Rapid method of Friedel-Crafts alkylation of phloroglucinol by microwave in dry media and reusable catalyst

Article abstract of DOI:10.4067/S0717-97072015000300020

A new rapid and efficient method for the synthesis of a series of alkylated phloroglucinols using conventional microwave is reported 4 phloroglucinol derivatives (4, 5, 6 and 7) were synthesized with good yields (～50%) by a Friedel-Crafts reaction through

Full text of DOI:10.4067/S0717-97072015000300020

J. Chil. Chem. Soc., 60, Nº 3 (2015)
RAPID METHOD OF FRIEDEL-CRAFTS ALKYLATION OF PHLOROGLUCINOL BY
MICROWAVE IN DRY MEDIAAND REUSABLE CATALYST
1
,2
2
2
1,2
ALEJANDRA P.VERGARA , JAVIER A.CONTRERAS , MAURICIO E. OSORIO AND MARCELA A. CARVAJAL *
1
2
Centro de Biotecnología “DAL” y Laboratorio de Productos Naturales, Departamento de Química, Universidad Técnica Federico Santa María,
Av. España 1680, Postal code 2390123, Valparaíso, Chile.
ABSTRACT
A new rapid and efficient method for the synthesis of a series of alkylated phloroglucinols using conventional microwave is reported 4 phloroglucinol deriva-
tives (4, 5, 6 and 7) were synthesized with good yields (~50%) by a Friedel-Crafts reaction through an Electrophilic Aromatic Substitution mechanism between
geraniol/prenol and phloroglucinol, using reusable SiO and AgNO as the best catalyst tested without solvents under microwave irradiation.
2
3
Keywords: Microwave synthesis; alkylated phloroglucinol; AgNO3
1
. INTRODUCTION
Here, we report an eco-friendly synthetic procedure focusing on conven-
tional microwave-assisted reactions for the synthesis of alkylated phloroglu-
Nowadays, Organic Chemistry is becoming increasingly based on find-
ing new technologies and alternative processes to existing ones that will be
environmentally friendlier and less toxic (Green Chemistry). Organic synthe-
sis processes are not exempt from this trend, because many of these involve
solvents or solutions difficult to recycle after reaction and in some cases are
highly toxic. Chemical synthesis assisted by microwave is a powerful tool,
which when applied to a wide range of chemical reactions allows for important
contributions such as: reducing reaction times, high yields, avoiding collateral
and substitute products, and the use of toxic solvents.
cinol (alkylated Prenyl and Geranyl) using AgNO as a catalyst and silica gel
3
as reaction support. On the other hand, the orientation in electrophilic aromatic
substitution of the geranyl and prenyl chain was directed in ortho position ac-
cording to the location the OH groups in the aromatic system.
2. EXPERIMENTAL
All purchased chemical reagents (Merck or Sigma-Aldrich) were of the
highest purity commercially available, and were used without previous purifi-
cation. Microwave irradiation was carried out with a domestic microwave oven
(Thomas TH-18MCB, operating at 2450MHz). IR spectra were recorded as
thin films in an FT-IR Nicolet 6700 spectrometer and frequencies are reported
Prenylated and geranylated phenols correspond to an interesting group
of marine and plant natural products, with a wide variety of biological ac-
1
,2
3
4
tivities described, including anti-inflammatory , antifungal , anti-HIV , anti-
5
6,7
-1
Alzheimer activity , and most frequently - antineoplastic properties Ortho-
Prenylated phenols and Ortho-Geranylated play an important role in mediating
many biological processes. Such an important structural motif needs a general
strategy for its preparation, particularly for systems in which other aromatic
hydroxyl residues are differentiated or present, as is often the case with natural
in cm . Mass spectra were obtained by a Bruker Daltonics Microflex MALDI-
TOF (Bruker Daltonics Inc., MA-USA), in positive ion mode and negative
ion mode using detection by reflection with α-cyano-4-hydroxycinnamic acid
(CHCA) and 2,5-dihydroxybenzoic acid (DHB) (1 mg/mL, from Thermo Sci-
entific Pierce) as matrices.To control the spectrometer the FLEXCONTROL
3.0 program was used (Bruker Daltonik GmbH, Alemania). Data analysis was
performed with the mMass v. 5.5.0 program.
8
therapeutic products containing this pharmacophore . Terpenylphenols are iso-
lated from natural sources with very low yield, and for that reason during the
past few decades considerable research effort has focused on obtaining these
compounds by synthesis. Within the alkylated phenols of interest in the area
of Biology, the phloroglucinol derivatives can be highlighted. Their structural
complexity when phloroglucinol is alkylated draws attention; because in gener-
al, it is a challenge to attempt to incorporate nonpolar chains in a tri-substituted
aromatic ring with OH groups (electron donating group).Among the most com-
mon synthetic strategies reported for the introduction of nonpolar chains in an
aromatic ring (C-Alkylation) are: Friedel-Crafts reactions, Michael addition
and multistep processes consisting of a neutral-pathway leading to the early
O-alkylation, followed by a series of ionic rearrangements resulting finally in
1
13
1
H-, C- DEPT 135, sel. 1D H NOESY, 2D HSQC and 2D HMBC spectra
were recorded in CDCl solutions and are referenced to the residual peaks of
3
1
13
CHCl at δ 7.26 ppm and δ 77.0 ppm for H and C, respectively, on a Bruker
Avance 400 Digital NMR spectrometer, operating at 400.1 MHz for H and
100.6 MHz for C. Chemical shifts (δ) are reported in ppm and coupling con-
stants (J) are given in Hz. Silica gel (60, 200-400 mesh) was used for C.C. and
silica gel plates HF-254 for TLC. TLC spots were detected by heating after
spraying with 25% H SO in H O.
3
1
1
3
2
4
2
2.1. Synthesis of Prenyl-, and Geranyl- Phloroglucinols
9
C-alkylations. There are many publications that report different methods for
The alkylated derivatives of phloroglucinol were prepared by irradiation
at 52.35 W microwave power (according to the Standard Test Method for Cali-
bration of Microwave Ovens, ASTM) of a mixture of phloroglucinol (1) and
SiO -AgNO . The reaction mixture was irradiated at different times depending
accomplishing these coupling reactions in the synthesis of prenyl phenols and
8
,10-12
geranylphenols
, most with low yields and using highly toxic homoge-
13,14
neous and heterogeneous (solid) catalysts such as HF, H SO , AlCl , or BF
.
2
4
3
3
2
3
But there are no reports of Friedel-Crafts allylation of the phloroglucinol mol-
ecule, via microwave mediated Electrophilic Aromatic Substitution (EAS).
Reporting shortage can be due to the fact that the phloroglucinol molecule is
rich in electrons for which it tends to suffer oxidation during synthesis. Using
microwaves decreases the likelihood of oxidation by reducing reaction times.
Accordingly, the development of more efficient methods is still in demand.
Late transition metals -the so-called coinage metals- are widely used for
on the type of allyl alcohol used, geraniol (2) or prenol (3) (Scheme 1). The
reaction to produce derivatives of geranylated phloroglucinol was performed
in microwaveable glass bottles (250 ml) with a lid. For every 50 grams of
silica gel impregnated with AgNO (prepared with a saturated solution of the
3
dissolved salt in an ethanol water mixture 1:1), 15 grams (119 mmol) of com-
mercial phloroglucinol and 37 grams (240 mmol) of commercial geraniol are
added (molar ratio 1:2); the mixture is homogenized and is introduced into
the domestic microwave at its minimum power (52.35 W) at 50°C ± 5°C. Af-
ter irradiation time between each round, the temperature is measured in the
sample and the reaction is quenched, immersing the flask in ice water (close
to 4 °C) (between each round it is checked whether the reaction is complete
by TLC). Round is understood as each time the bottle was subjected to micro-
wave irradiation. The samples were subjected to different irradiation times and
rounds, so as to determine the optimum reaction conditions. Once the rounds
are completed, both the aroma and color of the mixture change; this indicates
that the product is already synthesized. The dry mixture is again subjected to
microwave irradiation under the same conditions. In subsequent times after the
1
5
various organic transformations , these include copper, silver, and gold. There
are certain advantages of silver catalysts that make them a very appealing al-
ternative. Shorter reaction times, increased stability toward exposure to air or
moisture, and ease of preparation and storage of the catalyst are some of the
highly beneficial properties of silver catalysts. Silver (I) is considered to be a
mild oxidizing agent, suitable for efficient oxidation of primary and second-
ary alcohols to aldehydes and ketones. Owing to such properties, Ag CO and
2
3
AgNO (the complex of AgNO with ammonia is well-known as Tollens’ re-
3
3
agent) are commonly used for the preparation of carbonyls from the corre-
1
6
sponding alcohols under mild conditions .
e-mail: marcela.carvajal@usm.cl
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J. Chil. Chem. Soc., 60, Nº 3 (2015)
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first reaction, only silica-AgNO is added, impregnated with phloroglucinol
21.9 (C-1´); 17.7 (CH -C7´); 16.1 (CH -C3´). IR (cm ): 3440, 2967, 2923,
3 3
+
3
recovered from the filtrate of the same above reaction, plus 6 grams (39 mmol)
of geraniol in each repetition; thus ensuring that all the phloroglucinol reacts.
This process is repeated until all the initial phloroglucinol has reacted. After
2849, 1622, 1449, 1376. HRMS (MALDI-TOF, m/z): [M+H] calculated for
C H O , 399.2899; observed, 399.2587 (intensity 37%).
(E)-2-(3-methylbuta-2-enyl)-1,3,5-trihydroxy benzene:
(12.34g, 49.9%); H-NMR: 5.94 (s, 2H, H-4 and H-6); 5.24 (br.t., 1H, H-2´);
3.33 (d, J = 7.1 Hz, 2H, H-1´); 1.81 (s, 3H, CH -C3´); 1.75 (s, 3H, H-4´). C-
NMR: 155.7 (C-1 y C-3), 155.0 (C-5), 135.4 (C-3´), 122.0 (C-2´), 105.9 (C-2),
2
6
39
3
Compound
6
1
the reaction, the AgNO must be removed from the reaction. This is done by
3
1
3
doing 2 washes in a 1:1 ratio saturated solution of NaCl and dichloromethane
in a separating funnel.
The reaction to produce prenylated phloroglucinol derivatives was per-
formed in microwaveable glass bottles (250 ml) with lids. For every 50 grams
3
−
1
96.0 (C-4 and C-6), 25.8 (C-4´), 22.0 (C-1´), 17.8 (CH -C3´); IR (cm ): 3391
3
(OH), 2974 (C-H alkane), 2926 (C-H alkane), 1616 (C=C aromatic), 1517,
1465, 1375, 1284, 1230, 1144.
of silica gel impregnated with AgNO (prepared with a saturated solution of the
3
dissolved salt in an ethanol water mixture 1:1), 15 grams (119 mmol) of com-
mercial phloroglucinol, and 20.47 grams (238 mmol) of commercial prenol
Compound 7 2,6-bis-((E)-(3-methylbuta-2-enyl)-1,3,5-trihydroxy ben-
zene: (5.3188g, 18.1%); H-NMR: 5.95 (s, 1H, H-4); 5.51 (1-OH); 5.24 (br.
1
(
molar ratio 1:2) are added; the mixture is homogenized and irradiated at mini-
t.,2H, H-2´); 5.02 (3,5-OH); 3.34 (d, J = 7.0 Hz, 4H, H-1´); 1.82 (s, 6H, CH -
3
1
3
mum power (52.35 W) at 50°C ± 5°C. After the irradiation time between each
round, the temperature of the sample is measured and the reaction is cooled,
immersing the glass bottles in ice water (around 4 °C). The dry mixture is
again subjected to microwave irradiation with the same conditions of micro-
C3´); 1.76 (s, 6H, H-4´). C-RMN: 154.0 (C-1); 153.1 (C-3 and C-5); 135.2
(C-3´); 122.2 (C-2’); 106.0 (C-2 and C-6); 95.9 (C-4); 39.6 (C-4´); 25.8 (C-4´);
−
1
22.3 (C-1´); 17.8 (CH -C3´). IR (cm ): 3434 (OH), 2971, 2915, 2857 (C-H
3
alkanes), 1623 (C=C aromatic), 1508, 1449, 1375, 1260, 1226, 1168, 1085.
wave power and time. After the first reaction only silica-AgNO impregnated
3
with phloroglucinol recovered from the filtrate in the same above reaction is
added, plus 5 grams (58 mmol) of prenol each repetition; thus ensuring that all
the phloroglucinol react. This process is repeated until all the starting phloro-
glucinol has reacted; this can be verified by TLC monitoring. After the reaction,
3. RESULTS AND DISCUSSION
The best reaction conditions depended on the nature of the allyl alcohol
used. Based on this it was possible to determine that for the alkylation of phlo-
roglucinol with geraniol, the optimum time of each round of radiation (at low
power: 52.35W) was 5 minutes, with 4-5 rounds of irradiation (See yields in
Table 1). Experimentally we observed that when more than 5 minutes of ir-
radiation time elapsed the sample overheated, lowering the expected yield of
the reaction. This reaction protocol allowed us to use a total of 15 grams of
phloroglucinol distributed equally among several bottles, repeating the reaction
the AgNO must be removed from the reaction; this is done by doing 2 washes
3
in a 1:1 ratio NaCl and dichloromethane saturated solution in a separating fun-
nel.
The mixtures obtained from the synthesis of prenyl- and geranyl-deriva-
tives were not stirred during the reaction. The crude product was isolated by
silica gel column chromatography with 15% ethyl acetate in n-hexane, and the
compounds were characterized by NMR, IR and Mass spectra.
process 4-5 times (rounds), reusing the same silica-AgNO and phloroglucinol
3
until the starting material could not observed by TLC (Figure 1).On the other
hand, the ideal times for mixing with prenol were shorter than those with gera-
niol, 4-6 rounds of 2 minutes maximum each. This reaction protocol allowed us
to use a total of 15 grams of phloroglucinol equally distributed among several
bottles, repeating the reaction process 4-6 times (rounds), reusing the same
2
.2. Characterization Data
Compound 4(E)-2-(3,7-dimethylocta-2,6-dienyl)-1,3,5-trihydroxy ben-
1
zene: (14.2435g, 45.6%); H-NMR: 5.95 (s, 2H, H-4 and H-6); 5.24 (br.t., 1H,
H-2´); 5.04 (br.t., 1H, H-6´); 3.34 (d, J = 6.9 Hz, 2H, H-1´); 2.08 (m, 4H,
H-4´ and H-5’); 1.78 (s, 3H, CH -C3´); 1.66 (s, 3H, H-8´); 1.58 (s, 3H, CH -
initial silica-AgNO and phloroglucinol until the starting material could not be
3
3
3
1
3
C7´). C-NMR: 155.7 (C-1 y C-3), 154.9 (C-5), 139.0 (C-3´), 132.1 (C-7´),
23.7 (C-6´), 121.9 (C-2´), 106.0 (C-2), 96.0 (C-4 and C-6), 39.6 (C-4´), 26.3
seen by TLC (Figure 1).Similar to the reaction with geraniol, in the alkylation
with prenol the irradiation time is critical to the success of the reaction- in this
case after 2 minutes the start of calcination of the reagents is observed.
In both cases of alkylation, with prenol or geraniol, the predominance of
the mono-alkylated molecule with yield percentages of about 50% is observed,
and in a smaller fraction the dialkylated molecules observed with lower values.
It should be noted that the yields observed reflect better results when the alkyla-
tion involves a shorter carbon chain as in the case of prenol; this may be due to
a possible steric effect.
1
(
3
−
1
C-5´), 25.6 (C-8´), 21.9 (C-1´), 17.7 (CH -C3´); 16.1 (CH -C7´); IR (cm ):
397, 2967, 2925, 1706, 1620, 1515, 1463, 1377.
Compound 5 2,6-bis-((E)-(3,7-dimethylocta-2,6-dienyl)-1,3,5-trihydroxy
benzene:(3.38g, 7.1%); H-NMR: 5.96 (s, 1H, H-4); 5.24 (br. t.,2H, H-2´); 5.04
br. t., 2H, H-6´); 3.34 (d, J = 6.9 Hz, 4H, H-1´); 2.08 (m, 8H, H-4’and 5´); 1.78
s, 6H, CH -C3´); 1.66 (s, 6H, H-8´); 1.58 (s, 6H, CH -C7´). C-RMN: 155.7
C-1); 154.9 (C-3 and C-5); 138.9 (C-3´); 132.1 (C-7´); 123.7 (C-6´); 122.2
C-2’); 106.0 (C-2 and C-6); 96.0 (C-4); 39.6 (C-4´); 26.3 (C-5´); 25.6 (C-8´);
3
3
1
(
(
(
(
13
3
3
Scheme 1 Alkylation of phloroglucinol with allylic alcohol.
In search for the best conditions of alkylation, standardized tests were per-
ing breaks, which can only be achieved successfully with the support being
impregnated with the catalyst.
The reaction of alkylation of phloroglucinol resulted in 4 compounds, 2
mono-alkylated compounds (4, 6) and 2 di-alkylated compounds (5, 7), where
compound 5 correspond to a new compound (Table 3).
formed using the coupling reaction of phloroglucinol with geraniol keeping
track of the mono-alkylated product, in such a way as to imitate the conditions
for the case of the coupling with prenol. The strategy was to choose four cata-
1
7,18
lysts, indicated in literature , that were used in such reactions, which were
used in conjunction with 2 solid supports (SiO and K10). To carry out the
Regioselectivity is fundamental for this methodology and is achieved from
the key step of Ag coordination to both the phenol and allylic alcohol. Af-
2
+
reaction, the starting materials in 3 different types of solvent were added (these
solvents were chosen by their degree of polarity which allowed the dissolv-
ing of phloroglucinol with geraniol, acetonitrile > ethanol > dichloromethane)
and the absence of them (Free Solvents), evaluating the irradiation time and
temperature. Time is a key point in the reaction method; it was observed that
prolonged exposure to irradiation (more than 5 minutes in each round) causes
an increase in the solvent temperature, directly affecting the reaction efficiency
ter coordination, the allylic residue could be placed in the nearest position to
the phenol substrate. Immediately afterwards the active ortho position of the
phenol ring could attack and then react with the allylic carbon with positive
charge density. Similar alkylation mechanism was proposed for C-acylation
of phenols and naphtols derivatives catalyzed by modified ZnCl on Al O as
2
2
3
1
9-20
catalyst under solvent-free and microwave conditions . A possible interac-
(
yield). Whereas when the solvent variable was removed, more irradiation time
tion of Ag (I) complex coordinate to allylic alcohol with the possible formation
2
1
was given to the reaction, obtaining better performance (10x). Temperature is
an important factor to consider because if it increases rapidly it destroys the
starting material (allyl alcohol); having this variable controlled, it is possible
to improve the performance giving successive rounds of irradiation with cool-
of highly reactive allylic carbocationic intermediates was reported . Also, the
allylation position was primarily the less sterically hindered of all the mol-
ecules produced.
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J. Chil. Chem. Soc., 60, Nº 3 (2015)
Figure 1.Diagram of synthesis protocol of alkylated phloroglucinols by
microwave irradiation.
Table 1. Different Lewis acid and supporting material used to catalyze the Friedel-Crafts reaction between phloroglucinol and geraniol.
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J. Chil. Chem. Soc., 60, Nº 3 (2015)
Once certain critical variables are determined, work is done with the different physicochemical properties of the support together with the catalyst. Table 2
shows the variables that were evaluated to improve the synthesis; at this stage various solid supports were used with and without catalyst (silver nitrate), obtaining
the yields described in the table.
Table 2. Different supports for the geranylation of phloroglucinol using silver nitrate as catalyst.
Entry
Reagent
Yields %
1
2
3
4
5
6
7
8
Montmorillonite K10
5
12
4
AgNO -K10
3
SiO acid
2
SiO basic
4
2
SiO neutra
5
2
AgNO -SiO acid
35
40
49
3
2
AgNO -SiO basic
3
2
AgNO -SiO neutral
3
2
Table 3. Reaction allyl alcohol of aromatics with silver nitrate adsorbed on silica gel.
4
. CONCLUSIONS
reaction due to the probable stabilization of the double bond allyl. The use of
microwaves, despite being in this case a domestic and non-professional ap-
paratus, shows that the reaction by heating occurs in short irradiation times (2
to 5 minutes at low power), since it is limited by the physicochemical proper-
ties of allyl alcohol which is sensitive to temperature. The conditions of this
methodology allow for the production of higher amounts (grams) in a short
time without using solvents- beating the reaction yields reported by classical
methods of synthesis, and reaching yields close to 50%.The conditions of this
methodology allow to produce higher amounts in the order of grams in a short
time without spending solvents, beating reaction yields reported by classical
methods of synthesis, reaching yields close to 50%.
The importance of these compounds (alkylated derivatives of floroglu-
cinol) lies in their biological potential, which is widely described. To propose
a synthesis method of short time and low cost (compared to classical synthesis
methods) that promotes protection of the environment is an interesting alter-
native, when increasing production is necessary. This methodology differs in
many respects from conventional chemical synthesis based on Friedel-Crafts
reaction. This protocol provides the synthesis procedure in a dry atmosphere
without organic solvents that dissolve reaction reagents. The support used for
this “dry” reaction is silica gel that facilitates the provision of phloroglucinol
during the reaction. Using AgNO , a less toxic catalyst instead of the com-
3
monly used BF , AlCl , SnCl , AuCl , etc. was shown to be beneficial to the
3
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4
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J. Chil. Chem. Soc., 60, Nº 3 (2015)
ACKNOWLEDGEMENTS
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1
0. Talhi, Q.; Silva, A. M.S.Curr. Org. Chem.17, 1067 (2013)
Financial support from the FONDECYT (Research Grant N°11121440)
is gratefully acknowledged. We also thank Dr. Manuel González (Universidad
Nacional de Rosario, Argentina) for his help in NMR analysis and advice.
11. Masao,Tsukayama.; Makoto, Kikuchi.;Yasuhiko, Kawamura.Chem.
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