Letter
Cite This: Org. Lett. 2018, 20, 6332−6335 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
*
S Supporting Information
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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.
The polarity of C−O bonds makes them a ubiquitous target
for heterolytic cleavage in synthetic strategies. Classic
approaches include addition of Brønsted or Lewis acids,
transition metal catalysis, and nucleophilic displacement or
elimination of aryloxy ethers.1−6 The mildness of a given C−O
cleavage method is predicated on the bond polarity of the
starting ether, making generic dialkyl ethers a challenging class
of C−O bonds to cleave.
Boron tribromide (BBr3) is well-used in the conversion of
aryl alkyl ethers to aryl alcohols (Scheme 1).5 Despite such
Scheme 1. BBr3-Mediated Cleavage of Ethers
utility, BBr3 has been employed only sporadically to dialkyl
ethers, perhaps because of unpredictable regioselectivity
outcomes.2,3,7,8 In contrast, Guindon’s reagent (Me2BBr) has
been more systematically investigated in dialkyl ether cleavage,
and while it provides superior conversions to the alcohol
product compared with BBr3, Guindon’s reagent is expensive
© 2018 American Chemical Society
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 (<5%). This suggests a kinetic
preference for nucleophilic displacement of the C−O bond by
bromide.
When a second equivalent of diethyl ether is added to the
EtOBX2 reaction mixture and the mixture is subsequently
warmed to room temperature, the three boron signals further
Received: July 25, 2018
Published: September 28, 2018
6332 DOI: 10.1021/acs.orglett.8b02356
Org. Lett. 2018, 20, 6332−6335
Organic Letters Letter

Scheme 2. Boron-Mediated Cleavage Monitored by 11B coalesce into (EtO)2BCl (M) and (EtO)2BBr (N) in a ratio of
NMR Spectroscopy >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.
6333 DOI: 10.1021/acs.orglett.8b02356
Org. Lett. 2018, 20, 6332−6335
Organic Letters Letter

Table 1. Comparison of BX3 Mixtures for Ether Cleavagea 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
allyl system.15 Not only do propargyl ethers result in marginal
alcohol bromide
entry BX3 additive product (%)b (%)c yields, but borylation byproducts (likely from bromoborylation
1 method A: 0.5 equiv of BBr3 70 63
of the alkyne) are observed in the crude 11B NMR spectra. In
2 method B: 0.25 equiv of BBr3 and 90 70
contrast, the suitable performance of substrates with tertiary
0.25 equiv of BCl3 carbon ethers, such as compounds 5 and 6, supports the
3 method C: 0.33 equiv of BBr3 and 99 92 potential for a carbocation intermediate as described by Sousa
0.33 equiv of BCl3 and Silva.13
a
Reactions were performed at 0.6 M in a CH2Cl2/CDCl3 mixture and The allyl group provides additional value because the
were allowed to come to room temperature over 16 h. bConversion to resulting allyl halide can be removed by vacuum following
alcohol determined by 1H NMR spectroscopy with an internal completion of the reaction, thus facilitating clean isolation of
standard following aqueous workup. cConversion to allyl halide the alcohol. This observation prompted a screen of various allyl
determined by NMR spectroscopy with an internal standard prior to ethers (Table 3). In all cases, the mixture of BBr3 and BCl3
aqueous workup.
outperformed BBr3 alone, with significant improvements for
secondary alkyl allyl ethers (entries 5−9). The main by-
Table 2. Selectivity Profile of Various Alkyl Substratesa
products of reactions with these secondary ethers were secon-
dary halides and a precipitate presumed to be B2O3 in addition

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 = a
Reactions were performed at 0.6 M in a CH2Cl2/CDCl3 mixture or
not determined.
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.

6334 DOI: 10.1021/acs.orglett.8b02356

Org. Lett. 2018, 20, 6332−6335
Organic Letters Letter

to allyl halides. Importantly, chiral ethers retained their

chirality when converted to the corresponding alcohols. No
■
*
ASSOCIATED CONTENT
S Supporting Information
erosion of diastereomeric purity was observed for menthol
The Supporting Information is available free of charge on the
ether 16 or norbornyl ether 17.
ACS Publications website at DOI: 10.1021/acs.or-
We next sought to investigate the robustness of the ether
glett.8b02356.
cleavage reaction in the presence of various additives (Table
4).17 Similar to BBr3-mediated aryl ether cleavage methods,2,3 Descriptions of all synthetic methods and character-
ization data, including NMR spectra, for all starting
Table 4. Screen for Functional Group Tolerancea materials and products as well as NMR data for
pertinent intermediates and degradation of additives in
the ether cleavage reaction (PDF)

■ AUTHOR INFORMATION
Corresponding Author
entry additive equiv of BBr3 equiv of BCl3 NMR yield (%)b *fjwillia@ualberta.ca
1 ethyl acetate 0.33 0.33 92 ORCID
2 cyclohexene 0.33 0.33 99
3 dibutyl sulfide 0.33 0.33 20 Florence J. Williams: 0000-0003-2416-3843
4 dibutyl sulfide 0.83 0.83 95 Author Contributions
5 acetonitrile 0.33 0.33 19 †
B.J.P.A. and N.T. contributed equally.
6 acetonitrile 0.83 0.83 91
Notes
7 methanol 0.33 0.33 17
The authors declare no competing financial interest.

■
8 methanol 0.83 0.83 32
9 triethylamine 0.33 0.33 16
10 triethylamine 0.83 0.83 93
ACKNOWLEDGMENTS
11 pyridine 0.33 0.33 20 This work was supported by ACS PRF Grant 59191-ND-1 and
NSERC DG Grant RGPIN-2016-04843.

12 pyridine 0.83 0.83 96
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 (1) Guo, Q.; Miyaji, T.; Gao, G.; Hara, R.; Takahashi, T. Chem.
Yields were determined by NMR spectroscopy with an internal
standard.
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 antici-
pate 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.
6335
■
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