Ammonium ylides for the diastereoselective synthesis of glycidic amides

Article abstract of DOI:10.1039/c0cc04821f

A highly trans-selective protocol for the synthesis of glycidic amides was developed. This approach gave access to oxiranes by reacting stabilised ammonium ylides bearing an α-carbonyl group and aromatic aldehydes in moderate to good yields.

Full text of DOI:10.1039/c0cc04821f

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COMMUNICATION
Ammonium ylides for the diastereoselective synthesis of glycidic amidesw
Mario Waser,* Richard Herchl and Norbert Muller
¨
Received 5th November 2010, Accepted 30th November 2010
DOI: 10.1039/c0cc04821f
A highly trans-selective protocol for the synthesis of glycidic
amides was developed. This approach gave access to oxiranes by
reacting stabilised ammonium ylides bearing an a-carbonyl
group and aromatic aldehydes in moderate to good yields.
syntheses with ammonium ylides bearing an a-carbonyl group
have been reported so far.9
However, from the few reported examples it was
clearly proven by Jonczyk et al.11 that cyano-stabilised ylides
(being less stabilised than esters)15 undergo such reactions
under biphasic conditions in moderate yield. Furthermore,
less stabilised benzylic ylides give access to trans-selective
formation of stilbene oxides in moderate to good yields.13
Thus, it seems reasonable that similarly stabilised ammonium
ylides might be successfully employed for epoxide formation.
Based on a recent investigation of the stability of ylides,15
we reasoned that amide based ammonium ylides (being less
stabilised than cyano-based ylides, but higher stabilised than
benzylic), might undergo oxirane formation when reacted with
aldehydes since they should be sufficiently balanced with
respect to nucleophilicity and leaving group ability. Due to
the high interest in glycidic amides,4 an ammonium ylide based
synthetic approach would thus significantly broaden the scope
of this methodology.
The (dia-)stereoselective synthesis of glycidic amides and esters
has attracted considerable interest over the last few decades
mainly due to the high potential of these compounds as
synthetically useful intermediates in a variety of organic
syntheses. Ylides have proven to be very powerful synthons
for the formation of epoxides1–4 providing alternatives to the
oxidation of a,b-unsaturated carbonyl compounds5,6 or the
Darzens reaction between a-halo esters or amides and carbonyl
groups.7 The synthesis of oxirane rings by reacting a sulfur
ylide with an aldehyde or ketone was introduced around
50 years ago1 and a variety of applications using chiral
sulfonium ylides either in stoichiometric or even in catalytic
quantities have been reported.2–4 Next to sulfur ylides the use
of ammonium ylides for C–C bond formation has attracted
considerable interest over the last few years.8–14 Gaunt et al.
showed that cinchona alkaloid catalysts are highly useful for
stereoselective cyclopropanations proceeding via an
ammonium ylide mechanism.8 Besides the syntheses of cyclo-
propanes the diastereoselective formation of epoxides in
analogy to the Corey–Chaykovsky reaction has been
described.11–13 However, this synthetically useful transformation
has so far been limited to benzylic ammonium ylides13 and
cyano-stabilised ammonium ylides11,12 giving the corresponding
oxiranes in moderate yields only, whereas ester-stabilised
ylides did not yield the epoxides.14 Previous 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 4 S 4 N 4 P.9
Furthermore, the presence of a carbonyl group a to the leaving
group (stabilised ylides) significantly increases the barrier
to ring closure. Altogether, these investigations clearly
demonstrate why ammonium ylides are less suited for epoxide
formation than sulfur ylides and rationalize why no oxirane
We therefore focused on the development of reactions
between DABCO-derived amide-based ammonium ylides
and aromatic aldehydes (Scheme 1).
Initial attempts were carried out reacting a small excess of
benzaldehyde (1) with the diethylamide-derived ammonium
salt 2 in dry THF using t-BuOK (1.2 equiv.) as the base at
room temperature (Table 1, entry 1). After 24 h, full conversion
of 1 was observed and the trans-configured glycidic amide 3
could be isolated in 32% yield. Noteworthy, not even trace
1
amounts of the cis-diastereomer were obtained (judged by H
NMR). As we had observed a significant decrease in yield
(o20%) using lower quality THF, addition of molecular
sieves (4 A) to the reaction mixture was tested, resulting in
an improved yield of 47% (entry 2). However, besides the
target product, large amounts of benzyl alcohol and benzoic
acid resulting from base mediated Cannizzaro disproportionation
of 1 accompanied by unidentified decomposition products of 2
were obtained. Unfortunately, neither addition of tetrabutyl-
ammonium bromide,16 nor reducing the reaction temperature
improved suppression of these side reactions. Also using other
Institute of Organic Chemistry, Johannes Kepler University Linz,
Altenbergerstraße 69, 4040 Linz, Austria.
E-mail: Mario.waser@jku.at; Fax: +43 732 2468 8747;
Tel: +43 732 2468 8748
w Electronic supplementary information (ESI) available: Experimental
part including analytical and spectroscopic data of all new
compounds. See DOI: 10.1039/c0cc04821f
Scheme 1 Targeted use of amide-based ammonium ylides for epoxide
formation.
c
2170 Chem. Commun., 2011, 47, 2170–2172
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Table 1 Screening of conditions for the reaction of 1 and 2
Table 2 Reaction of different amide derived ylides with 1
Entry
1
Amide
Salt
Product
Yielda (%)
67
transb (%)
499
Yielda transb
T (1C) t (h) 1 : 2 (%) (%)
Entry Solvent
Base
2
3
1
2
THF t-BuOK
THF (4 A) t-BuOK
0 - 25 24 1.2
0 - 25 24 1.2
0 - 25 24 1.2
0 - 25 24 1.2
0 - 25 24 1.2
0 - 25 24 1.2
0 - 25 24 1.2
32
47
23
0
0
0
45
55
55
67
77
50
76
62
499
499
499
499
499
499
499
499
499
499
499
499
499
499
3
THF
KOH
KOH
Cs2CO3
4
5
6
EtOH
CH3CN
CH3CN (aq) KOH
2
3
4
6
5
7
72
24
499
499
7
8
DMSO
THF (4 A) t-BuOK
t-BuOK
0 - 25 24
2
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50% NaOH 0 - 25 24 1.2
10
11
12
13
14
50% NaOH 0 - 25 24
50% NaOH 0 - 25 24
2
3
50% NaOH 0 - 25 24 0.5
4
8
9
58
499
50% NaOH 40
50% KOH 0 - 25 24
8
3
3
a
b
Isolated yields. Determined by 1H NMR of the crude product.
a
b
Isolated yields. Determined by H NMR of the crude product.
1
solvent/base combinations (entries 3–7 in Table 1 give a
representative overview of only a few of the tested conditions),
no improvement could be achieved. Noteworthy, some of the
conditions which were reported to be very successful in sulfur
ylide transformations (e.g. entry 6)17 gave absolutely no
conversion in our case. The only significant product formation
was observed when using t-BuOK in DMSO (45%, entry 7).
As disproportionation of 1 was found to be the major limiting
factor, 2 equiv. of aldehyde were used next (entry 8), but the
yield could only be improved slightly (55%), and large
amounts of the Cannizzaro products were formed.
time (424 h) resulted in a significant decomposition of the
epoxide product. Using 50% KOH (aq) as the base resulted in
a reduced yield of 62% only (entry 14). Neither lower
temperature, nor varying the amount of base or solvent ratios
(e.g. less H2O) and concentrations improved the yield any more.
Using quinuclidine-based ammonium salts instead of
DABCO-derived ones gave 3 in 15% yield only, whereas
quinine as the amine part did not give any product, indicating
the importance of leaving group ability for this reaction.
Having developed a reliable biphasic procedure for the
highly trans-selective synthesis of 3 in a reasonable yield, we
next investigated the use of other amide-derived ylides in the
reaction with 1 (2 equiv.)18 under these conditions (Table 2).
It was clearly shown that all other amides give the products
in high trans-selectivity too. Furthermore, other tertiary
amides (entries 2 and 4, Table 2) give yields comparable to
the test reaction between 1 and 2. However, using the secondary
amide 6, the corresponding glycidic amide 7 could only be
isolated in a reduced yield of 24% (entry 3). In this case, an
increased amount of benzoic acid was obtained, due to
autoxidation of unreacted 1. Accordingly, this lower yield is
due to a significantly reduced reactivity of the secondary
amide-derived salt 6 (a similar tendency for sulfur ylides was
reported by Aggarwal et al.4b).
Accordingly, even with only equimolar amounts of base the
disproportionation of the aldehyde limited the yield in all
these homogeneous or liquid/solid experiments (entries 1–8).
Therefore we investigated biphasic conditions in analogy to
those reported by Jonczyk et al.11 Carrying out the reaction in
a 2 : 1 mixture of CH2Cl2 and 50% NaOH (aq) at ambient
temperature (25 1C), full conversion of 1 was observed
within 24 h. The oxirane 3 was obtained in 55% yield with
excellent trans-selectivity (entry 9). Although a big excess of
base (B100 equiv.) was necessary to achieve a reliable
performance, the Cannizzaro reaction was well suppressed
and only negligible amounts of benzyl alcohol could be
detected. However, although all reactions were performed
under inert conditions (Ar-atmosphere), considerable amounts
of benzoic acid were formed presumably by autoxidation of 1.
To overcome this limitation, the relative amount of 1 was
doubled (entry 10). This increased the yield to 67% after a 24 h
reaction time (longer reaction times did not improve the yield
anymore). With 3 equiv. of 1 the yield was 77% (entry 11),
while using an excess of ammonium salt 2, the yield dropped to
50% (entry 12). This clearly underscores that indeed the
decomposition of 1 is the yield-limiting factor. Running the
reaction at elevated temperature (40 1C, with excess 1) resulted
in good conversion after 8 h, giving 3 in 76% (entry 13).
Noteworthy, carrying out the reaction at 40 1C for a longer
Finally, reaction of 2 with other aromatic aldehydes was
investigated (Table 3). All reactions were first carried out
under the standard conditions using 2 equiv. of the aldehyde
(cond. A) to get a clear picture about the influence of the
different substituents on the reactivity (entries 1–3, 5, 7, 9). All
aldehydes reacted to the trans-epoxides exclusively. However,
whereas the similarly activated aldehydes 10 and 12 gave the
glycidic amides 11 and 13 in good yields (entries 2–4), the
conversion of the more electron-rich anisaldehyde 14 was
significantly lower resulting in a reduced yield of 47% after
24 h. As expected, Cannizzaro reaction was no problem in this
case but high amounts of unreacted 14 were found. The even
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2170–2172 2171

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ylides possessing an a-carbonyl group have been successfully
employed in oxirane formation.
Table 3 Reaction of different aromatic aldehydes with 2
This work was supported by the Austrian Science Funds
(FWF) Project No. P22508-N17.
Notes and references
Yieldb transc
Entry Ar
Aldehyde Product Cond.a (%)
(%)
1 (a) E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1962, 84,
867; (b) E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965,
87, 1353; (c) A. W. Johnson and R. B. Lacount, Chem. Ind., 1958,
1440.
2 (a) V. K. Aggarwal, in Comprehensive Asymmetric Catalysis,
ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer,
New York, 1999, vol. 2, p. 679; (b) E. M. McGarrigle,
E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches and
V. K. Aggarwal, Chem. Rev., 2007, 107, 5841.
3 (a) O. Illa, M. Arshad, A. Ros, E. M. McGarrigle and
V. K. Aggarwal, J. Am. Chem. Soc., 2010, 132, 1828;
(b) J. Zanardi, C. Leriverend, D. Aubert, K. Julienne and
P. Metzner, J. Org. Chem., 2001, 66, 5620; (c) M. Davoust,
J.-F. Briere, P.-A. Jaffres and P. Metzner, J. Org. Chem., 2005,
70, 4166.
4 For syntheses of glycidic amides see: (a) Y.-G. Zhou, X.-L. Hou,
L.-X. Dai, L.-J. Xia and M.-H. Tang, J. Chem. Soc., Perkin Trans.
1, 1999, 77; (b) 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, 2105; (c) V. K. Aggarwal, G. Hynd, W. Picoul and J.-L. Vasse,
J. Am. Chem. Soc., 2002, 124, 9964.
5 M. J. Porter and J. Skidmore, Chem. Commun., 2000, 1215.
6 For impressive examples see: (a) T. Nemoto, H. Kakei,
V. Gnanadesikan, S.-Y. Tosaki, T. Ohshima and M. Shibasaki,
J. Am. Chem. Soc., 2002, 124, 14544; (b) S. Matsunaga,
T. Kinoshita, S. Okada, S. Harada and M. Shibasaki, J. Am.
Chem. Soc., 2004, 126, 7559.
7 For two different stereoselective approaches see: (a) S. Arai,
K. Tokumaru and T. Aoyama, Tetrahedron Lett., 2004, 45, 1845;
(b) E. J. Corey and S. Choi, Tetrahedron Lett., 1991, 32, 2857.
8 (a) M. J. Gaunt and C. C. C. Johansson, Chem. Rev., 2007, 107,
5596; (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,
6024; (c) C. D. Papageorgiou, M. A. Cubillo de Dios, S. V. Ley and
M. J. Gaunt, Angew. Chem., Int. Ed., 2004, 43, 4641;
(d) N. Bremeyer, S. C. Smith, S. V. Ley and M. J. Gaunt,
Angew. Chem., Int. Ed., 2004, 43, 2681; (e) C. D. Papageorgiou,
S. V. Ley and M. J. Gaunt, Angew. Chem., Int. Ed., 2003, 42, 828.
9 (a) R. Robiette, M. Conza and V. K. Aggarwal, Org. Biomol.
Chem., 2006, 4, 621; (b) V. K. Aggarwal, J. N. Harvey and
R. Robiette, Angew. Chem., Int. Ed., 2005, 44, 5468.
1
2
3
4
5
6
7
8
9
10
Ph–
1
3
A
A
A
Ad
A
B
A
B
A
C
67
68
72
82
499
499
499
499
499
499
499
4-MeC6H4–
4-ClC6H4–
4-ClC6H4–
4-MeOC6H4– 14
4-MeOC6H4– 14
4-Me2NC6H4– 16
4-Me2NC6H4– 16
4-NO2C6H4– 18
4-NO2C6H4– 18
10
12
12
11
13
13
15
15
17
17
19
19
47
50
o5e
o20e,f 499
o10e,g 499
o10e,g 499
a
A: 0 - 25 1C, 24 h; 100 equiv. NaOH; B: 40 1C, 24 h, 100 equiv.
b
c
NaOH; C: 0 1C, 24 h, 50 equiv. NaOH Isolated yields. Determined
d
e
by 1H NMR of the crude product. 3 equiv. of 12 were used. Judged
by 1H NMR of the crude product. The product decomposed during
f
g
column chromatography. Complete Cannizzaro decomposition of 18.
more electron rich dimethylaminobenzaldehyde 16 showed
only minor conversion, giving just traces of product under
standard conditions. By contrast, the highly electron-deficient
nitrobenzaldehyde 18 was fully consumed within 24 h, but
giving mainly the corresponding Cannizzaro products and less
than 10% of the product 19 even at reduced temperature and
using less base (entries 9 and 10). Reaction of the deactivated
14 at elevated temperature (40 1C, entry 6) resulted in almost
full conversion of 14 after 24 h, giving 15 in 50% accompanied
with unidentified by-products. This can be rationalized by
decomposition of the aldehyde 14 as well as the oxirane 15
under these harsher basic conditions. On the other hand, even
under these conditions, 16 was found to be rather unreactive
yielding less than 20% of 17 (entry 8).
Accordingly, the aptitude of different aldehydes for this type
of reaction strongly depends on their electronic properties.
Whereas similarly activated aldehydes like 1, 10, and 12 give
the glycidic amides in good yields, the electron poor 18 is
prone to rapid Cannizzaro decomposition under the highly
basic conditions. On the other hand, electron rich aldehydes
like 14 and 16 are significantly less reactive.
10 C.-Y. Zhu, X.-M. Deng, X.-L. Sun, J.-C. Zheng and Y. Tang,
Chem. Commun., 2008, 738.
11 For the use of cyano-stabilised ammonium ylides see: (a) A.
Kowalkowska, D. Sucholbiak and A. Jonczyk, Eur. J. Org. Chem.,
2005, 925; (b) A. Jonczyk and A. Konarska, Synlett, 1999, 1085.
12 A. Alex, B. Larmanjat, J. Marrot, F. Couty and O. David,
Chem. Commun., 2007, 2500.
13 For benzylic ammonium ylides see: T. Kimachi, H. Kinoshita,
K. Kusaka, Y. Takeuchi, M. Aoe and M. Ju-ichi, Synlett, 2005,
842.
14 Y. Wang, Z. Chen, A. Mi and W. Hu, Chem. Commun., 2004, 2486.
15 An extensive study about ylide stability has recently been reported:
Y. Fu, H.-J. Wang, S.-S. Chong, Q.-X. Guo and L. Liu, J. Org.
Chem., 2009, 74, 810.
16 Ammonium additives might suppress Cannizzaro reactions:
G. W. Gokel, H. M. Gerdes and N. W. Rebert, Tetrahedron Lett.,
1976, 17, 653.
In conclusion, although ammonium ylides bearing an
a-carbonyl group are less reactive in oxirane synthesis than
sulfur ylides, excellent trans-selectivity and acceptable yields
could be achieved by reacting amide-derived ammonium ylides
with aromatic aldehydes. Key to success is the use of biphasic
conditions together with a two-fold excess of aldehyde. The
reaction is tolerant to different tertiary amide groups whereas
secondary amides are less reactive. Using differently activated
aldehydes, the outcome was strongly dependent on the
electronic properties of the electrophile. Thus, it seems reasonable
that this reaction is very close to the limit of what is possible
with ammonium ylides. Nevertheless, to the best of our
knowledge, this is the first time that stabilised ammonium
17 K. Julienne and P. Metzner, J. Org. Chem., 1998, 63, 4532.
18 Using 2 equiv. of aldehyde represents a good compromise between
required amount of starting materials and obtained yield.
c
2172 Chem. Commun., 2011, 47, 2170–2172
This journal is The Royal Society of Chemistry 2011