Deep eutectic solvent as solvent and catalyst: One-pot synthesis of 1,3-dinitropropanes: Via tandem Henry reaction/Michael addition

Article abstract of DOI:10.1039/d0ob01516d

The Henry reaction was performed using microwave heating within the deep eutectic solvent (DES) choline chloride/urea (ChCl/urea) which acted as both the catalyst and solvent for the reaction. The optimisation of the conditions (temperature, heating mode,

Full text of DOI:10.1039/d0ob01516d

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ARTICLE
Deep eutectic solvent as solvent and catalyst: One-pot synthesis
of 1,3-dinitropropanes via tandem Henry reaction/Michael
addition
Received 00th January 20xx,
Accepted 00th January 20xx
Greta Colombo Dugoni,a Alessandro Sacchetti a* and Andrea Melea,b
The Henry reaction was performed using microwave heating within the deep eutectic solvent (DES) choline chloride/urea
(ChCl/urea) which acted as both the catalyst and solvent for the reaction. The optimisation of the conditions (temperature,
heating mode, time, DES) allowed 1,3-dinitropropane derivatives to be obtained via tandem Henry reaction/Michael
addition, in one step from a range of different aromatic aldehydes in high yields and under mild reaction conditions.
DOI: 10.1039/x0xx00000x
energy demand and more environmentally friendly processes is
considered an important goal.10
Two important issues should be considered when dealing with
Introduction
In organic synthesis, reactions leading to the formation of
carbon–carbon bonds are fundamental for the design of
complex molecular systems. A large class of C-C bond formation
reactions are based on the coupling between nucleophiles –
typically carbanions or their equivalents – and electrophiles.
Among the carbanions, nitronate ions, derived from the
deprotonation of nitroalkanes, have the advantage of being
easier and less demanding to prepare with respect to other
classes of carbanions. Consequently, nitroalkanes1 appear to be
the ideal synthetic building blocks due to their efficient and
versatile reactivity profile. The Henry reaction,2 also known as
the nitroaldol reaction, is a powerful C–C bond formation
reaction leading to nitro-derivatives. The reaction consists of
the coupling of a nucleophilic nitroalkane with an electrophilic
aldehyde or ketone to produce β-nitro alcohol (Scheme 1). β-
nitro alcohols are considered valuable synthetic intermediates
in the synthesis of polyaminoalcohols, polyhydroxylated amines
and natural products.3 The Henry reaction usually occurs under
basic catalysis. Common basic catalysts used are carbonates,
alkali metal hydroxides, alkoxides, or organic nitrogen bases.
The asymmetric Henry reaction has also been reported to occur
using metal catalysis,4 organocatalysis5 and biocatalysis6. The
emerging trend of the chemical industry adopting more
sustainable processes has stimulated many studies on the
Henry reaction and the synthesis of nitro derivatives in an eco-
friendly way. Proposed sustainable approaches include the use
of synthetic routes featuring heterogeneous catalysis,7 green
and non-toxic solvents8 and microwave irradiation.9 In general,
the development of new efficient technologies with lower
the Henry reaction: i) Selectivity. The Henry reaction may in
some cases lead to three different products: the β-nitro alcohol
1a, the dehydration product 1b and the 1,3-dinitropropane 1c
(see Scheme 1). These latter compounds are important building
blocks for many applications and their synthesis through other
approaches is challenging. ii) Catalysis. As mentioned above, the
Henry reaction often requires metal catalysis, thus introducing
in the synthetic cycle elements of potential environmental
impact.
In this paper, we report on a synthetic approach designed to
address the issues mentioned above. The method proposed
here is based on a one-step synthesis mediated by microwave
irradiation and carried out in some selected deep eutectic
solvents (DES) as reaction media. Interestingly, the DES used
went beyond the role of solvent, showing a catalytic effect too.
Unexpectedly, the reaction conditions described here led to the
serendipitous finding of a highly selective, mild and efficient
synthetic route to challenging 1,3-dinitroderivatives (vide infra).
In recent years, DES were proposed as a new class of
environmentally green solvent and extensively tested as
reaction media.11 The concept of DES was first proposed by
Abbott in 200312 as a mixture of Lewis and Brönsted acids and
bases which led to significant melting point depression at the
eutectic point.12
Compared to conventional organic solvents, DES show low
melting points, low volatility, and thus are often non-
flammable. In addition, DES can be designed to be
biodegradable, non-toxic and inexpensive. The preparation of
DES is often simple and seldom requires purification steps.
These properties make DES good candidates as reaction media
for synthesis,13 electrochemistry,14 nanomaterials fabrication,15
biochemistry,16 separation,17 biomass processing,18 and
chemical analysis.19 The most popular DES are obtained by
mixing ammonium or phosphonium salts as hydrogen bond
acceptors (HBA), with a variety of hydrogen-bond donors (HBD).
a. Department of Chemistry, Materials and Chemical Engineering “G. Natta”,
Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy.
b. CNR-ICRM Istituto di Chimica del Riconoscimento Molecolare, “U.O.S. Milano
Politecnico”, Via L. Mancinelli, 7, 20131 Milano, Italy.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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The most popular DES is a mixture of choline chloride (ChCl), a formed. The prepared DES was cooled and used for the Henry
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DOI: 10.1039/D0OB01516D
biodegradable and non-toxic ammonium salt, and urea in a 1:2 reaction without any purification.
molar ratio. This DES is sometimes referred to as reline. The
easy sample preparation has allowed a large library of DES to be
obtained with the possibility of modulating the physical and
chemical properties by appropriate selection of the two
components, HBD and HBA.
O
Cl
2
H2N
N
OH
NH2
Figure 2 Structure of DES ChCl/urea, (Choline Chloride/Urea 1:2)
Stimulated by the positive features of the DES summarized
above, and during the study of the Henry reaction in DES, we
envisaged the possible use of DES as solvent and catalyst by
choosing the DES appropriate formulation. In a first report, the
Henry reaction has been investigated by Shankarling with the
use of catalytic amounts of ChCl/urea in methanol.20 When 20%
of DES ChCl/urea was employed, the expected nitroaldol adduct
was obtained in good yields from different aromatic aldehydes
(Figure 1). Later, Zheng21 reported the enzyme-catalyzed Henry
reaction using DES as co-catalysts. The lipase from Aspergillus
niger (lipase AS) showed excellent catalytic activity towards
aromatic aldehydes in water containing the presence of 30% of
ChCl/glycerol in the molar ratio 1:2 (Figure 1). In both works, the
reaction was run in molecular solvent and the DES was
introduced only in catalytic amounts. Starting from these
findings, we studied the Henry reaction in pure DES without
other solvents, thus combining the catalytic and solvent role.
OH
O
CH3NO2
NO2
O N
+
NO2
+
NO2
2
R
R
R
H
R
c
b
a
1a,b,c R = p-FC6H4
Scheme 1 Model Henry reaction and possible products a-c
Scheme 1 sketches the three different products that in principle
can be obtained from the reaction of a generic aromatic
aldehyde with nitromethane: i) the expected nitroaldol adduct
1a, ii) the β-nitrostyrene derivative 1b, resulting from
dehydration of 1a, and iii) the bis-adduct 1c, obtained by the
addition of a second molecule of nitromethane to intermediate
1b. In a first attempt, p-fluorobenzaldehyde was reacted with 5
equivalents of nitromethane in 10 equivalents of DES ChCl/urea
for 24h. The effect of temperature was investigated by running
the reaction at 20°C (rt) and after heating to 50°C and 80°C.
Results are reported in Table 1.
OH
DES 20%,
Table 1 Results of the reaction between nitromethane and p-fluorobenzaldehyde.
NO2
Shankarling at al., 2012
Zheng at al., 2016
present work
methanol
Ar
Producta yield%b
69-95%
OH
Entry
Temperature
1a
0
1b
0
1c
17
O
lipase AS,
water/DES
1
2
3
4d
20°C
50°C
80°C
50°C
NO2
CH3NO2
Ar
0
ndc
31
0
ndc
0
90
Ndc
28
Ar
H
14-91%
NO2
100%DES
NO2
Reaction conditions: aldehyde 0.4 mmol, nitromethane 2.0 mmol, DES 4.0 mmol,
24h. aAr = p-FC6H4. bYield was evaluated by 1H-NMR on the crude (see experimental
section for details). cFormation of unidentified by-products. dReaction with 2 equiv.
of nitromethane
Ar
Figure 1 Application of DES in the Henry reaction
The reaction between 4-fluorobenzaldehyde and nitromethane
in pure DES ChCl/urea (Figure 2) is used here as a model
reaction. DES ChCl/urea is expected to act as a catalyst in this
reaction due to the presence of urea in its formulation. In fact,
it is known from the literature that urea derivatives can
efficiently promote the Henry reaction through the activation of
nitromethane.22 Further examples of reaction conditions
described in this work include: i) the use of different
temperatures, ii) the presence of triethylamine (TEA), iii) the
use of substituted aldehydes, iv) tests on selected ketones, v)
tests on ChCl based DES with different HBD and vi) tests on DES
based on choline acetate (ChOAc). Finally, the possibility of DES
recycling is reported and briefly discussed.
Table 1 shows some unprecedented results: the Henry reaction
can be driven to the dinitro-derivatives with excellent selectivity
and conversion with the only product observed being 1c.
Neither the expected nitroaldol 1a nor the elimination product
1b were detected in the reaction mixture. Compound 1c is the
result of a tandem Henry reaction/Michael addition between p-
fluorobenzaldehyde and nitromethane. Product 1a is first
formed according to the classical Henry reaction. 1a then
spontaneously undergoes the elimination of water leading to
the intermediate β-nitrostyrene 1b which, in turn, undergoes a
Michael addition of a second molecule of nitromethane to the
double bond to afford the 1,3-dinitropropane derivative 1c. This
mechanism is independent of the reaction temperature: at 20°C
only 1c is formed in 17% yield. At 50°C the 1,3-dinitropropane
product is obtained in excellent yield (90%) after 24h. Increasing
the temperature to 80°C for 24h produced an inseparable
mixture of unidentified by-products. When 2 equiv. of
nitromethane were used, the selectivity decreased yielding an
almost equimolar mixture of 1a and 1c. Notably, 1b could not
Results and discussion
In this study, the DES ChCl/urea was prepared according to the
procedures reported in the literature. Briefly, the preparation
consisted of mixing ChCl or ChOAc (HBA) with different HBDs,
urea or glycolic acid (GlyA). The mixture was stirred at 80°C for
30 min until a homogeneous and transparent solution was
2 | J. Name., 2012, 00, 1-3
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be detected in the mixture. This observation suggests that once
1b is formed, it rapidly reacts with nitromethane to afford 1c.
This highly selective route towards the synthesis of the 1,3-
dinitropropane derivatives is indeed interesting. 1,3-
dinitropropane derivatives are building blocks with a versatile
reactivity profile making them ideal synthetic precursors for
diverse functional and structural groups. The reduction of the
nitro moiety produces 1,3 diamines, important structural
motives existing in many natural products and active
pharmaceutical ingredients.23 1,3-dinitropropane derivatives
are precursors of different targets such as heterocycles,24
benzene derivatives,25 carbohydrates,26 and cyclohexane
derivatives.27 The use of 1,3-dinitropropane derivatives as key
building blocks for biologically active substances, including a
novel oxazolidinone antibacterial candidate, has also been
reported.28 Several examples of the synthesis of 1,3-
dinitroalkanes can be found in the literature. The conventional
synthesis of 1,3-dinitroalkanes was performed under basic
condition via Michael addition of nitroalkanes to nitroolefins
under basic catalysis, usually affording the products in low or
moderate yields29 due to the formation of polymeric
byproducts. Some attempts at developing one-pot synthetic
procedures starting from the aldehyde have also been reported.
Good results were obtained in the presence of different
heterogeneous catalysts like basic alumina,30 KF-NaHCO3,31
silica-alumina supported amines32 or, alternatively, with Ni-
phosphine species33 or by electrochemical synthesis.34
Table 2 MW-irradiated Henry reaction screening.
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DOI: 10.1039/D0OB01516D
TEA
(equiv.)
Producta yield%b
Entry
Temperature
Time
1a
0
1b
0
1c
9
1
2
3
4
5c
50°C
80°C
50°C
80°C
80°C
1 h
2 h
2 h
2 h
2 h
0
0
5
5
5
0
0
0
0
0
96
58
72
22
38
29
18
aAr = pF-C6H4. b Yield was evaluated by 1H-NMR on the crude. c Reaction done with
one equivalent of nitromethane.
In another experiment, we investigated the use of triethylamine
(TEA) as an additional basic catalyst to facilitate the formation
of the nitroaldol adduct, the first step towards the formation of
the 1,3-dinitropropane derivatives. 5 equivalents of TEA were
added to the reaction mixture at 50°C (entry 3) and 80°C (entry
4). Under these conditions, 1a was isolated in 38% and 29%
yield, respectively, together with 1c as the major product (58%
and 72% yield). These results suggest that the amine interacts
with the DES in some way to decrease its catalytic activity. The
result is an evident decrease of the reaction selectivity. We then
tried to completely reverse the selectivity towards 1a by using
a stoichiometric amount of nitromethane (entry 5), but a
mixture of 1a and 1c was obtained. Interestingly, 1b was not
detected in any circumstances, thus suggesting that, once the
β-nitrostyrene is formed, the second addition of nitromethane
is very fast.
Stimulated by these findings, we tried to improve the procedure
to shorten the reaction time and to achieve higher yields. To this
end, we investigated the use of microwave irradiation to heat
the reaction mixture.
We then explored the general applicability of our approach by
treating different aromatic aldehydes under the optimized
reaction conditions (Table 3).
Table 3 Screening of the reaction with different aldehydes.
Microwave (MW) assisted chemistry offers several advantages
with respect to conventional heating methods, such as reduced
processing time and lower energy costs. For MW-assisted
heating, the use of strong MW absorbing solvents is mandatory.
Additionally, physical and chemical properties like high thermal
stability and low vapour pressure are desirable, due to the risks
associated with the use of pressurised reaction vessels.35 DESs
are in general good solvents for microwave heating.36 DES
ChCl/urea, is particularly suitable due its ionic nature and very
low vapour pressure.
The influence of microwave irradiation on the reaction between
nitromethane and p-fluorobenzaldehyde was thus investigated,
starting with 5 equivalents of nitromethane in 10 equivalents of
DES ChCl/urea, at different temperatures and reaction times.
The aim was to determine the conditions that could achieve the
highest yield of the product 1c in the shortest time. Indeed, the
reaction time could be reduced from 24 h (thermal heating) to
only 2 h (MW heating). The results are reported in Table 2.
At 50°C after 1h a poor 9% yield was obtained which could be
NO2
NO2
O
CH3NO2 5 equiv.
Ar
H
Ar
ChClU 10 equiv.
80°C (MW), 2h
2
3
Entry
Ar
Product
3a
3b
3c
3d
3e
3f
3g
3h
Yielda
96
93
92
96
78b
65b
71b
58b
1
2
3
4
5
6
7
8
p-FC6H4
p-BrC6H4
p-OHC6H4
Ph
p-MeC6H4
p-ClC6H4
p-MeOC6H4
o-BrC6H4
aYield was evaluated by 1H-NMR on the crude (see experimental section for
details). bProducts were purified by chromatography
improved to 96% at 80°C after only 2h. It is worth mentioning The 1,3-dinitropropane derivative 3 was obtained as the main
that, although the formation of a complex mixture of products product in all of the cases. This finding confirms the intrinsic
was observed to take place under conventional heating at 80°C selectivity of the Henry reaction in the DES ChCl/urea with MW
for 24 h (Table 1, entry 3), the use of MW led to shortened irradiation. Excellent yields were observed with benzaldehyde
reaction time, thereby preserving the integrity of the system.
and halogen-substituted aromatic aldehydes (entries 1, 2 and
4). As expected, the presence of substituents with +I or +M
electronic effects on the aromatic ring made the substrates less
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reactive, leading to lower yields (entries 5 and 7), with the
exception of the phenol derivative 3c (entry 3). Ortho
substituted aldehydes suffered from steric hindrance, affording
the product 3h in moderate yield (entry 8). Unfortunately, the
reaction carried out on aliphatic aldehydes isovaleraldehyde
and butyraldehyde gave only an inseparable mixture of
byproducts.
View Article Online
DOI: 10.1039/D0OB01516D
The results of these investigations are summarized in Table 5.
The replacement of chloride ions with acetate (ChOAc/Urea,
entry 2) led to an unwanted mixture of by-products. A tentative
explanation could be that the presence of acetate ions could
change the reaction mechanism and inhibit the selective
formation of 1,3 dinitro compound. The tests on choline
chloride-glycolic acid (ChCl/GlyA, entry 3) and choline acetate-
glycolic acid (ChOAc/GlyA, entry 4) confirmed the importance of
the presence of urea for the catalytic activity (no Henry-adduct
observed). Interestingly, the use of ChOAc/GlyA produced the
partial oxidation of the aldehyde to the corresponding
carboxylic acid. Studies on this result are ongoing in our
laboratories.
O
NO2
NO2
CH3CH2CH2NO2 5 equiv.
H
ChClU 10 equiv.
80°C (MW), 2h
88%
F
F
4
Scheme 2. Reaction between p-fluorobenzaldehyde and nitropropane.
Table 5. Study of the effect of DES in the model optimized reaction (nitromethane and
p-fluorobenzaldehyde)
When nitropropane was used instead of nitromethane,
compound 4 was obtained in 88% yield as a syn/anti 1:1 mixture
of diastereoisomers (Scheme 2).
Entry
DES
Product (yield%)a
1c (96%)
mixture of byproducts
N.R.
1
2
3
4
ChCl/urea
ChOAc/urea
ChCl/GlyA
ChOAc/GlyA
OH
O
CH3NO2 5 equiv.
NO2
5a R = Ph, 92%
5b R = Et, 90%
R
R
CF3
ChClU 10 equiv.
80°C (MW), 2h
p-fluorobenzoic acid (67%)
CF3
aYield was evaluated by 1H-NMR on the crude.
Scheme 3. Reaction between nitromethane and trifluoromethylketones.
Urea-based catalysts are known to work in these reactions by
hydrogen bonding catalysis.39 On the bases of the results
previously discussed, a possible mechanism for the formation of
the 1,3-dinitropropane derivative can be postulated. The
proposed mechanism is provided in Scheme 4. In the first step,
urea activates nitromethane by forming a hydrogen-bonded
complex, thus promoting the formation of the nitronate ion which
The reactivity towards ketones was also investigated. Usually,
ketones are much less reactive than aldehydes. Nevertheless,
good yields can be obtained from the Henry reaction with the
activated trifluoromethylketones as substrates,37 particularly
with the use of MW irradiation.38 We then reacted
nitromethane with both acetophenone and 2,2,2-
trifluoroacetophenone under optimized conditions. No reaction
occurred with acetophenone, whereas the reaction of the
activated 2,2,2-trifluoroacetophenone produced the nitroaldol
5a in excellent yield (92%) (Scheme 3). In any case no trace of
the dinitro adduct was detected. Excellent yields (90% yield,
Scheme 3) were also achieved in the reaction of 1,1,1-
trifluorobutan-2-one with nitromethane to afford the nitroaldol
5b. Isatin, a non-enolizable activated ketone, was subjected to
the same reaction conditions but in this case no significant
reaction occurred with only traces of the nitroaldol derivatives
detected in the crude by 1H NMR.
A preliminary exploration of the role of the HBA (chloride or
acetate ions present in ChCl and ChOAc, respectively) and HBD
(urea or glycolic acid) of the DES on the outcome of the reaction
was also carried out. The possible combinations of the two
components to form a DES are indicated in Table 4. The use of
the DES in Table 4 is expected to provide a first indication of the
influence of HBA and HBD on the reaction selectivity and yields.
reacts witht he aldehyde to form the intermediate β-nitro alcohol
This step is also facilitated by the basic environment provided by the
DES ChCl/urea 39
In the same way, the H-bond interactions between
.
.
urea and the aldehyde increase the electrophilicity of the carbonyl
carbon atom.
OH
N
O
O
N
H
O
O
Cl
NO2
O
H
H
O
N
H
N
N
H
N
H
OH
N
N
H
H
O
3
O
H
-H2O
O
H
H
O
H
N
N
H
R
N
R
R
H
a
b
O
Scheme 4 Proposed mechanism for the Henry reaction in the DES ChCl/urea 18
. The β-
nitro alcohol a intermediate is dehydrated to the β-nitrostyrene b which
undergoes a Michael addition of a nitronate ion.
After the β-nitrostyrene b is formed by elimination of water, a
possible cooperative action of both the urea and the choline
components of the DES is proposed to explain the high
reactivity towards the formation of the 1,3-dinitropropane
Table 4. DESs prepared for this study
Entry
HBA
HBD
Molar
ratio
1:2
1:2
1:1
Abbreviation
1
2
3
4
Choline Chloride
Choline Acetate
Choline Chloride
Choline Acetate
Urea
Urea
Glycolic Acid
Glycolic Acid
ChCl/Urea product. Choline can activate β-nitrostyrene by coordination of
ChOAc/Urea
ChCl/GlyA
ChOAc/GlyA
both the ammonium and the hydroxy group. Similar
interactions have been observed in the solid state.40
1:1
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Figure 4. Recovery yield (%) of ChCl/urea for four cycles of the reaction (blue bars)
Finally, the ability to recycle the DES was studied. The recycling
of a catalyst and solvent is a key variable for both the economic
and environmental sustainability of the process. The tests on
DES recycling were carried out on the model reaction between
p-fluorobenzaldehyde and nitromethane in ChCl/urea. The
reaction was performed under the optimized conditions (1:5:10
equiv. at 80°C under MW irradiation for 2h). The product was
recovered by extraction with dichloromethane. The DES was
separated from the organic phase, recovered, and re-used as a
solvent for a subsequent reaction by the addition of new
and catalyst performance of DES (%) (yellow bars).
View Article Online
DOI: 10.1039/D0OB01516D
Conclusions
In conclusion, an efficient and straightforward synthesis of
symmetric 1,3-dinitropropanes in DES ChCl/urea using MW
irradiation was presented in this work. The reaction products
were obtained in high yields for several aldehydes, with both
nitromethane and nitropropane. The proposed approach
appears to be less efficient with ketones, except for activated
trifluoromethyl ketones which were converted into the
nitroaldol adduct in very high yields. The reaction outcomes
suggest a reaction mechanism that involves both choline and
urea to explain the high reactivity of the system. The
serendipitous finding of excellent selectivity and yields of the
tandem Henry reaction/Michael addition under DES-MW
conditions represents a mild, efficient and facile synthesis to
challenging 1,3-dinitropropane derivatives.
1
reagents. Its purity was checked by H NMR spectroscopy. As
shown in Figure 3, there are no differences between the fresh
and the recycled DESs. Throughout the four cycles, ChCl/urea
maintained its chemical structure and its ability to catalyse the
reaction. Moreover, there was no evidence of any reagents or
products in the recycled solvent.
Experimental
General information
All reagents and solvents were purchased from commercial
sources
and
used
without
further
purification.
The reactions were carried out under atmospheric air.
1
The H and 13C NMR spectra were recorded on a Bruker 400
spectrometer (1H NMR, 400 MHz; 13C NMR, 100MHz). The
spectra were recorded at room temperature, unless otherwise
indicated, in CDCl3, with tetramethylsilane (TMS, δ = 0.0 ppm)
used as the internal standard.
DESs preparation
Figure 3 1H NMR spectra of fresh and the recycled DES after different reaction
DESs were prepared according to one of the most used
procedures reported in the literature. Briefly, the preparation
involved the combination of choline choline chloride (HBA) with
urea or glycolic acid (HBDs), according to the molar ratio
reported in Table 4, at 80°C. This mixture was stirred for 30 min
until a homogeneous and transparent solution was formed.
The prepared DESs were cooled and used for our solubility tests
without any purification. The water content of freshly prepared
DES was determined using a Karl Fischer (KF) coulometric
titrator from Mettler Toledo and was found to be 0.96% for
ChCl/urea, 1.40% for ChCl/GlyA, 0.54% for ChOAc/urea and
0.74% for ChOAc/GlyA.
cycles.
In Figure 4 the performance and the recovery of the DES are
reported for four cycles. As can be seen, the ability to catalyse
the reaction is maintained (95-84%). The mass of recovered DES
remains relatively high with about 90% being retained in the
fourth cycle.
General procedure for Henry reactions
In a typical procedure, the desired DES (10 equiv.) was
transferred to a 5 mL vessel. Nitromethane or nitropropane (5
equiv.) and the aldehyde or ketone (1 equiv.) were then added
in one portion. The reaction vessel was irradiated with MW and
maintained at the indicated temperature for the desired time.
At the end of the reaction, the mixture was extracted with
dichloromethane (3 × 5 mL). The collected organic phases were
washed with water (2 × 15mL) to eliminate traces of DES. The
combined organic phases were dried over Na2SO4 and the
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10 (a) L. Vaccaro, European J. Org. Chem., 2020,
solvent was removed under reduced pressure. The resulting
View Article Online
DOI:10.1002/ejoc.202000131. (b) CD. OJ.I:C1l0a.r1k0e3,9/WD0.OCB.0T1u5,16OD.
Levers, A. Bröhl and J. P. Hallett, Chem. Rev., 2018, 118, 747–
800.
1
crude mixture was dissolved in CDCl3 for H-NMR analysis.
1
Conversions were calculated from H-NMR on the crude and
then converted in yields (as calculated from the total amount of
material recovered after reaction work-up).
When necessary, the crude was purified by column
chromatography (hexane/ethyl acetate 8:2).
Analytical data for compounds 3a-e41 and 542 were in agreement
with the literature.
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1-(3,5-dinitroheptan-4-yl)-4-fluorobenzene 4. 88% yield after
chromatographic purification. The product was obtained as an
1
inseparable 1:1 mixture of syn/anti stereoisomers. H NMR
(CDCl3), A+B isomers: δ(ppm) 7.03 (m, 4H, ArH), 5.00 (td, J =
10.2, 3.4 Hz, 1H, B), 4.63 (ddd, J = 10.9, 7.8, 2.6 Hz, 1H, A), 4.55
(dt, J = 9.4, 4.7 Hz, 1H, B), 3.95 (t, J = 7.8 Hz, 1H, A), 3.69 (dd, J =
10.5, 4.6 Hz,1H, B), 1.94-1.49 (m, 2H, A,B), 1.34-0.80 (t, J = 7.8
Hz, 3H, A,B). 13C NMR (CDCl3), A+B isomers: δ(ppm) 164.0-161.5
(A+B), 130.5 (A+B), 128.4 (A+B), 116.15 (A+B), 90.64 (A), 89.90-
89.34 (B), 51.38 (A), 50.64 (B), 26.12-24.39 (B), 23.58 (A), 10.58
(A), 10.21-9.65 (B). Anal. Calcd. for C13H17FN2O4: C, 54.92; H,
6.03; F, 6.68; N, 9.85; O, 22.51. Found: C,54.78; H, 6,12; N, 9,92.
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Acknowledgements
G.C.D. thanks Politecnico di Milano for her Inter-Departments
PhD scholarship. The authors acknowledge Barbara Corsico
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