Aliphatically-Substituted Dihydropyrrolones
26 mmol) in 50 mL of anhydrous ether was added slowly, over
Chem. Res. Toxicol., Vol. 9, No. 6, 1996 973
4
over MgSO . GC-MS analysis indicated 79% conversion of 9 to
1
a 10-min period, boron trifluoride etherate (26.9 mL, 105 mmol).
After an additional hour of stirring at room temperature, the
reaction was complete, as monitored by GC-MS. The solution
7c. After concentration, the residue was purified through
preparative reversed-phase HPLC, extraction and drying pro-
cesses, to yield 0.54 g of compound 7c (1.8 mmol, 64%). CIMS:
was washed with 0.1 M NaHCO
3
solution (2 × 30 mL) and with
301 {6, M + H}, 283 {1, 301 - H
(SCH CH O)}, 61 {2, HSCH CH
2
O}, 223 {4}, 103 {100, CH
}.
3
C-
3
0 mL of saturated NaCl solution, dried over MgSO
4
, and
2
2
2
2
concentrated. Distillation yielded 17.5 g of compound 9, 95%.
GC-MS analysis indicated a purity of 96%. EIMS: 176 {1, M +
4
-Bu tyl-2,3,5-d eca n etr ion e (6c). Ten milliliters of 20%
hydrochloric acid was added to 0.54 g of compound 7c, and the
mixture was stirred for 1 h. The ether-soluble portion was
extracted, and after evaporation of the solvent, dilution with 1
mL of acetonitrile, and purification using preparative reversed-
phase HPLC, 0.26 g (1.1 mmol, 61%) of compound 6c was
obtained. GC-MS analysis indicated purity of 88%. EIMS: 241
4, M + H}, 223 {2, 241 - H
50, COCH (CH CH }, 71 {30, CH
00 MHz): δ 0.86 (t, 3H), 0.88 (t, 3H), 1.2-1.4 (br m, 8H), 1.48
s, 3H, CH
NMR (DMSO-d
22.8, 26.0, 28.8, 31.5, 31.6, 103.0 (CdCOH-), 112.2 (-COHd),
187.2 (-COCd), 203.4 (CH CO-).
H}, 116 {6}, 103 {100, CH
3
C(SCH
2 2 2 2
CH O)}, 61 {11, HSCH CH },
5
9 {16}; CIMS: 177 {12, M + H}, 116 {100}, 103 {64,
1
CH
3
C(SCH
Cl, 500 MHz): δ 1.22 (t, 3H, OCH
C(SCH CH O)}, 3.03 (m, 2H, SCH CH
CH ), 4.18 (m, 1H, CH CHHO), 4.32 (m, 1H, CH
C-NMR (CD Cl, 500 MHz): δ 14.0 (OCH CH ), 26.2 (CH
3.7 (OCH CH S), 62.1 (OCH CH ), 72.8 (OCH CH S), 89.1
CCOOEt), 172.2 (COOEt).
-(2-Meth yl-[1,3]oxa th iola n -2-yl)bu ta n e-1,3-d ion e (7b).
.6 g of NaH (60% in oil, 66 mmol) was washed three times with
2
CH
2
O)}, 89 {23}, 61 {52, HSCH
CH
O), 4.11 (m, 2H,
CHHO);
C),
2
CH
2
}; H-NMR
(CD
3
2
3
), 1.73 {s, 3H,
CH
3
2
2
2
2
OCH
2
3
2
2
{
{
5
2
O}, 197 {100, M - (CH
3
CO)}, 99
1
3
1
3
2
3
3
)
3
COCO}; H-NMR (CD Cl,
2
2
3
3
3
3
(
2
2
2
3
2
2
13
(
3
CO), 1.62 (m, 2H), 2.05 (t, 2H), 2.47 (t, 2H); C-
1
6
, 500 MHz): δ 14.0 (2CH -), 21.3, 22.5, 22.6,
3
2
dry hexane, and twice with dry THF. Subsequently, another
0 mL of THF was added, followed by 5.3 g of compound 9 (30
3
2
Eth yl 2-Oxoh exa n oa te (10). Oxalyl chloride (4.14 mL, 47.4
mmol) in 50 mL of methylene chloride in a 500 mL 3-neck flask
was cooled in a dry ice/acetone bath; 8.06 g of DMSO (103.4
mmol) in 20 mL of CH Cl was added over 5 min. Ten minutes
later, 4.4 g (27.5 mmol) of ethyl-2-hydroxyhexanoate in 20 mL
of CH Cl2 was added over a 5 min period. The solution was
allowed to warm to -60 °C and stirred for 15 min before 30 mL
of triethylamine (215.2 mmol) was added. The solution was
allowed to warm to room temperature. Water (60 mL) was
added and the mixture was stirred for 10 min. The organic layer
was separated and washed with 3 M HCl, excess water, and
mmol). Acetone (4.4 mL, 60 mmol) was added dropwise into
the stirred slurry. After additional stirring for 20 min, 20 mL
of saturated NaHCO
evaporator, and 20 mL of ethyl ether was added for extraction.
The organic layer was washed with saturated NaHCO
(2 × 20
mL) and saturated NaCl solution (20 mL) and dried over MgSO
3
was added. THF was removed on a rotary
2
2
3
2
4
.
After concentration, the residue was distilled under vacuum to
yield 4.7 g of compound 7b (25 mmol, 83%). GC-MS analysis
indicated a purity of 98%. EIMS: 189 {2, M + H}, 170 {1},
1
29 {3}, 103 {100, CH
3 2 2 2
C(SCH CH O)}, 85 {14}, 61 {13, HSCH -
CH }, 59 {14}; CIMS: 189 {100, M + H}, 171 {20}, 157 {16},
2
saturated NaHCO solution. Concentration yielded compound
3
1
29 {71}, 111 {47, 129 - H
9 {18}, 61 {52, HSCH CH
C(SCH
.95 (m, 1H, SCHHCH
m, 1H, CH CHHO), 4.21 (m, 1H, SCH
COCHdCOH); C-NMR (CD
2
O}, 103 {61, CH
3
C(SCH
2
CH
2
O)},
10 quantitatively (4.40 g, 101%). GC-MS analysis gave a purity
of 94%. CIMS: 159 {7, M + H}, 85 {100, COCH CH CH CH },
1
8
2
2
}; H-NMR (CD
3
Cl, 500 MHz):
2
2
2
3
1
δ 1.64 {s, 3H, CH
2
(
3
2
CH
2
O)}, 1.97 (s, 3H, CH
3
COHd),
O), 4.05
CHHO), 5.72 (s, 1H,
Cl, 500 MHz): δ 24.2, 26.4, 33.8,
2 3 3 3
57 {3, (CH ) CH }; H-NMR (CD Cl, 500 MHz): δ 0.93 (t, 3H,
2
O), 3.02 (m, 1H, SCHHCH
2
3 2 2 3 3 2 3
CH CH CH -), 1.34 (m, 2H, CH CH CH -), 1.38 (t, 3H, CH -
2
2
2 3 2 2 2
CH O-), 1.62 (m, 2H, CH CH CH -), 2.84 (t, 2H, -CH CO-), 4.32
1
3
13
3
3 2 3
(q, 2H, CH CH O-); C-NMR (CD Cl, 500 MHz): δ 14.0, 22.2,
7
2.3, 93.0, 93.9, 189.4, 196.5.
,3,5-Hexa n etr ion e (6b). A solution of 1.0 g of compound
b (5.3 mmol) in aqueous 80% acetonitrile (20 mL) was added
25.2, 39.0, 62.3, 70.6, 161.5 (COOEt), 194.7 (COCOOEt).
2
2-Bu t yl-[1,3]d it h iola n e-2-ca r b oxylic Acid E t h yl E st er
(8). To a stirred solution of compound 10 (4.40 g, 27.8 mmol)
and 1,2-ethanedithiol (4.20 mL, 50.0 mmol) in 20 mL of
anhydrous ether was added slowly, over 20 min, boron trifluo-
ride-etherate (12.8 mL, 50 mmol). After overnight stirring at
room temperature, the solution was washed with saturated
7
at room temperature to a vigorously stirred mixture of mercuric
chloride (3.18 g, 11.7 mmol) and mercuric oxide (1.26 g, 5.8
mmol), in the same solvent (100 mL). The mixture was stirred
overnight under nitrogen. The organic phase was decanted. The
residue was washed with CH
organic phases were combined, washed with saturated NaHCO
SO . After
removal of the solvents, a yellow oil remained along with some
white precipitate. Acetonitrile (10 mL) was added and a clear
solution obtained after filtration through a glass wool-fritted
funnel. The yellow filtrate was dried over nitrogen flow.
Finally, 0.57 g (4.5 mmol) of yellow compound 6b was obtained
in a yield of 84%. GC-MS analysis indicated purity of 96%.
2
Cl
2
/ether (1/1, 2 × 60 mL). The
NaHCO
solution and dried over MgSO
ethanol and 1.9 g (10 mmol) of p-toluenesulfonic acid were added
and the mixture was stirred for 24 h at room temperature.
Ethanol was removed under vacuum, and the residue taken up
in ether was washed with saturated Na
with 20 mL of saturated NaCl solution and dried over MgSO
Ether was removed, and 6.7 g (28.6 mmol) of compound 8 was
quantitatively obtained. CIMS 235 {4, M + H}, 161 {100,
CH (CH ) C(SCH CH S)}, 89 {16}.
3 2 3 2 2
3
solution (2 × 20 mL) and once with 20 mL NaCl
3
4
. After concentration, 10 mL of
solution (2 × 60 mL), and dried over anhydrous Na
2
4
2 3
CO solution and once
4
.
CIMS: 129 {7, M + H}, 111 {3, 129 - H
2
O}, 99 {2}, 85 {100,
}, 72 {9}, 69 {6}, 58 {4}; H-NMR (DMSO-d , 500
CO-), 5.42 (s,
CN, 500 MHz): 1st tautomer δ
CO), 5.33 (s, 1H,-
), 2.35 (s, 3H,
, 500 MHz): δ 17.5 (CH CO-), 22.2
COHd), 100.6 (-CHdCOH-), 105.0 (-COHd), 188.7 (-CO-
CO-).
-Bu t yl-(2-m e t h yl-[1,3]oxa t h iola n -2-yl)oct a n e -1,3-d i-
1
COCH
2
COCH
3
6
2-Bu t yl-[1,3]d it h iola n e-2-ca r boxylic Acid (11). Com-
pound 8 (1.94 g, 8.29 mmol) and LiOH‚H O (0.870 g, 20.7 mmol)
MHz): δ 1.34 (s, 3H, dCOHCH
3
3
), 2.19 (s, 3H, CH
3
2
1
1
1
H, -CHdCOH-); H-NMR (CD
.41 (s, 3H, dCOHCH
were added into 20 mL of water. The solution was heated under
reflux for 1 h, cooled, and washed with ethyl ether (2 × 20 mL).
The pH of the aqueous layer was adjusted to 1-2 with 10% HCl.
Ethyl ether (2 × 20 mL) was used for extraction. The solution
3
), 2.20 (s, 3H, CH
3
CHdCOH-), 2nd tautomer δ 2.21 (s, 3H, -COCH
3
1
3
-COCH
3
); C-NMR (DMSO-d
6
3
(CH
3
was dried over MgSO , and the solvent was removed under
4
CHd), 201.6 (CH
3
vacuum. Product 11 (0.74 g, 3.6 mmol, 43%) was obtained.
HRCIMS: (M + H)/ z calcd for C
8
H
15
O
2
S
2
207.0513, found
2
1
2
2
07.0518. H-NMR (CD Cl, 500 MHz): δ 0.81 (t, 3H), 1.25 (m,
H), 1.36 (m, 2H), 1.61 (t, 2H), 3.29 (m, 2H), 3.35 (m, 2H).
3
on e (7c). NaH (0.13 g; 60% in oil, 3.3 mmol) was washed 3
times with dry hexane, and twice with THF. Another 5.0 mL
of THF was added, followed by 0.53 g of compound 9 (3.0 mmol).
2-Bu tyl-[1,3]d ith iola n e-2-ca r bon yl Ch lor id e (12). Com-
6
-Undecanone (0.67 g, 4.0 mmol) was added dropwise into the
resulting stirred slurry. After additional stirring for 20 min,
0 mL of saturated NaHCO solution was added and the
solution partially concentrated. Ethyl ether (10 mL) was added
and the organic layer washed with saturated NaHCO solution
2 × 10 mL) and saturated NaCl solution (10 mL), and dried
pound 11 (0.50 g, 2.4 mmol) was added to 5 mL of benzene,
followed by 1.44 g (0.89 mL, 12.1 mmol) of thionyl chloride. The
solution was stirred 0.5 h before removal of benzene and the
excess of thionyl chloride on a water aspirator; the product was
immediately used for the following reaction (see Scheme 4).
1
3
3
(
3 2 3
EIMS: 226 {22, M + H}, 224 {48, M}, 161 {100, CH (CH ) -