August 2014
3-Substituted Analogues of Tenuazonic Acid
E213
À
(
br, 1H, OH). HRMS for C H NO S (M À H) : 262.0907.
Data for 2,5-dihydro-4-hydroxy-5-isobutyl-N-methyl-2-oxo-
1
4
16
2
Found: 262.0900.
1H-pyrrole- 3-carboxamide (9a). Yield 66.0%. A white solid;
ꢀ
1
ꢀ
1
Data for 5b.
Yield 55.3%; mp 146–148 C; H NMR
mp 129 C. H NMR (400 MHz, CDCl
(CH ), 1.41–1.52 (m, 1H, CH ), 1.69–1.86 (m, 2H, CH
(CH ), 2.93 (d, J= 4.4 Hz, 3H, NCH ), 4.12–4.20 (m, 1H,
3
) d 0.97–1.00 (m, 6H, CH
(
(
400 MHz, DMSO-d ) d 0.87–0.90 (m, 6H, (CH ) ), 1.15–1.22
3
)
2
2
2
+CH
6
3 2
m, 1H, CH(CH ) ), 1.54–1.60 (m, 1H, CH ), 1.71–1.83 (m, 1H,
3
)
2
3
3
2
2
CH ), 2.15 (s, 3H), 3.88–3.96 (m, 1H, CHNH), 7.75 (br, 1H, NH),
CHNH), 6.06 (br, 1H, NH), 7.52 (br, 1H, NH), 8.07 (br, 1H, OH).
2
À
À
9 2
11.38 (br, 1H, OH). HRMS (ESI) for C H14NO S (MÀ H) :
HRMS for C10
H
15
N
2
O
3
(M À H) : 211.1088. Found: 211.1085.
200.0751. Found: 200.0750.
Data for 2,5-dihydro-4-hydroxy-5-isobutyl-2-oxo-N-propyl-
1
H-pyrrole-3-carboxamide (9b). Yield 43.5%. A white solid;
Synthetic procedure for 4-hydroxy-5-isobutyl-3-
phenylsulfonyl)-1H-pyrrol-2(5H)-one (6a) and 4-hydroxy-5-
isobutyl-3-(methylsulfonyl)-1H-pyrrol-2(5H)-one (6b). H O2
ꢀ
1
mp 123–125 C. H NMR (400 MHz, CDCl ) d 0.94–1.00
3
(
(
m, 9H, CH(CH ) + CH CH ), 1.42–1.49 (m, 1H, CHCH ),
3
2
2
3
2
2
1
.56–1.66 (m, 2H, CH
2
CH
3
), 1.71–1.85 (m, 2H, CHCH
2
+ CH
(
5
30%, 0.92g, 24 mmol) was added to a suspension of compound
a or 5b (1.0 mmol) in acetic acid (5mL). After stirring at 35 C
ꢀ
3 2 2
(CH ) ), 3.2 (q, J = 6.8 Hz, 2H, NCH ), 4.12–4.16 (m, 1H,
CHNH) 5.97 (br, 1H, NH), 7.59 (br, 1H, NH), 9.92 (br, 1H, OH).
HRMS for C H N O (MÀ H) : 239.1401. Found: 239.1408.
for 2 h, the reaction solution was concentrated. The residue was
recrystallized from ethanol and ethyl acetate to give white powder
À
12 19 2 3
Data for N-tert-butyl-2,5-dihydro-4-hydroxy-5-isobutyl-2-
6
a or 6b.
Data for 6a.
ꢀ
1
oxo-1H-pyrrole- 3-carboxamide (9c).
Yield 72.5%. A white
) d 0.97–1.00
+CH(CH ),
.69–1.89 (m, 2H, CHCH ), 4.07–4.13 (m, 1H, CHNH), 5.87
Yield 84.8%; mp 150 C decomp; H NMR
1
ꢀ
solid; mp 195–198 C. H NMR (400 MHz, CDCl
3
(
(
400MHz, DMSO-d ) d 0.83–0.85 (m, 6H, (CH ) ), 1.18–1.24
6 3 2
(m, 6H, CH(CH
3
)
2
), 1.39–1.48 (m, 10H, C(CH
3
)
3
3 2
)
m, 1H, CH(CH ) ), 1.54–1.60 (m, 1H, CH ), 1.66–1.75 (m, 1H,
3
2
2
1
2
CH ), 3.95–4.02 (m, 1H, CHNH), 7.56–7.67 (m, 3H, Ar–H), 7.91
2
(br, 1H, NH), 7.53 (br, 1H, NH), 7.94 (br, 1H, OH). HRMS for
(
(
d, J = 7.2 Hz, 3H, ArH + NH). HRMS (ESI) for C15
H
20NO
5
S
À
C
13
H
21
N
2
O
3
(M À H) : 253.1558. Found: 253.1552.
À
M+ CH
3
OH–H) : 294.0806. Found: 294.0814.
Data for N-(4-Chlorophenyl)-2,5-dihydro-4-hydroxy-5-isobutyl-
ꢀ
1
Data for 6b. Yield 25.3%; mp 231 C; H NMR (400 MHz,
DMSO-d ) d 0.90 (d, J=7.2Hz, 6H, (CH ) ), 1.28–1.35 (m, 1H,
2-oxo- 1H-pyrrole-3-carboxamide (9d).
Yield 59.1%. A white
6
3 2
ꢀ
1
solid; mp 160 C. H NMR (400 MHz, CDCl ) d 1.02 (d, J=6.0Hz,
3
CH(CH ) ), 1.50–1.57 (m, 1H, CH ), 1.73–1.85 (m, 1H, CH ),
3
2
2
2
6H, CH(CH ) ), 1.46–1.56 (m, 1H, CH(CH ) ), 1.76–1.87 (m, 2H,
3 2 3 2
3
1
2
.34 (s, 3H, SCH ), 4.14–4.17 (m, 1H, CHNH), 8.78 (br, 1H, NH),
3
CHCH
d, J= 8.8 Hz, 2H, ArH), 7.31 (d, J= 8.8 Hz, 2H, ArH), 7.53
br, 1H, NH), 9.57 (br, 1H, OH). HRMS for C H ClN O
2
), 4.22–4.26 (m, 1H, CHNH), 5.91 (br, 1H, NH), 7.31
+
5.12 (br, 1H, OH). HRMS for C H NO S (M+CH OH + H) :
10
20
5
3
(
(
34.0795. Found: 234.0794.
15
16
2 3
À
Methyl 2-(3-ethoxy-3-oxopropanamido)-4-methylpentanoate
(M À H) : 307.0855. Found: 307.0862.
(
(
7). To a stirred solution of leucine methyl ester hydrochloride
18.07 g, 100 mmol) in dichloromethane (200 mL) at 0 C
Data for N-benzyl-2,5-dihydro-4-hydroxy-5-isobutyl-2-oxo-
ꢀ
1H-pyrrole- 3-carboxamide (9e). Yield 68.1%; A white solid;
mp 168–171 C. H NMR (400 MHz, CDCl ) d 0.96–0.99
ꢀ
1
were successively added triethylamine (10.12 g, 100 mmol),
3
monomethyl malonate (13.2 g, 100 mmol), and EDCÁHCl
(m, 6H, CH(CH ) ), 1.41–1.49 (m, 1H, CH(CH ) ), 1.71–1.84
3
2
3 2
(
20.13 g, 105 mmol). The mixture was stirred overnight at room
(m, 2H, CHCH ), 4.14–4.17 (m, 1H, CHNH), 4.55 (d, J = 6.4 Hz,
2
temperature, then washed with 1M hydrochloric acid and brine,
dried over anhydrous sodium sulfate, and evaporated to give
compound 7 (20.13 g, 78. 4%) as colorless oil.
2H, NHCH ), 5.84 (br, 1H, NH), 6.43 (br, 1H, OH or CHCO),
7.27–7.36 (m, 5H, ArH), 7.94 (br, 1H, NH). HRMS for
2
À
C
16
H
19
N
2
O
3
(MÀ H) : 287.1401. Found: 287.1403.
Data for N-(4-fluorobenzyl)-2,5-dihydro-4-hydroxy-5-isobutyl-
-oxo-1H-pyrrole- 3-carboxamide (9f). Yield 65.4%. A white
solid; mp 173–175 C. H NMR (400 MHz, CDCl ) d 0.94–1.01
m, 6H, CH(CH ), 1.41–1.51 (m, 1H, CH(CH ), 1.69–1.82 (m,
), 3.28 (br, 1H, CHCO), 4.12–4.19 (m, 1H, CHNH),
.51 (d, J= 6.0 Hz, 2H, NHCH ), 5.71 (br, 1H, NH), 6.99–7.05
Synthesis of methyl 2,5-dihydro-4-hydroxy-5-isobutyl-2-oxo-
2
1H-pyrrole- 3-carboxlate (8). Metal sodium (0.26 g, 11.47 mmol)
ꢀ
1
3
was added to anhydrous methanol (10 mL). After sodium disappeared,
compound 7 (3.50 g, 13.50 mmol) was added, and the mixture was
refluxed for 1.5 h then was concentrated. The resulting solid was
dissolved in water and washed with dichloromethane. Then, the
aqueous solution was acidified with 2M HCl and extracted with
ethyl acetate, washed with brine, dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The residue was
recrystallized from ethyl acetate to give compound 8 (1.23 g, 64.8%)
(
)
3 2
3 2
)
2H, CHCH
2
4
2
(
m, 2H, ArH), 7.26–7.31 (m, 2H, ArH), 7.94 (br, 1H, NH).
À
HRMS for C15
Data for
isopropylisoxazol-5-yl)methyl)- 2-oxo-1H-pyrrole-3-carboxamide
H
16FN
2
O
3
(M À H) : 305.1307. Found: 305.1302.
2,5-dihydro-4-hydroxy-5-isobutyl-N-((3-
ꢀ
1
1
(
(
(
(
(
9g).
400 MHz, DMSO-d
m, 6H, CH(CH
m, 1H, CH CH), 1.71–1.87 (m, 1H, CH(CH
m, 1H, CH(CH ) ), 3.88–3.94 (m, 0.54H, CHNH) + 4.06–
Yield 46.2%. A white solid; mp 167–170 C. H NMR
) d 0.86–0.92 (m, 6H, CH(CH ), 1.18–1.21
), 1.26–1.34 (m, 1H, CH CH), 1.51–1.60
), 2.90–3.03
ꢀ
ꢀ
as a white solid. mp 98–100 C (lit. [20] 98–101 C). H NMR
400 MHz, CDCl ) d 0.99 (d, J= 6.0 Hz, 6H, CH(CH ), 1.45–1.53
m, 1H, CH CH), 1.71–1.85 (m, 2H, CH CH + CH(CH ), 3.93
s, 3H, OCH ), 4.18–4.21 (m, 1H, CHNH), 5.77 (br, 1H, NH).
General synthetic procedure for 2,5-dihydro-4-hydroxy-5-
6
3 2
)
(
(
(
3
3 2
)
3
)
2
2
2
2
3 2
)
2
3 2
)
3
3
2
4.03 (m, 0.46H, CHNH), 4.28 (d, J = 5.8 Hz, 1.08H, NHCH2),
isobutyl-2-oxo-1H-pyrrole-3-carboxamides (9). To a 35-mL
microwave reaction tube were added a substituted amine (5.0 mmol)
and compound 8 (1.07 g, 5.0 mmol) in THF (20 mL), and the tube
+4.55 (d, J = 5.8 Hz, 0.92H, NHCH ), 4.30 (s, 0.54H, CHCO),
6.27 (s, 0.54H, Ar–H), + 6.35 (s, 0.46H, Ar–H), 7.12–7.16
2
(m, 1H, NH), 8.32 (br, 0.46H, NH) 8.55 (br, 0.54H, NH).
ꢀ
À
was sealed and stirred at 100 C for 15 min with microwave heating
HRMS for C H N O (M À H) : 320.1616. Found: 320.1619.
1
6 22 3 4
at 100 W. The reaction mixture was then concentrated; the residue
was dissolved in ethyl acetate and washed with diluted hydrochloric
acid then brine, dried over anhydrous sodium sulfate, evaporated,
and recrystallized from ethyl acetate to give compound 9.
Data for 2,5-dihydro-4-hydroxy-5-isobutyl-2-oxo-N-((3-
phenylisoxazol-5-yl)methyl)-1H-pyrrole-3-carboxamide (9h). Yield
ꢀ
1
38.1%. A white solid; mp 217 C. H NMR (400 MHz, CDCl ) d
3
0.98–1.01 (m, 6H, CH(CH ) ), 1.44–1.53 (m, 1H, CH(CH ) ),
3
2
3 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet