Suzuki-miyaura cross-coupling of heteroaryl halides and arylboronic acids in continuous flow

Article abstract of DOI:10.1021/ol202052q

General continuous-flow conditions for the Suzuki-Miyaura cross-coupling of heteroaryl halides and (hetero)arylboronic acids have been developed. A wide range of heterobiaryl products is obtained in excellent yields (20 examples) employing low catalyst loadings (0.05-1.5 mol % Pd).

Full text of DOI:10.1021/ol202052q

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5180–5183
SuzukiÀMiyaura Cross-Coupling of
Heteroaryl Halides and Arylboronic Acids
in Continuous Flow
€
Timothy Noel* and Andrew J. Musacchio
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
tnoel@mit.edu
Received July 28, 2011
ABSTRACT
General continuous-flow conditions for the SuzukiÀMiyaura cross-coupling of heteroaryl halides and (hetero)arylboronic acids have
been developed. A wide range of heterobiaryl products is obtained in excellent yields (20 examples) employing low catalyst loadings
(0.05À1.5 mol % Pd).
Heterobiaryl compounds are a prevalent structural mo-
tif in many pharmaceuticals and other biologically active
molecules.1 The palladium-catalyzed SuzukiÀMiyaura
cross-coupling reaction (SMC) is arguably the most versa-
tile method to construct such CÀC bonds,2 since it facil-
itates the efficient coupling of (hetero)aryl halides and
pseudohalides with (hetero)arylboronic acids. Recently,
considerable attention has been focused on the devel-
opment of continuous-flow versions of the SMC
reaction.3,4 Continuous-flow microreactors offer sev-
eral advantages as compared to traditional batch re-
actors, such as enhanced heat and mass transfer, precise
control over residence/reaction times, and the typically
facile transition between laboratory and production
scale processes in flow.4,5 Despite a number of reports
in this area, the use of heterocyclic coupling partners
has been largely neglected.3 This may be in part due to
the fact that cross-coupling reactions with heteroaryl
substrates have proven challenging as compared to the
analogous couplings of simpler substrates and thus
typically require the use of highly active catalyst
systems.6,7 Furthermore, it is known that five-mem-
bered 2-heteroarylboronic acids are prone to rapid
decomposition via protodeboronation under aqueous
(1) (a) Zhao, D.; You, J.; Hu, C. Chem.;Eur. J. 2011, 17, 5466–5492.
(b) Slagt, V. F.; de Vries, A. H. M.; de Vries, J. G.; Kellogg, R. M. Org.
Process Res. Dev. 2010, 14, 30–47. (c) Hughes, R. A.; Moody, C. J.
Angew. Chem., Int. Ed. 2007, 46, 7930–7954.
(2) For some selected reviews about the SuzukiÀMiyaura cross-
coupling: (a) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41,
1461–1473. (b) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reac-
tions; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York, 2004; pp
41À123. (c) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 115, 2419–
2440. (d) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(3) For some selected examples of SuzukiÀMiyaura cross-coupling
€
in flow: (a) Noel, T.; Kuhn, S.; Musacchio, A. J.; Jensen, K. F.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 5943–5946. (b)
Glasnov, T. N.; Kappe, C. O. Adv. Synth. Catal. 2010, 352, 3089–
3097. (c) Yamada, Y. M. A.; Watanabe, T.; Beppu, T.; Fukuyama, N.;
Torii, K.; Uozumi, Y. Chem.;Eur. J. 2010, 16, 11311–11319. (d)
Theberge, A. B.; Whyte, G.; Frenzel, M.; Fidalgo, L. M.; Wootton,
R. C. R.; Huck, W. T. S. Chem. Commun. 2009, 6225–6227. (e) Uozumi,
Y.; Yamada, Y. M. A.; Beppu, T.; Fukuyama, N.; Ueno, M.; Kitamori,
T. J. Am. Chem. Soc. 2006, 128, 15994–15995. (f) Baxendale, I. R.;
Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Chem.;Eur. J. 2006,
12, 4407–4416. (g) Shore, G.; Morin, S.; Organ, M. G. Angew. Chem.,
Int. Ed. 2006, 45, 2761–2766. (h) Comer, E.; Organ, M. G. J. Am. Chem.
Soc. 2005, 127, 8160–8167.
(5) For some selected reviews about flow chemistry: (a) Hartman,
R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem., Int. Ed. 2011, 50,
7502–7519. (b) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680.
(c) Frost, C. G.; Mutton, L. Green Chem. 2010, 12, 1687–1703. (d) Geyer,
K.; Gustafsson, T.; Seeberger, P. H. Synlett 2009, 2382–2391.
(e) Yoshida, J.-i.; Nagaki, A.; Yamada, T. Chem.;Eur. J. 2008, 14,
7450–7459. (f) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan,
A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300–2318.
(6) Tyrrell, E.; Brookes, P. Synthesis 2004, 4, 469–483.
(7) (a) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073–14075. (b) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 6686–6687.
€
(4) For a review about cross-coupling in continuous flow: Noel, T.;
Buchwald, S. L. Chem. Soc. Rev., DOI: 10.1039/c1cs15075h.
r
10.1021/ol202052q
Published on Web 09/07/2011
2011 American Chemical Society

basic conditions.7a Moreover, heterocyclic compounds
are highly polar and thus poorly soluble in most or-
ganic solvents, which is a concern in microfluidic
systems since significant amounts of precipitate are
difficult to introduce in flow systems and can cause
the reactor to clog. Given these potential challenges,
particularly with regards to boronic acid stability, we
felt that the rapid and efficient generation of the
catalytically active L1Pd(0) species was crucial to the
success of the SMC of heteroaryls in flow. To this end,
Buchwald has reported the use of dialkylbiaryl mono-
phosphine-ligated palladacycles P1À4, which can be
quickly and efficiently activated in the presence of a
base (Figure 1).7,8 Herein, we report the development of
general conditions for the continuous-flow SMC cou-
pling of heteroaryl halides and pseudohalides with
(hetero)arylboronic acids using these palladacycles at
low catalyst loadings.
avoid clogging. Using 0.5 mol % XPhos precatalyst P1,
K3PO4 as a base, tetrabutylammonium bromide (TBAB)
as a phase transfer catalyst in NMP/H2O (1:1), and
2-chloro-6-methoxypyridine was successfully coupled with
2,4-difluorophenylboronic acid (Table 1, entry 1). When
precatalysts P2 and P3 (with SPhos and BrettPhos as
ligands) were employed, incomplete conversion was ob-
tained after 90 s (Table 1, entries 2 and 3).9 With second
generation XPhos precatalyst P4, full conversion was also
obtained in 90 s (Table 1, entry 1). We chose to use this
second generation XPhos precatalyst (P4) because it is
readily synthesized in a one-pot procedure from commer-
cially available starting materials and can be easily acti-
vated with weak bases at room temperature.7a Further
reaction optimization studies revealed that K3PO4 was
optimal as compared to other weak bases (Table 1, entries
5 and 6). While the use of toluene, t-BuOH, and dioxane as
solvents provided product in excellent yields, highly polar
boronic acids were insoluble in these solvents, making it
incompatible with continuous flow (Table 1, entries 7À9).
Table 1. Optimization of the SuzukiÀMiyaura Reaction of
2-Chloro-6-methoxypyridine with 2,4-Difluorophenylboronic
Acid in Batcha
entry
precatalyst
solvent
base
yield (GC)b
1
2
3
4
5
6
7
8
9
P1
P2
P3
P4
P4
P4
P4
P4
P4
NMP
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
98
35
0
NMP
NMP
NMP
99
43
9
NMP
NMP
Figure 1. Dialkylbiarylphosphine ligands and palladium preca-
talysts used in this study.
toluene
t-BuOH
dioxane
98
99
99
a Reaction conditions: HetArCl (0.5 mmol), ArB(OH)2 (0.75 mmol),
precatalyst (0.5 mol %), solvent (1 mL), 4 M aq base solution (0.5 mL),
0.1 M aq TBAB (0.5 mL) at 90 °C for 90 s. b GC yield, using biphenyl as
an internal standard.
We initiated our investigation by examining the reaction
of 2-chloro-6-methoxypyridine with 2,4-difluorophenyl-
boronic acid under batch conditions (Table 1). We antici-
pated that a biphasic solvent system, which ensures a
complete dissolution of both inorganic and organic solids,
would be highly preferable in a continuous-flow setting to
With optimized batch conditions in hand, a microfluidic
system was assembled as shown in Figure 2. A solution of
(8) For use of these precatalysts in continuous-flow chemistry:
(a) Hartman, R. L.; Naber, J. R.; Zaborenko, N.; Buchwald, S. L.;
Jensen, K. F. Org. Process Res. Dev. 2010, 14, 1347–1357. (b) Naber,
J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 9469–9474. (c)
(9) For use of SPhos and BrettPhos in SuzukiÀMiyaura cross-
coupling: (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2004, 43, 1871–1876. (b) Barder, T. E.;
Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 4685–4696. (c) Altman, R. A.; Buchwald, S. L. Nat. Protoc. 2007, 2,
3115–3121. (d) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3358–3366. (e) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett.
2009, 11, 3954–3957.
€
Noel, T.; Naber, J. R.; Hartman, R. L.; McMullen, J. P.; Jensen, K. F.;
Buchwald, S. L. Chem. Sci. 2011, 2, 287–290. (d) See also ref 3a. (e) Li, P.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 6396–6400. (f) Kuhn,
€
S.; Noel, T.; Gu, L.; Heider, P. L.; Jensen, K. F. Lab Chip 2011, 11, 2488–
2492.
Org. Lett., Vol. 13, No. 19, 2011
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heteroaryl halide, arylboronic acid, and XPhos precatalyst
P4 in NMP was combined with aqueous streams of TBAB
and K3PO4, respectively. This biphasic mixture was sub-
sequently introduced in a 400 μL packed-bed reactor
(stainless steel spheres, 60À125 μm packing), which has
been shown to improve the interfacial contact between the
two immiscible phases.8b Upon exiting the packed-bed
reactor, the reaction mixture was quenched with water
and ethyl acetate (EtOAc). When NMP/H2O (1:1) was
used as the solvent system in continuous flow, we observed
that, upon combining the organic stream and the water
stream, arylboronic acid precipitated out of the solution,
which caused instant clogging of the microreactor. How-
ever, by employing an NMP/toluene/H2O (4:1:5) mixture,
the organic phase was sufficiently apolar to decrease the
solubility of H2O in NMP and thus prevent precipitation
of arylboronic acid.
examples involve the SMC coupling between a hetero-
aryl halide and a heteroarylboronic acid.
Figure 3. Substrate scope of the continuous-flow Suzu-
kiÀMiyaura cross-coupling of heteroaryl halides and (hetero)-
arylboronic acids. Reaction conditions: ArX (1.0 equiv), ArB-
(OH)2 (1.5 equiv), precatalyst P4 (x mol %), NMP/toluene
(4:1), 4 M aq K3PO4, 0.1 M aq TBAB at 90 °C, 3 min resi-
dence time. Isolated yield on a 2 mmol scale. Note: (a) 40 s
residence time.
Figure 2. Schematic representation of the microreactor setup
for continuous-flow palladium-catalyzed SuzukiÀMiyaura
cross-coupling reactions employing heteroaryl halides and
(hetero)arylboronic acids.
We then focused our attention on the development of
continuous-flow protocols employing particularly low cat-
alyst loadings (Figure 4). The ability to perform SMC
reactions in flow with low catalyst loadings is of great
importance for process development since it significantly
reduces the palladium cost and simplifies removal of palla-
dium residues from the target molecule. For the reaction
between 2-chloro-6-methoxypyridine and 3-thienylboronic
acid, incomplete conversion to heterobiaryl 2a was observed
at 90 °C in the presence of 0.05 mol % of XPhos precatalyst
P4. Having observed during optimization studies that
Next, we set out to explore the scope of this SMC
reaction in continuous flow (Figure 3). A wide array of
heterocyclic aryl chlorides and bromides, including
2-pyridyl, 3-pyridyl, 6-quinolinyl, 1-isoquinolinyl,
5-pyrimidinyl, 2-pyrimidinyl, 2-pyrazinyl, 3-thiophe-
nyl, 4-pyrazolyl, and 5-benzoxazolyl halides, could be
efficiently coupled with a broad range of arylboronic
acids within a 3 min residence time in good to excellent
isolated yields. It is noteworthy that many of these
5182
Org. Lett., Vol. 13, No. 19, 2011

higher temperatures led to lower conversions, we surmised
that competitive protodeboronation was problematic. In-
deed, by lowering the temperature to 60 °C and employing a
reaction time of 5 min, there was a decrease in the quantity of
protodeboronation observed and, hence, heterobiaryl 2a
could be obtained in excellent isolated yield. It should be
noted that this result represents the lowest palladium load-
ing that has been reported for an SMC reaction carried out
under continuous-flow conditions.10 Having addressed the
problem of protodeboronation, we wondered if we could
utilize five-membered 2-heteroarylboronic acids. These
boronic acids are known to quickly protodeboronate at
elevated temperatures when employing aqueous bases.7a
In our microfluidic system, successful coupling was obtained
with only 0.2 mol % of XPhos precatalyst P4 at 60 °C and a
5 min residence time.
Figure 5. Formation of heterocyclic biaryls on a 10 mmol scale.
Reaction conditions: HetArCl (1.0 equiv), ArB(OH)2 (1.5
equiv), precatalyst P4 (0.5 mol %), NMP/toluene (4:1), 4 M
aq K3PO4, 0.1 M aq TBAB at 90 °C, 3 min residence time.
Isolated yield on a 10 mmol scale.
coupling reactions for 5 h without any interruption to
collect 10 mmol of the corresponding biaryl heterocycles.
In summary, we have developed a general continuous-
flow process for the SuzukiÀMiyaura cross-coupling of
heteroaryl halides and (hetero)arylboronic acids. A wide
range of heterobiaryl components could be obtained in
good to excellent yields. Noteworthy are the use of low
catalyst loadings, unstable 2-heteroarylboronic acids, and
the possibility to scale up the reaction very efficiently. Key
to the success of this process was (i) the use of an XPhos
precatalyst (P4), which guarantees fast activation of the
catalytically active species; (ii) the use of a biphasic solvent
system, which ensures good solubility of both organic and
inorganic solids; and (iii) the use of a packed-bed reactor,
which improvesthecontactbetween theimmisciblephases.
Figure 4. Formation of heterocyclic biaryls using low catalyst
loadings and unstable 2-heteroarylboronic acids. Reaction con-
ditions: HetArX (1.0 equiv), ArB(OH)2 (1.5 equiv), precatalyst
P4 (x mol %), XPhos L1 (x mol %), NMP/toluene (4:1), 4 M aq
K3PO4, 0.1 M aq TBAB at 60 °C, 5 min residence time. Isolated
yield on a 2 mmol scale.
Acknowledgment. T.N. and A.J.M. thank the Novartis
International AG for funding. The authors would like to
acknowledge the support of Professor S. L. Buchwald
(Department of Chemistry, Massachusetts Institute of
Technology). T.N. is a Fulbright Postdoctoral Fellow. A.
J.M. is an Undergraduate Research Opportunities Pro-
gram (U.R.O.P.) student at Massachusetts Institute of
Technology.
The efficiency of a biphasic reaction in a batch reactor is
highly dependent on the effectiveness of the mixing pro-
cess. To scale up such a process in batch, these reaction
conditions require advanced and specialized mixing de-
vices, such as special designs in agitator blades or the
installation of baffles in the reactor. However, with our
microfluidic system, we were able to scale up the reaction
conditions very efficiently just by extending the operating
time of the device (Figure 5). We were able to run SMC
Supporting Information Available. Details on the
equipment setup, experimental procedures, and spectral
data for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) For an example that utilizes 0.25 mol % Pd(PPh3)4 for the SMC
coupling between nonheteroaryl coupling partners: see ref 3b.
Org. Lett., Vol. 13, No. 19, 2011
5183