Selective Mono-reduction of Pyrrole-2,5 and 2,4-Dicarboxylates

Abstract

Pyrrole-2,5-dicarboxylates were rapidly and selectively reduced to the corresponding mono-alcohol using 3 eq of diisobutylaluminum hydride at 0°C. Pyrrole-2,4-dicarboxylate showed the same reactivity; however, the selectivity decreased with pyrrole-3,4-dicarboxylate. When the nitrogen atom of the pyrrole-2,5-dicarboxylate is protected with a benzyl group, selective mono-reduction does not occur. Considering that furan-2,5-dicarboxylates did not give the corresponding mono-alcohol under the same conditions, the unprotected nitrogen atom of pyrrole apparently plays an important role in this selective mono-reduction.

The pyrrole ring is an important heterocycle in fields such as medicinal, material and natural product chemistry. Much attention has been focused on highly substituted pyrroles including 3,4-diaryl groups found in a class of alkaloids^1–12) (Fig. 1). We previously reported a synthetic reaction of 3,4-diarylpyrrole-2,5-dicarboxylates from α-diazoesters through a [3,3]-sigmatropic rearrangement of azine, which was also applied to the formal syntheses of polycitones (1) and permethyl storniamide (3b)^13,14) (Chart 1). This reaction is a very concise method but is not directly applicable to the preparation of unsymmetric pyrrole found in Ningalin B (4b)⁸⁾ and lamellarins (5).^9–12) Such a limitation could be compensated by an efficient desymmetrization. Boger and Patel reported that hydrolysis of pyrrole dicarboxylate 6 gave mono acid 7 in good yield upon treatment with an equivalent of lithium hydroxide at room temperature¹⁵⁾ (Chart 2, example 1). Panda and colleagues applied this method to the desymmetrization of pyrrole dicarboxylate 8 for generating mono acid 9, which was a synthetic intermediate of sapphyrin¹⁶⁾ (example 2). In another case, Yanagisawa and colleagues reported desymmetrization of N-benzyl pyrrole dicarboxylate 10 by treatment with diisobutylaluminum hydride (DIBAH) at a low temperature¹⁷⁾ (example 3). These methods showed acceptable selectivity but needed a very long reaction time. To our knowledge selective mono-reduction of N-non-protected pyrrole dicarboxylates has not been reported so far. We describe here rapid and selective mono-reduction of N-non-protected pyrrole dicarboxylates, which was found during our independent trial to obtain unsymmetric pyrroles.

Fig. 1. Natural Products Containing Pyrrole Moiety

Chart 1

i) Isoamyl nitrite, AcOH, CHCl₃, 70°C; ii) PnBu₃, IPE; iii) SOCl₂, EtOH, 90°C (in a sealed tube); iv) aq KOH, MeOH; v) L-selectride^®, THF.

Chart 2

Pyrrole dicarboxylate 12a was subjected to reduction with DIBAH in tetrahydrofuran (THF) at room temperature (Table 1, entry 1). In this case, 12a was completely consumed and mono-alcohol 13a was obtained in 63% yield. Changing solvent to toluene resulted in an increased yield of 13a at 0°C (entry 2). Interestingly, there was almost not reduction of second ester group despite highly excess addition of DIBAH (entry 3).

Table 1. Reduction of 12a with DIBAH

Entry	Reagents	Equivalent	Solvent	Temp.	Time (min)	Yields (%)
						13a	sm recover
1	DIBAH	5	THF	r.t.	60	63	0
2	DIBAH	4	Toluene	0°C	40	86	6
3	DIBAH	8	Toluene	0°C	50	78	0

To evaluate the scope of such selectivity, we next carried out reactions of several 3,4-diaryl pyrrole dicarboxylates with DIBAH in toluene at 0°C (Table 2). Thorough and careful experiments revealed that at least three equivalents of DIBAH were necessary for complete consumption of the starting material. Reduction of 12b–f afforded the corresponding mono-alcohol 13b–f in good yields, irrespective of the electron-withdrawing or electron-donating nature of the substituent on the aromatic ring. It is also noteworthy that a gas, which should be hydrogen, evolved vigorously while adding DIBAH dropwise in all cases.

Table 2. Reduction of Various Diaryl Pyrrole Diesters with DIBAH

Entry	Ar	Yield (%)		Entry	Ar	Yield (%)
1	Ph	85	13b	4		82	13e
2		83	13c	5		94	13f
3		90	13d

Further experiments with a range of mono- and dicarboxylates gave notable results (Table 3). The presence of an aryl group was not essential for the selective mono-reduction; pyrrole-2,5-dicarboxylate (12g)^18,19) with no aryl groups reacted with DIBAH to give mono-alcohol 13g in 80% yield (entry 1). Interestingly, treatment of unsymmetric pyrrole dicarboxylate (12h)²⁰⁾ under the same conditions resulted in the reduction of only an ester group at the 4-position to generate mono-alcohol 13h in 86% yield²¹⁾ (entry 2). In contrast, the reaction of pyrrole-3,4-dicarboxylate (12i)²²⁾ generated both mono-alcohol 13i (36%) and diol 14 (26%) along with recovery of the starting material (entry 3). Interestingly, whereas reductions of 12g and h gave rise to vigorous generation of hydrogen gas, the same reaction of 12i proceeded without its generation. Protection of the nitrogen atom led to complete loss of selectivity; N-benzyl-pyrrole dicarboxylate 15 reacted with DIBAH at −40°C to afford the corresponding diol in 79% yield (entry 4). Also, reaction of furan-2,5-dicarboxylate (17) occurred with less mono-selectivity to afford diol 19 as a major product (entry 5). These results demonstrated that the presence of an N–H bond and at least one ester group adjacent to nitrogen seem to be essential for the selective mono-reduction. We next carried out reduction of pyrrole monocarboxylates in order to reveal the origin of the unique selectivity that is observed in a specific kind of dicarboxylates. Both 20 and 22²³⁾ reacted with DIBAH to afford the corresponding alcohol without vigorous generation of hydrogen gas (entries 6, 7). Also, reduction of carboxylate 13b, which was obtained by selective mono-reduction of 12b, proceeded without vigorous gas generation to give diol 24 in 21% yield along with recovery of the substrate (entry 8).

Table 3. Reduction of Various Diesters with DIBAH

Entry	Pyrrole diesters	DIBAH (eq)	Time (min)		Products (Yield)
1		4	80		sm recover (15%)
2		4	50		sm recover (14%)
3		4	50			sm recover (14%)
4		4.7	30
5		3	90			sm recover (40%)
6		3	90		sm recover (15%)
7		2	30
8		3	45		sm recover (68%)

Reduction was performed in toluene at 0°C except for entry 4 (−40°C).

Based on these results, the tentative mechanism for the selective mono-reduction is proposed (Chart 3). The reduction is initiated with coordination of DIBAH with an ester group. Since the N–H acidity of 12a–g is increased by the duplicate electron-withdrawing effect of two ester groups, hydride in DIBAH removes the proton on the neighboring nitrogen to generate aluminum enolate A along with evolution of hydrogen. The resulting enolate structure should be stabilized by chelation with pyrrole nitrogen. As a result, only the remaining ester group in A reacts with DIBAH to afford the corresponding carboxylate 13a–g via an intermediate B. The site-selectivity for 12h can also be explained by a similar pathway through the reduction of intermediate C. Acidity of 12i would also be high, but both ester groups are away from the NH group. Therefore, 12i directly reacts with DIBAH, i.e., without formation of aluminum enolate, to give also a diol 14 product along with carboxylate 13i. On the other hand, the N–H acidity of carboxylates 13b and 20 is not sufficient for the formation of aluminum enolate, and hydride in DIBAH can therefore attack their carbonyl carbon.

Chart 3

In conclusion, we found selective mono-reduction of pyrrole 2,5- or 2,4-carboxylates upon treatment with DIBAH in toluene at 0°C. Although further investigation is needed, the remarkable selectivity can currently be considered to correlate with formation of aluminum enolate having chelation with pyrrole nitrogen. The formation necessitates high N–H acidity on the pyrrole ring and at least one ester group at the 2-position. The findings provide a practical method for desymmetrization of pyrrole dicarboxylates. Further trials to elucidate the reaction mechanism are underway.

Experimental

General

¹H- and ¹³C-NMR spectra were recorded on a JEOL JNM-ECX 400 and JNM-ECZ 400S/L1 spectrometers at 400 and 100 MHz, respectively. Chemical shifts were expressed in δ parts per million with tetramethylsilane as internal standard (δ=0 ppm) for ¹H-NMR. Chemical shifts of carbon signals were referenced to CDCl₃ (δ_C=77.0 ppm). The following abbreviations are used: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, and br=broad. IR spectra were recorded on a SHIMADZU IR Prestige-21. MS were recorded on a JEOL JMS-GCmate II. Melting points were determined on a Yanagimoto MP-S3 micro melting point apparatus and were uncorrected. All reagents and solvents were purchased from commercial sources and used without further purification.

Dimethyl 3,4-Diphenyl-1H-pyrrole-2,5-dicarboxylate (12b)

Colorless crystal, mp 199.3–201.3°C; ¹H-NMR (400 MHz, CDCl₃) δ: 9.88 (br s, 1H), 7.24–7.16 (m, 6H), 7.14–7.08 (m, 4H), 3.76 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 160.72 (C), 132.80 (C), 131.50 (C), 130.73 (CH), 127.33 (CH), 126.98 (CH), 121.22 (C), 51.79 (CH₃); IR (KBr) 3310, 1713, 1296, 1242 cm⁻¹; high resolution (HR)-MS (electron ionization (EI)) Calcd for C₂₀H₁₇NO₄ 335.1158. Found 335.1181.

Diethyl 3,4-Diphenyl-N-benzyl Pyrrole (15)

To a solution of the compound 12a (147.2 mg, 0.405 mmol) in acetone (4 mL) was added potassium carbonate (279.9 mg, 2.025 mmol) and benzyl bromide (0.150 mL, 1.264 mmol) at 0°C. The reaction mixture was stirred at room temperature for 20 h, then quenched with H₂O and extracted with ethyl acetate for three times. The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with n-hexane–EtOAc (6 : 1) to give N-benzyl pyrrole 15 (143.2 mg, 0.324 mmol, 80%). Recrystallized from ethyl acetate–hexane to give colorless crystal; mp 117.0–118.0°C; ¹H-NMR (400 MHz, CDCl₃) δ: 7.29 (m, 2H), 7.21 (m, 1H), 7.17–7.11(m, 8H), 7.08–7.04 (m, 4H), 6.09 (s, 2H), 3.97 (q, J=7.2 Hz, 4H), 0.81 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 161.54 (C), 138.71 (C), 134.49 (C), 131.22 (C), 130.39 (CH), 128.40 (CH), 127.14 (CH), 126.94 (CH), 126.41 (CH), 126.37 (CH), 124.55 (C), 60.46 (CH₂), 49.38 (CH₂), 13.28 (CH₃); IR (KBr) 2986, 1713, 1296, 1196 cm⁻¹; HR-MS (EI) Calcd for C₂₉H₂₇NO₄ 453.1940. Found 453.1931.

Dimethyl Furan-2,5-dicarboxylates (17)

To a solution of the compound 2,5-furandicarboxylic acid (204.4 mg, 1.309 mmol) in MeOH (13 mL) was added thionyl chloride (0.955 mL, 13.09 mmol) at 0°C. The reaction mixture was refluxed for 40 min, then quenched with saturated aqueous NaHCO₃ and extracted with ethyl acetate for three times. The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with n-hexane–EtOAc (3 : 1) to give 17 (231.9 mg, 0.130 mmol, 86%). Recrystallized from ethyl acetate–hexane to give colorless crystal; mp 110.0–111.5°C; ¹H-NMR (400 MHz, CDCl₃) δ: 7.22 (s, 2H), 3.94 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 158.39 (C), 146.64 (C), 118.45 (CH), 52.37 (CH₃); IR (KBr) 1728, 1281 cm⁻¹; HR-MS (EI) Calcd for C₈H₈O₅ 184.0372. Found 184.0376.

Typical Experimental Procedure for Reduction of Pyrrole Dicaboxylates

To a solution of the compound 12a (35.7 mg, 0.098 mmol) in toluene (1 mL) was added DIBAH (1.0 M in toluene, 0.4 mL, 0.39 mmol) at 0°C under an argon atmosphere. After being stirred for 45 min, then quenched with saturated aqueous Rochelle salt and extracted with EtOAc for three times. The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with n-hexane–EtOAc (1 : 1) to give alcohol 13a (27.1 mg, 0.084 mmol, 86%) as reddish solid. Recrystallized from ethyl acetate/ hexane to give colorless crystal.

Ethyl 3,4-Diphenyl-5-(hydroxymethyl)-1H-pyrrole-2-carboxylate (13a)

Colorless crystal; mp 138.5–139.0°C; ¹H-NMR (400 MHz, CDCl₃) δ: 10.30 (s, 1H), 7.22–7.13 (m, 8H), 7.04–6.99 (m, 2H), 4.72 (s, 2H), 4.15 (q, J=7.2 Hz, 2H), 1.09 (t, J=7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 162.24 (C), 134.23 (C), 133.74 (C), 133.10 (C), 130.85 (CH), 130.75 (C), 130.08 (CH), 127.95 (CH), 127.16 (CH), 126.57 (CH), 126.20 (CH), 124.16 (C), 118.29 (C), 60.47 (CH₂), 56.52 (CH₂), 13.84 (CH₃); IR (KBr) 3372, 1659, 1404, 1281 cm⁻¹; HR-MS (EI) Calcd for C₂₀H₁₉NO₃ 321.1365. Found 321.1379.

Methyl 3,4-Diphenyl-5-(hydroxymethyl)-1H-pyrrole-2-carboxylate (13b)

Colorless crystal; mp 178.4–179.9°C; ¹H-NMR (400 MHz, DMSO-d₆) δ: 11.86 (s, 1H), 7.25–7.00 (m, 10H), 5.11 (t, J=4.8 Hz, 1H), 4.37 (d, J=5.2 Hz, 2H), 3.62 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 160.90 (C), 134.75 (C), 134.47 (C), 134.27 (C), 130.76 (CH), 130.03 (CH), 129.59 (C), 127.96 (CH), 127.39 (CH), 126.51 (CH), 126.03 (CH), 123.77 (C), 117.20 (C), 54.22 (CH₂), 50.99 (CH₃); IR (KBr) 3441, 3194, 1667, 1296 cm⁻¹; HR-MS (EI) Calcd for C₁₉H₁₇NO₃ 307.1208. Found 307.1237.

Methyl 3,4-Bis(4-chlorophenyl)-5-(hydroxymethyl)-1H-pyrrole-2-carboxylate (13c)

Colorless crystal; mp 161.5–162.5°C; ¹H-NMR (400 MHz, CDCl₃) δ: 10.09 (s, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 4.71 (s, 2H), 3.72 (s, 3H), 2.77 (s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 162.02 (C), 132.97 (C), 132.87 (C), 132.54 (C), 132.17 (C), 132.03 (CH), 131.83 (C), 131.25 (CH), 129.31 (C), 128.42 (CH), 127.76 (CH), 122.88 (C), 118.16 (C), 56.50 (CH₂), 51.55 (CH₃); IR (KBr) 3503, 3348, 3271, 3171, 1690, 1450, 1288, 1265 cm⁻¹; HR-MS (EI) Calcd for C₁₉H₁₅Cl₂NO₃ 375.0429. Found 375.0424.

Methyl 3,4-Bis(4-methoxyphenyl)-5-(hydroxymethyl)-1H-pyrrole-2-carboxylate (13d)

Brown oil; ¹H-NMR (400 MHz, CDCl₃) δ: 9.86 (s, 1H), 7.10 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H), 6.76 (dd, J=8.4, 5.7 Hz, 4H), 4.70 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 2.45 (br s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 162.12 (C), 158.33 (C), 158.06 (C), 132.64 (C), 131.88 (CH), 131.17 (CH), 130.48 (C), 126.30 (C), 126.12 (C), 123.79 (C), 117.71 (C), 113.54 (CH), 112.85 (CH), 56.71 (CH₂), 55.11 (CH₃), 55.06 (CH₃), 51.33 (CH₃); IR (film) 3310, 3005, 2951, 2835, 1663, 1612 cm⁻¹; HR-MS (EI) Calcd for C₂₁H₂₁NO₅ 367.1420. Found 367.1431.

Methyl 3,4-Bis(3,4-dimethoxyphenyl)-5-(hydroxymethyl)-1H-pyrrole-2-carboxylate (13e)

Pink amorphous; ¹H-NMR (400 MHz, CDCl₃) δ: 9.91 (s, 1H), 6.80–6.72 (m, 4H), 6.64 (d, J=8.4 Hz, 1H), 6.51 (s, 1H), 4.76 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.67 (s, 3H), 3.58 (s, 3H), 2.4 (br s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 162.09 (C), 148.30 (C), 147.82 (C), 147.79 (C), 147.50 (C), 132.63 (C), 130.34 (C), 126.58 (C), 126.43 (C), 123.91 (C), 123.27 (CH), 122.11 (CH), 117.65 (C), 114.38 (CH), 113.57 (CH), 110.81 (CH), 110.30 (CH), 56.69 (CH₂), 55.75 (CH₃), 55.73 (CH₃), 55.69 (CH₃), 55.57 (CH₃), 51.51 (CH₃); IR (film) 3456, 3310, 3009, 2947, 2839, 1690, 1528, 1443, 1250 cm⁻¹; HR-MS (EI) Calcd for C₂₃H₂₅NO₇ 427.1631. Found 427.1620.

Methyl 3,4-Bis(3,4,5-trimethoxyphenyl)-5-(hydroxymethyl)-1H-pyrrole-2-carboxylate (13f)

Pink amorphous; ¹H-NMR (400 MHz, CDCl₃) δ: 10.00 (s, 1H), 6.47 (s, 2H), 6.29 (s, 2H), 4.78 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.67 (s, 6H), 3.65 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 161.90 (C), 152.71 (C), 152.25 (C), 136.91 (C), 136.52 (C), 132.68 (C), 130.24 (C), 129.40 (C), 129.27 (C), 124.06 (C), 117.63 (C), 108.38 (CH), 107.29 (CH), 60.84 (CH₃×2),²⁴⁾ 56.56 (CH₂), 55.99 (CH₃), 55.94 (CH₃), 51.44 (CH₃); IR (film) 3456, 3310, 2994, 2940, 2832, 1690, 1582, 1458, 1412, 1234, 1126 cm⁻¹; HR-MS (EI) Calcd for C₂₅H₂₉NO₉ 487.1842. Found 487.1818.

Methyl 5-(Hydroxymethyl)-1H-pyrrole-2-carboxylate (13g)

Pale brown crystal; mp 83.0–84.0°C; ¹H-NMR (400 MHz, CDCl₃) δ: 10.30 (br s, 1H), 6.81 (t, J=3.2 Hz, 1H), 6.08 (t, J=3.2 Hz, 1H), 4.62 (s, 2H), 3.81 (s, 3H), 3.58 (s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 162.35 (C), 137.20 (C), 122.08 (C), 115.99 (CH), 108.47 (CH), 57.56 (CH₂), 51.51 (CH₃); IR (KBr) 3414, 3198, 1670, 1493, 1335, 1231 cm⁻¹; HR-MS (EI) Calcd for C₇H₉NO₃ 155.0582. Found 155.0556.

Ethyl 4-(Hydroxymethyl)-1H-pyrrole-2-carboxylate (13h)

Colorless crystal; mp 81.0–81.5°C; ¹H-NMR (400 MHz, CDCl₃) δ: 9.55 (br s, 1H), 6.94–6.88 (m, 2H), 4.56 (s, 2H), 4.31 (q, J=7.6 Hz, 2H), 2.18 (br s, 1H), 1.34 (t, J=7.6 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 161.33 (C), 125.68 (C), 123.08 (C), 121.48 (CH), 114.39 (CH), 60.39 (CH₂), 58.18 (CH₂), 14.34 (CH₃); IR (KBr) 3310, 1690, 1443, 1412, 1204 cm⁻¹; HR-MS (EI) Calcd for C₈H₁₁NO₃ 169.0739. Found 169.0764.

Ethyl 4-(Hydroxymethyl)-1H-pyrrole-3-carboxylate (13i)

Colorless oil; ¹H-NMR (400 MHz, CD₃OD) δ: 7.36 (d, J=2.0 Hz, 1H), 6.74 (s, 1H), 4.68 (s, 2H), 4.25 (q, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H); ¹³C-NMR (100 MHz, CD₃OD) δ: 167.82 (C), 126.39 (CH), 126.20 (C), 118.95 (CH), 114.11 (C), 60.81 (CH₂), 58.31 (CH₂), 14.73 (CH₃); IR (film) 3310, 1674 cm⁻¹; HR-MS (EI) Calcd for C₈H₁₁NO₃ 169.0739. Found 169.0734.

3,4-Dihydroxymethyl-1H-pyrrole (14)

Bright brown color oil; ¹H-NMR (400 MHz, CD₃OD) δ: 6.70 (s, 2H), 4.54 (s, 4H); ¹³C-NMR (100 MHz, CD₃OD) δ: 122.79 (C), 118.43 (CH), 57.44 (CH₂); IR (film) 3348 cm⁻¹; HR-MS (EI) Calcd for C₆H₉NO₂ 127.0633. Found 127.0655.

2,5-Dihydroxymethyl-3,4-diphenyl-N-benzyl Pyrrole (16)

Colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.40–7.15 (m, 15H), 5.52 (s, 2H), 4.54 (s, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ: 138.55 (C), 134.88 (C), 130.43 (CH), 129.64 (C), 129.00 (CH), 127.97 (CH), 127.49 (CH), 126.02 (CH), 125.70 (CH), 123.93 (C), 54.90 (CH₂), 47.51 (CH₂); IR (film) 3372, 2924 cm⁻¹; HR-MS (EI) Calcd for C₂₅H₂₃NO₂ 369.1729. Found 369.1757.

Methyl 5-(Hydroxymethyl)-furan-2-carboxylate (18)

Colorless oil; ¹H-NMR spectra was in good accordance with that of reported one.²⁵⁾

2,5-Dihydroxymethylfurane (19)

Colorless crystal; mp 74.5–75.5°C; ¹H-NMR (400 MHz, CD₃OH) δ: 6.23 (s, 2H), 4.48 (s, 4H); ¹³C-NMR (100 MHz, CD₃OH) δ: 155.76 (C), 109.12 (CH), 57.47 (CH₂); IR (KBr) 3333, 1404, 1196 cm⁻¹; HR-MS (EI) Calcd for C₆H₈O₃ 128.0473. Found 128.0473.

2-Hydroxymethyl-1H-pyrrole (21)

Brown oil; ¹H-NMR (400 MHz, CD₃OH) δ: 8.47 (br s, 1H), 6.77 (s, 1H), 6.18–6.10 (m, 2H), 4.60 (s, 2H), 1.91 (br s, 1H); ¹³C-NMR (100 MHz, CD₃OH) δ: 131.04 (C), 118.50 (CH), 108.32 (CH), 107.03 (CH), 58.07 (CH₂); IR (film) 3372, 2924 cm⁻¹; HR-MS (EI) Calcd for C₅H₇NO 97.0557. Found 97.0528.

3-Hydroxymethyl-1H-pyrrole (23)

Colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ: 8.34 (br s, 1H), 6.77 (s, 1H), 6.74 (quint, J=2.4 Hz, 1H), 6.25 (s, 1H), 4.58 (s, 2H), 1.70 (br s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 123.71 (C), 118.44 (CH), 116.41 (CH), 107.97 (CH), 58.66 (CH₂); IR (film) 3395, 2932, 2878 cm⁻¹; HR-MS (EI) Calcd for C₅H₇NO 97.0524. Found 97.0528.

2,5-Dihydroxymethyl-3,4-diphenyl-1H-pyrrole (24)

Brown oil (unstable); ¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (br s, 1H), 7.40–7.00 (m, 10H), 4.72 (s, 4H); IR (film) 3318 cm⁻¹; HR-MS (EI) Calcd for C₁₈H₁₇NO₂ 279.1259. Found 279.1304.

Acknowledgments

This study was supported in part by a Grant from the Strategic Research Foundation Grant-in-Aid Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, 2014–2018 (S1411005). E. Y. appreciates financial support from The Naito Foundation.

Conflict of Interest

The authors declare no conflict of interest.

References and Notes

• 1) Rudi A., Goldberg I., Stein Z., Frolow F., Benayahu Y., Schleyer M., Kashman Y., J. Org. Chem., 59, 999–1003 (1994).
• 2) Rudi A., Evan T., Aknin M., Kashman Y., J. Nat. Prod., 63, 832–833 (2000).
• 3) Kreipl A. T., Reid C., Steglich W., Org. Lett., 4, 3287–3288 (2002).
• 4) Fröde R., Hinze C., Josten I., Schmidt B., Steffan B., Steglich W., Tetrahedron Lett., 35, 1689–1690 (1994).
• 5) Hashimoto T., Yasuda A., Akazawa K., Takaoka S., Tori M., Asakawa Y., Tetrahedron Lett., 35, 2559–2560 (1994).
• 6) Palermo J. A., Rodriguez Brasco M. F., Seldes A. M., Tetrahedron, 52, 2727–2734 (1996).
• 7) Boger D. L., Boyce C. W., Labroli M. A., Sehon C. A., Jin Q., J. Am. Chem. Soc., 121, 54–62 (1999).
• 8) Kang H., Fenical W., J. Org. Chem., 62, 3254–3262 (1997).
• 9) Andersen R. J., Faulkner D. J., He C. H., Van Duyne G. D., Clardy J., J. Am. Chem. Soc., 107, 5492–5495 (1985).
• 10) Fan H., Peng J., Hamann M. T., Hu J. F., Chem. Rev., 108, 264–287 (2008).
• 11) Ridley C. P., Reddy M. V. R., Rocha G., Bushman F. D., Faulkner D. J., Bioorg. Med. Chem., 10, 3285–3290 (2002).
• 12) Reddy S. M., Srinivasulu M., Satyanarayana N., Kondapi A. K., Venkateswarlu Y., Tetrahedron, 61, 9242–9247 (2005).
• 13) Yasui E., Wada M., Takamura N., Tetrahedron Lett., 50, 4762–4765 (2009).
• 14) Yasui E., Wada M., Nagumo S., Takamura N., Tetrahedron, 69, 4325–4330 (2013).
• 15) Boger D. L., Patel M., J. Org. Chem., 53, 1405–1415 (1988).
• 16) Rana A., Kumar B. S., Panda P. K., Org. Lett., 17, 3030–3033 (2015).
• 17) Yoshida K., Hayashi K., Yanagisawa A., Org. Lett., 13, 4762–4765 (2011).
• 18) Dimethyl pyrrole-2,5-dicarboxylate was synthesized according to reported procedures, see: Barker P., Gendler P., Rapoport H., J. Org. Chem., 43, 4849–4853 (1978).
• 19) Hong F., Zaidi J., Pang Y.-P., Cusack B., Richelson E., J. Chem. Soc., Perkin Trans. 1, 1997, 2997–3003 (1997).
• 20) Diethyl pyrrole-2,4-dicarboxylate 12h was synthesized according to a reported procedure, see: Fink B. E., Vite G. D., Mastalerz H., Kadow J. F., Kim S.-H., Leavitt K. J., Du K., Crews D., Mitt T., Wong T. W., Hunt J. T., Vyas D. M., Tokarski J. S., Bioorg. Med. Chem. Lett., 15, 4774–4779 (2005).
• 21) Commercially available ethyl 4-formylpyrrole-2-carboxylate (Sigma-Aldrich) was used to obtain the alcohol by reduction with NaBH₄. ¹H-NMR spectroscopic analysis of this alcohol was consistent with that of 13h.
• 22) Diethyl 3,4-pyrroledicarboxylate is commercially available (Sigma-Aldrich).
• 23) Krayer M., Ptaszek M., Kim H.-J., Meneely K. R., Fan D., Secor K., Lindsey J. S., J. Org. Chem., 75, 1016–1039 (2010).
• 24) This peak consists of two kinds of carbons which are not equal value.
• 25) Schmuck C., Machon U., Eur. J. Org. Chem., 2006, 4385–4392 (2006).