A stereoselective synthesis of 1,6-diphenyl-1,3,5-hexatrienes utilising 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane as a two-carbon alkenyl building block

Article abstract of DOI:10.1039/b507900d

A number of 1,6-diphenyl-1,3,5-hexatrienes of varying alkene geometries were stereoselectively prepared from just two starting materials: iodobenzene and 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane via a series of Heck, Suzuki-Miyaura and stereocontrolled iododeboronation reactions. These results demonstrate how 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane can be used as a genuine two-carbon vinyl-dianion building block in stereocontrolled polyene synthesis. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b507900d

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A R T I C L E
A stereoselective synthesis of 1,6-diphenyl-1,3,5-hexatrienes utilising
4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane as a two-carbon alkenyl
building block
Andrew P. Lightfoot,a Steven J. R. Twiddleb and Andrew Whiting*b
a GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow,
Essex, UK CM19 5AW
b The Department of Chemistry, University of Durham, Science Laboratories, South Road,
Durham, UK DH1 3LE. E-mail: andy.whiting@durham.ac.uk; Fax: 0191 496221/487672;
Tel: 0191 3342000
Received 6th June 2005, Accepted 24th June 2005
First published as an Advance Article on the web 20th July 2005
A number of 1,6-diphenyl-1,3,5-hexatrienes of varying alkene geometries were stereoselectively prepared from
just two starting materials: iodobenzene and 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane via a series of
Heck, Suzuki–Miyaura and stereocontrolled iododeboronation reactions. These results demonstrate how
4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane can be used as a genuine two-carbon vinyl-dianion building block
in stereocontrolled polyene synthesis.
Introduction
The development of efficient strategies for the stereoselective
synthesis of polyenes which can be applied to complex natural
product synthesis is an important goal.1 Indeed, this has been
the subject of ongoing investigations within our group, result-
ing in the development of methodology employing a pinacol
vinylboronate ester to act as an alkenyl building block,2 and the
process showed some early success culminating in the synthesis
of the natural product and selective herbicide phthoxazolin A.3
Further development in the application to the synthesis of a
further natural product, viridenomycin,4 was hampered by a
Scheme 1
number of practicality issues involving the use of the pinacol
vinylboronate ester.
Results and discussion
Recently we reported the development of an alternative
vinylboronate ester, 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane
3,5 which was free of a number of preparatory and physical
problems associated with the pinacol form. Under palladium
catalysed coupling conditions the ester 3 can undergo Heck
coupling reactions with a range of substrates generating the
desired products with greater selectivity and in increased yields.5
The substituted alkenylboronate ester can also undergo stere-
ocontrolled iododeboronation reactions to generate E- or Z-
iodoalkenes.6 Again, the ester of 2-methyl-2,4-pentanediol has
been shown to give superior yields of the desired product albeit
with the same high selectivity.7 Most recently we have reported
the selective use of 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane
in Suzuki–Miyaura reactions to prepare a number of styrenes
and dienes.8 These reported results demonstrate that we have
developed procedures where the vinylboronate ester can act as a
vinyl-dianion equivalent being able to react exclusively at either
end along the Heck or Suzuki–Miyaura pathways, dependent on
the conditions employed to perform the reaction. This is further
exemplified by results presented in this paper.
Herein we demonstrate how the three reactions discussed
can be used in combination to prepare polyene systems; in the
present case, the diphenylhexatriene model systems. The prod-
ucts are prepared from just two starting materials: iodobenzene,
of which there are two units providing each aryl fragment,
and three 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane 3 units
which provide each alkene unit of the triene proving how the
vinylboronate ester can be genuinelybe regardedas atwo-carbon
alkenyl building block (see Scheme 1).
The first part of the synthesis required the preparation of
our key building block reagent, 4,4,6-trimethyl-2-vinyl-1,3,2-
dioxaborinane 3. This is effected following the procedure
outlined in eqn. (1) which is robust and can be performed easily
on multi-gram scale to give the desired product 3 in consistently
high yields after distillation.
(1)
The initial reaction along the proposed synthetic route to
the trienes was the Heck coupling of iodobenzene 2 with the
vinylboronate ester 3 (Scheme 2). This first reaction links the
aryl group and one of the three alkenyl units and use of the
standard coupling conditions generally gives a small amount
of Suzuki–Miyaura product (Table 1, entry 1), although on
occasion complete selectivity can be obtained. The styrene side-
product 6 can be easily separated from the desired boronate 5;
however, its presence reduces the control over the system and the
yield of the desired product 5. Other reaction conditions were
therefore investigated to develop a procedure that consistently
gave complete Heck selectivity.
A number of examples exist in the literature in which metal
additives have been used in Heck coupling reactions. Thallium(I)
salts, particularly TlOAc, have been shown to induce a rate
accelerating effect on the Heck coupling process over a range
of organic electrophiles.9 In addition, silver(I) salts have been
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
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 6 7 – 3 1 7 2
3 1 6 7
©

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Scheme 2 Reagents and conditions: a) Pd(OAc)2 (5 mol%), PPh3 (15 mol%), nBu3N (1.2 equiv.), AgOAc (1.2 equiv.), 3 (1.2 equiv.), toluene, 110 ◦C,
24 h; b) (i) NaOMe/MeOH (1.2 equiv.), THF, −78 ◦C, 30 min, (ii) ICl/DCM (1.2 equiv.), −78 ◦C to rt, 2 h; c) (i) ICl/DCM (1.2 equiv.), DCM,
−78 ◦C, 4 h, (ii) NaOMe/MeOH (1.2 equiv.), −78 ◦C to rt, 30 min; d) Pd(PPh3)4 (5 mol%), Ag2O (2 equiv.), 7a or 7b (1 equiv.), THF, 65 ◦C, 24 h.
Table 1 Optimised Heck coupling of vinylboronate 3 with iodobenzene
2 and styryl iodides 7
our group giving either the E- or Z-alkenyl iodide with very
high geometrical purity using iodine monochloride and sodium
methoxide.6 The order of reagent addition determines the stere-
ochemical outcome: initial treatment with sodium methoxide
before addition of the ICl affords the E-styryl iodide 7a, whereas
reaction with ICl followed by sodium methoxide generates the Z-
styryl iodide 7b [eqn. (3)]. The ester of 2-methyl-2,4-pentanediol
again gives improved yields over the pinacol form albeit with
the same level of selectivity. Using these reaction conditions both
styryl iodides were prepared in high yields (7a = 86%, 7b = 95%)
and with what is of greater significance very high geometrical
purity (7a = 98%, 7b = 96%). It is noteworthy that the quality
of the ICl reagent is of extreme importance, particularly with
regard to the level of conversion of the starting material and
hence the yield of the reaction.
Entry
Iodide
Additive
H : S–Ma
Yield (%)b
1
2
3
4
5
6
7
2
—
91 : 9
100 : 0
100 : 0
84 : 16
88 : 12
65 : 35
100 : 0
73
86
88
51
55
46
58
2
TlOAc
AgOAc
TlOAc
AgOAc
TlOAc
AgOAc
2
7a
7a
7b
7b
a The product ratio was derived from the 1H NMR of the crude reaction
material. b The yield quoted is the isolated yield after purification by
silica gel chromatography.
shown to have a similar effect, and of particular relevance,
allowing the preparation of dienes from the coupling of E- or Z-
alkenyl iodides with allylic alcohols whilst retaining the alkene
geometries.10 A comparative study of the use of TlOAc and
AgOAc in the Heck reaction was performed for the preparation
of conjugated dienyl aromatics from aromatic iodides and
dienes.11 Both additives gave impressive yields, with TlOAc
giving slightly higher values; however, in every case isomerisation
of the starting alkene occurred and, as a consequence, only the
E,E-dienes were obtained, showing that this strategy for the
preparation of such systems is unfortunately flawed.
We therefore examined both thallium(I) and silver(I) acetates
as additives to determine their effect on this Heck reaction [eqn.
(2)], paying particular attention to the ratio of the Heck : Suzuki–
Miyaura products formed. As is shown in Table 1 (entries 2 and
3), the use of both metal acetate additives resulted in complete se-
lectivity of the reaction for the desired Heck product, the styryl-
boronate 5 from the reaction of the vinylboronate ester 3 with
iodobenzene 2, which allows the isolation of the desired styryl-
boronate 5 in greater yields than without the metal salt additive.
(3)
After the successful iododeboronation reactions, the second
alkenyl unit was introduced through another Heck coupling
reaction of the vinylboronate 3, but on this occasion, with the
E- and Z-alkenyl iodides 7a and 7b respectively. To date, the
coupling of aryl systems had been predominantly explored using
the 2-methyl-2,4-pentanediol boronate ester derivatives, rather
than alkenyl; however, the conditions for these couplings were
based on those developed for the aryl systems.
A series of screening reactions was therefore carried out
to determine what the preferred coupling conditions for the
preparation of dienylboronates 8 from styryl iodides 7 and vinyl-
boronate 3 were; the results are shown in Table 2. The first thing
to note is the very poor Heck selectivity shown for both iodides
7a and 7b under the standard conditions (Table 2, entries 2 and
9), which in the case of the E-iodide 7a favours the formation of
the Suzuki–Miyaura product. This contrasts dramatically with
the results obtained for iodobenzene and a number of other aryl
substrates where the by-product formation was minimal.5 This
surprising result led us to investigate a further range of reaction
variables to assess their impact upon the Heck : Suzuki–Miyaura
selectivity of the coupling reaction (Table 2).
The standard coupling conditions (Table 2, entries 2 and 9)
established the ‘natural’ selectivities of the coupling of each
iodide, and the effect of other variables on this ratio was
then investigated. Initially, and most obviously, the choice of
palladium ligand was examined; however, variations of the
phosphine ligands had a minimal effect on the product ratio
(Table 2, entries 2–5), and there was very little variation in the
selectivity. It was also expected that the use of bulky bidentate
ligands would have a dramatic effect on the selectivity of the
(2)
With the desired Heck product 5 in hand, the next step
was to convert it into both the alkenyl iodides 7. Conditions
for the iododeboronation reactions have been developed in
3 1 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 6 7 – 3 1 7 2

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Table 2 Heck coupling of the vinylboronate 3 with styryl iodides 7: variables and their influence on the Heck : Suzuki–Miyaura product ratio
Entry
Iodide
Ligand
Base
Solvent
Additive
T/◦C
Conversion (%)a
H : S–Mb ratio
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
7b
7b
7b
7b
7b
7b
7b
7b
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
—
PPh3
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu2NH
nBuNH2
nBu3N
nBu3N
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Acetonitrile
Acetonitrile
Acetonitrile
Toluene
Toluene
—
—
—
—
—
—
TlOAc
AgOAc
—
—
—
—
—
—
—
—
TlOAc
AgOAc
110
110
110
110
110
110
110
110
110
110
110
110
78
100
100
100
100
100
13
100
100
100
63
0
36
15
49
58 : 42c
53 : 47
32 : 68
58 : 42
54 : 46
100 : 0
65 : 35
100 : 0
34 : 66
29 : 71
—
43 : 57
30 : 70
35 : 65
35 : 65
26 : 74
84 : 16
88 : 12
P(o-tolyl)3
PtBu3
P(2-furyl)3
1,10-Phenanthroline
PPh3
PPh3
PPh3
BINAPd
DUPHOSe
XANTHPHOSf
PPh3
PPh3
PPh3
PPh3
PPh3
78
78
78
110
110
37
84
100
100
PPh3
a Determined from the ratio of starting iodide to products in the 1H NMR of the crude reaction material. b The product ratio was derived from the
1H NMR of the crude reaction material. c Isomerisation of the Z-alkene to the E-form occurred for both products. d 2,2ꢀ-Bis(diphenylphosphino)-
1,1ꢀbinaphthalene. e (−)-1,2-Bis[(2R,5R)-2,5-dimethylphospholano)benzene. f 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
reaction (Table 2, entries 10–12). However, there was a small
degree of change in selectivity but a dramatic reduction in the
conversion of the reaction. Indeed, in the case of the DUPHOS
ligand, the reaction failed altogether. The use of the amine ligand
1,10-phenanthroline (Table 2, entry 6) resulted in a dramatic
increase in Heck selectivity; however, the conversion under these
conditions is very low at just 13%. This led to testing the reaction
in the absence of any ligand (Table 2, entry 1). Surprisingly, this
gave full conversion and a product ratio comparable with those
obtained previously; however, isomerisation of the Z-alkene
occurred, so that both of the products possessed an internal E-
alkene. The isomerisation of the Z-alkene most likely occurs in
the coupled products rather than during the reaction. The lack of
an added ligand would result in stabilisation of the palladium(0)
species through p-coordination of the products, and any allyl-
cation formation, however, would lead to the isomerisation to
give the all E-alkenyl product.
Changing the solvent from toluene to acetonitrile, both at
reflux, resulted in a reduction in conversion (Table 2, entries 9
and 14); however, this can most likely be attributed to the lower
temperature of the reaction, rather than any significant solvent
effect. Indeed, using toluene at a lower temperature induces a
lower conversion (Table 2, entry 13).
Three different bases were also used for this reaction (Table 2,
entries 14–16), tri-n-butylamine, di-n-butylamine and n-
butylamine. It was hoped the different steric and basicity
effects would perhaps perturb the Heck selectivity obtained
using tri-n-butylamine, but no significant changes in product
selectivity were obtained and as identified above the low levels of
conversion obtained can be attributed to performing the reaction
in refluxing acetonitrile.
The use of the metal additives, i.e. thallium(I) and silver(I) ac-
etates (Table 2, entries 7, 8, 17 and 18) was the only variable that
resulted in a dramatic change in product selectivity. The Heck
selectivity of the E-styryl iodide 7a coupling swung dramatically
in favour of the Heck product when using both additives (Table 2,
entries 17 and 18). There was little difference between using
either thallium or silver, both additives being suitable for scale
up and isolation of the product diene 8a in good yields. The
optimised reactions are shown in Table 1 (entries 4 and 5).
There was a more marked difference in using the two different
metal additives when coupling the Z-styryl iodide 7b to the
vinylboronate 3 (Table 2, entries 7 and 8). Although both
thallium(I) and silver(I) acetate increased the Heck selectivity
compared to that without additive (Table 2, entry 2), the increase
in selectivity was more modest using the thallium salt compared
to silver, which gave complete Heck selectivity. This was further
demonstrated by reaction scale up and isolation of the desired
Z,E-dienylboronate 8b (Table 1, entries 6 and 7). In all cases,
the expected retention of alkenyl iodide geometry was observed,
with no isomerisation under these reaction conditions.
Hence, an overall survey of Table 2 shows that the only
really significant factor in boosting Heck selectivity is the
presence of the metal additives, thallium(I) or silver(I) acetate,
and that these should be used (if required), and to achieve
high conversions the reactions should be performed in refluxing
toluene. Also, the preferable base and palladium ligand (Table 2)
are triphenylphosphine and tri-n-butylamine respectively. These
conditions were scaled up and applied to the synthesis of the
desired triene 1 syntheses, via formation of the dienylboronates
8, as shown in Table 1. Completion of the syntheses of trienes
1 required Suzuki–Miyaura couplings of the dienylboronates 8a
and 8b to be performed with the E- and Z-alkenyl iodides 7a and
7b [eqn. (4)], which in turn were prepared as outlined previously
[eqn. (3)] with high geometric purity from the styrylboronate
5. The conditions used were the same as those that had
proved to be successful in our study involving the reactivity
of the vinylboronate ester 3 in Suzuki–Miyaura reactions.8 For
the coupling of 7a and 7b, the choice of base was of vital
importance: the use of ‘hard’ alkoxide and hydroxide bases
led to the elimination of HI from the substrates resulting in
phenylacetylene formation and reduced amounts, if any, of the
desired coupled product. This led to the use of silver(I) oxide as
the base.8,12 This proved to be successful allowing the coupling
reactions [eqn. (4)] to generate the desired trienes 1 with no side-
product formation. These key coupling steps were consequently
performed in the presence of silver(I) oxide, the results of which
are shown in Table 3.
(4)
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 6 7 – 3 1 7 2
3 1 6 9

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or silver is to force halide decomplexation of palladium15 (i.e.
decomplexation of 9 via acetoxy complex 10) in less stabilised
situations, i.e. when coupling medium and electron-rich alkenyl
iodides. Addition of these salts not only results in a less
coordinatively saturated (kinetically more reactive) palladium
complex,16 but also promotes the formation of cationic pal-
ladium complex17 11b via halide–acetate ligand exchange and
acetate decomplexation; a process which is known to have
profound effects on the regiocontrol of Heck reactions with
vinyl ethers.15 Overall, kinetically reactive cationic palladium
complexes 11 produce chemoselective coupling to provide the
Heck coupled products observed.
Table 3 Suzuki–Miyaura coupling reactions of the dienylboronate
esters
Entry
Iodide
Boronate
Product
Yield (%)a
1
2
3
4
7a
7a
7b
7b
8a
8b
8a
8b
1a
1b
1b
1c
67
48
49
64
a Isolated yield after silica gel chromatography.
Overall, the reactions proceeded in good yields and as with the
Suzuki–Miyaura couplings of the boronate 3 the use of silver(I)
oxide allowed coupling with no phenylacetylene formation. The
dienylboronate esters 5 show similar levels of reactivity to the
vinylboronate systems and, importantly, no alkene isomerisation
was observed under the reaction conditions developed. However,
the triene products 1 are susceptible to isomerisation to the all-
E-form 1a, either under heating above the reaction temperature
of 65 ◦C, as reinforced by identical melting points, or even
upon storage at room temperature over a few months which
was observed in the cases of 1b and 1c.
Having demonstrated the overall strategy for efficiently and
stereoselectively producing trienes 1, we are left to consider
exactly why thallium(I) and silver(I) salts are necessary in order
to avoid the unwanted production of Suzuki–Miyaura products
in the approaches to products 8 [see eqn. (2), and Tables 1 and 2].
These results augment our previous work in the area, coupling
aryl halides with vinylboronate esters,2 which does not require
the co-addition of metal salts, except when using heteroaromatic
halides.13 Iodides certainly perform better than bromides, as is
the case with alkenyl halides, with alkenyl bromides proving
unreactive under Heck coupling conditions.6 Electron deficient
iodoalkenes (e.g. iodo acrylate) fail to undergo Heck coupling
at all with hindered vinylboronate esters14 even with the co-
addition of thallium or silver salts, though they react efficiently
to give the Suzuki–Miyaura products. Although further detailed
mechanistic studies are required, we believe that all the current
evidence points in the direction of the need to have a cationic
palladium species in order to drive the Heck coupling pathway
and avoid the formation of Suzuki–Miyaura products, i.e. as
outlined in Scheme 3.
Conclusion
The successful syntheses of these 1,6-diphenyl-1,3,5-hexatriene
model systems using just three key reactions demonstrates the
strength of this strategy in the preparation of polyenes with full
control over the alkene geometries. The ability to control the
iododeboronation reactions to give either E- or Z-iodoalkenes
and the coupling of the alkenylboronates to give either the Heck
and Suzuki–Miyaura products simply through variation of the
reaction conditions has been demonstrated and is the backbone
of the strategy. It is important to note that the order in which
the polyenes are constructed has little effect on the yields and
geometrical purity. This is demonstrated when examining the
preparation of the E,E,Z- and Z,E,E-trienes, the point in the
reaction sequence at which the Z-alkene unit is introduced has
little effect on the end result showing that the sensitive Z-alkene
is stable to the reaction conditions required to perform each of
the key reactions of the strategy.
Further results on the application of this strategy to the
synthesis of natural prodcuts which contain polyene units and
their biological acivity will be reported in due course.
Experimental
General experimental
All IR spectra were recorded on a Perkin-Elmer 298 spec-
trometer employing NaCl plates or KBr discs. All 1H and
13C NMR spectra were recorded on either a Varian Mercury-
400, Bruker Avance-400 or Varian Inova-500 spectrometers. 11
B
NMR spectra were recorded on the Bruker Avance-400 at a
frequency of 128 MHz. Chemical shifts are expressed as parts
per million downfield from the internal standard TMS with all
samples run in CDCl3. Mass spectrometry was performed on
either a Micromass Autospec, Finnigan MAT 95 XP or Finnigan
MAT 900 XLT. Column chromatography was performed
on Davisil Silica gel, 60 mesh. TLC was performed on Polygram
SIL G/UV254 plastic-backed silica gel plates with visualization
achieved using a UV lamp, or by staining with KMnO4. All
glassware was oven dried (130 ◦C) before use and cooled under
a positive pressure of argon. Solvents were dried by distillation
from CaH2 (DCM, Toluene) or sodium-benzophenone ketyl
(THF). All reactions were performed at room temperature unless
otherwise stated. All other materials were purchased directly
from either Aldrich or Lancaster (as was) and used without
further purification, unless stated otherwise.
Warning: All reactions involving thallium salts produce
insoluble residues which are collected by Celite filtration. These
residues should be treated as hazardous waste.
Scheme 3
4,4,6-Trimethyl-2-vinyl-1,3,2-dioxaborolane 3
Thus, use of aryl halide substrates favours the formation of
a cationic palladium intermediate 11a by dissociation of iodide
ion from palladium(II) complex 9, as does the better leaving char-
acteristics of iodide versus bromide. Electron deficient alkenes
favour destabilisation of any cationic palladium species such
as 11a, hence forcing the reaction down the Suzuki–Miyaura
route from complex 9. The major impact of either thallium
Vinylmagnesium bromide 4 (100 cm3 of a 1.0 M solution in
THF, 100 mmol) was added dropwise over 1 hour to a stirred
solution of anhydrous trimethylborate (10.2 cm3, 18 mmol)
in dry THF (100 cm3) at −78 ◦C under argon. The reaction
was left to stir for a further hour before warming to room
temperature and allowing the addition of 20% HCl (44 cm3).
3 1 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 6 7 – 3 1 7 2

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After 10 min, a solution of 2-methyl-2,4-pentanediol (11.34 cm3,
90 mmol) in Et2O (9 cm3) was added and the reaction was
stirred for a further hour. The two phases were separated and
the aqueous phase extracted with Et2O (100 cm3), the combined
organic extracts were washed with saturated aq. NaHCO3 (2 ×
100 cm3) and water (2 × 100 cm3), dried (MgSO4) and the solvent
evaporated to afford the crude product as a yellow oil. Kugelro¨◦hr
distillation yielded 3 (11.3 g, 82%) as a clear oil, bp 50–55 C
(0.46 mm Hg) (lit.18 57–58 ◦C, 22 mm Hg); mmax/cm−1 3064, 2975,
1616, 1419 and 1391; dH (500 MHz) 1.28 (3H, d, J = 6.0 Hz,
CHMe), 1.31 (6H, s, CMe2), 1.52 (1H, t, J 12.0, CHH), 1.80
(1H, dd, J 14.0 and 3.0, CHH), 4.23 (1H, m, CHMe), 5.82
(2H, m, olefinic) and 6.05 (1H, dd, J 19.0 and 5.0, olefinic); dC
(125 MHz) 23.4 (CHMe), 28.3 (CMe2), 31.4 (CMe2), 46.1 (CH2),
65.0 (CHMe), 71.0 (CMe2), 134.1 (olefinic); dB (128 MHz) 25.7;
m/z (EI) 154 (M+), 139, 59 (100) and 43; (found: M+, 154.1156;
C8H15O2B+ requires 154.1160).
silica gel chromatography (9 : 1, petroleum ether–Et2O as eluant)
provided 7b (1.4 g, 95%) as a yellow oil. Characterisation data
were consistent with the literature.21
4,4,6-Trimethyl-2-(4-phenylbuta-1E,3E-dienyl)-
1,3,2-dioxaborinane 8a
To a dried Schlenk-like tube under a positive pressure of
argon was added Pd(OAc)2 (9 mg, 0.04 mmol), PPh3 (31 mg,
0.12 mmol) and AgOAc (0.16 g, 0.96 mmol). Syringe addition of
toluene (5 cm3), iodide 7a (0.18 g, 0.80 mmol) and vinylboronate
3 (0.15 g, 0.96 mmol) was followed by degassing using the freeze–
◦
pump–thaw method (3×) before heating to 110 C. After 24 h
the reaction was cooled and diluted with Et2O (40 cm3) before
passing through Celite and washing with 10% HCl (20 cm3) and
brine (20 cm3). Drying (MgSO4) and solvent removal yielded
the crude product as a brown oil. Purification by silica gel
chromatography (95 : 5, hexane–Et2O) afforded 8a (0.11 g, 55%)
as a yellow oil; mmax/cm−1 3058, 3023, 2973, 2934, 1622, 1602,
1447, 1417, 1391, 1301 and 1249; dH (500 MHz) 1.31–1.34 (9H,
m, 3 × Me), 1.55 (1H, t, J = 13.0 Hz, boronate CHH), 1.82
(1H, dd, J 14.0 and 3.0, boronate CHH), 4.23–4.30 (1H, m, O–
4,4,6-Trimethyl-2-styryl-1,3,2-dioxaborinane 5
Dry toluene (10 cm3) was added to a Schlenk-like tube with
stirring under a positive pressure of argon containing Pd(OAc)2
(9 mg, 0.04 mmol), PPh3 (31 mg, 0.12 mmol) and AgOAc
(0.16 g, 0.96 mmol) forming a suspension. Tri-n-butylamine
(0.23 cm3, 0.96 mmol), iodobenzene 2 (0.09 cm3, 0.8 mmol) and
vinylboronate 3 (0.15 g, 0.96 mmol) were added and the solution
was degassed using the freeze–pump–thaw method (3×), before
heating to 110 ◦C. After 24 h, the reaction mixture was diluted
with Et2O (40 cm3) and passed through Celite before washing
with 10% HCl (20 cm3), water (20 cm3) and brine (20 cm3).
Drying (MgSO4) and solvent removal provided the crude
product as a brown oil. Kugel◦ro¨hr distillation provided 5 (0.16 g,
88%) as a clear oil, bp 95–100 C (0.38 mm Hg) (lit.19 101–104 ◦C,
0.2 mm Hg); mmax/cm−1 3023, 2973, 1624, 1576 and 1494; dH
(500 MHz) 1.33 (3H, d, J = 6.0 Hz, CHMe), 1.35 (6H, d, J 3.0,
CMe2), 1.57 (1H, t, J 12.0, CHH), 1.83 (1H, dd, J 14.0 and 3.0,
CHH), 4.29 (1H, m, CHMe), 6.12 (1H, d, J 18.5, olefinic), 7.31
(4H, m, 3Ar–H and 1 olefinic) and 7.49 (2H, d, J 8.0, Ar–H); dC
(125 MHz) 23.4 (CHMe), 28.4 (CMe2), 31.5 (CMe2), 46.2 (CH2),
65.1 (CHMe), 71.2 (CMe2), 127.2 (Ar), 128.5 (Ar), 128.7 (Ar),
138.2 (Ar) and 146.7 (olefinic); dB (128 MHz) 26.9; m/z (EI)
230 (M+), 215, 130 (100), 91, 77 and 51; (found: M+, 230.1478;
C14H19O2B+ requires 230.1482).
=
=
CHMe–), 5.64 (1H, d, J 17.0, Ph–CH CH–CH CHB), 6.69
(1H, d, J 15.5, Ph–CH CH–CH CHB), 6.85 (1H, dd, J 15.5
=
=
=
=
and 10.5, Ph–CH CH–CH CHB, 7.11 (1H, dd, J 17.5 and
=
=
10.5, Ph–CH CH–CH CHB), 7.25 (1H, t, J 7.5, Ar–H), 7.33
(2H, t, J 7.5, Ar–H) and 7.44 (2H, d, J 7.5, Ar–H); dC (126 MHz)
23.4 (Me), 28.4 (Me), 31.5 (Me), 46.2 (boronate CHH), 65.0 (O–
CHMe–), 71.1 (O–CMe2–), 126.9 (Ar), 128.1 (Ar), 128.8 (Ar),
131.3 (olefinic), 135.0 (olefinic), 137.4 (Ar) and 147.1 (olefinic);
dB (160 MHz) 26.0; m/z (EI) 256 (M+), 241, 185, 156, 128, 84,
77, 69, 55 and 43 (100); (ES+ found: MH+ 257.1708; C16H22O2B+
requires 257.1707).
4,4,6-Trimethyl-2-(4-phenylbuta-1E,3Z-dienyl)-
1,3,2-dioxaborinane 8b
To a dried Schlenk-like tube under a positive pressure of argon
was added Pd(OAc)2 (74.1 mg, 0.33 mmol), PPh3 (260 mg,
0.99 mmol) and AgOAc (1.31 g, 1.82 mmol). Syringe addition of
toluene (10 cm3), iodide 7b (1.5 g, 6.52 mmol) and vinylboronate
3 (1.20 g, 7.82 mmol) was followed by degassing using the freeze–
◦
pump–thaw method (3×) before heating to 110 C. After 24 h
the reaction was cooled and diluted with EtOAc (50 cm3) before
passing through Celite and washing with 10% HCl (50 cm3) and
brine (50 cm3). Drying (MgSO4) and solvent removal yielded
the crude product as a brown oil. Purification by silica gel
chromatography (98 : 2, hexane–Et2O) afforded 8b (0.98 g, 58%)
as a thick orange oil; mmax/cm−1 3057, 3023, 2973, 2934, 1623,
1599, 1591, 1492, 1447, 1408, 1390, 1369 and 1305; dH (500 MHz)
1.27–1.37 (9H, m, 3 × Me), 1.52 (1H, dd, J = 13.5 and
12.0 Hz, boronate CHH), 1.80 (1H, dd, J 14.0 and 3.0, boronate
CHH), 4.20–4.27 (1H, m, boronate OCHMe), 5.69 (1H, d, J
E-Styryl iodide 7a
To a stirred solution of boronate 5◦(2.0 g, 8.70 mmol) in dry
THF (25 cm3) under argon at −78 C in the absence of light,
was added dropwise NaOMe (20.9 cm3 of a 0.5 M solution in
MeOH, 10.44 mmol). ICl (10.4 cm3 of a 1.0 M solution in DCM,
10.4 mmol) was added over 5 min and the reaction was allowed
to warm to room temperature. After 2 h, the reaction was
diluted with Et2O (60 cm3) before washing with 5% aq. Na2S2O5
(70 cm3), water (70 cm3) and brine (70 cm3) before drying
(MgSO4) and solvent removal to afford the crude product.
Purification by silica gel chromatography (9 : 1, petroleum
ether–Et2O as eluant) provided 7a (1.7 g, 86%) as a yellow oil.
Characterisation data were consistent with the literature.20
=
=
=
17.0, CHB), 6.32 (1H, t, J 11.5, PhCH CH–CH CHB),
6.51 (1H, d, J 11.5, PhCH CH–CH CHB), 7.30–7.38 (5H,
=
=
=
m, Ar–H) and 7.48 (1H, dd, J 17.5 and 12.0, PhCH CH–
CH CHB); dC (100 MHz) 23.1, 28.1 and 31.2 (each Me), 46.0
(BCH2), 65.0 (OCHMe), 70.8 (CMe2), 127.1 (Ar), 128.2 (Ar),
129.2 (Ar), 131.7 (olefinic), 132.5 (olefinic), 137.5 (Ar), 142.5
(olefinic); dB (128 MHz) 25.7; m/z (EI) 256 (M+), 241, 185, 156,
129, 128 (100), 115, 91, 77, 69, 55 and 43; (ES+ found: MH+
257.1705; C16H22O2B+ requires 257.1707).
=
Z-Styryl iodide 7b
To a stirred solution of boronate 5 (1.5 g, 6.52 mmol) in
dry DCM (20 cm3) under argon, in the absence of light at
−78 ◦C was added ICl (7.83 cm3 of a 1.0 M solution in DCM,
7.83 mmol) dropwise over a period of 5 min. After stirring
for 4 h, NaOMe (15.65 cm3 of a 0.5 M solution in MeOH,
7.83 mol) was added and the reaction left for a further 30 min
to warm to room temperature. The reaction mixture was diluted
with Et2O (60 cm3), washed with 5% aq. Na2S2O5 (50 cm3),
water (50 cm3) and brine (50 cm3) before drying (MgSO4) and
solvent removal to afford the crude product. Purification by
1,6-Diphenyl-1,3,5-hexatrienes 1a–c
Pd(PPh3)4 (0.36 lmol, 42 mg) and Ag2O (1.45 mmol, 0.34 g)
was dissolved with stirring under argon in freshly distilled THF
(8 cm3). To this was added the iodide 7a or 7b (0.72 mmol,
0.17 g) and the boronate 8a or 8b (0.72 mmol, 0.19 g). The
reaction was then heated at reflux for 24 h before cooling
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 6 7 – 3 1 7 2
3 1 7 1

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and diluting with diethyl ether followed by washing through
Celite. Solvent removal yielded the crude product which could
be purified by silica gel chromatography (96 : 4, hexane–Et2O).
The characterisations for all products 1a–c are consistent with
literature values.22
7 A. P. Lightfoot, S. J. R. Twiddle and A. Whiting, Tetrahedron Lett.,
2004, 45, 8557.
8 A. P. Lightfoot, S. J. R. Twiddle and A. Whiting, Synlett., 2005, 3,
529.
9 R. Grigg, V. Loganathan, S. Sukirthalingam and V. Sridharan,
Tetrahedron Lett., 1990, 31, 6573; R. Grigg and V. Sridharan,
Tetrahedron Lett., 1993, 34, 7471.
10 T. Jeffery, J. Chem. Soc., Chem. Commun., 1991, 324.
11 T. Jeffery, Tetrahedron Lett., 1992, 33, 1989.
12 J. Uenishi, J. Beau, R. W. Armstrong and Y. Kishi, J. Am. Chem.
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13 S. K. Stewart and A. Whiting, J. Organomet. Chem., 1994, 482, 293.
14 G. Maw, C. Thirsk and A. Whiting, Tetrahedron Lett., 2001, 42,
8387.
Acknowledgements
We are gratefull to the EPSRC for a DTA award to S. J. R. T., to
GlaxoSmithKline Pharmaceuticals for a CASE award, and the
EPSRC mass spectrometry service at the Univeristy of Wales,
Swansea.
15 W. Cabri, I. Candiani, A. Bedeschi and S. Penco, J. Org. Chem., 1992,
57, 1481.
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3 1 7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 6 7 – 3 1 7 2