- Email: [email protected]
cyclization cascade
Accepted Manuscript Regioselective synthesis of bifuroxanyl systems with the 3nitrobifuroxanyl core via a one-pot acylation/nitrosation/cyclization cascade Leonid L. Fershtat, Alexander A. Larin, Margarita A. Epishina, Alexander S Kulikov, Igor V. Ovchinnikov, Ivan V. Ananyev, Nina N. Makhova PII: DOI: Reference:
S0040-4039(16)30998-4 http://dx.doi.org/10.1016/j.tetlet.2016.08.011 TETL 47982
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
24 June 2016 28 July 2016 3 August 2016
Please cite this article as: Fershtat, L.L., Larin, A.A., Epishina, M.A., Kulikov, A.S., Ovchinnikov, I.V., Ananyev, I.V., Makhova, N.N., Regioselective synthesis of bifuroxanyl systems with the 3nitrobifuroxanyl core via a one-pot acylation/nitrosation/cyclization cascade, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet. 2016.08.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Regioselective synthesis of bifuroxanyl systems with the 3-nitrobifuroxanyl core via a one-pot acylation/nitrosation/cyclization cascade Leonid L. Fershtat,a Alexander A. Larin,a Margarita A. Epishina, Alexander S Kulikov, a Igor V. Ovchinnikov,a Ivan V. Ananyev,b Nina N. Makhovaa* a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky prosp., 119991, Moscow, Russian Federation. Phone: +7 (499) 1355326; Fax: +7 (499) 1355328; E-mail: [email protected] b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,28 Vavilova str., 119991 Moscow, Russian Federation. Fax: +7 (499) 135 5085. E-mail: [email protected]
Abstract. A regioselective method for the synthesis of previously unknown bifuroxanyl systems containing the 3-nitrobifuroxanyl core, based on a cascade of one-pot reactions comprising of the acylation of dinitromethane sodium salt with furoxanyl hydroxamic acid chlorides, nitrosation of the acylation product with NaNO2/AcOH/AcONa, and intramolecular cyclization of the nitrosation product to give the 3-nitrobifuroxanyl moiety, has been developed.
Keywords: bifuroxanyl systems; 3-nitrobifuroxanyl core; acylation; nitrosation; cyclization; cascade reactions.
Since the significant discoveries of Nobel Prize winners, Furchgott, Ignarro, and Murad, in the late 1990s, nitric oxide (NO) has been recognized as an ubiquitous and crucial regulator molecule for cellular metabolism, affecting various physiological and pathophysiological processes. One of the most active areas of medicinal chemistry is the search for compounds
capable of releasing NO (NO donors) and the design of novel NO-donor hybrid drugs capable of releasing this vitally important regulator in the body, either enzymatically, or independently of NO synthases. Compounds that combine NO release while maintaining the activity of the native drug have proved to be useful for the treatment of cardiovascular, inflammatory, bacterial, fungal, viral, parasitic, and ocular diseases as well as cancer. 1 Different types of compounds have been synthesized and tested as NO donors.2 Among them, the furoxan moiety has been the subject of increased attention, pioneered by Gasco, owing to the ability of furoxans to release NO under physiological conditions. This ability to release NO depends on the nature of the substituents on the furoxan ring carbon atoms.3 In particular, the isomeric 3(4)aryl-4(3)nitrofuroxans were found to be among the most effective NO donors, with the 3-nitro isomer being more effective. 4 In addition, nitrofuroxans have attracted attention as potential components of energetic formulations due to a positive formation enthalpy and the presence of two active oxygen atoms in the molecule.5 Our research group has significant experience in the chemistry of furoxans, including the synthesis of effective NO donors.6 Recently, we reported a series of novel polynuclear heterocyclic structures containing, along with the furoxan ring, pharmacophoric and/or energy rich poly-nitrogen and nitrogen-oxygen heterocycles (1,2,3- and 1,2,4-triazoles, 1,2,4- and 1,3,4-oxadiazoles, tetrazole, pyridine, and tetrahydroisoquinoline).7 One can assume that the synthesis of bifuroxanyl systems comprising of nitrofuroxanyl moieties would give rise both to compounds with increased ability to release NO and new high-energy compounds. Few representatives of bifuroxanyl structures are known. The first synthesis of such a structure in low yield was based on the thermolysis of benzotrifuroxan at 200 °C.8 The second approach to bifuroxanyl structures based on the regioselective synthesis of 3,3′-diamino-4,4′bifuroxan 1 by oxidation of tetraoxime 2 under the action of bromine in the presence of hydrochloric acid was recently published by Klapötke and co-workers.5d Compound 1 was isomerized into the thermodynamically more preferable 4,4′-diamino-3,3′-bifuroxan 3. The oxidation of the latter with a mixture of 50% H2O2, conc. H2SO4, and (NH4)2S2O8 resulted in the formation of 4,4′-dinitro-3,3′-bifuroxan 4 in low yield (Scheme 1).
Scheme 1. Known route for the formation of bifuroxanyl structures.5d
Meanwhile, bifuroxanyl structures comprising of the 3-nitrofuroxanyl moiety are so far unknown. Herein, we present our research directed towards the development of a regioselective method for the synthesis of bifuroxanyl systems with the 3-nitrobifuroxanyl core, based on a cascade of one-pot reactions comprising of the acylation of dinitromethane sodium salt with furoxanyl hydroxamic acid chlorides, followed by nitrosation of the formed intermediates using NaNO2/AcOH/AcONa and regioselective intramolecular cyclization of the nitrosation product to give the target 3-nitrobifuroxanyl structures. As an initial basis for the synthesis of bifuroxanyl structures containing the 3nitrobifuroxanyl core, we selected a method previously developed in our laboratory for the preparation of 3-nitro-4-arylfuroxans 5 comprising of nitrosation of the dipotassium salts of 2aryl-2-hydroxyimino-1,1-dinitroethane 6 with NaNO2 in AcOH in the presence of AcOK.9 Salts 6 were prepared by the acylation of dinitromethane sodium salt (DNMNa) with arylhydroxamic acid chlorides followed by multi-step purification. Two isomers of arylnitrofuroxans 5 and 5′ were formed in a 1:1 ratio upon treatment of dipotassium salts 6 with N2O4 as the nitrosating agent (Scheme 2).
Scheme 2. Synthesis of arylnitrofuroxans via nitrosation of the dipotassium salts 6.
The main disadvantage of this method is the essential isolation of dipotassium salts 6, which are dangerous to handle. For this reason, we decided to develop an approach for the construction of the 3-nitrobifuroxanyl core based on a cascade of one-pot reactions using furoxanyl hydroxamic acid chlorides 7, without isolation of the intermediates. Initial compounds 7 were synthesized via a two-step protocol from cyanofuroxans 8, using a recently developed procedure.7d
The
reaction
of
cyanofuroxans
8a-h
with
hydroxylamine
afforded
(aminohydroxamoyl)furoxans 9a-h in high yields, which were easily transformed into (chlorohydroxamoyl)furoxans 7a-h using NaNO2 in the presence of HCl (Scheme 3, ESI). 3(Chlorohydroxamoyl)-4-nitrofuroxan 7i was prepared by nucleophilic substitution of the nitro group in (4-nitrofuroxan-3-yl)nitrolic acid10 using concentrated hydrochloric acid. In addition, we synthesized 4-(chlorohydroxamoyl)-3-cyanofuroxan 7j according to a literature procedure.11
Scheme 3. Synthesis of the initial furoxanylhydroxamic acid chlorides 7. Cyanofuroxans 8a-e are known compounds,7d while substrates 8f-h were synthesized for the first time by dehydration of the corresponding amides 10a-c, which were in turn prepared by nucleophilic substitution of the nitro group in nitrofuroxancarboxylic acid amide 11 upon treatment with the appropriate nucleophiles (Scheme 4).
Scheme 4. Synthesis of previously unknown precursors 10a-c and 8f-h.
The investigation began by screening conditions for the acylation of DNMNa with (chlorohydroxamoyl)furoxans 7. 3-(Chlorohydroxamoyl)-4-phenylfuroxan 7a was chosen as a model substrate. The first step (acylation of DNMNa) was carried out in dry DMF at 0-5 °C for 72 h. To form the anion of the dinitromethyl moiety for subsequent nitrosation, two equivalents of DNMNa were necessary. NaNO2/AcOH, N2O4, NOBF4, and tBuONO were investigated as reagents in the presence of AcONa for the nitrosation of intermediate 12a. First, NaNO2/AcOH was utilised as the nitrosating reagent. Five equivalents of NaNO2 and 4.5 equivalents of AcONa were initially used to perform the nitrosation of 12a and to transform the dinitromethane that formed as a by-product in the reaction mixture after acylation (Table 1, entry 1). The 7a:DNMNa and 7a:NaNO2 molar ratios were varied. An increase of the 7a:DNMNa molar ratio to 1:2.2 resulted in a higher yield of compound 13a (Entry 2), whereas the yield of 13a decreased at the 7a:DNMNa molar ratio of 1:3 (Entry 3). This decrease was caused by the consumption of NaNO2/AcOH by excess DNMNa. The 7a:NaNO2 molar ratio 1:5 proved to be insufficient (Entry 2), while the best 7a:NaNO2 molar ratio was 1:6 (Entry 4). Increasing the 7a:NaNO2 molar ratio to 1:7 resulted in a similar yield of compound 13a. In all cases, the reaction was completely regioselective and afforded 3-nitro-4-(4-phenyfuroxan-3-yl)furoxan 13a. Utilization of N2O4 as the nitrosating reagent also resulted in the regioselective formation of compound 13a, contrary to the reaction in Scheme 2, but in lower yields (Entries 6-8). A mixture of 3- and 4-
nitro isomeric structures was obtained upon nitrosation of intermediate 12a with NOBF4 (Entry 9). tBuONO proved to be ineffective for the preparation of the desired product (Entry 10).
Table 1. Screening of the reaction conditions for the preparation of 3-nitro-4-(4-phenyfuroxan-3yl)furoxan 13a.
Entry
DNMNa (equiv.)
Nitrosation system
1 2 3 4 5 6 7 8 9 10
2.0 2.2 3.0 2.2 2.2 2.2 2.2 2.2 2.2 2.2
NaNO2/AcOH NaNO2/AcOH NaNO2/AcOH NaNO2/AcOH NaNO2/AcOH N2O4/CCl4 N2O4/CCl4 N2O4/CCl4 NOBF4 t BuONO
equiv. of nitrosating reagent 5.0 5.0 5.0 6.0 7.0 5.0 6.0 7.0 6.0 5.0
Yield 13a (%)a 20 27 14 40 38 27 30 31 24b Tracec
a
Isolated yield.
b
Mixture of 3- and 4-nitroisomers in a 1:1 ratio according to 14N NMR spectroscopy.
с
Determined by 1H and 14N NMR spectroscopy.
With the optimized conditions in hand, we performed the one-pot regioselective synthesis of bifuroxanyl systems incorporating the 3-nitrobifuroxanyl core 13a-j in moderate to good yields (Table 2). It is especially important to note that all reactions proceeded successfully, irrespective of the position of the chlorohydroxamoyl group at the C(3) or C(4) carbon of the furoxan ring and were tolerant of the nature of the second substituent. Table 2. Substrate scope for one-pot synthesis of compounds 13a-j.a
a
Isolated yields.
A plausible mechanism for the one-pot regioselective synthesis of bifuroxanyl systems 13 is outlined in Scheme 5. It includes a cascade of the following one-pot reactions: acylation of DNMNa with (chlorohydroxamoyl)furoxan 7 giving 2-furoxanyl-2-oximino-1,1-dinitroethane sodium salt 12 (which is formed due to the increased acidity of the dinitromethyl fragment compared to the dinitromethane), nitrosation of the dinitromethyl anion derived from this salt with NaNO2/AcOH/AcONa to afford the dinitro nitroso derivative with simultaneous formation of the sodium salt of the oxime fragment (intermediate 14), and intramolecular attack of the oxime anion in this intermediate on the nitroso-group nitrogen atom, followed by NaNO2 elimination yielding the 3-nitrofuroxanyl moiety (Scheme 5).
Scheme 5. A plausible mechanism for the 3-nitrobifuroxan 13 formation.
All of the synthesized 3-nitrobifuroxan derivatives 13a-j were characterized by spectral 1
( H,
13
C,
14
N NMR spectroscopy, mass spectrometry, and IR) and analytical methods. The
location of nitro group at the C(3) carbon atom of the furoxan ring was determined by 14N NMR – the signal of the 3-nitro group moved upfield by 3.7-4.7 ppm relative to the 4-nitro group signal.12 Finally, we confirmed the structures of the bifuroxanyl derivatives using single-crystal X-ray diffraction of representative compounds 13a,b (Fig. 1).
Figure 1. General view of molecules 13a and 13b. Atoms are represented by probability ellipsoids of atomic vibrations (ρ=50%).
In summary, a simple, general, and efficient method for the synthesis of previously unknown bifuroxanyl systems with a 3-nitrobifuroxanyl core 13 has been developed. The method is based on a one-pot reaction cascade comprising acylation of DNMNa with furoxanyl hydroxamic acid chlorides, nitrosation of the acylation product using NaNO2/AcOH/AcONa, and intramolecular cyclization of the nitrosation product to give the 3-nitrofuroxanyl moiety. The target compounds are formed completely regioselectively in moderate and good yields, irrespective of the position of the chlorohydroxamoyl group at either the C(3) or C(4) carbon atom of the furoxan ring or the second substituent nature. 13 The advantages of this method are operational simplicity, step economy, and the use of environmentally friendly reagents (NaNO2, AcOH, AcONa). To the best of our knowledge, the developed method is a new approach to the construction of bifuroxanyl systems and, furthermore, it may be effective for the preparation of 4-hetaryl-3-nitrofuroxans by using other hetarylhydroxamic acid chlorides.
Acknowledgements The synthetic part of this work was supported by the Russian Science Foundation (Project No 14-50-00126) and X-ray structural study was supported by Russian Foundation for Basic Research (Grant No 16-29-01042).
Supplementary data Supplementary data associated with this article can be found, in the online version, at
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2005, p. 13; (c) Scatena, R.; Bottoni, P.; Pontoglio, A.; Giardina, B. Current Med. Chem. 2010, 17, 61; (d) Krause, P.; Waetzig, E.; Acil, H.; Koenig, S.; UnthanFechner, K.; Tsikas, D.; Probst, I. Nitric Oxide. 2010, 23, 220; (e) Serafim, R. A. M.; Primi, M. C.; Trossini, G. H. G.; Ferreira, E. I. Current Med. Chem. 2012, 19, 386. 2. (a) Granik, V. G.; Grigoriev, N. B. Nitric oxide (NO). New Route to Drug Design, (in Russian). Vuzovskaya Kniga: Moscow, Russia, 2004, p. 180; (b) Al-Sa’doni, H.; Ferro, A. Clinic Sci. 2000, 98, 507. 3. For selected examples, see: (a) Jovene, C.; Chugunova, E. A.; Goumont, R. MiniRev. Med. Chem. 2013, 13, 1089; (b) Cena, C.; Bertinaria, M.; Boschi, D.; Giorgis, M.; Gasco, A. ARKIVOC. 2006, 7, 301; (c) Nikonov, G. N.; Bobrov, S. 1.2.5Oxadiazoles. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier: Amsterdam, The Netherlands, 2008; Vol. 5, pp 316-393; (d) Lazzarato, L.; Cena, C.; Rolando, B.; Marini, E.; Lolli, M. L.; Guglielmo, S.; Guaita, E.; Morini, G.; Coruzzi, G.; Fruttero, R.; Gasco, A. Bioorg. Med. Chem. 2011, 19, 5852; (e) Borretto, E.; Lazzarato, L.; Spallotta, F.; Cencioni, C.; D'Alessandra, Yu.; Gaetano, C.; Fruttero, R.; Gasco, A. ACS Med. Chem. Lett. 2013, 4, 994; (f) Guglielmo, S.; Cortese, D.; Vottero, F.; Rolando, B.; Kommer, V. P.; Williams, D. L.; Fruttero, R.; Gasco, A. Eur. J. Med. Chem. 2014, 84, 135. 4. Ferioli, R.; Folco, G. C.; Ferretti, C.; Gasco, A. M.; Medana, C.; Fruttero, R.; Civelli, M.; Gasco, A. Brit. J. Pharmacol. 1995, 114, 816. 5. For selected examples, see: (a) Stepanov, A. I.; Dashko D. V.; Astrat’ev, A. A. Centr. Eur. J. Energ. Mater. 2012, 9, 329; (b) Pepekin, V. I.; Korsunskii, B. L.; Matyushin, Yu. N. Comb. Expl. Shock Wave (Engl Transl). 2008, 44, 110; (c) Chizhov, A. O.; Makhova, N. N.; Kuchurov, I. V.; Sheremetev A. B.; Zlotin, S. G. Mendeleev Commun. 2014, 24, 165; (d) Fischer, D.; Klapötke, T. M.; Stierstorfer, J. Eur. J. Inorg. Chem. 2014, 5808; (e) Makhova, N. N.; Kulikov, A. C. Russ. Chem. Rev. 2013, 82, 1007; (f) Fershtat, L. L.; Ovchinnikov, I. V.; Makhova, N. N. Tetrahedron Lett. 2014, 55, 2398. 6. For selected examples, see: (a) Kots, A. Ya.; Grafov, M. A.; Khropov, Yu. V.; Betin, V. L.; Belushkina, N. N.; Busyrgina, O. G.; Yazykova, M. Yu.; Ovchinnikov, I. V.; Kulikov, A. S.; Makhova, N. N.; Medvedeva, N. A.; Bulargina, T. V.; Severina, I. S. Br. J. Pharmacol. 2000, 129, 1163; (b) Makhova, N. N.; Ovchinnikov, I. V.; Kulikov, A. S.; Molotov, S. I.; Baryshnikova, E. L. Pure Appl. Chem. 2004, 76, 1691; (c) Ovchinnikov, I. V.; Finogenov, A O.; Epishina, M. A.; Strelenko, Yu. A.; Makhova,
N. N. Mendeleev Commun. 2009, 19, 217; (d) Finogenov, A. O.; Epishina, M. A.; Kulikov, A. S.; Makhova, N. N.; Anan’ev, I. V.; Tartakovsky, V. A. Russ. Chem. Bull., Int. Ed. 2010, 59, 2108; (e) Finogenov, A. O.; Epishina, M. A.; Ovchinnikov, I. V.; Kulikov, A. S.; Anan’ev, I. V.; Makhova, N. N. Russ. Chem. Bull., Int. Ed. 2011, 60, 339; (f) Makhova, N. N.; Kulikov, A. S. Russ. Chem. Rev. 2013, 82, 1007; (g) Finogenov, A. O.; Kulikov, A. S.; Epishina, M. A.; Ovchinnikov, I. V.; Nelyubina, Y. V.; Makhova, N. N. J. Heterocycl. Chem. 2013, 50, 135. 7. For recent publication, see: (a) Fershtat, L. L.; Epishina, M. A.; Kulikov, A. S.; Struchkova, M. I.; Makhova, N. N. Chem. Heterocycl. Compd. 2015, 51, 176; (b) Fershtat, L. L.; Epishina, M. A.; Kulikov, A. S.; Makhova, N. N. Mendeleev Commun. 2015, 25, 36; (c) Fershtat, L. L.; Ashirbaev, S. S.; Kulikov, A. S.; Kachala, V. V.; Makhova, N. N. Mendeleev Commun. 2015, 25, 257; (d) Fershtat, L. L.; Epishina, M. A.; Kulikov, A. S.; Ovchinnikov, I. V.; Ananyev, I. V.; Makhova, N. N. Tetrahedron 2015, 71, 6764; (e) Fershtat, L. L.; Ananyev, I. V.; Makhova, N. N. RSC Adv. 2015, 5, 47248; (f) Fershtat, L. L.; Epishina, M. A.; Ovchinnikov, I. V.; Makhova, N. N. Chem. Heterocycl. Compd. 2015, 51, 754; (g) Zlotin. S. G.; Churakov, A. M.; Luk’yanov, O. A.; Makhova, N. N.; Sukhorukov, A. Yu.; Tartakovsky, V. A. Mendeleev Commun. 2015, 25, 399; (h) Fershtat, L.L.; Larin, A. A.; Epishina, M. A.; Ovchinnikov, I. V.; Ananyev, I. V.; Makhova, N. N. RSC Adv. 2016, 6, 31526. 8. Gumanov, L. L.; Korsunskii, B. L. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1700. 9. (a) Ovchinnikov, I. V.; Finogenov, A. O.; Epishina, M. A.; Kulikov, A. S.; Strelenko, Yu. A.; Makhova, N. N. Russ. Chem. Bull., Int. Ed. 2009, 58, 2137; (b) Ovchinnikov, I. V.; Strelenko, Yu. A; Popov, N. A.; Finogenov, A. O.; Makhova, N. N. Russ. Chem. Bull., Int. Ed. 2011, 60, 855. 10. Rakitin, O. A.; Khaibulina, E. A.; Godovikova, T. I.; Ogurtsov, B. A.; Khmelnit’skii, L. I. Chem. Heterocycl. Compd. 1993, 1117. 11. Sizova, E. V.; Romanova, T. V.; Mel’nikova, S. F.; Tselinskii, I. V. Russ. J. Org. Chem. 2005, 41, 1802. 12. Fershtat, L. L.; Struchkova, M. I.; Goloveshkin, A. S.; Bushmarinov, I. S.; Makhova, N. N. Heteroat. Chem. 2014, 25, 226. 13. General procedure for the synthesis of bifuroxans 13: A solution of the corresponding chloroxime (1.0 mmol) in DMF (2 mL) was added dropwise to a magnetically stirred and ice-cooled solution of DNMNa (0.282 g, 2.2 mmol) in DMF (2 mL). The
resulting mixture was stirred at 0-5 °C for 30 min and left to stand in a refrigerator for 72 h. Then, anhydrous AcONa (0.369 g, 4.5 mmol) was added in one portion with stirring at 0-5 °C and stirred for an additional 30 min. AcOH (7 mL) was added with stirring at 0-5 °C followed by the addition of NaNO2 (0.414 g, 6.0 mmol) in one portion. The reaction mixture was stirred for 15 min at 0-5 °C, then the ice bath was removed and the mixture allowed to warm to room temperature and stirred for an additional 4 h. The reaction mixture was then poured into cold water (40 mL), stirred for 1 h, and the formed solid collected by filtration, washed with water and dried in air. Compounds 13b,c,h-j were extracted with CHCl3 (3x10 mL), the combined organic layers washed with water (3x40 mL) and dried over MgSO4. Evaporation of the solvent under reduced pressure (T ≤ 23 °C) afforded title compounds. Caution! Several compounds prepared in this work (e.g. bifuroxans 13c,i and DNMNa) are energetic compounds which are sensitive to impact, friction, and electric discharge; thus, safety precautions should be taken.
Highlights
A new method for the formation of the bifuroxan system has been developed. Target 3-nitrobifuroxans were synthesized through a one-pot acylation/nitrosation/cyclization cascade. The reaction proceeds regioselectively under very mild conditions.
S0040-4039(16)30998-4 http://dx.doi.org/10.1016/j.tetlet.2016.08.011 TETL 47982
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
24 June 2016 28 July 2016 3 August 2016
Please cite this article as: Fershtat, L.L., Larin, A.A., Epishina, M.A., Kulikov, A.S., Ovchinnikov, I.V., Ananyev, I.V., Makhova, N.N., Regioselective synthesis of bifuroxanyl systems with the 3nitrobifuroxanyl core via a one-pot acylation/nitrosation/cyclization cascade, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet. 2016.08.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Regioselective synthesis of bifuroxanyl systems with the 3-nitrobifuroxanyl core via a one-pot acylation/nitrosation/cyclization cascade Leonid L. Fershtat,a Alexander A. Larin,a Margarita A. Epishina, Alexander S Kulikov, a Igor V. Ovchinnikov,a Ivan V. Ananyev,b Nina N. Makhovaa* a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky prosp., 119991, Moscow, Russian Federation. Phone: +7 (499) 1355326; Fax: +7 (499) 1355328; E-mail: [email protected] b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,28 Vavilova str., 119991 Moscow, Russian Federation. Fax: +7 (499) 135 5085. E-mail: [email protected]
Abstract. A regioselective method for the synthesis of previously unknown bifuroxanyl systems containing the 3-nitrobifuroxanyl core, based on a cascade of one-pot reactions comprising of the acylation of dinitromethane sodium salt with furoxanyl hydroxamic acid chlorides, nitrosation of the acylation product with NaNO2/AcOH/AcONa, and intramolecular cyclization of the nitrosation product to give the 3-nitrobifuroxanyl moiety, has been developed.
Keywords: bifuroxanyl systems; 3-nitrobifuroxanyl core; acylation; nitrosation; cyclization; cascade reactions.
Since the significant discoveries of Nobel Prize winners, Furchgott, Ignarro, and Murad, in the late 1990s, nitric oxide (NO) has been recognized as an ubiquitous and crucial regulator molecule for cellular metabolism, affecting various physiological and pathophysiological processes. One of the most active areas of medicinal chemistry is the search for compounds
capable of releasing NO (NO donors) and the design of novel NO-donor hybrid drugs capable of releasing this vitally important regulator in the body, either enzymatically, or independently of NO synthases. Compounds that combine NO release while maintaining the activity of the native drug have proved to be useful for the treatment of cardiovascular, inflammatory, bacterial, fungal, viral, parasitic, and ocular diseases as well as cancer. 1 Different types of compounds have been synthesized and tested as NO donors.2 Among them, the furoxan moiety has been the subject of increased attention, pioneered by Gasco, owing to the ability of furoxans to release NO under physiological conditions. This ability to release NO depends on the nature of the substituents on the furoxan ring carbon atoms.3 In particular, the isomeric 3(4)aryl-4(3)nitrofuroxans were found to be among the most effective NO donors, with the 3-nitro isomer being more effective. 4 In addition, nitrofuroxans have attracted attention as potential components of energetic formulations due to a positive formation enthalpy and the presence of two active oxygen atoms in the molecule.5 Our research group has significant experience in the chemistry of furoxans, including the synthesis of effective NO donors.6 Recently, we reported a series of novel polynuclear heterocyclic structures containing, along with the furoxan ring, pharmacophoric and/or energy rich poly-nitrogen and nitrogen-oxygen heterocycles (1,2,3- and 1,2,4-triazoles, 1,2,4- and 1,3,4-oxadiazoles, tetrazole, pyridine, and tetrahydroisoquinoline).7 One can assume that the synthesis of bifuroxanyl systems comprising of nitrofuroxanyl moieties would give rise both to compounds with increased ability to release NO and new high-energy compounds. Few representatives of bifuroxanyl structures are known. The first synthesis of such a structure in low yield was based on the thermolysis of benzotrifuroxan at 200 °C.8 The second approach to bifuroxanyl structures based on the regioselective synthesis of 3,3′-diamino-4,4′bifuroxan 1 by oxidation of tetraoxime 2 under the action of bromine in the presence of hydrochloric acid was recently published by Klapötke and co-workers.5d Compound 1 was isomerized into the thermodynamically more preferable 4,4′-diamino-3,3′-bifuroxan 3. The oxidation of the latter with a mixture of 50% H2O2, conc. H2SO4, and (NH4)2S2O8 resulted in the formation of 4,4′-dinitro-3,3′-bifuroxan 4 in low yield (Scheme 1).
Scheme 1. Known route for the formation of bifuroxanyl structures.5d
Meanwhile, bifuroxanyl structures comprising of the 3-nitrofuroxanyl moiety are so far unknown. Herein, we present our research directed towards the development of a regioselective method for the synthesis of bifuroxanyl systems with the 3-nitrobifuroxanyl core, based on a cascade of one-pot reactions comprising of the acylation of dinitromethane sodium salt with furoxanyl hydroxamic acid chlorides, followed by nitrosation of the formed intermediates using NaNO2/AcOH/AcONa and regioselective intramolecular cyclization of the nitrosation product to give the target 3-nitrobifuroxanyl structures. As an initial basis for the synthesis of bifuroxanyl structures containing the 3nitrobifuroxanyl core, we selected a method previously developed in our laboratory for the preparation of 3-nitro-4-arylfuroxans 5 comprising of nitrosation of the dipotassium salts of 2aryl-2-hydroxyimino-1,1-dinitroethane 6 with NaNO2 in AcOH in the presence of AcOK.9 Salts 6 were prepared by the acylation of dinitromethane sodium salt (DNMNa) with arylhydroxamic acid chlorides followed by multi-step purification. Two isomers of arylnitrofuroxans 5 and 5′ were formed in a 1:1 ratio upon treatment of dipotassium salts 6 with N2O4 as the nitrosating agent (Scheme 2).
Scheme 2. Synthesis of arylnitrofuroxans via nitrosation of the dipotassium salts 6.
The main disadvantage of this method is the essential isolation of dipotassium salts 6, which are dangerous to handle. For this reason, we decided to develop an approach for the construction of the 3-nitrobifuroxanyl core based on a cascade of one-pot reactions using furoxanyl hydroxamic acid chlorides 7, without isolation of the intermediates. Initial compounds 7 were synthesized via a two-step protocol from cyanofuroxans 8, using a recently developed procedure.7d
The
reaction
of
cyanofuroxans
8a-h
with
hydroxylamine
afforded
(aminohydroxamoyl)furoxans 9a-h in high yields, which were easily transformed into (chlorohydroxamoyl)furoxans 7a-h using NaNO2 in the presence of HCl (Scheme 3, ESI). 3(Chlorohydroxamoyl)-4-nitrofuroxan 7i was prepared by nucleophilic substitution of the nitro group in (4-nitrofuroxan-3-yl)nitrolic acid10 using concentrated hydrochloric acid. In addition, we synthesized 4-(chlorohydroxamoyl)-3-cyanofuroxan 7j according to a literature procedure.11
Scheme 3. Synthesis of the initial furoxanylhydroxamic acid chlorides 7. Cyanofuroxans 8a-e are known compounds,7d while substrates 8f-h were synthesized for the first time by dehydration of the corresponding amides 10a-c, which were in turn prepared by nucleophilic substitution of the nitro group in nitrofuroxancarboxylic acid amide 11 upon treatment with the appropriate nucleophiles (Scheme 4).
Scheme 4. Synthesis of previously unknown precursors 10a-c and 8f-h.
The investigation began by screening conditions for the acylation of DNMNa with (chlorohydroxamoyl)furoxans 7. 3-(Chlorohydroxamoyl)-4-phenylfuroxan 7a was chosen as a model substrate. The first step (acylation of DNMNa) was carried out in dry DMF at 0-5 °C for 72 h. To form the anion of the dinitromethyl moiety for subsequent nitrosation, two equivalents of DNMNa were necessary. NaNO2/AcOH, N2O4, NOBF4, and tBuONO were investigated as reagents in the presence of AcONa for the nitrosation of intermediate 12a. First, NaNO2/AcOH was utilised as the nitrosating reagent. Five equivalents of NaNO2 and 4.5 equivalents of AcONa were initially used to perform the nitrosation of 12a and to transform the dinitromethane that formed as a by-product in the reaction mixture after acylation (Table 1, entry 1). The 7a:DNMNa and 7a:NaNO2 molar ratios were varied. An increase of the 7a:DNMNa molar ratio to 1:2.2 resulted in a higher yield of compound 13a (Entry 2), whereas the yield of 13a decreased at the 7a:DNMNa molar ratio of 1:3 (Entry 3). This decrease was caused by the consumption of NaNO2/AcOH by excess DNMNa. The 7a:NaNO2 molar ratio 1:5 proved to be insufficient (Entry 2), while the best 7a:NaNO2 molar ratio was 1:6 (Entry 4). Increasing the 7a:NaNO2 molar ratio to 1:7 resulted in a similar yield of compound 13a. In all cases, the reaction was completely regioselective and afforded 3-nitro-4-(4-phenyfuroxan-3-yl)furoxan 13a. Utilization of N2O4 as the nitrosating reagent also resulted in the regioselective formation of compound 13a, contrary to the reaction in Scheme 2, but in lower yields (Entries 6-8). A mixture of 3- and 4-
nitro isomeric structures was obtained upon nitrosation of intermediate 12a with NOBF4 (Entry 9). tBuONO proved to be ineffective for the preparation of the desired product (Entry 10).
Table 1. Screening of the reaction conditions for the preparation of 3-nitro-4-(4-phenyfuroxan-3yl)furoxan 13a.
Entry
DNMNa (equiv.)
Nitrosation system
1 2 3 4 5 6 7 8 9 10
2.0 2.2 3.0 2.2 2.2 2.2 2.2 2.2 2.2 2.2
NaNO2/AcOH NaNO2/AcOH NaNO2/AcOH NaNO2/AcOH NaNO2/AcOH N2O4/CCl4 N2O4/CCl4 N2O4/CCl4 NOBF4 t BuONO
equiv. of nitrosating reagent 5.0 5.0 5.0 6.0 7.0 5.0 6.0 7.0 6.0 5.0
Yield 13a (%)a 20 27 14 40 38 27 30 31 24b Tracec
a
Isolated yield.
b
Mixture of 3- and 4-nitroisomers in a 1:1 ratio according to 14N NMR spectroscopy.
с
Determined by 1H and 14N NMR spectroscopy.
With the optimized conditions in hand, we performed the one-pot regioselective synthesis of bifuroxanyl systems incorporating the 3-nitrobifuroxanyl core 13a-j in moderate to good yields (Table 2). It is especially important to note that all reactions proceeded successfully, irrespective of the position of the chlorohydroxamoyl group at the C(3) or C(4) carbon of the furoxan ring and were tolerant of the nature of the second substituent. Table 2. Substrate scope for one-pot synthesis of compounds 13a-j.a
a
Isolated yields.
A plausible mechanism for the one-pot regioselective synthesis of bifuroxanyl systems 13 is outlined in Scheme 5. It includes a cascade of the following one-pot reactions: acylation of DNMNa with (chlorohydroxamoyl)furoxan 7 giving 2-furoxanyl-2-oximino-1,1-dinitroethane sodium salt 12 (which is formed due to the increased acidity of the dinitromethyl fragment compared to the dinitromethane), nitrosation of the dinitromethyl anion derived from this salt with NaNO2/AcOH/AcONa to afford the dinitro nitroso derivative with simultaneous formation of the sodium salt of the oxime fragment (intermediate 14), and intramolecular attack of the oxime anion in this intermediate on the nitroso-group nitrogen atom, followed by NaNO2 elimination yielding the 3-nitrofuroxanyl moiety (Scheme 5).
Scheme 5. A plausible mechanism for the 3-nitrobifuroxan 13 formation.
All of the synthesized 3-nitrobifuroxan derivatives 13a-j were characterized by spectral 1
( H,
13
C,
14
N NMR spectroscopy, mass spectrometry, and IR) and analytical methods. The
location of nitro group at the C(3) carbon atom of the furoxan ring was determined by 14N NMR – the signal of the 3-nitro group moved upfield by 3.7-4.7 ppm relative to the 4-nitro group signal.12 Finally, we confirmed the structures of the bifuroxanyl derivatives using single-crystal X-ray diffraction of representative compounds 13a,b (Fig. 1).
Figure 1. General view of molecules 13a and 13b. Atoms are represented by probability ellipsoids of atomic vibrations (ρ=50%).
In summary, a simple, general, and efficient method for the synthesis of previously unknown bifuroxanyl systems with a 3-nitrobifuroxanyl core 13 has been developed. The method is based on a one-pot reaction cascade comprising acylation of DNMNa with furoxanyl hydroxamic acid chlorides, nitrosation of the acylation product using NaNO2/AcOH/AcONa, and intramolecular cyclization of the nitrosation product to give the 3-nitrofuroxanyl moiety. The target compounds are formed completely regioselectively in moderate and good yields, irrespective of the position of the chlorohydroxamoyl group at either the C(3) or C(4) carbon atom of the furoxan ring or the second substituent nature. 13 The advantages of this method are operational simplicity, step economy, and the use of environmentally friendly reagents (NaNO2, AcOH, AcONa). To the best of our knowledge, the developed method is a new approach to the construction of bifuroxanyl systems and, furthermore, it may be effective for the preparation of 4-hetaryl-3-nitrofuroxans by using other hetarylhydroxamic acid chlorides.
Acknowledgements The synthetic part of this work was supported by the Russian Science Foundation (Project No 14-50-00126) and X-ray structural study was supported by Russian Foundation for Basic Research (Grant No 16-29-01042).
Supplementary data Supplementary data associated with this article can be found, in the online version, at
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N. N. Mendeleev Commun. 2009, 19, 217; (d) Finogenov, A. O.; Epishina, M. A.; Kulikov, A. S.; Makhova, N. N.; Anan’ev, I. V.; Tartakovsky, V. A. Russ. Chem. Bull., Int. Ed. 2010, 59, 2108; (e) Finogenov, A. O.; Epishina, M. A.; Ovchinnikov, I. V.; Kulikov, A. S.; Anan’ev, I. V.; Makhova, N. N. Russ. Chem. Bull., Int. Ed. 2011, 60, 339; (f) Makhova, N. N.; Kulikov, A. S. Russ. Chem. Rev. 2013, 82, 1007; (g) Finogenov, A. O.; Kulikov, A. S.; Epishina, M. A.; Ovchinnikov, I. V.; Nelyubina, Y. V.; Makhova, N. N. J. Heterocycl. Chem. 2013, 50, 135. 7. For recent publication, see: (a) Fershtat, L. L.; Epishina, M. A.; Kulikov, A. S.; Struchkova, M. I.; Makhova, N. N. Chem. Heterocycl. Compd. 2015, 51, 176; (b) Fershtat, L. L.; Epishina, M. A.; Kulikov, A. S.; Makhova, N. N. Mendeleev Commun. 2015, 25, 36; (c) Fershtat, L. L.; Ashirbaev, S. S.; Kulikov, A. S.; Kachala, V. V.; Makhova, N. N. Mendeleev Commun. 2015, 25, 257; (d) Fershtat, L. L.; Epishina, M. A.; Kulikov, A. S.; Ovchinnikov, I. V.; Ananyev, I. V.; Makhova, N. N. Tetrahedron 2015, 71, 6764; (e) Fershtat, L. L.; Ananyev, I. V.; Makhova, N. N. RSC Adv. 2015, 5, 47248; (f) Fershtat, L. L.; Epishina, M. A.; Ovchinnikov, I. V.; Makhova, N. N. Chem. Heterocycl. Compd. 2015, 51, 754; (g) Zlotin. S. G.; Churakov, A. M.; Luk’yanov, O. A.; Makhova, N. N.; Sukhorukov, A. Yu.; Tartakovsky, V. A. Mendeleev Commun. 2015, 25, 399; (h) Fershtat, L.L.; Larin, A. A.; Epishina, M. A.; Ovchinnikov, I. V.; Ananyev, I. V.; Makhova, N. N. RSC Adv. 2016, 6, 31526. 8. Gumanov, L. L.; Korsunskii, B. L. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1700. 9. (a) Ovchinnikov, I. V.; Finogenov, A. O.; Epishina, M. A.; Kulikov, A. S.; Strelenko, Yu. A.; Makhova, N. N. Russ. Chem. Bull., Int. Ed. 2009, 58, 2137; (b) Ovchinnikov, I. V.; Strelenko, Yu. A; Popov, N. A.; Finogenov, A. O.; Makhova, N. N. Russ. Chem. Bull., Int. Ed. 2011, 60, 855. 10. Rakitin, O. A.; Khaibulina, E. A.; Godovikova, T. I.; Ogurtsov, B. A.; Khmelnit’skii, L. I. Chem. Heterocycl. Compd. 1993, 1117. 11. Sizova, E. V.; Romanova, T. V.; Mel’nikova, S. F.; Tselinskii, I. V. Russ. J. Org. Chem. 2005, 41, 1802. 12. Fershtat, L. L.; Struchkova, M. I.; Goloveshkin, A. S.; Bushmarinov, I. S.; Makhova, N. N. Heteroat. Chem. 2014, 25, 226. 13. General procedure for the synthesis of bifuroxans 13: A solution of the corresponding chloroxime (1.0 mmol) in DMF (2 mL) was added dropwise to a magnetically stirred and ice-cooled solution of DNMNa (0.282 g, 2.2 mmol) in DMF (2 mL). The
resulting mixture was stirred at 0-5 °C for 30 min and left to stand in a refrigerator for 72 h. Then, anhydrous AcONa (0.369 g, 4.5 mmol) was added in one portion with stirring at 0-5 °C and stirred for an additional 30 min. AcOH (7 mL) was added with stirring at 0-5 °C followed by the addition of NaNO2 (0.414 g, 6.0 mmol) in one portion. The reaction mixture was stirred for 15 min at 0-5 °C, then the ice bath was removed and the mixture allowed to warm to room temperature and stirred for an additional 4 h. The reaction mixture was then poured into cold water (40 mL), stirred for 1 h, and the formed solid collected by filtration, washed with water and dried in air. Compounds 13b,c,h-j were extracted with CHCl3 (3x10 mL), the combined organic layers washed with water (3x40 mL) and dried over MgSO4. Evaporation of the solvent under reduced pressure (T ≤ 23 °C) afforded title compounds. Caution! Several compounds prepared in this work (e.g. bifuroxans 13c,i and DNMNa) are energetic compounds which are sensitive to impact, friction, and electric discharge; thus, safety precautions should be taken.
Highlights
A new method for the formation of the bifuroxan system has been developed. Target 3-nitrobifuroxans were synthesized through a one-pot acylation/nitrosation/cyclization cascade. The reaction proceeds regioselectively under very mild conditions.