2-Methylsulfanylbenzo[f]isoquinoline

Faisal Jamshaid; Musharraf N. Khan; Karl Hemming

doi:10.3390/M860

,

and

Department of Chemical Sciences, School of Applied Sciences, University of Huddersfield, HD1 3DH, UK

^*

Author to whom correspondence should be addressed.

Molbank2015, 2015(2), M860;https://doi.org/10.3390/M860

Version Notes

Order Reprints

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 [1,2,3,4,5,6,7,8]. Benzo[f]isoquinolines 1 [1,2,3,4] 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 [5,6,7,8] 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].

Figure 1. Benzoisoquinolines.

Scheme 1. Synthesis of 2-methylthiobenzo[f]isoquinoline 4.

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.

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 [11,12,13]. Electrocyclic ring closure then occurs onto the more reactive and favored naphthyl 1-position [14,15,16] 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 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%), R_f = 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 υ_max (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.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

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

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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef] [PubMed]
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. [Google Scholar] [CrossRef] [PubMed]
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. [Google Scholar] [CrossRef] [PubMed]
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. [Google Scholar] [CrossRef] [PubMed]
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. [Google Scholar] [CrossRef] [PubMed]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef] [PubMed]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef]
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. [Google Scholar] [CrossRef]

© 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/).