Nickel-catalyzed formal [3 + 2]-cycloaddition of 2H-azirines with 1,3-dicarbonyl compounds for the synthesis of pyrroles

Article abstract of DOI:10.1016/j.tetlet.2020.152319

An efficient nickel-catalyzed formal [3 + 2]-cycloaddition of 2H-azirines with 1,3-dicarbonyl compounds for the synthesis of tetrasubstituted pyrroles has been developed. This transformation involves cleavage of the C[dbnd]N double bond and the construction of new C[sbnd]C and C[sbnd]N bonds. The reaction employs readily available starting materials, tolerates a wide range of functional groups, and affords tetrasubstituted pyrroles in good to high yields under mild reaction conditions. A gram-scale reaction was performed to demonstrate the scale-up applicability of this synthetic method.

Full text of DOI:10.1016/j.tetlet.2020.152319

Tetrahedron Letters 61 (2020) 152319
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nickel-catalyzed formal [3 + 2]-cycloaddition of 2H-azirines with
1,3-dicarbonyl compounds for the synthesis of pyrroles
a
a
Mi-Na Zhao a, , Gui-Wan Ning , De-Suo Yang , Peng Gao a,b, Ming-Jin Fan a, Li-Fang Zhao a
⇑
a Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, Shaanxi 721013, PR China
b Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an
710127, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient nickel-catalyzed formal [3 + 2]-cycloaddition of 2H-azirines with 1,3-dicarbonyl compounds
for the synthesis of tetrasubstituted pyrroles has been developed. This transformation involves cleavage
of the C@N double bond and the construction of new CAC and CAN bonds. The reaction employs readily
available starting materials, tolerates a wide range of functional groups, and affords tetrasubstituted pyr-
roles in good to high yields under mild reaction conditions. A gram-scale reaction was performed to
demonstrate the scale-up applicability of this synthetic method.
Received 27 June 2020
Revised 23 July 2020
Accepted 30 July 2020
Available online 16 August 2020
Keywords:
Ó 2020 Elsevier Ltd. All rights reserved.
Cycloaddition reaction
Nickel-catalyzed
2H-Azirines
Pyrroles
Introduction
Recently, an elegant Fe(II)-catalyzed homolytic cleavage of the
CAN single bond of 2H-azirines and sequential radical cyclization
Pyrroles are an extremely privileged heterocyclic class com-
monly found in natural products, drugs, and functional materials
and are also used as intermediates for the synthesis of bioactive
molecules [1]. As a consequence, a wealth of synthetic methods
have been developed for the construction of pyrrole rings [2]. Clas-
sical methodologies such as the Knorr reaction [3], Hantzsch reac-
tion [4], and Paal-Knorr reaction [5] as well as multicomponent
reactions [6], dehydrogenative coupling reactions [7], and transi-
tion-metal catalyzed cyclization reactions [8], have been devel-
oped for the synthesis of substituted pyrroles. Despite these
advances, versatile and flexible methods for the synthesis of mul-
tisubstituted pyrroles from readily available starting materials
remains an important goal within synthetic chemistry.
2H-Azirines are powerful building blocks for the synthesis of
various azaheterocycles due to their high ring strain and corre-
sponding unique reactivity [9]. Accordingly, numerous valuable
organic transformations of 2H-azirines have been documented
[10]. Three general types of ring-opening reactions of 2H-azirines,
such as nucleophilic addition to the C@N bond [11], transition-
metal-assisted heterolytic CAN single bond cleavage [12], and vis-
ible-light-induced CAC bond cleavage [13], have attracted exten-
sive attention.
with enamides for the synthesis of pyrroles was developed by
Guan and co-workers (Scheme 1a) [14]. Although progress has
been achieved in this area, the development of new catalytic sys-
tems for the construction of N-heterocycles using 2H-azirines as
substrates under mild reaction conditions is still desirable. In
1977, the Ni-catalyzed synthesis of pyrroles from 2H-azirines and
activated ketones was reported by Schuchardt and co-workers
[15]. However, the scope of substrates for the reaction is limited.
Herein, we report an efficient nickel-catalyzed formal [3 + 2]-
cycloaddition of 2H-azirines with 1,3-dicarbonyl compounds for
the synthesis of tetrasubstituted pyrroles (Scheme 1b).
Results and discussion
We commenced our investigation with optimization studies
using the model [3 + 2]-cycloaddition of 2,3-diphenyl-2H-azirine
1a and acetylacetone 2a (Table 1). Gratifyingly, when FeCl2 was
used as the catalyst, the desired tetrasubstituted pyrrole 3aa was
obtained in 25% yield in toluene at 80 °C (Table 1, entry 1). Differ-
ent solvents such as DCE, CH3CN, and 1,4-dioxane were screened
(Table 1, entries 2–4). CH3CN was found to be the most suitable
solvent for the reaction, providing 3aa in 59% yield (Table 1, entry
3). Further experiments showed that Ni(OAc)2 was the most effec-
tive catalyst giving the desired pyrrole 3aa in 90% yield (Table 1,
entries 5–8). Notably, no reaction occurred in the absence of the
⇑
Corresponding author.
E-mail address: zhaomina@bjwlxy.edu.cn (M.-N. Zhao).
https://doi.org/10.1016/j.tetlet.2020.152319
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
M.-N. Zhao et al. / Tetrahedron Letters 61 (2020) 152319
2H-Azirines with electron-withdrawing substituents on Ar1, such
as fluoro, chloro, and bromo and sensitive functional groups such
as iodo, were well tolerated and afforded the corresponding pyr-
roles 3ia-3la in good yields. In addition, the 2-naphthyl group
was also compatible and gave the desired pyrrole 3ma in 80% yield.
Subsequently, substrates bearing various functional groups on
Ar2 were investigated (Scheme 3). 2H-Azirines with methyl, phe-
nyl, or halogen groups such as fluoro, chloro, and bromo on Ar2,
gave the corresponding pyrroles 3na-3va in 40–95% yield. The X-
ray crystallographic analysis of 3sa not only unambiguously deter-
mined the configuration of the molecule but also confirmed that
C@N double bond cleavage of the 2H-azirines was involved in
the reaction (CCDC 1955552) [16]. These results indicated that
the electronic nature of the groups on Ar2 has little effect on the
reaction. However, steric effects play a role in the reaction. 2,4,6-
Trimethyl substituted 2H-azirine 1q afforded the desired pyrrole
3qa in only 40% yield. Furthermore, when 3,4-dichloro substituted
2H-azirine 1v was employed as a disubstituted substrate, the reac-
tion proceeded well to give the desired pyrrole 3va in 88% yield.
In an attempt to provide access to a broader range of pyrroles,
the reaction with different substituents on Ar1 and Ar2 was inves-
tigated (Scheme 4). Gratifyingly, 2H-azirines 1w-1z proceeded
smoothly to give the corresponding pyrroles 3wa-3za in 89–95%
yield.
Scheme 1. Transition-metal catalyzed synthesis of pyrroles from 2H-azirines.
Ni(OAc)2 catalyst (Table 1, entry 9). The reaction temperature was
also varied; the yield of 3aa was further increased to 92% when the
reaction was conducted at 60 °C (Table 1, entries 10–11). More-
over, changing the molar ratio of [2a]/[1a] or conducting the reac-
tion under an argon atmosphere resulted in no improvement
(Table 1, entries 12–13). Finally, the optimal reaction conditions
were determined as: 1a (0.2 mmol), 2a (0.3 mmol) and Ni(OAc)2
(10 mol%) in CH3CN at 60 °C.
With the optimized reaction conditions established, a series of
2H-azirines were investigated in order to extend the substrate
scope. Variations of the Ar1 group on the C@N double bond moiety
of 2H-azirines were first examined (Scheme 2). 2H-Azirines with
electron-donating groups on Ar1, such as methyl, ethyl, tert-butyl,
and methoxyl, afforded the corresponding pyrroles 3aa-3ha in 81–
98% yield. 2H-Azirines with Ar1 bearing ortho-substituted groups
such as 1c and 1d proceeded smoothly to give the desired pyrroles
3ca and 3da in 96% and 87% yield, respectively, suggesting that
the transformation was insensitive to the steric hindrance of Ar1.
Furthermore, various 1,3-dicarbonyl compounds 2 were inves-
tigated to extend the substrate scope (Scheme 5). Expectedly,
phenyl(2,4,5-triphenyl-1H-pyrrol-3-yl)methanone
3ab
was
obtained in 89% yield using 1,3-diphenylpropane-1,3-dione 2b
(Scheme 5, eq. 1). 1-Phenylbutane-1,3-dione 2c gave two regioi-
somers 3ac and 3ac’ in 56% and 31% yield, respectively (Scheme 5,
eq. 2). However, ethyl acetoacetate 2d and methyl acetoacetate
2e produced the corresponding pyrroles 3ad and 3ae in only
22% and 13% yield, respectively, under slightly modified condi-
tions (Scheme 5, eq. 3).
To demonstrate the synthetic utility of this reaction, a gram-
scale (6 mmol, 1.16 g) reaction was performed under the standard
conditions. Expectedly, 1-(2-methyl-4,5-diphenyl-1H-pyrrol-3-yl)
ethan-1-one 3aa was formed in 87% yield (Scheme 6, eq. 1).
Table 1
Optimization of the reaction conditions.a
Entry
Catalyst
Solvent
Temp (oC)
Yield 3aa (%)
1
2
3
4
5
6
7
8
FeCl2
FeCl2
FeCl2
FeCl2
Cu(OAc)2
Ni(acac)2
NiCl2
Ni(OAc)2
—
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
toluene
DCE
80
80
80
80
80
80
80
80
80
60
40
60
60
25
45
59
33
79
86
72
90
0
92
85
80
81
CH3CN
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12b
13c
a
b
c
Reagents and conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (10 mol%), solvent (3 mL); isolated yield.
2a (0.2 mmol) was added.
Reaction was performed under argon.

M.-N. Zhao et al. / Tetrahedron Letters 61 (2020) 152319
3
Scheme 3. Substrate scope with respect to Ar2. Reagents and conditions:
1
(0.2 mmol), 2a (0.3 mmol), Ni(OAc)2 (10 mol%), CH3CN (3 mL), 60 °C, 6 h, isolated
yield.
Scheme 2. Substrate scope with respect to Ar1. Reagents and conditions:
1
(0.2 mmol), 2a (0.3 mmol), Ni(OAc)2 (10 mol%), CH3CN (3 mL), 60 °C, 6 h, isolated
yield.
To gain insights into the reaction mechanism, control experi-
ments were performed as highlighted in Scheme 6. When the rad-
ical scavenger 2,2,6,6-tetramethylpiperdine-1-oxyl (TEMPO), or
butylated hydroxytoluene (BHT) was added to the reaction, the
desired product 3aa was obtained in 83% and 85% yield, respec-
tively (Scheme 6, eq. 2 and 3). These results ruled out the possibil-
ity of a free radical reaction mechanism.
Scheme 4. Ni-catalyzed cycloaddition of various 2H-azirines and acetylacetone 2a.
Reagents and conditions: 1 (0.2 mmol), 2a (0.3 mmol), Ni(OAc)2 (10 mol%), CH3CN
(3 mL), 60 °C, 6 h, isolated yield.
On the basis of the above results and previous studies [11,17], a
tentative mechanism was proposed for the Ni-catalyzed cycloaddi-
tion reaction (Scheme 7). First, the enolization of acetylacetone 2
occurred in the presence of Ni(OAc)2 to give Ni(II) enolate A. Next,
nucleophilic addition of enolate A to the imine bond of 2H-azirines
1 afforded aziridine intermediate B. Intramolecular nucleophilic
addition followed by ring-opening of aziridine intermediate B gave
intermediate C. Finally, protonation of intermediate C with acetic
acid followed by dehydration produced pyrrole 3 and regenerated
the Ni(OAc)2 catalyst.
bonyl compounds for the synthesis of tetrasubstituted pyrroles.
The reaction proceeded through intra- and intermolecular reac-
tions of the strained azirine ring, involving nucleophilic addition
to the C@N bond and ring-opening of the aziridine ring. The reac-
tion exhibits good functional group tolerance, mild reaction condi-
tions and good to high yields. Further scope and mechanistic
studies of the reaction are underway in our laboratory.
Declaration of Competing Interest
Conclusion
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
In summary, we have developed an efficient Ni(OAc)2-catalyzed
formal [3 + 2]-cycloaddition reaction of 2H-azirines and 1,3-dicar-

4
M.-N. Zhao et al. / Tetrahedron Letters 61 (2020) 152319
Acknowledgments
This work was supported by generous grants from the Natural
Science Foundation of Shaanxi Province (No. 2018JQ2031), Scien-
tific Research Foundation of Shaanxi Provincial Key Laboratory
(No. 19JS006), the PhD scientific research project of Baoji Univer-
sity of Arts and Sciences (No. ZK2018057), and China Postdoctoral
Science Foundation (No. 2019T120936).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152319.
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