Hosomi-Sakurai reactions of silacyclohexenes

Article abstract of DOI:10.1039/b709318g

Silacyclic allyl silanes, derived from silene-diene Diels-Alder reactions, combine with acetals in the presence of Lewis acids to afford, following oxidation of the intermediate fluorosilane, either butane-1,4-diols or tetrahydronaphthalenes containing fo

Full text of DOI:10.1039/b709318g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Hosomi–Sakurai reactions of silacyclohexenes†
Nicholas J. Hughes,a Robert D. C. Pullin,a Mahesh J. Sanganee,b Jonathan D. Sellars,a Patrick. G. Steel*a and
Michael J. Turnera
Received 19th June 2007, Accepted 10th July 2007
First published as an Advance Article on the web 31st July 2007
DOI: 10.1039/b709318g
Silacyclic allyl silanes, derived from silene–diene Diels–Alder reactions, combine with acetals in the
presence of Lewis acids to afford, following oxidation of the intermediate fluorosilane, either
butane-1,4-diols or tetrahydronaphthalenes containing four contiguous chiral centres with moderate to
good diastereoselectivity.
Introduction
Originally considered to be objects of solely theoretical interest,
silenes, compounds containing a silicon carbon double bond, have
been demonstrated to be accessible species.1–3 Although a number
of silenes are isolable, Fig. 1,4–11 most are highly reactive transient
species that exhibit a unique reactivity profile, Fig. 2.
Fig. 2
functionalised organosilanes suitable for further elaboration in
a synthetic context.13–16 We have previously shown that simple
aryl and alkyl silenes, prepared through a sila modified Peterson
reaction, combine with a range of simple alkyl dienes to afford
silacyclohexenes with good levels of diastereoselectivity, Scheme 1.
Following reduction of the double bond and conversion of the Si–
Ph group to a Si–F unit, oxidative extrusion of the silicon centre
afforded 1,4-diols and d-lactones in good yield.14 Alternatively,
oxidation of the double bond provided access to the corresponding
epoxide and diol respectively.17 Both of these undergo facile acid
mediated fragmentation, presumably through the intermediacy of
a b-Si stabilised carbocation, to afford the allylic alcohol 15.
This suggested that these silacyclohexenes could function as an
allyl silane. Such species are widely used in organic chemistry
and have been shown to undergo reactions involving both
the silicon and olefinic moieties.18 Probably the most common
application in synthesis is the Hosomi–Sakurai reaction.19–21 This
transformation, which involves the Lewis acid promoted addition
of allyl silanes to acetals and related electrophiles, is considered to
follow a pathway involving addition of the carbon electrophile to
the alkene leading to the formation of a carbocation intermediate
stabilised by the presence of the b-silicon atom. Such a process
requires efficient orbital overlap between the developing empty Pp
orbital on the carbocation and a co-planar C–Si r-bond, structure
16, Fig. 3.
Fig. 1
Reflecting this, most research into the chemistry of silenes has
focused on fundamental aspects of structure and reactivity with
relatively little effort to explore these reagents in a more applied
context.12 With this in mind we have initiated a programme of work
to study the use of silene cycloaddition chemistry to provide highly
aDepartment of Chemistry, University of Durham, Science Laboratories,
South Road, Durham, DH1 3LE, UK. E-mail: p.g.steel@durham.ac.uk
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
† Electronic supplementary information (ESI) available: Characterisation
data for silacycloadducts 10c and 10d, and Sakurai products 36–39, 41–44,
46 and 48–60. See DOI: 10.1039/b709318g
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Scheme 2
Scheme 1 Reagents: i. nBuLi, LiBr, 1,3-pentadiene, THF, −20 ◦C; ii. H2,
Pd–C; iii. BF3·2AcOH then H2O2, KHCO3, THF, MeOH; iv. TPAP, NMO,
DCM; v. DMDO, acetone, DCM then SiO2; vi. OsO4, NMO, acetone, H2O.
Fig. 3
Whilst such an alignment is trivial in acyclic systems this is
not the case for cyclic substrates. Although reactions of various
related silacyclic substrates with simple electrophiles (H+) have
been described e.g. Scheme 2,22–25 there is only one example of an
analogous reaction involving a carbon centred electrophile. This
involves the unique rigid bridgehead allylsilane 23, described by
Shea et al., in which the silicon atom is held at an angle of 78◦
Scheme 3
26
=
to the C C plane, thus enforcing the required orbital overlap.
In this report we describe the full details of our studies on the
use of silacyclic allyl silanes derived from silene-diene Diels–Alder
reactions in the Hosomi–Sakurai reaction to provide access to
either butane-1,4-diols or tetrahydronaphthols with 4 contiguous
chiral centres.27
combined with Ph(SiMe3)2SiMgBr 26, prepared by treatment
of PhSi(SiMe3)3 with KOtBu followed by transmetallation with
MgBr2, to afford the silyl alcohols 8. These on treatment with
nBuLi and LiBr in the presence of the appropriate diene at
−20 ◦C afforded the silacyclohexenes as an inseparable mixture of
diastereoisomers. In all cases the major diastereoisomer obtained
10, was consistent with a pathway proceeding via the preferential
formation of a Z(Si) silene and subsequent [4 + 2] reaction with
the diene through an endo Si–Ph transition state.14
Results and discussion
Following the precedents established in our earlier work, each
of the silacyclic allylsilanes used in this study was prepared in a
standard way, Scheme 3. The appropriate aldehyde 25a–d was
With the silacycles in hand, attention then turned to the Sakurai
reaction. Initial attempts to generate the oxonium ion from an
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acetal prior to addition of the cycloadducts were unsuccessful
leading to an intractable mixture of products. However, addition of
BF3·OEt2 to a precooled (0 ◦C) mixture of the silacyclohexene 10a
and benzaldehyde dimethyl acetal in DCM afforded, after aqueous
workup and purification by flash column chromatography, the
anticipated silyl fluoride 29a in 60% yield, as a 1.6 : 1 mixture of
stereoisomers (Scheme 4) as ascertained by 19F NMR spectroscopy
[dF = −184.72 (d, J = 15.8 Hz); dF = −185.57 (d, J = 17.8 Hz)],
Fig. 4.
proceed with retention of configuration at carbon,28 this suggested
that the silyl fluoride was formed as a single Si stereoisomer and
the mixture of isomers reflects the relative configurations at C-1
and C-2. Whilst the silyl fluoride proved to be a stable species,
amenable to chromatography, it is possible to combine the two
stages. After complete consumption of the silacyclohexene and a
simple aqueous work-up, the crude reaction product is directly
subjected to the oxidation process to afford the same product
mixture in comparable yields.
A second experiment using 4-methoxybenzaldehyde dimethyl
acetal was then undertaken. However, in this case, the addition
of BF3·OEt2 to the mixture of silacyclohexene 10a and acetal
led directly to the formation of the non-conjugated diene 31 in
47% yield. We account for this product, Scheme 5, through a
sequence of steps involving initial addition of the oxonium ion to
the silacycle followed by generation of a vinylogous oxacarbenium
ion (p-quinone methide) 33. Intramolecular hydride transfer to
afford a silicon stabilised carbocation which undergoes rapid
fluoride promoted desilylation to generate the second alkene.
Importantly, in this case, the product was formed as a single
diastereoisomer suggesting that the initial addition of the oxonium
ion to the silacycle occurs stereoselectively to the face syn to the
trimethylsilyl group of the starting silacyclohexene and the mixture
of isomers observed with benzaldehyde dimethyl acetal reflects
alternative configurations at the methoxy bearing carbon centre
(C-1). Ultimately the relative stereochemistry of the major isomer
from this reaction 30as was established as the 1,2-syn, 2,3-anti,
3,4-anti configuration by single crystal X-ray diffraction, Fig. 5a.
Scheme 4
Scheme 5
Fig. 4 19F NMR spectrum (376 MHz, CDCl3) of silyl fluoride 29a.
The regiochemistry is consistent with electrophilic addition to
the allyl silane to form a carbocation intermediate stabilised by a b-
silicon substituent followed by fluoride promoted fragmentation.
At this stage it was not possible to determine the relative
stereochemistry of either component and the mixture of isomers
was oxidised by treatment with 35% w/w H2O2 in the presence of
KHCO3 to yield the monoprotected 1,4-diol (30a) in 80% yield.
Importantly, this compound was also produced as a 1.6 : 1 mixture
of diastereoisomers. Given that the Tamao oxidation is known to
Fig. 5 (a) ORTEP structure of 30as (co-crystalline phenol omitted for
clarity; ellipsoids at 50% probability level). (b) ORTEP structure of 45
(ellipsoids at 50% probability level).
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Table 1 Hosomi-Sakurai reaction of silacycles 10 with acetals
Formation of the non-conjugated diene through trapping of
the benzylic oxonium ion by hydride migration suggested that
further carbon–carbon bond formation could be combined with
the Sakurai reaction if a suitable nucleophile could be incorporated
into the silene precursor. Gratifyingly, reaction of a phenyl
substituted silacycle with 4-methoxybenzaldehyde dimethyl acetal
in the presence of BF3·OEt2 at 0 ◦C afforded, after Tamao
oxidation, the tetralol 35 in moderate yield as a 5 : 1 mixture of
stereoisomers, Scheme 6. As before the intermediate silyl fluoride
34 can be isolated but there appears to be no material advantage
in doing so. Moreover the diastereomeric ratio is unchanged on
oxidation of the silyl fluoride to tetralol indicating that as before
the silicon centre is a single stereoisomer and the mixture of
diastereoisomers reflects alternative configurations at the benzylic
carbon, C-1. The relative stereochemistry of the major isomer was
assigned on the basis of 1H NMR coupling constants and NOESY
experiments, Fig. 6.
Entry
Silacycle
Acetal (R3)
Product
Yield (dr)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
10a
10a
10a
10a
10a
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10d
10d
10d
10d
10c
10c
C6H5
30
31
36
37
38
39
40c
41
42
43
44
45
46
nr
nr
nr
47
35
48
49
50
51
52
53
54
55
56
57
58
59
60
50% (2 : 1)
47% (1 : 0)
23% (2 : 1)b
23% (2 : 1)
21% (2 : 1)b
55% (2 : 1)b
8% (2 : 1)
50% (8 : 3 : 2)
46% (3 : 1)
63% (7 : 4 : 2)
32% (2 : 1)
36% (1 : 2)
22% (1 : 1)
—
4-MeOC6H4
4-CF3C6H4
4-BrC6H4
CH3
C6H5
C6H5
4-CF3C6H4
4-BrC6H4
4-NO2C6H4
CH3
c-C6H11
C6H13
4-NMe2C6H4
2,4-(MeO)2C6H3
2-Furyl
2-Thienyl
4-MeOC6H4
C6H4CH CH
4-MeC6H4
c
—
—
<5% (nd)
27% (5 : 1)b
44% (7 : 2)
23% (2 : 1)d
34% (2 : 1)
16% (9 : 1)
17% (9 : 1)
11% (9 : 1)
32% (1 : 0)
28% (1 : 0)
20% (1 : 0)
15% (13 : 1)
20% (3 : 1)
18% (1 : 0)
15% (3 : 1)
=
2,4-Me2C6H3
2-Me-4-MeOC6H3
3,4-(MeO)2C6H3
3,4-(OCH2O) C6H3
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4-(MeO)2C6H3
4 -MeOC6H4
2,4-Me2C6H3
4-MeOC6H4
2,4-Me2C6H3
Scheme 6
a dr determined from NMR of crude reaction mixture. b Yield for a
two stage conversion involving isolation of intermediate silyl fluoride.
c 2-Phenyl dioxane used—product 40 is 1,4-diphenyl-3-ethenyl-4-(3ꢀ-
hydroxypropoxy)-2-methylbutan-1-ol (stereochemistry not determined).
d Final reaction temperature = 25 ◦C.
Fig. 6 Selected NOESY correlations (
for 35.
) and coupling constants (---)
Using the “single pot” process a range of acetals have been
explored, Table 1 entries 1–13. With alkyl substituted silacycles
(e.g. 10a) both aromatic and alkyl acetals react to form butane
diols although somewhat lower yields are observed with alkyl
acetals. In general, more reactive electron deficient oxonium ions
react more efficiently, Table 1 entry 8 and 10, although with
these small amounts of an as yet unidentified third stereoisomer
can be observed in the product mixture. In contrast, the use of
acetals that can form very stable oxonium ions lead to extensive
decomposition with no evidence for any Sakurai type products
(entries 14–16). Attempts to use aldehydes as the electrophile either
with BF3·OEt2 or using fluoride anion initiation were equally
unproductive. The use of other Lewis acids (TiCl4, TMSOTf,
Sc(OTf)3) is viable and leads to similar isomer ratios although
in somewhat reduced yields. This possibly reflects the benefits of
forming a strong Si–F bond. Consistent with the need for a fluorine
atom (nucleophile) to promote the fragmentation, attempts to use
sub-stoichiometric amounts of BF3·OEt2 led to diminished yields.
In most cases the major diastereoisomer produced had the syn,
anti, anti stereochemistry although use of cyclohexyl dimethyl
acetal afforded the alternative anti, anti anti product 45 as the
major isomer, Fig. 5b. Reaction of C-2 substituted aryl silacycles
(10b,c,d) with aryl acetals which can promote the formation of
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a benzylic carbocation affords tetralols via secondary cationic
cyclisation, Table 1, entries 17–31. The limitation for this process
is, as noted above, that if the first oxonium ion is too stable then the
initial Sakurai reaction is not competitive with decomposition of
the silacycle. The somewhat lower yields for this two step process
are probably due to difficulties in achieving efficient conversion in
this first step with the more electron rich (less reactive) substrates
required to promote the formation of the second oxonium ion.
However, the diastereoselectivity increases with electron donating
ability of the acetal suggesting that in this series the major isomer
reflects thermodynamic control. Consistent with this observation
use of tolyldimethylacetal at 0 ◦C affords a mixture of the butane
diol and tetralol 49 whilst allowing the reaction to warm to room
temperature for a prolonged period (6 h) affords the tetralol as the
exclusive product.
These results can be rationalised by a unified pathway involving
initial generation of the oxonium ion from the acetal followed
by Sakurai reaction with the silacyclohexene. This requires co-
planarity of the C–Si and alkene p-orbital which can only be
efficiently achieved when the silacycle adopts a pseudo boat
structure 62, Scheme 7. Whilst this is possible for the major
silacycle isomer the alternative diastereoisomer 69 is inhibited
from adopting such a conformation by eclipsing interactions
between the Si–Ph and C-2 substituent. Consistent with such
a proposal when the less reactive acetals are used at lower
temperatures it is possible to re-isolate small quantities of the
starting silacycle that are enriched in the minor isomers whilst the
use of more reactive oxonium ions (acetals) can lead to reaction
via other less favourable conformers. The observed selectivity is
then a matter of approach of the electrophile to the least hindered
(convex) face of the conformation of the major isomer 62, i.e. that
which avoids prow interactions between the C-3 methyl group
and a C-6 hydrogen. This generates the observed 2,3-anti, 3,4-anti
configuration. The C-1 configuration is then a matter of synclinal
63 or antiperiplanar 64 alignment of the oxonium ion with the
allylsilane such that the aryl group is orientated in an “exo” fash-
ion. The formation of the observed products suggests the former
is of lower energy although reasons for the reversal of selectivity
with cyclohexane carboxaldehyde dimethyl acetal are not obvious.
The preferential formation of the 1,2 anti configuration in the
cationic cyclisation to give the tetralol skeleton has considerable
precedent in the lignan synthesis literature.29–32 Such an outcome
is consistent with cyclisation proceeding through a chair-like tran-
sition state with all substituents occupying an equatorial position
67. However, as suggested above, thermodynamic control cannot
be excluded particularly with acetals containing more electron
donating substituents as these enhance the reversibility of the
process.
In conclusion, this work has demonstrated that silacyclohex-4-
enes, derivedfromsilene–diene cycloadditions are viable substrates
for the Hosomi–Sakurai reaction with both aryl and alkyl acetals.
Following Tamao oxidation of the resultant silyl fluoride mono-
protected cyclobutane diols can be obtained in moderate yield
and diastereoselectivity. Moreover, when aryl acetals containing
ortho or para electron-donating substituents are combined with
silacyclohexenes containing a C-2 aryl substituent a further
cyclisation occurs to afford the tetralol skeleton found in many
lignan natural products. Future work will focus on enhancing the
stereochemical control observed in each step of this cascade and
Scheme 7
applying the methodology to the synthesis of target structures.
Results of these studies will be reported in due course.
Experimental
All air and/or moisture sensitive reactions were carried out under
an argon atmosphere. Solvents were purified and dried following
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established protocols. Petrol refers to petroleum spirit boiling in
the 40–60 ◦C range. Ether refers to diethyl ether. Lithium bromide
was dried by heating at 100 ◦C at 0.06 mmHg for 3 h. Magnesium
bromide was synthesised by addition of 1,2-dibromoethane to
an equivalent amount of magnesium in ether. Aldehydes and
dienes were distilled, immediately prior to use, from anhydrous
calcium sulfate and sodium borohydride, respectively. All other
commercially available reagents were used as received unless
otherwise stated. Flash column chromatography was performed
according to the method of Still et al. using 200–400 mesh silica
gel.33 Yields refer to isolated yields of products of greater than 95%
purity as determined by 1H + 13C NMR spectroscopy or elemental
analysis (Durham University Microanalytical Laboratory).
Melting points were determined using Gallenkamp melting
point apparatus and are uncorrected. Infrared spectra were
recorded using a Diamond ATR (attenuated total reflection)
accessory (Golden Gate) or as a solution in chloroform via
transmission IR cells on a Perkin-Elmer FT-IR 1600 spectrometer.
Unless otherwise stated 1H NMR spectra were recorded in CDCl3
on Varian Mercury 200, Varian Unity-300, Varian VXR-400 or
Varian Inova-500 and are reported as follows; chemical shift
d (ppm) (number of protons, multiplicity, coupling constant J
(Hz), assignment). Residual protic solvent CHCl3 (dH = 7.26) was
used as the internal reference. 13C NMR spectra were recorded
at 63 MHz or 126 MHz, using the central resonance of CDCl3
(dC = 77.0 ppm) as the internal reference. 29Si NMR spectra were
recorded at 99 MHz on Varian Inova-500. 19F NMR spectra were
recorded at 376 MHz or 282 MHz on Varian VXR-400 or Varian
Unity-300 respectively. All chemical shifts are quoted in parts
per million relative to tetramethylsilane (dH = 0.00 ppm) and
coupling constants are given in Hertz. All 13C spectra were proton
decoupled. Assignment of spectra was carried out using DEPT,
COSY, HSQC and NOESY experiments.
in the next stage or purified by flash chromatography to afford the
silyl fluoride species.
Stage 2. The crude organic material from stage 1 or purified
silyl fluoride species was dissolved in methanol : THF (5 ml, 1 : 1)
and treated with KHCO3 (1.0 mmol) and a 35% w/w solution of
H2O2 (4.0 mmol) at room temperature. The reaction mixture was
then heated under reflux for 5 h and then poured into Na2S2O3 and
extracted with EtOAc (3 × 10 ml). The combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo. Flash
chromatography (petrol, ether [95 : 5], [9 : 1], [4 : 1]) afforded the
desired mono-protected 1,4-diols or tetralol.
(1RS*,2R*,3S*,4R*,(Si)R*)-3,5-Dimethyl-2-ethenyl-4-(1ꢀ-fluoro-
2ꢀ,2ꢀ,2ꢀ-trimethyl-1ꢀ-phenyldisilyl)-1-methoxy-1-phenylhexane 29a
Silacycle 10a (0.35 g, 1.1 mmol) was combined with benzaldehyde
dimethylacetal to give the title silyl fluoride 29a as a pale yellow
oil as a (2 : 1) mixture of diastereoisomers (0.3 g, 60%); Rf 0.6
(petrol–ether 95 : 5). mmax (thin film) 2926, 2918, 1675, 1651, 1536,
1454, 1428, 1359, 1245, 1189, 1105, 916, 836, 800, 735, 729, 699,
543 cm−1; NMR data given for major isomer dH (500 MHz, CDCl3)
7.50–7.49 (2H, m, Ar-H), 7.35–7.33 (2H, m, Ar-H), 7.32–7.30 (4H,
=
m, Ar-H), 7.19–7.17 (2H, m, Ar-H), 5.70 (1H, dt, J 17, 10, CH),
=
4.95 (1H, d, J 10, CHH), 4.51 (1H, bs, 1-H), 4.44 (1H, d, J
=
17, CHH), 3.29 (3H, s, OCH3), 2.56 (1H, m, 3-H), 2.20 (1H,
bt, J 10, 2-H), 1.97 (1H, m, 5-H), 1.35 (3H, d, J 7, 3-CH3),
1.03 (3H, 5-CH3), 0.62 (3H, d, J 7, 6-H3), 0.13 (9H, s, Si(CH3)3);
=
dC (126 MHz, CDCl3) 141.5 (Ar-C), 137.3 ( CH), 137.0 (Ar-C),
132.7 (Ar-C), 132.6 (Ar-C), 129.0 (Ar-C), 127.7 (Ar-C), 127.2 (Ar-
=
C), 126.8 (Ar-C), 118.5 ( CH2), 65.86 (C-1), 57.44 (OCH3), 57.42
(C-2), 38.8 (C-4), 35.7 (C-3), 26.2 (C-5), 25.9 (5-CH3), 24.0 (C-
6), 16.6 (3-CH3), −2.1 (Si(CH3)3); dF (300 MHz, CDCl3) −185.6
Gas chromatography-mass spectra (GCMS, EI or CI) were
obtained using a Thermo TRACE mass spectrometer. Elec-
trospray mass spectra (ES) were obtained on a Micromass
LCT mass spectrometer. High resolution mass spectra were
obtained using a Thermo LTQ mass spectrometer (ES) at the
University of Durham, or performed by the EPSRC National
Mass Spectrometry Service Centre, University of Wales, Swansea.
Detailed experimental procedures describing the formation and
characterisation of the silene silacycloadducts 10a and 10b and the
X-ray crystallography for 30as has previously been reported.13,14,27
Characterisation data for silacycloadducts 10c and 10d, and
Sakurai products 36–39, 41–44, 46 and 48–60 can be found in
the ESI.†
+
(1F, d, J 18, Si-F); m/z (CI) 460 (MNH4 , 100%), 428 (35%), 411
(M+ − (OCH3), 40%); HRMS (ES+) Found MNH4 , 460.2863,
+
C26H39FOSi2NH4 requires M+ 460.2862.
(3R*,4S*,5R*,6S*)-2,4-Dimethyl-5-ethenyl-6-methoxy-6-
phenylhexan-3-ol 30
Oxidation of fluorosilane 29 (0.3 g, 0.6 mmol) afforded the title
alcohol 30 as a colourless oil as a (2 : 1) mixture of diastereoisomers
(0.1 g, 80%); Rf 0.4 (petrol–ether 9 : 1). mmax (thin film) 3326 (broad,
OH), 2958, 2874, 2834, 1605, 1594, 1498, 1471, 1454, 1363, 1233,
1066, 992, 918, 752, 691 cm−1; NMR data given for the major
isomer 30as dH (500 MHz, CDCl3) 7.34–7.31 (2H, m, Ar-H), 7.27–
=
7.23 (3H, m, Ar-H), 6.04 (1H, ddd, J 17, 10, 10, 5-CH ), 5.09
Standard procedure for the Hosomi–Sakurai reaction of silacycles
10
=
=
(1H, dd, J 10, 2, CHH), 4.76 (1H, dd, J 17, 2, CHH), 4.48 (1H,
d, J 4, 6-H), 3.76 (1H, d, J 3, OH), 3.28 (1H, m, 3-H), 3.23 (3H, s,
OCH3), 2.26 (1H, m, 5-H), 1.82 (1H, m, 4-H), 1.74 (1H, m, 2-H),
1.00 (3H, d, J 7, 2-CH3), 0.86 (3H, d, J 7, 4-CH3), 0.81 (3H, d, J
Stage 1. A solution of silacycle (0.3 mmol) in dichloromethane
(5 ml) was treated with the appropriate acetal (0.6 mmol) and
cooled to 0 ◦C. The solution was then treated with BF3·Et2O
([0.5 M] in DCM, 0.3 mmol) and stirred at 0 ◦C for 6 h.
The reaction mixture was then poured into aq. NH4Cl and
extracted with dichloromethane (3 × 10 ml). The combined
organic layers were dried over MgSO4, filtered and concentrated.
The concentrated organic material could then be utilised directly
=
7, 1-H3); dC (126 MHz, CDCl3) 140.7 (ipso-Ar-C), 134.3 (CH ),
128.0 (Ar-C), 127.4 (Ar-C), 127.3 (Ar-C), 118.8 ( CH2), 86.9 (C-
6), 76.9 (C-3), 57.8 (C-5), 57.0 (OCH3), 40.9 (C-4), 29.6 (C-2),
20.7 (2-CH3), 17.4 (4-CH3), 13.6 (C-1); m/z (ES+) 285 (MNa+);
HRMS (ES+) MNa+ Found 285.1825, C17H26O2Na requires M+
285.1825.
=
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(2ꢀR*,3ꢀS*)-1-(3ꢀ,5ꢀ-Dimethyl-2ꢀ-ethenylhex-4ꢀ-enyl)-4-
methoxybenzene 31
1301, 1261, 1245, 1177, 1115, 1026, 913 cm−1; NMR data for major
isomer dH (500 MHz, CD3COCD3) 7.68 (1H, d, J 10, 8-H), 7.20
(1H, m, 7-H), 7.09–7.04 (3H, m, 6-H, Ar-H), 6.86 (2H, d, J 11,
Ar-H), 6.75 (1H, d, J 10, 5-H), 5.96 (1H, ddd, J 20, 11, 9, 3-
A solution of silacycle 10a (0.05 g, 0.2 mmol) in dichloromethane
(5 ml) was cooled to −78 ◦C and treated with 4-methoxy-
benzaldehyde dimethylacetal (0.1 ml, 0.3 mmol), then BF3·Et2O
(0.03 ml, 0.2 mmol) and the reaction mixture stirred at room
temperature for 12 h. The reaction was poured into NH4Cl
and extracted with dichloromethane (3 × 10 ml). The combined
organic layers were dried over MgSO4, filtered, concentrated and
dried in vacuo. Flash chromatography (petrol–ether [98 : 2], [95 :
5], [9 : 1]) afforded the title compound as a colourless oil (0.02 g,
47%); Rf 0.7 (pet. ether–ether 9 : 1); mmax (thin film) 2955, 2927,
2871, 2833, 2362, 2337, 1510, 1440, 1299, 1243, 1175, 1038, 910,
=
=
CH ), 5.14 (1H, t, J 8, 5, 1-H), 4.91 (2H, m, CH2), 4.41 (1H,
d, J 8, -OH), 3.99 (1H, d, J 12, 4-H), 3.79 (3H, s, OCH3), 2.82
(1H, ddd, J 12, 3, 2, 3-H), 2.35 (1H, qdd, J 7, 5, 3, 2-H), 0.94 (3H,
d, J 9, 2-CH3); dC (126 MHz, CD3COCD3) 159.7 (Ar-C), 142.0
=
(3-CH ), 140.8 (Ar-C), 140.5 (Ar-C), 139.6 (Ar-C), 136.7 (Ar-
C), 136.3 (Ar-C), 131.9 (Ar-C), 128.1 (C-8), 128.0 (C-7), 116.5
=
(3-CH CH2), 115.1 (Ar-C), 72.8 (C-1), 56.1 (OCH3), 51.9 (C-3),
48.3 (C-4), 41.0 (C-2), 8.7 (2-CH3); m/z (ES+) 317 (MNa+).
(1S*,2S*,3R*,4R*)-4-Cyclohexyl-3-ethenyl-4-methoxy-2-methyl-
1-phenylbutan-1-ol 45
834 cm−1; dH (500 MHz, CDCl3) 7.02 (2H, d, J 9, Ar-H), 6.80 (2H,
ꢀ
=
d, J 9, Ar-H), 5.68 (1H, ddd, J 17, 11, 10, 2 -CH ), 5.00 (1H, d, J
ꢀ
=
=
11, 4 -H), 4.85 (1H, d, J 11, CHH), 4.82 (1H, d, J 17, CHH),
3.78 (3H, s, -OCH3), 2.55 (2H, dd, J 14, 6, 1-H2), 2.44 (1H, m,
2ꢀ-H), 2.24 (1H, m, 3ꢀ-H), 1.73 (3H, s, 6ꢀ-H3), 1.57 (3H, s, 5ꢀ-CH3),
0.92 (3H, d, J 7, 3ꢀ-CH3); dC (126 MHz, CDCl3) 157.5 (C-4), 139.4
Reaction of silacycle 10b and cyclohexanecarboxaldehyde
dimethylacetal afforded, following column chromatography, the
title alcohol 45 as a colourless oil as a 1 : 2 mixture of diastereo-
isomers (36%); mp 106–108; Rf 0.3 (petrol–ether 9 : 1); mmax (thin
film) 3324 (broad, OH), 3068, 3038, 2930, 2853, 2358, 2241, 1716,
1602, 1540, 1455, 1078, 1010, 834 cm−1; dH (500 MHz, CDCl3)
major isomer 7.32–7.30 (5H, m, Ar-H), 6.10 (1H, ddd, J 17, 10,
ꢀ
ꢀ
ꢀ
=
(2 -CH ), 133.2 (C-1), 131.2 (C-5 ), 130.0 (Ar-C), 127.3 (C-4 ),
ꢀ
=
115.9 ( CH2), 113.4 (Ar-C), 55.2 (OCH3), 51.9 (C-2 ), 38.2 (C-
1ꢀ), 35.3 (C-3ꢀ), 26.0 (C-6ꢀ), 19.5 (3ꢀ-CH3), 18.1 (5ꢀ-CH3); m/z (CI,
NH3) 262 (MNH4 , 15%), 245 (M+, 65%), 161 (10%), 121 (100%);
+
=
=
=
10, 3-CH ), 5.19 (1H, d, J 10, CHH), 5.10 (1H, d, J 17, CHH),
4.32 (1H, d, J 10, 1-H), 3.58 (3H, s, OCH3), 3.06 (1H, t, J 6, 4-H),
2.45 (1H, m, 3-H), 2.14 (1H, m, 2-H), 1.98 (1H, d, J 14), 1.80–
1.69 (3H, m), 1.62–1.59 (1H, d, J 14), 1.31–1.16 (4H, m), 1.10–1.01
(2H, m), 0.65 (3H, d, J 7, 2-CH3); dC (126 MHz, CDCl3) 144.7
HRMS (ES+) Found M+ 245.1896, C17H24O requires M+ 245.1900.
(1R*,2R*,3R*,4S*,(Si)R*)-1-(1ꢀ-Fluoro-2ꢀ,2ꢀ,2ꢀ-trimethyl-1ꢀ-
phenyldisilyl)-4-(4ꢀꢀ-methoxyphenyl)-2-methyl-3-ethenyl-1,2,3,
4-tetrahydronaphthalene 34
=
(ipso-Ar-C), 137.3 (3-CH ), 128.1 (Ar-C), 127.1 (Ar-C), 126.8
=
(Ar-C), 117.5 ( CH2), 89.5 (C-4), 76.0 (C-1), 61.6 (OCH3), 51.0
Silacycle 10b (0.6 g, 1.8 mmol) was combined with 4-methoxy-
benzaldehyde dimethylacetal to give the title compound as a
colourless gum (0.4 g, 44%); Rf 0.3 (petrol–ether 95 : 5) as a 5 :
1 mixture of diastereoisomers; mmax (thin film) 1609, 1509, 1487,
1442, 1427, 1301, 1243, 1175, 1105, 1036, 912, 835 cm−1; NMR
data given for major isomer dH (500 MHz, CDCl3) 7.66–7.64 (2H,
m, Ar-H), 7.44–7.42 (3H, m, Ar-H), 7.38 (1H, m, Ar-H), 7.25
(1H, m, Ar-H), 6.98–6.96 (3H, m, Ar-H), 6.80–6.77 (3H, m, Ar-
(C-3), 41.0 (4-CH), 40.3 (C-2), 30.0 (CH2), 29.6 (CH2) 26.5 (CH2),
26.3 (CH2), 26.0 (CH2), 17.7 (2-CH3); m/z (ES+) 325 (MNa+), 627
(2MNa+); HRMS (ES+) FoundMNa+ 325.2137, C20H30O2 requires
M+ 325.2138.
X-Ray crystallography
X-Ray diffraction experiment was carried out at T = 120 K on
=
=
H), 5.71 (1H, m, 3-CH ), 4.87 (1H, d, J 10, CHH), 4.76 (1H,
a Siemens 3-circle diffractometer with a SMART 1K CCD area
=
d, J 17, CHH), 3.87 (1H, d, J 11, 4-H), 3.78 (3H, s, OCH3),
¯
detector, using graphite-monochromated Mo-Ka radiation (k =
3.25 (1H, m, 1-H), 2.62 (1H, m, 3-H), 2.31 (1H, m, 2-H), 1.05
(3H, d, J 7, 2-CH3), 0.14 (9H, s, Si(CH3)3); dC (126 MHz, CDCl3)
˚
0.71073 A) and a Cryostream (Oxford Cryosystems) open-flow
N2 cryostat. The structure was solved by direct methods using
SIR92 program,34 and refined by full-matrix least squares (against
F2) using CRYSTALS software (version 12.80).35 Crystal data: 45,
C20H30O2, M = 302.46, monoclinic, space group P21/c (No. 14),
=
157.8 (Ar-C), 140.2 (3-CH ), 139.9 (Ar-C), 138.0 (Ar-C), 135.2
(Ar-C), 136.8 (Ar-C), 136.4 (Ar-C), 133.2 (Ar-C), 130.9 (Ar-C),
130.4 (Ar-C), 129.7 (Ar-C), 128.2 (Ar-C), 125.9 (Ar-C), 125.5
=
(Ar-C), 116.0 ( CH2), 113.5 (Ar-C), 55.1 (OCH3), 52.7 (C-3),
◦
˚
a = 16.9623(4), b = 9.9591(2), c = 11.0721(3) A, b = 96.287(1) ,
46.3 (C-4), 38.7 (C-1), 34.4 (C-2), 12.8 (2-CH3), −1.4 (Si(CH3)3);
dF (300 MHz, CDCl3) −183.5 (1F, d, J 7, Si-F); m/z (ES+)
497 (MNa+), 971 (2M+ − 2OCH3); HRMS (ES+) Found MNa+
497.2107, C29H35Si2OFNa requires M+ 497.2103).
3
−3
−1
˚
U = 1859.15(8) A , Z = 4, Dc = 1.081 g cm , l = 0.07 mm , 23555
reflections with 2h ≤ 61◦, semi-empirical absorption correction
on Laue equivalents,36 Rint = 0.023, R(F) = 0.039 on 2621 data
with I ≥ 2r(I), wR(F2) = 0.143 on all 5273 unique data. CCDC
reference number 298852. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b709318g
(1R*,2R*,3R*,4S*)-4-(4ꢀ-Methoxyphenyl)-2-methyl-3-ethenyl-
1,2,3,4-tetrahydronaphthalen-1-ol 35
Following stage 2 of the standard procedure fluorosilane 34 (0.37 g,
0.7 mmol) was oxidised to afford, following chromatography, the
title tetralol as a white solid (0.085 g, 61%) as a 5 : 1 mixture of
diastereoisomers; Rf 0.1 (petrol–ether 9 : 1); mp 122–124; Found
C, 81.15%; H, 7.59%; required for C20H22O2: C, 81.59%; H, 7.53%.
mmax (thin film) 3350 (broad, OH), 2961, 2907, 1611, 1511, 1451,
Acknowledgements
We thank the EPSRC (DTA studentships to JDS and NJH)
and GlaxoSmithKline for financial support of this work (CASE
award to NJH). The EPSRC Mass Spectrometry Service for
accurate mass determinations. Dr A. M. Kenwright for assistance
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Org. Biomol. Chem., 2007, 5, 2841–2848 | 2847
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with NMR experiments, Dr M. Jones for mass spectra and
Dr A. S. Batsanov for help with the X-ray data.
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2848 | Org. Biomol. Chem., 2007, 5, 2841–2848
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