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Article

Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling

by
Saba Kanwal
1,
Noor-ul- Ann
1,
Saman Fatima
1,
Abdul-Hamid Emwas
2,
Meshari Alazmi
3,4,
Xin Gao
3,
Maha Ibrar
1,
Rahman Shah Zaib Saleem
1 and
Ghayoor Abbas Chotana
1,*
1
Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science & Engineering (SBASSE), Lahore University of Management Sciences (LUMS), Lahore 54792, Pakistan
2
Core Labs, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
3
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
4
College of Computer Science and Engineering, University of Ha’il, P.O. Box 2440, Ha’il 81481, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(9), 2106; https://doi.org/10.3390/molecules25092106
Submission received: 11 April 2020 / Revised: 26 April 2020 / Accepted: 29 April 2020 / Published: 30 April 2020
(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)
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Versions Notes

Abstract

:
A convenient two-step preparation of NH-free 5-aryl-pyrrole-2-carboxylates is described. The synthetic route consists of catalytic borylation of commercially available pyrrole-2-carboxylate ester followed by Suzuki coupling without going through pyrrole N–H protection and deprotection steps. The resulting 5-aryl substituted pyrrole-2-carboxylates were synthesized in good- to excellent yields. This synthetic route can tolerate a variety of functional groups including those with acidic protons on the aryl bromide coupling partner. This methodology is also applicable for cross-coupling with heteroaryl bromides to yield pyrrole-thiophene, pyrrole-pyridine, and 2,3’-bi-pyrrole based bi-heteroaryls.

Graphical Abstract

1. Introduction

5-Aryl 1H-Pyrrole-2-carboxylate esters constitute an important class of pyrrole derivatives [1,2]. This structural motif is present in several natural products and their analogs such as Lamellarins [3,4,5,6,7] (topoisomerase I inhibitor, MDR reversal agent, and anti-HIV agent), and arylated hymenialdisine [8,9] (ChK2 inhibitor), as well as in several other biologically active compounds with anti-HIV [10,11,12,13,14], antibacterial [15], antimitotic [16], and cytotoxic [17] activities (Figure 1). 5-Aryl 1H-Pyrrole-2-carboxylate esters and their derivatives have also found applications, for example, as organic fluorescent materials [18,19], anion receptors/molecular logic gates [20], and as building blocks for metal organic frameworks [21] and helical asymmetric architectures [22,23]. As a consequence of their widespread applications, there has been burgeoning interest in developing new and efficient methodologies for quick access to this structural motif.
Traditional approaches to access 5-aryl pyrrole-2-carboxylates consist of long protracted routes involving construction of pyrrole ring from acyclic precursors [24,25,26]. During the last decade, several new methodologies have also been developed for the pyrrole cyclization reaction including multicomponent reactions [27], cycloadditions [28,29,30,31,32,33,34], Michael additions [35], isomerization [36], rearrangement [37], and photocatalysis [38,39]. A major disadvantage of these cyclization reactions is the preparation of highly functionalized precursors (Figure 2).
With the advent of transition metal-catalyzed reactions [40,41,42,43,44], derivatization of preformed pyrrole ring has grown as an alternate strategy for the synthesis of arylated pyrroles. However, preparation of pyrrole-based organometallic reagents employing halogen-metal exchange requires Boc-protection of the acidic N-H proton (Figure 2) [45]. To circumvent the preparation of organometallic reagents, direct arylation reactions have evolved. Unfortunately, direct arylation reactions are generally limited to N-protected pyrroles [46,47,48,49,50,51], and have been reported to be incompatible for the installation of highly electron-rich aryl groups [52]. Moreover, due to very harsh reaction conditions limiting the functional group tolerance, such arylations are rendered incapable of preparing heteroaryl substituted pyrroles. Hence, there is a need to develop new short synthetic routes devoid of these limitations which can also facilitate access to unconventional scaffolds in search of novel medicinally active compounds and organic materials.
Transition metal-catalyzed Suzuki coupling reactions require much milder conditions as compared to direct arylation reactions thereby allowing a broad functional group compatibility. Pyrrole 2-carboxylate esters, which are readily commercially available, can potentially be an excellent starting point for the preparation of 5-arylpyrrole-2-carboxylates by electrophilic halogenation and subsequent Suzuki coupling. However, halogenation of pyrrole 2-carboxylate esters yields a 1:1 mixture of 4- and 5-functionalized pyrroles whose separation is cumbersome [53,54]. Isomerically pure 5-halo substituted pyrrole-2-carboxylate require tedious preparation and are generally synthesized in N-protected form [55,56]. Preparation of the corresponding 5-boronic ester derivative also requires N-protection [57] or blockage of the 3- and 4-positions [21,22,58]. This N-protection/deprotection and blocking elongates the synthetic route and also reduces atom economy. Development of a Suzuki coupling route for the synthesis of 5-arylpyrrole-2-carboxylates that obviates the protection-deprotection and blocking steps is highly desirable.
The groups of Smith-Maleczka and Hartwig-Miyaura have reported an iridium-catalyzed borylation reaction which can directly functionalize aromatic C−H bond to a boronic ester group [59,60,61,62]. This methodology has also been successfully utilized to prepare heteroarylboronic esters of pyrroles [63,64,65], indoles [66,67,68,69], thiophenes [70], pyridines [71,72,73], and other heteroaromatics [74]. This reaction can tolerate pyrrole N-H functional group and hence does not need N-protection for the synthesis of pyrroleboronic esters. N-H free pyrroles are easily borylated on the 2-position while N-protection can be used to direct borylation at the 3-position [75,76]. N-Boc protected 3-borylated pyrroles have been employed in Suzuki coupling to access 3-arylpyrroles [77]. On the other side, N−H unprotected pyrroleboronic esters have been much less utilized for Suzuki coupling [78]. Our group has been interested in exploring catalytic C–H borylation reactions for organic synthesis [72,79,80,81,82,83,84,85,86]. A recent report about failure of installation of highly electron-rich aromatic substituent on pyrrole by direct arylation [52] prompted us to investigate Suzuki coupling route for this purpose. Herein, we describe the application of iridium-catalyzed borylation−Suzuki coupling route for a concise two-step synthesis of 5-aryl pyrrole-2-carboxylates.

2. Results and Discussion

Methyl-1H-pyrrole-2-carboxylate was subjected to iridium-catalyzed borylation, by using a slightly modified literature protocol [87], to prepare methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Scheme 1). Pinacol borane (H−BPin) was preferred over bis(pinacolato)diboron (B2Pin2) as the borylating agent because of its ability to solubilize pyrrole substrate in the absence of any solvent. The borylation reaction was scaled up to 40 mmol scale and the borylated pyrrole was isolated on 10-gram scale with >99% yield.
This N-H free borylated pyrrole has a long shelf life as no apparent decomposition was detected by GC-MS even after two years. The borylated pyrrole 1 was subsequently subjected to Suzuki coupling to synthesize 5-aryl substituted pyrrole-2-carboxylates. The pyrrole boronic ester easily underwent Suzuki-coupling with (hetero)aryl bromides using Buchwald’s Pd(OAc)2/SPhos catalyst system [88] as well as by the Pd(PPh3)4 catalyst (Scheme 2).
A variety of electron-rich and electron-deficient aryl bromides were utilized as coupling partners. Aryl bromides having para (entries 2a – 2h), meta (entries 2j – 2o), and ortho substituents (entries 2i and 2x) were successfully employed in Suzuki coupling and the corresponding 5-arylated pyrroles were isolated in good to excellent yields. Further, the reaction proceeded well with disubstituted (entries 2p – 2u), trisubstituted (entries 2v and 2w), and tetrasubstituted (entry 2x) aryl bromides. Entry 2v shows installation of highly electron-rich aromatic ring which was not possible via direct arylation [52]. Chloro-substituted aryl bromides (entries 2k, 2q, and 2w) were selectively coupled at the C–Br bond. Aryl bromides with acidic protons (entries 2s and 2t) were also tolerated demonstrating the advantage of this route over pyrrole anion arylation protocol reported by Sadighi et al. [89]. Besides aryl bromides, aryl iodides (entries 2p and 2q) and aryl chlorides (2j) can also be utilized.
Suzuki coupling with heteroaryl halides was also examined to synthesize 5-heteroaryl substituted pyrrole-2-carboxylates (Scheme 3). Heteroaryl bromides of thiophene (entries 3a–3c) [34], pyrrole (3d) [90], and pyridine (3e) [38] all gave excellent isolated yields of corresponding bi-heteroaryl products. During the formation of 3d, very small amounts (~5–7%) of two homocoupling products (originating by the homocouplings of boronic ester, and bromopyrrole, with themselves) were also observed by GC-MS. However, the cross-coupled product was formed as the major product and was isolated in 75% yield. This entry (3d) again signifies the advantage of the current route over direct pyrrole arylation protocols, which cannot be used to prepare such NH-free 2,3’-bi-pyrroles [91,92].

3. Materials and Methods

3.1. General Considerations and Starting Materials

All reactions were carried out under nitrogen atmosphere, without the use of glove box or Schlenk line. Chemicals and reagents were purchased from Sigma-Aldrich Corp® (St. Louis, MO, USA), Combi-Blocks, Inc. (San Diego, CA, USA), and Strem Chemicals, Inc. (Newburyport, MA, USA), and were used without further purification unless otherwise noted. Ethyl acetate, n-hexane and dichloromethane were purchased from local suppliers and were distilled before use. Catalytic borylation and all the Suzuki cross-coupling reactions were carried out in inert atmosphere in 25 mL Schlenk flasks (0–4 mm Valve, 175 mm OAH) purchased from Chemglass Life Sciences. Analytical thin-layer chromatography (TLC) was carried out using 200 µm thick silica gel 60 matrix TLC Plates (Aluminum (Al) Silica, indicator F–254, EMD Millipore). Visualization was achieved under a UV lamp (254 nm and 365 nm). Column chromatography was carried out using SiliaFlash® P60 (particle size: 40–63 µm, 230–400 mesh) purchased from SiliCycle Inc. All reported yields are for isolated materials. Reaction times and yields are not optimized. HBPin = pinacolborane; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridyl; SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
Infrared spectra were recorded as neat using a Bruker Alpha-P IR instrument in the ATR geometry with a diamond ATR unit. Melting points were taken on Electrothermal IA9100 melting point apparatus and are uncorrected. Reactions were monitored by a GC–MS operating in EI mode. Column type: TR-5MS, 5% phenyl polysilphenylene-siloxane, 30 m × 0.25 mm ID × 0.25 µm. GC–MS method: injector 250 °C, oven 50 °C (1 min), 50 to 250 °C (20 °C min–1), 250 °C (10 min); carrier gas: He (1.5 mL min–1). Accurate mass determinations (HRMS) were obtained using an Orbitrap mass spectrometer.
1H NMR spectra (see Supplementary Materials) were recorded at 700.130 MHz and 13C NMR spectra were recorded at 176.048 MHz at ambient temperatures. The chemical shifts in 1H NMR spectra are reported using TMS as internal standard and were referenced with the residual proton resonances of the corresponding deuterated solvent (CDCl3: 7.26 ppm). The chemical shifts in the 13C NMR spectra are reported relative to TMS (δ = 0) or the central peak of CDCl3 (δ = 77.23) for calibration. The abbreviations used for the chemical shifts are as; s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), tt (triplet of triplet), tq (triplet of quartet), ttd (triplet of triplet of doublet), m (unresolved multiplet), and br (broad). All coupling constants are apparent J values measured at the indicated field strengths. In 13C NMR spectra of arylboronic ester, the carbon atom attached to the boron atom of BPin group is typically not observed due to broadening from and coupling with boron.
Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (1) In a fume hood, an oven dried Schlenk flask equipped with magnetic stirring bar was filled with nitrogen and evacuated (three cycles). Under nitrogen atmosphere [Ir(OMe)(COD)]2 (133 mg, 0.2 mmol, 0.5 mol% Ir), 4,4′-di-tert-butyl-2,2′-bipyridine (107 mg, 0.40 mmol, 1 mol%), and pinacolborane (HBPin) (8.706 mL, 7.679 g, 60 mmol, 1.5 equiv) were added. Methyl-1H-pyrrole-2-carboxylate (5.0 g, 40 mmol, 1 equiv) was added under nitrogen atmosphere. The Schlenk flask was closed and the reaction mixture was heated at 50 °C in an oil bath for 0.5 h. The progress of reaction was monitored by GC-MS and TLC. Upon completion of reaction, the Schlenk flask was cooled to room temperature and exposed to air. The reaction mixture was taken out by dissolving in dichloromethane and the volatiles were removed under reduced pressure using rotary evaporator. The crude product was purified by column chromatography. Colorless solid; yield: 10.02 g (99.9%); mp 121–123 °C; Rf = 0.45 (hexanes–CH2Cl2 1:1). FT-IR (ATR): 3321, 2994, 2956, 1688, 1556, 1438, 1379, 1303, 1214, 1197, 1138, 1000, 852, 775, 693, 616, 528 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.48 (br s, 1 H), 6.91 (apparent t, J = 2.8 Hz, 1 H), 6.77 (apparent t, J = 2.8 Hz, 1 H), 3.86 (s, 3 H), 1.33 (s, 12 H, 4 CH3 of BPin). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.2 (C=O), 126.5 (C), 120.6 (CH), 115.5 (CH), 84.2 (2 C), 51.6 (OCH3), 24.7 (4 CH3 of BPin). GC-MS (EI): m/z (%) = 251 (74) (M)+, 236 (21), 220 (13), 208 (86), 204 (23), 194 (38), 190 (12), 176 (100), 165 (21), 150 (42), 134 (18), 120 (23). HRMS (APCI-Orbitrap): m/z [M + H]+ calcd for C12H19BNO4: 252.14017; found: 252.13957.

3.2. Suzuki Coupling

3.2.1. General Suzuki Procedure A Employing Pd(OAc)2 and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos)

In a fume hood, an oven dried Schlenk flask equipped with magnetic stirring bar was filled with nitrogen and evacuated (three cycles). Under nitrogen atmosphere palladium acetate Pd(OAc)2 (2.24 mg, 0.01 mmol, 1 mol%), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) (8.2 mg, 0.02 mmol, 2 mol%), aryl bromide (1.5 mmol, 1.5 equiv), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv), potassium phosphate (K3PO4) (318 mg, 1.5 mmol, 1.5 equiv), and dimethoxyethane (DME) (1.5 mL) were added. Liquid substrates were added via micropipette under nitrogen atmosphere. The Schlenk flask was closed and the reaction mixture was heated at 60–80 °C in an oil bath. The progress of reaction was monitored by GC-MS and TLC. Upon completion of reaction, the Schlenk flask was cooled to room temperature and exposed to air. The reaction mixture was taken out by dissolving in dichloromethane and the volatiles were removed under reduced pressure using a rotary evaporator. The crude product was purified by column chromatography (silica gel; hexanes–CH2Cl2).

3.2.2. General Suzuki Procedure B Employing Palladium Tetrakistriphenylphosphine Pd(PPh3)4

The general Suzuki Procedure A was employed using palladium tetrakistriphenylphosphine Pd(PPh3)4 (34.7 mg, 0.03 mmol, 3 mol%) as catalyst instead of Pd(OAc)2/SPhos.
Synthesis of 5-Aryl 1H-Pyrrole-2-Carboxylate Esters.
Methyl 5-(p-tolyl)-1H-pyrrole-2-carboxylate (2a) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 4-bromotoluene (185 µL, 257 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 200 mg (93%); mp 168–170 °C; Rf = 0.4 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3315, 2944, 2852, 1677, 1470, 1437,1336, 1264, 1243, 1003, 786, 658 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.59 (br s, 1 H), 7.49 (d, J = 7.8 Hz, 2 H), 7.20 (d, J = 7.8 Hz, 2 H), 6.95 (apparent t, J = 2.8 Hz, 1 H), 6.50 (apparent t, J = 3.0 Hz, 1 H), 3.87 (s, 3 H), 2.37 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.8 (C=O), 137.7 (C), 137.2 (C), 129.6 (2 CH), 128.5 (C), 124.7 (2 CH), 122.6 (C), 116.9 (CH), 107.6 (CH), 51.6 (OCH3), 21.2 (CH3). GC-MS (EI): m/z (%) = 215 (100) (M)+, 183 (95), 155 (43), 140 (11), 128 (13), 115 (9). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H14NO2: 216.10191; found: 216.10195.
Methyl 5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (2b) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 4-bromoanisole (188 µL, 281 mg, 1.5 mmol, 1.5 equiv) for 36 h. Colorless solid; yield: 202 mg (87%); mp 151–152 °C, lit[39] 144–146 °C; Rf = 0.45 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3320, 3116, 3003, 2913, 2835, 1683, 1611, 1563, 1474, 1436, 1269, 1243, 1188, 1121, 1046, 1025, 938, 919, 874, 830, 792, 759, 659, 610 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.40 (br s, 1 H), 7.51 (d, J = 8.7 Hz, 2 H), 6.94 (m, 3 H), 6.44 (apparent t, J = 3.0, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.7 (C=O), 159.3 (C), 137.0 (C), 126.2 (2 CH), 124.2 (C), 122.4 (C), 117.0 (CH), 114.4 (2 CH), 107.1 (CH), 55.4 (OCH3), 51.5 (OCH3). GC-MS (EI): m/z (%) = 231 (73) (M)+, 199 (100), 184 (7), 171 (45), 156 (21), 145 (9), 141 (3), 128 (21). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H14NO3: 232.09682; found: 232.09864.
Methyl 5-(4-(dimethylamino)phenyl)-1H-pyrrole-2-carboxylate (2c) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 4-bromo-N,N-dimethylaniline (299 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 170 mg (71%); mp 175–176 °C; Rf = 0.40 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3327, 3269, 2945, 2926, 1675, 1612, 1557, 1474, 1421, 1147, 1067, 1041, 104, 813, 787 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.24 (br s, 1 H), 7.45 (d, J = 8.3 Hz, 2 H), 6.94 (s, 1 H), 6.74 (d, J = 8.3 Hz, 2 H), 6.39 (s, 1 H), 3.86 (s, 3 H), 2.99 (s, 6 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.7 (C=O), 150.1 (C), 137.9 (C), 125.8 (2 CH), 121.6 (C), 119.5 (C), 117.1 (CH), 112.5 (2 CH), 106.2 (CH), 51.4 (OCH3), 40.4 (2 CH3). GC-MS (EI): m/z (%) = 244 (56) (M)+, 212 (100), 184 (45), 169 (15), 158 (7), 140 (7), 115 (3), 106 (3). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H17N2O2: 245.12845; found: 245.12843.
Methyl 5-(4-(tert-butyl)phenyl)-1H-pyrrole-2-carboxylate (2d) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 1-bromo-4-tert-butylbenzene (260 µL, 320 mg, 1.5 mmol, 1.5 equiv) for 36 h. Colorless solid; yield: 205 mg (80%); mp 152–153 °C, lit[39] 149–150 °C; Rf = 0.40 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3293, 3259, 2953, 2863, 1681, 1573, 1287, 1195, 1004, 825, 669 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.50 (br s, 1 H), 7.52 (d, J = 8.1 Hz, 2 H), 7.42 (d, J = 8.1 Hz, 2 H), 6.95 (s, 1 H), 6.51 (d, J = 2.6 Hz, 1 H), 3.87 (s, 3 H), 1.33 (s, 9 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.8 (C=O), 150.9 (C), 137.1 (C), 128.5 (C), 125.9 (2 CH), 124.6 (2 CH), 122.6 (C), 116.9 (CH), 107.7 (CH), 51.6 (OCH3), 34.6 (C), 31.2 (3 CH3). GC-MS (EI): m/z (%) = 257 (32) (M)+, 242 (40), 225 (10), 210 (100), 182 (5), 170 (2), 167 (2), 155 (12), 141 (2), 127 (2), 115 (2). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C16H20NO2: 258.14886; found: 258.14870.
Methyl 5-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2-carboxylate (2e) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 1-bromo-4-(trifluoromethoxy) benzene (223 µL, 362 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 220 mg (77%); mp 165–166 °C; Rf = 0.40 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3314, 3030, 2957, 1687, 1562, 1473, 1439, 1208, 1190, 1149, 1050, 967, 850, 755, 732, 657 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.78 (br s, 1 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.25 (d, J = 8.7 Hz, 2 H), 6.96 (apparent t, J = 3.3 Hz, 1 H), 6.53 (apparent t, J = 3.3 Hz, 1 H), 3.87 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.8 (C=O), 148.6 (C), 135.7 (C), 130.2 (C), 126.3 (2 CH), 123.5 (C), 121.5 (2 CH), 120.4 (q, 1JC-F = 258 Hz, OCF3), 117.0 (CH), 108.5 (CH), 51.7 (OCH3). GC-MS (EI): m/z (%) = 285 (43) (M)+, 253 (100), 225 (86), 199 (40), 184 (5), 156 (38), 139 (23), 133 (7), 128 (27), 101 (5). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H11F3NO3: 286.06855; found: 286.06873.
Methyl 5-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate (2f) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 4-bromobenzotrifluoride (210 µL, 338 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 257 mg (96%); mp 198–199 °C, lit[39] 196–197 °C; Rf = 0.20 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3312, 1686, 1617, 1586, 1523, 1475, 1329, 1250, 1194, 1109, 1048, 1007, 801, 760, 692 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.70 (br s, 1 H), 7.70 (d, J = 8.1 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 2 H), 6.98 (apparent t, J = 3.1 Hz, 1 H), 6.63 (apparent t, J = 3.1 Hz, 1 H), 3.89 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.7 (C=O), 135.2 (C), 134.6 (C), 129.4 (q, 2JC-F = 32.7 Hz, C), 126.0 (q, 3JC-F = 3.1 Hz, 2 CH), 124.8 (2 CH), 124.1 (C), 124.0 (q, 1JC-F = 271.6 Hz, CF3), 117.0 (CH), 109.3 (CH), 51.8 (OCH3). GC-MS (EI): m/z (%) = 269 (56) (M)+, 237 (100), 218 (6), 209 (40), 189 (10), 183 (26), 163 (2), 158 (2), 140 (47), 133 (6). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H11F3NO2: 270.07364; found: 270.07360.
Methyl 5-(4-cyanophenyl)-1H-pyrrole-2-carboxylate (2g) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 4-bromobenzonitrile (273 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 198 mg (88%); mp 256–257 °C; Rf = 0.20 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3306, 2955, 2219, 1688, 1606, 1573, 1437, 1337, 1319, 1283, 1188, 1069, 1007, 939, 806, 726 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.39 (br s, 1 H), 7.70 (d, J = 8.1 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 2 H), 6.98 (s, 1 H), 6.67 (apparent t, J = 2.8 Hz, 1 H), 3.90 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.4 (C=O), 135.3 (C), 134.2 (C), 132.9 (2 CH), 124.8 (2 CH), 124.7 (C), 118.7 (C), 116.9 (CH), 110.8 (C), 110.1 (CH), 51.9 (OCH3). GC-MS (EI): m/z (%) = 226 (85) (M)+, 194 (100), 166 (46), 139 (25), 113 (7), 88 (2). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H11N2O2: 227.08150; found: 227.08171.
Methyl 5-(4-(ethoxycarbonyl)phenyl)-1H-pyrrole-2-carboxylate (2h) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and ethyl 4-bromobenzoate (245 µL, 344 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 188 mg (69%); mp 168–169 °C; Rf = 0.1 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3317, 2983, 2966, 1703, 1683, 1607, 1474, 1436, 1367, 1260, 1187, 1067, 939, 863, 770, 758, 656 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.77 (br s, 1 H), 8.07 (d, J = 8.2 Hz, 2 H), 7.66 (dd, J = 8.2, 1.9 Hz, 2 H), 6.98 (dd, J = 3.6, 2.5 Hz, 1 H), 6.65 (apparent t, J = 3.5 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 3.89 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 166.2 (C=O), 161.7 (C=O), 135.7 (C), 135.3 (C), 130.3 (2 CH), 129.3 (C), 124.4 (2 CH), 124.0 (C), 117.0 (CH), 109.4 (CH), 61.1 (CH2), 51.8 (OCH3), 14.3 (CH3). GC-MS (EI): m/z (%) = 273 (66) (M)+, 241 (100), 228 (10), 213 (67), 196 (68), 185 (8), 168 (15), 158 (6), 140 (18), 114 (5), 113 (6). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C15H16NO4: 274.10738; found: 274.10780.
Methyl 5-(2-(dimethylamino)phenyl)-1H-pyrrole-2-carboxylate (2i) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 2-bromo-N,N-dimethylaniline (215 µL, 300.1 mg, 1.5 mmol, 1.5 equiv) for 48 h. Light yellow liquid; yield: 154 mg (63%); Rf = 0.30 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3301, 3117, 2984, 2947, 2832, 2790, 1694, 1499, 1384, 1328, 1284, 1183, 1105, 995, 796, 749, 657 cm−1. 1H NMR (700 MHz, CDCl3): δ = 11.75 (br s, 1 H), 7.62 (dd, J = 8.1, 0.8 Hz, 1 H), 7.24 (m, 2 H), 7.12 (m, 1 H), 6.93 (dd, J = 3.8, 2.7 Hz, 1 H), 6.57 (dd, J = 3.8, 2.5 Hz, 1 H), 3.87 (s, 3 H), 2.71 (s, 6 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.6 (C=O), 150.4 (C), 135.9 (C), 128.1 (CH), 128.0 (CH), 125.1 (C), 124.4 (CH), 121.8 (C), 120.4 (CH), 115.7 (CH), 108.0 (CH), 51.4 (OCH3), 44.7 (2 CH3). GC-MS (EI): m/z (%) = 244 (86) (M)+, 212 (95), 184 (100), 168 (26), 144 (17), 131 (13), 115 (13). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H17N2O2: 245.12845; found: 245.12799.
Methyl 5-(m-tolyl)-1H-pyrrole-2-carboxylate (2j) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 3-bromotoluene (182 µL, 257 mg, 1.5 mmol, 1.5 equiv) for 48 h. Light yellow solid; yield: 168 mg (78%); mp 119–121 °C, lit[39] 118–119 °C; Rf = 0.20 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3326, 3017, 2950, 2918, 2850, 1686, 1597, 1498, 1471, 1438, 1335, 1271, 1195, 1099, 1072, 1004, 955, 872, 794 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.57 (br s, 1 H), 7.39 (m, 2 H), 7.28 (t, J = 7.4, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 6.95 (s, 1 H), 6.52 (s, 1 H), 3.86 (s, 3 H), 2.39 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.8 (C=O), 138.6 (C), 137.1 (C), 131.2 (C), 128.9 (CH), 128.6 (CH), 125.5 (CH), 122.8 (C), 121.9 (CH), 116.9 (CH), 107.9 (CH), 51.6 (OCH3), 21.5 (CH3). GC-MS (EI): m/z (%) = 215 (100) (M)+, 183 (95), 155 (34), 140 (9), 129 (12), 115 (12), 77 (2). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H14NO2: 216.10191; found: 216.10165.
Methyl 5-(3-chlorophenyl)-1H-pyrrole-2-carboxylate (2k) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 1-bromo-3-chlorobenzene (176 µL, 287 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 190 mg (81%); mp 133–134 °C; Rf = 0.20 (hexanes–CH2Cl2 1:1). FT-IR (ATR): 3317, 2953, 2926, 2851, 1736, 1689, 1599, 1460, 1435, 1332, 1309, 1271, 1149, 1101, 992, 924, 871, 777, 690, 626 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.72 (br s, 1 H), 7.58 (s, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 6.96 (apparent t, J = 3.1 Hz, 1 H), 6.55 (apparent t, J = 3.2 Hz, 1 H), 3.88 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.7 (C=O), 135.4 (C), 134.9 (C), 133.1 (C), 130.2 (CH), 127.6 (CH), 124.9 (CH), 123.6 (C), 122.9 (CH), 116.9 (CH), 108.7 (CH), 51.8 (OCH3). GC-MS (EI): m/z (%) = 235 (66) (M)+, 237 (20) (M+2)+, 205 (31), 203 (100), 175 (26), 149 (12), 140 (43), 114 (6). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H11ClNO2: 236.04728; found: 236.04736.
Methyl 5-(3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate (2l) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 3-bromobenzotrifluoride (210 µL, 338 mg, 1.5 mmol, 1.5 equiv) for 48 h. Light green solid; yield: 226 mg (84%); mp 152–154 °C; Rf = 0.20 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3331, 2952, 2923, 1683, 1445, 1321, 1283, 1194, 998, 896, 786, 757, 689, 616 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.86 (br s, 1 H), 7.82 (s, 1 H), 7.78 (d, J = 7.4 Hz, 1 H), 7.55–7.51 (m, 2 H), 6.98 (dd, J = 3.5, 2.5 Hz, 1 H), 6.61 (apparent t, J = 3.2 Hz, 1 H), 3.87 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.8 (C=O), 135.4 (C), 132.2 (C), 131.5 (q, 2JC-F = 32.0 Hz, C), 129.5 (CH), 127.9 (CH), 124.2 (q, 3JC-F = 3.5 Hz, CH), 124.0 (q, 1JC-F = 272 Hz, CF3), 123.8 (C), 121.6 (q, 3JC-F = 3.6 Hz, CH), 117.0 (CH), 109.0 (CH), 51.8 (OCH3). GC-MS (EI): m/z (%) = 269 (56) (M)+, 237 (100), 218 (7), 209 (42), 189 (12), 183 (27), 163 (3), 158 (3), 140 (54), 133 (5). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H11F3NO2: 270.07364; found: 270.07340.
Methyl 5-(4-acetylphenyl)-1H-pyrrole-2-carboxylate (2m) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 3′-bromoacetophenone (198 µL, 299 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 117 mg (48%); mp 147–148 °C; Rf = 0.20 (hexanes–CH2Cl2 1:1). FT-IR (ATR): 3333, 2960, 1681, 1605, 1588, 1439, 1355, 1280, 1241, 1186, 1151, 1069, 955, 925, 798 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.68 (br s, 1 H), 8.17 (s, 1 H), 7.87 (d, J = 7.7 Hz, 1 H), 7.79 (d, J = 7.7 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 6.98 (s, 1 H), 6.62 (apparent t, J = 2.9 Hz, 1 H), 3.88 (s, 3 H), 2.65 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 197.8 (C=O of ketone), 161.6 (C=O), 137.7 (C), 135.7 (C), 131.9 (C), 129.3 (CH), 129.2 (CH), 127.6 (CH), 124.1 (CH), 123.6 (C), 116.9 (CH), 108.7 (CH), 51.7 (OCH3), 26.8 (CH3). GC-MS (EI): m/z (%) = 243 (84) (M)+, 211 (82), 196 (100), 168 (16), 157 (4), 140 (17), 127 (2), 114 (7). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H14NO3: 244.09682; found: 244.09700.
Methyl 5-(3-(methoxycarbonyl)phenyl)-1H-pyrrole-2-carboxylate (2n) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and methyl 3-bromobenzoate (323 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 187 mg (72%); mp 161–162 °C; Rf = 0.20 (hexanes–CH2Cl2 1:1). FT-IR (ATR): 3353, 3023, 2959, 2851, 1716, 1681, 1473, 1343, 1301, 1280, 1188, 1108, 1055, 1008, 977, 901, 781, 725, 644 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.43 (br s, 1 H), 8.23 (s, 1 H), 7.96 (d, J = 7.7 Hz, 1 H), 7.76 (d, J = 7.7 Hz, 1 H), 7.49 (t, J = 7.7 Hz, 1 H), 6.97 (apparent t, J = 2.8 Hz, 1 H), 6.62 (apparent t, J = 3.1Hz, 1 H), 3.96 (s, 3 H), 3.89 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 166.7 (C=O), 161.5 (C=O), 135.5 (C), 131.6 (C), 130.9 (C), 129.2 (CH), 128.9 (CH), 128.6 (CH), 125.5 (CH), 123.5 (C), 116.8 (CH), 108.6 (CH), 52.4 (OCH3), 51.7 (OCH3). GC-MS (EI): m/z (%) = 259 (66) (M)+, 227 (100), 199 (8), 196 (30), 169 (35), 140 (18), 129 (2), 113 (5). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H14NO4: 260.09173; found: 260.09149.
Methyl 5-(3-nitrophenyl)-1H-pyrrole-2-carboxylate (2o) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 1-bromo-3-nitrobenzene (303 mg, 1.5 mmol, 1.5 equiv) for 48 h. Yellow solid; yield: 231 mg (94%); mp 201–203 °C; Rf = 0.30 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3324, 3302, 2955, 1675, 1566, 1496, 1463, 1340, 1310, 1265, 1193, 1150, 1105, 1005, 955, 899, 860, 703, 600, 579 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.57 (br s, 1 H), 8.42 (s, 1 H), 8.15 (dd, J = 8.1, 1.0 Hz, 1H), 7.89 (d, J = 7.7, 1 H), 7.60 (t, J = 8.0 Hz, 1 H), 6.99 (dd, J = 3.4, 2.5 Hz, 1 H), 6.68 (apparent t, J = 3.1 Hz, 1 H), 3.90 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.4 (C=O), 148.8 (C), 133.9 (C), 132.9 (C), 130.2 (CH), 130.1 (CH), 124.4 (C), 122.1 (CH), 119.3 (CH), 116.9 (CH), 109.5 (CH), 51.6 (OCH3). GC-MS (EI): m/z (%) = 246 (64) (M)+, 214 (100), 200 (3), 186 (9), 168 (26), 156 (4), 140 (29), 128 (4), 113 (9). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H11N2O4: 247.07133; found: 247.07103.
Methyl 5-(3,5-dimethylphenyl)-1H-pyrrole-2-carboxylate (2p) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 1-bromo-3,5-dimethylbenzene (204 µL, 278 mg, 1.5 mmol, 1.5 equiv) for 48 h.
Colorless solid; yield: 192 mg (84%); mp 100–101 °C; Rf = 0.50 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3299, 3033, 2953, 2915, 2852, 1686, 1599, 1494, 1423, 1290, 1243, 1212, 1044, 1005, 862 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.31 (br s, 1 H), 7.18 (s, 2 H), 6.95–6.94 (m, 2 H), 6.51 (dd, J = 3.8, 2.7 Hz, 1 H), 3.87 (s, 3 H), 2.35 (s, 6 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.6 (C=O), 138.6 (2 C), 137.1 (C), 131.1 (C), 129.5 (CH), 122.7 (C), 122.6 (2 CH), 116.8 (CH), 107.9 (CH), 51.5 (OCH3), 21.3 (2 CH3). GC-MS (EI): m/z (%) = 229 (71) (M)+, 197 (100), 169 (26), 154 (22), 143 (8), 129 (9), 115 (4). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H16NO2: 230.11756; found: 230.11724.
Methyl 5-(3,5-dichlorophenyl)-1H-pyrrole-2-carboxylate (2q) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 1-bromo-3,5-dichlorobenzene (339 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 197 mg (73%); mp 183–185 °C; Rf = 0.50 (hexanes–CH2Cl2 1:1). FT-IR (ATR): 3290, 3005, 2954, 1682, 1595, 1492, 1431, 1272, 1151, 1101, 992, 926, 848, 757, 703, 622 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.65 (br s, 1 H), 7.45 (s, 2 H), 7.28 (s, 1 H), 6.96 (s, 1 H), 6.56 (s, 1 H), 3.90 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.6 (C=O), 135.6 (2 C), 134.1 (C), 133.9 (C), 127.4 (CH), 124.2 (C), 123.1 (2 CH), 116.9 (CH), 109.4 (CH), 51.9 (OCH3). GC-MS (EI): m/z (%) = 269 (37) (M)+, 271 (23) (M+2)+, 237 (100), 209 (25), 183 (14), 174 (46), 148 (6), 139 (4). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H10Cl2NO2: 270.00831; found: 270.00846.
Methyl 5-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate (2r) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 1-bromo-3,5-bis(trifluoromethyl) benzene (259 µL, 440 mg, 1.5 mmol, 1.5 equiv) for 24 h. Colorless solid; yield: 256 mg (76%); mp 167–168 °C; Rf = 0.60 (hexanes–CH2Cl2 1:1). FT-IR (ATR): 3305, 3136, 2963, 1668, 1330, 1273, 1039, 1007, 680 cm−1. 1H NMR (700 MHz, CDCl3): δ = 10.19 (br s, 1 H), 8.00 (s, 2 H), 7.77 (s, 1 H), 7.00 (dd, J = 3.4, 2.5 Hz, 1 H), 6.69 (apparent t, J = 3.1 Hz, 1H), 3.86 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 162.0 (C=O), 133.9 (C), 133.5 (C), 132.4 (q, 2JC-F = 33.3 Hz, 2 C), 124.8 (C), 124.7 (d, 3JC-F = 2.9 Hz, 2 CH), 123.2 (q, 1JC-F = 272.6 Hz, 2 CF3), 120.8 (m, 3JC-F = 3.6 Hz, CH), 117.2 (CH), 110.0 (CH), 51.9 (OCH3). GC-MS (EI): m/z (%) = 337 (32) (M)+, 305 (61), 286 (8), 277 (12), 257 (12), 251 (29), 238 (7), 231 (4), 207 (100), 182 (10), 158 (7). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H10F6NO2: 338.06102; found: 338.06112.
Methyl 5-(3-amino-5-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate (2s) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 3-bromo-5-(trifluoromethyl) aniline (211 µL, 360 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 248 mg (87%); mp 203–205 °C; Rf = 0.10 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3422, 3321, 3208, 3135, 3032, 2958, 1688, 1610, 1465, 1442, 1356, 1292, 1154, 1004, 882, 793, 751, 630 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.24 (br s, 1 H), 7.15 (s, 1 H), 6.98 (s, 1 H), 6.95 (apparent t, J = 3.1 Hz, 1 H), 6.83 (s, 1 H), 6.54 (apparent t, J = 3.1 Hz, 1 H), 3.96 (br s, 2 H), 3.89 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.4 (C=O), 147.3 (C), 135.4 (C), 133.0 (C), 132.5 (q, 2JC-F = 32 Hz, C), 123.9 (q, 1JC-F = 272.2 Hz, CF3), 123.5 (C), 116.7 (CH), 113.6 (CH), 111.5 (d, J = 3.7, CH), 110.6 (d, J = 3.7, CH), 108.7 (CH), 51.7 (OCH3). GC-MS (EI): m/z (%) = 284 (42) (M)+, 252 (100), 233 (4), 224 (37), 205 (4), 198 (17), 176 (6), 155 (37), 151 (5), 128 (3), 126 (3). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H12F3N2O2: 285.08454; found: 285.08465.
Methyl 5-(3-chloro-5-hydroxyphenyl)-1H-pyrrole-2-carboxylate (2t) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 3-bromo-5-chlorophenol (311 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 145 mg (58%); mp 164 °C; Rf = 0.1 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3356, 3254, 3231, 2955, 1661, 1616, 1579, 1500, 1444, 1347, 1288, 1226, 1164, 1052, 1008, 991, 908, 878, 755, 696, 557 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.84 (br s, 1 H), 7.15 (s, 1 H), 7.07 (s, 1 H), 6.94 (s, 1H), 6.83 (s, 1 H), 6.60 (br s, 1 H), 6.53 (s, 1H), 3.91 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 162.4 (C=O), 156.6 (C), 135.7 (C), 135.3 (C), 133.9 (C), 123.3 (C), 117.8 (CH), 117.3 (CH), 115.0 (CH), 109.8 (CH), 108.7 (CH), 51.9 (OCH3). GC-MS (EI): m/z (%) = 251 (42) (M)+, 253 (13) (M+2)+, 221 (31), 219 (100), 193 (8), 191 (25), 166 (3), 164 (9), 156 (28), 128 (6), 101 (4). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H11ClNO3: 252.04220; found: 252.04268.
Methyl 5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrole-2-carboxylate (2u) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 5-bromo-2,2-difluorobenzo[d] [1,3]dioxole (204 µL, 356 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 224 mg (80%); mp 171–173 °C; Rf = 0.30 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3315, 3142, 2961, 1680, 1619, 1514, 1472, 1441, 1387, 1288, 1241, 1060, 1044, 1003, 964, 938, 826, 765, 704, 634 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.81 (br s, 1 H), 7.38 (s, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 7.09 (d, J = 8.3 Hz, 1 H), 6.96 (apparent t, J = 2.7 Hz, 1 H), 6.48 (apparent t, J = 2.8 Hz, 1 H), 3.89 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.9 (C=O), 144.3 (C), 143.2 (C), 135.8 (C), 131.6 (t, 1JC-F = 256 Hz, CF2), 128.0 (C), 123.3 (C), 120.4 (CH), 117.0 (CH), 109.9 (CH), 108.4 (CH), 106.5 (CH), 51.8 (OCH3). GC-MS (EI): m/z (%) = 281 (51) (M)+, 249 (100), 221 (77), 195 (21), 155 (24), 127 (43), 101 (5), 75 (3). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H10F2NO4: 282.05724; found: 282.05724.
Methyl 5-(3,4,5-trimethoxyphenyl)-1H-pyrrole-2-carboxylate (2v) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 5-bromo-1,2,3-trimethoxybenzene (371 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 246 mg (85%); mp 105–107 °C; Rf = 0.50 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3302, 2995, 2941, 2838, 1677, 1568, 1565, 1476, 1425, 1378, 1238, 1219, 1189, 1042, 999, 927, 832, 700, 662, 613 cm−1. 1H NMR (700 MHz, CDCl3): δ = δ 9.54 (br s, 1 H), 6.95 (dd, J = 3.8, 2.4 Hz, 1 H), 6.76 (s, 2 H), 6.47 (dd, J = 3.8, 2.7 Hz, 1 H), 3.91 (s, 6 H), 3.87 (s, 3 H), 3.85 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.8 (C=O), 153.7 (2 C), 137.9 (C), 137.2 (C), 127.2 (C), 122.8 (C), 116.9 (CH), 108.0 (CH), 102.3 (2 CH), 61.0 (OCH3), 56.2 (2 OCH3), 51.6 (OCH3). GC-MS (EI): m/z (%) = 291 (43) (M)+, 259 (65), 244 (100), 216 (31), 212 (7), 205 (4), 201 (9), 188 (7), 186 (6), 173 (5), 161 (8), 130 (8). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C15H18NO5: 292.11795; found: 292.11762.
Methyl 5-(3,4,5-trichlorophenyl)-1H-pyrrole-2-carboxylate (2w) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 5-bromo-1,2,3-trichlorobenzene (390 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 79 mg (26%); mp 236–238 °C; Rf = 0.1 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3306, 3075, 2954, 1665, 1593, 1566, 1492, 1437, 1334, 1282, 1217, 1090, 1054, 1006, 927, 784, 759, 697 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.38 (br s, 1 H), 7.56 (s, 2 H), 6.95 (apparent t, J = 3.2 Hz, 1 H), 6.56 (apparent t, J = 3.5 Hz, 1 H), 3.90 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.3 (C=O), 134.9 (2 C), 132.9 (C), 131.3 (C), 130.2 (C), 124.6 (2 CH), 124.4 (C), 116.8 (CH), 109.6 (CH), 51.6 (OCH3). GC-MS (EI): m/z (%) = 303 (36) (M)+, 305 (35) (M+2)+, 273 (100), 247 (12), 245 (35), 243 (35), 219 (24), 217 (24), 212 (11), 210 (59), 208 (99), 182 (10), 173 (11). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H9Cl3NO2: 303.96934; found: 303.96995.
Methyl 5-(anthracen-9-yl)-1H-pyrrole-2-carboxylate (2x) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 9-bromoanthracene (386 mg, 1.5 mmol, 1.5 equiv) for 36 h. Light yellow solid; yield: 129 mg (43%); mp 202–207 °C; Rf = 0.50 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3280, 3052, 2951, 2895, 1667, 1555, 1494, 1403, 1212, 1173, 1133, 1042, 963, 931, 890, 851, 740, 656 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.50 (br s, 1 H), 8.50 (s, 1 H), 8.01 (d, J = 8.4, 2 H), 7.82 (dd, J = 8.7, 0.7 Hz, 2 H), 7.46 (ddd, J = 8.3, 6.5, 1.0 Hz, 2 H), 7.42 (ddd, J = 8.6, 6.4, 1.2 Hz, 2 H), 7.16 (dd, J = 3.4, 2.7 Hz, 1 H), 6.50 (dd, J = 3.6, 2.7 Hz, 1 H), 3.71 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.7 (C=O), 133.0 (C), 131.4 (2 C), 131.1 (2 C), 128.4 (2 CH), 128.2 (CH), 126.6 (C), 126.3 (2 CH), 126.1 (2 CH), 125.4 (2 CH), 122.9 (C), 115.9 (CH), 113.6 (CH), 51.4 (OCH3). GC-MS (EI): m/z (%) = 301 (41) (M)+, 269 (85), 241 (100), 216 (16), 120 (2), 108 (2). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C20H16NO2: 302.11756; found: 302.11771.
Methyl 5-(thiophen-2-yl)-1H-pyrrole-2-carboxylate (3a) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 2-bromothiophene (145 µL, 245 mg, 1.5 mmol, 1.5 equiv) for 48 h. Yellow solid; yield: 190 mg (92%); mp 109 °C, lit[39] 105–106 °C; Rf = 0.30 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3303, 3101, 3071, 2945, 2841, 1687, 1522, 1477, 1321, 1267, 1140, 1085, 887, 753 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.47 (br s, 1 H), 7.25 (d, J = 4.0 Hz, 1 H), 7.23 (d, J = 4.0 Hz, 1 H), 7.04 (apparent t, J = 4.6 Hz, 1 H), 6.92 (apparent t, J = 3.2 Hz, 1 H), 6.43 (apparent t, J = 3.2 Hz, 1 H), 3.87 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.5 (C=O), 134.4 (C), 131.4 (C), 127.8 (CH), 124.6 (CH), 123.1 (CH), 122.6 (C), 116.8 (CH), 108.5 (CH), 51.7 (OCH3). GC-MS (EI): m/z (%) = 207 (100) (M)+, 175 (84), 147 (58), 121 (12), 103 (6), 93 (6), 77 (3). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C10H10NO2S: 208.04268; found: 208.04268.
Methyl 5-(5-formylthiophen-2-yl)-1H-pyrrole-2-carboxylate (3b) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 5-bromothiophene-2-carbaldehyde (178 µL, 287 mg, 1.5 mmol, 1.5 equiv) for 48 h. Yellow solid; yield: 181 mg (77%); mp 227–230 °C; Rf = 0.20 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3312, 2824, 2795, 1692, 1649, 1575, 1492, 1436, 1375, 1300, 1228, 1148, 1075, 998, 818 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.89 (s, 1 H), 9.29 (br s, 1 H), 7.71 (d, J = 4.0 Hz, 1 H), 7.27 (d, J = 4.0 Hz, 1 H), 6.94 (apparent t, J = 2.4 Hz, 1 H), 6.61 (apparent t, J = 3.1 Hz, 1 H), 3.90 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 182.4 (C=O), 161.1 (C=O), 143.6 (C), 141.8 (CH), 137.3 (CH), 129.6 (C), 124.5 (C), 123.3 (CH), 116.9 (CH), 110.9 (CH), 51.9 (OCH3). GC-MS (EI): m/z (%) = 235 (92) (M)+, 203 (100), 175 (37), 146 (24), 121 (9), 103 (4). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C11H10NO3S: 236.03759; found: 236.03645.
Methyl 5-(5-methylthiophen-3-yl)-1H-pyrrole-2-carboxylate (3c) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 4-bromo-2-methylthiophene (168 µL, 266 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 190 mg (86%); mp 173–176 °C; Rf = 0.30 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3315, 3106, 2948, 2873, 1684, 1501, 1436, 1347, 1269, 1237, 1140, 1051, 1003, 929, 875, 786 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.47 (br s, 1 H), 7.18 (d, J = 1.0 Hz, 1 H), 6.98 (s, 1 H), 6.92 (apparent t, J = 3.1 Hz, 1 H), 6.36 (apparent, J = 3.2 Hz, 1 H), 3.87 (s, 3 H), 2.50 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.8 (C=O), 141.0 (C), 133.4 (C), 132.6 (C), 123.5 (CH), 121.9 (C), 117.3 (CH), 116.7 (CH), 107.8 (CH), 51.6 (OCH3), 15.3 (CH3). GC-MS (EI): m/z (%) = 221 (100) (M)+, 189 (86), 161 (40), 146 (3), 135 (11), 128 (4), 116 (3), 91 (2), 89 (2). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C11H12NO2S: 222.05833; found: 222.05805.
Dimethyl 1H,1’H-[2,3’-bipyrrole]-5,5’-dicarboxylate (3d) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and methyl 4-bromo-1H-pyrrole-2-carboxylate (306 mg, 1.5 mmol, 1.5 equiv) for 48 h. Yellow solid; yield: 185 mg (75%); mp 203–206 °C; Rf = 0.20 (hexanes–CH2Cl2 1:3). FT-IR (ATR): 3320, 3291, 3134, 3001, 2950, 1680, 1610, 1549, 1513, 1442, 1359, 1192, 1069, 1008, 929, 754 cm−1. 1H NMR (700 MHz, CDCl3): δ = 9.23 (br s, 1 H), 9.15 (br s, 1 H), 7.18 (s, 1 H), 7.08 (s, 1 H), 6.92 (s, 1 H), 6.30 (apparent t, J = 2.9 Hz, 1 H), 3.89 (s, 3 H), 3.87 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 161.6 (C=O), 161.2 (C=O), 132.0 (C), 123.6 (C), 121.6 (C), 119.2 (CH), 118.2 (C), 116.8 (CH), 111.7 (CH), 106.9 (CH), 51.8 (OCH3), 51.5 (OCH3). GC-MS (EI): m/z (%) = 248 (72) (M)+, 216 (100), 184 (75), 156 (13), 129 (12), 102 (6). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H13N2O4: 249.08698; found: 249.08610.
Methyl 5-(pyridin-3-yl)-1H-pyrrole-2-carboxylate (3e) The general Suzuki procedure A was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 3-bromopyridine (145 µL, 237 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 155 mg (77%); mp 149–150 °C, lit[38] 147.9–149.4 °C; Rf = 0.20 (hexanes–EtOAc 2:1). FT-IR (ATR): 3312, 2952, 1683, 1561, 1469, 1333, 1276, 1194, 1121, 1076, 756 cm−1. 1H NMR (700 MHz, CDCl3): δ = 10.57 (br s, 1 H), 8.98 (d, J = 1.6 Hz, 1 H), 8.54 (d, J = 3.9 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.32 (dd, J = 7.8, 4.8 Hz, 1 H), 6.99 (apparent t, J = 3.4 Hz, 1 H), 6.60 (apparent t, J = 3.1 Hz, 1 H), 3.89 (s, 3 H). 13C NMR {1H} (176 MHz, CDCl3): δ = 162.0 (C=O), 148.5 (CH), 146.6 (CH), 134.0 (C), 132.3 (CH), 127.6 (C), 124.1 (C), 123.6 (CH), 117.1 (CH), 108.9 (CH), 51.9 (OCH3). GC-MS (EI): m/z (%) = 202 (100) (M)+, 170 (80), 142 (50), 115 (30), 89 (11), 63 (5). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C11H11N2O2: 203.08150; found: 203.08051.

4. Conclusions

In conclusion, methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate 1 was synthesized on 10-gram scale using iridium-catalyzed C–H borylation. The borylated pyrrole was successfully employed in Suzuki coupling reactions to prepare a variety of 5-(hetero)aryl substituted pyrrole-2-carboxylates. This catalytic borylation–Suzuki coupling synthetic route has several advantages over direct arylation protocols including compatibility with NH2, OH, and pyrrole N-H functional groups, retention of chloro substituents for further functionalization, installation of highly electron-rich aromatic rings, and preparation of bi-heteroaryls including α-β linked bi-pyrrole.

Supplementary Materials

The following are available online at https://www.mdpi.com/1420-3049/25/9/2106/s1, 1H and 13C NMR spectra of the synthesized compounds.

Author Contributions

Conceptualization, G.A.C.; methodology, G.A.C., and S.K.; validation, S.K., S.F., and M.I.; formal analysis, G.A.C.; investigation, S.K., N.-u.-A., S.F., A.-H.E., and M.A.; resources, X.G., and G.A.C.; data curation, A.-H.E., and G.A.C.; writing—original draft preparation, G.A.C., and S.K.; writing—review and editing, R.S.Z.S., S.F., M.I., and G.A.C.; visualization, G.A.C.; supervision, G.A.C.; project administration, G.A.C.; funding acquisition, M.A. and G.A.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by HIGHER EDUCATION COMMISION OF PAKISTAN, grant number NRPU-4426, and by LAHORE UNIVERSITY OF MANAGEMENT SCIENCES through start-up and faculty initiative fund to G.A.C.

Acknowledgments

We extend our acknowledgement to KAUST core labs facilities for NMR and HRMS measurements.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.
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Figure 1. Selected examples of 5-arylpyrrole-2-carboxylate based natural products, biologically active compounds, and organic materials.
Figure 1. Selected examples of 5-arylpyrrole-2-carboxylate based natural products, biologically active compounds, and organic materials.
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Figure 2. Various routes for the synthesis of aryl substituted pyrroles.
Figure 2. Various routes for the synthesis of aryl substituted pyrroles.
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Scheme 1. Iridium-catalyzed borylation of methyl 1-H pyrrole 2-carboxylate.
Scheme 1. Iridium-catalyzed borylation of methyl 1-H pyrrole 2-carboxylate.
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Scheme 2. Suzuki coupling reactions of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate with various aryl bromides.
Scheme 2. Suzuki coupling reactions of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate with various aryl bromides.
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Scheme 3. Suzuki couplings involving heteroaryl bromides.
Scheme 3. Suzuki couplings involving heteroaryl bromides.
Molecules 25 02106 sch003

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Kanwal, S.; Ann, N.-u.-; Fatima, S.; Emwas, A.-H.; Alazmi, M.; Gao, X.; Ibrar, M.; Zaib Saleem, R.S.; Chotana, G.A. Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling. Molecules 2020, 25, 2106. https://doi.org/10.3390/molecules25092106

AMA Style

Kanwal S, Ann N-u-, Fatima S, Emwas A-H, Alazmi M, Gao X, Ibrar M, Zaib Saleem RS, Chotana GA. Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling. Molecules. 2020; 25(9):2106. https://doi.org/10.3390/molecules25092106

Chicago/Turabian Style

Kanwal, Saba, Noor-ul- Ann, Saman Fatima, Abdul-Hamid Emwas, Meshari Alazmi, Xin Gao, Maha Ibrar, Rahman Shah Zaib Saleem, and Ghayoor Abbas Chotana. 2020. "Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling" Molecules 25, no. 9: 2106. https://doi.org/10.3390/molecules25092106

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