Significance of this protocol. Methanol is an inexpensive and less toxic bulk chemical, annual production is >100 million metric tons. Methanol is mostly utilized in the synthesis of various fine chemicals such as formaldehyde, acetic acid, dimethyl ether, etc. In the recent years, methanol has been employed as a C1 source in various organic transformations in presence of a transition-metal catalyst. The methyl group is an extremely important component in many pharmaceutical drugs and biologically active molecules. The addition of methyl groups often has a great impact on the biological and physical properties of these molecules, an effect known as the “magical methyl effect”. As an example, N-methylation of peptides and DNA increases their hydrophobicity, bioavailability, and enhances metabolic stability. Notably, approx. 67 % of all drug molecules, including numerous top-selling drugs, contain at least one methyl group.
The conventional synthesis of methylated molecules uses toxic/expensive reagents such as MeI, Me2Zn. The major drawbacks are the generation of stoichiometric amount of salt-waste and formation of over-alkylated product. Therefore, a sustainable synthesis of methylated molecule is highly desirable. In this consequence, use of methanol is attractive for the greener and more eco-friendly synthesis of the methylated molecules. In the last decades, ‘Borrowing Hydrogen (BH)’ approach has been explored for the methylation using methanol (Fig. 1). In the BH approach, transition-metal-catalysed dehydrogenation of methanol furnishes formaldehyde (HCHO) and metal hydride (M-H). Then, formaldehyde reacts with nucleophiles such as amines and amides and generates an unsaturated molecule, which is finally hydrogenated with the metal hydride to deliver the methylated molecule. However, the activation of methanol is challenging due to its high dehydrogenation energy (ΔH = +84 kJ mol−1) and an efficient catalytic system is essential for the effective and sustainable transformation of methanol to the value-added molecules.
Fig. 1. Mechanism of methylation with methanol.
Development of this protocol. a) N-Methylated amines. In 2017, we started this chemistry in the N-methylation of amines with methanol by using ruthenium catalyst and it showed an excellent reactivity. As the tandem synthesis has several benefits, we were then interested in exploring the direct conversion of nitro-compounds and nitriles to synthesize N-methylated amines by using methanol as the reducing and methylation reagents (Fig. 2). b) C-Methylation of ketones. We also explored C-methylation of ketones with methanol in presence of a ruthenium catalyst (up to 97% isolated yields). With this success, we then explored the multicomponent synthesis of several branch methylated products by using a ketones, alcohols, and methanol (Fig. 2). c) N-Methylated amides. In comparison to amine nitrogen, amide nitrogen is poorly nucleophilic in nature because of the resonance stability of the amide. Notably, with our catalytic system, we successfully achieved the N-methylation of amides with methanol. We then explored this chemistry with a 3d-metal (cobalt) catalyst (Fig. 2). By employing a cobalt catalyst, we successfully synthesized various N-methylated amides and quinazolinones from a nitrile by employing a water/methanol mixture (Fig. 2).
Fig. 2. Utilization of methanol in various transformations.
Overview. This protocol describes the ruthenium and cobalt-catalysed utilization of methanol in different types of methylation reactions and heterocycle synthesis (Fig. 3). Initially, we describe the synthesis of various tridentate ligands and their corresponding Ru(II) complexes and then detail how to apply these Ru(II) complexes and Co/ PP3 (PP3 = P(CH2CH2PPh2)3) in various methanol dehydrogenative coupling reactions. We discuss six different types of transformations by utilizing methanol or a methanol/water mixture. These transformations are: a) direct synthesis of N-methylated amines from nitro-compounds; b) tandem synthesis of N-methylated amines from nitriles; c) multi-component reactions (MCRs) with ketones, alcohols, and methanol; d) N-methylation of the amides; e) direct synthesis of N-methylated amides from nitriles by using H2O/MeOH mixture; and f) synthesis of quinazolinones from 2-aminobenzonitriles by using H2O/MeOH mixture. The catalytic systems described in this protocol works well for both small and preparative scale synthesis. These catalytic reactions are greener and more sustainable than conventional synthesis methods, with only H2 and/or H2O is formed as biproducts. The total time required for the catalytic experiments described in this protocol is 16–28 h, and operation time is 4 h. These protocols are simple and basic knowledge in organic synthesis should be sufficient to implement these transformations.
General experimental set-up. The experimental setup for all types of reaction described in this protocol are similar. Inside an argon-filled pressure tube, substrate, catalyst, base, and solvent are added, and then the tube is purged with argon before sealing with the screw cap. Next, the pressure tube is placed inside a pre-heated (110-150 °C) oil-bath. The progress of the reaction is monitored through GC/1H-NMR and afterwards the final product is purified and characterized.
Fig. 3. Protocol overview.
Key factors in the methylation experiments. a) Effect of Temperature. Temperature has a significant influence in methylation experiments using methanol. Due to the high dehydrogenation energy (ΔH = +84 kJ mol−1) of methanol, a temperature higher than the boiling point of methanol is essential. For all types of methylation reactions described here, a slight increase in reaction temperature increases the yields of the final products considerably. The high temperature probably helps to overcome the activation energy barrier for methanol dehydrogenation and metal hydride transfer (M-H) to the in-situ generated unsaturated molecules. b) Effect of coordinating solvent. Methylation can be performed by using a co-solvent. In this case, it is recommended to use a non-coordinating (benzene, toluene, etc) or less-coordinating (THF, 1,4-dioxane) co-solvent. Using strong coordinating co-solvent (acetonitrile, DMF, etc) results in poor yields of the desired products due to the blocking of the coordination site of the metal catalyst. c) Effect of solvent mixture. Mixing methanol with a non-polar or less-polar co-solvent has a strong effect on the methylation of amide molecules. During the methylation of amide using methanol, there is a possibility of the formation of methyl benzoate as a side product and we minimizes this side product formation by employing a solvent mixture.
For more detailed information, see our protocol “The use of methanol as a C1 building block” in Nature Protocols, 2024 (https://www.nature.com/articles/s41596-024-00978-0)