The Journal of Organic Chemistry
Article
1
29.4, 111.3, 108.3, 104.9, 54.9, 24.1. TOF-EI calcd for [C H NO ]
157.9, 155.8, 154.4, 142.1, 132.2, 132.0, 131.6, 131.3, 130.8, 124.8,
9
11
2
m/z 165.0789, found m/z 165.0743.
117.5, 115.7, 113.8, 106.4, 98.4, 94.8, 46.4, 12.7. ESI-HRMS calcd for
+
Synthesis of N-(3-Oxo-2,3-dihydrobenzofuran-6-yl)-
[
C H N O ] m/z 427.16523, found m/z 427.16504. Elem. Anal.
26
23
2
4
acetamide (3). A modified method was followed to synthesize
Calcd for C H ClN O : C, 59.26; H, 4.40; N, 5.32. Found: C, 59.12;
12
26 23
2
8
compound 3. Chloroacetyl chloride (6.52 g, 58.2 mmol) was added,
followed within 15 min by 4 g (24.2 mmol) of N-(3-methoxyphenyl)-
H, 4.53; N, 5.29.
Synthesis of AFR1E. Concentrated H SO (2 mL) was added to
2
4
acetamide, to a solution of 12.92 g (98.0 mmol) of AlCl in 20 mL of
3
an ethanol solution (10 mL) of compound AFR1 (527 mg, 1.0 mmol),
and the solution was heated to reflux for 4 h. After the sample had
cooled, ethanol was removed under reduced pressure and the residue
1
,2-dichloroethane at 0 °C under N . The mixture was stirred for 30
2
min at 0 °C, slowly warmed to room temperature, and further stirred
for 24 h. The brown mixture was added to 200 mL of ice−water and
200 mL of AcOEt. After the mixture had been vigorously stirred, the
was slowly diluted with 50 mL of H O followed by 2 mL of HClO ,
2
4
resulting precipitate [N-(3-methoxy-4-chloroacetylphenyl)acetamide]
was filtered off and dried under vacuum. The resulting solid was
introduced into 30 mL of EtOH; 2.64 g (32.2 mmol) of AcONa was
added, and then the mixture was heated under reflux for 24 h. EtOH
was removed under reduced pressure, and the mixture solid was
purified by silica gel chromatography using a 1:2 (v/v) petroleum
which was stirred to collect the resulting precipitate. After the sample
had dried, purification by silica gel chromatography using a CH Cl /
2
2
CH OH [100:1, 80:1, or 60:1 (v/v)] as the eluent gave AFR1E as a
3
1
dark-green solid (280 mg, 50%). Mp: 275−277 °C. H NMR (400
MHz, DMSO-d ): δ 8.26−8.22 (m, 1H), 7.96−7.92 (m, 2H), 7.86 (td,
6
1
H, J = 7.7 Hz, J = 1.2 Hz), 7.80 (s, 2H), 7.65 (d, 1H, J = 6.7 Hz),
1 2
ether/AcOEt mixture as the eluent to give 3 as a yellow solid (1.47 g,
1
7.28 (d, 1H, J = 2.3 Hz), 7.25 (d, 1H, J = 9.4 Hz), 7.18 (dd, 1H, J
=
1
3
2%). H NMR (400 MHz, DMSO-d ): δ 10.45 (s, 1H), 7.71 (d, 1H, J
6
9
.4 Hz, J = 2.3 Hz), 6.97 (dd, 1H, J = 9.0 Hz, J = 1.6 Hz), 6.69 (d,
2
1
2
=
1.4 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.14 (dd, 1H, J = 8.5 Hz, J = 1.6
1 2
13
1H, J = 1.6 Hz), 4.03 (q, 2H, J = 7.1 Hz), 3.61 (q, 4H, J = 7.0 Hz),
.20 (t, 6H, J = 7.0 Hz), 0.93 (t, 3H, J = 7.1 Hz). 13C NMR (100 MHz,
DMSO-d ): δ 165.3, 164.1, 159.1, 155.9, 154.0, 152.6, 140.4, 139.3,
Hz), 4.75 (s, 2H), 2.11 (s, 3H). C NMR (100 MHz, DMSO-d ): δ
6
1
197.5, 174.5, 169.4, 147.9, 124.2, 115.6, 113.4, 101.5, 75.2, 24.3. TOF-
EI calcd for [C H NO ] m/z 191.0582, found m/z 191.0534.
6
10
9
3
Synthesis of 3-(Diethylamino)phenyl Acetate (5). Ac O (765
133.4, 131.3, 131.2, 130.4, 129.4, 129.0, 124.5, 117.2, 115.0, 111.7,
104.4, 97.5, 93.6, 61.5, 45.1, 13.7, 12.5. ESI-HRMS calcd for
2
μL, 8 mmol), DMAP (31 mg, 0.25 mmol), and NEt (845 μL, 6
3
mmol) were successively added to an anhydrous CH Cl (10 mL)
+
2
2
[C H N O ] m/z 455.19653, found m/z 455.19629. Elem. Anal.
28
27
2
4
solution of 3-(diethylamino)phenol (852 mg, 5 mmol), which was
stirred for 12 h. The mixture solution was extracted with 100 mL of
CH Cl . The organic layer was washed with a saturated NaHCO (2 ×
Calcd for C H ClN O : C, 60.60; H, 4.90; N, 5.05. Found: C, 60.71;
28
27
2
8
H, 5.12; N, 5.09.
2
2
3
Synthesis of AFR2. Compound 3 (382 mg, 2.0 mmol) and
compound 8 (394 mg, 2.0 mmol) were successively added to
concentrated H SO (10 mL), which was heated at 100 °C for 4 h.
3
0 mL) solution and brine (2 × 30 mL) and dried with anhydrous
MgSO . After being dried, CH Cl was removed under reduced
4
2
2
2
4
pressure, and the final solution was purified by silica gel
After being cooled, the mixture was poured into ice−water, and then
perchloric acid (2 mL) was added. The resulting precipitate was
filtered off and washed with plenty of water. After the sample had
dried, purification by silica gel chromatography using a CH Cl /
chromatography using an 8:1 (v/v) petroleum ether/AcOEt mixture
1
as the eluent to give 5 as a light yellow oily liquid (1.02 g, 98%). H
NMR (400 MHz, CDCl ): δ 7.17 (t, 1H, J = 8.0 Hz), 6.54−6.48 (m,
3
1
1
1
H), 6.34 (d, 2H, J = 7.5 Hz), 3.32 (q, 4H, J = 7.1 Hz), 2.28 (s, 3H),
2
2
.15 (t, 6H, J = 7.1 Hz). 13C NMR (100 MHz, CDCl ): δ 170.6, 153.0,
3
CH OH mixture [80:1, 60:1, 40:1, or 20:1 (v/v)] as the eluent gave
3
50.0, 130.7, 110.1, 108.9, 105.6, 45.3, 22.2, 13.4. TOF-EI calcd for
1
AFR2 as a dark-blue solid (560 mg, 69%). Mp: 254−256 °C. H NMR
[
C H NO ] m/z 207.1259, found m/z 207.1293.
12 17 2
(400 MHz, DMSO-d ): δ 8.69 (d, J = 16.5 Hz, 1H), 7.95−7.83 (m,
6
Synthesis of 4-(Dimethylamino)-1′,1′,1′-trifluoro-2-hydrox-
2
H), 7.77 (s, 2H), 7.26 (d, J = 8.9 Hz, 1H), 7.16 (s, 1H), 6.94 (d, J =
yacetophenone (6). A modified method was followed to synthesize
14
8.9 Hz, 1H), 6.76 (s, 1H), 3.60 (q, J = 6.2 Hz, 4H), 1.20 (t, J = 7.0 Hz,
compound 6. A solution of 5 (2.04 g, 9.86 mmol) and trifluoroacetic
6
1
H). 13C NMR (100 MHz, 2:1 CD OD/CD Cl ): δ 166.1, 160.2,
anhydide (3.45 mL, 24.6 mmol) in Et O (20 mL) was refluxed for 3 h,
3 2 2
2
57.0, 156.4, 154.2, 143.6, 132.5, 126.4, 124.6, 117.7, 115.4, 113.4,
and the solvent was evaporated. The residue, dissolved in a mixture of
THF (40 mL) and 2 M aqueous hydrochloric acid (20 mL), was
stirred for 24 h at room temperature. The solution was concentrated
under reduced pressure, and the aqueous residue was extracted with
ether. The organic extract was washed with water and brine, dried, and
+
105.5, 97.8, 94.3, 46.1, 12.3. ESI-HRMS calcd for [C19H N O ] m/z
19 2 2
307.14410, found m/z 307.144409. Elem. Anal. Calcd for
C H ClN O : C, 56.09; H, 4.71; N, 6.89. Found: C, 55.91; H,
19
19
2
6
4
.78; N, 6.91.
Synthesis of AFR3. Compound 3 (382 mg, 2.0 mmol) and
evaporated. The residue was crystallized (petroleum ether) to give 4 as
1
yellow needles (1.03 g, 40%). H NMR (400 MHz, CDCl ): δ 11.83
3
compound 6 (522 mg, 2.0 mmol) were successively added to
(
s, 1H), 7.57 (dq, 1H, J = 9.4 Hz, J = 2.1 Hz), 6.27 (dd, 1H, J = 9.5
1
2
1
concentrated H SO (10 mL), which was heated at 100 °C for 8 h.
2
4
Hz, J = 2.6 Hz), 6.11 (d, 1H, J = 2.6 Hz), 3.44 (q, 4H, J = 7.1 Hz),
2
After being cooled, the mixture was poured into ice−water, and then
perchloric acid (2 mL) was added. The resulting precipitate was
filtered off and washed with plenty of water. After the sample had
dried, purification by silica gel chromatography using a CH Cl /
13
1
3
1
.23 (t, 6H, J = 7.1 Hz). C NMR (100 MHz, CDCl ): δ 180.2 (q, J =
3
4 Hz), 168.2, 156.1, 133.3 (q, J = 4 Hz), 118.3 (q, J = 287 Hz), 106.3,
05.2, 98.0, 45.9, 13.5 (F atom effect-induced split of 13C NMR).23 19
F
NMR (376 MHz, DMSO-d ): δ −68.6 (s, 3F). TOF-EI calcd for
2
2
6
[
C H F NO ] m/z 261.0977, found m/z 261.0950.
CH OH mixture [200:1, 150:1, 100:1, or 80:1 (v/v)] as the eluent
3
12
14
3
2
1
Synthesis of AFR1. Compound 3 (382 mg, 2.0 mmol) and
compound 7 (640 mg, 2.0 mmol) were successively added to
concentrated H SO (10 mL), which was heated at 100 °C for 4 h.
gave AFR3 as a green solid (105 mg, 11%). Mp: 265−268 °C. H
NMR (400 MHz, DMSO-d ): δ 8.60 (s, 2H), 7.94 (dd, 1H, J = 9.0
6
1
2
4
Hz, J = 1.9 Hz), 7.81 (d, 1H, J = 9.4 Hz), 7.29 (d, 1H, J = 9.5 Hz),
2
After being cooled, the mixture was poured into ice−water, and then
perchloric acid (2 mL) was added. The resulting precipitate was
filtered off and washed with plenty of water. After the sample had
dried, purification by silica gel chromatography using a CH Cl /
7
6
1
.22 (s, 1H), 7.01 (d, 1H, J = 9.0 Hz), 6.82 (s, 1H), 3.61 (q, 4H, J =
13
.9 Hz), 1.20 (t, 6H, J = 7.0 Hz). C NMR (100 MHz, DMSO-d ): δ
6
65.8, 161.8, 156.8, 155.5, 152.1, 140.9, 127.0, 126.0, 121.8 (d, J = 275
2
2
Hz), 118.9, 118.2 (d, J = 35 Hz), 115.3, 106.2, 104.9, 98.3, 94.3, 45.3,
12.8 (F atom effect-induced split of C NMR).
CH OH mixture [20:1, 10:1, 5:1, or 3:1 (v/v)] as the eluent gave
3
13
23 19
1
F NMR (376
AFR1 as a dark-blue solid (945 mg, 90%). Mp: 292−294 °C. H NMR
400 MHz, DMSO-d ): δ 13.22 (s, 1H), 8.16 (d, 1H, J = 7.5 Hz), 7.86
MHz, DMSO-d ): δ −56.4 (s, 3F). ESI-HRMS calcd for
(
6
6
+
[
C H F N O ] m/z 375.13149, found m/z 375.13133. Elem.
(
7
t, 1H, J = 7.4 Hz), 7.83−7.74 (m, 2H), 7.52 (d, 1H, J = 7.2 Hz),
20 18
3
2
2
1
.28−6.78 (m, 6H), 6.65 (s, 1H), 3.53 (q, 4H, J = 6.7 Hz), 1.17 (t, 6H,
Anal. Calcd for C20
5.84. Found: C, 50.09; H, 3.91; N, 5.82.
H
18ClF
3
N
2
O
6
· /
H
4
2
O: C, 50.12; H, 3.89; N,
13
J = 7.0 Hz). C NMR (100 MHz, CD OD): δ 166.0, 160.1, 158.5,
3
3
174
J. Org. Chem. 2015, 80, 3170−3175