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Synlett 2002(7): 1152-1154
DOI: 10.1055/s-2002-32578
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 2- and 3-Substituted N-Methylpyrroles

Elena Dvornikova, Krystyna KamieŇska-Trela*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw 01-224, Poland
Fax: +48(22)6326681; e-Mail: kkt@icho.edu.pl;
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Publication History

Received 17 April 2002
Publication Date:
07 February 2007 (online)

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Abstract

A reliable method of synthesis of 3-bromo-N-methylpyrrole by the use of N-bromosuccinimide and a catalytic amount of PBr3 is reported. The method described opens a facile route to a variety of 3-substituted pyrroles, which are otherwise difficult to access. In addition, conditions under which pure 2-bromo-N-methylpyrrole can be obtained have been established.

Key words

N-methylpyrrole - bromination - N-bromosuccinimide - 3-bromo-N-methylpyrrole - kinetically and thermodynamically controlled reactions

    References

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14

Typical procedure for the preparation of 3-bromo- N -methylpyrrole(2): N-Methylpyrrole (0.45 g, 5.6 mmol) was dissolved in THF (20 mL) and cooled to -78 °C (dry ice-acetone bath). PBr3 (0.1 g, 0.37 mmol; by syringe) and NBS (1.0 g, 5.6 mmol; by the use of glass-finger) were subsequently added, and the reaction mixture was stirred for 1 h at -78 °C. It was left overnight in a freezer (-10 °C) and afterwards Et3N (0.56 g, 5.6 mmol) and hexane (50 mL) were added. After stirring for 5 min, the precipitate was filtered off through a layer of 10 g of Al2O3 and the solution obtained dried over anhydrous Na2SO4. The solvents and excess of Et3N were removed under reduced pressure;
0.77 g (87%) of 3-bromo-N-methylpyrrole(2) was obtained as a bright yellow oil. The compound was stored at +4 °C for several weeks without any significant decomposition.
1H NMR (500.13 MHz, CDCl3, 30 °C): δ = 6.4 (t, 2 H, 4 J H2H5 = 2.4 Hz), 6.37 (t, 5 H), 6.0 (dd, 4 H, 4 J H2H4 = 1.7 Hz, 3 J H4H5 = 2.8 Hz), 3.4 (s, NCH 3); 13C NMR (125.75 MHz, CDCl3,
30 °C): δ = 121.5 (C5), 120.4 (C2), 110.1 (C4), 94.4 (C3), 35.6 (NCH 3 ). [22]

15

Typical procedure for the preparation of 2-bromo- N -methylpyrrole(3): To N-Methylpyrrole (0.38 g, 4.7 mmol) dissolved in THF (20 mL) and cooled in dry ice-acetone bath, NBS (0.84 g, 4.7 mmol) was added by the use of glass-finger. The reaction mixture was stirred for 1 h at -78 °C, and afterwards Et3N (0.47 g, 4.7 mmol) and hexane (50 mL) were added. After stirring for 5 min, the precipitate was filtered off through a layer of 10 g of Al2O3 and the solution dried over anhydrous Na2SO4. The solvents and excess of Et3N were removed under reduced pressure; 0.54 g (72%) of 2-bromo-N-methylpyrrole(3) as a bright yellow oil was obtained and stored for several weeks at +4 °C without any significant decomposition.
1H NMR (500.13 MHz, CDCl3, 30 °C): δ = 6.7 (dd, 5 H, 4 J H3H5 = 1.9 Hz, 3 J H4H5 = 2.9 Hz), 6.3 (dd, 3 H, 3 J H3H4 = 3.7 Hz), 6.2 (dd, 4 H), 3.6 (s, NCH 3); 13C NMR (125.75 MHz, CDCl3, 30 °C): δ = 122.2 (C5), 110.3 (C3), 108.6 (C4), 101.4 (C2), 34.6 (NCH 3). [22]

16

Typical procedure for the preparation of 3-substituted- N -methylpyrroles:3-triethylstannyl- N -methylpyrrole(5b): 3-Bromo-N-methylpyrrole (1.0 g, 6.24 mmol) was added dropwise to a stirred solution containing n-butyllithium in hexane
(6.87 mmol, 1.1 equiv), anhydrous THF (20 mL) and TMEDA (0.8 g, 6.87 mmol) at -78 °C (dry ice-acetone bath). After an additional period of 1 h, solution of triethylchlorstannane (1.66 g, 6.87 mmol) in dry THF (5 mL) was added dropwise for over 10 min. The cooling bath was then removed, the reaction mixture left for 4 h at room temperature and afterwards hydrolysed with water. The organic layer combined with ethereal extracts (3 × 15 mL) of the aqueous phase were dried over sodium sulphate and subsequently concentrated under reduced pressure. The yield of the crude product was 89% (1.58 g).
1H NMR (500.13 MHz, CDCl3, 30 °C): δ = 6.8 (t, 5 H, 4 J H2H4 ˜ 3 J H4H5 = 2.1 Hz), 6.6 (t, 2 H, 4 J H2H5 = 1.9 Hz), 6.2 (t, 4 H), 3.6 (s, NCH 3), 1.3 (t, 9 H, SnCH2 CH 3, 3 J = 7.7 Hz), 1.0 (q, 6 H, SnCH 2CH3); 13C NMR (125.75 MHz, CDCl3, 30 °C): δ = 127.4 (C2, 2 J SnC2 = 31.4 Hz), 122.3 (C5, 3 J SnC5 = 20 Hz), 114.8 (C4, 2 J SnC4 = 16.2 Hz), 111.4 (C3, 1 J SnC3 = 219.4 Hz), 35.1 (NCH 3), 10.6 (SnCH2 CH 3 , 2 J SnCH3 = 12.1 Hz), 0.3 (SnCH 2 CH3, 1 J SnCH2 = 178.9 Hz); 14N NMR (36.14 MHz, CDCl3, 30 °C): δ = -230.3 (s, NCH3); 117Sn NMR (178.2 MHz, CDCl3, 30 °C): δ = -50.6 (s, SnEt). HMRS: m/z calcd for C9H16N120Sn: 258.03047; found: 258.03054 (peak corresponding to M-29).

17

3-Trimethylsilylo- N -methylpyrrole(5a): Was obtained according to the procedure in ref. [16] starting from 1.0 g (6.24 mmol) of 3-bromo-N-methylpyrrole and using trimethylchlorosilane (0.74 g, 6.87 mmol). Yield of 5a was 0.83 g, (87%).
1H NMR (500.13 MHz, CDCl3, 30 °C): δ = 6.9 (m, 5 H, H2), 6.6 (t, 4 H, 4 J H2H4 ˜ 3 J H4H5 = 1.8 Hz), 3.9 (s, NCH 3 ), 0.6 (s, 9 H, SiCH 3 ); 13C NMR (125. 75 MHz, CDCl3, 30 °C): δ = 126.6 (C2), 122.3 (C5), 117.1 (C3), 112.9 (C4), 34.7 (NCH 3), -0.5 (SiCH 3); 14N NMR (36.14 MHz, CDCl3, 30 °C): δ = -225.5 (s, NCH3). [22]

18

3-Methylthio- N -methylpyrrole(5c): Was obtained according to the procedure described in ref. [16] starting from 1.0 g (6.24 mmol) of 3-bromo-N-methylpyrrole and using dimethyldisulfide (0.64 g, 6.87 mmol). Yield of 5c was 0.66 g, (83%).
1H NMR (500.13 MHz, CDCl3, 30 °C): δ = 6.6 (t, 2 H, 4 J H2H5 ca. 2 Hz), 6.4 (t, 5 H), 6.1 (dd, 4 H, 4 J H2H4 = 1.7 Hz, 4 J H4H5 = 2.7 Hz), 3.4 (s, NCH 3 ), 2.2 (s, SCH 3); 13C NMR (125.27, MHz, CDCl3, 30 °C): δ = 123.1 (C2), 121.7 (C5), 114.1 (C3), 111.3 (C4), 35.4 (NCH 3), 20.2 (SCH 3); 14N NMR (36.14, CDCl3, 30 °C): δ = -231.7 (s, NCH3). [22]

19

Compounds 2, 3, 5 are very sensitive to acids e.g. full decomposition occurs on SiO2.

21

The INADEQUATE spectra have been measured for all the compounds described in the present work and the determined 1 J CC couplings will be a subject of a separate paper.

22

All the data are in agreement with those reported in the literature.