Enamines in heterocyclic synthesis: A route to 4-substituted pyrazoles and condensed pyrazoles

Article abstract of DOI:10.1515/znb-2004-1009

The reaction of nitrile imines, generated in situ, from hydrazonoyl halides 3a-e with enamines 2a-c affords pyrazoles 8a-g. These pyrazoles have been used to prepare condensed pyrazoles.

Full text of DOI:10.1515/znb-2004-1009

Enamines in Heterocyclic Synthesis:
A Route to 4-Substituted Pyrazoles and Condensed Pyrazoles
Huwaida M. E. Hassaneen, Hamdi M. Hassaneen, and Mohamed H. Elnagdi
Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
Reprint requests to H. M. E. Hassaneen. E-mail: huwaidah@hotmail.com
Z. Naturforsch. 59b, 1132 – 1136 (2004); received May 17, 2004
The reaction of nitrile imines, generated in situ, from hydrazonoyl halides 3a – e with enamines
2a – c affords pyrazoles 8a – g. These pyrazoles have been used to prepare condensed pyrazoles.
Key words: Enamines, Hydrazonoyl Halides, Pyrazoles, Dimethylformamide Dimethylacetal
Y
X
Introduction
The significant biological and medicinal activities of
pyrazoles and condensed pyrazole derivatives [1 – 4]
has stimulated considerable recent interest in synthe-
sis and chemical reactivity of functionally substituted
pyrazoles [5 – 7]. 4-Amino-pyrazole-3-carboxylic es-
ters 1a, now used as intermediates for the synthe-
sis of Sildenafil (Viagra) and Allopurinol, are pre-
pared from acylpyruvates via a multistage synthetic ap-
proach [8 – 12]. 3,4-Diacylpyrazoles 1b are obtainable
either from reaction of enaminones with acyl hydra-
zonoyl halides [13] or from reaction of the latter with
β-diketones [14]. To our knowledge no general effi-
cient simple synthesis of 3-acyl-4-amino- or 3-acyl-4-
nitropyrazoles 1c,d has been reported although these
derivatives could be interesting intermediates for the
synthesis of biologically interesting condensed pyra-
zoles. In the present paper we report such a route.
Moreover, extension of synthetic methodology de-
scribed earlier by one of us [13] for the synthesis
of 3,4-diacylpyrazoles to enable synthesis of (methyl-
amino)pyrazolo[3,4-d]pyridazines will be reported.
N
R‘
N
Ar
1a:
b:
X=ROCO, Y= NH2
X=Y= RCO
c
:
X
=RCO, Y=NH2
d:
X=RCO,Y=NO2
N-acetonyl-phthalimide (4) and 4-nitrotoluene. These
products have been prepared earlier utilizing the same
reaction conditions [19– 21]. Although addition of ni-
trile imines to polymer-supported arylenamines [22]
and enaminones [23] has been reported earlier, to our
knowledge addition of hydrazonoyl halides to enam-
ines 2a– c has not yet been investigated.
2a – c reacted with hydrazonoyl halides 3a– e in
presence of triethylamine to yield products of con-
densation via dimethylamine hydrochloride elimina-
tion. It is believed that 3a – e initially generate ni-
trile imines 5a – e in situ and these then undergo 1,3-
dipolar cycloaddition to 2a – c yielding intermediate
cycloadducts that aromatize via dimethylamine elim-
ination. Two isomeric structures are possible for the
cycloadducts (6 and 7).
Results and Discussion
Aromatization of 6 would afford 8 while 7 would
1
In conjunction with our interest in exploring the yield 9 (Scheme 1). H NMR as will as chemical be-
potential utility of functionally substituted enam- havior of the formed pyrazoles indicated that they are
ines [13, 15 – 18], we report here a convenient syn- the 4-substituted derivates 8. Thus, 1H NMR spec-
thesis of different 3,4-substituted-1-arylpyrazolesfrom tra of reaction products showed pyrazole H-5 at δ ≈
enamines 2a– c and hydrazonoyl halides 3a – e, and 8.60 ppm which is very close to that predicted for
the conversion of the formed pyrazoles into condensed 8a – g. If the reaction product is isomeric 9 simulated
pyrazoles needed for biological evaluation. The re- spectra predict pyrazole ring H-4 at δ ≈ 6.5 ppm [24].
quired enamines 2a – c were prepared via reacting Moreover, reduction of 8a in a trial to obtain the
dimethylformamide dimethylacetal with nitromethane, 4-aminopyrazole 10 has afforded 12. It is believed
c
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H. M. E. Hassaneen et al. · Enamines In Heterocyclic Synthesis
1133
O
O
CH3
N
O
O
Cl
NH2
NH2
X
R
N
R
+
H3C
H3C
Z
n dust
+
N
N
8a
-
NH
Ar
N
Me2N
N
N
3a-e
N
N
N
2a
-
c
Ar
5a
-
e
Ph
Ph
Ph
4a
:
X
X
X
=
=
=
N
O2
b
:
p
h
t
h
a
li
m
i
do
-
CH2CO-
11
10
c:
C6H4NO2-p
O
O
O
O
N
X
NMe2
X
N
R
CH3
R
N
Ph
N
N
O
NMe2
N
4
N
Ar
Ar
NH2
N
6a-g
7a-g
12
N
N
O
Ph
O
N
X
R
R
Scheme 2.
Experimental Section
N
X
N
N
Ar
Ar
9a-g
8a-g
All melting points are uncorrected. IR spectra were
recorded in KBr disks using a Pye Unicam SP-3000 IR spec-
trophotometer and Testscan Shimadzu FT-IR 8000 series.
1H NMR spectra were recorded on Varian EM 390 spectrom-
eters with CDCl3 and [D6]-DMSO as solvents and TMS as
an internal standard; chemical shifts (δ) are reported in ppm.
Mass spectra were measured on a GCMS-QP 1000-EX Shi-
madzu. Elemental analyses were carried out at the microan-
alytical center, University of Cairo, Giza, Egypt.
3
,
8
,
9 a: R=CH3;
b: R=EtO; =NO2; Ar = C6H5
: R=CH3;
X=NO2; Ar = C6H5
X
c
X=
ph
ph
t
t
halimido-CH2CO-; Ar = C6H4Cl-
halimido-CH2CO-; Ar = C6H4Cl-
p
p
d: R=EtO;
e: R= EtO;
f: R=CH3;
g: R=EtO;
X=
X=
ph
=C6H4NO2-
=C6H4NO2-p; Ar = C6H4Cl-
thalimido-CH2CO-; Ar = C6H4CH3-p
X
p
; Ar = C6H4Cl-
p
X
p
Scheme 1.
General procedure for the preparation of 8a – g
that 8a initially yields intermediate 10 which under-
goes self-condensation to 11 that cylises further into 12
A mixture of enamine derivatives 2a – c (0.01 mol), hy-
(Scheme 2). Very similar condensation of 5-amino- drazonoyl halides 3a – e (0.01 mmol), triethylamine (1.01 g,
0.01 mol) in chloroform (30 ml) was refluxed for 4 h. The
solvent was evaporated under vacuo and the crude product
was collected and crystallized from ethanol.
pyrazoles on attempted C-4 acylation has been ob-
served [25].
On the other hand reaction of 8d with hy-
drazine hydrate afforded the (methylamino)pyrazolo-
pyridazine 13 in excellent yield. Acetylation of 13 with
acetic anhydride afforded (acetylmethylamino)pyr-
azolopyridazine whose 1H NMR spectrum indicated
that it exists at least in DMSO solution as a mix-
3-Acetyl-4-nitro-1-phenylpyrazole (8a)
Yellow crystals, 70% yield, m.p. 135 – 136 ◦C. – IR (KBr):
1
ν 1699 (C=O) cm−1. – H NMR (300 MHz, CDCl3): δ =
2.68 (s, 3H, CH3CO), 7.46 – 7.77 (m, 5H, arom-H), 8.67 (s,
ture of 14a and isomeric tautomeric 14b in 3:1 ratio 1H, pyrazole-5-H). – MS (EI, 70 eV): m/z (%) = 231 (31.5)
[M+], other major fragments: 216 (34), 142 (11), 104 (71),
(Scheme 3). Fixation of the cyclic hydrazide form 14b
77 (100), 51 (68). – C11H9N3O3 (231.2): calcd. C 57.14,
H 3.92, N 18.18; found C 57.20, H 3.89, N 18.16.
is due to hydrogen bonding. Similarly, reaction of 8c
with hydrazine hydrate has afforded the pyrazolo
[3,4-d]pyridazine 15.
In conclusion, cycloaddition of functionally substi-
tuted enamines to nitrile imines is an excellent route
to 3,4-difunctionally substituted pyrazoles that can be
readily converted into a variety of biologically interest-
ing condensed pyrazoles.
3-Ethoxycarbonyl-4-nitro-1-phenylpyrazole (8b)
Yellow crystals, 72% yield, m.p. 150 – 151 ◦C. – IR (KBr):
1
ν 1726 (C=O) cm−1. – H NMR (300 MHz, CDCl3): δ =
1.32 – 1.63 (t, 3H, J = 7 Hz, CH3), 4.41 – 4.55 (q, 2H,
J = 7 Hz, CH2), 7.43 – 7.74 (m, 5H, arom-H), 8.62 (s, 1H,
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1134
H. M. E. Hassaneen et al. · Enamines In Heterocyclic Synthesis
CH3
O
O
H
H
H
H
N
N
N
N
NH
N
N
CH3
N
NH2
Ac2O
O
O
H
O
NH2NH2 .H2O
N
N
N
8
d
N
N
N
Cl
14a
Cl
Cl
13
14
b
N
N
NH2
H3C
NH2NH2 .H2O
8c
N
N
Cl
15
Scheme 3.
pyrazole-5-H). – MS (EI, 70 eV): m/z (%) = 261 (53.0) major fragments: 277 (100), 249 (81), 77 (12), 51 (6). –
[M+], other major fragments: 233 (51), 216 (34), 149 (22),
22H16N3O5Cl (437.85): calcd. C 60.34, H 3.68, N 9.60;
C
129 (21), 116 (24), 104 (65), 77 (92), 75 (100), 51 (47). – found C 60.30, H 3.70, N 9.55.
C12H11N3O4 (261.2): calcd. C 55.17, H 4.24, N 16.09; found
2-(2-[3-Ethoxycarbonyl-1-(4-methylphenyl)pyrazol-4-yl]-2-
oxoethyl)isoindoline-1,3-dione (8e)
C 55.20, H 4.19, N 16.11.
2-(2-[3-Acetyl-1-(4-chlorophenyl)pyrazol-4-yl]-2-oxo-
ethyl)isoindoline-1,3-dione (8c)
◦
Yellow crystals, 73% yield, m. p. 182 C. – IR (KBr):
1775 (C=O), 1724 (C=O), 1689 (C=O) cm−1. –
ν
◦
Yellow crystals, 75% yield, m.p. 152 C. – IR (KBr):
1H NMR (300 MHz, CDCl3): δ = 1.43 – 1.50 (t, 3H, J =
7 Hz, CH3), 2.40 (s, 3H, CH3), 4.46 – 4.56 (q, 2H, J = 7 Hz,
CH2), 5.19 (s, 2H, CH2-olefinic), 7.26 – 7.90 (m, 8H, arom-
H), 8.44 (s, 1H, pyrazole-5-H). – MS (EI, 70 eV): m/z (%) =
417 (12.0) [M+], other major fragments: 257 (100), 229 (67),
91 (24), 77 (13), 51 (5). – C23H19N3O5 (417.38): calcd.
C 66.18, H 4.58, N 10.07; found C 66.13, H 4.57, N 10.03.
ν 1774 (C=O), 1717 (C=O), 1693 (C=O) cm−1. – 1H NMR
(300 MHz, CDCl3): δ = 2.77 (s, 3H, CH3CO), 5.22 (s,
2H, CH2-olefinic), 7.26 – 7.91 (m, 8H, arom-H), 8.50 (s, 1H,
pyrazole-5-H). – MS (EI, 70 eV): m/z (%) = 408 (8.0) [M+],
other major fragments: 247 (100), 77 (7), 51 (4). –
C21H14N3O4Cl (407.82): calcd. C 61.84, H 3.45, N 10.30;
found C 61.87, H 3.43, N 10.25.
3-Acetyl-1-(4-chlorophenyl)-4-(4-nitrophenyl)pyrazole (8f)
2-(2-[3-Ethoxycarbonyl-1-(4-chlorophenyl)pyrazol-4-yl]-2-
oxoethyl)isoindoline-1,3-dione (8d)
Dark yellow crystals, 66% yield, m.p. 242 ◦C. – IR
Pale yellow crystals, 73% yield, m.p. 182 ◦C. – IR (KBr): (KBr): ν 1690 (C=O) cm−1. – 1H NMR (300 MHz, CDCl3):
ν 1724 (C=O), 1708 (C=O), 1679 (C=O) cm−1. – 1H NMR δ = 2.72 (s, 3H, CH3CO), 7.26 – 7.91 (m, 8H, arom-H),
(300 MHz, [D6]-DMSO): δ = 1.25 – 1.33 (t, 3H, J = 7 Hz, 8.05 (s, 1H, pyrazole-5-H). – MS (EI, 70 eV): m/z (%) =
CH3), 4.27 – 4.31 (q, 2H, J = 7 Hz, CH2), 5.12 (s, 2H, CH2- 342 (68.5) [M+], other major fragments: 326 (100), 75 (18),
olefinic), 7.35 – 7.94 (m, 8H, arom-H), 9.53 (s, 1H, pyrazole- 51 (7). – C17H12N3O3Cl (341.77): calcd. C 59.74, H 3.53,
5-H). – MS (EI, 70 eV): m/z (%) = 438 (12.6) [M+], other N 12.29; found C 59.69, H 3.50, N 12.27.
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H. M. E. Hassaneen et al. · Enamines In Heterocyclic Synthesis
1135
3-Ethoxycarbonyl-1-(4-chlorophenyl)-4-(4-nitrophenyl)pyr-
azole (8g)
70 eV): m/z (%) = 276 (55.9) [M+], 247 (100), 230 (50),
111 (57), 75 (38), 51 (19). – C12H10N5OCl (275.72): calcd.
C 52.27, H 3.65, N 25.40; found C 52.30, H 3.62, N 25.35.
Dark yellow crystals, 69% yield, m.p. 177 ◦C. – IR
(KBr): ν 1719 (C=O) cm−1. – 1H NMR (300 MHz,
CDCl3): δ = 1.35 – 1.40 (t, 3H, J = 7 Hz, CH3), 4.34 –
4.45 (q, 2H, J = 7 Hz, CH2), 7.26 – 7.90 (m, 8H, arom-H),
8.04 (s, 1H, pyrazole-5-H). – MS (EI, 70 eV): m/z (%) =
372 (100) [M+], other major fragments: 299 (66), 75 (32),
51 (12). – C18H14N3O4Cl (371.79): calcd. C 58.15, H 3.79,
N 11.30; found C 58.11, H 3.77, N 11.23.
N-[2-(4-Chlorophenyl)-7-oxo-6,7-dihydro-2H-pyrazolo
[3,4-d]pyridazin-4-ylmethyl]acetamide (14)
A solution of 13 (2.76 g, 0.01 mol) in acetic anhy-
dride (20 ml) was refluxed for 3 h. The reaction mixture
was cooled and the solid that separated was collected and
crystallized from dimethylformamide to give 14, (2.15 g,
◦
78%), m.p. 260 C. – IR (KBr): ν 3296 (NH), 3121 (NH),
1709 (C=O) 1691 (C=O) cm−1. – 1H NMR (300 MHz, [D6]-
DMSO) of 14a: δ = 1.91 (s, 3H, CH3CO), 2.61 (s, 2H,
CH2-olefinic), 3.30 (br, 2H, 2NH), 7.70 – 8.07 (m, 4H, arom-
H), 9.20 (s, 1H, pyrazole-H-3) and 1H NMR (300 MHz,
[D6]-DMSO) of 14b: δ = 1.88 (s, 3H, CH3CO), 3.30 (br,
3H, 3NH), 4.44 – 4.46 (d, 2H, CH-olefinic), 7.70 – 8.07 (m,
4H, arom-H), 9.42 (s, 1H, pyrazole-3-H). – MS (EI,
70 eV): m/z (%) = 318 (48.2) [M+], other major fragments:
274 (100), 75 (6), 51 (3). – C14H12N5O2Cl (317.75): calcd.
C 52.91, H 3.80, N 22.04; found C 52.90, H 3.77, N 22.10.
3-(7-Methyl-2-phenyl-2H-pyrazolo[4,3-e]pyridin-5-yl)-1-
phenyl-1H-pyrazol-4-yl-amine (12)
A suspension of nitro compound 8a (1.16 g, 0.005 mol)
and Zn dust (0.01 mol) in methanol (3 ml) was stirred with
◦
hydrazinium monoformate (2 ml) at 20 C. The reaction
mixture was filtered through celite. The organic layer was
evaporated and the residue was triturated with chloroform
where it solidified. The crude product was collected to give
◦
12, (0.59 g, 51%), m.p. 310 C. – IR (KBr): ν 3298, 3363
1
(NH2) cm−1. – Insoluble in common H NMR solvents. –
MS (EI, 70 eV): m/z (%) = 366 (30.3) [M+], other major
fragments: 313 (23), 230 (23), 171 (10), 137 (11), 121 (12),
114 (56), 73 (10), 55 (100). – C22H18N6 (366.38): calcd.
C 72.12, H 4.94, N 22.94; found C 72.07, H 4.90, N 22.92.
4-Aminomethyl-2-(4-chlorophenyl)-7-methyl-2,6-dihydro-
pyrazolo[3,4-d]pyridazine (15)
A mixture of 8c (4.07 g, 0.01 mol) and hydrazine hy-
drate (5 ml, 85%) was refluxed for 5 min. The reaction mix-
ture was left to cool and the solid product was collected
and crystallized from dimethylformamide to give 15, (3.26 g,
4-Aminomethyl-2-(4-chlorophenyl)-2,6-dihydropyr-
azolo[3,4-d]pyridazin-7-one (13)
A mixture of 8d (4.38 g, 0.01 mol) and hydrazine hydrate 80%), m.p. 174 ◦C. – IR (KBr): ν 3337, 3289 (NH2) cm−1
(5 ml, 85%) was refluxed for 5 min. The reaction mixture
was left to cool and the solid product was collected and crys-
.
–
1H NMR (300 MHz, [D6]-DMSO): δ = 1.62 (s, 3H,
CH3CO); 2.50 (s, 2H, CH2-olefinic), 3.92 (br, 2H, NH2),
tallized from dimethylformamide to give 13, (3.50 g, 80%), 7.42 – 8.15 (m, 4H, arom-H), 9.60 (s, 1H, pyrazole-3-H). –
MS (EI, 70 eV): m/z (%) = 274 (7.7) [M+], other major
fragments: 243 (55), 162 (87), 104 (100), 75 (62), 51 (56).
◦
m.p. 299 C. – IR (KBr): ν 3337, 3289 (NH2), 3199 (NH),
1665 (C=O) cm−1 – 1H NMR (300 MHz, [D6]-DMSO): δ =
2.50 (s, 2H, CH2-olefinic), 3.23 (br, 3H, NH, NH2), 7.64 – – C13H12N5Cl (273.75): calcd. C 57.04, H 4.41, N 25.58;
found C 57.09, H 4.39, N 25.50.
8.08 (m, 4H, arom-H), 9.41 (s, 1H, pyrazole-3-H). – MS (EI,
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