A novel N-formyl-2-pyrazoline derivative was synthesized by reaction of an α,β- unsaturated ketone with hydrazine hydrate and formic acid in aqueous 2-methoxyethanol reaction media. The Clean reaction conditions, simple workup procedure and short reaction time giving high yields of product are notable advantages of method. The structure of the title compound was established by IR, 1H NMR, 13C NMR and analytical data.

Zangade, Sainath B

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Journal of Progressive Research in Chemistry [JPRC]ISSN 2454-3136Volume 4, Issue 3 available at www.scitecresearch.com/journals/index.php/jprc 201SCITECH Volume 4, Issue 3RESEARCH ORGANISATION May 20, 2017Journal of Progressive Research in Chemistrywww.scitecresearch.comAqueous 2-Methoxyethanol Reaction Media: Synthesis of Some 4, 5-Dihydro-Pyrazole-1-Carbaldehyde DerivativeSainath Zangade*Department of Chemistry, Madhavrao Patil ACS College, Palam, Dist. Parbhani-431720 (M S) India.E mail: drsbz@rediffmail.comAbstractA novel N-formyl-2-pyrazoline derivative was synthesized by reaction of an α,β- unsaturated ketone with hydrazinehydrate and formic acid in aqueous 2-methoxyethanol reaction media. The Clean reaction conditions, simple workupprocedure and short reaction time giving high yields of product are notable advantages of method. The structure of thetitle compound was established by IR, 1H NMR, 13C NMR and analytical data.Keywords: Aqueous 2-methoxyethanol; N-formyl-2-pyrazoline; α,β- unsaturated ketone; hydrazine hydrate.1. IntroductionPyrazolines constitute an important heterocyclic class of organic compounds with diverse chemical and pharmacologicalapplications [1] and therefore they are useful in drug research. Pyrazolines with a phenyl group at 5-position possess goodfilm-forming properties, exhibit excellent characteristics of blue photoluminescence and electroluminescence [2].2. Review of LiteraturePyrazolines are extensively useful synthons in organic chemistry and also important in the development of theory inheterocyclic chemistry. These compounds are also well known for their pronounced biological activities includingantimicrobial [3], antitubercular [4], antiamoebic activity and cytotoxicity[5], anti-inflammatory [6], anticancer [7],antitumor [8], antiamoebic [9], anticonvulsant [10], anti-infective [11] andantidiabetic [12] properties.Synthesis of bicyclic pyrazolines were reported by condensation of 2,6-diarylidenecyclohexanones with hydrazine hydrate[13]. Acetone and acetophenones on base catalyzed condensation with substituted aldehyde affords α,β-unsaturatedcarbonyl compound which on treatment with hydrazine hydrate and formic acid yielded a 2-pyrazoline [14]. In view ofthese observations; it was thought worthwhile to synthesize some new different substituted pyrazolines 3a-d by reactingchalcones with hydrazine hydrate and formic acid in aqueous 2-methoxyethanol as an alternative reaction media.3. Material and Methodology3.1 ChemicalAll chemicals, solvents and reagents used in the present study were of analytical grade purchased from Sigma, SD Fine, orSpectrochem.3.2 Physical MeasurementMelting points were determined in an open capillary tube and are uncorrected. The reactions were carried out in aqueous2-methoxyethanol solvent (10 mL: 10 mL, v/v). Purification of the compounds was indicated using TLC (mixture of ethylacetate and hexane, 0.20 mL : 0.20 Ml, vv). IR spectra were recorded in KBr on a Perkin-Elmer spectrometer. 1H NMRspectra were recorded on a Gemini 300-MHZ instrument in DMSO as solvent and TMS as an internal standard. The massspectra were recorded on EISHIMADZU-GC-MS spectrometer. Elemental analyses were performed on a Perkin-Elmer240 CHN elemental analyzer.Journal of Progressive Research in Chemistry [JPRC]ISSN 2454-3136Volume 4, Issue 3 available at www.scitecresearch.com/journals/index.php/jprc 2023.3 Typical Procedure for Synthesis of Chalcones 2a-dTo a mixture of different substituted benzaldehyde 1a-d (0.02 mol) and acetone 2 (0.01 mol) in ethanol, 10 % aqueoussodium hydroxide (10 ml) was added drop by drop with constant stirring at 0-5 0C. After complete addition of NaOHsolution, the reaction mixture left to stand in ice bath for 20 min. Then obtained light yellow coloured solid was filteredwashed with cold water and crystallized from ethanol to give the corresponding chalcones derivative 2a-d. The physicaldata of synthesized chalcones are given in Table-1.3.4 Typical Procedure for Synthesis of 4, 5-dihydro-pyrazole-1-carbaldehyde.A mixture of Chalcones 2a-d (0.01 mol) hydrazine hydrate (0.02 mol) and formic acid (2ml) was dissolved in aqueous 2-methoxyethanol (20 ml). The reaction mixture was refluxed for 3 hours. The progress of reaction was monitored by TLC.After completion, reaction solution get cooled to room temperature and poured into crushed ice, obtained crude productwas filtered washed with cold water and recrystallized from mixture of ethanol: dioxane to give the product 3a-d. Thephysical data of synthesized chalcones are given in Table-2.NNROHCR3RR1R3R1CHORR1R3OHCRR3R1+H3C CH3O+Stiring0-50CNaOH / EtOHHCRR1R3CH COCH CHR R1R3Aqueous 2-MethoxyethanolNH2NH2, HCOOHReflux for 3 hr.1a-d 1a-d22a-d3a-dScheme 1 : Synthesis of some 4,5-dihydro-pyrazole-1-carbaldehyde derivativeR2 R2R2 R2R2R21,5-Bis-(4-fluoro-phenyl)-penta-1,4-dien-3-one. (2a): IR (KBr): 1655 (C=O), 1618 (C=C), 2940 (CH) Cm-1. 1H NMR(300 MHZ, DMSO) δ 6.78 (d, J = 16.5 HZ, 2H, Hα), δ 7.36 (d, J = 16.5 HZ, 2H, Hβ), δ 7.20-7.80 (m, 8H, Ar-H). MS m/z:270 (M+). Anal. Cacld for C17H12OF2: C, 75.55; H, 4.44. Found: C, 75.67; H, 4.46.1,5-Bis-(4-chloro-phenyl)-penta-1,4-dien-3-one. (2b): IR (KBr): 1655 (C=O), 1615 (C=C), 2946 (CH) Cm-1. 1H NMR(300 MHZ, DMSO) δ 6.75 (d, J = 16.5 HZ, 2H, Hα), δ 7.38 (d, J = 16.5 HZ, 2H, Hβ), δ 7.13-7.73 (m, 8H, Ar-H). MS m/z:303 (M+). Anal. Cacld for C17H12OCl2: C, 67.32; H, 3.96. Found: C, 67.41; H, 4.02.1,5-Bis-(5-chloro-2-hydroxy-phenyl)-penta-1,4-dien-3-one. (2c): IR (KBr): 3360 (OH), 1653 (C=O), 1620 (C=C), 2964(CH) Cm-1. 1H NMR (300 MHZ, DMSO) δ 6.72 (d, J = 16.5 HZ, 2H, Hα), δ 7.35 (d, J = 16.5 HZ, 2H, Hβ), δ 7.17-7.59 (m,6H, Ar-H), δ 12.15 (s, 2H, OH). MS m/z: 335 (M+). Anal. Cacld for C17H12O3Cl2: C, 60.89; H, 3.58. Found: C, 60.92; H,3.60.1,5-Bis-(3-iodo-4,5-dimethoxy-phenyl)-penta-1,4-dien-3-one. (2d): IR (KBr): 1654 (C=O), 1623 (C=C), 2978 (CH)Cm-1. 1H NMR (300 MHZ, DMSO) δ 3.8 (s, 12H, four OCH3), δ 6.70 (d, J = 16.5 HZ, 2H, Hα), δ 7.33 (d, J = 16.5 HZ, 2H,Hβ), δ 7.23-7.68 (m, 4H, Ar-H). MS m/z: 606 (M+). Anal. Cacld for C21H20O5I2: C, 41.58; H, 3.30. Found: C, 41.64; H,3.34.5-(4-Fluoro-phenyl)-3-[2-(4-fluoro-phenyl)-vinyl]-4,5-dihydro-pyrazole-1-carbaldehyde. (3a): IR (KBr): 1628(C=O), 1578 (C=N) Cm-1. 1H NMR (300 MHZ, DMSO) δ 3.25 (dd, J = 5.0, 17.8 HZ, 1H, HA), δ 3.65 (dd, J = 12.0, 17.8HZ, 1H, HB), δ 5.49 (dd, J = 5.1, 12.1 HZ, 1H, HX), δ 6.78 (d, J = 16.2 HZ, 1H, Hα), δ 7.17 (d, J = 16.2 HZ, 1H, Hβ), δ7.31-7.68 (m, 8H, Ar-H), δ 8.90 (s, 1H, CHO). 13C NMR (DMSO) 160.42 (C=O), 143.70 (C=N), 135.28 (Cβ, C=C doublebond), 137.88 (C, Ar-C), 135.57 (C, Ar-C) 134.74 (2CH, of two Ar-C), 130.53 (2CH, of two Ar-C), 128.50 (2CH, of twoAr-C), 120.42 (2CH, of two Ar-C) 118.32 (Cα, C=C double bond), 50.47 (-CH), 38.42 (-CH2). MS m/z: 312 (M+).Anal.Cacld for C18H14F2N2O: C, 69.23; H, 4.48. Found: C, 69.35; H, 5.53.Journal of Progressive Research in Chemistry [JPRC]ISSN 2454-3136Volume 4, Issue 3 available at www.scitecresearch.com/journals/index.php/jprc 2035-(4-Chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-4,5-dihydro-pyrazole-1-carbaldehyde. (3b): IR (KBr): 1630(C=O), 1581 (C=N) Cm-1. 1H NMR (300 MHZ, DMSO) δ 3.23 (dd, J = 5.0, 17.8 HZ, 1H, HA), δ 3.64 (dd, J = 12.0, 17.8HZ, 1H, HB), δ 5.50 (dd, J = 5.1, 12.1 HZ, 1H, HX), δ 6.78 (d, J = 16.2 HZ, 1H, Hα), δ 7.17 (d, J = 16.2 HZ, 1H, Hβ), δ7.29-7.69 (m, 8H, Ar-H), δ 8.90 (s, 1H, CHO). 13C NMR (DMSO) 160.47 (C=O), 143.68 (C=N), 135.26 (Cβ, C=C doublebond), 137.84 (C, Ar-C), 135.55 (C, Ar-C) 134.76 (2CH, of two Ar-C), 130.51 (2CH, of two Ar-C), 128.53 (2CH, of twoAr-C), 120.46 (2CH, of two Ar-C) 118.34 (Cα, C=C double bond), 50.42 (-CH), 38.40 (-CH2). MS m/z: 344 (M+).Anal.Cacld for C18H14Cl2N2O: C, 62.79; H, 4.06. Found: C, 62.75; H, 4.12.5-(5-Chloro-2-hydroxy-phenyl)-3-[2-(5-chloro-2-hydroxy-phenyl)-vinyl]-4,5-dihydro-pyrazole-1-carbaldehyde.(3c): IR (KBr): 3385 (OH), 1632 (C=O), 1585 (C=N) Cm-1. 1H NMR (300 MHZ, DMSO) δ 3.28 (dd, J = 5.0, 17.8 HZ,1H, HA), δ 3.64 (dd, J = 12.0, 17.8 HZ, 1H, HB), δ 5.51 (dd, J = 5.1, 12.1 HZ, 1H, HX), δ 6.78 (d, J = 16.2 HZ, 1H, Hα), δ7.17 (d, J = 16.2 HZ, 1H, Hβ), δ 7.25-7.71 (m, 6H, Ar-H), δ 8.90 (s, 1H, CHO), 10.78 (s, 2H, two OH). 13C NMR (DMSO)160.45 (C=O), 143.70 (C=N), 135.28 (Cβ, C=C double bond), 137.80 (C, Ar-C), 135.57 (C, Ar-C) 134.79 (2CH, of twoAr-C), 130.48 (2CH, of two Ar-C), 128.59 (2CH, of two Ar-C), 120.42 (2CH, of two Ar-C) 118.36 (Cα, C=C doublebond), 50.40 (-CH), 38.43 (-CH2). MS m/z: 376 (M+). Anal.Cacld for C18H14O3Cl2N2: C, 57.44; H, 3.72. Found: C,57.50; H, 3.75.5-(3-Iodo-4,5-dimethoxy-phenyl)-3-[2-(3-iodo-4,5-dimethoxy-phenyl)-vinyl]-4,5-dihydro-pyrazole-1-carbaldehyde.(3d): IR (KBr): 1632 (C=O), 1585 (C=N) Cm-1. 1H NMR (300 MHZ, DMSO) δ 3.76 (s, 12H, fourOCH3), δ 3.27 (dd, J =5.0, 17.8 HZ, 1H, HA), δ 3.62 (dd, J = 12.0, 17.8 HZ, 1H, HB), δ 5.50 (dd, J = 5.1, 12.1 HZ, 1H, HX), δ 6.78 (d, J = 16.2HZ, 1H, Hα), δ 7.17 (d, J = 16.2 HZ, 1H, Hβ), δ 7.29-7.74 (m, 4H, Ar-H), δ 8.90 (s, 1H, CHO). 13C NMR (DMSO) 167.12(4C of two paraAr-ome) 160.47 (C=O), 143.77 (C=N), 135.30 (Cβ, C=C double bond), 137.67 (C, Ar-C), 135.61 (C, Ar-C) 134.75 (2CH, of two Ar-C), 130.50 (2CH, of two Ar-C), 128.55 (2CH, of two Ar-C), 120.48 (2CH, of two Ar-C)118.32 (Cα, C=C double bond), 50.43 (-CH), 38.48 (-CH2). MS m/z: 648 (M+). Anal.Cacld for C22H22O5I2N2: C, 40.74;H, 3.39. Found: C, 40.81; H, 3.43.4. Table 1: Physical data of synthesized Chalcones (2a-d)5. Table 2: Physical Data of Newly Synthesized 4.5-dihydro-pyrazole-1-carbaldehyde derivatives (3a-d)Table 2: Physical Data of Newly Synthesized 4.5-dihydro-pyrazole-1-carbaldehyde derivatives (3a-d)Product R R1 R2 R3 Yield (%) Melting Point (0C)3a H H F H 79 138-1403b H H Cl H 80 118-1203c OH H H Cl 76 135-1373d H I OCH3 OCH3 83 147-1496. Results and DiscussionIn continuation of earlier research work [14-18], in present investigation here, reported the synthesis of new series of 4, 5-dihydro-pyrazole-1-carbaldehyde derivatives. The starting chalcones 2a-d were prepared by classical Claisen-Schmidtcondensation involving base-catalyzed condensation of the desired carbonyl compounds followed by dehydration formingα,β-unsaturated carbonyl compounds. Synthesis of 4, 5-dihydro-pyrazole-1-carbaldehyde were attempted by reacting α,β-unsaturated carbonyl compounds (chalcones) with hydrazine hydrate and formic acid in presence of 2-methoxyethanol assolvent (Scheme-1). Recently the formation of 2-pyrazoline was reported by the reaction of chalcones with hydrazinehydrate take place in various conditions using acetic acid [19], formic acid [20], or pyridine [21] as solvent. However,Table 1: Physical data of synthesized Chalcones (2a-d)Product R R1 R2 R3 Yield (%) Melting Point(0C)2a H H F H 78 129-1312b H H Cl H 82 137-1392c OH H H Cl 84 152-1552d H I OCH3 OCH3 75 160-162Journal of Progressive Research in Chemistry [JPRC]ISSN 2454-3136Volume 4, Issue 3 available at www.scitecresearch.com/journals/index.php/jprc 204many of these reported procedures have one or more disadvantages such as use of expensive catalyst, low selectivity,harsh reaction conditions, low yield, relatively long reaction time and environmental concern. After some preliminaryobservation we found that aqueous 2-methoxyethanol as an efficient reaction medium in terms of clean reactionconditions, not expensive, decreasing reaction time giving high yields of desired product.The formation of chalcones 2a-d was confirmed by IR spectra, absence of a band around 1710-1720 Cm-1due to theketonic C=O stretch and the appearance of characteristic band near 1655 Cm-1and near 1620 Cm-1due to α,β-unsaturatedcarbonyl group and ν (C=C) respectively. In 1H NMR spectrum of chalcones two doublet in range at δ 6.75 (H-α, J = 16.5HZ) and δ 7.35 (H-β, J = 16.5 HZ) suggested the presence of olefin protons at α,β-position to the carbonyl group. The IRspectrum of newly synthesized 2-pyrazolines 3a-d showed a strong band for carbonyl group near 1632 Cm-1and band at1585 Cm-1due to C=N. In the 1H NMR spectra, an ABX pattern was observed for HA, HB and HX proton which appear aspair of doublets near δ 3.28, 3.65 and 5.50 ppm. Trans olefin proton appears asdoublets near δ 6.85 and 7.14 ppm with J =16 HZ. The singlet of CHO appeared at δ 8.90 ppm which conforms the N-H of 2-pyrazoline replaced by N-CHO group.This also conforms on the basis of silver mirror test [22].7. ConclusionIn summary, we have synthesized of some new series of 4, 5-dihydro-pyrazole-1-carbaldehyde derivative by condensationof chalcones with hydrazine hydrate and formic acid in aqueous 2-methoxyethanol as efficient and alternative reactionsolvent. The advantages of present protocol are simplicity of operation, high yields of products and avoidance ofexpensive catalyst and usage of volatile organic solvent.8. References[1] Amir, M, Kuumar, H and Khan, S A, (2008). Synthesis and pharmacological evaluation of pyrazolinederivatives as new anti-inflammatory and analgesic agents. Bioorganic Medicinal Chemistry Letters, 18(3),918-922.[2] Zhang, X H, Wu, S K, Gao, Z Q, Lee, S T and Kwong, H L, (2000). Pyrazoline derivatives for blue coloremitter in organic electroluminescent devices. Thin Solid Film, 371 (1-2), 40-46.[3] Bhargava, S and Rajwanshi, L K, (2013). Synthesis of some novel pyrido [2, 3-d]pyrimidine derivatives andtheir antimicrobial investigation. Indian Journal of Chemistry, 52B (03), 448-452.[4] Krainets, I V, Amer, M, Bezuglyi, P A, Gorokhova, O V, Sidorenko, L V and Turov A V, (2002). 4-Hydroxy-2-quinolones. 56. 4-(Adamant-1-yl) thiazolyl-2-amides of 1-R-4-hydroxy-2-oxoquinoline-3-carboxylic acidsas potential antitubercular agents. Chemistry of Heterocyclic Compounds, 38 (5), 571–575.[5] [5] Faisal,H, Attar, S, Sadiq, U and Amir, A, (2010). Synthesis, characterization, antiamoebic activity andcytotoxicity of novel series of pyrazoline derivatives bearing quinoline tail. European Journal of MedicinalChemistry, 45 (10), 4669–4675.[6] Barsoum, F F, Hosni, H M and Girgis, A S, (2006). Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory and molluscicidal properties. Bioorganic Medicinal Chemistry Letters, 14 (11), 3929–3937.[7] Rostom, S A F, Badr, M H, Abdel Razik, H A, Ashour, H M A and Abdel Wahab, A E, (2011). Synthesis ofsome pyrazolines and pyrimidines derived from polymethoxy chalcones as Anticancer and Antimicrobialagent. Archiv der Pharmazie Chemistry in Life Sciences, 1-16.[8] Insuasty, B, Chamizo, L, Munoz, J, Tigreros, A, Quiroga, J, Abonia, R, Nogueras, M and Cobo,  J, (2012).Synthesis of 1-substituted 3-aryl-5-aryl (hetaryl)-2-pyrazolines and study of their antitumor activity. Archivder Pharmazie Chemistry in Life Sciences, 345, 275-286.[9] Bhat, A R, Athar, F and Azam, A, (2009). Bis-pyrazolines: Synthesis, characterization and antiamoebicactivity as inhibitors of growth of Entamoeba histolytica. European Journal of Medicinal Chemistry, 44 (1),426-431.[10] Archana; Srivastava, V.K.; Chandra, R.; Kumar, A, (2002). Synthesis of potential quinazolinonyl pyrazolinesand quinazolinyl isoxazolines as anticonvulsant agents. Indian Journal of Chemistry Section B, 41, 2371-2375.[11] Sivakumar, P M, Seenivasan, S P, Kumar, V and Doble, M, (2010). Novel 1, 3, 5-triphenyl-2-pyrazolines asanti-infective agents. Bioorganic Medicinal Chemistry Letters, 20 (10), 3169-3172.[12] Ahn, J H, Kim, H M, Jung, S H, Kang, S K, Kim, K R, Rhee, S D,Yang, S D, Cheon, H G and Kim, S S,(2004). Synthesis and DP-IV inhibition of cyano-pyrazoline derivatives as potent anti-diabetic agents.Bioorganic Medicinal Chemistry Letters, 14 (17), 4461-4465.Journal of Progressive Research in Chemistry [JPRC]ISSN 2454-3136Volume 4, Issue 3 available at www.scitecresearch.com/journals/index.php/jprc 205[13] Khalaf Ali, A, El-Shafei Ahmed, K and El-Sayed Ahmed M, (1982). Synthesis of some new bicyclicpyrazoline derivatives. Journal of Heterocyclic Chemistry, 19(3), 609-612.[14] Zangade, S, Shinde, A, Patil, A and Vibhute, Y, (2012). An efficient and facile ring closure of2’‐hydroxychalcones under irradiation of tungsten light. European Journal of Chemistry, 3 (2), 208-212.[15] Zangade, S B, Shinde, A T, Chavan, S B, Mokle, S S and Vibhute, Y B, (2013). Photocyclisation of 2’-hydroxychalcones into 2- pyrazolines under irradiation of solar energy. European Chemical Bulletin, 2 (4),208-210.[16] Zangade, S B, Mokle, S S, Shinde, A T and Vibhute, Y B, (2013). An atom efficient, green synthesis of 2-pyrazoline derivatives under solvent-free conditions using grinding technique. Green Chemistry Letters andReviews, 6(2), 123-127.[17] Zangade, S B, Shinde, A T, Vibhute, A Y and Vibhute, Y B, (2012). An Improved Synthesis and BiologicalEvaluation of Some New 4, 5-dihydro-pyrazole-1-Carbaldehyde Derivatives. Pakistan Journal of Chemistry,2(1), 1-6.[18] Zangade, S, Mokle, S, Chavan, S and Vibhute, Y, (2011). 2-Methoxyethanol as an alternative reaction solventfor the synthesis of 1, 5-benzodiazepines under microwave irradiation. Orbital: The Electronic Journal ofChemistry, 3(3), 144-149.[19] Raiford, L C and Peterson, W J, (1937). Identification of phenylhydrazones and isomeric pyrazolines obtainedfrom chalcones. Journal of Organic Chemistry, 1(6), 544-551.[20] Pramod, S, Negi, J S, Pant, G J, Rawant Mohan, S M and Budakoti, A, (2009). 5-(3-Nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde. Molbank, M 614.[21] Levai, A, (1998). Fused heterocycles. 8 An efficient procedure for the stereoselective synthesis of trans-2,3,3a,4-tetrahydro-3-aryl-2-phenyl[1]benzopyrano[4,3-c]pyrazoles and their [1]benzothiopyrano analoguesJournal of Heterocyclic Chemistry,  35(1), 13-16.[22] Furniss, B S, Hannaford, A J, Smith, P W and Tatchell, A R, (2004). Vogel’s Textbook of Practical OrganicChemistry, 5th Edn.; Pearson Education, India.Author BiographyDr. S B Zanagde presently working as Assistant Professorat Madhavraopatil ACS College, Palam,Dist. Parbhani(M S), India.He obtained his Master degree from S R T M University, Nanded in 2007. He has awarded by Ph.D.degree under the supervision of Dr. Yeshwant B. Vibhute in the year of 2011.Presently he has over seven year’s research experience in the field of heterocyclic chemistry. His areaof interest is to develop new methods for synthesis of organic heterocyclic compounds. He haspublished over 40 research articles in reputed journals.

Aqueous 2-methoxyethanol Reaction media: Synthesis of some 4,5-dihydro-pyrazole-1-carbaldehyde derivative

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Aqueous 2-methoxyethanol Reaction media: Synthesis of some 4,5-dihydro-pyrazole-1-carbaldehyde derivative

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