Stereoselective preparation of (E)-α-bromoacrylates from mixtures of brominated ando phosphonates

Article abstract of DOI:10.1055/s-2004-831166

We prepared 69:31-11:89 mixtures of phosphonates 6b and 7b containing two phenoxy substituents, a CO₂Et group, and 1 or 2 bromine atoms, respectively, at the interspersed methylene group. Deprotonating 64:36 mixtures of these reagents with NaH

Full text of DOI:10.1055/s-2004-831166

PAPER
2135
Stereoselective Preparation of (E)-a-Bromoacrylates from Mixtures of
Brominated Ando Phosphonates
(
E
)-
a
-Bromoacr
h
ylates from
o
Ando Phosph
m
onates as Olpp, Reinhard Brückner*
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstr. 21, 79104 Freiburg, Germany
Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
Received 31 March 2004; revised 24 May 2004
could also employ the brominated phosphonates 4a,b to
conduct Horner–Wadsworth–Emmons (‘HWE’) reac-
tions.14 Takai’s syntheses of trans-configured 1-iodoole-
fins from aldehydes and iodoform15 were extended using
Abstract: We prepared 69:31–11:89 mixtures of phosphonates 6b
and 7b containing two phenoxy substituents, a CO2Et group, and 1
or 2 bromine atoms, respectively, at the interspersed methylene
group. Deprotonating 64:36 mixtures of these reagents with NaH
and adding a variety of aldehydes at 0 °C provided unsaturated a- methyl tribromoacetate (5a) in a similar fashion, which
bromoesters. Yields were typically 70–99% and E-selectivities (i.e.
led to brominated cinnamic esters 3a (R = anisyl, pipero-
nyl) with very high Z-selectivity.16
ester and b-substituent cis) 80:20–98:2. Similarly, we proceeded via
the chlorinated phosphonate 49 to the unsaturated a-chloroester 51
with E:Z = 94:6 (80%).
O
P
O
O
Key words: a-bromoacrylates, brominated alkenes, a-chloroacry-
lates, chlorinated alkenes, Horner–Wadsworth–Emmons olefina-
tion, a,b-unsaturated esters
F3C-CH2O
X
Ph3P
F3C-CH2O
X
Br
Br
2a X = OMe
b X = OEt
1a X = OMe
b X = OEt
c X = NMe(OMe)
The stereoselective synthesis of olefins, especially of ole-
fins with a trisubstituted double bond, is an area of ongo-
ing interest.1 a-Brominated a,b-unsaturated esters (‘a-
bromoacrylates’) – besides many other compounds – turn
out to be versatile precursors for the construction of such
olefins. This is because their Csp2–Br bond has been en-
gaged in many transition metal-catalyzed C,C bond form-
ing reactions2 such as Stille couplings,3 Suzuki
couplings,3b,d Sonogashira couplings,4 and copper-cata-
lyzed trifluoromethylations.3d,5 In addition, a-bromoacry-
lates were converted into 1,3-dienes by reduction of the
ester moiety, further olefination, and C,C coupling.6 Apart
from that, a-bromoacrylates were used in Diels–Alder
reactions,7 tandem Michael additions/cyclizations (→
aziridines, cyclopropanes, benzotetrahydrofurans, pyro-
glutamates),8 radical cyclizations,9 dehydrobrominations
(→ alkynoic acids10) as well as for carbapenem11 and oth-
er natural product syntheses.12
ref.3d,17
:
ref.13
:
base;
R
R
O ;
O ;
O
Z-selective
E-selective
R
X
Br
3a X = OMe
b X = OEt
ref.14
:
present study:
base;
c X = NMe(OMe)
base;
R
R
ref.16
:
O ;
O ;
poorly Z-selective
E-selective
CrCl2
Ar
O ;
Z-selective
O
P
O
O
P
O
O
Almost all applications of a-bromoacrylates hinge on
their being stereopure. This makes accessing these com-
pounds only worthwhile if stereocontrol is comprised. Ar-
guably, the most important stereocontrolled syntheses of
a-bromoacrylates 3a,b – and other a-brominated deriva-
tives of a,b-unsaturated carboxylic acids e. g. 3c – consti-
tute C2-extensions of aldehydes (Scheme 1). Until
recently, these transformations were effected by Wittig re-
Br
Br Br
5a
PhO
EtO
OEt
X
OMe
PhO
EtO
Br R´
Br
6b R´ = H
7b R´ = Br
4a X = OMe
b X = OEt
Scheme 1 C2-Elongating syntheses of a-bromoacrylates
actions of brominated phosphoranes 1a,b if the a-bro- The only E-selective syntheses of methyl a-bromoacry-
moacrylates were to be exclusively Z-configured (i. e., lates 3a and the corresponding ethyl esters 3b were report-
ester and b-substituent trans).13 When it sufficed that the ed by Kogen and Tago3d,17a,b and by Qing and Zhang,17c
a-bromoacrylates were preponderantly Z-configured, one respectively. The E-configured Weinreb amide analogs 3c
were obtained in a similar manner by Deslongchamps et
al.17d All three groups adopted the Still–Gennari variant of
SYNTHESIS 2004, No. 13, pp 2135–2152
Advanced online publication: 13.08.2004
x
x.
x
x
.
2
0
0
4
the HWE reaction
– starting from bromine-free
DOI: 10.1055/s-2004-831166; Art ID: T03504SS
© Georg Thieme Verlag Stuttgart · New York

2136
T. Olpp, R. Brückner
PAPER
trifluoroethylphosphonates18 – to using bromine-contain- alkylation with ethyl bromoacetate (Scheme 2); 2. depro-
ing trifluoroethylphosphonates 2a–c.
tonation followed by bromination (Table 1).
What we disclose here is an adoption of the Ando variant
of the HWE reaction – which starts from bromine-free
arylphosphonates19 – to employing (a mixture of) phe-
nylphosphonates 6b and 7b containing 1 and 2 bromine
atoms, respectively. As we found, a-bromoacrylates 3b
are obtained from 6b/7b and aldehydes almost as E-selec-
tively as from 2a,c. In turn, the preparation of 6b/7b re-
quires less labor than the preparation of 2a,c. It costs less,
is considerably higher yielding, and easily amenable to
molar scale. Moreover, our phosphonates 6b/7b could be
stored without decomposition at room temperature where-
as Kogen’s reagent 2a requires storage at –20 °C.3d All
these should make our findings interesting for the synthet-
ic community.
NaH;
BrCH2CO2Et (1.0 equiv)
O
P
O
P
O
PhO
PhO
H
OEt
PhO
PhO
THF,
0 °C – r.t.
8
9b 86%
NaH (2.0 equiv);
O
P
O
BrCH2CO2Et (2.0 equiv)
PhO
OEt
OEt
PhO
THF,
0 °C – r.t.
O
10 56%
The reagent mixture 6b/7b was obtained from diphenyl
phosphite (8) in two steps: 1. deprotonation followed by
Scheme 2 Improved synthesis of Ando’s reagent19b,e 9b
Table 1 Obtaining Brominated HWE Reagents 6b/7ba
O
P
O
O
P
O
O
P
O
‘Reaction conditions’
PhO
+
PhO
PhO
OEt
OEt
OEt
PhO
PhO
PhO
Br Br
7b
Br
9b
6b
Entry Reaction Conditions
Yield Re-
covered
9b (%)
Yield Mono- Yield Di-
bromination bromination 9b + 6b + 7b nation:Di-
Total Yield
Monobromi- Bromine
Transfer
6b (%)
7b (%)
(%)
0
bromination from Re-
(6b:7b)
agent (%)b
1
2
NBS (1.1 equiv), benzoyl peroxide
(0.1 equiv), CCl4, 60 °C, 21 h
0
0
0
–
-
DBU (1.3 equiv), THF,
–78 °C, 10 min; Br2 (1.0 equiv), –78 °C,
30 min
33
22
43
98
34:66
60:40
110
80
3
DBU (1.3 equiv), THF,
15
34
23
72
–78 °C, 10 min; CBr4 (1.2 equiv), THF,
–78 °C, 30 min
4
5
6
NaH (1.0 equiv), DME, 0 °C, 1 h; Br2
(1.0 equiv), r.t., 4 h
5.4
32
55
1.2
57
94
96
81
36:64
65:35
–
146
106
–
NaH (1.0 equiv), THF, r.t., 20 min; Br2 12
(1.07 equiv), r.t., 2 h
29
NaH (1.0 equiv), THF,
–78 °C, 15 min; Br2 (1.0 equiv), –78 °C,
30 min
78
ca. 1.5
7
8
NaH (1.0 equiv), THF, r.t., 20 min; Br2
(2.03 equiv), r.t., 30 min
8.8
35
45
12
5.2
53
27
87
12
96
94
99
46
40:60
62:38
11:89
31:69
71
99
NaH (1.0 equiv), THF, 0 °C, 1 h; NBS 22
(1.0 equiv), r.t., 24 h
9
NaH (1.0 equiv), THF, r.t., 20 min; NBS trace
(1.86 equiv), r.t., 30 min
100
25
10
NaH (1.0 equiv), THF, r.t., 20 min; CBr4 12
(1.19 equiv), r.t.,70 min
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2137
Table 1 Obtaining Brominated HWE Reagents 6b/7ba (continued)
O
P
O
O
P
O
O
P
O
‘Reaction conditions’
PhO
+
PhO
PhO
OEt
OEt
OEt
PhO
PhO
PhO
Br Br
7b
Br
9b
6b
Entry Reaction Conditions
Yield Re-
covered
9b (%)
Yield Mono- Yield Di-
bromination bromination 9b + 6b + 7b nation:Di-
Total Yield
Monobromi- Bromine
Transfer
bromination from Re-
6b (%)
7b (%)
(%)
100
95
(6b:7b)
agent (%)b
11
12
13
14
15
NaH (1.0 equiv), THF, r.t., 20 min;
Br2(CH)2Br2 (1.24 equiv), r.t., 2 h
100
11
11
66
11
0
59
58
0
0
26
27
0
–
–
NaH (1.0 equiv), THF, r.t., 20 min;
Br(CCl2)2Br (1.24 equiv), r.t., 1.5 h
69:31
69:31
–
96
61
NaH (1.0 equiv), THF, r.t., 20 min;
Br(CCl2)2Br (1.80 equiv), r.t., 1.5 h
97
NaH (1.0 equiv), THF, r.t., 20 min;
Br(CF2)2Br (1.24 equiv), r.t., 2 h
66
–
NaH (1.0 equiv), THF, r.t., 20 min;
2,4,4,6-tetrabromocyclohexa-2,5-dien-
1-one (1.0 equiv)
48
39
98
55:45
124
102
16
LDA (1.2 equiv), –78 °C,
1 h; Br2 (1.0 equiv),
–78 °C, 60 min
11
50
26
87
66:34
17
18
LDA (1.2 equiv), r.t., 20 min; Br2
(0.98 equiv), r.t., 30 min
21
47
51
29
30
97
85
62:38
63:37
109
111
LDA (1.2 equiv), TMSCl (1.0 equiv)
–78 °C, 1 h;
4.4
Br2 (1.0 equiv), –78 °C, 60 min
a For reasons unknown, the reactions presented in entries 2–10 and 16–18 provided also some monochlorophosphonate 49 (up to 3 mol%)
and bromochlorophosphonate 52 (cf. Experimental Part; up to 11 mol%). These compounds could neither be separated nor readily (by 1H
NMR analysis) quantified. The formation of these contaminants reduces somewhat the precision of the respective numbers in Table 1. Only
the preparations of entries 12, 13, and 15 provided 6b and 7b free from 49 and 52.
b For values >100%, the combined yields of 6b and 7b surpassed the amount of electrophilic bromine present in the reagent used; hence, in
these cases, some unaccounted-for oxidation must have occurred.
Step 1 afforded Ando’s phosphonate 9b in 86% yield brominating agent (NBS, entries 1,8,9; Br2, entries 2, 4–7,
when NaH in THF was used as the deprotonating agent 16–18; CBr4, entries 3,10; dibromotetrachloroethane, en-
and if one equivalent of ethyl bromoacetate were added to tries 12–13; dibromotetrafluoroethane, entry 14; tetrabro-
the reaction mixture very slowly (Scheme 2). This reac- mocyclohexadieneone, entry 15) or the temperature
tion was performed on a 300 g scale without any drop in (anywhere between –78 °C and r.t.). The best ratio favor-
the yield. If the same amount of ethyl bromoacetate was ing 6b vs. 7b was 69:31 (using 1.0 equiv of NaH and 1.80
added too fast, the bisalkylation product 10 formed as a equiv of dibromotetrachloroethane; 97% yield, entry 13).
contaminant (while 10 resulted free from 9b and in 56% The optimum value in the opposite direction was 11:89
yield using two equivalents both of the base and the alky- (using 1.0 equiv of NaH and 1.86 equiv of NBS; 99%
lating agent). Ando’s one-step synthesis 8 → 9b had yield, entry 9).
yielded trace amounts of 9b using NaH/DMSO and 77%
Our failure to realize the chemoselective monobromina-
tion of the phenyloxylated phosphonato ester 9b contrasts
under the best conditions (Et3N/CH2Cl2).19e
Step 2 of our synthesis, namely the bromination of phos- with the facile monobromination of the ethoxylated phos-
phonate 9b, failed to become the desired chemoselective phonato ester 11b (→ 4b; Scheme 3). On the other hand,
monobromination (→ 6b; Table 1). Invariably this trans- it finds a parallel in the fact that we were unable to mono-
formation suffered from some accompanying if not dom- brominate the trifluoroethoxylated phosphonato ester 12a
inating dibromination (→ 7b) and possibly also from (Scheme 4). There, too, was a competition of no, mono-
incomplete conversion of the starting material. This re- (→ 2a), and dibromination (→ 13a). Clearly, the en-
mained so irrespective of the base (no base, entry 1; DBU, hanced electron-withdrawal in Ando-type 6b or Still–
entries 2–3; NaH, entries 4–15; LDA, entries 16–18), the Gennari-type bromophosphonates 2a versus the absence
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2138
T. Olpp, R. Brückner
PAPER
unreacted 7b 12%
O
P
O
O
O
a
P
EtO
EtO
EtO
OEt
+
OEt
EtO
Br
O
P
O
O
P
O
a
11b
4b 98%
PhO
PhO
OEt
OEt
PhO
PhO
Br
Scheme 3 a) NaH (1.1 equiv), DME, r.t., 1 h; Br2 (1.0 equiv), 0 °C,
Br Br
7b
15 min; r.t., 2 h
6b 54%
+
of this effect in the ‘standard’ bromophosphonate 4b
makes the difference.
O
P
O
PhO
OEt
However, we encountered a notable difference between
the Ando-type 7b and Still–Gennari-type dibromophos-
phonates 13a. The former did not form at all when 9b was
subjected to the dibromination conditions published17a,b
for 12a – and which we could reproduce (Scheme 4). In-
stead, 9b decomposed completely.
PhO
9b 19%
Scheme 5 a) SnCl2·2 H2O (1.2 equiv), EtOH, –40 °C, 10 min
the olefination product 14 (Table 2). Surprisingly, the
yields rose as high as 99% (entries 1, 23, 25–28, 33). This
was entirely unexpected since the consumption of mono-
bromophosphonate 6b was just 0.83 equivalent which
should have limited the maximum yield of 14 to 83%.
That this was surpassed by up to 16 additional percents
means that some dibromophosphonate 7b must transform
into deprotonated monobromophosphonate 6b under the
reaction conditions, thereby being channeled into the de-
sired pathway, too. Responsible for this could be the
diphenylphosphate by-product or a phenoxide ion ex-
pelled therefrom.
Trying to get around these difficulties, we treated a pure
sample of the Ando-type dibromophosphonate 7b – sepa-
rated from a 90:10 7b:6b mixture by careful flash chroma-
tography on silica gel20 – with stannous chloride
(Scheme 5). We expected a selective reduction 7b → 6b
because of the close similarity to the known3d,17a,b reduc-
tion of the analogous Still-Gennari-type dibromophos-
phonate 13a (→ 2a). However, our intended
monoreduction (→ 6b, 53%) was at the same time incom-
plete – we reisolated 12% 7b – and overdone – we found
19% bis(debromination).
Starting to fear that, given these difficulties, we might
have to quit our approach, we tested doing HWE chemis-
try with the (almost) best we possessed, namely with a
64:36 mixture of monobromophosphonate 6b and dibro-
mophosphonate 7b, notwithstanding. In THF, 6b/7b was
deprotonated with potassium carbonate, DBU, Triton B,
potassium tert-butoxide, KHMDS, LDA or NaH, added
anisaldehyde, and in all instances observed formation of
E:Z selectivities in the model study of Table 2 reached
92:8 (entry 33) at best and 90:10 under several conditions
(entries 16, 23, 27). The temperature dependence of this
selectivity was such that 0 °C/room temperature entailed
the highest values (entries 9, 14, 23) with a slight drop-off
towards 66 °C (cf. entries 10, 15, and 26, respectively)
and a steep drop-off towards –78 °C (cf. entries 7, 12, and
19, respectively).
unreacted 12a 18%
We applied the experimentally slightly more convenient
conditions of entry 23 of Table 2 (→ E:Z = 90:10, 99%
yield) to a variety of other aldehydes (Table 3) rather than
the very best conditions of entry 33/Table 2 (→
E:Z = 92:8, 99% yield). We were pleased to find that other
aromatic aldehydes (Table 3, entries 2,3), a,b-unsaturated
aldehydes (entries 4–7), simple aliphatic aldehydes (en-
tries 8–11), and a-oxygenated (entries 12–14) aldehydes
as well as an a-amino- (entry 15) or a b-amino-substituted
aldehyde (entry 16) were amenable to the bromoolefina-
tion protocol. Unless these aldehydes were sterically hin-
dered, yields were 70–99%. Too hindered substrates were
pivalaldehyde (entry 11; → 31%, the remainder of the al-
dehyde decomposing) and the trimethylated cyclohexadi-
enecarbaldehyde of entry 7 (→ no conversion at all). In
half of the cases the E:Z ratios were better than 90:10. The
other ones were 80:20–90:10. The top result was
E:Z = 98:2 observed starting from the a-oxygenated alde-
hyde of entry 14.
+
O
P
O
O
P
O
a
F3C-CH2O
F3C-CH2O
OMe
OMe
F3C-CH2O
F3C-CH2O
Br
12a
2a 27%
+
O
P
O
b
F3C-CH2O
OMe
F3C-CH2O
Br Br
13a 53%
13a 47%
(without 12a or 2a)
Scheme 4 a) NaH (1.0 equiv), DME, r.t., 1 h; Br2 (1.0 equiv), 0 °C,
15 min; r.t., 2 h; b) NaOH (7 equiv), Br2 (3.5 equiv), H2O, 0 °C, 30
min
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2139
Table 2 HWE Reaction Between Phosphonates 6b/7ba and Anisaldehyde: Optimizing the Reaction Conditions
‘Base’ (1.20 equiv),
O
‘Additive’ (1.20 equiv),
O
P
O
O
P
O
Br
‘Solvent’, 10 min;
OEt
PhO
+
:
+
PhO
OEt
OEt
Br
PhO
PhO
Br Br
MeO
O
OEt
MeO
O
Br
,
MeO
‘Temp.’, ‘Time’
6b
(64
36)
7b
0.47 equiv
E-14
Z-14
0.83 equiv
isolated as mixture
Entry
Base
Additive
Solvent Temp
(°C)
Time
(min)
Conversion of
Anisaldehyde
(%)
Yield after
E:Z-Selec-
Chromatography tivityb
(%)
1
2
K2CO3
–
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
CH2Cl2
r. t.
–78
r. t.
0
23 h
80
30
4 h
80
30
85
30
30
10
30
75
30
30
10
30
75
30
80
30
30
30
30
30
120
10
30
30
100
76
99
79:21
31:69
37:63
74:26
32:68
64:36
44:56
80:20
82:18
79:21
81:19
54:46
82:18
83:17
78:22
90:10
69:31
53:47
39:61
76:24
87:13
89:11
90:10
87:13
89:11
83:19
90:10
71:29
c
DBU
DBU
DBU
–
–
c
3
–
100
90
–
c
4
NaBr
–
c
5
Triton Bd
Triton Bd
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
–
–78
r. t.
–78
0
100
90
–
6
–
60
c
7
–
88
–
8
–
95
92
90
88
77
9
–
r. t.
66
100
100
96
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
–
18-crown-6
r. t.
–78
0
c
KHMDS (0.5 M in toluene)
KHMDS (0.5 M in toluene)
KHMDS (0.5 M in toluene)
KHMDS (0.5 M in toluene)
KHMDS (0.5 M in toluene)
LDA
–
51
–
c
–
80
–
–
r. t.
66
100
68
90
c
–
–
18-crown-6
r. t.
–78
0
100
100
100
63
81
79
–
–
–
–
–
–
–
–
–
–
–
–
c
LDA
–
c
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
–78
–30
–20
–10
0
–
c
91
–
79
66
78
99
92
100
100
100
100
100
100
c
10
–
r. t.
66
99
99
99
99
0
0
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2140
T. Olpp, R. Brückner
PAPER
Table 2 HWE Reaction Between Phosphonates 6b/7ba and Anisaldehyde: Optimizing the Reaction Conditions (continued)
‘Base’ (1.20 equiv),
O
‘Additive’ (1.20 equiv),
O
P
O
O
P
O
Br
‘Solvent’, 10 min;
OEt
PhO
+
:
+
PhO
OEt
OEt
Br
PhO
PhO
Br Br
MeO
O
OEt
MeO
O
Br
,
MeO
‘Temp.’, ‘Time’
6b
(64
36)
7b
0.47 equiv
E-14
Z-14
0.83 equiv
isolated as mixture
Entry
Base
Additive
Solvent Temp
(°C)
Time
(min)
Conversion of
Anisaldehyde
(%)
Yield after
E:Z-Selec-
Chromatography tivityb
(%)
c
29
30
31
32
33
34
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
NaH (60% in mineral oil)
–
DME
dioxane
THF
0
0
0
0
0
0
30
30
30
30
30
30
100
82
–
–
–
–
63:37
52:48
51.49
69:31
92:8
c
c
c
–
15-crown-5
47
cryptand 222 THF
69
NaBr
LiBr
THF
THF
100
90
99
c
–
74:26
a These reactions were realized with a mixture of monobromophosphonate 6b and dibromophosphonate 7b which was contaminated with 1.7
mol% of the monochlorophosphonate 49 and 9.4 mol% of the analogous bromochlorophosphonate (52; cf. Experimental Part). As a conse-
quence, the resulting bromoacrylates 14 were accompanied by some of the chloroacrylates 51 (cf. also Scheme 8 below). The numerical values
given in Table 2 for conversion, yield, and E:Z-ratios are somewhat approximate since in our NMR-analysis we assumed that 1.7 + 9.4 = 11.1
mol% chloroacrylate 51 occurred in bromoacrylate 14 and that 51 resulted with the same conversion, yield, and E:Z-selectivity as 14. Table 3,
entry 1 shows a preparation of 14 free from 51 (99% yield) and Scheme 8 (see below) a preparation of 51 free from 14 (80% yield).
b The E/Z-ratio was determined by integration of the MeO signal in the 1H NMR spectrum of the crude product (dMeO,E = 3.81, dMeO,Z = 3.85);
the olefin protons could not be used for that purpose because d=CH,Z was superimposed by dPhO of unreacted reagent.
c Yield not determined because of unsatisfactory E/Z-ratio.
d Triton B = BnNMe3 OH–.
+
Table 3 HWE Reactions Between Phosphonates 6b/7b and Various Aldehydes
O
P
O
O
P
O
O
NaH, THF, 0 °C, 10 min;
Br
+
:
PhO
+
PhO
OEt
OEt
R
R
OEt
PhO
PhO
RCH=O
Br Br
Br
Br
O
OEt
(anisaldehyde,
6b
(64
36)
7b
15, 17, ..., 41, 43),
0 °C contd., ‘Time’
E-14, 16, 18, ..., 42, 44
Z-14, 16, 18, ..., 42, 44
isolated as E:Z mixtures
Entry
1
R
Aldehyde 6b
7b
NaH
Time
Prod-
uct
Yield after E:Z Select- Separation
Chromato- ivity
graphy(%)
(equiv) (equiv) (equiv) (min)
anisalde- 0.77
hyde
0.43
0.46
1.00
1.00
30
90
14
16
99
97
90:10
86:14
inseparable
inseparable
MeO
MeO
2
15
0.83
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2141
Table 3 HWE Reactions Between Phosphonates 6b/7b and Various Aldehydes (continued)
O
P
O
O
P
O
O
NaH, THF, 0 °C, 10 min;
Br
+
:
PhO
+
PhO
OEt
OEt
R
R
OEt
PhO
PhO
RCH=O
Br Br
Br
Br
O
OEt
(anisaldehyde,
6b
(64
36)
7b
15, 17, ..., 41, 43),
0 °C contd., ‘Time’
E-14, 16, 18, ..., 42, 44
Z-14, 16, 18, ..., 42, 44
isolated as E:Z mixtures
Entry
3
R
Aldehyde 6b
7b
NaH
Time
Prod-
uct
Yield after E:Z Select- Separation
Chromato- ivity
graphy(%)
(equiv) (equiv) (equiv) (min)
17
0.83
0.46
1.00
30
18
80
82:18
yes
(difficult)
O
4
5
19
21
0.83
0.75
0.46
0.41
1.00
1.00
60
40
20
22
70
81
84:16
83:17
yes
(difficult)
yesa
(difficult)
Br
6
7
23
25
0.84
0.83
0.47
0.47
1.00
1.00
30
24
26
72
80:20
–
inseparable
–
AcO
1320
0
(no reaction)
8
9
27
29
0.77
0.83
0.43
0.46
1.00
1.00
30
45
28
30
97
98
86:14
91:9
yes
(difficult)
yes
(difficult)
10
11
12
31
33
35
0.83
0.83
0.70
0.46
0.46
0.39
1.00
1.00
0.83
30
420
60
32
34
36
74
31
70
94:6
97:3
93:7
yes
inseparable
yesa
O
TBSO
O
13
14
15
37
39
41
0.76
0.75
0.83
0.44
0.42
0.46
0.83
0.80
1.00
30
90
38
40
42
75
81
85
95:5
98:2
yesa
yesa
O
MeO2C
O
O
MeO2C
O
210
no Z-isomer detected
NHZ
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2142
T. Olpp, R. Brückner
PAPER
Table 3 HWE Reactions Between Phosphonates 6b/7b and Various Aldehydes (continued)
O
P
O
O
P
O
O
NaH, THF, 0 °C, 10 min;
Br
+
:
PhO
+
PhO
OEt
OEt
R
R
OEt
PhO
PhO
RCH=O
Br Br
Br
Br
O
OEt
(anisaldehyde,
6b
(64
36)
7b
15, 17, ..., 41, 43),
0 °C contd., ‘Time’
E-14, 16, 18, ..., 42, 44
Z-14, 16, 18, ..., 42, 44
isolated as E:Z mixtures
Entry
16
R
Aldehyde 6b
7b
NaH
Time
Prod-
uct
Yield after E:Z Select- Separation
Chromato- ivity
graphy(%)
(equiv) (equiv) (equiv) (min)
43
0.83
0.46
1.00
30
44
90
93:7
yes
NHZ
a This preparation was realized with a mixture of monobromophosphonate 6b and dibromophosphonate 7b which was contaminated with 1.7
mol% of the monochlorophosphonate 49 and 9.4 mol% of the analogous bromochlorophosphonate (52; cf. Experimental Part). As a conse-
quence, the resulting bromoacrylate was accompanied by its chlorine analogue. The latter was inseparable by flash chromatography and there-
fore constituted 10, 4, 9, and 7 weight% of the isolated samples of 22, 36, 38, and 40, respectively. The yield of bromoacrylate and the
equivalents of 6b and 7b in these cases refer to ‘the amount of aldehyde used minus the amount of aldehyde incorporated into the chloroacry-
late’. Obviously, using pure 6b/7b would spare this complication.
Ando’s bromine-free arylphosphonate 9b could be im- matropic 1,7-H shift, which provided the isomer (E)-48,
proved with respect to the stereoselectivity of carbonyl i.e., a fully conjugated hexatrienoic ester.
olefinations upon replacement of the phenyloxy by certain
Our early specimens of the bromophosphonate mixture
other aryloxy groups, for example by a-naphthyloxy.19b
6b/7b contained a small amount of the monochlorinated
One might expect a similar selectivity enhancement in the
brominated reagent described here. However, we have not
probed this yet.
analogs of both compounds. Until we noticed we had
wondered what the – quite minor – contaminants in the a-
bromoacrylates subsequently obtained were. From then
The stereochemical assignments of Table 3 are mostly on it was clear that the contaminating chlorine analog of
1
based upon H NMR shift criteria (Table 4). In a pair of
isomers, 3-H is deshielded when it is cis to the CO2Et
group (1st criterion), and 4-H is deshielded when it is cis
OH
O
to the CO2Et group (2nd criterion). Exceptionally, we
needed to take [14 and (E)-44] – or additionally took [22,
(E)-28, (E)-34, 36, (E)-42] – recourse to a 3rd criterion. It
is the magnitude of the 3-bond coupling between 13C-1
and 3-1H and was observed by gated-decoupled 1-dimen-
sional 13C NMR spectroscopy. These couplings are larger
when the bonds between C-1 and 3-H possess a zigzag
rather than U-shaped array.21 ‘Zigzag 13C-1/3-1H cou-
plings’ are 10.6–11.2 Hz in the E-isomers of 14, 22, 28,
34, 36, 42, and 44 as opposed to the ‘U-shaped 13C-1/3-1H
couplings’ of 4.2–5.5 Hz in (Z)-14, (Z)-22, and (Z)-36.
a
HO
Br
TBSO
Br
O
O
CO2Et
O
E-36
45 99%
b
Bu3Sn
46
Scheme 6 shows the follow-up chemistry of an a-bro-
moacrylate. It depends on its having been made accessible
with the E configuration. In the first reaction, pure a-bro-
moacrylate (E)-36 was subjected to an acid-catalyzed
transacetalization followed by an in situ lactonization.
The result was a 99% yield of the g-(a-hydroxyalkyl)-sub-
stituted butenolide 45. Butenolides like this figure as key
intermediates in the stereocontrolled synthesis of Z-con-
figured g-alkylidenebutenolides.22 In the second follow-
up reaction, the a-bromoacrylate (E)-36 was Stille-
coupled2a with dienylstannane 46.23 The primary product
must have been (E)-47. This, however, underwent a sig-
2
3
O
O
1
4
~[1,7]-H
TBSO
TBSO
5
7
6
O
CO2Et
O
CO2Et
E-47
E-48 61%.
Scheme 6 a) p-TsOH (0.1 equiv), MeOH, reflux, 10 min; b) E-36
(1.3 equiv), 46 (1.0 equiv), Pd2dba3·CHCl3 (0.1 equiv), P(2-furyl)3
(0.6 equiv), CuI (1.65 equiv), NMP, 25 °C, 27 h
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2143
Table 4 Elucidation of C=C bond Configurations by 1H NMR (500
MHz, CDCl3) and 13C NMR (126 MHz) Spectroscopy (both in
CDCl3)
bromophosphonate 6b had undertaken its share of the
HWE chemistry and provided some a-chloroacrylate
thereby. The origin of this stray chlorine has left us mar-
velling. It showed up when ‘brominating’ the deprotonat-
ed phosphonate 9b with NBS, Br2 or CBr4. Zero chlorine
was incorporated using dibromotetrachloroethane as the
brominating agent following the procedure of entries 12–
13/Table 1 or using 2,4,4,6-tetrabromo-2,5-cyclohexadi-
en-1-one (Table 1, entry 15).
H
H
3
O
1
4
R′
Br
4
3
R′
OEt
1
H
O
OEt
H
Br
E-14, 16, 18, 20, 22,
22, 24, 26, 28, 30,
32, 34, 36, 38, 40,
42, 44
Z-14, 16, 18, 20, 22,
22, 24, 26, 28, 30,
32, 34, 36, 38, 40,
42, 44
The mentioned chloroacrylate formation was an incen-
tive, though, to briefly check it out in its own right. To that
end, we chlorinated the deprotonated phosphonate 9b ar-
bitrarily, namely with NCS (Scheme 7). This furnished
76% of a 11:47:42 (mol:mol:mol) mixture of the non-,
mono- and dichlorinated phosphonates 9b, 49, and 50, re-
spectively. The Ando-type monochlorophosphonate 49
could be separated from this mixture by repetitive flash
chromatography on silica gel,20 albeit not in analytically
pure form due to the presence of a yet unidentified impu-
rity.
Com- 1H NMR
13C NMR
pound
d3-H
d4-H
3JC-1,3-H (Hz)
E
Z
E
Z
E
Z
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
7.29
7.31
7.17
7.08
7.14
6.74
–
8.17
8.18
8.16
7.62
7.68
7.70
–
–
–
10.6
5.5
a
a
–
–
–
–
a
a
–
–
–
–
a
a
7.05
7.31
–
6.50
6.66
–
–
–
unreacted 9b 8%
10.6
4.2
+
a
a
O
P
O
O
P
O
–
–
a
PhO
PhO
OEt
OEt
–
–
–
–
PhO
PhO
Cl
a
6.66
6.47
6.44
6.17
6.59
6.61
6.60
7.29
7.09
7.08
7.45
7.26
7.26
2.49
2.93
3.23
–
2.34
2.57
2.86
–
11.2
–
49 36%
9b
a
a
–
–
+
a
a
–
–
O
P
O
a
PhO
11.1
10.9
–
OEt
PhO
Cl Cl
5.06
5.08
5.11
4.90
4.73
4.73
4.6
50 32%
a
a
–
–
Scheme 7 a) NaH (1.2 equiv), NCS (1.2 equiv), THF, r.t., 40 min
b
a
a
–
–
–
6.48c
6.41
–
4.86c
4.81
–
10.9e
–
–
d
d
d
When a THF solution of compound 49 was first treated
with NaH and then combined with anisaldehyde, 80% of
the chloroacrylates (E)- and (Z)-51 resulted as a 94:6 mix-
ture (Scheme 8). Their stereochemical assignments stem
from the chemical shift of the respective olefin proton: 3-
H is deshielded when it is cis to the CO2Et group, i.e.,
when the double bond configuration is Z, i.e., in the minor
isomer.
f
f
44
6.69
–
2.55 and –f
2.73g
11.2
–
a Not determined.
b Amount of this compound in the mixture too small for identifying
its 3-H resonance.
c 1H NMR spectrum of isomer (E)-42 showed line-broadening at
+27 °C but sharp lines of two carbamate rotamers at –10 °C (80:20 ra-
tio; data of major rotamer in top row, of minor rotamer below) and
modified lines at +50 °C (e. g., one doublet for 3-H rather than two
doublets at –10 °C, but not everywhere sharp lines of a rapidly inter-
converting mixture).
Reagent 49 should be as versatile to obtain E-configured
chloroacrylates from aldehydes as, in the present study,
reagents 6b/7b were established to be for the preparation
of E-configured bromoacrylates from aldehydes.
d Isomer (Z)-42 was not detected.
e Value for major rotamer; the minor rotamer’s resonances were too
weak for determining 3JC,H
.
Products were purified by flash chromatography20 on Macherey-
f (Z)-44 could not be isolated in pure form which makes signal attri-
butions risky.
1
Nagel silica gel 60 (details given in parentheses). H [TMS (0.00
ppm) as internal standard in CDCl3] and 13C NMR [CDCl3 (77.00
ppm) as internal standard in CDCl3]: Bruker AM 400 or DRX 500;
31P NMR [H3PO4 (0.00 ppm) as internal standard in CDCl3]: Varian
Mercury VX 300. Integrals are in accord with assignments; cou-
g 4-HA and 4-HB resonances.
1
pling constants are given in Hz. The assignments of H and 13C
NMR resonances refer to the IUPAC nomenclature; primed num-
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2144
T. Olpp, R. Brückner
PAPER
δ = 7.13
were detected. If instead of 1,2-dibromotetrachloroethane Br2 was
used (Table 1, entry 5) for bromination, small amounts of the chlo-
rinated phosphonate 49 as well as ethyl bromochloro(diphe-
nylphosphono)acetate (52) were formed.
H
O
Cl
6b
MeO
OEt
Rf = 0.49 (cyclohexane–EtOAc, 1:1).
E-51
94
IR (neat): 3070, 2980, 2940, 1740, 1590, 1490, 1460, 1290, 1205,
1185, 1160, 1025, 1010, 765, 685 cm–1.
1H NMR (500.0 MHz, CDCl3): d = 1.26 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 4.27 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 4.64 (d, 1 H, 2J2,P = 13.7
Hz, 2-H), 7.19–7.28 (m, 6 H, Ar-H), 7.32–7.37 (m, 4 H, Ar-H).
O
P
O
a)
PhO
:
+
OEt
δ = 7.85
PhO
Cl
6
O
H
O
MeO
49
OEt
13C NMR (125.7 MHz, CDCl3): d = 13.8 (C-2¢), 34.9 (d,
3
1J2,P = 150.2 Hz, C-2), 63.5 (C-1¢), 120.47 (d, J2¢¢,P = 4.9 Hz) and
Cl
MeO
3
120.51 (d, J2¢¢,P = 4.9 Hz; 2 × 2 × C-2¢¢), 125.7 and 125.8 (2 × C-
Z-51
2
4¢¢), 129.8 and 129.9 (2 × 2 × C-3¢¢), 150.1 (d, J1¢¢,P = 8.8 Hz) and
150.2 (d, 2J1¢¢,P = 9.1 Hz, 2 × C-1¢¢), 164.1 (C-1).
31P NMR (121.5 MHz, CDCl3): d = 5.34.
80% (as a mixture)
Scheme 8 a) 49 (1.2 equiv), NaH (1.2 equiv), THF, 0 °C, 50 min
MS (EI, 70 eV): m/z (%) = 398 (100, M+), 320 (82), 305 (22).
Anal. Calcd for C16H16BrO5P (399.2): C, 48.14; H, 4.04. Found: C,
48.35; H, 4.13.
bers belong to the side-chain. NMR: Dr. M. Keller, Institut für Or-
ganische Chemie und Biochemie, Universität Freiburg.
Combustion analyses: E. Hickl, Institut für Organische Chemie und
Biochemie, Universität Freiburg. MS: Dr. J. Wörth, Institut für Or-
ganische Chemie und Biochemie, Universität Freiburg. IR spectra:
FTIR Perkin-Elmer Spectrum 1000 spectrophotometer. Optical ro-
tations measured with a Perkin-Elmer polarimeter 341 at 589 nm
7b
Rf = 0.51 (cyclohexane–EtOAc, 1:1).
IR (neat): 3070, 2985, 2935, 1735, 1590, 1490, 1490, 1455, 1395,
1365, 1290, 1205, 1180, 1155, 1095, 1070, 1020, 955, 905, 835
cm–1.
1H NMR (500.0 MHz, CDCl3): d = 1.27 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 4.31 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 7.19–7.23 (m, 2 H, Ar-
H), 7.26–7.30 (m, 4 H, Ar-H), 7.32–7.37 (m, 4 H, Ar-H).
and calculated according to the Drude equation {[a]nJ = (aexp
×
100)/(c × d)}; rotational values are the average of 5 measurements
of a in given solution of the respective sample. Melting points: Dr.
Tottoli apparatus (Fa. Büchi), uncorrected.
13C NMR (125.7 MHz, CDCl3): d = 13.6 (C-2¢), 45.5 (d,
Ethyl Bromo(diphenylphosphono)acetate (6b) in a 69:31 Mix-
ture with Ethyl Dibromo(diphenylphosphono)acetate (7b)
Entry 12, Table 1: To a solution of phosphonate 9b (5.94 g, 18.5
mmol) in THF (40 mL) was added NaH (60% in mineral oil, 741
mg, 18.5 mmol, 1.0 equiv) portionwise at r.t. during a period of 5
min. After 20 min at r. t., the gas evolution had ceased and 1,2-di-
bromotetrachloroethane (7.26 g, 22.3 mmol, 1.2 equiv) was added
in one portion. A few seconds after the addition a white precipitate
had formed. After 5 min reaction time, H2O (40 mL) was added.
The mixture was extracted with MTBE (3 × 150 mL). The com-
bined organic layers were dried (Na2SO4) and evaporated under re-
duced pressure. The residue (8.59 g) was separated from the rest of
the brominating reagent and H2O by flash chromatography [∆ 10
cm, h 8 cm, cyclohexane–EtOAc, 5:1 (6 L), 1–50 (100 mL), frac-
tion 1: 14–39, fraction 2: 40–47]. The mixtures of the products were
obtained as hygroscopic colorless oils [fraction 1: 5.294 g, contain-
ing 9b: 0.069 g, 1.2%; 6b: 3.189 g, 43.1%; 7b: 2.039 g, 23.0% (total
67% of a 1.8:64.0:34.2-mixture consisting of 9b, 6b, and 7b); frac-
tion 2: 1.946 g, containing 9b: 0.805 g, 13.5%; 6b: 1.004 g, 13.5%;
7b: 0.137 g, 1.4%; (total 28% of a 47.5:47.5:5.0-mixture consisting
of 9b, 6b, and 7b); total yield: 9b: 15%, 7b: 57%, 6b: 23%, total:
95%].
1J2,P = 167.1 Hz, C-2), 65.0 (C-1¢), 120.4 (d, 3J2¢¢,P = 4.5 Hz, 4 × C-
2
2¢¢), 125.7 (2 × C-4¢¢), 129.7 (4 × C-3¢¢), 150.9 (d, J1¢¢,P = 9.4 Hz,
2 × C-1¢¢), 163.0 (C-1).
31P NMR (121.5 MHz, CDCl3): d = –0.97.
MS (EI, 70 eV): m/z (%) = 476 (46, M+), 398 (42), 383 (10), 320
(21), 245 (100).
Anal. Calcd for C16H15Br2O5P (478.1): C, 40.20; H, 3.16. Found: C,
40.25; H, 3.20.
Ethyl (Diphenylphosphono)acetate (9b)
A 2-L three-necked flask equipped with a 250-mL dropping funnel
was charged with NaH (60% in mineral oil, 41.55 g, 1.039 mol, 1.0
equiv) and anhyd THF (800 mL). Diphenyl phosphite (8; 200.0 mL,
243.4 g, 1.039 mol) was added dropwise to the well-stirred suspen-
sion at 0 °C during a period of 3 h. After 1 h at 0 °C, the gas evolu-
tion had ceased and the reaction mixture became a clear orange
solution. Subsequently ethyl bromoacetate (115.0 mL, 173.5 g,
1.039 mol, 1.0 equiv) was added dropwise over a period of 3 h,
while a white solid started precipitating. The cooling bath was re-
moved and the reaction mixture was stirred at r.t. for further 12 h. A
sat. aq solution of NH4Cl (100 mL) and H2O (200 mL) were added
to the mixture. The organic layer was separated and the aqueous lay-
er was extracted with MTBE (3 × 500 mL). The combined organic
layers were dried (MgSO4) and the solvents were removed under re-
duced pressure. The orange oil (325 g) was purified by flash chro-
matography [∆ 10 cm, h 16 cm, cyclohexane–EtOAc, 4:1 (13 L),
1–25 (500 mL), 9b: 4–20]. After removal of the solvents under re-
duced pressure (12 h, 1 mbar), the oil (301 g) was transferred to a
separatory funnel. After 12 h, a film of H2O had formed on the prod-
uct. Separation from H2O and further drying in vacuum (12 h, 1
mbar) gave 9b (285.1 g, 86%) as a hygroscopic colorless oil.
If the reaction was carried out on a small scale (1 mmol), the reac-
tion time had little influence on the bromination ratio (Table 1).
However, the scale described above required a very short reaction
time to limit dibromination. The compositions of the above mix-
tures were determined by integration of the following 1H NMR sig-
nals: 2-H for 6b, 1¢-CH2 for 7b and 2-CH2 for 9b. Only mixtures
corresponding to fraction 1 above were employed for further olefi-
nation reactions. This fraction contained 2.3 mmol of the phospho-
nates 6b/7b per g mixture. The amount of 9b in these mixtures was
neglected because in any cases no olefination byproducts of 9b
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2145
If the reaction is carried out on a smaller scale (100 mmol) the dry-
ing procedure after the chromatography is not necessary. Alterna-
tively the product can be purified by distillation; bp 174 °C,
3 × 10–4 mbar; Rf = 0.46 (cyclohexane–EtOAc, 1:1).
consumption of the aldehyde and a white precipitate had formed.
H2O was added and the mixture was extracted with MTBE (3 ×).
The combined extracts were dried (Na2SO4) and the solvents were
evaporated under reduced pressure. The residue was purified by
flash chromatography.
IR (neat): 3065, 2980, 2930, 1735, 1590, 1490, 1455, 1400, 1365,
1285, 1185, 1160, 1110, 1070, 1025, 1010, 940, 820, 760, 685 cm–1.
Ethyl 2-Bromo-3-(4-methoxyphenyl)propenoate (14)
1H NMR (500.0 MHz, CDCl3): d = 1.25 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 3.27 (d, 2 H, 2J2,P = 21.8 Hz, 2-CH2), 4.21 (q, 2 H, J1¢,2¢ = 7.1,
According to the general olefination procedure, a 64:36 mixture of
6b/7b [753.5 mg, containing 60 wt% 6b: 452.1 mg, 1.133 mmol,
0.77 equiv; 40 wt% 7b: 301.4 mg, 630.4 mmol, 0.43 equiv (total: 1.2
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
59.2 mg, 1.48 mmol, 1.0 equiv) and anisaldehyde (180 mL, 202 mg,
1.48 mmol) were reacted for 30 min in THF (20 mL). Flash chro-
matography [∆ 3 cm, h 21 cm, cyclohexane–EtOAc 6:1 (700 mL),
1–25 (20 mL), 14: 9–13] provided the title compounds (E)-14 and
(Z)-14 [(416.8 mg, 99%, (E)-14:(Z)-14 = 90:10] as a colorless oil.
The E:Z ratio of 14 prior to chromatography was 90:10 according to
1H NMR spectroscopy; Rf = 0.41 (cyclohexane–EtOAc, 3:1).
4
1¢-CH2), 7.18 (ttd, 2 H, Jortho = 7.4 Hz, Jmeta = 6JH,P = 1.1 Hz, Ar-
Hpara), 7.21–7.25 (m, 4 H, Ar-Hortho), 7.30–7.34 (m, 4 H, Ar-Hmeta).
13C NMR (125.7 MHz, CDCl3): d = 14.0 (C-2¢), 34.1 (d,
1J2,P = 137.2 Hz, C-2), 61.9 (C-1¢), 120.6 (d, 3J2¢¢,P = 4.5 Hz, 4 × C-
2
2¢¢), 125.5 (2 × C-4¢¢), 129.8 (4 × C-3¢¢), 150.0 (d, J1¢¢,P = 8.5 Hz,
2 × C-1¢¢), 164.7 (d, 2J1,P = 6.7 Hz, C-1).
31P NMR (121.5 MHz, CDCl3): d = 12.99.
MS (EI, 70 eV): m/z (%) = 320 (46, M+), 227 (32), 199 (100).
Anal. Calcd for C16H17O5P (320.3): C, 60.00; H, 5.35. Found: C,
59.73; H, 5.63.
IR (neat): 2980, 2935, 2900, 2835, 1735, 1600, 1570, 1515, 1490,
1465, 1440, 1420, 1370, 1335, 1305, 1235, 1165, 1115, 1090, 1020,
965, 885 cm–1.
Diethyl 2-(Diphenylphosphono)succinate (10)
1H NMR [500.0 MHz, CDCl3; (E)-14:(Z)-14 = 90:10]: (E)-14:
d = 1.24 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 3.81 (s, 3 H, OCH3), 4.24
(q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.83–6.86 (mc, 2 Harom, 3¢¢-CH),
7.25–7.29 (mc, 2 Harom, 2¢¢-CH), 7.29 (s, 1 H, 3-CH); (Z)-14:
d = 1.38 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 3.85 (s, 3 H, OCH3), 4.34
(q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.93–6.96 (mc, 2 Harom, 3¢¢-CH),
7.87–7.92 (mc, 2 Harom, 2¢¢-CH), 8.17 (s, 1 H, 3-H).
13C NMR [125.7 MHz, CDCl3; (E)-14:(Z)-14 = 90:10]: (E)-14:
d = 13.8 (C-2¢), 55.3 (OCH3), 62.2 (C-1¢), 109.4 (C-2), 113.8
(2 × C-3¢¢), 127.3 (C-1¢¢), 130.1 (2 × C-2¢¢), 139.7 (C-3), 160.2 (C-
4¢¢), 164.6 (C-1); (Z)-14: d = 14.2 (C-2¢), 55.4 (OCH3), 62.6 (C-1¢),
110.3 (C-2), 113.9 (2 × C-3¢¢), 126.2 (C-1¢¢), 132.4 (2 × C-2¢¢),
140.2 (C-3), 161.2 (C-4¢¢), 163.6 (C-1).
To a suspension of NaH (60% in mineral oil, 2.88 g, 72.0 mmol, 2.0
equiv) in THF (100 mL) was added diphenyl phosphite (6.93 mL,
8.43 g, 36.0 mmol, 1.0 equiv) dropwise at 0 °C during a period of
20 min. After 35 min, the gas evolution had ceased and ethyl bro-
moacetate (7.97 mL, 12.0 g, 72.0 mmol, 2.0 equiv) was added drop-
wise over a period of 20 min. The cooling bath was removed and the
reaction mixture was stirred at r.t. for 12 h. A sat. aq solution of
NH4Cl (200 mL) was added to the mixture. The organic layer was
separated and the aqueous layer was extracted with MTBE (3 × 200
mL). The combined organic layers were dried (MgSO4) and the sol-
vents were removed under reduced pressure. The residue was puri-
fied by flash chromatography [∆ 10 cm, h 12 cm, cyclohexane–
EtOAc, 4:1 (5 L), 1–45 (100 mL), 10: 23–38] and the product (8.18
g, 56%) was obtained as a hygroscopic colorless oil; Rf = 0.47 (cy-
clohexane–EtOAc, 1:1).
MS (CI, 70 eV): m/z (%) = 285 (100, [M + H]+).
Anal. Calcd for C12H13BrO3 (285.1): C, 50.55; H, 4.60. Found: C,
50.51; H, 4.70.
IR (neat): 3065, 2985, 2935, 1770, 1735, 1590, 1490, 1455, 1410,
1375, 1280, 1185, 1095, 1070, 1025, 940, 845 cm–1.
1H NMR (499.9 MHz, CDCl3): d = 1.26 and 1.29 (2 t, 3 H each,
Ethyl 2-Bromo-3-(3-methoxyphenyl)propenoate (16)
According to the general olefination procedure, a 64:36 mixture of
6b/7b [586.4 mg, containing 60 wt% 6b: 351.8 mg, 881.5 mmol,
0.83 equiv; 40 wt.-% 7b: 234.6 mg, 490.6 mmol, 0.46 equiv (total:
1.3 equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral
oil, 42.4 mg, 1.06 mmol, 1.0 equiv) and 3-methoxybenzaldehyde
(15, 129 mL, 144 mg, 1.06 mmol) were reacted for 90 min in THF
(15 mL). Flash chromatography [∆ 3 cm, h 21 cm, cyclohexane–
EtOAc, 6:1 (700 mL), 1–25 (20 mL), 16: 10–16] provided the title
compound (294.0 mg, 97%, (E)-16:(Z)-16 = 86:14) as a colorless
oil. The E:Z ratio of 16 prior to chromatography was 86:14 accord-
ing to 1H NMR spectroscopy; Rf = 0.40 (cyclohexane–EtOAc, 3:1).
J2¢,1¢ = J2¢¢,1¢¢ = 7.1 Hz, 2¢-CH3, 2¢¢-CH3), AB signal (dA = 3.01,
2
3
dB = 3.25, 2 H, JAB = 17.4 Hz, split by JA,P = 10.0 Hz, JA,2 = 3.4
3
Hz and JB,2 = 11.5 Hz, JB,P = 7.7 Hz, 3-CH2), 3.80 (ddd, 1 H,
2J2,P = 24.7 Hz, J2,3-H(B) = 11.5 Hz, J2,3-H(A) = 3.4 Hz, 2-H), 4.17 and
4.28 (2 mc, 2 H each, 1¢-CH2, 1¢¢-CH2), 7.17–7.22 (m, 6 H, Ar-H),
7.31–7.34 (m, 4 H, Ar-H).
13C NMR (125.7 MHz, CDCl3): d = 14.0 and 14.1 (C-2¢, C-2¢¢), 31.4
(d, 2J3,P = 2.1 Hz, C-3), 41.5 (d, 1J2,P = 134.4 Hz, C-2), 61.3 and 62.2
3
(C-1¢, C-1¢¢), 120.4 and 120.5 (2 d, J2¢¢¢,P = 4.5 Hz, 2 × 2 × C-2¢¢¢),
125.49 and 125.54 (2 × C-4¢¢¢), 129.79 and 129.82 (2 × 2 × C-3¢¢¢),
2
2
150.02 (d, J1¢¢¢,P = 8.2) and 150.03 (d, J1¢¢¢,P = 9.1 Hz, 2 × C-1¢¢¢),
167.3 (d, JC,P = 6.1 Hz) and 170.7 (d, JC,P = 20.3 Hz; C-1, C-4).
IR (neat): 2940, 1725, 1600, 1580, 1490, 1460, 1435, 1370, 1325,
1265, 1215, 1160, 1040, 670 cm–1.
31P NMR (121.4 MHz, CDCl3): d = 14.80.
MS (CI, 120 eV): m/z (%) = 407 (100, [M + H]+).
1H NMR [499.9 MHz, CDCl3; (E)-16:(Z)-16 = 86:14]: (E)-16:
d = 1.20 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 3.79 (s, 3 H, OCH3), 4.22
(q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.82–6.84 (m, 1 H, 2¢¢-CH), 6.84–
6.88 (m, 2 Harom, Ar-H), 7.24 (dd, 1 H, J5¢¢,4¢¢ = J5¢¢,6¢¢ = 7.9 Hz, 5¢¢-
CH), 7.31 (s, 1 H, 3-H); (Z)-16: d = 1.39 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 3.84 (s, 3 H, OCH3), 4.35 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.98
Anal. Calcd for C20H23O7P (406.4): C, 59.11; H, 5.70. Found: C,
59.11; H, 5.84.
Olefination of 6b/7b; General Procedure
To a solution of a 64:36 (mol:mol) mixture of the phosphonates 6b/
7b (2.3 mmol of the phosphonates 6b/7b per g mixture, 1.2 equiv)
in THF (10–20 mL per g of phosphonate mixture) was added NaH
(60% in mineral oil, 1.2 equiv) portionwise at 0 °C. After the gas
evolution had ceased (10 min), the aldehyde (1 equiv, pure or as a
solution in an appropriate amount of THF) was added. The reaction
mixture was stirred at 0 °C until the TLC indicated the complete
(dmc, 1 Harom, JAr-H,5¢¢ = 8.1 Hz, Ar-H), 7.34 (dd, 1 Harom
5¢¢,4¢¢ = J5¢¢,6¢¢ = 7.9 Hz, 5¢¢-CH), 7.38 (dmc, 1 Harom, JAr-H,5¢¢ = 7.7 Hz,
Ar-H), 7.46–7.47 (m, 1 Harom, 2¢¢-CH), 8.18 (s, 1 H, 3-H).
,
J
13C NMR [125.7 MHz, CDCl3; (E)-16:(Z)-16 = 86:14]: (E)-16:
d = 13.7 (C-2¢), 55.2 (OCH3), 62.3 (C-1¢), 111.9 (C-2), 113.4,
114.6, 120.6 and 129.4 (4 × CHarom), 136.1 (C-1¢¢), 139.1 (C-3),
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2146
T. Olpp, R. Brückner
PAPER
159.5 (C-3¢¢), 164.4 (C-1); (Z)-16: d = 14.2 (C-2¢), 55.33 (OCH3),
62.8 (C-1¢), 115.0, 116.2, 123.1 (3 × CHarom), 140.6 (C-3).
1 H, J5,4 = 13.9 Hz, J5,6 = 7.0 Hz, 5-H), AB signal (dA = 7.05,
dB = 7.08, 1 H each, JAB = 11.2 Hz, A branch split as dq, 3JA,5 = 13.8
4
Hz, JA,6 = 1.5 Hz, A: 4-H, B: 3-H); (2Z)-20: d = 1.34 (t, 3 H,
MS (EI, 70 eV): m/z (%) = 284 (28, M+), 205 (72), 177 (100).
J
2¢,1¢ = 7.1 Hz, 2¢-CH3), 1.91 (dd, 3 H, J6,5 = 6.8 Hz, 4J6,4 = 1.6 Hz,
HRMS (EI): m/z calcd for C12H13BrO3 (M+): 284.0048; found:
284.0047.
6-CH3), 4.28 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.34 (dqd, 1 H,
J5,4 = 15.1 Hz, J5,6 = 6.8 Hz, J5,3 = 0.7 Hz, 5-H), 6.50 (ddq, 1 H,
4
4
J4,5 = 15.2 Hz, J4,3 = 10.5 Hz, J4,6 = 1.7 Hz, 4-H), 7.62 (d, 1 H,
Ethyl 2-Bromo-3-(2-furyl)propenoate (18)
J3,4 = 10.5 Hz, 3-H).
According to the general olefination procedure, a 64:36 mixture of
6b/7b [915.6 mg, containing 60 wt% 6b: 549.4 mg, 1.377 mmol,
0.83 equiv; 40 wt% 7b: 366.2 mg, 766.1 mmol, 0.46 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
66.3 mg, 1.66 mmol, 1.0 equiv) and furfural (18, 173 mL, 159 mg,
1.66 mmol) were reacted for 30 min in THF (15 mL). Flash chro-
matography [∆ 3.5 cm, h 22 cm, cyclohexane–EtOAc, 20:1
(630 mL), 1–20 (20 mL), cyclohexane–EtOAc, 10:1 (330 mL), 21–
35 (20 mL), 18: 13–25] provided the title compounds (E)-18 and
(Z)-18 (366.4 mg, 80%, (E)-18:(Z)-18 = 82:18) as a colorless oil,
which became dark after several days. The E:Z ratio of 18 prior to
13C NMR [125.7 MHz, CDCl3; (2E)-20:(2Z)-20 = 84:16]: (2E)-20:
d = 14.1 (C-2¢), 18.7 (C-6), 62.1 (C-1¢), 108.9 (C-2), 128.4 and
140.7 (C-4, C-5), 146.1 (C-3), 162.9 (C-1).
MS (CI, 250 eV): m/z (%) = 219 (100, [M + H]+), 175 (20).
Ethyl (4E,6E)-2,7-Dibromo-6-methylhepta-2,4,6-trienoate (22)
According to the general olefination procedure, a 57:32:9:2 mixture
of 6b/7b/52/49 [407.2 mg, containing 53.2 wt% 6b: 218.2 mg,
546.9 mmol, 0.68 equiv; 35.7 wt% 7b: 143.8 mg, 300.8 mmol, 0.38
equiv; 9.4 wt% 52: 38.3 mg, 85.2 mmol, 0.11 equiv; 1.7 wt% 49: 6.9
mg, 20 mmol, 0.024 equiv (total: 1.2 equiv); 2.2 mmol 6b/7b/52/49
per g mixture], NaH (60% in mineral oil, 32.0 mg, 800 mmol, 1.0
equiv) and (2E,4E)-5-bromo-4-methylpenta-2,4-dienal24 (21; 140.0
mg, 799.9 mmol) were reacted for 40 min in THF (10 mL). Flash
chromatography [∆ 3 cm, h 23 cm, cyclohexane–EtOAc, 6:1
(700 mL), 1–25 (20 mL), 22 and 2-chloro-2-debromo-22: 5–9] pro-
vided the title compounds (2E)-22 and (2Z)-22 (210.4 mg, 82%,
(2E)-22:(2Z)-22:2-chloro-2-debromo-22 = 75:15:10 mol:mol:mol)
as a colorless oil. The E:Z ratio of 22 prior to chromatography was
83:17 according to 1H NMR spectroscopy.
1
chromatography was 82:18 according to H NMR spectroscopy;
Rf = 0.35 (cyclohexane–EtOAc, 10:1).
IR (neat): 3150, 2985, 2940, 2905, 1725, 1615, 1470, 1395, 1365,
1345, 1250, 1225, 1145, 1090, 1025, 885, 750, 710 cm–1.
1H NMR [499.9 MHz, CDCl3; (E)-18:(Z)-18 = 97:3]: (E)-18:
d = 1.36 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 4.34 (q, 2 H, J1¢,2¢ = 7.1 Hz,
1¢-CH2), 6.45 (ddd, 1 H, J4¢¢,3¢¢ = 3.6 Hz, J4¢¢,5¢¢ = 1.8 Hz, 5J4¢¢,3 = 0.5
Hz, 4¢¢-CH), 7.01 (ddd, 1 H, J3¢¢,4¢¢ = 3.5 Hz, 4J3¢¢,5¢¢ = 4J3¢¢,3 = 0.6 Hz,
3¢¢-CH), 7.17 (s, 1 H, 3-H), 7.45 (dd, 1 H, J5¢¢,4¢¢ = 1.8 Hz, 4J5¢¢,3¢¢ = 0.7
Hz, 5¢¢-CH).
1H NMR [400.1 MHz, CDCl3; (E)-18:(Z)-18 = 82:18]: (Z)-18:
d = 1.37 (t, 3 H, J2¢,1¢ = 7.3 Hz, 2¢-CH3), 4.33 (q, 2 H, J1¢,2¢ = 7.3 Hz,
1¢-CH2), 6.57 (dd, 1 H, J4¢¢,3¢¢ = 3.9 Hz, J4¢¢,5¢¢ = 1.7 Hz, 4¢¢-CH), 7.60
(d, 1 H, J5¢¢,4¢¢ = 1.7 Hz, 5¢¢-CH), 8.16 (s, 1 H, 3-H).
(2E)-22
Rf = 0.64 (cyclohexane–EtOAc, 5:1).
IR (neat): 3065, 2980, 2925, 1715, 1700, 1595, 1560, 1455, 1370,
1345, 1315, 1255, 1220, 1150, 1025, 970 cm–1.
13C NMR [100.6 MHz, CDCl3; (E)-18:(Z)-18 = 82:18]: (E)-18:
d = 14.0 (C-2¢), 62.3 (C-1¢), 107.7 (C-2), 112.2 and 114.9 (C-3¢¢, C-
4¢¢), 128.4 (C-5¢¢), 144.1 (C-3), 149.4 (C-2¢¢), 163.7 (C-1); (Z)-18:
d = 14.2 (C-2¢), 62.6 (C-1¢), 109.9 (C-2), 112.5 and 116.7 (C-3¢¢, C-
4¢¢), 129.0 (C-5¢¢), 144.9 (C-3), 150.0 (C-2¢¢), 163.0 (C-1).
MS (EI, 70 eV): m/z (%) = 244 (94, M+), 216 (18), 137 (100).
HRMS (EI): m/z calcd for C9H9BrO3 (M+), 243.9735; found:
1H NMR (500.0 MHz, CDCl3): d = 1.37 (t, 3 H, J2¢,1¢ = 7.2 Hz, 2¢-
CH3), 1.99 (d, 3 H, 4J6-Me,7 = 1.2 Hz, 6-CH3), 4.30 (q, 2 H, J1¢,2¢ = 7.2
Hz, 1¢-CH2), 6.46 (ddd, 1 H, J5,4 = 15.1 Hz, 4J5,7 = 4J5,3 = 0.8 Hz, 5-
H), 6.55 (hardly resolved qdd, 1 H, 4J7,6-Me = 4J7,5 = 5J7,4 = 0.8 Hz, 7-
H), 7.14 (dd, 1 H, J3,4 = 11.4 Hz, 4J3,5 = 0.8 Hz, 3-H), 7.31 (ddd, 1
H, J4,5 = 15.3 Hz, J4,3 = 11.4 Hz, 5J4,7 = 0.6 Hz, 4-H).
13C NMR (125.7 MHz, CDCl3): d = 14.1 and 15.3 (C-2¢, 6-CH3),
62.2 (C-1¢), 111.7 (C-2), 114.6 (C-7), 125.3, 140.9 and 145.5 (C-3,
C-4, C-5), 139.9 (C-6), 162.8 (C-1).
243.9741.
Anal. Calcd for C9H9BrO3 (245.1): C, 44.11; H, 3.70. Found: C,
43.77; H, 3.62.
MS (EI, 70 eV): m/z (%) = 322 (26, M+), 215 (70), 91 (100).
HRMS (EI): m/z calcd for C10H12Br2O2 (M+), 321.9204; found:
Ethyl (2E,4E)-2-Bromohexa-2,4-dienoate (20)
321.9206.
According to the general olefination procedure, a 64:36 mixture of
6b/7b [733.6 mg, containing 60 wt% 6b: 440.2 mg, 1.103 mmol,
0.83 equiv; 40 wt% 7b: 293.4 mg, 613.9 mmol, 0.46 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
45.6 mg, 1.33 mmol, 1.0 equiv) and trans-crotonaldehyde (19; 109
mL, 93.4 mg, 1.33 mmol, contains 3.4% cis-crotonaldehyde) were
reacted for 60 min in THF (15 mL). Flash chromatography [∆ 3 cm,
h 23 cm, cyclohexane–EtOAc, 100:1 (700 mL), 1–30 (20 mL), cy-
clohexane–EtOAc, 50:1 (400 mL), 31–50 (20 mL), 20: 31–38] pro-
vided the title compounds (E)-20 and (Z)-20 [203.7 mg, 70%,
(2E,4E)-20:(2Z,4E)-20:(2E,4Z)-20:(2Z,4Z)-20 = 76.2:17.5:3.9:2.4]
as a colorless oil. The E:Z ratio of 20 prior to chromatography was
84:16 according to 1H NMR spectroscopy; Rf = 0.15 (cyclohexane–
EtOAc, 20:1).
(2Z)-22
Rf = 0.56 (cyclohexane–EtOAc, 5:1).
IR (neat): 3080, 2980, 2920, 1700, 1600, 1560, 1455, 1365, 1320,
1260, 1235, 1155, 1045, 975 cm–1.
1H NMR (500.0 MHz, CDCl3): d = 1.35 (t, 3 H, J2¢,1¢ = 7.2 Hz, 2¢-
CH3), 2.04 (d, 3 H, 4J6-Me,7 = 1.2 Hz, 6-CH3), 4.30 (q, 2 H, J1¢,2¢ = 7.2
Hz, 1¢-CH2), 6.61 (mc, 1 H, 7-H), AB signal (dA = 6.66, dB = 6.71, 1
H each, 2JAB = 15.3 Hz, split by JA,3 = 9.6 Hz, A: 4-H, B: 5-H), 7.68
(d, 1 H, J3,4 = 9.7 Hz, 3-H).
13C NMR (125.7 MHz, CDCl3): d = 14.2 and 15.2 (C-2¢, 6-CH3),
62.5 (C-1¢), 115.2 (C-2), 115.6 (C-7), 125.7, 140.7 and 142.2 (C-3,
C-4, C-5), 139.9 (C-6), 162.9 (C-1).
IR (neat): 2980, 2930, 1730, 1635, 1590, 1445, 1370, 1310, 1245,
1165, 1095, 1040, 970, 750 cm–1.
1H NMR [499.9 MHz, CDCl3; (2E)-20:(2Z)-20 = 84:16]: (2E)-20:
d = 1.36 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 1.84 (dd, 3 H, J6,5 = 6.8 Hz,
4J6,4 = 1.5 Hz, 6-CH3), 4.29 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.08 (dq,
Ethyl (4E)-6-Acetoxy-2-bromo-4-methylhexa-2,4-dienoate (24)
According to the general olefination procedure a 64:36 mixture of
6b/7b [621.2 mg, containing 60 wt% 6b: 372.7 mg, 934.1 mmol,
0.84 equiv; 40 wt% 7b: 248.5 mg, 519.8 mmol, 0.47 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2147
44.4 mg, 1.11 mmol, 1.0 equiv) and (E)-4-acetoxy-2-methylbut-2-
enal25 (23; 158 mg, 1.11 mmol) were reacted for 30 min in THF (10
mL). Flash chromatography [∆ 3 cm, h 20 cm, cyclohexane–
EtOAc, 5:1 (600 mL), 1–25 (20 mL), 24: 10–15] provided the title
compounds (E)-24 and (Z)-24 (232.1 mg, 72%, (E)-24:(Z)-
24 = 80:20) as a colorless oil. The E:Z ratio of 24 prior to chroma-
tography was 80:20 according to 1H NMR spectroscopy; Rf = 0.40
(cyclohexane–EtOAc, 1:1).
compounds (E)-30 and (Z)-30 (464.8 mg, 98%, (E)-30:(Z)-
30 = 91:9) as a colorless oil. The E:Z ratio of 30 prior to chromatog-
raphy was 91:9 according to 1H NMR spectroscopy.
(E)-30
Rf = 0.59 (cyclohexane–EtOAc, 3:1).
IR (neat): 2980, 2930, 2855, 1725, 1610, 1450, 1370, 1340, 1240,
1215, 1145, 1095, 1025, 980, 945, 905, 755 cm–1.
1H NMR [499.9 MHz, CDCl3; (E)-30:(Z)-30 = 89:11]: d = 1.08–
1.32 (m, 5 H, 5 × cyclohexyl-H), superimposed in part by 1.34 (t, 3
H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 1.64–1.68 (m, 1 H, 1 × cyclohexyl-H),
IR (neat): 2985, 2940, 1735, 1595, 1445, 1365, 1230, 1025, 960
cm–1.
1H NMR [400.1 MHz, CDCl3; (2E)-24:(2Z)-24 = 80:20]: (2E)-24:
d = 1.32 (t, 3 H, J2¢,1¢ = 7.3 Hz, 2¢-CH3), 1.81 (br s, 3 H, 4-CH3), 2.06
(s, 3 H, 6-OCOCH3), 4.26 (q, 2 H, J1¢,2¢ = 7.3 Hz, 1¢-CH2), 4.63 (d,
2 H, J6,5 = 6.9 Hz, 6-CH2), 5.65 (mc, probably interpretable as tqd,
1 H, J5,6 = 6.9 Hz, 4J5,4-Me = 4J5,3 = 1.3 Hz, 5-H), 6.74 (br s, 1 H, 3-
H); (2Z)-24: d = 1.34 (t, 3 H, J2¢,1¢ = 7.3 Hz, 2¢-CH3), 2.06 and 2.08
(2 s, 3 H each, 4-CH3, 6-OCOCH3), 4.29 (q, 2 H, J1¢,2¢ = 7.3 Hz, 1¢-
CH2), 4.73 (d, 2 H, J6,5 = 6.9 Hz, 6-CH2), 6.07 (tmc, 1 H, J5,6 = ca.
6.9 Hz, 5-H), 7.70 (br s, 1 H, 3-H).
1.71–1.77 (m, 4 H, 4 × cyclohexyl-H), 2.93 (dtt, 1 H, J1¢¢,3
=
J
1¢¢,2¢¢-H(ax) = 10.8 Hz, J1¢¢,2¢¢-H(eq) = 3.5 Hz, 1¢¢-H), 4.27 (q, 2 H,
J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.47 (d, 1 H, J3,1¢¢ = 10.0 Hz, 3-H).
13C NMR [125.7 MHz, CDCl3; (E)-30:(Z)-30 = 89:11]: d = 14.0 (C-
2¢), 25.4, 25.7 and 32.1 (2 × C-2¢¢, 2 × C-3¢¢, C-4¢¢), 40.4 (C-1¢¢),
62.0 (C-1¢), 109.9 (C-2), 153.1 (C-3), 163.0 (C-1).
MS (EI, 70 eV): m/z (%) = 260 (28, M+), 67 (100).
HRMS (EI): m/z calcd for C11H17BrO2 (M+): 260.0412; found:
MS (EI, 70 eV): m/z (%) = 290 (3, M+), 217 (26), 43 (100).
HRMS (EI): m/z calcd for C11H15BrO4 (M+), 290.0154; found:
260.0412.
(Z)-30
290.0153.
Rf = 0.59 (cyclohexane–EtOAc, 3:1).
Ethyl 2-Bromooct-2-enoate (28)
1H NMR (400.1 MHz, CDCl3): d = 1.16–1.41 (m,
5 H,
According to the general olefination procedure a 64:36 mixture of
6b/7b [1.018 g, containing 60 wt% 6b: 610.8 mg, 1.530 mmol, 0.77
equiv; 40 wt% 7b: 407.2 mg, 851.7 mmol, 0.43 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
80.0 mg, 2.00 mmol, 1.0 equiv) and hexanal (27, 240 mL, 200 mg,
2.00 mmol) were reacted for 30 min in THF (20 mL). Flash chro-
matography [∆ 3 cm, h 19 cm, cyclohexane–EtOAc, 60:1
(600 mL), 1–25 (20 mL), 28: 5–14] provided the title compounds
(E)-28 and (Z)-28 (485.1 mg, 97%, (E)-28:(Z)-28 = 86:14) as a col-
orless oil. The E:Z ratio of 28 prior to chromatography was 86:14
according to 1H NMR spectroscopy; Rf = 0.58 (cyclohexane–
EtOAc, 5:1).
5 × cyclohexyl-H), 1.33 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 1.67–1.76
(m, 5 H, 5 × cyclohexyl-H), 2.57 (dtt, 1 H, J1¢¢,3 = J1¢¢,2¢¢-H(ax) = 9.5
Hz, J1¢¢,2¢¢-H(eq) = 3.4 Hz, 1¢¢-CH), 4.27 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-
CH2), 7.09 (d, 1 H, J3,1¢¢ = 9.5 Hz, 3-H).
13C NMR (100.6 MHz, CDCl3): d = 14.1 (C-2¢), 25.3 and 30.7
(2 × C-2¢¢, 2 × C-3¢¢), 25.8 (C-4¢¢), 41.2 (C-1¢¢), 62.3 (C-1¢), 114.3
(C-2), 150.3 (C-3), 162.8 (C-1).
Ethyl 2-Bromo-4-methylpent-2-enoate (32)
According to the general olefination procedure, a 64:36 mixture of
6b/7b [926.6 mg, containing 60 wt% 6b: 556.0 mg, 1.393 mmol,
0.83 equiv; 40 wt% 7b: 370.6 mg, 775.4 mmol, 0.46 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
67.3 mg, 1.68 mmol, 1.0 equiv) and 2-methylpropionaldehyde (31;
160 mL, 121 mg, 1.68 mmol) were reacted for 30 min in THF (15
mL). Flash chromatography [∆ 3.5 cm, h 20 cm, cyclohexane–
EtOAc, 40:1 (400 mL), 1–10 (20 mL), cyclohexane–EtOAc, 20:1
(400 mL), 11–30 (20 mL), fraction 1: 9–19, fraction 2: 21–23] pro-
vided the title compounds (E)-32 and (Z)-32 (fraction 1: 261.9 mg,
71%, (E)-32:(Z)-32 = 97:3, fraction 2: 10.1 mg, 2.8%, (E)-32:(Z)-
32 = 13:87, total yield: 74%) as colorless oils. The E:Z ratio of 32
prior to chromatography was 94:6 according to 1H NMR spectros-
copy.
IR (neat): 2930, 2860, 1735, 1625, 1455, 1370, 1255, 1135, 1095,
1045, 950, 865 cm–1.
1H NMR [500.0 MHz, CDCl3; (E)-28:(Z)-28 = 94:6]: (E)-28:
d = 0.89 (t, 3 H, J8,7 = 7.1 Hz, 8-CH3), 1.27–1.35 (m, 4 H, 6-CH2, 7-
CH2), superimposed by 1.34 (t, 3 H, J2¢,1¢ = 7.2 Hz, 2¢-CH3), 1.46 (tt,
2 H, J5,4 = J5,6 = 7.4 Hz, 5-CH2), 2.49 (dt, 2 H, J4,3 = J4,5 = 7.6 Hz,
4-CH2), 4.270 (q, 2 H, J1¢,2¢ = 7.2 Hz, 1¢-CH2), 6.66 (t, 1 H, J3,4 = 7.8
Hz, 3-H); (Z)-28: d = 2.34 (dt, 2 H, J4,3 = J4,5 = 7.4 Hz, 4-CH2),
4.275 (q, 2 H, J1¢,2¢ = 7.2 Hz, 1¢-CH2), 7.29 (t, 1 H, J3,4 = 7.2 Hz, 3-
H).
13C NMR [125.7 MHz, CDCl3; (E)-28:(Z)-28 = 94:6]: (E)-28:
d = 13.9 (C-8), 14.1 (C-2¢), 22.4 (C-7), 28.4, 31.3 and 31.4 (C-4, C-
5, C-6), 62.0 (C-1¢), 111.0 (C-2), 148.7 (C-3), 163.0 (C-1); (Z)-28:
d = 14.2 (C-2¢), 27.2, 31.4 and 32.1 (C-4, C-5, C-6), 62.3 (C-1¢),
146.3 (C-3).
(E)-32
Rf = 0.32 (cyclohexane–EtOAc, 20:1).
IR (neat): 2970, 2935, 2870, 1700, 1615, 1465, 1370, 1345, 1295,
1220, 1170, 1145, 1095, 1030, 935, 890, 805, 755 cm–1.
1H NMR (300.1 MHz, CDCl3): d = 1.05 (d, 6 H, J5,4/J4-Me,4 = 6.6
Hz, 5-CH3, 4-CH3), 1.34 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 3.23 (dqq,
1 H, J4,3 = 10.2 Hz, J4,5 = J4,4-Me = 6.6 Hz, 4-H), 4.27 (q, 2 H,
MS (CI, 250 eV): m/z (%) = 249 (100, [M + H]+).
Anal. Calcd for C10H17BrO2 (249.1): C, 48.21; H, 6.88. Found: C,
47.97; H, 6.91.
J
1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.44 (d, 1 H, J3,4 = 10.1 Hz, 3-H).
Ethyl 2-Bromo-3-cyclohexylpropenoate (30)
13C NMR (125.7 MHz, CDCl3): d = 14.0 (C-2¢), 22.1 (C-5, 4-CH3),
30.8 (C-4), 62.0 (C-1¢), 109.5 (C-2), 154.3 (C-3), 163.0 (C-1).
MS (EI, 70 eV): m/z (%) = 220 (42, M+), 192 (44), 59 (100).
According to the general olefination procedure, a 64:36 mixture of
6b/7b [1.004 g, containing 60 wt% 6b: 602.4 mg, 1.510 mmol, 0.83
equiv; 40 wt% 7b: 401.6 mg, 840.2 mmol, 0.46 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
72.8 mg, 1.82 mmol, 1.0 equiv) and cyclohexanecarboxaldehyde
(29; 220 mL, 203 mg, 1.82 mmol) were reacted for 45 min in THF
(20 mL). Flash chromatography [∆ 3 cm, h 24 cm, cyclohexane–
EtOAc, 5:1 (600 mL), 1–20 (20 mL), 30: 5–9] provided the title
Anal. Calcd for C8H13BrO2 (221.1): C, 43.46; H, 5.93. Found: C,
43.15; H, 5.81.
(Z)-32
Rf = 0.27 (cyclohexane–EtOAc, 20:1).
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2148
T. Olpp, R. Brückner
PAPER
1H NMR (499.9 MHz, CDCl3): d = 1.09 (d, 6 H, J5,4/J4-Me,4 = 6.7
Hz, 5-CH3, 4-CH3), 1.34 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 2.86 (dqq,
1 H, J4,3 = 9.3 Hz, J4,5 = J4,4-Me = 6.7 Hz, 4-H), 4.27 (q, 2 H,
pressure. The residue was purified by flash chromatography [∆ 4
cm, h 25 cm, cyclohexane–EtOAc, 20:1 (1050 mL), 1–11 (50 mL),
cyclohexane–EtOAc, 10:1 (1100 mL), 12–36 (50 mL), (E)-36: 9–
17, (Z)-36: 23–27]. The products [(E)-36: 74.5 mg, 27%; (Z)-36:
145.4 mg, 52%, total: 79%] were obtained as colorless oils. The E:Z
J1¢,2¢ = 7.1 Hz, 1¢-CH2), 7.08 (d, 1 H, J3,4 = 9.4 Hz, 3-H).
13C NMR (125.7 MHz, CDCl3): d = 14.2 (C-2¢), 20.9 (C-5, 4-CH3),
31.7 (C-4), 62.4 (C-1¢), 114.2 (C-2), 151.9 (C-3), 162.7 (C-1).
1
ratio of 36 prior to chromatography was 36:64 according to H
NMR spectroscopy.
Ethyl 2-Bromo-4,4-dimethylpent-2-enoate (34)
(E)-36
According to the general olefination procedure, a 64:36 mixture of
6b/7b [911.8 mg, containing 60 wt% 6b: 547.1 mg, 1.371 mmol,
0.83 equiv; 40 wt% 7b: 364.7 mg, 763.0 mmol, 0.46 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
66.1 mg, 1.65 mmol, 1.0 equiv) and pivalaldehyde (33; 180 mL, 142
mg, 1.65 mmol) were reacted for 7 h in THF (15 mL). Flash chro-
matography [∆ 3.5 cm, h 21 cm, cyclohexane–EtOAc, 40:1
(500 mL), 1–15 (20 mL), cyclohexane–EtOAc, 20:1 (400 mL), 16–
30 (20 mL), 34: 10–18] provided the title compounds (E)-34 and
(Z)-34 [119.5 mg, 31%, (E)-34:(Z)-34 = 97:3] as a colorless oil. The
E:Z ratio of 34 prior to chromatography was 97:3 according to 1H
NMR spectroscopy; Rf = 0.30 (cyclohexane–EtOAc, 20:1).
Rf = 0.42 (cyclohexane:EtOAc 5:1); [a]D20 –5.9 (c = 1.17, CHCl3).
IR (neat): 2985, 2960, 2930, 2860, 1720, 1625, 1460, 1370, 1300,
1255, 1215, 1170, 1145, 1100, 1025, 945, 835, 785 cm–1.
1H NMR (500.0 MHz, CDCl3): d = 0.06 and 0.07 [2 s, 3 H each,
Si(CH3)2], 0.89 [s, 9 H, SiC(CH3)3], 1.34 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 1.42 and 1.43 [2 s, 6 H, C(CH3)2], AB signal (dA = 3.78,
dB = 3.80, 2 H, 2JAB = 11.1 Hz, split by JA,5 = 5.1 Hz, JB,5 = 4.2 Hz,
6-CH2), 3.85 (ddd, 1 H, J5,4 = 7.7 Hz, J5,6(A) = J5,6(B) = 4.5 Hz, 5-H),
4.27 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 5.06 (dd, 1 H, J4,3 = J4,5 = 8.2
Hz, 4-H), 6.59 (d, 1 H, J3,4 = 8.8 Hz, 3-H).
13C NMR (125.7 MHz, CDCl3): d = –5.39 and –5.37 [Si(CH3)2],
14.0 (C-2¢), 18.3 [SiC(CH3)3], 25.9 [SiC(CH3)3], 26.98 and 27.02
[C(CH3)2], 62.5 (C-1¢), 63.0 (C-6), 75.3 (C-4), 81.5 (C-5), 110.2
[C(CH3)2], 115.3 (C-2), 143.3 (C-3), 162.3 (C-1).
IR (neat): 2965, 2910, 2870, 1730, 1635, 1480, 1465, 1370, 1340,
1225, 1195, 1095, 1040, 1025, 895, 695 cm–1.
1H NMR [499.9 MHz, CDCl3; (E)-34:(Z)-34 = 97:3]: (E)-34:
d = 1.12 (s, 9 H, 5-CH3, 2 × 4-CH3), 1.34 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 4.26 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.17 (s, 1 H, 3-H); (Z)-
34: d = 1.27 (s, 9 H, 5-CH3, 2 × 4-CH3), 1.33 (t, 3 H, J2¢,1¢ = 7.1 Hz,
2¢-CH3), 4.43 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 7.45 (s, 1 H, 3-H).
13C NMR [125.7 MHz, CDCl3; (E)-34:(Z)-34 = 97:3]: (E)-34:
d = 13.8 (C-2¢), 29.2 (C-5, 2 × 4-CH3), 36.1 (C-4), 62.0 (C-1¢),
107.3 (C-2), 147.3 (C-3), 165.2 (C-1); (Z)-34: d = 28.8 (C-5, 2 × 4-
CH3), 62.5 (C-1¢), 153.7 (C-3).
MS (APCI): m/z (%) = 440 (42, [M + H2O]+), 423 (72, [M + H]+),
365 (100).
Anal. Calcd for C17H31BrO5Si (423.4): C, 48.22; H, 7.38. Found: C,
48.46; H, 7.28.
(Z)-36
Rf = 0.32 (cyclohexane–EtOAc, 5:1); [a]D20 –5.0 (c = 1.17, CHCl3).
IR (neat): 2980, 2935, 2850, 1730, 1635, 1600, 1465, 1370, 1255,
1170, 1140, 1085, 1030, 840, 780 cm–1.
MS (EI, 70 eV): m/z (%) = 234 (27, M+), 219 (16), 109 (100).
1H NMR (500.0 MHz, CDCl3): d = 0.07 and 0.08 [2 s, 3 H each,
Si(CH3)2], 0.90 [s, 9 H, SiC(CH3)3], 1.34 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 1.45 [s, 6 H, C(CH3)2], AB signal (dA = 3.76, dB = 3.84, 2 H,
2JAB = 11.1 Hz, split by JA,5 = 4.0 Hz, JB,5 = 4.0 Hz, 6-CH2), 3.91
(ddd, 1 H, J5,4 = 7.8 Hz, J5,6(A) = J5,6(B) = 3.9 Hz, 5-H), 4.30 (mc, 2 H,
1¢-CH2), 4.90 (dd, 1 H, J4,3 = J4,5 = 8.1 Hz, 4-H), 7.26 (d, 1 H,
Anal. Calcd for C9H15BrO2 (235.1): C, 45.98; H, 6.43. Found: C,
45.76; H, 6.41.
Ethyl (4S,5S)-2-Bromo-6-(tert-butyldimethylsiloxy)-4,5-dihy-
droxy-4,5-O,O-isopropylidenehex-2-enoate (36)
According to the general olefination procedure, a 57:32:9:2 mixture
of 6b/7b/52/49 [2.226 g, containing 53.2 wt% 6b: 1.184 g, 2.967
mmol, 0.68 equiv; 35.7 wt% 7b: 794.7 mg, 1.663 mmol, 0.38 equiv;
9.4 wt% 52: 209.5 mg, 466.0 mmol, 0.11 equiv; 1.7 wt% 49: 37.8
mg, 107 mmol, 0.024 equiv (total: 1.2 equiv); 2.2 mmol 6b/7b/52/
49 per g mixture], NaH (60% in mineral oil, 145.1 mg, 3.629 mmol,
0.83 equiv) and (2R,3S)-4-(tert-butyldimethylsiloxy)-2,3-dihy-
droxy-2,3-O,O-isopropylidenebutanal26 (35; 1.200 g, 4.373 mmol)
were reacted for 60 min in THF (30 mL). Flash chromatography [∆
6 cm, h 22 cm, cyclohexane–EtOAc, 33:1 (3090 mL), 1–18 (120
mL), cyclohexane–EtOAc, 20:1 (2100 mL), 19–38 (120 mL), (E)-
36 and 2-chloro-2-debromo-36: 15–23] provided the title com-
pound (E)-36 and its chlorine analogue (1.295 g, 70%, (E)-36:2-
chloro-2-debromo-36 = 96:4 mol:mol) as a colorless oil. The E:Z
ratio of 36 prior to chromatography was 93:7 according to 1H NMR
spectroscopy.
J3,4 = 8.3 Hz, 3-H).
13C NMR (125.7 MHz, CDCl3): d = –5.5 and –5.4 [Si(CH3)2], 14.1
(C-2¢), 18.3 [SiC(CH3)3], 25.9 [SiC(CH3)3], 26.9 and 27.0
[C(CH3)2], 62.3 (C-6), 62.8 (C-1¢), 76.8 (C-4), 81.3 (C-5), 110.5
[C(CH3)2], 118.5 (C-2), 142.0 (C-3), 161.9 (C-1).
MS (APCI): m/z (%) = 440 (100, [M + H2O]+), 423 (30, [M + H]+),
365 (14).
Anal. Calcd for C17H31BrO5Si (423.4): C, 48.22; H, 7.38. Found: C,
48.79; H, 7.45.
Ethyl (4S,5S,6E)-2-Bromo-4,5-dihydroxy-4,5-O,O-isopropy-
lidene-7-(methoxycarbonyl)-6-methylhepta-2,6-dienoate (38)
According to the general olefination procedure, a 57:32:9:2 mixture
of 6b/7b/52/49 [1.740 g, containing 53.2 wt% 6b: 925.7 mg, 2.230
mmol, 0.71 equiv; 35.7 wt% 7b: 621.2 mg, 1.280 mmol, 0.41 equiv;
9.4 wt% 52: 163.6 mg, 364.3 mmol, 0.12 equiv; 1.7 wt% 49: 29.6
mg, 83.6 mmol, 0.026 equiv (total: 1.2 equiv); 2.2 mmol 6b/7b/52/
49 per g mixture], NaH (60% in mineral oil, 105.0 mg, 2.625 mmol,
0.83 equiv) and methyl (2E,4S,5R)-4,5-dihydroxy-4,5-O,O-isopro-
pylidene-3-methyl-6-oxohex-2-enoate27 (37; 720.0 mg, 3.155
mmol) were reacted for 30 min in THF (30 mL). Flash chromatog-
raphy [∆ 5 cm, h 22 cm, cyclohexane–EtOAc, 15:1 (3200 mL), 1–
19 (120 mL), cyclohexane–EtOAc, 12:1 (975 mL), 20–27 (120
mL), 38 and 2-chloro-2-debromo-38: 12–19] provided the title
compounds (2E)-38 and (2Z)-38 and their chlorine analogue (888.9
mg, 75%, (2E)-38:2-chloro-2-debromo-38:(2Z)-38 = 87:10:3
A specimen of pure (Z)-36 (for comparison) and a chlorine-free
specimen of (E)-36 (for the subsequent conversion into lactone 45)
were prepared as follows: To a solution of phosphonate 4b (298 mg,
984 mmol, 1.5 equiv) in THF (5 mL) NaH (60% in mineral oil, 44.6
mg, 1.12 mmol, 1.7 equiv) was added portionwise at 0 °C during a
period of 5 min. After 10 min at 0 °C, the gas evolution had ceased
and (2R,3S)-4-(tert-butyldimethylsiloxy)-2,3-dihydroxy-2,3-O,O-
isopropylidenebutanal26 (35; 180 mg, 656 mol) in THF (2 mL) was
added. The reaction mixture was stirred for 90 min, while a white
precipitate was formed. H2O (5 mL) was added and the mixture was
extracted with MTBE (3 × 10 mL). The combined extracts were
dried (Na2SO4) and the solvents were evaporated under reduced
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2149
mol:mol:mol) as a colorless oil. The E:Z ratio of 38 prior to chroma-
IR (neat): 2985, 2940, 1715, 1645, 1615, 1435, 1370, 1310, 1275,
1220, 1165, 1040, 1025, 980, 825, 665 cm–1.
tography was 95:5 according to 1H NMR spectroscopy.
A specimen of pure (Z)-38 and a chlorine-free specimen of (E)-38
were prepared in analogy to the second procedure described for pre-
paring compound 36.
1H NMR (500.0 MHz, CDCl3): d = 1.27 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 1.46 and 1.48 [2 s, 3 H each, C(CH3)2], 1.93 (d, 3 H,
4J6-Me,7 = 1.2 Hz, 6-CH3), 3.75 (s, 3 H, OCH3), 4.18 (br d, 1 H,
J
5,4 = 8.2 Hz, 5-H), 4.19 (q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 5.11 (dd, 1
(2E)-38
H, J4,5 = J4,3 = 8.4 Hz, 4-H), 5.90 (d, 1 H, 3J9,8 = 15.2 Hz, 9-H), 6.22
(dmc, 1 H, J7,8 = ca. 11.7 Hz, 7-H), 6.60 (d, 1 H, J3,4 = 8.5 Hz, 3-H),
7.56 (dd, 1 H, J8,9 = 15.2 Hz, J8,7 = 11.5 Hz, 8-H).
20
Rf = 0.31 (cyclohexane–EtOAc, 5:1); [a]D –30.6 (c = 0.75,
CHCl3).
13C NMR (125.7 MHz, CDCl3): d = 12.9 (6-CH3), 13.9 (C-2¢), 26.8
and 27.0 [C(CH3)2], 51.6 (OCH3), 62.7 (C-1¢), 76.5 (C-4), 84.9 (C-
5), 110.4 [C(CH3)2], 115.6 (C-2), 121.8 (C-9), 125.5 (C-7), 139.5
(C-8), 142.5 (C-6), 142.7 (C-3), 162.0 (C-1), 167.5 (9-C=O).
IR (neat): 2990, 2950, 1720, 1660, 1630, 1435, 1370, 1295, 1225,
1160, 1080, 1045, 895, 865, 830 cm–1.
1H NMR (500.0 MHz, CDCl3): d = 1.29 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-
CH3), 1.46 and 1.47 [2 s, 3 H each, C(CH3)2], 2.15 (d, 3 H,
4J6-Me,7 = 1.4 Hz, 6-CH3), 3.70 (s, 3 H, OCH3), 4.15 (hardly resolved
dd, 1 H, J5,4 = 8.2 Hz, 4J5,7 = 0.8 Hz, 5-H), 4.22 (q, 2 H, J1¢,2¢ = 7.1
Hz, 1¢-CH2), 5.08 (dd, 1 H, J4,5 = J4,3 = 8.5 Hz, 4-H), 5.96 (qd, 1 H,
4J7,6-Me = 4J7,5 = 1.3 Hz, 7-H), 6.61 (d, 1 H, J3,4 = 8.8 Hz, 3-H).
MS (EI, 70 eV): m/z (%) = 387 (10, [M – CH3]+), 192 (100).
Anal. Calcd for C17H23BrO6 (403.3): C, 50.63; H, 5.75. Found: C,
50.62; H, 5.81.
13C NMR (125.7 MHz, CDCl3): d = 13.9 (C-2¢), 14.5 (6-CH3), 26.7
and 27.0 [C(CH3)2], 51.1 (OCH3), 62.8 (C-1¢), 76.9 (C-4), 84.3 (C-
5), 110.7 [C(CH3)2], 116.3 (C-2), 117.1 (C-7), 142.1 (C-3), 153.0
(C-6), 162.0 (C-1), 166.5 (7-C=O).
Ethyl (2E,4S)-4-[(Benzyloxy)carbonylamino]-2-bromo-5-meth-
ylhex-2-enoate (42)
According to the general olefination procedure, a 64:36 mixture of
6b/7b [360.3 mg, containing 60 wt% 6b: 216.2 mg, 542.6 mmol,
0.83 equiv; 40 wt% 7b: 144.1 mg, 301.5 mmol, 0.46 equiv (total: 1.3
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
26.1 mg, 653 mmol, 1.0 equiv) and (S)-2-(benzyloxycarbonylami-
no)-3-methylbutanal28 (41; 153.1 mg, 653.3 mmol) were reacted for
3.5 h in THF (10 mL). Flash chromatography [∆ 2.5 cm, h 18 cm,
cyclohexane–EtOAc 5:1 (500 mL), 1–15 (20 mL), cyclohexane–
EtOAc 4:1 (500 mL), 16–40 (20 mL), (E)-42: 10–17, unreacted 6b/
7b: 18–21] provided the title compound (E)-42 (212.5 mg, 85%) as
a colorless oil. (Z)-42 was not detected; Rf = 0.65 (cyclohexane–
EtOAc 1:1); [a]D20 +18.6 (c = 0.81, CHCl3).
MS (CI, 40 eV): m/z (%) = 377 (28, [M + H]+), 318 (100).
Anal. Calcd for C15H21BrO6 (377.2): C, 47.76; H, 5.61. Found: C,
47.81; H, 5.76.
(2Z)-38
Rf = 0.25 (cyclohexane–EtOAc, 5:1).
IR (neat): 2980, 2925, 2855, 1730, 1715, 1650, 1560, 1535, 1495,
1455, 1370, 1260, 1220, 1160, 1080, 1045, 1035, 875, 820 cm–1.
1H NMR (500.0 MHz, CDCl3): d = 1.35 (t, 3 H, J2¢,1¢ = 7.2 Hz, 2-
CH3), 1.49 and 1.51 [2 s, 3 H each, C(CH3)2], 2.19 (d, 3 H,
4J6-Me,7 = 1.4 Hz, 6-CH3), 3.72 (s, 3 H, OCH3), 4.26 (dd, 1 H,
IR (neat): 3330, 2965, 2875, 1720, 1615, 1530, 1455, 1390, 1370,
1300, 1215, 1100, 1020, 905, 775, 740, 700 cm–1.
J
5,4 = 8.2 Hz, 4J5,7 = 0.8 Hz, 5-H), 4.31 (mc, 2 H, 1¢-CH2), 4.73 (dd,
1H NMR (499.9 MHz, 263 K, CDCl3, major:minor
rotamer = 80:20): major rotamer: d = 0.96 and 0.965 (2 d, 3 H each,
J5-Me,5/J6,5 = 6.8/6.9 Hz, 5-CH3, 6-CH3), 1.37 (t, 3 H, J2¢,1¢ = 7.1 Hz,
2¢-CH3), 1.90 (dqq, 1 H, J5,4 = J5,5-Me = J5,6 = 6.8 Hz, 5-H), 4.31 (q,
2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 4.86 (ddd, 1 H, J4,3 = J4,NH = 9.1 Hz,
1 H, J4,5 = J4,3 = 8.2 Hz, 4-H), 6.01 (qd, 1 H, 4J7,6-Me = 4J7,5 = 1.3 Hz,
7-H), 7.26 (d, 1 H, J3,4 = 8.8 Hz, 3-H).
13C NMR (125.7 MHz, CDCl3): d = 14.1 (C-2¢), 14.4 (6-CH3), 26.7
and 26.9 [C(CH3)2], 51.2 (OCH3), 63.0 (C-1¢), 78.9 (C-4), 84.0 (C-
5), 111.2 [C(CH3)2], 117.6 (C-7), 120.0 (C-2), 140.4 (C-3), 152.6
(C-6), 161.6 (C-1), 166.4 (7-C=O).
J
4,5 = 6.6 Hz, 4-H), 4.99 (d, 1 H, JNH,4 = 8.8 Hz, NH), 5.08 (s, 2 H,
benzyl-CH2), 6.48 (d, 1 H, J3,4 = 9.5 Hz, 3-H), 7.30–7.41 (m, 5 H,
Ar-H); minor rotamer: d = 0.94 and 0.972 (2 d, 3 H each, J5-Me,5
MS (CI, 40 eV): m/z (%) = 394 (100, [M + NH4]+), 377 (24, [M +
/
H]+).
J6,5 = ca. 7.0 Hz, 6-CH3, 5-CH3), 1.16 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3),
1.76 (dqq, 1 H, J5,4 = J5,5-Me = J5,6 = 6.8 Hz, 5-H), 3.97–4.03 (m, 2
H, 1¢-H2), 4.79–4.84 (m, 1 H, 4-H), 4.94 (d, 1 H, JNH,4 = 8.8 Hz,
NH), 5.09 (s, 2 H, benzyl-CH2), 6.41 (d, 1 H, J3,4 = 9.7 Hz, 3-H),
7.30–7.41 (m, 5 H, Ar-H).
13C NMR (125.7 MHz, 263 K, CDCl3, major:minor
rotamer = 80:20): major rotamer: d = 14.0 (C-2¢), 18.1 and 19.0 (5-
CH3, C-6), 32.2 (C-5), 56.0 (C-4), 62.6 (C-1¢), 66.9 (benzyl-CH2),
113.3 (C-2), 128.3 (3 × CHarom), 128.5 (2 × CHarom), 135.9 (Cipso),
146.3 (C-3), 155.6 (carbamate-CO), 162.4 (C-1); minor rotamer:
d = 13.8 (C-2¢), 18.3 and 18.9 (5-CH3, 6-C), 32.1 (C-5), 56.6 (C-4),
62.4 (C-1¢), 67.1 (benzyl-CH2), 112.9 (C-2), 127.8 (2 × CHarom),
128.0 (Cpara), 128.4 (2 × CHarom), 135.8 (Cipso), 146.9 (C-3), 156.1
(carbamate-CO), 162.2 (C-1).
HRMS (EI): m/z calcd for C14H18BrO6 ([M – CH3]+): 361.0287;
found: 361.0288.
Ethyl (2E,4S,5S,6E,8E)-2-Bromo-4,5-dihydroxy-4,5-O,O-iso-
propylidene-9-(methoxycarbonyl)-6-methylnona-2,6,8-
trienoate (40)
According to the general olefination procedure, a 57:32:9:2 mixture
of 6b/7b/52/49 [1.057 g, containing 53.2 wt% 6b: 562.3 mg, 1.409
mmol, 0.71 equiv; 35.7 wt% 7b : 377.3 mg, 789.4 mmol, 0.40 equiv;
9.4 wt% 52: 99.4 mg, 221 mmol, 0.11 equiv; 1.7 wt% 49: 18.0 mg,
50.7 mmol, 0.025 equiv (total: 1.2 equiv); 2.2 mmol 6b/7b/52/49 per
g mixture], NaH (60% in mineral oil, 63.8 mg, 1.59 mmol, 0.80
equiv) and methyl (2E,4E,6S,7R)-6,7-dihydroxy-6,7-O,O-isopro-
pylidene-5-methyl-8-oxoocta-2,4-dienoate27 (39; 506.8 mg, 1.993
mmol) were reacted for 90 min in THF (25 mL). Flash chromatog-
raphy [∆ 5.5 cm, h 20 cm, cyclohexane–EtOAc, 10:1 (3300 mL),
1–26 (100 mL), 40 and 2-chloro-2-debromo-40: 11–22] provided
the title compound 40 and its chlorine analogue (651.1 mg, 81%,
40:2-chloro-2-debromo-40 = 93:7 mol:mol) as a colorless oil. The
E:Z ratio of 40 prior to chromatography was 98:2 according to 1H
MS (EI, 70 eV): m/z (%) = 383 (7, M+), 340 (16), 91 (100).
Anal. Calcd for C17H22BrNO4 (384.2): C, 53.14; H, 5.77; N, 3.65.
Found: C, 53.16; H, 5.77; N, 3.56.
Ethyl (2E,5S)-5-[(Benzyloxy)carbonylamino]-2-bromo-6-meth-
ylhept-2-enoate (44)
According to the general olefination procedure, a 64:36 mixture of
6b/7b [336.7 mg, containing 60 wt% 6b: 202.0 mg, 506.3 mmol,
0.83 equiv; 40 wt% 7b: 134.7 mg, 281.8 mmol, 0.46 equiv (total: 1.3
20
NMR spectroscopy; Rf = 0.65 (cyclohexane–EtOAc, 1:1); [a]D
–17.4 (c = 0.96, CHCl3).
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2150
T. Olpp, R. Brückner
PAPER
equiv); 2.3 mmol 6b/7b per g mixture], NaH (60% in mineral oil,
24.4 mg, 611 mmol, 1.0 equiv) and (R)-3-(benzyloxycarbonylami-
no)-4-methylpentanal29 (43; 152.2 mg, 610.5 mmol) were reacted
for 30 min in THF (10 mL). Flash chromatography [∆ 2.5 cm, h 17
cm, cyclohexane–EtOAc 4:1 (600 mL), 1–20 (20 mL), cyclohex-
ane–EtOAc 3:1 (200 mL), 21–30 (20 mL), (E)-44: 9–13, (Z)-44 and
unreacted 7b: 14–18, unreacted 6b: 22–25] provided the title com-
pound (E)-44 (204.9 mg, 84%) as a white solid. The E:Z ratio of 44
prior to chromatography was 93:7 according to 1H NMR spectros-
271.6 mmol) in NMP (4 mL) were added. The reaction mixture was
then degassed by freezing with liquid nitrogen under vacuum and
thawing under argon. After 3 degassing cycles, CuI (85.3 mg, 448
mmol, 1.65 equiv) was added and the mixture was stirred at r.t. for
27 h. The mixture was poured onto a sat. aq solution of NH4Cl (20
mL) and extracted with EtOAc (3 × 60 mL). The combined extracts
were washed with water (5 × 150 mL) to remove the high boiling
solvent. The organic layer was dried (Na2SO4) and the solvent was
evaporated under reduced pressure. After flash chromatography [∆
4 cm, h 34 cm, cyclohexane–EtOAc, 25:1 (1040 mL), 1–25 (20
mL), cyclohexane–EtOAc, 20:1 (1575 mL), 26–85 (20 mL), (E)-
48: 46–60, dba and P(2-furyl)3: 74–85] compound (E)-48 (90.4 mg,
68%) was obtained as a colorless oil; Rf = 0.21 (cyclohexane–
EtOAc, 10:1); [a]D20+45.2 (c = 1.05, CHCl3).
20
copy; Rf = 0.59 (cyclohexane–EtOAc, 1:1); mp 60–62 °C; [a]D
–54.5 (c = 1.17, CHCl3).
IR (neat): 3310, 2960, 1705, 1690, 1540, 1365, 1340, 1310, 1230,
1115, 1025, 915, 750, 695 cm–1.
1H NMR (499.9 MHz, CDCl3): d = 0.91 and 0.93 (2 d, 3 H each,
IR (neat): 2955, 2930, 2860, 1700, 1620, 1460, 1380, 1370, 1250,
1200, 1170, 1145, 1095, 1010, 905, 840, 780 cm–1.
J6-Me,6/J7,6 = 6.8/6.9 Hz, 6-CH3, 7-CH3), 1.32 (t, 3 H, J2¢,1¢ = 7.1 Hz,
2¢-CH3), 1.79 (dqq, 1 H, J6,5 = J6,6-Me = J6,7 = 6.6 Hz, 6-H), AB sig-
nal (dA = 2.55, dB = 2.73, 2 H, 2JAB = 15.1 Hz, split by JA,3 = 7.1 Hz,
1H NMR (500.0 MHz, CDCl3): d = 0.05 and 0.06 [2 s, 3 H each,
Si(CH3)2], 0.89 [s, 9 H, SiC(CH3)3], 1.10 and 1.12 [2 s, 6 H, 2¢¢-
(CH3)2], 1.29 (t, 3 H, J2¢¢¢,1¢¢¢ = 7.1 Hz, 2¢¢¢-CH3), 1.36 and 1.41 [2 s,
3 H each, C(CH3)2], 1.51–1.54 (m, 2 H, 3¢¢-CH2), 1.68–1.74 (m, 2
H, 4¢¢-CH2), 2.21–2.30 (m, 2 H, 5¢¢-CH2), 2.78–2.80 (m, 2 H, 3-
CH2), AB signal (dA = 3.65, dB = 3.74, 2 H, 2JAB = 11.0 Hz, split by
JA,5 = 4.3 Hz, JB,5 = JB,3 = 9.5 Hz, 4-CH2), 3.67 (dddd, 1 H,
J5,4-H(B) = J5,NH = 9.5 Hz, J5,6 = J5,4-H(A) = 4.8 Hz, 5-H), 4.24 (q, 2 H,
1¢,2¢ = 7.1 Hz, 1¢-CH2), 4.92 (br d, 1 H, JNH,5 = 9.5 Hz, NH), AB sig-
J
2
nal (dA = 5.07, dB = 5.12, 2 H, JAB = 12.4 Hz, benzyl-CH2), 6.69
(dd, 1 H, J3, 4-H(B) = 8.7 Hz, J3, 4-H(A) = 7.3 Hz, 3-H), 7.29–7.38 (m,
5 H, Ar-H).
J
A,5 = 4.5 Hz, JB,5 = 3.8 Hz, 6-CH2), 3.78 (ddd, 1 H, J5,4 = 7.9 Hz,
J5,6-H(A) = J5,6-H(B) = 4.0 Hz, 5-H), 4.07 (hardly resolved dt, 1 H,
4,5 = 7.8 Hz, J4,3 = 6.3 Hz, 4-H), 4.19 (q, 2 H, J1¢¢¢,2¢¢¢ = 7.1 Hz, 1¢¢¢-
13C NMR (125.7 MHz, CDCl3): d = 14.0 (C-2¢), 17.8 and 18.9 (C-
7, 6-CH3), 32.4 (C-6), 33.9 (C-4), 55.7 (C-5), 62.3 (C-1¢), 66.6 (ben-
zyl-CH2), 112.8 (C-2), 127.9, 128.0 and 128.5 (5 × CHarom), 136.6
(Cipso), 145.1 (C-3), 156.4 (carbamate-CO), 163.1 (C-1).
J
CH2), 4.68 (d, 1 H, 2J6¢¢ =CH(Z),6¢¢ =CH(E) = 2.5 Hz, 6¢¢ =CHZ), 5.14 (dt,
1 H, J6¢¢ =CH(E),6¢¢ =CH(Z) = 2.5 Hz, J6¢¢ =CH(E),5¢¢ = 1.2 Hz, 6¢¢ =CHE),
6.34 (d, 1 H, J2¢,1¢ = 11.5 Hz, 2¢-H), 7.72 (d, 1 H, J1¢,2¢ = 11.4 Hz, 1¢-
2
4
MS (EI, 70 eV): m/z (%) = 397 (0.1, M+), 354 (1), 91 (100).
H).
13C NMR (125.7 MHz, CDCl3): d = –5.4 and –5.3 (2 × SiCH3), 14.3
(C-2¢¢¢), 18.4 [SiC(CH3)3], 23.1 (C-4¢¢), 25.9 [SiC(CH3)3], 27.0 and
27.4 [C(CH3)2], 27.6 and 27.7 [2¢¢-(CH3)2], 31.0 (C-3), 37.0 (C-5¢¢),
38.9 (C-2¢¢), 41.3 (C-3¢¢), 60.4 (C-1¢¢¢), 63.3 (C-6), 76.9 (C-4), 81.6
(C-5), 108.6 [C(CH3)2], 115.0 (6¢¢ =CH2), 116.3 (C-2¢), 125.4 (C-2),
139.3 (C-1¢), 145.3, 160.9 and 168.4 (C-1, C-1¢¢, C-6¢¢).
MS (ESI): m/z (%) = 1007 (100, [2 M + Na]+), 515 (58, [M + Na]+).
HRMS (EI): m/z calcd for C27H45O5Si ([M – CH3]+): 477.3036;
Anal. Calcd for C18H24BrNO4 (398.3): C, 54.28; H, 6.07; N, 3.52.
Found: C, 54.23; H, 6.02; N, 3.62.
(5S)-3-Bromo-5-[(1S)-1,2-dihydroxyethyl]-2(5H)-furanone (45)
To a solution of bromoacrylate (E)-36 (isomerically pure, chlorine-
free; 219.5 mg, 518.4 mmol) in MeOH (10 mL) was added p-tolue-
nesulfonic acid monohydrate (20.0 mg, 105 mmol, 20 mol%) was
added. The mixture was refluxed for 10 min. After cooling to r.t.,
the mixture was evaporated under reduced pressure. The crude
product was separated from the catalyst by flash chromatography
[∆ 2.5 cm, h 17 cm, cyclohexane–EtOAc, 1:2 (600 mL), 1–20 (20
mL), cyclohexane–EtOAc, 1:3 (600 mL), 21–40 (20 mL), 45: 21–
36] and the product (115.5 mg, 99%) was obtained as a white solid;
Rf = 0.25 (EtOAc); mp 107–109 °C; [a]D20 –20.5 (c = 1.12, CHCl3).
found: 477.3040.
Anal. Calcd for C28H48O5Si (492.8): C, 68.25; H, 9.82. Found: C,
67.70; H, 9.57.
Ethyl Chloro(diphenylphosphono)acetate (49) Separated from
a 11:47:42 Mixture with Ethyl (Diphenylphosphono)acetate
(9b) and Ethyl Dichloro(diphenylphosphono)acetate (50)
To a solution of phosphonate 9b (642 mg, 2.00 mmol) in THF (10
mL) was added NaH (60% in mineral oil, 96.0 mg, 2.40 mmol, 1.2
equiv) portionwise at r.t. during a period of 5 min. After 10 min at
r.t., the gas evolution had ceased and N-chlorosuccinimide (320 mg,
2.40 mmol, 1.2 equiv) was added in one portion. After 40 min, H2O
(20 mL) was added and the resulting mixture was extracted with
MTBE (3 × 20 mL). The combined organic extracts were dried
(Na2SO4) and evaporated under reduced pressure. The residue
(712 mg) was separated by flash chromatography [∆ 3 cm, h 20
cm, cyclohexane–EtOAc, 5:1 (600 mL), 1–25 (20 mL), cyclohex-
ane–EtOAc, 1:1 (300 mL), 26–40 (20 mL), 49: 11–17, 50: 21–26,
9b: 28–30]. The products [49: 256.3 mg, 36%; 50: 250.9 mg, 32%;
recovered 9b: 47.9 mg, 7.5%; total yield: 76%] were obtained as hy-
groscopic colorless oils.
IR (neat): 3420, 3090, 2930, 2885, 1770, 1605, 1560, 1455, 1260,
1160, 1105, 1025, 980, 880 cm–1.
1H NMR (500.0 MHz, CDCl3): d = 1.82 (br s, 2 H, 2 × OH), AB sig-
nal (dA = 3.79, dB = 3.84, 2 H, 2JAB = 11.4 Hz, split by JA,1¢ = 5.1 Hz,
JB,1¢ = 4.5 Hz, 2¢-CH2), 3.91 (ddd, 1 H, J1¢,2¢¢-H(A) = J1¢,2¢¢-H(B) =
J1¢,5 = 4.8 Hz, 1¢-H), 5.11 (dd, 1 H, J5,1¢ = 4.7 Hz, J5,4 = 1.7 Hz, 5-H),
7.58 (d, 1 H, J4,5 = 1.9 Hz, 4-H).
13C NMR (125.7 MHz, CDCl3): d = 62.8 (C-2¢), 71.6 (C-1¢), 83.4
(C-5), 113.9 (C-3), 149.8 (C-4), 168.0 (C-2).
MS (CI, 120 eV): m/z (%) = 223 (64, [M + H]+), 205 (9), 69 (100).
Anal. Calcd for C6H7BrO4 (223.0): C, 32.31; H, 3.16. Found: C,
33.06; H, 3.32.
Ethyl (2E,4S,5S)-6-(tert-Butyldimethylsiloxy)-2-[(2Z)-2-(2,2-
dimethyl-6-methylenecyclohexylidene)ethylidene]-4,5-dihy-
droxy-4,5-O,O-isopropylidenehexanoate (E-48)
A suspension of Pd2dba3·CHCl3 (28.1 mg, 27.2 mmol, 10 mol%) and
tri(2-furyl)phosphine (37.8 mg, 163 mmol, 60 mol%) in NMP (4
mL) was stirred under argon at r.t. for 30 min. After a clear yellow
solution had formed, dienylstannane 4623 (155.1 mg, 353.1 mmol,
1.3 equiv) in NMP (4 mL) and bromoacrylate (E)-36 (115.0 mg,
49
Rf = 0.53 (cyclohexane–EtOAc, 1:1).
IR (neat): 3070, 2985, 2940, 1760, 1590, 1495, 1370, 1285, 1180,
1025, 965, 760, 690 cm–1.
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

PAPER
(E)-a-Bromoacrylates from Ando Phosphonates
2151
1H NMR (400.1 MHz, CDCl3): d = 1.28 (t, 3 H, J2¢,1¢ = 7.3 Hz, 2¢-
CH3), 4.29 (q, 2 H, J1¢,2¢ = 7.3 Hz, 1¢-CH2), 4.79 (d, 1 H, 2J2,P = 15.9
Hz, 2-H), 7.19–7.30 (m, 6 H, Ar-H), 7.31–7.37 (m, 4 H, Ar-H).
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Chem. 2002, 67, 5669.
(9) (a) Satoh, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1991, 56, 2278. (b) Kawaguchi, M.; Satoh, S.; Mori,
M.; Shibasaki, M. Chem. Lett. 1992, 395. (c) Allan, G. M.;
Parsons, A. F.; Pons, J.-F. Synlett 2002, 1431.
13C NMR (100.1 MHz, CDCl3): d = 13.9 (C-2¢), 49.8 (d,
1J2,P = 149.7 Hz, C-2), 63.5 (C-1¢), 120.48 and 120.51 (2 d,
3J2¢¢,P = 3.6 Hz, 2 × 2 × C-2¢¢), 125.76 and 125.82 (2 × C-4¢¢), 129.8
2
and 129.9 (2 × 2 × C-3¢¢), 150.0 and 150.1 (2 d, J1¢¢,P = 8.7 Hz,
2 × C-1¢¢), 163.9 (C-1).
31P NMR (121.5 MHz, CDCl3): d = 4.96.
MS (EI, 70 eV): m/z (%) = 353 (100, M+).
HRMS (EI): m/z calcd for C16H16ClO5P (M+): 354.0424; found:
354.0434.
Ethyl 2-Chloro-3-(4-methoxyphenyl)propenoate (51)
To a solution of phosphonate 49 (204.2 mg, 575.7 mmol, 1.2 equiv)
in THF (10 mL) was added NaH (60% in mineral oil, 96.0 mg, 2.40
mmol, 1.2 equiv) portionwise at 0 °C during a period of 5 min. After
10 min at 0 °C, the gas evolution had ceased and 4-methoxybenzal-
dehyde (58.1 mL, 65.3 mg, 480 mmol) was added. The reaction mix-
ture was stirred for 50 min, while a white precipitate was formed.
H2O (10 mL) was added and the mixture was extracted with MTBE
(3 × 20 mL). The combined extracts were dried (Na2SO4) and the
solvents were evaporated under reduced pressure. The residue was
purified by flash chromatography [∆ 3.5 cm, h 20 cm, cyclohex-
ane–EtOAc, 12.5:1 (500 mL), 1–15 (20 mL), cyclohexane–EtOAc,
8:1 (340 mL), 16–35 (20 mL), 51: 23–30], while the isomers could
not be separated. The products [92.3 mg, 80%, (E)-51:(Z)-
51 = 94:6] were obtained as a colorless oil; Rf = 0.31 (cyclohexane–
EtOAc, 5:1).
IR (neat): 2980, 1725, 1605, 1510, 1460, 1370, 1300, 1260, 1220,
1180, 1115, 1030, 830 cm–1.
1H NMR [499.9 MHz, CDCl3; (E)-51:(Z)-51 = 94:6]: (E)-51:
d = 1.24 (t, 3 H, J2¢,1¢ = 7.1 Hz, 2¢-CH3), 3.81 (s, 3 H, OCH3), 4.24
(q, 2 H, J1¢,2¢ = 7.1 Hz, 1¢-CH2), 6.84–6.89 (m, 2 H, 2 × 3¢¢-H), 7.13
(s, 1 H, 3-H), 7.29–7.32 (m, 2 H, 2 × 2¢¢-H); (Z)-51: d = 1.38 (t, 3 H,
J
2¢,1¢ = 7.1 Hz, 2¢-CH3), 3.85 (s, 3 H, OCH3), 4.34 (q, 2 H, J1¢,2¢ = 7.1
Hz, 1¢-CH2), 6.93–6.96 (mc, 2 H, 2 × 3¢¢-H), 7.84–7.87 (mc, 2 H,
2 × 2¢¢-H), superimposed by 7.85 (s, 1 H, 3-H).
13C NMR [125.7 MHz, CDCl3; (E)-51:(Z)-51 = 94:6]: (E)-51:
d = 13.8 (C-2¢), 55.3 (OCH3), 62.1 (C-1¢), 113.7 (2 × C-3¢¢), 120.8
(C-2), 126.2 (C-1¢¢), 130.5 (2 × C-2¢¢), 137.2 (C-3), 160.2 and 163.7
(C-4¢¢, C-1); (Z)-51: d = 14.2 (C-2¢), 55.3 (OCH3), 62.4 (C-1¢),
114.0 (2 × C-3¢¢), 132.7 (2 × C-2¢¢), 136.4 (C-3), 161.1 (C-4¢¢ or
C-1).
MS (EI, 70 eV): m/z (%) = 240 (100, M+).
Anal. Calcd for C12H13ClO3 (240.7): C, 59.88; H, 5.44. Found: C,
59.83; H, 5.58.
Ethyl Bromochloro(diphenylphosphono)acetate (52)
This compound arose as a contaminant in some preparations of
ethyl bromo(diphenylphosphono)acetate (6b)/dibromo(diphenyl-
phosphono)acetate (7b) (as mentioned above).
MS (EI, 70 eV): m/z (%) = 432 (26, M+), 240 (100).
Acknowledgment
(10) Kakehi, A.; Ito, S.; Sa, H. Chem. Pharm. Bull. 1999, 47,
1607.
We are indebted to Alexandra Müller for skillful preparative sup-
port. T. O. thanks the Fonds der Chemischen Industrie for a Kekulé
doctoral stipend.
(11) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 111.
(12) (a) Smith, A. B. III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 1995, 117, 12011. (b) Smith, A. B. III;
Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu,
Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 2000, 122, 8654.
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York

2152
T. Olpp, R. Brückner
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(29) Aldehyde 43 was generously provided by Professor J.
Podlech, Universität Karlsruhe.
Synthesis 2004, No. 13, 2135–2152 © Thieme Stuttgart · New York