Green and catalyst-free one-pot synthesis of anthranilamide Schiff bases: An approach toward sirtinol

Article abstract of DOI:10.1080/00397911.2013.833627

A novel and simple method for the green one-pot synthesis of anthranilamide Schiff bases is described. The reported Schiff bases are obtained via the reaction of isatoic anhydride, amines, and aromatic aldehydes in water at room temperature, without using any catalysts. No cyclization toward 2,3-dihydro-4(1H)-quinazolinones occurred in this method and anthranilamide Schiff bases were produced exclusively. This approach offers a green method to prepare the medicinally important Schiff base sirtinol and other bioactive anthranilamide Schiff bases. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.] Copyright

Full text of DOI:10.1080/00397911.2013.833627

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Green and Catalyst-Free One-Pot
Synthesis of Anthranilamide Schiff Bases:
An Approach Toward Sirtinol
Seyed Mostafa Ebrahimi a , Mohammad Mahdavi a , Saeed Emami b
,
Mina Saeedi a , Mehdi Asadi a , Loghman Firoozpour c , Mehdi Khoobi
a , Kouros Divsalar d , Abbas Shafiee a & Alireza Foroumadi a c
a Department of Medicinal Chemistry , Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medicinal Sciences , Tehran , Iran
b Department of Medicinal Chemistry and Pharmaceutical Sciences
Research Center , Faculty of Pharmacy, Mazandaran University of
Medical Sciences , Sari , Iran
c Drug Design and Development Research Center , Tehran University
of Medicinal Sciences , Tehran , Iran
d Neuroscience Research Center , Institute of Neuropharmacology,
Kerman University of Medicinal Sciences , Kerman , Iran
Accepted author version posted online: 28 Oct 2013.Published
online: 27 Dec 2013.
To cite this article: Seyed Mostafa Ebrahimi , Mohammad Mahdavi , Saeed Emami , Mina Saeedi ,
Mehdi Asadi , Loghman Firoozpour , Mehdi Khoobi , Kouros Divsalar , Abbas Shafiee & Alireza
Foroumadi (2014) Green and Catalyst-Free One-Pot Synthesis of Anthranilamide Schiff Bases:
An Approach Toward Sirtinol, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 44:5, 665-673, DOI: 10.1080/00397911.2013.833627
To link to this article: http://dx.doi.org/10.1080/00397911.2013.833627
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Synthetic Communications1, 44: 665–673, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.833627
GREEN AND CATALYST-FREE ONE-POT SYNTHESIS
OF ANTHRANILAMIDE SCHIFF BASES: AN APPROACH
TOWARD SIRTINOL
Seyed Mostafa Ebrahimi,1 Mohammad Mahdavi,1
Saeed Emami,2 Mina Saeedi,1 Mehdi Asadi,1
Loghman Firoozpour,3 Mehdi Khoobi,1 Kouros Divsalar,4
Abbas Shafiee,1 and Alireza Foroumadi1,3
1Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of Medicinal
Sciences, Tehran, Iran
2Department of Medicinal Chemistry and Pharmaceutical Sciences Research
Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences,
Sari, Iran
3Drug Design and Development Research Center, Tehran University of
Medicinal Sciences, Tehran, Iran
4Neuroscience Research Center, Institute of Neuropharmacology, Kerman
University of Medicinal Sciences, Kerman, Iran
GRAPHICAL ABSTRACT
Abstract A novel and simple method for the green one-pot synthesis of anthranilamide
Schiff bases is described. The reported Schiff bases are obtained via the reaction of isatoic
anhydride, amines, and aromatic aldehydes in water at room temperature, without using any
catalysts. No cyclization toward 2,3-dihydro-4(1H)-quinazolinones occurred in this method
and anthranilamide Schiff bases were produced exclusively. This approach offers a green
method to prepare the medicinally important Schiff base sirtinol and other bioactive
anthranilamide Schiff bases.
Received July 20, 2013.
Address correspondence to Alireza Foroumadi, Department of Medicinal Chemistry, Faculty of
Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences,
Tehran, Iran. E-mail: aforoumadi@yahoo.com
665

666
S. M. EBRAHIMI ET AL.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 2-Aryl-N-substituted-benzamides; isatoic anhydride; multicomponent
reactions (MCRs); Schiff base
INTRODUCTION
Isatoic anhydrides are generally used as useful building blocks in the synthesis
of heterocyclic compounds such as quinazolinones, quinazolones, quinazolinediones,
pyrroloquinazolones, benzimidazolones, and phthalimides with therapeutic inter-
est.[1] Moreover, isatoic anhydrides are also used as intermediates in the synthesis
of anthranilic acid and anthranilamide derivatives with various biological activities
including anticancer,[2] VEGFR tyrosine kinase inhibitory,[3] factor Xa inhibitory,[4]
and insecticidal activities.[5]
Multicomponent reactions (MCRs), because of their atom economy, simple pro-
cedures, straightforward reaction design, facile execution, and convergence, are some of
the best tools in synthesis of organic compounds.[6] The utmost attribute of MCRs is the
inherent formation of several bonds to construct complex molecules in one operation,
ideally without isolation of intermediates.[7] These highly step-economical reactions are
particularly appealing in the context of target-oriented synthesis. They also bear the
promise of novelty in terms of process and compound-related intellectual property.[6]
In this context, three-component condensation of an isatoic anhydride, a
primary amine, and an aromatic aldehyde has been widely investigated under a
variety of catalysts such as p-TsOH,[8] silica sulfuric acid,[9] Al(H2PO4)3,[10]
KAl(SO4)2 ꢀ 12H2O (alum),[11] [bmim]BF4,[12] zinc perfluorooctanoate,[13] and gal-
lium triflate.[14] Using these catalysts or other conditions[15] led to the formation
of 4(3H)-quinazolinones 4 or 2,3-dihydro-4(1H)-quinazolinones 5 because of their
stability (Scheme 1). To the best of our knowledge, there is no report for the pro-
duction of another compound in this reaction. Following our research program
on MCRs using isatoic anhydride as starting material,[16] we found that when the
latter reaction is carried out at room temperature in water, surprisingly 4(3H)-
quinazolinones 4 or 2,3-dihydro-4(1H)-quinazolinones 5 are not obtained, and
instead the anthranilamide Schiff bases 6 are produced (Scheme 2).
Scheme 1. Three-component reaction of isatoic anhydride 1, amines 2, and aldehydes 3.

ANTHRANILAMIDE SCHIFF BASES
667
Scheme 2. One-pot synthesis of anthranilamide Schiff bases 6.
Accordingly, herein we present a novel synthetic method for the construction
of anthranilamide Schiff bases 6 via a green three-component reaction involving
commercially available starting materials.
RESULTS AND DISCUSSION
It is important to note that there is only one report for the synthesis of 6, which
is prepared by a multistep reaction from anthranilic acid using extensive and danger-
ous reagents such as thionyl chloride and pyridine.[17]
As shown in Scheme 2, a mixture of isatoic anhydride 1, amine 2, and aldehyde
3 undergoes a 1:1:1 addition reaction at ambient temperature in water to produce
the corresponding anthranilamide Schiff bases 6a–m in 65–92% yields (Table 1).
All the reactions reached completion within 2–3 h. As shown in Table 1, the gener-
ality of the reaction toward various amines and benzaldehydes was explored. The
results indicated that the direct three-component reactions worked well with aniline,
benzylamine, furfurylamine, and substituted benzylamine. Also the reactions with a
range of benzaldehydes carrying either electron-donating or withdrawing groups on
the benzene ring afforded desired products in good yields.
The structures of the compounds 6 were deduced on the basis of infrared (IR),
1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis. Repre-
sentatively, the IR spectrum of 6h showed absorptions at 3337 (NH), 1713 (strong,
C O) and 1633 (strong, C N) cmꢁ1. The mass spectrum of 6h displayed the molecu-
=
=
lar ion (Mþ) peak at m=z ¼ 378. The H NMR spectrum of 6h exhibited two singlet
1
signals recognized as arising from CH of the imine and OMe groups (d ¼ 8.53 and
3.56 ppm, respectively). One doublet signal at 4.50 ppm and one triplet signal at
9.34 ppm (J ¼ 5.5 Hz) are due to the CH2 and NH groups, respectively. Character-
istic signals with appropriate chemical shifts and coupling constants for the 12 pro-
tons of the aromatic moieties were observed in the aromatic region of the spectrum.
1
The H decoupled 13C NMR spectrum of 6h showed 18 distinct resonances, in
agreement with the proposed structure.
Among various Schiff bases reported here, sirtinol (Fig. 1) attracted our
attention. Sirtinol, 2-((2-hydroxynaphthalen-1-yl)methyleneamino)-N-(1-pheny-
lethyl)benzamide (6m), acts as a specific and a direct inhibitor of sirtuin class of his-
tone deacetylase (HDAC) activity.[18] Synthesis of Schiff bases similar to sirtinol
rarely has been discussed in the literature.[17,18] As shown in Table 1, when the reac-
tion of an equimolar mixture of isatoic anhydride, 1-phenylethanamine, and
2-hydroxynaphthalene-1-carbaldehyde was conducted in water at room temperature,
after 3 h the expected product, sirtinol (6m), was obtained in good yield (87%).

668
S. M. EBRAHIMI ET AL.
Table 1. Synthesis of anthranilamide Schiff bases 6a–h by one-pot reaction of isatoic anhydride, an
amine, and an aldehyde in water under catalyst-free conditions at room temperature
Entry
Amine 2
Aldehyde 3
Product 6
Mp (ꢂC)
Yield (%)
1
120–122
84
2
3
4
124–125
144–145
142–143
85
86
65
92
5
179–180
6
165–166
83
(Continued )

ANTHRANILAMIDE SCHIFF BASES
669
Table 1. Continued
Entry
Amine 2
Aldehyde 3
Product 6
Mp (ꢂC)
Yield (%)
7
113–114
83
70
8
156–157
9
112–113
80
10
11
12
131–132
144–146
167–168
75
75
82
13
220–222
87
aIsolated yields.

670
S. M. EBRAHIMI ET AL.
Figure 1. Structure of a medicinally important anthranilamide Schiff base, sirtinol.
Scheme 3. Proposed mechanism for the formation of 6.
A mechanistic rationalization for this reaction is provided in Scheme 3. It is
conceivable that initially isatoic anhydride 1 can convert to compound 7 via ring
opening by nucleophilic attack of amine 2 to the carbonyl group, which then
undergoes a decarboxylation. This generated anthranilamide could convert to the
titled product 6 by simple condensation with aldehyde 3.
A literature survey indicates that condensation of the aromatic aldehyde with
the amino group of type 7 compounds in the presence of p-TsOH=DDQ,[19] I2,[20]
FeCl3,[21] CuCl2,[22] TiCl4=Zn,[23] chiral phosphoric acid,[24] and ionic liquid=water[25]
undergoes cyclization to afford the dihydroquinazoline product 5. In our method, no
cyclization toward 2,3-dihydro-4(1H)-quinazolinones occurred and anthranilamide
Schiff bases were produced exclusively.
CONCLUSION
In conclusion, we have described a simple, highly efficient, and straightforward
protocol for the exclusive synthesis of anthranilamide Schiff bases 6 in water at ambi-
ent temperature without using any catalysts. Furthermore, the procedure offers sev-
eral advantages including simple experimental procedure, excellent yields of the
products, clean reactions, simple workup, and low cost, which make it a useful and
attractive strategy in the synthesis of the medicinally important Schiff base sirtinol.

ANTHRANILAMIDE SCHIFF BASES
671
EXPERIMENTAL
Melting points were taken on a Kofler hot-stage apparatus and are
uncorrected. 1H and 13C NMR spectra were recorded on Bruker FT-500, using tetra-
methylsilane (TMS) as an internal standard. The infrared (IR) spectra were obtained
on a Nicolet Magna FT-IR 550 spectrophotometer (KBr disks). Mass spectra were
recorded on an Agilent Technology (HP) mass spectrometer operating at an ioniza-
tion potential of 70 eV. Elemental analyses were carried out with a Perkin-Elmer
model 240-C apparatus.
Synthesis of Anthranilamide Schiff Bases 6a–m
A mixture of isatoic anhydride (1 mmol), amine (1 mmol), and aromatic alde-
hyde (1 mmol) in H2O (5 mL) was stirred at room temperature for 2–3 h. After the
completion of reaction (checked by thin-layer chromatography, TLC), the precipi-
tate was filtered off and recrystallized from ethanol to give the pure compound 6.
2-(4-Chlorobenzylideneamino)-N-benzylbenzamide (6a)
Yield: 84%; mp 120–122 ꢂC; IR (KBr): 3251, 3055, 2950, 2862, 1646, 1620,
1566 cmꢁ1
;
1H NMR (DMSO-d6, 500 MHz): dH ¼ 9.09 (t, J ¼ 5.6 Hz, 1H, NH),
8.61 (s, 1H, NCH), 7.86 (dd, J ¼ 7.7, 1.5 Hz, 1H, ArH), 7.78 (d, J ¼ 8.5 Hz, 2H,
ArH), 7.55 (dd, J ¼ 7.7, 1.5 Hz, 1H, ArH), 7.52 (d, J ¼ 8.5 Hz, 2H, ArH), 7.38 (dt,
J ¼ 7.7, 1.5 Hz, 1H, ArH), 7.35–7.25 (m, 6H, ArH), 4.50 (d, J ¼ 5.6 Hz, 2H,
NCH2); 13C NMR (DMSO-d6, 125 MHz,): dC ¼ 165.9, 161.2, 148.7, 139.0, 136.6,
134.3, 131.6, 130.6, 129.4, 129.0, 128.9, 128.3, 127.5, 126.9, 126.2, 119.2, 42.9; MS
m=z (%) ¼ 350 ([M]þ þ 2], 10), 348 ([M]þ, 30), 257 (100), 237 (61), 214 (42), 180
(41), 152 (31), 106 (80), 77 (35), 51 (14). Anal. calcd. for C21H17ClN2O: C, 72.31;
H, 4.91; N, 8.03. Found: C, 72.05; H, 4.72; N, 8.28.
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra are available via the
Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
This research was supported by grants from the research council of Tehran
University of Medical Sciences and the Iran National Science Foundation (INSF).
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