Highly diastereoselective Diels-Alder cycloadditions of 9R-(1-methoxyethyl)anthracene with p-benzoquinone

Article abstract of DOI:10.1039/b603819k

Diels-Alder cycloadditions of p-benzoquinone with 9R-(1-methoxyethyl) anthracene provides a 60: 40 ratio of cycloadducts when heated at reflux in xylene. Mechanistic studies to explore the origins of this selectivity have shown that at lower temperatures the kinetic product predominates, giving a 96: 4 ratio of cycloadducts. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b603819k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly diastereoselective Diels–Alder cycloadditions of
9R-(1-methoxyethyl)anthracene with p-benzoquinone
Harry Adams, Simon Jones* and Isaac Ojea-Jimenez
Received 14th March 2006, Accepted 13th April 2006
First published as an Advance Article on the web 8th May 2006
DOI: 10.1039/b603819k
Diels–Alder cycloadditions of p-benzoquinone with 9R-(1-methoxyethyl)anthracene provides a 60 : 40
ratio of cycloadducts when heated at reflux in xylene. Mechanistic studies to explore the origins of this
selectivity have shown that at lower temperatures the kinetic product predominates, giving a 96 : 4 ratio
of cycloadducts.
leaves of Lagerstroemia indica.5 Although these three com-
pounds have been prepared from ethyl (1R,2S)-5,5-ethylendioxy-
2-hydroxycyclohexanecarboxylate, the synthetic routes are gener-
ally arduous giving low overall yields.6
Introduction
The importance of p-benzoquinone and its derivatives as synthetic
building blocks have been amply demonstrated by their extensive
use in natural product synthesis.1 For example, the asymmetric
synthesis of (+)-cyclophellitol 1, an inactivator of b-glucosidase
isolated from the mushroom Phellinus sp., has been recently de-
scribed via a synthetic pathway relying upon a palladium-catalysed
kinetic resolution of the racemic conduritol B tetraacetate 2, easily
accessed from p-benzoquinone 3 (Scheme 1).2
The literature contains a large number of examples of
Diels–Alder reactions with p-benzoquinone 3, including re-
action with cyclopentadiene,7 cycloheptadiene,8 butadiene,9
trans,trans-1,4-diphenylbuta-1,3-diene,10 and an isodicyclopenta-
diene derivative.11 Given this precedent, cycloadditions of p-
benzoquinone 3 to the 9R-(methoxyethyl)anthracene 7 appeared
to be an attractive alternative for further development of a chiral
auxiliary strategy that employs a key Diels–Alder/retro Diels–
Alder reaction that we12,13,14 and others15 have been developing.
The resulting cycloadduct would be highly functionalised and
as such would offer wide scope as a key building block for the
synthesis of target molecules based upon a cyclohexane backbone.
A number of functional group transformations were envisaged
with this substrate (Scheme 2).
Scheme 1 Synthesis of (+)-cyclophellitol 1.
Moreover, the cyclohexane epoxide backbone is a common
framework found in a huge range of structurally diverse naturally
occurring compounds isolated mainly from fungi and higher
plants. Many of these highly oxygenated six-membered rings
have attracted synthetic interest because of their varied biological
properties (Fig. 1).3
Fig. 1 Cyclohexane epoxide natural products.
For example, bromoxone 4 was isolated from the marine acorn
worm4 and showed potent anti-tumour activity against P388
cells in vitro, while related epiepoformin 5 and epiepoxydon
6, inhibitors of lettuce seed germination, were isolated from
an unidentified fungus separated from diseased carpemyrtle
Scheme 2 Diastereoselective Diels–Alder addition.
Thus, the carbonyl groups facilitate both 1,2-nucleophilic addi-
tion and enolate alkylation, while the enone may be functionalised
through standard electrophilic and Michael addition reactions.
The work described herein describes our investigation of the
viability of the Diels–Alder reaction of anthracene derivatives
Department of Chemistry, University of Sheffield, Dainton Building, Brook
Hill, Sheffield, UK. E-mail: simon.jones@sheffield.ac.uk; Fax: +44 (0)114
222 9346; Tel: +44 (0)114 222 9483
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with p-benzoquinone and attempts to rationalise the selectivity
observed.
adopting a fully planar conformation in the transition state and
therefore diminishing p-stacking interactions with the dienophile.
However, given that maleic anhydride and N-methylmaleimide in
toluene or benzene react more slowly with anthracene 8 than with
ether 7,12 it is perhaps more likely that the apparently slow reaction
rate here is based on the existence of a competing retro Diels–Alder
reaction.
Results and discussion
Thermal cycloadditions
An initial assay was conducted to investigate the difference in the
relative reaction rates of anthracene 8 and 9-substituted methyl
ether 7 with p-benzoquinone 3 by heating at reflux in mixed xylenes
for 24 h and sampling each reaction at selected time intervals
(Scheme 3, Table 1, Chart 1).
The stereochemical outcome of the thermal cycloaddition of p-
benzoquinone 3 with the ether 7 was then considered (Scheme 4).
Scheme 3 Thermal Diels–Alder cycloadditions.
Table 1 Diels–Alder cycloadditions of anthracene 8 and ether 7 with
p-benzoquinone 3 in mixed xylenes at reflux
Conversion (%)a
Scheme 4 Diastereoisomers formed from the cycloaddition reaction.
Time/h
9
10 & 11
Analysis of the crude 1H NMR spectrum indicated a conversion
of 60% from starting material into a mixture of the two possible
diastereoisomers 10 and 11 in an approximate ratio of 60 :
40, respectively, determined by integration of the appropriate
signals. Separation by flash column chromatography afforded both
diastereoisomers in a 31 and 27% yield, respectively, and their
relative stereochemistry was confirmed by single crystal X-ray
diffraction (Fig. 2).
1
2
5
15
24
75
81
98
14
20
32
41
60
100
100
a Conversion calculated from the ratio of signals for the starting material
and product(s) in the 1H NMR spectrum.
Cycloadduct 10 crystallised as a hemi-dichloromethane solvate
with the dichloromethane on a twofold axis and clearly shows the
orientation of the methoxy group away from the carbonyl with
the methyl substituent antiperiplanar to the ring system which is
in good agreement with the previous elucidated structures of the
cycloadducts from maleic anhydride and N-methylmaleimide.12 By
contrast the conformation of the 9-substituent in isomer 11 locates
the methoxy group antiperiplanar to the newly formed ring system
with the methyl substituent oriented away from the carbonyl,
possibly due to strong steric and electrostatic repulsions. It is also
noteworthy to mention the shallow boat conformation of the 2-
ene-1,4-dione ring in structure 10, in which C15–C16 and C19–
˚
C20 bonds are coplanar (rms deviation 0.011 A). The two carbonyl
moieties represented by the sets of atoms C15/C19/C17/O1 and
˚
C16/C20/C18/O2 (rms deviation 0.007 and 0.010 A, respectively)
are bent away from the underlying phenyl ring with dihedral angles
with the previous plane C15/C16/C20/C19 of 25.0 and 13.1◦,
respectively. This conformation is similar to that reported for the
crystal structure of the addition product 9 from the reaction of
p-benzoquinone and anthracene.16 Somewhat surprisingly the six-
membered diketone ring in structure 11 adopts a flat conformation
in which all atoms involved (C15/C16/C17/C18/C19/C20) fall in
Chart 1 Reactions rates of anthracene 8 and ether 7 with p-benzoqui-
none 3.
From the rate profiles, the methoxyethyl substituent at the 9-
position of anthracene causes a six fold decrease in the apparent
reaction rate, kobs, when compared with anthracene 8. This could
be a consequence of the substituted anthracene ring system not
˚
a plane (rms deviation 0.049 A). The carbonyl groups O1/C17 and
O2/C18 have now dihedral angles with this plane of 4.0 and 10.1◦,
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Scheme 5 Reversibility of Diels–Alder reaction.
Scheme 6 Reversibility of Diels–Alder reaction.
Both cycloadducts 10 and 11 were found to partially cleave back
producing the ether 7 in 45 and 67% yields, respectively. Such
results confirmed a lower stability associated with benzoquinone-
derived cycloadducts 10 and 11 under thermal conditions in
comparison to maleate-based cycloadducts, which show very little
cycloreversion.13 The increased amount of cleavage obtained for
the syn-diastereoisomer 11 is also in agreement with what would
be predicted from the X-ray crystal structure, owing the more
constrained conformation adopted when compared to the anti-
cycloadduct 10. Interestingly, the crude mixture from the cleavage
reaction of the anti-cycloadduct 10 was an 80 : 20 mixture
of 10 : 11, which indicated that the reaction was not totally
equilibrated under the conditions given and illustrated the slow
forward process taking place with this diastereoisomer at this
temperature. Similarly, the reaction of the syn-cycloadduct 11 also
returned increased amounts of the initial diastereoisomer as a 35 :
65 mixture of 10 : 11. These results confirmed an equilibrium for
this reaction taking place under the conditions studied.
Fig. 2 X-Ray structures of diastereoisomers 10 and 11, respectively.
Ellipsoids shown at 50% probability.
respectively, this resulting in a considerably more constrained
conformation of the rigid bicyclic system.
The reversibility of the Diels–Alder reactions of the cycloadduct
9 and the isolated single diastereoisomer 10 were investigated by
refluxing with equimolar amounts of N-methylmaleimide 12 in
toluene for 5 h (Scheme 5). Analysis indicated the appearance of
the crossover cycloadducts 13 and 14 in 16 and 100% conversion,
respectively, as determined by integration of the appropriate
signals in the 1H NMR spectra. Such results confirmed the
existence of a retro Diels–Alder reaction in equilibrium with the
forward cycloaddition which thus explained their relative rates of
formation noted earlier.
The facile reversibility encountered in the Diels–Alder reaction
of the ether 7 and p-benzoquinone 3 suggests an explanation of
the diastereoselectivity based on the thermodynamic stability of
the products. Molecular modelling studies of the ground state
conformations were carried out for the two addition products
Additionally, both isolated single diastereoisomers 10 and
11 were resubjected to the original cycloaddition conditions in
toluene (Scheme 6).
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Table 2 Molecular modelling of diastereoisomers 10 and 11
a
Cycloadduct DHf
Calculated Keq
Predicted drb
61 : 39
Observed drb
60 : 40
10
11
−20.24 0.77
−20.04
a Obtained from the calculated energy differences at 110 ◦C. b Ratio (anti :
syn).
10 and 11. The predicted equilibrium constant for the two
diastereoisomers obtained fromtheir calculated heats offormation
agree reasonably well with the observed experimental results
(Table 2).
Investigation of the mechanism of the Diels–Alder reaction
The poor diastereoselectivity observed for the Diels–Alder re-
action of the ether 7 to p-benzoquinone 3 was intriguing when
compared to the highly diastereoselective systems (>98% de) found
with maleate-type dienophiles.12 This was further confounded by
measuring oxygen–oxygen distances between the methoxy group
and the proximal carbonyl group as well as appropriate bond
angles (x) in the◦ X-ray crystal structure of addition product
Scheme 7 Possible epimerisation by radical abstraction.
pretation of these reactions is still controversial in some respects.19
The choice between the concerted and the stepwise mechanism
by radical or zwitterionic intermediates cannot always be made
easily. Recently many kinetic studies of substituent and solvent
effects have appeared.20 In addition, electron-transfer processes
via charge-transfer interactions between anthracene dienes and
dienophiles, including p-benzoquinone, in the transition state of
Diels–Alder reactions have recently been reported.21,22 Such a step-
wise process would naturally lead to poor stereocontrol, especially
if initial attack occurred at the position distal to the stereodirecting
group.
˚
10 (3.1 A, 111.1 ) and comparing to these of the addition
◦
˚
products of ether 7 with maleic ◦anhydride (3.5 A, 114.1 ) and
˚
N-methylmaleimide (3.5 A, 112.7 ) (Fig. 3).
However, direct experimental evidence to demonstrate the
existence of a charge transfer complex was difficult to determine
using in situ UV/Vis measurements of the reactions. Attempts to
detect the semiquinone radical anion were carried out as described
in the literature,23 by measuring the change in initial absorbance
of different concentrations of ether 7 and p-benzoquinone 3 at
various wavelengths with a UV/Vis spectrometer in deaerated
chloroform at 298 K, but unfortunately no absorption maxima
could be observed around the area expected for this species (kmax
=
Fig. 3 Atom distances taken from X-ray crystallographic information.
422 nm)22 presumably due to the very short lifetimes of such radical
species. Although this cannot rule out a possible stepwise reaction
mechanism, further work would be needed to demonstrate the
existence of an intermediate charge transfer complex.
The similar distances and bond angles noted suggest that
comparable electronic and/or steric factors should be involved in
the transition states of the respective cycloadditions if the reactions
proceeded through the same reaction mechanism, which vastly
contrast with the observed difference in the selectivity.
Lewis acid catalysed Diels–Alder reactions
Initial thoughts to account for the stereochemical outcome
were based upon a possible epimerisation of the stereogenic
centre of the addition products 10 and/or 11 through radical
abstraction of the methine proton and epimerisation (Scheme 7).
Such an argument was supported by the previous use of p-
benzoquinone 3 as a reagent for the oxidation of aryl conjugated
allylic alcohols under similar conditions to those used herein
(xylene, 120 ◦C).17 However, this was ruled out by subjecting the
isolated single diastereoisomer 10 to thermal cleavage as described
earlier (Scheme 6), which led to the ether derivative 7 with a specific
rotation identical to the starting material.
Following recent examples in the literature, which reported
remarkable selectivity for Diels–Alder additions catalysed by
a new family of Lewis acid complexes derived from pyridyl-
bis(oxazoline) ligands and samarium and gadolinium triflates,24
attempts to enhance the selectivity of the Diels–Alder cycload-
ditions of ether 7 and p-benzoquinone 3 were carried out under
similar conditions. A ligand–metal triflate survey was performed
by heating reactants at 70 ◦C in CH3CN in a range of different lig-
ands (bipy 15, BEN 16, N,Nꢀ-dibenzylidenepropane-1,3-diamine
17 and 4,4ꢀ,5,5ꢀ-tetrahydro-4,4,4ꢀ,4ꢀ-tetramethyl-2,2ꢀ-bioxazole 18)
and metal triflates (Mg2+, Cu2+, Sc3+, Y3+, La3+, Gd3+). The highest
reactivity was observed when the bisoxazole ligand 18 was used
in combination of Cu2+ and Y3+ as catalyst systems for periods
of 16 h (Table 3). However, exposing the reaction under longer
This led us to consider an alternative reaction may be proceed-
ing. Although the synthetic potential of cycloaddition reactions
was outlined by Diels and Alder long ago,18 the mechanistic inter-
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Table 3 Lewis acid catalysed Diels–Alder cycloadditions of ether 7 with p-benzoquinone 3a
Conversion (%) (ratio of diastereoisomers anti : syn)b
M(OTf)n–ligand
Blank
Blank
11 (98 : 8)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Mg(OTf)2
Cu(OTf)2
Sc(OTf)3
Y(OTf)3
La(OTf)3
Gd(OTf)3
11 (97 : 3)
11 (100 : 0)
12 (85 : 15)
12 (88 : 12)
11 (90 : 10)
7 (100 : 0)
11 (98 : 2)
11 (95 : 5)
14 (86 : 14)
14 (87 : 13)
9 (90 : 10)
11 (96 : 4)
11 (100 : 0)
13 (96 : 4)
16 (81 : 19)
15 (90 : 10)
10 (100 : 0)
9 (97 : 3)
9 (96 : 4)
35 (87 : 13)
16 (81 : 19)
20 (87 : 13)
15 (90 : 10)
10 (95 : 5)
a Reactions performed with ether 7 and p-benzoquinone 3 in a 1 : 1 ratio in CH3CN at 70 ◦C for 16 h. b Calculated from the integral of the signals
corresponding to starting material and addition products in the 1H NMR spectrum.
reaction times (48 h) led to decomposition of the starting materials.
On the other hand, encouraging results were obtained for those
background reactions in the absence of catalyst when heated in
CH3CN at 70 ◦C, achieving a 56% conversion after 48 h and a 93 :
7 ratio in favour of diastereoisomer 10.
(96 : 4) was obtained at the lowest temperature (70 ◦C), which
also gave the highest conversion (67%). These were, therefore,
accepted as the optimised conditions for the Diels–Alder reaction
of ether 7 and p-benzoquinone 3. In addition, slow cooling of the
reaction mixture caused precipitation of product crystals making
the purification step by flash column chromatography unnecessary
and affording the desired cycloadduct 10 in an enhanced 62% yield
and >98% de This optimised procedure, under the new conditions,
fulfilled the crucial requirement of high diastereoselectivity in the
addition step and widely enhanced the potential of the described
methodology.
To investigate the extent of the retro Diels–Alder reaction under
these optimised conditions, both isolated single diastereoisomers
10 and 11 were subjected to thermal cleavage by heating at 70 ◦C in
toluene for 48 h in the presence and absence of N-methylmaleimide
12 (1 eq.) (Table 5). Interestingly, only cycloadduct 10 could
be partially cleaved back at this temperature affording similar
conversions to both ether 7 andmaleimide adduct 14. The outcome
of this retro Diels–Alder reaction (22–29%) is in agreement with
the unconverted ether 7 observed previously for the forward
process (33%), which indicates a complete re-equilibration of both
reactions after 48 h. In addition, the diastereoisomer returned was
identical to starting material 10, which confirms that only the
kinetic product 10 is formed under these reaction conditions.
The enhanced conversion and selectivity obtained in the cy-
cloaddition of ether 7 and p-benzoquinone 3 at low temperatures
(70 ◦C) in conjunction with the decreased competing retro Diels–
Alder reaction observed for both addition products 10 and 11,
now suggested an explanation based upon kinetic control being
Thermal additions at lower temperature
These preliminary results led to a more detailed study into the role
of the temperature in the outcome of the Diels–Alder reaction of
ether derivative 7 and p-benzoquinone 3. Reactants were heated
in toluene at different temperatures for 48 h and the conversions
and relative ratios of diastereoisomers 10 and 11 were determined
by integration of the appropriate signals in the 1H NMR spectra
of the crude material (Table 4).
As the temperature of the reaction was increased, the amount
of addition products obtained was seen to decrease. These results
were somewhat surprising since it was expected for thermal
cycloadditions to show an increased reactivity at elevated temper-
atures of reaction, as anticipated for the additions of anthracene
8. This apparent anomalous reactivity could be explained by
the retro Diels–Alder reaction for these compounds being more
facile at high temperatures. Interestingly, the reactions at lower
temperature showed a higher selectivity in favour of the anti-
diastereoisomer, which agrees with the previous reactions carried
out in CH3CN. Subsequently, the highest diastereoselectivity
Table 4 Diels–Alder cycloaddition of ether 7 with p-benzoquinone 3 at
different temperaturesa
Temperature (◦C)
Conversion (%)b
drc
Table 5 Retro Diels–Alder exchange reactions of adducts 10 and 11a
70
80
90
100
110
67
52
46
45
31
96 : 4
93 : 7
88 : 12
82 : 18
58 : 42
Conversion to 7 (%)b
Conversion to 14 (%)b
No maleimide
1 eq. N-methyl maleimide
10
11
29
0
22
0
a Reactions performed with ether 7 and p-benzoquinone 3 in a 1 : 1 ratio in
toluene at specified temperature for 48 h. b Ratio calculated by integration
of the signals corresponding to starting material and addition products 10
and 11 in the 1H NMR spectrum. c Ratio calculated by integration of the
signals corresponding to each diastereoisomer 10 : 11, respectively.
a Reactions performed with et◦her 7 with and without N-methyl maleimide
in a 1 : 1 ratio in toluene at 70 C for 48 h. b Ratio calculated by integration
of the signals corresponding to starting material and addition products in
the 1H NMR spectrum.
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more satisfactory to explain the diastereoselectivity. Therefore, a
similar rationalisation to those previously used in the additions of
maleate dienophiles could be used to explain the facial selectivity
in Diels–Alder reactions of p-benzoquinone 3 at low tempera-
ture (70 ◦C). Subsequently, the dienophile would preferentially
approach the ether 7 by the opposite face to the methyl group,
and the selectivity would be established through minimisation of
electrostatic repulsions between the dienophile carbonyl oxygen
and the methoxy group of the diene to yield the anti-cycloadduct
10 (Fig. 4).15
Glassware was flame dried and cooled in vacuo before use and all
reactions were carried out under nitrogen unless otherwise stated.
TLC was carried out using Merk aluminium TLC sheets (silica
gel 60 F254). Visualisation of the TLC plates was carried out using
a UV lamp or by dipping in KMnO4 then exposure by heating.
Flash column chromatography was carried out with Fluorochem
Limited Silica Gel 40–63u 60A.
Melting points were measured on a Gallenkamp apparatus and
are uncorrected. Specific rotations were performed on a Optical
Activity LTD. AA-10 aut◦omatic polarimeter at 589 nm (Na D-
line) and measured at 20 C unless otherwise stated. [a]D values
are given in 10−1 deg cm2 g−1. All infrared spectra were recorded on
a Perkin Elmer Spectrum RX/FT-IR system with a DuraSampl
1
IR II ATR accessory. 250 and 300 MHz H NMR were carried
out on a AC-250 or Avance 300 instrument respectively supported
by an Aspect 200 or Aspect 300 data system. 100 MHz 13C
NMR were carried out on a Bruker AMX-400 spectrometer.
500 MHz 1H NMR and 125 MHz 13C NMR were carried out on
JEOL (Japan Electron Optical Limited) k 500 MHz spectrometer.
Residual proton signals from the deuterated solvents were used
as references [chloroform (1H 7.25 ppm, 13C 77 ppm)]. Coupling
constants were measured in Hz. Mass spectra were recorded on a
Micromass Autospec M spectrometer. Elemental microanalysis
was performed using a Perkin Elmer 2400 CHNS/0 Series II
elemental analyzer. Elemental analysis for some cycloadducts was
calculated taking into account the percentage of CH2Cl2 in the
product crystals since removal was proved to be difficult. These
arguments were also supported by the appearance of solvent
molecules in the X-ray crystal structures. Chlorine analysis was
determined by the classical wet method of elemental anion analysis
using the Scho¨niger oxygen flask combustion method. UV-Vis
spectra were recorded on a Varian Cary 50 spectrometer.
Fig. 4 Models for diastereoselection.
Thermal additions of cyclohexenone derivatives
Attempts at the thermal Diels–Alder reaction of ether 7 with
the new range of cyclohexenone derivatives 19–22 (Fig. 5) were
◦
performed by both heating the reactants at 160 C in a Fischer-
Porter apparatus at 20 bar in toluene for 48 h and also by the
optimised conditions (toluene, 70 ◦C, 48 h).
Data collected were measured on a Bruker Smart CCD area
detector with Oxford Cryosystems low temperature system. Single
crystals of compounds 10 and 11 were grown by liquid diffusion
from dichloromethane–petrol (40–60), mounted in inert oil and
transferred to the cold gas stream of the diffractometer.
Fig. 5 Other cyclohexenone dienophiles.
Minimised structures were generated using molecular modelling
calculations with Quantum CAChe software (version 3.2, Oxford
Molecular Ltd) by first minimising using MM3 parameters,
followed by PM3 parameters.
The following compounds were prepared by following estab-
lished literature procedures: 7,12 16,26 17,27 18.28
However, quite disappointingly, only unreacted starting ma-
terials could be observed in all the cases. These results, which
are in agreement with similar studies in the literature,25 indicated
that the absence of a second ketone functionality and/or double
bond moiety make the enone derivatives 19–22 less reactive
than p-benzoquinone 3. Experiments examining the reactivity of
substituted benzoquinones are currently underway.
General procedure for the thermal Diels–Alder reactions of
compounds 7 and 8 with p-benzoquinone 3
Conclusion
A solution of anthracene 7 or 8 (3.0 mmol) and p-benzoquinone
(4.6 mmol) in dry degassed solvent (5 cm3) was heated at reflux
and a sample removed at a specified time interval as appropriate.
Removal of the solvent produced the desired cycloadduct (conver-
sion calculated from 1H NMR spectrum).
We have successfully developed a highly diastereoselective cycload-
dition protocol for accessing densely functionalised benzoquinone
building blocks. The potential application of this methodology to
the synthesis of structurally related targets is enormous and is
currently under investigation.
Preparation of 4a, 9,9a,10-tetrahydro-9,10-[1ꢀ,2ꢀ]-
benzenoanthracene-1,4-dione (9)29
Experimental
All solvents used were freshly dried over sodium except CH2Cl2
which was dried over LiAlH4. Et3N was distilled over KOH. p-
Benzoquinone was recrystallised from petrol 60–80. A xylenes
mixture was used in all reactions in xylene unless otherwise stated.
Anthracene 8 (0.5 g, 2.8 mmol) and p-benzoquinone 3 (0.45 g,
4.2 mmol) were heated under reflux in xylene (5 cm3) for 5 h.
The hot solution was poured into a beaker and cooled overnight
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◦
at 5 C. The solid formed was filtered, washed with cold xylene
12893 reflections measured, 4210 unique (Rint = 0.0443) which
were used in all calculations. The final wR(F2) was 0.1205 (all
data).
(20 cm3) and petrol 40–60 (20 cm3) and the solvent evaporated to
yield the◦title compound 9 (0.65 g, 81%) as yellow crystals: mp
231–233 C (from petrol 40–60) (lit.,30 227–232 ◦C); dH (250 MHz;
CDCl3; Me4Si) 3.14 (2H, s, COCH), 4.86 (2H, s, 9-H and 10-H),
6.31 (2H, s, C CH), 7.05–7.11 (2H, m, ArCH), 7.16–7.20 (4H,
m, ArCH), and 7.38–7.41 (2H, m, ArCH).
Crystal structure determination of compound 11†
=
Crystal data. C23H20O3, M = 344.39, monoclinic, a =
3
˚
˚
16.221(8), b = 7.386(4), c = 28.003(13) A, U = 3250(3) A , T =
150(2) K, space group C2/c, Z = 8, l(Mo Ka) = 0.092 mm−1,
17536 reflections measured, 3733 unique (Rint = 0.0704) which
were used in all calculations. The final wR(F2) was 0.1525 (all
data).
Preparation of (4aR,9aS)-4a,9,9a,10-tetrahydro-9-[(1R)-1-
methoxyethyl]-9,10[1ꢀ,2ꢀ]-benzenoanthracene-1,4-dione (10) and
(4aS,9aR)-4a,9,9a,10-tetrahydro-9-[(1R)-1-methoxyethyl]-
9,10[1ꢀ,2ꢀ]-benzenoanthracene-1,4-dione (11)
(R)-9-(1-Methoxyethyl)anthracene 7 (0.71 g, 3.0 mmol) and p-
benzoquinone 3 (0.50 g, 4.6 mmol) were heated at reflux in dry
degassed xylene for 24 h. Removal of the solvent gave a mixture of
two diastereoisomers in a 60 : 40 ratio (60% conversion calculated
from 1H NMR spectrum). Separation of the diastereoisomers was
carried out by flash column chromatography (from 50 to 100%
CH2Cl2–petrol 40–60). Compound 10 (31%) as yellow crystals:
mp 164–166 ◦C (from CH2Cl2–petrol 40–60); [a]2D2 −140.0 (c 1 in
CHCl3); (found: C, 80.1; H, 5.7. Calc. for C23H20O3: C, 80.2; H,
General procedure for the competition experiment between
cycloadducts 8, 10 and 11 with N-methylmaleimide 12 under
thermal conditions
A solution of cycloadduct (0.16 mmol) and N-methylmaleimide 12
(0.02, 0.18 mmol) was heated under reflux for 5 h in dry degassed
toluene (5 cm3). Removal of the solvent produced the desired
cycloadduct (conversion calculated from 1H NMR spectrum). 1H
NMR data for cycloadducts 13 and 14 were in accordance with
the literature.31,12
5.85%); mmax (ATR)/cm−1 1663 (CO), 1458 (C C); dH (250 MHz;
=
CDCl3; Me4Si) 1.81 (3H, d, J 6.2, CH3CH), 3.01 (1H, dd, J 2.4 and
8.9, COCH), 3.46 (1H, d, J 8.9, COCH), 3.69 (3H, s, OCH3), 4.44
(1H, q, J 6.2, CH3CH), 4.61 (1H, d, J 2.4, PhCHCH), 6.02 (2H, s,
General procedure for the retro Diels–Alder reactions of
compounds 10 and 11 under thermal conditions
=
2 × C CH), 7.06–7.24 (6H, m, ArCH), 7.35–7.40 (1H, m, ArCH),
A solution of adduct 10 or 11 (0.05 g, 0.2 mmol) in dry toluene
(5 cm3) was heated under reflux for 24 h. Removal of the solvent
produced ether 7 in 47 and 70% conversion and unreacted
cycloadducts 10 and 11 in 80 : 20 and 35 : 65 ratios, respectively
7.93–7.97 (1H, m, ArCH); dC (100 MHz; CDCl3; Me4Si) 16.5
(CH3), 50.1 (CH), 51.1 (CH), 52.0 (CH), 56.4 (9-C and OCH3),
74.0 (CH3CH), 123.4 (ArCH), 123.5 (ArCH), 125.1 (ArCH),
125.8 (ArCH), 126.4 (ArCH), 126.6 (ArCH), 126.7 (ArCH), 127.1
1
(conversions and ratios calculated from H NMR). Purification
=
(ArCH), 138.1 (C C), 138.4 (ArC), 138.8 (ArC), 139.8 (ArC),
+
by flash column chromatography (50% CH2Cl2–petrol 40–60)
afforded (R)-9-(1-methoxyethyl)anthracene 7 in 45 and 67% yields,
respectively, each of >98% ee.
=
141.3 (C C), 142.7 (ArC), 197.8 (CO), 199.2 (CO); m/z (ES )
367.1294 (M + Na+, 100%. C23H20O3Na requires 367.1310), 259
(15), 205 (8).
Compound 11 (27%) as yellow crystals: mp 166–168 ◦C (from
CH2Cl2–petrol 40–60); [a]2D2 +120.0 (c 1 in CHCl3); (found: C,
73.95; H, 5.5; Cl, 7.0. Calc. for C23H20O3·0.395 CH2Cl2: C, 74.3;
Attempted procedure for detection of the semiquinone radical anion
using in situ UV/Vis measurements
H, 5.6; Cl, 7.4%); mmax (ATR)/cm−1 1661 (CO), 1457 (C C); dH
=
A CHCl3 solution (0.8 cm3) containing p-benzoquinone 3 (10−4 M)
and different concentrations of (R)-9-(1-methoxyethyl)anthracene
7 (0.1, 0.25, 0.5, 1 and 2 eq.) in a square plastic cuvette (1 mm)
was deaerated by bubbling with nitrogen gas for 5 min. A wave-
length scan was then carried out (200–400 nm) using a UV/Vis
spectrometer but only the absorption maxima corresponding to p-
benzoquinone 3 (242 nm) and (R)-9-(1-methoxyethyl)anthracene
7 (243, 258, 331, 348, 366 and 385 nm) were observed in all the
cases.
(250 MHz; CDCl3; Me4Si) 1.97 (3H, d, J 6.4, CH3CH), 3.12–
3.27 (2H, m, COCH and COCH), 3.61 (3H, s, OCH3), 4.37 (1H,
q, J 6.4, CH3CH), 4.58 (1H, d, J 2.1, PhCHCH), 6.08 (2H, d,
=
J 1.2, 2 × C CH), 7.08–7.21 (6H, m, ArCH), 7.36–7.39 (1H,
m, ArCH), 7.89–7.92 (1H, m, ArCH); dC (100 MHz; CDCl3;
Me4Si) 14.0 (CH3), 50.3 (CH), 50.9 (CH), 52.0 (CH), 55.1 (9-
C), 56.8 (OCH3), 76.8 (CH3CH), 123.6 (ArCH), 124.2 (ArCH),
125.1 (ArCH), 126.3 (ArCH), 126.7 (ArCH), 127.0 (ArCH), 127.4
=
(ArCH), 127.5 (ArCH), 139.0 (C C), 139.3 (ArC), 140.3 (ArC),
=
141.1 (ArC), 141.6 (C C), 143.6 (ArC), 198.3 (CO), 199.2 (CO);
m/z (EI+) 344.1416 (M+, 0.15%. C23H20O3 requires 344.1412), 236
General procedure for the Lewis acid catalysed Diels–Alder
reactions of ether 7 with p-benzoquinone 3
(96), 235 (94), 221 (100), 205 (39), 178 (30).
(R)-9-(1-Methoxyethyl)anthracene 7 (20 mg, 0.08 mmol) and p-
benzoquinone 3 (14 mg, 0.12 mmol) were added to a pre-stirred
solution either in the presence or absence of ligand (20% mol)
and metal triflate (20% mol) in dry degassed CH3CN (2 cm3). The
resulting mixture was heated at 70 ◦C for 16 h and allowed to
cool to rt. The solution was filtered through silica gel with CH2Cl2
washing (10 cm3) and the solvent removed (conversions calculated
from the 1H NMR spectra).
Crystal structure determination of compound 10†
Crystal data. C23.50H21ClO3, M = 386.85, monoclinic, a =
3
˚
˚
13.5591(16), b = 9.7766(12), c = 27.715(3) A, U = 3639.8(8) A ,
T = 150(2) K, space group C2/c, Z = 8, l(Mo Ka) = 0.233 mm−1,
† CCDC reference numbers 601816–601817. For crystallographic data in
CIF format see DOI: 10.1039/b603819k
2302 | Org. Biomol. Chem., 2006, 4, 2296–2303
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Improved method for the preparation of (4aR,9aS)-4a,9,9a,10-
tetrahydro-9-[(1R)-1-methoxyethyl]-9,10[1ꢀ,2ꢀ]-benzenoanthracene-
1,4-dione 10 with enhanced diastereoselectivity
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(R)-9-(1-Methoxyethyl)anthracene 7 (0.70 g, 3.0 mmol) and p-
benzoquinone 3 (0.50 g, 4.6 mmol) were heated at 70 ◦C in toluene
(5 cm3) for 48 h. Slow cooling produced yellow crystals of the title
1
compound 10 (0.63 g, 62%) (>98% de from H NMR spectrum)
which were filtered, washed with petrol 40–60 (3 × 5 cm3) and
dried in vacuo.
General procedure for the retro Diels–Alder reactions of
compounds 10 and 11 at 70 ◦C
A solution of cycloadduct (0.16 mmol) in the presence and absence
of N-methylmaleimide 12 (0.02, 0.18 mmol) in dry degassed
toluene (5 cm3) was heated at 70 ◦C for 48 h. Removal of the
solvent produced the desired cycloadduct (conversion calculated
from 1H NMR spectrum).
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