The reactions of 2-ethoxymethylidene-3-oxo esters and their analogues with 5-aminotetrazole as a way to novel azaheterocycles

Article abstract of DOI:10.3762/bjoc.11.44

The interaction of 2-ethoxymethylidene-3-oxo esters and their analogues with 5-aminotetrazole is an efficient synthetic approach to novel azaheterocycles. 2-Ethoxymethylidene-3-oxo esters bearing alkyl substituents react with 5-aminotetrazole to form ethyl 2-azido-4-alkylpyrimidine-5-carboxylates which are capable of subsequent nucleophilic substitution. The use of diethyl 2-ethoxymethylidenemalonate in this reaction resulted in ethyl 7-hydroxytetrazolo[1,5-a]pyrimidine-6-carboxylate, while ethyl 2-ethoxymethylidenecyanoacetate yielded 5-[2,6-diamino-3,5-bis(ethoxycarbonyl)pyridinium-1-yl]tetrazol-1-ide through an alternative pathway. Ethyl 2-benzoyl-3-ethoxyprop-2-enoate reacted with 5-aminotetrazole by two reaction routes to form ethyl 2-benzoyl-3-(1H-tetrazol-5-ylamino)prop-2-enoate and ethyl 7-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-yl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate.

Full text of DOI:10.3762/bjoc.11.44

The reactions of 2-ethoxymethylidene-3-oxo esters and their
analogues with 5-aminotetrazole as a way to
novel azaheterocycles
Marina V. Goryaeva*, Yanina V. Burgart, Marina A. Ezhikova, Mikhail I. Kodess
and Viktor I. Saloutin
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 385–391.
Postovsky Institute of Organic Synthesis, Ural Branch, Russian
Academy of Sciences, 22 S. Kovalevskoy St., 620137 Ekaterinburg,
Russia
doi:10.3762/bjoc.11.44
Received: 28 October 2014
Accepted: 10 March 2015
Published: 23 March 2015
Email:
Marina V. Goryaeva* - pmv@ios.uran.ru
Associate Editor: T. J. J. Müller
* Corresponding author
© 2015 Goryaeva et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
5-aminotetrazole; cyclisation; diethyl 2-ethoxymethylidenemalonate;
2-ethoxymethylidene-3-oxo esters; ethyl
2-ethoxymethylidenecyanoacetate
Abstract
The interaction of 2-ethoxymethylidene-3-oxo esters and their analogues with 5-aminotetrazole is an efficient synthetic approach to
novel azaheterocycles. 2-Ethoxymethylidene-3-oxo esters bearing alkyl substituents react with 5-aminotetrazole to form ethyl
2-azido-4-alkylpyrimidine-5-carboxylates which are capable of subsequent nucleophilic substitution. The use of diethyl
2-ethoxymethylidenemalonate in this reaction resulted in ethyl 7-hydroxytetrazolo[1,5-a]pyrimidine-6-carboxylate, while ethyl
2-ethoxymethylidenecyanoacetate yielded 5-[2,6-diamino-3,5-bis(ethoxycarbonyl)pyridinium-1-yl]tetrazol-1-ide through an alter-
native pathway. Ethyl 2-benzoyl-3-ethoxyprop-2-enoate reacted with 5-aminotetrazole by two reaction routes to form ethyl
2-benzoyl-3-(1H-tetrazol-5-ylamino)prop-2-enoate and ethyl 7-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-yl)-5-phenyl-4,7-dihydrote-
trazolo[1,5-a]pyrimidine-6-carboxylate.
Introduction
2-Ethoxymethylidene-1,3-dicarbonyl compounds are widely wide spectrum of biological activity due to structural similarity
recognized as valuable building blocks in designing various with nitrogenous bases, is of a special interest [2-5].
open-chain and heterocyclic compounds, including those used
in medical practice [1]. The possibility to generate pyrimidine Interaction of non-fluorinated 2-ethoxymethylidene-3-oxo
and azolopyrimidine systems based thereon, which exhibit a esters with aminoazoles either stops at the formation of open-
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Beilstein J. Org. Chem. 2015, 11, 385–391.
chain 2-(azolylamino)methylidene-3-oxo esters [6] or leads lower basicity of 5-AT (pKb = 12.18 [21]) compared with other
directly to azolo[1,5-a]pyrimidines [7-9] depending on the aminoazoles and the ability of its derivatives to azide–tetrazole
structure of the starting reagents and reaction conditions. We isomerism [22,23].
have recently found that the cyclization of polyfluoroalkyl-
containing 2-ethoxymethylidene-3-oxo esters with aminoazoles The present paper focuses on studying the peculiarities of inter-
in contrast to non-fluorinated analogues results in the stable action of 2-ethoxymethylidene-3-oxo esters 1a–d and their
dihydroazolo[1,5-a]pyrimidines containing a gem-aminoal- analogues (diethyl 2-ethoxymethylidenemalonate (1e), ethyl
cohol fragment at the polyfluoroalkyl substituent [10,11]. The 2-ethoxymethylidenecyanoacetate (1f)) with 5-AT as a syn-
reactions of ethyl 2-ethoxymethylidene-3-oxo-3-(polyfluo- thetic approach to various azahetrocycles.
roalkyl)propionates with 3-amino-5-hydroxypyrazole allowed
to obtain not only dihydropyrazolo[1,5-a]pyrimidines but also Results and Discussion
pyrazolo[3,4-b]pyridines due to the peculiarities of the binucle- It has been found that 2-ethoxymethylidene-3-oxo esters 1a–c
ophile used [12].
react with 5-AT in ethanol under reflux to form inseparable
mixtures of the products, and while conducting this reaction in
To the best of our knowledge, there is no published data about refluxing 1,4-dioxane even for a prolonged time (32 h) we
the interaction of 2-ethoxymethylidene-3-oxo esters and their observed incomplete conversion of the starting material and low
analogues with 5-aminotetrazole (5-AT), although these reac- selectivity of transformations. However, 2-azidopyrimidines
tions can be used to generate functionalized tetrazolo[1,5- 2a–c instead of the expected tetrazolylaminomethylidene-3-oxo
a]pyrimidines. Derivatives of these heterocycles are promising esters В or tetrazolo[1,5-a]pyrimidines С, D were obtained in
objects for biological testing, because substances possessing 2,2,2-trifluoroethanol (TFE) under reflux (Scheme 1).
apoptotic and antitumor [13], antiviral [14], antimicrobial and
antioxidant activity [15] have been found among them. The Apparently, at first esters 1a–c interact with 5-AT at the
known tetrazolo[1,5-a]pyrimidines were synthesized by cyclo- ethoxymethylidene group to give adduct A, which after the
condensation of 5-AT with 1,3-dicarbonyl compounds or their elimination of ethanol affords the intermediate tetrazolylamino-
derivatives [16]. Moreover, a convenient method for obtaining methylidene derivative B. As a result of regiospecific addition
this heterocyclic skeleton is the three-component Biginelli con- of NH-group to acyl fragment, the intermediate B gives dihy-
densation of 3-oxo esters, aldehyde and 5-AT [17,18] or its drotetrazolo[1,5-a]pyrimidine C, which is further transformed
modification starting from 2-benzylidene-3-oxo esters and into tetrazolo[1,5-a]pyrimidine D after elimination of water.
5-AT [19,20].
Because of the ability of tetrazole to ring opening at the N1–N8
bond, tetrazolo[1,5-a]pyrimidine D undergoes azide–tetrazole
It may be expected that the use of 5-AT as a nucleophile in the isomerism to form isomeric 2-azidopyrimidines 2a–c. The
reactions with 2-ethoxymethylidene-3-oxo esters will alter the electron-withdrawing substituents in the heterocycle are
traditional ways of cyclization. Such changes may be caused by known to facilitate the opening of the fused tetrazole ring
Scheme 1: Interaction of 2-ethoxymethylidene-3-oxo esters 1a–c with 5-AT. R = CF3 (a), (CF2)2H (b), Me (c). Conditions, i: TFE, Δ, 32–38 h; ii: Air,
rt, 12 days; iii: EtOH, rt, 9 days.
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Beilstein J. Org. Chem. 2015, 11, 385–391.
because of decreased electron density at the bridgehead nitrogen The formation of bis-heterocycle 3 is due to the unique struc-
atom [24]. Obviously, the ethoxycarbonyl group at C-6 in com- ture of the starting 2-azidopyrimidine 2c bearing the nucle-
pounds 2a–c leads to a significant decrease in the stability of ophilic Me group and the electrophilic CH centre. Evidently,
the tetrazole ring and shifts the equilibrium towards the azide Me group of pyrimidine 2c reacts with CH-active centre of the
isomer.
another pyrimidine molecule through the formation of inter-
mediate E followed by azido-tetrazole rearrangement.
The azide structure of compounds 2a–c was confirmed by the
presence of absorption bands at ν 2144–2146 cm–1, which are In addition, we have found that the use of catalytic amounts of
typical for the vibration of the azide group in the IR sperctrum sodium acetate in the reaction of fluorinated esters 1a,b with
[25]. The 13C NMR spectra of compounds 2a–c in CDCl3 5-AT in 1,4-dioxane under reflux leads to the formation of ethyl
showed the resonance of the carbon atom C-2 at δ 2-amino-4-(polyfluoroalkyl)pyrimidine-5-carboxylates 4a,b
163.39–163.89 ppm, which is characteristic of the azide form (Scheme 2). In the case of 1a (R = CF3), ethyl 2-(1H-tetrazol-5-
[22,23].
ylamino)-4-(trifluoromethyl)-pyrimidine-5-carboxylate (5) was
isolated as a by-product in the reaction of ester 1a and 5-AT
In contrast to polyfluoroalkylated analogues 2a,b, 4-methyl-2- (Scheme 2).
azidopyrimidine 2c is not stable and converts into compound 3
during standing on open air for 9 days without a solvent. Apparently, in this reaction azidopyrimidines 2a,b acted as
Compound 3 was obtained also by the reaction of ester intermediates that were decomposed under heating in 1,4-
1c with 5-AT in ethanol at room temperature; dioxane with elimination of nitrogen and nitrenes [26]
azidopyrimidine 2с was detected by TLC as an intermediate in (Scheme 2). The latter can cleave a hydrogen atom from the
this reaction.
other substrates (in our case, from 5-AT) to yield 2-aminopy-
rimidines 4a,b.
The structure of bis-heterocycle 3 was confirmed by 1H and 13C
NMR spectra, including 2D 1H,13C HSQC/HMBC experiments. In addition, the counter synthesis of pyrimidines 4a,b was real-
So, in the 13C NMR spectrum the signal of C-3a carbon of the ized by the reaction of esters 1a,b with guanidine carbonate
one heterocyclic fragment was observed at δ 149.71 ppm, which under similar conditions (Scheme 2). Earlier, pyrimidine 4a that
is characteristic of the bridgehead carbon atom in 4,7-dihydrote- exhibited antiviral activity against HSV-1 was obtained by
trazolopyrimidines [20]; and the signal of C-2' carbon of cyclization of ethyl 2-dimethylaminomethyliden-4,4,4-trifluo-
another hetaryl moiety was observed at δ 163.41 ppm, which is roacetoacetate [27].
typical for the C-2 carbon in 2-azidopyrimidines 2a–c. The
HMBC cross-peaks between NH proton (δ 10.7 ppm) and The formation of 2-(tetrazolylamino)pyrimidine 5 is the result
carbons of the methyl group (δ 19.42 ppm), C-6 (δ 97.77 ppm) of nucleophilic substitution of the azide group in intermediate
and C-3a (δ 149.71 ppm) in tetrazolopyrimidine fragment, as 2a by the aminotetrazole fragment, as the azide group is a good
well as cross-peaks between H-6’ proton (δ 9.02 ppm) and C-5’ nucleofuge [28]. Indeed, the reaction of azidopyrimidine 2a
(δ 120.17 ppm) and C-2’ (δ 163.41 ppm) carbons in azidopy- with 5-AT made it possible to obtain 2-(tetrazolylamino)pyrim-
rimidine system supported structure 3.
idine 5 in good yield (Scheme 2).
Scheme 2: Synthesis of pyrimidines 4a,b and 5. R= CF3 (a), (CF2)2H (b). Conditions: i: 1,4-dioxane, NaOAc, Δ, 16–18 h; ii DMF, NaOAc, 80 °C,
24–26 h; iii: 1,4-dioxane, Et3N, Δ, 40 h.
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Beilstein J. Org. Chem. 2015, 11, 385–391.
The structure of pyrimidine 5 was confirmed by X-ray diffrac- one set of the signals corresponding to the tetrazole form with a
tion analysis (Figure 1).
resonance of C-3a at δ 158.63 ppm. Two low-field carbons C-7
and C-3a (δC 153.48 and 158.63 ppm) in the 13C NMR spec-
trum cannot be distinguished by HMBC experiment, since both
give cross-peaks with the proton H-5 due to the constant 3JC,H
through three bonds. However, the value of the constant for
bridgehead carbon C-3a should be greater than that for C-7
[29,30]. The values of the spin–spin coupling constants
obtained from the proton-coupled 13C NMR spectrum
(3JC-3a,H-5 = 16.6 Hz, 3JC-7,H-5 = 7.6 Hz) enable us to assign the
shift at δ 158.63 ppm to the C-3a carbon.
We carried out a series of 2D 1H,15N HMBC experiments for
compound 7 varying evolution delay time. In the HMBC
spectra correlations between the CH proton (δH = 8.7 ppm) and
three 15N atoms at δN = 210.6, 247.4, 306.3 ppm were
observed. Based on the published data [22,31], we have
assigned these chemical shifts to nitrogens N-4, N-8, and N-3,
Figure 1: X-ray crystal structure of compound 5 (ORTEP drawing,
50% probability level).
Further in this reaction we used 2-ethoxymethylidenemalonate respectively, in the structure 7. In the HMBC spectrum of an
(1e) as an analogue of 3-oxo esters having the ester fragment alternative isomeric structure of ethyl-5-hydroxytetrazolo[1,5-
instead of an acyl group. So the interaction of diester 1e with a]pyrimidine-6-carboxylate formed as a result of tetrazole
5-AT in refluxing ethanol in the presence of catalytic amounts rearrangement, it should be expected the intense correlation
of triethylamine proceeded in a classical way and resulted in between CH-proton and tetrazole nitrogen with the chemical
2-tetrazolylaminomethylidene malonate 6 that was cyclised in shift in the range of 350–400 ppm. However such correlation
ethyl-7-hydroxytetrazolo[1,5-a]pyrimidine-6-carboxylate (7) did not appear in HMBC experiments, which allows us to
(Scheme 3). The most suitable condition for the formation of exclude this structure from consideration.
heterocycle 7 was a prolonged refluxing in ethanol in the pres-
ence of triethylamine. In the absence of catalyst, the complete We have found that replacing of the alkyl group by the phenyl
conversion of diester 1e into amino derivative 6 was not residue in 3-oxo ester affects the reaction with 5-AT. So the
observed even after refluxing for 48 h. Cyclization of com- reaction of ethyl 2-benzoyl-3-ethoxyprop-2-enoate (1d) with
pound 6 into tetrazolopyrimidine 7 was performed under 5-AT in ethanol under reflux led to a complex mixture of prod-
prolonged heating without the base.
ucts. Separation of the reaction mixture by column chromatog-
raphy afforded only ethyl benzoylacetate (8) that is likely to be
The structure of tetrazolo[1,5-a]pyrimidine 7 was confirmed by formed as a result of decomposition of starting ester 1d. The
IR, 1H, 13C, 2D 1H,13C and 2D 1H,15N HMBC NMR spectra. decomposition of 2-alkoxymethylidene-containing 3-oxo esters
Thus, the IR spectrum of compound 7 in the solid state did not and their analogues to the corresponding esters in the reactions
have the absorption band of the azide group at ν 2100–2200 with N- and C-nucleophiles is known [32,33].
cm−1, but contained the absorption bands of hydroxy groups
O–H (ν 3419 cm−1) and carbonyl fragments C=O (ν 1715 When this reaction was carried out in refluxing TFE, we also
cm-1). The 1H and 13C NMR spectra in DMSO-d6 contained obtained a mixture of products. However, in this case we
Scheme 3: Interaction of 2-ethoxymethylidene malonate 1e with 5-AT. Conditions: i: EtOH, Et3N, Δ; ii: EtOH, Δ.
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Beilstein J. Org. Chem. 2015, 11, 385–391.
Scheme 4: The reaction of 3-oxo ester 1d with 5-AT. Conditions, i: TFE, Δ, 48 h.
managed to isolate tetrazolylaminomethylidene derivative 9 and connectivities with protons OCH2 (C-9 and C-1') and Hortho
compound 10 in addition to ester 8 (Scheme 4). (C-3').
Ethyl 2-benzoyl-3-(1H-tetrazol-5-ylamino)prop-2-enoate (9) It can be assumed the formation of heterocycle 10 proceeds via
exists as a mixture of Z-and E-isomers stabilized by the tetrazolopyrimidine intermediate F (Scheme 4). The mass spec-
intramolecular H-bond in contrast to the symmetrical malonate trum of amino derivative 9 shows the possibility of tetrazolopy-
derivative 6.
rimidine F formation since it has the peak of (m/z 269 [M −
H2O]+). Then tetrazolopyrimidine F adds benzoylacetic ester
The structure of compound 10 was established by 1H and 13C (8) as a C-nucleophile at the electrophilic CH-center. The reac-
NMR including 2D 1H,13C HSQC/HMBC spectra. According tion is accompanied by tetrazole rearrangement through the for-
to the 1D NMR spectra, compound 10 has two ethoxycarbonyl mation of intermediate G to give heterocycle 10. Compound 10
groups, two phenyl moieties, two sp3-C atoms of methine group was isolated as one diastereomer, but the relative configuration
with vicinal coupling constant JH2'-H7 = 2.8 Hz, and NH-group of its stereogenic centers was not determined.
(δ 10.48 ppm). The protonated carbons of 10 were directly
assigned through the 1JCH connectivities provided by the HSQC Moreover, we studied the reaction of ethyl 2-ethoxymethyli-
experiment. The most informative cross-peaks of HMBC spec- denecyanoacetate (1f) with 5-AT. It has been found that this
trum in CDCl3 for compound 10 were as follows: H-2'→C-1', reaction does not occur either in refluxing ethanol or in
C-3'; H-2'→C-6, C-7; H-7→C-5, C-6, C-9, and C-1'; NH→C-6, refluxing TFE, but addition of catalytic amounts of triethyl-
C-3a, Cipso. The carbonyl carbons were identified by long-range amine resulted in compound 11 in good yield (Scheme 5).
Scheme 5: Interaction of ester 1f with 5-AT. Conditions i: EtOH (or TFE), Et3N, Δ, 40–60 min; ii: AcOH (or EtOH, AcOH), Δ, 32 h.
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The IR spectrum of compound 11 has strong absorption bands Conclusion
of the amino group (ν 3292, 3238 cm−1) and the carbonyl In summary, we can conclude that 2-ethoxymethylidene-substi-
substituent (ν 1699 cm−1). The 1H NMR spectral data allowed tuted esters 1a–f show different ability to react with 5-AT
us to conclude that the molecule of compound 11 is symmetric depending on their structure. Besides, these conversions differ
and bears one methine proton, two amino groups and two from known cyclisations with other aminoazoles [7-12]. These
ethoxycarbonyl substituents. The final structure of compound differences can be explained by the properties of 5-AT. Thus,
11 as 5-[2,6-diamino-3,5-bis(ethoxycarbonyl)pyridinium-1- due to the tendency of the tetrazole ring towards isomerisation
yl]tetrazol-1-ide was confirmed by X-ray diffraction (Figure 2). to an azide group, 3-oxo esters 1a–c with alkyl substituents
form 2-azidopyrimidines 2a–c that are capable for further modi-
fication at the electrophilic centre C-6 and the azide group.
Another difference is the weak basicity of 5-AT, which requires
the basic catalysis in the reaction of 2-ethoxymethylidenecyano-
acetate 1f with 5-AT. This resulted in an alternative reaction
pathway with a partial decomposition of the starting ester 1f to
cyanoacetic ester 12 and subsequent formation of pyridine 11.
Thus, we have found an effective and simple reaction for the
preparation of substituted pyrimidine and pyridine derivatives.
The resulting compounds are important pharmacophores or may
be used as a starting material for synthesis of other functional-
ized pyrimidines through nucleophilic substitution.
Supporting Information
Supporting Information File 1
Experimental section and the copies of all 1H, 13C, and 19F
Figure 2: X-ray crystal structure of compound 11 (ORTEP drawing,
NMR spectra of all new compounds.
50% probability level).
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-44-S1.pdf]
The preparation of compound 11 in the reaction of ester 1f with
5-AT was unexpected, because it is known that ester 1f inter-
acts with 3-amino-1,2,4-triazole in refluxing ethanol [8] and
Acknowledgements
with substituted 5-amino-1,2,4-triazoles in acetic acid [34] to
afford triazolo[1,5-a]pyrimidines. However, we did not observe
the complete conversion of ester 1f in the reaction with 5-AT
even under prolonged reflux in acetic acid. According to
GC–MS data, the reaction mixture contained cyanoacetic ester
(12) (m/z 113 [М]+) and ethyl 3-(1H-tetrazol-5-ylamino)prop-2-
enoate (13) (m/z 182 [М + 2]+) along with ester 1f (m/z 169
[М]+) (Scheme 5).
This research was financially supported by the Russian Founda-
tion for Basic Research (Grant 13-03-00617), the Ural Branch
of Russian Academy of Sciences (Project 15-21-3-9) and the
State Program for Supporting of Leading Scientific School of
the Russian Federation (Grant 3656.2014.3).
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