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Short Note

6-(4-(2-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl)-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione)

Small Molecule Synthesis Facility, Duke University, Durham, NC 27708, USA
Molbank 2009, 2009(4), M638; https://doi.org/10.3390/M638
Submission received: 9 October 2009 / Accepted: 2 November 2009 / Published: 5 November 2009

Abstract

:
Microwave irradiation of maleimide with an excess of furan in water exclusively yields the corresponding exo-cycloadduct in good yield (87%) in 1 hour at 90 °C. Alkylation of the imido nitrogen with tetraethylene glycol under Mitsunobu conditions gives the ROMP monomer in 81% yield.

Graphical Abstract

1. Introduction

Alkylation of 7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide with tetraethylene glycol under Mitsunobu conditions gives an amphiphilic ROMP monomer [1]. Attempts to reproduce this alkylation in our facility fell far short of the reported yield and isolation of the product required lengthy chromatographic purification over a slow solvent gradient. Faced with potential production of the monomer on a multi-gram scale, a more efficient synthesis and purification protocol was necessary. Since the poorly reproducible alkylation was conducted with an endo:exo (1.5:1) mixture, it was surmised that dicarboximide stereochemistry might affect the outcome of the alkylation step. Specifically, the nitrogen of the exo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide isomer was thought to be less sterically hindered than that of the endo isomer. Conventional methods of exo-isomer preparation typically require heating solutions of maleimide and furan under high pressure conditions [2,3]. The Diels-Alder adduct can also be obtained under milder conditions (e.g., stirring the organic solutions of the two reactants for 1 to 9 days at room temperature) but at a cost of stereochemical selectivity (endo:exo, 1.5:1 to 7:3) [2,4,5]. Given the recent report of exo-selectivity preference in water [5] and by the successful application of maleimide in Diels-Alder reactions under microwave conditions [6], attempting the cycloaddition under these combined conditions seemed a reasonable approach to the desired product. By heating an aqueous mixture of maleimide and furan under microwave irradiation for 1 hour at 90 °C, the exo isomer precipitated from solution. Alkylation of this exo-dicarboximide under Mitsunobu conditions gave the desired product in 81%. Furthermore the final product was rapidly eluted from a short column of silica gel under isocratic solvent conditions.
Molbank 2009 m638 i001

2. Experimental

2.1. endo/exo-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide: Conventional method

A mixture of maleimide (0.42 g, 4.3 mmol), furan (0.48 mL, 6.6 mmol) and Et2O (6 mL) were stirred at room temperature for 9 days. The resulting precipitate was isolated by vacuum filtration and dried in vacuo overnight. Recrystallization from benzene gave the cycloaddition adduct as a white solid (0.30 g, 42%) which was shown by 1H NMR to be a mixture of isomers (endo:exo; 1.5:1) [2].
1H NMR (CDCl3, 300 MHz): δ 8.05 (bs, 1H), 7.70 (bs, 1H, endo isomer), 6.52 (s, 2H, endo isomer), 6.49 (s, 2H), 5.33–5.31 (m, 4H), 3.57 (dd, J = 1.8 Hz, 3.6 Hz, 2H, endo isomer), 2.85 (s, 2H).
EIMS m/z: 165 ([M]+).

2.2. exo-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide: Microwave method

A mixture of maleimide (0.855 g, 8.8 mmol), furan (1.1 mL, 15 mmol) and H2O (10 mL) was heated in a 35 mL microwave reaction vessel to 90 °C (100W) for 1 h. The white crystalline material that precipitated upon cooling to room temperature was isolated by vacuum filtration, rinsed with H2O (2 × 5 mL) and dried in vacuo overnight (1.3 g, 87%). M.p.: 160.0-161.5 °C (Literature: 162 °C [2]).
1H NMR (CDCl3, 300 MHz): δ 8.05 (bs, 1H), 6.49 (s, 2H), 5.28 (s, 2H), 2.85 (s, 2H).
13C NMR (CDCl3, 75 MHz): δ 177.7, 135.9, 83.5, 55.9.
EIMS m/z: 165 ([M]+).

2.3. Mitsunobu alkylation of the exo-imide

Over a period of 10 minutes, diisopropyl azodicarboxylate (94%, 4.3 mL, 16 mmol) was added dropwise to a stirred, cooled (0 °C) solution of the exo-imide (2.31 g, 14.0 mmol), PPh3 (4.2 g, 16 mmol), and tetraethylene glycol (12 mL, 70 mmol) in anhydrous THF (120 mL). The cooling bath was removed and the reaction mixture was stirred for 16 h, then concentrated to dryness under reduced pressure. The resulting oily residue was partitioned between diethyl ether (100 mL) and H2O (50 mL). The aqueous phase was separated and the organic phase was extracted with H2O (2 × 50 mL). The combined aqueous extracts were extracted with CHCl3 (3 × 50 mL). The chloroform extracts were combined and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure giving a yellow oily residue. Purification by silica gel flash column chromatography (2.5% methanol in dichloromethane) afforded the product as a clear, yellow oil (4.2 g, 81%).
1H NMR (CDCl3, 300 MHz): δ 6.46 (s, 2H), 5.22 (s, 2H), 3.66-3.56 (m, 20H), 2.83 (s, 2H), 2.61 (t, J = 6.0 Hz, 2H).
13C NMR (CDCl3, 75 MHz): δ 176.2, 134.5, 83.9, 69.8, 64.9, 61.5, 55.2, 41.0.
EIMS m/z: 364 ([M+Na]+).

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

References and Notes

  1. Breitenkamp, K.; Emrick, T. Amphiphilic Ruthenium Benzylidene Metathesis Catalyst with PEG-Substituted Pyridine Ligands. J. Polym. Sci. Part A: Polym. Chem. 2005, 43, 5715–5721. [Google Scholar] [CrossRef]
  2. Kwart, H.; Burchuk, I. Isomerism and Adduct Stability in the Diels-Alder Reaction: The Adducts of Furan and Maleimide. J. Am. Chem. Soc. 1952, 74, 3094–3097. [Google Scholar] [CrossRef]
  3. Wang, Y.; Cai, J.; Rauscher, H.; Behm, R.J.; Goedel, W.A. Maleimido-Terminated Self-Assembled Monolayers. Chem. Eur. J. 2005, 11, 3968–3978. [Google Scholar] [CrossRef] [PubMed]
  4. Lu, Z.K.; Weber, R.; Tweig, R.J. Improved Synthesis of DCDHF Fluorophores with Maleimide Functional Groups. Tetrahedron Lett. 2006, 47, 7213–7217. [Google Scholar] [CrossRef] [PubMed]
  5. Rulisek, L.; Sebek, P.; Havlas, V.; Hrabal, R.; Capek, P.; Svatos, A. An Experimental and Theoretical Study of Selectivity of Furan-Maleic Anhydride and Furan-Maleimide Diels-Alder Reactions. J. Org. Chem. 2005, 70, 6295–6302. [Google Scholar] [CrossRef] [PubMed]
  6. Kristof, K.; Marijan, K. Microwave-Assisted Diels-Alder Reaction of 2H-Pyran-2-ones with Maleimides Towards Fused Bicyclo[2.2.2]octenes. Heterocycles 2007, 73, 481–491. [Google Scholar]

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MDPI and ACS Style

Gooden, D.M. 6-(4-(2-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl)-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione). Molbank 2009, 2009, M638. https://doi.org/10.3390/M638

AMA Style

Gooden DM. 6-(4-(2-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl)-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione). Molbank. 2009; 2009(4):M638. https://doi.org/10.3390/M638

Chicago/Turabian Style

Gooden, David M. 2009. "6-(4-(2-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl)-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione)" Molbank 2009, no. 4: M638. https://doi.org/10.3390/M638

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