Microwave-assisted synthesis of borneol esters and their antimicrobial activity

Article abstract of DOI:10.1080/14786419.2017.1399380

Seventeen borneol esters (1–17) were synthesised by conventional and microwave-assisted methodology using DIC/DMAP, and seven are described for the first time (8, 9, 10, 12, 13, 16 and 17). The microwave-assisted methodology was carried out without use of solvents, displayed short reaction times, and showed equal or higher yields for all the long-chain esters and three aromatic compounds (11, 12 and 14) when compared to the conventional approach. All the borneol esters were evaluated against the bacteria Streptococcus sanguinis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and the fungus Candida albicans. Compounds 12, 13 and 14 displayed promising antibacterial activity with a MIC equal to ampicilin (62.5?mg?mL^?1) for some microorganisms. In fact, bornyl 3′,4′-dimethoxybenzoate (13) was active against all tested bacteria and fungus.

Full text of DOI:10.1080/14786419.2017.1399380

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Microwave-assisted synthesis of borneol esters
and their antimicrobial activity
Aline Teixeira Maciel e Silva, Vinícius Viana Pereira, Jacqueline Aparecida
Takahashi, Roqueline Rodrigues Silva & Lucienir Pains Duarte
To cite this article: Aline Teixeira Maciel e Silva, Vinícius Viana Pereira, Jacqueline Aparecida
Takahashi, Roqueline Rodrigues Silva & Lucienir Pains Duarte (2017): Microwave-assisted
synthesis of borneol esters and their antimicrobial activity, Natural Product Research, DOI:
10.1080/14786419.2017.1399380
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Date: 14 November 2017, At: 08:29

Natural Product research, 2017
https://doi.org/10.1080/14786419.2017.1399380
Microwave-assisted synthesis of borneol esters and their
antimicrobial activity
Aline Teixeira Maciel e Silvaa, Vinícius Viana Pereiraa, Jacqueline Aparecida Takahashib
Roqueline Rodrigues Silvac and Lucienir Pains Duarteb
,
aFaculdade de Farmácia, universidade Federal de Minas Gerais, Belo horizonte, Brazil; bdepartamento
de Química, universidade Federal de Minas Gerais, Belo horizonte, Brazil; cdepartamento de Química,
universidade Federal dos Vales do Jequitinhonha e Mucuri, diamantina, Brazil
ABSTRACT
ARTICLE HISTORY
received 28 June 2017
accepted 8 october 2017
Seventeen borneol esters (1–17) were synthesised by conventional
and microwave-assisted methodology using DIC/DMAP, and seven
are described for the first time (8, 9, 10, 12, 13, 16 and 17). The
microwave-assisted methodology was carried out without use of
solvents, displayed short reaction times, and showed equal or higher
yields for all the long-chain esters and three aromatic compounds
(11, 12 and 14) when compared to the conventional approach. All
the borneol esters were evaluated against the bacteria Streptococcus
sanguinis, Staphylococcus aureus, Escherichia coli, Pseudomonas
aeruginosa and the fungus Candida albicans. Compounds 12, 13
and 14 displayed promising antibacterial activity with a MIC equal
to ampicilin (62.5 mg mL−1) for some microorganisms. In fact, bornyl
3′,4′-dimethoxybenzoate (13) was active against all tested bacteria
and fungus.
KEYWORDS
Borneol esters; microwave
irradiation; dIc/dMaP;
antibacterial activity
1. Introduction
During centuries, natural products have been an excellent source of starting materials for
new drugs discovery (Mishra and Tiwari 2011). The great structural diversity of these phyto-
constituents results in different pharmacological actions. For instance, many classes of sec-
ondary metabolites are responsible for antimicrobial activity from plants, including phenolics,
quinones, saponins, flavonoids and terpenes (Gyawali and Ibrahim 2014).
Borneol is a bicyclic monoterpene encountered in the essential oil of numerous medicinal
plants such as Dipterocarpus turbinatus, Rosmarinus officinalis, Salvia officinalis, Valeriana
CONTACT lucienir Pains duarte
lucienir@gmail.com
supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2017.1399380.
© 2017 Informa uK limited, trading as taylor & Francis Group

2
A. T. M. E SILVA ET AL.
officinalis and Matricaria chamomilla. This terpene is used for the treatment of sore throats,
canker sores, wounds, burns, skin infections and other purposes in Chinese popular medicine
(Liu et al. 2011). It has been frequently associated with many drugs for the treatment of
Central Nervous System (CNS) diseases like Alzheimer and cerebral vascular accident (Yu
et al. 2013). Also, previous studies have shown the analgesic, anti-inflammatory, anti-oxidant
and antibacterial actions of borneol (Candan et al. 2003; Horváthová et al. 2009; Liu et al.
2011).
Borneol esters are also found in plants, even though their distribution is restricted to a
few families. For example, hydroxycinnamic borneol esters were previously isolated from
Eupatorium deltoideum (Asteraceae), Piper caninum (Piperaceae) and Cistus genus (Cistaceae).
Natural esters of this kind show a broad spectrum of biological activities such as antibacterial,
antitrypanosomal and inhibitor of human neutrophil elastase (Siedle et al. 2003; Ogungbe
et al. 2010; Venditti et al. 2015). For instance, bornyl caffeate and coumarate demonstrated
a high antibacterial activity (MIC ranging from 0.50 to 15.5 μM) (Setzer et al. 1999), showing
the need for further investigation on this class of compounds.
Since borneol esters present a potential for diverse therapeutic properties and its occur-
rence is not widespread in nature, synthetic derivatives have been obtained and tested for
its biological activities (Perng et al. 1979; Corrêa et al. 2012; Vasconcelos et al. 2012; Silva
et al. 2016). Vasconcelos et al. (2012) studied the biological activity of bornyl salicylate that
showed high anti-inflammatory activity and no signs of acute toxicity. In a previous work,
we prepared a series of borneol esters and the benzoate derivative presented pronounced
cytostatic and antioedematogenic actions (Silva et al. 2016). However, just a few papers
describe the antibacterial potential of borneol derivatives and its synthesis employing the
microwave-assisted method.
Microwave-assisted synthesis has been widely studied because of its shorter reaction,
higher yields and lower amounts of side products compared to conventional methods
(Herrero et al. 2010; Yu et al. 2010). Furthermore, it is considered an environmental/user
friendly approach due to the possibility of solvent free reactions (Lidström et al. 2001; Khan
et al. 2008).
The present work reports the synthesis of seventeen borneol esters using DIC/DMAP,
long-chain carboxylic acids and a series of aromatic acids as starting materials. The synthesis
was carried out by microwave-assisted method and compared with the conventional
method. All the borneol ester derivatives were evaluated for its antibacterial and antifungal
activities.
2. Results and discussion
2.1. Synthesis and chemical characterisation
The synthesis of the borneol analogues was carried out using DIC/DMAP reagents through
both the conventional and microwave-assisted methods. Seventeen compounds were syn-
thesised and seven new compounds are described for the first time (8, 9, 10, 12, 13, 16 and
1
17). All borneol esters were characterised by IR, HR-ESI-MS, H and 13C NMR spectra. The
carbonyl ester group was confirmed for the compounds 1–17 by the presence of a 13C NMR
signal in the region of δC 165–175 ppm and an intense IR absorption band ranging from
1708 to 1782 cm−1. Complete NMR and HR-ESI-MS analysis confirmed the structures for all
the compounds, which are shown with the general synthesis in Figure 1.

NATURAL PRODUCT RESEARCH
3
Table 1 shows the reaction conditions and yields for the seventeen derivatives (1–17).
The reaction time was significantly reduced from 1 to 72 h (conventional method) to 5 min
(microwave-assisted method). Although microwave reactions occur in the absence of sol-
vent, heating from 25 to 170 °C was required to liquefy the reactants, which were solid at
room temperature.
For the long-chain acids, the microwave-assisted method provided superior or equal
yields compared to the conventional method. For example, the reaction with octadecanoic
acid enhanced the yield from 65 to 92% for the synthesis of compound 7.
The reaction with butanedioic acid furnished the expected product 8 (monosubstituted)
with a yield of 35% using the conventional method. Attempts to improve this yield were
performed with higher temperatures, but they were unproductive because of the acid
decomposition. The microwave-assisted method led to product 9 (disubstituted) and 10
(formed by rearrangement of the isourea intermediate) with similar yields. These results may
be explained by the characteristics of microwave-assisted reactions, which induce rapid
rotation of the polarised dipoles in the molecules. This effect enhances heat due to friction
and increases the effective contact among the reagents and atoms, especially in solvent-free
systems, furnishing disubstituted or rearrangement products (Stadler and Kappe 2001; de
la Hoz et al. 2005).
A diverse series of aromatic acids (presenting a heteroatom or electron-donating/with-
drawing groups) were investigated, but the results varied depending on the starting material.
The microwave-assisted method showed an improvement for obtaining compounds 11, 12
and 14, whereas the conventional method presented higher yields for compounds 13, 15,
16 and 17. Therefore, no relationship between the synthetic approaches and substituents
in the aromatic ring was observed.
Finally, the yields of the borneol ester synthesis varied between the two employed meth-
odologies depending on the starting materials. For the long-chain acids 2–7 and the aromatic
O
DIC/DMAP
R
O
HO
CHCl3 or MW irradiation
R
R
Borneol ester
Borneol ester
O
O
1
2
n = 2
n = 4
10
N
H
N
3
4
5
6
7
n = 6
R2, R3, R4, R5 = H
11
12
13
14
15
H3C
n = 8
n
R2, R3, R5 = H; R4 = OCH3
n = 10
n = 12
n = 14
R2
R3
R4
R
2, R5 = H; R3, R4 = OCH3
R2 = H; R3, R4, R5 = OCH3
R2, R4 = H; R3, R5 = NO2
R5
R4 = H; R2 = OH; R3, R5 = NO2
16
O
8
R1 = H
R1
O
9
R1 = Borneol
N
17
Figure 1. synthesis of borneol esters using dIc/dMaP reagents.

4
A. T. M. E SILVA ET AL.
Table 1. conditions and yields for the synthesis of borneol esters (1–17) by conventional and micro-
wave-assisted methods.
Methods using DIC/DMAP
Conventionala
Microwave-assistedb
Carboxilic acid
Time (h)
Yield % (product)
Temperature (°C)
Yield % (product)
hexanoic
octanoic
decanoic
dodecanoic
tetradecanoic
hexadecanoic
octadecanoic
Butanedioic
2
1
3
14
2
1
62 (1)
79 (2)
70
70
70
70
70
70
70
25
61 (1)
93 (2)
85 (3)
95 (3)
72 (4)
76 (4)
82 (5)
87 (5)
73 (6)
82 (6)
19
26
65 (7)
92 (7)
35 (8)
17 (9)
20 (9)
17 (10)
81 (11)
50 (12)
60 (13)
80 (14)
75 (15)
21 (16)
Benzoic
4
24
72
5
1
21
59 (11)
30 (12)
77 (13)
54 (14)
84 (15)
41 (16)
120
130
130
130
130
170
4-methoxy-benzoic
3,4-di-methoxy-benzoic
3,4,5-tri-methoxy-benzoic
3,5-di-nitro-benzoic
2-hydroxy-3,5-di-nitro-ben-
zoic
Nicotinic
3
72 (17)
70
60 (17)
aconventional method was performed at room temperature.
bthe time reaction of microwave-assisted synthesis was 5 min.
acids 11, 12 and 14, the microwave-assisted methodology provided the best results.
Although the attempt to produce a borneol ester with a free carboxylic group was successful
using the conventional method, the microwave-assisted method did not lead to the expected
compound, probably due to the role of the solvent. Despite these limitations, solvent-free
reactions employing the microwave-assisted methodology display shorter reaction times
and demonstrate themselves as a useful approach for further synthetic studies on natural
products. Also, the lack of organic solvents reduces the need of excess chemicals and waste
disposal, characterising this approach as an eco-friendly green methodology (Sanseverino
2002; Loupy 2004).
2.2. Antimicrobial activity
Table 2 summarises the overall results of the antimicrobial assay. The long-chain borneol
esters (1–7) showed no antimicrobial potential except for compound 4, which was slightly
active (MIC50 = 500 μg mL−1) against Pseudomonas aeruginosa. The esters from butanedioic
acid displayed no activity for tests apart from the rearranged compound 10, which presented
action against Candida albicans (MIC50 = 500 μg mL−1).
For the aromatic esters (11–17), the methoxylated compounds 12, 13 and 14 presented
the best results for the antimicrobial test. Compound 12 and 13 demonstrated activity
against all tested microorganisms, revealing a broad-spectrum potential. These substances
displayed the same activity of the standard drug ampicilin for the Gram-positive Streptococcus
sanguinis (compound 12) and for the Gram-negative Escherichia coli (compound 13). In fact,
compound 13 showed all results below or equal to MIC50 = 125 μg mL−1, including for the
fungus C. albicans. Compound 14 was the most selective against the Gram-positive bacteria,
displaying a MIC50 equal to the standard (62.5 μg mL−1). The aromatic portion with an elec-
tron-donating group (methoxyl) may play an important role for this biological assay.

NATURAL PRODUCT RESEARCH
5
Table 2. antimicrobial activity of borneol and its esters (1–17).
a
MIC50 (μg mL−1
)
S. sanguinis ATCC
S. aureus ATCC
E. coli ATCC
25922
P. aeruginosa
ATCC 27853
C. albicans ATCC
Compound
49456
25923
18804
Borneol
1
2
3
4
5
6
7
8
9
10
11
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
62.5
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
125
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
250
>500
>500
>500
>500
500
>500
>500
>500
>500
>500
>500
>500
500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
500
>500
250
12
13
14
15
16
125
62.5
>500
>500
>500
62.5
125
62.5
>500
>500
>500
62.5
62.5
250
>500
>500
>500
62.5
125
125
>500
>500
>500
>500
-
>500
>500
>500
>500
62.5
17
standardb
aeach experiment was run for three times, and the results are presented as average values.
bampicilin for bacteria (with the exception of P. aeruginosa, which presented resistance) and miconazole for fungus.
3. Conclusion
Seventeen borneol esters were synthesised using DIC/DMAP reagents through conventional
and microwave-assisted methods. Seven new compounds are described for the first time
(8, 9, 10, 12, 13, 16 and 17). The microwave-assisted method displayed equal or higher yields
than the conventional one for all the long-chain esters. However, for the aromatic esters, the
results varied between the approaches, depending on the employed acid. These results were
better for compounds 11, 12 and 14 using the microwave-assisted procedure, whereas the
conventional procedure was more efficient for compounds 13, 15, 16 and 17. Despite these
facts, microwave-assisted method presented major advantages such as shorter reaction
times and absence of the solvent.
Among all the synthetised compounds, the methoxylated aromatic esters showed the
best results for the antimicrobial assay. Compound 12, 13 and 14 displayed an activity equal
to the standard ampicillin (MIC50 = 62.5 μg mL−1). In fact, bornyl 3′,4′-dimethoxybenzoate
(13) was active for all tested microorganisms, including the fungus C. albicans (MIC50
=
125 μg mL−1).
Supplementary material
The NMR and HR-ESIMS data (Figures S1–S44) for this article can be accessed online.
Acknowledgements
Authors are grateful to the english reviewer Salomão Bento V. Rodrigues

6
A. T. M. E SILVA ET AL.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
Authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior and Fundação de Amparo à Pesquisa do Estado de
Minas Gerais for financial support.
ORCID
Jacqueline Aparecida Takahashi
http://orcid.org/0000-0002-8831-1609
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