Benzoic Acid Congeners of Bilirubin
max
415
and 30 mL of CHCl3, and treated for 10 min with ethereal
diazomethane (generated from 30 mmol of N-nitroso-N-meth-
ylurea). Excess CH2N2 was destroyed with acetic acid, and the
solvents were evaporated under vacuum. The residue was
purified by radial chromatography (2-4% CH3OH in CHCl3-
CH2Cl2 ) 1:1 v/v) and after recrystallization from CH2Cl2-
CH3OH, 1.36 g (75%) of bright yellow dipyrrinone 5m was
posed without melting at 309-331 °C; UV-vis ꢀ
38,000,
max
401
max
408
ꢀ
37,400 (benzene), ꢀ
38,300 (CHCl3), ꢀmax 39,100 (CH3-
411
OH), ꢀ4m0a0x 37,400 (CH3CN), ꢀmax 37,000 (DMSO); NMR data in
Tables 1 and 2; HRMS (FAB, 3-NBA) calcd for C21H22N2O3
350.1630; found 350.1628, ∆ ) 0.2 mDa, error 0.6 ppm.
8-(p-Ca r boxyp h en yl)-3-eth yl-2,7,9-tr im eth yl-1,10-d ih y-
d r o-11H-d ip yr r in -1-on e (4p). This dipyrrinone acid was
prepared in 95% yield. It decomposed without melting at 322-
409
max
430
max
408
obtained: mp 272-273 °C; UV-vis ꢀ
30,300, ꢀ
45,900
max
(benzene), ꢀ
41,300 (CHCl3), ꢀmax 42,500 (CH3OH), ꢀmax
max
416
max
401
max
408
405
409
397
343 °C; UV-vis ꢀ
39,600, ꢀ
39,100 (benzene), ꢀ
36,900 (CH3CN), ꢀmax 40,000 (DMSO); 1H NMR (CDCl3) δ
1.21 (3H, t, J ) 7.6 4H08z), 1.97 (3H, s), 2.18 (3H, s), 2.48 (3H, s),
2.58 (2H, q, J ) 7.6 Hz), 3.94 (3H, s), 6.22 (1H, s), 7.48 (1H,
m), 7.49 (1H, m), 7.96 (1H, m), 7.98 (1H, m), 10.63 (1H, br. s),
11.39 (1H, br. s) ppm; 13C NMR (CDCl3) δ 8.6, 10.3, 12.3, 15.0,
18.0, 52.1, 101.0, 122.7, 122.9, 123.0, 123.8, 127.0, 127.9, 128.2,
130.2, 130.9, 131.9, 134.3, 136.2, 148.5, 167.3, 174.3 ppm. Anal.
Calcd for C22H24N2O3 (364.4): C, 72.50; H, 6.64; N, 7.69.
Found: C, 72.24; H, 6.48; N, 7.44.
39,800 (CHCl3), ꢀmax 41,000 (CH3OH), ꢀmax 39,900 (CH3CN),
411
398
ꢀm41a1x 38,100, ꢀsh 37,500 (DMSO); NMR data in Tables 1 and 2;
403
HRMS (FAB, 3-NBA) calcd for C21H22N2O3 350.1630; found
350.1629, ∆ ) 0.1 mDa, error 0.3 ppm.
Gen er a l P r oced u r e for Syn th eses of Mesobiliver d in
Ester s An a logu es 3. To a solution of 2.00 mmol of the
corresponding dipyrrinone ester (5o, 5m or 5p) in 440 mL of
CH2Cl2 was added p-chloranil (1.23 g, 5.00 mmol) followed by
22 mL of 97% formic acid, and the mixture was heated at
reflux for 24 h. The reaction volume was reduced by distillation
to one-half, and reflux was continued for 6 h. Then the mixture
was chilled overnight at -20 °C. The separated yellow solid
was removed by filtration and discarded. The blue filtrate was
carefully neutralized with 5% aqueous NaHCO3 and then
washed with 4% aqueous NaOH (2 × 100 mL) and H2O (4 ×
100 mL). After drying (anhydrous Na2SO4), filtration, and
evaporation of the solvent under vacuum, the residue was
purified by radial chromatography (gradient CH2Cl2-CH3-
CO2H-CH3OH ) 100:3.2 to 100:3:7 v/v/v). The combined pure
fractions were washed with 1% aqueous NaHCO3 and H2O and
then dried (anhydrous Na2SO4). After filtration, the solvent
was evaporated under vacuum and the residue was recrystal-
lized from CHCl3-hexane to afford pure mesobiliverdin esters
3.
3-Eth yl-8-(p-isobu toxycar bon ylph en yl)-2,7,9-tr im eth yl-
1,10-d ih yd r o-11H-d ip yr r in -1-on e (5p). Following the pro-
cedure from above 1.44 g (5 mmol) of monopyrrole 8p was
converted to 1.42 g (81%) of crude dipyrrinone acid 4p
(containing ∼10% of methyl ester). This amount was treated
for 2 h at reflux with a mixture of 25 mL of 10% aqueous
NaOH and 50 mL of ethanol. After cooling, the ethanol solvent
was evaporated under vacuum. The residue was diluted with
cold water (25 mL) and acidified at 0 °C with 10% aqueous
HCl. The reprecipitated 4p was collected by filtration, washed
with water, and dried for 48 h under vacuum (P2O5).
A mixture of 1.30 g (3.7 mmol) of this purified acid, 1.79 g
(5.5 mmol) of cesium carbonate, 30 mL of anhydrous dimeth-
ylformamide and 1.3 mL (11.1 mmol) of isobutyl iodide was
heated for 18 h at 80 °C. After cooling the mixture was
partitioned between 300 mL of CHCl3 and 300 mL of H2O. The
organic layer was washed with water (3 × 100 mL) and dried
(Na2SO4), and after filtration, the solvent was evaporated
under vacuum. The residue was purified by radial chroma-
tography (eluent 2-3% CH3OH in CH2Cl2) and the pure
material was recrystallized from CH3OH-CH2Cl2 to afford
1.18 g (58% based on 8p) of bright yellow isobutyl ester 5p:
3,17-Dieth yl-8,12-bis(o-m eth oxyca r bon ylp h en yl)-2,7,-
13,18-tetr a m eth yl-(21H,24H)-bilin -1,19-d ion e (3o). This
mesobiliverdin ester was synthesized in 84% yield as previ-
ously described from dipyrrinone 5o:15 mp 284-288 °C (lit.15
mp 284-8°C); UV-vis ꢀm65a0x 18,300, ꢀ3m7a5x 65,100 (benzene), ꢀmax
646
max
17,200; ꢀ
OH), ꢀ
66,400 (CHCl3), ꢀmax 17,100, ꢀmax 66,300 (CH3-
375
max
648
370
max
367
sh
431
max
410
17,400, ꢀ
67,700 (CH3CN), ꢀmax 19,500, ꢀmax
648 375
mp 263-264 °C; UV-vis ꢀ
33,900, ꢀ
49,000 (benzene),
647
max
43,900 (CHCl3), ꢀmax 46,100 (CH3OH), ꢀmax 40,400 (CH3-
66,400 (DMSO).
ꢀ
406
411
397
CN), ꢀ4m1a2x 43,200, ꢀsh 42,300 (DMSO); 1H NMR (CDCl3) δ 1.05
3,17-Dieth yl-8,12-bis(m -m eth oxyca r bon ylp h en yl)-2,7,-
13,18-tetr a m eth yl-(21H,24H)-bilin -1,19-d ion e (3m ). This
mesobiliverdin ester was synthesized in 85% yield: mp 269-
404
(6H, d, J ) 6.7 Hz), 1.20 (3H, t, J ) 7.7 Hz), 1.97 (3H, s), 2.11
(1H, m), 2.20 (3H, s), 2.50 (3H, s), 2.58 (2H, q, J ) 7.7 Hz),
4.13 (2H, d, J ) 6.5 Hz), 6.21 (1H, s), 7.37 (2H, d, J ) 8.3 Hz),
8.09 (2H, d, J ) 8.3 Hz), 10.65 (1H, br. s), 11.38 (1H, br. s)
ppm; 13C NMR (CDCl3) δ 8.6, 10.4, 12.5, 15.0, 18.0, 19.2, 28.0,
70.9, 100.9, 122.8, 123.0, 123.2, 123.7, 127.8, 128.0, 129.5,
129.6, 132.1, 140.8, 148.6, 166.8, 174.3 ppm. Anal. Calcd for
max
647
max
375
max
639
271 °C; UV-vis ꢀ
19,900, ꢀ
67,500 (benzene), ꢀ
max
18,100, ꢀ
70,100 (CHCl3), ꢀmax 18,500, ꢀmax 71,000 (CH3-
375
max
632
638
370
max
366
OH), ꢀ
18,200, ꢀ
70,500 (CH3CN), ꢀmax 22,500, ꢀmax
630 375
1
68,100 (DMSO); H NMR (CDCl3) δ 1.24 (6H, t, J ) 7.6 Hz),
1.84 (6H, s), 2.14 (6H, s), 2.54 (4H, q, J ) 7.6 Hz), 3.93 (6H,
s), 6.00 (2H, s), 6.47 (1H, s), 7.45 (2H, m), 7.48 (2H, m), 7.96
(2H, m), 7.97 (2H, m), 8.47 (2H, br. s) ppm; 13C NMR (CDCl3)
δ 8.4, 10.2, 14.4, 17.9, 52.2, 96.1, 118.5, 127.9, 128.4, 128.5,
128.8, 130.4, 130.8, 134.0, 134.2, 139.3, 140.6 141.5, 146.8,
150.0, 166.8, 172.6 ppm. Anal. Calcd for C43H42N4O6 (710.8):
C, 72.66; H, 5.96; N, 7.88. Found: C, 72.49; H, 5.78; N, 7.88.
C
25H30N2O3 (406.5): C, 73.86; H, 7.44; N, 6.89. Found: C,
74.22; H, 7.64; N, 6.90.
Gen er a l P r oced u r e for Syn th eses of Dip yr r in on e
Acid s 4. A mixture of 1 mmol of the corresponding ester 5o,15
5m , or 5p, 10 mL of 10% aqueous NaOH, and 25 mL of ethanol
was heated at reflux for 3 h. After cooling, the ethanol solvent
was removed under vacuum. The residue was diluted with 10
mL of water and acidified at 0 °C with 10% aqueous HCl. The
precipitated product was collected by filtration, washed with
water (3 × 10 mL), and dried under vacuum for 24 h (P2O5).
3,17-Dieth yl-8,12-bis(p-isobu toxyca r bon ylp h en yl)-2,7,-
13,18-tetr a m eth yl-(21H,24H)-bilin -1,19-d ion e (3p). This
compound was obtained in 80% yield: mp 265-266 °C; UV-
vis ꢀm65a4x 19,700, ꢀ3m7a8x 70,300 (benzene), ꢀm65a1x 18,200, ꢀ3m7a5x 74,300
(CHCl3), ꢀmax 18,500, ꢀmax 77,300 (CH3OH), ꢀmax 18,400, ꢀmax
8-(o-Ca r boxyp h en yl)-3-eth yl-2,7,9-tr im eth yl-1,10-d ih y-
d r o-11H-d ip yr r in -1-on e (4o). The acid 4o was isolated in
94% yield. It decomposed without melting at 287-314 °C; UV-
644
371
639
371
76,200 (CH3CN), ꢀmax 21,700, ꢀmax 72,100 (DMSO); 1H NMR
(CDCl3) δ 1.03 (12H, d, J ) 6.73H78z), 1.24 (6H, t, J ) 7.6 Hz),
1.83 (6H, s), 2.10 (2H, m), 2.14 (6H, s), 2.54 (4H, q, J ) 7.6
Hz), 4.12 (4H, d, J ) 6.6 Hz), 6.02 (2H, s), 6.53 (1H, s), 7.34
(4H, d, J ) 8.2 Hz), 8.08 (4H, d, J ) 8.2 Hz), 8.40 (2H, br. s)
ppm; 13C NMR (CDCl3) δ 8.3, 10.3, 14.4, 17.9, 19.2, 27.9, 71.1,
95.9, 118.4, 128.3, 128.8, 129.4, 129.66, 129.70, 138.4, 139.4,
140.6, 141.5, 146.8, 150.0, 166.3, 172.5 ppm. Anal. Calcd for
637
max
405
max
405
vis ꢀ
35,900 (benzene), ꢀ
35,000 (CHCl3), ꢀmax 36,000
411
(CH3OH), ꢀmax 35,400 (CH3CN), ꢀmax 35,100 (DMSO); NMR
data in Ta3b9l8es 1 and 2; HRMS40(5FAB, 3-NBA) calcd for
C
21H22N2O3 350.1630; found 350.1635, ∆ ) -0.5 mDa, error
-1.3 ppm.
8-(m -Ca r b oxyp h en yl)-3-et h yl-2,7,9-t r im et h yl-1,10-d i-
h yd r o-11H-d ip yr r in -1-on e (4m ). Following the general pro-
cedure above, acid 4m was obtained in 98% yield. It decom-
C
49H54N4O6 (795.0): C, 74.03; H, 6.85; N, 7.05. Found: C,
74.00; H, 6.78; N, 7.00.
J . Org. Chem, Vol. 68, No. 20, 2003 7603