Quinones, alkylation preparation

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

The procedure described above has been used to prepare various alkylated 1,4-benzoquinones and 1,4-napthoquinones,2-3 including some naturally occurring quinones.4 A few examples are listed in Table I to show the scope of the method. 

The UV-Vis spectral detection of an intermediate in the catalytic reductive alkylation reaction provides only circumstantial evidence of the quinone methide species. If the bioreductive alkylating agent has a 13C label at the methide center, then a 13C-NMR could provide chemical shift evidence of the methide intermediate. Although this concept is simple, the synthesis of such 13C-labeled materials may not be trivial. We carried out the synthesis of the 13C-labeled prekinamycin shown in Scheme 7.5 and prepared its quinone methide by catalytic reduction in an N2 glove box. An enriched 13C-NMR spectrum of this reaction mixture was obtained within 100 min of the catalytic reduction (the time of the peak intermediate concentration in Fig. 7.2). This spectrum clearly shows the chemical shift associated with the quinone methide along with those of decomposition products (Fig. 7.3). 

Another formal total synthesis of ( )-yohimbine has been worked out by Wenkert et al. (229) by preparing O-methylhexadehydroyohimbine (420), which was first prepared by Kametani and co-workers (224-226) as a key intermediate toward ( )-yohimbine. In Wenkert s approach, pyridinium salt 427 was y-alkylated with acetoacetic ester anion. The product 428 then underwent intramolecular condensation, affording tetracyclic quinone 429. Methylation of 429... 

A new synthetic route to alkyl-substituted quinones has relied on the photochemical reaction of 2,3-dichloro-l,4-naphthoquinone with a thiophene derivative (77CL851). Irradiation of a benzene solution of the quinone and thiophene by a high pressure mercury lamp gave photoadduct (295) in 56% yield. Desulfurization of this compound over Raney nickel (W-7) gave the 2-butyl-1,4-naphthoquinone derivative (296 Scheme 62). Alkyl-substituted quinones such as coenzyme Q and vitamin K, compounds of important biological activity, could possibly be prepared through such methodology. 

The manumycin family were isolated from Streptomyces parvulus (Tii 64) and possess a wide range of biological properties. Taylor and co-workers synthesized manumycin A (7) via the quinone monoacetal (131), which was prepared by PIDA oxidation, followed by epoxidation and alkylation on the cyclohexa-dienone (130) [90] (Scheme 8). Other members of the mamumycin family of antibiotics such as alisamycin, asukamycin, and ( )-nisamycin (8) have been synthesized by similar strategies [91]. 

Topaquinone (TPQ), the oxidized form of 2,4,5-trihydroxyphenylalanine (TOPA), is the cofactor of copper-containing amine oxidases. The following model compounds have been prepared in order to understand the catalytic function of TPQ the jV-pivaloyl derivative of 6-hydroxydopamine in aqueous acetonitrile [38] topaquinone hydantoin and a series of 2-hydroxy-5-alkyl-l,4-benzoquinones in anhydrous acetonitrile (o- as well as />-quinones) [39] 2-hydroxy-5-methy 1-1,4-benzoquinone in aqueous system [40] and 2,5-dihydroxy-1,4-benzoquinone [41]. Reaction of model compounds with 3-pyrrolines revealed why copper-quinopro-tein amine oxidases cannot oxidize a secondary N [42], The studies clearly showed that certain model compounds do not require the presence of Cu for benzylamine oxidation whereas TPQ does [38,40] the aminotransferase mechanism proceeds via the -quinone form [39] the 470 nm band can be ascribed to a 71-71 transition of TPQ in />-quinonic form with the C-4 hydroxyl ionized but hydrogen bonded to some residue [40] hydrazines attack at the C-5 carbonyl, forming an adduct in the azo form [41], Electrochemical characterization has been carried out for free TPQ [43],... 

A synthesis of lapachol using reaction conditions better than those used by Fieser was carried out by Fridman et al [149].They used the lithium salt of 2-hydroxy-1,4-naphthoquinone prepared in situ instead of the silver salt used for Fieser [150]. The lithium salt was prepared in situ by addition of lithium hydride to the frozen solution of the quinone in dimethyl sulfoxide, Fig. (14). As the solution thawed, the lithium quinone was slowly formed and was then alkylated with 3,3-dimethylallyl bromide. Lapachol was thus obtained in 40% yield. 

A total synthesis of ( )-royleanone from 5,7,8-trimethoxy-l-tetralone (123) has been described.129 The tetralone was converted into the tricyclic ketone (124), which was in turn converted into 11,12,14-trimethoxypodocarpatriene (125). Demethyla-tion and oxidation afforded the quinone (126 R = H) which was alkylated to give royleanone (126 R = Pr ). Synthetic studies in the resin acid series have led130 to the preparation of the dicarboxylic acid (127) with a cis a/b ring junction. The preparation of some tetracyclic ketones as intermediates for gibberellin synthesis has been described.131 132 The key reaction involves photolysis of a diazoketone (128) to afford the tetracyclic system (129). In a synthesis of phyllocladene from abietic acid... 

Reaction of the monocyanoethyl-protected TTF 738 with cesium hydroxide in a mixture of methanol and DMF led to the deprotected thiolate, which was further alkylated with the bromobutyl-substituted MOM-triptycene 739 to give the MOM-TTF 740 in 89% yield (MOM = methoxymethyl). The MOM protecting group was removed quantitatively under acidic conditions and the resulting hydroquinone was oxidized to yield the TTF-quinone 741 in 54% yield (Scheme 109). The preparation of the pyrrolo-TTF derivatives 25 was accomplished in a similar way <1998JOC1198>. 

Oxidation of 3-phenyl-7-hydroxybenzothiophene with Fremy s salt afforded, in almost equal amounts, 3-phenyl derivatives of 156 and 157 (70MI3). Difficulties were encountered in the preparation of quinones from substituted alkyl benzothienyl-3-acetates. The only successful conversion of ethyl 6-hydroxy-5-methoxybenzothienyl-3-acetate was in a two-phase system with either aqueous periodate or thallate. The quinone was obtained in low yield (79JHC231). Some exteneded analogs could be prepared directly from the hydrocarbons with chromic acid (53CB366 56JCS3435). 

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