Catalytic Chan-Lam coupling using a 'tube-in-tube' reactor to deliver molecular oxygen as an oxidant

Article abstract of DOI:10.3762/bjoc.12.156

A flow system to perform Chan-Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

Full text of DOI:10.3762/bjoc.12.156

Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to
deliver molecular oxygen as an oxidant
Carl J. Mallia1, Paul M. Burton2, Alexander M. R. Smith2, Gary C. Walter2
and Ian R. Baxendale*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1598–1607.
1Department of Chemistry, Durham University, South Road, Durham,
DH1 3LE, United Kingdom and 2Syngenta, Jealott's Hill International
Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
doi:10.3762/bjoc.12.156
Received: 14 May 2016
Accepted: 13 July 2016
Published: 26 July 2016
Email:
Ian R. Baxendale* - i.r.baxendale@durham.ac.uk
This article is part of the Thematic Series "Automated chemical
synthesis".
* Corresponding author
Keywords:
Associate Editor: A. Kirschning
Chan–Lam coupling; flow chemistry; gases in flow; oxygen;
“tube-in-tube”
© 2016 Mallia et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing mo-
lecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has
been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures.
A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over ex-
tended reaction times.
Introduction
The functionalisation of aromatic and aliphatic amines has wide range of substrates, including anilines, which did not react
received considerable attention due to the number of biological- very well with the previous conditions. However, despite the
ly active compounds represented by these classes. For this improvements achieved with the Buchwald–Hartwig coupling,
reason different synthetic methods for C–N bond formation limitations such as sensitivity to air and moisture, functional
have been developed (Scheme 1) over the years with the general group tolerance and the high cost of palladium, reignited the
goal to overcome the shortcomings of the original Ullman [1] search for an improved method.
and Goldberg [2] methods relating to the harsh reaction condi-
tions they employ. After a closer look at the work of Mitiga [3] In 1998, the groups of Chan [8], Evans [9] and Lam [10] inde-
on the Stille coupling reactions, Hartwig [4] and Buchwald [5] pendently reported upon mild methods for C(aryl)–N and
independently proposed a catalytic mechanism and later re- C(aryl)–O coupling reactions. Their methods made use of stoi-
ported a tin free aryl–amine coupling reaction [6,7]. This major chiometric amounts of copper(II) acetate as the catalyst and
breakthrough made the C–N coupling reaction accessible to a boronic acids as the aryl donors. In the presence of a base, the
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Scheme 1: Comparison of early C–N and C–O coupling reactions.
coupling could be performed at room temperature. These reac- duces waste. Employing oxygen gas as an oxidant is preferred
tions were subsequently shown to work with a large number of as it is cheap, renewable and environmentally benign. We there-
nucleophiles and tolerated a variety of substrates, making the fore set out to develop a more atom economical way of
process one of the most efficient ways for C–N/O coupling catalysing the Chan–Lam reaction using a sub-stoichiometric
[11]. Several modifications of the Chan–Lam reaction have amount of copper and oxygen gas as the oxidant.
been reported, expanding its scope and it has since been used to
synthesise several biologically active compounds [11,12].
The use of oxygen provides the necessary oxidant to reoxidise
the Cu(I) that forms after the C–N reductive elimination back to
In 2009 the groups of Stevens and van der Eycken reported on Cu(II), allowing for sub-stoichiometric amounts of copper cata-
the Chan–Lam reaction as a continuous flow protocol using lyst to be used [15,16]. Based upon our previous experience of
copper(II) acetate (1.0 equiv), pyridine (2.0 equiv) and triethyl- using the reverse “tube-in-tube” reactor with other gases, it was
amine (1.0 equiv) in dichloromethane [13]. Generally, when decided that oxygen would be delivered via this reactor set-up
using anilines or phenols as the nucleophilic partner, moderate (Figure 1).
to good yields were obtained (56–71% yields, 9 examples).
More recently the Tranmer group reported the use of a copper- Results and Discussion
filled column as a catalyst with TEMPO as the co-oxidant in In our initial screening, four different organic solvents with
acetonitrile (acetic acid additive) with moderate to good yields good oxygen absorption were investigated (toluene, dichloro-
of the coupled products being obtained (25–79% yields, 16 ex- methane, acetonitrile and ethyl acetate), however, Cu(OAc)2
amples) [14]. The use of a copper tubing which serves as both was only completely soluble in dichloromethane. Consequently
the reactor and the catalyst with tert-butyl peroxybenzoate as dichloromethane was used as the reaction solvent. Unfortu-
the oxidant in acetonitrile was also described but was outper- nately pumping dichloromethane through the HPLC pumps,
formed by the copper filled column system. Although the use of used as part of the flow system, initially presented some issues.
elemental copper is potentially an improvement on the use of This was mainly due to cavitation which occurred just before
stiochiometric copper(II) acetate in continuous flow, the use of the pump inlet, attributed to the shear forces present, causing
TEMPO or tert-butyl peroxybenzoate as a co-oxidant intro- outgassing (air). These bubbles, if allowed to enter the system
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Figure 1: General flow scheme for catalytic Chan–Lam reaction.
disturbed the flow (or impaired the pump), resulting in unstable 4–8, Table 1). A general increase in the yield of 19 was ob-
flow. The problem was solved when the dichloromoethane used tained on going from atmospheric to 10 bar after which a slight
was sonicated (30 min of sonication per 500 mL of solvent) decrease in yield was encountered at higher pressures
prior to use, it was then maintained under positive pressure at (Figure 2). This same decrease in yield was also observed when
the inlet throughout the experiment (N2 balloon was used for going from 10 bar to 12 bar of oxygen using 0.25 equiv of
the positive pressure).
copper acetate (entries 9 and 10, Table 1).
In an effort to identify the optimum conditions for the reaction When the amount of copper acetate was reduced to 0.1 equiv a
process, the amount of copper catalyst and the oxygen pressure drastic decrease in yield was observed indicating that the TOF
were studied (Table 1).
of the catalyst prevented achievement of good yields within the
time limits (residence time) of the flow reactor (entry 11,
A set of control experiments with no oxygen was run and the Table 1). A decrease in yield was also observed when the
amount of copper acetate catalyst was lowered from 1 to amount of boronic acid used was decreased to 1.4 equiv and
0.25 equiv (entries 1–3, Table 1). As anticipated, with no 1.1 equiv, respectively (entries 12 and 13, Table 1). Changing
oxidant to reoxidize the catalyst, the yield of 19 dropped in the temperature from 20 °C to 50 °C did not greatly affect the
proportion to the amount of catalyst used. Next, whilst main- yields obtained, with 40 °C giving the most promising result
taining the amount of copper acetate (0.5 equiv), the effect of (entries 14–16, Table 1). However, it was observed that less
the oxygen pressure on conversion was investigated (entries particulate matter was formed in the reactor when higher tem-
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Table 1: Optimisation of the Chan–Lam reaction in continuous flow.
Entry
1
Cu(OAc)2 (equiv)
1.00
Boronic acid (equiv)
Temperature (°C)
O2 pressure (bar)
NMR conversion (%)a
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.4
1.1
1.6
1.6
1.6
1.6
1.6
20
20
20
20
20
20
20
20
20
20
20
20
20
30
40
50
40
40
0
66
48
25
81
85
97
85
83
94
87
50
56
48
87
95
88
93
76
2
0.50
0
3
0.25
0
4
0.50
4
5
0.50
8
6
0.50
10
12
14
10
12
10
10
10
10
10
10
10
10
7
0.50
8
0.50
9
0.25
10
11
12
13
14
15
16
17b
18c
0.25
0.10
0.25
0.25
0.25
0.25
0.25
0.25
0.25
aYields calculated using 1,3,5-trimethoxybenzene as an internal NMR standard and represents the average of two runs. b1.5 equiv of pyridine,
c0.5 equiv of pyridine.
peratures were used (40 and 50 °C), which helps in avoiding The amount of triethylamine was not varied as its quantity was
possible reactor blockages. Finally, the amount of pyridine required to ensure the boronic acid remained soluble in the
added was also studied. Decreasing the amount of pyridine dichloromethane solvent.
(0.5 equiv, entry 18, Table 1) resulted in a lower yield (76%)
while increasing the amount of pyridine (1.5 equiv, entry 18, To determine the time needed to reach steady state in the
Table 1) did not produce any noticeable change in the yield reactor, samples were periodically collected (every 2 min via an
(93%). This indicates that the pyridine plays an important role autosampler) and analysed by 1H NMR spectroscopy using
in this coupling reaction which could be both due to its effect as 1,3,5-trimethoxybenzene as an internal standard. As expected,
a ligand and/or its solubility enhancement of the copper acetate. the product started eluting after 120 min which corresponds
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with the theoretical residence time. A lower yield was initially
obtained for 120 min (85% yield) which then rapidly increased
to 98% yield at 125 min. The yield then stabilised from 135 min
at 96% indicating steady state was achieved.
As it had been determined that the amount of arylboronic acid
excess could not be lowered (entries 12 and 13, Table 1), the
use of a polymer supported scavenger was tested in an effort to
sequester the excess boronic acid. A column of QP-DMA, a
polymer-supported tertiary amine base, was placed in-line after
the “tube-in-tube” reactor (Figure 1). It was found that this was
sufficient to remove the majority of boronic acid without
affecting the yield of the product (Figure 3). Ultimately as the
Figure 2: Observed trend for the effect of changing oxygen pressure
on the NMR yield of 19.
Figure 3: Comparison of 1H NMR spectra of non-purified (top) and QP-DMA purified (bottom) continuous flow synthesis of compound 20.
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products were required for biological screening they were still ed yield of 26% and also underwent some epimerisation (25,
purified by column chromatography, however, the reduction of 53% ee determined by chiral HPLC, Scheme 2). Additionally, a
the boronic acid excess made the chromatography far easier.
small amount of the product (25) reacted further with phenyl-
boronic acid through the phenol to give 26 in 3% isolated yield.
In the case of L-leucine methyl ester an isolated yield of 60%
Reaction scoping and library preparation
Using the optimised conditions determined for the synthesis of was realised, but this substrate also underwent partial epimeri-
compound 19, a small library was prepared to demonstrate the sation (27, 71% ee determined by chiral HPLC, Scheme 2).
scope of the reaction conditions. Excellent isolated yields were
obtained when anilines were used as the nucleophilic partner Using N-heterocyclic substrates as the nucleophilic partner with
with both 4-methoxyphenylboronic acid (90% yield of 21) and a range of different phenylboronic acids generally gave good
phenylboronic acid (92% yield of 22) as the aryl donors isolated yields (19, 20, 28–35, Scheme 2). Using a pyradizine as
(Scheme 2). Phenylboronic acid also gave a moderate isolated a nucleophilic partner an 81% yield was obtained for the forma-
yield when coupled with 3-amino-5-bromopyridine as the tion of 20. However, using 3,4-dimethyl-1H-1,2,4-triazol-
nucleophile (50% yield of 23, Scheme 2) and a good isolated 5(4H)-one (39), which was synthesised using a literature proce-
yield with the electron withdrawing 4-chloroaniline (71% yield dure [17,18] (Scheme 3), with 3,4-dimethoxyphenylboronic
of 24, Scheme 2). Using L-tyrosine methyl ester as the nucleo- acid gave a lower yield of 26% (28, Scheme 2). It is not yet
phile with phenylboronic acid, unfortunately, gave a poor isolat- clear as to why such a low conversion and isolated yield was
Scheme 2: Scope of the catalytic Chan–Lam reaction in continuous flow.
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Scheme 3: Syntheses of substrate 39.
obtained although the reduced nucleophilicity and higher poten- boronic acids. Lower yields were also encountered for both
tial for coordination of the triazole to the copper catalyst might electron-rich (65% yield) and electron-poor (38% yield)
inhibit catalyst turnover and account for this.
2-substituted phenylboronic acids, most likely due to steric
factors (31 and 35, Scheme 2).
Alternatively, using 3-phenyl-1H-pyrazole (18) as the nucleo-
phile with a number of different phenylboronic acids gave mod- It is noteworthy that for all of the 3-phenyl-1H-pyrazole
erate to good yields (38–82% yields). In general electron-rich couplings, only the 1,3-disubsituted pyrazole products were ob-
phenylboronic acids (19, 29–32, Scheme 2) gave better yields tained with no 1,5-disubsituted isomers being detected. The
than electron poor ones (33–35, Scheme 2). This is probably regioselectivity of the 1,3-disubsituted pyrazoles was con-
due to the more favourable thermodynamics with an increase in firmed by NOESY NMR experiments (30, 33 and 35, Figures
the electropositive nature of boron, which in turn increases the 4–6) as well as comparison to known published data. In addi-
rate of the transmetallation step. Changing the group at the tion, an X-ray crystal structure for compound 33 was obtained
4-position of the phenylboronic acid gave good yields for both and the connectivity confirmed. It was noted that several exam-
electron-rich (19, 79% yield) and electron-poor (33, 76% yield) ples of literature reported cases where mixtures of regioisomers
phenylboronic acids. On the other hand changing the group at had been obtained were wrongly assigned.
the 3-position of the phenylboronic acid gave good yields for
electron-rich (30 and 32, 77% and 82% yields, respectively) but The process described does have certain limitations. For certain
only a moderate yield of 40% for electron-poor (34) phenyl- nucleophilic substrates no products were obtained when C–N
Figure 4: NOESY NMR spectrum for 30 with the characteristic NOESY signal encircled.
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Beilstein J. Org. Chem. 2016, 12, 1598–1607.
Figure 5: NOESY NMR spectrum for 33 with the characteristic NOESY signal encircled.
Figure 6: NOESY NMR spectrum for 35 with the characteristic NOESY signal encircled.
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Beilstein J. Org. Chem. 2016, 12, 1598–1607.
coupling with 4-methoxyphenylboronic acid (17) was attempted experiment when compared to the 79% isolated yield obtained
(Figure 7). In the case of substrate 40 precipitation occurred as for the shorter run experiment. The consistency of the yields ob-
soon as the two solutions came into contact at the T-piece tained indicates that the process is robust and without modifica-
mixer, which was probably due to strong coordination to the tion can reliably deliver 0.216 g h−1 of 19 at 81% isolated yield.
copper acetate by the imidazole ring. This made running this
reaction problematic in flow due to the occurrence of reactor Conclusion
blocking. Other substrates proved unreactive. In the case of The use of flow chemistry for the C–N coupling through a cata-
starting materials 41–43 the reduced nucleophilicity of these lytic Chan–Lam reaction has allowed for a safe and efficient
substrates might account for the lack of conversion. By compar- introduction of oxygen through a reverse “tube-in-tube” reactor.
ison, all three substrates (41–43) also failed to react under batch Optimisation of the reaction conditions allowed for a scalable
conditions using 2 equiv of Cu(OAc)2, 2 equiv of NEt3 and and efficient way for the continuous synthesis of a number of
1 equiv of pyridine at 40 °C for 48 h confirming their low reac- functionalised aromatic and aliphatic amines including a num-
tivity.
ber of 1,3-disubstituted pyrazoles which were selectively ob-
tained over the regioisomeric 1,5-disubstituted products. When
compared to other published protocols it is clear that the use of
Reaction scaling
Finally, the robustness of the process and potential for scala- sub-stoichiometric amounts of the copper catalysts presents an
bility of the general reaction conditions was demonstrated by advantage over the stoichiometric amount used in the original
the synthesis of 19 at a 10 mmol scale, a factor of fourteen flow studies [13]. Additionally, the use of oxygen as the oxidant
times the original 0.7 mmol test reaction (Scheme 4). A slightly offers improved atom economy over the use of systems such as
improved isolated yield (81%) was obtained for the larger scale TEMPO and tert-butyl peroxybenzoate [14]. We believe this
Figure 7: Substrates that gave no products in flow.
Scheme 4: Scale-up procedure for 19.
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Warning: Oxygen is a highly flammable gas
and all reactions were carried out in well
ventilated fume cupboards
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For the flow process, 0.781 mmol of the amine was dissolved in
5.5 mL of dichloromethane followed by 1.25 mmol of the
boronic acid and NEt3 (0.039 g, 54 µL, 0.391 mmol). Another
solution containing Cu(OAc)2·H2O (0.195 mmol, 0.25 equiv),
NEt3 (0.039 g, 54 µL, 0.391 mmol) and pyridine (0.062 g,
63 µL, 0.781 mmol) in 5.5 mL of dichloromethane was also
prepared. The two solutions were separately introduced in a
5 mL loop as shown in Table 1. The pumps were each set at
0.125 mL/min to achieve a residence time of 2 h. Two reverse
“tube-in-tube” reactors (supplied by Vapourtec) were used in
series to achieve a combined reactor volume of 30 mL which
were heated at 40 ºC. The reaction mixture was then passed
through an Omnifit column (r = 0.33 cm, h = 10.00 cm) filled
with QP-DMA followed by a back pressure regulator (175 psi).
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silica to remove most of the excess copper present and the
organic solvent from eluent evaporated under reduced pressure.
The resultant crude material was then purified using flash chro-
matography.
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Supporting Information
Supporting Information File 1
Experimental procedures and characterization data for all
new compounds.
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Acknowledgements
We would like to acknowledge the funding and support from
the Royal Society (to I.R.B.; UF130576) and EPSRC/Syngenta
(to C.J.M.; Grant No. EPSRC 000228396) that has enabled this
work to be undertaken. Furthermore, we are grateful to Dr A.
Batsanov (Durham University, Department of Chemistry) for
solving the X-ray structure.
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