QUINOXALINE DERIVATIVES

VIII. THE EFFECT OF ELECTRON-DONATING GROUPS ON THE FORMATION OF CERTAIN QUINOXALINECARBOXYANILIDE N-OXIDES AND THEIR REARRANGEMENT'

Y u s u ~ AHMAD, M. S. HXBIB~ , NI. IQBXL, A'I. I I~RXM QGRESHI, AND ZIXGDDIN Chemical Research Division, Central Laboratories, Pakrstan Cozlncll of Scientzfic and Indl~strial Research,

Karachi, Pakistan

Received June 25, lOG5

ABSTRACT

Introduction of methyl or ~nethoxy groups into the benzene ring of quinoxalinecarboxy- anilide (Id), malces the resulting anilides less prone to "abnormal" oxidation (1). Normal N-

\

oxides (IIJaud IIj) were obtained from the anilides If and I j in which the cyclic 'NH was un- /

protected. The methyl-substituted anilides Ig and 112, however, on oxidation withberacetic acid gave the hydroxy derivatives (Vg and Vh) instead of the N-oxides (IIg and IIIz). ?'he methoxy- substituted arlilides Ik and I1 did not give the hydroxy derivatives Vk and VL nor the expected 1V-oxides I lk and 111. All the N-oxides (IIc, IIJ, II?', and IIj) on rearrangement with sulfuric acid yielded the corresponding a~nines IVe, IVJ, IVi, and IVj. In spite of the slow rate of rearrangement of these N-oxides, attempts to isolate the intermediate hydrox,mninospiro- lactams (I [ I ) were unsuccessful.

The novel conversion of quinoxalinecarboxyai~ilide N-oxide (IIa) in cold s~llphuric acid to the amine (IVa) has been postulated (2) to proceed by intraniolecular electrophilic substitution of the anilide ring by C-2 of the quinoxaline moiety. The AT-oxide group intensifies the electrophilic property of C-2 and seems to be necessary for subsequent decarboxylation and dehydration by a cyclic mechanism (2). In the absence of the K-oxide function the anilide (Ia) has been shown (3) to rearrange to the spirolactam (VIa), lvhich unlike the postulated but unstable intermediate (IIIa) in the conversion of I I a to IVa, is quite stable and has been isolated in quantitative yield. These rearrangements are com- paratively slower in ethanolic hydrogen chloride than in concentrated sulphuric acid, and i t has been possible to isolate (3) the hydroxyamino-spirolactam (VIIIa) in the rearrange- ment of the pyrazine N-oxide (VIIa). The strongly electrophilic character of C-2 in the quinoxaline N-oxide (IIa) and its derivatives is probably responsible for the marked instability of its hydroxyainino-spirolactarn intermediate (IIIa) and the iinpossibility of isolating this compound.

This is further borne out in the preparation of the N-oxides. I t has been observed (1) that if both or either of the cyclic or acyclic NI-I groups in the anilide (Id) are not protected by methyl groups, Ib, Ic, and Id on oxidation with hydrogen peroxide in acetic acid, instead of giving the corresponding N-oxides (IIb, IIc, and IId) give the corresponding hydroxy derivatives (Vb, Vc, and Vd), i.e. the anilide side-chain in each case is replaced by an OH group. I-Iowever, the anilide (Ia), in which both the N H groups are protected by methyl groups, or Ib (R" = Ac), in which the anilide NH is methylated and a lliild protection is afforded to the heterocyclic NH, each give the corresponding nor~nal N- oxides IIa and IIb (R" = Ac). In the corresponding pyrazine analogues, the carboxy- anilide (VIIb without oxygen on All), which bears no protection on its cyclic aniide- nitrogen, on oxidation gives the normal N-oxide (VIIb). The inarlced electrophilic nature of the 2-position in 3-hydroxyquinoxaline-2-carboxyanilides has been considered ( I ) to be

'For Par t VII see ref. 6. 2Present address: Burroughs \iVeIlcome & Co. (Paltistan) Ltd., D/43 S.I.T.E., Karachi.

Canadian Journal of Chemistry. Volume 43 (1965)

3424

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AI-IMAD ET AL.: QUINOSALINE DERIVATIVES 34'35

responsible for these "abnormal" oxidations. This hypothesis is further supported by the fact that in analogous quinoxaline anilide (If), in which two electron-donating methyl groups at position G and 7 soi-ne\\lhat decrease the strongly electrophilic nature of C-2, the protection of the cyclic amide-nitrogen became unnecessary, and normal S-oxide (IIf) could be obtained froin the seiniprotected anilide (If) with peracetic acid. The fully protected anilide (Ie), of course, gave the normal N-oxide (Ire). Ho\vever, the protection

I of the anilide NI-I was still necessary, as both of the anilides (Ig and Ih) underwent "abnormal" oxidation with peracetic acid and gave the hydroxy coinpounds (Vg and Vh).

C O N R Ph

rc

\ N/ c O N R Ph

I ~ R R ' R" R"' I I i R R' I<" I<"'

Under I S lower right coltm~n should be, R' = CI, R' = H.

In place of the inethyl groups at positions G and 7 in the above quinoxaline anilides, introduction of two inethoxy groups, \vhich are even stronger electron donators, \vould have further reduced the electrophilic nature of the C-2 in the nlolecule, and this was shown. The anilide (Ik) in which the acyclic NH group is unprotected, and the anilide (11) in which both the acyclic and cyclic NH groups are unprotected, on oxidation with peracetic acid did not give the corresponding hydroxy derivatives (Vk and VZ), which for

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3426 CASADIAN JOURNAL O F CHEMISTRY. VOL. 43, 19G5

the purpose of con~parison were synthesized through an unambiguous route. However, the compounds that mere obtained by this oxidation were not even the N-oxides (IIk and IIL), since they did not undergo the usual decomposition even in warm concentrated sulphuric acid, and mere recovered unchanged. The constitution of these new compounds, which \\rere isolated in poor yields, is under further investigation. The fully protected anilide (Ii) and the other semiprotected anilide (Ij), as expected, gave the normal N-oxides ( I I i and IIj).

The unsubstituted quinoxalinecarboxyanilide N-oxide (IIa) in concentrated sulphuric acid a t 0' has been reported (2,4,5) to undergo rearrangement to give the amine (IVa) and also an insoluble compound, for which the quinoxalinoquinoxaline structure (IXa) has been proposed (4, 5). The derivatives (IInz and IIn) of this N-oxide which bear chlorine atoms a t positions 6 and 7, undergo this transformation a t 0' even faster, and a larger amount of quinoxalinoquinoxaline type of compound (IXb or IXc) is formed in each case. On the other hand the N-oxides (IIe, IIf, IIi , IIj) are recovered unchanged from cold concentrated sulphuric acid, and to effect their rearrangement and conversion to the corresponding amines (IVe, IVf, IVi, and IVj) it is necessary to heat the mixture a t 75' for about an hour, during which process there is virtually no formation of quinoxalino- quinoxaline-type compounds. This can also be attributed to a decrease of the electrophilic character of the C-2 in these quinoxaline N-oxides caused by the introduction of electron- releasing groups in their benzene rings.

Attempts to isolate the intermediate hydroxyamino-spirolactams (IIIe, IIIf, IIIi , and IIIj) by heating the corresponding N-oxides (IIe, IIf, I I i , and IIj) with ethanolic hydrogen chloride were unsuccessful, because the rearrangement rate of these N-oxides is even slower than that of the pyrazine N-oxide (VIIa). All four quinoxaline N-oxides were recovered unchanged after they were heated for 8 h with ethanolic hydrogen chloride on a water bath.

EXPERIMENTAL

Infrared spectra were measured in Nujol mull.

General Procedure for the Preparation of N-Oxides The appropriate quinoxalinecarboxyanilide (1 g), acetic acid (10 ml), and 30% hydrogen peroxide (1 ml)

were heated together a t 55' and two further quantities of hydrogen peroxide (0.5 ml each) were added after intervals of 24 and 48 h. After a total 72 h of heating (6), the acetic acid was removed under reduced pressure and the residue was crystallized to give the N-oxide. S-Hydroxy-6,7-dimetkyl-6-(N-methyl-N-phenylcarbamoyl) quinoxaline I-Oxide (IIf) 3-Hydroxy-6,7-dimethyl-2-(N-methyl-N-phenylcarbamoyl) quinoxaline (If) (7), when treated with acetic

acid and hydrogen peroxide as described above, gave yellow plates (from ethanol) of the I-oxide (IIf), yield 5575, m.p. 266-267' (decomp.).

Anal. Calcd. for ClaH17N303: N, 13.0. Found: N, 12.8. S,~-DiJzydro-~,6,7-trimethyl-2-(N-methyl-N-phenylcarba~noyl)-S-oxopuinalne I-Oxide (I Ie) (a) 3,4-Dihydro-4,6,7-trimethyl-2-(N-methyl-N-phenylcarbamoyl)-3-oxoquinoxaline (Ie) (7), when simi-

larly treated, gave yellow plates (from ethanol) of the 4-methyl I-oxide (IIe), yield 40%, m.p. 263-264' (decomp.).

Anal. Calcd. for C19HlgN303: C, 67.6; H, 5.7; N, 12.5. Found: C, 67.6; H, 5.7; N, 12.2. (b) The 1-oxide (IIf), when treated with methyl sulphate in the presenceof anhydrous potassium carbonate

in acetone, gave the 4-methyl 1-oxide (IIe), m.p. 263" (decomp.), in good yield, identical (mixed melting point and infrared spectrum) with a sample obtained a s described in (a). S-Hydroxy-6,7-dimethosiy-b(N-methyl-N-phenylcarbantoyl) quinoxaline I-Oxide (I Ij) 3-Hydroxy-6,7-dimethoxy-2-(N-methyl-N-phenylcarbamoyl) quinoxaline (Ij) (7), when similarly treated,

gave yellow needles (from ethanol) of the I-oxide (IIj), yield 30%, m.p. 272-273" (decomp.). Anal. Calcd. for ClaH17N306: C, 60.8; H, 4.8; N, 11.8. Found: C, 60.5; H, 4.5; N, 11.7. S,~-DiAydro-6,7-dimethoxy-~methyl-6-(N-methyl-N-phenylcarbamoyl)-S-oxop~inoxaline I-Oxide (I Ii) (a) 3,4-Dihydro-6,7-diinethoxy-4-methyl-2-(N-methyl-N-phei~yl-carbamoyl)-3-oxoquinoxaline (Ii) (7),

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when similarly treated, gave, in 457, yield, yellow needles (from ethanol) of the 4-inethyl I-oxide (IIi) , 111.p. 250-251".

Anal. Calcd. for C ~ ~ H I & J ~ O ~ . F ~ ~ O : C, 58.9; H, 4.9; N, 10.85. Found: C, 59.1; H , 4.9; N, 11.1. (b) The 1-oxide (IIj) on being treated with methyl sulphate in the presence of anhydrous potassiuln

carbonate in acetone gave in good yield yellow needles (from ethanol) of the 4-methyl 1-oxide (IIi) , 1n.p. 350-25l0, identical (mixed melting point and infrared spectrum) with a sample obtained as described in (a).

General Proced~~re for the Deconrposition of N-Oxides in Concentrated Sztlplturic Acid

I Finely powdered N-oxide (1 g) in concentrated sulphuric acid (5 ml) was vigorously stirred while being

heated a t 75O till the evolution of COz was complete (about 1 h). The cooled mixture was poured on ice, then neutralized with aqueous sodium hydroxide. The precipitate was collected and crystallized from ethanol a s orange needles. Yield 50-80%.

3-Hydroxy-6,7-dimelhyl-2-(0-metltylaminophenyl) Quinomline (IVf) The 1-oxide (IIf), when treated as above, gave the amine (IVf), m.p. 238-240". Anal. Calcd. for C17N17N30: N, 15.1. Found: N, 15.1. S,4-Dihydro-4,6,7-t~i?netl~yl-2-(o-~~zethylaminophenyl)-S-0x0qz~in0xali~ze (IVe) The I-oxide (IIe), when similarly treated, gave the 4-methylamine (IVe), m.p. 163-1634". Anal. Calcd. for C I ~ H I D N ~ O : C, 73.7; H , 6.5; N, 14.3. Found: C, 73.4; H, 6.4; N, 13.9. S-Hydroxy-6,7-dinzetl~oxy-2-(o-metl~yla~ninopl~nyl) Quinoxaline (IVj) The 1-oxide (IIj), when similarly treated, gave the anzine (IVj), m.p. 230-231" (decomp.). Anal. Calcd. for C17H17N303: C, 65.6; H , 5.5; N, 13.5. Found: C, 65.9; H, 5.7; N, 13.6. S,~-Dikyd~o-6,7-dintethoxy-4-metltyl-2-(o-methyla~ni~zopltenyl)-3-oxoq~1inoxalim (IVi) The 1-oxide (IIi), when similarly treated, gave the 4-metltylantine (IVi), m.p. 159-161". Anal. Calcd. for C I ~ H I & J ~ O ~ : C, 66.5; H, 5.9; N, 12.9. Found: C, 66.9; H, 6.5; N , 13.0. S,~-Dikydro-4,6,7-t~inzethyl-2-(N-phenylcarbanzoyl)-S-ox0q1~inoxaline (Ig) 3,4-Dihydro-4,6,7-trimethyl-3-oxoquinoxaline-2-carboxylic acid (1.5 g), thionyl chloride (20 ml), a n d

benzene (20 ml) were heated under reflux for 1 h. The solid that was obtained after the thionyl chloride and benzene were removed under reduced pressure, was suspended in dry benzene and a solution of aniline (6 ml) in benzene (10 ml) was added drop by drop. The mixture was shaken for 10 min and washed with dilute hydrochloric acid. The anilide (Ig) that was thus separated was crystallized from ethanol as yellow needles, yield 100%, m.p. 210-212'.

Anal. Calcd. for C1sHlrN3Oz: C, 70.3; H , 5.6; N, 13.7. Found: C, 70.3; I-I, 5.5; N, 13.2. 2,s-Diltydroxy-6,7-dimetltyl Qzrinoxaline (Vlt) (a) An attempted preparation of the 1-oxide of 3-hydroxy-6,7-dimethyl-2-(N-phenyl~arbamo~l) quinoxa-

line (Ilt) by the general procedure described above for the preparation of N-oxides, led to the formation of dzl~ydroxyqz~inomline (VIA) (colorless needles from acetic acid), yield 8OyO, m.p. >325", identical (infrared spectrum) with the synthetic sample obtained a s described in (b).

(b) 4,j-Dimethyl-o-phenylenediamine, prepared by the hydrogenation of 4,s-dimethyl-2-nitroaniline (4 g) in ethanol (100 ml) over Pd-C, and without separation from ethanolic solution, was heated with ethyl oxalate (15 g) under reflux for 3 h. When the mixture was cooled a solid separated out, and was crystallized from acetic acid (charcoal) as colorless microneedles of the dihydroxyquinoxaline (Vh), m.p. >32S0.

Anal. Calcd. for CIOI-110N20z: C, 63.2; H , 5.3. Found: C, 62.8; H , 5.1. S,~-Dikydro-2-lzydroxy-4,6,7-t~i?netlzyl-S-oxoquinoxaline (Vg) In a similar way the attempted preparation of the 1-oxide of the anilide (Ig) afforded in good yield 4-nzetltyl

Jzydroxyqz~inoxaline (Vg) (colorless needles from ethanol), 1n.p. > 325'. Anal. Calcd. for CI~I-II?N?O~: C, 64.7; N, 5.9; N, 13.7. Found: C, 65.4; H , 6.2; N, 13.4. When this compound (Vg) was treated with methyl sulphate in the presence of anhydrous potass i~~m

carbonate in acetone, it gave, in good yield, colorless needles (from acetone) of 1,2,S,4-tetrahydro-1,4,6,7- tetrametlzyl-2,S-dioxoqz~inosaline (Ve), m.p. 305", identical with the product obtained by methylation of the authentic Vh described above under (b) (infrared s p e c t r ~ ~ m and mixed m.p. 305").

Anal. Calcd. for C1&I14N\T?03: C, 66.0; H , 6.5. Found: C, 66.4; H , 6.4.

Attempted Preparation of the I-Oxides of S,4-Dihyd~o-6,7-diinethoxy-2-(N-phenylcarba~~~oyl)-S-oxoqz~iiroxalii~e (11) and S,4-Dihydro-6,7-diinethoxy-4-nzetl~yl-2-(N-phetylca~banoyl)-S-oxoqz~inoxaline (Ik)

Both of the anilides (I1 and Ik), when they were treated as above (and under various other experimental conditions) with hydrogen peroxide and acetic acid, yielded some unidentifiable compounds. The anilide (11) gave a colorless compound, n1.p. 245-347", which was different (m.p. and infrared spectrum) from the expected 2,s-dihydrosy-6,7-dimetlroxy qztinoxaline (Vl) (colorless needles from acetic acid, 1n.p. >32j0.

Anal. Calcd. for CioHioN?Oa: C, 54.05; H, 4.5; N, 12.6. Found: C, 54.32; 1-1, 4.25; N, 12.6.) prepared by heating together 4,5-dimethoxy-o-phenylenediar~line and ethyl oxalate under reflux for 3 h. The anilide (Ik) gave a yellow solid (crystallized from ethanol), m.p. 170" (decomp.), which also did not show the properties of an N-oxide, and was not the other expected compound Vk.

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34% CANADIAN JOURNAL OF CI-IEMISTRY. VOL. 43, 1966

ACKNOWLEDGMENT

We thank Dr. S. Siddiqui, Chairman of this Council, for his interest and encouragement. We also extend thanks to Dr. H. T. Openshaw and the Wellcome Research Laboratories, Kent (U.I<.), through whose courtesy the analyses reported above were carried out in England; and to hIiss M . Quadeeln for help in experimental work.

REFERENCES 1. hI. S. HABIB and C. \Y. REES. J. Chem. Soc. 3386 (1960). 2. M. S. HABIB and C. IV. REES. 1. Chem. Soc. 3371 (1960). 3. M. S. I-IABIB and C. \\'. REES. J . Chetn. Soc. 123 (1962). 4. J. \IT. CLARK-LEWIS and G. I;. KATEKAR. J . Chem. Soc. 2825 (1959). 5. E. H. USHEWOOD and M. A. ~VHITELEY. J. Chem. Soc. 123, 1069 (1923). 6. Y. AHIIAD, M. S. HABIB, M. IQBAL, RiI. I. QURESHI, and ZIAUDDIN. Bull. Chem. Soc. Japan. I n press. 7. Y. AHJIAU, i\4. S. HABIB, PI. IQBAL, &I. I . QURESHI. J. Chem. Soc. 4053 (1964).

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