A one-pot, single-solvent process for tandem, catalyzed C-H borylation-Suzuki-Miyaura cross-coupling sequences

Article abstract of DOI:10.1055/s-0028-1087374

Methyl tert-butyl ether is a suitable solvent for iridium-catalyzed C-H borylation followed, in the same pot, by palladium-catalyzed Suzuki-Miyaura cross-coupling sequences, giving high yields of biaryls. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087374

CLUSTER
147
A One-Pot, Single-Solvent Process for Tandem, Catalyzed C–H Borylation–
Suzuki–Miyaura Cross-Coupling Sequences
T
andem, Cata
e
C
–H
t
eion–Suzukr
H
s-Coupling arrisson,a James Morris,b Patrick G. Steel,*a Todd B. Marder*a
a
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK
Fax +44(191)3844737; E-mail: todd.marder@durham.ac.uk; E-mail: p.g.steel@durham.ac.uk
Syngenta Ltd., Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK
b
Received 12 September 2008
quences. A number of ‘one-pot’ procedures have been
described that elaborate the arylboronate ester products of
aromatic C–H borylation providing phenols,12 arylchlo-
rides and bromides,13 arylboronic acids and trifluorobo-
rates,14 alkyl- and arylanilines,15 aryl ethers,15 arylamine
boronate esters,16 chiral a,a-diaryl methylammonium
chlorides17 and for use in Suzuki–Miyaura cross-cou-
plings.7,18
Abstract: Methyl tert-butyl ether is a suitable solvent for iridium-
catalyzed C–H borylation followed, in the same pot, by palladium-
catalyzed Suzuki–Miyaura cross-coupling sequences, giving high
yields of biaryls.
Key words: biaryls, cross-coupling, homogeneous catalysis, bor-
onate ester, tandem reactions
Aryl and heteroaryl boronates1 are very important organic
intermediates, for example, in applications in a variety of
transformations including Suzuki–Miyaura cross-cou-
pling reactions,2 copper-catalyzed C–O and C–N coupling
reactions,3 and rhodium-catalyzed conjugate additions to
carbonyl compounds.4 Following our observation of sub-
stoichiometric arene borylation during the formation of
novel [(h6-arene)Ir(Bcat)3] (cat = 1,2-O2C6H4) complexes
from reaction of [(cod)Ir(h-indenyl)] with excess HBcat
in aromatic solvents,5 Ishiyama, Miyaura, and Hartwig et
al.6 and Smith et al.7 have developed in situ Ir catalysts for
the borylation of aromatic C–H bonds under mild condi-
tions, employing [(cod)Ir(X)] precursors (X = Cl, OMe,
h-indenyl) in the presence of bidentate ligands. The most
widely used system at present employs [(cod)Ir(m-OMe)]2
(1) plus 4,4¢-di-tert-butyl-2,2¢-bipyridine.8 Density func-
tional theory (DFT) calculations by Sakaki and co-work-
ers,9 in agreement with the experimental data, suggest that
the key catalytic intermediate that leads to C–H activation
Hindering further development of this ‘one-pot’ technol-
ogy is the fact that coordinating solvents, typically em-
ployed for Suzuki–Miyaura cross-couplings, are
generally incompatible with the iridium-catalyzed boryla-
tion reactions, and thus solvents need to be changed be-
tween steps. This prompted us to explore alternative
solvent systems, which might be compatible with both
steps, thus reducing waste and cost in tandem-reaction se-
quences. We report herein that widely available MTBE is
such a solvent, allowing C–H borylation–Suzuki–
Miyaura cross-couplings to be conducted in sequence in a
single pot and in a single solvent.
We commenced our study by examining the borylation of
m-xylene in a range of solvents known to be compatible
with the Suzuki–Miyaura reaction. However, in line with
earlier reports,6b those containing coordinating atoms
(e.g., DMF, MeCN, dioxane) proved ineffective, with re-
actions occurring only slowly and leading to poor conver-
sions. Speculating that coordination to the active site in
the Ir catalyst was the cause of this inhibition, we then
sought solvents in which this could be prevented by sim-
ple steric effects and thus explored the use of 2-MeTHF
and MTBE. Whilst both proved to be effective for the ar-
omatic C–H borylation reaction, the latter, reflecting its
earlier use as a fuel additive and its low tendency to form
peroxides, is widely available at low cost and, conse-
quently, we opted to focus on this solvent.
is
the
sterically
encumbered,
five-coordinate
[Ir(Bpin)3L2]species [Bpin = B(OCMe2CMe2O)]. Steric
hindrance in this intermediate accounts for the selectivity
observed with these catalyst systems, as borylation typi-
cally avoids positions ortho to either substituents or to
ring junctions. We have taken advantage of this selectivity
to prepare novel pyrene-2,7-bis(boronate) and perylene-
2,5,8,11-tetra(boronate) esters amongst other polycyclic
aryl boronates.10
Although, for similar reasons, MTBE has been widely
used in process chemistry for a number of years, we are
not aware of it having been previously employed in the
Suzuki–Miyaura reaction. Consequently, we undertook a
simple, preliminary evaluation using purified phenyl bo-
ronic acid following the standard Suzuki–Miyaura reac-
tion conditions we have used in our earlier chemistry
[PhB(OH)2 (1 mmol), MTBE (2.4 mL), H2O (0.8 mL), 4-
MeC6H4I (1.1 mmol), Pd(dppf)Cl2 (2 mol%), K2CO3 (2
mmol)]. Pleasingly, this afforded the desired cross-cou-
pled product, albeit at 75% conversion and contaminated
The concept of reducing the number of different opera-
tions in a synthesis is a fundamental component in the op-
timization process.11 A classic way to achieve this is to run
multiple or tandem reactions in a single vessel. Given the
versatile nature of aryl boronic acids the direct C–H bory-
lation has become an attractive method in these se-
SYNLETT 2009, No. 1, pp 0147–0150
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087374; Art ID: S08408ST
© Georg Thieme Verlag Stuttgart · New York

148
P. Harrisson et al.
CLUSTER
Table 2 One-Pot Borylation of 1-R1-3-R2-C6H4 followed by
Suzuki–Miyaura Coupling with 4-IC6H4CO2Me in MTBE
by homocoupled product (Ph–Ph) arising from PhB(OH)2
which was inseparable from the desired material due to
the structural similarities of the two molecules.
R1
R1
i. 0.5[Ir]2, dtbpy (3 mol%)
B2pin2 (1.0 equiv)
MTBE, 80 °C, 6 h
Having established that the Suzuki–Miyaura reaction
could be undertaken in MTBE, we then explored the tan-
dem sequence. Following complete borylation of m-xy-
lene at the 5-position to give its pinacolboronate ester
(GC-MS), water, methyl 4-iodobenzoate, Pd(dppf)Cl2,
and K2CO3 were added, and the solution was heated at
80 °C. After 3 hours, minimal amounts of cross-coupled
product could be detected, whilst heating for 14 hours af-
forded 30% of the desired coupled product with the major
product being the initial arene arising from protodebory-
lation. In order to improve the process, we then undertook
a simple screen of different bases, catalysts, and stoichi-
ometry, using isolated 3,5-Me2C6H3Bpin, as shown in
Table 1.
Ar
ii. Pd(dppf)Cl2 (3 mol%)
ArI (1.2 equiv), KOH (5.0 equiv)
MTBE–H2O, 80 °C, 3 h
R2
R2
[Ar = 4-MeO2CC6H4-]
Entry
1
R1
R2
Yield (%)a
Me
Me
Me
CF3
CF3
MeO
MeO
MeO
Br
90
93
94
94
93
91
94
94
92
92
87
92
94
94
2
Cl
3
Cl
4
Br
5
Br
Initial attempts to vary the stoichiometry of the base
proved ineffectual, and the first significant success was
observed when using Ba(OH)2·8H2O as the base (entries
9 and 10). However, this reagent led to handling difficul-
ties with a thick slurry being formed during the reaction,
complicating product isolation. As a result of this finding,
6
Cl
7
MeO
8
Br
9
Cl
Cl
10
11
12
13
14
MeO
Me
CF3
Br
Table 1 Coupling of 3,5-Me2C6H3Bpin with 4-IC6H4CO2Me in
2.4 mL of MTBE
CN
Me
Me
Me
Pd, base, ArI
MTBE–H2O, 80 °C, 3 h
CN
Bpin
Ar
[Ar = 4-MeO2CC6H4-]
CF3
CF3
Me
2,6-Cl2C5H2N
Entry Catalysta Base
(equiv)
H2O
(mL)
Time
(h)
Conversion
a Yield of isolated, purified products.
(%)b
different hydroxide bases were examined, with both
NaOH and KOH giving near stoichiometric conversion to
the desired product within 3 hours (entries 12–14), the lat-
ter proving marginally more effective, giving complete
conversion with only 2.5 equivalents as compared to the 5
equivalents required for NaOH. Significantly, the reaction
without water present showed no conversion to product
with only starting materials present by GC-MS analysis
(entry 15).
1
2
A
A
A
B
A
B
A
A
B
A
A
A
A
A
A
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (3.5)
K2CO3 (4.5)
KF (3.5)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.0
3
12
3
0
30
0
3
4
3
0
5
3
0
6
3
0
7
K3PO4 (2.5)
NaOH (2.5)
Ba(OH)2 (2.0)c
Ba(OH)2 (2.5)c
BaCO3 (2.5)
NaOH (5.0)
KOH (2.5)
3
29
90
92
100
0
With optimized conditions identified, preparative experi-
ments showed the process to be effective giving high
yields across a range of simple 1,3-disubstituted arenes
bearing both electron-donating and -withdrawing groups
including bromides and chlorides (Table 2). Moreover,
this tandem reaction sequence can also be used for suit-
ably substituted heterocycles (e.g., Scheme 1).
8
3
9
3
10
11
12
13
14
15
3
3
3
100
100
100
0
i. 0.5[Ir]2, dtbpy (3 mol%)
B2pin2 (1.0 equiv)
MTBE, 80 °C, 6 h
Cl
Cl
3
N
N
Ar
KOH (5.0)
3
ii. Pd(dppf)Cl2 (3 mol%)
ArI (1.2 equiv), KOH (5.0 equiv)
MTBE–H2O, 80 °C, 3 h
Cl
Cl
NaOH (5.0)
3
94%
[Ar = 4-MeO2CC6H4-]
a A: Pd(dppf)Cl2 (3 mol%); B: Pd(PPh3)2Cl2 (3 mol%).
b GC-MS ratios.
Scheme 1 Tandem reaction with 2,6-dichloropyridine and methyl
c Ba(OH)2·8H2O used.
4-iodobenzoate
Synlett 2009, No. 1, 147–150 © Thieme Stuttgart · New York

CLUSTER
Tandem Catalyzed C–H Borylation–Suzuki–Miyaura Cross–Coupling
149
and B2pin2 (713 mg, 2.75 mmol) into a vial and then adding MTBE
(26.4 mL). The vial was sealed with a rubber septum and then shak-
en with the solution developing a deep red color. Under N2, a
Youngs tap tube was charged with B2pin2 (200 mg, 0.79 mmol) fol-
lowed by 1,3-bis(trifluoromethyl)benzene (214 mg, 155 mL, 1.0
mmol). Methyl-tert-butyl ether (0.4 mL) was added followed by the
catalyst stock solution (2.0 mL; catalyst loading = 3 mol%, 1.0
mmol B2pin2). The reaction was heated for 6 h at 80 °C in an alumi-
num heating block with cooling. Degassed H2O (1.0 mL) was then
added, followed by Pd(dppf)Cl2 (21 mg, 3 mol%), KOH (240 mg,
5.0 mmol), and methyl 4-iodobenzoate (314 mg, 1.2 mmol), and the
reaction was heated for 3 h at 80 °C. The solution was then passed
through a plug of Celite and washed through with EtOAc (200 mL).
The solvent was removed under reduced pressure. The resulting oil
was purified by silica flash column chromatography using 5%
EtOAc–hexane to afford the cross-coupled biaryl product methyl
4-[3¢,5¢-bis(trifluoromethyl)phenyl]benzoate (329 mg, 94%); mp
103–104 °C (from hexane). 1H NMR (700 MHz, CDCl3): d = 8.19
(d, 2 H, J = 8.2 Hz), 8.04 (s, 2 H), 7.92 (s, 1 H), 7.69 (d, 2 H, J = 8.2
Hz), 3.95 (s, 3 H). 13C NMR (175 MHz, CDCl3): d = 166.9, 142.8,
142.5, 132.8, 132.6, 130.9, 127.6, 124.4, 122.8, 122.4, 52.7. 19F
NMR (376 MHz, CDCl3): d = –63.22. GC-MS (EI): m/z = 348 [M]+;
all data are in agreement with that previously reported.19
Similarly, the cross-coupling partner is not restricted to
the more reactive iodoarenes, with both aryl bromides and
chlorides being viable (Table 3), the latter being only
moderately efficient affording 50% product after a three-
hour reaction time. Isolated yields of products (Table 3,
entries 1, 3–8, 10) proved to be comparable of those esti-
mated from GC-MS (D ≤ 5%). Small amounts of biaryls
arising from homocoupling of the boronate ester were ob-
served by GC-MS, and when the products were purified
by chromatography on silica gel (entries 1, 3–8, 10), the
homocoupling product was isolated in 6% yield, consis-
tent with the amount required for reduction of 3 mol% pal-
ladium(II) to palladium(0).
Table 3 One-Pot Borylation of m-Xylene Followed by Suzuki–
Miyaura Coupling with 4-XC6H4Y in MTBE
i. 0.5[Ir]2, dtbpy (3 mol%)
B2pin2 (1.0 equiv)
Me
Me
Me
Me
MTBE, 80 °C, 6 h
Y
ii. Pd(dppf)Cl2 (3 mol%)
XC6H4Y (1.2 equiv)
KOH (5.0 equiv)
MTBE–H2O, 80 °C, 3 h
Acknowledgment
Entry
X
I
Y
Yield (%)a,b
>95 (90)c
>95d
We thank the EPSRC and Syngenta (CASE award to PH) for finan-
cial support of this work, AllyChem Co. Ltd. for a generous gift of
B2pin2, Dr. A. M. Kenwright for assistance with NMR experiments,
and Dr. M. Jones for mass spectra.
1
2
CO2Me
Me
I
3
I
CF3
>95 (91)c
92 (90)c
94 (93)c
>95 (92)c
92 (92)c
86 (84)
References
4
I
OMe
NO2
CO2Me
CN
(1) Boronic Acids: Preparation and Applications in Organic
Synthesis and Medicine; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, 2005.
(2) Suzuki, A.; Miyaura, N. Chem. Rev. 1995, 95, 2451.
(3) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark,
C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863.
(4) (a) Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7,
2571. (b) Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett.
2005, 7, 2885.
5
I
6
Br
Br
Br
Br
Cl
7
8
NMe2
Me
9
94d
50 (50)c,e
(5) Nguyen, P.; Blom, H. P.; Westcott, S. A.; Taylor, N. J.;
Marder, T. B. J. Am. Chem. Soc. 1993, 115, 9329.
(6) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.;
Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
390. (b) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N.
Angew. Chem. Int. Ed. 2002, 41, 3056.
10
CN
a Yields determined by GC-MS analysis. Isolated, purified yield in pa-
rentheses.
b Small amounts of biaryl arising from homocoupling of the arylbor-
onate ester detected in all cases by GC-MS.
c Homocoupled product (6%) arising from the aryl boronate isolated.
d No attempt was made to separate homocoupled byproduct from
cross-coupled product.
(7) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith,
M. R. Science 2002, 295, 305.
(8) Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2003, 680,
3.
e Unreacted boronate ester (44%) was detected.
(9) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. J. Am. Chem.
Soc. 2003, 125, 16114.
(10) Coventry, D. N.; Batsanov, A. S.; Goeta, A. E.; Howard,
J. A. K.; Marder, T. B.; Perutz, R. N. Chem. Commun. 2005,
2172.
(11) Sheldon, R. A. Chem. Commun. 2008, 3352.
(12) (a) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. J. Am.
Chem. Soc. 2003, 125, 7792. (b) Shi, F.; Smith, M. R.;
Maleczka, R. E. Org. Lett. 2006, 8, 1411.
(13) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc.
2007, 129, 15434.
In conclusion, MTBE represents an effective and econom-
ically viable solvent that permits a truly one-pot tandem
C–H borylation–Suzuki–Miyaura cross-coupling to be
carried out providing substituted biaryls in high yields.
Typical Procedure for ‘One-Pot’ Borylation of Bis-1,3-(trifluo-
romethyl)benzene and Subsequent Suzuki–Miyaura Cross-
Coupling to Methyl 4-Iodobenzoate
Under N2, a catalyst stock solution was prepared by weighing
[Ir(OMe)cod]2 (731 mg, 0.4 mmol Ir), dtbpy (105 mg, 0.4 mmol)
(14) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett.
2007, 9, 757.
Synlett 2009, No. 1, 147–150 © Thieme Stuttgart · New York

150
P. Harrisson et al.
CLUSTER
(15) Tzschucke, C.; Murphy, J. M.; Hartwig, J. F. Org. Lett.
2007, 9, 761.
(16) Holmes, D.; Chotana, G. A.; Maleczka, R. E.; Smith, M. R.
Org. Lett. 2006, 8, 1407.
(17) Boebel, T. A.; Hartwig, J. F. Tetrahedron 2008, 64, 6824.
(18) (a) Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.;
Batsanov, A. S.; Howard, J. A. K.; Perutz, R. N.; Marder,
T. B. Angew. Chem. Int. Ed. 2006, 45, 489. (b) Paul, S.;
Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E.;
Smith, M. R. J. Am. Chem. Soc. 2006, 128, 15552.
(c) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N.
Chem. Commun. 2003, 2924. (d) Kikuchi, T.; Nobuta, Y.;
Umeda, J.; Yamamoto, Y.; Ishiyama, T.; Miyaura, N.
Tetrahedron 2008, 64, 4967.
(19) Blettner, C. G.; König, W. A.; Stenzel, W.; Schotten, T.
J. Org. Chem. 1999, 64, 3885.
Synlett 2009, No. 1, 147–150 © Thieme Stuttgart · New York

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