SYNTHESIS OF NEW HOMODRIMANE SESQUITERPENOIDS CONTAINING DIAZINE, 1,2,4-TRIAZOLE AND CARBAZOLE RINGS

The present paper reports on six step synthesis of 11-homodrim-6,8-dien-12-oic acid N-substituted amides containing diazine, 1,2,4-triazole and carbazole rings based on commercially available sclareolide. The mentioned compounds were prepared for the first time by interaction of the generated in situ acyl chloride with some heterocyclic amines: 2and 4-aminopyrimidine, 2-aminopyrazine, 5-amino-1,2,4-triazole and N-aminocarbazole. Their structures were fully elucidated by elemental and spectral analyses (IR, 1 H and 13 C NMR).

As a continuation of our research into the synthesis of novel compounds containing both terpenic and heterocyclic fragments and in order to obtain a cumulative biological potential of the homodrimane structure and related heterocycles, herein we report the synthesis of some new homodrimane sesquiterpenoids with azaheterocyclic fragments.

Results and discussion
As the starting material for the synthesis of homodrimane compounds with diazine, triazole and carbazole units was used methyl 11homodrim-6,8-dien-12-oate 2 obtained before from commercially available sclareolide 1 in 4 steps, with an overall yield of 85% [11] (Scheme 1). The saponification of ester 2 led to acid 3 in 96% yield and its structure was confirmed by IR, 1 H, and 13 C NMR data.
The 11-homodrim-6,8-dien-12-oic acid chloride 4 (generated in situ from acid 3) was treated with 4-aminopyrimidine 5a, 2-aminopyrazine 5b, 2-aminopyrimidine 5c, 5-amino-1,2,4-triazole 8 and N-aminocarbazole 9 [7,8]. The reactions are highly selective only for monoacyl amides 6a, 6b, 10 and 11 in 69%, 35%, 30% and 40% yields, respectively (see Scheme 2 and Table 1). In the case of 5-amino-1,2,4-triazole 8, an analysis of the spectral data of the reaction product showed that this amine reacted with acid chloride 4 in a tautomeric form and the resulting amide 10 contained an NH 2 group. In the case of 2-aminopyrimidine 5c, monoacyl amide 6c and bis-acylamide 7 were also obtained in 40% and 25% yields, respectively (see Scheme 2 and Table 1). Scheme 2. Synthesis of new homodrimane sesquiterpenoids containing diazine, 1,2,4-triazole and carbazole rings. Reagents and conditions: CH 2 Cl 2 , 20ºC, 5-10 h, 25-69%. With the exception of amide 10, all the other N-substituted amides resulted from condensation of primary amine groups with acyl chloride 4. Virtually, all the secondary amides may react again with acyl chloride but, according to the experimental data, only monoacyl amide 6c underwent bis-acylation to give 7. Probably, this occurred, as a result of delocalization of nonbonding electrons of nitrogen to the adjacent carbonyl group (resonance of the amide bond) that reduced the reactivity of amides versus amines. In addition to this, the resonance structures for amides 6a-c also show delocalization over the aromatic cycle so the aryl substituents determine their reactivity. Probably, the reaction time is important in order for the bis-acylation to occur.

Conclusions
Starting from commercially available sclareolide 1, a series of novel compounds 6a-c, 7, 10 and 11, containing both homodrimane and heterocyclic (diazine, 1,2,4-triazole and carbazole) fragments, were synthesized and their structures were confirmed using IR, NMR spectroscopy ( 1 H and, 13  In the case of 5-amino-1,2,4-triazole 8, analysis of the spectral data of the reaction product showed that the amine reacted with acyl chloride 4 in its tautomeric form and the resulting amide 10 contained an amino group. In the case of 2-aminopyrimidine 5c, besides monoacyl amide 6c, bis-acylamide 7 was also obtained, because of an unusual one pot bis-acylation.

Generalities
Melting points (m.p.) were taken on a Boetius hot stage apparatus.
Optical rotations were determined on a Jasco DIP 370 polarimeter with a 1 dm microcell, in CHCl 3 and MeOH.
The IR spectra were registered on a Spectrum-100FT-IR spectrometer (Perkin-Elmer) by the ATR technique. 1 H and 13 C NMR spectra were recorded in CDCl 3 and DMSO-d 6 on a Bruker Avance DRX 400 spectrometer. Chemical shifts are given in ppm in the δ scale and referred to CHCl 3 (δ H at 7.26 ppm) and to CDCl 3 (δ C 77.00 ppm), respectively, and to DMSO-d 6 (δ H at 2.50 ppm) and to DMSO-d 6 (δ C 39.52 ppm), respectively. The coupling constants (J) are reported in Hertz (Hz). The H, H-COSY, H, C-HSQC and H, C-HMBC experiments were recorded using standard pulse sequences, in the version with z-gradients, as delivered by Bruker Corporation. Carbon substitution degrees were established by the DEPT pulse sequence.
For the analytical TLC, Merck silica gel plates 60G in 0.25 mm layers were used. The TLC plates were sprayed with concentrated H 2 SO 4 and heated at 80°C. The column chromatography was carried out on the Across Organics silica gel (60-200 mesh) using dichloromethane and the gradient mixture of CH 2 Cl 2 and MeOH.
All solvents were purified and dried by standard techniques before use. Solutions in organic solvents were dried over anhydrous Na 2 SO 4 , then filtered and evaporated under reduced pressure.