A Simple, Rapid and Mild One Pot Synthesis of Benzene Ring Acylated and Demethylated Analogues of Harmine under Solvent-free Conditions

A simple, rapid, solvent-free, room temperature one pot synthesis of benzene ring acylated and demethylated analogues of harmine using acyl halides/acid anhydrides and AlCl3 has been developed. Eight different acyl halides/acid anhydrides were used in the synthesis. The resulting mixture of products was separated by column chromatography to afford 10- and 12-monoacyl analogues, along with 10,12-diacyl-11-hydroxy products. In five cases the corresponding 10-acyl-11-hydroxy analogues were also obtained. Yields from the eight syntheses (29 products in total) were in the 6-34% range and all compounds were fully characterized.


Introduction
Solvent-free chemical syntheses have recently received much attention. These processes are not only environmentally benign, but also economically beneficial because toxic wastes can be minimized or eliminated, so the costs of waste treatment are also reduced. An additional attractive feature is their operational simplicity. Thus, there are now over 500 published papers describing solvent-free reactions giving quantitative yields on the gram and kilogram scale that support the effectiveness of the method [1][2][3][4].
Friedel-Crafts acylation is one of the most important protocols for the formation of C-C bonds between aromatic rings and aliphatic moieties. This method generally requires addition of a Lewis acid catalyst such as AlCl 3 to a well-stirred mixture of an alkyl or acyl halide and an aromatic compound under inert conditions. Usually, these reactions require high temperatures, long reaction times and tedious workups [5][6]. Recently, Friedel-Crafts acylation of alkoxybenzenes was achieved efficiently by a reaction with aliphatic acid anhydrides in the presence of catalytic amounts of aluminum hydrogensulfate, Al(HSO 4 ) 3 , both in nitromethane and under solvent-free conditions, but these reactions required high temperaures (70 o C) for completion [7]. Although the acetylation of aryl ethers using acetic anhydride in the presence of zeolites under mild conditions in a solvent-free system gave the corresponding para-acetylated products in high yields, these reactions also required high temperatures (120 o C) and occurred only in activated aromatic compounds [8]. The use of metal triflates in ionic liquids for Friedel-Crafts acylation have also been reported, but it is again limited to highly activated substrates and also requires high temperatures [9].

Results and Discussion
The solid phase reaction of harmine (1) with different acylating agents (acetic anhydride, propionyl chloride, butyric anhydride, iso-butyric anhydride, valeryl chloride, hexanoyl chloride, heptanoyl chloride and capryloyl chloride) in the presence of AlCl 3 yielded mono acyl derivatives without demethylation as well as mono and diacyl derivatives with demethylation. The acylation took place at the carbons ortho to the methoxy group (C-10 acylated products 2-9) and (C-12 acylated products 10-17). Acylation with demethylation of the C-11 OCH 3 group yielded both monoacyl (C- 10-acyl,11hydroxy 18-22) and diacyl (C-10,12-diacyl,11-hydroxy 23-30)  These reaction products were separated by silica gel column chromatography. It was noted that 10acyl derivatives were obtained as the major products. The remaining derivatives were also obtained in acceptable yields (Table 1). No 10-acyl-11-hydroxy derivatives could be isolated in the present work from the products of the reaction with acetic anhydride (entry A), valeryl chloride (entry E) and capryloyl chloride (entry H). All these harmine derivatives are reported for the first time. The 10,12diacyl-11-hydroxy products may be formed from 10-acyl-11-hydroxy compounds through direct Friedel-Crafts acylation at C-12, or may be obtained after esterification of phenolic OH, through Fries rearrangement in the presence of AlCl 3 [15]. The demethylation of 11-OCH 3 in the presence of Lewis acid (AlCl 3 ) may be due to the electron withdrawing effect of the 10-acyl group and the pyridine ring of harmine. The resulting phenolic OH facilitates the introduction of second acyl group in the benzene ring and considerable quantities of 10,12-diacyl-11-hydroxy derivatives of harmine were obtained under these solvent-free conditions. Earlier it has been reported that phenols do not react satisfactorily with Friedel-Crafts reagent in solvents because of their reaction with Lewis acids (Ar-OH + AlCl 3 Ar-O-AlCl 2 + HCl) resulting in compounds which are usually only sparingly soluble in the reaction medium and hence slow down the reactions [16]. It is important to note that under the same reaction conditions Ghiaci and Asghari [17] reported O-acylated phenols but in the present studies no Oacylated product was obtained. Further, under these reaction conditions no acylation of the pyridine ring of 1 occurred.  Tables 2 and 3) and comparison of the spectral data with reported values of similar compounds [13,[18][19]. For the 10-acyl analogues (see compound 3 in Table 2), the characteristic H-9 and H-12 peaks appeared in the 1 H-NMR spectra as one-proton singlets at ~ δ 8.5 and 7.1, respectively, confirming the substitution at C-10. The 1 H-NMR spectra of 12-acyl analogues (compound 11) characteristically showed two sets of one-proton doublets at ~ δ 8.2 and 6.9, assigned to H-9 and H-10 respectively, showing the substitution on C-12. For 10-acyl demethylated analogues (compound 18), the characteristic peaks of H-9 and H-12 appeared as oneproton singlets at ~ δ 8.8 and 6.9, respectively, whereas for 10,12-diacyl demethylated analogues (compound 24), the characteristic H-9 peak appeared as a one-proton singlet at ~ δ 8.7 and a peak for chelated phenolic OH appeared at ~ δ 14 in CDCl 3 in the 1 H-NMR spectra. The demethylation was also confirmed from their high resolution mass spectral data (See Experimental). The 13 C-NMR signals of quaternary carbons were particularly assigned on the basis of HMBC connectivities observed for these carbons with various protons. The typical HMBC connectivities of various protons with different carbons are also shown in Figure 1 for compound 24.

Conclusions
In this study new benzene ring substituted and demethylated derivatives of harmine were obtained for the first time in one-pot using acyl halides/acid anhydride and AlCl 3 under solvent-free conditions at room temperature after short reaction times. The derivatives obtained in these studies are being screened for potential biological activities such as anti-cancer, anti-bacterial, anti-fungal, CNS and anti-hypertensive properties. The results will be reported in due course. Further the β-carboline alkaloids possessing acyl substituents on C-10 and C-12 are rare in nature, hence the spectral data presented in this communication should be a useful contribution to the structural elucidation of related natural products.

General
Melting points were determined using a Buchi-535 melting point apparatus and are uncorrected. Ultraviolet spectra were measured on a Hitachi-3200 spectrophotometer. Infrared spectra were recorded on a Bruker VECTOR 22 spectrophotometer. The 1 H-and 13 C-NMR spectra were recorded at 400 and 100 MHz, respectively, on a Bruker Avance 400 spectrometer. Mass spectra were run on a Jeol JMS-HX110 (high resolution, E.I. probe, 70 eV) and a Varian MAT-312 (low resolution, E.I. probe, 70 eV) instrument.