Synthesis 1,2-bis ((3-methylbut-2-en-1-yl)oxy) -4-(((3methylbut-2-en-1-yl)oxy)methyl)benzene

Abstrak—Kojic acid and arbutin are materials that are used to inhibit melanogenesis, but in their development, these two compounds have an adverse effect on the skin. 3,4dihydroxybenzaldehyde is a simple phenol compound whose derivatives are used as flavorers and fragrance. The research carried out aims to obtain 3,4-dihydroxybenzaldehyde derivatives in the form of 1,2-bis((3-methylbut-2-en-1-yl)oxy) 4(((3-methylbut-2-en-1-yl)oxy)methyl)benzene which is estimated based on its structure is able to inhibit melanogenesis, and has a similar structure to the commercial fragrance of methyl diantilis. The synthesis of the target compound is carried out in three step. The first step involves the alkylation of 3,4dihydroxybenzaldehyde with 3,3-dimethylalyl bromide and sodium hydride in the dimethylformamide solvent at room temperature to obtain 3,4-bis ((3-methylbut-2-en-1-il) benzaldehyde. Reduction of formyl 3,4-bis((3-methylbut-2-en-1il) benzaldehyde which is carried out in the second stage with sodium borohydride in ethanol obtained 3,4-bis((3-methylbut-2en-1-yl)oxy)phenyl)methanol. Etherification 3,4-bis ((3methylbut-2-en-1-il)oxy)phenyl)methanol with 3,3-dimethylalyl bromide and sodium hydride in the solvent dimethylformamide at room temperature is obtained target compound 1,2-bis((3methylbut-2-en-1-il)oxy)-4-(((3-methylbut-2-en-1 il)oxy)methyl)benzene whose structure is determined by NMR, mass, and IR spectroscopy.


I. INTRODUCTION
AVING healthy skin is what everyone wants, especially women. Cosmetics is one way of skincare, which among others plays a role in preventing the occurrence of hyperpigmentation [1]. Kojic acid (1) and arbutin (2) are used to inhibit hyperpigmentation, but in its development, these two compounds have an impact on the skin. Arbutin (2) can cause allergies, and long-term use will worsen hyperpigmentation, whereas kojic acid (1) can cause skin irritation [1], [2]. Arung et al (2007) [3] succeeded in separating several compounds (3) from jackfruit plants (Artocapus heterophyllus) which have activity as melanogenesis inhibitors. The three compounds can be seen in Figure 1. The compounds (3) separated from the plant were tested for their bioactivity against melanoma B16 cells with kojic acid (1) and arbutin (2) as positive controls. The results can be seen in Table 1. Table 1 shows that in general compounds (3a-f) have better melanogenesis inhibiting activities than kojic acid (1) and arbutin (2) against melanoma B16 cells. The data shows that the presence of 3-methyl-2butenyl groups plays a role in inhibiting melanogenesis as can be seen in the IC50 value, the more 3-methyl-2-butenyl groups can increase their activity in inhibiting melanogenesis.
Literature studies that have been carried out provide inspiration to synthesize compound (6) which is designed to have activity as an inhibitor of melanogenesis and has a similar structure to methyl dianthilis. The synthesis of the target compound (6) was suggested by a retrosynthetic analysis approach as can be seen in Figure 3.

A. Tools and Materials
The experiment was carried out using laboratory equipment as follows:

A. Synthesis 3,4-bis((3-methylbut-2-en-1-il)benzaldehyde (8)
Synthesis of 3,4-bis((3-methylbut-2-en-1-il)benzaldehyde (8) was carried out in two stages. The first step involved the reaction of 3,4-dihydroxybenzaldehyde with sodium hydride in DMF solvent at room temperature for 15 minutes; in the second stage the reaction results in the first stage were further reacted with 3,3-dimethylalyl bromide and the ongoing reaction was monitored by TLC, the reaction results were then added with cold distilled water (30 mL), and extracted with dichloromethane (3x10 mL). The obtained organic phase was combined, washed with distilled water (15 mL), dried with anhydrous magnesium sulfate, and evaporated at low pressure to obtain a clear liquid of 0.22 grams. The subsequent synthesis was purified using gravity column chromatography with silica gel GF 60 and the mobile phase of n-hexane: ethyl acetate (9:1) The chromatography column gravity results obtained 27 fractions, fractions 14-25 which showed a single stain then combined, evaporated at low pressure, and tested for purity by TLC.
Identification of the structure of the pure synthesized compound with an NMR spectrometer given a 1 H NMR spectrum. The 1 H NMR spectrum showed six signals from upfield to downfield with an integration ratio of 6:6:4:2:1:2:1. The prenyl group gave four signals as follows: two singlet signals with a 6: 6 integration in the chemical shift () 1.73 and 1.76 ppm were signals from the protons of the two methyl groups; doublet signal doublet with integration 4 at 64 4.64 (J  = 17.4; 6.2 Hz) ppm is the signal of the protons of the two methylene groups, and the multiplex signal with integration 2 at  5.47-5.49 ppm is a signal from two protons of a metin group. A doublet signal with integration 1 at  6.94 (d, J = 8 Hz) ppm is a signal from one aromatic proton, a multiplex signal with integration 2 at  7.38-7.41 ppm was a signal of two aromatic protons, and singlet signals with integration 1 at   ppm were signals from protons of formal groups.

B. Synthesis 3,4-bis((3-methylbut-2-en-1il)oxy)phenyl)methanol (7)
Synthesis of 3,4-bis((3-methylbut-2-en-1il)oxy)phenyl)methanol (7) was carried out by reducing the formyl group of 3,4-bis((3-methylbut-2-en-1il)benzaldehyde (8) with sodium borohydride carried out in ethanol at room temperature The ongoing reaction was monitored by TLC. The TLC results showed that the reaction has been completed after the reaction has lasted for 15 minutes. The reduction results were then added with a 10% sodium hydroxide solution (10 mL), then extracted with dichloromethane (3x10 mL) The organic phase obtained was combined, washed with distilled water (30 mL), dried with anhydrous magnesium sulfate, and evaporated at low pressure to obtain the synthesis results in the form of yellow liquid as much as 0.041 grams.
The identification of the reduced structure with NMR spectrometers gives 1 H NMR spectrum. The 1 H NMR spectrum clearly showed that the singlet signal of the formal group at   ppm was not visible, this showed that the reduction was successful. The prenyl group gave four signals as follows: two singlet signals with 6: 6 integration at 1.73 and 1.79 ppm respectively were signals of the protons of two methyl groups; singlet signals with integration 6 at  4.95 ppm were signals from protons of two methylene groups (including methylene protons from hydroxymethyl groups), and multiplet signals with integration 2 at  5.46-5.48 ppm were signals from two protons of a metin group. Multiplet signal with integration 3 at pada 6,82-6,94 ppm was a signal of three aromatic protons.
The synthesized product was further purified by gravity column chromatography with silica gel GF stationary phase and n-hexane: ethyl acetate (10:1) mobile phase. Fractions 25-31 which showed a single stain were then combined, evaporated at low pressure, and tested for purity by TLC. Analysis of the results of the reaction by gas chromatography mass spectrometers showed a major peak with a retention time of 32.836 minutes. The spectrum showed the peak of the molecular ion at m/z 344.2 which corresponds to the relative mass of 1,2-bis((3-methylbut-2-en-1-il)oxy)-4-((3methylbut-2-en -1-il)oxy)metl)-benzene (6). The compound molecule ion (6) released successive isoprene molecules so that fragments with peaks at m/z 276, 208, and 140 are produced. Fragments with peaks at m/z 208 then release 3methyl-2-butenal molecules resulting in fragments with a peak at m/z 124 (base peak). Release of hydrogen gas from a fragment with a peak at m/z 140 produced fragments with a peak at m/z 138. Molecular ion compounds (6) also undergo fragmentation to form prenyl cations with peaks at m/z 69 which subsequently release etuna and hydrogen to form cations with peaks at m/z 43 and 41.
V. ACKNOWLEDGMENT