The effect of ortho-substitution on the efficacy of biphenyls in mediating electron transfer from lithium

Article abstract of DOI:10.1016/j.tet.2009.04.057

A systematic study into the effect of increasing ortho-substitution of a range of biphenyls with respect to their ability to mediate electron transfer from lithium metal is described. A synthetic investigation has demonstrated the requirements for effecti

Full text of DOI:10.1016/j.tet.2009.04.057

Tetrahedron 65 (2009) 5377–5384
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The effect of ortho-substitution on the efficacy of biphenyls
in mediating electron transfer from lithium
,
a
b
b,
*
Timothy J. Donohoe a , Neil M. Kershaw , Ronan Baron , Richard G. Compton
*
a Department of Chemistry, Chemistry Research Laboratory, Oxford University, Mansfield Road, Oxford OX1 3TA, UK
b Department of Chemistry, Physical and Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford OX1 3QZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A systematic study into the effect of increasing ortho-substitution of a range of biphenyls with respect to
their ability to mediate electron transfer from lithium metal is described. A synthetic investigation has
demonstrated the requirements for effective mediation. The electrochemical reduction of the mediators
and of the two substrates was studied in THF, 0.1 M TBAP, at platinum microelectrodes both at room
temperature and at low temperature. The formal potentials, E0f extracted from the cyclic voltammograms,
are in agreement with results of the synthetic study and computational calculations also provide
a correlation.
Received 17 February 2009
Received in revised form 1 April 2009
Accepted 17 April 2009
Available online 24 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
tertiary alkyl chlorides4 and heterocycles5 have been reduced
employing DBB as the mediator; the reductive ring opening of
Arene-mediated homogeneous electron transfer for the re-
ductive cleavage of functional groups is widely employed in syn-
thetic organic chemistry and is frequently preferred to direct
reduction by an alkali metal. Indeed, we have recently explained
why biaryl mediated electron transfer from lithium metal is faster
than direct reduction in terms of the relative activation energies of
the different steps.1 Typically, lithium metal is reacted with an
arene, which may be present in a sub-stoichiometric quantity, and
substrate, with the aromatic radical anion being generated in situ
(Scheme 1).
In particular, 4,40-di-tert-butyl-1,10-biphenyl (DBB) has attracted
much interest as being one of the most effective mediators for re-
ductive lithiation reactions. Over the past few decades many ex-
amples of the use of this mediator have been reported. For example,
a range of functional groups, which include thioethers,2 acetals,3
oxygen-containing benzo-fused heterocycles,6 structural modifi-
cation of carbohydrates7 and reductive lithiation of
a-amino ni-
triles8 have also been reported. In addition, we have investigated
a number of applications of DBB-mediated reduction including the
total syntheses of (þ)-hyacinthacine A7,9 and several other pyrro-
lizidine alkaloids.10 The formation of enantiopure pyrroline build-
ing blocks for natural product synthesis11 and in the partial
reduction of heterocycles12 has also been achieved.
As part of our continuing interest in arene-mediated processes
we recently reported a study into why some mediators are more
effective reducing agents than others.13 It was concluded that more
reducing radical anions were superior mediators, demonstrated by
a comparison of formal potentials and a synthetic study. Herein we
describe the results of an investigation to systematically probe the
effect of ortho-substitution on the ability of a biphenyl to act as an
efficient mediator. Detailed synthetic studies and electrochemical
measurements of the mediators and substrates are discussed. A
computational study is also described so as to provide a compre-
hensive picture of the influence of ortho-substitution and biaryl
structure on the ability of an arene to participate in electron
transfer from lithium metal.
+
Li
+
Li
reductive cleavage
of the R–X bond
R–X
R–X
+
+
2. Results and discussion
2.1. Synthetic study
Scheme 1.
Considering the prototype biphenyl electron transfer media-
* Corresponding authors.
E-mail address: timothy.donohoe@chem.ox.ac.uk (T.J. Donohoe).
tor, DBB 1, it was recognised that all analogues would benefit
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.057

5378
T.J. Donohoe et al. / Tetrahedron 65 (2009) 5377–5384
SPh / I
mediators
Me
MeO
Me
Me
Me
OMe
8 / 9
i)
mediator
Li
mediator
1-7
MeO
OMe
12
Me
Me
Me
Scheme 4. Reagents and conditions: (i) mediator (3 equiv), Li (18 equiv), THF, 0 ꢁC, 3 h
and then 8/9, –78 ꢁC, 30 min.
tBu
Me
2
Me
3
Me
4
Both DBB 1 and 4,40-dimethylbiphenyl 2 are commercially
available. Biaryls 4 and 7 were synthesised by oxidative dimerisa-
tion of the appropriate Grignard reagent14 and 3, 5 and 6 were
prepared via Suzuki coupling15 (Scheme 2).
Me
Me
Me
tBu
Substrates 8 and 9 were synthesised from a common precursor
11 in two steps from the commercially available alcohol 10. Mesy-
lation occurred in excellent yield and displacement with thio-
phenolate generated 8. Similarly, treatment under Finkelstein
conditions furnished iodide 9 (Scheme 3).
At the outset, it was anticipated that, along with DBB 1, 4,40-
biphenyl 2 would act as a competent mediator. In addition it was
recognised that bimesityl 7 was unlikely to mediate electron
transfer; the four ortho-substituents would render the phenyl rings
orthogonal to one another, preventing any delocalisation. Three key
questions were considered:
Me
Me
Me
Me Me
Me Me
Me
Me
DBB 1
Me
5
Me
6
Me
7
substrates
SPh
I
MeO
MeO
OMe
OMe
9
ꢀ At what point would the increased steric congestion at the
ortho position lead to a cessation of mediation?
8
ꢀ Would there be a gradual decline in mediator ability or would
Figure 1. List of proposed mediators and substrates.
there be an ‘all-or-nothing’ response?
ꢀ Would analytical techniques such as electrochemistry and
molecular modelling be able to rationalise, and ultimately
predict, the outcome of synthetic studies?
Br
Br
Me
Me
Me
Each potential mediator 2–7 and DBB 1 were treated with
lithium metal (6 equiv) followed by either phenyl sulfide 8 or io-
dide 9. The yield of the corresponding reduced product 12 and/or
recovered starting material was then obtained. In addition, a key
control experiment was carried out in the absence of any mediator to
ascertain whether any direct reduction of 8 or 9 by lithium metal
was taking place (Scheme 4).
Me
Me
i)
aryl bromide
4 (70%) or 7 (45%)
Me
Me
I
Br
Me
The results of this study are summarised in Table 1. Most im-
portantly, it was demonstrated that direct reduction of the sub-
strates with lithium was not a competing process (Table 1, entry 1).
Thus, the yields obtained with 1–7 would be a true reflection of
their efficacy as mediators of electron transfer. Both 2 and 3 acted as
competent mediators, giving essentially identical yields of 12 to
DBB 1 (Table 1, entries 2–7). In stark contrast, none of 4–7 furnished
any reduction product (Table 1, entries 8–15), with only starting
material being recovered in each case. In all examples the mediator
could be recovered in essentially quantitative yield, raising the
possibility of developing a catalytic system.16
Me
Me
B(OH)2
Me
B(OH)2
Me
Me
boronic acid
+
aryl halide
ii)
3 (84%) or 5 (90%) or 6 (80%)
Scheme 2. Reagents and conditions: (i) aryl bromide (1 equiv), Mg (5 equiv), THF, 0 ꢁ
to reflux, 3 h and then FeCl3 (6 mol %), BIPY (12 mol %), O2, 30 min; (ii) boronic acid
(3 equiv), aryl halide (1 equiv), Pd(OAc)2 (0.4 equiv), P(o-tol)3 (0.8 equiv),
Ba(OH)2$8H2O (3.1 equiv), DME/H2O (6.6:1), reflux, 16 h.
C
Clearly, more than a single ortho-substituent was not tolerated
with respect to mediator ability. The fact that the potential me-
diators gave either comparable results to DBB 1 or no reduction at
all was also interesting. In order to probe these empirical obser-
vations further, the electrochemical properties of 1–7 and 8,9
were investigated using both ambient and cryoelectrochemical
analysis.
from substitution at the positions para to the biaryl bond in
order to suppress radical dimerisation during reduction. Thus,
a range of biphenyls with increasing substitution at the position
ortho to the biaryl bond was identified 2–7. Two substrates,
which are efficiently reduced by DBB were utilised in this study
8 and 9 (Fig. 1).
OH
OMs
SPh / I
i)
ii) or iii)
quant.
MeO
MeO
MeO
OMe
10
OMe
11
OMe
8 / 9
Scheme 3. Reagents and conditions: (i) MsCl, Et3N, DCM, 0 ꢁC to rt, quant; (ii) PhSH, NaOMe, THF/MeOH (5:1), rt, 92%; (iii) NaI, acetone, rt, 96%.

T.J. Donohoe et al. / Tetrahedron 65 (2009) 5377–5384
5379
Table 1
similar conditions to arene-mediated electron transfer from lith-
ium reactions in THF at low temperature. Electrochemical studies
allow access to many physical parameters that are useful in un-
derstanding how a molecule will react. Using THF as the electrolyte
solvent is particularly interesting in regard of the large cathodic
potential window available for electrochemical measure-
ments.1,13,17–21 In contrast to macroelectrodes, microelectrodes al-
low the acquisition of voltammograms that are negligibly affected
by the high resistivity of the medium.21,22 Moreover, by working at
low temperature both the electron transfer kinetics and reaction
kinetics are attenuated thus allowing more insight into the mech-
anisms that are involved.17,18 These electrochemical studies show,
in this case, an agreement between the solution electron transfer
results and intrinsic physical parameters.
Yields for the sequence depicted in Scheme 2
Entry
Mediator
Substrate
Yield of 12 (%)
1
2
3
4
5
6
7
8
d
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
8
9
8
9
8
9
8
9
8
9
8
9
0a
95
97
93
93
93
94
0a
0a
0a
0a
0a
0a
0a
0a
9
10
11
12
13
14
15
2.2.1. Electrochemical studies of the mediators at room temperature
The electrochemical reduction of the mediators was studied in
THF, 0.1 M tetrabutylammonium perchlorate (TBAP), at platinum
microelectrodes. The biaryl/biaryl radical anions were found to be
chemically reversible for compounds 1–3 while for compounds 4–7
no peak or wave could be observed within the potential window
defined by the solvent electrolysis. No following or preceding
a
Quantitative recovery of starting material.
2.2. Electrochemical study
Over the past few years, our laboratories have focused on the
development of electrochemical studies that are undertaken under
Figure 2. Experimental (solid line) and theoretical (dotted line) voltammograms for the reduction of 1, 2 and 3 in THF, 0.1 M TBAP, obtained at 293 K at a 10 mm diameter Pt disc
microelectrode at various scan rates. (A), (B) and (C) correspond to voltammograms obtained for compound 1, 4.98 mM, respectively, at 0.01, 0.1 and 20 V sꢂ1. (D), (E) and (F)
correspond to voltammograms obtained for compound 2, 7.5 mM, respectively, at 0.01, 0.1 and 20 V sꢂ1. (G), (H) and (I) correspond to voltammograms obtained for compound 3,
6.38 mM, respectively, at 0.01, 0.1 and 20 V sꢂ1
.

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T.J. Donohoe et al. / Tetrahedron 65 (2009) 5377–5384
Table 2
the modelled voltammograms that were obtained for 1, 2 and 3. It is
clear that an acceptable fitting of the experimental curves can be
obtained over a wide range of scan rates. The values of the physical
parameters extracted are reported in Table 2.
Values of the diffusion coefficient, D, of the heterogeneous kinetic constant, k0, and
of the formal potential, E0f , for the biphenyls at 293 K, obtained from the modelling of
the cyclic voltammograms obtained at a 10
0.1 M TBAP
mm disc platinum microelectrode in THF,
The difference between DA and DB shows that the biphenyl
radical anion that is generated diffuses much more slowly than the
biphenyl molecule. We explain this phenomenon by the occurrence
of an ion pairing between the biphenyl parent radical anion and the
tert-butylammonium cation used as an electrolyte ion in the solu-
tion.21 It can be also observed that compounds 1, 2 and 3 have very
similar values of the formal potential, E0f , which relates to their
similar thermodynamic capacity in accepting an electron and
which is in agreement with the synthetic studies.
Compound
DA/10ꢂ5
DB/10ꢂ5
k0/cm sꢂ1
E0f /V
a
cm2 sꢂ1
cm2 sꢂ1
1a
2
1.15ꢃ0.1
1.75ꢃ0.1
1.26ꢃ0.1
0.46ꢃ0.05
0.30ꢃ0.05
0.25ꢃ0.05
0.030ꢃ0.001
0.016ꢃ0.001
0.018ꢃ0.001
ꢂ3.27ꢃ0.03
ꢂ3.22ꢃ0.03
ꢂ3.25ꢃ0.03
0.5ꢃ0.05
0.5ꢃ0.05
0.5ꢃ0.05
3
a
Values concerning compound 1 are reported from Ref. 1.
chemical reaction was observed for any of the mediators. The cyclic
voltammograms were modelled allowing the determination of the
diffusion coefficient of the biaryl, DA, of the diffusion coefficient of
the biaryl radical anion, DB, of the formal potential, E0f , of the
transfer coefficient, a, and of the standard heterogeneous kinetic
constant for the electron transfer, k0 within the Butler–Volner
formalism.
In practice the three voltammograms obtained at 0.01, 0.1 and
20 V sꢂ1 were fitted for 2 and 3. Similar studies had been performed
previously for compound 1.1 Figure 2 shows the experimental and
2.2.2. Electrochemical studies of the mediators at low temperature
(cryoelectrochemistry)
In order to accurately model conditions that are used for syn-
thetic solution electron transfer studies, the electrochemical stud-
ies were performed at low temperature, 192 K (Fig. 3).
Again, well defined electrochemical waves and peaks could be
observed for compounds 1–3. However, no peak or wave could
be properly observed for potential mediators 4–7 although the
beginning of a signal could be observed just before the limit of the
Figure 3. Experimental (solid line) and theoretical (dotted line) voltammograms for the reduction of 1, 2 and 3 in THF, 0.1 M TBAP, obtained at 192 K at a 10 mm diameter Pt disc
microelectrode at various scan rates. (A), (B) and (C) correspond to voltammograms obtained for compound 1, 4.98 mM, respectively, at 0.01, 0.1 and 20 V sꢂ1. (D), (E) and (F)
correspond to voltammograms obtained for compound 2, 7.5 mM, respectively, at 0.01, 0.1 and 20 V sꢂ1. (G), (H) and (I) correspond to voltammograms obtained for compound 3,
6.38 mM, respectively, at 0.01, 0.1 and 20 V sꢂ1
.

T.J. Donohoe et al. / Tetrahedron 65 (2009) 5377–5384
5381
Table 3
Me
Me
Values of the diffusion coefficient, D, of the heterogeneous kinetic constant, k0, and
of the formal potential, E0f , for the mediators at 192 K, obtained from the modelling
of the cyclic voltammograms obtained at a 10
THF, 0.1 M TBAP
Me
Me
θ
mm disc platinum microelectrode in
Figure 5. Dihedral angle, q.
Compound
DA/10ꢂ5
DB/10ꢂ5
k0/cm sꢂ1
E0f /V
a
cm2 sꢂ1
cm2 sꢂ1
1a
2
0.27ꢃ0.1
0.58ꢃ0.1
0.39ꢃ0.1
0.03ꢃ0.01
0.07ꢃ0.01
0.04ꢃ0.01
0.005ꢃ0.001
0.005ꢃ0.001
0.003ꢃ0.001
ꢂ3.20ꢃ0.03
ꢂ3.18ꢃ0.03
ꢂ3.21ꢃ0.03
0.5ꢃ0.05
0.5ꢃ0.05
0.5ꢃ0.05
more negative than the formal potential of compounds 1, 2 and 3.
The reduction of compound 9 starts at ꢂ2.7 V/(Fc/Fcþ PF6ꢂ) and
exhibits a strong absorption onto the electrode upon reduction
rendering the voltammogram poorly resolved. It can be concluded
from these data that the radical anions corresponding to com-
pounds 1, 2 and 3 are potentially good electron donors for sub-
strates 8 and 9 for which the direct reduction is slow (kinetically
controlled).
These electrochemical studies confirm that mediators 1–3 are
well suited both for the heterogeneous electron transfer from
lithium and for the homogeneous electron transfer to the chosen
substrates. In agreement with the solution electron transfer ex-
periments, it was also found that the formal potentials, E0f , of
compounds 4–7 are too negative to allow any of the heterogeneous
and homogeneous electron transfers cited above.
3
a
Values concerning compound 1 are reported from Ref. 1.
potential window. The values of the physical parameters extracted
for the modelling of the voltammograms for compounds 1–3 are
reported in Table 3.
As far as compounds 4–7 are concerned, it could be concluded
from the experimental curves, that the values of their formal po-
tential, E0f , are more negative than ꢂ3.6 V/(Fc/Fcþ PFꢂ6 ). As far as the
reduction of Liþ is concerned values of E0f that were obtained in
previous studies were ꢂ3.48 and ꢂ3.43 V/(Fc/Fcþ PF6ꢂ), respectively,
at 295 and 243 K.23 It is possible to estimate the value of E0f at 192 K
to be ꢂ3.38 V/(Fc/Fcþ PF6ꢂ) by extrapolation. It is then clear that the
‘reducing power’ of lithium is sufficient to proceed to an electron
exchange with compounds 1, 2 and 3 but not with 4–7, presumably
due to their being little conjugation between the two rings.
2.3. Computational study
Having successfully correlated the synthetic observations with
electrochemical analysis of both the potential mediators and sub-
strates, a computational study was undertaken. It seemed likely
2.2.3. Electrochemical studies of the substrates
that the dihedral angle, q, between the two rings would provide
useful information regarding the ability of a potential mediator to
transfer an electron from lithium metal (Fig. 5).
The cyclic voltammetry of compound 8 shows that, while the
curves obtained are not well resolved at 298 K (because its re-
duction takes place at close proximity to the limit of the potential
window), well defined voltammograms are obtained at 192 K
(Fig. 4).
It has been shown that the conformation of substituted bi-
phenyls will be determined predominately by two factors:24
This illustrates the fact, as previously described, that a wider
potential window is obtained when working at low temperature
and consequently certain substrates that could not be studied at
room temperature can be studied when using cryoelectrochemical
techniques. Compound 8 is irreversibly reduced and its reduction
starts at a potential of ꢂ3.5 V/(Fc/Fcþ PF6ꢂ) at 192 K. Its reduction is
believed to involve an irreversible, dissociative, two electron
transfer and its thermodynamic formal potential will be lower
than the kinetically controlled potential at which the reduction can
actually be observed and hence the formal potential of 8 will be
ꢀ
p-delocalisation between both rings;
ꢀ coulombic repulsion between the ortho-substituents.
Conformational analyses of biphenyl have been the subject of
several investigations; in the gas phase it has been demonstrated
that the dihedral angle,
q
, between the two rings is 42ꢁ,25 and in
solution a value of
q
of 32ꢁ has been found.26 However, the crystal
structure of biphenyl indicates that the molecule is completely
planar.27 In contrast, DBB 1 has been shown to have essentially the
same conformation in both the gas and crystalline phase, with
a value of q
of about 40ꢁ.28 This is presumably due to the steric bulk
of the tert-butyl groups disrupting crystal packing to some extent,
preventing the molecule becoming planar. Thus, it seems likely that
the planar conformation of biphenyl in the crystalline phase is due
to packing effects.
Although several investigations into the effect of ortho-sub-
stitution on the conformation of biphenyls have been detailed,29
a systematic study of this kind has yet to be reported. Minimum
energy calculations, to determine the value of
q for DBB 1 and bi-
phenyls 2–7, were performed using the Hartree-Fock 6-31G
*
Table 4
Calculated dihedral angle (
q)
Entry
Biphenyl
Dihedral
angle,
q
(ꢁ)
1
2
3
4
5
6
7
1
2
3
4
5
6
7
40
40
53
88
89
90
90
Figure 4. Voltammograms corresponding to the reduction of compound 8, 5.83 mM,
in THF, 0.1 M TBAP, obtained at a 10
curve (a) was recorded at 298 K and curve (b) at 192 K.
m ;
m diameter Pt disc microelectrode at 20 V sꢂ1

5382
T.J. Donohoe et al. / Tetrahedron 65 (2009) 5377–5384
method as implemented in Spartan’08. The geometry was opti-
mised at 10ꢁ intervals, including all the degrees of freedom except
via cannula to a flame-dried Schlenk tube containing FeCl3
(6 mol %) and 2,20-bipyridine (12 mol %) in THF (5 mL/mmol). The
vessel was evacuated and back filled with oxygen three times and
the reaction mixture was stirred at room temperature for 30 min.
The reaction mixture was diluted with ethyl acetate (10 mL/mmol)
and adsorbed onto SiO2. Purification by flash column chromatog-
raphy (SiO2; petroleum ether) gave the desired compounds in be-
tween 80 and 90% yield. 1H and 13C NMR spectra of 4 and 7 were in
accord with literature values.32,33
the dihedral angle
q. The resulting rotational potential curves were
analysed to determine the value of
q
corresponding to the mini-
mum energy. The results are summarised in Table 4.
Calculated dihedral angles of ca. 90ꢁ for 4–7 correlate to those
biphenyls that were not competent mediators (Table 2, entries 4–
7). The calculations for
were in accordance with literature values28 and 3, with one ortho-
substituent had a value of
of 53ꢁ (Table 2, entries 1–3). It should be
q of both DBB 1 and its dimethyl congener 2
q
noted, however, that these calculations were performed on the
neutral species and the conformation of the corresponding radical
anion may not correlate.30 Nevertheless, it seems likely that these
values offer a qualitative analysis of the effect of ortho-substitution
on the ability of biphenyls to act as mediators of electron transfer;
a calculated dihedral angles that approaches 90ꢁ is a good indicator
that the biphenyl will not be able to transfer an electron easily from
lithium metal surface. This implies that efficient conjugation be-
tween the two rings is necessary for a biphenyl to be an effective
mediator of electron transfer.
4.1.2. Suzuki coupling
A solution of the appropriate boronic acid (3 equiv), aryl halide
(1 equiv), Pd(OAc)2 (0.4 equiv), P(o-tol)3 (0.8 equiv) and
Ba(OH)2$8H2O (3.1 equiv) in a mixture of dimethoxyethane and
water (6.6:1; 10 mL/mmol) was heated at 50 ꢁC for 16 h. The re-
action mixture was washed with saturated aqueous NH4Cl (10 mL/
mmol) and then filtered through a pad of Celite, washing with
diethyl ether. The filtrate was concentrated in vacuo and purified by
flash column chromatography (SiO2; petroleum ether) to give the
desired compounds in between 40 and 70% yield. 1H and 13C NMR
spectra of 3, 5 and 6 were in accord with literature values.34–36
3. Conclusions
4.1.3. Syntheses of substrates 8 and 9
DBB 1 and biphenyls 2 and 3 are effective mediators of electron
transfer from lithium metal, with little difference in performance in
the synthetic study. Electrochemical measurements are in agree-
ment with this observation and indicate that all have very similar
formal potentials, E0f . Similarly, biphenyls 4–7 have electrochemical
potentials, which should render them ineffective mediatorsda
result borne out in the synthetic investigation. Considering the
dihedral angle, q, of 1–7 as an indicator of mediator competency
has also been shown to be in general agreement with our
observations.
4.1.3.1. Synthesis of mesylate 11. Methanesulfonyl chloride (10.1 mL,
130 mmol) was added dropwise to a solution of triethylamine
(21 mL, 153 mmol) and 3-(30,40-dimethoxyphenyl)-1-propanol (10 g,
52 mmol) in CH2Cl2 (170 mL) at 0 ꢁC. The resulting yellow suspen-
sion was stirred at room temperature for 2 h and then quenched by
addition of a saturated aqueous solution of NaHCO3 (100 mL). The
resulting biphasic mixture was separated and the aqueous layer was
extracted with CH2Cl2 (3ꢄ100 mL). The combined organic extracts
were dried over MgSO4 and concentrated in vacuo to yield mesylate
11 (14 g, 100%), which was sufficiently pure to be used directly.
4. Experimental
4.1.3.2. Synthesis of 8. Thiophenol (8.5 mL, 83.0 mmol) was added
to a solution of NaOCH3 (4.5 g, 83.0 mmol) in THF/CH3OH (5:1;
25 mL) at room temperature. The reaction was stirred at room
temperature for 30 min and then a solution of mesylate 11 (3.5 g,
12.8 mmol) in THF/CH3OH (5:1; 11 mL) was added. The reaction
mixture was stirred at room temperature for 16 h and then
quenched by addition of a saturated aqueous solution of NH4Cl and
the product was extracted with diethyl ether (3ꢄ30 mL). The
combined organic extracts were dried over MgSO4 and concen-
trated in vacuo. Purification by flash column chromatography (SiO2;
petroleum ether to petroleum ether/diethyl ether; 9:1) yielded 8
(3.4 g, 92%) as a colourless solid. Mp 75–78 ꢁC; nmax (KBr disc)/cmꢂ1
2997, 2934, 2833, 1589, 1515, 1480, 1463, 1264, 1236, 1156, 1029; dH
(400 MHz; CDCl3) 7.34–7.26 (4H, m, 4ꢄArH), 7.20–7.16 (1H, m,
1ꢄArH), 6.74–6.71 (2H, m, 2ꢄArH), 3.87 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 2.93 (2H, t, J 7.2, C(30)H2), 2.73 (2H, t, J 7.2, C(10)H2), 1.97 (2H,
wquintet, J 7.2, C(10)H2); dC (100 MHz; CDCl3) 148.7, 147.1, 136.5,
133.7, 128.9, 128.7, 125.7, 120.2, 111.6, 111.0, 55.8, 55.7, 34.1, 32.6,
30.6; m/z (ESI) 311 ([MþNa]þ, 100%); HRMS (ESI) C17H20O2SNa
([MþNa]þ) requires 311.1082, found 311.1074.
4.1. General procedures and methods
Unless otherwise specified, all reactions were carried out under
an atmosphere of argon. Tetrahydrofuran (THF) was purified by
filtration through two columns of activated alumina (grade DD-2)
as supplied by Alcoa, employing the method of Grubbs.31 Aceto-
nitrile, dichloromethane and toluene were dried by passing
through activated alumina columns (activated basic aluminium
oxide, Brockmann I, standard grade, w150 mesh, 58 Å) as supplied
by Aldrich. Methanol was purified by distillation over calcium hy-
dride, and stored over molecular sieves (4 Å). Other solvents were
used as supplied without further purification. Reactions were
monitored by thin-layer chromatography (TLC) carried out on al-
uminium plates pre-coated with Merck silica gel 60 F254. Flash
column chromatography was performed using Merck silica gel 60
(4.3–6.3 mm). Melting points were recorded using a Leica VMTG
heated-stage microscope and are uncorrected. Infrared spectra
were recorded on a Bruker Tensor 27 Fourier Transform spec-
trometer, as a thin film between NaCl plates or as a KBr disc. Proton
(1H) and carbon (13C) NMR were recorded using a Bruker AV400
(400 MHz and 100 MHz). Mass spectra (m/z) and accurate mass
(HRMS) were recorded on an Agilent 6890 Series GC system for
chemical ionisation (CI) and on a Fisons Platform II for electrospray
ionisation (ESI).
4.1.3.3. Synthesis of 9. NaI (9.6 g, 63.9 mmol) was added to a solu-
tion of mesylate 11 (3.5 g, 12.8 mmol) in acetone (36 mL). The
resulting suspension was stirred at room temperature for 16 h and
then filtered through a pad of Celite and concentrated in vacuo.
Purification by flash column chromatography (SiO2; petroleum
ether/diethyl ether; 9:1) yielded 9 (3.7 g, 96%) as a pale yellow oil.
nmax (film)/cmꢂ1 2933, 2832, 1590, 1516, 1464, 1418, 1262, 1237,
1157, 1029; dH (400 MHz; CDCl3) 6.79 (1H, d, J 8.0, 1ꢄArH), 6.74–
6.72 (2H, m, 2ꢄArH), 3.87 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.16 (2H,
t, J 7.0, C(30)H2), 2.67 (2H, t, J 7.0, C(10)H2), 2.10 (2H, wquintet, J 7.0,
4.1.1. Oxidative dimerisation of Grignard reagents
The aryl bromide (1 equiv) was added to a mixture of magne-
sium turnings (5 equiv), I2 (one crystal) and THF (5 mL/mmol) at
0 ꢁC. The reaction mixture was heated at reflux for 3 h and then
allowed to cool to room temperature. The solution was transferred

T.J. Donohoe et al. / Tetrahedron 65 (2009) 5377–5384
5383
C(10)H2); dC (100 MHz; CDCl3) 148.7, 147.1, 132.8, 120.3, 111.7, 111.1,
55.8, 55.7, 35.6, 34.9, 6.5; m/z (ESI) 329 ([MþNa]þ, 100%); HRMS
(ESI) C11H15IO2Na ([MþNa]þ) requires 329.0014, found 329.0015.
For cryoelectrochemical measurements, the electrochemical cell
was immersed in an ethanol bath thermostated by a Julabo FT902
Immersion cooler.
4.1.4. Mediated reductions
4.2.3. Fitting of experimental voltammograms
Lithium metal (18 equiv) was added to a solution of the appro-
priate mediator (3 equiv) in THF (100 mL/mmol) in a flame-dried
Schenk tube under a constant flow of argon at 0 ꢁC. The reaction
mixture was stirred at 0 ꢁC for 3 h and then cooled to –78 ꢁC. A pre-
cooled (–78 ꢁC) solution of either 8 or 9 (1 equiv) in THF (10 mL/
mmol) was and then added via cannula and the reaction mixture
was stirred at –78 ꢁC for 30 min. The reaction was quenched by
transfer via cannula to a saturated aqueous solution of NH4Cl
(50 mL/mmol) and the product was extracted with diethyl ether
(3ꢄ20 mL/mmol). The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. The mixture was purified by
flash column chromatography (SiO2; petroleum ether to petroleum
ether/diethyl ether; 9:1).
Experimental voltammograms obtained at macroelectrodes
were modelled using the software DigisimÒ. Experimental vol-
tammograms obtained at microelectrodes were modelled using
a simulation program developed in our laboratory.38
Acknowledgements
We would like to thank the ESPRC for funding this project (EP/
E017738/1).
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