An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol

Article abstract of DOI:10.1016/j.tet.2007.06.071

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol has been devised. This new route increases the throughput and yield of the diene product by circumventing a low yielding preparation of boronic acid intermediate as well as removing the need to use multi-gram quantities of highly toxic thallium salts. In the process of developing this new route, a higher yielding preparation of (E)-3-hydroxyprop-1-enylboronic acid was also achieved.

Full text of DOI:10.1016/j.tet.2007.06.071

Tetrahedron 63 (2007) 9124–9128
An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-
2,4-dien-1-ol*
Paul A. Clarke,a,b, Gabriele A. Rolla,a,b Andrew P. Cridlandb and Andrew A. Gilla
*
aDepartment of Chemistry, University of York, Heslington, York, YO10 5DD, UK
bSchool of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Received 24 May 2007; revised 16 June 2007; accepted 21 June 2007
Available online 27 June 2007
Abstract—An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol has been devised. This new route increases the
throughput and yield of the diene product by circumventing a low yielding preparation of boronic acid intermediate as well as removing
the need to use multi-gram quantities of highly toxic thallium salts. In the process of developing this new route, a higher yielding preparation
of (E)-3-hydroxyprop-1-enylboronic acid was also achieved.
Ó 2007 Elsevier Ltd. All rights reserved.
PMBO
PMBO
OSEM
1. Introduction
HO
OBn
The efficient synthesis of functionalized dienes with defined
double bond geometries (Fig. 1) is an important goal in or-
ganic synthesis,1 as they are frequently used as intermediates
in the construction of natural products. Such dienes are usu-
ally desired as precursors to Diels–Alder cyclisations, or as
substrates for other stereocentre generating reactions like di-
hydroxylations and epoxidations. In all of these instances the
geometries of the double bonds are of paramount impor-
tance, as it translates generally into the stereochemistry pres-
ent in the product.
Br
CO2Me
1
2
OPMB
HO
Cl
OH
MeO
3
4
Br
CO2Et
Figure 1.
We and others have had cause to synthesise such dienes en
route to a number of natural products. For example, several
groups have reported strategies towards fragments of hexa-
cyclinic acid2 or the related FR1828773 via Diels–Alder re-
actions of systems similar to those in Figure 1. We on the
other hand, required significant quantities of diene 1 for
our approach to the AB-rings of hexacyclinic acid.4 Simi-
larly, Nicolaou required diene 2 for his synthesis of zara-
gozic acid A,5 while Roush needed triene 3 for the
synthesis of the superstolides6 and Evans synthesised diene
4 en route to the callipeltoside A side chain7 (Fig. 1).
In the cases of dienes 1, 3 and 4 a synthetic strategy was
adopted, which involved formation of the diene’s C2–C3
single bond, by use of a Suzuki reaction of a vinyl halide
with boronic acid 54,6,7 (Scheme 1). Roush has shown that
regioselective cross-couplings are possible between boronic
acids and 1,1-dibromoalkenes, since the rates of palla-
dium(0) catalysed cross-coupling reactions of E-1-bromo-
alkenes are substantially greater than for those reactions
with Z-1-bromoalkenes. Roush also found that standard Su-
zuki cross-coupling conditions (cat. Pd(PPh3)4, aq NaOH,
PhH, reflux) gave low yields, but the use of Kishi’s modifi-
cation (replacing NaOH with TlOH) led to an increased
rate of reaction, such that sluggish Suzuki couplings often
reached completion rapidly when TlOH was used.8 More re-
cently, Roush demonstrated that the unstable TlOH can be
substituted for TlOEt with retention of reactivity and selec-
tivity.9 The high yield and convergence of this coupling are
attractive, and as such this was our preferred route to 1.
While on paper this looks an attractive disconnection, in
practise it suffers from a number of attributes, which make
it less desirable.
*
Taken in part from the Ph.D. thesis of Andrew P. Cridland, University of
Nottingham, 2007.
Keywords: Functionalised dienes; Hexacyclinic acid; (E)-3-Hydroxyprop-
1-enylboronic acid; Scaleable synthesis.
* Corresponding author at present address: Department of Chemistry,
University of York, Heslington, York, YO10 5DD, UK. Tel.: +44 1904
432614; e-mail: pac507@york.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.071

P. A. Clarke et al. / Tetrahedron 63 (2007) 9124–9128
9125
Br
improved synthesis of diene 1, which increased the overall
yield of 1, and removed the need to synthesize boronic acid
5 and the large quantities of highly toxic thallium salts.
HO
Br
Br
HO
B(OH)2
B(OH)2
OBn
1 Br
5
6
OBn
Cl
Br
i
HO
B(OH)2
HO
HO
Cl
HO
5
HO
Br
4
5
7
iii
Br
OBn
O
ii
Br
1
Br
Scheme 1.
OBn
H
OBn
6
Scheme 2. Reagents and conditions: (i) catecholborane, 25–30%; (ii) PPh3,
CBr4, CH2Cl2, 0 ꢀC, 87% and (iii) 10 mol % Pd(PPh3)4, THF, water,
Tl2CO3, 77%.
2. Results and discussion
The two 3-carbon fragments required for the Suzuki strategy
are both known compounds synthesised in one step from
commercially available starting materials. 1,1-Dibromo-3-
benzyloxyprop-1-ene 6 was produced in good yield from
(benzyloxy)acetaldehyde using Corey–Fuchs methodology
(Scheme 2).10 However, the primary problem with this ap-
proach to the synthesis of 1 (Scheme 2) is the synthesis of
boronic acid 5, which was originally reported by Roush, al-
though no experimental details were given in that or subse-
quent reports.6 Our initial attempts at the hydroboration of
propargyl alcohol were met with failure, but a more thorough
experimental procedure, obtained via personal correspon-
dence with the original author,11 did permit its synthesis.
The synthesis of 5 can be achieved by the slow addition of
catecholborane to neat propargyl alcohol at 0 ꢀC under argon
to give the catecholborane ester. Hydrolysis with water pro-
duced a white foam, which was saturated with NaCl and ex-
haustively extracted with EtOAc followed by flash column
chromatography.11 This generated 5 in an abysmal 7% yield.
Removal of the extraction conditions and direct application
of the aqueous mixture to flash silica resulted in an increase
in the isolated yield of 5 to 10–12%. However, it proved ap-
parent that the extended purification times were detrimental
to the yield of the product, and addressing this problem
directly was difficult. In our highest yielding procedure
two-solvent systems were required for chromatography:
EtOAc–petrol ether (40–60) (1:1) to remove the catechol,
followed by CH2Cl2–MeOH (9:1) to remove the boronic
acid 5. On a large scale this resulted to the product being ex-
posed to silica for up to 4 h. It was reasoned that using a larger
grain of silica could speed up the purification procedure and
prevent excessive decomposition of the product. Thus, when
the two-solvent system of chromatographic purification was
run using Kieselgel 60 (0.2–0.5 mm) the chromatography
time required was reduced and the yield of 5 increased to
25–30%.12 The subsequent Suzuki reaction proceeded well
and in 77% yield. However, this yield was only obtainable
when Tl2CO3 was used as the base in order to suppress the
formation of triene by reaction of a further equivalent of 5
Our second generation synthesis of 1 (Scheme 3) began with
the mono-benzylation of cis-buten-1,4-diol with NaH, BnCl
and n-Bu4NI in THF/DMSO in 78% yield.14 Parikh–Doering
oxidation generated aldehyde 9 quantitatively in which iso-
merisation of the double bond had taken place. Treatment
of 9 with bromine followed by the addition of pyridine
generated a-bromoaldehyde 10 in 70% yield.15,16 Wittig ole-
fination installed the second double bond as a single (E)-
geometric isomer in 64% yield. Further enhancement of the
yield of this oxidation–bromination-Wittig sequence could
be achieved by the addition of (triphenylphosphoranylide-
ne)acetate to the bromination reaction 1 h after the addition
of pyridine.15,16 This generated 11 in an improved yield of
70% over the bromination-Wittig steps. Reduction of ester
11 with DIBAL-H gave diene 1 in 92% yield. Spectroscopic
analysis of 1 showed it to be identical to the compound pro-
duced by our procedure reported previously.4 Furthermore
we found that it was possible to telescope several of the steps
in this second generation synthesis together. Bromination
was achieved by the direct addition of bromine and pyridine
to aldehyde 9. This was followed by addition of the ylide for
the Wittig reaction when the bromination was seen to be com-
plete by analysis of an aliquot of the reaction mixture by 1H
NMR. Ester 11 was isolated from the reaction by precipita-
tion of the triphenylphosphine oxide with Et2O–petrol ether
(40–60) 3:1. Crude 11 was then treated with DIBAL-H and
the resultant desired bromodiene 1 was isolated by filtration
through a plug of silica in 64% yield over three steps.
OH
OH
O
i
ii
iii
8
9
OH
O
OBn
OBn
vi
OH
vii
Br
MeO2C
iv
Br
Br
v
with the bromodiene 1.3c Use of less toxic Ba(OH)2 or
13
Cs2CO3 led to much longer reaction times and reduced yields
of 37% and 39%, respectively. Even Roush’s reported condi-
tions utilising TlOEt9 only delivered the product in 42%
yield. However, as we desired to generate multi-gram quan-
tities of 1 for our synthesis this required the use of large
amounts of toxic Tl2CO3. For example generating 13 g of
diene 1 necessitated the use of 50 g of Tl2CO3. This coupled
with the crippling yields for the formation of 5 forced us to re-
evaluate our synthesis. We now wish to disclose our
10
11
1
OBn
OBn
OBn
Scheme 3. Reagents and conditions: (i) NaH, BnCl, n-Bu4NI, THF/DMSO,
60 ꢀC, 78%; (ii) SO3$Py, DIPEA, CH2Cl2, rt, 100%; (iii) Br2, 30 min, Py,
CH2Cl2, 0 ꢀC, 62%; (iv) MeO2CCHPPh3, CH2Cl2, 64%; (v) DIBAL-H/hex-
ane, THF, ꢁ78 ꢀC, 92%; (vi) Br2, 30 min, Py, CH2Cl2, 0 ꢀC, 1 h then
MeO2CCHPPh3 70% (two steps) and (vii) Br2, 30 min, Py, CH2Cl2, 0 ꢀC,
1 h then MeO2CCHPPh3, DIBAL-H/hexane, THF, ꢁ78 ꢀC, 64% (three
steps).

9126
P. A. Clarke et al. / Tetrahedron 63 (2007) 9124–9128
3. Conclusions
0 ꢀC was added bromine (15.6 ml, 302 mmol), the mixture
was stirred for 15 min at 0 ꢀC then treated with pyridine
(93.2 ml, 1.15 mol) and stirred for a further 1 h at 0 ꢀC.
Methyl (triphenylphosphoranylidene)acetate (192.7 g,
576 mmol) was then added, and the reaction mixture was
stirred for 24 h at rt and concentrated in vacuo. The bulk
of triphenylphosphine oxide was removed by trituration of
the crude solid with Et2O–petroleum ether (40–60) 3:1 fol-
lowed by filtration and concentrated in vacuo, which gave
a brown solid. The brown solid was then triturated with
hot petroleum ether (40–60), filtered and concentrated in
vacuo, which gave a brown solid (84.9 g, crude). A 1 M so-
lution of DIBAL-H (543 ml) in hexane was added to a solu-
tion of crude 6-benzyloxy-4-bromo-hexa-2,4-dienoic acid
methyl ester (84.9 g) in THF (1.1 l) over 2 h. After 30 min
the reaction was diluted with EtOAc (1 l), quenched with
10% solution of Rochelles’ salt (1 l) and stirred for 8 h.
The organic layer was washed with 10% Rochelles’ salt
(2ꢂ400 ml) and brine (200 ml). The aqueous layer was
extracted with EtOAc (3ꢂ1 l) and the combined organic
layers were washed with 10% Rochelles’ salt (2ꢂ400 ml)
and brine (400 ml). The combined organic layers were dried
(MgSO4), concentrated in vacuo and subjected to filtration
over a plug of silica to give a pale yellow oil (51.4 g, 63%
over four steps).
We have developed an improved procedure for the synthesis
and isolation of boronic acid 5, although for our purposes
even this improved procedure was insufficient to solve
our supply problem of diene 1. Therefore we had to develop
a second generation synthesis of 1, which takes place in five
steps and can provide over 50 g of 1, without the use of toxic
thallium salts. The improved second generation route pro-
vides 1 in an overall yield of 51% compared to our original
synthesis, which supplied it in only 19% yield.
4. Experimental
4.1. General
All melting points are uncorrected. Reaction progress was
monitored using glass-backed TLC plates pre-coated with
silica UV254 and visualised by using either UV radiation
(254 nm), ceric ammonium molybdate or anisaldehyde
stains. Column chromatography was performed using silica
gel 60 (220–240 mesh), with the solvent systems indicated in
the relevant experimental procedures. Dichloromethane was
distilled from calcium hydride; tetrahydrofuran and diethyl
ether were distilled from sodium/benzophenone ketyl,
DMSO was distilled from calcium hydride prior to use. Hex-
ane was distilled prior to use. All other reagents were used as
received from commercial suppliers unless stated otherwise
in the appropriate text.
nmax (solution; CHCl3) 3616, 2922, 2863, 1651, 1614, 1454,
1088 cmꢁ1. dH (400 MHz; CDCl3) 7.37–7.27 (5H, m, Ph),
6.31 (1H, d, J¼15.0 Hz, H3), 6.25 (1H, dt, J¼15.0 and
5.0 Hz, H2), 6.19 (1H, t, J¼6.0 Hz, 5-H), 4.54 (2H, s, H7),
4.31 (4H, apparent d, J¼5.0 Hz, H1 and H6) ppm. dC
(100 MHz; CDCl3) 137.9 (C, Ph), 134.2 (CH, C2), 130.8
(CH, C5), 128.9 (CH, C3), 128.4 (CH, Ph), 127.8 (CH,
Ph), 127.8 (CH, Ph), 125.1 (C, C4), 72.7 (CH2, C7), 69.6
(CH2, C6), 62.4 (CH2, C1) ppm. MS m/z (CI) 302 and 300
([1:1, (M+NH4)+], 286 and 284 (1:1, [M+H]+), 204
(M+HꢁBr)+; found M+NH4 300.0594, C13H1979BrNO2 re-
quires M+NH4 300.0594.
4.1.1. (2E,4Z)-6-(Benzyloxy)-4-bromohexa-2,4-dien-1-
ol 1.
4.1.1.1. Original synthesis coupling of boronic acid 5
and bromide 6. Nitrogen was bubbled through a solution
of dibromoalkene 6 (18.1 g, 59.2 mmol) and boronic acid
5 (6.64 g, 65.2 mmol) in THF–water (3:1, 400 ml) at rt for
2 h. Under a flow of N2, Pd(PPh3)4 (3.42 g, 2.96 mmol)
and Tl2CO3 (50.0 g, 107 mmol) were added sequentially
and the resulting green-brown solution with pale precipitate
was stirred at rt for 44 h. The suspension was added to a 1 M
aqueous solution of NaHSO4 (150 ml) and then stirred until
gas evolution ceased (1 h). The mixture was filtered through
Celite, then extracted with EtOAc (2ꢂ150 ml). The com-
bined organics were washed with brine (150 ml), dried
(MgSO4), filtered and concentrated in vacuo to leave a crude
brown oil (22.1 g, overweight). Flash chromatography (pet-
rol ether (40–60)–EtOAc, 2:1) afforded an orange oil 1
(13.0 g, 77%).
4.1.4. (E)-3-Hydroxyprop-1-enylboronic acid 5. Catechol-
borane (113 ml, 833 mol) was added to neat propargyl al-
cohol (23.6 ml, 407 mmol) at 0 ꢀC under N2 at a rate of
2 ml minꢁ1 (CARE: gas evolution) with vigorous stirring.
The clear solution was allowed to warm to rt over 1 h dur-
ing which time it solidified (CARE: exotherm). The solid
was held at rt for 20 h. Water (5ꢂ10 ml) was added at
1 h intervals (CARE: gas evolution) and the mixture al-
lowed to stir for 24 h. The solid did not dissolve com-
pletely, so water (20 ml) was added and the mixture
stirred for a further 24 h. The resulting white foam was
added directly to a column of silica (w750 g; Kieselgel
60 (0.2–0.5 mm)). Elution with EtOAc–petroleum ether
(40–60) (1:1, 5 l) removed the catechol byproduct, then
MeOH (5–15%) in CH2Cl2 removed the product. Con-
centration in vacuo left a light-brown foam 5 (16.6 g,
40%). nmax (Nujol) 3375, 1642, 1334, 1197, 1085, 1001,
4.1.2. From ester 11. A 1 M solution of DIBAL-H (10.6 ml)
in hexane was added to a solution of 6-benzyloxy-4-bromo-
hexa-2,4-dienoic acid methyl ester (1.10 g, 3.54 mmol) in
THF (15 ml). After 15 min the reaction was quenched with
10% solution of Rochelles’ salt (15 ml) and stirred for 8 h.
After extraction of the aqueous layer with EtOAc
(3ꢂ15 ml) the combined organic layers were washed with
brine (10 ml), 10% solution of Rochelles’ salt (15 ml) and
brine (10 ml); dried (MgSO4) and concentrated in vacuo to
give a pale yellow oil (920 mg, 92%).
916, 775, 737 cmꢁ1
. dH (400 MHz; CD3OD) 6.57
(1H, dt, J¼18.0 and 4.0 Hz, H2), 5.81 (1H, dt, J¼18.0
and 2.0 Hz, H1), 4.11 (2H, dd, J¼4.0 and 2.0 Hz, H3)
ppm. dC (125 MHz; CD3OD) 153.1 (CH, C2), 66.2 (CH2,
C3) ppm. MS m/z (ESꢁ) 100 and 101 [1:4, (MꢁH)ꢁ];
found (EIꢁ) MꢁH 101.0405 C3H7O3B requires MꢁH
101.0405.
4.1.3. The telescoped procedure. To a solution of 4-benzyl-
oxy-but-2-enal (50.76 g, 288 mmol) in CH2Cl2 (600 ml) at

P. A. Clarke et al. / Tetrahedron 63 (2007) 9124–9128
9127
4.1.5. 3-(Benzyloxy)-1,1-dibromoprop-1-ene 6. To a solu-
tion of PPh3 (26.5 g, 101 mmol) in CH2Cl2 (150 ml) at 0 ꢀC
under Ar was added a solution of CBr4 (14.6 g, 43.9 mmol)
in CH2Cl2 (50 ml) at a rate of 1 ml minꢁ1, and the resulting
red solution was stirred at 0 ꢀC for 1 h. A solution of benzyl-
oxyacetaldehyde (5.06 g, 33.7 mmol) in CH2Cl2 (100 ml)
was added at a rate of 1 ml minꢁ1 then the solution was
stirred at 0 ꢀC warming to rt over 1 h, and at rt for a further
13 h. A saturated aqueous solution of NH4Cl (150 ml) was
added, the organic layers were separated and washed with
water (150 ml) and the combined aqueous layers were ex-
tracted with CH2Cl2 (3ꢂ100 ml). The combined organics
were washed with brine (200 ml), dried (MgSO4), filtered
and concentrated in vacuo to give a yellow solid. Hexane
(250 ml) was added and the suspension stirred for 14 h.
The solvent was decanted, then hexane (100 ml) added to
the residue and the suspension treated with sonication for
30 min. The suspension was filtered, and the combined
organics concentrated in vacuo to leave a pale yellow oil 6
(9.03 g, 87%). dH (270 MHz; CDCl3) 7.37–7.30 (5H, m,
Ph), 6.65 (1H, t, J¼6.0 Hz, H2), 4.53 (2H, s, H4), 4.06
(2H, d, J¼6.0 Hz, H3) ppm. Data in agreement with the
literature.17
131.8 (CH, C2), 128.5 (CH, Ph), 127.9 (CH, Ph), 127.6
(CH, Ph), 73.0 (CH2, C5), 68.5 (CH2, C4) ppm. MS
(ESI) m/z 199 (M+Na)+, 177 (M+H)+ and 159 (M+Hꢁ
H2O)+; found M+H 177.0910, C11H13O2 requires M+H
177.0916.
4.1.8. 4-Benzyloxy-2-bromo-but-2-enal 10. To a solution
of 4-benzyloxy-but-2-enal (23.2 g, 132 mmol) in CH2Cl2
(250 ml) was added bromine (7.15 ml, 139 mmol), the mix-
ture was stirred for 10 min at rt and then cooled at 0 ꢀC,
treated with pyridine (42 ml, 528 mmol) and stirred for a fur-
ther 30 min at 0 ꢀC. The reaction mixture was diluted with
Et2O (700 ml) then washed with 0.5 M HCl (5ꢂ150 ml)
and brine (2ꢂ100 ml) and dried (MgSO4). Concentration
in vacuo gave a brown oil (20.8 g, 62%). nmax (film) 3063,
3030, 2860, 1701, 1628, 1454, 1349, 1138, 1110, 741,
699 cmꢁ1. dH (400 MHz; CDCl3) 9.19 (1H, s, H1), 7.40–
7.32 (5H, m, Ph), 7.33 (1H, t, J¼5.0 Hz, H3), 4.61 (2H, s,
H5), 4.45 (2H, d, J¼5.0 Hz, H4) ppm. dC (100 MHz;
CDCl3) 185.0 (CH, C1), 151.9 (CH, C3), 137.0 (C, Ph),
128.6 (CH, Ph), 128.1 (CH, Ph), 127.9 (CH, Ph), 126.7 (C,
C2), 73.4 (CH2, C5), 69.4 (CH2, C4) ppm. MS (CI) m/z
274, 272 [1:1 (M+H2O)+]; found (ES+) M+Na 276.9835,
C11H1179BrNaO2 requires M+Na 276.9040.
4.1.6. 4-Benzyloxy-but-2-en-1-ol 8. Neat cis-buten-1,4-diol
(15 g, 170 mmol) was added to a suspension of NaH, 60%
dispersion in oil (7.5 g, 187 mmol) in 4:1 THF–DMSO
(375 ml) and stirred at 0 ꢀC. After 30 min a solution of
benzyl chloride (20.5 g, 162 mmol) in THF (200 ml) was
added over 15 min followed by the addition of n-Bu4NI
(6.3 g, 17 mmol). The reaction mixture was stirred at
60 ꢀC for 12 h, cooled to rt, diluted with water (700 ml)
and extracted with Et2O (3ꢂ700 ml). The combined organic
layers were washed with brine (200 ml), dried (MgSO4)
and concentrated in vacuo. Distillation at 0.2 mbar and
110 ꢀC gave a colourless oil (22.5 g, 78%). nmax (film)
3386, 3028, 2923, 2861, 1454, 1387, 1207, 1071, 1028,
738, 699 cmꢁ1. dH (400 MHz; CDCl3) 7.38–7.28 (5H, m,
Ph), 5.75 (1H, m, H2), 5.73 (1H, m, H3), 5.53 (2H, s, H5),
4.19 (2H, t, J¼5.7 Hz, H1), 4.11 (2H, dd, J¼6.1, 0.6 Hz,
H4), 1.78 (1H, t, J¼5.7 Hz, OH) ppm. dC (100 MHz;
CDCl3) 137.7 (C, Ph), 132.4 (CH, C2), 128.4 (CH, C3),
128.0 (CH, Ph), 127.8 (CH, Ph), 127.7 (CH, Ph), 72.4
(CH2, C5), 65.5 (CH2, C4), 58.5 (CH2, C1) ppm. MS
(ES+) m/z 201 (M+Na)+, 179 (M+H)+ and 161
(M+HꢁH2O)+; found M+H 179.1067, C11H15O2 requires
M+H 179.1072.
4.1.9. 6-Benzyloxy-4-bromo-hexa-2,4-dienoic acid meth-
yl ester 11. To a solution of 4-benzyloxy-2-bromo-but-
2-enal (972 mg, 3.81 mmol) in CH2Cl2 (1.5 ml) methyl
(triphenylphosphoranylidene)acetate (2.55 g, 7.63 mmol)
was added. The reaction mixture was stirred for 10 h at rt
and concentrated in vacuo. Column chromatography (petro-
leum ether (40–60)–Et2O 5:1) gave a light yellow semi solid
(755 mg, 64%).
4.1.10. The telescoped procedure. To a solution of 4-
benzyloxy-but-2-enal (577 mg, 3.27 mmol) in CH2Cl2
(6.5 ml) was added bromine (0.177 ml, 3.44 mmol), the
mixture was stirred for 10 min at rt and then cooled at
0 ꢀC, pyridine (1.1 ml, 13.1 mmol) was then added and the
mixture was stirred for 1 h. Methyl (triphenylphosphoranyl-
idene)acetate (2.19 g, 6.55 mmol) was added after this time
and the reaction mixture was stirred for a further 24 h at rt
and then concentrated in vacuo. The bulk of triphenylphos-
phine oxide was removed triturating the crude solid with
hot petroleum ether (40–60) and decanting the solution
away from the residue. Concentration of the decanted petro-
leum ether under reduced pressure gave an orange oil. Col-
umn chromatography (petroleum ether (40–60)–Et2O 5:1)
gave a light yellow semi solid (710 mg, 70% over three
steps).
4.1.7. 4-Benzyloxy-but-2-enal 9. To a solution of 4-benzyl-
oxy-but-2-en-1-ol (22.5 g, 126 mmol) in CH2Cl2 (240 ml)
was added DMSO (45 ml) followed by DIPEA (55 ml,
316 mmol). To this mixture SO3Py (40.2 g, 253 mmol)
was added over 10 min in five portions. The reaction mixture
was stirred for 1 h at rt, diluted with CH2Cl2 (300 ml),
washed with 0.5 M HCl (3ꢂ150 ml) and brine (2ꢂ100 ml)
then dried (MgSO4) and concentrated in vacuo to give an
orange oil (22.2 g, >99%). nmax (film) 3064, 3031, 2844,
nmax (film) 2950, 1717, 1635, 1456, 1436, 1307, 1154, 1105,
734, 698 cmꢁ1. dH (400 MHz; CDCl3) 7.39–7.29 (5H, m,
Ph), 7.28 (1H, dd, J¼14.8, 0.7 Hz, H3), 6.57 (1H, tt,
J¼5.5, 0.7 Hz, H5), 6.25 (1H, dd, J¼14.8, 0.7 Hz, H2),
4.55 (2H, s, benzylic CH2), 4.33 (2H, d, J¼5.5 Hz, H6),
3.78 (3H, s, CH3) ppm. dC (100 MHz; CDCl3) 166.6 (C,
C1), 142.4 (CH, C3), 139.3 (CH, C5), 137.4 (C, Ph), 128.5
(CH, Ph), 127.9 (CH, Ph), 127.8 (CH, Ph), 122.9 (CH,
C2), 122.5 (C, C4), 73.0 (CH2, C7), 69.7 (CH2, C6), 51.8
(CH3, C11) ppm. MS (ES+) m/z 335 and 333 [1:1,
(M+Na)+], 313, 311 [1:1, (M+H)+]; found M+H 311.0277,
C14H1679BrO3 requires M+H 311.0283.
2730, 1690, 1468, 1361, 1113, 1026, 968, 739, 699 cmꢁ1
.
dH (400 MHz; CDCl3) 9.59 (1H, d, J¼8.0 Hz, H1), 7.39–
7.30 (1H, m, Ph), 6.85 (1H, dt, J¼15.8, 4.1 Hz, H3), 6.41
(1H, ddt, J¼15.8, 8.0, 1.9 Hz, H2), 4.60 (2H, s, H5),
4.29 (2H, dd, J¼4.1, 1.9 Hz, H4) ppm. dC (100 MHz;
CDCl3) 193.3 (CH, C1), 153.0 (CH, C3), 137.4 (C, Ph),

9128
P. A. Clarke et al. / Tetrahedron 63 (2007) 9124–9128
5. Nicolaou, K. C.; Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.;
Acknowledgements
Leresche, J. E.; Tssuri, T.; Naniwa, Y.; De Riccardis, F.
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We thank the EPSRC (GR/S77301/01) and Merck, Sharp
and Dohme for studentship funding (GR), the EPSRC/Uni-
versity of Nottingham for award of a DTA (APC) and Astra-
Zeneca for an unrestricted research award (PAC).
9. Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.;
Roush, W. R. Org. Lett. 2000, 2, 2691.
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