Elsevier

Tetrahedron

Volume 62, Issue 25, 19 June 2006, Pages 6050-6060
Tetrahedron

Derivatives of arylhydrazonic acids. Part 3: Stereochemical rearrangement of Z-oxanilo-N1-dialkyl-N2-arylamidrazones

https://doi.org/10.1016/j.tet.2006.04.001Get rights and content

Abstract

Oxanilo-N1-dialkyl-N2-arylamidrazones have been prepared by nucleophilic substitution of the chloride function of appropriate hydrazonoyl chlorides. Relative stabilities of Z- and E-isomers, calculated with the RHF/6-31G ab initio method, range between 0.7 and 2.1 kcal/mol. The Z-isomer is detected to be thermodynamically more stable for studied compounds. X-ray structure determination of 2-dimethylamino-N-phenyl-2-phenylhydrazonoacetamide revealed E- and Z-isomers (ratio 1:1) in the crystal. The different intra- and intermolecular hydrogen bond interactions, which are identified in solid state of compounds, are dissolved in polar solvents. All compounds were found to form E/Z-equilibrium in solution. In some cases E-isomers could be separated and fully characterized.

Introduction

Compounds with an open-chain or cyclic amidrazone structure represent a class of substances with various interesting biological activities. They have been found to be effective towards cholinesterase,2 nucleoside hydrolase3 or glycosidase.4 Their antiinflammatory5 and lipoxygenase or cyclooxygenase inhibiting properties6 are already known.

Recently we reported about the synthesis of α-carbonyl substituted, open-chain amidrazones, which demonstrate inhibitory activity against soybean lipoxygenase-1 and human 5-lipoxygenase.7 To correlate the biological activity with the structure of amidrazones, their exact structural elucidation is required. N2-Arylsubstituted amidrazones with an α-carbonyl function can exist in the hydrazono (1), azo–enol (2) or azo (3) tautomeric form (see Scheme 1), each of which exhibits geometric isomerism. In literature, structure 1 is indicated to predominate.

Nearly all structures of N2-arylamidrazones determined by X-ray diffraction analysis were found to be Z-configured.8, 9, 10 The structure of Z- and E-isomers of C-phosphoryl substituted formamidrazones was reported by Buzykin.11 Cunningham et al.12 describe E/Z-N2-aryl-N1-dimethylethaneamidrazones, which bear at N2 an additional methyl group. It was observed that uncatalyzed isomerization could be slowed by the presence of a disubstituted N2-nitrogen. Since amidines are configurationally less stable, more attention has yet been given to isomerism of corresponding amidoximes,13 imidates14 and hydrazonates.15

Starting from hydrazonoyl chlorides 4, we have synthesized further derivatives of N1-dialkyl-N2-aryl substituted oxaniloamidrazones 58.

In the presence of a base in aprotic solvents hydrazonoyl chlorides react to form 1,3-dipolar ions. Kinetic studies demonstrated that base catalyzed dehydrochlorination of hydrazonoyl chlorides like 4 proceed in a fast step to the anion, which is followed by the slow abstraction of chloride to form nitrilimine. Studies referred to solvent mixture dioxane/water and triethylamine as base.16 Furthermore, the nucleophile can substitute the chloride function. To explain mechanism of substitution at the carbon–nitrogen double bond, extensive investigations were undertaken by Rowe and Hegarty.17, 18, 19, 20 Preferably, N-disubstituted hydrazonoyl halides Aryl–C(X)double bondN–N(Me)Aryl 9 were studied, which cannot form nitrilimines under base conditions. Modes of reaction of the halide with a nucleophile are conceivable:

  • -

    SN1 type slow scission of the carbon–halogen bond to yield an intermediate azocarbenium ion;

  • -

    direct (SN2) displacement of halogen by a nucleophile.

Reaction in polar solvents like acetone/water or dioxane/water proceeds following the dissociative mechanism (SN1, DN+AN).18 In less polar solvents, an addition–elimination mechanism (SN2, AN+DN) predominates. The rate determining step of SN2 varies depending on solvent and base. With a strong base, the addition is discussed to be rate determining (AN#)14 whereas in most nonpolar solvent like benzene with secondary amines the elimination was noted to be the rate determining step (SN#).17

Considering that amidrazones 58 were prepared using dioxane as solvent, first step of reaction is assumed to lead to the abstraction of proton by base followed by an addition–elimination pathway. The stereospecifical formation of Z-isomers is explainable with both mechanisms. In case of SN1, the nucleophile attacks the carbenium ion in trans position to the imino lone pair.12 On the other hand following SN2, the lone pair has such a configuration in the transition state that the stereospecifically trans elimination can occur.18 All these data indicate, that the reaction of 4 with amines leads to Z-configured amidrazones.

Here we report for the first time on the separation and fully characterization of E-isomers besides Z-isomers of N2-arylamidrazones.

Section snippets

Results and discussion

The preparation of hydrazonoyl chlorides 4 is well known because of their extensive use in 1,3-dipolar cycloaddition reactions. The synthesis of derivatives 4a4j, 4l, 4m and 4o4q is described in literature (lit. see Section 3). According to the reported procedures hydrazonoyl chlorides 4k and 4n were additionally prepared. The substitution pattern of compound 4 is shown in Table 1.

The structural assignment of 4 in solid state and in solution was reported.21 Amidrazones 58 were obtained by

General remarks

The quantum chemical calculations of the interesting compounds were carried out using the GAMESS program.22 Optimized geometries and total energies of the E- and Z-isomers were calculated using the RHF/6-31G ab initio method. The input structures for the individual compounds were generated on the basis of the determined X-ray structures of 5a and 7g using the SYBYL6.9 program.23

Melting points were determined with a Kofler hot-stage apparatus and are uncorrected. NMR spectra were recorded on a

References and notes (27)

  • G. Drutkowski et al.

    Tetrahedron

    (2002)
  • A.S. Shawali et al.

    Tetrahedron

    (1971)
  • J. Debord et al.

    J. Enzym. Inhib.

    (1997)
  • H. Deng et al.

    Biochemistry

    (1996)
  • E.S.H. El Ashry et al.

    Pharmazie

    (2000)
  • J.M. Robert et al.

    Arzneim.-Forsch./Drug Res.

    (1997)
  • P. Provost et al.

    J. Pharmacol. Exp. Ther.

    (1996)
  • P. Frohberg et al.

    Arch. Pharm. (Weinheim, Ger.)

    (1995)
  • A. Meijere et al.

    Mendeleev Commun.

    (1999)
  • H. Graf et al.

    Chem. Ber.

    (1987)
  • R.L. Harlow et al.

    J. Cryst. Mol. Struct.

    (1975)
  • B.I. Buzykin et al.

    Zh. Obshch. Khim.

    (1995)
  • I.D. Cunningham et al.

    J. Chem. Soc., Perkin Trans. 2

    (1986)
  • Cited by (0)

    See Ref. 1 for Part 2.

    View full text