A Complete 1 H and 13 C NMR data assignment for N-Benzo[1,3]dioxol-5-ylmethyl-2-(2,2,2-trichloroacetylamino) benzamide*

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1 A Complete 1 H and 13 C NMR data assignment for N-Benzo[1,3]dioxol Asian Chemistry Letters Vol. 14, No. 3 (2010) A Complete 1 H and 13 C NMR data assignment for N-Benzo[1,3]dioxol-5-ylmethyl-2-(2,2,2-trichloroacetylamino) benzamide* J S Petrov and P N Penchev Faculty of Chemistry, University of Plovdiv, 24 Tsar Assen Str., BG-4000 Plovdiv, Bulgaria Complete assignments of the 1 H and 13 C NMR chemical shifts for N-benzo[1,3]dioxol-5-ylmethyl-2-(2,2,2- trichloroacetylamino)benzamide were done by means of one- and two-dimensional NMR techniques, including 1 H 1 H CSY, HMQC and HMBC spectra. Ab initio quantum chemistry calculations confirmed the proposed assignments. All mid-ir spectral bands are given as reference data. Anita Publications. All rights reserved. 1 Introduction A number of 2,4(1H,3H)-quinazolinediones have shown biological activity as anticonvulsants and psychosedatives [1]. They attract attention as pharmacophores, as serotonin S 2 -receptor antagonists used for the treatment of hypertension [2] or inhibitors of puromycin-sensitive aminopeptidase showing tumor cell invasion inhibition [3]. In the course of developing a method for the synthesis of 3-substituted 2,4(1H,3H)- quinazolinediones we included as a last step of synthetic approach a base-induced intramolecular cyclization of 2-(trichloroacetylamino)benzamides leading to corresponding 2,4(1H,3H)-quinazolinediones [4]. 3' 2' 1' 10 N a 2 4' 5' 6' N 8' Cl 9' Cl Cl 6 7 7a 1 Fig. 1. Structure of N-Benzo[1,3]dioxol-5-ylmethyl-2-(2,2,2-trichloroacetylamino)benzamide 1. The numbering of the atoms is only for spectral assignments. Because of the key role of the 2-(trichloroacetylamino)benzamides in formation of the quinazolinedione moiety in our proposed mechanism of the reaction [4], we report here our further study which was directed to spectral investigation of the structure of N-benzo[1,3]dioxol-5-ylmethyl-2-(2,2,2- trichloroacetylamino) benzamide 1 (Fig. 1) as a characteristic representative of these intermediate compounds. In addition, the present study supplies fully-assigned 1 H and 13 C NMR spectra which will serve as valuable reference data. Corresponding author : plamen@uni-plovdiv.bg (Dr P N Penchev)

2 274 J S Petrov and P N Penchev Fig. 2. Aromatic part of 1 H NMR spectrum. The integrals of the signals are shown at the bottom of the multiplets.

3 A Complete 1 H and 13 C NMR data assignment for N-Benzo[1,3]dioxol Results and Discussion The 13 C NMR spectrum of 1 showed 17 signals and DEPT displayed 9 resonances, consisting of 7 CH and 2 CH 2. The two highest signals in 13 C NMR spectrum, ppm and , are for the carbonyl groups. The proton at carbon 2 (7.89 ppm) and those at carbon 8 (4.40 ppm) and that at nitrogen 9 (9.51 ppm) show strong HMBC correlations with the ppm signal (see Table 1), identifying it as carbon 10. The two highest signals in 1 H NMR spectrum, ppm (singlet) and 9.51 ppm (triplet) are for the NH protons. The latter signal shows HMBC correlation with ppm (carbon 10) and 1 H 1 H CSY correlation with the protons at carbon 8 that is why it is assigned to the amido group between the two benzene rings (atom #9). The aromatic part of 1 H spectrum is given in Fig. 2. The doublets at 8.34 ppm and 7.89 ppm are for protons at carbons 5 and 2, and the triplets at 7.64 ppm and 7.33 ppm for protons at carbons 4 and 3. It was expected these signals to be doublet of doublets and, respectively, triplet of doublets but the sample is measured by a high concentration of mol l 1. The protons of the other aromatic ring give singlet at 6.90 ppm (at carbon 4), and doublets at 6.84 ppm (at carbon 7) and 6.81 ppm (at carbon 6). Table 1. 1 H and 13 C NMR spectral data and 1 H 1 H CSY and HMBC correlations for 1 [ MHz ( 1 H) and MHz ( 13 C)] a Atom ( 13 C)ppm DEPT b ( 1 H)ppm Multiplicity(J, Hz) 1 H 1 H CSY b HMBC b CH s 3a, 7a 3a C CH 6.90 s 8 c, 6 c, 7 d 6, 7a, C CH 6.81 d (7.8) 7, 4 c, 8 c 4, 7a, CH 6.84 d (7.8) 6, 4 d 5, 3a 7a C CH d (5.7) 9, 4 c, 6 c 4, 5, 6, 10 9(NH) 9.51 t (5.7) 8 10, 8 c C C CH 7.89 d (7.8) 3, 4 c 4, 6, 10, 1 d CH 7.33 t (7.8) 4, 2, 5 c 1, 5, 2 c, 4 d, 6 d CH 7.64 t (7.8) 5, 3, 2 c 2, 6, 5 c CH 8.34 d (7.8) 4, 3 c 1, 3, 6 c, 10 d C 7 (NH) s (a) (b) (c) (d) C C In DMS-d6 solution. All these assignments were in agreement with CSY, HMQC b and HMBC spectra. Abbreviations: DEPT, Distortionless Enhancement by Polarization Transfer spectrum; 1 H 1 H CSY protonproton homonuclear correlation spectrum; HMQC, Heteronuclear Multiple Quantum Correlation experiment; HMBC, Long range 1 H 13 C Heteronuclear Multiple Bond Correlation experiment. These correlations are weak. These correlations are extremely weak.

4 276 J S Petrov and P N Penchev A full set of 1 H and 13 C NMR assigned spectral data for the compound 1 are given in the Table 1 together with 2D data; the strength of 2D correlations is given also (see footnotes c and d in Table 1). Heteronuclear Multiple Quantum Correlation experiment (HMQC) was used to assign proton signals to the corresponding carbon signals. For the CH coupling in benzene rings, as described in the literature [5], usually only meta (vicinal) coupling ( 3 J CH ) are resolved. The measured HMBC correlations confirmed that definitely: for the first benzene ring the strong couplings are H 4 C 6, H 4 C 7a, H 6 C 4, H6 C 7a, H 7 C 5, H 7 C 3a, and for the second H 2 C 4, H 2 C 6, H 3 C 1, H 3 C 5, H4 C 2, H4 C 6, H 5 C 1, H 5 C 3. 1 H 1 H CSY, see Table 1, confirmed additionally the arrangement of the protons in the rings. Proton signals of the two methylene groups, singlet at 5.95 ppm and doublet at 4.40 ppm, were assigned unambiguously because the first one gives two HMBC correlations (with carbons 3a and 7a) and the second one shows a strong 1 H 1 H CSY correlation with proton at nitrogen 9 and two weak 1 H- 1 H CSY correlations with protons at carbons 4 and 6; the latter two correlations confirmed also the arrangement of the protons at carbons 4 and 6. Furthermore, 1 H signal of methylene protons at carbon 8 gives four strong HMBC correlations with carbons 4, 5, 6 and 10. The arrangement of the protons at carbons 2, 3, 4 and 5 is additionally confirmed by the strong HMBC correlation of H 2 C 10. (a) Table 2. Calculated 1 H and 13 C NMR spectral data for 1 Atom ( 13 C), exp a ppm ( 13 C), calcppm ( 1 H), expppm ( 1 H), calcppm b 3a a c 9(NH) (NH) (b) (c) Abbreviations: exp, experimental value; calc, value calculated with quantum chemistry (for the used method see the text). Average between 5.79 ppm and 5.60 ppm. Average between 5.41 ppm and 3.45 ppm.

5 A Complete 1 H and 13 C NMR data assignment for N-Benzo[1,3]dioxol The 13 C NMR spectrum from Table 1 was searched in a database of nearly 39,000 fully-assigned 13 C NMR spectra compiled by Prof. Morton Munk (Arizona State University). The search method, so called interpretive library search, is developed by one of the authors (P.N.P.) and Prof. Munk and is still not published. It retrieves substructures common to both the unknown and reference compounds and estimates the probability of substructure-presence by a comprehensive statistics. The benzo[1,3]dioxole moiety appeared as a substructure present in the compound 1 with a high probability; several scores of reference compounds are present in the database which have 13C chemical shifts assignments of benzo[1,3]dioxole moiety similar to those proposed by us. Additionally, there are two reference compounds in this database, 5-Nitrofuran-2-carboxylic acid {2-[(pyridin-2-ylmethyl)carbamoyl]phenyl}amide and 5-Nitrofuran-2-carboxylic acid {2-[(thiophen-2-ylmethyl)carbamoyl]phenyl}amide, which have an ortho-substituted benzene ring with two amides attached in the same manner as in compound 1. Their 13 C NMR spectra have assignments for that benzene ring very similar to the assignments suggested by us. To additionally verify the proposed assignments, quantum chemistry calculations were performed by using the Gaussian 98, Revision A.7 [6]. For the geometry optimization the B3LYP density functional with 6-31G(d) basis set was used and for the 1 H and 13 C NMR spectra prediction a HF/6-31G(d) calculation was performed at the optimized geometry. The predicted chemical shifts are given in Table 2. The 13 C shift prediction has a standard error of 4.5 ppm with a maximum deviation of 10.8 ppm (for carbon 2), and for 1 H shift has a standard error of 1.6 ppm with a maximum deviation of 4.8 ppm (for hydrogen at N-9); since the two protons of both methylene groups are magnetically equivalent in the measured 1 H NMR spectrum an average of their predicted values is used. The calculated shifts for carbons 1 and 6 are in agreement with the proposed assignment. As a whole, the ranking of the calculated shifts in each benzene ring agrees with that of measured ones except for carbons 1 and 5 which have very close shifts, ppm and ppm, respectively. 3 Experimental Compound 1 was found to possess the molecular formula C 17 H 13 Cl 3 N 2 4 [4]. 1 H, 13 C and 2D NMR spectra were recorded on a Bruker Avance II+ 600MHz NMR spectrometer operating at MHz (1H) and MHz (13C), using TMS as internal standard and DMS-d6 as solvent. Chemical shifts ( ) are expressed in ppm and coupling constants (J) in Hertz. 1D and 2D NMR spectra were recorded using the standard Bruker pulse sequence. For 1 H, 13 C NMR and 2D NMR spectral data of 1 see Table 1. IR spectrum was registered in KBr pellet on a Perkin-Elmer 1750 FT-IR Spectrometer from 4000 cm 1 to 450 cm 1 at resolution 4 cm 1 with 9 scans. A curved baseline correction was performed with the instrument function FLAT to obtain the real band intensities cited below. IR spectral bands of 1, max (cm 1 )/Transmittance (%): 3315/32.1, 3243/53.6, 3108/77.0, 3073/72.9, 3038/78.4, 2992/78.4, 2974/78.4, 2938/75.6, 2884/67.8, 2778/80.5, 1867/96.5, 1718/23.0, 1707/16.0, 1631/20.6, 1601/ 17.7, 1587/39.1, 1548/20.2, 1516/10.0, 1504/11.7, 1490/26.5, 1446/10.7, 1356/54.1, 1312/44.4, 1295/27.5, 1256/ 12.9, 1232/50.3, 1197/53.6, 1172/69.7, 1125/79.8, 1099/62.5, 1045/22.7, 983/77.0, 956/89.7, 938/42.4, 920/75.6, 883/49.9, 817/18.1, 794/70.3, 777/48.1, 764/30.4, 728/67.2, 716/62.5, 690/47.7, 661/28.8, 602/82.0, 575/69.1, 550/ 87.3, 512/69.1. References 1. Hayao S, Havera H J, Strycker W G, Leipzig T J, Kulp R A, Hartzler H E, J Med Chem, 8(1965) Meuldermans W, Hendrickx J, Woestenborghs R, Van Peer A, Lauwers W, De Cree J, Heykants J, J Arzneim.- Forsch/Drug Res, 38(1988)789.

6 278 J S Petrov and P N Penchev 3. Kakuta H, Tanatani A, Nagasawa K, Hashimoto Y, Chem Pharm Bull, 51(2003) Petrov J S, Andreev G, rg Prep Proced Int, 37(2005) Breitmaier E, Structure Elucidation by NMR in rganic Chemistry: A Practical Guide, (John Wiley & Sons: Chichester, U K), 2002, p Gaussian 98, Revision A.7, Frisch M J, Trucks G W, Schlegel H B, Scuseria G E, Robb M A, Cheeseman J R, V G Zakrzewski, J A Montgomery, (Jr), R E Stratmann, J C Burant, S Dapprich, J M Millam, A D Daniels, K N Kudin, M C Strain, Farkas, J Tomasi, V Barone, M Cossi, R Cammi, B Mennucci, C Pomelli, C Adamo, S Clifford, J chterski, G A Petersson, P Y Ayala, Q Cui, K Morokuma, D K Malick, A D Rabuck, K Raghavachari, J B Foresman, J Cioslowski, J V rtiz, A G Baboul, B B Stefanov, G Liu, A Liashenko, P Piskorz, I Komaromi, R Gomperts, R L Martin, D J Fox, T Keith, M A Al-Laham, C Y Peng, A Nanayakkara, C Gonzalez, M Challacombe, P M W Gill, B Johnson, W Chen, M W Wong, J L Andres, C Gonzalez, M Head-Gordon, E S Replogle, and J A Pople, Gaussian, Inc, Pittsburgh PA, [Received: ; accepted: ]