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Annual Volume
Org. Synth. 2019, 96, 124-136
DOI: 10.15227/orgsyn.096.0124
Discussion Addendum for: Protection of Alcohols using 2-Benzyloxy-1-methylpyridinium Trifluoromethanesulfonate: Methyl (R)-(-)-3-Benzyloxy-2-methyl Propanoate
Harvey F. Fulo, Philip A. Albiniak,§ and Gregory B. Dudley*1
Original Article: Org. Synth. 2007, 84, 295
Benzyl ethers are important protecting groups in organic synthesis2, but traditional installation methods, such as the Williamson ether synthesis or reaction of an alcohol with benzyl trichloroacetimidate, often limit their formation with substrates containing functional groups unable to tolerate strongly basic or acidic conditions, respectively.3 As a complementary option, we offered 2-benzyloxy-1-methylpyridinium triflate (BnOPT, 1).4 Benzyl transfer occurs upon mild heating in the presence of an alcohol. The proposed mechanism for the benzylation involves an SN1-like pathway in which thermal ionization of BnOPT produces a reactive phenylcarbenium species which is then trapped by a nucleophilic alcohol. The thermal and nearly neutral conditions circumvent the need for relatively harsh reagents in the reaction mixture.5,6,7
In our initial reports, we described the reactivity of simple alcohols with BnOPT (Table 1).5 Primary and secondary alcohols (2-5) produce the corresponding benzyl ethers in good to excellent yields, while tertiary alcohols (6-7) provide variable results that appear to depend on the susceptibility to E1-like elimination. Simple phenols can also be benzylated; however, protocols using Mitsunobu conditions8 are generally superior with respect to the efficiency of the reaction.
Table 1. Benzylation of representative substrates using BnOPT
Carboxylic acids are viable substrates for benzylation (Table 1).6 Alkyl (9), vinyl (10), alkynyl (11), and aryl carboxylic acids (12) all react smoothly in forming benzyl esters in excellent yields. Triethylamine (Et3N) is the optimal base for efficient esterification, in contrast to MgO for benzyl etherification of alcohols. (This change in base can impact chemoselectivity; vide infra.)5,6
Arenes are susceptible to Friedel-Crafts benzylation under similar mild thermal conditions (Table 1, 13-17).7 Electron-rich arenes react the fastest providing good to excellent yields. Interestingly, the reaction of N,N-dimethylaniline (22) occurred via an N-methyl to benzyl exchange instead of the expected electrophilic aromatic substitution (Scheme 1). This illustrates that amines can also trap the putative phenylcarbenium species released during the thermal activation of BnOPT.
Benzylation can generally be achieved chemoselectively using BnOPT with Et3N in the presence of alcohols, amides, and other functional groups. The base not only activates the carboxylic acid, but it also impedes further reaction by quenching excess benzyl electrophiles.6 Esters 18-21 were all obtained in high yields without evidence of the competing ether formation or N-benzylation. On the other hand, chemoselective benzylation of alcohols can also be achieved using BnOPT with MgO, including in the presence of carboxylic acids (vide infra, especially 48 in Figure 2).
Scheme 1. N-methyl - benzyl exchange between BnOPT and N,N-dimethylaniline
Since our 2007 Organic Syntheses report, which described the optimized preparation of BnOPT, its effectiveness in the protection of alcohols has been noted in many literature reports (Figure 1).9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27 The benzyl ethers of simple primary and secondary alcohols (24-30) were obtained in good to excellent yields (60-95%).9,10,11,12,13,14,15 Many of these benzylations were not (or would not likely have been) successful under traditional Williamson ether and trichloroacetimidate reaction conditions, owing to their respective requirements for basic and acidic conditions.
Figure 1. Protection of various alcohols using BnOPT
BnOPT can also benzylate an α-hydroxyalkylboronate ester (31) with a modest yield of 33%.16 Although the yield was modest, this is the first report for this kind of substrate. Likewise, Kato and Sodeoka showed that 4-O-benzyl monosaccharide 32 can be obtained directly from the unreactive 4-hydroxygalactoside using BnOPT.17 Previous attempts to furnish the ether using standard benzylation protocols were unsuccessful due to the presence of a benzoyl neighboring group.
Taber and Nelson reported a particularly interesting example in 2011: their target ether 33 was obtained with retention of carbinol stereochemistry, while the basic conditions of Williamson etherification provided the epimeric ether with complete inversion at the carbinol center.18
Syntheses of 34 and 39 were troublesome using traditional methods because the harsh conditions produced complex mixture of products. The use of BnOPT provided optimal yields of the desired products.19,24 Similarly, 35, 37 and 38 avoided elimination, lactonization and formation of cyclic phosphates, respectively, when synthesized in the neutral medium.20,22,24 Ethers 36, 40, 41 and 42 were also successfully produced without decomposition of the starting material.21,25,26,27
The mild and nearly neutral conditions associated with the use of BnOPT is the main advantage of the benzylation protocol. Additional examples of chemoselectivity in the presence of potentially labile functional groups are presented in Figure 2. Benzylation using the standard conditions provided ethers 43-47 in good yields (70-95%).28,29,30,31,32 No reactions involving the nitrogen functionality were observed. In 2014, Reynolds and co-workers were able to benzylate the hydroxyl group of 5-hydroxyhexanoic acid.33 The group was able to deactivate the carboxylic acid and obtain ether 48 in 76% yield using MgO as the acid scavenger. In the same year, the group of Shibasaki obtained 49 in 38% yield from the reaction of a diol with BnOPT.34 Interestingly, the doubly benzylated product was not formed despite using 3 equiv of the salt.
Figure 2. Selective benzylation of alcohols
BnOPT was utilized by Lassaletta and co-workers in 2010 with a nitrogen-based nucleophile after conventional alkylating methods resulted in S-benzylation instead of the desired N-benzylated product (Scheme 2).35 Here, the reaction was conducted at room temperature using polar solvents.
Scheme 2. BnOPT benzylation of an amine
Thermal benzylation using BnOPT can also be conducted under microwave heating, as outlined in Table 2.36 Yields from the microwave reactions were often (but not always) higher than analogous reactions conducted under conventional heating, and the stoichiometry of BnOPT in many cases could be reduced from 2.0 equiv to 1.2 equiv under microwave heating. Reaction times were systematically reduced, as would be expected due to conducting the microwave reactions at higher temperatures.
Table 2. MW-assisted benzyl transfer reactions of BnOPT with various substrates
Microwave-specific heating effects on thermal benzyl transfer reactions have been reported using an analog of BnOPT in which the triflate anion is replaced with the tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF) anion using a simple metathesis reaction (Scheme 3).37 The resulting 2-benzyloxy-1-methylpyridinium BArF salt (BnOPB, 53) is more lipophilic and hydrocarbon-soluble than BnOPT.
Scheme 3. Synthesis of BnOPB
Like benzyl ethers, para-methoxybenzyl (PMB) ethers can also be synthesized using transfer salts. The reactive lepidinium intermediate 55 is generated in situ upon treatment of the lepidine derivative 54 with MeOTf at 0 °C (Scheme 4). The PMB transfer to alcohols occurs within 30-60 mins at room temperature to afford the corresponding ethers. Magnesium oxide (MgO) is included as an acid scavenger to help maintain neutral conditions.38 Paquette and co-workers reported a variation of the procedure that does not require the use of MeOTf, in which PMBO-lepidine is activated using methyl tosylate or camphorsulfonic acid, and MgO is not employed.39
Scheme 4. Synthesis of PMB ethers
Analogs of BnOPT that incorporate halogens (Cl, Br and I) have been developed to prepare halobenzyl ethers,40 which create additional flexibility in benzyl protecting group strategies.41 The Albiniak group has continued to expand the utility of oxypyridinium salts with a focus on varying the electrophilic transfer component. In 2014, the in situ generation of 2-tert-butoxy-1-methylpyridinium triflate (58) for the etherification of alcohols was reported (Scheme 5).42 Transfer of the t-butyl group onto an acceptor alcohol is significantly faster than benzyl transfer using BnOPT; it is typically complete within 1.5 h at 23 °C as opposed to 24 h at 83 °C. This procedure allows for the facile synthesis of t-butyl ethers without the need for isobutylene gas, or acidic or basic additives.
Scheme 5. Synthesis of t-butyl ethers
2-Allyloxy-1-methylpyridinium triflate can be generated in situ and employed as an allyl source for converting carboxylic acids into the corresponding allyl esters (Scheme 6).43 As opposed to the benzylation of carboxylic acids with BnOPT, Et3N was not a very efficient base for this transformation, but more reactive conditions using K2CO3 were required. The reaction times were also much shorter for allyl esterification (1-2 vs. 24 h) and the crude product mixtures contained some of the corresponding methyl ester product. These results suggest that the allyl transfer mechanism is more dependent on the nucleophilic partner, and may be less SN1-like. The desired products were obtained in high yields under neutral conditions making the procedure a valuable option for allylations.
Scheme 6. Synthesis of allyl esters
BnOPT is unique as it is preactivated, effective under neutral, mild conditions, and it does not disturb many sensitive functional groups in complex molecules. The literature reports mentioned earlier in the text are testaments to this, making the salt an important and generally applicable tool for the benzylation of alcohols and other functional groups. With the added convenience of MW heating, and the introduction of new derivatives to transfer other reactive electrophilic components, these protocols add versatility to protecting group strategies in organic synthesis.

References and Notes
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Harvey F. Fulo obtained his B.S. degree in chemistry in 2010 and M.S. degree in agricultural chemistry in 2016 from University of the Philippines Los Baños. He is currently a PhD candidate in chemistry at West Virginia University under the supervision of Dr. Gregory Dudley.
Philip A. Albiniak received his undergraduate degrees with honors in chemistry and biochemistry from the College of Charleston. He earned his Ph.D. in bioorganic chemistry at Princeton University with Marty Semmelhack, followed by a postdoctoral appointment at Florida State University with Greg Dudley. He is currently an Associate Professor of Chemistry at Ball State University. His research group focuses on the design of new reagents and their applications to new synthetic methods.
Gregory B. Dudley is the Eberly Family Distinguished Professor of Chemistry and Chair of the C. Eugene Bennett Department of Chemistry at West Virginia University in Morgantown, WV. The current mission of his research program is to impact the drug discovery and development process by contributing fundamental knowledge in organic chemistry, including new strategies, tactics, and research tools for best practices in organic synthesis.