Synthesis of 12-ethoxy-3-oxo-4-phenylquino[3,2-c ][1,3]diazocines via Vilsmeier-Haack reaction

Application of' Vil~meier condition on 4-hydroxyquinaldincs give potentially useful Intermediates 4-chloro-3-formyl-2-(l· hydroxyethcnc-1-yl)quinolim•s, which arc utilized to prepare IJUino[3,2-cU1,3jdiazocincs on treatment with N-phcnylurca.

In recent past there has been a widespread interest on the application of Vilsmeier reagent in organic syntheses. Earlier reports reveal the reagent to be a mild and efficient formylating agent for reactive aromatic and heteroaromatic substrates 1 . The versatility of the reaction has been further extended as an activating agent for acylhalo addition 2 and ring annulation~. Moreover. a wide variety of alkene deriv-<ltives~. carbonyl compounds-'. activated methyl and methylene groups 6 as well as oxygen and nitrogen neucleophiles 7 efficiently react with Vilsmeier-Haack reagent to yield the corresponding iminium salts. The intramolecular cyclization potential of halomethyleniminium salts formed under Vilsmeier condition and microwave induced Vilsmeier conditions have been reporteds. The classical Yilsmeier-Haack reaction involves electrophilic substitution of an activated aromatic ring with a halomethyleniminium salt to yield the corresponding iminium species. which facilitates easy entry into large number of novel heterocyclic systems.
The capability of the reagent to generate a broad spectrum of iminium species has been explored further for the construction of lc jannelated nitrogen and oxygen heterocycles via 4-l:hloro·3-fonnylquina1Jines obtainable from 4-hydroxyquinaldines9 by Vilsmeier-Haack reaction. .

Results and discussion
It was presumed that the Vilsmeier-Haack reaction on 4-hydroxyquinaldines (l) (previously prepared from con·esponding aniline and ethyl acetoacetate followed by subsequent cyclization of the P-anilinocrotonates) could provide a utility intermediate for the preparation of several substituted [c]annelated heterocyclic compounds 10 . The reaction was carried out at 100° for I S-20 h, using the Vilsmeier-Haack reagent derived from phosphorus oxychloride-598 dimethylformamide in situ. The reaction yielded a mixture of products, which were separated by using silica gel column chromatography. The analytical and spectroscopic data confirmed the products as 4-chloro-3-formyl-2-(2· hydroxyethene-1-yl)quinoline (2), 4-hydroxy-3-formylquinaldine (3) and 4-chloroquinaldine (4) in good yields (Scheme I). The reaction of Vilsmeier reagent on 4-hydroxyquinaldines (1) at I 00° resulted in the formation of 4-chloro-3-formyl-2-(2-hydroxyethene-1-yl)quinolines (2a·e), which could be further utilized for the construction of a novel nitrogen heterocyclic ring system.
The Vilsmeier-Haack reagents are usually applied for the formylation of aromatic and heteroaromatic compounds. These are the chloromethyleniminium species responsible for the formylation (Scheme 2). As in our reaction, the chloromethyleniminium species obtained in situ Note from phosphorus oxychloride-dimethylformamide react with the active methyl group of 4-hydroxyquinaldine (1) to yield 6. Another fonnylation occurs at the aromatic C 1 of the quinaldine leading to the iminium compound 8. Since Scheme 2 these iminium !>alts have the ~pecial ability to replace the hydroxyl group at aromatic c-! by the nucleophiles like chlorine. bromine etc., they have led to the formation of 4chloroquinaldine (4) in minor yield~ and also to the replacement of hydroxy group by the chloro group forming 4-quinolines. The vinyl denvative was treated with Nphenylurea in alcoholic potassium hydroxide !.olution and retluxed for two hours. Atter the solvent was removed under reduced pressure. the residue was poured onto crushed ice and extracted with ethyl acetate. The silica gel column chromatography of the extract atforded the Jesired compound~ 12a-e using petroleum ether-ethyl acetate as the eluent!> (Scheme 3).
The reaction proceeded via the corresponding Nphenylhydrazone. Subsequent cyclization yieldeJ the Jiazocine. The yields, reaction time and the temperature at which the reaction was carried out are shown in Table I.
the ca~e of 4-hydroxyquinaldine (la) and 8-methyl-4hydroxyquinaldine (lb), the reaction was completed within 15 hand w1th 5,8-dimethyl-4-hydroxyquinaldine (le), in 20 h a!. monitored by the TLC Having prepared the new intermediate!>, 2a-c we were able to carry out the intended synthe-.is of some annulated Thin layer chromatography was used to monitor the reactions and the purity of product!>. M.p'>. were determined on a Boetiu!> Microheatmg table (Japan) and are uncorrected. IR spectra (KBr) were recorded on a Shimadzu 8201 Ff spectrophotometer, 1 H and 13 C NMR spectra (CDCI 3 ) on a Bruker AMX-400 MHz ~pectrometer with TMS as internal standard and mass !>pectra on a Jeol D-300 spectrometer (70 eV). C. H, N analyses were carried out on a Perkin-Elmer 240 analyser.

Geneml procedure .
Vilsmeter-Haack reaction on .J-Izvdro'(yquinaldine: The Vilsrneier reagent wa!> prepared by taking N,N-dimethylformamide (3.X6 mi. 0.05 mol) at 0-5". Pho!>phorus oxychloride (13 04 ml, 0.014 mol) was added to it dropwise ove a period of 30 min with constant stirring and the resultant mixture was stirred for another I h. The appropriate 4hydroxyquinaldine (la-e) was added to the Vilsmeier reagent. The mixture was !>tirred for 30 min at RT and was then kept on a water-bath at I 00" for the period of time stated in Table I Atter the reaction was over (monitored through TLC), the react1on mixture was poured onto cru!>hed ice (500 g) with constant stirring and set a!>ide overnight. The precipitate obtained on neutralization with 4 N NaOH was washed with water and extracted using ethyl acetate. The silica gel chromatography of ethyl acetate soluble product afforded three compounds 4. 3 and 2 using petroleum ether. petroleum ether-ethyl acetate (94: 6) and petroleum ether-ethyl acetate (85 : 15), respectively. The product!i were recrystallized with methanol and were identified by the analytical and spectroscopic data.