2-Bromo-N-(p-toluenesulfonyl)pyrrole: A Robust Derivative of 2-Bromopyrrole

Abstract

2-Bromo-N-(p-toluenesulfonyl)pyrrole (2), a crystalline stable derivative of 2-bromopyrrole (1) has been prepared in 80% yield by bromination of pyrrole, followed by conversion to the N-(p-toluenesulfonyl) derivative. This compound is stable indefinitely at ambient temperature. Compound 2 is an excellent substrate for Suzuki coupling with arylboronic acids.

2-arylpyrroles - radical reactions - Suzuki coupling - palladium catalysis - p-toluenesulfonyl protecting group

References

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21b

Although the ¹H NMR data reported by these authors agree with ours, these authors report a mp of 122-123 °C, while in several preparations of 2, we find a mp of 105-106 °C (see ref. [23] ).

22 Knight LW. Padgett CW. Huffman JW. Pennington WT. Acta Crystallogr., Sect. E  2003,  59:  762 

23

Experimental Procedure for the Preparation of 2. To a solution of 3.1 mL of 1 (44.7 mmol) in 120 mL of freshly distilled THF in a flame-dried flask under N₂ at -78 °C was added 6.53 g (22.4 mmol) of 1,3-dibromo-5,5-dimethyl-hydantoin. The mixture was stirred for 30 min and allowed to stand for an additional 3.5 h under ambient room light at -78 °C. To this solution were added 4 mL of Bu₃N and 180 mL of freshly distilled Et₂O and the mixture was stirred for 10 min at -78 °C. The resulting gray precipitate was removed by filtration(vacuum) and the solution was concentrated in vacuo to remove the Et₂O. To this solution was added 17.04 g (89.4 mmol) of p-toluenesulfonyl chloride and the inert atmosphere was reestablished. The solution was cooled to 0 °C and 5.36 g (134.0 mmol) of NaH (60% in mineral oil) was added cautiously. The mixture was stirred for 18 h at ambient temperature and 60 mL of H₂O were added. The mixture was extracted with Et₂O and the ether extracts were washed with successive portions of 1 M HCl and sat. aq NaHCO₃. This mixture was combined with an equal volume of 2 M NaOH and was stirred for 2 h at r.t. The layers were separated and the organic extract was washed repeatedly with H₂O and 2 M NaOH. The organic layer was dried (MgSO₄) and concentrated in vacuo to give a light brown solid. Recrystallization from isopropyl alcohol gave 10.73 g (80%) of 2-bromo-1-(p-toluenesulfonyl)pyr-role as a white crystalline solid: mp 105-106 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.43 (s, 3 H), 6.23-6.29 (m, 2 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.46 (dd, J = 2.0, 3.5 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 2 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 145.5, 135.1, 129.9, 127.8, 124.2, 117.9, 113.5, 112.5, 100.0, 21.7. MS (EI): m/z (%) = 301 (27), 299 (28), 155 (56), 91 (100). Anal. Calcd for C₁₁H₁₀BrNO₂S: C, 44.02; H, 3.36; N, 4.67. Found: C, 44.65; H, 3.36; N, 4.67. Although this compound is homogeneous to TLC, GC/MS, ¹H and ¹³C NMR, aceptable analytical data could not be obtained.

24 Miyaura N. Yanagi T. Suzuki A. Synth. Commun.  1981,  11:  513 

25

Experimental Procedure for the Preparation of 4 (Ar = 4-Methoxyphenyl). A mixture of 0.020 g (0.02 mmol) of Pd(PPh₃)₄ and 4.4 mL of distilled toluene was stirred under an inert atmosphere for 5 min at ambient temperature, and 0.470 g (1.6 mmol) of 2-bromo-N-p-toluenesulfonylpyrrole was added as a solid, followed by 0.256 g (2.4 mmol) of Na₂CO₃ in 2.2 ml of H₂O. To this mixture was added 0.250 g (1.6 mmol) of 4-methoxy-phenylboronic acid in 3 mL of 95% EtOH. The mixture was heated at reflux for 6 h, cooled to ambient temperature, and extracted into EtOAc. The combined organic extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo to give a brown solid. Recrystallization from 2-propanol gave 0.412 g (80%) of 2-(4-methoxyphenyl)-N-tosylpyrrole as a white crystalline solid: mp 120-121 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.34 (s, 3 H), 3.84 (s, 3 H), 6.10 (dd, J = 1.8, 3.0 Hz, 1 H), 6.28 (t, J = 3.4 Hz, 1 H), 6.81-6.86 (m, 2 H), 7.09-7.17 (m, 4 H), 7.25-7.26 (m, 2 H), 7.41 (dd, J = 1.8, 3.1 Hz, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.5, 55.2, 111.9, 112.7, 115.3, 123.7, 127.1, 129.3, 132.2. MS (EI): m/z (%) = 327 (17), 172 (100). Anal. Calcd for C₁₈H₁₇NO₃S: C, 66.03; H, 5.23; N, 4.28. Found: C, 66.27; H, 5.31; N, 4.31.
Compound 3 (Ar = Phenyl): mp 123-124 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.35 (s, 3 H), 6.15 (dd, J = 1.7, 3.2 Hz, 1 H), 6.30 (t, J = 3.3 Hz, 1 H), 7.09 (d, J = 8.3 Hz, 2 H), 7.21-7.38 (m, 7 H), 7.44 (dd, J = 1.7, 3.3 Hz, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.6, 112.0, 115.7, 124.1, 127.1, 127.3, 128.2, 129.3, 130.9, 131.4, 135.6, 136.0, 144.6. MS (EI): m/z (%) = 297 (38), 142 (100). Anal. Calcd for C₁₇H₁₅NO₂S: C, 68.66; H, 5.08, N, 4.71. Found: C, 68.39; H, 5.03, N, 4.56.
Compound 3 (Ar = 4-Methylphenyl): mp 120-121 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.34 (s, 3 H), 2.39 (s, 3 H), 6.11 (dd, J = 1.7, 3.2 Hz, 1 H), 6.28 (t, J = 3.3 Hz, 1 H), 7.06-7.12 (m, 6 H), 7.24-7.16 (m, 2 H), 7.41 (dd, J = 1.8, 3.3 Hz, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.3, 21.5, 112.0, 115.5, 123.9, 127.0, 128.0, 128.5, 129.3, 130.7, 135.7, 136.1, 138.0, 144.5. MS (EI): m/z (%) = 311 (40), 156 (100). Anal. Calcd for C₁₈H₁₇NO₂S: C, 69.43; H, 5.50, N, 4.50. Found: C, 69.69; H, 5.51, N, 4.42.
Compound 3 (Ar = 3-Chlorophenyl): mp 91-92 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.37 (s, 3 H), 6.16-6.17 (m, 1 H), 6.30 (t, J = 3.2 Hz, 1 H), 7.04-7.34 (m, 8 H), 7.45-7.46 (m, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.5, 111.9, 116.1, 124.4, 127.0, 128.2, 128.7, 129.2, 129.4, 130.6, 133.1, 134.1, 135.4, 145.0. MS (EI): m/z (%) = 331 (37), 176 (100). Anal. Calcd for C₁₇H₁₄ClNO₂S: C, 61.53; H, 4.25; N, 4.22. Found: C, 61.25; H, 4.34; N, 4.25.
Compound 3 (Ar = 1-Naphthyl): mp 146-147 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.18 (s, 3 H), 6.26 (dd, J = 1.7, 2.2 Hz, 1 H), 6.41 (t, J = 3.3 Hz, 1 H), 6.79 (d, J = 8, 2 Hz, 2 H), 7.03 (d, J = 8.3 Hz, 2 H), 7.09-7.26 (m, 2 H), 7.33-7.44 (m, 3 H), 7.59 (dd, J = 1.7, 3.3 Hz, 1 H), 7.77 (d, J = 8.2 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.3, 111.0, 116.5, 122.8, 124.4, 125.3, 125.8, 127.2, 127.6, 128.6, 129.0, 129.1, 130.5, 131.9, 132.9, 133.7, 135.0, 144.4. MS (EI): m/z (%) = 347(34), 192(100); Anal. Calcd for C₂₁H₁₇NO₂S: C, 72.60; H, 4.93; N, 4.03. Found: C, 72.36; H, 4.96; N, 3.99.
Compound 3 (Ar = 3-Nitrophenyl): pale pink gum. ¹H NMR (300 MHz, CDCl₃): δ = 2.36 (s, 3 H), 6.27 (dd, J = 1.7, 3.1 Hz, 1 H), 6.36 (t, J = 3.3 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 2 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.49 (dd, J = 1.6, 3.9 Hz, 1 H), 7.53 (d, J = 7.9 Hz, 1 H), 7.68 (dt, J = 1.3, 7.7 Hz, 1 H), 7.94 (t, J = 1.9 Hz, 1 H), 8.18-8.22 (m, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.5, 112.4, 117.1, 122.9, 125.0, 125.1, 126.8, 128.3, 129.6, 133.0, 135.3, 136.9, 145.3, 147.3. MS (EI): m/z (%) = 342 (100), 203 (26). HRMS calcd for C₁₇H₁₄N₂O₄S: 342.0674. Found: 342.0670.

26

A mixture of 0.050 g (0.15 mmol) of 2-(4-methoxyphenyl)-N-tosylpyrrole in 0.6 mL of EtOH and 0.2 mL of 15% ethanolic NaOH was stirred at reflux temperature for 3 h. The solution was concentrated in vacuo; the residue was dissolved in CH₂Cl₂ and washed with H₂O. The organic layer was dried (MgSO₄) and concentrated in vacuo to give 0.025 g (97%) of 2-(4-methoxyphenyl)pyrrole as a white solid: mp 143-144 °C (lit. mp 147 °C²⁷). ¹H NMR (300 MHz, CDCl₃): δ = 3.81 (s, 3 H), 6.27 (dd, J = 2.8, 5.7 Hz, 1 H), 6.40 (t, J = 3.5 Hz, 1 H), 6.79 (dd, J = 2.4, 3.9 Hz, 1 H), 6.88-6.91 (m, 2 H), 7.36-7.39 (m, 2 H), 8.32 (br s, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 55.3, 104.8, 109.9, 114.3, 118.1, 125.2, 125.9, 132.1, 158.2. MS (EI): m/z (%) = 245 (7), 173 (70), 158 (100). The spectroscopic data agree with those reported previously. [27]

27 Laatsch H. Pudleiner H. Liebigs Ann. Chem.  1989,  863