Scandium and dimethylaminopyridine catalyzed dehydrative coupling of secondary benzylic and primary alcohols to synthesize unsymmetrical ethers
We developed a direct catalytic condensation of benzylic alcohols and primary alcohols to synthesize unsymmetrical ethers in one step, catalyzed by scandium triflate and p-dimethylaminopyridine (DMAP). Preliminary experiments give some insight into the mechanism of the reaction, though suggest that the process is quite complex.We suspect the rapid formation of a dimer from a secondary benzylic alcohol via a carbocation intermediate precedes unsymmetrical ether formation.
Introduction<!>Results and Discussion<!>Conclusions
<p>The direct modification of functional groups is an ongoing challenge in synthetic organic chemistry. Alcohols are abundant and easily accessible via a variety of transformations and are thus attractive substrates for further modification. However, alcohols typically require derivatization or preactivation to enable their use in coupling or substitution reactions. The desire for chemoselective, direct transformation of alcohols into alternate functional groups has been identified as a key goal in the pharmaceutical industry. 1 While there are now a number of protocols to do so, 2 direct condensation of two symmetrical alcohols to form ethers represents a significant challenge. Recent work in the syntheses of unsymmetrical ethers have relied on gold catalysts, 3 solid-phase thiazolium salts, 4 ruthenium catalysts, 5 and boronic acid activation. 6 We discovered that when 3-hydroxydihydrobenzofuran 1a was exposed to a Lewis acid catalyst and primary alcohol, direct substitution to the unsymmetrical ethers occurred. We report application of this chemistry to a variety of secondary and tertiary benzylic alcohols, as well as some preliminary mechanistic investigations (Scheme 1). 1 University of Nevada, Reno Department of Chemistry; Reno Nevada USA 2 Westlake University Department of Chemistry; Hangzhou China † These authors contributed equally to this work Scheme 1. The synthesis of unsymmetrical ethers via a direct catalytic substitution.</p><p>13 examples 14-88% yields DCE (0.25 M) 0 °C-rt, 24 h R 2 Sc(OTf)3 (10 mol%) DMAP (10 mol%) HO</p><!><p>Initial screening studies used 3-hydroxydihydrobenzofuran 1a as substrate for reactions with prenol. Scandium triflate is a well-known Lewis acid catalyst for dehydrogenation of alcohols in a variety of applications. 7 Appling catalytic amounts of scandium triflate led to full consumption of 1a at room temperature in acetonitrile after 30 minutes; however, only trace amounts of the desired ether substitution product was detected, along with significant amounts of benzofuran from competing elimination chemistry. Copper, 8 ytterbium, 9 and bismuth triflates 10 all led to incomplete consumption of 1a under otherwise identical conditions, and yielded only trace amounts of the substitution product, despite precedence for their ability to enable direct ionization of alcohols. Both zinc triflate, able to catalyze the direct cyanation of benzylic alcohols at 100 °C, 11 and zinc chloride, known for dehydration of alcohols to form ethers at room temperature, 12 were unreactive towards 1a at room temperature. Similarly, copper catalysts known to ionize allylic alcohols at room 13 or elevated temperatures 14 were ineffective at this dehydrogenative benzylic ether formation from 1a.</p><p>As the preliminary reactions performed using scandium triflate as the catalyst led to the complete consumption of the 1a, albeit with low selectivity for ether formation, we then screened various reaction conditions in the coupling of 3a with neopentyl alcohol 2a to optimize for formation of the desired ether. Ultimately, we found that performing the reaction in the polar aprotic dichloroethane (DCE) and initiating the reaction at 0 °C was optimal as increasing the temperature led to complete formation of benzofuran 4, and keeping the reaction at lower temperatures slowed the reaction down substantially. However, in the absence of an exogenous ligand, that was at the expense of formation of ether 3a (Table 1, entry 1). We examined amino acids as ligands, which are an inexpensive source of diverse functionality, with 1a and neopentyl alcohol 2a as substrates (Table 1, entries 2-7). Heteroaromatic L-histidine led to full consumption of 1a and a modest yield of the desired 3a. Applying basic amino acids L-lysine and L-arginine as ligands improved the relative conversion to 3a, though the isolated yield was slightly diminished (entry 3, 4). Other aromatic amino acid ligands, L-tryptophan and L-phenylalanine performed poorly, and incomplete consumption of 1a was observed (entry 5, 6). Although use of glycine as ligand gave comparable product ratios to L-histidine, the yield was poor. We were interested in identifying the particular chemical motif of L-histidine that allowed it to function as an effective ligand for selective direct substitution of a benzylic alcohol. Imidazole as a ligand led to poor conversion and selectivity for 3a (entry 8). N-Substitution at the 1 or 3 position of the imidazole ring of L-histidine improved selectivity for 3a and modestly improved yield, but did not give full conversion of 1a (entries 9, 10). Converting the carboxylic acid of L-histidine to the methyl ester resulted in an improvement in isolated yield of 3a relative to the parent amino acid (entry 11 vs 2), but the yield was still only moderate at 44%. We rationalized that the Lewis basic ligands were modulating the relative Lewis acidity of the scandium catalyst, and were pleased to find that employing 4-dimethylaminopyridine in conjunction with Sc(OTf)3 led to the formation of 3a in 58% isolated yield (entry 12). Increasing catalyst loading to 20 mol% did not result in a significant increase in isolated yield of 3a, and decreasing the loading to 5 mol% only slowed the reaction down, and did not improve selectivity for 3a over 4.</p><p>The unusual success of DMAP in combination with Sc(OTf)3 15 promoted us to evaluate other nitrogen bases, both mono-and bidentate (Table 2). Guanidine•HCl and guanidine derivatives led to exclusive production of benzofuran 4, unless functionalized with an electron donating group (entries 1-3 versus entries 4-6). Bidentate ligands slowed the consumption of 1a substantially, consistent with decreased reactivity with excess DMAP (vide infra). While the catalyst derived from bipyridines L7 and L8 were able to successfully generate some ether 3a, the catalysts derived from phenanthrolines L9 and L10 led only to formation of benzofuran 4, perhaps due to the increased basicity of the phenanthrolines relative to bypyridines. 16 Most reactions that employed pyridine-derived ligands produced moderate amounts of ether 3a, with the exception of 2,6-lutidine L16 and 2,6-ditertbutylpyridine L17, which only produced benzofuran 4. 17 DMAP L13, 2-phenylpyridine L18, and 2,6-bis(diethylamino)pyridine L20 were equally effective, and DMAP L13 was selected for further studies as it is inexpensive, easily handled, and not as susceptible to decomposition as L20. 18</p><p>We then finally looked at the effect of DMAP loading relative to scandium (Scheme 2); unsurprisingly, we found that increasing DMAP to 20 mol% (2 equiv. relative to scandium), the reaction between either 1a or 1i and neopentyl alcohol 2a was slowed, and the isolated yields of ethers 3a and 3i were reduced. Further increasing the loading of DMAP to 30 mol% (reaction with 1a) or 50 mol% (reaction with 1l), the reaction was shut down entirely, and no ether or elimination product could be detected. These results are consistent with the reduced ability of catalysts derived from bidentate ligands to promote the reaction, and further supports that the DMAP ligand is tuning the Lewis acidity of scandium to control the reaction and favor substitution reactions. With optimized conditions in hand, we evaluated the scope of the reaction with respect to the nature of the benzylic alcohol component (Table 3). While the reaction between 2a and 1a gave ether 3a in 58% yield, an analogous 3hydroxy-5-methoxydihydrobenzofuran 1b substrate was unreactive under identical conditions. However, 5-bromo-3hydroxydihydrobenzofuran 1c as substrate gave a modest 37% yield of the corresponding ether 3c with incomplete consumption of 1c. One could predict that a carbocation generated from 1b would be more stabilized and therefore less reactive than a carbocation generated from either 1a or 1c; 19 given that we have evidence of the possibility of carbocation intermediates (vide infra), that could justify the lack of reactivity of 1b. The reaction of indanol 1d with 2a gave 50% yield of ether 3d as estimated by the crude 1 H NMR spectrum of the reaction mixture, which could not be separated cleanly from the competing elimination product, indene 4d.</p><p>We then evaluated the direct substitution of dihydrochromenols and tetrahydronapthalenols in the presence of scandium and DMAP. Dihydrochromenols 1e and 1f were suitable substrates, and ethers 3e and 3f were formed in 40% and 70% yield, respectively, in high conversion and selectivity. However, tetrahydronaphalenol 3g was produced in only 26% yield and reaction with the quaternary 1h led gave exclusive elimination to dihydronaphthalene 4h. We next evaluated the utility of acyclic benzhydrols and secondary benzylic alcohols in the substitution chemistry. The parent benzyhydrol, as well as the di-p-fluorosubstituted variant were only moderately good substrates, and ethers 3i and 3j were produced in relatively low yields. In contrast, the bis(p-methoxyphenyl)methanol was an excellent substrate, and ether 3k was produced in nearly quantitative yield. With those data in hand, we evaluated several secondary benzylic alcohols with one aryl and one alkyl ligand (substrates 1l-1t). Unfortunately, but unsurprisingly, only substrates with a methoxy group were reactive (1l-1n). The reaction was most successful when the methoxy group was in the para position, and ether 3l was isolated in 86% yield; the more sterically encumbered ethers 3m and 3n were isolated in lower yields. Benzylic alcohols with electron withdrawing groups were entirely unreactive under the optimized conditions, consistent with the necessity for generating a cationic intermediate.</p><p>As ether 3l was produced in high yield, we next examined the scope of the reaction of 1l with various primary alcohol nucleophiles (Table 4). Most alcohols examined gave moderate to high yields of the unsymmetrical ether (5b-5j).</p><p>Simply primary and allylic alcohols were effective coupling partners (2b-2d) to yield ethers 5b-5d, as were alcohols containing β-substitution (2e and 2f to give 5e and 5f). Notably, furfural alcohol 2g and highly activated benzylic alcohol 2h could also be employed, and the unsymmetrical ethers 5g and 5h were isolated in high yields, with no detection of byproducts arising from ionization of 2g or 2h.</p><p>We then sought to employ amino alcohols as coupling partners for direct ether formation. Though unprotected amino alcohols were unreactive in this process, N-tosyl-3-aminopropanol 2i and N-tosyl-(S)-valinol 2j were both able to couple with benzylic alcohol 1i, and ethers 5i and 5j were isolated in high yields, albeit with no diastereoselectivity in the case of 5j (1:1 dr). An analogous reaction with N-Boc valinol was unsuccessful; the consumption of 1i was incomplete, and the only identifiable products were p-methoxystryene and dimer 6.  In most experiments in Table 4, we couldn't detect any significant amount of elimination product to p-methoxystyrene or the product of homodimerization of 1l. However, when the primary alcohol was omitted from the reaction, homodimer 6 was isolated in high yields and moderate diasteroselectivity (Scheme 3, equation a). p-Methoxybenzyl alcohol 1k was unreactive under the standard reaction conditions (equation b). Those results suggested that we should have been able to selectively couple an activated benzylic alcohol with an unprotected diol, and thus we evaluated several diol coupling partners with benzylic alcohol 1l under our optimized conditions (Scheme 3, equations c-e). We found that both 1,2-propane diol (Scheme 3c) and 1,3-butanediol (Scheme 3d) were unreactive under optimized conditions, nor were styrene of dimer 6 detected. We hypothesized that the lack of reactivity was due to the diol chelating the Lewis acid catalyst, rendering it unable to promote any reaction. 20 We reasoned that a longer chain between the secondary and primary alcohols would be less likely to form a chelate with scandium, and exposed 1i to 1,4-pentanediol under optimized conditions (Scheme 3e). Unlike reactions with primary alcohols that generally went to completion within 20 hours (Table 3), the reaction with 1,4-pentanediol was very slow, and reasonable conversion was observed only after 3 days. We attribute this to some amount of scandium-diol chelate forming; however, this would form a 7-membered chelate, which wasn't as stable as the 5-and 6-membered chelates that would have formed from 1,2-propane and 1,3-butanediols and scandium, respectively. Thus, some active catalyst was present in solution and could promote the reaction between 1l and pentanediol, yielding 51% yield of a 2.6:1 mixture of 7a and 7b as 1:1 mixtures of diastereomers.</p><p>To further probe that hypothesis, we employed methoxyethanol as a substrate, and ether 8 was isolated in 43% yield (Scheme 3f). This supports our hypothesis above, and protecting one of the alcohols makes the deoxygenated substrate a poorer ligand for scandium, enabling the catalytic dehydrogenative coupling. Scheme 3. Selectivity for reaction of benzylic alcohol with primary versus secondary alcohols. An exogenous secondary aliphatic alcohol was able to selectively react with alcohol 1l, and ether 9 was formed in 52% yield, with only 7% of the benzylic dimer 6 isolated (Scheme 3g). This could be due to decreased steric encumbrance about isopropanol relative to benzylic alcohol 1l, increased nucleophilicity of the aliphatic alcohol, or a combination of both factors.</p><p>In the intramolecular competition experiment between primary and secondary alcohols, the primary alcohol out competed the secondary alcohol in a 2.6:1 ratio (Scheme 3e); a similar result was observed in an intermolecular competition reaction with alcohol 1l and an equimolar mixture of ethanol and isopropanol; ether 5c was favored over ether 9 in a 2:1 ratio, with only a small amount of benzylic dimer isolated (Scheme 3g). similar observations, where the catalytic activation of benzylic alcohols rapidly formed a dimer, which was slowly converted to arylated species via Friedel-Crafts-type reactivity. When ether 3l was exposed to benzyl alcohol 1l, the dimer 6 could be isolated in 30% yield (equation c); similarly, when ether 3l was exposed to water, benzyl alcohol was isolated in 25% yield (equation d). However, when a mixture of dimers of benzhydrol derivatives were combined in the absence of an alcohol or water nucleophile under otherwise standard reaction conditions, no reaction was observed (equation e), consistent with the necessity of an alcohol or water nucleophile to initiate ionization of the ethers. Similarly, the styrene elimination product was unreactive under the standard reaction conditions (equation f).</p><p>Thus, we have derived a preliminary mechanistic scenario (Figure 1). The target ether 3 is clearly accessible from dimeric ether 6, though it is difficult to assess relative rates of formation of 3 from 1 and 6 (k1 vs k3) due to the complexity of the reaction. Hydrolysis to starting alcohol 1 occurs from both 3 and 6 (k-1 and k-2, respectively), though those relative rates do not appear to weigh significantly on the overall rate to formation of 3. The rate of formation of dimer 6 is much faster than direct formation of 3 from 1 (k2 >> k1). Competing elimination appears to only occur from the starting alcohol 1, and formation of the styrene is irreversible and off cycle, as it is not reactive under the reaction conditions. Finally, we were also able to demonstrate that this chemistry may employ aromatic nucleophiles in a Friedel-Crafts type alkylation (Scheme 5). 23 The reaction between 1a and indole produced 38% yield of alkylated indole 11. Further examination of aromatic nucleophiles showed promising results towards of catalytic electrophilic aromatic substitution chemistry, results for which are forthcoming. Scheme 5. Reaction of indole with a benzylic alcohol via a Friedel-Crafts-like reaction.</p><!><p>In summary, we have developed a simple and selective method for producing unsymmetrical ethers via catalytic substitution of benzylic alcohols with primary alcohols. Preliminary mechanistic investigations suggest that the reaction is more SN1-like than SN2-like due to racemization of enantiopure starting alcohols, but the dynamics are complex. The relative rates of formation of dimer 6 and ether 3 are k2 > k1 >> k3, where dimer formation occurs faster than unsymmetrical ether from the alcohol 1, and the dimer is much more slowly converted to the ether 3;</p><p>the overall process has complex kinetics due to competing and reversible side reactions. Further detailed mechanistic studies are warranted to understand both the nature of the catalyst and the origin of selectivity, and will be reported in due course.</p>