An efficient reverse Diels–Alder approach for the synthesis of N-alkyl bismaleimides Venkataramanarao Rao a,c , Suryakiran Navath a , Mohankumar Kottur c , James R. McElhanon b , Dominic V. McGrath a,⇑ a Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA b Organic Materials Department, Sandia National Laboratories, Albuquerque, NM 87185, USA c Cosmic Discoveries, Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India article info Article history: Received 28 May 2013 Revised 28 June 2013 Accepted 1 July 2013 Available online 6 July 2013 Keywords: N-Alkylated bis-maleimide Retro-Diels–Alder reaction L-Tartaric acid Furan protected maleimide Cross linkers abstract Bismaleimides are useful precursors for Diels–Alder reactions, Michael additions, and thiol–maleimide based conjugation for the synthesis of materials and polymers. Use of bismaleimide cross linkers for gen- erating polymers, bioconjugate molecules, and useful imaging molecules is an active area of research. An efficient and practical synthetic protocol for N-alkyl bis-maleimide cross linkers starting from furan pro- tected maleimide employing a reverse Diels–Alder reaction is reported. Ó 2013 Elsevier Ltd. All rights reserved. Introduction Bismaleimides (BMIs) 1 (R = aryl, alkyl) are versatile building blocks in polymer synthesis. BMIs 1 are used for the synthesis of high molecular weight, step-growth polymers, and serve as effec- tive cross-linkers. 1,2 BMI thermosetting addition polyimide resins are the key components of aeroengines and aircraft because of their high temperature stability, hot–wet strength, and fatigue resistance. 3,4 Maleimide endgroups on prepolymers allow for poly- merization and crosslinking by a variety of pathways 3 including thermal curing, polymerization by conjugate addition with diamines, 5,6 bisphenols, or bisthiols, cycloaddition reactions without elimination of side products, 7 and radical mediated polymerization. 8,9 The maleimide moiety’s noted reactivity toward nucleophilic functional groups, particularly thiols and others of biological rele- vance, 10 as well as its propensity to undergo Diels–Alder cycload- ditions, has also led to its use for site-specific biomolecule ligation and modification. BMI crosslinkers are commonly used to explore and characterize protein structure or interactions by site- specific biomolecule modification (i.e. click chemistry), 11 and forming crosslinks between sites in a protein oligomer or interaction can assist in determining intra- and intermolecular dis- tances. N-Alkyl bismaleimides 2–4 find application as water solu- ble thiol-reactive homobifunctional cross-linkers. 11 BMIs 3 have found application in the production of multimeric forms of the T- cell surface glycoprotein CD 4 through a sugar-based crosslinking strategy, 12 synthesis of bradykinin (BK) antagonist dimers, 13 and crosslinking of diene-modified DNA. 14 As part of our ongoing research interest in the synthesis of ther- mally responsive dendritic polymers, 15 we required N-alkyl BMIs (e.g. 2–4) in gram quantities. Although commercially available, the high cost of commercial BMIs has driven us to look for an effi- cient and economic synthesis of these compounds in our laboratory. 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.07.002 ⇑ Corresponding author. Tel.: +1 520 6264690; fax: +1 520 6218407. E-mail address: mcgrath@u.arizona.edu (D.V. McGrath). OH OH N N O O O O N N O O O O n 4 2 3a-i : n = 0-8 N N O O O O 1 R N O O O N O O 3 Tetrahedron Letters 54 (2013) 5011–5013 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet