Quinoxaline ketones cyclization

CINNOLINES AND QUINOXALINES Replacement of a methine in oxolinic acid (46) by nitrogen is apparently consistent with retention of antibacterial activity. One approach begins with reduction of nitroacetophenone 144 to afford the corresponding aminoketone (145). Treatment of this intermediate with nitrous acid leads to the diazonium salt the diazonium group condenses with the ketone methylene group (as its enol form) to lead to the cyclized product, cinnoline 147. Bromination proceeds at the position adjacent the enol grouping (148) ... 

Imines 73, generated in situ from 2-aminoquinoxalines 72 and ketones in acetic acid, are transformed spontaneously into pyrrolo[2,3-Zt]quinoxalines 76 (Scheme 22) (02RCR707). The SNH cyclization seems to proceed by equilibrium amounts of enamine 74. Adducts 75 are oxidized, apparently, with air oxygen or cation 72H7... 

The furo[2,3-b]quinoxalines 20 are formed only in cases where the keto group in the intermediate quinoxalinyl ketone 19 is enolizable. If enolization is not possible, the reaction is completed by the formation of product 19 (Scheme 15) (72YZ736). Therefore, it is not surprising that / -dicarbonyl compounds, which are considerably enolized, undergo a very smooth cyclization with tetrachloropyrazine with ethyl acetoacetate, furo [2,3-b] pyrazine is obtained in good yield (Scheme 15) (83JHC365). 

Treatment of 2-(l,2-dibromoethenyl)quinoxalines 57 with Na2CS3 affords thieno[2,3- ]quinoxalines 59. Addition of the thiocarbonate to the side chain generates 58. Intramolecular cyclization of 58 with loss of CS2 and NaBr leads to 59 (Scheme 14) <2001J(P1)154>. Azulenothiophenes 61 are prepared from azulene derivatives 60 by the reaction with thioacetamide (Scheme 15) <2002H(58)405>. Similar reactions of furyl ketones 62 afford thieno[3,4-3]furans 63 <1998JHC71>. 

The alternative formation of quinoxalines 205 and benzodiazepines 206 can be understood with the help of the proposed reaction mechanism (Scheme 2.14). 1,2-DABs 155a, b, f, m react with ketone 204 to form an imino-intennediate, which by A-protonation and C-deprotonation may form a zwitterion. In the case of the 2-substituted pyridine in MeOH solution, it is proposed that this intermediate cyclizes and is dehydrogenated to form quinoxaline derivadves 205. The formation of quinoxaline derivatives is limited to those reactions in which the aiyl group is 2-pyridyl and there still remains a question over the oxidation to the final product. When the zwitterionic intermediate reacts at carbon with another equivalent of the ketone, a new intermediate could be formed which could undergo further cyclisa-tion to give benzodiazepine derivatives 206. 

One of the most widespread and most widely used among methods for the synthesis of pyrrolo[ 1,2-a]quinoxaUnes is the method involving the intramolecular cycliza-tion of derivatives of quinoxaline with substituents at position 2 and containing at least three carbon atoms with reaction centers capable of nucleophilic attack. Quinoxalines 1, containing a ycarbonylalkyl substituent at position 2 (ketones, carboxylic acids, esters) undergo intramolecular cyclization under the influence of acids with the formation of pyrroloquinoxalines 2-4 (Scheme 3.1) (Kumashiro 1961 Taylor and Hand 1962, 1963 Cheeseman and Roy 1969). 

The transition-metal-catalyzed formation of pyridine-type six-membered rings was reported by Mukhopadhyay and Kundu in 2000 [94], Bis-tosylamides of 1,2-diaminobenzene derivatives 193 undergo an unusual pyrazine formation by 6-exo-dig cyclization to give l-(quinoxalin-2-yl)ketones 194 in moderate yields by treatment with 10 mol % Cul in the presence of K2CO3 (Scheme 19.49). A reaction mechanism was not proposed. 

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