Transition-Metal-Free Cross-Coupling Reactions in Dynamic Thin Films To Access Pyrimidine and Quinoxaline Analogues

Article abstract of DOI:10.1002/ejoc.201600830

The vortex fluidic device (VFD) is effective in modulating the synthesis of pyrimidine and quinoxaline-based compounds at room temperature and in high yield. The formation of the C–N bond occurs in the absence of a transition-metal catalyst, which avoids the contamination of the products with trace amounts of a transition metal. The systematic investigation of the operating parameters for the microfluidic platform in the confined operation mode established an optimum tilt angle of 45° for a 10 mm diameter borosilicate glass tube rotating at 5000 rpm.

Full text of DOI:10.1002/ejoc.201600830

DOI: 10.1002/ejoc.201600830
Full Paper
Reactions in Dynamic Thin Films
Transition-Metal-Free Cross-Coupling Reactions in Dynamic Thin
Films To Access Pyrimidine and Quinoxaline Analogues
Louisa A. Ho,[a] Colin L. Raston,*[b] and Keith A. Stubbs*[a]
Abstract: The vortex fluidic device (VFD) is effective in modu- trace amounts of a transition metal. The systematic investiga-
lating the synthesis of pyrimidine and quinoxaline-based com- tion of the operating parameters for the microfluidic platform
pounds at room temperature and in high yield. The formation in the confined operation mode established an optimum tilt
of the C–N bond occurs in the absence of a transition-metal angle of 45° for a 10 mm diameter borosilicate glass tube rotat-
catalyst, which avoids the contamination of the products with ing at 5000 rpm.
Introduction
ors, but these require larger volumes of liquid to operate, are
inherently expensive and have limited residence times.[11] The
thickness of the film depends not only on the rotational speed
of the tube but also on other operational parameters including
the volume of the liquid within and the diameter of the tube
and its tilt angle relative to the horizontal position.[8] In addi-
tion, the mode of operation for the device is also critical to
control the shear forces occurring in the reactions (for a finite
volume of liquid in the tube), which arise from Stewartson/
Ekman layers and other fluid dynamic processes,[13] including
vibrationally induced Faraday waves on the surface of the
film.[14,15] Under a continuous-flow mode of operation, the jet
feeds deliver reagents at the base of the tube, where rapid
micromixing and additional shear forces occur as the solution
moves up against the tube. The VFD has been widely applied
in the syntheses of nanomaterials and nanoparticles,[16–20] in-
cluding the exfoliation of graphene,[13] the controlled slicing of
carbon nanotubes,[21] the process of protein folding[22] as well
as, more recently, in synthesis and industry.[8,14,15,23–29] It has
also been effectively employed in multistep syntheses by a sin-
gle pass-through the device.[28]
Bond-forming reactions are an important part of organic chem-
istry and are the basis for the synthesis of natural products and
compounds used in industrial applications and drug develop-
ment. The advancement of new methods to generate chemical
bonds has focused on the use of transition-metal-based cata-
lysts to facilitate these transformations. These include the use
of palladium,[1] copper[2] and more recently nickel.[3] To date,
limited work has been done to develop green-chemical proc-
esses that eliminate the use of potentially toxic materials and
avoid the further depletion of metals such as palladium. In ad-
dition, the development of green-chemical methods to stream-
line these processes and to reduce the formation of byproducts,
the consumption of energy and the generation of waste upon
purification is required for the future development of sustain-
able technologies.
There is an increasing interest in the use of microfluidic reac-
tors to overcome such limitations. As a result of their design,
these reactors enable not only the synthesis of organic mol-
ecules[4–11] but also the rapid preparation of products. For ex-
ample, the confinement within a channel enables the rapid mix-
ing of reaction components typically under laminar flow condi-
tions,[6,9,12] while reactions in thin films enable rapid heat and
mass transfer.[8,11]
Cross-coupling reactions, notably those used for the forma-
tion of C–N bonds, are a class of chemical reactions that would
greatly benefit from the further development of sustainable
and green-chemical methods. This type of reaction is important
in synthetic organic chemistry and is normally achieved by us-
ing activated aromatic substrates[30] or metal-based chemis-
try[31,32] and, more recently, the use of microfluidic reac-
tors.[33,34] Avoiding metal-based systems is especially important
to eliminate product contamination with toxic metals. To this
end, we have demonstrated a proof-of-concept approach for
C–N cross-coupling reactions by using a VFD in the absence of
a transition-metal catalyst.[26]
The vortex fluidic device (VFD, see the Supporting Informa-
tion) is a recent addition to the field of microfluidic reactors.[8]
This device is simple in design and relies on the high-speed
rotation of a tube, within the system, to generate a thin film.
The VFD is related to spinning-disc and rotating-tube process-
[a] School of Chemistry and Biochemistry, University of Western Australia,
35 Stirling Highway, Crawley, WA 6009, Australia
E-mail: keith.stubbs@uwa.edu.au
www.web.uwa.edu.au/people/keith.stubbs
[b] School of Chemical and Physical Sciences, Flinders University,
Sturt Rd., Bedford Park, SA 5042, Australia
Given the importance of this type of coupling chemistry in
natural-product synthesis and drug development, we pro-
ceeded to investigate scaffolds that could potentially be utilized
for this purpose. Furthermore, the investigation can help to
confirm the benefit of a VFD in the synthesis of organic mol-
E-mail: colin.raston@flinders.edu.au
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600830.
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ecules to overcome reaction limitations such as inefficient mix-
ing, heat transfer associated with traditional batch processing,
as well as reproducibility. The use of transition-metal-free reac-
tion conditions is advantageous in the search for more benign
reaction processes.
Results and Discussion
We focused on the synthesis of pyrimidine and quinoxaline
scaffolds because these compound classes play an important
role as starting materials in the synthesis of biologically active
molecules and as lead structures in drug development (Fig-
ure 1).[35–38]
Figure 1. Examples of bioactive compounds that feature a pyrimidine or quin-
oxaline scaffold.
As previously demonstrated, an important strategy for the
optimization of VFD reactions involves the identification of the
optimal operating parameters to achieve the highest possible
yields. In the present study, we used aryl chlorides, namely 2-
chloropyrimidine and 2-chloroquinoxaline, in a reaction with
morpholine. We first used conditions that had been established
in earlier studies,[26] that is, a 3500 rpm rotational speed and a
45° tilt angle at 100 °C for 12 h, with an aqueous solution of
potassium phosphate as the reaction medium (Figure 2A), al-
though we knew that the these would have to be reoptimized
for the current investigation. We also used the confined opera-
tion mode, which is most easily comparable to classic batch
conditions.
reaction time to facilitate the conversion, as well as the reaction
temperature, was initially examined. Under the above-men-
tioned conditions, we found that the reactions reached comple-
tion within 2 h, which is a marked improvement over previous
work that employed similar compounds and methods (see the
Supporting Information, Figure 2A).[26,39] It is worth noting that
previous green syntheses of 1 and 2[39] required extensive reac-
tion times (i.e., 18 h), high temperatures and the use of a toxic
base, while metal-based methods required the use of toxic met-
als and high catalytic loadings.[40] However, a reaction time of
After 12 h, both pyrimidine 1 and quinoxaline 2 were gratify- 2 h requires a reaction temperature of 100 °C, as lower tempera-
ingly produced in good yields of 72 and 79 %, respectively. The tures lead to decreased yields (see the Supporting Information).
Figure 2. (A) Model reactions to investigate the utility of the VFD. (B) Variation in the isolated product yields for the reaction between the aryl chloride and
morpholine upon changing the rotational speed and tilt angle of the VFD. The model reaction was carried out in aqueous K3PO4 solution at 100 °C for 2 h.
All reactions were conducted in triplicate with the average yield shown. Errors are within 2 %.
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The operational parameters of the VFD, including rotational sumption of starting material with TLC, we found that none of
speed and angle of inclination of the tube, can be varied the batch reactions were completed after 2 h, and up to 8 h
and dramatically affect the yields of the organic reac- were required for some to reach completion (e.g., azepane and
tions.[8,23,24,26,28,29] Accordingly, we undertook a systematic dibutylamine with 2-chloroquinoxaline). We also found that the
study to vary the parameters of the above-mentioned model obtained yields were consistently lower than those obtained by
reactions to gain insight into the effect that these parameters using a VFD. Again, this gives credibility to the ability of VFDs
have on the corresponding yields (Figure 2B). Interestingly the to create thin films, which enable rapid heat and mass transfer
optimal reaction conditions favoured moderate rotational and the formation of Faraday waves for the efficient conversion
speeds.
of reactants.
An increase in the product yield was observed as the rota-
Table 1. Synthesis of various alkylaminopyrimidines and alkylaminoquinoxal-
ines by using a VFD (5000 rpm, 45° tilt angle at 100 °C, 2 h). The yields of
reactions conducted under batch conditions are in parentheses (consump-
tion of starting material monitored by TLC).
tional speed increased, but at the highest speed, the yield
dropped (Figure 2B). This trend in the yields was observed at
all of the examined tilt angles and is consistent with the pres-
ence of a Faraday wave at 5000 rpm[14,15] (otherwise the yields
should increase with increasing speed) and/or a breakdown in
the Stewartson/Ekman layers as the film becomes thinner at
higher speeds. Increasing the tilt angle from 30 to 45° also
raised the yields, but slightly lower yields were observed for the
reactions conducted at a 60° tilt angle. These observations are
consistent with previous studies that employed a VFD, in which
a tilt angle of 45° has been shown to be optimal for a number
of different processes. This angle corresponds to the maximum
cross vector of gravity and centrifugal force, which appears to
introduce greater shear stress within the thin film and, thus,
shorter diffusion paths.
The results also give further credence to the notion that the
parameters of the VFD reaction must be specifically optimized,
similar to what must be done for other microfluidic and flow
reactor devices. Interestingly, the optimum conditions also cor-
respond to results of optimal protein folding studies, which sim-
ilarly used a VFD that contained a 10 mm NMR tube with a
single bearing at the bottom of the tube and a Teflon guide
for the upper section of the tube.[22] In a separate study, an
improvement in yield was observed in esterification reactions
that use the same design of the VFD, that is, a rotational speed
of approximately 5250 rpm and a 45° tilt angle, which is as-
cribed to the presence of Faraday waves in the thin film that
result from the resonance of the vibrations in the bearing at a
rotational speed.[15] It is worth noting, that the improvement in
the esterification reactions disappears at this speed when using
a double bearing system.
In the present study, at the optimum speed and tilt angle,
mechanical energy from the vibrationally induced Faraday
waves may result in a variation of pressure that lowers the acti-
vation energy of the reaction similar to that of the reaction in
the presence of a transition metal. This could arise from a more
favourable collapse of the transition state for the reactions.[15b]
With suitable reaction conditions in hand, we systematically
broadened the scope of amine substrates to demonstrate the
utility of the method (Table 1). Gratifyingly, the conditions are
Conclusions
indeed amenable to different alkyl- and arylamines, and the We have demonstrated the use of a VFD in the preparation of
obtained yields of known compounds are comparable to those both alkylaminopyrimidines and alkylaminoquinoxalines in
reported for different methods, including transition-metal-cata- high yields without the need for a transition-metal catalyst. The
lyzed variants.[40] We also conducted all reactions under batch efficiency of these reactions and the yields of the obtained
conditions by using a traditional round-bottom flask and con- products are higher than those obtained by the corresponding
ventional heating, to establish the ability of the VFD to increase batch reactions. These studies further demonstrate the utility
the efficiency of these transformations. By monitoring the con- of the VFD as a viable option in organic synthesis to explore
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ucts of the batch reactions are consistent with those of the products
of the VFD reactions.
new synthetic routes towards targets of interest. It is worth not-
ing that the VFD is a relatively inexpensive microfluidic plat-
form, and the present results highlight its versatility in synthesis
similar to conventional microfluidic reactors that have recently
been used for similar chemical reactions, which require high
temperature and pressure.[33,34] In addition, the results further
demonstrate the need to fine-tune the parameters of the VFD
specifically to reactions of interest and further highlight the im-
portance of Faraday waves, which arise from the resonance of
vibrations in the bearings at a given rotational speed and im-
part mechanical energy into the thin film.
4-(Pyrimidin-2-yl)morpholine (1): The reaction was conducted
with morpholine to give 1 (225 mg, 86 %) as a colourless oil; Rf =
0.24 (EtOAc/hexane, 1:4). The 1H and 13C NMR spectroscopic data
are consistent with those values in the literature.[39] 1H NMR
(500 MHz, CDCl3): δ = 8.30 (d, J = 4.7 Hz, 2 H), 6.50 (t, J = 4.7 Hz, 1
H), 3.81–3.72 (m, 8 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 161.9,
157.8, 110.4, 66.9, 44.3 ppm.
4-(Quinoxalin-2-yl)morpholine (2): The reaction was conducted
with morpholine to give 2 (320 mg, 93 %) as a yellow solid; Rf =
0.19 (EtOAc/hexane, 1:4). M.p. 85–86 °C; ref.[41] m.p. 87–89 °C. The
1H and 13C NMR spectroscopic data are consistent with those values
in the literature.[42] 1H NMR (500 MHz, CDCl3): δ = 8.54 (s, 1 H), 7.90–
7.87 [m (app dd), 1 H], 7.70–7.67 [m (app dd), 1 H], 7.60–7.55
[m (app dt), 1 H], 7.43–7.38 [m (app dt), 1 H], 3.87–3.83 (m, 4 H),
3.77–3.72 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.4, 141.6,
137.2, 135.5, 130.3, 128.8, 126.7, 125.2, 66.7, 45.1 ppm.
Experimental Section
General Methods: The 1H and 13C NMR spectra were recorded with
a Bruker AV600 (600 MHz for 1H NMR and 151 MHz for 13C NMR)
spectrometer. CDCl3 was used as the NMR solvent, and the residual
1
CHCl3 (δ = 7.26 ppm for H NMR) and CDCl3 (δ = 77.0 ppm for 13C
2-(Pyrrolidin-1-yl)pyrimidine (3): The reaction was conducted
with pyrrolidine to give 3 (200 mg, 84 %) as a colourless oil; Rf =
0.20 (EtOAc/hexane, 1:4). The 1H and 13C NMR spectroscopic data
are consistent with those values in the literature.[39] 1H NMR
(500 MHz, CDCl3): δ = 8.27 (d, J = 4.8 Hz, 2 H), 6.41 (t, J = 4.8 Hz, 1
H), 3.56–3.51 (m, 4 H), 2.00–1.93 (m, 4 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 160.3, 157.8, 108.9, 46.6, 25.6 ppm.
NMR) were used as the internal standards. High-resolution mass
spectra were recorded with a Waters LCT Premier XE spectrometer
and performed in the W-mode by using the ESI ionization method
and MeCN/water (9:1) as the matrix solution. Infrared spectra for
new compounds were recorded with a PerkinElmer Spectrum One
Fourier transform infrared spectrometer fitted with an attenuated
total reflectance (ATR) attachment. Flash chromatography was per-
formed on silica gel (BDH) with the specified solvents. Thin layer
chromatography (TLC) was performed on Merck silica gel 60 F254
aluminium-backed plates that were visualized by heating (>200 °C)
after treating them with a 5 % solution of sulfuric acid in EtOH. All
solvents were distilled prior to use.
2-(Piperidin-1-yl)pyrimidine (4): The reaction was conducted with
piperidine to give 4 (232 mg, 89 %) as a colourless oil; Rf = 0.59
(EtOAc/hexane, 1:4). The 1H and 13C NMR spectroscopic data are
consistent with those values in the literature.[39] 1H NMR (500 MHz,
CDCl3): δ = 8.25 (d, J = 4.7 Hz, 2 H), 6.38 (t, J = 4.7 Hz, 1 H), 3.77–
3.73 (m, 4 H), 1.68–1.54 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 161.8, 157.8, 109.1, 44.8, 25.8, 25.0 ppm.
General Procedure for Cross-Coupling Reactions
Optimization: The aryl chloride (1.60 mmol) and morpholine
(1.60 mmol) were added to a solution of K3PO4 (580 mg, 3.20 mmol)
and water (900 μL) in a 10 mm borosilicate glass tube (standard
10 mm NMR tube). The tube was then rotated in the VFD at various
rotational speeds (2000, 3500, 5000, or 7000 rpm) and tilt angles
(30°, 45°, or 60°) and then heated at 100 °C for 2 h. The reaction
mixture was cooled and then diluted with EtOAc (30 mL). The or-
1-(Pyrimidin-2-yl)azepane (5): The reaction was conducted with
azepane to give 5 (229 mg, 81 %) as a colourless oil; Rf = 0.45
(EtOAc/hexane, 1:4). The 1H and 13C NMR spectroscopic data are
consistent with those values in the literature.[39] 1H NMR (500 MHz,
CDCl3): δ = 8.26 (d, J = 4.7 Hz, 2 H), 6.38 (t, J = 4.7 Hz, 1 H), 3.74–
3.70 (m, 4 H), 1.80–1.72 (m, 4 H), 1.57–1.51 (m, 4 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 161.6, 157.7, 108.8, 47.1, 28.0, 27.4 ppm.
ganic mixture was washed with K2CO3 (0.1
M aqueous solution,
N,N-Dibutylpyrimidin-2-amine (6): The reaction was conducted
with dibutylamine to give 6 (264 mg, 80 %) as a colourless oil; Rf =
40 mL), dried with MgSO4 and filtered. The solvents were evapo-
rated. The residue was purified by flash chromatography (EtOAc/
hexane, 1:9–3:7) to give the target compounds. All reactions were
conducted in triplicate with the average yield reported. The errors
obtained are within 2 %.
0.66 (EtOAc/hexane, 1:4). IR (ATR): ν = 1587 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 8.25 (d, J = 4.7 Hz, 2 H), 6.37 (t, J = 4.7 Hz, 1 H), 3.56–
3.50 [m (app t), 4 H], 1.62–1.54 [m (app sextet), 4 H], 1.39–1.30 [m
(app sextet), 4 H], 0.93 (t, J = 7.3 Hz, 6 H, 4′-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 161.6, 157.6, 108.7, 47.6, 30.0, 20.4, 14.2 ppm.
HRMS (ESI): calcd. for C12H22N3 [M + H]+ 208.1814; found 208.1822.
VFD Processing: The aryl chloride (1.60 mmol) and the appropriate
amine (1.60 mmol) were added to a solution of K3PO4 (580 mg,
3.20 mmol) and water (900 μL) in a 10 mm borosilicate glass tube.
The tube was then rotated in the VFD at 5000 rpm with a tilt angle
of 45° and then heated at 100 °C for 2 h. The mixture was then
treated as in the optimization procedure above. All reactions were
conducted in triplicate with the average yield reported. The errors
obtained are within 2 %.
1-(Pyrimidin-2-yl)piperidin-3-ol (7): The reaction was conducted
with 3-hydroxypiperidine to give 7 (257 mg, 90 %) as a colourless
1
oil; Rf = 0.17 (EtOAc/hexane, 3:7). IR (ATR): ν = 3350, 1582 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 8.27 (d, J = 4.7 Hz, 2 H), 6.44 (t, J =
4.7 Hz, 1 H), 4.17–4.11 (m, 1 H), 3.99–3.92 (m, 1 H), 3.82 (septet, J =
3.8 Hz, 1 H), 3.58–3.48 (m, 2 H), 2.58 (s, 1 H, OH), 2.00–1.90 (m, 1
H), 1.89–1.80 (m, 1 H), 1.69–1.59 (m, 1 H), 1.57–1.48 (m, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 162.2, 157.9, 109.8, 66.6, 50.8, 44.3,
32.9, 22.4 ppm. HRMS (ESI): calcd. for C9H14N3O [M + H]+ 180.1137;
found 180.1137.
Batch Processing: The aryl chloride (1.60 mmol) and the appropri-
ate amine (1.60 mmol) were added to a solution of K3PO4 (580 mg,
3.20 mmol) and water (900 μL) in a 5 mL round-bottom flask. The
mixture was then heated at 100 °C until the reaction reached com-
pletion (monitored by TLC). The mixture was then treated as in
the optimization procedure above. All reactions were conducted in
2-(4-Phenylpiperazin-1-yl)pyrimidine (8): The reaction was con-
triplicate with the average yield reported. The errors obtained are
ducted with N-phenylpiperazine to give 8 (341 mg, 89 %) as a tan
1
1
within 2 %. The H and 13C NMR spectroscopic data of the prod- solid; Rf = 0.25 (EtOAc/hexane, 1:4). M.p. 74–75 °C. The H and 13C
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NMR spectroscopic data are consistent with those values in the
literature.[39] 1H NMR (500 MHz, CDCl3): δ = 8.34 (d, J = 4.7 Hz, 2 H),
7.32–7.27 [m (app t), 2 H], 7.00–6.97 [m (app d), 2 H], 6.91–6.87 [m
(app t), 1 H], 6.51 (t, J = 4.7 Hz, 1 H), 4.01–3.97 (m, 4 H), 3.28–3.24
(m, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 161.8, 157.9, 151.5,
129.3, 120.2, 116.6, 110.2, 49.4, 43.8 ppm.
[m (app dt), 1 H], 7.34–7.29 [m (app dt), 1 H], 3.67–3.60 (m, 4 H),
2.08–2.01 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 150.7, 142.6,
136.6, 136.4, 130.0, 128.9, 126.2, 123.7, 46.7, 25.5 ppm. HRMS (ESI):
calcd. for C12H14N3 [M + H]+ 200.1188; found 200.1193.
2-(Piperidin-1-yl)quinoxaline (16): The reaction was conducted
with piperidine to give 16 (296 mg, 87 %) as a yellow solid; Rf =
0.38 (EtOAc/hexane, 1:4). M.p. 61–63 °C; ref.[41] m.p. 62–63 °C. The
1H and 13C NMR spectroscopic data are consistent with those values
in the literature.[40] 1H NMR (500 MHz, CDCl3): δ = 8.57 (s, 1 H), 7.86–
7.83 [m (app dd), 1 H], 7.67–7.64 [m (app dd), 1 H], 7.56–7.52 [m
(app dt), 1 H], 7.37–7.33 [m (app dt), 1 H], 3.79–3.73 (m, 4 H), 1.74–
1.66 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.6, 142.0,
136.6, 136.1, 130.0, 128.7, 126.5, 124.4, 46.0, 25.8, 24.7 ppm.
N-Hexylpyrimidin-2-amine (9): The reaction was conducted with
hexylamine to give 9 (240 mg, 84 %) as a colourless oil; Rf = 0.22
(EtOAc/hexane, 1:4). The 1H and 13C NMR spectroscopic data are
consistent with those values in the literature values.[43] 1H NMR
(500 MHz, CDCl3): δ = 8.24 (d, J = 4.8 Hz, 2 H), 6.47 (t, J = 4.8 Hz, 1
H), 5.33 (br. s, 1 H, NH), 3.40–3.35 (m, 2 H), 1.62–1.56 (m, 2 H), 1.40–
1.26 (m, 6 H), 0.89–0.85 [m (app t), 3 H] ppm. 13C NMR (125 MHz,
CDCl3): δ = 162.6, 158.1, 110.3, 41.6, 31.7, 29.7, 26.8, 22.7, 14.1 ppm.
2-(Azepan-1-yl)quinoxaline (17): The reaction was conducted
with azepane to give 17 (301 mg, 83 %) as a yellow solid; Rf = 0.61
N-Cyclopropylpyrimidin-2-amine (10): The reaction was con-
ducted with cyclopropylamine to give 10 (187 mg, 87 %) as a white
solid; Rf = 0.10 (EtOAc/hexane, 3:7). M.p. 89–92 °C; ref.[43] m.p. 89–
(EtOAc/hexane, 1:4). M.p. 86–89 °C; ref.[45] m.p. 90 °C. IR (ATR): ν =
˜
1579 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.86–7.83
1
91 °C. The H and 13C NMR spectroscopic data are consistent with
[m (app dd), 1 H], 7.66–7.63 [m (app dd), 1 H], 7.54–7.51 [m (app
dt), 1 H], 7.33–7.30 [m (app dt), 1 H], 3.81–3.77 (m, 4 H), 1.89–1.82
(m, 4 H), 1.60–1.55 (m, 4 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
151.7, 142.5, 136.4, 135.2, 129.9, 128.7, 126.4, 123.7, 47.6, 27.9,
27.0 ppm. HRMS (ESI): calcd. for C14H18N3 [M + H]+ 228.1501; found
228.1500.
those values in the literature.[43] 1H NMR (500 MHz, CDCl3): δ = 8.30
(d, J = 4.7 Hz, 2 H), 6.54 (t, J = 4.7 Hz, 1 H), 5.88 (br. s, 1 H, NH),
2.77–2.71 (m, 1 H), 0.83–0.78 (m, 2 H), 0.54–0.50 (2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 163.5, 158.1, 111.1, 23.9, 7.4 ppm.
N-Cyclobutylpyrimidin-2-amine (11): The reaction was conducted
with cyclobutylamine to give 11 (200 mg, 84 %) as a white solid;
Rf = 0.26 (EtOAc/hexane, 3:7). M.p. 68–70 °C. The 1H and 13C NMR
spectroscopic data are consistent with those values in the litera-
ture.[44] 1H NMR (500 MHz, CDCl3): δ = 8.24 (d, J = 4.8 Hz, 2 H), 6.48
(t, J = 4.8 Hz, 1 H), 5.71 (br. s, 1 H, NH), 4.47–4.38 (m, 1 H), 2.44–
2.36 (m, 2 H), 1.92–1.82 (m, 2 H), 1.77–1.66 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 161.5, 157.9, 110.4, 46.3, 31.5, 15.0 ppm.
N,N-Dibutylquinoxalin-2-amine (18): The reaction was conducted
with dibutylamine to give 18 (320 mg, 78 %) as a yellow solid; Rf =
1
0.36 (EtOAc/hexane, 1:9). M.p. 63–64 °C. IR (ATR): ν = 1578 cm–1. H
˜
NMR (600 MHz, CDCl3): δ = 8.41 (s, 1 H), 7.85–7.82 [m (app dd), 1
H], 7.65–7.62 [m (app dd), 1 H], 7.54–7.50 [m (app dt), 1 H], 7.33–
7.29 [m (app dt), 1 H], 3.62–3.58 (m, 4 H), 1.69–1.63 (m, 4 H), 1.44–
1.37 (m, 4 H), 1.00–0.96 [m (app t), 6 H] ppm. 13C NMR (151 MHz,
CDCl3): δ = 151.5, 142.5, 136.2, 135.3, 129.9, 128.7, 126.4, 123.7,
48.3, 30.2, 20.3, 14.1 ppm. HRMS (ESI): calcd. for C16H24N3 [M + H]+
258.1970; found 258.1974.
N-Cyclohexylpyrimidin-2-amine (12): The reaction was conducted
with cyclohexylamine to give 12 (229 mg, 81 %) as a white solid;
Rf = 0.37 (EtOAc/hexane, 1:4). M.p. 88–89 °C; ref.[43] m.p. 87–89 °C.
The 1H and 13C NMR spectroscopic data are consistent with those
values in the literature.[39] 1H NMR (500 MHz, CDCl3): δ = 8.23 (d,
J = 4.7 Hz, 2 H), 6.45 (t, J = 4.7 Hz, 1 H), 5.24 (s, 1 H, NH), 3.83–3.74
(m, 1 H), 2.06–1.98 (m, 2 H), 1.76–1.68 (m, 2 H), 1.64–1.57 (m, 1 H),
1.45–1.34 (m, 2 H), 1.25–1.15 (m, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 161.7, 158.0, 110.0, 49.5, 33.2, 25.7, 24.8 ppm.
1-(Quinoxalin-2-yl)piperidin-3-ol (19): The reaction was con-
ducted with 3-hydroxypiperidine to give 19 (264 mg, 72 %) as a
yellow solid; Rf = 0.13 (EtOAc/hexane, 2:3). M.p. 109–111 °C. IR (ATR):
ν = 3265, 1588 cm–1 1H NMR (600 MHz, CDCl3): δ = 8.56 (s, 1 H),
.
˜
7.86–7.84 [m (app dd), 1 H], 7.65–7.62 [m (app dd), 1 H], 7.56–7.52
[m (app dt), 1 H), 7.38–7.34 [m (app dt), 1 H], 4.02–3.97 (m (app
dd), 1 H], 3.97–3.92 [m (app septet), 1 H], 3.85–3.79 (m, 1 H), 3.66–
3.55 (m, 2 H), 3.24 (br. s, 1 H, OH), 1.99–1.88 (m, 2 H), 1.74–1.67 (m,
1 H), 1.64–1.57 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 152.9,
141.6, 136.6, 136.3, 130.2, 128.6, 126.4, 124.9, 66.4, 51.6, 45.9, 32.7,
22.2 ppm. HRMS (ESI): calcd. for C13H16N3O [M + H]+ 230.1293;
found 230.1289.
N-Benzylpyrimidin-2-amine (13): The reaction was conducted
with benzylamine to give 13 (242 mg, 82 %) as a white solid; Rf =
0.23 (EtOAc/hexane, 1:4). M.p. 79–80 °C; ref.[43] m.p. 79–81 °C. The
1H and 13C NMR spectroscopic data are consistent with those values
in the literature.[43] 1H NMR (500 MHz, CDCl3): δ = 8.17 (s, 2 H), 7.39–
7.24 (m, 5 H), 6.51–6.48 [m (app t), 1 H], 6.13 (s, 1 H, NH), 4.65–4.62
[m (app d), 2 H] ppm. 13C NMR (125 MHz, CDCl3): δ = 162.4, 158.1,
139.2, 128.7, 127.7, 127.3, 110.8, 45.6 ppm.
2-(4-Phenylpiperazin-1-yl)quinoxaline (20): The reaction was
conducted with N-phenylpiperazine to give 20 (422 mg, 91 %) as
an orange solid; Rf = 0.25 (EtOAc/hexane, 1:4). M.p. 115–116 °C. IR
N-(4-Methoxybenzyl)pyrimidin-2-amine (14): The reaction was
conducted with 4-methoxybenzylamine to give 14 (288 mg, 84 %)
as a white solid; Rf = 0.14 (EtOAc/hexane, 1:4). M.p. 101–104 °C;
ref.[43] m.p. 101–103 °C. The 1H and 13C NMR spectroscopic data are
consistent with those values in the literature.[39] 1H NMR (500 MHz,
CDCl3): δ = 8.15 (s, 2 H), 7.29–7.25 [m (app d), 2 H], 6.88–6.83
[m (app d), 2 H), 6.47 (t, J = 4.8 Hz, 1 H), 6.17 (s, 1 H, NH), 4.56–4.52
[m (app d), 2 H], 3.78 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
162.3, 158.9, 158.1, 131.2, 129.0, 114.0, 110.6, 55.4, 45.0 ppm.
(ATR): ν = 1578 cm–1 1H NMR (600 MHz, CDCl3): δ = 8.64 (s, 1 H),
.
˜
7.92–7.90 [m (app dd), 1 H], 7.73–7.71 [m (app dd), 1 H], 7.61–7.58
[m (app dt), 1 H], 7.44–7.41 [m (app dt), 1 H], 7.33–7.30 (m, 2 H),
7.01–6.98 (m, 2 H), 6.94–6.91 (m, 1 H), 3.98–3.94 (m, 4 H), 3.38–3.34
(m, 4 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 152.3, 151.2, 141.7,
137.1, 135.8, 130.3, 129.4, 128.8, 126.7, 125.1, 120.5, 116.6, 49.3,
44.9 ppm. HRMS (ESI): calcd. for C18H19N4 [M + H]+ 291.1610; found
291.1599.
2-(Pyrrolidin-1-yl)quinoxaline (15): The reaction was conducted
with pyrrolidine to give 15 (283 mg, 89 %) as a yellow solid; Rf =
N-Hexylquinoxalin-2-amine (21): The reaction was conducted
with hexylamine to give 21 (311 mg, 85 %) as a yellow solid;
0.23 (EtOAc/hexane, 1:4). M.p. 85–88 °C; ref.[45] m.p. 89 °C. IR (ATR): Rf = 0.27 (EtOAc/hexane, 1:4). M.p. 46–47 °C. IR (ATR): ν = 3263,
˜
ν = 1577 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.31 (s, 1 H), 7.87–
1585 cm–1 1H NMR (600 MHz, CDCl3): δ = 8.16 (s, 1 H), 7.85–7.83
.
˜
7.83 [m (app dd), 1 H], 7.69–7.66 [m (app dd), 1 H), 7.55–7.51
[m (app dd), 1 H], 7.69–7.66 [m (app dd), 1 H], 7.55–7.51 [m (app
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dt), 1 H], 7.35–7.31 [m (app dt), 1 H], 5.13–5.09 (m, 1 H), 3.52–3.47
(m, 2 H), 1.67–1.61 (m, 2 H), 1.42–1.36 (m, 2 H), 1.34–1.27 (m, 4 H),
0.90–0.85 (m, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 152.1, 142.1,
138.5, 137.1, 130.0, 128.8, 126.3, 124.2, 41.3, 31.6, 29.4, 26.8, 22.6,
14.1 ppm. HRMS (ESI): calcd. for C14H20N3 [M + H]+ 230.1657; found
230.1655.
Acknowledgments
Support of this work by the Australian Research Council, the
Government of South Australia and the Centre for Microscopy,
Characterisation and Analysis at the University of Western Aus-
tralia is acknowledged.
N-Cyclopropylquinoxalin-2-amine (22): The reaction was con-
ducted with cyclopropylamine to give 22 (248 mg, 84 %) as a yellow
Keywords: Synthetic methods · Cross-coupling · Nitrogen
heterocycles · Thin films · Green chemistry
solid; Rf = 0.23 (EtOAc/hexane, 3:7). M.p. 84–85 °C. IR (ATR): ν =
˜
1
3216, 1584 cm–1. H NMR (600 MHz, CDCl3): δ = 8.54 (s, 1 H), 7.91–
7.88 [m (app dd), 1 H], 7.69–7.66 [m (app dd), 1 H], 7.58–7.54 [m
(app dt), 1 H], 7.41–7.37 [m (app dt), 1 H], 5.66 (s, 1 H), 2.82–2.73
(m, 1 H), 0.94–0.88 (m, 2 H), 0.66–0.61 (m, 2 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 153.0, 141.9, 137.9, 136.8, 130.2, 129.0, 126.3,
124.8, 23.8, 8.1 ppm. HRMS (ESI): calcd. for C11H12N3 [M + H]+
186.1031; found 186.1030.
[1] C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus,
Angew. Chem. Int. Ed. 2012, 51, 5062; Angew. Chem. 2012, 124, 5150.
[2] G. Evano, C. Theunissen, A. Pradal, Nat. Prod. Rep. 2013, 30, 1467.
[3] S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509, 299.
[4] A. J. deMello, Nature 2006, 442, 394.
[5] N. M. Smith, B. Corry, K. S. Iyer, M. Norret, C. L. Raston, Lab Chip 2009, 9,
2021.
[6] C. Lee, C. Chang, Y. Wang, L. Fu, Int. J. Mol. Sci. 2011, 12, 3263.
[7] M. Faustini, J. Kim, G. Jeong, J. Kim, H. Moon, W. Ahn, D. Kim, J. Am.
Chem. Soc. 2013, 135, 14619.
[8] L. Yasmin, X. Chen, K. A. Stubbs, C. L. Raston, Sci. Rep. 2013, 3, 2282.
[9] S. G. Newman, K. F. Jensen, Green Chem. 2013, 15, 1456.
[10] L. Y. Yeo, J. R. Friend, Biomicrofluidics 2009, 3, 012002.
[11] X. Chen, N. M. Smith, K. S. Iyer, C. L. Raston, Chem. Soc. Rev. 2014, 43,
1387.
N-Cyclobutylquinoxalin-2-amine (23): The reaction was con-
ducted with cyclobutylamine to give 23 (274 mg, 86 %) as a yellow
solid; Rf = 0.33 (EtOAc/hexane, 3:7). M.p. 95–97 °C. IR (ATR): ν =
˜
1
3274, 1584 cm–1. H NMR (600 MHz, CDCl3): δ = 8.15 (s, 1 H), 7.86–
7.65 [m (app dd), 1 H], 7.67–7.65 [m (app dd), 1 H], 7.56–7.53
[m (app dt), 1 H], 7.37–7.33 [m (app dt), 1 H], 5.22–5.18 (m, 1 H),
4.61–4.53 (m, 1 H), 2.53–2.46 (m, 2 H), 1.97–1.88 (m, 2 H), 1.84–1.76
(m, 2 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 151.1, 142.1, 138.0,
137.3, 130.1, 128.9, 126.4, 124.4, 46.5, 31.6, 15.3 ppm. HRMS (ESI):
calcd. for C12H14N3 [M + H]+ 200.1188; found 200.1181.
[12] S. V. Ley, D. E. Fitzpatrick, R. J. Ingham, R. M. Myers, Angew. Chem. Int. Ed.
2015, 54, 3449; Angew. Chem. 2015, 127, 3514.
[13] X. Chen, J. F. Dobson, C. L. Raston, Chem. Commun. 2012, 48, 3703.
[14] J. Britton, S. B. Dalziel, C. L. Raston, RSC Adv. 2015, 5, 1655.
[15] a) J. Britton, S. B. Dalziel, C. L. Raston, Green Chem. 2016, 18, 2193; b) J.
Britton, L. M. Meneghini, C. L. Raston, G. A. Weiss, Angew. Chem. Int. Ed.
2016, 55, 11387; Angew. Chem. 2016, 128, 11559.
[16] F. M. Yasin, R. A. Boulos, B. Y. Hong, A. Cornejo, K. S. Iyer, L. Gao, H. T.
Chua, C. L. Raston, Chem. Commun. 2012, 48, 10102.
[17] X. Chen, R. A. Boulos, P. Eggers, C. L. Raston, Chem. Commun. 2012, 48,
11407.
[18] M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith, C. L. Raston, Green Chem.
2013, 15, 650.
[19] E. Eroglu, N. J. D'Alonzo, S. M. Smith, C. L. Raston, Nanoscale 2013, 5,
2627.
[20] C. L. Tong, C. Yu, K. S. Iyer, C. L. Raston, RSC Adv. 2013, 3, 18767.
[21] K. Vimalanathan, J. R. Gascooke, I. Suarez-Martinez, N. A. Marks, H. Ku-
mari, C. J. Garvey, J. L. Atwood, W. D. Lawrance, C. L. Raston, Sci. Rep.
2016, 6, 22865.
[22] T. Z. Yuan, C. F. Ormonde, S. T. Kudlacek, S. Kunche, J. N. Smith, W. A.
Brown, K. M. Pugliese, T. J. Olsen, M. Iftikhar, C. L. Raston, G. A. Weiss,
ChemBioChem 2015, 16, 393.
[23] L. Yasmin, T. Coyle, K. A. Stubbs, C. L. Raston, Chem. Commun. 2013, 49,
10932.
[24] L. Yasmin, K. A. Stubbs, C. L. Raston, Tetrahedron Lett. 2014, 55, 2246.
[25] J. Britton, C. L. Raston, RSC Adv. 2014, 4, 49850.
[26] M. N. Gandy, C. L. Raston, K. A. Stubbs, Org. Biomol. Chem. 2014, 12,
4594.
N-Cyclohexylquinoxalin-2-amine (24): The reaction was con-
ducted with cyclohexylamine to give 24 (301 mg, 83 %) as a white
solid; Rf = 0.28 (EtOAc/hexane, 1:4). M.p. 122–123 °C. IR (ATR): ν =
˜
1
3286, 1583 cm–1. H NMR (600 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.84–
7.82 [m (app dd), 1 H], 7.67–7.64 [m (app dd), 1 H], 7.55–7.52
[m (app dt), 1 H], 7.35–7.32 [m (app dt), 1 H], 4.90–4.83 (m, 1 H),
4.04–3.97 (m, 1 H), 2.16–2.07 (m, 2 H), 1.81–1.73 (m, 2 H), 1.70–1.63
(m, 1 H), 1.51–1.41 (m, 2 H), 1.30–1.18 (m, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 151.4, 142.2, 138.6, 137.1, 130.0, 128.9, 126.3,
124.1, 49.5, 33.2, 25.8, 24.9 ppm. HRMS (ESI): calcd. for C14H18N3 [M
+ H]+ 228.1501; found 228.1505.
N-Benzylquinoxalin-2-amine (25): The reaction was conducted
with benzylamine to give 25 (312 mg, 83 %) as a yellow solid; Rf =
0.16 (EtOAc/hexane, 1:4). M.p. 68–69 °C; ref.[41] m.p. 70–72 °C. IR
1
(ATR): ν = 3292, 1583 cm–1. H NMR (600 MHz, CDCl3): δ = 8.18 (s,
˜
1 H), 7.89–7.86 [m (app dd), 1 H], 7.74–7.71 [m (app dd), 1 H], 7.60–
7.56 [m (app dt), 1 H], 7.42–7.33 (m, 5 H), 7.32–7.28 (m, 1 H), 5.30–
5.24 (m, 1 H), 4.76–4.73 [m (app d), 2 H] ppm. 13C NMR (151 MHz,
CDCl3): δ = 151.7, 142.0, 138.6, 138.4, 137.5, 130.2, 128.9, 128.8,
128.1, 127.7, 126.5, 124.6, 45.4 ppm. HRMS (ESI): calcd. for C15H14N3
[M + H]+ 236.1188; found 236.1178.
[27] J. Britton, C. L. Raston, RSC Adv. 2015, 5, 2276.
[28] a) J. Britton, J. M. Chalker, C. L. Raston, Chem. Eur. J. 2015, 21, 10660; b)
J. Britton, J. W. Castle, G. A. Weiss, C. L. Raston, Chem. Eur. J. 2016, 22,
10773.
N-(4-Methoxybenzyl)quinoxalin-2-amine (26): The reaction was
conducted with 4-methoxybenzylamine to give 26 (360 mg, 85 %)
[29] M. N. Gandy, C. L. Raston, K. A. Stubbs, Chem. Commun. 2015, 51, 11041.
[30] J. F. Bunnett, R. E. Zahler, Chem. Rev. 1951, 49, 273.
[31] G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054.
[32] A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 131.
[33] M. Charaschanya, A. R. Bogdan, Y. Wang, S. W. Djuric, Tetrahedron Lett.
2016, 57, 1035.
[34] M. P. Alam, B. Jagodzinska, J. Campagna, P. Spilman, V. John, Tetrahedron
Lett. 2016, 57, 2059.
[35] A. F. Pozharskii, A. T. Soldatenkov, A. R. Katritzky, Heterocycles in Life and
Society, John Wiley and Sons, New York, 1997.
as a white solid; Rf = 0.28 (EtOAc/hexane, 3:7). M.p. 86–87 °C. IR
1
(ATR): ν = 3280, 1582 cm–1. H NMR (600 MHz, CDCl3): δ = 8.17 (s,
˜
1 H), 7.88–7.85 [m (app dd), 1 H], 7.73–7.71 [m (app dd), 1 H], 7.59–
7.56 [m (app dt), 1 H], 7.40–7.36 [m (app dt), 1 H], 7.34–7.31 [m
(app d), 2 H], 6.90–6.87 [m (app d), 2 H], 5.20–5.15 (m, 1 H), 4.68–
4.65 [m (app d), 2 H], 3.79 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 159.3, 151.7, 142.0, 138.5, 137.4, 130.6, 130.2, 129.5, 128.9, 126.5,
124.5, 114.3, 55.4, 45.0 ppm. HRMS (ESI): calcd. for C16H16N3O [M +
H]+ 266.1293; found 266.1304.
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[36] H. Gao, E. F. Yamasaki, K. K. Chan, L. L. Shen, R. M. Snapka, Cancer Res.
2000, 60, 5937.
[37] A. Nzila, J. Antimicrob. Chemother. 2006, 57, 1043.
[38] H. D. Chapman, Poult. Sci. 2009, 88, 813.
[39] K. Walsh, H. F. Sneddon, C. J. Moody, ChemSusChem 2013, 6, 1455.
[40] G. Toma, K. Fujita, R. Yamaguchi, Eur. J. Org. Chem. 2009, 4586.
[41] G. W. H. Cheeseman, J. Chem. Soc. 1957, 3236.
[42] A. Molnar, S. Boros, K. Simon, I. Hermecz, C. Gonczi, ARKIVOC 2010, 199.
[43] D. S. Ermolat'ev, E. V. Van der Eycken, J. Org. Chem. 2008, 73, 6691.
[44] H. P. L. Steenackers, D. S. Ermolat'ev, B. Savaliya, A. D. Weerdt, D. De Cos-
ter, A. Shah, E. V. Van der Eycken, D. E. De Vos, J. Vanderleyden, S. C. J.
De Keersmaecker, J. Med. Chem. 2011, 54, 472.
[45] W. A. Skinner, H. T. Crawford, H. Tong, D. Skidmore, H. I. Maibach, J.
Pharm. Sci. 1976, 65, 1404.
Received: October 7, 2016
Published Online: ■
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Reactions in Dynamic Thin Films
L. A. Ho, C. L. Raston,*
K. A. Stubbs* ........................................ 1–8
Transition-Metal-Free
Cross-Cou-
pling Reactions in Dynamic Thin
Films To Access Pyrimidine and
Quinoxaline Analogues
A vortex fluidic device (VFD) is effec- in high yields. The formation of the
tive in modulating the synthesis of C–N bond occurs in the absence of a
pyrimidine- and quinoxaline-based transition-metal catalyst.
compounds at room temperature and
DOI: 10.1002/ejoc.201600830
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