Convenient Synthesis of Polyaza-2-(heteroaryl)pyridine Derivatives

Article abstract of DOI:10.1002/jhet.3076

A simple and efficient method for the synthesis of new heterocyclic compounds containing pyridine and 1,3-pyrimidine units has been developed. It is based on the reaction of the appropriate enaminone with some N-nucleophiles.

Full text of DOI:10.1002/jhet.3076

Month 2018
Convenient Synthesis of Polyaza-2-(heteroaryl)pyridine Derivatives
*
Ghada S. Masaret
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Mecca, Saudi Arabia
*
E-mail: ghadamasaret@yahoo.com
Received August 13, 2017
DOI 10.1002/jhet.3076
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient method for the synthesis of new heterocyclic compounds containing pyridine and
1,3-pyrimidine units has been developed. It is based on the reaction of the appropriate enaminone with some
N-nucleophiles.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
has been reported that there are many review articles that
deal with the synthesis of pyridine derivatives from
enaminones [5–9].
In view of our interest in developing efficient synthesis
of 2-pyridine derivatives by utilizing the enaminones as
starting material, we report here several approaches to the
synthesis of pyridine derivatives using compound 2 as a
precursor.
Enaminones are chemical compounds consisting of an
amino group linked through a C═C to a carbonyl group.
They are versatile synthetic intermediate that combine the
ambident nucleophilicity of enamines with the ambident
electrophilicity of enones.
Enaminone derivatives are highly reactive intermediates
extensively used for synthesis of heterocyclic compounds.
On the other hand, a great deal of interest has been focused
on the synthesis of the functionalized pyridine derivatives
due to their biological activity [1,2]. Some 2-pyridine
derivatives are considered as cardiotonic agents such as
milrinone and as potential human immunodeficiency
virus 1-specific transcriptase inhibitors [3,4]. Moreover, it
RESULTS AND DISCUSSION
Firstly, 2-pyridylacetophenone was formed by the
reaction of α-picoline with benzonitrile or ethyl acetate in
© 2018 Wiley Periodicals, Inc.

G. S. Masaret
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the presence of n-butyllithium according to the reported
method [10,11] (Scheme 1).
The required enaminone 2 can be easily prepared
derivative 6 (Scheme 3). When the same reaction was
carried out in refluxing, DMF solution catalyzed by TEA
gave the corresponding benzodiazepine derivative 7
(Scheme 3). Compound 7 was also obtained when 6 was
refluxed in DMF containing a catalytic amount of TEA.
The structures of 6 and 7 were established on the basis of
their spectral and elemental analysis data. Thus, the IR
spectrum of 6 showed the presence of absorption
frequencies at 3430 and 3310 cmꢀ1 due to NH2 and NH
functions. The IR spectrum of 7 revealed the absence of a
in excellent yield by the treatment of
1
with
dimethylformamide/dimethyl acetal (DMF/DMA) in
refluxing dry xylene (Scheme 1). The structure of 2 was
deduced from 1H-NMR spectroscopic data. In the 1H-
NMR spectrum of 2, the two methyl and methine protons
appeared as two singlets at δ 3.25 and 7.30 ppm,
respectively. In compound 2, there are three nucleophilic
sites (a, c, and e) and two electrophilic sites (b and d).
Thus, the reaction of 2 with different types of
nucleophiles under different reaction conditions gave 2-
substituted pyridine derivatives.
The reaction of equimolar amounts of the
monoenaminone 2 with ethylenediamine in refluxing
ethanol gave the respective enaminone 3. On the other
hand, when this reaction was carried out in refluxing
DMF catalyzed by triethylamine (TEA) afforded the
corresponding pyridyldiazepine derivative 4 (Scheme 2).
The structures 3 and 4 were established on the basis of
both elemental and spectral data. Moreover, compound 4
was confirmed by an alternative synthesis. Thus,
refluxing compound 3 in DMF in the presence of a
catalytic amount of TEA gave a product that proved
identical in all respects [infrared (IR), 1H-NMR, and
mass spectra] to 4.
1
NH2 function at 3400 cmꢀ1 region. Also, the H-NMR
spectrum of 7 showed, in addition to the expected signals,
a singlet at δ 5.50 ppm corresponding to C2–H of diazepine.
On the other hand, compound 2 refluxed with o-
phenylenediamine in molar ratio 2:1 in boiling ethanol
afforded the corresponding bis(enaminone) derivative 8
(Scheme 3). The IR spectrum showed absorption band at
3330 and 1710 cmꢀ1 due to NH and CO functions.
The work was extended further to study the behavior of
2 towards the action of heterocyclic amines. Thus,
compound 2 readily reacted with 5-aminopyrazole in
boiling ethanol yielding the corresponding enaminone 9
(Scheme 4). The elemental analyses and spectral data
were in accordance with the proposed structure.
Its IR spectrum showed a broad NH2 band in the region
3430 cmꢀ1 and the CO function group at 1700 cmꢀ1. Also,
1H-NMR spectrum revealed two singlet signals at δ
6.22 ppm assignable to (D2O exchangeable) NH2 protons
and at δ 6.82 ppm due to olefinic CH proton, two doublet
signals at δ 6.62 and 7.32 ppm with the same coupling
constant J = 7 Hz assignable to H-3 and H-4 of the
pyrazole ring residue, respectively. The mass spectrum
Compound 2 (2 mmol) heated with ethylenediamine
(1 mmol) in refluxing ethanol afforded the bis(enaminone)
5 (Scheme 2).
1H-NMR spectra of compounds 3 and 4 showed, in
each case, two CH2 groups as triplet–triplet in the
region 2.77–3.67 ppm, while in compound 5, the CH2
protons appeared as singlet at δ 3.72 ppm. The mass
spectra of 3, 4, and 5 showed the molecular ion peaks at
m/z = 267, 249, and 474, respectively, corresponding to
the molecular formula C16H17N3O, C16H15N3, and
C30H26N4O2, respectively. These mass spectra showed, in
addition to the molecular ion peak, a fragment ion peak
at m/z corresponding to the 2-pyridyl radical cation.
Moreover, assignment of compound 4 is consistent with
literature report [12].
revealed the molecular ion peak at m/z
= 290
corresponding to the molecular formula C17H14N4O.
Compound 9 heated in DMF solution catalyzed with
TEA or refluxed in glacial acetic acid afforded only one
isolable product, which identified as 5-phenyl-
6-(pyridine-2-yl)pyrazolo[1,5-a]pyrimidine (10). Structure
10 was established on the basis of spectral and elemental
analysis data. The IR spectrum showed the absence of
both the CO and NH2 bands present in the spectra of the
starting enaminone 9. Also, the 1H-NMR spectrum
showed singlet signal at δ 9.25 ppm assignable to CH of
pyrimidine ring, two doublet signals at δ 6.25 and
Similarly, heating of compound 2 with o-phenylene
diamine in refluxing ethanol afforded the enaminone
Scheme 1. Synthesis of 2-pyridylacetophenone (1) and 3-(dimethylamino)-1-phenyl-2-(pyridine-2-yl)prop-2-en-1-one (2). DMF/DMA,
dimethylformamide/dimethyl acetal.
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Convenient Synthesis of Polyaza-2-(heteroaryl)pyridine Derivatives
Scheme 2. Reaction of compound 2 with ethylene diamine in different solvents. DMF, dimethylformamide; TEA, triethylamine.
Scheme 3. Reaction of compound 2 with o-phenylene diamine in different solvents. DMF, dimethylformamide; TEA, triethylamine.
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G. S. Masaret
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Scheme 4. Reactions of compound 2 with 5-amino pyrazole and 2-amino imidazole. DMF, dimethylformamide; TEA, triethylamine. [Color figure can be
viewed at wileyonlinelibrary.com]
7.45 ppm with the same coupling constant J = 7.2 Hz. The
assigned structure 10 was confirmed by an alternative
synthesis. Thus, the reaction of 2 with 5-aminopyrazole
in refluxing DMF in presence of TEA or heating in
glacial acetic acid gave a product that proved identical in
beside two doublets at δ 7.00 and 7.25 ppm assignable to
two imidazole protons and singlet signal at δ 9.02 ppm
due to CH pyrimidine ring. Formation of 12 is assumed
to proceed via the proposed mechanism as shown in
Scheme 4.
1
all respects (mp, IR, H-NMR, and mass spectra) to 10.
The reactivity of the enaminone 2 towards 3-amino-
1,2,4-triazole was next studied to shed some light on its
site selectivity, such a reaction can led to one or more of
four possible condensation products 13–16. This is
because of the following: (1) 3-amino-1,2,4-triazole can
exist in one of the two tautomeric forms, namely, 3-
amino-4H-1,2,4-triazole and 3-amino-2H-1,2,4-triazole
and (2) the reaction of each tautomer with an
enaminone can proceed through two possible pathways
involving initial attack by either exocyclic NH2 group
or the cyclic NH group. The expected products are thus
13–16 (5-Ar-6-phenyl-[1,2,4]triazolo[4,3-a]pyrimidine,
7-Ar-6-phenyl-[1,2,4]triazolo[4,3-a]pyrimidine, 7-Ar-
6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine, and 5-Ar-6-
phenyl-[1,2,4]triazolo[1,5-a]pyrimidine, respectively)
as shown in Schemes 5 and 6. In our hands, the
reaction of 2 with 3-amino-1,2,4-triazole in refluxing
DMF containing a catalytic amount of TEA or by
refluxing in glacial acetic acid yielded, in each case,
This reaction can proceed through two possible routes to
give 7-substituted pyrazolo[1,5-a]pyrimidine (route A)
and/or its 5-substituted isomer (route B) (Scheme 4).
However, literature reports indicate that such a reaction is
site selective as it afforded in most cases 5-substituted
isomer. In our hands, the reaction proceeded by route B
to give 10.
Formation of 10 is assumed to proceed via Michael-type
addition of the most basic ring-N in pyrazole followed by
intramolecular cyclodehydration and dimethylamine
elimination under the reaction condition.
Similarly, compound 2 reacted with 2-aminoimidazol
in boiling DMF containing TEA to afford
imidazolopyrimidine derivative 12 (Scheme 4). The
structure of 12 was established based on its elemental
analysis and spectroscopic studies. Thus, the IR showed
1
the absence of both CO and NH2 function groups. Its H-
NMR spectrum showed the absence of N(CH3)2 signals,
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Convenient Synthesis of Polyaza-2-(heteroaryl)pyridine Derivatives
only one isolable product. The separated product was
identified as 7-(pyridin-2-yl)-6-phenyl-[1,2,4]triazolo[1,5-
a]pyrimidine (15) and not their isomers 13, 14, and 16.
Structure 15 was confirmed on the basis of elemental
and spectral analyses. The IR spectrum showed the
absence of CO and NH2 groups present in the starting
proton and CH pyrimidine proton, respectively. Such
assignments are consistent with literature reports on H-
1
NMR spectra of 1,2,4-triazolo[1,5-a]pyrimidine and its
[4,3-a] isomers [13]. To account for the formation of 15,
it is suggested that the reaction start with Michael-type
addition of the exocyclic NH2 group of the amine to the
activated double bond of 2 followed by elimination of
1
material. H-NMR spectrum showed two singlet signals
at δ 8.62 and 9.23 ppm attributable to CH triazole
dimethylamine
and
dehydrative
cyclization
by
Scheme 5. Proposed mechanism for the synthesis of triazolo pyrimidines. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 6. Synthesis of 7-(pyridin-2-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (15). [Color figure can be viewed at wileyonlinelibrary.com]
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G. S. Masaret
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condensation of the cyclic NH group with the enone
moiety. Such result found a great agreement with the
previously reported work [12,14]. However, various
literature reports indicate that such a reaction is site
selective and regioselective [12,14].
The work was further extended to study the behavior of
2 towards the action of some amidines. Thus, the reaction
of 2 with five equivalents of each of acetamidine HCl
and sodium ethoxide in boiling ethanol resulted in the
formation of pyridyl pyrimidine 17 in excellent yield
(Scheme 7).
Similar reaction of
2
with five equivalents of
benzamidine HCl and five equivalents of sodium
ethoxide in refluxing ethanol resulted in the formation of
pyridyl pyrimidine derivative 18 (Scheme 7).
Enaminone 2 reacted also with pinene-2-carboxamidine
HCl 19 (it was prepared according to the previously
reported procedure [14]) to give pyridylpyrimidine 20
(Scheme 7).
The general mechanistic pathways for the formation of
the pyrimidine from the corresponding enaminone with
amidines can be rationalized as shown in Scheme 8.
The structure of compounds 17, 18, and 20 was
confirmed by elemental and spectral data. The IR spectra,
in general, showed the absence of C═O function group in
Scheme 7. Reaction of compound 2 with different amidines.
the region 1700 cmꢀ1. The H-NMR spectra, in general,
1
revealed the absence of –N(CH3)2 signals. The mass
spectra showed the molecular ion peaks at m/z (%) = 247
(25), 309 (100), and 353 (45), respectively, corresponding
to the molecular formula C16H13N3, C21H15N3, and
C24H23N3, respectively.
EXPERIMENTAL
Instruments. All melting points are incorrect in degree
centigrade and determined on Gallenkamp electric melting
point apparatus. The IR spectra were recorded (KBr disk)
on a Mattson 5000 FTIR spectrometer at the Faculty of
Science, Mansoura University, Egypt. The 1H-NMR spec-
tra were determined on a Bruker WPSY 400-MHz spec-
trometer with tetramethylsilane as an internal standard,
and the chemical shifts are in δ ppm using dimethyl sulfox-
ide (DMSO-d6) as a solvent. The mass spectra were re-
corded at 70 eV with Varian MAT 311 at the
Microanalytical Center, Faculty of Science, Cairo
Scheme 8. Proposed mechanism for the reaction of enaminone 2 with different amidines.
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Convenient Synthesis of Polyaza-2-(heteroaryl)pyridine Derivatives
University. Elemental analyses (C, H, and N) were carried
out at the Faculty of Science, Cairo University. The results
were found to be in a good agreement ( 0.03) with the cal-
culated values.
Synthesis of 2-pyridylacetophenone (1). It was prepared
Yield 60–66%; mp 257°C; IR (KBr): ν/cmꢀ1 = 3320
(NH); H-NMR (DMSO-d6) δ (ppm) = 3.47 (t, 2H, CH2–
1
NH), 3.67 (t, 2H, CH2–N), 5.23 (s, 1H, CH═C), 7.45–7.69
(m, 8H, Ar–H), 8.45 (d, 1H, C6–H pyridine), 8.72 (s, 1H,
NH). 13C-NMR (100 MHz, DMSO-d6) δ (ppm): 46.9,
57.6, 120.9, 122.7, 128.8, 129.2, 131.0, 137.0, 139.2,
144.1, 148.8, 155.7, 164.6; MS (EI, 70 eV): m/z (%) = 249
(M+, 100), 206 (25), 103 (90), 97 (20), 77 (60), 69 (30),
57 (100). Anal. Calcd for C16H15N3 (249.32): C, 77.08; H,
6.06; N, 16.85%. Found: C, 76.95; H, 5.86; N, 16.71%.
according to the reported procedure in 75%, mp
40–42°C; MS: m/z (%) = 198 (M+, 100%), lit. [10,11]
(mp 39–44°C).
Synthesis of 3-(dimethylamino)-1-phenyl-2-(pyridine-2-yl)
prop-2-en-1-one (2). A mixture of 2-pyridylacetophenone
(1) (0.01 mol) and DMF–DMA (0.01 mol) was refluxed in
dry xylene for 6 h. The mixture was then left to cool at
room temperature, filtered off, dried, and recrystallized
from ethanol to give 2 in 68% yield.
Synthesis of 3,30-(ethane-1,2-diylbis(azanediyl))bis(1-phenyl-
2-(pyridin-2-yl)prop-2-en-1-one) (5).
A
mixture of
enaminone 2 (0.025 mol) and ethylenediamine (0.01 mol)
was refluxed in boiling EtOH (30 mL) for 6 h. The
reaction mixture was left to cool at room temperature.
The separated solid material was filtered off, dried, and
recrystallized from EtOH to give 5 in yield 78%.
1
Mp 178°C; IR (KBr): ν/cmꢀ1 = 1710 (CO); H-NMR
(DMSO-d6) δ (ppm) = 3.25 (s, 6H, 2CH3), 7.30 (s, 1H,
CH), 7.50–7.75 (m, 8H, Ar–H), 8.30 (d, 1H, C6–H
pyridine); 13C-NMR (100 MHz, DMSO-d6) δ (ppm):
44.5, 118.3, 120.1, 122.7, 128.5, 129.2, 134.5, 137.0,
137.9, 148.8, 155.7, 156.9, 197.5; MS (EI, 70 eV): m/z
(%) = 252 (M+, 100), 208 (15), 131 (35), 92 (95), 91
(25), 90 (10), 77 (70). Anal. Calcd for C16H16N2O
(252.32): C, 76.16; H, 6.39; N, 11.10%. Found: C, 76.02;
H, 6.25; N, 11.00%.
Mp 281°C; IR (KBr): ν/cmꢀ1 = 3310 (NH), 1705 (CO);
1H-NMR (DMSO-d6) δ (ppm) = 3.72 (s, 4H, 2CH2), 7.35
(s, 1H, CH), 7.56–7.81 (m, 16 H, Ar–H), 8.50 (d, 2H,
2C6–H pyridine), 10.13 (s, 2H, 2NH). 13C-NMR
(100 MHz, DMSO-d6) δ (ppm): 46.1, 120.1, 122.3,
122.7, 123.6, 128.5, 129.2, 134.5, 137.0, 137.9, 146.0,
148.8, 155.7, 197.5; MS (EI, 70 eV): m/z (%) = 474 (M+,
100), 237 (70), 132 (25), 105 (30), 78 (15), 70 (25).
Anal. Calcd for C30H26N4O2 (474.56): C, 75.93; H, 5.52;
N, 11.81%. Found: C, 75.81; H, 5.48; N, 11.76%.
Synthesis of 3-((2-aminoethyl)amino)-1-phenyl-2-(pyridin-2-
yl)prop-2-en-1-one (3).
To a solution of enaminone 2
(0.01 mol) in absolute ethanol (30 mL) was added
ethylene diamine (0.01 mol) dropwise. The reaction
mixture was refluxed for 4 h. The mixture was cooled at
room temperature. The separated solid material was
filtered off, dried, and recrystallized from ethanol to give
3 in 75% yield.
Synthesis of 3-((2-aminophenyl)amino)-1-phenyl-2-(pyridin-
2-yl)prop-2-en-1-one (6).
A mixture of enaminone 2
(0.01 mol) and o-phenylenediamine (0.01 mol) was
refluxed in boiling EtOH for 6 h. The reaction mixture
was left to cool at room temperature. The precipitate
solid product was filtered off, dried, and recrystallized
from EtOH to give 6 in 71% yield.
Mp 210°C; IR (KBr): ν/cmꢀ1 = 3410 (NH2), 3305 (NH),
1710 (CO), 1602 (C═C); 1H-NMR (DMSO-d6)
δ
(ppm) = 1.50 (s, 2H, NH2), 2.77 (t, 2H, CH2NH2), 3.67
(t, 2H, CH2NH), 7.20–7.82 (m, 9H, CH + Ar–H), 8.45
(d, 1H, C6–H pyridine), 10.03 (s, 1H, NH). 13C-NMR
(100 MHz, DMSO-d6) δ (ppm): 44.5 (2CH3), 120.1
(C═), 120.9–137.9 (9C–Ar), 149.1 (C═N), 156.0 (C═C–
N), 166.7 (N═C), 197.0 (C═O), 145 (2C), 152.5; MS
(EI, 70 eV): m/z (%) = 267 (M+, 100), 237 (20), 208
(80), 131 (30), 98 (10), 97 (10), 85 (50), 83 (45). Anal.
Calcd for C16H17N3O (267.33): C, 71.89; H, 6.41; N,
15.72%. Found: C, 71.81; H, 6.38; N, 15.67%.
Mp 187°C; IR (KBr): ν/cmꢀ1 = 3430 (NH2), 3310 (NH),
1710 (C═O); 1H-NMR (DMSO-d6) δ (ppm) = 5.31 (s, 2H,
NH2), 7.52 (s, 1H, CH), 7.62–7.80 (m, 12H, Ar–H), 8.51
(d, 2H, C6–H pyridine). 11.12 (s, 1H, NH); MS (EI,
70 eV): m/z (%) = 315 (M+, 100), 238 (20), 223 (25),
132 (20), 118 (15), 107 (25), 93 (25), 77 (20). Anal.
Calcd for C20H17N3O (315.38): C, 76.17; H, 5.43; N,
13.32%. Found: C, 75.96; H, 5.38; N, 13.30%.
Synthesis of 4-phenyl-3-(pyridin-2-yl)-1H-benzo[b][1,4]
diazepine (7). Method A.
A mixture of enaminone 2
Synthesis of 5-phenyl-6-(pyridin-2-yl)-2,3-dihydro-1H-1,4-
(0.01 mol) and o-phenylenediamine in DMF (30 mL)
containing a catalytic amount of TEA (four drops) was
heated for 6 h. The reaction mixture was left to cool at
room temperature. The separated solid was filtered off,
dried, and recrystallized from EtOH to give 7 in 75% yield.
diazepine (4). Method A.
An equimolar amount of
enaminone 2 (0.01 mol) and ethylenediamine (0.01 mol)
in DMF (30 mL) with few drops of TEA (four drops)
was heated for 6 h. The reaction mixture was left to cool
at room temperature. The precipitated solid material was
filtered off, dried, and recrystallized from ethanol to give 4.
1
Mp 265°C; IR (KBr): ν/cmꢀ1 = 3310 (NH); H-NMR
(DMSO-d6) δ (ppm) = 5.50 (s, 1H, CH), 7.39–7.71 (m,
12H, Ar–H), 8.52 (d, 1H, C6–H pyridine), 9.52 (s, 1H,
NH). 13C-NMR (100 MHz, DMSO-d6) δ (ppm): 108.0,
113.5, 120.9, 122.7, 123.5, 124.1, 126.5, 128.8, 129.2,
Method B.
When compound 3 was refluxed in DMF
(30 mL) catalyzed with TEA (four drops) and left to
cool, it gave compound 4.
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131.0, 133.1, 137.0, 138.2, 141.6, 148.8, 155.7, 164.6; MS
(EI, 70 eV): m/z (%) = 297 (M+, 100), 206 (25), 103 (75),
91 (20), 78 (40), 76 (20). Anal. Calcd for C20H15N3
(297.36): C, 80.78; H, 5.08; N, 14.13%. Found: C, 80.70;
H, 5.00; N, 14.10%.
9.25 (s, 1H, CH═C pyrimidine). 13C-NMR (100 MHz,
DMSO-d6) δ (ppm): 96.9, 120.5, 123.6, 127.5, 128.7,
129.2, 131.6, 137.2, 144.7, 148.2, 149.2, 154.6, 158.6,
161.2; MS (EI, 70 eV): m/z (%) = 272 (M+, 30), 206
(20), 103 (80), 96 (40), 91 (15), 78 (20), 66 (70). Anal.
Calcd for C17H12N4 (272.31): C, 74.98; H, 4.44; N,
20.58%. Found: C, 74.95; H, 4.39; N, 20.51%.
Method B.
Refluxing compound 6 in boiling DMF
containing a catalytic amount of TEA for 8 h after
working up afforded compound 7.
Synthesis of 3,30-(1,2-phenylenebis(azanediyl))bis(1-phenyl-
Method B.
Compound 9 (0.01 mol) was refluxed in
boiling DMF (30 mL) with few drops of TEA (four
drops) or glacial acetic acid for 6 h. The reaction mixture
was cooled at room temperature. The solid product was
filtered off, dried, and recrystallized from EtOH to give
compound 10 in 65% yield.
2-(pyridin-2-yl)prop-2-en-1-one) (8).
A
mixture of
enaminone (0.025 mol) and o-phenylenediamine
(0.01 mol) was refluxed in absolute EtOH (30 mL) for
8 h. The reaction mixture was then left to cool at room
temperature. The separated solid material was filtered off,
dried, and recrystallized from EtOH to give compound 8
in 60% yield.
Synthesis
of
7-phenyl-6-(pyridin-2-yl)imidazo[1,2-a]
pyrimidine (12). An equimolar amount of enaminone 2
(0.01 mol) and 2-aminoimidazole (0.01 mol) was
refluxed in boiling DMF containing TEA for 6 h. The
reaction mixture was left to cool, and the separated solid
material was filtered off, dried, and recrystallized from
EtOH to give 12 in 75% yield.
Mp >300°C; IR (KBr): ν/cmꢀ1 = 3330 (NH), 1710
(CO); 1H-NMR (DMSO-d6) δ (ppm) = 7.39–7.81 (m,
20H, Ar–H), 7.95 (d, 2H, 2C6–H pyridine), 11.08 (s, 2H,
2NH). 13C-NMR (100 MHz, DMSO-d6) δ (ppm): 46.1,
116.9, 119.5, 120.2, 120.9, 122.7, 128.5, 129.2, 131.3,
134.5, 137.0, 137.9, 147.1, 148.8, 155.7, 197.5; MS (EI,
70 eV): m/z (%) = 522 (M+, 100), 299 (25), 223 (15),
209 (10), 145 (10), 105 (50), 91 (15), 78 (20). Anal.
Calcd for C34H26N4O2 (522.21): C, 78.14; H, 5.01; N,
10.72%. Found: C, 78.07; H, 5.00; N, 10.70%.
1
Mp 260°C; IR (KBr): ν/cmꢀ1 = 1620 (C═N); H-NMR
(DMSO-d6) δ (ppm) = 7.00 (d, 1H, J = 7.00 Hz, CH–
imidazole), 7.25 (d, 1H, J = 7.00 Hz, CH–imidazole),
7.60–7.79 (m, 8H, Ar–H), 8.51 (d, 1H, C6H–pyridine),
9.02 (s, 1H, CH–pyrimidine); MS (EI, 70 eV): m/z
(%) = 272 (M+, 30), 206 (30), 168 (20), 104 (15), 102
(40), 82 (10), 80 (30), 74 (10), 66 (40). Anal. Calcd for
C17H12N4 (272.31): C, 74.98; H, 4.44; N, 20.58%.
Found: C, 74.90; H, 4.40; N, 20.52%.
Synthesis
of
3-(5-amino-1H-pyrazol-1-yl)-1-phenyl-2-
(pyridin-2-yl)prop-2-en-1-one (9).
A
mixture of
2
(0.01 mol) and 5-aminopyrazole (0.01 mol) was refluxed
in boiling EtOH (30 mL) for 6 h. The reaction product
was left to cool. The separated solid product was filtered
off and recrystallized from ethanol to give 9 in 80% yield.
Mp 210°C; IR (KBr): ν/cmꢀ1 = 3430 (NH2), 1700 (CO),
1590 (C═C); 1H-NMR (DMSO-d6) δ (ppm) = 6.22 (s, 2H,
NH2), 6.62 (d, 1H, J = 7.00 Hz, CH–pyrazole), 6.82 (s,
1H, CH═C), 7.32 (d, 1H, J = 7.00 Hz, CH–N pyrazole),
7.62–7.80 (m, 8H, Ar–H), 8.51 (d, 1H, C6–H pyridine);
13C-NMR (100 MHz, DMSO-d6) δ (ppm): 96.9, 120.5,
123.6, 127.5, 128.7, 129.2, 131.6, 137.2, 144.7, 148.2,
149.2, 154.6, 158.6, 161.2; MS (EI, 70 eV): m/z (%) = 290
(M+, 100), 274 (20), 208 (15), 131 (35), 95 (30), 77 (35).
Anal. Calcd for C17H14N4O (290.33): C, 70.33; H, 4.86;
N, 19.30%. Found: C, 70.31; H, 4.82; N, 19.25%.
Synthesis of 7-(pyridin-2-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]
pyrimidine (15).
A mixture of equimolar quantities of
enaminone 2 (0.01 mol) and 3-amino-1H-[1,2,4]-triazole
was refluxed in DMF solution catalyzed with TEA for 8 h.
The reaction mixture was left to cool at room temperature.
The separated solid product was filtered off, dried, and
recrystallized from ethanol to give 15 in 70% yield.
1
Mp 245°C; IR (KBr): ν/cmꢀ1 = 1610 (C═N); H-NMR
(DMSO-d6) δ (ppm) = 7.70–8.01 (m, 8H, Ar–H), 8.62 (s,
1H, C3H triazole), 8.71 (d, 1H, C6H–pyridine), 9.01 (s,
1H, C5H–pyrimidine); MS (EI, 70 eV): m/z (%) = 273
(M+, 25), 196 (30), 169 (35), 102 (20), 97 (35), 83 (45),
77 (25), 67 (45), 57 (80). Anal. Calcd for C16H11N5
(273.30): C, 70.32; H, 4.06; N, 25.63%. Found: C, 70.30;
H, 4.00; N, 25.60%.
Synthesis
of
5-phenyl-6-(pyridin-2-yl)pyrazolo[1,5-a]
pyrimidine (10). Method A.
An equimolar amount of 2
Reaction of enaminone
procedure.
derivatives,
benzamidine hydrochloride, and pinene-2-carboxamidine
hydrochloride (19) (0.052 mol) was refluxed in boiling
EtOH in the presence of sodium ethoxide (prepared from
1.2 g sodium and 30 mL absolute EtOH) (0.05 mol) for
6 h. The reaction mixture was left to cool at room
temperature then filtered. The filtrate was concentrated
2
with amidines.
General
A mixture of 2 (0.01 mol) and amidine
namely, acetamidine hydrochloride,
(0.01 mol) and 5-aminopyrazole (0.01 mol) was refluxed
in DMF solution containing a catalytic amount of TEA or
glacial acetic acid for 6 h. The reaction mixture was
filtered off, dried, and recrystallized from EtOH to give
10 in 72% yield.
1
Mp 218°C; IR (KBr): ν/cmꢀ1 = 1600 (C═N); H-NMR
(DMSO-d6) δ (ppm) = 6.25 (d, 1H, J = 7.2 Hz, CH–
pyrazole), 7.45 (d, 1H, J = 7.20 Hz, CH═N pyrazole),
7.60–7.85 (m, 8H, Ar–H), 8.52 (d, 1H, C6H–pyridine),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Convenient Synthesis of Polyaza-2-(heteroaryl)pyridine Derivatives
REFERENCES AND NOTES
and purified by column chromatography using n-
hexane : AcOEt 6:1 as eluent.
2-Methyl-4-phenyl-5-(pyridin-2-yl)pyrimidine (17).
[1] Lahaus, G.; Dittmar, W. S. Africa patent, 6906036; Chem
Abstr 1988, 73, 720308.
[2] Youngdale, G. A. U.S. patent, 4288440; Chem. Abstr. 1982,
96, 6596c.
Yield
85%; mp 120°C; IR (KBr): ν/cmꢀ1 = 1620 (C═N); H-
NMR (DMSO-d6) δ (ppm) = 2.30 (s, 3H, CH3), 7.50–
7.85 (m, 8H, Ar–H), 8.51 (d, 1H, C6H–pyridine), 9.35 (s,
1H, CH); MS (EI, 70 eV): m/z (%) = 247 (M+, 25), 170
(25), 155 (30), 129 (30), 98 (20), 82 (35), 77 (25), 67
(30). Anal. Calcd for C16H13N3 (247.30): C, 77.71; H,
1
[3] Dorigo, P.; Gaion, R. M.; Belluco, P.; Fraccarollo, D.;
Maragno, I.; Mostil, I.; Orsini, F. J Med Chem 1993, 36, 2475.
[4] Dolle, V.; Nguyen, E. C. H.; Aubertin, A. M.; Kirn, A.;
Andreola, M. I.; Jamieson, G.; Bisagni, E. J Med Chem 1995, 38, 4679.
[5] Gaber, H. M.; Bagley, M. C.; Muhammad, Z. A.; Gomha, S.
M. RSC Adv 2017, 7, 14562.
[6] Stanovnik, B. Org Prep Proc Int 2014, 46, 24.
[7] Stanovnik, B.; Svete, J. Chem Rev 2004, 104, 2433.
[8] Bezenšek, J.; Prek, B.; Grošelj, U.; Kasunič, M.; Svete, J.;
Stanovnik, B. Tetrahedron 2012, 68, 4719.
[9] Prek, B.; Bezenšek, J.; Kasunič, M.; Grošelj, U.; Svete, J.;
Stanovnik, B. Tetrahedron 2014, 70, 2359.
[10] Markus, G.; Holger, K.; Klaus, W.; Thomas, M. Inorg Chimica
Acta 2013, 401, 38.
[11] Muir Calum, W.; Kennedy Alan, R.; Redmond Joanna, M.;
Watson Allan, J. B. Org Biomol Chem 2013, 11, 3337.
[12] Hassanien, A. A. J Chem Res 2004, 2004, 536.
[13] Salgado, A.; Varela, C.; Collazo, A. M. G.; Pevarello, P. Mag
Res Chem 2010, 48, 614.
5.30; N, 16.99%. Found: C, 77.68; H, 5.20; N, 16.88%.
2,4-Diphenyl-5-(pyridin-2-yl)pyrimidine (18). Yield 81%;
mp 180°C; IR (KBr): ν/cmꢀ1 = 1610 (C═N), 1500 (Ph);
1H-NMR (DMSO-d6) δ (ppm) = 7.70–8.09 (m, 13H, Ar–
H), 8.55 (d, 1H, C6H–pyridine), 9.02 (s, 1H, CH); MS
(EI, 70 eV): m/z (%) = 309 (M+, 100), 231 (10), 154
(10), 103 (10), 97 (35), 83 (45), 77 (20), 69 (50). Anal.
Calcd for C21H15N3 (309.37): C, 81.53; H, 4.89; N,
13.58%. Found: C, 81.50; H, 4.85; N, 13.54%.
2-Pinino-4-phenyl-5-(pyridine-2-yl)pyrimidine (20). Yield
76%; mp 80°C; IR (KBr): ν/cmꢀ1 = 1610 (C═N), 1600
(C═C); 1H-NMR (DMSO-d6) δ (ppm) = 1.03 (s, 6H,
2CH3), 1.38 (d, 1H, J = 8 Hz, CH), 1.72 (d, 1H,
J = 8 Hz, CH), 2.07 (m, 1H, CH), 2.19 (m, 2H, CH2),
2.70 (t, 2H, J = 6 Hz, CH2), 6.01 (t, 1H, J = 6 Hz, CH),
7.32–7.81 (m, 8H, Ar–H), 8.59 (d, 1H, C6H–pyridine),
9.57 (s, 1H, C4H–pyrimidine); MS (EI, 70 eV): m/z
(%) = 353 (M+, 45), 232 (20), 155 (15), 123 (30), 81
(40), 77 (20), 57 (30). Anal. Calcd for C24H23N3
(353.47): C, 81.55; H, 6.56; N, 11.89%. Found: C, 81.45;
H, 6.55; N, 11.80%.
[14] Pezet, F.; Routaboul, L.; Daran, J.-C.; SaSaki, I.; Ait-Haddou,
H.; Balavoine, G. G. A. Tetrahedron 2000, 56, 8489.
SUPPORTING INFORMATION
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet