Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents

Article abstract of DOI:10.3762/bjoc.13.90

A synthesis of tetrasubstituted pyrazoles containing two, three or four pyridinyl substituents is described. Hence, the reaction of 1,3-dipyridinyl-1,3-propanediones with 2-hydrazinopyridine or phenylhydrazine, respectively, affords the corresponding 1,3,5-trisubstituted pyrazoles. Iodination at the 4-position of the pyrazole nucleus by treatment with I₂/HIO₃ gives the appropriate 4-iodopyrazoles which served as starting materials for different cross-coupling reactions. Finally, Negishi cross-coupling employing organozinc halides and Pd catalysts turned out to be the method of choice to obtain the desired tetrasubstituted pyrazoles. The formation of different unexpected reaction products is described. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N) were undertaken with all products prepared. Moreover, the structure of a condensation product was confirmed by crystal structure analysis.

Full text of DOI:10.3762/bjoc.13.90

Synthesis of tetrasubstituted pyrazoles containing
pyridinyl substituents
Josef Jansa1,2,3, Ramona Schmidt1, Ashenafi Damtew Mamuye1, Laura Castoldi1,
Alexander Roller4, Vittorio Pace1 and Wolfgang Holzer*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 895–902.
1Division of Drug Synthesis, Department of Pharmaceutical
Chemistry, Faculty of Life Sciences, University of Vienna,
Althanstrasse 14, A-1090 Vienna, Austria, 2Research Institute for
Organic Syntheses (VUOS), Rybitví 296, CZ-533 54
Pardubice-Rybitví, Czech Republic, 3Department of Organic
Chemistry, Faculty of Science, Palacký University, 17. listopadu
1192/12, CZ-771 46 Olomouc, Czech Republic and 4X-ray Structure
Analysis Centre, Faculty of Chemistry, University of Vienna,
Währinger Straße 42, A-1090 Vienna, Austria
doi:10.3762/bjoc.13.90
Received: 14 February 2017
Accepted: 24 April 2017
Published: 12 May 2017
Associate Editor: I. R. Baxendale
© 2017 Jansa et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Wolfgang Holzer* - wolfgang.holzer@univie.ac.at
* Corresponding author
Keywords:
Negishi coupling; NMR (1H; 13C; 15N); pyrazole; pyridine; X-ray
structure analysis
Abstract
A synthesis of tetrasubstituted pyrazoles containing two, three or four pyridinyl substituents is described. Hence, the reaction of
1,3-dipyridinyl-1,3-propanediones with 2-hydrazinopyridine or phenylhydrazine, respectively, affords the corresponding 1,3,5-
trisubstituted pyrazoles. Iodination at the 4-position of the pyrazole nucleus by treatment with I2/HIO3 gives the appropriate
4-iodopyrazoles which served as starting materials for different cross-coupling reactions. Finally, Negishi cross-coupling employ-
ing organozinc halides and Pd catalysts turned out to be the method of choice to obtain the desired tetrasubstituted pyrazoles. The
formation of different unexpected reaction products is described. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were
undertaken with all products prepared. Moreover, the structure of a condensation product was confirmed by crystal structure
analysis.
Introduction
The pyrazole nucleus is a frequently occurring motif in many ligands of complexing agents [9-11]. Multiaryl-substituted
pharmaceuticals [1,2] and biologically active compounds [3,4], pyrazoles are of special interest, with some drug molecules such
agrochemicals [5], dyes [6], fluorescent materials [7,8] and as the nonsteroidal anti-inflammatory agent Lonazolac [12] or
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the well-known COX-2 inhibitor Celecoxib [13] as prominent zation via Negishi cross-coupling [23,24] or halogen–lithium
representatives. Moreover, tetrasubstituted pyrazoles have exchange reaction (Scheme 1). The resulting compounds
shown to act, for instance, as estrogen receptor antagonists amongst others seem to be interesting as potential complexing
[14,15], endothelin antagonists [16], lipoxygenase inhibitors agents.
[17] and special luminophores [18]. For such fully substituted
Results and Discussion
pyrazoles different synthetic approaches have been published.
The most common strategies employ reactions of 1,3-dicar- Chemistry
bonyl compounds or α,β-unsaturated carbonyl compounds with Synthesis of 4-iodopyrazoles 3a–d
substituted hydrazines [4,6,19]. To overcome the drawbacks of As starting materials the symmetrical 1,3-diketones 1a and 1b
this method, namely insufficient regioselectivity [20], other were employed, which were obtained by condensation of ethyl
accesses such as, for instance, regioselective metalations of 2- or 3-pyridinecarboxylates with the appropriate 2- or
N-protected pyrazoles [21] or sequential cross-coupling reac- 3-acetylpyridines following known procedures [25,26]. Reac-
tions starting from 3-iodopyrazole [22] have been described. tion of 1a and 1b with 2-hydrazinopyridine and phenylhydra-
Herein, we report the synthesis of fully substituted pyrazoles zine, respectively, afforded the tri(hetero)arylpyrazoles 2a–d
containing at least two pyridinyl substituents by combining the which were further converted into the corresponding 4-iodopy-
before mentioned approaches: reaction of 1,3-dipyridinyl-1,3- razole derivatives 3a–d by treatment with I2/HIO3 in acetic acid
diketones with arylhydrazines, halogenation of the resulting at 80 °C (Scheme 2). The latter iodination method turned
1,3,5-triarylpyrazoles in the 4-position and further functionali- out to be superior to the reaction of compounds 2 with
Scheme 1: Envisaged general approach for the synthesis of the title compounds.
Scheme 2: Synthesis of 4-iodopyrazoles of type 3.
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N-iodosuccinimide. Species 3a–d served as educts for Cross-coupling reactions
the investigations concerning further functionalization at Initial attempts to react 4-bromopyrazole 5 – obtained from
pyrazole C-4.
reaction of 2a with N-bromosuccinimide – with phenylboronic
acid (or 3-pyridineboronic acid, respectively) in the course of a
Suzuki cross-coupling procedure [27,28] under different reac-
Carboxylation of 4-iodopyrazoles 3a–d
The lithium–iodine exchange proceeded quickly and quantita- tion conditions (for instance Cs2CO3/DMF; Na2CO3/DMF;
tively in case of 3,5-di(pyridin-2-yl)-substituted derivatives Cs2CO3/dioxane–H2O; Na2CO3/dioxane–H2O; Pd(PPh3)4)
3a,b upon treatment with 1.1 equivalents of n-BuLi at −78 °C. always led to dehalogenation and thus to the isolation of 2a as
Subsequent reaction with CO2 led to almost complete conver- the main reaction product accompanied by some biphenyl
sion to 4a,b as detected by TLC (Scheme 3). In contrast, with (Scheme 4). As well, realizing the reaction under microwave
3,5-di(pyridin-3-yl)-substituted derivatives 3c,d, the lithiation assistance (150 °C, 800 W) led to the same result. Employing
reaction was slower and not fully complete, also the subsequent the corresponding iodo derivative 3a as the starting material
reaction with CO2 was more sluggish in comparison to 3a,b again resulted mainly in the formation of 2a (4 equiv Na2CO3/
what resulted in lower yields. The increased reactivity of 3a,b EtOH–H2O 4:1/Pd(dppf)Cl2 5 mol %, 24 h reflux, [29])
compared to 3c,d may be explained by the ability of the former (Scheme 4). The reaction of 3a with phenylmagnesium bro-
to stabilize the intermediate organolithium species by chelation mide under modified ‘Kumada’-conditions [30] (Scheme 4)
due to the pyridine nitrogen atoms. The 4-pyrazolecarboxylates once more gave 2a (dehalogenation) and biphenyl.
4a,b are capable to form intramolecular hydrogen bonds of the
carboxylic OH proton with the neighbouring pyridine nitrogen Subjecting 3a and phenyllithium under the conditions of a
atoms, which is manifested by large chemical shift values ‘Feringa’-coupling [31] resulted in a complex mixture with 2a
(≈18 ppm, in CDCl3) of the concerning OH proton in the as the main product, but also containing biphenyl, traces of the
1H NMR spectra. The marked decrease of the 15N chemical desired product 6a, the homocoupling dimer 7a as well as a
shift of the nitrogen atom of the pyridine attached at pyrazole compound 8, obviously resulting from attack of PhLi to the
C-5 compared to those of the corresponding nitrogen atoms in pyridine system attached to pyrazole N-1 (Scheme 4).
compounds 2a,b and 3a,b (whereas the 15N shift of the pyri-
dine moiety attached to pyrazole C-3 only slightly differs for Negishi cross-couplings with 4-iodopyrazoles 3a–d
compounds 2a,b, 3a,b and 4a,b) strongly hints to the involve- The Negishi cross-coupling reaction with organozinc com-
ment of the former into an intramolecular hydrogen bond as in- pounds [23,24] is a valuable tool for the formation of
dicated in Scheme 3.
C–C bonds, particularly in the presence of functional groups.
Scheme 3: Lithium–halogen exchange and subsequent carboxylation with iodopyrazoles 3a–d.
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Scheme 4: Attempted cross-coupling reactions with 4-halopyrazoles 5 and 3a.
The employed organozinc reagents are relatively reactive (25%) was isolated. Such homocoupling and dehalogenation
nucleophiles undergoing rapid transmetalation with appropriate processes have been also observed in the course of related
transition metal species, for instance palladium salts. This Pd-catalyzed cross-coupling reactions, such as, for instance, in
method has been successfully applied in the synthesis of Suzuki–Miyaura reactions [38]. In contrast, the corresponding
bi(hetero)aryls [32-34] and thus also in those of C-substituted 2-pyridinyl or 2-thienyl organozinc congeners gave much better
pyrazoles [35,36]. In our case, the reaction of iodopyrazoles results with nearly no homocoupling side reactions and only
3a,b with different organozinc derivatives (Scheme 5) few amounts of dehalogenation products observed. The
proceeded smoothly leading to the coupling products 6a,b and reactions were carried out either using 2 equivalents of
9a,b–11a,b in variable yields (19–87%). Firstly, the Pd(PPh3)4 commercially available RZnBr or 3 equivalents of in-situ-pre-
was employed as the catalyst for the reaction of 3a to 9a but pared RZnCl (see Supporting Information File 1). Similarly as
low conversion and considerable dehalogenation were ob- observed in the course of the lithiation/carboxylation reactions
served. Utilization of Pd(dppf)Cl2 as catalyst in THF brought (Scheme 3), low reactivity was detected with precursors 3c,d
much better selectivity, because dehalogenation was practically resulting in conversion rates below 30% (Scheme 5, lowest
not observed, but the conversion was still unsatisfying. Despite trace).
of these results, cocatalysis with CuI [37] was tested and
showed a significant rate-enhancing effect and low portion of An interesting compound was isolated in low yield (≈14%)
dehalogenation. Interestingly, the lowest yields were obtained from the mixture obtained upon the reaction of 3a with
with phenylzinc halides, here the homocoupling products 7a,b (phenylethynyl)zinc bromide. By careful NMR and HRMS
emerged as the predominant reaction products (Scheme 5, analysis the pyrazolo[3,4-a]quinolizin-6-ium structure 12 was
middle trace), probably due to preferable halogen–zinc established, which was confirmed by single crystal X-ray struc-
exchange and subsequent homocoupling. Interestingly, such ture analysis (see Supporting Information File 1), proving also
sterically hindered halides provided homocoupling products iodide as the corresponding anion [39] which acts as a leaving
7a,b in good yields (66% and 48%, respectively). The selec- group in the coupling reaction and also could origin from the
tivity towards these compounds increased with the excess of CuI co-catalyst. A possible explanation for the formation of the
phenylzinc halide. In a model reaction employing 3b and condensation product 12 consists in intramolecular cyclization
2 equivalents of PhZnBr, a mixture of 7b (48%), the desired of the intermediate 4-alkynylpyrazole under the reaction condi-
coupling product 6b (27%) and dehalogenation product 2b tions (Scheme 6).
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Beilstein J. Org. Chem. 2017, 13, 895–902.
Scheme 5: Negishi couplings with 4-iodopyrazoles 3a,b.
Scheme 6: Formation of pyrazoloquinolizin-6-ium iodide 12 upon reaction of 3a with (phenylethynyl)zinc bromide.
NMR spectroscopic investigations
however, by recordings in acetone-d6 solution. Whereas
In Supporting Information File 1 the NMR spectroscopic data for 1a the enol/keto ratio is ≈6.6:1, for the 3-pyridinyl
of all compounds treated within this study are indicated. Full congener 1b it was found to be 187:1. Switching to the
and unambiguous assignment of 1H, 13C and nearly all more polar solvent DMSO-d6 enhances the amount of
15N NMR resonances was achieved by combining standard the keto form to ≈3% (ratio 35:1). The enol forms of
NMR techniques [40], such as fully 1H-coupled 13C NMR spec- compounds 1 show the characteristically large chemical
tra, APT, gs-HSQC, gs-HMBC, gs-HSQC-TOCSY, COSY, shifts for the OH proton (1a: 15.94 ppm, 1b: 16.52 ppm, in
TOCSY and NOESY spectroscopy.
CDCl3).
The 1H and 13C NMR spectra (in CDCl3 solution) of precur- 4-Iodopyrazoles 3a–d are characterized by a marked upfield
sors 1 denote these compounds to be predominantly present in shift of the signal due to pyrazole C-4 compared the corre-
the enol form (Scheme 7). This is in contrast to ref. [25], where sponding precursors 2a–d as a result of the heavy-atom α-effect
only traces of the enol form were detected for 1a, of the iodine atom.
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Scheme 7: Prototropic tautomerism of compound 1a.
The different hydrogen bonding situation in carboxylic acids
4a–d and the resultant consequences for the concerned
15N NMR chemicals shifts have been already mentioned before
(see also Scheme 3).
For all compounds carrying several pyridine moieties in the
same molecule the individual azine systems could be unambigu-
ously discriminated. Expectedly, in all cases the 15N NMR
chemical shifts of the pyridine nitrogens of the azine ring at-
tached to pyrazole N-1 are somewhat smaller than those of the
corresponding pyridine N-atoms in systems attached to pyra-
zole C-3, C-5 (or C-4), whereas the C-3-pyridine nitrogen atom
in many cases was the most deshielded one. The pyridinium-
type nitrogen (N-6) in condensed system 12 shows a character-
istic upfield shift (δN-6 −176.2 ppm) compared to the ‘usual’
15N NMR chemical shifts of 2-pyridinyl systems attached to
pyrazole C-5 (δ ≈ −62 to −70 ppm). This is in perfect agree-
ment with the ≈100 ppm upfield shift observed when switching
from pyridine to pyridine hydrochloride [41,42].
Figure 1: 1H NMR (in italics), 13C NMR and 15N NMR (in bold) chemi-
cal shifts of compound 9a (in CDCl3).
Other interesting phenomena are the unusually large 1H NMR congeners 3c,d gave markedly lower conversion rates in all
chemical shifts for protons H-3 (and more rare H-5) at the pyri- reactions investigated.
dine rings (in pyridine itself δH-3/5 is ≈7.4ppm). Thus, for
instance, in 11a H-3 of C-3 pyridine shows a chemical shift of
Supporting Information
8.09 ppm (whereas the corresponding H-5 has only 7.22 ppm).
A possible explanation is the proximity to nitrogen lone-pairs of
Supporting Information File 1
pyrazole N-2 (or adjacent pyridine-N lone-pairs in suitable con-
formations) which affect the mentioned protons by electrostatic
field effects resulting in markedly higher chemical shifts – as
shown, for instance for 2,2’-bipyridines [43,44] and other
comparable systems [45].
Experimental details and characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-90-S1.pdf]
Acknowledgements
In Figure 1, complete NMR data for the tetrapyridinylpyrazole
9a are displayed, which permits to follow some of the trends
regarding chemical shift considerations discussed above.
We thank Mrs. Fatehme Keramati for experimental contribu-
tions. Josef Jansa thanks Palacký University for awarding a
study visit at the University of Vienna (grant project CZ.1.07/
2.2.00/28.0184). Ashenafi Damtew Mamuye thanks the Univer-
sity of Sassari (Italy) for awarding a Ph.D. visiting grant for a
stay at the University of Vienna.
Conclusion
Pd-catalyzed cross-coupling reactions of iodopyrazoles 3a,b
under standard conditions are characterized by the occurrence
of different (unwanted) products resulting mainly from dehalo-
genation and homocoupling processes. Nevertheless, the
Negishi coupling here seems to be the method of choice for
C–C bond formations at pyrazole C-4. In contrast, 3-pyridinyl
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