Ultrasound-assisted synthesis of 2-amino-1,3,4-oxadiazoles through NBS-mediated oxidative cyclization of semicarbazones

Article abstract of DOI:10.1080/00397911.2017.1324626

A ultrasound-assisted oxidative cyclization of semicarbazones using N-bromosuccinimide in the presence of sodium acetate was established providing efficient and rapid access to a variety of 2-amino-1,3,4-oxadiazoles. Moreover, the new synthetic protocol provides a simple procedure utilizing a safer oxidizing system that affords the target products in high regioselectivity, satisfactory yields, and elevated purities.

Full text of DOI:10.1080/00397911.2017.1324626

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Ultrasound-Assisted Synthesis of 2-Amino-1,3,4-
Oxadiazoles via NBS-Mediated Oxidative
Cyclization of Semicarbazones
Ana Flávia Borsoi, Mateus Emanuel Coldeira, Kenia Pissinate, Fernanda
Souza Macchi, Luiz Augusto Basso, Diógenes Santiago Santos & Pablo
Machado
To cite this article: Ana Flávia Borsoi, Mateus Emanuel Coldeira, Kenia Pissinate, Fernanda
Souza Macchi, Luiz Augusto Basso, Diógenes Santiago Santos & Pablo Machado (2017):
Ultrasound-Assisted Synthesis of 2-Amino-1,3,4-Oxadiazoles via NBS-Mediated Oxidative
Cyclization of Semicarbazones, Synthetic Communications, DOI: 10.1080/00397911.2017.1324626
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1324626
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Date: 06 May 2017, At: 04:31

Ultrasound-Assisted Synthesis of 2-Amino-1,3,4-Oxadiazoles via NBS-Mediated
Oxidative Cyclization of Semicarbazones
Ana Flávia Borsoi1, Mateus Emanuel Coldeira1, Kenia Pissinate1, Fernanda Souza
Macchi1,2, Luiz Augusto Basso1,2,3, Diógenes Santiago Santos1,2,4,, Pablo Machado1,2,4
1Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em
Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul,
Porto Alegre, Rio Grande do Sul, Brazil 2Programa de Pós-graduação em Biologia
Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto
Alegre, Rio Grande do Sul, Brazil 3Programa de Pós-Graduação em Medicina e Ciências
da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio
Grande do Sul, Brazil 4Programa de Pós-Graduação em Biotecnologia Farmacêutica,
Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul,
Brazil
Corresponding authors E-mail: diogenes@pucrs.br (D.S. Santos);
pablo.machado@pucrs.br (P. Machado)
#These authors contributed equally to this work.
Abstract
A ultrasound-assisted oxidative cyclization of semicarbazones using NBS in the presence
of sodium acetate was established providing efficient and rapid access to a variety of 2-
amino-1,3,4-oxadiazoles. Moreover, the new synthetic protocol provides a simple
procedure utilizing a safer oxidizing system that affords the target products in high
regioselectivity, satisfactory yields, and elevated purities.
Graphical Abstract
1

KEYWORDS: 1,3,4-oxadiazole, sonochemical conditions, NBS, cyclization,
semicarbazones
INTRODUCTION
Heterocycles are described as the largest of the divisions of organic chemistry.[1] Their
utilization in areas such as medicinal chemistry, materials science, and organic synthesis
has increased over the years.[1,2] In particular, 1,3,4-oxadiazole-containing molecules
have attracted significant interest among the medicinal and synthetic organic chemistry
communities.[3,4] These compounds have shown a wide range of pharmaceutical and
biological activities including antitubercular,[5] antimicrobial,[6] antitrypanosomal,[7] anti-
inflammatory,[8] antihypertensive,[9] sedative-hypnotic,[10] antidiabetic[11] and
anticancer[12] properties. The widespread use of 1,3,4-oxadiazoles as scaffolds in drug
discovery campaigns has been justified by their singular electronic properties, favorable
metabolic profiles, and their use in bioisosteric replacement with amide, ester or
carboxylic acid groups.[13,14] In addition, the 1,3,4-oxadiazole system comprises part of
the structure of marketed drugs such as the antiretroviral drug raltegravir; a first in class
HIV integrase inhibitor.[15] Considering synthetic organic chemistry applications, 1,3,4-
oxadiazoles have been used as azadienes in tandem [4 + 2]/[3 + 2] cycloaddition
reactions[16] and as substrates for heterocyclic rearrangements produced by ANRORC
processes.[17] Specifically, the presence of an amino group at the 2-position of 1,3,4-
oxadiazoles improves the synthetic possibilities of this system, facilitating the synthesis
of more complex molecules.
2

As an alternative to classical methods, cavitation phenomenon generated using ultrasound
has been used to enhance the rates of a large variety of chemical reactions and
processes.[1,18,19] The singular conditions attained during ultrasound-assisted methods
have leaded to products in more environmentally benign and sustainable protocols by
avoiding the extensive use of hazardous reactants or solvents, harsh reaction conditions,
and toxic catalysts.[1,18,19] Moreover, the use of ultrasound has been associated with
increased selectivity, lower energy consumption for desired transformations, and
significant reduction in the reaction times.
Several methods have been reported in the literature for the synthesis of 2-amino-1,3,4-
oxadiazoles.[3,4] However, to the best of our knowledge, there is no method describing the
synthesis of these compounds by cyclization of semicarbazones under ultrasound
conditions. Existing sonochemical-based methods have described the treatment of
trichloroacetamidoxime with acyl chlorides[20] and the reaction between benzoic acid
derivatives and (N-isocyanimino)triphenylphosphorane in the presence[21] or absence[22]
of acenaphthoquinone for the synthesis of the desired compounds. The few procedures
devoted to the synthesis of 2-amino-1,3,4-oxadiazoles by direct cyclization of
semicarbazones have used hazardous oxidizing agents with limited scalability and
laborious workup protocols.[10,23–27] Recently, the synthesis of these compounds from
semicarbazones was revisited using molecular iodine in the presence of potassium
carbonate[28] and, in another method, using tetrabromomethane under photoredox
conditions, with eosin Y acting as a catalyst[29] for the O-heterocyclizations.
3

As part of our ongoing research we were interested in the development of more efficient
methods for organic synthesis using economical materials that are safe and easy to
handle, aiming to use them in further drug discovery projects. Therefore, because a wide
range of applications for the use of 1,3,4-oxadiazole-based compounds, in an attempt to
improve synthesis, a new ultrasound-assisted oxidative method for the cyclization of
semicarbazones is described. Herein, the synthetic protocol employed N-
bromosuccinimide (NBS) as a bromine source in the presence of sodium acetate. The
evaluation of other N-halo-succinimides as oxidizing agents and the proposed chemical
mechanism are also described.
RESULTS AND DISCUSSION
The approach for obtaining the 2-amino-1,3,4-oxadiazoles was accomplished in two
synthetic steps. First, semicarbazones 1 were synthesized from the condensation reaction
of semicarbazide hydrochloride with benzaldehydes or naphthaldehydes in the presence
of sodium acetate (NaOAc). The products were obtained in reflux of ethanol for 2 h, with
yields of 72–98% (Supplementary information). The subsequent synthetic step involved
intramolecular C-O bond formation from sonochemical-assisted oxidative cyclization of
semicarbazones, obtaining the desired 2-amino-1,3,4-oxadiazoles. Initially, the oxidative
system was investigated using the semicarbazone 1a, which was previously prepared in a
condensation reaction of benzaldehyde with semicarbazide hydrochloride.
4

First, the time and molar ratio required to obtain the 2-amino-1,3,4-oxadiazole 2a were
investigated (Scheme 1). Considering the reaction times, better results were obtained
when the reaction mixtures containing acetic acid (AcOH) as solvent in the presence of
NBS and NaOAc were sonicated for 15 min. In addition, the 1: 1.1: 1.1 molar ratios
between semicarbazone 1a, NBS, and NaOAc, respectively, provided higher yields when
compared to the equimolar concentrations (Scheme 1, Entry 5 – 8). Increasing the molar
ratio of the reagents, the product 2a was isolated with more impurities which were
difficult to separate in the subsequent purification step. It is noteworthy that the absence
of sodium acetate or changing the solvent (acetic acid) significantly reduced the
conversion to the compound 2a (Scheme 1, Entry 9 and 10). The presence of base in the
reaction medium has been reported as being preponderant in obtaining the sole 2-amino-
1,3,4-oxadiazole products via semicarbazone-based ring closure.[30] In this system, the
amino group can compete with an oxygen atom during the cyclization step, leading to the
formation of triazolone derivative compounds.[30] According to spectroscopic and
spectrometric experiments, exclusive O-heterocyclization was observed in our proposed
methodology. With the aim of verifying the catalytic effect of the ultrasonic waves on the
synthetic process under study, the synthesis of compound 2a was performed under
conventional thermal heating using the same experimental conditions used in the
ultrasound-assisted protocol. After 15 min at 110 ° C the reaction provided a mixture of
1a:2a in a ratio of 22:78 based on HPLC determination (Scheme 1, Entry 11).
Furthermore, semicarbazone 1a was subjected to the above optimal oxidative cyclization
conditions (AcOH, NBS, NaOAc, ))), 25 – 110 °C, 15 min) using N-Chlorosuccinimide
5

(NCS) or N-Iodosuccinimide (NIS) as oxidant agents instead of NBS. Both reagents
furnished a mixture of the start material (1a) and the cyclized product (2a). Based on
HPLC determinations, NCS furnished a mixture of 1a:2a in a close ratio of 48:52
whereas NIS afforded the semicarbazone 1a and 1,3,4-oxadiazole 2a in a proportion of
34:66 (Scheme 1, Entry 12 and 13). Moreover, other unidentified products were also
isolated in these protocols. Despite these unsatisfactory results with NCS and NIS their
use, after optimization, should not be discounted. NCS, for example, has been described
in cyclization reactions of structurally diverse acyl hydrazones in the presence of DBU as
base.[31]
To further explore the scalability and robustness of this new procedure, the synthesis of
compound 2a was performed on a scale up to five and ten times larger (5 and 10 mmol).
The reactions were successfully accomplished leading to 1,3,4-oxadiazole 2a with yield
in both scales of 65% and elevated purity (˃ 95%).
Using the template procedure developed for 2a, a range of semicarbazone (1b–m)
synthesized from benzaldehydes bearing both electron-donating and electron-
withdrawing groups afforded the 2-amino-1,3,4-oxadiazoles (2b−m) with 57–92% yields
(Scheme 2). Moreover, other aromatic aldehydes, such as 1- and 2-naphthaldehyde as
well as aliphatic aldehydes were able to form the target heterocyclic compounds in
satisfactory yields without further adaptation in reaction times or conditions. All
synthesized compounds showed physical, spectroscopic, and spectrometric data
consistent with their proposed chemical structures (Supplementary information).
6

Finally, we examined the NBS-NaOAc oxidizing system under conventional conditions
in order to compare with the previously developed ultrasound procedure. Using
conventional stirring, better results were obtained when NBS was added to a solution
containing semicarbazone 1a in AcOH at 0 °C. The resulting mixture was stirred for 30
min while the temperature was allowed to warm up to 25 °C. Afterwards, sodium acetate
was added to the reaction and the mixture was stirred for an additional 60 min leading to
2-amino-1,3,4-oxadiazoles 2a-h and 2j-m with 53–87% yields (Scheme 2). It is
important to mention that semicarbazone 1i did not lead to the cyclization product under
conventional stirring conditions. This result indicated a possible competition between the
deprotection and heterocyclization reactions in the tested conditions. Conventional
stirring provided the compounds in similar yields to those obtained in the ultrasound-
assisted method. However, whereas the 2-amino-1,3,4-oxadiazoles were synthesized
under conventional conditions in 90 min, the sonochemical protocol furnished the
products in 15 min.
Interestingly, when the semicarbazone obtained from 4-(dimethylamino)benzaldehyde
was submitted to the above-described O-cyclization conditions the electrophilic aromatic
substitution product was obtained in a mixture of 74:26 with the starting semicarbazone.
NBS has been used also in regioselective electrophilic substitution of electron rich
aromatic rings.[32] It is important to mention that under our tested conditions, ring
bromination of the semicarbazones 1a–m was not observed according to spectroscopy, or
in high-resolution mass spectrometry assays.
7

The proposed mechanism for obtaining the 2-amino-1,3,4-oxadiazoles 2 starts with the
formation of the intermediate hydrazonyl bromide 3 after treatment of semicarbazones 1
with NBS in the presence of AcOH.[30] Supporting the formation of this intermediate, a
hydrazonyl chloride derivative has been isolated and characterized before cyclization to
form the five-membered ring 2.[33] Subsequent 1,3-dipolar elimination yields nitrilimines
4 which are prone to 1,5-electrocyclization to furnish the heterocyclic compounds 2
(Scheme 3).[34]
EXPERIMENTAL
General Procedure For The Preparation Of 2-Amino-1,3,4-Oxadiazoles Under
Ultrasound Conditions
Semicarbazone 1 (1 mmol), NBS (0.196 g, 1.1 mmol), and sodium acetate (0.090 g, 1.1
mmol) were mixed in acetic acid (20 mL) in a 50-mL beaker. The reaction mixture was
sonicated for 15 min using an ultrasonic probe. Afterward, the resulting solution was
poured into cool water and the solid obtained was filtered and washed with water. Finally
the product was dried under reduced pressure. Compounds 2e and 2m did not precipitate
and were extracted from water with chloroform (3 x 15 mL). The products were isolated
in satisfactory purity.
5-Phenyl-1,3,4-oxadiazol-2-amine (2a): Yield 62%; m.p.: 238-239 °C (m.p.: 242-243
°C)[27]; HPLC 97% (tR = 14.50 min); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (br,
2H, NH2), 7.53-7.55 (m, 3H, Ph), 7.82-7.84 (m, 2H, Ph); 13C NMR (100 MHz, DMSO-
8

d6) δ ppm 124.4, 125.0, 129.1, 130.3, 157.3, 163.9; (13C NMR (100 MHz, DMSO-d6) δ
124.8, 125.4, 129.6, 130.8, 157.7, 164.3)[27]; FTMS (ESI) m/z 162.0654 [M + H]+; calcd
for C8H7N3O: 162.0662.
CONCLUSION
In summary, 2-amino-1,3,4-oxadiazoles have been successfully prepared via cyclization
of semicarbazones using NBS and NaOAc under ultrasound conditions. The simplicity of
execution coupled with the low cost of reagents and reactants, short reaction times (15
min), satisfactory yields (56-92%), and purity of the isolated products make this process
attractive. Additionally, the methodology enabled the creation of the products under
metal-free and mild conditions making the scale-up of the synthetic protocol easier.
Finally, the use of a safer oxidant system compared to those already reported permitted
the generation of compounds with important pharmaceutical applications through a
method that has lower environmental and operational costs.
SUPPLEMENTARY MATERIAL
Supporting Information: Experimental synthetic details, spectroscopic and spectrometric
data, 1H and 13C NMR spectra for new compounds, HPLC traces. This material can be
found via the ‘‘Supplementary Content’’ section of this article’s webpage.’’
ACKNOWLEDGEMENTS
This work was supported by funds from the National Institute of Science and Technology
on Tuberculosis (INCT-TB). L. A. Basso, D. S. Santos, and P. Machado are Research
9

Career Awardees of the National Research Council of Brazil (CNPq). The fellowships
from FAPERGS (A. F. Borsoi), CNPq (M. E. Coldeira), and CAPES (F. S. Macchi) are
also acknowledged.
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12

Scheme 1. Reagents and conditions: i) = Solvent, NXS, presence or absence of NaOAc,
ultrasound or conventional, 25 – 110 °C, 5 – 20 min. aIsolated yields. bReaction
performed without NaOAc; mixture 1a:2a ratio 38:62. cMixture 1a:2a ratio 36:64.
dReaction performed under conventional thermal heating (110 °C); mixture 1a:2a ratio
22:78.eMixture 1a:2a ratio 48:52. fMixture 1a:2a ratio 34:66.
13

Scheme 2. Reagents and conditions: i ) = AcOH, NBS, NaOAc, ))), 25 – 110 °C, 15 min.
a
ii ) = (1) AcOH, NBS, 0 – 25 °C, 30 min; (2) NaOAc, 25 °C, 60 min. Isolated yields.
bUltrasound-assited method. cConventional stirring method. dThis compound was not
obtained in the conventional stirring method.
14

Scheme 3. Proposed mechanism for NBS-mediated synthesis of 2-amino-1,3,4-
oxadiazoles from semicarbazones.
15