Assessment of non-standard reaction conditions for asymmetric 1,3-dipolar organocatalytic cycloaddition of nitrone with α,β-unsaturated aldehydes

Article abstract of DOI:10.1515/chempap-2015-0020

Non-standard experimental conditions can often enhance organocatalytic reactions considerably. The current study explores the effectiveness of a range of non-standard reaction conditions for the asymmetric organocatalytic 1,3-dipolar cycloaddition of a nitrone with α,β-unsaturated aldehydes. The influence of ionic liquids, high-pressure conditions, ultrasound, microwave irradiation and ballmilling was tested as well as the flow process. Because of the low reactivity of the nitrone and unsaturated aldehydes in the 1,3-dipolar cycloaddition, cycloadducts were isolated in only moderate yields from the majority of experiments. However, high diastereo- and enantioselectivities were observed in ionic liquids under solvent-free conditions and in the flow reactor.

Full text of DOI:10.1515/chempap-2015-0020

Chemical Papers 69 (5) 737–746 (2015)
DOI: 10.1515/chempap-2015-0020
ORIGINAL PAPER
Assessment of non-standard reaction conditions for asymmetric
1,3-dipolar organocatalytic cycloaddition of nitrone
with α,β-unsaturated aldehydes
a
a
b
aMelinda Mojzesová, Mária Mečiarová, Ambroz Almássy, Roger Marti,
aRadovan Šebesta*
aDepartment of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava,
Mlynská dolina CH-2, 84215 Bratislava, Slovakia
bHES-SO Haute école spécialisée de Suisse occidentale, Ecole d’ingénieurs et d’architectes de Fribourg, Institut ChemTech,
Bd Pérolles 80, 1700 Fribourg, Switzerland
Received 8 September 2014; Revised 4 November 2014; Accepted 5 November 2014
Non-standard experimental conditions can often enhance organocatalytic reactions considerably.
The current study explores the effectiveness of a range of non-standard reaction conditions for the
asymmetric organocatalytic 1,3-dipolar cycloaddition of a nitrone with α,β-unsaturated aldehydes.
The influence of ionic liquids, high-pressure conditions, ultrasound, microwave irradiation and ball-
milling was tested as well as the flow process. Because of the low reactivity of the nitrone and
unsaturated aldehydes in the 1,3-dipolar cycloaddition, cycloadducts were isolated in only moderate
yields from the majority of experiments. However, high diastereo- and enantioselectivities were
observed in ionic liquids under solvent-free conditions and in the flow reactor.
c
ꢀ 2014 Institute of Chemistry, Slovak Academy of Sciences
Keywords: dipolar cycloaddition, ball-milling, flow reactor, ionic liquids, microwave, ultrasound
Introduction
dipolar cycloadditions (Xing & Wang, 2012; Stanley
& Sibi, 2008) a variety of organocatalysed cycloaddi-
tions has recently been developed (Pellissier, 2012).
In the first example of stereoselective organocat-
alytic 1,3-dipolar cycloaddition, Jen et al. (2000)
showed that chiral imidazolidinones activated α,β-
unsaturated aldehydes through the formation of chiral
iminium salts and these salts acted as dipolarophiles
in the cycloaddition with nitrones. Imidazolidinones
also catalyse several other variants of 1,3-dipolar cy-
cloadditions (Selim et al., 2012). Puglisi et al. (2004)
used a PEG-immobilised imidazolidinone as a catalyst
in dipolar cycloadditions. Ionically-tagged MacMil-
lan’s imidazolidinone was also an effective catalyst
for the cycloaddition of nitrones with crotonaldehyde.
The catalyst was re-used in five reaction cycles with-
out any deleterious effect on the reaction (Shen et
al., 2012). Recycling was also possible with the imi-
Dipolar cycloaddition is a powerful synthetic tool
for the formation of many biologically active com-
pounds (Kobayashi & J¨orgensen, 2002). Azides, ni-
trones and azomethine ylides are some of the typ-
ical 1,3-dipoles for the synthesis of structures with
biological relevance (Pellissier, 2007). 1,3-Dipolar cy-
cloadditions of nitrones with alkenes lead to isoxa-
zolidines with up to three new contiguous stereocen-
tres. These compounds are useful building blocks for
the synthesis of various biologically active compounds,
such as amino acids, alkaloids, pharmaceuticals (in-
hibitors of HIV, HSV, HCV) (Najera & Sansano,
2009), agrochemicals and natural compounds, e.g. ho-
bartine (Gribble & Barden, 1985) and anisomycin
(Ballini et al., 1992).
Apart from the traditional Lewis acid-catalysed
*Corresponding author, e-mail: radovan.sebesta@fns.uniba.sk
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M. Mojzesová et al./Chemical Papers 69 (5) 737–746 (2015)
dazolidinone catalyst attached to magnetic nanopar-
ticles (Pagoti et al., 2013). Apart from imidazolidi-
nones, pyrrolidine derivatives also act as suitable cat-
alysts for some dipolar cycloadditions. Nitrones un-
derwent 1,3-dipolar cycloadditions with 1-cycloalkene-
1-carboxaldehydes catalysed by a variety of pyrro-
lidinium salts to afford fused exo-bicyclic isoxazo-
lidines (Karlsson & H¨ogberg, 2002, 2003). Rios et
al. (2007) described the dipolar cycloadditions of ni-
trones with α,β-unsaturated aldehydes catalysed by
diphenylprolinol derivatives which provided moderate
yields and high diastereo- and enantioselectivity. The
pyrrolidine-derived, Jo¨rgensen–Hayashi organocata-
lyst was also used in the regiospecific, highly chemo-,
diastereo- and enantioselective one-pot cascade syn-
thesis of tricyclic bis-oxazolidines (Vesely et al., 2008).
The triflate salt of the J¨orgensen–Hayashi catalyst
provided the corresponding isoxazolidines with good
yields and high diastereoselectivities and enantioselec-
tivities (Chow et al., 2007).
non-standard experimental techniques can have a pos-
itive impact on organocatalytic reactions (Toma et
al., 2011; Hernández & Juaristi, 2012; Chauhan &
Chimni, 2012; Bruckmann et al., 2008). Accordingly,
it was decided to examine the effects of several non-
standard experimental conditions on organocatalysed
dipolar cycloadditions. This paper details the results
of the study of organocatalytic 1,3-dipolar cycloaddi-
tions of a prototypical nitrone to unsaturated alde-
hydes in ionic liquids. In addition, non-conventional
activation methods such as high pressure, solvent-free
conditions, microwave irradiation, ultrasound and flow
techniques were evaluated.
Experimental
NMR spectra were recorded on a Varian NMR Sys-
tem 300 (USA) instrument (300 MHz for 1H NMR,
75 MHz for 13C NMR). Chemical shifts are given in
δ relative to TMS. Flash chromatography (FC) was
˚
Other organocatalysts were also useful. For in-
stance, camphor-derived hydrazides catalysed the
asymmetric cycloadditions of nitrones with α,β-un-
saturated aldehydes, but the diastereoselectivities
were lower than those achieved with MacMillan’s imi-
dazolidinones. On the other hand, the use of hydrazide
catalysts afforded access to the exo cycloadduct, which
was otherwise difficult to obtain from acyclic dipo-
larophiles (Lemay et al., 2007). The cycloadditions
of nitrones with nitroolefins catalysed with chiral
thiourea-derived catalysts proceeded with good yields,
excellent diastereoselectivities and high enantioselec-
tivities (Du et al., 2008). Chiral phosphoramide-
catalysed 1,3-dipolar cycloadditions of diaryl nitrones
with ethyl vinyl ether afforded the corresponding
products with good yields (Jiao et al., 2008). An
asymmetric formal [3 + 2] nitrone cycloaddition us-
ing N-Boc- and N-Cbz-protected N-hydroxy-α-amido
sulphones as nitrone precursors with glutaconates was
catalysed with cinchona alkaloid-derived ammonium
salts (Gioia et al., 2009). A cinchona alkaloid-derived
catalyst was used in a domino reaction of nitroolefins
with 2-allyl malonates involving Michael addition and
cyclisation (Raimondi et al., 2010). 1,3-dipolar cy-
cloadditions of various nitrones to crotonaldehyde can
also be catalysed by hybrid diamines obtained from
(S)-BINAM and amino acids (Weselin´ski et al., 2009,
2011, 2012). Organocatalytic dipolar cycloadditions
are also useful reaction steps in domino sequences
(Zhu et al., 2009; Tan et al., 2010; Chua et al., 2010).
A considerable disadvantage of organocatalytic
dipolar cycloadditions is the long reaction times
needed to obtain products with reasonable yields. In
particular, the reactions of nitrones often extend over
several days. Almost all the 1,3-dipolar cycloadditions
of nitrones described were carried out in organic sol-
vents or in a mixture of organic solvents and H2O.
The use of ionic liquids, microwave irradiation or other
performed on silica gel 60 A, 0.035–0.070 nm, from
Fluka (Germany). Thin-layer chromatography (TLC)
was performed on Merck (Germany) TLC-plates sil-
ica gel 60, F-254. Enantiomeric excesses were deter-
mined by HPLC on a Chiralcel AD-H (Daicel, USA)
column using hexane/i-PrOH as a mobile phase and
UV detection. Microwave reactions were performed in
a Microwave Synthesis Reactor Monowave 300 (An-
ton Paar, Austria; IR sensor for temperature control,
sealed vessel), the sonochemical reaction proceeded
in an ultrasonic cleaning bath Kraintek 6 (Slovakia;
20 kHz) and a vibrational ball mill MM400 (Retsch,
Germany; 20 Hz) was used for the solvent-free reac-
tions. N-benzylidene-1-phenylmethanamine oxide (I )
was prepared according to the procedure described
in the literature (Mečiarová et al., 2013). Catalysts
Cat-I, Cat-III, Cat-V–Cat-VIII were purchased from
Sigma–Aldrich (USA). Cat-II and Cat-IV were pre-
pared according to the literature (Chow et al., 2007;
Jen et al., 2010).
Procedure for synthesis of (3R,4S,5R)-2-
benzyl-4-formyl- sb5-methyl-3-phenylisoxazo-
lidine (endo-IIIa)
Procedure for the reaction in CH2Cl2: the catalyst
(0.05 mmol) was added to the stirred solution of ni-
trone I (53 mg; 0.25 mmol) in CH2Cl2. The mixture
was cooled to 5◦C or heated to 40◦C then crotonalde-
hyde (IIa; 60 L, 0.75 mmol) was added to the flask
drop-wise. A further amount of IIa was added to the
mixture at 0.5 h intervals (5 × 20 L; 0.25 mmol).
The mixture was stirred for the time given in Table 2,
then concentrated under vacuum and the residue was
analysed by 1H NMR spectroscopy to establish the
endo/exo ratio. The crude product was then purified
by flash chromatography (SiO2, hexane/AcOEt (ϕr =
7 : 3) to afford the product as an oil.
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Table 1. Physical and spectral data of prepared compounds
Compound Physical and spectral data
739
Reference
m.p. 155–158◦C
1H NMR (300 MHz, D6-DMSO), δ: 7.39–7.29 (m, 5H, in Ph), 4.69 (m, 1H,
COCH), 3.34 (dd, J = 15.2 Hz, J = 3.2 Hz, 1H, CH2Ph), 2.98 (dd, J = 15.1 Hz, Jen et al. (2000)
J = 10.7 Hz, 1H, CH2Ph), 2.80 (s, 3H, CH3NCO), 1.63 (s, 3H, CH3), 1.49 (s,
3H, CH3)
m.p. 148–150◦C
1H NMR (300 MHz, CDCl3), δ: 8.44 (bs, 1H), 7.39–7.33 (m, 10H, 2 × Ph),
6.47 (bs, 1H), 4.79 (bs, 1H, NHCH), 3.28–3.16 (m, 1H, CH2), 2.67 (bs, 1H, Chow et al. (2007)
CH2), 2.37–2.25 (m, 1H, CH2), 2.07–1.89 (m, 2H, CH2), 1.61–1.45 (m, 1H,
CH2), –0.09 (s, 9H, Me3Si)
1
—
H NMR (300 MHz, CDCl3), δ: 9.79 (d, J = 2.4 Hz 1H, CH O), 7.45–7.25
—
(m, 10H, Ph and CH2Ph), 4.57 (dq, J = 12.0 Hz, J = 5.9 Hz, 1H, CHCH3),
4.16 (d, J = 7.8 Hz, 1H, CHPh), 4.03 (d, J = 14.3 Hz, 1H, CH2Ph), 3.84 (d, Puglisi et al. (2004)
—
J = 14.3 Hz, 1H, CH2P), 3.14 (m, 1H, CHCH O), 1.51 (d, J = 6.2 Hz, 3H,
—
CH3)
1H NMR (300 MHz, CDCl3), δ: 7.44–7.19 (m, 10H, Ph and CH2Ph), 4.22–
4.09 (m, 1H, CHON), 3.99 (d, J = 14.4 Hz, 1H, CH2Ph), 3.79 (d, J = 14.4 Hz,
1H, CH2Ph), 3.74–3.69 (m, 2H, CH2OH), 3.63 (d, J = 8.4 Hz 1H, CHPh),
2.38–2.29 (m, 1H, CHCH2OH), 1.43 (d, J = 6.2 Hz, 3H, CH3)
HPLC (Chiralcel AD-H; hexane/EtOH (ϕr = 95 : 5); 0.8 mL min−1, λ =
216 nm): tR (major) = 20.10 min, tR (minor) = 15.09 min
Puglisi et al. (2004)
1
—
H NMR (300 MHz, CDCl3), δ: 9.79 (d, J = 2.4 Hz, 1H, CH O,), 7.43–7.20
—
(m, 10H, Ph and CH2Ph), 4.26 (td, J = 7.5 Hz, J = 5.6 Hz, 1H, CHCH2CH3),
4.13 (d, J = 7.8 Hz, 1H, CHPh), 3.99 (d, J = 14.4 Hz, 1H, CH2Ph), 3.79 (d, Shen et al. (2012)
J = 14.4 Hz, 1H, CH2Ph), 3.17–3.12 (m, 1H, CHCHO), 2.07–1.93 (m, 1H,
CH2CH3), 1.79–1.65 (m, 1H, CH2CH3), 0.96 (t, J = 7.4 Hz, 3H, CH2CH3)
1H NMR (300 MHz, CDCl3), δ: 7.38–7.13 (m, 10H, Ph and CH2Ph), 4.16–
4.13 (m, 1H, CHON), 3.95 (d, J = 14.7 Hz, 1H, CH2Ph), 3.84–3.79 (m, 1H,
CH2Ph), 3.71–3.62 (m, 2H, CH2OH), 3.56 (d, J = 8.2 Hz, 1H, CHPh), 2.38–
2.28 (m, 1H, CHCH2OH), 1.64–1.57 (m, 2H, CH2CH3), 0.96 (t, J = 7.4 Hz,
3H, CH2CH3)
13C NMR (75 MHz, CDCl3), δ: 139.6 (Cq in Ph), 138.1 (Cq in Ph), 128.7 Shen et al. (2012)
(CHPh), 128.3 (CHPh), 128.0 (CHPh), 127.9 (CHPh), 127.8 (CHPh), 126.8
(CHPh), 81.4 (CHON), 73.9 (CHNO), 63.1 (CH2Ph), 60.4 (CH2OH), 59.7
(CHCH2OH), 28.6 (CH2CH3), 10.4 (CH2CH3)
HPLC (Chiralcel AD-H; hexane/IPA (ϕr = 97 : 3); 2 mL min−1, λ = 213 nm):
tR (major) = 15.54 min, tR (minor) = 11.33 min
1
—
H NMR (300 MHz, CDCl3), δ: 9.78 (d, J = 2.5 Hz, 1H, CH O), 7.43–7.23
—
(m, 10H, Ph a CH2Ph), 4.38–4.32 (m, 1H, CHON), 4.13 (d, J = 7.8 Hz, 1H,
CHPh), 3.99 (d, J = 14.4 Hz, 1H, CH2Ph), 3.80 (d, J = 14.4 Hz, 1H, CH2Ph),
—
3.17–3.11 (m, 1H, CHCH O), 2.07–1.92 (m, 1H, CH2CH2CH3), 1.70–1.58
—
(m, 1H, CH2CH2CH3), 1.48–1.33 (m, 2H, CH2CH2CH3), 0.93 (t, J = 7.4 Hz,
Shen et al. (2012)
3H, CH2CH2CH3)
13
—
C NMR (75 MHz, CDCl3), δ: 198.8 (CH O), 138.3 (Cq in Ph), 137.4 (Cq
—
in Ph), 130.0 (CHPh), 128.9 (CHPh), 128.4 (CHPh), 128.1 (CHPh), 127.6
(CHPh), 127.0 (CHPh), 77.3 (CHON), 71.0 (CHNO), 70.4 (CHCH=O), 59.3
(CH2Ph), 37.6 (CH2CH2CH3), 19.2 (CH2CH2CH3), 13.9 (CH2CH2CH3)
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M. Mojzesová et al./Chemical Papers 69 (5) 737–746 (2015)
Table 1. (continued)
Compound
Physical and spectral data
Reference
1H NMR (300 MHz, CDCl3), δ: 7.45–7.20 (m, 10H, Ph and CH2Ph), 4.23–
4.20 (m, 1H, CHON), 4.01–3.93 (m, 2H, CH2Ph), 3.81–3.71 (m, 2H, CH2OH),
3.56 (d, J = 8.2 Hz, 1H, CHPh), 2.45–2.36 (m, 1H, CHCH2OH), 2.07–2.00
(m, 1H, CH2CH2CH3), 1.97–1.85 (m, 1H, CH2CH2CH3), 1.67–1.56 (m, 2H,
CH2CH2CH3), 0.93 (t, J = 7.3 Hz 3H, CH2CH3)
HPLC (Chiralcel AD-H; hexane/IPA (ϕr = 97 : 3); 2 mL min−1, λ = 217 nm):
tR (major) = 18.76 min, tR (minor) = 12.92 min
Shen et al. (2012)
Table 2. Dipolar cycloaddition of nitrone I with aldehydes IIa–IIc in ionic liquids
Entry
Catalyst
Aldehyde
Reaction conditions
Yield/%
Endo/exo ratioa
Enantiomeric ratio
of endo-IIb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Cat-I
Cat-I
IIa
IIa
IIa
IIa
IIa
IIb
IIb
IIb
IIb
IIb
IIb
IIb
IIb
IIb
IIb
IIb
IIc
CH2Cl2, 5◦C, 4 d
IL-I, 5◦C, 4 d
45
47
20
21
48
32
24
17
47
51
35
30
34
30
40
0
62 : 38
80 : 20
92 : 8
55 : 45
51 : 49
56 : 44
91 : 9
69 : 31
Cat-IV · HOTf
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-II · HOTf
Cat-V
IL-I, 5◦C, 5 d
IL-I, 5◦C, 5 d
IL-I, 40◦C, 3 d
79 : 21
64 : 36
69 : 31
63 : 37
69 : 31
83 : 17
76 : 24
83 : 17
72 : 28
77 : 23
50 : 50
77 : 23
–
IL-I, H2O, r.t., 3 d
IL-II, H2O, r.t., 3 d
IL-III, H2O, r.t., 3 d
IL-IV, H2O, r.t., 3 d
IL-V, H2O, r.t., 3 d
IL-V, H2O, r.t., 3 d
IL-V, H2O, r.t., 3 d
IL-V, H2O, r.t., 3 d
IL-V, H2O, r.t., 3 d
IL-V, H2O, r.t., 3 d
IL-VI, H2O, r.t., 3 d
IL-V, H2O, r.t., 3 d
54 : 46
52 : 48
56 : 44 (90 : 10)c
75 : 25 (77 : 23)c
66 : 34 (85 : 15)c
n.d.
73 : 27
52 : 48
83 : 17
77 : 23
Cat-VIII
Cat-III
Cat-VII
Cat-IV · HCl
–
Cat-IV · HCl
32
63 : 37
72 : 28
Reactions were carried out with 0.25 mmol of nitrone I and 0.05 mmol of organocatalyst. a) Determined by 1H NMR of crude prod-
uct; b) enantiomeric ratio was determined by HPLC on chiral stationary phase (aldehyde III was first converted into corresponding
alcohol IV); c) enantiomeric purity of exo-IIIb; r.t. – ambient temperature.
Reaction in ILs: reactions were performed in the
same way as in CH2Cl2. A small amount of H2O
(5 mL) was added to the mixture prior to the ex-
traction with t-BuOMe. The organic layer was dried
(Na2SO4), filtered, concentrated and the residue was
analysed by 1H NMR spectroscopy to establish the
endo/exo ratio. The crude product was purified by
flash chromatography as per the reaction in CH2Cl2.
Procedure for the microwave reaction: nitrone I
(53 mg; 0.25 mmol), catalyst (0.05 mmol) and IIa
(0.165 mL; 2 mmol) were dissolved in CH2Cl2 and ir-
radiated in the MW reactor at 90◦C for 6 h. The mix-
ture was concentrated under vacuum and the residue
was analysed by 1H NMR spectroscopy to establish
the endo/exo ratio. The crude product was purified by
flash chromatography, as per the reaction in CH2Cl2.
Procedure for the reaction in high pressure reactor:
nitrone I (53 mg; 0.25 mmol), catalyst (0.05 mmol)
and IIa (0.165 mL; 2 mmol) were dissolved in CH2Cl2
in a special tube, then placed in a high-pressure re-
actor at 13 MPa for the time given in Table 2. The
mixture was then concentrated under vacuum and the
tablish the endo/exo ratio. The crude product was pu-
rified by flash chromatography, as per the reaction in
CH2Cl2.
Procedure for the reaction in ball mill: the ball-
milling reactor was filled with I (53 mg; 0.25 mmol),
catalyst (0.05 mmol) and IIa (0.165 mL; 2 mmol) and
the contents ground for the time given in Table 2.
The reaction mixture was washed with CH2Cl2, con-
centrated under vacuum and the residue was analysed
by 1H NMR spectroscopy to establish the endo/exo
ratio. The crude product was purified by flash chro-
matography as per the reaction in CH2Cl2.
Procedure for synthesis of (4S,5R)-2-benzyl-5-
ethyl-4-formyl-3-phenylisoxazolidine
(endo-IIIb)
Nitrone I (50 mg, 0.237 mmol) was added to the
mixture of pent-2-enal (116 L, 1.183 mmol), cata-
lyst (0.040 mmol), H2O (2 L, 0.12 mmol) and well-
dried ionic liquid (2 mL) and the mixture was stirred
at 20◦C. The reaction course was monitored by TLC
analysis (SiO2, hexane/AcOEt (ϕr = 3 : 1)) and an-
1
residue was analysed by H NMR spectroscopy to es-
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741
Fig. 1. Dipolar cycloaddition of nitrone I with aldehydes II.
other portion of pent-2-enal (23 L, 0.237 mmol) was
added after 20 h and 48 h. After 64 h, the mix-
ture was extracted with t-BuOMe (8 × 3 mL). The
combined organic extracts were washed with water
(2 × 5 mL) and brine (5 mL), dried (Na2SO4) and
the solvent evaporated. The products were separated
by flash chromatography (SiO2, hexane/Et2O (ϕr =
20 : 1), λ = 213 nm) (Shen et al., 2012).
tracts were washed with water (2 × 5 mL) and brine
(5 mL), dried (Na2SO4) and the solvent evaporated,
then the products were separated by flash chromatog-
raphy (SiO2, hexane/Et2O (ϕr = 20 : 1), λ = 213 nm)
(Shen et al., 2012).
General procedure for reduction of III to IV
Reaction in the flow microreactor: the reaction was
conducted in a reactor consisting of an 0.5 mL-mixing
unit and a 24 mL-heated (60◦C or 80◦C) retention
unit and three inlets (Fig. 3). The reagents were intro-
duced using a syringe pump. The solution of aldehyde
(12.5 mmol) was introduced into one inlet at a flow-
rate of 0.05 mL min−1, while a solution of the catalyst
(0.5 mmol) and H2O (1.25 mmol) in the same solvent
was introduced from the other inlet at the same flow-
rate. The total output was 0.1 mL min−1. After mix-
ing these reagents, I (2.5 mmol) was introduced via
the third inlet in the same solvent at a flow-rate of
0.1 mL min−1. The total output was 0.2 mL min−1
(2 h of residence time). The collected solution was
concentrated under reduced pressure and the residues
were purified by flash chromatography (SiO2, hep-
tane/AcOEt (ϕr = 10 : 1)) to afford the title com-
pound.
To the solution of IIIa–IIIc in absolute EtOH
(1 mL), NaBH4 (3 eq.) was added. The reaction
was quenched with H2O and after 30 min the mix-
ture was extracted with CH2Cl2 (3 × 10 mL). The
organic phase was dried (Na2SO4), filtered, concen-
trated and purified by flash chromatography (SiO2,
hexane/AcOEt (ϕr = 7 : 3)) (Shen et al., 2012).
Results and discussion
The dipolar cycloaddition of (Z)-N-benzylidene-1-
phenylmethanamine oxide (I ) with α,β-unsaturated
aldehydes II affords isoxazolidines III. These isoxazo-
lidines are typically obtained as a mixture of endo and
exo-diastereoisomers (Fig. 1).
Endo-diastereoisomers were separated by flash
chromatography and converted to corresponding al-
cohols IV by NaBH4 reduction (Fig. 2). The absolute
configurations of alcohols IV were determined by com-
paring the retention times of chiral-phase HPLC with
the values in the literature; see experimental section
for details.
Procedure for synthesis of (4S,5R)-2-benzyl-4-
formyl-3-phenyl-5-propylisoxazolidine
(endo-IIIc)
A range of organocatalysts Cat-I–Cat-VIII (Fig. 3)
was tested in the reactions of nitrone I with aldehy-
des II. As a selection principle, the catalyst’s capac-
ity to participate in an iminium activation was cho-
sen, as dipolar cycloadditions with α,β-unsaturated
aldehydes proceed via the corresponding iminium
salt generated from the aldehyde (Jen et al., 2000).
Accordingly, proline methyl ester (Cat-I), two pro-
linol silyl ethers (Cat-II and Cat-III) and several
MacMillan-type imidazolidinones (Cat-IV–Cat-VIII)
were used.
Nitrone I (53 mg, 0.25 mmol) was added to the
mixture of hex-2-enal (120 L, 1.00 mmol), cata-
lyst Cat-IV · HCl (13 mg, 0.05 mmol), H2O (2 L,
0.125 mmol) and well-dried ionic liquid IL-VI (2 mL)
and the mixture was stirred at 20◦C. The reaction
course was monitored by TLC analysis (SiO2, hex-
ane/AcOEt (ϕr = 3 : 1)). Other portions of hex-2-enal
(120 L, 1.00 mmol) were added after 20 h and after
48 h (60 L, 0.5 mmol). The mixture was extracted
with t-BuOMe (8 × 3 mL). The combined organic ex-
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M. Mojzesová et al./Chemical Papers 69 (5) 737–746 (2015)
Fig. 2. Reduction of aldehydes III to alcohols IV.
Fig. 3. Organocatalysts used in this study.
Dipolar cycloaddition in ionic liquids
ever, this also led to decreases in diastereoselectivity
(endo/exo 64 : 36) and enantioselectivity (e.r. 69 : 31,
for endo-IIIa).
For purposes of comparison, the study began with
the reaction of nitrone I with crotonaldehyde (IIa)
in CH2Cl2 as one of the classical organic solvents.
These types of dipolar cycloaddition reactions are,
typically, quite slow, the reaction of nitrone I with
aldehyde IIa and catalyst Cat-I at 5◦C serving as a
good example. After 4 d, the isoxazoline IIIa was iso-
lated with an overall yield of 45 %, with mediocre
diastereoselectivity (endo/exo = 62 : 38) and virtu-
ally no enantioselectivity. In the ionic liquid 1-butyl-3-
methylimidazolium tetrafluoroborate ([bmim]BF4, IL-
I; Fig. 2), the yield and enantiomeric ratio were sim-
ilar to those in CH2Cl2, but the diastereoselectivity
increased to 80 : 20 (Table 2, Entries 1 and 2). Di-
astereoselectivity increased yet further (endo/exo =
92 : 8) when the MacMillan catalyst Cat-IV · HOTf
was used, although the product IIIa was isolated with
only a 20 % yield. When the catalyst Cat-IV · HCl was
employed in [bmim]BF4 (IL-I) at 5◦C; the product IIIa
was isolated with a 21 % yield with an endo/exo ratio
of 79 : 21 and e.r. (endo) 91 : 9. An increase in the
reaction temperature to 40◦C resulted in increasing
the yield of isoxazoline IIIa from 21 % to 48 %. How-
As cycloadditions of crotonaldehyde (IIa) in ionic
liquids afforded promising results, 1,3-dipolar cycload-
ditions of nitrone I with pent-2-enal (IIb) in various
ionic liquids were also studied. The structures of the
ionic liquids used are depicted in Fig. 4.
Ionic liquids IL-I–IL-III and IL-VI are miscible
with H2O, in contrast with ionic liquids IL-IV and
IL-V. This property had an intriguing effect on the
enantioselectivity of the reaction. The presence of H2O
is essential for achieving high conversion, as well as
good stereoselectivity. However, a further increase in
the amount of H2O reduced both the yield and enan-
tioselectivity. The best results were attained using 50
mole % of H2O (Lemay et al., 2007). Cycloadditions
of nitrone I with aldehyde IIb in ionic liquids were per-
formed using catalyst Cat-IV · HCl at ambient tem-
perature over 3 d and H2O (50 mole %) was added to
the mixtures to enhance the catalytic turnovers. The
product IIIb was obtained with rather low yields in the
experiments with the ionic liquids IL-I–IL-III. Also,
diastereoselectivities were only moderate (endo/exo
ratio of 63 : 37–69 : 31) and the reactions were al-
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M. Mojzesová et al./Chemical Papers 69 (5) 737–746 (2015)
743
Fig. 4. Structures of ionic liquids.
most non-enantioselective as the enantiomeric purity
of product IIIb was negligible (e.r. 52 : 48–56 : 44)
(Table 2, Entries 6–8). Interestingly, the exo-product
from the reaction in IL-III was obtained with e.r.
90 : 10. The situation was different with the ionic liq-
uids immiscible with H2O. Under otherwise identical
conditions, the chemical yield as well as the diastere-
omeric and enantiomeric purity of the isoxazoline IIIb
increased. The product IIIb was isolated with a 47 %
yield and with an endo/exo ratio of 83 : 17, when IL-IV
was used as a solvent. The endo-isomer was obtained
with e.r. of 75 : 25 and the exo-isomer with e.r. of
77 : 23 (Table 2, Entry 9). The cycloaddition of nitrone
I with aldehyde IIb proceeded similarly in ionic liquid
IL-V. Product IIIb was isolated with a 51 % yield and
its diastereomeric composition was endo/exo 76 : 24.
The enantiomeric purity of compound endo-IIIb de-
creased slightly to 66 : 34, whereas the enantiomeric
ratio for exo-IIIb increased to 85 : 15 (Table 2, Entry
10). The cycloaddition of nitrone I with aldehyde IIb
in phosphonium ionic liquid IL-VI did not take place
at all.
The cycloadditions of nitrone I with aldehyde IIb
afforded product IIIb with the highest yield in ionic
liquid IL-V. However, the enantiomeric purity of prod-
uct IIIb was relatively low with catalyst Cat-IV · HCl.
Accordingly, several other organocatalysts were tested
in this ionic liquid (Table 2, Entries 12–16). The best
diastereoselectivity (endo/exo = 83 : 17) was attained
with catalyst Cat-II · HOTf. On the other hand, the
highest enantioselectivity of the cycloaddition was ob-
served when catalyst Cat-III was used (e.r. (endo-IIIb)
83 : 17).
ing Cat-IV · HCl in ionic liquid IL-V with 50 mole %
of H2O afforded product IIIc with a 32 % yield with
an endo/exo ratio of 63 : 37 and e.r. (endo) of 72 : 28
(Table 2, Entry 17). The dipolar cycloaddition of ni-
trone I did not proceed with cinnamaldehyde (IId),
oct-2-enal (IIe) neither with non-2-enal (IIf ) under
the same conditions. In general, complex mixtures of
products were obtained from these reactions.
Other non-standard reaction conditions
To improve the yields and selectivities of the dipo-
lar cycloadditions of nitrone I with aldehydes II, these
reactions were carried out under several other non-
standard reaction conditions. Solvent-free conditions
in a ball mill, ionic liquids under ultrasonic as well as
microwave irradiation, reaction under high pressure
and reaction in a flow system were evaluated.
Mechanochemical activation during ball-milling of-
ten increases reaction rate due to higher reactant con-
centrations and more effective molecular contacts un-
der solvent-free conditions (James et al., 2012). In the
ball mill, product IIIa was obtained with a 28 % yield
with an endo/exo ratio of 89 : 11 and high enan-
tiomeric purity e.r. (endo) of 94 : 6 (Table 3, Entry
1). The reaction was conducted in the vibrational ball
mill in two or four 90 min cycles (3 h or 6 h in to-
tal). The longer reaction time, 6 h, had no effect on
the reaction outcome (Table 3, Entry 2). Although
the yield appears to be rather low, it should be noted
that several days are required to obtain a similar re-
sult in the solution. It is unclear why the yield did not
improve with time, but this may be due to catalyst de-
composition as a result of mechanochemical stress or
the intrinsically higher temperatures entailed during
ball-milling. Similar results were also obtained with
aldehyde IIb. The corresponding product IIIb was iso-
lated with a 30 % yield and with an endo/exo ratio of
67 : 33 and enantiomer ratio of 73 : 27 (endo-IIIb) (Ta-
ble 3, Entry 3). As one of the reactants is a liquid, the
The low yields of cycloadducts were also caused,
at least in part, by the instability of starting α,β-
unsaturated aldehydes in the presence of the catalyst
in ionic liquids. A blank experiment, without the ni-
trone, revealed that aldehyde IIb decomposed to a sig-
nificant degree after 24 h.
The reaction of nitrone I with hex-2-enal (IIc) us-
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M. Mojzesová et al./Chemical Papers 69 (5) 737–746 (2015)
Table 3. Dipolar cycloaddition of nitrone I with aldehydes IIa and IIb under various conditions
Entry
Catalyst
Reaction conditions
Yield/%
Endo/exo ratioa Enantiomeric ratio
of endo-IIIb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-II · HOTf
Cat-IV · HCl
Cat-IV · HCl
Cat-VI
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
Cat-IV · HCl
ball-milling, 3 h
ball-milling, 6 h
ball-milling, 3 h
ball-milling, 3 h + Celite
ball-milling, 6 h
CH2Cl2, MW, 6 h, 80◦C, 0.8 MPa
CH2Cl2, 13 MPa, 24 h
CH2Cl2, 13 MPa, 24 h
IL-I, ultrasound, 16 h
IL-V, ultrasound, 20 h
IL-IV, MW, 5 h, 90◦C
flow microreactor, CH2Cl2, 2 h, r.t.e
flow microreactor, MeNO2, 2 h, 60◦Ce
flow microreactor, MeNO2, 2 h, 80◦Ce
28
24
30
34
23
46
35
21
40
37
0
89 : 11
88 : 12
67 : 33
67 : 33
79 : 21
83 : 17
86 : 14
83 : 17
71 : 29
66 : 34
–
94 : 6 (IIIa)
90 : 10 (IIIa)
73 : 27 (IIIb)
76 : 24 (IIIb)d
85 : 15 (IIIa)
79 : 21 (IIIa)
84 : 16 (IIIa)
72 : 28 (IIIa)
68 : 32 (IIIa)
54 : 46 (IIIb)
–
ꢀc
14
22
28
66 : 34
99 : 1
99 : 1
81 : 19 (IIIb)
94 : 6(IIIb)
97 : 3 (IIIb)
Reactions were carried out with 0.25 mmol of nitrone (I) and 0.05 mmol of organocatalyst, reactions in flow microreactors with
2.5 mmol of I and 0.5 mmol of Cat-IV · HCl. a) Determined by 1H NMR of crude product; b) enantiomeric ratio was determined
ꢀ
by HPLC on chiral stationary phase (aldehyde III was first converted into corresponding alcohol IV); c) 200 mg Celite was used;
d) e.r. for exo-IIIb 71 : 29; e) residence time in reactor.
addition of an inert solid material was tried; this often
helps in such situations under solvent-free conditions
(Thorwirth et al., 2010). An addition of Celiteꢀ led
to a slightly higher yield of isoxazolidine IIIb (34 %)
(Table 3, Entry 4). The activity of catalyst Cat-II ·
HOTf in the ball mill was also evaluated, but it was
less effective than catalyst Cat-IV · HCl (Table 3, En-
try 5).
The dipolar cycloadditions of nitrone I with
cyclohex-2-enone, cyclopent-2-enone, (E)-nitrostyrene
and 1-benzyl-1H-pyrrole-2,5-dione under solvent-free
conditions in the ball mill for 3 h using Cat-IV · HCl
did not proceed and only unreacted starting materi-
als were detected in the reaction mixtures. The reac-
tion of the nitrostyrene was also performed with chiral
thiourea derivatives in the ball mill, but without any
positive effect on the reaction.
It is known that cycloaddition reactions entail large
negative changes in the volume of activation as the
reaction progress from starting material via transi-
tion state to products (Turro et al., 1987). As a re-
sult of this effect, cycloadditions often proceed better
under high pressure. Accordingly, the cycloaddition
of nitrone I with crotonaldehyde (IIa) using catalyst
Cat-IV · HCl was performed under increased pressure.
The first experiment was performed under microwave
irradiation in a closed reaction vessel. When a low-
boiling solvent is used in such a case, the pressure in
the vessel increases as the temperature rises above its
boiling point. CH2Cl2 was used at 80◦C, which gener-
ated a pressure of approximately 800 kPa. After 6 h,
product IIIa was isolated with a 46 % yield with a high
endo/exo ratio (83 : 17) and mediocre enantiomer pu-
rity (e.r. 79 : 21) (Table 3, Entry 6). Surprisingly, the
reaction at a considerably higher pressure (13 MPa)
in a high-pressure reactor resulted in a lower yield
(35 %), but similar diastereoselectivity (d.r. 86 : 14)
and slightly better enantioselectivity (e.r. 84 : 16) (Ta-
ble 3, Entry 7). When catalyst Cat-VI was used in-
stead of Cat-IV · HCl, the overall yield of product IIIa
declined to 21 %, the endo/exo ratio was unchanged
and the enantiomer purity decreased to e.r. of 72 : 28
(Table 3, Entry 8).
Ultrasound accelerates a number of organic reac-
tions as a result of the extreme temperatures and pres-
sures which occur during cavitation (Cravotto & Cin-
tas, 2006). Accordingly, the cycloaddition of nitrone I
with aldehydes IIa and IIb was evaluated under ultra-
sonic conditions. The reaction of crotonaldehyde (IIa)
afforded product IIIa with a 40 % yield in ionic liq-
uid IL-I (Table 3, Entry 9). The addition using alde-
hyde IIb proceeded similarly in ionic liquid IL-V un-
der ultrasonic irradiation. After 20 h, product IIIb was
isolated with a 37 % yield with a diastereomeric ra-
tio of approximately 2 : 1. Both adducts endo- and
exo-IIIb were obtained in almost racemic form, pos-
sibly due to the forcing conditions under ultrasonic
irradiation (Table 3, Entry 10). A notable feature of
the ultrasound application is a significant reduction
in the reaction time. To obtain a similar yield un-
der standard conditions, a much longer time, often
several days, was needed. An attempt was also made
to test the effect of microwaves without higher pres-
sures, hence an experiment was performed in one of
the ionic liquids, because ionic liquids have negligible
vapour pressure and as highly polar media transmit
microwave energy effectively. However, the reaction of
nitrone I with aldehyde IIb in ionic liquid IL-IV under
microwave irradiation was not accelerated and only
the starting material was detected after 5 h at 90◦C
(Table 3, Entry 11).
Finally, the possibility of adapting the dipolar cy-
cloaddition to continuous flow conditions was exam-
ined. Continuous flow is of particular interest in con-
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M. Mojzesová et al./Chemical Papers 69 (5) 737–746 (2015)
745
Fig. 5. Experimental set-up for reactions in flow microreactor: 1 – T-mixer (Teflon); 2 – residence time unit 0.5 mL (Teflon tubing);
3 – LTF MS mixer (glass); 4 – residence time unit 24 mL (Teflon tubing); 5 – heating bath.
nection with an immobilised catalyst (Puglisi et al.,
2013). It has not, however, been so thoroughly inves-
tigated for homogeneous catalytic reactions (Zhao &
Ding, 2013). For this purpose, the instrument set-up
represented in Fig. 5 was used. In the initial experi-
ments, product IIIb was obtained with a 14 % yield
with an endo/exo ratio of 66 : 34 and e.r. (endo) of
81 : 19, when CH2Cl2 was used as a solvent. Slightly
better yields were achieved in nitromethane, which
is the best solvent under standard conditions (22 %
at 60◦C and 28 % at 80◦C). Interestingly, the re-
action proceeded highly diastereoselectively as only
diastereoisomerendo-IIIb was detected in the crude re-
action mixture. In addition, product IIIb was obtained
with a high enantiomeric purity e.r. of 94 : 6 at 60◦C
and 97 : 3 at 80◦C (Table 3, Entries 12–14). The main
limitation applying to the flow system is also a very
slow reaction. In the flow reactor, residence time can-
not be prolonged deliberately, which limits the obtain-
ing of high yields of the products. Nevertheless, the
efficiency of the flow system is evident, as isoxazoline
IIIb was obtained with a 28 % yield in only 2 h.
conditions, the endo isomer was isolated with a high
enantiomeric purity e.r. of 94 : 6. Even higher selec-
tivities were observed in the flow microreactor, where
the reaction of pent-2-enal in nitromethane afforded
the product with an endo/exo ratio of 99 : 1 and an
enantiomer ratio of 97 : 3.
Acknowledgements. The authors are grateful for the finan-
cial support received from the Slovak Grant Agency VEGA,
grant no. 1/0543/11 and the Slovak Research and Development
Agency, grant no. APVV-0067-11. This publication is the re-
sult of the project implementation: 26240120025 supported by
the Research & Development Operational Programme funded
by the European Regional Development Fund. We also wish to
thank Prof. Štefan Toma for fruitful discussions.
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