Catalyst-Free Synthesis of Borylated Lactones from Esters via Electrophilic Oxyboration

Article abstract of DOI:10.1021/jacs.5b12989

A catalyst-free oxyboration reaction of alkynes is developed. The resulting borylated isocoumarins and 2-pyrones are isolated as boronic acids, pinacolboronate esters, or potassium organotrifluoroborate salts, providing a variety of bench-stable organobor

Full text of DOI:10.1021/jacs.5b12989

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Communication
Catalyst-Free Synthesis of Borylated Lactones
from Esters via Electrophilic Oxyboration
Darius J. Faizi, Adena Issaian, Ashlee J. Davis, and Suzanne A. Blum
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12989 • Publication Date (Web): 05 Feb 2016
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Catalyst-Free Synthesis of Borylated Lactones from Esters
via Electrophilic Oxyboration
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Darius J. Faizi, Adena Issaian, Ashlee J. Davis, and Suzanne A. Blum*
Department of Chemistry, University of California, Irvine, Irvine, California 92617–2025, United States
Supporting Information Placeholder
ABSTRACT: The catalyst-free oxyboration reaction of alkynes
is developed. The resulting borylated isocoumarins and 2-pyrones
are isolated as boronic acids, pinacolboronate esters, or potassium
organotrifluoroborate salts, thus providing a variety of bench sta-
ble organoboron building blocks for downstream functionaliza-
tion. This method has functional group compatibility, is scalable,
and proceeds with readily available materials: B-
chlorocatecholborane and methyl esters. Mechanistic studies indi-
cate that the B-chlorocatecholborane acts as a carbophilic Lewis
acid toward the alkyne, providing a mechanistically distinct path-
way for oxyboration that avoids B–O σ bond formation and that
enables this catalyst-free route.
Figure 1. (a) Previously reported electrophilic cycliza-
Addition reactions of boron reagents to carbon–carbon π sys-
tion/dealkylation methods to generate O-heterocycles from ethers
tems have provided powerful routes to organoboron compounds
for over 65 years.1–6 The first oxyboration reaction of carbon–
carbon π systems, however, was only recently reported in 2014,7,8
or esters. (b) Previously reported heterocycle-forming B–X σ-
bond addition. (c) This work demonstrating mechanistically dis-
tinct oxyboration.
possibly due to the high strength of B–O σ bonds (~136
Given that boron halides are known to dealkylate esters to gen-
kcal/mol).9 This reaction proceeded through a B–O σ bond inter-
erate B–O σ bonds,28,29 we anticipated that boron trihalides should
promote oxyboration of 1a due to previously reported carbobora-
mediate and required a gold catalyst. We herein report a boron
reagent that promotes oxyboration of alkynes in the absence of a
tion and haloboration reactivity with alkynes.30 To our surprise,
catalyst. This reaction does not proceed via a B–O σ bond inter-
both trihalogenated boron sources BBr3 and BCl3 (Table 1, entries
mediate, instead accessing an electrophilic oxycyclization path-
1 and 2, respectively) failed to yield any desired borylated iso-
way. The fact that boron is able to access an oxycyclization path-
coumarin 3aa. B-Chlorocatecholborane (ClBcat), on the other
way—previously known only for other elements10–16—provides
hand, which to our knowledge has not been previously used for
the first example of an important class of mechanistically distinct
alkyne activation, provided the borylated isocoumarin in yields of
oxyboration reactions, which yield borylated heterocycles without
25% and 75% at 45 oC and 100 oC, respectively (entries 3 and 4).
the use of strongly basic reagents17 or transition metal catalysts
The use of B-bromocatecholborane, which is known to demethyl-
(Figure 1).18,19 The absence of previously reported oxybora-
ate methyl esters more quickly than ClBcat (and thus would be
tion/cyclization reactions with electrophilic boron may be due to
expected to yield 2 more quickly or at the same rate),31 provided a
competitive formation of boron–oxygen bonds, formation of
lower isolated yield of the desired oxyboration product (entry 5).
which are here shown surprisingly to inhibit oxyboration rather
These results provided an early indication that the operative oxy-
than promote it. We herein apply this method to the synthesis of
boration pathway proceeded without initial dealkylation/B–O σ-
bond formation and thus may be mechanistically distinct from
important biological activity20,21 but with few prior reports of their
borylated isocoumarins and 2-pyrones, classes of compounds with
borylated analogs.22–24 We envision that demonstration of this
mechanistically distinct pathway for oxyboration will open up
new pathways for the practical synthesis of borylated heterocyclic
building blocks for drug discovery and materials synthesis.
prior reports that proceeded through the B–O σ bond.
The commercially available ClBcat (1.4 equiv) was identified
o
as the electrophile that provided the best yield, and 100 C was
identified as the optimal temperature at 1.0 M concentration with
the mass balance at lower temperatures being starting material
(see SI for optimization data).
Primary competing strategies to synthesize borylated heterocy-
cles include lithiation/electrophilic trapping17 and transition met-
al-catalyzed borylation.18,19,25 The few prior reports of borylated
lactones employed Pd-catalyzed cross coupling26 and lithia-
tion/borylation.27 The oxyboration strategy demonstrated here
provides complementary functional group tolerance to these lead-
ing alternative borylation strategies.
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observed in the crude H NMR spectrum. Compound 3f is the
Table 1. Boron Reagent Variation
1
2
3
4
5
6
7
8
only product formed from 5-exo-dig cyclization (see SI for char-
acterization data). Consistent with the mechanistic proposal, for-
mation of the unobserved 6-endo-dig product would have required
disfavored build up of primary cationic character on the terminal
carbon of the unsubstituted alkyne (vide infra).
O
O
O
pinacol
(3 equiv)
O
O
[B] (1.4 equiv)
OCH3
Ph
NEt3, rt, 1 h
toluene, 24 h
temp
Ph
Ph
[B]
2a
Bpin
1a
3aa
Table 2. Synthesis of Borylated Isocoumarins and 2-
Pyrones via the Oxyboration Reactiona,b
Entry
Boron Electrophile [B]
Temp
Yield (%)a
3aa
pinacol
(3 equiv)
NEt3, rt, 1 h
b
O
O
O
1
2
3
4
5
BBr3
0
45 °C
45 °C
ClBcat
(1.4 equiv)
9
OCH3
R1
O
O
b
OR
BCl3
0
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toluene, 100 o
C
R1
R1
H2O, rt, 3 or 24 h
OR
–
20 24 h
Bcat
[B]
B-chlorocatecholborane
B-chlorocatecholborane
B-bromocatecholborane
25
75
48
45 °C
KHF2 (4 equiv)
H2O, 1 h
1
2
3a
[B] = Bpin, B(OH)2, BF3K
100 °C
100 °C
Ph
O
O
O
O
O
O
O
O
Ph
Ph
nBu
MeO2C
Ph
aIsolated yield. b1.0 M solution in DCM.
Bpin
[B]
Bpin
3b 97%
Bpin
3aa [B] = Bpin 75%
3c 65%
3d
66%
3ab
3ac
[B] = B(OH)2 66%
[B] = BF3K 63%
The product isolation scope and substrate scope were next in-
vestigated (Table 2). For synthetic variety, the products can be
isolated three different ways: as the pinacolboronic ester (3aa),
the boronic acid (3ab), or the potassium organotrifluoroborate salt
(3ac). Each method provides complementary advantages. Pina-
colboronic esters are stable toward silica gel chromatography,
provided the best isolated yield for the test compound, and can be
easily cross-coupled under basic conditions; it was therefore cho-
sen as the preferred isolation method.32 Boronic acids, although
not as bench stable as the other options, are a preferred transition
metal-catalyzed cross coupling partner and provide the best atom
economy.33 Potassium organotrifluoroborates, although slightly
lower yielding, provide a column-free workup procedure after
oxyboration, making them a practical target for large-scale syn-
thesis.34,35 The use of B-chloropinacolborane rather than ClBcat,
which would provide a direct route to analogous isolable prod-
ucts, was avoided due to this reagent’s lack of commercial availa-
O
O
O
O
O
Br
O
O
O
CN
CO2Et
( )3
Bpin
Bpin
3h 39%
B(OH)2
61%
Cl
Bpin
3e
3f
3g
60%
55%
O
O
O
O
O
O
O
O
O
O
O
O
Cl
( )6
Ph
S
S
Bpin
77%
Bpin
3k
Bpin
3m
Bpin
Bpin
3p
Bpin
71%
c
3j
3n
47%
3i
41%
59%
56%
aIsolated yield. bBlue molecules contain functional groups not
c
compatible with other leading borylation strategies. From ethyl
ester.
bility and poor thermal stability (decomposition above -70 C),36
o
which would preclude oxyboration reactions above this tempera-
ture.
We attempted an alternative oxyboration through the corre-
sponding carboxylic acid rather than methyl ester. An intractable
product mixture was produced. The route from the methyl ester is
fortunately much cleaner. The methyl esters are also bench stable
and therefore a more practical synthetic precursor than the o-
alkynylbenzoic acids, which decompose via tautomeriza-
tion/cyclization.
Figure 2. X-ray crystallographic structure of 3aa confirming 6-
membered ring formation, with the thermal ellipsoids shown at
50% probability (B, yellow; C, gray; O, red).
Mechanistic studies. Two mechanistic pathways were consid-
ered for this oxyboration reaction (Scheme 1). In the top path-
way, dealkylation occurs first to produce intermediate 4, followed
by the oxyboration/cyclization with the alkyne. In the bottom
pathway, however, boron-induced electrophilic cyclization, possi-
bly through a formal vinylic cation, 5, or alternatively directly
from 1 to 6, as has been proposed for alkyne activation by
BCl3,38,39 precedes dealkylation (bottom). Cyclized oxocarbenium
ion 6 is then primed for rapid dealkylation due to the increased
positive charge on the oxygen. The oxygen in 4 would be less
nucleophilic toward cyclization than the oxygen in 5 due to dona-
tion of the electron density of the carboxy group into the empty p
orbital on boron. This decrease in nucleophilicity may rationalize
why direct dealkylation of 1 via the top pathway inhibits the oxy-
boration reaction rather than promotes it.
Functional groups that can be tolerated with this oxyboration
strategy include esters, cyanides, aryl bromides and chlorides, and
thiophenes, which are incompatible with competing lithia-
tion/borylation routes and/or palladium catalyzed oxidative addi-
tion routes. The tolerance towards esters (3c) was particularly
noteworthy given that these boron reagents are known to dealkyl-
ate esters; this tolerance was examined further in mechanistic
studies (vide infra). Similarly, the tolerance of alkynes distal to
esters (3d) implies that independent reactivity of the alkyne (e.g.,
haloboration5,6) is not part of the operative pathway. An aromatic
backbone was not a requirement for the oxyboration reaction.
Alkenyl esters also underwent the oxyboration reaction to produce
2-pyrones 3k–3p, albeit in lower yields. Because of the reactivity
of B-chlorocatecholborane, ethers, an O-TBDPS protecting group,
furans, and a ketone with α protons were not tolerated by the
oxyboration reaction.
If demethylation occurred before cyclization, in the operable
pathway to the oxyboration product, then the similar esters (a and
b) in 1c should demethylate at similar rates (Scheme 2). This
demethylation would produce intermediates 7 and 8 in approxi-
mately equal quantities, resulting in formation of 3c and 9. Prod-
uct 9 is not observed, however, in the crude reaction mixture by
The oxyboration reaction could theoretically produce either the
regioisomer from 5-exo-dig or 6-endo-dig cyclization.37 X-ray
crystallographic analysis of 3aa confirmed that it was the product
of 6-endo-dig cyclization (Figure 2). No other regioisomer was
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1H NMR spectroscopy. Product 3c was isolated in 65% yield,
ethyl esters remain unreacted.31 This result provides further evi-
1
2
3
4
5
6
7
with the majority of the mass balance being unreacted 1c. There-
fore, ester b demethylates significantly faster than ester a, con-
sistent with cyclization preceding demethylation. The position
dence that cyclization precedes dealkylation in the pathway that
generates the oxyboration product, because when dealkylation
occurs rapidly at ambient temperature, presumably generating B–
O σ bonds, oxyboration does not occur even at elevated tempera-
tures.
Scheme 1. Two proposed pathways: demethylation-
cyclization through B–O bond (top) and cyclization-
demethylation without B–O bond formation (bottom).
Table 3. Mechanistic Insight from O-Alkyl Group Vari-
ance of the Oxyboration Reaction
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Entry
R
1H NMR Yield (%)a 3aa
1
2
3
4
Me
Et
81
68
60
0
iPr
tBu
of ester a does not permit cyclization, thus it does not have access
to that pathway for demethylation. This data is inconsistent with
operation of the top pathway (dealkylation-cyclization) and is
consistent with the bottom pathway (cyclization-dealkylation) in
the overall oxyboration reaction.
aYield determined relative to mesitylene internal standard.
Synthetic applications. The oxyboration reaction provides scal-
able access to borylated building blocks of bioactive cores (eq 2).
Subjecting 2.5 g of methyl benzoate ester 1g to the standard oxy-
boration reaction conditions yielded 2.5 g (71%) of the desired
borylated isocoumarin 3g. Compound 3g is the 4-borylated ana-
logue of the marine natural product chloroaurone, isolated from
Spatoglossum variabile.41
Scheme 2. Intramolecular Competition Experiment
Moreover, the boron functional group provides a handle for
downstream functionalization of the newly formed lactone core.
One example of this utility is demonstrated in the synthesis of
isochroman-1,4-diones, biologically relevant compounds.42,43 The
previously reported synthesis of 12 employed chromium trioxide
and sulfuric acid.44 Subjecting butyl alkynyl ester 1b to the stand-
ard oxyboration conditions, followed by oxidative workup, fur-
nished 12 in 56% yield over two steps in one pot (eq 3). The
utility of these borylated isocoumarins in the construction of new
C–C bonds was highlighted in a Suzuki crosss-coupling reaction
of borylated lactone 3g with p-fluoroiodobenzene to generate
isocoumarin 13 (eq 4).
To further probe the operative mechanism, demethylation of
test compound 10 was examined. Compound 10 has no alkyne;
therefore, if demethylation occurs, it must proceed directly, rather
than through a precyclization pathway. Under identical conditions
that produced compound 3aa from 1a in 75% isolated yield, com-
pound 10 led to no detectible decrease in starting methyl ester as
determined by 1H NMR spectroscopy relative to 1,3,5-
triisopropylbenzene internal standard (<5%, eq 1). No borenium
species were detected via 11B NMR spectroscopy, in contrast to
the arene borylation conditions reported by Ingleson.40 Thus, the
rate of reactivity of methyl esters with ClBcat in the absence of
tethered alkynes is insufficiently rapid to account for the observed
oxyboration reactivity. This data further supports that cyclization
precedes demethylation in the operative oxyboration reaction
mechanism (Scheme 1, bottom).
Various O-alkyl esters were examined with the oxyboration
method (Table 3). The oxyboration reaction tolerated methyl,
1
ethyl, and isopropyl groups with iterative reductions in H NMR
Extension of the mechanistic concept to other systems. Having
established the feasibility of using an external boron electrophile
to generate borylated isocoumarin products, we explored the ap-
plicability of the oxyboration strategy to synthesize borylated
isoxazoles, an important pharmaceutical heterocyclic motif (eq
5).45,46 Treatment of O-methyl oxime 14 with ClBcat at 100–110
oC for 72 h furnished the desired borylated isoxazole 15 in 35%
yield. This illustrates the potential for the mechanistic concept to
yields. The t-butyl ester, in contrast, failed to furnish any of the
desired borylated isocoumarin, despite successful dealkylation, as
characterized by isobutylene formation and the quantification of
1
the benzoic acid derivative of 1a in 68% H NMR spectroscopy
yield. This detection is consistent with the reported ability of
ClBcat to dealkylate t-butyl esters at ambient temperature while
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be applied to other systems to generate value-added borylated
heterocycles from simple alkylated heteroatoms.
1
2
3
4
5
6
7
8
In summary, this reaction is the first report of a transition-metal
free oxyboration reaction that adds boron and oxygen to carbon–
carbon π systems. It is also the first formal carboxyboration—
addition of the CO2 group and boron—across alkynes. This new
reactivity is enabled by dioxaborole activation of an alkyne to
promote oxycyclization.47 The reactivity lessons learned converge
on employing electrophilic boron reagents with the right balance
of carbophilicity vs. oxyphilicity, and with substrates exhibiting
slow competitive dealkylation prior to cyclization. These balances
enable the desired reactivity by avoiding competitive formation of
the strong B–O σ bond, which prevents oxyboration reactivity
under these catalyst free conditions. These balances are conven-
iently achieved with commercially available ClBcat and readily
available methyl ester substrates. This scalable method can toler-
ate a variety of functional groups that are incompatible with the
alternative strongly basic or oxidative-addition pathways that
comprise other leading borylation strategies. Additional mecha-
nistic studies and substrate class expansions are currently ongoing
in our research group. We envision that this mechanistically dis-
tinct oxyborylation strategy will serve as a springboard toward
broader application of catalyst-free boron–element addition reac-
tions to generate valuable borylated heterocyclic products.
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ASSOCIATED CONTENT
Supporting Information
Full experimental procedures and characterization data, including
CIF data for 3aa. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
blums@uci.edu
Notes
The authors declare the following competing financial interest(s):
Provisional patent applications (no. 61/836,391 and no.
61/906,040) have been filed by the University of California.
ACKNOWLEDGMENT
This work was supported by
a grant from the NIH
(1R01GM098512-01), the University of California, Irvine, and an
Allergan Foundation Graduate Fellowship to D.J.F. We thank
Ms. Nicole. A. Nava and Dr. Mohammad Al-Amin for synthesis
of starting materials. We thank Dr. Joseph W. Ziller and Mr. Ja-
son R. Jones for X-ray diffraction analysis, and Dr. Phillip R.
Dennison for NMR spectroscopy assistance.
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VCH: Weinheim, 2001; pp 1−46.
(3) Barbeyron, R.; Benedetti, E.; Cossy, J.; Vasseur, J.; Arseniyadis, S.;
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(47) Electrophilic activation of C−C π systems in other contexts has been
reported employing the more electrophilic boron reagents (e.g., BCl3,
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systems (BO2X). For examples, see citations 6, 40 and also: a) Hans-
mann, M. M.; Melen, R. L.; Rominger, F.; Hashmi, A. S. K.; Stephan, D.
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Hansmann, M. M.; Melen, R. L. Organometallics 2015, 34, 5298–5309; c)
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• new reactivity
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