Dedicated to Gavin Bain on the occasion of his retirement, in acknowledgement of his
many years of service within the Department of Pure and Applied Chemistry at the University
of Strathclyde.
Published as part of the Bürgenstock Special Section 2019 Future Stars in Organic Chemistry
Key words nickel catalysis - cross-coupling - robustness screening - reaction mechanisms -
structure–activity relationships
Palladium-catalysed cross-coupling reactions are amongst the most widely deployed
tools in the synthesis of fine chemicals, pharmaceuticals, and agrochemicals, due
to their robustness, functional group tolerance, and their ability to use reagents
such as boronic acids and boronic esters; these reagents are typically straightforward
to prepare on scale and are usually stable under ambient conditions.[1 ]
[2 ]
[3 ]
[4 ] The development of nickel-catalysed reactions of this type is a subject of much
recent research, with a variety of new reactions taking advantage of the different
properties of nickel versus palladium.[5 ] A full and detailed evaluation of the reactivity differences between these two metals
is important to understand their capabilities, and to underpin the development of
new synthetic chemistry methodology.[6 ] It is known that nickel will react with a wide range of substrates[7 ] and that nickel(I) intermediates can arise through comproportionation[7 ]
[8 ] or halide abstraction[9 ]
[10 ]
[11 ]
[12 ] during catalytic reactions. West and Watson have recently conducted a comparative
study of nickel- and palladium-dppf complexes in Suzuki–Miyaura reactions.[13 ] However, the functional group tolerance of nickel versus palladium catalysis, and
the underlying reasons behind why these can differ so much, has not yet been fully
and satisfactorily understood.
We have recently disclosed that aldehydes and ketones have a significant influence
on the outcomes of nickel-catalysed Suzuki–Miyaura reactions [Scheme [1 ] (a)].[4 ] When these groups are substituents on the aryl halide, they lead to a significantly
enhanced rate of oxidative addition and can be used to enable site-selective catalysis;
when these groups are substituents on exogenous additives as part of a robustness
screen[14 ] they inhibit the catalytic reaction. A series of competition reactions established
that aryl halides with aldehyde or ketone (but not ester) substituents will undergo
cross-coupling in the presence of other aryl halides that do not have these substituents,
to the point that the normal order of reactivity of different organohalides (I > Br
> Cl) is overridden.
Scheme 1 (a) Previous work in understanding functional group effects on nickel catalysis.
(b) A comparison of nickel and palladium.
Here, we report our studies of the analogous palladium-catalysed reactions, applying
our methodology to measure reaction selectivity, and utilising a robustness screen
to understand the effects, if any, of a wider range of functional groups on the outcomes
of nickel- and palladium-catalysed Suzuki–Miyaura reactions [Scheme [1 ] (b)].
All reactions were carried out under the conditions in Scheme [2 ] (a).[4 ] [PdCl2 (dppf)] (1 ) was used in place of [NiCl(o -tol)(dppf)] (2 ) for the palladium-catalysed reactions [dppf = 1,1′-bis(diphenylphosphino)ferrocene];
complexes 1 and 2 often offer comparable reactivity in Suzuki–Miyaura reactions.[13 ] Our reaction conditions require only a slight excess of boronic acid in order to
activate the MII pre-catalyst via transmetalation and reductive elimination.[8 ] The outcomes of the reactions described here were determined using GC-FID analysis
with n -dodecane as an internal standard; the apparatus was calibrated using authentic samples
of each substrate and product, which were used to prepare solutions containing known
ratios of substrate to internal standard.
Scheme 2 Conditions for cross-coupling reactions for (a) single substrates and (b) competition
reactions
We have previously[4 ] conducted competition reactions in both a THF/water (4:1 v /v ) mixture and in toluene with 10 equivalents of water, which gave comparable results,
while robustness screening reactions were performed in toluene; here, all reactions
were performed in the THF/water solvent system as this avoids issues with clumping
of the base and instead forms a homogeneous biphasic mixture.
Reactions were performed in which 1 equivalent of a substituted aryl bromide (p -YC6 H4 Br, S1 –S19 ) and 1 equivalent of bromobenzene competed for 1 equivalent of boronic acid [Scheme
[2 ] (b)]. The conversion to each of the two possible products (P1 to P19 or 4-methylbiphenyl) was quantified by GC-FID analysis, and the resulting data were
interpreted using Equation 1, which defines the selectivity for the cross-coupling
of the substituted aryl bromide. A value of 1 represents a reaction that is entirely
selective for the cross-coupling of p -YC6 H4 Br, and a value of –1 represents a reaction that is entirely selective for the cross-coupling
of bromobenzene.
Equation 1 Measurement of selectivity in competition reactions between an aryl bromide and bromobenzene,
yielding products A and B , respectively
For each competition reaction, the selectivity number was plotted versus σp , which quantifies the net electron-donating or -withdrawing property of substituent
Y (Figure [1 ]);[15 ] some of the data have been reported previously,[4 ] but this study adds several additional data points. Data points are colour coded
according to whether they feature a coordinating π-system (nitrile, ketone, aldehyde,
imine, alkene, alkyne; green points) or not (blue points).
Figure 1 (a) Selectivity data for cross-coupling reactions catalysed by [NiCl(o -tol)(dppf)] (2 ). (b) Selectivity data for cross-coupling competition reactions catalysed by [PdCl2 (dppf)] (1 ). Green points indicate functional groups with potentially coordinating π-systems,
while blue points indicate functional groups without this feature.
The plot for nickel [Figure [1 ] (a)] shows a relatively flat profile for the blue points (except S7 (R = SMe) and S15 (R = SOMe), showing that selectivity in these reactions is relatively insensitive
to the electronic properties of the aryl halide. Species with known coordinating groups
such as ketones, aldehydes, nitrile, alkene, and alkynes show enhanced selectivity
in these Suzuki–Miyaura reactions. Future work will further investigate the effect
of the sulfide and sulfoxide groups on reaction selectivity, as these can potentially
coordinate transition metals via the lone pair(s) on the relatively soft sulfur.
The plot for the palladium-catalysed reactions (using 1 ) is consistent with the accepted trend that electron-poor aryl bromides undergo more
rapid oxidative addition than electron-rich aryl bromides [Figure [1 ] (b)].[16 ] The results here are significantly different from those obtained with nickel catalyst
2 . The trend is dominated by electronic effects but some selectivity is seen for the
functional groups that might coordinate metal centres via a π-system. These reactions
are far less selective than the corresponding nickel-catalysed competition reactions.
These data establish that coordinating functional groups have much less of an effect
in palladium catalysis than they do in nickel catalysis, and so a robustness screen[14 ] was carried out with additives A1 to A18 to understand whether additives with coordinating functional groups affect the outcomes
of prototypical Suzuki–Miyaura reactions (Scheme [3 ]). In these reactions, 1 equivalent of each additive was added to the reaction of
p -(trifluoromethyl)bromobenzene with p -tolylboronic acid. GC-FID analysis was used to quantify the conversion of the reaction;
this technique therefore allows us to rapidly assess whether the additive interferes
with the reaction. Reactions were initially carried out with 5 mol% of 1 or 2 . The results of this robustness screen show little or no inhibition of the palladium-catalysed
reactions by most of these additives; in the majority of cases, high (>90%) conversions
are observed. This is in stark contrast to the results with nickel catalysis, where
many functional groups inhibit an otherwise productive cross-coupling reaction. Imines
and phenylacetylene also had a significant impact on the outcomes of nickel-catalysed
reactions, but stilbene and benzonitrile had only a modest effect. Only phenylacetylene
had an impact on the yields of palladium-catalysed reactions. The robustness screen
was repeated with only 1 mol% of 1 to understand whether this would make the reaction more susceptible to poisoning
by additives; this had little impact on the yields of the reactions, generally decreasing
them by only a few percent. For the nickel-catalysed reactions, attempts were made
to correlate reaction inhibition to selectivity data from Figure [1 ], but there is no clear correlation here.
Scheme 3 Outcomes of robustness screening reactions with 1 (1 mol% or 5 mol%) and 2 (5 mol%). Yellow is used to highlight yields between 25% and 80%, while red is used
to highlight yields below 25%. All data are averages of at least two replicates and
are obtained from calibrated GC-FID analyses of reaction mixtures, using n -dodecane as an internal standard.
These experimental observations were probed further using density functional theory
(DFT) calculations. All computational data in this manuscript are reported in THF
solution, consistent with experimental work. Complexes 3 (Ni) and 4 (Pd) were considered to have Grel = 0, as these are the M0 complexes that will arise from the activation of 2 or 1 , respectively, by transmetalation with p -tolylboronic acid (Scheme [4 ]). These arene ligands can be replaced by aryl halide substrates; these can co-ordinate
to the metal centre to form an η2 -complex (A ), which then undergoes oxidative addition (TS-AB ) to form [M(Ar)Br(dppf)] (B ). Alternatively, some substrates can coordinate to M0 through their functional groups (A′ ). The values of interest are (i) the relative energies of A and A′ , and (ii) the barrier from A to TS-AB for oxidative addition. If A′ is much lower in energy than A then this might decrease the rate of oxidative addition. The results of these calculations
are recorded in Table [1 ] for both the palladium and the nickel complexes. We did not directly compare the
turnover numbers for nickel and palladium; the transmetalation step is not modelled
here, as there are multiple possible mechanisms for boronic acid transmetalation.[17 ]
[18 ] Instead, we have used DFT data to reveal the nature of the competition between the
reversible coordination of M0 to functional groups and the (irreversible) oxidative addition step.
Scheme 4 Structures studied using density functional theory
Table 1 Free Energies in kcal mol–1 , Relative to Complexes 3 (for Ni) or 4 (for Pd), of the Pre-Oxidative Addition η2 -Complexes (A ), the Oxidative Addition Transition State (TS-AB ), the Oxidative Addition Product (B ), and the η2 -Complex with the Substituent (A′ ) for the Reactions of 3 and 4 with the Substrates in Scheme [4 ]
Y
Nickel 3
Palladium 4
A
A′
TS-AB
B
A vs A′
a
TS-AB vs A
A
A′
TS-AB
B
A vs A′
a
TS-AB vs A
SO2 Me
–9.5
–2.8
–35.0
6.7
–3.3
6.9
–27.9
10.2
CN
–9.5
–11.1
–3.6
–34.9
1.5
5.9
–3.0
0.9
7.9
–27.4
–3.9
10.9
CF3
–7.9
–1.2
–33.3
6.7
–0.3
8.5
–25.9
8.8
COMe
–9.3
–12.6
–2.0
–33.1
3.3
7.3
–2.1
–0.2
8.3
–26.0
–1.9
10.4
SOMe
–7.4
0.9
–32.9
8.3
–0.8
9.1
–25.8
9.9
CO2 Me
–7.5
–3.5
–1.6
–32.1
–4.0
5.9
–1.7
4.5
8.9
–25.0
–6.2
10.6
CHO
–10.3
–16.0
–2.6
–33.5
5.7
7.7
–3.0
–2.5
7.9
–26.0
–0.5
11.0
C(H)=NHPh
–8.7
–17.7
–2.0
–32.9
9.0
6.7
–0.4
–6.8
8.3
–24.4
6.4
8.7
CONH2
–6.6
0.4
–1.9
–32.2
–7.0
4.7
–1.1
6.6
9.2
–25.7
–7.6
10.3
OCF3
–6.3
–0.8
–33.1
5.5
–0.4
9.9
–26.2
10.3
C(H)=NOMe
–7.7
–13.1
–1.3
–31.9
5.4
6.4
1.0
–2.5
10.1
–24.4
3.5
9.1
C≡CH
–7.0
–22.4
–1.6
–32.3
15.4
5.4
0.1
–8.9
9.7
–24.8
9.0
9.6
C≡CPh
–6.5
–23.9
–1.2
–31.8
17.3
5.4
–0.1
–9.7
9.8
–24.0
9.5
9.9
H
–3.8
1.5
–30.1
5.2
2.4
11.4
–22.9
9.0
SMe
–5.4
0.7
–30.6
6.1
1.1
10.2
–22.8
9.1
C(H)=CHPh
–5.1
–20.1
1.0
–31.6
15.0
6.2
–0.2
–10.0
10.4
–22.8
9.7
10.6
OMe
–1.5
2.6
–28.3
4.2
3.3
11.9
–22.8
8.6
NHPh
–4.7
2.1
–27.8
6.8
1.7
12.5
–22.4
10.9
NMe2
–2.0
3.3
–25.3
5.3
3.7
14.0
–19.9
10.2
a Red shading indicates that A is lower in energy than A′ . Blue shading indicates that A′ is lower in energy than A .
These data show that the oxidative addition reactions of dppf-Ni0 present much lower barriers and are much more exergonic than those for dppf-Pd0 , consistent with established reactivity trends.[6 ] Oxidative addition is unlikely to be the rate-determining step in these nickel-catalysed
reactions. For nickel, complexes of the form A′ are typically much lower in energy than the corresponding complexes of type A , and it is this effect, and a facile ‘ring-walking’ process that is proposed to lead
to the observed selectivity for substrates with coordinating functional groups.[4 ]
,
[19 ]
[20 ]
[21 ]
[22 ] For those substrates with amide and ester functional groups the pre-oxidative addition
complex A is lower in energy than A′ . There are unfortunately no clear correlations between the energy of A′ and the selectivity of cross-coupling reactions or the degree of reaction inhibition.
For palladium, none of the A′ complexes for carbonyl-containing aryl halides were found to be lower in energy than
the corresponding pre-oxidative addition η2 -complexes. The coordination of various other functional groups to the Pd0 complex (forming A′ ) is often exergonic, but far less so than for nickel.[20 ]
[23 ] This goes some way to explaining the lack of selectivity in competition experiments
and the lack of any significant inhibition by any of these additives in the robustness
screening studies. A search of the Cambridge Structural Database reveals only one
palladium–ketone complex, but this is in the form of a benzophenone-derived bisphosphine
ligand in which the coordination of two phosphines forces the ketone to interact with
the Pd0 centre also.[24 ] There is one example of a structurally characterised imine complex of Pd0 .[25 ]
The coordination of aldehydes and ketones to Ni0 has been studied in depth by Love and Kennepohl, using a variety of experimental
and computational techniques.[26 ]
[27 ] All of the η2 -complexes A′ in this work are square planar; attempts to locate tetrahedral complexes were unsuccessful,
with the structure optimising to the square planar geometry in each case. While the
strength of coordination of palladium to functional groups is evidently much lower
than in the case of nickel, the reasons behind the observed square planar geometry
– donation from a bidentate phosphine into the same d orbital used for d →π* back-bonding – are likely to be the same. Several plots were constructed to visualise
these differences in behaviour between palladium and nickel. Plots of Grel (TS-AB ) versus σp give reasonably good linear correlations that have very similar slopes for Pd and
Ni (–4.1 vs –4.2) [Figure [2 ] (a)]. However, when ΔG‡ (A →TS-AB ) is plotted versus σp the plot is almost flat, although there is significant scatter [Figure [2 ] (b)]; each substituent influences the free energies (Grel ) of the pre-oxidative addition η2 -complex A and oxidative addition transition state TS-AB almost equally. These data, combined with the experimental data in Figure [1 ], suggest that for palladium catalysis the oxidative addition event may be rate-determining,
and TS-AB may be the turnover-determining transition state.[28 ] In contrast, coordination effects clearly dominate in nickel catalysis, with more
subtle differences in the electronic properties of the substituents having little
effect.
Figure 2 (a) Plot of Grel (TS-AB ) versus σp for palladium (red ) and nickel (blue ). (b) Plot of ΔG‡ (A →TS-AB ) versus σp for palladium (red ) and nickel (blue ). (c) Plot of ΔG(A′ –A ) for palladium versus ΔG(A′ –A ) for nickel.
The relative energies of A versus A′ were compared for palladium versus nickel [Figure [2 ] (c)]. A good linear correlation was obtained, albeit with nickel favouring A′ over A in most cases. This is further evidence of the same interactions at work for both
palladium and nickel; these simply manifest less strongly in the case of palladium,
leading to the lack of significant engagement of these functional groups with the
Pd0 catalyst, and therefore the lack of leverageable selectivity or observable inhibition
in catalysis.
While we present a significant experimental and computational dataset that interrogates
functional group effects in cross-coupling catalysis, particularly with nickel, a
quantitative link and a robust quantitatively predictive model remain to be established.
Semi-quantitatively, where complex A′ is lower in energy than A for nickel catalysis, then we would expect selective cross-coupling of the corresponding
aryl halide and the inhibition of cross-coupling reactions by an additive featuring
this functional group. The same does not hold for palladium: imines, alkynes, and
alkenes should show interesting behaviour based on the difference between the energies
of A and A′ , but experimental observations are limited to some inhibition of catalysis by phenylacetylene.
A limitation of our approach here is that we have no time-resolved studies, and so
the difference in behaviour may be due to differences in rates or relative rates of
key steps.
In conclusion, a detailed and systematic comparison of palladium and nickel and their
interactions with potentially coordinating functional groups is reported, and key
differences between these two metals are highlighted. Data comprise: measured selectivities
from competition experiments; the measurement of the (lack of) inhibition of reactions
in which functionalised additives are present; and DFT calculations of the coordination
of these functional groups and the oxidative addition pathways of the corresponding
aryl bromides. Together, these data show that nickel and palladium interact with functional
groups in a considerably different manner. Nickel will strongly interact with many
functional groups, resulting in selective cross-coupling reactions, but at the cost
of reduced functional group tolerance. Palladium derives no selectivity benefits from
these functionalised aryl halides, but therefore shows much better functional group
tolerance. This work contributes towards our understanding of cross-coupling catalysis
by highlighting differences in the behaviour of palladium and nickel catalysis, and
its implications for the application of cross-coupling chemistry in organic synthesis.
Complex 1 was obtained from commercial sources and used as supplied. Complex 2 was prepared according to a literature method.[29 ] Most aryl halides (S1 –S5 , S7 –S11 , S13 , S14 , S16 –S19 ) and additives (A1 –A5 , A7 –A10 , A12 –A16 , A18 ) were obtained from commercial sources and used as supplied; synthetic methods and
characterisation data for those that were prepared can be found below or in our previous
manuscripts.[4 ]
[30 ] Samples of most products (P1 –P5 , P9 –P11 , P13 , P14 , P16 , P17 , P19 ) were prepared by cross-coupling catalysis, and the data for these are reported below
or in our previous study.[4 ] Anhydrous, O2 -free THF was obtained from an Innovative Technologies PureSolv apparatus. Distilled
H2 O was degassed by sparging with N2 or argon before use. K3 PO4 was obtained from commercial sources, dried overnight in a vacuum oven (50 °C) before
use, and stored in a desiccator.
NMR spectra were obtained using a Bruker AV3-400 instrument with a liquid N2 Prodigy cryoprobe. 1 H NMR spectra are referenced to residual protonated solvent,[31 ] 13 C NMR spectra are referenced to solvent signals,[31 ] and 19 F spectra are externally referenced to CFCl3 . GC-MS analyses were performed using an Agilent 7890A gas chromatograph fitted with
a RESTEK RXi-5Sil column (30 m × 0.32 mm I.D. × 0.25 μm) and an Agilent 5975C MSD
running in EI mode. GC-FID analyses were carried out using an Agilent 7890A gas chromatograph
fitted with an Agilent HP5 column (30 m × 0.25 mm I.D. × 0.25 μm).
DFT calculations were carried out in Gaussian 09 (Rev. D.01)[32 ] at the B3LYP level of theory, with Grimme D3 dispersive corrections.[33 ] Geometry optimisations were carried out without symmetry constraints, using the
6-31G(d) basis set for H, C N, O, P, and S, the LANL2DZ(dp) basis set and pseudopotential
for Br, and the LANL2TZ(f) basis set and pseudopotential for Fe, Ni, and Pd. Energies
were refined using single point calculations in which 6-311+G(d,p) was used for all
atoms except Br, Fe, Ni, and Pd. Solvation (THF) was applied throughout, using the
SMD implicit solvent model. The nature of each stationary point was confirmed using
frequency calculations.
Synthetic Cross-Coupling Reactions; General Procedure
Synthetic Cross-Coupling Reactions; General Procedure
A microwave vial equipped with a stir bar was charged with 4-tolylboronic acid (1.1
mmol, 1.1 equiv.), [PdCl2 (dppf)] (2 ), and K3 PO4 (3 mmol, 3 equiv.). If the aryl halide was a solid, this was charged at this time
also (1 mmol, 1 equiv.). The vial was sealed with a crimp cap and evacuated and backfilled
three times with N2 or argon. The vial was then charged with anhyd, O2 -free toluene or THF and the aryl halide if liquid (1 mmol, 1 equiv.). Degassed H2 O was also added at this stage, if used. The reaction mixture was stirred for 2 h
at 85 °C, then cooled to r.t., and quenched by piercing the septum. The reaction mixture
was filtered through Celite, evaporated to dryness, and purified by column chromatography
on silica gel.
Cross-Coupling Competition Reactions; General Procedure
Cross-Coupling Competition Reactions; General Procedure
A microwave vial equipped with a stir bar was charged with 4-tolylboronic acid (0.25
mmol, 1 equiv.), [PdCl2 (dppf)] or [NiCl(o -tol)-(dppf)] (5 mol%), and K3 PO4 (0.75 mmol, 3 equiv.). If the substituted aryl halide was a solid, this was charged
at this time also (0.25 mmol, 1 equiv.). The vial was sealed with a crimp cap and
evacuated and backfilled three times with N2 or argon. The vial was then charged with anhyd, O2 -free THF (0.8 mL), bromobenzene (0.25 mmol, 1 equiv.), and the substituted aryl halide
if liquid (0.25 mmol, 1 equiv.). Degassed H2 O (0.2 mL) was also added. The reaction was stirred for 2 h at 85 °C, then cooled
to r.t., and quenched by piercing the septum. An accurately-known mass of n -dodecane was added, the reaction was mixed, and a sample was taken, filtered, and
diluted in CHCl3 for GC analysis.
Robustness Screening; General Procedure
Robustness Screening; General Procedure
A microwave vial equipped with a stir bar was charged with 4-tolylboronic acid (0.275
mmol, 1.1 equiv.), [PdCl2 (dppf)] or [NiCl(o -tol)(dppf)] (1 or 5 mol%), and K3 PO4 (0.75 mmol, 3 equiv.). If the additive was a solid, this was charged at this time
also (0.25 mmol, 1 equiv.). The vial was sealed with a crimp cap and evacuated and
backfilled three times with N2 or argon. The vial was then charged with anhyd, O2 -free THF (0.8 mL), bromobenzene (0.25 mmol, 1 equiv), and the additive if liquid
(0.25 mmol, 1 equiv). Degassed H2 O (0.2 mL) was also added. The reaction mixture was stirred for 2 h at 85 °C then
cooled to r.t. and quenched by piercing the septum. An accurately-known mass of n -dodecane was added, the reaction was mixed, and a sample was taken, filtered, and
diluted in CHCl3 for GC analysis.
(E )-1-Bromo-4-styrylbenzene (S6)
(E )-1-Bromo-4-styrylbenzene (S6)
Benzyltriphenylphosphonium chloride (2.547 g, 6.6 mmol) was added to a 100 mL round-bottomed
flask equipped with a stirrer bar. A suspension of LiOH·H2 O (0.370 g, 8.7 mmol) in i -PrOH (50 mL) was added and the mixture was stirred at r.t. for 20 min. 4-Bromobenzaldehyde
(1.003 g, 6.2 mmol) was added and the reaction mixture was stirred at reflux for 16
h. Once cooled to r.t., the reaction mixture was extracted with EtOAc (75 mL) and
washed with brine (75 mL). The organic phase was dried (MgSO4 ), filtered, and evaporated under reduced pressure. The product was recrystallised
from EtOH to give a white powder; yield: 1.103 g (67%); mp 138–140 °C.
IR (ATR, neat): 3014, 1999, 1493 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.70–7.54 (m, 4 H, Ar CH), 7.41–7.37 (m, 4 H, Ar CH), 7.31 (d, J = 7.0 Hz, 1 H, Ar CH), 7.13 (d, J = 16.7 Hz, 1 H, CH=CH), 7.06 (d, J = 16.7 Hz, 1 H, CH=CH).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 136.5, 135.8, 131.3, 128.9, 128.3, 127.5, 127.4, 126.9, 126.1, 120.8.
MS (GC-MS, EI): m /z = 258 [M]+ .
(E )-1-(4-Bromophenyl)-N -phenylmethanimine (S12)
(E )-1-(4-Bromophenyl)-N -phenylmethanimine (S12)
4-Bromobenzaldehyde (501.2 mg, 2.7 mmol) was added to a microwave vial equipped with
a stirrer bar and molecular sieves. The vial was closed using a septum-fitted crimp
cap and purged and backfilled with N2 . Aniline (0.246 mL, 2.7 mmol, 1 equiv.) and anhyd toluene (2.5 mL) were added and
the mixture was heated using microwave irradiation at 200 °C for 4 h. Once cooled
to r.t., the reaction mixture was extracted with H2 O (150 mL) and Et2 O (3 × 50 mL). The organic layers were combined, dried (MgSO4 ), and filtered. The solvent was removed under reduced pressure and the product was
recrystallised from DCM/pentane to give a yellow amorphous solid; yield: 100.3 mg
(14%).
IR (ATR, neat): 3040, 2880, 1904, 1622, 1584, 1564, 1501, 1485 cm–1 .
1 H NMR (CD3 CN, 400 MHz): δ = 8.55 (s, 1 H, CHN), 7.88–7.84 (m, 2 H, Ar CH), 7.72–7.70 (m, 2 H,
Ar CH), 7.47–7.43 (m, 2 H, Ar CH), 7.29–7.26 (m, 2 H, Ar CH), 7.23 (d, J = 6.1 Hz, 1 H, Ar CH).
13 C{1 H} NMR (CD3 CN, 101 MHz): δ = 158.8, 131.5, 129.7, 129.5, 128.8, 125.7, 124.7, 120.6, 120.4.
MS (GC-MS, EI): m /z = 259.0 [M]+ .
1-Bromo-4-(methylsulfinyl)benzene (S15)
1-Bromo-4-(methylsulfinyl)benzene (S15)
4-Bromothioanisole (998.6 mg, 4.9 mmol) was added to a 100 mL round-bottomed flask
equipped with a stirrer bar and dissolved in DCM (20 mL). A solution of m CPBA (1.593 g, 1.2 equiv.) in DCM (10 mL) was added to the solution at 0 °C over 5
min, and the reaction mixture was stirred at r.t. for 12 h. The reaction mixture was
diluted with sat. aq NaHCO3 (100 mL) and extracted with DCM (2 × 50 mL). The organic layers were combined, dried
(MgSO4 ), and filtered. The solvent was removed under reduced pressure and the product was
recrystallised from DCM/hexane to give a white solid; yield: 472.0 mg (47%); mp 80–82 °C.
IR (ATR, neat): 2990, 2911, 1570, 1470 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.70 (d, J = 8.1 Hz, 2 H, Ar CH), 7.5 (d, J = 8.4 Hz, 2 H, Ar CH), 2.74 (s, 3 H, CH3 ).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 144.4, 132.1, 125.0, 124.7, 43.5.
Analytical data are consistent with the literature.[34 ]
(E )-4-Methyl-4′-styryl-1,1-biphenyl (P6)
(E )-4-Methyl-4′-styryl-1,1-biphenyl (P6)
Synthesised according to the general procedure for synthetic cross-coupling reactions
using (E )-1-bromo-4-styrylbenzene (259.5 mg, 1 mmol), 4-tolylboronic acid (149.2 mg, 1.1 mmol),
2 (6.8 mg, 1 mol%), and K3 PO4 (635.7 mg, 3 mmol) in a 4:1 (v /v ) THF/H2 O mixture (2 mL). The desired product was purified by recrystallisation from hexane/DCM
to yield a white solid; yield: 251.9 mg (93%); mp 226–228 °C.
IR (ATR, neat): 3021, 2914, 2046, 1755, 1578, 1493 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.61 (s, 4 H, Ar CH), 7.56–7.54 (m, 4, Ar CH), 7.41–7.38 (m, 2, Ar
CH), 7.27 (s, 1 H, Ar CH), 7.17 (s, 2 H, CH), 2.43 (CH3 ).
MS (GC-MS, EI): m /z = 270.1 [M]+ .
Analytical data are consistent with the literature.[35 ]
Methyl(4′-methyl-[1,1′-biphenyl]-4-yl)sulfane (P7)
Methyl(4′-methyl-[1,1′-biphenyl]-4-yl)sulfane (P7)
Synthesised according to the general procedure for synthetic cross-coupling reactions
using 4-bromothioanisole (203.8 mg, 1 mmol), 4-tolylboronic acid (148.5 mg, 1.1 mmol),
2 (7.1 mg, 1 mol%), and K3 PO4 (636.9 mg, 3 mmol) in a 4/1 (v /v ) THF/H2 O mixture (2 mL). The desired product was purified by recrystallisation from hexane/DCM
to yield a white solid; yield: 171.2 mg (80%); mp 120–122 °C.
1 H NMR (CDCl3 , 400 MHz): δ = 7.55–7.49 (m, 4 H, Ar CH), 7.35 (d, J = 9.1 Hz, 2 H, Ar CH), 7.27 (d, J = 9.1 Hz, 2 H, Ar CH), 2.55 (s, 3 H, SCH3 ), 2.42 (s, 3 H, ArCH
3 ).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 137.6 (Ar C), 137.2 (Ar C), 136.7 (Ar C), 136.5 (Ar C), 129.0 (Ar
CH), 126.8 (Ar CH), 126.6 (Ar CH), 126.2 (Ar CH), 20.6 (SCH3 ), 15.5 (ArC H3 ).
MS (GC-MS, EI): m /z = 214.1 [M]+ .
4-Methyl-4′-(phenylethynyl)-1,1′-biphenyl (P8)
4-Methyl-4′-(phenylethynyl)-1,1′-biphenyl (P8)
Synthesised according to the general procedure for synthetic cross-coupling reactions
using 1-bromo-4-(phenylethynyl)benzene (257.4 mg, 1 mmol), 4-tolylboronic acid (149.3
mg, 1.1 mmol), 2 (7.4 mg, 1 mol%), and K3 PO4 (638.1 mg, 3 mmol) in anhyd toluene (2 mL). The desired product was purified by passing
the reaction mixture through a pad of silica gel and evaporating the solvent under
reduced pressure to yield a white solid; yield: 141.2 mg (53%); mp 160–162 °C.
IR (ATR, neat): 3021, 1578, 1493 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.65–7.58 (m, 6 H, Ar CH), 7.56 (d, J = 8.1 Hz, 2 H, Ar CH), 7.42–7.37 (m, 3 H, Ar CH), 7.30 (d, J = 7.8 Hz, 2 H, Ar CH), 2.44 (s, 3 H, CH3 ).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 140.4 (Ar C), 137.02 (Ar C), 136.99 (Ar C), 131.5 (Ar CH), 131.1 (Ar
CH), 129.1 (Ar CH), 127.9 (Ar CH), 127.7 (A r C), 126.4 (Ar CH), 126.3 (Ar CH), 122.9
(Ar C), 121.4 (Ar C), 89.5 (C≡C), 88.9 (C≡C), 20.6 (CH3 ).
MS (GC-MS, EI): m /z = 268.1 [M]+ .
Analytical data are consistent with the literature.[36 ]
(E )-1-(4′-Methyl-[1,1′-biphenyl]-4-yl)-N -phenylmethanimine (P12)
(E )-1-(4′-Methyl-[1,1′-biphenyl]-4-yl)-N -phenylmethanimine (P12)
Synthesised according to the general procedure for synthetic cross-coupling reactions
using (E )-1-(4-bromophenyl)-N -phenylmethanimine (261.0 mg, 1 mmol), 4-tolylboronic acid (149.4 mg, 1.1 mmol),
2 (7.2 mg, 1 mol%), and K3 PO4 (637.1 mg, 3 mmol) in a 4:1 (v /v ) THF/H2 O mixture (2 mL). The desired product was purified by recrystallisation from hexane/DCM
to yield a pale orange/brown solid; yield: 225.1 mg (83%); mp 134–136 °C.
IR (ATR, neat): 3048, 2976, 2355, 1531 cm–1 .
1 H NMR (CD3 CN, 400 MHz): δ = 8.61 (s, 1 H, CHN), 8.00 (d, J = 8.1 Hz, 2 H, Ar CH), 7.79 (d, J = 8.1 Hz, 2 H, Ar CH), 7.64 (d, J = 8.1 Hz, 2 H, Ar CH), 7.46 (t, J = 8.6 Hz, 2 H, Ar CH), 7.34 (d, J = 8.6 Hz, 2 H, Ar CH), 7.29–7.27 (m, 3 H, Ar CH), 2.42 (s, 3 H, CH3 ).
13 C{1 H} NMR (CD3 CN, 101 MHz): δ = 159.6, 151.6, 143.1, 137.6, 136.5, 134.8, 129.2, 128.8, 128.7, 126.6,
126.4, 125.5, 120.4, 19.7.
MS (GC-MS, EI): m /z = 268.1 [M]+ .
4-Methyl-4′-(methylsulfinyl)-1,1′-biphenyl (P15)
4-Methyl-4′-(methylsulfinyl)-1,1′-biphenyl (P15)
Synthesised according to the general procedure for synthetic cross-coupling reactions
using 1-bromo-4-(methylsulfinyl)benzene (218.4 mg, 1 mmol), 4-tolylboronic acid (147.1
mg, 1.1 mmol), 2 (7.5 mg, 1 mol%), and K3 PO4 (633.1 mg, 3 mmol) in a 4:1 (v /v ) THF/H2 O mixture (2 mL). The desired product was purified by passing through a silica gel
plug and eluting with hexane, then EtOAc, then MeOH to yield a white solid; yield:
105.3 mg (46%); mp 140–142 °C.
1 H NMR (CDCl3 , 400 MHz): δ = 7.74 (d, J = 8.3 Hz, 4 H, Ar CH), 7.53 (d, J = 7.5 Hz, 2 H, Ar CH), 7.30 (d, J = 8.3 Hz, 2 H, Ar CH), 2.79 (s, 3 H, CH3 ), 2.44 (s, 3 H, CH3 ).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 143.7, 143.6, 137.6, 136.4, 129.2, 127.4, 126.6, 123.6, 43.6, 20.6.
MS (GC-MS, EI): m /z = 230.1 [M]+ .
4′-Methyl-[1,1′-biphenyl]-4-carbonitrile (P18)
4′-Methyl-[1,1′-biphenyl]-4-carbonitrile (P18)
Synthesised according to the general procedure for synthetic cross-coupling reactions
using 4-bromobenzonitrile (182.0 mg, 1 mmol), 4-tolylboronic acid (148.4 mg, 1.1 mmol),
2 (7.2 mg, 1 mol%), and K3 PO4 (634.2 mg, 3 mmol) in anhyd toluene (2 mL). The desired product was purified by flash
column chromatography on silica gel using 5% EtOAc/hexane (Rf
= 0.32) to yield a white solid; yield: 148.5 mg (77%); mp 110–112 °C.
IR (ATR, neat): 3464, 3055, 2995, 1709, 1582, 1476 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.73 (d, J = 8.3 Hz, 2 H, Ar CH), 7.69 (d, J = 8.3 Hz, 2 H, Ar CH), 7.52 (d, J = 8.0 Hz, 2 H, Ar CH), 7.32 (d, J = 8.2 Hz, 2 H, Ar CH), 2.45 (s, 3 H, CH3 ).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 145.1, 138.3, 135.8, 132.1 (2 C), 129.4 (2 C), 127.0 (2 C), 126.6
(2 C), 118.5, 110.1, 20.7.
MS (GC-MS, EI): m /z = 193.1 [M]+ .
Analytical data are consistent with the literature.[37 ]
(E )-Benzaldehyde O -Methyl Oxime (A6)
(E )-Benzaldehyde O -Methyl Oxime (A6)
Methoxyamine hydrochloride (231.4 mg, 2.7 mmol) was added to a microwave vial equipped
with a stirrer bar and molecular sieves. The vial was closed using a septum-fitted
crimp cap and purged and backfilled with N2 . Benzaldehyde (0.276 mL, 2.7 mmol, 1 equiv.), pyridine (0.220 mL, 2.7 mmol, 1 equiv.),
and anhyd toluene (2.5 mL) were added and the mixture was heated using microwave irradiation
at 200 °C for 4 h. Once cooled to r.t., the reaction mixture was extracted with H2 O (150 mL) and Et2 O (3 × 50 mL). The organic layers were combined, dried (MgSO4 ), and filtered. The solvent was removed under reduced pressure and the product was
recrystallised from DCM/pentane to give a pale straw-coloured amorphous solid; yield:
241.3 mg (65%).
IR (ATR, neat): 3069, 2936, 2816, 1690, 1603, 1452 cm–1 .
1 H NMR (CD3 CN, 400 MHz): δ = 8.14 (s, 1 H, CH NOMe), 7.64–7.61 (m, 2 H, Ar CH), 7.44–7.43 (m, 3 H, Ar CH), 3.95 (s, 3 H, CH3 ).
13 C{1 H} NMR (CD3 CN, 101 MHz): δ = 148.0, 129.4, 129.1, 128.3, 126.3, 60.9.
MS (GC-MS, EI): m /z = 135.1 [M]+ .
Analytical data are consistent with the literature.[38 ]
(Methylsulfinyl)benzene (A11)
(Methylsulfinyl)benzene (A11)
Thioanisole (0.950 mL, 8.1 mmol) was added to a 100 mL round-bottomed flask equipped
with a stirrer bar and dissolved in DCM (20 mL). A solution of m CPBA (2.084 g, 12.2 mmol, 1.5 equiv.) in DCM (10 mL) was added to the solution at
0 °C over 5 min, and the reaction mixture was stirred at r.t. for 12 h. The reaction
mixture was diluted with sat. aq NaHCO3 (100 mL) and extracted with DCM (2 × 50 mL). The organic layers were combined, dried
(MgSO4 ), and filtered. The solvent was removed under reduced pressure and the product was
recrystallised from DCM/hexane to give a viscous colourless liquid; yield: 411.2 mg
(36%).
IR (ATR, neat): 3464, 3055, 2995, 2913, 1709, 1582, 1476 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.52–7.50 (m, 2 H, Ar CH), 7.39–7.34 (m, 3 H, Ar CH), 2.57 (s, 3 H,
CH3 ).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 145.0, 130.5, 128.8, 122.9, 43.2.
MS (GC-MS, EI): m /z = 140.0 [M]+ .
Analytical data are consistent with the literature.[34 ]
(E )-1,2-Diphenylethene (A17)
(E )-1,2-Diphenylethene (A17)
Benzyltriphenylphosphonium chloride (3.842 g, 9.9 mmol) was added to a 100 mL round-bottomed
flask equipped with a stirrer bar. A suspension of LiOH·H2 O (0.557 g, 13.2 mmol) in i -PrOH (50 mL) was added and the mixture was stirred at r.t. for 20 min. Benzaldehyde
(0.960 mL, 9.4 mmol) was added and the reaction mixture was stirred at reflux for
16 h. Once cooled to r.t., the reaction mixture was extracted with EtOAc (75 mL) and
washed with brine (75 mL). The organic phase was dried (MgSO4 ), filtered, and evaporated under reduced pressure. The product was recrystallised
from EtOH to give a white powder; yield: 1.412 g (83%); 124–126 °C.
IR (ATR, neat): 3059, 3021, 1597, 1576, 1495 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.56 (d, J = 7.8 Hz, 4 H, Ar CH), 7.40 (t, J = 7.5 Hz, 4 H, Ar CH), 7.30 (t, J = 7.0 Hz, 2 H, Ar CH), 7.16 (s, 2 H, CH=CH).
13 C{1 H} NMR (CDCl3 , 101 MHz): δ = 136.9, 128.23, 128.20, 127.1, 126.0.
MS (GC-MS, EI): m /z = 180.1 [M]+ .
Analytical data are consistent with the literature.[39 ]
