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

doi:10.1016/j.tet.2012.12.007

Tetrahedron

Volume 69, Issue 4, 28 January 2013, Pages 1279-1284

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Abstract

1,3-Dipolar cycloaddition of nitrile oxides to 4-aryl-2-alkylthio-1-azetines gave a series of oxadiazabicyclo[3.2.0]heptenes as single diastereoisomers. Heating these cycloadducts in toluene resulted in an overall [2+2]-cycloreversion to give 5-alkylthio-3-aryl-1,2,4-oxadiazoles. In this process, the 1-azetine behaves as a thiocyanate equivalent. When the nitrile oxide substituent was 2-azidobenzene, the azide could be converted into a 1,2,3-triazole giving a (1,2,4-oxadiazolo)-(1,2,3-triazolo)-1,2-disubstituted benzene. 1,2,4-Oxadiazoles are sought after in medicinal chemistry and materials sciences.

Graphical abstract

Introduction

1,2,4-Oxadiazoles have attracted attention due to their biological activity, often related to their bioisosteric nature and use in medicinal chemistry.¹ This area has been extensively reviewed¹ and a selection of recent compounds of interest is shown in Fig. 1. Compound 1 is one of a series of 1,2,4-oxadiazoles that are potent EthR inhibitors that boost ethionamide activity in the treatment of multi-drug resistant tuberculosis.² Compound 2 is of interest as a combretastatin A-4 analogue with higher efficacy as an antimitotic agent.³ Thiol linked 1,2,4-oxadiazoles 3 that have electron withdrawing aryl substituents show great potency towards androgen independent prostrate cancer cell-lines.⁴ Compound 4 is an excellent in vivo sphingosine phosphate receptor-1 (S1P₁) selective modulator that suppresses the development of autoimmune diseases including multiple sclerosis and adjuvant-induced arthritis models.⁵ Compound 5 is representative of a potent class of tankyrase (TNKS1/2) dual inhibitors that show no activity at poly(ADP-ribose) polymerase (PARP1 and 2) domains, and are inhibitors of the Wnt pathway whose dysregulation is a key priority in multiple diseases including several cancers.⁶ In 2011 the first 1,2,4-oxadiazole natural products, phidianidines A (6, X=Br) and B (6, X=H), were isolated7, 7(a)—from a marine opisthobranch source—and their synthesis reported shortly thereafter.^7b 1,2,4-Oxadiazoles are also of interest in materials research¹ with recent examples including bent-core⁸ and bent-rod liquid crystals⁹ with stable liquid phases over broad temperature ranges. 3-Nitro-5-substituted-1,2,4-oxadiazoles, such as compound 7 are reported as ‘explosophoric’ energetic, insensitive high explosives.¹⁰ Finally, the use of pyridyl-1,2,4-oxadiazoles¹¹ and bis-1,2,4-oxadiazole¹² as ligands that chelate Ni^II, Cu^II, Zn^II and Pd^II has been reported, together with a report that bis(pyridyl)-1,2,4-oxadiazole Cu^II complexes display promising activity as DNA groove binders.¹³

1,2,4-Oxadiazoles are most commonly constructed using 1,3-dipolar cycloadditions between nitrile oxides and nitriles1, 14 or from the reactions of a nitrile-derived amidoxime with a carboxylic acid derivative.1, 15 In this report, we show that 5-alkylthio-1,2,4-oxadiazoles 10 can be obtained from a formal [2+2]-cycloreversion of the oxadiazabicyclo[3.2.0]heptenes 9 [Scheme 1], which in turn are readily constructed from the 1,3-dipolar cycloaddition of a nitrile oxide to a 4-aryl-1-azetine 8. In this process, the 1-azetine acts as an equivalent for the nitrile species R¹S–CN, known as either an alkyl thiocyanate or an alkyl thiocyanic ester.¹⁶

Section snippets

Results and discussion

This work has its origins in our studies [Scheme 2] that focused upon the synthesis of azabicycles 13 from the reaction of cyclic imines 11 with cyclopropenones 12, where the latter function as all-carbon 1,3-dipole equivalents 14.¹⁷ When the imine 11 was a 4-aryl-1-azetine the intermediate bicycles 13a (n=1) gave the tetra-substituted pyridines 16.¹⁸ We postulated that this transformation proceeded through a [2+2] cycloreversion to give a non-isolable, high-energy azacyclopentadienone 15 and a

Conclusions

1,3-Dipolar cycloadditions of nitrile oxides to 4-aryl-2-alkylthio-1-azetines gave oxadiazabicyclo[3.2.0]heptenes that underwent a formal [2+2]-cycloreversion and loss of a styrene to furnish 5-alkylthio-3-aryl-1,2,4-oxadiazoles. The use of 2-azido-benzonitrile oxide allowed subsequent 1,3-dipolar cycloaddition of DMAD to the azide (‘click’ reaction) in order to furnish the 1-(1,2,4-oxadiazolo)-2-(1,2,3-triazolo)-substituted benzene 10i. In these processes, a 2-alkylthio-1-azetine functions as

General

All reactions were conducted using oven-dried glassware under nitrogen dried through 4 Å molecular sieves and delivered through a gas manifold. Work-up procedures were carried out in air. All solvents were purchased from Fisher Chemicals and were of analytical grade. Anhydrous grade solvents were freshly distilled using a continuous still under nitrogen. Acetone was dried overnight over 3 Å molecular sieves (10% w/v), and then distilled over freshly activated 3 Å molecular sieves over 3–4 h.

Acknowledgements

We thank the University of Huddersfield for studentships and fee-waiver bursaries (to M.N.K., P.O'G. and A.P.), and Dr. Neil McLay, University of Huddersfield, for NMR and mass spectroscopic support. We are grateful to the EPSRC National Mass Spectrometry Service, University of Wales, Swansea for HRMS.

References and notes (24)

M. Flipo et al.
J. Med. Chem.
(2012)
G. Shanker et al.
Tetrahedron
(2011)
H. Gallardo et al.
Tetrahedron
(2011)
Z. Fu et al.
Chem.—Eur. J.
(2012)
Recent...N. Nishiwaki et al.
Org. Biomol. Chem.
(2011)
R.R. Kumar et al.
Bioorg. Med. Chem.
(2011)
Recent...B. Kaboudin et al.
Tetrahedron Lett.
(2011)
A. Palumbo Piccionello et al.
Eur. J. Med. Chem.
(2012)
V.V.R. Kondakal et al.
Tetrahedron Lett.
(2012)
P.A. O'Gorman et al.
Tetrahedron Lett.
(2008)
K. Hemming et al.
Tetrahedron Lett.
(2006)
K. Hemming et al.
Org. Lett.
(2012)
K. Hemming et al.
Synlett
(2004)
...K. HemmingK. Hemming
J. Chem. Res., Synop.
(2001)
A. Pace et al.
Org. Biomol. Chem.
(2009)
J. Boström et al.
J. Med. Chem.
(2012)
K. Goldberg et al.
Med. Chem. Commun.
(2012)

B.C. Das et al.

Tetrahedron Lett.

(2012)

G.L. Khatik et al.

Bioorg. Med. Chem. Lett.

(2012)

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

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General

Acknowledgements

J. Med. Chem.

Tetrahedron

Tetrahedron

Chem.—Eur. J.

Org. Biomol. Chem.

Bioorg. Med. Chem.

Tetrahedron Lett.

Eur. J. Med. Chem.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Org. Lett.

Synlett

J. Chem. Res., Synop.

Org. Biomol. Chem.

J. Med. Chem.

Med. Chem. Commun.

Tetrahedron Lett.

Bioorg. Med. Chem. Lett.