Direct uncatalyzed amination of 2-chloropyridine using a flow reactor

Article abstract of DOI:10.1055/s-2007-985574

Chloropyridines are efficiently converted into 2-amino-pyridines by uncatalyzed nucleophilic aromatic substitution (S_NAr) in NMP using a continuous-flow reactor. A variety of secondary amines undergo S_NAr with both electron-rich and electron-deficient 2-chloropyridines to afford 2-aminopyridines in good to excellent yield. The flow reactor, which provides a short reaction time and high temperatures up to 300°C, can overcome the activation barrier for reactions with unactivated substrates. Short reaction times result in fewer side products and can afford milligram to multigram quantities of product using continuous flow. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985574

LETTER
2257
Direct Uncatalyzed Amination of 2-Chloropyridine Using a Flow Reactor
D
irec
t
U
ncatalyze
r
d Amin
u
ation of 2-Ch
c
loropyridin
e
e
C. Hamper,* Eden Tesfu
Pfizer Inc., Global Research & Development, Medicinal Chemistry, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA
E-mail: bruce.c.hamper@pfizer.com
Received 3 April 2007
Abstract: Chloropyridines are efficiently converted into 2-amino-
pyridines by uncatalyzed nucleophilic aromatic substitution (SNAr)
N
in NMP using a continuous-flow reactor. A variety of secondary
amines undergo SNAr with both electron-rich and electron-deficient
2-chloropyridines to afford 2-aminopyridines in good to excellent
yield. The flow reactor, which provides a short reaction time and
high temperatures up to 300 °C, can overcome the activation barrier
for reactions with unactivated substrates. Short reaction times result
in fewer side products and can afford milligram to multigram
quantities of product using continuous flow.
H
N
N
60 °C, 8 kbar, 4 d (72%)5
N
Cl
or
2
1a
DMSO, 100 °C, sealed tube,
2 d (88%)6
or
MW, neat (40%)7
Scheme 1 Preparation of 2-piperidinylpyridine 2 by SNAr batch
reactions in pressurized vessels.
Key words: amination, nucleophilic aromatic substitution, flow
synthesis, microflow reactor
batch reactions, flow reactors can enhance the scope of
chemical reactions, provide higher yields, and afford
products of higher purity.12 Batch-pressurized vessels,
which have been used for SNAr reactions with 2-chloropy-
ridine, have drawbacks due to the necessity of specialized
equipment and the requirement in many facilities for sep-
arate labs for handling associated safety issues. These
vessels must be depressurized to sample the reactions and
require a significant amount of setup time for individual
reactions. By comparison, a mesofluidic flow reactor
allows sampling of the reaction a few minutes after intro-
duction of the reactants and can be used sequentially for
reactions with no additional setup time.
Aminopyridines are valuable structural motifs found in a
variety of pharmaceutical agents,1 ligands for transition-
metal complexes,2 fluorescent dyes,3 and agricultural
products.4 Electron-deficient 2-halopyridines readily un-
dergo nucleophilic aromatic substitution (SNAr) reactions
to provide 2-aminopyridines, however, the scope of un-
catalyzed reaction is narrow and requires harsh conditions
for unactivated substrates such as unsubstituted 2-chloro-
pyridine. Hashimoto et al.5 reported a 72% yield of 2-pip-
eridinylpyridine (2) from 2-chloropyridine and piperidine
after 4 days at 60 °C and 8 kbar pressure (Scheme 1).
Grube et al.6 reported an 88% yield of 2 from a DMSO
solution heated in a sealed tube at 100 °C for 2 days. Un-
catalyzed reactions have been carried out with microwave
conditions to provide good yields of displacement
products from 2-bromopyridines, but yields from 2-chlo-
ropyridine were significantly lower affording only 40% of
2.7 Buchwald–Hartwig couplings8 and nickel-catalyzed
reactions9 have been successfully used to prepare 2-ami-
nopyridines and while very effective, these methods result
in the generation of waste associated with the transition
metals and their ligands.10 Previous reports of SNAr in
flow reactors have been limited to intramolecular
reactions or microwave-enhanced reactions of activated
substrates.11 To our knowledge this is the first report of
flow reaction conditions for SNAr reactions of unactivated
substrates such as 2-chloropyridine.
In this report, we disclose the preliminary results of an in-
vestigation using a custom-built flow reactor for noncata-
lytic SNAr reactions with unreactive substrates 1a–d with
secondary amines. The flow reactor was designed to pro-
vide high temperatures up to 300 °C in order to overcome
the activation barrier for reactions with typically unreac-
tive or unactivated substrates and provide reaction times
that were suitable for the residence time of the flow de-
vice. A careful balance of reactor temperature and flow
rate must be achieved to get good yields of high purity
products.13 Fortunately, reaction conditions can be quick-
ly assessed in flow devices (compared to batch reactors).
Flow reactors have the advantage of allowing fast turn-
around times for testing of individual reaction parameters
and, with the advent of automated analysis, provide facile
optimization of reaction conditions.
We envisioned taking advantage of the high temperatures
and fast residence times of a flow-reactor system for the
direct uncatalyzed preparation of 2-aminopyridines from
secondary amines and 2-chloropyridines. Compared to
Many of the current flow reactors under evaluation use
specialized glass chips or columns and custom-built
devices for temperature control.14 It occurred to us that a
much simpler device could be assembled from an alu-
minum holder and stainless steel tubing using a standard
laboratory hot plate for temperature control (Figure 1).
SYNLETT 2007, No. 14, pp 2257–2261
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3
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Advanced online publication: 13.08.2007
DOI: 10.1055/s-2007-985574; Art ID: S01807ST
© Georg Thieme Verlag Stuttgart · New York

2258
B. C. Hamper, E. Tesfu
LETTER
atures with the standard hotplate. Except for the initial
lower-temperature runs, all of the reactions in this study
were carried out with the more efficient spiral-coil heater.
Delivery of reagents to the heated tube reactors was
provided by an HPLC pump and a pressure regulator was
attached to the outlet of the reactor to allow operation at
temperatures above the boiling point of the solvents and
reagents (Figure 2).
Figure 1 A) Aluminum spool with 44 turns (10 m) of 1/16¢¢ stain-
less steel tubing. B) Flat aluminum reactor with 10 m of a spiral coil
of 1/16¢¢ stainless steel tubing.
Flow reactors prepared from stainless steel tubing are sim-
ple to construct with standard laboratory equipment and
have some significant advantages over glass or polymeric
materials due to common use in HPLC apparatus and in-
herent ability to contain higher pressures. With the appro-
priate control of pressure with HPLC pumps and pressure
regulators, HPLC grade stainless steel tubing allows one
to achieve pressures that are usually limited to specialized
systems such as steel autoclaves or Parr reactors. Our
flow-reactor device consists of a stainless-steel tube
(1/16¢¢ o.d. × 0.020¢¢ i.d. × 10 m) wrapped around an alu-
minum spool that can be heated with a thermocouple-con-
trolled hotplate from room temperature to 300 °C. The
aluminum spool (Figure 1, A) was custom-built by our
machine shop to fit snugly on top of a commercially avail-
able hotplate. A fitting for an external thermocouple was
built into the body of the spool to allow direct control of
temperature using the features of the commercial digital
hotplate. The spool has a diameter and height of 7.6 cm
(3 in), which, assuming 16 turns per inch height of the
spool, allows for 48 complete turns of the 1/16¢¢ stainless-
steel tubing. This corresponds to a holding capacity of
10 m length of tubing and a calculated total volume for the
reactor of 2.03 mL. In practice we obtained slightly less
than 48 turns due to inconsistencies in tubing diameter
and the difficulty of keeping each turn perfectly straight.
This design allows for simple maintenance of the reactor,
since either end can be recut and cleaned to remove poten-
tial plugs or restrictions. It also allows for simple retooling
of reactor by replacement of the tubing with tubing of
different internal diameters, length, and total volume.
Figure 2 Schematic of flow-reactor system using HPLC pump,
pressure detector, manual injector, aluminum reactor with coil of
stainless steel tubing (1/16¢¢ od × 0.020¢¢ id × 10 m), backpressure
regulator (1000 psi), and fraction collector.
As an initial test reaction we investigated SNAr of 2-chlo-
ropyridine (1a) with piperidine to afford 2 (Table 1). A
0.5 M solution of equimolar amounts of the substrates in
DMF was transferred to the injection loop and introduced
to the flow reactor using DMF as a push solvent. At 150
°C no product was observed, however, a small amount of
2-piperidylpyridine (2) was observed at 200 °C (entry 1).
An increase in temperature to 240 °C resulted in an im-
provement in conversion to 47% (entry 2). Further im-
provement was obtained by using two equivalents of
piperidine (entry 3, 76%) and by decreasing the flow rate
to 0.1 mL/min complete conversion into 2 was observed
(entry 4). The yields obtained with DMF as a solvent were
lower than the conversion of starting material suggesting
the presence of significant side products. The GC-MS
analysis and comparison with authentic material showed
2-dimethylaminopyridine as the major side product from
the DMF trials, which would be expected on addition of
dimethylamine to 2-chloropyridine. To improve the over-
all yield, we investigated alternative solvents, which
would reduce or eliminate the dimethylamino product.
Dimethylacetamide (DMA) showed a slight improve-
ment, however, the dimethylamino-derived side product
was still observed (entry 5). N-Methylpyrrolidinone
(NMP) gave excellent conversion and yield of the desired
product and as expected completely eliminated any side
products from decomposition of the solvent (entry 6).
Our first reactor, which consisted of 44 turns of tubing and
had a measured volume of 2.0 mL, was successfully used
in the initial studies but was found to have a maximum
high temperature of 240 °C. To improve the efficiency of
the heat transfer to the stainless-steel tubing, we prepared
a second reactor that consisted of a single-layer spiral coil
of tubing (Figure 1, B). A similar aluminum machined
block was prepared which allowed for a single-layer spiral
coil with an initial coil diameter of 1.0¢¢ and a final dia-
meter of 6.0¢¢. The coil of this configuration required the
same 10 m length of tubing and provided a comparable to-
tal volume of about 2.0 mL. Since this block has both a
bottom and top plate, much better heat transfer to the re-
actor tubing was observed. The spiral-coil reactor was
routinely heated to 260 °C and can achieve higher temper-
Using the optimized conditions obtained from the reaction
of 2-chloropyridine with piperidine (Table 1, entry 6), a
variety of secondary amines was investigated (Scheme 2).
All of these compounds were prepared from 500 mL solu-
tions using a single injection with the system in analytical
mode. With the exception of N-benzylpiperazine product
8 (47% yield), all of the reactions of cyclic secondary
amines with 2-chloropyridine gave good to excellent
Synlett 2007, No. 14, 2257–2261 © Thieme Stuttgart · New York

LETTER
Direct Uncatalyzed Amination of 2-Chloropyridine
2259
Table 1 Optimization of SNAr Flow Reaction of 1a with Piperidine
N
H
N
N
N
Cl
flow rate, solvent, temp.
1a
2
Entrya
Piperidine (equiv)
Flow rateb (mL/min) Solvent
Temp (°C)
200
Yield of 2c
9
1
2
3
4
5
6
1
0.5
0.5
0.5
0.1
0.1
0.1
DMF
DMF
DMF
DMF
DMA
NMP
1
240
47
2
240
76 (52)
100 (63)
100 (76)
100 (100)
2
240
2.2
2.2
260
260
a All reactions were carried out on 0.1 mmol scale as 0.5 M solution of 2-chloropyridine in solvent. Entries 1–4 used the reactor spool A; entries
5 and 6 used spiral-coil reactor B.
b Flow rate of 0.5 mL/min = residence time of 4.0 min; 0.1 mL/min = 20 min.
c Conversions determined by GC-MS; yields in parentheses determined by comparison with internal standard.
yields of the desired products (57–88% yield of isolated mixture of the des-bromo compound and desired product
product). Functional groups such as alcohols, ethers, and 14 was observed. By lowering the reactor temperature to
tertiary amines were all tolerated under the standard 200 °C, we were able to eliminate formation of the des-
reaction conditions. The reaction conditions were directly bromo side product and obtain selective displacement of
applicable for SNAr of 2-chloroquinoline and 2-chloro- the ortho-chloro group to give a 68% yield of piperazi-
pyrazine affording 56–82% yields of isolated products 11, nylpyridine 14.
12, and 13. In the case of 2-chloro-3-bromopyridine, a
R1
R1
R2
R3
HN
+
R2
N
N
thermocouple-controlled
flow reactor (200–260 °C)
N
Cl
R3
1a–d
3–14
N
N
N
N
N
N
N
N
O
N
3 (63%)
4 (78%)
5 (50%)
6 (56%)
N
N
N
N
N
N
N
N
O
OH
N
N
N
8 (47%)
10 (71%)
9 (57%)
7 (69%)
Br
N
N
N
N
N
N
N
N
N
N
N
O
13 (56%)
14 (76%)
11 (82%)
12 (80%)
Scheme 2 Aminoarenes prepared with isolated yields.
Synlett 2007, No. 14, 2257–2261 © Thieme Stuttgart · New York

2260
B. C. Hamper, E. Tesfu
LETTER
NMP, 260 °C
N
+
N
N
N
0.1mL/min,
N
Cl
spiral-coil flow reactor
1.94 g isolated (3.5 h)
(88%)
N
H
1a
15
16
Scheme 3 Preparative-scale flow reaction for synthesis of aminopyridine 16.
product was obtained by collection of the reactor eluant between 21
and 24 min after injection. Formation of the product was validated
and quantified using GC with internal standard and/or NMR with
internal standard. The desired product was isolated by preparative
reverse-phase chromatography of the collected fractions (41.4 mm
i.d. × 50 mm C18; MeCN–H2O). Alternatively, the collected
fractions were treated with 5 mL H2O and extracted three times with
5 mL of CH2Cl2. The combined organic extracts were washed with
5 mL of sat. brine, dried over MgSO4, and concentrated in vacuo.
The final product was purified by normal-phase chromatography.
A demonstration of the preparative ability of the system
was carried out using 1a and pyrrolidine 15 for the prepa-
ration of N,N-diethyl-1-(pyridine-2-yl)pyrrolidin-3-
amine (16, Scheme 3). A 20 mL mixture of 0.5 M 1a and
1.1 M 15 in NMP was introduced to the flow reactor by
direct introduction into the pump (preparative mode) to
provide continuous, uninterrupted reaction. Using a flow
rate of 0.1 mL/min, individual reactants were subjected to
a residence time of 25 minutes in the heated portion of the
system and a total run time of 3.5 hours. The solution of
product in NMP was purified by reverse-phase LC to
afford 1.94 g of 16 in 88% yield.
1-(2-Methoxyethyl)-4-(pyridine-2-yl) piperazine (9)
The final product was purified by normal-phase chromatography
using a gradient solvent of 20% EtOAc (0.1% Et3N) in heptane to
100% EtOAc (0.1% Et3N) to afford 0.31 g (57%) of an oil. 1H NMR
(400 MHz, CHCl3-d1): d = 2.51–2.58 (m, 6 H), 3.29 (s, 3 H), 3.44–
3.52 (m, 6 H), 6.52 (dd, 1 H), 6.55 (d, J = 8.59 Hz, 1 H), 7.38 (ddd,
J = 8.66, 7.05, 2.01 Hz, 1 H), 8.11 (dd, J = 4.97, 1.21 Hz, 1 H) ppm.
13C NMR (100 MHz, CHCl3-d1): d = 45.20, 53.57, 58.21, 59.07,
70.27, 107.15, 113.35, 137.55, 148.09, 159.70 ppm. GC-MS: tR =
12.143 min. LRMS (EI): m/z calcd for C12H19N3O: 221.15; found:
221 [M+]. HRMS (70eV): m/z calcd [M+ + 1]: 222.1601; found:
222.1559.
A facile SNAr reaction of 2-chloroarenes and secondary
amines has been successfully demonstrated using a stain-
less-steel-tube flow reactor at elevated temperatures in
NMP. This approach can be utilized to prepare synthetic
targets from unactivated chloropyridines and related chlo-
roarenes that are free from metal contaminants and other
impurities. The synthetic protocol is amenable for prepa-
ration of libraries of compounds and for the scale-up of
single compounds. Flow apparatus have an advantage for
scanning different reaction conditions allowing optimiza-
tion of temperature, stoichiometry, residence time, and
solvent in a very efficient manner. Direct analysis of the
reaction products by real-time flow allows direct feedback
to the operator and shortens the cycle time between anal-
ysis of reaction conditions and setup of the next experi-
ment. Furthermore, once the optimum reaction conditions
are established the reaction can be scaled up to provide
virtually any quantity by running the flow reactor for
longer periods of time. We have demonstrated the ability
of the heated flow reactor to prepare 0.5 g per hour of 2-
aminopyridine 6. Studies to expand the scope of the SNAr
reactions are currently in progress.
Acknowledgment
We gratefully acknowledge Craig Markovich for preparation of the
aluminum heating blocks and consultation for design aspects of the
apparatus. We also acknowledge Shentiang Yang for assistance in
1
obtaining the H NMR data and James Doom for assistance with
analytical instrumentation.
References and Notes
(1) For examples of 2-aminopyridine structural motifs in
pharmaceuticals, see: (a) Landriscina, M.; Prudovsky, I.;
Carreira, C. M.; Soldi, R.; Tarantini, F.; Maciag, T. J. Biol.
Chem. 2000, 275, 32753. (b) Rabasseda, X.; Hopkins, S. J.
Drugs Today 1994, 30, 557. (c) Heykants, J.; Pardoel, L.;
Janssen, P. A. Arzneim. Forsch. 1971, 21, 982. (d) Huttrer,
C. P.; Djerassi, C.; Beears, W. L.; Mayer, R. L.; Scholz, C.
R. J. Am. Chem. Soc. 1946, 68, 1999.
(2) (a) Deeken, S.; Proch, S.; Casini, E.; Braun, H. F.; Mechtler,
C.; Marschner, C.; Motz, G.; Kempe, R. Inorg. Chem. 2006,
45, 1871. (b) Kempe, R.; Brenner, S.; Perdita, A.
Organometallics 1996, 15, 1071.
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Trans. 2 1996, 613.
(4) Henrie, R. N. II WO 8702665, 1987; Chem. Abstr. 1988,
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General Procedure for Nucleophilic Aromatic Substitution of
2-Chloroarenes
The flow system was equilibrated to a constant flow rate of 0.1 mL/
min of NMP through the flow reactor [spiral-coil reactor B, stain-
less steel tubing 10 m × 1/16¢¢ o.d. (0.020¢¢ i.d.)] and preheated to
260 °C with a steady backpressure of 1000 psi. Constant backpres-
sure was provided by cartridge-type pressure regulator (Upchurch
Scientific Inc, www.upchurch.com, Cat.# P-796; U-469). A 0.5 M
NMP solution of the 2-chloroarene 1a–d with 2.2 equiv of amine
was prepared from 2.5 mmol of 1a–d, 5.5 mmol of amine and 5 mL
of NMP. The Rheodyne injector of the flow system was fitted with
a 5 mL injection loop and the loop filled with the NMP solution of
reagents. The reaction mixture was manually injected into the flow
reactor and, using the NMP system solvent to maintain a constant
flow rate of 0.1 mL/min, resulted in a residence time of 20 min. The
(5) Hashimoto, M.; Izuchi, N.; Sakata, K. Heterocycles 1988,
27, 319.
(6) Grube, H.; Suhr, H. Chem. Ber. 1969, 102, 1570.
(7) Narayan, S.; Seelhammer, T.; Gawley, R. E. Tetrahedron
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Synlett 2007, No. 14, 2257–2261 © Thieme Stuttgart · New York

LETTER
Direct Uncatalyzed Amination of 2-Chloropyridine
2261
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67, 3029.
(10) For an example of a Suzuki-type coupling in the absence of
transition-metal catalyst, see: Leadbeater, N. E.; Marco, M.
Angew. Chem. Int. Ed. 2003, 42, 1407.
(12) See leading examples and references therein: (a) Tanaka,
K.; Motomatsu, S.; Koyama, K.; Tanaka, S.; Fukase, K. Org.
Lett. 2007, 9, 299. (b) Wiles, C.; Watts, P.; Haswell, S. J.
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(e) Kawaguchi, T.; Miyata, H.; Ataka, K.; Mai, K.; Yoshida,
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(11) (a) Comer and Organ, J. Am. Chem. Soc. 2005, 127, 8160.
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(14) In addition, the reactions we wished to investigate required
pressures and temperatures beyond the range of
commercially available chip-based devices.
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