The Reactivity of 2-Ethoxy-4-Chloroquinazoline and Its Use in Synthesis of Novel Quinazoline Derivatives

The behavior of 2-ethoxy-4-chloroquinazoline 2 towards various nitrogen nucleophiles, namely: thiosemicarbazide, sodium azide, glucosamine, ethanol, and hydrazine hydrate has been discussed. Also, the behavior of 4-(2-ethoxyquinazolin-4-yl)thiosemicarbazide towards one-carbon, for example, ethyl chloroformate, and two-carbon donors, for example, ethyl chloroacetate and diethyl oxalate has been investigated. On the other hand, new 5-ethoxy-2-substituted[1,2,4]-triazolo-[1,5-c]quinazoline derivatives have been obtained by ring closure accompanied with Dimroth rearrangement through the interaction of compound 2 with hydrazides of acetic, benzoic, crotonic, cinnamic, 2-furoic, and phthalimidoacetic acids. Structures of the novel products were confirmed by elemental, IR, MS, and 1H-NMR spectral analyses.


Introduction
Quinazolines are a big family of heterocyclic compounds, which have shown broad variety of biological activity profiles [1,2], for example, analgesic, narcotic, diuretic, antihypertensive, antimalarial, sedative, hypoglycaemic, antibiotic, antitumoral, and many others. It has been found [3] that the biological activity strongly depends on the type and place of the substituents in their molecules.
Out of the wide substitution patterns known, 4aminoquinazolines are useful as fungicides [4,5], anti-inflammatory [6,7], anticancer [8,9], antimicrobial, and antihypertensive agents [10,11]. Some 4-anilinoquinazolines have been found to be potential and highly selective inhibitors of human immunoglobulin E [12] and epidermal growth factor receptor tyrosine kinase [13] which regulates the cell growth and proliferation, so they can work as potent antiallergic or anticancer agents, respectively. Among the broad synthetic pathways for aminoquinazoline preparation [14,15] the substitution of chlorine atom in 4-chloroquinazolines by amines is the shortest and cheapest one. On the other hand, it is well known that heterocycle-bearing Nglycosides play a significant role as inhibitors, for example, the tetrazole-bearing N-glycosides used as SGLT2 inhibitors [16] where their hypoglycemic activity is tested in vivo by mice oral glucose tolerance test (OGTT). In the current paper we report the synthesis of 4-aminoquinazolinebearing N-glycosides in a similar way, with exception of the endocyclic 2 • nitrogen atom attached to the glucose moiety.
Glucosamine is one of the constituents of chitin, chitosan, and mucopolysaccharides and has important biomedical applications, including pharmaceutical preparations for treating cartilage diseases of joints [26][27][28][29][30]. Such preparations include often glucosamine hydrochloride or sulfate and chondroitin sulfate. In this paper we invented reaction of the 4-chloroquinazoline 2 with glucosamine hydrochloride in the presence of sodium bicarbonate in methanol to afford product 8 (α and β anomers) (Scheme 4). Structures of 8 (α + β) were assigned by TLC and 1 H-NMR spectra. The 1 H-NMR spectra for 8 (α + β) showed H-1 doublets at 5.05 and 4.80 ppm, characteristic for the α and β anomers, respectively [31]. Moreover, the TLC data obtained at room temperature including silica gel and a mixture of ethyl acetate : hexane (3 : 1) indicated that derivative 8 presented two spots, with R f value for β anomer being double that for α.
Recently, it was reported that 4-substituted-aminoquinazolines are exploited as potent antitumor compounds (human breast carcinoma cell line in which EGFR is highly expressed) [32]. Herein we synthesized 4-hydrazinoquinazoline 9 by reacting compound 2 with hydrazine hydrate in boiling ethanol (Scheme 5). During the synthesis of product 9, variable quantities of derivatives 10 and 11 were also obtained as shown by mass spectral data. Product 11, in its hydrochloride form, was obtained due to the reaction of derivative 2 with absolute ethanol during synthesis of derivative 9.
Also, as a good substrate for one-carbon donors, product 2 reacted with acid hydrazides, namely: acetic, benzoic, crotonic, cinnamic, furoic, and phthalimidoacetic hydrazides affording first the 2-acylated-1-(2-ethoxyquinazolin-4-yl) hydrazine products which, on heating, rearranged giving the imidamide tautomer (Scheme 6) and then cyclized losing water to give the triazoloquinazolines 12a-f, respectively. Whereas the literature indicates the possibility for the Dimroth rearrangement [33], we have been unable to unambiguously verify the structures of 12, and the proposed structures are on the basis of mass spectral fragments observed.

Experimental
All melting points recorded are uncorrected. The IR spectra were recorded on a Pye Unicam SP 1200 spectrophotometer using KBr wafer technique. The 1 H-NMR spectra were determined on a Varian FT-200, Brucker AC-200 MHz spectrophotometry experiment using TMS as an internal standard. Chemical shifts (δ) are expressed in ppm. The mass spectra were determined using MP model NS-5988 and Shimadzu single focusing mass spectrometer (70 eV).
The 2-ethoxy(4H)-3,1-benzoxazin-4-one was prepared according to methods available in the literature [34] and was immediately used after preparation, prior to each synthesis to avoid moisture.

Reaction of 4-chloro-2-ethoxyquinazoline 2 with hydra-
zine. An emulsion of product 2 (0.01 mol) and hydrazine hydrate (0.05 mol) in benzene (15 mL) was stirred for 2 h. The benzene-insoluble gum obtained was treated and washed with water, dried, and recrystallized from ethanol giving reddish brown crystals of product 9. Evaporation of solvent, from the benzene-soluble fraction gave a residue that was rinsed with water and dried. Recrystallization of the residue from absolute ethanol gave a mixture containing product 10 according to mass spectrum. Evaporation of the ethanolic mother liquor, extraction of the resulting residue with chloroform, evaporation of solvent and treatment of the residue with ether afforded product 11 as hydrochloride. The presence of halogen was verified by a green flame with a copper wire.

General
Procedure for the Synthesis of Compounds 12af. A mixture of equimolar amounts of compound 2 and the acid hydrazides namely: acetic, benzoic, crotonic, cinnamic, furoic, and phthalimidoacetic hydrazides (0.01 mol) was heated on an oil bath for 3 h (6 h in the case of phthalimidoacetic hydrazides). The precipitate that separated out was filtered, washed, dried, and then crystallized from ethanol affording crystals 12a-f, respectively.