Reactions under Pressure: Synthesis of Functionally Substituted Arylhydrazonal Derivatives as Precursors of Novel Pyridazines and Nicotinates

Article abstract of DOI:10.1134/S1070363220040234

Abstract: Q-tube assisted multicomponent synthesis of novel arylhydrazonals, pyridazines and nicotinates has been explored. The target molecules have been prepared via one pot reaction of arylhydrazonals with activated methylene nitriles in either ethanol

Full text of DOI:10.1134/S1070363220040234

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 4, pp. 710–719. © Pleiades Publishing, Ltd., 2020.
Reactions under Pressure: Synthesis of Functionally Substituted
Arylhydrazonal Derivatives as Precursors
of Novel Pyridazines and Nicotinates
K. M. Al Zaydia,b,*, M. A. Al-Johania,c, N. F. Alqahtania,b, S. M. Mousallya,b, and N. Hilmy Elnagdid
a Department of Chemistry, Faculty of Sciences–AL Faisaliah, King Abdulaziz University, Jeddah, 21533 Saudi Arabia
b Chemistry Department, Faculty of Sciences, University of Jeddah, Jeddah, 21589 Saudi Arabia
c College of Science at Yanbu–Taibah University, Almadinah Almunawarah, Almadinah, 41477 Saudi Arabia
d Faculty of Pharmacy, Modern University for Technology and Information, Cairo, 11571 Egypt
*e-mail: kmalzaydi@uj.edu.sa
Received February 17, 2020; revised April 3, 2020; accepted April 10, 2020
Abstract—Q-tube assisted multicomponent synthesis of novel arylhydrazonals, pyridazines and nicotinates has
been explored. The target molecules have been prepared via one pot reaction of arylhydrazonals with activated
methylene nitriles in either ethanolic piperidine, dimethyl acetylene dicarboxylate (DMAD), 1,4-diazobicyclo[2.2.2]-
octane (DABCO), or Ph3P under pressure. Such conditions make reaction time much shorter and yields higher as
compared with those conducted under conventional conditions. The structures of products have been determined
by X-ray crystallography and spectroscopic methods.
Keywords: arylhydrazonals, Q-tubes, pyridazines, nicotinates, reactions under pressure, green chemistry
DOI: 10.1134/S1070363220040234
INTRODUCTION
300 NMR spectrometer using CDCl3 or DMSO-d6 as
solvents. Chemical shifts were referenced to the solvent
signals. IR and NMR spectral data were collected at
the Micro analytical Center, Cairo University, Egypt.
Elemental analysis was carried out on a Perkin–Elmer
2400 Analyzer. Mass spectra were measured on a MS-
5988 GS-MS Hewlett–Packard spectrometer, EI technique
at 70 eV. Elemental analysis and MS were carried out at
the Regional Center for Mycology and Biotechnology,
Al-Azhar University, Cairo, Egypt. X-ray crystallography
analysis was carried out on a Kappa CCD Enraf Nonius
FR 590 diffractometer at the National Research Center,
Dokki, Cairo, Egypt. Microwave irradiation experiments
were carried out using a Monowave 300 single-mode
Anton Paar GmbH microwave reactor. Ultrasonication
was carried out with a microprocessor controlled-2004,
high-intensity ultrasonic processor (750 W). Q-Tube-
assisted reactions were performed in a Q-tube-safe
pressure reactor, Q Labtech.
Reactions under pressure in Q-tubes have proven to be
a faster and cleaner approach to chemical transformations
thus addressing most of the green chemistry principles
[1]. To date, there are more than 50 papers devoted to the
successful use of high pressure processes in Q-tubes [2].
In this study, we have developed a new general approach
to synthesis of functionally substituted 2-arylhydrazonals
3 as precursors for biologically active pyridazine and
nicotinate derivatives utilizing Q-tubes. Their reactivity
with malononitrile, ethyl 2-cyanoacetate and 3-oxo-3-
phenylpropanenitrile under pressure in ethanol/piperidine
and dimethylacetylenedicarboxylate (DMAD) in the
presence of DABCO or Ph3P is studied. The products
formed under pressure have been compared with those
formed upon conventional heating, microwave or
ultrasound irradiation.
EXPERIMENTAL
Melting points were measured on a Gallenkamp
Electrothermal melting point apparatus and are
uncorrected. IR spectra were recorded on an 80486-pc
FTIR Shimadzu spectrophotometer using KBr pellets.
NMR spectra were measured on a Varian Mercury VX-
General procedure for arylhydrazonals 3j, 3k, 3l,
3m. Cold solutions (0–5°C) of compounds 2a–2d were
prepared by adding cold solution of sodium nitrite (1 g
in 10 mL of H2O) to cold solution of 10 mmol of aryl
amine 2Aa–2Ad in 5 mL of conc. HCl upon stirring.
710

REACTIONS UNDER PRESSURE: SYNTHESIS OF FUNCTIONALLY SUBSTITUTED
711
The corresponding crude product was added to cold
solution of (10 mmol, 1.32 g) 4,4-dimethoxybutanone
16 in ethanol–sodium acetate mixture (50 mL EtOH,
added to 1 g sodium acetate dissolved in 10 mL H2O).
The mixture was stirred at room temperature for 1 h, and
the solid precipitate was filtered off and crystallized from
EtOH to give the corresponding pure product.
of 10 mmol of the appropriate arylhydrazonal derivative
3a–3g with 10 mmol of an activated methylene nitrile
derivative 8a–8c, piperidine (5 drops) and 10 mLof EtOH
was added into a 35-mL pressure Q-tube furnished by Q
Labtech. A Teflon septum was placed on top of the tube,
and the tube was capped. The mixture was heated in an
oil bath at 160°C for 0.5–3 h. The solid product formed
was filtered off and crystallized from EtOH.
3-Oxo-2-(2-phenylhydrazono)butanal (3j). Yield
62%, mp126–127°C. IR spectrum, ν cm–1: 3439 (NH),
3025 (CH, aromatic), 2929 (CH aliphatic), 2865 (CH,
aldehyde), 1668 (C=O aldehyde), 1641 (C=O ketone).
1H NMR spectrum, δ, ppm: 2.31, 2.33, 2.39 (6H, 2CH3),
7.24–7.56 (4H,Ar-H), 9.44, 9.92 (1H, CHO), 14.13, 14.4
(1H, NH). 13C NMR spectrum, δC, ppm: 116.61, 116.72,
120.68, 120.72, 125.98, 126.11, 129.48, 132.14, 141.25,
186.90, 189.56, 196.19. Found, %: C, 63.10; H, 5.35; N,
14.70. C10H10N2O2. Calculated, %: C, 63.15; H, 5.30; N,
14.73. M 190.20.
6-Benzoyl-3-oxo-2-(4-methylphenyl)-2,3-dihydro-
pyridazine-4-carbonitrile (17b). Yield 99%, mp 106°C.
IR spectrum, ν cm–1: 2220 (CN), 1659, 1590 (C=O). 1H
NMR spectrum: δ, ppm: 2.34 (3H, CH3), 7.29–8.02 (9H,
Ar-H), 8.56 (1H, pyridazine H-5). Found, %: C 71.9; H
4.2; N 13.4. C19H13N3O2. Calculated, %: C 72.37; H 4.16;
N 13.33. M 315.33.
6-(4-Chlorobenzoyl)-3-oxo-2-phenyl-2,3-dihydro-
pyridazine-4-carbonitrile (17g). Yield 97%, mp
210–212°C. IR spectrum, ν, cm–1: 2235 (CN), 1690,
1651 (C=O). 1H NMR spectrum, δ, ppm: 7.49–8.04 (9H,
Ar-H), 8.76 (1H, pyridazine H-5). 13C NMR spectrum,
δ, ppm: 113.58, 115.19, 125.58, 128.56, 128.92, 129.24,
132.32, 133.44, 138.43, 138.61, 140.44, 141.27, 156.12,
186.99. Found, %: C 64.30; H 3.98; Cl 11.01; N 12.32.
C18H10ClN3O2. Calculated, %: C 64.39; H 3.00; Cl, 10.56;
N 12.52. M 235.74.
3-Oxo-2-[2-(4-methylphenyl)hydrazono]butanal
(3k). Yield 62%, mp 112–113°C. IR spectrum, ν, cm–1:
3435 (NH), 3019 (CH, aromatic), 2922 (CH, aliphatic),
2856 (CH, aldehyde), 1666 (C=O, aldehyde), 1634
1
(C=O, ketone). H NMR spectrum: δ, ppm: 2.31, 2.33,
2.39 (6H, 2CH3), 7.28–7.55 (4H, Ar-H), 9.44, 9.91 (1H,
CHO), 14.2, 14.5 (1H, NH). Found, %: C 64.70; H 5.89;
N 13.69. C11H12N2O2. Calculated, %: C 64.69; H 5.92;
N 13.72. M 204.23.
2-Oxo-6-phenyl-5-(phenyldiazenyl)-1,2-dihyd-
ropyridine-3-carbonitrile (18a). Yield 98%, mp 119–
120°C. IR spectrum, ν, cm–1: 3434 (NH), 2229 (CN),
2-[2-(4-Nitrophenyl)hydrazono]-3-oxobutanal (3l).
Yield 91%, mp 172°C. IR spectrum, ν, cm–1: 3441 (NH),
3079 (CH, aromatic), 2924 (CH, aldehyde), 1671 (C=O,
1
1635(C=O). H NMR spectrum, δ, ppm: 7.54–7.86
(10H, 9Ar-H and NH), 8.51 (1H, pyridine H-4). 13C
NMR spectrum, δ, ppm: 114.64, 120.65, 122.84, 127.91,
129.52, 130.10, 131.21, 131.84, 132.61, 136.05, 139.51,
151.87, 157.97, 162.85. Found, %: C 71.87; H 4.2; N
17.98. C18H12N4O. Calculated, %: C 71.99; H 4.03; N
18.66. M 300.31.
1
aldehyde), 1601 (C=O, ketone). H NMR spectrum: δ,
ppm: 2.35, 2.44 (3H, CH3), 7.28–8.31 (4H, Ar-H), 9.49,
9.96, 11.82 (1H, CHO), 13.89, 14.1 (1H, NH). 13C NMR
spectrum, δ, ppm: 24.17, 113.00, 116.71, 125.24, 125.75,
138.57, 140.70, 148.82, 187.52, 196.43. Found, %: C
51.12; H 3.80; N 17.9. C10H9N3O4. Calculated, %: C
51.07; H 3.86; N 17.87. M 235.20.
2-Oxo-6-(thiophen-2-yl)-5-[4-methylphenyl)di-
azenyl]-1,2-dihydropyridine-3-carbonitrile (18e).
Yield 96, mp 190–192°C. IR spectrum, ν, cm–1: 3433
2-[2-(4-Chlorophenyl)hydrazono]-3-oxobutanal
(3m). Yield 32%, mp 130°C. IR spectrum, ν, cm–1:
3444 (NH), 3081 (CH, aromatic), 2884 (CH, aldehyde),
1
(NH), 2225 (CN), 1629 (C=O). H NMR spectrum, δ,
ppm: 2.4 (3H, CH3), 7.21–8.16 (7H, 4Ar-H, 3H-thiophene
and NH), 8.39 (1H, pyridine H-4). Found, %: C 63.23;
H 4.05; N 17.67. C17H12N4OS. Calculated, %: C 63.73;
H 3.78; N 17.49. M 320.37.
1
1666 (C=O, aldehyde), 1634 (C=O, ketone). H NMR
spectrum: δ, ppm: 2.40, 2.513 (3H, CH3), 7.48–7.70 (4H,
Ar-H), 9.43, 9.93 (1H, CHO), 14.3 (1H, NH). Found,
%: C 53.51; H 4.2; Cl 15.70; N 12.36. C10H9ClN2O2.
Calculated, %: C 53.47; H 4.04; Cl 15.78; N 12.47. M
224.13.
6-(4-Chlorophenyl)-2-oxo-5-(phenyldiazenyl)-
1,2-dihydropyridine-3-carbonitrile (18g). Yield 98%,
mp 161–162°C. IR spectrum, ν cm–1: 3438 (NH), 2234
(CN), 1636 (C=O). 1H NMR spectrum, δ, ppm: 7.59–7.91
(10H, 9Ar-H and NH), 8.55 (1H, pyridine H-4). Found,
Generalprocedureofthereactionofarylhydrazonals
3 with activated methylene nitriles 8a–8c. A mixture
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AL ZAYDI et al.
%: C 63.23; H 4.31; Cl 11.03; N 17.21%. C18H11ClN4O.
Calculated, C 64.58; H 3.31; Cl 10.59; N 16.74. M 334.76.
A teflon septum was placed on top of the tube and it was
capped. The mixture was heated in an oil bath at 160°C
for 1 h. The solid product was filtered off and crystallized
from EtOH.
3-Benzoyl-5-(phenyldiazenyl)-6-(thiophen-2-yl)-
pyridin-2(1H)-one (19d). Yield 99%, mp 277–278°C.
IR spectrum, ν, cm–1: 3433 (NH), 1652, 1661 (2C=O).
1H NMR spectrum, δ, ppm: 7.29–8.00 (14H, 10Ar-H,
3H-thiopheneand NH), 8.20 (1H, pyridine H-4). Found,
%: C 68.40; H 4.05; N 11.04. C22H15N3O2S. Calculated,
%: C 68.55; H 3.92; N 10.90. M 385.44.
Dimethyl 6-benzoyl-2-(4-methylphenyl)-2,3-
dihydropyridazine-3,4-dicarboxylate (27b) (method
3). Yield 89%, mp 148–150°C. IR spectrum, ν, cm–1:
3066 (CH aromatic), 2951 (CH aliphatic), 1757, 1704
1
(2C=O ester), 1630 (C=O ketone). H NMR spectrum,
δ, ppm: 2.30 (3H, CH3), 3.66, 3.84 (3H, 2OCH3), 6.22
(1H, pyridazine H-3), 7.22–7.91 (9H, Ar-H), 7.60 (1H,
pyridazine H-5). 13C NMR spectrum, δ, ppm: 20.33,
52.60, 53.15, 116.84, 118.11, 121.65, 128.09, 129.82,
129.98, 132.37, 135.17, 136.67, 139.27, 141.84, 164.29,
168.15, 184.20. Found, %: C 67.44; H 4.95; N 7.88.
C22H20N2O5. Calculated, %: C 67.34; H 5.14; N 7.14.
M 392.40.
3-Benzoyl-6-(thiophen-2-yl)-5-[(4-methylphenyl)-
diazenyl]pyridin-2(1H)-one (19e). Yield 99%, mp
162–163°C. IR spectrum, ν, cm–1: 3434 (NH), 1664,
1
1587 (2C=O). H NMR spectrum, δ, ppm: 2.4 (3H,
CH3), 7.28–7.95 (13H, 9Ar-H, 3H-thiopheneand NH),
8.18 (1H, pyridine H-4). Found, %: C 69.87; H 3.99; N
11.04. C23H17N3O2S. Calculated, %: C 69.15; H 4.29; N
10.52. M 399.46.
Dimethyl-6-benzoyl-2-(4-nitrophenyl)-2,3-dihyd-
ropyridazine-3,4-dicarboxylate (27c) (method 3). Yield
80%, mp 172–174°C. IR spectrum, ν, cm–1: 3081 (CH
aromatic), 2953 (CH aliphatic), 1740, 1713 (2C=O ester),
3-Benzoyl-6-(4-chlorophenyl)-5-(phenyldiazenyl)-
pyridin-2(1H)-one (19g). Yield 98%, mp 148–149°C. IR
1
spectrum, ν, cm–1: 3429 (NH), 1649, 1583 (2C=O). H
NMR spectrum, δ, ppm: 7.56–7.96 (15H,Ar-H and NH),
8.24 (1H, pyridine H-4). Found, %: C 68.98; H 4.05; Cl
8.98; N 10.04. C24H16ClN3O2. Calculated, %: C 69.65;
H 3.90; Cl 8.57; N 10.15. M 413.86.
1
1637 (C=O ketone). H NMR spectrum, δ, ppm: 3.67,
3.87 (3H, 2OCH3), 6.38 (1H, pyridazine H-3), 7.58–8.29
(10H, Ar-H and H-5 pyridazine). Found, %: C 60.04; H
3.98; N 8.21. C21H17N3O7. Calculated, %: C 59.57; H
4.05; N 9.93. M 423.38.
General procedure for the reaction of arylhyd-
razonal derivatives 3 with DMAD. Method 1 (Δ).
A mixture of 10 mmol of Ph3P (2.6 mL) or DABCO
(1.12 mL) with 10 mmol of an appropriate compound 3b,
3c, 3g, 3h in CH2Cl2 (10 mL) was stirred in a stoppered
flask for 2 h at room temperature, then 10 mmol of DMAD
(1.24 mL) in CH2Cl2 (10 mL) were added, and the mixture
was stirred for 24-48 h at room temperature. The solvent
was evaporated, and the resulting solid product was
filtered off, washed with EtOH, dried and crystallized
from EtOH to give the corresponding pure compound
27b, 27c, 27g, 27h.
Dimethyl-6-(4-chlorobenzoyl)-2-phenyl-2,3-dihyd-
ropyridazine-3,4-dicarboxylate (27g) (method 3). Yield
87%, mp 171–172°C. IR spectrum, ν, cm–1: 3024 (CH
aromatic), 2954 (CH aliphatic), 1744, 1707 (2C=O ester),
1
1642 (C=O ketone). H NMR spectrum, δ, ppm: 3.66,
3.85 (3H, 2OCH3), 6.28 (1H, pyridazine H-3), 7.27–7.94
(10H, Ar-H and H-5 pyridazine). 13C NMR spectrum, δ,
ppm: 20.33, 52.60, 53.15, 116.84, 118.11, 121.65, 128.09,
129.82, 129.98, 132.37, 135.17, 136.67, 139.27, 141.84,
164.29, 168.15, 184.20. Found, %: C 61.56; H 4.43; Cl
8.43; N 6.98. C21H17ClN2O5. Calculated, %: C 61.10; H
4.15; Cl 8.59; N 6.79. M 412.82.
Method 2 (ultrasound). A mixture of 10 mmol of an
appropriate compound 3b, 3c, 3g, or 3h with 10 mmol
of Ph3P (2.6 mL) or DABCO (1.12 mL) and 10 mmol
of DMAD (1.24 mL) in 50 mL of CH2Cl2 was heated
under US at 40°C for 3 h and then cooled down to room
temperature. The solid product was filtered off and
crystallized from EtOH.
Dimethyl-6-(4-chlorobenzoyl)-2-(4-methylphenyl)-
2,3-dihydropyridazine-3,4-dicarboxylate (27h)
(method 3). Yield 92%, mp 124-–25°C. IR spectrum,
ν, cm–1: 3080 (CH aromatic), 2955 (CH aliphatic),
1742, 1715 (2C=O ester), 1631 (C=O ketone). 1H NMR
spectrum, δ, ppm: 2.31 (3H, CH3), 3.66, 3.84 (3H,
2OCH3), 6.22 (1H, pyridazine H-3), 7.24–7.92 (9H,Ar-H
and H-5 pyridazine). Found, %: C 62.02; H 4.39; Cl 8.89;
N 6.78. C22H19ClN2O5. Calculated, %: C 61.90; H 4.49;
Cl 8.31; N 6.56. M 426.85.
Method 3 (Q-tube). A mixture of 10 mmol of a
compound 3b, 3c, 3g, 3h with 10 mmol of Ph3P (2.6 mL)
or DABCO (1.12 mL) and 10 mL of CH2Cl2 was added
into a 35-mL pressure Q-tube furnished by Q Labtech.
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REACTIONS UNDER PRESSURE: SYNTHESIS OF FUNCTIONALLY SUBSTITUTED
713
Scheme 1. Reported reactions of 2-arylhydrazonals 3 as precursors for preparation of heterocyclic compounds.
O
+
ArN N Cl–
+
O
H2N
R
X
O
2
R
1
N
HO
X
N
O
Ar
O
Ar
12A
(75ꢀ80%)
Ac2O/'
O
X
NH2OH·HCl
AcOH/ NH4OAc
CHO
O
N
R
4b
X
'
R
DABCO
N
N
N
N
N
3
NHAr
Ar
X
10
2
H
C
l
O
C
Ar
5
Y
X
R
(79ꢀ95%)
6
C N
X
O
N
X
Y
X
N
R
8
N
Ar
N
X = CN
Ar
7
9
OH
N
O
O
O
NH2
X
X
O
N
X
X
R
X
HN
R
N
N
N
R
N
N
NH
R
R
Ar
NAr
N
Ar
NAr
N
NAr
11
12
13
14
15
R = CH3 (1, 3, 5, 7, 9, 11–15); Ar = C6H5 (2, 3, 5, 7, 9, 10, 11–15);
X = COOEt (4a, 5a, 11a–15a), CN (4b, 5b, 8b, 9, 11b–15b), COOMe (6, 7, 8a);
Y = COOMe (6, 7).
RESULTS AND DISCUSSION
under the mentioned reaction conditions [5].Asubsequent
article [6] proved that compound 9 was formed in
the reaction of 3 with activated methylene nitriles.
The structure of the product was based on its X-ray
crystallography [6]. It was suggested that compound 12
was formed upon the reaction carried out in the presence
of an excess of NH4OAc [7]. All these approaches
confirmed that the reaction of arylhydrazonal derivatives
3 with activated methylenes was highly dependent on the
process conditions. This has encouraged us to explore
Al-Awadi et al. [3] prepared 6-aroylpyridazine 5 by
heating arylhydrazonals 3 with acrylonitrile or methyl
vinyl ketone in the presence of DABCO utilizing MW
irradiation without solvents (Scheme 1). It was previously
suggested that the compound 13 could be formed upon
treatment of 3 with ethyl cyanoacetate in the presence
of a mixture of acetic acid and ammonium acetate [4].
Later, this assumption was found to be false, as actually
pyridazinones 12 or arylazonicotinates 15 were formed
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714
AL ZAYDI et al.
Scheme 2. Possible conformations of arylhydrazonals 3 (3A: E-form, 3B: Z-form, 3C: enol form, 3D and 3E: two tautomeric
forms of the anti-structure).
H
O
O
H
N
R
N
R
O
O
CHO
N
R
O
H
NH
O
H
R
OH
Ar
3D
N
N
N
N
O
H
X
X
R
O
X
3C
3B
Z-form
3A
E-form
+
N
NH
Ar
3E
R = CH3 (3A–3E); Ar = C6H5 (3D, 3E); X = COOEt, CN (3A–3C).
chemical processes of arylhydrazonal derivatives 3 under
specific conditions under pressure in Q-tubes.
derivatives, we first explored 4,4-dimethoxybutan-
2-one or 3,3-dimethoxy-1-phenylpropan-1-one 16
as starting materials instead of enaminones 1a–1c.
Thus, coupling of 16 with aromatic diazonium salts
2a–2d afforded compounds 3j–3m in moderate yields
(Scheme 3). The obtained coupling products were
To develop a new general approach to synthesis of
functionally substituted 2-arylhydrazonals 3 utilizing
green and economically sound methods as precursors
for biologically active pyridazines and nicotinate
1
characterized by IR, H and 13C NMR spectra. Crystal
structure of 3b was approached by X-ray analysis.
Although compounds 3a–3m had been previously
mentioned (Fig. 1) as intermediates in equilibrium
between 3A and 3B, 1H NMR spectra of compounds 3j,
3k, 3m in DMSO-d6 demonstrated two signals at 9.9
and 9.4 ppm with the total integration of one proton,
which indicated an equilibrium mixture between E- (3A)
and Z-forms (3B) for these compounds, accordingly
1
(Scheme 2). Their H NMR spectra demonstrated a
signal at 14.13–14.4 ppm for NH proton. Two singlets at
2.48 and 2.51 ppm with a total integration of 3H indicated
presence of the CH3 group in the equilibrium between
Z- and E-forms.
On the other hand, 1H NMR spectrum of compound
3l contained three signals at 9.4, 9.9, and 11.8 ppm
with total integration of 1H indicating an equilibrium
mixture of the E- (3A), Z- (3B) and the enol forms (3C),
accordingly. Energy measurements for these compounds
suggested that the direct transformation of structure E
into Z required rotation around the double bond, which
was almost impossible. The indirect transformation
from E to Z could be possible via three steps starting
Fig. 1. X-Ray structure of (E)-3-oxo-2-(2-phenylhydrazono)-
butanal (3j) [8].
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REACTIONS UNDER PRESSURE: SYNTHESIS OF FUNCTIONALLY SUBSTITUTED
715
Scheme 3. Synthesis of substituted 2-arylhydrazonals 3j–3m.
NH2
X
2A
NaNO2/HCl
0qC
ꢁ
O
OMe
OMe
O
N{N Clꢀ
H3C
R
NMe2
16
R = Ph (1a), p-ClC6H4 (1b),
2-thienyl (1c)
X
2aꢀ2d
O
CHO
R
N
H
N
X
3aꢀ3m
2A: X = H (a), CH3 (b), NO2 (c), Cl (d); 3: X = H (a, d, g, j), CH3 (b, e, h, k), NO2 (c, f, i, l); R = Ph (a–c),
2-thienyl (d–f), p-ClC6H4 (g–i), CH3 (j–m).
with proton shift to structure 3C with an energy barrier
of –8.786 kcal/mol, which was higher than the thermal
barrier of free rotation, followed by two other rotations
around the single bonds. These results indicated that the
solid crystalline form could have only one conformer,
either E or Z, but not a mixture. X-Ray crystal study of
the compound demonstrated that the anti-structure (3D)
was the sole product of that reaction. In fact, the above
was supported by stereoelectronic requirements that could
be met only that way.
The next stage of the study was devoted to reactivity of
arylhydrazonal derivatives 3 toward malononitrile, ethyl
acetoacetate and malononitrile in Q-tubes. According
to the accumulated data, under pressure the reaction
was directed either to formation of the product 12 or 15
depending on the type of active methylene reagent 8.
Compound 3 could be condensed with malononitrile
in a Q-tube that made it possible to carry out various
types of accelerated reactions that appeared to be more
favorable than MW or conventional heating (Scheme 4).
The products obtained in a Q-tube were different from
those obtained in the reactions at ambient pressure
(Table 2). The reaction of compounds 3 with
benzoylacetonitrile afforded products 19 that were
The bond lengths indicated nitrogen lone pair
delocalization. The bond angles of N2, N4, C10, C6, and
O1 suggest their hybridization close to sp2 (Table 1).
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AL ZAYDI et al.
Table 2. High pressure synthesis data of compounds 17–19
Table 1. Selected bond lengths and angles for 3b
Bond
O1–C6
N2–N4
N2–C11
O3–C18
N4–C10
d, Å
Angle
φ, deg
119.7
120.4
Compound
Time, min
Yield, %
75
1.228
1.309
1.418
1.221
1.320
N4–N2–C11
N2–N4–C10
17b
60
30
60
60
60
60
60
60
17g
18a
18e
18g
19d
19e
19g
73
88
86
88
89
different from the products obtained by Bahbahani (12A)
upon heating [10]. According to X-ray crystallography
of compounds 17, despite the sterical congestion of the
conformation, the product again adopted the structure that
followed the stereoelectronic requirements [9]. Scheme 5
presents a suggested mechanism of the reaction of 3 with
activated methylene reagents 8 under pressure in Q-tubes.
89
88
The reaction of 2-arylhydrazonal derivatives 3b, 3c,
3g, 3h with DMAD carried out in the presence of Ph3P or
DABCO as a catalyst in CH2Cl2 at room temperature for
24–48 h, or under ultrasonication or in Q-tube afforded the
Scheme 4. Syntheses of arylazonicotinates 18a, 18e, 18g, pridazinones 17b, 17g and arylazonicotinates 19d, 19e, 19g under
high pressure.
O
CHO
R
N
CN
NH
H2C
+
Y
8aꢀ8c
X
3a, 3b, 3d, 3e, 3g
EtOH, pip
Q-tube
8a
8c
8b
O
R
R
NH
CN
O
NH
R
O
N
N
N
O
N
N
X
N
X
COPh
CN
18a, 18e, 18g
19d, 19e, 19g
X
17b, 17g
Y = COOEt (8a), COPh (8b), CN (8c); R = Ph (3a, 3b, 17b, 18a), 2-thienyl (3d, 3e, 18e, 19d, 19e),
p-ClC6H4 (3g, 17g, 18g, 19g); X = H (3a, 3d, 3g, 17g, 18a, 18g, 19d, 19g), CH3 (3b, 3e, 17b, 18e, 19e).
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REACTIONS UNDER PRESSURE: SYNTHESIS OF FUNCTIONALLY SUBSTITUTED
717
Scheme 5. A suggested mechanism of the reaction of 3 with active methylene reagents 8 under pressure.
CN
NC
X
O
H2C
X
3
R
EtOH, pip
Q-tube
N-NHAr
20
NH
OH
O
N
NH
N
NH2
X
X
X
X
X = CO2Et, COPh
Dimroth
H2N
R
X = CN
NH4OAc
ꢀH2O
O
HN
N
R
R
R
N
N
N
NAr
NAr
NAr
Ar
14
22
15
21
X = CN (14, 22), COOEt, COPh (15), H (20, 21).
corresponding 2,3-dihydropyridazine-3,4-dicarboxylates
27b, 27c, 27g, 27h. We believe that the reaction
proceeded via the initial addition of Ph3P to DMAD with
formation of 23 followed by attack at the formyl carbonyl
group of 24, cyclization of which via intermediates 25
and 26 gave the end product (Scheme 6). The above
speculations supported the fact that application of US
and a Q-tube played a decisive role in the rapid synthesis
of dihydropyridazine-3,4-dicarboxylates 27b, 27c, 27g,
27h (Table 3). The structures of these compounds were
elucidated from their spectral data. The same reaction
under US irradiation at 70°C proceeded faster (3 h) than
under conventional method. The same compounds were
also synthesized in a Q-tube at 160°C in only 1 h.
CONCLUSIONS
Condensation of aryl hydrazonal derivatives 3 with
malononitrile, ethyl cyanoacetate and benzoyl acetonitrile
under pressure generally proceeds much faster and/or with
higher yields than under conventional heating or upon
ultrasonication. Pressure favors formation of transition
states corresponding to the lowest activation volumes.
Products of condensation of benzoylacetonitrile and
malononitrile with 3 under pressure are different from
those accumulated under conventional heating in open
tubes. The approach to the reaction of 2-arylhydrazonals
3 with DMAD in the presence of Ph3P or DABCO at
room temperature either upon ultrasonication or under
Table 3. Comparison of synthesis of compounds 27b, 27c, 27g, 27h under conventional heating, ultrasonication and in a Q-tube
Conventional method (room temperature)
Ph332P
DABCO
Ultrasonication (70°C)
Ph3P DABCO
Q-tube (160°C)
Ph3P or DABCO
Product
time, h yield, % time, h yield, % time, h yield, % time, h yield, % time, h yield, %
27b
27c
27g
27h
24
24
24
24
50
60
77
92
30
44
48
48
54
83
98
98
3
3
3
3
60
75
69
70
3
3
3
3
79
80
89
90
1
1
1
1
89
80
87
92
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718
AL ZAYDI et al.
Scheme 6. Probable mechanism of 2-arylhydrazonal derivatives 3b, 3c, 3g, 3h reaction with DMAD in the presence of Ph3P or
DABCO in a Q-tube.
CO2Me
CO2Me
CH2Cl2
Ph3P
O
CHO
NH
R
ꢀ
O
O
CO2Me
N
room temperature
or US or Q-tube
CO2Me
ꢁ
ꢀ
R
PPh3
ꢁ
ꢁ
N
CO2Me
MeO2C
PPh3
NH
X
23
3b, 3c, 3g, 3h
X
24
PPh3
O
O
O
R
CO2Me
CO2Me
R
CO2Me
CO2Me
N
N
NH
NH
X
X
26
25
Carbene
insertion
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
R
R
R
HN
N
N
N
N
X
N
X
X
28
29
27
R = Ph (3b, 3c), p-ClC6H4 (3g, 3h); X = CH3 (3a, 3h), NO2 (3b), H (3c).
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REACTIONS UNDER PRESSURE: SYNTHESIS OF FUNCTIONALLY SUBSTITUTED
719
vol. 64, p. 8202.
pressure confirms higher efficiency of the latter factor in
https://doi.org/10.1016/j.tet.2008.06.026
the synthesis of substituted dihydropyridazine derivatives.
4. Zaky, O.S., Moustafa, M.S., Selim, M.A., El-
Maghraby, A.M., and Elnagdi, M.H., Molecules, 2012,
vol. 17, no. 5, p. 5924.
FUNDING
This project was funded by the Deanship of Scientific
Research (DSR) at King Abdulaziz University, Jeddah, under
grant no. 2-363-36-RG. The authors, therefore, acknowledge
with thanks DSR technical and financial support.
https://doi.org/10.3390/molecules17055924
5. Moustafa, M.S., Al-Mousawi, S.M., and Elnagdi, M.H.,
RSC Adv., 2016, vol. 6, p. 90840.
https://doi.org/10.1039/C6RA19535K
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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