Baoan Song

C Palomo

Deyu Hu

E Gomez-Bengoa

F Chemla

F Liu

GB Rowland

H Zhang

J Song

J Wu

JA Murry

M Koparır

M Petrini

Pinaki S Bhadury

S Kobayashi

S Mazzotta

Song Yang

TC Wabnitz

VJ Ram

Xiangyang Li

XM Zheng

Yi Jin

Z Chen

Zhenchao Wang

Chemistry Central Journal

English

PubMed

Springer - Publisher Connector

RESEARCH ARTICLE Open Access
Inorganic base-catalyzed formation of antivirally
active N-substituted benzamides from a-amido
sulfones and N-nucleophile
Yi Jin, Baoan Song*, Deyu Hu, Xiangyang Li, Pinaki S Bhadury, Zhenchao Wang and Song Yang*
Abstract
Background: Heteronucleophiles as well as carbanionic reagents can be used to react with a-amido sulfones, thus
giving the opportunity to prepare a large array of amino derivatives. Since, novel 1,3,4-oxadiazole-2-thiol derivatives
can serve as potent nucleophiles, we employed 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the nucleophilic
source of nitrogen in the reaction with a-amido sulfones.
Results: A series of N-substituted benzamides bearing 1,3,4-oxadiazol unit were prepared for the first time by the
reaction of in situ generated protected imine from a-amido sulfones with 5-subsititued phenyl-1,3,4-oxadiazole-2-
thiols as the source of nitrogen nucleophile. Some of the synthesized products displayed favourable antiviral
activity against cucumber mosaic virus (CMV) in preliminary antiviral activity tests. The title compounds 5c, 5o and
5r revealed curative activity of 42.2%, 48.7% and 40.5%, respectively against CMV (inhibitory rate) compared to the
commercial standard Ningnanmycin (53.4%) at 500 μg/mL.
Conclusion: A practical synthetic route to N-benzoyl-a-amido sulfones by the reaction of 5-subsititued phenyl-
1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophiles with in situ generated protected imine from
N-benzoyl-a-amido sulfones is presented. The reaction catalyzed by an inorganic base has considerable significance
to exploit the potential of a-amido sulfones in organic synthesis.
Background
a-Amido sulfones are known for their wide range of
application in asymmetric synthesis [1]. Different carba-
nionic nucleophiles can be reacted with a-amido sul-
fones, affording a wide variety of amino derivatives
[2-7]. In addition, considerable research has been con-
ducted on the reaction of nitrogen nucleophiles and a,
b-unsaturated carbonyls [8-11]. Heteronucleophiles as
well as carbanionic reagents can react with a-amido sul-
fones, thus giving the opportunity to prepare a large
array of amino derivatives. Furthermore, a series of
amino derivatives containing 1, 3, 4-oxadiazole ring
were synthesized by the reaction of 1, 3, 4-oxadiazole-2-
thiol with suitably substituted amines and formaldehyde
in ethanol [12]. Based on these reports, we executed an
inorganic base-mediated reaction of 5-subsititued phe-
nyl-1, 3, 4-oxadiazole-2-thiols as the source of nitrogen
nucleophiles with N-benzoyl-a-amido sulfones to pro-
duce N, N-aminals. Interestingly, the resulting com-
pounds bearing a 1, 3, 4-oxadiazole ring are often
associated with significant fungicidal and insecticidal
activities [13-15]. Nevertheless, as of today, there has
been no report on antiviral activities of N-substituted
benzamides bearing 1,3,4-oxadiazol unit. We report syn-
thetic and antiviral studies of the title compounds in the
ensuing sections.
Results and Discussion
The synthetic route to the title N-substituted benzamides
5 is shown in Scheme 1. In order to prepare the key elec-
trophilic component N-benzoyl-a-amido sulfones 4 for
the final reaction, a three components reaction involving
aromatic aldehyde, benzamide and sodium sulfonate was
used by modifying the procedure reported by Chemla [16].
The reaction was fast, free of any significant side products
* Correspondence: basong@gzu.edu.cn; fcc.syang@gzu.edu.cn
State Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Research and Development Center for
Fine Chemicals, Guizhou University, Guiyang 550025, China
Jin et al. Chemistry Central Journal 2011, 5:21
http://journal.chemistrycentral.com/content/5/1/21
© 2011 Jin et al
formation and the pure product was isolated in moderate
yield through recrystallization. The sulfones were charac-
terized by 1H NMR, 13C NMR and IR spectral data.
Finally, reaction of nitrogen nucleophiles 3 with N-ben-
zoyl-a-amido sulfones in the presence of basic catalyst
KOH in CH2Cl2 at room temperature afforded the desired
N-substituted benzamides 5 bearing 1,3,4-oxadiazol group
[Additional file 1]. The reaction conditions were optimized
by taking compound 5a as the model. The effect of differ-
ent solvents and bases was studied at room temperature
with a fixed reaction time of 24 h (Table 1). Under these
conditions, dichloromethane (CH2Cl2) provided the pro-
duct in higher yield compared to toluene, tetrahydrofuran
(THF) or acetonitrile. Amongst the various bases screened
for the experiment, KOH gave the best result and higher
conversion was achieved when 1.2 equiv of KOH was used
instead of 1.0 equiv. Under optimized conditions, the iso-
lated yield of the N-substituted benzamides 5a reached as
high as 70% when the reaction mixture was stirred for
24 h in CH2Cl2 using 1.2 equiv of KOH.
Antiviral activity and structure-activity relationship
The results of in vivo antiviral activity studies of the
N-substituted benzamides 5a-5u against CMV are given in
Table 2. Ningnanmycin was used as the reference antiviral
agent. Most of the compounds showed promising results
in terms of curative bioactivities at 500 μg/mL. The com-
parison of the antiviral activity of the products with com-
mercial reference leads to the following conclusions: (a)
The antiviral activity is affected by the type of the substitu-
ents present in the compound. The compounds containing
2-fluorophenyl or 4-fluorophenyl group showed better
anti-CMV activity compared with those derived from
other groups. In particular, N-substituted benzamides 5o
(R1 = o-F, R2 = p-Cl) and 5c (R1 = p-F, R2 = m-Cl) dis-
played moderate curative rates (48.7% and 42.2%, respec-
tively) against CMV at the concentration of 500 μg/mL.
These values were comparable to the curative rate (53.4%)
shown by the commercial reference Ningnanmycin, and
superior to other compounds bearing different substitu-
ents. (b) Substituents have a certain influence on the activ-
ity. Compared with the compounds 5o and 5c bearing
suitably substituted aryl substituents, the compounds bear-
ing an unsubstituted phenyl ring, such as 5a and 5n,
showed lower inhibitory activities. (c) The structural modi-
fication caused by changing the substituents (R1 and R2) in
Table 1 Effect of different solvents and bases for the
synthesis of 5aa
Entry Solvent Base Equiv Yield (%) c
1 Toluene KOH 1.2 30
2 THF KOH 1.2 58
3 CH3CN KOH 1.2 63
4 CH2Cl2 KOH 1.2 70
5 b CH2Cl2 KOH 1.0 64
6 CH2Cl2 Na2CO3 1.2 52
7 CH2Cl2 NaOH 1.2 65
a Unless otherwise noted, reactions were carried out with 0.5 mmol (1.0
equiv) of 4a, 0.6 mmol (1.2 equiv) of 3a in 5.0 mL solvent and 1 mL H2O using
0.6 mmol (1.2 equiv) of basic catalyst at room temperature for 24 h. b
Reaction was carried out with 0.5 mmol (1.0 equiv) of KOH at room
temperature for 24 h. c Isolated yield after chromatographic purification.
Scheme 1 Synthetic sequence to N-substituted benzamide analogues 5 containing 1,3,4-oxadiazole ring.
Jin et al. Chemistry Central Journal 2011, 5:21
http://journal.chemistrycentral.com/content/5/1/21
Page 2 of 4
the phenyl ring have a wide impact on anti-viral activity of
the prepared compounds. Bioactivity of various com-
pounds having the same substituents at different positions
of the phenyl ring is various. Thus, amongst the com-
pounds 5b, 5c, 5o and 5p containing the same substituents
at different positions of the phenyl ring, the compound 5o
carrying 4-chloro and 2-fluoro groups in their respective
phenyl rings exhibited better bioactivity than others.
Although these compounds, in general, exhibited slightly
lower activity in comparison with the commercial refer-
ence Ningnanmycin at the concentration of 500 μg/mL,
some suitably substituted N-substituted benzamides bear-
ing 1,3,4-oxadiazol moiety showed favourable antiviral
activity in the preliminary studies. Subtle structural varia-
tion might lead to enhancement of activity and should be
the direction of future research.
Experimental
Chemistry
The melting points of the products were determined on an
XT-4 binocular microscope (Beijing Tech Instrument Co.,
China) and were not corrected. The IR spectra were
recorded on a Bruker VECTOR 22 spectrometer in a KBr
disk. 1H NMR (500 MHz), 13C NMR (125 MHz) and 19F
NMR (470 MHz) spectral analyses were performed on a
JEOL-ECX 500 NMR spectrometer at room temperature
using TMS as an internal standard and CDCl3 as the
solvent. Elemental analysis was performed on an Elemen-
tar Vario-III CHN analyzer. Analytical TLC was per-
formed on silica gel GF254. Column chromatographic
purification was carried out using silica gel. All the sol-
vents and materials were of analytical-grade. Intermediate
1, intermediate 2 and 5-subsititued phenyl-1,3,4-oxadia-
zole-2-thiol 3 were prepared according to the reported
methods [17,18] and used without further purifications
[Additional file 2].
Antiviral biological assay
The leaves of Nicotiana tabacum L. inoculated with
CMV were selected and grinded in phosphate buffer and
filtered through double-layer pledget. The filtrate was
centrifuged at 8000 g and the supernatant liquid was the
crude extract of virus. The whole experiment was carried
out at 4°C. Absorbance values were estimated at 260 nm
using an ultraviolet spectro-photometer.
virus concn = (A260 × dilution ratio)/E0.1%, 260 nm1 cm
Preparation of medicaments
Tested compounds and 2% Ningnanmycin aqua used as
a reference antiviral agent were first dissolved in mini-
mum volume of N, N-dimethylformamide (DMF) and
then diluted with distilled water containing 1% Tween
20 at 500 μg/mL concentration.
Curative effect of compounds against CMV in vivo
Growing leaves of Chenopodium amaranticolor of the
same age were selected. Crude extracts of CMV were
dipped and inoculated with a brush on the whole leaves,
which were previously scattered with silicon carbide. The
leaves were washed by water after inoculation for 0.5 h
and then dried. The compound solution was smeared on
the left side of leaves, and the solvent was smeared on
the right side for control. All plants were cultivated at 28
±1°C with an illumination of 10000 Lux. The local lesion
numbers appearing 6-7 d after inoculation were counted.
Three repetitions were conducted for each compounds.
The inhibition rate of the compound was calculated
according to the following formula (av denotes average):
inhibition rate(%) =
av local lesion no. of right leave
(not treated with compound)
− av local lesion no. of left leave
(smeared with compound)
av local lesion no. of right leave
(not treated with compound)
×100%
Conclusion
We have demonstrated a general and practical route for
the synthesis of the N-substituted benzamides bearing
1,3,4-oxadiazol moiety in the presence of an inorganic
base as the catalyst. The reaction of 5-subsititued
Table 2 Curative effect of the title compounds 5 against
CMV in vivo a
Agent R1 R2 Curative effect (%)
5a m-Cl H 24.2
5b m-Cl o-F 35.1
5c m-Cl p-F 42.2
5d m-Cl o-Cl 30.6
5e m-Cl p-Cl 28.2
5f m-Cl o-OCH3 22.9
5g m-Cl p-CH3 27.5
5h m-Cl o-NO2 32.1
5i m-Cl p-NO2 38.5
5j m-Cl m-NO2 36.0
5k H p-CH3 27.8
5l H p-NO2 35.0
5m H p-F 36.0
5n p-Cl H 26.2
5o p-Cl o-F 48.7
5p p-Cl p-F 35.8
5q p-Cl p-CH3 36.4
5r p-Cl o-OCH3 40.5
5s p-Cl o-Cl 37.9
5t p-Cl p-Cl 30.2
5u p-Cl p-NO2 27.2
Ningnanmycin 53.4
a All antiviral tests were carried out at the concentration of 500 μg/mL.
Jin et al. Chemistry Central Journal 2011, 5:21
http://journal.chemistrycentral.com/content/5/1/21
Page 3 of 4
phenyl-1,3,4-oxadiazole-2-thiol which serves as the
source of N-nucleophile with in situ generated protected
imine from N-benzoyl-a-amido sulfones provides a
ready access to a series of structurally diverse N, N-
aminals. The antiviral tests indicated that some of the
synthesized compounds possessed of moderately high
curative activity against CMV. The structure of the tar-
get products needs to be optimized to enhance their
antiviral activity. Further studies on mechanistic aspects,
enantioselectivities and asymmetric variants of catalysts
for this reaction are currently being investigated in our
group.
Additional material
Additional file 1: Yield and elemental analyses data for title
compounds 5a-u. Which contains the table about structure, yield and
elemental analyses data for title compounds 5a-u.
Additional file 2: Experimental details and data of title compounds
5a-u. Which includes the experimental procedure, spectroscopic data of
intermediate 3, intermediate 4, title compounds 5a-u, copies of 1H NMR
and 13C NMR.
Acknowledgements
We gratefully acknowledge the generous financial support received from the
National Key Project for Basic Research (2010CB126105, 2010CB134504) and
the National Natural Science Foundation of China (20872021).
Authors’ contributions
The current study is an outcome of constructive discussion with BAS, SY, LHJ
and DYH who offered necessary guidance to YJ to carry out his synthesis
and characterization experiments. YJ was also involved in the drafting of the
manuscript. XW performed the antiviral tests; HXQ carried out the 1H NMR,
13C NMR and 19F NMR spectral analyses. ZCW and WMX participated in the
scientific discussion pertaining to the manuscript. BAS and associate PSB
were involved in revising the manuscript. All authors read and approved the
final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 30 January 2011 Accepted: 5 May 2011 Published: 5 May 2011
References
1. Petrini M: α-Amido sulfones as stable precursors of reactive N-acylimino
derivatives. Chem Rev 2005, 105:3949-3977.
2. Murry JA, Frantz DE, Soheili A, Tillyer R, Grabowski EJJ, Reider PJ: Synthesis
of α-amido ketones via organic catalysis: thiazolium-catalyzed cross-
coupling of aldehydes with acylimines. J Am Chem Soc 2001,
123:9696-9697.
3. Palomo C, Oiarbide M, Laso A, López R: Catalytic enantioselective aza-
Henry reaction with broad substrate scope. J Am Chem Soc 2005,
127:17622-17623.
4. Song J, Shih HW, Deng L: Asymmetric Mannich reactions with in situ
generation of carbamate-protected imines by an organic catalyst. Org
Lett 2007, 9:603-606.
5. Gomez-Bengoa E, Linden A, Lόpez R, Múgica-Mendiola I, Oiarbide M,
Palomo C: Asymmetric aza-Henry reaction under phase transfer catalysis:
an experimental and theoretical study. J Am Chem Soc 2008,
130:7955-7966.
6. Zhang H, Syed S, Barbas CF: Highly enantio- and diastereoselective
Mannich reactions of glycine Schiff bases with in situ generated N-Boc-
imines catalyzed by a cinchona alkaloid thiourea. Org Lett 2010,
12:708-711.
7. Mazzotta S, Gramigna L, Bernardi L, Ricci A: One-pot synthesis of optically
active β-amino-α-methylene carbonyl derivatives from α-amidosulfones
using quinine-based phase-transfer catalysts. Org Process Res Dev 2010,
14:687-691.
8. Kobayashi S, Kakumoto K, Sugiura M: Transition metal salts-catalyzed aza-
Michael reactions of enones with carbamates. Org Lett 2002, 4:1319-1322.
9. Wabnitz TC, Spencer JB: A general, Brønsted acid-catalyzed hetero-
Michael addition of nitrogen, oxygen, and sulfur nucleophiles. Org Lett
2003, 5:2141-2144.
10. Palomo C, Oiarbide M, Halder R, Kelso M, Gómez-Bengoa E, García JM:
Catalytic enantioselective conjugate addition of carbamates. J Am Chem
Soc 2004, 126:9188-9189.
11. Rowland GB, Zhan H, Rowland EB, Chennamadhavuni S, Wang Y, Antilla JC:
Brønsted acid-catalyzed imine amidation. J Am Chem Soc 2005,
127:15696-15697.
12. Koparır M, Çetin A, Cansız A: 5-Furan-2yl134oxadiazole-2-thiol, 5-furan-2yl-
4H124 triazole-3-thiol and their thiol-thione tautomerism. Molecules 2005,
10:475-480.
13. Wu J, Song BA, Chen HJ, Bhadury PS, Hu DY: Synthesis and antifungal
activity of 5-chloro-6-phenylpyridazin-3(2H)-one derivatives. Molecules
2009, 14:3676-3687.
14. Zheng XM, Li Z, Wang YL, Chen WD, Huang QH, Liu CX, Song GH:
Syntheses and insecticidal activities of novel 2,5-disubstituted 1,3,4-
oxadiazoles. J Fluorine Chem 2003, 123:163-169.
15. Ram VJ, Vlietinck AJ: Chemotherapeutical agents. VII. synthesis and
pesticidal activities of sulphides and sulphones derived from bis[4-aryl-
1,2,4-triazoline-5-thione-3-yl]alkane and 5-phenyl-1,3,4-oxadiazole-2-
thione. J Heterocycl Chem 1988, 25:253-256.
16. Chemla F, Hebbe V, Normant JF: An easy synthesis of aliphatic and
aromatic N-sulfonyl aldimines. Synthesis 2000, 32:75-77.
17. Chen Z, Xu WM, Liu KM, Yang S, Fan HT, Bhadury PS, Hu DY, Zhang YP:
Synthesis and antiviral activity of 5-(4-chlorophenyl)-1,3,4-thiadiazole
sulfonamides. Molecules 2010, 15:9046-9056.
18. Liu F, Luo XQ, Song BA, Bhadury PS, Yang S, Jin LH, Xue W, Hu DY:
Synthesis and antifungal activity of novel sulfoxide derivatives
containing trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-
oxadiazole moiety. Bioorg Med Chem 2008, 16:3632-3640.
doi:10.1186/1752-153X-5-21
Cite this article as: Jin et al.: Inorganic base-catalyzed formation of
antivirally active N-substituted benzamides from a-amido sulfones and
N-nucleophile. Chemistry Central Journal 2011 5:21.
Open access provides opportunities to our 
colleagues in other parts of the globe, by allowing 
anyone to view the content free of charge.
Publish with ChemistryCentral and every
scientist can read your work free of charge
W. Jeffery Hurst, The Hershey Company.
available free of charge to the entire scientific community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours     you keep the copyright
Submit your manuscript here:
http://www.chemistrycentral.com/manuscript/
Jin et al. Chemistry Central Journal 2011, 5:21
http://journal.chemistrycentral.com/content/5/1/21
Page 4 of 4


Inorganic base-catalyzed formation of antivirally active N-substituted benzamides from α-amido sulfones and N-nucleophile

Crossref

A: One-pot synthesis of optically active β-amino-α-methylene carbonyl derivatives from α-amidosulfones using quinine-based phase-transfer catalysts. Org Process Res Dev

Asymmetric aza-Henry reaction under phase transfer catalysis: an experimental and theoretical study.

Asymmetric Mannich reactions with in situ generation of carbamate-protected imines by an organic catalyst. Org Lett

Barbas CF: Highly enantio- and diastereoselective Mannich reactions of glycine Schiff bases with in situ generated N-Bocimines catalyzed by a cinchona alkaloid thiourea. Org Lett

CansızA :5-Furan-2yl134oxadiazole-2-thiol, 5-furan-2yl4H124 triazole-3-thiol and their thiol-thione tautomerism. Molecules

Catalytic enantioselective azaHenry reaction with broad substrate scope.

Gómez-Bengoa E, García JM: Catalytic enantioselective conjugate addition of carbamates.

JB: A general, Brønsted acid-catalyzed heteroMichael addition of nitrogen, oxygen, and sulfur nucleophiles. Org Lett

JC: Brønsted acid-catalyzed imine amidation.

Normant JF: An easy synthesis of aliphatic and aromatic N-sulfonyl aldimines. Synthesis

PJ: Synthesis of α-amido ketones via organic catalysis: thiazolium-catalyzed crosscoupling of aldehydes with acylimines.

Song GH: Syntheses and insecticidal activities of novel 2,5-disubstituted 1,3,4-oxadiazoles. J Fluorine Chem

Synthesis and antifungal activity of 5-chloro-6-phenylpyridazin-3(2H)-one derivatives. Molecules

Synthesis and antifungal activity of novel sulfoxide derivatives containing trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-oxadiazole moiety. Bioorg Med Chem

Transition metal salts-catalyzed azaMichael reactions of enones with carbamates. Org Lett

Vlietinck AJ: Chemotherapeutical agents. VII. synthesis and pesticidal activities of sulphides and sulphones derived from bis[4-aryl1,2,4-triazoline-5-thione-3-yl]alkane and 5-phenyl-1,3,4-oxadiazole-2-thione. J Heterocycl Chem

YP: Synthesis and antiviral activity of 5-(4-chlorophenyl)-1,3,4-thiadiazole sulfonamides. Molecules

α-Amido sulfones as stable precursors of reactive N-acylimino derivatives. Chem Rev

file:///data/remote/core/dit/data/Springer-OA/pdf/730/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMTc1Mi0xNTNYLTUtMjEucGRm.pdf

Inorganic base-catalyzed formation of antivirally active N-substituted benzamides from α-amido sulfones and N-nucleophile

Abstract

Similar works

Full text

Available Versions

Springer - Publisher Connector

Springer - Publisher Connector

Crossref