Organophosphane-catalyzed direct β-acylation of 4-arylidene pyrazolones and 5-arylidene thiazolones with acyl chlorides

Article abstract of DOI:10.1021/acs.orglett.0c02408

An efficient method for the direct β-acylation of arylidene pyrazolones and thiazolones with acyl chlorides in the presence of a base catalyzed by organophosphanes is reported. A variety of functionalized 4-arylidene pyrazolone and 5-arylidene thiazolone derivatives were prepared under metal-free and mild conditions via a tandem phospha-Michael addition/O-acylation/intramolecular cyclization/rearrangement sequence. Our mechanistic investigations revealed that the reaction is highly stereospecific to provide exclusively cis-isomers, and the methodology can also be scaled up with similar efficacy.

Full text of DOI:10.1021/acs.orglett.0c02408

pubs.acs.org/OrgLett
Letter
Organophosphane-Catalyzed Direct β‑Acylation of 4‑Arylidene
Pyrazolones and 5‑Arylidene Thiazolones with Acyl Chlorides
Pankaj V. Khairnar, Yin-Hsiang Su, Yung-Chang Chen, Athukuri Edukondalu, Yi-Ru Chen,
and Wenwei Lin*
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ABSTRACT: An efficient method for the direct β-acylation of arylidene pyrazolones and thiazolones with acyl chlorides in the
presence of a base catalyzed by organophosphanes is reported. A variety of functionalized 4-arylidene pyrazolone and 5-arylidene
thiazolone derivatives were prepared under metal-free and mild conditions via a tandem phospha-Michael addition/O-acylation/
intramolecular cyclization/rearrangement sequence. Our mechanistic investigations revealed that the reaction is highly stereospecific
to provide exclusively cis-isomers, and the methodology can also be scaled up with similar efficacy.
Scheme 1. (a) Phospha-1,6-addition for Annulations6 and (b)
rganophosphane-catalyzed reactions are ubiquitous in
Phospha-1,4-addition for β-Acylation
Oorganic synthesis due to their potential to construct a wide
range of natural products and biologically active molecules.1
Due to the inevitable discoveries in the area of phosphine
catalysis, it emerged as a powerful tool for the synthesis of
valuable heteroarenes and heterocycles in drug discovery.2 In
contrast, the direct transformation of electron-deficient non-
functionalized alkene C−H bonds into C−C bonds is a
fundamental challenge and has substantial benefits in synthetic
organic chemistry.3 Consequently, significant efforts have been
made to develop elegant methods for the generation of C−C
bonds by utilizing transition-metal catalysts and organometallic
reagents.4 Because of the eminence of this transformation, the
development of efficient methods under mild and metal-free
conditions is highly desirable.
Pyrazolones are privileged heterocycle scaffolds possessing
important biological and pharmacological activities, and their
the results for providing the direct β-acylated products instead of
the annulation reactions are quite different.6,7 Previously, we
chemistry has been extensively studied over the past few
decades.5 Very recently, we have demonstrated a novel method
have also reported the direct β-acylation of 1,3-dicarbonyl
compounds such as 1,3-indanediones, acyclic 1,3-diketones, and
for the preferential synthesis of the spiropentadiene pyrazolones
and 1H-oxepino[2,3-c]pyrazoles in a diversity-oriented manner
by a tandem phospha-1,6-addition of PBu3 to doubly conjugated
anhydrides with acyl chlorides in the presence of base promoted
by the organophosphanes.8 In this context, we report a method
pyrazolones in the presence of acyl chlorides and Et3N via (4+1)
and (6+1) annulation reactions (Scheme 1a).6 As a continuation
Received: July 19, 2020
of our effort toward the exploration of organophosphane
chemistry,7 we were interested in the extension of this reaction
to the phospha-1,4-addition of phosphine to appropriately
designed α,β-unsaturated arylidene pyrazolones, and other
heterocyclic compounds such as thiazolones. To our surprise,
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Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
for the synthesis of functionalized pyrazolones and thiazolones
from the corresponding α,β-unsaturated arylidene heterocyclic
compounds, and acyl chlorides catalyzed by a tertiary phosphine
via direct β-acylation (Scheme 1b).
diffraction analysis further unambiguously confirmed the
structure of product 3aa as in the exclusive Z-isomer.9
Having established the optimal conditions, we set out to
explore the scope of the direct β-acylation reaction (Scheme 2).
Initially, we started our investigation by treating 4-
benzylidene pyrazolone derivative (1a) with PBu3 (1.1 equiv)
and benzoyl chloride (2a, 1.2 equiv) in the presence of Et3N (1.5
equiv) in THF at 30 °C (entry 1, Table 1). The product cis-(Z)-
Scheme 2. Synthesis of Functionalized Pyrazolones 3 via β-
Acylation
a,b
a
Table 1. Optimization for β-Acylation of Pyrazolone 3aa
b
entry
PR3
PBu3
PBu3
base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA
DBU
DABCO
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
solvent
t (h)
3aa (%)
c
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
Et2O
EtOAc
THF
THF
8
8
8
10
6
6
10
6
6
4
8
8
10
6
10
8
58
57
84
72
92
94
2
2
3
4
5
6
7
8
9
PMe2Ph
PEt2Ph
PPh2Et
PPh2Me
PPh3
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
99
d
10 (70)
12 (60)
d
10
11
12
13
14
59
89
85
90
82
86
a
The reactions were carried out with 1 (0.2 mmol), PPh2Me (20 mol
%), DIPEA (1.5 equiv), and R4COCl 2 (1.2 equiv) in dry THF (2.0
mL) under an argon atmosphere at 30 °C. Isolated yield. Overall
yield of product (E/Z)-3. The E:Z ratio of 3 is 1:6. TFAA (2.0
b
c
d
e
e
15
f
equiv) was used.
16
a
The reactions were carried out with compound 1a (0.2 mmol), PR3
(20 mol %), a base (1.5 equiv), and PhCOCl (2a) (1.2 equiv) in a dry
At first, different substitutions (R1−R3) on 4-arylidene
pyrazolones 1 were examined under the reaction conditions.
b
solvent (2.0 mL) under an argon atmosphere at 30 °C. The yield of
product 3aa was determined by NMR analysis of the crude reaction
i
Substrates 1a−1d bearing Me, Pr, CF3, and Ph groups as R1
c
mixture using Ph3CH as an internal standard. PBu3 (1.1 equiv) was
d
e
substituents reacted with PhCOCl (2a) to afford β-acylated
products 3aa−3da, respectively, in good to excellent yields. We
also tested the various R2 and R3 substituents of the substrates
under the standard conditions. Regardless of the electronic and
steric influence of the substituent, all of the substrates 1e−1k
furnished the desired products 3ea−3ka, respectively, in high
yields. Interestingly, with heteroaryl R3 substituents of substrates
1l−1n (R3 = 2-furyl, 2-thienyl, and 3-thienyl) subjected to 2a,
the corresponding products 3la−3na were obtained in a 1:2
mixture of the E- and Z-isomers with excellent overall yields.
Fortunately, the E- and Z-isomers of products 3la−3na can be
easily separated, and their structures were further confirmed by
X-ray diffraction analysis.9 Surprised by the formation of the
unexpected trans isomer in our protocol, which is the
stereospecific reaction according to the proposed mechanism,
we examined further control experiments (see Scheme 3).
used. The numbers in parentheses refer to the yields of 1a. PPh2Me
f
(10 mol %) was used. Addition sequence: PPh2Me, PhCOCl (2a),
and DIPEA.
3aa was obtained in 58% yield in 8 h under the Wittig reaction
conditions. After extensive characterization,9 we realized that it
is a β-acylated product cis-(Z)-3aa instead of a Wittig product.
For instance, we decided to perform a reaction of 1a with 2a
under the catalytic conditions of PBu3. To our delight, 20 mol %
PBu3 also furnished product 3aa in yields similar to the
stoichiometric amount of PBu3 (entry 2). Several other
phosphines have also been examined (entries 3−7), and most
of them performed well; PPh2Me was found to be the best to
afford 3aa in 94% yield within 6 h (entry 6). To identify the
optimal conditions, different bases and various solvents were
screened (entries 8−14). Gratifyingly, product 3aa was found in
99% yield by using N,N-diisopropylethylamine (DIPEA) as a
base in THF (entry 8). With a further decrease in the level of
PPh2Me to 10 mol %, the reaction provided an only 82% yield of
product 3aa in 10 h (entry 15). Evaluation of other factors such
as equivalents of base, 2a, and addition sequence (entry 16; see
the Supporting Information for detailed optimization) estab-
lished the optimal conditions for 3aa as listed in entry 8. X-ray
Scheme 3. Control Experiments for E/Z Phenomenon of 3la
B
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Furthermore, different acyl chlorides 2 were also investigated
under the standard reaction conditions. In general, all of the acyl
chlorides reacted well with 1a to furnish the desired products in
high yields, irrespective of the electronic and steric nature of the
substituent. Interestingly, acyl chlorides 2k and 2l bearing
heteroaryl groups such as 2-furyl and 2-thienyl groups were well-
tolerated in the reaction, furnishing products 3ak and 3al,
respectively, in ≤96% yields with a 1:6 ratio of the E/Z-isomers,
where a similar phenomenon was also found in the case of R3
being a heteroaryl substituent. Unfortunately, we could not
isolate the products in their pure forms (E- or Z-isomers) using
column chromatography or crystallization. It is delightful to find
that acetyl chloride (2m) and trifluoroacetic anhydride (TFAA,
2n) reacted with 1a to afford the desired products 3am and 3an
in 78% and 92% yields, respectively. In addition, pentafluoro
aroyl (2o) and cinnamoyl (2p) chlorides also participated in the
reaction, albeit providing moderate yields of products 3ao and
3ap.
Next, we have examined several experiments to understand
the E/Z phenomenon of the products [3la−3na (Scheme 3 and
Supporting Information)]. Unfortunately, our efforts to isolate
the starting materials (E)-1l and (Z)-1l in pure form were
unsuccessful to further test in our reaction conditions. To our
delight, products trans-(E)-3la and cis-(Z)-3la were successfully
separated by using column chromatography. Furthermore, we
have investigated the reactions of trans-(E)-3la and cis-(Z)-3la
using PPh2Me (20 mol %) in THF for 8 h at 30 °C. Surprisingly,
both reactions provided a mixture of products trans-(E)-3la and
cis-(Z)-3la in a 1:2 ratio. This clearly indicates that the products
react with PPh2Me to lead to isomerization under the standard
conditions. It is possible that the second phospha-Michael
addition of PR3 to 3la or the ion−dipole interactions between
electron-deficient heteroatom and phosphine when 3la is in its
resonance form could provide product 3la in different E and Z
ratios, presumably, due to the single bond rotation of the
corresponding zwitterion in equilibrium (see the Supporting
Information). It could be the reason for the formation of
products (3la−3na) in E/Z-isomers in a stereospecific reaction.
On the basis of the results and previous reports,7,8 the
plausible mechanism is depicted in Scheme 4. The initial
phospha-Michael addition of PPh2Me to (E/Z)-1 generates
phosphorus zwitterion A that further undergoes O-acylation
with acyl chloride 2 to result in phosphonium salt B. The
deprotonation of B in the presence of base provides ylide C,
which upon subsequent intramolecular cyclization would
furnish betaine intermediate D. The cleavage of the C−O
bond of betaine D and the regeneration of PPh2Me afford the β-
acylated adduct in high yields. It is worth noting that the
corresponding Wittig product was not found, which is expected
to form under the reaction conditions.
Inspired by the promising results of β-acylation of
pyrazolones, next we turned our attention to test other
heterocyclic compounds such as 5-arylidene thiazolones 4,
which make up an important class of other heterocycles
extensively found in a wide range of bioactive natural products
and potent biologically active molecules.10 Accordingly, we have
performed the reaction of 5-benzylidene thiazolone (4a) with
PhCOCl (2a) under the standard conditions of 3. The desired
product cis-(E)-5aa was obtained in only 40% yield after 10 h.
Afterward, we decided to screen the reaction conditions for
product cis-(E)-5aa. Via the systematic evaluation of phos-
phines, bases, solvents, and various other factors, the optimal
conditions were obtained (see the Supporting Information for
detailed optimization).
Having optimized the reaction conditions, we investigated the
scope of the other substrates (Scheme 5). In general, substrate 4
bearing different R1 and R3 substituents tested with PhCOCl 2a
and all of the substrates 4a−4h furnished products 5aa−5ha,
respectively, in good to excellent yields. In contrast to product 3,
the substrates with R3 as heteroaryl groups afforded desired
products 5ia and 5ja in ≤97% yields, exclusively in cis-form.11
Scheme 5. Synthesis of Functionalized Thiazolones 5 via β-
a,b
Acylation
Scheme 4. Plausible Mechanism for β-Acylation
a
The reactions were carried out with 4 (0.2 mmol), PBu3 (20 mol %),
R3COCl 2 (1.2 equiv), and Et3N (1.5 equiv) in dry THF (2.0 mL)
under an argon atmosphere at 30 °C. Isolated yield. The
stereochemistry of the compound is cis-(Z)-5ia. The E:Z ratio is
b
c
d
e
1:10. TFAA (2.0 equiv) and PEt2Ph (20 mol %) were used.
C
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Furthermore, various acyl chlorides were also examined with 4a
in the reaction, furnishing the corresponding β-acylated
products 5ab−5al in high yields, regardless of the electronic
and steric influence. Notably, aliphatic acetyl chloride 2m was
subjected to 4a, to furnish the corresponding product (E/Z)-
5am in 45% yield in a 10:1 ratio. In addition, TFAA 2n was also
tested in the reaction by using PEt2Ph as a catalyst, and desired
product 5an was obtained in 86% yield within 3 h.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02408.
■
sı
Optimization data, mechanistic studies, experimental
procedures, characterization data, and spectra of all
compounds (PDF)
Our reaction conditions are allowed to generate complex
molecule 6 via direct double β-acylation of 1a. A reaction of
terephthaloyl chloride 2q with a double amount of 1a furnished
complex molecule 6 in 86% yield within 6 h (Scheme 6a).
Accession Codes
CCDC 1960454, 1960456−1960457, 1960460, 1972709,
1972711, 2003052, 2004424, 2006275, and 2006528 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.
Scheme 6. (a) Synthesis of Complex Molecule 6 via Double β-
Acylation and (b) Gram-Scale Synthesis of 3 and 5
AUTHOR INFORMATION
Corresponding Author
■
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
Yin-Hsiang Su − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan, R.O.C.
Yung-Chang Chen − 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
Furthermore, to test the synthetic utility of our protocol, several
gram-scale reactions of 1 and 4 with different acyl chlorides have
been performed. All substrates furnished desired products 3aa,
3la, 3ma, 5aa, 5ab, and 5ea in 78−95% yields with substantial
quantities under the standard conditions (Scheme 6b).
Normal University, Taipei 11677, Taiwan, R.O.C.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02408
In summary, we have demonstrated a new method for the
synthesis of functionalized arylidene pyrazolones and thiazo-
lones in good to excellent yields via direct β-acylation of the
corresponding pyrazolones and thiazolones under metal-free
and mild conditions in a one-pot reaction. 4-Arylidene
pyrazolones 1 and 5-arylidene thiazolones 4 reacted with acyl
chlorides 2 in the presence of a base to install a keto functionality
at the β-position of 1 and 4, proceeding via a phospha-Michael/
O-acylation/intramolecular cyclization/rearrangement se-
quence catalyzed by organophosphanes. This stereospecific
protocol could be performed in gram-scale reactions to provide a
substantial amount of the corresponding products with similar
efficiency. We have found that the phospha-1,4-addition of
phosphine to conjugated pyrazolones proceeds via the direct β-
acylation reaction under the catalytic conditions, whereas the
phospha-1,6-addition of phosphine to doubly conjugated
pyrazolones generates the annulated products under the Wittig
reaction conditions.6 Further exploration of this strategy to
construct the biologically valuable motif is currently underway in
our laboratory and will be reported in due course.
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.
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(11) We have investigated the reactions of products cis-(Z)-5ia and
cis-(E)-5ja with 20 mol % and 1 equiv of PBu3 in THF for 8 h at 30 °C,
but the mixture of E and Z (cis and trans) isomers has not been observed
in either case. See the Supporting Information for experimental details.
E
https://dx.doi.org/10.1021/acs.orglett.0c02408
Org. Lett. XXXX, XXX, XXX−XXX