Synthesis of a 10-Oxo-Bilirubin
J. Am. Chem. Soc., Vol. 121, No. 40, 1999 9263
the solvent was removed under reduced pressure, and the residue was
7.32 Hz, 2H), 6.69 (s, 1H), 7.26 (d, J ) 7.82 Hz, 2H), 7.77 (d, J )
7.82 Hz), 9.25 (s, 1H, NH) ppm. 13C NMR (75 MHz) δ: 9.60, 14.38,
17.27, 21.28, 120.47, 120.91, 122.92, 126.41, 129.50, 130.79, 140.16,
143.25 ppm.
crystallized from dichloromethane-hexane to yield 5, 7.05 g (87%)
1
yield: mp 137-139 °C (lit. 127 °C,33 132-134 °C34). H NMR (300
MHz): δ 1.54 (s, 18H), 2.23 (s, 6H), 2.47 (t, J ) 7.32 Hz, 4H), 2.74
(t, J ) 7.32 Hz, 4H), 3.93 (s, 6H), 8.69 (s, 2H), ppm. 13C NMR (75
MHz) δ: 10.38 (pyrr-CH3), 19.15, 22.43, 28.30, 34.51, 51.46, 80.12,
119.50, 119.83, 125.39, 129.05, 160.94, 173.46 ppm.
An Improved Synthesis of p-Toluenesulfonylisocyanide (TosMIC).
In a one liter round-bottom flask, equipped with a mechanical stirrer
and a reflux condenser, were placed sodium p-toluenesulfinate hydrate
(80 g, 97%, 0.43 mol), paraformaldehyde (39 g, 1.31 mol, 3.0 molar
equiv), formamide (69 mL, 1.76 mol, 4.0 molar equiv), and formic
acid (99%, 83 mL, 2.18 mol, 5.0 molar equiv). The mixture was heated
slowly to 90 °C and stirred for 2 h at the same temperature before
being poured into ice-salt (500 g of ice and 50 g of salt). After 2 h, the
white crystalline product was collected by suction filtration, washed
with cold water (2 × 30 mL), and dried in a desiccator over phosphorus
pentoxide under vacuum to yield N-(p-toluenesulfonylmethyl)forma-
mide (84 g, 90%), which was sufficiently pure for the next step. It had
mp 104-107 °C (lit.19 106-110 °C). 1H NMR (300 MHz) δ: 2.34 (s,
3H, CH3), 4.69 (d, J ) 6.83 Hz, 2H, CH2), 6.85 (brs, 1H, NH, 7.34 (d,
J ) 8.3 Hz, 2H, 2,6-Ar-H), 7.80 (d, J ) 8.3 Hz, 2H, 3,5-Ar-H),
8.07 (s, 1H, CHO) ppm. 13C NMR (75 MHz) δ: 21.49 (CH3), 58.79
(CH2), 128.69 (2,6-Ar), 129.89 (3,5-Ar), 133.67 (1-Ar), 145.51 (4-Ar),
160.39 (CHO) ppm.
5,5′-Diformyl-4,4′-dimethyl-3,3′-bis-(methoxycarbonylethyl)-2,2′-
dipyrrylmethane (4). Finely ground 5,5′-bis(tert-butoxycarbonyl)-4,4′-
dimethyl-3,3′-bis-(methoxycarbonylethyl)-2,2′-dipyrryl-methane (5) (0.64
g, 1.17 mmol) was added in portions (100 mg) to cooled (∼0 °C)
trifluoroacetic acid (3 mL) with stirring. Effervescence was observed.
After bubbling ceased, trimethyl orthoformate (0.6 mL, 0.58 g, 5.5
mmol, 4.7 molar equiv) was added at once. The mixture was stirred
for another 5 min at 0° before pouring into water (50 mL). The product
was precipitated as pink solid using dilute ammonia (10%) to adjust
the pH to 8. The solid was collected by suction filtration, washed with
water (5 × 50 mL), and dried before recrystallizing from dichlo-
romethane-hexane to yield 4 (0.38 g, 80%): mp 179-180 °C (lit.33
179-181 °C). IR (KBr, film) ν: 3412, 3236, 2931, 1731, 1619, 1508,
1
1443, 1378, 1303, 1249, 1167, 1061, 961, 737, 607 cm-1. H NMR
(300 MHz) δ: 2.29 (s, 6H), 2.53 (t, J ) 6.80 Hz, 4H), 2.80 (t, J )
6.80 Hz, 4H), 3.71 (s, 6H), 4.05 (s, 2H), 9.46 (s, 2H), 10.21 (s, 2H)
ppm. 13C NMR (75 MHz) δ: 8.70, 18.86, 22.38, 34.04, 51.70, 120.91,
128.85, 134.71, 173.47, 176.48 ppm.
A three-neck round-bottom flask, equipped with a mechanical stirrer,
reflux condenser, drying tube containing anhydrous calcium chloride,
thermometer, and 100 mL dropping funnel was charged with N-p-
toluenesulfonylmethylformamide (69 g, 0.32 mol), dry tetrahydrofuran
(150 mL), anhydrous ether (60 mL), and triethylamine (140 mL). The
stirred suspension was chilled to -5 °C using an ice-salt bath. Then
a solution of phosphorus oxychloride (53 g, 0.35 mol, 1.07 molar equiv)
in dry tetrahydrofuran (40 mL) was added dropwise from the dropping
funnel at a rate such that the temperature was maintained between -5
°C and 0 °C. During the reaction, the N-(p-tolyl-sulfonylmethyl)-
formamide gradually dissolved and triethylamine salts precipitated. Near
the completion of the reaction the white suspension slowly turned
brown. After being stirred for another 30 min at 0 °C, the mixture was
poured into two liters of ice-water with continuous stirring. The solid
material dissolved to give a clear, dark-brown solution before the
product began to separate as a fine, brown crystalline solid. The mixture
was stirred for 30 min at 0 °C, and the precipitate was collected by
suction filtration and washed with cold water (100 mL). After drying
in air, TosMIC was obtained (60 g, 95%) that is pure enough for
5,5′-Diformyl-4,4′-dimethyl-3,3′-bis(methoxycarbonylethyl)-
2,2′dipyrryl ketone (3). 5,5′-Diformyl-4,4′-dimethyl-3,3′-bis(methoxy-
carbonylethyl)-2,2′dipyrrylmethane (4) (1.79 g, 4.4 mmol) was dissolved
in acetic acid (40 mL) by heating on a water bath to 40 °C. After
removing the water bath, a solution of ceric (IV) ammonium nitrate
(CAN, 14.6 g, 26.7 mmol, 6 molar equiv) in acetic acid (20 mL) and
water (20 mL) (CAN was first dissolved in water, then diluted with
acetic acid) was added dropwise over 10 min at room temperature.
The color of the solution turned from dark brown to red, then light
red, yellow, and finally to an orange color. The mixture was allowed
to stir for an additional 20 min at room temperature before pouring
into ice-water (∼200 mL). After extraction with dichloromethane (3
× 100 mL), the combined extracts were washed successively with water
(2 × 50 mL), 5% aqueous sodium bicarbonate (50 mL), and brine (50
mL). The solution was dried over anhydrous sodium sulfate and
concentrated (rotovap). The residue was crystallized from 80%
methanol-water to give the desired product 3, (963 mg, 52%): mp
206-208 °C (lit.33 207-208 °C). IR (KBr, film) ν: 3213, 3001, 2931,
2860, 1731, 1637, 1543, 1461, 1372, 1290, 1237, 1172, 1073, 897,
1
synthetic purposes. It had mp 112-114 °C (lit.19 111-114 °C). H
NMR (300 MHz) δ: 2.50 (s, 3H, CH3), 4.58 (s, 2H, CH2), 7.46 (d, J
) 7.84 Hz, 2H, 2,6-Ar), 7.91 (d, J ) 7.84 Hz, 2H, 3,5-Ar) ppm. 13C
NMR (75 MHz) δ: 21.59 (CH3), 60.91 (CH2), 129.24 (2,6-Ar), 130.16
(3,5-Ar), 131.96 (1-Ar), 146.68 (4-Ar), 166.08 (NdC) ppm.
1
861, 826, 726, 609 cm-1. H NMR (300 MHz): δ 2.41 (s, 6H), 2.67
(t, J ) 7.32 Hz, 4H), 3.63 (s, 6H), 9.12 (s, 2H), 11.31 (s, 2H) ppm. 13
C
5-Bromo-4-methyl-3-ethyl-2-tosyl-pyrrole (9). 2-Tosyl-2-ethyl-4-
methylpyrrole (8) (13.35 g, 0.05 mol) was dissolved in dichloromethane
(150 mL) and chilled to -5 °C using an ice-salt bath. Then, a solution
of bromine (8.12 g, 0.05 mol, 1.0 molar equiv) in dichloromethane
(100 mL) was added dropwise over 20 min. After the addition was
complete, the reaction was allowed to stir for a further 10 min at the
same temperature. Dilute aqueous ammonia (10%, 200 mL) was added
dropwise to neutralize the acid; the organic layer was separated; and
the aqueous layer was extracted with dichloromethane (3 × 100 mL).
The combined organic phases were washed with saturated sodium
bicarbonate (2 × 100 mL), water (100 mL), and brine (100 mL). After
drying over anhydrous sodium sulfate, the solvent was evaporated, and
the crude brown product was crystallized from dichloromethane-
hexane to yield a white product (9) (16.5 g, 95% yield): 162-164 °C
(lit.37 163-164 °C). IR (KBr, film) ν: 3260, 2970, 2931, 2884, 1596,
NMR (75 MHz) δ 8.05, 18.82, 33.96, 51.23, 129.79, 130.60, 130.83,
133.77, 173.15, 178.18 ppm.
2-Tosyl-3-ethyl-4-methylpyrrole (8). This compound appears in the
literature35 with no experimental details or spectroscopic properties.
2-Nitro-3-pentanol was prepared according to a literature procedure36
and acetylated to give 2-nitro-3-acetoxy-pentane. To a mixture of
tosylmethyl isocycanide (TosMIC, 46 g, 0.24 mol, 1.0 molar equiv)
and 1,1,3,3-tetramethylguanidine (63 mL, 58 g, 0.5 mol, 2.1 molar
equiv), a solution of 2-nitro-3-acetoxypropane (42 g, 0.24 mol) in dry
THF (100 mL) and 2-propanol (100 mL) was added dropwise over 1
h. The mixture was allowed to stir at room temperature for 70 h before
removing all solvent (rotovap). The resulting dark-brown oil was taken
up in 80% aqueous methanol, and the desired product (8) (35 g, 55%
yield) was obtained after chilling at -20 °C for several hours: mp
114-116 °C. IR (KBr, film) ν: 3307, 2960, 2916, 2872, 1443, 1296,
1213, 1184, 1137, 1084, 808, 708, 661, 585 cm-1. 1H NMR (300 MHz)
δ: 0.98 (t, J ) 7.32 Hz, 3H), 1.96 (s, 3H), 2.38 (s, 3H), 2.63 (q, J )
1
1490, 1367, 1302, 1202, 1167, 1137, 1102, 808, 714, 579 cm-1. H
NMR (300 MHz) δ: 0.97 (t, J ) 7.32 Hz, 3H), 2.30 (s, 3H), 2.40 (s,
3H), 2.46 (q, J ) 7.32 Hz, 2H), 7.24 (d, J ) 7.80 Hz, 2H), 7.79 (d, J
) 7.80 Hz, 2H), 9.16 (s, 1H, NH) ppm. 13C NMR (75 MHz) δ: 9.23,
14.97, 21.40, 21.66, 106.19, 121.20, 122.30, 129.10, 131.01, 139.45,
142.64, 145.20 ppm. GC-MS m/z (%): 343 [M+ + 1] (93), 342 [M+]
(100), 278 (8), 263 (7), 204 (29), 188 (20), 140 (44), 106 (60), 65 (63)
amu.
(33) Clezy, P. S.; Fookes, C. J. R.; Liepa, A. J. Austral. J. Chem. 1972,
25, 1979-1990.
(34) Ono, N.; Kawamura, H.; Bougauchi, M.; Maruyama, K. Tetrahedron
1990, 46, 7483-7496.
(35) Kohori, K.; Kimoshita, H.; Inomata, K. Chem. Lett. 1995, 799-
800.
(36) Kambe, S.; Yasuda, H. Bull. Chem. Soc. Jpn. 1968, 41, 1444-
1446.
(37) Kinoshita, H.; Hayashi, Y.; Murata, Y.; Inomata, K. Chem. Lett.
1993, 1437-1440.