Electronic effects in 1,3-dipolar cycloaddition reactions of N-alkyl and N-benzyl nitrones with dipolarophiles

Article abstract of DOI:10.1039/c1ob06144e

1,3-Dipolar cycloadditions afforded fast access to isoxazolidines bearing N-alkyl or N-benzyl substituents. The electronic properties of the substituents in the nitrones define the activity of the dipoles and modulate diastereoselectivity in the non-catal

Full text of DOI:10.1039/c1ob06144e

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PAPER
Electronic effects in 1,3-dipolar cycloaddition reactions of N-alkyl and
N-benzyl nitrones with dipolarophiles†
Andrei Ba˘doiu and E. Peter Ku¨ndig*
Received 11th July 2011, Accepted 30th August 2011
DOI: 10.1039/c1ob06144e
1,3-Dipolar cycloadditions afforded fast access to isoxazolidines bearing N-alkyl or N-benzyl
substituents. The electronic properties of the substituents in the nitrones define the activity of the
dipoles and modulate diastereoselectivity in the non-catalyzed reactions. Using a chiral one-point
binding ruthenium Lewis acid catalyst, products were obtained in good yields and with excellent regio-,
diastereo-, and enantioselectivity.
are less reactive dipoles when compared to diaryl- and cyclic
Introduction
nitrones.14 However, modularity, ease of synthesis, and stability
2010 was a special year for the 1,3-dipolar cycloadditions (1,3-
are the key characteristics of these dipoles and explain their
DCs). Along with 50 years of continuous evolution and expansion
widespread use in synthesis (Fig. 1).
in the field, we celebrated the 90th anniversary of the father of
this chemistry, Prof. Rolf Huisgen.1 Cycloadditions have always
attracted the interest of the scientific community through the
apparent practical simplicity that hides a complex mechanism, the
elegant end efficient access to cyclic compounds, and the versatility
of both starting materials and products.2 Recent developments in
asymmetric catalysis have further emphasized the value of 1,3-DCs
as fast and clean reactions towards functionalized, enantiopure
N,O-heterocyclic compounds.3
We have previously reported efficient and selective homoge-
neous chiral catalysts for the Diels–Alder reactions of enals4,5
and enones6 with dienes, intramolecular Diels–Alder reactions,7
as well as 1,4-additions of thiols to enones.8 The catalysts that were
developed are monocationic, one-point binding Cp-complexes of
iron(II), and Cp- and indenyl-complexes of ruthenium(II) that bear
electron-poor diphosphinite ligands to enhance the Lewis acidity
and control the chiral environment around the metal.
Exploring the versatility of these chiral Lewis acid catalysts,
we turned our attention to 1,3-DCs and provided the first
examples of asymmetric metal-catalyzed reactions of nitrones9 and
nitrile oxides10 with enals. This field has seen rapid development
with efficient metal-based catalysts11 and organocatalysts12 being
reported in the literature.
Fig. 1 Properties and reactivity of common nitrone classes.
Asymmetric catalytic 1,3-DCs have entered the field
resolutely.15,16 The seminal work of MacMillan and coworkers
on using organocatalysts allowed for the use of simpler and
more versatile monodentate dipolarophiles.12a Since then, several
other organic12 and metal-based catalysts11g–o have been found to
successfully catalyze 1,3-DC reactions with N-“alkyl” nitrones.
In the present article, we extend our initial findings in the Ru-
catalyzed 1,3-DC of N-alkyl and N-benzyl nitrones with enals17
and investigate intriguing selectivity aspects observed for the non-
catalyzed reactions with the same dipoles.
Results and discussion
In this context, we studied in depth the reactions with diaryl-
nitrones and showed that regioselectivity is a function of the
substituents on the nitrone.13 N-Alkyl and N-benzyl nitrones
Non-catalyzed reactions
Variation of the electronic properties of the nitrones. In order
to assess reactivity, selectivity, and to obtain clear HPLC signals
for the racemic isoxazolidine products, a series of N-Me, a-(4-
substituted)-Ph nitrones 17a–n were synthesized by condensation
of N-Me hydroxylamine hydrochloride with the corresponding
substituted benzaldehydes.18 1H NMR analysis at r. t. showed only
the Z isomer present in solution.
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest
Ansermet, CH-1211, Geneva 4, Switzerland. E-mail: peter.kundig@
unige.ch; Fax: (+)41-22-379-3215
† Electronic supplementary information (ESI) available: General experi-
mental information, data on solvent and temperature optimization, full
experimental procedures and characterization data for all compounds. See
DOI: 10.1039/c1ob06144e
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Table 1 Uncatalyzed 1,3-DCs of N-Me, a-aryl nitrones 1a–n and
methacrolein (3)a
led to a mixture of diastereomers 2m (endo major). On the other
hand, nitrone 1n,22 bearing a 2-pyridyl fragment as the EWG
aromatic part, proved to be particularly reactive in its reaction
with methacrolein (3). Isoxazolidine 2n was isolated in quantitative
yield and with excellent regio- and diastereoselectivity (endo).
Keeping only the 4-substituted derivatives (steric factors and/or
more complex effects occur in the case of 2-F-Ph and the
pentafluoro examples) and ordering the diastereomeric ratios ac-
cording to the Hammett electronic parameter, a linear correlation
between diastereoselectivity and substitution can be observed
for the series.23 The correlation can be quantified by plotting
Entry
Ar
Nitrone
Yield (%)b
endo/exoc
1
2
3
4
5
6
7
8
4-NMe2-C6H4-
4-OMe-C6H4-
4-Me-C6H4-
4-H-C6H4-
4-F-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
4-CF3-C6H4-
4-CN-C6H4-
4-NO2-C6H4-
2-F-C6H4-
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
40
65
75
65
85
87
90
92
78
75
85
93
95
94
17/83
31/69
37/63
40/60
43/57
49/51
52/48
62/38
72/28
73/27
55/45
43/57
86/14
95/5
+
the sP electronic parameter24 as a function of log[(endo-R/exo-
R)/(endo-H/exo-H)] (Fig. 2).25 A correlation factor (R2) of 0.9354
was obtained, suggesting a significant degree of linearity of the
dependence.
9
10
11
12
13
14
C6F5-
6
h -C6H4-Cr(CO)3-
2-Py-
a All reactions were carried out under N2, using 1a–n (0.5 mmol) and 3
(1 mmol), in 1 mL of dry solvent. b Isolated yield. c Determined by 1H
NMR analysis.
The cycloaddition reactions were carried out with a 50% excess
of the enal (with respect to the nitrone), in CH2Cl2, at r. t. At
the end of the reaction (checked by TLC, 72 h reaction time on
average), the unreacted nitrones were precipitated with pentane
and the crude product was filtered through a plug of cotton.
Signals for the endo and exo diastereomers were assigned by 1H
NMR analysis. Analysis was complicated by signal broadening in
the case of the endo diastereomers. This phenomenon is known
to occur due to inversion at the nitrogen atom taking place on
Fig. 2 Hammett plot showing the linear correlation between the elec-
tronic parameter of the substituents on the nitrones and the endo/exo
ratio of the products obtained in the non-catalyzed 1,3-DCs of N-Me,
a-aryl nitrones 1a–n with methacrolein (3).
1
the H NMR-timescale.19 NOE analysis was inconclusive for the
assignment of the signals corresponding to the two diastereomers.
However, based on an analogy of chemical shifts for isoxazolidines
previously obtained from diarylnitrones,13 we could distinguish
and assign 1H NMR shifts to each of the two diastereomers.
Low to moderate yields reflect the long reaction times needed
in the case of nitrones bearing electron donating groups (EDGs).
The reactions were frequently accompanied by decomposition of
the dipole and/or polymerization of methacrolein (Table 1, entries
1–4).
Interestingly, both the endo and the exo diastereomers of the
3,5-substituted regioisomer were obtained in ratios varying with
the electronic properties of the substituents on the nitrone. Thus,
EDGs on the nitrone a-aryl substituent led to a mixture of
products with the exo product being the major diastereoisomer,
while in the cases where electron withdrawing groups (EWGs) are
placed on the nitrone a-aryl substituent, it is the endo product
that becomes the major diastereoisomer. Similar observations are
reported in the literature.20
No such effects were observed for the non-catalyzed reactions
of methacrolein (3) with diarylnitrones carried out in the same
conditions.13b However, in the case of the Ru-catalyzed asymmetric
1,3-DC of methacrolein (3) with substituted diarylnitrones, the
regioselectivity was found to vary with the electronic properties
of the nitrone.13 Interestingly, in the case of the N-Me nitrones, in
the absence of a catalyst this trend is observed in the diastereose-
lectivity. The variation is not as extreme as for the diarylnitrones,
but shows how small variations can have important effects on the
outcome of the cycloaddition reaction.
The standardized trendline assigned to this semilogarithmic
equation in Fig. 2 gives r (the reaction constant) equal to -0.11
(0.93 correlation factor). The very small value of the reaction
constant indicates that there is little, if any, charge transfer in the
transition state (TS). Moreover, the moderate correlation factor
for the linear dependence does not allow for a clear picture of the
reaction mechanism.
In order to evaluate the effects of substitution on reaction
rate for the non-catalyzed and the ruthenium-catalyzed 1,3-DCs,
the EWG-substituted aryl was replaced with other EWG-like
aromatic moieties. Nitrones 1m and 1n reacted smoothly at r.
t. in CH2Cl2 (5 days) with methacrolein (3) to give the expected
isoxazolidines in quantitative yield. Nitrone 1m, bearing a Cr(CO)3
moiety, was previously prepared in this laboratory.21 Nitrone 1m
Variation of the substituents at the nitrogen of the nitrone.
Nitrones bearing various substituents at the nitrogen atom of
the nitrone were synthesized in order to expand the range of
transformations that can be carried out on the isoxazolidine core
following the 1,3-DC reaction.
In this series, the N-i-Pr and -t-Bu nitrones 1o and 1p,
respectively, gave the products in moderate yields despite long
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Table 2 Non-catalyzed 1,3-DCs of N-substituted, a-aryl nitrones 1o–s
and methacrolein (3)a
reaction times, non-activated alkenes did not give any product
under the mild conditions used here.
While difficult to interpret, the observed correlation between
the endo/exo ratio of the products and the electronic character
of the substituents confirms that for a type II 1,3-DC both types
of frontier molecular orbital interactions are important in the TS.
Minute modifications of the electronic properties of either of the
reaction partners appear to strongly influence the TS and thus the
outcome of the reaction.
Entry
R
Nitrone
Yield (%)b
endo/exoc
The observed variation of diastereoselectivity with the electronic
properties of the dipole is rather rare.20 In the past, we have
shown how electronic factors can influence regioselectivity (with
diarylnitrones)13 and enantioselectivity (with aryl nitrile oxides).10
Interestingly, no catalyst is employed in this case and the reaction
is carried out under mild conditions. Although a number of groups
have attempted to rationalize regio- and diastereoselectivity
through computational studies, no clear picture has emerged so
far.20a,26
1
2
3
4
5
i-Pr
1o
1p
1q
1r
1s
65
75
65
85
87
>95/5
93/7
84/16
79/21
93/7
t-Bu
Bn
PMB
DPM
a All reactions were carried out under N2, using 1o–s (0.5 mmol) and 3
(1 mmol), in 1 mL of dry solvent. b Isolated yield, full conversion of the
nitrone (up to 2 weeks). c Determined by 1H NMR analysis. i-Pr: iso-
propyl; t-Bu: tert-butyl; Bn: benzyl; PMB: para-methoxy-benzyl; DPM:
diphenylmethyl.
Two factors should be taken into account when considering
diastereoselectivity: the structure of the reaction partners (i.e.
E/Z isomerism), and the interactions in the TS. For this specific
transformation, the general opinion is that E/Z isomerism is
responsible for the observed selectivities. However, with few
exceptions,27 all examples use high temperatures, making indeed
nitrone isomerization a possiblity.28 Our results and recent studies
suggest that at r. t. the nitrones are found exclusively in the Z-
configuration.29 Thus, we can conclude that the geometry of the
reaction partners is not responsible for the observed selectivity
inversion.
reaction times (up to 2 weeks at r. t., Table 2, entries 1 and 2)
and a two-fold excess of methacrolein (3). On the other hand,
the N-Bn, -PMB, and -DPM-substituted nitrones 1q, 1r, and
1s, respectively, proved to be more reactive, giving stable 3,5-
substituted isoxazolidines in good yields (entries 3–5).
Good yields and diastereoselectivities (in favor of the endo
isomer) can be obtained in the non-catalyzed reaction using these
dipoles. No particular trend is observed when changing substitu-
tion and solely the 3,5-substituted regioisomers are isolated.
Information about the reaction mechanism can be extracted
from the data presented above. While the Hammett plot does not
show a perfectly linear correlation, it suggests an asynchronous
concerted mechanism with little or no charge transfer in the
TS (confirmed by computational studies).30,31 In addition, the
lack of solvent effects reinforces the argument for a concerted
transformation.2,32–33 Interestingly, a similar inversion of diastere-
oselectivity is observed when varying the electronic properties in
the dipolarophile (Table 3); this is typical for type II 1,3-DCs,
where HOMO–LUMO interactions of both reacting partners are
possible and can influence the outcome of the reaction.2 Finally,
increasing the bulk on the dipole has little influence on the
selectivity (as shown in Table 2), suggesting that steric factors
do not play a role in the diastereoselection process.
Variation of the dipolarophiles. Non-catalyzed reactions of
N-Me, a-(4-CF3)-Ph nitrone 1h with various activated alkenes
were also carried out in order to assess the effects on selectivity
(Table 3). Only the 3,5-substituted isoxazolidines are obtained
with methacrolein (3), methyl methacrylate (4), 2-methyl-3-buten-
2-one (5), and methacrylonitrile (6). Also, in this case, diastereos-
electivity was found to be in good correlation with the Hammett
parameter of the group in the 2-substituted-propylene; an increase
in the EWG character of the substituent leads to an increased
amount of the exo diastereomer being formed. However, the
comparison with the classic Hammett correlations does not apply
in this case and remains purely illustrative.23 Despite extended
Table 3 Non-catalyzed 1,3-DCs of nitrone 1h and dipolarophiles 3–6a
Thus, subtle variations in the electronic properties of either
reaction partners lead to important changes in the ratio of the
endo/exo isomers formed, possibly through secondary orbital
interactions that occur in the TS. Unfortunately, computational
studies so far have not provided more answers.
Ru-catalyzed reactions
+24
Entry
R
Yield (%)b
endo/exoc
sP
The catalyst of choice for this transformation is (R,R)-11, a robust
and easy to prepare monocationic ruthenium complex5 that has
proved active and selective for a number of transformations.5–11,13,17
1
2
3
4
CHO (3)
CO2Me (4)
COMe (5)
CN (6)
92
64
60
30
60/40
56/44
50/50
33/67
+0.42
+0.45
+0.50
+0.66
Variation of substituents on the a-aryl part of the nitrone. An
optimized set of conditions33 was previously applied to the reaction
of methacrolein (3) with a series of substituted N-methyl, a-aryl
nitrones 1a–l.17 As noted above, reactivity is a function of the
a All reactions were carried out under N2, using 1h (0.5 mmol) and 3–6
(1 mmol), in 1 mL of dry solvent. b Isolated yield. c Determined by 1H
NMR analysis.
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Table 4 Ru-catalyzed 1,3-DCs of N-substituted, a-aryl nitrones 1h,o–s
and methacrolein (3)a
electronic character of the nitrone, even in the presence of the
ruthenium catalyst.
Electron-rich dipoles 1a–c proved unreactive and could be
recovered quantitatively at the end of the reaction, together
with the intact catalyst. Applying harsher reaction conditions or
increasing the catalyst loading did not improve the results. Con-
versely, nitrones 1d–l, bearing EWG substituents, led to formation
of 3,5-substituted isoxazolidines with very good diastereo- and
enantioselectivity. The best selectivity was obtained when using
the N-Me, a-(4-Br-Ph) nitrone 1g, with 97.7% ee.17
Entry R (nitrone) T/◦C
Yield (%)b
endo/exoc ee (%) endod
Within the series, two dipoles stood apart: while reaction with
nitro-substituted nitrone 1j proved sluggish and provided the
product in moderate yield and with decreased diastereoselectivity,
reaction with the nitrile-substituted nitrone 1i led to no product
whatsoever. This reinforces our previous findings on substrates
bearing Lewis-basic groups that lead to competitive binding to
the Lewis acid, thus reducing efficiency or even shutting down the
catalytic cycle.13
Less common EWG-like aromatic moieties can also be used
with good results. The authors have a long-standing interest in
the chemistry of chromium arene complexes.34 When attaching a
Cr(CO)3 moiety on an arene, the electron density on the aromatic
ring is markedly decreased, rendering the whole fragment electron-
poor. Confirming this hypothesis, nitrone 1m, bearing the Cr(CO)3
moiety on the aryl part, gave excellent yield and selectivities
(Scheme 1, top).
117
2
3
4
5
Me (1h)
-5
85
50e
19e
95
80
94
94/6
95/5
95/5
>95/5
>95/5
>95/5
92
79
59
87
90
69
i-Pr (1o)
t-Bu (1p)
Bn (1q)
r. t.
r. t.
+5
PMB (1r)
DPM (1s)
+5
+10
6
a All reactions were carried out under N2, using (R,R)-11 (5 mol%),
1h,o–s (0.5 mmol) and 3 (1 mmol), in 1 mL of dry CH2Cl2. b Isolated
yield. c Determined by 1H NMR analysis. d Determined by HPLC analysis
of the corresponding primary alcohol. i-Pr: iso-propyl; t-Bu: tert-butyl;
Bn: benzyl; PMB: para-methoxy-benzyl; DPM: diphenylmethyl. e Full
conversion not reached.
nitrones bearing i-Pr, t-Bu, Bn, PMB, and DPM groups at the N
(Table 4).
As in the case of the non-catalyzed reactions, the N-i-Pr (1o) and
-t-Bu (1p) nitrones reacted very slowly at r. t. and decomposed
during the long reaction time; despite the good endo selectivity,
enantioselectivities were moderate with these dipoles (entries 2
and 3) when compared with the N-Me analogue (entry 1).
Nitrones bearing benzyl groups on the nitrogen atom are
extremely valuable for applications in synthesis as these moieties
act as versatile protecting groups. We were pleased to find that
the N-Bn (1q) and -PMB (1r) nitrones afforded the expected
endo-3,5-substituted isoxazolidines 2q–r with high yields and
enantioselectivities (entries 4 and 5).
Maruoka and coworkers recently provided new examples of
nitrones bearing removable groups at the nitrogen atom of the ni-
trone, moving from the N-Bn to the N-DPM nitrones. Contrary to
the N-Bn nitrones (which give the endo-3,5-substituted adducts),
the endo-3,4-isoxazolidines were obtained exclusively with good
yields and enantioselectivity. Moreover, the DPM group could be
easily removed through oxidation, leaving the isoxazolidine ring
intact.11n–o We tested an analogous nitrone (1s) with our catalytic
system; unfortunately, not only the nitrone reacts slowly, but the
endo-3,5-substituted isoxazolidine 2s is obtained with moderate
enantioselectivity (entry 6). Too much steric bulk on the nitrone
appears to slow down the catalytic cycle and leads to an erosion
of the enantioselectivity by formation of racemic product through
background (thermal) reaction.
Scheme 1 Ru-catalyzed 1,3-DC reactions of methacrolein (3) with N-Me,
a-aryl nitrones 1m–n (the reactions were carried out under N2, using
(R,R)-11 (0.025 mmol), 1m–n (0.5 mmol) and 3 (0.75 mmol), in 1 mL of
dry solvent; isolated yields reported, diastereomeric ratio determined by
1H NMR analysis and enantiomeric ratio determined by HPLC analysis).
On the same principle, using a 2-pyridyl fragment as the aryl
part on the nitrone led to exclusive formation of the endo-3,5-
substituted adduct 2n with excellent enantioselectivity (Scheme 1,
bottom).
Determination of the absolute configuration of the adducts and
rationalization of selectivity. The reaction of methacrolein (3)
with nitrone 1g bearing a para-bromo substituent on the a-aryl
part of the dipole led, in the presence of pre-catalyst (R,R)-11,
to the endo-3,5-substituted isoxazolidine 2g in high yield and
excellent enantiopurity. The product readily crystallized at r. t. by
vapor diffusion from an Et2O–pentane system yielding transparent
prisms. A single crystal was analyzed by X-ray diffraction.17
Variation of the substituents at the nitrogen of the nitrone. The
variation of the substituents on the nitrogen of the nitrone greatly
influences both the electronic and steric properties of a dipole,
leading to important changes in the reaction outcome. In order
to investigate such effects, the range of dipoles was extended to
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◦
1
The absolute configuration thus determined corresponds to
C1(S), C3(S) and is the one expected from a top-endo approach
of the Z-nitrone to the more accessible Ca-SiCC face of the double
bond of methacrolein (3) coordinated in the chiral pocket of the
[RuCp(R,R-BIPHOP-F)(acetone)][SbF6] complex (R,R)-11. This
can be visualized by means of the X-ray-based models (Fig. 3).
at -30 C. Diastereomeric ratios are determined by H NMR of
the crude mixture. Clear signals for the racemic mixture can be
observed in the HPLC analysis of the corresponding primary
alcohols obtained by a standard NaBH4 reduction in ethanol
(CHIRACEL OD, Grad. 99+1–90+10, 0.75 mL min-1, 100 min,
254 nm or CHIRALPACK AD, Grad 99+1–85+15, 0.5 mL min-1,
80 min, 254); n values are given in cm-1, d values are given in ppm,
J values are given in Hz, tR (retention times) are given in minutes.
Some products proved too unstable for MS analysis; data for the
corresponding primary alcohols is available in the ESI.†
rac-5-Methyl-3-(4-trifluoromethyl-phenyl)-2-methyl-isoxazo-
line-5-carbaldehyde (rac-2h). Obtained according to the general
procedure in 92% yield (endo/exo 62/38): nmax/cm-1 (film) 762,
839, 894, 979, 1019, 1068, 1123, 1165, 1324, 1378, 1421, 1474,
1520, 1620, 1735, 2853, 2963; dH (300 MHz, CDCl3) 1.46 (3H, s,
Me), 2.18–2.23 (1H, dd, J 9, 13, H-C4), 3.01–3.06 (1H, bdd, J 9,
13, H-C4), 3.76 (1H, bs, J 9, H-C3), 7.48–7.50 (2H, d, J 9, H-Cm),
7.61–7.63 (2H, d, J 9, H-Co), 9.68 (1H, s, CHO); dC (100.6 MHz,
CDCl3) 21.1, 33.5, 47.5, 85.4, 122.8, 125.5, 125.9, 128.1, 130.3,
130.6, 142.8, 201.5.
Fig. 3 Model showing the approach of N-Me, a-(4-Br-Ph) nitrone (1g)
to the accessible Ca-Si face of the C–C double bond of methacrolein (3)
coordinated in the chiral pocket of the catalyst (R,R)-11.17
rac-5-Methyl-3-(2-pyridyl)-2-methyl-isoxazoline-5-carbaldehy-
de (rac-2n). Obtained according to the general procedure in 94%
yield (endo/exo 95/5): nmax/cm-1 (CH2Cl2) 621, 639, 698, 749,
761, 807, 978, 1020, 1036, 1090, 1133, 1290, 1381, 1435, 1472,
1519, 1590, 1641, 1732, 2871, 2930, 2960, 3061; dH (400 MHz,
CDCl3) 1.43 (3H, s, CH3), 2.53–2.59 (1H, dd, J 8, 12, H-C4), 2.76
(3H, s, N-CH3), 2.77–2.82 (1H, dd, J 8, 12, H-C4-endo), 3.83–
3.88 (1H, bt, J 8, H-C3), 7.24-7.27 (1H, m, H-Carom), 7.34–7.36
(1H, bd, H-Carom), 7.70-7.74 (1H, m, H-Carom), 8.57–8.58 (1H,
bm, H-Carom), 9.78 (1H, s, CHO-endo); dC (100.6 MHz, CDCl3)
19.1, 43.3, 74.5, 84.7, 86.0, 121.9, 123.0, 123.2, 137.1, 149.4, 158.8,
204.8; HRMS (ESI+): Exact mass calculated for C11H15N2O2 [M +
H]+: 207.1128. Found: 207.1132.
The same results were previously obtained when using
diarylnitrones13 and nitrile oxides10 as dipoles. Diastereo- and
enantioselectivity are exclusively under catalyst control. Regios-
electivity in this case is under dipole control and appears to be
directed by the substituent at the N of the nitrone.
Conclusions
The study of the scope and versatility of the 1,3-DCs with N-
alkyl and N-benzyl nitrones with enals exposed intriguing and
unprecedented trends in diastereoselectivity in the non-catalyzed
reactions.
On the other hand, the Ru-catalyzed reactions proved to be
robust, efficient, and selective for a whole range of substrates.
Electronic effects are key to activating the dipoles for the cycload-
dition reaction. Synthetically relevant isoxazolidines bearing the
methyl and benzyl groups at the N could thus be obtained in good
yields and with high regio-, diastereo-, and enantioselectivity.
rac-5-Methyl-3-(4-trifluoromethyl-phenyl)-2-iso-propyl-isoxazo-
line-5-carbaldehyde (rac-2o). Obtained according to the general
procedure in 34% yield (endo/exo >95/5): nmax/cm-1 (CH2Cl2)
734, 838, 909, 1019, 1067, 1124, 1165, 1324, 1369, 1421, 1457,
1619, 1733, 2978; dH (400 MHz, CDCl3) 1.00–1.02 (6H, d, J = 6
Hz, CH3), 2.07–2.12 (1H, ddd, J 0.5, 7, 13, H-C4), 2.80–2.89 (1H,
hept, J 6, CH), 3.11–3.16 (1H, dd, J 7, 13, H-C4), 4.22–4.25 (1H, t,
J 7, H-C3), 7.53–7.55 (2H, d, J 8, H-Carom), 7.58–7.60 (2H, d, J 8,
H-Carom), 9.66 (1H, d, J 0.5, CHO); dC (100.6 MHz, CDCl3) 16.7,
19.7, 19.9, 21.6, 46.9, 125.7, 128.0, 128.1, 129.7, 130.0, 205.5; MS
(TS) m/z = 302.5 (M+1), 216.3, 191.3, 190.3, 174.5, 172.5, 159.3;
HRMS (ESI+): Exact mass calculated for C15H19F3NO2 [M + H]+:
302.1371. Found: 302.1362.
Experimental section—selected examples33
General experimental procedure for non-catalyzed reactions
In a 50 mL Schlenk tube equipped with a magnetic stirring bar,
a solution of the nitrone (0.5 mmol, 1 equiv.) in CH2Cl2 (2 mL)
is stirred at r. t. to give a clear solution. Methacrolein (1 mmol,
2 equiv.) is added dropwise, by syringe, at r. t. The reaction mixture
is stirred at r. t. until TLC analysis (SiO2, AcOEt/cyclohexane 2/3
or CH2Cl2) shows no unreacted nitrone. Addition of dry pentane
(10 mL), filtration of the precipitated nitrone through a plug of
cotton in a Pasteur pipette and in vacuo removal of solvents leads to
rac-5-Methyl-3-(4-trifluoromethyl-phenyl)-2-diphenylmethyl-
isoxazoline-5-carbaldehyde (rac-2s). Obtained according to the
general procedure in 68% yield (endo/exo 93/7): nmax/cm-1
(CH2Cl2) 730, 904, 1019, 1068, 1124, 1165, 1326, 1455, 1735, 2969;
d
H (400 MHz, CDCl3) 1.32 (4H, bs, CH and CH3), 3.25–3.30 (1H,
bdd, J 9, 13, H-C4), 4.31–4.34 (1H, dd, J 5, 9, H-C4), 4.75 (1H,
bs, H-C3), 7.14–7.54 (14H, m, H-Carom), 9.57 (1H, bs, CHO);
dC (100.6 MHz, CDCl3) 17.7, 19.6, 21.2, 31.2, 46.9, 125.4, 125.7,
127.7, 128.0, 128.3, 128.6, 128.7, 129.7, 130.0, 194.2.
an oil. Purification by a quick filtration through a SiO2 plug (Hdry
=
5 cm, Ue = 1 cm) with CH2Cl2 gives viscous, clear oils that solidify
118 | Org. Biomol. Chem., 2012, 10, 114–121
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General procedure for reactions catalyzed by (R,R)-11
(TS) m/z = 302.5 (M+1), 216.3, 191.3, 190.3, 174.5, 172.5, 159.3;
HRMS (ESI+): Exact mass calculated for C15H19F3NO2 [M + H]+:
302.1371. Found: 302.1362.
In a 50 mL Schlenk tube equipped with a magnetic stirring
bar, the catalyst (36 mg, 0.025 mmol, 5 mol%) is loaded and
CH2Cl2 (1 mL) is added. The solution is stirred at the appropriate
temperature and methacrolein (62 mL, 0.75 mmol, 1.5 equiv.) is
added. The mixture is stirred for further 20 min before addition
of the corresponding nitrone (0.5 mmol, 1 equiv.) as a solid and
in one portion. The extent of the reaction is followed by TLC
analysis (SiO2, AcOEt/cyclohexane 2/3 or CH2Cl2) until no traces
of nitrone are observed. Pentane is added to precipitate the catalyst
and most of the unreacted nitrone, and the reaction mixture is
(3S,5S)-5-Methyl-3-(4-trifluoromethyl-phenyl)-2-diphenylme-
thyl-isoxazoline-5-carbaldehyde (S,S-2s). Obtained according to
the general procedure in 94% yield (endo/exo 95/5): nmax/cm-1
(CH2Cl2) 730, 904, 1019, 1068, 1124, 1165, 1326, 1455, 1735, 2969;
d
H (400 MHz, CDCl3) 1.32 (4H, bs, CH and CH3), 3.25–3.30 (1H,
bdd, J 9, 13, H-C4), 4.31–4.34 (1H, dd, J 5, 9, H-C4), 4.75 (1H,
bs, H-C3), 7.14–7.54 (14H, m, H-Carom), 9.57 (1H, bs, CHO);
dC (100.6 MHz, CDCl3) 17.7, 19.6, 21.2, 31.2, 46.9, 125.4, 125.7,
127.7, 128.0, 128.3, 128.6, 128.7, 129.7, 130.0, 194.2.
passed through a plug of Celite 545 (P3-frit, Celite 545, Hdry
=
1.5 cm, Ue = 2 cm) followed by in vacuo removal of volatiles.
Purification by a quick filtration through a SiO2 plug (Hdry = 5 cm,
Ue =◦1 cm) with CH2Cl2 gives viscous, clear oils that solidify at
Acknowledgements
We would like to thank the Swiss National Science Foundation
for financial support and Marle`ne Berthod for synthesis of
intermediates. We are grateful to Prof. Je´roˆme Lacour, Prof. Jiri
Mareda and Daniel Emery for helpful discussions.
1
-30 C. Diastereomeric ratios are determined by H NMR of
the crude mixture. Enantiomeric excess is determined by HPLC
analysis of the corresponding primary alcohols obtained by a
standard NaBH4 reduction in ethanol (CHIRACEL OD, Grad.
99+1–90+10, 0.75 mL min-1, 100 min, 254 nm or CHIRALPACK
AD, Grad 99+1–85+15, 0.5 mL min-1, 80 min, 254). Given data
is for the 3,5-endo isomer in the mixture. Some products proved
too unstable for MS analysis; data for the corresponding primary
alcohols is available in the ESI.†
Notes and References
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(3S,5S)-5-Methyl-3-(4-trifluoromethyl-phenyl)-2-methyl-isoxa-
zoline-5-carbaldehyde (S,S-2h).17 Obtained according to the gen-
eral procedure in 85% yield (endo/exo 94/6): nmax/cm-1 (film) 762,
839, 894, 979, 1019, 1068, 1123, 1165, 1324, 1378, 1421, 1474,
1520, 1620, 1735, 2853, 2963; dH (300 MHz, CDCl3) 1.46 (3H, s,
Me), 2.18–2.23 (1H, dd, J 9, 13, H-C4), 3.01–3.06 (1H, bdd, J 9,
13, H-C4), 3.76 (1H, bs, J 9, H-C3), 7.48–7.50 (2H, d, J 9, H-Cm),
7.61–7.63 (2H, d, J 9, H-Co), 9.68 (1H, s, CHO); dC (100.6 MHz,
CDCl3) 21.1, 33.5, 47.5, 85.4, 122.8, 125.5, 125.9, 128.1, 130.3,
130.6, 142.8, 201.5.
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(3S,5S)-5-Methyl-3-(2-pyridyl)-2-methyl-isoxazoline-5-carbal-
dehyde (S,S-2n). Obtained according to the general procedure
in 94% yield (endo/exo 95/5): nmax/cm-1 (CH2Cl2) 621, 639, 698,
749, 761, 807, 978, 1020, 1036, 1090, 1133, 1290, 1381, 1435, 1472,
1519, 1590, 1641, 1732, 2871, 2930, 2960, 3061; dH (400 MHz,
CDCl3) 1.43 (3H, s, CH3), 2.53–2.59 (1H, dd, J 8, 12, H-C4), 2.76
(3H, s, N-CH3), 2.77–2.82 (1H, dd, J 8, 12, H-C4-endo), 3.83-
3.88 (1H, bt, J 8, H-C3), 7.24–7.27 (1H, m, H-Carom), 7.34–7.36
(1H, bd, H-Carom), 7.70–7.74 (1H, m, H-Carom), 8.57–8.58 (1H,
bm, H-Carom), 9.78 (1H, s, CHO-endo); dC (100.6 MHz, CDCl3)
19.1, 43.3, 74.5, 84.7, 86.0, 121.9, 123.0, 123.2, 137.1, 149.4, 158.8,
204.8; HRMS (ESI+): Exact mass calculated for C11H15N2O2 [M +
H]+: 207.1128. Found: 207.1132.
(3S,5S)-5-Methyl-3-(4-trifluoromethyl-phenyl)-2-iso-propyl-
isoxazoline-5-carbaldehyde (S,S-2o). Obtained according to the
general procedure in 50% yield (endo/exo 95/5): nmax/cm-1
(CH2Cl2) 734, 838, 909, 1019, 1067, 1124, 1165, 1324, 1369, 1421,
1457, 1619, 1733, 2978; dH (400 MHz, CDCl3) 1.00–1.02 (6H, d,
J 6, CH3), 2.07–2.12 (1H, ddd, J 0.5, 7, 13, H-C4), 2.80–2.89 (1H,
hept, J 6, CH), 3.11–3.16 (1H, dd, J 7, 13, H-C4), 4.22–4.25 (1H, t,
J 7, H-C3), 7.53–7.55 (2H, d, J 8, H-Carom), 7.58–7.60 (2H, d, J 8,
H-Carom), 9.66 (1H, d, J 0.5, CHO); dC (100.6 MHz, CDCl3) 16.7,
19.7, 19.9, 21.6, 46.9, 125.7, 128.0, 128.1, 129.7, 130.0, 205.5; MS
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