Reactions with dimethylformamide-dimethylacetal: Synthesis and reactions of several new pyrjdjne and pyrazolo[3,4-&]pyridine derivatives

Article abstract of DOI:10.1002/hc.20312

6-Aminopyridine-2(1H)-thiones 1a,b reacted with dimethylformamide- dimethylacetal (DMF-DMA) to give the corresponding 6-{[(N,N-dimethylamino) methylene]amino}pyridine derivatives 2a,b. The latter compounds reacted with hydrazine hydrate to afford the 3,6-

Full text of DOI:10.1002/hc.20312

Heteroatom Chemistry
Volume 18, Number 4, 2007
Reactions with Dimethylformamide-
Dimethylacetal: Synthesis and Reactions
of Several New Pyridine and
Pyrazolo[3,4-b]pyridine Derivatives
Mohamed A. A. Elneairy,1 Mohamed A. M. Gad-Elkareem,2
and Adel M. Taha1
1Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
2Department of Chemistry, Faculty of Science, Al-Azhar University (Assiut Branch), Assiut 71524,
A. R. Egypt
Received 15 December 2005; revised 12 March 2006
this research group. Several publications demon-
ABSTRACT: 6-Aminopyridine-2(1H)-thiones 1a,b
strated this research effort [1–9]. This is because
reacted
(DMF-DMA) to give the corresponding 6-{[(N,N-
dimethylamino)methylene]amino}pyridine deriva-
with
dimethylformamide-dimethylacetal
these derivatives possess diverse biological activ-
ities and are widely used in pharmaceutical and
medicinal preparations. The pyridine ring found
in acetylcholine, enhancement useful in the treat-
ment of Alzheimer disease [10], and has antitummer
[11], antiaminesic [12], and antimicrolial [7] activ-
ities. Moreover, pyridine-3-carbonitriles were used
as cardiotonic [13,14] and antiviral [15] agents, and
pyridine-3,5-dicarbonitriles were reported to have
antiproliferative activity on human cancer cell lines
[16]. On the other hand, pyrazolo[3,4-b]pyridines
were used as antimicrobials [5,7,17], inhibitors of
cyclin-dependent kinases [18], antimalarial [19], and
antiproliferative [20]. The above findings stimulated
the interest for the synthesis of additional new num-
bers of these derivatives that are required in medic-
inal chemistry programs.
tives 2a,b. The latter compounds reacted with
hydrazine hydrate to afford the 3,6-diamino-1H-
pyrazolo[3,4-b]pyridine derivative 4 and 3-amino-5-
hydrazino-1H-pyrazolo[4ꢀ,3ꢀ:5,6]pyrido[2,3-d]pyrimi-
dine derivative 7, respectively. Compound 4 con-
densed with DMF-DMA to yield the 3,6-bis{[(N,N-
dimethylamino)methylene]amino}-1H-pyrazolo-
[3,4-b]pyridine derivative 10, which reacted with
malononitrile to give the corresponding pyridopyra-
ꢁ
C
zolopyrimidine derivative 15. 2007 Wiley Periodicals,
Inc. Heteroatom Chem 18:399–404, 2007; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20312
INTRODUCTION
RESULTS AND DISCUSSION
Synthesis and characterization of pyridines and
pyrazolo[3,4-b]pyridines became the main target of
It
has
been
found
that
6-amino-4-(4-
methoxyphenyl)-2-thioxo-1,2-dihydropyridine-
3,5-dicarbonitrile (1a) [21] reacted with dimethyl-
formamide-dimethylacetal (DMF-DMA) in dry
xylene to afford a reaction product of molecular
Correspondence to: Mohamed A. M. Gad-Elkareem; e-mail:
m65gad@yahoo.com.
2007 Wiley Periodicals, Inc.
c
ꢀ
399

400 Elneairy, Gad-Elkareem, and Taha
formula C17H15N5OS corresponding to equimolecu-
lar addition of 1a to the reagent followed by loss
of two molecules of methanol. The IR spectrum
of this reaction product showed the absence of
the band of the amino group. The newly intro-
duced N,N-dimethylaminomethylene group was
detected in the 1H NMR spectrum of the reac-
tion product as a singlet signal at δ = 3.17 (two
CH3) and 8.91 (N CH) ppm. Based on the above
data, together with the data of elemental analy-
sis, this reaction product could be formulated as
6-{[(N,N-dimethylamino)methylene]amino}-4-(4-
methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-
dicarbonitrile (2a).
ing
6-amino-4-aryl-2-methylthiopyridine-3,5-
dicarbonitriles 8a,b, which in turn reacted
with one molecule of DMF-DMA to give
the corresponding 6-{[(N,N-dimethylamino)-
methylene]amino}-4-aryl-2-methylthiopyridine-
3,5-dicarbonitriles 9a,b. The structure of each
of 8a,b and 9a,b was established on the basis of
elemental analysis, and IR and 1H NMR spectral
data studies (cf. the Experimental section).
(b) Compound 4 could be prepared directly by re-
acting 8a with boiling hydrazine hydrate.
(c) Compound 9a reacted with boiling hydrazine
hydrate to give directly compound 4 with the
same analytical and spectral data as those
of 4 obtained by the other two methods de-
scribed before. The formation of 4 in this re-
action is assumed to proceed via the first for-
mation of the nonisolable hydrazino derivative
3a which could then be cyclized via addition
to the nitrile function at position 3 and N,N-
dimethylaminomethylene exchange of the hy-
drazino at position 6 under the applied reaction
conditions leading to regeneration of the amino
group [23] at that position and hence formation
of 4 (cf. Scheme 1).
Analogously, 6-amino-4-(2-furyl)-2-thioxo-1,2-
dihydropyridine-3,5-dicarbonitrile (1b) [22] reacted
with the same reagent to give the correspond-
ing
6-{[(N,N-dimethylamino)methylene]amino}-
4-(2-furyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbo-
nitrile (2b), whose structure was established on
the basis of elemental and spectral backgrounds as
previously reported for 2a (cf. Scheme 1 and the
Experimental section).
The synthetic potential of each of 2a,b was
demonstrated via their reaction with hydrazine hy-
drate under reflux to give different reaction prod-
ucts. The product of the reaction of 2a with hy-
drazine hydrate showed among its signals those of
two amino, one imino (3451, 3339, 3216, 3153 cm−1),
and one nitrile (2200 cm−1) functions in its IR spec-
trum. Its 1H NMR spectrum revealed the presence of
D2O exchangeable two NH2 (δ = 4.35, 6.75 ppm) and
one NH (δ = 11.86 ppm) groups. This reaction prod-
uct could then be formulated as the 3,6-diamino-1H-
pyrazolo[3,4-b]pyridine derivative 4.
(d) Compound 9b reacted also with boiling hy-
drazine hydrate to give directly compound
7 with the same analytical and spectral data
as those of 7 obtained by the other method
described before. The formation of 7 in this
reaction is assumed to proceed via the first
formation of the nonisolable hydrazino deriva-
tive 3b that undergoes two cyclization steps
which are both addition to the nitrile functions
at positions 3 and 5 leading to the formation
of the corresponding nonisolable 6-amino-5-
iminopyrazolo[4ꢀ,3ꢀ:5,6]pyrido[2,3-d]pyrimidine
derivative 5. Compound 5 could then lose
one molecule of dimethylamine to give the
nonisolable intermediate 6. Compound 6 under-
went Dimroth rearrangement [24] to give the
corresponding final isolable product 3-amino-
5-hydrazinopyrazolo[4ꢀ,3ꢀ:5,6]pyrido[2,3-d]pyri-
midine derivative 7 (cf. Scheme 1).
On the contrary, the IR spectrum of the prod-
uct of the reaction of 2b with hydrazine hydrate
showed the complete disappearance of the absorp-
tion bands of the nitrile functions. Instead new ab-
sorption bands of two NH2 and two NH groups were
detected. The signals of the NH2 and NH protons
(δ = 4.99, 6.68, 7.55, and 11.69 ppm) were D2O ex-
1
changed in the H NMR spectrum, which also re-
vealed the signal of 7H-pyrimidine at δ = 8.85 ppm.
Based on the above data this reaction product
could be formulated as the 3-amino-5-hydrazino-
1H-pyrazolo[4ꢀ,3ꢀ:5,6]pyrido[2,3-d]pyrimidine deri-
vative 7 (cf. Scheme 1 and the Experimental section).
An unequivocal support for the structure of each
of 4 and 7 was achieved via their synthesis through
other routes as follows:
Several interesting reactions took place start-
ing from the diamino-pyrazolopyridine derivative
4. Thus, it has been found that 4 reacted with
two molecules of DMF-DMA in boiling dry xy-
lene to give a reaction product of molecular
formula C20H22N8O corresponding to the addition
of two molecules of the reagent to one molecule
of 4 followed by the loss of four molecules of
methanol. The IR spectrum of this reaction product
(a) Compounds 1a,b were reacted each with one
molecule of methyl iodide in DMF/potassium
hydroxide solution to give the correspond-
Heteroatom Chemistry DOI 10.1002/hc

Reactions with Dimethylformamide-Dimethylacetal 401
Ar
Ar
Ar
NC
N
CN
S
CN
S
NC
NC
CN
DMF-DMA
xylene
CH3I
(Me)2N
N
H
H2N
N
H
H2N
N
SCH3
8a,b
1a,b
2a,b
N2H4.H2O
-H2S
Ar
8a
N2H4.H2O
Ar
NH2
NC
NC
CN
3a
NH2NH
DMF-DMA
NC
N
H2NN=CHNMe2 -
H2N
N
N
(Me)2N
N
H
N
NHNH2
H
4
Ar
3a, b
CN
N2H4.H2O
- CH3SH
3b
Ar
(Me)2N
N
N
SCH3
9a, b
NH
NH
Ar
NH2
N
NH2
H2N
H2N
HNMe2 -
N
N
N
N
N
Me2N
N
H
N
5
N
N
H
H
6
Dimroth
rearrang.
1-3,8,9a, Ar = C6 H4 OCH3-4
b, Ar = C4 H3O-2
H2N
N
NH Ar
5-7, Ar = C4H3O-2
NH2
N
N
N
N
H
7
SCHEME 1
showed the presence of the bands of one NH
(3185 cm−1) and one CN (2215 cm−1) group only.
Its 1H NMR spectrum revealed the presence of
one NH (12.14 ppm) (D2O exchangeable), two
N(CH3)2 (3.09 and 3.18 ppm), and two N CH
(8.59 ppm) groups. On the above backgrounds,
this reaction product could be formulated as the
3,6-bis{[( N,N-dimethylamino)methylene]amino}-
1H-pyrazolo[3,4-b]pyridine derivative 10 (cf.
Scheme 2 and the Experimental section).
Compound 10 reacted with malononitrile
(11a) to give a reaction product of molecular
formula C18H12N8O corresponding to the addi-
tion of two molecules of 11a to one molecule
of 10 followed by loss of one molecule of N,N-
dimethylaminodicyanoethylene and one molecule
of dimethylamine. The IR spectrum of this re-
action product showed the presence of two NH2
(3442, 3351, 3211 cm−1) and two CN (2213 cm−1)
groups. While the H NMR spectrum revealed only
1
signals of two NH2 protons at δ = 4.74, 6.77 ppm,
a new singlet signal at δ = 8.40 ppm corresponds
to the 2H-pyrimidine ring and OCH3 group in
addition to the aromatic protons. The reaction
product was thus formulated as 4,8-diamino-10-
(4-methoxyphenyl)pyrido[2ꢀ,3ꢀ:3,4]pyrazolo[1,5-a]-
pyrimidine-3,9-dicarbonitrile (15) most likely
formed via the intermediacy of the nonisolable
adducts 12, 13, and 14, respectively (cf. Scheme 2
and the Experimental section).
In contrast to the behavior of 10 toward
malononitrile (11a), it reacted with ethyl cyanoac-
etate (11b) under practically the same reaction con-
ditions to undergo N,N-dimethylaminomethylene
Heteroatom Chemistry DOI 10.1002/hc

402 Elneairy, Gad-Elkareem, and Taha
Ar
Ar
N
NMe2
NH2
N
NC
NC
N
DMF-DMA
2 moles
N
N
H2N
N
N
H
Me2N
N
H
10
R = CO2Et
12b
4
RCH2CN
11a,b
Ar
Ar
N
H
NMe2
H
NMe2
CN
H
CN
H
N
N
R
NC
NC
NC
R = CN
H
H
R
CN
NH
NH
12a
NC
NC
N
N
N
Me2N
N
Me2N
N
H
H
12a,b
13
- Me2NCH=C(CN)2
Ar
N
H
Ar
NC
N
NMe2
H
NC
N
-HNMe2
N
N
H2N
N
H2N
N
N
CN
CN
NH
NH2
15
14
11-12a, R = CN
b, R = Co2Et
Ar = C6 H4OCH3-4
SCHEME 2
exchange reaction [23] to give back the original com-
pound 4 with almost the same analytical, physical
(mp and mixed mp), and spectral data as for 4 previ-
ously reported (cf. Scheme 2 and the Experimental
section).
Reactions with DMF-DMA in Dry Xylene:
General Procedure
To a solution of the appropriate 1a,b, 8a,b (0.01 mol)
or 4 (0.02 mol) in dry xylene (30 mL), DMF-DMA
(0.012 mol or 0.024 mol) was added and the reac-
tion mixture was then heated under reflux for 3–5 h.
The solid so obtained after cooling was collected by
filtration and crystallized from the proper solvent to
yield 2a,b, 9a,b, or 10, respectively.
EXPERIMENTAL
Melting points were measured with a Gallenkamp
apparatus and are uncorrected. IR spectra in
KBr discs were recorded on a Bruker Vector 22
FT-IR spectrophotometer. 1H NMR spectra were de-
termined in DMSO-d6 and CDCl3 at 300 MHz on a
Varian Mercury VX spectrometer using TMS as an
internal standard. Chemical shifts are expressed as
δ ppm and J as Hz units. Elemental analyses were
carried out at the Microanalytical Center of Cairo
University. Compounds 1a [21] and 1b [22] were
prepared according to the literature procedures.
In all the 1H NMR spectra∗ = Lost after D2O
exchange.
6-{[(N,N-Dimethylamino)methylene]amino}-4-
(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-
dicarbonitrile (2a).◦ Yellow crystals from dioxan
(63%), mp 280–282 C; IR (cm−1) ν 3148 (NH), 2221,
1
2209 (two CN), 1624 (N C); H NMR (DMSO-d6)
δ 3.17 (s, 6H, N(CH3)2), 3.86 (s, 3H, OCH3), 7.11–7.55
(m, 5H, NH∗ & Ar H), 8.91 (s, 1H, N CH). Anal.
For C17H15N5OS (337) Calcd: C, 60. 52; H, 4.48; N,
20.76; S, 9.50. Found: C, 60.80; H, 4.80; N, 21.00; S,
9.20%.
Heteroatom Chemistry DOI 10.1002/hc

Reactions with Dimethylformamide-Dimethylacetal 403
6-{[(N,N-Dimethylamino)methylene]amino}-4-
(2-furyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbo-
nitrile (2b). Brown crystals from dioxan (58%),
mp 180◦ C; IR (cm−1) ν 3145 (NH), 2212 (CN), 1625
(N C). Anal. For C14H11N5OS (297) Calcd: C, 53.79;
H, 3.47; N, 28.95; S, 5.52. Found: C, 54.00; H, 3.70;
N, 28.70; S, 5.30%.
Ar H), 7.45 (d, J = 8.0 Hz, 2H, Ar H). Anal. For
C15H12N4OS (296) Calcd: C, 60.79; H, 4.08; N, 18.91;
S, 10.82. Found: C, 61.00; H, 4.30; N, 18.60; S,
11.00%.
6-Amino-4-(2-furyl)-2-methylthiopyridine-3,5-di-
carbonitrile (8b). Brown crystals from ethanol
(75%), mp 215◦ C ; IR (cm−1) ν 3388, 3305 (NH2),
2216 (CN), 1617 (N C). Anal. For C12H8N4OS (256)
Calcd: C, 56.24; H, 3.15; N, 21.86; S, 12.51. Found:
C, 56.60; H, 3.50; N, 21.60; S, 12.70%.
6-{[(N,N-Dimethylamino)methylene]amino}-4-(4-
methoxyphenyl)-2-methylthiopyridine-3,5-dicarbonit-
rile (9a). Yellow crystals from DMF (67%), mp
305–306◦ C; IR (cm−1) ν 2209 (CN), 1625 (N C).
Anal. For C18H17N5OS (351) Calcd: C, 61.52; H, 4.88;
N, 19.93; S, 9.12. Found: C, 61.80; H, 4.50; N, 20.20;
S, 8.80%.
Reactions with Hydrazine Hydrate: General
Procedure
A solution of the appropriate 2a,b, 8a, or 9a,b
(0.01 mol) in hydrazine hydrate (20 mL) was heated
under reflux for 6 h and then cooled. The solid so
obtained was collected by filtration and crystallized
from the proper solvent to yield 4 or 7, respectively.
6-{[(N,N-Dimethylamino)methylene]amino}-4-(2-
furyl)-2-methylthio-pyridine-3,5-dicarbonitrile (9b).
Pale yellow crystals from dioxan (63%), mp 230–
231◦ C; IR (cm−1) ν 2212 (CN), 1625 (N C); 1H NMR
(CDCl3) δ 2.60 (s, 3H, CH3), 3.27 (s, 6H, N(CH3)2),
6.64 (2d, 1H, 4H-furyl), 7.56 (d, J = 3.6 Hz, 1H,
3H-furyl), 7.72 (d, J = 2.0 Hz, 1H, 5H-furyl), 8.77 (s,
1H, N CH). Anal. For C15H13N5OS (311) Calcd: C,
57.86; H, 4.88; N, 22.49; S, 10.30. Found: C, 58.20;
H, 4.50; N, 22.20; S, 10.00%.
3,6-Diamino-4-(4-methoxyphenyl)-1H-pyrazolo-
[3,4-b]pyridine-5-carbonitrile (4). Orange crystals
from ethanol (65%), mp 320–322◦ C; IR (cm−1) ν
3451, 3339, 3216, 3153 (two NH2, NH), 2200 (CN),
1610 (N C); 1H NMR (DMSO-d6) δ 3.87 (s, 3H,
OCH3), 4.35 (s, 2H, NH∗2), 6.75 (s, 2H, NH2∗) 7.13
(d, J = 8.0 Hz, 2H, Ar H), 7.45 (d, J = 8.0 Hz, 2H,
Ar H), 11.86 (s, 1H, NH∗). Anal. For C14H12N6O
(280) Calcd: C, 59.99; H, 4.32; N, 29.98. Found: C,
59.60; H, 4.60; N, 30.20%.
3,6-Bis{[(N,N-Dimethylamino)methylene]amino}-
4-(4-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (10). Orange crystals from dioxan
(58%), mp 300–302◦ C; IR (cm−1) ν 3185 (NH), 2215
(CN), 1625 (N C); 1H NMR (DMSO-d6) δ 3.09 (s, 6H,
N(CH3)2), 3.18 (s, 6H, N(CH3)2), 3.84 (s, 3H, OCH3),
7.14 (d, J = 8.0 Hz, 2H, Ar H), 7.46 (d, J = 8.0 Hz,
2H, Ar H), 8.59 (s, 2H, two N CH), 12.14 (s, 1H,
NH∗). Anal. For C20H22N8O (390) Calcd: C, 61.52; H,
5.68; N, 28.70. Found: C, 61.80; H, 5.30; N, 28.50%.
3-Amino-4-(2-furyl)-5-hydrazino-1H-pyrazolo-
[4ꢀ,3ꢀ:5,6]pyrido[2,3-d]pyrimidine (7). Pale yellow
crystals from DMF (66%), mp >350◦ C; IR (cm−1) ν
3419, 3324, 3218, 3122 (two NH2, two NH), 1634
(N C); 1H NMR (DMSO-d6) δ 4.99 (s, 2H, NH∗2),
6.68 (s, 2H, NH∗2) 6.90–7.50 (m, 3H, furyl), 7.55 (s,
1H, NH∗), 8.85 (s, 1H, 2H-pyrimidine), 11.59 (s, 1H,
NH∗). Anal. For C12H10N8O (282) Calcd: C, 51.06; H,
3.57; N, 39.70. Found: C, 51.30; H, 3.30; N, 40.00%.
Reaction of 1a,b with Methyliodide
A solution of the appropriate 1a,b (0.01 mol) in DMF
(20 mL) containing 0.01 mol of KOH was treated
with methyl iodide (0.01 mol). The reaction mixtures
were stirred at room temperature for 2 h, poured
onto ice-cold water, and neutralized with dilute HCl
(10%). The precipitates that formed were collected
by filtration and crystallized from ethanol to yield
8a,b, respectively.
Reaction of 10 with 11a,b
A solution of 10 (0.01 mol) in glacial acetic acid
(20 mL) was treated with 11a,b (0.02 mol). The re-
action mixture was heated under reflux for 4 h and
then cooled. The solid products obtained were col-
lected by filtration and crystallized from the proper
solvent to yield 15 and 4, respectively.
6-Amino-4-(4-methoxyphenyl)-2-methylthiopyri-
dine-3,5-dicarbonitrile (8a). White crystals from
ethanol (78%), mp 230–232◦ C; IR (cm−1) ν 3468,
3363 (NH2), 2212 (CN), 1614 (N C); 1H NMR
(DMSO-d6) δ 2.71 (s, 3H, SCH3), 3.86 (s, 3H,
OCH3), 5.30 (s, 2H, NH∗2), 7.16 (d, J = 8.0 Hz, 2H,
4,8-Diamino-10-(4-methoxyphenyl)pyrido-
[2ꢀ,3ꢀ:3,4]pyrazolo[1,5-a]pyrimidine-3,9-dicarbo-
nitrile (15). Orange crystals from AcOH (57%), mp
260–261◦ C; IR (cm−1) ν 3442, 3351, 3211 (two NH2),
Heteroatom Chemistry DOI 10.1002/hc

404 Elneairy, Gad-Elkareem, and Taha
1
[12] Ammar, Y. A.; Ghorab, M. M.; El-Sharief, A. M.
Sh.; Mohamed Sh. I. Heteroat Chem 2002, 13,
199.
[13] Bekhit, A. A.; Baraka, A. M. Eur J Med Chem 2005,
40, 1405.
[14] Krauze, A.; V¯ıtolin¸a, R.; Garaliene, V.; St¯ıle, L.;
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2213 (CN), 1610 (N C); H NMR (DMSO-d6) δ 3.88
(s, 3H, OCH3), 4.74 (s, 2H, NH∗2), 6.77 (s, 2H, NH2∗)
7.13 (d, J = 8.0 Hz, 2H, Ar H), 7.50 (d, J = 8.0 Hz,
2H, Ar H), 8.40 (s, 1H, 2H-pyrimidine). Anal. For
C18H12N8O (356) Calcd: C, 60.67; H, 3.39; N, 31.45.
Found: C, 60.40; H, 3.60; N, 31.20%.
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