Metal-Free and Fecl3-Catalyzed Synthesis of Azines and 3,5
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Indian Journal of Chemistry Vol. 57B, March 2018, pp. 362-373 Metal-free and FeCl 3-catalyzed synthesis of azines and 3,5-diphenyl-1H-pyrazole from hydrazones and/or ketones monitored by high resolution ESI +-MS Jamal Lasri* & Ali I Ismail Department of Chemistry, Rabigh College of Science and Arts, P.O. Box 344, King Abdulaziz University, Jeddah, Saudi Arabia E-mail: [email protected] Received 23 August 2016; accepted (revised) 24 May 2017 9-Fluorenone azine 2a or benzophenone azine 2b have been synthesized, respectively, by treatment of 9-fluorenone hydrazone 1a or benzophenone hydrazone 1b with FeCl 3 Lewis acid catalyst in CHCl 3. Treatment of 1a and 1b with FeCl 3 affords the asymmetrical azine 1-(diphenylmethylene)-2-(9 H-fluoren-9-ylidene)hydrazine 2c . 1,3-Diphenyl-2-propenone 3 reacts with hydrazine to produce 1-(( E)-1,3-diphenylallylidene)hydrazine 3a . Under prolonged heating, 3a undergoes a cyclization to yield 3,5-diphenyl-1H-pyrazole 4. Chalcone 3 reacts with 1a or 1b to produce a mixture of 4 and 2a or 4 and 2b , respectively. The reaction of cyclohexanone 5 with hydrazine leads to the formation of 1,2-dicyclohexylidene hydrazine 6. Ketone 5 reacts with 1a or 1b to give the asymmetrical azine product 6a or 6b , respectively. The progress of the reactions has been monitored by electrospray ionization mass spectrometry (ESI-MS), and the compounds have been characterized by elemental analyses, IR, 1H, 13 C and DEPT-135 NMR spectroscopy and also by high resolution ESI +-MS. + Keywords : Hydrazones, ketones, azines, 3,5-diphenyl-1H-pyrazole, FeCl 3 Lewis acid catalyst, ESI -MS Azines (R 2C=N–N=CR 2) have recently received combination of N-heterocyclic carbenes (NHC) with attention due to their unusual reactivity and spectral diazoalkanes 14 which show structural trends properties. For example, azines showed great non- consistent with delocalization within the azine linear optical (NLO) characteristics 1. Also, they have framework 15 . been used as ligands in organometallic chemistry 2. On the other hand, the synthesis of 3,5- Azines are 2,3-diaza comparable to 1,3-butadiene, disubstituted pyrazoles remains of great interest therefore, they participate in an unusual 1,3-dipolar because they have displayed a wide range of cycloaddition (the criss-cross cycloaddition) with biological activities such as in inhibiting lung cancer dienophiles providing an easy route to five cell growth 16 . For many years, numerous methods membered heterocycles 3. Azines also undergo have been developed in order to synthesize this class [2 + 3] cycloadditions as an ene-fragment 4. Aceto- of heterocycles 17 . The synthesis of 3,5-disubstituted phenone azines have been involved in many studies 5 pyrazoles by condensation of 1,3-diketones with using crystallographic data 6, NMR spectroscopic hydrazine or its derivatives is the most widely used measurements 7, and theoretical calculations 8. There method 18 . Unfortunately, this condensation leads to are several reported methods for the preparation of the formation of undesired isomers as major azines. They can be prepared by reaction of aldehydes components 19-21 . There are some studies reporting the and ketones with hydrazine sulfate, in the presence of synthesis of pyrazole derivatives using chalcones 9 22 CH 3CO 2Na/CaCl 2, under microwave irradiation , by as starting materials . For example, 3,5-disubstituted refluxing ketones with hydrazine hydrate in acidic pyrazoles can be prepared by condensation of ethanolic solution 10 , or by reaction of carbonyl chalcones, hydrazine and sulfur in ethanol 23 or by compounds with hydrazine in the presence of reaction of chalcones, hydrazine and Na 2S2O8 using molecular iodine 11 . Azines can also be synthesized by mechano-chemical ball-milling technique 24 . oxidation of hydrazones using in situ generated The development of high resolution mass 12 Et 4NO 2 , or by reaction of hydrazones with spectrometry (HRMS) has made it possible to N-bromosuccinimide (NBS) 13 . Azines with use them in monitoring chemical reactions and extreme push–pull substituents were prepared by the intermediates 25 . The advantage of using electrospray LASRI & ISMAIL: SYNTHESIS OF AZINES 363 ionization mass spectrometry (ESI-MS) is that the catalysts for the synthesis of azines monitored by high reaction mixture can be used without purification. resolution ESI +-MS has not yet been reported, Also, the HRMS can easily differentiate products we have decided to investigate the role of even for compounds with very close chemical bis(propionitrile)platinum(II) complex [PtCl 2(NCEt) 2] structures and formulas. Therefore, ESI-MS provides and other metal ions looking for best metal catalyst a great tool to monitor the progress of the chemical for the azine synthesis. reaction in real time. Hence, the reaction of 9-fluorenone hydrazone 1a Herein, we would like (i) to investigate the best was carried out in the presence of one of the following metal-catalyst for the synthesis of symmetrical and metal salts (or metal complexes) [PtCl 2(NCEt) 2], asymmetrical azines starting from 9-fluorenone K2PtCl 4, PtCl 2, PdCl 2, ZnCl 2, CoCl 2.6H 2O, hydrazone and/or benzophenone hydrazone, (ii) to CuSO 4.5H 2O, FeS, FeCl 2.4H 2O or FeCl 3, and studied prepare new asymmetrical azines by acid-free under different conditions (time of reaction, condensation of cyclohexanone with hydrazones, temperature and solvent). The progress of the reaction (iii) to synthesize 3,5-diphenyl-1H-pyrazole by was monitored by high resolution ESI +-MS and the condensation of chalcone with hydrazine without the 9-fluorenone azine 2a was confirmed by elemental addition of any oxidant, and (iv) to propose analysis, IR and 1H, 13 C and DEPT-135 NMR mechanisms for those types of transformations based spectroscopy and also by HRMS. on the results obtained from ESI +-MS, NMR, and The reaction is highly dependent on the nature of IR spectra. the metal ion employed. Also, it depends on the reaction time, temperature, and on the type of solvent Results and Discussion used. In all cases, we observed that the reactions This work was inspired by our previous study of under reflux gave better yields than at RT. Also, the reaction of bis(organonitrile) platinum(II) 26 we concluded that chloroform gave better yields complex [PtCl 2(NCR) 2] with a nucleophile such as than methanol. 9-fluorenone hydrazone. Small amount of one new When comparing the catalytic activity of the product was obtained which was then isolated from metal salts we observed that very poor yields of the reaction mixture by column chromatography and 9-fluorenone azine 2a ( ca . 7%) were obtained characterized by NMR spectroscopy and HRMS, and when using [PtCl 2(NCEt) 2] or K 2PtCl 4 (Table I, identified as a 9-fluorenone azine. entry 3; Figure 1). By employing PtCl 2 or PdCl 2 Because, to our knowledge, the use of metals as as catalysts 2a was obtained in ca . 18% yield 100 80 60 Reflux RT 40 20 0 Figure 1 — The effect of changing metal-catalyst on the yield of 9-fluorenone azine 2a , at RT (dark grey) or under conventional solvent reflux (light grey), reaction time: 24 h 364 INDIAN J. CHEM., SEC B, MARCH 2018 Table I — Reaction of 9-fluorenone hydrazone 1a or benzophenone hydrazone 1b under different conditions a Entry Compd Product Conditions Time (h) Solvent Catalyst Yield (%) b 1 1a 2a Reflux 24 CHCl 3 None 5 2 1a 2a RT 24 CHCl 3 None 3 3 1a 2a Reflux 24 CHCl 3 PtCl 2(NCEt) 2 7 4 1a 2a RT 24 CHCl 3 PtCl 2(NCEt) 2 3 5 1a 2a Reflux 24 H2O/MeOH (2:3) K2PtCl 4 5 6 1a 2a RT 24 H2O/MeOH (2:3) K2PtCl 4 3 7 1a 2a Reflux 24 CHCl 3 PtCl 2 17 8 1a 2a RT 24 CHCl 3 PtCl 2 13 9 1a 2a Reflux 24 CHCl 3 PdCl 2 18 10 1a 2a RT 24 CHCl 3 PdCl 2 5 11 1a 2a Reflux 24 CHCl 3 ZnCl 2 40 12 1a 2a RT 24 CHCl 3 ZnCl 2 17 13 1a 2a Reflux 24 CHCl 3 CoCl 2.6H 2O 21 14 1a 2a RT 24 MeOH CoCl 2.6H 2O 10 15 1a 2a Reflux 1 CHCl 3 CuSO 4.5H 2O 5 16 1a 2a Reflux 24 CHCl 3 CuSO 4.5H 2O 9 17 1a 2a RT 24 CHCl 3 CuSO 4.5H 2O 6 18 1a 2a Reflux 24 CHCl 3 FeS 2 19 1a 2a RT 24 CHCl 3 FeS 1 20 1a 2a Reflux 24 CHCl 3 FeCl 2.4H 2O 14 21 1a 2a RT 24 CHCl 3 FeCl 2.4H 2O 8 22 1a 2a Reflux 24 CHCl 3 FeCl 3 99 23 1a 2a RT 24 CHCl 3 FeCl 3 70 24 1a 2a Reflux 24 MeOH FeCl 3 67 25 1a 2a RT 24 MeOH FeCl 3 43 26 1a 2a Reflux 0.25 CHCl 3 FeCl 3 39 27 1a 2a Reflux 0.60 CHCl 3 FeCl 3 79 28 1a 2a Reflux 0.75 CHCl 3 FeCl 3 88 29 1a 2a Reflux 1.17 CHCl 3 FeCl 3 94 30 1a 2a Reflux 2 CHCl 3 FeCl 3 96 31 1b 2b Reflux 2 CHCl 3 FeCl 3 73 32 1b 2b Reflux 3 CHCl 3 FeCl 3 99 33 1b 2b RT 2 CHCl 3 FeCl 3 30 34 1b 2b RT 24 CHCl 3 FeCl 3 80 35 1b 2b RT 72 CHCl 3 FeCl 3 85 36 1b 2b RT 120 CHCl 3 FeCl 3 88 a Reaction conditions: 9-fluorenone hydrazone 1a or benzophenone hydrazone 1b (1.029 mmol), solvent (5 mL) and metal catalyst (0.511 mmol).