Polycyclic N-heterocyclic compounds 83: Synthesis of 2,4-disubstituted 5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidines and 2,4,5-Trisubstituted 5,6-Dihydro[1]benzofuro[2′,3′:5,6]pyrano[4,3-d] pyrimidines from 4-Chloro-5,6-dihydro[1]benzofuro[3

Article abstract of DOI:10.1002/jhet.1900

Treatment of 2-substituted 4-chloro-5,6-dihydro[1]benzofuro[3′, 2′:2,3]oxepino[4,5-d]pyrimidines with simple alcohols and thiols as nucleophile afforded 2-substituted 4-alkoxy (or sulfanyl) derivatives. In the case of alkoxide nucleophiles, rearranged rea

Full text of DOI:10.1002/jhet.1900

788
Polycyclic N-Heterocyclic Compounds 83: Synthesis of 2,4-Disubstituted
5,6-Dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]pyrimidines and 2,4,
5-Trisubstituted 5,6-Dihydro[1]benzofuro[20,30:5,6]pyrano[4,3-d]pyrimidines
from 4-Chloro-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]pyrimidines
Vol 51
a
b
b
b
*
Kensuke Okuda, Jun-ichi Takano, Takashi Hirota, and Kenji Sasaki
aLaboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
bLaboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku,
Okayama 700-8530, Japan
*
E-mail: okuda@gifu-pu.ac.jp
Received July 31, 2012
DOI 10.1002/jhet.1900
Published online 6 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
Treatment of 2-substituted 4-chloro-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]pyrimidines with
simple alcohols and thiols as nucleophile afforded 2-substituted 4-alkoxy (or sulfanyl) derivatives. In the
case of alkoxide nucleophiles, rearranged reaction products were also obtained. X-ray crystallography was
used to support the structure assignment of the rearranged product.
J Hetercycl Chem, 51, 788 (2014).
Previously, we reported preparation and biological evalu-
ation of 4-chloro-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidines (1) and their 4-amino derivatives (2) as
part of our research to develop anti-platelet aggregation
agents (Figure 1) [1]. Certain of the compounds had potency
comparable with aspirin, so we made the decision to study
structure-activity relationships in this series. Herein, we
describe the further elaboration of 1 to 2,4-disubstituted 5,
6-dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]pyrimidines
(3, 4, 6, 8, and 9) using several oxygen and sulfur nucleo-
philes. During these transformations, we isolated rearranged
byproducts 5 and 7.
analysis. Formation of 5d and 5e can be rationalized by
invoking a [1,2] Wittig type rearrangement, wherein sodium
ethoxide functions as a base as well as a nucleophile [2].
Considering that formation of 5 is dependent on the substitu-
ent at the 2-position of 1, the anion stabilizing effect of the
2-aryl group clearly facilitates this rearrangement reaction.
Intrigued by this type of rearrangement reaction with
sodium ethoxide, we examined reaction of other alkoxides
with 1d. First, sodium n-propoxide was tested, but this
reaction afforded only the usual substituted product (6) in
20% yield (Scheme 2). In the case of sodium isopropoxide,
the reaction gave a complex mixture judged by TLC anal-
ysis, and we were unable to isolate any pure product.
Finally, reaction with tert-butoxide gave the rearranged
compound 7. As expected, tert-butoxide did not serve as
a nucleophile, and the reactive 4-chlorine was retained in
the reaction product. X-ray crystallographic analysis of
the 4-chloro-5-methyl derivative (7) confirmed that the
structures of compounds (5 and 7) contained a new ring
system (Figure 2) [3]. The proposed reaction mechanism
is shown in Scheme 3.
First, methoxide and ethoxide were used as nucleophiles
to replace the reactive 4-chlorine atom of compound 1 to
give 3a–e (24–85%) and 4a–e (37–43%), respectively
(Scheme 1). In the case of 1d and 1e, both of which have
an aryl group at the 2 position instead of alkyl or H, reac-
tion with sodium ethoxide, also produced the rearranged
1
byproducts 5d and 5e. In the H NMR spectrum of 5d,
the ethoxy group was clearly indicated by the 3H triplet
resonance at 1.48 ppm and 2H double quartet resonance at
4.64ppm. In addition, a 3H doublet resonance appeared at
1.60ppm, and 1H quartet resonance appeared at 5.94 ppm,
strongly indicating the presence of the 2-methylpyrane
moiety, whereas the two 2H triplet resonances at 3.42 and
4.57ppm that correspond to the oxepine H5 and H6 of 1d
[1] were absent. These data are consistent with the structure
of 5d. Assignment of this structure was further supported by
FAB-MS and elemental analysis. The structure of 5e was
similarly supported by spectroscopic and instrumental
Finally, ethylene glycol and 2-sulfanylethanol were used
as nucleophiles in reactions with 1 to give 8a–e (25–79%)
and 9a–e (55–87%), respectively (Scheme 4). The biological
properties of the new products will be examined in due course
with the goal of developing new pharmaceutical agents.
EXPERIMENTAL
All melting points were determined on a Yanagimoto (Kyoto,
Japan) micro-melting point apparatus, and are uncorrected.
© 2013 HeteroCorporation

May 2014
Polycyclic N-Heterocyclic Compounds 83
789
General procedure for synthesis of 2-substituted 4-methoxy-
5,6-dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]pyrimidines
(3a–e).
In the case of 1a and 1c, a solution of compound
(200 mg) in methanol (5.0mL) was heated at 60ꢁC with
potassium carbonate (2 equiv) for an appropriate time. After
removal of inorganic salt by filtration, the filtrate was evaporated
in vacuo. Ice-water (50 mL) was poured into the residue; the
resulting precipitate was collected on a filter and recrystallized
from acetonitrile. In the case of 1b, 1d, and 1e, a solution of
compound (200 mg) was refluxed with sodium methoxide [freshly
prepared from Na metal (2 equiv) and anhydrous methanol
(10 mL)] for an appropriate time. After removal of solvent in
vacuo, ice-water (50 mL) was poured into the residue and the
resulting precipitate was recrystallized from acetonitrile.
Figure 1. Substrate (1) and product (2).
4-Methoxy-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]
pyrimidine (3a).
The reaction was stirred at 60ꢁC for 1.5 h
Elemental analyses were performed on a Yanagimoto MT-5 CHN
Corder elemental analyzer. The FAB-mass (m-nitrobenzyl alco-
hol was used as the matrix) and ESI–MS were obtained on a
VG (UK) 70-SE mass spectrometer or a Micromass (Manchester,
UK) AutoSpec-OA-Tof. The IR spectra were recorded on a
Japan Spectroscopic (Hachioji, Japan) diffraction grating A-102
or FT/IR-200 spectrophotometer, and frequencies are expressed
in cmꢀ1. The 1H NMR spectra were recorded on a Varian
(Palo Alto, CA) VXR-200 instrument with tetramethylsilane as
an internal standard. Chemical shifts are given in parts per million
(d) and J values in Hertz, and the signals are designated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; dq, double
quartet; sex, sextet; br, broad; and m, multiplet. Column
chromatography was performed on silica gel (IR-60-63-210-W,
Daiso, Osaka, Japan). TLC was carried out on Kieselgel 60
F254 (Merck, Darmstadt, Germany) or silica gel 70FM (Wako,
Osaka, Japan).
The structure on X-ray analysis was solved by direct methods
with MITHRIL [4] and DIRDIF [5] and refined by the full-matrix
least squares method by using TEXSAN [6]. H atoms were found
by different synthesis and refined isotopically. The displacement
ellipsoids were drawn with the aid of ORTEP II [7]. Most of the
calculations were performed on a VAX 3100 computer using
TEXSAN at the X-ray Laboratory of Okayama University.
to produce, after workup, 3a (68%) as colorless needles, mp
209–210ꢁC. 1H NMR (200MHz, deuterochloroform): d 3.25 (2H,
br t, J = 4.5 Hz, H5), 4.04 (3H, s, CH3), 4.49 (2H, br t, J = 4.5 Hz,
H6), 7.23–7.68 (4H, m, H8, 9, 10, and 11), 8.78 (1H, s, H2);
FAB-MS: m/z 269 (MH+). Anal. Calcd for C15H12N2O3: C,
67.16; H, 4.51; N, 10.44. Found: C, 67.03; H, 4.63; N, 10.45.
4-Methoxy-2-methyl-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidine (3b).
The reaction was refluxed for 1h to
produce 3b (63%) as colorless needles, mp 204–205ꢁC. 1H NMR
(200 MHz, deuterochloroform): d 2.72 (3H, s, 2-CH3), 3.20
(2H, br t, J = 4.3 Hz, H5), 4.01 (3H, s, OCH3), 4.46 (2H, br t,
J = 4.3Hz, H6) 7.21–7.66 (4H, m, H8, 9, 10, and 11); ESI–MS:
m/z 283 (MH+). Anal. Calcd for C16H14N2O3: C, 68.07; H, 5.00;
N, 9.92. Found: C, 68.10; H, 5.02; N, 9.87.
2-Ethyl-4-methoxy-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidine (3c). The reaction was stirred at 60ꢁC for 2 h
to produce 3c (24%) as colorless needles, mp 104–105ꢁC. 1H
NMR (200 MHz, deuterochloroform): d 1.41 (3H, t, J = 7.6 Hz,
CH2CH3), 2.99 (2H, q, J = 7.6 Hz, CH2CH3), 3.21 (2H, br t,
J = 4.3Hz, H5), 4.02 (3H, s, OCH3), 4.46 (2H, br t, J = 4.3 Hz,
H6), 7.21–7.68 (4H, m, H8, 9, 10, and 11); FAB-MS: m/z 297
(MH+). Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45.
Found: C, 68.54; H, 5.49; N, 9.57.
Scheme 1. Preparation of 3, 4, and rearranged product 5.
Scheme 2. Synthesis of 6 and 7.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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K. Okuda, J. Takano, T. Hirota, and K. Sasaki
Vol 51
1H NMR (200MHz, deuterochloroform): d 2.44 (3H, s, 40-CH3),
3.27 (2H, br t, J = 4.2 Hz, H5), 4.14 (3H, s, OCH3), 4.50 (2H, br t,
J = 4.2Hz, H6), 7.22–7.69 (6H, m, H8, 9, 10, 11, and 30, 50), 8.47
(2H, d, J = 8.2 Hz, H20 and 60); ESI–MS: m/z 359 (MH+). Anal.
Calcd for C22H18N2O3: C, 73.73; H, 5.06; N, 7.82. Found: C,
74.08; H, 5.30; N, 7.90.
General procedure for synthesis of 2-substituted 4-ethoxy-5,6-
dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]pyrimidines
(4a–e) and rearranged compounds (5d and 5e). In the case of
1a and 1c, a solution of compound (200 mg) in dry ethanol
(5.0mL) was heated at 60ꢁC (1a) or refluxed (1c) with potassium
carbonate (2 equiv) for an appropriate time. After removal of
inorganic salts by filtration, the filtrate was evaporated in vacuo.
Ice-water (50 mL) was poured into the residue, and the resulting
precipitate was collected on
a
filter and purified by
recrystallization or chromatography on silica gel followed by
recrystallization to give 4a and 4c. In the case of 1b, 1d, and 1e, a
solution of compound (200mg) was refluxed with sodium
ethoxide (freshly prepared from Na metal (2 equiv) and anhydrous
ethanol (10 mL)) for an appropriate time. After removal of solvent
in vacuo, ice-water (50mL) was poured into the residue, and the
resulting precipitate was purified by chromatography on silica gel
followed by recrystallization from a suitable solvent to give 4b,
4d, 5d, 4e, and 5e, as described in the succeeding text.
Figure 2. ORTEP representation of 7.
4-Methoxy-2-phenyl-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
4-Ethoxy-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]
pyrimidine (4a). The reaction was stirred at 60ꢁC for 23 h, and
the product was recrystallized from acetonitrile to give 4a (43%)
as colorless plates, mp 176–178ꢁC. 1H NMR (200MHz,
deuterochloroform): d 1.44 (3H, t, J = 7.2 Hz, CH3), 3.25 (2H, br
t, J = 4.5 Hz, H5), 4.47 (2H, q, J = 7.2 Hz, CH2CH3), 4.49 (2H, br
t, J = 4.5 Hz, H6), 7.23–7.68 (4H, m, H8, 9, 10, and 11), 8.75
(1H, s, H2); FAB-MS: m/z 283 (MH+). Anal. Calcd for
C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 68.15; H,
5.12; N, 10.10.
[4,5-d]pyrimidine (3d). The reaction was refluxed for 115 h to
1
produce 3d (82%) as colorless plates, mp 222–224ꢁC. H NMR
(200 MHz, deuterochloroform): d 3.28 (2H, br t, J=4.2Hz, H5),
4.14 (3H, s, OCH3), 4.50 (2H, br t, J= 4.2 Hz, H6), 7.22–7.68 (7H,
m, H8, 9, 10, 11, and 30, 40, 50), 8.54–8.63 (2H, m, H20 and 60);
FAB-MS: m/z 345 (MH+). Anal. Calcd for C21H16N2O3: C, 73.24;
H, 4.68; N, 8.13. Found: C, 73.54; H, 4.81; N, 8.10.
4-Methoxy-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro[30,20:2,3]
oxepino[4,5-d]pyrimidine (3e).
The reaction was refluxed for
120 h to produce 3e (85%) as colorless needles, mp 220–223ꢁC.
Scheme 3. The proposed mechanism for formation of 7.
Scheme 4. Preparation of 8 and 9.
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Polycyclic N-Heterocyclic Compounds 83
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4-Ethoxy-2-methyl-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidine (4b). The reaction was refluxed for 2 h, and the
product was recrystallized from acetonitrile to give 4b (37%) as
colorless needles, mp 181–183ꢁC. 1H NMR (200 MHz,
deuterochloroform): d 1.42 (3H, t, J=7.1Hz, CH2CH3), 2.70 (3H, s,
2-CH3), 3.21 (2H, br t, J= 4.2 Hz, H5), 4.46 (2H, q, J=7.1Hz,
CH2CH3), 4.47 (2H, br t, J=4.2Hz, H6), 7.22–7.68 (4H, m, H8, 9,
10, and 11); ESI–MS: m/z 297 (MH+). Anal. Calcd for C17H16N2O3:
C, 68.91; H, 5.44; N, 9.45. Found: C, 68.77; H, 5.50; N, 9.45.
4-Ethoxy-2-ethyl-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
J = 8.1 Hz, H20 and 60); FAB-MS: m/z 373 (MH+). Anal. Calcd
for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 74.20;
H, 5.58; N, 7.52.
2-Phenyl-4-propoxy-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidine (6). A solution of 1d (100 mg, 0.287mmol)
was stirred at 80ꢁC with sodium propoxide (freshly prepared from
Na metal (2 equiv) and anhydrous 1-propanol (5.0 mL)) for 4 h.
After removal of solvent in vacuo, ice-water (50 mL) was added to
the residue, and the mixture was extracted with ethyl acetate
(50 mL ꢂ 3). The combined organic layer was washed with saturated
brine, dried over anhydrous magnesium sulfate, and evaporated in
vacuo. The residue was chromatographed on silica gel. The eluate of
n-hexane/ethyl acetate (38:1) was evaporated in vacuo, and the
residue was recrystallized from cyclohexane to give 6 (21 mg, 20%)
as colorless needles, mp 170–171ꢁC. 1H NMR (200 MHz,
deuterochloroform): d 1.09 (3H, t, J=7.4Hz, CH3), 1.90 (2H, sex,
J=7.4Hz, CH2CH3), 3.29 (2H, br t, J=4.3Hz, H5), 4.52 (2H, br t,
J=4.3Hz, H6), 4.52 (2H, br t, J=7.4Hz, CH2CH2CH3), 7.22–7.68
(7H, m, H8, 9, 10, 11, and 30, 40, 50), 8.52–8.63 (2H, m, H20 and 60);
FAB-MS: m/z 373 (MH+). Anal. Calcd for C23H20N2O3: C, 74.18;
H, 5.41; N, 7.52. Found: C, 73.96; H, 5.55; N, 7.55.
[4,5-d]pyrimidine (4c).
The reaction was refluxed for 120 h,
and the residue was chromatographed on silica gel. The eluate of
n-hexane/ethyl acetate (24:1) was evaporated in vacuo, and the
residue was recrystallized from acetonitrile to give 4c (42%) as
colorless needles, mp 171–174ꢁC. 1H NMR (200 MHz,
deuterochloroform): d 1.39, 1.43 (each 3H, each t, J = 7.1, 7.2 Hz,
2 ꢂ CH3), 2.97 (2H, q, J = 7.1 Hz, 2-CH2CH3), 3.21 (2H, br t,
J = 4.3 Hz, H5), 4.47 (2H, br t, J = 4.3 Hz, H6), 4.49 (2H, q,
J = 7.2 Hz, OCH2CH3), 7.21–7.67 (4H, m, H8, 9, 10, and 11);
FAB-MS: m/z 311 (MH+). Anal. Calcd for C18H18N2O3: C,
69.66; H, 5.85; N, 9.03. Found: C, 69.68; H, 5.79; N, 8.89.
4-Ethoxy-2-phenyl-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidine (4d) and 4-ethoxy-5-methyl-2-phenyl[1]
4-Chloro-5-methyl-2-phenyl-5,6-dihydro[1]benzofuro[20,30:5,6]
pyrano[4,3-d]pyrimidine (7).
To a solution of 1d (200 mg,
benzofuro[20,30:5,6]pyrano[4,3-d]pyrimidine (5d).
The reaction
0.573 mmol) in dry tert-butyl alcohol (10 mL) was added potassium
tert-butoxide (110 mg, 1.00 mmol), and the reaction was refluxed for
1.5 h. After evaporation of solvent in vacuo, ice-water (100 mL) was
added to the residue. The precipitated solid was collected on a filter
and recrystallized from acetonitrile to give 7 (11 mg, 6%) as colorless
was refluxed for 5 h, and the residue was chromatographed on silica
gel. The eluate of n-hexane/ethyl acetate (99:1) was evaporated in
vacuo, and the residue was recrystallized from n-hexane to give 5d
(9%) as colorless needles. A further eluate of n-hexane/ethyl acetate
(49:1) was evaporated in vacuo, and the residue was recrystallized
from acetone to give 4d (40%) as colorless needles. 4d: mp
1
plates, mp 188–191ꢁC. H NMR (200 MHz, deuterochloroform): d
1.70 (3H, d, J=7.0Hz, CH3), 6.01 (1H, q, J=7.0Hz, H5), 7.31–7.68
(7H, H7, 8, 9, 10, and 30, 40, 50), 8.46–8.57 (2H, m, H20 and 60); ESI–
MS: m/z 349 (MH+), 351 (MH+ +2). Anal. Calcd for C20H13ClN2O2:
C, 68.87; H, 3.76; N, 8.03. Found: C, 68.95; H, 3.98; N, 7.98.
1
195–196ꢁC. H NMR (200 MHz, deuterochloroform): d 1.49 (3H,
t, J=7.1Hz, CH3), 3.28 (2H, br t, J= 4.2 Hz, H5), 4.51 (2H, br t,
J=4.2Hz, H6), 4.62 (2H, q, J=7.1Hz, CH2CH3), 7.22–7.69 (7H,
m, H8, 9, 10, 11, and 30, 40, 50), 8.51–8.62 (2H, m, H20 and 60);
FAB-MS: m/z 359 (MH+). Anal. Calcd for C22H18N2O3: C, 73.73;
H, 5.06; N, 7.82. Found: C, 73.73; H, 5.21; N, 7.73. 5d: mp
130ꢁC. 1H NMR (200 MHz, deuterochloroform): d 1.48 (3H, t,
J=7.1Hz, CH2CH3), 1.60 (3H, d, J=6.6Hz, 5-CH3), 4.64 (2H, dq,
J= 7.1, 2.0 Hz, 4-CH2CH3), 5.94 (1H, q, J=6.6Hz, H5), 7.23–7.68
(7H, m, H7, 8, 9, 10, and 30, 40, 50), 8.47–8.58 (2H, m, H20 and 60);
FAB-MS: m/z 359 (MH+). Anal. Calcd for C22H18N2O3: C, 73.73;
H, 5.06; N, 7.82. Found: C, 73.59; H, 5.22; N, 7.83.
Crystal structure analysis of 7 [3]. Crystals for X-ray analysis
were grown from an acetonitrile solution by slow evaporation. This
analytical sample was dried around 100ꢁC under vacuum and
subjected to X-ray crystallographic analysis. Crystal data
C20H13N2O2Cl; M= 348.79; monoclinic, space group P21/n,
a = 7.811(4), b = 10.803 (2), c = 19.276(4)Å, b = 94.82(3)ꢁ,
V = 1621(2)Å3; Z = 4; Dc = 1.429 g cmꢀ3
0.280 ꢂ 0.150 ꢂ 0.440 mm was examined by the o-2θ scan
technique using graphite-monochromated MoK radiation
. A crystal of size
a
4-Ethoxy-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro[30,20:2,3]
oxepino[4,5-d]pyrimidine (4e) and 4-ethoxy-5-methyl-2-(4-
methylphenyl)[1]benzofuro[20,30:5,6]pyrano[4,3-d]pyrimidine
(l = 0.71073Å). Cell dimensions were obtained from 25
reflections (21.0 < 2θ < 22.0ꢁ). A total of 3210 unique data points
were obtained, and 1752 of these having I > 3.00 s (I) were used
in the refinement; R = 0.064, Rw = 0.056, S = 3.83.
General procedure for synthesis of 2-substituted 4-(2-
hydroxyethoxy)-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino[4,5-d]
pyrimidine (8a–e). To a solution of 1a–e (200mg) in dry 1,4-
dioxane (2.0 mL) was added ethylene glycol (2.0 mL) and
potassium carbonate (2 equiv), and the reaction was stirred at
80ꢁC for an appropriate time. After removal of solvent in vacuo,
ice-water (50mL) was poured into the residue. The precipitated
solid was collected on a filter. The product was purified by
recrystallization and/or chromatography on silica gel, as described
in the succeeding text.
(5e).
The reaction was refluxed for 40h, and the residue was
chromatographed on silica gel. The eluate of n-hexane/benzene
(2:1) was evaporated in vacuo, and the residue was recrystallized
from n-hexane to give 5e (4%) as colorless needles. A further
eluate of n-hexane/benzene (1:2) was evaporated in vacuo, and
the residue was recrystallized from acetonitrile to give 4e (41%)
as colorless needles. 4e: mp 229–231ꢁC. 1H NMR (200 MHz,
deuterochloroform): d 1.49 (3H, t, J=7.1Hz, CH2CH3), 2.44 (3H, s,
20-CH3), 3.27 (2H, br t, J=4.2Hz, H5), 4.50 (2H, br t, J=4.2Hz,
H6), 4.61 (2H, q, J=7.1Hz, 4-CH2CH3), 7.23–7.69 (6H, m, H8, 9,
10, 11, and 30, 50), 8.45 (2H, d, J = 8.9 Hz, H20 and 60); ESI–MS:
m/z 373 (MH+). Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N,
4-(2-Hydroxyethoxy)-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidine (8a). The reaction was stirred at 80ꢁC for 4h,
and the product was recrystallized from acetonitrile to give 8a (25%)
as colorless needles, mp 210–212ꢁC. IR (potassium bromide): 3310
(OH) cmꢀ1; 1H NMR (200 MHz, deuterochloroform): d 2.01 (1H, br,
1
7.52. Found: C, 74.58; H, 5.64; N, 7.60. 5e: mp 145–147ꢁC. H
NMR (200 MHz, deuterochloroform): d 1.47 (3H, t, J=7.1Hz, 4-
CH2CH3), 1.60 (3H, d, J=6.6Hz, 5-CHCH3), 2.43 (3H, s, 20-CH3),
4.62 (2H, dq, J= 7.1, 2.0 Hz, 4-CH2CH3), 5.92 (1H, q, J=6.6Hz,
H5), 7.23–7.68 (6H, m, H7, 8, 9, 10, and 30, 50), 8.41 (2H, d,
Journal of Heterocyclic Chemistry
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K. Okuda, J. Takano, T. Hirota, and K. Sasaki
Vol 51
deuterium oxide exchangeable, OH), 3.28 (2H, br t, J=4.2Hz, H5),
3.96–4.05 (2H, m, CH2OH), 4.50 (2H, br t, J=4.2Hz, H6), 4.55–4.65
(2H, m, OCH2), 7.22–7.68 (4H, m, H8, 9, 10, and 11), 8.74 (1H, s,
H2); FAB-MS: m/z 299 (MH+). Anal. Calcd for C16H14N2O4: C,
64.42; H, 4.73; N, 9.39. Found: C, 64.13; H, 4.86; N. 9.58.
4-(2-Hydroxyethylsulfanyl)-5,6-dihydro[1]benzofuro[30,20:2,3]
oxepino[4,5-d]pyrimidine (9a). The reaction was stirred at 80ꢁC
for 11 h to produce, after workup, 9a (55%) as colorless needlꢀe1s,
1H NMR (200MHz, DMSO-d6): d 3.19 (2H, br t, J = 4.3 Hz, H5),
3.28–3.38 (2H, m, SCH2), 3.64 (2H, q, J = 5.8 Hz, CH2OH), 4.55
(2H, br t, J = 4.3 Hz, H6), 5.05 (1H, t, J = 5.8 Hz, deuterium oxide
exchangeable, OH), 7.23–7.78 (4H, m, H8, 9, 10, and 11), 8.85
(1H, s, H2); FAB-MS: m/z 315 (MH+). Anal. Calcd for
C16H14N2O3S: C, 61.13; H, 4.49; N, 8.91. Found: C, 61.19; H,
4.63; N, 9.04.
mp 227–229ꢁC. IR (potassium bromide): 3450 (OH) cm
;
4-(2-Hydroxyethoxy)-2-methyl-5,6-dihydro[1]benzofuro[30,20:2,3]
oxepino[4,5-d]pyrimidine (8b). The reaction was stirred at 80ꢁC for
1.5 h, and the product was recrystallized from chloroform to give 8b
(74%) as colorless needles, mp 247–248ꢁC. IR (potassium bromide):
1
3320 (OH) cmꢀ1; H NMR (200 MHz, deuterochloroform): d 2.71
(3H, s, CH3), 3.23 (2H, br t, J = 4.3 Hz, H5), 3.61 (1H, br t,
J = 4.7 Hz, deuterium oxide exchangeable, OH), 3.99 (2H, m,
CH2OH), 4.48 (2H, br t, J = 4.3 Hz, H6), 4.56–4.62 (2H, m,
OCH2), 7.21–7.68 (4H, m, H8, 9, 10, and 11); ESI–MS: m/z 313
(MH+). Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N, 8.97.
Found: C, 65.59; H, 5.34; N, 8.95.
4-(2-Hydroxyethylsulfanyl)-2-methyl-5,6-dihydro[1]benzofuro
[30,20:2,3]oxepino[4,5-d]pyrimidine (9b).
The reaction was
refluxed for 6 h to produce 9b (73%) as colorless needles, mp
1
187–189ꢁC. IR (potassium bromide): 3200 (OH) cmꢀ1; H NMR
(200 MHz, deuterochloroform): d 2.76 (3H, s, CH3), 3.23 (2H, br
t, J = 4.2 Hz, H5), 3.44 (2H, br t, J = 5.2 Hz, SCH2), 4.41 (2H, br
t, J = 5.2 Hz, CH2OH), 4.50 (3H, br t, J = 4.2 Hz, and br, changed
to 2H with addition of deuterium oxide, H6 and OH), 7.23–7.69
(4H, m, H8, 9, 10, and 11); ESI–MS: m/z 329 (MH+). Anal.
Calcd for C17H16N2O3S: C, 62.18; H, 4.91; N, 8.53. Found: C,
61.90; H, 4.97; N, 8.92.
2-Ethyl-4-(2-hydroxyethoxy)-5,6-dihydro[1]benzofuro[30,20:2,3]
oxepino[4,5-d]pyrimidine (8c). The reaction was stirred at 80ꢁC for
7 h, and the product was recrystallized from acetonitrile to give 8c
(79%) as colorless needles, mp 226–227ꢁC. IR (potassium bromide):
1
3330 (OH) cmꢀ1; H NMR (200 MHz, deuterochloroform): d 1.40
(3H, t, J=7.7Hz, CH3), 2.99 (2H, q, J=7.7Hz, CH2CH3), 3.23 (2H,
br t, J= 4.2 Hz, H5), 3.63 (1H, br, deuterium oxide exchangeable,
OH), 4.00 (2H, br, CH2OH), 4.48 (2H, br t, J = 4.2 Hz, H6),
4.55–4.66 (2H, m, OCH2), 7.21–7.67 (4H, m, H8, 9, 10, and
11); FAB-MS: m/z 327 (MH+). Anal. Calcd for C18H18N2O4:
C, 66.25; H, 5.56; N, 8.58. Found: C,66.06; H, 5.51; N, 8.45.
4-(2-Hydroxyethoxy)-2-phenyl-5,6-dihydro[1]benzofuro[30,20:2,3]
oxepino[4,5-d]pyrimidine (8d). The reaction was stirred at 80ꢁC
for 4 h, and the precipitated solid was chromatographed on
silica gel. The eluate of n-hexane/ethyl acetate (3:2) was
evaporated in vacuo, and the residue was recrystallized from ethyl
acetate to give 8d (29%) as colorless plates, mp 222–223ꢁC. IR
2-Ethyl-4-(2-hydroxyethylsulfanyl)-5,6-dihydro[1]benzofuro
[30,20:2,3]oxepino[4,5-d]pyrimidine (9c).
The reaction was
refluxed for 4.5 h to produce 9c (87%) as colorless needles, mp
1
165–166ꢁC. IR (potassium bromide): 3350 (OH) cmꢀ1; H NMR
(200 MHz, deuterochloroform): d 1.42 (3H, t, J = 7.6 Hz, CH3),
3.03 (2H, q, J = 7.6 Hz, CH2CH3), 3.23 (2H, br d, J = 4.2 Hz, H5),
3.46 (2H, br t, J = 5.3Hz, SCH2), 3.96–4.06 (2H, m, CH2OH),
4.15 (1H, br, deuterium oxide exchangeable, OH), 4.50 (2H, br t,
J = 4.2Hz, H6), 7.22–7.69 (4H, m, H8, 9, 10, and 11); FAB-MS:
m/z 343 (MH+). Anal. Calcd for C18H18N2O3S: C, 63.14; H, 5.30;
N, 8.18. Found: C, 63.25; H, 5.37; N, 8.09.
(potassium bromide): 3500 (OH) cmꢀ1
;
1H NMR (200 MHz,
4-(2-Hydroxyethylsulfanyl)-2-phenyl-5,6-dihydro[1]benzofuro
deuterochloroform): d 2.80 (1H, br, deuterium oxide exchangeable,
OH), 3.31 (2H, br t, J= 4.2 Hz, H5), 4.04–4.13 (2H, m, CH2OH),
4.53 (2H, br t, J= 4.2 Hz, H6), 4.69–4.78 (2H, m, OCH2),
7.22–7.71 (7H, H8, 9, 10, 11, and 30, 40, 50), 8.45–8.60 (2H, m, H20
and 60); FAB-MS: m/z 375 (MH+). Anal. Calcd for C22H18N2O4: C,
70.58; H, 4.85; N, 7.48. Found: C, 70.81; H, 5.03; N, 7.49.
4-(2-Hydroxyethoxy)-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro
[30,20:2,3]oxepino[4,5-d]pyrimidine (8e). The reaction was stirred
at 80ꢁC for 6 h, and the precipitated solid was chromatographed on
silica gel. The eluate of n-hexane/ethyl acetate (3:2) was evaporated in
vacuo, and the residue was recrystallized from acetonitrile to give 8e
(25%) as colorless needles, mp 249–251ꢁC. IR (potassium bromide):
3420 (OH)cmꢀ1; 1H NMR (200MHz, deuterochloroform): d 2.44
(3H, s, CH3), 2.92 (1H, br, deuterium oxide exchangeable, OH),
3.30 (2H, br t, J = 4.2 Hz, H5), 4.02–4.13 (2H, m, CH2OH), 4.52
(2H, br t, J = 4.2Hz, H6), 4.68–4.77 (2H, m, OCH2), 7.23–7.71
(6H, m, H8, 9, 10, 11, and 30, 50), 8.40 (2H, d, J = 8.3 Hz, H20 and
60); FAB-MS: m/z 389 (MH+). Anal. Calcd for C23H20N2O4: C,
71.12; H, 5.19; N, 7.21. Found: C, 71.23; H, 5.33; N, 7.21.
General procedure for synthesis of 2-substituted 4-(2-
hydroxyethylsulfanyl)-5,6-dihydro[1]benzofuro[30,20:2,3]oxepino
[4,5-d]pyrimidine (9a–e). To a solution of 1 (1a, 100 mg, 1b–e,
200mg) in dry 1,4-dioxane (2.0mL) was added 2-sulfanylethanol
(2 equiv) and potassium carbonate (2 equiv), and the reaction was
stirred at the temperature and time described in the succeeding text
for the specific examples. After evaporation of solvent in vacuo,
ice-water (50 mL) was added to the residue. The precipitated solid
was collected on a filter then recrystallized from acetonitrile.
[30,20:2,3]oxepino[4,5-d]pyrimidine (9d).
The reaction was
refluxed for 22 h to produce 9d (73%) as colorless needles, mp
1
188–190ꢁC. IR (potassium bromide): 3240 (OH) cmꢀ1; H NMR:
(200 MHz, deuterochloroform): d 3.08 (1H, br t, J=5.0Hz,
deuterium oxide exchangeable, OH), 3.28 (2H, br t, J=4.2Hz, H5),
3.61 (2H, t, J=5.0Hz, SCH2), 4.06 (2H, br q, J=5.0Hz, CH2OH),
4.53 (2H, br t, J= 4.2 Hz, H6), 7.23–7.71 (7H, m, H8, 9, 10, 11,
and 30, 40, 50), 8.46–8.58 (2H, m, H20 and 60); ESI–MS: m/z 391
(MH+). Anal. Calcd for C22H18N2O3S: C, 67.67; H, 4.65; N, 7.17.
Found: C, 67.65; H, 4.83; N, 7.21.
4-(2-Hydroxyethylsulfanyl)-2-(4-methylphenyl)-5,6-dihydro
[1]benzofuro[30,20:2,3]oxepino[4,5-d]pyrimidine (9e).
The
reaction was refluxed for 3.5 h to produce 9e (85%) as colorlꢀes1s
prisms, mp 227–228ꢁC. IR (potassium bromide): 3430 (OH) cm
;
1H NMR (200 MHz, deuterochloroform): d 2.44 (3H, s, CH3), 3.18
(1H, br t, J= 5.3 Hz, deuterium oxide exchangeable, OH), 3.27 (2H,
br t, J=4.2Hz, H5), 3.60 (2H, t, J=5.3Hz, SCH2), 4.05 (2H, br q,
J=5.3Hz, CH2OH), 4.54 (2H, br t, J=4.2Hz, H6), 7.23–7.71 (6H,
m, H8, 9, 10, 11, and 30, 50), 8.41 (2H, d, J=8.4Hz, H20 and 60);
ESI–MS: m/z 405 (MH+). Anal. Calcd for C23H20N2O3S: C, 68.30;
H, 4.98; N, 6.93. Found: C, 68.50; H, 5.13; N, 7.04.
Acknowledgments. The authors are grateful to the SC-NMR
Laboratory of Okayama University for 200 MHz 1H NMR
experiments. They also thank Prof. Setsuo Kashino (deceased)
(Department of Chemistry, Faculty of Science, Okayama
University) for his experimental assistance for X-ray crystallography
analysis and Dr. K. L. Kirk (NIDDK, NIH) for helpful suggestions.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Polycyclic N-Heterocyclic Compounds 83
793
REFERENCES AND NOTES
Cambridge, CB2 1EZ, UK [fax: +44 01223 336033 or e-mail:
deposit@ccdccamacuk].
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obtained free of charge on application to CCDC, 12 Union Road,
[4] Gilmore, C. J. J Appl Cryst 1984, 17, 42.
[5] Beurskens, P. T. DIRDIF. Direct Methods for Difference Structures
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[6] Molecular Structure Corporation, TEXSAN. 1985.
[7] Johnson, C. K. ORTEP II. 1976.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet