86 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1
Doherty et al.
compound 46a, 4-methyl-trans-cinnamic acid and 1,4-benzo-
dioxan-6-amine provided the title compound (54%) as pale-
yellow crystals. Mp: 173-175 °C. 1H NMR (DMSO-d6): δ 2.32
(s, 3 H), 4.20 (d, J ) 9.6 Hz, 2 H), 4.21 (d, J ) 9.2 Hz, 2 H),
6.70 (d, J ) 15.6 Hz, 1 H), 6.79 (d, J ) 8.8 Hz, 1 H), 7.03 (dd,
J ) 2.4, 8.8 Hz, 1 H), 7.24 (d, J ) 7.6 Hz, 2 H), 7.35 (d, J ) 2.4
Hz, 1 H), 7.49 (d, J ) 8.4 Hz, 2 H), 7.50 (d, J ) 15.6 Hz, 1 H),
10.00 (s, 1 H). MS (ESI, pos. ion) m/z: 296 (M + 1). Anal.
(C18H17NO3): C, H, N.
7.63 (s, 1 H), 10.02 (s, 1 H). MS (ESI, pos. ion) m/z: 338 (M +
1). Anal. (C21H23NO3): C, H, N.
(E)-3-(4-Bromophenyl)-N-(2,3-dihydrobenzo[b][1,4]-
dioxin-6-yl)acrylamide (48i). Following the procedure de-
scribed for compound 46a, 4-bromo-trans-cinnamic acid and
1,4-benzodioxan-6-amine provided the title compound (43%)
as pale-yellow needles. Mp: 180-182 °C. 1H NMR (DMSO-
d6): δ 4.21 (d, J ) 9.0 Hz, 2 H), 4.22 (d, J ) 9.3 Hz, 2 H), 6.78
(d, J ) 14.2 Hz, 1 H), 6.81 (d, J ) 8.6 Hz, 1 H), 7.04 (dd, J )
2.3, 8.7 Hz, 1 H), 7.36 (d, J ) 2.2 Hz, 1 H), 7.52 (d, J ) 15.8
Hz, 1 H), 7.56 (d, J ) 8.5 Hz, 2 H), 7.64 (d, J ) 8.4 Hz, 2 H),
10.07 (s, 1 H). MS (ESI, pos. ion) m/z: 360, 362 (M + 1, M +
3). Anal. (C17H14BrNO3): C, H, N, Br.
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-eth-
ylphenyl)acrylamide (48c). Analogous to the procedure
described for compound 47a, triethyl phosphonoacetate, 4-eth-
ylbenzaldehyde, and 1,4-benzodioxan-6-amine provided the
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(E)-3-(4-Chlorophenyl)-N-(2,3-dihydrobenzo[b][1,4]-
dioxin-6-yl)acrylamide (48j). Following the procedure de-
scribed for compound 46a, 4-chloro-trans-cinnamic acid and
1,4-benzodioxan-6-amine provided the title compound (37%)
title compound as pale-yellow crystals. Mp: 119-120 °C. H
NMR (DMSO-d6): δ 1.02 (t, J ) 7.6 Hz, 3 H), 2.62 (q, J ) 7.6
Hz, 2 H), 4.20 (d, J ) 9.2 Hz, 2 H), 4.21 (d, J ) 9.2 Hz, 2 H),
6.71 (d, J ) 15.6 Hz, 1 H), 6.79 (d, J ) 8.8 Hz, 1 H), 7.04 (dd,
J ) 2.4, 8.8 Hz, 1 H), 7.27 (d, J ) 8.0 Hz, 2 H), 7.36 (d, J ) 2.0
Hz, 1 H), 7.50 (d, J ) 15.2 Hz, 1 H), 7.51 (d, J ) 8.4 Hz, 2 H),
10.00 (s, 1 H). MS (ESI, pos. ion) m/z: 310 (M + 1). Anal.
(C19H19NO3): C, H, N.
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as pale-tan crystals. Mp: 187-188 °C. H NMR (DMSO-d6):
δ 4.22 (d, J ) 9.1 Hz, 2 H), 4.23 (d, J ) 9.2 Hz, 2 H), 6.78 (d,
J ) 15.7 Hz, 1 H), 6.82 (d, J ) 8.7 Hz, 1 H), 7.05 (dd, J ) 2.3,
8.7 Hz, 1 H), 7.37 (d, J ) 2.2 Hz, 1 H), 7.51 (d, J ) 8.5 Hz, 2
H), 7.55 (d, J ) 15.9 Hz, 1 H), 7.64 (d, J ) 8.5 Hz, 2 H), 10.08
(s, 1 H). MS (ESI, pos. ion) m/z: 316 (M + 1). Anal.
(C17H14ClNO3): C, H, N, Cl.
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-iso-
propylphenyl)acrylamide (48d). Following the procedure
described for compound 46a, 4-isopropyl-trans-cinnamic acid
and 1,4-benzodioxan-6-amine provided the title compound
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-fluo-
rophenyl)acrylamide (48k). Following the procedure de-
scribed for compound 46a, 4-fluoro-trans-cinnamic acid and
1,4-benzodioxan-6-amine provided the title compound (50%)
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(43%) as white crystals. Mp: 165-166 °C. H NMR (DMSO-
d6): δ 1.33 (d, J ) 7.2 Hz, 6 H), 2.90 (sept, J ) 6.8 Hz, 1 H),
4.20 (d, J ) 9.2 Hz, 2 H), 4.21 (d, J ) 9.6 Hz, 2 H), 6.71 (d, J
) 15.6 Hz, 1 H), 6.79 (d, J ) 8.8 Hz, 1 H), 7.04 (dd, J ) 2.4,
8.4 Hz, 1 H), 7.30 (d, J ) 8.0 Hz, 2 H), 7.36 (d, J ) 2.4 Hz, 1
H), 7.50 (d, J ) 16.0 Hz, 1 H), 7.52 (d, J ) 8.0 Hz, 2 H), 10.01
(s, 1 H). MS (ESI, pos. ion) m/z: 324 (M + 1). Anal.
(C20H21NO3): C, H, N.
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as pale-tan crystals. Mp: 195-196 °C. H NMR (DMSO-d6):
δ 4.22 (d, J ) 9.3 Hz, 2 H), 4.23 (d, J ) 9.3 Hz, 2 H), 6.72 (d,
J ) 15.7 Hz, 1 H), 6.81 (d, J ) 8.7 Hz, 1 H), 7.05 (dd, J ) 2.3,
8.7 Hz, 1 H), 7.29 (t, J ) 8.8 Hz, 2 H), 7.37 (d, J ) 2.2 Hz, 1
H), 7.56 (d, J ) 15.7 Hz, 1 H), 7.68 (dd, J ) 5.7, 8.5 Hz, 2 H),
10.05 (s, 1 H). MS (ESI, pos. ion) m/z: 300 (M + 1). Anal.
(C17H14FNO3): C, H, N, F.
(E)-3-(4-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-
6-yl)acrylamide (48f). Analogous to the procedure described
for compound 47a, triethyl phosphonoacetate, 4-n-butylbenz-
aldehyde, and 1,4-benzodioxan-6-amine provided the title
compound as pale-yellow crystals. Mp: 120-121 °C. 1H NMR
(DMSO-d6): δ 0.91 (t, J ) 7.2 Hz, 3H), 1.27-1.36 (m, 2 H),
1.53-1.60 (m, 2 H), 2.61 (t, J ) 7.6 Hz, 2 H), 4.20-4.23 (m, 4
H), 6.72 (d, J ) 15.6 Hz, 1 H), 6.81 (d, J ) 8.4 Hz, 1 H), 7.05
(dd, J ) 2.4, 8.8 Hz, 1 H), 7.27 (d, J ) 8.0 Hz, 2 H), 7.37 (d, J
) 2.0 Hz, 1 H), 7.50-7.53 (m, 3 H), 10.02 (s, 1 H). MS (ESI,
pos. ion) m/z: 338 (M + 1). Anal. (C21H23NO3): C, H, N.
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-biphe-
nyl)acrylamide (48g). Following the procedure described for
compound 46a, 4-phenyl-trans-cinnamic acid and 1,4-benzo-
dioxan-6-amine provided the title compound (13%) as pale-
yellow needles. Mp: 204-205 °C. 1H NMR (DMSO-d6): δ 4.23
(d, J ) 9.5 Hz, 2 H), 4.24 (d, J ) 9.6 Hz, 2 H), 6.82 (d, J )
11.6 Hz, 1 H), 6.83 (d, J ) 12.8 Hz, 1 H), 7.07 (dd, J ) 2.3, 8.7
Hz, 1 H), 7.40 (m, 2 H), 7.5 (m, 2 H), 7.61 (d, J ) 15.7 Hz, 1
H), 7.70-7.78 (m, 6 H), 10.08 (s, 1 H). MS (ESI, pos. ion) m/z:
358 (M + 1). Anal. Calcd for C23H19NO3: C, 77.29; H, 5.36; N,
3.92. Found: C, 76.11; H, 5.40; N, 3.81.
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-nitro-
phenyl)acrylamide (48l). Following the procedure described
for compound 46a, 4-nitro-trans-cinnamic acid and 1,4-ben-
zodioxan-6-amine provided the title compound (30%) as bright-
yellow crystals. Mp: 247-248 °C. 1H NMR (DMSO-d6): δ 4.23
(d, J ) 8.7 Hz, 2 H), 4.24 (d, J ) 9.0 Hz, 2 H), 6.83 (d, J ) 8.7
Hz, 1 H), 6.96 (d, J ) 15.8 Hz, 1 H), 7.07 (dd, J ) 2.3, 8.7 Hz,
1 H), 7.39 (d, J ) 2.3 Hz, 1 H), 7.67 (d, J ) 15.7 Hz, 1 H), 7.88
(d, J ) 8.7 Hz, 2 H), 8.30 (d, J ) 8.7 Hz, 2 H), 10.22 (s, 1 H).
MS (ESI, pos. ion) m/z: 327 (M + 1). Anal. (C17H14N2O5): C,
H, N.
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-(tri-
fluoromethyl)phenyl)acrylamide (48m). Following the
procedure described for compound 46a, 4-trifluoromethyl-
trans-cinnamic acid and 1,4-benzodioxan-6-amine provided the
title compound (33%) as yellow needles. Mp: 200-201 °C. 1H
NMR (DMSO-d6): δ 4.22 (d, J ) 9.0 Hz, 2 H), 4.23 (d, J ) 9.1
Hz, 2 H), 6.82 (d, J ) 8.7 Hz, 1 H), 6.90 (d, J ) 15.8 Hz, 1 H),
7.06 (dd, J ) 2.3, 8.7 Hz, 1 H), 7.38 (d, J ) 2.3 Hz, 1 H), 7.62
(d, J ) 15.7 Hz, 1 H), 7.80 (d, J ) 11.9 Hz, 2 H), 7.83 (d, J )
11.6 Hz, 2 H), 10.16 (s, 1 H). MS (ESI, pos. ion) m/z: 350 (M
+ 1). Anal. (C18H14F3NO3): C, H, N, F.
(E)-3-(3-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]-
dioxin-6-yl)acrylamide (48h). Analogous to the procedure
of Torii et al.,45 to a round-bottomed flask was added 1-tert-
butyl-3-methylbenzene (1.0 g, 6.8 mmol), ammonium cerium-
(IV) nitrate (18 g, 30 mmol), and 50% aq AcOH (150 mL). The
reaction mixture was stirred at 90 °C for 1.5 h, allowed to cool
to 25 °C, and extracted with 10% EtOAc in hexane. The organic
extract was concentrated in vacuo to provide 3-tert-butylbenz-
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-meth-
oxyphenyl)acrylamide (48n). Following the procedure de-
scribed for compound 46a, 4-methoxy-trans-cinnamic acid and
1,4-benzodioxan-6-amine provided the title compound (38%)
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as white crystals. Mp: 179-180 °C. H NMR (DMSO-d6): δ
3.80 (s, 3 H), 4.22 (d, J ) 9.4 Hz, 2 H), 4.23 (d, J ) 9.7 Hz, 2
H), 6.63 (d, J ) 15.7 Hz, 1 H), 6.81 (d, J ) 8.7 Hz, 1 H), 7.01
(d, J ) 8.7 Hz, 2 H), 7.05 (dd, J ) 2.2, 8.7 Hz, 1 H), 7.37 (d, J
) 2.1 Hz, 1 H), 7.50 (d, J ) 15.7 Hz, 1 H), 7.56 (d, J ) 8.7 Hz,
2 H), 9.96 (s, 1 H). MS (ESI, pos. ion) m/z: 312 (M + 1). Anal.
Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
68.60; H, 5.46; N, 4.41.
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aldehyde in a crude quantitative yield. H NMR (DMSO-d6):
δ 1.32 (s, 9 H), 7.53 (t, J ) 8 Hz, 1 H), 7.72 (d, J ) 7.2 Hz, 1
H), 7.76 (d, J ) 7.6 Hz, 1 H), 7.92 (s, 1 H), 10.01 (s, 1 H).
Analogous to the procedure described for compound 47a,
triethyl phosphonoacetate, 3-tert-butylbenzaldehyde, and 1,4-
benzodioxan-6-amine provided the title compound as white
(E)-N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-hydroxy-
phenyl)acrylamide (48o). Following the procedure described
for compound 46a, 4-hydroxy-trans-cinnamic acid and 1,4-
benzodioxan-6-amine provided the title compound (53%) as
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crystals. Mp: 168-170 °C. H NMR (DMSO-d6): δ 1.30 (s, 9
H), 4.20 (d, J ) 9.2 Hz, 2 H), 4.21 (d, J ) 9.6 Hz, 2 H), 6.77 (d,
J ) 15.2 Hz, 1 H), 6.80 (d, J ) 8.4 Hz, 1 H), 7.05 (dd, J ) 2.4,
8.8 Hz, 1 H), 7.36-7.42 (m, 4 H), 7.55 (d, J ) 15.6 Hz, 1 H),
1
pale-tan crystals. Mp: 205-207 °C. H NMR (DMSO-d6): δ