DBU: An efficient base catalyst for synthesis of the new oxazolo[5,4-d]pyrimidine derivatives

Article abstract of DOI:10.1080/00397911.2014.910527

New types of oxazolo[5,4-d]pyrimidines were synthesized via 1,8-diazabicyclo[5,4,0]undec-7-ene-catalyzed heteroannulation of 2-substituted 5-amino-4-cyano-1,3-oxazoles with various isothiocyanates.

Full text of DOI:10.1080/00397911.2014.910527

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DBU: An Efficient Base Catalyst for
Synthesis of the New Oxazolo[5,4-
d]pyrimidine Derivatives
Ahmad Nikseresht a , Mehdi Bakavoli b & Samad Shoghpour Bayraq b
a Department of Chemistry , Payame Noor University , Tehran , Iran
b Department of Chemistry, School of Sciences , Ferdowsi University
of Mashhad , Mashhad , Iran
Accepted author version posted online: 08 May 2014.Published
online: 02 Jul 2014.
To cite this article: Ahmad Nikseresht , Mehdi Bakavoli & Samad Shoghpour Bayraq (2014) DBU: An
Efficient Base Catalyst for Synthesis of the New Oxazolo[5,4-d]pyrimidine Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:18, 2662-2668, DOI: 10.1080/00397911.2014.910527
To link to this article: http://dx.doi.org/10.1080/00397911.2014.910527
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Synthetic Communications1, 44: 2662–2668, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.910527
DBU: AN EFFICIENT BASE CATALYST FOR SYNTHESIS
OF THE NEW OXAZOLO[5,4-D]PYRIMIDINE
DERIVATIVES
Ahmad Nikseresht,1 Mehdi Bakavoli,2 and
Samad Shoghpour Bayraq2
1Department of Chemistry, Payame Noor University, Tehran, Iran
2Department of Chemistry, School of Sciences, Ferdowsi University of
Mashhad, Mashhad, Iran
GRAPHICAL ABSTRACT
Abstract New types of oxazolo[5,4-d]pyrimidines were synthesized via 1,8-diazabicyclo-
[5,4,0]undec-7-ene-catalyzed heteroannulation of 2-substituted 5-amino-4-cyano-1,3-
oxazoles with various isothiocyanates.
Keywords Aminomalononitrile tosylate; 1,8-diazabicyclo[5,4,0]undec-7-ene; 1,3-
dicyclohexylcarbodiimide; heteroannulation; isothiocyanate; oxazolopyrimidine
INTRODUCTION
The 1,3-oxazole framework represents an important structural motif in
a number of biological activities and pharmaceuticals,[1] including anticancer and
anti-HIV=AIDS activity.[2] Thus, a number of methods for their synthesis have been
reported in the literature that mainly involve reactions of aminomalononitrile tosy-
late (AMNT) with various aryl or alkyl acid chlorides and acid anhydrides.[1,3] Also,
oxazolopyrimidine derivatives are known subunits in many biologically active com-
pounds, as well as in receptor tyrosine kinase such as VEGFR2 (vascular endothelial
Received January 22, 2014.
Address correspondence to Ahmad Nikseresht, Department of Chemistry, Payame Noor
University, 19395-4697 Tehran, Iran. E-mail: a_nik55@yahoo.com
2662

DBU: AN EFFICIENT BASE CATALYST
2663
Figure 1. Pyrrolopyrimidines were shown to be potent EGFR inhibitors[5] and the proposed general
structure of the oxazolopyrimidine structure.
growth factor receptor 2, KDR) or EGFR (epidermal growth factor receptor) that play
crucial roles in a variety of diseases, such as cancer.[4] Recently, some pyrrolopyrimi-
dines were shown to be potent EGFR inhibitors,[5,6,9] such as compound 1 and 2. Thus,
it is expected that the resulting compounds would show biological activity. Compound
3 depicts the general structure of the target oxazolopyrimidine (Fig. 1). Bicyclic
pyrimidine ring system can be prepared by various cyclocondensation procedures such
as two major routes, either starting from 5-amino 4-cyano-oxazoles or in three steps
from commercially available 5-amino-4,6-dihydroxy-pyrimidine.[4–9] In connection
with an ongoing synthesis program, we are interested in the development of a new
route for the preparation of new types of oxazolo[5,4-d]pyrimidines via 1,8-
diazabicyclo[5,4,0]undec-7-ene (DBU)–catalyzed heteroannulation of 2-substituted
5-amino-4-cyano-1,3-oxazoles with various isothiocyanates. DBU has been recognized
as a strong hindered organic base with low nucleophilicity and it finds increasing use in
the synthesis.[10–13] The use of DBU is evidently advantageous over the commonly used
strong bases such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide
(LHMDS), with which low temperatures must be employed.
To the best of our knowledge, there are no literature precedents for using DBU
as the base in generation of the new oxazolo[5,4-d]pyrimidines derivatives via
condensation of highly functionalized 1,3-oxazoles with various isothiocyanates.
RESULTS AND DISCUSSION
In continuation of our investigation for the synthesis of 1,3-oxazole
derivatives,[14] we now introduce new types of highly functionalized 1,3-oxazoles.
Thus, a solution of aminomalononitriletosylate (AMNT) in 1-methyl-2-pyrrolidi-
none was reacted with corresponding aryl acid chloride at room temperature
(Scheme 1). The standard procedure worked especially well in yielding the desired
products 4 (yield 92%), although long reaction times (around 7 days) were required.
For the other procedure used to synthesize 5, we employed aminomalononitriletosy-
late (AMNT) in pyridine with corresponding carboxylic acid at room temperature.
The carboxyl activating reagent, 1,3-dicyclohexylcarbodiimide (DCC), was used to
synthesize compounds 5 (Scheme 2). This convenient method affords 5-amino-4-
cyano-2-(4-nitrophenyl)-1,3-oxazole 5 directly from acids and AMNT and avoids
the prior step of preparation of acid chlorides. The DCC coupling method has
broader applications. For example, 2-hydroxy oxazole can be prepared directly from

2664
A. NIKSERESHT, M. BAKAVOLI, AND S. S. BAYRAQ
Scheme 1. Synthesis of the 5-amino-2-benzhydryl-4-cyano-1,3-oxazole (4).
hydroxyl acids. All new compounds communicated in this work showed good
analytical and spectroscopic data (see Experimental). Furthermore, the 13C NMR
spectra have been assigned via heteronuclear multiple bond correlation (HMBC)
and heteronuclear single quantum coherence (HSQC) experiments and are in good
agreement with those previously reported for other 1,3-oxazoles.
The target oxazolopyrimidines can be synthesized via one major routes, start-
ing from 5-amino-4-cyano-1,3-oxazoles by employing 1,8-diazabicyclo[5,4,0]undec-
7-ene (DBU) under argon using aryl and alkylisothiocyanates (Scheme 3). When this
reaction was repeated at room temperature, no desired product formation was
observed. However, the product formation was also observed when the reaction
was carried out in DMF at 60 ꢀC using excess of DBU. The yield was inferior
(50%), however, and the reaction were not completed even after overnight. Thus,
refluxing all the components in presence excess of DBU in DMF at 120 ꢀC proved
to be optimum conditions for this reaction. Under these conditions, the reaction with
1,3-oxazoles (4 and 5) afforded the forecasted products (6 and 7) in good yields
(81–90%).
Careful literature analysis revealed that a variety of bases with pka ranges from
4 to 11 have been used for some condensation reactions. We speculated that use of
neutral organic bases that have high basicity, and can form a stable protonated
species, may suppress other side reactions. DBU fulfills these requirements and
has been used in many organic transformations in recent years.[15] it is a sterically
hindered amidine base and especially useful where side reactions due to the inherent
nucleophilicity of a basic nitrogen are a problem.[16] DBU is one of the strongest
organic neutral base (pka ¼ 12) and the effect of the adjacent nitrogen stabilizes
the protonated species.
Relying on the concept of DBU catalysis, we believe that greater basicity and
stability of DBU-Hþ effectively increases the efficiency of the reaction.[17,18] The
structures of these compounds have been confirmed by spectroscopic analysis (see
Scheme 2. Synthesis of the 5-amino-4-cyano-2-(4-nitrophenyl)-1,3-oxazole (5).

DBU: AN EFFICIENT BASE CATALYST
2665
Scheme 3. Synthesis of the oxazolo[5, 4-d]pyrimidine-5(4H)-thiones analogs 6 and 7.
Experimental). For example, the IR spectrum of compound 6 was devoid of the
stretching vibration bands at 3341, 3310, and 2220 cmꢁ1 for NH2 and CN absorption
of the precursor but instead showed new absorption bands at 3392, 3330, 1692, and
1
1257 cmꢁ1 for NH2, C N, and C S groups, respectively. The H NMR spectra in
dimethylsulfoxide (DMSO-d6) showed two broad singlets at 9.90 and 5.06 due to
NH2 and CH groups respectively, as well as a singlet 3.68 corresponding to methyl
group and the characteristic signals at 7.14–7.48 for phenyl groups. High-resolution
mass spectra of the compound 6 showed the molecular ion peak at m=z 441.138 and
439.123 corresponding to the MHþ and M-Hþ, respectively.
=
=
EXPERIMENTAL
Reactions were monitored by thin-layer chromatography (TLC) using pre-
coated silica-gel aluminum plates. Detection was done by ultraviolet (UV) (254 nm)
followed by dipping in either sulfuric acid in EtOH (10%) or 0.5% phosphomolybdic
acid in 95% EtOH solutions and subsequent charring at 200 ꢀC or dipping in a 1%
aqueous potassium permanganate solution and air drying. Anhydrous MgSO4 was
used to dry organic solutions during workup, and the removal of solvents was car-
ried out under vacuum with a rotary evaporator. Melting points were determined on
a Buchi510 and are uncorrected. IR spectra were obtained on a Bruker Alpha-P
1
FTIR Diamond ATR spectrophotometer. H NMR and 13C NMR spectra were
recorded with a Bruker 400 spectrometer, using tetramethylsilane as internal stan-
dard. All the assignments for proton and carbon were made via two-dimensional
correlation spectroscopy (2D COSY), HSQC, and HMBC experiments. High-
resolution mass spectra were obtained by a Thermo Scientific Exactive High
Resolution MS (ESI probe).
Procedure for the Synthesis of 5-Amino-2-benzhydryl-
4-cyano-1,3-oxazole (4)
In continuation of our investigation for the synthesis of 1,3-oxazole deriva-
tives,[12] 1.0–1.1 equiv of the diphenylacetyl chloride was added in one portion to
a stirred solution of aminomalononitrile tosylate (AMNT) (2.71 g, 8.60 mmol) in
1-methyl-2-pyrrolidinone (20 mL). The reaction mixture was stirred at room tem-
perature until the reaction was complete. Then, the mixture was diluted with a

2666
A. NIKSERESHT, M. BAKAVOLI, AND S. S. BAYRAQ
mixture of EtOAc and Et2O (1:1) and washed with water, 10% aqueous NaHCO3,
and water. The organic layer was dried, the solvent was evaporated in vacuo, and
the crude product was purified by flash silica-gel chromatography (1:1, PE=EtOAc).
5-Amino-2-benzhydryl-4-cyano-1,3-oxazole (4)
Yield (92%) as white crystals; mp 163–166 ꢀC; IR nmax 3341, 3310, 3139, 2923,
2852, 2220, 1660, 1591, 1158, 696, 744 cmꢁ1;1H NMR (DMSO-d6, 400 MHz) d 7.70
(br s, NH2, 2 H), 7.2–7.4 (m, 10Harom.), 5.59 (s, CH, 1 H); 13C NMR (DMSO-d6,
100 MHz) d 162.34 (C5), 152.65 (C2), 139.49 (2 C, 2C10), 128.55 (4 C, 2C30, 2C50),
128.44 (4 C, 2C20, 2 C60), 127.13 (2 C, 2 C40), 115.44 (CN), 82.52 (C4), 49.23
(CH). HR MS: m=z calcd. for C17H12ON3 (M-Hþ) 274.099; found 274.098; m=z
calcd. for C17H14ON3(MHþ) 276.113; found 276.113.[12]
Procedure for the Synthesis of 5-Amino-4-cyano-2-(4-nitrophenyl)-
1,3-oxazole (5)
4-Nitrobenzoic acid (1.39 g, 8.15 mmol) and 1, 3-dicyclohexylcarbodiimide
(DCC), (1.77 g, 8.6 mmol) were added to a stirred solution of aminomalononitrile
tosylate (AMNT) (2.71 g, 8.60 mmol) in pyridine (40 mL), and the reaction mixture
was stirred at room temperature until the reaction was complete. The white precipi-
tate (dicyclohexylurea) was removed by filtration and the filtrate was concentrated in
vacuo to give a residue, which was purified by flash silica-gel chromatography (1:1,
PE=EtOAc) to give product 5.
5-Amino-4-cyano-2-(4-nitrophenyl)-1,3-oxazole (5)
Yield (78%) as yellow crystals: mp 274–277 ꢀC; IR nmax 3285, 3227, 2221, 1668,
1597, 1514, 1319, 1057, 852 cmꢁ1; 1H NMR (DMSO-d6, 400 MHz) d 8.26 (br s, NH2,
3
3
2 H), 8.33 (dd, J ¼ 8.8 Hz, H20, H60, 2 H), 7.95 (dd, J ¼ 8.8 Hz, H30, H50, 2 H); 13C
NMR (DMSO-d6, 100 MHz) d 162.8 (C5), 147.47 (2C, C2, C40), 131.27 (C10), 125.74
(2C, C20, C60), 124.50 (2C, C30, C50), 114.87 (CN), 85.54 (C4). HR MS: m=z calcd.
for C10H5O3N4 (M-Hþ) 229.037; found 229.036.[12]
General Method for the Synthesis of Oxazolo[5,4-d]pyrimidine-
5(4H)-thiones (6 and 7)
The corresponding aryl and alkylisothiocyanates (0.8–0.95 equiv.) and the
oxazoles 4 and 5 (1.0 equiv.) were added to a solution of DBU (1.0–1.1 equiv) in
dry DMF (5 mL) under argon. The mixture was reacted at 120 ꢀC until the reaction
was complete. Thus, water and a solution of HCl (1 M) were added until PH 9. Then,
the precipitate was filtered off and purified to give compound 6 and 7.
7-amino-2-benzhydryl-6-(4-methoxyphenyl)-oxazolo[5,4-d]-
pyrimidine-5(4H)-thione (6)
Yield (90%) as white crystals; mp 273–276 ꢀC; IR nmax 3392, 3330, 2954, 2852,
1692, 1509, 1257, 693, 738 cmꢁ1; 1H NMR (DMSO-d6, 400 MHz) d 9.90 (br s, NH2,

DBU: AN EFFICIENT BASE CATALYST
2667
2 H), 7.46 (m, 2 H40, 2 H), 7.31 (m, 2 H30, 2 H50, 4 H), 7.23 (m, 2 H20, 2 H60, 4H), 7.15
(m, H300, H500, 2H), 6.73 (d, H200, H600, 2H), 5.06 (s, CH, 1 H), 3.68 (s, CH3, 3 H); 13C
NMR (DMSO-d6, 100 MHz) d 170.27, 158.9 (C2), 154 (C3a), 150 (2 C, C7, C400), 114
(C7a), 140 (2 C, 2C10), 131 (2 C, C200, C600), 129 (4 C, 2C30, 2C50), 128.4 (4 C, 2 C20, 2
C60), 128.5 (C100), 127 (2 C, 2 C40), 110.86 (2C, C300, C500), 55 (CH3), 50 (CH); HR
MS: m=z calcd. for C25H21O2N4S MHþ 441.138; found 441.138; and m=z calcd.
for C25H19O2N4S M-Hþ 439.123; found 439.123.[12]
ACKNOWLEDGMENTS
This work is dedicated to Professor Han Zuilhof and Tom Wennekes of the
laboratory of Organic Chemistry at Wageningen University for their technical
assistance of this research.
SUPPLEMENTARY MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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