2
J. Bao, G. K. Tranmer / Tetrahedron Letters xxx (2016) xxx–xxx
cost-effective, readily available copper source that is easily scal-
able, producing a preferred flow technique for the generation of
C–N bonds. Herein we report on the use of both copper tubing,
and copper powder as a reusable catalyst to invoke the formation
of new C–N bonds, through the cross coupling of arylboronic acids
and amines.
trimethylamine (TEA) as a base, and 1.0 equivalents (equiv) each
of the aniline and boronic acid in dichloromethane (DCM) as sol-
vent. It was only until the base was switched to pyridine that we
were able to find desired product. After numerous test reactions,
the highest isolated yield we were able to obtain was 24% when
the reaction was performed at 13° C and 1.5 equiv of boronic acid
was used, with pyridine, DCM and 2.0 equiv of myristic acid. Fol-
lowing several other test reactions, we were unable to surpass
the 24% benchmark and decided to alter our optimization reactions
to include the addition of an internal oxidant, as in Table 2.
During this phase of the project, we were pleased to discover
that the use of tert-butyl peroxybenzoate (1.5 equiv) gave superior
yields in comparison to our previous efforts. The use of DCM,
1.5 equiv aniline, 1.0 equiv boronic acid, 40° C at a flow rate of
0.3 mL/min gave an isolated yield 50% for diphenylamine. The
use of tetrahydrofuran (THF) or 2-propanol did not yield any pro-
duct, while methanol gave a decreased yield of 30%. We found that
acetonitrile (MeCN) gave the highest isolated yields (58%), and due
to this result and the fact that we found it easier to work with at
higher temperatures, we decided to select MeCN as our solvent
of choice for this reaction. We also found that decreasing the
equivalents of the oxidant to 0.5 gave a proportional decrease in
yield. Several other oxidants were studied, however, only benzoyl
peroxide was found to give the desired product, although in a
smaller isolated yield of 21%. Further reactions were carried out
for optimization purposes which varied solvent, base, oxidant
and equivalence of oxidant, however, we were unable to find con-
ditions that were superior to the 58% isolated yield provided by
1.5 equiv of tert-butyl peroxybenzoate (tBPB) in MeCN at 40° C.19
Mechanistically, one could make the argument that these types
of reactions can occur on the surface of the solid copper metal
(heterogeneous), or proceed via dissolved copper (homogenous).
It is certain, however, that copper metal must be present for the
reactions to occur, and that a certain level of copper leaching is
often observed when solid copper flow reactors are employed.16
For our reactions, a copper coil reactor was initially used, and uti-
lized for well over 100+ test-optimization reactions. At this point, a
small amount of ‘pitting’ was observed on the inner surface of the
openings of the copper coil reactor, indicating, at the very least,
that some copper was leaching from the reactor. In the interest
of safety, and as a means to employ a more cost-effective solid cop-
per flow reactor, we continued our optimization reactions using a
glass Omnifit column (6.6 Â 150 mm) filled with solid copper
powder, typically 5.5 cm of column height. We found the copper
Initially, we set out to explore the formation for C–N bonds
using solid copper flow reactors and looked to the literature for
representative methods. To our surprise, other than ‘click’ chem-
istry reactions, we could not find any precedence for the solid cop-
per mediated formation of C–N bonds under continuous flow
conditions. The solution phase copper-mediated N-arylation of
arylboronic acids has been explored, however, using a continuous
flow microreactor18 rather than a solid copper reactor. The article
describes a continuous flow procedure which utilizes classic cop-
per-mediated batch conditions (Cu(OAc)2, dichloromethane, base,
room temperature) to perform the N-arylation of anilines. In this
case however, a microfluidic reactor is used in which starting
material is progressed at a rate of 0.2 mL/min, and requires
120 min of residence time for highest rates of conversion. The com-
munication reported only 5 successful C–N coupling products, in
moderate yields (56-73%), however, 1.0 equiv of copper acetate is
required. We set out to develop an N-arylation reaction which uti-
lized a reusable solid copper reactor as a method to invoke this
transformation that was applicable to a wider range of amines,
and would set the foundation for a generalized reaction that would
not require the addition of any copper catalyst, but rely on the use
of a solid copper flow reactor to perform the reaction in much more
cost-effective, efficient and scalable manner.
Initially, we set out to optimize the reaction using a solid copper
flow reactor through the use of either copper tubing, or a column
packed with copper powder. Extensive optimization studies were
carried out that varied the copper reactor, solvent, base, oxidant,
organoboron reactant (arylboronic acids vs. aryl trifluoroborates)
and amine coupling partner. We experienced solubility issues
when trying to use aryl trifluoroborates as coupling partners, and
as a result, focused our optimization studies solely on the use of
arylboronic acids. A summary of the key optimization parameters
is highlighted in Table 1. To perform our reactions, we used a
Vapourtec R2 pumping module which is connected to an R4 reac-
tor module which held our solid copper flow reactor. The Vapour-
tec R2 system contains two HPLC-style pumps connected to
sample loops which were used to introduce our starting material.
Initially, we utilized a 10 mL copper coil which is commercially
available from Vapourtec as our solid copper source due to its syn-
thetic utility and the ease in which it can be heated to high temper-
atures using a Vapourtec R4 reactor module. Our first reactions
mimicked ‘classic’ Chan-Lam reaction conditions, using
Table 2
Optimization of solid copper coil C–N arylation
H
N
NH2
+
B(OH)2
10mL
Table 1
Copper
Coil
Solid copper C–N arylation under classic conditions
1.5 eq.
1.0 eq.
0.3 mL/min.
H
N
NH2
+
B(OH)2
10mL
Solvent
Oxidant
Oxidant (equiv)
Temp (°C)
Yielda
Copper
Coil
THF
2-Propanol
DCM
tBu-Peroxybenzoate
tBu-Peroxybenzoate
tBu-Peroxybenzoate
tBu-Peroxybenzoate
tBu-Peroxybenzoate
tBu-Peroxybenzoate
tBu-Peroxybenzoate
Di-tbutyl peroxide
Di-tbutyl peroxide
Hydrogen peroxide
Benzoyl peroxide
1.5
1.5
1.5
1.5
0.5
1.5
0.5
1.5
1.5
1.5
1.5
40
40
40
40
40
40
40
40
100
40
40
0
0
1.0 eq.
0.5 mL/min.
50
30
11
58
26
0
0
0
21
MeOH
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Solvent
Base (5.0 equiv)
Temp (°C)
Boronic acid (equiv)
Yieldb
DCM
DCM
Triethylamine
Pyridine
60
60
80
130
160
1.0
1.0
1.0
1.5a
1.0
0
10
13
24
0
DCM
Pyridine
DCM
Pyridine
Toluene
Pyridine
a
2.0 equiv of myristic acid used as additive.
Isolated yields (%).
b
a
Isolated yields (%).