Selective Lewis acid complexation of 2-hydroxyethyl esters using competitive Diels-Alder reactions as a mechanistic probe

Article abstract of DOI:10.1016/S0040-4020(99)01071-6

Competitive Diels-Alder reactions involving ethyl acrylate, 2- hydroxyethyl acrylate and 2-methoxyethyl acrylate indicate that certain Lewis acids (e.g. EtAlCl₂) selectively complex to the 2-hydroxyethyl ester group. Studies using ethyl 2-hydroxyethyl fumarate support these findings. ¹³C NMR spectroscopy provides some evidence regarding the nature of the interactions between 2-hydroxyethyl esters and EtAlCl₂. The influence of EtAlCl₂ on the level of diastereocontrol observed in the Diels-Alder reactions of (2R*,3R*)-2-(3-hydroxy)butyl acrylate is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01071-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1127–1134
Selective Lewis Acid Complexation of 2-Hydroxyethyl Esters
using Competitive Diels–Alder Reactions as a Mechanistic Probe
*
Gary Clapham and Michael Shipman
School of Chemistry, University of Exeter, Stocker Road, Exeter, Devon EX4 4QD, UK
Received 7 October 1999; revised 17 November 1999; accepted 2 December 1999
Abstract—Competitive Diels–Alder reactions involving ethyl acrylate, 2-hydroxyethyl acrylate and 2-methoxyethyl acrylate indicate that
certain Lewis acids (e.g. EtAlCl2) selectively complex to the 2-hydroxyethyl ester group. Studies using ethyl 2-hydroxyethyl fumarate
support these findings. 13C NMR spectroscopy provides some evidence regarding the nature of the interactions between 2-hydroxyethyl
esters and EtAlCl2. The influence of EtAlCl2 on the level of diastereocontrol observed in the Diels–Alder reactions of (2Rء,3Rء)-2-(3-
hydroxy)butyl acrylate is described. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
As synthetic chemists strive to make increasingly more
complex target molecules, the ability to selectively activate
one functional group in the presence of other similar chemi-
cal functionality is becoming increasingly more important.
In pioneering studies, Yamamoto has shown that the highly
sterically hindered Lewis acid, methylaluminium bis(2,6-di-
tert-butyl-4-methylphenoxide) (MAD), can be used to
selectively complex to the least hindered ester carbonyl
group of unsymmetrical fumarates (e.g. tert-butyl methyl
fumarate),1 as well as other Lewis basic functional groups.2
Other workers have used small changes in the electronic
structure of one of the fumarate carbonyl groups to accom-
plish selectivity in binding. For example, Brown has shown
that complexation to either the ester or the thionoester
group of dimethyl monothionofumarate can be accom-
plished by careful choice of either a hard or soft Lewis
acid.3 Investigations using (E)-MeO2C–CHyCH–COSMe4
and (E)-RCO–CHyCH–COSMe5 have also been described.
In a recent development, it has been demonstrated that
(2-pyridyl)methyl esters can be selectively complexed in
the presence of benzyl esters using transition metal salts.6
esters. The concept is illustrated using fumarate 1 in
Scheme 1. We envisaged that upon addition of a suitable
Lewis acid, a covalent bond between the Lewis acid and
fumarate 1 would produce complex 2 as a result of ligand
exchange. Subsequent intramolecular complexation of the
Lewis acid centre to the carboxyl group would produce
chelated complex 3 in which the 2-hydroxyethyl ester has
been selectively complexed.7 These studies were inspired,
in part, by the work of Roush et al. who had examined the
Lewis acid mediated intramolecular Diels–Alder reactions
of highly sensitive triene substrates bearing 2-hydroxyethyl
esters.8 Significantly, we envisaged that products containing
2-hydroxyethyl esters could be chemoselectively cleaved to
the corresponding carboxylic acids via the b-haloethyl
esters (vide infra).9
Results and Discussion
We chose the Diels–Alder reaction as a mechanistic probe
for Lewis acid complexation because binding of a Lewis
acid to a dienophile is known to dramatically accelerate
the rate of the subsequent [4pϩ2p] cycloaddition
reaction.10 We have performed both intermolecular and
We conceived of a simple way to complex and selectively
activate 2-hydroxyethyl esters in the presence of other alkyl
Scheme 1.
Keywords: Diels–Alder reactions; EtAlCl2; (2Rء,3Rء)-2-(3-hydroxy)butyl acrylate; 2-hydroxyethyl esters; selective Lewis acid complexation.
* Corresponding author. Tel.: ϩ1392-263469; fax: ϩ1392-263434; e-mail: m.shipman@exeter.ac.uk
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01071-6

1128
G. Clapham, M. Shipman / Tetrahedron 56 (2000) 1127–1134
Table 1.
Entry
Reaction conditionsa
Products (ratio)b
Conversion (%)b
1
2
3
4
5
CH2Cl2, 0ЊC
6:7 (50:50)
6:7 (43:57)
6:7 (19:81)
6:7 (31:69)
6:7 (17:83)
Ͻ1
14
43
Ͻ3
10
BF3.Et2O, CH2Cl2, 0ЊC
TiCl4, iPr2EtN, CH2Cl2, 0ЊC
SnCl4, iPr2EtN, CH2Cl2, 0ЊC
EtAlCl2, CH2Cl2, 0ЊC
a Reactions performed using 1:1:1 molar ratio of the two acrylates and 1,3-cyclopentadiene.
b Determined by GC.
intramolecular competition experiments to ascertain the
levels of selectivity that can be accomplished and these
studies are described in the following sections.
uent, we have undertaken some similar competition
experiments between 2-hydroxyethyl acrylate 5 and 2-meth-
oxyethyl acrylate 8 (Scheme 2). While we have observed
that cycloadduct 7 is produced as the major product (7:9;
63:37) even under simple thermal conditions (1,3-cyclo-
pentadiene (1 equiv.), toluene, 110ЊC), the preference for
the formation of this cycloadduct (7:9; 97:3) is much greater
in the presence of ethyl aluminium dichloride (1,3-cyclo-
pentadiene (1 equiv.), CH2Cl2, 0ЊC).
Intermolecular competition experiments
By undertaking intermolecular competition experiments
using acrylates bearing different ester groups and analysing
the product mixture, we hoped to determine if selective
Lewis acid binding to the 2-hydroxyethyl ester group
could be achieved. Initial experiments to identify suitable
Lewis acids focused on experiments involving ethyl
acrylate and 2-hydroxyethyl acrylate, a selection of the
results are presented in Table 1. Ethyl aluminium dichloride
was found to be the most selective Lewis acid (Entry 5)
albeit with only low levels of conversion under these
reaction conditions. However, in the absence of ethyl
acrylate, 2-hydroxyethyl acrylate 5 can be converted into
cycloadduct 7 (endo:exo; 95:5) in near quantitative yield
[EtAlCl2 (1 equiv.), 1,3-cyclopentadiene (3 equiv.) Ϫ78ЊC,
12 h].
To study the complexation of 2-hydroxyethyl esters by ethyl
aluminium dichloride, more directly, we recorded the 13C
NMR spectrum of 2-hydroxyethyl acrylate 5 in dideuterio-
dichloromethane at 25ЊC. Upon addition of one equivalent
of the Lewis acid, significant downfield shifts of the car-
bonyl group (d 166.1!171.1, 173.1), one of the olefinics (d
128.2, 130.6!125.1, 125.8, 140.8, 141.7) and one of the
ether carbons atoms (d 61.0, 66.1!62.9, 63.4, 74.0, 74.7)
were observed. These chemical shifts changes are consistent
with the formation of a complex such as 11 (Scheme 3).
However, to our surprise, two signals in near equal amounts
were observed for each carbon atom of the complexed
2-hydroxyethyl ester. This may indicate that we are observ-
ing both s-cis and s-trans conformations of complex 11 on
the NMR timescale. Alternatively, we may be observing
monomer 11 in equilibrium with a symmetrical dimer
To ascertain whether these findings arise from the formation
of a genuine complex between the hydroxyl group of the
ester and the Lewis acid, and are not simply due to some
other electronic effect associated with the b-oxygen substit-
Scheme 2.
Scheme 3.

G. Clapham, M. Shipman / Tetrahedron 56 (2000) 1127–1134
1129
Scheme 4. Reagents and conditions: (i) (COCl)2, DMF (cat.); (ii) HOCH2CH2OH, Et3N, 0ЊC, DMAP, CHCl3, 69% (from 13); (iii) HOCH2CH2OMe, Et3N, 0ЊC,
DMAP, CH2Cl2, 48% (from 13).
such as 12. Significantly however, we do not feel that
monomeric, non-chelated structure 10 is consistent with
the recorded 13C NMR spectrum as no large downfield
shift of the carbonyl carbon atom would be expected in
this complex.
The structure and relative stereochemistry of lactone 19
were established using a combination of NMR experiments.
Assignments were made using HETCOR, COSY and
HMQC experiments. Subsequent nOe measurements estab-
lished the relative stereochemistries within this lactone.
Strong enhancements between H-9!H-2 (8.3%); H-8!H-
6 (2.1%); H-80!H-3 (2.1%); H-2!H-9 (8.4%) were used in
conjunction with other enhancements to confirm the relative
spatial disposition of H-2, H-3, H-6 and H-9. Working back
from the structure of this lactone, we conclude that the ethyl
aluminium dichloride mediated Diels–Alder cycloaddition
of fumarate 1 yields diester 15 as the major product. To
account for this stereochemical outcome, we suggest selec-
tive complexation to the 2-hydroxyethyl ester is occurring
such that this ester moiety preferentially adopts the endo
orientation in the Diels–Alder reaction.10
Intramolecular competition experiments
Using fumarate 1, we have evaluated the selective
complexation of ethyl aluminium dichloride to a 2-hydroxy-
ethyl ester in the presence of an ethyl ester contained within
the same molecule. This fumarate was made from commer-
cially available carboxylic acid 13 in 69% yield via the
corresponding acid chloride (Scheme 4). In order to evalu-
ate the role of the hydroxyl group within 1, fumarate 14
containing the corresponding methyl ether was made in an
unoptimised 48% yield.
Fumarate 1 was reacted with isoprene under both thermal
and ethyl aluminium dichloride mediated conditions. In this
case, reasonable levels of regiochemical control were
achieved in the presence of one equivalent of the Lewis
acid although unfortunately we have not been able to
unambiguously determine which regioisomer is predomi-
nant (Table 2). Interestingly, when the hydroxyl group of
the fumarate was blocked as the corresponding methyl ether
(ie 14) no appreciable regioselectivity was seen.
Reaction of fumarate 1 with one equivalent of ethyl
aluminium dichloride and 1,3-cyclopentadiene at Ϫ78ЊC
overnight furnished cycloadducts 15 and 16 in a 75:25
1
ratio as judged by H NMR spectroscopy (Scheme 5). In
contrast, thermolysis of this fumarate with excess 1,3-cyclo-
pentadiene (110ЊC, 3 h, 71%) produced essentially equal
quantities of these two cycloadducts (51:49 ratio). Unfortu-
nately, cycloadducts 15 and 16 were inseparable by silica
gel chromatography, so the relative stereochemistry of the
major adduct could not be determined at this point. The
mixture was converted into the corresponding monoacids
17 and 18 via the corresponding 2-iodoethyl esters by
implementation of a zinc induced b-elimination strategy.9
Thus, we were able to chemoselectively cleave the
2-hydroxyethyl ester in the presence of a simple ethyl
ester group. Subjection of the resulting 72:28 mixture of
carboxylic acids 17 and 18 to iodolactonisation conditions
resulted in the isolation of a single lactone 19 in 63% yield.
In view of relatively high yield, we conclude that this
lactone must ultimately be derived from the major cyclo-
adduct.
Studies using 2-(3-hydroxy)butyl acrylate
We have briefly examined the possibility of effecting
diastereocontrolled Diels–Alder reactions using 2-hydroxy-
ethyl acrylates containing asymmetric centres. Acrylate
(2Rء,3Rء)-20 was made in one step from (2Rء,3Rء)-2,3-
dihydroxybutane and acryloyl chloride, albeit in a rather
low but unoptimised 21% yield. The major byproduct in
this reaction (39% yield) was the corresponding diester of
2,3-dihydroxybutane. Treatment of (2Rء,3Rء)-20 with 1,3-
cyclopentadiene in refluxing toluene yielded cycloadduct 21
as a mixture of all four possible diastereomers (Scheme 6).
Scheme 5.

1130
G. Clapham, M. Shipman / Tetrahedron 56 (2000) 1127–1134
Table 2.
Entry
Fumarate
Reaction conditions
Product (ratio)a
Yield (%)b
1
2
3
4
1 (RˆH)
Toluene, 110ЊC, 12 h
EtAlCl2, CH2Cl2, 0ЊC, 12 h
Toluene, 110ЊC, 12 h
RˆH (52:48)
RˆH (76:24)
RˆMe (48:52)
RˆMe (52:48)
95
81
99
76
1 (RˆH)
14 (RˆMe)
14 (RˆMe)
EtAlCl2, CH2Cl2, 0ЊC, 12 h
a Determined by 1H NMR analysis.
b Yield of isolated material after column chromatography.
Scheme 6. Reagents and conditions: (i) acryloyl chloride, Et3N, 0ЊC, CH2Cl2, 21%; (ii) toluene, 1,3-cyclopentadiene, 110ЊC, 99%; (iii) EtAlCl2, 1,3-
cyclopentadiene, 0ЊC, CH2Cl2, 82%.
˚
The two endo diastereomers were produced as the major
products (endo:exo; 71:29) with a small preference in
favour of one of these endo diastereomers (ca. 60:40) as
distilled from CaH2 and stored over 4 A molecular sieves.
Reactions were performed under an inert atmosphere in
oven dried glassware unless otherwise stated. H and 13C
1
1
determined by H and 13C NMR spectroscopy. Using one
NMR spectra were recorded at 300 and 75 MHz on a Bruker
ACF-300 instrument, 400 and 100 MHz on a Bruker DRX-
400 instrument in d-chloroform unless otherwise stated.
Chemical shifts are recorded in ppm relative to TMS or
residual protic solvent. Mass spectra were recorded on a
Kratos Profile HV3 mass spectrometer. Infrared spectra
(4000–600 cmϪ1) were recorded on a Nicolet Magna-550
FT infrared spectrometer using internal calibration, samples
were recorded as thin films between sodium chloride plates.
Capillary GLC analysis was performed using a Shimadzu
GC-14A oven using a BP20 25M column. Injector tempera-
ture 150ЊC, detector temperature 150ЊC, a ramped oven
program was used throughout: 4 min at 70ЊC then ramped
at 10ЊC/min to 200ЊC.
equivalent of ethyl aluminium dichloride at 0ЊC, cyclo-
adduct 21 was produced from acrylate 20 and 1,3-cyclo-
pentadiene in 82% yield with much improved endo
selectivity (endo:exo; 9:1). Unfortunately, the two endo
diastereomers were again produced in near equal quantities
(ca. 33:67) indicating that little facial selectivity is being
observed in diene addition to Lewis acid complexed
acrylate 20. It is however of interest to note that the major
endo diastereomer in this cycloaddition was the minor endo
diastereomer in the thermal reaction.
In conclusion, we have obtained evidence, which indicates
that 2-hydroxyethyl esters can be selectively complexed and
activated in the presence of other alkyl esters using ethyl
aluminium dichloride as the Lewis acid. Furthermore, we
have demonstrated that these 2-hydroxyethyl esters can be
selectively converted to carboxylic acids via the corre-
sponding b-iodoethyl esters.
Ethyl bicyclo[2.2.1]hept-2-ene-5-carboxylate (6).11
A
solution of ethyl acrylate 4 (0.54 ml, 4.98 mmol) and 1,3-
cyclopentadiene (1.2 ml, ca. 14.5 mmol) in toluene (20 ml)
was heated under reflux for 3 h and then allowed to cool to
room temperature. Removal of the solvent in vacuo and
subsequent column chromatography (10% ethyl acetate/
90% light petroleum) gave 6 (710 mg, 86%) as a colourless
oil and as a 69:31 mixture of endo:exo isomers as deter-
Experimental
General
mined by H NMR spectroscopy. nmax/cmϪ1 2978, 2947,
1
1733, 1186, 1178; dH (300 MHz) 6.18 (0.69H, dd, Jˆ5.6,
3.1 Hz), 6.13–6.11 (0.62H, m), 5.92 (0.69H, dd, Jˆ5.6,
2.9 Hz), 4.18–4.04 (2H, m), 3.20 (0.69H, br s), 3.03 (0.31
H, br s), 2.96–2.90 (1.69H, m), 2.21 (0.31H, m), 1.94–1.85
(1H, m), 1.56–1.21 (6H, m); dC (100 MHz) major endo
isomer 174.6 (s), 137.6 (d), 132.3 (d), 60.0 (t), 49.5 (t),
45.6 (d), 43.3 (d), 42.5 (d), 29.2 (t), 14.2 (q); m/z 167
(Mϩ), 155, 127. Found (Mϩ): 166.0992; C10H14O2 requires
166.0994. GC retention times: 11.6 min (exo); 11.8 min
(endo).
Light petroleum refers to that boiling in the 40–60ЊC range.
Dimethylformamide (DMF) and dichloromethane (DCM)
were distilled from CaH2 under nitrogen, immediately
prior to use. Reagents were used as received from commer-
cial sources with the exception of the following; acryloyl
chloride which was distilled prior to use; 1,3-cyclopenta-
diene which was cracked and distilled from LiAlH4 under
nitrogen immediately prior to use; triethylamine which was
stored over KOH; and diisopropylethylamine which was

G. Clapham, M. Shipman / Tetrahedron 56 (2000) 1127–1134
1131
2-Hydroxyethyl bicyclo[2.2.1]hept-2-ene-5-carboxylate
(7). A solution of 2-hydroxyethyl acrylate 5 (0.57 ml,
4.96 mmol) and 1,3-cyclopentadiene (1.2 ml, ca. 14.5
mmol) in toluene (20 ml) was heated under reflux for 3 h
and then allowed to cool to room temperature. Removal of
the solvent in vacuo and subsequent column chromato-
graphy (40% ethyl acetate/60% light petroleum) gave 7
(882 mg, 98%) as a colourless oil and as a 71:29 mixture
Intermolecular competition reaction involving 2-hydroxy-
ethyl acrylate (5) and 2-methoxyethyl acrylate (8)
under thermal conditions. To a stirred solution of
2-hydroxyethyl acrylate 5 (0.57 ml, 4.96 mmol) and
2-methoxyethyl acrylate 8 (0.65 g, ca. 4.99 mmol) in
toluene (15 ml) at room temperature, was added 1,3-cyclo-
pentadiene (0.40 ml, 4.86 mmol). The solution was heated
to reflux for 3 h then an aliquot was removed from the
reaction mixture and the cycloadduct ratio determined by
GC (7:9; 63:37).
1
of endo:exo isomers as determined by H NMR spectro-
scopy. nmax/cmϪ1 3447, 2974, 2948, 2877, 1733, 1456,
1336, 1272, 1177, 1036, 890, 838; dH (300 MHz) 6.21
(0.71H, dd, Jˆ5.6, 3.0 Hz), 6.19 (0.58H, m), 5.92 (0.71H,
dd, Jˆ5.6, 2.9 Hz), 4.24 (0.58H, m), 4.18 (1.42H, m), 3.90–
3.80 (2H, m), 3.22 (0.71H, br s), 3.05 (0.29H, br s), 3.01–
2.97 (1.71H, m), 2.92 (1H, OH), 2.26 (0.29H, m), 1.96–1.88
(1H, m), 1.50–1.23 (3H, m); dC (100 MHz) major endo
isomer 174.8 (s), 137.8 (d), 132.4 (d), 69.7 (t), 60.0 (t),
49.5 (t), 45.7 (d), 43.4 (d), 42.6 (d), 29.3 (t); m/z 182
(Mϩ), 117, 66; Found (Mϩ): 182.0943; C10H14O3 requires
182.0943. GC retention time: 18.5 min (exoϩendo).
Intermolecular competition reaction involving 2-hydroxy-
ethyl acrylate (5) and 2-methoxyethyl acrylate (8) in the
presence of ethyl aluminium dichloride. To a stirred solu-
tion of 2-hydroxyethyl acrylate 5 (0.57 ml, 4.96 mmol) in
DCM (10 ml), at 0ЊC, was added ethyl aluminium dichlor-
ide (1.0 M in hexanes, 5.00 ml, 5.00 mmol). After 10 min,
2-methoxyethyl acrylate 8 (0.65 g, 4.99 mmol) was added
and after a further 15 min, 1,3-cyclopentadiene (0.40 ml, ca.
4.86 mmol) was added. After 1 h, an aliquot was removed
and poured into saturated sodium bicarbonate solution (ca.
1 ml) and extracted with ether (ca. 1 ml). The ether layer
was dried (Na2SO4) and the cycloadduct ratio determined by
GC (7:9; 97:3).
2-Methoxyethyl bicyclo[2.2.1]hept-2-ene-5-carboxylate
(9). A solution of 2-methoxyethyl acrylate 8 (0.65 g,
4.99 mmol) and 1,3-cyclopentadiene (1.2 ml, ca. 14.5
mmol) in toluene (20 ml) was heated under reflux for 5 h
and then allowed to cool to room temperature. Removal of
the solvent in vacuo and subsequent column chromato-
graphy (15% ethyl acetate/85% light petroleum) gave 9
(0.95 g, 97%) as a colourless oil and as a 70:30 mixture of
endo:exo isomers as determined by 1H NMR spectroscopy.
nmax/cmϪ1 2976, 2947, 2878, 1733, 1450, 1175, 1130; dH
(300 MHz) 6.17 (0.7H, dd, Jˆ5.6, 3.1 Hz), 6.11–6.08
(0.6H, m), 5.92 (0.7H, dd, Jˆ5.6, 2.9 Hz), 4.24–4.14 (2H,
m), 3.60–3.53 (2H, m), 3.38 (2.1H, s), 3.37 (0.9H, s), 3.21
(0.7H, br s), 3.03 (0.3 H, br s), 3.00–2.94 (0.7H, m), 2.89
(1H, m), 2.26 (0.3H, m), 1.93–1.85 (1H, m), 1.54–1.24 (3H,
m); dC (100 MHz) major endo isomer 174.7 (s), 137.7 (d),
132.3 (d), 70.6 (t), 63.2 (t), 58.9 (q), 49.6 (t), 45.7 (d), 43.2
(d), 42.5 (d), 29.3 (t); m/z 196 (Mϩ), 131, 120, 99, 91, 77, 66,
59, 55, 51; Found (Mϩ): 196.1106; C11H16O3 requires
196.1099. GC retention times: 17.9 min (exo); 18.0 min
(endo).
Ethyl 2-hydroxyethyl fumarate (1). To a stirred solution
of ethyl hydrogen fumarate 13 (14.4 g, 100 mmol) in
chloroform (500 ml) at 0ЊC was added oxalyl chloride
(8.72 ml, 100 mmol) and a catalytic amount of DMF
(0.20 ml). After 10 min, the solution was allowed to warm
to room temperature and stirred overnight. This solution
was then added, via cannula, to a stirred solution of ethylene
glycol (28.0 ml, 502 mmol), triethylamine (35.0 ml,
251 mmol) and DMAP (1.22 g, 10.0 mmol) in chloroform
(1000 ml) at 0ЊC. After 4 h, aqueous sodium bicarbonate
solution was added. The organic layer was separated,
washed with brine (200 ml), dried (Na2SO4) and the solvent
removed in vacuo to give the crude product. Column
chromatography (40% ethyl acetate/60% light petroleum)
gave 1 (13.0 g, 69%) as a colourless oil. nmax/cmϪ1 3502,
2983, 1732, 1646, 1302, 1263, 1159; dH (400 MHz) 6.87
(2H, m), 4.53 (2H, m), 4.25 (2H, q, Jˆ7.1 Hz), 3.87 (2H,
m), 3.01 (1H, br s, OH), 1.31 (3H, t, Jˆ7.1 Hz); dC
(100 MHz, CD2Cl2) 165.1 (s), 164.9 (s), 134.0 (d), 133.0
(d), 66.8 (t), 61.4 (t), 60.5 (t), 13.8 (q); m/z 189 (MHϩ),
171 (MHϩϪH2O), 145, 127, 117, 99, 85; Found (Mϩ):
188.0693; C8H12O5 requires 188.0685.
Intermolecular competition experiments involving ethyl
acrylate (4) and 2-hydroxyethyl acrylate (5) in the
presence of Lewis acids. All reactions were performed by
stirring 4 (5.0 mmol), 5 (5.0 mmol) and the appropriate
Lewis acid (5 mmol) in DCM (total volumeˆ15 ml) at
0ЊC for 15 min. Di(isopropyl)ethylamine (5 mmol) was
added to the reactions involving titanium (IV) chloride
and tin (IV) chloride. Then, 1,3-cyclopentadiene (5 mmol)
was added to the acrylate/Lewis acid mixture. After 1 h at
0ЊC, an aliquot was removed from the reaction mixture,
quenched with saturated sodium bicarbonate solution (ca.
1 ml) and extracted with ether (ca. 1 ml). The ether layer
was dried (Na2SO4) then analysed by GC to determine the
relative amounts of both the acrylates and cycloadducts
contained within the mixture. The GC system was calibrated
prior to these experiments by injecting mixtures of the acryl-
ates and cycloadducts in predetermined compositions
Ethyl 2-methoxyethyl fumarate (14). To a stirred solution
of ethyl hydrogen fumarate 13 (2.00 g, 13.9 mmol) in DCM
(50 ml) at 0ЊC was added oxalyl chloride (1.21 ml,
13.9 mmol) and DMF (2 drops). The solution was stirred
at 0ЊC for 10 min and allowed to warm to room temperature
and stirred for another 4.5 h. To this solution at 0ЊC was then
added triethylamine (2.90 ml, 20.8 mmol), DMAP (0.17 g,
1.39 mmol) followed by 2-methoxyethanol (2.20 ml,
27.9 mmol) in DCM (50 ml). After stirring overnight,
aqueous sodium bicarbonate solution (50 ml) was added
and the mixture extracted with DCM (2×100 ml). The
organic layers were combined, washed with brine (50 ml),
dried (Na2SO4) and the solvent removed in vacuo to give the
crude product. Column chromatography (10% ethyl acetate/
90% light petroleum) gave 14 (1.34 g, 48%) as a colourless
1
measured using H NMR spectroscopy. The results from
these competition experiments are presented in Table 1
(see Results and Discussion).

1132
G. Clapham, M. Shipman / Tetrahedron 56 (2000) 1127–1134
oil. nmax/cmϪ1 2984, 1722, 1646, 1299, 1260, 1157, 1039;
dH (300 MHz) 6.88 (2H, m), 4.36–4.33 (2H, m), 4.25 (2H,
q, Jˆ7.1 Hz), 3.65–3.62 (2H, m), 3.39 (3H, s), 1.31 (3H, t,
Jˆ7.1 Hz); dC (100 MHz) 164.9 (s), 164.8 (s), 134.0 (d),
133.1 (d), 70.2 (t), 64.2 (t), 61.3 (t), 58.9 (q), 14.0 (q); m/z
203 (MHϩ), 172, 157, 127, 99, 58; Found (Mϩ): 202.0843;
C9H14O5 requires 202.0841.
3.36 (0.25H, t, Jˆ4.1 Hz), 3.33–3.25 (3H, m), 3.18 (0.25H,
m), 3.13 (0.75H, m), 2.73 (0.25H, dd, Jˆ4.5, 1.8 Hz), 2.68
(0.75H, dd, Jˆ4.5, 1.8 Hz), 1.61 (1H, m), 1.46 (1H, m), 1.28
(2.25H, t, Jˆ7.1 Hz), 1.24 (0.75H, t, Jˆ7.1 Hz); dC
(100 MHz) (major compound) 174.2 (s), 172.6 (s), 137.7
(d), 135.1 (d), 64.6 (t), 60.9 (t), 47.8 (d), 47.7 (d), 47.4 (t),
47.3 (d), 45.7 (d), 14.2 (q), 0.4 (t, CH2I); m/z 364 (Mϩ), 319,
299, 155, 66; Found (Mϩ): 364.0171; C13H17IO4 requires
364.0172.
Reaction of ethyl 2-hydroxyethyl fumarate (1) with 1,3-
cyclopentadiene under ethyl aluminium dichloride
mediated conditions. To a solution of fumarate 1 (3.76 g,
20.0 mmol) in DCM (40 ml) was added ethyl aluminium
dichloride (1.0 M in hexanes, 20.0 ml, 20.0 mmol) and the
solution stirred for 15 min, then cooled to Ϫ78ЊC. 1,3-
Cyclopentadiene (3.40 ml, ca. 34 mmol) was added and
the solution stirred overnight. Sodium bicarbonate solution
(30 ml) was carefully added and the aqueous layer extracted
with DCM (2×). The organic layers were combined, dried
(Na2SO4) and the solvent removed in vacuo. Column
chromatography (40% ethyl acetate/60% light petroleum)
gave 15 and 16 (4.97 g, 98%) as a colourless oil and as a
(1Rء,2Rء,3Sء,6Rء)-1-Ethyl bicyclo[2.2.1]hept-4-ene-1,2-
dicarboxylate (17) and (1Rء,2Rء,3Rء,6Sء)-1-ethyl bicyclo-
[2.2.1]hept-4-ene-1,2-dicarboxylate (18). To a stirred
solution of the iodides produced in the experiment above
(75:25 ratio, 1.00 g, 2.75 mmol) in acetic acid (10 ml) was
added zinc powder (2.00 g, 30.6 mmol). The suspension
was stirred for 15 h, water (10 ml) was then added and the
mixture extracted with DCM (3×50 ml). The organic layers
were combined, dried (Na2SO4) and the solvent removed in
vacuo to give the crude product. Column chromatography
(20% ethyl acetate/80% light petroleum) gave 17 and 18
1
75:25 mixture of isomers as determined by H NMR spec-
(472 mg, 82%) as a colourless oil and as a 72:28 mixture
troscopy. nmax/cmϪ1 3447, 2982, 1728, 1456, 1267, 1185,
1033; dH (300 MHz) 6.30–6.26 (1H, m), 6.10–6.07 (1H,
m), 4.24–4.08 (4H, m), 3.82–3.75 (2H, m), 3.41 (0.75H,
t, Jˆ4.1 Hz), 3.35 (0.25H, t, Jˆ4.1 Hz), 3.28 (1H, br s),
3.19–3.01 (2H, m), 2.70 (0.25H, dd, Jˆ4.5, 1.4 Hz), 2.66
(0.75H, dd, Jˆ4.4, 1.4 Hz), 1.62–1.61 (1H, m), 1.47–1.44
(1H, m), 1.27 (2.25H, t, 7.1 Hz), 1.26 (0.75H, t, 7.1 Hz); dC
(100 MHz) (major compound) 174.4 (s), 173.5 (s), 137.5
(d), 135.0 (d), 66.0 (t), 60.8 (t), 60.7 (t), 47.8 (d), 47.6 (d),
47.22 (d), 47.17 (t), 45.6 (d), 14.1 (q); m/z 254 (Mϩ), 237
(MHϩϪH2O), 209, 189, 171, 127, 66; Found (Mϩ):
254.1150; C13H18O5 requires 254.1154.
of isomers as determined by H NMR spectroscopy. nmax
/
1
cmϪ1 3400–2800, 2984, 1726, 1701, 1183; dH (300 MHz)
6.28 (1H, m), 6.12 (0.72H, dd, Jˆ2.6, 5.5 Hz), 6.06 (0.28H,
dd, Jˆ2.7, 5.5 Hz), 4.19–4.05 (2H, m), 3.43 (0.72H, t,
Jˆ4.5 Hz), 3.34 (0.28H, t, Jˆ3.8 Hz), 3.28 (1H, br s),
3.17 (0.28H, br s), 3.12 (0.72H, br s), 2.72 (0.28H, d,
Jˆ4.5 Hz), 2.62 (0.72H, d, Jˆ4.5 Hz), 1.62–1.59 (1H, m),
1.47–1.44 (1H, m), 1.29–1.19 (3H, m), carboxylic acid
hydrogen not observed; dC (100 MHz) (major isomer)
179.4 (s), 174.2 (s), 137.7 (d), 135.2 (d), 61.0 (t), 47.9,
47.8, 47.3, 47.2, 45.6 (4×d, 1×t), 14.2 (q); m/z 210 (Mϩ),
192 (MϩϪH2O), 165, 145, 66; Found (Mϩ): 210.0892;
C11H14O4 requires 210.0892.
Reaction of ethyl 2-hydroxyethyl fumarate (1) with 1,3-
cyclopentadiene under thermal conditions. A stirred
solution of fumarate 1 (188 mg, 1.00 mmol) and 1,3-cyclo-
pentadiene (0.50 ml, ca. 6.1 mmol) in toluene (5 ml) was
heated under refluxed for 3 h. The solvent was removed in
vacuo to give the crude product. Column chromatography
(40% ethyl acetate/60% light petroleum) gave 15 and 16
(180 mg, 71%) as a colourless oil as a 51:49 mixture of
isomers as determined by 1H NMR spectroscopy. All
other spectroscopic data in agreement with those described
above.
Ethyl
2-iodo-5-oxo-4-oxa-tricyclo[4.2.1.03,7]nonane-9-
carboxylate (19). To a stirred solution of acids 17 and 18
(72:28 ratio, 319 mg, 1.52 mmol) in DCM (5 ml) was added
sodium hydrogen carbonate (0.60 g, 7.14 mmol), water
(15 ml), potassium iodide (2.37 g, 14.3 mmol) and iodine
(1.20 g, 4.73 mmol). The mixture was stirred for 18 h,
then saturated sodium thiosulfate solution (10 ml) was
added. The mixture was extracted with DCM (2×50 ml).
The organic layers were combined, washed with water
(20 ml), dried (Na2SO4) and the solvent removed in vacuo
to give the crude product. Column chromatography (10%
ethyl acetate/90% light petroleum) gave 19 (326 mg, 63%)
as a colourless solid (mp 103–104ЊC). nmax/cmϪ1 3056,
2986, 1798, 1784, 1732, 1265, 1244, 1195, 1008; dH
(400 MHz) 5.10 (1H, d, Jˆ5.0 Hz, H-3), 4.16 (2H, m,
OCH2), 3.87 (1H, d, Jˆ2.7 Hz, H-2), 3.19 (1H, m, H-7),
3.07 (1H, br d, Jˆ4.8 Hz, H-6), 2.99 (1H, br s, H-1), 2.80
(1H, br s, H-9), 2.29 (1H, m, H-8), 1.95 (1H, m, H-80), 1.25
(3H, t, Jˆ7.1 Hz); dC (100 MHz) 177.2 (s, lactone), 170.1
(s), 88.4 (d, C-3), 61.9 (t), 50.5 (d, C-1), 50.3 (d, C-9), 46.1
(d, C-7), 40.9 (d, C-6), 35.0 (t, C-8), 28.0 (d, C-2), 14.1 (q);
m/z 336 (Mϩ), 291, 209, 181, 153, 135, 123, 107, 91, 69, 55;
Found (Mϩ): 335.9866; C11H13IO4 requires 335.9859.
(1Rء,2Rء,3Sء,6Rء)-1-Ethyl 2-(2-iodoethyl) bicyclo[2.2.1]-
hept-4-ene-1,2-dicarboxylate and (1Rء,2Rء,3Rء,6Sء)-1-
ethyl 2-(2-iodoethyl) bicyclo[2.2.1]hept-4-ene-1,2-dicar-
boxylate. To a stirred solution of alcohols 15 and 16
(75:25 ratio, 2.00 g, 7.87 mmol) in acetonitrile (40 ml)
and ether (80 ml) at 0ЊC was added imidazole (0.79 g,
11.6 mmol), triphenylphosphine (3.35 g, 12.8 mmol) and
iodine (2.20 g, 8.67 mmol). After 20 min, ether (150 ml)
was added, the mixture filtered and the solvent removed
in vacuo to give the crude product. Column chromatography
(5% ether/95% light petroleum) gave the title compounds
(2.36 g, 82%) as a colourless oil and as a 75:25 mixture of
1
isomers by H NMR spectroscopy. nmax/cmϪ1 2981, 1728,
1264, 1179; dH (400 MHz) 6.30–6.28 (1H, m), 6.12 (0.75H,
dd, Jˆ5.6, 2.8 Hz), 6.07 (0.25H, dd, Jˆ5.6, 2.8 Hz), 4.40–
4.26 (2H, m), 4.19–4.05 (2H, m), 3.42 (0.75H, t, Jˆ4.1 Hz),
Reaction of ethyl 2-methoxyethyl fumarate (14) with
isoprene under thermal conditions. A solution of fumarate
14 (203 mg, 1.00 mmol) and isoprene (1.00 ml, 10.0 mmol)

G. Clapham, M. Shipman / Tetrahedron 56 (2000) 1127–1134
1133
in toluene (10 ml) was heated under reflux for 12 h and then
allowed to cool to room temperature. Removal of the
solvent in vacuo and subsequent column chromatography
(10% ethyl acetate/90% light petroleum) gave (1Rء,2Rء)-
2-ethyl 1-(2-methoxyethyl) 4-methylcyclohex-4-ene-1,2-
dicarboxylate and (1Rء,2Rء)-1-ethyl 2-(2-methoxyethyl)
4-methylcyclohex-4-ene-1,2-dicarboxylate (270 mg, 99%)
as a colourless oil and as a 48:52 mixture of isomers as
determined by 1H NMR. nmax/cmϪ1 2973, 2931, 1735,
1446, 1181; dH (300 MHz) 5.36 (1H, m), 4.23–4.19 (2H,
m), 4.15–4.08 (2H, m) 3.57–3.54 (2H, m), 3.36 (1.44H, s),
3.35 (1.56H, s), 2.91–2.76 (2H, m), 2.42–2.00 (4H, m), 1.64
(3H, br s), 1.23 (1.56H, t, Jˆ7.1 Hz), 1.22 (1.44H, t,
Jˆ7.1 Hz); dC (100 MHz) 175.0 (s), 174.82 (s), 174.80
(s), 174.7 (s), 132.2 (s), 132.1 (s), 119.0 (d), 118.9 (d),
70.4 (t, 2 carbons coincident), 63.5 (t, 2 carbons coincident),
60.50 (t), 60.47 (t), 58.9 (q, 2 carbons coincident), 41.8 (d),
41.7 (d), 41.2 (d), 41.1 (d), 32.5 (t), 32.4 (t), 28.1 (t), 28.0 (t),
23.0 (q, 2 carbons coincident), 14.1 (q, 2 carbons coinci-
dent); m/z 270 (Mϩ), 225, 194, 166, 93; Found (Mϩ):
270.1469; C14H22O5 requires 270.1467.
bicarbonate solution was added cautiously, the layers sepa-
rated, and the aqueous layer further extracted with DCM
(2×). The organic layers were combined, dried (Na2SO4)
and the solvent removed in vacuo to give the crude product.
Column chromatography (40% ethyl acetate/60% light
petroleum) gave (1Rء,2Rء)-2-ethyl 1-(2-hydroxyethyl)
4-methylcyclohex-4-ene-1,2-dicarboxylate and (1Rء,2Rء)-
1-ethyl 2-(2-hydroxyethyl) 4-methylcyclohex-4-ene-1,2-
dicarboxylate (207 mg, 81%) as a colourless oil and as a
76:24 mixture of isomers as determined by 1H NMR. nmax
/
cmϪ1 3446, 2961, 2934, 1733, 1446, 1379, 1312, 1235,
1184, 1075, 1035; dH (300 MHz) 5.34 (1H, m), 4.25–4.07
(4H, m), 3.75 (2H, m), 2.89–2.66 (3H, m), 2.32–1.96 (4H,
m), 1.64 (3H, s), 1.21 (2.28H, t, Jˆ7.1 Hz), 1.20 (0.72H, t,
Jˆ7.1 Hz); dC (100 MHz) (major isomer reported) 175.3
(s), 175.1 (s), 132.2 (s), 118.9 (d), 66.2 (t), 60.9 (t), 60.8
(t), 42.1 (d), 41.4 (d), 32.5 (t), 28.2 (t), 22.9 (q), 14.1 (q); m/z
256 (Mϩ), 238, 211, 182, 166, 93; Found (Mϩ): 256.1312;
C13H20O5 requires 256.1311.
(2Rء,3Rء)-2-(3-Hydroxy)butyl acrylate (20). To a stirred
solution of (2Rء,3Rء)-2,3-dihydroxybutane (6.80 ml,
75.1 mmol), triethylamine (11.2 ml, 80.4 mmol) in DCM
(200 ml), at 0ЊC, was added acryloyl chloride (6.1 ml,
75.1 mmol) dropwise in DCM (200 ml). After stirring over-
night, water (100 ml) was added, the organic layer separated
and the aqueous layer reextracted with DCM (2×). The
combined organic layers were washed with water (50 ml),
dried (Na2SO4), and the solvent removed in vacuo to give
the crude product. Column chromatography (40% ethyl
acetate/60% light petroleum) gave 20 (2.22 g, 21%) as a
colourless oil. nmax/cmϪ1 3447, 2982, 2940, 1708, 1637,
1407, 1296, 985; dH (300 MHz) 6.42 (1H, dd, Jˆ17.3,
1.5 Hz), 6.13 (1H, dd, Jˆ17.3, 10.3 Hz), 5.83 (1H, dd,
Jˆ10.3, 1.5 Hz), 4.95 (1H, dq, Jˆ3.3, 6.5 Hz), 3.92 (1H,
m), 1.90 (1H, br s, OH), 1.25 (3H, d, Jˆ6.5 Hz), 1.18 (3H, d,
Jˆ6.5 Hz); dC (100 MHz) 165.8 (s), 130.9 (t), 128.6 (d),
74.6 (d), 69.5 (d), 17.9 (q), 14.2 (q); m/z 127
(MHϩϪH2O); Found (Mϩ): 144.0780; C7H12O3 requires
144.0786.
Reaction of ethyl 2-methoxyethyl fumarate (14) with
isoprene under ethyl aluminium dichloride mediated
conditions. To a stirred solution of fumarate 14 (203 mg,
1.00 mmol) in DCM (3 ml) at 0ЊC was added ethyl alu-
minium dichloride (1.0 M in hexanes, 1.05 ml,
1.05 mmol). After 15 min, isoprene (1.0 ml, 10.0 mmol)
was added and the solution stirred for 12 h at 0ЊC. Sodium
bicarbonate solution (10 ml) was added cautiously, and the
mixture extracted with DCM (2×50 ml). The organic layers
were combined, washed with brine (20 ml), dried (Na2SO4)
and the solvent removed in vacuo to give the crude product.
Column chromatography (10% ethyl acetate/90% light
petroleum) gave (1Rء,2Rء)-2-ethyl 1-(2-methoxyethyl)
4-methylcyclohex-4-ene-1,2-dicarboxylate and (1Rء,2Rء)-
1-ethyl 2-(2-methoxyethyl) 4-methylcyclohex-4-ene-1,2-
dicarboxylate (205 mg, 76%) as a colourless oil and as a
52:48 mixture of isomers as determined by 1H NMR. Other
spectroscopic data as described above.
Reaction of ethyl 2-hydroxyethyl fumarate (1) with
isoprene under thermal conditions. A stirred solution of
fumarate 1 (200 mg, 1.06 mmol) and isoprene (0.30 ml,
3.00 mmol) in toluene (10 ml) was heated under reflux for
12 h and then allowed to cool to room temperature.
Removal of the solvent in vacuo and subsequent column
chromatography (40% ethyl acetate/60% light petroleum)
gave (1Rء,2Rء)-2-ethyl 1-(2-hydroxyethyl) 4-methylcyclo-
hex-4-ene-1,2-dicarboxylate and (1Rء,2Rء)-1-ethyl 2-(2-
hydroxyethyl) 4-methylcyclohex-4-ene-1,2-dicarboxylate
(257 mg, 95%) as a colourless oil and as a 52:48 mixture
of isomers as determined by 1H spectroscopy. Other spectro-
scopic data as described below.
Reaction of 2-(3-hydroxy)butyl acrylate (20) with 1,3-
cyclopentadiene under thermal conditions. A stirred solu-
tion of acrylate (2Rء,3Rء)-20 (200 mg, 1.39 mmol) and 1,3-
cyclopentadiene (0.40 ml, ca. 4.8 mmol) in toluene (15 ml)
was heated under reflux for 3 h and then allowed to cool to
room temperature. Removal of the solvent in vacuo and
subsequent column chromatography (40% ethyl acetate/
60% light petroleum) gave 21 (288 mg, 99%) as a colourless
oil and as a 71:29 mixture of endo:exo isomers, with the two
endo diastereomers produced in ca. 60:40 ratio as deter-
1
mined by H and 13C NMR spectroscopy. nmax/cmϪ1 3446,
2978, 2943, 1730, 1192, 1090; dH (400 MHz) 6.20 (0.71H,
m), 6.16–6.09 (0.58H, m), 5.93 (0.71H, m), 4.90–4.76 (1H,
m), 3.88–3.81 (1H, m), 3.21 (0.71H, br s), 3.03 (0.29H, br
s), 3.00–2.91 (1.71H, m), 2.24–2.21 (0.29H, m), 2.03–1.86
(2H, m), 1.55–1.26 (3H, m), 1.24–1.13 (6H, m); m/z 210
(Mϩ), 166, 145, 121, 66; Found (Mϩ): 210.1259; C12H18O3
requires 210.1256.
Reaction of ethyl 2-hydroxyethyl fumarate (1) with
isoprene under ethyl aluminium dichloride mediated
conditions. To a stirred solution of fumarate 1 (188 mg,
1.00 mmol) in DCM (3 ml) was added ethyl aluminium
dichloride (1.0 M in hexanes, 1.05 ml, 1.05 mmol) and the
resulting solution was stirred for 15 min before being cooled
to 0ЊC. Isoprene (1.0 ml, 10.0 mmol) was added and the
solution stirred for 12 h. After which time, aqueous sodium
Reaction of 2-(3-hydroxy)butyl acrylate (20) with 1,3-
cyclopentadiene using ethyl aluminum dichloride. To a
stirred solution of 20 (720 mg, 4.99 mmol) in DCM (10 ml)

1134
G. Clapham, M. Shipman / Tetrahedron 56 (2000) 1127–1134
was added ethyl aluminium dichloride (1.0 M in hexanes,
5.0 ml, 5.00 mmol). The solution was cooled to 0ЊC and 1,3-
cyclopentadiene (1.5 ml, ca. 18.2 mmol) was added. After
stirring overnight, the reaction was quenched with aqueous
sodium bicarbonate solution and the mixture extracted
with DCM (2×50 ml). The organic layers were combined,
dried (Na2SO4) and the solvent removed in vacuo to give the
crude product. Column chromatography (40% ethyl acetate/
60% light petroleum) gave 21 (859 mg, 82%) as a colourless
oil and as a 9:1 mixture of endo:exo isomers, with the two
endo diastereomers produced in ca. 33:67 ratio as deter-
References
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9. For examples, see (a) Pearson, A. J.; Zhang, P.; Lee, K. J. Org.
Chem. 1996, 61, 6581. (b) Braum, G.; Braun, P.; Kowalczyk, D.;
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1
mined by H and 13C NMR spectroscopy. dC (100 MHz)
major endo diastereomer 174.3 (s), 137.9 (d), 132.2 (d),
74.1 (d), 69.7 (d), 49.6 (t), 45.8 (d), 43.6 (d), 42.5 (d),
29.2 (t), 17.8 (q), 14.2 (q); other spectroscopic data as
described above.
2-Hydroxyethyl acrylate (5) with ethyl aluminium
dichloride. To a stirred solution of 2-hydroxyethyl acrylate
5
(57.0 ml, 4.96 mmol) in dideuterodichloromethane
(1.00 ml) was added ethyl aluminium dichloride (1.0 M in
hexanes, 0.50 ml, 0.50 mmol). After 0.25 h, the solution
(0.5 ml) was transferred to an oven dried NMR tube, via
syringe and analysed by 13C NMR spectroscopy. dC
(100 MHz) 173.1 (s), 171.1 (s), 141.7 (t), 140.8 (t), 125.8
(d), 125.1 (d), 74.7 (t), 74.0 (t), 63.4 (t), 62.9 (t).
10. For a discussion on this topic, see Fleming, I. Frontier Orbitals
and Organic Chemical Reactions; Wiley: New York, 1976;
pp 161–165.
Acknowledgements
11. Bruson, H. A. J. Am. Chem. Soc. 1942, 64, 2457.
12. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf.
Comput. Sci. 1996, 36, 746.
We are grateful to EPSRC (GR/J73490) for financial
support of this work. We are indebted to Dr Franck Suzenet
for rechecking one of our experiments. We are indebted to
the EPSRC Chemical Database Service at Daresbury.12