An Efficient, Mild and Solvent-Free Synthesis of Benzene Ring Acylated Harmalines

A facile synthesis of a series of benzene ring acylated analogues of harmaline has been achieved by Friedel-Crafts acylation under solvent-free conditions at room temperature using acyl halides/acid anhydrides and AlCl3. The reaction afforded 10- and 12-acyl analogues of harmaline in good yield, along with minor quantities of N-acyl-tryptamines and 8-acyl analogues of N-acyltryptamines.

Chemical modifications of natural product have been the major means to explore more potent analogues. The Friedel-Crafts acylation is an important method for the preparation of aromatic ketones OPEN ACCESS by the reaction of aromatic substrate with acylating agent in the presence of Lewis acid catalyst. The optimization of these preparative processes is of great importance due to the considerable practical value of the aromatic ketone products as these compounds constitute fundamental intermediates in the pharmaceutical, fragrance, flavour, dye and agrochemical industries [13][14][15].
Due to increasing environmental concerns, the solvent-free chemical synthesis has received much attention now a day. These processes are much appealing as they are environmentally benign, economical and provide an opportunity to work with an open vessel requiring short reaction time and simple work up [16][17][18][19]. We have previously reported the Friedel-Crafts acylation of N-acetyl tetrahydroharmine under solvent-free conditions which resulted in synthesis of a series of its 10-acyl and 12-acyl analogues in high overall yields [20]. As a continuation of our studies in this direction, we have attempted the reaction of harmaline (1) with Friedel-Crafts reagents (acyl halides/acid anhydrides and AlCl 3 ) at room temperature and under solvent-free conditions. As a result 10-acyl (2−10) and 12acyl (11−19) analogues of harmaline were obtained in high overall yield along with several N-acyl tryptamines (20−28) and 8-acyl analogues of N-acyltryptamines (29−31) as minor products. All compounds were characterized with the help of spectral studies. Except for compound 20, all derivatives are new.

Results and Discussion
In order to investigate whether harmaline undergoes acylation conveniently on the benzene ring in the presence of the sensitive imine-enamine functionality in the present studies Friedel-Crafts acylation under solvent-free conditions was undertaken. Friedel-Crafts reaction on 1 was carried out with the following reagents: acetic anhydride, propanoyl chloride, butyric anhydride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride and decanoyl chloride (entries A to I) in the presence of AlCl 3 under solvent-free conditions (vide Experimental). As a result 10-acyl (2−10) and 12-acyl (11−19) derivatives of 1 were obtained in high overall yield, along with minor quantities of the N-acyl (20−28) and 8,N-diacyl tryptamines (29−31) resulting from pyrido ring opening (Scheme 1). It may be noted that by changing the quantity of the catalyst either the N-acyl or aromatic-acyl product was formed as the major product, as discussed below.
The N-acyl tryptamine derivatives 20−28 were obtained in high yield when a lower quantity of AlCl 3 (~200 mg) was used. Under these conditions the reaction further afforded minor quantities of the 8-acyl analogues of N-acyltryptamines 29−31. The pyrido ring opening during acylation was reported earlier [10]. However, on increasing the quantity of catalyst (~400 mg) the results were in favour of aromatic acylation leading to 10-acyl (2−10) and 12-acyl (11−19) analogues of harmaline with minor quantities of 20-31. Grinding the catalyst first with harmaline for a few minutes also reduces Nacylation due to catalyst's association with imino nitrogen. It is also worth noting that the 10-acylated regioisomers 2−10 were obtained in good yield on increasing the carbon chain in the acylating reagents ( Table 1, entries C to I). These derivatives have been characterized by spectral studies including IR, EIMS, HREIMS, 1D, ( 1 H-NMR and 13 C-NMR; Broad Band decoupled, DEPT) and 2D-NMR ( 1 H, 1 H COSY, TOCSY, HMQC and HMBC) (see Experimental) and comparison of spectral data with reported values of similar compounds [20][21][22][23][24][25]. For the 10-acyl analogues of harmaline 2−10, the presence of two singlets at ~δ 7.9 and 6.9 in the 1 H-NMR spectra assignable to H-9 and H-12 respectively was in accord with substitution on C-10 position of harmaline. The 1 H-NMR spectra of 12-acyl analogues 11−19 displayed two characteristic sets of one proton doublets at ~δ 7.7 (J = 8.8 Hz) and 6.9 (J = 8. 8 Hz) assigned to H-9 and H-10 respectively, showing the substitution on C-12. For compounds 20−28, characteristic peaks of H-5, H-6 and H-8 appeared in the 1 H-NMR spectra as one proton doublets, double doublets and doublets at ~δ 7.55 (J = 8.8 Hz), 6.79 (J = 8.8 and 2.0 Hz) and 6.75 (J = 2.0 Hz), respectively, suggesting no acylation on benzene ring. However, the presence of a triplet and a quartet at δ 3.28 (J = 6.9 Hz) and 3.54 (J = 6.9) assignable to H-1′ and H-2′ respectively of N-acylamidoethyl group and a three-proton sharp singlet for 2-acetyl group at δ 2.61 were highly suggestive of Nacylation and subsequent pyrido ring opening of harmaline during aqueous workup. Molecular ion peaks in the EIMS and HREIMS also confirmed these results. The 1 H-NMR spectra of compounds 29−31 showed substitution both on benzene ring and pyrido nitrogen and concomitant pyrido ring opening. A set of two mutually coupled downfield doublets at δ 7.86 and 6.88 with a 8.8 Hz coupling constant clearly indicated substitution on C-8 of tryptamine which corresponds to C-12 in harmaline. Further the mass and 1 H-NMR analysis of crude reaction products indicated the presence of corresponding 6,N-diacyltryptamine derivatives also, which could not be separated in the present studies. Formation of 6,N-diacyl and 8,N-diacyltryptamine derivatives in minor quantities indicates that the 2-acetyl group in tryptamine deactivated the benzene ring. The 13 C-NMR signals of quaternary carbons were particularly assigned on the basis of HMBC connectivities observed for these carbons with various protons which are shown in Figure 1 and 2 for 10-and 12-acyl analogues of harmaline, and Figure 3 and 4 for N-acyl and 8, N-diacyl analogues of tryptamine respectively.

General
The melting points were determined using a Buchi-535 melting point apparatus and are uncorrected. Infrared spectra were recorded on a Bruker VECTOR 22 spectrophotometer. The 1 H-and 13 C-NMR spectra were recorded on a Bruker Avance 400 spectrometer operating at 400 MHz ( 1 H) and 100 MHz ( 13 C). Mass spectra were run on a Jeol JMS-HX110 (high-resolution, E.I. probe, 70 eV) and a Varian MAT 311 A (low resolution, E.I. probe, 70 eV) instrument. Harmaline (1) used in the present studies was isolated from the seeds of P. harmala using the procedure described by Siddiqui [26].

General Procedure for Solvent-Free Friedel-Crafts Acylation
A mixture of 1 (100 mg, 0.47 mmol), acylating agent (2.5 mL) and anhydrous AlCl 3 (400 mg, 3.00 mmol) was thoroughly ground in an agate mortar and pestle for 45 min in fume cupboard and then kept at room temperature for 1 h. The reaction mixture was then poured into crushed ice, basified with 30% NH 3 and extracted with EtOAc. The EtOAc layer was washed with water, dried (Na 2 SO 4 ) and freed of solvent under reduced pressure. A solid mass thus obtained afforded compounds 2−31 (Table 1) (20