4,4′-(Pyrrolo[3,2-b]pyrrole-1,4-diyl)dianiline

Abstract

4,4′-(Pyrrolo[3,2-b]pyrrole-1,4-diyl)dianiline was synthesized in one step from benzene-1,4-diamine and ethylene glycol with Pd/Al₂O₃ and ZnO. The title compound was characterized by means of NMR techniques and HRMS mass spectrometry.

1. Introduction

Nitrogen-containing heterocycles, such as pyridine, quinoline, and pyrrole, are found to be present in the vast majority of drugs; therefore, they are considered to be distinctive building blocks in the pharmaceutical industry. An analysis of the database of U.S. FDA approved drugs has pointed out that 59% of small molecule drugs contain a nitrogen-containing heterocycle [1].

In previous works employing ortho or meta benzene-diamine 1 (o, m), compounds 2 and 3 were prepared in excellent yields [2,3] (Scheme 1). Diamine 1 reacted with ethylene glycol, with Pd/C or Pt/Al₂O₃ as the catalyst. Importantly, ZnO was also required as the co-catalyst. These reactions were performed at 150 or 175 °C during 24–48 h. The formation of compounds 2 and 3 was explained by Borrowing Hydrogen [4,5,6] /Hydrogen Autotransfer [7] (BH/HA)-based mechanisms. Specifically, Acceptorless Dehydrogenative Condensation (ADC) [8,9] is responsible for the formation of those compounds. In this work, we report the results obtained with the para isomer of diamine 1.

2. Results

The reaction between benzene-1,4-diamine (1) with ethylene glycol/water in the conditions described by our research group resulted in intractable mixtures. However, when neat ethylene glycol was used as the solvent, we isolated by chromatography an oil that HRMS gives, with a molecular ion at 289.1442 amu corresponding to a C₁₈H₁₆N₄ formula. The ¹H NMR showed two AB systems, one with two doublets at 6.71 and 7.27 ppm (J = 9 Hz, 8H), and the second at 6.27 and 6.96 ppm (J = 3 Hz, 4H). In the ¹³C NMR, only seven aromatic signals were observed—four CH and three quaternary carbons. Bidimensional correlations (H,H COSY, HSQC, and HMBC; see Supplementary Materials) allowed the structural elucidation of this compound as 4,4′-(pyrrolo [3,2-b]pyrrole-1,4-diyl)dianiline (4). Pyrrolo[3,2-b]pyrrole-containing compounds have many important applications in different fields. [10] The compound 4 was formed with two units of benzene-1,4-diamine and three units of ethylene glycol. A plausible mechanism based on an ADC process is proposed in Scheme 2.

As can be seen, the dehydrogenation of ethylene glycol provides in situ glyceraldehyde. Condensation with 1 affords imine I-1. Intermediates I-1, I-2, and I-3 are under tautomeric equilibrium. A second imine formation between amino aldehyde I-3 and 1 provides intermediate II. After this, a second molecule of glyceraldehyde reacts to produce III-1. III-1 and III-2 are, again, under tautomeric equilibrium; however, III-2 can undergo intramolecular enamine/imine addition, yielding cyclic intermediate IV-1. Water elimination affords structure IV-2 that, after deprotonation, generates amino pyrrole V. A third molecule of glyceraldehyde produces VI-1 that also presents a tautomeric equilibrium towards VI-2 and VI-3. Intramolecular electrophilic aromatic substitution in VI-3 generates intermediate VII-1, after re-aromatization of VII-2 compound 4 is obtained. A final water elimination yields compound 4. The whole reaction involves two molecules of 1 and three of ethylene glycol. Water and molecular hydrogen are the unique side products. The overall yield was low (15%); however, by thin layer chromatography and NMR, unreacted diamine 1 could be identified.

3. Materials and Methods

Starting materials, if commercially available, were purchased and used as such. ZnO nanoparticles were purchased from Sigma Aldrich (Europe) (<100 nm particle size (DLS), <0 nm average particle size (APS), 20 wt % in H₂O). ¹H and ¹³C nuclear magnetic resonance (NMR) spectra were recorded at 300 and 75 MHz in CDCL₃. Chemical shifts are reported in δ units, parts per million (ppm), and were measured relative to the signals for residual chloroform. Coupling constants (J) are given in Hertz (Hz). Multiplicities are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). HRMS were recorded using TOF electrospray ionization (ESI-positive). IR spectra were recorded using FT-IR ATR, the solvents used were of spectroscopic or equivalent grade. Water was twice distilled and passed through a Millipore apparatus. All reaction mixtures were filtered through a 0.45 μm PTFE 25 mm syringe filter.

Synthesis of 4,4′-(Pyrrolo[3,2-b]pyrrole-1,4-diyl)dianiline (4)

Benzene-1,4-diamine 1 (2 mmol), 1.7% of Pt/Al₂O₃ (132.5 mg), 4.5% of ZnO nanoparticles (21.5 μL), and ethylene glycol (4 mL) were mixed manually inside a 50 mL quick-thread glass reaction tube. The tube was sealed with an Easy-On PTFE cap and put into a Carousel 12 Plus reaction station at 175 °C for 48 h. The reaction mixture was cooled to room temperature, and it needed to be opened carefully to depressurize the tube. After that, 25 mL of ethyl acetate was added, and the crude was filtered through a 0.45 μm PTFE filter. The reaction mixture was extracted with distilled water (3 × 10 mL), and the organic layer was dried with Na₂SO₄, filtered, and concentrated to afford the reaction crude that was checked by ¹H-NMR. The crude reaction product was purified by chromatography (Silica gel, Hexane/Ethyl Acetate from 3:1 to 1:3 v:v) as a brown oil identified as the 4,4′-(pyrrolo[3,2-b]pyrrole-1,4-diyl)dianiline (4) (47 mg, yield 15%). ¹H-NMR (300 MHz, Cl₃CD); δ: 7.26 (d, J = 9 Hz, 4H), 6.95 (d, J = 3 Hz, 2H), 6.70 (d, J = 9 Hz, 4H), 6.27 (d, J = 3 Hz, 2H), 0.7 (sa,4H). ¹³C-NMR (75 MHz, Cl₃CD); δ: 143.4(C), 133.2(C), 128.1(C), 121.3(CH), 121.1(CH), 116.1(CH), 93.6(CH). HRMS: [M + H⁺] calc. for C18H16N4: 289.1448; found: 289.14425. IR (ATR): 3771, 2922, 2851, 1632, 1516, 1421, 1273, 1177, 825, 689 cm⁻¹. UV-vis (5 × 10⁻⁴ M in methanol): λ_max 206, 240, and 298 nm.