An unusual thionyl chloride-promoted c?c bond formation to obtain 4,4'-bipyrazolones

Article abstract of DOI:10.3762/bjoc.14.110

Dialkyl 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylates are readily obtained by the reaction of 5-hydroxypyrazole-4-carboxylates in refluxing thionyl chloride. The obtained diesters can be transformed into the corresponding 4,4'-bipyrazoles via alkaline hy

Full text of DOI:10.3762/bjoc.14.110

An unusual thionyl chloride-promoted C−C bond formation to
obtain 4,4'-bipyrazolones
Gernot A. Eller1, Gytė Vilkauskaitė1,2, Algirdas Šačkus2,3, Vytas Martynaitis2,
Ashenafi Damtew Mamuye1, Vittorio Pace1 and Wolfgang Holzer*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1287–1292.
1Department of Pharmaceutical Chemistry, Faculty of Life Sciences,
University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria,
2Department of Organic Chemistry, Kaunas University of Technology,
Radvilėnų pl. 19, LT-50254 Kaunas, Lithuania and 3Institute of
Synthetic Chemistry, Kaunas University of Technology, K. Baršausko
g. 59, LT-51423, Kaunas, Lithuania
doi:10.3762/bjoc.14.110
Received: 05 March 2018
Accepted: 14 May 2018
Published: 04 June 2018
Associate Editor: T. P. Yoon
Email:
Wolfgang Holzer* - wolfgang.holzer@univie.ac.at
© 2018 Eller et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
dimerization; NMR (1H; 13C; 15N); pyrazolones; thionyl chloride; X-ray
structure analysis
Abstract
Dialkyl 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylates are readily obtained by the reaction of 5-hydroxypyrazole-4-carboxylates in
refluxing thionyl chloride. The obtained diesters can be transformed into the corresponding 4,4'-bipyrazoles via alkaline hydrolysis
and subsequent decarboxylation. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products pre-
pared. Moreover, the structure of a representative 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylate was confirmed by X-ray crystal
structure analysis.
Introduction
Many biologically active substances, therein several drug mole- uents at the pyrazole C4 position, like 5-chloropyrazole-4-
cules, agrochemicals, dyestuffs, compounds for optoelectronic carbaldehydes or 4-esters, turned out to be particularly useful
purposes, complexing ligands and more contain a pyrazole due to the easy conversion of the chloro substituent into other
nucleus [1-8]. Condensed pyrazoles are of special interest, as a functional groups or its nature as a good leaving group in ring-
commonly used example the phosphodiesterase 5 (PDE5) inhib- closure reactions. In this respect we were interested in a conve-
itor sildenafil (Viagra®) can be mentioned [1]. In a series of nient access to 1-substituted or 1,3-disubstituted 5-chloropyra-
former publications we described the synthesis of condensed zole-4-carboxylates required as valuable precursors for further
pyrazole systems using various 4,5-disubstituted pyrazole deriv- functionalizations. Such compounds have been mainly pre-
atives as precursors for the annellation reaction [9-16]. pared from the corresponding 5-aminopyrazole-4-carboxylates
Amongst these precursors 5-chloropyrazoles carrying C-substit- via (non-aqueous) diazotation and subsequent reaction with
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appropriate chlorine sources [17,18]. Additionally, some years
ago we have presented a synthetic approach upon Vilsmeier
reaction of 1-phenylpyrazolones with DMF/excessive POCl3 to
afford 5-chloropyrazole-4-carbaldehydes, which were oxidized
to the corresponding acids (KMnO4) and subsequently con-
verted into the ethyl esters by treatment with EtOH/H2SO4 [15].
However, as the latter approach is tedious and the former one
uses toxic substances we envisaged to convert the easily avail-
able 5-hydroxypyrazole-4-carboxylates 1 into the correspond-
ing 5-chloro derivatives 2 by the action of an appropriate chlori-
nating agent such as POCl3 or SOCl2 (Scheme 1). Such conver-
sions of a hydroxy (oxo) into a chloro function is very common
with many N-heterocyclic systems, such as, for instance the
transformations of 2-pyridones into 2-chloropyridines or 3-pyri-
dazinones into 3-chloropyridazines [19,20]. In the course of the
preparation of substituted 6H-pyrazolo[4,3-d][1,2]oxazoles we
thus obtained the required 4-benzoyl-5-chloropyrazoles by
treatment of the relevant 4-benzoyl-5-hydroxypyrazoles with
POCl3 [21].
Scheme 2: Synthesis of bipyrazolone 3a.
Scheme 1: Envisaged approach for the synthesis of 5-chloropyrazole-
4-carboxylates 2.
Results and Discussion
Chemistry
Figure 1: Signal of the OCH2 ester protons of reaction product 3a
(500 MHz, CDCl3).
However, the attempted reaction of ester 1a (R1 = Ph, R2 = H,
R = Et) with POCl3 left the starting material untouched, simi- firmed the molecular formula. The non-equivalence of the
larly by treatment of 1a with oxalyl chloride no conversion OCH2 protons of the ester functions can be smoothly explained
occurred (Scheme 2). In contrast, treatment of 1a with exces- by the presence of an asymmetric carbon atom at pyrazole
sive thionyl chloride at reflux temperature resulted in a defined C4/C4'. As the NMR spectra displayed a single set of signals,
reaction product which, however, could not be the desired regarding the stereochemistry a racemic mixture or the meso-
5-chloro derivative 2a according to – amongst others – a much form came into consideration.
too large chemical shift of pyrazole C5 (δ 165.6 ppm) com-
pared to the expected one (δ 131.3 ppm) [15]. Moreover, the The single crystal X-ray analysis disclosed that the molecule of
OCH2 protons revealed to be of diastereotopic character which the newly obtained compound 3a consists of two pyrazolone
hints to the presence of a chiral center in the molecule residues, which are directly connected to each other by a single
(Figure 1), while the molecular weight obtained by HRMS mea- covalent carbon–carbon bond between the asymmetric sp3-
surement ([M + Na]+ 485.1432) testified about the possible for- hybridized C4 and C4' carbon atoms to form a species with rela-
mation of a dimeric structure.
tive (4R*,4'R*)-configuration (Figure 2). The bond length of the
single C4–C4' bond is 1.544(3) Å, while the dihedral angle
Lastly, by X-ray crystal structure analysis the obtained product C5–C4–C4'–C5' is 47.94°. The packaging of the chiral mole-
could be determined as the dimeric structure 3a (Scheme 2, cules (4R,4'R)-3a and (4S,4'S)-3a into a racemic crystal occurs
Figure 2). In addition, HRMS and elemental analysis con- in such a way that mirror enantiomers are interconnected to
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Beilstein J. Org. Chem. 2018, 14, 1287–1292.
Figure 3: Arrangement (4R,4'R)- and (4S,4'S)-3a enantiomers in the
crystal unit drawn with 50% displacement ellipsoids. The hydrogen
bonds are shown by dashed lines. Supplementary crystallographic
data for compound 3a can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif (CCDC 979625).
Figure 2: ORTEP-plot of the crystal structure of compound 3a drawn
with 50% displacement ellipsoids [(4S,4'S)-3a enantiomer is shown
only]. The length of the C4–C4' bond connecting the two pyrazolone
units is 1.544(3) Å. For details see the Supporting Information File 1.
SOCl2) and in all cases the corresponding dimers of type 3 were
obtained in moderate to good yields (Scheme 3).
In order to check if these dimerization reactions also occur with
other 5-hydroxypyrazoles carrying a C=O function at pyrazole
C4 we subjected ketone 4 and hydrazide 5 to the same reaction
each other by weak intermolecular hydrogen bonds (C–H···O
2.523 Å, 130.64°, Figure 3).
In the following, related 5-hydroxypyrazol-4-carboxylates 1b–i conditions. In both cases, a plethora of unidentified products
were subjected to the same reaction conditions (refluxing resulted (Scheme 4). In contrast, with aldehyde 6 a reaction
Scheme 3: Synthesis of compounds 3a–i.
Scheme 4: Reaction of different 5-hydroxypyrazoles with thionyl chloride.
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product could be isolated in moderate yield, which can be Moreover, we investigated the reaction of 1a with SO2Cl2.
assigned to structure 7 considering NMR data and mass spectra Here, two reaction products – 8 and 9 – were isolated, whereas
(Scheme 4).
in both cases chlorination not only at the pyrazole C4 but also in
the 4-position of the phenyl ring took place (Scheme 5).
The dehydrogenative homocoupling of 2-pyrazolin-5-ones (or
pyrazolidin-5-ones) is well documented in the literature and
proceeds under different reaction conditions such as, for
instance, by air oxidation [22], under O2 atmosphere using an
O2 balloon [23], by organic peroxides [24], phenoxy radicals
[25], by treatment with phenylhydrazine at high temperatures
[26,27], by nitrosation and subsequent heating [28], by heating
with an aqueous NaHSO3 solution [29], and by photochemistry
[30,31]. In nearly all cases these reactions have been carried out
with 2-pyrazolin-5-ones unsubstituted at pyrazole C4 position
or with derivatives carrying an alkyl or aryl substituent at the
latter carbon atom. In contrast, only very few examples are de-
scribed for pyrazolones with a C=O substructure attached to
Scheme 5: Reaction of 1a with sulfuryl chloride.
pyrazole C4. Thus, 3-methyl-1-phenyl-4-toluoyl-5-pyrazolone The reaction mechanism for the transformation 1 → 3 is
(= (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(4-methyl- unclear. Dimerization by air oxidation can be ruled out as per-
phenyl)methanone) upon treatment with oxovanadium(V) com- forming the reaction under N2 atmosphere provided the same
pounds afforded the corresponding 2,2',4,4'-tetrahydro-3H,3'H- result. It should be mentioned that for the oxovanadium(V)-
4,4'-bipyrazole-3,3'-dione, whereas it was shown by EPR spec- mediated dimerization of 4-aroyl-5-hydroxypyrazoles
troscopy and by cyclic voltammetry that the reaction obviously mentioned above a radical mechanism was postulated [32].
proceeds via a radical mechanism [32]. To the best of our However, in Scheme 6 we propose a hypothetical mechanism
knowledge, the only such dimeric species with ester functions at comprising a redox cyclization of an intermediate di(pyrazolyl)
pyrazole C4, namely diethyl 1,1'-dimethyl-5,5'-dioxo-1,1',5,5'- sulfite under elimination of sulfur monoxide.
tetrahydro-4H,4'H-4,4'-bipyrazole-4,4'-dicarboxylate (structure
3 with R1 = Me, R2 = H, R = Et) has been obtained – amongst Finally, it was shown by means of some selected examples, that
other reaction products – by UV–vis irradiation of 4-ethoxy-2- compounds of type 3 can be converted into the corresponding
methyl-5-morpholino-3(2H)-pyridazinone (emorfazone) in bipyrazoles 10 upon alkaline hydrolysis and subsequent
acetonitrile [31].
decarboxylation (Scheme 7). According to the NMR spectra,
Scheme 6: Possible reaction mechanism for the transformation 1 → 3.
Scheme 7: Preparation of bipyrazoles 10.
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Beilstein J. Org. Chem. 2018, 14, 1287–1292.
ORCID® iDs
Vittorio Pace - https://orcid.org/0000-0003-3037-5930
compounds 10 are obviously present as 5-hydroxypyrazoles due
to the absence of a proton attached to pyrazole C4.
References
NMR spectroscopic investigation
1. Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances, 3rd ed.; Thieme: Stuttgart/New York, Germany/USA,
1999.
In Supporting Information File 1 the NMR spectroscopic data
of all compounds treated within this study are indicated. Full
and unambiguous assignment of 1H, 13C and nearly all
15N NMR resonances was achieved by combining standard
NMR techniques [33], such as fully 1H-coupled 13C NMR spec-
tra, APT, gs-HSQC, gs-HMBC, gs-HSQC-TOCSY, COSY,
TOCSY and NOESY spectroscopy. Figure 4 shows the thus
assigned 1H, 13C and 15N NMR chemical shifts for model com-
pound 3a.
2. Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Pyrazoles as drugs:
facts and fantasies. In Targets In Heterocyclic Systems: Chemistry and
Properties; Attanasi, O. A.; Spinelli, D., Eds.; Italian Society of
Chemistry: Rome, 2002; Vol. 6, p 52.
3. Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A.
Chem. Rev. 2011, 111, 6984–7034. doi:10.1021/cr2000459
4. Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman. New J. Chem. 2017, 41,
16–41. doi:10.1039/C6NJ03181A
5. Pèrez-Fernández, R.; Goya, P.; Elguero, J. ARKIVOC 2014, No. ii,
233–293. doi:10.3998/ark.5550190.p008.131
6. Schmidt, A.; Dreger, A. Curr. Org. Chem. 2011, 15, 1423–1463.
doi:10.2174/138527211795378263
7. Lamberth, C. Heterocycles 2007, 71, 1467–1502.
doi:10.3987/REV-07-613
8. Elguero, J. Pyrazoles and their Benzo Derivatives. In Comprehensive
Heterocyclic Chemistry; Katrizky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984; Vol. 5, pp 167–303.
9. Milišiūnaitė, V.; Arbačiauskienė, E.; Bieliauskas, A.; Vilkauskaitė, G.;
Šačkus, A.; Holzer, W. Tetrahedron 2015, 71, 3385–3395.
doi:10.1016/j.tet.2015.03.092
10.Vilkauskaitė, G.; Schaaf, P.; Šačkus, A.; Krystof, V.; Holzer, W.
ARKIVOC 2014, No. ii, 135–149. doi:10.3998/ark.5550190.p008.188
11.Palka, B.; Di Capua, A.; Anzini, M.; Vilkauskaitė, G.; Šačkus, A.;
Holzer, W. Beilstein J. Org. Chem. 2014, 10, 1759–1764.
doi:10.3762/bjoc.10.183
Figure 4: 1H NMR (italics), 13C NMR (normal letters) and 15N NMR (in
bold) chemical shifts of 3a (in CDCl3).
12.Holzer, W.; Vilkauskaitė, G.; Arbačiauskienė, E.; Šačkus, A.
Beilstein J. Org. Chem. 2012, 8, 2223–2229. doi:10.3762/bjoc.8.251
13.Arbačiauskienė, E.; Vilkauskaitė, G.; Šačkus, A.; Holzer, W.
Eur. J. Org. Chem. 2011, 1880–1890. doi:10.1002/ejoc.201001560
14.Eller, G. A.; Vilkauskaitė, G.; Arbačiauskienė, E.; Šačkus, A.;
Holzer, W. Synth. Commun. 2011, 41, 541–547.
Conclusion
The reaction of 5-hydroxypyrazole-4-carboxylates 1 with
thionyl chloride does not lead to the corresponding 5-chloropy-
razole congeners but induces dimerization to afford the rele-
vant dialkyl 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylates of
type 3.
doi:10.1080/00397911003629382
15.Datterl, B.; Tröstner, N.; Kucharski, D.; Holzer, W. Molecules 2010, 15,
6106–6126. doi:10.3390/molecules15096106
16.Fuchs, F. C.; Eller, G. A.; Holzer, W. Molecules 2009, 14, 3814–3832.
doi:10.3390/molecules14093814
Supporting Information
17.Beck, J. R.; Gajewski, R. P.; Lynch, M. P.; Wright, F. L.
J. Heterocycl. Chem. 1987, 24, 267–270. doi:10.1002/jhet.5570240151
18.Yamamoto, S.; Morimoto, K.; Sato, T. J. Heterocycl. Chem. 1991, 28,
1545–1547. doi:10.1002/jhet.5570280613
Supporting Information File 1
Experimental details and compound characterization.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-110-S1.pdf]
19.Comins, D. L.; Joseph, S. P. Pyridines and their Benzo Derivatives:
Reactivity at the Ring. In Comprehensive Heterocyclic Chemistry II;
Katrizky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon: Oxford,
1997; Vol. 5, p 63.
20.Haider, N.; Holzer, W. Sci. Synth. 2004, 16, 125–249.
21.Holzer, W.; Hahn, K. J. Heterocycl. Chem. 2003, 40, 303–308.
doi:10.1002/jhet.5570400216
Acknowledgements
Ashenafi Damtew Mamuye thanks the University of Sassari
(Italy) for awarding a Ph.D. visiting grant for a stay at the
University of Vienna (Austria). The authors are grateful to Mr.
S. Belyakov (Latvian Institute of Organic Synthesis, Riga) for
performing the X-ray analysis and to one of the referees for
assistance with the proposed reaction mechanism.
22.Veibel, S. Acta Chem. Scand. 1972, 26, 3685–3690.
doi:10.3891/acta.chem.scand.26-3685
23.Sheng, X.; Zhang, J.; Yang, H.; Jiang, G. Org. Lett. 2017, 19,
2618–2621. doi:10.1021/acs.orglett.7b00951
1291

Beilstein J. Org. Chem. 2018, 14, 1287–1292.
24.Xue, F.; Bao, X.; Zou, L.; Qu, J.; Wang, B. Adv. Synth. Catal. 2016,
358, 3971–3976. doi:10.1002/adsc.201601070
25.Schulz, M.; Meske, M. J. Prakt. Chem./Chem.-Ztg. 1993, 335,
607–615. doi:10.1002/prac.19933350706
26.Knorr, L.; Haber, F. Ber. Dtsch. Chem. Ges. 1894, 27, 1151–1167.
doi:10.1002/cber.189402701233
27.Bernstein, J.; Stearns, B.; Dexter, M.; Lott, W. A. J. Am. Chem. Soc.
1947, 69, 1147–1150. doi:10.1021/ja01197a047
28.Hüttel, R.; Authaler, A. Chem. Ber. 1963, 96, 2879–2893.
doi:10.1002/cber.19630961109
29.Li, Z.; Chu, G.; Zeng, Y.; Zhu, L.; Ye, H.; Huang, H.; Li, W.; Chao, Y.;
Yu, L. Chin. Pat. CN 10218083 A, Sept 14, 2011.
Chem. Abstr. 2011, 1173728.
30.Eğe, S. N.; Tien, C. J.; Dlesk, A.; Potter, B. E.; Eagleson, B. K.
J. Chem. Soc., Chem. Commun. 1972, 682–683.
doi:10.1039/C39720000682
31.Maki, Y.; Shimada, K.; Sako, M.; Kitade, Y.; Hirota, K.
Chem. Pharm. Bull. 1988, 36, 1714–1720. doi:10.1248/cpb.36.1714
32.Remya, P. N.; Suresh, C. H.; Reddy, M. L. P. Polyhedron 2007, 26,
5016–5022. doi:10.1016/j.poly.2007.07.020
33.Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More Basic NMR
Experiments: A Practical Course – Second Expanded Edition;
Wiley–VCH: Weinheim, Germany, 1998.
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