Iron-Catalyzed Radical Cycloaddition of 2H-Azirines and Enamides for the Synthesis of Pyrroles

Article abstract of DOI:10.1021/acs.orglett.7b04007

A novel and efficient Fe-catalyzed radical cycloaddition of 2H-azirines and enamides for the synthesis of substituted pyrroles has been developed. The radical cycloaddition reaction proceeded through a conceptually new Fe(II)-catalyzed homolytic cleavage of C-N bond of 2H-azirines sequential radical cyclization with enamides. The reaction used readily available starting materials, tolerated various functional groups, and afforded valuable triaryl-substituted pyrroles in good to high yields under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b04007

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Radical Cycloaddition of 2H‑Azirines and Enamides
for the Synthesis of Pyrroles
Mi-Na Zhao,†,‡ Zhi-Hui Ren,† De-Suo Yang,‡ and Zheng-Hui Guan*,†
†Key Laboratory of Synthetic and Nature Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials
Science, Northwest University, Xi’an 710127, P. R. China
‡Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences,
Baoji 721013, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient Fe-catalyzed radical cycloaddition
of 2H-azirines and enamides for the synthesis of substituted pyrroles
has been developed. The radical cycloaddition reaction proceeded
through a conceptually new Fe(II)-catalyzed homolytic cleavage of C−
N bond of 2H-azirines sequential radical cyclization with enamides. The
reaction used readily available starting materials, tolerated various
functional groups, and afforded valuable triaryl-substituted pyrroles in
good to high yields under mild reaction conditions.
Scheme 1. Transition-Metal-Catalyzed Cycloaddition of 2H-
Azirines/Aziridines
2H-Azirines, the smallest nitrogen-containing three-membered
ring, represent a highly important class of compounds found in
natural products and biological active compounds.1 Due to
their high ring strain and easy ring opening, 2H-azirines are also
powerful building blocks in organic synthesis.2,3 In particular,
the ring-opening reactions of 2H-azirines for the synthesis of
various azaheterocycles, such as indoles,4 pyrroles,5 pyridines,6
and pyrazines,7 have attracted extensive attention in the past
decade. For example, Rh-catalyzed ring-expansion of 2-vinyl-
2H-azirines for the synthesis of pyrroles has been developed by
Park and co-workers (Scheme 1a).8 The Au-catalyzed ring-
expansion of 2-propargyl-2H-azirines for the synthesis of
pyridines has been developed by the group of Gagosz (Scheme
1b).6a However, the ring-opening of 2H-azirines was still
generally involved in the heterolytic C−N single-bond-cleavage
mode, thus restricting the broader utility of 2H-azirines.
Therefore, the development of a novel ring-opening mode to
exploit the new reactions of 2H-azirines is an urgent but
challenging task.
Very recently, elegant Ti(III)-catalyzed homolytic cleavage of
the C−N single bond of N-acylaziridines sequential with radical
coupling with alkenes has been developed independently by the
groups of Lin9 and Gansauer10 (Scheme 1c). In these reactions,
̈
the polar C−N single bond was homolytically cleaved in the
presence of a redox-active Ti(III) catalyst,11 thus initiating the
radical-coupling reaction. We hypothesized that a radical ring
opening of 2H-azirines might occur in the presence of redox-
active transition-metal catalysis,12 thus providing a new ring-
opening mode of 2H-azirines for versatile reactions. In this
paper, we describe a conceptually new Fe(II)-catalyzed radical
ring opening of 2H-azirines sequential cycloaddition with
enamides for the synthesis of substituted pyrroles (Scheme 1).
The Fe-catalyzed ring-opening reaction opens a novel mode for
radical cycloaddition reactions of 2H-azirines.
We began our study with the transition-metal-catalyzed
radical cycloaddition of 2H-azirines and enamides because the
easily accessible and versatile enamides would make the
coupling reaction highly flexible and broadly useful.13,14
Therefore, the cycloaddition reaction of 2,3-diphenyl-2H-
Received: December 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b04007
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
azirine 1a and enamide 2a was conducted in the presence of
various transition-metal catalysts (Table 1, entries 1−6).
a
Table 1. Optimization of the Reaction Conditions
entry
catalyst
solvent
T (°C)
yield (%)
b
1
Cp*TiCl3
Cp*TiCl3
Cp*TiCl3
CuBr2
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
25
0
0
b
2
25
b
3
100
100
100
100
100
100
100
100
100
100
100
100
100
80
7
4
5
<5
<5
0
Cu(TFA)2
[M]
c
6
7
FeCl2
12
8
8
FeCl2
9
FeCl2
toluene
DCE
26
74
62
70
61
65
0
10
11
12
13
14
15
16
17
FeCl2
FeCl3
DCE
Fe(OTf)2
Fe(OTf)3
FeBr3
DCE
DCE
DCE
DCE
FeCl2
DCE
0
FeCl2
DCE
120
85
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (10
b
mol %), solvent (2 mL); isolated yield. Zn dust (20 mol %) was
added. [Rh(cod)Cl2]2, Rh2(OAc)4, Ru(cod)Cl2, NiCl2, or Ni(OAc)2
c
was used as the catalyst.
Figure 1. Fe-catalyzed cycloaddition of 2H-azirine 1a and various
enamides. Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), FeCl2
(10 mol %), DCE (2 mL); isolated yield.
However, after several attempts, only 7% yield of the desired
pyrrole 3aa was observed in the presence of Ti(III) catalyst in
CH3CN at 100 °C (Table 1, entries 1−3). Copper catalysts
gave only a trace amount of the product 3aa (Table 1, entries 4
and 5), whereas no reaction occurred when Rh, Ru, or Ni
catalyst was employed in the reaction (Table 1, entry 6).
Gratifyingly, a 12% yield of cycloaddition product 2,3,5-
triphenyl-1H-pyrrole 3aa was obtained when FeCl2 was used as
the catalyst (Table 1, entry 7). This primary result prompted us
to focus on the Fe-catalyzed cycloaddition of 2H-azirines and
enamides. Then, different solvents such as THF, toluene, and
DCE were screened to optimize the reaction conditions (Table
1, entries 8−10). DCE was found to be the most suitable
solvent for the reaction, providing 3aa in 74% yield (Table 1,
entry 10). Further experiments showed that other Fe catalysts,
such as FeCl3, Fe(OTf)2, Fe(OTf)3, and FeBr3, were inferior to
FeCl2 (Table 1, entries 11−14). Notably, Fe catalyst plays a
vital role in the reaction. No reaction occurred in the absence of
the iron catalyst (Table 1, entry 15). Finally, the reaction
temperature was also varied, and 120 °C gave the best result,
improving the yield of 3aa to 85% (Table 1, entries 16 and 17).
Having optimized the reaction conditions, a series of
enamides were investigated for extending the substrate scope
(Figure 1). Enamides with electron-neutral or electron-
donating groups on aryl rings, such as alkyl, methoxyl, phenyl,
and amido, all gave the corresponding trisubstituted pyrroles
3ab−ah in high yields. Enamides with an electron-withdrawing
group such as fluoro, chloro, bromo, and trifluoromethyl were
well tolerated in the reaction, generating the corresponding
pyrroles 3ai−am in 50−88% yields. The structure of 3aj was
unambiguously confirmed by X-ray diffraction analysis. o-
Methyl- and chloro-substituted enamides gave the desired
pyrroles 3ac and 3ak in 50% and 52% yields, probably due to
steric hindrance of the substrates. Furthermore, 2-naphthyl
enamide 2n and thienyl enamide 2o proceeded smoothly as
well to give the desired pyrroles 3an−ao in 81% and 66%
yields, respectively. In addition, the desired tetrasubstituted
pyrrole 3ap was obtained in 46% yield when β-methyl-
substituted enamide 2p was used as the substrate. However,
no reaction occurred when an aliphatic enamide such as N-(3,3-
dimethylbut-1-en-2-yl)acetamide 2q or N-vinylacetamide 2r
was used as the substrate.
Subsequently, the scope of 2H-azirines was investigated, and
the results are summarized in Figure 2. Variations of the R3
group on the CN double bond moiety of 2H-azirines were
first examined. Both electron-donating (1b−f) and electron-
withdrawing (1g,h) groups on the aryl ring were successfully
introduced, thus providing the corresponding pyrroles 3ba−ha
in 64−87% yields. 2H-Azirine with an o-methyl group on the
phenyl ring afforded the pyrrole 3ca in 87% yield, implying that
the transformation was insensitive to steric hindrance of the
2H-azirines. The 2-naphthyl group was also compatible to
provide the desired pyrrole 3ia in 60% yield. However, 3-
methyl-2-phenyl-2H-azirine 1j was inactive under the reaction
conditions. Notably, the electronic nature of the R4 substituent
had little effect on this reaction. Various aromatic substituents
on R4 were tolerated to give the corresponding trisubstituted
pyrroles 3ka−na in 69−72% yields. In addition, the 3-phenyl-
B
DOI: 10.1021/acs.orglett.7b04007
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
homolytic radical ring opening of 2H-azirine should be involved
in the transformation.
On the basis of the above results, a tentative mechanism for
the Fe-catalyzed cycloaddition reaction is proposed in Scheme
3.9−12,15 First, the reductive radial ring opening of 2H-azirine 1
Scheme 3. Proposed Mechanism for Fe-Catalyzed
Cycloaddition of 2H-Azirines and Enamides
occurred in the presence of Fe(II) to give a secondary radical
intermediate A. Next, radical coupling of intermediate A and
enamide 2 afforded the tertiary radical intermediate B. Then
oxidative radical ring closure of intermediate B gave the
intermediate C. Simultaneously, the active Fe(II) catalyst was
released to facilitate the next catalytic cycle. Finally, elimination
of a molecular of amide (NH2Ac) sequential with tautomeriza-
tion produced the pyrrole 3.
In summary, we have developed an unprecedented Fe(II)-
catalyzed ring opening of 2H-azirines and cycloaddition with
enamides for the synthesis of pyrroles. The homolytic C−N
bond cleavage and radical coupling with enamides proceeded
under mild overall redox-neutral conditions. This novel Fe(II)-
catalyzed radical ring opening mode of 2H-azirines allowed the
rapid synthesis of valuable triaryl-substituted pyrroles in high
yields. The method shows broad substrate scope and good
functional group tolerance. Further studies on the Fe-catalyzed
transformations of 2H-azirines are in progress in our laboratory.
Figure 2. Fe-catalyzed cycloaddition of various 2H-azirines and
enamide 2a. Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol),
FeCl2 (10 mol %), DCE (2 mL); isolated yield.
2H-azirine 1o also successfully performed the cycloaddition
reaction to give the 2,5-diphenyl-1H-pyrrole 3oa in 56% yield.
Furthermore, the trisubstituted pyrroles with different aryl
groups 3ng and 3nj were synthesized in 75% and 76% yields,
respectively, by the cycloaddition reaction (Scheme 2, eq 1).
Scheme 2. Preliminary Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b04007.
Detailed experimental procedures, characterization data,
and NMR spectra for all products (PDF)
Accession Codes
CCDC 1590238−1590239 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
These trisubstituted pyrrole products 3ng−nj not only clearly
confirmed that the C−N single bond cleavage of 2H-azirines
was involved in the reaction but also suggested the
regioselectivity of the reaction. To gain insight into the ring-
opening mechanism, the radical-trapping experiment has been
conducted as well (Scheme 2, eq 2). The TEMPO-trapped
product 4 was obtained in 62% yield, indicating that the
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guanzhh@nwu.edu.cn.
ORCID
De-Suo Yang: 0000-0002-7190-3122
C
DOI: 10.1021/acs.orglett.7b04007
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the National
Natural Science Foundation of China (21622203 and
21472147), China Postdoctoral Science Foundation funded
project (2017M620466), Fund of Northwest University
(334100035), and the PhD scientific research project of Baoji
University of Arts and Sciences (ZK2018057).
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