Diol desymmetrization as an approach to the synthesis of unsymmetrical dienyl diesters

Article abstract of DOI:10.1016/j.tet.2007.07.089

The tandem oxidation/Wittig olefination of unactivated diols utilizing manganese dioxide produces α,β-unsaturated hydroxy esters in high yields in a highly effective desymmetrization process. The formation of small quantities of the corresponding lactones suggests that the reaction may proceed through a lactol intermediate in some cases. The α,β-unsaturated hydroxy esters are transformed into symmetrical or unsymmetrical dienyl diesters using a second oxidation/Wittig olefination sequence mediated by PCC.

Full text of DOI:10.1016/j.tet.2007.07.089

Tetrahedron 63 (2007) 10528–10533
Diol desymmetrization as an approach to the
synthesis of unsymmetrical dienyl diesters
*
David J. Phillips, Kathryn S. Pillinger, Wei Li, Angela E. Taylor and Andrew E. Graham
Department of Chemistry, University of Wales Swansea, Swansea SA2 8PP, UK
Received 31 May 2007; revised 9 July 2007; accepted 20 July 2007
Available online 31 July 2007
Abstract—The tandem oxidation/Wittig olefination of unactivated diols utilizing manganese dioxide produces a,b-unsaturated hydroxy es-
ters in high yields in a highly effective desymmetrization process. The formation of small quantities of the corresponding lactones suggests
that the reaction may proceed through a lactol intermediate in some cases. The a,b-unsaturated hydroxy esters are transformed into symmet-
rical or unsymmetrical dienyl diesters using a second oxidation/Wittig olefination sequence mediated by PCC.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
application of tandem reaction sequences to the homologa-
tion of unactivated diols has proved to be highly problem-
atic.9 Barrett demonstrated that while 1,2-ethanediol
undergoes a double oxidation/homologation sequence using
the Dess–Martin periodinane as oxidant, the corresponding
dienyl diester is not produced from 1,3-propanediol.4 In
this case, ethyl (E)-2,4-pentadienoate 1 is formed by a com-
peting elimination from 3-hydroxypropanal (Scheme 1).
Similarly, Taylor has reported that 1,2-diols undergo oxida-
tive cleavage in the presence of manganese dioxide,10 and
also that the attempted tandem oxidation/Wittig reaction of
1,3-propanediol with manganese dioxide in refluxing tolu-
ene produces only products derived from oxidative degrada-
tion.11
The development of tandem preparative procedures, where
a number of transformations are carried out in a one-pot pro-
cess, offers significant advantages such as a reduction in the
number of synthetic steps realizing a significant improve-
ment in efficiency.1 A number of groups have reported the
development of such tandem sequences, in particular for
the direct transformation of alcohols to olefins using Wittig
chemistry. The Wittig reaction remains one of the most ef-
fective synthetic methods for the introduction of a double
bond,2,3 however, its utility is limited when applied to car-
bonyl compounds, particularly aldehydes, that are difficult
to isolate due to their instability, toxicity or volatility. The
application of tandem oxidation/olefination processes cir-
cumvents these shortcomings and a range of oxidizing re-
agents have been employed including manganese dioxide,4
barium permanganate,5 Dess–Martin periodinane,6 tetrapro-
pylammonium perruthenate (TPAP),7 and ortho-iodoben-
zoic acid.8
We required an efficient route for the synthesis of a series of
dienyl diesters, and were attracted to the potential simplicity
and flexibility of this approach provided that undesirable
elimination and degradation reactions could be avoided. In
this paper we disclose the realization of this goal, in addition
to the development of a highly effective desymmetrization
protocol for unactivated diols leading to an efficient method
for the synthesis of a,b-unsaturated hydroxy esters.
The range of alcohols investigated admirably demonstrates
the generality of this synthetic approach, however, the
Dess-Martin
Periodinane
MnO2
Oxidative
degradtion
HO
OH
CO2Et
Ph3P=CHCO2Et
Ph3P=CHCO2Et
1
R1O2C
Scheme 1. Tandem oxidation/Wittig reactions of 1,3-propanediol.
CO2R2
Keywords: a,b-Unsaturated hydroxy esters; Tandem oxidation/olefination; Manganese dioxide; Diol desymmetrization.
* Corresponding author. Fax: +44 1792 295747; e-mail: a.e.graham@swansea.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.089

D. J. Phillips et al. / Tetrahedron 63 (2007) 10528–10533
10529
2. Results and discussion
mono-oxidized material as the major product regardless of
the quantity of oxidant used (Table 1).15
Our initial goal was to limit the extent of the competing ox-
idative degradation and elimination reactions, which we en-
visaged may be achieved by moderating the oxidizing ability
of the oxidant. It has been demonstrated that there is consid-
erable variation in the oxidizing capacity of manganese di-
oxide and that this property is related to the morphology
of the crystallites.12 With this in mind we investigated
a range of commercially available grades of manganese
dioxide to determine the variability in their oxidizing
ability, and were gratified to observe that reaction of 1,2-
ethanediol with Wittig reagents 2 (Ph3P]CHCO2Et) and 3
(Ph3P]C(CH3)CO2Et) with manganese dioxide (Aldrich,
10 mm, 90%) at room temperature produced the correspond-
ing dienyl diesters in good yields.13 Surprisingly, reactions
involving longer chain diols furnished only small quantities
of dienyl diester and instead produced a,b-unsaturated
hydroxy esters as the major product.14 The yield of a,b-
unsaturated hydroxy ester was highly dependent on the
grade of manganese dioxide employed with 1,3-propane-
diol, 1,4-butanediol, and 1,5-pentanediol giving only trace
amounts of products when alternate grades were used. The
oxidation proceeds with impressive selectivity to give the
We noted during these studies that in the case of 1,4- and 1,5-
diols, the yields of the a,b-unsaturated hydroxy product
were reduced by a competing oxidative cyclization, which
produced the corresponding lactone products. These reac-
tions provided small quantities of these materials as by-
products in a highly capricious reaction suggesting that, in
these cases, the desymmetrization process may proceed
through a lactol intermediate.16 We therefore investigated
the manganese dioxide-mediated oxidative cyclization reac-
tion of 1,5-pentanediol as a model substrate to understand
further the desymmetrization reaction (Table 2). Reactions
at room temperature produced high conversions of the diol
to lactol and lactone products, and significant quantities of
the lactone were produced on carrying out the reaction in
chloroform under reflux conditions.
The desymmetrization of symmetrical diols has attracted
considerable attention due to the lack of convenient methods
by which the transformation can be carried out.17 Further-
more, the oxidative cyclization of diols to lactones typically
involves co-reagents, harsh reaction conditions or utilizes
Table 1. Synthesis of a,b-unsaturated hydroxy esters
MnO2 (20 equiv), CH2Cl2, rt
CO2Et
HO
HO
OH
R = H or Me
2 or 3 (2.4 equiv)
n
n
R
Entry
1
Diol
Time (h)
24
Producta
Yield (%)b,c
79
HO
HO
CO2Et
HO
HO
OH
4
CO2Et
2
3
4
5
6
7
8
24
24
48
8
66
71
91
70d
66
52
52
OH
5
HO
CO2Et
HO
OH
6
HO
HO
CO2Et
HO
HO
HO
OH
OH
OH
6
CO2Et
6
24
24
24
HO
CO2Et
7
HO
CO2Et
HO
OH
8
HO
HO
OH
CO2Et
9
HO
CO2Et
HO
9
24
56
OH
10
a
Reactions in CH2Cl2 using Aldrich 10 mm MnO2.
Reactions producedw5% Z-isomer.
Reactions produced <5% diester.
b
c
d
At reflux in CH2Cl2 with 10 equiv of manganese dioxide.

10530
D. J. Phillips et al. / Tetrahedron 63 (2007) 10528–10533
Table 2. Manganese dioxide-mediated oxidative cyclization of 1,5-pentane-
diol
Indeed, when the a,b-unsaturated hydroxy esters were iso-
lated and subjected to a second oxidation/Wittig protocol,
only traces of the dienyl diesters were isolated. Additional
experiments utilizing activated manganese dioxide, ex-
tended reaction times or elevated temperatures furnished
only moderate (20–25%) yields with the balance of material
being unreacted alcohol. The desired dienyl diesters, how-
ever, were obtained by oxidation of the a,b-unsaturated
hydroxy esters using silica supported pyridinium chloro-
chromate (PCC)21 followed by trapping of the intermediate
aldehydes with Wittig reagents 2 or 11 (Ph3P]CHCO2Me)
in a sequential one-pot procedure.
MnO2, (20 equiv)
HO
OH
O
O
Entry
Conditionsa
Conversionb (%)
1
2
3
4
CH2Cl2, 20 h, rt
CH3Cl, 20 h, rt
CH3Cl, 4 h, reflux
CH3Cl, 24 h, reflux
30c
57c
29c
91
a
Diol was used as supplied (Aldrich).
Determined from 1H NMR spectrum of the crude reaction mixture.
b
c
Containsw40% lactol.
Initial one-pot reactions involving the addition of silica
supported PCC at the start of the reaction followed after 2 h
by the Wittig reagent resulted in efficient generation of the
intermediate aldehyde, however, this was not converted to
significant yields of the diester even after protracted reaction
times (up to 48 h). This is presumably due to the reprotona-
tion of the Wittig reagent due to the acidic nature of the
oxidant. We therefore sought to control the acidity of the re-
action conditions by the addition of a buffering agent, such as
imidazole, which would suppress the reprotonation of the
Wittig reagent.22 Our initial studies showed that oxidation
over a 2 h period followed by simultaneous addition of
2 equiv of imidazole and Wittig reagent produced reasonable
yields of diester. Further improvements in yields were ob-
tained by leaving the oxidation step for 4 h and introducing
the imidazole 1 h before the Wittig reagent followed by an
additional 19 h stirring. Under these conditions, the desired
diester products were produced in good yields (Table 3).23
expensive metal catalysts.18 Thus, manganese dioxide pro-
vides a potentially mild and inexpensive alternative to cur-
rent methodologies and our recent results in this area will
be the subject of a subsequent publication.19 The a,b-unsat-
urated hydroxy esters produced in this process are highly
versatile intermediates that have found widespread use in
numerous synthetic pathways and in natural product synthe-
sis.20 Our protocol, in which desymmetrization is achieved
in a one-pot tandem procedure directly from the diol, avoids
the requirement for protection/deprotection strategies or the
use of air sensitive reagents and results in a significant
improvement in efficiency.
While the a,b-unsaturated hydroxy esters 4–10 were pro-
duced efficiently, the yields of dienyl diesters were poor
and could not be improved using this one-pot approach.
Table 3. PCC-mediated synthesis of dienyl diesers
R1
R1
PCC (2 equiv), CH2Cl2, rt
Imidazole (2 equiv)
HO
R2O2C
CO2Et
CO2Et
n
n
2 or 11 (2.4 equiv)
R1 = H or Me
n = 2 or 3
R2 = Me or Et
Entry
1
Ester
Product
Yield (%)a
83
CO2Et
HO
CO2Et
EtO2C
EtO2C
MeO2C
12
6
CO2Et
2
3
4
5
73
65
69
74
HO
HO
CO2Et
7
13
CO2Et
CO2Et
6
14
MeO2C
EtO2C
CO2Et
HO
CO2Et
7
15
HO
CO2Et
CO2Et
8
16
HO
MeO2C
CO2Et
CO2Et
6
70
17
8
a
Reactions producedw5% E,Z-isomer.

D. J. Phillips et al. / Tetrahedron 63 (2007) 10528–10533
10531
3. Conclusions
200 mmol) in dichloromethane (80 ml) was stirred for 24 h
at room temperature. At this time the manganese dioxide
was removed by filtration through a Celite pad, which was
then washed with additional dichloromethane (2ꢂ10 ml).
The solvent was then removed in vacuo to give an orange
oil, which was purified by column chromatography (hex-
ane/20% ethyl acetate–hexane) to give the title compound
4 (1.14 g, 79%) as a yellow oil. IR nmax (film)/cmꢀ1 (neat)
In summary, the tandem oxidation/Wittig homologation
protocol leads to the highly effective desymmetrization
of unactivated diols, and serves as a highly efficient pro-
tocol for the synthesis of a,b-unsaturated hydroxy esters
without the requirement for prior protecting group manip-
ulation. The competing oxidative degradation and elimi-
nation reactions previously observed are avoided by
moderation of the oxidative capacity of the oxidant, which
is achieved by judicious choice of the grade of manganese
dioxide employed. It is assumed that in the case of 1,4-
and 1,5-diols, the desymmetrization process proceeds
through the initial formation of the lactol intermediate,
which undergoes subsequent reaction in the presence of
the ylide to produce the corresponding a,b-unsaturated
hydroxy esters. Reactions of 1,5-pentanediol under reflux
temperatures in the absence of Wittig reagents produced
good conversions to the corresponding lactone products.
The intermediate a,b-unsaturated hydroxy esters are re-
markably resistant to further oxidation reactions but are
converted to dienyl diesters in good yields by oxidation
with silica supported pyridinium chlorochromate. Subse-
quent trapping of the intermediate aldehydes provides
access to both symmetrical and unsymmetrical dienyl
diesters.
1
3422, 1714, 1653, 1267, 1162, 1038; H NMR (400 MHz;
CDCl3) d¼1.25 (3H, t, J¼7 Hz), 2.20 (1H, br s, OH), 2.46
(2H, dq, J¼7, 1 Hz), 3.76 (2H, t, J¼7 Hz), 4.20 (2H, q,
J¼7 Hz), 5.91 (1H, dt, J¼16, 1 Hz), 6.95 (1H, dt, J¼16,
7 Hz); 13C NMR (100 MHz; CDCl3) d¼166.9, 145.8,
123.9, 61.3, 60.8, 35.8, 14.6; MS (ES, NH3) m/z 162
(M+NH4)+, 145 (M+H)+; HRMS (ES, NH3) calculated for
C7H16O3N (M+NH4)+ 162.1125; found (M+NH4)+
162.1124.
4.2.2. E-5-Hydroxy-2-methyl-pent-2-enoic acid ethyl
ester (5). The title compound (150 mg, 66%) was obtained
as a yellow oil. IR nmax (film)/cmꢀ1 (neat) 3417, 2936,
1706, 1650, 1272, 1194, 1038; 1H NMR (400 MHz;
CDCl3) d¼1.30 (3H, t, J¼7 Hz), 1.87 (3H, d, J¼1 Hz),
2.05 (1H, br s, OH), 2.46 (2H, dq, J¼7, 1 Hz), 3.76 (2H, t,
J¼7 Hz), 4.19 (2H, q, J¼7 Hz), 6.95 (1H, dt, J¼7, 1 Hz);
13C NMR (100 MHz; CDCl3) d¼168.1, 138.0, 130.1, 61.4,
60.6, 32.1, 14.3, 12.6; MS (CI, NH3) m/z 176 (M+NH4)+,
159 (M+H)+; HRMS (CI, NH3) calculated for C8H18O3N
(M+NH4)+ 176.1281; found (M+NH4)+ 176.1282.
4. Experimental
4.1. General methods
4.2.3. E-6-Hydroxy-hex-2-enoic acid ethyl ester (6). The
title compound (615 mg, 71%) was obtained as a colorless
oil. IR nmax (film)/cmꢀ1 (neat) 3419, 1715, 1699, 1269,
1195, 1037; 1H NMR (400 MHz; CDCl3) 1.25 (3H, t,
J¼7 Hz), 1.65 (2H, pent, J¼7 Hz), 2.25 (2H, dq, J¼7,
1 Hz), 2.55 (br s, 1H, OH), 3.60 (2H, t, J¼7 Hz), 4.15
(2H, q, J¼7 Hz), 5.85 (1H, dt, J¼16, 1 Hz), 6.95 (1H, dt,
J¼16, 7 Hz); 13C NMR (100 MHz; CDCl3) d¼167.2,
149.0, 122.0, 62.1, 60.7, 31.2, 28.9, 14.6; MS (CI, NH3)
m/z 176 (M+NH4)+, 159 (M+H)+; HRMS (CI, NH3) calcu-
lated for C8H18O3N (M+NH4)+ 176.1281; found
(M+NH4)+ 176.1279.
Commercially available reagents were used without further
purification. Flash chromatography was carried out using
Merck Kieselgel 60 H silica or Matrex silica 60. Analytical
thin layer chromatography was carried out using aluminum-
backed plates coated with Merck Kieselgel 60 GF254 that
were visualized under UV light (at 254 and/or 360 nm) or us-
ing potassium permanganate solution (1% in water) fol-
lowed by charring. Infra-red (IR) spectra were recorded in
the range 4000–600 cmꢀ1 as neat oils or solids and are re-
ported in cmꢀ1. Nuclear magnetic resonance (NMR) spectra
were recorded on a Bruker 400 MHz spectrometer in CDCl3
at 25 ꢁC unless stated otherwise and are reported in parts per
million; J values are recorded in hertz and multiplicities are
expressed by the usual conventions. Low-resolution mass
spectra (MS) were determined using the ionization tech-
nique stated. ES refers to electrospray ionization, CI refers
to chemical ionization (ammonia) and EI refers to electron
impact ionization. High-resolution mass spectra (HRMS)
were obtained courtesy of the EPSRC Mass Spectrometry
Service University of Wales Swansea, UK using the ioniza-
tion method specified. Removal of solvent refers to evapora-
tion at reduced pressure using a rotary evaporator followed
by the removal of trace volatiles using a vacuum pump.
4.2.4. E-6-Hydroxy-2-methyl-hex-2-enoic acid ethyl ester
(7). The title compound (1.13 g, 66%) was obtained as a col-
orless oil. IR nmax (film)/cmꢀ1 (neat) 3421, 1705, 1648,
1
1259, 1125, 1090; H NMR (400 MHz; CDCl3) 1.18 (3H,
t, J¼7 Hz), 1.45 (1H, br s, OH), 1.60–1.75 (2H, m), 1.80
(3H, s), 2.25 (2H, dq, J¼7, 1 Hz), 3.65 (2H, t, J¼7 Hz),
4.15 (2H, q, J¼7 Hz), 6.70 (1H, t, J¼7 Hz); 13C NMR
(100 MHz; CDCl3) d¼168.7, 141.8, 128.7, 62.5, 60.9,
31.8, 25.4, 14.6, 12.7; MS (CI, NH3) m/z 190 (M+NH4)+,
173 (M+H)+; HRMS (CI, NH3) calculated for C9H17O3
(M+H)+ 173.1172; found (M+H)+ 173.1174.
4.2.5. E-7-Hydroxy-hept-2-enoic acid ethyl ester (8). The
title compound (96 mg, 52%) was obtained as a colorless oil.
IR nmax (film)/cmꢀ1 (neat) 3410, 1716, 1652, 1266, 1186,
4.2. General procedure for the desymmetrization of
unactivated diols
1
1096; H NMR (400 MHz; CDCl3) 1.20 (3H, t, J¼7 Hz),
4.2.1. E-5-Hydroxy-pent-2-enoic acid ethyl ester (4). A
mixture of 1,3-propanediol (762 mg, 10 mmol), (ethoxycar-
bonylmethylene)triphenylphosphorane 2 (2.4 equiv, 8.37 g,
24 mmol), and manganese dioxide (20 equiv, 17.44 g,
1.40–1.55 (4H, m), 1.60 (1H, br s, OH), 2.15–2.25 (2H,
m), 3.55 (2H, t, J¼7 Hz), 4.15 (2H, q, J¼7 Hz), 5.80 (1H,
d, J¼16 Hz), 6.95 (1H, dt, J¼16, 7 Hz); 13C NMR
(100 MHz; CDCl3) d¼167.1, 149.3, 122.0, 62.9, 60.6,

10532
D. J. Phillips et al. / Tetrahedron 63 (2007) 10528–10533
32.5, 32.3, 24.6, 14.7; MS (CI, NH3) m/z 190 (M+NH4)+,
173 (M+H)+; HRMS (CI, NH3) calculated for C9H17O3
(M+H)+ 173.1172; found (M+H)+ 173.1172.
168.3, 166.8, 147.8, 140.2, 129.4, 122.5, 60.9, 60.7, 31.4,
27.5, 14.6, 12.8; MS (CI, NH3) m/z 258 (M+NH4)+, 241
(M+H)+; HRMS (CI, NH3) calculated for C13H24O4N
(M+NH4)+ 258.1700; found (M+NH4)+ 258.1697.
4.2.6. E-7-Hydroxy-2-methyl-hept-2-enoic acid ethyl es-
ter (9). The title compound (163 mg, 52%) was obtained
as a colorless oil. IR nmax (film)/cmꢀ1 (neat) 3390, 1706,
1655, 1367, 1252, 1092; 1H NMR (400 MHz; CDCl3) 1.05
(3H, t, J¼7 Hz), 1.20 (1H, br s, OH), 1.25–1.45 (4H, m),
1.65 (3H, s), 1.95–2.15 (2H, m), 3.45 (2H, t, J¼7 Hz),
4.00 (2H, q, J¼7 Hz), 6.60 (1H, t, J¼7 Hz); 13C NMR
(100 MHz; CDCl3) d¼168.7, 142.2, 128.4, 63.0, 60.9,
32.7, 28.7, 25.2, 14.7, 12.8; MS (CI, NH3) m/z 204
(M+NH4)+, 187 (M+H)+; HRMS (CI, NH3) calculated for
C10H19O3 (M+H)+ 187.1329; found (M+H)+ 187.1328.
4.3.3. E,E-Octa-2,6-dienedioic acid ethyl methyl ester
(14). The title compound (167 mg, 65%) was obtained as
a colorless oil. IR nmax (film)/cmꢀ1 (neat) 2984, 1716,
1
1655, 1368, 1267, 1094; H NMR (400 MHz; CDCl3) 1.30
(3H, t, J¼7 Hz), 2.35–2.40 (4H, m), 3.75 (3H, s), 4.19
(2H, q, J¼7 Hz), 5.80–5.85 (2H, m), 6.90–7.00 (2H, m);
13C NMR (100 MHz; CDCl3) d¼167.2, 166.7, 147.6,
147.2, 122.8, 122.3, 60.7, 51.9, 30.9, 30.8, 14.6; MS (CI,
NH3) m/z 230 (M+NH4)+, 213 (M+H)+; HRMS (CI, NH3)
calculated for C11H20O4N (M+NH4)+ 230.1387; found
(M+NH4)+ 230.1388.
4.2.7. E-8-Hydroxy-oct-2-enoic acid ethyl ester (10). The
title compound (180 mg, 56%) was obtained as a colorless
oil. IR nmax (film)/cmꢀ1 (neat) 3425, 1717, 1652, 1266,
1182, 1095; 1H NMR (400 MHz; CDCl3) 1.31 (3H, t,
J¼7 Hz), 1.38–1.66 (7H, m), 2.24 (2H, m), 3.67 (2H, t,
J¼7 Hz), 4.20 (2H, q, J¼7 Hz), 5.84 (1H, dt, J¼16,
1.5 Hz), 6.98 (1H, dt, J¼16, 7 Hz); 13C NMR (100 MHz;
CDCl3) d¼167.2, 149.5, 121.8, 63.1, 60.6, 32.9, 32.5,
28.2, 25.7, 14.7; MS (CI, NH3) m/z 204 (M+NH4)+, 187
(M+H)+; HRMS (CI, NH3) calculated for C10H22O3N
(M+NH4)+ 204.1594; found (M+NH4)+ 204.1595.
4.3.4. E,E-2-Methyl-octa-2,6-dienedioic acid ethyl methyl
ester (15). The title compound (310 mg, 69%) was obtained
as a colorless oil. IR nmax (film)/cmꢀ1 (neat) 2982, 1707,
1
1652, 1367, 1260, 1094; H NMR (400 MHz; CDCl3) 1.21
(3H, t, J¼7 Hz), 1.74 (3H, d, J¼1 Hz), 2.27 (4H, m), 3.64
(3H, s), 4.10 (2H, q, J¼7 Hz), 5.77 (1H, dt, J¼16, 1 Hz),
6.60–6.65 (1H, m), 6.80–6.85 (1H, m); 13C NMR
(100 MHz; CDCl3) d¼168.3, 167.2, 148.1, 140.2, 129.4,
122.1, 60.9, 51.8, 31.4, 27.5, 14.6, 12.8; MS (CI, NH3) m/z
244 (M+NH4)+, 227 (M+H)+; HRMS (CI, NH3) calculated
for C12H22O4N (M+NH4)+ 244.1543; found (M+NH4)+
244.1453.
4.3. General procedure for the PCC-mediated synthesis
of dienyl diesters
4.3.5. E,E-Nona-2,7-dienedioic acid diethyl ester (16).
The title compound (87 mg, 74%) was obtained as a colorless
oil. IR nmax (film)/cmꢀ1 (neat) 2982, 1715, 1653, 1367,
4.3.1. E,E-Octa-2,6-dienedioic acid diethyl ester (12). A
mixture of E-6-hydroxy-hex-2-enoic acid ethyl ester
(167 mg, 1.06 mmol) 6 and pyridinium chlorochromate
(2 equiv, 0.46 g, 2.12 mmol, ground with 2 wt equiv of
silica, 0.92 g) was stirred for 4 h at room temperature in
dichloromethane (50 ml). Imidazole (2 equiv, 0.14 g,
2.12 mmol) was added and the reaction mixture stirred for
a further 1 h. The addition of (ethoxycarbonylmethylene)tri-
phenylphosphorane 2 (2.4 equiv, 0.88 g, 2.54 mmol) was
followed by 19 h of stirring. At this time the silica supported
pyridinium chlorochromate was removed by filtration
through a Celite pad, which was then washed with additional
dichloromethane (2ꢂ50 ml). The solvent was then removed
in vacuo to give an orange/brown oil, which was purified by
column chromatography (hexane/10% ethyl acetate–hex-
ane) to give to give the title compound 12 (199 mg, 83%) as
a colorless oil. IR nmax (film)/cmꢀ1 (neat) 2982, 1714, 1654,
1
1263, 1177, 1096; H NMR (400 MHz; CDCl3) 1.29 (6H,
t, J¼7 Hz), 1.66 (2H, pent, J¼7 Hz), 2.24 (4H, m), 4.20
(4H, q, J¼7 Hz), 5.83 (2H, dd, J¼16, 1 Hz), 6.92 (2H, dt,
J¼16, 7 Hz); 13C NMR (100 MHz; CDCl3) d¼166.5,
148.0, 122.0, 60.2, 31.4, 26.3, 14.3; MS (CI, NH3) m/z 258
(M+NH4)+, 241 (M+H)+; HRMS (CI, NH3) calculated for
C13H21O4 (M+H)+ 241.1434; found (M+H)+ 241.1431.
4.3.6. E,E-Nona-2,7-dienedioic acid ethyl methyl ester
(17). The title compound (94 mg, 70%) was obtained as
a colorless oil. IR nmax (film)/cmꢀ1 (neat) 2984, 1717,
1655, 1368, 1266, 1175, 1097; 1H NMR (400 MHz;
CDCl3) 1.22 (3H, t, J¼7 Hz), 1.57 (2H, pent, J¼7 Hz),
2.15–2.25 (4H, m), 3.66 (3H, s), 4.12 (2H, q, J¼7 Hz),
5.76 (2H, dt, J¼16, 1 Hz), 6.85 (1H, dt, J¼16, 7 Hz), 6.90
(1H, dt, J¼16, 7 Hz); 13C NMR d¼(100 MHz; CDCl3)
167.3, 166.9, 148.8, 148.4, 122.4, 122.0, 60.6, 51.9, 31.8,
31.7, 26.7, 14.7; MS (CI, NH3) m/z 240 (M+NH4)+, 227
(M+H)+; HRMS (CI, NH3) calculated for C12H22O4N
(M+NH4)+ 244.1543; found (M+NH4)+ 244.1547.
1
1368, 1265, 1095; H NMR (400 MHz; CDCl3) 1.28 (6H,
t, J¼7 Hz), 2.35–2.40 (4H, m), 4.18 (4H, q, J¼7 Hz),
5.84 (2H, d, J¼16 Hz), 6.90–6.95 (2H, m); 13C NMR
d¼(100 MHz; CDCl3) 166.7, 147.3, 123.0, 60.7, 30.8,
14.6; MS (CI, NH3) m/z 244 (M+NH4)+, 227 (M+H)+;
HRMS (CI, NH3) calculated for C12H22O4N (M+NH4)+
244.1543; found (M+NH4)+ 244.1542.
Acknowledgements
4.3.2. E,E-2-Methyl-octa-2,6-dienedioic acid diethyl ester
(13). The title compound (351 mg, 73%) was obtained as
a colorless oil. IR nmax (film)/cmꢀ1 (neat) 2982, 1707,
1652, 1367, 1259, 1094; 1H NMR (400 MHz; CDCl3) 1.19
(6H, t, J¼7 Hz), 1.75 (3H, s), 2.20–2.30 (4H, m), 4.10
(4H, q, J¼7 Hz), 5.76 (1H, d, J¼16 Hz), 6.60–6.65 (1H,
m) 6.85–6.95 (1H, m); 13C NMR d¼(100 MHz; CDCl3)
These studies have enjoyed generous financial support
from the Engineering and Physical Sciences Research
Council (D.J.P) and Pfizer Global Research and Develop-
ment, Sandwich (K.S.P). The authors thank the EPSRC
National Mass Spectrometry Service, University of Wales
Swansea, UK.

D. J. Phillips et al. / Tetrahedron 63 (2007) 10528–10533
10533
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