Unexpected Z-stereoselectivity in the Ramberg-Baecklund reaction of diarylsulfones leading to cis-stilbenes: The effect of aryl substituants and application in the synthesis of the integrastatin nucleus

Article abstract of DOI:10.1039/b418426b

With certain substituent patterns, benzyl benzyl sulfone systems have been found to give unexpectedly high Z-stereoselectivity (up to E : Z = 1 : 16) in the Meyers variant of the Ramberg-Baecklund reaction. A range of sulfones, bearing various aryl substi

Full text of DOI:10.1039/b418426b

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A R T I C L E
¨
Unexpected Z-stereoselectivity in the Ramberg–Backlund reaction
of diarylsulfones leading to cis-stilbenes: the effect of aryl
substituents and application in the synthesis of the integrastatin
nucleus
Jonathan S. Foot,a Gerard M. P. Giblin,b A. C. Whitwooda and R. J. K. Taylor*a
a Department of Chemistry, University of York, Heslington, York, UK YO10 5DD.
E-mail: rjkt1@york.ac.uk; Tel: 01904 432606
b Department of Medicinal Chemistry, Neurology and GI CEDD, GlaxoSmithKline,
New Frontiers Science Park North, Harlow, UK CM19 5AW
Received 8th December 2004, Accepted 12th January 2005
First published as an Advance Article on the web 9th February 2005
With certain substituent patterns, benzyl benzyl sulfone systems have been found to give unexpectedly high
Z-stereoselectivity (up to E : Z = 1 : 16) in the Meyers variant of the Ramberg–Ba¨cklund reaction. A range of
sulfones, bearing various aryl substituents, were explored to rationalize this unprecedented selectivity for Z-stilbene
systems. This high level of double bond stereocontrol has also been utilized in the synthesis of integrastatin nucleus,
the core of two highly bioactive anti-HIV compounds.
At first glance this reaction seemed unremarkable, but a
Introduction
comparison with literature stilbene syntheses highlighted two
major discrepancies. The first of these was the fact that any cis-
product had been formed in a RBR synthesis. In general, benzyl
benzyl sulfone systems undergo the RBR to afford solely trans-
stilbene products, as has been shown by Bordwell and Cooper
(Scheme 2(a)),6 Neureiter,7 Meyers et al. (Scheme 2(b)),5 and
more recently, Chan et al. (Scheme 2(c)).8
Stilbene systems are found throughout nature and are present
in many man-made, biologically active compounds, the most
R
recognizable of which is the widely prescribed drug Tamoxifenꢀ
1 (Fig. 1), used for the treatment of breast cancer.1 Other
interesting examples include combretastatin A-4 2, an anti-
tumour compound,2 and N-(1-mercaptomethyl-2-phenylethyl)-
2,3-diphenylacrylamide 3, which has been found to inhibit the
endothelin converting enzyme (ECE), an enzyme involved in
vascoconstriction.3 All three of these molecules are based on
cis-stilbenes.
Fig. 1 TamoxifenꢀR 1, combretastatin 2 and E-N(R)-(1-mercapto-
methyl-2-phenylethyl)-2,3-diphenylacrylamide 3.
During investigations into the synthesis of the HIV-1
integrase-inhibiting integrastatin natural products (4 and 5,
Fig. 2),4 we found that sulfone 6 underwent the Ramberg–
Ba¨cklund reaction (RBR), using Meyers’ conditions,5 to give
the key olefin intermediate 7 in good yield and in a 1 : 1 ratio of
E and Z-isomers (Scheme 1).
Scheme 2 Previous benzyl benzyl sulfone RBR studies.
Although it is widely accepted that in the course of the
reaction the cis-episulfone intermediate 9 is formed preferen-
tially (Scheme 3), deuterium-labelling experiments by Tokura
et al.9 have shown that phenyl substituents are sufficiently anion-
stabilizing to ensure a fast epimerization of the episulfone thus
affording exclusively the trans-stilbene product (also Scheme 3).
The second unexpected factor in our findings was that KOH–
tBuOH was employed as the base system, a method that has been
shown, even in aliphatic systems, to promote the epimerization
of the intermediate episulfone to give the trans-products. In-
depth base vs. selectivity studies by both Neureiter7 and Scholz
and Burtscher10 have highlighted this property, and it has been
used to great effect in aliphatic systems (where the cis-products,
e.g. 12, usually predominate) as shown in Scheme 4.
Fig. 2 The integrastatins.
The “high” Z-selectivity that had been observed with sulfone
6 was consequently of great interest, and further work was
undertaken to try to rationalize this result.
Scheme 1 Exposure of sulfone 6 to Meyers’ conditions.
7 5 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 3 Reaction pathway of the RBR in stilbene systems.
Fig. 3 Proposed p-stacking for sulfone 14.
These sulfones were then treated with potassium hydroxide
and carbon tetrachloride in aqueous tert-butanol under stan-
dard Meyers conditions. The stereochemical outcomes of these
reactions are shown in Table 1.
Table 1 suggests that the observed selectivity is not solely due
to p-stacking. Comparison of sulfones 27 and 29 (entries [iv]
and [vii]) with sulfones 28 and 30 (entries [v] and [viii]) shows a
much higher selectivity for the cis-isomer when the hydroxyethyl
moiety is present. If, indeed, p-stacking was the reason for
the cis-selectivity, then it should be expected that the sulfones
with the most powerful electron withdrawing group (the nitro
group) would afford the cis-olefins in the greatest proportions,
providing an electron donating group is also present on the
opposing aromatic ring. This is not the case, and the only nitro-
containing sulfone to give any appreciable amount of the cis-
isomer is sulfone 28 (entry [v]), with a ratio of E : Z = 1 : 1.
When there are only two substituents present on the sulfone,
and disubstituted stilbenes are formed (entries [vii]–[xi]), the
effect of the hydroxyethyl group is again apparent, with the
sulfones bearing this group (29 and 31) the only systems to
afford any of the cis-olefin product. The other three sulfones,
30, 32 and 33, yield solely the trans-isomer of the corresponding
olefin, as would be expected from the literature studies.
Furthermore, comparison of entries [vii] and [ix] shows equal
selectivity for the cis-product (E : Z = 2 : 3) from sulfones 29
and 31. These results highlight the apparent unimportance of
the methoxy substituents of the second aryl ring.
Scheme 4 Treatment of a-chloroethyl ethyl sulfone with different
bases.7
Results and discussion
In the published examples of RBR-formed stilbene systems,
most possessed unsubstituted aryl groups. It was decided,
therefore, to investigate the effect of altering the ketal group
in sulfone system 6, and to this end ketone 13 and alcohol
14 were synthesized and exposed to the same RBR conditions
(Scheme 5).
This apparent reliance on the hydroxyethyl group for the high
cis-selectivities suggests a revised mechanism for the RBR in our
stilbene systems:
Scheme 5 RBR of sulfones 13 and 14.
Assuming that the formation of the cis-episulfone is favoured
in our systems, as is predicted,5–10 then both the acidity of the
benzylic protons and the strength of the base should favour fast
epimerization to the trans-isomer. We propose that the observed
cis-selectivity in these studies is due to an intramolecular base-
promoted extrusion of SO2, which is taking place before full
epimerization of the intermediate episulfone 42 occurs, therefore
retaining the cis-configuration in the product. This process
would proceed by way of a 5-exo-tet ring breaking process to give
43,16 which would then break down to afford Z-16 (Scheme 7).
This proposed mechanism can now be used to explain all of
the observed results. The highest proportion of cis-product is
consistently seen when the free hydroxyethyl group is present.
The reduction in selectivity when forming disubstituted, as
opposed to trisubstituted olefins, is likely to be a statistical effect,
due to the presence of twice as many epimerisable protons in the
intermediate episulfone, leading to a higher proportion of trans-
product.
Surprisingly, these sulfones produced even larger proportions
of the cis-stilbene products, affording the olefins 15 and 16 in 1 : 8
and 1 : 16 E : Z ratios, respectively. The absolute stereochemistry
of the olefin double bond was confirmed through NOE analysis
of 15. To our knowledge, this observed cis-selectivity is the
largest of any reported for the synthesis of stilbenes by the
RBR.11
Initial theories as to the reason for this cis-preference centered
on the electronics of the aromatic rings. One suggestion was
that the sulfones might be undergoing p-stacking to minimize
the interaction between the surfaces of the molecules with the
solvent molecules, and thus directing a cis-alignment from the
beginning (Fig. 3).
To investigate this theory further, a range of sulfones were
synthesized (20 and 27–33, Scheme 6) through coupling of
benzyl halides 21–23 with thiols 18 and 24–26 using the
standard procedures outlined in Scheme 6. Of the coupling
partners, compounds 22, 23 and 26 were commercially available,
whilst compounds 21 and 25 were synthesized via literature
procedures.12,13 Novel thiols 18 and 24 were prepared by treating
the known compounds, 1-(2-benzyloxyphenyl)-ethanol (17)14
and 1-(2-methoxyphenyl)-ethanol15 respectively, with Lawes-
son’s reagent.
The high Z-stereoselectivity apparent when the methyl ketone
functionality is present (sulfone 13, entry [ii]) can be explained by
considering the enolate form of the ketone, which it is presumed
will be present in some quantity under the highly basic reaction
conditions to effect the SO2 extrusion process. This can also
go through a five-membered transition state (analogous to 14),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3
7 5 7

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Scheme 6 Synthetic route to the sulfones.
Table 1 Results of the RBR experiments using KOH–aq. tBuOH in CCl4
Alkenea
Sulfone
Sulfone
Alkenea
[i]
[vii]
[ii]
[viii]
[ix]
[x]
[iii]
[iv]
[v]
[xi]
[vi]
a E : Z ratios quoted as percentage composition of total yield, to the nearest 5%, from 1H-NMR spectra. b Ratios calculated from isolated isomers.
7 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3

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Scheme 7 Proposed intramolecular base-promoted SO2 extrusion from
episulfone 42.
selectively affording the cis-product, in only a slightly lower
proportion than 14.
The reasonable Z-stereoselectivity showed with sulfones 6 and
20 (entries [i] and [vi]) can also be explained by this theory,
with the oxygen lone pairs on the ortho-alkoxy substituent
(rather than a formal anion) responsible for the intramolecular
extrusion. The higher selectivity observed with 20 over 6 is
possibly due to the reduced steric hindrance of the methyl ether
compared to the ketal group.
The only other example in which the cis-product is observed
is a nitro-example where an a-methyl group is also present (entry
[v]). It is thought that the cis-selectivity in this case may be due
to nitro-group involvement in sulfur dioxide extrusion.
Fig. 4 ORTEP drawing of integrastatin nucleus 45 (50% probability
thermal ellipsoids).18
These results extend the scope of the RBR in synthetic chem-
istry, as shown by the synthesis of the integrastatin nucleus 45.
Experimental
( )-1-(2-Benzyloxyphenyl)-ethanethiol, 18 and
( )-1-(2-methoxyphenyl)-ethanethiol, 24
Exploiting the selectivity in synthesis
(a) To a stirred solution of 1-(2-benzyloxyphenyl)-ethanol
(4.36 g, 19.0 mmol) in dichloromethane (300 mL) under nitrogen
was added Lawesson’s reagent (4.64 g, 11.0 mmol). The reaction
mixture was stirred at room temperature for 28 hours and
the solvent was then removed in vacuo to give a yellow gum
(6.20 g). Purification by flash chromatography, eluting with
9 : 1 petroleum ether–ethyl acetate, afforded the title compound
18 (3.00 g, 65%) as a pale yellow oil; RF [petroleum ether–
ethyl acetate (4 : 1)] 0.44; mmax (neat)/cm−1 2968, 2560 (SH),
1241; dH (CDCl3, 270 MHz) 1.67 (3 H, d, J 7.0 Hz, CH3), 2.15
(1 H, d, J 6.2 Hz, SH), 4.69 (1 H, dq, J 7.0, 6.2 Hz, CH), 5.14
(2 H, s, CH2), 6.94–6.97 (2 H, m, 2 ArH), 7.18–7.44 (7 H, m,
7 ArH); dC (CDCl3, 67.9 MHz) 24.6 (CH3), 31.8 (CH), 70.3
(CH2), 112.1 (ArH), 121.3 (ArH), 126.5 (ArH), 127.4 (2 ArH),
128.1 (2 ArH), 128.8 (2 ArH), 137.2 (C), 155.2 (C)—1 quaternary
carbon signal not observed; m/z (CI) 262 (MNH4+, 25%), 211
(100); [Found MNH4+, 262.1268 (error = 0.8 ppm). C15H16OS
requires: MNH4+, 262.1266].
The importance of this work has been highlighted in the
synthesis of the integrastatin nucleus 45 (Scheme 8). We
demonstrated that only the cis-isomer 15 undergoes a Lewis
acid-promoted cyclisation, which is thought to proceed by
using the olefin double bond to hold the starting olefin in the
reactive conformation (impossible with the trans-isomer), to give
tetracycle 44 (confirmed by X-ray crystallography17). Various
benzylic oxidation trials on this tetracycle have shown that by
R
utilization of a PDC–tBuOOH complex formed on Celiteꢀ at
low temperature, the integrastain nucleus 45 can be formed in a
yield of 61% from the sulfone 14.17
(b) Thiol 24 was prepared in an identical procedure to that for
18 and isolated in a 58% yield as a colourless oil; RF [petroleum
ether–ethyl acetate (4 : 1)] 0.47; mmax (neat)/cm−1 2965, 1491,
1244, 753; dH (CDCl3, 400 MHz) 1.65 (3 H, d, J 6.8 Hz, CH3),
2.12 (1 H, d, J 6.0 Hz, SH), 3.87 (3 H, s, OCH3), 4.61 (1 H, dq,
CH), 6.87 (1 H, d, J 7.6 Hz, ArH), 6.96 (1 H, dd, J 7.6, 7.2 Hz,
ArH), 7.18–7.21 (1 H, m, ArH), 7.40 (1 H, d, J 7.6 Hz, ArH);
dC (CDCl3, 100 MHz) 24.9 (CH3), 31.9 (CH), 55.8 (OCH3),
111.0 (ArH), 121.2 (ArH), 126.6 (ArH), 128.3 (ArH), 134.5
(C), 156.3 (Ar(C)O); m/z (CI) 186 (MNH4+, 24%), 135 (100);
[Found MNH4+, 186.0950 (error = 1.2 ppm). C9H12OS requires:
MNH4+, 186.0953].
Scheme 8 Synthesis of the integrastatin nucleus.
The structure of the integrastatin nucleus has been further
ascertained through X-ray analysis of the crystalline product
(Fig. 4).
( )-2-{2-[1-(2-Benzyloxyphenyl)-ethylsulfanylmethyl]-phenyl}-
2-methyl-[1,3]dioxolane, 19
Conclusions
To a stirred solution of 18 (3.06 g, 12.5 mmol) in ethanol (60 mL)
was added powdered potassium hydroxide (0.74 g, 13.2 mmol).
The resultant mixture was cooled to 0 ◦C and a solution of 21
(3.39 g, 13.2 mmol) in ethanol (40 mL) added dropwise over 10
minutes. The reaction was allowed to warm to room temperature
and stirred for 18 hours. The solvent was then removed in vacuo
and the residue extracted with dichloromethane, washing with
water and saturated sodium chloride solution, before drying
over magnesium sulfate. Filtration and removal of the solvent
Through investigations into various benzyl sulfone systems, we
have been able to demonstrate a remarkable cis-selectivity in
the Ramberg–Ba¨cklund reaction leading to disubstituted and
particularly trisubstituted stilbenes. The Z-stereochemistries
attained are the highest yet recorded in the literature for stilbenes
(up to a 95% composition of the cis-isomer has been observed),
and have been achieved through manipulation of aryl groups
remote from the central sulfone system.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3
7 5 9

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in vacuo gave a clear gum. Purification by flash chromatography,
eluting with 19 : 1 petroleum ether–ethyl acetate, afforded the
title compound 19 (4.67 g, 89%) as a clear oil; RF [petroleum
ether–ethyl acetate (4 : 1)] 0.31; mmax (neat)/cm−1 2970, 1450,
1239, 1038; dH (CDCl3, 400 MHz) 1.56 (3 H, d, J 7.0 Hz, CH3),
1.62 (3 H, s, CH3), 3.68–3.71 (2 H, m, 2 CH), 3.90 (2 H, s, CH2),
3.93–3.96 (2 H, m, 2 CH), 4.72 (1 H, q, J 7.0 Hz, CH), 5.10
(2 H, s, CH2), 6.95 (1 H, d, J 6.2 Hz, ArH), 7.02 (1 H, dd, J 7.7,
7.7 Hz, ArH), 7.10–7.12 (2 H, m, 2 ArH), 7.22–7.26 (2 H, m,
2 ArH), 7.30–7.45 (5 H, m, 5 ArH), 7.51 (1 H, d, J 7.6 Hz, ArH),
7.59 (1 H, d, J 7.6 Hz, ArH); dC (CDCl3, 100 MHz) 22.0 (CH3),
27.6 (CH3), 33.5 (CH2), 37.2 (CH), 64.3 (2 CH2), 70.4 (CH2),
109.3 (C), 112.0 (ArH), 121.4 (ArH), 126.5 (ArH), 126.7 (ArH),
127.4 (2 ArH), 127.9 (ArH), 128.0 (ArH), 128.1 (ArH), 128.2
(ArH), 128.7 (2 ArH), 131.6 (ArH), 132.8 (C), 136.4 (C), 140.5
(C), 155.9 (Ar(C)O)—1 quaternary carbon signal not observed;
m/z (CI) 421 (MH+, 100%); [Found MH+, 421.1837 (error =
0.1 ppm). C26H28O3S requires: MH+, 421.1837].
128.2 (ArH), 128.5 (2 ArH), 128.8 (2 ArH), 129.4 (ArH), 130.0
(ArH), 131.0 (ArH), 133.7 (ArH), 136.4 (C), 140.5 (C), 156.1
(Ar(C)O), 202.5 (ketone); m/z (CI) 426 (MNH4+, 60%), 228
(95), 211 (100); [Found MNH4+, 426.1742 (error = 0.6 ppm).
C24H24O4S requires: MNH4+, 262.1266].
( )-1-{2-[1-(2-Benzyloxyphenyl)ethanesulfonylmethyl]-phenyl}-
ethanol, 14
To a stirred solution of 13 (1.17 g, 2.9 mmol) in ethanol (15 mL)
at room temperature was added sodium borohydride (0.22 g,
5.8 mmol). The reaction was stirred at room temperature for
6 hours. The solvent was then removed in vacuo and the residue
extracted with ethyl acetate, washing with water and brine and
drying over sodium sulfate. Filtration and removal of the solvent
in vacuo afforded a 1 : 1 mixture of diastereomers of the title
compound 14 (1.15 g, 98%) as a colourless gum; RF [petroleum
ether–ethyl acetate (1 : 1)] 0.26; mmax (neat)/cm−1 3490 (OH),
1734, 1245; dH (CDCl3, 400 MHz) 1.33 (3 H, d, J 6.4 Hz, CH3),
1.38 (3 H, d, J 6.4 Hz, CH3), 1.76 (6 H, m, 2 CH3), 2.77 (2 H, brs,
2 OH), 4.05 (1 H, d, J 13.6 Hz, CH2), 4.12 (1 H, d, J 13.6 Hz,
CH2), 4.23 (1 H, d, J 13.6 Hz, CH2), 4.33 (1 H, d, J 13.6 Hz,
CH2), 4.71 (1 H, q, J 6.4 Hz, CH), 4.82 (1 H, q, J 6.4 Hz, CH),
5.06–5.19 (6 H, m, 2 CH2), 7.07–7.18 (8 H, m, 8 ArH), 7.34–
7.50 (16 H, m, 16 ArH), 7.62 (1 H, d, J 8.0 Hz, ArH), 7.64 (1 H,
d, J 8.0 Hz, ArH); dC (CDCl3, 100 MHz) 13.6 (CH3), 14.9 (CH3),
22.7 (CH3), 23.1 (CH3), 51.3 (2 CH2), 55.4 (2 CH), 71.4 (2 CH2),
74.3 (CH), 74.4 (CH), 112.4 (2 ArH), 122.1 (2 ArH), 124.3
(2 C), 126.4 (2 ArH), 127.4 (2 ArH), 127.5 (2 ArH), 127.8
(4 ArH), 128.7 (6 ArH), 128.8 (2 ArH), 129.8 (2 C), 130.3
(2 ArH), 132.4 (2 ArH), 135.3 (2 C), 143.4 (2 C), 156.4
(2 Ar(C)O); m/z (CI) 428 (MNH4+, 6%), 211 (100); [Found
MNH4+, 428.1896 (error = 0.1 ppm). C24H26O4S requires:
MNH4+, 428.1896].
( )-2-{2-[1-(2-Benzyloxyphenyl)-ethanesulfonylmethyl]-
phenyl}-2-methyl-[1,3]dioxolane, 6
To a stirred solution of 19 (1.14 g, 2.7 mmol) and sodium hydro-
gen carbonate (0.94 g, 10.2 mmol) in dichloromethane (30 mL)
and water (5 mL) at 0 ◦C, was added meta-chloroperbenzoic
acid (1.40 g, 8.1 mmol). The reaction mixture was allowed
to stir for a further 30 minutes at 0 ◦C, then warmed to
room temperature and stirred for 16 hours. Saturated sodium
metabisulfite solution was then added and the organic layer
extracted with dichloromethane, washing with saturated sodium
hydrogen carbonate solution and saturated sodium chloride
solution, before drying over sodium sulfate. Filtration and
removal of the solvent in vacuo and purification by flash
chromatography, eluting with 3 : 1 petroleum ether–ethyl acetate,
afforded the title compound 6 (1.11 g, 91%) as a white solid; RF
[petroleum ether–ethyl acetate (4 : 1)] 0.15; mp 137–140 ◦C;
(Found C, 69.3; H, 6.3. C26H28O5S requires: C, 69.0; H, 6.2%);
mmax (nujol)/cm−1 2725, 1297, 1043; dH (CDCl3, 400 MHz) 1.42
(3 H, s, CH3), 1.75 (3 H, d, J 6.6 Hz, CH3), 3.67–3.70 (2 H,
m, 2 CH), 3.81–3.83 (2 H, m, 2 CH), 4.55 (2 H, d, J 7.6 Hz,
CH2), 5.11 (1 H, q, J 6.6 Hz, CH), 5.14 (2 H, d, J 6.4 Hz, CH2),
7.04–7.07 (2 H, m, 2 ArH), 7.23–7.27 (2 H, m, 2 ArH), 7.34–7.47
(5 H, m, 5 ArH), 7.56 (2 H, d, J 7.8 Hz, 2 ArH), 7.64 (2 H, d,
J 7.8 Hz, 2 ArH); dC (CDCl3, 67.9 MHz) 13.5 (CH3), 28.0 (CH3),
53.0 (CH2), 55.6 (CH), 64.3 (2 CH2), 70.8 (CH2), 108.9 (C), 112.2
(ArH), 121.7 (ArH), 123.7 (C), 125.1 (C), 126.9 (ArH), 127.7
(2 ArH), 128.2 (ArH), 128.4 (ArH), 128.5 (ArH), 128.9 (3 ArH),
129.9 (ArH), 130.1 (ArH), 132.7 (C), 143.0 (C), 156.2 (Ar(C)O);
m/z (CI) 453 (MH+, 25%), 211 (100); [Found MH+, 453.1737
(error = 0.2 ppm). C26H28O5S requires: MH+, 453.173].
( )-1-(2-Benzyloxyphenyl)-ethylsulfonylmethyl-[2-(1-methoxy-
ethyl)]-phenyl, 20
To a stirred solution of 14 (0.28 g, 0.7 mmol) in THF (8 mL)
at 0 ◦C under nitrogen was added sodium hydride (60% w/w
in mineral oil, 0.03 g, 0.8 mmol). The reaction was stirred for
30 minutes at 0 ◦C before addition of methyl iodide (50 lL,
0.8 mmol). The mixture was then warmed to room temperature
and allowed to stir for 3 hours. The solvent was removed in
vacuo, and the residue extracted with ethyl acetate, washing
with water and brine and drying over magnesium sulfate.
Filtration and removal of the solvent in vacuo gave a yellow
oil (0.21 g). Purification by flash chromatography, eluting with
3 : 1 petroleum ether–ethyl acetate, afforded a 1 : 1 mixture
of diastereomers of the title compound 20 (0.09 g, 30%) as a
yellow oil; RF [petroleum ether–ethyl acetate (1 : 1)] 0.43; mmax
(neat)/cm−1 2977, 1600, 1312, 1134 (SO2); dH (CDCl3, 400 MHz)
1.18 (3 H, d, J 6.4 Hz, CH3), 1.26 (3 H, d, J 6.4 Hz, CH3), 1.76
(6 H, d, J 7.0 Hz, 2 CH3), 3.05 (3 H, s, OCH3), 3.09 (3 H, s,
OCH3), 4.03 (1 H, d, J 6.7 Hz, CH2), 4.06 (1 H, d, J 6.7 Hz,
CH2), 4.10 (1 H, d, J 6.7 Hz, CH2), 4.14 (1 H, d, J 6.7 Hz, CH2),
4.26 (1 H, q, J 6.4 Hz, CH), 4.36 (1 H, q, J 6.4 Hz, CH), 5.05–
5.14 (6 H, m, 2 CH2; 2 CH), 7.06–7.19 (8 H, m, 8 ArH), 7.31–7.48
(16 H, m, 16 ArH), 7.66 (2 H, d, J 6.8 Hz, ArH); dC (CDCl3,
100 MHz) 13.2 (CH3), 14.3 (CH3), 22.6 (CH3), 23.0 (CH3), 52.3
(2 CH2), 55.3 (CH), 55.4 (CH), 56.4 (2 OCH3), 71.0 (2 CH2), 75.4
(CH), 75.5 (CH), 112.3 (2 ArH), 122.0 (2 ArH), 124.3 (2 C),
126.3 (2 ArH), 127.4 (2 ArH), 127.5 (2 ArH), 127.7 (4 ArH),
128.6 (6 ArH), 128.9 (2 ArH), 129.8 (2 C), 130.3 (2 ArH), 132.4
(2 ArH), 136.3 (2 C), 144.2 (2 C), 156.0 (2 Ar(C)O); m/z (CI) 442
(MNH4+, 100%); [Found MNH4+, 442.2055 (error = 0.3 ppm).
C25H28O4S requires: MNH4+, 442.2052].
( )-1-{2-[1-(2-Benzyloxyphenyl)ethanesulfonylmethyl]-phenyl}-
ethanone, 13
To a stirred solution of 6 (1.30 g, 2.9 mmol) in dichloromethane
(30 mL) was added tin(II) chloride dihydrate (1.30 g, 5.8 mmol)
and the reaction stirred for 8 hours. The reaction mixture was
R
then filtered through Celiteꢀ and the solvent removed in vacuo
to give a colourless gum. Purification by flash chromatography,
eluting with 3 : 2 petroleum ether–ethyl acetate, afforded the title
compound 13 (1.18 g, 100%) as a colourless oil; RF [petroleum
ether–ethyl acetate (2 : 1)] 0.23; mmax (neat)/cm−1 1734, 1693 (CO),
1312 (SO2), 1133 (SO2); dH (CDCl3, 400 MHz) 1.71 (3 H, d, J
7.0 Hz, CH3), 2.56 (3 H, s, CH3), 4.44 (1 H, d, J 12.9 Hz, CH2),
4.68 (1 H, d, J 12.9 Hz, CH2), 5.03 (1 H, q, J 7.0 Hz, CH), 5.11
(1 H, d, J 11.6 Hz, CH2), 5.21 (1 H, d, J 11.6 Hz, CH2), 7.04–
7.09 (2 H, m, 2 ArH), 7.22–7.25 (1 H, m, ArH), 7.32–7.50 (8 H,
m, 8 ArH), 7.60–7.63 (2 H, m, 2 ArH); dC (CDCl3, 100 MHz)
13.5 (CH3), 29.3 (CH3), 52.2 (CH2), 55.4 (CH), 70.8 (CH2),
112.3 (ArH), 121.7 (ArH), 123.2 (C), 125.1 (C), 127.6 (2 ArH),
In a similar manner to the procedures described above
sulfones 27–33 were prepared.
7 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3

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4.99 (1 H, q, J 6.4 Hz, CH), 7.25–7.28 (2 H, m, 2 ArH), 7.40–
7.44 (6 H, m, 6 ArH), 7.56 (1 H, d, J 7.6 Hz, ArH); dC (CDCl3,
100 MHz) 23.8 (CH3), 54.9 (CH2), 59.8 (CH2), 67.2 (CH), 123.9
(C), 127.6 (ArH), 127.9 (C), 128.2 (ArH), 129.5 (2 ArH), 129.6
(ArH), 130.2 (ArH), 131.2 (2 ArH), 132.9 (ArH), 146.2 (C); m/z
(CI) 308 (MNH4+, 5%), 273 (100); [Found MNH4+, 308.1325
(error = 1.6 ppm). C16H18O3S requires: MNH4+, 308.1320].
( )-1-{2-[1-(2-Methoxyphenyl)-ethanesulfonylmethyl]-phenyl}-
ethanol, 27
Isolated as a 1 : 1 mixture of diastereomers in an overall yield of
56% (4 steps) as a creamy white oil; RF [petroleum ether–ethyl
acetate (4 : 1)] 0.08; mmax (neat)/cm−1 3355 (OH), 1265, 739; dH
(CDCl3, 400 MHz) 1.36 (3 H, d, J 6.4 Hz, CH3), 1.47 (3 H, d,
J 6.4 Hz, CH3), 1.76 (6 H, 2 d, J 7.7 Hz, 2 CH3), 2.82 (1 H, s,
OH), 2.91 (1 H, s, OH), 3.89 (3 H, s, OCH3), 3.92 (3 H, s, OCH3),
4.11 (2 H, m, CH2), 4.29 (1 H, d, J 13.4 Hz, CH2), 4.36 (1 H,
d, J 13.4 Hz, CH2), 4.75 (1 H, q, J 6.4 Hz, CH), 4.97 (1 H, q,
J 6.4 Hz, CH), 5.04–5.07 (2 H, m, 2 CH), 6.94–6.97 (2 H, m,
ArH), 7.08–7.26 (6 H, m, 6 ArH), 7.37–7.41 (4 H, m, 4 ArH),
7.50–7.53 (2 H, m, 2 ArH), 7.60 (1 H, d, J 7.6 Hz, ArH), 7.65
(1 H, d, J 7.6 Hz, ArH); m/z (CI) 352 (MNH4+, 3.5%), 152
(45), 135 (100); [Found MNH4+, 352.1583 (error = 1.3 ppm).
C18H22O4S requires: MNH4+, 352.1578].
(2-Nitro)-phenylmethanesulfonylmethylphenyl, 32
Isolated in an overall yield of 81% (2 steps) as a white solid; RF
[petroleum ether–ethyl acetate (4 : 1)] 0.30; mp 132–135 ◦C;
mmax (nujol)/cm−1 1460, 1308 (SO2), 1121 (SO2); dH (CDCl3,
400 MHz) 4.32 (2 H, s, CH2), 4.72 (2 H, s, CH2), 7.40–7.48 (5 H,
m, 5 ArH), 7.54–7.57 (3 H, m, 3 ArH), 8.09 (1 H, d, J 8.0 Hz,
ArH); dC (CDCl3, 100 MHz) 54.8 (CH2), 60.7 (CH2), 122.7
(C), 126.2 (ArH), 127.5 (C), 129.5 (2 ArH), 129.7 (ArH), 130.6
(ArH), 131.2 (2 ArH), 133.9 (ArH), 134.6 (ArH)–Ar(C)NO2
signal not observed; m/z (CI) 309 (MNH4+, 20%), 262 (60), 108
(100); [Found MNH4+, 309.0908 (error = 0.3 ppm). C14H13NO4S
requires: MNH4+, 309.0909].
Due to the complex nature of the diastereomeric mixture, it
proved impossible to fully assign the 13C-NMR spectrum.
1-(2-Methoxyphenyl)-ethylsulfonylmethyl-(2-nitro)-phenyl, 28
Isolated in an overall yield of 82% (2 steps) as a white solid;
RF [petroleum ether–ethyl acetate (4 : 1)] 0.19; mp 155–158 ◦C;
mmax (nujol)/cm−1 1461, 1377 (SO2), 1115; dH (CDCl3, 400 MHz)
1.73 (3 H, d, J 7.2 Hz, CH3), 3.92 (3 H, s, OCH3), 4.35 (1 H,
d, J 13.3 Hz, CH2), 4.83 (1 H, d, J 13.3 Hz, CH2), 5.06 (1 H,
q, J 7.2 Hz, CH), 6.96 (1 H, d, J 8.0 Hz, ArH), 7.07 (1 H, dd,
J 8.0, 8.0 Hz, ArH), 7.35–7.38 (2 H, m, 2 ArH), 7.53–7.55 (3 H,
m, 3 ArH), 8.03 (1 H, d, J 8.0 Hz, ArH); dC (CDCl3, 100 MHz)
13.4 (CH3), 53.0 (CH2), 56.1 (OCH3), 56.3 (CH), 111.1 (ArH),
122.0 (ArH), 127.7 (C), 122.8 (C), 126.0 (ArH), 129.8 (ArH),
130.1 (ArH), 130.7 (ArH), 133.4 (ArH), 134.4 (ArH), 150.3
(Ar(C)NO2), 157.0 (Ar(C)O); m/z (CI) 353 (MNH4+, 3.5%), 135
(100); [Found MNH4+, 353.1176 (error = 1.3 ppm). C16H17NO5S
requires: MNH4+, 353.1171].
(2-Methoxy)-phenylmethanesulfonylmethylphenyl, 33
Isolated in an overall yield of 63% (2 steps) as a white solid;
RF [petroleum ether–ethyl acetate (4 : 1)] 0.26; mp 92–95 ◦C;
mmax (nujol)/cm−1 1461, 1303 (SO2), 1157 (SO2); dH (CDCl3,
400 MHz) 3.88 (3 H, s, OCH3), 4.12 (2 H, s, CH2), 4.36 (2 H,
s, CH2), 6.95 (1 H, d, J 8.4 Hz ArH), 7.02 (1 H, dd, J 7.6,
7.6 Hz, ArH), 7.34–7.39 (6 H, m, 6 ArH), 7.44 (1 H, d, J 7.6 Hz,
ArH); dC (CDCl3, 100 MHz) 53.5 (CH2), 56.0 (OCH3), 58.3
(CH2), 111.4 (ArH), 117.0 (C), 121.6 (ArH), 127.6 (C), 129.1
(2 ArH), 129.2 (ArH), 131.0 (ArH), 131.5 (2 ArH), 133.1 (ArH),
157.8 (Ar(C)O); m/z (CI) 294 (MNH4+, 6%), 277 (MH+, 2), 121
(100); [Found MNH4+, 294.1163 (error = 0.2 ppm). C15H16O3S
requires: MNH4+, 294.1164].
( )-1-[2-(2,4-Dimethoxyphenylmethanesulfonylmethyl)-phenyl]-
ethanol, 29
Representative RBR procedure
2-{2-[2-(2-Benzyloxyphenyl)-propenyl]-phenyl}-2-methyl-[1,3]-
dioxolane, 7. To a stirred solution of 6 (0.28 g, 0.6 mmol) in
carbon tetrachloride (4 mL), tert-butanol (4 mL) and water
(0.7 mL), was added powdered potassium hydroxide (0.74 g,
13.0 mmol). The reaction mixture was then heated at 80 ◦C for
14 hours. The solvent was then removed in vacuo and the residue
extracted with ethyl acetate, washing with water and saturated
sodium chloride solution and drying over magnesium sulfate.
Filtration and removal of the solvent in vacuo gave a brown
oil (0.25 g). Purification by flash chromatography, eluting with
14 : 1 petroleum ether–ethyl acetate, afforded a 1 : 1 mixture
of Z and E isomers of the title compound 7 (0.20 g, 83%) as a
colourless oil. These isomers were separated using preparative
HPLC (MeCN–AcOH, mixed gradient solvent system);
Isolated in an overall yield of 19% (4 steps) as a white solid; RF
[petroleum ether–ethyl acetate (4 : 1)] 0.12; mp 101–104 ◦C; dH
(CDCl3, 400 MHz) 1.45 (3 H, d, J 6.4 Hz, CH3), 2.96 (1 H, s,
OH), 3.85 (3 H, s, OCH3), 3.88 (3 H, s, OCH3), 4.33–4.39 (4 H,
m, 2 CH2), 4.96 (1 H, q, J 6.4 Hz, CH), 6.53 (1 H, s, ArH), 6.57
(1 H, d, J 8.0 Hz, ArH), 7.23–7.27 (2 H, m, 2 ArH), 7.37–7.41
(2 H, m, 2 ArH), 7.53 (1 H, d, J 8.0 Hz, ArH); this compound
was immediately subjected to the RBR due to problems with
stability.
(2,4-Dimethoxy)-phenylmethanesulfonylmethyl-(2-nitro)-phenyl,
30
Isolated in an overall yield of 78% (2 steps) as an orange glass;
RF [petroleum ether–ethyl acetate (4 : 1)] 0.16; mp 119–122 ◦C;
mmax (nujol)/cm−1 1613, 1348 (SO2), 1157 (SO2); dH (CDCl3,
400 MHz) 3.84 (3 H, s, OCH3), 3.89 (3 H, s, OCH3), 4.38 (2 H,
s, CH2), 4.71 (2 H, s, CH2), 6.53–6.57 (2 H, m, 2 ArH), 7.34 (1 H,
d, J 8.4 Hz, ArH), 7.49–7.60 (3 H, m, 3 ArH), 8.06 (1 H, d, J
7.6 Hz, ArH); dC (CDCl3, 100 MHz) 54.0 (CH2), 54.8 (CH2), 55.9
(OCH3), 56.1 (OCH3), 99.3 (ArH), 105.7 (ArH), 108.8 (C), 122.7
(C), 126.0 (ArH), 130.2 (ArH), 133.5 (ArH), 133.8 (ArH), 134.5
(ArH) 150.5 (Ar(C)NO2), 158.8 (Ar(C)O), 162.3 (Ar(C)O); m/z
(CI) 369 (MNH4+, 15%), 151 (100); [Found MNH4+, 369.1125
(error = 1.3 ppm). C16H17NO6S requires: MNH4+, 369.1120].
Z-7: RF [petroleum ether–ethyl acetate (4 : 1)] 0.48; mmax
(neat)/cm−1 2886, 1596, 1039; dH (CDCl3, 400 MHz) 1.59 (3 H, s,
CH3), 1.97 (3 H, s, CH3), 3.63–3.65 (2 H, m, 2 CH), 3.90–3.92
(2 H, m, 2 CH), 5.05 (2 H, s, CH2), 6.89–6.94 (2 H, m, 2 ArH),
6.90 (1 H, s, vinyl CH), 7.16–7.37 (10 H, m, 10 ArH), 7.51
(1 H, d, J 8.0 Hz, ArH); dC (CDCl3, 100 MHz) 19.0 (CH3),
26.6 (CH3), 64.4 (2 CH2), 70.6 (CH2), 109.7 (C), 112.8 (ArH),
121.4 (ArH), 126.3 (ArH), 126.9 (ArH), 127.6 (2 ArH), 127.9
(ArH), 128.1 (ArH), 128.8 (2 ArH), 130.1 (ArH), 130.4 (vinyl
CH), 131.7 (ArH), 135.8 (C), 136.6 (C), 136.7 (C), 137.8 (C),
141.1 (C), 156.4 (Ar(C)O)—1 ArH signal not observed; m/z (CI)
387 (MH+, 90%), 325 (100); [Found MH+, 387.1959 (error =
0.4 ppm). C26H26O3 requires: MH+, 387.1960].
( )-1-(2-Phenylmethanesulfonylmethylphenyl)-ethanol, 31
E-7: RF [petroleum ether–ethyl acetate (4 : 1)] 0.48; mmax
(neat)/cm−1 2886, 1237, 1040; dH (CDCl3, 400 MHz) 1.70 (3 H, s,
CH3), 2.18 (3 H, s, CH3), 3.703.73 (2 H, m, 2 CH), 3.96–3.99
(2 H, m, 2 CH), 5.02 (2 H, s, CH2), 6.68 (1 H, dd, J 8.0, 8.0 Hz,
ArH), 6.74–6.79 (4 H, m, 4 ArH), 6.94–6.97 (1 H, m, ArH), 7.03
Isolated in an overall yield of 45% (4 steps) as a clear gum; RF
[petroleum ether–ethyl acetate (4 : 1)] 0.15; mmax (neat)/cm−1 3320
(OH), 1122; dH (CDCl3, 400 MHz) 1.46 (3 H, d, J 6.4 Hz, CH3),
2.80 (1 H, s, OH), 4.31 (2 H, s, CH2), 4.37 (2 H, d, J 5.6 Hz, CH2),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3
7 6 1

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(1 H, dd, J 8.0, 8.0 Hz, ArH), 7.12 (1 H, brs, vinyl CH), 7.20–
7.25 (5 H, m, 5 ArH), 7.41 (1 H, d, J 7.6 Hz, ArH); dC (CDCl3,
100 MHz) 26.4 (CH3), 26.9 (CH3), 64.6 (2 CH2), 70.1 (CH2),
109.9 (C), 112.5 (ArH), 121.2 (ArH), 125.7 (ArH), 126.2 (vinyl
CH), 127.3 (2 ArH), 127.5 (ArH), 127.6 (ArH), 128.0 (ArH),
128.2 (ArH), 128.9 (2 ArH), 130.4 (ArH), 131.4 (ArH), 132.3
(C), 136.4 (C), 136.6 (C), 137.8 (C), 140.2 (C), 156.4 (Ar(C)O);
m/z (CI) 387 (MH+, 100%), 325 (85); [Found MH+, 387.1968
(error = 2.1 ppm). C26H26O3 requires: MH+, 387.1960].
In a similar manner to the procedure described above, olefins
15 (see later for corresponding data), 16 and 34–41 were
prepared.
MeOH]+, 100%); [Found [MH − MeOH]+, 327.1746 (error =
0.8 ppm). C25H26O2 requires: [MH − MeOH]+, 327.1749].
Due to the complex nature of the isomeric mixture, it proved
impossible to fully assign the 13C-NMR spectrum.
( )-1-{2-[2-(2,4-Dimethoxyphenyl)-vinyl]-phenyl}-ethanol, 37.
Isolated as a 2 : 3 mixture of E : Z-isomers (separable), in an
84% combined yield, both as clear oils;
Z-37: RF [petroleum ether–ethyl acetate (4 : 1)] 0.45; mmax
(neat)/cm−1 3412 (OH), 2967, 1608; dH (CDCl3, 400 MHz) 1.43
(3 H, d, J 6.4 Hz, CH3), 1.85 (1 H, brs, OH), 3.73 (3 H, s, OCH3),
3.77 (3 H, s, OCH3), 5.15 (1 H, q, J 6.4 Hz, CH), 6.18 (1 H, d, J
8.8 Hz, ArH), 6.40 (1 H, s, ArH), 6.66 (1 H, d, J 12.0 Hz, vinyl
CH), 6.78 (2 H, m, 1 ArH and 1 vinyl CH), 7.08–7.13 (2 H, m,
ArH), 7.22–7.25 (1 H, m, ArH), 7.53 (1 H, d, J 7.6 Hz, ArH);
dC (CDCl3, 100 MHz) 24.2 (CH3), 55.7 (OCH3), 55.8 (OCH3),
67.5 (CH), 98.7 (ArH), 104.5 (ArH), 118.7 (C), 125.3 (ArH),
126.3 (vinyl CH), 126.9 (vinyl CH), 127.5 (ArH), 127.8 (ArH),
129.8 (ArH), 130.7 (ArH), 136.3 (C), 143.7 (C), 158.7 (Ar(C)O),
160.6 (Ar(C)O); m/z (CI) 285 (MH+, 15%) 267 (100), 151 (25);
[Found MH+, 285.1488 (error = 0.9 ppm). C18H20O3 requires:
MH+, 285.1491].
E-37: RF [petroleum ether–ethyl acetate (4 : 1)] 0.41; mmax
(neat)/cm−1 3412 (OH), 2968, 1608; dH (CDCl3, 400 MHz) 1.51
(3 H, d, J 6.4 Hz, CH3), 1.86 (1 H, brs, OH), 3.83 (3 H, s,
OCH3), 3.86 (3 H, s, OCH3), 5.31 (1 H, q, J 6.4 Hz, CH), 6.47
(1 H, s, ArH), 6.52 (1 H, d, J 8.4 Hz, ArH), 7.22–7.27 (3 H, m 2
ArH and 1 vinyl CH), 7.34 (1 H, d, J 16.4 Hz, vinyl CH), 7.49
(1 H, d, J 8.4 Hz, ArH), 7.51–7.54 (1 H, m, ArH), 7.58–7.61
(1 H, m, ArH); dC (CDCl3, 100 MHz) 24.7 (CH3), 55.8 (OCH3),
55.9 (OCH3), 67.5 (CH), 99.0 (ArH), 105.4 (ArH), 120.1 (C),
124.3 (vinyl CH), 125.1 (ArH), 126.3 (vinyl CH), 126.4 (ArH),
127.8 (ArH), 127.9 (ArH), 128.0 (ArH), 136.3 (C), 143.1 (C),
158.5 (Ar(C)O), 161.0 (Ar(C)O); m/z (CI) 285 (MH+, 10%),
267 (100), 151 (20); [Found MH+, 285.1491 (error = 0.1 ppm).
C18H20O3 requires: MH+, 285.1491].
Z-( )-2-{2-[2-(2-Benzyloxyphenyl)-propenyl]-phenyl}-ethanol,
16. Isolated as a 1 : 16 mixture of E : Z-isomers (inseparable),
in an 89% yield, as a yellow oil; RF [petroleum ether–ethyl
acetate (4 : 1)] 0.25; vmax (neat)/cm−1 3400 (OH), 2857, 1447; dH
(CDCl3, 400 MHz) 1.36 (3 H, d, J 5.6 Hz, CH3), 1.83 (1 H, brs,
OH), 2.01 (3 H, s, CH3), 5.08 (1 H, q, J 5.6 Hz, CH), 5.12 (2 H,
s, CH2), 6.63 (1 H, brs, vinyl CH), 7.01–7.04 (2 H, m, 2 ArH),
7.26–7.45 (10 H, m, 10 ArH), 7.55 (1 H, d, J 7.2 Hz, ArH);
dC (CDCl3, 100 MHz) 18.9 (CH3), 29.8 (CH3), 67.4 (CH), 70.4
(CH2), 112.4 (ArH), 121.1 (ArH), 124.6 (ArH), 126.9 (ArH),
127.4 (ArH), 127.5 (2 ArH), 127.7 (ArH), 128.0 (ArH), 128.4
(ArH), 128.6 (2 ArH), 129.6 (C), 129.8 (ArH), 134.6 (C), 135.6
(C), 137.3 (C), 138.4 (vinyl CH), 144.3 (C), 155.9 (Ar(C)O);
m/z (CI) 344 ([M − H2O]NH4+, 20%), 327 ([M − H2O]+, 100);
[Found [M − H2O]NH4+, 344.2004 (error = 3.2 ppm). C24H24O2
requires: [M − H2O]NH4+, 344.2014].
Z-( )-2-{2-[2-(2-Methoxyphenyl)-propenyl]-phenyl}-ethanol,
34. Isolated as a 1 : 9 mixture of E : Z-isomers (inseparable),
in a 59% yield, as a colourless oil; RF [petroleum ether–ethyl
acetate (4 : 1)] 0.23; mmax (neat)/cm−1 3398 (OH), 2971, 1489,
1251; dH (CDCl3, 400 MHz) 1.49 (3 H, d, J 7.6 Hz, CH3), 1.99
(3 H, s, CH3), 2.28 (1 H, s, OH), 3.86 (3 H, s, OCH3), 5.13 (1 H,
q, J 7.6 Hz, CH), 6.63 (1 H, brs, vinyl CH), 6.95 (3 H, m,
3 ArH), 7.25–7.31 (4 H, m, 4 ArH), 7.54 (1 H, d, J 8.0 Hz,
ArH); dC (CDCl3, 100 MHz) 19.1 (CH3), 23.9 (CH3), 55.9
(OCH3), 67.9 (CH), 111.4 (ArH), 121.0 (ArH), 125.0 (ArH),
127.1 (vinyl CH), 127.2 (ArH), 127.6 (ArH), 128.7 (ArH), 129.6
(ArH), 130.2 (ArH), 134.4 (C), 136.1 (C), 138.5 (C), 144.4 (C),
157.0 (Ar(C)O); m/z (EI) 268 (M+, 1%), 135 (100); [Found M+,
268.1466 (error = 0.9 ppm). C18H20O2 requires: M+, 268.1463].
E-1-(2,4-Dimethoxyphenyl)-2-(2-nitrophenyl)-ethene, 38. Iso-
lated as exclusively the E-isomer, in a 47% yield, as an orange
glass; RF [petroleum ether–ethyl acetate (4 : 1)] 0.37; mp 94–
97 ◦C; mmax (nujol)/cm−1 1514, 1461, 1160; dH (CDCl3, 400 MHz)
3.85 (3 H, s, OCH3), 3.87 (3 H, s, OCH3), 6.47 (1 H, s, ArH), 6.53
(1 H, d, J 8.0 Hz, ArH), 7.35 (1 H, t, J 8.4 Hz, ArH), 7.39 (1 H, d,
J 16.2 Hz, vinyl CH), 7.51–7.55 (3 H, m, 2 ArH and 1 vinyl CH),
7.80 (1 H, d, J 7.6 Hz, ArH), 7.91 (1 H, d, J 7.6 Hz, ArH); dC
(CDCl3, 100 MHz) 55.8 (OCH3), 55.9 (OCH3), 98.9 (ArH), 105.5
(ArH), 119.1 (C), 121.7 (vinyl CH), 125.0 (ArH), 127.5 (ArH),
128.3 (vinyl CH), 128.6 (ArH), 129.1 (ArH), 133.2 (ArH), 134.3
(C), 148.3 (Ar(C)NO2), 158.9 (Ar(C)O), 161.7 (Ar(C)O); m/z
(EI) 285 (M+, 75%), 165 (90), 149 (100); [Found M+, 285.1006
(error = 1.8 ppm). C16H15NO4 requires: M+, 285.1001].
2-(2-Methoxyphenyl)-1-(2-nitrophenyl)-propene, 35. Isola-
ted as a 1 : 1 mixture of E : Z-isomers (inseparable), in a 36%
yield, as a bright yellow oil; RF [petroleum ether–ethyl acetate
(4 : 1)] 0.45; mmax (neat)/cm−1 2959, 1523, 1346, 752; dH (CDCl3,
400 MHz) 2.05 (3 H, s, CH3), 2.22 (3 H, s, CH3), 3.68 (3 H, s,
OCH3), 3.86 (3 H, s, OCH3), 6.75–6.98 (7 H, m, 7 ArH), 7.13–
7.16 (2 H, m, 2 ArH), 7.30–7.38 (3 H, m, 3 ArH), 7.54–7.59 (2 H,
m, 2 ArH), 7.83–7.85 (1 H, m, 1 ArH), 8.02 (1 H, d, J 8.0 Hz);
m/z (CI) 287 (MNH4+, 100%), 270 (MH+, 45), 238 (65); [Found
MH+, 270.1130 (error = 0.1 ppm). C16H15NO3 requires: MH+,
270.1130].
( )-1-(2-Styrylphenyl)-ethanol, 39. Isolated as a 2 : 3 mix-
ture of E : Z-isomers (inseparable), in an 83% yield, as a clear oil;
RF [petroleum ether–ethyl acetate (4 : 1)] 0.38; mmax (neat)/cm−1
3356 (OH), 2973, 1446, 1072; dH (CDCl3, 400 MHz) 1.41 (3 H,
d, J 6.4 Hz, Z-CH3), 1.51 (3 H, d, J 6.4 Hz, E-CH3), 1.77
(1 H, brs, Z-OH), 1.92 (1 H, brs, E-OH), 5.12 (1 H, q, J 6.4 Hz,
Z-CH), 5.29 (1 H, q, J 6.4 Hz, E-CH), 6.63 (1 H, d, J 12.2 Hz,
Z-vinyl CH), 6.73 (1 H, d, J 12.2 Hz, Z-vinyl CH), 6.97 (1 H, d,
J 16.0 Hz, E-vinyl CH), 7.46 (1 H, d, J 16.0 Hz, E-vinyl CH),
remaining aromatic (ArH) signals at 7.05, 7.13, 7.25–7.38 and
7.49–7.59 all multiplets (m)—unable to define E/Z or integrals;
m/z (EI) 224 (M+, 10%), 133 (55), 91 (100); [Found M+, 224.1202
(error = 0.2 ppm). C16H16O requires: M+, 224.1201].
Due to the complex nature of the isomeric mixture, it proved
impossible to fully assign the 13C-NMR spectrum.
( )-2-(2-Benzyloxyphenyl)-1-[2-(1-methoxyethyl)phenyl]-pro-
pene, 36. Isolated as a 3 : 7 mixture of E : Z-isomers
(inseparable), in a 90% yield, as a clear gum; RF [petroleum
ether–ethyl acetate (4 : 1)] 0.48; mmax (neat)/cm−1 3064, 2975,
1447, 1224; dH (CDCl3, 400 MHz) 1.34 (3 H, d, J 6.4 Hz,
Z-CH3), 1.39 (3 H, d, J 6.4 Hz, E-CH3), 2.03 (3 H, s, Z-CH3),
2.27 (3 H, s, E-CH3), 3.16 (3 H, s, Z-OCH3), 3.21 (3 H, s,
E-OCH3), 4.59 (1 H, q, J 6.4 Hz, Z-CH), 4.69 (1 H, q, J
6.4 Hz, E-CH), 5.13 (CH2 signal for both isomers), 6.61 (1 H,
brs, Z-CH), 6.68 (1 H, brs, E-CH), remaining aromatic (ArH)
signals at 6.74, 6.85, 7.01, 7.13 and 7.22–7.50 all multiplets
(m)—unable to define E/Z or integrals; m/z (CI) 327 ([MH −
Due to the complex nature of the isomeric mixture, it proved
impossible to fully assign the 13C-NMR spectrum.
E-1-(2-Nitrophenyl)-2-phenylethene, 40. Isolated as exclu-
sively the E-isomer, in a 32% yield, as a yellow gum; RF
[petroleum ether–ethyl acetate (4 : 1)] 0.52; dH (CDCl3, 400 MHz)
7.08 (1 H, d, J 16.0 Hz, vinyl CH), 7.31–7.42 (4 H, m, 3 ArH and
7 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3

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1 vinyl CH), 7.53–7.62 (4 H, m, 4 ArH), 7.76 (1 H, d, J 8.0 Hz,
ArH), 7.96 (1 H, d, J 8.0 Hz, ArH).
yellow gum (0.050 g). Purification by flash chromatography,
eluting with 15 : 1 petroleum ether–ethyl acetate, afforded
unreacted 44 (0.014 g, 47% recovered) together with the title
compound 45 (0.013 g, 41%–77% based on recovered starting
material) as white crystals; RF [petroleum ether–ethyl acetate
(4 : 1)] 0.40; mp 145–148 ◦C; vmax (nujol)/cm−1 1704, 916; dH
(CDCl3, 400 MHz) 1.86 (3 H, s, CH3), 2.04 (3 H, s, CH3), 6.76
(1 H, d, J 8.0 Hz, ArH), 6.90 (1 H, dd, J 7.6, 7.6 Hz, ArH),
7.12–7.17 (2 H, m, 2 ArH), 7.41 (1 H, dd, J 7.6, 7.6 Hz, ArH),
7.52 (1 H, dd, J 7.7, 7.7 Hz, ArH), 7.63 (1 H, dd, J 7.7, 7.7 Hz,
ArH), 7.97 (1 H, d, J 7.7 Hz, ArH); dC (CD3CN:CDCl3 1:1,
100 MHz) 19.6 (CH3), 25.9 (CH3), 77.1 (C), 96.3 (C), 116.3
(ArH), 120.7 (C), 121.1 (ArH), 124.7 (ArH), 125.1 (2 ArH),
126.7 (C), 128.8 (ArH), 129.2 (ArH), 134.3 (ArH), 139.7 (C),
149.6 (Ar(C)O), 192.9 (ketone); m/z (CI) 267 (MH+, 100%);
[Found MH+, 267.1022 (error = 0.2 ppm). C17H14O3 requires:
MH+, 267.1021].
Data consistent with literature.19
E-1-(2-Methoxyphenyl)-2-phenylethene, 41. Isolated as ex-
clusively the E-isomer, in an 80% yield, as a white s◦olid; RF
[petroleum ether–ethyl acetate (4 : 1)] 0.58; mp 54–56 C (lit.19
56–59 ◦C); dH (CDCl3, 400 MHz) 3.89 (3 H, s, OCH3), 6.90 (1 H,
d, J 8.0 Hz, ArH), 6.97 (1 H, t, J 7.6 Hz, ArH), 7.10 (1 H, d, J
16.8 Hz, vinyl CH), 7.22–7.25 (2 H, m, 2 ArH), 7.35 (2 H, dd, J
7.2, 7.2 Hz, 2 ArH), 7.48 (1 H, d, J 16.8 Hz, vinyl CH), 7.53 (2 H,
dd, J 7.2, 7.2 Hz, 2 ArH), 7.60 (1 H, d, J 7.6 Hz, ArH).
Data consistent with literature.20
Z-2-{2-[2-(2-Benzyloxyphenyl)-propenyl]-phenyl}-ethanone, 15
via MnO2 oxidation of 16. To a stirred solution of 16
(0.42 g, 1.22 mmol) in dichloromethane (20 mL) was added
manganese(IV) dioxide (1.04 g, 12.2 mmol) and the reaction
mixture heated at reflux. After 16 hours a further portion of
manganese(IV) dioxide (1.04 g, 12.2 mmol) was added and
CCDC reference number 257403. See http://www.rsc.org/
suppdata/ob/b4/b418426b/ for crystallographic data in .cif or
other electronic format.
R
heating continued for 4 hours. Filtration through Celiteꢀ,
washing with dichloromethane, and subsequent removal of
solvent in vacuo afforded the title compound 15 (0.39 g, 94%)
as a yellow gum; RF [petroleum ether–ethyl acetate (4 : 1)] 0.39;
mmax (neat)/cm−1 2922, 1682 (CO), 1254; dH (CDCl3, 400 MHz)
1.96 (3 H, s, CH3), 2.45 (3 H, s, CH3), 5.04 (2 H, s, CH2),
6.71 (1 H, s, vinyl CH), 6.88–6.91 (2 H, m, 2 ArH), 7.18–7.40
(10 H, m, 10 ArH), 7.60 (1 H, d, J 7.6 Hz); dC (CDCl3, 100 MHz)
19.1 (CH3), 30.5 (CH3), 70.8 (CH2), 112.9 (ArH), 121.5 (ArH),
127.1 (ArH), 127.7 (2 ArH), 128.3 (CH), 128.9 (2 ArH), 129.0
(ArH), 129.3 (ArH), 129.5 (C), 130.0 (ArH), 131.3 (ArH), 131.4
(ArH), 135.1 (C), 137.6 (C), 137.9 (C), 138.5 (C), 139.3 (C), 156.4
(Ar(C)O), 202.8 (ketone)—1 ArH signal not observed; m/z (CI)
343 (MH+, 100%); [Found MH+, 343.1699 (error = 0.3 ppm).
C24H22O2 requires: MH+, 343.1698].
Acknowledgements
We would like to thank the EPSRC and GlaxoSmithKline for
their financial support (J.S.F) and Dr Julie Quayle (GSK) for
assistance with the NOE experiments.
References
1 For a recent review on the therapeutic properties of Tamoxifen, see:
J. Schwartz, Front. Biosci., 2004, 9, 2827 and references therein.
2 M. Cushman, D. Nagarathnam, D. Gopal, H.-M. He, C. M. Lin and
E. Hamel, J. Med. Chem., 1992, 35, 2293.
3 P. J. Kukkola, N. A. Bilci, W. X. Kozak, P. Savage and A. Y. Yeng,
Bioorg. Med. Chem. Lett., 1996, 6, 619.
4 S. B. Singh, D. L. Fink, D. S. Quamina, F. Pelaez, A. Teran, P. Felock
and D. J. Hazuda, Tetrahedron Lett., 2002, 43, 2351.
5 C. Y. Meyers, A. M. Malte and W. S. Matthews, J. Am. Chem. Soc.,
1969, 91, 7510.
6 F. G. Bordwell and G. D. Cooper, J. Am. Chem. Soc., 1951, 73, 5187.
7 N. P. Neureiter, J. Am. Chem. Soc., 1966, 88, 558.
8 T.-L. Chan, S. Fong, Y. Li, T.-O. Man and C.-D. Poon, J. Chem. Soc.,
Chem. Commun., 1994, 1771.
9 N. Tokura, T. Nagai and S. Matsumura, J. Org. Chem., 1966, 31, 349.
10 D. Scholz and P. Burtscher, Liebigs Ann. Chem., 1985, 517.
11 G. Casy and R. J. K. Taylor, Org. React., 2003, 62, 357; L. Paquette,
Org. React., 1977, 25, 1.
12 E. Reimann and H. Renz, Arch. Pharm., 1993, 326, 253.
13 S. Vetter, Synth. Commun., 1998, 28, 3219.
14 G. W. Rewcastle, G. J. Atwell, B. C. Baguley, M. Boyd and L. L.
Thomsen, J. Med. Chem., 1991, 34, 2864.
( )-1,9-Dimethyl-16,17-dioxa-tetracyclo[7,7,1,02,7,010,15]hepta-
deca-2,4,6,10,12,14-hexaene, 44. To a stirred solution of 15
(16 : 1 Z : E, 0.55 g, 1.6 mmol) in dichloromethane (40 mL)
was added tin(II) chloride (3.63 g, 16.1 mmol). The reaction was
allowed to stir at room temperature for 2 days, filtered through
R
Celiteꢀ, and the solvent removed in vacuo to give an orange oil
(0.520 g). Purification by flash chromatography, eluting with 9 :
1 petroleum ether–ethyl acetate, afforded the title compound 44
(0.38 g, 94%) as a white solid; RF [Petroleum ether–ethyl acetate
(4 : 1)] 0.42; mp 112–114 ◦C; mmax (nujol)/cm−1 1115, 901; dH
(CDCl3, 400 MHz) 1.74 (3 H, s, CH3), 1.96 (3 H, s, CH3), 2.92
(1 H, d, J 16.0 Hz, CH2), 3.27 (1 H, d, J 16.0 Hz, CH2), 6.68
(1 H, d, J 8.0 Hz, ArH), 6.82 (1 H, dd, J 7.6, 7.6 Hz, ArH),
6.99–7.07 (3 H, m, 3 ArH), 7.14–7.26 (2 H, m, 2 ArH), 7.43
(1 H, d, J 8.0 Hz, ArH); dC (CDCl3, 100 MHz) 26.6 (CH3), 27.6
(CH3), 43.0 (CH2), 73.1 (C), 97.6 (C), 116.8 (ArH), 120.7 (ArH),
124.6 (ArH), 125.7 (ArH), 126.7 (ArH), 128.1 (ArH), 128.2
(2 ArH), 133.2 (C), 135.8 (C), 140.8 (C), 151.0 (Ar(C)O);
m/z (CI) 253 (MH+, 100%); [Found MH+, 253.1234 (error =
2.1 ppm). C17H16O2 requires: MH+, 253.1228].
15 T. Hayashi, Y. Matsumoto, I. Yonetatsu and Y. Ito, Tetrahedron
Asymmetry, 1991, 2, 601.
16 J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734; for a more
detailed discussion dealing with the structurally similar episulfonium
ion systems, see: P. Bird, J. Eames, A. G. Fallis, R. V. H. Jones, M.
Roddis, C. F. Sturino, S. O’Sullivan, S. Warren, M. S. Westwell and
J. Worrall, Tetrahedron Lett., 1995, 36, 1909 and references therein.
17 J. S. Foot, G. M. P. Giblin and R. J. K. Taylor, Org. Lett., 2003, 23,
4441.
CCDC reference number 219622. See http://www.rsc.org/
suppdata/ob/b4/b418426b/ for crystallographic data in .cif or
other electronic format.
18 Crystal data for 45: Empirical formula = C17H14O3; Formula
˚
weight = 266.28; Unit cell dimensions: a =◦9.2508(9) A, a =
◦
˚
100.325(2) ; b = 9.3130(9) A, b = 90.360(2) ; c = 15.5363(15)
◦
3
˚
˚
A, c = 99.592(2) ; Volume = 1297.5(2) A ; Temperature/Space
( )-1,9-Dimethyl-16,17-dioxa-tetracyclo[7,7,1,02,7,010,15]hepta-
deca-2,4,6,10,12,14-hexaen-8-one, 45. To a stirred solution
of 44 (0.03 g, 0.12 mmol), PDC (0.260 g◦, 0.70 mmol) and
¯
group = 115(2) K/P1; Z = 4; Linear absortion coefficient =
0.093 mm−1; Reflections collected = 10629; Independent col-
lections
=
4551 [R(int)
=
0.0382]; Final
R
indices [I
>
R
Celiteꢀ (0.20 g) in benzene (3.5 mL) at 6–10 C under nitrogen,
2r(I)] = R1 = 0.0427, wR2 = 0.0917; R indices (all data) =
R1 = 0.0713, wR2 = 0.1019. CCDC reference number 257403.
See http://www.rsc.org/suppdata/ob/b4/b418426b/ for crystallo-
graphic data in .cif or other electronic format.
was added TBHP (5.5 M in decane, 0.13 mL, 0.7 mmol). The
reaction mixture was stirred below 10 ◦C for 4 days, with further
addition of TBHP (2 × 0.13 mL) after 36 h and 72 h. The
19 J. Wang, Y. Fu and Y. Hu, Angew. Chem., Int. Ed., 2002, 2757.
20 P. S. Kendurkar and R. S. Tewari, J. Organomet. Chem., 1975, 85,
173.
R
mixture was then filtered through a pad of Celiteꢀ, washing
with ethyl acetate, and the solvent removed in vacuo to give a
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 5 6 – 7 6 3
7 6 3