Asymmetric syntheses of three-membered heterocycles using chiral amide-based ammonium ylides

Article abstract of DOI:10.1039/c4ob02318h

The use of carbonyl-stabilised ammonium ylides to access chiral glycidic amides and the corresponding aziridines has so far been limited to racemic trans-selective protocols. We herein report the development of an asymmetric approach to access such compou

Full text of DOI:10.1039/c4ob02318h

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Journal Name
RSCPublishing
ARTICLE
Asymmetric Syntheses of ThreeꢀMembered
Heterocycles Using Chiral AmideꢀBased Ammonium
Ylides
Cite this: DOI: 10.1039/x0xx00000x
Mathias Pichler,a Johanna Novacek,a Raphaël Robiette,b Vanessa Poscher,a
Markus Himmelsbach,c Uwe Monkowius,d Norbert Müller,a and Mario Wasera,*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
The use of carbonylꢀstabilised ammonium ylides to access chiral glycidic amides and the
corresponding aziridines has so far been limited to racemic transꢀselective protocols. We
herein report the development of an asymmetric approach to access such compounds with high
levels of stereoselectivity using easily accessible chiral auxiliaryꢀbased ammonium ylides. The
use of phenylglycinol as the chiral auxiliary was found to be superior to Evans or
pseudoephedrineꢀbased auxiliaries resulting in good to excellent stereoselectivities in both,
epoxidation and aziridination reactions.
www.rsc.org/
6
and explore their potential in asymmetric threeꢀmembered
Introduction
ring heterocycleꢀforming reactions (Scheme 1). The main focus
was on the development of a protocol for epoxidation reactions
first, followed by
aziridinations.
The use of onium ylides has emerged as a powerful strategy for
(dia)ꢀstereoselective epoxide, aziridine, and cyclopropane
syntheses.1,2 Whereas sulfonium ylides have been very
frequently used for a variety of often very selective threeꢀring
forming reactions,3,4 easily available ammonium ylides have
been less routinely employed in the past.5ꢀ9 Especially the use of
chiral amines to render such reactions enantioselective has been
mainly limited to cyclopropanations5 so far. Indeed, their use in
asymmetric epoxidation and aziridination reactions was found
to be rather difficult, mainly due to the weaker leaving group
ability of the amine group compared to the use of sulfonium
ylides.6,7,9
a proof of concept for asymmetric
We have recently introduced a highly transꢀselective
protocol for the synthesis of glycidic amides and the
corresponding aziridines by reacting amideꢀstabilised achiral
ammonium ylide precursors
1 with aldehydes 2 or imines 3
(Scheme 1).7,9b Key to high yields was the use of
trimethylamine as the amine leaving group, whereas the use of
sterically more demanding chiral amines like Cinchona
alkaloids did not result in any product formation. Due to this
limitation, alternative strategies to control the absolute
stereochemistry in these epoxide and aziridine forming
reactions are necessary. The use of chiral auxiliary containing
amides to control the face selectivity in enolate reactions is a
very commonly employed and powerful strategy for numerous
Scheme 1: Recently developed racemic trans-epoxidation and aziridination
protocol and the targeted auxiliary-based stereoselective approach.
applications.10 A few examples about their use in sulfonium Results and discussion
ylideꢀmediated reactions have been reported in the past11 but the
use of chiral amideꢀbased ammonium ylides has, to the best of
our knowledge, not been reported yet. We have therefore
undertaken a systematic study about the use of different classes
of chiral auxiliaries to access chiral ammonium ylide precursors
Our main focus was on three different classes of auxiliaries: αꢀ
amino acid based oxazolidinones (Evans auxiliaries)12 to obtain
ammonium salts 6A, pseudoephedrine13ꢀderived ammonium
salts 6B, and
αꢀamino acid based 1,3ꢀoxazolidineꢀcontaining
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salt 6C. Synthesis of all three classes could be straightforwardly hand occurs via a baseꢀmediated epoxide opening of 10 as
achieved by reacting bromoacetyl bromide with the indicated by the increasing amount of 12 formed under
auxiliaries first, followed by treatment of the
acetamides with trimethylamine (Scheme 2).
7
prolonged reaction conditions. This is a known transformation
which was already described by Teran et al. when using
sulfonium ylides.11d Interestingly, in their case no formation of
11 was observed during the epoxidation and the transformation
of 10 to 12 required the use of sodium as a base in a distinct
step, whereas in our experiments significant amounts of 12
were detected under either conditions (> 20%). Compound 12
was always formed as a single diastereomer which fully
matched the analytical data reported before.11d This also
suggests that the initial epoxide formation occurs with a high
level of face differentiation. However, due to the rather fast
cyclization of the starting material to give 11 and the baseꢀ
mediated epoxide opening, we were not able to obtain
reasonable amounts (> 30%) of epoxide 10 in any case. To
overcome this obstacle, we tested the Oꢀprotected ammonium
salts 6B’’ (Scheme 4b). Unfortunately this turned out to be nonꢀ
satisfactory as the face selectivity was found to be rather low
giving a mixture of diastereomers beside significant amounts of
various decomposition products (due to the initial lack of
selectivity the reaction conditions were not further optimized).
αꢀbromo
8
Scheme 2: Tested chiral ammonium salts 6.
We started testing the applicability of these ammonium salts
for the asymmetric epoxidation with benzaldehyde (2a) first.
Our recently developed protocol for the synthesis of epoxides
4
(Scheme 1) required use of a large excess of aqueous NaOH (>
100 eq.).7 Initial experiments with ammonium salts 6A resulted
in hydrolysis of the auxiliary under these strongly basic
conditions. Surprisingly, under relatively mild and weaker basic
conditions, using Cs2CO3 as a solid base, full hydrolysis of the
auxiliary also occurred (Scheme 3).14 Unfortunately, we were
never able to suppress this hydrolysis of the amide bond and in
no case formation of epoxide product could be observed. One
possible mechanistic explanation for this extraordinary baseꢀ
sensitivity of these usually rather baseꢀstable amide motives10,12
may be an in situ ketene formation under the basic conditions.
We could however not obtain experimental evidence supporting
this hypothesis.
Scheme 4: Use of the pseudoephedrine containing ammonium salts 6B
.
Scheme 3: Attempted use of the Evans auxiliary containing ammonium salts 6A
.
Because of the limited applicability of the Evans
oxazolidinones and pseudoephedrine as chiral auxiliaries for
our ammonium ylideꢀmediated epoxidation we next turned our
attention on the use of 1,3ꢀoxazolidineꢀcontaining auxiliaries.
These are less commonly employed in asymmetric
transformations as compared to oxazolidinones or
pseudoephedrine. However, we reasoned that the corresponding
ammonium salts 6C may work well for our target reaction as
they should be stable under the basic reaction conditions and
the addition step should hopefully proceed with satisfying faceꢀ
selectivity too. In addition, during the initial phase of this
project, Teran et al. reported the use of chiral 1,3ꢀoxazolidines
(derived from the reaction of phenylglycinol (14) with different
aldehydes) in sulfur ylideꢀmediated epoxidation reactions.11e
Interestingly, they found that the absolute configuration of the
Next, we put our focus on the use of the pseudoephedrine
based ammonium salts 6B for the targeted epoxidation.
Pseudophedrine has recently been reported as a useful auxiliary
in sulfonium ylideꢀmediated epoxidation reactions.11d First
experiments using the freeꢀOH containing ammonium ylide
precursor 6B’ indicated formation of the target epoxide 10 as a
1
single transꢀdiastereomer (as far as it could be judged by H
NMR analysis of the crude product where 10 is present as a
mixture of rotamers) and the two cyclization products 11 and
12 (Scheme 4a). Formation of 11 was also observed during the
preparation of the ammonium acetamide 6B’. Unfortunately 11
turned out to be the main product under a variety of different
conditions (always at least 50%). Formation of 12 on the other
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product 16 depends exclusively on the configuration of the allowed us to identify different conditions which all gave the
phenylglycinol moiety (C4) – and not on the configuration of target epoxide 17a with very high diastereoselectivity and with
the newly installed stereogenic center (C2) of the auxiliary. We isolated yields >70%.
opted for a slightly different approach by carrying out the
oxazolidine formation by reacting (R)ꢀ14 with acetone, which
proceeds very quickly giving the auxiliary in high yield and
purity. We anticipated that this ketoneꢀbased 1,3ꢀoxazolidine
should show a higher stability under basic conditions than
aldehydeꢀbased ones and should therefore be suitable for our
approach. The ylide precursor 6C could then easily be obtained
in two more steps (Scheme 5).
Table 1: Identification of the optimum reaction conditions for the epoxidation
using the chiral ammonium ylide precursor 6C.
Entry
2a
(eq.)
Solv.
Base (eq.)
T
[°C]
t
Yielda
[%]
d.r.b
[h]
[%]
(trans)c
> 98
1
2
4
2
2
1
2
2
2
2
2
2
2
2
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Cs2CO3
(6x)
NaOH (aq)
(140x)
K2CO3
(20x)
Cs2CO3
(1x)
Cs2CO3
(20x)
Cs2CO3
(20x)
Cs2CO3
(20x)
Cs2CO3
(20x)
Cs2CO3
(20x)
Cs2CO3
(20x)
Cs2CO3
(20x)
Cs2CO3
(20x)
Cs2CO3
(20x)
25
25
25
25
25
25
25
25
25
60
60e
25
60e
24
24
24
24
24
72
24
24
72
24
3
35
n.r.
n.r.
< 10
50d
74
n.d.
n.d.
3
4
> 98
> 98
> 98
n.d.
5
6
7
n.r.
50d
72
Scheme 5: Use of phenylglycinol
ammonium salts for asymmetric epoxidation reactions.
(14)
to access chiral sulfonium11e and
8
toluene
toluene
toluene
toluene
iꢀPrOH
iꢀPrOH
> 98
> 98
> 98
> 98
> 98
> 98
9
In the initial epoxidation experiment of 6C with
benzaldehyde (2a) in dichloromethane (using 6 eq. of Cs2CO3
10
11
12
13
73
as a solid base) epoxide 17a was formed as a single trans
ꢀ
75
diastereomer. Based on this promising result a systematic
screening of different conditions was undertaken (Table 1 gives
an overview about the most significant results obtained herein).
In our attempts to determine the bestꢀsuited base and the
optimum stoichiometric ratio we found that the strongly basic
aqueous conditions that worked well in our racemic protocol7
did not give any product herein (entry 2). The use of K2CO3
24
3
78
84
a) isolated yield; b) determined by 1H NMR of the crude reaction mixture; c) in
neither experiment any cisꢀdiastereomer could be detected; d) incomplete
(entry 3) or an equimolar amount of Cs2CO3 (entry 4) yielded conversion of 6C; e) carried out in an ultrasonic bath.
also almost no product. However, an excess of Cs2CO3 and two
equivalents of aldehyde allowed us to obtain transꢀ17a in 50%
The absolute configuration of 17a was unambiguously
proven by two different methods. First Xꢀray diffraction
isolated yield after 24 h and in 74% after 72 h reaction time
(entries 5 and 6). As expected from our previous experience
using amideꢀstabilised ammonium ylides7 no cisꢀepoxide was
formed under either conditions. In addition, also no second
diastereoisomeric transꢀepoxide could be observed in NMR
spectra of the crude reaction mixture, illustrating that this chiral
auxiliary leads to a high faceꢀdifferentiation in the ylide
addition step. Further screening of different solvents showed
analysis of crystals of 17a proved the (2R,3S)ꢀconfiguration of
the transꢀepoxyamide moiety.15 In addition 17a was also
transferred into the known epoxyalcohol 18 upon treatment
with LiBHEt3. Comparison of the specific optical rotation with
literature values of 1811a,11e also confirmed this absolute
configuration of the epoxy moiety (Scheme 6). Unfortunately,
this transformation did not allow us to recover the auxiliary.
that toluene and iꢀPrOH can also be used as solvents for this
reaction. Whereas the reaction was found to be slow in toluene,
requiring either a prolonged reaction time (entry 9) or a higher
reaction temperature (entry 10) to obtain 17a in good yield,
reactions in iꢀPrOH were usually significantly faster (entry 12).
However, hereby also, significant amounts of Cannizzaro
disproportionation products of benzaldehyde could be detected
whereas this side reaction is less pronounced in toluene. In
addition, we also found that these reactions can be accelerated
by ultrasonication, giving 17a in comparable quality and yield
after 3 h (entries 11 and 13). Accordingly, this screening
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Scheme 6: Molecular structure of 17a and conversion into the known
epoxyalcohol 18
.
In order to get an insight into the interpretation of the
observed high diastereoselectivity in all these epoxidation
reactions, we undertook DFT calculations investigating the
geometry of the most stable conformer of the ylide.16,17 It
turned out that (Z)ꢀylides are significantly more stable than (E)ꢀ
ylides (Scheme 7). This can most probably be accounted for by
destabilizing steric interactions between the ammonium group
and the auxiliary in the (
electrostatic interactions between the ammonium group and the
enolate oxygen in the ( )ꢀylide in
)ꢀisomer.18 In addition, the (
which the phenyl group blocks the Reꢀface of the ꢀcarbon
E)ꢀylide and the presence of stabilizing
Z
Z
α
(
(Z)ꢀylideRe) is thermodynamically more stable than the one
where the Siꢀface is shielded ((Z)ꢀylideSi) (Scheme 7, upper
part).
Based on these results, the observed stereoselectivity could
be explained by addition of the most stable ylide ((Z)ꢀylideRe
to benzaldehyde 2a via the Siꢀface (Scheme 7, lower part).17
)
Scheme 7: DFT calculations of the ylide geometry (relative energies given in
brackets) and proposed rationale for observed diastereoselectivity.16
With a set of high yielding reaction conditions available we
next investigated the application scope of this epoxidation
reaction. As shown in Table 2 a series of different aldehydes
was tested. Notably, in neither case any cisꢀepoxide and no
second transꢀdiastereomer could be detected. Due to the faster
reaction rate of the parent benzaldehyde 2a in iꢀPrOH at room
temperature the majority of the reactions were carried out under
these conditions (cond. A). These worked reasonably fine for a
series of aromatic aldehydes such as paraꢀ or orthoꢀmethyl
benzaldehydes (entries 3 and 4), halideꢀsubstituted ones (entries
5 and 6) and the biphenyl carbaldehyde 2f (entry 7). Also the
more electronꢀrich paraꢀmethoxy benzaldehyde 2g could be
reacted in good yield under these conditions, whereas the less
active dimethylamino benzaldehyde 2h required harsher
conditions (60 °C in toluene) to obtain the epoxide 17h in good
crude yield. Remarkably, this was the first time that this
aldehyde could be successfully used in any of our ammonium
ylideꢀmediated epoxidation reactions.7 Unfortunately, epoxide
17h quickly decomposed during different purification methods.
As expected, the more reactive cyanoꢀ and nitrobenzaldehydes
2i and 2j did not give any epoxide under the standard
conditions (cond. A) but mainly the corresponding Cannizzaro
disproportionation products. However, carrying out the reaction
in toluene as a less polar solvent at room temperature allowed
us to obtain the epoxides 17i and 17j in reasonable isolated
yields. Notably, for the first time we have been able to use the
aliphatic aldehyde 2k (entry 12) to obtain the corresponding
epoxide in moderate yield. Such enolisable aldehydes had
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primarily undergone self aldol condensation reactions under the 3d the formation of olefins 20c and 20d was reduced, but still
strongly basic conditions developed previously.7 Now the use of not totally suppressed (entries 3 and 4). Again, formation of the
Cs2CO3 in toluene allowed us to overcome this limitation to minor transꢀaziridine and cisꢀdiastereomer was observed too.
some extent now. Similar yield was obtained when reacting While the isolated yield of 19c may be a bit lower because of a
cyclohexanecarbaldehyde (2l) under these conditions (entry reduced rate of addition due to the orthoꢀsubstituent, the more
13).
electronꢀrich pꢀmethoxy containing 19d was found to be totally
unstable on silica gel and also partially decomposed during
alumina column chromatography.19 The naphthylꢀbased imine
3e performed similarly to imine 3b (compare entries 5 and 2)
giving the major transꢀaziridine 19e in a reasonable isolated
yield of 59%. By contrast, the less electronꢀrich bromineꢀ
substituted 3f gave the olefin 20f as the main product (entry 6),
while, as expected, the electronꢀpoor 3g did not allow us to
obtain any aziridine at all (entry 7).
Table 2: Application scope of the asymmetric epoxidation using amide 6C.
Entry
R
Ald.
Prod.
Cond.a
Yieldb
[%]
78
73
80
79
75
85
89
d.r.c
[%]
Table 3: Asymmetric aziridination using amide 6C.
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
2a
17a
A
B
A
A
A
A
A
A
B
C
C
D
D
> 98
> 98
> 98
> 98
> 98
> 98
> 98
> 98
> 98
> 98
> 98
> 98
> 98
4ꢀMeC6H4ꢀ
2ꢀMeC6H4ꢀ
4ꢀClC6H4ꢀ
2b
2c
2d
2e
2f
2g
2h
2i
17b
17c
17d
17e
17f
17g
17h
17i
4ꢀBrC6H4ꢀ
4ꢀPhC6H4ꢀ
4ꢀMeOC6H4ꢀ
4ꢀMe2NC6H4ꢀ
4ꢀCNC6H4ꢀ
3ꢀNO2C6H4ꢀ
nꢀDecylꢀ
73
(60)d
62
Entry
PG
Ar
Ph
3
19 (d.r.)a,b
[%]
20 [%]a Yield [%]
(transꢀ19)c
2j
2k
2l
17j
17k
17l
68
42
39
1
2
3
4
5
6
7
Tos
Boc
3a
3b
> 98 trans d
82 (87/3/10)b
96 (85/3/12)b
95 (88/3/9)b
77 (85/3/12)b
39 (86/0/14)b
n.d.
n.d.
18
4
39 (70)e
62
Cyclohexylꢀ
a) A: iꢀPrOH, 25 °C, 24 h, Cs2CO3 (s, 20 eq.); B: toluene, 60 °C, 24 h,
2ꢀMeC6H4ꢀ 3c
4ꢀMeOC6H4ꢀ 3d
Naphtꢀ2ꢀyl 3e
56
Cs2CO3 (s, 20 eq.); C: toluene, 25 °C, 72 h, Cs2CO3 (s, 20 eq.); D: toluene,
25 °C, 24 h, Cs2CO3 (s, 20 eq.); b) isolated yield; c) determined by 1H NMR of
the crude reaction mixture; d) full decomposition on silica gel, crude NMR
yield given in brackets.
5
57 (75)f
58
23
61
> 99
4ꢀBrC6H4ꢀ
3ꢀNO2C6H4ꢀ 3g
3f
32
n.d.
Based on the detailed knowledge obtained on the use of the a) determined by 1H NMR of the crude reaction mixture; b) values in brackets
give the diastereomeric ratios of aziridines (transmajor/transminor/cis) ꢀ only one
cisꢀisomer could be detected; c) isolated yield of the major transꢀaziridine;
d) only one transꢀaziridine detected; e) partial decomposition on silica gel,
crude NMR yield given in brackets; f) full decomposition on silica gel and
partial on alumina, crude NMR yield given in brackets.
chiral amide 6C for asymmetric ylideꢀmediated epoxidations at
hand, we carried out a short screening to test the potential of
this concept for the related aziridination reaction (Table 3). In
analogy to our previous experience using achiral amides
racemic aziridinations9b the use of Cs2CO3 in CH2Cl2 was also
found superior here compared to the use of ꢀPrOH or toluene
6 for
i
as solvents. Interestingly, the use of Nꢀtosyl imine 3a allowed
the synthesis of the transꢀaziridine 19a in high selectivity (entry
1). Unfortunately this compound was found to be relatively
The absolute configuration of the major transꢀaziridine was
determined by anomalous Xꢀray diffraction analysis of crystals
of bromineꢀcontaining 19f. Again, in analogy to the epoxidation
unstable and partially decomposed under
a variety of
reaction, the (2
R,3S)ꢀconfiguration of the transꢀheterocyclic
purification conditions. This may be attributed to the rather
strained nature of this transꢀaziridine with the bulky tosyl group
being cis to either the phenyl group or the chiral auxiliary.4c The
use of NꢀBoc imine 3b gave an interesting result (entry 2).
Formation of the expected major transꢀaziridine 19b (isolated
in 61% yield) was accompanied by minor amounts of the
moiety was found for the major isomer (Fig. 1).15
second transꢀaziridine as well as around 10% of cis
Besides this reduced stereoselectivity in the aziridine formation
(compared to epoxidation) also notable amounts of the
unsaturated ꢀamino amide 20b were obtained. Formation of
ꢀ19b.
α,βꢀ
β
analogous olefins was already observed during our previous
racemic studies but only when using electronꢀpoor NꢀBoc
benzaldimines (e.g. NO2ꢀsubstituted) or heteroaromatic NꢀBoc
aldimines, whereas not even traces thereof could be detected
Fig. 1: Molecular structure of 19f
.
using more electronꢀrich imines like 3b 9b
Unfortunately we
.
were not able to suppress formation of 20 by changing the
reaction conditions (in contrast: using less base gave a larger
amount of 20). When using more electronꢀrich imines 3c and
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298 K): 1.64 (s, 3H), 1.87 (s, 3H), 3.45 (d, 1H,
J = 11.0 Hz),
Experimental
3.52 (d, 1H, = 11.0 Hz), 3.94 (dd, 1H, J1 = 9.0 Hz,
J
J2 = 2.7 Hz), 4.41 (dd, 1H, J1 = 9.0 Hz, J2 = 6.5 Hz), 5.07 (dd,
1H, J1 = 6.5 Hz, J2 = 2.7 Hz), 7.25 ꢀ 7.45 (m, 5H) ppm.
General
1Hꢀ and 13CꢀNMR spectra were recorded on a Bruker Avance
DRX 500 MHz spectrometer, a Bruker Avance III 300 MHz
spectrometer, and on
Compound 8C (2.57 g, 8.6 mmol) was dissolved in THF
(26 mL) and NMe3 (2.50 mL, 20.4 mmol, 1.2 eq., 33 %
solution in EtOH) was added. After stirring for 24 h at r.t. the
solvent was removed with vacuum distillation. The crude
product (purity >90%) was purified by column chromatography
(heptanes → CH2Cl2:MeOH = 5:1) to give the ammonium salt
a Bruker Avance III 700 MHz
spectrometer with TCI cryoprobe. All NMR spectra were
referenced using the residual 1H solvent peak as secondary
reference. High resolution mass spectra were obtained using a
Thermo Fisher Scientific LTQ Orbitrap XL with an Ion Max
API Source. All analyses were made in the positive ionisation
mode. IR spectra were recorded on a Bruker Tensor 27 FTꢀIR
spectrometer with ATR unit. All chemicals were purchased
from commercial suppliers and used without further
purification unless otherwise stated. All reactions were
performed under an Arꢀatmosphere. CH2Cl2 was distilled over
P2O5 and stored under Ar (it was not necessary to dry CH2Cl2
prior to every experiment and usually this quality could be used
successfully in these reactions over the course of 3ꢀ4 weeks
after distillation). Singleꢀcrystal structure analyses were carried
out on a Bruker Smart X2S diffractometer operating with Moꢀ
Kα radiation (λ= 0.71073 Å).
6C in 90% yield (2.90 g, 8.1 mmol) as a white foam. [α]
22 (c =
D
1
0.6, CH2Cl2) = ꢀ92; HꢀNMR (700 MHz, δ, CDCl3, 298 K):
1.65 (s, 3H), 1.86 (s, 3H), 2.98 (d, 1H, = 16.3 Hz), 3.44 (s,
9H), 3.91 (dd, 1H, J1 = 9.2 Hz, J2 = 1.7 Hz), 4.46 (dd, 1H, J1
9.2 Hz, J2 = 6.5 Hz), 5.83 (dd, 1H, J1 = 6.5 Hz, J2 = 1.7 Hz),
6.07 (d, 1H,
= 16.3 Hz), 7.28 ꢀ 7.51 (m, 5H) ppm; 13C NMR
(176 MHz, δ, CDCl3, 298 K): 23.5, 25.5, 54.7, 60.1, 64.8, 71.8,
97.5, 126.8, 128.5, 129.5, 140.5, 161.0 ppm; IR (film):
J
=
J
=
3011, 2987, 2937, 2882, 1654, 1434, 1412, 1378, 1351, 1237,
1204, 1133, 1064, 1048, 923, 896, 843, 703, 664, 604, 579,
+
563, 517, 501 cmꢀ1; HRMS (ESI): m/z calcd for C16H25N2O2 :
277.1910 [M]+; found: 277.1904.
Geometry optimization has been performed using the Jaguar
8.0 pseudospectral program package using the wellꢀestablished
B3LYP hybrid density functional with the D3 dispersion
correction and the standard split valence polarized 6ꢀ31G* basis
as implemented in Jaguar. All the optimization calculations
were carried out using the PoissonꢀBoltzmann polarizable
continuum method as incorporated in Jaguar, and parameters
General Epoxidation Procedure Using Ammonium Amide 6C
Ammonium salt 6C was dissolved in the appropriate solvent
(20 mL/mmol ammonium salt) and Cs2CO3 (20 eq.) was added
to the reaction mixture. After 5 min the aldehyde (2 eq) was
added and the suspension was stirred for the indicated time at
the given temperature. The reaction was quenched with water
and extracted with toluene. The organic phase was washed with
brine and dried with anhydrous Na2SO4, filtrated and the
solvent was removed under reduced pressure. The epoxide was
for CH2Cl2. Energies were obtained by single point energy
calculations at the B3LYPꢀD3/6ꢀ311+G**(CH2Cl2) level. The
correct nature of each stationary point has been checked by
performing frequency calculations at the B3LYP/6ꢀ
31G*(CH2Cl2) level of theory. Thermal and entropic
contributions to free energy (at 298.15 K) and zeroꢀpoint
energy have been obtained from these frequency calculations.
We have made a systematic attempt to locate all possible local
minima, with the data presented referring to the lowest energy
form.
purified
by
column
chromatography
(silica
gel,
heptanes:EtOAc = 7:3).
trans-Epoxide 17a
Obtained in 78% (1 mmol scale) as a white solid after column
22
chromatography (Cond. A). [
1H NMR (700 MHz, δ, CDCl3, 298 K): 1.72 (s, 3H), 1.88 (s,
3H), 3.22 (d, 1H, = 1.8 Hz), 3.68 (d, 1H, = 1.8 Hz), 3.90
α
]
(c = 1.4, CH2Cl2) = ꢀ178;
D
J
J
Ammonium Amide 6C
(R)ꢀ14 (3.00 g, 21.9 mmol) was dissolved in 50 mL acetone and
(dd, 1H, J1 = 9.2 Hz, J2 = 4.2 Hz), 4.41 (dd, 1H, J1 = 9.2 Hz, J2
= 6.6 Hz), 5.10 (dd, 1H, J1 = 6.6 Hz, J2 = 4.2 Hz), 6.78 (m, 2H),
7. 00 ꢀ 7.20 (m, 8H) ppm; 13C NMR (176 MHz, δ, CDCl3,
298 K): 24.3, 25.1, 58.4, 58.9, 61.5, 72.1, 97.3, 125.9, 126.1,
128.4, 128.5, 128.7, 129.4, 135.3, 140.6, 164.2 ppm; IR (film):
= 3032, 2989, 2933, 2873, 1658, 1458, 1437, 1387, 1363,
1252, 1205, 1081, 1066, 894, 849, 772, 749, 695, 660, 596,
552, 513 cmꢀ1; HRMS (ESI): m/z calcd for C20H21NO3:
324.1594 [M + H]+; found: 324.1595.
3.2 g anhydrous MgSO4 were added and the reaction mixture
was stirred for 3 h at 20°C. After filtration and evaporation to
dryness the product 21 was obtained in 95% (3.68 g,
20.7 mmol) and used without further purification. The 1Hꢀ
NMRꢀspectrum is in full accordance to literature.20
1HꢀNMR (300 MHz, δ, CDCl3, 298 K): 1.45 (s, 3H), 1.52 (s,
3H), 2.04 (b, 1H), 3.71 (t, 1H,
J
= 7.8 Hz), 4.29 (t, 1H,
J =
7.8 Hz), 4.54 (t, 1H,
ppm.
J = 7.8 Hz), 7.26 ꢀ 7.41 (m, 5H, ArꢀH)
General Procedure for the Preparation of Aziridines
Compound 21 (3.68 g, 20.7 mmol) was dissolved in 25 mL
CH2Cl2 and 83 mL aqueous saturated Na2CO3 solution were
A mixture of 6C (0.4 mmol), aldimine
3 (2 eq.), and Cs2CO3
(20 eq.) in CH2Cl2 (8 mL) was vigorously stirred for 24 h at
room temperature. CH2Cl2 and brine were added and the phases
separated. The aqueous layer was extracted twice with CH2Cl2,
the combined organic layers were extracted with brine and the
aqueous layer was reꢀextracted twice with CH2Cl2. The
combined organic layers were dried over Na2SO4, filtrated,
evaporated, and dried in vacuo. Column chromatography (silica
gel, heptanes/EtOAc = 20:1 – 2:1) gave the aziridines 19 in the
reported yields. In most cases the minor cisꢀisomers and the
olefins 20 could not be obtained in pure form.
added. Then bromide
7 (2.9 mL, 21.7 mmol, 1.05 eq.) was
added and the mixture was vigorously stirred for 4 h. After
addition of aqueous saturated NaHCO3 the aqueous layer was
separated and washed three times with 20 mL CH2Cl2. The
combined organic phases were dried over anhydrous MgSO4,
filtrated and the solvent removed under reduced pressure. The
product was purified by column chromatography (silica gel,
heptanes:EtOAc = 5:1) to give 8C (2.57 g, 8.6 mmol, 41 %
1
yield) as a lightꢀbrown solid. The HꢀNMRꢀspectrum was in
accordance to literature.21 1HꢀNMR (300 MHz, δ, CDCl3,
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 8
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4OB02318H
trans-NꢀBoc Aziridine 19b
23
1
2
3
For reviews see: (a) V. K. Aggarwal, in Comprehensive
Asymmetric Catalysis, eds. E. N. Jacobsen, A. Pfaltz and H.
Yamamoto, Springer, New York, 1999, vol. 2, 679; (b) E. M.
McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches
and V. K. Aggarwal, Chem. Rev., 2007, 107, 5841ꢀ5883.
For seminal contributions about sulfur ylides see: (a) A. W.
Obtained in 62% as a colourless residue. [
α
]
(c = 1.6,
D
1
CH2Cl2) = ꢀ110; H NMR (500 MHz,
δ
, CDCl3, 298 K): 1.48
= 2.5 Hz), 3.69
= 9.1, 3.5 Hz), 4.47 (dd,
= 6.8, 3.5 Hz), 6.88 (d, 2H,
= 6.9 Hz), 7.19 – 7.28 (m, 8H) ppm; 13C NMR (125 MHz,
(s, 9H), 1.73 (s, 3H), 1.89 (s, 3H), 2.87 (d, 1H,
(d, 1H, = 2.5 Hz), 3.96 (dd, 1H,
1H, = 9.1, 6.8 Hz), 5.28 (dd, 1H,
J
J
J
J
J
Johnson and R. B. Lacount, Chem. Ind., 1958, 1440ꢀ1441; (b)
J
δ
,
E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1962, 84
,
CDCl3, 298 K): 23.8, 25.0, 28.0, 44.5, 44.8, 61.5, 71.6, 81.7,
96.8, 125.7, 126.5, 127.7, 128.0, 128.1, 129.1, 135.3, 140.9,
159.2, 163.7 ppm; IR (film):
1715, 1652, 1433, 1395, 1364, 1333, 1253, 1223, 1204, 1074,
1053, 819, 755, 746, 705, 691, 635 cmꢀ1; HRMS (ESI): m/z
calcd for C25H30N2O4: 423.2278 [M + H]+; found: 423.2287.
867ꢀ868; (c) E. J. Corey and M. Chaykovsky, J. Am. Chem.
Soc., 1965, 87, 1353ꢀ1364.
= 3009, 2984, 2935, 2868,
For selected examples highlighting the use of sulfur ylides in
epoxidation reactions see: (a) O. Illa, M. Arshad, A. Ros, E. M.
McGarrigle and V. K. Aggarwal, J. Am. Chem. Soc., 2010,
132, 1828ꢀ1830; (b) J. Zanardi, C. Leriverend, D. Aubert, K.
Julienne and P. Metzner, J. Org. Chem., 2001, 66, 5620ꢀ5623;
(c) M. Davoust, J.ꢀF. Briere, P.ꢀA. Jaffres and P. Metzner, J.
Org. Chem., 2005, 70, 4166ꢀ4169; (d) V. K. Aggarwal and J.
Richardson, Chem. Commun., 2003, 2644ꢀ2651; (e) Y.ꢀG.
Zhou, X.ꢀL. Hou, L.ꢀX. Dai, L.ꢀJ. Xia and M.ꢀH. Tang, J.
Chem. Soc., Perkin Trans. 1, 1999, 77ꢀ80; (f) V. K. Aggarwal,
J. P. H. Charmant, D. Fuentes, J. N. Harvey, G. Hynd, D.
Ohara, W. Picoul, R. Robiette, C. Smith, J.ꢀL. Vasse and C. L.
Winn, J. Am. Chem. Soc., 2006, 128, 2105ꢀ2114; (g) V. K.
Aggarwal, G. Hynd, W. Picoul and J.ꢀL. Vasse, J. Am. Chem.
Soc., 2002, 124, 9964ꢀ9965; (h) O. Illa, M. Namutebi, C. Saha,
M. Ostovar, C. C. Chen, M. F. Haddow, S. NocquetꢀThibault,
M. Lusi, E. M. McGarrigle and V. K. Aggarwal, J. Am. Chem.
Soc., 2003, 135, 11951ꢀ11966; (i) A. SolladieꢀCavallo, A.
DiepꢀVohuule, J. Org. Chem. 1995, 60, 3494ꢀ3498.
Conclusions
The use of easily available phenylglycinol as a chiral auxiliary
in ammonium ylideꢀmediated reactions was found to be a
promising strategy to obtain chiral threeꢀmembered ring
heterocycles with good to excellent stereoselectivities and in
good yields. In general it was found that the epoxidation
reaction is rather broad in its application scope giving glycidic
amides as single stereoisomers in all cases. The aziridination is
slightly less selective giving the major transꢀisomer with at
least 85% diastereoselectivity but, depending on the electronic
4
For the use of sulfur ylides in aziridine synthesis see: (a) A.ꢀH.
nature of the starting imine, with varying amounts of an
unsaturated ꢀamino amide sideꢀproduct.
α,βꢀ
Li, L.ꢀX. Dai and X.ꢀLꢀ Hou, J. Chem. Soc., Perkin Trans. 1
,
β
1996, 867ꢀ869; (b) V. K. Aggarwal, M. Ferrara, C. J. O’Brien,
A. Thompson, R. V. H. Jones and R. Fieldhouse, J. Chem.
Soc., Perkin Trans. 1, 2001, 1635ꢀ1643; (c) R. Robiette, J.
Org. Chem., 2006, 71, 2726ꢀ2734; (d) T. Saito, M. Sakairi and
D. Akiba, Tetrahedron Lett., 2001, 42, 5451ꢀ5454; (e) V. K.
Aggarwal, E. Alonso, G. Fang, M. Ferrara, G. Hynd and M.
Porcelloni, Angew. Chem., Int. Ed. 2001, 40, 1433ꢀ1436; (f) V.
K. Aggarwal and J.ꢀL. Vasse, Org. Lett. 2003, 5, 3987ꢀ3990;
(g) A. SolladieꢀCavallo, M. Roje, R. Welter, V. Sunjiç, J. Org.
Chem. 2004, 69, 1409ꢀ1412.
Acknowledgements
This work was supported by the Austrian Science Funds
(FWF): Project No. P26387ꢀN28. Computational resources
have been provided by the supercomputing facilities of the
Université catholique de Louvain (CISM/UCL) and the
Consortium des Équipements de Calcul Intensif en Fédération
Wallonie Bruxelles (CÉCI) funded by the Fond de la Recherche
Scientifique de Belgique (F.R.S.ꢀFNRS) under convention
2.5020.11. The NMR spectrometers used were acquired in
collaboration with the University of South Bohemia (CZ) with
financial support from the European Union through the EFRE
INTERREG IV ETCꢀATꢀCZ program (project M00146,
"RERIꢀuasb"). RR is a Chercheur qualifié of the F.R.S.ꢀFNRS.
5
For ammonium ylide mediated cyclopropanations see: (a) M. J.
Gaunt and C. C. C. Johansson, Chem. Rev., 2007, 107, 5596ꢀ
5605; (b) C. C. C. Johansson, N. Bremeyer, S. V. Ley, D. R.
Owen, S. C. Smith and M. J. Gaunt, Angew. Chem. Int. Ed.
2006, 45, 6024ꢀ6028; (c) C. D. Papageorgiou, M. A. Cubillo
de Dios, S. V. Ley and M. J. Gaunt, Angew. Chem. Int. Ed.
,
,
2004, 43, 4641ꢀ4644; (d) N. Bremeyer, S. C. Smith, S. V. Ley
and M. J. Gaunt, Angew. Chem. Int. Ed., 2004, 43, 2681ꢀ2684;
(e) C. D. Papageorgiou, S. V. Ley and M. J. Gaunt, Angew.
Chem. Int. Ed., 2003, 42, 828ꢀ831; (f) S. Kojima, K. Hiroike
and K. Ohkata, Tetrahedron Lett., 2004, 45, 3565ꢀ3568; (g) S.
Yamada, J. Yamamoto and E. Ohta, Tetrahedron Lett., 2007,
48, 855ꢀ858; (h) N. Kanomata, R. Sakaguchi, K. Sekine, S.
Yamashita and H. Tanaka, Adv. Synth. Catal., 2010, 352
,
2966ꢀ2978.
6
For benzylic ammonium ylide mediated epoxidations see: (a)
T. Kimachi, H. Kinoshita, K. Kusaka, Y. Takeuchi, M. Aoe
and M. Juꢀichi, Synlett, 2005, 842ꢀ844; (b) H. Kinoshita, A.
Ihoriya, M. Juꢀichi and T. Kimachi, Synlett, 2010, 2330ꢀ2334;
(c) R. Robiette, M. Conza and V. K. Aggarwal, Org. Biomol.
Notes and references
a
Institute of Organic Chemistry, Johannes Kepler University Linz,
Altenbergerstraße 69, 4040 Linz, Austria. Fax: +43 732 2468 8747; Tel:
+43 732 2468 8748; E-mail: Mario.waser@jku.at
b
Institute of Condensed Matter and Nanosciences, Université catholique
Chem., 2006,
For amideꢀstabilised ammonium ylide mediated epoxidations
see: (a) M. Waser, R. Herchl and N. Müller, Chem. Commun.
2011, 47, 2170ꢀ2172; (b) R. Herchl, M. Stiftinger and M.
Waser, Org. Biomol. Chem., 2011, , 7023ꢀ7027.
4, 621ꢀ623.
de Louvain, Place Louis Pasteur 1 box L4.01.02, 1348 Louvain-la-Neuve,
Belgium.
7
8
,
c
Institute of Analytical Chemistry, Johannes Kepler University Linz,
Altenbergerstraße 69, 4040 Linz, Austria.
9
d
Institute of Inorganic Chemistry, Johannes Kepler University Linz,
For cyanoꢀstabilised ammonium ylide mediated epoxidations
see: a) A. Kowalkowska, D. Sucholbiak and A. Jonczyk, Eur.
J. Org. Chem., 2005, 925ꢀ933; (b) A. Jonczyk and A.
Altenbergerstraße 69, 4040 Linz, Austria.
Electronic Supplementary Information (ESI) available: [experimental and
computational details, characterization of new compounds, and copies of
NMR spectra]. See DOI: 10.1039/b000000x/
Konarska, Synlett
, 1999, 1085ꢀ1087; (c) A. Alex, B.
Larmanjat, J. Marrot, F. Couty and O. David, Chem. Commun.
,
2007, 2500ꢀ2502.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

Organic & Biomolecular Chemistry
Page 8 of 8
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4OB02318H
9
For ammonium ylideꢀmediated aziridinations see: (a) L. D. S.
Yadav, R. Kapoor and Garima, Synlett, 2009, 3123ꢀ3126; (b)
S. Aichhorn, G. N. Gururaja, M. Reisinger and M. Waser, RSC
Adv., 2013, 3, 4552ꢀ4557.
10 For selected reviews see: (a) A. H. Hoveyda, D. A. Evans and
G. C. Fu, Chem. Rev., 1993, 93, 1307ꢀ1370; (b) P. Arya and H.
Qin, Tetrahedron, 2000, 56, 917ꢀ947; (c) D. A. Evans and J. T.
Shaw, Actualite Chimique, 2003, 35ꢀ38; (d) D. J. Ager, I.
Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835ꢀ875.
11 For chiral amide containing sulfonium ylides in epoxidations
see: (a) F. Sarabia, S. Chammaa, M. GaricaꢀCastro and F.
MartinꢀGalvez, Chem. Commun., 2009, 5763ꢀ5765; (b) D. M.
Aparicio, J. L. Teran, D. Gnecco, A. Galindo, J. R. Juarez, M.
L. Orea and A. Mendoza, Tetrahedron: Asymmetry, 2009, 20
,
2764ꢀ2768; (c) F. Sarabia, C. VivarꢀGarcia, M. GaricaꢀCastro
and J. MartinꢀOrtiz, J. Org. Chem., 2011, 76, 3139ꢀ3150; (d)
D. M. Aparicio, D. Gnecco, J. R. Juarez, M. L. Orea, A.
Mendoza, N. Waksman, R. Salazar, M. ForesꢀAlamo and J. L.
Teran, Tetrahedron, 2012, 68
, 10252ꢀ10256; (e) P. G.
Gordillo, D. M. Aparicio, M. Flores, A. Mendoza, L. Orea, J.
R. Juarez, G. Huelgas, D. Gnecco and J. L. Teran, Eur. J. Org.
Chem., 2013, 5561ꢀ5565.
12 Seminal report describing the use of these auxiliaries: D. A.
Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981,
103, 2127ꢀ2129.
13 Seminal reports about the use as a chiral auxiliary: (a) M.
Larcheveque, E. Ignatova and T. Cuvigny, Tetrahedron Lett.
,
1978, 19, 3961ꢀ3964; (b) A. G. Myers, B. H. Yang, H. Chen
and J. L. Gleason, J. Am. Chem. Soc., 1994, 116, 9361ꢀ9362.
14 These conditions were found to be useful for the parent
epoxidation of ammonium salts
1 with different aldehydes: S.
Aichhorn, On the Diastereoselective Synthesis of Aziridines
and Epoxides using Nitrogen Ylides, Diploma Thesis, Institute
of Organic Chemistry, Johannes Kepler University Linz, 2012.
15 a) CCDC 1023711 (Cambrige Crystallographic Data Centre,
www.ccdc.cam.ac.uk)
contains
the
supplementary
crystallographic data for 17a. b) CCDC 1030561 (Cambrige
Crystallographic Data Centre, www.ccdc.cam.ac.uk) contains
the supplementary crystallographic data for 19f
.
16 Calculations were carried out at the B3LYPꢀD3/6ꢀ
311+G**(CH2Cl2)//B3LYPꢀD3/6ꢀ31G*(CH2Cl2) level using
Jaguar, version 8.0, Schrodinger, LLC, New York, NY, 2011.
Reported energies are free energies (kcal/mol) relative to
reactants in their most stable conformation.
17 Systematic more general computational studies delineating
ammonium ylide mediated epoxidation reactions will be an
integral part of our future research in this field.
18 For computational studies showing preference of
(Z)ꢀ
configuration in sulfonium and phosphonium ylides see Ref.
[3f] and: R. Robiette, J. Richardson, V. K. Aggarwal and J. N.
Harvey, J. Am. Chem. Soc., 2005, 127, 13468ꢀ13469.
19 The aziridines were generally less stable than the epoxides
especially at higher temperature or under acidic conditions.
20 S. Kanemasa and K. Onimura, Tetrahedron 1992, 48, 8631ꢀ
8644.
21 R. J. R. Lumby, P. M. Joensuu and H. W. Lam, Tetrahedron
2008, 64, 7729ꢀ7740.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012