The first synthesis of phenylpropanoid derivative bromophenols including natural products: Formation of an indene derivative compound

Article abstract of DOI:10.1016/j.tet.2020.131016

Synthesis of the natural bromophenols 3,4-dibromo-5-(butoxymethyl)benzene-1,2-diol, (E)-3-(2,3-dibromo-4,5-dihydroxyphenyl)-2-methylacrylaldehyde (7), 3,4-dibromo-5-(3-hydroxy-2-methylpropyl)benzene-1,2-diol and 3-(2,3-dibromo-4,5-dihydroxyphenyl)-2-pheny

Full text of DOI:10.1016/j.tet.2020.131016

Journal Pre-proof
The first synthesis of phenylpropanoid derivative bromophenols including natural
products: Formation of an indene derivative compound
Cetin Bayrak, Abdullah Menzek
PII:
S0040-4020(20)30118-6
https://doi.org/10.1016/j.tet.2020.131016
TET 131016
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 November 2019
Revised Date: 28 January 2020
Accepted Date: 1 February 2020
Please cite this article as: Bayrak C, Menzek A, The first synthesis of phenylpropanoid derivative
bromophenols including natural products: Formation of an indene derivative compound, Tetrahedron
(2020), doi: https://doi.org/10.1016/j.tet.2020.131016.
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GRAPHICAL ABSTRACT

The first synthesis of phenylpropanoid derivative bromophenols including
natural products: Formation of an indene derivative compound
Cetin Bayrak a,b and Abdullah Menzek a,*
a Department of Chemistry, Faculty of Science, Ataturk University, Erzurum 25240, Turkey
b Dogubayazit Ahmed-i Hani Vocational School, Agri Ibrahim Cecen University, Agri 04400, Turkey
Abstract: The first s Synthesis of the natural bromophenols 3,4-dibromo-5-(butoxymethyl)benzene-1,2-diol, (E)-3-(2,3-dibromo-
4,5-dihydroxyphenyl)-2-methylacrylaldehyde (7), 3,4-dibromo-5-(3-hydroxy-2-methylpropyl)benzene-1,2-diol and 3-(2,3-
dibromo-4,5-dihydroxyphenyl)-2-phenylpropanoic acid is reported for the first time. An indene-derived compound (12) was
formed during the attempts to synthesize of the bromophenol 7. The formation of compound 12 is discussed.
Keywords: AlCl3, bromination, condensation, indene-derived compound, natural bromophenol.
*Correspondence: amenzek@atauni.edu.tr. Tel.: (: +90-442-231-4423); amenzek@atauni.edu.tr
1

1. Introduction
Many bromophenols including natural products exhibit important biological activities such as antioxidant1-4
cytotoxicity5, glucose 6-phosphate dehydrogenase6, carbonic anhydrase7-9 feeding deterrent10, aldose reductase
,
,
inhibitory11, antiviral12 and anticancer activities13. The natural bromophenol compounds 1-9 were isolated from marine life
such as the red algae Rhodomela confervoides and Symphyocladia latiuscula (Figure 1)1,3,5,6,14,15
Figure 1. Some biologically active natural bromophenols.
We reported the first synthesis of many bromophenols including natural bromophenols8,7,16-22. To the best of our
knowledge, there are no reports on the synthesis of the bromophenols 6-9 having biological activities3,5,6,15 have not yet
been synthesized. In this work Herein, the first synthesis of these natural products 6-9 is reported for the first time.
2. Results and Discussion
The groups on the benzene rings of natural bromophenols 6-9 are the same while other parts of them are different.
For the synthesis of these bromophenols and their derivatives, our method involves the preparingartion of aromatic rings
including the corresponding groups and then connecting them to the corresponding compounds. In addition to the synthesis
of natural bromophenols, synthesis of their derivatives was also planned because they may have biological activities.
Firstly, the aldehyde 10 was prepared from the starting material vanillin by the previously published methods8,7,19-24. Then
condensation product 11 was obtained from the reaction of benzaldehyde derivative 10 with propanal at room temperature
(RT) 25
.
2

For the synthesis of the natural bromophenol 7, a demethylation reaction with BBr3 of compound 11 was
7,8,19-22
performed because demethylation of the aryl methyl ethers was done previously achieved with BBr3
(Scheme 1).
However, instead of the expected natural bromophenol 7, a different product was obtained from this reaction (Scheme 1).
Scheme 1. An attempt to synthesize compound and the formation of indene derivative 12.
When Examination of the 1H-NMR spectrum of the product was investigated, revealed five singlet peaks at 6.51,
5.29, 4.07, 3.85 and 2.13 ppm were found. None of these singlets should belong to the hydrogen of the aldehyde group
because they are present in the higher areas. The last three (at 4.07, 3.85 and 2.13 ppm) should belong to OMe, OMe and
Me groups, respectively. The singlet peaks at 6.51 and 5.29 ppm in the 1H-NMR spectrum should belong to CH, and these
CH groups should resonate at 128.75 and 48.40 ppm in the 13C-NMR spectrum. In the 1H- and 13C-NMR spectrum, there is
an aromatic or olefinic CH resonating at 128.75 ppm. Therefore, the product should be indene derivative 12. The
hHydrogen (CHBr) resonating at 5.29 ppm should be CHBr because it is both benzylic and allylic. Therefore, the product
should be indene derivative 12. The Br in the CHBr may be a OH such as CHOH. However, the chemical shift of the CH
hydrogen in this CHOH should be at a field lower than at 48.40 ppm in the 13C-NMR spectrum. The HRMS spectrum of 12
also confirm the structure as (M-H) calcd. For C12H1079Br3O2: 422.8231; Found: 422.8285.
For the formation of indene derivative 12, we can propose the mechanism in Scheme 2. The first interaction is
between the oxygen atom of the aldehyde group in 11 and the Lewis acid BBr3. Structure 14 is a resonance structures of the
formed intermediate formed 13. By electrophilic aromatic substitution, intermediate 19 16 may be obtained from 14 or 16
via 18 15. Benzylic OH or its derivatives are converted to benzylic bromides in the reaction medium with BBr316-22. The
-
nucleophilic substitution reaction of intermediate 19 16 with Br gives indene derivative 12. In For the formation of
indene derivative 12, an electrocyclic ring closure reaction may also be considered as an alternative. way26 (Sankararaman
2005). When a parts of the structures 14 and 15 is thought of as a pentadienyl cation (4nπ), it may be converted to 17 15 ,
3

whose structure is the resonance structure of 18 by conrotatory ring closure. It was reported that cinnamic aldehyde
derivatives were converted into the corresponding indene derivatives in the presence of BF3.OEt2/CH(OMe)3,27,
FeCl3/CH(OMe)3,28, FeCl3/Ac2O29 and AlCl330 by electrophilic aromatic substitution.
Scheme 2. The mechanism for the formation of compound 12.
Another way was considered for the synthesis of the natural product 7. Aromatic OMOM groups such as aromatic
OMe are stable in basic medium and they are obtained by reactions of OH groups with MOMCl (methoxymethylchloride).
The known31 aldehyde 18 was obtained from reactions of compound 10 with BBr3 and MOMCl, consecutively, via 17.
After aldehyde 18 with propanal was allowed to reacted with propanal in basic medium, hydrolysis of the product formed,
product 19 in acidic medium afforded the natural bromophenol 7 (Scheme 3).
Scheme 3. Synthesis of the natural bromophenol 7.
4

In the synthesis of the other natural product compound 8, reduction of the α,β-unsaturated aldehyde groups in
compounds 11 or 19 to saturated aldehyde groups is important. Therefore, it was attempted to reduce induce compounds 11
or 19 using the reducing agents mentioned in the literature32-34 (Scheme 4). However, neither compound 20 nor 21 was
obtained from these reactions.
Scheme 4. Attempts to synthesize the natural bromophenol 8.
Scheme 5. Synthesis of the natural bromophenol 8.
For the synthesis of the natural bromophenol 8, another method was also considered. For this, aldehyde 22,
propionic anhydride and triethylamine (NEt3) were mixed (at RT for 10 min), and then the mixture was refluxed (for 4h),
cooled (0 °C) and refluxed with H2SO4 (catalytic) in MeOH. Ester 23 was obtained from these reactions via acid 24
because the corresponding acid such as intermediate 24 occurs in during these reactions as an intermediate 20. (Buckles
and Bremer 1963) (Scheme 5). Aldehyde 22 was used rather than vanillin in the reaction because of both the rate and yield
of the reaction. Reduction of ester 23 with metallic Na and tert-butyl alcohol (t-BuOH) in tetrahydrofuran (THF) gave
5

product 25 having OMe, and two OH (aromatic and aliphatic) groups by Birch reduction35-37. Compound 25 was treated
reacted with molecular bromine (Br2) in CHCl3 and compound 26 was obtained. Electron-rich benzene rings rapidly give
an aromatic electrophilic substitution reaction with Br216-24. Reaction of the product 26 with BBr3 in CH2Cl2 gave the
natural bromophenol 8 (Scheme 5).
The natural bromophenol 9 is a saturated acid with two benzene rings, one of which has two OH and two Br
groups. Reduction of the double bonds of the α,β-unsaturated carbonyl groups in 11 and 19 could not be carried out.
Therefore, our method is stated as (i), (ii), and (iii) for the synthesis of 9 was as follows: (i) The sStarting material from
was a corresponding aromatic aldehyde including OMe groups in the case of OH groups; (ii) Ccondensation of this
aldehyde was performed with phenyl acetic acid and followed by esterification with MeOH; (iii) Ccatalytic
hydrogenation,38, bromination, and demethylation of product formed were conducted consecutively. (iv) Substitution of Br
atoms into the aromatic ring; (v) Demethylation. The condensation of 27 with phenyl acetic acid, conversion of
intermediate acid to ester 28, reduction of ester 28 with catalytic hydrogen, bromination of 29 with molecular bromine and
demethylation of dibromide 30 with BBr3 were carried out, consecutively (Scheme 6). The natural bromophenol 9 was
synthesized as a result of these reactions.
Scheme 6. Synthesis of the natural bromophenol 9.
6

Scheme 7. Synthesis of derivatives 36 and 37 belonging to of the natural bromophenol 31.
Synthesis of the antioxidant natural bromophenol 3139 and its derivatives is important because to the best of our
knowledge it is not known to the best of our knowledge has not been reported. Similar to the synthesis of compound 29,
ester 33 was synthesized from the starting material aldehyde 27 via 32. The reaction of ester 33 with molecular bromine
(2.0 equiv.) in AcOH in darkness gave the products 34 and 35. The presence of an AB system (as d and dd) in the aromatic
regions of both products also indicates that there is a Br in the ortho position of OMe in rings with single OMe.
Demethylation of compounds 34 and 35 with BBr3 gave bromophenols in high yield as derivatives 36 and 37 of natural
bromophenol 31. In the bromination of ester 33 because of the directions of groups in the aromatic rings, compound 35
should be formed first, and then compound 34 should be formed from 35. A precursor compound of natural bromophenol
31 should not occur in the bromination of ester 33 due to these reactions. A derivative whose structure has a tert-butyl (t-
Bu) group at the para (p) position of OMe in the ring with two OMe groups as auxiliary groups of ester 33 may be
synthesized. Probably, the precursor compound will occur in this bromination. However, we have not attempted to
synthesize the precursor compound yet.
Scheme 8. Synthesis of the natural bromophenol 6.
7

The natural product 6, an ether, is an inhibitor of glucose 6-phosphate dehydrogenase enzyme6. The synthesis of
the natural product 6 may be planned from reactions of the benzyl bromide derivative 38 with n-butanol or n-buthoxide and
BBr3. This method was not used because benzyl ether is unstable in the reactions of BBr319. For the synthesis of natural
bromophenol 6, compound 39 was prepared (from the reaction of 38 with MeO) and reacted with BBr3 in CH2Cl2 under N2
for 10 min at 0 °C. Then the mixture was refluxed with n-BuOH for 3 h and the natural bromophenol 6 was purified by
column chromatography (Scheme 8).
3. Conclusion
In conclusion, tThe first synthesis of natural bromophenol compounds 6-9 were was successfully realized from
the corresponding reactions. The reaction of α,β-unsaturated aldehyde compound 11 with BBr3 gave the indene derivative
12. According tTo the best of our knowledge, synthesis of an indene derivative from the reaction of α,β-unsaturated
aldehyde such as 11 with BBr3 is has not known be reported previously. The formation of an indene-derivative in the
presence of BBr3 is a new reaction. This should be a new reaction. Also Moreover, the compounds 36 and 37 which is are
derivatives of natural product 31 were synthesized.
4. Experimental section
4.1. General Experimental Procedures
1
The solvents were purified and dried by known methods. For all compounds, values as well as M.p, IR spectra, H
and 13C NMR spectra, chemical shift and elemental analyses were obtained as explained previously22,40. Preparative thick-
layer chromatography was used with 1 mm of silica gel 60 PF (Merck, Darmstadt, Germany) on glass plates. HRMS data
were obtained by LC-MS-TOF electrospray ionization (1200/6210, Agilent).
4.1.1. Experimental Text (E)-3-(2,3-Dibromo-4,5-dimethoxyphenyl)-2-methylacrylaldehyde (11).
A solution of the aldehyde 10 (3.0 g, 9.30 mmol) in a mixture of EtOH (50 mL) and THF (5 mL) was cooled at 0 °oC
using an ice-water bath, and cold propanal (0.64 g, 11.16 mmol, < 0 °oC,) and solution of NaOH (10%, 0 °oC, 10 mL) were
slowly added. After the reaction mixture was stirred for 30 min at 0 °oC, the cold bath was removed and the mixture was
stirred for 24 h. The solvent was removed under vacuum and the crude product was extracted with EtOAc (2 × 30 mL).
The combined extracts were dried over Na2SO4 and the solvent was removed in the evaporator. under vacuum. The residue
was purified by column chromatography on silica gel (10 g) using EtOAc/hexane (2:8) eluent. Compound 11 (2.41 g, 90%)
was obtained as a yellow solid. M.p: 110-113 °oC; Rf = 0.32 EtOAc/Hexane (1:9); IR (CH2Cl2, vmax cm-1): 2922, 1681,
1
1583, 1466, 1378, 1302, 1264, 1206, 1191, 1072; H-NMR (400 MHz, CDCl3): 9.66 (s, CHO, 1H), 7.40 (s, 1H), 6.92 (s,
1H), 3.89 (s, OCH3, 3H), 3.88 (s, OCH3, 3H), 1.93 (s, CH3, 3H); 13C-NMR (100 MHz, CDCl3): 194.77 (CO), 152.62 (C),
148.86 (CH), 148.38 (C), 139.79 (C), 131.88 (C), 122.04 (C), 117.41 (C), 112.87 (CH), 60.61 (OCH3), 55.96 (OCH3),
10.56 (CH3); Elemental Anal. Calcd (%) for C12H12Br2O3: C 39.59, H 3.32. Found: C 40.03, H 3.33.
4.1.2. (1R*)-1,4,5-Tribromo-6,7-dimethoxy-2-methyl-1H-indene (12).
A solution of compound 11 (1.0 g, 2.74 mmol) in CH2Cl2 (10 mL) under N2 gas was cooled to 0 °oC using an ice-
water bath and BBr3 (1.38 g, 5.49 mmol) was added by the aid of a syringe. The resulting mixture was allowed to stir under
N2 for 10 min at 0 °oC. After removal of the cold bath, was removed, the mixture was stirred for 10 h at RT and cooled
8

again to 0 °oC. MeOH (10 mL) was added dropwise and then the solvent was removed in the evaporator. under vacuum.
The crude product was extracted with EtOAc (2 × 25 mL). The combined extracts were dried over Na2SO4 and the solvent
was removed in the evaporator. under vacuum. Compound 12 (997 mg, 85%) was obtained as a black solid. M.p: 125-127
°oC; Rf = 0.71 EtOAc/Hexane (1:9); IR (CH2Cl2, vmax cm-1): 2923, 2848, 1459, 1398, 1320, 1266, 1199, 1116, 1042, 967;
1H-NMR (400 MHz, CDCl3): 6.51 (s, 1H), 5.29 (s, CHBr, 1H). 4.07 (s, OCH3, 3H), 3.85 (s, OCH3, 3H), 2.13 (s, CH3, 3H);
13C-NMR (100 MHz, CDCl3): 149.64 (C), 148.10 (2 C), 140.75 (C), 135.55 (C), 128.75 (CH), 122.24 (C), 111.29 (C),
60.94 (OMe), 60.80 (OMe), 48.40 (CH2Br) 14.52 (CH3); Elemental Anal. Calcd (%) for C12H11Br3O2: C 33.76, H 2.60.
Found: C 33.61, H 2.61. HRMS: m/z (M-H) calcd. For C12H1079Br3O2: 422.8231; Found: 422.8285.
4.1.3. (E)-3-(2,3-Dibromo-4,5-bis(methoxymethoxy)phenyl)-2-methylacrylaldehyde (19).
The standard procedure described for the synthesis of 11 was performed for this reaction. Prepared 31 tThe Pprepared
compound 1831 (2.0 g, 5.2 mmol), propanal (0.30 g, 5.2 mmol) and NaOH (10%, 0 °oC, 10 mL) were used and the product
19 (2.0 g, 90%) was obtained as a white solid. M.p: 42-44 °oC; Rf = 0.17 EtOAc/Hexane (1:9); IR (CH2Cl2, vmax cm-1):
2916, 2824, 1686, 1541, 1455, 1369, 1285, 1156, 1092; 1H-NMR (400 MHz, CDCl3): 9.64 (s, CHO, 1H), 7.36 (s, 1H), 7.24
(s, 1H), 5.24 (s, OCH2, 2H), 5.20 (s, OCH2, 2H), 3.66 (s, OCH3, 3H), 3.48 (s, OCH3, 3H), 1.91 (s, CH3, 3H); 13C-NMR
(100 MHz, CDCl3): 195.42 (CO), 149.58 (C), 148.59 (CH), 145.97 (C), 139.85 (C), 132.72 (C), 122.81 (C), 119.73 (C),
116.93 (CH), 98.62 (OCH2), 95.80 (OCH2), 57.97 (OCH3), 56.41 (OCH3), 10.84 (CH3); Elemental Anal. Calcd (%) for
C14H16Br2O5: C 39.65, H 3.80. Found: C 39.49, H 3.79.
4.1.4. (E)-3-(2,3-Dibromo-4,5-dihydroxyphenyl)-2 methylacrylaldehyde (7): Standard procedure for the demethylation.
To a solution of compound 19 (0.5 g, 1.17 mmol) in THF (10 mL), was added HCl (3.0 M, 2.0 mL) was added. After
the solution was stirred in at 80 °oC for 24 h, the reaction mixture was cooled to RT and the solvent was removed in the
evaporator. under vacuum. H2O (10 mlL) and EtOAc (10 mL) was were added and the mixture extracted with EtOAc (2 ×x
25 mL). The combined extracts were dried over Na2SO4 and the solvent was removed in the evaporator. under vacuum.
1
Natural product 7 (443 mg, 95%) was obtained as a yellow solid. M.p: 158-160 °oC [(138-140 °oC) 41]. H-NMR (400
MHz, Acetone-d6): 9.65 (s, CHO, 1H), 9.30 (bs, aromatic OH, 1H), 8.88 (bs, aromatic OH, 1H), 7.44 (s, 1H), 7.17 (s, 1H),
1.86 (s, CH3, 3H); 13C-NMR (100 MHz, Acetone-d6): 195.41 (CO), 148.93 (CH), 145.70 (C), 144.61 (C), 139.11 (C),
127.52 (C), 116.59 (C), 115.75 (CH), 113.38 (C), 10.15 (CH3); HRMS: m/z (M-H) calcd. For C10H779Br81BrO3: 334.8741;
Found: 334.8750.
4.1.5. Methyl (E)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-2-methylacrylate (23): Standard procedure for methyl ester
of condensed product.
A mixture of compound 22 (1.00 g, 4.33 mmol), NEt3 (4.0 mL) and propionic anhydride (6.0 mL) was added
prepared. After the mixture was stirred in 80 °oC for 4 h and the reaction was stopped, the reaction mixture was cooled at 0
°oC and HCl (18%, 8.0 mL) and H2O (20 mL) were added. Then, the reaction mixture was stirred for 1h more at RT and
extracted with CH2Cl2 (2 ×x 50 mL). The combined extracts were dried over Na2SO4 and the solvent was removed under
vacuum. After MeOH (10 mL) and a catalytic amount of p-toluene sulfonic acid (HOTs, 5.0 mg) were added, the mixture
was refluxed for 24 h and extracted with CH2Cl2 (2 × 50 mL). The combined organic extracts were dried over Na2SO4 and
the solvent was removed in the evaporator. under vacuum. The residue was purified by column chromatography on silica
gel (10 g) using EtOAc/hexane (4:6) as eluent. Compound 23 (1.05 g, 92%) was obtained as a white solid. M.p: 90-92 °oC;
9

Rf = 0.39 EtOAc/Hexane (2:8); IR (CH2Cl2, vmax cm-1): 2951, 2846, 1709, 1575, 1501, 1417, 1342, 1285, 1253, 1115; 1H
NMR (400 MHz, CDCl3): 7.53 (s, 1H), 7.18 (s, 1H), 6.83 (s, 1H), 6.12 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 2.12 (s, 3H); 13
C
NMR (100 MHz, CDCl3): 169.23 (CO), 147.21 (C), 143.55 (C), 137.80 (CH), 129.07 (C), 127.73 (C), 126.59 (CH), 111.66
(CH), 108.52 (C), 56.59 (OMe), 52.37 (OMe), 14.34 (CH3); HRMS: m/z (M-H) calcd. For C12H1281BrO4: 300.9898; Found:
300.9920.
After the mixture stirring at 80 ° C for 4 h and the reaction cooling at 0 °C,
4.1.6. (E)-3-(3-Bromo-5-methoxy-4-(propionyloxy)phenyl)-2-methylacrylic acid (24).
A mixture of compound 22 (0.6 g, 2.6 mmol), NEt3 (4.0 mL) and propionic anhydride (6.0 mL) was added prepared.
After the mixture was stirred at in 80 °oC for 4 h and the reaction was cooled at to 0 °oC, HCl (18%, 8.0 mL) and H2O (20
mL) were added. Then, the reaction mixture was stirred for 1 h more at RT as addition and extracted with CH2Cl2 (2 ×x 30
mL). The combined extracts were dried over Na2SO4 and the solvent was removed in the evaporator. under vacuum. The
compound 24 (0.81 g, 91%) was obtained as a white solid. M.p: 140-142 °oC; Rf = 0.33 EtOAc/Hexane (2:5); IR (CH2Cl2,
vmax cm-1): 3435, 2923, 1770, 1675, 1568, 1487, 1450, 1413, 1272, 1128, 1047, 952; 1H NMR (400 MHz, CDCl3): 7.71 (s,
1H), 6.92 (s, 1H), 3.84 (s, OMe, 3H), 2.68 (q, CH2, J = 7.5 Hz, 2H), 2.15 (s, CH3, 3H), 1.32 (t, CH3, J = 7.5 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): 173.64 (CO), 171.34 (CO), 152.33 (C), 139.14 (CH), 138.12 (C), 134.87 (C), 128.91 (C), 125.63
(CH), 117.40 (C), 112.72 (CH), 56.31 (OMe), 27.30 (CH2), 13.76 (CH3), 9.16 (CH3); Elemental Anal. Calcd (%) for
C14H15BrO5: C 49.00, H 4.41. Found: C 48.83, H 4.43.
4.1.7. (2R*)-4-(3-Hydroxy-2-methylpropyl)-2-methoxyphenol (25).
To a stirred solution of compound 23 (2.0 g, 6.64 mmol) in THF (50 mL) was added metallic Na (1.53 g, 66.42
mmol) in small pieces amounts over a period of 10 minute at RT, and then a solution of t-BuOH (4.,92 g, 66.,42 mmol) in
THF (120 mlL) was slowly added. After the mixture was refluxed for 24 h, it was stopped, cooled at RT, and excess of
sodium in the reaction mixture was filtered off. The mixture was cooled at to 0 °oC and EtOH (25 mL) was slowly and
carefully added for neutralization. After the removal of solvent, and then solution of HCl (3%, 25 mL) was slowly added,
the mixture was extracted with EtOAc (2 × 20 mL), the combined organic extracts were dried over Na2SO4 and the solvent
was removed in the evaporator. under vacuum. Purification of the residue on silica gel (20 g) by column chromatography
eluting with EtOAc/hexane (1/4) gave compound 25 (1.00 g, 77%) as a yellow solid. M.p: 70-72 °oC; Rf = 0.32
1
EtOAc/Hexane (2:5); IR (CH2Cl2, vmax cm-1): 3434, 2075, 1516, 1463, 1376, 1271, 1126, 1033; H NMR (400 MHz,
CDCl3): 6.81 (d, A part of AB system, J = 8.0 Hz, 1H), 6.69–6.58 (m, 2H, ArH), 6.03 (bs, OH, 1H), 3.81 (s, OCH3, 3H),
3.51 (dd, A part of AB system J = 10.6, 6.0 Hz, 1H), 3.45 (dd, B part of AB system J = 10.6, 6.1 Hz, 1H), 2.67 (dd, A part
of AB system, J = 13.6, 6.2 Hz, 1H), 2.32 (dd, B part of AB system J = 13.6, 8.1 Hz, 1H), 2.13–1.76 (m, 1H), 0.89 (d, J =
6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): 146.72 (C), 143.94 (C), 132.78 (C), 121.94 (CH), 114.53 (CH), 112.02 (CH),
67.80 (CH2OH), 56.09 (OMe), 39.60, 38.11, 16.69 (CH3); HRMS: m/z (M) calcd. For C11H16O3: 196.1099; Found:
196.1102.
4.1.8. (2R*)-3-(2,3-Dibromo-4-hydroxy-5-methoxyphenyl)-2-methylpropanoic acid (26): Standard procedure for
bromination.
To a solution of compound 25 (400 mg, 2.04 mmol) in CHCl3 (15 mL) at RT, was added molecular bromine (716.61
mg, 4.48 mmol) was added in the lightless medium darkness. After the reaction mixture was stirred at under the same
10

conditions for 24 h and volatile compounds was were removed in the evaporator under vacuum., the residue was purified
by column chromatography on silica gel (10 g) using EtOAc/hexane (1:4) as eluent. Compound 26 (600 mg, 83%) was
obtained as a brown liquid. Rf = 0.17 EtOAc/Hexane (2:5); IR (CH2Cl2, vmax cm-1): 3434, 2083, 1487, 1396, 1270, 1193,
1059; 1H NMR (400 MHz, CDCl3): 6.68 (s, 1H), 3.83 (s, OCH3, 3H), 3.53 (dd, A part of AB system, J = 10.7, 5.5 Hz, 1H),
3.48 (dd, B part of AB system J = 10.7, 5.8 Hz, 1H), 2.89 (dd, A part of AB system J = 13.6, 6.5 Hz, 1H), 2.52 (dd, B part
of AB system, J = 13.6, 8.0 Hz, 1H), 2.06-1.93 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): 146.08
(C), 142.89 (C), 133.13 (C), 118.03 (C), 112.55 (CH), 112.45 (C), 67.51 (CH2O), 56.72 (OMe), 41.29, 36.69, 16.66 (CH3);
Elemental Anal. Calcd (%) for C11H14Br2O3: C 37.32, H 3.99. Found: C 37.16, H 3.97.
4.1.9. (2R*)-3,4-Dibromo-5-(3-hydroxy-2-methylpropyl)benzene-1,2-diol (8).
This reaction was performed according to the standard procedure described in for the synthesis of natural
bromophenol 7. In the reaction, compound 29 (0.20 g, 0.56 mmol), CH2Cl2 (10 mL) and BBr3 (311.35 mg, 1.24 mmol)
were used. The residue was purified by column chromatography on silica gel (10 g) using MeOH/CH2CI2 (3:97) as eluent.
1
Natural product 8 (140 mg 73%) was obtained as a yellow gum brown liquid; [(Ggummy) 41]. H NMR (400 MHz,
Acetone-d6): 9.05-7.98 (m, 2H), 6.86 (s, 1H), 3.77 (s, 1H), 3.58–3.31 (m, 2H), 2.87 (dd, A part of AB system, J = 13.4, 6.1
Hz, 1H), 2.49 (dd, B part of AB system J = 13.4, 8.0 Hz, 1H), 2.08-2.05 (m, 1H), 0.92 (d, CH3, J = 6.5 Hz, 3H); 13C NMR
(100 MHz, Acetone-d6): 145.41 (C), 143.57 (C), 134.07 (C), 117.64 (CH), 116.62 (C), 113.89 (C), 67.11 (CH2O), 41.45
(CH2), 37.38 (CH), 16.85 (CH3); HRMS: m/z (M-H) calcd. For C10H1179Br81BrO3: 338.9054; Found: 338.9060.
4.1.10. Methyl (E)-3-(3,4-dimethoxyphenyl)-2-phenylacrylate (28).
The standard procedure described for the synthesis of 23 was performed for this reaction. Compound 27 (1.0 g, 12.04
mmol), NEt3 (4.0 mL), acetic anhydride (6.0 mL) and phenyl acetic acid (1.64 g, 12.04 mmol) were used in this reactions,
and the compound 28 (2.75 g, 90%) was obtained as a yellow liquid; Rf = 0.60 EtOAc/Hexane (2:5); IR (CH2Cl2, vmax cm-
1
1): 2839, 2065, 1635, 1510, 1464, 1248, 1143, 1024; H NMR (400 MHz, CDCl3): 7.80 (s, olefinic, 1H), 7.44–7.38 (m,
2H), 7.36–7.31 (m, 1H), 7.28–7.23 (m, 2H), 6.83 (dd, A part of AB system, J = 8.4, 2.1 Hz, 1H), 6.71 (d, B part of AB
system, J = 8.4 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H), 3.81 (s, OCH3, 3H), 3.76 (s, OCH3, 3H), 3.36 (s, OCH3, 3H); 13C NMR
(100 MHz, CDCl3): 168.62 (CO), 150.24 (C), 148.40 (C), 140.74 (C) 140.68 (CH), 136.78 (C), 130.17 (CH), 129.05 (CH),
127.93 (CH), 127.57 (CH), 125.85 (C), 112.46 (CH), 110.70 (CH), 55.97 (OCH3), 55.27 (OCH3), 52.48 (OCH3); Elemental
Anal. Calcd (%) for C18H18O4: C 72.47, H 6.08. Found: C 72.21, H 6.07.
4.1.11. (2R*)-Methyl 3-(3,4-dimethoxyphenyl)-2-phenylpropanoate (29).
To a solution of compound 28 (2.0 g, 6.7 mmol) in MeOH (60 mL) was added Pd-C (5.0 mg) was added. After the
air in the flask was evacuated under vacuum and hydrogen gas was sent into the flask,. Tthe reaction mixture was stirred
for 48 h at RT. After the reaction was complete, the catalyst (Pd-C) was filtered off and the solvent was evaporated.
Compound 29 (1.80 g, 90%) was obtained as a yellow liquid; Rf = 0.41 EtOAc/Hexane (1:5); IR (CH2Cl2, vmax cm-1): 2953,
2928, 2852, 1735, 1516, 1465, 1264, 1238, 1157, 1029; 1H NMR (400 MHz, CDCl3): 7.33-7.28 (m, 5H), 6.74 (d, A part of
AB system, J = 8.2 Hz, 1H), 6.67 (dd, B part of AB system, J = 8.2, 1.7 Hz, 1H, ArH), 6.56 (d, J = 1.7 Hz, 1H), 3.82 (s,
OCH3, 3H), 3.82–3.78 (m, CH, 1H). 3.76 (s, OCH3, 3H), 3.61 (s, OCH3, 3H), 3.35 (dd, A part of AB system, J = 13.7, 8.5
Hz, CH2, 1H), 2.98 (dd, B part of AB system, J = 13.7, 7.0 Hz, CH2, 1H); 13C NMR (100 MHz, CDCl3): 174.13 (CO),
148.80 (C), 147.75 (C), 138.78 (C), 131.81 (C), 128.85 (CH), 128.26 (CH), 127.58 (CH), 121.12 (CH), 112.49 (CH),
11

111.32 (CH), 56.03 (OCH3), 55.93 (OCH3), 54.09 (OCH3), 52.21 (CH), 39.71 (CH2); Elemental Anal. Calcd (%) for
C18H20O4: C 71.98, H 6.71. Found: C 72.25, H 6.71.
4.1.12. (R*)-Methyl 3-(2,3-dibromo-4,5-dimethoxyphenyl)-2-phenylpropanoate (30).
To a solution of compound 29 (0.5 g, 1.66 mmol) in AcOH (10 mL) was added molecular bromine (665 mg, 4.16
mmol) was added in the lightless medium darkness. After the reaction mixture was stirred at 60 °oC for 16 h and was
cooled to RT, H2O (20 mlL) was added, and the mixture was extracted with EtOAc (2 × 30 mlL). The combined organic
extracts were dried over Na2SO4, the solvent was removed in the evaporator. under vacuum and the residue was purified by
column chromatography on silica gel (20 g) using EtOAc/hexane (1:9) as eluent. Compound 30 (265 mg, 35%) was
obtained as yellow liquid; Rf = 0.35 EtOAc/Hexane (1:9); IR (CH2Cl2, vmax cm-1): 2939, 2845, 1735, 1584, 1550, 1470,
1423, 1378, 1308, 1261, 1200, 1163, 1060, 1007; 1H NMR (400 MHz, CDCl3): 7.36–7.22 (m, 5H), 6.57 (s, 1H), 3.97 (dd, J
= 8.5, 6.6 Hz, CH, 1H), 3.80 (s, OCH3, 3H), 3.67 (s, OCH3, 3H), 3.62 (s, OCH3, 3H), 3.55 (dd, A part of AB system, J =
13.6, 8.5 Hz, 1H), 3.13 (dd, B part of AB system, J = 13.6, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): 173.66 (CO),
152.21 (C), 146.54 (C), 138.51 (C), 135.72 (C), 128.98 (CH), 128.11 (CH), 127.75 (CH), 121.95 (C), 117.70 (C), 114.68
(CH), 60.70 (OCH3), 56.27 (OCH3), 52.34 (OCH3), 51.19 (CH), 42.15 (CH2); Elemental Anal. Calcd (%) for C18H18Br2O4:
C 47.19, H 3.96. Found: C 47.05, H 3.98.
4.1.13. (R*)-3-(2,3-dibromo-4,5-dihydroxyphenyl)-2-phenylpropanoic acid (9).
This reaction was performed according to the standard procedure described in for the synthesis of natural
bromophenol 7. The cCompound 30 (0.3 g, 0.65 mmol), BBr3 (492 mg, 1.96 mmol) and CH2Cl2 (15 mlL) were used, and
natural product 9 (245 mg, 90%) was obtained as a white solid. M.p: 122-124 °oC; [(brown gum)15 (Zhao et al 2004]]; 1H
NMR (400 MHz, Acetone-d6): 11.25-10.50 (m, OH, 1H), 8.74 (s, OH, 1H), 8.19 (s, OH, 1H), 7.47–7.20 (m, 5H), 6.78 (s,
1H), 3.99 (dd, J = 8.9, 6.1 Hz, CH, 1H), 3.44 (dd, A part of AB system, J = 13.8, 8.9 Hz, CH2, 1H), 3.07 (dd, B part of AB
system, J = 13.8, 6.1 Hz, CH2, 1H); 13C NMR (100 MHz, Acetone-d6): 173.50 (CO), 144.63 (C), 143.38 (C), 139.35 (C),
131.36 (C), 128.79 (CH), 128.04 (CH), 127.47 (CH), 117.10 (CH), 117.02 (C), 115.97 (C), 51.29 (CH), 41.18 (CH2);
HRMS: m/z (M-H) calcd. For C15H1179Br2O4: 412.9024; Found: 412.9042.
4.1.14. (E)-Methyl 3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)acrylate (32).
The standard procedure described for the synthesis of 23 and 24 was performed for this reaction. Compound 27 (1.0
g, 6.02 mmol), triethylamine (4.0 mL), acetic anhydride (6.0 mL), and p-methoxyphenylacetic acid (1.0 g, 6.02 mmol), and
a catalytic amount of p-toluene sulfonic acid (HOTs, 5.0 mg) was were used and compound 32 (1.24 g, 85%) was obtained
as a yellow solid. M.p: 68-70 °oC; Rf = 0.30 EtOAc/Hexane (1:5); IR (CH2Cl2, vmax cm-1): 2952, 2835, 1705, 1643, 1512,
1427, 1337, 1248, 1146, 1090, 1025; 1H NMR (400 MHz, CDCl3): 7.75 (s, 1H), 7.16 (d, AA’ part of AA’BB’ system, J =
8.5 Hz, 2H), 6.93 (d, BB’ part of AA’BB’ system, J = 8.4 Hz, 2H), 6.81 (d, A part of AB system, J = 6.5 Hz, 1H), 6.70 (d,
B part of AB system, J = 8.4 Hz, 1H), 6.47 (bs, 1H), 3.81 (s, OMe, 3H), 3.79 (s, OMe, 3H), 3.76 (s, OMe, 3H), 3.44 (s,
OMe, 3H); 13C NMR (100 MHz, CDCl3): 168.85 (CO), 159.40 (C), 150.12 (C), 148.38 (C), 140.51 (CH), 131.38 (CH),
129.89 (C), 128.74 (C), 127.80 (C), 125.53 (CH), 114.50 (CH), 112.66 (CH), 110.73 (CH), 55.96 (OMe), 55.48 (OMe),
55.35 (OMe), 52.44 (OMe). HRMS: m/z (M) calcd. For C19H20O5: 328.1311; found: 328.1312.
4.1.15. (R*)-Methyl 3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)propanoate (33).
12

The standard procedure described for the synthesis of 29 was performed for this reaction. Compound 32 (0.4 g, 6.7
1.22 mmol), MeOH (50 mL), Pd-C (5.0 mg) and H2 gas were used. Compound 33 (380 mg, 94%) was obtained as a white
solid. M.p: 60-72 °oC; Rf = 0.32 EtOAc/hexane (1:5); IR (CH2Cl2, vmax cm-1): 2999, 2952, 2836, 1735, 1610, 1513, 1465,
1259, 1157, 1030; 1H NMR (400 MHz, CDCl3): 7.20 (d, AA’ part of AA’BB’ system, J = 8.6 Hz, 2H), 6.82 (d, BB’ part of
AA’BB’ system, J = 8.6 Hz, 2H), 6.72 (d, A part of AB system, J = 8.2 Hz, 1H), 6.64 (dd, B part of AB system J = 8.2, 1.7
Hz, 1H), 6.56 (bs, 1H), 3.90-3.75 (m, 1H), 3.80 (s, OMe, 3H), 3.76 (s, OMe, 3H), 3.74 (s, OMe, 3H), 3.58 (s, OMe, 3H),
3.31 (dd, A part of AB system, J = 13.7, 8.5 Hz, 1H), 2.93 (dd, B part of AB system, J = 13.7, 7.1 Hz, 1H); 13C NMR (100
MHz, CDCl3): 174.36 (CO), 159.09 (C), 148.80 (C), 147.71 (C), 131.90 (C), 130.93 (C), 129.25 (CH), 121.13 (CH),
114.20 (CH), 112.49 (CH), 111.31 (CH), 56.00 (OMe), 55.92 (OMe), 55.40 (OMe), 53.17 (OMe), 52.10 (CH), 39.75
(CH2); Elemental Anal. Calcd (%) for C19H22O5: C 69.07, H 6.71. Found: C 69.05, H 6.70.
4.1.16. Bromination of compounds 33.
The standard procedure described for the synthesis of 30 was performed for this reaction. Compound 33 (0.4 g, 1.21
mmol), AcOH (15 mL) and Br2 (619.15 mg, 3.87 mmol) were used, and compound 34 (279 mg, 40%) was obtained as a
yellow solid and as well as compound 35 (208 mg, 35%) were obtained.
4.1.17. (2R*)-Methyl 2-(3-bromo-4-methoxyphenyl)-3-(2,3-dibromo-4,5-dimethoxyphenyl)propanoate (34).
M.p: 86-88 °oC; Rf = 0.35 EtOAc / Hexane (1.5:8.5); IR (CH2Cl2, vmax cm-1): 2082, 1639, 1497, 1470, 1284, 1258,
1163, 1056; 1H NMR (400 MHz, CDCl3): 7.51 (d, J = 2.2 Hz, 1H), 7.16 (dd, A part of AB system, J = 8.5, 2.2 Hz, 1H),
6.82 (d, B part of AB system, J = 8.5 Hz, 1H), 6.62 (s, 1H), 3.91 (dd, A part of AB system, J = 8.8, 6.5 Hz, 1H), 3.86 (s,
OMe, 3H), 3.81 (s, OMe, 3H), 3.72 (s, OMe, 3H), 3.62 (s, OMe, 3H), 3.49 (dd, A part of AB system, J = 13.6, 8.8 Hz, 1H),
3.10 (dd, B part of AB system, J = 13.6, 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): 173.42 (CO), 155.53 (C), 152.28 (C),
146.64 (C), 135.53 (C), 132.69 (CH), 132.04 (C), 128.35 (CH), 121.95 (C), 117.71 (C), 114.65 (CH), 112.18 (CH), 112.04
(C), 60.73 (OMe), 56.51 (OMe), 56.33 (OMe), 52.50 (OMe), 49.97 (CH), 42.05 (CH2); HRMS: m/z (M) calcd. For
C19H1979Br3O5: 563.8783; Found: 563.8773.
4.1.18. (2R*)-Methyl 3-(2-bromo-4,5-dimethoxyphenyl)-2-(3-bromo-4-methoxyphenyl)propanoate (35).
M.p: 97-99 °oC; Rf = 0.28 EtOAc/Hexane (1:5); IR (CH2Cl2, vmax cm-1): 2925, 2850, 1734, 1602, 1498, 1463, 1440,
1384, 1260, 1219, 1056; 1H NMR (400 MHz, CDCl3): 7.54 (bs, 1H), 7.17 (dd, A part of AB system, J = 8.4, 1.9 Hz, 1H).
6.98 (s, 1H), 6.81 (d, B part of AB system J = 8.4 Hz, 1H), 6.55 (s, 1H), 3.91-385 (m, 1H), 3.86 (s, OMe, 3H), 3.83 (s,
OMe, 3H), 3.73 (s, OMe, 3H), 3.62 (s, OMe, 3H), 3.37 (dd, A part of AB system, J = 13.7, 8.7 Hz, 1H), 3.02 (dd, B part of
AB system J = 13.6, 6.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): 173.45 (CO), 155.23 (C), 148.30 (C), 147.98 (C), 132.55
(CH), 131.99 (C), 129.79 (C), 128.18 (CH), 115.47 (CH), 114.36 (C), 114.15 (CH), 111.90 (CH), 111.75 (C), 56.25
(OMe), 56.09 (OMe), 55.95 (OMe), 52.12, 50.22, 39.81 (s); Elemental Anal. Calcd (%) for C19H20Br2O5: C 46.75, H 4.13.
Found: C 46.65, H 4.12.
4.1.19. (2R*)-Methyl 3-(2-bromo-4,5-dihydroxyphenyl)-2-(3-bromo-4-hydroxyphenyl)propanoate (36).
This reaction was performed according to the standard procedure described in for the synthesis of the natural
bromophenol 7. Compound 35 (0.2 g, 409.69 µmol), BBr3 (410.55 mg, 1.64 mmol), and CH2Cl2 (15 mlL) were used and
compound 36 (154 mg, 86%) were was obtained as a brown liquid; Rf = 0.57 CH2Cl2/MeOH (9:1); IR (CH2Cl2, vmax cm-1):
13

3243, 2924, 1704, 1602, 1495, 1469, 1274, 1179; 1H NMR (400 MHz, Acetone-d6): 7.53 (d, J = 1.9 Hz, 1H), 7.20 (dd, A
part of AB system, J = 8.4, 2.0 Hz, 1H), 7.04 (s, 1H), 6.98 (d, B part of AB system, J = 8.4 Hz, 1H), 6.75 (s, 1H), 3.94 –
3.89 (m, 1H), 3.31 (dd, A part of AB system, J = 13.8, 8.6 Hz, 1H), 2.98 (dd, B part of AB system J = 13.8, 8.6 Hz, 1H);
13C NMR (100 MHz, Acetone-d6): 174.77 (CO), 154.10 (C), 145.70 (C), 145.41 (C), 133.12 (CH), 132.76 (C), 130.13 (C),
129.31 (CH), 119.94 (CH), 118.92 (CH), 117.34 (CH), 113.53 (C), 110.40 (C), 51.07, 39.93; Elemental Anal. Calcd (%)
for C15H12Br2O5: C 41.70, H 2.80. Found: C 41.61, H 2.81; HRMS: m/z (M-H) calcd. For C15H1179Br2O5: 428.8973; Found:
428.9009.
4.1.20. (2R*)-Methyl 3-(2-bromo-4,5-dihydroxyphenyl)-2-(2,3-dibromo-4-hydroxyphenyl)propanoate (37).
This reaction was performed according to the standard procedure described in for the synthesis of natural
bromophenol 7. Compound 34 (0.3 g, 529.,04 µmol), BBr3 (530.,14 mg, 1.,12 mmol) and CH2Cl2 (15 mlL) were used and
compound 37 (244 mg, 90%) was obtained as a brown liquid; Rf = 0.46 CH2Cl2/MeOH (9:1); IR (CH2Cl2, vmax cm-1): 3373,
2928, 1705, 1603, 1578, 1495, 1471, 1407, 1358, 1275, 1180, 1045; 1H NMR (400 MHz, Acetone-d6): 8.87 (bs, 2H), 8.25
(bs, 1H), 7.52 (s, 1H), 7.18 (d, A part of AB system, J = 8.3 Hz, 1H), 6.96 (d, B part of AB system, J = 8.3 Hz, 1H), 6.77
(s, 1H), 3.96–3.80 (m, 1H), 3.40 (dd, A part of AB system, J = 13.8, 8.6 Hz, 1H), 3.04 (dd, B part of AB system, J = 13.8,
6.4 Hz, 1H); 13C NMR (100 MHz, Acetone-d6): 173.73 (CO), 153.48 (C), 144.70 (C), 143.37 (C), 132.38 (CH), 131.97
(C), 131.11 (C), 128.58 (CH), 117.06 (CH), 116.66 (CH), 116.01 (C), 113.20 (C), 109.73 (C), 50.10, 41.16; Elemental
Anal. Calcd (%) for C15H11Br3O5: C 35.26, H 2.17. Found: C 35.17, H 2.15; HRMS: m/z (M-H) calcd. For C15H1179Br3O5:
506.8078; Found: 506.8095.
4.1.21. Natural bromopheol 3,4-dibromo-5-(butoxymethyl)benzene-1,2-diol (6).
This reaction was performed according to the standard procedure described in for the synthesis of the natural
bromophenol 7. Compound 39 (0.4 g, 1.,18 mmol), BBr3 (589.,44 mg, 2.,35 mmol), CH2Cl2 (15 mlL) and n-BuOH (5.0
mL) were used, and natural product 6 (130 mg 31%) was obtained as a pale brown liquid; [(yellow liquid)6]; Rf = 0.45;
MeOH / CH2Cl2 (2:98); 1H NMR (400 MHz, CDCl3): 6.97 (s, 1H,), 6.50-6.30 (m, OH, 1H), 6.10-5.90 (m, OH, 1H), 4.48
(s, benzyl CH2, 2H), 3.56 (t, J = 6.7 Hz, CH2, 2H), 1.69–1.58 (m, CH2, 2H), 1.47–1.34 (m, CH2, 2H), 0.92 (t, J = 7.4 Hz,
CH3, 3H); 13C NMR (100 MHz, CDCl3): 143.67 (C), 141.65 (C), 131.53 (C), 115.64 (CH), 114.84 (C), 113.58 (C), 73.32
(OCH2), 71.20 (OCH2), 31.86 (CH2), 19.57 (CH2), 14.16 (CH3); HRMS: m/z (M-H) calcd. For C11H1379Br2O3: 350.9231;
Found: 350.9231.
Acknowledgments: This study was financed by TÜBITAK - The Scientific and Technological Research Council of Turkey
(Project No: 113Z702) and realized in at Ataturk University, Faculty of Science, Department of Chemistry. We are grateful
to both institutes for their supports.
Supplementary Material: Experimental and NMR spectra of synthesized compounds are available in the supplementary
material, which are cited in the appropriate place in the text. https:
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Highlights
1- The first synthesis of biological active natural bromphenols by good yields were realized.
2- Inden-derivative 12 was synthesized from reaction of BBr3 with benzne ring bearing
OMe, Br and conjugated aldehyde moiety. Formation reaction of a indene derivative
during demethylation with BBr3 is new.
3- The first synthesis of bromophenols 36 and 37, isomers of 3-(3-bromo-4,5-
dihydroxyphenyl)-2-(3,5-dibromo-4-hydroxyphenyl)propanoic acid (31), were also
realized.