Trimethylsilylethanol and its derived protecting reagents

Figure 1 Trimethylsilyl ethanol and its related protective reagents

Trimethylsilylethanol is a colorless liquid with a boiling point of 71-73°C/35mmHg. Trimethylsilyl ethanol is a reagent with a wide range of uses. It can be used as a protective reagent for carboxylic acids, and it is also the main raw material for the synthesis of other related protective reagents.

Reaction with carboxylic acid gives 2-trimethylsilyl ethyl ester. The 2-trimethylsilyl ethyl group can be removed under acidic conditions or alkaline conditions; it can be removed by conventional hydrolysis or in a non-aqueous environment. Acid/base hydrolysis is a common method for removing all ester bonds and will not be repeated here. We focus on the removal methods in non-aqueous environments. Under anhydrous conditions, trimethylsilyl ethyl ester can be removed by TBAF under mildly basic conditions, or by trifluoroacetic acid under acidic conditions. For example, when we were preparing a succinate compound 2, we used trimethylsilyl ethanol as the protecting group of the carboxylic acid, and when removing it, we could obtain it in a higher yield by using trifluoroacetic acid or TBAF The desired target product, while the other ester bond of the succinate was not affected.

Figure 2 The removal method of trimethylsilyl ethyl ester

Trimethylsilyl ethanol is also the main raw material for the synthesis of other related protective reagents. The main protective reagents derived from trimethylsilyl ethanol include SEM-Cl, Teoc-OSU, Teoc-NT, Teoc-ONP, and Teoc-OBT. Among them, Teoc-OSU, Teoc-NT, Teoc-ONP, and Teoc-OBT are all carbonate-based protective reagents, while SEM-Cl is a chloromethyl ether-based protective reagent. Common chloromethyl ether reagents also include (chloromethyl) methyl ether, (chloromethyl) ethyl ether, (chloromethyl) benzyl ether, 2-methoxyethoxymethyl chloride, etc..

Figure 3 Several chloromethyl-protecting reagents

Carbonate-protecting reagents are mainly used to protect common amino groups such as primary and secondary amines, while SEM-Cl is not only used to protect alcoholic hydroxyl groups but also commonly used to protect highly acidic nitrogen atoms on heterocyclic rings.

HOSU, p-nitrophenol, HOBT, and nitroimidazole (NT) in Teoc-OSU, Teoc-ONP, Teoc-OBT, and Teoc-NT are all leaving groups. Except for p-nitrophenol, several other leaving groups are more water-soluble and can be easily removed by washing with water or a weak alkaline solution after the reaction. There are many ways to remove Teoc-protected amino groups, but the most commonly used method is to use the bond-forming interaction between fluoride ions and silicon atoms in a neutral environment. This removal condition avoids the use of strong acid, strong base, oxidation, reduction, and other conditions, and can protect the functional groups in the compound that are not resistant to these conditions.

Figure 4 Teoc protecting group and removal of SEM protecting group

The chlorine atom in SEM-Cl is highly reactive, and alcoholic hydroxyl groups can react with it under weak alkaline conditions such as DIEA. The SEM-protecting group is relatively stable under weakly acidic conditions and is not easy to remove. For example, under acidic conditions that hydrolyze THP, TBDMS, and MOM groups, the SEM protecting group can exist stably, but under strongly acidic conditions (such as trifluoroacetic acid), SEM will be removed. The most common way to remove the SEM-protecting group is to react with fluoride ion reagents such as TBAF, and the product is obtained after elimination.

In addition to protecting alcoholic hydroxyl groups, another common use of SEM-Cl is to protect reactive nitrogen atoms on heterocyclic rings. For example, during the synthesis of the antirheumatic drug baricitinib, SEM was used to protect the active nitrogen atom on the pyrimidopyrrole heterocycle.

Figure 5 Baricitinib and its key intermediates

Trimethylsilyl ethanol and its related protective reagents have important and extensive uses in organic synthesis. Haofan Bio has been committed to the research development and production of condensation reagents and protective reagents for 20 years and has accumulated rich experience and formed its characteristics. The company sells trimethylsilyl alcohol and related protective reagents, welcome to inquire.