Decarboxylative biaryl synthesis in a continuous flow reactor

Article abstract of DOI:10.1039/c0cc05708h

A practical protocol was developed that allows performing decarboxylative cross-coupling reactions in continuous flow reactors. Various biaryls were thus synthesized from aromatic carboxylic acids and aryl triflates using a Cu/Pd-catalyst system.

Full text of DOI:10.1039/c0cc05708h

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COMMUNICATION
Decarboxylative biaryl synthesis in a continuous flow reactorw
Paul P. Lange,a Lukas J. Gooßen,*a Philip Podmore,b Toby Underwood*b and
Nunzio Sciammettac
Received 21st December 2010, Accepted 13th January 2011
DOI: 10.1039/c0cc05708h
A practical protocol was developed that allows performing
decarboxylative cross-coupling reactions in continuous flow reactors.
Various biaryls were thus synthesized from aromatic carboxylic
acids and aryl triflates using a Cu/Pd-catalyst system.
they require high temperatures that are hard to reach and
safely control in larger batch reactors.
In the development of a flow-based protocol for decarboxy-
lative couplings, a major obstacle had to be overcome. Using
established protocols, the reaction mixtures are slurries with
large amounts of suspended solids that arise from the low
solubility of the carboxylate salts and copper precursors in
N-methylpyrrolidinone (NMP). Reactions in suspension require
especially modified flow-through equipment that is unavailable
in most laboratories.16
The formation of biaryl substructures is a key step in the synthesis
of many biologically active compounds. Established synthetic
methods include transition metal-catalysed cross-couplings1
and C–H-activation reactions.2 Recently, decarboxylative
cross-couplings have evolved as an advantageous alternative.
In this regiospecific C–C-bond forming reaction, carboxylate
salts replace organometallic reagents as sources of carbon
nucleophiles.3 The decarboxylation step leads to the generation
of an organometallic aryl nucleophile and is mediated by a
Cu-,4 Ag-,5 Pd-,6 or Rh-species.7 The cross-coupling step with
aryl halides8 or sulfonates9 has been achieved with Pd-10
and Cu-catalysts.11 Over the last years a steadily increasing
number of decarboxylative reactions have been reported, and
have established this concept as a widely applicable synthetic
methodology.12
Our initial investigations thus focussed on identifying a way
to fully dissolve all reaction components at room temperature
in a minimal amount of solvent. Preformed potassium 2-nitro-
benzoate did not fully dissolve in NMP. However, we discovered
that upon mixing our model substrate 2-nitrobenzoic acid with
an equivalent amount of the soluble base KOtBu, the deproto-
nation took place reliably, and clear 0.2 M solutions in NMP
were obtained. We attributed this to an additional solubilising
t
effect of the BuOH released. Of all the copper precursors
tested, only commercial CuNO3(phen)(PPh3)2 had a sufficient
solubility in NMP. A range of Pd sources including Pd(acac)2
were found to be reasonably soluble.
In order to further increase the attractiveness of decarboxy-
lative couplings for industrial applications, it is essential to
adapt them to state-of-the-art-reaction technologies such as
microwave heating10a,13,14 or continuous flow processes.15 The
key advantages of reactions performed in flow reactors (Scheme 1)
over traditional batch reactions are the superior heat and mass
transfer, the increased process safety, the ease of scale-up, and
the possibility to include automated product purification and
solvent recycling technologies. This technology should be of
particular assistance for decarboxylative cross-couplings, as
The appropriate choice of the electrophilic coupling partner
is also crucial. In the coupling of aryl halides, potassium
halides are formed, which precipitate during the reaction. In
contrast, the coupling of aryl triflates generates NMP-soluble
potassium triflate. The added benefit of using aryl triflates as
electrophiles is that they can be coupled with a wider range of
carboxylic acids.9a,b
Based on the results of these initial investigations, we
prepared a 0.2 M solution of 2-nitrobenzoic acid, KOtBu and
4-tolyl triflate in NMP and added catalytic amounts of
CuNO3(phen)(PPh3)2 and Pd(acac)2. When this solution was
passed through a stainless steel coil (10 mL) on a Vapourtec
R2+/R4 reactor17 heated to 140 1C at a rate of 0.33 mL minꢀ1
(30 min residence time), the desired biaryl 3aa was formed in
an encouraging 14% yield (Table 1, entry 1).
Scheme 1 Reactor setup for decarboxylative cross-couplings.
a FB Chemie – Organische Chemie, TU Kaiserslautern,
Erwin-Schroedinger-Strasse, Geb. 54, 67663, Kaiserslautern,
Germany. E-mail: goossen@chemie.uni-kl.de
Increasing the residence time to 60 min and the reactor
temperature to 160 1C improved the yield to 57% (entry 2).
The same results were obtained without added PPh3 demon-
strating that the phosphine released from the Cu-catalyst
suffices to stabilize the Pd catalyst (entry 3). Further lowering
the flow rate did not have an extra benefit.
b Chemical Technology Group, Sandwich Chemistry,
Pfizer Global R&D, Ramsgate Road, Sandwich, Kent,
UK CT13 9NJ
c Lead Discovery, Sandwich Chemistry, Pfizer Global R&D,
Ramsgate Road, Sandwich, Kent, UK CT13 9NJ
w Electronic supplementary information (ESI) available: Experimental
data and procedures for all compounds. See DOI: 10.1039/c0cc05708h
Among all Pd sources tested, only Pd(OAc)2 was found
to be superior to Pd(acac)2 whereas most preformed Pd
c
3628 Chem. Commun., 2011, 47, 3628–3630
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Table 1 Optimisation of reaction conditionsa
Table 2 Scope of the transformationa
a
Reaction conditions: 0.48 mmol 2-nitrobenzoic acid, 0.4 mmol
4-tolyl triflate, Pd-catalyst, ligand/base, 2 mL NMP, flow rate
0.167 mL minꢀ1 (60 min). Conversions were determined by GC analysis
using n-tetradecane as the internal standard. b Flow-rate: 0.33 mL minꢀ1
c
(30 min). Isolated yield. dppf: 1,10-bis(diphenylphosphino)ferrocene,
dtbf: 1,10-bis(di-tert-butylphosphino)ferrocene.
complexes were ineffective (entries 5–7). At a higher tempera-
ture (170 1C) even better results were achieved (entry 8).
However, above this temperature, the selectivity dropped, and
considerable amounts of homocoupling products were formed.
An optimal balance between decarboxylation and cross-
coupling was achieved using 5 mol% of CuNO3(phen)(PPh3)2
and 2 mol% of Pd(OAc)2 (entries 11–14). At lower catalyst
loadings, the yields dropped (entry 14). Under optimised
conditions (5 mol% CuNO3(phen)(PPh3)2, 2 mol% Pd(OAc)2,
KOtBu, 170 1C, 1 h) a 75% conversion based on the aryl
triflate was achieved. The desired biaryl was formed almost
exclusively, side products arising from protodecarboxylation
or homocoupling were detected only in trace amounts. This
level of selectivity is unprecedented in batch procedures and its
origin is still unclear. When performing a comparative batch
reaction under identical conditions, low yields were obtained
and protodecarboxylation became the main reaction pathway
(Scheme 2).
a
Reaction conditions: 0.40 mmol aryl triflate, 5 mol% CuNO3(phen)-
(PPh3)2, 2 mol% Pd(OAc)2, 2 mL NMP, 170 1C, flow-rate: 0.167 mL minꢀ1
(60 min). Isolated yields. b 0.48 mmol carboxylic acid, 0.48 mmol
KOtBu. 0.48 mmol tetraethylammonium carboxylate. GC yield.
c
d
deprotonation step, precluding their use following the standard
procedure. For these compounds, an alternative method was
developed, which involves their conversion into tetraethyl-
ammonium salts. After deprotonation with tetraethylammo-
nium hydroxide, the carboxylates were precipitated from
methanol by the addition of ethyl acetate and redissolved in
the NMP reaction solution. This modification extended the scope
with regard to the carboxylic acid coupling partner.
In comparison to batch reactions9b comparable yields
were obtained in shorter reaction time (e.g. 3aa: 91% vs. 71%,
3da: 72% vs. 72% in 1 h rather than 16 h). Under microwave
conditions9b the reaction gives comparable yields within
5 min (3aa: 84% vs. 71%, 3da: 73% vs. 72%), but only on
sub-millimolar scales. The successful coupling of the electron-
deficient, sensitive triflate 2d in a record yield demonstrates
that the flow conditions are milder than those of batch reac-
tions. Even under microwave conditions biaryl 3ad had been
obtained in only 23% yield along with considerable amounts
of transesterification.9b
Scheme 2 Comparison between batch and flow.
This illustrates that the protocol is effective only for flow-
through conditions, whereas in batch reactions, the presence
t
of BuOH inevitably leads to protodecarboxylation.
We investigated the scope of the new protocol in the
coupling of various carboxylic acids and aryl triflates (Table 2).
2-Nitrosubstituted benzoic acids, thiazole, 2-benzofuran and
2-thiophene substrates were coupled in good yields. Unfortunately,
some other potassium carboxylates precipitated during the
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3628–3630 3629

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At this stage, there are still limitations with regard to
the substrate scope which we hope to overcome with new
catalyst generations and optimized flow reactor setups. For
example, meta-substituted and a-oxo-carboxylic acids were
only coupled in low yields.
Notes and references
1 Metal-catalyzed cross-coupling reactions, eds. A. de Meijere and
F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004.
2 D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107,
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3 L. J. Gooßen, G. Deng and L. M. Levy, Science, 2006, 313,
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B. Melzer, Adv. Synth. Catal., 2007, 349, 2241; (b) L. J. Gooßen,
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5 (a) L. J. Gooßen, C. Linder, N. Rodrıguez, P. P. Lange and
A. Fromm, Chem. Commun., 2009, 7173; (b) J. Cornella,
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430.
In order to demonstrate how easily this flow protocol can be
scaled up, we adjusted the setup and operated the reactor in a
continuous flow mode by aspirating material from a 50 mL
stock solution under otherwise unchanged conditions. Within
6 h, we thus synthesized 1.2 g (56%) of 2-nitro-40-methyl-
biphenyl (Scheme 3).
6 J. S. Dickstein, C. A. Mulrooney, E. M. O’Brien, B. J. Morgan and
M. C. Kozlowski, Org. Lett., 2007, 9, 2441.
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Scheme 3 Biaryl synthesis using continuous flow.
With the long-term aim of a fully automated process for
decarboxylative cross-coupling reactions, we probed into the
development of an in-line purification unit (Scheme 4). In order
to separate the product from unreacted substrates and the
NMP solvent, the flow system was supplemented with a vessel
filled with HCl and dichloromethane (DCM). This allowed a
solvent switch from NMP to volatile DCM. Subsequent in-line
filtration of the organic layer through a silica cartridge afforded
the desired biaryl in 71% yield as a 7 : 1 mixture with
remaining NMP.
12 For reviews see: (a) L. J. Gooßen, N. Rodrıguez and K. Gooßen,
Angew. Chem., Int. Ed., 2008, 47, 3100; (b) L. J. Gooßen, F. Collet
and K. Gooßen, Isr. J. Chem., 2010, 50, 617.
13 Microwave Assisted Organic Synthesis, ed. J. P. Tierney and
P. Lidstrom, Blackwell Publishing Ltd., 1st edn, 2010.
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R. H. Crabtree, Chem. Commun., 2008, 6312; (b) L. J. Gooßen,
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J. Hartung, Adv. Synth. Catal., 2009, 351, 2667.
15 For selected reviews see: (a) P. Watts and S. J. Haswell, Chem. Soc.
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Scheme 4 Complete flow setup including in-line purification.
In conclusion, a catalyst system and a reactor layout were
developed that for the first time allows performing decarboxy-
lative cross-coupling reactions in a continuous flow reactor.
This is an important milestone towards implementing this
modern C–C-bond forming strategy as a standard tool in
academic and industrial laboratories.
We thank David Fox for helpful discussion, and NanoKat
and the Deutsche Forschungsgemeinschaft for funding.
17 www.vapourtec.co.uk.
c
3630 Chem. Commun., 2011, 47, 3628–3630
This journal is The Royal Society of Chemistry 2011