A queer product of the Beirut reaction with dimedone-AM1

analysis

Lemi Turker*, Erdem Dura

Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey

Received 15 March 2002; accepted 8 May 2002

Abstract

Dimedone reacted with benzofuraxane in the presence of Et3N. The expected products were quinoxaline derivatives but an

unexpected compound was obtained in low yield. The structural identification of the product was done spectrally and a

mechanism for its formation was proposed by the aid of AM1 type semiempirical calculations. q 2002 Elsevier Science B.V.

All rights reserved.

Keywords: Benzofurazan oxide; Beirut reaction; Dimedone; AM1 calculations

1. Introduction

The Beirut reaction, imported to the chemical

literature in 1965 [1–3] makes use of the reaction of

benzofuroxan (see Fig. 1) with enamines, enols,

phenols, a,b-unsaturated ketones, etc. [4–6], to

produce mainly quinoxaline-N-oxides.

The continuous interest in the basic aspects of the

chemistry of this class of the aromatic-N-oxides by the

pharmaceutical sector of chemical industry resulted in

the synthesis of a large number of new derivatives of

these compounds for the purpose of examining their

antibacterial activity. Indeed some of them were

found to be active and are sold on the market (eg.

Carbodox and Alaquindox).

The benzofuroxan (1) (BFO, benzofurazan oxide,

3,4-benzo-11,2,5,oxadiazole-2-oxide or 2,1,3-ben-

zoxadiazole-1-oxide) has an additional six-membered

aromatic ring system adjacent to the monocyclic

1,2,5-oxadiazole oxides, the furaxanes (Fig. 1). Fig. 2

shows the general reaction of BFO with 1,3-diketones

[7]. Note that two isomeric structures are expected

whenever 1,3-diketone is not symmetrical.

In the present study, the Beirut reaction in between

BFO and dimedone 2 (see Fig. 1) has been studied and

an unexpected product is reported together with some

theoretical analysis at the level of AM1 type

semiempirical calculations.

2. Experimental

Five millilitre of ethanolic solution of dimedone

(3.5 £ 1023 mol, 0.48 g), 0.25 g (1.75 £ 1023 mol)

BFO and 10 ml triethylamine were mixed and

refluxed for 6 h. The reaction mixture was separated

by TLC (CHCl3). The orange coloured zone ðRf ¼

0:33Þ was isolated (0.03 g, 5%).

The nuclear magnetic resonance (1H and 13C)

0166-1280/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved.

PII: S0 16 6 -1 28 0 (0 2) 00 3 11 -1

Journal of Molecular Structure (Theochem) 593 (2002) 143–147

www.elsevier.com/locate/theochem

* Corresponding author. Tel.: þ90-312-210-3244; fax: þ90-312-

210-1280.

E-mail address: lturker@metu.edu.tr (L. Turker).

spectra were recorded on a Bruker AF400 (400 MHz)

spectrometer. Chemical shifts are reported in parts per

million (d ) downfield from an internal tetramethyl

silane reference. Infrared spectra were recorded on a

Perkin–Elmer 1600 series FT-IR spectrometer.

3. Method

In the present treatise, the geometry optimizations

of all the structures leading to energy minima were

achieved by using AM1 self-consistent fields mol-

ecular orbital (SCF MO) [8] method at the restricted

Hartree–Fock (RHF) level [9]. The optimizations

were obtained by the application of the steepest-

descent method followed by conjugate gradient

methods, Fletcher–Rieves and Polak–Ribiere, con-

secutively (convergence limit of 4.18 £ 1024 kJ/mol

(0.0001 kcal/mol) and RMS gradient of 4.18 £ 107

(kJ/M mol) (0.001 kcal/(A mol))). All these compu-

tations were performed by using the Hyperchem

(release 5.1) and ChemPlus (2.0) package programs.

4. Results and discussion

Dimedone (5,5-dimethyl-1,3-cyclohexadione) 2

is a cyclic symmetrical b-dicarbonyl compound. It

has two potential sites to undergo Beirut reaction.

The most active methylene group is the site in

between two keto groups whereas there exist two

less active sites. Fig. 3 shows the structures of the

Fig. 1. Structures of BFO and dimedone.

Fig. 2. The reaction of BFO with 1,3-diketones.

Fig. 3. The expected quinoxaline-N-oxides from BFO and dimedone

reaction.

L. Turker, E. Dura / Journal of Molecular Structure (Theochem) 593 (2002) 143–147144

quinoxaline-N-oxides expected from the Beirut reac-

tion occurring between BFO and active and less active

sites of dimedone. However, in the present study

among the various products, the one shown in Fig. 4

was obtained as the unexpected compound (3).

The structure elucidation of compound 3 was done

by FT-IR, 1H-NMR, COSY, HMQC, HMBC and

Mass Spectroscopy.

In the IR spectrum, the weak diffused peaks in

between 3600 and 3800 cm21 suggests the hydrogen

bonding. Also it is clear to see the CyO stretching

vibration of carbonyl group of ketone at 1737 cm21.

For the structure determination mainly 1H-NMR

spectroscopy was used. The four aromatic protons of

compound 3 arise at the aromatic region as two

doublets and two triplets.

The two doublets at 8.45 and 7.9 ppm arise from

the protons on carbons labelled 1 and 4, respectively.

The ortho coupling ðj12 ¼ j34Þ is measured as 8 Hz for

these two protons. Also the meta coupling ðj13 ¼ j42Þ

of the same protons is observed in the expanded

spectrum insignificantly. The two triplets at 7.75 and

Fig. 4. Structure of the unexpected compound obtained from BFO

and dimedone.

Fig. 5. The dimerization products of dimedone.

Table 1

Various energies of some of the structures presently considered

Compound no. Total energy Binding energy Heats of formation

4 2319,723 217,518.7 2535.18

5 2319,702 217,497.0 2513.44

6 2319,701 217,496.4 2512.90

7 2466,802 222,896.1 8.20

8 2466,794 222,888.1 16.23

9 2466,799 222,893.4 10.96

10 2466,797 222,891.0 13.29

11 2466,815 222,908.6 24.30

15 2433,305 222,098.0 121.17

Energies in kJ/mol.

Fig. 6. Possible products of the Beirut reaction from BFO and

compound 4 (the bonding between N and O atoms is coordinate

covalent).

L. Turker, E. Dura / Journal of Molecular Structure (Theochem) 593 (2002) 143–147 145

Fig. 7. A series of reaction leading to the experimentally obtained product.

L. Turker, E. Dura / Journal of Molecular Structure (Theochem) 593 (2002) 143–147146

7.65 ppm arise from the protons on carbon atoms 2

and 3, respectively. The equivalent ortho coupling

ðj21 ¼ j23 ¼ j32 ¼ j34Þ of each proton with the two

adjacent protons is measured as 6 Hz and the meta

coupling ðj24 ¼ j31Þ as 1.4 Hz.

The correlations between these four aromatic

protons are also observed as crosspeaks in COSY

spectrum. The low field acidic proton raised at

11.6 ppm is due to the proton of the hydroxyl group

attached to nitrogen. The connectivity of hydroxyl

group to a heteroatom is satisfied with the absence of

any carbon coupling in the HMBC spectrum. The

olefinic proton labelled H6 gives a singlet at 5.30 ppm

as expected. The correlation of this olefinic proton

with its sp2 type carbon can be seen in the HMQC

spectrum. The two methylenic protons adjacent to the

carbonyl group arise at around 5.1 ppm as a singlet of

two protons and the other two methylenic diastreo-

topic protons give two doublets at around 3 ppm (2.75

and 3.30 ppm). The correlations between the two-

diastreotopic methylenic protons are also seen as

crosspeaks in the COSY spectrum. The twelve-methyl

protons are observed in the aliphatic region as two

singlets. The mass spectrum of compound 3 has a

molecular ion peak at 362 which is consistent with the

molecular weight of the assigned product.

The unexpected nature of product 3 directed us to

propose a mechanism for its formation by the help of

theoretical contemplations. The geometry optimized

dimedone molecule has CS symmetry. Chemically, of

its three active methylenic groups, two are indis-

tinguishable. Obviously, the one flanked by two

carbonyl groups is the most active one because of

the more acidic nature of the hydrogens on the

methylenic carbon. Thus, the dimerization of (self-

condensation product) of dimedone should mainly

occur involving the most reactive methylenic carbon

to yield compound 4 and from the less reactive

methylenic group to produce compounds 5 and 6 (see

Fig. 5). Table 1 shows the various energies of

compounds 4–6. All these molecules should be stable

(the total and binding energies) and exothermic (the

heats of formation). Of these three structures, 4 is

more likely to form thermally. Compound 4 may

undergo the Beirut reaction in four different ways to

form structures 7–10 (Fig. 6). Table 1 also shows the

various energies of structures 7–10.

These are stable but endothermic structures. The

most favourable structure is 7. After formation of

compound 7, possibly a series of reactions occur in the

presence of base (Et3N) in aqueous medium (see Fig.

7). Note that structures 7 and 11 are isomers of each

other and 11 is an exothermic structure and more

stable than 7 (see Table 1). A base attack on 11 to

remove one of the a-hydrogens (see Fig. 7) initiates a

conjugate addition to produce 12, which may yield 13

and 14. The later one produces compound 3 by water

elimination. Compound 3 is the experimentally

obtained structure which may undergo 1,4-proton

tautomerism to produce tautomer 15. However, the

calculations reveal that structure 3 is more stable and

less endothermic than 15 (see Table 1).

5. Conclusion

A b-dicarbonyl compound like dimedone may give

various products with BFO through congruent reac-

tions because it possesses more than one active

methylene groups. In general, in syntheses if further

consecutive reactions occur on any of the products,

even the structure elucidation of them could be

possible by means of modern techniques, to write

plausible mechanisms for their formations in some

cases it is not a straightforward task to do but requires

the aid of theoretical methods. Of course, mechanisms

are essential to understand the chemical reactions at

the molecular level.

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L. Turker, E. Dura / Journal of Molecular Structure (Theochem) 593 (2002) 143–147 147