Zinc-mediated reactions on salicylaldehyde for Botrytis cinerea control

Article abstract of DOI:10.1016/j.cclet.2019.08.053

Botrytis cinerea is a necrotrophic fungus that affects various plant species. Chemical control is a necessity and as much as possible, eco-friendly conditions and bioresources to obtain these chemicals should be used. In this context, a series of products was obtained from salicylaldehyde using zinc as a powerful reagent and tested for antifungal activity against Botrytis cinerea

Full text of DOI:10.1016/j.cclet.2019.08.053

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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Zinc-mediated reactions on salicylaldehyde for Botrytis cinerea control
Antoine Franchea, Claire Imbsb, Antoine Fayeullea, Franck Merlierc, Muriel Billambozd,
Estelle Léonardb,
*
a
Sorbonne University, Université de technologie de Compiègne, ESCOM, EA TIMR 4297, Centre de recherche de Royallieu, CS 60319, 60203 Compiègne cedex,
France
b
ESCOM, UTC, EA TIMR 4297, 1 allée du Réseau Jean-Marie Buckmaster, 60200 Compiègne, France
Sorbonne Universités, Université de Technologie de Compiègne, Génie Enzymatique et Cellulaire (GEC), UMR-CNRS 7025, CS 60319, 60203 Compiègne Cedex,
c
France
d
Laboratoire de chimie durable et santé, Yncrea Hauts-de-France, HEI, 13 rue de Toul, 59046 Lille Cedex, France
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 12 July 2019
Received in revised form 9 August 2019
Accepted 28 August 2019
Available online xxx
Botrytis cinerea is a necrotrophic fungus that affects various plant species. Chemical control is a necessity
and as much as possible, eco-friendly conditions and bioresources to obtain these chemicals should be
used. In this context, a series of products was obtained from salicylaldehyde using zinc as a powerful
reagent and tested for antifungal activity against Botrytis cinerea
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Salicylaldehyde
Zinc-mediated reactions
Green solvents
Alkoxymethylphenol
PEG-cresol
Botrytis cinerea control
Botrytis cinerea is mainly responsible for the so-called grey rot
on various plants. Principal targets are onions [1], beans [2],
tomatoes [3], but also grapevines [4,5] and over 230 plant species
over the world [6]. Unfortunately, resistance phenomena were
observed towards various treatments. Botrytis cinerea tolerates
chlorinated nitrobenzene antifungals [7] as well as benzimidazoles
[8], and dicarboxymides [5,9]. However, molecules containing
phenol and/or alkoxybenzenes are commercialized for their
antifungal activity against Botrytis cinerea (Fig. 1).
New chemicals based on these phenols and/or alkoxybenzenes
cores can be synthesized, using as much as possible eco-friendly
conditions and bioresources to obtain these chemicals. In this
context, salicylaldehyde was first discovered in 1838, from
Filipendula vulgaris [11] and possessed simultaneously a phenol
group that might be interesting against Botrytis cinerea and an
aldehyde moiety, which is a useful group for functionalization
especially into ether group. For this ether formation from carbonyl
moiety can be cited for example, the use of functionalized silanes
and catalysts [12–14], of frustrated Lewis pair catalysts hydro-
genation with alkyl orthoformate [15], or of tin reagents [16]. The
reductants can be also either complex hydrides [17] or dihydrogen
on Pd/Ru [18,19]. But to the best of our knowledge, no zinc reaction
in polar solvents was used to achieve this reaction. Moreover,
reduction of carbonyl compounds thanks to zinc-mercury amal-
gam is well-known as Clemmensen reaction [20]. But Clemmen-
sen-like reactions in the absence of mercury remain discreet
[21,22]. Other reactions leading to hydrocarbons from carbonyls
can be used [23], as for example Huang-Minion modification of
Wolff-Kishner reduction under microwave irradiation [24,25].
However zinc, by its low cost, its good performances in reduction
or coupling and its compatibility with many solvents is a prime
reagent to obtain biocides from o-salicylaldehyde.
First, zinc-mediated Clemmensen reduction was performed on
o-salicylaldehyde (1) by using green solvents as ethanol, water,
glycerol or without solvent. These reactions were performed under
microwave irradiation, and reaction temperature was modulated
from 150 ꢀC to 190 ꢀC.
From Table 1 can be deduced that amongst the green solvent
used (EtOH, water, glycerol, entries 1-3) or without solvent (entry
4), ethanol is the best solvent for the reaction leading to 44%
isolated yield at 150 ꢀC. Indeed, when water was used as solvent
(entry 2) or if no solvent was added (entry 4), miscibility problem
between acetic acid and salicylaldehyde was observed. To
investigate whether the content of AcOEt at the end of reaction
* Corresponding author.
E-mail address: e.leonard@escom.fr (E. Léonard).
https://doi.org/10.1016/j.cclet.2019.08.053
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Franche, et al., Zinc-mediated reactions on salicylaldehyde for Botrytis cinerea control, Chin. Chem. Lett.
(2019), https://doi.org/10.1016/j.cclet.2019.08.053

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Scheme 1. Synthesis of compound 3.
Fig. 1. Active ingredients of A: Mevalone (SUMIAGRO); B: Kenja (SUMMIT AGRO); C:
Teldor1 (BAYER) [10].
Table 1
Optimization of the reaction conditions.a
Entry
Solvent
Temperature (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
EtOH
150
150
150
150
150
30
160
170
180
190
44
19
23
2
11
5
45
48
56
38
Water
Glycerol
c
-
AcOEt
EtOH
EtOH
EtOH
EtOH
EtOH
Fig. 2. Synthesis of compound 4. Gas chromatography yield using naphthalene as
internal standard.
responsible for the yields obtained with EtOH. Then the reaction
performed at 30 ꢀC (entry 6) only led to 5% yield, whereas at 160 ꢀC
(entry 7) and 170 ꢀC (entry 8) the yields obtained were just below
50%. Increasing the temperature to 180 ꢀC (entry 9) seemed to be
the best one leading to 56% yield, whereas at 190 ꢀC (entry 10), the
molecule 2 was only obtained in 38% yield.
a
Reaction conditions: salicylaldehyde (3 mmol), zinc (15 mmol, 5 equiv.) in 6 mL
mixture of solvent/AcOH(5/1, v/v), MW 15 min.
b
Gas chromatography yield using naphthalene as internal standard.
In this case, as no solvent was used, only 1 mL AcOH was added.
c
was responsible for the good yield with EtOH, a reaction with
AcOEt as solvent was performed (entry 5) and led only to a yield of
11% in compound 2 leading to the conclusion that AcOEt was not
Then, under microwave irradiation at 180 ꢀC for 15 min,
o-salicylaldehyde (1) was reduced to o-cresol and was used
Table 2
Conversion and selectivity of the reaction using various metal source.a
Entry
M (equiv.)
EtOH/H2O/AcOH (v/v/v)
Conversion (%)b
Selectivity 4/5 (%)b
1
2
3
4
5
6
7
8
9
10
Zn (5)
Mg (5)
Al (5)
Fe (5)
Cu (5)
Zn (5)
Zn (5)
Zn (1)
Zn (3)
Zn (6)
9/0/1
9/0/1
9/0/1
9/0/1
9/0/1
6/3/0
4.5/4.5/1
9/0/1
9/0/1
9/0/1
77
4
58
74
0
95/5
NDc
0/100
2/98
NDc
5
NDc
58
48
55
67
72/28
69/31
87/13
95/5
a
Reaction conditions: salicylaldehyde (3 mmol), M (n equiv.) in a 6 mL mixture of EtOH/H2O/AcOH (v/v/v), MW 15 min, 150 ꢀC.
Gas chromatography conversion and selectivity using naphthalene as internal standard.
ND = Not determined.
b
c
Please cite this article in press as: A. Franche, et al., Zinc-mediated reactions on salicylaldehyde for Botrytis cinerea control, Chin. Chem. Lett.
(2019), https://doi.org/10.1016/j.cclet.2019.08.053

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3
green-light (green, step 1) and orange-light (usable, step 2)
according to Pfizer “traffic light” of environmental solvent impact
[28].
In a second time, as alkoxyphenols could have a real importance
against Botrytis cinerea, zinc-mediated reductive coupling reaction
between o-salicylaldehyde (1) and ethanol was performed for the
reaction optimization. As seen on Fig. 2, from 100 ꢀC to 150 ꢀC, the
yields of 4 increased from 33% to 73%, and then from 150 ꢀC to
200 ꢀC, they decreased to 50%. Indeed, because of the zinc ability to
heat up to 500 ꢀC under microwave irradiation, it can be supposed
that above 150 ꢀC in reaction media, some degradation may occur.
Then, various metals such as magnesium, aluminum, iron, and
copper powders were tested and compared to zinc. The results
(Table 2) suggest that only zinc is reactive for the alcohol-carbonyl
reductive coupling (entry 1).
Scheme 2. Proposed mechanism of the formation of 4.
without purification for a nucleophilic substitution with tri-
ethylene glycol monomethyl ether [26] leading to compound 3,
with an overall isolated yield of 44% (Scheme 1). This one-pot/two-
step procedure is in accordance with some of the principles of
green chemistry [27].
Indeed, we had to take into account that some metals can
perform homo-pinacol coupling (Zn, Mg), or reduction to
compound 5 (Al, Fe) in addition to product 4. Mg, Al, Fe and Cu
(entries 2-5) gave poor yields of product 4 (Table 2). In our case, the
Indeed, if the yield of reaction remains modest, these two steps
are in accordance with eco-friendly chemistry. Indeed, solvents are
Table 3
Scope of the reaction.
Entry
1
R
R'
Alcohol
C2H5OH
Product
Yield (%)a
73
H
OH
4 [32]
2
3
4
H
H
H
OH
OH
OH
C4H9OH
6 [33,34]
59
26
C6H13OH
7
8
b
-
b
5
H
OH
9
-
6
H
OH
H
10
11
12
24
c
7
Br
H
C2H5OH
C2H5OH
-
supp8
OH
61d
a
Isolated yields.
b
c
Only neopentyl acetate (entry 4) or tert-butyl acetate (entry 5) were obtained.
Only 4-bromobenzylalcohol was obtained.
The volume ratio of EtOH/AcOH was 1/1 (v/v) and (E)-hex-2-enal was added as co-reagent.
d
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(2019), https://doi.org/10.1016/j.cclet.2019.08.053

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Table 4
MIC measurements (mg/mL)
Compound
Inhibitory rate (%)
50
70
90
Ketoconazole
Amphotericin B
3
6
7
2
15
>30
50
50
20
>30
>30
ND
ND
20
7.5
30
40
10
69%. Pinacol 12 did not give any inhibitory rate, but the most active
compound was clearly and significantly hexyloxymethylphenol 7
with an inhibition rate of 100%.
Fig. 3. Inhibitory rates of Botrytis cinerea by compounds 1, 2, 3, 4, 6, 7 and 12 at a
concentration of 50 mg/mL.
So MIC (minimum inhibitory concentration) was chosen to be
performed on compounds 3, 6 and 7. As molecules having
antifungal activities on plant pathogens usually act on respiration
(thiram, mancozeb, captan, dichlofluanid, tolylfluanid); Cyto-
chrome b (strobilurins); β-tubulin (MBC-generating pesticides);
Osmoregulation (dicarboxymides); Sterol biosynthesis (Fenhex-
amide) or Hydrolytic enzymes secretion (anilinopyrimidines) [35],
our molecules 3, 6 and 7 were compared to positive control
standards Ketoconazole [36] and Amphotericin B [37] which were
chosen due to their capability to interact with membrane
ergosterol. Table 4 confirms the interest of compound 7, which
enables to reach 50 and 70% of inhibition with lower concen-
trations than the two other tested compounds. The compound 7
even enables to reach 90% of inhibition, which was not possible
with the two other molecules for the tested concentration range.
Compared to positive controls, results of compound 7 remain
interesting. Indeed even if Ketoconazole and Amphotericin B
trigger 50% of inhibition with lower concentrations, they do not
reaction with Mg gave homo-pinacol coupling in 24% yield, where
no Pinacol coupling was observed when zinc was used. As
mentioned above, one of the most known side-reaction of the
envisioned one is called Bouveault-Blanc reaction, and consists in
reduction of carbonyl into alcohol moiety usually using sodium as
reductant. Under our best conditions (using zinc, under microwave
irradiation, at 150 ꢀC for 15 min.), the selectivity of compound 4
over hydroxybenzyl alcohol 5 was depending on the presence or
absence of acetic acid and water. Indeed, in the presence of water
but not acetic acid (entry 6), only 5% of conversion was observed,
whereas in the presence of acetic acid and water (entry 7), 58%
conversion was obtained, but with a lower selectivity than without
water (entry 1). Moreover, as the reaction took place in the surface
of the zinc powder, 5 equiv. of zinc were necessary to obtain the
best yield of compound 4 (entries 1, 8-10).
For the formation of compound 4, two mechanistic pathways
could be envisioned (Scheme 2): the upper one uses first ethanol in
acidic conditions to obtain the oxonium ion [29]. Then zinc in
acetic acid leads to the reached ether. The other pathway is the
two-electron reduction of the aldehyde [30], followed by the
ethanol addition. As the reaction directly performed from the
benzylic alcohol 5 [31] did not succeed, that led us to suggest the
upper pathway as a mechanism for the reaction (Scheme 2).
To evaluate the scope of the reaction, the reaction was
performed on butyl alcohol and hexyl alcohol, and hexenyl alcohol
(Table 3, entries 2, 3 and 6).
enable to reach 90% for 20
fungal strain.
mg/mL as the compound 7 does for this
To conclude a series of biocides from o-salicylaldehyde by using
zinc was obtained, which possesses good performances in
reductive ether formation, Clemmensen-like reaction, or hetero-
pinacol coupling. Alkoxyphenol compounds proved to be particu-
larly interesting for Botrytis cinerea control. In this context, studies
are ongoing within the team to design new antifungal agents from
other bioresources.
It is noticeable that, due to the microwave ability to act on polar
molecules, the bigger is the aliphatic chain length of alkyl alcohols,
the worse is the reaction yield. So in our conditions, products 4, 6, 7
and 10 were obtained in 73%, 59%, 26% and 24%, respectively
(entries 1, 2, 3 and 6). When more hindered alcohols were chosen
as neopentyl alcohol (entry 4) and tert-butyl alcohol (entry 5) no
attended product was obtained. Reaction on bromobenzaldehyde
did not give the attended product (entry 7). Finally, as salicy-
laldehyde was not able in our conditions to give any homo-pinacol
coupling, we tested the reaction with a ratio EtOH/AcOH (1:1, v/v)
to minimize the ether formation and added hexenal (entry 8)
which gave product 12 of hetero-pinacol coupling in 61% yield
(entry 8). For more details about the syntheses, please see the
Supporting information.
Acknowledgments
Authors would like to thank ESCOM for funding, as well as
Wallonie-Bruxelles International et le Fonds National de la
Recherche Scientifique pour la communauté française de Belgique,
Ministère des Affaires Etrangères et du Développement Interna-
tional (MAEDI) et Ambassade de France en Belgique pour la France
and by the Region of Picardie, France (cofunding of equipment
under CPER 2007–2020 project). Authors would also like to thank
Ministère de l’Education Nationale de la Recherche et de la
Technologie for Research fellowships.
Appendix A. Supplementary data
Some of the synthesized compounds were evaluated for their in
vitro antifungal potential against Botrytis cinerea (MUCL000399).
First the compounds were tested on the mycelium of Botrytis
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.08.053.
cinerea at a concentration of 50 mg/mL and gave the inhibition
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Botrytis cinerea than the starting material salicylaldehyde 1. Cresol
2 had an effect just above 60%, which can be compared to
ethyloxymethylphenol 4. Compound 3 seems to be less efficient
than cresol 2 and butyloxymethylphenol 6 had inhibition rates of
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Please cite this article in press as: A. Franche, et al., Zinc-mediated reactions on salicylaldehyde for Botrytis cinerea control, Chin. Chem. Lett.
(2019), https://doi.org/10.1016/j.cclet.2019.08.053