Preparation of methoxy-substituted para-benzoquinones

A facile route to 5-substituted 2-methoxy-para-benzoquinones from 5-substituted 2-methoxyphenols is described. Spectral data of the compounds is discussed. The cyclovoltammographic behaviour of some of the 2-methoxy-parabenzoquinones is shown. The synthetic route is also used to prepare steroid-methoxy-para-benzoquinone hybrids.


Introduction:
Quinones are distributed widely in living organisms.Some of the more familiar ones are plastoquinone and phylloquinone, both quinones needed in photosynthesis, and ubiquinone, also known as coenzyme Q10, which participates in the aerobic cellular respiration.All of the above are substituted p-benzoquinones.Anthracyclines can be viewed as having a quinoid group.A number of members of this family such as daunorubicin and doxorubicin are used in cancer chemotherapy.Also menadione (2-methylnaphtho-1,4-quinone), which is sold as a nutritional supplement as a vitamin K mimic, has been viewed as a potential drug for prostate cancer treatment (Jamison 2001).Overall, in 1991, quinones constituted the second largest group of cytotoxins used in chemical cancer therapy, after specifically alkylating agents such as mustards (O'Brien 1991), with about 1500 quinones already tested in 1974 (Driscoll et al. 1974).Quinones have a number of actions in the body.In strongly dividing cells, their most influential action is the interaction with DNA material which may lead to DNA damage or to changed DNA resulting in cell mutations (O'Brien 1991).In non-dividing cells or in cells at rest the main action of the quinones is a possible alkylation of proteins through their thiol or amino groups (O'Brien 1991).Most important, though, is the reduction of the quinones to the respective semiquinone radicals by reductase.The semiquinone radicals in turn reduce oxygen to superoxide radicals and reform as quinones.The superoxide radicals, which are usually scavenged in the body by the enzyme superoxide dismutase, are very toxic and lead among others the oxidation of cystein residues to cystine in proteins and the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) (O'Brien 1991).
It has been found that the protein NAD(P)H:quinone oxidoreductase (QR1) is overexpressed in many human solid tumours such as adrenal, thyroid, breast, ovarian, colon, and non-small-cell lung cancer (Siegel and Ross 2000).This enzyme poses a possible target for quinone drugs.Recently, the crystal structure of the protein complexed to different synthetic quinones has been published (Faig et al. 2001).Among other details, it had been shown that the protein is relatively flexible to ligand differently substituted quinones, which may bind to QR1 in different orientations.With the known cancer activity of anthracyclines and the idea of utilizing steroidal moieties and drug delivery systems, anthracyline-steroid hybrids (Dao et al., 2012) such as 7 (Figure 1) (Hartman et al., 1990) were synthesized and their biological activity was investigated.These studies were extended to dihydroxyarenoquinone containing steroids such as 1, 2 and 3 (de Riccardis et al., 1997;de Riccardis et al., 1998), then to quinoid containing steroid 4 (Fujiwara et al., 2011) and steroidal mimic 5 (Kaliappan & Ravikumar, 2005).The Thiemann group had communicated the annelated steroidal anthraquinone 6 previously (Ribeiro Morais et al. 2005).
Against this background, the authors have studied simple ways to synthesize substituted quinones, also with the aim of linking quinoid structures to steroidal bodies.Also, the authors have been interested to study the electrochemical response of p-benzoquinones.In continuation of our work on alkyl substituted quinones (AlAzani 2015), we present here an easy access to methoxysubstituted 1,4-benzoquinones that can also be linked to steroidal moieties.

a.) Synthesis
In recent times, we have developed a short route to amidoethylquinones (Al Soom 2016a, AlAzani 2015), alkylquinones and their derivatives.The route starts from commercially available 2,5dimethoxybenzaldehyde 8 which is converted to cinnamate 9.This is hydrogenated to phenylpropionate 10 (NaBH4, AcOH, Pd/C) (Russo 2011, al Soom 2016b) and hydrolyzed to phenylpropionic acid 11.The phenylpropionic acid is converted to either an amide or an ester by a modified Appel reaction (BrCCl3, PPh3, CH2Cl2) (AlAzani 2016) which links the quinone precursor to a second moiety of interest, either as a potential drug delivery system or for other purposes.In the last step the 1,4-dimethoxy-substituted phenyl group is converted to the p-quinoid in a conventional way using cerium ammonium nitrate (CAN).A typical example of such an approach is shown in Scheme 1, where the quinoid moiety is connected to cholesterol (12) at C3 via an ester function to give 14 (Al Soom 2016a).Scheme 1. Overall reaction sequence to 3-cholesteryl 1,4-quinon-2-ylpropionate 14 Here, we had wanted to explore a similar approach starting out with 3-hydroxy-4-methoxybenzaldehyde with the idea of finally converting the 3-hydroxy-4-methoxyphenyl group to an ortho-quinone system.3-Hydroxy-4-methoxybenzaldehyde (25) could either be protected as its O-benzyl derivative 26 and then converted by Wittig reaction to the corresponding cinnamate 27 or reacted directly by Wittig reaction to the hydroxy-substituted cinnamate 32.Reductive hydrogenation (NaBH4, AcOH, Pd/C) of both the benzyloxy-substituted cinnamate and the hydroxyl-substituted cinnamate provides, after hydrolysis, 3-hydroxy-4-methoxyphenylpropionic acid (31).This can be esterified or amidated to compounds 15.

Starting material
Product (Yield) 16d n = 4 (63%)  The conversion of 3-hydroxy-4-methoxyarenes to methoxyquinones was also used to link a methoxyquinone to cholesterol as shown in Scheme 6.In all, the transformation from 3-hydroxy-4-methoxyphenylpropionamides and 3-hydroxy-4-methoxyphenylpropionates to the corresponding methoxyquinones, pursued in this contribution, is worth a more comprehensive study.
The UV-VIS spectra of the acquired quinones were measured in CH2Cl2 and CH3CN (Table 2).
No appreciable solvent effect was noted, however.The isolated alkyl-substituted quinones show an intense absorption at  = 245 -250 nm and a weaker absorption band at  = 305 -325 nm (see Table 5), while the carboxyl-substituted quinone xx absorbs at λ = 245 nm and λ = 325 nm.The methoxy substituted quinones display an intense absorption at  = 265 nm and a weaker absorption band at  = 350 -360 nm, meaning that both absorption bands are shifted towards lower energy versus the isolated quinone systems.
According to the literature, both absorptions that were observed are related to -* transitions.n-* Transitions have been reported to be very weak and at longer wavelengths (400-500 nm and 650 nm, respectively) (Orlando et al. 1968, Kuboyama 1962).These were not specifically looked for in our case.Structural and orbital calculations of 2-methoxy-5-methyl-1,4-benzoquinone and 2-methyl-1,4-benzoquinone indicated a bathochromic shift of the 2-methoxy-5-alkyl substituted benzoquinone versus the 2-alkyl substituted benzoquinone of about Δλ = 15 nm, which was also found experimentally, without reproducing the exact λmax of the electronic transitions (Figure 2).Also, in continuation of our studies of the electrochemical behavior of substituted quinones (AlAzani 2013, Gomez-Berenguer 2012), we have subjected methoxyquinone 16d to a cyclovoltammographic study in acetonitrile/H2O (95:5) (Figure 3).

Conclusion and future target:
Here, it could be shown that alkylated 3-hydroxy-4-methoxyarenes can be oxidized to methoxy substituted quinones.This strategy was also used to prepare quinone-steroidal hybrids (eg., quinone-cholesterol hybrids).In the UV spectra, the methoxy-substituted alkylquinones exhibit a slight bathochromic shift as compared to alkylquinones themselves.Future targets remain estradiol-quinone hybrids of type 38 and 39 (Figure 4).A corresponding estradiol bound to a pquinoid moiety through C17(OH) via an ester linkage has already been synthesized along the synthetic lines shown above.

Figure 1 .
Figure 1.Overview of steroid derived quinone hybrids and steroid mimic quinone hybrids from the literature.

Figure 4 .
Figure 4. Future targets of this work

Table 1 .
(Reed and Moore 1988)xy-4-methoxyphenylpropionate and 3-hydroxy-4methoxyphenylpropionamides 15 to alkoxycarbonylethyl-methoxy-quinone and amidoethyl-methoxy-quinones 16 with cerium ammonium nitrate (CAN) in a mixture of CH3CN and H2O.The conversion of the hydroxyl-methoxyarene to the methoxyquinone system is of interest and not trivial as, as said above, it could have been envisaged that an ortho-quinone (minus methoxy group) would form as there is some precedence for this as in the synthesis of isopsoralenquinone 18 (Scheme 2)(Reed and Moore 1988).
(Reed and Moore 1988)f isopsoralenquinone (18) by CAN oxidation of 17(Reed and Moore 1988).There are some examples, however, where an oxo group is introduced para to a hydroxy-or methoxy group upon reaction with CAN, if the para-position is available.Examples are given in Schemes 3, 4 and 5. Scheme 3. Oxidation of bromonaphthol 19 to naphthoquinone 20 with CAN(Wu et el.2011)