Temperature effects on stereocontrol in the Horner-Wadsworth-Emmons condensation of α-phosphono lactones

Article abstract of DOI:10.1021/jo070722+

(Chemical Equation Presented) The Horner-Wadsworth-Emmons condensation of some α-phosphono lactones has been examined for conditions that impact product stereochemistry. The temperature employed to quench the reaction was found to be a major factor. For example, after the diethyl phosphonate derivative of γ-butyrolactone was treated with potassium hexamethyldisilazane, 18-crown-6, and propionaldehyde at -78°C in THF, an aliquot transferred to a flask at ～30°C gave almost exclusively the Z-olefin product, while one allowed to warm to room temperature over several hours greatly favored the E-olefin.

Full text of DOI:10.1021/jo070722+

lactones (e.g., 2) from lactones (1) via an intermediate enolate
(Scheme 1). In a later study, the R-phosphono lactones were
condensed with propionaldehyde under different standard HWE
protocols, and conditions were reported that favored formation
of either the E- or the Z-alkylidene product (3 or 4).8 While
conditions then reported as Z-selective have been applied in
other systems,9 a recent report also found predominance of the
Z-olefin isomer under what appeared to be the conditions
originally reported to favor the E-isomer.10 In the recent case,
treatment of the R-phosphono lactone 2 with potassium hex-
amethyldisilazane (KHMDS), 18-crown-6, and butyraldehyde
gave predominant formation of the Z-isomer (1:18, E/Z),10 while
reaction of phosphonate 2 with propionaldehyde had been
reported to afford almost exclusively the E-isomer 3.8 This has
prompted us to reexamine the HWE condensations of phos-
phonate 2 and some closely related compounds in more detail.
The results of these studies suggest that it is possible to obtain
either olefin isomer 3 or 4 from this condensation with only
small changes in the reaction conditions.
Temperature Effects on Stereocontrol in the
Horner-Wadsworth-Emmons Condensation of
r-Phosphono Lactones
Jose S. Yu and David F. Wiemer*
Department of Chemistry, UniVersity of Iowa,
Iowa City, Iowa 52242-1294
daVid-wiemer@uiowa.edu
ReceiVed April 6, 2007
SCHEME 1. Prior Syntheses and HWE Condensations of
Phosphonate 26-8
The Horner-Wadsworth-Emmons condensation of some
R-phosphono lactones has been examined for conditions that
impact product stereochemistry. The temperature employed
to quench the reaction was found to be a major factor. For
example, after the diethyl phosphonate derivative of γ-butyro-
lactone was treated with potassium hexamethyldisilazane, 18-
crown-6, and propionaldehyde at -78 °C in THF, an aliquot
transferred to a flask at ∼30 °C gave almost exclusively the
Z-olefin product, while one allowed to warm to room
temperature over several hours greatly favored the E-olefin.
The Horner-Wadsworth-Emmons (HWE) condensation has
become an important method for preparation of R,â-unsaturated
esters.1 In its earliest descriptions,2 this reaction of an R-phos-
phono ester with an aldehyde or ketone was used to obtain the
E-olefin isomer, but several more recent studies have revealed
strategies that can be employed to favor the Z-olefin. The
Z-selective reactions generally have used carefully chosen
phosphonate esters, including trifluoroethyl3 or substituted
phenyl esters,4,5 but the reaction also is known to be sensitive
to the presence of additives that complex with the cation3,5
among other factors.1
1
Because the H NMR spectra of compounds 3 and 4 show
significant differences in the resonance of the vinylic hydrogen11
(δ 6.74 for compound 3 and δ 6.22 for compound 4), at the
outset of these studies it was assumed that in each report the
observed products were due to a minor difference in the
conditions rather than any incorrect assignment. Because
commercial sources of KHMDS provide both toluene and THF
solutions, we first examined whether a difference in solvent
composition might explain the observed results. As shown in
Table 1, in the first trial the R-phosphono lactone 2 in THF at
-78 °C was treated with a room-temperature solution of
KHMDS in toluene, propionaldehyde was added, and the
reaction mixture was forced to warm rather quickly to room
temperature (<1 h). These conditions provided almost exclu-
sively the Z-isomer 4, as determined by analysis of the 1H NMR
Some years ago, we reported the use of electrophilic
phosphorus reagents such as diethyl chlorophosphate6 or diethyl
chlorophosphite followed by oxidation7 to obtain R-phosphono
(1) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
(2) (a) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1958, 91,
61-63. (b) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem.
Ber. 1959, 92, 2499-2505. (c) Wadsworth, W. S., Jr.; Emmons, W. D. J.
Am. Chem. Soc. 1961, 83, 1733-1738.
(3) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(4) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105-4108. (b) Ando, K.
J. Org. Chem. 1997, 62, 1934-1939. (c) Ando, K. J. Org. Chem. 1999,
64, 6815-6821.
(5) (a) Touchard, F. P. Tetrahedron Lett. 2004, 45, 5519-5523. (b)
Touchard, F. P.; Capelle, N.; Mercier, M. AdV. Synth. Catal. 2005, 347,
707-711. (c) Touchard, F. P. Eur. J. Org. Chem. 2005, 1790-1794.
(6) (a) Jackson, J. A.; Hammond, G. B.; Wiemer, D. F. J. Org. Chem.
1989, 54, 4750-4754. (b) Calogeropoulou, T.; Hammond, G. B.; Wiemer,
D. F. J. Org. Chem. 1987, 52, 4185-4190.
(8) Lee, K.; Jackson, J. A.; Wiemer, D. F. J. Org. Chem. 1993, 58, 5967-
5971.
(9) Sudau, A.; Mu¨nch, W.; Bats, J.-W.; Nubbemeyer, U. Eur. J. Org.
Chem. 2002, 3315-3325.
(10) Jung, M. E.; Murakami, M. Org. Lett. 2007, 9, 461-463.
(11) Minami, T.; Niki, I.; Agawa, T. J. Org. Chem. 1974, 39, 3236-
3238.
(7) Lee, K.; Wiemer, D. F. J. Org. Chem. 1991, 56, 5556-5560.
10.1021/jo070722+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/13/2007
J. Org. Chem. 2007, 72, 6263-6265
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TABLE 1. HWE Condensations of Phosphonate 2
time to
reach rt
yield
(%)a
trial
base
18-crown-6
E/Z
1
2
3
4
5
6
KHMDS/toluene
KHMDS/THF
KHMDS/THF (cold)
KHMDS/THF
KHMDS/THF
KHMDS/THF
yes
yes
yes
no
yes
yes
<1 h
1:30
all Z
1:42
1:20
68
61
nd
70
77
58
<1 h
<1 h
<1 h
immediate 1:90
g3 h all E
a nd ) not determined.
SCHEME 2. Temperature Effects on HWE Condensations
of Phosphonates 2, 5, and 8
FIGURE 1. Vinylic resonances in the 1H NMR spectra of the products
from a single reaction of phosphonate 2 and propionaldehyde, divided
and quenched (a) with immediate warming to room temperature (4)
and (b) with gradual warming (3).
mixture gave nearly pure E-olefin 3 (∼70:1, E/Z, Figure 1).
Thus, the reported difference in the stereochemical outcome of
this reaction8,10 probably was due to different interpretations of
the common phrase “allowed to warm to room temperature”.
To test these reaction conditions with other lactones, phos-
phonates 5 and 8 were prepared through the methods described
earlier.6-8 After treatment of phosphonate 5 with 18-crown-6
and KHMDS at -78 °C in THF, propionaldehyde was added
and the reaction mixture was split into two portions. The aliquot
transferred via cannula to a flask at room temperature clearly
favored formation of the Z-olefin 7 (1:50, E/Z), while the portion
allowed to reach room temperature over the course of about 3
h gave only the E-isomer 6. With the six-membered ring
R-phosphono lactone 8, the same pattern was observed. After
phosphonate 8, 18-crown-6, and KHMDS were allowed to react
at -78 °C in THF for 30 min, propionaldehyde was added and
the reaction was split. The portion transferred to a flask at room
temperature showed only the Z-isomer, while the aliquot allowed
to warm slowly to room temperature favored the E-isomer by
a ratio of ∼90:1.
spectrum of the product. When the same conditions of temper-
ature and time were used with addition of a room temperature
solution of KHMDS in THF, only the Z-isomer was observed
(trial 2), and addition of a cold solution of KHMDS in THF
did not affect the outcome significantly (trial 3). When the
original conditions were employed in the absence of 18-crown-
6, once again the Z-isomer predominated (trial 4). Because the
stereochemistry of the HWE condensation is known to result
from a complex set of equilibria,4c the effect of temperature
also was examined. In the most productive of these experiments,
phosphonate 2 was treated with KHMDS and 18-crown-6 in
THF at -78 °C and propionaldehyde was added at that
temperature, but then the reaction vessel was transferred to a
water bath at ∼30 °C to promote more rapid warming. This set
of conditions gave only the Z-product 4 (trial 5). However, when
the reaction mixture was allowed to reach room temperature
very slowly (over more than 3 h), only the E-isomer 3 was
observed (trial 6). These two experiments appeared to indicate
that the speed with which the reaction mixture reached room
temperature was the important variable.
To isolate this variable and verify this conclusion, the reaction
was repeated, and phosphonate 2, KHMDS, and 18-crown-6
were allowed to react at -78 °C in THF for 30 min,
propionaldehyde was added, and then the reaction was split into
two portions (Scheme 2). One aliquot was transferred by cannula
to a flask standing in an ∼30 °C water bath, and this sample
gave nearly pure Z-olefin 4 (1:90, E/Z, Figure 1). The other
half of the same reaction mixture was kept in the -78 °C bath
and the solid dry ice was removed, but the reaction flask was
kept in the cooling bath and allowed to warm to room
temperature over the course of 3 h. This portion of the reaction
A final experiment shed some light on the mechanistic basis
for the observed selectivity. For this experiment, phosphonate
2 was treated with KHMDS, 18-crown-6, and propionaldehyde
at -78 °C (-76 °C by internal thermometer) as described above,
and aliquots were removed at 30, 60, 90, and 120 min and
quickly brought to room temperature. In each case, the Z-olefin
isomer greatly predominated, and even the last aliquot gave an
E/Z ratio of 1:70. By analogy to the equilibria described for
R-phosphono ester condensations,12 this suggests that formation
of an erythro adduct (or cis disubstituted oxaphosphetane) is
favored under the initial reaction conditions and that this species
does not equilibrate appreciably within this time span at this
low temperature. When aliquots are brought to room temperature
quickly, phosphate elimination is rapid, irreversible, and gives
the Z-olefin. In contrast, when the reaction mixture is allowed
to warm to room temperature slowly, equilibration of an erythro
adduct to a threo adduct (or trans disubstituted oxaphosphetane)
and subsequent phosphate elimination would afford the E-olefin
isomer.
(12) Thompson, S. K.; Heathcock, C. H. J. Org. Chem. 1990, 55, 3386-
3388.
6264 J. Org. Chem., Vol. 72, No. 16, 2007

room temperature was added 18-crown-6 (1.58 g, 5.9 mmol). The
reaction mixture was cooled to -78 °C and allowed to stir for an
additional 5 min before KHMDS (1.50 mL, 0.91 M in THF, 1.3
mmol) was added. A pale yellow solution was formed immediately.
After this solution was stirred for 30 min, propionaldehyde (0.11
mL, 1.4 mmol) was added dropwise via syringe over 2 min.
Immediately after addition of the aldehyde, the reaction flask was
placed in an ∼30 °C water bath and allowed to stir for an additional
3 h. After addition of saturated NH4Cl, the reaction mixture was
extracted with ether, and the combined organic layer was washed
with water and brine and then dried (MgSO4). Removal of solvent
in Vacuo gave a mixture of compounds 4 and 3 in a ratio of ∼90:
1. Purification by flash chromatography (silica gel, 25% EtOAc in
hexanes) afforded pure compound 4 (115 mg, 77%). The 1H NMR
data for compound 4 was identical with that previously reported.11
In conclusion, these studies of HWE condensations of
R-phosphono lactones have determined that the specific strategy
employed under the phrase “allowed to warm to room temper-
ature” is a variable that plays a key role in the stereochemical
course of the reaction. Either the Z- or the E-olefin product can
be obtained with high selectivity depending upon whether the
reaction is brought to room temperature quickly or allowed to
warm slowly. This suggests that there may be more flexibility
in controlling the stereochemical outcome of HWE reactions
with lactones than previously recognized and further enhances
the importance of this condensation.13
Experimental Section
(E)-3-Propylidenedihydrofuran-2(3H)-one (3). To a solution
of R-phosphono lactone 2 (285 mg, 1.3 mmol) in THF (30 mL) at
room temperature was added 18-crown-6 (1.70 g, 6.4 mmol). The
reaction mixture was cooled to -78 °C in an acetone/dry ice bath
and allowed to stir for an additional 5 min before KHMDS (1.60
mL, 0.91 M in THF, 1.4 mmol) was added. A pale yellow solution
was formed immediately, and this solution was stirred for 30 min
before propionaldehyde (0.12 mL, 1.5 mmol) was added dropwise
via syringe over 2 min. Immediately after the aldehyde addition,
the remaining solid dry ice was removed from the bath and the
cold acetone was allowed to warm gradually to room temperature
over the course of 3 h. After addition of saturated NH4Cl, the
aqueous layer was extracted with ether, the combined ether extract
was washed with water (50 mL) and brine (50 mL) and then dried
(MgSO4). Removal of solvent under reduced pressure afforded a
yellow oil that was purified via flash chromatography (silica gel,
25% EtOAc in hexanes) to yield pure lactone 3 (92 mg, 58%).
The 1H NMR data for compound 3 was identical with that
previously reported.11
General Procedure for Split Reactions. After preparation of
the reaction as described above, and immediately following addition
of the aldehyde, a portion of the cold reaction mixture was
transferred via cannula to a flask under argon in an ∼30 °C water
bath. This aliquot of the reaction mixture then was allowed to react
for an additional 3 h, while the remainder of the reaction mixture
was allowed to gradually warm to room temperature over 3 h. After
saturated NH4Cl was added to both reaction mixtures, each was
extracted by the same method. Following removal of solvents from
both fractions, the olefin isomer ratio was determined via integration
1
of the H NMR resonance of each vinylic hydrogen.
Acknowledgment. This note is dedicated to the memory of
Prof. Leopold Horner, 1911-2005. We thank Prof. Michael E.
Jung for disclosing the results of his recent work prior to
publication. Financial support from the Roy J. Carver Charitable
Trust is gratefully acknowledged.
(Z)-3-Propylidenedihydrofuran-2(3H)-one (4). To a solution
of R-phosphono lactone 2 (264 mg, 1.2 mmol) in THF (30 mL) at
Supporting Information Available: General experimental
procedures and complete 1H NMR spectra for compounds 3 and 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Wiemer, D. F. Synthesis and Applications of Phosphonates Prepared
Through Electrophilic Phosphorus Reagents. Presented in part in the Horner
Symposium at the 17th International Conference on Phosphorus Chemistry,
Xiamen, PRC, April 19, 2007.
JO070722+
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