Microwave assisted solvent free amination of halo-(pyridine or pyrimidine) without transition metal catalyst

Article abstract of DOI:10.1016/j.tetlet.2003.11.030

A solvent free direct amination of halo-(pyridine or pyrimidine) has been developed in good to high yields under computer-controlled microwave irradiation without transition metal catalyst. This reaction is a solvent and metal free, useful method for coupling of halo-(pyridine or pyrimidine) with pyrrolidine and piperidine derivatives by nucleophilic aromatic substitution (S_NAr).

Full text of DOI:10.1016/j.tetlet.2003.11.030

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 757–759
Microwave assisted solvent free amination of halo-(pyridine
or pyrimidine) without transition metal catalyst
Sanjay Narayan, Troy Seelhammerꢀ and Robert E. Gawley*
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA
Received 22 October 2003; revised 7 November 2003; accepted 10 November 2003
Abstract—A solvent free direct amination of halo-(pyridine or pyrimidine) has been developed in good to high yields under
computer-controlled microwave irradiation without transition metal catalyst. This reaction is a solvent and metal free, useful
method for coupling of halo-(pyridine or pyrimidine) with pyrrolidine and piperidine derivatives by nucleophilic aromatic substi-
tution (SNAr).
Ó 2003 Elsevier Ltd. All rights reserved.
In the past few years, the utilization of microwave
irradiation in chemical transformations has attracted
considerable interest and is of significant importance in
the search for green synthesis and sustainable chemistry.
Microwave-mediated protocols have been widely
applied for the formation of carbon–hetero atom and
carbon–carbon bonds (aromatic substitution, cyclo-
addition, cyclization, and catalysis).1 Many of these
reactions have been demonstrated to result in higher
yield and selectivity under microwave irradiation
compared to conventional methods.2
free amination of halo-(pyridine or pyrimidine) using
microwave techniques has not been described.
Herein we report the results of a preliminary investiga-
tion into computer-controlled microwave9 assisted
amination of halo-(pyridine or pyrimidine) with piper-
idine and pyrrolidine derivatives. In contrast to most
other C–N bond forming protocols the valuable features
of our reported reaction includes (i) a shorter reaction
time and high yields; (ii) the elimination of a transition-
metal catalyst; and (iii) solvent free reaction approach
to green chemistry.
Aminopyridines are commonly used as ligands (inor-
ganic and organometallic chemistry),3 fluorescent dyes4
and the aminopyridine moiety is present in pharma-
ceuticals.5 Aminolysis of halo-pyridines usually requires
somewhat rigorous reaction conditions, for example,
temperatures higher than 150 °C, pressure 6–8 kbar6 and
often the presence of catalysts (such as acids, Zn, Cu,
Pd, or Ni complexes).7 Highly negative activation vol-
umes are reported for SNAr reactions with secondary
amines (ꢀ)70 cm3/mol) in certain cases.8 In general the
use of transition metal catalysts leads to generation of
waste (hazards associated with metals) and solvent dis-
posal. To the best of our knowledge, metal and solvent
As a starting point, we studied the microwave assisted
coupling of 2-bromopyridine (2a) with pyrrolidine (1a)
(Scheme 1). Table 1 shows the results of this optimiza-
tion studies, which were conducted using a computer-
controlled microwave equipped with an internal tem-
perature/pressure monitoring probe. Initially, we tried
K2CO3 (in water), or triethylamine (in toluene), but in
both cases TLC analysis indicated the presence of
unreacted 2-bromopyridine. Solvent free conditions
solvent, Base
N
+
Condition
Br
N
H
N
N
Keywords: SNAr; Microwave; Amination; Halopyridine; N-(Pyr-
idyl)piperidine; N-(Pyridyl)pyrrolidine.
1a
2a
* Corresponding author. Tel.: +1-479-575-6933; fax: +1-479-575-5178;
e-mail: bgawley@uark.edu
3a
ꢀ
Summer REU student, Concordia College, MN, USA.
Scheme 1. Optimization studies.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.030

758
S. Narayan et al. / Tetrahedron Letters 45 (2004) 757–759
Table 1. Optimization studies9
Entry
1a
(equiv)
2a
(equiv)
Base
Solvent
Condition
(temperature/time)
3a
(Yield, %)
1
2
3
1
1
1
1
K2CO3
Et3N
None
Water
Toluene
None
120 °C/20 min
120 °C/20 min
120 °C/20 min
40
40
92
1
2.25
using 2.15 equiv of pyrrolidine gave a better yield;
additionally, this reaction was found to be insensitive to
air or moisture, so one can use water as a co-solvent.
idine in the presence of NaO-t-Bu afforded a mixture of
3- and 4-substituted products indicating that the reac-
tion proceeds via benzyne like intermediates under these
conditions.2b;11
We further investigated the coupling reaction of differ-
ent halo-(pyridines or pyrimidines) with several pyrr-
olidines and piperidines. From the results shown in
Table 2,10 it can be seen that the yields for the piperidine
are less than the corresponding pyrrolidine. The reac-
tions of 2- and 4-halopyridines give very good yield but
as expected, 3-halopyridine is less reactive. The micro-
wave assisted reaction of 3-bromopyridine with pyrrol-
In the case of entry 12, we used water as solvent because
of the low solubility of 4-chloropyridinehydrochloride
(2eÆHCl) salt in piperidine. Best yields were obtained
by heating at 130 °C for 30 min in most of the cases
(Scheme 2). In the case of entries 16 and 17, we used
NaOH as a base in water to give desired product. In the
case of entry 16 we used the temperature 120 °C because
Table 2. Direct amination of halo-pyridine or -pyrimidine with amines9;10
Entry
Amine
Halo-pyridine or -pyrimidine
Product (%)a
1
Pyrrolidine (1a)
1a
2-Bromopyridine (2a)
2-Chloropyridine (2b)
3a (92)
3a (90)
3b (<5)
3b (<2)
3c (85)
3c (85)
3d (83)
3e (88)
3e (40)
3f (<1)
3f (<1)
3g (25), (85)b
3g (75)
3h (83)
3i (65)
2
3
1a
1a
3-Bromopyridine (2c)
3-Chloropyridine (2d)
4
5
1a
1a
4-ChloropyridineÆHCl (2eÆHCl)
2e (Free base)
6
7
1a
Piperidine (1b)
2-Chloropyrimidine (2f)
2a
8
9
1b
1b
2b
2c
10
11
12
13
14
15
16
17
1b
1b
2d
2eÆHCl
2e (free base)
1b
1b
1cc
1dÆHId
1eÆHIe
2f
2a
2a
2a
3j (60)
3k (55)
a Isolated yield.
b Water as a co-solvent.
c 2 equiv NaH in DMF.
d 2 equiv NaOH in water, 120 °C.
e 2 equiv NaOH in water, 150 °C.
°
130 C, 30 Min
(CH )n
(CH2)n
+
R'X
2
N
H
N
Microwave (50-200 watts)
R
R
R'
1
2
3
1a: R=H, H; n = 1
1b: R=H, H; n = 2
1c: R==O; n = 1
1d: R=H; SnBu3, n = 1
1e: R=H; SnBu3, n = 2
2a: 2-bromopyridine
2b: 2-chloropyridine
2c: 3-bromopyridine
2d: 3-chloropyridine
2e: 4-chloropyridine
2f: 2-chloropyrimidine
3a: R=H, H; n =1; R’ = 2-pyridyl
3b: R=H, H; n =1; R’ = 3-pyridyl
3c: R=H, H; n =1; R’ = 4-pyridyl
3d: R=H, H; n =1; R’ = 2-pyrimidyl
3e: R=H, H; n =2; R’ = 2-pyridyl
3f: R=H, H; n =2; R’ = 3-pyridyl
3g: R=H, H; n =2; R’ = 4-pyridyl
3h: R=H, H; n =2; R’ = 2-pyrimidyl
3i: R==O; n =1; R’ = 2-pyridyl
3j: R=H, SnBu3; n=1; R’ = 2-pyridyl
3k: R=H, SnBu3; n=2; R’ = 2-pyridyl
Scheme 2.

S. Narayan et al. / Tetrahedron Letters 45 (2004) 757–759
759
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the product decomposed at 130 °C when heated for
20 min. But in the case of entry 17 the reaction was very
slow, so 150 °C for 30 min was required. We have found
that this method is effective for making chiralstannyl
compound in moderate yield.
The microwave assisted solvent free amination of the
halo-(pyridine or pyrimidine) C–N bond can be
achieved by this method without solvent and metal
catalyst. This method has also shown potential in the
synthesis of enantioenriched N-(2-pyridyl)-2-tributyl-
stannyl-pyrrolidine (3j) or -piperidine (3k), which are the
object of ongoing research.12
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9. In this work, we used a CEM Discover microwave
apparatus, which is equipped with internal probe that
monitors reaction temperature and pressure, and main-
tains the desired temperature by computer control. Even
with water as a co-solvent the pressure did not exceed 50–
60 psi at 130 °C.
10. Typical experimental procedure: N-(2-pyrimidine)pyrroli-
dine (3h). The pyrrolidine (2.0 mL, 1.72 g, 24.2 mmol), was
added slowly in a 10 mL microwave vial containing 2-
chloropyrimidine (0.50 g, 4.37 mmol). The vial was sealed
by a crimped cap and was placed in a CEM Discover
microwave apparatus. The initial power supplied was
150 W; once the temperature reached 130 °C, the instru-
ment adjusted the power to maintain constant tempera-
ture. The total heating time of the reaction was 30 min.
After completion of the reaction, the reaction mixture was
cooled, diluted with dichloromethane (25 mL), washed
with Na2CO3 solution, water, and finally with brine. The
organic layer was dried over MgSO4, filtered, and the
solvent was removed in vacuo. The crude product was
purified by column chromatography (EE/hexane, 20:80) to
give 0.540 g (83%). 1H NMR (270 MHz, CDCl3):7a 8.26
(m, 2H), 6.40 (m, 1H), 3.52 (m, 4H), 1.94 (m, 4H). 13C
NMR (67 MHz, CDCl3): d 160.3, 157.7, 108.9, 46.6, 25.6.
11. During this experiment we found that by applying high
power (250 W), the pressure rose out of instrument
control, causing the crimped seal to fail. Therefore, we
used 50 W for NaOtBu containing experiments.
Acknowledgements
This work was generously supported by the NIH (GM-
56271). T.S. acknowledges support from NSF in the
2003 summer REU program. Microwave (CEM dis-
cover) and NMR equipment used this work was pur-
chased with support from NIH (P20 R15569) and the
Arkansas Biosciences Institute.
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