Abstract
Tandem mass spectrometry is used to predict the chemical transformations of 2-pyrimidinyloxy-N-arylbenzyl amine derivatives. Compound 1, N-2-2-4,6- dimethoxypyrimidin-2-yloxy benzylamino phenyl benzamide was selected as a model to present our idea. The CID reactions of protonated 1 include an intramolecular S N 2 reaction and a cyclodehydration reaction. Under in-source CID conditions, deprotonated 1 undergoes a Smiles rearrangement reaction and then dissociates to the ion at m/z 349. Theoretical computations were invoked to shed light on the reaction mechanisms of 1 by the semiempirical PM3 method. These studies of gas-phase reactions show the reactivity of some potential reaction centers in this molecule, which inspired us to explore the solution phase analogous reactions of 1. Further experiments show that 1 has two analogous reactions in acidic solution: the acid-catalyzed cyclodehydration reaction and the acid-catalyzed Smiles rearrangement reaction. Moreover, 1 undergoes the base-catalyzed Smiles rearrangement under basic conditions. The present study demonstrates that mass spectrometry can play an important role in predicting the chemical solution phase transformations of 2-pyrimidinyloxy-N-arylbenzyl amine derivatives.
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Farran, A.; Ruiz, S. Application of Solid-Phase Extraction and Micellar Electrokinetic Capillary Chromatography to the Study of Hydrolytic and Photolytic Degradation of Phenoxy Acid and Phenylurea Herbicides. J. Chromatogr. A. 2004, 1024, 267–274.
Corcia, A. D.; Costantino, A.; Crescenzi, C.; Samperi, R. Quantification of Phenylurea Herbicides and Their Free and Humic Acid-Associated Metabolites in Natural Waters. J. Chromatogr. A. 1999, 852, 465–474.
Sabika, H.; Jeannot, R.; Rondeau, B. Multiresidue Methods Using Solid-phase Extraction Techniques for Monitoring Priority Pesticides, Including Triazines and Degradation Products, in Ground and Surface Waters. J. Chromatogr. A. 2000, 885, 217–236.
Bertrand, C.; Witczak-Legrand, A.; Sabadie, J.; Cooper, J. F. Alcoholysis, Chemical Hydrolysis, and Degradation on Various Minerals. J. Agric. Food Chem. 2003, 51, 7717–7721.
Lin, C. H.; Lerch, R. N.; Garrett, H. E.; George, M. F. Degradation of Isoxaflutole (Balance) Herbicide by Hypochlorite in Tap Water. J. Agric. Food Chem. 2003, 51, 8011–8014.
Vincze, A.; Yinon, J. Tandem Mass Spectrometric Collision-Induced Dissociation Study of in s-Triazines an Ion Trap Mass Spectrometer. J. Mass Spectrom. 1997, 32, 1320–1331.
Budde, W. L. Analytical Mass Spectrometry of Herbicides. Mass Spectrom. Rev. 2004, 23, 1–24.
Pico, Y.; Blasco, C.; Font, G. Environmental and Food Applications of LC-Tandem Mass Spectrometry in Pesticide-Residue Analysis: An Overview. Mass Spectrom. Rev. 2004, 23, 45–85.
Glish, G. L.; Cooks, R. G. The Fischer Indole Synthesis and Pinacol Rearrangement in the Mass Spectrometer. J. Am. Chem. Soc. 1978, 100, 6720–6725.
Lobodin, V. V.; Ovcharenko, V. V.; Pihlaja, K.; Morzherin, Y. Y.; Lebedev, A.T. “Tert-Amino Effect” Induced by Electron Ionization and Comparison with Thermal Reaction in Solution. Rapid Commun. Mass Spectrom. 2004, 18, 724–728.
Bowie, J. H. Twenty-Five Years of Negative Ion Studies at Adelaide. Org. Mass Spectrom. 1993, 28, 1407–1413.
Eichinger, P. C. H.; Dua, S.; Bowie, J. H. A Comparison of Skeletal Rearrangement Reactions of Even-Electron Anions in Solution and in the Gas Phase. Int. J. Mass Spectrom. 1994, 133, 1–12.
Chen, H.; Chen, H. W.; Cooks, R. G.; Bagheri, H. Generation of Arylnitrenium Ions by Nitro-Reduction and Gas-Phase Synthesis of N-Heterocycles. J. Am. Soc. Mass Spectrom. 2004, 15, 1675–1688.
Mcluckey, S. A.; Glish, G. L.; Busch, K. L. Mass Spectrometry/Mass Spectrometry: Techniques and Applications of Tandem Mass Spectrometry; VCH Publishers, Inc.: New York, 1988; pp 173–277.
Porter, C. J.; Beynon, J. H.; Ast, T. The Modern Mass Spectrometer—A Complete Chemical Laboratory. Org. Mass Spectrom. 1981, 16, 101–114.
Patents for 2-pyrimidinyloxy-N-arylbenzyl amine derivatives: Lu, L.; Chen, J.; Cai, X.; Li, M. Z.; Wu, Y.; Wang, Y. H. China Patent, CN 1323788-A, 2001; Chem. Abstr. 2002, 137, 74803.
Lu, L.; Chen, J.; Wu, J.; Ling, W.; Mao, L. S.; Li, M. Z.; Cai, X.; Peng, W. L.; Wu, Y.; Wu, S. G.; Wang, H. J.; Wang, G. C.; Cui, H.; Han, S. D.; Qiu, W. L.; Wang, Y. H. World Patent, WO 200234724-A1, 2002; Chem. Abstr. 2002, 136, 355244.
Wang, H. Y.; Guo, Y. L.; Lu, L. Studies of Rearrangement Reactions of Protonated and Lithium Cationized 2-Pyrimidinyloxy-N-Arylbenzylamine Derivatives by MALDI-FT-ICR Mass Spectrometry. J. Am. Soc. Mass Spectrom. 2004, 15, 1820–1832.
Wang, H. Y.; Zhang, X.; Guo, Y. L.; Tang, Q. H.; Lu, L. Sulfonamide Bond Cleavage in Benzenesulfonamides and Rearrangement of the Resulting p-Aminophenylsulfonyl Cations: Application to a 2-Pyrimidinyl-Oxybenzyl-Aminobenzenesulfon Amide Herbicide. Rapid Commun. Mass Spectrom. 2005, 19, 1696–1702.
Wang, H. Y.; Zhang, X.; Guo, Y. L.; Lu, L. Mass Spectrometric Studies of the Gas Phase Retro-Michael Type Fragmentation Reactions of 2-Hydroxybenzyl-N-Pyrimidinylamine Derivatives. J. Am. Soc. Mass Spectrom. 2005, 16, 1561–1573.
Wang, H. Y.; Liao, Y. X.; Guo, Y. L.; Tang, Q. H.; Lu, L. Interesting Acid Catalyzed O-N-Type Smiles Rearrangement Reactions of 2-Pyrimidinyloxy-N-Arylbenzylamine Derivatives. Synlett. 2005, 8, 1239–1242.
Gauthier, J. W.; Trautman, T. R.; Jacobson, D. B. Sustained Off-Resonance Irradiation for CAD Involving FTMS. CAD Technique that Emulates Infrared Multiphoton Dissociation. Anal. Chim. Acta. 1991, 246, 211–225.
Marshall, A. G.; Hendrickson, C. L.; Jackson, G. S. Fourier Transform Ion Cyclotron Resonance Mass Spectrometry: A Primer. Mass Spectrom. Rev. 1998, 17, 1–35.
Gabelica, V.; Pauw, E. D. Internal Energy and Fragmentation of Ions Produced in Electrospray Sources. Mass Spectrom. Rev. 2005, 24, 566–587.
PC Spartan Pro, version 1,0,7, Wavefunction Inc., Von Karman, Suite 370, Irvine, CA, Jun. 14, 2001.
Stewart, J. J. P.; Davis, L. P.; Burggraf, L. W. Semiempirical Calculations of Molecular Trajectories: Method and Applications to Some Simple Molecular Systems. J. Comp. Chem. 1987, 8, 1117–1123.
Stewart, J. J. P. Optimization of Parameters for Semiempirical Methods. I. J. Comp. Chem. 1989, 10. 209–220.
Stewart, J. J. P. Optimization of Parameters for Semiempirical Methods. II. J. Comp. Chem. 1989, 10, 221–264.
Qin, X. Z. Tandem Mass Spectrum of a Farnesyl Transferase Inhibitor Gas-Phase Rearrangements Involving Imidazole. J. Mass Spectrom. 2001, 36, 911–917.
Qin, X. Z. Tandem Mass Spectrum of a Growth Hormone Secretagogue: Amide Bond Cleavage and Resultant Gas-Phase Rearrangement. J. Am. Soc. Mass Spectrom. 2002, 13, 371–377.
Wysocki, V. H.; Tsaprailis, G.; Smith, L. L.; Breci, L. A. Mobile and Localized Protons: A Framework for Understanding Peptide Dissociation. J. Mass Spectrom. 2000, 35, 1399–1406.
Farrugia, J. M.; Taverner, T.; O’Hair, R. A. J. Side-Chain Involvement in the Fragmentation Reactions of the Protonated Methyl Esters of Histidine and Its Peptides. Int. J. Mass Spectrom. 2001, 209, 99–112.
Paizs, B.; Suhai, S. Fragmentation Pathways of Protonated Peptides. Mass Spectrom. Rev. 2005, 24, 508–548.
Ritter, J. J.; Minieri, P. P. A New Reaction of Nitriles. I. Amides from Alkenes. J. Am. Chem. Soc. 1948, 70, 4045–4048.
Ritter, J. J.; Kalish, J. A New Reaction of Nitriles. II. Synthesis of t-Carbinamines. J. Am. Chem. Soc. 1948, 70, 4049–4050.
Bulent, B.; Viktorya, A.; Chava, L. Elimination of Water from the Carboxyl Group of GlyGlyH+. J. Am. Soc. Mass Spectrom. 2003, 14, 1192–1203.
Bowie, J. H. The Fragmentation of Even-Electron Organic Negative Ion. Mass Spectrom. Rev. 1990, 9, 349–379.
Eichinger, P. C. H.; Bowie, J. H.; Hayes, R. H. The Gas-Phase Smiles Rearrangement: A Heavy Atom Labeling Study. J. Am. Chem. Soc. 1989, 111, 4224–4227.
Eichinger, P. C. H.; Bowie, J. H. The Gas-Phase Smiles Rearrangement. The Effect of Ring Substitution. An Oxygen-18 Labeling Study. Org. Mass Spectrom. 1992, 27, 995–999.
Chen, H.; Chen, H. W.; Cooks, R. G. Meisenheimer Complexes Bonded at Carbon and at Oxygen. J. Am. Soc. Mass Spectrom. 2004, 15, 998–1004.
Warren, L. A.; Smiles, S. Iso-β-Naphthol Sulphide. J. Chem. Soc. 1930, 178, 956–963.
Truce, W. E.; Kreider, E. M.; Brand, W. W. The Smiles and Related Rearrangements of Aromatic Systems. Organic Reaction. Vol. XVIII; Wiley: New York, 1970, 99–215.
Radl, S. Aromatic Nucleophilic Denitrocyclization Reactions. Advances in Heterocyclic Chemistry. Vol. LXXXIII; Academic: San Diego, 2002, 189–257.
Kleb, K. G. New Rearrangement of the Smiles Reaction Type. Angew. Chem. Int. Ed. 1968, 7, 291.
Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Observation of O-N-Type Smiles Rearrangement in Certain Alkyl Aryl Nitro Compounds. Synthesis 2002, 16, 2421–2425.
Rodig, O. R.; Collier, R. E.; Schlatzer, R. K. Pyridine Chemistry. I. The Smiles Rearrangement of the 3-Amino-2, 2′-Dipyridyl Sulfide System. J. Org. Chem. 1964, 29, 2652–2658.
Shin, J. M.; Cho, Y. M.; Sachs, G. Chemistry of Covalent Inhibition of the Gastric (H+, K+)-ATPase by Proton Pump Inhibitors. J. Am. Chem. Soc. 2004, 7800–7811.
Peterson, J.; Allikmaa, V.; Subbi, J.; Pehk, T.; Lopp, M. Structural Deviations in Poly(amidoamine) Dendrimers: A MALDI-TOF MS Analysis. Eur. Polymer J. 2003, 39, 33–42.
He, M.; McLuckey, S. A. Tandem Mass Spectrometry of Half-Generation PAMAM Dendrimer Anions. Rapid Commun. Mass Spectrom. 2004, 18, 960–972.
Grimmett, M. R. Imidazole and Benzimidazole Synthesis; Academic Press: San Diego, 2005, 72–76.
Fonseca, T.; Gigante, B.; Gilchrist, T. L. A Short Synthesis of Phenanthro[2,3-d]Imidazoles from Dehydroabietic Acid. Application of the Methodology as a Convenient Route to Benzimidazoles. Tetrahedron. 2001, 57, 1793–1799.
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Published online January 18, 2006
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Wang, H.Y., Zhang, X., Guo, Y.L. et al. Using tandem mass spectrometry to predict chemical transformations of 2-pyrimidinyloxy-N-arylbenzyl amine derivatives in solution. The official journal of The American Society for Mass Spectrometry 17, 253–263 (2006). https://doi.org/10.1016/j.jasms.2005.11.001
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DOI: https://doi.org/10.1016/j.jasms.2005.11.001