Polycyclic N-heterocyclic compounds. Part 61: A novel Truce–Smiles type rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give cycloalkeno[1,2-d]furo[2,3-b]pyridines☆
Introduction
Rearrangement reactions are powerful tools in organic synthesis because simple, readily obtained precursors frequently produce molecules of much higher complexity. Among the many name rearrangement reactions that have been developed is the Truce–Smiles rearrangement, a useful procedure that involves formation of carbon–carbon bonds of an aryl ring with concomitant breaking of a carbon–heteroatom bond.2, 3
As a part of our continuing program on the synthesis of polycyclic N-heterocyclic compounds for medicinal applications, we have developed a general one step preparation of aromatic ring-fused furo[2,3-b]pyridines (2) from aryl-1-carbonitriles having a 3-cyanopropoxy group adjacent to the cyano (carbonitrile) group (1). This transformation of 1 to 2 is carried out by the action of potassium tert-butoxide on 1 and corresponds to a Truce–Smiles rearrangement reaction followed by an intramolecular cyclization (Scheme 1).4, 5, 6, 7
We have now explored the extension of this reaction sequence to 2-(3-cyanopropoxy)cycloalkene-1-carbonitriles (3). One can assume that a base-generated carbanion nucleophile adjacent to a nitrile group will undergo Michael addition (Scheme 2). If β-elimination takes place, the resulting oxyanion could be trapped by intramolecular nitrile groups sequentially to give 5-aminocycloalkeno[1,2-d]furo[2,3-b]pyridines (4). A Truce–Smiles rearrangement occurs by an intramolecular nucleophilic aromatic substitution at an ipso position,2 but to date there has been no precedent for this type of rearrangement for aliphatic alkenes such as 3. We wish to report herein the details of a novel Truce–Smiles type rearrangement reaction for a series of cycloalkenyl substrates 3.
Section snippets
Results and discussion
The starting 2-oxocycloalkanecarbonitriles (5a–c) were readily prepared from the corresponding commercially available alkanedicarbonitriles by Thorpe–Ziegler condensation, followed by an acid hydrolysis of the resulting enamine.8, 9 Reaction of 5 with 4-chlorobutyronitrile in the presence of potassium carbonate in DMF gave 2-(3-cyanopropoxy)cycloalkene-1-carbonitrile (3a–c) in moderate yield (Scheme 3). In the IR spectrum of 3, two cyano absorption bands at 2200–2270 cm−1 appeared and the
Conclusion
In summary, reaction of 2-(3-cyanopropoxy)cycloalkene-1-carbonitrile (3) with a base gave 5-aminocycloalkeno[1,2-d]furo[2,3-b]pyridines (4) via a Truce–Smiles type rearrangement followed by an intramolecular cyclization. We are currently exploring their further derivatization at the 5-position for development of potential pharmaceutics.
General
All melting points were determined on a Yanagimoto micro-melting point apparatus, and are uncorrected. Elemental analyses were performed on a Yanagimoto MT-5 CHN Corder elemental analyzer. The FAB-mass spectra were obtained on a VG 70 mass spectrometer and m-nitrobenzyl alcohol was used as a matrix. The IR spectra were recorded on a Japan Spectroscopic IRA-102 diffraction grating infrared spectrophotometer or FT/IR-200 spectrophotometer and frequencies are expressed in cm−1. The 1H NMR spectra
Acknowledgments
We are grateful to the SC-NMR Laboratory of Okayama University for 200 and 500 MHz 1H NMR experiments. We also thank Dr. K. L. Kirk (NIDDK, NIH) for helpful suggestions.
References and notes (12)
- et al.
Heterocycles
(1995) - et al.
J. Heterocycl. Chem.
(1996) - et al.
J. Heterocycl. Chem.
(1999) - et al.
Chem. Pharm. Bull.
(2009) Chem. Soc. Rev.
(2008)- et al.
Tetrahedron Lett.
(2000)et al.Tetrahedron
(2004)et al.Tetrahedron Lett.
(2004)Synlett
(2008)
Cited by (18)
Six-membered ring systems. Pyridines and benzo derivatives
2011, Progress in Heterocyclic ChemistryCitation Excerpt :Some of the most creative syntheses rely on rearrangement reactions to furnish the pyridine ring system. Okuda et al. performed a novel pyridine synthesis via a Truce–Smiles rearrangement 〈TL903〉. This impressive rearrangement generates two fused rings in one pot, though yields and generality could be improved (Scheme 13).
Cycloalka[c]pyridine derivatives. Methods of synthesis and chemical properties
2017, Russian Journal of Organic ChemistryModern Aspects of the Smiles Rearrangement
2017, Chemistry - A European JournalSeveral species of nucleophiles in the smiles rearrangement
2017, Current Organic ChemistryNHC-Organocatalyzed C<inf>Ar</inf>−O Bond Cleavage: Mild Access to 2-Hydroxybenzophenones
2017, Angewandte Chemie - International EditionThe Truce-Smiles rearrangement and related reactions: A review
2017, Canadian Journal of Chemistry
H activation of neighboring carbons. In supramolecular chemistry, pyridines link metal organic frameworks and pyridinium salts provide cationic structures for nanodevices. These structures have found use in biological systems, as revealed by several blockbuster drugs and a host of new natural products. This review discusses novel preparations, reactions, functionalizations, and applications of pyridine, quinoline, and isoquinoline reported during 2010.