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Synlett 2008(2): 185-188  
DOI: 10.1055/s-2007-1000880
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Tetrasubstituted 2-Aryl-3-arylsulfonyl Pyrroles: Unexpected Regioselectivity in Directed ortho-Metallation Reactions

Nick Bailey, Emmanuel Demont*, Neil Garton, Hui-Xian Seow
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Fax: +44(127)9627685; e-Mail: emmanuel.h.demont@gsk.com;
Further Information

Publication History

Received 10 September 2007
Publication Date:
21 December 2007 (online)

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Abstract

3-Arylsulfonyl pyrroles can be readily obtained from 3-Br-TIPS pyrrole via halogen-metal exchange and subsequent sulfonylation. The regioselectivity of the subsequent directed ortho-metallation (DOM) reaction in order to functionalise the C-2 position depends on the nature of the base (LTMP, n- or s-BuLi) and the N-substituent (SEM or Boc) used. The bulk of the N-substituent also strongly influences the yield of the subsequent Suzuki coupling with 2-iodo-3-arylsulfonyl pyrrole derivatives.

Key words

phenylsulfonyl fluoride - 3-sulfonyl pyrrole - directed ortho-metallation - palladium - Suzuki coupling

2

A search for the pyrrole core in WDI database retrieved more than 160 hits.

15

In a previous attempt using 2-Br-3-PhSO2 pyrrole, no Suzuki coupling was effective, possibly due to the acidity of the N-1 hydrogen; results to be published.

17

At 100 °C, the ratio of 10 and 6b was 1.85:1 according to the 1H NMR of the crude reaction. This ratio was at least 95:5 at 50 °C. Lower temperatures were not considered.

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Regioselectivity of every reaction leading to 13 was confirmed unambiguously by NOE experiments. Compound 13 (pale yellow solid) has the following characteristics: mp 152-153 °C. 1H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3 H), 7.14 (d, J = 6.8 Hz, 2 H), 7.28 (d, J = 7.2 Hz, 2 H), 7.42-7.48 (m, 5 H), 7.51-7.55 (m, 1 H), 7.55 (s, 1 H), 9.65 (s, 1 H). 13C NMR (100.6 MHz, CDCl3): δ = 34.4, 124.1, 125.1, 127.2, 127.3, 128.4, 128.6, 130.1, 130.6, 130.8, 132.7, 142.0, 143.1, 180.0. MS (ESI): m/z = 326.0 [M + H]+.

20

Typical Procedures:
Compound 5b: To a solution of 3-bromo-1-[tris(1-methyl­-ethyl)silyl]-1H-pyrrole (12.8 g, 42.4 mmol, 1 equiv) in THF (200 mL) at -78 °C under nitrogen was slowly added n-BuLi (2.5 M in hexanes, 17.8 mL, 44.5 mmol, 1.05 equiv) over 3 min and the resulting mixture was stirred for 15 min at this temperature. Phenylsulfonyl fluoride (7.5 g, 46.6 mmol, 1.1 equiv) in THF (20 mL) was added via syringe over 5 min and the resulting mixture was stirred for 45 min at this temperature, then partitioned between EtOAc (200 mL) and brine (100 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (200 mL) and TBAF (1 M in THF, 42 mL, 1 equiv) was added and the resulting mixture was stirred for 30 min and then dissolved with EtOAc (200 mL). The organic phase was washed with a sat. aq NaHCO3 solution (3 × 30 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (isohexane-EtOAc, 3:1 → 1:1) gave 3-(phen­-ylsulfonyl)-1H-pyrrole (5b; 5.53 g, 63%) as a white solid; mp 145-145 °C. 1H NMR (400 MHz, CDCl3): δ = 6.48 (m, 1 H), 6.78 (m, 1 H), 7.38 (m, 1 H), 7.45-7.55 (m, 3 H), 7.92 (m, 2 H).13C NMR (100.6 MHz, CDCl3): δ = 108.4, 120.4, 122.4, 124.6, 127.2, 129.0, 132.6, 143.3. MS (ESI): m/z = 208.1 [M + H]+.
Compound 9: To a solution 3-(phenylsulfonyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-pyrrole (1.3 g, 3.86 mmol, 1 equiv) in THF (30 mL) at -78 °C under nitrogen was added LTMP (0.5 N in THF, 8.9 mL, 4.45 mmol, 1.15 equiv) over 1 min and the resulting mixture was stirred at this temperature for 50 min. Iodine (1.22 g, 4.82 mmol, 1.25 equiv) in THF (7 mL) was slowly added via syringe over 1 min. After 2 min, the mixture was partitioned between EtOAc (100 mL) and a 10% aq Na2S2O3 solution (100 mL). The two layers were vigorously stirred for 5 min. Brine (10 mL) was added and the two layers were separated. The aqueous layer was extracted with EtOAc (20 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (isohexane-EtOAc, 95:5 → 4:1) gave 2-iodo-3-(phenyl­-sulfonyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-pyrrole (9; 1.71 g, 96%) as a white solid; mp 75-76 °C. 1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 9 H), 0.94 (t, J = 8.8 Hz, 2 H), 3.54 (t, J = 8.8 Hz, 2 H), 5.29 (s, 2 H), 6.94 (d, J = 3.2 Hz, 1 H), 7.13 (d, J = 3.2 Hz, 1 H), 7.52-7.63 (m, 3 H), 8.06 (d, J = 6.4 Hz, 2 H).13C NMR (100.6 MHz, CDCl3): δ = 0.0, 19.1, 68.0, 76.9, 81.1, 114.4, 127.5, 128.8, 130.3, 131.1, 134.2, 143.8. MS (ESI): m/z = no molecular ion.
Compound 10: A flask was charged under nitrogen with 2-iodo-3-(phenylsulfonyl)-1-({[2-(trimethylsilyl)eth­-yl]oxy}methyl)-1H-pyrrole (9; 1.04 g, 2.25 mmol, 1 equiv), Pd(OAc)2 (50 mg, 0.22 mmol, 0.1 equiv), K3PO4 (952 mg, 4.49 mmol, 2 equiv), 2′-(dicyclohexylphosphanyl)-N,N-dimethyl-2-biphenylamine (176 mg, 0.45 mmol, 0.2 equiv) and PhB(OH)2 (411 mg, 3.37 mmol, 1.5 equiv), then toluene (20 mL) was added and the resulting mixture was stirred at 50 °C for 4 h and then cooled to r.t. The mixture was dissolved with EtOAc (50 mL) and the organic phase was washed with a sat. NaHCO3 solution, then with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (isohexane-EtOAc: 9:1 → 3:1) gave 10 (790 mg, 85%) as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = 0.0 (s, 9 H), 0.83 (t, J = 8.4 Hz, 2 H), 3.36 (t, J = 8.4 Hz, 2 H), 5.01 (s, 2 H), 6.87 (d, J = 2.8 Hz, 1 H), 6.92 (d, J = 2.8 Hz, 1 H). 7.26-7.56 (m, 10 H).13C NMR (100.6 MHz, CDCl3): δ = 0.0, 67.7, 77.4, 111.6, 124.8, 128.4, 129.4, 129.9, 130.1, 130.7, 132.9, 133.6, 137.7, 144.7. MS (ES): m/z = 413.9 [M + H]+.