One-Pot, Three-Step Synthesis of Benzoxazinones via Use of the Bpin Group as a Masked Nucleophile

Article abstract of DOI:10.1021/acs.orglett.1c00623

The utilization of the Bpin group as a pronucleophile to facilitate the assembly of cyclic carbamates has been achieved. This one-pot process involves an initial copper-catalyzed borylation, a subsequent C-B bond oxidation to generate the reactive alcohol

Full text of DOI:10.1021/acs.orglett.1c00623

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Letter
One-Pot, Three-Step Synthesis of Benzoxazinones via Use of the
Bpin Group as a Masked Nucleophile
Egor M. Larin, Alexa Torelli, Joachim Loup, and Mark Lautens*
Cite This: Org. Lett. 2021, 23, 2720−2725
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ABSTRACT: The utilization of the Bpin group as a pronucleo-
phile to facilitate the assembly of cyclic carbamates has been
achieved. This one-pot process involves an initial copper-catalyzed
borylation, a subsequent C−B bond oxidation to generate the
reactive alcohol intermediate, and a cyclization. We report the use
of this efficient, scalable, and simple method toward the synthesis
of a wide range of benzoxazinone scaffolds, including enantiose-
lective results. Subsequent transformations into useful scaffolds
showcase the utility of this strategy.
he carbamate moiety is an important and common
regioselectivity, generated organometallic intermediate, and the
subsequent reactivity of that intermediate (Scheme 1a).6
Consequently, numerous reports of borylative cyclization
processes have been developed utilizing styrene and related
olefins, but far less attention has been devoted to borylative
cyclization processes derived from Michael acceptors.5c,7
Borylative cyclization of Michael acceptors remains largely
limited to the interception of in situ generated nucleophilic
copper enolates with tethered electrophiles (Scheme 1b, top).8
We instead postulated that the organoboronate handle
contains significant pronucleophilic potential, via C−B bond
functionalization,9 and wanted to exploit this in a cyclization
strategy (Scheme 1b, bottom).10
T
functional group that appears in a wide range of
biologically active and synthetically useful compounds.1 In
particular, benzo-fused cyclic carbamate moieties, such as the
benzoxazinone scaffold, are of interest due to their biological
activity (Figure 1).2 Although several methods have been
We have recently demonstrated a variety of cyclization
strategies utilizing the carbamoyl chloride functional group as
the terminating electrophile, in order to access amide-
containing molecules.11 To generate the desired benzoxazi-
none scaffold, we envisioned the newly installed Bpin group
could be transformed into an hydroxyl group, which could then
undergo cyclization with the tethered carbamoyl chloride to
form the key carbamate linkage (Scheme 1c).12 We had
foreseen the potential challenge associated with choosing a
suitable tethered electrophile; namely being unreactive to the
initial organocopper species, but sufficiently reactive with the
Figure 1. Bioactive Benzoxazinone Derivatives.
described to assemble these polycyclic scaffolds, including
using CO and CO2 insertions,3a−c oxidative methods,3d,e and
processes relying on strong bases or stoichiometric organo-
metallic reagents,3f−i strategies aimed at targeting the mild and
simple construction of these molecules warrant further
investigation. We present an operationally facile and
conceptually novel method of constructing the benzoxazinone
scaffold.
Copper-catalyzed borylation has become a highly popular
and reliable method for the selective functionalization of
various π-acceptors.4,5 It is notable that in the case of olefin π-
acceptors, copper-catalyzed borylative additions across styrenes
and related alkenes have developed largely in parallel to the
investigation of analogous borylations across Michael acceptor
systems.5 Nonetheless, these two related processes constitute
disparate borylation strategies, manifesting in differences of
Received: February 21, 2021
Published: March 10, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00623
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2720−2725
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Letter
a
Scheme 1. Copper-Catalyzed Borylation and Its Use in
Cyclizations
Table 1. Optimization of Reaction Conditions
entry
ligand
dppe
dppBz
dppf
SIMes-HBF4
PPh3
PPh3
ligand loading
solvent
yield (%)
1
2
3
4
5
6
7
8
6.0 mol %
6.0 mol %
6.0 mol %
6.0 mol %
12 mol %
4.0 mol %
4.0 mol %
4.0 mol %
THF
THF
THF
THF
THF
THF
Et2O
MTBE
36
35
60
42
75
b
81 (80)
PPh3
PPh3
61
66
a
The reaction was carried out on 0.2 mmol of 1a, in solvent (4.0 mL),
under argon. Oxidant and water (2.0 mL) were added directly to the
1
reaction vial, unless stated otherwise. Yields were determined by H
b
NMR. Value in parentheses is the isolated yield.
With the optimized reaction conditions in hand, we set out
to assess the breadth of this methodology (Scheme 2). The
presence of an ortho-substituent on the tethered benzyl group
did not adversely impact the reaction (2b). Notably, a
substrate containing an aryl−iodide bond underwent a
chemoselective reaction (2c). The overall sequence occurred
with slightly lower efficiency when using the p-CF3 benzyl
group, delivering the corresponding product in moderate yield
(2d). In contrast, substrate containing an electron-rich benzyl
substituent generated the product in high yields (2e).
Benzoxazinones with other N-substituents such as the N-
methyl, or a tethered ferrocenyl group, could also be obtained
in slightly lower but nonetheless good yields (2f, 2g).
Substituents on the aryl backbone were also investigated in
the reaction. The reaction was highly sensitive to the
electronics of the substituent at para to the carbamoyl
chloride. In particular, the carbamoyl chloride group in
substrates corresponding to 2h and 2i decomposed more
readily into the corresponding aniline, as evidenced by crude
1H NMR, and thereby lead to much lower overall product
yield, in contrast to 2j and 2k, which were obtained in good
yields. This level of sensitivity was not observed in substrates
bearing substituents para to the Michael acceptor group, with
the electron-poor 2l being obtained in only slightly reduced
yield compared to the substrate 2m, which bears a methyl
group in that position. In the case of substrates with electron-
rich backbones, the reaction was slightly less efficient but the
products were nonetheless generated in good to high yields
(2n−2o). Finally, a methyl group ortho to the carbamoyl
chloride led to very high yields of product 2p.
resulting hydroxyl group. A carbamoyl chloride proved capable
of surviving the initial formation of the organometallic species,
in contrast to our previous reports wherein the benzylic copper
species reacted directly to form an amide bond.8b,d
Initial studies were conducted utilizing dppe as the ligand in
the presence of substoichiometric base in THF (Table 1, entry
1), followed by standard oxidation conditions which delivered
the desired cyclization product in promising yields. During our
investigations, we found that the oxidation of the boryl
intermediate and subsequent cyclization was highly efficient,
yielding near quantitative conversion to the products.
However, the initial borylation step proved to be challenging
due to decomposition of the carbamoyl chloride group to the
corresponding aniline. We reasoned that this byproduct could
be avoided through the judicious choice of catalyst. The use of
other bidentate phosphine ligands gave mixed results in terms
of improving overall reaction efficiency (entries 2 and 3). The
use of NHC ligand also did not significantly improve the yield
(entry 4). However, the use of a monodentate phosphine,
PPh3, gave better results (entry 5). A 1:1 ligand/copper ratio
proved to be optimal (entry 6). The use of MeOH in the
reaction was necessary for efficient recycling of the catalyst,
and its absence impacted the reproducibility of the reaction.6c,d
Screening of other ethereal solvents (entries 7 and 8) did not
further improve the efficiency of this reaction. Importantly, the
use of THF allowed for an operationally simple, direct one-pot
oxidation using a water-soluble oxidant.
We were interested in assessing the feasibility of other
Michael acceptors participating in the conjugate addition step.
The reaction worked quite well with other ester groups, and we
observed the steric bulk of the ester positively correlating with
higher yields (2q, 2r). Gratifyingly, the reaction could also be
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Letter
a
a
Scheme 2. Racemic Reaction Scope
Scheme 3. Enantioselectivity Results
a
All yields reported are isolated yields. Enantiopurity was determined
using chiral HPLC. See the Supporting Information for details.
a
All yields reported are isolated yields.
benzoxazinone 2a and good er. Electronic effects on the aryl
backbone largely followed the same trend as in the racemic
reaction, with highly electron-donating or withdrawing
substituents resulting in diminished yields. Of note, the lowest
enantiomeric ratios were observed for the electron-rich 2j, and
the substrate containing the o-methyl substituent (2n). The
effect of the Michael acceptor on the reaction yields also
roughly followed a similar trend as the racemic reaction, with
the benzoxazinone bearing the larger ethyl ester (2q) being
obtained in higher yield, and the amide-containing benzox-
azinone (2s) formed in reduced yield, but very high er.
In an effort to ascertain reaction scalability, we performed
the one-pot, three-step benzoxazinone synthesis on both a 1.0
mmol and 1.0 g scale (Scheme 4a). In both cases, only a slight
decrease in yield was observed. We were interested in
furthering the structural complexity of the generated
benzoxazinone through several derivatization strategies
(Scheme 4b). We based our approach upon an initial selective
reduction of the ester group into the corresponding alcohol.
The hydroxyl group could be efficiently transformed into the
applied to generate an amide containing benzoxazinone
through the use of an α,β-unsaturated amide Michael acceptor,
albeit with slightly reduced yield (2s).
Based on the seminal reports from Yun,13 we were interested
in probing the impact of a chiral ligand on the preparation of
enantiomerically enriched benzoxazinones. The Josiphos-
family ligand, SL-J001-1, has been used in several method-
ologies focused on an enantioselective borylative conjugate
addition of α,β-unsaturated carbonyl compounds.8a−c We
found that SL-J001-1 generated the desired enantioenriched
benzoxazinone (2a) in 66% yield and with a high enantiomeric
ratio (Scheme 3). As before, this reaction is not impacted by
the presence of aryl−iodide bonds, generating 2c in good yield
and er. Surprisingly, the p-methoxybenzyl benzoxazinone 2e
was produced in slightly lower yield in comparison with the
racemic reaction, albeit high er. In contrast, benzoxazinones
containing the N-methyl (2f) or the N-ferrocenyl (2g) groups
were synthesized in greater efficiency than the model
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a
Scheme 4. Reaction Scale-Up and Derivatizations
Experimental procedures, compound characterization
1
data, H/13C/19F NMR spectra, HPLC spectra, and X-
ray data (PDF)
Accession Codes
CCDC 2053102 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Mark Lautens − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada; orcid.org/0000-0002-0179-
2914; Email: mark.lautens@utoronto.ca
Authors
Egor M. Larin − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada; orcid.org/0000-0003-
4986-1373
Alexa Torelli − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto, Ontario M5S
3H6, Canada; orcid.org/0000-0002-6800-7706
Joachim Loup − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada; orcid.org/0000-0002-
0033-5033
a
All yields reported are isolated yields. See the Supporting
Information for detailed experimental details.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00623
tosylate group (3) in good yield over two steps. Alternatively,
we could efficiently transform the hydroxyl group into the
azide group via a Mitsunobu reaction. This azide could then be
used in a copper-catalyzed azide−alkyne cycloaddition to
generate the biologically valuable triazole moiety tethered to
the benzoxazinone (4).14 Through the use of stoichiometric
KOtBu, a formal decarbonylation of the carbamate to uncover
the corresponding aminodiol moiety could be achieved to
generate the product 5 in good yield. Finally, we were
delighted that the PMB substituent could be selectively
removed using a standard CAN reaction to yield the
deprotected analog 6 (Scheme 4c).15
In summary, we reported a novel sequence to access
benzoxazinone scaffolds. More broadly, we believe this
reaction demonstrates the viability of a cyclization strategy,
utilizing the pronucleophilic character of the Bpin group. The
strategy employs simple α,β-unsaturated esters or amides
tethered to a carbamoyl chloride, which acts as a latent
electrophile. The reported one-pot, three-step protocol is mild
and scalable, can be applied to synthesize a broad range of
benzoxazinone scaffolds, and could be applied in an
enantioselective format.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science and Engineering Research
Council (NSERC), the University of Toronto, and Kennar-
shore Inc. for financial support. E.M.L. thanks NSERC for a
postgraduate scholarship (CGS-D). A.T. thanks NSERC for a
postgraduate scholarship (PGS-D). J.L. thanks the Swiss
National Science Foundation (SNSF) for a postdoctoral
fellowship (Grant No. P2SKP2_187649). We thank Iuliia
Polishchuk (KAUST) for synthesis of some starting materials,
and Austin Marchese (University of Toronto) for helpful
discussions. Dr. Alan Lough (University of Toronto) is
thanked for single-crystal X-ray structural analysis of 2g.
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NOTE ADDED AFTER ASAP PUBLICATION
Scheme 4 was corrected on March 12, 2021.
■
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