Diversity-Oriented Synthesis of Spiropentadiene Pyrazolones and 1 H-Oxepino[2,3- c]pyrazoles from Doubly Conjugated Pyrazolones via Intramolecular Wittig Reaction

Article abstract of DOI:10.1021/acs.orglett.0c01552

An efficient method for the diversity-oriented synthesis of spiropentadiene pyrazolones and 1H-oxepino[2,3-c]pyrazoles is reported. The methodology attributes O-acylation of phosphorus zwitterions which were formed by a tandem phospha-1,6-addition of PBu3 to α,β,γ,δ-unsaturated pyrazolones, further generating betaine intermediates that preferentially resulted in the aforementioned cyclic products in a diversity-oriented manner. The mechanistic investigations revealed that formation of the betaines is the key step to provide the products via an intramolecular Wittig reaction or an unprecedented δ-C-acylation/cyclization/Wittig reaction.

Full text of DOI:10.1021/acs.orglett.0c01552

pubs.acs.org/OrgLett
Letter
Diversity-Oriented Synthesis of Spiropentadiene Pyrazolones and
1H‑Oxepino[2,3‑c]pyrazoles from Doubly Conjugated Pyrazolones
via Intramolecular Wittig Reaction
Pankaj V. Khairnar, Chi-Yi Wu, Yi-Fang Lin, Athukuri Edukondalu, Yi-Ru Chen, and Wenwei Lin*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01552
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An efficient method for the diversity-oriented
synthesis of spiropentadiene pyrazolones and 1H-oxepino[2,3-
c]pyrazoles is reported. The methodology attributes O-acylation of
phosphorus zwitterions which were formed by a tandem phospha-
1,6-addition of PBu3 to α,β,γ,δ-unsaturated pyrazolones, further
generating betaine intermediates that preferentially resulted in the
aforementioned cyclic products in a diversity-oriented manner. The
mechanistic investigations revealed that formation of the betaines is
the key step to provide the products via an intramolecular Wittig
reaction or an unprecedented δ-C-acylation/cyclization/Wittig reaction.
Scheme 1. Previous Methods and Our Strategy for Diversity-
Oriented Synthesis
iversity-oriented synthesis is a potential approach to
Dgenerate vast libraries of small molecules with structurally
diversified skeletons, and it has attracted much attention to the
synthetic community due to its efficiency toward the
construction of valuable heterocycles in the area of drug
discovery.1 In recent years, the development of the Wittig
reaction led to multifaceted applications toward the diversity-
oriented synthesis of heteroarenes and heterocycles.2 Remark-
ably, the activation of remote positions to access the spiro and
fused compounds in a diversity-oriented manner is of foremost
interest.
Pyrazolone is a privileged heterocycle scaffold extensively
found in medicinally important compounds exhibiting a wide
range of biological and pharmacological activities.3 In particular,
4-spiro-5-pyrazolones act as promising pharmacophores,4 and
significant efforts have been focused on the synthesis of spiro six-
membered rings over the last several years.5 However, methods
to prepare five-membered ring bearing spiro-pyrazolones were
rarely explored.6 Recently, You, Yao, and Waldmann independ-
ently developed Rh-catalyzed (3 + 2) annulation reactions to
afford the spiropentadiene pyrazolones by employing pyrazo-
lone derivatives and alkynes in the presence of Cu(OAc)2
(Scheme 1a).7 On the other hand, the oxepine core is also
widely found in many molecules with pharmacological
importance, but the methods to construct oxepine ring
8
́
embedded heterocycles are scarcely reported. In 2014, Gulias
Received: May 6, 2020
and co-workers disclosed Rh-catalyzed (5 + 2) annulation
reaction for the synthesis of benzoxepines under the oxidative
conditions.9 This methodology further extended to generate the
spiro compounds via (3 + 2) annulation, relying on the steric
hindrance of the substrate (Scheme 1b).10 Owing to the
pharmacological importance of these highly appealing skeletons,
https://dx.doi.org/10.1021/acs.orglett.0c01552
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
the development of an efficient method that could generate both
of these privileged heterocycles in a diversity-oriented manner is
highly desirable.
Scheme 3. Scope of the (4 + 1) Annulation Reaction for 3
Our group has long been devoted toward the in situ
generation of phosphorus zwitterions or phosphonium salts
for their subsequent Wittig reaction.11 In continuation of the
legacy of our research, we were interested in the development of
new methods for the diversity-oriented synthesis of privileged
heterocycle scaffolds. In this context, we report a novel metal-
free method for the efficient synthesis of spiropentadiene
pyrazolones and 1H-oxepino[2,3-c]pyrazoles in a diversity-
oriented manner (Scheme 1c). It is worthy to note that the
method to construct the spiro compounds proceeds via an
unprecedented C-acylation at the remote δ-position of the
conjugated carbonyl compounds.
Our initial plan was to develop a new method for the synthesis
of oxepines 4 through a tandem phospha-1,6-addition/O-
acylation/Wittig reaction strategy. Accordingly, we examined
the reaction of the readily accessible α,β,γ,δ-unsaturated
pyrazolone 1a, PBu3, and PhCOCl (2a) in the presence of
Et3N at 30 °C. To our surprise, the spiropentadiene derivative
3aa was found along with the dephosphorated compound E/Z-
5aa (see the SI). In one instance, we realized that it would be the
C−O bond cleavage of the betaine which formed an initial δ-C-
acylated intermediate proceeding subsequent cyclization/Wittig
reaction sequence to result in such a viable outcome. Surprised
by the unprecedented δ-C-acylation/Wittig reaction sequence,
we started our investigation to find the optimal reaction
conditions. Upon screening of phosphines, different bases,
solvents, and various other factors (see the SI for the detailed
optimization), the optimal conditions were established as shown
in Scheme 2.
a
The reactions were carried out with 1 (0.3 mmol), PBu3 (1.1 equiv),
Et3N (1.5 equiv), and 2 (1.2 equiv) in dry CH3CN (3.0 mL) under
b
c
argon at 30 °C. Isolated yield. Gram scale of 1a (3 mmol, 1.082 g).
d
e
The numbers in parentheses refer to the yields of 4. The numbers in
parentheses refer to the NMR yield of the dephosphorated product 5.
f
g
h
Reaction at 70 °C. Acetic anhydride was used. Trifluoroacetic
i
anhydride was used. Benzoic anhydride was used.
ortho-position. For example, 2l (R5 = 2-OMeC6H4) was less
reactive with 1a at 30 °C, but the corresponding product 3al was
obtained in 86% yield at 70 °C within 3 h. In addition, to
examine the electronic effect in our protocol, a substrate bearing
4-NO2C6H4 (1g) with 2h was employed. To our delight, the
corresponding products 3gh and 4gh were obtained in 76% and
12% yields, respectively. When the ratios of 3ah/4ah (1:1) and
3gh/4gh (7:1) are compared, it clearly indicates that the strong
electron-withdrawing ability of NO2 group enhances the C−O
bond cleavage of betaine to result in a higher amount of the spiro
product.
Scheme 2. Optimal Conditions for 3aa
To understand the steric influence in the reaction, we have
constructed the molecular models for the formation of possible
betaine intermediates (Scheme 4 and the SI). The formation of
Having established the optimal reaction conditions, the scope
of the substrates was further investigated (Scheme 3). Substrates
bearing R1 as aliphatic groups 1a−1c reacted well with 2a to
furnish the desired products 3aa−3ca in up to 84% yields.
Unfortunately, our efforts to prepare starting materials bearing
R1 as an aryl group were unsuccessful. Furthermore, we
investigated the influence of R2 and R3 substituents. All of the
substrates 1d−1j furnished the spiro products 3da−3ja in
excellent yields, irrespective of the electronic and steric nature of
the substituent.
Scheme 4. Molecular Models for Betaine Intermediate
Formation
Next, we tested the various acyl chlorides 2 under the optimal
conditions to prepare a series of R5-substituted spiro products 3.
In general, aroyl chlorides bearing para- and meta-substituents
furnished the corresponding products 3ab−3ag in good to high
yields, regardless of the electronic nature. However, a significant
steric influence was noticed when the ortho-substituted aroyl
chlorides were tested in the reaction conditions. The sterically
hindered acyl chlorides 2h (R5 = 2-ClC6H4) and 2i (R5 = 2-
BrC6H4) have a pronounced effect on the selectivity of the
reaction outcome to afford nearly 1:1 ratio of the corresponding
spiro products 3ah−3ai and oxepines 4ah−4ai. We have also
found a significant electronic effect besides the steric influence at
the betaine II with pseudo-equatorial R5 is more favorable than
III with pseudo-axial R5, which further undergoes the C−O
bond cleavage to generate the spiro products 3. Presumably, I
with the less hindered R5 gives the preferred intermediate II,
leading exclusively to the spiro products 3. When an ortho-
substituted aroyl chloride, such as 2h or 2i, is subjected in the
B
https://dx.doi.org/10.1021/acs.orglett.0c01552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
reaction with 1a, it gives a more steric interaction of the ortho-
substituted aryl and its surrounded bulky ethyl ester and PBu3
groups of the betaine II. Therefore, it results in a lower difference
of energy levels of the provided betaines II and III, giving rise to
products 3 and 4 with lower selectivity. This interesting
phenomenon opens up the possibility to achieve two different
products in a diversity-oriented manner by the selection of acyl
chlorides.
Inspired by the results from the ortho-substituted aroyl
chlorides, we turned our attention to develop a method for the
synthesis of oxepino[2,3-c]pyrazoles 4 which is our initial
objective of O-acylation/Wittig reaction. To find the optimal
conditions, other factors such as solvent, base, and temperature
were evaluated (see the SI for the detailed optimization). It was
delightful to find that the oxepino[2,3-c]pyrazole 4ah was
obtained in 87% yield exclusively when 1a was treated with PBu3
and 2h in the presence of Et3N in Et2O at 70 °C in a sealed tube
(Scheme 5). The formation of the dephosphorated compound
steric hindrance is enhanced by the hindered acyl chlorides that
would drive the reaction toward the betaine III for the formation
of oxepines 4 (Scheme 4). Interestingly, the o-OMe aroyl
chloride 2l provided the oxepine 4al in only 32% yield along
with the spiro product 3al in 61% yield. Presumably, the OMe
group is smaller in size when compared with other o-aryl
substitutions, resulting in more amount of less hindered betaine
II.12 Although the role of the solvent is not clear, it could be
understood that in addition to the solvent effect, the steric
hindrance is crucial for the formation of the betaine III to result
in the desired products in good yields. Furthermore, a gram-
scale reaction of 1a could be performed under the same
conditions to afford 4ah in 81% yield, albeit after longer reaction
time.
In order to investigate the mechanism, we have performed
several control experiments (see the SI). We found that solvent
has a profound effect on the selective synthesis of spiro and
oxepine compounds along with the steric hindrance from the
acyl chloride. To find the intermediates, the reactions of
phosphonium zwitterion 6a with acyl chlorides 2a/2h have been
examined, and the progress of the reaction was monitored by 31P
NMR analysis.13 The zwitterion peak at 36.7 ppm was converted
into two peaks at 39.2/37.3 ppm in CH3CN or 39.0/37.3 ppm in
Et2O with different ratios by using acyl chloride 2a or 2h,
respectively (Figure 1). It could be understood that the
zwitterion would generate the O-acylated intermediates 7 in E
and Z forms which were further confirmed by the ESI-HRMS
analysis.
a,b
Scheme 5. Scope of the (6 + 1) Annulation Reaction for 4
a
The reactions were carried out with 1 (0.3 mmol), PBu3 (1.1 equiv),
Et3N (1.5 equiv), 2 (1.2 equiv) in dry Et2O (3.0 mL) at 70 °C in a
b
c
sealed tube. Isolated yield. Gram scale of 1a (3 mmol, 1.082 g).
d
The numbers in parentheses refer to the yields of 3.
E/Z-5 shows that the ylide I is not fully converted into the
products 3/4 under ambient conditions in Et2O. It clearly
indicates that the temperature is critical for providing oxepines 4
in high yields.
With optimal conditions in hand, we further investigated the
effect of different substitutions (R1−R4) of pyrazolone 1 with o-
chloroaroyl chloride 2h (Scheme 5). The reaction of substrates
(1b and 1c) bearing isopropyl and CH2CO2Et groups as R1 with
2h afforded the desired products 4bh and 4ch in excellent yields.
Regardless of the electronic and steric nature of the substituent,
substrates bearing different R2 and R3 groups, such as 1d−1j,
also furnished the corresponding products 4dh−4jh in up to
97% yields. Similar phenomena in regard with the electronic
effect on R2 were also observed in the cases of 1g and 2h. Under
our reaction conditions, the desired oxepine 4gh and the spiro
product 3gh were afforded in 61% and 31% yields, respectively,
whereas 1a and 2h gave only 4ah in 87% yield.
Figure 1. 31P NMR analysis of intermediates 6a and E/Z-7aa/7ah.
Furthermore, the effectiveness of our protocol was demon-
strated by employing our reported catalytic Wittig reaction
conditions with 1a and 2h in the presence of phosphine oxide 8
or 9 (Scheme 6a).14,15 To our delight, the desired oxepine 4ah
Scheme 6. Synthesis of 4ah and 10
Furthermore, various ortho-substituted aroyl chlorides were
investigated in the reaction conditions with 1a. The aroyl
chloride 2i (R5 = 2-BrC6H4) afforded the desired oxepine 4ai in
80% yield within 4 h. When 1-naphthyl and pentafluoroaryl acyl
chlorides (2j and 2k) were subjected to 1a, a similar trend as that
in Scheme 3 was observed but the selectivity was reversed in
Et2O. The corresponding oxepines 4aj and 4ak were obtained in
73% and 70% yields along with 15% and 21% yields of the spiro
products 3aj and 3ak, respectively. It clearly indicates that the
C
https://dx.doi.org/10.1021/acs.orglett.0c01552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 7. Plausible Mechanism for 3 and 4
was obtained in up to 53% yields in both reactions. We also
examined the reaction of terephthaloyl dichloride (2q) with 1a
under the standard conditions for synthesis of 3. Interestingly,
the product 10 bearing two spiro centers was afforded as a single
diastereomer in 54% yield (Scheme 6b).
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 Author
On the basis of the results and control experiments, a plausible
mechanism is depicted in Scheme 7. The reaction is initiated by
the phospha-1,6-addition of PBu3 at the δ-position of 1 to
generate the phosphorus zwitterion 6 that further undergoes O-
acylation to result in the phosphonium salts E/Z-7. The
deprotonation of E/Z-7 by Et3N furnishes ylide I, and further
intramolecular cyclization of I provides the betaines II and/or
III. The cleavage of the C−O bond of betaine II would facilitate
the formation of the δ−acylated enolic intermediate IV, which
upon subsequent cyclization and Wittig reaction leads to the
spiro product 3 via an intermediate V. On the other hand, when
the steric hindrance enhanced by the ortho-substituted aroyl
chlorides, betaine III is selectively generated in Et2O to further
proceed the Wittig reaction, furnishing the oxepine 4.
In summary, the efficient synthesis of spiropentadiene
pyrazolones and oxepino[2,3-c]pyrazoles was demonstrated in
a diversity-oriented manner. The reaction of α,β,γ,δ-unsaturated
pyrazolones, PBu3, and acyl chloride in the presence of Et3N
afforded the spiropentadiene pyrazolones in high yields via an
unprecedented phospha-1,6-addition/O-acylation/δ-C-acyla-
tion/cyclization/Wittig reaction sequence. In addition, a series
of oxepino[2,3-c]pyrazoles were prepared in good to high yields
via tandem phospha-1,6-addition/O-acylation/Wittig reaction.
Our investigations revealed that the nature of the solvent and the
steric hindrance of acyl chlorides dominated the preferential
formation of plausible betaines II or III, which plays a pivotal
role to result in the spiro or fused product, respectively. Further
investigations to employ this method for diversity-oriented
synthesis of other cyclic compounds are underway in our
laboratory.
■
Wenwei Lin − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan R.O.C.; orcid.org/
0000-0002-1121-072X; Email: wenweilin@ntnu.edu.tw
Authors
Pankaj V. Khairnar − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan R.O.C.;
orcid.org/0000-0001-8352-3314
Chi-Yi Wu − Department of Chemistry, National Taiwan Normal
University, Taipei 11677, Taiwan R.O.C.
Yi-Fang Lin − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan R.O.C.
Athukuri Edukondalu − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan R.O.C.;
orcid.org/0000-0003-4593-3843
Yi-Ru Chen − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan R.O.C.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01552
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology of
the Republic of China (MOST 107-2628-M-003-001-MY3) for
financial support.
REFERENCES
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01552.
■
■
(1) (a) Galloway, W. R.; Isidro-Llobet, A.; Spring, D. R. Diversity-
oriented synthesis as a tool for the discovery of novel biologically active
small molecules. Nat. Commun. 2010, 1, 80. (b) Burke, M. D.;
Schreiber, S. L. A planning strategy for diversity-oriented synthesis.
Angew. Chem., Int. Ed. 2004, 43, 46−58.
(2) (a) Khairnar, P. V.; Lung, T.-H.; Lin, Y.-J.; Wu, C.−Y.; Koppolu, S.
R.; Edukondalu, A.; Karanam, P.; Lin, W. An Intramolecular Wittig
Approach towards Heteroarenes: Facile Synthesis of Pyrazoles,
Isoxazoles and Chromenone-oximes. Org. Lett. 2019, 21, 4219−4223.
(b) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Phosphine
Organocatalysis. Chem. Rev. 2018, 118, 10049−10293. (c) Rocha, D.
H. A.; Pinto, D. C. G. A.; Silva, A. M. S. Applications of the Wittig
Reaction on the Synthesis of Natural and Natural-Analogue
sı
Optimization data, mechanistic studies, experimental
procedures, characterization data, and spectra of all
compounds (PDF)
Accession Codes
CCDC 1950758, 1972121, 1986342, 1995003, 1995844, and
1997280 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
D
https://dx.doi.org/10.1021/acs.orglett.0c01552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Heterocyclic Compounds. Eur. J. Org. Chem. 2018, 2018, 2443−2457.
(d) Yang, S.-M.; Wang, C.-Y.; Lin, C.-K.; Karanam, P.; Reddy, G. M.;
Tsai, Y.-L.; Lin, W. Diversity-Oriented Synthesis of Furo[3,2-
c]coumarins and Benzofuranyl Chromenones through Chemoselective
Acylation/Wittig Reaction. Angew. Chem., Int. Ed. 2018, 57, 1668−
1672. (e) Karanam, P.; Reddy, G. M.; Lin, W. Strategic Exploitation of
the Wittig Reaction: Facile Synthesis of Heteroaromatics and
Multifunctional Olefins. Synlett 2018, 29, 2608−2622.
Rissanen, K.; Raabe, G.; Enders, D. Asymmetric, Three-Component,
One-Pot Synthesis of Spiropyrazolones and 2,5-Chromenediones from
Aldol Condensation/NHC-Catalyzed Annulation Reactions. Chem. -
Eur. J. 2016, 22, 5123−5127. (d) Li, J.-H.; Du, D.-M. Phosphine-
Catalyzed Cascade Reaction of Unsaturated Pyrazolones with Alkyne
Derivatives: Efficient Synthesis of Pyrano[2,3-c]pyrazoles and Spiro-
cyclopentanone-pyrazolones. Adv. Synth. Catal. 2015, 357, 3986−3994.
(e) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu,
Y. Asymmetric Synthesis of Spiropyrazolones through PhosphineCa-
talyzed [4 + 1] Annulation. Angew. Chem., Int. Ed. 2014, 53, 5643−
5647.
(3) (a) Liu, S.; Bao, X.; Wang, B. Pyrazolone: a powerful synthon for
asymmetric diverse derivatizations. Chem. Commun. 2018, 54, 11515−
11529. (b) Chauhan, P.; Mahajan, S.; Enders, D. Asymmetric synthesis
of pyrazoles and pyrazolones employing the reactivity of pyrazolin-5-
one derivatives. Chem. Commun. 2015, 51, 12890−12907. (c) Hadi, V.;
Koh, Y.-H.; Sanchez, T. W.; Barrios, D.; Neamati, N.; Jung, K. W.
Development of the next generation of HIV-1 integrase inhibitors:
Pyrazolone as a novel inhibitor scaffold. Bioorg. Med. Chem. Lett. 2010,
20, 6854−6857. (d) Varvounis, G. Chapter 2 Pyrazol-3-ones. Part IV:
Synthesis and Applications. Adv. Heterocycl. Chem. 2009, 98, 143−224.
(e) Castagnolo, D.; De Logu, A.; Radi, M.; Bechi, B.; Manetti, F.;
Magnani, M.; Supino, S.; Meleddu, R.; Chisu, L.; Botta, M. Synthesis,
biological evaluation and SAR study of novel pyrazole analogues as
inhibitors of Mycobacterium tuberculosis. Bioorg. Med. Chem. 2008, 16,
8587−8591. (f) Manetti, F.; Magnani, M.; Castagnolo, D.; Passalacqua,
L.; Botta, M.; Corelli, F.; Saddi, M.; Deidda, D.; De Logu, A. Ligand-
Based Virtual Screening, Parallel Solution-Phase and Microwave-
Assisted Synthesis as Tools to Identify and Synthesize New Inhibitors
of Mycobacterium tuberculosis. ChemMedChem 2006, 1, 973−989.
(4) (a) Wang, L.; Yang, Z.; Ni, T.; Shi, W.; Guo, Y.; Li, K.; Shi, A.; Wu,
S.; Sheng, C. Discovery of pyrazolone spirocyclohexadienone
derivatives with potent antitumor activity. Bioorg. Med. Chem. Lett.
2020, 30, 126662−126666. (b) Ding, A.; Meazza, M.; Guo, H.; Yang, J.
W.; Rios, R. New development in the enantioselective synthesis of spiro
compounds. Chem. Soc. Rev. 2018, 47, 5946−5996. (c) Amata, E.;
Bland, N. D.; Campbell, R. K.; Pollastri, M. P. Evaluation of pyrrolidine
and pyrazolone derivatives as inhibitors of trypanosomal phosphodies-
terase B1 (TbrPDEB1). Tetrahedron Lett. 2015, 56, 2832−2835.
(d) Chande, M. S.; Barve, P. A.; Suryanarayan, V. Synthesis and
antimicrobial activity of novel spiro compounds with pyrazolone and
pyrazolthione moiety. J. Heterocycl. Chem. 2007, 44, 49−53.
(7) (a) Li, H.; Gontla, R.; Flegel, J.; Merten, C.; Ziegler, S.;
Antonchick, A. P.; Waldmann, H. Enantioselective Formal C(sp3)−H
Bond Activation in the Synthesis of Bioactive Spiropyrazolone
Derivatives. Angew. Chem., Int. Ed. 2019, 58, 307−311. (b) Zheng, J.;
Li, P.; Gu, M.; Lin, A.; Yao, H. Synthesis of Spiropentadiene
Pyrazolones by Rh(III)-Catalyzed Formal sp3 C−H Activation/
Annulation. Org. Lett. 2017, 19, 2829−2832. (c) Zheng, J.; Wang, S.-
B.; Zheng, C.; You, S.-L. Asymmetric Synthesis of Spiropyrazolones by
Rhodium-Catalyzed C(sp2)−H Functionalization/Annulation Reac-
tions. Angew. Chem., Int. Ed. 2017, 56, 4540−4544.
(8) (a) Gulías, M.; Marcos-Atanes, D.; Mascarenas, J. L.; Font, M.
̃
Practical, Large-Scale Preparation of Benzoxepines and Coumarins
through Rhodium(III)-Catalyzed C−H Activation/Annulation Reac-
tions. Org. Process Res. Dev. 2019, 23, 1669−1673. (b) Bakthadoss, M.;
Sivakumar, N.; Devaraj, A. Synthesis of benzoxepinopyrrolidines/
spiropyrrolidines via oxa-Pictet−Spengler and [3 + 2] cycloaddition
reactions. Tetrahedron Lett. 2015, 56, 4980−4983. (c) Narita, K.;
Nakamura, K.; Abe, Y.; Katoh, T. Total Synthesis of Bauhinoxepin J: A
Biologically Active Dibenzo[b,f ]oxepin Isolated from Bauhinia
purpurea. Eur. J. Org. Chem. 2011, 2011, 4985−4988. (d) Sprogoe,
K.; Manniche, S.; Larsen, T. O.; Christophersen, C. Janoxepin and
brevicompanine B: antiplasmodial metabolites from the fungus
Aspergillus janus. Tetrahedron 2005, 61, 8718−8721.
(9) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.; Gulías,
̃ ̃
M. Straightforward Assembly of Benzoxepines by Means of a
Rhodium(III)-Catalyzed C−H Functionalization of o-Vinylphenols. J.
Am. Chem. Soc. 2014, 136, 834−837.
(10) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.;
̃ ̃
(5) (a) Li, J. H.; Cui, Z.-H.; Du, D.-M. Diastereo- and enantioselective
construction of cyclohexanone-fused spirospyrazolones containing four
consecutive stereocenters through asymmetric sequential reactions.
Org. Chem. Front. 2016, 3, 1087−1090. (b) Chauhan, P.; Mahajan, S.;
Loh, C. C. J.; Raabe, G.; Enders, D. Streocontrolled Construction of Six
Vicinal Stereogenic Centers on Spiropyrazolones via Organocascade
Michael/Michael/1,2-Addition Reactions. Org. Lett. 2014, 16, 2954−
2957. (c) Li, J.-H.; Du, D.-M. Organocatalyzed Cascade Aza-Michael/
Michael Addition for the Asymmetric Construction of Highly
Functionalized Spiropyrazolone Tetrahydroquinolines. Chem. - Asian
J. 2014, 9, 3278−3286. (d) Zhang, J.-X.; Li, N.-K.; Liu, Z.-M.; Huang,
X.-F.; Geng, Z.-C.; Wang, X.-W. Enantioselective Synthesis of
Unsymmetrical Diaryl-Substituted Spirocyclohexanone pyrazolones
through a Cascade [4 + 2] Double Michael Addition. Adv. Synth. Catal.
2013, 355, 797−808. (e) Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano,
A.; Rios, R. Highly enantioselective cascade synthesis of spiropyr-
Gulías, M. Rhodium(III)-Catalyzed Dearomatizing (3 + 2) Annulation
of 2-Alkenylphenols and Alkynes. J. Am. Chem. Soc. 2014, 136, 7607−
7610.
(11) (a) Liou, Y.-C.; Su, Y.-H.; Ku, K.-C.; Edukondalu, A.; Lin, C.-K.;
Ke, Y.-S.; Karanam, P.; Lee, C.-J.; Lin, W. Organophosphane Promoted
Synthesis of Functionalized α,β-Unsaturated Alkenes and Furanones
via Direct β-Acylation. Org. Lett. 2019, 21, 8339−8343. (b) Liou, Y.-C.;
Karanam, P.; Jang, Y.-J.; Lin, W. Synthesis of Functionalized
Benzofurans from para-Quinone Methides via Phospha-1,6-Addition/
O-Acylation/Wittig Pathway. Org. Lett. 2019, 21, 8008−8012.
(c) Chen, Y.-R.; Reddy, G. M.; Hong, S.-H.; Wang, Y.-Z.; Yu, J.-K.;
Lin, W. Four-Component Synthesis of Phosphonium Salts: Application
Toward an Alternative Approach to Cross-Coupling for the Synthesis
of Bis-Heteroarenes. Angew. Chem., Int. Ed. 2017, 56, 5106−5110.
(d) Lee, C.-J.; Tsai, C.-C.; Hong, S.-H.; Chang, G.-H.; Yang, M.-C.;
̈
Mohlmann, L.; Lin, W. Preparation of Furo[3,2-c]coumarins from 3-
́
azolones. Org. Biomol. Chem. 2011, 9, 6519−6523. (f) Companyo, X.;
Cinnamoyl-4-hydroxy-2H-chromen-2-ones and Acyl Chlorides: A
Bu3P-Mediated C-Acylation/Cyclization Sequence. Angew. Chem., Int.
Ed. 2015, 54, 8502−8505. (e) Lee, C.-J.; Sheu, C.-N.; Tsai, C.-C.; Wu,
Z.-Z.; Lin, W. Direct β-acylation of 2-arylidene-1,3-indandiones with
acyl chlorides catalyzed by organophosphanes. Chem. Commun. 2014,
50, 5304−5306. (f) Tsai, Y.-L.; Fan, Y.-S.; Lee, C.-J.; Huang, C.-H.;
Das, U.; Lin, W. An efficient synthesis of trisubstituted oxazoles via
chemoselective O-acylations and intramolecular Wittig reactions.
Chem. Commun. 2013, 49, 10266. (g) Lee, C.-J.; Jang, Y.-J.; Wu, Z.-
Z.; Lin, W. Preparation of Functional Phosphorus Zwitterions from
Activated Alkanes, Aldehydes, and Tributylphosphine: Synthesis of
Polysubstituted Furo[3,2-c]coumarins. Org. Lett. 2012, 14, 1906.
(h) Kao, T.-T.; Syu, S.-e.; Jhang, Y.-W.; Lin, W. Preparation of
Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano, A.; Rios, R.
Organocatalytic synthesis of spiro compounds via a cascade
Michael−Michael-aldol reaction. Chem. Commun. 2010, 46, 6953−
6955.
(6) (a) Tan, C.-Y.; Lu, H.; Zhang, J.-L.; Liu, J.-Y.; Xu, P.-F.
Asymmetric Organocatalytic [4 + 1] Annulations Involving a Polarity
Reversal Process: A Tandem Catalytic Approach to Highly Function-
alized Spiropyrazolone Derivatives. J. Org. Chem. 2020, 85, 594−602.
(b) Hack, D.; Du
Rubenach, L.; Mertens, L.; Raabe, G.; Schoenebeck, F.; Enders, D.
̈
rr, A. B.; Deckers, K.; Chauhan, P.; Seling, N.;
̈
Asymmetric Synthesis of Spiropyrazolones by Sequential Organo- and
Silver Catalysis. Angew. Chem., Int. Ed. 2016, 55, 1797−1800. (c) Wang,
L.; Li, S.; Chauhan, P.; Hack, D.; Philipps, A. R.; Puttreddy, R.;
E
https://dx.doi.org/10.1021/acs.orglett.0c01552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Tetrasubstituted Furans via Intramolecular Wittig Reactions with
Phosphorus Ylides as Intermediates. Org. Lett. 2010, 12, 3066−3069.
(12) Belot, V.; Farran, D.; Jean, M.; Albalat, M.; Vanthuyne, N.;
Roussel, C. Steric Scale of Common Substituents from Rotational
Barriers of N-(o-Substituted aryl)thiazoline-2-thione Atropisomers. J.
Org. Chem. 2017, 82, 10188−10200.
(13) The reactions of zwitterion 6a with different acyl chlorides were
examined and monitored by 31P NMR and ESI-HRMS analysis (see the
Supporting Information for the experimental details).
(14) Lee, C.-J.; Chang, T.-H.; Yu, J.-K.; Reddy, G. M.; Hsiao, M.-Y.;
Lin, W. Synthesis of Functionalized Furans via Chemoselective
Reduction/Wittig Reaction Using Catalytic Triethylamine and
Phosphine. Org. Lett. 2016, 18, 3758−3761.
(15) We attempted to examine the reaction of 1a with 2a in the
presence of catalytic phosphine oxide 8/9 following our protocol in
CH3CN at 70 °C in a sealed tube. Unfortunately, in both the cases the
spiro product 3aa was generated in poor yields (see the Supporting
Information for the experimental details).
F
https://dx.doi.org/10.1021/acs.orglett.0c01552
Org. Lett. XXXX, XXX, XXX−XXX