Synthesis of new 6- and 8-Alkenyl-3,7,3’,4’-Tetramethoxyquercetin derivatives by microwave-assisted Heck coupling

Article abstract of DOI:10.1080/00397911.2019.1636398

A series of flavonoid derivatives were synthesized from 6- and 8-iodo-3,7,3’4’-tetramethoxy-quercetin with terminal alkenes by microwave-assisted palladium-catalyzed Heck coupling. These alkenes include n-butyl acrylate, 2-methyl-3-buten-2-ol, acrylonitrile, and styrene, providing 10 new substituted flavonoid compounds obtained with moderate to good yields.

Full text of DOI:10.1080/00397911.2019.1636398

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of new 6- and 8-Alkenyl-3,7,3’,4’-
Tetramethoxyquercetin derivatives by microwave-
assisted Heck coupling
Ingrid T. L. Ramos, Tania M. S. Silva & Celso A. Camara
To cite this article: Ingrid T. L. Ramos, Tania M. S. Silva & Celso A. Camara (2019): Synthesis
of new 6- and 8-Alkenyl-3,7,3’,4’-Tetramethoxyquercetin derivatives by microwave-assisted Heck
coupling, Synthetic Communications, DOI: 10.1080/00397911.2019.1636398
To link to this article: https://doi.org/10.1080/00397911.2019.1636398
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Published online: 12 Jul 2019.
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https://doi.org/10.1080/00397911.2019.1636398
Synthesis of new 6- and 8-Alkenyl-3,7,3’,4’-
Tetramethoxyquercetin derivatives by microwave-assisted
Heck coupling
Ingrid T. L. Ramos , Tania M. S. Silva , and Celso A. Camara
Departamento de Qu ꢀı mica, Universidade Federal Rural de Pernambuco, Recife, PE, Brazil
ABSTRACT
ARTICLE HISTORY
A series of flavonoid derivatives were synthesized from 6- and
Received 7 May 2019
8
-iodo-3,7,3’4’-tetramethoxy-quercetin with terminal alkenes by
KEYWORDS
microwave-assisted palladium-catalyzed Heck coupling. These
alkenes include n-butyl acrylate, 2-methyl-3-buten-2-ol, acrylonitrile,
and styrene, providing 10 new substituted flavonoid compounds
obtained with moderate to good yields.
Coupling reactions;
flavonoids; Heck reaction;
microwave; palladium
catalytic; quercetin
GRAPHICAL ABSTRACT
Introduction
Flavonoids are a large group of phenolic compounds with various biological activities
including anticancer, anti-inflammatory, antioxidant, antileishmanial and anti-HIV,
[
1–5]
among others.
Quercetin is an abundant flavonoid found in the plant kingdom and
[
6]
display many of these biological activities, making it a target of many studies. In syn-
thesis, for example, quercetin derivatives have been used as intermediary for the obten-
tion of new anthocyanidins by regioselective iodination followed by Suzuki–Miyaura
coupling reaction. Prenylated-derived flavonoids have attracted some interest in this
particular field because this structural feature increases the lipophilicity and increases
[
7]
[
8,9]
affinity to biological membranes.
discusses the structure–activity relationship between prenylated flavonoids and their bio-
Chen et al., in 2013, published a review which
[
10]
activities.
Frequently, C-prenylation of flavonoids naturally occurs on ring A at C-6/
0
0
[11]
C-8 and ring B at C-3 and C-5 .
There are several synthetic strategies for the prepar-
It is noteworthy that the vast majority of these strategies
introduces the alkyl side chain on the flavonoid precursors, prior to the construction of
[
12]
ation of these compounds.
[
13]
the complete flavonoid nucleus.
For example, four natural chalcones bearing prenyl
CONTACT Celso A. Camara
ccelso@gmail.com Federal Rural University of Pernambuco, Campus Dois Irmaos, St
Manoel de Medeiros, Recife, zip code 52171-900, PE, Brazil.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
I. T. L. RAMOS ET AL.
O
O
O
O
O
Br
O
O
O
Ph
Pd(OAc) , P(o-tol) , NEt
2
3
3
Ph
Cl
OH
DMF
,
MW, 160°C
0 min.
Cl
OH
3
1
8
Scheme 1. Synthesis of flavonoid derivative by Heck reaction.
or geranyl groups were synthesized by using regioselective iodination and the
[
14]
Suzuki–Miyaura coupling reaction as key steps.
Heck reaction is widely used for the formation of carbon–carbon bonds starting from
[
15,16]
alkenes and an electrophile.
This method and other palladium-catalyzed coupling
have an important role in organic synthesis, material sciences, and pharmaceutical
[
17]
industries.
shorter, more efficient and cleaner reactions.
flavonoids derivatives obtained by Heck reaction (Scheme 1).
Previously, we reported a greener regioselective iodination method to obtain 6- and
Furthermore, the auxiliary use of microwave irradiation can lead to
[
15]
Dahlen demonstrated synthesis of some
[
18]
0
0
[19]
8
-iodo-3,7,3 ,4 -tetramethoxy-quercetin (1 and 2, see later).
strate the development of the Heck reaction from these suitable starting regioisomeric
-iodo- and 8-iodo-flavonoids with terminal alkenes by microwave-assisted C–C cou-
In this work, we demon-
6
pling methodology.
Results and discussion
We chose to initially use the same procedure described in the literature, using palladium
ꢀ
diacetate, tri-o-tolyl phosphine, triethylamine, and DMF in 30 min at 160 C in a
focused MW (Entry 1, Table 1), to perform the microwave assisted Heck coupling with
[
18]
the iodo-derivatives and 2-methyl-3-buten-2-ol as the alkene.
In an attempt to avoid
the previous chromatographic separation of the regioisomeric mixture of 6- and -8-iodo
[
19]
flavonoids 1 and 2 (Table 1) as obtained from the iodination reaction,
we choose to
work in the coupling Heck reaction and perform the separation a posteriori.
The approach proved to be of little use but was useful in refining some of the reaction
conditions employed, especially reaction time and the correct temperature necessary to
consume the electrophile, as revealed by TLC chromatography (entries 1–3). The deha-
0
0
logenation of the mixture to 3,7,3 4 -tetramethoxyquercetin derivatives (1 þ 2) was a
side reaction observed by TLC inspection, and in order to avoid its formation we
decided to acetylate the free 5-hydroxyl in the mixture generating the corresponding
acetate mixture 3 þ 4 (entry 2), and also observe the change of the alkene to a more
electrophilic n-butyl acrylate, instead of 2-methyl-3-buten-2-ol with the use of conven-
tional heating (entry 2). After 24 h the acetylated mixture remained intact in this condi-
tion reaction (entry 2). The use of MW resulted in a successful reaction after 105 min
using n-butyl acrylate, resulting in the isolation of 81% of a mixture of 6- and 8-isomers
(
5a þ 6a) already deacetylated, probably due to the more drastic reaction conditions or
after the workup used (entry 3, see experimental conditions). The mixture (5a þ 6a)
proved to be difficult to separate using column chromatography with several different

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Table 1. Conditions tested to obtain the new 3,7,3’,4’-tetramethoxy-quercetin derivatives.
Entry
Substrate
Alkene (eq.)
Base (eq.)
Time (min)
Yield (%)/Product
a
b
1
2
1 þ 2
2-methyl-3-buten-2-ol (2)
n-butyl acrylate (2)
n-butyl acrylate (2)
n-butyl acrylate (4)
n-butyl acrylate (4)
2-methyl-3-buten-2-ol (4)
2-methyl-3-buten-2-ol (4)
2-methyl-3-buten-2-ol (4)
acrylonitrile (4)
NEt
NEt
NEt
3
3
3
(2)
(2)
(2)
30
31.5
c
3 1 4
>24 h
105
100
90
90
95
90
90
90
100
90
b
3
4
5
6
7
8
9
3 1 4
81
4
1
1
1
2
2
2
1
1
2
b
DIPEA (4)
DIPEA (4)
DIPEA (4)
DIPEA (4)
DIPEA (4)
DIPEA (4)
DIPEA (6)
DIPEA (6)
DIPEA (4)
DIPEA (4)
d
66/5a
66/6a
67/6b; 17/8
33/6b; 35/8
35/5b
37/5c
d
1
1
1
1
a
0
1
2
3
acrylonitrile (4)
acrylonitrile (6)
styrene (4)
27
39/6c
55/6d
55/5d
styrene (4)
90
ꢀ
c
MW (160 C); Yield of the mixture of isomers; Conventional heating; Yield of the dehalogenation product 3,7,3’,4’-
tetramethoxy-quercetin.
eluents (entry 3). At this point, we decided to use the single 8-iodo-derivative (1) as the
acetate derivative (4), obtained in 75% yield, while the use of the isomeric acetate 3
from compound 1 yielded only 60%. We also substituted the base to diisopropyl-ethyl-
amine (DIPEA) instead of triethylamine, resulting in the expected 8-alkenyl-substituted
coupling product (5a) in 66% yield (entry 4). We believe the acetate was also hydro-
lyzed during work-up. The 6-iodo regio-isomer (1) results in the expected (6a) in a
similar yield of 66% (entry 5), and in the new conditions tested (double equivalents of
base and electrophile), was unnecessary to use the acetate 3. In spite of achieving the
target molecule, an acetylation of the product 6a was still carried out in order to obtain
the corresponding acetylated product 7 in 65% yield (see experimental section).
These improved reaction conditions were used in the attempts to obtain the alkenyl
derivatives from 2-methyl-3-buten-2-ol as the alkene. Thus, the 6-iodo isomer (1)
yielded a mixture of two compounds (scheme 2), the diene (6b) in 67% yield and the
cyclized derivative (8) in 17% yield after 90 min reaction (entry 6).
The product 6b could be rationalized as the result of the dehydration reaction of the
expected 3-hydroxy-3-methyl-butenyl side chain, due to the drastic conditions
employed. The product 8 was probably the result of a palladium-promoted cyclization
[
20]
6
b.
increase of compound 8 from 17 to 35% yield and a consequent decrease in the yield of
b, from 67 to 33%.
We observe that a slight increment in time of only 5 min (entry 7) results in an
6

4
I. T. L. RAMOS ET AL.
Scheme 2. Formation of dihydropyran derivative 8 and diene 6b from dehydration during Heck reac-
tion of iodo-derivative 1 with alkene 2-methyl-3-buten-2-ol.
The 8-iodo derivative 2 reacting with 2-methyl-3-buten-2-ol using the previously
described reaction conditions results in the coupling product 5b with only 35% yield
(entry 8). A large amount of dehalogenated product was observed by TLC inspection,
probably due to the minor reactivity of the 8-position in comparison with the 6
[
21]
regioisomer.
Attempts to improve the yield in this reaction were unsuccessful,
including changes in temperature and amount of base.
With the use of an electron-withdrawing alkene, acrylonitrile, the 8-iodo-derivative 2
gave the expected coupling Heck product with 37% yield (entry 9), with the formation
of dehalogenation products as described above. The increment of base results in the
dehalogenated product as the solely identifiable product at 27% yield (entry 10). The 6-
iodo derivative 1 behaved similarly, resulting in the corresponding coupling Heck prod-
uct 6c in 39% yield (entry 11). When the styrene was used as an alkene, the products
5
d and 6d were obtained as expected both with 55% yield, enhancing methodology’s
efficiency. (entries 12 and 13).
The described method proved useful in the obtention of a new series of C6- and C8-
alkenyl substituted flavonoids as coupling Heck products, which are all novel as far as
we know. In this method, alkenes with electron donating and withdrawing properties
showed similar performances in the catalyzed coupling Heck reaction.
Experimental
General information
1
H and 13C NMR spectra were recorded on a Varian unity plus-300 or 400 MHz
spectrometer (Varian, Palo Alto, CA) in CDCl . All IR spectra were recorded on a FT-
3
IR BOMEM MB-Series 100 spectrophotometer (ABB, Zurich, Switzerland) using KBr
pellets. High-resolution mass spectra were obtained by electrospray on a Waters LC-
MS-ESI-TOF spectrometer (Waters, Milford, MA). Microwave reactions were conducted
in a focused microwave (FMW) power delivery system, using a CEM Discover Synthesis
(Model 908005, 0–300 W, 2455 MHz, CEM Corporation, Matthews, NC). For the syn-
thesis, the power was 150 W, and the temperature achieved during the procedure was
ꢀ
1
00 C. The reactions were performed in sealed glass vessels (capacity 10 mL). Melting
points are uncorrected and were determined with an electrically heated block apparatus
BIO SAM-PFM II. Monitoring of the course of the reactions was performed by GF254
thin layer chromatography (TLC) and the column chromatography was performed on
silica gel G60 (70–230 mesh, Merck). All solvents and reagents were purchased from
commercial suppliers (Sigma-Aldrich, Alfa Aesar, Cin ꢀe tica, Din ^a mica), and used as

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5
received or purified by standard procedures. The derivatives 6-iodo- 1 and 8-iodo-
0 0
[19]
3
,7,3 ,4 -tetramethoxy-quercetin 2 were obtained by previous work.
General procedure for Heck reactions
A solution of the appropriate 6- or 8-iodo flavonoid (150 mg, 0.31 mmol), Pd(OAc)2
(
(
6.95 mg, 0.031 mmol), Pd(o-tolyl) (18.8 mg, 0.062 mmol), N, N-diisopropylethylamine
3
159.9 mg, 1.24 mmol), and appropriate alkene (1.24 mmol) in DMF (1.5 mL) in a
ꢀ
microwave 10 mL sealed vial was heated in a microwave cavity for 90 min at 100 C and
150 W. The mixture was filtered through Celite with dichlorometane. The filtrate was
acidified with HCl (10%) and extracted with dichloromethane (3 ꢁ 10 mL). The com-
bined organic phases were washed with saturated NaHCO solution, and the combined
3
organic phases were dried over anhydrous Na SO before the solvent was removed
2
4
under vacuum. The residue was purified using column chromatography on silica gel
and a mixture of hexane/dichloromethane/ethyl acetate/methanol as eluents.
Spectral characterization data of compound 5a and 6a
3
-[2-(3,4-Dimethoxy-phenyl)-5-hydroxy-3,7-dimethoxy-4-oxo-4H-chromen-8-yl]-acrylic
acid butyl ester 5a
Chromatographic elution with hexane (64 mL)/dichloromethane (21 mL)/ethyl acetate
ꢀ
(
(
1
–
1
2
3
15 mL)/methanol (0.2 mL), obtained as a yellow solid (mp 174–176 C) in 66%
ꢂ1
60.7 mg, 0.125 mmol) yield; IR (KBr) ꢀ/cm 2930, 1696, 1651, 1592, 1450, 1265, 1172,
1
017 820; H NMR (400 MHz, CDCl ,) d 13.29 (s, 1H, 5-OH), 8.18 (d, 1H, J ¼ 16.24,
3
0
0
CH ¼ CHCO–), 7.84 (dd, 1H, J ¼ 8.8, 2.2, 6 -CH), 7.71 (d, 1H, J ¼ 2.2, 2 -CH), 7.02 (d,
0
H, J ¼ 8.8, 5 -CH), 6.83 (d, 1H, J ¼ 16.24, –CH ¼ CHCO–), 6.42 (s, 1H, 6-CH), 4.20 (t,
H, J ¼ 6.6, –CH O–), 4.01 (s, 3H, –OCH ), 3.99 (s, 3H, –OCH ), 3.98 (s, 3H, –OCH ),
2
3
3
3
.89 (s, 3H, –OCH ), 1.69 (qui, 2H, J 6.6, –CH CH O–), 1.44 (sex, 2H, J 7.44,
3
2
2
H CCH –), 0.96 (t, 3H, J 7.44, H CCH –);13C NMR (100 MHz, CDCl ,) d 178.8, 168.1,
3
2
3
2
3
1
1
64.7, 163.8, 156.3, 154.6, 151.5, 149.0, 138.9, 132.9, 122.6, 122.5, 119.5, 110.9, 110.8,
05.6, 103.2, 95.1, 64.1, 60.1, 56.3, 56.0, 30.8, 29.6, 19.1, 13.7; LC-ESI-MS (positive
þ
mode) m/z, observed: 485.1803; C H O [M þ H] requires: 485.1806.
2
6
28 9
3
-[2-(3,4-Dimethoxy-phenyl)-5-hydroxy-3,7-dimethoxy-4-oxo-4H-chromen-6-yl]-acrylic
acid butyl ester 6a
Chromatographic elution with hexane (64 mL)/dichloromethane (21 mL)/ethyl acetate
ꢀ
(
15 mL)/methanol (0.2 mL), obtained as a yellow solid (mp 175–177 C) in 66%
ꢂ1
(
85.4 mg, 0.176 mmol) yield; IR (KBr) ꢀ/cm 2958, 1707, 1601, 1459, 1271, 1155, 872;
1
H NMR (400 MHz, CDCl ,) d 13.79 (s, 1H, 5-OH), 8.04 (d, 1H, J ¼ 16.16,
3
0
0
–
(
4
2
CH ¼ CHCO–), 7.73 (dd, 1H, J ¼ 8.32, 1.96, 6 -CH), 7.68 (d, 1H, J ¼ 1.96, 2 -CH), 6.98
0
d, 1H, J ¼ 8.32, 5 -CH), 6.97 (d, 1H, J ¼ 16.16, –CH ¼ CHCO–), 6.42 (s, 1H, 8-CH),
.18 (t, 2H, J ¼ 6.84, –CH O–), 3.97 (s, 9H, –OCH ), 3.87 (s, 3H, –OCH ), 1.68 (qui,
2
3
3
H, J ¼ 6.84, –CH CH O–), 1.43 (sex, 2H, J ¼ 7.32, H CCH –), 0.96 (t, 3H, J ¼ 7.32,
2
2
3
2
H CCH –); 13C NMR (100 MHz, CDCl ) d 178.7, 168.4, 164.0, 161.8, 157.0, 155.8,
3
2
3

6
I. T. L. RAMOS ET AL.
1
5
51.5, 148.8, 139.1, 133.3, 122.5, 122.2, 120.7, 111.2, 110.8, 107.7, 105.6, 89.6, 64.1, 60.1,
6.2, 56.0, 55.9, 30.8, 19.2, 13.7; LC-ESI-MS (positive mode) m/z, observed: 485.1809;
þ
C H O [M þ H] requires: 485.1806.
2
6
28 9
Full experimental for all compounds can be found in the Supplementary Information.
Conclusions
0
0
In this work, a series of novel 3,7,3 4 -tetramethoxy-quercetin derivatives were obtained
by palladium-catalyzed Heck Coupling applying microwave irradiation with 35–67%
yield. These compounds are an important intermediary to future reactions.
Acknowledgments
This study was partially funded by the Coordena c¸ ~a o de Aperfei c¸ oamento de Pessoal de N ꢀı vel
Superior - Brasil (CAPES) - Fundinginance Code 001. We are grateful to CNPq, CAPES and
FACEPE (PRONEM 0741.1.06/14) for financial support, Analytical Center of DQF-UFPE and
CENAPESQ-UFRPE. We are also grateful to Prof. Eduardo J. Oliveira (UFVJM) for useful
suggestions.
ORCID
Ingrid T. L. Ramos
Tania M. S. Silva
Celso A. Camara
http://orcid.org/0000-0001-9902-6646
http://orcid.org/0000-0003-1887-2598
http://orcid.org/0000-0001-8748-8560
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