Identification of the best-suited leaving group for the diastereoselective synthesis of glycidic amides from stabilised ammonium ylides and aldehydes

Article abstract of DOI:10.1039/c1ob05721a

In comparison to the use of sulfur ylides, the use of ammonium ylides for the synthesis of epoxides is significantly less developed. As a part of our systematic investigations concerning the use of amide-stabilised ammonium ylides for the synthesis of glycidic amides we have focused on the identification of the best-suited amino leaving group for this purpose. Whereas tertiary amines like quinuclidine or cinchona alkaloids were found to be not suited for epoxide formation, trimethylamine was found to be the leaving group of choice, yielding trans-glycidic amides in excellent yields of > 90%.

Full text of DOI:10.1039/c1ob05721a

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PAPER
Identification of the best-suited leaving group for the diastereoselective
synthesis of glycidic amides from stabilised ammonium ylides and aldehydes†
Richard Herchl,a Martin Stiftingerb and Mario Waser*a
Received 6th May 2011, Accepted 24th June 2011
DOI: 10.1039/c1ob05721a
In comparison to the use of sulfur ylides, the use of ammonium ylides for the synthesis of epoxides is
significantly less developed. As a part of our systematic investigations concerning the use of
amide-stabilised ammonium ylides for the synthesis of glycidic amides we have focused on the
identification of the best-suited amino leaving group for this purpose. Whereas tertiary amines like
quinuclidine or cinchona alkaloids were found to be not suited for epoxide formation, trimethylamine
was found to be the leaving group of choice, yielding trans-glycidic amides in excellent yields of > 90%.
We have recently developed a highly trans-selective protocol for
the synthesis of glycidic amides by reacting aromatic aldehydes
Introduction
with stabilised amide-derived ammonium ylides.8 Key to success
in this approach was the use of biphasic conditions together with
a two-fold excess of aldehyde to give the corresponding glycidic
amides in moderate to good yields (Scheme 1).
The use of ylides for the (dia-)stereoselective synthesis of epoxides
starting from carbonyl compounds has attracted considerable
interest over the last decades.1–8 The straightforward use of
easily available carbonyl electrophiles in combination with ylide
nucleophiles makes this method a highly useful alternative to other
epoxide forming reactions like oxidations of double bonds9 or the
classical Darzens reaction.10
The synthesis of an oxirane ring by addition of a sulfur ylide to
an aldehyde or ketone was introduced in the 1960s1 and a variety
of applications using chiral sulfonium ylides either as auxiliaries
or in a catalytic fashion have been reported so far.2–4 Besides the
use of sulfur ylides, ammonium ylides have also been successfully
employed in different (dia-)stereoselective C–C bond forming
reactions over the last years.5–8,11–15 Gaunt et al. showed that
the addition of a-halo carbonyl compounds to a,b-unsaturated
Michael acceptors in the presence of catalytic amounts of cinchona
alkaloids gives access to almost enantiopure cyclopropanes via in
situ formation of a chiral ammonium ylide.11 However, with respect
to the syntheses of epoxides or aziridines only a few examples have
been reported so far. Whilst the diastereoselective synthesis of
aziridines can be accomplished using DABCO-derived stabilised
ammonium ylides,14 the synthesis of epoxides has so far mainly
been limited to semi-stabilised benzylic ammonium ylides7 and
cyano-stabilised5 ammonium ylides. In addition, it was shown that
more stabilised ester-derived ammonium ylides do not undergo
epoxide formation.15
Scheme 1 Amide-based ammonium ylides for epoxide formation.8
However, although it was shown for the first time that am-
monium ylides bearing an a-carbonyl group can successfully be
employed in oxirane syntheses, it must be clearly pointed out
that this reaction is very close to the limit of what is possible
with ammonium ylides. This can be illustrated by the fact that
the yields were strongly dependent on the electronic properties
of the aldehydes.8 Whereas electron neutral aldehydes reacted in
moderate to good yields (up to 72%), more electron rich aldehydes
reacted much more slowly. On the other hand, electron deficient
aldehydes were prone to rapid Cannizzaro decomposition under
the highly basic reaction conditions.
Due to the high potential of this type of reaction for the
diastereoselective synthesis of glycidic amides we therefore decided
to carry out additional investigations to get a clearer picture about
the potential and the limitations of this methodology.
aInstitute of Organic Chemistry, Johannes Kepler University Linz, Altenberg-
erstraße 69, 4040 Linz, Austria. E-mail: Mario.waser@jku.at; Fax: +43 732
2468 8747; Tel: +43 732 2468 8748
Results and discussion
Recent studies by Aggarwal et al. clearly showed that a key factor
in ylide-based epoxide formation reactions is the leaving group
quality of the onium group, which decreases in the order O >
S > N > P. 13 Accordingly, ammonium ylides are less reactive in
epoxide forming reactions than sulfur ylides. Furthermore, the
bInstitute of Analytical Chemistry, Johannes Kepler University Linz, Al-
tenbergerstraße 69, 4040 Linz, Austria
† Electronic supplementary information (ESI) available: Experimental
details including analytical and spectroscopic data of new compounds.
See DOI: 10.1039/c1ob05721a
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Table 1 Identification of the best-suited amine leaving group
presence of a carbonyl group a to the leaving group (stabilised
ylides) significantly increases the barrier to ring closure.
It is noteworthy that the high trans-selectivity observed in the
reaction of amide-stabilised ammonium ylides with aldehydes
(Scheme 1)8 is in full accordance with results published for epox-
idations using amide-stabilised sulfur ylides.4 Thus, in analogy
to studies by Aggarwal et al.,3d it can be assumed that addition
of the ylide to the aldehyde gives the synclinal anti-betaine A
first (Scheme 2). Bond rotation then leads to the antiperiplanar
anti-betaine B, which, upon ring closure, yields the trans-oxirane.
Systematic investigations by Aggarwal et al. revealed that for
stabilised sulfonium ylides formation of syn- and anti-betaines
is reversible, but bond rotation towards antiperiplanar betaines B
is more hindered for syn-betaines (which would give cis-oxiranes)
than for anti-betaines, thus favouring trans-epoxide formation.3d,13
Although we have no direct experimental or computational
evidence yet, it seems reasonable that the high trans-selectivity
using amide-derived ammonium ylides might be due to similar
reasons.
Entry
Amine (R3N)
Salt
Yielda (%)
1
2
3
4
5
DABCO
Quinuclidine
Quinine-OMe
Et3N
3
4
5
6
7
67
32
0
41
92
Me3N
a Isolated yields.
Entry 1 represents the recently developed standard reaction
using DABCO-derived ammonium salt 3 as the nucleophile (67%
yield).8 Replacing DABCO for quinuclidine (salt 4), the yield
dropped significantly (32%). This significant decrease in yield is
in contrast to recent reports by Aggarwal et al.7c and Kimachi
et al.7a describing either similar or only slightly reduced yields in
the syntheses of stilbene oxides using DABCO- or quinuclidine-
derived benzylic ammonium ylides. Furthermore, using cinchona
alkaloid based ylides (e.g. O-methyl protected quinine based salt
5, entry 3) absolutely no product formation was observed.
Employing triethylamine as the amine component (entry 4)
the yield was still significantly lower compared to DABCO. Of
note, in all these lower yielding experiments (entries 2–4), NMR
spectra of the crude products showed significant amounts of
unidentified decomposition products. However, when we changed
to trimethylamine (Me3N) (salt 7, entry 5) almost quantitative
conversion of 7 to the epoxide product 2 was observed. Using
just 1.2 equiv. of 1 the yield decreased to 58% illustrating that
decomposition of 1 is the limiting factor hereby.
Scheme 2 Formation of trans-oxiranes via the anti-betaines A and B.
During our initial investigations, the biphasic combination of
CH2Cl2 and aqueous NaOH (50%) (100 equiv.) was found to
be superior over monophasic or liquid/solid conditions.8 During
these investigations, aldehyde- and ylide-derived by- or decompo-
sition products were observed. Whereas activated aldehydes (e.g.
p-nitro) mainly gave Cannizzaro disproportionation byproducts,
more electron neutral or electron rich aldehydes were found to
be more stable under the chosen conditions.16 With respect to the
ylide, a reasonable consumption was observed in all experiments,
even if no product was formed. Although the formed by-products
could not be clearly identified, it seems reasonable that not only the
ylides themselves decompose, but also the intermediate betaines
(A and B) undergo some decomposition. This is also supported
by the fact that it was never possible to quantitatively re-isolate
the aldehyde (respectively benzyl alcohol and benzoic acid), even
if no epoxide product was formed. It can therefore be rationalized
that some betaine is always formed but the reduced leaving group
ability of the amino group makes ring closure be the limiting step
in this reaction.
The striking differences in reactivity should mainly be due to
the different leaving group abilities of the different amines and
less due to different nucleophilicities as all ammonium ylides
are supposed to be highly nucleophilic.7,13 As species with lower
basicity are supposed to have a higher leaving group ability17 it
is obvious why quinuclidine (pKa = 11.4)18a and triethylamine
(pKa = 10.7)18b are not as good leaving groups as DABCO (pKa =
8.9)18a and trimethylamine (pKa = 9.8).18b However, this fact alone
does not explain why Me3N is by far the best leaving group
whereas cinchona alkaloids (pKa of quinine = 8.7)18c do not
yield any product at all. The missing reactivity of the cinchona-
derived salt 5 is not fully understood yet as these compounds
should be good nucleophiles as demonstrated by Gaunt et al.11
However, one might reason that bond rotation towards the
required antiperiplanar betaine B has a much higher activation
barrier than in the case of small amine groups due to repulsion
between the large quinoline group of quinine and the phenyl group
of the benzaldehyde,19 which would explain why we just observed
formation of decomposition products. On the other hand, the high
yields using 7 may therefore be attributed to the smallest steric
hindrance among the employed amino groups, thus facilitating
bond rotation towards the required antiperiplanar betaine B.
It is noteworthy that even less stabilised cinchona-derived
benzylic ammonium ylides, which should be more reactive, did
not yield any epoxides under the biphasic conditions. This is
Therefore, we decided to investigate the influence of the leaving
group on the reaction outcome and to determine the best-suited
amino group for our approach. As summarised in Table 1,
several tertiary amines were used to synthesise the corresponding
quaternary ammonium ylides 3–7 and tested in the reaction with
benzaldehyde (1) under biphasic conditions.
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Table 2 Reaction of different aldehydes with 7
On the other hand, using more electron deficient aldehydes
like the nitro aldehydes 24 and 26 or the pyridyl carbaldehyde
28, mainly Cannizzaro decomposition products were observed
(entries 10–12). Although the nitroaldehydes 24 and 26 could be
converted into the corresponding epoxides 25 and 27 in rather low
yields only (entries 10, 11), a beneficial effect of the leaving group
was observed as reaction of 24 with 3 was found to give epoxide
25 in trace amounts only.8 Nevertheless, these highly activated
aldehydes (the same counts for 28) are too unstable under the
highly basic reaction conditions and neither carrying out these
reactions at lower temperatures nor using less base did improve
the result.
Using the lauric aldehyde 30, full consumption of the aldehyde
was observed but no epoxide 31 could be obtained. As an NMR
spectrum of the crude product showed signals in the olefinic
region, a self-aldol condensation under the highly basic conditions
seems to be the dominant reaction of 30. In contrast, the reaction
of 7 with cyclohexanecarboxaldehyde (32) gave the targeted trans-
epoxide 33 in 54%. Although the yield was lower than for most
aromatic aldehydes, it was clearly shown that a-branched aliphatic
aldehydes, which cannot undergo self-condensation reactions, are
suitable electrophiles for ylide-based epoxidations. Accordingly,
despite the highly basic conditions, the scope of this reaction is
not just limited to aldehydes without a-H only.
Entry
R
Aldehyde
Product
Yielda,b (%)
1
2
3
4
5
6
7
8
Ph-
1
2
92 (67)b
95 (68)b
90
4-MeC6H4-
2-MeC6H4-
4-ClC6H4-
4-BrC6H4-
4-Biphenyl-
4-MeOC6H4-
2-MeOC6H4-
4-Me2NC6H4-
4-NO2C6H4-
3-NO2C6H4-
3-Pyridyl-
8
9
10
12
14
16
18
20
22
24
26
28
30
32
11
13
15
17
19
21
23
25
27
29
31
33
90 (72)b
97
93
83 (47)b
98
9
<5c
10
11
12
13
14
17d (<10)b
12d
<10c,d
n-Undecyl-
Cyclohexyl-
0e
54
a Isolated yields. b Yields obtained using DABCO salt 3 are given in brack-
1
ets (taken from Ref. 8) c Determined by H NMR of the crude product.
d Large amounts of Cannizzaro decomposition products. e Decomposition
of aldehyde.
in full accordance with a recent report by Kimachi et al. on
the syntheses of stilbene oxides using cinchona-derived benzylic
ammonium ylides in THF (t-BuOK as a base).7b Surprisingly, this
group identified brucine as a suitable chiral amine for the syntheses
of enantioenriched stilbene oxides.7b
Next, a screening of other trimethylamine-derived amide-based
ylides in the reaction with 1 (2 equiv.) was undertaken (Table 3).
Table 3 Reaction of different trimethylamine-derived ylides with 1
Accordingly, these results clearly point out the high importance
of the appropriate leaving group for this reaction.
Having identified trimethylamine as the amino group of choice,
we next screened the reaction of 7 with several aldehydes (2
equiv.)16 under standard conditions (Table 2).
Entry
1
Amide
Salt
Product
Yielda (%)
92
Reactions with a variety of different aromatic aldehydes (entries
1–8) gave the corresponding trans-configured glycidic amides in
good to excellent yields. In average the yields were about 20 to 30%
higher compared to the DABCO-based epoxidations.8 In addition,
it was found that the Me3N-derived salt 7 is also superior upon
reaction with electron rich aldehydes like the anisaldehydes 18
and 20 (entries 7 and 8). Whereas the DABCO salt 3 gave the p-
methoxy substituted glycidic amide 19 in 47% only under standard
conditions,8 reaction of salt 7 with aldehyde 18 gave the oxirane
19 in 83% isolated yield (entry 7). Furthermore, the o-methoxy
aldehyde 20 was found to be even more reactive furnishing epoxide
21 almost quantitatively. However, using the even more electron
rich aldehyde 22 as an electrophile, only traces of product were
observed in the NMR spectrum of the crude product. Also
carrying out the reaction at higher temperature did not improve
the conversion significantly (<10% in situ). Furthermore, the
starting aldehyde was reisolated almost quantitatively. This is
absolutely identical to our recent result using DABCO-derived
salts and therefore suggests that the electron rich aldehyde 22 is
not electrophilic enough for betaine formation. As the results for
DABCO- and Me3N-derived ylides are the same it can be reasoned
that both ylides are similarly nucleophilic. This also implies that
the higher reactivity of 7 with more electron neutral aldehydes
(entries 1–8, Table 2) is really due to an enhanced leaving group
ability of Me3N.
7
3
2
34
35
74
3
4
36
38
37
39
49
93
5
6
40
42
41
43
86
0
a Isolated yields.
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Other tertiary amides (entries 2, 4, and 5) gave yields comparable
to the test reaction between 1 and 7. Using the secondary amide
36, the corresponding glycidic amide 37 could be isolated in 49%
(entry 3). This lower yield for secondary amides is in accordance
with our recent results using DABCO-derived ammonium salts
where a low yield of 24% only was obtained in the synthesis of 37.8
As an increased amount of Cannizzaro products was formed, the
lower yield seems to be due to a significantly reduced reactivity
of the secondary amide-derived salt 36 (similar results for sulfur
ylides were reported by Aggarwal et al.4b). Unfortunately, the
use of Weinreb amide 42 did not yield any epoxide 43. Hereby,
the aldehyde 1 (besides Cannizzaro products) was almost fully
recovered whereas the ammonium salt 42 totally decomposed.
Finally, we were also interested whether the scope of
this methodology can be expanded to even more stabilised
ester-derived ammonium ylides. However, the reaction of
trimethylamine-derived ester-based ammonium ylides with ben-
zaldehyde totally failed and not even traces of the epoxides could
be obtained. Accordingly, although we have identified the best-
suited leaving group and reaction conditions with respect to the
synthesis of glycidic amides, the corresponding glycidic esters are
still not accessible.
Shimadzu IR Affinity-1 Fourier transform infrared spectrometer.
All chemicals were purchased from commercial suppliers and used
without further purification unless otherwise stated. All reactions
were performed under an Ar-atmosphere.
General procedure for the syntheses of Me3N-ammonium salts
One equivalent of Me3N (33% solution in EtOH) was added
to a solution of one equivalent of the a-bromo amide in THF
(10 mL g-1 amide) and stirred for 24 h at room temperature. The
resulting solid was filtered off, washed with EtOAc (3¥), and dried
in vacuo to give the product in sufficient purity for the epoxide
formation reaction.
Ammonium salt 7
Prepared from 2-bromo-N,N-diethylacetamide20 (8.92 g,
45.9 mmol) in 88% (10.27 g, 40.5 mmol). White solid. M.p.:
186–188 ◦C; 1H NMR (500 MHz, d, CDCl3, 298 K): 1.14 (t, J =
7.3 Hz, 3H), 1.27 (t, J = 7.3 Hz, 3H), 3.36 (q, J = 7.3 Hz, 2H),
3.47 (q, J = 7.3 Hz, 2H), 3.63 (s, 9H), 5.00 (s, 2H) ppm; 13C NMR
(125 MHz, d, CDCl3, 298 K): 12.9 (CH3-), 14.5 (CH3-), 41.0
(-CH2-), 42.0 (-CH2-), 54.7 (-N+(CH3)3), 63.2 (-CH2CO-), 162.4
¯
(-CO-) ppm; IR (film): n = 3003, 2978, 2945, 1639, 1483, 1467,
Conclusions
1446, 1433, 1384, 1357, 1278, 1238, 1215, 1139, 1097, 1078, 1022,
975, 954, 927, 894 cm-1; HRMS (ESI): m/z calcd for C9H21N2O+:
173.1654 [M+]; found: 173.1651.
It was shown that the use of ammonium ylides bearing an a-
carbonyl group for the syntheses of epoxides is highly dependent
on the choice of the employed leaving group. Whereas trimethy-
lamine and DABCO were found to be suitable amino groups giving
access to trans-configured glycidic amides in good to excellent
yields, other tertiary amines were found to be less suited. Especially
cinchona alkaloid-derived ammonium ylides were found to be
absolutely unreactive in the syntheses of glycidic amides as well
as in the syntheses of stilbene oxides. The scope of the reaction
was found to be rather broad for several aromatic aldehydes and
different amides and excellent yields of >90% could be obtained.
Only highly electron rich as well as highly electron deficient
aldehydes were found to be less suited. Whereas electron rich
aldehydes are not electrophilic enough for this reaction, more
activated aldehydes were found to mainly undergo Cannizzaro
decomposition mainly. On the other hand, it was also shown that
enolisable a-branched aldehydes do undergo epoxide formation
under the highly basic reaction conditions whereas unbranched
ones do not yield any epoxides due to self-aldol condensation. On
the other hand, ester-derived ammonium ylides were not reactive
under the developed conditions.
General procedure for the preparation of epoxides
A vigorously stirred solution of ammonium salt (1 mmol) in
CH2Cl2 (10 mL) was cooled to 0 ◦C, followed by addition of
50% NaOH (5 mL). After 5 min the aldehyde (2 mmol) wa◦s added
in one portion. The biphasic mixture was warmed to 25 C over
1 h and vigorously stirred for 23 h. After extraction with EtOAc,
the organic layer was washed with brine, dried over Na2SO4
and evaporated to dryness. Column chromatography (silica gel,
heptanes/EtOAc = 7 : 3) gave the glycidic amides in the reported
yields.
trans-N,N-Diethyl-3-phenyloxirane-2-carboxamide (2)
Obtained in 92% as a white to yellow solid. Analytical data are
in full accordance with those reported in literature.4a 1H NMR
(500 MHz, d, CDCl3, 298 K): 1.16 (t, J = 7.3 Hz, 3H), 1.20 (t, J =
7.3 Hz, 3H), 3.40–3.51 (m, 4H), 3.58 (d, J = 1.4 Hz, 1H), 4.09 (d,
J = 1.4 Hz, 1H), 7.32–7.39 (m, 5H) ppm; 13C NMR (125 MHz,
d, CDCl3, 298 K): 13.1, 15.0, 41.0, 41.6, 57.3, 57.7, 125.8, 128.6,
Experimental section
¯
128.7, 135.9, 165.8 ppm; IR (film): n = 2972, 2933, 2873, 1643,
1487, 1450, 1409, 1365, 1271, 1217, 1145, 1095, 1076, 893, 754,
698, 617 cm-1; HRMS (ESI): m/z calcd for C13H17NO2: 220.1332
[M + H]+; found: 220.1329.
General
Melting points were measured on a Kofler melting point micro-
scope (Reichert, Vienna). 1H- and 13C-NMR spectra were recorded
on a Bruker Avance DRX 500 MHz spectrometer using a TXI
cryoprobe with z-gradient coil and on a Bruker Avance DPX
200 MHz spectrometer. All NMR spectra were referenced on the
solvent peak. High resolution mass spectra were obtained using an
Agilent 6520 Q-TOF mass spectrometer with an ESI source and
an Agilent G1607A coaxial sprayer. IR spectra were recorded on a
Acknowledgements
This work was supported by the Austrian Science Funds (FWF):
Project No. P22508-N17. We are grateful to Prof. Dr Norbert
Mu¨ller for inspiring discussions and to Andrea Zollner and Martin
Strnad for assistance with the lab work.
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10 For stereoselective Darzens approaches see: (a) S. Arai, K. Tokumaru
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Commun., 2000, 1215–1225; (b) T. Nemoto, H. Kakei, V. Gnanade-
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16 Although all reactions were carried out under inert conditions, varying
amounts of benzoic acids were observed in several cases presumably
due to autoxidation of the aldehydes. Thus 2 equiv. of aldehyde were
used to obtain a reasonable compromise between yield and required
amount of starting material.
17 This means correlating a kinetic property (leaving group ability) with
a thermodynamic property (basicity): K. P. C. Vollhardt and N. E.
Schore, Organic Chemistry, W. H. Freeman, New York, 1998.
18 pKa values in H2O: (a) E. A. Castro, M. Aliaga, P. R. Campodonico, J.
R. Leis, L. Garcia-Rio and J. G. Santos, J. Phys. Org. Chem., 2008, 21,
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19 It has been shown that bond rotation towards betaines B is the crucial
step in epoxidations using stabilised ylides (see Ref [3d]).
20 T. Hama, X. Liu, D. A. Culkin and J. F. Hartwig, J. Am. Chem. Soc.,
2003, 125, 11176–11177.
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