Borinic Acid-Catalyzed, Regioselective Ring Opening of 3,4-Epoxy Alcohols

Article abstract of DOI:10.1021/acs.orglett.8b02295

Diarylborinic acids (Ar₂BOH) catalyze the C3-selective ring opening of 3,4-epoxy alcohols with aniline, dialkylamine and arenethiol nucleophiles. The regiochemical outcome is consistent with a catalytic tethering mechanism in which the borinic acid interacts with both the electrophile and the nucleophile. The rate acceleration resulting from this induced intramolecularity effect is sufficient to overcome steric biases that would otherwise favor C4-selective opening of the substituted epoxy alcohols.

Full text of DOI:10.1021/acs.orglett.8b02295

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Borinic Acid-Catalyzed, Regioselective Ring Opening of 3,4-Epoxy
Alcohols
Grace Wang, Graham E. Garrett, and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George St., Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: Diarylborinic acids (Ar2BOH) catalyze the C3-
selective ring opening of 3,4-epoxy alcohols with aniline,
dialkylamine and arenethiol nucleophiles. The regiochemical
outcome is consistent with a catalytic tethering mechanism in
which the borinic acid interacts with both the electrophile and
the nucleophile. The rate acceleration resulting from this
induced intramolecularity effect is sufficient to overcome steric biases that would otherwise favor C4-selective opening of the
substituted epoxy alcohols.
ing-opening reactions of epoxides are a useful class of
methods for carbon−heteroatom and carbon−carbon
Scheme 1. Proposed Mechanism for Borinic Acid-Catalyzed
Chloroacylation of 2,3-Epoxy Alcohols, and Extension to
3,4-Epoxy Alcohol Substrates
R
bond formation.1 Challenges related to control of stereo-
selectivity and regioselectivity have prompted the development
of new protocols and catalysts for such transformations.2,3
With regard to the latter issue, the introduction of a functional
group capable of interacting with a Lewis acidic reagent or
catalyst has enabled regioselective ring openings of substrates
lacking a strong electronic or steric bias. 2,3-Epoxy alcohols
and their derivatives have been especially useful for such
transformations.3−8 One-carbon homologation to the 3,4-
epoxy alcohol congeners changes the situation significantly:
few methods for regioselective ring opening of such substrates
have been reported. Nickel-catalyzed aminolysis and arylation
reactions developed by Yamamoto and co-workers,9,10 and a
europium(III) trifluoromethanesulfonate-catalyzed methanol-
ysis reported by the Iwabuchi group,11 are important examples
of C4-selective processes. Here, we report a method for C3-
selective ring-opening of 3,4-epoxy alcohols using an electron-
deficient diarylborinic acid (Ar2BOH) as catalyst. Aniline
derivatives are particularly efficient nucleophiles in this process,
but reactions of arenethiols and dialkylamines are also
demonstrated. The C3-selectivity, which apparently results
from induced intramolecularity via a catalytic tethering
mechanism,12−16 is sufficiently robust as to overcome steric
bias in substrates that would otherwise favor attack at the 4-
position.
instead suggested internal delivery of chloride via an adduct
such as A. This unexpected observation prompted us to
explore borinic acids as catalysts for the ring openings of 3,4-
epoxy alcohols. Other relevant precedents include the studies
by Miyashita and co-workers regarding the organoboron-
promoted ring openings of 2,3-epoxy alcohols,7 as well as
several reported organoboron-catalyzed or organoboron-
promoted transformations of alcohol-bearing substrates that
have been proposed to operate through tethering mecha-
nisms.19−23
Our group has developed borinic-acid-catalyzed site-
selective chloroacylation and chlorosulfonylation reactions of
2,3-epoxy alcohols.17 Kinetics experiments and computational
modeling suggested that the organoboron catalyst influenced
the site selectivity of both the ring-opening and O-
functionalization steps through the formation of a borinic
ester intermediate (see Scheme 1).18 While exploring the scope
of this process, we applied the chloroacylation protocol to a
single 3,4-epoxy alcohol substrate (compound 2a), and
obtained product 3.17 The C3-selective ring-opening was
inconsistent with chelation by the borinic acid catalyst, but
A survey of catalysts (see the Supporting Information (SI))
revealed that bis(para-fluorophenyl)borinic acid (1b)24
Received: July 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02295
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Letter
a
Scheme 2. Borinic Acid-Catalyzed, C3-Selective Ring Openings of 2b with Aniline, Dialkylamine and Arenethiol Nucleophiles
a
Yields (0.2−1.0 mmol scale) after purification by silica gel chromatography.
a
Scheme 3. Variation of the 3,4-Epoxy Alcohol Electrophile
a
Yield of the mixture of regioisomers (0.2 mmol scale) after purification by silica gel chromatography. Compounds 5b′ and 5c were each isolated as
a mixture with a substituted tetrahydrofuran side product.
displayed particularly high activity for the addition of aniline to
trans-disubstituted 3,4-epoxy alcohol (2b) (product 4a; see
Scheme 2). Consistent with the result obtained upon
chloroacylation of 2a and the proposed catalytic tethering
mechanism, the ring opening was C3-selective (>19:1, as
judged by analysis of the unpurified reaction mixture by H
NMR spectroscopy). Whereas functionalization of the
relatively stable five-membered borinic ester adduct by
acylation or sulfonylation was needed for catalyst turnover in
the reactions of 2,3-epoxy alcohols,18 this was not the case for
the aminolysis of 2b: turnover was presumably achieved by
simple protonolysis of the B−O bond. On 1 mmol scale with 4
mol % of catalyst 1b, product 4a was isolated in 99% yield.
The scope of nucleophiles capable of participating in the
borinic acid-catalyzed, C3-selective ring-opening process
proved to be quite broad (see Scheme 2). A variety of
1
B
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Letter
substituted anilines, as well as N-alkylated derivatives, were
tolerated (products 4a−4j). Dialkylamines reacted at lower
rates, but synthetically useful yields of products 4k and 4l were
obtained at higher catalyst loadings. The process was also
applicable to arenethiols (products 4m−4o). Whereas the
aminolysis reactions were conducted without attempts to
exclude air or moisture, the use of an inert argon atmosphere
provided an improvement in yields for reactions of thiol
nucleophiles. Ring openings of 2b with alkylthiols were less
efficient, resulting in 36% and 30% yields of the C3-substituted
products from 1-hexanethiol and benzyl mercaptan, respec-
tively (see the SI). Limitations were also encountered using
phenol (<5% yield) and benzyl alcohol (24% NMR assay
yield) as coupling partners. Nucleophilic attack by the OH
group of 2b, leading to epoxy alcohol cyclization and/or
dimerization, was the major competing process in the reactions
of alkylthiol and alcohol nucleophiles.
Scheme 4. Experimental and Computational Results
Consistent with a Catalytic Tethering Mechanism
a
Variation of the structure of the 3,4-epoxy alcohol substrate
was also investigated (see Scheme 3). The regioselectivity was
sensitive to the configuration of the epoxide; cis-configured 2d′
gave a lower C3:C4 selectivity than trans-2d, and aminolysis
was accompanied by the formation of a tetrahydrofuran side
product arising from cyclization of the OH group onto the
epoxide. The lower efficiency of the aminolysis of 2d′ is
presumably a result of increased steric hindrance in the
transition state for organoboron-mediated delivery of the
nucleophile. Substitution patterns for which steric effects
would be expected to favor C4-selective ring opening were
evaluated using substrates 2e−2j. Although the yields and
levels of regioselectivity were generally lower than those
obtained using trans-disubstituted substrates, the ability of the
borinic acid catalyst to favor the “contrasteric” outcome in
these cases is noteworthy.25,26
a
The gas-phase transition-state structure was calculated at the
B3LYP/6-31G(d,p) level of theory.
experimental information regarding proton transfer steps in the
catalytic cycle is lacking at this time.
In a recent mechanistic study of organoboron-catalyzed
condensations of amines and carboxylic acids, Whiting and co-
workers showed that a diarylborinic acid that had been
reported to act as a catalyst for such a process was inactive and,
instead, served as a precursor to the active arylboronic acid.28
Considering that borinic acids can be converted to boronic
acids through oxidation or protonolysis of a C−B bond,29
addressing this possibility may be advisible when developing
processes that appear to operate via borinic acid catalysis.
Accordingly, we compared the activities of 1b and boronic acid
1c as catalysts for aminolysis of 2f (Scheme 5). Boronic acid 1c
was significantly less active than 1b. Aminolysis occurred to a
detectable extent using the more Lewis acidic arylboronic acid
1d, but the product of ring opening at the 4-position was
An unexpected result was obtained using substrate 2k: the
observation of C4-selective aminolysis was not only at odds
with the selectivity pattern evident from the other borinic acid-
catalyzed ring openings depicted in Scheme 3, but also with
the general preference for formation of trans-diaxial products
upon ring opening of cyclohexene-derived epoxides (the Furst-
̈
Scheme 5. Experiments Relevant to the Catalytic Cycle for
Epoxide Aminolysis
Plattner rule).27 The lack of reactivity of 2k′, in which the
epoxy and hydroxyl groups are cis-configured, provided
indirect evidence that the catalytic tethering mechanism was
operative for 2k. We tentatively propose that intramolecular
delivery occurs through a boatlike transition state in the case of
2k, although further experimentation and computational
modeling are needed. Additions of 2-naphthalenethiol to
representative substrates were also performed (products 5j, 5j′,
5k, and 5l).
a
Evidence in support of a mechanism involving intra-
molecular delivery of a bound nucleophile from a tetracoordi-
nate borinic ester is summarized in Scheme 4. Epoxide 6,
having a benzyl ether group in place of the OH group of 2b,
was unreactive under the optimized conditions. A transition
state structure for diphenylborinic acid-mediated ring opening
of truncated model compound 7 by aniline was identified using
density functional theory (DFT) calculations (B3LYP/6-
31G(d,p), gas phase). This preliminary computational result
demonstrates that a feasible transition-state geometry exists for
the catalytic tethering mechanism, but more mechanistic work
is needed to put this proposal on solid ground. For instance,
the calculations invoked an anionic borinic ester-aniline adduct
that was converted to an alkoxide upon ring opening, but
a
1
Yields of 5d and 4a were determined by H NMR spectroscopy,
using a quantitative internal standard.
C
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favored. The results indicate that the borinic acid derivative is
indeed the active catalyst for this transformation.
ACKNOWLEDGMENTS
■
This work was supported by the NSERC, the McLean
Foundation, the Canada Foundation for Innovation (Project
Nos. 17545 and 19119) and the Province of Ontario.
Computations were performed on resources and with support
provided by the Centre for Advanced Computing (CAC) at
Queen’s University in Kingston, Ontario. The CAC is funded
by the Canada Foundation for Innovation, the Government of
Ontario and Queen’s University.
To probe this issue further, the reaction of substrate 2b with
aniline was monitored by in situ NMR spectroscopy in d3-
acetonitrile (see Scheme 5). Clean conversion of starting
material to product 4a was observed, without detectable
buildup of any intermediate species or side products. No
induction period was evident, which is consistent with the
borinic acid serving as the active catalyst in this transformation.
11B NMR spectra acquired while the reaction was underway
showed a resonance at 43 ppm corresponding to a
tricoordinate diarylborinic acid derivative, and no higher-field
signals consistent with a tetracoordinate adduct.30 Whereas
tetracoordinate adducts have been detected by 11B NMR
spectroscopy in borinic acid-catalyzed reactions of 2,3-epoxy
alcohols,31 it appears that the catalyst resting state for
aminolysis of 2b is tricoordinate. Variable time normalization
analysis32 of concentration versus time data from reactions
conducted at two catalyst loadings (5 and 10 mol %) indicated
first-order kinetics in 1b. Determination of the full rate law for
the catalytic reaction and elucidation of the effects of
nucleophilicity and pKa on reaction rate are among the issues
to be addressed in future mechanistic studies.
In conclusion, diarylborinic acid catalysis has been used to
achieve C3-selective ring openings of 3,4-epoxy alcohols with
amine and thiol nucleophiles. This protocol complements the
existing methodology for C4-selective ring opening,9 and
enables the selective synthesis of products arising from attack
at the more sterically hindered position of the substituted
epoxy alcohols. The proposed tethering mechanism represents
a new mode of catalytic reactivity for borinic acids. While two-
point binding of a diol or related substrate to generate a
reactive, tetracoordinate organoboron nucleophile has been
applied extensively by our group33−35 and by other
researchers,36−38 forming such a complex by simultaneous
coordination of nucleophile and electrophile offers new
possibilities for reaction design. Borinic acids may hold
promise for the development of new catalytic processes that
take advantage of temporary intramolecularity to achieve rate
acceleration.
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02295.
(13) Tan, K. L. Induced intramolecularity: an effective strategy in
catalysis. ACS Catal. 2011, 1, 877−886.
Experimental procedures, characterization data, kinetics
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Corresponding Author
*E-mail: mtaylor@chem.utoronto.ca.
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Graham E. Garrett: 0000-0001-8558-2027
Mark S. Taylor: 0000-0003-3424-4380
Notes
The authors declare no competing financial interest.
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