d was prepared as for 4a from 3d
(5.4 g, 19.6 mmol) and 2.5 g (21.1 mmol) of propargyl bromide
in 98.4% yield as a yellow oil: 1H NMR (CDCl3) δ 7.29-7.12
(m, 5H), 4.16 (q, J ) 7.32 Hz, 4H), 2.82 (d, J ) 2.44 Hz, 2H),
2.65 (m, 2H), 2.10 (m, 2H), 1.98 (t, J ) 2.44 Hz, 1H), 1.54 (m,
2H), 1.22 (t, J ) 7.32 Hz, 6H).
2-Na p h th a len -1-ylm eth yl-2-p r op a r gylm a lon ic Acid Di-
eth yl Ester (4e). Compound 4e was synthesized as for 4a
from 3e (1.4 g, 4.7 mmol) and 625 mg (5.2 mmol) of propargyl
bromide in 86.3% yield as a yellow oil: 1H NMR (CDCl3) δ
8.00-7.37 (m, 7H), 4.10 (q, J ) 7.14 Hz, 4H), 3.90 (s, 2H), 2.72
(d, J ) 2.57 Hz, 2H), 2.20 (t, J ) 2.56 Hz, 1H), 1. (t, J ) 7.14
Hz, 6H).
2-Ben zyl-2-p r op a r gylm a lon ic Acid Dieth yl Ester (4f).
Compound 4f was prepared as for 4a from 3f (1.2 g, 4.8 mmol)
and 625 mg (5.2 mmol) of propargyl bromide in 73.0% yield
as a yellow oil: 1H NMR (CDCl3) δ 7.27-7.15 (m, 5H), 4.20
(q, J ) 7.06 Hz, 4H), 3.39 (s, 2H), 2.68 (d, J ) 2.42 Hz, 2H),
2.14 (t, J ) 2.42 Hz, 1H), 1.25 (t, J ) 7.06 Hz, 6H).
2-P h en eth yl-2-p r op a r gylm a lon ic Acid Dieth yl Ester
(4g). Compound 4g was synthesized as for 4a from 3g (1.26
g, 4.8 mmol) and 625 mg (5.2 mmol) of propargyl bromide in
75.7% yield as a yellow oil: 1H NMR (CDCl3) δ 7.30-7.18 (m,
5H), 4.21 (q, J ) 7.20 Hz, 4H), 2.92 (d, J ) 2.56 Hz, 2H), 2.53
(t, J ) 7.60 Hz, 2H), 2.38 (t, J ) 7.60 Hz, 2H), 2.04 (t, J )
2.56 Hz, 1H), 1.26 (t, J ) 7.20 Hz, 6H).
2-(4-P h en ylbu tyl)-2-p r op a r gylm a lon ic Acid Dieth yl
Ester (4h ). Compound 4h was prepared as for 4a from 3h
(2.0 g, 6.85 mmol) and 883 mg (7.4 mmol) of propargyl bromide
in 79.6% yield as a yellow oil: 1H NMR (CDCl3) δ 7.27-7.14
(m, 5H), 4.18 (q, J ) 7.33 Hz, 4H), 2.79 (d, J ) 2.56 Hz, 2H),
2.60 (t, J ) 7.69 Hz, 2H), 2.07 (m, 2H), 1.98 (t, J ) 2.56 Hz,
1H), 1.65 (m, 2H), 1.21 (m, 8H).
Meth od D. 2-Cin n a m yl-2-p r op a r gylm a lon ic Acid (5a ).
To a solution of 2.60 g (8.3 mmol) of 4a in 20 mL of EtOH,
was added 20 mL of 2 N NaOH. The resulting mixture was
heated at reflux for 3 h. The ethanol was removed by
evaporation, and the remaining aqueous portion was washed
with chloroform. The washed aqueous portion was acidified
to pH 2 with cold HCl and extracted with chloroform. The
extracts were pooled, dried over anhydrous Na2SO4, and
concentrated to provide 2.08 g of 5a in 97.4% yield as a yellow
oil: 1H NMR (CDCl3) δ 9.77 (broad s, 2H), 7.35-7.21 (m, 5H),
6.59 (d, J ) 15.74 Hz, 1H), 6.06 (dt, J 1 ) 7.69 Hz, J 2 ) 15.74
2-Cycloh exylm eth yl-2-p r op a r gylm a lon ic Acid (11a ).
Compound 11a was synthesized as for 5a from 10a (650 mg,
2.2 mmol) in 97.0% yield as a yellow oil: 1H NMR (CDCl3) δ
9.01 (broad s, 2H), 2.84 (d, J ) 2.57 Hz, 2H), 2.04 (t, J ) 2.57
Hz, 1H), 1.99 (d, J ) 6.06 Hz, 2H), 1.64-0.95 (m, 11H); ESI-
MS m/z 239 (M+ + 1).
2-Hexyl-2-p r op a r gylm a lon ic Acid (11b). Compound 11b
was prepared as for 5a from 10b (580 mg, 2 mmol) in 99.0%
yield as a yellow oil: 1H NMR (CDCl3) δ 8.29 (broad s, 2H),
2.83 (d, J ) 2.56 Hz, 2H), 2.00-0.84 (m, 14H); ESI-MS m/z
225 (M+ - 1).
2-Hep tyl-2-p r op a r gylm a lon ic Acid (11c). Compound 11c
was synthesized as for 5a from 10c (1.03 g, 3.48 mmol) in
98.2% yield as a yellow oil: 1H NMR (CDCl3) δ 7.88 (broad s,
2H), 2.83 (d, J ) 2.57 Hz, 2H), 2.00-0.82 (m, 16 H); ESI-MS
m/z 239 (M+ - 1).
2-Octyl-2-p r op a r gylm a lon ic Acid (11d ). Compound 11d
was prepared as for 5a from 10d (1.21 g, 3.90 mmol) in 97.0%
yield as a yellow oil: 1H NMR (CDCl3) δ 8.29 (broad s, 2H),
2.83 (d, J ) 2.56 Hz, 2H), 2.04 (m, 3H), 1.24 (m, 12H), 0.86 (t,
J ) 6.22 Hz, 3H); ESI-MS m/z 253 (M+ - 1).
2-Non yl-2-p r op a r gylm a lon ic Acid (11e). Compound 11e
was synthesized as for 5a from 10e (1.06 g, 3.27 mmol) in
98.2% yield as a yellow oil: 1H NMR (CDCl3) δ 8.31 (broad s,
2H), 2.83 (d, J ) 2.56 Hz, 2H), 2.03 (m, 3H), 1.23 (m, 14H),
0.85 (t, J ) 6.77 Hz, 3H); ESI-MS m/z 267 (M+ - 1).
2-Na p h t h a len -2-ylm et h yl-2-p r op a r gylm a lon ic Acid
(11f). Compound 11f was prepared as for 5a from 10f (2.30 g,
6.8 mmol) in 99.0% yield as a white solid (mp 156-158 °C,
dec): 1H NMR (CD3OD) δ 7.77 (m, 4H), 7.43 (m, 3H), 3.51 (s,
2H), 2.61 (d, J ) 2.48 Hz, 2H), 2.00 (t, J ) 2.48 Hz, 1H).
2-[tr a n s-4-(Tr iflu or om eth yl)cin n am yl]-4-pen tyn oic Acid
(25). Compound 25 was synthesized as for 5a from 24 (620
mg, 2 mmol) in 98.0% yield as a pale-yellow oil: 1H NMR
(CDCl3) δ 9.05 (broad s, 1H), 7.52 (d, J ) 8.06 Hz, 2H), 7.40
(d, J ) 8.54 Hz, 2H), 6.50 (d, J ) 15.87 Hz, 1H), 6.23 (dt, J 1
)
7.33 Hz, J 2 ) 15.87 Hz, 1H), 2.77 (m, 1H), 2.71-2.60 (m, 2H),
2.59-2.54 (m, 1H), 2.51-2.46 (m, 1H), 2.04 (t, J ) 2.68 Hz,