Synthesis and Some Reactions of 3-chloro-2-(cyanomethylene)- 1,2-dihydroquinoxalines

2,3-Dichloroquinoxaline and some of its derivatives have been reacted with malononitrile and ethyl cyanoacetate to yield a variety of


Introduction
The two reactive chlorine atoms in 2,3-dichloroquionoxaline (1a) are prone to nucleophilic displacement reactions by a wide variety of nucleophiles which react in a stepwise manner [1,2]: The reaction of 2,3-dichloroquinoxaline (1a) with carbanions generated from active methylene compounds has not been fully investigated.Pratt and Keresztesy [3] have reported the synthesis of indolizino -and dihydroindolizinoquinoxalines from either the reaction of 1a with ethyl cyanoacetate and isoquinoline in a one-step process, or the isolation of the monosubstituted intermediates derived from the reaction with ethyl cyanoacetate or malononitrile, followed by the treatment of the reaction products with isoquinoline or pyridine.Novel colored compounds containing the dicyano-methylidene groups conjugated with other chromophores have also been reported [4][5][6][7].In the present paper, detailed synthesis, analysis and spectroscopic properties of some colored quinoxaline compounds containing the ethoxycarbonylcyanomethylene and dicyanomethylene groups are reported.

Results and Discussion
2,3-Dichloroquinoxaline and its derivatives 1a-d were prepared following the procedure of Komin and Carmack [8], by treatment of 1,2,3,4-tetrahydroquinoxaline-2,3-diones with thionyl chloride in the presence of dimethylformamide (DMF).The reaction of dichloroquinoxalines 1a-d and the appropriate active methylene compounds (ethyl cyanoacetate or malononitrile) in dimethoxyethane, with sodium hydride as a base, gave good yields of colored crystals of a variety of 3-chloro-2-(cyanomethylene)-1,2-dihydroquinoxaline derivatives as isomeric mixtures of 2 and 3 (Scheme 1).The main reaction products 2 were isolated in pure form, whereas the isomers 3 have been detected only by their NMR-spectra.The structures of the newly synthesized compounds were assigned by their IR-spectra, 1 H-and 13 C-NMR spectra (see Experimental section).
The products can occur as tautomers 2 and 2', however, according to their 1 H-NMR spectra the compounds exist mainly as the 2-(cyanomethylene)-1,2-dihydroquinoxaline derivatives 2 or 3 (in CDCl 3 or DMSO-d 6 ), with the NH protons (exchangeable with D 2 O) showing broad singlets in the downfield region (in the range δ 10.99-14.49ppm).In the 13 C-NMR spectra, the central carbon in the =C(CN)R grouping resonates as a quartenary carbon in the δ 41.9-69.3ppm region, according to Attached Proton Test (APT) experiments.This is in the region reported for the 13 C-chemical shifts of the central carbon of the =C(CN) 2 in some compounds containing the dicyanomethylene group [9][10][11][12].
The 2-position of 6-substituted-2,3-dichloroquinoxalines is presumed to be preferentially attacked by nucleophiles, especially when the substituent at the 6-position is electron-withdrawing, based on greater stability of the intermediate σ-complex and molecular orbital calculations [13].Inspection of the 1 H-NMR spectra of the reaction products shows that they are mixtures of 6-and 7-substituted isomers 2 and 3, of which the 6-isomer 2 was isolated as the main product.We have failed to observe the replacement of the second chlorine atom of 1 by the active methylene compounds even when large excesses of the carbanions were employed.However, nucleophilic replacement of the second chlorine atom occurred with sodium azide and hydrazine.For example, both 3-chloro-2-(ethoxycarbonylcyanomethylene)-1,2-dihydroquinoxaline (2a) and 3-chloro-2-(dicyanomethylene)-1,2-dihydroquinoxaline (2e) reacted with sodium azide in dimethylformamide (DMF) to afford the tetrazolo[1,5-a]quinoxaline derivatives 4a (86 % yield) and 4b (85 % yield), respectively.Compound 2a also reacted with hydrazine in DMF to give the crystalline derivative 5 in 53 % yield.
Scheme 1 The infrared spectra of 2a -2d, 4a and 5 further show that in the solid state, these compounds exist in the methylidene tautomeric form, most probably with an intramolecular hydrogen bond, as shown by the presence, in each infrared spectrum, of carbonyl absorptions at around 1650-1630 cm -1 , instead of the normal absorption expected at > 1700 cm -1 for unconjugated esters.In addition, all the quinoxaline derivatives showed IR absorption bands at around 2200 cm -1 , characteristic of the cyano group.The predominant existence of 4a and 4b in the tetrazolo forms was supported by the absence of absorption bands at around 2140 cm -1 in their IR spectra, as expected for the azido (N 3 ) group.
As mentioned earlier, excess hydrazine converted 2a into 5 at room temperature.The ester group (COOEt) does not react under these mild conditions, showing that it is deactivated, most probably due to conjugation of the carbonyl function of the COOEt with the NH group in the HN-C=C-C=O(OR) system [14], and the -NH … O=C-hydrogen bonding.
The yields, infrared, 1 H-and 13 C-NMR spectral and analytical data for the dicyanomethanides, 6, are given in the Experimental section.In the 13 C-NMR spectra, the cyano groups resonate at around δ 120.7 ppm, compared to δ 116.5 ppm observed for the cyano groups in the starting material and related structures 2.
The formation of the dicyanoquinoxalinemethanides 6, instead of the reported dicyanoindolizinoquinoxalines 9, may account for the observation of Pratt and Keresztesy [3] that hydrogen cyanide could not be eliminated from their products.Also in the same report, they suggested structure 10 (based on analysis only) for the product obtained upon heating 3-chloro-2-(ethoxycarbonylcyanomethylene)-1,2-dihydroquinoxaline (2a) with quinoxaline.However, in the present studies, the main product obtained upon reacting 2a with quinoxaline is 2-chloro-3-cyanomethylquinoxaline (8), as proven by analysis, 1 H-NMR and mass spectral data. in nm (log ε), sh = shoulder).Infrared spectra were recorded on a Buck spectrometer as potassium bromide pellets. 1 H-and 13 C-NMR were recorded as CDCl 3 or DMSO-d 6 solutions on a Bruker-AC-250 or JEOL-JNM-GX 400-MHz spectrometers (δ in ppm relative to Me 4 Si and H 3 PO 4 ).Mass spectra (E1-MS) were recorded on a Finnigan MAT 312 machine [in m/z (rel.%)].
The 3-chloro-2-(cyanomethylene)-1,2-dihydroquinoxalines were prepared by reacting 2,3-dichloroquinoxaline derivatives 1a-d with the appropriate active methylene compound in the presence of sodium hydride.This is exemplified by the preparation of compound 2a as follows: ethyl cyanoacetate (1.1 mL, 10 mmoles) was added dropwise with stirring to a suspension of sodium hydride (0.25 g, 10.4 mmoles) in dimethoxyethane (20 mL).After the addition, the stirring was continued for 30 min.and then 2,3-dichloroquinoxaline (1.0 g, 5 mmoles) was added.The reaction mixture was stirred at room temperature for 3 h and then heated under reflux for 1 h.The dimethoxyethane was removed on a rotatory evaporator in vacuo and the resulting residue was treated with cold aqueous hydrochloric acid to give a yellow product.This was filtered, washed with cold water, dried and then recrystallized from ethanol to give yellow crystals of 3-chloro-2-(ethoxycarbonylcyanomethylene)-1,2-dihydroquinoxaline (2a, yield: 85%); m.p. 175-177°C (lit.[3]

The Reaction of 2a and 2e with Sodium Azide.
A solution of 2a (0.5 g, 1.8 mmoles) in DMF (20 mL) was stirred with sodium azide (0.3 g, 4.6 mmoles) at room temperature for 12 h.The reaction mixture was poured into water and the resulting solid filtered, washed with water and dried in the oven.It was then recrystallized from ethanol to give tetrazolo [1,5-a]

Typical Procedure for the Synthesis of Dicyano(3-pyridinium-1-ylquinoxalin-2-yl)methanides 6a-c from 2e
To a solution of 2e (0.5 g, 2.2.mmoles) in absolute EtOH (40 mL) was added pyridine (3.5 mL, 43 mmoles) and the resulting solution refluxed for 6 h.The reaction mixture was cooled and the colored solid was filtered off, washed with EtOH and then dried in vacuo to give 0.56 g of dicyano( 3

Reaction of 2a with Quinoxaline
A mixture of 2a (1.0 g, 3.6 mmoles) and quinoxaline (1.1 g, 8.5 mmoles) in dimethoxyethane (50 mL) was heated under reflux for 20 h.TLC showed the presence of two main spots, corresponding to the starting material 2a and the main reaction product, 2-chloro-3-cyanomethylquinoxaline (8).Separation was achieved by column chromatography (silica gel) to give 8 as orange crystals (0.