Studies with functionally substituted N-alkylazoles: The reactivity of 1-(3,5-dimethylpyrazol-1-yl)-Acetone towards electrophilic reagents

Article abstract of DOI:10.1002/jhet.5570380324

The reaction of 1-(3,5-dimethylpyrazol-1-yl)acetone 4 with aromatic diazonium salts afforded the corresponding arylhydrazones 5a,b that were converted into pyridazines 6a,b and 8 via condensation with active methylene nitriles and dimethylformamide dimethylacetal, respectively. Condensation of 4 with phenylhydrazine afforded the phenylhydrazone 10, which could be converted into the indolylpyrazole 11 on treatment with ethanolic hydrochloric acid. Compound 4 also reacted with nitrous acid, benzylidenemalononitrile to yield a variety of substituted new pyrazoles.

Full text of DOI:10.1002/jhet.5570380324

May-Jun 2001
Studies with Functionally Substituted N-Alkylazoles:
The Reactivity of 1-(3,5-Dimethylpyrazol-1-yl)-
Acetone towards Electrophilic Reagents
685
Mona Hassan Mohamed [a], Mervat Mohammed Abdel-Khalik [b]
and Mohamed Hilmy Elnagdi* [a]
[a] Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
[b] Department of Chemistry, Girls College for Arts, Science and Education,
Ain Shams University, Heliopolis, Cairo, A. R. Egypt.
Received December 26, 2000
The reaction of 1-(3,5-dimethylpyrazol-1-yl)acetone 4 with aromatic diazonium salts afforded the
corresponding arylhydrazones 5a,b that were converted into pyridazines 6a,b and 8 via condensation with
active methylene nitriles and dimethylformamide dimethylacetal, respectively. Condensation of 4 with
phenylhydrazine afforded the phenylhydrazone 10, which could be converted into the indolylpyrazole 11 on
treatment with ethanolic hydrochloric acid. Compound 4 also reacted with nitrous acid, benzyl-
idenemalononitrile to yield a variety of substituted new pyrazoles.
J. Heterocyclic Chem., 38, 685 (2001).
The reactivity of functionally substituted N-alkyl-
1
H NMR spectrum of compound 4 displayed three single
pyridinium salts 1 and N-alkylbenzotriazoles 2 towards
electrophiles has been extensively studied in the past [1-6].
Both 1 and 2 are capable of affording carbaniones under mild
conditions, as a result of the stabilizing effect of π-deficient
ring nitrogen that is exerted on such carbanions. Although
carbanions resulting from proton abstraction from
N-alkylpyrazoles might also be stabilized by the ring
nitrogen electron attracting inductive effect, reactivity of
such species towards nitrogen and carbon electrophiles has,
to our knowledge, not been reported, although this may open
new route for preparing otherwise not readily obtainable
biologically interesting pyrazole derivatives [7,8]. We report
here results of our investigation on the reactivity of 4 towards
nitrogen and carbon electrophiles. The work enabled the
synthesis of several new pyrazolylazines and functionally
substituted pyrazoles that seem interesting as potential
agrochemical and/or pharmaceuticals. Thus compound 4
could be readily prepared via reacting 3,5-dimethyl-1H-
pyrazole with chloroacetone in refluxing toluene and in
presence of an equimolecular amount of triethylamine. The
lines readily recognizable as arising from the methyl groups
at C-5 and C-3 at δ = 2.01 and 2.17 ppm respectively and at
δ = 2.13 ppm for the acetyl group along with two singlets at
δ = 4.70 and 5.83 ppm for the methylene and pyrazolyl 4-H
protons. The data thus find parallelism to that reported for
similar systems [9].
Compound 4 coupled readily with aromatic diazonium
salts in ethanolic sodium hydroxide to yield the
corresponding arylhydrazones 5a,b in good yields
(Scheme 1).
Similar to the reported behavior of acetylarylhydrazonyl
derivatives [10-12], compound 5a condensed readily with
ethyl cyanoacetate and with malononitrile to yield the pyri-
dazin-6-ones 6a and pyridazin-6-imines 6b respectively.
Typical to the reported behavior of 4-methylpyridazine-5-
carbonitriles [13-14] towards sulfur, coumpound 6a reacted
with sulfur in refluxing DMF and in presence of piperidine
to yield the thienopyridazines 7. Compound 5a also con-
densed with dimethylformamide dimethylacetal to yield the
pyrazolylpyridazines 8 Compound 5a condensed with

686
Vol. 38
M. H. Mohamed, M. M. Abdel-Khalik and M. H. Elnagdi
phenylhydrazine to yield the diphenylhydrazone 9 that has
also been obtained by an alternative method, via coupling
the phenylhydrazone 10 with benzenediazonium chloride.
The reaction of 4 with phenylhydrazine hydrochloride
resulted directly in the formation of indoylpyrazoles 11,
which most likely resulted from the rearrangement of
intermediary 10. Compound 10 could be prepared via
condensing 4 with phenylhydrazine in refluxing acetic acid.
This could be rearranged into 11 on reflux in ethanolic
hydrochloric acid (Scheme 2).

May-Jun 2001
687
Studies with Functionally Substituted N-Alkylazoles
Anal. Calcd. for C
21.86. Found: C, 65.48; H, 6.20; N, 21.85.
H
N O (256.30): C, 65.60; H, 6.29; N,
Compound 4 reacted with nitrous acid to yield a product
14 16
4
of molecular formula C H N O that could be 12 or 13.
8
11 3 2
13
Structure 13 is established based on the C NMR which
revealed the presence of two carbonyl carbons resonating
at δ = 178.4 and 176.2 ppm. Moreover signals at 1680 and
1695 cm in the IR spectra reveal the presence of two-
carbonyl groups and a signal at 3210 cm reveals the pres-
1-(3,5-Dimethylpyrazol-1-yl)-1-p-tolylhydrazonopropane-2-one
(5b).
Compound 5b was obtained in 83% yield (2.24 g), mp 168-169°;
-1
-1
1
ir: 3210 (NH), 1679 cm (CO); H NMR (CDCl ): δ 1.85 (s, 3H,
3
-1
CH
), 2.02 (s, 3H, CH
), 2.15 (s, 3H, CH
3pyrazolyl C-5
3pyrazolyl C-3 3 tolyl
ence of an NH group. Compound 4 also reacted with
benzylidenemalononitrile to yield the addition product 14
and elimination of hydrogen molecule. Several isomeric
structures seemed possible for the reaction product as
initial addition of both active methylene and active methyl
in 4 can be envisioned. Structures 14 could be established
for the reaction product via initially condensing 4 with
benzaldehyde and subsequent treatment of the formed
arylidene derivative 15 with malononitrile (Scheme 3).
In conclusion, it may be stated that a pyrazolyl moiety
activates adjacent N-methylene to proton loss in a fashion
similar to what is established for benzotriazolyl moiety.
), 2.18 (s, 3H, COCH ), 5.85 (s, 1H, pyrazolyl 4-H), 7.21-7.92
(m, 4H, arom. H), 9.38 (s, 1H, NH); ms: m/z 270 (M ).
C-4
3
+
Anal. Calcd. for C
H N O (270.33): C, 66.66; H, 6.71; N,
15 18 4
20.73. Found: C, 66.36; H, 6.70; N, 20.72.
General Procedure for the Preparation of (6a,b).
Each of malononitrile (0.66 g, 10 mmoles) or ethylcyanoacetate
(1.13 g, 10 mmoles) was added to 5a (2.56 g, 10 mmoles) in the
presence of acetic acid (1 ml) and anhydrous ammonium acetate
o
(1 g). The reaction mixture was heated at 120 for 15 minutes, then
triturated with ethanol. The solid product, so formed, was collected
by filtration and crystallized from ethanol.
6-Oxo-4-methyl-1-phenyl-3-(3',5'-dimethylpyrazol-1'-yl)-
pyridazine-5-carbonitrile (6a).
EXPERIMENTAL
Compound 6a was obtained in 90% yield (2.74 g), mp
-1
1
169-170°; ir: 2231 (CN), 1683 cm (CO); H NMR (CDCl ): δ
All melting points are uncorrected. IR spectra were recorded as
KBr disks on a Pye Unicam SP 1000 spectrometer. H NMR
spectra were obtained on a Varian EM 390-300MHz
3
1
2.15 (s, 3H, CH
(s, 3H, CH
), 2.19 (s, 3H, CH
), 2.50
3pyrazolyl C-5
3pyrazolyl C-3
), 5.85 (s, 1H, pyrazolyl 4-H), 7.52-7.85
3 pyridazinyl C-4
+
(m, 5H, arom. H); ms: m/z 305 (M ).
spectrometer with DMSO-d or CDCl as solvent and TMS as an
6
3
Anal. Calcd. for C
H N O (305.33): C, 66.87; H, 4.95; N,
22.94. Found: C, 66.68; H, 4.90; N, 22.86.
internal standards and chemical shifts expressed ppm (δ).
Elemental analyses were obtained from the Microanalytical Unit
at Cairo University, Giza, Egypt.
17 15 5
6-Imino-4-methyl-1-phenyl-3-(3',5'-dimethylpyrazol-1'-yl)-
pyridazine-5-carbonitrile (6b).
3,5-Dimethylpyrazol-1-yl-acetone (4).
Compound 6b was obtained in 86% yield (2.61 g), mp
A solution of 3,5-dimethylpyrazole (0.96 g, 10 mmoles) in dry
toluene (30 ml) was treated with chloroacetone (0.92 g,
10 mmoles) in presence of triethylamine (1 ml). The reaction
mixture was refluxed for 5 hours. The solvent was evaporated
under vacuum and the solid product, so formed, was collected by
-1
1
185-186°; ir: 3215 (NH), 2204 cm (CN); H NMR (CDCl ): δ
3
2.12 (s, 3H, CH
(s, 3H, CH
(m, 5H, arom. H), 9.15 (s, 1H, NH); ms: m/z 304 (M ).
), 2.15 (s, 3H, CH
), 5.85 (s, 1H, pyrazolyl 4-H), 7.50-7.85
), 2.61
3pyrazolyl C-5
3pyrazolyl C-3
3 pyridazinyl C-4
+
Anal. Calcd. for C
27.62. Found: C, 67.09; H, 5.29; N, 27.41.
H N (304.35): C, 67.08; H, 5.30; N,
filtration and crystallized from benzene to give beige crystals;
17 16 6
-1
yield: 1.21 g (80%), mp 67-68°; ir: 2960, 2840 (CH ), 1685 cm
3
1
(CO); H NMR (CDCl ): δ 2.01 (s, 3H, CH
), 2.13
3
3pyrazolyl C-5
7-Amino-2-phenyl-4-(3',5'-dimethylpyrazol-1'-yl)-thieno-
[3,4-d]-pyridazin-1-one (7).
(s, 3H, CH
), 2.17 (s, 3H, COCH ), 4.70 (s, 2H, CH ),
3pyrazolyl C-3
3 2
+
5.83 (s, 1H, pyrazolyl 4-H); ms: m/z 152 (M ).
Anal. Calcd. for C H N O (152.19): C, 63.13; H, 7.95; N,
Elemental sulfur (0.32 g, 10 mmoles) was added to a solution of
6a (3.05 g, 10 mmoles) in dimethylformamide (30 ml) in the
presence of piperidine (0.5 ml). The reaction mixture was heated for
5 hours. The solvent was reduced to half its volume, poured onto
water and neutralized with hydrochloric acid. The solid product, so
8
12 2
18.41. Found: C, 62.99; H, 8.10; N, 18.28.
General Procedure for the Preparation of (5a,b).
A cold solution of aryldiazonium chloride (30 mmoles),
prepared as described earlier [4], was added to a solution of 4
(10 mmoles) in ethanol (50 ml) containing sodium acetate (3 g).
The reaction mixture was stirred at room temperature for 2 hours,
and left overnight in the refrigerator. The solid product, so
formed, was collected by filtration and crystallized from ethanol.
formed, was collected by filtration and crystallized from ethanol;
-1
yield: 2.02 (60%), mp 195-196°; ir: 3420, 3310 (NH ), 1680 cm
2
1
(CO); H NMR (CDCl ): δ 2.05 (s, 3H, CH
), 2.19
3
3pyrazolyl C-5
(s, 3H, CH
), 5.75 (s, 1H, thienyl 5-H), 6.26 (s, 1H, pyra-
3pyrazolyl C-3
+
zolyl 4-H), 7.05-7.75 (m, 7H, arom. H, NH ); ms: m/z 337 (M ).
2
Anal. Calcd. for C
20.76. Found: C, 60.62; H, 4.36; N, 20.75.
H N OS (337.33): C, 60.53; H, 4.48; N,
17 15 5
1-(3,5-Dimethylpyrazol-1-yl)-1-phenylhydrazonopropan-2-one
(5a).
1,4-Dihydro-3-(3',5'-dimethylpyrazol-1'-yl)-1-phenylpyridazin-
4-one (8).
Compound 5a was obtained in 76% yield (1.92 g), mp 84-85°;
-1
1
ir: 3215 (NH), 1679 cm (CO); H NMR (CDCl ): δ 2.02 (s, 3H,
3
CH
), 2.15 (s, 3H, CH
), 2.19 (s, 3H,
A mixture of 5a (2.56 g, 10 mmoles) in dimethylformamide
dimethylacetal (1.19 g, 10 mmoles) in toluene (30 ml) was heated
for 16 hours. The solvent was evaporated under vacuum and the
3pyrazolyl C-5
3pyrazolyl C-3
COCH ), 5.85 (s, 1H, pyrazolyl 4-H), 7.21-7.78 (m, 5H, arom.
3
+
H), 9.85 (s, 1H, NH); ms: m/z 256 (M ).

688
Vol. 38
M. H. Mohamed, M. M. Abdel-Khalik and M. H. Elnagdi
solid product, so formed, was collected by filtration and
crystallized from ethanol to give red crystals; yield: 2.08 g
overnight. The solid product obtained was collected by filtration
and crystallized from benzene as white crystals; yield: 1.26 g
(70%), mp 259-260° ; ir: 3210 (NH), 1680, 1695 (CO) cm ; H
NMR (DMSO-d ): δ 2.06 (s, 3H, CH ), 2.56 (s, 3H,
6 3pyrazolyl C-5
-1
1
-1 1
(78%), mp 137-138°; ir: 1710 cm (CO); H NMR (DMSO-d ):
6
δ 1.99 (s, 3H, CH
), 2.19 (s, 3H, CH
6.07 (s, 1H, pyrazolyl 4-H), 7.02-7.85 (m, 7H, arom H).
Anal. Calcd. for C N O (266.29): C, 67.65; H, 5.30; N,
),
3pyrazolyl C-5
3pyrazolyl C-3
CH
), 2.35 (s, 3H, CH ), 6.35 (s, 1H, pyrazole H-4),
3pyrazolyl C-3
3
13
H
8.12 (br s, 1H, NH); C NMR (DMSO): δ 178.4 (CO), 176.2
(CO), 132.3, 129.6, 106.2 (pyrazolyl C), 24.30, 24.10, 22.5
(3CH ); ms: m/z 181 (M ).
15 14
4
21.04. Found: C, 67.52; H, 5.30; N, 21.03.
3',5'-Dimethyl-1-(1,2-diphenylhydrazonopropanyl)-pyrazole (9).
Method A.
+
3
Anal. Calcd. for C H N O (181.19): C, 53.03; H, 6.12; N,
8
11 3 2
23.19. Found: C, 53.17; H, 6.08; N, 23.06.
6-Amino-4-hydroxy-2-phenyl-3-(3',5'-dimethylpyrazol-1'-
yl)benzonitrile (14).
A mixture of 5a (2.56 g, 10 mmoles) and phenylhydrazine
(1.08 g, 10 mmoles) and acetic acid (1 ml) was heated at 120° for
10 minutes. The reaction mixture was triturated with ethanol, the
solid product, so formed, was collected by filtration and crystal-
lized from ethanol to give red crystals in a yield of 75%.
Method A.
To a solution of 4 (1.52 g, 10 mmoles) in dioxan (30 ml), ben-
zylidenemalononitrile (1.54 g, 10 mmoles) was added in the pres-
ence of few drops of piperidine. The reaction mixture was heated
under reflux for 6 hours. The solvent was reduced under vacuum,
diluted with water and acidified with dilute HCl. The solid prod-
uct obtained was collected by filtration and crystallized from
ethanol as green crystals in a yield of 70%.
Method B.
A cold solution of benzenediazonium chloride (prepared as
previously discussed in compound 5a), was added to a solution of
compound 10 (1.82 g, 10 mmoles) in 50 ml ethanol containing 2
g NaOH. The reaction mixture was stirred for 1 hour. at room
temperature and was left overnight in the refrigerator. The solid
product, so formed, was collected by filtration and crystallized
from ethanol to give red crystals in a yield of 64%; yield: 2.60 g
Method B.
To a solution of 15 (2.40 g, 10 mmoles) in dioxan (30 ml),
malononitrile (0.66 g, 10 mmoles) was added in the presence of few
drops of piperidine. The reaction mixture was heated under reflux
for 6 hours. The solvent was reduced under vacuum, diluted with
water and acidified with dilute HCl. The solid product obtained was
collected by filtration and crystallized from ethanol as green crystals
63%; yield: 2.12 g (70%) (method A), mp 141-142°; ir: 3465 (OH),
-1
1
(75%), mp 167-168°; ir: 3431 (NH), 2980, 2850 (CH ) cm ;
H
3
NMR (DMSO-d ): δ 1.89 (s, 3H, CH
), 2.55 (s, 3H,
), 2.65 (s, 3H, CH ), 6.35 (s, 1H, pyrazole 4-H),
6
3pyrazolyl C-5
CH
3pyrazolyl C-3
3
7.28-7.83 (m, 10H, arom. H), 8.12 (br s, 1H, NH), 8.15 (br s, 1H,
NH).
Anal. Calcd. for C
H N (346.42): C, 69.34; H, 6.40; N,
20 22 6
-1
1
24.26. Found: C, 69.35; H, 6.42; N, 24.48.
3420, 3328 (NH ), 2208 cm (CN); H NMR (DMSO-d ): δ 2.01
2
6
(s, 3H, CH
), 2.25 (s, 3H, CH
), 6.35 (s, 1H,
3pyrazolyl C-5
3pyrazolyl C-3
1-(3′,5′-Dimethylpyrazol-1′-yl)-2-phenylhydrazonopropane (10).
pyrazole 4-H), 7.35-7.65 (m, 6H, arom. H), 8.72 (br s, 2H, NH ),
2
+
A mixture of 4 (1.52 g, 10 mmoles) and phenylhydrazine in
presence of acetic acid (1 ml) was heated at 120° for 10 minutes.
The reaction mixture was triturated with ethanol, the solid prod-
uct, so formed, was collected by filtration and crystallized from
ethanol to give yellow crystals; yield: 2.17 (90%), mp 128-129°;
9.65 (s, 1H, OH); ms: m/z304 (M ).
Anal. Calcd. for C
H N O (304.34): C, 71.03; H, 5.30; N,
18 16 4
18.41. Found: C, 57.19; H, 7.88; N, 25.30.
2-(3',5'-Dimethylpyrazol-1'-yl)-1-phenylbutene-3-one (15).
-1
1
ir: 3238 cm (NH); H NMR (DMSO-d ): δ 1.89 (s, 3H,
To a solution of 4 (1.52 g, 10 mmoles) in dioxan (30 ml),
benzaldehyde (1.06 g, 10 mmoles) was added in the presence of
few drops of piperidine. The reaction mixture was heated under
reflux for 15 minutes. The solvent was reduced under vacuum,
diluted with water and acidified with dilute HCl. The solid
product obtained was collected by filtration and crystallized from
ethanol as yellow crystals; yield: 1.99 g (83%), mp 123-124°; ir:
6
CH
), 2.52 (s, 3H, CH
), 2.65 (s, 3H, CH ),
3pyrazolyl C-5
3pyrazolyl C-3 3
4.45 (s, 2H, CH ), 6.82 (s, 1H, pyrazolyl 4-H), 7.23-7.55 (m, 5H,
2
arom H.), 8.20 (br s, 1H, NH).
Anal. Calcd. for C
H N (242.32): C 69.39, H 7.49, N 23.12;
14 18 4
found C 69.19, H 7.60, N 23.30.
3-(3',5'-Dimethylpyrazol-1'-yl)-2-methylindole (11).
-1
1
1710 cm (CO); H NMR (DMSO-d ): δ 2.05 (s, 3H,
6
A mixture of compound 4 (1.52 g, 10 mmoles) and phenyl-
hydrazine hydrochloride (1.44 g, 10 mmoles) in dioxane (30 ml)
was heated for 5 hours. The solvent was evaporated under
vacuum and crystallized from ethanol as brown crystals; yield:
CH
), 2.35 (s, 3H, CH
), 2.65 (s, 3H, CH ),
3pyrazolyl C-5
3pyrazolyl C-3 3
5.67 (s, 1H, olefinic-H), 6.35 (s, 1H, pyrazolyl 4-H), 7.25-7.68
+
(m, 5H, arom. H). ms: m/z 240 (M ).
Anal. Calcd. for C
H N O (240.29): C, 74.97; H, 6.71; N,
15 17 2
-1
1
1.80 g (80%), mp 259-260° ; ir: 3.210 cm (NH); H NMR
(DMSO-d ): δ 2.02 (s, 3H, CH ), 2.19 (s, 3H,
11.66. Found: C, 74.66; H, 6.97; N, 11.61.
6
3pyrazolyl C-5
CH
), 2.21 (s, 3H, CH
), 6.04 (s, 1H, pyra-
3pyrazolyl C-3
3 indolyl C-2
REFERENCES AND NOTES
zolyl 4-H), 6.99-7.38 (m, 4H, arom. H.), 11.33 (br s, 1H, NH).
Anal. Calcd. for C N (225.28): C, 74.64; H, 6.71; N,
H
14 15
3
[1] M. Kolb, Synthesis, 171 (1990).
[2] F. Al-Omran, A. A. El-Khair and M. H. Elnagdi, Org. Prep.
Proced. Int., 30, 211 (1998).
[3] Y. Matsuda, S. Ide, K. Furuno, T. Itou, C. Motokawa and
Y. Chiyomaru, Tetrahedron, 49, 9947 (1993).
[4] A. A. Al-Naggar, M. M. Abdel-Khalik and M. H. Elnagdi,
J. Chem. Research (S) 648-649 (1999), (M) 2801 (1999).
18.65. Found: C, 74.66; H, 6.67; N, 18.67.
1-(3',5'-Dimethylpyrazol-1'-yl)-N-acetylformamide (13).
To a cold solution of 4 (1.52 g, 10 mmoles) in (30 ml) acetic
acid, a solution of sodium nitrite was added (0.7 g, 10 mmoles)
was added drop wise at 0° . The reaction mixture was left

May-Jun 2001
689
Studies with Functionally Substituted N-Alkylazoles
[5] M. H. Elnagdi, M. M. Abdel-Khalik and S. M. Agami,
Synthesis, 1166 (2000).
[10] M. H Elnagdi, F. M. Abdelrazek, N. S. Ibrahim and
A. W. Erian, Tetrahedron, 45, 3597 (1989).
[6] F. Al-Omran, N. Al-Awadi, O. Yousef and M. H. Elnagdi,
J. Heterocyclic Chem., 3,167 (2000).
[11] M. H. Elnagdi, F. A. Abdul-Aal, N. M. Taha and Y. M. Yassin,
Z. Naturforsch, 45b, 389 (1990).
[7] S. M. Desenko, S. A. Komykhov, V. D. Orlov and H. Meier,
J. Heterocyclic Chem., 35, 989 (1998).
[8] J. Quiroga, B. Insuasty, S. Craz, P. Hernandez, A. Bolafios,
R. Moreno, A. Hormoza and R. H. de Almeidas, ibid., 35, 1333 (1998).
[9] A. R. Katritzky, Handbook of Heterocyclic Chemistry,
Pergamon Press. 101 (1985).
[12] S. El-Kousy, I. El-Sakka, H. R. El-Torgoman and
M. H. Elnagdi, Collect. Czech. Chem. Commun., 55, 2977 (1990).
[13] M. H. Elnagdi, A. M. Negm and A. W. Erian, Liebigs Ann.
Chem., 1255 (1989).
[14] F. Al-Omran, M. M. Abdel-Khalik, H. Al-Awadi and
M. H. Elnagdi, Tetrahedron, 52, 11915 (1996).