Green chemistry: microwave-assisted facile synthesis

Journal of Sulfur Chemistry

ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20

Green chemistry: microwave-assisted facile synthesis of 6-imino-1,3,4-thiadiazenes from reaction of thiocarbohydrazones with malononitrile dimer N.A.A. Elkanzi, Nesrin M. Morsy, Ashraf A. Aly, Tamer El Malah & Ahmed M. Shawky To cite this article: N.A.A. Elkanzi, Nesrin M. Morsy, Ashraf A. Aly, Tamer El Malah & Ahmed M. Shawky (2015): Green chemistry: microwave-assisted facile synthesis of 6-imino-1,3,4thiadiazenes from reaction of thiocarbohydrazones with malononitrile dimer, Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2015.1103243 To link to this article: http://dx.doi.org/10.1080/17415993.2015.1103243

Published online: 04 Nov 2015.

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Date: 17 November 2015, At: 00:00

JOURNAL OF SULFUR CHEMISTRY, 2015 http://dx.doi.org/10.1080/17415993.2015.1103243

Green chemistry: microwave-assisted facile synthesis of 6-imino-1,3,4-thiadiazenes from reaction of thiocarbohydrazones with malononitrile dimer N.A.A. Elkanzia,b , Nesrin M. Morsya,c , Ashraf A. Alyd , Tamer El Malahe and Ahmed M. Shawkyf

Downloaded by [] at 00:00 17 November 2015

a Chemistry Department, College of Science, AlJouf University, Sakaka, KSA; b Chemistry Department, College of Science, Aswan University, Aswan, Egypt; c Department of Organometallic and Organometalloid Chemistry, National Research Centre, Dokki, Egypt; d Chemistry Department, Faculty of Science, Minia University, El-Minia, Egypt; e Photochemistry Department, National Research Centre, Dokki, Egypt; f Science and Technology Unit (STU), Umm Al-Qura University, Mecca, KSA

ABSTRACT

ARTICLE HISTORY

The reactions of thiocarbohydrazones with malononitrile dimer under microwave irradiation are reported. These reactions give 6imino-1,3,4-thiadiazines in good yields. The structures of products were elucidated by MS, IR and NMR spectra together with elemental analyses. The reaction mechanism was discussed.

Received 19 August 2015 Revised 22 September 2015 Accepted 30 September 2015 KEYWORDS

Thiocarbohydrazones malononitrile dimer; microwave irradiation; conjugated addition; 6-imino-1; 3; 4-thiadiazines

Introduction In the past, microwave chemistry was often used only when all other options to perform a particular reaction had failed, or when exceedingly long reaction times or high temperatures were required to complete a reaction. This practice is now slowly changing and, due to the growing availability of microwave reactors in many laboratories, routine synthetic transformations are now also being carried out by microwave heating.[1–3] Reactions, using microwave irradiation (MI), have the following advantages over conventional heating: uniform heating occurs throughout the material, the process speed is increased, there is higher efficiency in reduction of heat generated from unwanted side reactions, purity of the final product is better, reproducibility is improved, environmental heat loss can be avoided, and there is reduction in the waste produced by the heating reaction vessel.[4]

CONTACT Ashraf A. Aly © 2015 Taylor & Francis

[email protected], [email protected]


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N.A.A. ELKANZI ET AL.

In literature, thiocarbohydrazide Schiff bases have still shed more light due to their biological activities including antibacterial,[5–10] antifungal,[11,12] anticancer [13,14] and herbicidal activities.[10] In addition, thiadiazines, which are important heterocyclic compounds, exhibit a wide spectrum of biological activity.[4] Molecules bearing the 1,3,4-thiadiazine core have received attention due to the wide range of therapeutic [15] anti-inflammatory,[16] antiHIV [17] and antidepressant activities.[18] A literature survey showed that the most common route for the synthesis of 1,3,4-thiadiazine derivatives was via the condensation of semithiocarbazides and α-halo-ketones. In addition, the diversity of the possible thiadiazines from this method is limited due to the use of only two starting materials. Increasing the number of starting materials to more than two would increase the diversity and would open the method to comprehensive QSAR studies of this category of compounds.[19–22] As part of our ongoing interest in the field, Aly et al. have recently reported on the synthesis of pyrimidin-2-thiones from reactions of amidrazonethiols with 2-amino-1,1,2ethenetricarbonitrile and their antitumor activity was evaluated.[23] Additionally, mercapto pyrazoles were synthesized by reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate with amidrazones.[24] 2-Aminoprop-1-ene-1,1,3-tricarbonitrile (1) (i.e. malononitrile dimer) has proved to be an excellent precursor to condensed pyridines, pyridazines and pyrazoles.[25–27] It is surely believed that carbohydrazones and thiocarbohydrazones are next higher homologues of potentially active semicarbazones and thiosemicarbazones. That is of course due to the presence of the extra hydrazino-nucleophilic nitrogen-binding center. According to the aforementioned and in the present work, we have explored the reactivity of thiocarbohydrazones via the nucleophilicity of nitrogens and sulfur atoms during the reactions of selected thiocarbahydrazones with 1. To elucidate the tautomeric states that might be formed we used IR, 1 H NMR, 13 C NMR, 2D NMR as well as mass spectrometry and elemental analyses.

Results and discussion Recently, Aly et al. reported that malononitrile dimer 1 reacted with amidines 2 in DMF catalyzed by a few drops of piperidine. The reaction proceeded to yield mainly one single product 3 in 70–89% yields [28] (Scheme 1). However when using the previous conditions, thiocarbohydrazones 4a–g did not react smoothly with malononitrile dimer 1. Low yields of compounds 5a–g were obtained (10–25%). With the optimal conditions in hand, we irradiated the reaction mixture of 4a–g and 1 with microwaves. Fortunately the reactions proceeded to give compounds 5a–g after few minutes in good yields (60–80%, Scheme 2). In the present work, we choose compounds 4a–g having aryl groups with electrondonating and -withdrawing substituents on the benzene ring to examine their effect on the course of reaction. The yield is higher in case of electron-donating substituents as the yield in the p-methoxy substituent of 5b reached 80%. On the other hand, when we choose compound 5c as an example, the withdrawing ability of the nitro group decreases the yield to 60% (see the experimental section). Compounds 5a–g showed IR absorptions at ν = 3350–3150 cm–1 corresponding to the NH2 and NH groups, respectively, and the band between 2220 and 2215 cm–1 was assigned as CN groups. The mass spectroscopy of 5a–g showed stable molecular ions due to the effective cleavage between the heterocyclic ring and the two exocyclic carbons in

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Scheme 1. Pyrimidines from reaction of 1 with amidines 2.

Scheme 2. 6-Imino-1,3,4-thiadiazines 5a–g from reaction of 1 with 4a–g.

Figure 1. Repeated fragmentation patterns in mass spectroscopy of compounds 5a–g.

C-2 and C-5. So repeated ion peak signals at m/z = 181 (A species) and at m/z = 129 (species B) were noted in the fragmentation pattern of all compounds 5a–g (Figure 1). As an example, the mass spectra and elemental analysis of compound 5a as another example proved its chemical formula as C13 H11 N7 S. The base peak in all substituents appeared at m/z = 181, whereas the molecular ion peak at m/z = 297. The IR spectrum showed the NH2 and NH groups at ν = 3320–3130 cm–1 , whereas the nitrile groups were absorbed at ν = 2220 cm–1 . The CH2 resonated in the 1 H NMR spectrum at δ H = 2.85 and its carbon at δ C = 22.80. Most indicative are the three azomethine carbons which appeared at δ C = 169.00, 164.00 and 154.00 ppm related to C-2, C-6 and CH = N carbons. It needs to be mentioned that the exocyclic carbon (C-5) appeared at δ C = 90.00, whereas its adjacent carbon at δ C = 170.00 (see the experimental section). Additionally, the protons of NH2 and imino-NH appeared at δ H = 5.30 and 9.40 ppm, respectively. Another example is shown for compound 5c. The gross formula C13 H10 N8 O2 S for 5c was confirmed by elemental analysis and mass spectrum, which exhibited the molecular ion at m/z = 342 (28%). The 1 H NMR spectrum of 5c in DMSO-d6 revealed one broad signal exchangeable with D2 O at δ H = 5.70 and another at δ H = 9.80 for NH2 and NH

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Figure 2. Compound 5 and its alternative isomer 9.

Scheme 3. Proposed mechanism for the formation of compounds 5a–g.

protons. Ar-C-1’appeared at δ C = 138.6, whereas Ar-C-NO2 resonated at δ C = 150.00. Distinctive protons and carbon signals of napthyl moiety were noted for compound 5f (see the experimental section). In 5g, the methyl protons at position 3 of furan moiety appeared at δ H = 2.24 ppm, whereas H-3 and H-4 as two doublets (J = 7 Hz) at δ H = 6.92 and 6.28 (experimental section). It has been previously reported that malononitrile dimer 1 usually reacts with its active methylene under basic conditions.[25,26] Therefore, the alternative structure 9 could be expected to be formed. However, its structure can simply be ruled out on the basis of 1 H NMR, since in structure 5, the CH2 protons appeared clearly. Moreover, no additional NH2 protons were distinguished. Besides the 13 C NMR spectra confirmed the disappearance of the thione carbon signal (Figure 2). Mechanistically, the proposed formation of compounds 5a–g can be explained as hydrazine-NH2 addition of 4 (Scheme 2) on the active electrophilic carbon in 1 (Scheme 2) to form salt 6 (Scheme 3). Thereafter a molecule of HCN was removed to from intermediate 7. Then cyclization was then occurred to afford intermediate 8 (Scheme 3). Air oxidation of 8 under the reaction condition would ultimately afford 5 (Scheme 3). In summary, we report here that the reaction of thiocarbohydrazone derivatives with malononitrile dimer under MI produces substituted 6-imino-1,3,4-thiadiazines in good yields. The advantages of the reported method are the following: simple, available starting materials, short reaction time (min), simple work-up, no pollution resulting from a solvent and good yield order.


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Experimental All the solvents such as acetonitrile, methanol, chloroform and ethanol were purchased from Merck Chemical Co. and were used without further purification. TLC was performed on analytical Merck 9385 silica aluminum sheets (Kieselgel 60) with a PF254 indicator. TLCs were viewed under ν = 254 nm. Melting points (mps) were determined on a Stuart electrothermal mp apparatus and are uncorrected. The IR spectra were recorded as KBr disks on a Bruker infrared spectrophotometer, Faculty of Science, Minia University. NMR spectra were measured on a Bruker AV-400 spectrometer (400 MHz for 1 H, 100MHz for 13 C) at Florida Institute of Technology. Electron impact mass spectra were recorded with a JEOL JMS-600 spectrometer at an ionization voltage of 70 eV at Florida Institute of Technology, Blvd University, California, USA. The elemental analyses were carried out in the Microanalytical Center, Assuit, Egypt.


Starting materials Malononitrile dimer (1) was prepared according to published procedures.[25,26] Thiocarbohydrazones 4a–g were prepared according to literature.[29]

Reactions of thiocarbohydrazones 4a–g with malononitrile dimer (1) General procedure Equimolar amounts of compounds 4a–g (1 mmol) and 1 (0.132 g, 1 mmol) were mixed together and irradiated in a microwave oven. The reaction mixture was heated (monitored by TLC) for 5–10 min. Then the mixture was cooled and 50 mL of absolute ethanol was added. The formed precipitate was filtered and washed by ethanol and recrystallized from the proper solvent to yield the corresponding compounds 5a–g. 3 -Amino-3-[3-(2 -benzylidene)hydrazono)-6-imino-2H-1,3,4-thiadiazin-5(6H)ylidene]-propanenitrile (5a). This compound was obtained as yellow crystals (EtOEt) (0.214 g, 72%), m.p. 180–2°C; IR: 3340–3150 (m, NH2 and NH), 3010, (m, Ar-CH), 2220 (CN), 1610 (C=N), 1550 (C=C) cm–1 ; 1 H NMR (DMSO-d6 ): δ H = 9.40 (s, 1H, iminoNH), 8.40 (s, 1H, CH = N), 7.20–7.10 (dd, 2H, J = 8.0, 1.0 Hz, Ph-H), 6.80–6.50 (m, 3H, Ph-H), 5.80 (bs, 2H, NH2 ), 2.85 (bs, 2H, CH2 ); 13 C nmr (DMSO-d6 ): δ C = 170.00 (vinyl-C-NH2 ), 169.00 (C-2), 164.00 (C-6), 154.00 (CH = N), 138.7 (Ph-C), 128.5, 127.2 (Ph-2CH), 126.20 (p-Ph-CH), 113.60 (CN), 90.00 (C-5), 22.80 (CH2 ) ppm; ms: m/z 297 (M+ , 26), 181 (34),130 (40), 76 (28). Anal. Calcd. for C13 H11 N7 S (297.34): C, 52.51; H, 3.73; N, 32.98. Found: C, 52.40; H, 3.80; N, 32.90. 3 -Amino-3-[3-(2 -p-methoxybenzylidene)hydrazono)-6-imino-2H-1,3,4-thiadiazin-5 (6H)-ylidene]-propanenitrile (5b). This compound was obtained as yellow crystals (AcOEt) (0.262 g, 80%), m.p. 164–6 °C; IR: 3350–3160 (m, NH2 and NH), 3060, (m, Ar-CH), 2960 (Aliph-CH), 2220 (s, CN), 1615 (C=N), 1550 (C=C) cm–1 ; 1 H NMR (DMSO-d6 ): δ H = 9.54 (s, 1H, imino-NH), 8.42 (s, 1H, CH = N), 7.60–7.50 (dd, 2H, J = 8.0, 1.0 Hz, Ar-H), 6.40–6.30 (dd, 2H, J = 7.8, 1.0 Hz, Ar-H), 5.72 (bs, 2H, NH2 ), 3.95 (s, 3H, OCH3 ), 2.90 (bs, 2H, CH2 ); 13 C nmr (DMSO-d6 ): δ C = 170.60 (vinyl-C-NH2 ), 169.00 (C-2), 164.60 (C-6), 154.00 (CH = N), 150.00 (Ar-C-OCH3 ), 128.00 (Ar-C), 127.4, 124.6 (Ar2CH), 114.00 (CN), 90.08 (C-5), 54.00 (OCH3 ), 24.60 (CH2 ) ppm; ms: m/z 311 (M+ , 30),


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194 (22), 181 (36), 130 (38), 92 (24), 77 (26). Anal. Calcd. for C14H13N7OS (327.36): C, 51.36; H, 4.00; N, 29.95. Found: C, 51.43; H, 4.10; N, 30.60. 3 -Amino-3-[3-(2 -p-nitrobenzylidene)hydrazono)-6-imino-2H-1,3,4-thiadiazin-5(6H)ylidene]-propanenitrile (5c). This compound was obtained as yellow crystals (EtOH) (0.205 g, 60%), m.p. 220–2 °C; IR: 3340–3150 (m, NH2 and NH), 3050, (m, Ar-CH), 2215 (s, CN), 1620 (C=N), 1560 (C=C) cm–1 ; 1 H NMR (DMSO-d6 ): δ H = 9.80 (s, 1H, iminoNH), 8.40 (s, 1H, CH = N), 8.30–8.25 (dd, 2H, J = 7.8, 1.0 Hz, Ar-H), 8.10–8.05 (dd, 2H, J = 7.8, 1.0 Hz, Ar-H), 5.70 (bs, 2H, NH2 ), 2.90 (bs, 2H, CH2 ); 13 C nmr (DMSO-d6 ): δ C = 170.00 (vinyl-C-NH2 ), 169.20 (C-2), 164.00 (C-6), 153.00 (CH = N), 150.00 (Ar-CNO2 ), 138.60 (Ar-C), 127.6, 124.8 (Ar-2CH), 115.00 (CN), 88.18 (C-5), 25.20 (CH2 ) ppm; ms: m/z 342 (M+ , 28), 194 (22), 181 (32), 149 (40), 130 (34), 122 (26), 77 (34). Anal. Calcd. for C13 H10 N8 O2 S (342.34): C, 45.61; H, 2.94; N, 32.73. Found: C, 45.50; H, 2.80; N, 32.65. 3 -Amino-3-[3-(2 -p-hydroxybenzylidene)-hydrazono)-6-imino-2H-1,3,4-thiadiazin-5 (6H)-ylidene]-propanenitrile (5d). This compound was obtained as yellowish brown crystals (AcOEt) (0.204 g, 65%), m.p. 222–4°C; IR: 3450 (s, OH), 3350–3140 (m, NH2 and NH), 3060, (m, Ar-CH), 2215 (s, CN), 1610 (C=N), 1550 (C=C) cm–1 ; 1 H NMR (DMSO-d6 ): δ H = 9.82 (s, 1H, imino-NH), 9.40 (s, 1H, OH), 8.38 (s, 1H, CH = N), 7.30–7.26 (dd, 2H, J = 8.0, 1.0 Hz, Ar-H), 6.40–6.35 (dd, 2H, J = 8.0, 1.0 Hz, Ar-H), 5.62 (bs, 2H, NH2 ), 2.80 (bs, 2H, CH2 ); 13 C nmr (DMSO-d6 ): δ C = 170.60 (vinyl-C-NH2 ), 169.20 (C-2), 164.20 (C-6), 154.00 (CH = N), 150.00 (Ar-C-OH), 134.00 (Ar-C), 128.00 (Ar-2CH), 118.00 (Ar2CH), 115.00 (CN), 88.00 (C-5), 25.80 (CH2 ) ppm; ms: m/z 314 (M+1 , 28), 313 (M+ , 32), 194 (22), 181 (34), 129 (36), 106 (24), 93 (38), 77 (40). Anal. Calcd. for C13 H11 N7 OS (313.34): C, 49.83; H, 3.54; N, 31.29. Found: C, 50.00; H, 3.60; N, 31.40. 3 -Amino-3-[3-(2 -p-aminobenzylidene)-hydrazono)-6-imino-2H-1,3,4-thiadiazin-5 (6H)-ylidene]-propanenitrile (5e). This compound was obtained as orange crystals (MeOH) (0.302 g, 65%), m.p. 250–2 °C; IR: 3370–3160 (m, 2NH2 and NH), 3040, (m, Ar-CH), 2218 (s, CN), 1620 (C=N), 1560 (C=C) cm–1 ; 1 H NMR (DMSO-d6 ): δ H = 9.80 (s, 1H, iminoNH), 8.40 (s, 1H, CH = N), 7.40–7.34 (dd, 2H, J = 8.0, 1.0 Hz, Ar-H), 6.72–6.66 (dd, 2H, J = 8.0, 1.0 Hz, Ar-H), 6.20 (bs, 2H, NH2 -Ar), 5.60 (bs, 2H, NH2 ), 2.84 (bs, 2H, CH2 ); 13 C nmr (DMSO-d6 ): δ C = 170.40 (vinyl-C-NH2 ), 169.00 (C-2), 164.00 (C-6), 148.90 (Ar-CNH2 ), 152.90 (CH = N), 128.00 (Ar-2CH), 122.00 (Ar-2CH), 115.40 (CN), 88.20 (C-5), 25.60 (CH2 ) ppm; ms: m/z 313 (M+1 , 24), 312 (M+ , 34), 194 (22), 181 (32), 149 (38), 132 (24), 129 (34), 94 (34), 77 (24). Anal. Calcd. for C13 H12 N8 S (312.35): C, 49.99; H, 3.87; N, 35.87. Found: C, 50.12; H, 3.70; N, 35.66. 3 -Amino-3-[3-(2 -naphthalen-1-ylmezthylene)-hydrazono)-6-imino-2H-1,3,4thiadiazin-5(6H)-ylidene]-propanenitrile (5f). This compound was obtained as yellowish brown crystals (EtOEt) (0.243 g, 75%), m.p. 230–2°C; IR: 3330–3150 (m, NH2 and NH), 3080–3010 (m, Ar-CH), 2215 (s, CN), 1625 (C=N), 1560 (C=C) cm–1 ; 1 H NMR (DMSOd6 ): δ H = 9.82 (s, 1H, imino-NH), 8.40 (s, 1H, CH = N), 7.90–7.80 (m, 2H, Naphth-H), 7.70–7.64 (m, 1H, Naphth-H), 7.50–7.30 (m, 4H, Naphth-H), 5.80 (bs, 2H, NH2 ), 2.90 (bs, 2H, CH2 ); 13 C nmr (DMSO-d6 ): δ C = 170.10 (vinyl-C-NH2 ), 169.30 (C-2), 160.20 (C-6), 154.00 (CH = N), 134.00 (Naphth-C), 131.00 (Naphth-C-4 ), 130.40 (Naphth-C), 128.60 (Naphth-C), 128.0 (Naphth-CH), 126.60 (Naphth-2CH), 127.2, 126.6, 126.00 (NaphthCH), 115.00 (CN), 88.20 (C-5), 25.60 (CH2 ) ppm; m/z 347 (M+ , 28), 194 (22), 181 (32), 168 (38), 134 (24), 131 (30), 126 (26). Anal. Calcd. for C17 H13 N7 S (347.40): C, 58.77; H, 3.77; N, 28.22. Found: C, 58.90; H, 3.90; N, 28.20.


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3 -Amino-3-[3-(2 -(5-methylfuran)-hydrazono)-6-imino-2H-1,3,4-thiadiazin-5(6H)ylidene]-propanenitrile (5g). This compound was obtained as orange crystals (AcOEt) (195.86 g, 65%), m.p. 216–2°C; IR: 3350–3150 (m, NH2 and NH), 3020 (m, Ar-CH), 2860 (Aliph-CH), 2215 (s, CN), 1610 (s, C=N), 1560 (C=C), 1110 (C–O) cm–1 ; 1 H NMR (DMSO-d6 ): δ H = 9.90 (s, 1H, imino-NH), 8.40 (s, 1H, CH = N), 6.92–6.86 (d, 1H, J = 7.0 Hz, furan-H), 6.28–6.24 (d, 1H, J = 7.0 Hz, furan-H), 5.62 (bs, 2H, NH2 ), 2.80 (bs, 2H, CH2 ), 22.4 (s, 3H, 5-CH3 -furan); 13 C nmr (DMSO-d6 ): δ C = 170.60 (vinyl-C-NH2 ), 169.00 (C-2), 164.00 (C-6), 154.00 (furan-C-5 ), 152.90 (CH = N), 147.30 (furan-C-2 ), 111.00, 108.00 (furan-CH), 115.00 (CN), 88.00 (C-5), 25.80 (CH2 ), 14.00 (CH3 -furan) ppm; ms: m/z 302 (M+1 , 28), 301 (M+ , 32), 206 (30), 181 (30), 129 (34), 94 (34), 82 (40). Anal. Calcd. for C12 H11 N7 OS (301.33): C, 47.83; H, 3.68; N, 32.54. Found: C, 47.72; H, 3.74; N, 32.60.

Disclosure statement Downloaded by [] at 00:00 17 November 2015

No potential conflict of interest was reported by the authors.

Funding The authors thank Aljouf University for its complete financial support (Project No. 35/340).

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