Communication
doi.org/10.1002/chem.202100390
Chemistry—A European Journal
Synthesis of Spirocycles via Ni-Catalyzed Intramolecular
Coupling of Thioesters and Olefins
Wenfei Liu+,[a] Wenhua Xu+,[a] Juanjuan Wang,[a] Hong Lu,[a] Peng-Fei Xu,[b] and Hao Wei*[a]
Abstract: A nickel-catalyzed intramolecular coupling of
thioesters and olefins has been developed for the efficient
synthesis of spirocycles, a privileged scaffold commonly
found in natural products. This transformation is character-
ized by the simultaneous transfer of both acyl and thiol
moieties to the alkene, with the suppression of decarbon-
ylation and β-hydrogen elimination. Initial mechanistic
investigations are consistent with an oxidative addition/
olefin insertion/reductive elimination mechanism. The in-
corporated methylene sulfide substituent can undergo a
variety of further reactions to increase molecular diversity
and complexity. These results demonstrate that thioester
derivatives can be used as powerful building blocks for the
assembly of complex scaffolds.
Figure 1. Representative natural products containing spirocyclic scaffolds
tethered allyl fragment.[4] Recently, the Newman group ex-
panded the scope of this methodology to include aromatic
esters (Figure 2A).[5]
Spirocycles are valuable skeletons that are ubiquitous in natural
products and widely used in the preparation of catalysts,
ligands, agrochemicals, and pharmaceuticals (Figure 1).[1] Spiro-
cyclic scaffolds present unique advantages in drug develop-
ment, because their dense and rigid structures can reduce the
conformational entropy penalty resulting from binding to a
target protein in a favorable geometry.[2] In light of this, there is
a fundamental need to develop efficient methods to access
these compounds from readily available precursors.
In recent years, carboxylic acid derivatives have shown
potential as alternatives to conventionally used organohalides
in transition-metal-catalyzed cross-coupling reactions.[3] The use
of carboxylic acid derivatives as coupling partners offers several
advantages such as low-cost, ease of handling, facile prepara-
tion and the absence of halogenated waste. In 2017, Garg and
Stanley independently reported intramolecular cyclization via
the intramolecular coupling of an aromatic amide and a
Inspired by these seminal works, we propose that valuable
spirocyclic skeletons could be formed by intramolecular
coupling between a carboxylic acid derivative and an olefin. To
prevent wastage of the remaining heteroatom fragment, a
more constructive process entails cleavage of the C(=O)À Z
single bond and addition both fragments across an olefin,
thereby enabling the simultaneous formation of new CÀ C and
CÀ Z bonds (Figure 2B).[6] However, the use of aliphatic carbox-
ylic acid derivatives for the synthesis of spirocyclic skeletons via
this strategy remains formidably challenging because of two
major side reactions: 1) the coupling of aliphatic carboxylic acid
derivatives is exacerbated due to competing decarbonylative
elimination,[7] which is rapid and efficient when transition-metal
catalysts are employed. Thus, if olefin insertion is slow,
decarbonylative product formation will dominate;[8] 2) common
alkyl-metal intermediates tend to undergo β-hydride elimina-
tion side reactions rather than the desired CÀ Z bond
formation.[9]
Sulfur-containing compounds often possess various bio-
logical activities and serve important functions in the pharma-
ceutical industry.[10] Approximately 20% of all FDA-approved
drugs are organosulfur compounds.[10c] Thioesters are more
reactive than the analogous oxoesters and amides due to the
poorer orbital overlap between the sulfur atom and the
carbonyl group.[11] It was expected that the oxidative addition
of a transition metal into the CÀ S bond of thioesters would
proceed under relatively mild conditions,[12] thus preventing the
competing decarbonylation.[13] Consequently, a “cut and sew”
sequence between a thioester and an olefin can be envisaged
to proceed via olefin migratory insertion and reductive
[a] W. Liu,+ Dr. W. Xu,+ J. Wang, Dr. H. Lu, Prof. Dr. H. Wei
Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry
of Education, College of Chemistry & Materials Science
Northwest University
Xi’an 710069 (P. R. China)
E-mail: 20154894@nwu.edu.cn
[b] Prof. Dr. P.-F. Xu
Key Laboratory of Applied Organic Chemistry College of Chemistry and
Chemical Engineering, Lanzhou University
Lanzhou 730000 (P. R. China)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2021, 27, 1–7
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