Regioselective Suzuki Cross-Coupling Reactions at the 2-Position of Di- and Tribrominated Pyrroles

Abstract

The 2,3,4-tribromopyrrole 4 and the 2,3-dibromopyrrole 10 were shown to undergo regioselective Suzuki cross-coupling ­reactions at the 2-position. After optimization best yields in the ­reaction with 4-tert-butylphenyl boronic acid (5a) were 68% and 86%. Other boronic acids 5 were employed in the reaction with pyrrole 4 and gave the monosubstitution products 6 in 33-52% yield. A subsequent cross-coupling at positions C-3 and C-4 could be achieved on 3,4-dibromopyrrole 6a (84% yield).

catalysis - cross-coupling - heterocycles - palladium - pyrroles - regioselectivity

References

1a Li JJ. Gribble GW. Palladium in Heterocyclic Chemistry   Pergamon Press; Oxford: 2000. 

1b Kalinin VN. Synthesis  1992,  413 

2 Review: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 

3a Bach T. Krüger L. Tetrahedron Lett.  1998,  39:  1729 

3b Bach T. Krüger L. Synlett  1998,  1185 

3c Bach T. Krüger L. Eur. J. Org. Chem.  1999,  2045 

4 For cross-coupling studies by other groups on 2,3-dibromofurans, see: Brandsma L. Vasilevsky SF. Verkruijsse HD. Application of Transition Metal Catalysts in Organic Synthesis   Springer; Berlin: 1999.  p.223 

5a Bach T. Bartels M. Synlett  2001,  1284 

5b Bach T. Bartels M. Tetrahedron Lett.  2002,  43:  9125 

5c Bach T. Bartels M. Synthesis  2003,  925 

6 For related cross-coupling studies by other groups, see: Lin S.-Y. Chen C.-L. Lee Y.-J. J. Org. Chem.  2003,  68:  2968 

7a Bach T. Heuser S. Tetrahedron Lett.  2000,  41:  1707 

7b Bach T. Heuser S. Angew. Chem. Int. Ed.  2001,  40:  3184 

7c Bach T. Heuser S. Synlett  2002,  2089 

7d Bach T. Heuser S. Chem. Eur. J.  2002,  8:  5585 

7e Bach T. Heuser S. J. Org. Chem.  2002,  67:  5789 

7f Spieß A. Heckmann G. Bach T. Synlett  2004,  131 

7g Heckmann G. Bach T. Angew. Chem. Int. Ed.  2005,  44:  1199 

For cross-coupling studies by other groups on 2,4-dibromothiazole, see:

8a Nicolaou KC. He Y. Roshangar F. King NP. Vourloumis D. Li T. Angew. Chem. Int. Ed.  1998,  37:  84 

8b Nicolaou KC. King NP. Finlay MRV. He V. Roshangar F. Vourloumis D. Vallberg H. Sarabia F. Ninkovic S. Hepworth D. Bioorg. Med. Chem.  1999,  7:  665 

8c Shao J. Panek JS. Org. Lett.  2004,  6:  3083 

9 Iwao M. Takeuchi T. Fujikawa N. Fukuda T. Ishibashi F. Tetrahedron Lett.  2003,  44:  4443 

10a Muchowski JM. Naef R. Helv. Chim. Acta  1984,  67:  1168 

10b Bray BL. Mathies PH. Naef R. Solas DR. Tidwell TT. Artis DR. Muchowski JM. J. Org. Chem.  1990,  55:  6317 

10c Banwell MG. Flynn BL. Hamel E. Hockless DCR. Chem. Commun.  1997,  207 

10d Garg NK. Caspi DD. Stoltz BM. J. Am. Chem. Soc.  2004,  126:  9552 

10e Marfil M. Albericio F. Álvarez M. Tetrahedron  2004,  60:  8659 

11a Chan H.-W. Chan P.-C. Liu J.-H. Wong HNC. Chem. Commun.  1997,  1515 

11b Liu J.-H. Chan H.-W. Wong HNC. J. Org. Chem.  2000,  65:  3574 

11c Liu J.-H. Yang Q.-C. Mak TCW. Wong HNC. J. Org. Chem.  2000,  65:  3587 

11d Handy ST. Zhang Y. Bregman H. J. Org. Chem.  2004,  69:  2362 

12 Blicke FF. Blake ES. J. Am. Chem. Soc.  1930,  52:  235 

13 Balaganesan B. Shen W.-J. Chen CH. Tetrahedron Lett.  2003,  44:  5747 

14a Miyaura N. Yamada K. Suzuki A. Tetrahedron Lett.  1979,  20:  3437 

14b Miyaura N. Yamada K. Suginome H. Suzuki A. J. Am. Chem. Soc.  1985,  107:  972 

14c Review: Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 

15 Farina V. Krishnan B. J. Am. Chem. Soc.  1991,  113:  9585 

16

Typical Procedure.
A Schlenk flask was charged with tribromopyrrole 4 (188 mg, 0.5 mmol), boronic acid 5a (107 mg, 0.6 mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol) and Cs₂CO₃ (198 mg, 0.6 mmol). The flask was evacuated and flushed with argon (five cycles). Mesitylene (5 mL), EtOH (1 mL) and H₂O (1 mL) were added. The flask was once again purged with argon. The reaction mixture was heated to 150 °C and stirred for 20 h. Then, H₂O (4 mL) was added and the aqueous layer was extracted with toluene (3 × 5 mL). The combined organic layers were washed with H₂O (25 mL) and brine (25 mL) and dried over Na₂SO₄. After filtration and removal of the solvents the crude product was purified by flash chromatograpy (silica, pentane-Et₂O, 3:1) to give pyrrole 6a (142 mg, 0.33 mmol, 66%) as a white solid; mp 162-164 °C. ¹H NMR (360 MHz, CDCl₃): δ = 1.36 (s, 9 H), 1.38 (t, ³ J = 7.2 Hz, 3 H), 4.34 (q, ³ J = 7.2 Hz, 2 H), 7.49 (d, ³ J = 8.4 Hz, 2 H), 7.62 (d, ³ J = 8.4 Hz, 2 H), 9.55 (br s, 1 H) ppm. ¹³C NMR (90.6 MHz, CDCl₃): δ = 14.5, 31.4, 35.0, 61.4, 101.1, 108.0, 120.3, 126.0, 127.3, 127.3, 134.0, 152.5, 160.0 ppm. Anal. Calcd for C₁₇H₁₉Br₂NO₂ (429.15): C, 47.58; H, 4.46; N, 3.26. Found: C, 47.37; H, 4.42; N, 3.09.

17 Morgan KJ. Morrey DP. Tetrahedron  1966,  22:  57