Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Reliably Regioselective Dialkyl Ether Cleavage with Mixed Boron Trihalides Bren Jordan P. Atienza,† Nam Truong,† and Florence J. Williams* Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2
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S Supporting Information *
ABSTRACT: A protocol for the regioselective cleavage of unsymmetrical alkyl ethers to generate alkyl alcohol and alkyl bromide products is described. A mixture of trihaloboranes triggers this conversion and exhibits improved reactivity profiles (regioselectivity and yield) compared with BBr3 alone. Additionally, this procedure allows the efficient synthesis of (B−Cl) dialkyl boronate esters. There are limited methods to generate acyclic dialkoxyboryl chlorides, and these intermediates constitute important synthons in main-group chemistry. to purchase and nontrivial to generate.9−11 Herein we report a practical method for ether cleavage using substoichiometric BBr3 in concert with BCl3. This reagent mixture exhibits improved regioselectivity and overall yields compared with BBr3 alone. Furthermore, NMR studies show an unanticipated dynamic equilibrium resulting in the preferential generation of alkyl bromide rather than alkyl chloride byproducts along with alkoxyboryl chloride intermediates. Boron trichloride often forms stable coordination complexes with ethers without triggering cleavage of unactivated substrates.2 However, homoleptic boron halides are known to readily undergo ligand exchange to form heteroleptic boron complexes.12 Therefore, we sought to investigate whether boranes with both chloride and bromide ligands would retain sufficient activity for the cleavage of alkyl ethers and, if so, would exhibit altered selectivity profiles. We began by investigating the distribution of the boron species produced from a 1:1 mixture of BCl3 and BBr3 in dichloromethane (Scheme 2). The resulting trihaloboranes (BCl3, BCl2Br, BBr2Cl, and BBr3) favored the heteroleptic complexes over a wide range of temperatures (−78 °C to rt). The ether complexes of each species were observed upon addition of diethyl ether at −78 °C. To our satisfaction, warming to room temperature resulted in three new boron signals that were assigned as a mixture of EtOBX2 compounds, where X = Br or Cl. 1H NMR spectroscopy confirmed that ethyl bromide was formed as a byproduct, with only a trace amount of ethyl chloride (10:1, respectively, in addition to triethyl borate and small amounts of EtOBCl2, either uncoordinated (I) or coordinated to Et2O (L). The 1H NMR spectra show the ethyl chloride production to be ∼5%, demonstrating that the reaction slows or stalls once all of the bromides have been utilized (see the Supporting Information (SI)). It should be noted that in further substrate scope evaluations (vide infra), intermediates analogous to I and L are not observed and higher levels of chloride byproducts are produced, though never above 25%. Collectively, these observations provide evidence of a Curtin− Hammett scenario dictated by fast halide exchange between boron compounds and slow nucleophilic attack of activated ethers. The mechanism of BBr3-mediated demethylation of aryl methyl ethers was initially investigated by Sousa and Silva13 then further refined by Korich and Lord.14 Collectively, this work established that a bimolecular mechanism is operative in aryl ethers, involving attack of activated ethern−BXn adducts by an external bromide. For mixed alkyl ether cleavage by BBr3, Sousa and Silva concluded that a similar bimolecular mechanism was operative in the case of linear primary alkyl ethers. However, for tertiary and secondary branched ethers, they proposed a pseudo-unimolecular pathway wherein the C− O bond of the ether is stretched, forming a “nascent carbocation.” This carbocation is then deprotonated by a bromide from the resulting alkoxyboron species, forming an alkene. Subsequently, HBr adds back to the alkene to produce the final alkylboron species.13 In a related mechanistic proposal, Finn and co-workers suggested a unimolecular mechanism for cleavage of propargyl aryl ethers to generate allenyl halide products due to the reactivity of the propargyl leaving group.15 The major product of our reaction sequence, dialkoxyboryl chloride, has historically been accessed by disproportionation of trialkyl borates and BCl3.16 Synthesis of dialkoxyboryl chlorides using ether cleavage avoids pregeneration of the desired trialkyl borate. Therefore, such an ether cleavage strategy may prove valuable for generating dialkoxyboryl chlorides with unusual alkyl groups. Aqueous workup quickly converts these dialkoxyboryl halide intermediates to the corresponding alcohol and boric acid byproducts. Despite the preference for alkyl bromide formation, only 0.25 equiv of BBr3 was needed to achieve full cleavage of 1 equivalent of ether. The intermediate EtOBCl2 (I) has previously been reported as a competent reagent for ether cleavage at room temperature (in contrast to BCl3) and therefore is assumed to be responsible for the remaining 25% of ether cleavage.2 Nevertheless, we sought to investigate whether 0.33 equivalents of both BBr3 and BCl3 would produce improved results. Table 1 shows that 0.25 equiv/0.25 equiv (method B, entry 2) and 0.33 equiv/0.33 equiv of BBr3/ BCl3 (method C, entry 3) outcompete BBr3 alone (method A, entry 1). A more systematic screen was then performed to evaluate various dialkyl substrates (Table 2). In all applications of method B, except in entry 5, which was complicated by degradation of the propargyl group, NMR analysis of the crude reaction material showed the same dialkoxyboryl halide mixtures at a >10:1 ratio of chloride to bromide. Method C resulted in a mixture of dialkoxy- and monoalkoxyboryl halides because of the extra equivalents of boryl halide reagents relative to ether. B
DOI: 10.1021/acs.orglett.8b02356 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Comparison of BX3 Mixtures for Ether Cleavagea
entry 1 2 3
BX3 additive method A: 0.5 equiv of BBr3 method B: 0.25 equiv of BBr3 and 0.25 equiv of BCl3 method C: 0.33 equiv of BBr3 and 0.33 equiv of BCl3
alcohol product (%)b
allyl bromide (%)c
70 90
63 70
99
92
While propargyl ethers proved to be less suited to this method (Table 2, entry 5), both benzyl and allyl groups were very cleanly deprotected (Table 2, entry 6 and Table 1, entry 2, respectively). On the basis of these observations, we can postulate that the unimolecular depropargylation mechanism proposed by Finn and co-workers is likely not operative in this system.15 Not only do propargyl ethers result in marginal yields, but borylation byproducts (likely from bromoborylation of the alkyne) are observed in the crude 11B NMR spectra. In contrast, the suitable performance of substrates with tertiary carbon ethers, such as compounds 5 and 6, supports the potential for a carbocation intermediate as described by Sousa and Silva.13 The allyl group provides additional value because the resulting allyl halide can be removed by vacuum following completion of the reaction, thus facilitating clean isolation of the alcohol. This observation prompted a screen of various allyl ethers (Table 3). In all cases, the mixture of BBr3 and BCl3 outperformed BBr3 alone, with significant improvements for secondary alkyl allyl ethers (entries 5−9). The main byproducts of reactions with these secondary ethers were secondary halides and a precipitate presumed to be B2O3 in addition
a
Reactions were performed at 0.6 M in a CH2Cl2/CDCl3 mixture and were allowed to come to room temperature over 16 h. bConversion to alcohol determined by 1H NMR spectroscopy with an internal standard following aqueous workup. cConversion to allyl halide determined by NMR spectroscopy with an internal standard prior to aqueous workup.
Table 2. Selectivity Profile of Various Alkyl Substratesa
Table 3. Screen of Allyl Ethersa
a Reactions were performed at 0.6 M in a CH2Cl2/CDCl3 mixture or in CH2Cl2 alone and were allowed to come to room temperature over 16 h. bIsolated yields as averages of at least two trials (except where otherwise stated). c1H NMR conversions based on an internal standard prior to workup. dEvidence of boron addition to the alkyne of the propargyl group was observed in the 11B NMR spectrum. ND = not determined.
a Reactions were performed at 0.6 M in a CH2Cl2/CDCl3 mixture or in CH2Cl2 alone and were allowed to come to room temperature over 16 h. The isolated yields reported are averages of at least two trials.
C
DOI: 10.1021/acs.orglett.8b02356 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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to allyl halides. Importantly, chiral ethers retained their chirality when converted to the corresponding alcohols. No erosion of diastereomeric purity was observed for menthol ether 16 or norbornyl ether 17. We next sought to investigate the robustness of the ether cleavage reaction in the presence of various additives (Table 4).17 Similar to BBr3-mediated aryl ether cleavage methods,2,3
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02356. Descriptions of all synthetic methods and characterization data, including NMR spectra, for all starting materials and products as well as NMR data for pertinent intermediates and degradation of additives in the ether cleavage reaction (PDF)
Table 4. Screen for Functional Group Tolerancea
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AUTHOR INFORMATION
Corresponding Author entry
additive
equiv of BBr3
equiv of BCl3
NMR yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12
ethyl acetate cyclohexene dibutyl sulfide dibutyl sulfide acetonitrile acetonitrile methanol methanol triethylamine triethylamine pyridine pyridine
0.33 0.33 0.33 0.83 0.33 0.83 0.33 0.83 0.33 0.83 0.33 0.83
0.33 0.33 0.33 0.83 0.33 0.83 0.33 0.83 0.33 0.83 0.33 0.83
92 99 20 95 19 91 17 32 16 93 20 96
*
[email protected] ORCID
Florence J. Williams: 0000-0003-2416-3843 Author Contributions †
B.J.P.A. and N.T. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by ACS PRF Grant 59191-ND-1 and NSERC DG Grant RGPIN-2016-04843.
a Reactions were performed at 0.6 M in a CH2Cl2/CDCl3 mixture or in CH2Cl2 and were allowed to come to room temperature over 16 h. b Yields were determined by NMR spectroscopy with an internal standard.
REFERENCES
(1) Guo, Q.; Miyaji, T.; Gao, G.; Hara, R.; Takahashi, T. Chem. Commun. 2001, 1018−1019. (2) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 1983, 249−282. (3) Ranu, B. C.; Bhar, S. Org. Prep. Proced. Int. 1996, 28, 371−409. (4) van der Boom, M. E.; Liou, S.-Y.; Ben-David, Y.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 1998, 120, 6531−6541. (5) Wuts, P. G. M.; Greene, T. W. Protection for Phenols and Catechols. In Greene’s Protective Groups in Organic Synthesis; John Wiley & Sons: Hoboken, NJ, 2006; pp 367−430. (6) Wuts, P. G. M.; Greene, T. W. Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols. In Greene’s Protective Groups in Organic Synthesis; John Wiley & Sons: Hoboken, NJ, 2006; pp 26− 200. (7) Benton, F. L.; Dillon, T. E. J. Am. Chem. Soc. 1942, 64, 1128− 1129. (8) Weissman, S. A.; Zewge, D. Tetrahedron 2005, 61, 7833−7863. (9) Guindon, Y.; Yoakim, C.; Morton, H. E. Tetrahedron Lett. 1983, 24, 2969−2972. (10) Guindon, Y.; Anderson, P. C.; Yao, Q. Bromodimethylborane. In Encyclopedia of Reagents for Organic Synthesis; Wiley, 2009; DOI: 10.1002/047084289X.rb289.pub2. (11) Nöth, H.; Vahrenkamp, H. Beiträge zur chemie des bors XLI. Darstellung von organylborhalogeniden. J. Organomet. Chem. 1968, 11, 399−405. (12) Boyd, P. D. W.; Taylor, M. J. Inorg. Chim. Acta 1992, 193, 1−3. (13) Sousa, C.; Silva, J. P. Eur. J. Org. Chem. 2013, 2013, 5195− 5199. (14) Kosak, T. M.; Conrad, H. A.; Korich, A. L.; Lord, R. L. Eur. J. Org. Chem. 2015, 2015, 7460−7467. (15) Punna, S.; Meunier, S.; Finn, M. G. Org. Lett. 2004, 6, 2777− 2779. (16) Cardillo, G.; Di Martino, E.; Gentilucci, L.; Tomasini, C.; Tomasoni, L. Tetrahedron: Asymmetry 1995, 6, 1957−1963. (17) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597−601.
it was found that Lewis basic functional groups sometimes necessitated an additional equivalent of boron trihalide to provide optimized ether cleavage yields. Degredation of the additives was also investigated under the ether cleavage conditions (see the SI). In summary, we have disclosed an efficient protocol to cleave ethers utilizing a combination of BCl3 and BBr3, which expands the utility of Lewis acid-mediated ether cleavage. The Lewis acid combination generates heteroleptic boryl halides, which are likely active agents for ether cleavage, and addresses a traditional challenge of BBr3-mediated alkyl ether cleaveage: poor regioselectivity in unsymmetrical substrates. We anticipate that these heteroleptic boron halides may find use in other transformations classically mediated (or catalyzed) by homoleptic boron halides. Moreover, the method described herein requires substoichiometric boron halide reagents and results in no observable racemization when chiral ethers are converted to their corresponding chiral alcohols. Interestingly, the heteroleptic boryl halide mixtures also show a dynamic kinetic preference to generate alkyl bromide and boryl chloride intermediates. In all of the examples reported, the mixture of boron halides outcompetes boron tribromide alone, and therefore, this approach represents a superior strategy for the clean conversion of alkyl ethers to alkyl alcohol and alkyl halide products. D
DOI: 10.1021/acs.orglett.8b02356 Org. Lett. XXXX, XXX, XXX−XXX
