Z-selective Horner-Wadsworth-Emmons reaction of ethyl (diarylphosphono)acetates using sodium iodide and DBU

Full text of DOI:10.1021/jo000068x

J . Org. Chem. 2000, 65, 4745-4749
4745
The construction of Z-R,â-unsaturated esters is also a
synthetic problem of great interest.5 Recently, one of us6
reported the preparation of ethyl (diarylphosphono)-
acetates (1) and the HWE reaction of 1 with various types
of aldehydes in the presence of an inexpensive base, NaH
or Triton B in THF. This method provides a simple,
economical, and highly selective route to a wide range of
Z-R,â-unsaturated esters in almost quantitative yields.
Since reagents of type 1 are useful in synthesis,7,8 we
decided to explore milder conditions for the reaction of 1
with functionalized aldehydes.9
Z-Selective Hor n er -Wa d sw or th -Em m on s
Rea ction of Eth yl
(Dia r ylp h osp h on o)a ceta tes Usin g Sod iu m
Iod id e a n d DBU
Kaori Ando*
College of Education, University of the Ryukyus,
Nishihara-cho, Okinawa 903-0213, J apan
Tohru Oishi and Masahiro Hirama
Department of Chemistry, Graduate School of Science,
Tohoku University, Sendai 980-8578, J apan
Hiroaki Ohno and Toshiro Ibuka†
Resu lts
Graduate School of Pharmaceutical Sciences, Kyoto
University, Sakyo-ku, Kyoto 606-8501, J apan
Z-Selective Hor n er -Wa d sw or th -Em m on s Rea c-
tion of Eth yl (Dia r ylp h osp h on o)a ceta te in th e P r es-
en ce of Am in e. The HWE reaction of ethyl (diphe-
nylphosphono)acetate 1a 6d with 2-ethylhexanal in the
presence of amine base was performed in order to
establish the best reaction conditions (Table 1). Following
the Masamune-Roush procedure,2 1a in acetonitrile was
treated with DBU in the presence of LiCl, followed by
the addition of 2-ethylhexanal at 0 °C. The reaction is
complete within 1.5 h, and an 80:20 ratio of Z:E products
2a 6b was obtained in 97% yield (entry 1). In the absence
of LiCl, the reaction proceeds slowly to give a 67:33 ratio
of Z:E in 72% yield, after 15 h at room temperature (entry
2). Since NaH was the best base for the reaction of 1 with
aliphatic aldehydes, sodium salts were expected to give
higher Z-selectivities. When NaBr or NaI was used
instead of LiCl, 86-87% Z-selectivities were obtained
(entries 3 and 4). Lowering the temperature improved
the selectivity (91%, entry 5), but a change of solvent was
warranted as a result of the poor solubility of the salts
at low temperature, and because acetonitrile’s freezing
point (-48 °C) precluded low-temperature reactions.
When the reaction was performed in THF by warming
the mixture from -78 to 0 °C over 1-2 h, use of NaI gave
ando@edu.u-ryukyu.ac.jp
Received J anuary 18, 2000
The Horner-Wadsworth-Emmons (HWE) reaction is
a widely used method for the preparation of R,â-unsatur-
ated esters.1 The phosphonate anions are strongly nu-
cleophilic and react readily with aldehydes to form olefins
and water-soluble phosphate esters. Generally, the HWE
reaction is performed in the presence of a relatively
strong base such as n-butyllithium, potassium tert-
butoxide, or sodium hydride. When the aldehyde is
sensitive to strong bases, i.e., racemization, aldol con-
densation, or decomposition of the aldehyde is prone to
occur, milder conditions are preferable. One and one-half
decades ago, Masamune, Roush, and co-workers reported
that a weak base, either 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) or diisopropylethylamine in acetonitrile, can
be used for the HWE reaction in the presence of lithium
chloride.2,3 Under these conditions, E-R,â-unsaturated
esters were obtained in good yields. Conventional meth-
ods resulted in low yields or varying degrees of racem-
ization in the course of olefination. The Masamune-
Roush method is now widely used in synthesis.4
(5) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-
4408. (b) Breuer, E.; Bannet, D. M. Tetrahedron Lett. 1977, 1141-
1144. Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873-3888. Patois,
C.; Savignac, P. Tetrahedron Lett. 1991, 32, 1317-1320. Kokin, K.;
Motoyoshiya, J .; Hayashi, S.; Aoyama, H. Synth. Commun. 1997, 27,
2387-2392.
(6) (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.
1998, 63, 8411-8416. (d) Ando, K. J . Org. Chem. 1999, 64, 8406-
8408. Now both 1a and 1b are commercially available from Tokyo
Kasei Kogyo Co., Ltd.
† Deceased on J anuary 20, 2000.
(1) Reviews of Horner-Wadsworth-Emmons reaction: Maryanoff,
B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927. Boutagy, J .; Thomas,
R. Chem. Rev. 1974, 74, 87-99. For asymmetric versions of the HWE
reaction, see: Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369-
379.
(2) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai T. Tetrahedron Lett. 1984, 25,
2183-2186.
(3) The similar HWE reactions using LiBr or MgBr2 in the presence
(7) Ishii, K.; Ohno, H.; Takemoto, Y.; Ibuka, T. Synlett 1999, 228-
230. Ishii, K.; Ohno, H.; Takemoto, Y.; Osawa, E.; Yamaoka, Y.; Fujii,
N.; Ibuka, T. J . Chem. Soc., Perkin Trans. 1 1999, 2155-2163.
(8) Padro´n, J . M.; Kokotos, G.; Mart´ın, T.; Markidis, T.; Gibbons,
W. A.; Mart´ın, V. S. Tetrahedron: Asymmetry 1998, 9, 3381-3394.
Monache, G. D.; Misiti, D.; Zappia, G. Tetrahedron: Asymmetry 1999,
10, 2961-2973. Abiko, A.; Masamune, S. Tetrahedron Lett. 1996, 37,
1077-1080. Kreuder, R.; Rein, T.; Reiser, O. Tetrahedron Lett. 1997,
38, 9035-9038. Zhang, T. Y.; O’Toole J . C.; Dunigan, J . M. Tetrahedron
Lett. 1998, 39, 1461-1464.
of triethylaminea or Sn(OSO2CF3) in the presence of N-ethylpip-
2
eridineb were reported. (a) Rathke, M. W.; Nowak, M. J . Org. Chem.
1985, 50, 2624-2626. (b) Sano, S.; Yokoyama, K.; Fukushima, M.; Yagi,
T.; Nagao, Y. J . Chem. Soc., Chem. Commun. 1997, 559-560. Sano,
S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998, 777-779.
(4) Some examples: Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.;
Campos, K. R. J . Am. Chem. Soc. 1999, 121, 6816-6826. Bender, J .
A.; Arif, A. M.; West, F. G. J . Am. Chem. Soc. 1999, 121, 7443-7444.
Evans, D. A.; Barnes, D. M.; J ohnson, J . S.; Lectka, T.; Matt, P. v.;
Miller, S. J .; Murry, J . A.; Norcross, R. D.; Shaughnessy, E. A.; Campos,
K. R. J . Am. Chem. Soc. 1999, 121, 7582-7594. Micalizio, G. C.; Roush,
W. R. Tetrahedron Lett. 1999, 40, 3351-3354. Roush, W. R.; Sciotti,
R. J . J . Am. Chem. Soc. 1994, 116, 6457-6458. Keck, G. E.; Palani,
A.; McHardy, S. F. J . Org. Chem. 1994, 59, 3113-3122. Ley, S. V.;
Norman, J .; Pinel, C. Tetrahedron Lett. 1994, 35, 2095-2098.
(9) 9.Z-Selective HWE reactions of Still’s reagent5a under Masam-
une-Roush condition were reported, but the selectivities were moder-
ate except for one case:9a (a) Ru¨bsam, F.; Evers, A. M.; Michel, C.;
Giannis, A. Tetrahedron 1997, 53, 1707-1714. (b) Hammond, G. B.;
Cox, M. B.; Wiemer, D. F. J . Org. Chem. 1990, 55, 128-132; Rathke,
M. W.; Bouhlel, E. Synth. Commun. 1990, 20, 869-875.
10.1021/jo000068x CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/22/2000

4746 J . Org. Chem., Vol. 65, No. 15, 2000
Notes
Ta ble 1. HWE Rea ction of 1a a n d 2-Eth ylh exa n a l in th e
P r esen ce of DBUa
benzaldehyde at -78 °C, 88% Z-selectivity was obtained
in 100% yield (entry 1). This result is comparable to the
one using NaH (85% Z, 100% yield).6b Since Triton B is
the most practical base and KHMDS/18-crown-6 is the
most effective base for the reaction with benzaldehyde
(and 2E-hexenal),6b the coordination ability of Na+ seemed
to be too strong for the reaction with benzaldehyde. We
therefore decided to use hexamethylphosphoramide
(HMPA) (ca u tion : HMPA is a highly toxic agent) as a
powerful ligand for the metal cation, which was expected
to reduce the coordination of the metal cation to the
reagent 1. We were glad to observe that the reaction gave
93% Z-selectivity in 86% yield, in the presence of HMPA
(2 equiv).11 Furthermore, 3 or 4 equiv of HMPA gave the
same selectivity (entries 3 and 4). In the presence of KI
instead of NaI, the deprotonation of 1a seemed very slow,
but the HWE reaction occurred by the addition of
benzaldehyde at 0 °C to give 67% Z-selectivity in 86%
yield (entry 6). The addition of HMPA (4 equiv) after
deprotonation with LiCl/DBU gave only a trace amount
of the product (entry 7). Since the reaction of 1a with
2-ethylhexanal occurred in the presence of LiCl in THF
(entry 10 in Table 1), HMPA seemed to accelerate
protonation of the phophonate enolate with DBU‚HCl.
Finally, we performed the reaction of 1b using the best
conditions in entry 2. Disappointingly, 1b showed a lower
selectivity than 1a (entry 9). In addition, the observed
selectivity was much lower than that obtained using
Triton B (88% vs 97%). Thus, the reaction with benzal-
dehyde is best performed by using the conditions de-
scribed in entry 2. It is interesting to note that the HWE
reaction of 1a with benzaldehyde using NaH in THF/
HMPA (2 equiv) gave much higher Z-selectivity (93%)
than using NaH in THF (85%)6b (entry 5).
entry
MX
solvent
conditions
% yieldb
Z:E
1
2
3
4
5
6
7
8
9
LiCl
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
THF
THF
THF
0 °C, 1.5 h
rt, 15 h
0 °C, 3 h
97
80:20
67:33
86:14
87:13
91:9
87:13
94:6
83:17
84:16
80:20
72 (13)
85 (6)
97
90 (9)
58 (23)
96
17 (80)
53 (38)
85 (15)
NaBr
NaI
NaI
LiCl
NaI
NaBr
NaBr
LiCl
0 °C, 3 h
-30 °C, 3 h
-40 °C, 3 h
-78 f 0 °C
-78 f 0 °C
0 °C, 3 h
10
-78 f 0 °C
a
1a was treated with DBU (1.1 equiv) in the presence of MX
(1.2 equiv) at 0 °C for 10 min, and then the reaction with aldehyde
b
was performed. The numbers in parentheses are the recovered
yields of 1a (%).
Sch em e 1
Ta ble 2. HWE Rea ction of 1a a n d 1b in th e P r esen ce of
Na I a n d DBU in THF a
entry reagent
RCHO
% yield Z:E
(NaH)6b
1
2
3
4
5
6
1a
1b
1a
1b
1a
1b
BuCHEtCHO
BuCHEtCHO
cyclohexylCHO
cyclohexylCHO
n-C7H15CHO
n-C7H15CHO
96
91
97
92
94
93
94:6 94:6 (100%)
96:4 96:4 (96%)
91:9 91:9 (98%)
95:5 95:5 (100%)
92:8 90:10 (100%)
93:7 94:6 (97%)
a
After 1 was treated with NaI (1.2 equiv) and DBU (1.1 equiv)
in THF at 0 °C for 10 min, the reaction with aldehyde was
performed (-78 to 0 °C).
The reaction with 2E-hexenal was performed analo-
gously. In the absence of HMPA, the Z-selectivity was
81%. Upon adding HMPA (2 eq), the selectivity was 83%
for 1a and 78% for 1b.
an excellent result (94% Z-selectivity in 96% yield, entry
7). On the other hand, both NaBr and LiCl in THF gave
lower yields compared to the reaction in acetonitrile
(entries 8-10). Thus, whereas the original Masamune-
Roush procedure showed a moderate Z-selectivity, the
modified method (NaI/DBU/THF) gives the Z-olefins
highly selectively. The Z:E ratios of all the HWE products
2 were determined by integration of the vinyl proton
Z-Selective Hor n er -Wa d sw or th -Em m on s Rea c-
tion of F u n ction a lized Ald eh yd es Usin g Na I-DBU.
Recently, Ibuka and co-workers reported the reaction of
1a with R-aminoaldehydes 3-5 using NaH in THF
(method B) or LiCl/iPr2EtN/CH3CN (method C).7 In the
present study, we compared those results with the
reaction using NaI/DBU/THF (method A) (Table 4). The
aldehydes 3-5 were prepared by Swern oxidation of the
corresponding R-amino alcohols and used without puri-
fication for the HWE reaction. The yields were calculated
from the starting alcohols. Method A in this study gave
81-94% Z-selectivities in 54-89% yields. On the other
hand, both methods B and C gave much lower Z-
selectivities and lower yields. It is not clear why method
B (NaH) gave low Z-selectivities. The Z-isomers obtained
from the aldehydes 3b and 4b were isolated by column
chromatography, and their optical rotations were mea-
sured. No racemization was detected in these cases. The
results in Table 4 show that the HWE reaction of reagent
1a , using NaI/DBU/THF method, can be applied to the
preparation of various Z-γ-amino-R,â-unsaturated esters
6 without accompanying racemization (Scheme 2).
We further performed the reaction of 1b with alde-
hydes 7 and 8. When we applied the NaI/DBU/THF
1
signals in the 500 MHz H NMR spectra.
Next, we examined the reaction of 1a and 1b10 with
aliphatic aldehydes in THF (Scheme 1). The results are
summarized in Table 2 along with the results using NaH
as a base.6b After the treatment of 1b with DBU and NaI
in THF at 0 °C, followed by the addition of 2-ethylhexanal
at -78 °C, the reaction mixture was allowed to warm to
0 °C over 1-2 h whereupon 96% Z-selectivity was
observed (entry 2). When the same procedure was applied
to the reaction of 1a and 1b with cyclohexanecarboxal-
dehyde, 91% and 95% Z-selectivities were obtained,
respectively. In the reaction with n-octyl aldehyde, 1a
and 1b showed 92% and 93% Z-selectivity, respectively.
These results are comparable with the results obtained
using NaH as a base.6b
The results of the reaction with benzaldehyde and 2E-
hexenal are summarized in Table 3, along with the
results using Triton B.6b When 1a was treated with DBU
and NaI in THF at 0 °C, followed by the reaction with
(10) Following the improved preparation procedure of 1a ,6d the
reagent 1b was prepared via ditolyphosphite in 44% yield. Although
the yield was not higher than the original method,6b the isolation of
the product was easier than the original one.
(11) HMPA was added to the mixture after deprotonation with NaI/
DBU. In the presence of 1 equiv of HMPA, the Z-selectivity of the
reaction was not reproducible. We did the reaction four times and got
89%, 90%, 91%, 93% Z-selectivities in 93-94% yields.

Notes
J . Org. Chem., Vol. 65, No. 15, 2000 4747
Ta ble 3. HWE Rea ction of 1a a n d 1b in th e P r esen ce of DBU in THF a
HMPA
(equiv)
entry
reagent
RCHO
MX
conditions
% yieldb
Z:E
(Triton B)6b
93:7 (98%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1b
1a
1a
1b
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
NaI
NaI
NaI
NaI
NaHc
KI
LiCl
NaI
NaI
NaI
NaI
NaI
-78 °C, 2 h
-78 °C, 2 h
-78 °C, 2 h
-78 °C, 3 h
-78 °C, 2 h
0 °C, 2 h
-78 °C, 2 h
-78 °C, 2 h
-78 °C, 2 h
-78 f 0 °C
-78 f 0 °C
-78 f 0 °C
100
88:12
93:7
93:7
93:7
93:7
67:33
2
3
4
2
86(14)
82(18)
83(17)
87(11)
86(14)
trace
92(7)
86(14)
94
4
2
85:15
88:12
81:19
83:17
78:22
PhCHO
97:3 (100%)
10
11
12
2E-hexenal
2E-hexenal
2E-hexenal
2
2
86(6)
82(13)
89:11 (97%)
93:7 (100%)
a
b
1 was treated with MX (1.2 equiv) and DBU (1.1 equiv) in THF at 0 °C, and then the reaction with aldehyde was performed. The
numbers in parentheses are the recovered yields of 1 (%). c DBU was not used.
Ta ble 4. HWE Rea ction of 1a a n d r-Am in oa ld eh yd es 3-5
Ta ble 5. HWE Rea ction of 1b a n d Ald eh yd es 7-9 in
THF a
in th e P r esen ce of Na I a n d DBU in THF (Meth od A)a
method A
entry RCHO % yield Z:E % yield Z:E % yield Z:E
method B7
method C7
method A
method B
method D
entry RCHO % yield Z:E % yield Z:E % yield
Z:E
1
2
3
4
5
6
3a
3b
4a
4b
4c
5
66
54
82
92:8
81:19
94:6
87:13
82:18
83:17
29
46
29
86
50:50
67:33
50:50
69:31
1
2
3
7
8
9
83
∼10
91
94:6
96:4
83
91
91
92:8
93:7
70:30
59
95
78:22
75:2512
89
a
Method A: 1b (1.0 equiv), NaI (1.2 equiv), DBU (1.1 equiv),
89b
86b
61
61
50:50
46:54
THF. Method B: 1b (1.0 equiv), NaH (1.4 equiv), THF. In both
methods A and B, all reactions were performed by warming the
mixture from -78 to 0 °C over 1-2 h. Method D: (CF3CH2O)2P(O)-
CH2CO2Me (1.5 equiv), KHMDS in toluene (1.4 equiv), 18-crown-6
(5.0 equiv), THF, -78 °C, 30 min.
a
Method A: 1a (1.0 equiv), NaI (1.2 equiv), DBU (1.1 equiv),
THF. Method B: 1a (1.0 equiv), NaH (1.2 equiv), THF. Method
C: 1a (1.0 equiv), i-Pr2NEt (1.0 equiv), LiCl (1.0 equiv), CH3CN-
THF. All reactions were performed by warming the mixture from
-78 to 0 °C over 0.5-3 h. 1a (1.5 equiv), NaI (1.7 equiv), DBU
(1.6 equiv).
b
reaction without purification, the yields of these HWE
reactions are almost quantitative. The reaction of 1b and
8 provided an interesting example, which showed the
limitation of method A (entry 2). When the reaction of
1b and 8 was performed using NaI/DBU/THF (method
A), only a trace amount of the product was obtained.
On the other hand, NaH gave both an excellent Z-
selectivity (93%) and a high yield (91%). These results
can be explained by the predominant formation of the
aminohemiacetal 8′, which cannot react with the anion
derived from 1b. Under the strongly basic conditions
(NaH), 8′ is interchangeable with the aldehyde form 8,
which can react with the anion derived from 1b. To
confirm this explanation, we performed the reaction of
1b with aldehyde 9, which is the N-protected form of 8.
In this case, an excellent result was obtained using NaI/
DBU/THF (96% Z, 91% yield) (entry 3), and only moder-
ate selectivity was obtained using NaH. It is not clear
why the selectivity dropped by using NaH. We would
like to add that the reactions of Still’s reagent (CF3-
CH2O)2P(O)CH2CO2Me with 8 and 912 in the presence of
KHMDS and 18-crown-6 in THF (method D) gave only
moderate Z-selectivities in both cases.
Sch em e 2
Sch em e 3
Discu ssion
As Masamune and Roush suggested, a metal cation
most likely forms a complex with a phosphonate reagent,
as shown in 1′, and thereby enhances the acidity of 1
(Scheme 4). Therefore, 1 can be easily deprotonated using
a much weaker base such as an amine. In this study, we
showed that the combination of NaI and DBU worked
nicely for the Z-selective HWE reaction of 1. The reaction
also occurs in the presence of LiCl, NaBr, or KI. However,
procedure (method A) to the reaction of 1b and 7, 94%
Z-selectivity was obtained in 83% yield (Scheme 3 and
entry 1 in Table 5). The reaction of 1b and 7 using NaH
(method B) gave a slightly less Z-selective result (92%).
Since the aldehydes 7-9 were prepared by Swern oxida-
tion of the corresponding alcohols and used for the HWE
(12) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S. Synlett 1995, 404-
406.

4748 J . Org. Chem., Vol. 65, No. 15, 2000
Notes
Sch em e 4
and/or low Z-selectivities. Furthermore, we have dem-
onstrated one exception in which the aldehyde 8 takes
an aminohemiacetal form 8′ predominantly. In this case,
the conventional NaH procedure gave an excellent result.
Undoubtedly, the above method expands the scope and
utility of the Z-selective HWE reagents 1.
Exp er im en ta l Section
Tetrahydrofuran (THF) was distilled from sodium/benzophe-
none just before use. All reactions were conducted under an
argon atmosphere. All 1H NMR spectra were recorded in CDCl3.
Eth yl (Di-o-tolylp h osp h on o)a ceta te (1b). To a solution of
imidazole (2.084 g, 30 mmol) in CH2Cl2 (20 mL) was added PCl3
(0.88 mL, 10 mmol) and then o-cresol (2.07 mL, 20 mmol) at 0
°C. After stirring for 30 min, H2O (0.18 mL, 10 mmol) was added.
The salt was removed by filtration, and the filtrate was treated
with ethyl bromoacetate (0.935 mL, 8 mmol) and triethylamine
(1.69 mL, 12 mmol) at 0 °C for 10 min. The mixture was stirred
for 1 h at room temperature. The reaction was quenched with
water (20 mL). The usual extraction and column chromatogra-
phy (silica gel 35 g/hexane-AcOEt (8:1 to 5:1)) provided 1b
(1.216 g, yield 44% from ethyl bromoacetate) as a colorless oil.
in those cases, Z-selectivities were just moderate. We
noticed some solvent effects. From the results in Table 1
(especially entries 1, 3, and 8-10), it may be concluded
that the deprotonation of the phosphonate reagent 1 is
easier in CH3CN than in THF. Both LiCl and NaBr are
effective metal salts for this reaction in CH3CN but not
in THF. This can be explained by the donor number of
solvent13 (0.36 for CH3CN, 0.52 for THF, 1.00 for HMPA).
The coordination of metal cation to the phosphonate
reagent is stronger in a weaker donor solvent (CH3CN)
than in a moderately electron-donating solvent (THF).
Thus, the deprotonation occurred in CH3CN effectively,
but the deprotonation in THF using LiCl or NaBr was
incomplete. In a stronger donor solvent (THF/HMPA), the
reaction using NaI or LiCl is accompanied to some extent
by the equilibration between 1 and A. Therefore, some
quantity of 1 was recovered (see Table 3).
HWE Rea ction w ith 2-Eth ylh exa n a l (En tr y 7 in Ta ble
1) (Meth od A). A solution of 1a (0.30 mmol) in THF (3 mL)
was treated with NaI (0.054 g, 0.36 mmol) and DBU (0.51 mL,
0.33 mmol) at 0 °C for 10 min. After the mixture was cooled to
-78 °C, 2-ethylhexanal (0.052 mL, 0.33 mmol) was added. After
10 min, the resulting mixture was warmed to 0 °C over 1.5 h.
The reaction was quenched with saturated NH4Cl, followed by
the usual extraction. After the Z:E ratio of the crude mixture
was determined by 500 MHz 1H NMR, ethyl 4-ethyloctenate6b
was isolated by flash chromatography as a colorless oil. The
reactions in Tables 2, 4, and 5 (method A) were performed in a
similar way.
HWE Rea ction w ith Ben za ld eh yd e (En tr y 2 in Ta ble 3).
A solution of 1a (0.30 mmol) in THF (6 mL) was treated with
NaI (0.054 g, 0.36 mmol) and DBU (0.51 mL, 0.33 mmol) at 0
°C for 10 min followed by HMPA (0.132 mL, 0.76 mmol) for 5
min. After the mixture was cooled to -78 °C, benzaldehyde (0.52
mL, 0.33 mmol) was added. The reaction was quenched 2 h later.
The following reaction procedure was the same as method A.
Eth yl (4S,2Z)-4-[N-(ter t-bu toxyca r bon yl)a m in o]-5-m eth -
yl-2-h exen oa te (en tr y 3 in Ta ble 4): colorless oil; [R]30D +102°
(c 1.18, CHCl3); 1H NMR (270 MHz) δ 0.94 (3H, d, J ) 7.0 Hz),
0.95 (3H, d, J ) 6.5 Hz), 1.30 (3H, t, J ) 7.0 Hz), 1.43 (9H, s),
1.85-2.05 (1H, m), 4.18 (2H, q, J ) 7.0 Hz), 4.80-5.01 (2H, m),
5.84 (1H, d, J ) 11.9 Hz), 6.00-6.12 (1H, m); MS (FAB) m/e
272 ((M + H)+), 228, 216 (base peak), 172, 155, 128, 126, 109,
57; HRMS (FAB) calcd for C14H26NO4 ((M + H)+) 272.1862, found
272.1854. To confirm the selectivity, the E-isomer was separately
prepared as follows.
From both the experimental results1 and ab initio
calculations,14 this HWE reaction most likely occurs
following the mechanism shown in Scheme 4. The phos-
phonate enolate A reacts with an aldehyde to form the
intermediate B, in which the stereochemistry of the
developing double bond is established. This is followed
by oxaphosphetane formation (C), pseudorotation, P-C
bond cleavage, and O-C bond cleavage and finally, the
Z-olefin formation. When benzaldehyde or 2E-hexenal is
used as aldehyde, electron-withdrawing phenyl or vinyl
group reduces the nucleophilicity of oxyanion in B.
Therefore, the reversibility of the initial carbon-carbon
bond-formation step rendered to reduces the Z-selectivity.
HMPA coordinates to the metal cation and reduces the
coordination of the metal cation to the oxyanion in B,
thereby enhancing its reactivity. Thus, better Z-selectivi-
ties were obtained in the presence of HMPA (entry 2-5,
9 and 11 in Table 3).
Eth yl (4S,2E)-4-[N-(ter t-bu toxyca r bon yl)a m in o]-5-m eth -
yl-2-h exen oa te. To a solution of (i-PrO)2P(O)CH2CO2Et (0.55
mmol) in toluene (2 mL) was added n-BuLi in n-hexane (0.359
mL, 0.55 mmol) at 0 °C. After 10 min, the aldehyde 4a (obtained
from the alcohol (0.5 mmol)) in toluene (1 mL) was added at 0
°C, and the resulting mixture was stirred for 1 h at this
temperature. The following procedure was the same as described
in method A. After the Z:E ratio of the crude mixture was
determined by 270 MHz 1H NMR, the product was isolated by
flash chromatography as a colorless oil (83 mg, 61% yield; E:Z
In summary, the HWE reaction of 1 using NaI/DBU/
THF gives good to excellent yields of Z-R,â-unsaturated
esters in high stereoselectivities. The reaction conditions
are mild, and all of the reagents used for this method
are easily available. The method allows the use of base-
labile aldehydes whereas the reaction using the NaH-
THF or other conventional methods resulted in low yields
) 95:5): [R]31 +1.2° (c 0.690, CHCl3); 1H NMR (270 MHz) δ
D
(13) Gutmann, V.; Wychera, E. Inorg. Nucl. Chem. Lett. 1966, 2,
257-260. Gutmann, V. The Donor-Acceptor Approach to Molecular
Interactions; Plenum Press: New York, 1978.
(14) For mechanistic studies of the HWE reaction using ab initio
calculations: Ando, K. J . Org. Chem. 1999, 64, 6815-6821 and
references therein.
0.92 (3H, d, J ) 7.0 Hz), 0.94 (3H, d, J ) 7.0 Hz), 1.29 (3H, t, J
) 7.3 Hz), 1.45 (9H, s), 1.81-1.94 (1H, m), 4.14-4.24 (1H, m),
4.20 (2H, q, J ) 7.3 Hz), 4.55-4.64 (1H, m), 5.92 (1H, dd, J )
15.4, 1.6 Hz), 6.86 (1H, dd, J ) 15.4, 5.4 Hz); MS (FAB) m/e 272
((M + H)+), 216, 172, 128, 126 (base peak), 57; HRMS (FAB)
calcd for C14H26NO4 ((M + H)+) 272.1862, found 272.1863.
(15) Zeng, H. Huaxue Shiji 1995, 17, 47-48.

Notes
Eth yl (4S,2Z)-4,5-(Cycloh exylid en oxy)p en ten oa te15 (En -
J . Org. Chem., Vol. 65, No. 15, 2000 4749
E t h yl (4S,2Z)-7-[N-(ter t-b u t oxyca r b on yl)-N-(b en zoyl)-
a m in o]-4-[(ter t-bu tyld im eth ylsilyl)oxy]h ep ten oa te (en tr y
tr y 1 in Ta ble 5). After the Z:E ratio of the crude mixture was
determined by 500 MHz 1H NMR, the product was isolated by
3 in Ta ble 5): colorless oil; [R]30 -5.5° (c 1.04, CHCl3) for
D
flash chromatography as a colorless oil: [R]27 +85.4° (c 1.03,
method A; [R]30 -5.0° (c 0.82, CHCl3) for method B; H NMR
1
D
D
CHCl3) for method A; [R]27 +84.6° (c 1.05, CHCl3) for method
(200 MHz) δ 0.01 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.14 (9H, s),
1.28 (2H, t, J ) 7.2 Hz), 1.50-1.90 (4H, m), 3.75-3.87 (1H, m),
4.16 (2H, q, J ) 7.2 Hz), 5.26-5.40 (1H, m), 5.69 (1H, dd, J )
11.8, 1.3 Hz), 6.16 (1H, dd, J ) 11.8, 8.1 Hz), 7.31-7.70 (5H,
m); 13C NMR (50 MHz) δ -4.87, -4.58, 14.24, 18.10, 24.66, 25.83,
27.36, 34.82, 45.74, 60.11, 68.52, 82.71, 117.98, 127.35, 127.99,
130.79, 138.20, 153.17, 153.52, 165.77, 173.18; MALDI-TOF MS
m/e calcd for C27H43O6NSiNa ((M + Na)+) 528.2755, found
528.2693. Anal. Calcd for C27H43O6NSi: C, 64.13; H, 8.57; N,
2.77. Found: C, 63.99; H, 8.82; N, 2.71.
D
B; 1H NMR (200 MHz) δ 1.28 (3H, t, J ) 7.1 Hz), 1.34-1.47
(2H, m), 1.51-1.72 (8H, m), 3.61 (1H, dd, J ) 8.3, 6.8 Hz), 4.17
(2H, q, J ) 7.1 Hz), 4.36 (1H, dd, J ) 8.3, 6.8 Hz), 5.50 (1H, dq,
J ) 6.8, 1.7 Hz), 5.83 (1H, dd, J ) 11.7, 1.7 Hz), 6.36 (1H, dd, J
) 11.7, 6.8 Hz); 13C NMR (50 MHz) δ 14.16, 23.81, 25.12, 34.89,
36.20, 60.39, 69.31, 73.14, 110.38, 120.64, 149.54, 165.65; MS
(CI) m/e 240 (M+), 125 (base peak). Anal. Calcd for C13H20O4:
C, 64.98; H, 8.39. Found: C, 64.95; H, 8.10.
Eth yl (4S,2Z)-7-[N-(ter t-bu toxyca r bon yl)a m in o]-4-(ter t-
bu tyld im eth ylsilyl)oxy]h ep ten oa te (en tr y 2 in Ta ble 5):
colorless oil; [R]28 -9.8° (c 0.80, CHCl3) for method B; 1H NMR
D
(200 MHz) δ 0.00 (3H, s), 0.04 (3H, s), 0.87 (9H, s), 1.29 (2H, t,
J ) 7.1 Hz), 1.43 (9H, s), 1.44-1.60 (4H, m), 3.04-3.22 (2H, m),
4.17 (2H, q, J ) 7.1 Hz), 5.24-5.36 (2H, m), 5.70 (1H, dd, J )
11.7, 1.2 Hz), 6.16 (1H, dd, J ) 11.7, 8.0 Hz); 13C NMR (50 MHz)
δ -4.87, -4.55, 14.23, 18.09, 25.53, 25.82, 28.42, 34.40, 40.30,
60.20, 68.41, 117.84, 153.59, 155.96, 165.89; MS (CI) m/e 402
((M + H)+), 244 (base peak). Anal. Calcd for C20H39O5NSi: C,
59.81; H, 9.79; N, 3.49. Found: C, 59.68; H, 9.93; N, 3.38.
Ack n ow led gm en t. K.A. is grateful for the Grant-
in-Aid for Scientific Research (C) from J apan Society
for the Promotion of Science for part of the financial
support. We thank Professor Tohru Fukuyama (Tokyo
University) for suggesting that we do this research.
J O000068X