Microwave irradiation-assisted amination of 2-chloropyridine derivatives with amide solvents

Article abstract of DOI:10.1080/00397911.2010.515360

A simple, quick, and high-yielding microwave-assisted synthesis of 2-(N,Ndimethyl) amine- and 2-aminopyridine derivatives is reported here for the first time in the reaction of 2-chloro substituted pyridines with amide solvents such as dimethylformamide or formamide, without transition-metal catalysts. Taylor & Francis Group, LLC.

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Microwave Irradiation–Assisted
Amination of 2-Chloropyridine
Derivatives with Amide Solvents
Abdelouahid Samadi a , Daniel Silva b , Mourad Chioua a , Maria do
Carmo Carreiras b & José Marco-Contelles a
a Laboratorio de Radicales Libres y Química Computacional, Madrid,
Spain
b iMEd. UL, Research Institute for Medicines and Pharmaceutical
Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
To cite this article: Abdelouahid Samadi , Daniel Silva , Mourad Chioua , Maria do Carmo Carreiras &
José Marco-Contelles (2011): Microwave Irradiation–Assisted Amination of 2-Chloropyridine Derivatives
with Amide Solvents, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:19, 2859-2869
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Synthetic Communications1, 41: 2859–2869, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515360
MICROWAVE IRRADIATION–ASSISTED AMINATION
OF 2-CHLOROPYRIDINE DERIVATIVES WITH
AMIDE SOLVENTS
Abdelouahid Samadi,1 Daniel Silva,2 Mourad Chioua,1
2
Maria do Carmo Carreiras, and Jose Marco-Contelles
1
´
1
´
Laboratorio de Radicales Libres y Quımica Computacional, Madrid, Spain
2iMEd. UL, Research Institute for Medicines and Pharmaceutical Sciences,
Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
GRAPHICAL ABSTRACT
Abstract A simple, quick, and high-yielding microwave-assisted synthesis of 2-(N,N-
dimethyl)amine- and 2-aminopyridine derivatives is reported here for the first time in the
reaction of 2-chloro substituted pyridines with amide solvents such as dimethylformamide
or formamide, without transition-metal catalysts.
Keywords Amides; amination; 2-aminopyridines; 2-chloropyridines; 2-(N,N-dimethyl)-
aminopyridines; microwave irradiation
INTRODUCTION
The 2-aminopyiridine functional motif is present in a number of important
biologically active compounds, such as the nitric oxide synthase (NOS) inhibitors
bearing
the
2-amino-4-methylpyridine
nucleus,[1]
the
antiproliferative
2,6-dibenzylamino-3,5-dicyanopyridines,[2a] and the antitumoral 2-amimo-4-aryl-
6-dialkylamino-3,5-dicyanopyridines.[2b] 2-Aminopyridines have been also investi-
gated as starting precursors in organic synthesis and as useful chelating ligands for
catalytic and organometallic applications.[3] The synthesis of 2-aminopyridine
Received May 7, 2010.
Address correspondence to Abdelouahid Samadi or Jose Marco-Contelles, Laboratorio de
´
Radicales Libres y Quımica Computacional (IQOG, CSIC), C=Juan de la Cierva3, 28006 Madrid,
´
Spain. E-mail: samadi@iqog.csic.es; iqoc21@iqog.csic.es
2859

2860
A. SAMADI ET AL.
derivatives has been extensively reviewed.[4] The usual methods for the synthesis of
2-aminopyridines start either by N-akylation of N-alkyl pyridinium salts[5,6] or by
substitution of 2-halopyridines,[7] a method that usually requires the presence of
organometallic complexes as catalysts,[8] high temperatures, and pressure.[9]
Very interestingly, the amination of other ring systems such as 4-chloro-2-aryl-
quinolines has been reported in yields ranging from 11% to 91%, using common
amide solvents, such as dimethylformamide (DMF) or formamide, as source of
the amines by heating at reflux overnight.[10] The dimethylamino group has been also
installed in [1,8]-naphtyridines by palladium-catalyzed reaction of halonaphthyri-
dines with DMF in aqueous medium.[11] N,N-Dimethylamination of chloropyrida-
zines with DMF under reflux either in the presence or absence of copper powder
as catalyst has been reported.[12] 2-Chloropyrazine and 2-bromopyridine react easily
with N-methylformamide or N,N-dimethylformamide in the presence of potass-
ium hydroxide.[13] A recent article by Muzart
[14]
reviews the use of DMF as a
source of carbon monoxide, dimethylamine, and other species involved in the
reaction. DMF is considered an excellent polar solvent for various classes of
compounds.
With these precedents in mind, and because of the well-known advantages
and uses of microwave irradiation in organic synthesis (dramatic increases in
yields, rates, and purities of products),[15] we now report here the first microwave
irradiation–assisted reaction of differently substituted 2-chloropyridines with
DMF and formamide to give the corresponding 2-amino substituted pyridines in
short reaction times, mild reaction conditions, and excellent yields.[16]
RESULTS AND DISCUSSION
In our study, DMF gave more satisfactory results when used as a reaction
medium. Nevertheless, through optimization runs, some results revealed that
microwave-assisted rapid decomposition of DMF under specific reaction conditions
can be a source of dimethylamine, which in the presence of chloropyridin generates
the corresponding products. Table 1 lists the 2-dimethylaminopyridine derivatives
formed by reaction of 2-chloropyridine derivatives and dimethylformamide under
microwave irradiation. As precursors, we selected commercial 2-chloropyridines 1–
6, readily available 2-amino-6-chloropyridine-3,5-dicarbonitrile 7,[17] and 2-amino-6-
chloro-4-phenylpyridine-3,5-dicarbonitrile 8.[18] Under the standard experimental
conditions, the reaction of 2-chloronicotinonitrile 1 cleanly gave the expected
2-(N,N-dimethylamino)nicotinonitrile 12[16,19] in good yield. 2-Chloronicotinalde-
hyde (2) afforded 2-(N,N-dimethylamino)nicotinaldehyde 13.[20] With 3-amino-2-
cholorpyridine 3, no reaction was found after 5 h of irradiation in the same experi-
mental conditions. Similarly, the reaction of 2-chloro-5-methanolpyridine 4 with
DMF gave the unexpected 2-chloro-5-(N,N-dimethylmethylamine)pyridine 14 in
5% yield and 2-dimethylamino-5-[(N,N-dimethylamino)methyl]pyridin 15 in 75%
yield. To confirm this result, we reacted the compound 2-chloro-5-(chloromethyl)-
pyridine (5) with DMF to give the same products 14 and 15 in 50% and 33% yields,
respectively. Compound 6, after reaction with DMF, gave the product 16.[21] Siu
et al.[22] have described the dimethylamine amination product of 2-chloro-3-
cyanopyridine derivative in DMF under microwave irradiation. Similarly, in

MICROWAVE IRRADIATION–ASSISTED AMINATION
2861
Table 1. Amination of 2-chloropyridine derivatives 1–8 with dimethylformamide under microwave
irradiation
Entry
a
Precursors
Product
Temp. (ꢀC)
180
Time
Yield (%)
96
25 min
b
c
180
180
15 min
87
no reaction
5 h
—
d
e
180
180
175 min
5 min
5 þ 73
10 þ 65
f
160
150
2 min
86
61
g
15 min
h
180
3 min
74
our cases, the reaction of precursors 7 and 8 with DMF gave 2-amino-6-(N,N-
dimethylamino)pyridine-3,5-dicarbonitrile 17[23] and 2-amino-6-(N,N-dimethyl-
amino)-4-phenylpyridine-3,5-dicarbonitrile 18, respectively. Consequently, it is clear
that the ability of displacement of chloro atom in a pyridine ring by the dimethyl-
amine is highly influenced by the substitution on the pyridine ring.
Compounds containing two chloro atoms such as the 2,6-dicholopyridine deri-
vatives also have been used as precursors (Table 2). Commercially available pyridine
9, 2,6-dichloropyridine-3,5-dicarbonitrile 10,[24] and 2,6-dichloro-4-phenylpyridine-
3,5-dicarbonitrile 11[25] were irradiated in the presence of DMF. Compound 9 gave

2862
A. SAMADI ET AL.
Table 2. Amination of 2,6-dichloropyridine derivatives 9–11 with DMF under microwave irradiation
Entry
a
Precursors
Product
Temp. (ꢀC)
180
Time
120
Yield (%)
98
b
c
180
150
14 h
100
92
1
d
150
3
54
only the monosubtituted 6-chloro-2-N,N-dimethylaminopyridine 19 in quantitative
yield after irradiating it for 2 h. Its conversion to 2,6-bis(N,N-dimethylamino)pyri-
dine 20[26] was achieved after 14 h by irradiating it at 180 ꢀC. However, compounds
10 and 11 afforded only disubstituted derivatives 21 and 22, respectively, in very
short reaction times. The differences in reactivity between compounds 9 and 10 or
11 could be attributed probably to the positive activating effect resulting from the
nitrile groups present at the C3 and C5 positions in the pyridine regarding the
substitution of both chloro atoms.
The efficiency of this amination process, using DMF as the dimethylamine
source, depends on the experimental conditions, and the reaction of chloropyridine
derivatives with DMF was found to be temperature dependent. For compound 8, the
reaction takes place in 15 min at 150 ꢀC, but at 180 ꢀC the reaction was over in 3 min.
Standard heating reaction conditions also have been carried out to compare
results with those obtained by microwave irradiation. Thus, compounds 7 and 8 were
refluxed with DMF in the same experimental conditions. As shown in Table 3, the
amination was rapid and complete within 15 and 3 min, whereas it required 12 h
at 180 ꢀC under conventional thermal conditions.
Attempts to conduct the reaction with formamide in some cases cause an
uncontrollable high pressure in the reaction vessel. The cause of the high pressure
may be attributed to the liberation of carbon monoxide and ammonia gases. In
the case of DMF, the pressure in the reaction vessel during the reaction was rela-
tively low. The reaction was carried out using compounds 1, 5, and 7–9 (Table 4).
Irradiation of compound 1 in the presence of formamide afforded 2-hydroxy-
nicotinonitrile 23.[27] Irradiation of compound 5 gave exclusively the commercially

MICROWAVE IRRADIATION–ASSISTED AMINATION
Table 3. Reaction of compounds 7 and 8 with DMF under thermal heating and microwave irradiation
Thermal heating MWI
Time Yield (%)
2863
Entry
Precursor
Product
Time
Yield (%)
a
7
8
17
18
12 h
12 h
20
50
15 min
3 min
61
74
b
available product 4. Irradiation of compound 7 afforded 2,6-diaminopyridine-3,5-
dicarbonitrile 24[28] and 2-hydroxy-6-aminopyridine-3,5-dicarbonitrile 25.[29]
Similarly, for compound 8, after irradiation afforded compounds 2,6-diamino-4-
phenylpyridine-3,5-dicarbonitrile 26[15] and 2-hydroxy-6-amino-4-phenylpyridine-
3,5-dicarbonitrile 27.[30] No reaction was found after irradiating compound 9
30 min at 180 ꢀC.
The structure of the new reaction products has been established by their ana-
lytical and spectroscopic data, and when known, by comparison of these values with
those reported in literature.
Concerning the mechanism of the amination reaction, some researchers [16,22,31]
pointed that DMF easily decompose to form dimethylamine and carbon monoxide
under microwave irradiation. Due to its nucleophilic character, the formed dimethy-
lamine should react with 2-chloropyridine to give the formation of 2-dimethylamino-
pyridine derivatives. It was observed that the yield of the reaction is strongly
Table 4. Amination of chloropyridine derivatives 1, 5, 7–9 with formamide under microwave irradiation
Temp.
(ꢀC)
Yield
(%)
Entry
a
Precursors
Product
Time
20
180
180
180
30
57
b
c
1
15
30 þ 43
d
e
180
180
3
44 þ 47
No reaction
30
–

2864
A. SAMADI ET AL.
Scheme 1. Possible intermediates in the amination reaction of 2-chloroquinoliones and 2-chloropyridines
with DMF and formamide, under microwave irradiation.
influenced by the substituent present on the aromatic ring.[32] In our work, com-
pound 9 gave the disubstituted derivative 20 in 14 h, whereas compound 10 provided
the disubstituted compound 21 in a short reaction time. Theses differences in reac-
tivity were attributed to the presence of the two nitrile groups in molecule 10. A simi-
lar result was obtained when we used formamide. The amination of 2-chloropyridine
in the presence of formamide also depends on the subsistent on the aromatic ring.
However, it remains to be explained the diverse reactivity observed depended on
the amide used. For the amination of 4-chloro-2-phenylquinolines[10] and 2-chlopyr-
idines, we think that the critical intermediates could be species AH(Me) or BH(Me)
(Scheme 1), which under the reaction conditions should evolve to the final product in
a concerted fragmentation process, liberating HCl, which should be neutralized in
the reaction medium.
In conclusion, we have reported for the first time microwave-assisted amina-
tion of substituted 2-chloropyridine using amides as solvent and as the amine source
to give 2-amino- and 2-N,N-dimethylamino substituted pyridines in a very efficient
process under mild reaction conditions. As expected, the reaction times and chemical
yields were superior to the results obtained for a similar reaction under conventional
conditions.[10]
EXPERIMENTAL
Melting points were determined on a Kofler-type microscope and are uncor-
1
rected. H NMR and 13C NMR spectra were recorded at room temperature (rt) in
CDCl3 or dimethylsulfoxide (DMSO-d6) at 300, 400, or 500 MHz and at 75.4,
100.6, or 125.6 MHz, respectively, using solvent peaks [CDCl3: 7.27 (D), 77.2 (C)
ppm and DMSO-d6 2.50 (D) and 39.7 (C) ppm] as internal reference. The assignment
1
of chemical shifts is based on standard NMR experiments [1H, 13C, H-1H corre-
1
lation spectroscopy (COSY), H-13C heteronuclear multiple quantum correlation
(HMQC), heteronuclear multiple bond correlation (HMBC), dimensionless enhance-
ment by polarization transfer (DEPT)]. Mass spectra were recorded on a gas
chromatography=mass spectrometry (GC=MS) instrument with an atmospheric

MICROWAVE IRRADIATION–ASSISTED AMINATION
2865
pressure ionization-electrospray (API-ES) ionization source. Elemental analyses were
´
´
performed at the Instituto de Quımica Organica General (CSIC, Spain). Thin-layer
chromatography (TLC) was performed on silica F254 and detection by ultraviolet light
at 254 nm or by spraying with phosphomolybdic-H2SO4 dying reagent. Where anhy-
drous solvents were needed, they were purified following the usual procedures. Column
chromatography was performed on silica gel 60 (230 mesh). Reactions under microwave
irradiation were performed in a Biotage system equipped with electromagnetic sample
stirrer and with temperature and power control. The reaction was performed in a
10-mL or 30-mL glass tube equipped with septa.
General Methods for the Synthesis of 2-(Dimethylamino)pyridine
Derivatives
Method A-1 general method with MWI. A solution of compounds 1–11
(1.5 mmol) in DMF (5 mL) was placed in a 10-mL glass tube equipped with septa.
The reaction mixture was stirred for 30 s, and then exposed to microwave irradiation
at 250 W at temperatures and times shown in Table 1. After completion showed by
TLC (hexane=AcOEt, 3=2, v=v or CH2Cl2=MeOH, 10=1, v=v), the reaction mixture
was concentrated and the residue was purified by column chromatography to yield
the corresponding product.
Method A-2 general method for classical heating. A solution of com-
pounds 7 or 8 (0.393 mmol) in dry DMF (2 mL) was heated to reflux for 12 h. After
complete reaction (TLC analysis), the solvent was removed under vacuum, and the
residue was purified by column chromatography (hexane=EtOAc, 3=2, v=v) to yield
compounds 17 (14.7 mg, 20%) and 18 (50.6 mg, 50%).
Method B General Method for the Synthesis of 2-Aminopyridine
Derivatives
A solution of compounds 1, 5, and 7–9 (1.5 mmol) in formamide (10 mL) was
placed in a 30 mL glass tube equipped with septa. The reaction mixture was stirred
for 30 s and then irradiated for the times and temperatures showed in Table 4. After
complete reaction (TLC analysis) (hexane=AcOEt, 3=2), the reaction mixture was
diluted with water, and the precipitate was filtered and washed with water. The resi-
due was purified by column chromatography (CH2Cl2=MeOH, 25=1 to 10=1, v=v) to
yield the corresponding compounds shown in Table 4.
Selected Data
2-Chloro-5-[(N,N-dimethylamino)methyl]pyridine (14). Following the
general procedure and starting from precursor 5 (243 mg, 1.5 mmol), compound 14
was obtained as a yellow oil (25.5 mg, 10%): Rf ¼ 0.32 (CH2Cl2=MeOH, 10=1,
v=v); IR (KBr) n 3391, 2960, 2924, 2852, 2664, 1660, 1614, 1462, 1261, 1104, 1021,
1
810. H NMR (300 MHz, CDCl3) d 8.27 (d, J ¼ 2.4 Hz, 1 H), 7.63 (dd, J ¼ 8.1 and
2.4 Hz, 1 H), 7.27 (d, J ¼ 8.1 Hz, 1 H), 3.38 (s, 2H, CH2), 2.21 (s, 6H, NMe2);
13C NMR (75 MHz, DMSO-d6) d 150.4 (C2), 150.2 (C6), 139.7 (C4), 133.6 (C5),

2866
A. SAMADI ET AL.
124.2 (C3), 60.7 (CH2), 45.5 (2 ꢁ CH3); MS (EI) m=z (%): 170 (34) [M]þ, 135 (43)
[M ꢂ Cl]þ, 126 (55) [M – NMe2]þ.
2-N,N-Dimethylamino-5-[(N,N-dimethylamino)methyl]pyridine
(15).
Following the general procedure and starting from precursor 4 (215.5 mg, 1.5 mmol),
compound 15 (196 mg, 73%) was obtained as a light yellow solid: Rf ¼ 0.07 (CH2Cl2=
MeOH, 10=1, v=v); mp 187–189 ꢀC; IR (KBr) n 3412, 2930, 2662, 1611, 1520,
1
1403 cmꢂ1; H NMR (300 MHz, CDCl3) d 8.05 (d, J ¼ 2.4 Hz, H6, 1H), 7.91 (dd,
J ¼ 8.9 and 2.5 Hz, H4, 1H), 6.56 (d, J ¼ 8.9 Hz, H3, 1H), 3.99 (s, 2H, CH2), 3.09
(s, 6H, NMe2), 2.69 (s, 6H, NMe2); 13C NMR (75 MHz, DMSO-d6) d 159.6 (C2),
149.8 (C6), 139.6 (C4), 111.2 (C5), 106.2 (C3), 58.7 (CH2), 41.6 (2 ꢁ CH3), 37.9
(2 ꢁ CH3); MS (EI) m=z (%): 179 (19) [M]þ, 135 (100) [M - NMe2]þ. Anal. calcd.
for C10H17N3: C, 67.00; H, 9.56; N, 23.44. Found: C, 66.91; H, 9.44; N, 23.32.
2-Amino-6-(N,N-dimethylamino)-4-phenylpyridine-3,5-dicarbonitrile
(18). Following the general procedure and starting from precursor 8 (190 mg,
1.5 mmol) compound 18 was obtained as a white solid (0.145 g, 74%): Rf ¼ 0.63
(CH2C2=AcOEt, 10=1, v=v); mp 251–253 ꢀC; IR (KBr) n 3473, 3320, 3221, 2210,
1
1624, 1586, 1570, 1550, 1515, 1491, 1420, 1400, 1228 cmꢂ1; H NMR (300 MHz,
CDCl3) d 7.43–7.54 (m, 5 ꢁ CH-ar), 735 (s, NH2, 2H), 3.21 (s, 6H, 2 ꢁ CH3); 13C
NMR (75 MHz, DMSO-d6) d 162.4 (C), 160.6 (C), 159.8 (C), 135.9 (C), 130.3
(CH), 129.1 (2 ꢁ CH), 129.0 (2 ꢁ CH), 118.5 (CN), 116.8 (CN), 81.0 (C-CN), 80.6
(C-CN), 40.46 (2 ꢁ CH3); MS (EI) m=z (%): 262 (110) [M – H]þ, 263 (50) [M]þ. Anal.
calcd. for C15H13N5 (263.117): C, 68.42; H, 4.98; N, 26.60. Found: C, 68.19; H, 4.90;
N, 26.31.
2-(N,N-Dimethylamino)-6-chloropyridine (19). Following the general pro-
cedure and starting from precursor 9 (220 mg, 1.5 mol), compound 19 (228 mg, 98%)
was obtained as a yellow oil: Rf ¼ 0.2 (hexane=CH2C2, 3=2, v=v); 1H NMR
(300 MHz, CDCl3) d 7.35 (dd, J ¼ 8.4 and 7.5 Hz, H4, 1H), 6.51 (d, J ¼ 7.4 Hz,
H3, 1H), 6.34 (d, J ¼ 8.4 Hz, H5, 1H), 3.06 (s, 6H, NMe2); 13C NMR (75 MHz,
DMSO-d6) d 159.4 (C2), 149.5 (C6), 139.5 (C4), 110.5 (C5), 103.8 (C3), 38.2
(2 ꢁ CH3); MS (EI) m=z (%): 156 (65) [M]þ, 141 (87) [M ꢂ Me]þ; 127 (100)
[M ꢂ 2CH3]þ.
2,6-Bis-(N,N-dimethylamino)pyridine-3,5-dicarbonitrile (21). Following
the general procedure and starting from precursor 10 (48.2 mg, 0.24 mmol), com-
pound 21 was obtained after 1 min of microwave irradiation as a light yellow solid
(32.4 mg, 92%): Rf ¼ 0.23 (hexane=ethyl acetate 3:1, v=v); mp 170–172 ꢀC; IR
1
(KBr) n 2935, 2202, 1603, 1526 cmꢂ1; H NMR (400 MHz, DMSO-d6) d 8.04 (s,
1H, H-4py, 1H), 3.20 (12 H, s, 4 N-CH3); 13C NMR (100 MHz, DMSO-d6) d
156.9 (C-2, C-6 py), 153.0 (C-4 py), 118.8 (2 CN), 78.90 (C-3, C-5 py), 39.6 (4
CH3); MS (EI) m=z (%): 215 (100) [M]þ, 200 (39) [M – CH3]þ, 186 (99) [M ꢂ
2CH3 þ H]þ. Anal. calcd. for C11H13N5: C, 61.38; H, 6.09; N, 32.54. Found: C,
61.22; H, 5.91; N, 32.36.
2,6-Bis-(N,N-dimethylamino)-4-phenylpyridine-3,5-dicarbonitrile (22).
Following the general procedure and starting from precursor 11, compound 22
was obtained after 1 min of microwave irradiation as a white solid (90.7 mg, 54%):

MICROWAVE IRRADIATION–ASSISTED AMINATION
2867
Rf ¼ 0.20 (hexane=ethyl acetate 3:1, v=v); mp 227–229 ꢀC; IR (KBr) n 2939, 2204,
1
1582, 1526 cmꢂ1; H NMR (400 MHz, DMSO-d6) d 7.49 (brs, 5 H, C6H5), 3.31 (s,
6 H, 2 N-CH3), 3.32 (s, 6 H, 2 N-CH3); 13C NMR (100 MHz, DMSO-d6) d 164.9
(C-4 py), 158.9 (C-2, C-6 py), 135.5 (C0-1 Ph), 130.2 (C0-4 Ph), 129.0 (C0-2, C0-6
Ph), 128.6 (C0-3, C0-5 Ph), 118.2 (2 ꢁ CN), 81.1 (C-3, C-5 py), 40.5 (4 ꢁ CH3); MS
(EI) m=z (%): 291 (80) [M]þ, 290 (100) [M – H]þ, 276 (25) [M – CH3]þ. Anal. calcd.
for C17H17N5: C, 70.08; H, 5.88; N, 24.04. Found: C, 69.82; H, 5.59; N, 23.96.
ACKNOWLEDGMENTS
The present work has been supported by MEC Grant SAF2006-08764-C02-01,
Comunidad de Madrid (S=SAL-0275-2006), Instituto de Salud Carlos III [RETIC
RENEVAS (RD06=0026=1002)], and AECI (A=07492=07). A. S. thanks CSCI for
the JAE-doc contract. M. C. thanks the Instituto de Salud Carlos III (Ministerio
de Salud y Consumo) for a postdoctoral fellowship.
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