Potassium Acetate-Catalyzed Double Decarboxylative Transannulation to Access Highly Functionalized Pyrroles

Article abstract of DOI:10.1021/acs.orglett.0c03621

The development of new synthetic strategies for the efficient construction of versatile pyrrole pharmacores, especially in an operationally simple and environmentally benign fashion, still remains a momentous yet challenging goal. Here, we report a KOAc-catalyzed double decarboxylative transannulation between readily accessible oxazolones and isoxazolidinediones. This transformation represents a new way for skeletal remodeling by utilizing CO2 moiety as traceless activating and directing groups in both reaction partners. The synthetic value is evidenced by the rapid preparation of a broad spectrum of highly functionalized 3-carbamoyl-4-aryl pyrroles in good to excellent yields with exclusive regio-control, including the important Atorvastatin core.

Full text of DOI:10.1021/acs.orglett.0c03621

pubs.acs.org/OrgLett
Letter
Potassium Acetate-Catalyzed Double Decarboxylative
Transannulation To Access Highly Functionalized Pyrroles
Jun-Kuan Li, Biying Zhou, Yu-Chen Tian, Chunman Jia, Xiao-Song Xue, Fa-Guang Zhang,*
and Jun-An Ma*
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ABSTRACT: The development of new synthetic strategies for the
efficient construction of versatile pyrrole pharmacores, especially in
an operationally simple and environmentally benign fashion, still
remains a momentous yet challenging goal. Here, we report a
KOAc-catalyzed double decarboxylative transannulation between
readily accessible oxazolones and isoxazolidinediones. This trans-
formation represents a new way for skeletal remodeling by utilizing
CO2 moiety as traceless activating and directing groups in both
reaction partners. The synthetic value is evidenced by the rapid
preparation of a broad spectrum of highly functionalized 3-carbamoyl-4-aryl pyrroles in good to excellent yields with exclusive regio-
control, including the important Atorvastatin core.
ransition-metal catalysis has been among the most vibrant
fields in modern synthetic chemistry. Over the past
T
decades, research efforts have mainly focused on many
precious transition-metal catalysts.1 Notably, the lack of long-
term sustainability and the toxicity of these noble metals has
led to a renewed interest in the development of Earth-
abundant base metal species for use in catalysis.2 Catalysts
derived from Earth-abundant base metals undoubtedly offer
synthetic chemists more opportunities than we can imagine. In
this context, potassium is the sixth-most abundant metal
element in the Earth’s crust,3 and traditionally it has been
mainly employed as simple alkali-metal bases. Interestingly, the
potential of potassium in catalysis and organic synthesis has
begun to attract significantly increasing attention in recent
years. For example, in a series of pioneering studies, potassium
alkoxides have found versatile applications in carbon−carbon
and carbon−heteroatom bond-forming reactions, including
heteroaromatic C−H silylation,4 aromatic C−H arylation,5
heteroaromatic C−H iodination,6 and alkyne hydrocarbox-
ylation.7 Despite these remarkable advances, the development
of more reaction varieties with potassium catalysts is certainly
still of much interest and significance.8
Figure 1. Representative bioactive molecules featuring a tetra-
substituted pyrrole motif.
chlorin, and porphyrinogen molecules) and functional
materials (man-made batteries and solar cells).16 The broad
biological activities and attractive physicochemical properties
of tetra-substituted pyrroles, as well as their industrial relevance
have long motivated the development of new and practical
Tetra-substituted pyrroles are an important class of N-
heterocyclic motifs present in many pharmaceutical agents,
agrochemical ingredients, and natural products.9 Several
representative compounds include Atorvastatin (a cholester-
ol-lowering drug),10 Sunitinib (an anticancer drug),11
Licofelone (a dual COX/LOX inhibitor),12 FPL-64176 (a
Ca-channel activator),13 Chlorfenapyr (an agrochemical
pesticide),14 and marine alkaloids Polycitones and Stornia-
mides15 (Figure 1). Tetra-substituted pyrroles are also found
widely in life system (pigment heme, chlorophyll, bacterio-
Received: November 2, 2020
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© XXXX American Chemical Society
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methods for their construction.17 In particular, the exploitation
of novel substrates and strategies under mild conditions with
good functional group tolerance is still in high demand.
Consistent with our continuing interest in directed cyclo-
addition reactions,18 here we report a novel double
decarboxylative transannulation process catalyzed by inex-
pensive and readily available potassium acetate (KOAc) (see
Scheme 1).19 This alkali-metal salt catalyst-triggered trans-
Scheme 2. Substrate Scope of (a) Isoxazolidinediones 2 and
(b) Oxazol-5-(4H)-ones 1
Scheme 1. KOAc-Catalyzed Decarboxylative
Transannulation for the Synthesis of Tetrasubstituted NH-
Pyrroles
formation of oxazolones and isoxazolidinediones provides an
efficient route to a broad range of tetra-substituted 3-
carbamoyl-4-aryl NH-pyrroles in good yields and with
exclusive regioselectivities. The cleavage of the weak N−O
bond in isoxazolidinedione serves as a key in triggering the
second decarboxylation and ultimately leads to the formation
of the pyrrole ring.
After extensive screening studies, we found that the use of an
alkali-metal acetate (KOAc) as a catalyst delivered the desired
product 3a as a single regioisomer in up to 92% yield (see
Table S1 in the Supporting Information (SI)). Having
established optimal conditions for the KOAc-catalyzed double
decarboxylative transannulation reaction, the scope was first
assessed with oxazolone 1a and a series of isoxazolidine-3,5-
diones 2 (Scheme 2a). A variety of aromatic substituents (Ar1)
featuring various electronic properties (electron-donating and
electron-withdrawing) and located patterns (para-, meta-, and
ortho-) are all compatible, thus providing highly functionalized
pyrroles 3b−3n in yields of 60%−98% with constantly
excellent regioselectivity. Two types of naphthyl-derived
substrates, as well as 2-furyl and 2-thienyl ones, also underwent
the desired decarboxylative transannulation with uniformly
good results (products 3o−3r). A change of substituents on
the amide moiety was well-tolerated, as exemplified by the
smooth generation of compound 3s and 3u′. It is noteworthy
that the current catalytic system can tolerate an E/Z mixture of
isoxazolidine-3,5-diones 2. The ability to transform the E/Z
mixture of 2 is crucial to practical synthesis of various
tetrasubstituted NH-pyrroles.
Subsequently, a broad array of oxazolones 1 reacted with
isoxazolidinedione 2a under the optimized conditions, and the
results are outlined in Scheme 2b. Various alkyl substituents
that include methyl, ethyl, isopropyl, isobutyl, sec-butyl, benzyl,
cyclopropyl, alkenyl, alkynyl, thioether, and cyclohexyl groups
were well accommodated, delivering the products 3t−3d′ in
yields of 60%−94%. Variations on the aryl units of oxazolones
1 had no significant effect on the reaction performance,
including phenyl-derived substrates bearing alkyl, alkoxyl,
trifluoromethyl groups or a halogen at different positions
(products 3e′−3k′). Reactions of oxazolones containing
naphthyl or heteroaryl groups also occurred smoothly,
producing the corresponding pyrroles 3l′−3q′ in up to 97%
yield. The bromo-substituted thienyl pyrroles may serve as
potential building blocks for the preparation of novel small-
molecule optoelectronic materials.20
This KOAc-catalyzed double decarboxylative transannula-
tion reaction can further be applied for the expedient
preparation of triaryl-substituted pyrroles with excellent
regioselectivity. As illustrated in Scheme 3, a series of highly
functionalized pyrroles 4a−4k bearing three precisely arranged
aryl groups were readily obtained in practical yields as a single
detectable regioisomer under operationally simple conditions.
B
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alkynyl amide 6, respectively). In these two cases, no desired
pyrrole 3a was observed (Scheme 5a). This result not only
illustrated the critical role of employing the CO2 moiety as a
traceless activating and directing group in the reaction design,
but it also indicated that the first transannulation step could
occur prior to the ring-opening event. Monitoring the reaction
mixture of oxazolone 1a with isoxazolidinedione 2a under
Scheme 3. Synthesis of Tri-aryl-substituted Pyrroles
1
standard conditions by 19F NMR and H NMR also indicated
the in-situ formation of possible intermediate species (see
Figures S1 and S2 in the SI). To verify this hypothesis,
TMSCHN2 was used to intercept the model reaction when it
was conducted at 0 °C in THF. To our delight, a spirocyclic
compound 7 was obtained in 25% yield (confirmed by X-ray
crystallography analysis; see Scheme 5b), thereby strongly
supporting the presence of respective spirocyclic intermediate
before decarboxylation during the reaction process.
To further elucidate the origin of excellent regioselectivity in
this double decarboxylative transannulation reaction, the
density functional theory (DFT) calculations were performed
at the SMD (DCE)-M06/6-311++G(d,p)//SMD(DCE)-
M06/6-31g(d) level of theory (Scheme 5c). In the favored
pathway I (in black), the 1,4-nucleophilic attack at the C2
position of isoxazolidinedione 2a occurred with an energy
barrier of 4.2 kcal/mol (via the transition state endo-Ts-Ia).
Subsequently, spirocyclic intermediate endo-Int-Ic was formed
after the ring opening via the transition state endo-Ts-Ib, then
intramolecular addition event via the transition state endo-Ts-
Ic with energy barriers of 13.4 and 1.8 kcal/mol, respectively.
Note that the K+ cation was found to be simultaneously
binding with oxygen of the carbonyl group in both reaction
partners from the starting endo-Ts-Ia until the formation of
intermediate endo-Int-Ic. Based on the computed energy
profile, the decarboxylation process is estimated to be the rate-
determining step with an overall free-energy requirement of
19.8 kcal/mol (from endo-Int-Ic to endo-Ts-Id). On the
other hand, the nucleophilic attack at the C4 position of
isoxazolidinedione 1b, following with the concerted intra-
molecular addition and ring-opening event involving a single
transition state exo-Ts-IIb, has a much higher barrier of 29.8
kcal/mol (in the disfavored pathway II; shown in red in
Scheme 5c). This major difference may account for the
preference of pathway I over II, which is consistent with the
experimental outcome that 3t was exclusively formed.
Note that the regioselective synthesis of such highly
substituted pyrroles 4g−4k, possessing three different aryl
groups, is otherwise difficult to access.
Subsequently, the utility of the present protocol was further
highlighted by the regiodivergent construction of pyrroles 3r′−
3t′ (Scheme 4). By virtue of switching the substituents on the
oxazolone motif, the corresponding regioisomer 3r′ (relative to
3a) was prepared in 65% yield. Similarly, both tetrasubstituted
NH-pyrroles 3s′ and 3t′ were obtained as a single regioisomer
in yields of 62% and 55%, respectively. The structures of these
regioisomers were unambiguously determined by X-ray
crystallography analysis of compounds 3a, 3s′, and 3t′.
Furthermore, the same good result was obtained when the
model transannulation reaction was conducted on a gram scale,
thus delivering 3.6 g of 3a with 89% yield in one pot. Notably,
3a could function as a very valuable synthon, which was
directly converted to the cholesterol-lowering drug Atorvasta-
tin (Scheme 4).21 In addition, the SN2 substitution reaction of
3a with 2-(2-bromoethyl)-1,3-dioxolane gave N-alkylated
pyrrole 8 in 51% isolation yield, which is a key compound
that is a known intermediate in the synthesis of the
Atorvastatin analogue 9.22
To gain insight into the reaction mechanism, we initially
attempted to perform the transannulation reaction between
oxazolone 1a and two acyclic derivatives of isoxazolidinedione
2a as potential intermediates (acyclic alkenyl amide 5 and
On the basis of the combined experimental and computa-
tional results, a plausible mechanism was deduced as depicted
Scheme 4. Regiodivergent Synthesis of Polysubstituted Pyrroles and Synthesis of Atorvastatin and Its Analogue 9
C
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Scheme 5. Depictions of (a, b) Mechanistic Studies, (c) DFT Calculations, and (d) Proposed Mechanism
in Scheme 5d. In the presence of a basic potassium salt,
oxazolone 1b is first deprotonated and 1,4-nucleophilic attacks
at the C2 position of isoxazolidinedione 2a in an endo manner.
The key spirocyclic intermediate endo-Int-Ic would be formed
after stepwise events consisting of ring opening and intra-
molecular addition. Subsequently, two rounds of decarbox-
ylation proceed rapidly to produce a pyrrole precursor endo-
Int-Ie. Finally, the desired pyrrole product 3t will be generated
after fast occurring of KOAc-assisted 1,3-hydrogen shift
(isomerization).
application of this tactic to other substrate classes are ongoing
in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03621.
Experimental procedures, characterization data, NMR
spectra, and computational details (PDF)
Accession Codes
In summary, a novel KOAc-catalyzed double decarboxylative
transannulation reaction by taking advantage of traceless
activating and directing strategy has been devised for the first
time. This skeletal remodeling transformation provides an
effective method for the expedient preparation of tetrasub-
stituted 3-carbamoyl-4-aryl NH-pyrroles with a wide substrate
scope and excellent level of regioselectivity. The mild, robust,
environmentally friendly, and operationally simple features
render this strategy very practical for the divergent synthesis of
versatile pyrrole pharmacores, as demonstrated by the
preparation of various Atorvastatin analogues in a chemo-
divergent and regiodivergent manner. Further studies on the
CCDC 1938705−1938707 and 1947323 contain the supple-
mentary 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
Corresponding Authors
■
Fa-Guang Zhang − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
D
https://dx.doi.org/10.1021/acs.orglett.0c03621
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Organic Letters
and Tianjin Collaborative Innovation Centre of Chemical
pubs.acs.org/OrgLett
Letter
Analysis and Testing Center of Tianjin University for NMR
experiments.
Science & Engineering, Tianjin University, Tianjin 300072,
People’s Republic of China; Joint School of National
University of Singapore and Tianjin University, International
Campus of Tianjin University, Binhai New City, Fuzhou
350207, People’s Republic of China; orcid.org/0000-
0002-0251-0456; Email: zhangfg1987@tju.edu.cn
Jun-An Ma − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Centre of Chemical
Science & Engineering, Tianjin University, Tianjin 300072,
People’s Republic of China; Joint School of National
University of Singapore and Tianjin University, International
Campus of Tianjin University, Binhai New City, Fuzhou
350207, People’s Republic of China; State Key Laboratory of
Elemento-Organic Chemistry, Nankai University, Tianjin
300071, People’s Republic of China; Email: majun_an68@
tju.edu.cn
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Authors
Jun-Kuan Li − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Centre of Chemical
Science & Engineering, Tianjin University, Tianjin 300072,
People’s Republic of China; Joint School of National
University of Singapore and Tianjin University, International
Campus of Tianjin University, Binhai New City, Fuzhou
350207, People’s Republic of China
Biying Zhou − State Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s
Republic of China
Yu-Chen Tian − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Centre of Chemical
Science & Engineering, Tianjin University, Tianjin 300072,
People’s Republic of China; Joint School of National
University of Singapore and Tianjin University, International
Campus of Tianjin University, Binhai New City, Fuzhou
350207, People’s Republic of China
Chunman Jia − Hainan Provincial Key Lab of Fine Chemistry,
Hainan University, Haikou, Hainan 570228, People’s
Republic of China
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Key Research and
Development Program of China (No. 2019YFA0905100),
National Natural Science Foundation of China (Nos.
21772142, 21901181, and 21961142015), and Tianjin
Municipal Science & Technology Commission (No.
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