2500
J. A. Butera et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2495–2501
were added, and the mixture was stirred at rt overnight.
trituration with petroleum ether afforded 1.18 g (39%) of
3-[2-oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-ethoxy-cy-
clobut-3-ene-1,2-dione as a light yellow solid: 1H NMR
(DMSO-d6): d 11.51 (s, 1H), 7.60 (ABq, 2H), 7.24 (ABq,
2H), 4.59 (q, 2H), 1.89 (s, 3H), 1.19 (t, 3H). This
intermediate (0.350 g, 1.07 mmol) and 2-amino-3,3-di-
methylbutane (0.13 mL, 0.998 mmol) were stirred together
in ethanol (6 mL) at rt overnight. Diethyl ether (25 mL)
was added and the precipitated product was collected by
filtration. It was stirred in diethyl ether/petroleum ether
overnight, filtered, and dried in vacuo to afford 0.15 g
(37%) of 3-[2-oxo-1-(4-trifluoromethyl-phenyl)-propyl]-
4-(1,1,1-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione
(12.2) as an off-white solid (1H NMR in CDCl3 suggested
the presence of both the keto and enol forms in about an
Dilution with diethyl ether (200 mL) followed by aqueous
work up with NH4Cl, 10% KF, and brine afforded crude
product, which was dissolved in hot ethyl acetate, decol-
orized (charcoal), and filtered. The filtrate was treated with
hexane and allowed to cool. 3-Isopropoxy-4-(4-methoxy-
phenyl)-cyclobut-3-ene-1,2-dione precipitated as a light
1
yellow solid (2.46 g, 54%): H NMR (DMSO-d6): d 7.89
(d, 2H), 7.15 (d, 2H), 5.45 (hept, 1H), 3.82 (s, 3H), 1.48 (d,
6H). To
a solution of the intermediate (0.150 g,
0.609 mmol) in ethanol (3 mL) was added 1,1-dimethyl-
2-phenyl-ethylamine (0.182 g, 1.22 mmol). The mixture
was stirred at 70 °C overnight, then filtered hot through a
pad of silica gel. The filtrate was concentrated and the
resulting residue was recrystallized from ethyl acetate/
hexanes to give 0.170 g (83%) of 3-(1,1-dimethyl-2-phenyl-
ethylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione
(8.3) as a tan solid: mp 150–151 °C; 1H NMR (DMSO-d6):
d 8.28 (s, 1H), 8.00 (m, 2H), 7.28 (m, 2H), 7.26 (m, 1H),
7.13 (m, 2H), 7.09 (m, 2H), 3.82 (s, 3H), 3.10 (s, 2H), 1.42
(s, 6H); MS (m/z) 335 [M+]. Anal. Calcd for C21H21NO3:
C, 75.20; H, 6.31; N, 4.18. Found: C, 74.35; H, 6.41; N,
3.90. Compound 9.2: To a heterogeneous mixture of CuI
(178 mg, 0.932 mmol) and NaI (2.09 g, 14.0 mmol) in
anhydrous DMF (5.0 mL) was added 4-methoxybenzyl
chloride. The reaction mixture, was stirred for 30 min at
rt, whereupon a solution of 3-isopropoxy-4-(tri-n-butyl-
stannyl)-3-cyclobut-3-ene-1,2-dione (4.00 g, 9.32 mmol) in
DMF (5.0 mL) was added, followed by addition of the
benzylchlorobis-(triphenylphosphine)palladium(II) cata-
lyst (530 mg, 0.699 mmol). Upon stirring at rt for 2 h,
the mixture was diluted with ethyl acetate (250 mL), and
subjected to aqueous work up with saturated NH4Cl, 10%
KF and brine (100 mL). The organic phase was dried over
Na2SO4/charcoal and submitted to flash chromatography
(40% ether–petroleum ether) affording 3-(4-methoxy-benz-
1
8:1 ratio): mp 178.2–179.8 °C; H NMR (CDCl3): d 11.74
(s, 1H), 7.73 (ABq, 2H), 7.39 (ABq, 2H), 3.92 (m, 1H),
1.86 (s, 3H), 0.93 (d, 3H), 0.69 (s, 9H); MS (m/z) 381 [M+].
Anal. Calcd for C20H22NO3F3: C, 62.98; H, 5.81; N, 3.67.
Found: C, 62.67; H, 5.72; N, 3.56. Compound 16.2: To a
heterogeneous mixture of CrCl2 (3.98 g, 32.4 mmol) in
THF (40 mL) at 0 °C was added via syringe pump over 1 h
(in the total absence of light) a solution of 4-bromobenz-
aldehyde (1.00 g, 5.40 mmol) and CHI3 (4.25 g,
10.8 mmol) in THF (20 mL). The cold bath was removed,
and the mixture stirred at rt for 1 h. The reaction mixture
was diluted with 1:1 ether–hexanes (200 mL), then filtered
through a short pad of SiO2, and concentrated to give
crude (E)-1-iodo-2-(4-bromophenyl)ethylene. The com-
pound (5.4 mmol) was used as is and treated with CuI
(0.103 g, 0.54 mmol), benzylchlorobis-(triphenylphos-
phine)palladium(II) (0.307 g, 0.42 mmol), and 3-isoprop-
oxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione (3.11
mL, 8.27 mmol) in DMF (18 mL) at rt (in the dark). An
aqueous workup and filtration through a plug of silica gel
afforded 0.298 g (17%) of 4-isopropoxy-3-[(E)-2-(4-bromo-
yl)-4-isopropoxy-cyclobut-3-ene-1,2-dione
as
golden
phenyl)-vinyl]-cyclobut-3-ene-1,2-dione as a dark oil,
which was used directly in the next step. To this
intermediate (0.288 g, 0.898 mmol) in ethanol (3.5 mL)
brown oil (1.04 g, 43%): 1H NMR (CDCl3): d 7.20
(ABq, 2H), 6.85 (ABq, 2H), 5.38 (hept, 1H), 3.83 (s,
2H), 3.79 (s, 3H), 1.43 (d, 6H). In a manner similar to
compound 8.3, the intermediate (350 mg, 1.34 mmol) was
dissolved in anhydrous isopropyl alcohol (7.0 mL) and
was treated with 2-amino-3,3-dimethylbutane (272 mg,
2.69 mmol) at rt, affording 0.124 g (31%) of 3-(4-methoxy-
benzyl)-4-(1,2,2-trimethyl-propylamino)cyclobut-3-ene-1,2-
dione (9.2) one-quarter hydrate (1H NMR in DMSO-d6
suggested the presence of amide rotamers in a ratio of
approximately 3:1): mp 137.4–138.1 °C; 1H NMR
(DMSO-d6): d 8.63 (d, 1H), 7.16 (ABq, 2H), 6.87 (ABq,
2H), 3.90 (m, 1H), 3.70 (s, 2H), 1.15 (d, 3H), 0.84 (s, 9H);
MS (m/z) 301 [M+]. Anal. Calcd for C18H23NO3Æ0.25
H2O: C, 70.68; H, 7.74; N, 4.58. Found: C, 70.43; H, 7.77;
N, 4.55. Compound 12.2: A solution of 1-[(4-trifluoro-
methyl)phenyl]-2-propanone16 (1.86 g, 9.208 mmol) in
THF (10 mL) was added dropwise (under N2) to a cooled
(ꢀ78 °C) solution of potassium bis(trimethylsilyl)amide
(19.3 mL; 0.5 M in toluene, 9.67 mmol) in THF/diethyl
ether (1:1 ratio, 80 mL). The mixture stirred at ꢀ78 °C for
15 min and was then stirred at rt for 2.5 h. The enolate
solution was cooled to ꢀ78 °C and added by cannula to a
cooled (ꢀ78 °C) flask containing diethyl squarate
(1.50 mL, 10.13 mmol) in THF/diethyl ether (1:1 ratio,
20 mL). The reaction was stirred for 15 min at ꢀ78 °C and
was then allowed to warm to rt over a 1 h. The reaction
was concentrated to give a residue, which was partitioned
between 0.1 N HCl and ethyl acetate. The organic phase
was washed with brine, dried (MgSO4), and concentrated
to give crude product. Purification by flash column
chromatography (2:1 hexanes/ethyl acetate) followed by
was
added
2-amino-3,3-dimethylbutane
(241 lL,
1.80 mmol). The mixture was stirred at rt overnight,
diluted with methanol and filtered. The solid was washed
with cold methanol, and dried in vacuo at 60 °C to afford
3-[(E)-2-(4-bromo-phenyl)-vinyl]-4-(1,2,2-trimethyl-propyl-
amino)-cyclobut-3-ene-1,2-dione (127 mg, 39%) (16.2) as
a hygroscopic yellow solid (1H NMR in DMSO-d6
suggested the presence of amide rotamers in a ratio of
approximately 4:1): mp 192.3–192.9 °C; 1H NMR
(DMSO-d6): d 8.87 (d, 1H), 7.71 (m, 5H), 7.46 (d, 1H),
4.02 (dq, 1H), 1.19 (d, 3H), 0.90 (s, 9H); IR (KBr) 3310,
2970, 1760, 1705, 1575, 1480, 1430, 1300, 1220, 1160, 1070,
1005, 975, 875, 820, 800 cmꢀ1; MS (m/z) 361/363 [M+].
Anal. Calcd for C18H20BrNO2: C, 59.68; H, 5.56; N, 3.87.
Found: C, 59.55; H, 5.38; N, 3.72.
13. Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55,
5359.
14. Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie, S. S.;
Stille, J. K. J. Am. Chem. Soc. 1984, 106, 6417.
15. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408.
16. Saari, W. S.; Williams, J.; Britcher, S. F.; Wolf, D. E.;
Kuehl, F. A. J. Med. Chem. 1967, 10, 1008.
17. Protocol for determination of in vitro relaxant properties
in bladder and aortic tissue reported in: Butera, J. A.;
Antane, S. A.; Hirth, B. H.; Lennox, J. R.; Sheldon, J. H.;
Norton, N. W.; Warga, D.; Argentieri, T. M. Bioorg. Med.
Chem. Lett. 2001, 11, 2093.
18. Brief cell EP protocol: Human bronchial smooth muscle
cells were acquired from Clonetics (Walkersville, MD) and