Preparation and in situ use of unstable N-alkyl α-diazo-γ-butyrolactams in RhII-catalyzed X–H insertion reactions

Article abstract of DOI:10.3762/bjoc.16.55

N-Alkyl α-diazo-γ-butyrolactams, previously found to be unstable and to undergo unproductive dimerization to bishydrazones, were successfully converted immediately to various X–H insertion products with alcohols, aromatic amines and thiols via an in situ

Full text of DOI:10.3762/bjoc.16.55

Preparation and in situ use of unstable N-alkyl α-diazo-
γ-butyrolactams in RhII-catalyzed X–H insertion reactions
Maria Eremeyeva, Daniil Zhukovsky, Dmitry Dar’in and Mikhail Krasavin*§
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 607–610.
Laboratory of Chemical Pharmacology, Institute of Chemistry, Saint
Petersburg State University, 26 Universitetskii prospect, Peterhof
198504, Russian Federation
doi:10.3762/bjoc.16.55
Received: 06 February 2020
Accepted: 26 March 2020
Published: 02 April 2020
Email:
Mikhail Krasavin* - m.krasavin@spbu.ru
Associate Editor: T. J. J. Müller
* Corresponding author
§ http://krasavin-group.org
© 2020 Eremeyeva et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
in situ reactions; N-alkyl 2-pyrrolidones; RhII-catalyzed insertion
reactions; stability of diazo compounds
Abstract
N-Alkyl α-diazo-γ-butyrolactams, previously found to be unstable and to undergo unproductive dimerization to bishydrazones,
were successfully converted immediately to various X–H insertion products with alcohols, aromatic amines and thiols via an in situ
RhII-catalyzed reaction. With aliphatic amines or unreactive, sterically hindered anilines, the reactions tended to yield enamine
adducts.
Introduction
Recently, we described the first synthesis and subsequent trans- ported by the fact that ortho-substituted N-aryl derivatives 1 (in
formations of a rare type of cyclic α-diazocarbonyl compounds, which the conjugation of the aromatic ring with the lone pair of
namely, α-diazo-γ-butyrolactams [1]. In particular, N-aryl- the lactam nitrogen atom is reduced due to the sterically forced
α-diazo-γ-butyrolactams 1 were efficiently transformed into loss of the coplanarity between the aromatic ring and the
pyrrolinones 2 upon the treatment with AgOTf (1 mol %) and aminocarbonyl moiety) are as unstable as the N-alkyl deriva-
into α-alkoxy derivatives 3 via Rh2(OAc)4-catalyzed O–H tives 4 [1].
insertion reactions with various alcohols. In contrast, N-alkyl-
α-diazo-γ-butyrolactams 4 did not undergo these reactions Faced with this serious limitation of the reactivity scope, we set
typical of α-diazocarbonyl compounds, as they rapidly dimer- off to investigate the possibility of using unstable compounds 4
ized to give bishydrazones 5 (Figure 1). The instability of in situ, promptly after their formation, in various RhII-cata-
N-alkyl-α-diazo-γ-butyrolactams 4 compared to the N-aryl lyzed X–H insertion reactions, particularly the recently de-
counterparts 1, was most likely related to the reduced electron- scribed rhodium carbene insertion into O–H [1], N–H [2] and
withdrawing character of the lactam carbonyl group in the S–H [3] bonds of alcohols, aromatic amines, and thiols, respec-
former compared to the latter. This assumption is further sup- tively. Herein, we report the results of these studies.
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Beilstein J. Org. Chem. 2020, 16, 607–610.
Results and Discussion
Three N-alkyl-α-ethoxalyl-γ-lactams 6a–c, prepared by oxalyla-
tion of the respective γ-lactams as decribed previously [1],
underwent a rapid diazo transfer reaction via the conventional
protocol [4,5] employing 4-nitrobenzenesulfonyl azide and
DBU. A quick filtration through a plug of alumina (in lieu of
silica gel, which led to decomposition of the diazo compounds
4a–c), and addition of an alcohol, a thiol, or an aromatic amine
along with a RhII catalyst resulted in a rapid insertion reaction
and the isolation of the desired α-substituted γ-lactams 7a–o in
modest yields (Scheme 1). It should be noted that, after some
experimentation, the reactions with alcohols and thiols were
found to be efficiently catalyzed by 1 mol % of Rh2(OAc)4 and
completed within 30 min. For aromatic amines, this catalyst
proved inefficient and was replaced by 0.5 mol % of Rh2(esp)2.
The attempted change of the catalyst to Rh2(esp)2 in the reac-
Figure 1: Previously reported uses of α-diazo-γ-butyrolactams 1 and
4.
Scheme 1: Generation and in situ RhII-catalyzed X–H insertion reactions of the diazo compounds 4a–c. Conditions: aRhII catalyst: 1 mol %
Rh2(OAc)4 for X = O or S and 0.5 mol % Rh2(esp)2 for X = NR′′.
608

Beilstein J. Org. Chem. 2020, 16, 607–610.
tions with alcohols and thiols (which earlier gave a remarkable reactions are rapid, albeit moderately yielding. Despite the latter
improvement of the product yields of NH-insertion reactions drawback, the range of 1,3-disubstituted 2-pyrrolidones attain-
[2]) resulted in no notable improvement in this case.
able via the intermediate formation of α-diazo-γ-butyrolactams
was substantially expanded, thereby making this approach more
The only attempt to employ an aliphatic amine, cyclopropyl- useful for potential medicinal chemistry exploration of these
amine (which would presumably be less reactive in the RhII- disubstituted γ-lactams.
catalyzed insertion reaction [2]) resulted in the formation of a
sole identifiable product – enamine 8a, isolated chromatograph-
ically from a complex mixture of unidentified byproducts. The
Supporting Information
formation of 8a (that was also observed previously, along with
Supporting Information File 1
the expected, saturated coupling product of the RhII-catalyzed
reaction of cyclopropylamine with N-phenyl-α-diazo-2-pyrroli-
done [2]) can be rationalized, as proposed previously [2], either
by the oxidation of diazolactam 6c to a respective ketone (a
process described in the literature for other α-diazocarbonyl
compounds [6]), followed by a nucleophilic attack of cyclo-
propylamine. Alternatively, the formation of the enamine prod-
uct could be envisaged via the reaction of the amine with bis-
hydrazone 5, which would have formed, if the N–H insertion
pathway was not sufficiently rapid. Both assumptions are in line
with the formation of the similar enamine coupling product 8b,
that we observed with 2,6-dimethylaniline. With this unreac-
tive, sterically hindered aromatic amine, 6c is likely to undergo
General experimental information, synthetic procedures,
analytical data and NMR spectra for the reported
compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-55-S1.pdf]
Acknowledgements
We are grateful to the Research Centre for Magnetic Reso-
nance and the Centre for Chemical Analysis and Materials
Research of Saint Petersburg State University Research Park for
the analytical data.
either the unwanted N2→O oxidation or dimerize to bis- Funding
hydrazone 5, whereupon the resulting intermediate would be This research was supported by the Russian Science Founda-
eventually trapped by the aniline to give 8b (Scheme 2). The tion (project grant 19-33-90016).
viability of either (or both) of these possibilities is currently in-
ORCID® iDs
vestigated. It should be noted that a similar Rh2(esp)2-cata-
lyzed reaction of one of the N-aryl-α-diazo-γ-butyrolactams 1
with 2,6-dimethylaniline previously gave an excellent yield of
Dmitry Dar’in - https://orcid.org/0000-0002-0413-7413
Mikhail Krasavin - https://orcid.org/0000-0002-0200-4772
the N–H insertion product [2].
Preprint
A non-peer-reviewed version of this article has been previously published
Conclusion
as a preprint doi:10.3762/bxiv.2020.15.v1
We demonstrated that the scope of α-diazo-γ-butyrolactams
being capable to undergo RhII-catalyzed X–H insertion reac-
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