SITE SELECTIVITY IN REACTIONS OF HYDRAZONOYL HALIDES WITH HETEROCYCLES CONTAINING AMINO AND THIONE GROUPS LEADING TO FUSED HETEROCYCLES OF POTENTIAL ANTIMICROBIAL ACTIVITY © 2014 r. M. E. A. Khalifa", M. A. Amin",b, M. A. N. Mosselhi",c' #
aDepartment of Chemistry, Faculty of Science, Taif University, P.O. 888, Taif, Saudi Arabia bDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt cDepartment of Chemistry, Faculty of Science, Cairo University, 12613-Giza, Egypt Received April 25, 2013; in final form June 20, 2013
Reaction of hydrazonoyl halides with 6-(benzylidenamino)-2-thioxo-2,3-dihydro-1#-pyrimidin-4-one and 2,3-diaminoquinazolin-4-one site-selectively afforded 3-substituted-7-(benzylidenamino)-1-phenyl-[1,2,4]triazolo[4,3-a]-pyrimidin-5(1#)-ones, [1,2,4,5]tetrazino[6,1-b]quinazolin-6(4#)-one, and 3-meth-yl-2-(4-substituted-phenylhydrazo)-[1,2,4]triazino[3,2-b]quinazolin-10-ones in good yields. The structures of the newly synthesized compounds were elucidated by chemical evidence and their iR, 1H, 13C NMR, and MS spectra. Furthermore, some of the products were screened against different strains of bacteria and fungi.
Keywords: hydrazonoyl halide, site-selectivity, quinazoline, pyrimidine, antimicrobial activity DOI: 10.7868/S0132342314010072
INTRODUCTION
The regioselectivity in the reactions of hydrazonoyl halides has been widely employed in the synthesis ofhet-erocyclic derivatives [1—10]. Also the reactions of hydrazonoyl halides with aminoazoles, aminoazines, and various types of heterocyclic thiones provided convenient strategies for synthesis of fused heterocycles [11—16]. From this point ofview and in continuation ofpart of our program aimed at developing new convenient approaches for synthesis of fused heterocycles via utility of hydrazonoyl halides (I) as starting materials and heterocycles containing amino and/or thione groups, we wish to report the results of our study of the reactions of 6-(ben-zyhdenamino)-2-thioxo-2,3-dihydro-1#-pyrimidin-4-one (II) or 2,3-diaminoquinazolin-4-one (IX) with hydrazonoyl halides (I). Our objective of such a study is to shed some light on the site selectivity in such reactions as they can in principle lead to the formation of3-substitut-ed-7-(benzylidenamino)-1-phenyl-[1,2,4]triazolo[4,3-a]pyrimidin-5(1#)-ones (V), 1,3-diphenyl-1#-[1,2,4,5]tetrazino[6,1- 6]quinazolin-6(4#) - one (XI), and 3-methyl-2-(4-substituted-phenylhydrazono)-1,2-dihydro-[1,2,4]triazino[3,2-]quinazolin-10-one derivatives (XrVb—d) (Schemes 1, 2). The studied reactions were found to be site selective and provide new general access to various fused quinazoline and pyrimidine derivatives. Fused quinazolines are reported to be bioac-
# Corresponding author (phone: 00966-5-4377-2635; e-mail: mosselhi2008@hotmail.com).
tive: there are cytotoxic compounds with potential antitumoral activity [17] and various therapeutic agents, such as anticancer agents [18] and anticonvulsants [19]. Triazinoquinazoline derivatives are reported to be good DNA-binding fluorophores [20—23].
Furthermore, it is reported that pyrimidines are of chemical and pharmacological interest [24] and compounds containing the pyrimidine ring system have been shown to possess antibacterial [25], antifungal [26], antimalarial [27], anticonvulsant [28], and antitumor [29] activities.
RESULTS AND DISCUSSION
Synthesis. The starting hydrazonoyl chlorides (I) [3, 30, 31] and 6-(benzylidenamino)-2-thioxo-2,3-dihydro-1#-pyrimidin-4-one (II) [32] and 2,3-di-aminoquinazolin-4-one (IX) [33] were prepared by literature methods. The reaction of (II) with each of the hydrazonoyl chlorides (Ia—j) in refluxing mixture of dioxane and dimethylformamide and in the presence of triethylamine afforded in each case a single product as indicated by TLC analysis of the crude product, whose mass spectrum and elemental analysis proved it to contain no sulfur. This finding excludes the possible formation of 6-(3-substituted-1-aryl-5-phenyl-l#-1,2,4-triazol-4(5#)-yl-2,3-dihydro-2-thioxo-py-rimidin-4(1#)-one (VI) (Scheme 1). The structure of the product was identified as 3-substituted-7-(ben-zylidenamino)-1-aryl-[1,2,4]triazolo[4,3-a]-pyrim-
O
S^N N=CHC6H5 H II
+
Cl
R—C—NNHAr I
Dioxane/DMF Et3N/A "
HN
O
iN.
N-Ar
N-CH
C6H
6H5
VI
I, V R Ar
a C6H5 C6H5
b CH3CO C6H5
c CH3CO C6H4- CH3- 4
d CH3CO C6H4- -Cl-4
e C2H5OCO C6H5
f C2H5OCO C6H4- CH3- 4
g C2H5OCO C6H4- -Cl-4
h C6H5NHCO C6H5
i c6h5nhco C6H4- CH3- 4
j c6h5nhco C6H4- -Cl-4
O
аг-nh \HN il
A A
^C—Si N N^CHC^
O
HN^l H
VII
nh2
r
III
s ^ O
R—"C HN
I xk-H—N—N N
I
N=CHC6H5
Ar
IV
-H2S
O
R-
C-N-
N
-nan
I
Ar
^CHC6H5 V
PhCHO DMF
A
va, R = Ar = Ph
O
Ph-
C-
N
—N
-nan
I
Ph
nh2
VIII
Cl
Ph—C=NNHPh Ia
Dioxane/Et3N, A
Scheme 1. Synthesis of 3-substituted-7-(benzylidenamino)-1-aryl-[1,2,4]triazolo-[4,3-a]-pyrimidin-5(1H)-ones (Va—j ).
idin-5(1#)-ones (V) (Scheme 1). This assignment is based on their elemental and spectral (IR, MS, and 1H and 13C NMR) analyses (see Experimental). Compound (Va) is taken as a typical example, its 1H NMR spectrum showed a singlet signal in the region of 5 6.7 assigned to H-6 of the pyrimidine ring residue and a singlet signal in the region 5 of 7.93 assigned to N7=CH. 13C NMR spectrum of (Va) showed signals at
S 118 (C6), [(Ar-C, 120.5, 125.3-131.1, 149.1 (N1-C)], 155.2 (C3), 158.5 (C7), 162.2 (C5=O), 163.1 (N4=C), 164.2 (N7=C). 13C NMR spectrum of (Va), revealed the signals of the carbonyl carbon of the pyri-midinone ring residue at S 162.2. Such chemical shift value is similar to that of annulated pyrimidines with N3 pyrrole type [7]. IR spectra of (Va ) revealed absorption bands at 1605 cm-1 (CO at C-5). The assignment of the formation of (Va ) was further manifested
O
,nh9
N
Cl
+ c6h^^nnhc6h:
6H5
Dioxane/Et3N A "
N NH2 IX
O
Ia
H
O
H
N—N—C—C6H5
NNHC6H5
NH2 X
-NH3
N V^ 6 5
, - ,N N N
I
C6H5
XI
NH2 XII
-NH3 (b)
O
H I
N^NNHC6H4-X-4
cK -,N
N N CH3
O
COCH3
XIV
H I
N Y
. . ,N N N I
C6H4X-4
XIII
b, X = H; c, X = CH3; d, X = Cl
Scheme 2. Synthesis of 1,3-diphenyl-[1,2,4,5]tetrazino[6,1-b]quinazolin-6(4H)-one (XI) and 3-methyl-2-(4-substitutedphenylhydrazo)-[1,2,4]triazino[3,2-b]quinazolin-10-ones (XIVb—d).
by alternate synthesis. Thus, treatment of 6-amino-2-thioxouracil (6-amino-4-oxopyrimidine-2-thione) (VII) with hydrazonoyl chloride (Ia) in dioxane in the presence of triethylamine under reflux led to evolution of methanethiol and the formation of product (VIII) [11]. The reaction of the latter with benzaldehyde in refluxing DMF afforded a product that proved to be identical in all respects (mp., mixed mp., and IR) with compound (Va) (Scheme 1).The direct formation of products (V) from the reaction of compound (II) with hydrazonoyl chloride I indicates that the intermediate thiohydrazonate esters (III) underwent Smiles rearrangement [34] to give the corresponding thiohy-drazides (IV), which in situ underwent cyclization with concurrent elimination of hydrogen sulfide gas to give (V) as end products (Scheme 1). All attempts to isolate the intermediates (III) and (IV) failed since
they were consumed as soon as they were formed under the employed reaction conditions. On the other hand, refluxing equimolar quantities of hydrazonoyl chloride (Ia) with 2,3-diaminoquinazolin-4-one (IX) in dioxane in the presence of triethylamine gave a single product, as indicated by TLC analysis of the crude product. The structure of the product was identified as 1,3-diphenyl-[1,2,4,5]tetrazino[6,1-&]quinazolin-6(4#)-one (XI), which may be formed via the intermediate (X) (Scheme 2). By the same manner, when the reaction of each of hydrazonoyl halides (Ib—d) with (IX) in a mixture of dioxane and dimethylformamide in the presence of triethylamine also gave a single product as indicated by TLC analysis of the crude product. The structures of such products were identified as 3-methyl-2-(4-substituted-phenylhydrazo)-[1,2,4]triazino[3,2-b]quinazolin-10-ones (XIVb—d), and not the corre-
Antibacterial and antifungal activities of the synthesized compounds (\&—c, e, f, h) (XI), and (XIVb—d)
IZD*, mm/mg compound tested
Compound No. Gram negative bacteria Gram positive bacteria fungi
EC SA AF CA
Control: DMSO 0.0 0.0 0.0 0.0
Tetracycline (antibacterial agent) 30 29 - -
Amphotericin B (antifungal agent) - - 16 19
(Va) 15 14 0 10
(Vb) 16 12 0 12
(Vc) 12 12 0 13
(Ve) 16 15 0 13
(Vf) 13 16 0 10
(Vh) 14 13 0 12
(XI) 13 15 0 13
(XIVd) 14 13 0 10
* IZD, Inhibition zone diameter; IZD = 2—10 mm beyond control, low activity; IZD = 25—35 mm beyond control, high activity.
IZD = 11—24 mm beyond control, moderate activity;
sp onding [1,2,4,5] tetrazino [ 6,1 - b]quinazolin-6(4#)-one (XIII). The reaction of (Ib—d) with (IX) proceeds through nucleophilic substitution followed by cyclocondensation. Confirmatory evidence for the structure assignment for compounds (XI) and (XIVb—d) was provided by spectroscopic data (IR, MS and 1H and 13C NMR). The 1H NMR of product (XI) revealed only aromatic protons at 8 7.20—8.10 and NH proton at 8 11.50, which is D2O exchangeable, and no NH2 protons found. These spectral data are convenient with the proposed structure of 1,3-diphenyl-[1,2,4,5]tetrazino[6,1-b]quinazolin-6(4Jff) - one (XI) which may be formed via the intermediate (X). IR Spectra of products (XIVb—d) showed only CO absorption band of quinazoline moiety at 1660—1675 cm-1, while their 1H NMR revealed characteristic peaks of 3-CH3 at 8 2.9-3.01 and their 13C NMR showed only CO signal at 8 162.5-163.0. The spectral data presented here indicate collectively that such compounds (XIVb—d) exist predominantly in the structures of 3-methyl-2-(4-substituted-phenylhydrazo)-[1,2,4]triazino[3,2-b] quinazolin-10-ones.
Antimicrobial activity. The compounds were tested in vitro against gram negative anaerobic bacteria Escherichia coli (EC) and gram positive bacteria Staphylococcus
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