Rh(III)-Catalyzed Regioselective Annulations of 3-Arylisoxazolones and 3-Aryl-1,4,2-dioxazol-5-ones with Propargyl Alcohols: Access to 4-Arylisoquinolines and 4-Arylisoquinolones

Article abstract of DOI:10.1021/acs.orglett.1c02049

The Rh(III)-catalyzed dual directing group assisted C-H activation/annulation of 3-arylisoxazolones with propargyl alcohols has been developed, which expands the application scope of isoxazolones in organic synthesis. This protocol also worked well with 3

Full text of DOI:10.1021/acs.orglett.1c02049

pubs.acs.org/OrgLett
Letter
Rh(III)-Catalyzed Regioselective Annulations of 3‑Arylisoxazolones
and 3‑Aryl-1,4,2-dioxazol-5-ones with Propargyl Alcohols: Access to
4‑Arylisoquinolines and 4-Arylisoquinolones
Tong-Tong Wang,∥ Hai-Shan Jin,∥ Man-Man Cao, Ru-Bing Wang,* and Li-Ming Zhao*
Cite This: Org. Lett. 2021, 23, 5952−5957
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ABSTRACT: The Rh(III)-catalyzed dual directing group assisted C−H activation/annulation of 3-arylisoxazolones with propargyl
alcohols has been developed, which expands the application scope of isoxazolones in organic synthesis. This protocol also worked
well with 3-aryl-1,4,2-dioxazol-5-ones to produce synthetically and biologically important 4-arylisoquinolones.
Scheme 1. Research Background
soxazolones are very interesting as valuable building blocks
in organic synthesis because of their diverse modes of
I
reaction.1 Consequently, significant advances have been made
in spirocyclization of activated methylene with polar multiple
bonds,2 transition-metal-catalyzed N−O bond insertions,3
decarboxylation of the isoxazolone ring,4 and arylideneisox-
azolone-based conjugated additions.5 However, isoxazolones
have rarely been explored as directing groups in the field of C−
H functionalization. In 2020, Cui et al. described a Rh(III)-
catalyzed ring-opening/C−H bond annulation of 3-arylisox-
azolone with maleimides (Scheme 1a).6 Recently, Shang et al.
developed the Rh(III)-catalyzed cascade C−H activation/
cyclization of 3-arylisoxazolones with cyclic 2-diazo-1,3-
diketones (Scheme 1b).7 Despite impressive innovations,
both reactions are limited to the chemistry of 3-arylisox-
azolones with nonalkyne coupling partners for the synthesis of
isoquinoline-fused polycyclic compounds. Arguably, annula-
tion reactions with alkynes are one of the most popular
methods of this type.8 However, reports on this type of
reactions with alkynes are rather rare. To the best of our
knowledge, so far only one example of cascade C−H
activation/annulation of 3-arylisoxazolones with alkyne cou-
pling partners was described. The pioneering work by Chiba
reported a Rh(III)-catalyzed C−H activation/annulation of
aryl ketone O-acyloxime with internal alkynes to access
quinolines. Further, they extended the methodology to 3-
arylisoxazolones by employing isoxazolones as a directing
group (Scheme 1c).9 Despite this elegant achievement, some
important challenges are far from being addressed. The scope
of internal alkynes as a coupling partner is still limited (mainly
symmetrical diphenylacetylene). Further, regioselectivity of the
insertion step is an unsolved problem when an unsymmetrical
Received: June 18, 2021
Published: July 29, 2021
https://doi.org/10.1021/acs.orglett.1c02049
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5952−5957
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a
alkyne is involved in the reaction, in which the nucleophile
always adds to the phenyl-substituted alkyne carbon atom.
Motivated by the aforementioned information and in line with
our ongoing interest in C−H functionalization,10 we decided
to explore the possibility of designing a new C−H activation/
annulation of 3-arylisoxazolones to reverse the regioselectivity
of alkyne insertion (Scheme 1d).
Table 1. Optimization of the Reaction Conditions
Propargyl alcohols are important classes of functionalized
alkynes with an inherent hydroxyl group that can be easily
accessible from terminal alkynes and carbonyl compounds.11
There are a few reports of using tertiary propargyl alcohol such
as 2-methyl-4-phenylbut-3-yn-2-ol as a coupling partner with
different directing groups (DGs) to obtain benzo-fused
heterocyclic compounds in transition-metal-catalyzed C−H
functionalization.12 As seen from these reports, one of the
advantages of using this kind of functionalized alkynes as a
coupling partner is the binding affinity potential of the
hydroxyl group with the transition-metal catalyst which can
control the regioselectivity for the insertion of unsymmetrical
alkyne.13 Inspired by these pioneering works, we envisioned an
isoxazolone-directed C−H activation reaction with propargyl
alcohols that can lead to a simple ring-opening/C−H bond
activation followed by regioselective intramolecular annulation,
where isoxazolone can function as a traceless DG paving the
way to the formation of 3-hydroxyalkyl-4-arylisoquinoline
derivatives and the hydroxyl group of propargyl alcohol can
provide an interaction with metal catalyst as the second
traceless DG to control the regioselectivity of the reaction
(Scheme 2).
temp
time
(h)
b
c
entry catalyst
additive
solvent
(°C)
yield (%)
1
A
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
Zn(OAc)2
AgOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
TFE
60
60
60
60
60
60
60
60
40
25
40
40
40
40
40
2
2
2
2
2
2
2
2
4
14
4
4
4
4
NR
NR
NR
54
61
58
2
B
3
4
5
6
7
8
9
10
11
12
13
14
15
C
D
D
D
D
D
D
D
D
D
D
D
D
57
65
70
d
80 (61)
37
50
54
46
65
MeOH
THF
DCM
4
a
Reactions were conducted with 1a (0.1 mmol), 2a (0.15 mmol),
b
catalyst, and additive in solvent (1.5 mL). Catalyst A = [RuCl2(p-
cymene)]2. Catalyst B = Cp*Co(CO)I2. Catalyst C = [Cp*IrCl2]2.
c
d
Catalyst D = [Cp*RhCl2]2. Isolated yields. 1.0 mmol scale reaction.
Scheme 2. Dual DG-Assisted Regioselective Annulation of
3-Arylisoxazolones with Propargyl Alcohols
(entry 8). Encouraged by these results, we lowered the
reaction temperature successively (entries 9 and 10). The
results showed that the reaction could proceed smoothly under
more mild conditions. At 25 °C, the product yield was 80%,
although the reaction required 14 h reach completion (entry
10). Other reaction parameters were also evaluated, but with
no further improvement. For instance, other solvents,
including MeCN, trifluoroethanol (TFE), MeOH, tetrahy-
drofuran (THF), and dichloromethane (DCM), all led to low
yields (entries 11−15 vs entry 9). Thus, the conditions of entry
10 were selected as the optimal conditions. To showcase the
scalability of this method, a 1.0 mmol scale version of the
model reaction was then examined. Without further
optimization, the product 3aa was obtained in 61% yield
(entry 10).
Under the optimized conditions, the scope of this trans-
formation was investigated (Scheme 3). First, the suitability of
3-aryl-5-isoxazolones 1 was examined by using 2-methyl-4-
phenylbut-3-yn-2-ol 2a as a model substrate. As shown in
Scheme 3, various para-substituted 3-aryl-5-isoxazolones 1b−
1f bearing an electron-donating alkoxyl (OMe) and alkyl (Me)
or electron-withdrawing halogen (F, Cl, and Br) substituents
could react with 2a smoothly to furnish cyclization products
3ba−3fa in good yields. Moreover, the trifluoromethyl group,
as a useful structural motif in many biologically active
molecules,14 also afforded the corresponding product 3ga,
albeit with low yield. The low yield could be due to the
strongly electron-withdrawing effect of the CF3 group. Besides
para-substituted 3-aryl-5-isoxazolones, meta- and ortho-sub-
stitutions were also well tolerated in this reaction. For example,
the introduction of a phenyl ring with a m-methyl or m-
bromine group allowed the annulation reaction to give the
products 3ha and 3ia with excellent regioselectivity in 65 and
Initially, we conducted a test reaction between 3-phenyl-5-
isoxazolone 1a and 2-methyl-4-phenylbut-3-yn-2-ol 2a with 5
mol % catalysts [RuCl2(p-cymene)]2/ Cp*Co(CO)I2/
[Cp*IrCl2]2 and additive NaOAc (1.0 equiv) at 60 °C for 2
h in dichloroethane (DCE), which did not afford the expected
product (Table 1, entries 1−3). Fortunately, attempts with 5
mol % of the [Cp*RhCl2]2 catalyst in the place of other
catalysts along with the aforementioned reaction conditions led
to the desired product 3aa in 54% yield (entry 4). In the crude
NMR of this reaction, no regioisomer of 3aa was observed,
thus confirming the regioselectivity of the reaction. A
subsequent nuclear Overhauser effect (NOE) experiment
further confirmed the position of the tertiary alcohol at C-3.
The structure of 3aa was further confirmed by single-crystal X-
ray diffraction analysis (CCDC 2088321). When other
additives such as KOAc, Zn(OAc)2, AgOAc, and CsOAc
(entries 5−8) were used as the additive, the reaction worked
better, producing 3aa in 57−65% yield. Among them, CsOAc
was the most effective one for the reaction with 65% yield
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substituted 5-isoxazolones such as 4-methyl-3-phenylisoxazo-
lone are not suitable reaction substrates currently because their
reactions with 2a did not give synthetically significant yields of
products under the present conditions.
Scheme 3. Substrate Scope for the Synthesis of 4-
Arylisoquinolines
a
After realizing the construction of 4-arylisoquinolines
through the simple cascade C−H activation/annulation, we
conceived that the variation of the DG on the phenyl ring of
compound 1 (from isoxazolone to dioxazolone) may result in
the formation of 4-arylisoquinolone (Scheme 4). We initially
Scheme 4. Substrate Scope for the Synthesis of 4-
a
Arylisoquinolones
a
Reactions were run on 0.1 mmol scale under the optimal conditions.
Yields for isolated products.
56% yields, respectively. For 1 bearing an ortho-substituent
such as 1j and 1k, the reaction also took place regioselectively
on the less hindered ortho site to give 3ja and 3ka. We next set
out to evaluate the tolerance of various propargyl alcohols 2 to
our optimized reaction conditions. The results showed that
while propargyl alcohols bearing electron-donating (2b, 2c, 2g,
and 2h) and electron-withdrawing (2d−2f) substituents on the
phenyl ring were all suitable substrates to form the 4-
arylisoquinoline products, the use of substituted propargyl
alcohols leads to lower yields of the products (37−55%) when
compared to the unsubstituted propargyl alcohol 2a. When a
2-thienyl propargyl alcohol (2i) was subjected to the optimal
reaction conditions, the reaction still work well to deliver the
product 3ai in 61% yield. The coupling reaction could also be
extended to include propargyl alcohol 2j bearing a cyclohexyl
group as the R2 and R3 moieties, in which the reaction
proceeded smoothly under standard reaction conditions to
form compound 3aj in 54% yield. To see if the reaction is
suitable for other R2 and R3 units, the standard conditions were
applied to 2,4-diphenylbut-3-yn-2-ol 2k and 1,1,3-triphenyl-
prop-2-yn-1-ol 2l. However, neither of them gave the desired
product, probably due to the steric hindrance effect. Finally,
various substituted 3-aryl-5-isoxazolones 1 and propargyl
alcohols 2 were subjected to the above optimal reaction
conditions. To our delight, when there were substituents on
both phenyl rings, the reaction could also produce the target
products 3be, 3eb, and 3cc in good yields. Unfortunately, 4-
a
Reactions were run on 0.1 mmol scale under the optimized
b
conditions. Yields for isolated products. 1.0 mmol scale reaction.
attempted to react 3-phenyl-1,4,2-dioxazol-5-one 4a with 2a
using the developed protocol. Fortunately, our methodology is
equally efficient for the synthesis of 4-arylisoquinolone systems
and the desired product 5aa could be prepared in good yield
by a slight modification of the experimental procedure. While
performing this study, it was found that the yield was actually
higher when the reaction was carried out in TFE solvent
compared with other solvents, so all of the reactions with
dioxazolones 4a−4l were run in TFE. As shown in Scheme 4,
when 3-phenyl-1,4,2-dioxazol-5-ones bearing various substitu-
ents were used as the substrate, the corresponding 4-
arylisoquinolones were also obtained in good yield. We
examined both electron-donating and electron-withdrawing
groups on both aromatic rings in a manner similar to the
investigation of 4-arylisoquinolines (Scheme 3). Various
substrates with different substituents at the aromatic rings of
1,4,2-dioxazol-5-ones and propargyl alcohols were easily
converted to the corresponding cyclization products in
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moderate to good yields. It is worth noting that multi-
substituted 3-phenyl 1,4,2-dioxazol-5-one 4k and heterocyclic
3-(thiophen-2-yl)-1,4,2-dioxazol-5-one 4l were all uneventfully
accommodated. However, no desired products 5ia and 5ja
were observed when using the substrate possessing an ortho
substituent at the phenyl ring (4i and 4j), probably attributed
to the ortho-position effect of the substituent.
group in the propargyl alcohol is essential for the selective
formation of 4-aryl-substituted products 3 and 4. On the other
hand, primary alcohol 2o also resulted in contrary
regioselectivity compared with tertiary alcohols, affording 3-
phenyl-substituted product 10. This result showed that the
steric hindrance between gem-dimethyl and the C5-H of the
substrates 1 and 4 might also be another reason for the
regioselectivity in the present reaction.13b,15
On the basis of the experimental data obtained from control
experiments and previous reports on Rh-catalyzed C−H
activation reactions,13,16 a possible reaction mechanism was
proposed (Scheme S1). Initially, the reaction of [Cp*RhCl2]2
complex with CsOAc forms an active catalyst Cp*Rh(OAc)2
A. Next, coordination of the nitrogen atom of the substrate 1
to A then undergoes a C−H activation to afford the five-
membered rhodacycle B. The regioselective coordinative
insertion of propargyl alcohol 2 into the C−Rh bond of
complex B affords a seven-membered rhodacycle D, which
would undergo the reductive elimination to generate
intermediate E and rhodium(I) species. The intermediate E
can be oxidized by the O−N bond to form rhodium(III)
species F which is protonated to furnish the 4-arylisoquinoline
3 and regenerates the active catalyst for the next catalytic cycle.
On the other hand, it should be noted that Glorius et al. have
proposed an alternative mechanism for these kinds of systems
where N−O bond cleavage occurs before reductive elimination
to give a Rh(V) nitrene intermediate.17
To highlight the synthetic utility of this methodology,
several chemical transformations were carried out (Scheme 5).
Scheme 5. Further Transformations
In summary, we have developed an efficient Rh(III)-
catalyzed C−H activation/annulation reaction between tertiary
propargyl alcohols and 3-arylisoxazolones or 3-aryl-1,4,2-
dioxazol-5-ones, which involves the significant challenges
associated with controlling regioselectivity for the insertion
of unsymmetrical alkyne. The hydroxyl group at the propargyl
alcohol moiety behaved as the second traceless DG to control
the regioselectivity of the reaction, leading to the selective
formation of 3-hydroxyalkyl-4-arylisoquinoline or 4-arylisoqui-
nolone derivatives rather than the 3-arylisoquinoline or 3-
arylisoquinolone ones. To the best of our knowledge, this
represents the first example of regioselective coupling between
alkynes and 3-arylisoxazolones or 3-aryl-1,4,2-dioxazol-5-ones.
Treatment of 3-hydroxyalkyl-4-phenylisoquinoline 3aa with
BF3·OEt2 in DCE at 100 °C afford fused polycyclic compound
6 in 91% yield. In addition, N-oxide 7 can be readily obtained
by m-chloroperoxybenzoic acid (m-CPBA) oxidation of the
parent isoquinoline 3aa in DCM. The cyclization reaction of
5aa was also achieved by BF3·OEt2 in DCE to give compound
8 in 80% yield.
To gain more insights into the effect of the hydroxyl group
for these transformations, several control experiments were
conducted (Scheme 6). A control experiment between 1a and
1-(prop-1-ynyl)benzene 2m led to the formation of 3-phenyl-
substituted product 9 with contrary regioselectivity compared
with progargyl alcohols. When 2-methyl-4-phenylbut-3-yn-2-yl
acetate 2n was subjected to the standard conditions, no
reaction was observed. These results showed that the hydroxyl
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02049.
Experimental procedures, characterization data, copies of
NMR spectra of compounds, and X-ray crystal structure
of 3aa (PDF)
Scheme 6. Control Experiments
Accession Codes
CCDC 2088321 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 Authors
■
Ru-Bing Wang − State Key Laboratory of Bioactive Substance
and Function of Natural Medicines, Institute of Materia
Medica, Chinese Academy of Medical Sciences and Peking
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Union Medical College, Beijing 100050, China;
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Letter
Kohigashi, S.; Ohe, K. Palladium-catalyzed decarboxylative intra-
molecular aziridination from 4H-isoxazol-5-ones leading to 1-
azabicyclo[3.1.0]hex-2-enes. Angew. Chem., Int. Ed. 2011, 50, 11470.
(c) Okamoto, K.; Shimbayashi, T.; Tamura, E.; Ohe, K. Palladium-
Catalyzed Aza-Wittig-Type Condensation of Isoxazol-5(4H)-ones
with Aldehydes. Chem. - Eur. J. 2014, 20, 1490.
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C.; Palombi, L.; Massa, A. On the Necessity of One-Pot Tautomer
Trapping in Asymmetric Michael Reactions of Arylideneisoxazol-5-
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P.; Laviós, A.; Sanz-Marco, A.; Vila, C.; Pedro, J. R.; Blay, G.
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Benzylideneisoxazol-5(4H)-one Derivatives and Isocyanoacetate
Esters. Adv. Synth. Catal. 2020, 362, 3564.
(6) Wan, T.; Pi, C.; Wu, Y.-J.; Cui, X.-L. Rh(III)-Catalyzed [4 + 2]
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(7) Hu, W.; He, X.; Zhou, T.; Zuo, Y.; Zhang, S.; Yang, T.; Shang, Y.
Construction of isoxazolone-fused phenanthridines via Rh-catalyzed
cascade C-H activation/cyclization of 3-arylisoxazolones with cyclic 2-
diazo-1,3-diketones. Org. Biomol. Chem. 2021, 19, 552.
Email: wangrubing@imm.ac.cn
Li-Ming Zhao − School of Chemistry and Materials Science,
Jiangsu Normal University, Xuzhou 221116 Jiangsu, China;
State Key Laboratory of Bioactive Substance and Function of
Natural Medicines, Institute of Materia Medica, Chinese
Academy of Medical Sciences and Peking Union Medical
College, Beijing 100050, China; orcid.org/0000-0002-
7917-8754; Email: lmzhao@jsnu.edu.cn
Authors
Tong-Tong Wang − School of Chemistry and Materials
Science, Jiangsu Normal University, Xuzhou 221116 Jiangsu,
China
Hai-Shan Jin − School of Chemistry and Materials Science,
Jiangsu Normal University, Xuzhou 221116 Jiangsu, China
Man-Man Cao − School of Chemistry and Materials Science,
Jiangsu Normal University, Xuzhou 221116 Jiangsu, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02049
(8) (a) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Formal [4 + 1]
Annulation Reactions in the Synthesis of Carbocyclic and
Heterocyclic Systems. Chem. Rev. 2015, 115, 5301. (b) Zhu, R.-Y.;
Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. A Simple and Versatile Amide
Directing Group for C-H Functionalizations. Angew. Chem., Int. Ed.
2016, 55, 10578.
Author Contributions
∥T.-T.W. and H.-S.J. contributed equally.
Notes
The authors declare no competing financial interest.
(9) Too, P. C.; Wang, Y.-F.; Chiba, S. Rhodium(III)-Catalyzed
Synthesis of Isoquinolines from Aryl Ketone O-Acyloxime Derivatives
and Internal Alkynes. Org. Lett. 2010, 12, 5688.
(10) (a) Wang, Y.-J.; Wang, T.-T.; Yao, L.; Wang, Q.-L.; Zhao, L.-M.
Access to 4-Alkenylated Coumarins via Ruthenium-Catalyzed Olefinic
C-H Alkenylation of Coumarins with Modifiable and Removable
Directing Groups. J. Org. Chem. 2020, 85, 9514. (b) Du, Y.-Z.; Wang,
Y.-J.; Zhao, Q.-Y.; Zhao, L.-M. Selective Synthesis of 5-Alkylated and
5-Alkenylated Chromones via Catalytic C-H Coupling of Chromones
with Allyl Alcohols. Eur. J. Org. Chem. 2021, 2021, 2411.
ACKNOWLEDGMENTS
■
This work was supported by the Science and Technology
Support Program of Jiangsu Province (BE2017643) and State
Key Laboratory of Bioactive Substance and Function of
Natural Medicines, Institute of Materia Medica, Chinese
Academy of Medical Sciences and Peking Union Medical
College (GTZK201905).
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