Delineation of the factors governing reactivity and selectivity in epoxide formation from ammonium ylides and aldehydes

Article abstract of DOI:10.1039/b516926g

Diastereoselectivity in reactions of aryl-stabilised ammonium ylides are highly sensitive to the nature of the amine and the ylide substituent. DFT calculations are consistent with a mechanism in which reversibility in betaine formation [despite the high energy (and therefore instability) of ammonium ylides] is finely balanced due to the high barrier to ring closure. The Royal Society of Chemistry.

Full text of DOI:10.1039/b516926g

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Delineation of the factors governing reactivity and selectivity in epoxide
formation from ammonium ylides and aldehydes†
Rapha e¨ l Robiette, Matteo Conza and Varinder K. Aggarwal*
Received 29th November 2005, Accepted 10th January 2006
First published as an Advance Article on the web 20th January 2006
DOI: 10.1039/b516926g
Diastereoselectivity in reactions of aryl-stabilised ammonium
ylides are highly sensitive to the nature of the amine and
the ylide substituent. DFT calculations are consistent with
a mechanism in which reversibility in betaine formation [de-
spite the high energy (and therefore instability) of ammonium
ylides] is finely balanced due to the high barrier to ring closure.
benzyltriethylammonium salts with base and benzaldehyde gave
epoxides with moderate to high yields and diastereoselectivities
depending on the electronic nature of the benzyl group.
The results of our studies on the reactions of ylides 1 and 2 with
benzaldehyde are given in Table 1.
Our results show a clear general correlation between the electron
rich/poor character of the ylidic aromatic ring and the observed
yield and diastereoselectivity (Table 1): stabilisation of the ylide
leads to good yields and diastereoselectivities while ylides bearing
an electron-donating group react with generally poorer yields and
much lower selectivities.
The use of DABCO (instead of quinuclidine) as the amino group
did not affect yield, indicating that ring closure is not a significant
problem in the reaction of aryl-stabilized ammonium ylides.
However, it did affect diastereoselectivity: DABCO derivatives
gave a systematically lower trans : cis ratio compared to the
corresponding quinuclidine derivatives.
12
There has been considerable interest in the development of
stereoselective methods to prepare epoxides. While most methods
1
have concentrated on alkene oxidation, we have focused our
efforts on the epoxidation of carbonyl compounds. In this context,
we have reported an efficient catalytic and asymmetric process
converting carbonyl compounds directly into epoxides using sulfur
2
ylides. We asked ourselves whether ammonium ylides could also
3
be used to effect the same transformation. The very few examples
of ammonium ylide reactions with aldehydes also encouraged us
to study this area further.
4
5
The lower yields in the case of substitution by an electron-
donating group can be accounted for by the lower stability of the
Wittig and Sato had shown that non- and phenyl-stabilsed
ammonium ylides react with carbonyl compounds to give b-
9
6
ylides and hence a larger propensity to give side reactions. The
hydroxyammonium salts whilst Jo n´ czyk had found that cyano-
origin of the changes in diastereoselectivity with substitution on
the other hand is less apparent.
In epoxidation reactions of phenyl-stabilised sulfur ylides,
experimental and computational studies showed that the observed
high trans selectivity was the result of a similar rate of formation
stabilised ylides gave the corresponding epoxides. Yields in al-
most all of these cases were only moderate. Only a handful of
examples of the ring closure of b-hydroxyammonium salts to give
7
epoxides has been reported. Thus, it was not clear whether the
dearth of literature examples of ammonium ylide epoxidations
was due to ylide instability (prone to Stevens or Sommelet–
3,8
Hauser rearrangements ) versus reactivity (ammonium ylides are
Table 1 Influence of ylide stabilisation and the nature of ammonium
group on yield and diastereoselectivity
expected to have high nucleophilicity, due to the low stabilisation
9
of the negative charge ) or because of problems in ring closure, or
both.
In considering reactivity toward aldehydes versus stability issues,
we chose aryl-stabilised ammonium ylides and used cyclic amines
derived from six membered rings to minimize the propensity for
Stevens rearrangement since ring expansion to a seven membered
2b
ring should be less favourable.
If ring closure was problematic, we sought to explore this
issue by investigating both quinuclidine and DABCO derivatives
a
b
Entry
Substrate
R
Yield (%)
trans : cis
(
respectively ylides 1 and 2), the latter being a better leaving
10
group. Indeed, we have previously highlighted the importance
of leaving group ability in all of the important reactions of
onium ylides including additions to aldehydes. During the
1
2
3
4
5
6
7
8
9
1a
2a
1b
2b
1c
2c
1d
2d
1e
2e
OMe
OMe
Me
Me
H
H
Cl
Cl
CF
CF
38
41
60
43
41
42
77
71
77
77
61 : 39
50 : 50
65 : 35
56 : 44
92 : 8
70 : 30
96 : 4
92 : 8
99 : 1
99 : 1
11
course of our studies, Kimachi et al. reported that reactions of
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK
BS6 1TS. E-mail: v.aggarwal@bristol.ac.uk; Fax: +44(0)1179298611;
Tel: +44(0)1179546315
3
3
1
0
†
Electronic supplementary information (ESI) available: Experimental
a
b
1
procedures, computational details, and a list of Cartesian coordinates and
total energies for all species. See DOI: 10.1039/b516926g
Isolated yields. Determined by H NMR on the crude mixture.
This journal is © The Royal Society of Chemistry 2006
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of both syn and anti betaines where formation of the syn betaine
was reversible but the anti betaine was non-reversible. In the
ammonium group. A previous study on reactivity in onium ylide
reactions showed indeed that leaving group ability decreased in the
2d
11
present case (ammonium ylides), the much lower stabilisation of
order OMe
2
, SMe
2
, NMe
3
, PMe . Because of the poor leaving
3
9
the ylide would be expected to lead to systematic non-reversibility
group ability of ammonium ions, the elimination step is rate deter-
mining in the reaction of ammonium ylides with aldehydes. This
also accounts for the isolation of b-hydroxyammonium salts upon
of the initial addition step, which would therefore also be the
selectivity determining step. This intuitive reasoning, however,
does not explain the observed trends.
4,5
work-up of the reaction of ammonium ylides with aldehydes.
Another consequence of the high barrier to ring closure is that
This leads to the question: what is the origin of the decrease
in selectivity when using less stabilised ylides or upon changing
the amine from quinuclidine to DABCO derivatives? What are the
factors governing selectivity in ammonium ylide reactions with
aldehydes? In order to answer these questions, we have investigated
the energy profile of the reaction of ylide 3 with benzaldehyde
15
the elimination TS is close in energy to the reactants. Due to the
poor leaving group ability of the ammonium group, and despite
the high energy of the reactants, betaine formation is thus likely to
be somewhat prone to reversibility. This is of great importance in
determining selectivity. Indeed, if no reversal occurs, the selectivity
determining step is the addition step, whereas if betaine formation
is reversible, selectivity is determined by the relative energy of the
two diastereomeric elimination TSs.
13
by computational means (Fig. 1). Calculations were carried
out at the B3LYP/6-31 + G**//B3LYP/6-31G* level of theory
including a continuum description of THF as solvent.‡
The observed influence of ylide stabilisation on selectivity can
thus now be understood (Fig. 2): substitution of the ylide by
an electron-withdrawing group decreases the relative energy of
16
reactants but does not affect, or if anything increases the barrier
to ring closure (see below), thus rendering betaine formation more
reversible. Selectivity is thereby determined at the ring closure step,
which explains the observed high preference for trans epoxides. In
contrast, when the ylide is substituted by an electron-donating
group, relative energy of the reactants increases and the barrier
to ring closure is, if anything, reduced. Selectivity in these cases is
thereby determined at the addition step, which, due to its absence
of enthalpic barrier, must occur with no (or very low) selectivity.
−
1
Fig. 1 Computed‡ potential energy surface (kcal mol ) for stilbene oxide
formation from 3 and benzaldehyde.
The mechanistic sequence is similar to that in sulfur ylide
2d
reactions: addition of the ylide to the aldehyde generates a
betaine intermediate, torsional rotation converts the cisoid betaine
into the transoid conformer with the two charged groups anti to
each other, and finally ring closure, with concomitant expulsion
of the amine, gives the corresponding epoxide.
Fig. 2 Origin of observed variations in diastereoselectivity according to
ylide stabilisation in reactions of ammonium ylides with aldehydes.
The observed decrease in selectivity when using DABCO
derivatives (ylides from 2) instead of quinuclidine (ylides from
1) can be explained following the same reasoning: DABCO is a
9
As a result of the low stabilisation of reactants, the initial
addition step is found to be fairly exothermic. Two isomeric
betaines can be formed during this step, an anti and a syn
diastereomer, with both being found to be equally stable. Due
to the high nucleophilicity of the ylide, betaine formation occurs
10
better leaving group than quinuclidine, which means that the
barrier to ring closure is lower in reactions of ylides 2 relative to
ylides 1. Relative energy of reactants on the other hand should not
be significantly affected by the nature of the ammonium group. The
use of DABCO derived ammonium ylides thus leads to a decrease
in the reversal of betaine formation, and hence to a reduction in
selectivity.
14
without enthalpic barrier (for comparison, the corresponding
−
1
2d
barrier in the case of sulfur ylides was ca. 4.5 kcal mol ). This
means that no (or very low) selectivity is expected for this step; syn
and anti betaines should be formed in a ca. 50 : 50 ratio.
One of the most significant differences between the sulfur ylide
and the ammonium ylide reactions is the high barrier to elimina-
tion, 12.5 and 14.4 kcal mol , from cisoid betaine, for anti and syn
The above analysis has important implications for carbonyl-
stabilised ammonium ylides. Although such ylides have been
−
1
17
18
effective in cyclopropanation reactions, we and others have
been unsuccessful in effecting reactions with aldehydes (Scheme 1).
isomers respectively (for comparison, in the sulfur ylide case these
−
12d
19
barriers are respectively 1.3 and 5.4 kcal mol ). This difference
can be accounted for by the poor leaving group ability of the
Previous studies showed that the presence of a carbonyl group
a to the leaving group (sulfonium) leads to a substantial increase
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6
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3
For reviews on ammonium ylides chemistry, see: (a) J. A. Vanecko, H.
Wan and F. G. West, Tetrahedron, 2006, 62, 1043–1062; (b) J. S. Clark,
Nitrogen, Oxygen and Sulfur Ylide Chemistry: A Practical Approach
in Chemistry, Oxford University Press, Oxford, UK, 2002; (c) I. E.
Mark o´ , Comprehensive Organic Synthesis, vol. 3, ed. B. M. Trost and
I. Fleming, Pergamon Press, Oxford, 1991, p. 913.
4
5
G. Wittig and R. Polster, Justus Liebigs Ann. Chem., 1956, 599, 1–12.
Y. Maeda and Y. Sato, J. Chem. Soc., Perkin Trans. 1, 1997, 12, 1491–
1493.
Scheme 1 Problems with epoxide formation from ester-stabilized ammo-
nium ylides.
6
(a) A. Jo n´ czyk and A. Konorska, SYNLETT, 1999, 7, 1085–1087; (b) A.
Kowalkowska, D. Sucholbiak and A. Jo n´ czyk, Eur. J. Org. Chem., 2005,
1
9, 925–933.
in the barrier to ring closure (the barriers to ring closure, from
7 For the most recent example see: O. Cervinka and V. Struzka, Collect.
Czech. Chem. Commun., 1990, 55, 2685–91.
(a) R. Br u¨ kner, Comprehensive Organic Synthesis, vol. 6, ed. B. M. Trost
and I. Fleming, Pergamon Press, Oxford, 1991, p. 873; (b) Y. Maeda
and Y. Sato, J. Chem. Soc., Perkin Trans. 1, 1997, 12, 1491–1493.
−
1
the anti betaine, for Ph and CONMe are 1.8 and 6.0 kcal mol ,
2
8
respectively). In the case of the sulfonium group, this does not
prevent epoxidation from occurring but the combination of this
with the poor leaving group ability of the ammonium group makes
this barrier too high in this case and no epoxide is formed.
9 Stabilisation of the negative charge in a of the onium group can
be estimated by the pK of the corresponding onium salt. The pK
values (in DMSO) of Me NCH Ph and Me SCH Ph are 31.9 and 17.8,
a
a
3
2
2
2
In conclusion, we have shown that yield and diastereoselectiivity
in reactions of aryl-stabilized ammonium ylides with aldehydes
are strongly influenced by the nature of the amine and the
ylide substituent. Electron-deficient aromatics, which are able to
stabilise the ylide, give good yields whereas electron-rich aromatics,
which destabilise the ylide, give poor yields. Perhaps the most
surprising result from this study is the ease of reversal of betaine
formation, despite the high energy of the ammonium ylide. This
is a consequence of the high barrier to ring closure due to the
poor leaving group ability of the amine. Reversibility in betaine
formation is very finely balanced: groups that stabilise the ylide
and/or increase the barrier to ring closure (electron-deficient aryl
groups) lead to reversibility and high trans selectivity whilst groups
that destabilise the ylide and/or reduce the barrier to ring closure
respectively, showing a much lower stability of the ammonium ylide
compared to its sulfonium analogue. For a discussion of ylide stability,
see (a) J.-P. Cheng, B. Liu, Y. Zhao, Y. Sun, X.-M. Zhang and Y.
Lu, J. Org. Chem., 1999, 64, 604–610; (b) T. Naito, S. Nagase and H.
Yamataka, J. Am. Chem. Soc., 1994, 116, 10080–10088.
0 It has been shown previously that leaving group ability (kinetic
property) correlates with the thermodynamic property of basicity
for leaving groups bonded through the same atom (e.g. for dif-
1
3
ferent R N leaving groups); species with low basicity have high
leaving group ability (see K. P. C. Vollhardt and N. E. Schore,
Organic Chemistry, W. H. Freeman, New York, 1998). DABCO is
a weaker base than quinuclidine (respective pK
a
values in DMSO
table
are 8.9 and 9.8; see D. H. Ripin and D. A. Evans’ pK
a
at http://daecr1.harvard.edu/pdf/evans_pKa_table.pdf) and is thus
expected to have increased leaving group ability as compared to
quinuclidine.
1
1
1 V. K. Aggarwal, J. N. Harvey and R. Robiette, Angew. Chem., Int. Ed.,
2
005, 44, 5468–5471.
(
electron-rich aryl groups, better amine leaving group) lead to
2 T. Kimachi, H. Kinoshita, K. Kusaka, Y. Takeuchi, M. Aoe and M.
reduced reversibility and lower trans selectivity. The failure of
ester-stabilised ylides to form epoxides can be accounted for by
the further increase in barrier to ring closure. Thus, the success
of ammonium ylide epoxidation is critically dependant on ylide
stability vs reactivity toward aldehydes and the barrier to ring
closure.
The authors thank J. N. Harvey for helpful discussions, Merck
and Pfizer for unrestricted grants, EPSRC and Novartis Stiftung
for a grant to M. C.
Ju-ichi, SYNLETT, 2005, 5, 842–844.
13 For related computational studies (on sulfur ylide mediated epoxi-
dations), see ref. 2d and (a) M. A. Silva, B. R. Bellenie and J. M.
Goodman, Org. Lett., 2004, 6, 2559–2562; (b) M. K. Lindvall and
A. M. P. Koskinen, J. Org. Chem., 1999, 64, 4596–4606.
14 A set of constrained geometry optimization at successively smaller
values of the C–C distance was carried out to check that the interaction
between reactants is indeed uniformly attractive.
1
5 The energies reported here are electronic energies, while kinetics depend
on the corresponding free energies, so entropic considerations need to
be taken into account. For addition of the ylide and epoxidation to
occur without reversion to reactants, the elimination TS needs to lie
lower in free energy than the variational TS for cleavage into reactants.
As a rough estimate, the loose, variational cleavage TS may have a
slightly higher entropy (hence more favourable free energy) than the
tighter elimination TS, but this should not make the relative free
energies drastically different to the relative potential energies. The
cleavage TS will have a potential energy very close to, if a bit lower than,
that of the reactants. The small difference in potential energy between
the two TS shown in Fig. 1 will translate into a small difference in their
free energies, so that changes in substitution could quite easily tune the
system either into fully reversible behaviour or completely irreversible
behaviour—as suggested by experimental evidence.
Notes and references
‡
Calculations were carried out as stated for both the geometry opti-
mization and the single point energy calculation using the Jaguar 4.0
pseudospectral program package. This method has been selected to be
the most adequate for the studied system after investigation of the model
20
reaction of CH
see the ESI for full details). Relative energies correspond to electronic
energies at the indicated levels of theory.
2 2 3
O with CH NMe at a variety of different levels of theory
(
1
(a) T. Katsuki, in Comprehensive Asymmetric Catalysis II, ed. E. N.
Jacobsen, A. Pfaltz and H. Yamamoto, Springer-Verlag, Berlin, 1999,
pp. 621–648.
16 It is worth noting, however, that stabilisation of the ylide might lead to
the emergence of a barrier to addition.
17 (a) C. D Papageorgiou, M. A. Cubillo de Dios, S. V. Ley and M. J.
Gaunt, Angew. Chem., Int. Ed., 2004, 43, 4641–4644; (b) N. Bremeyer,
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18 W. Yuanhua, C. Zhiyong, M. Aiqiao; and H. Wenhao, Chem. Commun.,
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2
20 Jaguar 4.0, Schr o¨ dinger, Inc., Portland, OR, 1991–2000.
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 621–623 | 623