Catalytic enantioselective epoxidation of nitroalkenes

Article abstract of DOI:10.1039/c6cc03539f

Nitroepoxides are potentially exploitable as synthons with vicinal electrophilic centers. Nevertheless, although advances have been made in the field, enantioselective epoxidation of nitroalkenes is still a challenging process. Herein we show a convenient procedure for the preparation of optically active nitroepoxides in high enantiomeric excess and high chemical yield. The kinetic data of the best catalyst have been examined using computational methods based on DFT calculations. Interestingly, the results demonstrate that the enantioselectivity of the epoxidation of nitroalkenes by this kind of catalyst is not only kinetically but also thermodynamically controlled.

Full text of DOI:10.1039/c6cc03539f

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DOI: 10.1039/C6CC03539F
Catalytic Enantioselective Epoxidation of Nitroalkenes
A. Vidal-Albalat,a K. Świderek,b, c J. Izquierdo,a S. Rodríguez,a V. Molinerb and F. V. González*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Nitroepoxides are potentially exploitable as synthons with vicinal
electrophilic centers. Nevertheless, although advances have been
made in the field, enantioselective epoxidation of nitroalkenes is
still
a challenging process. Herein we show a convenient
procedure for the preparation of optically active nitroepoxides in
high enantiomeric excess and high chemical yield. The kinetic data
of the best catalyst have been examined by computational
methods based on DFT calculations. Interestingly, the results
demonstrate that the enantioselectivity of the epoxidation of
nitroalkenes by this kind of catalyst is not only kinetically but
thermodynamically controlled.
Nitroepoxides are an underdeveloped class of compounds with
wide potential for use in chemical synthesis.1 Nitroepoxides
represent strained systems displaying two highly oxidized
vicinal positions by nature of their chemical connectivity and
hence are potentially exploitable as synthons with vicinal
electrophilic centers. Recently we reported the transformation
of nitroepoxides into 1,2-diamines2 and saturated 1,4-diamino
heterocycles such as piperazines and tetrahydroquinoxalines3
(Scheme 1). Also the preparation of 1,2-aminoalcohols starting
from nitroepoxides has been reported.4 Hence nitroepoxides
are interesting precursors for the preparation of chiral 1,2-
difunctionalized compounds. Although advances have been
Scheme 1. Derivatizations of nitroepoxides into chiral compounds.
We started the study of the enantioselective epoxidation of
nitroalkenes by using catalyst A, readily prepared through
benzylation of cinchonine,6 and a-methyl nitrostyrene 1a as a
model compound. Early conditions including the use of catalyst
A in 10 mol %, sodium hypochlorite (4.5 % active chlorine
aqueous solution) and dichloromethane (0.15
M
of
nitroalkene) gave full conversion of α-methyl nitrostyrene 1a
into nitroepoxide 2a (entry 1, Table 1). The best organic
phase/aqueous phase ratio in terms of conversion and
enantioselectivity resulted to be 2/1. All other assayed
oxidants as tert-butyl hydroperoxide and hydrogen peroxide
did not afford desired nitroepoxide. Adequate stirring of the
reaction mixture to maximize the interphase reaction surface
was found to be a key factor as already reported for similar
reactions.9
Then initial reaction conditions were changed in order to
increase enantioselectivity. By increasing the concentration of
nitroalkene in dichloromethane to 0.3 M, enantioselectivity
improved slightly (entry 2, table 1). The effect of catalyst load
was also tested with no significative increase of
made
for
preparing
enantiopure
nitroepoxides,4-5
enantioselective epoxidation of nitroalkenes has remained a
challenging process.4 Herein we describe the first
enantioselective epoxidation of nitroalkenes.
Chiral quaternary ammonium salts derived from cinchona
alkaloids have been employed as efficient catalysts in the
epoxidation of chalcones6-10 and other asymmetric reactions
such as the alkylation of ketones.11-12
enantioselectivity for 20 mol
% and a reduction of
enantioselectivity when 5 mol % of catalyst A was used (entry
3). Solvent screening revealed chloroform as a better solvent
than dichloromethane by increasing enantiomeric ratio up to
74/26 (entry 4, table 1). Water miscible solvents such as
methanol and tetrahydrofuran did not afford reaction product
and toluene was not a good solvent for catalyst A, probably
due to low solubility (entry 5).
a. Departament de Química Inorgànica i Orgànica
Universitat Jaume I, Castelló, Spain. E-mail: fgonzale@uji.es
b. Departament de Química Física i Analítica
Universitat Jaume I, Castelló, Spain
c. Institute of Applied Radiation Chemistry
Lodz University of Technology, Łódź, Poland
†Electronic Supplementary Information (ESI) available: Procedures, copies of NMR
spectra, Chromatograms, Computational studies and crystal data. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of epoxidation reaction[a]
Then catalyst screening was carried out. Among all prepared
quaternary ammonium salts derived from cinchonine, catalyst
B having an ortho-susbstituent at the benzyl group did not
improve the reaction, and catalysts C and D (entries 7-8)
displaying para-substituents improved the enantioselectivity
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DOI: 10.1039/C6CC03539F
O
NO2
NO2
10 mol% catalyst
Ph
Ph
Me
Me
NaOCl
7
2a
1a
respect to catalyst A. We were pleased to find that catalyst E1
having a 9-anthracenylmethyl substituent gave even higher
enantioselectivity (entry 9).
Conc.
t
e.r.
Conv.
(%)[c]
Entry
catalyst
solvent
T (ºC)
(M)
0.15
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.6
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
(h)
(%)[b]
Optimization of the reaction conditions with catalyst E1 were
next assayed. The concentration of the reaction was confirmed
to be 0.3 molar as the best option (entry 9 vs. entry 10). When
carbon tetrachloride was used as a solvent instead of
chloroform, enantiomeric excess increased (entry 11). To avoid
the use of carbon tetrachloride as non-environmentally
friendly solvent, toluene was also assayed giving a similar
result to carbon tetrachloride (entry 12), although the reaction
resulted to be slower.
Curiously, catalyst F1 having non-planar and bulky substituent
2,5-diphenyl benzyl13 (entry 13) gave opposite enantiomer
compared to catalyst E1 in low enantioselectivity. O-Allyl
derivative catalysts E2 and F2 gave opposite enantiomer
compared to catalyst E1 (entries 14-15), denoting the
importance of free hydroxyl group for controlling
enantioselectivity.
1
2
A
A
DCM
DCM
DCM
CHCl3
Tol.
23
23
23
23
23
23
23
23
23
23
23
23
23
23
23
0
2
2
58/42
59/41
54/46
74/26
ND[e]
100
94
3[d]
4
A
2
70
A
2
70
5
A
24
2
20
6
B
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CCl4
Tol.
53/47
81/19
81/19
83/17
78/22
89/11
87/13
41/59
25/75
33/67
90/10
97/3
65
7
C
2
94
8
D
3.5
2
100
100
100
100
100
80
9
E1
E1
E1
E1
F1
F2
E2
E1
E1
G
10
11
12
13
14
15
16
17
18
19d
2.5
2
Finally, a range of temperatures between 0
were next assayed in order to increase enantioselectivity. A
temperature of -20 C (entry 17) was found to be the best
ºC and -40 ºC
6
º
situation committed for the highest enantiomeric ratio (97/3)
and high chemical yield (92 % isolated yield) and prevent
freezing the aqueous phase of the reaction mixture. 8 % was
established as the minimum catalyst load (entry 19). This
reaction has been scaled up to 200 mg of nitroalkene 1a.
Pseudoenantiomer catalyst G gave reverse enantioselectivity
(entry 18) compared to cinchonine-derived counterpart E1, and
enantioselectivity was lower. Determination of the absolute
configuration of compound 2a was carried out by X-ray
analysis, which proved to be the (2S, 3R) enantiomer (Scheme
2).13
Tol.
4
Tol.
5
96
Tol.
4.5
16
16
24
16
90
Tol.
100
92[f]
100
92[f]
Tol.
-20
-20
-20
Tol.
18/82
97/3
E1
Tol.
The tolerance of this catalytic enantioselective epoxidation to
the presence of different substituents in alpha and beta
positions of the nitroalkene was then evaluated (Scheme 2).
Nitroalkenes having an aryl group at the beta position and an
alkyl group at the alpha position (1a-1f and 1j-1m, Scheme 2)
afforded the corresponding nitroepoxide in high
stereoselection and high chemical yield. If both substituents
are aryl groups (1g), then corresponding nitroepoxide is also
obtained with high enantioselectivity and high chemical yield.
Finally epoxidation reaction was assayed over a nitroalkene
having alkyl groups at both positions (compound 1h and 1i), in
this case the reaction was not enantioselective and afforded
nitroepoxide in low chemical yield (Scheme 2). This result
denotes that the group in beta position needs to be an aryl
group for reaction to be efficient. Beta-disubstituted
nitroalkenes could not be assayed due to the limitations
associated with their preparation.
HO
HO
HO
N
N
F
N
R'
Br
Br
Br
N
N
N
C, R'=4-trifluoromethyl benzyl
D, R'=4-iodobenzyl
B
A
1
RO
RO
N
2
N
N
Ph
3
4
5
OH
N
Br
F1, R=H
F2, R=Allyl
Br
N
N
Br
E1, R=H
E2, R=Allyl
G
Ph
[a] NaOCl as 4.5 % active chlorine aqueous solution. Organic phase/aqueous
phase 2/1. [b] Determined by HPLC ChiralPak IA. [c] Conversion measured by 1H
NMR of the crude reaction mixtures. [d] 5 mol % of catalyst for entry 3; 8 mol %
of catalyst for entry 19. [e] Not determined. [f] Isolated chemical yield.
2 | J. Name., 2012, 00, 1-3
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Fig.1 Gas phase PES computed at B97d/6-31+G(d,p) level as a function of the dihedral
angles describing the relative orientation of the quinolone moiety and -OH group of E1
catalyst. See 2D figure of E1 in Table 1 for numbering of the atoms.
Information). Interestingly, while the conformation of just the
E1 catalyst is comparable to the one observed for other
cinchona-based catalysts,19 this is not the case when
comparing the RCs. Indeed our most stable RCs for the
epoxidation, that come from the A conformation of E1 catalyst
in Fig 1, show π-π stacking interactions between the catalyst
and the substrate (Figure 2), which was not detected in the
indanone-catalyst complexes previously reported for the
cinchoninium ion asymmetric phase transfer catalysed
alkylation reaction.[18] Moreover, the ClO- moiety interacts by a
hydrogen bond with the hydroxyl group of the catalyst in both
RCs dictating the orientation and interaction between the
nitroalkene and the catalyst. The difference between both RCs
structures depends on the π-π stacking interaction that is
established between the nitroalkene and the aryl substituent
of the catalyst; while RC in A.II.1 interacts through the
anthracenyl moiety of the catalyst, RC in A.II.2 interacts
through the quinoline moiety. Interestingly, there is no
significant difference in energy between both conformations.
Nevertheless, this is not the case when comparing the
transition states, TSs, and product complexes, PCs, that
connect with the RCs. Thus, the reaction from RC A.II.1 shows
lower energy barrier than the reaction from RC A.II.2 (8.4 vs.
12.5 kcal·mol-1), and more stable PCs (-44.2 and -41.4 kcal·mol-
1, respectively). Importantly, the nitroepoxides that are
obtained in both reactions are different enantiomers: (2S,3R)-
nitroepoxide in reaction from A.II.1 and (2R,3S)-nitroepoxide in
reaction from A.II.2. According to the relative energies of their
corresponding TSs and PCs, (2S,3R)-nitroepoxide would be the
most favorable enantiomer when employing catalysts E1 from
the thermodynamic and kinetic point of view. This
computational result is in very good agreement with the
experimental data reported in Table 1 entry 17, where 2S,3R
enantiomer is obtained in a 97/3 ratio.
Scheme 2. Epoxidation of nitroalkenes.a
In order to explain the experimental data, quantum molecular
simulations have been employed to study the observed
catalytic enantioselective epoxidation of nitroalkene 1a by
catalyst E1. All calculations have been carried out in toluene
solution with the conductor-like polarizable continuum model
(CPCM),14 as implemented in Gaussian 09 package.15 The
calculations have been performed at density functional theory
(DFT) level with the B97d hybrid functional,16 which has been
proved to provide exceptionally good performance for non-
covalently bound systems16 involving large polynuclear
aromatic molecules.17 (see Supporting Information for details
of the computational methods). The selected reaction was the
one corresponding to the entry 17 in Table 1. The first step of
the study was exploring the possible conformers adopted by
the catalyst E1 in toluene. In this regard, a Potential Energy
Surface (PES) has been generated as a function of the dihedral
angles describing the relative orientation of the quinoline
moiety (Figure 1), similarly to previous conformational analysis
of different cinchona alkaloid scaffolds.18
All possible conformations of E1 catalyst were explored
(Supporting Information). From the two lowest energy E1
conformers, A and B in Figure 1, the study of the binding of the
ClO- and the nitroalkene 1a substrate provides different
reactant complex, RC, conformations (see Supporting
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A deep analysis of the RCs, TSs and PCs structures reveals that unfavorably constrained if a π-π stacking interaction appears
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DOI: 10.1039/C6CC03539F
the π-π stacking interaction between the aromatic rings of the with the quinoline moiety of the catalyst.
catalysts and the substrate are important to stabilize and to This work was partially supported by Spanish Ministerio de
orient the two moieties in RCs. This explains that the Economía y Competitividad (ref. CTQ2015-66223-C2-1-P),
epoxidation of nitroalkenes 2h and 2i, having no aromatic Generalitat Valenciana (PROMETEOII/2014/022), and Polish
substituent, were not enantioselective. Nevertheless, the Ministry of Science and Higher Education ("Iuventus Plus"
presence of hydrogen bond interactions and the most project 0478/IP3/2015/73, 2015-2016). A.V.-A. thanks
favourable conformation of the catalyst appear to be the Generalitat Valenciana for a PhD grant (VALi+D Program). We
factor determining the relative energies of TSs and PCs that, in thank Serveis Centrals d’Instrumentació Científica and the
turn, determines the ratio of obtained enantiomers.
Servei d’Informàtica of Universitat Jaume I for technical
support and computational resources, respectively.
Notes and references
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Fig.2 Optimized structures and relative energies of RC, TS and PC of the
epoxidation of nitroalkene 1a catalyzed by E1 starting from the most stable
conformations of the 1a–ClO-–E1 reactant complexes.
It is important to point out that the epoxidation of nitroalkene
1a catalyzed with E1 has been also studied from different
conformers (see Supporting Information). Any alternative
reaction path has been revealed as not only
thermodynamically but kinetically less favourable than the
reaction from A.II.1 displayed in Figure 2.
In summary, we report herein an enantioselective epoxidation
of nitroalkenes using cinchonine-derived E1 as a catalyst and
sodium hypochlorite as an oxidant. The process represents an
efficient preparation of enantiopure nitroepoxides with wide
potential for use in chemical synthesis. Our theoretical
analysis, based on DFT calculations, shows that the
enantioselectivity of the catalyst is dictated not so much by the
π-π stacking interaction established between the aromatic
rings of the catalyst and the substrate but by the relative
orientations of the three reactive species that are in fact
13 The crystal structures have been deposited at the CCDC and
allocated the deposition numbers: CCDC 1455126 and
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4 | J. Name., 2012, 00, 1-3
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