A Novel Approach to the Synthesis of Highly Functionalized Pyrroles

Abstract

A new and efficient one-pot synthesis of polysubstituted pyrrole derivatives by a three-component reaction between dialkyl acetylenedicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals is described. The reactions were performed in dichloro­methane at room temperature and neutral conditions and afforded high yields of products.

pyrrole derivatives - dialkyl acetylenedicarboxylates - triphenylphosphine - multicomponent reaction - intramolecular ­Wittig reaction

References and Notes

1 Yates FS. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Boulton AJ. McKillop A. Pergamon; Oxford: 1984.  p.511 

2 Jones RA. In Pyrroles: The synthesis, Reactivity, and Physical Properties of Substituted Pyrroles   Part 2:  Wiley; New York: 1992. 

3 Gilchrist TL. J. Chem. Soc., Perkin Trans. 1  2001,  2491 

4 Trost BM. Dake GR. J. Am. Chem. Soc.  1997,  119:  7595 

5 Nair V. Nair JS. Vinod AU. Rath NP. J. Chem. Soc., Perkin Trans. 1  1997,  329 

6 Anary-Abbasinejad M. Anaraki-Ardakani H. Hosseini-Mehdiabad H. Phosphorus, Sulfur Silicon Relat. Elem.  2008,  183:  1440 

7 Yavari I. Hekmat-Shoar R. Zonouzi A. Tetrahedron Lett.  1998,  39:  2391 

8 Yavari I. Adib M. Hojabri L. Tetrahedron  2002,  58:  7213 

9 Anary-Abbasinejad M. Mosslemin MH. Hassanabadi A. Tabatabaee M. Synth. Commun.  2008,  38:  3700 

10 Evans LA. Griffiths KE. Guthmann H. Murphy PJ. Tetrahedron Lett.  2002,  43:  299 

11 Mosslemin MH. Yavari I. Anary-Abbasinejad M. Nateghi MR. Synthesis  2004,  1029 

12 Anary-Abbasinejad M. Anaraki-Ardakani H. Dehghan A. Hassanabadi A. Seyedmir MR. J. Chem. Res.  2007,  574 

13

General Procedure for the Preparation of Compounds 6a-h
To a magnetically stirred solution of Ph₃P (1 mmol) and aniline derivative (1 mmol) in CH₂Cl₂ (10 mL) was added dropwise a mixture of dialkyl acetylenedicarboxylate (1 mmol) in CH₂Cl₂ (3 mL) at r.t. over 2 min. The reaction mixture was then stirred for one more minute. Arylglyoxal (1 mmol) was added, and the reaction mixture was stirred for more 24 h. Solvent was evaporated, and the residue was purified by column chromatography on SiO₂ using EtOAc-hexane (1:4) mixture as eluent.

14

Dimethyl 5-(4-Nitrophenyl)-1-(phenyl)-pyrrole-2,3-dicarboxylate (6a)
Yellow powder, mp 115-117 ˚C. IR (KBr): ν_max = 1716, 1720 (C=O) cm^-¹. Anal. Calcd (%) for C₂₀H₁₆N₂O₆ (380.35): C, 63.16; H, 4.24; N, 7.37. Found: C, 63.27; H, 4.19; N, 7.65. ^¹H NMR (500 MHz, CDCl₃): δ = 3.72 and 3.85 (6 H, 2 s, 2 OCH₃), 7.09 (1 H, s, CH of pyrrole), 7.34 (2 H, m, 2 CH of C₆H₅), 7.48 (3 H, m, 3 CH of C₆H₅), 7.58 (2 H, d, J = 9 Hz, 2 CH of C₆H₄NO₂), 8.20 (2 H, d, J = 9 Hz, 2 CH of C₆H₄NO₂). ^¹³C NMR (125.8 MH_Z, CDCl₃): δ = 52.6 and 52.9 (2 OCH₃), 121.2, 123.3, 124.3, 125.4, 126.3, 126.6, 128.8, 129.3, 129.6, 139.3, 140.5, 147.1 (arom.), 160.8 and 166.3 (2 C=O, ester). MS: m/z (%) = 380 (100) [M⁺ ].

15

Dimethyl 1-(4-Methylphenyl)-5-(4-nitrophenyl)-pyrrole-2,3-dicarboxylate (6b)
Yellow powder, mp 148-150 ˚C. IR (KBr): ν_max = 1717 (C=O) cm^-¹. Anal. Calcd (%) for C₂₁H₁₈N₂O₆ (394.38): C, 63.96; H, 4.60; N, 7.10. Found: C, 63.67; H, 4.71; N, 7.29. ^¹H NMR (500 MHz, CDCl₃): δ = 2.24 (3 H, s, CH₃), 3.55 and 3.67 (6 H, 2 S, 2 OCH₃), 6.87 (1 H, s, CH pyrrol), 7.07 (4 H, m, arom.), 7.41 (2 H, d, J = 9 Hz, 2 CH arom.), 8.05 (2 H, d, J = 9 Hz, 2 CH arom.). ^¹³C NMR (500 MHz, CDCl₃): δ = 21.2 (CH₃), 52.2 and 52.5 (2 OCH₃), 120.6, 122.7, 123.9, 125.7, 126.2, 128.3, 129.7, 131.1, 136.4, 139.0, 140.1, 146.7 (arom.), 160.4, 166.7 (2 C=O, ester). MS: m/z (%) = 394 (100) [M⁺ ].

16

Di( tert -butyl) 1-(4-Methylphenyl)-5-(4-nitrophenyl)-pyrrole-2,3-dicarboxylate (6c)
Yellow oil. IR (KBr): ν_max = 1709 (C=O, ester) cm^-¹. Anal. Calcd (%) for C₂₇H₃₀N₂O₆ (478.54): C, 67.77; H, 6.32; N, 5.85. Found: C, 67.92; H, 6.10; N, 5.97. ^¹H NMR (500 MHz, CDCl₃): δ = 1.31 (9 H, s, t-Bu), 1.48 (9 H, s, t-Bu), 2.41 (3 H, s, CH₃₎, 6.91 (1 H, s, CH pyrrole(, 7.19 (4 H, m, arom.), 7.58 and 8.20 (4 H, 2 d, ^³ J _HH = 8 Hz, arom.). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.5 (CH₃), 28.2 and 28.4 (6 CH₃ of 2 t-Bu), 82.3 and 82.7 (2 C of 2 t-Bu), 121.5, 123.2, 124.0, 125.1, 126.2, 128.1, 129.2, 130.0, 137.5, 139.0, 141.4, 146.9 (arom.), 159.6 and 164.5 (2 C=O, ester). MS: m/z (%) = 478 (90) [M⁺ ].

17

Dimethyl 5-(4-Bromophenyl)-1-(4-methylphenyl)-pyrrole-2,3-dicarboxylate (6d)
Yellow oil. IR (KBr): ν_max = 1719 (C=O, ester) cm^-¹. Anal. Calcd (%) for C₂₁H₁₈BrNO₄ (428.28): C, 58.89; H, 4.24; N, 3.27. Found: C, 58.97; H, 4.19; N, 3.55. ^¹H NMR (500 MHz, CDCl₃): δ = 2.41 (3 H, s, CH₃), 3.72 and 3.83 (6 H, 2 s, 2 OCH₃), 6.95 (1 H, s, CH pyrrole), 7.22 (4 H, m, 4 CH arom.), 7.30 (2 H, d, J = 9 Hz, 2 CH arom.), 7.49 (2 H, d, J = 9 Hz, 2 CH arom.). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.6 (CH₃), 52.5 and 52.8 (2 OCH₃), 121.4, 121.6, 124.1, 124.4, 126.1, 126.2, 129.9, 130.0, 132.1, 132.7, 137.2, 139.1 (arom.), 160.9 and 166.8 (2 C=O, ester). MS: m/z (%) = 427 (95) [M⁺ ].

18

Diethyl 5-(4-Bromophenyl)-1-(4-methylphenyl)-pyrrole-2,3-dicarboxylate (6e)
Yellow oil. IR (KBr): ν_max = 1720 (C=O, ester) cm^-¹. Anal. Calcd (%) for C₂₃H₂₂BrNO₄ (456.33): C, 60.54; H, 4.86; N, 3.07. Found: C, 60.29; H, 4.69; N, 3.31. ^¹H NMR (500 MHz, CDCl₃): δ = 1.17 and 1.30 (6 H, 2 t, ^³ J _HH = 7 Hz, 2 CH₃), 2.42 (3 H, s, CH₃), 4.16 and 4.31 (4 H, 2 q, ^³ J _HH = 7 Hz, 2 OCH₂)_, 6.93 (1 H, s, CH pyrrole), 7.22 (4 H, m, 4 CH arom.), 7.32 (2 H, d, J = 9 Hz, 2 CH arom.), 7.48 (2 H, d, J = 9 Hz, 2 CH arom.). ^¹³C NMR (125 MHz, CDCl₃): δ = 14.3, 14.6 and 21.6 (3 CH₃), 61.4 and 61.7 (2 OCH₂), 121.5, 121.6, 124.0, 124.5, 126.0, 126.3, 128.9, 130.2, 132.0, 132.8, 137.3, 139.0 (arom.), 160.4 and 166.3 (2 C=O, ester). MS: m/z (%) = 455 (77) [M⁺ ].

19

Dimethyl 1-(4-Methoxyphenyl)-5-(4-nitrophenyl)-pyrrole-2,3-dicarboxylate (6f)
Yellow powder; mp 159-161 ˚C. IR (KBr): ν_max = 1731, 1729 (C=O, ester) cm^-¹. Anal. Calcd (%) for C₂₁H₁₈N₂O₇ (410.38): C, 61.46; H, 4.42; N, 6.83. Found: C, 61.52; H, 4.19; N, 7.07. ^¹H NMR (500 MHz, CDCl₃): δ = 3.73 and 3.85 (6 H, 2 s, 2 OCH₃), 3.86 (3 H, s, OCH₃), 7.05 (1 H, s, CH pyrrole), 6.95 (2 H, d, J = 8 Hz, 2 CH arom.), 7.28 (2 H, d, J = 8 Hz, 2 CH arom.), 7.60 (2 H, d, J = 8 Hz, 2 CH arom.), 8.22 (2 H, d, J = 8 Hz, 2 CH arom.). ^¹³C NMR (125 MHz, CDCl₃): δ = 52.6 and 52.9 (2 OCH₃), 56.0 (OCH₃), 114.6, 116.9, 120.9, 123.0, 124.3, 126.9, 127.6, 128.7, 132.2, 140.6, 147.1, 160.23 (arom.), 160.8 and 166.4 (2 C=O, ester). MS: m/z (%) = 410 (61) [M⁺ ].

20

Diethyl 5-(4-Bromophenyl)-1-(4-methoxyphenyl)-pyrrole-2,3-dicarboxylate (6g)
Yellow powder; mp 149-151 ˚C. IR (KBr): ν_max = 1714, 1711 (C=O, ester) cm^-¹. Anal. Calcd (%) for C₂₃H₂₂BrNO₅ (472.33): C, 58.49; H, 4.69; N, 2.97. Found: C, 58.25; H, 4.51; N, 3.11. ^¹H NMR (500 MH_Z, CDCl₃): δ = 1.16 and 1.27 (6 H, 2 t, ^³ J _HH = 7 Hz, 2 CH₃), 3.82 (3 H, s, OCH₃), 4.15 and 4.29 (4 H, 2 q, ^³ J _HH = 7 Hz, 2 OCH₂)_, 6.91 (1 H, s, CH pyrrole), 6.92, 7.24, 7.30 and 7.46 (8 H, 4 d, ^³ J _HH = 8 H_Z, arom.). ^¹³C NMR (125 MHz, CDCl₃): δ = 14.3 and 14.5 (2 CH₃), 55.9 (OCH₃), 61.3 and 61.8 (2 OCH₂), 114.4, 116.9, 121.4, 123.8, 124.6, 126.2, 127.7, 129.9, 132.0, 132.7, 132.8 and 160.1 (arom.), 160.4 and 166.4 (2 C=O, ester). MS: m/z (%) = 471 (73) [M⁺ ].

21

Dimethyl 5-(4-Bromophenyl)-1-(4-chlorophenyl)-pyrrole-2,3-dicarboxylate (6h)
Yellow oil. IR (KBr): ν_max = 1718 (C=O) cm^-¹. Anal. Calcd (%) for C₂₀H₁₅BrClNO₄ (448.69): C, 53.54; H, 3.37; N, 3.12. Found: C, 53.20; H, 3.19; N, 3.35. ^¹H NMR (500 MHz, CDCl₃): δ = 3.72 and 3.84 (6 H, 2 s, 2 OCH₃), 6.94 (1 H, s, CH of pyrrole), 7.29 (4 H, m, 4 CH arom.), 7.42 (2 H, d, J = 9 Hz, 2 CH arom.), 7.50 (2 H, d, J = 9 Hz, 2 CH arom.). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 52.5 and 52.9 (2 OCH₃), 121.8, 122.3, 123.9, 124.5, 126.1, 127.9, 129.6, 129.8, 132.3, 132.6, 135.0, 138.2 (arom.), 160.6 and 166.7 (2 C=O, ester). MS: m/z (%) = 447 (37) [M⁺ ].