An efficient synthesis of 8-substituted Odoratine derivatives by the Suzuki coupling reaction

Article abstract of DOI:10.1007/s12039-016-1042-z

An efficient method for the preparation of 8-substituted odoratine [(3-(3 ^′, 4 ^′-methylenedioxyphenyl)-5,6,7-trimethoxyisoflavone] derivatives, structurally similar to glaziovianin A, a known cytotoxic substance, has been described.

Full text of DOI:10.1007/s12039-016-1042-z

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1042-z
An efficient synthesis of 8-substituted Odoratine derivatives by the
Suzuki coupling reaction
P RAVI KUMARa,b, C BALAKRISHNAa, B MURALIa, RAMAKRISHNA GUDIPATIa,
PRASANTA K HOTAc, AVINASH B CHAUDHARYa, A JAYA SHREEb,
SATYANARAYANA YENNAMa and MANORANJAN BEHERAa,∗
aDepartment of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., Plot Nos 125(part) & 126, IDA, Mallapur,
Hyderabad 500 076, Telangana, India
bCentre for Chemical Sciences and Technology, Institute of Science and Technology, JNT University,
Kukatpally, Hyderabad 500 085, Telangana, India
cDepartment of Chemistry, School of Sciences, HNBG University, Srinagar (Garhwal), Uttarakhand 246 174,
India
e-mail: Manoranjan.Behera@gvkbio.com
MS received 19 August 2015; revised 21 October 2015; accepted 8 January 2016
Abstract. An efficient method for the preparation of 8-substituted odoratine [(3-(3ꢁ, 4ꢁ-methylenedioxyphenyl)-
5,6,7-trimethoxyisoflavone] derivatives, structurally similar to glaziovianin A, a known cytotoxic substance, has
been described. The key steps in the synthesis are site selective bromination reaction followed by Suzuki cou-
pling reaction in very good yield. The structural assignment of the bromo derivative was determined utilizing
2D-HMBC and NOEs NMR techniques.
Keywords. Odoratine; suzuki coupling; isoflavones; fries rearrangement; bromination.
1. Introduction
various aryl as well as alkyl group by Suzuki coupling
reaction at the 8-position. Odoratine is a good starting
point for halogenation as all the position of ring A is
blocked except the 8th position.
The isoflavonoids are an important subgroup of flavonoids
mainly present in the species of Leguminosae family.1,2
Glaziovianin A is a novel isoflavone derivative iso-
lated from the leaves of the Brazilian tree Asteelia
glazioviana.3 It exhibits a broad spectrum of cytotoxic-
ity against a panel of 39 human cancer lines.4 Recently
it has been reported that glaziovianin A and its deriva-
tives are microtubule dynamics inhibitors by extending
the time lag of tubulin polyemrization without chang-
ing the net amount of polymerized tubulin in vitro.5
The seminal work has been done on glaziovianin A by
Kigoshi et al., which throws some light on the structure-
cytotoxicity relationship.6 One position of ring A that
was not studied is the 8-position of isoflavone; this may
be due to synthetic difficulties or unavailability of the
required starting material.7,8 Survey of literature shows
that 8-aryl substitution has increased the potency of
the molecule.9–14 For example, TP34 (figure 1) shows
PTP1B-selective and IC50 values were many fold
lower than other formyl chromone derivative.15 In this
context, we plan to derivatize odoratine, a naturally
occurring isoflavone which is structurally similar to
glaziovianin A by halogenation reaction and introduce
Odoratine [(3-(3ꢁ, 4ꢁ-methylenedioxyphenyl)-5,6,7-
trimethoxyisoflavone] (7) was isolated from Dipteryx
odorata Wild (Aubl.) (common name, sarrapia in
Venezuela or cumaru in Brazil).16–18 It has also been
isolated from the chloroform extract of the heartwood
of Cordyla Africana.19 There is some ambiguity for
the common name of this natural product viz., 5,6,7-
trimethoxy-3ꢁ, 4ꢁ-methylenedioxyisoflavone. Some of
the authors are using odoratin, odorantin and odoratine
for the same compound 7.20–23 We are using the name
odoratine coined by Nakano, as the structure of the
compound 7 was confirmed by him for the first time.24
There are a few reports for the synthesis of Odoratine
using the classical condensation reaction. Krishnamurti
and Seshagiri25 have prepared the Odoratine by Friedel-
Crafts acylation followed by cyclization reaction.
Chatterjea et al.,26 have used two different approaches
for the synthesis of Odoratine. First method involves a
Wessely-Moser rearrangement and the second method
involves the cyanohydrins approach. This reported six
step synthesis suffers from several disadvantages such
as, (a) it is very difficult to handle toxic reagent viz.,
∗For correspondence

P Ravi Kumar et al.
Figure 1. Structures of biologically active chromone derivatives.
KCN; (b) Use of diazomethane in large scale is not disadvantages. Also, some of these methods involve
advisable due to explosive nature of diazomethane; (c) acid catalyzed rearrangement reaction of epoxide and
Long cyclization period using moisture sensitive ZnCl2 a nuclear hydroxylation reaction which are not gen-
and use of H2SO4 in the final step make this process eral in nature. There are no reports in the literature
less attractive in large scale synthesis. Bhardwaj and co- for the synthesis of Odoratine and its derivatives using
workers27 also have synthesized Odoratine using two Pd-catalyzed cross-coupling reaction to the best of our
different routes using 2ꢁ-hydroxy-4ꢁ,5ꢁ,6ꢁ-trimethoxy- knowledge.
3,4-methylenedioxychalkone and 2,4,6-trihydroxy-3ꢁ,
During our research program on synthesis of nat-
4ꢁ-methylenedioxydesoxybenzoin as the required inter- ural products and derivatives for potential biological
mediates. All these synthesis involve a number of activity,28 we choose odoratine as it can also be con-
cumbersome steps, inconsistent results and the yields sidered as derivative of glaziovianin A (figure 1) and
are also poor. The disadvantages of the Friedel-Crafts can be used as potential inhibitor of tubulin polymer-
acylation are harsh reaction condition, regio-chemical ization. Herein we wish to report an efficient synthesis
uncertainties and instability of the requisite phenacetyl of odoratine and its derivatives using a simple protocol
halides. Long cyclization period, use of expensive start- involving the Suzuki-Miyaura coupling reaction as the
ing material and preparation of desoxybenzoin are other key step (scheme 1). Retro synthetic analysis shows that
Scheme 1. The synthesis of odoratine 7 using Suzuki Coupling.

Synthesis of Odoratine derivatives
3-iodo chromone can be prepared from the correspond- mL). The reaction mixture was stirred at 70◦C for 2
ing enaminone via iodo-cyclization reaction.29,30 We h. TLC analysis (30% ethyl acetate/ pet ether) showed
envisioned that the Suzuki coupling reaction31,32 could completion of reaction. Then the reaction mixture was
be used to synthesize odoratine using the boronic acid quenched with water and extracted with ethyl acetate.
6a, which can be prepared from the bromo compound 6 The organic phase was washed with water, brine and
in the final step.
dried over anhydrous Na2SO4. The solvent was evapo-
rated and the crude product was charged on silica gel
column. Elution of the column with 10% ethyl acetate /
pet ether gave the compound 3 (2.90 g, 96%) as white
2. Experimental
1
solid. H NMR (400 MHz, CDCl3): δ 13.40 (s, 1H,
2.1 Materials and characterization
Ar-OH), 6.22 (s, 1H, Ar-H), 4.00 (s, 3H, OCH3), 3.59
(s, 3H, OCH3), 3.58 (s, 3H, OCH3), 2.40 (s, 3H, COCH3);
MS (EI) m/z 227 (M+1, 100).
Dry solvents were purchased from chemical suppli-
ers and used without further purification. All melting
points were taken in open capillaries and are uncor-
rected. Analytical thin-layer chromatography (TLC)
was performed on commercially available Merck TLC
Silica gel 60 F254. Silica gel column chromatography
was performed on silica gel 60 (spherical 100-200
μm). FTIR spectra were recorded on Perkin-Elmer
FT/IR-4000 spectrophotometer and only the character-
istic peaks are reported. Mass spectra were scanned
2.1c Experimental procedure for the preparation of 3-
(dimethylamino)-1-(6-hydroxy-2,3,4-trimethoxyphenyl)
prop-2-en-1-one (4): DMF-DMA (8.87 mL, 66.37
mmol) was added drop wise to a solution of compound
3 (5 g, 22.12 mmol) in DMF (25 mL). The reaction
mixture was stirred at 100◦C for 16 h. TLC analysis
(40% ethyl acetate/ pet ether) showed completion of
reaction. The solvent was evaporated and the reaction
mixture was quenched with ice during the process
solids were precipitated out. The solids were filtered
and dried under vacuum to give the compound 4 (5.2 g,
83%) as yellow crystals; M.p. 112-116◦C; IR (KBr,
ν, cm−1): 3174, 2942, 2403, 1847, 1619, 1532, 1357,
1
on a Shimadzu LCMS 2010 spectrometer. H NMR
spectra were recorded on Varian-400 (400 MHz) spec-
1
trometer. Chemical shifts of H NMR spectra were
reported relative to tetramethylsilane. 13C NMR spec-
tra were recorded on Varian-400 (100 MHz) spectrom-
eter. Chemical shifts of 13C NMR spectra were reported
to relative to CDCl3 (77.0). Splitting patterns were
reported as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; dd, double doublet; br, broad.
1
1237, 1022; H NMR (400 MHz, CDCl3): δ 14.80
(s, 1H, Ar-OH), 7.96 (dd, J = 12.4 Hz, 1H, =CH),
6.33 (dd, J = 12.4 Hz, 1H, =CH), 6.24 (s, 1H, Ar-H),
3.92 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 3.19 (bs, 3H, NCH3), 2.94 (bs, 3H, NCH3);
LC-MS m/z 282.06 (98.2%, M+H+).
2.1a Experimental procedure for the preparation of
3,4,5-Trimethoxyphenyl acetate (2): A mixture of
3,4,5-trimethoxyphenol (5 g, 27 mmol) and sodium
acetate (5 g, 60 mmol) in acetic anhydride (25 mL,
265 mmol) was heated at 110◦C for 2 h. TLC analy-
sis (30% ethyl acetate/ pet ether) showed completion
of the reaction. Then the reaction mixture was concen-
trated under reduced pressure, diluted with water and
extracted with dichloromethane thrice. The combined
organic layer was washed with water and dried over
anhydrous Na2SO4. The solvent was evaporated and the
crude product was charged on silica gel column. Elution
of the column with 20% ethyl acetate/ pet ether gave
the compound 2 (5.91 g, 96%) as white solid. 1H NMR
(400 MHz, CDCl3): δ 6.25 (s, 2H, Ar-H), 3.82 (s, 9H,
3-OCH3), 2.25 (s, 3H, OCOCH3); MS (EI) m/z 227
(M+1, 100).
2.1d Experimental procedure for the preparation of
3-iodo-5,6,7-trimethoxy-4H-chromen-4-one (5): To a
stirred solution of compound 4 (4 g, 14.23 mmol) in
MeOH (80 mL), iodine (4.3 g, 17.08 mmol) was added
at 0◦C under nitrogen atmosphere. Then the reaction
mixture was stirred at room temperature for 3 h. TLC
analysis (30% ethyl acetate/ pet ether) showed com-
pletion of reaction. Then, the resulting solids were
filtered and washed with diethyl ether to give the com-
pound 5 (4.2 g, 81% yield) as light brown solid; M.p.
183-185◦C; IR (KBr, ν, cm−1): 3434, 2943, 1629, 1614,
1414, 1285, 1127, 1094; 1H NMR (400 MHz, DMSO-
d6): δ 8.68 (s, 1H, H-2), 7.04 (s, 1H, Ar-H), 4.12 (s, 3H,
OCH3), 3.98 (s, 3H, OCH3), 3.95 (s, 3H, OCH3); 13C
2.1b Experimental procedure for the preparation of NMR (100 MHz, CDCl3): δ 171.1 (C-4), 158.1 (C-2),
1-(6-Hydroxy-2, 3, 4 trimethoxyphenyl) ethanone (3): 155.7 (C-7), 154.4 (C-5), 152.4 (C-9), 140.8 (C-6),
BF3OEt2 (6 mL) was added drop wise to a solution of 111.2 (C-10), 95.9 (C-8), 88.7 (C-3), 62.1 (OCH3-5),
compound 2 (3 g, 13.3 mmol) in glacial acetic acid (10 61.4 (OCH3-6), 56.3 (OCH3-7); LC-MS m/z 362.97

P Ravi Kumar et al.
(99.4%, M+H+); ESI-HRMS calculated for C12H12O5I
OCH3); 13C NMR (100 MHz, CDCl3): δ 174.2 (C-4),
157.8 (C-7), 154.7 (C-9), 153.0 (C-5), 152.6 (C-2),
148.5 (C-3ꢁ), 147.3 (C-4ꢁ), 140.7 (C-6), 125.89 (C-1ꢁ),
125.83 (C-3), 115.6 (C-6ꢁ), 113.6 (C-10), 112.9 (C-5ꢁ),
111.9 (C-2ꢁ), 101.9 (OCH2O-3ꢁ, 4ꢁ), 96.1 (C-8), 62.1
(OCH3-5), 61.5 (OCH3-6), 56.2 (OCH3-7); LC-MS
m/z 435.00 (97.5%, M+H+); ESI-HRMS calculated
for C19H16O7Br [M+H]+: 435.0079, Found: 435.0252.
[M+H]+: 362.9730, Found: 362.9763.
2.1e Experimental procedure for the preparation of
[(3-(3ꢁ, 4ꢁ-methylenedioxyphenyl)-5,6,7-trimethoxyiso-
flavone] (7): To a solution of compound 5 (1 g, 2.76
mmol) in degassed toluene (10 mL) and ethanol (5 mL),
compound 6a (0.687 g, 4.14 mmol), 2M Na2CO3 (4.14
mL, 8.28 mmol) and Pd(PPh3)4 (0.466 g, 0.41 mmol)
was added under argon atmosphere. Then, the reaction
mixture was refluxed for 5 h. TLC analysis (10% ethyl
acetate/ chloroform) showed completion of reaction.
Then reaction mixture was diluted with ethyl acetate
and washed with water, brine and dried over Na2SO4.
The solvent was evaporated and the crude product was
charged on silica gel column. Elution of the column
with 5% ethyl acetate/ chloroform gave the compound
7 (900 mg, 91%) as white solid; M.p. 176-180◦C; IR
(KBr, ν, cm−1): 2938, 1643, 1618, 1600, 1453, 1247,
1131; 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H, H-2),
7.08 (d, J = 1.6 Hz, 1H, Ar-H), 6.92 (dd, J = 2.0 Hz,
1H, Ar-H), 6.82 (d, J = 8.0 Hz, 1H, Ar-H), 6.58 (s, 1H,
Ar-H), 5.96 (s, 2H, OCH2O), 3.95 (s, 6H, 2-OCH3),
3.90 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3):
δ 174.9 (C-4), 157.7 (C-7), 154.5 (C-5), 152.9 (C-2),
150.5 (C-9), 147.5 (C-3ꢁ), 147.5 (C-4ꢁ), 140.5 (C-6),
125.6 (C-1ꢁ), 125.4 (C-3), 122.4 (C-6ꢁ), 113.5 (C-10),
109.9 (C-2ꢁ), 108.2 (C-5ꢁ), 101.0 (OCH2O-3ꢁ,4ꢁ), 96.0
(C-8), 62.0 (OCH3-5), 61.4 (OCH3-6), 56.2 (OCH3-
7); LC-MS m/z 357.09 (99.5%, M+H+); ESI-HRMS
calculated for C19H17O7 [M+H]+: 357.0974, Found:
357.0965.
2.1g Experimental procedure for the preparation
of 8-bromo-3-(6-bromobenzo[d][1,3]dioxol-5-yl)-5,6,
7-trimethoxy-4H-chromen-4-one (8a): To a stirred
solution of compound 7 (0.1 g, 0.28 mmol) in acetoni-
trile (5 mL), NBS (0.075 g, 0.42 mmol) was added at
0◦C and stirred at RT for 24 h. TLC analysis (20%
ethyl acetate/pet ether) showed completion of the reac-
tion. Then, reaction mixture was concentrated under
vacuum, diluted with water and extracted with ethyl
acetate. The organic phase was washed with water
and dried over anhydrous Na2SO4. The solvent was
evaporated and the crude product was charged on sil-
ica gel column. Elution of the column with 5% ethyl
acetate/pet ether gave the compound 8a (0.128 g, 91%)
as white solid; M.p. 200-205◦C; IR (KBr, ν, cm−1):
2944, 1639, 1584, 1480, 1397, 1292, 1236, 1030;
1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H, H-2),
7.11 (s, 1H, Ar-H), 6.79 (s, 1H, Ar-H), 6.01 (s, 2H,
OCH2O), 4.07 (s, 3H, OCH3), 3.96 (s, 3H, OCH3),
3.95 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3):
δ 174.2 (C-4), 156.0 (C-7), 153.1 (C-2), 153.0 (C-5),
150.7 (C-9), 148.7 (C-3ꢁ), 147.3 (C-4ꢁ), 144.8 (C-6),
125.9 (C-1ꢁ), 125.2 (C-3), 116.5 (C-5ꢁ), 115.6 (C-2ꢁ),
113.0 (C-6ꢁ), 111.7 (C-10), 102.0 (OCH2O-3ꢁ, 4ꢁ), 101.2
(C-8), 62.3 (OCH3-5), 61.8 (OCH3-6), 61.5 (OCH3-7);
LC-MS m/z 512.91 (97.5%, M+H+); ESI-HRMS cal-
culated for C19H15O7Br2 [M+H]+: 512.9185, Found:
512.9421.
2.1f Experimental procedure for the preparation of
3-(6-bromobenzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-
4H-chromen-4-one (8): To a stirred solution of
compound 7 (0.2 g, 0.56 mmol) in chloroform (10 mL),
bromine (0.089 g, 0.56 mmol) was added at 0◦C
and stirred at RT for 24 h. TLC analysis (20% ethyl 2.1h Experimental procedure for the preparation of 8-
acetate/pet ether) showed completion of the reac- bromo-3-iodo-5,6,7-trimethoxy-4H-chromen-4-one (9):
tion. Then reaction mixture was concentrated under To a stirred solution of compound 5 (3.5 g, 9.66 mmol)
vacuum, diluted with water and extracted with ethyl in carbon tetrachloride (40 mL), benzoyl peroxide
acetate. The organic phase was washed with water (0.701 g, 2.90 mmol) and N-bromosuccinimide (3.44
and dried over anhydrous Na2SO4. The solvent was g, 19.33 mmol) was added under nitrogen atmosphere.
evaporated and the crude product was charged on silica Then, the reaction mixture was refluxed for 14 h. TLC
gel column. Elution of the column with 5% ethyl analysis (30% ethyl acetate/ pet ether) showed comple-
acetate/pet ether gave the compound 8 (0.12 g, 50%) tion of the reaction. Then, reaction mixture was concen-
as white solid; M.p. 214-217◦C; IR (KBr, ν, cm−1): trated under vacuum, diluted with water and extracted
1
2944, 1644, 1602, 1475, 1294, 1233, 1131; H NMR with ethyl acetate. The organic phase was washed with
(400 MHz, CDCl3): δ 7.74 (s, 1H, H-2), 7.11 (s, 1H, water and dried over anhydrous Na2SO4. The solvent
Ar-H), 6.82 (s, 1H, Ar-H), 6.72 (s, 1H, Ar-H), 6.00 was evaporated and the crude product was charged
(s, 2H, OCH2O), 4.06 (s, 6H, 2OCH3), 3.98 (s, 3H, on silica gel column. Elution of the column with 8%

Synthesis of Odoratine derivatives
ethyl acetate/ pet ether gave the compound 9 (3.90 the crude product was charged on silica gel column.
g, 91.6%) as white solid; M.p. 155-158◦C; IR (KBr, Elution of the column with 20-30% ethyl acetate/ pet
ν, cm−1): 2947, 1651, 1599, 1464, 1401, 1277, 1093; ether gave the compounds 11a-j.
1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H, H-2),
4.06 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3): δ 171.1 (C-4),
156.3 (C-2), 156.1 (C-7), 152.6 (C-5), 150.5 (C-9),
145.0 (C-6), 114.0 (C-10), 100.9 (C-8), 88.2 (C-3), 62.2
(OCH3-5), 61.7 (OCH3-6), 61.5 (OCH3-7); LC-MS
m/z 440.88 (97.5%, M+H+); ESI-HRMS calculated
for C12H11O5BrI [M+H]+: 440.8835, Found: 440.8881.
2.2a 3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-
8-p-tolyl-4H-chromen-4-one (11a): White solid; M.p.
171-175◦C; IR (KBr, ν, cm−1): 3434, 2934, 1646,
1457, 1396, 1239, 1034, 816, 517; 1H NMR (400 MHz,
DMSO-d6): δ 8.20 (s, 1H, H-2), 7.25-7.30 (m, 4H,
Ar-H), 7.08 (d, J = 1.2 Hz, 1H, Ar-H), 6.90-7.00
(m, 2H, Ar-H), 6.02 (s, 2H, OCH2O), 3.85-3.90
(d, J = 6.4 Hz, 6H, 2-OCH3), 3.70 (s, 3H, OCH3),
2.38 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ
175.5 (C-4), 155.8 (C-7), 152.7 (C-2), 151.1 (C-5),
151.1 (C-3ꢁ), 147.6 (C-4ꢁ), 147.6 (C-9), 144.4 (C-6),
137.6 (C-4ꢁꢁ), 130.3 (C-3ꢁꢁ,5ꢁꢁ), 128.9 (C-1ꢁꢁ), 128.6
(C-2ꢁꢁ,6ꢁꢁ), 125.6 (C-1ꢁ), 125.0 (C-3), 122.4 (C-6ꢁ),
120.8 (C-2ꢁ), 116.0 (C-5ꢁ), 109.9 (C-8), 108.3 (C-10),
101.1 (OCH2 O-3ꢁ,4ꢁ), 62.1 (OCH3-5), 61.5 (OCH3-6),
61.4 (OCH3-7), 21.3 (CH3-4ꢁꢁ); LC-MS m/z 447.14
(98.2%, M+H+); ESI-HRMS calculated for C26H23O7
[M+H]+: 447.1437, Found: 447.1444.
2.1i Experimental procedure for the preparation
of 3-(benzo[1,3]dioxol-5-yl)-8-bromo-3-iodo-5,6,7-
trimethoxy-4H-chromen-4-one(10): To a solution of
compound 9 (1 g, 2.27 mmol) in degassed toluene
(10 mL) and ethanol (5 mL), compound 6a (0.452 g,
2.72 mmol), 2M Na2CO3 (3.40 mL, 6.81 mmol) and
Pd(PPh3)4 (0.250 g, 0.22 mmol) were added under
argon atmosphere. Then, the reaction mixture was
refluxed for 5 h. TLC analysis (30% ethyl acetate/
pet ether) showed completion of the reaction. Then,
the reaction mixture was diluted with ethyl acetate
and washed with water, brine and dried over Na2SO4.
The solvent was evaporated and the crude product was
charged on silica gel column. Elution of the column
with 20% ethyl acetate/ pet ether gave the compound
10 (840 mg, 85%) as white solid; M.p. 163-165◦C; IR
(KBr, ν, cm−1): 3433, 2946, 1648, 1462, 1407, 1251,
1012; 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H, H-2),
7.06 (s, 1H, Ar-H), 6.94 (d, J = 8.0 Hz, 1H, Ar-H), 6.86
(d, J = 8.0 Hz, 1H, Ar-H), 6.00 (s, 2H, OCH2O), 4.05
(s, 3H, OCH3), 3.98 (s, 3H, OCH3), 3.94 (s, 3H, OCH3);
13C NMR (100 MHz, DMSO-d6): δ 173.6 (C-4), 155.2
(C-7),152.4(C-2),152.3(C-5),149.9(C-3ꢁ),147.0 (C-4ꢁ),
146.9 (C-9), 144.1 (C-6), 125.0 (C-1ꢁ), 123.9 (C-3),
122.6 (C-6ꢁ), 115.9 (C-2ꢁ), 109.5 (C-5ꢁ), 108.0 (C-10),
101.0 (OCH2O-3ꢁ,4ꢁ), 100.4 (C-8), 61.8 (OCH3-5),
61.6 (OCH3-6), 61.3 (OCH3-7); LC-MS m/z 435.00
(99%, M+H+); ESI-HRMS calculated for C19H16O7Br
[M+H]+: 435.0079, Found: 435.0077.
2.2b 3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-
8-(4-methoxyphenyl)-4H-chromen-4-one (11b): White
solid; M.p. 160-164◦C; IR (KBr, ν, cm−1): 3436,
1
2937, 1644, 1244, 1034, 816; H NMR (400 MHz,
DMSO-d6): δ 8.20 (s, 1H, H-2), 7.32 (d, J = 8.8
Hz, 2H, Ar-H), 6.91-7.10 (m, 5H, Ar-H), 6.02 (s, 2H,
OCH2O), 3.85-3.91 (d, J = 7.2 Hz, 6H, 2-OCH3),
3.80 (s, 3H, OCH3), 3.62 (s, 3H, OCH3); 13C NMR
(100 MHz, CDCl3): δ 175.5 (C-4), 159.2 (C-4ꢁꢁ), 155.9
(C-7), 152.6 (C-2), 151.2 (C-5), 151.0 (C-3ꢁ), 147.6
(C-4ꢁꢁ), 147.6 (C-9), 144.4 (C-6), 131.6 (C-2ꢁꢁ, 6ꢁꢁ), 125.6
(C-1 ), 125.0 (C-1ꢁꢁ), 123.7 (C-3), 122.4 (C-6ꢁ), 120.5
(C-3ꢁꢁ, 5ꢁꢁ), 116.0 (C-2ꢁ), 113.7 (C-5ꢁ), 109.9 (C-8),
108.3 (C-10), 101.1 (OCH2O-3ꢁ, 4ꢁ), 62.1 (OCH3-5),
61.5 (OCH3-6), 61.3 (OCH3-7), 55.2 (OCH3-4ꢁꢁ);
LC-MS m/z 463.13 (99%, M+H+); ESI-HRMS cal-
culated for C26H23O8 [M+H]+: 463.1353, Found:
463.1393.
2.2 General procedure for the preparation of
compounds 11a-j
2.2c 4-(3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-
4-oxo-4H-chromen-8-yl)benzonitrile (11c): White
To a solution of compound 10 (0.23 mmol) in degassed solid; M.p. 173-177◦C; IR (KBr, ν, cm−1): 3429, 2936,
toluene (5 mL), boronic acid (0.46 mmol), 2M K3PO4 2226, 1647, 1459, 1395, 1239, 1059, 1009, 816, 559;
(0.69 mmol) and Pd(PPh3)4 (0.011 mmol) were added 1H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H, H-2),
under argon atmosphere. Then, the reaction mixture 7.95 (d, J = 8.4 Hz, 2H, Ar-H), 7.63 (d, J = 8.0 Hz,
was refluxed for 14 h. Then, the reaction mixture was 2H, Ar-H), 7.08 (s, 1H, Ar-H), 6.96 (m, 2H, Ar-H),
diluted with ethyl acetate and washed with water, brine 6.02 (s, 2H, Ar-H), 3.85-3.90 (d, J = 2.8 Hz, 6H,
and dried over Na2SO4. The solvent was evaporated and 2-OCH3), 3.80 (s, 3H, OCH3); 13C NMR (100 MHz,

P Ravi Kumar et al.
CDCl3): δ 173.8 (C-4), 154.8 (C-7), 152.9 (C-2), 152.1 2.2f 3-(benzo[d][1,3]dioxol-5-yl)-8-(3,4-difluorophenyl)-
(C-5), 150.0 (C-3ꢁ, 4ꢁ), 145.8 (C-9, 1ꢁꢁ), 143.6 (C-6), 5,6,7-trimethoxy-4H-chromen-4-one (11f): White solid;
136.7 (C-3ꢁꢁ, 5ꢁꢁ), 131.9 (C-2ꢁꢁ, 6ꢁꢁ), 131.6 (C-1ꢁ), 125.3 M.p. 113-117◦C; IR (KBr, ν, cm−1): 3449, 2937, 1643,
(C-3), 123.7 (C-6ꢁ), 122.4 (CN-4ꢁꢁ), 118.6 (C-4ꢁꢁ), 115.3 1392, 1246, 1038, 765, 576; 1H NMR (400 MHz, CDCl3):
(C-2ꢁ), 110.6 (C-5ꢁ), 109.4 (C-8), 107.9 (C-10), 100.9 δ 7.72 (s, 1H, H-2), 7.2-7.34 (m, 2H, Ar-H), 7.12 (s, 1H,
(OCH2O-3ꢁ, 4ꢁ), 61.7 (OCH3-5), 61.3 (OCH3-6), 61.3 Ar-H), 7.04 (s, 1H, Ar-H), 6.91 (d, J = 8.0 Hz, 1H,
(OCH3-7); LC-MS m/z 458.12 (98%, M+H+); ESI- Ar-H), 6.84 (d, J = 8.0 Hz, 1H, Ar-H), 5.97 (s, 2H,
HRMS calculated for C26H20O7N [M+H]+: 458.1206, OCH2O), 4.01 (s, 3H, OCH3), 3.97 (s, 3H, OCH3),
Found: 458.1240.
3.80 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3): δ
175.2 (C-4), 155.6 (C-7) (J C-F 213.3), 153.5 (C-2),
151.3 (C-5), 150.8 (C-3ꢁꢁ), 148.8 (C-3ꢁ) (J C-F 247.4),
147.7 (C-4ꢁꢁ), 147.6 (C-4ꢁ), 144.3 (C-9), 128.4 (C-6),
126.9 (C-1ꢁꢁ), 125.3 (C-6ꢁꢁ), 122.4 (C-1ꢁ), 119.8 (C-3),
119.6 (C-6ꢁ), 118.6 (C-2ꢁꢁ), 117.1 (C-5ꢁꢁ), 116.9 (C-2ꢁ),
116.0 (C-5ꢁ), 109.8 (C-8), 108.3 (C-10), 101.1
(OCH2O-3ꢁ, 4ꢁ), 62.1 (OCH3-5), 61.8 (OCH3-6), 61.4
(OCH3-7); LC-MS m/z 469.10 (96.8%, M+H+); ESI-
HRMS calculated for C25H19O7F2 [M+H]+: 469.1099,
Found: 469.1121.
2.2d Methyl 3-(3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-
trimethoxy-4-oxo-4H-chromen-8-yl)benzoate
(11d):
White solid; M.p. 174-179◦C; IR (KBr, ν, cm−1): 3414,
1
2944, 1716, 1646, 1456, 1237, 1063, 759, 513; H
NMR (400 MHz, CDCl3): δ 8.10 (m, 2H, Ar-H), 7.70
(s, 1H, Ar-H), 7.52-7.60 (m, 2H, Ar-H), 7.05 (s, 1H,
Ar-H), 6.90 (d, J = 8.0 Hz, 1H, Ar-H), 6.80 (d, J =
7.6 Hz, 1H, Ar-H), 5.95 (s, 2H, OCH2O), 4.01 (s, 3H,
OCOCH3), 3.97 (s, 3H, OCH3), 3.92 (s, 3H, OCH3),
3.80 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3):
δ 175.3 (C-4), 166.8 (C=O-3ꢁꢁ), 155.7 (C-7), 153.3
(C-2), 151.0 (C-5), 150.9 (C-3ꢁ), 147.6 (C-4ꢁ), 144.3
(C-9), 135.0 (C-1ꢁꢁ), 132.1 (C-6), 131.8 (C-6ꢁꢁ), 130.3
(C-3ꢁꢁ), 129.0 (C-2ꢁꢁ, 4ꢁꢁ), 128.2 (C-5ꢁꢁ), 125.4 (C-1ꢁ),
125.2 (C-3), 122.5 (C-6ꢁ), 119.7 (C-2ꢁ), 116.0 (C-5ꢁ),
109.9 (C-8), 108.3 (C-10), 101.12 (OCH2O-3ꢁ, 4ꢁ),
62.1 (OCH3-5), 61.5 (OCH3-6), 61.5 (OCH3-7), 52.1
(OCH3-3ꢁꢁ); LC-MS m/z 491.13 (96%, M+H+); ESI-
HRMS calculated for C27H23O9 [M+H]+: 491.1342,
Found: 491.1354.
2.2g 3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-8-
(thiophen-3-yl)-4H-chromen-4-one (11g): White crys-
tals; M.p. 120-124◦C; IR (KBr, ν, cm−1): 3432, 3102,
2937, 1643, 1400, 1239, 1016, 793, 505; 1H NMR (400
MHz, CDCl3): δ 7.82 (s, 1H, H-2), 7.42-7.48 (m, 2H,
Ar-H), 7.23 (s, 1H, Ar-H), 7.12 (s, 1H, Ar-H), 6.92
(dd, J = 1.4 Hz, 1H, Ar-H), 6.84 (d, J = 7.6 Hz, 1H,
Ar-H), 5.97 (s, 2H, OCH2O), 4.01 (s, 3H, OCH3), 3.97
(s, 3H, OCH3), 3.80 (s, 3H, OCH3); 13C NMR (100
MHz, CDCl3): δ 175.4 (C-4), 156.0 (C-7), 152.8 (C-5),
151.1 (C-2), 150.9 (C-3ꢁ), 147.6 (C-4ꢁ), 144.5 (C-9),
130.4 (C-1ꢁꢁ), 129.5 (C-6), 125.5 (C-2ꢁꢁ, 3ꢁꢁ), 125.4
(C-1ꢁ), 125.1 (C-5ꢁꢁ), 124.5 (C-3), 122.4 (C-6ꢁ), 116.1
(C-2ꢁ), 115.8 (C-5ꢁ), 109.9 (C-8), 108.3 (C-10), 101.1
(OCH2O-3ꢁ, 4ꢁ), 62.1 (OCH3-5), 61.5 (OCH3-6), 61.3
(OCH3-7); LC-MS m/z 439.04 (96.5%, M+H+); ESI-
HRMS calculated for C23H19O7S [M+H]+: 439.0449,
Found: 439.0452.
2.2e (E)-3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-
8-styryl-4H-chromen-4-one (11e): White solid; M.p.
119-124◦C; IR (KBr, ν, cm−1): 3636, 2936, 1640,
1
1459, 1402, 1253, 1109, 1033, 817, 690, 526; H
NMR (400 MHz, CDCl3): δ 7.93 (s, 1H, H-2), 7.52-
7.61 (m, 3H, Ar-H), 7.28-7.42 (m, 4H, Ar-H), 7.1
(d, J = 1.6 Hz, 1H, =CH), 6.95-6.98 (dd, J = 1.6
Hz, 1H, Ar-H), 6.86 (d, J = 8.0 Hz, 1H, =CH), 6.0 2.2h 3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-8-
(s, 2H,OCH2O), 4.01 (s, 3H, OCH3), 3.97 (s, 3H, methyl-4H-chromen-4-one (11h): Off- white solid; M.p.
OCH3), 3.92 (s, 3H, OCH3); 13C NMR (100 MHz, 101-105◦C; IR (KBr, ν, cm−1): 3431, 2924, 2179, 1643,
CDCl3): δ 175.4 (C-4), 156.2 (C-2), 153.2 (C-5), 1401, 1237, 1033, 812, 615, 493; 1H NMR (400 MHz,
152.5 (C-7), 151.6 (C-3ꢁ), 150.7 (C-4ꢁ), 147.6 (C-9), CDCl3): δ 7.9 (s, 1H, H-2), 7.1 (d, J = 1.6 Hz, 1H, Ar-H),
144.5 (C-6), 138.0 (C-1ꢁꢁ), 134.6 (=CH-8), 128.7 6.98 (dd, J = 1.4 Hz, 1H, Ar-H), 6.85 (d, J = 8.4 Hz,
(=CH-1ꢁꢁ), 127.9 (C-3ꢁꢁ, 5ꢁꢁ), 126.5 (C-2ꢁꢁ, 6ꢁꢁ), 125.4 1H, Ar-H), 5.97 (s, 2H, OCH2O), 4.01 (s, 3H, OCH3),
(C-4ꢁꢁ), 125.3 (C-1ꢁ), 122.5 (C-3), 117.4 (C-6ꢁ), 116.4 3.97 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 2.3 (s, 3H,
(C-10), 116.2 (C-2ꢁ), 109.9 (C-5ꢁ), 108.3 (C-8), 101.1 CH3); 13C NMR (100 MHz, CDCl3): δ 175.6 (C-4),
(OCH2O-3ꢁ, 4ꢁ), 62.1 (OCH3-5), 61.5 (OCH3-6), 61.1 166.0 (C-9), 152.0 (C-2), 151.1 (C-5), 151.0 (C-7),
(OCH3-7); LC-MS m/z 459.14 (98.5%, M+H+); ESI- 147.6 (C-3ꢁ), 147.5 (C-4ꢁ), 144.1 (C-6), 125.7 (C-1ꢁ),
HRMS calculated for C27H23O7 [M+H]+: 459.1444, 125.0 (C-3), 122.5 (C-6ꢁ), 115.9 (C-2ꢁ), 115.8 (C-8),
Found: 459.1486.
109.9 (C-5ꢁ), 108.3 (C-10), 101.1 (OCH2O-3ꢁ, 4ꢁ),

Synthesis of Odoratine derivatives
62.0 (OCH3-5), 61.4 (OCH3-6), 61.1 (OCH3-7), 8.6 rearrangement in the presence of BF3.Et2O/AcOH to
(CH3-8); LC-MS m/z 371.11 (95.5%, M+H+); ESI- give the required o-hydroxyacetophenone derivative 3.
HRMS calculated for C20H19O7 [M+H]+: 371.1131, Enaminone 4 was prepared by reaction of the acetophe-
Found: 371.1160.
none 3 with DMF-DMA. The enaminone was charac-
terized by 1H-NMR and LC-MS data. An initial attempt
to cyclize the enaminone using I2 in DMF was not
successful. This may be due to poor solubility of enam-
inone in DMF and we have observed some undesired
products by LC-MS (Liquid Chromatography Mass
Spectra) analysis. But by changing the solvent from
DMF to MeOH the enaminone 4 was smoothly con-
verted into iodo-chromone 5, ready for the Suzuki
coupling reaction. Compound 5 was characterized by
1H-NMR, 13C-NMR and LC-MS data. The characteris-
2.2i 3,8-di(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-
4H-chromen-4-one (11i): White crystals; M.p. 131-
136◦C; IR (KBr, ν, cm−1): 3434, 2893, 1650, 1464,
1
1233, 1039, 796, 554; H NMR (400 MHz, CDCl3):
δ 7.74 (s, 1H, H-2), 7.06 (d, J = 0.8 Hz, 1H, Ar-H),
6.83-6.94 (m, 5H, Ar-H), 6.02 (s, 2H, OCH2O), 5.94
(s, 2H, OCH2O), 4.01 (s, 3H, OCH3), 3.97 (s, 3H, OCH3),
3.80 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3): δ
175.4 (C-4), 155.9 (C-7), 152.8 (C-2), 151.2 (C-5),
151.0 (C-3ꢁꢁ), 147.6 (C-3ꢁ), 147.5 (C-4ꢁ), 147.2 (C-9),
144.3 (C-4ꢁꢁ), 125.5 (C-6), 125.1 (C-1ꢁꢁ), 125.0 (C-1ꢁ),
124.0 (C-3), 122.4 (C-6ꢁꢁ), 120.4 (C-2ꢁꢁ), 116.0 (C-2ꢁ),
110.0 (C-5ꢁꢁ), 109.9 (C-5ꢁ), 108.3 (C-8), 108.2 (C-10),
101.2 (OCH2O-3ꢁꢁ, 4ꢁꢁ), 101.1 (OCH2O-3ꢁ, 4ꢁ), 62.1
(OCH3-5), 61.5 (OCH3-6), 61.4 (OCH3-7); LC-MS
m/z 477.11 (98.6%, M+H+); ESI-HRMS calculated
for C26H21O9 [M+H]+: 477.1190, Found: 477.1186.
1
tic chromone ring C proton at δ 8.6 in H-NMR con-
firms the formation of compound 5. The IR spectrum
of compound 5 shows the carbonyl peak at 1630 cm−1.
Since the boronic acid 6a was expensive, we prepared
the boronic acid 6a from corresponding bromo deriva-
tive 6. The iodo-chromone reacted with boronic acid 6a
under the Suzuki reaction condition to give odoratine 7
in very good yield. The odoratine was characterized by
1H-NMR, 13C-NMR and LC-MS data consistent with
the reported value.19
2.2j 3-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-8-
(quinolin-3-yl)-4H-chromen-4-one (11j): White solid;
M.p. 103-107◦C; IR (KBr, ν, cm−1): 3435, 2927, 1645,
1458, 1236, 1018, 786, 637, 549; 1H NMR (400 MHz,
CDCl3): δ 8.94 (s, 1H, H-2), 8.24 (s, 1H, Ar-H), 8.20
(d, J = 8.4 Hz, 1H, Ar-H), 7.9 (d, J = 7.6 Hz, 1H, Ar-H),
7.8 (m, 1H, Ar-H), 7.7 (s, 1H, Ar-H), 7.6 (t, J = 7.4 Hz,
1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.92 (d, J = 8.4 Hz,
1H, Ar-H), 6.84 (d, J = 8.0 Hz, 1H, Ar-H), 5.94 (s, 2H,
OCH2O), 4.01 (s, 3H, OCH3), 3.97 (s, 3H, OCH3),
3.85 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3):
δ175.2 (C-4), 156.0 (C-7), 153.9 (C-5), 152.0 (C-2),
151.2 (C-2ꢁꢁ), 150.9 (C-3ꢁ), 147.7 (C-4ꢁ), 147.6 (C-9),
147.2 (C-9ꢁꢁ), 144.4 (C-8ꢁꢁ), 137.6 (C-6), 129.8 (C-10ꢁꢁ),
129.2 (C-1ꢁꢁ), 127.9 (C-7ꢁꢁ), 127.7 (C-5ꢁꢁ), 126.6 (C-4ꢁꢁ),
125.45 (C-6ꢁꢁ), 125.2 (C-1ꢁ), 125.1 (C-3), 122.5 (C-6ꢁ),
117.0 (C-2ꢁ), 116.1 (C-5ꢁ), 109.9 (C-8), 108.3 (C-10),
101.1 (OCH2O-3ꢁ, 4ꢁ), 62.2 ((OCH3-5), 61.6 (OCH3-6),
61.61 (OCH3-7); LC-MS m/z 484.13 (98.7%, M+H+);
ESI-HRMS calculated for C28H22O7N [M+H]+:
484.1368, Found: 484.1396.
After synthesizing the natural product odoratine, we
planned to quickly make a few derivatives. In this con-
text, bromination of the compound 7 was screened
using various reaction conditions (table 1). Among the
conditions screened, NBS in both the solvents CH3CN
and CCl4 gave dibrominated compound 8a. The com-
1
pound 8a was charaterized by H-NMR, 13C-NMR,
NOESY and LC-MS data. The disapperance of peak at
δ 6.6 confirm the introduction of one bromine on ring
A. In the NOESY (Nuclear Overhauser Effect Spec-
troscopy) sepctra of 8a correlation were found between
the protons of Ha of ring C and Hb of ring B (scheme 2).
Table 1. Bromination of odoratine.
Entry
Conditions
Time Yield (%)a
1
2
3
4
5
6
7
8
9
KBrO3, oxone, MeOH
DDB, dioxane, diethyl ether
NBS, CH3CN
24 h
24 h
24 h
24 h
24 h
24 h
24 h
9 h
42
20
91b
65b
45
78
38
58
0
NBS, CCl4
Br2, CHCl3
NBS, H2SO4, THF
NBS, Bz2O, CCl4
NBS, CH3CN, hυc
KBr, HNO3, Ac2O
3. Results and Discussion
9 h
The synthesis of odoratine commenced with commer-
cially available 3,4,5-trimethoxy-phenol 1 (scheme 1).
The phenol 1 was acetylated with acetic anhydride
in the presence of NaOAc to produce o-acetylated
derivative 2. Compound 2 was subjected to the Fries
aDetermined by analysis of the crude reaction mixture by
analytical LC/MS.
bDibrominated product formed.
cThe reaction was performed under 100W electricity bulb.

P Ravi Kumar et al.
Scheme 2. Bromination of odoratine and NOE and HMBC correlation study.
Although by using NBS/H2SO4/THF condition the con- dioxolane ring is helping the electrophilic bromination
version was good, it was very difficult to extract the reaction to occur in ring B.
crude reaction mixture during work up procedure using
Then, we diverted our attention to bromination of the
water. Using Br2 in CHCl3 condition, we could iso- 3-iodo-chromone 5 to get 8-bromo-chromone derivative
late mono-brominated compound 8 in milligram quanti- (scheme 3). We believe that there will be difference in
ties. Initially we thought the mono-brominated product reactivities of iodo compounds vs bromo compounds in
to be compound 10 not the comound 8. To confirm Suzuki coupling reaction condition.
1
the position of bromine, H NMR studies was con-
Initially, bromination of the compound 5 was per-
ducted. The presence of characteristic proton at δ 6.8 formed in NBS/CH3CN condition which gave poor
and disappearance of peak at δ 6.9 in 1H-NMR indi- yield of the compound 9. Screening of optimal
cates the formation of the compound 8. The structure condition was performed again using various sol-
of the compound 8 was further confirmed by NOESY vents, reagents and temperature. Among the conditions
and HMBC (Heteronuclear Multiple-Bond Correlation) screened, we found that NBS/Bz2O/CCl4 gave better
studies (scheme 2). H-9 of ring C is giving HMBC cor- yield compared to all other conditions. The compound 9
1
relation with C-12, C-10 and C-6. Similarly, H-16 of was characterized by H-NMR, 13C-NMR and LC-MS
ring A is giving correlation with C-14 and C-13 of the data. An IR spectrum of the compound 9 shows the car-
same ring A and C-7 of ring B is giving HMBC cor- bonyl peaks at 1651cm−1. The characteristic chromone
relation with C-8, C-3 and C-5, which shows that Br ring C proton at δ 8.2 and disappearance of proton at δ
is attached to C-5 of ring B. May be the presence of 7.0 in 1H-NMR confirms formation of compound 9.
Scheme 3. Derivatization of odoratine at 8-position by Suzuki coupling.

Synthesis of Odoratine derivatives
After synthesizing the key building block 9, it But unfortunately using the same reaction condi-
was subjected to the Suzuki reaction with boronic tion (Pd(PPh3)4/Na2CO3/toluene/EtOH/H2O), the com-
acid 6a using Pd(PPh3)4/Na2CO3/toluene/EtOH/H2O pound 10 did not yield any Suzuki product 11a
condition to give compound 10 in good yield. As even after prolonged reaction time and use of excess
expected (iodo vs bromo), we have isolated only reagents. Then, the Suzuki reaction condition of the
mono-aryl product 10 using 1.2 equivalent of the compound 10 with 4-methyl-phenyl boronic acid was
boronic acid 6a in the Suzuki reaction condition. tried using K3PO4/Pd(PPh3)4/toluene condition and
Table 2. List of 8-substituted odoratine derivatives.
Entry
Product
Yield (%)
Entry
Product
Yield
92
1
97
6
2
81
7
79
3
98
8
62
4
70
9
95
5
82
10
94

P Ravi Kumar et al.
4. Hayakawa I, Shioda S, Ikedo A and Kogishi H 2014
gratifyingly, we could isolate the compound 11a in
good yield.
Bull. Chem. Soc. Jpn. 87 544
5. Chinen T, Kazami S, Nagumo Y, Hayakawa I, Ikedo A,
Takagi M, Yokosuka A, Imamoto N, Mimaki Y, Kigoshi
H, Osada H and Usui T 2013 ACS Chem. Bio. 8 884
6. Ikedo A, Hayakawa I, Usui T, Kazami S, Osada H and
Kigoshi H 2010 Bioorg. Med. Chem. Lett. 20 5402
7. Hayakawa I, Ikedo A and Kigoshi H 2007 Chem. Lett.
36 1382
8. Hayakawa I, Ikedo A, Chinen T, Usui T and Kigoshi H
2012 Bioorg. Med. Chem. 20 5745
9. Boland G M and Donnelly D M 1998 Nat. Prod. Rep.
241
Once the Suzuki reaction condition was standard-
ized, various boronic acids were subjected to cross-
coupling reaction to give the compounds 11a-11j
(table 2). All compounds, 11a-11j were well character-
ized by 1H-NMR, LC-MS and 13C-NMR (for unknown
compounds). As indicated in table 2, both the electron
withdrawing (entry 3) as well as electron donating
group (entry 2) on aryl boronic acid gave similar yield
of the cross-coupling product. The alkyl (entry 5) as
well heteroaryl (entry 7) boronic acid also gave good 10. Li Y H, Fu H G, Su F, Gao L M, Tang S, Bi C W, Li Y
H, Wang Y X and Song D Q 2013 Chemistry Central J.
7 117
11. Mukne A P, Viswanathan V and Phadatare A G 2011
Pharmacogn. Rev. 5 13
12. Malla P, Kumar R and Kumar M 2013 Chem. Biol. Drug
Des. 82 71
yield of the coupling product.
It is noteworthy to mention here that previously inac-
cessible methyl (entry 8) and 5-benzo-dioxole deriva-
tives (entry 9) were synthesized using this method.
13. Shim Y S, Kim K C, Chi D Y, Lee K H and Cho H 2003
Bioorg. Med. Chem. 13 2561
4. Conclusions
14. Kim J, Seunghee Hong and Sungwoo Hong 2011
Bioorg. Med. Chem. Lett. 21 6977
We have developed an efficient and versatile synthetic
protocol to synthesize the 8-substituted odoratine
derivatives in very good yield for the first time. Site-
selective bromination of odoratine has been demon-
strated using two different routes. 2D (1H-13C) HMBC
measurements can be readily utilized for the unam-
biguous structural characterization of the site-selective
brominated product.
15. Shim Y S, Kim K C, Lee K A, Shrestha S, Lee K H,
Kim C K and Cho H 2005 Bioorg. Med. Chem. 13 1325
16. Griffiths L A 1962 J. Expt. Bot. 13 169
17. Haskins F A and Gorz H 1963 J. Science 139 496
18. Lehn J M and Ourisson G 1962 Bull. Soc. Chim. France
1133
19. Campbell R V M and Tannock J 1973 J. Chem. Soc.
Perkin Trans. I 2222
20. Ngamga D, Yankep E, Tane P, Bezabih M, Ngadjui B T,
Fomum Z T and Abegaz B M 2005 Z. Naturforsch., B:
Chem. Sci. 60b 973
21. Combes S, Finet J P and Siri D 2002 J. Chem. Soc.
Perkin Trans. I 38
22. Yankep E, Njamen D, Fotsing M T, Fomum Z T,
Mbanya J C, Giner R M, Recio M C, Manez S and Rios
J L 2003 J. Nat. Prod. 66 1288
23. Antus S, Farkas L, Kardos-Balogh Z and Nogradi M
1975 Chem. Ber. 108 3883
Supplementary Information (SI)
The spectroscopic data (1H-NMR, 13C-NMR, IR and
HRMS) of synthesized compounds are presented in the
Supplementary Information, available at www.ias.ac.in/
chemsci.
24. Nakano T, Alonso J, Grillet R and Martin A 1979 J.
Chem. Soc. Perkin Trans. I 2107
Acknowledgements
25. Krishnamurti M and Seshagiri S N 1976 Ind. J. Chem.
Authors are grateful to GVK Biosciences management
for the financial support. We thank Dr. Sudhir Kumar
Singh for encouragement and motivation. Help from the
analytical department for the analytical data is appre-
ciated. PKH gratefully acknowledges UGC, New Delhi
for providing UGC-FRPS research start-up grant.
14B 222
26. Chatterjea J N, Shaw S C and Fatma A 1985 J. Ind.
Chem. Soc. 62 990
27. Bhardwaj D K, Jain R K, Malhotra V P and Sharma A
K 1983 Proc. Ind. Nat. Sci. Acad. 49A 168
28. (a) Ravi Kumar P, Behera M, Sambaiah M, Venu K,
Nagaraju P, Jaya Shree A and Satyanarayana Y 2014 J.
Amino Acid ID 721291; (b) Ravi Kumar P, Behera M,
Raghavulu K, Jaya Shree A and Satyanarayana Y 2012
Tetrahedron Lett. 53 4108
References
1. Kinoshita T, Ichinose K and Sankawa U 1990 Tetrahe-
dron Lett. 31 7355
29. Elassar Abdel-Zaher A and El-Khair Adel A 2003 Tetra-
hedron 59 8463
2. Singh O V and Muthukrishnan M 2005 Ind. J. Chem. 30. Biegasiewicz K F, Denis J D, Carrol V M and Priefer R
44B 2575
2010 Tetrahedron Lett. 51 4408
3. Yokosuka A, Haraguchi M, Usui T, Kazami S, Osada H, 31. Miyaura N and Suzuki A 1995 Chem. Rev. 95 2457
Yamori T and Mimaki Y 2007 Bioorg. Med. Chem. Lett. 32. Kotha S, Lahiri K and Dhurke K 2002 Tetrahedron 58
17 3091
9633