Use of activated enol ethers in the synthesis of pyrazoles: Reactions with hydrazine and a study of pyrazole tautomerism

Article abstract of DOI:10.3762/bjoc.10.70

Activated enol ethers derived from esters or the dinitrile of malonic acid, or from pentane-2,4-dione were treated with hydrazine hydrate. The structures of the obtained products - pyrazoles 5 - were studied with a focus on tautomerism and supramolecular structure. A reverse addition of the reagents led to the isolation of two novel products, namely bis-enehydrazines 6 with an unsymmetrical arrangement of the formally equivalent subunits.

Full text of DOI:10.3762/bjoc.10.70

Use of activated enol ethers in the synthesis of
pyrazoles: reactions with hydrazine and a
study of pyrazole tautomerism
Denisa Tarabová1, Stanislava Šoralová2,3, Martin Breza2, Marek Fronc2,
Wolfgang Holzer4 and Viktor Milata*1
Full Research Paper
Open Access
Address:
Department of Organic Chemistry, Faculty of Chemical and Food
Technology, Slovak University of Technology, Radlinského 9, SK-812
7 Bratislava, Slovakia, 2Department of Physical Chemistry, Faculty
Beilstein J. Org. Chem. 2014, 10, 752–760.
1
doi:10.3762/bjoc.10.70
3
Received: 10 December 2013
Accepted: 14 March 2014
Published: 01 April 2014
of Chemical and Food Technology, Slovak University of Technology,
Radlinského 9, SK-812 37 Bratislava, Slovakia, 3Department of
Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius
University in Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia
and 4Department of Drug and Natural Product Synthesis, Vienna
University, Althanstrasse 14, A-1090 Vienna, Austria
Dedicated to Professor Rosa María Claramunt Vallespí on the occasion of
her 65th anniversary.
Associate Editor: P. R. Schreiner
Email:
Viktor Milata* - viktor.milata@stuba.sk
© 2014 Tarabová et al; licensee Beilstein-Institut.
License and terms: see end of document.
*
Corresponding author
Keywords:
bis-enehydrazines; enol ethers; NMR; pyrazole; tautomerism
Abstract
Activated enol ethers derived from esters or the dinitrile of malonic acid, or from pentane-2,4-dione were treated with hydrazine
hydrate. The structures of the obtained products – pyrazoles 5 – were studied with a focus on tautomerism and supramolecular
structure. A reverse addition of the reagents led to the isolation of two novel products, namely bis-enehydrazines 6 with an unsym-
metrical arrangement of the formally equivalent subunits.
Introduction
Enol ethers are reactive species frequently used in organic syn- as amines, thiols, alcohols or C-anions [2] under the conditions
thesis [1]. They react predominantly with electrophiles. The of nucleophilic vinylic substitution [3]. When using bi- or
introduction of one or more strong electron-withdrawing groups trifunctional nucleophiles, cyclic or bicyclic products are
at the other end of the double bond from the alkoxy group formed. Activated enol ethers thus represent trifunctional elec-
causes an inversion of electron demand. These activated enol trophiles and are useful building blocks for the introduction of a
ethers react surprisingly easily with various nucleophiles such three carbon fragment into the resulting molecule. Thus, the
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Beilstein J. Org. Chem. 2014, 10, 752–760.
reaction of enol ethers with hydrazines produces pyrazoles, with Upon reaction of hydrazine with symmetrical enol ethers, only a
amidines pyrimidines, with hydroxylamine isoxazoles, and with single product is formed, which is capable of annular
anilines quinolines/ones are formed [2].
prototropic tautomerism [5,6]. In contrast, the use of „asym-
metric“ enol ethers, that is, R1, R1 in 2 and 3 are not equal, may
Electron-accepting groups can include ester, cyano, acetyl, nitro lead to two different pyrazoles, both of which exhibit
and trifluoroacetyl moieties. Thus, the simplest way to obtain tautomerism). However, depending on the different reactivities
activated enol ethers 3 is the condensation of active methylene of the electron-withdrawing groups R1 only a single product is
components 2 such as malonic acid derivatives (esters, nitrile), formed (Scheme 2) [7].
(
trifluoro)acetoacetic acid derivatives (esters, nitrile), acetylace-
tone, and nitroacetates with trialkyl orthoformate 1 (Scheme 1). Results and Discussion
Transesterification can be avoided if 1 bears the same alkyl In this work we have studied reactions of symmetric enol ethers
group as 2. The reaction can be carried out with or without with hydrazine hydrate according to Scheme 2. The enol ethers
Lewis acid catalysis [2].
ethoxymethylidenemalononitrile (EMMN, 3a), dimethyl
methoxymethylidenemalonate (MMMM, 3b), diethyl
ethoxymethylidenemalonate (EMME, 3c), and 3-(ethoxy-
methylidene)pentane-2,4-dione (EMAA, 3d) were employed.
Three-component reactions (hydrazine + trialkylorthoformate +
active methylidene component) were not studied.
The products resulting from the reaction of a hydrazine hydrate
with activated symmetrical enol ethers 3 are shown in
Scheme 3.
Scheme 1: Preparation of enol ethers.
Pyrazoles constitute a large group of pharmacologically active
compounds and are mostly prepared by reacting hydrazines
with suitable 1,3-dielectrophiles. The synthesis of pyrazoles and
related compounds can be implemented by four different
approaches:
1
2
. reaction of (substituted) hydrazines with β-functional
compounds or their equivalents (the most frequently
used method),
Scheme 3: Pyrazoles 5.
. 1,3-dipolar cycloaddition with diazo compounds as a It is well known that the reaction of hydrazine hydrate with
source of N–N linkage,
alkoxymethylidenemalononitrile affords 3-amino-1H-pyrazole-
4-carbonitrile (5a) [8-13]. Eight tautomeric forms of 5a could
3
4
. degradation of fused pyrazoles or
. rearrangement of other monocyclic heterocycles under theoretically be expected (Figure 1). Five of these tauromeric
chemical, thermal or photochemical conditions [4].
forms carry an amino substituent, which is denoted by the third
Scheme 2: Reaction of enol ethers with hydrazine hydrate.
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Beilstein J. Org. Chem. 2014, 10, 752–760.
character being an A in the numbering of these tautomers and are possible for ester compounds 5b and 5c are shown in
the fourth number giving the position of one hydrogen. Three of Figure 3, with the last character of the label being an E indi-
the tautomeric forms of 5a are characterized by an exocyclic cates enol, O denotes oxo, and (Z,E) – HO vs OH/=O
imino function. This is denoted by the third character I in the
numbering and the fourth and fifth numbers giving the posi-
tions of two hydrogens.
Figure 3: Tautomers of 5b (R = Me), 5c (R = Et).
Compound 5b was previously prepared by a ring contraction of
pyrimidine-2,4-dione [19]. It is known from the literature that
after the reaction of ethoxymethylideneacetylacetone (3d) with
hydrazine hydrate 1-(3-methyl-1H-pyrazol-4-yl)ethanone (5d)
Figure 1: Tautomers of 5a.
is produced [20]. The latter bears the tautomerizable acetyl
group so that the tautomeric characteristics are different from
When dimethyl methoxymethylidenemalonate (3b) is used, the previous case and similar to that of 5a (Figure 4). Here, Z/E
methyl 3-hydroxy-1H-pyrazole-4-carboxylate (5b) is formed. refers to the mutual positions of methyl groups.
Analogously, reaction of diethyl ethoxymethylenemalonate (3c)
gives the corresponding ethyl 3-hydroxy-1H-pyrazole-4-
carboxylate (5c) [14-18]. The Reaction of enol ethers 3b and 3c
with hydrazine hydrate at rt for 10 min gave products of an SNV
reaction, 4b and 4c. These then underwent intramolecular
cyclization to yield 5b and 5c. Due to oxo–enol tautomerism
eight tautomers are theoretically possible (Figure 2). The
labeling scheme of the tautomers of 5b uses an E to indicate the
(
en)ol form and an O to indicate the oxo form.
Figure 4: Tautomers of 5d.
Compared to the procedure described by Mitkidou et al. [20],
we were able to prepare 5d in one step, in a shorter time (1 h
heated under reflux in EtOH) and with a higher yield of 88%.
Mitkidou et al. prepared 5d in a two-step synthesis [20] (8 h
heated under reflux in toluene 55% yield or 2 h in CHCl3) in
6
9% yield. Other preparations of 5d were carried out in aqueous
media [21-23].
Figure 2: Tautomers of 5b (R = Me), 5c (R = Et).
Enol ethers with different alkoxy groups afforded the same
products. Reactions were carried out in ethanol or without a
However, more tautomeric forms of the ester species are solvent. If the ratio enol ether/hydrazine is 1:1, as in the case of
theoretically possible as the C-4 substituent can also be the reaction with 3c, the formation of 7-aminopyrazolo[1,5-
involved in tautomerism. For instance, additional species, which a]pyrimidine-3,6-dicarbonitrile could be expected as a
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Beilstein J. Org. Chem. 2014, 10, 752–760.
byproduct [24,25]. When hydrazine hydrochloride is used [14], O7–C12–O8–C13 to C6 and O3–C10–O4–C11 to C3), while
ethyl 3-ethoxypyrazole-4-carboxylate was obtained in 41% the fourth carbonyl group exhibits an E conformation
yield and the expected ethyl 3-oxo-2,3-dihydropyrazole-4- (O1–C1–O2–C9 to C3). Torsion angles between the carbonyl
carboxylate (5c, oxo form) in 37% yield. The first product was and double C=C bond are 15.9(3)°, 11.1(3)°, 0.6(3)° for the first
obtained as an oil, whereas compound 5c was afforded as a three ester groups (C6–C7–C8–O5, C6–C7–C12–O7,
white powder.
C3–C2–C10–O3) and 152.28(17)° for the last one
O1–C1–C2–C3) (Supporting Information File 1, Table S5).
(
The reversal of the addition by adding hydrazine hydrate drop-
wise to the stirred enol ether led to the bis-N,N´-product 6a in N5–H5A forms an intramolecular hydrogen bond with O3 and
0% yield as a colorless crystalline product and 6b (43% yield) an intermolecular hydrogen bond with O4. N6–H6A forms an
6
as yellowish crystals. This product could not be thermally intramolecular hydrogen bond with O5, while both also form an
cyclized into the corresponding pyrazole derivative, presum- intermolecular hydrogen bond with O5 from the next molecule
ably due to the reduced nucleophilicity of the hydrazine as shown in Table S2. These two hydrogen bonds are in a rhom-
nitrogen bearing the electron-deficient vinyl substituent boid arrangement with angles H6A–O5–H6A 86.10(5)° and
(
Scheme 4). The structure of 6a was confirmed by spectro- O5–H6A–O5 93.90(5)°. Selected interatomic distances, bond
scopic analysis, elemental analysis, and X-ray structure analysis and torsion angles are presented in Supporting Information
Figure 5). File 1, Tables S2, S4 and S5.
(
A sample of compound 6a was recrystallized by slow evapor- NMR measurements
ation from chloroform. X-ray diffraction data (Supporting Infor- The spectra of compounds 5a–d are characterized by broad to
mation File 1, Tables S1–S5) were collected on an Oxford very broad resonance lines, hinting at dynamic processes related
Diffraction Gemini R diffractometer equipped with a Ruby to prototropic tautomerism. It was attempted to record spectra in
CCD detector and Mo Kα sealed-tube source at rt. Data reduc- CDCl3 – where a rapid exchange between tautomeric forms was
tion was performed with Oxford Diffraction CrysAlis RED expected – and in DMSO-d6 solution – where we assumed
version 1.171.33.42 software [26]. The crystal structure was slower interconversion rates due to the acceptor properties of
solved and refined with SHELXS97 [27].
this solvent. However, the solubility in CDCl3 turned out to be
very low for the studied compounds, so that only 1H NMR
The molecule consists of the two parts rotated around the N–N spectra could be obtained from very dilute solutions in this
bond, with the torsion angle C3–N5–N6–C6 −77.0(2)°, while solvent. For all compounds the marked line broadening did not
the N–N bond and adjacent C=C bonds are highly planar with permit the determination of 13C,1H spin coupling constants of
torsion angles 174.09(15)° for C2–C3–N5–N6 and 177.71(16)° the pyrazole C-atoms which, in certain cases, may be employed
for N5–N6–C6–C7. Correspondent bond lengths in the mole- for a rough estimation of the tautomeric composition [28,29].
cule show only minor variations. Three carbonyl bonds in the
ester groups display a Z conformation with regard to the carbon The 1H and 13C NMR spectra of aminonitrile 5a showed one set
atom of the double bond (O5–C8–O6–C14 and of broad signals. The 13C chemical shifts of the pyrazole
Scheme 4: Reactions of hydrazine hydrate with dialkyl alkoxymethylidenemalonates.
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Beilstein J. Org. Chem. 2014, 10, 752–760.
Figure 5: Crystal structure and crystal packing of compound 6a.
C-atoms (δ pyrazole C3(5) 154.1 ppm, δ pyrazole C-4 Methyl 3-hydroxypyrazole-4-carboxylate (5b) shows a distinct
3.5 ppm, and δ of the quaternary pyrazole C5(3) 140.0 ppm) dynamic behavior in DMSO-d6 solution, resulting in broad lines
7
resemble those of ‘fixed’ N-methyl compound 5-amino-1- in the 1H and in the 13C NMR spectra. Comparison of the 13C
methyl-1H-pyrazole-4-carbonitrile (δ C3 139.8 ppm, δ C4 chemical shifts with those of the fixed N-methyl derivatives
7
2.1 ppm, δ C5 151.4 ppm). Thus, it can be assumed that methyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate and
isomer 5aA2 provides a marked contribution to the tautomeric methyl 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylate exhibits
mixture. However, NOE measurement between the pyrazole- a good agreement with the former. Therefore, species 5bE1 can
CH and pyrazole NH hints at the simultaneous presence of be assumed to have the largest contribution to the overall
species 5aA1, where the protons involved are spatially close. tautomeric mixture. It is known from the literature that - given
The noticeable contribution of 5al12 is improbable due to the such a type of compounds – oxo-forms and forms with
presence of an NH2 group in the 1H NMR spectrum. No exocyclic double bonds do not play an important role. The
isomers with sp3 hybridized ring C-atoms or excocyclic double corresponding ethyl ester 5c exhibits the same characteristics as
bonds were detected at all and thus can, at the most, play a its methyl congener 5b. As found with 5c dominance of
marginal role.
tautomer 5cA1 can also be deduced from an inspection of the
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Beilstein J. Org. Chem. 2014, 10, 752–760.
1
3C NMR spectrum in DMSO-d6 solution. In Supporting Infor- Quantum-chemical calculations
mation File 1, Tables S6 and S7 signals for compounds 5a–d in To support the experimental results were also performed DFT
CDCl3 and DMSO-d6 solution are reported whenever measure- (Density Functional Theory method) calculations by using the
ment was possible.
B3LYP hybrid functional [31-33] and 6-311++G** basis sets of
the Gaussian basis set library [34]. The SCRF theory via the
An interesting feature was observed in the NMR spectra of IEFPCM (Integral Equation Formalism Polarizable Continuum
compound 6a (Figure 6) (IUPAC name: tetramethyl 2,2'-(1,2- Model) model including the effect of the solution was applied to
hydrazinediyldimethylylidene)dimalonate). In CDCl3 solution a optimize the geometries in (m)ethanol and DMSO. The stability
mixture of the symmetrical form A and an unsymmetrical, of the obtained structures was proven by vibrational analysis
tautomeric form B was observed (ratio A:B ~ 2:3, Figure 6). (no imaginary vibrations).
The symmetric structure of A can be derived from the fact that
in the 1H,15N HMBC spectrum of A there is only one 15N reso- NMR chemical shifts δ (in ppm) were evaluated from the
nance. This resonance consists of residual signals from the corresponding absolute shieldings σ calculated for vacuum
incompletely suppressed direct coupling (1J(15N,1H) geometry by using the Gauge-Independent Atomic Orbital
~
105.9 Hz) and an additional correlation caused by the geminal (GIAO) method [35] at B3LYP/6-311++G** level of theory
2
J(N–N–H) coupling. The compound is stabilized by strong according to the linear equation
intramolecular hydrogen bonds between the NH and the ‘cis’-
located ester carbonyl O-atom. This situation gives rise to a
sharp, deshielded resonance of NH (δ 10.38 ppm), which is split
into a doublet (3J = 11.0 Hz) due to the coupling with the
(1)
alkene-H (δ 8.05 ppm). The ester moiety involved in the with a = 31.0 ± 0.8 ppm , b = −0.97 ± 0.03 for X = 1H [36],
intramolecular hydrogen bond exhibits a marked downfield a = 175.7 ± 0.2 ppm , b = −0.963 ± 0.003 for X = 13C [37] and
shift for C=O (δ 168.5 ppm) in comparison to the other ester a = −152.0 ± 1.1 ppm , b = −0.946 ± 0.008 for X = 15N [37].
carbonyl C-atom (δ 164.7 ppm), which is typical for such a situ- The Gaussian09 [34] software was used for all calculations.
ation [30]. The small chemical shift for the quaternary alkene
C-atom (δ 93.0 ppm) is characteristic for a polarized C=C bond Products 5 are formed during reactions in which the propor-
in this push–pull configuration. One half of the isomer B shows tions of tautomers can theoretically correspond to the propor-
the same characteristics as A , that is, the intramolecular tion of tautomers by the Boltzmann distribution obtained from
hydrogen bond between NH and the ester C=O. However, the theoretical calculations at 293.15 K. However, the calculated
second half of the molecule has two equivalent ester moieties proportion of tautomers does not include the effects of the reac-
and a C=N bond instead of a C=C bond leading to an sp3 tion conditions and kinetics factors on the final proportion of
hybridized C-atom (δ 54.8 ppm) between the equivalent methyl individual tautomers in solution.
ester groups. The two different N-atoms in B have 15N chem-
ical shifts of −48.1 ppm (C=N) and −211.7 ppm (=N–NH) Total electronic IEFPCM-B3LYP/6-311++G** energies with
(
Figure 6).
zero-point corrections E(DFT) and relative energies of
Figure 6: Key 1H (red), 13C (black) and 15N (blue) NMR chemical shifts (δ, ppm) in isomers A and B of compound 6a. [DFT data are in square
brackets.]
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Beilstein J. Org. Chem. 2014, 10, 752–760.
tautomers ΔE(DFT) of studied compounds are summarized in Measured NMR spectra indicate two tautomers of compound 6a
Supporting Information File 1, Tables S8–S11. The most stable in chloroform solutions which differ in a single H atom pos-
structural form in the 5a series is the 5aA1 tautomer (56% in ition within the central >C–C–N–N–C–C< chain (at N or at
ethanol) closely followed by the 5aA2 tautomer (44% in tertiary C atom). A third tautomer with both H atoms at tertiary
ethanol), which is less stable in both ethanol and DMSO by C atoms was not detected. DFT geometry optimization
only 0.6 and 0.4 kJ·mol−1, respectively. The remaining confirmed the existence of all three tautomers (Figure 7,
tautomers are probably absent in solution because Supporting Information File 1, Tables S2–S5 and S14) but
their energies are more than 85 kJ·mol−1 higher than the 5aA1 because of energy reasons the relative population of the C
tautomer in both solutions (Supporting Information File 1, conformer must be vanishing in agreement with experimental
Table S8). This is in agreement with experimental NMR data. This was confirmed by calculated NMR spectra
spectra.
(Supporting Information File 1, Table S15). Nevertheless, DFT
data indicate a much lower proportion of the B conformer than
For the 5b series the most stable tautomer is 5bE1 (83% in implied by the experimental data. In contrast to the A tautomer,
methanol) followed by 5bE2 (17% in methanol), which is less the B and C tautomers have planar >C–C–N–N–C–C< chains.
stable by approximately 4 kJ·mol−1 both in methanol and
DMSO. The remaining tautomers are again probably absent in
both solutions because their energies are significantly higher in
comparison with the most stable 5bE1 tautomer. The tautomers
without hydrogens at pyrazole nitrogen atoms (5bE3, 5bE4,
5
bE5, 5bO45, 5bE4Z and 5bE4E) exhibit the lowest stability
(
energy difference is ca 60 kJ mol−1) (Supporting Information
File 1, Table S9). This is in agreement with experimental NMR
spectra.
As expected, in the case of the 5c series the most stable
tautomer is 5cE1 (83% in ethanol) followed by 5cE2 (17% in
ethanol), which is less stable by approximately 4 kJ·mol−1 both
in ethanol and DMSO, similar to the 5b series. The remaining
tautomers are not present in solution and the stability depend-
ence on the presence of hydrogen at pyrazole nitrogen atoms is
similar as above (Supporting Information File 1, Table S10).
This is in agreement with experimental NMR spectra.
In the 5d series, the most stable tautomer is 5dA2 (70% in
ethanol) followed by 5dA1 (30%) which is less stable by
2
kJ·mol−1 both in ethanol and DMSO. The remaining
tautomers have no hydrogens at pyrazole nitrogen atoms and
their energies are higher by more than 95 kJ·mol−1 higher
compared to the two most stable tautomers (Supporting Infor-
mation File 1, Table S11).
All stable tautomers of the 5a–d series (Supporting Information
File 1, Tables S12 and S13) present in solutions have one
hydrogen atom at one of the pyrazole nitrogen atoms and, as
indicated by the calculated NMR spectra in DMSO, the shift of
this hydrogen should be 7.9–8.7 ppm. The single hydrogen at
the pyrazole carbons (the same carbon atom in all tautomers of
all series) has a shift of 7.2–7.7 ppm and its carbon has a shift of
1
26.4–143.3 ppm. The calculated shift differences are insuffi-
cient to identify the tautomer in solutions and can only be used
to exclude some tautomers.
Figure 7: DFT optimized isomers of compound 6a. (Distances are in
Å, angles are in degrees.)
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Beilstein J. Org. Chem. 2014, 10, 752–760.
X-ray and DFT optimized structures of the A tautomer exhibit and APVV-0038-11) and the Scientific Grant Agency of the
significant differences in torsional angles only (see Supporting Slovak Republic (Project VEGA 1/0829/14).
Information File 1, Tables S2–S5) ascribable to solid state
effects. The accuracy of the calculated NMR data is insufficient References
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