Nova Biotechnol Chim (2017) 16(2): 147-151 DOI: 10.1515/nbec-2017-0020  Corresponding author: renata.gasparova@ucm.sk Nova Biotechnologica et Chimica NMR spectroscopic properties of furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine derivatives Ivana Zemanová and Renata Gašparová Department of Chemistry, Faculty of Natural Sciences, University of SS. Cyril and Methodius in Trnava, Nám. J. Herdu 2, Trnava, SK-917 01, Slovak Republic Article info Article history: Received: 12 th June 2017 Accepted: 4 th July 2017 Keywords: Chemical shift furo[3,2-b][pyrrole NMR spectroscopy Abstract The 1 H and 13 C NMR spectroscopic properties of a series of furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones and -thiones were investigated. The influence of various electron donating as well as electron withdrawing substituents at C-5 or N-7 on 1 H NMR chemical shifts as well as 13 C chemical shifts at C8 were observed. The 5-chloromethyl group had a little influence on the chemical shift of H-7 proton and the 8-thione group causes deshielding of H-7 as well as H-5 protons in comparison with the C-8 carbonyl group.  University of SS. Cyril and Methodius in Trnava Introduction Furo[3,2-b]pyrroles are isosteres of the indole ring system in which the benzene ring is replaced by the furan ring. Efficient synthetic routes to these heterocycles are of great interest (Krutošíková et al. 1992; Beccalli et al. 2008; Zhao et al. 2014) as the furo[3,2-b]pyrrole core has been found in compounds with diverse biological activities (Sparey et al. 2008; Fehér et al. 2010) or they are used as the fluorescent dyes (Umezawa et al. 2008). Heterocyclic compounds containing five- and six-membered nitrogen heterocyclic rings have also attracted the attention due to the fact that they exhibit many biological interactions (Astakhina et al. 2016). In addition, 1,2,4-triazin-6-one is structural system found in numerous natural and synthetic biologically active compounds with a wide range of biological activity including anti- inflammatory (George et al. 2015) or anticonvulsant (El-Gendy et al. 2008). We have recently reported the synthesis of furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)- ones with interesting antibacterial activity (Zemanová et al. 2017), but more complex spectroscopic studies were realised only on benzothieno[3,2-d]-1,2,3-triazines (Lauria et al. 2014) or 7-aryl-7H-pyrazolo[3,4-d]-[1,2,3]triazin- 4-ols (Khutova et al. 2012). Therefore we report here on the NMR spectroscopic properties of the full series. Results and Discussion The title compounds 1a-1c (Fig. 1) are well accessible from methyl 4H-furo[3,2-b]pyrrole-5- carboxylate via its hydrazinolysis and subsequent cyclization of hydrazides with orthoesters (triethyl orthoformate, triethyl orthochloroacetate or triethyl orthoacetate) in dimethylformamide. Resulting furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)- ones 1 were obtained in 69-75%. The carbonyl group at C-8 of triazine ring of 1a can be easily thionated by reaction with phosphorus pentasulfide in pyridine to give thione 2a in 85% yield Alkylation or acylation of triazines 1a and 2a with alkylhalides (CH3I, n-C6H9Br, ClCH2CO2Me) Bereitgestellt von Slovenská poľnohospodárska knižnica | Heruntergeladen 28.02.20 08:20 UTC Nova Biotechnol Chim (2017) 16(2): 147-151 148 Fig. 1. Structure of furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones 1 and thiones 2. or acetic anhydride in dimethylformamide in the presence of sodium hydride provided 7-substituted triazinones 1d-1h or thiones 2b, 2c (Fig.1) in 45-72 % yields (Zemanová et al. 2017). 1 H NMR Spectroscopy The influence of various substituents (C5)-R and (N7)-R 1 on 1 H NMR chemical shifts of the protons in triazinones 1 and triazinethiones 2 were investigated (Table 1).The influence of C-5 substituent (H, CH2Cl, CH3) on chemical shifts of the protons of derivatives 1a-1c showed the slight increasing of the chemical shift value of H-7 proton in case of electron withdrawing group (CH2Cl) at C-5 (Fig. 2). Table 1. 1 H NMR chemical shifts of furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones 1a-1h and thiones 2a-2c in DMSO-d6. X R R1 1a O H H 1b O CH2Cl H 1c O CH3 H 1d O H CH3 1e O H n-C4H9 1f O H CH2Ph 1g O H CH2CO2CH3 1h O H COCH3 2a S H H 2b S H CH3 2c S H CH2CO2CH3 Chemical shift (ppm) H-2 H-3 H-5 H-7 H-9 other 1a 8.00 7.11 8.75 11.81 7.14 - 1b 7.97 6.67 - 12.09 6.88 5:09 (CH2) 1c 7.99 7.15 - 11.65 7.10 2.60 (CH3) 1d 7.99 7.09 8.81 - 7.14 3.56 (CH3) 1e 7.99 7.09 8.82 - 7.13 3.99 (t,CH2), 1.73 (sextet, CH2), 1.37 (sextet, CH2), 0.93 (t, CH3) 1f 8.01 7.09 8.83 - 7.19 5.17 (CH2) 1g 8.01 7.09 8.83 - 7.20 4.77 (CH2), 3.67 (CH3) 1h 8.09 7.11 8.83 - 7.39 2.59 (CH2) 2a 8.09 7.15 9.16 13.29 7.29 - 2b 8.31 7.34 10.98 - 7:76 4.17 (CH3) 2c 8.11 7.15 9.24 - 7.36 5.32 (CH2), 3.67 (CH3) Fig. 2. The influence of substituent on C-5 of 1a-1c on the chemical shifts of protons in 1 H NMR. Bereitgestellt von Slovenská poľnohospodárska knižnica | Heruntergeladen 28.02.20 08:20 UTC Nova Biotechnol Chim (2017) 16(2): 147-151 149 As it is shown in Table 1, the presence either electron withdraving either electron donating substituents at N-7 has no significant influence on the chemical shifts of protons in compounds 1d-1h in comparison with N-7 unsubstituted derivative 1a. The values of H-2 shifts are in 7.99-8.09 ppm region, H-3 resonate in 7.09-7.11 ppm. In case of H-5 the range is only 8.81-8.83 ppm. The chemical shifts of H-9 are in 7.14 - 7.39 ppm range (Fig. 3).When the carbonyl group at C-8 was replaced by thione, the chemical shifts of H-2 and H-3 were not significantly influenced, but the shifts of H-5 significantly deshielded to 9.16 - 10.98 ppm. Deshielding of H-7 protons is not so remarkable, except 2b with value 7.76 ppm (Fig. 4). 13 C NMR Spectroscopy There was very little variation in the C-8 (C=O) signal of triazinones 1a-1h (Table 1). The range was only 153.7-154.6 ppm. C-8a carbons resonate at 123.6-125.7 ppm and C-5 carbons resonate at 127.7-35.7 ppm, respectively. When the carbonyl group is replaced by thione, the value of C-8 signal of 2a-2c has deshielded and appear at 173.1-162.3 ppm region, signals of C-8a appear at 130.5-130.9 ppm and C-5 at 131.6-144.8 ppm region, respectively (Table 2). Fig. 3.The influence of substituent on N-7 of 1a, 1d-1h on the chemical shifts of protons in 1 H NMR. Fig. 4. The influence of C-8 thione group of 2a-2c on the chemical shifts of protons in 1 H NMR in comparison with C-8 carbonyl compounds 1a, 1d and 1g. Bereitgestellt von Slovenská poľnohospodárska knižnica | Heruntergeladen 28.02.20 08:20 UTC Nova Biotechnol Chim (2017) 16(2): 147-151 150 Table 2. 13 C NMR chemical shifts of furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones 1a-1h and thiones 2a-2c in DMSO-d6. Chemical shift (ppm) C-2 C-3 C-3a C-5 C-8 C-8a C-9 C-9a 1a 149.5 100.0 123.5 127.7 155.2 124.8 92.4 148.4 1b - - - - - - - - 1c 149.8 101.7 123.9 135.7 155.3 125.6 92.9 148.9 1d 149.9 100.6 123.8 127.8 154.6 124.9 93.0 149.2 1e 150.0 100.6 123.8 128.0 154.3 124.9 93.3 149.3 1f 149.7 100.1 123.5 128.3 153.9 124.2 93.2 148.7 1g 149.7 99.8 123.5 127.5 153.7 123.6 93.2 148.3 1h 151.6 100.7 124.3 128.6 154.4 125.7 97.6 149.2 2a 150.5 100.2 123.9 131.7 173.1 130.5 95.3 149.4 2b 157.7 106.1 125.9 144.8 162.3 130.9 99.7 156.5 2c 150.9 100.4 127.9 131.6 167.4 130.6 96.8 150.9 The 13 C NMR spectrum was unmeasurable because of the low solubility of 1b. Conclusions The chemical shifts in 1 H and 13 C NMR spectra of series of furo[2',3':4,5]pyrrolo[1,2- d][1,2,4]triazin-8(7H)-ones were investigated. 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