Next Article in Journal
Previous Article in Journal
Article Menu

Export Article

Molbank 2014, 2014(1), M820; doi:10.3390/M820

Short Note
2-(4-(2-Chloroacetamido)-1-methyl-1H-pyrrole-2-carboxamido)ethyl Acetate
Department of Chemistry, Jordan University of Science and Technology, Irbid 22110, Jordan
College of Applied Medical Sciences-Al Ahsa, King Saud bin Abdulaziz University for Health Sciences, Al-Ahsa 31982, Kingdom of Saudi Arabia
Received: 20 December 2013 / Accepted: 27 February 2014 / Published: 5 March 2014


The title compound 2-(4-(2-chloroacetamido)-1-methyl-1H-pyrrole-2-carboxamido)ethyl acetate was synthesized. The structure of the compound was fully characterized by 1H-NMR, 13C-NMR and mass spectral analysis.
lexitropsins; pyrrole-2-carboxamide; DNA-alkylating agents


Lexitropsins, i.e., “information reading molecules”, such as the crescent-shaped naturally occurring antitumor antibiotic netropsin, bind reversibly with the minor groove of double helical DNA to sequences rich with adjacent AT base pairs [1,2,3]. These pyrrole carboxamide skeletons have been used as vehicles for delivering anticancer drugs to DNA sequences blocking its template function [4,5]. In the course of our work on the synthesis of lexitropsins [6,7,8,9,10,11], literature search revealed that 1-methyl-1H-pyrrole-2-carboxamides carrying an alkylating unit such as a chloroacetamido group at C-4 have not been prepared. Therefore, 2-(4-(2-chloroacetamido)-1-methyl-1H-pyrrole-2-carboxamido)ethyl acetate (5), a new pyrrole carboxamide possessing an alkylating unit, was prepared as shown in Scheme 1. The product synthesized with a satisfactory yield was fully characterized by nuclear magnetic resonance and mass spectrometry.

Results and Discussion

We have synthesized the amide 3 starting from 2-trichloroacetyl-1-methyl-4-nitropyrrole (1) [12,13] according to Scheme 1, in two steps; the first was performed by acyl nucleophilic substitution of the trichloromethyl leaving group by ethanolamine to afford amide 2 and the second by protecting the hydroxyl group with an acetyl group to furnish ester 3 [14].
The chloroacetyl group was then introduced by a sequence of two steps. Reduction of the nitro group in the ester 3 to the corresponding amine 4 was best accomplished in MeOH using H2/Pd(C). It is worth noting that amine 4 decomposes easily. Conducting these reactions without degassing furnished the title compound in low yield after tedious purification by column chromatography. Therefore, the solution of 3 in MeOH in the presence of the catalyst was degassed with N2 prior to the reduction process. After completion of the reaction (by TLC) the reaction mixture was concentrated and then the residue was dissolved in degassed CH2Cl2 containing Et3N. Finally, the reaction mixture was concentrated and the title compound 5 was then purified by silica gel chromatography. The required compound 5 obtained in 70% overall yield from 3 was characterized by 1H-NMR, 13C-NMR and mass spectral data.


2-(4-(2-Chloroacetamido)-1-methyl-1H-pyrrole-2-carboxamido)ethyl Acetate

A solution of 3 (2.55 g, 10.0 mmol) and Pd/C (0.30 g of 3%) in MeOH (200 mL) was degassed with N2 for 10 min and then the resulting solution was hydrogenated using Shaker Hydrogenation Apparatus for 3 h at 30 psi. After concentration under reduced pressure, the residue was dissolved in degassed CH2Cl2 (50 mL) containing Et3N (2 mL). The resulting mixture was added dropwise to a degassed solution of chloroacetyl chloride (1.68 g, 15 mmol) in CH2Cl2 (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was extracted by EtOAc (2 × 100 mL). The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 1:3 hexane/EtOAc) to give the title compound 5 (2.10 g, 70%) as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 2.08 (s, 3H), 3.59 (q, J = 5.2 Hz, 2H), 3.89 (s, 3H), 4.15 (s, 2H), 4.22 (t, J = 5.2 Hz, 2H, O-CH2), 6.28 (s, 1H, aromatic-H), 6.56 (d, J = 1.5 Hz, 1H, aromatic-H), 7.11 (t, J = 1.6 Hz, 1H, NH), 8.17 (s,1H, N-H); 13C-NMR (100 MHz, CDCl3): δ 20.6, 36.4, 38.5, 42.3, 63.1, 103.2, 118.9, 119.9, 123.2, 161.2, 162.8, 171.1; MS-ESI m/z calcd for C12H17N3O435Cl [M+H]+ 302.08, found, 302.06. Anal. Calcd. for C12H16N3O4Cl: C, 47.77%; H, 5.34%; Cl, 11.75%; N, 13.93%. Found: C, 47.83%; H, 5.41%; N, 13.85%.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3Supplementary File 4


This work was supported by the Deanship of Research at Jordan University of Science and Technology.

Conflict of Interest

The author declares no conflict of interest.


  1. Zimmer, C. Effects of the antibiotics netropsin and distamycin A on the structure and function of nucleic acids. Prog. Nucleic Acid Res. Mol. Biol. 1975, 15, 285–291. [Google Scholar] [PubMed]
  2. Lown, J.W. Lexitropsins in antiviral drug development. Antiviral Res. 1992, 17, 179–185. [Google Scholar] [CrossRef]
  3. Arcamone, F.; Penco, S.; Orezzi, P.; Nicolella, V.; Pirelli, A. Structure and synthesis of distamycin. Nature 1964, 203, 1064–1065. [Google Scholar] [CrossRef] [PubMed]
  4. Khan, G.S.; Shah, A.; Rehman, Z.U.; Barker, D. Chemistry of DNA minor groove binding agents. J. Photochem. Photobiol. B 2012, 115, 105–118. [Google Scholar] [CrossRef] [PubMed]
  5. Romagnoli, R.; Baraldi, P.G.; Iaconinoto, M.A.; Carrion, M.D.; Tabrizi, M.; A. Gambari, R.; Borgatti, M.; Heilmann, J. Synthesis and biological activity of alpha-bromoacryloyl lexitropsin conjugates. Eur. J. Med. Chem. 2005, 40, 1123–1128. [Google Scholar] [CrossRef] [PubMed]
  6. Al-Said, N.H.; Shawakfeh, K.Q. Synthetic studies towards bis-heterodimeric netropsin analogs. Jordan J. Chem. 2007, 2, 125–132. [Google Scholar]
  7. Al-Said, N.H.; Klaib, S. Synthesis of a C-2 stapled bis-lexitropsin. Monatsh. Chem. 2007, 138, 573–577. [Google Scholar] [CrossRef]
  8. Al-Said, N.H. Synthesis of a terminally linked homodimeric bis-distamycin analog. Monatsh. Chem. 2006, 137, 1535–1541. [Google Scholar] [CrossRef]
  9. Zhao, R.; Al-Said, N.H.; Sternbach, D.L.; Lown, J.W. Camptothecin and minor-groove binder hybrid molecules: Synthesis, inhibition of topoisomerase I, and anticancer cytotoxicity in vitro. J. Med. Chem. 1997, 40, 216–225. [Google Scholar] [CrossRef] [PubMed]
  10. Gupta, R.; Al-Said, N.H.; Oreski, B.; Lown, J.W. Design, synthesis and topoisomerase II inhibition activity of 4'-demethylepipodopyllotoxine-lexitropsin conjugate. Anticancer Drug Des. 1996, 11, 325–338. [Google Scholar] [PubMed]
  11. Al-Said, N.H.; Lown, J.W. A convenient synthesis of cross-linked homodimeric lexitropsins. Synth. Comm. 1995, 25, 1059–1070. [Google Scholar] [CrossRef]
  12. Belanger, P. Electrophilic substitutions on 2-trichloroacetylpyrrole. Tetrahedron Lett. 1979, 27, 2505–2508. [Google Scholar] [CrossRef]
  13. Rahman, K.M.; Jackson, P.J.M.; James, C.J.; Basu, P.; Hartley, J.A.; de la Fuente, M.; Schatzlein, A.; Robson, M.; Pedley, R.B.; Pepper, C.; et al. GC-Targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models. J. Med. Chem. 2013, 56, 2911–2935. [Google Scholar] [CrossRef] [PubMed]
  14. Breen, D.; Kennedy, A.R.; Suckling, C.J. A divergent synthesis of minor groove binders with tail group variation. Org. Biomol. Chem. 2009, 7, 178–186. [Google Scholar] [CrossRef] [PubMed]
Scheme 1. Synthesis of 2-(4-(2-chloroacetamido)-1-methyl-1H-pyrrole-2-carboxamido)ethyl acetate (5).
Scheme 1. Synthesis of 2-(4-(2-chloroacetamido)-1-methyl-1H-pyrrole-2-carboxamido)ethyl acetate (5).
Molbank 2014 m820 sch001
Molbank EISSN 1422-8599 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top