Dimethylisosorbide (DMI) as a Bio-Derived Solvent for Pd-Catalyzed Cross-Coupling Reactions

Article abstract of DOI:10.1055/s-0037-1611054

Palladium-catalyzed bond-forming reactions, such as the ?-Suzuki-Miyaura and Mizoroki-Heck reactions, are some of the most broadly utilized reactions within the chemical industry. These reactions frequently employ hazardous solvents; however, to adhere to increasing sustainability pressures and restrictions regarding the use of such solvents, alternatives are highly sought after. Here we demonstrate the utility of dimethyl isosorbide (DMI) as a bio-derived solvent in several benchmark Pd-catalyzed reactions: Suzuki-Miyaura (13 examples, 62-100% yield), Mizoroki-Heck (13 examples, 47-91% yield), and Sonogashira (12 examples, 65-98% yield).

Full text of DOI:10.1055/s-0037-1611054

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
K. L. Wilson et al.
Letter
Synlett
Dimethylisosorbide (DMI) as a Bio-Derived Solvent for
Pd-Catalyzed Cross-Coupling Reactions
Kirsty L. Wilsona
Jane Murrayb
X
R1
R2
R2
Helen F. Sneddonc
Craig Jamiesona
Allan J. B. Watson*d
Sonogashira
R1
12 examples
65–98% yield
0
0
0
0
0-
0
0
2
1-
5
8
2
4-
2
8
6
MeO
DMI
H
H
O
Mizoroki-Heck
R2
a Department of Pure and Applied Chemistry, University of
Strathclyde, Thomas Graham Building, 295 Cathedral Street,
Glasgow, G1 1XL, UK
Renewable source
Low toxicity
R1
X
O
R1
R2
13 examples
47–91% yield
OMe
b Merck KgaA, Frankfurter Straße 250, 64293 Darmstadt, Germany
c Green Chemistry Performance Unit, GlaxoSmithKline, Medicines
Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire,
SG1 2NY, UK
Suzuki-Miyaura
R2
d EastChem, School of Chemistry, University of St Andrews, North
Haugh, St Andrews, KY16 9ST, UK
aw260@st-andrews.ac.uk
R1
X
B(OH)2
13 examples
62–100% yield
R1
R2
Received: 09.08.2018
Accepted after revision: 04.09.2018
Published online: 28.09.2018
The use of biomass feedstocks in the development of
new chemical products is a growing area within Green
Chemistry, aiming to minimize dependence on petroleum-
based chemicals and overall environmental impact of the
chemical industries.16–23 However the uptake of neoteric
solvents can often be slow when application is under-
explored. Some recent examples of the applications of
new solvents include studies on γ-valerolactone and
DOI: 10.1055/s-0037-1611054; Art ID: st-2018-d0509-l
Abstract Palladium-catalyzed bond-forming reactions, such as the
Suzuki–Miyaura and Mizoroki–Heck reactions, are some of the most
broadly utilized reactions within the chemical industry. These reactions
frequently employ hazardous solvents; however, to adhere to increas-
ing sustainability pressures and restrictions regarding the use of such
solvents, alternatives are highly sought after. Here we demonstrate the
utility of dimethyl isosorbide (DMI) as a bio-derived solvent in several
benchmark Pd-catalyzed reactions: Suzuki–Miyaura (13 examples, 62–
100% yield), Mizoroki–Heck (13 examples, 47–91% yield), and Sonogas-
hira (12 examples, 65–98% yield).
CyreneTM 24–34
.
Derived from glucose via the platform molecule sorbitol
(Figure 1), dimethyl isosorbide (DMI) has found application
in the formulation of cosmetics and pharmaceuticals.35–38
Despite displaying similar Hansen solubility parameters
(HSP)39 to traditional dipolar aprotic solvents and some
promising investigations into the use of DMI within amide
bond formation,40,41 its broader application within organic
synthesis, in particular transition-metal catalysis, is under-
developed. Herein we report the use of DMI as a viable al-
ternative to solvents of concern within key C–C bond-form-
ing reactions widely used in synthetic organic chemistry.
Key words cross-coupling, green chemistry, palladium, solvents
Continuing endeavors by leading industrial companies
and academic groups place solvent replacement strategies
at the forefront of green chemistry initiatives. The search
for alternative solvents is, in part, driven by health, safety,
and environmental issues regarding the use of solvents of
concern.1–6 For example, dipolar aprotic solvents such as
DMF and NMP are teratogenic, whilst 1,4-dioxane is car-
cinogenic. As such, these solvents, in addition to many oth-
ers, have fallen under strict regulation.
Subsequently, solvent selection has become a key focus
within the pharmaceutical sector, with many groups devel-
oping tools and methods to rank existing solvents based on
risks posed or favorable physical properties.7–13 These
guides allow the end user to assess and adjust their reaction
manifold by aiding in the identification of a suitable solvent
alternative which adheres to best practice in safety guide-
lines and regulation.14,15 Despite these efforts, direct substi-
tution can be challenging particularly with dipolar aprotics.
The unique physical properties of these solvents make
them indispensable to practitioners and, as such, novel al-
ternatives are required.
DMI
MeO
H
OH OH
• B. Pt.: 234 °C
• Density: 1.15 g/mL
O
OH
HO
δ
δ
δ
H = 7.5 MPa1/2
D = 17.6 MPa1/2
P = 7.1 MPa1/2
• HSP:
O
OH OH
sorbitol
H
OMe
Figure 1 Sorbitol as the platform molecule in the synthesis of DMI
Palladium-catalyzed bond-forming reactions are an im-
portant tool within the pharmaceutical arena and are often
key steps in the syntheses of modern drug compounds
(Scheme 1).42–46 Reactions such as the Suzuki–Miyaura
(SM)47,48 and Mizoroki–Heck (MH),49 allow for late-stage
derivatization and divergent syntheses from readily avail-
able materials, and the Sonogashira reaction facilitates the
installation of an internal alkyne,50 a versatile functional
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
K. L. Wilson et al.
Letter
Synlett
Table 1 Reaction Optimization of Suzuki–Miyaura Conditionsa
Pd(dppf)Cl2 (4 mol%)
X
R2
B(OR)2
R1
R1
R2
K3PO4 (3 equiv.), H2O (5 equiv.)
DMI, 60 °C, 1 h
Pd(dppf)Cl2 (X mol%)
Br
1
2
3b–m
B(OH)2
H2O (5 equiv.)
K3PO4 (3 equiv.)
DMI, T °C, 1 h
Boronic acids
Me
p-Tol
p-Tol
Me
p-Tol
1a
2a
3a
F3C
O2N
MeO
Entry
Reaction conditions
Conversion (%)b
3b, 80%
3c, 88%
3d, 81%
1
2
3
4
5
6
30 °C, Pd(dppf)Cl2 (4 mol%)
40 °C, Pd(dppf)Cl2 (4 mol%)
60 °C, Pd(dppf)Cl2 (4 mol%)
40 °C, Pd(dppf)Cl2 (2 mol%)
40 °C, Pd(dppf)Cl2 (1 mol%)
40 °C, Pd(dppf)Cl2 (0.5 mol%)
72
93
F
O
100
92
Ph
Ph
CN
Me
MeO
3e, 69%a
3f, quant.c
3g, 65%b
92
80
Boronic esters
N
N
Ph
p-Tol
a 4-Bromotoluene (1 equiv., 0.25 mmol), phenylboronic acid (1 equiv.,
0.25 mmol), K3PO4 (3 equiv., 0.75 mmol), H2O (5 equiv., 1.25 mmol),
DMI (1 mL, 0.25 M).
Cl
N
b NMR conversion given as an average over 2 reactions.
N
SO2Ph
3h, 87%d
3i, 86%
3j, 62%c
group and important intermediate for subsequent elabora-
tion. The robustness of these transformations often relies
on the use of solvents of concern. THF and 1,4-dioxane are
common solvents used for the SM reaction whilst DMF is
the traditional medium within the Sonogashira reaction.51
p-Tol
p-Tol
BocN
3k, 81%
S
F3CO
3l, 78%
3m, 92%b,c
Scheme 2 DMI-based Suzuki–Miyaura reaction. Reagents and condi-
tions: Pd(dppf)Cl2·CH2Cl2 (4 mol%), organoboron (1 equiv., 0.25 mmol),
aryl/vinyl (pseudo)halide (1 equiv., 0.25 mmol), K3PO4 (3 equiv., 0.75
mmol), DMI (1 mL), 1 h, 60 °C. a X = OTf. b X = Cl, Pd(OAc)2 (4 mol%),
SPhos (8 mol%). c Pd cat. (2 mol%, 0.005 mmol). d 1.2 equiv. phenylbo-
ronic acid.
a) Suzuki-Miyaura cross-coupling
· Rapid synthesis of biaryl
R2
Pd cat.
base
X
B(OR)2
chemotypes
R2
R1
R1
· Commercial building blocks
· Highest usage cross-coupling
reaction
b) Mizoroki-Heck
· Generation of functionalized
olefins
· Versatile functional group
Pd cat.
base
X
R2
R2
R1
R1
strate classes, we found it was necessary to use a slightly
higher catalyst loading of 4 mol%. With these conditions
(Table 1, entry 3), we were able to carry out the coupling of
a range of aromatic (3b,l) and vinyl (3g,k) boronic acids and
pinacol esters in high yield. Additionally, as is standard
within the SM cross-coupling, electrophile variation was
well tolerated (3c,e,m). Aromatics bearing electron-with-
drawing and electron-donating groups were comparable in
efficiency.
We next focused on the optimization of the MH cross-
coupling (Table 2). Initial screening of the iodobenzene (4a)
system using Pd(PPh3)2Cl2 catalyst revealed excellent reac-
tivity at 80 °C with complete conversion to the desired
product 6a in 8 hours (Table 2, entry 1). We were subse-
quently able to reduce reaction time (Table 2, entry 2) but
found that lower temperatures resulted in a loss of conver-
sion (Table 2, entry 3). These conditions were then applied
to the bromobenzene (4a′) system with only trace amounts
of product observed (Table 2, entry 4). However, by increas-
ing the temperature, we found we were able to achieve high
conversion over 24 hours (Table 2, entry 6).
· High frequency reaction
c) Sonogashira cross-coupling
R2
· Generation of internal alkynes
· Versatile functional group
· High frequency reaction
Pd cat.
I
R1
R2
R1
Cu cat.
base
Scheme 1 The most common cross-coupling reactions in pharma
Our aim was to assess whether DMI was viable as a me-
dium for these most common cross-coupling processes. We
began our investigations by assessing the utility of DMI
within the SM cross-coupling of phenylboronic acid and p-
bromotoluene (Table 1). Using conditions established with-
in our laboratories,52 an initial temperature screen demon-
strated that the coupling could be carried out with high
conversions at 40 °C in 1 h (Table 1, entry 2). Additionally,
the catalyst loading could be reduced to as low as 1 mol%
before any significant erosion of conversion was observed.
Whilst we were able to synthesize a small range of sub-
strates (Scheme 2, 3f,j,m) using 2 mol% catalyst loading at
60 °C, to accommodate a broader efficiency within the sub-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
K. L. Wilson et al.
Letter
Synlett
Table 2 Reaction Optimization of Mizoroki–Heck Conditionsa
Pd(dppf)Cl2·CH2Cl2 (5 mol%)
Et3N (3 equiv.), DMI, T °C, t h
X
R2
R2
R1
R1
O
4
5
6b–m
X
O
Pd(PPh3)2Cl2 (5 mol%)
OMe
OMe
Et3N (3 equiv.)
DMI, T °C, t h
O
O
O
4a, X = I
5a
6a
4a', X = Br
4f, X = I, R = NO2
OMe
OMe
Me
OMe
Entry
Reaction conditions
Conversion (%)b
OMe
O
NO2
6b, 91%a
6c, 68%a
6d, 83%a
1
2
3
4
5
6
7
8
9
4a Pd(PPh3)2Cl2, 80 °C, 8 h
4a Pd(PPh3)2Cl2, 80 °C, 1 h
4a Pd(PPh3)2Cl2, 60 °C, 1 h
4a′ Pd(PPh3)2Cl2, 80 °C, 1 h
4a′ Pd(PPh3)2Cl2, 80 °C, 24 h
4a′ Pd(PPh3)2Cl2, 115 °C, 24 h
4f Pd(PPh3)2Cl2, 80 °C, 1 h
4f Pd(PPh3)4, 80 °C, 1 h
100
100
12
<1
81
98
0
O
O
O
OMe
O2N
OMe
OMe
MeO
F3C
6e, 68%b
6f, 85%a
6i, 50%b
6l, 76%a,c
6g, 72%b
6j, 63%b,c
6m, 47%a
O
O
O
O
Me
F
OMe
Me
0
N
4f Pd(dppf)Cl2, 80 °C, 1 h
85
N
Me
6h, 86%b
aIodobenzene (4a), bromobenzene (4a′), or 4-iodonitrobenzene
(4f, 1 equiv., 0.25 mmol), 5a (2 equiv., 0.5 mmol), Pd cat. (5 mol%,
0.013 mmol), Et3N (3 equiv., 0.75 mmol), and DMI (1 mL, 0.25 M).
bNMR conversion given as an average over 2 reactions.
O
O
Ph
NMe2
Ph
O2N
MeO
Cl
Upon moving to investigate the scope of the reaction,
we noticed that whilst coupling proceeded efficiently with
electron-rich haloarenes, the coupling of 4-iodonitroben-
zene 4f using Pd(PPh3)2Cl2 was unsuccessful (Table 2, entry
7). However, following a brief catalyst screen, Pd(dppf)Cl2
was found to deliver high reactivity and could facilitate the
coupling in good isolated yield (Table 2, entry 9).
6k, 86%a,c
Scheme 3 DMI-based Mizoroki–Heck reaction. Reagents and condi-
tions: Pd(dppf)Cl2·CH2Cl2 (5 mol%, 0.013 mmol), aryl halide (1 equiv.,
0.25 mmol), olefin (2 equiv., 0.5 mmol), Et3N (3 equiv., 0.75 mmol),
DMI (1 mL). a X = I, 1 h, 80 °C. b X = Br, 24 h, 115 °C. c K3PO4 (3 equiv.,
0.75 mmol) used as base.
This catalyst system was effective when used to exam-
ine the substrate scope (Scheme 3). Good efficiency was ob-
served in the coupling of both aryl iodides (6c,e) and bro-
mides (6j,h) and allowed for the coupling of electron-rich
(6b,e) and electron-deficient (6d,g) arenes. Additionally,
some variance of activated alkene 5 could be tolerated with
the coupling of methyl vinyl ketone, phenyl vinyl ketone,
and N,N-dimethylacrylamide undergoing successful cou-
pling to furnish 6i,k,m, respectively.
Finally, we concluded our study on the use of DMI in Pd-
catalyzed bond-forming reactions by investigating its appli-
cation within the Sonogashira reaction. Using previously
optimized conditions,31 we found that the coupling of 4-
fluoroiodobenzene with phenylacetylene, to deliver 9a,
proceeded smoothly and in high yield, based on this result
further optimization of the manifold was not deemed nec-
essary.
dergoing conversion into 9f with an 84% isolated yield. Sim-
ilarly, a variety of groups were tolerated on the alkyne, with
aryl (9h), vinyl (9l), and alkyl (9j) functionality coupling
successfully. In addition, alkynes substituted with modifi-
able groups such as BMIDA and TIPS, furnished products 9g
and 9k in high yields.
With regards to practicality, DMI has a high boiling
point and issues may be expected in terms of its removal
from products. In our hands, we found that standard aque-
ous washing procedures were sufficient to remove the ma-
jority of DMI from the crude products, with any remaining
traces removed during purification by column chromatog-
raphy. In this context, DMI can be viewed as having similar
purification considerations as would be typically required
when using DMF or NMP.
In summary, we have shown the compatibility of the
bio-based solvent DMI as an alternative to solvents of con-
cern, within Pd-catalyzed bond-forming processes. Each
transformation (SM, MH, and Sonogashira), displays excel-
lent generality within the investigation of scope and facili-
tated the preparation of a range of small molecules. No po-
tential limitations (such as sensitivity towards reagents)
were identified throughout this study, and the nonmuta-
Accordingly, these conditions were applied to a brief
substrate scope (Scheme 4). A range of aryl iodides were
coupled under mild conditions in 1 hour, with multiple
substitution patterns tolerated around the aryl ring (9b,d,j).
In addition, electron-deficient aryl bromides also demon-
strated compatibility, with 5-bromo-2-nitropyridine un-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
K. L. Wilson et al.
Letter
Synlett
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Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%)
Et3N (1.1 equiv), DMI (0.5 M), 25 °C, 1 h
I
R1
R2
R1
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8
9a–l
Ph
Ph
Ph
O2N
F
MeO
9a, 92%
9b, 97%
9c, 98%
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Ph
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Cl
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O
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9g, 88%
9h, 87%
9i, 65%
Me
TIPS
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OMe
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Scheme 4 DMI-based Sonogashira coupling. Reagents and conditions:
Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), aryl halide (1 equiv., 0.25 mmol),
alkyne (1.05 equiv., 0.26 mmol), Et3N (3 equiv., 0.75 mmol), DMI (0.5
mL), 1 h, 25 °C. a 5-Bromo-2-nitropyridine as coupling partner.
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Funding Information
We thank the University of Strathclyde for a PhD studentship (KLW)
and Merck KGaA, Darmstadt, Germany, for financial and material sup-
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)(
Acknowledgment
We thank GSK for provision of dimethyl isosorbide, and the EPSRC UK
National Mass Spectrometry Facility at Swansea University for analy-
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EtOAc in petroleum ether) to afford the title compound as a
white solid (42.9 mg, quant.). 1H NMR (400 MHz, CDCl3): δ =
7.62 (dd, J = 8.3, 1.2 Hz, 2 H), 7.53 (d, J = 8.1 Hz, 2 H), 7.46 (t,
J = 7.6 Hz, 2 H), 7.38–7.33 (m, 1 H), 7.29 (d, J = 7.9 Hz, 2 H), 2.43
(s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 141.3, 138.5, 137.2,
129.6, 128.9, 127.1, 21.2.
(55) General Procedure for Mizoroki–Heck Coupling in DMI
To an oven-dried
5 mL microwave vessel was added
(38) Luzzi, L. A.; Ma, J. K. H. US 4228162, 1980.
Pd(dppf)Cl2·CH2Cl2 (5 mol%) and aryl halide (1 equiv.). The
vessel was capped and purged with N2 before addition of DMI (1
mL, 0.25 M), alkene coupling partner (2 equiv.), and Et3N (3
equiv.). The reaction mixture was heated to either 80 °C (X = I)
or 115 °C (X = Br) and maintained at this temperature with stir-
ring for 1 h (X = I) or 24 h (X = Br) before the vessel was vented
and decapped. The solution was then diluted with EtOAc (10
mL) and washed with water (2 × 20 mL) and brine (2 × 20 mL).
The organics were then passed through a hydrophobic frit and
concentrated under reduced pressure to give a residue, which
was purified by flash chromatography (silica gel) to afford the
product.
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Chem. 2017, 19, 952.
(41) Jad, Y. E.; Govender, T.; Kruger, H. G.; El-Faham, A.; de la Torre,
B. G.; Albericio, F. Org. Process Res. Dev. 2017, 21, 365.
(42) King, A. O.; Yasuda, N. Palladium-Catalyzed Cross-Coupling Reac-
tions in the Synthesis of Pharmaceuticals; Springer: Heidelberg,
2004.
(43) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.
2005, 44, 4442.
Methyl Cinnamate (6a)
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Drug Discovery; Royal Society of Chemistry: Cambridge, 2016.
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(48) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(49) Oestreich, M. The Mizoroki–Heck Reaction; Wiley: Chichester,
2009.
Prepared according to the General Procedure using
Pd(dppf)Cl2·CH2Cl2 (10.2 mg, 0.013 mmol, 5 mol%), iodoben-
zene (4a, 28 μL, 0.25 mmol, 1 equiv.), methyl acrylate (5a, 45 μL,
0.5 mmol, 2 equiv.), Et3N (105 μL, 0.75 mmol, 3 equiv.), DMI (1
mL, 0.25 M). After 1 h, the reaction mixture was subjected to
the purification method outlined in the General Procedure
(silica gel, 0–5% EtOAc in petroleum ether) to afford the title
compound as a white solid (40 mg, 99%). 1H NMR (500 MHz,
CDCl3): δ = 7.70 (d, J = 16.0 Hz, 1 H), 7.53 (dd, J = 6.6, 2.8 Hz, 2
(50) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
(51) Sigma-Aldrich, Cross-Coupling Reaction Manual: Desk Refer-
H), 7.41–7.37 (m, 3 H), 6.45 (d, J = 16.0 Hz, 1 H), 3.81 (s, 3 H). 13
C
ence,
https://www.sigmaaldrich.com/content/dam/sigma-
NMR (101 MHz, CDCl3): δ = 167.6, 145.0, 134.6, 130.4, 129.0,
128.2, 117.9, 51.8.
(56) General Procedure for Sonogashira Coupling in DMI
aldrich/docs/Aldrich/Method/1/83784-Cross-Coupling-Selec-
tion-Brochure.pdf (accessed August 2018).
(52) Fyfe, J. W. B.; Valverde, E.; Seath, C. P.; Kennedy, A. R.; Redmond,
J. M.; Anderson, N. A.; Watson, A. J. B. Chem. Eur. J. 2015, 21,
8951.
(53) Australian NICNAS: Regulatory Information on DMI
https://www.nicnas.gov.au/search?query = arlasolve+dmi&coll
ection = nicnas-meta (accessed August 2018).
To an oven-dried 5 mL microwave vessel was added
Pd(PPh3)2Cl2 (2 mol%), aryl halide (1 equiv.), and alkyne cou-
pling partner (1.05 equiv.). The vessel was capped and purged
with N2 before addition of DMI (0.5 mL, 0.5 M), and Et3N (1.1
equiv.). The reaction mixture was maintained at room tempera-
ture (25 °C) with stirring for 1 h before the vessel was vented
and decapped. The solution was then diluted with EtOAc (10
mL) and washed with water (2 × 20 mL) and brine (2 × 20 mL).
The organics were then passed through a hydrophobic frit and
concentrated under reduced pressure to give a residue, which
was purified by flash chromatography (silica gel) to afford the
product.
(54) General Procedure for Suzuki–Miyaura Coupling in DMI
To an oven-dried
5 mL microwave vessel was added
Pd(dppf)Cl2·CH2Cl2 (4 mol%), aryl halide/pseudohalide (1
equiv.), organoboron (1 equiv.), and K3PO4 (3 equiv.). The vessel
was then capped and purged with N2 before addition of DMI (1
mL, 0.25 M) and H2O (5 equiv.). The reaction mixture was
heated to 60 °C and maintained at this temperature with stir-
ring for 1 h before the vessel was vented and decapped. The
solution was then diluted with EtOAc (10 mL) and washed with
water (2 × 20 mL) and brine (2 × 20 mL). The organics were then
passed through a hydrophobic frit and concentrated under
reduced pressure to give a residue, which was purified by flash
chromatography (silica gel) to afford the product.
1-Fluoro-4-(phenylethynyl)benzene (9a)
Prepared according to the General Procedure using Pd(PPh3)2Cl2
(3.5 mg, 0.005 mmol, 2 mol%), 4-fluoroiodobenzene (7a, 29 μL,
0.25 mmol, 1 equiv.), phenylacetylene (8a, 29 μL, 0.26 mmol,
1.05 equiv.), Et3N (38 μL, 0.28 mmol, 1.1 equiv.), DMI (0.5 mL,
0.5 M). After 1 h, the reaction mixture was subjected to the
purification method outlined in the General Procedure (silica
gel, 0–5% EtOAc in petroleum ether) to afford the title com-
pound as a white solid (45 mg, 92%). 1H NMR (500 MHz, CDCl3):
δ = 7.55–7.50 (m, 4 H), 7.38–7.33 (m, 3 H), 7.05 (t, J = 8.7 Hz, 2
H). 13C NMR (126 MHz, CDCl3): δ = 162.7 (d, 1J = 249.6 Hz), 133.6
4-Phenyltoluene (3a)
Prepared according to the General Procedure using
Pd(dppf)Cl2·CH2Cl2 (8.2 mg, 0.01 mmol, 4 mol%), bromotoluene
(1a, 43 mg, 0.25 mmol, 1 equiv.), phenylboronic acid (2a, 30.5
mg, 0.25 mmol, 1 equiv.), K3PO4 (159 mg, 0.75 mmol, 3 equiv.),
DMI (1 mL, 0.25 M), and H2O (23 μL, 1.25 mmol, 5 equiv.). After
1 h, the reaction mixture was subjected to the purification
method outlined in the General Procedure (silica gel, 0–5%
3
4
(d, J = 8.2 Hz), 131.7, 128.5, 128.5, 123.3, 119.5 (d, J = 3.4 Hz),
115.8 (d, 2J = 22.4 Hz), 89.2, 88.4. 19F NMR (471 MHz, CDCl3): δ =
–110.98.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E