J. T. Gupton et al. / Tetrahedron 62 (2006) 8243–8255
8253
a few drops of water were added to induce crystallization.
The precipitate was collected by suction filtration and dried
in vacuo (Kugelrohr) to yield a fine white powder (0.436 g,
89% yield), which exhibited the following properties: mp
solution was allowed to warm to room temperature and
stirred for 16 h. The solvents were removed in vacuo and
the resulting aqueous mixture was transferred to a separatory
funnel and extracted with ethyl acetate (3ꢂ50 mL). The
combined organic extracts were filtered through a cotton
plug and concentrated in vacuo followed by drying in vacuo
(Kugelrohr) to give a reddish brown solid (0.157 g). HPLC
analysis of the crude product on a C-18 reverse phase column
with a methanol/water gradient indicated that the material
was 77.8% Rigidin (96% in situ yield). A 50 mg sample of
the crude product was subjected to flash chromatography
on a C-18 reverse phase column with a methanol/water gra-
dient and this resulted in 0.030 g of a light yellow solid,
which exhibited physical properties3a,4,5 identical to those
1
157–158 ꢁC; H NMR (CDCl3) d 7.56 (d, J¼9.0 Hz, 2H),
7.16 (d, J¼9.0 Hz, 2H), 7.04 (d, J¼8.0 Hz, 1H), 6.82 (d,
J¼9.0 Hz, 2H), 6.75 (d, J¼9.0 Hz, 2H), 6.46 (d, J¼2.5 Hz,
1H), 6.45 (dd, J¼2.5, 8.0 Hz, 1H), 4.30 (d, J¼5.0 Hz, 2H),
3.82 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H), and 3.67 (s, 3H);
13C NMR (CDCl3) d 39.2, 54.6, 54.7, 54.9, 55.0, 98.1,
104.3, 113.3, 114.1, 116.6, 123.6, 127.8, 130.0, 130.5,
131.6, 132.1, 158.5, 159.7, 159.9, 161.3, 163.3, 165.5, and
185.5; IR (neat) 3403, 3244, 1707, and 1621 cmꢀ1; HRMS
(EI) m/z calcd for C30H28N2O8 544.1846, found 544.1846.
1
reported for Rigidin: mp>325 ꢁC (lit.3>300 ꢁC); H NMR
4.1.15. 3-(2,4-Dimethoxybenzyl)-6-(4-methoxybenzoyl)-
5-(4-methoxyphenyl)-1,7-dihydropyrrolo[2,3-d]pyrimi-
dine-2,4-dione (40a). Into an argon blanketed, three-neck,
round-bottom flask equipped with a thermometer, condenser,
septa, and magnetic stir bar were placed 3-(2,4-dimeth-
oxybenzylcarbamoyl)-5-(4-methoxybenzoyl)-4-(4-meth-
oxyphenyl)pyrrole-2-carboxylic acid (39a) (0.355 g,
0.65 mmol) and toluene (12 mL). Triethylamine (0.14 mL,
1.00 mmol) was added dropwise followed by diphenylphos-
phorylazide (0.22 mL, 1.00 mmol). The reaction mixture
was then refluxed for 9 h and then stirred at room temperature
for 16 h. The solvent was removed in vacuo and the residue
was subjected to flash chromatography (gradient elution
with EtOAc/hexanes) to provide a light yellow solid
(0.242 g, 69% yield), which exhibited the following proper-
ties: mp 196–200 ꢁC; 1H NMR (CDCl3) d 10.43 (br s, 1H),
10.10 (br s, 1H), 7.41 (d, J¼9.0 Hz, 2H), 7.15 (d,
J¼9.0 Hz, 2H), 6.96 (d, J¼8.0 Hz, 1H), 6.59 (d, J¼9.0 Hz,
2H), 6.55 (d, J¼9.0 Hz, 2H), 6.46 (d, J¼2.4 Hz, 1H), 6.39
(d of d, J¼2.4, 8.0 Hz, 1H), 5.18 (s, 2H), 3.84 (s, 3H), 3.74
(s, 6H), and 3.70 (s, 3H); 13C NMR (CDCl3) d 38.9, 55.1,
55.2, 55.3, 55.7, 98.7, 99.3, 104.3, 112.8, 112.9, 117.6,
123.8, 125.5, 127.3, 129.5, 130.9, 131.5, 132.6, 139.5,
151.4, 157.9, 159.1, 159.6, 159.9, 162.4, and 186.5; IR
(neat) 1712 and 1663 cmꢀ1; HRMS (EI) m/z calcd for
C30H27N3O7 541.1849, found 541.1836.
(DMSO-d6) d 11.73 (br s, 1H), 11.17 (br s, 1H), 10.62 (br
s, 1H), 9.99 (br s, 1H), 9.72 (br s, 1H), 7.30 (d, J¼9.0 Hz,
2H), 6.95 (d, J¼9.0 Hz, 2H), 6.48 (d, J¼9.0 Hz, 2H), and
6.45 (d, J¼9.0 Hz, 2H); 13C NMR (DMSO-d6) d 98.6,
114.3, 114.8, 123.2, 125.4, 128.5, 129.1, 132.0, 132.7,
141.6, 151.1, 156.9, 160.2, 161.2, and 185.7; IR (neat)
3215, 1695, 1568, 1434, 1413, and 1258 cmꢀ1; HRMS
(ES, MꢀH) m/z calcd for C19H12N3O5 362.0777, found
362.0774.
4.1.17. 3-Methylcarbamoyl-5-(4-methoxybenzoyl)-4-(4-
methoxyphenyl)pyrrole-2-carboxylic acid ethyl ester
(38b). Into a 7 mL microwave reaction vessel, which had
been equipped with a magnetic stir bar, were placed molyb-
denum hexacarbonyl (0.228 g, 0.865 mmol), palladium(II)
acetate (.058 g, 0.087 mmol), 3-iodo-5-(4-methoxy-
benzoyl)-4-(4-methoxyphenyl)pyrrole-2-carboxylic acid ethyl
ester9 (35a) (0.437 g, 0.865 mmol), and tetrahydrofuran
(4 mL). Then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL,
2.60 mmol) was added and the reaction vessel was capped.
Through the septum was added 1.30 mL (2 M in THF,
2.60 mmol) of N-methyl amine. The reaction mixture was
stirred for 5 min and subjected to microwave irradiation
for 45 min at 100 ꢁC (15–20 W). The reaction mixture was
filtered through a plug of sand, silica, and Celite and the
plug was washed with tetrahydrofuran (50 mL). The filtrate
was concentrated in vacuo and the residue was adsorbed onto
silica gel and purified by flash chromatography (gradient
elution with ethyl acetate/hexanes) to yield 0.240 g (64.5%
yield) of a yellow solid, which exhibited the following prop-
4.1.16. Rigidin (1). A solution of 3-(2,4-dimethoxybenzyl)-
6-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1,7-dihydro-
pyrrolo[2,3-d]pyrimidine-2,4-dione (40a) (0.190 g, 0.350 mmol)
in methylene chloride (25 mL) was prepared in a three-neck
50 mL round-bottom flask equipped with a condenser, ther-
mometer, septa, and magnetic stir bar. The solution was
placed under an argon atmosphere and cooled to ꢀ78 ꢁC
in an acetone/dry ice bath. A 1 M solution of boron tribro-
mide in methylene chloride (7 mL, 7.00 mmol) was added
to the reaction mixture slowly over 5 min and the reaction
set-up was protected from the light. The reaction mixture
was allowed to slowly equilibrate to room temperature
over 8 h and then stirred for 60 h. After cooling the reaction
mixture to ꢀ78 ꢁC an additional amount of boron tribromide
solution (2.5 mL) was added slowly over 3 min and the reac-
tion mixture was allowed to equilibrate to room temperature
and stirred for 20 h. The reaction mixture was cooled in an
ice/water bath and quenched with slow addition of methanol
to a total of 40 mL. This mixture was stirred in an ice bath for
5 h and 20 mL of water was added followed by the careful
addition of 5% aqueous NaOH (30 mL) to a pH of 6. This
1
erties: mp 85–86 ꢁC; H NMR (CDCl3) d 9.89 (br s, 1H),
7.48 (d, J¼9.0 Hz, 2H), 7.08 (d, J¼9.0 Hz, 2H), 6.64 (d,
J¼9.0 Hz, 2H), 6.59 (d, J¼9.0 Hz, 2H), 6.29 (broad absorp-
tion, 1H), 4.43 (q, J¼7.0 Hz, 2H), 3.76 (s, 3H), 3.73 (s, 3H),
2.87 (d, J¼5.0 Hz, 3H), and 1.42 (t, J¼7.0 Hz, 3H); 13C
NMR (CDCl3) d 14.3, 26.6, 55.2, 55.4, 61.7, 113.1, 113.4,
122.2, 125.0, 125.6, 129.0, 129.8, 130.1, 131.5, 131.9,
158.9, 159.9, 163.0, 164.9, and 186.2; IR (neat) 3266,
1704, and 1627 cmꢀ1; HRMS (ES, M+H) m/z calcd for
C24H25N2O6 437.1707, found 437.1712.
4.1.18. 3-Methylcarbamoyl-5-(4-methoxybenzoyl)-4-(4-
methoxyphenyl)pyrrole-2-carboxylic acid (39b). Into
a round-bottom flask equipped with reflux condenser and
magnetic stir bar were placed 0.254 g (0.582 mmol) of
3-methylcarbamoyl-5-(4-methoxybenzoyl)-4-(4-methoxy-
phenyl)pyrrole-2-carboxylic acid ethyl ester (38b), 0.098 g
(1.75 mmol) of potassium hydroxide, and 30 mL of a 1:1