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There are some studies reporting the synthesis of pyrazole derivatives using chalcones as starting materials22. For example, 3,5-disubstituted pyrazoles can be ...
Indian Journal of Chemistry Vol. 57B, March 2018, pp. 362-373

Metal-free and FeCl3-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 FeCl3 Lewis acid catalyst in CHCl3. Treatment of 1a and 1b with FeCl3 affords the asymmetrical azine 1-(diphenylmethylene)-2-(9H-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, 13C and DEPT-135 NMR spectroscopy and also by high resolution ESI+-MS. Keywords: Hydrazones, ketones, azines, 3,5-diphenyl-1H-pyrazole, FeCl3 Lewis acid catalyst, ESI+-MS

Azines (R2C=N–N=CR2) have recently received attention due to their unusual reactivity and spectral properties. For example, azines showed great nonlinear optical (NLO) characteristics1. Also, they have been used as ligands in organometallic chemistry2. Azines are 2,3-diaza comparable to 1,3-butadiene, therefore, they participate in an unusual 1,3-dipolar cycloaddition (the criss-cross cycloaddition) with dienophiles providing an easy route to five membered heterocycles3. Azines also undergo [2 + 3] cycloadditions as an ene-fragment4. Acetophenone azines have been involved in many studies5 using crystallographic data6, NMR spectroscopic measurements7, and theoretical calculations8. There are several reported methods for the preparation of azines. They can be prepared by reaction of aldehydes and ketones with hydrazine sulfate, in the presence of CH3CO2Na/CaCl2, under microwave irradiation9, by refluxing ketones with hydrazine hydrate in acidic ethanolic solution10, or by reaction of carbonyl compounds with hydrazine in the presence of molecular iodine11. Azines can also be synthesized by oxidation of hydrazones using in situ generated Et4NO212, or by reaction of hydrazones with N-bromosuccinimide (NBS)13. Azines with extreme push–pull substituents were prepared by the

combination of N-heterocyclic carbenes (NHC) with diazoalkanes14 which show structural trends consistent with delocalization within the azine framework15. On the other hand, the synthesis of 3,5disubstituted pyrazoles remains of great interest because they have displayed a wide range of biological activities such as in inhibiting lung cancer cell growth16. For many years, numerous methods have been developed in order to synthesize this class of heterocycles17. The synthesis of 3,5-disubstituted pyrazoles by condensation of 1,3-diketones with hydrazine or its derivatives is the most widely used method18. Unfortunately, this condensation leads to the formation of undesired isomers as major components19-21. There are some studies reporting the synthesis of pyrazole derivatives using chalcones as starting materials22. For example, 3,5-disubstituted pyrazoles can be prepared by condensation of chalcones, hydrazine and sulfur in ethanol23 or by reaction of chalcones, hydrazine and Na2S2O8 using mechano-chemical ball-milling technique24. The development of high resolution mass spectrometry (HRMS) has made it possible to use them in monitoring chemical reactions and intermediates25. The advantage of using electrospray

LASRI & ISMAIL: SYNTHESIS OF AZINES

ionization mass spectrometry (ESI-MS) is that the reaction mixture can be used without purification. Also, the HRMS can easily differentiate products even for compounds with very close chemical structures and formulas. Therefore, ESI-MS provides a great tool to monitor the progress of the chemical reaction in real time. Herein, we would like (i) to investigate the best metal-catalyst for the synthesis of symmetrical and asymmetrical azines starting from 9-fluorenone hydrazone and/or benzophenone hydrazone, (ii) to prepare new asymmetrical azines by acid-free condensation of cyclohexanone with hydrazones, (iii) to synthesize 3,5-diphenyl-1H-pyrazole by condensation of chalcone with hydrazine without the addition of any oxidant, and (iv) to propose mechanisms for those types of transformations based on the results obtained from ESI+-MS, NMR, and IR spectra. Results and Discussion This work was inspired by our previous study of the reaction of bis(organonitrile) platinum(II) complex [PtCl2(NCR)2] with a nucleophile26 such as 9-fluorenone hydrazone. Small amount of one new product was obtained which was then isolated from the reaction mixture by column chromatography and characterized by NMR spectroscopy and HRMS, and identified as a 9-fluorenone azine. Because, to our knowledge, the use of metals as

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catalysts for the synthesis of azines monitored by high resolution ESI+-MS has not yet been reported, we have decided to investigate the role of bis(propionitrile)platinum(II) complex [PtCl2(NCEt)2] and other metal ions looking for best metal catalyst for the azine synthesis. Hence, the reaction of 9-fluorenone hydrazone 1a was carried out in the presence of one of the following metal salts (or metal complexes) [PtCl2(NCEt)2], K2PtCl4, PtCl2, PdCl2, ZnCl2, CoCl2.6H2O, CuSO4.5H2O, FeS, FeCl2.4H2O or FeCl3, and studied under different conditions (time of reaction, temperature and solvent). The progress of the reaction was monitored by high resolution ESI+-MS and the 9-fluorenone azine 2a was confirmed by elemental analysis, IR and 1H, 13C and DEPT-135 NMR spectroscopy and also by HRMS. The reaction is highly dependent on the nature of the metal ion employed. Also, it depends on the reaction time, temperature, and on the type of solvent used. In all cases, we observed that the reactions under reflux gave better yields than at RT. Also, we concluded that chloroform gave better yields than methanol. When comparing the catalytic activity of the metal salts we observed that very poor yields of 9-fluorenone azine 2a (ca. 7%) were obtained when using [PtCl2(NCEt)2] or K2PtCl4 (Table I, entry 3; Figure 1). By employing PtCl2 or PdCl2 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

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Table I — Reaction of 9-fluorenone hydrazone 1a or benzophenone hydrazone 1b under different conditionsa Entry

Compd

Product

Conditions

Time (h)

Solvent

Catalyst

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1b 1b

2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2b 2b 2b 2b

Reflux RT Reflux RT Reflux RT Reflux RT Reflux RT Reflux RT Reflux RT Reflux Reflux RT Reflux RT Reflux RT Reflux RT Reflux RT Reflux Reflux Reflux Reflux Reflux Reflux Reflux RT RT RT RT

24 24 24 24 24 24 24 24 24 24 24 24 24 24 1 24 24 24 24 24 24 24 24 24 24 0.25 0.60 0.75 1.17 2 2 3 2 24 72 120

CHCl3 CHCl3 CHCl3 CHCl3 H2O/MeOH (2:3) H2O/MeOH (2:3) CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 MeOH CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 MeOH MeOH CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3

None None PtCl2(NCEt)2 PtCl2(NCEt)2 K2PtCl4 K2PtCl4 PtCl2 PtCl2 PdCl2 PdCl2 ZnCl2 ZnCl2 CoCl2.6H2O CoCl2.6H2O CuSO4.5H2O CuSO4.5H2O CuSO4.5H2O FeS FeS FeCl2.4H2O FeCl2.4H2O FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3

5 3 7 3 5 3 17 13 18 5 40 17 21 10 5 9 6 2 1 14 8 99 70 67 43 39 79 88 94 96 73 99 30 80 85 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 ZnCl2, CoCl2.6H2O, CuSO4.5H2O, FeS and FeCl2.4H2O we observed that ZnCl2 was a better catalyst and gave 2a in 40% yield under reflux in chloroform for 24 h (Table I, entry 11; Figure 1). Surprisingly, the best yields of 96 and 99% of 2a were obtained when FeCl3 was employed under reflux in CHCl3 for 2 or 24 h, respectively (Scheme I; Table I, entries 22 and 30; Figure 1).

Refluxing 9-fluorenone hydrazone 1a in chloroform, in the absence of any metal salt for 24 h, affords 9-fluorenoneazine 2a in 5% yield (Table I, entry 1) indicating that the reaction is metal catalysed. Similarly, the benzophenone azine 2b was synthesized, in 99% yield, starting from benzophenone hydrazone 1b and using the same reaction protocol (FeCl3, CHCl3, reflux for 3 h) (Scheme II; Table I, entry 32).

LASRI & ISMAIL: SYNTHESIS OF AZINES

N

FeCl3

NH2

365

N

N

CHCl3 reflux, 2 h

1a

2a (96%)

Scheme I — Synthesis of 9-fluorenone azine 2a

Ph

Ph

FeCl3 N

NH2

Ph N

CHCl3 reflux, 3 h

Ph 1b

N

Ph

Ph 2b (99%)

Scheme II — Synthesis of benzophenone azine 2b H

R N

N

R

H

R

FeCl3

R N

NH2

N

NH

H

H

R 2

H N

FeCl3

FeCl3

NH2 N

R

N

1

R R

R

R 1

R H N R

R N

R

2

- H2NNH2

R

NH2

- FeCl3

N H

N

N

R R

R

Scheme III — Proposed mechanism for the synthesis of azine 2 from hydrazone 1 catalysed by FeCl3

We believe that the reactions (Scheme I and Scheme II) start by coordination of FeCl3 Lewis acid catalyst to the terminal nitrogen of hydrazone 1, this coordination enhances the electrophilicity of the

imino-carbon atom of 1 which can readily undergo nucleophilic attack by the amino moiety NH2 of the uncoordinated hydrazone 1 to produce, after elimination of FeCl3 and hydrazine10b, the azine 2 (Scheme III).

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An asymmetrical azine such as 1-(diphenylmethylene)-2-(9H-fluoren-9-ylidene)hydrazine 2c was also synthesized in 74% yield by reaction of 1a and 1b, in refluxing chloroform for 1.5 h, in the presence of FeCl3 (Scheme IV). The reaction of 1a with 1b in the absence of FeCl3, refluxed in chloroform for 3 days, affords 2c in a very poor yield indicating that the reaction is metal catalysed.

The products (Scheme IV) were identified by ESI+-MS. The high resolution high accuracy mass spectrometry allows the differentiation between 2a, 2b and 2c (m/z 357, 359 and 361, respectively), which was done using the isotope pattern of each compound. The reaction yield can be then calculated based on the m/z intensities (Figure 2).

Ph 1a +

1b

FeCl3 CHCl3 reflux, 1.5 h

2a (1%)

+

2b (7%)

N

+

N

Ph 2c (74%)

Scheme IV — Synthesis of 1-(diphenylmethylene)-2-(9H-fluoren-9-ylidene)hydrazine 2c from 1a and 1b catalysed by FeCl3

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

Compound 2c was then purified by column chromatography and characterized by elemental analysis, IR, 1H, 13C and DEPT-135 NMR spectroscopy and also by high resolution ESI+-MS (Experimental Section and Electronic Supplementary Information). To the best of our knowledge, this is the first FeCl3catalysed synthesis of asymmetrical azine 2c from 9-fluorenone hydrazone 1a and benzophenone hydrazone 1b. It was reported27 that 2c was synthesized by condensation of a ketone (benzophenone) with 9-fluorenone hydrazone using acetic acid in ethanol. In that report27, azine 2c was characterized only by X-ray diffraction analysis. In this part of the work, 1,3-diphenyl-2-propenone (also called chalcone) 3 was selected for further synthesis of a variety of compounds with useful applications. Herein, the reaction of 3 with hydrazine, refluxed in ethanol for 15 min, produces the 1-((E)1,3-diphenylallylidene)hydrazine 3a in 90% yield (Scheme V). Due to its high reactivity, compound 3a was directly characterized by HRMS, IR and NMR without purification by silica-gel column chromatography. In the 13C NMR spectrum, the observed signal at δ 161.6 confirms the formation of the hydrazone 3a. To the best of our knowledge, this is the first characterization of the highly reactive hydrazone 3a by IR, 1H and 13C NMR, and ESI+-MS methods. Under reflux, in EtOH for 16 h, 3a converts to 3,5diphenyl-1H-pyrazole 4 (65% yield) and dihydrogen (Scheme V). On the other hand, the 50% conversion of 3a to 4 was observed at RT without solvent after 3 days. In contrast to the previous reports23,24, this study shows that 3,5-diphenyl-1H-pyrazole 4 can be obtained in 65% yield from chalcone 3 by reflux in EtOH without the need of any added oxidant. On the other hand, we were interested to study the possibility of the synthesis of symmetrical

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azine 1,2-bis((E)-1,3-diphenylallylidene)hydrazine by homocoupling of the in situ generated 1-((E)-1,3diphenylallylidene)hydrazine 3a in the presence of FeCl3, and, also the possibility of the synthesis of asymmetrical azine 1-((E)-1,3-diphenylallylidene)-2(diphenylmethylene)hydrazine by reaction of 3a with benzophenonehydrazone 1b in the presence of FeCl3. In both cases, the expected azine products were neither detected by mass spectrometry nor by NMR spectroscopy probably due to their high reactivity. Hence, the reaction of the in situ generated hydrazone 3a with benzophenone hydrazone 1b in the presence of FeCl3, refluxed in ethanol for 2 h, affords a mixture of 3,5-diphenyl-1H-pyrazole 4 and benzophenone azine 2b in ca. 5% and 7% yield, respectively (Scheme VI). The product yield was calculated using the ratio of m/z intensities from ESI+-MS compared to their native starting material i.e. the yield of the product 4 is based on the ratio of m/z of 4 divided by the sum of m/z of 4 and 3a. In this section, the previously unknown reaction between chalcone 3 and 9-fluorenone hydrazone 1a was also investigated. Hence, the condensation reaction of 3 with 1a, in refluxing ethanol for 16 h, affords 9-fluorenone azine 2a and 3,5-diphenyl-1Hpyrazole 4 in 35% and 53% yield, respectively (Scheme VII, reaction a). Similarly, the reaction of 3 with benzophenone hydrazone 1b, in refluxing ethanol for 16 h, produces a mixture of benzophenone azine 2b and 3,5diphenyl-1H-pyrazole 4 in 79% and 20% yield, respectively (Scheme VII, reaction b), based on ratio of m/z intensities from ESI+-MS of the product to that of its native starting material. We believe that the reaction of Scheme VII is carried out by the attack of the amino moiety of hydrazone 1 to the carbonyl group of chalcone 3 to produce the azine intermediate 1-((E)-1,3NH2

O

N

Ph +

H2NNH2.H2O

reflux, 16 h

N

N

- H2

Ph 3

Ph

EtOH

reflux, 15 min Ph

Ph

Ph

EtOH

3a (90%)

4

H

(65%)

Scheme V — Synthesis of 1-((E)-1,3-diphenylallylidene)hydrazine 3a and 3,5-diphenyl-1H-pyrazole 4 from chalcone 3

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368 Ph

Ph N

Ph

NH2

N

N

Ph 3a

Ph

Ph FeCl3

+

EtOH reflux, 2 h

Ph N Ph

Ph N

1b

Ph

Ph

NH2

Ph N

+

N

N Ph 4

Ph 2b

H

(7%)

(5%)

Scheme VI — Reaction of the in situ generated 1-((E)-1,3-diphenylallylidene)hydrazine 3a with benzophenonehydrazone 1b in the presence of FeCl3

O

2b (79%)

Ph

1b +

4 (20%)

EtOH reflux, 16 h (b)

Ph

3

1a EtOH reflux, 16 h (a)

2a (35%)

+

4 (53%)

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. This asymmetrical azine seems to be highly reactive and undergoes a nucleophilic attack from its diaryl imino sp2-carbon atom by the amino NH2 moiety of hydrazone 1 to afford an intermediate which contains a unique sp3-carbon atom. After that, this intermediate undergoes C-N bond cleavage to furnish the azine 2 and hydrazone 3a intermediate which cyclizes to give 2,3-dihydro-3,5-diphenyl-1H-pyrazole. This latter intermediate is rapidly dehydrogenated to yield the final 3,5-diphenyl-1H-pyrazole 4 (Scheme VIII). In this reaction hydrazone 1 is a source of nitrogen for 3,5-diphenyl-1H-pyrazole 4. On the other hand, the condensation reaction of cyclohexanone 5 with hydrazine, in refluxing EtOH for 4 h, affords 1,2-dicyclohexylidenehydrazine 6, in 30% yield (Scheme IX, reaction a). In this reaction no cyclohexanone hydrazone was detected by ESI+-MS. Cyclohexanone 5 reacts with 9-fluorenone hydrazone 1a, in refluxing EtOH for 16 h, to furnish the

asymmetrical azine product 1-cyclohexylidene-2(9H-fluoren-9-ylidene)hydrazine 6a in 95% yield (Scheme IX, reaction b), whose structure was confirmed by elemental analysis, IR, NMR and ESI+-MS. Similarly, cyclohexanone 5 reacts with benzophenone hydrazone 1b under the same experimental conditions to produce the 1-cyclohexylidene-2-(diphenylmethylene) hydrazine 6b in 99% yield (Scheme IX, reaction c). Interestingly, after 2 months at RT and without solvent, compound 6b undergoes a retroaddition followed by homocoupling of two molecules of 1b to afford the benzophenone azine 2b which was confirmed by IR and NMR and also by ESI+-MS. The spectral analysis shows no traces of 6b and its conversion to 2b is quantitative. Experimental Section Solvents and reagents were obtained from commercial sources and used as received. For TLC, silica gel plates with F-254 indicator were used. H, C and N elemental analyses were carried out by the

LASRI & ISMAIL: SYNTHESIS OF AZINES

R

369

R R

N R

NH2

N

N

O

R

-H2O

+

R

N

NH2

1

Ph 1

Ph 3 Ph Ph

R

R NH NH

Ph

R

Ph

N

R

R N N

+ N

NH2

R

R

N

2

R

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 University. 1H, 13C and DEPT-135 NMR spectra (in CDCl3 or MeOD-d4) were measured using Bruker Avance III HD 600 MHz (AscendTM Magnet) spectrometer at ambient temperature. 1H, 13C and DEPT-135 chemical shifts (δ) are expressed in ppm relative to TMS. Fourier Transform Infrared spectra (400–4000 cm−1) was made using Alpha Bruker FTIR instrument by fusing the compounds in KBr disc. The progress of the reactions was monitored by high resolution high accuracy (down to 5 ppm error) electrospray ionization mass spectrometry (MicrOTOF II mass spectrometer from Bruker). This technique allows the differentiation between any two compounds even with very little difference in the

molecular formula. Also, it can be used for the reaction mixture without further cleaning or separation and at ambient conditions. The product yield was determined based on the intensity of the m/z of the product divided by the summation of the m/z of the starting material(s) and product(s). The calculation is based on the approximation that the starting materials and products have same efficiency in producing ions in the ESI+-MS. We believe that this approximation is valid especially for molecules with similar molecular structures. The injection of the compounds was conducted using electrospray ionization source. The measured mass spectra were recorded using positive mode at the range of m/z 100–500 with 3.5 kV electrospray voltage.

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N 1a

O

N

H2NNH2.H2O

N

EtOH reflux, 4 h (a)

H 6h EtO x, 1 lu ref (b)

16 OH Et lux, f re (c)

5

N

6a (95%)

h

1b

Ph

6 (30%)

N

N 6b (99%)

Ph

Scheme IX — Syntheses of 1,2-dicyclohexylidenehydrazine 6 (reaction a), 1-cyclohexylidene-2-(9H-fluoren-9-ylidene)hydrazine 6a (reaction b), and 1-cyclohexylidene-2-(diphenylmethylene)hydrazine 6b (reaction c)

Acetonitrile and 1% hydrofluoric acid diluted solution was used as electrospray solution (95% acetonitrile: 5% diluted HF). A solution of about 1×10−4 M was made from the compound and pure acetonitrile solvent. A mixture of 50 µL of previous solution and about 2.0 mL of the electrospray solution was mixed and introduced into the mass spectrometer using syringe pump at a flow rate of 100 µL/hr. The collision energy (CID) was set at 20 eV to obtain the tandem mass spectrum (MS2) of the trapped peak. Synthesis of symmetrical azines, 2a-b To a solution of 9-fluorenone hydrazone 1a (200 mg, 1.029 mmol) or benzophenone hydrazone 1b (202 mg, 1.029 mmol) in chloroform (5 mL) was added to iron(III) chloride (82.7 mg, 0.511 mmol) and the mixture was refluxed for 2 or 3 h, respectively. The compound was then purified by silica-gel column chromatography using chloroform as an eluent. The product was identified as 9-fluorenone azine 2a or benzophenone azine 2b, and obtained in 96% or 99% yield, respectively.

9-Fluorenone azine, 2a28: m.p.265°C. IR (KBr): 3453, 3050, 1623, 1598, 1445, 1428, 1305, 1098, 940 cm−1; 1H NMR (CDCl3): δ 7.27 (t, 2H, JHH = 7.6 Hz, CHar), 7.42 (t, 2H, JHH = 7.5 Hz, CHar), 7.43 (t, 2H, JHH = 7.4 Hz, CHar), 7.49 (t, 2H, JHH = 7.5 Hz, CHar), 7.68 (dd, 4H, JHH = 3.9 and 7.4 Hz, CHar), 8.08 (d, 2H, JHH = 7.4 Hz, CHar), 8.17 (d, 2H, JHH = 7.6 Hz, CHar); 13C NMR (CDCl3): δ 120.0, 120.1, 122.9, 128.2, 128.3, 129.9, 131.0, 131.4 (CHar), 131.3, 136.5, 141.3, 142.3 (Car), 154.9 (C=N); DEPT-135 NMR (CDCl3): δ 120.0, 120.1, 122.9, 128.2, 128.3, 129.9, 131.0, 131.4 (CHar); ESI+-MS: m/z 357.1373 [M+H]+. Tandem MS m/z 196.1, 178.1, 169.1, 151.1. Anal. Calcd for C26H16N2: C, 87.62; H, 4.52; N, 7.86. Found: C, 87.77; H,4.81; N, 7.45%. Benzophenone azine, 2b29: m.p.162°C. IR (KBr): 3442, 1637, 1628, 1561, 1489, 1444, 1320 cm−1; 1 H NMR (CDCl3): δ 7.32 (t, 4H, JHH = 7.6 Hz, CHar), 7.37 (t, 6H, JHH = 7.6 Hz, CHar), 7.42 (d, 6H, JHH = 7.3 Hz, CHar), 7.50 (d, 4H, JHH = 7.5 Hz, CHar); 13 C NMR (CDCl3): δ 127.9, 128.0, 128.3, 128.6, 128.7, 129.3, 129.6, 130.0, 132.4 (CHar), 135.5, 138.1

LASRI & ISMAIL: SYNTHESIS OF AZINES

(Car), 159.0 (C=N); DEPT-135 NMR (CDCl3): δ 127.9, 128.0, 128.3, 128.6, 128.7, 129.3, 129.6, 130.0, 132.4 (CHar); ESI+-MS: m/z 361.1700 [M+H]+. Tandem MS m/z 180.1. Anal. Calcd for C26H20N2: C, 86.64; H, 5.59; N, 7.77. Found: C, 86.35; H,5.75; N, 7.89%. Synthesis of asymmetrical azine, 2c To a solution of 9-fluorenone hydrazone 1a (200 mg, 1.029 mmol) and benzophenone hydrazone 1b (202 mg, 1.029 mmol) in chloroform (5 mL) was added iron(III) chloride (82.7 mg, 0.511 mmol) and the mixture was refluxed for 1.5 h. The compound was then purified by silica-gel column chromatography using chloroform as an eluent. The product was identified as 1-(diphenylmethylene)2-(9H-fluoren-9-ylidene)hydrazine 2c and obtained in 74% yield. 1-(Diphenylmethylene)-2-(9H-fluoren-9-ylidene) hydrazine, 2c: m.p.199°C. IR (KBr): 3448, 1607, 1594, 1489, 1445, 1319 cm−1; 1H NMR (CDCl3): δ 7.24-7.31 (m, 4H, CHar), 7.38-7.46 (m, 5H, CHar), 7.48-7.52 (m, 3H, CHar), 7.63 (d, 1H, JHH = 7.5 Hz, CHar), 7.68 (t, 2H, JHH = 7.6 Hz, CHar), 7.86 (d, 2H, JHH = 7.9 Hz, CHar), 8.16 (d, 1H, JHH = 7.6 Hz, CHar); 13 C NMR (CDCl3): δ 119.7, 120.0, 122.7, 127.7, 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, 142.2 (Car), 156.1, 159.9 (C=N); DEPT-135 NMR (CDCl3): δ 119.7, 120.0, 122.7, 127.7, 128.0, 128.2, 128.3, 129.1, 129.2, 129.3, 130.0, 130.1, 130.5, 131.1 (CHar); ESI+-MS: m/z 359.1557 [M+H]+. Tandem MS m/z180.1, 77.0. Anal. Calcd for C26H18N2: C, 87.12; H, 5.06; N, 7.82. Found: C, 87.24; H,5.18; N, 7.73%. Synthesis of hydrazone, 3a To a solution of 1,3-diphenyl-2-propenone 3 (200 mg, 0.960 mmol) in EtOH (5 mL) was added hydrazine hydrate (57.7 mg, 1.153 mmol) and the mixture was refluxed for 15 min. After evaporation of the solvent in vacuo the compound was characterized directly without further purification by silica-gel column chromatography due to its high reactivity, and it was identified as 1-((E)-1,3-diphenylallylidene) hydrazine 3a and obtained in 90% yield. 1-((E)-1,3-diphenylallylidene)hydrazine, 3a: IR (KBr): 3422, 1670, 1598, 1492, 1449 cm−1; 1H NMR (MeOD-d4), δ:7.29 (t, 1H, JHH = 7.3 Hz, CHar), 7.35-7.38 (m, 4H, CHandCHar), 7.39-7.43 (m, 5H, CHandCHar), 7.69 (d, 2H, JHH = 7.0 Hz, CHar); 13 C NMR (MeOD-d4): δ 125.7, 126.2, 127.2, 128.3,

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128.4, 128.7 (CHar), 132.6, 142.5 (Car), 151.6 (HC=CH), 161.6 (C=N); ESI+-MS: m/z 223.1240 [M+H]+. Tandem MS m/z 206.1, 179.1, 119.1, 106.1. Synthesis of pyrazole, 4 To a solution of chalcone 3 (200 mg, 0.960 mmol) in EtOH (5 mL) was added hydrazine hydrate (57.7 mg, 1.153 mmol) and the mixture was refluxed for 16 h. After evaporation of the solvent in vacuo the compound was purified by silica-gel column chromatography using chloroform as an eluent, then was characterized by IR, NMR and ESI+-MS, and identified as 3,5-diphenyl-1H-pyrazole 4 (65% yield). 3,5-Diphenyl-1H-pyrazole, 430: m.p.200°C. IR (KBr): 3408, 1637 cm−1; 1H NMR (CDCl3): δ 4.94 (bs, 1H, NH), 6.88 (s, 1H, CH), 7.36-7.44 (m, 6H, CHar), 7.75 (d, 4H, JHH = 7.8 Hz, CHar); 13C NMR (CDCl3): δ 100.4 (CH), 125.9, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 130.1, 133.1 (CHar), 130.4 (Car), 148.4 (C=N) and (C=CH); DEPT-135 NMR (CDCl3): δ 100.4 (CH), 125.9, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 130.1, 133.1 (CHar); ESI+-MS: m/z 221.10656 [M+H]+. Tandem MS m/z 194.1, 167.1, 119.1, 106.1. Anal. Calcd for C15H12N2: C, 81.79; H, 5.49; N, 12.72. Found: C, 81.87; H,5.55; N, 12.87%. Synthesis of symmetrical azine, 6 To a solution of cyclohexanone 5 (200 mg, 2.037 mmol) in EtOH (5 mL) was added hydrazine hydrate (122 mg, 2.444 mmol) and the mixture was refluxed for 4 h. After evaporation of the solvent in vacuo the compound was purified by silica-gel column chromatography using chloroform as an eluent, then was characterized by IR, NMR and ESI+-MS, and identified as 1,2-dicyclohexylidenehydrazine 6 (30% yield). 1,2-Dicyclohexylidenehydrazine, 63b: m.p.36°C. IR (KBr): 3449, 1637 cm−1; 1H NMR (CDCl3): δ 1.59-1.61 (m, 8H, CH2), 1.70-1.72 (m, 4H, CH2), 2.31 (t, 4H, JHH = 6.4 Hz, CH2), 2.35 (t, 4H, JHH = 6.4 Hz, CH2); 13 C NMR (CDCl3): δ 25.9, 26.3, 27.5, 27.9, 35.6 (CH2), 165.5 (C=N); DEPT-135 NMR (CDCl3): δ 25.9, 26.3, 27.5, 27.9, 35.6 (CH2); ESI+-MS: m/z 193.1693 [M+H]+. Tandem MS m/z 176.1 and 98.1, 96.1. Anal. Calcd for C12H20N2: C, 74.95; H, 10.48; N, 14.57. Found: C, 75.13; H,10.69; N, 14.43%. Synthesis of asymmetrical azines, 6a-b To a solution of cyclohexanone 5 (200 mg, 2.037 mmol) in EtOH (5 mL) was added 9-fluorenone

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hydrazone 1a (396 mg, 2.037 mmol) or benzophenone hydrazone 1b (400 mg, 2.037 mmol) and the mixture was refluxed for 16 h. After evaporation of the solvent in vacuo the compound was purified by silicagel column chromatography using chloroform as an eluent, then was characterized by IR, NMR and ESI+-MS, and identified as 1-cyclohexylidene-2-(9Hfluoren-9-ylidene)hydrazine 6a (95% yield) or 1-cyclohexylidene-2-(diphenylmethylene)hydrazine 6b (99% yield), respectively. 1-Cyclohexylidene-2-(9H-fluoren-9-ylidene) hydrazine, 6a: m.p.80°C. IR (KBr): 3444, 1628, 1610, 1448 cm−1; 1H NMR (CDCl3): δ 1.69 (dt, 4H, JHH = 2.8 and 6.4 Hz, CH2), 1.87-1.90 (m, 2H, CH2), 2.57 (t, 2H, JHH = 6.6 Hz, CH2), 2.60 (t, 2H, JHH = 6.4 Hz, CH2), 7.29 (t, 1H, JHH = 7.5 Hz, CHar), 7.33 (t, 1H, JHH = 7.4 Hz, CHar), 7.42 (t, 1H, JHH = 7.5 Hz, CHar), 7.43 (t, 1H, JHH = 7.5 Hz, CHar), 7.63 (d, 1H, JHH = 7.5 Hz, CHar), 7.66 (d, 1H, JHH = 7.4 Hz, CHar), 7.90 (d, 1H, JHH = 7.5 Hz, CHar), 8.18 (d, 1H, JHH = 7.5 Hz, CHar); 13C NMR (CDCl3): δ 25.8, 26.4, 27.4, 28.7, 35.5 (CH2), 119.7, 119.9, 122.4, 127.9, 128.0, 129.4, 130.4, 130.9 (CHar), 131.6, 136.9, 140.9, 142.2 (Car), 154.7 (C=N), 166.3 (C=Ncyclohexyl); DEPT-135 NMR (CDCl3): δ 25.8, 26.4, 27.4, 28.7, 35.5 (CH2), 119.7, 119.9, 122.4, 127.9, 128.0, 129.4, 130.4, 130.9 (CHar); ESI+-MS: m/z 275.1538 [M+H]+. Tandem MS m/z 180.1, 96.1. Anal. Calcd for C19H18N2: C, 83.18; H,6.61; N, 10.21. Found: C, 83.24; H,6.77; N, 10.35%. 1-Cyclohexylidene-2-(diphenylmethylene)hydrazine, 6b: m.p.75°C. IR (KBr): 3443, 1635, 1559, 1492, 1444 cm−1; 1H NMR (CDCl3): δ 1.62-1.67 (m, 6H, CH2), 2.28 (bs, 2H, CH2), 2.52 (bs, 2H, CH2), 7.22-7.67 (m, 9H, CHar), 7.83 (d, 1H, JHH = 6.9 Hz, CHar); 13C NMR (CDCl3): δ 25.8, 26.2, 27.2, 29.1, 35.3 (CH2), 126.5, 127.9, 128.0, 128.1, 128.3, 128.4, 129.2, 129.3, 130.1, 132.4 (CHar), 135.5, 137.6 (Car), 158.9 (C=N), 165.2 (C=Ncyclohexyl); DEPT-135 NMR (CDCl3): δ 25.8, 26.2, 27.2, 29.1, 35.3 (CH2), 126.5, 127.9, 128.0, 128.1, 128.3, 128.4, 129.2, 129.3, 130.1, 132.4 (CHar); ESI+-MS: m/z 277.1705 [M+H]+. Tandem MS m/z 182.1, 180.1, 104.1, 96.1, 69.1. Anal. Calcd for C19H20N2: C, 82.57; H, 7.29; N, 10.14. Found: C, 82.86; H,7.55; N, 10.27%. Conclusion In this study, we have tested various metals as catalysts for the synthesis of 9-fluorenone azine from 9-fluorenone hydrazone under different reaction

conditions. We have found that FeCl3 Lewis acid catalyst is the best metal catalyst for this type of reaction. The reaction also depends on the reaction time, temperature, and on the type of solvent used. By applying the same reaction protocol we have also succeeded to synthesize benzophenone azine from benzophenone hydrazone. Furthermore, we have prepared an asymmetrical azine by combination of 9-fluorenone hydrazone and benzophenone hydrazone in the presence of FeCl3 Lewis acid catalyst. To the best of our knowledge, this is the first FeCl3-catalysed synthesis of an asymmetrical azine by combination of two different hydrazones. The progress of the catalytic reactions was monitored by high resolution ESI+-MS. On the other hand, the condensation reaction of chalcone with 9-fluorenone hydrazone affords 9-fluorenone azine and 3,5-diphenyl-1H-pyrazole. Similarly, chalcone reacts with benzophenone hydrazone to produce a mixture of benzophenone azine and 3,5-diphenyl-1H-pyrazole. Moreover, the proposed mechanism of these reactions was discussed. Finally, cyclohexanone reacts with 9-fluorenone hydrazone or benzophenone hydrazone to furnish asymmetrical azines, in very good yields, without the need of any added acid catalyst or promoter. Supplementary Information 1 H and 13C NMR, and ESI+-MS spectra are given in the Electronic Supplementary Information available at http://nopr.niscair.res.in/handle/123456789/60. Acknowledgment This project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. (G-1436-662104). The authors, therefore, acknowledge with thanks DSR for technical and financial support. References 1

2 3

4

(a) Chen G S, Anthamatten M, Barnes C L & Glaser R, Angew Chem Int Ed, 33 (1994) 1081; (b) Wolff J J & Wortmann R, Adv Phys Org Chem, 32 (1999) 121. Son S U, Park K H, Jung I G, Chung Y K & Lah M S, Organometallics, 21 (2002) 5366. (a) Grashey R & Padwa A, ‘Azomethine imines’ in 1,3-Dipolar Cycloaddition Chemistry, edited by Taylort D C & Weissberger A (General Heterocyclic Chemistry Series, John Wiley and Sons, New York) 1 (1984) 733; (b) Verner J & Potáček M, Molecules, 11 (2006) 34. Schweizer E E, Cao Z, Rheingold A L & Bruch M, J Org Chem, 58 (1993) 4339.

LASRI & ISMAIL: SYNTHESIS OF AZINES

5 6 7 8 9

10

11 12 13 14

15

16 17 18 19 20 21

Chen G S, Anthamatten M, Barnes C L & Glaser R, J Org Chem, 59 (1994) 4336. Chen G S, Wilbur J K, Barnes C L & Glaser R, J ChemSoc Perkin Trans 2, (1995) 2311. Lewis M & Glaser R, J Org Chem, 67 (2002) 1441. Glaser R, Dendi L R, Knotts N & Barnes C L, Cryst Growth Des, 3 (2003) 291. Loghmani-Khouzani H, Sadeghi M M M, Safari J, Abdorrezaie M S & Jafarpisheh M, J Chem Res (S), (2001) 80. (a) Glaser R, Chen G S, Anthamatten M & Barnes C L, J Chem Soc Perkin Trans 2, (1995) 1449; (b) Szmant H H & McGinnis C, J Am Chem Soc, 72 (1950) 2890. Nanjundaswamy H M & Pasha M A, Synth Commun, 37 (2007) 3417. Kumar R & Singh K N, Indian J Chem, 40B (2001) 579. Barakat M Z, Abd El-Wahab M F & El-Sadr M M, J Am ChemSoc, 77 (1955) 1670. Hopkins J M, Bowdridge M, Robertson K N, Cameron T S, Jenkins H A & Clyburne J A C, J Org Chem, 66 (2001) 5713. Choytun D D, Langlois L D, Johansson T P, MacDonald C L B, Leach G W, Weinberg N & Clyburne J A C, Chem Commun, (2004) 1842. Pawar R B & Mulwad V V, Chem Heterocycl Compd, 40 (2004) 219. Stanovnik B & Svete J, Sci Synt, 12 (2002) 15. Heller S T & Natarajan S R, Org Lett, 8 (2006) 2675. Murray W, Wachter M, Barton D & Korero-Kelly Y, Synthesis, 1 (1991) 18. Luo Y & Potvin P G, J Org Chem, 59 (1994) 1761. Katrizky A R, Wang M, Zhang S & Voronkov M V, J Org Chem, 66 (2001) 6787.

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22 Huang Y R & Katzenellenbogen J A, Org Lett, 2 (2000) 2833. 23 Outirite M, Lebrini M, Lagrenée M & Bentiss F, J Heterocycl Chem, 45 (2008) 503. 24 Zhang Z, Tan Y-J, Wang C-S & Wu H-H, Heterocycles, 89 (2014) 103. 25 Lasri J, Kopylovich M N, Guedes da Silva M F C, Januário Charmier M A & PombeiroA J L, Chem Eur J, 14 (2008) 9312. 26 (a) Lasri J, Kuznetsov M L, Guedes da Silva M F C & Pombeiro A J L, Inorg Chem, 51 (2012) 10774; (b) Kopylovich M N, Karabach Y Yu, Guedes da Silva M F C, Figiel P J, Lasri J & Pombeiro A J L, Chem Eur J, 18 (2012) 899; (c) Kopylovich M N, Lasri J, Guedes da Silva M F C & Pombeiro A J L, Eur J Inorg Chem, (2011) 377; (d) Figiel P J, Kopylovich M N, Lasri J, Guedes da Silva M F C, Fraústo da Silva J J R & Pombeiro A J L, Chem Commun, 46 (2010) 2766; (e) Lasri J, Guedes da Silva M F C, Januário Charmier M A & Pombeiro A J L, Eur J Inorg Chem, (2008) 3668; (f) Lasri J, Januário Charmier M A, Guedes da Silva M F C & Pombeiro A J L, Dalton Trans, (2007) 3259; (g) Lasri J, Januário Charmier M A, Guedes da Silva M F C & Pombeiro A J L, Dalton Trans, (2006) 5062. 27 Archana R, Anbazhagan R, Sankaran K R,Thiruvalluvara A & Butcher R J, Acta Cryst, E66 (2010) o345. 28 (a) Lasri J, Eltayeb N E & Ismail A I, J Mol Struct, 1121 (2016) 35; (b) Djukic J-P, Michon C, Pfeffer M, Gruber-Kyritsakas N & de Cian A, J Organomet Chem, 696 (2011) 3268. 29 Seyfried M S, Linden A, Mloston G & Heimgartner H, Helv Chim Acta, 92 (2009) 1800. 30 Aggarwal V K, de Vicente J & Bonnert R V, J Org Chem, 68 (2003) 5381.