Benzyl Ether: Preparation Methods and Its Multifunctions

Benzyl ether is defined as a protective group for hydroxyl functions that can be installed under various conditions, including basic, acidic, or neutral environments. It is also characterized by the ability to undergo removal through methods such as hydrogenolysis and other reduction techniques. Benzyl ethers offer a versatile means of protection for the hydroxyl group, being installed under basic (benzyl bromide, sodium hydride, DMF; benzyl bromide, sodium hydride, tetrabutylammonium iodide, THF), acidic (benzyl trichloroacetimidate, triflic acid; phenyldiazomethane, tetrafluoroboric acid) or neutral (benzyl bromide, silver triflate) conditions. It serves as a valuable solvent in polymer, plastic, and coating manufacturing processes, and it can also function as a fuel in specific applications. The mechanism of action of benzyl ether can be attributed to its propensity to form robust hydrogen bonds with other molecules. These hydrogen bonds, characterized by their strength, enable it to act as a catalyst in specific reactions.

The Use of Benzyl Ethers as Temporary Protecting Groups

The synthesis of complex molecules such as biopolymers relies on protective groups to ensure chemo-, regio-, and stereoselectivity. Protecting groups are of central importance to carbohydrate construction, where a host of hydroxyl groups have to be masked. Benzyl ethers are stable over a wide range of conditions, making them an ideal protecting group that is removed only at the very end of the synthesis. For this very reason, however, benzyl ether cleavage requires harsh reduction/oxidation processes, such as catalytic hydrogenolysis, Birch reduction, or oxidation with ozone or BCl3, which are incompatible with many functional groups and are hazardous. Methods for the mild and selective cleavage of benzyl ethers would render them attractive temporary protective groups that would conceptually change the strategic approach toward the synthesis of complex glycans. Full conversion of the starting material and excellent selectivity toward the desired product were achieved using stoichiometric amounts of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (E3DDQ*/DDQ–• = 3.18 V vs SCE) and green-light irradiation (525 nm) in wet dichloromethane. [1]

The proper choice of irradiation source is crucial for reaching high selectivities of benzyl ether cleavage in batch. Green-light irradiation (525 nm) was superior over blue light (440 nm) in suppressing the formation of side products during batch reactions. A biphasic continuous-flow system helped to reduce the reaction times. Precise control of the reaction time and efficient irradiation in flow enabled the use of 440 nm to significantly reduce reaction times while maintaining high selectivities. Slowing down a chemical reaction to avoid selectivity problems is a common strategy in batch. Continuous-flow chemistry can help to overcome selectivity issues, as it offers precise control over the reaction time and better irradiation. The photooxidative debenzylation overcomes the current limitations of benzyl ethers as protecting groups that arise from the harsh conditions necessary for their cleavage. The methodology enables the use of benzyl ethers as a temporary protective group and is attractive for the development of new synthetic routes in glycan synthesis.

Hemilabile Benzyl Ether Enables γ-C(sp3)–H Carbonylation

Alcohol is one of the most abundant structural motifs in the bioactive natural products and synthetic intermediates. Therefore, various strategies for the selective C–H functionalization of alcohols have been developed. Among them, selective C–H functionalizations of alcohol derived substrates through intramolecular nitrene insertion or radical abstraction have been most extensively investigated and applied to the synthesis of natural products. Three key design elements are crucial for this development: 1) a readily removable benzyl ether as the directing moiety to control the regioselectivity, 2) a covalently attached ligand to accelerate the C–H activation, 3) the labile ether dissociation to create vacant coordination site to allow carbonylation and olefination to proceed. Mindful of practicality of this approach, we employed a broadly used benzyl ether linkage so that the alcohol products can be furnished by a standard deprotection.[2]

Guided by the ligand development for C(sp3)–H activation and computational studies in our laboratory, we have developed hemilabile benzyl ether directing group to enable γ- and δ-C(sp3)–H functionalization of alcohols. Both the acceleration from the internal ligand and the lability of the ether to dissociate during the catalytic cycle is essential. The practicality of the benzyl ether linkage is also an advantageous feature of this reaction. Notably, Pd-catalyzed C(sp3)–H olefination with ethylene was achieved for the first time.

Convenient method for preparing benzyl ethers and esters

As organic and medicinal chemists tackle synthetic targets of ever increasing complexity, the need for specialized reagents and protecting groups increases. Few protecting groups are as widely used as the benzyl (Bn) group, but protection of complex alcohol substrates as benzyl ethers is often frustrated by the need to employ basic or acidic conditions that may not be compatible with intricate systems. 2-Benzyloxypyridine was prepared in 97% yield by heating a mixture of benzyl alcohol, 2-chloropyridine (1.1 equiv), and solid potassium hydroxide at reflux in toluene for 1 h. This protocol differs slightly from those previously reported, which included 18-crown-6 (5 mol%); omission of 18-crown-6 simplifies the process.[3]

Neutral, isolable pyridinium triflate salts are suitable for the synthesis of halobenzyl ethers, which are emerging from their niche in natural products synthesis because of their growing importance in carbohydrate chemistry. The experiment outlined suggests that the observations described in this article for the synthesis of benzyl ethers are equally relevant for the synthesis of halobenzyl ethers A new protocol for the synthesis of benzyl ethers is described using 2-benzyloxypyridine and methyl triflate in lieu of benzyl trichloroacetimidate and triflic acid. N-Methylation of 2-benzyloxypyridine gives rise to an active benzyl transfer reagent in situ, presumably in much the same way as N-protonation activates benzyl trichloroacetimidate.

References

[1]Cavedon C, Sletten ET, Madani A, Niemeyer O, Seeberger PH, Pieber B. Visible-Light-Mediated Oxidative Debenzylation Enables the Use of Benzyl Ethers as Temporary Protecting Groups. Org Lett. 2021 Jan 15;23(2):514-518. doi: 10.1021/acs.orglett.0c04026. Epub 2021 Jan 5. PMID: 33400534; PMCID: PMC7880570.

[2]Tanaka K, Ewing WR, Yu JQ. Hemilabile Benzyl Ether Enables γ-C(sp3)-H Carbonylation and Olefination of Alcohols. J Am Chem Soc. 2019 Oct 2;141(39):15494-15497. doi: 10.1021/jacs.9b08238. Epub 2019 Sep 18. PMID: 31519108; PMCID: PMC6776245.

[3]Lopez SS, Dudley GB. Convenient method for preparing benzyl ethers and esters using 2-benzyloxypyridine. Beilstein J Org Chem. 2008;4:44. doi: 10.3762/bjoc.4.44. Epub 2008 Nov 26. PMID: 19104674; PMCID: PMC2605620.

You may like