Catalyst-Free Regioselective [3+2] Cycloadditions of α,β-unsaturated N-arylnitrones with Alkenes to Access Functionalized Isoxazolidines: A DFT Study

Article abstract of DOI:10.1002/asia.201901754

The catalyst-free regioselective [3+2]-cycloaddition of α,β-unsaturated N-arylnitrones with alkenes are developed. The series of synthetically important functionalized isoxazolidines are prepared in good to excellent yields by step economic pathway under ligand and transition-metal-free conditions. The regioselective cycloaddition pathway supported by control experiment and computational study.

Full text of DOI:10.1002/asia.201901754

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Catalyst-Free Regioselective (3+2)-Cycloadditions of α,
β-unsaturated N -arylnitrones with Alkenes to Access
Functionalized Isoxazolidines: A DFT Study
Authors: Arnab Ghosh, Manoj Mane, Haridas Rode, Siddappa Patil,
Balasubramanian Sridhar, and Ramesh Dateer
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Catalyst-Free Regioselective (3+2)-Cycloadditions of α, β-unsaturated
N-arylnitrones with Alkenes to Access Functionalized Isoxazolidines:
A DFT Study
Arnab Ghosh[a], Manoj V. Mane[b,c], Haridas B. Rode[d,e], Siddappa A. Patil[a], Balasubramanian Sridhar[f]
and Ramesh B. Dateer*[a]
[a]Centre for Nano and Material Sciences, Jain University, Jain Global Campus, , Bangalore, Karnataka 562112, India. Email: d.ramesh@jainuniversity.ac.in
[b]Physical Chemistry Division, CSIR − National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
[c]KAUST Catalysis Centre, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
[d]Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana 500007, India.
[e]Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh- 201 002, India.
[f]Center for X-ray crystallography Analytical Department, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana 500007.
13-16
Abstract: The catalyst-free regioselective [3+2]-cycloaddition of α,
β-unsaturated N-arylnitrones with alkenes are developed. The series
of synthetically important functionalized isoxazolidines are prepared
in good to excellent yields by step economic pathway under ligand
and transition metal-free condition. The regioselective cycloaddition
pathway supported by control experiment and computational study.
the construction of isoxazolidines including cycloadditions
,
annulation17, cascade reaction,18 and others19 (Scheme 1a). For
instance, Jorgensen and co-workers reported the first cascade
1,3-dipolar cycloaddition on the remote olefin with good to
excellent regio- and stereo-selectivity by iminium-ion activation
process with
a secondary amine catalyst. (Scheme 1b).
Typically, these strategies require the utilization of either
transition-metal catalysts or organocatalyst which still suffer from
high cost and complicated purifying procedures. During the
preparation of this manuscript, Yang et. al.20 reported, catalyst-
free cycloaddition of oxa(aza)bicyclic alkenes with nitrones as
the 1,3-dipolar cycloaddition under mild conditions, which can
afford the new products of fused bicyclic tetrahydroisoxazoles
(Scheme 1c). The reactions occur diastereoselectively, with a
notable exo- and anti-preference and thus, observed
diastereoselectivity trends as predicted by DFT calculations.
Despite the success of these important and valuable strategies
for isoxazolidine synthesis, more efficient, convenient,
regioselective and preactivation-free cycloaddition strategy
integrating the use α, β unsaturated N-aryl nitrone under metal-
free condition are still highly appealing. Therefore, while
pursuing our interest
Introduction
The N-substituted α,β-unsaturated nitrones are powerful
synthons because the double bond in nitrones can be introduced
into the target molecules through various transformations.1
Neverthless, control cycloaddition reactions of α, β-unsaturated
systems is a challenge as multiple reaction sites are available.2
Particularly, for cycloaddition reactions of α, β-unsaturated
nitrone, the challenge is not only to control which olefin reacts in
the cycloaddition, but also to control the regioselectivity.3
Moreover, 1,3-dipolar cycloaddition reactions of nitrones with
olefins is a very useful methodology for the formation of
isoxazolidines.4 These heterocycles are present in different
bioactive compounds5 and have been applied as precursors for
the asymmetric synthesis of natural products6 and
pharmaceutically importaint molecules7 (Fig 1). In addition, a
number of molecules containing isoxazolidine ring have
attracted much attention as nucleoside analogues.8
Nevertheless, isoxazolidines are also vital and versatile
intermediates due to the ease of reductive N−O bond cleavage9,
2a which can be converted into a β-amino acids,10 chiral and 1,3-
amino alcohol,11 very often applied in organic chemistry.12
Scheme 1: Strategies for synthesis of functionalized isoxazolidines
Fig. 1 Natural products containing isoxazolidines unit.
in the reactivity of nitrones21 as precursors for the synthesis of
functionalized molecules, we are interested to test the reactivity
of α, β-unsaturated N-aryl nitrones with alkenes. In this context,
Therefore, it is not surprising that great effort has been devoted
to the development of novel, efficient and practical methods for
1
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herewith, we report step and atom-economic pathway for
regioslective [3+2]-cycloadditions of α, β-unsaturated N-
With an optimized condition in hand, the scope of reaction
is investigated using differently substituted C-alkyl nitrones (1c –
1j) with ethyl vinyl ether 2a (Scheme 2). Initially, C-alkyl
substituted nitrones (1c–1i) prepared from electronically diverse
cinamaldehyde reacts smoothly with ethyl vinyl ether furnishing
desired [3+2]-cycloadducts 3c–3i in 63–86% yield. Interestingly,
C-alkyl substituted nitrone prepared form 2-napthyl substituted
cinamaldehyde provides desired product 3j in moderate yield.
arylnitrones with alkenes to form
a highly functionalized
isoxazolidine under catalyst and ligand-free condition (Scheme
1d). Importantly, the computational studies is demonstrated in
this work.
Results and Discussion
We commenced our studies by examining the reaction
parameters in reaction of (Z)-N-((E)-3-phenylallylidene) aniline
oxide 1a (0.5 mmol) and ethyl vinyl ether 2a (5.0 equiv) in THF
(3.0 mL) solvent at 25 °C (Table 1). The newly formed products
were isolated by column chromatography and analyzed by 1H
and 13C NMR spectroscopy which indicates regioselective
formation of isoxazolidines 3a (31%) via [3+2]-cycloaddition
reaction while, formation of 4 (47%) may occur presumably due
to nitrone hydrolysis by trace amount of water present in THF22
(entry 1). Further, significant improvement in the reaction
efficiency is noticed while using dry THF with 4 Å molecular
sieves and product 3a was furnished in 48% yield (entry 2). In
addition, the reaction efficiency was further stimulated by
heating the reaction mixture to 60 °C and product 3a was
obtained in 78% yield (entry 3). Gratifyingly, further improvement
in the yield is observed using excess (10.0 equiv.) Ethyl vinyl
ether (entry 4). The significant loss in yield is observed with less
equiv. of ethyl vinyl ether (See supporting information for details).
Scheme 2: Scope of with C-alkyl substituted nitrones with alkene. [a]Reaction
condition: 1a, 1c-1j (0.5 mmol), 2a (10.0 equiv), 4 Å MS in THF (3.0 mL) at
60 °C in 6h. [b]Yields are reported after purification form silica gel column
chromatography (average of two run).
Table 1. Optimization of reaction condition[a]
In continuation, the scope of reaction is subsequently
tested with N-aryl substituted nitrones (1k-1r; Scheme 3).
Initially, electron donating substituents such as 4-methyl, 3-
methyl group on N-aryl ring of nitrone are treated with ethyl vinyl
ether which works smoothly and provides desired cycloadduct
3k and 3l in 71 and 73% yield, respectively. While, electron
withdrawing substituents such as 3-chloro, 4-chloro, 4-fluoro, 4-
bromo and 4-iodo furnishes cycloadducts 3m–3q in 72–83%
yield.
S.
N
Solvent
Temp(°C)/ Yield (%)[b] (3/4)
time (h)
1
2
3
4
5
6
7
8
OR = OEt (5), 2a Wet THF
25/18
25/24
60/12
60/6
3a (31) / 4 (47)
3a (48) / 4 (15)
3a (78) / 4 (~5)
3a (87) / 4 (trace)
3b (65) / 4 (15)
3a (71) / 4 (trace)
3a (58) / 4 (10)
3a (63) / 4 (trace)
= OEt (5), 2a
= OEt (5), 2a
= OEt (10), 2a
= Ph (10), 2b
THF
THF
THF
THF
60/8
= OEt (10), 2a Toluene
= OEt (10), 2a CH3CN
= OEt (10), 2a 1,4-dioxane
60/12
60/18
60/12
[a]Reaction condition: 1a (0.5 mmol), 2 (3-10 equiv), 4 Å MS, solvent (3.0 mL)
at 25-60 °C in 8-24 h. [b]Yields are reported after purification from silica column
chromatography (average of two run).
This indicates that, ethyl vinyl ether may undergo polymerization
at higher temperature. Interestingly, subjecting styrene as an
alkene precursor instead of ethyl vinyl ether works smoothly
furnishing desired cycloadduct 3b in 65 % yield (entry 5). Further,
change in solvent to toluene, acetonitrile and 1,4-dioxane
furnishes the moderate yield (entries 6-8), while other solvents
such as dichloromethane, ethanol, chloroform furnishes poor
yield (See the supporting information for more details).
Scheme 3. Scope of N-aryl substituted nitrone with alkenes. [a]Reaction
condition: 1k-1r (0.5 mmol), 2a (10.0 equiv), 4 Å MS in THF (3.0 mL) at 60 °C.
[b]yields are reported after purification form silica gel column chromatography
(average of two run).
2
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Further, N-(4-phenyl)nitrone also tolerates by furnishing desired
product 3r in 65% yield. Interestingly, structure of compound 3n
is unambiguously confirmed by X-ray crystallographic analysis
indicating the trans geometry of tethered alkene substituent.
Density functional theory (DFT) calculations23 were
performed to shed light on the mechanism of catalyst-free [3+2]
cycloaddition reaction. We performed calculations at the M06-
2X/6-311+G(d,p) level of theory in THF as solvent with Gaussian
09 set of programs (for computational details see supporting
information). In order to rationalize the regioselectivity of the
reaction, firstly we optimize the diene and dienophile and the
electronic effects taken under consideration.24 The frontier
molecular orbitals (FMO) and their energies are shown in Figure
2. The energy difference between HOMO of the nitrones (-6.94
eV) and LUMO of dienophile (-0.48 eV) are smaller, as
compared to the HOMO of dienophile (-7.78 eV) and LUMO of
nitrones (-1.65 eV). Based on FMO it is evident that this reaction
is HOMO controlled nitrones.
we considered all the commutative pathways, the most likely
pathway is illustrated in Figure 3(a). In such a process, 1n and
alkene gives adduct complex which is 8.5 kcal/mol higher in
energy. Subsequently, [3+2]-cycloaddition of 1n and C=C of an
alkene to form 3n, traversing the transition state 1n‐TS with an
overall barrier of 29.90 kcal/mol. The barrier calculated for this
step is consistent with the reaction condition. Interestingly the
formation of the product is exergonic from the starting material
by 16.57 kcal/mol. Figure 3(b) highlights the structural
differences in the five transition states, in which for [3+2]-
cycloaddition are 1n-TS, 1n-TS_1, 1n-TS_2, 1n-TS_3 and for
the [5+2]-cycloaddition is 1n-TS_4 reported. Importantly, the
crystal structure of compound 3n is demonstrated.
Our protocol can be scaled up in gram scale without
affecting the chemical yield (eq. 1).
Given the unique features of the metal free [3+2]-
cycloaddition reaction, we became intrigued in unravelling its
mode of action. To this end, we performed competition
experiments using nitrones (1a and 1a’) with ethyl vinyl ether 2a
under standard condition. The reaction is stopped in 2h and
Fig. 2. 3D-plots of the frontier molecular orbitals (HOMO and LUMO) of 1n
and 2a.
1
crude reaction mass is analyzed by H NMR indicating that, the
rate of formation of 3a:3a’ is in comparable ratio (eq. 2, See SI
1
for crude H NMR and computational study). This proves that,
reaction is highly regioselective irrespective of type of nitrone
used for cycloaddition (eq. 2). Further, we have also performed
one-pot25
synthesis
of
isoxazolidines
directly
from
cinamaldehyde and nitrobenzene (eq. 3). The in-situ formed
nitrone intermediate is obtained simply by filtration and utilized
without further purification for the reaction with ethyl vinyl ether
forming a desired product in 49% yield (eq. 3, See SI for more
details).
Scheme 4: Control experiments
Conclusions
In conclusion, the transition metal-free and step economic synthesis
of isoxazolidines is successfully developed using α, β-unsaturated
nitrone and ethyl vinyl ether. The various electronically biased C-
alkyl and N-aryl substituted nitrones are tolerated for the synthesis of
polyfunctionalized isoxazolidines in good to excellent yields. The
DFT calculation and the control experiments supports the
regioselective [3+2]- cycloaddition pathway and products formation
is confirmed by X-ray analysis. The feasibility of reaction condition is
studied by performing one-pot reaction and gram scale synthesis.
Fig. 3. a) Free energy profile for the [3+2] cycloaddition. b) Optimzed
geometris of possible TS structures for [3+2] and [5+2] cycloaddition reaction.
Free energy values at M06-2x/6-311+G(d,p) level of theory in THF as the
solvent. All bonds distances are given in Å.
In order to determine the selectivity of the reaction, on the
basis of control experiments, we believe that this reaction occurs
through one-step [3+2] cycloaddition mechanism. In this context,
3
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The authors thank, DST-SERB, Government of India, for the
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Keywords: regioselective • isoxazolidines • DFT study • nitrone
cycloaddition • metal and ligand free
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4
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Table of Content
Text for Table of Contents: The metal-free synthesis of isoxazolidines is successfully developed using α, β-unsaturated
nitrone and ethyl vinyl ether. The wide substrate scope was studied and feasibility of reaction was studied by performing
one-pot reaction and gram scale synthesis. The DFT calculation and the control experiments supports the regioselective
[3+2]- cycloaddition pathway and products formation is confirmed by X-ray analysis.
+
+
THF, 4 Å MS
60° C
5
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