Employing α-Diazocarbonyl Compound Chemistry in the Assembly of Medicinally Important Aryl(alkyl)thiolactam Scaffold

Article abstract of DOI:10.1002/ejoc.201900944

RH₂(OAc)₄-catalyzed coupling of α-diazo-γ-butyrolactams with a wide range of aliphatic and aromatic thiols leads to α-aryl(alkyl)thiolactams in generally good yields. The transformation was found to be tolerant to sterically hindered thiols in contrast to analogous O–H insertion. Moreover, the same diazo lactams can be easily converted to β-aryl(alkyl)thiolactams in two steps using one-pot protocol. Consequently, the continued synthetic exploration of α-diazo-γ-butyrolactams paves the way toward two medicinally important scaffolds.

Full text of DOI:10.1002/ejoc.201900944

A Journal of
Accepted Article
Title: Employing α-diazocarbonyl compound chemistry in the assembly
of medicinally important aryl(alkyl)thiolactam scaffold
Authors: Darina Barkhatova, Daniil Zhukovsky, Dmitry Dar'in, and
Mikhail Krasavin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900944
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10.1002/ejoc.201900944
European Journal of Organic Chemistry
Employing α-diazocarbonyl compound chemistry in the assembly of
medicinally important aryl(alkyl)thiolactam scaffold
Darina Barkhatova, Daniil Zhukovsky, Dr. Dmitry Dar’in and Prof. Dr. Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
E-mail: m.krasavin@spbu.ru
http://www.krasavin-group.org/
Supporting information and ORCID(s) from the author(s) for this article are available on the
WWW under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
ABSTRACT
Rh2(OAc)4-catalyzed coupling of α-diazo-γ-butyrolactams with a wide range of aliphatic and
aromatic thiols leads to α-aryl(alkyl)thiolactams in generally good yields. The transformation
was found to be tolerant to sterically hindered thiols in contrast to analogous O-H insertion.
Moreover, the same diazo lactams can be easily converted to β-aryl(alkyl)thiolactams in two
steps using one-pot protocol. Consequently, the continued synthetic exploration of α-diazo-γ-
butyrolactams paves the way toward two medicinally important scaffolds.
Introduction
Despite its more than century-old history, chemistry of diazo compounds is still undergoing
active development with many classes of diazo compounds remaining understudied.[1]–[4] One
such class we have been recently exploring in classical Rh(II)-catalyzed OH- and NH-insertion
[5][6]
reactions is represented by α-diazo-γ-butyrolactams.
It recently came to our attention that
SH-insertion reactions[7-10] for these diazo compounds also remain virtually unknown. It clearly
appeared as a synthetic approach worth investigating as this mild[11]–[13] transformation would
lead to α-aryl(alkyl)thio-γ-butyrolactams. In the vast majority of cases such α-
aryl(alkyl)thiolactams are prepared by alkene cyclizations (only for β-allyl derivatives)[14]–[16] or
by reaction between corresponding lithium enolates and disulfides.[17][18] At the same time this
core is featured (as such or in various S-oxidized forms) in several biologically active
compounds. Illustrative examples include Boerhinger-Ingelheim’s cannabinoid cb2 receptor
ligands 1,[19] Takeda’s RBP4 lowering agents 2 for the treatment of diabetes,[20] Vertex’s sodium
channel blocker 3,[21] Eli Lilly’s 11-HSD1 inhibitor 4 for the treatment of hyperglycemia-
associated diseases,[22] Exelixis’s P70S6 kinase inhibitor 5[23] and Boerhinger-Ingelheim’s non-
nucleoside RT inhibitor 6 patented as a treatment for HIV-1[24] (Figure 1). Thus, developing a
streamlined entry into the α-aryl(alkyl)thiolactam core using the diazo chemistry to facilitate its
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10.1002/ejoc.201900944
European Journal of Organic Chemistry
utilization in the medicinal chemistry pursuits became our goal. Herein, we describe our positive
developments in this regard.
Figure 1. Examples of biologically active compounds featuring an α-aryl(alkyl)thiolactam core
in various forms of S-oxidation.
Results and discussion
The initial attempt to employ the literature conditions[13][25][26] to carry out catalytic
decomposition of N-phenyl α-diazo-γ-butyrolactam (7a) in the presence of thiophenol (8a) with
Rh2(OAc)4 as a catalyst resulted in the corresponding product (9a) obtained in 78% yield.
Therefore, we decided to use this catalyst throughout this study. With workable conditions in
hand, we investigated the generality of this transformation (Scheme 1).
A number of aromatic (8a-d) and aliphatic (8e-i) thiols were employed in this reaction. No
particular dependence of the reaction yield on the electronic properties of the arylthiols and the
reaction yield was observed. In case of aliphatic thiols, the reaction proceeded also quite well
and demonstrated notable tolerance to sterically demanding reagents. This was in contrast to the
previously investigated analogous O-H insertion reaction: with cyclohexanol, the corresponding
alkoxy product was obtained in mere 36% yield whereas the reaction with tert-butanol
completely failed.[5] Such a difference in reactivity can be rationalized by C-O bond being
significantly shorter compared to C-S bond. With 5-fold excess of 1,2-ethanedithiol (8i) only
mono coupling product was obtained. This is a particularly valuable finding in light of the
recently reported exploration of monosubstituted 1,2-ethanedithiols (similar to 9i) as zinc-
binding groups on natural product largazole analogs for the development of histone deacetylase
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10.1002/ejoc.201900944
European Journal of Organic Chemistry
inhibitors.[27] S-H insertion product 9j clearly belongs to the 2-alkylthiobenzothiazole scaffold
widespread in the bioactive compound domain.[28]–[30] We also attempted to involve diazo lactam
7a in the reaction with thiobenzoic acid[31] but no corresponding product was observed.
Afterwards several different diazo lactams (7b-f) were examined in this transformation but no
significant relationship between the electronic properties of the aryl substituent at the nitrogen
atom and the reaction yields was noted.
Scheme 1. Rh2(OAc)4-catalyzed S-H insertion reactions of α-diazo-γ-butyrolactams 7a-f.
Considering the facility we discovered at introducing thio groups at the -position of -
butyrolactam ring using Rh(II)-catalyzed S-H insertion approach, we thought of exploring the
same diazo compounds as precursors to -thio-substituted -butyrolactam scaffold. The latter has
a documented utility in medicinal chemistry as illustrated by such compounds as Girapharma’s
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10.1002/ejoc.201900944
European Journal of Organic Chemistry
adenosine receptor antagonist 10,[32] Hoffmann-La Roche’s anti-hepatitis B virus agent 11[33] and
Takeda’s matrix metalloproteinase inhibitor 12[34] (Figure 2).
Figure 2. Examples of biologically active compounds featuring a -aryl(alkyl)thiolactam core in
various forms of S-oxidation.
In order to access the -thio-substituted -butyrolactam scafford, we decided to take advantage
of the earlier described facile and high-yielding conversion of α-diazo-γ-butyrolactams into their
3-pyrrolin-2-one counterparts in the presence of silver triflate.[5] Such compounds possess and
electron-deficient double bond and can therefore be expected to act as a Michael acceptor for
nucleophilic attack by thiolates giving corresponding β-aryl(alkyl)thiolactams.[35]
These two reactions were put in succession within one protocol. The intermediate pyrrol-3-ene-
2-one 13 was not isolated and, after filtration through a plug of silica gel, was concentrated and
re-dissolved in THF where it was further exposed to a thiol/triethylamine mixture. Room
temperature reaction conducted overnight delivered the expected corresponding β-
aryl(alkyl)thiolactams 14a-c in moderate to good yields over two steps (Scheme 2).
Scheme 2. One-pot preparation of β-aryl(alkyl)thiolactams 14a-c.
Conclusion
The described approaches to introducing aryl(alkyl)thio groups at -butyrolactam moiety offer
streamlined opportunities for exploring the substitution patterns around two medicinally
important scaffolds. The practical simplicity and the speed of the -substitution method makes it
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10.1002/ejoc.201900944
European Journal of Organic Chemistry
particularly amenable to fast analog generation in parallel format. The -substitution method
involves a slower (yet practically rather convenient) Michael addition to pyrrol-3-one-2-one
precursor rapidly generated from the same diazo compound as the -substituted series is made
from.
ASSOCIATED CONTENT
Supporting Information
Experimental procedure, analytical data and copies of the 1H and 13C NMR spectra.
AUTHOR INFORMATION
Corresponding Author
* E-mail: m.krasavin@spbu.ru.
ORCID
Dmitry Dar’in: 0000-0002-0413-7413
Mikhail Krasavin: 0000-0002-0200-4772.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Science Foundation (project grant 19-75-30008). We
thank Research Centre for Magnetic Resonance and the Center for Chemical Analysis and
Materials Research of Saint Petersburg State University Research Park for obtaining the
analytical data.
KEYWORDS: -diazo lactams; arylthio lactams; alkylthio lactams; S-H insertion; rhodium(II)
catalysis; γ-butyrolactams
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Graphical abstract
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10.1002/ejoc.201900944
European Journal of Organic Chemistry
TOC text
The Rh(II)-catalyzed S-H insertion reaction of α-diazo-γ-butyrolactams provides a
straightforward access to α-aryl(alkyl)thiolactams. The same diazo lactams can be easily
converted to β-aryl(alkyl)thiolactams through a Ag(I)-catalyzed β-hydride shift followed by a
sulfa-Michael addition. These two reactions of α-diazo-γ-butyrolactams pave the way toward
two medicinally important scaffolds.
Key topic
Diazo compounds
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