Simple and Clean Photo-induced Methylation of Heteroarenes with MeOH Wenbo Liu, Xiaobo Yang, Zhong-Zhen Zhou, Chao-Jun Li  Chem  Volume 2, Issue 5, Pages 688-702 (May 2017) DOI: 10.1016/j.chempr.2017.03.009 Copyright © 2017 Elsevier Inc. Terms and Conditions

Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Representative Examples to Demonstrate the Impact of the Methyl Group on Molecule Function (A) Thymine and uracil differ at one methyl group. (B) Five natural amino acids differ only in the number and position of the methyl group. (C) An example to demonstrate the “magic methyl effect.” Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Spectroscopic Investigation of the Impact of Acid (A) UV-visible spectra of 2-methylquinoline (0.1 M) with (green line) and without (blue line) TFA (1.2 equivalent). (B) Fluorescence quenching by MeOH in the absence of acid. (C) Fluorescence quenching by MeOH in the presence of acid. (D) Stern-Volmer analysis of this reaction with and without acid. The concentration of the 2-methylquinoline is 0.1 M, and the exciting wavelength is 300 nm. Please also see Figures S2–S5. Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Scheme 1 Benign Approaches to Methylation of Heteroarenes from Various Methyl Radical Sources Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Scheme 2 Research Design Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Scheme 3 Scope of the Heteroarenes All reactions were conducted under the optimized conditions, and the yields were isolated on the basis of heteroarenes for an average of two parallel runs unless otherwise specified. 31, 33, and 34: yield is from 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. 33, 34, and 42: the reaction conditions were 0.1 mmol heteroarenes, 1 mL MeOH, 0.2 mmol benzophenone, 0.12 mmol TFA, and air for 6 hr at room temperature under UV light. 35, 36, and 41: the reaction conditions were 0.1 mmol heteroarenes, 0.8 mL MeOH, 0.2 mL water, 1 mL DCM, and 0.12 mmol TFA under air at room temperature at the specified time. 45: instead of CH3OH, CD3OD was used for this substrate. Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Scheme 4 Deuterium Labeling Studies Reaction conditions: 2-methylquinoline 13 (0.1 mmol), solvent (specified amount), TFA (0.12 mmol), hv, and argon for 6 hr. The yield was determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. 56: 66% D in this compound indicates that there are two D atoms and one H atom, which can be identified by 1H NMR and GC-MS (see Supplemental Information). Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Scheme 5 Mechanistic Studies for Probing the Potential Intermediate 31% D in 58 indicates that the two regular protons in this compound are deuterated by 31%. Besides these two regular protons, the third proton is a D atom, which can be identified by 1H NMR and GC-MS (see Supplemental Information). Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Scheme 6 Proposed Mechanism for the Methylation of 2-Methylquinoline 13 Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Scheme 7 Proposed Mechanism for Conversion of 57 to 16 Chem 2017 2, 688-702DOI: (10.1016/j.chempr.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions