REGIOSELECTIVITY OF BROMINATION WITH MOLECULAR BROMINE IN EUGENOL AND ITS DERIVATIVES AND APPLICATION OF BROMOEUGENOL DERIVATIVES FOR THE SYNTHESIS OF CONIFERYL ESTERS

• Main Author: Arifin, Budi
• Format: Dissertations
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/65757
• Institution: Institut Teknologi Bandung

Eugenol (4-allyl-2-methoxyphenol, 1) is the main component in clove essential oil. Modification of allyl, methoxy, and phenol groups has resulted in various high-value derivative products of 1. Bromination is a form of modification of 1 and has been reported using molecular bromine (Br2), modified Br2 reagent, and oxybromination reagent. Br2 adds the allyl group, before substituting the aromatic ring. Aromatic bromination of 1 is an important chemical modification, especially for the synthesis of natural products from lignan and neolignan groups. In this study, eugenol (1) was used as a starting material for the synthesis of podophyllotoxin (8), an aryltetralin lactone lignan which is active as anticancer and antiviral. The key reaction used is the intramolecular tandem-Heck reaction on the 6-bromoconiferyl ester. The use of 1 as a starting material and the tandem-Heck reaction has not been reported in the synthesis of 8. Synthesis of 6-bromoconiferyl esters requires aromatic bromination of 1 at C-5. Aromatic bromination of 1 always takes place at C-6 and has not been reported at C-5. In contrast, aromatic bromination of eugenyl benzoate (10) and methyleugenol (12) with Br2 was reported to take place at C-5. Therefore, in this study, bromination studies have been carried out with Br2 in chloroform (CHCl3) in 1 and four derivatives of 1, namely eugenyl acetate and benzoate and benzyl- and methyleugenol (9–12). The course of the reactions was monitored by TLC, the products were isolated by column chromatography and the molecular structure was determined based on the NMR and mass spectra. All of the studied eugenol derivatives underwent aromatic bromination at C-5 after bromination of the allyl group. Eugenyl acetate (9) forms dibromide (13) and then tribromide (14) with 1.2 equiv of Br2. Aromatic bromination triggers the hydrolysis of acetyl esters, resulting in the formation of dibromide (15) and tribromides I and II (16 and 17a, b) of eugenol, which amounts increase with excess Br2 (2.4 and 3.6 equiv). The second aromatic bromination has also formed eugenol tetrabromide (18). Eugenyl benzoate (10) forms dibromide (19) with 1.2 equiv of Br2 and tribromide (20) with excess Br2. Benzyleugenol (11) predominantly forms dibromide (21a, b) with 1.2 equiv of Br2, then predominately forms tribromide (22) with 2.4 equiv of Br2. The benzyl ether cleavage became massive with 3.6 equiv of Br2, resulting in 16 and 18 as the major products. The bromination of methyleugenol (12) has different reaction steps. First, Br2 reacts with 12 to form dibromide (24) which immediately forms tribromide II (23). Isomerization of 23 then forms tribromide I (25) along with further conversion of 24 to 23 until an equilibrium composition (approx. 1:3) of 23 and 25 is achieved. Overall, 13 brominated products (13–25) were successfully synthesized in this study. Products 20 and 25 have been reported, eleven other products are first reported in this study. Compounds 17 and 21 are a pair of conformational isomers, which are separated on TLC with a small Rf difference. In addition to adopting a 'stable' mean conformation, the 2,3-dibromopropyl side chain in these two products is thought to have an all-gauche 'unstable' conformation which is stabilized under certain conditions. Further research is needed to confirm this conformation. Product 23 is interesting for further study because it can be modified, for example, to form benzocyclobutene derivatives. The aromatic ring of tribromides 14, 20, 22, 23, and 25 are all substituted by bromine atom at C-5. Meanwhile, bromination of eugenol (1) with 2.4 equiv Br2 in this study resulted in eugenol tribromide II (17), which aromatic ring is substituted by bromine atom at C-6, and tetrabromide (18). Thus, the protection of phenol at 1 has changed the regioselectivity of aromatic bromination from C-6 to C-5. This regioselectivity shift has not been reported in 9 and 11. This study showed that the acetyl and benzyl protection resulted in the same regioselectivity shift as the benzoyl and methyl protection in 10 and 12 which has been reported. The different activating or deactivating properties of the protecting groups have no effect on the bromination orientation. Yet, the bromination rate is still affected. The results of this study indicate that benzoyl protecting group most deactivates and conversely, methyl protecting group most activates the aromatic ring. It is then utilized to synthesize coniferyl esters from eugenyl benzoate dibromide (19) and 6-bromoconiferyl esters from methyleugenol tribromide I (25). The esters are formed through dehydrobromination and nucleophilic substitution of the vicinal dibromide structure. Reaction of 19 with acetic and benzoic acid gave coniferyl esters 27 and 28 with overall yields of 39% and 22% from 1. Reaction of 25 with acetic, cinnamic and acrylic acids gave 6-bromoconiferyl esters 29–31 with overall yields of 47%, 49%, and 42% from 1. The formation of non-allylic alkene by-products in the dehydrobromination step contributes to the moderate yields. Although the yield is not yet optimal, the utilization of eugenol (1) for the synthesis of coniferyl esters and 6-bromoconiferyl esters is potential to provide great added value for Indonesian clove products. The 6-bromoconiferyl ester can be utilized for synthesis of more complex natural products. In this study, ester 31 was used to synthese analogue of 8. However, the Heck cyclization reaction under various reaction conditions did not produce the desired reaction product. Instead, hydrolysis and oxidation of the ester 31 occur to form alcohol 32 and aldehyde 33.