Next Article in Journal
2-Methylsulfanylbenzo[f]isoquinoline
Previous Article in Journal
2-Fluoro-N-methyl-N-({(3S,4S)-4-[2-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isochromen-3-yl}methyl)ethanamine
 
 
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Short Note

3-({5-Bromo-4-[pyrrolidin-1-yl]pyrimidin-2-yl}amino)phenol

Division of Chemistry and Environmental Science, School of Science and the Environment, Faculty of Science and Engineering, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK
Molbank 2015, 2015(2), M859; https://doi.org/10.3390/M859
Received: 25 April 2015 / Accepted: 18 May 2015 / Published: 21 May 2015

Abstract

:
Re-investigation of the 1H-NMR spectrum reported for 15-bromo-4-oxa-2,9-diaza-1(2,4)-pyrimidine-3(1,3)-benzenacyclononaphane (2) prepared via a Mitsunobu-mediated macroether cyclisation led to a proposed structural isomer (3). The title compound (3) was prepared via a two-step protocol and assigned using 1H, 13C-NMR and LC-MS.

Graphical Abstract

Macrocycles are an important class of organic compounds defined as containing cyclic systems of 12 or more atoms [1]. Macrocycles have garnered much attention recently in medicinal chemistry due to their ability to access biologically relevant conformations [2,3,4]. There are a variety of macrocyclisation strategies available [5] in particular we were interested in the intra-molecular Mitsunobu reaction that has been used to prepare kinase inhibitor scaffolds [6,7]. Lücking et al. [8] have reported a high dilution intra-molecular Mitsunobu reaction to macrocycle 2 (Scheme 1) that possessed micromolar activity against CDK2 and anti-proliferative effects towards MCF7 cells. We were intrigued by the stated 1H-NMR spectrum for 2 which showed the four methylene groups occurred at 3.30 ppm (m, 4H) and 1.90 ppm (m, 4H). We therefore considered whether there is a choice of two intra-molecular Mitsunobu reactions—one that delivers compound 2 and one that delivers compound 3. To address this question we prepared the novel isomer, 3.
Our synthesis of 3 (Scheme 2) commenced with pyrrolidine mediated displacement of the more reactive C-Cl bond in 4 which afforded 5 in modest yield after trituration. The synthesis of 3 was accomplished using an analogous SNAr procedure to that reported by Lücking et al. [8]. Chromatographic separation and trituration afforded a sample of 3 in modest yield under identical elution conditions. 1H and 13C NMR spectra of intermediate 5 and product 3 are provided in the supplementary materials.
Interestingly, the 1H-NMR spectrum obtained for 3 matches the signals reported [8] for 2 for all the aryl and exchangeable protons. Two sets of multiplets consisting of 4 protons each was observed for 3. However, the symmetrical methylene peaks adjacent to the nitrogen occurred further downfield at 3.75–3.70 ppm (m, 4 H) versus the 3.30 ppm (m, 4H) reported for 2 [9]. In conclusion, we have prepared a novel structural isomer 3 of compound 2.

Experimental Section

General Information

Reactions were carried out under argon. Organic solutions were dried over Na2SO4. Starting materials and solvents were purchased from commercial suppliers and were used without further purification. Flash silica chromatography was performed using Merck silica gel 60 (0.025–0.04 mm). 1H and 13C-NMR spectra were recorded using a JEOL ECS 400 NMR Spectrometer. Chemical shifts (δ) are reported relative to TMS (δ = 0) and/or referenced to the solvent in which they were measured. High-resolution mass spectrometry analysis was performed on an Agilent 6450 LC-MS/MS.

Synthesis of 3-((5-Bromo-4-(pyrrolidin-1-yl)pyrimidin-2-yl)amino)phenol (3)

Triethylamine (1.0 mL, 7.3 mmol) and pyrrolidine (0.55 mL, 6.6 mmol) are added to a stirred solution of 5-bromo-2,4-dichloropyrimidine (4) (0.84 mL, 6.6 mmol) in acetonitrile (6 mL). The reaction mixture was stirred at room temperature overnight. After 12 h, the precipitate that formed was filtered off. The filtrate was concentrated in vacuo and triturated with isopropyl ether. 5-Bromo-2-chloro-4-(pyrrolidin-1-yl)pyrimidine (5) was obtained, 0.67 g (2.5 mmol, 38%) [10]. HCl (4 M in dioxane, 0.12 mL) is added to 3-aminophenol (53 mg, 0.49 mmol) and 5-Bromo-2-chloro-4-(pyrrolidin-1-yl)pyrimidine (5) (132 mg, 0.51 mmol) in acetonitrile (1.5 mL), and the reaction mixture was stirred at reflux for 12 h. After cooling to room temperature, the reaction mixture is concentrated in vacuo. Water (1.0 mL) was added, and the organic layer extracted with ethyl acetate (5 mL × 2). The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/methanol; 9:1), and the crude product obtained was triturated with isopropyl ether. The title compound 3 was obtained as a white powder, 44 mg (0.13 mmol, 27%).
1H-NMR (400 MHz, d6-DMSO) δ 9.20 (s, 1H), 9.10 (s, 1H), 8.03 (s, 1H), 7.23–7.21 (m, 1H), 7.12–7.09 (m, 1H), 6.99 (dd, J = 7.8 Hz, 1H), 6.33–6.29 (m, 1H), 3.75–3.70 (m, 4H), 1.89–1.84 (m, 4H).
13C-NMR (100 MHz, d6-DMSO) δ 159.0, 157.4, 156.9, 141.8, 128.9, 109.6, 108.2, 105.7, 90.1, 49.5, 25.1.
LC-MS (TOF, 2.0 min) Rt = 0.243 min; m/z (ESI) 335 (M79Br+H), 337 (M81Br+H).
Hi-Res LC-MS (ESI) m/z calcd for C14H1679BrN4O (M+H) 335.0507, found 335.0477.
Melting point range: 159–160 °C.

Supplementary materials

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

Acknowledgments

AMJ thanks Manchester Metropolitan University for funding and MMU analytical services for running NMR and MS analyses.

Author Contributions

AMJ performed the experiments and wrote the manuscript.

Conflicts of Interest

The author declares no conflict of interest.

References and Notes

  1. Driggers, E.M.; Hale, S.P.; Lee, J.; Terrett, N.K. The exploration of macrocycles for drug discovery—an underexploited structural class. Nat. Rev. Drug Discov. 2008, 7, 608–624. [Google Scholar] [CrossRef] [PubMed]
  2. Peña, S.; Scarone, L.; Serra, G. Macrocycles as potential therapeutic agents in neglected diseases. Future Med. Chem. 2015, 7, 355–382. [Google Scholar]
  3. Mallinson, J.; Collins, I. Macrocycles in New Drug Discovery. Future Med. Chem. 2012, 4, 1409–1438. [Google Scholar] [CrossRef] [PubMed]
  4. Yudin, A.K. Macrocycles: Lessons from the distant past, recent developments, and future directions. Chem. Sci. 2015, 6, 30–49. [Google Scholar] [CrossRef]
  5. Hussain, A.; Yousuf, S.K.; Mukherjee, D. Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs). RSC Adv. 2014, 4, 43241–43257. [Google Scholar] [CrossRef]
  6. Dakas, P.-Y.; Barluenga, S.; Totzke, F.; Zirrgiebel, U.; Winssinger, N. Modular synthesis of radicicol A and related resorcylic acid lactones, potent kinase inhibitors. Angew. Chem. Int. Ed. Engl. 2007, 46, 6899–6902. [Google Scholar] [CrossRef] [PubMed]
  7. Dakas, P.-Y.; Jogireddy, R.; Valot, G.; Barluenga, S.; Winssinger, N. Divergent syntheses of resorcylic acid lactones: L-783277, LL-Z1640– 2, and hypothemycin. Chem. Eur. J. 2009, 15, 11490–11497. [Google Scholar] [CrossRef] [PubMed]
  8. Lücking, U.; Siemeister, G.; Schäfer, M.; Briem, H.; Krüger, M.; Lienau, P.; Jautelat, R. Macrocyclic Aminopyrimidines as Multitarget CDK and VEGF-R Inhibitors with Potent Antiproliferative Activities. ChemMedChem 2007, 2, 63–67. [Google Scholar] [CrossRef] [PubMed]
  9. The water signal in d6-DMSO occurs as a broad singlet at 3.33 ppm. Gottlieb, H.E.; Kotlyar, V.; Nudelman, A. NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities. J. Org. Chem. 1997, 62, 7512–7515. [Google Scholar]
  10. Data obtained for 5-Bromo-2-chloro-4-(pyrrolidin-1-yl)pyrimidine (5). 1H-NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 3.75–3.69 (m, 4 H), 1.89–1.85 (m, 4H); 13C-NMR (100 MHz, d6-DMSO) δ 159.9, 157.8, 157.4, 100.0, 50.0, 25.1; LC-MS (TOF, 2.0 min) Rt = 0.173 min; m/z (ESI) 262 (M79Br+H), 264 (M81Br+H). Hi-Res LC-MS (ESI) m/z calcd for C8H979BrClN3 (M+H) 261.9747, found 261.9743.
Scheme 1. Lücking et al. [8] route to macrocyclic scaffold 2 and our postulated isomer 3.
Scheme 1. Lücking et al. [8] route to macrocyclic scaffold 2 and our postulated isomer 3.
Molbank 2015 m859 sch001
Scheme 2. Synthetic route to 3.
Scheme 2. Synthetic route to 3.
Molbank 2015 m859 sch002

Share and Cite

MDPI and ACS Style

Jones, A.M. 3-({5-Bromo-4-[pyrrolidin-1-yl]pyrimidin-2-yl}amino)phenol. Molbank 2015, 2015, M859. https://doi.org/10.3390/M859

AMA Style

Jones AM. 3-({5-Bromo-4-[pyrrolidin-1-yl]pyrimidin-2-yl}amino)phenol. Molbank. 2015; 2015(2):M859. https://doi.org/10.3390/M859

Chicago/Turabian Style

Jones, Alan M. 2015. "3-({5-Bromo-4-[pyrrolidin-1-yl]pyrimidin-2-yl}amino)phenol" Molbank 2015, no. 2: M859. https://doi.org/10.3390/M859

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop