N-phenyl-2-[(trichloroacetyl)amino]benzamide*

Transcription

1 Asian Chemistry Letters Vol. 15, No 1 (2011) A complete 1 H and 13 C NMR data assignment for N-phenyl-2-[(trichloroacetyl)amino]benzamide* P N Penchev and J S Petrov Faculty of Chemistry, University of Plovdiv, 24 Tsar Assen Str., BG-4000 Plovdiv, Bulgaria plamen@uni-plovdiv.bg *This article is dedicated to Professor George Andreev, University of Plovdiv, on the occasion of his 70 th anniversary Complete assignments of the 1 H and 13 C NMR chemical shifts for N-phenyl-2-[(trichloroacetyl)amino]benzamide were done by means of one- and two-dimensional NMR techniques, including 1 H 1 H COSY, HSQC and HMBC spectra. 1 Introduction In a previous communication we reported on the synthesis of 3-substituted 2,4(1H,3H)- quinazolinediones [1], representatives of the class of compounds possessing variety of biological activities [2-5]. Some of these compounds are 3-phenyl-2,4(1H,3H)-quinazolinedione and its analogues. The synthetic approach of their preparation includes base-induced intramolecular cyclization of 2- [(trichloroacetyl)amino]benzamides. The elucidation of the path of the reaction and the study of its scope and synthetic applications bring to need the further spectral investigation of N-phenyl-2- [(trichloroacetyl)amino]benzamide 1 as a general structural moiety of the used at the cyclization stage of the reaction 2-[(trichloroacetyl)amino]benzanilides. 3' 4' 2' 5' 1' 6' O O 8 N Cl N 8' 9' Cl Cl Fig. 1. Structure of N-phenyl-2-[(trichloroacetyl)amino]benzamide 1. The numbering of the atoms is only for spectral assignments. 2 Results and Discussion Compound 1 was found to possess the molecular formula C 15 H 11 Cl 3 N 2 O 2 [1]. The 13 C NMR spectrum of 1 showed 13 signals and DEPT displayed 7 resonances; in both spectra the resonances at ppm and are with higher intensity (nearly double intensity compared to the others) which suggests that each of them corresponds to two magnetically equivalent carbon atoms. The signal at ppm is for C-3/5 and that at is for C-2/6. The two signals in 13 C NMR spectrum with highest shift, ppm and , are for the carbonyl groups, respectively, C-8 and C-8. These four assignments are confirmed by the 2D spectra (see discussion that follows). The aromatic part of 1 H spectrum is given in Fig. 2, and the corresponding assignment in Table 1. The multiplets A at 8.29 ppm and B at 8.03 ppm are for protons at carbons 5 and 2 ; as expected they are doublets of doublets. The multiplet for proton at carbon 4 (triplet of doublets) is overlapped with the Corresponding author: petrov@uni-plovdiv.bg (Dr J S Petrov)

2 J S Petrov and P N Penchev multiplet for protons at carbons 2 and 6 (giving multiplet C with an integral of three); the right doublet of H- 4 can be seen from the left expansion in Fig. 2. The multiplet for proton at carbon 3 (triplet of doublets) is very close to the multiplet for protons at carbons 3 and 5 see the middle expansion in Fig. 2. The last multiplet, F, is triplet of triplets, as can be seen from the right expansion in Fig. 2. It belongs to the proton at carbon 4. The five protons in the phenyl ring represent an AA MM X system, whose analysis is hampered by the above mentioned overlap. A close insight into the three multiplets of these five protons gives three shift values 7.71 ppm for protons 2 and 6, 7.40 ppm for protons 3 and 5, and 7.17 ppm for proton 4. These values agree with those extracted from HSQC spectrum, given in Fig. 3. Table 1. 1 H and 13 C NMR spectral data and 1 H- 1 H COSY and HMBC correlations for 1 [ MHz ( 1 H) and MHz ( 13 C)] a Atom δ ( 13 C) DEPT b δ (1 H) Multiplicity ppm ppm (J, Hz) 1 H- 1 H COSY b HMBC b C CH 7.71 e) 4 c 4, CH 7.40 e) 2, 6 1, CH 7.17 tt (7.4, 1.2) 2, 6, 1 c, 3 c, 5 c CH 7.40 e) 2, 6, 3, 5 1, CH 7.71 e) 4 c 2, 4 7 (NH) s 8, 2, C C CH 8.03 dd (7.9, 1.2) 3, 4 d 8, 4, 6, 1 d, 5 d CH 7.43 td (7.7, 1.1) 2, 4, 5 d 1, 5, 4 c CH 7.70 e) td (7.9, 1.5) 2 d, 3, 5 2, CH 8.29 dd (8.3, 0.9) 4, 3 d 1, 3, 6 c, 2 d C 7 (NH) s 5, 8, 1 c C C a) In DMSO-d 6 solution. All these assignments were in agreement with COSY, HSQC b and HMBC spectra. b) Abbreviations: DEPT, Distortionless Enhancement by Polarization Transfer spectrum; 1 H- 1 H COSY proton-proton homonuclear correlation spectrum; HMBC, Long range 1 H- 13 C Heteronuclear Multiple Bond Correlation experiment. c) These correlations are weak. d) These correlations are extremely weak. e) These values were taken from HSQC. Heteronuclear Single Quantum Coherence experiment (HSQC) was used to assign proton signals to the corresponding carbon signals; the seven HSQC correlations are well separated see Fig. 3. Two of them (for H-3/5 and H-2/6) has nearly double intensity compared to the others: that agree with the above mentioned intensity of their 13 C and DEPT-135 NMR resonances. The two signals in 1 H NMR spectrum with highest shift, ppm (singlet) and ppm (singlet) are for the NH protons, N-7 and N-7. The proton at carbon 2 (8.03 ppm) and that at nitrogen 7 (10.65 ppm) show strong HMBC correlations with the ppm signal (see Table 1), assigning the latter signal to carbon 8. On the other side, the proton at nitrogen 7 (12.44 ppm) show strong HMBC correlations with C-5 ( ppm) and the ppm signal, assigning the latter ( ppm) to C-8. The proton at nitrogen 7 (12.44 ppm) show also a weak HMBC correlation to C-1 ( ppm) but both NH protons are at three-bond distance to C-1 and the assignment of the latter is confirmed by the meta (vicinal) couplings in ortho substituted benzene ring (see discussion that follows).

3 A complete 1 H and 13 C NMR data assignment Additionally, the proton at nitrogen 7 (10.65 ppm) show also a strong HMBC correlation with ppm, thus allowing the assignment of the latter value to C-2/6. There are three aromatic carbons in 1, C-1, C-6 and C-1, with no hydrogen attached to them. The assignment of their 13 C-NMR signals can be done with the aid of HMBC. The aromatic part of HMBC spectrum of 1 is given in Fig 4. For the CH coupling in benzene ring, as described in the literature [6], only the meta (vicinal) coupling ( 3 J CH ) is usually resolved. The measured HMBC correlations (see also Table 1) confirmed that definitely: for phenyl ring the strong meta (vicinal) HMBC couplings are H 2 C 4, H 2 C 6, H 3 C 1, H 3 C 5, H 4 C 2, H 4 C 6, H 5 C 1, H 5 C 3, H 6 C 2, H 6 C 4 and for the ortho-substituted benzene moiety these strong couplings are H 2 C 4, H 2 C 6, H 3 C 1, H 3 C 5, H 4 C 2, H 4 C 6, H 5 C 1, H 5 C 3. There are several weak HMBC correlations H 5 C 6, H 3 C 4, H 4 C 1, H 4 C 3/5 and several extremely weak H 2 C 1, H 2 C 5, H 5 C 2 see Fig 4 which are in agreement with the proposed assignments. There are strong 1 H- 1 H COSY correlations (see Table 1) between H 3/5 H 2/6, H 3/5 H 4, H 2 H 3, H 4 H 5. 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). Fig. 2. Aromatic part of 1 H NMR spectrum. The integrals of the signals are shown at the bottom of the multiplets. The upper three multiplets are expansions of multiplets C, D together with E and F.

4 J S Petrov and P N Penchev Fig. 3. Detail of the HSQC spectrum of 1. 1D trace (left) is 13 C DEPT-135 NMR spectrum and 1D trace (top) is 1 H NMR spectrum. Fig. 4. Detail of the aromatic part of the HMBC spectrum of 1. 1D trace (left) is 13 C NMR spectrum and 1D trace (top) is 1 H NMR spectrum. The contour levels is set higher and a number of imperfections can be seen.

5 A complete 1 H and 13 C NMR data assignment It was expected that some shift predictions can confirm our assignments. The predicted chemical shifts by the incremental method implemented in ChemDraw Ultra [7] are given in Table 2. The 13 C shift predictions made by the incremental method have a standard error of 3.0 ppm with a maximum deviation of 8.2 ppm (for carbon 9 ) and those for 1 H shift (without NH protons) have a standard error of 0.22 ppm with a maximum deviation of 0.47 ppm (for proton at carbon 5 ). As seen from Table 2, the 13 C shift predictions rank correctly the carbon signals in the phenyl ring. The 1 H shift predictions rank also correctly the three phenyl signals. Both predictions failed ranking in the other ring. Table 2. Calculated 1 H and 13 C NMR spectral data for 1 δ( 13 C), exp a δ( 13 C), calc a Atom DEPT a δ(1 H), exp a ppm ppm ppm C CH CH CH CH CH (NH) b C C CH CH CH CH C 7 (NH) b C C δ( 1 H), calc a ppm a) Abbreviations: exp, experimental value; calc, value calculated by ChemDraw [7]; Distortionless Enhancement by Polarization Transfer spectrum. b) Rough estimation quality as given by ChemDraw. 3 Experimental 1 H, 13 C and 2D NMR spectra were recorded on a Bruker Avance II+ 600MHz NMR spectrometer operating at MHz ( 1 H) and MHz ( 13 C), using TMS as internal standard and DMSO-d 6 as solvent. Chemical shifts (δ) 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. Acknowledgements A thankful acknowledgement is made of the financial support of the National Science Fund for the purchase of Bruker Avance II+ 600 NMR spectrometer in the framework of the Program Promotion of the Research Potential through Unique Scientific Equipment Project UNA-17/2005. References 1 Petrov J.S.; Andreev G.N. Synthesis of 2,4(1H,3H)-quinazolinedione and 3-substituted 2,4(1H,3H)- quinazolinediones. Org. Prep. Proced. Int. 2005, 37, Van Nueten JM.; Janssen PA.; Van Beek J.; Xhonneux R.; Verbeuren TJ.; Vanhoutte PM. Vascular effects of ketanserin (R ), a novel antagonist of 5-HT2 serotonergic receptors. J. Pharmacol. Exp. Ther. 1981, 218,

6 J S Petrov and P N Penchev 3 Choo H.P.; Kim M.; Lee S.K.; Kimb S.W.; Chung I.K. Solid-Phase Combinatorial Synthesis and Cytotoxicity of 3-Aryl-2,4-quinazolindiones. Bioorgan. Med. Chem. 2002, 10, Kakuta H.; Tanatani A.; Nagasawa K.; Hashimoto Y. Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton. Chem. Pharm. Bull. 2003, 51, Huang C.; Meng X.; Cui J.; Li Z. Synthesis of 3-N-Sugar-substituted-2,4(1H, 3H)-quinazolinediones as Anti- Angiogenesis Agents. Molecules 2009, 14, Breitmaier E. Structure Elucidation By NMR in Organic Chemistry: A Practical Guide. John Wiley & Sons: Chichester, U.K., 2002; 258 pp. 7 ChemDraw Ultra ( ), Cambridge Soft Corporation, 100 Cambridge Park Drive, Cambridge, MA, 02140, USA. [Received: ; accepted: ]