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Structural analysis of N,N-diacyl-1,4-dihydropyrazine by variable-temperature NMR and DFT calculation
Journal of Molecular Structure 1134 (2017) 606e610
Contents lists available at ScienceDirect
Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc
Structural analysis of N,N-diacyl-1,4-dihydropyrazine by variabletemperature NMR and DFT calculation Xiu-qing Song, Hong-bo Tan, Hong Yan*, Yu Chang College of Life Science and Bio-engineering, Beijing University of Technology, Beijing, 100124, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 November 2016 Received in revised form 4 January 2017 Accepted 4 January 2017 Available online 6 January 2017
N,N-diacyl-1,4-dihydropyrazine derivatives (1) were prepared via an efficient microwave-assisted synthesis. 1 was isolated and unambiguously confirmed by NMR spectra and high-resolution mass spectrometry. The NMR spectra of 1 showed complicated rather than conventional spectroscopy. Variabletemperature experiments and DFT calculation (PES) were used to investigate this phenomenon. DFT calculations confirmed that the structures of the two rotamers of 1 correspond to those determined by NMR in solution, and gave the syn-anti interconversion barriers of rotamers. The results showed that two isomers exist in solution (deuterated solvent) at room temperature, resulting in complicated NMR spectra. © 2017 Elsevier B.V. All rights reserved.
Keywords: 1,4-Dihydropyrazine Microwave-assisted synthesis Conformational isomerism Variable-temperature NMR Density-functional theory (DFT)
1. Introduction The 1,4-dihydropyrazine has attracted much interest as a structural moiety due to its cyclic 8p-electron conjugation, which is called ‘antiaromatic’ character [1e4]. The antiaromatic compounds with 4np electronic structures usually have a high HOMO level and low LUMO level, namely, a small HOMO-LUMO gap relative to aromatic compounds with [4nþ2]p electronic structures [5e7]. These characteristics of antiaromatic compounds are favorable for release and/or acceptance of electrons and absorption of light in the visible and/or near-infrared (NIR) regions. The antiaromatic 1,4dihydropyrazine have recently attracted interest as promising substrate for its reactivity study [8e10]. To complement our initial synthesis of this system [11e13], we now report the preparation of representative N,N-diacyl-1,4-dihydropyrazine (1) and assignment of the spatial structure effects on the NMR spectra (Scheme 1).
2. Experimental methods 2.1. Physical measurements All chemicals were purchased from commercial sources and
* Corresponding author. E-mail address: [email protected] (H. Yan). http://dx.doi.org/10.1016/j.molstruc.2017.01.019 0022-2860/© 2017 Elsevier B.V. All rights reserved.
used without further purification. Thin-layer chromatography (TLC) was conducted on silica-gel 60 F254 plates (Merck KGaA). Melting points were determined on a XT-5A digital melting-point apparatus and are uncorrected. 1H NMR spectra and 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer at 400 and 100 MHz using DMSO-d6 as the solvent and tetramethylsilane (TMS) as the internal standard. High-resolution mass spectral (HRMS) analyses were carried out using a VG 70SE mass spectrometer from Manchester, UK, which was operated in electron impact or electrospray ionization mode. 2.2. Chemical synthesis The 1a and 1b were prepared by the reaction of pyrazine and acid anhydride catalyzed by zinc powder [14]. To simplify the experimental procedures and shorten the reaction time, microwave irradiation was used as an efficient heating source for organic reactions. The effects of changes in the microwave power, temperature, and reaction time are discussed, giving the best conditions (eg, 1a) (Table 1). So, 1a and 1b were prepared from pyrazine via an efficient microwave-assisted synthesis at max power 100 W at 140 C for 30 min, giving a higher yield (75% and 70%) than the conventional reflux method (44% and 11%) [14] (Scheme 2). And 1c was synthesized by the treatment of 1,4dihydropyrazine bis (vinyl phosphate) with triethylammonium formate, palladium acetate, and triphenylphosphine in THF, giving
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607
291.1125.
Scheme 1. Structure of N,N-diacyl-1,4-dihydropyrazine (1).
Table 1 Yield of 1a in different conditions. Temperature ( C)
80
Power (W) Time (min) Yield (%)a
80 15 <30
a
140 100 30 <30
120 45 <30
80 15 60
160 100 30 75
120 45 65
80 15 55
100 30 70
120 45 60
Isolated yield.
2.2.2. Procedure for the preparation of 1c To a solution of bisvinylphosphate (1.28 mmol) in DME (5 mL), Pd(OAc)2 (0.10 mmol, 8 mol %) and PPh3 (0.21 mmol) were added under argon. Then, the flask was evacuated and backfilled with argon three times and was stirred for 5 min. At room temperature, this solution was then transferred dropwise into a degassed solution of formic acid (6.40 mmol) and triethylamine (7.68 mmol) in DME (5 mL). The reaction mixture was refluxed for 2 h. After cooling, the mixture was filtered through Celite and was washed with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate ¼ 98:2) to give 1c as a white solid, yield 46%; mp: 103e105 C (lit. [15] mp: 104e105 C). 1H NMR (400 MHz, CDCl3): d (ppm) 1.48 (br s, 18H, CH3), 5.80 (br s, 1H, ]CH), 5.91e5.97 (m, 2H, ]CH), 6.07 (br s, 1H, ]CH); 13C NMR (100 MHz, CDCl3): d (ppm) 28.3, 81.9, 110.5, 111.0, 111.6, 112.0, 148.4, 148.5; HRMS (ESI), m/z calcd 283.1652 for C18H15N2O2 [MþH]þ, found 283.1655. 2.3. NMR characterization
Scheme 2. Synthesis of N,N-diacyl-1,4-dihydropyrazine(1a and 1b).
a yield 46% [15] (Scheme 3). 2.2.1. General procedure for the preparation of 1a and 1b A mixture of pyrazine (20 mmol), zinc powder (46 mmol) and acid anhydride (24 mmol) were irradiated in a 100 mL vial using microwave system operating at maximal microwave power up to 100 W at 140 C for 25 min. After cooling, the precipitate was filtered and H2O and ethyl acetate were added. The organic phase was washed with brine, dried over Na2SO4, concentrated under vacuum and recrystallised from methanol, resulting in target compounds 1a and 1b. 1,4-diacetyl-1,4-dihydropyrazine (1a): Colorless crystals, yield 75%, mp: 188e190 C (lit [14] mp: 188e191 C). 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.04 (s, 3H, CH3), 2.05 (s, 3H, CH3), 6.13e6.14 (m, 1H, ]CH), 6.29 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz, ]CH), 6.34 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz, ]CH), 6.48e6.49 (m, 1H, ]CH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 20.8, 21.0, 109.9, 111.9, 112.8, 114.8, 163.3, 163.4; HRMS (ESI), m/z calcd 167.0815 for C8H11N2O2 [MþH]þ, found 167.0810. 1,4-dibenzoyl-1,4-dihydropyrazine (1b): Yellow needles, yield 70%; mp: 195e197 C (lit [14] mp: 193e199 C). 1H NMR (400 MHz, DMSO-d6): d (ppm) 5.85 (br s, 1H, ]CH), 6.17 (br s, 1H, ]CH), 6.51 (br s, 1H, ]CH), 6.85 (br s, 1H, ]CH), 7.51e7.56 (m, 10H, AreH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 128.2, 129.2, 131.5, 133.4, 163.3; HRMS (ESI), m/z calcd 291.1128 for C18H15N2O2 [MþH]þ, found
Scheme 3. Synthesis of N,N-diacyl-1,4-dihydropyrazine(1c).
NMR spectra were obtained at 400 MHz for 1H and at 100 MHz for 13C. The assignments of the 1H and 13C signals were obtained by bidimensional experiments (HSQC and HMBC sequences). The variable-temperature spectra were recorded at 400 MHz for 1H NMR and 100 MHz for 13C NMR; temperature calibration and line shape simulation methods were described elsewhere [16]. The structures of N,N-diacyl-1,4-dihydropyrazines (1) were characterized by 1H NMR spectra. The NMR of 1 showed complicated spectra of four unsaturated protons on pyrazine ring, which are depicted in Fig. 1. 1a showed two multiplets and two double doublets, 1b showed four broad singlets, and 1c showed two singlets and a quartet-like peak. The occurrence of this phenomenon may be the result of the conformation isomerism of diacyl groups of 1 in solution (deuterated solvent) by the groups of Refs. [17e19]. In the 1H NMR spectrum of 1a, there were two single peaks from the methyl groups at d 2.01 and 2.05 ppm, two multiplets from the enamine group at d 6.14 and 6.49 ppm, and two doublets of doublets from the enamine group at d 6.29 and 6.34 ppm. The complicated spectra resulted from the conformation isomerism of 1a because of the anti- and syn-orientations of the two acetyl groups on the ring (Fig. 2). The anti-isomer of 1a showed two doublets of doublets because of the coupling effects. For example, proton ]C5H (anti) was coupled with ]C6H (anti) (3J ¼ 6.74 Hz) and remotely coupled with ]C3H (anti) (4J ¼ 1.72 Hz), giving a doublet of doublets at d 6.29 ppm. For syn-isomer of 1a, protons ] C5H (syn) and ]C6H (syn) were in magnetic inequivalence, so proton ]C5H (syn) was not coupled with ]C6H (syn), just remotely coupled with ]C2H (syn) (4J < 1.00 Hz), showing a multiplet at d 6.14 ppm. The correlations of ]C2H/]C5H (anti) and ]C5H/] C6H (syn) proton signals with the 2.04 and 2.05 ppm siglet signals in the H-H COSY spectrum provided the means to assign these two siglets to the methyl protons (anti) and methyl protons (syn) respectively (Fig. 3). Referring to the NMR analysis of 1a, the signals in 1H NMR spectrum of 1b and 1c were also assigned, which are depicted in Table 2. 1b and 1c also showed similarly complex NMR spectra due to acyl groups (Bz and Boc) on the pyrazine ring. Because of the influences of different acyl groups, 1a, 1b and 1c displayed similar but distinguishing NMR spectra. After comparison of 1H NMR spectra in Fig. 1, an interesting phenomenon was observed. The room-temperature 1H NMR spectrum of 1b showed almost the same peak shapes as that of variable-temperature 1H NMR
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Fig. 1. Expansion of low-field of 1H NMR spectra of 1 at 298 K.
spectrum of 1a at 333 K; And the room-temperature 1H NMR spectrum of 1c showed almost the same peak shapes as that of variable-temperature 1H NMR spectrum of 1a at 313 K. This may result from their natural properties owing to different acyl groups on the pyrazine ring: different acyl groups cause different interconversion-speed of 1 at room temperature. 2.4. Variable-temperature NMR
Fig. 2. Expansion of low-field of 1H NMR spectrum of 1a in DMSO-d6.
Variable-temperature 1H NMR spectrua were used to further analyze the structure of 1a, using different temperature at 298 K, 313 K, 333 K, 353 K and 373 K (Fig. 4). With increasing temperature (333 K), the interconversion between the two conformers should be accelerated, making the 1H NMR spectrum simplified, especially for the peaks at lower field, at which the unsaturated protons on pyrazine ring just showed four single peaks. At the greatest temperature (373 K), the anti and syn orientations of conformers interconverts rapidly with each other and cannot be distinguished on the NMR scale: the 1H NMR spectrum showed the simplest peak shape, with only one single peak for four unsaturated protons and one single peak for protons of two methyl groups. Similarly, in the variable-temperature 13C NMR spectrum of 1a (373 K), two carbonyls showed a single peak, four unsaturated carbons showed a broad peak and two methyls showed a single peak (Fig. 5). The complicated nature of the spectra resulted from the conformational isomerism of 1a because of the two acetyl groups on the ring. Different conformational isomers resulted in a different chemical environment of protons and then different shift values, giving complex NMR spectra of 1a. 3. Calculation details
Fig. 3. Expansion of H-H COSY spectrum of 1a in DMSO-d6.
The geometries of 1 have been optimized using DFT/B3LYP method in singlet ground state. The potential energy surface (PES) scan for the selected dihedral angle of 1 has been performed to identify stable conformer at the B3LYP/6-31G (d, p) level of density functional theory (DFT) in Gaussian 09W software package [20]. The Eigen values obtained from the scan output reveals that, the structure positioning the dihedral angle (red) at 0 (<90 ) and 180 (>90 ) possess minimum energy among others. As shown by DFT calculations, it estimates a high energy barrier
X.-q. Song et al. / Journal of Molecular Structure 1134 (2017) 606e610
609
Table 2 NMR data of compounds 1a, 1b and 1c.
1a 1b 1c
R
]C5H/]C6H (syn)
]C2H/]C5H (anti)
]C3H/]C6H (anti)
]C2H/]C3H (syn)
2.04 (s, 3H) 2.05 (s, 3H) 7.51e7.56 (m, 10H) 1.48 (br s, 18H)
6.13e6.14 (m, 1H)
6.29 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz)
6.34 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz)
6.48e6.49 (m, 1H)
5.85 (br s, 1H) 5.80 (br s, 1H)
6.17 (br s, 1H) 5.91e5.97 (m, 2H)
6.51 (br s, 1H)
6.85 (br s, 1H) 6.07 (br s, 1H)
Fig. 4. Variable-temperature 1H NMR spectrum of 1a in DMSO-d6.
Fig. 5. Variable-temperature
13
between anti- and syn isomers of 1, demonstrating that two isomers exist in solution (deuterated solvent) at room temperature, resulting in similar but distinguishing NMR spectra of 1. The syn-toanti interconversion occurs via an energy barrier of 39.88 kJ/mol for 1a, 43.35 kJ/mol for 1b and 21.05 kJ/mol for 1c (Fig. 6). The energy barrier of 1a (39.88 kJ/mol) is lower than that of 1b (43.35 kJ/mol) but higher than that of 1c (21.05 kJ/mol), so the room-temperature 1 H NMR spectrum of 1c showed almost the same peak shapes as that of the room-temperature 1H NMR spectrum of 1a at 313 K and the room-temperature 1H NMR spectrum of 1b showed almost the
C NMR spectrum of 1a in DMSO-d6.
same peak shapes as that of variable-temperature 1H NMR spectrum of 1a at 333 K. 4. Conclusions N,N-diacyl-1,4-dihydropyrazines 1a and 1b were prepared via an efficient microwave-assisted synthesis with yields 75% and 70% respectively. 1c was synthesized by the treatment of 1,4dihydropyrazine bis(vinyl phosphate) with triethylammonium formate, palladium acetate, and triphenylphosphine in THF, with
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X.-q. Song et al. / Journal of Molecular Structure 1134 (2017) 606e610
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2017.01.019.
References
Fig. 6. Potential energy surface scan for the selected (red) dihedral angle of 1 (in DMSO). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
yield 46%. Complicated NMR spectra of these three compounds reflected conformation isomerism of N,N-diacyl-1,4dihydropyrazine derivatives (1) in solution (deuterated solvent) at room temperature, and 1,4-diacetyl-1,4-dihydropyrazine (1a) was chosen as a representative compound to analyze the complexity of the spectrum in details. 1H NMR and H-H COSY spectra indicated that the complicated spectra resulted from the conformation isomerism of 1a because of the anti- and syn-orientations of the two acetyl groups on the ring. Variable-temperature NMR experiments of 1a supported that the complicated nature of the spectra resulted from the conformational isomerism of 1a because of the two acetyl groups on the ring in a different chemical environment of protons. DFT calculations of 1 estimates a high energy barrier between anti- and syn-isomers and confirm that the structures of the two rotamers correspond to those determined by NMR in solution.
Acknowledgments This work was financially supported by the Key Projects in the National Science & Technology Pillar Program (No. 2012ZX10001007-008-002) and Advanced Medical Instruments of Beijing University of Technology (No. JJ015790201202).
[1] H.S. Rzepa, Lemniscular hexaphyrins as examples of aromatic and anti€ bius molecules, Org. Lett. 10 (2008) 949e952. aromatic double-twist Mo [2] D.R. Brook, B. Noll, T. Koch, Carbonyl and thiocarbonyl stabilized 1,4dihydropyrazines: synthesis and characterization, J. Chem. Soc. Perkin Trans. 1 (1998) 289e292. [3] W. Kaim, Zur” Antiaromatizit€ at, von 1,4-Dihydropyrazinen, Angew. Chem. 93 (1981) 620e621. [4] J. Armand, C. Bois, M. Philoche-Levisalles, M.J. Pouet, M.P. Simonnin, Structure in the solid state and conformational analysis in solution of 1,4-diacetyl-1,4dihydro-2,3-diphenylpyrazine, a potential antiaromatic heterocyclic compound, Can. J. Chem. 60 (1982) 349e354. [5] R. Breslow, Antiaromaticity, Accounts Chem. Res. 6 (1973) 393e398. €felinger, A.R. Katritzky, [6] T. Krygowski, M. Cyranski, Z. Czarnocki, G. Ha Aromaticity: a theoretical concept of immense practical importance, Tetrahedron 56 (2000) 1783e1796. [7] V. Minkin, M. Glukhovtsev, B.Y. Simkin, Aromaticity, and Antiaromaticity. Electronic and Structural Effects, Chapter 6, Wiley, New York, 1994. [8] D.J. Brook, R.C. Haltiwanger, T.H. Koch, Synthesis, structure, and reactivity of an antiaromatic, 2, 5-dicarboxy-stabilized 1,4-dihydropyrazine, J. Am. Chem. Soc. 114 (1992) 6017e6023. [9] D.J. Brook, B.C. Noll, T.H. Koch, Dioxygen oxidation of a stable 1,4dihydropyrazine, J. Organ. Chem. 62 (1997) 6767e6772. [10] A. Rodrigues, P.M. Ferreira, L.S. Monteiro, Synthesis and reactivity of a 1,4dihydropyrazine derivative, Tetrahedron 60 (2004) 8489e8496. [11] H.B. Tan, X.Q. Song, H. Yan, Photochemical oxidation of N,N-bis-(tert-butoxycarbonyl)-1,4-dihydropyrazine derivatives, Heterocycl. Commun. 21 (2015) 83e88. [12] H.B. Tan, Q.D. Zhong, H. Yan, Studies on the photochemical oxidation of N, Ndiacyl-1,4-dihydropyrazine derivatives, Synth. Commun. (2016) 1e10. [13] H.X. Xin, W.J. Sun, H. Yan, X.Q. Song, Photochemical ring contraction of 1-aryl1,4-dihydropyrazine to 1-aryl-1H-imidazole, J. Photochem. Photobiol. A 267 (2013) 49e54. [14] R. Gottlieb, W. Pfleiderer, Organic electrochemistry. III. Chemical and electrochemical synthesis of 1,4-diacyl-1,4-dihydropyrazines, Liebigs Ann. Chem. (1981) 1451e1456. [15] M. Chaignaud, I. Gillaizeau, N. Ouhamou, G. Coudert, New highlights in the synthesis and reactivity of 1, 4-dihydropyrazine derivatives, Tetrahedron 64 (2008) 8059e8066. [16] D. Casarini, L. Lunazzi, A. Mazzanti, Recent advances in stereodynamics and conformational analysis by dynamic nmr and theoretical calculations, Eur. J. Org. Chem. 2010 (2010) 2035e2056. [17] C. Coluccini, S. Grilli, L. Lunazzi, A. Mazzanti, Conformational studies by dynamic NMR. 94.1 cogwheel pathway for the stereomutations of durene derivatives containing the mesityl ring, J. Org. Chem. 68 (2003) 7266e7273. [18] M. Landman, R. Fraser, L. Twigge, J. Conradie, Fischer aminocarbene conformers containing a 2-thienyl or 2-furyl ring: a crystallographic, NMR, and DFT study, J. Coord. Chem. 68 (2015) 2388e2408. [19] E. Wyrzykiewicz, A. Blaszczyk, New isomeric N-substituted hydrazones of 2-, 3- and 4-pyridinecarboxaldehydes and methyl-3-pyridylketone, J. Heterocycl. Chem. 37 (2000) 975e981. [20] M. Frisch, G.W. Trucks, H.B. Schlegel, et al., Gaussian 09, Revision A. 02, Inc, Wallingford, CT, 2009.
Contents lists available at ScienceDirect
Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc
Structural analysis of N,N-diacyl-1,4-dihydropyrazine by variabletemperature NMR and DFT calculation Xiu-qing Song, Hong-bo Tan, Hong Yan*, Yu Chang College of Life Science and Bio-engineering, Beijing University of Technology, Beijing, 100124, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 November 2016 Received in revised form 4 January 2017 Accepted 4 January 2017 Available online 6 January 2017
N,N-diacyl-1,4-dihydropyrazine derivatives (1) were prepared via an efficient microwave-assisted synthesis. 1 was isolated and unambiguously confirmed by NMR spectra and high-resolution mass spectrometry. The NMR spectra of 1 showed complicated rather than conventional spectroscopy. Variabletemperature experiments and DFT calculation (PES) were used to investigate this phenomenon. DFT calculations confirmed that the structures of the two rotamers of 1 correspond to those determined by NMR in solution, and gave the syn-anti interconversion barriers of rotamers. The results showed that two isomers exist in solution (deuterated solvent) at room temperature, resulting in complicated NMR spectra. © 2017 Elsevier B.V. All rights reserved.
Keywords: 1,4-Dihydropyrazine Microwave-assisted synthesis Conformational isomerism Variable-temperature NMR Density-functional theory (DFT)
1. Introduction The 1,4-dihydropyrazine has attracted much interest as a structural moiety due to its cyclic 8p-electron conjugation, which is called ‘antiaromatic’ character [1e4]. The antiaromatic compounds with 4np electronic structures usually have a high HOMO level and low LUMO level, namely, a small HOMO-LUMO gap relative to aromatic compounds with [4nþ2]p electronic structures [5e7]. These characteristics of antiaromatic compounds are favorable for release and/or acceptance of electrons and absorption of light in the visible and/or near-infrared (NIR) regions. The antiaromatic 1,4dihydropyrazine have recently attracted interest as promising substrate for its reactivity study [8e10]. To complement our initial synthesis of this system [11e13], we now report the preparation of representative N,N-diacyl-1,4-dihydropyrazine (1) and assignment of the spatial structure effects on the NMR spectra (Scheme 1).
2. Experimental methods 2.1. Physical measurements All chemicals were purchased from commercial sources and
* Corresponding author. E-mail address: [email protected] (H. Yan). http://dx.doi.org/10.1016/j.molstruc.2017.01.019 0022-2860/© 2017 Elsevier B.V. All rights reserved.
used without further purification. Thin-layer chromatography (TLC) was conducted on silica-gel 60 F254 plates (Merck KGaA). Melting points were determined on a XT-5A digital melting-point apparatus and are uncorrected. 1H NMR spectra and 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer at 400 and 100 MHz using DMSO-d6 as the solvent and tetramethylsilane (TMS) as the internal standard. High-resolution mass spectral (HRMS) analyses were carried out using a VG 70SE mass spectrometer from Manchester, UK, which was operated in electron impact or electrospray ionization mode. 2.2. Chemical synthesis The 1a and 1b were prepared by the reaction of pyrazine and acid anhydride catalyzed by zinc powder [14]. To simplify the experimental procedures and shorten the reaction time, microwave irradiation was used as an efficient heating source for organic reactions. The effects of changes in the microwave power, temperature, and reaction time are discussed, giving the best conditions (eg, 1a) (Table 1). So, 1a and 1b were prepared from pyrazine via an efficient microwave-assisted synthesis at max power 100 W at 140 C for 30 min, giving a higher yield (75% and 70%) than the conventional reflux method (44% and 11%) [14] (Scheme 2). And 1c was synthesized by the treatment of 1,4dihydropyrazine bis (vinyl phosphate) with triethylammonium formate, palladium acetate, and triphenylphosphine in THF, giving
X.-q. Song et al. / Journal of Molecular Structure 1134 (2017) 606e610
607
291.1125.
Scheme 1. Structure of N,N-diacyl-1,4-dihydropyrazine (1).
Table 1 Yield of 1a in different conditions. Temperature ( C)
80
Power (W) Time (min) Yield (%)a
80 15 <30
a
140 100 30 <30
120 45 <30
80 15 60
160 100 30 75
120 45 65
80 15 55
100 30 70
120 45 60
Isolated yield.
2.2.2. Procedure for the preparation of 1c To a solution of bisvinylphosphate (1.28 mmol) in DME (5 mL), Pd(OAc)2 (0.10 mmol, 8 mol %) and PPh3 (0.21 mmol) were added under argon. Then, the flask was evacuated and backfilled with argon three times and was stirred for 5 min. At room temperature, this solution was then transferred dropwise into a degassed solution of formic acid (6.40 mmol) and triethylamine (7.68 mmol) in DME (5 mL). The reaction mixture was refluxed for 2 h. After cooling, the mixture was filtered through Celite and was washed with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate ¼ 98:2) to give 1c as a white solid, yield 46%; mp: 103e105 C (lit. [15] mp: 104e105 C). 1H NMR (400 MHz, CDCl3): d (ppm) 1.48 (br s, 18H, CH3), 5.80 (br s, 1H, ]CH), 5.91e5.97 (m, 2H, ]CH), 6.07 (br s, 1H, ]CH); 13C NMR (100 MHz, CDCl3): d (ppm) 28.3, 81.9, 110.5, 111.0, 111.6, 112.0, 148.4, 148.5; HRMS (ESI), m/z calcd 283.1652 for C18H15N2O2 [MþH]þ, found 283.1655. 2.3. NMR characterization
Scheme 2. Synthesis of N,N-diacyl-1,4-dihydropyrazine(1a and 1b).
a yield 46% [15] (Scheme 3). 2.2.1. General procedure for the preparation of 1a and 1b A mixture of pyrazine (20 mmol), zinc powder (46 mmol) and acid anhydride (24 mmol) were irradiated in a 100 mL vial using microwave system operating at maximal microwave power up to 100 W at 140 C for 25 min. After cooling, the precipitate was filtered and H2O and ethyl acetate were added. The organic phase was washed with brine, dried over Na2SO4, concentrated under vacuum and recrystallised from methanol, resulting in target compounds 1a and 1b. 1,4-diacetyl-1,4-dihydropyrazine (1a): Colorless crystals, yield 75%, mp: 188e190 C (lit [14] mp: 188e191 C). 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.04 (s, 3H, CH3), 2.05 (s, 3H, CH3), 6.13e6.14 (m, 1H, ]CH), 6.29 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz, ]CH), 6.34 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz, ]CH), 6.48e6.49 (m, 1H, ]CH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 20.8, 21.0, 109.9, 111.9, 112.8, 114.8, 163.3, 163.4; HRMS (ESI), m/z calcd 167.0815 for C8H11N2O2 [MþH]þ, found 167.0810. 1,4-dibenzoyl-1,4-dihydropyrazine (1b): Yellow needles, yield 70%; mp: 195e197 C (lit [14] mp: 193e199 C). 1H NMR (400 MHz, DMSO-d6): d (ppm) 5.85 (br s, 1H, ]CH), 6.17 (br s, 1H, ]CH), 6.51 (br s, 1H, ]CH), 6.85 (br s, 1H, ]CH), 7.51e7.56 (m, 10H, AreH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 128.2, 129.2, 131.5, 133.4, 163.3; HRMS (ESI), m/z calcd 291.1128 for C18H15N2O2 [MþH]þ, found
Scheme 3. Synthesis of N,N-diacyl-1,4-dihydropyrazine(1c).
NMR spectra were obtained at 400 MHz for 1H and at 100 MHz for 13C. The assignments of the 1H and 13C signals were obtained by bidimensional experiments (HSQC and HMBC sequences). The variable-temperature spectra were recorded at 400 MHz for 1H NMR and 100 MHz for 13C NMR; temperature calibration and line shape simulation methods were described elsewhere [16]. The structures of N,N-diacyl-1,4-dihydropyrazines (1) were characterized by 1H NMR spectra. The NMR of 1 showed complicated spectra of four unsaturated protons on pyrazine ring, which are depicted in Fig. 1. 1a showed two multiplets and two double doublets, 1b showed four broad singlets, and 1c showed two singlets and a quartet-like peak. The occurrence of this phenomenon may be the result of the conformation isomerism of diacyl groups of 1 in solution (deuterated solvent) by the groups of Refs. [17e19]. In the 1H NMR spectrum of 1a, there were two single peaks from the methyl groups at d 2.01 and 2.05 ppm, two multiplets from the enamine group at d 6.14 and 6.49 ppm, and two doublets of doublets from the enamine group at d 6.29 and 6.34 ppm. The complicated spectra resulted from the conformation isomerism of 1a because of the anti- and syn-orientations of the two acetyl groups on the ring (Fig. 2). The anti-isomer of 1a showed two doublets of doublets because of the coupling effects. For example, proton ]C5H (anti) was coupled with ]C6H (anti) (3J ¼ 6.74 Hz) and remotely coupled with ]C3H (anti) (4J ¼ 1.72 Hz), giving a doublet of doublets at d 6.29 ppm. For syn-isomer of 1a, protons ] C5H (syn) and ]C6H (syn) were in magnetic inequivalence, so proton ]C5H (syn) was not coupled with ]C6H (syn), just remotely coupled with ]C2H (syn) (4J < 1.00 Hz), showing a multiplet at d 6.14 ppm. The correlations of ]C2H/]C5H (anti) and ]C5H/] C6H (syn) proton signals with the 2.04 and 2.05 ppm siglet signals in the H-H COSY spectrum provided the means to assign these two siglets to the methyl protons (anti) and methyl protons (syn) respectively (Fig. 3). Referring to the NMR analysis of 1a, the signals in 1H NMR spectrum of 1b and 1c were also assigned, which are depicted in Table 2. 1b and 1c also showed similarly complex NMR spectra due to acyl groups (Bz and Boc) on the pyrazine ring. Because of the influences of different acyl groups, 1a, 1b and 1c displayed similar but distinguishing NMR spectra. After comparison of 1H NMR spectra in Fig. 1, an interesting phenomenon was observed. The room-temperature 1H NMR spectrum of 1b showed almost the same peak shapes as that of variable-temperature 1H NMR
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Fig. 1. Expansion of low-field of 1H NMR spectra of 1 at 298 K.
spectrum of 1a at 333 K; And the room-temperature 1H NMR spectrum of 1c showed almost the same peak shapes as that of variable-temperature 1H NMR spectrum of 1a at 313 K. This may result from their natural properties owing to different acyl groups on the pyrazine ring: different acyl groups cause different interconversion-speed of 1 at room temperature. 2.4. Variable-temperature NMR
Fig. 2. Expansion of low-field of 1H NMR spectrum of 1a in DMSO-d6.
Variable-temperature 1H NMR spectrua were used to further analyze the structure of 1a, using different temperature at 298 K, 313 K, 333 K, 353 K and 373 K (Fig. 4). With increasing temperature (333 K), the interconversion between the two conformers should be accelerated, making the 1H NMR spectrum simplified, especially for the peaks at lower field, at which the unsaturated protons on pyrazine ring just showed four single peaks. At the greatest temperature (373 K), the anti and syn orientations of conformers interconverts rapidly with each other and cannot be distinguished on the NMR scale: the 1H NMR spectrum showed the simplest peak shape, with only one single peak for four unsaturated protons and one single peak for protons of two methyl groups. Similarly, in the variable-temperature 13C NMR spectrum of 1a (373 K), two carbonyls showed a single peak, four unsaturated carbons showed a broad peak and two methyls showed a single peak (Fig. 5). The complicated nature of the spectra resulted from the conformational isomerism of 1a because of the two acetyl groups on the ring. Different conformational isomers resulted in a different chemical environment of protons and then different shift values, giving complex NMR spectra of 1a. 3. Calculation details
Fig. 3. Expansion of H-H COSY spectrum of 1a in DMSO-d6.
The geometries of 1 have been optimized using DFT/B3LYP method in singlet ground state. The potential energy surface (PES) scan for the selected dihedral angle of 1 has been performed to identify stable conformer at the B3LYP/6-31G (d, p) level of density functional theory (DFT) in Gaussian 09W software package [20]. The Eigen values obtained from the scan output reveals that, the structure positioning the dihedral angle (red) at 0 (<90 ) and 180 (>90 ) possess minimum energy among others. As shown by DFT calculations, it estimates a high energy barrier
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609
Table 2 NMR data of compounds 1a, 1b and 1c.
1a 1b 1c
R
]C5H/]C6H (syn)
]C2H/]C5H (anti)
]C3H/]C6H (anti)
]C2H/]C3H (syn)
2.04 (s, 3H) 2.05 (s, 3H) 7.51e7.56 (m, 10H) 1.48 (br s, 18H)
6.13e6.14 (m, 1H)
6.29 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz)
6.34 (dd, 1H, 3J ¼ 6.74 Hz, 4J ¼ 1.72 Hz)
6.48e6.49 (m, 1H)
5.85 (br s, 1H) 5.80 (br s, 1H)
6.17 (br s, 1H) 5.91e5.97 (m, 2H)
6.51 (br s, 1H)
6.85 (br s, 1H) 6.07 (br s, 1H)
Fig. 4. Variable-temperature 1H NMR spectrum of 1a in DMSO-d6.
Fig. 5. Variable-temperature
13
between anti- and syn isomers of 1, demonstrating that two isomers exist in solution (deuterated solvent) at room temperature, resulting in similar but distinguishing NMR spectra of 1. The syn-toanti interconversion occurs via an energy barrier of 39.88 kJ/mol for 1a, 43.35 kJ/mol for 1b and 21.05 kJ/mol for 1c (Fig. 6). The energy barrier of 1a (39.88 kJ/mol) is lower than that of 1b (43.35 kJ/mol) but higher than that of 1c (21.05 kJ/mol), so the room-temperature 1 H NMR spectrum of 1c showed almost the same peak shapes as that of the room-temperature 1H NMR spectrum of 1a at 313 K and the room-temperature 1H NMR spectrum of 1b showed almost the
C NMR spectrum of 1a in DMSO-d6.
same peak shapes as that of variable-temperature 1H NMR spectrum of 1a at 333 K. 4. Conclusions N,N-diacyl-1,4-dihydropyrazines 1a and 1b were prepared via an efficient microwave-assisted synthesis with yields 75% and 70% respectively. 1c was synthesized by the treatment of 1,4dihydropyrazine bis(vinyl phosphate) with triethylammonium formate, palladium acetate, and triphenylphosphine in THF, with
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Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2017.01.019.
References
Fig. 6. Potential energy surface scan for the selected (red) dihedral angle of 1 (in DMSO). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
yield 46%. Complicated NMR spectra of these three compounds reflected conformation isomerism of N,N-diacyl-1,4dihydropyrazine derivatives (1) in solution (deuterated solvent) at room temperature, and 1,4-diacetyl-1,4-dihydropyrazine (1a) was chosen as a representative compound to analyze the complexity of the spectrum in details. 1H NMR and H-H COSY spectra indicated that the complicated spectra resulted from the conformation isomerism of 1a because of the anti- and syn-orientations of the two acetyl groups on the ring. Variable-temperature NMR experiments of 1a supported that the complicated nature of the spectra resulted from the conformational isomerism of 1a because of the two acetyl groups on the ring in a different chemical environment of protons. DFT calculations of 1 estimates a high energy barrier between anti- and syn-isomers and confirm that the structures of the two rotamers correspond to those determined by NMR in solution.
Acknowledgments This work was financially supported by the Key Projects in the National Science & Technology Pillar Program (No. 2012ZX10001007-008-002) and Advanced Medical Instruments of Beijing University of Technology (No. JJ015790201202).
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