484 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2
Alexander et al.
triphosgene (13.3 g, 44.8 mmol). N,N-Dimethylaniline (32 g,
264 mmol) dissolved in ethylenedichloride (50 mL) was added
dropwise in the course of 1 h to the reaction mixture, which
was maintained at -5 to 5 °C. The reaction mixture was
allowed to warm to room temperature and left to stir overnight.
It was washed with water, 1 N hydrochloric acid, water, and
brine. The organic layer was dried over sodium sulfate and
evaporated to furnish a light green solid, which was crystal-
lized from hexane to obtain the pure dioxolenone (18.56 g,
1699, 1609, 1518, 1272 cm-1; EIMS m/e 222 (M+), 148, 135,
121. Anal. (C11H10O5) C, H.
(5-Met h yl-2-oxo-1,3-d ioxol-4-en -4-yl)m et h yl p -Nit r o-
p h en yl Ca r bon a t e (3a ). 4-(Hydroxymethyl)-5-methyl-1,3-
dioxolenone18 (5.59 g, 43 mmol) and pyridine (3.74 g, 47 mmol)
were dissolved in chloroform (50 mL) and cooled in an ice bath.
4-Nitrophenyl chloroformate (9.46 g, 47 mmol) dissolved in
chloroform (50 mL) was added dropwise to the above solution.
After the reaction mixture was stirred for 16 h at room
temperature, it was cooled in ice and was washed successively
with ice-cold 1% aqueous sodium hydroxide, 1 N hydrochloric
acid, water, and brine. The organic layer was dried over
sodium sulfate and evaporated to obtain a solid (11.2 g), which
was crystallized from chloroform-hexane to furnish the pure
4-nitrophenyl carbonate 3a (9.11 g, 81%): mp 116-117 °C;
1H NMR (CDCl3) δ 2.23 (s, 3 H, Me), 5.05 (s, 2 H, CH2), 7.41
(d, 2 H, ArH), 8.3 (d, 2 H, ArH); 13C NMR (CDCl3) δ 9.43, 58.07
(CH2), 121.69, 125.35, 132.15, 141.42, 145.57, 151.66 (vinylene
CdO), 152.19, 155.05 (CdO); IR (KBr) 1811 (CdO), 1779
(CdO), 1525, 1247, 1207 cm-1. Anal. (C12H9NO8) C, H, N.
(5-P h en yl-2-oxo-1,3-d ioxol-4-en -4-yl)m et h yl p -n it r o-
p h en yl ca r bon a te (3b): mp 157-158 °C (from benzene-
hexane); 1H NMR (CDCl3) δ 5.31 (s, 2 H, CH2), 7.4-7.58 (m, 7
H, ArH), 8.30 (d, J ) 9 Hz, 2 H, ArH); 13C NMR (CDCl3) δ
59.43 (CH2), 121.68, 123.83, 125.41, 126.26, 129.35, 130.91,
142.75, 145.74, 150.89 (vinylene CdO), 152.15, 155.15 (CdO);
1
78.7%) as colorless crystals: mp 96-97 °C; H NMR (CDCl3)
δ 2.31 (s, 3 H, Me), 3.83 (s, 3 H, OMe), 6.96 (d, J ) 4.6 Hz,
ArH), 7.38 (d, J ) 4.6 Hz, ArH); 13C NMR (CDCl3) δ 10.45,
55.3, 114.41, 117.96, 126.69, 133.61, 137.35, 152.29 (vinylene
CdO), 160.06; IR (KBr) 1805 (CdO), 1517, 1260 cm-1; EIMS
m/e 206 (M+), 134, 119. Anal. (C11H10O4) C, H.
4-P h en yl-5-m eth yl-1,3-d ioxol-4-en -2-on e (1b):20,21 mp
1
84-85 °C (CCl4); H NMR (CDCl3) δ 2.37 (s, 3 H, Me), 7.39-
7.47 (m, 5 H, ArH); 13C NMR (CDCl3) δ 10.7, 125.04, 125.53,
128.93, 128.97, 135.04, 137.37, 152.14 (vinylene CdO); IR
(KBr) 1814 (CdO), 1245, 1199 cm-1; EIMS m/e 176, 104, 78.
4-(Br om om et h yl)-5-(p -m et h oxyp h en yl)-1,3-d ioxol-4-
en -2-on e. N-Bromosuccinimide (9.5 g, 53.3 mmol) and benzoyl
peroxide (500 mg) were added to a solution of 1c (10 g, 48.5
mmol) in freshly distilled carbon tetrachloride (250 mL). The
reaction mixture was refluxed under an argon atmosphere for
16 h. It was cooled in an ice bath and filtered. The filtrate
was washed with water and brine and dried over sodium
sulfate. The residue obtained on evaporation (14.4 g) was
crystallized from carbon tetrachloride to furnish the pure
bromomethyl derivative (8.34 g, 60%) as a light yellow solid.
This compound had a tendency to decompose on standing at
room temperature: 1H NMR (CDCl3) δ 3.87 (s, 3 H, Me), 4.43
(s, 2 H, CH2), 7.03 (d, J ) 9 Hz, ArH), 7.47 (d, J ) 9 Hz, ArH);
13C NMR (CDCl3) δ 19.94 (CH2Br), 55.44, 114.8, 116.49, 127.62,
128.42, 132.74, 139.93, 150.89 (CdO), 161.20; IR (KBr) 1821
(CdO), 1691, 1607, 1252 cm-1; EIMS m/e 286, 285 (M+), 205
(M+ - Br).
IR (KBr) 1815 (CdO), 1781 (CdO), 1519, 1242, 1216 cm-1
;
EIMS m/e 357 (M+), 175. Anal. (C17H11NO8) C, H, N.
(5-(p -Me t h o x y p h e n y l)-2-o x o -1,3-d io x o l-4-e n -4-y l)-
m eth yl p-n itr op h en yl ca r bon a te (3c): mp 129-130 °C
(from chloroform-hexane); 1H NMR (CDCl3) δ 3.86 (s, 3 H,
OMe), 5.29 (s, 2 H, CH2), 7.01 (d, J ) 8.8 Hz, 2 H, anisyl H),
7.42 (d, J ) 9.1 Hz, 2 H, ArH), 7.54 (d, J ) 8.8 Hz, anisyl H),
8.31 (d, J ) 9.1 Hz, ArH); 13C NMR (CDCl3) δ 55.45, 59.6 (CH2),
114.83, 116.05, 121.68, 125.37, 127.93, 130.14, 142.92, 145.69,
151.05 (vinylene CdO), 152.16, 155.17 (CdO), 161.57; IR (KBr)
1826 (CdO), 1771 (CdO), 1616, 1521, 1252, 1213 cm-1; EIMS
m/e 387 (M+), 343, 300, 258. Anal (C18H13NO9) C, H, N.
4-[[(3′,4′-Dim et h oxyp h en et h yl)ca r b a m oyl]m et h yl]-5-
p h en yl-1,3-d ioxol-4-en -2-on e (5b). A solution of 3,4-dimeth-
oxyphenethylamine (0.905 g, 5 mmol) and (5-phenyl-2-oxo-1,3-
dioxol-4-en-4-yl)methyl p-nitrophenyl carbonate (3b) (1.79 g,
5 mmol) in dimethylformamide (10 mL) was stirred at room
temperature for 16 h. The reaction mixture was diluted with
water (100 mL) and extracted with ethyl acetate. The organic
extract was washed successively with water, 1 N hydrochloric
acid, ice-cold 2% aqueous sodium carbonate, water, and brine.
The extract was dried over sodium sulfate and evaporated to
obtain a light yellow foam (2.01 g), which was purified by
preparative TLC using a Chromatotron on silica gel plates.
Elution with ethyl acetate-hexane (35:65) gave the pure
carbamate 5a (1.47 g, 74%) as an oil which solidified on
standing. An analytical sample was prepared by crystalliza-
tion from chloroform-hexane: mp 111-112 °C; 1H NMR
(CDCl3) δ 2.78 (t, J ) 7 Hz, 2 H, ArCH2), 3.45-3.55 (m, 2 H,
NHCH2), 3.89 (s, 6 H, OMe), 4.86 (m, 1 H, NH), 5.14 (s, 2 H,
CH2), 6.73-6.86 (m, 3 H, ArH), 7.48-7.53 (m, 3 H, ArH), 7.61-
7.66 (m, 2 H, ArH); 13C NMR (CDCl3) δ 35.49, 42.42, 55.5,
55.86, 55.91, 111.52, 111.98, 120.69, 124.28, 126.03, 129.13,
130.28, 130.83, 133.45, 141.13, 147.87, 149.15, 151.34 (vinylene
CdO), 155.26 (CdO); IR (KBr) 3370 (NH), 1826 (CdO), 1718
(CdO), 1516, 1235 cm-1; FABMS m/e 399 (M+), 208, 175;
HRMS calcd for C21H21NO7 399.1318, found 399.1317. Anal.
(C21H21NO7) C, H, N.
4-(Br om om eth yl)-5-p h en yl-1,3-d ioxol-4-en -2-on e:13 mp
1
96-97 °C (hexane); H NMR (CDCl3) δ 4.44 (s, 2 H, CH2Br),
7.47-7.55 (m, 5 H, ArH); 13C NMR (CDCl3) δ 19.45 (CH2Br),
124.18, 125.91, 129.32, 130.42, 134.11, 139.69, 150.72 (CdO);
IR (KBr) 1823 (CdO); EIMS m/e 254, 256 (M+), 175, 103,
104, 77.
4-(Hydr oxym eth yl)-5-ph en yl-1,3-dioxol-4-en -2-on e (2b).
To an ice-cold solution of the above 4-(bromomethyl)-5-phenyl-
1,3-dioxol-4-en-2-one (6.49 g, 25.4 mmol) and formic acid (2.07
g, 44 mol) in acetonitrile (20 mL) was added dropwise trieth-
ylamine (4.13 g, 41 mmol) in the course of 10 min. After 20
min at ice bath temperature, the reaction mixture was stirred
at room temperature for 90 min. It was diluted with water to
about 150 mL and extracted with ethyl acetate. The organic
extract was washed successively with water, aqueous sodium
bicarbonate, water, and brine and dried over sodium sulfate.
Evaporation of the solvent gave an oily residue (5.29 g, 94.6%);
1H NMR (CDCl3) δ 5.20 (s, 2 H, CH2), 7.47-7.59 (m, 5 H, ArH),
8.17 (s, 1 H, formyl H).
The above formyl ester (5.29 g, 24 mmol) was dissolved in
methanol (50 mL) and diluted with water (15 mL). Concen-
trated hydrochloric acid (0.5 mL) was added to the reaction
mixture and stirred at room temperature for 2 h. Most of the
methanol was evaporated off, and the residue taken up in ethyl
acetate was washed with water, aqueous sodium bicarbonate,
water, and brine. The organic layer on drying over sodium
sulfate and evaporation furnished a solid (4.59 g, 99%) which
was crystallized from chloroform-hexane to give the pure 2b
4-[[(3′,4′-Dim et h oxyp h en et h yl)ca r b a m oyl]m et h yl]-5-
m eth yl-1,3-d ioxol-4-en -2-on e (5a ): 1H NMR (CDCl3) δ 2.17
(s, 3 H, Me), 2.76 (t, J ) 7 Hz, 2 H, ArCH2), 3.42 (m, 2 H,
NHCH2), 3.86 (s, 3 H, OMe), 3.87 (s, 3 H, OMe), 4.8 (s, 2 H,
CH2), 4.97 (t, br, 1 H, NH), 6.7-6.83 (m, 3 H, ArH); 13C NMR
(CDCl3) δ 9.18, 35.38, 42.25, 53.94 (vinylic CH2), 55.71, 55.76,
111.19, 111.72, 120.56, 130.75, 133.91, 139.71, 147.6, 148.88,
152.15 (vinylene CdO), 155.26 (CdO); IR (film) 3368 (NH),
1818 (CdO), 1722 (CdO), 1519, 1267 cm-1; EIMS m/e 337 (M+),
207, 164, 151, 130. Anal. (C16H19NO7) C, H, N.
1
(4.26 g, 92%): mp 97-98 °C; H NMR (CDCl3) δ 2.73 (t, J )
4.7 Hz, 1 H, OH), 4.66 (d, J ) 4.7 Hz, 2 H, CH2), 7.45-7.58
(m, 5 H, ArH); 13C NMR (CDCl3) δ 54.12 (CH2), 124.45, 125.93,
129.08, 131.1, 137.08, 140.04, 151.97 (vinylene CdO); EIMS
m/e 192 (M+), 118, 105, 91, 77. Anal. (C10H8O4) C, H.
4-(Hyd r oxym eth yl)-5-(p-m eth oxyp h en yl)-1,3-d ioxol-4-
en -2-on e (2c): mp 100-101 °C (from chloroform-hexane); 1H
NMR (CDCl3) δ 3.85 (s, 3 H, OMe), 4.64 (s, 2 H, CH2), 6.98 (d,
J ) 9 Hz, 2 H, ArH), 7.48 (d, J ) 9 Hz, 2 H, ArH); 13C NMR
(CDCl3) δ 54.26 (CH2), 55.41, 114.61, 116.92, 127.65, 135.73,
140.21, 151.95 (vinylene CdO), 160.99; IR (KBr) 3474, 1811,
4-[[(3′,4′-Dim et h oxyp h en et h yl)ca r b a m oyl]m et h yl]-5-
(p-m eth oxyp h en yl)-1,3-d ioxol-4-en -2-on e (5c): mp 109-