Pd-Catalyzed Decarboxylative Cyclization of Trifluoromethyl Vinyl Benzoxazinanones with Sulfur Ylides: Access to Trifluoromethyl Dihydroquinolines

Article abstract of DOI:10.1021/acs.orglett.9b00330

An unprecedented Pd-catalyzed decarboxylative cyclization of 4-trifluoromethyl-4-vinyl benzoxazinanones (4) with sulfur ylides (2) is reported. While the reactions of 4-vinyl/4-CF₃ benzoxazinanones (1a/1c) with 2 furnished the 3-vinyl/3-CF₃ indolines (3a/3c), via an attack on the C₁ carbon of the π-allyl/benzyl zwitterionic intermediates, 4 was converted into 4-trifluoromethyl-dihydroquinolines (5) in good yields via an attack on the C₃ carbon of the π-allyl intermediate. The corresponding methyl-substituted analogues afford different products via an attack on the C₂ carbon.

Full text of DOI:10.1021/acs.orglett.9b00330

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Decarboxylative Cyclization of Trifluoromethyl Vinyl
Benzoxazinanones with Sulfur Ylides: Access to Trifluoromethyl
Dihydroquinolines
Nagender Punna,† Kyosuke Harada,† Jun Zhou,† and Norio Shibata*,†,‡
†Department of Nanopharmaceutical Sciences & Department of Life Science and Applied Chemistry, Nagoya Institute of
Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
‡Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua, China
S
* Supporting Information
ABSTRACT: An unprecedented Pd-catalyzed decarboxylative cyclization of 4-
trifluoromethyl-4-vinyl benzoxazinanones (4) with sulfur ylides (2) is reported.
While the reactions of 4-vinyl/4-CF3 benzoxazinanones (1a/1c) with 2
furnished the 3-vinyl/3-CF3 indolines (3a/3c), via an attack on the C1 carbon
of the π-allyl/benzyl zwitterionic intermediates, 4 was converted into 4-
trifluoromethyl-dihydroquinolines (5) in good yields via an attack on the C3
carbon of the π-allyl intermediate. The corresponding methyl-substituted
analogues afford different products via an attack on the C2 carbon.
he generation of a variety of functionalized heterocyclic
compounds has been a long-standing objective within
T
pharmaceutical companies, given that such compounds
represent pharmacophores that are ubiquitous in many
naturally occurring biologically active compounds.1 During
the past few years, 4-vinyl benzoxazinanone (1a) has emerged
as a powerful and versatile synthon for the generation of
multiply substituted medium-sized heterocyclic compounds,
which include both structural scaffolds used in the
pharmaceutical industry and novel heterocyclic skeletons
with potential biological appeal.2 In the presence of Pd-based
catalysts, 1a is susceptible to decarboxylation, which leads to
the generation of a zwitterionic π-allyl Pd-intermediate (Ia)
that can be trapped by suitable interceptors to furnish highly
substituted heterocycles via cycloaddition reactions.2a The
formation of a variety of heterocyclic skeletons based on this
strategy can be effectively achieved by judicious selection of
the interceptor.2 A representative example of a Pd-catalyzed
interceptive decarboxylative allylic cycloaddition (IDAC) of
benzoxazinanones with sulfur ylides (2) to furnish 3-vinyl
indoline 3a via a [4 + 1] cycloaddition has been reported by
Xiao and co-workers in 2014 (Figure 1a; X = vinyl).2d In 2016,
Xiao and co-workers applied this strategy to the Cu-catalyzed
reaction between 4-propargyl benzoxazinanone (1b) and 2 to
give 3-alkynyl indoline (3b).3a
The propargyl group acts as a trigger for the decarboxylation
that forms the zwitterionic Cu-allenylidene intermediate Ib,
followed by a [4 + 1] cycloaddition (Figure 1a; X = propargyl).
This type of cycloaddition reaction using both 1a and 1b has
been intensively expanded by several research groups in recent
years using a diverse variety of interceptors to create a
multitude of heterocycles.2,3 While this type of cycloaddition
reaction is believed to require an unsaturated carbon-based
functional group at the 4-position to initiate the decarbox-
Figure 1. Previous work via C1 attack (a) and present work via C2 and
C3 attacks of a π-allyl Pd intermediate (b, c).
ylation, we extended the scope in 2018 to the 4-trifluoromethyl
(CF3) substituent.4 Specifically, 4-CF3 benzoxazinanone (1c)
Received: January 26, 2019
© XXXX American Chemical Society
A
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Letter
readily reacts with 2 under the similar Pd-catalyzed conditions
to provide 3-CF3-indolines (3c) (Figure 1a; X = CF3).4a The
highly electrophilic trifluoromethyl-substituted zwitterionic π-
benzyl Pd-intermediate Ic is proposed for the interceptive
decarboxylative benzylic cycloaddition (IDBC) reaction.
Independent of the specific reaction pathway (Figure 1a),
the nucleophile 2 always attacks at the same benzylic position
of 1 (C1-attack). To further expand this strategy, we were
interested in 4-trifluoromethyl 4-vinyl benzoxazinanone 4,
which contains a stereogenic tetrasubstituted carbon center.
Under Pd-catalyzed conditions, we envisioned that both CF3
and vinyl moieties should induce the decarboxylative cyclo-
addition of 4 with 2 to provide the corresponding 3-CF3-3-
vinyl-indolines 3d via the [4 + 1] cycloaddition. Consequently,
the tetrasubstituted carbon center of 4 should be preserved in
the indoline products (3d) (Figure 1b). However, the obtained
results differed significantly from our expectations. We herein
report the Pd-catalyzed decarboxylative cyclization of 4 with 2
to afford 2-substituted 4-trifluoromethyl-1,2-dihydroquinolines
(5) in good to high yield. Moreover, in the absence of 2, 2-
unsubstituted 4-trifluoromethyl-1,2-dihydroquinolines (6)
were obtained exclusively in high yield (Figure 1c). An
unexpected rare terminal C3-attack rather than the well-
established C1-attack is crucial for this transformation. It
should be noted that the corresponding methyl-analogues (7)
furnished exomethylene indoline (8) via a rare intramolecular
C2-attack.5
10% yield (entry 3) because of the high solubility of substrates
in DCM when compared to toluene.
With the optimal conditions for the formation of 5 in hand,
we examined the scope of this reaction by treating 4a with a
variety of sulfur ylides (2b−j). As shown in Scheme 1, all ylide
Scheme 1. Scope with Respect to the Sulfur Ylides (2) for
a
the Formation of 5 via Intermolecular Cyclization
To generate 3d, we initially attempted the reaction of 4a
with 2a under the best conditions reported for the reaction of
1c and 2 to give 3c,4a i.e., 5 mol % Pd2(dba)3·CHCl3 and 10
mol % PCy3 in CH2Cl2. However, under these conditions, only
complex mixtures were obtained (Table 1, entry 1). After
a
Experiments were carried out using 4a (0.15 mmol), 2b−j (0.30
mmol), and Pd(PPh3)4 (0.015 mmol) in 1.0 mL of dry toluene.
Isolated yields are shown together with 19F NMR yields using internal
standard PhCF3 in parentheses. In all cases, the intramolecular
cyclization products (6a) were formed in <20% yield.
Table 1. Optimization of the Reaction Conditions for the
Catalytic Decarboxylative Cyclization of 4a with 2a
derivatives were well tolerated under the applied reaction
conditions and the corresponding products (5ab−aj) were
obtained in moderate to good yield (≤84%). Substrates
bearing electron-donating groups such as 4-Me (2b) and 4-
MeO (2c) react smoothly to yield the desired products in
excellent yield (5ab, 82%; 5ac, 81%). Moreover, compounds
containing halogen substituents (2d, 4-F; 2e, 4-Cl; 2f, 4-Br)
were well tolerated and afforded the required CF3-1,2
dihydroquinolines in moderate to good yield (5ad, 72%; 5ae,
64%; 5af, 58%). Here, it should be noted that the product yield
decreases from 4-F substitution to 4-Br substitution.
Heteroaromatic sulfur ylides (2h, 2-furyl; 2i, 2-thiophenyl)
smoothly produced the desired products 5ah and 5ai in 52%
and 60% yield, respectively. Notably, cyclohexyl sulfur ylide 2j
efficiently delivered the corresponding trifluoromethyl 1,2-
dihydroquinoline in excellent yield (5aj, 84%). In all cases, the
intramolecular cyclization product (6a) was formed in <20%
yield.
a
5aa/6a
b
entry
1
Pd
solvent
ligand
(%)
5 mol % Pd2(dba)3·
CH2Cl2 10 mol % PCy3
−
CHCl3
2
3
10 mol % Pd(PPh3)4
10 mol % Pd(PPh3)4
toluene
CH2Cl2
−
−
82/16
10/70
a
Experiments were carried out using 4a (0.15 mmol), 2a (0.30
b
mmol), and Pd-source in 1.0 mL of dry solvent. Yields were
determined by 19F NMR spectroscopy using PhCF3 as an internal
standard.
extensive screening of combinations of palladium sources,
solvents, and ligands (Tables S1 and S2), the use of 10 mol %
Pd(PPh3)4 in toluene delivered the unexpected intermolecular
reaction product 4-(trifluoromethyl)-1,2-dihydroquinoline de-
rivative (5aa) in 82% yield instead of 3d, together with a small
amount of the intramolecular reaction product 6a (16% yield;
entry 2). An X-ray crystallography analysis of 5aa was carried
out to elucidate the solid-state structure of this unexpected
dihydroquinoline product (CCDC 1888925). It should be
noted that in CH2Cl2, under otherwise identical conditions,
the intra- vs intermolecular product distribution was reversed,
i.e., 6a was obtained in 70% yield, while 5aa was generated in
Furthermore, we examined the reaction scope with respect
to the CF3-vinyl benzoxazinanones; under the applied reaction
conditions, a variety of CF3-vinyl benzoxazinanone substrates
was well tolerated and resulted in the formation of the desired
CF3-1,2-dihydroquinolines in good yield (≤89%) (Scheme 2).
For example, methyl-substituted CF3-vinyl benzoxazinanone
4b reacted with different sulfur ylides 2 to yield the
corresponding products in low to moderate yield (5ba, 59%;
5bb, 65%; 5bd, 39%), whereas methoxy-substituted 4c
furnished the corresponding products in good yield (5ca,
69%; 5cb, 70%). In addition, substrates bearing chlorine (4d)
and fluorine (4e) substituents smoothly delivered the
B
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Scheme 2. Scope with Respect to CF3-Vinyl
Benzoxazinanones 4 for the Formation of 5
Scheme 3. Scope of CF3-Vinyl Benzoxazinanones 4 for the
Intramolecular Cyclization To Form 6
a
a
a
Experiments were carried out using 4a−l (0.15 mmol) and
Pd(PPh3)4 (0.015 mmol) in 1.0 mL of dry DCM. Yield percentages
refer to the isolated yield.
a
Experiments were carried out using 4b−f (0.15 mmol), 2a−d (0.30
Scheme 4. Subsequent Transformations of 5aa and 6g To
Demonstrate the Synthetic Utility of this Method
mmol), and Pd(PPh3)4 (0.015 mmol) in 1.0 mL of dry toluene.
Isolated yields are shown together with 19F NMR yields in
parentheses. In all cases, <20% of the intramolecular cyclization
products (6) were observed.
corresponding CF3-1,2-dihydroquinolines in good yields (5da,
75%; 5db, 80%; 5dc, 71%; 5ea, 70%). Compound 4f, which
contains an electron-withdrawing group (CF3) on the benzene
ring, was also well tolerated and afforded 5fa in excellent yield.
Subsequently, we turned our attention to the synthesis of
intramolecular cyclization products 6. Based on the results
obtained in Table 1 (entry 3), we used 10 mol % Pd(PPh3)4 in
CH2Cl2 in the absence of ylides for this transformation
(Scheme 3). As revealed in Scheme 3, CF3-vinyl benzox-
azinanones 4a−c, which contain electron-donating substituents
on the benzene ring (4b, Me; 4c, MeO) afforded the
intramolecular cyclization products in excellent yield (6a,
99%; 6b, 95%; 6c, 84%) under these reaction conditions.
Similarly, CF3-vinyl benzoxazinanones with electron-with-
drawing and halogen substituents (4f, CF3; 4d, Cl; 4e, F)
delivered the targeted products in good to excellent yield (6f,
90%; 6d, 84%; 6e, 97%). A variation of the vinyl group in CF3-
vinyl benzoxazinanones 4g−l also gave the corresponding
products in good to high yield (6g, 99%; 6h, 95%; 6i, 92%; 6j,
68%; 6k, 97%). It is noteworthy that pyridine-containing 4l
afforded CF3-1,2-dihydroquinoline 6l in 98% yield.
conditions resulted in the formation of complex mixtures,
while 4a furnished 5aa in 82% yield (Scheme 5a). Surprisingly,
the Pd-catalyzed intramolecular reaction of 7a in the absence
Scheme 5. Comparison of the Reaction Products Using
Methyl-Substituted Benzoxazinanones (7) Instead of CF3-
Benzoxazinanones (4) under Otherwise Identical Reaction
Conditions
To demonstrate the synthetic utility of the products, we
performed a couple of subsequent transformations as outlined
in Scheme 4. Intramolecular and intermolecular cyclization
reactions can be performed on the gram scale, and 5aa was
successfully reduced with NaBH4 to afford alcohol 9 in 90%
yield. The reaction of 6g with Mg in methanol resulted in the
formation of trifluoromethyl-substituted quinoline 10 in 93%
yield.
To understand the effect of the CF3 group on these
transformations, we carried out the same reactions using 4-
methyl-4-vinyl benzoxazinanones 7 instead of CF3-substrate
4a. The reaction of 7a with sulfur ylide 2a under the standard
C
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Letter
of sulfur ylide 2 proceeded differently and generated 2-methyl-
3-methylene-1-tosylindoline (8) in 95% yield (CCDC
1889136), while 4a was converted into 6a (Scheme 5b).
Moreover, 4-methyl-4-vinyl benzoxazinanone 7b, which
contains a styryl moiety, afforded the conjugated diene
product 11 in 91% yield, while CF3-analogue 4g was
transformed into 6g (Scheme 5c).
Pd-polarized aza-O-xylylenes Id′′ and VI (Figure 2c).
Although the electronic effect (CF3 vs Me) could also be
responsible for the change in selectivity (C1 vs C3), more
investigation including DFT calculation should be required for
further discussion.
In conclusion, we have disclosed a unique protocol that
delivers biologically attractive 1,2-dihydroquinolines7 5 and 6
in good yields from various CF3-vinyl benzoxazinanones 4 via
zwitterionic CF3-Pd-π-allyl intermediates. Interestingly, the
CF3 group plays a major role to obtain the corresponding
dihydroquinolines via a rare C3-terminal attack of the
zwitterionic π-allyl intermediate, whereas previously reported
reactions commonly proceed via a C1 attack. As fluorinated
heterocycles represent an important class of drug candidates,8
the present method can be considered as a useful addition to
the synthetic toolkit of medicinal chemists. On the other hand,
methyl-substituted benzoxazinanones (7) react differently and
afford products 8 and 11. The formation of 8 is also of great
importance, given that the reaction should proceed via a rare
C2-attack of the zwitterionic π-allyl intermediate. Details of the
reaction mechanism are currently under investigation using
DFT calculations, and the results will be reported in due
course.
Based on the obtained results in their entirety, we propose a
plausible mechanism for this reaction in Figure 2a. Initially, Pd-
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00330.
Synthesis and NMR spectra (PDF)
Accession Codes
CCDC 1888925 and 1889136 contain 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
■
Figure 2. Proposed reaction mechanism.
Corresponding Author
*E-mail: nozshiba@nitech.ac.jp.
ORCID
π-allyl zwitterionic intermediate Id could be formed by an
oxidative addition of the Pd(0) catalyst to the substrate 4a.
Consistent with previous reports,2d,4a sulfur ylide 2a could then
attack at the reactive allylic/benzylic C1 position, which would
be followed by an intramolecular [4 + 1] IDAC or IDBC
reaction to give the 3-allyl-3-trifluoromethyl indoline 3d (path
A). However, due to the steric hindrance of the CF3 moiety in
4a, 2a could also attack at the terminal C3 position of the
zwitterionic intermediate Id, which would lead to intermediate
II (path B).6 Upon elimination of the Me2S moiety,
intermediate III could be generated, which could undergo an
intramolecular Michael addition to form 1,2-DHQ 5aa. In the
absence of interceptor 2a, an intramolecular C3 attack from the
nitrogen to the terminal carbon atom would result in the
formation of the intramolecular cyclization product 6a (path
C). In the case of 7a, the zwitterionic π-allyl Pd-intermediate
Id′ would be isomerized to more stable endotype π-allyl Pd-
intermediate IV, and then the intramolecular cyclization would
proceed via a C2-attack of the nitrogen atom to afford
exomethylene indoline 8 (Figure 2b); styryl-substituted 7b
could furnish 11 by an extended conjugated elimination via
Norio Shibata: 0000-0002-3742-4064
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grants JP
18H02553 (KIBAN B) and JP 18H04401 (Middle Molecular
Strategy).
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