S-Methylation of a 4-(naphth-2-yl)-β-thiolactam gives an intermediate  4-(naphth-2-yl) substituted 1-azetine which undergoes a [2+2] ring-opening followed by electrocyclic ring closure of the resulting 2-azadiene to give a benzo[f]isoquinolin

Hemming, Karl

Jamshaid, Faisal

Khan, Musharraf

Molbank

English

S-Methylation of a 4-(naphth-2-yl)-β-thiolactam gives an intermediate  4-(naphth-2-yl) substituted 1-azetine which undergoes a [2+2] ring-opening followed by electrocyclic ring closure of the resulting 2-azadiene to give a benzo[f]isoquinoline

Faisal Jamshaid

Musharraf Khan

Karl Hemming

Multidisciplinary Digital Publishing Institute

2-Methylsulfanylbenzo[f]isoquinoline

University of Huddersfield Repository

University of Huddersfield RepositoryHemming, Karl, Jamshaid, Faisal and Khan, Musharraf2-Methylsulfanylbenzo[f]isoquinolineOriginal CitationHemming, Karl, Jamshaid, Faisal and Khan, Musharraf (2015) 2-Methylsulfanylbenzo[f]isoquinoline. Molbank, 2015 (M860). pp. 1-5. ISSN 1422-8559 This version is available at http://eprints.hud.ac.uk/24753/The University Repository is a digital collection of the research output of theUniversity, available on Open Access. Copyright and Moral Rights for the itemson this site are retained by the individual author and/or other copyright owners.Users may access full items free of charge; copies of full text items generallycan be reproduced, displayed or performed and given to third parties in anyformat or medium for personal research or study, educational or not-for-profitpurposes without prior permission or charge, provided:• The authors, title and full bibliographic details is credited in any copy;• A hyperlink and/or URL is included for the original metadata page; and• The content is not changed in any way.For more information, including our policy and submission procedure, pleasecontact the Repository Team at: E.mailbox@hud.ac.uk.http://eprints.hud.ac.uk/Molbank 2015, M860; doi:10.3390/M860  molbank ISSN 1422-8599 www.mdpi.com/journal/molbank Short Note 2-Methylsulfanylbenzo[f]isoquinoline Faisal Jamshaid, Musharraf N. Khan and Karl Hemming * Department of Chemical Sciences, School of Applied Sciences, University of Huddersfield,  HD1 3DH, UK * Author to whom correspondence should be addressed; E-Mail: k.hemming@hud.ac.uk;  Tel.: +44-1484-472188; Fax: +44-1484-472182. Academic Editor: Norbert Haider Received: 29 April 2015 / Accepted: 25 May 2015 / Published: 27 May 2015  Abstract: S-Methylation of a 4-(naphth-2-yl)-β-thiolactam gives an intermediate  4-(naphth-2-yl) substituted 1-azetine which undergoes a [2+2] ring-opening followed by electrocyclic ring closure of the resulting 2-azadiene to give a benzo[f]isoquinoline. Keywords: benzoisoquinoline; 1-azetine; naphthalene  Introduction Benzoisoquinolines (Figure 1) are relatively unexplored heterocycles which have attracted limited interest in the literature [1–8]. Benzo[f]isoquinolines 1 [1–4] are useful in the synthesis of aza-steroids [3] and have had their affinity for the 5-HT3 receptor explored [4]. Benzo[h]isoquinolines 2 have also been synthesized [5–8] and some of these have been shown to be potent inhibitors of ATP-competitive Chk1 kinase [8]. The benzo[g]isoquinoline nucleus 3 has also been reported [8]. In this short note, we wish to report the synthesis of the previously unreported 2-methylthiobenzo[f]isoquinoline 4 which is obtained from an unprecedented rearrangement of 2-methylthio-4-(naphth-2-yl)-1-azetine 5, shown in Scheme 1. Whilst benzo[f]isoquinolines and the isomeric 3-(naphth-1-yl)-1-azetines have been reported as common products obtained from reactions of dehydronaphthylalanines [1,2], the formation of benzoisoquinolines from 4-(naphth-2-yl)-1-azetines has not been reported. The isomeric  4-methylthiobenzo[f]isoquinoline 6, obtained via an entirely different route, has been reported [3]. OPEN ACCESS Molbank 2015  M860 (Page 2)    Figure 1. Benzoisoquinolines. Discussion 2-Methylthio-4-(naphth-2-yl)-1-azetine 5 (Scheme 1) has been synthesized by us before [9,10] and used in cycloaddition reactions. Previously, the 1-azetine was obtained by alkylation of the readily available [9,10] thiolactam 7, as shown in Scheme 1. When this reaction mixture is worked up and purified immediately, the 1-azetine is the major product, as already reported [9,10]. However, we have now found that when the crude 1-azetine reaction mixture from the reaction of thiolactam 7 with trimethyloxonium tetrafluoroborate is left overnight rather than used immediately, the 1-azetine is not the isolated product, but rearranges to give 2-methylthiobenzo[f]isoquinoline 4 (35% from 7) instead. A sample of the pure 1-azetine 5 underwent quantitative rearrangement to the isoquinoline 4 after storage in CDCl3 for one week, indicating that alkylation of the thiolactam 7 is the limiting step.  Scheme 1. Synthesis of 2-methylthiobenzo[f]isoquinoline 4. As shown in Scheme 2, we propose that the 1-azetine 5 undergoes ring-opening to the 2-azadiene 8, a thermal ring-opening process known in 1-azetines [11–13]. Electrocyclic ring closure then occurs onto the more reactive and favored naphthyl 1-position [14–16] as opposed to the alternative, less reactive, dis-favored 3-position. Loss of hydrogen and aromatization then gives the benzo[f]isoquinoline 4.  Scheme 2. Proposed mechanism. Experimental To 4-naphthylazetidin-2-thione 7 [9,10] (300 mg, 1.42 mmol) in dry dichloromethane (10 mL) in a 50 mL round-bottomed flask was added Meerwein’s salt (312 mg, 2.11 mmol) under an atmosphere of Molbank 2015  M860 (Page 3)   dry nitrogen. The mixture was stirred at room temperature for 1 h and then at reflux for 1 h. The solution was cooled to room temperature and added drop-wise to a 50% aqueous solution of potassium carbonate (10 mL) at −10 °C and left to warm to room temperature overnight. The resulting mixture was filtered through Celite and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 × 10 mL), and the combined organic extracts were dried (MgSO4). After filtration the solvent was removed under reduced pressure using a rotary evaporator to give a dark orange oil which was purified by silica column chromatography (hexane/EtOAc; 3:1) to give the product as a light yellow oil (112 mg, 35%), Rf = 0.48. The reaction was monitored by TLC, which was carried out on 0.20 mm Macherey-Nagel Alugram® Sil G/UV254 silica gel-60 F254 precoated aluminium plates (Fisher Scientific UK Ltd, Loughborough, UK) and visualisation was achieved using UV light. Column chromatography was performed on silica gel (0.063–0.200 mm, 60 Å) from the same supplier. Spectroscopic Data IR υmax (neat, cm−1): 3043 (w), 2955 (m), 1587 (m), 1556 (m), 1493 (m), 1441 (m), 1391 (m), 1144 (m), 1124 (s), 1073 (m), 835 (m), 748 (s). 1H-NMR: δ (400 MHz, CDCl3): 9.19 (1H, dd, J = 7.8, 1.6 Hz, ArH), 7.83 (1H, d, J = 8.4 Hz, ArH), 7.80 (1H, dd, J = 7.3, 1.8 Hz, ArH), 7.64–7.56 (3H, m, ArH), 7.53 (1H, d, J = 8.7 Hz, ArH), 7.29 (1H, d, J = 8.4 Hz, ArH), 2.77 (3H, s, Me). 13C-NMR δ (100 MHz, CDCl3): 158.51 (C), 146.18 (C), 134.63 (CH), 133.21 (C), 130.21 (C), 127.34 (CH), 127.04 (CH), 125.99 (CH), 125.41 (CH), 124.50 (CH), 123.72 (CH), 122.53 (C), 120.19 (CH), 13.26 (CH3). HRMS (ESI+, m/z) [M + H]+ for C14H12NS calculated 226.0685, measured 226.0692. Acknowledgments We acknowledge Neil McLay for NMR spectroscopy and mass spectrometry. Author Contributions Hemming designed the project and is the principal and corresponding author and wrote the text. Khan and Jamshaid conducted the practical work associated with this project and contributed equally. Conflicts of Interest The authors declare no conflict of interest. References and Notes 1. Hoshina, H.; Kubo, K.; Morita, A.; Sakurai, T. Formation of Isoquinoline and 1-Azetine Derivatives via Novel Photocyclization of Substituted α-Dehydrophenylalanines. Tetrahedron 2000, 56, 2941–2951. Molbank 2015  M860 (Page 4)   2. Maekawa, K.; Igarashi, T.; Kubo, K.; Sakurai, T. Electron transfer-initiated photocyclization of substituted N-acetyl-α-dehydro(1-naphthyl)alanines to 1,2-dihydrobenzo[f]quinoline derivatives: scope and limitations. Tetrahedron 2001, 57, 5515–5526. 3. Lalezari, I.; Nabahi, S. Polyazasteroids. III. 1,2,4-Triazolo[3,4-a]benzo[f]isoquinoline. Synthesis of the Diazaphenanthrene Alkaloid Perlolidine and its 1,8-Phenanthroline Isomer. J. Heterocycl. Chem. 1980, 17, 1761–1763.  4. Cappelli, A.; Anzini, M.; Vomero, S.; Canullo, L.; Mennuni, L.; Makovec, F.; Doucet, E.;  Hamon, M.; Menziani, M.C.; de Benedetti, P.G.; et al. Novel Potent and Selective Central 5-HT3 Receptor Ligands Provided with Different Intrinsic Efficacy. J. Med. Chem. 1999, 42, 1556–1575.  5. Wang, H.; Yu, Y.; Hong, X.; Xu, B. Mn(II)/O2-promoted oxidative annulation of vinyl isocyanides with boronic acids: Synthesis of multi-substituted isoquinolines. Chem. Commun. 2014, 50, 13485–13488. 6. Lechel, T.; Dash, J.; Eidamshaus, C.; Brüdgam, I.; Lentz, D.; Reissig, H.-U. A three-component synthesis of β-alkoxy-β-keto-enamides—flexible precursors for 4-hydroxypyridine derivatives and their palladium-catalysed reactions. Org. Biomol. Chem. 2010, 8, 3007–3014.  7. Villuendas, P.; Urriolabeitia, E.P. Primary Amines as Directing Groups in the Ru-Catalyzed Synthesis of Isoquinolines, Benzoisoquinolines and Thienopyridines. J. Org. Chem. 2013, 78, 5254–5263. 8. Garbaccio, R.M.; Huang, S.; Tasber, E.S.; Fraley, M.E.; Yan, Y.; Munshi, S.; Ikuta, M.; Kuo, L.; Kreatsoulas, C.; Stirdivant, S.; et al. Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase. Bioorg. Med. Chem. Lett. 2007, 17, 6280–6285. 9. Hemming, K.; Khan, M.N.; O’Gorman, P.A.; Pitard, A. 1,2,4-Oxadiazoles from cycloreversions of oxadiazabicyclo[3.2.0]heptenes: 1-Azetines as thiocyanate equivalents. Tetrahedron 2013, 69, 1279–1284. 10. Hemming, K.; Khan, M.N.; Kondakal, V.V.R.; Pitard, A.; Qamar, M.I.; Rice, C.R. Pyridines from Azabicyclo[3.2.0]hept-2-en-4-ones through a Proposed Azacyclopentadienone. Org. Lett. 2012, 14, 126–129. 11. Novikov, M.S.; Smetanin, I.A.; Khlebnikov, A.F.; Rostovskii, N.V.; Yufit, D.S. Synthesis of electron-poor 4-halo-2-azabuta-1,3-dienes by Rh(II)-catalyzed diazo ester-azirine coupling.  2-Azabuta-1,3-diene-2,3-dihydroazete valence isomerism. Tetrahedron Lett. 2012, 53, 5777–5780.  12. Sugie, M.; Takeo, H.; Matsumura, C. A Study of the Thermal Decomposition and Dehydrochlorination of N-Chloroazetidine: Microwave Spectra of N-Chloromethylenimine,  1-Azetine, and 2-Azabutadiene. J. Am. Chem. Soc. 1989, 111, 906–910. 13. Guillemin, J.C.; Denis, J.M.; Lablache-Combier, A. 1-Azetine: Thermal Ring Opening to  2-Azabutadiene. J. Am. Chem. Soc. 1981, 103, 468–469. 14. Deutsch, J.; Prescott, H.A.; Müller, D.; Kemnitz, E.; Lieske, H. Acylation of naphthalenes and anthracene on sulfated zirconia. J. Catal. 2005, 231, 269–278.  15. Sörgel, S.; Azap, C.; Reissig, H.-U. Preparation of Highly Substituted Naphthaldehyde Derivatives—A Regioselective Approach to Building Blocks for the Synthesis of Rubromycins. Eur. J. Org. Chem. 2006, 2006, 4405–4418.   Molbank 2015  M860 (Page 5)   16. Grigg, R.; Kongkathip, N.; Kongkathip, B.; Luangkamin, S.; Dondas, H.A. Palladium catalysed reaction of allene with phenols. Phenoxymethyl-1,3-dienes and their further reactions. Tetrahedron 2001, 57, 7965–7978. © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). 

1-Azetine: Thermal Ring Opening to 2-Azabutadiene.

1,2,4-Oxadiazoles from cycloreversions of oxadiazabicyclo[3.2.0]heptenes: 1-Azetines as thiocyanate equivalents. Tetrahedron

A Study of the Thermal Decomposition and Dehydrochlorination of N-Chloroazetidine: Microwave Spectra of N-Chloromethylenimine, 1-Azetine, and 2-Azabutadiene.

A three-component synthesis of β-alkoxy-β-keto-enamides—flexible precursors for 4-hydroxypyridine derivatives and their palladium-catalysed reactions.

Acylation of naphthalenes and anthracene on sulfated zirconia.

Mn(II)/O2-promoted oxidative annulation of vinyl isocyanides with boronic acids: Synthesis of multi-substituted isoquinolines.

Palladium catalysed reaction of allene with phenols. Phenoxymethyl-1,3-dienes and their further reactions. Tetrahedron

Preparation of Highly Substituted Naphthaldehyde Derivatives—A Regioselective Approach to Building Blocks for the Synthesis of Rubromycins.

Primary Amines as Directing Groups in the Ru-Catalyzed Synthesis of Isoquinolines, Benzoisoquinolines

Pyridines from Azabicyclo[3.2.0]hept-2-en-4-ones through a Proposed Azacyclopentadienone.

Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.

Synthesis of electron-poor 4-halo-2-azabuta-1,3-dienes by Rh(II)-catalyzed diazo ester-azirine coupling. 2-Azabuta-1,3-diene-2,3-dihydroazete valence isomerism. Tetrahedron Lett.

Musharraf N. Khan

Directory of Open Access Journals

Crossref

S-Methylation of a 4-(naphth-2-yl)-β-thiolactam gives an intermediate 4-(naphth-2-yl) substituted 1-azetine which undergoes a [2+2] ring-opening followed by electrocyclic ring closure of the resulting 2-azadiene to give a benzo[f]isoquinoline

Huddersfield Research Portal

2-Methylsulfanylbenzo[f]isoquinoline

Abstract

Similar works

Full text

Available Versions

Multidisciplinary Digital Publishing Institute

University of Huddersfield Repository

Directory of Open Access Journals

Crossref

Huddersfield Research Portal