1,4-Benzoquinone, 2-alkyl-3- synthesis

Lin, A. J. Shansky, C. W. Sartorelli, A. C. Potential bioreductive alkylating agents. 3. Synthesis and antineoplastic activity of acetoxymethyl and corresponding ethyl carbamate derivatives of benzoquinones. J. Med. Chem. 1974, 17, 558-561. 

Ebel s method is an adaptation of the Stoermer synthesis of benzo-[h]furans and involves the 0-alkylation of a phenolate anion (229, Scheme 58) with a 2-halocyclohexanone (230). The resultant 2-phenoxycyclo-hexanone 231 is then cyclized by poly phosphoric acid, usually at 100°C, or sometimes by concentrated sulfuric acid, to afford a 1,2,3,4-tetrahydrodi-benzofuran (232). Dehydrogenation to the dibenzofuran is often effected with palladized charcoal, but 2,3-dichloro-5,6-dicyano-l,4-benzoquinone ... 

The oxidation of N-alkylated pyridinium salts (1) with alkaline ferricyanide was first reported by Decker (1892CB443) and provides a standard method for the synthesis of 2-pyridones (2) (430SC(2)419). Potassium permanganate or hydrogen peroxide in alkaline solution (70T2953) as well as p-benzoquinones (63ACS2250) also perform this oxidation. However, these reagents are much less specific than ferricyanide. 

Bamford-Stevens reaction of the tosylhydrazones of the readily available tetrahydrofuran-3-ones provides a useful synthesis of 2,3-dihydrofurans which may be dehydrogenated to furans with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (66CJC1083). Tetrahydrofuran-2-ones (y-butyrolactones) may be alkylated in the 3-position with LDA and an alkyl halide. The products on reaction with phenyl selenylchloride and LDA, and subsequent oxidation, yield 3-alkylfuran-2(5//)-ones reducible with DIBAL to furans (75JOC542). 

In a Nenintzescu indole synthesis with 2-alkyl-l,4-benzoquinones (3) and 3-aminocrotonates (4) (Scheme 1), two isomeric products (5) and (6) were formed. The compound 5 was already identified as 5-hydroxy-6-alkylindole-3-carboxylic ester. For compound 6, there was ambiguity as to whether there was 4- or 7- alkyl substitution. The following solution was obtained ... 

The mode of reaction of fulvenes with o-quinones varies with structure. As illustrated below, 7,7-disubstituted fulvenes (91) react with o-benzoquinone and alkyl substituted o-quinones to give bridged diones 90,91) (92). The regiochemistry of these reactions was determined by photobisdecarbonylation to 93. Subsequent oxidation with chloranil provided a synthesis of benzofulvenes (94). 

For the synthesis of the non-diene analogue 65, which bears a benzyl group in the terminal position (Scheme 17), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) cleavage of the p-methoxybenzyl (PMB) ether at the C15-position did not proceed in the presence of the benzyl moiety (oxidation of the methylene in allylic-benzylic-position in C23-position). Therefore, we inverted the order of the first two steps (1) DDQ deprotection on 44 and (2) nickel-catalyzed cross-coupling reaction performed on a free primary alcohol in C15 position. After this minor modification, completion of the synthesis followed the established route Suzuki-Miyaura crosscoupling reaction between alkyl iodide 73 (via its trialkylboronate species) and vinyl iodide 60 to yield 74 selective carbamate installation and final deprotection to afford DDM analogue 65. 

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