Continuous flow glassware reactors for the laboratory. Synthesis of 2-alkoxy-4-aminotrifluoropyridine derivatives from pentafluoropyridine

Article abstract of DOI:10.1016/j.jfluchem.2007.07.010

Simple, general use continuous flow glassware reactors that are constructed by standard glass blowing techniques have been designed and used for various nucleophilic aromatic substitution reactions. The glassware flow reactors, consisting of a reaction channel that is 0.5 mm in diameter and may possess a range of inlet and outlet ports, provide the opportunity for research scientists to use inexpensive, conveniently operated continuous flow methodology in the laboratory environment. A short series of 2-alkoxy-4-aminotrifluoropyridine derivatives was prepared from pentafluoropyridine in a single continuous flow process by sequential nucleophilic aromatic substitution.

Full text of DOI:10.1016/j.jfluchem.2007.07.010

Journal of Fluorine Chemistry 128 (2007) 1439–1443
www.elsevier.com/locate/fluor
Continuous flow glassware reactors for the laboratory
Synthesis of 2-alkoxy-4-aminotrifluoropyridine derivatives
from pentafluoropyridine
* **
Richard D. Chambers , Graham Sandford , Jelena Trmcic
Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
Received 20 June 2007; received in revised form 10 July 2007; accepted 12 July 2007
Available online 1 August 2007
Dedicated to our good friend Professor Neil Bartlett on the occasion of his 75th birthday.
Abstract
Simple, general use continuous flow glassware reactors that are constructed by standard glass blowing techniques have been designed and used
for various nucleophilic aromatic substitution reactions. The glassware flow reactors, consisting of a reaction channel that is 0.5 mm in diameter
and may possess a range of inlet and outlet ports, provide the opportunity for research scientists to use inexpensive, conveniently operated
continuous flow methodology in the laboratory environment. A short series of 2-alkoxy-4-aminotrifluoropyridine derivatives was prepared from
pentafluoropyridine in a single continuous flow process by sequential nucleophilic aromatic substitution.
#
2007 Elsevier B.V. All rights reserved.
Keywords: Continuous flow reactor; Microreactor; Heterocycles; Perfluoroheteroaromatic
1
. Introduction
different operating requirements of the batch-wise and con-
tinuous flow reaction procedures.
Continuous flow processes are the methods of choice for the
The recent developments in microreactor technology [1–8]
and the use of such devices as continuous flow reactor systems
may help to persuade research chemists to use continuous flow
procedures as a laboratory technique for synthesis. However,
sometimes very complex fabrication procedures and associated
difficult, expensive engineering that is required for the
production of many microreactor devices, as well as the lack
of general availability of such apparatus to laboratories that do
not have access to the necessary engineering skills, has made
general adoption of these potentially very useful reaction
systems relatively slow.
synthesis of many industrial products on both the pilot-plant and
manufacturing scales for many reasons, including increased
control, lack of downtime, quality control and improved safety.
In stark contrast, many research laboratories do not possess
equipmentthat may be used forperforming exploratory reactions
by a continuous flow technique and chemists have continued to
use ‘batch’ methodology in standard glassware reaction vessels
for many years with, of course, great success. Consequently,
subsequent development of novel reaction methodology and
synthetic strategies that are established in the laboratory are
sometimes difficult to scale-up. In many cases, synthetic
sequences must be adapted, and sometimes completely changed,
when taking a process from laboratory through to pilot-plant and
manufacturing scale to accommodate the limitations and
Inan attempt to alleviate theproblemof general availabilityof
continuousflow reactorstoresearch scientists, wedescribe here a
design for continuous flow reaction apparatus that may be
constructed from glass by standard scientific glass blowing
techniques. The design is simple and easily constructed
glassware and in this paper we demonstrate the use of the
apparatus for various nucleophilic aromatic substitution pro-
cesses, with the ultimate aim of changing chemists’ attitudes
towards using continuous flow processes in the laboratory.
*
Corresponding author. Tel.: +44 191 334 2020; fax: +44 191 384 4737.
*
* Corresponding author. Tel.: +44 191 334 2039; fax: +44 191 384 4737.
E-mail addresses: r.d.chambers@durham.ac.uk (R.D. Chambers),
graham.sandford@durham.ac.uk (G. Sandford).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.07.010

1440
R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 1439–1443
Table 1
2
. Results and discussion
Synthesis of 4-dialkylamino tetrafluoropyridine derivatives using a continuous
flow glassware reactor
We have designed and constructed simple continuous flow
reactors using borosilicate glass and common scientific
glassblowing techniques and an example is shown in Fig. 1.
Essentially, a T-piece of glass tubing, with 0.5 mm internal
diameter, is first constructed and forms the reaction micro-
channel of the device. The T-piece is then enclosed in a larger
outer glass tube, rather like a simple reflux condenser fitted with
a very small bore inner tube, and ground glass joints attached to
the ends of each piece of tubing. Fluid inlet and outlet ports to
the outer glass tube that allows the circulation of cooling or
heating fluid around the microchannel tubing completes the
design. The reactor channel is approximately 130 mm long in
this case, but, of course, this may be varied according to a
particular application.
R R NH
1
2
Product
Yield (%)
7
2
Reagents are introduced simultaneously into the reactor
channel by standard syringe pumps that are attached to the glass
TM
joint by appropriate Swagelok fittings and product mixtures
59
are collected from the outlet. The whole apparatus may be
constructed by a scientific glassblower in 10–15 min and no
special techniques or fittings are required. Of course, this
simple design may be adapted easily to provide multiple inlet
ports as appropriate for specific reactions.
6
8
As part of a wider project in the development of the
chemistry of perfluorinated heterocyclic systems [9] for
applications in the synthesis of scaffolds for drug discovery
[
10,11], multi-functional heterocyclic derivatives [12],
5
4
macrocycles, heteraryl glycosyl donors and polyfunctional
ring-fused systems [13], we have used a continuous flow
reactor, such as that illustrated in Fig. 1, as a reaction vessel
for a short series of simple chemical transformations
involving reactions of pentafluoropyridine 1 and a series of
amines 2 to give the corresponding 4-aminopyridine
derivatives 3 (Table 1). In all cases, two equivalents of
amine are used so that one equivalent is available to neutralise
the HF byproduct, maximising yields.
Each reaction proceeds by nucleophilic aromatic substitu-
tion, as shown in Table 1, providing examples of what may be
achieved using this simple technology. In each case, reagents
were added simultaneously by syringe pump drive into the two
inlet ports and, after passage down the glass channel, collected
from the outlet into a vessel that contained water or aqueous
base solution, thus quenching the reaction immediately after
exiting from the flow reactor. Heating fluid was circulated at
50 8C through the outer glass jacket by a cryostat.
One of the key benefits of using continuous flow
methodology is the very efficient way in which reactions
may be optimised [3] by simple adjustment of flow rates and
operating temperature and scale is simply time dependent.
Reaction of pentafluoropyridine with diethylamine is only
required to be carried out until just 0.5 ml of product mixture
1
9
has been collected and analysis of the small sample by
F
NMR provides a very rapid indication of conversion and yield.
Adjustments of flow rate and the temperature of the circulating
liquid around the microreactor channel and subsequent analysis
allows the simple optimisation of the reaction within a few
Fig. 1. Continuous flow glassware reactor.

R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 1439–1443
1441
Table 2
Reaction optimisation
T (8C)
Flow rate
pentafluoropyridine
Flow rate
Conv.
(%)
diethylamine
ꢀ1
ꢀ1
(ml h
)
(ml h
)
2
2
3
4
4
5
4
4
5
2
7
3
4.5
4.5
59
86
4.5
9 (4 equiv.)
0.5
0.5
67
0.25
0.25
0.25
0.25
69
0.25
78
0.25
100
hours. An example of such a process is shown in Table 2, in
which reaction of pentafluoropyridine with diethylamine is
1
9
optimised to 100% conversion as determined by F NMR of
the crude product mixture. We find that lowering the flow rate
of each component, thus increasing the residence time of the
reagents in the microchannels, coupled with heating the
reaction to 50 8C gives very clean reaction to a single product in
1
00% conversion. As the boiling point of acetonitrile is 80 8C,
reaction temperatures above 50 8C were not assessed.
Above, we established that, using a continuous flow
glassware reactor (130 mm in length), conversion of penta-
fluoropyridine into the corresponding 4-monosubsituted pro-
duct is quantitative. The 4-substituted product is, of course,
susceptible towards further nucleophilic attack and we were
interested in exploring the possibility of performing two
nucleophilic substitution reactions in series using pentafluor-
opyridine as the starting material without the need for work-up
after the first step. Consequently, we constructed a continuous
flow reactor that possesses three inlet ports, with the third inlet
located approximately 130 mm along the reactor channels as
shown in Fig. 2.
Solutions of one equivalent of pentafluoropyridine 1 and two
equivalents of an amine 2 in dry acetonitrile were simulta-
neously injected into the reactor via inlets A and B,
Fig. 2. Continuous flow glassware reactor for sequential chemical transforma-
tions.
ꢀ
1
respectively, at a flow rate of 1 ml h . Furthermore, excess
sodium alkoxide 4 in the corresponding alcohol was introduced
into the reactor via inlet C, half way along the reactor, using the
3. Experimental
ꢀ1
same flow rate (1 ml h ). Products arising from two sequential
nucleophilic substitution reactions were collected from the
single flow reactor, isolated and purified. A range of
disubstituted trifluoropyridine derivatives 5 were prepared
from pentafluoroyridine and these are collated in Table 3.
In summary, simple glassware continuous flow reactors are
now available that may be constructed very inexpensively and
used for the study of chemical transformations using flow
systems by all research chemists. We have demonstrated the use
of the glass reactors in processes involving nucleophilic
aromatic substitution reactions of pentafluoropyridine, provid-
ing an indication of the possibilities offered by this simple
technology.
3.1. General
All starting materials were obtained commercially (Aldrich,
Lancaster or Fluorochem) All solvents were dried using
literature procedures. NMR spectra were recorded in deuterio-
chloroform, unless otherwise stated, on a Varian VXR 400S
1
NMR spectrometer operating at 400 MHz ( H NMR), 376 MHz
1
9
13
( F NMR) and 100 MHz ( C NMR) with tetramethylsilane
and trichlorofluoromethane as internal standards. Mass spectra
were recorded on a Fisons VG-Trio 1000 Spectrometer coupled
with a Hewlett-Packard 5890 series II gas chromatograph using
a 25 m HP1 (methyl-silicone) column. Elemental analyses were

1442
R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 1439–1443
Table 3
opyridin-4-amine 3a (0.60g, 72%) as a colourless oil; (found C,
48.4; H, 4.4; N, 12.4. C H F N requires C, 48.6; H, 4.5; N,
Synthesis of 2-alkoxy-4-dialkylamino pyridine derivatives using two-step
continuous flow glassware reactor
9 10 4 2
1
2.6%); d ꢀ95.4 (2F, m, F-2), ꢀ165.2 (m, F-3); d 0.94 (3H, t,
F
H
3
3
J
m, J 7.6, NHCH CH ), 3.54 (2H, t, J 6.6, NHCH ), 4.65
7.2, CH ), 1.39 (2H, sextet, J 6.5, CH CH ), 1.62 (2H,
HH 3 HH 2 3
3
3
HH
2
2
HH
2
(2H, s, NH); dC 13.7 (s, CH ), 19.8 (s, CH CH ), 32.9 (s,
NHCH CH ), 44.8 (s, NHCH ), 132.3 (dm, J 246.9, C-3);
3 2 3
1
2
2
2
CF
1
+
38.0 (m, C-4), 144.5 (dm, J 236.2, C-2); m/z (EI ) 222
1
CF
+
[M] , 20%), 179 (100).
(
R
1
R
2
NH
R
3
ONa
Product
Yield (%)
7
6
3.2.2. N,N-Diethyl-2,3,5,6-tetrafluoropyridin-4-amine 3b
N,N-Diethylamine (1.09 g, 15 mmol) in acetonitrile (5 ml,
ꢀ
1
.5 ml h ) and pentafluoropyridine (1.26 g, 7.5 mmol) in
4
ꢀ
1
acetonitrile (5 ml, 4.5 ml h ) gave N,N-diethyl-2,3,5,6-tetra-
fluoropyridin-4-amine 3b (1.79 g, 59%) as a yellow oil; (found
C, 48.6; H, 4.3; N, 12.3. C H F N requires C, 48.6; H, 4.5;
75
1
0 10 4 2
N, 12.6%); d ꢀ96.6 (2F, m, F-2), ꢀ157.3 (2F, m, F-3); d 1.17
F
H
3
3H, t, J 6.8, CH ), 3.44 (2H, q, J 7.1, CH ); d 13.9 (s,
3
(
CH ), 46.8 (s, CH ), 134.0 (dm, J 249.0, C-3), 139.6 (dm,
HH 3 HH 2 c
1
3
2
CF
2
1
+
7
8
8
6
JCF 12.4, C-4), 145.7 (dm, J 239.3, C-2); m/z (EI ) 222
CF
+
[M] , 80%), 207 (85), 179 (100).
(
3
.2.3. 2,3,5,6-Tetrafluoro-4-(piperidin-1-yl)-pyridine 3c
Piperidine (0.63 g, 7.5 mmol) in acetonitrile (5 ml,
ꢀ
1
0.5 ml h ) and pentafluoropyridine (0.63 g, 3.75 mmol) in
1
acetonitrile (5 ml, 0.5 ml h ) gave 2,3,5,6-tetrafluoro-4-
ꢀ
(piperidin-1-yl)-pyridine 3c (0.63 g, 68%) as a yellow oil;
(
found C, 51.2; H, 4.0; N, 11.6. C H F N requires C, 51.3; H,
0 10 4 2
1
4
1
2
1
.3; N, 12.0%); d ꢀ94.7 (1F, m, F-2), ꢀ155.5 (1F, m, F-3); d
F
H
0
.6–1.9 (6H, m, CH ), 3.5 (4H, m, N-CH ); d 24.1 (s, C-4 ),
2
2
C
0
1
6.5 (s, C-3 ), 51.6 (s, –NCH ), 134.2 (dm, J 253.6, C-3),
2
CF
1
40.9 (m, C-4), 145.4 (dm, J 240.0, C-2); m/z (EI ) 246
+
CF
+
obtained on an Exeter Analytical CE-440 elemental analyser.
Melting points and boiling points were recorded at atmospheric
pressure unless otherwise stated and are uncorrected. Column
chromatography was carried out on silica gel (Merck no.
([M] , 40%), 233 (100), 177 (75).
3.2.4. 2,3,5,6-Tetrafluoro-N-phenylpyridin-4-amine 3d
Aniline (0.75 g, 7.5 mmol) in acetonitile (5 ml, 0.5 ml h
ꢀ
1
)
and pentafluoropyridine (0.63 g, 3.75 mmol) in acetonitrile
109385, particle size 0.040–0.063 mm) and TLC analysis was
performed on silica gel TLC plates (Merck).
ꢀ1
(5 ml, 0.5 ml h ) gave 2,3,5,6-tetrafluoro-N-phenylpyridin-4-
amine 3d (0.49 g, 54%) as an off-white solid; (found C, 54.4; H,
2.4; N, 11.8. C H F N requires C, 54.6; H, 2.5; N, 11.6%); d
F
3
.2. One step reactor—general procedure
1
1
6
4
2
ꢀ
92.7 (1F, m, F-2), ꢀ155.9 (1F, m, F-3); d 6.32 (1H, m, N-H),
H
0
0
A solution of the amine 2 in acetonitrile and a solution of
pentafluoropyridine 1 in acetonitrile were passed simulta-
7.0–7.4 (5H, m, ArH); d 121.9 (s, C-2 ), 125.6 (s, C-4 ), 129.1
C
0 0
(s, C-3 ), 132.2 (dm, J 252.2, C-3), 138.1 (s, C-1 ), 140.2 (m,
CF
1
1
+
+
neously at RT through the reactor via inlets 1 and 2, respectively
(
C-4), 144.4 (dm, J 223.8, C-2); m/z (EI ) 242 ([M] , 73%),
CF
222 (90), 51 (100).
Fig. 1) at a prescribed flow rate controlled by a syringe pump.
The product mixture was collected upon emerging from the
reactor in a receiving vessel that contained water (50 ml). The
aqueous phase was extracted with dichloromethane
3.3. Sequential nucleophilic substitution reactions—
general procedure
(
3 ꢁ 20 ml). The organic extracts were dried (MgSO ) and
4
evaporated to give the crude product 3 which could be purified
by either column chromatography on silica gel using hexane/
dichloromethane as the eluant.
These reactions were performed using the three-inlet reactor
(Fig. 2). A solution of the amine 2 in acetonitrile, a solution of
pentafluoropyridine 1 in acetonitrile and a solution of the
alkoxide 4 in the corresponding alcohol were passed
simultaneously through the reactor via inlets A, B and C,
respectively (Fig. 2) at a prescribed flow rate controlled by a
syringe pump. Heating fluid was circulated by a cryostat at
50 8C through the apparatus. The product mixture was collected
3
.2.1. N-Butyl-2,3,5,6-tetrafluoropyridin-4-amine 3a
N-Butyl amine (0.52 g, 7.5 mmol) in acetonitrile (5 ml,
ꢀ1
0
acetonitrile (5 ml, 0.5 ml h ) gave N-butyl-2,3,5,6-tetrafluor-
.5 ml h ) and pentafluoropyridine (0.63 g, 3.75 mmol) in
1
ꢀ

R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 1439–1443
1443
3
in a receiving vessel that contained water (50 ml). The aqueous
phase was extracted with dichloromethane (3 ꢁ 20 ml). The
ꢀ155.4 (1F, m, F-3), 162.8 (1F, m, F-5); d 0.98 (3H, t, J
H
HH
3
7.4, CH CH ), 1.14 (6H, t, J 6.7, NCH CH ), 1.81 (2H,
2
3
HH
2
3
3
sextet, J
3
7.2, CH CH ), 3.35 (4H, q, J
organic extracts were dried (MgSO ) and evaporated to give the
4
6.9, NCH2),
HH
HH
2
3
3
4.18 (2H, t, J
crude product 5 which could be purified by either column
chromatography on silica gel using hexane/dichloromethane as
the eluant.
6.8, OCH ); d 10.5 (s, OCH CH CH ),
HH 2 C 2 2 3
13.8 (s, NCH CH ), 22.5 (s, OCH CH CH ), 46.7 (s, NCH ),
3
1
68.6 (s, OCH ), 133.3 (dd, J 245.7, J 28.5, C-3), 136.1
2
3
3
2
2
2
2
CF
CF
1
3
(
1
dd, J 248.0, J 4.6, C-5), 137.9 (m, C-4), 146.1 (dd,
CF CF
2
2
3
3
.3.1. N-Butyl-2,3,5-trifluoro-6-propoxypyridin-4-amine
a
JCF 232.9, J 13.3, C-2), 146.4 (dd, J 15.9, J 13.4, C-
CF CF CF
+
6); m/z (EI ) 262 ([M] , 75%), 247 (97), 205 (98), 176.7
+
5
ꢀ
1
n-Butylamine (0.58 g, 8 mmol, 0.5 ml h ) in acetonitrile
(100).
ꢀ
1
5 ml), pentafluoropyridine (0.59 g, 3.5 mmol, 0.5 ml h ) in
(
acetonitrile (5 ml) and sodium n-propoxide (4 mmol,
3
.3.4. 4-(2,3,5-Trifluoro-6-propoxypyridin-4-yl)
morpholine 5d
Morpholine (0.70 g, 8 mmol, 1 ml h ) in acetonitrile
ꢀ1
0
.5 ml h ) in propanol (10 ml) gave N-butyl-2,3,5-trifluoro-6-
propoxypyridin-4-amine 5a (0.70 g, 76%) as a yellow oil; (found
C, 54.7; H, 6.8; N, 10.9. C H N F O requires C, 54.9; H, 6.5;
ꢀ
1
ꢀ
1
1
2
17
2
3
(5 ml), pentafluoropyridine (0.59 g, 3.5 mmol, 1 ml h ) in
ꢀ
1
N, 10.7%); d ꢀ99.3 (1F, m, F-2), ꢀ166.0 (1F, m, F-3), ꢀ171.5
F
acetonitrile (5 ml) and sodium n-propoxide (4 mmol, 1 ml h )
3
3
(1F, m, F-5); d 0.87 (3H, t, J 7.7, CH ), 0.94 (3H, t, J 8.4,
H HH 3 HH
CH ), 1.32 (2H, m, NCH CH CH ), 1.51 (2H, m, NCH CH ),
in propanol (5 ml) gave 4-(2,3,5-trifluoro-6-propoxypyridin-4-
yl) morpholine 5d (0.83 g, 86%) as a colourless liquid: (found
C, 52.0; H, 5.4; N, 9.9. C H F N O requires C, 52.2; H, 5.4;
3
2
2
2
2
2
3
1
6
.73 (2H, m, OCH CH ), 3.52 (2H, m, NCH ), 4.13 (2H, t, J
2 2 2 HH
1
2 15 3 2 2
.5, OCH ), 4.32 (1H, br s, NH); d 10.4 (s, OCH CH CH ) 13.8
3
2
C
2
2
N, 10.1%); d ꢀ96.0 (1F, m, F-2), ꢀ154.6 (1F, m, F-3), ꢀ161.9
F
3
(1F, m, F-5); dH 0.98 (3H, t, J
(
OCH CH CH ), 33.1 (s, NCH CH CH CH ), 44.7 (s,
s, NCH CH CH CH ), 20.1 (s, NCH CH CH CH ), 22.4 (s,
2 2 2 3 2 2 2 3
6.2, CH ), 1.76 (2H, m,
HH 3
3
2
2
3
2
2
2
3
CH CH ), 3.37 (4H, t, J 4.8, CH N), 3.69 (4H, m, CH -O),
2 3 HH 2 2
1
NCH CH CH CH ), 68.7 (s, OCH CH CH ), 129.3 (dd, J
3
4.19 (2H, t, J
2
2
2
3
2
2
3
3
CF
7.0, CH O); d 10.6 (s, CH ), 22.4 (s,
HH 2 C 3
2
1
2
42.5, J 32.1, C-3), 132.2(dd, J 243.5, J 6.2, C-5), 136.3
CF CF CF
CH CH ), 50.8 (s, CH N), 67.4 (s, CH O), 68.7 (s, OCH ),
2 3 2 2 2
1
2
2
1
2
1
(
m, C-4), 145.2 (dd, J 228.3, J 13.9, C-2), 145.9 (dd, J
CF CF CF
132.2 (dd, J 248.5, J 30.9, C-3), 136.8 (dd, J 245.4,
CF CF CF
4
+
+
3
1
2
1
6.1, J 12.3, C-6); m/z (EI ) 262 ([M] , 44%), 219 (82), 177
CF
JCF 6.1, C-5), 138.3 (m, C-4), 145.4 (dd, J 235.3, J 15.3,
CF CF
2
C-2), 146.6 (dd, J 15.3, J 2.2, C-6); m/z (EI ) 276 ([M] ,
3
+
+
(
100).
CF
CF
19%), 234 (72), 176 (100).
3
.3.2. N-Butyl-2,3,5-trifluoro-6-isopropoxypyridin-4-amine
b
5
Acknowledgments
ꢀ
1
n-Butylamine (0.58 g, 8 mmol, 0.5 ml h ) in acetonitrile
ꢀ
1
5 ml), pentafluoropyridine (0.59 g, 3.5 mmol, 0.5 ml h ) in
(
acetonitrile (5 ml) and sodium iso-propoxide (4 mmol,
We thank the EPSRC Crystal Faraday Partnership for
funding and Mr. Peter Coyne for scientific glassblowing.
ꢀ
1
.5 ml h ) in iso-propanol (5 ml) gave N-butyl-2,3,5-tri-
0
fluoro-6-isopropoxypyridin-4-amine 5b (0.69 g, 75%) as a
References
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1
2 17 2 3
requires C, 54.9; H, 6.5; N, 10.7%); d ꢀ97.1 (1F, m, F-2),
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3
ꢀ
165.0 (1F, m, F-3), ꢀ171.4 (1F, m, F-5); d 0.94 (3H, t, J
H
HH
3
.3, CH CH ), 1.32 (6H, d, J 7.6, CHCH ), 1.35 (2H, m,
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2
2
2
2
2
2
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4.29 (1H, br s, NH), 5.13 (1H, sept, JHH 5.8, OCH); d 14.1 (s,
C
CH CH ), 20.1 (s, CH CH ), 22.1 (s, CHCH ), 33.1 (s,
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2
3
2
3
3
1
NCH CH ), 44.8 (s, NCH ), 69.8 (s, OCH), 128.3 (dd, J
CF
2
2
2
2
1
3
[5] R.D. Chambers, M.A. Fox, D. Holling, T. Nakano, T. Okazoe, G.
Sandford, Lab. Chip 5 (2005) 191–198.
2
44.5, J 31.4, C-3), 133.5 (dd, J 241.2, J 5.6, C-5),
CF CF CF
1
36.3 (m, C-4); 143.5 (dd, J 218.8, J 13.7, C-2), 147.8
2
1
CF
CF
[
6] R.D. Chambers, M.A. Fox, G. Sandford, Lab. Chip 5 (2005) 1132–1139.
2
3
+
+
(
(
dd, J 14.6, J 13.1, C-2); m/z (EI ) 262 ([M] , 40%), 220
CF CF
[7] R.D. Chambers, D. Holling, A.J. Rees, G. Sandford, J. Fluorine Chem. 119
(2003) 81–82.
43), 177 (100).
[
8] R.D. Chambers, D. Holling, R.C.H. Spink, G. Sandford, Lab. Chip 1
2001) 132–137.
9] R.D. Chambers, C.R. Sargent, Adv. Heterocycl. Chem. 28 (1981) 1–
1.
(
3
.3.3. N,N-Diethyl-2,3,5-trifluoro-6-propoxypyridin-4-
amine 5c
[
7
ꢀ
1
N,N-Diethylamine (0.58 g, 8 mmol, 0.5 ml h ) in acet-
[
[
[
10] G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong, J. Org. Chem.
70 (2005) 7208–7216.
onitrile (5 ml), pentafluoropyridine (0.59 g, 3.5 mmol,
0
ꢀ1
11] A. Baron, G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong, J.
Org. Chem. 70 (2005) 9377–9381.
.5 ml h ) in acetonitrile (5 ml) and sodium n-propoxide
ꢀ1
(
4 mmol, 0.5 ml h ) in propanol (10 ml) gave N,N-diethyl-
,3,5-trifluoro-6-propoxypyridin-4-amine 5c (0.71 g, 78%) as
an orange oil; (found C, 54.8; H, 6.6; N, 10.6. C H N F O
12] R.D. Chambers, M.A. Hassan, P.R. Hoskin, A. Kenwright, P. Richmond,
G. Sandford, J. Fluorine Chem. 111 (2001) 135–146.
2
1
2
17
2
3
[13] R.D. Chambers, P.R. Hoskin, G. Sandford, D.S. Yufit, J.A.K. Howard, J.
Chem. Soc., Perkin Trans. 1 (2001) 2788–2795.
requires C, 54.9; H, 6.5; N, 10.7%); d ꢀ97.2 (1F, m, F-2),
F