HETEROCYCLES

Paper | Special issue | Vol. 77, No. 2, 2009, pp. 1105-1122
Received, 31st July, 2008, Accepted, 3rd October, 2008, Published online, 6th October, 2008.
DOI: 10.3987/COM-08-S(F)89

■ A General Method for the Synthesis of N-Unsubstituted 3,4-Diarylpyrrole-2,5-dicarboxylates

Tsutomu Fukuda, Yukie Hayashida, and Masatomo Iwao*

Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A general method for the synthesis of N-unsubstituted 3,4-diarylpyrrole-2,5-dicarboxylates (3) has been developed. The key reactions involved are the Hinsberg-type synthesis of dimethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (6) followed by palladium-catalyzed Suzuki-Miyaura coupling of its bis-triflate derivative (7). The N-benzyl protecting group of the resulting 3,4-diarylpyrrole-2,5-dicarboxylates (8) is cleanly removed under hydrogenolytic or solvolytic conditions.

INTRODUCTION
Pyrrole moieties possessing two aryl groups at the 3- and 4-positions appear frequently in marine natural products, such as lamellarins,1 lukianols,2 ningalins,3 storniamides,4 polycitones,5 purpurone,6 halitulin,7 and dictyodendrins.8 These natural products have attracted considerable attention due to their unique structures and highly useful biological activities. As the result, a number of synthetic approaches have been developed so far.1b,9 These syntheses can be divided into two classes depending on the construction method of 3,4-diarylpyrrole scaffold. The first employed de novo ring construction of the pyrrole ring via titanium-mediated reaction,10 biomimetic synthesis,11 N-ylide-mediated cyclization,12 intra- or intermolecular [3+2] cycloaddition,13,14 Diels-Alder cyclization of azadiene,15 vinylogous iminium ion-mediated ring formation,16,17 and aminoquinone-mediated cyclization.18 The second utilized regioselective arylation of preexisting pyrrole core by palladium-catalyzed cross-coupling and related reactions.19
In 2003, we reported a short and flexible route to 3,4-diarylpyrrole marine alkaloids.20 The key reactions involved are the synthesis of N-substituted dimethyl 3,4-dihydroxypyrrole-2,5-dicarboxylates via Hinsberg-type reaction followed by palladium-catalyzed Suzuki-Miyaura coupling of their bis-triflate
derivatives. This strategy has been successfully applied to the total synthesis of biologically significant lamellarins D, L, N and α 20-sulfate.21 In this paper, we report further application of this strategy for the synthesis of N-unsubstituted dimethyl 3,4-diarylpyrrole-2,5-dicarboxylates.

RESULTS AND DISCUSSION
Initially, we examined Suzuki-Miyaura coupling of dimethyl 3,4-bis(trifluoromethanesulfonyloxy)- pyrrole-2,5-dicarboxylate (1) with 4-methoxyphenylboronic acid (2a). Under the previously established conditions,20 bis-triflate (1) was treated with 2a (3.0 equiv.) and aqueous Na2CO3 in the presence of a catalytic amount of Pd(PPh3)4 in refluxing THF for 20 h, however, only trace amount (3%) of the desired 3,4-bis(4-methoxyphenyl)pyrrole (3a) was obtained and unreacted 1 was recovered in 68% yield (Scheme 1).

This result suggested N-protection of bis-triflate (1) may be indispensable for the smooth cross-coupling.22 Thus, we decided to test the cross-coupling of N-benzyl protected bis-triflate (7). The synthesis of 7 is shown in Scheme 2. Benzylamine (4) was alkylated with methyl bromoacetate to give N-benzyliminodiacetate (5) in 90% yield. Hinsberg reaction of 5 with dimethyl oxalate using NaH as a base afforded 3,4-dihydroxypyrrole (6) in 88% yield. The conventional conditions using NaOMe in MeOH afforded 6 in much lower yield (58%).23 Triflation of 6 with trifluoromethanesulfonic anhydride in pyridine gave the bis-triflate (7) in 96% yield.

The results of the cross-coupling of 7 with a variety of arylboronic acids (2a-i) are summarized in Table 1. In contrast to the reaction of 1, 7 reacted with 2a-i quite smoothly to give 3,4-diarylated products 8a-i in excellent yields. The reactions were not affected by electronic or steric effects of the substituents on the aryl ring of the boronic acids.

Having established the cross-coupling reactions of 7, we next carried out debenzylation of 8 to produce N-unsubstituted 3,4-diarylpyrroles (3). The results are summarized in Table 2. 3,4-Diarylpyrroles (8a-i) were treated with Pearlman’s catalyst24 and ammonium formate in refluxing EtOH to give the debenzylated compounds (3) in excellent yields, except for compound (8e). In this case, hydrogenolysis of C-Cl bonds on the aryl groups also proceeded and 3,4-diphenylpyrrole (3b) was isolated (entry 5). Fortunately, however, deprotection of 8e was cleanly effected under solvolytic conditions25 (Scheme 3).
Since an efficient synthesis of 3,4-symmetrically arylated pyrroles (3a-i) was established, we next examined the stepwise cross-coupling with different arylboronic acids to produce 3,4-unsymmetrically arylated pyrrole (11) (Scheme 4). Thus, the bis-triflate (7) was treated with 1.0 equiv. of 3,4-dimethoxyphenylboronic acid (2g) to give the mono-arylated pyrrole (9) in 75% yield accompanied by 8% of 8g. The second cross-coupling of 9 with 4-methoxyphenylboronic acid (2a) gave the 3,4-differentially arylated pyrrole (10) in excellent yield. Hydrogenolysis of 10 gave the deprotected 11 in 69% yield.

Finally, we briefly describe the utility of our procedure for the synthesis of natural products. Recently,

we reported the short-step synthesis of lamellarins O, P, Q, and R using 13 as a common intermediate.26 This key intermediate was prepared in two steps from 3c by partial hydrolysis and decarboxylation (Scheme 5).

It is also noteworthy, that the 3,4-diarylpyrroles (3h) and (3i) were utilized as the key intermediates in the synthesis of permethyl storniamide A and ningalin A, respectively, by Boger et al.15a (Scheme 6).
In conclusion, we have developed an efficient procedure to produce N-unsubstituted

3,4-diarylpyrrole-2,5-dicarboxylates. This method can be utilized for the synthesis of 3,4-diarylpyrrole marine natural products and their analogues.

EXPERIMENTAL
Melting points were determined with a Yanagimoto micro melting points apparatus and are uncorrected. IR spectra were obtained with a Perkin-Elmer System 2000 instrument. NMR spectra were recorded on a JEOL JNM-AL400 instrument (400 MHz for 1H and 100 MHz for 13C) using tetramethylsilane as an internal standard. High resolution mass spectra were recorded on a JEOL JMS-700N spectrometer. Flash chromatography was conducted on Silica Gel 60N, 40-50 m (Kanto Chemical Co., Inc.). Column chromatography was conducted on Silica Gel 60N, 63-210 m (Kanto Chemical Co., Inc.) or Chromatorex NH-DM1020 silica gel (Fuji Silysia Chemical Ltd.). Dry THF were distilled from Na-benzophenone ketyl under argon immediately before use.

Dimethyl 3,4-bis(trifluoromethanesulfonyloxy)pyrrole-2,5-dicarboxylate (1)
Under an argon atmosphere, a suspension of dimethyl oxalate (2.36 g, 20.0 mmol) and NaH (60% dispersion in mineral oil, 1.63 g, ca. 40.8 mmol, prewashed with hexane) in THF (10 mL) was heated to reflux. To this suspension was added dropwise a solution of dimethyl iminodiacetate (1.61 g, 10.0 mmol) in THF (30 mL) under reflux. After being refluxed for additional 3 h, the reaction mixture was cooled to rt, quenched with acetic acid (3 mL) and evaporated under reduced pressure. The residue was poured into ice-cold water and the suspension was acidified with 2 M aqueous HCl to pH 3. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give dimethyl 3,4-dihydroxypyrrole-2,5-dicarboxylate as pale yellow powder (1.50 g, 70%). Recrystallization from MeOH gave pale yellow powder. Mp 180-210 °C (decomp) (sealed capillary); IR (KBr): 3399, 3302, 1701, 1565, 1500, 1438, 1311, 1194, 1157 cm–1; 1H NMR (400 MHz, acetone-d6): δ 3.84 (s, 6H), 7.53 (s, 2H), 9.89 (s, 1H); 13C NMR (100 MHz, acetone-d6): δ 51.7, 109.9, 138.5, 162.4. Anal. Calcd for C8H9NO6: C, 44.66; H, 4.22; N, 6.51. Found: C, 44.90; H, 4.33; N, 6.30.
Under an argon atmosphere, trifluoromethanesulfonic anhydride (3.70 mL, 22.6 mmol) was added as a neat liquid to a solution of dimethyl 3,4-dihydroxypyrrole-2,5-dicarboxylate (2.19 g, 10.2 mmol) in pyridine (20 mL) at 0 °C. After being stirred for 3 h, the reaction mixture was quenched with water at the same temperature and allowed to warm to rt. The product was extracted with Et2O and the extract was washed successively with 3 M aqueous HCl, water, and brine, and dried over Na2SO4. The solvent was removed by evaporation and the residue was purified by column chromatography over Silica Gel 60N (hexane-EtOAc=2:1) to give 1 as colorless solid (4.27 g, 87%). Recrystallization from Et2O-hexane gave colorless needles. Mp 122-122.5 °C; IR (KBr): 3307, 3273, 1738, 1714, 1439, 1297, 1228, 1135 cm-1; 1H NMR (400 MHz, CDCl3): δ 4.00 (s, 6H), 10.42 (br s, 1H); 13C NMR (100 MHz, CDCl3): 52.9, 115.9, 118.4 (q, J= 320 Hz), 127.4, 158.0. Anal. Calcd for C10H7F6NO10S2: C, 25.06; H, 1.47; N, 2.92. Found: C, 24.99; H, 1.22; N, 2.87.

Suzuki-Miyaura coupling of bis-triflate (1) with arylboronic acids (2a).
Under an argon atmosphere, a degassed solution of Na2CO3 (700 mg, 6.60 mmol) in water (2.0 mL) was added to a solution of 1 (479 mg, 1.00 mmol), 2a (456 mg, 3.00 mmol) and Pd(PPh3)4 (46.2 mg, 40.0 µmol) in THF (20 mL) at rt and the mixture was refluxed for 20 h. The mixture was cooled to rt and evaporated under reduced pressure. The residue was diluted with water, adjusted to pH 3 with 1 M aqueous HCl, and saturated with NaCl. The products were extracted with CH2Cl2 and the extract was washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified successively by flash chromatography over Silica Gel 60N (toluene-EtOAc=5:1~EtOAc) and column chromatography over Chromatorex NH-DM1020 silica gel (hexane-EtOAc=3:1) to give 3a as colorless solid (12.0 mg, 3%) and unreacted 1 (326 mg, 68%).

Dimethyl N-benzyliminodiacetate (5)
Methyl bromoacetate (90 mL, 0.951 mol) was added as a neat liquid to a suspension of benzylamine (4) (49 mL, 0.449 mol) and NaHCO3 (159 g, 1.89 mol) in MeCN (700 mL) at rt. The mixture was refluxed for 2 h and then cooled to rt. After removal of inorganic salts by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by distillation (112 °C/ 0.2 mmHg) to give 5 as pale yellow oil (101 g, 90%). IR (neat): 1746, 1454, 1436, 1202, 1010 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.56 (s, 4H), 3.70 (s, 6H), 3.91 (s, 2H), 7.23-7.29 (m, 1H), 7.29-7.35 (m, 2H), 7.35-7.40 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 51.5, 54.0, 58.0, 127.4, 128.4, 129.0, 138.1, 171.6. HREIMS m/z. Calcd for C13H17NO4 (M+): 251.1158. Found: 251.1155.

Dimethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (6)
Under an argon atmosphere, a suspension of dimethyl oxalate (14.9 g, 126 mmol) and NaH (60% dispersion in mineral oil, 10.0 g, ca. 250 mmol, prewashed with hexane) in THF (80 mL) was heated to reflux. To this suspension was added dropwise a solution of 5 (15.7 g, 62.5 mmol) in THF (150 mL) under reflux. After being refluxed for additional 3 h, the reaction mixture was cooled to rt, quenched with acetic acid (16 mL) and evaporated under reduced pressure. The residue was poured into ice-cold water and the suspension was acidified with 2 M aqueous HCl to pH 3. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give 6 as pale brown powder (16.8 g, 88%). Recrystallization from MeOH gave pale brown powder. Mp 166.5-167 °C; IR (KBr): 3365, 1692, 1658, 1509, 1461, 1296, 1195, 1160 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.85 (s, 6H), 5.75 (s, 2H), 6.90-6.94 (m, 2H), 7.16-7.20 (m, 3H), 7.65 (br s, 2H); 13C NMR (100 MHz, CDCl3): δ 49.3, 51.8, 111.0, 125.6, 126.9, 128.4, 138.9, 139.4, 162.5. Anal. Calcd for C15H15NO6: C, 59.01; H, 4.95; N, 4.59. Found: C, 59.07; H, 4.85; N, 4.55.

Dimethyl N-benzyl-3,4-bis(trifluoromethanesulfonyloxy)pyrrole-2,5-dicarboxylate (7)
Under an argon atmosphere, trifluoromethanesulfonic anhydride (18.2 mL, 108 mmol) was added as a neat liquid to a solution of 6 (15.0 g, 49.1 mmol) in pyridine (75 mL) at 0 °C. After being stirred for 1 h, the reaction mixture was quenched with water at the same temperature and allowed to warm to rt. The product was extracted with Et2O and the extract was washed successively with 3 M aqueous HCl, water, and brine, and dried over Na2SO4. The solvent was removed by evaporation and the residue was purified by column chromatography over Silica Gel 60N (hexane-EtOAc=5:1) to give 7 as colorless solid (26.9 g, 96%). Recrystallization from Et2O-hexane gave colorless granules. Mp 70.5-71 °C; IR (KBr): 1745, 1438, 1289, 1248, 1211, 1134 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.88 (s, 6H), 6.19 (s, 2H), 6.95-7.02 (m, 2H), 7.21-7.34 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 49.8, 52.4, 117.6, 118.4 (q, J= 320 Hz), 126.0, 127.6, 128.3, 128.7, 136.2, 158.0. Anal. Calcd for C17H13F6NO10S2: C, 35.86; H, 2.30; N, 2.46. Found: C, 35.64; H, 2.12; N, 2.42.

Suzuki-Miyaura coupling of bis-triflate (7) with arylboronic acids (2). General procedure
Under an argon atmosphere, a degassed solution of Na2CO3 (2.10 g, 19.8 mmol) in water (6.0 mL) was added to a solution of 7 (3.02 mmol), 2 (9.02 mmol) and Pd(PPh3)4 (140 mg, 0.121 mmol) in THF (60 mL) at rt and the mixture was refluxed for 20 h. The mixture was cooled to rt and evaporated under reduced pressure. The product was extracted with CH2Cl2 and the extract was washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to give 8.

Dimethyl N-benzyl-3,4-bis(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (8a)
According to the general procedure, 7 (1.72 g, 3.02 mmol) and 2a (1.37 g, 9.02 mmol) were reacted. After chromatographic purification over Silica Gel 60N (toluene~toluene-EtOAc=10:1), 8a was obtained as colorless solid (1.45 g, 99%). Recrystallization from CH2Cl2-hexane gave colorless granules. Mp 142-143 °C; IR (KBr): 1717, 1694, 1534, 1431, 1293, 1246, 1203, 1032 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.52 (s, 6H), 3.75 (s, 6H), 6.01 (s, 2H), 6.69-6.73 (m, 4H), 6.93-6.96 (m, 4H), 7.07-7.11 (m, 2H), 7.18-7.24 (m, 1H), 7.26-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.7, 51.4, 55.1, 112.7, 124.4, 126.2, 126.4, 126.9, 128.4, 130.9, 131.4, 138.6, 158.1, 162.0. Anal. Calcd for C29H27NO6: C, 71.74; H, 5.61; N, 2.88. Found: C, 71.52; H, 5.62; N, 2.84.

Dimethyl N-benzyl-3,4-diphenylpyrrole-2,5-dicarboxylate (8b)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2b (1.10 g, 9.00 mmol) were reacted. After chromatographic purification over Silica Gel 60N (toluene), 8b was obtained as colorless solid (1.25 g, 98%). Recrystallization from Et2O-pentane gave colorless needles. Mp 138-139 °C; IR (KBr): 1716, 1435, 1296, 1228, 1201, 1173 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.49 (s, 6H), 6.05 (s, 2H), 7.01-7.06 (m, 4H), 7.09-7.25 (m, 9H), 7.27-7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.6, 51.4, 124.4, 126.2, 126.4, 126.9, 127.1, 128.3, 130.2, 131.1, 134.0, 138.4, 161.8. Anal. Calcd for C27H23NO4: C, 76.22; H, 5.45; N, 3.29. Found: C, 76.05; H, 5.38; N, 3.22.

Dimethyl N-benzyl-3,4-bis(4-isopropoxyphenyl)pyrrole-2,5-dicarboxylate (8c)
According to the general procedure, 7 (5.29 g, 9.29 mmol) and 2c (5.02 g, 27.9 mmol) were reacted. After chromatographic purification over Silica Gel 60N (toluene~toluene-EtOAc=10:1), 8c was obtained as colorless solid (5.02 g, quant.). Recrystallization from Et2O-pentane gave colorless. Mp 140-141 °C; IR (KBr): 1713, 1531, 1435, 1298, 1244, 1201, 1182 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J= 6.1 Hz, 12H), 3.52 (s, 6H), 4.43-4.53 (m, 2H), 6.00 (s, 2H), 6.68-6.72 (m, 4H), 6.90-6.94 (m, 4H), 7.07-7.10 (m, 2H), 7.18-7.23 (m, 1H), 7.26-7.31 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 22.0, 49.6, 51.3, 69.7, 114.7, 124.3, 126.2, 126.2, 126.9, 128.3, 130.8, 131.4, 138.6, 156.3, 162.0. Anal. Calcd for C33H35NO6: C, 73.18; H, 6.51; N, 2.59. Found: C, 73.31; H, 6.63; N, 2.47.

Dimethyl N-benzyl-3,4-bis(4-fluorophenyl)pyrrole-2,5-dicarboxylate (8d)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2d (1.26 g, 9.01 mmol) were reacted. After chromatographic purification over Silica Gel 60N (toluene), 8d was obtained as colorless solid (1.37 g, 99%). Recrystallization from CH2Cl2-hexane gave colorless granules. Mp 126.5-127.5 °C; IR (KBr): 1714, 1534, 1436, 1299, 1225, 1201, 1176 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.52 (s, 6H), 6.05 (s, 2H), 6.84-6.91 (m, 4H), 6.95-7.01 (m, 4H), 7.08-7.11 (m, 2H), 7.20-7.26 (m, 1H), 7.27-7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.8, 51.5, 114.3 (d, J= 21 Hz), 124.5, 126.3, 127.1, 128.5, 129.9 (d, J= 3.3 Hz), 130.3, 131.9 (d, J= 8.3 Hz), 138.4, 161.6 (d, J= 245 Hz), 161.6. Anal. Calcd for C27H21F2NO4: C, 70.28; H, 4.59; N, 3.04. Found: C, 70.56; H, 4.61; N, 2.98.

Dimethyl N-benzyl-3,4-bis(4-chlorophenyl)pyrrole-2,5-dicarboxylate (8e)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2e (1.41 g, 9.02 mmol) were reacted. After chromatographic purification over Silica Gel 60N (toluene), 8e was obtained as colorless solid (1.45 g, 98%). Recrystallization from CH2Cl2-hexane gave colorless prisms. Mp 128-129 °C; IR (KBr): 1707, 1455, 1434, 1292, 1196, 1171, 1102, 1020 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.52 (s, 6H), 6.05 (s, 2H), 6.93-6.96 (m, 4H), 7.07-7.11 (m, 2H), 7.14-7.18 (m, 4H), 7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.8, 51.6, 124.5, 126.3, 127.1, 127.6, 128.5, 129.9, 131.6, 132.4, 132.7, 138.2, 161.5. Anal. Calcd for C27H21Cl2NO4: C, 65.60; H, 4.28; N, 2.83. Found: C, 65.54; H, 4.27; N, 2.72.

Dimethyl N-benzyl-3,4-bis(2-methoxyphenyl)pyrrole-2,5-dicarboxylate (8f)
According to the general procedure, 7 (564 mg, 0.990 mmol) and 2f (453 mg, 2.98 mmol) were reacted. After successive purification by column chromatography over Silica Gel 60N (toluene-EtOAc=20:1~10:1) and column chromatography over Silica Gel 60N (hexane-CH2Cl2=1:5), 8f was obtained as colorless solid (466 mg, 97%). Recrystallization from CH2Cl2-Et2O gave colorless granules. Mp 168.5-169.5 °C; IR (KBr): 1721, 1698, 1438, 1291, 1248, 1201, 1176, 1029 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.47 (s, 6H), 3.57 (s, 6H), 6.10 (s, 2H), 6.69-6.77 (m, 4H), 6.86-6.90 (m, 2H), 7.09-7.15 (m, 4H), 7.16-7.22 (m, 1H), 7.25-7.31 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.6, 51.2, 55.3, 110.0, 119.6, 124.0, 125.1, 126.2, 126.7, 127.2, 127.9, 128.3, 131.3, 138.9, 156.8, 161.9. Anal. Calcd for C29H27NO6: C, 71.74; H, 5.61; N, 2.88. Found: C, 71.62; H, 5.71; N, 2.72.

Dimethyl N-benzyl-3,4-bis(3,4-dimethoxyphenyl)pyrrole-2,5-dicarboxylate (8g)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2g (1.64 g, 9.01 mmol) were reacted. After chromatographic purification over Silica Gel 60N (toluene-EtOAc=5:1), 8g was obtained as colorless solid (1.62 g, 99%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp 154.5-155.5 °C; IR (KBr): 1718, 1532, 1439, 1318, 1235, 1206, 1178, 1028 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.56 (s, 6H), 3.65 (s, 6H), 3.84 (s, 6H), 6.00 (s, 2H), 6.55 (d, J= 1.7 Hz, 2H), 6.61 (dd, J= 1.7 and 8.1 Hz, 2H), 6.71 (d, J= 8.1 Hz, 2H), 7.11-7.14 (m, 2H), 7.20-7.26 (m, 1H), 7.28-7.34 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.6, 51.5, 55.7, 110.1, 113.8, 122.7, 124.3, 126.3, 126.6, 127.0, 128.4, 130.6, 138.4, 147.5, 147.7, 162.0. Anal. Calcd for C31H31NO8: C, 68.25; H, 5.73; N, 2.57. Found: C, 68.09; H, 5.86; N, 2.51.

Dimethyl N-benzyl-3,4-bis(3,4,5-trimethoxyphenyl)pyrrole-2,5-dicarboxylate (8h)
According to the general procedure, 7 (410 mg, 0.720 mmol) and 2h (455 mg, 2.15 mmol) were reacted. After successive purification by column chromatography over Silica Gel 60N (toluene-EtOAc=10:1~5:1) and column chromatography over Chromatorex NH-DM1020 silica gel (toluene-EtOAc=10:1), 8h was obtained as colorless solid (418 mg, 96%). Recrystallization from CH2Cl2-Et2O gave colorless granules. Mp 159.5-160.5 °C; IR (KBr): 1717, 1582, 1434, 1341, 1279, 1239, 1196, 1128, 1099, 1001 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.59 (s, 6H), 3.64 (s, 12H), 3.81 (s, 6H), 5.99 (s, 2H), 6.28 (s, 4H), 7.13-7.18 (m, 2H), 7.22-7.24 (m, 1H), 7.27-7.35 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.7, 51.7, 56.1, 60.9, 107.9, 124.2, 126.4, 127.1, 128.4, 129.4, 130.4, 136.8, 138.2, 152.2, 161.9. Anal. Calcd for C33H35NO10: C, 65.44; H, 5.82; N, 2.31. Found: C, 65.73; H, 5.87; N, 2.19.

Dimethyl N-benzyl-3,4-bis(4,5-dimethoxy-2-methoxymethoxyphenyl)pyrrole-2,5-dicarboxylate (8i)
According to the general procedure, 7 (2.29 g, 4.02 mmol) and 2i (2.90 g, 12.0 mmol) were reacted. After successive purification by column chromatography over Silica Gel 60N (hexane-EtOAc=1:1) and column chromatography over Chromatorex NH-DM1020 silica gel (hexane-EtOAc=2:1), 8i was obtained as colorless solid (2.65 g, 99%). Recrystallization from CH2Cl2-Et2O gave colorless granules. Mp 139.5-140.5 °C; IR (KBr): 1722, 1703, 1533, 1439, 1288, 1214, 1078, 1031, 1005 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.28 (s, 6H), 3.55 (s, 6H), 3.56 (s, 6H), 3.83 (s, 6H), 4.83 (br s, 4H), 6.06 (s, 2H), 6.47 (br s, 2H), 6.68 (s, 2H), 7.12-7.16 (m, 2H), 7.19-7.24 (m, 1H), 7.26-7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.5, 51.5, 55.8, 55.9, 56.0, 96.6, 101.7, 114.4, 117.1, 125.3, 126.5, 126.8, 127.0, 128.4, 138.9, 143.7, 148.5, 149.2, 162.2. Anal. Calcd for C35H39NO12: C, 63.15; H, 5.91; N, 2.10. Found: C, 63.12; H, 5.97; N, 1.99.

Synthesis of dimethyl 3,4-diarylpyrrole-2,5-dicarboxylates (3). General procedure
Under an argon atmosphere, ammonium formate (1.53 g, 24.3 mmol) was added portionwise to a mixture of 8 (0.801 mmol), Pearlman’s catalyst (129 mg), and EtOH (16 mL) at rt. After being refluxed for an appropriate reaction time shown in Table 2, the mixture was cooled to rt and passed through a pad of Celite. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography to give 3.

Dimethyl 3,4-bis(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (3a)
According to the general procedure, 8a (389 mg, 0.801 mmol) and Pearlman’s catalyst (129 mg) were reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3a was obtained as colorless solid (308 mg, 97%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp 195.5-196 °C; IR (KBr): 3351, 1710, 1537, 1469, 1438, 1311, 1249, 1181 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.77 (s, 12H), 6.73-6.77 (m, 4H), 7.01-7.05 (m, 4H), 9.80 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.7, 55.0, 112.8, 121.0, 125.0, 131.1, 131.8, 158.3, 160.6. Anal. Calcd for C22H21NO6: C, 66.83; H, 5.35; N, 3.54. Found: C, 66.75; H, 5.44; N, 3.45.

Dimethyl 3,4-diphenylpyrrole-2,5-dicarboxylate (3b)
According to the general procedure, 8b (3.68 g, 8.64 mmol) and Pearlman’s catalyst (368 mg) were reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3b was obtained as colorless solid (2.89 g, quant.). Recrystallization from CH2Cl2-Et2O gave colorless cube. Mp 195-196 °C; IR (KBr): 3310, 1710, 1462, 1429, 1297, 1242, 1157 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 6H), 7.08-7.13 (m, 4H), 7.17-7.21 (m, 6H), 9.89 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.7, 121.1, 126.8, 127.2, 130.6, 131.4, 132.7, 160.5. Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.62; H, 5.19; N, 4.12.

Dimethyl 3,4-bis(4-isopropoxyphenyl)pyrrole-2,5-dicarboxylate (3c)
According to the general procedure, 8c (7.02 g, 13.0 mmol) and Pearlman’s catalyst (751 mg) were reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3c was obtained as colorless solid (5.56 g, 95%). Recrystallization from CH2Cl2-pentane gave colorless granules. Mp 148-149 °C; IR (KBr): 3290, 1703, 1534, 1464, 1297, 1246, 1185, 1120, 1106, 955 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.31 (d, J= 6.1 Hz, 12H), 3.77 (s, 6H), 4.44-4.55 (m, 2H), 6.70-6.74 (m, 4H), 6.98-7.02 (m, 4H), 9.80 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 22.1, 51.7, 69.6, 114.6, 120.9, 124.7, 131.2, 131.8, 156.7, 160.6. Anal. Calcd for C26H29NO6: C, 69.16; H, 6.47; N, 3.10. Found: C, 69.16; H, 6.36; N, 3.01.

Dimethyl 3,4-bis(4-fluorophenyl)pyrrole-2,5-dicarboxylate (3d)
According to the general procedure, 8d (462 mg, 1.00 mmol) and Pearlman’s catalyst (49 mg) were reacted. After chromatographic purification over Silica Gel 60N (hexane-CH2Cl2=1:5), 3d was obtained as colorless solid (329 mg, 89%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp 174-175 °C; IR (KBr): 3319, 1725, 1691, 1475, 1463, 1294, 1255, 1223, 1160 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.77 (s, 6H), 6.84-6.94 (m, 4H), 7.03-7.09 (m, 4H), 9.90 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.8, 114.4 (d, J= 22 Hz), 121.2, 128.4 (d, J= 3.3 Hz), 130.3, 132.2 (d, J= 8.3 Hz), 160.4, 161.8 (d, J= 246 Hz). Anal. Calcd for C20H15F2NO4: C, 64.69; H, 4.07; N, 3.77. Found: C, 64.58; H, 3.95; N, 3.68.

Dimethyl 3,4-bis(2-methoxyphenyl)pyrrole-2,5-dicarboxylate (3f)
According to the general procedure, 8f (195 mg, 0.402 mmol) and Pearlman’s catalyst (100 mg) were reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2~CH2Cl2-EtOAc=10:1), 3f was obtained as colorless solid (140 mg, 88%). Recrystallization from CH2Cl2-pentane gave colorless granules. Mp 203-205 °C; IR (KBr): 3290, 1713, 1694, 1470, 1434, 1300, 1270, 1248, 1157 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.53 (br s, 6H), 3.72 (s, 6H), 6.76 (dd, J= 1.0 and 7.5 Hz, 2H), 6.78 (dt, J= 1.0 and 7.5 Hz, 2H), 6.98 (dd, J= 1.8 and 7.5 Hz, 2H), 7.16 (dt, J= 1.8 and 7.5 Hz, 2H), 9.86 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.5, 55.1, 110.2, 119.5, 122.0, 122.7, 127.8, 128.4, 131.6, 157.0, 160.6. Anal. Calcd for C22H21NO6: C, 66.83; H, 5.35; N, 3.54. Found: C, 66.76; H, 5.41; N, 3.37.

Dimethyl 3,4-bis(3,4-dimethoxyphenyl)pyrrole-2,5-dicarboxylate (3g)
According to the general procedure, 8g (546 mg, 1.00 mmol) and Pearlman’s catalyst (55 mg) were reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3g was obtained as colorless solid (432 mg, 95%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp 168.5-169.5 °C; IR (KBr): 3313, 1719, 1683, 1531, 1469, 1438, 1319, 1279, 1245, 1138, 1024 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.64 (s, 6H), 3.79 (s, 6H), 3.85 (s, 6H), 6.61-6.63 (m, 2H), 6.71-6.77 (m, 4H), 9.83 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.8, 55.7, 55.7, 110.2, 114.2, 120.9, 123.2, 125.2, 131.1, 147.7, 147.9, 160.6. Anal. Calcd for C24H25NO8: C, 63.29; H, 5.53; N, 3.08. Found: C, 63.33; H, 5.47; N, 2.98.

Dimethyl 3,4-bis(3,4,5-trimethoxyphenyl)pyrrole-2,5-dicarboxylate (3h)
According to the general procedure, 8h (612 mg, 1.01 mmol) and Pearlman’s catalyst (67 mg) were reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3h was obtained as colorless solid (502 mg, 96%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp 166-167 °C; IR (KBr): 3273, 1730, 1702, 1586, 1480, 1460, 1412, 1344, 1239, 1124 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.65 (s, 12H), 3.83 (s, 12H), 6.38 (s, 4H), 9.90 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.9, 56.0, 60.8, 108.4, 120.9, 128.0, 131.0, 137.1, 152.2, 160.4. Anal. Calcd for C26H29NO10: C, 60.58; H, 5.67; N, 2.72. Found: C, 60.57; H, 5.68; N, 2.60.

Dimethyl 3,4-bis(4,5-dimethoxy-2-methoxymethoxyphenyl)pyrrole-2,5-dicarboxylate (3i)
According to the general procedure, 8i (1.22 g, 1.83 mmol) and Pearlman’s catalyst (128 mg) were reacted. After chromatographic purification over Silica Gel 60N (hexane-EtOAc=1:2), 3i was obtained as colorless solid (993 mg, 94%). Recrystallization from CH2Cl2-Et2O gave colorless granules. Mp 150.5-151.5 °C; IR (KBr): 3277, 1713, 1494, 1233, 1152, 1099, 1011 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.31 (br s, 6H), 3.58 (br s, 6H), 3.77 (s, 6H), 3.84 (s, 6H), 4.61 (br s, 1H), 4.85 (br s, 2H), 5.02 (br s, 1H), 6.50 (br s, 2H), 6.77 (br s, 2H), 9.84 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.7, 55.7, 55.9, 56.1, 96.8, 101.4, 114.5, 122.2, 127.6, 143.6, 149.0, 150.0, 160.8. Anal. Calcd for C28H33NO12: C, 58.43; H, 5.78; N, 2.43. Found: C, 58.48; H, 5.82; N, 2.26.

Dimethyl 3,4-bis(4-chlorophenyl)pyrrole-2,5-dicarboxylate (3e)
Under an argon atmosphere, a mixture of 8e (509 mg, 1.03 mmol), anisole (140 μL, 1.29 mmol), and 98% H2SO4 (36 µL, 0.68 mmol) in trifluoroacetic acid (1.2 mL) was refluxed for 0.5 h. After being cooled to rt, the mixture was evaporated under reduced pressure. The residue was basified with saturated aqueous NaHCO3 and the mixture was extracted with CH2Cl2. The extract was washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography over Silica Gel 60N (hexane-CH2Cl2=1:5~CH2Cl2) to give 3e as colorless solid (333 mg, 80%). Recrystallization from Et2O-pentane gave colorless granules. Mp 191.5-193 °C; IR (KBr): 3281, 1713, 1462, 1436, 1298, 1248, 1163, 1091, 1027 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.77 (s, 6H), 7.00-7.04 (m, 4H), 7.17-7.21 (m, 4H), 9.92 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.9, 121.3, 127.7, 129.9, 130.9, 131.9, 133.1, 160.2. HREIMS m/z. Calcd for C20H15Cl2NO4 (M+): 403.0378. Found: 403.0379.

Dimethyl N-benzyl-3-(3,4-dimethoxyphenyl)-4-(trifluoromethanesulfonyloxy)pyrrole-2,5- dicarboxylate (9)
Under an argon atmosphere, a degassed solution of Na2CO3 (4.23 g, 39.9 mmol) in water (12 mL) was added to a solution of 7 (3.46 g, 6.08 mmol), 2g (1.10 g, 6.05 mmol) and Pd(PPh3)4 (140 mg, 0.121 mmol) in THF (120 mL) at rt and the mixture was refluxed for 4 h. The mixture was cooled to rt and evaporated under reduced pressure. The products were extracted with CH2Cl2 and the extract was washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified successively by column chromatography over Silica Gel 60N (toluene~toluene-EtOAc=5:1) and over Silica Gel 60N (CH2Cl2) to give 9 as colorless solid (2.54 g, 75%), 3,4-diarylated 8g (258 mg, 8%), and unreacted 7 (461 mg, 13%). Recrystallization from CH2Cl2-hexane gave colorless granules. Mp 131-132 °C; IR (KBr): 1728, 1442, 1425, 1294, 1265, 1212, 1139 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.58 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 6.09 (s, 2H), 6.82-6.90 (m, 3H), 7.01-7.05 (m, 2H), 7.21-7.27 (m, 1H), 7.27-7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): 49.6, 51.9, 51.9, 55.8, 55.9, 110.5, 113.2, 117.8, 117.9 (q, J= 320 Hz), 121.9, 122.7, 123.2, 123.2, 126.1, 127.3, 128.5, 136.0, 137.3, 148.3, 148.8, 159.1, 160.8. Anal. Calcd for C24H22F3NO9S: C, 51.71; H, 3.98; N, 2.51. Found: C, 51.90; H, 3.93; N, 2.40.

Dimethyl N-benzyl-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (10)
Under an argon atmosphere, a degassed solution of Na2CO3 (2.10 g, 19.8 mmol) in water (6.0 mL) was added to a solution of 9 (1.67 g, 3.00 mmol), 2a (685 mg, 4.51 mmol) and Pd(PPh3)4 (145 mg, 0.125 mmol) in THF (60 mL) at rt and the mixture was refluxed for 20 h. The mixture was cooled to rt and evaporated under reduced pressure. The products were extracted with CH2Cl2 and the extract was washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified successively by column chromatography over Silica Gel 60N (toluene-EtOAc=10:1) and over Chromatorex NH-DM1020 silica gel (EtOAc) to give 10 as colorless solid (1.48 g, 96%). Recrystallization from CH2Cl2-hexane gave colorless granules. Mp 110.5-112 °C; IR (KBr): 1715, 1535, 1435, 1299, 1245, 1202, 1173, 1025 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.53 (s, 3H), 3.55 (s, 3H), 3.62 (s, 3H), 3.75 (s, 3H), 3.83 (s, 3H), 6.01 (s, 2H), 6.51 (d, J= 2.0 Hz, 1H), 6.62 (dd, J= 2.0 and 8.3 Hz, 1H), 6.70 (d, J= 8.3 Hz, 1H), 6.70-6.75 (m, 2H), 6.94-6.98 (m, 2H), 7.09-7.13 (m, 2H), 7.19-7.25 (m, 1H), 7.27-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3): 49.6, 51.4, 51.5, 55.0, 55.6, 55.6, 110.0, 112.7, 113.8, 122.7, 124.2, 124.4, 126.2, 126.5, 126.9, 128.3, 130.6, 130.8, 131.3, 138.5, 147.4, 147.6, 158.1, 161.9, 162.1. Anal. Calcd for C30H29NO7: C, 69.89; H, 5.67; N, 2.72. Found: C, 69.73; H, 5.64; N, 2.63.

Dimethyl 3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (11)
Under an argon atmosphere, ammonium formate (1.93 g, 30.6 mmol) was added portionwise to a mixture of 10 (523 mg, 1.01 mmol), Pearlman’s catalyst (51 mg), and EtOH (20 mL) at rt. After being refluxed for 3 h, the mixture was cooled to rt and passed through a pad of Celite. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over Silica Gel 60N (CH2Cl2) to give 11 as colorless solid (298 mg, 69%). Recrystallization from CH2Cl2-pentane gave colorless granules. Mp 181-182 °C; IR (KBr): 3282, 1721, 1702, 1463, 1299, 1249, 1190, 1024 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.61 (s, 3H), 3.77 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 3.85 (s, 3H), 6.56-6.58 (m, 1H), 6.72-6.79 (m, 4H), 7.01-7.06 (m, 2H), 9.82 (br s, 1H); 13C NMR (100 MHz, CDCl3): 51.7, 55.1, 55.6, 55.6, 110.0, 112.8, 114.2, 120.9, 121.0, 123.3, 125.1, 125.1, 131.1, 131.1, 131.7, 147.6, 147.7, 158.4, 160.6. HREIMS m/z. Calcd for C23H23NO7 (M+): 425.1475. Found: 425.1469.


3,4-Bis(4-isopropoxyphenyl)-5-methoxycarbonylpyrrole-2-carboxylic acid (12)
Under an argon atmosphere, 3c (2.71 g, 6.00 mmol) and LiOH·H2O (126 mg, 3.00 mmol) were dissolved in a degassed mixture of THF (36 mL), MeOH (12 mL), and water (12 mL). After being stirred for 44 h at rt, the mixture was acidified with 3 M aqueous HCl to pH 1 and evaporated under reduced pressure. The product was extracted with EtOAc and the extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography over Silica Gel 60N [hexane-EtOAc=1:1~EtOAc-water (upper phase)] to give 12 as colorless solid (1.23 g, 47%) and unreacted 3c (1.38 g, 51%). Recrystallization from CH2Cl2-pentane gave colorless powder. Mp 219-220 °C; IR (KBr): 3308, 1700, 1466, 1298, 1242, 1119, 952 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.22 (d, J= 6.0 Hz, 12H), 3.64 (s, 3H), 4.47-4.58 (m, 2H), 6.67-6.72 (m, 4H), 6.89-6.95 (m, 4H), 11.94 (br s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 21.7, 21.8, 51.1, 68.7, 68.7, 113.9, 114.0, 120.6, 122.5, 125.1, 125.3, 129.4, 130.0, 131.5, 131.6, 155.7, 155.8, 160.1, 161.2. Anal. Calcd for C25H27NO6: C, 68.63; H, 6.22; N, 3.20. Found: C, 68.63; H, 6.11; N, 3.14.

Methyl 3,4-bis(4-isopropoxyphenyl)pyrrole-2-carboxylate (13)
Under an argon atmosphere, a mixture of 12 (500 mg, 1.14 mmol) and copper(I) oxide (164 mg, 1.14 mmol) in quinoline (10 mL) was heated at 220 °C for 7 min. The mixture was cooled to rt and passed through a pad of Celite. The filtrate was diluted with CH2Cl2, washed successively with 6 M aqueous HCl, water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by flash chromatography over Silica Gel 60N (hexane-EtOAc=3:1) to give 13 as yellow solid (361 mg, 80%). Recrystallization from EtOAc-hexane gave yellow needles. The spectroscopic data are identical with those reported in ref. 26.

ACKNOWLEDGEMENTS
The authors acknowledge the Ministry of Education, Culture, Sports, Science and Technology of Japan for financial support; Grant-in-Aid for Scientific Research (B) (No. 20310135).


This paper is dedicated to Professor Emeritus, Tohoku University, Keiichiro Fukumoto on the occasion of his 75th birthday.

References

1. For recent reviews, see: (a) J. Kluza, P. Marchetti, and C. Bailly, ‘Modern Alkaloids: Structure, Isolation, Synthesis and Biology,’ ed. by E. Fattorusso and O. Taglialatela-Scafati, Wiley-VCH, Weinheim, 2008, pp. 171-187; (b) H. Fan, J. Peng, M. T. Hamann, and J.-F. Hu, Chem. Rev., 2008, 108, 264. CrossRef
2. W. Y. Yoshida, K. K. Lee, A. R. Carroll, and P. J. Scheuer, Helv. Chim. Acta, 1992, 75, 1721. CrossRef
3. H. Kang and W. Fenical, J. Org. Chem., 1997, 62, 3254. CrossRef
4. J. A. Palermo, M. F. R. Brasco, and A. M. Seldes, Tetrahedron, 1996, 52, 2727. CrossRef
5. (a) A. Rudi, I. Goldberg, Z. Stein, F. Frolow, Y. Benayahu, M. Schleyer, and Y. Kashman, J. Org. Chem., 1994, 59, 999. ; CrossRef (b) S. Loya, A. Rudi, Y. Kashman, and A. Hizi, Biochem. J., 1999, 344, 85; CrossRef (c) A. Rudi, T. Evan, M. Aknin, and Y. Kashman, J. Nat. Prod., 2000, 63, 832. CrossRef
6. G. W. Chan, T. Francis, D. R. Thureen, P. H. Offen, N. J. Pierce, J. W. Westley, R. K. Johnson, and D. J. Faulkner, J. Org. Chem., 1993, 58, 2544. CrossRef
7. Y. Kashman, G. Koren-Goldshlager, M. D. G. Gravalos, and M. Schleyer, Tetrahedron Lett., 1999, 40, 997. CrossRef
8. K. Warabi, S. Matsunaga, R. W. M. van Soest, and N. Fusetani, J. Org. Chem., 2003, 68, 2765. CrossRef
9. For reviews, see: (a) P. Cironi, F. Albericio, and M. Álvarez, Progress in Heterocyclic Chemistry, 2004, 16, 1; CrossRef (b) S. T. Handy and Y. Zhang, Org. Prep. Proc. Int., 2005, 37, 411; CrossRef (c) F. Bellina and R. Rossi, Tetrahedron, 2006, 62, 7213. CrossRef
10. A. Fürstner, H. Weintritt, and A. Hupperts, J. Org. Chem., 1995, 60, 6637. CrossRef
11. (a) A. Heim, A. Terpin, and W. Steglich, Angew. Chem., Int. Ed. Engl., 1997, 36, 155; CrossRef (b) H. Ebel, A. Terpin, and W. Steglich, Tetrahedron Lett., 1998, 39, 9165; CrossRef (c) C. Peschko and W. Steglich, Tetrahedron Lett., 2000, 41, 9477; CrossRef (d) C. Peschko, C. Winklhofer, and W. Steglich, Chem. Eur. J., 2000, 6, 1147; CrossRef (e) C. Peschko, C. Winklhofer, A. Terpin, and W. Steglich, Synthesis, 2006, 3048; CrossRef (f) C. Hinze, A. Kreipl, A. Terpin, and W. Steglich, Synthesis, 2007, 608. CrossRef
12. (a) F. Ishibashi, Y. Miyazaki, and M. Iwao, Tetrahedron, 1997, 53, 5951. ; CrossRef (b) S. Ruchirawat and T. Mutarapat, Tetrahedron Lett., 2001, 42, 1205; CrossRef (c) P. Ploypradith, W. Jinaglueng, C. Pavaro, and S. Ruchirawat, Tetrahedron Lett., 2003, 44, 1363; CrossRef (d) P. Ploypradith, C. Mahidol, P. Sahakitpichan, S. Wongbundit, and S. Ruchirawat, Angew. Chem. Int. Ed., 2004, 43, 866. CrossRef
13. (a) M. Banwell, B. Flynn, and D. Hockless, Chem. Commun., 1997, 2259; CrossRef (b) C. P. Ridley, M. V. R. Reddy, G. Rocha, F. D. Bushman, and D. J. Faulkner, Bioorg. Med. Chem., 2002, 10, 3285; CrossRef (c) P. Cironi, I. Manzanares, F. Albericio, and M. Álvarez, Org. Lett., 2003, 5, 2959; CrossRef (d) P. Cironi, C. Cuevas, F. Albericio, and M. Álvarez, Tetrahedron, 2004, 60, 8669; CrossRef (e) M. Díaz, E. Guitián, and L. Castedo, Synlett, 2001, 1164. CrossRef
14. J. L. Bullington, R. R. Wolff, and P. F. Jackson, J. Org. Chem., 2002, 67, 9439. CrossRef
15. (a) D. L. Boger, C. W. Boyce, M. A. Labroli, C. A. Sehon, and Q. Jin, J. Am. Chem. Soc., 1999, 121, 54; CrossRef (b) D. L. Boger, D. R. Soenen, C. W. Boyce, M. P. Hedrick, and Q. Jin, J. Org. Chem., 2000, 65, 2479; CrossRef (c) A. Hamasaki, J. M. Zimpleman, I. Hwang, and D. L. Boger, J. Am. Chem. Soc., 2005, 127, 10767. CrossRef
16. (a) J. T. Gupton, K. E. Krumpe, B. S. Burnham, T. M. Webb, J. S. Shuford, and J. A. Sikorski, Tetrahedron, 1999, 55, 14515; CrossRef (b) J. T. Gupton, S. C. Clough, R. B. Miller, J. R. Lukens, C. A. Henry, R. P. F. Kanters, and J. A. Sikorski, Tetrahedron, 2003, 59, 207; CrossRef (c) J. T. Gupton, R. B. Miller, K. E. Krumpe, S. C. Clough, E. J. Banner, R. P. F. Kanters, K. X. Du, K. M. Keertikar, N. E. Lauerman, J. M. Solano, B. R. Adams, D. W. Callahan, B. A. Little, A. B. Scharf, and J. A. Sikorski, Tetrahedron, 2005, 61, 1845. CrossRef
17. S. Kim, S. Son, and H. Kang, Bull. Korean Chem. Soc., 2001, 22, 1403.
18. A. Namsa-aid and S. Ruchirawat, Org. Lett., 2002, 4, 2633. CrossRef
19. (a) M. G. Banwell, B. L. Flynn, E. Hamel, and D. C. R. Hockless, Chem. Commun., 1997, 207; CrossRef (b) M. G. Banwell, B. L. Flynn, D. C. R. Hockless, R. W. Longmore, and A. D. Rae, Aust. J. Chem., 1999, 52, 755; CrossRef (c) J.-H. Liu, Q.-C. Yang, T. C. W. Mak, and H. N. C. Wong, J. Org. Chem., 2000, 65, 3587; CrossRef (d) A. Fürstner, H. Krause, and O. R. Thiel, Tetrahedron, 2002, 58, 6373; CrossRef (e) M. G. Banwell, A. M. Bray, A. J. Edwards, and D. J. Wong, J. Chem. Soc., Perkin Trans. 1, 2002, 1340; CrossRef (f) S. T. Handy, H. Bregman, J. Lewis, X. Zhang, and Y. Zhang, Tetrahedron Lett., 2003, 44, 427; CrossRef (g) M. R. Heinrich, W. Steglich, M. G. Banwell, and Y. Kashman, Tetrahedron, 2003, 59, 9239; CrossRef (h) S. T. Handy, Y. Zhang, and H. Bregman, J. Org. Chem., 2004, 69, 2362; CrossRef (i) C. A. Olsen, N. Parera, F. Albericio, and M. Álvarez, Tetrahedron Lett., 2005, 46, 2041; CrossRef (j) J. A. Smith, S. Ng, and J. White, Org. Biomol. Chem., 2006, 4, 2477; CrossRef (k) M. G. Banwell, T. E. Goodwin, S. Ng, J. A. Smith, and D. J. Wong, Eur. J. Org. Chem., 2006, 3043. CrossRef
20. M. Iwao, T. Takeuchi, N. Fujikawa, T. Fukuda, and F. Ishibashi, Tetrahedron Lett., 2003, 44, 4443. CrossRef
21. (a) N. Fujikawa, T. Ohta, T. Yamaguchi, T. Fukuda, F. Ishibashi, and M. Iwao, Tetrahedron, 2006, 62, 594; CrossRef (b) T. Yamaguchi, T. Fukuda, F. Ishibashi, and M. Iwao, Tetrahedron Lett., 2006, 47, 3755. CrossRef
22. S. F. Vasilevsky, S. V. Klyatskaya, E. V. Tretyakov, and J. Elguero, Heterocycles, 2003, 60, 879. CrossRef
23. A. Merz, R. Schropp, and J. Lex, Angew. Chem., Int. Ed. Engl., 1993, 32, 291. CrossRef
24. W. M. Pearlman, Tetrahedron Lett., 1967, 8, 1663. CrossRef
25. A. Merz, R. Schropp, and E. Dötterl, Synthesis, 1995, 795. CrossRef
26. T. Fukuda, E. Sudo, K. Shimokawa, and M. Iwao, Tetrahedron, 2008, 64, 328. CrossRef