Building Block for Supramolecular Anion-Binding Motifs
(w), 1387 (m), 1137 (m), 1112 (m), 1064 (m), 1036 (m), 843 (w),
1502 (m), 1452 (m), 1416 (m), 1383 (m), 1344 (m), 1268 (m), 1202
(s), 1152 (m), 1113 (m), 953 (w), 909 (w), 810 (w), 788 (w), 759 (m),
756 (m), 740 (m) cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.37–6.34
(m, 1 H, CH), 7.16–7.17 (m, 1 H, CH), 7.38–7.40 (m, 1 H, CH), 693 (m), 615 (w), 584 (w), 536 (w) cm–1. 1H NMR (400 MHz,
9.51 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 95.1
CDCl3): δ = 5.3 (s, 2 H, CH2), 7.32–7.41 (m, 6 H, CH), 7.52–7.54
(Cq), 112.0, 121.3 (both CH), 123.1 (Cq), 127.2 (CH), 173.3 (Cq) (m, 1 H, CH), 9.80 (s, 1 H, CH), 10.20 (NH) ppm. 13C NMR
ppm. HR-MS (EI): m/z calcd. for C6H4Cl3NO·+ (M·+) 210.9361,
(100 MHz, CDCl3): δ = 66.7 (CH2), 114.7, 127.5 (both CH), 128.2,
found 210.9358.
128.5, 128.6 (all CH), 128.7, 135.4, 160.7, 185.7 (all Cq) ppm. HR-
MS (EI): m/z calcd. for C13H11NO3 (M·+) 229.0741, found
·+
Benzyl 1H-Pyrrole-2-carboxylate (5):[8] A sodium benzylate solu-
tion, prepared from Na (1.08 g, 47.0 mmol, 0.2 equiv.) in freshly
distilled benzyl alcohol (26.8 mL, 259 mmol, 1.1 equiv.), was added
to a solution of 4 (50.0 g, 235 mmol, 1 equiv.) in chloroform
(50 mL). The resulting dark mixture was stirred for one hour at
room temperature and then 1 n hydrochloric acid (50 mL,
50.0 mmol, 0.2 equiv.) was added. After stirring for ten minutes the
organic solvent was first evaporated under reduced pressure and
the remaining aqueous reaction mixture was lyophilized after the
addition of another 100 mL of water to help remove the remaining
benzyl alcohol upon lyophilization. The crude black solid product
was purified by flash chromatography on silica gel (hexane/ethyl
acetate/dichloromethane, 70:15:15) to give the slightly yellow ben-
zyl ester 5 (44.9 g, 95%). Rf = 0.55 (SiO2, hexane/ethyl acetate/
229.0739.
5-(Benzyloxycarbonyl)-1H-pyrrole-2-carboxylic Acid (7): To a solu-
tion of the aldehyde 6a (17.2 g, 75.0 mmol, 1 equiv.) in acetone
(100 mL) a solution of KMnO4 (23.7 g, 150 mmol, 2 equiv.) in ace-
tone/water (1:1, 300 mL) was added drop wise over a period of
1 h. The solution was heated to 40 °C for 1 h and stirred at room
temperature for an additional hour. Sodium dithionite (1.31 g,
7.50 mmol, 0.1 equiv.) was added, stirred for ten minutes and then
filtered through a celite pad. The celite pad was thoroughly washed
with a 1 m aqueous sodium hydroxide solution (150 mL) and the
combined filtrates were acidified with 2 m hydrochloric acid. A col-
orless precipitate formed which was filtered off, washed with cold
2 m hydrochloric acid and dried with phosphorus pentoxide to give
the carboxylic acid 7 as a colorless powder (12.3 g, 67%). Rf = 0.59
(SiO2, dichloromethane/ethyl acetate+triethylamine, 5:5+1%);
dichloromethane, 70:15:15); m.p. 55 °C. FT-IR (KBr): ν = 3310 (s),
˜
3190 (s), 2325 (m), 2320 (m), 1696 (s), 1420 (s), 1320 (s), 1190 (s),
1130 (s), 735 (m), 745 (m), 765 (m) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 5.32 (s, 2 H, CH2), 6.26–6.28 (m, 1 H, pyrrole-CH),
6.94–6.97 (m, 1 H, CH), 6.98–6.99 (m, 1 H, CH), 7.32–7.44 (m,
5 H, CH), 9.19 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 66.1 (CH2), 110.7, 115.8 (both CH), 122.8 (Cq), 123.1
(CH), 128.3, 128.4, 128.7 (all CH), 136.3 (Cq), 161.0 (Cq) ppm.
m.p. 234 °C (decomp.). FT-IR (KBr): ν = 3287 (s), 2360 (m), 2350
˜
(m), 1731 (s), 1730 (s), 1684 (m), 1557 (m), 1277 (s), 770.4 (m),
770.3 (m) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 5.29 (s, 2 H,
CH2), 6.75–6.77 (m, 1 H, CH), 6.83–6.85 (m, 1 H, CH), 7.32–7.47
(m, 5 H, CH), 12.54 (s, 1 H, NH), 12.83 (br. s, 1 H, CO2H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 65.5 (CH2), 115.1, 115.6
(all CH), 125.9, 127.9 (both Cq), 128.0, 128.0, 128.4 (all CH), 136.2,
159.6, 161.2 (all Cq) ppm. HR-MS (EI): m/z calcd. for
·+
HR-MS (EI): m/z calcd. for C12H11NO2 (M·+) 201.0790, found
201.0793.
C13H11NO4 (M·+) 245.0687, found 245.0688.
·+
Benzyl 4-/5-Formyl-1H-pyrrole-2-carboxylates 6a and 6b:[11] Phos-
phoryl chloride (11.0 mL, 0.12 mol, 2 equiv.) was added drop wise
to dimethylformamide (23.4 mL, 0.3 mol, 5 equiv.) at 5–10 °C. Stir-
ring for 30 min produced the Vilsmeier reagent. The benzyl pyrrole-
carboxylate 5 (12.1 g, 0.06 mol, 1 equiv.) was dissolved in 250 mL
of dichloromethane and cooled to –15 °C, and the Vilsmeier rea-
gent was added drop wise over 15 min. The reaction mixture was
stirred at 0 °C for 3 h and then at room temperature for 24 h. A
saturated aqueous sodium hydrogen carbonate solution (150 mL)
was added, and the mixture was refluxed for 15 min. After filtering
the resulting solution, the organic layer was separated, washed
twice with brine (50 mL) and dried with MgSO4. The solvent was
evaporated first under reduced pressure and afterwards in high
vacuo to remove the DMF. Purification of the brown oil by flash
chromatography on silica gel (cyclohexane/ethyl acetate/dichloro-
methane, 70:15:15) gave the white to yellow 2,5-substituted product
6a (8.45 g, 62%) and the red 2,4-substituted side product 6b (4.50 g,
33%).
N-Boc-Guanidine (8):[12] A cooled solution of Boc2O (12.0 g,
55.0 mmol, 1 equiv.) in dioxane (100 mL) was added drop wise
within 8 h at 0 °C (ice bath) under vigorous stirring to a mixture
of guanidinium chloride (26.3 g, 275 mmol, 5 equiv.) in an aqueous
sodium hydroxide solution (12.1 g, 303 mol, 5.5 equiv. NaOH in
50 mL of water). The resulting suspension was stirred at room tem-
perature for additional 20 h and then extracted with ethyl acetate
(3 times with 100 mL). The combined organic phases were dried
(MgSO4) and evaporated under reduced pressure. The resulting
white crystals were dried in vacuo to yield 8 (8.51 g, 97%). Rf =
0.25 (SiO2, dichloromethane/methanol+triethylamine, 5:1+1%);
m.p. 165 °C (decomp.). FT-IR (KBr): ν = 3408 (s), 1650 (s), 1540
˜
(s), 1450 (m), 1311 (s), 1253 (m), 1142 (s), 1066 (s), 950 (w), 806
(m) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 1.34 (s, 9 H, CH3),
6.82 (br. s, 4 H, NH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
28.4 (CH3), 75.8, 162.8, 163.4 (all Cq) ppm. HR-MS (EI): m/z
calcd. for C6H13N3O2 (M·+) 159.101, found 159.101.
·+
Benzyl 5-Formyl-1H-pyrrole-2-carboxylate (6a): Rf = 0.55 (SiO2, cy-
clohexane/ethyl acetate/dichloromethane, 70:15:15); m.p. 105 °C.
Benzyl 5-(N-Boc-Guanidinocarbonyl)-1H-pyrrole-2-carboxylate (9):
A mixture of the mono ester 7 (2.45 g, 10.0 mmol, 1 equiv.), PyBOP
(5.72 g, 11.0 mmol, 1.1 equiv.) and N-methylmorpholine (2.45 mL,
22.0 mmol, 2.2 equiv.) was stirred in DMF (50 mL) at room tem-
perature for 30 min. Boc-Guanidine 8 (3.19 g, 20.0 mmol, 2 equiv.)
was added and the resulting solution stirred overnight. The yellow
solution was slowly poured into vigorously stirred water (150 mL)
causing the formation of a white solid precipitate which was dis-
solved in diethyl ether (150 mL). After phase separation the water/
DMF phase was extracted twice with diethyl ether (150 mL) the
solvent was evaporated and the crude product was further purified
by flash chromatography yielding a colorless powder 9 (3.59 g,
FT-IR (KBr): ν = 3280 (s), 2320 (m), 2350 (m), 1690 (s), 1700 (s),
˜
1550 (s), 1390 (s), 1340 (s), 1220 (s), 780 (m), 770 (m), 700 (m)
1
cm–1. H NMR (400 MHz, CDCl3): δ = 5.35 (s, 2 H, CH2), 6.93–
6.98 (m, 2 H, CH), 7.36–7.44 (m, 5 H, CH), 9.66 (s, 1 H, CH), 9.84
(br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 67.2
(CH2), 116.1, 119.9 (both CH), 128.3 (CH), 128.6, 128.7, 128.8 (all
CH), 134.7 (Cq), 135.4 (Cq), 160.3 (Cq), 180.5 (Cq) ppm. HR-MS
·+
(EI): m/z calcd. for C13H11NO3 (M·+) 229.0741, found 229.0739.
Benzyl 4-Formyl-1H-pyrrole-2-carboxylate (6b): Rf = 0.13 (SiO2, cy-
clohexane/ethyl acetate/dichloromethane, 70:15:15); m.p. 99 °C.
FT-IR (KBr): ν = 3138 (m), 2990 (m), 1707 (s), 1636 (s), 1567 (m),
93%). Rf
=
0.51 (SiO2, hexane/ethyl acetate+triethylamine,
˜
Eur. J. Org. Chem. 2008, 324–329
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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