A short and efficient construction of the dibenzo [ c , h ] chromen-6-one skeleton

We hereby report a major revision of the synthetic methodology for construction of the dibenzochromenone skeleton. Homophthalic acid derivatives were reacted with thionylchloride/DMF in the presence of NaN3. As the main product, dibenzochromenone derivatives were obtained. When the reaction was performed in the absence of NaN3, only isochromenones were formed. The mechanism of the formation of these products is discussed.


Introduction
Dibenzo[c,h]chromen-6-one 1 motifs are of considerable interest due to their biological activity and structural intricacies.They exhibit a wide range of biological activities.Arnottin I 2, a dibenzo[c,h]chromen-6-one derivative was first isolated by Ishikawa and coworkers in 1977, as a minor constituent from the bark of Xanthoxylum arnottianum. 2However, the structure of this compound was not determined until 1993 since the producing plant yielded only small quantities of the material. 3Gilvocarcins 3, 4, 4 a relatively small family of natural antibiotics having the dibenzo[c,h]chromenone skeleton, also exhibit diverse biological activity. 5he key step in syntheses of these compounds has been mainly metal-catalyzed aryl-aryl coupling reactions of the suitable substituted starting materials which were synthesized by multistep procedures.James and Snieckus used mainly Negishi/Suzuki cross coupling followed by a remote metallation (DreM)-carbamoyl migration strategy. 5Ishikawa et al. used palladiumcatalyzed coupling of o-bromobenzoates and 1-tetralones to construct the dibenzo[c,h]chromenone structure. 6Suzuki et al. used a three component system for the synthesis of defucogilvocarcin M 3. 7 Nickel-catalyzed synthesis of benzocoumarin derivatives and its application to the total synthesis of arnottin I 2 was achieved by Madan and Cheng. 8In this paper, we describe a concise procedure leading directly to the core skeleton of dibenzo[c,h]chromenone structure with some substituents resembling the arnottin I structure 2. Furthermore, the position of the substituents in the products should provide information about the mechanism of formation of the products.

Results and Discussion
Recently, we have treated homophthalic acid 5 with thionyl chloride, DMF, and sodium azide in the presence of tetrabutylammonium bromide as a catalyst.Unfortunately, the expected diazide 7 was not formed.The dibenzo[c,h]chromenone 1 was formed in 41% yield. 9,10In order to test the general applicability of this reaction for the formation of substituted dibenzo[c,h]chromenones, substituted homophthalic acids were used.First, the original reaction was reinvestigated.
N,N-Dimethyl(chlorosulfinyloxy)methaniminium chloride formed from thionyl chloride and dimethyl formamide is an efficient reagent for the synthesis of acyl azides from carboxylic acids. 10Therefore, homophthalic acid 5 was reacted with thionyl chloride, DMF, and sodium azide, in the presence of tetrabutylammonium bromide as a catalyst in methylene chloride, anticipating formation of the diazide 7.However, the desired diazide 7 was not formed.Besides the major product, 6H-dibenzo[c,h]chromen-6-one 1, an thioisocoumarin derivative 6 was isolated in 4% yield (Scheme 1).COSY, HMQC, and HMBC experiments were conducted to confirm the the assignment of the structure of 6.Two carbonyl carbons appeared at 191.3 and 183.1 ppm, the high field resonance being that for the five-membered ring carbonyl carbon.With the help a of COSYspectrum we were able to distinguish between the aromatic protons of two benzene rings.The HMBC specrum showed that the carbonyl carbon resonance at 183.1 (C-5) correlates with the doublet (H-4) resonating at 8.17 ppm.On the other hand, the carbonyl carbon resonance at 191.3 (C-11) correlated with the doublet at 7.5 ppm (H-10).These observations clearly show that the carbonyl groups are directly connected to different benzene rings.The quaternary carbon atom C-6a correlated with the doublet resonating at 7.17 (H-7) whereas the carbon atom C-11a correlated with the doublet at 8.95 ppm (H-1).Those findings support the proposed structure.The incorporation of a sulfur atom into the molecule was determined by elemental analysis as well as by its mass spectrum.With the isolation of this new isothiocoumarin derivative 6, the focus of the research was directed to the increase of its yield.The same reaction was carried out but in the absence of DMF.This procedure increased the yield of the isothiocoumarin derivative 6 from 4% to 17%.On the other hand, elemental sulfur and new condensation products such as 8, 9 and 10 were isolated in 8, 14, and 7% yields, respectively (Scheme 2).Interestingly, the major product 1, which was formed when the reaction was carried out in the presence of DMF, was not detected.This observation shows that DMF is involved in the formation of 6H-dibenzo[c,h]chromen-6-one 1.The spectral data of 8 was in agreement with those reported in the literature. 13The presence of three benzene rings in 9 was easily established by analysis of the 1 H-NMR spectrum.The 13 C-NMR spectrum had 22 lines for aromatic carbons.The carbonyl resonances observed at 191.8, 158.0 ppm are in agreement with the proposed structures.COSY, HMQC, and HMBC spectra also support the structure.Again with the help of the COSY spectrum, the connection of the aromatic protons was easily determined.The HMBC spectrum showed correlation of the carbonyl resonance at 191.8 (C-11) ppm with the doublet resonating at 7.59 (H-12) ppm.The other carbonyl carbon at 160.4 (C-5) correlated with the doublet at 8.30 (H-4) ppm.Furthermore, the carbon atom at 151.2 (C-6a) correlated with the doublet at 8.25 (H-7) ppm.Additionaly, the coupling constants between the protons H-7 and H-8 (J7,8 = 8.4 Hz) and H-8 and H-9 (J8,9 = 6.9 Hz) clearly showed the presence of a naphthalene unit in the proposed structure.The high resolution mass spectrum and the 1 H-NMR spectrum of 10 clearly indicated the presence of a nitrogen atom in the molecule.Nine proton resonances between 7.2-8.3ppm, where one of them resonates as singlet, support the structure.Furthermore, an IR absorption band at 2225 cm -1 demonstrated the presence of a nitrile group.Two dimensional NMR spectra were also in agreement with the proposed structure 10.
The sulfur containing product, indeno[1,2-c]isothiochromenone-5,11-dione 6 was synthesized independently, in quantitative yield, by reacting 8 with Na2S in THF and water (1:1).Therefore, we assume that sulfide anion formed under the reaction conditions by reduction of SOCl2 by NaN3, 14 substitutes oxygen atom in 8 to give 6.Sulfide anions formed under reaction conditions can undergo further reaction with excess SOCl2 present in the reaction media and produce elemental sulfur.In a separate reaction we successfully demonstrated that reaction of Na2S with SOCl2 in dichloromethane produces sulfur in a very fast process.

Scheme 3 Scheme 3
In order to test the scope of the procedure shown in Scheme 1, the reaction was carried out with two substituted homophthalic acids.Bromohomophthalic acid 11 was synthesized by direct bromination of homophthalic acid.It is well known that the bromination of aromatic compounds containing electron-withdrawing groups has been an area of concern.Homophthalic acid 5 was reacted with potassium bromate 15,16 in sulfuric acid to give the desired brominated diacid 11 in 44% yield.Bromohomophthalic acid 11 was reacted with thionyl chloride, DMF and sodium azide, under the same reaction conditions as described in Scheme 1, to give dibromodibenzochromenone derivative 12 in 37% yield.The 1 H-NMR spectrum was consistent with the proposed structure.In contrast to 1, this dibromo derivative 11 was found to be poorly soluble in organic solvents so that a 13 C-NMR spectrum could not be recorded.Additionally, a minor compound 13 (2%) was isolated.The structure was easily determined by comparison of the spectral data of 13 with those of 6.

Scheme 4
For the synthesis of 4-methoxyhomophthalic acid 16, a modified literature procedure was applied. 17Methoxybenzoic acid 14 was condensed with chloral hydrate to obtain the lactone 15, which was then reduced by zinc in acetic acid followed by hydrolysis to produce the methoxydiacid 16 (Scheme 4).With the synthesis of diacid 16, we were now able to assess its use for rapid and efficient generation of a dibenzochromenone skeleton, but with methoxyl substituents.Treatment of diacid 16 with thionyl chloride, DMF and sodium azide under the same reaction condition as reported for the synthesis of 12, resulted in the formation of the corresponding dimethoxydibenzochromenone derivative 17 in 45% (Scheme 4).The structure and especially the exact positions of the methoxyl groups were determined with the help of COSY, HSQC and HMBC experiments.

Scheme 5
During these reactions a nitrogen atom, arising from azide anion used in the reaction, was not incorporated in the products 12, 13 as well as 17.To determine the function of azide anion, the reaction with 16 was run in the absence of NaN3.Instead of the formation of a dibenzochromenone 17, an aminomethylene compound 18 was formed, which was converted to the isocoumarin derivative 19 18 by reaction with methanol saturated with hydrogen chloride (Scheme 5).

Conclusions
The reactions performed in our work show that the dibenzochromenone structure 1 can be easily generated, even with the substituted homophthalic acid derivatives, in 37-45% yields in a onepot reaction.Furthermore, the attempted azidination reactions homophthalic acid derivatives 5, 11, and 16 show that NaN3 plays an important role in determination the mode of the reaction.In the absence of NaN3, isocoumarin derivative 19 was formed from the reaction of 16 instead of the dibenzocoumarin derivative 17.The mechanism we propose is shown in Scheme 6.

Scheme 6
We suggest that the first step is the formation of the anhydride 20, which could then be regiospecifically opened up by the azide anion to the corresponding monoazide 21.Formation of an acyl azide activates the methylenic protons for further reaction.Intermolecular acylation of 21 with acyl chloride 22 followed by ring-closure would result in the formation of 24.This anhydride might undergo again ring-opening by azide anion attack to form -keto-acid carboxylate 25.Decarboxylation of 25 would lead to cyclization to form the key intermediate 26, which could easily be converted in the dibenzochromenone derivatives 1, 12, and 17 as well as into the nitrile 10.Recently, Threadgill et al. 19 obtained relevant information about the mechanism of the acylation of isocoumarin derivatives which strongly support our suggestion.Furthermore, the exact determination of the positions of the substituents in 12 and 17 supports our proposed mechanism.
The formation of the compounds having cyclopentadienone structures such 6, 8, 13 as well as 9, however, cannot be explained via this mechanism.As one can easily recognize from the position of the substituents in 13, for the construction of this skeleton requires a C-C connection of methylene groups of two homophthalic acid units.
Before such a C-C connection between the two methylene groups can take place, one of these groups should contain a good leaving group.We therefore assume, that firstly a chlorination on one of the methylene goups 20 takes place under the reaction conditions, followed by attack of the enol form of the second methylene group.Decarboxylation and cyclization can then lead to the compounds 8 and 13.

Experimental Section
General.Melting points were determined on a Thomas-Hoover capillary melting point apparatus.IR spectra were recorded on a Perkin Elmer 980 spectrometer.NMR spectra were recorded on a Bruker-Avance instrument at 400 MHz for 1 H and 100 MHz for 13 C NMR. Apparent splitting is given in all cases.Mass spectra were recorded on an Agilent 5975C spectrometer operating at an ionization potential of 70 eV.Column chromatography was performed on silica gel (60-mesh, Merck).TLC was carried out on Merck 0.2 mm silica gel 60 F254 analytical aluminum plates.