Synlett 2002(5): 0829-0831
DOI: 10.1055/s-2002-25351
LETTER
© Georg Thieme Verlag Stuttgart · New York

Suzuki Coupling Reactions in Heterocyclic Chemistry: Synthesis of 3-Substituted Pyrrolines and Pyrroles

Alain Hercoueta, Andreas Neua, Jean-François Peyronelb, Bertrand Carboni*a
a SESO, UMR CNRS 6510, Institut de Chimie, Université de Rennes, 1, Avenue du Général Leclerc, 35042 Rennes CEDEX, France
b Aventis Pharma, Paris Research Center, 13 quai Jules Guesde BP 14, 94403 Vitry sur Seine, France
e-Mail: bertrand.carboni@univ-rennes1.fr;
Further Information

Publication History

Received 1 February 2002
Publication Date:
07 February 2007 (online)

Abstract

A simple preparation of N-substituted 3-pyrroline boromic esters from primary amines is described. The Suzuki-Miyaura coupling of these heterocycles with aryl halides proceeds in good yields. Alternatively, oxidation with DDQ or MnO2 gives the corresponding pyrroles, which can be also engaged in subsequent palladium cross-coupling reactions.

    References

  • 1 Comprehensive Heterocyclic Chemistry II   Vol. 2:  Katritzky A. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  p.1-257  
  • 2a Sundberg RJ. In Comprehensive Heterocyclic Chemistry II   Vol. 2:  Katritzky A. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  p.119-206  
  • 2b Patel AV. Crabb TA. Second Supplements to the 2 nd Edition of Rodd’s Chemistry of Carbon Compounds, Heterocyclic Compounds, Part A: Three, Four and Five Membered Monoheterocyclic Compounds   Sainsbury M. Elsevier; Oxford: 1997.  p.457-556  
  • 2c Ketcha DM. In Progress in Heterocyclic Chemistry   Vol. 11:  Gribble G. W., Gilchrist T. L., Pergamon-Elsevier; Oxford: 1999.  p.124-143  
  • 2d Black DS. In Hetarenes and Related Ring Systems: Fully Unsaturated Small-Ring Heterocycles and Monocyclic Five-Membered Hetarenes with One Heteroatom   Vol. 9:  Maas G. Regitz M. Ley SV. Georg Thieme Verlag; Stuttgart, New York: 2001.  p.441-552  
  • 3 Anderson HJ. Loader CE. Synthesis  1985,  353 
  • 4 Campi EM. Fallon GD. Jackson WR. Nilsson Y. Aust. J. Chem.  1992,  45:  1167 
  • 5a Bean GP. In Pyrroles Part 1., The Synthese and the Physical and Chemical Aspects of the Pyrroles Ring   Jones RA. John Wiley and Sons; New York: 1990.  p.182-183  
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  • For some examples of synthesis and reactivity of pyrrole-2-boronic ester, see:
  • 9a Johnson CN. Stemp G. Anand N. Stephen SC. Gallagher T. Synlett  1998,  1025 
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  • 9d Martina S. Enkelmann V. Wegner G. Schluter AD. Synthesis  1991,  613 
  • 10 For a recent preparation of a N-(Boc)pyrrole-3-boronic ester, see: Renaud J. Ouellet SG. J. Am. Chem. Soc.  1998,  34:  7995 
  • 11 Kamabuchi A. Miyaura N. Suzuki A. Tetrahedron Lett.  1993,  34:  4827 
  • For similar reactions without the boronic moiety, see:
  • 12a Margaret M. Bowers N. Lee J. Jouille MM. Synth. Commun  1983,  13:  1117 
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13

A representative procedure is as follows: A solution of alkenylboronate 1 (1 mmol) and three equivalents of the amine in chloroform (5 mL) was stirred overnight at r.t. The residue obtained upon evaporation of the solvent was dissolved in 7 mL of acetonitrile and stirred for 2 h at r.t. with 6 mmol (828 mg) of K2CO3. Solids were removed by filtration and solvents were evaporated to dryness to afford a crude product, which was subjected to distillation under reduced pressure. Selected data: 2b: 1H NMR (300 MHz, CDCl3) δ 1.10 (d, J = 6.3 Hz, 6 H), 1.28 (s,12 H), 2.60 (sept, J = 6.3 Hz, 1 H), 3.52-3.63 (m, 4 H); 6.52 (s broad, 1 H). 13C NMR (75.5 MHz, CDCl3) δ 21.7, 24.7, 54.1, 59.0, 59.4, 83.3, 143.2. HRMS m/z calcd for C13H24BNO2 (M+) 237.1899, found 237.1902.

15

A representative procedure is as follows: A mixture of pyrroline boronic ester 2 (1 mmol), aryl halide (1.5 mmol), Pd(PPh3)4 (0.05 mmol) and CsF (4 mmol) in freshly distilled THF (10 mL) was heated at reflux under argon for 2 h. Saturated NH4Cl solution (10 mL) and diethyl ether (30 mL) were added to the cooled solution. Aqueous layer was extracted with diethyl ether and the combined extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and the resulting solution was treated with 1 mL of 1 M HCl. After eva-poration of the solvents, the mixture was washed with diethyl ether. The organic layer was discarded before treatment with 1 M NaOH (1 mL). The free pyrroline was extracted with CH2Cl2. Distillation of the solvent afforded oil, which was distilled with Kugelrohr. Selected data: 3e: 1H NMR (300 MHz, CDCl3) δ 2.32 (s, 3 H), 3.67-3.74 (m,
2 H), 3.85-3.93 (m, 4 H), 6.05 (dd, J = 1.7 and 2.0 Hz, 1 H), 6.25 (dd, J = 1.7 and 3.2 Hz, 1 H), 6.34 (dd, J = 2.0 and 3.2 Hz, 1 H), 7.10 (d, J = 7.9 Hz, 2 H), 7.25 (d, J = 7.9 Hz, 2 H), 7.35-7.40 (m, 1 H). 13C NMR (75.5 MHz, CDCl3) δ 21.2, 51.9, 59.6, 60.2, 107.6, 110.0, 120.7, 125.3, 129.1, 131.5, 137.3, 139.4, 142.0, 153.0. HRMS m/z calcd for C16H17NO (M+) 239.13101, found 239.1312.

17

A representative procedure is as follows: A chloroform solution (5 mL) of alkenylboronate 1 (1 mmol) and three equivalents of the amine was stirred overnight at r.t. The solvent was then evaporated in vacuo. After dilution of the residue in toluene (6 mL), 1 mmol of DDQ (227 mg) was added to the solution. The slurry was stirred at r.t. over night. The solvent was removed and the residue was washed with 2 × 20 mL of pentane, filtered through a pad of celite and concentrated in vacuo. The pyrrole 4 was purified by column chromatography on silica gel (EtOAc-heptane, 10:90). Selected data 4a: 1H NMR (300 MHz, CDCl3) δ 1.34 (s,
12 H), 5.05 (s, 2 H), 6.56 (t, J = 1.8 Hz, 1 H), 6.72 (t, J = 1.8 Hz, 1 H), 7.16-7.33 (m, 6 H). 13C NMR (75.5 MHz, CDCl3) δ 24.9, 53.4, 82.8, 114.6, 122.3, 127.4, 127.8, 128.8, 130.3, 137.6. HRMS m/z calcd for C17H22BNO2 (M+) 283.1743, found 283.11754.

19

A representative procedure is as follows: A mixture of pyr-roline 2b (1 mmol) and activated manganese oxide (870 mg, 10 mmol) in THF (12 mL) was heated under reflux for 48 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo The residue was purified by column chromatography on silica gel (EtOAc-Heptane, 10:90). Representative data for the selected compound 3e: 1H NMR (300 MHz, CDCl3) δ 1.30 (s, 12 H), 1.43 (d, J = 6.7 Hz, 6 H), 4.24 (sept., J = 6.7 Hz, 1 H), 6.47 (dd, J = 2.5 and 1.7 Hz, 1 H), 6.74 (t, J = 2.5 Hz, 1 H); 7.19 (t, J = 1.7 Hz, 1 H). 13C NMR (75.5 MHz, CDCl3) δ 23.9, 24.8, 50.9, 82.7, 113.7, 119.7, 127.3. HRMS m/z calcd for C13H22BNO2 (M+) 235.1746, found 235.11743.

20

A representative procedure is as follows: To a solution of pyrrole-3-boronate 4 (1 mmol) in THF (10 mL), under an argon atmosphere, were added CsCO3 (978 mg, 3 mmol), PdCl2(dppf)CH2Cl2 (72 mg, 0.090 mmol), aryl or heteroaryl iodide (290 mg, 1.5 mmol) and water (1 mL). The reaction mixture was stirred at reflux temperature for 18 h, then cooled to r.t. and partitioned between water (20 mL) and diethyl ether (50 mL × 3). The combined extracts were washed with 1 N HCl (20 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluting with EtOAc-Heptane 10:90). Selected data: 5b: 1H NMR (300 MHz, CDCl3) δ 5.06 (s, 2 H), 6.55 (dd, J = 1.8 and 2.8 Hz, 1 H), 6.73 (dd, J = 2.3 and 2.8 Hz, 1 H), 7.11 (dd, J = 2.3 and 1.8 Hz, 1 H), 7.20-7.35 (m, 5 H), 8.46-8.54 (m, 2 H). 13C NMR (75.5 MHz, CDCl3) δ 53.8, 106.8, 119.4, 119.7, 122.3, 123.1, 127.2, 128.0, 128.9, 137.2, 143.2, 149.9. HRMS m/z calcd for C16H14N2 (M+) 234.1157, found 234.1165.