Organocatalytic Asymmetric Cascade Michael-acyl Transfer Reaction between 2-Fluoro-1,3-diketones and Unsaturated Thiazolones: Access to Fluorinated 4-Acyloxy Thiazoles

Article abstract of DOI:10.1021/acs.orglett.1c02313

Quinine derived bifunctional urea catalyzed cascade Michael-acyl transfer reaction of 5-alkenyl thiazolones and monofluorinated β-diketones has been developed. The fluorine containing 4-acyloxy thiazoles were synthesized in high yields and good diastereo-and excellent enantioselectivities. Synthetic transformations, including synthesis of 4-hydroxy thiazoles, have been demonstrated.

Full text of DOI:10.1021/acs.orglett.1c02313

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Letter
Organocatalytic Asymmetric Cascade Michael-acyl Transfer Reaction
between 2‑Fluoro-1,3-diketones and Unsaturated Thiazolones:
Access to Fluorinated 4‑Acyloxy Thiazoles
Rayhan G. Biswas, Sumit K. Ray, Rajshekhar A. Unhale, and Vinod K. Singh*
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ABSTRACT: Quinine derived bifunctional urea catalyzed cascade Michael-acyl transfer reaction of 5-alkenyl thiazolones and
monofluorinated β-diketones has been developed. The fluorine containing 4-acyloxy thiazoles were synthesized in high yields and
good diastereo-and excellent enantioselectivities. Synthetic transformations, including synthesis of 4-hydroxy thiazoles, have been
demonstrated.
Scheme 1. Organocatalytic Asymmetric Synthesis of
Acyloxy Pyrazoles and Thiazoles via Michael-acyl Transfer
Reaction
tereoselective transformation employing acyl transfer is an
1
Simportant reaction in biological and synthetic chemistry.
Several enantioselective methods have been developed in the
past decades for the efficient incorporation of the acyl group in
organic molecules.2,3 Among various acyl transfer reagents4
discovered, α-nitroketones have been widely used because of
its remarkable nucleophilicity in the presence of suitable
organocatalyst.5 For instance, in 2011, the Yan,5a Wang,5b and
Kwong5c groups independently disclosed the bifunctional
pyrrolidine-based thiourea-tertiary amine, Indane amine-
thiourea and cinchona alkaloid derived thiourea catalyzed
asymmetric conjugate additions of α-nitroketones to β,γ-
unsaturated α-keto esters followed by acyl transfer. In 2018,
the Pan group efficiently utilized the α-nitroketone in
organocatalyzed Michael-acyl transfer reaction with three
different electrophiles o-hydroxycinnamaldehydes,5g γ/δ-hy-
droxyenones,5e and o-quinone methides generated in situ from
2-sulfonylmethylphenols in basic medium.5f The same research
group reported the asymmetric cascade Michael-acyl transfer
reaction between unsaturated pyrazolones and α-nitroketones
using a bifunctional thiourea catalyst for the synthesis of 3-
acyloxy pyrazoles (Scheme 1).5d
Thiazoles and thiazolones are important heterocyclic
skeleton present in many pharmacologically active substances.6
Thiazole compounds can be used as pharmacophores in drug
Furthermore, a variety of chiral 4-acyloxythiazole derivatives
have been synthesized by Du research group via cyclo-
hexanediamine derived bifunctional squaramide catalyzed
cascade Michael/hemiketalization/retro-aldol reaction of un-
saturated thiazolones with α-nitroketones. The reaction
afforded chiral 4-acyloxythiazole derivatives in high yields
(Scheme 1).5h
Received: July 10, 2021
https://doi.org/10.1021/acs.orglett.1c02313
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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design and discovery as they can bind to various enzymes and
receptors in vivo to display various biological activities7 It is
evident that 4-hydroxythiazole derivatives have wide applica-
tions on antagonists, inhibitors, and sterilization studies.8 For
instance, compound 1a is identified as selective TRPM8
antagonists and used in the treatment of inflammation,
ischemia, neurodegeneration, stroke, itch, etc.8f Compound
1b acts as a potent inhibitor of 5-lipoxygenase in vitro.8a−c
Compound 1c plays a major role as inhibitors of mitochondrial
respiration and has shown good controllability on the mycelial
growth of various fungal species in tests in vitro (Figure 1).8d,e
Furthermore, 4-hydroxythiazoles also have wide applications in
fluorescence chemistry.9
Table 1. Catalyst Screening and Selected Entries for the
Optimization of Reaction Conditions
a
b
c
d
entry
catalyst
solvent
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C6
C6
C6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
70
68
72
80
72
82
78
80
87
70
80
83:17
83:17
84:16
89:11
88:12
91:9
85:15
88:12
91:9
90
84
92
98
98
99
96
96
99
99
98
Figure 1. Bioactive 4-hydroxythiazole derivatives.
The β-dicarbonyl,3g,10 β-ketosulfone,10f,g and bis-fluorinated
β-diketone11 compounds are important paradigms of other
acyl transfer reagents used by several research groups.
However, to the best of our knowledge, monofluorinated β-
diketones have rarely been explored as a nucleophile12 and
never been used as a direct acyl transfer reagent in
stereoselective transformations despite its synthetic impor-
tance.11 Furthermore, it is well-known that introduction of
fluorine atom to nitrogen containing heterocyclic systems often
enhances their biological activities.13 Therefore, herein we
investigated the nucleophilic behaviors of 2-fluoro-1,3-
diketones in bifunctional organocatalyzed cascade Michael-
acyl transfer reaction with 5-alkenyl thiazolones to synthesize
fluorinated 4-acyloxythiazole derivatives.
e
9
10
11
toluene
CHCl3
77:23
87:13
a
Reactions were carried out using 0.1 mmol of 2a with 0.15 mmol of
b
3a in 1.5 mL solvent. Isolated yield of the major diastereomer.
c
Determined by 1H NMR analysis of the crude reaction mixture.
d
e
Determined by chiral HPLC analysis. Catalyst loading 5 mol %.
Our study was commenced by performing a model reaction
between 5-alkenyl thiazolone (2a) and 2-fluoro-1,3-diphenyl-
propane-1,3-dione (3a) with cinchonine derived thiourea
catalyst C1 in dichloromethane solvent at room temperature.
To our delight, the desired cascade Michael-acyl transfer
reaction took place, and the corresponding desired 4-acyloxy
thiazole was obtained in 70% yield, 83:17 dr, and 90%
enantioselectivity (Table 1, entry 1). The yield and
enantioselectivity were decreased when quinidine derived
thiourea catalyst C2 was used (entry 2). Bis-quinine derived
squaramide catalyst was also screened in the reaction, and
better yield (80%) and enantioselectivity (96% ee) were
achieved (entry 8). The cinchonidine derived catalysts C4 and
C5 (entries 4−5) were found to give better result in terms of
enantioselectivities (98% ee for both the catalysts) compared
to cinchonine derived catalysts C1 and C3 (entries 1, 3).
Gratifyingly, the quinine derived urea catalyst C6 found to be
efficient and afforded 4aa in 82% yield, 91:9 dr, and 99% ee
(entry 6).
After establishing the optimal conditions, the substrate scope
for the reaction was explored. Initially several 5-alkenyl
thiazolones (2a−2p) were subjected to the optimized reaction
conditions. Gratifyingly, a variety of fluorine containing 4-
acyloxy thiazoles were obtained in high yields, good diastereo-
and excellent enantioselectivities (Scheme 2). At the
beginning, various unsaturated thiazolones bearing para-
substituted phenyl ring at 2 positions (2b−2d) were employed,
and corresponding 4-acyl thiazoles (4ba−4da) were obtained
in impressive yields (up to 90%) and stereoselectivities (up to
93:7 dr and 99% ee). Then a series of thiazolones having ortho,
meta, or para substituted phenyl group at the alkene end (2e−
2m) were tested, and corresponding 4-acyloxy thiazoles (4ea−
4ma) were achieved in high yields (up to 92%), good
diastereoselectivities (up to 95:5 dr), and imposing enantio-
selectivities (up to 99% ee). However, lower diastereoselectiv-
ity and yield were observed in the case of electron withdrawing
substituent (2m) and different 4-halosubstituted aryl groups
containing thiazolones (2f, 2i−2j) afforded the Michael-acyl
transfer products (4fa, 4ia−4ja) with slightly lower diaster-
eoselectivities and hence the yields. Interestingly, when phenyl
group was replaced by naphthyl, the reaction proceeded
smoothly, giving the thiazole 4na in 88% yield with 92:8 dr and
98% ee. Eventually, heteroaromatic group containing thiazo-
To further improve the yield and diastereoselectivity, other
solvents were screened (entries 9−11). Finally, 1,2-dichloro-
ethane was found to be the best solvent for this transformation,
providing 4aa in 87% yield, 91:9 dr, and 99% enantioselectivity
(entry 9).
B
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on the phenyl ring resulted in smooth conversions and
afforded the thiazoles (4ac−4ae) in excellent yields and high
stereoselectivities.
Scheme 2. Scope of Unsaturated Thiazolones
Notably, the unsymmetric β-diketone bearing methyl group
at one end underwent the reaction smoothly, giving the
exclusive Michael-benzoyl transfer product 4af in 73% yield,
83:17 dr, and 96% ee. However, the methyl substitution at the
meta position deleteriously affected the diastereoselectivity as
well as the conversion, leading to the Michael-acyl transfer
product 4ab in 80% yield with 88:12 dr and 98% ee. To further
demonstrate the scope of the cascade Michael-acyl transfer
reaction, a number of 5-alkenyl thiazolones (2f−2h, 2j, and 2l)
were evaluated for the reaction with 2-fluoro-1,3-bis(4-
methoxyphenyl)propane-1,3-dione (3e) under the optimal
reaction conditions (Scheme 3). The experimental results
revealed that the electronic effect and the substitution pattern
of 2 have limited impact on the yields and diastereo- and
enantioselectivities of the corresponding products (4fe−2he,
4je, and 4le). Woefully, the bromine substitution at para
position on the phenyl ring has a detrimental effect on the
reaction, affording the thiazole 4fe in 82% yield, 89:11
diastereoselectivity with 96% ee.
To check the influence of electronic property of the phenyl
group on the acyl migration the para methoxy and para fluoro
substituted unsymmetric aromatic nucleophiles (3h, 3i) were
employed separately with 2a in the Michael-acyl transfer
reaction under the optimized conditions (see SI). Surprisingly,
the electronic nature of the phenyl ring had no effect on the
selectivity of the acyl migration, and 1:1 nonseparable mixture
of both the benzoyloxy (6ah, 6ai) and para substituted
benzoyloxy (5ah, 5ai) thiazoles were obtained (5ah+6ah, 89%
yield and 5ai+6ai, 87% yield). Unfortunately, because of the
nonseparable mixed products the diastereo- and enantiose-
lectivity could not be evaluated for these two pair of products.
However, the optical rotations of each pair have been recorded
separately.
lones (2o−2p) were engaged in the reaction, and the
thiophene containing acyloxy thiazole 4pa was obtained in
86% yield with 92:8 dr and 98% ee. However, in the case of
furyl substituted enone (2o), slightly lower yield (76%) and
stereoselectivities (87:13 dr, 95% ee) were detected for the
product 4oa.
Next, the generality of the reaction was further probed by
recruiting a variety of fluorinated β-diketones (3a−f), and the
corresponding fluorinated thiazoles (4ab−4af) were isolated in
high yields (up to 90%), good diastereoselectivities (up to 93:7
dr), and excellent enantioselectivities (up to 99%) (Scheme 3).
Several fluorinated β-diketones with either electron-with-
drawing and electron-donating groups at the para positions
Then, to demonstrate the synthetic utility of the protocol,
the acyloxy thiazole was further subjected to a few organic
transformations (Scheme 4). Initially, the 4-acyl thiazole 4ae
bearing para-methoxy groups was transformed to the
corresponding ester 7 without erosion of any enantiopurity
Scheme 3. Scope of Acyl Transfer Reagent
Scheme 4. Synthetic Transformations
C
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via Baeyer−Villiger oxidation. Enantioenriched thiazole 4aa
(99% ee) was exposed to NaOH (2 equiv) hydrolysis in an
ethanol−water mixture, and the corresponding alcohol 8 was
afforded with no loss of enantiomeric excess. The alcohol 8
was highly unstable in solvent and could easily be transformed
into the α,β-unsaturated ketone 9 (E/Z mixture 1:1) by
elimination treating with further NaOH. The thiazole 4aa was
directly transformed to the enone 9 by treating with excess
NaOH (4 equiv) for 10 h. The absolute stereochemistry of 4-
acyl thiazole 4fe was unequivocally determined by single-
crystal X-ray structure analysis, and the absolute stereo-
chemistry of other acyloxy thiazoles were assigned by analogy.
To examine the practical efficacy of the protocol, a larger
scale reaction was performed with the model substrates. It was
revealed that the methodology was sustainable and equally
effective for gram-scale synthesis of the fluorinated 4-acyloxy
thiazoles (see Supporting Information (SI)).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02313.
■
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Experimental details and analytical data (NMR, HPLC,
ESI-HRMS, crystallographic structure, and data of 4fe)
(PDF)
Accession Codes
CCDC 2081867 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 Author
■
A number of control experiments were performed to gain
insight into the role of nucleophiles in the cascade Michael-acyl
transfer reaction. At first, the fluorine atom was replaced by
hydrogen, chlorine, and bromine in the β-diketone (3j−3l)
and engaged in the reaction under optimized conditions.
Surprisingly, reaction did not proceed even after 24 h for all
three cases (see SI). This suggested that the electronegative
fluorine atom at the α-position especially increases the acidity
of the α-hydrogen of 3 and enables it to proceed Michael
addition on alkenyl thiazolones 2. Unfortunately, when both
the phenyl rings in 3a were replaced with an aliphatic group
such as ethyl (3g), a nonisolable complex mixture was
observed (see SI). Furthermore, the indirect acetylation of
the thiazolone 2a was performed by adding the acetic
anhydride (10) in the optimized reaction of the model
substrates (see SI). Gratifyingly the 4-acetyloxy thiazole 11 was
formed in 76% yield and 86% ee via Michael addition, followed
by intermolecular acyl transfer (see SI). The additional
interaction of catalyst C6 with the acetic anhydride probably
perturbs the transition state of the reaction, causing the lower
enantioselectivity in the product 11.
On the basis of the absolute stereochemistry of the cascade
Michael-acyl transfer product and the observed control
experiments, the mechanism of the reaction was proposed
(see SI). Because the Si face of enone 2a is blocked by the
bifunctional catalyst, Michael addition only takes place from
the Re face, and intermediate A is generated. Hemiketalization
of A leads to the formation of B, which undergoes retro-aldol
reaction to give intermediate C. The keto−enol tautomeriza-
tion of C provided the product 4aa.
Vinod K. Singh − Department of Chemistry, Indian Institute
of Technology Kanpur, Kanpur, Uttar Pradesh 208 016,
India; orcid.org/0000-0003-0928-5543;
Email: vinodks@iitk.ac.in
Authors
Rayhan G. Biswas − Department of Chemistry, Indian
Institute of Science Education and Research Bhopal, Bhopal,
Madhya Pradesh 462 066, India
Sumit K. Ray − Department of Chemistry, Kharagpur College,
Paschim Medinipur, West Bengal 721305, India
Rajshekhar A. Unhale − Department of Chemistry, Indian
Institute of Science Education and Research Bhopal, Bhopal,
Madhya Pradesh 462 066, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02313
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.K.S. acknowledges SERB for a J. C. Bose Fellowship (SR/
S2/JCB-17/2008) and a research grant (CRG/2018/000552).
S.K.R. thanks DST for the Inspire Faculty Award (DST/
INSPIRE/04/2016001704). R.G.B. and R.A.U. thank the
Indian Institute of Science Education and Research (IISER),
Bhopal, for fellowships.
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