Convergent Approach to Nonsymmetrical 2,5-Diester Pyrroles

Abstract

A convergent approach towards nonsymmetrical 2,5-diester pyrroles is described. The building blocks can be easily assembled in less than four steps allowing for facile construction of diversity. The synthesis uses a rhodium-catalyzed NH insertion, followed by a one-pot deprotection-condensation to yield the desired pyrroles.

Key words

pyrrole - rhodium catalysis - NH insertion - zinc deprotection - enamine

References and Notes

• 1a For examples of natural products bearing a pyrrole: Gupton JT. Topics in Heterocyclic Chemistry   Vol. 2:  Lee M. Springer; Berlin: 2006.  p.53 
• 1b Roth BD. inventors; US Patent  4681893. For drugs containing a pyrrole, one of the best-known examples is Lipitor^®:
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4

No pyrrole was observed when the keto enamine 2a was submitted under thermal or dehydrating conditions in the absence of zinc.

9

Optimization of the deprotection-cyclization involved screening for organic solvents, aqueous solvent (pH 1-14 buffer), metal used, quantity of zinc, temperature, and reaction time.

10

General Procedure for the Synthesis of Compounds 2a-i To a stirred solution of 8 (1.70 mmol) and Rh₂(oct)₄ (0.085 mmol) in CH₂Cl₂ (4 mL) at 20 ˚C was added a solution of 4 (3.40 mmol) in CH₂Cl₂ (2 mL) over a period of 20 min. The mixture was stirred for 1 h; gas evolution was observed. The reaction mixture was partitioned between CH₂Cl₂ and a sat. NaHCO₃ solution, back extracted with CH₂Cl₂. Combined organic layers were washed with brine, dried over MgSO₄, and concentrated under vacuum. Purification by flash chromatography (silica gel, 230-400 mesh; Merck) using hexanes-EtOAc yielded 2 as a pure product.
Methyl 2-{(1-Ethoxy-1,3-dioxo-3-phenylpropan-2-yl)[(2,2,2-trichloroethoxy)carbonyl]amino}-3-(phenylthio)acrylate (2a) ^¹H NMR (400 MHz, acetone-d ₆): δ = 8.12 (br, 1 H), 7.58-7.51 (m, 2 H), 7.53-7.45 (m, 3 H), 7.45-7.39 (m, 2 H), 7.38-7.30 (m, 2 H), 7.30-7.24 (m, 2 H), 4.83 (s, 2 H), 3.78 (q, J = 7.1 Hz, 2 H), 3.60 (s, 3 H), 0.79 (t, J = 7.1 Hz, 3 H) ppm. ^¹³C NMR (101 MHz, acetone-d ₆): δ = 165.9, 165.0, 159.8, 153.3, 149.7, 134.7, 133.7, 131.6, 131.1, 130.0, 129.7, 129.6, 128.1, 114.9, 112.3, 96.7, 75.2, 61.9, 52.1, 13.8 ppm. IR (neat): 3311 (br), 2982, 1715, 1439, 1268, 1179, 1128, 1034, 732. ESI-HRMS: m/z calcd for C₂₄H₂₂Cl₃NNaO₇S
[M + Na]: 598.0049; found: 598.0044.
General Procedure for the Synthesis of Compounds 1a-i
To a stirred solution 2 (0.35 mmol) in 2-PrOH (3.5 mL) and H₂O (0.627 mL, 35 mmol) was added zinc (228 mg, 3.5 mmol). Mixture was heated to 60 ˚C and stirred for 24 h. The suspension was filtered on Celite, then concentrated under vacuum. Purification by flash chromatography (silica gel, 230-400 mesh; Merck) using hexanes-EtOAc yielded 1 as a pure product.
2-Ethyl 5-Methyl 3-Phenyl-1 H -pyrrole-2,5-dicarboxylate (1a)
^¹H NMR (400 MHz, acetone-d ₆): δ = 11.43 (br, 1 H), 7.69-7.65 (m, 2 H), 7.42-7.39 (m, 3 H), 7.30 (s, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H) ppm. ^¹³C NMR (101 MHz, acetone-d ₆): δ = 164.2, 161.3, 141.7, 131.9, 130.6, 129.5, 128.5, 123.3, 118.8, 114.7, 60.2, 51.8, 14.5 ppm. IR (neat): 3706 (br), 3306, 2973, 1692, 1467, 1249, 1143, 1035, 757, 687. ESI-HRMS: m/z calcd for C₁₅H₁₆NO₄ [M + H]: 274.1074; found: 274.1077.