Substituted naphthoquinone synthesis

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

Compounds showing vitamin K activity are substituted naphthoquinones. The parent compound, 2-methyl-1,4-naphthoquinone, does show some biological activity as do other similar but synthetic compounds. The production of the complete naturally active forms is thought to depend upon the addition of an isoprene chain at position 3 on the aromatic ring. Differences in this side chain produce the various K vitamins (Figure 12.10). A most important physiological role of vitamin K is in the synthesis of the blood clotting factors, II (prothrombin), VII, IX and X. 

Anthraquinones. A regioselective synthesis of polyhydroxyanthraquinones is based on Dicls-Alder reactions of I with chloro-substituted naphthoquinones. An example is the synthesis of 1,6-dihydroxyanthraquinone (3) from 3-chlorojuglone (2). Analogous syntheses arc possible by use of vinylogous kctcnc acetals related to I. 

Bcnzofuran-4,7-dioncs have been synthesized regioselectively by [3 + 2] photoaddition of 2-hydroxy-1,4-benzoquinones with a range of alkenes (equation 185)664. The reaction occurs in 30-60% yield and is a useful method for the synthesis of the benzofuran ring system, which is important in natural products like acamelin665. Substituted naphthoquinones may also be used in this reaction666,667 and this has lead to a very simple two-step synthesis of maturinone. In a similar reaction, a [3 + 2] photoaddition reaction of 2-amino-1,4-naphthoquinones with electron-rich alkenes gave 13-82% yields of 2,3-dihydro-177-bcn/ /]indole-4,9-diones in a single-step process which involved photolysis followed by oxidation (equation 186)668,669. 

The photoenolization of the quinone (286) can be carried by irradiation at 313 or 365 nm in acid solution. The steady state irradiation has identified the product as the unstable hydroxylated compound (287) which is formed via the enol (288). The presence of this intermediate was detected in a laser flash study of the reaction. The quinones (289) undergo cyclization when irradiated with visible light.The mechanism by which the compounds (289) are transformed into the derivatives (290) involves the production of an excited state that is either a zwitterion or a biradical. After the transfer of a hydrogen the intermediate (291) is formed. It is within this species that cyclization occurs to give the final products. (2+2)-Cyclo-adducts such as (292) and oxetanes can be obtained by the photochemical addition of quinones to homobenzvalene. Interest in the photo-SET in quinone systems has led to the synthesis of the pyropheophytin substituted naphthoquinone dyads (293). A pulse radiolysis study of vitamin K in solution has been reported. 

A general regiocontrolled benzannulation reaction mediated by Pd2 (dba)3, in the presence of tri-2-furylphosphine, allows the synthesis of substituted naphthoquinones 23 from reaction of stan-nylquinones 21 and 4-chlorocyclobutenones 22 (eq 17). ... 

The synthesis of the naphthoquinone 116 is shown in Scheme 3.24. Bromination of juglone (118) afforded the dibromojuglone derivative 134. Protection of the phenol group as its methoxymethyl ether formed the product 135 (50 % yield over two steps). Finally, the C-3 bromide substituent was regioselectively substituted with methoxide by heating 135 in methanol in the presence of sodium carbonate (96 %). The methoxy group was installed to impart electronic bias to the naphthoquinone in the TASF(Et) coupling (vide infra). 

Sulfur-substituted 3-vinylpyrroles generated from A -methyl-3-thioace-tylpyrrole have been used to accomplish the synthesis of functionalized indoles by Diels-Alder cycloaddition. In the reactions with MA, NPMI, and naphthoquinone the [4 + 2]-cycloadducts were obtained with low to moderate yields and directly transformed to the corresponding indoles by treatment with DDQ (91CPB489). 

Quinone synthesis (13, 97-98 209-210). Liebeskind1 has reviewed the use of organolithiums for preparation of benzoquinones from cyclobutenedione and of the reaction of benzocyclobutenediones with C1Co[P(C6Hj)3]3 to form either benzoquinones or naphthoquinones. These routes are particularly useful for regioselective synthesis of highly substituted quinones. 

Compounds of type LXXIII cannot be made by the rearrangement of the 7-substituted allyl ethers, because these compounds yield LXXIV by inversion. a,7-Dimethylallyl bromide,16 7,7-dimethylallyl bromide,29 cinnamyl chloride,84 and phytyl bromide 86 (a vitamin K synthesis) have been used in C-alkylation procedures. The silver salt of 2-hydroxy-l,4-naphthoquinone is converted to a mixture of C-alkylation product and two isomeric ethers by treatment with allylic halides and benzyl halides. ... 

Diacyl peroxides are good agents for the alkylation of p-benzo- and 1,4-naphthoquinones having a free position in the quinoid ring, particularly when the normal- or iso-alkyl chains are desired (3( 60%). The method has been widely applied in the synthesis of 2-hydroxy-l,4-naphthoquinones substituted in the 3-position. The procedure consists in adding slowly a solution of the diacyl peroxide in ether to a solution of the quinone in acetic acid at 90-95°. 

A synthesis of the carbazolequinone alkaloid murrayaquinone-B, previously isolated from the root bark of Murraya euchrestifolia, is described and the compound was obtained in 13% yield (88JCS(P1)241). Photolysis of 2-amino-1,4-naphthoquinone afforded the pentacyclic quinone 61 (R = H) and some of its N-substituted derivatives (88TL591). From 2,3-dibromo-5,6-dimethyl-l,4-benzoquinone, ethyl acetoacetate, and pyridine, a derivative of the indoiequinone system related to 65 was prepared (87IJC180). 

A novel O-deprotection protocol involving anodic cleavage of aromatic ether (LXXXV) was effectively used in the total synthesis of the natural products alkannin and shikonin [Eq. (42)]. The electrolysis was conducted at a carbon anode in MeCN/ H2O with LiC104 as electrolyte, giving an 80% yield at 50% conversion [97]. Although both naphthoquinone tautomers were initially formed after trapping of the radical cation by water and loss of CH2O, the tautomer with alkyl substitution at the quinone double bond was more thermodynamically stable. 

Anthracene homologs can also be prepared in this way, by using derivatives of cyclohexadiene. Further, 1,4-naphthoquinone can be used as starting material (for a single diene synthesis) and the ethylene bridge may be substituted without destroying the ability of the product to split off the ethylene derivative. 

Methods for the synthesis of hetaryl-substituted 1,4-benzo- and 1,4-naphthoquinones 05KGS803. 

The first account on 1,2-dione/diamine condensation carried out mechanochemically was given by Zefirov, who investigated solid-phase synthesis of benzo[Mphenazme 3 by reaction of phenylenediamine 1 with 2,3-naphthoquinone 2 (Scheme 3.1) [1]. Synthesis was carried out in an SVM-0.4 vibrational ball mill (120mL chamber volume). Cascade reaction mechanism consists of the four reactions substitution, elimination, cyclization, and elimination. 

Kour and coworkers prepared substituted phenazines by cross-coupling benzoquinones with o-phenylenediamines in acetic acid at -10 °C (Scheme 49) (14SL495).The desired products were obtained in good-to-high yields. Furthermore this method was applied to the synthesis of benzo [a] phenazines by treating 1,4-naphthoquinone with o-phenylenediamines in the presence of copper acetate at 50°C. The products of this transformation were obtained in 70-78% yield. 

The substituted o-xylylene intermediates 18 and 19 demonstrate that electron-deficient substituents can be tolerated. The use of intermediates 17, 18, and 19 provide a convenient entry into the synthesis of 1,4-naphthoquinones with electron-withdrawing groups in the 2,3,6,7-positions as well as just in the 6,7-positions (Figure 7.5). 

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