Radical C-H arylations of (hetero)arenes catalysed by gallic acid

Article abstract of DOI:10.1039/c5cc09911k

Gallic acid efficiently catalyses radical arylations in water-acetone at room temperature. This methodology proved to be versatile and scalable. Therefore, it constitutes a greener alternative to arylation. Moreover, considering that gallic acid is an abundant vegetable tannin, this work also unleashes an alternative method for the reutilisation of bio-wastes.

Full text of DOI:10.1039/c5cc09911k

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DOI: 10.1039/C5CC09911K
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Radical C-H arylations of (hetero)arenes catalysed by gallic acid†
Marcelle D. Perretti,‡ Diego M. Monzón,‡ Fernando P. Crisóstomo, Víctor S. Martín and Romen
Carrillo*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Gallic acid efficiently catalyses radical arylations in water-acetone radical arylation at room temperature promoted by catalytic
at room temperature. This methodology proved to be versatile and amounts of gallic acid in sustainable solvents.
scalable. Therefore it constitutes
a greener alternative to
arylations. Moreover, considering that gallic acid is an abundant
vegetable tannin, this work also unleashes an alternative method
for the reutilisation of bio-wastes.
Arylations are undoubtedly one of the most important synthetic
methodologies nowadays. The reason seems obvious, taking
into account the plethora of biaryl compounds which found
applicability in many different fields from biomedicine to
materials science.1 At the same time, greener and more
sustainable chemical methodologies are demanded in order to
meet the increasing social and legal standards.2 Regarding
arylations, several metal-free processes have appeared
recently, being particularly attractive the direct C-H arylations.3
Indeed, the benefits of a metal-free methodology, are
reinforced due to the fact that no double functionalization of
the reacting points is required. Therefore less steps are
necessary and less waste is generated. An interesting approach
to such direct C-H arylations is the reduction of arenediazonium
ions by a suitable reducing agent.4,5,6,7,8,9,10 The aryl radical thus
Scheme 1 Gallic acid as promoter of radical arylations
As
a
first
attempt,
4-chlorobenzenediazonium
tetrafluoroborate (0.5mmol) was treated with 10mol% of gallic
acid in acetone (0.1M) in the presence of an excess of furan
(5mmol) to avoid 2,5-diarylations (Table 1). The yield of arylated
furan was disappointingly low (entry 1). However, when the
reaction was submitted exactly in the same conditions but in
acetone/water (3:1), then the yield obtained was much higher
(entry 2). Indeed, Bravo et al. have already pointed out the
relevance of some particular ionization forms of gallates in the
reduction of arenediazonium ions.15 Thus the role of water
could be allowing such ionization equilibria. As expected, the
same reaction with 1M aqueous solution of acetic acid led to
poor yield (entry 3). On the other hand, by using 1M aqueous
solution of NaHCO3 instead of water, a more violent reaction led
to no arylated compound (entry 4), but the reagents were
decomposed into unidentified polar products.16 Subsequently,
a series of experiments were performed in order to optimize the
solvent mixture. Reactions on water gave low yields (entry 5),
and acetone proved to be the best among all the different co-
solvents screened. Fortunately, the mixture acetone-water is an
acceptable option from an environmental point of view.17
generated can then undergo
a
homolytic aromatic
substitution.11 Obviously, the optimal scenario would make use
of a non-toxic reducing agent, from a renewable source. Gallic
acid seems to fit perfectly well: It is an inexpensive antioxidant
commonly used as food additive, which is present in
considerable amounts in bio-waste such as grape pomace or
oak bark.12,13,14 Moreover, there is evidence that gallic acid
derivatives can reduce arenediazonium ions, leading to an aryl
radical.15 Such solid starting point led us to develop a mild
Departamento de Química Orgánica, Instituto Universitario de Bio-Orgánica
“Antonio González” (IUBO), Centro de Investigaciones Biomédicas de Canarias
(CIBICAN), Universidad de La Laguna. Avda. Astrofísico Fco. Sánchez 2, Apdo.
Correos 456, 38200 – La Laguna, S/C. de Tenerife (Spain).
Phone: +34 922 318 583; e-mail: rocarril@ull.es
‡ These authors contributed equally to this work.
†Electronic Supplementary Information (ESI) available: [Experimental details,
characterization of the products and spectra]. See DOI: 10.1039/x0xx00000x
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Modification of the amount of gallic acid was detrimental for kind of antidiabetes compound which acts as a selective SGLT2
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the yield.18 Importantly, when no gallic acid was employed, only inhibitor.23
DOI: 10.1039/C5CC09911K
traces of final compound were obtained (entry 14). Additionally,
when the reaction was performed in the dark, yields were
unchanged, revealing that light has no effect on the coupling
(entry 15). Reducing the amount of furan to 2eq. led to slightly
lower yields (entry 16).19 And shorter reaction times were also
counterproductive (entry 17). Worth to mention, other
polyphenolic compounds were tested, and in all cases they
were less efficient initiators than gallic acid.20
Table 1 Optimization studiesa
Entry
1
2
3
4
5
6
7
8
Solvent
Acetone
Acetone/water (3:1)
Acetone/AcOHaq (1M) (3:1)
Acetone/NaHCO3 (1M) (3:1)
Water
DMSO/water (3:1)
Acetonitrile/water (3:1)
DMF/water (3:1)
Gallic acidb
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
20 mol%
5 mol%
2 mol%
1 mol%
0
10 mol%
10 mol%
10 mol%
Yield (%)c
14
74
27
traces
32
53
44
36
41
55
66
48
45
traces
74d
69e
68f
9
Ethanol/water (3:1)
Acetone/water (3:1)
Acetone/water (3:1)
Acetone/water (3:1)
Acetone/water (3:1)
Acetone/water (3:1)
Acetone/water (3:1)
Acetone/water (3:1)
Acetone/water (3:1)
10
11
12
13
14
15
16
17
a Reaction conditions: 0.5 mmol of diazonium salt, 5 mmol of furan, 4 ml of solvent,
12 h. b mol% respect to diazonium salt. c isolated yield. d In the dark. e With 1 mmol
of furan. f Reaction time 2h.
Scheme 2 Scope of the arylation of heteroarenes with various diazonium salts under the
optimised conditions . The yields are given for the isolated products.
Having optimized the reaction conditions, the scope of this
arylation was examined. Firstly heteroarenes such as furan,
thiophene and pyrroleBoc,21 were reacted with different
diazonium salts. The results are compiled in Scheme 2. As a
general trend, furan gave better yield than the other two
aromatic heterocycles. Indeed, in some cases excellent yields,
up to 96%, were achieved. Moreover, it is clearly seen that
electron withdrawing groups on the diazonium salts favour the
reaction and improve the yields, while electron donating groups
led to traces of product.22
The arylation of non-activated benzene is usually considered a
relatively complicated reaction. As Scheme 3 shows, the
arylation of benzene gave biphenyl products in yields analogous
to those obtained by other metal-free methodologies.3
As
a further proof of the synthetic potential of this
methodology, the arylation of thiophene with p-
fluorobenzenediazonium tetrafluoroborate was tested in a
gram scale (Scheme 4). Those precise reagents were chosen
because the final product is a precursor of canagliflozin, a new
Scheme 3 Arylation of benzene with various diazonium salts. The yields are given for the
isolated products.
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propyl gallate give moderate yields (Scheme 8a).20 These
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control experiments imply that the carbDoOxyI:la10te.10i3s9n/Co5tCdCi0r9e9c1t1lKy
involved in the reactivity and prove the key role of a free
hydroxy group at the para position. It is known that the radical
at 4OH in galloyl radical is stabilized by two hydrogen bond
interactions and by the captodative effect (Scheme 8b).25 In
fact, syringic acid, which lacks of H-bond stabilization, leads to
just traces of product (Scheme 8a).
Scheme 4 Gram-scale synthesis of canagliflozin precursor
As it is seen in Scheme 4, this scaled-up reaction proceeded
nicely in a reasonably good yield. Indeed, the analogous
palladium-based coupling, starts from 2-thienyl boronic acid,24
which requires at least two step of synthesis with a moderate
yield, and thus the global yield is lower than that presented
herein. Additionally, a one pot procedure from the aniline, by
generating the diazonium salt in situ, was assayed. Tert-butyl
nitrite was added to a solution of the aniline and furan in
acetone. Then, a solution of gallic acid (10 mol%) in
water/acetone (1:1) mixture was added dropwise. As it is shown
in Scheme 5, the yields obtained with such one pot
methodology are considerable lower, and yet it is very useful
for those anilines whose diazonium salts are unstable or difficult
to isolate, like the anthraquinone derivative 3h
.
Scheme 7 Suggested mechanism
Scheme 5 One pot arylation from anilines.
Reactivity
High
Low
In order to trap the hypothesized aryl radical generated in the
reaction, we added 2,2,6,6-tetramethylpiperidine-1-oxy radical
(TEMPO) to the reaction mixture (Scheme 6), and product 10
was successfully isolated in 81% yield.
Scheme 8 (a) Modifications on gallate vary reactivity. (b) Stabilization of galloyl radical.
Scheme 6 Aryl-radical entrapment by TEMPO
According to previous studies,15,26 the kinetic product of the
nucleophilic addition is the Z-diazo-ether, which can isomerize
into the thermodynamic E form, or decompose homolytically to
the corresponding aryl radical, nitrogen and galloyl radical.
Stabilization of galloyl radical makes it a good homolytic leaving
group, and therefore the homolytic degradation of Z-diazo-
While further mechanistic studies are required, a tentative
mechanism is depicted in Scheme 7, inspired by previous
reports. It is proposed that gallate undergoes a nucleophilic
addition with the diazonium salt through the hydroxy group at
the para position. Indeed, 3,4,5-trimethoxybenzoic acid
presents no reactivity with diazonium salts, while resorcinol and
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9
M. Hartmann, Y. Li and A. Studer, J. Am. Chem. Soc., 2012, 134,
ether is more favourable than other competitive pathways.
Analysis of the crude mixture by NMR and MS shows that gallic
acid is present in the reaction mixture after full conversion has
been reached, 20 thus proving its catalytic behaviour. Therefore,
16516-16519; M. Hartmann, C. G. DanDiOliuI:c1a0.a10n3Vd9ie/wCA5ACr.tiCcSl0etu9O9dn1eli1nrKe,
Chem. Commun., 2015, 51, 3121-3123.
10 D. Kosynkin, T. M. Bockman and J. K. Kochi, J. Am. Chem. Soc.,
1997, 119, 4846-4855.
11 A. Studer and D. P. Curran, Nat. Chem., 2014, 6, 765-773; A.
once the aryl radical undergoes
substitution giving radical , the gallate ion is regenerated by
means of the one electron oxidation of to cation II mediated
a homolytic aromatic
Studer and D. P. Curran, Angew. Chem. Int. Ed., 2011, 50
,
I
5018-5022.
I
́
12 M. R. Gonzalez-Centeno, M. Jourdes, A. Femenia, S. Simal, C.
by galloyl radical.27 After re-aromatization, the final product is
obtained.
́
Rossello and P.-L. Teissedre, J. Agric. Food Chem., 2013, 61
,
11579-11587; A. R. Fontana, A. Antoniolli and R. Bottini, J.
In summary, a greener and operationally simple direct C-H
arylation has been developed: Catalytic amounts of gallic acid
are able to promote a radical arylation of several heteroarenes
and benzene with arenediazonium salts. This metal-free
methodology is carried out at room temperature in acetone-
water. Sustainability of this arylation is reinforced due to the
fact that gallic acid is the simplest prototype of vegetable
tannins and it is considerable abundant in several bio-waste.
Actually, preliminary results prove that bio-waste rich in gallic
acid such as grape pomace can also promote this arylation.20
Therefore, the methodology herein described not only offers a
greener approach to arylations by using an inexpensive and
underexploited reagent in organic synthesis such as gallic acid;
it also paves the way for novel methods of waste utilization and
valorisation.
Agric. Food Chem., 2013, 61, 8987-9003; Y. Yilmaz and R. T.
Toledo, J. Agric. Food Chem., 2013, 61, 8987-9003.
13 For a microbe-catalyzed syntheses of gallic acid from glucose,
see: S. Kambourakis, K. M. Draths and J. W. Frost, J. Am. Chem.
Soc., 2000, 122, 9042-9043.
14 B. Badhani, N. Sharma and R. Kakkar, RSC Adv., 2015,
5,
27540-27557.
15 S. Losada-Barreiro, V. Sánchez-Paz, C. Bravo-Díaz, Helv. Chim.
Acta, 2007, 90, 1559-1573.
16 Further studies are being carried out to understand such a pH
dependent decomposition.
17 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A.
Johnson, H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and M.
Stefaniak, Green Chem., 2008, 10, 31-36; R. K. Henderson, C.
Jiménez-González, D. J. C. Constable, S. R. Alston, G. G. A.
Inglis, G. Fisher, J. Sherwood, S. P. Binksa and A. D. Curzons,
Green Chem., 2011, 13, 854-862; P. G. Jessop, Green Chem.,
2011, 13, 1391-1398.
This research was supported by the European Commission
(IMBRAIN project, FP7-REGPOT-2012-CT2012-31637-IMBRAIN)
and the Spanish MINECO (CTQ2014-56362-C2-1-P), cofinanced
by the European Regional Development Fund (ERDF). The
authors are also very grateful to Esteban Páez for supplying the
grape pomace.
18 It is known that in biphasic radical arylations, the amount of
catalyst in each phase is critical, which could explain why 20
mol% of catalyst gave lower yields. See: R. D. Baxter, Y. Liang,
X. Hong, T. A. Brown, R. N. Zare, K. N. Houk, P. S. Baran and D.
G. Blackmond, ACS Cent. Sci., 2015, 1, 456-462.
19 Even when 10 equivalents of furan are employed, excess of
reagent can be recovered by distillation, which preserve the
high sustainability of this methodology.
20 See the Supporting Information.
21 The protecting group of pyrrole is vital. Indeed, while t-
butoxycarbamate (Boc) allows for radical arylations, alkyl or
aryl N-protected pyrroles give the corresponding azo adduct.
See: A. Honraedt, M.-A. Raux, E. Le Grognec, D. Jacquemin and
F.-X. Felpin, Chem. Commun., 2014, 50, 5236-5238; S.
Gowrisankar and J. Seayad, Chem. Eur. J., 2014, 20, 12754-
12758.
22 Benzo-fused heterocycles were also tested in this reaction
(indole, benzofuran, benzoimidazol and thianaphthene),
although in all cases low yields and poor regioselectivities
were obtained.
23 S. Nomura, S. Sakamaki, M. Hongu, E. Kawanishi, Y. Koga, T.
Sakamoto, Y. Yamamoto, K. Ueta, H. Kimata, K.o Nakayama
and M. Tsuda-Tsukimoto, J. Med. Chem., 2010, 53, 6355-6360.
24 S. Vásquez-Céspedes, A. Ferry, L. Candish and F. Glorius,
Angew. Chem., Int. Ed., 2015, 54, 5772-5776; A. Valery, V. A.
Postnikov, Y. Odarchenko, A. V. Iovlev, V. V. Bruevich, A. Y.
Pereverzev, L. G. Kudryashova, V. V. Sobornov, L. Vidal, D.
Chernyshov, Y. N. Luponosov, O. V. Borshchev, N. M. Surin, S.
A. Ponomarenko, D. A. Ivanov and D. Y. Paraschuk, Cryst.
Growth Des., 2014, 14, 1726-1737.
Notes and references
1
J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire,
Chem. Rev., 2002, 102, 1359-1470, and references therein; J.-
P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651-2710.
P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39, 301-312.
C. L. Sun, H. Li, D. G. Yu, M. Yu, X. Zhou, X. Y. Lu, K. Huang, S.
2
3
F. Zheng, B. J. Li and Z. J. Shi, Nat. Chem., 2010, 2, 1044-1049;
E. Shirakawa, K. Itoh, T. Higashino and T. Hayashi, J. Am. Chem.
Soc., 2010, 132, 15537-15539; W. Liu, H. Cao, H. Zhang, H.
Zhang, K. H. Chung, C. He, H. B. Wang, F. Y. Kwong and A. W.
Lei, J. Am. Chem. Soc., 2010, 132
, 16737-16740; S.
Yanagisawa, K. Ueda, T. Taniguchi and K. Itami, Org. Lett.,
2008, 10, 4673-4676.
F. P. Crisóstomo, T. Martín and R. Carrillo, Angew. Chem., Int.
Ed., 2014, 53, 2181-2185.
D. Hari, P. Schroll and B. König, J. Am. Chem. Soc., 2012, 134
2958-2961.
S. Shaaban, A. Jolit, D. Petkova and N. Maulide, Chem.
Commun., 2015, 51, 13902-13905; S. Shaaban, A. Roller and
N. Maulide, Eur. J. Org. Chem., 2015, 2015, 7643-7647.
T. Amaya, D. Hata, T. Moriuchi and T. Hirao, Chem. Eur. J.,
2015, 21, 16427-16433.
J. Broggi, T. Terme and P. Vanelle, T. Angew. Chem., Int. Ed.,
2014, 53, 384-413; Koizumi, N. Bashir and J. A. Murphy, Tet.
Lett., 1997, 38, 7635-7638; M. Mahesh, J. A. Murphy, F.
LeStrat and H. P. Wessel, Beilstein J. Org. Chem. 2009, 5,
doi:10.3762/bjoc.5.1.
4
5
6
,
7
8
25 M. Leopoldini, T. Marino, N. Russo and M. Toscano, J. Phys.
Chem. A, 2004, 108, 4916-4922; R. Sustmann and H.-G. Korth,
Adv. Phys. Org. Chem., 1990, 26, 131-178.
26 T. J. Broxton and D. L. Roper, J. Org. Chem., 1976, 41, 2157-
2162; R. Pazo-Llorente, C. Bravo-Díaz and E. González-
Romero, Eur. J. Org. Chem., 2004, 2004, 3221-3226.
27 We cannot exclude an oxidation from
arenediazonium ion.
I to II mediated by the
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