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

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.

Key words

boronic esters - pyrroline - pyrrole - Suzuki-Miyaura 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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• 8 Chung YJ. Lee CW. Tetrahedron Lett.  2000,  41:  3423 
• 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 
• 9b Alvarez A. Guzman A. Ruiz A. Velarde E. Muchowski JM. J. Org. Chem.  1992,  57:  1653 
• 9c D’Alessio R. Rossi A. Synlett  1996,  513 
• 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.