Synthesis of Chiral 2-Substituted 1,4-Benzoxazin-3-ones via Iridium-Catalyzed Enantioselective Hydrogenation of Benzoxazinones

Article abstract of DOI:10.1021/acs.orglett.1c01701

An efficient iridium-catalyzed enantioselective hydrogenation of 2-alkylidene 1,4-benzoxazin-3-ones using our developed iPr-BiphPHOX as a ligand is reported. This method showed good functional group compatibility and delivered the corresponding reduced products in excellent yields (up to 99%) with excellent enantioselectivities (up to 99% ee). The reaction proceeded very well on a gram scale with low catalyst loadings (0.1 mol %), providing the product with no erosion in enantioselectivity. Additionally, three bioactive molecules can be easily obtained from the reduced products.

Full text of DOI:10.1021/acs.orglett.1c01701

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Letter
Synthesis of Chiral 2‑Substituted 1,4-Benzoxazin-3-ones via Iridium-
Catalyzed Enantioselective Hydrogenation of Benzoxazinones
Yu Nie, Jing Li, Jun Yan, Qianjia Yuan,* and Wanbin Zhang*
Cite This: Org. Lett. 2021, 23, 5373−5377
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ABSTRACT: An efficient iridium-catalyzed enantioselective hy-
drogenation of 2-alkylidene 1,4-benzoxazin-3-ones using our
developed iPr-BiphPHOX as a ligand is reported. This method
showed good functional group compatibility and delivered the
corresponding reduced products in excellent yields (up to 99%)
with excellent enantioselectivities (up to 99% ee). The reaction
proceeded very well on a gram scale with low catalyst loadings (0.1
mol %), providing the product with no erosion in enantioselec-
tivity. Additionally, three bioactive molecules can be easily obtained from the reduced products.
1,4-Benzoxazinones are core scaffolds in a variety of natural
products and bioactive molecules as well as useful building
blocks in organic synthesis (Figure 1).1 Many synthetic
Scheme 1. Catalytic Enantioselective Synthesis of Chiral 2-
Substituted 1,4-Benzoxazin-3-ones
Figure 1. Examples of bioactive compounds bearing 1,4-benzoxazin-3-
ones.
strategies have been reported for the construction of 1,4-
benzoxain-3-ones;2 however, most of the methods provide
racemic mixtures,2c−j and the methods for the preparation of
these chiral building blocks employ chiral starting materials and
require multistep synthetic sequences.2a,b Hence, developing
enantioselective catalytic strategies for the construction of
enantiomerically enriched 1,4-benzoxazin-3-ones is of great
importance; however, only a few examples of the construction of
chiral 1,4-benzoxazin-3-ones via enantioselective catalytic
reactions have been reported.3 In 2015, Stoltz and coworkers
synthesized 2,2-disubstituted 1,4-benzoxazin-3-ones via a
palladium-catalyzed enantioselective allylic substitution reaction
(Scheme 1a).3a In 2018, the Maruoka research group reported a
phase-transfer-catalyzed enantioselective synthesis of 2,2-
disubstituted 1,4-benzoxazin-3-ones (Scheme 1b).3b Therefore,
the development of a concise method for the synthesis of such
chiral compounds appears to be challenging but desirable.
Transition-metal-catalyzed enantioselective hydrogenation
has gained much attention in academia, and great success has
been achieved in industrial applications owing to its atom
economy, excellent enantioselectivity, and simple operation for
Received: May 20, 2021
Published: July 2, 2021
https://doi.org/10.1021/acs.orglett.1c01701
© 2021 American Chemical Society
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the construction of enantioenriched compounds.4 Since the
Pfaltz group’s pioneering work,5 iridium-catalyzed enantiose-
lective hydrogenation has attracted much attention due to its
excellent performance in the enantioselective reduction of
different types of CC bonds with/without functional groups.
Our group has developed axis-unfixed biphenylphosphine-
oxazoline ligands (BiphPHOX) that have shown excellent
performance in several types of transition-metal-catalyzed
enantioselective catalytic reactions,6 especially for iridium-
catalyzed enantioselective hydrogenations.6a−f,h−l Considering
the importance of 1,4-benzoxazin-3-ones and to further explore
our developed axis-unfixed biphenylphosphine-oxazoline li-
gands in the enantioselective hydrogenation reactions and the
methods for the construction of chiral heterocycles,7 herein we
report an Ir/BiphPHOX-catalyzed enantioselective hydro-
genation of 2-alkylidene 1,4-benzoxazin-3-ones for the prepara-
tion of chiral 2-substituted 1,4-benzoxazin-3-ones (Scheme 1).
Our developed BiphPHOX ligands showed excellent perform-
ance in the iridium-catalyzed enantioselective reduction of four-
and five-membered ring substrates bearing exocyclic CC
bonds but provided moderate enantiomeric ratios for the
enantioselective reduction of six-membered rings bearing
exocyclic CC bonds.6b,d The development of an efficient
enantioselective Ir/BiphPHOX-catalyzed hydrogenation of six-
membered rings bearing exocyclic CC bonds is desirable.
Optimization of the iridium-catalyzed enantioselective hydro-
genation reaction was carried out using N-benzyl-substituted
compound 1a as the model substrate for six-membered rings
bearing an exocyclic CC bond (Table 1). On the basis of our
previous reports,6 the ligands L1−L3 were tested under the
enantioselective hydrogenation conditions. To our delight, the
reaction proceeded very well and delivered the corresponding
product 2a with excellent enantioselectivities (entries 1−3). It
should be noted that the substituent on the oxazoline ring of the
ligand had no effect on the enantioselectivity of the reduced
product. The PHOX ligands L4 and L5 were also tested in this
reaction, and poor conversions and enantioselectivities were
obtained (entries 4 and 5). Next, the solvent (DCE, toluene, and
1,4-dioxane) for the reaction was investigated, and the reduced
products were all obtained with 96% ee (entries 6−8). The
hydrogen pressure and reaction time were also examined
(entries 9−11), both of which had an effect on the conversions
of the reaction. When the hydrogen pressure was decreased to
30 bar, the reaction proceeded very well and gave the reduced
product 2a with 97% ee (entry 9). Finally, the protecting group
on the nitrogen in the substrate was evaluated, and substrates
bearing N-phenyl and N-methyl groups delivered their
corresponding reduced products 2b and 2c with full conversions
with 89 and 78% ee, respectively; however, the N-free substrate
delivered a trace amount of product 2d. On the basis of the
above information, benzyl was selected as the nitrogen
protecting group, and the optimized reaction conditions are
shown in Table 1 (entry 9).
a
Table 1. Screening of the Reaction Conditions
b
c
d
entry
solvent
ligand
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
DCM
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
99
95
96
24
6
99
99
99
99
41
59
97
96
96
18
42
96
96
96
97
97
97
toluene
1,4-dioxane
o-xylene
o-xylene
o-xylene
e
9
10
11
f
eg
,
a
Reaction conditions: substrate 1 (0.2 mmol), substrate/catalyst (S/
C) = 100, solvent (2 mL), H2 (60 bar). Axial chirality of the catalyst
was S when ligands L1−L3 were used. Determined by H NMR
spectroscopy. Determined by HPLC with a chiral column. H2 (30
b
c
1
d
e
f
g
bar). H2 (20 bar). 12 h.
products (2p and 2q) were obtained in quantitative yields with
83 and 82% ee, respectively. The reduced products (2r−2t) with
two substituents on the phenyl ring were also obtained with
excellent enantioselectivities. The reduced product 2s was
obtained in 92% yield with 97% ee under modified reaction
conditions, the two oxygen atoms of the dimethoxy group may
coordinate to the catalyst, thus reducing its activity.6l When R2
was another aromatic ring, the reaction proceeded well and
delivered the corresponding reduced products (2u−2w) with
good to excellent enantioselectivities. Heteroaromatic rings are
also well tolerated in the reaction, such as 2-furanyl, 2-thienyl,
and 3-thienyl groups, delivering the corresponding reduced
products (2x−2z) in excellent yields. When R2 was an alkyl
substituent, the reaction also proceeded very well and afforded
the corresponding reduced products (2aa−2ac) with good to
excellent enantioselectivities. The cyclopropanyl group was also
tolerated in the reaction, giving the product 2ac in 98% yield
with 97% ee. Next, substrates with different R1 groups on the
1,4-benzoxazinone ring were examined. Substrates bearing an
electron-donating or electron-withdrawing group at various
positions of the 1,4-benzoxazinone ring delivered the reduced
products (2ad−2an) in excellent results. For a substrate bearing
a bromo atom on the 1,4-benzoxazinone ring with an R2
cyclopropanyl group, the product 2ao was obtained in 98%
yield with 97% ee. The absolute configuration of the product 2v
was determined to be (S) by X-ray single-crystal diffraction, and
the same sense of stereochemistry was assumed for the
remainder of the products. In addition, we designed and carried
With the optimized reaction conditions in hand (Table 1,
entry 9), the substrate scope was examined (Scheme 2). In
general, the optimized reaction conditions showed excellent
functional group compatibility. First, the substrates with
different substituted R2 groups were examined. When R2 was a
phenyl ring bearing different functional groups (electron-
donating or electron-withdrawing) at the para or meta positions,
all of the reduced products (2a and 2e−2o) were obtained in
excellent yields with excellent enantioselectivities; with a phenyl
ring bearing a substituent at the ortho position, the reduced
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a
Scheme 2. Scope of the Substrate
a
Reaction conditions: substrate 1 (0.2 mmol), (aS)-Ir/iPr-BiphPHOX (1 mol %), o-xylene (2 mL) under H2 (30 bar) at r.t. for 24 h. Isolated yield.
b
c
ee values were determined by HPLC with a chiral column. DCE as the solvent. H2 (60 bar) and 48 h.
out some control experiments, and the results showed that
structurally related compounds (2ap−2as and 3) do not achieve
the same levels of efficiency under the optimized reaction
conditions (Scheme 3).
Scheme 4. Reaction Efficiency and Transformations of the
Products
Scheme 3. Control Experiments
To demonstrate the efficiency and applications of this
iridium-catalyzed enantioselective hydrogenation reaction, a
gram-scale reaction was carried out with low catalyst loadings
(0.1 mol %), giving the reduced product 2ag in 98% yield with
97% ee (Scheme 4). Further transformations of the reduced
products were also conducted. Product 2a can be reduced with
9-BBN, providing 1,4-benzoxazine 3 in 88% yield with 97% ee
(Scheme 4a). The reduced products 2a, 2ag, and 2al in the
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presence of trifluoromethanesulfonic acid delivered the
corresponding N-free products 4, 6, and 8 in good yields.
Compound 4 was transformed to product 5 via a simple
substitution reaction, which is a CNS depressant and a
dopamine receptor antagonist (Scheme 4b).8 Product 6 can
be transformed to the ATP-sensitive potassium (KATP)
channel modulator 7 according to a reported method (Scheme
4c).9 Compound 8 is a key intermediate for the preparation of
bromodomain and extraterminal (BET) bromodomain inhib-
itor 9 (Scheme 4d).1i
In summary, an efficient iridium-catalyzed enantioselective
hydrogenation of 2-alkylidene 1,4-benzoxazin-3-ones using our
developed axis-unfixed biphenylphosphine-oxazoline ligand has
been developed, delivering chiral 2-substituted 1,4-benzoxazin-
3-ones in excellent yields (up to 99%) and with excellent
enantioselectivities (up to 99% ee). The reaction showed
excellent functional group compatibility, and proceeded very
well with low catalyst loadings (0.1 mol %) on a gram scale.
Additionally, three bioactive molecules can be obtained from the
reduced products.
Molecules, School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, Shanghai 200240, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01701
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (nos. 22001164, 22071150, 21991112,
21831005, 91856106, 21620102003), the National Key R&D
Program of China (no. 2018YFE0126800), the Shanghai
M u n i c i p a l E d u c a t i o n C o m m i s s i o n ( n o .
201701070002E00030), the Shanghai Pujiang Program
(20PJ1406400), and the startup funding from Shanghai Jiao
Tong University. We also thank the Instrumental Analysis
Center of Shanghai Jiao Tong University.
REFERENCES
■
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01701.
Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 2069776 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Qianjia Yuan − Shanghai Key Laboratory of Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, P. R. China; Email: yuanqianjia@sjtu.edu.cn
Wanbin Zhang − Shanghai Key Laboratory of Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, P. R. China; College of Chemistry, Zhengzhou
University, Zhengzhou 450052, P. R. China; orcid.org/
0000-0002-4788-4195; Email: wanbin@sjtu.edu.cn
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Authors
Yu Nie − Shanghai Key Laboratory of Molecular Engineering of
Chiral Drugs, Frontiers Science Center for Transformative
Molecules, School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, Shanghai 200240, P. R. China
Jing Li − Shanghai Key Laboratory of Molecular Engineering of
Chiral Drugs, Frontiers Science Center for Transformative
Molecules, School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, Shanghai 200240, P. R. China
Jun Yan − Shanghai Key Laboratory of Molecular Engineering of
Chiral Drugs, Frontiers Science Center for Transformative
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