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DOI: 10.1002/adsc.202100329
Synthesis of 1-Pyrroline by Denitrogenative Ring Expansion of
Cyclobutyl Azides under Thermal Conditions
Yuya Miki,a Naohito Tomita,a Kazuho Ban,a Hironao Sajiki,a,* and
Yoshinari Sawamaa, b,*
a
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
Fax: +81-58-230-8109
E-mail: sajiki@gifu-pu.ac.jp; sawama@gifu-pu.ac.jp
Current address
b
Graduate School of Pharmaceutical Sciences,
Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Manuscript received: May 25, 2021; Revised manuscript received: May 25, 2021;
Version of record online: ■■■, ■■■■
sion of cyclobutane carboxylamides with more than
Abstract: We herein report an efficient and system-
2 equiv. of phenyliodine(III) bis(trifluoroacetate).[3d]
atic synthesis of 1-pyrrolines from cyclobutyl azides
On the other hand, cyclopropyl azides underwent
under thermal and neutral conditions. The reaction
denitrogenative ring expansion under thermal condi-
proceeded without any additional reagents, and
tions to produce 1-azetines, while the reactivity of
nitrogen was generated as the sole by-product.
cyclobutyl azides was relatively lower (Scheme 1a).[4]
Furthermore, the generated 1-pyrrolines could be
However, only a few examples of the synthesis of 1-
continuously transformed into pyrroles, N-Boc-
amines, and oxaziridines in an one-pot manner.
pyrroline from cyclobutyl azides possessing specific
structures have been reported.[5–7] (3-Pyridyl)-cyclo-
butyl azide generated in situ from cyclobutanol using
the highly toxic hydrogen azide was transformed into a
Keywords: ring expansion; thermal conditions; cy-
1-pyrroline derivative by the strong acid-induced
clopropyl azide; one-pot reaction; heterocycles
Schmidt
rearrangement-type
ring
expansion
(Scheme 1b),[5] while 1-benzoyl-cyclobutyl azide was
transformed to 1-pyrroline in the presence of catalytic
Pyrrolines have a stable five-membered cyclic imine FeBr2 under thermal conditions[6] (Scheme 1c). Addi-
skeleton and are frequently found in natural products tionally, [2+2]-cycloaddition of vinyl azide with
and bioactive compounds.[1] They are also used as tetracyanoethylene and subsequent ring expansion
precursors[2] for the synthesis of pyrroles by gave the corresponding 1-pyrrolines at room temper-
oxidation[2a] and pyrrolidines via reduction.[2d] ature (the role of cyano group is unclear;
Although some synthetic methods have been Scheme 1d).[7] We herein demonstrate an efficient and
reported,[3] the applicable substrates are limited, and systematic synthesis of 1-pyrrolines (2) from cyclo-
there seems to be no systematic method for the butyl azides (1) in o-xylene under thermal and neutral
synthesis of 1-pyrrolines. The reaction of 4-chlorobu- conditions. Nitrogen was generated as the sole by-
tyronitrile with Grignard reagents gave imine inter- product. Furthermore, the generated 1-pyrrolines could
mediates, which underwent intramolecular nucleophilic continuously undergo further transformations in an
substitution to the chlorine substituent to produce 1- one-pot manner (Scheme 1e).
pyrrolines.[3a] Although N-vinylpyrrolidone derivatives
First, several solvents (0.4 mL) were screened using
could be converted to 1-pyrrolines via aminoketone 1-phenyl cyclobutyl azide (1a; 0.1 mmol) as a sub-
°
intermediates under the conditions using alkyl strate at 160 C (temperature of the external heating
lithium[3b] or ester derivatives,[3c] a strong acid or base device) under argon for 24 h (Table 1). The reaction
was required for steps such as the devinylation and performed in N,N-dimethylformamide (DMF) gave the
intramolecular annulation of aminoketone intermedi- desired 2-phenyl-1-pyrroline (2a) in 58% yield (en-
ates. 1-Pyrrolines could also be synthesized by the try 1). N,N-Dimethylacetamide (DMA) and dimethyl
Hofmann rearrangement and subsequent ring expan- sulfoxide (DMSO) were inefficient, and lower yields
Adv. Synth. Catal. 2021, 363, 1–5
1
© 2021 Wiley-VCH GmbH
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