Solvent-free ring cleavage hydrazinolysis of certain biginelli pyrimidines

Article abstract of DOI:10.1155/2018/6354742

Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring opening upon solvent-free reaction with hydrazine hydrate to give three products: pyrazole, arylidenehydrazines, and urea/thiourea, respectively. The nonisolable carbohydrazide intermediates are formed firstly followed by the intermolecular nucleophilic attack of terminal amino group of hydrazide function on sp² C6 rather than the sp³ C4 to give the ring adduct which was produced as a final product.

Full text of DOI:10.1155/2018/6354742

Hindawi
Journal of Chemistry
Volume 2018, Article ID 6354742, 6 pages
https://doi.org/10.1155/2018/6354742
Research Article
Solvent-Free Ring Cleavage Hydrazinolysis of
Certain Biginelli Pyrimidines
1
2
3,4
Mohamed A. Said, Wagdy M. Eldehna , Hazem A. Ghabbour ,
5
3,6
7
Maha M. Kabil, Nasser S. Al-shakliah, and Hatem A. Abdel-Aziz
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Department of Infection Control, King Saud University Medical City, Riyadh, Saudi Arabia
2
3
4
5
6
7
Department of Pharmaceutical Chemistry, College of Pharmacy, Aden University, Aden, Yemen
Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt
Correspondence should be addressed to Hazem A. Ghabbour; haghabbour@ksu.edu.sa
Received 1 October 2017; Revised 28 February 2018; Accepted 8 March 2018; Published 17 April 2018
Academic Editor: Teodorico C. Ramalho
Copyright © 2018 Mohamed A. Said et al. ꢀis is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring opening upon solvent-free reaction
with hydrazine hydrate to give three products: pyrazole, arylidenehydrazines, and urea/thiourea, respectively. ꢀe nonisolable
carbohydrazide intermediates are formed ꢁrstly followed by the intermolecular nucleophilic attack of terminal amino group of
2
3
hydrazide function on sp C6 rather than the sp C4 to give the ring adduct which was produced as a ꢁnal product.
1
. Introduction
(Figure 1). ꢀis reaction was reported by Biginelli and Gazz
in 1893 and was then catalyzed by acids [14]. DHPMs can
be obtained by few other synthetic protocols [9, 15–17] and
several improvements were made to obtain good reaction
conditions and better yields [11, 18–27].
Pyrimidine derivatives Uracil and ꢀymine are an integral
part of RNA and DNA, respectively. Compounds with
pyrimidine scaꢂolds exhibit wide range of diverse phar-
macological actions [1, 2] and biological activities [3] such
as anti-HIV agent Stavudine [4], antibiotic Fervennuline
DHPMs could be developed with six diversity points (R ,
1
X, ꢁ , R , R and R ) [28] (Figure 1). When R = H, DHPMs
3
4
5,
6
1
4
[
5], antihypertensive drug Minoxidil [6], and antibacterial
ꢀ
could be alkylated at ꢁ [29] whereas the formylation or
1
drug Sulfamethazine [7]. Pyrimidines of Biginelli type (3,4-
dihydropyrimidines, DHPMs) showed a broad spectrum
of biological activities such as anticancer agent, Monastrol
acylation of ꢁ of ꢀ furnishes the ꢁ -formylated or ꢁ -
3
3
3
acylated derivatives [30]. DHPMs ꢀ (X = S) could be alkylated
in the presence of base [30]. With respect to R , the reaction
(
Figure 1) [8, 9]. ꢀe straight forward synthesis of DHPMs
works best with aromatic aldehydes [31]. On the other hand,
resulted in the discovery of many important agents such
as calcium channel modulators, adrenergic receptor antago-
nists, and mitotic kinesin inhibitors, in addition to anticancer,
anti-inꢃammatory, antimicrobial, and antioxidant activities
when R is an ester group, free carboxylic acids can be
5
produced [32–34]. Finally, when R = Me, it can be subjected
6
to bromination [35, 36]. To the best of our knowledge, there
are no reports concerned with the accessibility of C6 for
the nucleophilic reaction by hydrazine hydrate. However, C5
esters reacted with hydrazine hydrate, in ethyl alcohol and in
the presence of H SO , to give hydrazidesꢄ [37, 38] (Figure 1).
[9–13].
Synthesis of DHPMs (ꢀ) is carried out through the
reaction of urea/thiourea ꢁ, aldehyde ꢂ, and ꢀ-ketone ꢃ
2
4

2
Journal of Chemistry
OH
R
4
R２
5
5
X
O
H．3
O
２1
+
２4-CHO
+
２5
N（2
N
H
X
．1
２6
２6
HN
O
3
1
2
２1
4
S
N
H
Biginelli product
3
２1
,4-dihydropyrimidines (DHPMs)
4 = Monastrol; when
= （, alkyl
２1 = （
２4
= （, alkyl, aryl
２ = 3-OH-＃ （
4
6
4
２5
２6
８
= ？ster, acyl, amide, nitro, nitrile ２5 = ＃OOEt
= （, alkyl, aryl
２6 = －？
= ／, S, NR
８ = ３
Ar
O
Ar
O
H
N
N（2
N（2
HN
N
H
HN
N
H
S
X
N
H
X
N
H
5
6
Fꢄꢅꢆꢇꢈ 1: ꢀe structure of 3,4-dihydropyrimidinones (DHPMs) ꢀ, anticancer agent Monastrol, hydrazide ꢄ, and thiosemicarbazone ꢅ.
ꢀ
e reaction of C5 esters with thiosemicarbazide, in acetone,
to aꢂord thiosemicarbazones ꢅ is reported (Figure 1) [39].
e latter data stimulate our interest to investigate the
Spectra were recorded on a Varian Mercury NMR spectrome-
1
ter. H spectrum was run at 400 MHz in deuterated dimethyl-
ꢀ
sulfoxide (DMSO-ꢂ ). Chemical shiꢉs are expressed in
6
reactivity of C5 ester towards hydrazine hydrate under
solvent-free conditions which produce three diꢂerent ring
cleavage products. ꢀis unexpected result leads us to perform
further extensive survey in literature to discover the eꢂect of
hydrazine hydrate on pyrimidines other than DHPMs.
Interestingly, the reported ꢁndings revealed that the
hydrazinolysis of pyrimidine-2(1H)-one (ꢆa), 4-methylpyr-
imidin-2(1H)-one (ꢆb), or 4,6-dimethylpyrimidin-2(1H)-
one (ꢆc) resulted in the formation of 1H-pyrazole (ꢇa), 3-
methyl-1H-pyrazole (ꢇb) and 3,5-dimethyl-1H-pyrazole (ꢇc),
respectively, in addition to urea (ꢁa) in each case (Figure 2)
values (ppm) using the solvent peak as internal standard. All
coupling constant (ꢃ) values are given in hertz. ꢀe abbrevia-
tions used are as follows: s: singlet; d: doublet; m: multiplet.
2
.2. General Procedure for the Synthesis of Ethyl 6-Methyl-4-
(
substituted)phenyl-2-(oxo/thioxo)-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylates 4a–4h. To a solution of urea (ꢁa)/thiou-
rea (ꢁb) (0.050 mol), diꢂerent aromatic aldehydes ꢂa–ꢂd
(
0.075 mol), and ethylacetoacetate ꢃa (0.075 mol) in ethanol
(
35 mL), a catalytic amount of CaCl (0.020 mol) was added.
2
ꢀ
e reaction mixture was heated under reꢃux for 2 h, and the
[
40]. Furthermore, we found that the reaction of pyrim-
progress of reaction was monitored by TLC. Aꢉer reaction
completion, the reaction mass was cooled and treated with
crushed ice. ꢀen the precipitated solid was ꢁltered oꢂ,
crystallized using methanol/water mixture, and then dried to
give DHPMs ꢀa–h.
idines ꢈa and ꢈb (R = H, R = Me) with hydrazine hydrate
gave pyrazoles ꢁꢉa and ꢁꢉb whereas the 2,4-dioxo-1,2,3,4-
tetrahydropyrimidine-5-carbaldehyde ꢈc (R = -CHO) gave
pyrazole derivative ꢁꢉc (Figure 2) [41]. ꢀese facts showed the
2
reactivity of sp C6 of pyrimidines towards hydrazine hydrate
and, subsequently, the ring opening of pyrimidine moiety.
Recently, we reported a unique behavior of hydrazine
hydrate towards certain benzofurans to produce phenolic-
based pyrazoles [42]. We also identiꢁed malonohydrazide as
reaction product besides salicylaldehyde azine upon the
reaction of ethyl 2-oxo-2H-chromene-3-carboxylate with
hydrazine hydrate [43]. In the light of previous data and in
continuation of our interest in the chemistry of hydrazine
hydrate towards certain heterocycles [44–48], we aim herein
to study the solvent-free reaction of hydrazine hydrate on C5
ester Biginelli pyrimidines ꢀa–ꢀh (Figure 3).
2
.3. Te Reaction of DHPMs Esters 4a–h with Hydrazine
Hydrate in Ethanol. To a solution of DHPMs ꢀa–h (0.01 mol)
in ethanol (20 mL), hydrazine hydrate (0.03 mol) was added.
ꢀ
ꢀ
en the reaction mixture was heated under reꢃux for 6 h.
e reaction progression was monitored using TLC, which
indicated that no reaction occurred [37].
2
.4. General Procedure for the Neat Reaction of DHPMs Esters
4
a–4h with Hydrazine Hydrate. A mixture of DHPMs ꢀa–ꢀh
(
0.01 mol) and excess hydrazine hydrate (5 mL) was heated
under reꢃux for 6 h. ꢀe reaction mixture was allowed to
cool and poured on crushed ice. ꢀe obtained solid product
ꢁ
ꢅa–ꢁꢅd was ꢁltered, crystallized from ethanol, and ꢁnally
2
. Experimental
dried. ꢀe evaporation of the ꢁltrate gave solid residue which
upon fractional crystallization from water gave the pyrazole
ꢁꢃ and urea (ꢁa)/thiourea (ꢁb), respectively.
2
.1. General. Melting points were measured with a Stuart
1
melting point apparatus and were uncorrected. H NMR

Journal of Chemistry
3
R
R
O
HN
N
（ N-N（
+
H
2
2
N（2
N
H
N
N
H
２1
O
２1
1a
8
a–8c
a, ２ = ２ = （
1
b, ２ = －？, ２ = （
1
7
a–7c
c, ２ = ２ = －？
1
O
O
9
9
a, R = H
b, R = Me
R
H
H
HN
HN
0a, 10b
N
H
N
H
+
O
1a
1
H
O
R
（2
N-N（2
a, R = H
N
b, R = Me
N
H
O
O
9
c, R = -CHO
（ O
H
NH
N
H
N
−
2
9
a–9c
H
N
a, R = H
1
0c
b, R = Me
c, R = CHO
Fꢄꢅꢆꢇꢈ 2: ꢀe reported reactions of hydrazine hydrate with pyrimidines ꢆa–7c and ꢈa–9c.
2
.4.1. 3-Methyl-1H-pyrazol-5-ol (13). Yield: 42–55% (for ꢀa–
3. Results and Discussion
∘
∘
1
ꢀ
h); m.p. 221–223 C (Lit. [49] m.p. 220–222 C); H-NMR
In a typical experimental procedure a solution of urea (R = H,
(
1
DMSO-ꢂ ) ꢄ (ppm): 2.47 (s, 3H, -CH3), 6.83 (s, 1H, Ar-H),
6
X = O, ꢁa)/thiourea (R = H, X = S, ꢁb), aldehydes ꢂa–ꢂd (R =
0.07 (s, 1H, OH), 12.10 (s, 1H, NH).
4
Ph, 4-MeC H , 4-MeO-C H , 4-Cl-C H ), and ethyl ace-
6
4
6
4
6
4
toacetate (R = COOEt, R = Me, ꢃa) in absolute ethanol was
5
6
2
6
.4.2. Benzylidenehydrazine (16a). Yield: 62% (for ꢀa) and
heated under reꢃux in the presence of catalytic amount of
∘
∘
1
7% (for ꢀe); m.p. 89–91 C (Lit. [50] m.p. 90–92 C); H-NMR
CaCl to give the required DHPM derivatives ꢀa–ꢀh. ꢀen,
2
(
DMSO-ꢂ ) ꢄ (ppm): 5.37 (s, 2H, NH , D O-exchangeable),
6
2
2
we heated DHPM derivatives ꢀa–ꢀh with hydrazine hydrate
in ethanol under reꢃux (6 h) but we gave no reaction [54]. ꢀe
reaction of DHPM derivatives ꢀa–ꢀh with excess amount of
hydrazine hydrate, in absence of ethanol, under reꢃux for 6 h
showed the disappearance of Biginelli pyrimidines ꢀa–ꢀh on
TLC. ꢀe latter reaction gave three products, none of them
being the expected hydrazide ꢁꢁa–ꢁꢁh.
7
.38–7.41 (m, 3H, Ar-H), 7.64 (d, J = 8.0 Hz, 2H, Ar-H,), 7.71 (s,
1H, CH=N).
2
ꢀ
.4.3. 4-Methylbenzylidenehydrazine (16b). Yield: 58% (for
∘
∘
b) and 69% (for ꢀf); m.p. 58-59 C (Lit. [51] m.p. 55-56 C);
1
H-NMR (DMSO-ꢂ ) ꢄ (ppm): 2.21 (s, 3H, CH ), 5.31 (s, 2H,
6
3
NH , D O-exchangeable), 6.96 (d, J = 8.0 Hz, 2H, Ar-H), 7.56
2
2
ꢀe analyses of the isolated products established their
assigned structure as pyrazole ꢁꢃ, arylidenehydrazines
(
d, J = 8.4 Hz, 2H, Ar-H), 7.70 (s, 1H, CH=N).
ꢁ
ꢅa–ꢁꢅd, and urea/thiourea ꢁa and ꢁb (Figure 3).
2
ꢀ
.4.4. 4-Methoxybenzylidenehydrazine (16c). Yield: 60% (for
ꢀe previous conclusions encouraged us to suppose a
∘
∘
c) and 66% (for ꢀg); m.p. 161-162 C (Lit. [52] m.p. 168 C);
mechanism for ring opening of DHPMs by hydrazine hydrate
(Figure 3). ꢀis reaction proceeds through the formation of
1
H-NMR (DMSO-ꢂ ) ꢄ (ppm): 3.82 (s, 3H, OCH ), 5.36 (s,
6
3
2
H, NH , D O-exchangeable), 6.92 (d, J = 8.4 Hz, 2H, Ar-H),
2
2
nonisolable intermediate carbohydrazide ꢁꢁa–ꢁꢁh at C5 fol-
7
.54 (d, J = 8.4 Hz, 2H, Ar-H), 7.75 (s, 1H, -CH=N).
2
lowed by nucleophilic attack of -NH of hydrazide on sp C6
2
3
rather than the sp C4 to give the ring opening adducts
ꢁꢂa–ꢁꢂh which produce pyrazole ꢁꢃ as ꢁnal product in
addition to arylidene of urea/thiourea ꢁꢀa–ꢁꢀh as nonisolable
intermediate. Additional hydrazinolysis of ꢁꢀa–ꢁꢀh gave
arylidenehydrazines ꢁꢅa–ꢁꢅd and urea/thiourea ꢁa and ꢁb as
end products.
2
.4.5. 4-Chlorobenzylidenehydrazine (16d). Yield: 62% (for
∘
∘
ꢀ
d) and 70% (for ꢀh); m.p. 59–61 C (Lit. [53] m.p. 57-58 C);
1
H-NMR (DMSO-ꢂ ) ꢄ (ppm): 5.38 (s, 2H, NH , D O-
6
2
2
exchangeable), 7.31 (d, J = 8.4 Hz, 2H, Ar-H), 7.70 (d, J =
8
.4 Hz, 2H, Ar-H), 7.77 (s, 1H, -CH=N).

4
Journal of Chemistry
X
Ar
N
O
X
Ar
O
H
N
H
Ar
O
H
N
（2
N-N（
2
H
N
H
X
H
H
X
O
neat reaction
−
N
H
N
N
H
∙∙ H
∙∙NH
N
EtOH
H
N
H
H
H 4a–4h
12a–12h
1
1a–11h
4
a
b
c
d
e
f
g
h
Ar
Ph
4-Me-＃ （
4-MeO-＃ （
4-Cl-＃ （ )
6 4
Ph
4-Me-＃ （
4-MeO-＃ （
X
O
O
O
O
S
S
S
S
X
H Ar
O
H
6
4
H
6
4
4
N
N
H
NH
N
H
12a–12h (A)
6
4
6
4-Cl-＃ （ )
6
4
X
H
Ar
O
N
H
H
N
H
N
NH
H
1
2a–12h (B)
H
∙
∙
H
N（2
HN
∙∙
X
H
X
（2
N-N（
2
+
N
O
HN
H
N
Ar
N
H
HN
H
N
Ar
H
13A
1
5a–15h
14a–14h
X
1
a
b
X
O
S
HN
H
N（2
+
Ar
N N（2
6a–16d
16
a
b
c
d
Ar
Ph
N
OH
N
1
H
13
1a, 1b
4-Me-＃6（4
4-MeO-＃6（4
4-Cl-＃6（4)
Fꢄꢅꢆꢇꢈ 3: ꢀe proposed mechanism for the reaction of DHPM derivatives ꢀa–ꢀh with hydrazine hydrate.
4
. Conclusion
Acknowledgments
ꢀ
e authors would like to extend their sincere appreciation to
We studied the action of hydrazine hydrate as N-nucleophile
on Biginelli pyrimidine esters ꢀa–ꢀh. ꢀey were subjected
to unexpected ring cleavage to give pyrazole ꢁꢃ, arylidene-
hydrazines ꢁꢅa–ꢁꢅd, and urea/thiourea ꢁa and ꢁb where the
reaction proceeded through C5 ester and C6.
the Deanship of Scientiꢁc Research at King Saud University
for its funding of this research through the Research Group,
Project no. RGP-1436-038.
Supplementary Materials
Conflicts of Interest
Graphical abstract ꢁgure shows the ring opening of cer-
tain Biginelli pyrimidines using hydrazine. (Supplementary
Materials)
ꢀ
e authors declare no conꢃicts of interest.

Journal of Chemistry
5
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