Facile and efficient one-pot procedure for thieno[2,3-e][1,2,3]triazolo[1, 5-a]pyrimidines preparation

Article abstract of DOI:10.1080/00397911.2013.840729

Base-catalyzed cycloaddition reactions of heterocyclic azides with activated nitriles were studied. Convenient, efficient, and high-yield synthetic method for thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines preparation from available starting reagents without complicated protocols was elaborated. Such an approach allows creation of broad combinatorial libraries for drug discovery. [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.]

Full text of DOI:10.1080/00397911.2013.840729

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Facile and Efficient One-Pot Procedure for Thieno[2,3-
e][1,2,3] Triazolo[1,5-a]Pyrimidines Preparation
Nazariy T. Pokhodylo a , Olga Ya. Shyyka a & Mykola D. Obushak a
a Department of Organic Chemistry , Ivan Franko National University of Lviv , Lviv , Ukraine
Accepted author version posted online: 08 Nov 2013.Published online: 08 Nov 2013.
To cite this article: Synthetic Communications (2013): Facile and Efficient One-Pot Procedure for Thieno[2,3-e][1,2,3]
Triazolo[1,5-a]Pyrimidines Preparation, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.840729
To link to this article: http://dx.doi.org/10.1080/00397911.2013.840729
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Facile and efficient one-pot procedure for thieno[2,3-e][1,2,3] triazolo[1,5-
a]pyrimidines preparation
Nazariy T. Pokhodylo1, Olga Ya. Shyyka1, Mykola D. Obushak1
1Department of Organic Chemistry, Ivan Franko National University of Lviv, Lviv,
Ukraine
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i
Mefodiya St. 6, Lviv 79005, Ukraine E-mail: pokhodylo@gmail.com
Abstract
Base-catalyzed cycloaddition reactions of heterocyclic azides with activated nitriles were
studied. Convenient, efficient and high-yield synthetic method for thieno[2,3-
e][1,2,3]triazolo[1,5-a]pyrimidines preparation from available starting reagents without
complicated protocols was elaborated. Such an approach allows to create broad
combinatorial libraries for drug discovery.
[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.]
KEYWORDS: thiophene, triazole, thieno[2,3-d]pyrimidin-4(3H)-one, domino reaction.
INTRODUCTION
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Thienopyrimidines are of significant importance due to their application in technical aims
and wide-ranging biological activities, including anticancer and antiviral agents. [1–6] In
addition, it is well-known that triazoles are also very attractive targets for combinatorial
library synthesis because of their broad range of pharmaceutical activities. [7–10]
Therefore, new methodology for the preparation of these compounds with both
heterocyclic frameworks is of interest and utility. However, synthesis of diverse
heterocyclic molecules from the readily available starting materials in a cost and time
effective manner is an enduring challenge for organic chemists. Recently, Pokhodylo and
co-workers have reported base-catalyzed cycloaddition reactions of new heterocyclic
azides with activated methylene compounds providing new ring systems of thieno[3,2-
e][1,2,3]triazolo[1,5-a]pyrimidines. [11] Alternatively, Ivachtchenko et al. have described
the preparation of a number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-
a]pyrimidines as new potent and selective 5-HT6 receptor antagonists. [12] Moreover,
such sulfonyl-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine derivatives have been
identified as potent HIV-1 replication inhibitors. [13] To develop new medicinally active
compounds with the thienotriazolopyrimidine core and to find the application of the
described synthetic approach, we continued investigation of the syntheses of such
heterocycles which were accessible by 1,3-dipolar cycloaddition reactions and could be
used to broaden the combinatorial libraries.
Herein, we report a convenient and mild method for the synthesis of thieno[2,3-
e][1,2,3]triazolo[1,5-a]pyrimidinones from thiophene-3-yl-azides and activated
methylene nitriles via 1,3-dipolar cycloaddition reaction.
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RESULTS AND DISCUSSIONS
The presented synthetic route is summarized in Scheme 1. In the first step 3-
aminothiophenes were prepared from the β-chloroacetonitriles, the latest ones could be
easily obtained from commercially available carbonyl compounds via the known
procedure. [14] In contrast to Gewald 2-aminothiophenes [11], 3-aminothiophenes were
transformed into the corresponding azides without any complicated procedures. Hence,
diazotization of amino derivatives was performed in concentrated hydrochloric acid and
conversion of the obtained diazonium salts into azides by the reaction with sodium azide
led to the formation of stable crystalline 3-azidothiophenes. Heterocyclic azides as 1,3-
dipolar agents proved to be feasible and highly reactive substances for the novel
polycyclic ring system construction. [11,15]
The anionic domino reaction of 3-azidothiophenes with nitriles occurred in the presence
of sodium methoxide in methanol at room temperature leading to the formation of
thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines. Under these conditions, the cycloaddition
reaction proceeded smoothly to completion and thienotriazolopyrimidines were isolated
in good yields and high purity. The mechanism of such reactions involves two stages. [11]
The azido group is supposed to attack the dipolarophile in the same way the anion of
methylene active acetonitrile does. The intermediate triazole 6, obtained from 1,3-dipolar
cycloaddition reaction, contains amino group, which has got a tendency to further
reaction with the carboxylate function providing to formation of the pyrimidine ring.
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It is known [16] that such a cyclization can take place in two ways (Scheme 2). The
direction of the reaction depends on the nature of R2-group in activated nitriles II.
Nitriles II with electron donating heterocycles (for example 5c) react with azides I
without formation of Dimroth’s type rearrangement products; only one regioisomer III B
was observed (Path B). However, this method has a limitation. In case of nitriles with
electron withdrawing substituents (ex. R2=Ph) (Path A) the mixture of regioisomers was
detected with a favour of regioisomer III A, what is not mentioned in the work [13] and
should be considered.
The structure of the polycyclic ring system was determined from the NMR spectroscopic
data.
CONCLUSION
In summary, we have described a simple, efficient, one-pot, regioselective synthesis of
the substituted thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines, which are suitable for the
evaluation of biological activity and further drug discovery.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury 400 instrument (400 MHz for 1H)
with TMS or deuterated solvent as an internal reference. Mass spectra were run using
Agilent 1100 series LC/MSD with an API-ES/APCI ionization mode. Satisfactory
elemental analyses were obtained for new compounds (C±0.17, H±0.21, N±0.19).
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General Procedure For The Preparation Of Azides 4a-C
Appropriate 3-aminothiophene 1 (0.02 mol) was dissolved in concentrated hydrochloric
acid (5 mL) and ice (15 g) was added. When the mixture was cooled to 0˚C, saturated
sodium nitrite (1.73 g; 0.025 mol) aqueous solution was added keeping the temperature
below 5˚C. After 10 min, resinous sediment (in case it was formed) should be filtered. To
the filtrated solution of the diazonium salt sodium azide (1.3 g; 0.02 mol) in 5 mL of
water was added dropwise. The solution was left for 15 min at room temperature and
azide was filtered. Azides were used without subsequent cleaning.
Methyl 3-Azidothiophene-2-Carboxylate 4a
Yield: 81 %; m.p.: 72ºС; 1H NMR (500 MHz, DMSO-d6): δ 7.34 (d, J = 4.9 Hz, 1H, ThH-
5), 6.71 (d, J = 5.0 Hz, 1H, ThH-4), 3,21 (s, 3H, CH3). 13C-NMR (125 MHz, CDCl3): δ
164.34 (CO), 134.10 (C-3), 132.99 (C-2), 126.16 (C-5), 123.55 (C-4). MS (m/z): 170
(M++1); anal. calcd. for C5H3N3O2S: C 35.50, H 1.79, N 24.84; found: C 35.67, H 1.91,
N 24.73.
General Procedure For The Preparation Of [2,3-E][1,2,3]Triazolo[1,5-
A]Pyrimidines 7a-H
Sodium (0.23 g, 0.01 mol) was added to 20 mL of absolute methanol. Nitrile 5 (0.01 mol)
and the appropriate azide 4 (0.01 mol) were slowly added to the obtained sodium
methylate solution. The mixture was kept for 30 min. The obtained solid was filtered,
washed with water and crystallized from ethanol.
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SUPPORTING INFORMATION
1H and 13C NMR spectra of all new compounds can be found via the ‘‘Supplementary
Content’’ section of this article’s webpage.
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Scheme 1. Synthetic route of thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines 7
construction
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Scheme 2. Regioselectivity of the cyclization reaction
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