Synthesis of functionalized cyclic boronates

Article abstract of DOI:10.1021/ol4029918

Deprotonation of a simple borylated allylic sulfone and subsequent alkylation with certain unsaturated electrophiles provide substrates that are easily converted into functionalized alkenyl boronates with ring sizes from five- to seven-membered. A Chan-Lam reaction on one such substrate afforded an alkoxyallylic sulfone that was readily converted via a (4 + 3)-cycloaddition to a polycycle possessing the ABC ring substructure of ingenol.

Full text of DOI:10.1021/ol4029918

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Cyclic Boronates
Erich Altenhofer and Michael Harmata*
Department of Chemistry, University of MissouriColumbia, Columbia, Missouri 65211, United States
S
* Supporting Information
ABSTRACT: Deprotonation of a simple borylated allylic sulfone and
subsequent alkylation with certain unsaturated electrophiles provide substrates
that are easily converted into functionalized alkenyl boronates with ring sizes
from five- to seven-membered. A Chan−Lam reaction on one such substrate
afforded an alkoxyallylic sulfone that was readily converted via a (4 + 3)-
cycloaddition to a polycycle possessing the ABC ring substructure of ingenol.
Scheme 1. RCM of a Boronate
n recent work, we demonstrated that allyl sulfones bearing a
Iboronic ester at the 2-position could be alkylated without
decomposition of the Lewis acidic boron moiety.1 The ability of
the boronic ester to tolerate anion formation permitted the
synthesis of alkylated products that could undergo further
transformations. We were able to demonstrate in a single case
that the alkylation product 1a could be cyclized under
metathesis conditions to produce the cyclopentene 2a in very
high yield. However, it was not known whether the scope of
that process would permit a more general development of the
reaction and whether we could begin to apply such products to
synthetic chemistry. In this work, we demonstrate that
functionalized cyclic systems bearing alkenylboron species are
generated via ruthenium-catalyzed ring-closing metathesis
(RCM) of alkylated products with good generality such that
access to five- through seven-membered rings is almost always
possible.
While inspired to pursue this study for a number of reasons,
we were particularly interested in using relatively simple
chemistry to prepare value-added chemicals in short order.
Uniquely structured organoboron compounds and boronates in
particular are in demand due to the popularity and power of the
Suzuki−Miyaura coupling reaction,2 whose application in
organic synthesis is well-known and continuing to grow.
We began our studies with the readily available alkylation
products derived from 3.1 Our initial attempts at generalizing
the process leading to 2a began with application of the reaction
conditions depicted in Scheme 1 to other substrates. The
results are summarized in Table 1.
and RCM, product 2b, were obtained. It was clear that a more
robust protocol for RCM was needed to effect the trans-
formation. Increasing the reaction temperature to 110 °C
(refluxing toluene) and using the Hoveyda−Grubbs second
generation catalyst 4b3 led to complete conversion of starting
material to the undesired isomerization product 2b in 80%
yield.
Perusal of the literature revealed that the likely cause of our
problem was due to formation of ruthenium hydride species
that catalyzed olefin isomerization.4 The isomerization could be
suppressed by addition of a catalytic amount of an oxidant.
Using 10% benzoquinone in conjunction with 4b allowed the
formation of the seven-membered ring product 2c; however,
the isomerization product 2b was still prevalent. After
considerable experimentation, it was found that, for substrate
1c, 2 equiv of the oxidant were required to block the formation
of 2b completely. An effort to increase the yield by dilution
resulted in a stalled reaction with only partial conversion of
starting material.
With a set of conditions in hand that effectively promoted
ring closure of our less reactive olefins, we subjected a group of
substrates to these conditions. Formation of trisubstituted
cyclopentene 2d was possible (Table 1, entry 3). However,
formation of the corresponding cyclohexene (2e) failed (Table
1, entry 4). The creation of cyclohexenyl boronates bearing
Synthesis of the cyclohexene 2b from 1b proceeded
uneventfully using the conditions that formed 2a, but the
yield was lower (Table 1, entry 1). Increasing the catalyst
loading from 5% to 10% had little effect on the reaction
outcome. For 1c, under these “standard” reaction conditions,
only starting material and the product of alkene isomerization
Received: October 17, 2013
Published: December 5, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
fused six- and seven-membered ring boronates also proceeded
in high yield (Table 1, entries 8−9). Attempts to prepare
heterocyclic boronates gave mixed results. While the synthesis
of azepine derivative 2k proceeded very well, the corresponding
oxepine could not be prepared, starting material being largely
recovered on attempts to effect the RCM of 1l. While problems
associated with metathesis reactions in systems bearing allylic
heteroatoms are known,6 this outcome was a surprise. Similar
results were realized in the attempted RCM of 1m, the eight-
membered ring analogue of 2k (Table 1, entry 12). It was also
interesting to find no evidence of dimerization for either 1l or
1m. This suggests a lack of reactivity or sequestration of catalyst
that is rapid and irreversible.
Table 1. RCM of Borylated Allylic Sulfones
We were curious about the possibility of using cyclic
boronates as precursors to cyclic alkoxyallylic sulfones,
compounds we had developed as progenitors of alkoxyallylic
cations that serve as dienophiles in intramolecular (4 + 3)-
cycloaddition reactions.7 To that end, treatment of 2c with
methanol in the presence of copper acetate afforded 5 in good
yield, though the reaction was slow (Scheme 2).8 Attempts to
Scheme 2. From Cyclic Boronate to (4 + 3)-Cycloadduct
speed up the process resulted in lower yields of product.
Another method exists to prepare compounds like 5, but
generally affords a lower yield of the desired seven-membered
ring.9 Deprotonation of 5 and alkylation with 6 afforded 7 in
good yield. Activation of 7 with TiCl4 gave an 81% yield of 8 as
the primary product of the reaction.10 The relative stereo-
chemistry of the reaction was established by X-ray analysis of
one of the stereoisomers of the reduction product 9. This
compound possesses a portion of the carbocyclic structure of
ingenol, though it lacks the proper “in−out” stereochemistry of
the natural product.11
a
A 0.1 M solution of diene in CH2Cl2 was purged with argon and
added to a pressure tube with 5 mol % of 4a. The tube was sealed with
a Teflon coated cap and heated for 2 h at 45 °C. A 0.005 M solution
of diene in toluene was purged with Ar and added to a pressure tube
with 10 mol % of 4b. The tube was sealed with a Teflon-coated cap
and heated at 110 °C for 24 h.
b
We also investigated the ability of sulfone 3 to undergo
metathesis in an intermolecular fashion. Grubbs and co-workers
reported that boronate 10 could undergo cross-metathesis with
simple olefins in fair yields (Scheme 3).12
Under identical conditions, we found that 3 engaged
productively in cross-metathesis with terminal, unfunctionalized
monoolefins to produce products in good yield, but with low
stereoselectivity. For example, using 1-hexene (13) and 4-
phenyl-1-butene (14), the corresponding products 15 and 16
were isolated in 73% and 78% yield, respectively, as mixtures of
stereoisomers (ca. 5:1 Z/E) (Scheme 4). However, all attempts
to engage alkenes bearing allylic alcohol, allylic ether, allylic
allylic substituents was very successful (Table 1, entries 5−7).
Indeed, the yields of all of the products in these cases were
higher than that of 2b, likely as a consequence of conforma-
tional effects in the starting materials.5 The synthesis of benzo-
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Organic Letters
Letter
Scheme 3. Cross-Metathesis of a Vinyl Boronate
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
and the Department of Chemistry at the University of
MissouriColumbia. We thank Frontier Scientific for a gift
of the precursor to 3. We thank Materia for a gift of several
metathesis catalysts. We thank Dr. Charles L. Barnes
(MissouriColumbia) for acquisition of X-ray data. We
thank Ms. Carissa S. Hampton (MissouriColumbia) for
assistance in preparing this manuscript. Dedicated to the
memory of Andrew Harmata (November 9, 1924−October 1,
2013).
REFERENCES
Scheme 4. Successful Cross-Metatheses of 3
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amine, or protected amine functional groups in the reaction
failed. Finally, it is worth mentioning that under harsher
conditions, rapid isomerization of the olefin occurred, leading
to the unexpected product 17 (Scheme 5). The fact that under
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these conditions only the product 17 could be isolated suggests
that isomerization, steric effects, and thermodynamic control
favor the least substituted product possible. This is either
starting material or the product shown, derived from the
isomerized alkene.
In conclusion, we have developed a route to functionalized,
cyclic boronates via a ring-closing metathesis reaction. While
acknowledging some limitations, the preparation of precursors
and execution of the ring closure is simple and should make
available a much wider array of value-added boronates than
those reported here. Further development of the process and
applications of the chemistry are in development. Results will
be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
1H and 13C NMR spectra. X-ray data on reduction product of 8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: harmatam@missouri.edu.
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/ol4029918 | Org. Lett. 2014, 16, 3−5