Iodine/CuI-mediated alkyne–carbonyl metathesis reaction: synthesis of 1-aryl-1,2-dihydrochromeno[2,3-b]azepine-3,6-dione

doi:10.1016/j.tet.2013.11.062

Tetrahedron

Volume 70, Issue 2, 14 January 2014, Pages 334-339

https://doi.org/10.1016/j.tet.2013.11.062 Get rights and content

Abstract

Iodine/cuprous iodide-mediated intramolecular alkyne–carbonyl metathesis reaction has been developed using 2-(N-aryl-N-propargyl)aminochromone-3-carbaldehyde as the substrate. It led to the synthesis of hitherto unreported chromeno[2,3-b]azepine-3,6-dione. The special features of this methodology are mild reaction conditions, 100% atom economy and use of inexpensive reagents. This is the first example of I₂/CuI-mediated alkyne–carbonyl metathesis reaction.

Graphical abstract

Introduction

Alkyne–carbonyl metathesis (ACM) reaction has emerged as an important methodology for the synthesis of α,β-unsaturated carbonyl compounds. The superiority of this method over aldol reaction or Wittig reaction is the atom economy. A few Lewis acids like In(OTf)₃ or GaCl₃,¹ Yb(OTf)₃,² AgSbF₆,³ FeX₃⁴ and BF₃·Et₂O⁵ acted as catalysts for ACM reaction. In all these cases ACM reaction has been reported using mostly non-terminal alkynes. Reports of ACM reaction using terminal alkynes are very few. SbF₅⁶ and HBr/Bmim OTs-catalyzed ACM reaction has been accomplished using terminal alkyne.⁷ Intramolecular ACM reaction has been reported using BF₃·Et₂O,⁸ AuCl₃/AgSbF₆ as combined catalyst,⁹ other gold catalysts,¹⁰ triflic acid (TfOH)¹¹ and FeCl₃.¹² Using these methodologies, mostly five and six membered carbocyclic and heterocyclic rings have been synthesized. ACM reaction using trifluoroacetic acid (TFA) on non-terminal 5-, 6- and 7- alkynals produced exo-cyclic ketones linked to five, six and seven-membered carbocycles, whereas terminal 5-alkynals gave endo carbocyclization to cyclohexenones.¹³ Synthesis of seven-membered heterocyclic ring using ACM reaction is scarce in the literature. Recently, gold-catalyzed cyclization reactions of O-propargyl ether of salicylaldehyde^14a and 2-[N-(prop-2-ynyl)-N-tosyl]aminobenzaldehydes^14b have been accomplished to form oxepinone and azepinone derivatives, respectively, in the presence of benzyl alcohol.¹⁴ Synthesis of benzoazepinone derivative from N-homopropargylaniline has been reported using m-CPBA for N-oxide formation and gold catalyst for a rearrangement reaction.¹⁵ A recent report^12a on the FeCl₃-catalyzed ACM reaction on alkynyl ether of salicylaldehyde showed that terminal alkynes failed to undergo ACM reaction. So, it would be of interest to synthesize seven-membered heterocyclic ring using terminal alkyne utilizing ACM reaction.

Azepinones fused with different heterocycles were used as a scaffold for the generation of a series of potential GABA agonists.¹⁶ Indole-fused benzoazepine was transformed into hepatitis C polymerase inhibitors.¹⁷ Hexahydrobenzothienopyridoazepinone derivatives are potent and selective 17β-hydroxy steroid dehydrogenase (HSD)1 inhibitors, for development of new treatment of breast tumours.¹⁸ Azepine sulfonamides are 11β-HSD1 inhibitors.¹⁹ In addition to the pharmaceutical importance, azepine moiety is also available in different natural products like aurantioclavine,²⁰ hinckdentine A,²¹ stemoamide²² and 13-epieostenine.²³

4-Oxo-4H-1-benzopyran (chromone) moiety is widely distributed in nature.²⁴ Many pharmaceutically important compounds bear chromone moiety at their central part.²⁵ We anticipate that the synthesis of azepinones fused with chromone moiety is of a great interest for the screening of their biological activities.

We envisaged the synthesis of chromeno[2,3-b]azepinones 5 using ACM reaction as a key step (Scheme 1). We report herein a novel route to 1-aryl-1,2-dihydrochromeno[2,3-b]azepine-3,6-dione under mild, environment-friendly conditions by ACM reaction using inexpensive reagents iodine and catalytic amount of CuI.

2-N-Arylaminochromone-3-carbaldehyde 3 has become an attractive building block for the synthesis of different polycyclic heterocycles.²⁶ N-Alkenylated derivative of 3 have been utilized for intramolecular nitrone–alkene cycloaddition reaction,27, 27(a) azomethine ylide–alkene cycloaddition reaction,^27b inverse electron demand hetero Diels–Alder reaction,^27c Povarov reaction,^27d and for the synthesis of polycyclic nitronates.^27e Here N-alkynylated analogue 4 bearing terminal alkyne has been explored for ACM reaction.

Section snippets

Results and discussion

The required substrate material for the ACM reaction was prepared by propargylation of 3 (Scheme 2). Compound 3 can be generated by the rearrangement of nitrone 2,^26a which is obtainable from aldehyde 1.

At first we searched for a suitable catalyst to accomplish the ACM reaction involving the terminal alkyne moiety and the aldehydic group in 4. For this purpose compound 4a was used as a model substrate to find out the suitable reaction condition. We tried with anhydrous FeCl₃, BF₃·Et₂O, InCl₃

Conclusion

In summary, we have reported the first example of I₂/CuI-mediated intramolecular alkyne–carbonyl metathesis reaction, where I₂ and CuI activates the carbonyl and alkyne component, respectively, and led to an efficient synthetic route to hitherto unreported 1-aryl-1,2-dihydrochromeno[2,3-b]azepine-3,6-dione. In contrast to earlier reports for oxepine or azepine synthesis utilizing ACM reaction, we have utilized inexpensive reagents iodine and CuI in place of expensive gold complexes.

General

The recorded mps are uncorrected. IR spectra were recorded in KBr on a Shimadzu FTIR spectrophotometer, IR Affinity-1, ¹H NMR/¹³C NMR spectra on a Bruker 300 MHz/75 MHz spectrometer in CDCl₃ unless stated otherwise, mass spectra on a Qtof micro YA 263 instrument and elemental analysis on a Perkin–Elmer 240c elemental analyzer. Light petroleum refers to the fraction with 60–80 °C. All chemicals used were of commercial grade and were used as such.

General experimental procedure for the preparation of 2-(N-aryl-N-prop-2-ynyl)aminochromone-3-carbaldehydes (4a–i)

A mixture of 2-(N

Acknowledgements

We gratefully acknowledge CSIR, New Delhi [Project no. 02(0029)/11/EMR-II] for financial assistance; IICB, Jadavpur for instrumental analysis and finally the college authority for providing research facilities. J.G. thanks CSIR for Junior Research Fellowship.

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Iodine/CuI-mediated alkyne–carbonyl metathesis reaction: synthesis of 1-aryl-1,2-dihydrochromeno[2,3-b]azepine-3,6-dione

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General

General experimental procedure for the preparation of 2-(N-aryl-N-prop-2-ynyl)aminochromone-3-carbaldehydes (4a–i)

Acknowledgements

Tetrahedron Lett.

Chem. Lett.

Org. Lett.

Tetrahedron

Tetrahedron Lett.

J. Heterocycl. Chem.

Synlett

Org. Lett.

J. Org. Chem.

Synlett

Synlett

Org. Lett.

Helv. Chim. Acta

Org. Lett.

Org. Lett.

Chem. Soc. Rev.

Chem. Soc. Rev.

Chem. Commun.