Highly Enantioselective Construction of Dihydrooxazines via Pd-Catalyzed Asymmetric Carboetherification

Article abstract of DOI:10.1021/acs.orglett.9b04123

A straightforward synthesis of highly enantioenriched 5,6-dihydro-4H-1,2-oxazines is realized by Pd-catalyzed asymmetric carboetherification of γ,δ-alkenyl oximes with (hetero)aryl and alkenyl halides in the presence of a commercially available bisphosphine ligand. The enantioenriched products can be facilely converted to functionalized alcohols with high fidelity of chiral transfer.

Full text of DOI:10.1021/acs.orglett.9b04123

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Enantioselective Construction of Dihydrooxazines via Pd-
Catalyzed Asymmetric Carboetherification
Na Li,† Baozhen Sun,† Shuang Liu,† Jinbo Zhao,*,†,‡ and Qian Zhang†
†Department of Chemistry, Key Laboratory of Functional Molecule Design and Synthesis of Jilin Province, Northeast Normal
University, Changchun, 130024, P. R. China
‡School of Chemistry and Biology, Changchun University of Technology, 2055 Yan’an Street, Changchun, 130012, P. R. China
S
* Supporting Information
ABSTRACT: A straightforward synthesis of highly enan-
tioenriched 5,6-dihydro-4H-1,2-oxazines is realized by Pd-
catalyzed asymmetric carboetherification of γ,δ-alkenyl oximes
with (hetero)aryl and alkenyl halides in the presence of a
commercially available bisphosphine ligand. The enantioen-
riched products can be facilely converted to functionalized
alcohols with high fidelity of chiral transfer.
he partially saturated six-membered cyclic oxime ether
(SCOE), 5,6-dihydro-4H-1,2-oxazine, is displayed in
bioactive natural products (Figure 1) and serves as versatile
Scheme 1. Strategies for the Synthesis of 5,6-Dihydro-4H-
1,2-oxazine Framework
T
Figure 1. Selected 1,2-oxazine-containing bioactive natural products.
synthetic intermediates that can be trivially manipulated to key
building blocks, such as 1,4-amino alcohols, various N- and O-
containing heterocycles, etc.1 Despite its high synthetic
versatility, however, this ring system has received much less
attention compared to its five membered congener, isooxazo-
line.2 Traditional synthetic approaches to this scaffold mainly
involve noncatalytic processes, such as hetero-Diels−Alder
reaction of in situ generated reactive α-nitrosoalkene,3
intramolecular SN2 reaction,4 electrophile-induced cyclization
of alkenyl oxime,5 among others (Scheme 1A, a−c). In
contrast, catalytic asymmetric syntheses of this scaffold are
highly underdeveloped.6 Most recently, Mukherjee et al.
reported a highly enantioselective organocatalytic iodocycliza-
tion approach en route to chiral 5,6-dihydro-4H-1,2-oxazines,7
as an extension to the strategy’s success in asymmetric
isoxazoline synthesis.8 Despite this advance, high enantiocon-
trol was only realized for construction of specialized structural
units, i.e., tertiary benzylic C−O moieties. In addition, the
diversity of electrophile is restricted. Furthermore, the few
enantioselective catalytic methods applicable to isoxazoline
syntheses9 are not amenable to dihydrooxazines. To access
chiral dihydrooxazines with complementary structural charac-
teristics and broader diversity, there still remains a significant
methodological gap. Thus, alternative approaches for the
asymmetric synthesis of this scaffold would be highly valuable.
Pd-catalyzed heterocyclization reactions represent a highly
enabling strategy for heterocycle synthesis.10 In this context,
olefin carboetherification has become a powerful tool for the
synthesis of various O-heterocycles during the past two
decades.10b,11 The first example of Pd-catalyzed carboether-
ification was reported in 2004 by Wolf and co-workers.12
A
breakthrough in enantioselective catalysis was realized by Wolf
in 2015 on the cyclization of alkenols to chiral tetrahydrofur-
Received: November 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04123
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Letter
an.13 The Tang14 and Mazet15 groups subsequently developed
asymmetric synthesis of chiral 1,4-benzodioxanes and
2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran, respectively. These
scarce yet elegant examples underscore the versatility and
prospect of asymmetric carboetherification in constructing
important O-heterocycles. On the other hand, readily available
alkenyl oximes have long been harnessed to access cyclic chiral
nitrone/oxime ethers via substrate-controlled diastereoselec-
tive synthesis, while catalyst-controlled bond formation
processes (e.g., Scheme 1A, d, M = catalyst) are expected to
hold promise for asymmetric synthesis of the important cyclic
nitrones and/or oxime ethers. To this end, we commenced on
investigating the Pd-catalyzed asymmetric cyclization/coupling
of γ,δ-alkenyl oxime with organohalides for the synthesis of
enantioenriched cyclic oxime ethers, with the aim to develop
highly enantioselective protocols for this important scaffold.
Herein we disclose that such a reaction can be realized with a
commercial bisphosphine ligand, which enables rapid con-
struction of various highly enantioenriched 5,6-dihydro-4H-
1,2-oxazines (Scheme 1B).
we interrogated the effect of several ligand scaffolds (L5−
L7).17 Notably, while (R)-BINAP(O) and (R)-BIPHEP(O)
were both sluggish in reactivity and selectivity, (R)-Segphos-
(O) showed a highly promising 50% ee. To our delight,
combining the favorable structural features of SegPhos with
more sterically hindered P-aryls resulted in higher selectivity, as
(R)-DTBM-SegPhos(O) (L8) delivered the product 3a in 81%
conversion, 80% yield, and 92% ee. Further increasing the
loading of halide and base, as well as elevating the temperature
to 100 °C, eventually led to 93% conversion, 84% isolated
yield, and 93% ee. According to Mazet’s report, in situ
oxidation of the bisphosphine could be realized using
Pd(OAc)2 in the presence of 40 mol % H2O.15 By following
this condition, we found that a 5 mmol scale reaction
uneventfully delivered product 3a in good yield with no
erosion of enantiocontrol (1.002 g, 70%, 92% ee).
Under the optimized conditions the scope of this trans-
formation was examined (Table 1). First, we examined the
a
Table 1. Scope of γ,δ-Vinyl Oximes
We started by examining the enantioselective coupling
cyclization of 4-chlorobromobenzene with γ,δ-alkenyloxime.
However, we observed sluggish reactivity with a variety of
bases (Table S1). Instead, in the presence of a fluoride base,
the corresponding silyl ether 1a in dioxane at 80 °C turned out
to be more productive with some prototype commercial
monophosphine ligands, among which (R)-MeO-MOP
retrieved product 3a in a moderate enantioselection of 50%
ee (L1, Scheme 2). Increasing the steric hindrance of the
Scheme 2. Survey of Chiral Ligands
a
b
1.5 equiv of 2a and CsF, 100 °C. 5 mmol scale with in situ
generated ligand from oxidation of (R, R)-DTBM-SegPhos (6 mol %)
with Pd(OAc)2 (5 mol %) and H2O (40 mol %).
a
Reaction conditions: alkenyl oxime ether (0.20 mmol), 2a (0.30
mmol, 1.5 equiv), Pd(dba)2 (5 mol %), (R)-DTBM-SegPhos(O) L8
(6 mol %), CsF (0.30 mmol, 1.5 equiv), dioxane (2 mL), 100 °C.
ethereal moiety led to a decrease of enantiocontrol, as BnO-
MOP (L2) was much less selective. However, the obvious
deviation from this trend by the ligand bearing a more bulkyl
O-cyclohexyl moiety (L3, 24% ee) suggests that steric and/or
electronic perturbation on the P-aryl may have a significant
beneficiary effect. In line with this hypothesis, a KenPhos
analogue L4, developed for the atroposelective Catellani-type
biaryl cross-coupling,16 was found to be more selective (72%
ee), showing the high significance of P-substituents. Inspired
by Mazet’s report on the efficiency of monophosphines derived
from partial oxidation of commercial bisphosphine ligands in
the related reaction of 2-bromophenol with dihydrofurans,15
b
brsm yield.
substitution effects on the aryl of alkenyl oxime silyl ether 1.
Various 4-substituents with distinct electronic properties were
found to have negligible effects on the reactivity or
enantioselectivity (3b−3f). Besides, 3- and 2-substitution was
also compatible. Albeit ortho-substitution led to a significantly
diminished yield, the enantiocontrol was exceptional (3h). 3,4-
Disubstitution (3i), electron-rich 2-thienyl (3j), and 2-
naphthyl (3k) were also accommodated. The absolute
B
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Letter
configuration of the products was unambiguously determined
by X-ray diffraction studies of 3k. A racemic α-phenyl
substituted substrate could also react, and the major
diasteromer 3l was obtained in 41% yield and a fair 46% ee,
indicating that the enantiodifferentiation of the chiral ligand L8
was counteracted by a bulkyl α-substituent of the substrate due
to intrinsic 1,3-asymmetric induction.18 α,α-Dimethyl sub-
stitution led to the corresponding nitrone product 4 in merely
6% ee (Scheme 3), which requires further optimization for the
substituted aryl (3v−3y), naphthyl (3z), and alkenyl (3zb)
substrates were all uneventfully accommodated. Electronically
distinct heterocyclic substrates were also applicable (N-
heterocycles 3zc−3ze; S-heterocycles 3zf and 3zg). These
results highlight the modularity of this process in the
incorporation of various C(sp2)-moieties onto the dihydroox-
azine scaffold.
For the construction of analogous five-membered cyclic
oxime ether, isoxazolines, the same ligand attained promising
enantioselectivity, as use of (R)-DTBM-SegPhos(O) delivered
isoxazoline 5 in a good 70% ee (Scheme 4). Notably, a number
Scheme 3. Pd-Catalyzed Cyclization of α,α-Disubstituted
γ,δ-Alkenyl Oxime Silyl Ether
Scheme 4. Pd-Catalyzed Asymmetric Carboetherification of
β,γ-Alkenyl Oxime
enantioselective process.19 Furthermore, the diazine product
3o could also be delivered with good enantioselectivity,
although the reactivity is somewhat lower.
Variation of the bromide under the conditions of in situ
generated ligand (Table 2) also showed the high versatility of
this process, as reaction of a panel of aryl bromides with
distinct electronic properties were also found insensitive to
electronic perturbation (3p−3u). Ortho-, meta-, and multi-
of other ligands demonstrating appreciable enantiocontrol for
the synthesis of dihydrozaines turned out to be ineffective
(Table S3). Further optimization will be required for these
substrates.
Due to the ready availability of the oxime derivatives from
their parent ketones, and the ease of N−O cleavage, the
current protocol can offer a unique ketone “δ,γ-carbooxygena-
tion”. Thus, the products of this study can be efficiently used
for the synthesis of various enantioenriched functionalized
alcohols upon reductive cleavage of the N−O bond. As such,
3a can be converted to γ-hydroxyl ketone 6 in a reasonable
yield with enantiomeric fidelity (Scheme 5).
a
Table 2. Scope of Organohalide
Scheme 5. Synthetic Elaboration
In conclusion, we have developed a straightforward
approach for the highly enantioselective synthesis of 6-
membered N,O-heterocycles 5,6-dihydro-4H-1,2-oxazine by
Pd-catalyzed asymmetric carboetherification of ω-vinyl oximes
directed by a commercially available phosphine ligand. The
products can be facilely converted to enantioenriched γ-
hydroxyketones and β-amino alcohol derivatives. Further
studies to improve the enantioselection for isoxazolines are
currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04123.
Experimental procedures and characterization data for
all new compounds (PDF)
Accession Codes
a
CCDC 1935678 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-
Reaction conditions: alkenyl oxime ether (0.20 mmol), aryl halide
(0.30 mmol, 1.5 equiv), Pd(OAc)2 (0.01 mmol, 5 mol %), (R)-
DTBM-SegPhos (0.012 mmol, 6 mol %), H2O (0.08 mmol, 1.5 μL,
40 mol %), CsF (0.30 mmol, 1.5 equiv), dioxane (2 mL), 100 °C.
C
DOI: 10.1021/acs.orglett.9b04123
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Organic Letters
Letter
(f) Garlets, Z. J.; White, D. R.; Wolfe, J. P. Asian J. Org. Chem. 2017,
6, 636−653.
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(11) Garlets, Z. J.; White, D. R.; Wolfe, J. P. Asian J. Org. Chem.
2017, 6, 636−653.
AUTHOR INFORMATION
■
(12) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620−
1621.
Corresponding Author
*E-mail: zhaojb100@nenu.edu.cn.
ORCID
(13) Hopkins, B. A.; Garlets, Z. J.; Wolfe, J. P. Angew. Chem., Int. Ed.
2015, 54, 13390−13392.
(14) Hu, N.; Li, K.; Wang, Z.; Tang, W. Angew. Chem., Int. Ed. 2016,
55, 5044−5048.
Jinbo Zhao: 0000-0002-5261-7366
Notes
(15) Borrajo-Calleja, G. M.; Bizet, V.; Mazet, C. J. Am. Chem. Soc.
2016, 138, 4014−4017.
The authors declare no competing financial interest.
(16) Ding, L.; Sui, X.; Gu, Z. ACS Catal. 2018, 8, 5630−5635.
(17) For leading references on bisphosphine monoxide ligands, see:
ACKNOWLEDGMENTS
̈
(a) Woste, T. H.; Oestreich, M. Chem. - Eur. J. 2011, 17, 11914−
■
11918. (b) Ji, Y.; Plata, E.; Regens, C. S.; Hay, M.; Schmidt, M.;
Razler, T.; Qiu, Y.; Geng, P.; Hsiao, Y.; Rosner, T.; Eastgate, M. D.;
Blackmond, D. G. J. Am. Chem. Soc. 2015, 137, 13272−13281. (c) Li,
H.; Belyk, K. M.; Yin, J.; Chen, Q.; Hyde, A.; Ji, Y.; Oliver, S.; Tudge,
M. T.; Campeau, L.-C.; Campos, K. R. J. Am. Chem. Soc. 2015, 137,
13728−13731.
Financial support from the National Natural Science
Foundation of China (21871045, 21831002), Natural Science
Foundation of the Jilin Province (20160519003JH,
20190201070JC), and the Fundamental Research Funds for
the Central Universities (2412017FZ014) is gratefully
acknowledged. We thank Prof. Zhenhua Gu of USTC for a
generous gift of ligands L3 and L5, and Dr. Kuizhan Shao of
Faculty of Chemistry, NENU for assistance in X-ray
crystallography.
(18) The minor cis-diastereomer, which was produced in a low yield
(ca. 5%) and difficult to purify and characterize, has a high 83% ee.
(19) Sun, B.; Liu, S.; Zhang, M.; Zhao, J.; Zhang, Q. Org. Chem.
Front. 2019, 6, 388−392.
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