A highly stereoselective synthesis of (E)-α-bromoacrylates

Article abstract of DOI:10.1016/S0040-4020(00)00811-5

Novel reagent, methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate (5a), was designed and prepared in order to efficiently synthesize (E)-α-bromoacrylates 7, from which widely useful precursors for various C-C bond formations were prepared. Horner-Wadsworth-Emmons (HWE) reaction of various aldehydes with 5a in the presence of t-BuOK and 18-C-6 gave corresponding (E)-α-bromoacrylate derivatives with high stereoselectivity and excellent yield. Using the product (E)-α-bromoacrylate 7s as a key intermediate, we succeeded in developing the most effective route of plaunotol synthesis via Suzuki cross-coupling. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00811-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8825±8831
A Highly Stereoselective Synthesis of (E)-a-Bromoacrylates
*
Keiko Tago and Hiroshi Kogen
Exploratory Chemistry Research Laboratories, Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 24 July 2000; accepted 11 September 2000
AbstractÐNovel reagent, methyl bis(2,2,2-tri¯uoroethoxy)bromophosphonoacetate (5a), was designed and prepared in order to ef®ciently
synthesize (E)-a-bromoacrylates 7, from which widely useful precursors for various C±C bond formations were prepared. Horner±
Wadsworth±Emmons (HWE) reaction of various aldehydes with 5a in the presence of t-BuOK and 18-C-6 gave corresponding (E)-a-
bromoacrylate derivatives with high stereoselectivity and excellent yield. Using the product (E)-a-bromoacrylate 7s as a key intermediate,
we succeeded in developing the most effective route of plaunotol synthesis via Suzuki cross-coupling. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
general method for the synthesis of (E)-a-bromoacrylates
would be a bene®cial synthetic achievement. (E)-a-Fluoro-
acrylates are synthesized stereoselectively by the HWE
reaction of diethoxy¯uorophosphonoacetate with lithium
base,10 but it is apparent that ¯uoroalkenes cannot be used
as precursors for C±C bond formation. Therefore, we
investigated HWE reagents and reaction conditions to
develop a stereoselective synthetic method for (E)-a-
bromoacrylates from which precursors for C±C bond
formation could be readily synthesized.
Many natural products possess various trisubstituted alkene
moieties, and highly stereoselective construction of tri-
substituted alkenes is one of the most challenging problems
in synthetic organic chemistry.1 Although many skillful and
selective synthetic methods for the preparation of this
important functional group have been devised for decades,2
there is still the need for a general and stereoselective
method for the ef®cient synthesis of trisubstituted alkenes.1
We anticipated that trisubstituted bromoalkenes, for
example, a-bromoacrylate derivatives, would provide a
useful method to synthesize various trisubstituted ole®ns
because vinyl bromides are widely used as precursors for
C±C bond formation. Reactions such as Suzuki coupling3 or
Stille coupling,4 are known to proceed with conservation of
ole®n geometry.
While the HWE reaction using diethoxyphosphonoacetate 3
shows a preference for the formation of the more stable,
disubstituted E-ole®ns,5a,11 Still's electrophilic bis(2,2,2-
tri¯uoroethoxy)phosphonoacetate 4 reacts with aldehydes
in the presence of KHMDS and 18-crown-6 ether (18-C-
6) to afford Z-a,b-unsaturated esters selectively.2a,12,13
Wittig and Horner±Wadsworth±Emmons (HWE) reactions,
which provide a direct introduction of C±C double bond
from carbonyl compounds, are powerful and attractive
methods for the construction of various alkenes.5 However,
there are some limitations to the stereoselective construction
of tri-and tetrasubstituted alkenes. It is known that the HWE
reaction with diethoxybromophosphonoacetate 1 and Wittig
reaction with the stabilized ylide 2 give (Z)-a-bromo-
acrylates predominantly (Scheme 1),6,7 and that there are
other general synthetic methods for (Z)-a-bromoacrylates.8
On the other hand, only a few procedures for the synthesis of
(E)-a-bromoacrylates have been reported in the literature9
and these procedures are generally not ef®cient because of
their multiple steps or limitation of substrate. Thus, a
Keywords: ole®nation; synthetic methods; stereocontrol; phosphonic acid
and derivatives.
* Corresponding author. Tel.: 181-3-3492-3131; fax: 181-3-5436-8570;
e-mail: hkogen@shina.sankyo.co.jp
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00811-5

8826
K. Tago, H. Kogen / Tetrahedron 56 (2000) 8825±8831
amount of unreacted dibromide and over-reduced product
6 were removed by ¯ash chromatography (dichloro-
methane/acetoneˆ50:1) using silica gel which was
pretreated with dichloromethane and 4 N HCl in ethyl ace-
tate because normal silica gel column chromatography
caused decomposition of 5a. Finally, the residue was
distilled under reduced pressure (bp 85±878C, 0.4 mmHg)
to give pure 5a (60% yield from 6), and puri®ed 5a was
stable enough to be stored in a freezer (2208C) for over
3 years without decomposition.
Scheme 2. (a) aq. NaOBr, 85%; (b) SnCl2´2H2O (0.96 equiv.), EtOH, H2O,
70%.
Still's reagent 4 is complementary to 3 for the stereoselec-
tivity of the HWE reaction. In view of the above fact, we
designed a novel reagent, bis(2,2,2-tri¯uoroethyl)bromo-
phosphonoacetate 5 anticipating that (E)-a-bromoacrylates
would be synthesized by the HWE reaction (Scheme 1).14
Here, we describe the preparation of a novel reagent 5 and
the E-selective HWE reaction of 5. Also we report the most
effective route to synthesize plaunotol, an antibacterial
agent against Helicobacter pylori, using (E)-a-bromo-
acrylate as a key intermediate.
The HWE reaction with 5a
The results of the HWE reaction between 1a or 5a and
aldehydes using potassium tert-butoxide (t-BuOK) are
summarized in Table 1. Excess amounts of t-BuOK reduced
the yield and stereoselectivity.16 Thus phosphonoacetates
were used slightly in excess of t-BuOK. E/Z ratios of the
product were determined by 1H NMR analysis of the crude
products and the geometry of a-bromoacrylate was deter-
mined by NOE analysis of the allylic alcohols which were
derived from the corresponding esters by DIBAL-H reduc-
tion. As we anticipated, HWE reactions with 5a and various
aldehydes proceeded with high E-selectivity (entries 1, 9,
11, and 15). Stereoselectivity was extremely diminished
when using DMF as solvent (entry 3). The HWE reaction
with 1a and benzaldehyde or cinnamylaldehyde gave (Z)-a-
bromoacrylate predominantly (entries 7, 8, and 10). In
contrast, the same reaction with aliphatic aldehydes
gave (E)-a-bromoacrylate (entries 13 and 16). A similar
tendency of stereoselectivity has been reported by Still.2a
Results and Discussion
Synthesis of novel HWE reagent 5a
The novel reagent 5a was readily prepared from methyl
a
bis(2,2,2-tri¯uoroethyl)phosphonoacetate (6)2a using
similar procedure to that reported by McKenna et al
(Scheme 2).15 Treatment of 6 with freshly prepared sodium
hypobromide afforded the corresponding dibromide, which
was subsequently reduced by one equivalent of SnCl2. The
reagent SnCl2´2H2O which was purchased from Aldrich
Chemical Co. gave the best result for reduction. A small
Table 1. Results of the HWE reaction with 1a or 5a and a range of aldehydes
Entry a
R
Reagent
Additive
Time (h)
Yield (%)b
E:Zc
1
Ph
5a
5a
5a
5a
5a
5a
1ag
1a
5a
1a
5a
5a
1a
1a
5a
1a
18-C-6
none
18-C-6
18-C-6
none
none
18-C-6
none
18-C-6
18-C-6
18-C-6
none
0.3
2
1.5
0.5
8
2.5
94
65
95
95
74
89
93
94
quant.
87
86
36
80
72
64
47
30:1
10:1
2:1
2
3d
4e
31:1
29:1
51:1
1:14
1:6
5e
6f
7
8
9
overnight
overnight
cinnamyl
17
5
2
1.5
5
5
E onlyh
1:2
10i
11j
12j
13i,j
14i,j
15j
16i,j
n-Bu
60:1
2:1
3:1
1:3
76:1
3:1
18-C-6
none
18-C-6
18-C-6
cyclohexyl
6.5
5
a One equiv. of aldehyde, 1.1 equiv. of 1a or 5a, 1.05 equiv. of t-BuOK, and 1.3 equiv. of additive were used.
b Isolated yield.
c Determined by 1H NMR analysis of the products.
d At 08C in DMF.
e KHMDS was used as a base.
f NaHMDS was used as a base.
g For preparation of 1a, see Ref. 14.
h Z-product cannot be detected by 1H NMR analysis.
i At 2408C.
j Aldehyde was distilled before it was used in the reaction.

K. Tago, H. Kogen / Tetrahedron 56 (2000) 8825±8831
8827
obtained by the combined use of t-BuOK and 18-C-6 (entry
6). When using LHMDS as a base, however, higher
temperature (even at rt) was needed to obtain the HWE
reaction with 5a and benzaldehyde, and both yield and
stereoselectivity were extremely decreased (38%, E/Zˆ
2:1).
Scheme 3.
For further evaluation of the applicability of this E-selective
reaction, we examined the HWE reaction using 5a with
various aldehydes (Scheme 3). As shown in Table 2, ole®-
nation of most aromatic aldehydes with 5a in the presence
of t-BuOK and 18-C-6 gave (E)-a-bromoacrylates 7 with
high stereoselectivities and excellent yields. The HWE reac-
tion of some aldehydes resulted in poor stereoselectivities;
the reaction of aromatic aldehydes possessing electron
donating groups were less reactive and stereoselective
(entries 5 and 10). Aromatic aldehydes possessing electron
withdrawing groups were highly reactive while their selec-
tivities were moderate (entries 6 and 7). Since 2,4-
dimethoxybenzaldehyde remained unreactive (entry 11),
we consider that the HWE reaction is very sensitive to
ortho-substitution of benzaldehyde.
Furthermore, stereoselectivity and/or yield of the HWE
reaction with 5a were markedly improved using 1.3 equiv.
of 18-C-6 as an additive (entries 1, 2 and 11, 12). Interest-
ingly, the addition of 18-C-6 reversed the stereoselectivity
as shown in entries 7 and 8, whereas a similar reaction with
benzaldehyde proceeded with high stereoselectivity in the
presence of 18-C-6. The HWE reaction of 5a and benzalde-
hyde using KHMDS as a base gave (E)-2-bromo-3-phenyl-
acrylate with high stereoselectivity, and the addition of 18-
C-6 promoted the reaction (entries 4 and 5). When using
NaHMDS as a base without additive, the yield and stereo-
selectivity of the HWE reaction were comparable to those
Table 2. Results of the HWE reaction with 5a and a range of aromatic
aldehydes
Entrya
R
Time (h)
0.3
Product
Yield (%)b E:Zc
The results of the HWE reaction with 5a and conjugated or
aliphatic aldehydes are shown in Table 3. The correspond-
ing (E)-a-bromoacrylates 7 were obtained from these
aldehydes with high stereoselectivities, though the reaction
of conjugated aldehydes proceeded slowly. However the E/
Z ratios and yields were suf®ciently high (entries 1 and 2).
When using branched aliphatic aldehydes, chemical yields
were comparatively low but high stereoselectivity still
remained (entries 5 and 6).
1
7a
94
94
98
30:1
30:1
28:1
2
3
4
7b
7c
1.5
4
5
7
2
7d
7e
89
83
14:1
10:1
This HWE reagent 5a provides an ef®cient and highly
stereoselective method to synthesize various (E)-a-bromo-
acrylates 7, which are very useful reagent for C±C bond
formation. We developed a general protocol for the stereo-
selective synthesis of trisubstituted alkenes from (E)-a-
bromoacrylates 7 via Pd-catalyzed cross-coupling reactions.14
Table 3. Results of the HWE reaction with 5a and a range of conjugated or
aliphatic aldehydes.
6
7
8
9
1.5
1
7f
7g
7h
7i
97
94
99
97
19:1
9:1
Entrya
R
Time (h) Product Yield (%)b E:Zc
1
17
7l
quant.
E onlyd
0.3
1
30:1
30:1
2e
3
5
3
7m
7n
84
75
15:1
32:1
4f
5f
n±Bu
i±Pr
2
1.5
7o
7p
86
43
60:1
41:1
10d
11d
12
overnight
7j
87
±
7:1
6f
7f
8
6.5
1.5
1
7q
7r
7s
64
96
85
76:1
26:1
overnight no reaction
E onlyd
1.5
7k
98
25:1
a See Scheme 3.
b Isolated yield.
c Determined by 1H NMR analysis of the products.
a See Scheme 3.
b Isolated yield.
d Z-product cannot be detected by H NMR analysis.
1
e At 2208C.
c Determined by H NMR analysis of the products.
1
f Aldehyde was distilled before it was used in the reaction.
d From 278 to 08C.

8828
K. Tago, H. Kogen / Tetrahedron 56 (2000) 8825±8831
prepared. (E)-a-Bromoacrylates 7 were synthesized stereo-
selectively and ef®ciently from 5a with various aldehydes in
the presence of t-BuOK and 18-C-6. Using the product 7s as
a key intermediate, we succeeded in developing the shortest
route for the synthesis of plaunotol (13) via Pd-catalyzed
cross-coupling.
Experimental
General methods
Unless otherwise noted, all reactions were carried out in
oven-dried glassware under a nitrogen atmosphere. Tetra-
hydrofuran (THF) was distilled from sodium metal/benzo-
phenone ketyl. Dichloromethane (CH2Cl2) was distilled
from calcium hydride. All other dry solvents were
purchased from Aldrich in SureSeale containers. All
other commercially obtained reagents were used as
1
supplied. H NMR and 13C NMR spectra were recorded
on a Varian 400 spectrometer. The following abbreviations
were used to explain the multiplicities: sˆsinglet, dˆdoublet,
tˆtriplet, qˆquartet, mˆmultiplet, brˆbroad. Infrared
spectra were recorded on a JASCO FT-IR-8900 spectro-
meter. Mass spectra were obtained on a JEOL HX-100, an
SX-102A or a JMS-AX-505H mass spectrometer. Analytical
TLC was performed on 0.25 mm pre-coated Merck silica gel
60 F254 plates. Flash column chromatography was performed
on Merck silica gel 60 (230±400 mesh).
Scheme 4. (a) MnO2, CH2Cl2, 79%; (b) MePPh3Br, n-BuLi, THF, 90%; (c)
Ac2O, Py, ether, 85%; (d) m-CPBA, CH2Cl2, 81%; (e) HIO4´H2O, THF±
H2O, 76%; (f) 5a, t-BuOK, 18-C-6, THF, 94%; (g) DIBAL-H, CH2Cl2,
57%; (h) 10, 9-BBN, THF, rt, then 12, PdCl2(dppf), Ph3As, Cs2CO3,
DMF, 508C, 77%.
Total synthesis of plaunotol via the HWE reaction
Using this (E)-a-bromoacrylate 7s as a key intermediate, we
investigated the most effective route to synthesize plaunotol
(13), the most important component of the Thai folk
medicine-Plau-noi.17 Plaunotol has antibacterial activity
against Helicobacter pylori,18 which is a causative agent
of, for example, gastric ulcer and gastric adenocarcinoma.
Several groups have achieved the total synthesis of plauno-
tol19 and previously, we have also developed a practical
total synthesis of plaunotol via Z-selective Wittig reaction
of a-acetal ketone.20 Construction of the C7±C8 trisubsti-
tuted allylic alcohol is the principal problem in the total
synthesis of plaunotol. Therefore, we applied our protocol
for constructing trisubustituted alkenes via (E)-a-bromo-
acrylates to the synthesis of plaunotol.
Methyl bis(tri¯uoroethyl)bromophosphonoacetate 5a
A solution of sodium hydroxide (40.0 g, 1.0 mol) in H2O
(120 ml) was cooled to 08C in an ice salt bath, and bromine
(25.5 ml, 0.50 mol) was slowly added while stirring for over
30 min such that the temperature of the mixture did not
exceed 108C. Methyl bis(2,2,2-tri¯uoroethyl)phosphono-
acetate (6) (50.0 g, 0.13 mol) was added to the solution
for 5 min, and to the resulting mixture was added H2O
(200 ml). Then, the mixture was extracted with chloroform
(CHCl3) (200 ml£1, 100 ml£2). The combined organic
extracts were washed with H2O (100 ml£4), dried over
MgSO4, and concentrated in vacuo after ®ltration. The
product was distilled under reduced pressure (bp 100±
1028C, 1 mmHg) to obtain methyl bis(2,2,2-tri¯uoroethyl)-
dibromophosphonoacetate (41.8 g, 85% yield) as a colorless
oil. This dibromide (21.3 g, 44.2 mmol) was dissolved in
EtOH (40 ml), and the solution was cooled to 2308C. A
solution of SnCl2´2H2O (12.9 g, 56.0 mmol) in H2O
(100 ml) was added to the reaction mixture for 40 min
such that the temperature did not exceed 2258C. After the
addition was completed, the reaction mixture was extracted
with CHCl3 (200 ml£1, 100 ml£1, 50 ml£2). The combined
extracts were washed with H2O (100 ml£4), dried over
MgSO4, and concentrated in vacuo after ®ltration. In order
to remove dibromide and 6, the residue was puri®ed by ¯ash
column chromatography. The column was packed with
silica gel (290 g) using a mixture of CH2Cl2 (750 ml) and
4 N HCl in ethyl acetate (30 ml). After rinsing the column
with the solvent (CH2Cl2:acetoneˆ50:1, 500 ml), the crude
product was applied and eluted (one fraction; 65 ml).
Combined fractions (from No. 7 to 20), which contained
only 5a, were concentrated in vacuo. The residue was
The new synthetic route of plaunotol (13) using 7s is
summarized in Scheme 4. Compound 10 and aldehyde 11
were readily prepared from commercially available geraniol
(8).20b,21 The HWE reaction with 5a and 11 gave 7s with
high stereoselectivity, and 7s was reduced by DIBAL-H to
yield diol 12, a precursor of Pd-catalyzed C±C bond forma-
tion. Finally the synthesis of plaunotol (13) was achieved
via Suzuki coupling of 10 and vinyl bromide 12. The spec-
troscopic data of synthetic product 13 (1H NMR and 13C
NMR) were identical with those of the authentic sample.
It is notable that the Suzuki coupling proceeded without
protecting the hydroxyl groups, making this the shortest
route for the total synthesis of plaunotol (13), completed
in only 6 steps from geraniol (8).
Conclusions
In conclusion, a novel HWE reagent 5a was designed and

K. Tago, H. Kogen / Tetrahedron 56 (2000) 8825±8831
8829
dissolved in CHCl3 (300 ml) and washed with H2O
(50 ml£4), dried over MgSO4, and concentrated in vacuo
after ®ltration. The residue was distilled under reduced
pressure (bp 85±878C, 0.4 mmHg) to obtain 5a (12.2 g,
70% yield) as a colorless oil: IR (®lm) nmax 3029, 2966,
1745, 1455, 1440, 1421, 1375, 1301, 1268, 1175, 1102,
1072, 1012, 964, 903, 886, 846, 808, 726, 659, 556, 535,
478, 448 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 3.87 (s,
3H), 4.45±4.60 (m, 5H); HRMS (FAB) calcd for
C7H9O5BrF6P (M1H)1 396.9275, obsd 396.9271; Anal.
Calcd for C7H8O5BrF6P: C, 21.18; H, 2.03. Found: C,
20.87; H, 2.14.
1074, 1025, 964, 904, 853, 804 cm21
;
1H NMR
(400 MHz, CDCl3) d 3.79 (3H, s), 3.86 (3H, s), 3.90 (3H,
s), 6.82 (1H, d, Jˆ8.2 Hz), 6.91 (1H, dd, Jˆ8.2, 2.0 Hz),
6.95 (1H, d, Jˆ2.0 Hz), 7.30 (1H, s); 13C NMR (100 MHz,
CDCl3) d 53.0, 55.85, 55.89, 108.8, 110.8, 111.3, 122.2,
127.4, 140.2, 148.7, 150.0, 165.1; HRMS (EI) calcd for
C12H13O4Br (M)1 299.9997, obsd 300.0004.
(E)-2-Bromo-3-(3,4,5-trimethoxyphenyl)acrylic
acid
methyl ester (7e). IR (CHCl3 soln.) nmax 2954, 2940,
2841, 1727, 1582, 1505, 1464, 1435, 1418, 1350, 1330,
1298, 1250, 1212, 1185, 1152, 1130, 1075, 1041, 1014,
1001, 978, 905, 837, 809 cm21 1H NMR (400 MHz,
;
CDCl3) d 3.79 (3H, s), 3.84 (6H, s), 3.86 (3H, s), 6.57
(2H, s), 7.27 (1H, s); 13C NMR (100 MHz, CDCl3) d 53.1,
56.1, 60.1, 105.8, 110.1, 130.0, 139.5, 152.9, 153.1, 165.1;
HRMS (EI) calcd for C13H15O5Br (M)1 330.0103, obsd
330.0102.
General procedure for HWE reaction
A solution of 1a or 5a (1.1 mmol) and 18-C-6/CH3CN
(397 mg, 1.3 mmol) in THF (8 ml) was cooled to 2788C.
Then 1.0 M of potassium tert-butoxide solution in THF
(1.05 ml, 1.05 mmol) was added to the solution. After
stirring for 30 min at 2788C, aldehyde (1.0 mmol) was
added to the reaction mixture and the stirring was continued.
When the reaction was completed, saturated aqueous NH4Cl
was added to the solution and the organic material was
extracted with AcOEt. The combined organic extracts
were washed with H2O and brine, dried over Na2SO4, and
concentrated in vacuo after ®ltration. The residue was
puri®ed by silica gel ¯ash chromatography to afford methyl
a-bromoacrylate.
(E)-2-Bromo-3-(4-nitrophenyl)acrylic acid methyl ester
(7f). Mp 80±818C; IR (CHCl3 soln.) nmax 2955, 1731, 1600,
1525, 1493, 1437, 1348, 1293, 1243, 1184, 1112, 1016,
1
1003, 882, 861, 850 cm21; H NMR (400 MHz, CDCl3) d
3.78 (3H, s), 7.44 (1H, s), 7.45 (2H, d, Jˆ8.7 Hz), 8.21 (2H,
d, Jˆ8.7 Hz); 13C NMR (100 MHz, CDCl3) d 53.3, 115.2,
123.7, 128.9, 138.2, 141.1, 147.6, 163.9; HRMS (FAB)
calcd for C10H8O4NBrK (M1K)1 323.9274, obsd
323.9272; Anal. Calcd for C10H8O4NBr: C, 41.99; H,
2.82; N, 4.90. Found: C, 41.90; H, 2.96; N, 4.71.
(E)-2-Bromo-3-phenylacrylic acid methyl ester (7a). IR
(CHCl3 soln.) nmax 2954, 1728, 1611, 1576, 1496, 1447,
1435, 1346, 1316, 1289, 1244, 1210, 1183, 1077, 1031,
(E)-2-Bromo-3-(3-nitrophenyl)acrylic acid methyl ester
(7g). Mp 79±808C; IR (CHCl3 soln.) nmax 3089, 2955, 1731,
1611, 1578, 1534, 1480, 1437, 1355, 1311, 1295, 1282,
1243, 1224, 1185, 1101, 1082, 1008, 907, 889, 869,
1018, 1007, 928, 902, 878, 831 cm21
;
1H NMR
(400 MHz, CDCl3) d 3.76 (3H, s), 7.26±7.38 (6H, m); 13C
NMR (100 MHz, CDCl3) d 53.0, 111.1, 128.1, 128.5, 129.0,
134.8, 140.1, 164.8; HRMS (EI) calcd for C10H9O2Br (M)1
239.9786, obsd 239.9788.
1
824 cm21; H NMR (400 MHz, CDCl3) d 3.80 (3H, s),
7.44 (1H, s), 7.54 (1H, t, Jˆ7.8 Hz), 7.61 (1H, d, Jˆ
7.8 Hz), 8.19±8.22 (2H, m); 13C NMR (100 MHz, CDCl3)
d 53.3, 114.6, 123.1, 123.6, 129.4, 134.0, 136.3, 138.1,
163.8, 170.3; HRMS (EI) calcd for C10H8O4NBr (M)1
284.9637, obsd 284.9639; Anal. Calcd for C10H8O4NBrz1/
3 H2O: C, 41.12; H, 2.99; N, 4.80. Found: C, 40.84; H, 2.72;
N, 4.60.
(E)-2-Bromo-3-(4-methoxyphenyl)acrylic acid methyl
ester (7b). IR (CHCl3 soln.) nmax 2954, 2937, 2911, 2841,
1724, 1605, 1575, 1511, 1464, 1437, 1422, 1349, 1300,
1257, 1223, 1206, 1176, 1115, 1033, 1004, 941, 908, 887,
831 cm21; 1H NMR (400 MHz, CDCl3) d 3.79 (3H, s), 3.82
(3H, s), 6.81 (2H, d, Jˆ9.5 Hz), 7.28 (2H, d, Jˆ9.5 Hz),
7.32 (1H, s); 13C NMR (100 MHz, CDCl3) d 53.0, 55.3,
108.7, 113.9, 127.2, 130.2, 132.5, 140.4, 160.3; HRMS
(EI) calcd for C11H11O3Br (M)1 269.9892, obsd 269.9892.
(E)-2-Bromo-3-(4-chlorophenyl)acrylic acid methyl
ester (7h). Mp 43±458C; IR (CHCl3 soln.) nmax 2954,
1728, 1611, 1592, 1496, 1448, 1436, 1404, 1343, 1304,
1275, 1244, 1216, 1183, 1099, 1015, 1005, 909, 883, 839,
824 cm21; 1H NMR (400 MHz, CDCl3) d 3.77 (3H, s), 7.23
(2H, dt, Jˆ8.8, 2.0 Hz), 7.32 (2H, dt, Jˆ8.8, 2.0 Hz), 7.33
(1H, s); 13C NMR (100 MHz, CDCl3) d 53.1, 111.8, 128.7,
129.5, 131.5, 133.1, 135.0, 164.5; HRMS (EI) calcd for
C10H8O2BrCl (M)1 273.9396, obsd 273.9402; Anal. Calcd
for C10H8O2BrCl: C, 43.59; H, 2.93. Found: C, 43.68; H, 2.89.
(E)-2-Bromo-3-(3-methoxyphenyl)acrylic acid methyl
ester (7c). IR (CHCl3 soln.) nmax 2954, 2914, 2839, 1729,
1600, 1579, 1489, 1466, 1456, 1435, 1341, 1292, 1261,
1216, 1184, 1151, 1142, 1087, 1051, 1042, 1019, 1009,
;
956, 937, 928, 906, 878, 825, 809 cm21 1H NMR
(400 MHz, CDCl3) d 3.77 (3H, s), 3.79 (3H, s), 6.80±6.89
(3H, m), 7.23±7.27 (1H, m), 7.32 (1H, s); 13C NMR
(100 MHz, CDCl3) d 53.0, 55.2, 111.2, 113.3, 114.8,
120.6, 129.5, 135.9, 139.5, 159.5, 164.9; HRMS (EI)
calcd for C11H11O3Br (M)1 269.9892, obsd 269.9989.
(E)-2-Bromo-3-(3-chlorophenyl)acrylic acid methyl
ester (7i). IR (CHCl3 soln.) nmax 2954, 1729, 1614, 1595,
1567, 1475, 1453, 1436, 1411, 1338, 1269, 1244, 1220,
1184, 1098, 1082, 1019, 1007, 925, 893, 872, 826,
1
809 cm21; H NMR (400 MHz, CDCl3) d 3.77 (3H, s),
7.15 (1H, d, Jˆ7.3 Hz), 7.25±7.33 (4H, m); 13C NMR
(100 MHz, CDCl3) d 53.3, 114.6, 123.1, 123.6, 129.4,
134.0, 136.3, 138.1, 163.8, 170.3; HRMS (EI) calcd for
C10H8O2BrCl (M)1 273.9396, obsd 273.9396.
(E)-2-Bromo-3-(3,4-dimethoxyphenyl)acrylic acid methyl
ester (7d). IR (CHCl3 soln.) nmax 4214, 2957, 2939, 2913,
2841, 1726, 1601, 1583, 1514, 1465, 1440, 1422, 1349,
1322, 1271, 1231, 1221, 1209, 1181, 1160, 1145, 1109,

8830
K. Tago, H. Kogen / Tetrahedron 56 (2000) 8825±8831
1
(E)-2-Bromo-3-(4-dimethylaminophenyl)acrylic
acid
1189, 1134, 1035, 1007, 990, 943, 878, 814, 803 cm21; H
methyl ester (7j). Mp 58±608C; IR (CHCl3 soln.)nmax
4214, 2953, 2902, 2865, 2812, 1717, 1609, 1591, 1524,
1483, 1445, 1437, 1414, 1367, 1324, 1305, 1273, 1250,
1223, 1212, 1183, 1167, 1145, 1131, 1065, 1045, 1021,
NMR (400 MHz, CDCl3) d 0.91 (3H, t, Jˆ7.3 Hz), 1.31±
1.48 (4H, m), 2.51 (2H, q, Jˆ7.6 Hz), 3.82 (3H, s), 6.69
(1H, t, Jˆ7.6 Hz); 13C NMR (100 MHz, CDCl3) d 13.8,
22.3, 30.9, 31.2, 52.8, 110.4, 149.5, 163.4; HRMS (EI)
calcd for C8H13O2Br (M)1 220.0099, obsd 220.0101.
1003, 947, 908, 819, 808 cm21 1H NMR (400 MHz,
;
CDCl3) d 2.99 (6H, s), 3.81 (3H, s), 6.62 (2H, d, Jˆ
8.8 Hz), 7.29 (1H, s), 7.30 (2H, d, Jˆ8.8 Hz); 13C NMR
(100 MHz, CDCl3) d 40.1, 52.8, 105.4, 111.4, 122.2,
130.7, 142.1, 150.9, 165.3; HRMS (EI) calcd for
C12H14O2NBr (M)1 283.0208, obsd 283.0216; Anal. Calcd
for C12H14O2NBrz1/4 H2O: C, 19.93; H, 5.02; N, 4.85.
Found: C, 49.71; H, 4.68; N, 4.78.
(E)-2-Bromo-4-methylpent-2-enoic acid methyl ester
(7p). IR (CHCl3 soln.) nmax 2971, 2956, 2933, 2906, 2872,
1718, 1614, 1467, 1447, 1437, 1354, 1311, 1297, 1245,
1
1169, 1147, 1100, 1010, 944, 931, 895, 837, 811 cm21; H
NMR (400 MHz, CDCl3) d 1.05 (6H, d, Jˆ6.6 Hz), 3.25
(1H, m), 3.82 (3H, s), 6.48 (1H, d, Jˆ10.2 Hz); 13C NMR
(100 MHz, CDCl3) d 22.1, 30.9, 52.8, 108.9, 155.1, 163.4;
HRMS (EI) calcd for C7H11O2Br (M)1 205.9942, obsd
205.9945.
(E)-2-Bromo-3-furan-2-ylacrylic acid methyl ester (7k).
IR (CHCl3 soln.) nmax 2954, 2846, 1726, 1595, 1556, 1474,
1457, 1437, 1390, 1349, 1251, 1211, 1183, 1153, 1145,
1
1093, 1022, 962, 931, 921, 907, 886, 829, 810 cm21; H
(E)-2-Bromo-3-cyclohexylacrylic acid methyl ester (7q).
IR (CHCl3 soln.) nmax 2932, 2854, 1717, 1610, 1449, 1437,
1363, 1346, 1291, 1267, 1247, 1207, 1187, 1146, 1096,
NMR (400 MHz, CDCl3) d 3.88 (3H, s), 6.47 (1H, dd,
Jˆ1.9, 3.5 Hz), 7.09 (1H, d, Jˆ3.5 Hz), 7.23 (1H, s), 7.47
(1H, d, Jˆ1.9 Hz); 13C NMR (100 MHz, CDCl3) d 53.0,
107.0, 112.4, 115.4, 129.4, 144.3, 149.3, 164.1; HRMS
(EI) calcd for C8H7O3Br (M)1 229.9579, obsd 229.9578.
1
1005, 964, 932, 903, 879, 811 cm21; H NMR (400 MHz,
CDCl3) d 1.07±1.37 (5H, m), 1.63±1.77 (5H, m), 2.91±3.01
(1H, m), 3.82 (3H, s), 6.50 (1H, d, Jˆ10.0 Hz); 13C NMR
(100 MHz, CDCl3) d 25.4, 25.7, 32.1, 40.4, 52.8, 109.1,
154.0, 163.4; HRMS (EI) calcd for C10H15O2Br (M)1
246.0255, obsd 246.0249.
(E, E)-2-Bromo-5-phenylpenta-2,4-dienoic acid methyl
ester (7l). IR (CHCl3 soln.) nmax 3083, 2954, 2846, 1713,
1613, 1579, 1568, 1490, 1448, 1436, 1357, 1329, 1316,
1302, 1268, 1246, 1222, 1206, 1189, 1181, 1160, 1146,
1110, 1172, 1045, 1030, 1016, 1000, 986, 975, 938, 910,
(E)-4-Benzyloxy-2-bromobut-2-enoic acid methyl ester
(7r). IR (CHCl3 soln.) nmax 3086, 2954, 2888, 2862, 1715,
1621, 1498, 1454, 1438, 1351, 1317, 1246, 1221, 1211,
1194, 1091, 1029, 987, 909, 879, 830, 811 cm21; 1H NMR
(400 MHz, CDCl3) d 3.80 (3H, s), 4.47 (2H, d, Jˆ5.1 Hz),
4.54 (2H, s), 6.91 (1H, t, Jˆ5.1 Hz), 7.29±7.38 (5H, m); 13C
NMR (100 MHz, CDCl3) d 53.1, 69.2, 72.9, 110.5, 127.8,
127.9, 128.5, 137.5, 148.0, 163.0; HRMS (EI) calcd for
C12H14O3Br (M1H)1 287.0106, obsd 287.0095.
1
882, 852, 810 cm21; H NMR (400 MHz, CDCl3) d 3.88
(3H, s), 6.83 (1H, d, Jˆ15.6 Hz), 7.31 (1H, d, Jˆ
11.5 Hz), 7.32±7.37 (3H, m), 7.50±7.52 (2H, m), 7.81
(1H, dd, Jˆ11.5, 15.6 Hz); 13C NMR (100 MHz, CDCl3)
d 53.0, 110.3, 124.9, 127.6, 128.8, 128.9, 129.4, 136.0,
141.7, 146.5, 163.3; HRMS (EI) calcd for C12H11O2Br
(M)1 265.9942, obsd 265.9933.
(E, E)-2-Bromo-5,9-dimethyldeca-2,4,8-trienoic acid
methyl ester (7m). IR (CHCl3 soln.) nmax 2970, 2953,
2930, 2917, 2857, 1708, 1618, 1565, 1436, 1371, 1320,
1246, 1216, 1206, 1185, 1137, 1107, 1043, 1102, 941,
(E, E)-8-Acetoxy-2-bromo-6-methylocta-2,6-dienoic acid
methyl ester (7s). IR (CHCl3 soln.) nmax 2954, 2848, 1724,
1672, 1613, 1437, 1384, 1367, 1357, 1306, 1252, 1213,
1
1181, 1116, 1079, 1023, 995, 956, 923, 878, 806 cm21; H
911, 822, 859, 825, 810 cm21
;
1H NMR (400 MHz,
NMR (400 MHz, CDCl3) d 1.71 (3H, s), 2.06 (3H, s), 2.19
(2H, t, Jˆ7.6 Hz), 2.66 (2H, q, Jˆ7.6 Hz), 3.82 (3H, s), 4.59
(2H, d, Jˆ7.1 Hz), 5.33±5.39 (1H, m), 6.65 (1H, t, Jˆ
7.6 Hz); 13C NMR (100 MHz, CDCl3) d 16.3, 21.0, 29.5,
38.1, 52.9, 61.1, 111.1, 119.8, 140.3, 148.2, 163.2, 171.0;
HRMS (FAB) calcd for C12H17O4BrK (M1K)1 342.9947,
obsd 342.9970.
CDCl3) d 1.61 (3H, s), 1.69 (3H, s), 1.84 (3H, s), 2.16
(4H, m), 3.83 (3H, s), 5.07±5.10 (1H, m), 6.86 (1H, d, Jˆ
11.7 Hz), 7.42 (1H, d, Jˆ11.7 Hz); 13C NMR (100 MHz,
CDCl3) d 17.2, 17.7, 25.7, 16.4, 40.7, 52.8, 108.3, 121.7,
132.3, 142.4, 151.1, 163.6; HRMS (EI) calcd for
C13H19O2Br (M)1 286.0568, obsd 286.0571.
(E)-2-Bromo-5-phenylpent-2-enoic acid methyl ester
(7n). IR (CHCl3 soln.) nmax 2954, 2929, 2862, 1718, 1611,
1497, 1454, 1437, 1354, 1306, 1247, 1224, 1173, 1087,
(E)-2-Bromo-6-methylocta-2,6-diene-1,8-diol (12).
A
solution of 7s (1.0 g, 3.3 mmol) in CH2Cl2 (20 ml) was
cooled to 2788C and to the solution was added DIBAL-H
(20 ml, 20 mmol). The reaction mixture was stirred at
2788C for 1 h. Then Na2SO4´10H2O (6 g) was added and
warmed up to rt. The mixture was ®ltered and the ®ltrate
was concentrated in vacuo. The residue was puri®ed by ¯ash
column chromatography (hexane/ethyl acetateˆ1:1) to give
allylic alcohol as a colorless solid (442 mg, 57% yield): mp
61±628C; IR (CHCl3 soln.) nmax 3676, 3610, 3445, 2932,
1732, 1668, 1664, 1646, 1603, 1457, 1448, 1385, 1351,
1246, 1220, 1189, 1109, 1078, 1037, 999, 922, 865,
1030, 1003, 909, 880, 843, 811 cm21
;
1H NMR
(400 MHz, CDCl3) d 2.75±2.87 (4H, m), 3.80 (3H, s),
6.71 (1H, t, Jˆ7.4 Hz), 7.18±7.23 (3H, m), 7.30 (2H, t,
Jˆ7.4 Hz); 13C NMR (100 MHz, CDCl3) d 33.0, 34.7,
52.9, 111.3, 126.3, 128.4, 128.5, 140.5, 147.9, 163.2;
HRMS (EI) calcd for C12H13O2Br (M)1 268.0099, obsd
268.0097.
(E)-2-Bromohept-2-enoic acid methyl ester (7o). IR
(CHCl3 soln.) nmax 2958, 2931, 2873, 2863, 1717, 1611,
1466, 1458, 1437, 1380, 1352, 1319, 1297, 1250, 1209,
1
844 cm21; H NMR (400 MHz, CDCl3) d 1.69 (3H, s),
1.75 (1H, br), 2.10 (2H, t, Jˆ7.2 Hz), 2.26 (2H, q, Jˆ

K. Tago, H. Kogen / Tetrahedron 56 (2000) 8825±8831
8831
6. (a) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733. (b) Grinev, G. V.; Chervenyuk, G. I.; Dombrovskii,
A. V. J. Gen. Chem. USSR 1969, 39, 1223. (c) Boeckmann, R. K.,
Jr.; Ko, S. S. J. Am. Chem. Soc. 1980, 102, 7146. (d) Semmelhack,
M. F.; Brickner, S. J. J. Am. Chem. Soc. 1981, 103, 3945. (e)
Tanouchi, T.; Kawamura, M.; Ohyama, I.; Kajiwara, I.; Iguchi,
Y.; Okada, T.; Miyamoto, T.; Taniguchi, K.; Hayashi, M. J. Med.
Chem. 1981, 24, 1149. (f) Danishefsky, S.; Chackalamannil, S.;
Harrison, P.; Silvestri, M.; Cole, P. J. Am. Chem. Soc. 1985, 107,
2474.
7.2 Hz), 2.49 (1H, br), 4.14 (2H, d, Jˆ7.5 Hz), 4.26 (2H, s),
5.42 (1H, tt, Jˆ7.2, 1.3 Hz), 6.00 (1H, t, Jˆ7.5 Hz); 13C
NMR (100 MHz, CDCl3) d 16.4, 27.9, 38.1, 59.0, 62.4,
124.9, 125.2, 133.9, 138.0; HRMS (FAB) calcd for
C9H15O2BrNa (M1Na)1 257.0153, obsd 257.0163.
Plaunotol (13). A solution of 10 (128 mg, 0.85 mmol) in
THF (1 ml) was cooled to 08C and to the solution was added
0.5 M of 9-BBN in THF (3.4 ml, 1.7 mmol). Then the reac-
tion mixture was stirred at rt for 4 h. After addition of water
(0.1 ml), the resulting mixture was concentrated in vacuo to
give a boron reagent. Compound 12 (100 mg, 0.43 mmol),
Cs2CO3 (250 mg, 0.76 mmol), PdCl2(dppf)´CH2Cl2 (7 mg,
2 mol%), and Ph3As (5 mg, 4 mol%) were dissolved in
DMF (3 ml) and stirred at rt for 10 min. Then, to the mixture
was added the boron reagent and stirred at 508C for 2.5 h.
The reaction mixture was poured into water and extracted
with ethyl acetate. The combined organic layers were
washed with water and brine, dried over Na2SO4, concen-
trated in vacuo after ®ltration. The residue was puri®ed by
Lobar column chromatography (RP-18, MeOH/H2Oˆ
80:20) to give 13 as a colorless oil (100 mg, 77% yield):
IR (®lm) nmax 3322, 2966, 2923, 2857, 1669, 1445, 1381,
7. (a) Gonzalez, M. S. P.; Aciego R. M. D.; Herrera, F. J. L.
Tetrahedron 1988, 44, 3715. (b) Sato, S.; Sodeoka, M.; Sasai,
H.; Shibasaki, M. J. Org. Chem. 1991, 56, 2278.
8. Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini, P.
Tetrahedron 1998, 54, 135.
9. (a) Nakamura, I.; Harada, K. Heterocycles 1978, 9, 473.
(b) Kolsaker, P.; Brobakke, K. Acta. Chem. Scand. B 1981, 35,
701. (c) Bestmann, H. J.; Dostalek, R.; Zimmermann, R. Chem.
Ber. 1992, 125, 2081.
10. Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. Rev. 1996, 96, 1641
references cited therein.
11. Etemad-Moghadam, G.; Seyden-Penne, J. Tetrahedron 1984,
40, 5153.
1
1006 cm21; H NMR (270 MHz, CDCl3) d 1.60 (6H, s,
12. Hensel, M. J.; Fuchs, P. L. Synth. Commun. 1986, 16, 1285.
13. For another Z-selective HWE reagents, see: (a) Ando, K.
Tetrahedron Lett. 1995, 36, 4105. (b) Ando, K. J. Org. Chem.
1997, 62, 1934.
CH3CvC£2), 1.69 (6H, s, CH3CvC£2), 1.93±2.28 (12H,
m, CH2CvC£6), 4.10 (2H, s, CH2OH), 4.14 (2H, d,
Jˆ7.0 Hz, CH2OH), 5.05±5.19 (2H, m, CvCH£2), 5.28
(1H, t, Jˆ7.4 Hz, CvCH), 5.40 (1H, t, Jˆ7.4 Hz,
CvCH); 13C NMR (100 MHz, CDCl3) d 16.1, 16.4, 17.7,
25.7, 25.9, 26.8, 26.9, 35.0, 39.4, 39.7, 59.2, 60.1, 124.0,
124.1, 124.3, 127.7, 131.4, 135.4, 138.9, 139.1; HRMS (EI),
calcd for C20H34O2 (M)1 306.2559, obsd 306.2554.
14. For a preliminary report, see; Tago, K.; Kogen, H. Org. Lett.
2000, 2, 1975.
15. McKenna, C. E.; Khawli, L. A. J. Org. Chem. 1986, 51, 5467.
16. Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725.
17. Ogiso, A.; Kitazawa, E.; Kurabayashi, M.; Sato, A.; Takaha-
shi, S.; Noguchi, H.; Kuwano, H.; Kobayashi, S.; Mishima, H.
Chem. Pharm. Bull. 1978, 26, 3117.
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