The Darzens condensation of α,β-unsaturated aldehydes and ketones

Article abstract of DOI:10.1016/j.tetlet.2011.01.046

The one-pot Darzens condensation of α,β-unsaturated aldehydes and ketones with enolates of an α-bromo ester or ketone is described.

Full text of DOI:10.1016/j.tetlet.2011.01.046

Tetrahedron Letters 52 (2011) 1277–1280
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The Darzens condensation of a,b-unsaturated aldehydes and ketones
⇑
Marie E. Krafft , Steven J. R. Twiddle, John W. Cran
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The one-pot Darzens condensation of
bromo ester or ketone is described.
a
,b-unsaturated aldehydes and ketones with enolates of an
a-
Received 7 December 2010
Revised 6 January 2011
Accepted 10 January 2011
Available online 18 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Darzens reaction
C–C bond formation
Aldol
Epoxy ester
The reaction of
basic conditions to generate
a
-halo esters with aldehydes and ketones under
bases for enolate generation such as LDA,9 LiHMDS10 and KHMDS,9
with pre-formation of the -halo ester enolate generally affording
a,b-epoxy esters was first demon-
a
strated in 1892 by Erlenmeyer.1 However, it was the extensive
study of the reaction by Darzens in the 1900’s that resulted in
the christening of the reaction.2 The procedure is extremely useful
for the preparation of functionalized molecules and as such, the
transformation has found application in a number of syntheses.
The reaction was fundamental to Schwartz’s synthesis of the cal-
cium channel blocker DiltiazemÒ and its analogues,3 while Steel’s
synthesis of Epiasarinin also featured the aforementioned reaction
as a key step.4 More recently research has focused on improved
asymmetric induction5 and expansion of the reaction scope to
encompass aziridine synthesis via the aza-Darzens reaction.6 In
the course of our studies we chose to utilize the Darzens reaction
en route to a synthetic target.
On studying the literature it became evident that a number of
aromatic and aliphatic aldehydes and ketones have been employed
in the reaction, however, the use of unsaturated substrates is lim-
ited. Examples do exist, which involve the use of crotonaldehyde7
and cinamaldehyde,8 however, both are two-step procedures that
pass through the isolated aldol product before further reaction
with base at elevated temperatures to induce epoxide formation.
a more efficient reaction. As a consequence we initially attempted
the reaction with ethyl chloroacetate and ethyl bromoacetate with
enolate generation through low temperature treatment with
LiHMDS10 followed by reaction with crotonaldehyde. The reaction
appeared capricious and depending on the reaction conditions em-
ployed, a range of products was observed (Eq. 1). In addition to the
desired epoxide 6, the aldol products 3 or 4, the condensation
product 5 and starting materials 1 or 2 were all obtained. A number
of reactions
O
O
O
O
X
Cl
OEt
OEt
OEt
i, ii
O
OEt
OH
X
ð1Þ
X=Cl 1
X=Br 2
X=Cl 3
X=Br 4
5
6
i) LiHMDS (1.0 equiv.), THF, -78 oC, 15 min.
ii) Crotonaldehyde (1.0 equiv.), T oC, 2 h.
Herein, we present examples of the successful application of
a,b-
were performed to identify the optimum conditions to achieve the
desired transformation (Table 1). At reduced temperatures (Table 1,
entries 1 and 2) reaction of ethyl chloroacetate resulted, in addition
to the starting ester, in the formation of only the aldol product; no
epoxide formation was observed. This is likely due to the poor leav-
ing group ability of the chloride anion. This was further demon-
strated when carrying out the reaction at 25 °C (Table 1, entry 3)
where the increased temperature favored elimination of the
hydroxyl group to form the condensation product 5 over epoxide
unsaturated substrates in the one-pot Darzens condensation and
provide further evidence regarding the mechanism involved in
these transformations.
In terms of substrate scope both
a-chloro and a-bromo esters
are primarily used. Literature procedures currently employ strong
⇑
Corresponding author.
E-mail address: mek@chem.fsu.edu (M.E. Krafft).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.046

1278
M. E. Krafft et al. / Tetrahedron Letters 52 (2011) 1277–1280
Table 1
Table 2
Optimization of reaction conditions (Eq. (1))
Reaction scope (Eq. 2)
Entry
Ester
T (°C)
Product distributiona
Epoxide 6
Cis:transa
Entry
Electrophile
Epoxide
CO2Et
Yielda (%)
57
Cis:transb
1/2
3/4
5
6
O
1
2
3
4
5
6
1
1
1
2
2
2
ꢀ78
ꢀ25
25
ꢀ78
ꢀ25
25
1
1
1
1
1
1
3.2
8.1
1.9
3.2
0.7
—
—
—
1.1
—
—
—
—
0.3
—
1
—
—
0:100
—
41:59
43:57
O
1
43:57
O
CO2Et
CO2Et
—
2.9
O
2
3
62
60
43:57
45:55
Determined from the 1H NMR spectrum of the crude reaction mixture.
a
formation. The b-elimination of hydroxide to form the enone has
been observed as a side reaction in previous studies, and is partic-
ularly prevalent in the case of chloride as the leaving group.11,12
Although only minimal epoxide formation was observed, complete
selectivity for the thermodynamically more stable trans-isomer was
obtained.
O
O
Et
Et
Reaction of ethyl bromoacetate at ꢀ78 °C (Table 1, entry 4) pro-
vided an identical result to that of the chloride (Table 1, entry 1).
However, the superior leaving group ability of the bromide re-
sulted in epoxide formation at ꢀ25 °C albeit with little selectivity
in geometry (Table 1, entry 5). Increasing the reaction temperature
further to 25 °C (Table 1, entry 6) enhanced epoxide formation but
with no discernible effect on the geometrical ratio. This was judged
to be the optimum temperature as higher temperatures resulted in
a large amount of decomposition. Extension of the reaction times
resulted in the formation of additional by-products affording the
epoxide in reduced quantities but with increased trans selectivity.
This changing ratio is most likely due to the preferential decompo-
sition of the less stable cis-epoxide than selective formation of the
trans-form. Employing more dilute conditions was also found to be
detrimental, leading to a more complex reaction mixture. Finally
we examined the effect of altering the ratio of bromoacetate to cro-
tonaldehyde on the yield. However, neither an excess of bromo-
acetate or crotonaldehyde lead to an improvement in the extent
of conversion to the epoxide. It should also be noted that no
1,4-addition products were observed under any of the reaction
conditions examined.
O
CO2Et
O
4
72
40:60
Bu
O
Bu
CO2Et
CO2Et
CO2Et
O
5
6
58
64
38:62
41:59
O
Et
O
Et
O
O
O
O
O
7
8
69
70
35:65
34:66
CO2Et
O
The optimal reaction conditions (Table 1, entry 6) were applied
to a range of a,b-unsaturated aldehydes and ketones with varying
substitution patterns (Table 2, Eq. 2) to test the generality of the
procedure.13 It was hoped that any observed differences arising
from altering the alkene substituents would provide insight into
the mechanistic intricacies of the transformation.
CO2Et
O
9
63
57
44
50:50
81:19c
50:50
O
O
CO2Et
Et
i, ii
OEt
O
O
OEt
R1
R3
10
11
R2
Br
ð2Þ
2
R4
CO2Et
O
i) LiHMDS (1.0 equiv.), THF, -78 oC, 15 min.
O
o
ii) Electrophile (1.0 equiv.), 25 C, 2 h.
The aldehydes possessed different substituents at the enone b-
position (Table 2, entries 1–4), enone -position (Table 2, entries 5
and 6) and both enone - and b-positions (Table 2, entries 7 and 8).
Ph
Ph
a
a
b
c
Isolated yield after purification by SiO2 column chromatography.
a
Determined from the 1H NMR spectrum of the crude reaction mixture.
Determined by 1H NMR NOE spectroscopy.
In all of these cases the optimized conditions afforded the desired
epoxides in good yields with limited variation. In most cases the
remainder of the mass balance was largely unreacted starting
material. There appears a slight tendency for higher yields with
an increase in the molecular weight of the epoxide, suggesting
product volatility may be the cause. In terms of epoxide geometry
there was surprisingly little selectivity through the variety of
substrates tried, a 2:3 ratio of cis:trans was generally observed.
tries 9–11). The reactions proceeded in a similar fashion to those of
the aldehydes with comparable yields. There was still very little
selectivity between the cis and trans-epoxide isomers except with
an ethyl ketone (entry 10) where a 4:1 ratio favoring the cis isomer
was obtained.
Several a,b-unsaturated ketones were also examined (Table 2, en-

M. E. Krafft et al. / Tetrahedron Letters 52 (2011) 1277–1280
1279
E(O)-enolate
OLi
EtO
Br
RCHO
RCHO
OEt
OEt
R
Li
Li
O
O
O
O
R
Br
Br
O
O
OLi
O
O
OLi
R
O
EtO
R
R
EtO
EtO
R
EtO
H
Br
Br
Cis-epoxide
Trans-epoxide
OEt
OEt
Li
R
O
Li
Br
O
O
Br
O
R
RCHO
RCHO
OLi
Br
EtO
Z(O)-enolate
Scheme 1.
In an attempt to influence the cis/trans selectivity of the reac-
tion through steric effects we performed the reaction with the t-
butyl ester 7 (Eq. 3). However, the t-butyl group appeared to have
little influence over the geometrical product ratio, undoubtedly
owing to its distance from the bond-forming site. Alternatively,
With regard to the mechanism in operation for the reaction,
previous studies on the formation of ,b-epoxy ketones from
-halo ketones invoked a dynamic equilibrium, which favors the
formation of the more thermodynamically stable trans-epox-
ide.13–15 It was shown that the treatment of the isolated aldol
products with base at ambient temperature afforded, in addition
a
a
using
a-bromopinacolone 8 we aimed to bring the steric bulk of
the t-butyl group closer to the reaction site. The reaction proceeded
as expected in a yield that was consistent with those obtained pre-
viously. However, much greater trans selectivity in the epoxide
product 10 (cis:trans, 10:90) was demonstrated thus allowing
exclusive isolation of the trans-isomer.
to the desired epoxide, the a-halo ester and aldehyde retro-aldol
products, and that the anti-aldol diastereoisomer cyclized to afford
the trans-epoxide via an anti-periplanar displacement of the halide.
However, in certain instances the syn-aldol product also generated
the trans-epoxide. Cyclization to generate the cis-epoxide can be
sufficiently hindered that the substrate undergoes the retro-aldol
before reforming the anti-isomer and eliminating to form the
trans-epoxide. Thus, the kinetic resolution process is fundamen-
tally more important than the relative stereochemistry of the ini-
tial aldol process.
Our results suggest that this dynamic equilibrium may be in
operation under the reaction conditions, exemplified by the consis-
tent isolation of starting materials (Tables 1 and 2, Scheme 1).
However, the relatively low selectivity observed for the reaction
of ethyl bromoacetate suggests that the transition state for cycliza-
tion from the anti-aldol product to form the trans-epoxide is not
significantly lower in energy than cyclization from the syn-aldol
O
O
i, ii
R
O
R
Br
ð3Þ
7 R=Ot
9
R=OtBu, 50%, 40:60 cis:trans
Bu
8 R=tBu
10 R=tBu, 56%, 10:90 cis:trans
i) LiHMDS (1.0 equiv.), THF, -78 oC, 15 min.
o
ii) Crotonaldehyde (1.0 equiv.), 25 C, 2 h.

1280
M. E. Krafft et al. / Tetrahedron Letters 52 (2011) 1277–1280
2. Darzens, G. Compt. Rend. 1911, 151, 883.
3. Schwartz, A.; Madan, P. B.; Mohacsi, E.; O’Brien, J. P.; Todaro, L. J.; Coffen, D. L. J.
Org. Chem. 1992, 57, 851.
to form the cis-epoxide. This indicates there is a minimal steric
interaction between the alkoxyl group of the ester and the alkene
substituents as the cis-epoxide is still formed under the reaction
conditions. The presence of the tert-butyl group, in the reaction
4. Aldous, D. J.; Dalencon, A. J.; Steel, P. G. Org. Lett. 2002, 4, 1159.
5. (a) Kinoshita, H.; Ihoriya, A.; Ju-ichi, M.; Kimachi, T. Synlett 2010, 2330; (b) Lui,
W.-J.; Lv, B.-D.; Gong, L.-Z. Angew. Chem., Int. Ed. 2009, 48, 6503; (c) Aggarwal,
V. K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd, G.; Ohara, D.; Picoul,
W.; Robiette, R.; Smith, C.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2006, 128,
2105.
6. (a) Moran-Ramallal, R.; Liz, R.; Gotor, V. J. Org. Chem. 2010, 75, 6614; (b)
Atsushi, T.; Kawashima, N.; Sato, K.; Omote, M.; Ando, A. Tetrahedron Lett. 2010,
51, 4246; (c) Valdez, S. C.; Leighton, J. L. J. Am. Chem. Soc. 2009, 131, 14638; (d)
Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445; For review see: (e)
Sweeney, J. Eur. J. Org. Chem. 2009, 4911.
7. Wang, Y.-C.; Li, C.-L.; Tseng, H.-L.; Chuang, S.-C.; Yan, T.-H. Tetrahedron:
Asymmetry 1999, 10, 3249.
8. Corey, E. J.; Choi, S. Tetrahedron Lett. 1991, 32, 2857.
9. Concellon, J. M.; Huerta, M. Tetrahedron Lett. 2003, 44, 1931.
10. Borch, R. F. Tetrahedron Lett. 1972, 13, 3761.
11. Field, L.; Carlile, C. G. J. Org. Chem. 1961, 26, 3170.
of
a-bromopinacolone, increases this steric interaction resulting
in much greater selectivity for the more thermodynamically stable
trans-epoxide in the halide displacement step. Thus the geometrical
outcome of epoxide formation is strongly influenced by the steric
nature of the enolate partner, substitution on the unsaturated
carbonyl electrophile has minimal impact.
In conclusion we have successfully developed the reaction con-
ditions for the Darzens condensation of a,b-unsaturated aldehyde
and ketone electrophiles, which can be applied to a range of
substrates to afford the desired epoxide in good yields. Where
a-bromo esters were employed, little selectivity for the cis or
trans-epoxide was observed, however, it was possible to bias the
reaction to give predominantly the trans -form when a t-butyl
ketone was employed.
12. Abdel-Magid, A.; Prigden, L. N.; Eggleston, D. S.; Lantos, I. J. Am. Chem. Soc.
1986, 108, 4595.
13. General procedure: A solution of LiHMDS (1.0 equiv, 2 mmol., 2 mL–1.0 M soln
in THF) was cooled to ꢀ78 °C under a positive pressure of argon before the drop
wise addition of ethyl bromoacetate (1.0 equiv, 2 mmol, 0.22 mL). After 15 min
the electrophile (1.0 equiv, 2 mmol) was added drop wise over 5 min and the
reaction allowed to warm to 25 °C where it was stirred for 2 h. The reaction
was quenched through the addition of 10% HCl (0.4 mL) before dilution with
Et2O (5 mL) and washing of the organic phase with 10% HCl (1.6 mL), H2O
(2 mL) and brine (2 mL). Drying (MgSO4) and solvent removal afforded the
crude product as orange oil. Purification was performed by silica column
chromatography (Hexane/EtOAc, 10:1, Rf ꢁ0.4).
Acknowledgments
We are grateful to the MDS Research Foundation and the NSF
for financial support, and Steven E. Frietag for the NOE spectral
data.
14. Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Tetrahedron 1999, 55, 6375.
15. Peppe, C.; das Chagas, R. P. Synlett 2006, 605.
References and notes
1. Erlenmeyer, E. Liebigs Ann. Chem. 1892, 271, 137.