Iridium-Catalyzed Cyclization of Isoxazolines and Alkenes: Divergent Access to Pyrrolidines, Pyrroles, and Carbazoles

Article abstract of DOI:10.1021/acs.orglett.6b02905

A heterogeneous iridium-complex-catalyzed N-O-cleaving rearrangement/cyclization of 2,3-dihydroisoxazoles with alkenes has been developed. It provides divergent access to multiple substituted pyrrolidines, pyrroles, and carbazoles. The iridium catalyst remains highly catalytic active after seven cycles. The gram-scale synthesis afforded a carbazole with strong bluish-violet fluorescence.

Full text of DOI:10.1021/acs.orglett.6b02905

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed Cyclization of Isoxazolines and Alkenes: Divergent
Access to Pyrrolidines, Pyrroles, and Carbazoles
†
,‡
†
†
†
†
,†
Zu-Feng Xiao, Ting-Hui Ding, Sheng-Wei Mao, Zaher Shah, Xiao-Shan Ning, and Yan-Biao Kang*
†
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡
College of Chemistry and Materials Science, Hubei Engineering University, Xiaogan, Hubei 432000, China
*
S Supporting Information
ABSTRACT: A heterogeneous iridium-complex-catalyzed N−O-cleaving rearrangement/cyclization of 2,3-dihydroisoxazoles
with alkenes has been developed. It provides divergent access to multiple substituted pyrrolidines, pyrroles, and carbazoles. The
iridium catalyst remains highly catalytic active after seven cycles. The gram-scale synthesis afforded a carbazole with strong bluish-
violet fluorescence.
yrrolidine and pyrrole heterocycles are core structures
forming six-membered rearrangement products. However, an
8% yield of pyrrole was observed by NMR spectroscopy. We
rationalized that the pyrrole was formed from the cyclization of
2,3-dihydroisoxazole and chalcone, where the chalcone was
generated via the isomerization of 2,3-dihydroisoxazole
(Scheme 1, bottom). Thus, the addition of extra chalcone
resulted in successful access to pyrroles. In this work, a
recyclable iridium-catalyst-promoted N−O-bond-cleaving cyc-
lization of 2,3-dihydroisoxazoles has been developed, providing
feasible access to pyrrolidines, pyrroles, and a carbazole with
strong bluish-violet fluorescence.
P
widely existing in natural products and bioactive
1
molecules. They are also important building blocks or
intermediates in organic synthesis or pharmaceuticals. Research
on diverse methods of synthesis of such heterocycles has alway2s
been a hot topic, attracting chemists to the challenge.
3
−7
Although many methods have been well-established,
the
synthesis of multiply substituted pyrrolidines and pyrroles is
more or less a challenge for traditional methods. We previously
reported a Ru-catalyzed N−O-cleaving rearrangement of N-
methyl isoxazolidines that provides feasible access to 1,3-
8
oxazinanes and 1,3-amino alcohols (Scheme 1). Compared
Initially, 2,3-dihydroisoxazole 1a and chalcone 2a were
9
,10
with isoxazolines, although 2,3-dihydroisoxazoles
bear a
subjected to the catalysis of 2.5 mol % [RuCl (p-cymene)]
2
2
11
relatively weak N−O bond, the N−O-cleaving isomerization
in toluene, and the desired product 3a was obtained in 60%
yield (Table 1, entry 1). The in situ-generated Ir-4,4′-
1
2
of 2,3-dihydroisoxazoles has barely been reported. Unfortu-
nately, 2,3-dihydroisoxazoles were found to be unsuccessful in
(Me) biPy complex gave 3a in 80% yield (entry 3), whereas
2
the in situ-generated Ru catalyst afforded 3a in 74% yield (entry
Scheme 1. N−O Cleavage: From Isoxazolidines to 2,3-
Dihydroisoxazoles
2). The replacement of 2,4,6-trimethylbenzoic acid (TMBA) by
t
BuCO H gave rise to an increase in the yield to 84%. Higher
2
temperature further increased the yield to 89% (entry 5). The
reactions in the absence of iridium or bipyridines were
unsuccessful (entries 6 and 7).
Next, various chalcones and 1,2-dihydroisozole 1a were
subjected to the standard reaction conditions, and the
corresponding pyrrolidines were obtained in good yields
(
Scheme 2). Both aryl- and heteroaryl-substituted enones 2
afforded the desired pyrrolidines 3 in 71−86% yield (3a, 3e, 3g,
Received: September 27, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02905
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Conditions
groups were examined, and the corresponding pyrrolidines
were obtained in up to 89% yield (3a, 3d, 3n, and 3o). When
substrates bearing alkyl substituents were subjected to the
reaction conditions, no target products were observed. This is a
limitation for this method.
The molecular structure of 3a was determined by single-
crystal X-ray diffraction (Figure 1). All of the substituents are
trans to each other.
b
entry
cat.
L
T (°C)
yield of 3a (%)
c
1
[Ru]
RuCl3
IrCl3
IrCl3
IrCl3
none
none
biPy
90
90
60
2
3
4,4′-(Me) biPy
4,4′-(Me) biPy
6,6′-(Me) biPy
6,6′-(Me) biPy
74
2
90
80
2
d
4
d
90
84
2
5
110
90
89
2
6
none
trace
d
e
7
6,6′-(Me) biPy
90
4
2
a
Conditions: 1a (0.5 mmol), 2a (0.6 mmol), cat. (5 mol %), 2,4,6-
trimethylbenzoic acid (TMBA) (0.15 mmol), toluene (2 mL), H O
Figure 1. Molecular structure of 3a.
2
b
1
(
18 μL), K CO (69 mg). Determined by H NMR spectroscopy.
2 3
d
c
[
RuCl (p-cymene)] (2.5 mol %). Pivalic acid instead of TMBA.
This N−O-cleaving rearrangement/cyclization reaction was
next applied to the one-pot direct synthesis of multiply
substituted pyrroles (Scheme 3). Various 4-oxazolines and
2
2
e
With 96% of 1a recovered.
a
Scheme 2. Scope of Pyrrolidines
a
Scheme 3. Scope of Pyrroles
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), IrCl (0.05 mol
3
%
), pivalic acid (0.075 mmol), K CO (0.5 mol), H O (18 μL),
2 3 2
toluene (2 mL), 110 °C, argon; then DDQ (1.0 mmol), 110 °C, argon.
alkenes were subjected to the cyclization/oxidation conditions
and afforded the desired pyrroles in up to 92% yield. A methyl
group is a stable N substituent that is tolerated in the DDQ
oxidation. Gram-scale syntheses gave 4e and 4f in 74% and 77%
yield, respectively.
The catalytic system was found to be suspended in the
solution, inspiring us to recycle the catalyst. After seven cycles,
the catalyst still performed well, giving an 81% yield (Scheme
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), IrCl (0.05 mol
), pivalic acid (0.075 mmol), K CO (0.5 mol), H O (18 μL),
2 3 2
b
3
%
toluene (2 mL), 110 °C, argon. On a 0.25 mol scale.
4
). For the expensive iridium catalyst, the recyclability is very
3
h, and 3i). Besides carbonyl groups, tosylstyrene and a
dienone were also suitable alkenes for construction of 3b and
c in 80% and 71% yield, respectively. A wide scope of alkyl
substituents such as methyl, benzyl, phenylethyl, and ethyl
important for industrial applications.
Pyrrole structures are the cores of carbazoles. Thus, this
method was applied in the synthesis of carbazoles (Scheme 5).
4f was subjected to the Pd(NCPh) Cl -catalyzed C−H bond
3
2
2
B
DOI: 10.1021/acs.orglett.6b02905
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Organic Letters
Letter
Scheme 4. Catalyst Recycling Experiments
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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.6b02905.
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Experimental details and spectroscopic data for all
products (PDF)
AUTHOR INFORMATION
■
*
Corresponding Author
(j) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010, 132,
ybkang@ustc.edu.cn
Notes
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ACKNOWLEDGMENTS
■
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We thank the National Natural Science Foundation of China
NNSFC 21672196, 21404096, and U1463202) and the Anhui
Provincial Natural Science Foundation (1608085MB24) for
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