Borinic Acid Catalyzed, Regioselective Chloroacylations and Chlorosulfonylations of 2,3-Epoxy Alcohols

Article abstract of DOI:10.1021/acs.orglett.5b01541

In the presence of a borinic acid derived catalyst, 2,3-epoxy alcohols undergo couplings with acyl and sulfonyl chlorides. This transformation directly generates O-acylated or O-sulfonylated chlorohydrin diols, with significant levels of regioselectivity for both the ring-opening and O-functionalization steps.

Full text of DOI:10.1021/acs.orglett.5b01541

Letter
pubs.acs.org/OrgLett
Borinic Acid Catalyzed, Regioselective Chloroacylations and
Chlorosulfonylations of 2,3-Epoxy Alcohols
Kashif Tanveer, Kareem Jarrah, and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: In the presence of a borinic acid derived catalyst, 2,3-
epoxy alcohols undergo couplings with acyl and sulfonyl chlorides.
This transformation directly generates O-acylated or O-sulfonylated
chlorohydrin diols, with significant levels of regioselectivity for both
the ring-opening and O-functionalization steps.
2,3-Epoxy alcohols are versatile building blocks that are readily
accessible from allylic alcohols using directed epoxidation
methods, including enantioselective variants.1 While presenting
diverse opportunities for synthetic manipulations, the 2,3-epoxy
alcohol motif presents challenges in regiocontrol. The problem
of regioselective epoxy alcohol ring opening (at C-2 versus C-3)
has been studied in depth, and protocols based on the use of
Lewis acid promoters and/or electronically biased substrates
have been developed.2 New developments continue to emerge,
including the recently reported catalytic methods for ring
opening of 2,3-epoxy alcohols.3 After epoxide opening, a second
regioselective transformation is often required to differentiate
OH groups in the 1,2- or 1,3-diol product. Chemists have
generally tackled these problems in regiocontrol independently,
using two-step reaction sequences. Herein, we describe organo-
boron-catalyzed couplings of acyl or sulfonyl chlorides with 2,3-
epoxy alcohols. These transformations directly generate O-
acylated or O-sulfonylated chlorohydrin diols, with significant
levels of regioselectivity for both the ring-opening and O-
functionalization steps.
The present results build on our group’s finding that borinic
acids (R2BOH) serve as catalysts for regioselective activation of
OH groups in 1,2- and 1,3-diol motifs (Scheme 1A).4 This mode
of catalysis can be used to achieve monoacylations, sulfonyla-
tions, alkylations, and glycosylations of di- and triols, including
carbohydrate derivatives. Mechanistic studies suggest that the
regioselectivity-determining step is the reaction of the electro-
phile with a tetracoordinate borinic ester generated by reversible
covalent binding of a substrate-derived diol group. We speculated
that a borinic ester of this type could be generated in an
alternative way by borinic acid promoted opening of a 2,3-epoxy
alcohol. Precedent for this idea includes the work of Miyashita
and co-workers, who employed boronic acids in stoichiometric
amounts as promoters of C2-selective ring openings of 2,3-epoxy
alcohols (Scheme 1B).5 If a borinic acid were to accelerate the
ring-opening step in a similar way, then the reaction of the
resulting borinic ester with an electrophile could close the
catalytic cycle, delivering a bis-functionalized product (Scheme
1C).
Scheme 1. Proposed Strategy for Regioselective Ring
Opening and Monofunctionalization of 2,3-Epoxy Alcohols
precatalyst 1a and diisopropylethylamine, conditions that we
have employed previously for monoacylations of diols, led to the
formation of monobenzoylated chlorohydrin 3a in 71% yield
along with epoxy ester 5a (Table 1).3c,6 The syn configuration of
3a was established by X-ray crystallography. In comparison to
methods for addition of “silyl−X” reagents across epoxides (e.g.,
halosilylations,7 azidosilylations,8 and cyanosilylations9), addi-
tions of “acyl−X” are under-developed. The closest precedent for
this type of reactivity is the organotin dichloride catalyzed
chloroacylation of epoxides reported by Shibata and co-
workers.10
The effects of varying the conditions for the reaction of 2a with
benzoyl chloride are summarized in Table 1. In addition to epoxy
ester 5a, the C2-chlorinated regioisomer 4a was observed as a
side product under certain conditions. A survey of bases revealed
that 1,8-bis(dimethylamino)naphthalene (Proton-sponge) pro-
vided superior results to i-Pr2NEt, whereas significantly lower
yields of 3a were obtained using Et3N, pyridine, and K2CO3. In
the absence of catalyst, chloroacylation of the epoxy alcohol was
Preliminary experiments revealed that treatment of cis-epoxy
alcohol 2a with benzoyl chloride (BzCl) in the presence of
Received: May 26, 2015
Published: June 26, 2015
© 2015 American Chemical Society
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Letter
Table 1. Optimization of Conditions for Chloroacylation of
Epoxy Alcohol 2a
Scheme 2. Chloroacylations of Epoxy Alcohols Catalyzed by
1a
a
a
a
a
entry
catalyst
base
i-Pr2NEt
3a
4a
5a
1
1a
1a
1a
1a
1a
70%
35%
50%
<5%
80%
<5%
<5%
5%
<5%
<5%
5%
30%
65%
20%
15%
10%
25%
30%
40%
25%
30%
15%
35%
10%
10%
2
Et3N
3
pyridine
4
K2CO3
<5%
5%
5
Proton-sponge
Proton-sponge
Proton-sponge
Proton-sponge
Proton-sponge
Proton-sponge
Proton-sponge
Proton-sponge
Proton-sponge
Proton-sponge
6
none
<5%
<5%
<5%
<5%
<5%
5%
7
PhB(OH)2
CeCl3·7H2O
MgI2
8
9
<5%
<5%
65%
35%
80%
80%
10
11
12
13
14
Cu(OAc)2
Ph2BOH
b
1b
10%
10%
5%
1c
1a
c
a
Yields were determined by 1H NMR spectroscopy analysis of
unpurified reaction mixtures using 1,3,5-trimethoxybenzene as an
b
c
internal standard. Bu4N+Cl− (1.0 equiv) was added. 0.2 equiv of
Proton-sponge (1,8-bis(dimethylamino)naphthalene) were used.
not observed, with the product of direct acylation being
generated in 24% yield. Other Lewis acid catalysts (PhB(OH)2,
CeCl3·7H2O, MgI2, and Cu(OAc)2) were ineffective in
promoting the chloroacylation reaction. The fact that free
diphenylborinic acid also catalyzed the formation of 3a is
consistent with the hypothesis that ethanolamine ester 1a acts a
precatalyst. Our previous studies of diol acylation suggest that
N,O-bis-benzoylation of the ethanolamine ligand triggers entry
of 1a into the catalytic cycle. The amine hydrochloride salt
generated upon ligand benzoylation could serve as the initial
source of Cl− for the epoxide ring opening. It may be that the
lower yield of 3a obtained using Ph2BOH instead of borinic ester
1a is related to the different Cl− concentrations generated using
these two precatalysts. We have previously reported that
heteraborinine-derived borinic acid 1b displays enhanced activity
for certain diol activation reactions, likely due to the high
nucleophilicity of its derived borinic esters. This catalyst was
inactive under the standard reaction conditions and displayed
only modest activity in the presence of Bu4N+Cl−. We speculate
that the lower Lewis acidity of 1b relative to Ph2BOH results in a
reduced rate of epoxide ring opening. However, electron-
deficient catalyst 1c did not provide improved results relative to
1a. The optimized reaction conditions thus involved the use of 1a
as the catalyst and Proton-sponge as the base: we found that the
loading of the latter could be reduced from 1.0 to 0.2 equiv
without a deleterious effect on the yield.
a
Regioselectivities were determined by 1H NMR spectral analysis prior
to purification. Isolated yields after purification are listed. Conditions
a: 1a (10 mol %), RCOCl (1.5 equiv), Proton-sponge (0.2 equiv)
CH2Cl2, 23 °C. Conditions b: 1a (10 mol %), BzCl (1.5−3.0 equiv), i-
Pr2NEt (1.5 equiv), CH2Cl2, 23 °C.
mixtures by 1H NMR spectroscopy. Isolated yields of the major
product after purification by silica gel chromatography are listed.
cis-2,3-Epoxycyclohexanol derivatives 2b−2d underwent C3-
selective epoxide ring opening and benzoylation at O-1. The
trans relationship between Cl and OH groups was confirmed for
product 3c by X-ray crystallography. Whereas 1-O-benzoylation
was anticipated on steric grounds for product 3a (benzoylation of
the primary over the secondary OH group being favored),
rationalizing the site of acylation in products 3b−3d is less
straightforward. Catalyst 1a is known to activate the equatorial
OH groups of cis-1,2-diol motifs in pyranosides.4 It is unclear
The chloroacylation protocol was applied to a range of
substituted epoxy alcohols (Scheme 2). Depending on the
substrate used, either Proton-sponge (0.2 equiv) or i-Pr2NEt (1.5
equiv) as the base provided the best results. The regioselectivity
data in Scheme 2 are based on analysis of unpurified reaction
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Letter
whether this effect is at play in the synthesis of 3b−3d, or
whether the preference for 1-O-benzoylation results from
deactivation of O-2 by the inductively electron-withdrawing
chloro substituent. Tertiary alcohol 2e was unreactive with BzCl,
but the use of a less hindered reagent (acetyl chloride) enabled
preparation of the 2-O-acylated chlorohydrin 3e. Steric effects
are likely responsible for the anomalous regiochemical outcome
of this reaction (acylation at O-2 rather than O-1). A cis-2,3-
epoxycyclopentanol derivative (2f) also underwent efficient
chloroacylation in the presence of 1a.
Scheme 3. Chlorosulfonylations of Epoxy Alcohols Catalyzed
by 1a
a
The reactions of substrates 2g−2j, derived from acyclic allylic
alcohols, illustrate effects of the identity and position of epoxide
substituents on the borinic acid catalyzed chloroacylation
reaction. 2-Substituted 2g and 2,3-disubstituted 2h were
converted to the products of 1,3-chloroacylation with high levels
of regiocontrol. However, the ring opening of benzyloxy-
substituted cis-epoxy alcohol 2i was less selective than that of
unfunctionalized 2a. Sharpless and co-workers reported that 2,3-
epoxy alcohols, ethers, and acetals undergo C3-selective ring
openings due to the inductive electron-withdrawing effect of the
oxygenated substituents.2a In the case of 2i, the CH2OH and
CH2OBn substituents exert opposing effects, thus leading to a
mixture of C2- and C3-chloro products. It should be noted that
the magnitude of the effect observed by Sharpless and co-workers
was rather modest, with regioisomer ratios generally not
exceeding 4:1. Thus, the borinic acid catalyst acts to enhance
the level of selectivity for attack of chloride at C-3. trans-Epoxy
alcohol 2j displayed diminished regioselectivity in the ring-
opening step relative to its cis isomer 2a. Given that Lewis acid
promoted, C3-selective ring openings of trans-epoxy alcohols
have been reported, a rationale for this difference in selectivities is
not apparent. Although the chloroacylation of 2j was not high-
yielding, this transformation demonstrated that the anti-
diastereomer 3j was not formed in detectable amounts from
the reaction of substrate 2a (and likewise, that syn-configured 3a
was not generated from 2j). Indeed, diastereomeric side products
were not evident in any of the reactions shown in Scheme 2,
suggesting an SN2-type inversion as has been documented for
other Lewis acid mediated protocols for preparation of
halohydrins from epoxides.
a
Regioselectivities were determined by 1H NMR spectral analysis prior
to purification. Isolated yields after purification are listed. Conditions
a: 1a (10 mol %), RSO2Cl (1.5 equiv), Proton-sponge (0.2 equiv)
CH2Cl2, 23 °C. Conditions b: 1a (10 mol %), RSO2Cl (1.5−3.0
equiv), i-Pr2NEt (1.5 equiv), CH2Cl2, 23 °C.
Scheme 4. Chloracylation of Epoxy Alcohols: Control
Experiments
The protocol was applied successfully to 3,4-epoxy alcohol 2k.
The C3-ring-opened product was obtained, as verified by analysis
of the chlorine-induced isotope shift in the 13C NMR spectrum.11
Variation of the acylating agent was also tolerated: coupling with
4-nitrobenzoyl chloride yielded the substituted ester 3l, and bis-
benzoate 3m was generated using benzoic anhydride in place of
BzCl. However, some limitations were encountered in this
regard: alkanoyl chlorides and chloroformates (e.g., butyryl
chloride, isobutyryl chloride, and benzyl chloroformate) did not
give rise to synthetically useful yields of chloroacylation using test
substrate 2b. Attempted fluoroacylation of 2b using benzoyl
fluoride resulted only in the formation of the corresponding
epoxy ester.
The use of sulfonyl chlorides under the conditions described
above resulted in the formation of monosulfonylated chlorohy-
drins 6a−6e (Scheme 3). Both para-toluenesulfonyl chloride
(TsCl) and 4-nitrobenzenesulfonyl chloride (NsCl) were
successfully employed in this transformation. The products
possess differentiated electrophilic sites in a 1,3-relationship and
present opportunities for further selective manipulations.12
To obtain preliminary information regarding the mechanism
of borinic acid catalyzed chloroacylation, the experiments shown
in Scheme 4 were conducted. Epoxy ester 5b was recovered
unchanged when subjected to BzCl and i-Pr2NEt, in the presence
of either catalytic or stoichiometric quantities of 1a (eq 1). This
result suggests that ring opening precedes alcohol acylation in the
catalytic cycle and indicates that the hydroxyl group is necessary
for epoxide activation by the borinic acid. Further support for the
former point was obtained by subjecting chlorohydrin diol 7 to
the reaction conditions, which resulted in the formation of
monobenzoate 3b (eq 2). In the absence of catalyst, the
benzoylation of 7 proceeded at a lower rate and with a low level
of selectivity for the opposite regioisomer (1.5:1 2-OBz/3-OBz).
The borinic acid thus influences the selectivity of the
benzoylation step. Finally, trans-2,3-epoxycyclohexanol 2l was
inert to the conditions of chloroacylation, presumably due to its
inability to interact with the borinic acid through two-point
binding (eq 3).
The experiments described above, as well as our mechanistic
studies of borinic acid catalyzed reactions of diols, are consistent
with the proposed catalytic cycle shown in Scheme 5.
Benzoylation of the ethanolamine ligand, which is required for
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Scheme 5. Proposed Catalytic Cycle
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and NMR
spectral data for all new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01541.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mtaylor@chem.utoronto.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding was provided by NSERC (Discovery Grant and Canada
Research Chairs Programs, Graduate Scholarship to K.T.,
Undergraduate Scholarship to K.J.), Boehringer Ingelheim
Ltd., and the Canada Foundation for Innovation (Projects
Nos. 17545 and 19119). We are grateful to Prof. Rob Batey
(Department of Chemistry, University of Toronto) for helpful
suggestions.
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DOI: 10.1021/acs.orglett.5b01541
Org. Lett. 2015, 17, 3482−3485