Microwave-mediated suzuki-miyaura cross-couplings of thioether- and ortho- substituted methylphenylboronic acid esters

Article abstract of DOI:10.1055/s-0032-1317205

Hiterto unsuccessful cross-couplings of ortho-substituted or thioether-substituted methylphenylboronates have now been achieved, under microwave conditions, enabling the synthesis of a library of novel biaryls. Tetrakis(triphenylphosphine)palladium and va

Full text of DOI:10.1055/s-0032-1317205

LETTER
▌2477
lMetteircrowave-Mediated Suzuki–Miyaura Cross-Couplings of Thioether- and
ortho-Substituted Methylphenylboronic Acid Esters
Cross-Couplings of Methylphenylboronic Acid Esters
Christine B. Baltus,a Neil J. Press,b John Spencer*1,a
a
School of Science, University of Greenwich at Medway, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK
b
Novartis Pharmaceuticals UK Ltd, Horsham, Sussex, RH12 5AB, UK
Fax +44(1273)876687; E-mail: j.spencer@sussex.ac.uk
Received: 04.07.2012; Accepted after revision: 14.08.2012
ed coupling conditions in water [Pd(OAc)2, TBAB].3
Abstract: Hiterto unsuccessful cross-couplings of ortho-substitut-
However, Itoh et al. recently found that Pd(PPh3)4 was an
effective catalyst for the thermally mediated SM coupling
ed or thioether-substituted methylphenylboronates have now been
achieved, under microwave conditions, enabling the synthesis of a
library of novel biaryls. Tetrakis(triphenylphosphine)palladium and
of bromobenzenethioethers with aqueous Na2CO3 in
various bases, for example, sodium carbonate or cesium fluoride, toluene4 which encouraged us to explore similar, albeit
were found to mediate the crucial C–C bond-forming cross-
coupling reaction.
microwave-mediated, conditions for the coupling of our
substituted methylphenylboronic acid esters (Scheme 1,
Key words: palladium, catalysis, cross-coupling, biaryls, micro-
waves
example below).
A rapid screen of precatalysts, bases, and solvents using a
parallel optimization method,5 with automated solution
dispensers, auto-sampler microwave, and an automated
LC–MS analyzer, enabled us to determine suitable condi-
tions for the coupling reactions of thioether-containing
boronates 1 (see Supporting Information). The reaction
optimization experiments were carried out on compound
1a with 1-bromo-4-nitrobenzene (2a) under microwave
irradiation at 130 °C for 10 minutes (Table 1).
We have previously found that the attempted Suzuki–
Miyaura (SM) coupling of sulfur-containing methyl-
phenylboronic esters or ortho-substituted methylphenyl-
boronic esters with aryl bromides was inefficient leading
to mixtures of largely protodeborylated product or starting
materials,2 when employing standard microwave-mediat-
Table 1 Opitimization of Reaction Conditions
O2N
N
O
Pd (cat.)
N
N
B
S
+
Br
MW, 130 °C, 10 min
O
S
N
NO2
3
1a
2
Entry
Aryl halide
Catalyst
(mol%)
Conditions6 Product
Yield
(%)a
N
N
NO2
1
2
2a
5
3
A
B
3a
91
85
Br
NO2
S
NO2
NO2
N
N
N
N
2b
2c
3a
3c
Br
Br
S
S
3
4
5
3
A
C
50
81
a Isolated yields after purification by chromatography. Conditions A: 1a (1.1 equiv), Pd(PPh3)4 (5 mol%), CsF (3 equiv), THF, 130 °C, 10 min,
microwave irradiation (maximum power 300 W). Conditions B: 1a (1.1 equiv), Pd(PPh3)4, Na2CO3 (3 equiv), toluene–EtOH–H2O (1:1:1), 150
°C, 10 min, microwave irradiation (maximum power 300 W). Conditions C: 1a (1.1 equiv), Pd(PPh3)4, Na2CO3 (3 equiv), toluene–EtOH–H2O
(1:1:1), 130 °C, 10 min, microwave irradiation (maximum power 300 W).
SYNLETT 2012, 23, 2477–2480
Advanced online publication: 21.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317205; Art ID: ST-2012-D0570-L
© Georg Thieme Verlag Stuttgart · New York

2478
C. B. Baltus et al.
LETTER
O
O
O
O
N
N
N
N
B
B
base
+
SH
S
Br
1a
Scheme 1
optimal since the biphenyl products were obtained in good
yields employing a relatively low catalyst loading.
Pd(PPh3)4
Na2CO3
O
Ar
B
Br Ar
RS
+
RS
toluene
EtOH
H2O
O
It is pertinent to mention that the SM coupling reaction is
better if the thioether-substituted boronic ester is purified
by chromatography on silica gel first. Hence, following
the preparation of 1, supported scavenger agents are usu-
ally unable to remove traces of thiol, which are known to
act as poisons towards palladium catalysts.4
1
2
3
MW, 130 °C, 10 min
O
H
MeS
Me2N
S
Pd(PPh3)4
Na2CO3
N
3e
38%a
O
3d
65%
N
Me
Ar
N
+
Br Ar
B
N
toluene
EtOH
O
5
H2O
Nu
6
MW, 130 °C, 10 min
4
Nu
N
N
S
MeS
3g
85%
3f
81%
O
N
N
6a
92%
Et2N
6b
76%
S
Me2N
MeS
Me2N
BocN
3h
64%
3i
58%
OMe
NH2
Scheme 2 Isolated yields given after purification by chromatography.
a Mixture with biphenyl/boronic ester (84:16), calculated yield by 1H
NMR.
N
Et2N
6c
63%a
6d
< 9%
O
Table 1 summarizes some of the results obtained. The re-
action was first achieved using an aryl bromide containing
an electron-withdrawing group to ensure favorable cou-
pling conditions. A number of salient observations can be
made: high reaction temperatures in the microwave do not
appear to be deleterious to reaction yields – at 150 °C an
85% yield for 3b was observed (Table 1, entry 2) and at
130 °C, a 91% yield for 3a was noted (Table 1, entry 1).
An electron-rich aryl bromide, 1-bromotoluene (2c), was
also tested, affording a moderate yield when using condi-
tions A (e.g., 50% yield, Table 1, entry 3) although a bet-
ter yield was observed when using conditions C (81%
yield, Table 1, entry 4). Conditions C were deemed to be
N
NO2
N
O
6e
79%
6f
88%
MeS
Scheme 4 Percentage yields given after purification by chromatogra-
phy. Mixture with protodeborylated product (87:13), calculated
a
yield by 1H NMR.
O
O
O
Pd
B
+
Br
O
MW, 150 °C, 10 min
Et2N
4a
5a
6a
Et2N
Scheme 3
Synlett 2012, 23, 2477–2480
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Couplings of Methylphenylboronic Acid Esters
2479
A range of sulfur-containing phenylboronic acid pinacol The best conditions found were once again where
esters were coupled in a SM reaction with several aryl Pd(PPh3)4 was used as precatalyst with either CsF as a
bromides using the previously established conditions C base in THF or with K3PO4 or Na2CO3 as base in toluene–
(Scheme 2). The biaryl products 3 were generally ob- EtOH–H2O (1:1:1). The latter conditions were selected
tained in very good yields, even with electron-rich aryl for the SM coupling of 2-substituted phenylboronic esters
bromide coupling partners, although moderate yields in order to synthesize a library of 2-substituted biaryls 6
were achieved when using a 2-substituted aryl bromide (Scheme 4). The latter were obtained mainly in good
(e.g., 85% for 3g, 58% for 3i).
yields (e.g., 92% for 6a, 88% for 6f) and this appears to
also operate for the coupling of a 2-substituted thioether
methylphenylboronic acid ester (to afford 6e), which,
gratifyingly, satisfies both the criteria that we wished to
resolve. However, a very low yield was observed for the
aniline product 6d.
Following on from the success of the optimization process
with thioether derivatives, a screen of catalysts, bases, li-
gands, and solvent systems was undertaken in order to op-
timize the coupling reactions of ortho-substituted
boronates using 2-(N,N-diethylaminomethyl)phenylbo-
ronic acid pinacol ester (4a) as the boronate coupling part- Once the optimal conditions for the SM coupling of ortho-
ner and 4-bromoacetophenone (5a) as the aryl bromide for substituted phenylboronic esters were ascertained, the
the SM coupling (Scheme 3, also Supporting Information, synthesis of a twenty-member library of ortho-substituted
Figure S2).
piperazin-1-ylmethylbiaryls was undertaken, which, post-
NO2
O2N
NO2
NO2
N
N
N
N
N
N
R1
N
R1
N
R1
N
R1
6g R1 = Boc (70%)
7a R1 = H (99%)
6h R1 = Boc (74%)
7b R1 = H (97%)
6i R1 = Boc (90%)
7c R1 = H (94%)
6j R1 = Boc (87%)
7d R1 = H (93%)
X
X
X
X
N
N
N
N
N
N
N
N
N
O
O
O
O
S
S
O
O
Y
8a X = NO2 (91%)
9a X = NH2 (99%)
8b X = NO2 (56%)
9b X = NH2 (69%)
8c X = NO2 Y = CN (54%)
9c X = NH2 Y = CH2NH2 (54%)
8d X = NO2 (43%)
9d X = NH2 (99%)
O
NH
OMe
O
H
HN
N
N
O
N
N
N
O
N
N
N
N
O
N
O
O
N
S
S
O
O
Me
NH
O
10a (36%)
10b (99%)
10c (29%)
10d (74%)
Figure 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2477–2480

2480
C. B. Baltus et al.
LETTER
1a (164 mg, 0.5 mmol,), 2a (111 mg, 0.55 mmol), CsF (228
mg, 1.5 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), and THF
(2 mL) were placed in a sealed microwave vial and stirred
under microwave irradiation (maximum power 300 W) at
130 °C for 10 min. The mixture was cooled to r.t., diluted
with EtOAc (20 mL) and H2O (10 mL), and extracted with
EtOAc. The organic layer was washed with a sat. NaCl
solution, dried over anhyd MgSO4, filtered, and
biphenyl synthesis (6g–j), used conditions recently re-
ported by us. Hence, Boc group removal (TFA–CH2Cl2,
then a basic wash), giving 7a–d, was followed by pipera-
zine functionalization to an amide or a sulfonamide, af-
fording 8a–d.2c The nitro group was reduced [flow-
chemistry hydrogenation (H-Cube) catalyzed by Raney
nickel], giving 9a–d, and the resulting amino group was
functionalized to an amide, a sulfonamide, or a pyrrole, fi-
nally yielding 10a–d (Figure 1).
concentrated under reduced pressure to give 269 mg of an
orange solid. The crude product was purified by
chromatography on silica gel (hexane–EtOAc, 8:2) to give
147 mg of the expected product as a yellow solid in 91%
yield. 1H NMR (400 MHz, CDCl3): δ = 8.55 (d, 2 H, J = 4.8
Hz), 8.29 (d, 2 H, J = 8.8 Hz), 7.72 (d, 2 H, J = 8.8 Hz), 7.57
(m, 4 H), 6.70 (dd, 1 H, J1 and 2 = 4.8 Hz), 4.47 (s, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.9, 157.3 (2 C), 147.2,
147.1, 138.8, 137.6, 129.9 (2 C), 127.7 (2 C), 127.5 (2 C),
124.1 (2 C), 116.7, 34.8 ppm. HRMS (ES): m/z calcd for
[C17H13O2N3S + H]+ 324.0801; found: 324.0805. Anal.
Calcd for C17H13N3O2S: C, 63.1; H, 4.1; N, 13.0. Found: C,
62.9; H, 4.1; N, 12.9.
In conclusion, our biphenyl-building methodology rely-
ing on an initial nucleophilic displacement of a bromo-
methylbenzene boronic acid ester is now complete since it
is now amenable to both 2-substituted and thioether-
containing boronate starting materials. Applications of
this reaction sequence include the synthesis of novel bi-
phenyls, with the potential for drug discovery, and poten-
tial ligands 3f–i for the synthesis of unsymmetrical SCN
pincer palladacycles,7 with potential for catalysis. Studies
in the latter direction are currently underway, having al-
ready yielded a number of interesting pincer pallada-
cycles,8 and will be reported in due course.
General Procedure for the SM Coupling of Sulfur-
Substituted Methylphenylboronic Esters Using
Conditions C: 2-[(3′-Nitrobiphenyl-4-
yl)methylthio]pyrimidine (3b)
1a (125 mg, 0.38 mmol), 3-bromonitrobenzene (2b, 85 mg,
0.42 mmol), Na2CO3 (121 mg, 1.14 mmol), Pd(PPh3)4 (12
mg, 0.01 mmol), toluene (1 mL), EtOH (1 mL), and H2O
(1 mL) were placed in a sealed microwave vial and stirred
under microwave irradiation (maximum power 300 W) at
130 °C for 10 min. The mixture was cooled to r.t., diluted
with EtOAc (20 mL) and H2O (10 mL), and extracted with
EtOAc. The organic layer was washed with a sat. NaCl
solution, dried over anhyd MgSO4, filtered, and
Acknowledgment
Novartis is thanked for funding this work (PhD award to C.B.B.).
The EPSRC Mass Spectrometry Unit (University of Swansea)
is thanked for HRMS measurements. Johnson Matthey PLC is
thanked for a loan of Pd salts.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
concentrated under reduced pressure to give 195 mg of a
brown oil. The crude product was purified by
m
o
ti
chromatography on silica gel (hexane–EtOAc, 8:2) to give
104 mg of the expected product as a yellow solid in 85%
yield. 1H NMR (400 MHz, CDCl3): δ = 8.53 (d, 2 H, J = 4.8
Hz), 4.41 (m, 1 H), 8.17 (dd, 1 H, J1 = 7.9 Hz, J2 = 2.2 Hz),
7.87 (d, 1 H, J = 7.9 Hz), 7.62–7.52 (m, 5 H), 6.98 (dd, 1 H,
J1 and 2 = 4.8 Hz), 4.46 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.9, 157.3 (2 C), 148.8, 142.5, 138.3, 137.5,
132.9, 129.9 (2 C), 129.7, 127.2 (2 C), 122.0, 121.8, 116.7,
34.8 ppm. HRMS (ES): m/z calcd for [C17H13O2N3S+H]+
324.0801; found: 324.0804. Anal. Calcd for C17H13N3O2S:
C, 63.1; H, 4.1; N, 13.0. Found: C, 62.9; H, 4.0; N, 13.1.
(7) (a) Kozlov, V. A.; Aleksanyan, D. V.; Nelyubina, Y. V.;
Lyssenko, K. A.; Vasil’ev, A. A.; Petrovskii, P. V.; Odinets,
I. L. Organometallics 2010, 29, 2054; and references cited
therein. (b) The Chemistry of Pincer Compounds, 1st ed.
Morales-Morales, D.; Jensen, C. M., Eds.; Elsevier:
Amsterdam/Oxford, 2007.
References and Notes
(1) Current address: Department of Chemistry, School of Life
Sciences, University of Sussex, Falmer, Brighton, BN1 9QJ,
UK.
(2) (a) Spencer, J.; Baltus, C. B.; Patel, H.; Press, N. J.; Callear,
S. K.; Male, L.; Coles, S. J. ACS Comb. Sci. 2011, 13, 24.
(b) Spencer, J.; Burd, A. P.; Adatia, T.; Goodwin, C. A.;
Merette, S. A. M.; Scully, M. F.; Deadman, J. J. Tetrahedron
2002, 58, 1551. (c) Spencer, J.; Baltus, C. B.; Press, N. J.;
Harrington, R. W.; Clegg, W. Tetrahedron Lett. 2011, 52,
3963.
(3) Leadbeater, N.; Marco, M. J. Org. Chem. 2003, 68, 888.
(4) Itoh, T.; Mase, T. J. Org. Chem. 2006, 71, 2203.
(5) A total of 27 conditions were evaluated: catalysts: PdCl2,
Pd(OAc)2, and Pd(PPh3)4; bases: CsF, K3PO4, and Na2CO3;
solvents: H2O, THF, and toluene–EtOH–H2O (1:1:1).
(6) General Procedure for the SM Coupling of Sulfur-
Substituted Methylphenylboronic Esters Using Conditions
A: 2-[(4′-Nitrobiphenyl-4-yl)methylthio]pyrimidine (3a)
(8) (a) Spencer, J.; Baltus, C. B.; Press, N. J. unpublished
results. (b) Baltus, C. B. PhD Thesis; University of
Greenwich: UK, 2011.
Synlett 2012, 23, 2477–2480
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