Unexpected synthesis of pyrazolone derivatives

Tetrahedron xxx (2015) 1e4

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Unexpected synthesis of pyrazolone derivatives Olena O. Shyshkina a, *, Volodymyr V. Medviediev a, Oleg V. Shishkin b, c, y, Andrii I. Kysil a, Yulian M. Volovenko a a

Department of Chemistry, Taras Shevchenko National University of Kyiv, 12 L. Tolstoho Str., Kyiv 01033, Ukraine Division of Functional Materials Chemistry, SSI “Institute for Single Crystals” of National Academy of Science of Ukraine, 60 Lenina Ave., Kharkiv 61001, Ukraine c Department of Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody Sq, Kharkiv 61122, Ukraine b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 November 2014 Received in revised form 17 December 2014 Accepted 23 December 2014 Available online xxx

Unexpected, but simple synthesis of 2,20 -[(3-oxo-3H-pyrazole-4,5-diyl)bis(sulfonyl-methylene)]dibenzoic acid was carried out via nitration of isothiochroman-4-one 2,2-dioxide in the environment of nitric acid. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Isothiochroman-4-one 2,2-dioxide Nitration Pyrazolone X-ray diffraction Cyclization

1. Introduction In many families from different countries, the pyrazolone derivatives, which include dipyrone, antipyrine, aminopyrine and propyphenazone, are widely used analgesics.1 However, the synthesis of pyrazolone ring always requires the participation of the NeN fragment (hydrazine, hydrazide, etc).2 At the same time, sulfones are an important class of compounds that have attracted considerable attention.3 Recognizing the value of this heterocyclic system, chemists continue to develop novel routes for their synthesis. In this paper we introduce the interesting behavior of isothiochromanones in the environment of nitric acid.

Finally, the structure of 2,20 -[(3-oxo-3H-pyrazole-4,5-diyl)bis(sulfonylmethylene)]dibenzoic acid (2a) was proved by X-ray diffraction (Fig. 1), because NMR and IR spectroscopy proved uninformative for interpretation of the structure of this compound. 1H NMR spectra showed the presence of the CH2 group and aromatic protons at 5.58 and 7.53e7.98 ppm, respectively. In the IR spectra there are characteristic intensive band groups of C]O at 1689 and 1630 cm1, but it became clear after the X-ray diffraction study. The molecules of compound 2a in the crystal occupy the special position at the 2 fold symmetry axis crossing via the N2 atom (Fig. 1). Pyrazolone ring is disordered over two positions with equal population.

R

2. Results and discussion The synthesis of isothiochromen-4-one 2,2-dioxides 1a,b has been previously described.4 Transformation of 1H-isothiochromen4(3H)-one 2,2-dioxide are scarcely reported in the literature5 and we resolved to amend this situation. When trying to perform nitration of sulfone 1a under conditions of HNO3/AcOH we synthesized pyrazolone 2a in 78% yield (Scheme 1). * Corresponding author. Tel.: þ38 067 984 1970; e-mail address: [email protected] (O.O. Shyshkina). y Deceased.

COOH

O

O

R

i or ii or iii S

O

O 1a,b

O

O

N

O

R

S S

N O

COOH 2a,b

i: 65% HNO3, RCOOH (R: Me, Et, CF3, CH3CH(Br) ii: 50% HNO3, AcOH or fuming HNO3, AcOH iii: 65% HNO3, heating; R: (a) H; (b) F Scheme 1. Synthesis of 2,20 -[(3-oxo-3H-pyrazole-4,5-diyl)bis(sulfonylmethylene)]dibenzoic acids.

http://dx.doi.org/10.1016/j.tet.2014.12.082 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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Fig. 1. Molecular structure of compound 2a according to X-ray diffraction data with the atom numbering used in the crystallographic analysis. Only one orientation of disordered pyrazolone ring is shown.

If the presence of nitrogen atoms in structure 2, can be to some extent understood, the presence of the additional carbon atom caused surprise. It has been suggested that the additional carbon originates from acetic acid by its oxidation. But the question arises. Which one carbon atom among two of available in acetic acid participates in the transformation? Therefore, acetic acid has been replaced by several other carboxylic acids (propionic acid, trifluoroacetic acid and 2-bromopropionic acid), but the product of the reaction was the same (Scheme 1). Therefore it is possible to suggest that the additional carbon originates from a third molecule of sulfone 1. To confirm this hypothesis we conducted the reaction using a nitric acid as reagent and solvent. Heating the solution of isothiochromanone 1a in 65% nitric acid for 5 min resulted in compound 2a in a yield of 92%. The reaction was accompanied by emission of gas.

The next task, which was successfully solved, was to investigate the influence of nitric acid concentration on the reaction rate. It turned out that replacement of 65% nitric acid with red fuming nitric acid significantly slows down the speed of the reaction, when using the acetic acid as solvent (from 7 days to 2 months). At the same time, when using 50% nitric acid, the reaction occurs more rapidly (4 days). Thus, we can assume that water participates in the formation of pyrazolone 2. Given the above, we proposed a mechanism for this reaction (Scheme 2). In the first step, the nitroenole 3 was formed by nitration of isothiochomanone 1. The crystals of compound 3 are unstable and decompose in air after a few minutes. The structure of compound 3 was proven by X-ray diffraction data only (Fig. 2) due to its high instability. The next steps are opening of the thiopyran ring, nitration of activated methylene group and addition of the second molecule of intermediate 4. We assume that next step is addition of a third molecule of intermediate 4 to the double bond of intermediate 5 with simultaneous elimination of nitric acid. The intermediate 6 is the result of elimination of 2-methyl-5-nitrobenzoic acid under stabilization of the molecule. The formation of 2-methyl-5nitrobenzoic acid results from coordinated orientation of substituents in the 2-methylbenzoic acid, which was eliminated during the reaction. Under the influence of SO2, as a reductant, there are full and partial reductions of the nitro groups, which can be regarded as aromatic and aliphatic nitro groups, respectively. At the same time we must remember that the nitrozo group is an analog of the carbonyl group. Consequently, we can assume that the next step is

Scheme 2. Possible mechanism of the reaction synthesis on the example of 2,20 -[(3-oxo-3H-pyrazole-4,5-diyl)bis(sulfonylmethylene)] dibenzoic acid (2a).

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standards. IR spectra were obtained on a Perkin Elmer BX II spectrometer in KBr tablets and are reported in cm1. Elemental analysis (C, H, N, S) determined by means of a Vario MICRO Cube CHNOS elemental analyzer (Elementar Analysensysteme GmbH). 4.1. 2,20 -[(3-Oxo-3H-pyrazole-4,5-diyl)bis(sulfonylmethylene)]di-benzoic acids 2a,b

Fig. 2. Molecular structure of nitroenole 3 according to X-ray diffraction data with the atom numbering used in the crystallographic analysis. Thermal ellipsoids are drawn at 50% probability level.

a reaction, which is similar to Knoevenagel condensation and form compound 2. To confirm the proposed mechanism a wet filter paper with an alcohol solution of iodine was appended during synthesis to neck flask. Discoloration of iodine on the filter paper (J2/2J) indicates that the evolved gas in the reaction is SO2. Featuring sulfur in the þ4 oxidation state, sulfur dioxide is a reducing agent. Given that the oxidation of sulfur dioxide is used in the production of sulfuric acid. It can be assumed that sulfur dioxide is oxidized to sulfate ion in the reduction of nitro groups. The presence of sulfate ions was proven by barium chloride. One more proof of the proposed mechanism is the presence in the filtrate of 2-methyl-5nitrobenzoic acid, which was identified by comparing the spectral data with the literature.6 Pyrazolone 2b was obtained in 80% yield on boiling in nitric acid (Scheme 1). The structure of compound 2b was confirmed using 1H NMR, which showed the presence of two signals from the methylene groups at 5.50 and 5.51 ppm, respectively. In the IR spectra there are characteristic intensive band groups of C]O like in the pyrazolone 2a. At the same time, nitration of thiopyranon 7 under identical condition (65% HNO3/AcOH) gave the acid 8 in yield of 86%. 4(Methylsulfonyl)butanoic acid (8) was identified by comparing the spectral data with the literature.7 The synthesis of thiopyran-3-one 1,1-dioxide 8 has been previously described (Scheme 3).8

O 65% HNO3 S

O

AcOH

O

O

O

HO

S

O

8

Scheme 3. Synthesis of 4-(methylsulfonyl)butanoic acid.

3. Conclusion In summary, we have described the novel, simple and interesting method for the synthesis of pyrazolone ring. 4. Experimental section All commercially available chemicals were purchased from Aldrich and Merck. Melting points were determined on a Mel-Temp capillary apparatus. 1H and 13C spectra were recorded on a Varian Mercury 400 spectrometer at 400.45 MHz and 100.70 MHz, respectively using DMSO-d6 as solvent and Me4Si as internal

A: To a solution of isothiochroman-4-one 2,2-dioxide 1a (0.2 g, 1 mmol) in carboxylic acid (2 ml) was added HNO3 (0.3 ml, 6.6 mmol, 65%), the mixture was left at room temperature for 7e30 days. The precipitate was filtered off, washed with MeOH (2 ml) and dried.

Carboxylic acid

Reaction time, days

Yield, %

CH3COOH CH3CH2COOH CF3COOH CH3CH(Br)COOH

7 8 30 17

78 50 69 32

B: Compound 1a (0.2 g, 1 mmol) was dissolved in acetic acid (2 ml). Then HNO3 (0.3 ml, 6.2 mmol, 50%) was added and the mixture was left at room temperature for 4 days. The precipitate was filtered off, washed with MeOH (2 ml) and dried. The compound 2a was obtained in 81% yield. C: To a solution of isothiochroman-4-one 2,2-dioxide 1a (0.2 g, 1 mmol) in acetic acid (2 ml) was added red fuming HNO3 (0.3 ml, 7.2 mmol), the mixture was left at room temperature for 2 months. The precipitate was filtered off, washed with MeOH (2 ml) and dried. The compound 2a was obtained in 49% yield. D: Compound 1a,b (1 mmol) was dissolved in nitric acid (1 ml, 22.1 mmol, 65%). Reaction mixture was heated at reflux for 5 min and then cooled to room temperature. The precipitate was filtered off, washed with methanol and dried. The compound 2a,b was obtained in 92% and 80% yields, respectively. 2a: White crystals from MeOH; mp 229e230  S; 1H NMR, ppm: d 5.58 (s, 4H, CH2), 7.53e7.59 (m, 4H, ArH), 7.65 (t, J¼7.0 Hz, 2H, ArH), 7.94 (d, J¼7.8 Hz, 1H, ArH), 7.97 (d, J¼7.8 Hz, 1H, ArH), 13.44 (br s, 2H, PH); 13C NMR, ppm: 59.4, 60.5, 114.8, 127.1, 127.9, 130.3, 130.4, 131.6, 131.6, 131.8, 132.2, 133.1, 135.3, 135.3, 155.2, 168.7, 168.8; IR, cm1: 3457OH, 1689C]O, 1630C]O, 1352SO2(as), 1132SO2(s). Analysis calculated for S19H14N2O9S2: S, 47.70; H, 2.95; N, 5.85; S, 13.40. Found: S, 48.03; H, 3.27; N, 6.01; S, 13.78. 2b: White crystals from MeOH; mp 226e228  S; 1H NMR, ppm: d 5.50 (s, 2H, CH2), 5.51 (s, 2H, CH2), 7.36 (m, 2H, ArH), 7.61e7.69 (m, 4H, ArH); 13C NMR, ppm: 58.0, 59.1, 113.7, 117.6 (2JC-F¼49 Hz), 117.8 (2JC-F¼55 Hz), 119.0 (2JC-F¼39 Hz), 119.2 (2JC-F¼45 Hz), 122.8, 123.6, 133.3, 133.7, 136.6, 136.7, 136.8, 154.2, 161.0 (1JC-F¼99 Hz), 163.4 (1JC1 F¼96 Hz), 166.8, 166.9; IR, cm : 3458OH, 1687C]O, 1632C]O, 1355SO2(as), 1138SO2(s). Analysis calculated for S19H12F2N2O9S2: S, 44.36; H, 2.35; N, 5.45; S, 11.47. Found: S, 44.21; H, 2.49; N, 5.51; S, 12.33. 4.2. 4-(Methylsulfonyl)butanoic acid 8 Compound 7 (0.15 g, 1 mmol) was dissolved in acetic acid (2 ml). Then HNO3 (0.3 ml, 6.2 mmol, 65%) was added and the mixture was left at room temperature for 24 h. The precipitate was filtered off and dried. The compound 8 was obtained in 86% yield. White crystals from MeOH; mp 134e136  S; Analysis calculated for S5H10O4S: S, 36.12; H, 6.06; S, 19.29. Found: S, 35.99; H, 6.26; S, 19.05.

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4.3. X-ray diffraction study of compounds 2a and 3 Intensities of reflections were measured on an automatic ‘Xcalibur 3’ diffractometer (graphite monochromated MoKa radiation, CCD-detector u scanning). All structures were solved by direct method using SHELX97 package.9 Positions of the hydrogen atoms were located from electron density difference maps and refined by ‘riding’ model with Uiso¼nUeq of carrier non-hydrogen atom (n¼1.5 for methyl group and n¼1.2 for other hydrogen atoms). Structures were refined by full-matrix least-squares method against F2 in anisotropic approximation for non-hydrogen atoms. Final atomic coordinates, geometrical parameters and crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: þ44 1223 336033; e-mail: [email protected]). CCDC dep. numbers for structures 2a and 3 are 1006992 and 1006990, respectively. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/products/csd/request/. Crystal data for 2a at 110 K: (C19H14N2O9S2, Mr¼478.44), a¼8.7857(4)  A, b¼10.4504(5)  A, c¼20.9088(8)  A, b¼97.450(4) , 3  V¼1903.52(15) A , space group S2/c, Z¼4, Dc¼1.669 g/sm3, m(MoKa)¼0.341 mm1, F(000)¼984. 6402 reflections measured up to 2qmax¼60.0 , 2762 unique (Rint¼0.0276), which were used in all calculations. Refinement was converged at wR2¼0.1341 (all data), R1¼0.0561 (2292 reflections with I>2s(I)), GoF¼1.09. Crystal data for 3 at 293 K: (C9H7NO5S, Mr¼241.11), a¼9.3424(12)  A, b¼9.7868(17)  A, c¼11.857(2)  A, a¼70.808(17) , b¼85.532(14) , g¼71.155(14) ,V¼968.5(3)  A3, space group P-1, Z¼4, Dc¼1.654 g/sm3, m(MoKa)¼0.339 mm1, F(000)¼496. 9115 reflections measured up to 2qmax¼60.1, 4873 unique (Rint¼0.0755), which were used in all calculations. Refinement was

converged at wR2¼0.2488 (all data), R1¼0.0861 (2222 reflections with I>2s(I)), GoF¼0.98. Acknowledgements The authors are grateful to the Analytical Department of Taras Shevchenko National University of Kyiv for performing spectral analysis and Prof. Victoria V. Lipson (Kharkiv, Ukraine), Mykola L. Babak (Kharkiv, Ukraine) for helpful discussion. Supplementary data Supplementary data (copies of the 1H NMR and 13C NMR spectra of 2a,b compounds) related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2014.12.082. References and notes 1. Brogden, R. N. Pyrazolone Deriv. Drugs 1986, 32, 60e70. 2. (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; John Wiley & Sons: New York, NY, 2001; p 1192; (b) Singh, S.; Husain, K.; Athar, F.; Azam, A. Eur. J. Pharm. Sci. 2005, 25, 255e262; (c) Dohutia, C.; Kaishap, P. P.; Chetia, D. Int. J. Pharm. Pharm. Sci. 2013, 5, 86e90. 3. Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon: Oxford, UK, 1993; p 381. 4. Shyshkina, O. O.; Tkachuk, T. M.; Volovnenko, T. A.; Volovenko, Y. M.; Zubatyuk, R. I.; Medviediev, V. V.; Shishkin, O. V. Tetrahedron Lett. 2012, 53, 4296e4299. 5. (a) Shyshkina, O. O.; Popov, K. S.; Gordivska, O. O.; Tkachuk, T. M.; Kovalenko, N. V.; Volovnenko, T. A.; Volovenko, Y. M. Chem. Heterocycl. Compd. 2011, 47, 923e945; (b) Tkachuk, T. M.; Shyshkina, O. O.; Volovnenko, T. A.; Volovenko, Y. M.; Zubatyuk, R. I.; Medviediev, V. V.; Shishkin, O. V. Monatsh. Chem. 2013, 144, 263e271. 6. Gobbi, S.; Cavalli, A.; Negri, M.; Schewe, K. E.; Belluti, F.; Piazzi, L.; Hartmann, R. W.; Recanatini, M.; Bisi, A. J. Med. Chem. 2007, 50, 3420e3422. 7. Truce, W. E.; Knospe, R. H. J. Am. Chem. Soc. 1955, 77, 5063e5067. 8. Shishkin, O. V.; Medvediev, V. V.; Zubatyuk, R. I.; Shyshkina, O. O.; Kovalenko, N. V.; Volovenko, Y. M. CrystEngComm 2012, 14, 8698e8707. 9. Sheldrick, G. Acta Cryst., Sect. A 2008, 64, 112e122.

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