First synthesis of fused-Δ1-pyrrolines via intramolecular 1,3-dipolar cycloaddition of ketoimine: A complete diastereoselective approach

Article abstract of DOI:10.1039/c0cc03873c

Intramolecular formal 1,3-dipolar cycloaddition of ketoimine is developed with PhIO for the first synthesis of fused-Δ¹-pyrrolines. The scope of the reaction, complete diastereoselectivity and its rationalization by a computational study are re

Full text of DOI:10.1039/c0cc03873c

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First synthesis of fused-D1-pyrrolines via intramolecular 1,3-dipolar
cycloaddition of ketoimine: A complete diastereoselective approachw
Palash Pandit, Nirbhik Chatterjee and Dilip K. Maiti*
Received 15th September 2010, Accepted 14th October 2010
DOI: 10.1039/c0cc03873c
Intramolecular formal 1,3-dipolar cycloaddition of ketoimine is
developed with PhIO for the first synthesis of fused-D1-pyrrolines.
The scope of the reaction, complete diastereoselectivity and its
rationalization by a computational study are reported.
Table 1 Development and optimization of the reactiona
Entry Reagentb Reaction conditions Conversion(%) 4, Yield(%)
1
2
3
PhI(OAc)2 CH2Cl2, rt, 10 h
No reaction
No reaction
—
—
—
PhICl2
PhIO-
TMSOTf
PhIO
CH2Cl2, rt, 10 h
CH2Cl2, À80 1C, 2.5 h Decomposed
1,3-Dipolar cycloaddition (DC) is an extremely powerful atom-
economical strategy in organic chemistry and its allied branches of
science toward construction of novel heterocyclic scaffolds.1–4
Relative to the conventional method, Lewis acid controlled
1,3-DC offers a significant improvement in the reaction rate, the
regioselectivity and/or stereoselectivity. In this regard, an intra-
molecular approach is more interesting due to the favorable
entropy and conformational restriction in its transition state.
1,3-DC of an azomethine ylide derived from aldimine has been
intensely studied to afford a pyrrolidine moiety.2 Surprisingly the
use of ketoimine has received only scant attention.3 Generation of
azomethine ylides from ketoimines and their intramolecular 1,3-
DC with an olefin with a tandem elimination process under an
organic Lewis acid cum oxidant has never been realized. This
approach would be attractive since it can achieve the first synthesis
of fused-D1-pyrroline. In a continuous effort to synthesize novel
heterocyclic functional molecules1c,5 especially under metal-free
mild reaction conditions, we have developed novel properties of
iodosobenzene (PhIO) to synthesize isoxazolines,5a imidazoles5b
and 1,2,4-triazoles.1c Expanding the interest of this powerful
reagent in a most fascinating synthetic approach, we herein report
the straightforward access of fused-D1-pyrroline (4) by the intra-
molecular formal 1,3-DC of ketoimine (1, Scheme 1) with PhIO.
The excellent Lewis acid property of PhIO has displayed excep-
tional stereoselectivity in the cycloaddition step and broad scope
toward other rapidly accessible and valuable heterocycles.
4
5
6
CH2Cl2, rt, 3 h
THF, rt, 3 h
MeCN, rt, 3 h
100
100
100
67c
66c
67c
PhIO
PhIO
a
b
c
Isolated yield (4a). 1.25 mol. Hydrolysed to ketone (B10–15%).
and devices.6,7 They have widespread availability in roasted
flavor foods, natural products and biosynthetic intermediates.7
The presence of a prochiral imine functionality and three stereo-
genic centers in its skeleton have made it a versatile synthon
toward varied biologically active compounds.8,9 Synthesis of
D1-pyrrolines is mainly addressed by metal Lewis acid
catalyzed intermolecular 1,3-DC of nitrile ylides, azaallyl anions,
azalactones,10 cyclization9 and photochemical reactions.11
We have started our study with the ketoimine 1a as the model
reaction for screening several hypervalent iodine(III)12 reagents as
organic Lewis acids. Most commonly used PhI(OAc)2, PhICl2
and PhIO-TMSOTf13 are not effective (entries 1–3, Table 1).
Gratifyingly, under the neutral and mild reaction conditions
PhIO served as an optimum Lewis acid for a cascade cyclization
process to furnish the desired fused-pyrroline (4a). Poor solubility
of PhIO in common organic solvents is explained due to its
bridged polymeric structure involving an intermolecular IÁÁÁO
interaction.12 However, it dissolves smoothly with progress of the
reaction (entries 4–6).
With this initial success, the substrate scope of the formal
D1-Pyrrolines and their analogues have found broad
applications as pharmaceuticals, pesticides, agrochemicals
cycloaddition reaction was explored with
a small series
of precursors (1b–g, entries 1–6, Table 2) toward rapidly
(2.0–5.0 h) accessible fused-D1-pyrrolines (4b–g) with moderate
yields (60–80%). We were surprised to see that only the ethyl
ester group in 4c (entry 2) was hydrolyzed, whereas other ester
groups were tolerated. Only one cycloadduct was found in each
individual case (entries 3–6) possessing cis absolute selectivity at
the newly generated C-C bond bearing a quaternary stereogenic
center, C9b. Surprisingly, the 1,3-DC reaction of O-cinnamyl
precursors (1a–c) produced only one diastereomer (4a–c) with
cis–cis (C3a-H-C9b-CH3 and C3-Ph-C3a-H) stereogenic centers.
The structure was determined by means of single crystal X-ray
diffraction studies (4a, Fig. 1)14 and spectroscopic analyses (see
ESIw). The moderate yield might be attributed to the hydrolysis
of ketoimines15 (10–15%) by the water molecule generated
during the oxidative dehydration process. Fabrication of nano-
structured organic materials involving noncovalent weak inter-
actions of the fused-heterocyclic scaffolds is in progress
(see ESIw).5b,c
Scheme 1 Construction of fused-pyrroline by 1,3-DC of ketoimine.
Department of Chemistry, University of Calcutta,
University College of Science, 92, A. P. C. Road, Kolkata-700009,
India. E-mail: maitidk@yahoo.com; Fax: +91-33-2351-9755;
Tel: +91-33-2350-9937
w Electronic supplementary information (ESI) available: Experimental
procedures, NMR spectra, characterization, DFT data, CIF file and
studies of weak noncovalent interactions. CCDC 773893. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc03873c
c
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Chem. Commun., 2011, 47, 1285–1287 1285

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Table 2 Synthesis of fused-pyrroline (4) and pyrrole (6)
Entry Ketoimine Pyrroline, Pyrrole Time(h) Yield(%)
Table 3 Construction of chiral imidazole from aldimine
1
3
70
Sugar-based chiral
imidazole
Time Yield
(h) (%)
Entry Chiral imine
2
3
4
5
2
5
4
3
80
62
71
60
1
5.0 82
4.0 82
5.0 80
2
3
6
7
5
4
61
70
4
5
4.0 72
3.5 78
8
9
5
4
72
62
However, an azomethine ylide-hypervalentiodane complex
of aldimine did not react with the olefin5b to follow the
intramolecular 1,3-DC pathway of ketoimine. It rapidly
(3.5–5.0 h) underwent intermolecular formal cycloaddition
with a strongly electron donating imine. Such an extraordinary
Lewis acid cum oxidation property of PhIO was utilized to
achieve highly functionalized sugar-based chiral imidazoles
(7, Table 3) in excellent yields (72–82%). Installation of two
sugar units was achieved side-by-side. The structure was
determined by means of single crystal X-ray diffraction
analysis (see ESIw). Imidazole is a common heterocyclic
scaffold of many natural products and its chiral analogues
had found special applications as effective reagents, catalysts,
receptors and pharmaceuticals.17
Fig. 1 Single crystal X-ray diffraction structure of 4a.
In contrast to Grigg’s commonly used method for generation
of azomethine ylides by 1,2-prototropic shift of a-aldiminoester
under strong heating conditions,4 formation of an azomethine
ylide dipolar complex with the powerful organic Lewis acid
proceeds through predominant coordination even with the
ketoimine (1a) at ambient temperature. The PhIO-activated
species (A) may exist in two alternative highly chelated
zwitterionic stereoisomers (I, II, Scheme 2) with varied orientation
of the methyl group. I and II follow the unidirectional formal
[3+2]-intramolecular cycloaddition pathway with the olefin
involving five membered transition states. The intermediates
III and IV undergo rapid construction of the double bond
To evaluate the scope and generality of the metal-free simple
synthetic protocol, the intramolecular 1,3-DC reaction of
unactivated propargylic precursors (2a–c, entries 7–9) was
investigated. This afforded very uncommon heterocyclic
scaffolds of fused-2H-pyrroles (6a–c) possessing quaternary
centers (C9b) with fast reaction rates (4–5 h) and moderate
yields (62–72%). Fused and highly substituted pyrroles are
important structural elements of many natural products and
have found widespread applications in medicinal chemistry,
catalysis and material science.16
c
1286 Chem. Commun., 2011, 47, 1285–1287
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1,3-DC of ketoimine under an organic Lewis acid cum oxidant.
The remarkable diastereoselectivity that was found experimentally
is predicted by a DFT study. This simple synthetic route is
extended toward synthesis of fused-pyrroles and sugar-based
chiral imidazoles.
We acknowledge the financial support of this work by the
DST (SR/S1/OC-22/2006), CRNN and CSIR (SRF), India.
Notes and references
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Scheme 2 Possible reaction path and DFT study.
Table 4 Geometry optimization of diastereomer 4a and 5a
Density functional theory
ab initio
B3LYP/
6-31G
B3LYP/
6-311G
B3LYP/
6-311G**
HF/6-31G
Energy
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aDE4a–5a
aE5a
À7.85
À730475.66
À730483.51
À6.81
À8.62
À9.01
À735192.83
À735199.64
À735359.41
À735368.03
À735578.28
À735587.29
aE4a
Energy reported in kcal molÀ1
.
a
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involving reductive elimination of the hypervalent-iodane
moiety toward diastereomers 4a(cis–cis) and 5a(trans–cis).
However, 5a was not found from the post-reaction mixture.
We have carried out geometry optimization of the
4a(cis–cis) and 5a(trans–cis) by both ab initio and density
functional theory (DFT) as implemented in the Gaussian 03
program.5a,c,18 Results in Table 4 reveal that 4a is the
thermodynamically stable product. The ground state energy
difference (DE4a–5a) between 4a (E4a) and 5a (E5a) is as high as
À9.01 kcal molÀ1. However, conformational and steric
outcome under kinetic control can be rationalized by comparing
the relative geometry and energy optimized transition state TS
III (between I and III) with the TS IV (between II and IV) at
the formal 1,3-DC step.5a,18c Each of the azomethine ylide
complexes of 67 atoms including iodine is computed in
B3LYP/6-311G** and LANL2DZ18b basis sets. TS III is
found as relatively more stable by À9.51 kcal molÀ1 compared
to TS IV. Thus, a lower activation energy barrier for TS III
drives the formal cycloaddition reaction in favor of the
complete diastereoselective synthesis of 4a.
In conclusion, we have for the first time demonstrated the
synthesis of fused-D1-pyrrolines by an intramolecular formal
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1285–1287 1287