Metal-Free and Fecl3-Catalyzed Synthesis of Azines and 3,5

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). b Yields were calculated based on high resolution mass spectrometry (HRMS).

(Table I, entry 9; Figure 1). Comparing ZnCl 2, Refluxing 9-fluorenone hydrazone 1a in CoCl 2.6H 2O, CuSO 4.5H 2O, FeS and FeCl 2.4H 2O we chloroform, in the absence of any metal salt for 24 h, observed that ZnCl 2 was a better catalyst and gave 2a affords 9-fluorenoneazine 2a in 5% yield (Table I, in 40% yield under reflux in chloroform for 24 h entry 1) indicating that the reaction is metal catalysed. (Table I, entry 11; Figure 1). Surprisingly, the best Similarly, the benzophenone azine 2b was yields of 96 and 99% of 2a were obtained when FeCl 3 synthesized, in 99% yield, starting from benzophenone was employed under reflux in CHCl 3 for 2 or 24 h, hydrazone 1b and using the same reaction protocol respectively (Scheme I; Table I, entries 22 and 30; (FeCl 3, CHCl 3, reflux for 3 h) (Scheme II; Table I, Figure 1). entry 32). LASRI & ISMAIL: SYNTHESIS OF AZINES 365

FeCl3 N NH2 N N CHCl3 reflux, 2 h

1a 2a (96%)

Scheme I — Synthesis of 9-fluorenone azine 2a

Ph Ph Ph FeCl3 N NH2 N N CHCl3 Ph reflux, 3 h Ph Ph 1b 2b

(99%)

Scheme II — Synthesis of benzophenone azine 2b

R H R H N N FeCl 3 H N N FeCl3 R H R R NH H FeCl3 2 N NH2 NH2 N R 1 N

R R R R 1

R H - FeCl3 N NH2 R R R - H2NNH2 N N N H N R R 2

R R

Scheme III — Proposed mechanism for the synthesis of azine 2 from hydrazone 1 catalysed by FeCl 3 We believe that the reactions (Scheme I and imino-carbon atom of 1 which can readily undergo Scheme II) start by coordination of FeCl 3 Lewis acid nucleophilic attack by the amino moiety NH 2 of the catalyst to the terminal nitrogen of hydrazone 1, uncoordinated hydrazone 1 to produce, after elimination 10b this coordination enhances the electrophilicity of the of FeCl 3 and hydrazine , the azine 2 (Scheme III). 366 INDIAN J. CHEM., SEC B, MARCH 2018

An asymmetrical azine such as 1-(diphenyl- The products (Scheme IV) were identified by methylene)-2-(9 H-fluoren-9-ylidene)hydrazine 2c was ESI +-MS. The high resolution high accuracy also synthesized in 74% yield by reaction of 1a and mass spectrometry allows the differentiation 1b , in refluxing chloroform for 1.5 h, in the presence between 2a , 2b and 2c ( m/z 357, 359 and 361, of FeCl 3 (Scheme IV). The reaction of 1a with 1b in respectively), which was done using the isotope the absence of FeCl 3, refluxed in chloroform for 3 pattern of each compound. The reaction yield days, affords 2c in a very poor yield indicating that can be then calculated based on the m/z intensities the reaction is metal catalysed. (Figure 2).

Ph FeCl3 1a + 1b 2a +2b + N N CHCl3 Ph reflux, 1.5 h (1%) (7%) 2c

(74%)

Scheme IV — Synthesis of 1-(diphenylmethylene)-2-(9H-fluoren-9-ylidene)hydrazine 2c from 1a and 1b catalysed by FeCl 3

Figure 2 — (a) The isotope pattern of the reaction mixture of 1a and 1b with different ratios of products; 2a , 2c , and 2b at roughly m/z 357, 359 and 361, respectively. (b) The calculated isotope pattern of the products after fitted for the best values of ratio LASRI & ISMAIL: SYNTHESIS OF AZINES 367

Compound 2c was then purified by column azine 1,2-bis(( E)-1,3-diphenylallylidene)hydrazine by chromatography and characterized by elemental homocoupling of the in situ generated 1-(( E)-1,3- analysis, IR, 1H, 13 C and DEPT-135 NMR spectroscopy diphenylallylidene)hydrazine 3a in the presence of + and also by high resolution ESI -MS (Experimental FeCl 3, and, also the possibility of the synthesis of Section and Electronic Supplementary Information). asymmetrical azine 1-(( E)-1,3-diphenylallylidene)-2- To the best of our knowledge, this is the first FeCl 3- (diphenylmethylene)hydrazine by reaction of 3a with catalysed synthesis of asymmetrical azine 2c from benzophenonehydrazone 1b in the presence of FeCl 3. 9-fluorenone hydrazone 1a and benzophenone In both cases, the expected azine products were hydrazone 1b . It was reported 27 that 2c was neither detected by mass spectrometry nor by NMR synthesized by condensation of a ketone (benzo- spectroscopy probably due to their high reactivity. phenone) with 9-fluorenone hydrazone using acetic Hence, the reaction of the in situ generated hydrazone acid in ethanol. In that report 27 , azine 2c was 3a with benzophenone hydrazone 1b in the presence characterized only by X-ray diffraction analysis. of FeCl 3, refluxed in ethanol for 2 h, affords a mixture In this part of the work, 1,3-diphenyl-2-propenone of 3,5-diphenyl-1H-pyrazole 4 and benzophenone (also called chalcone) 3 was selected for further azine 2b in ca . 5% and 7% yield, respectively synthesis of a variety of compounds with useful (Scheme VI). The product yield was calculated using applications. Herein, the reaction of 3 with hydrazine, the ratio of m/z intensities from ESI +-MS compared to refluxed in ethanol for 15 min, produces the 1-(( E)- their native starting material i.e. the yield of the 1,3-diphenylallylidene)hydrazine 3a in 90% yield product 4 is based on the ratio of m/z of 4 divided by (Scheme V). Due to its high reactivity, compound the sum of m/z of 4 and 3a . 3a was directly characterized by HRMS, IR and In this section, the previously unknown reaction NMR without purification by silica-gel column between chalcone 3 and 9-fluorenone hydrazone 1a chromatography. In the 13 C NMR spectrum, the was also investigated. Hence, the condensation observed signal at δ 161.6 confirms the formation of reaction of 3 with 1a , in refluxing ethanol for 16 h, the hydrazone 3a . To the best of our knowledge, this affords 9-fluorenone azine 2a and 3,5-diphenyl-1H- is the first characterization of the highly reactive pyrazole 4 in 35% and 53% yield, respectively hydrazone 3a by IR, 1H and 13 C NMR, and ESI +-MS (Scheme VII, reaction a). methods. Similarly, the reaction of 3 with benzophenone Under reflux, in EtOH for 16 h, 3a converts to 3,5- hydrazone 1b , in refluxing ethanol for 16 h, produces diphenyl-1H-pyrazole 4 (65% yield) and dihydrogen a mixture of benzophenone azine 2b and 3,5- (Scheme V). On the other hand, the 50% conversion diphenyl-1H-pyrazole 4 in 79% and 20% yield, of 3a to 4 was observed at RT without solvent after 3 respectively (Scheme VII, reaction b), based on ratio days. In contrast to the previous reports 23,24 , this of m/z intensities from ESI +-MS of the product to that study shows that 3,5-diphenyl-1H-pyrazole 4 can be of its native starting material. obtained in 65% yield from chalcone 3 by reflux in We believe that the reaction of Scheme VII is EtOH without the need of any added oxidant. carried out by the attack of the amino moiety of On the other hand, we were interested to hydrazone 1 to the carbonyl group of chalcone 3 study the possibility of the synthesis of symmetrical to produce the azine intermediate 1-(( E)-1,3-

NH2

O N

Ph Ph Ph Ph EtOH EtOH + H2NNH2.H2O reflux, 15 min reflux, 16 h N N - H Ph Ph 2 H 3 3a 4 (90%) (65%)

Scheme V — Synthesis of 1-(( E) -1,3-diphenylallylidene)hydrazine 3a and 3,5-diphenyl-1H-pyrazole 4 from chalcone 3 368 INDIAN J. CHEM., SEC B, MARCH 2018

Ph Ph Ph N NH2 N N Ph 3a Ph Ph

FeCl3 + EtOH Ph reflux, 2 h Ph Ph Ph Ph N NH2 + N N N N Ph 1b Ph Ph H 2b 4 (7%) (5%)

Scheme VI — Reaction of the in situ generated 1-(( E) -1,3-diphenylallylidene)hydrazine 3a with benzophenonehydrazone 1b in the presence of FeCl 3

O

Ph 1b 1a 2b + 4 2a + 4 EtOH (79%) (20%) EtOH (53%) reflux, 16 h reflux, 16 h (35%) Ph 3 (a) (b)

Scheme VII — Synthesis of 9-fluorenone azine 2a and 3,5-diphenyl-1H-pyrazole 4 (reaction a), and synthesis of benzophenone azine 2b and pyrazole 4 (reaction b) diphenylallylidene)-2-(diarylmethylene)hydrazine. asymmetrical azine product 1-cyclohexylidene-2- This asymmetrical azine seems to be highly reactive (9 H-fluoren-9-ylidene)hydrazine 6a in 95% yield and undergoes a nucleophilic attack from its diaryl (Scheme IX, reaction b), whose structure was confirmed 2 + imino sp -carbon atom by the amino NH 2 moiety of by elemental analysis, IR, NMR and ESI -MS. hydrazone 1 to afford an intermediate which contains Similarly, cyclohexanone 5 reacts with benzophenone a unique sp 3-carbon atom. After that, this intermediate hydrazone 1b under the same experimental conditions undergoes C-N bond cleavage to furnish the azine 2 to produce the 1-cyclohexylidene-2-(diphenylmethylene) and hydrazone 3a intermediate which cyclizes to give hydrazine 6b in 99% yield (Scheme IX, reaction c). 2,3-dihydro-3,5-diphenyl-1H-pyrazole. This latter Interestingly, after 2 months at RT and without intermediate is rapidly dehydrogenated to yield the solvent, compound 6b undergoes a retroaddition final 3,5-diphenyl-1H-pyrazole 4 (Scheme VIII). In followed by homocoupling of two molecules of 1b this reaction hydrazone 1 is a source of nitrogen for to afford the benzophenone azine 2b which was 3,5-diphenyl-1H-pyrazole 4. confirmed by IR and NMR and also by ESI +-MS. The On the other hand, the condensation reaction of spectral analysis shows no traces of 6b and its cyclohexanone 5 with hydrazine, in refluxing EtOH conversion to 2b is quantitative. for 4 h, affords 1,2-dicyclohexylidenehydrazine 6, in 30% yield (Scheme IX, reaction a). In this Experimental Section reaction no cyclohexanone hydrazone was detected Solvents and reagents were obtained from by ESI +-MS. commercial sources and used as received. For TLC, Cyclohexanone 5 reacts with 9-fluorenone hydrazone silica gel plates with F-254 indicator were used. H, C 1a , in refluxing EtOH for 16 h, to furnish the and N elemental analyses were carried out by the LASRI & ISMAIL: SYNTHESIS OF AZINES 369

R R R

N N NH2 R O R -H2O N 1 N NH2 + Ph R 1 Ph 3 Ph Ph

R R

NH NH N R Ph Ph R R N + N N R N NH2 R R 2 Ph 3a

Ph

Ph Ph

HN NH

- H2

Ph Ph

HN N 4

Scheme VIII — Proposed mechanism for the synthesis of azine 2 and 3,5-diphenyl-1H-pyrazole 4 from hydrazone 1 and chalcone 3

Microanalytical Service of the King Abdulaziz molecular formula. Also, it can be used for the University. 1H, 13 C and DEPT-135 NMR spectra (in reaction mixture without further cleaning or CDCl 3 or MeOD-d4) were measured using Bruker separation and at ambient conditions. The product Avance III HD 600 MHz (Ascend TM Magnet) yield was determined based on the intensity of the m/z spectrometer at ambient temperature. 1H, 13 C and of the product divided by the summation of the m/z of DEPT-135 chemical shifts ( δ) are expressed in ppm the starting material(s) and product(s). The calculation relative to TMS. Fourier Transform Infrared spectra is based on the approximation that the starting (400–4000 cm −1 ) was made using Alpha Bruker FTIR materials and products have same efficiency in instrument by fusing the compounds in KBr disc. The producing ions in the ESI +-MS. We believe that this progress of the reactions was monitored by high approximation is valid especially for molecules with resolution high accuracy (down to 5 ppm error) similar molecular structures. The injection of the electrospray ionization mass spectrometry (MicrOTOF compounds was conducted using electrospray II mass spectrometer from Bruker). This technique ionization source. The measured mass spectra were allows the differentiation between any two recorded using positive mode at the range of m/z compounds even with very little difference in the 100–500 with 3.5 kV electrospray voltage. 370 INDIAN J. CHEM., SEC B, MARCH 2018

N N

6a a 1 (95%) h H 6 tO 1 O E x, flu re (b)

N H2NNH2.H2O N EtOH reflux, 4 h (a) h H 16 5 tO , E ux fl ) re (c 1b

6 Ph

(30%) N N

6b Ph (99%)

Scheme IX — Syntheses of 1,2-dicyclohexylidenehydrazine 6 (reaction a), 1-cyclohexylidene-2-(9 H-fluoren-9-ylidene)hydrazine 6a (reaction b), and 1-cyclohexylidene-2-(diphenylmethylene)hydrazine 6b (reaction c) Acetonitrile and 1% hydrofluoric acid diluted solution 9-Fluorenone azine, 2a 28 : m.p.265°C. IR (KBr): was used as electrospray solution (95% acetonitrile: 3453, 3050, 1623, 1598, 1445, 1428, 1305, 1098, 940 −4 −1 1 5% diluted HF). A solution of about 1×10 M was cm ; H NMR (CDCl 3): δ 7.27 (t, 2H, JHH = 7.6 Hz, made from the compound and pure acetonitrile CHar ), 7.42 (t, 2H, JHH = 7.5 Hz, C Har ), 7.43 (t, 2H, solvent. A mixture of 50 µL of previous solution and JHH = 7.4 Hz, C Har ), 7.49 (t, 2H, JHH = 7.5 Hz, C Har ), about 2.0 mL of the electrospray solution was mixed 7.68 (dd, 4H, JHH = 3.9 and 7.4 Hz, C Har ), 8.08 (d, and introduced into the mass spectrometer using 2H, JHH = 7.4 Hz, C Har ), 8.17 (d, 2H, JHH = 7.6 Hz, 13 syringe pump at a flow rate of 100 µL/hr. The CHar ); C NMR (CDCl 3): δ 120.0, 120.1, 122.9, collision energy (CID) was set at 20 eV to obtain the 128.2, 128.3, 129.9, 131.0, 131.4 ( CHar ), 131.3, 136.5, 2 tandem mass spectrum (MS ) of the trapped peak. 141.3, 142.3 (C ar ), 154.9 ( C=N); DEPT-135 NMR (CDCl 3): δ 120.0, 120.1, 122.9, 128.2, 128.3, 129.9, + + Synthesis of symmetrical azines, 2a-b 131.0, 131.4 ( CHar ); ESI -MS: m/z 357.1373 [M+H] . To a solution of 9-fluorenone hydrazone 1a Tandem MS m/z 196.1, 178.1, 169.1, 151.1. Anal. (200 mg, 1.029 mmol) or benzophenone hydrazone Calcd for C 26 H16 N2: C, 87.62; H, 4.52; N, 7.86. 1b (202 mg, 1.029 mmol) in chloroform (5 mL) was Found: C, 87.77; H,4.81; N, 7.45%. added to iron(III) chloride (82.7 mg, 0.511 mmol) and Benzophenone azine, 2b 29 : m.p.162°C. IR (KBr): the mixture was refluxed for 2 or 3 h, respectively. 3442, 1637, 1628, 1561, 1489, 1444, 1320 cm −1 ; 1 The compound was then purified by silica-gel column H NMR (CDCl 3): δ 7.32 (t, 4H, JHH = 7.6 Hz, C Har ), chromatography using chloroform as an eluent. 7.37 (t, 6H, JHH = 7.6 Hz, C Har ), 7.42 (d, 6H, The product was identified as 9-fluorenone azine 2a JHH = 7.3 Hz, C Har ), 7.50 (d, 4H, JHH = 7.5 Hz, C Har ); 13 or benzophenone azine 2b , and obtained in 96% or C NMR (CDCl 3): δ 127.9, 128.0, 128.3, 128.6, 99% yield, respectively. 128.7, 129.3, 129.6, 130.0, 132.4 ( CHar ), 135.5, 138.1 LASRI & ISMAIL: SYNTHESIS OF AZINES 371

(C ar ), 159.0 ( C=N); DEPT-135 NMR (CDCl 3): 128.4, 128.7 ( CHar ), 132.6, 142.5 (C ar ), 151.6 δ 127.9, 128.0, 128.3, 128.6, 128.7, 129.3, 129.6, (H C=CH), 161.6 ( C=N); ESI +-MS: m/z 223.1240 + + + 130.0, 132.4 ( CHar ); ESI -MS: m/z 361.1700 [M+H] . [M+H] . Tandem MS m/z 206.1, 179.1, 119.1, 106.1. Tandem MS m/z 180.1. Anal. Calcd for C 26 H20 N2: C, 86.64; H, 5.59; N, 7.77. Found: C, 86.35; H,5.75; N, Synthesis of pyrazole, 4 7.89%. To a solution of chalcone 3 (200 mg, 0.960 mmol) in EtOH (5 mL) was added hydrazine hydrate Synthesis of asymmetrical azine, 2c (57.7 mg, 1.153 mmol) and the mixture was refluxed To a solution of 9-fluorenone hydrazone 1a for 16 h. After evaporation of the solvent in vacuo (200 mg, 1.029 mmol) and benzophenone hydrazone the compound was purified by silica-gel column 1b (202 mg, 1.029 mmol) in chloroform (5 mL) chromatography using chloroform as an eluent, then was added iron(III) chloride (82.7 mg, 0.511 mmol) + was characterized by IR, NMR and ESI -MS, and and the mixture was refluxed for 1.5 h. The identified as 3,5-diphenyl-1H-pyrazole 4 (65% yield). compound was then purified by silica-gel column 30 3,5-Diphenyl-1H-pyrazole, 4 : m.p.200°C. IR chromatography using chloroform as an eluent. −1 1 (KBr): 3408, 1637 cm ; H NMR (CDCl ): δ 4.94 The product was identified as 1-(diphenylmethylene)- 3 (bs, 1H, N H), 6.88 (s, 1H, C H), 7.36-7.44 (m, 6H, 2-(9 H-fluoren-9-ylidene)hydrazine 2c and obtained in 13 CH ), 7.75 (d, 4H, J = 7.8 Hz, C H ); C NMR 74% yield. ar HH ar (CDCl ): δ 100.4 ( CH), 125.9, 128.3, 128.4, 128.5, 1-(Diphenylmethylene)-2-(9 H-fluoren-9-ylidene) 3 128.6, 128.7, 128.8, 128.9, 130.1, 133.1 ( CH ), 130.4 hydrazine, 2c : m.p.199°C. IR (KBr): 3448, 1607, ar −1 1 (Car ), 148.4 ( C=N) and ( C=CH); DEPT-135 NMR 1594, 1489, 1445, 1319 cm ; H NMR (CDCl 3): (CDCl 3): δ 100.4 ( CH), 125.9, 128.3, 128.4, 128.5, δ 7.24-7.31 (m, 4H, C Har ), 7.38-7.46 (m, 5H, C Har ), 128.6, 128.7, 128.8, 128.9, 130.1, 133.1 ( CHar ); 7.48-7.52 (m, 3H, C H ), 7.63 (d, 1H, J = 7.5 Hz, + + ar HH ESI -MS: m/z 221.10656 [M+H] . Tandem MS m/z CH ), 7.68 (t, 2H, J = 7.6 Hz, C H ), 7.86 (d, 2H, ar HH ar 194.1, 167.1, 119.1, 106.1. Anal. Calcd for C H N : J = 7.9 Hz, C H ), 8.16 (d, 1H, J = 7.6 Hz, C H ); 15 12 2 HH ar HH ar C, 81.79; H, 5.49; N, 12.72. Found: C, 81.87; H,5.55; 13 C NMR (CDCl ): δ 119.7, 120.0, 122.7, 127.7, 3 N, 12.87%. 128.0, 128.2, 128.3, 129.1, 129.2, 129.3, 130.0, 130.1, 130.5, 131.1 ( CHar ), 131.7, 134.7, 136.8, 137.9, 140.9, Synthesis of symmetrical azine, 6 142.2 (C ar ), 156.1, 159.9 ( C=N); DEPT-135 NMR To a solution of cyclohexanone 5 (200 mg, 2.037 δ (CDCl 3): 119.7, 120.0, 122.7, 127.7, 128.0, 128.2, mmol) in EtOH (5 mL) was added hydrazine hydrate 128.3, 129.1, 129.2, 129.3, 130.0, 130.1, 130.5, 131.1 (122 mg, 2.444 mmol) and the mixture was refluxed + + (CHar ); ESI -MS: m/z 359.1557 [M+H] . Tandem MS for 4 h. After evaporation of the solvent in vacuo the m/z 180.1, 77.0. Anal. Calcd for C 26 H18 N2: C, 87.12; compound was purified by silica-gel column H, 5.06; N, 7.82. Found: C, 87.24; H,5.18; N, 7.73%. chromatography using chloroform as an eluent, then was characterized by IR, NMR and ESI +-MS, Synthesis of hydrazone, 3a and identified as 1,2-dicyclohexylidenehydrazine 6 To a solution of 1,3-diphenyl-2-propenone 3 (30% yield). (200 mg, 0.960 mmol) in EtOH (5 mL) was added 1,2-Dicyclohexylidenehydrazine, 6 3b : m.p.36°C. IR hydrazine hydrate (57.7 mg, 1.153 mmol) and the −1 1 (KBr): 3449, 1637 cm ; H NMR (CDCl 3): δ 1.59-1.61 mixture was refluxed for 15 min. After evaporation of (m, 8H, C H ), 1.70-1.72 (m, 4H, C H ), 2.31 (t, 4H, the solvent in vacuo the compound was characterized 2 2 JHH = 6.4 Hz, C H2), 2.35 (t, 4H, JHH = 6.4 Hz, C H2); directly without further purification by silica-gel 13 C NMR (CDCl ): δ 25.9, 26.3, 27.5, 27.9, 35.6 column chromatography due to its high reactivity, and 3 (CH2), 165.5 ( C=N); DEPT-135 NMR (CDCl 3): it was identified as 1-(( E)-1,3-diphenylallylidene) + δ 25.9, 26.3, 27.5, 27.9, 35.6 ( CH2); ESI -MS: m/z hydrazine 3a and obtained in 90% yield. 193.1693 [M+H] +. Tandem MS m/z 176.1 and 98.1, 1-(( E)-1,3-diphenylallylidene)hydrazine, 3a : IR 96.1. Anal. Calcd for C H N : C, 74.95; H, 10.48; −1 1 12 20 2 (KBr): 3422, 1670, 1598, 1492, 1449 cm ; H NMR N, 14.57. Found: C, 75.13; H,10.69; N, 14.43%. (MeOD-d4), δ:7.29 (t, 1H, JHH = 7.3 Hz, C Har ), 7.35-7.38 (m, 4H, C HandC Har ), 7.39-7.43 (m, 5H, Synthesis of asymmetrical azines, 6a-b CHandC Har ), 7.69 (d, 2H, JHH = 7.0 Hz, C Har ); To a solution of cyclohexanone 5 (200 mg, 2.037 13 C NMR (MeOD-d4): δ 125.7, 126.2, 127.2, 128.3, mmol) in EtOH (5 mL) was added 9-fluorenone 372 INDIAN J. CHEM., SEC B, MARCH 2018

hydrazone 1a (396 mg, 2.037 mmol) or benzophenone conditions. We have found that FeCl 3 Lewis acid hydrazone 1b (400 mg, 2.037 mmol) and the mixture catalyst is the best metal catalyst for this type of was refluxed for 16 h. After evaporation of the reaction. The reaction also depends on the reaction solvent in vacuo the compound was purified by silica- time, temperature, and on the type of solvent used. By gel column chromatography using chloroform as an applying the same reaction protocol we have also eluent, then was characterized by IR, NMR and succeeded to synthesize benzophenone azine from ESI +-MS, and identified as 1-cyclohexylidene-2-(9 H- benzophenone hydrazone. Furthermore, we have fluoren-9-ylidene)hydrazine 6a (95% yield) or prepared an asymmetrical azine by combination of 1-cyclohexylidene-2-(diphenylmethylene)hydrazine 9-fluorenone hydrazone and benzophenone hydrazone 6b (99% yield), respectively. in the presence of FeCl 3 Lewis acid catalyst. To the 1-Cyclohexylidene-2-(9 H-fluoren-9-ylidene) best of our knowledge, this is the first FeCl 3-catalysed hydrazine, 6a : m.p.80°C. IR (KBr): 3444, 1628, synthesis of an asymmetrical azine by combination of −1 1 1610, 1448 cm ; H NMR (CDCl 3): δ 1.69 (dt, 4H, two different hydrazones. The progress of the JHH = 2.8 and 6.4 Hz, C H2), 1.87-1.90 (m, 2H, C H2), catalytic reactions was monitored by high resolution + 2.57 (t, 2H, JHH = 6.6 Hz, C H2), 2.60 (t, 2H, JHH = 6.4 ESI -MS. Hz, C H2), 7.29 (t, 1H, JHH = 7.5 Hz, C Har ), 7.33 (t, On the other hand, the condensation reaction of 1H, JHH = 7.4 Hz, C Har ), 7.42 (t, 1H, JHH = 7.5 Hz, chalcone with 9-fluorenone hydrazone affords CHar ), 7.43 (t, 1H, JHH = 7.5 Hz, C Har ), 7.63 (d, 1H, 9-fluorenone azine and 3,5-diphenyl-1H-pyrazole. JHH = 7.5 Hz, C Har ), 7.66 (d, 1H, JHH = 7.4 Hz, C Har ), Similarly, chalcone reacts with benzophenone 7.90 (d, 1H, JHH = 7.5 Hz, C Har ), 8.18 (d, 1H, hydrazone to produce a mixture of benzophenone 13 JHH = 7.5 Hz, C Har ); C NMR (CDCl 3): δ 25.8, 26.4, azine and 3,5-diphenyl-1H-pyrazole. Moreover, the 27.4, 28.7, 35.5 ( CH2), 119.7, 119.9, 122.4, 127.9, proposed mechanism of these reactions was 128.0, 129.4, 130.4, 130.9 ( CHar ), 131.6, 136.9, 140.9, discussed. Finally, cyclohexanone reacts with 142.2 (C ar ), 154.7 ( C=N), 166.3 ( C=N cyclohexyl ); 9-fluorenone hydrazone or benzophenone hydrazone DEPT-135 NMR (CDCl 3): δ 25.8, 26.4, 27.4, 28.7, to furnish asymmetrical azines, in very good yields, 35.5 ( CH2), 119.7, 119.9, 122.4, 127.9, 128.0, 129.4, without the need of any added acid catalyst or + + 130.4, 130.9 ( CHar ); ESI -MS: m/z 275.1538 [M+H] . promoter. Tandem MS m/z 180.1, 96.1. Anal. Calcd for C19 H18 N2: C, 83.18; H,6.61; N, 10.21. Found: C, Supplementary Information 1 13 + 83.24; H,6.77; N, 10.35%. H and C NMR, and ESI -MS spectra are given 1-Cyclohexylidene-2-(diphenylmethylene)hydrazine, in the Electronic Supplementary Information available 6b : m.p.75°C. IR (KBr): 3443, 1635, 1559, 1492, at http://nopr.niscair.res.in/handle/123456789/60. −1 1 δ 1444 cm ; H NMR (CDCl 3): 1.62-1.67 (m, 6H, Acknowledgment CH2), 2.28 (bs, 2H, C H2), 2.52 (bs, 2H, C H2), This project was funded by the Deanship of 7.22-7.67 (m, 9H, C Har ), 7.83 (d, 1H, JHH = 6.9 Hz, 13 δ Scientific Research (DSR) at King Abdulaziz CHar ); C NMR (CDCl 3): 25.8, 26.2, 27.2, 29.1, University, Jeddah, under grant no. (G-1436-662- 35.3 ( CH2), 126.5, 127.9, 128.0, 128.1, 128.3, 128.4, 104). The authors, therefore, acknowledge with 129.2, 129.3, 130.1, 132.4 ( CHar ), 135.5, 137.6 (C ar ), thanks DSR for technical and financial support. 158.9 ( C=N), 165.2 ( C=N cyclohexyl ); DEPT-135 NMR δ (CDCl 3): 25.8, 26.2, 27.2, 29.1, 35.3 ( CH2), 126.5, References 127.9, 128.0, 128.1, 128.3, 128.4, 129.2, 129.3, 130.1, 1 (a) Chen G S, Anthamatten M, Barnes C L & Glaser R, + + 132.4 ( CHar ); ESI -MS: m/z 277.1705 [M+H] . Angew Chem Int Ed , 33 (1994) 1081; (b) Wolff J J & Tandem MS m/z 182.1, 180.1, 104.1, 96.1, 69.1. Anal. Wortmann R, Adv Phys Org Chem , 32 (1999) 121. 2 Son S U, Park K H, Jung I G, Chung Y K & Lah M S, Calcd for C 19 H20 N2: C, 82.57; H, 7.29; N, 10.14. Organometallics , 21 (2002) 5366. Found: C, 82.86; H,7.55; N, 10.27%. 3 (a) Grashey R & Padwa A, ‘Azomethine imines’ in 1,3-Dipolar Cycloaddition Chemistry , edited by Taylort D C Conclusion & Weissberger A (General Heterocyclic Chemistry Series, John Wiley and Sons, New York) 1 (1984) 733; (b) Verner J In this study, we have tested various metals as & Potá ček M, Molecules , 11 (2006) 34. catalysts for the synthesis of 9-fluorenone azine 4 Schweizer E E, Cao Z, Rheingold A L & Bruch M, from 9-fluorenone hydrazone under different reaction J Org Chem , 58 (1993) 4339. LASRI & ISMAIL: SYNTHESIS OF AZINES 373

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