2-methoxy-6-vinylnaphthalenes

Table 6 The effect of substituents in carbohydrate phosphine (28) on the asymmetric hydrocyanation of 2-methoxy-6-vinylnaphthalene.

The related field involving the hydrocarboxylation of alkenes is also under investigation11481, not least because of its potential importance in the synthesis of NSAI drugs. An indirect way to the latter compounds involves the hydro-vinylation of alkenes. For example catalysis of the reaction of ethylene with 2-methoxy-6-vinylnaphthalene at 70°C using (allylNiBr)2 and binaphthyl (63)... 

Other approaches that have been suggested include catalytic asymmetric hydroformylation of 2-methoxy-6-vinylnaphthalene (6) using a rhodium catalyst on BINAPHOS ligand followed by oxidation of the resultant aldehyde 7 to yield 5-naproxen (Scheme 6.3).22 However, the tendency of the aldehyde to racemize and the co-generation of the linear aldehyde isomer make the process less attractive. Other modifications related to this process include catalytic asymmetric hydroesterification,23 hydrocarboxylation,24 and hydrocyanation.25... 

Fig. 2. Prototypical phosphinites used as ligands in asymmetric hydrocyanation Table 1 Hydrocyanation of 2-methoxy-6-vinylnaphthalene effect of sugar backbone...

An example of an industrial Heck reaction of an aryl bromide is the announced synthesis of Naproxen by Albermarle. Toward that end, 2-bromo-6-methoxynaphthalene is reacted with ethylene in the presence of a homogeneous palladium catalyst. Apparently, as a ligand a sterically hindered basic phosphine is used. Known Pd-catalyzed hydro-carboxylation of 2-methoxy-6-vinylnaphthalene and subsequent resolution give access to Naproxen (Scheme 3). In addition, it was shown that Ketoprofen can be produced by a similar reaction sequence. 

The key step—the alkenylation—in the Naproxen process has also been developed with the so-called palladacycle catalyst on a kilogram scale by Hoechst AG and Hoechst-Celanese in 1995. Here, 2-methoxy-6-vinylnaphthalene was obtained in 89% yield at 20 bar ethylene pressure. High catalyst turnover numbers of ca. 10,000 were realized, but due to a shift in the company s strategy no further development was made. 

Enantiomeric excess was obtained by chiral HPLC using a Daicel Chiralcel OB column (styrene hydrocyanation 99 1 hexane/2-propanol 1.0 mL min 40°C. 6-methoxy-vinylnaphthalene hydrocyanation 93 7 hexane/2-propanol 0.5 mL min 40 C). 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

Variation in catalyst and ligand can lead to changes in both regio- and enantio-selectivity. For example, the hydroboration of vinyl arenes such as styrene and 6-methoxy-2-vinylnaphthalene can be directed to the internal secondary borane by use of Rh(COD)2BF4 as a catalyst.166 These reactions are enantioselective in the presence of a chiral phosphorus ligand. 

This same trend is produced upon addition of HCN to 4-isobutylstyrene, but in the case of 6-methoxy-2-vinylnaphthalene, all three ligands afford ca. 30% enantiomeric excess. 

The enantioselectivity increases dramatically when the ligands contain electron-withdrawing P-aryl substituents. Electron-donating substituents on the substrate give the highest ee (91% for 6-methoxy-2-vinylnaphthalene in apolar solvents). Mechanistic studies at room temperature have shown that at low concentration of HCN nickel zero species are the resting states, but at higher concentrations of HCN q3-benzyl nickel cyanide species were also observed. 

Although these reactions are highly versatile, so far they have not found significant industrial applications. The main reasons for this are relatively low thermal stabilities and turnover numbers of the catalytic systems, and the salt waste problem. However, Hoechst is trying to develop an industrial process for the manufacture of 6-methoxy 2-vinylnaphthalene by reaction 7.31. The precatalyst used is the dimeric phosphapallada cycle 7.63, which operates below a pressure of 20 atm and temperature of 130°C. 

There are several ways by which a palladium(II) species can be reduced to palladium(O). In the reaction to form 6 methoxy-2-vinylnaphthalene (Equation 11) reduction of the palladium(II) species to palladium(0) occurs with concomitant oxidation of the tertiary phosphine (Equation 15). 

HCN addition to 6-methoxy-2-vinylnaphthalene occurs readily at 25 °C in the presence of these optically active Ni complexes to give the branched nitrile exclusively and in high yield. The enantioselectivity (R versus S) of the... 

Methoxy-2-vinylnaphthalene (MVN) 30 is hydrocyanated under the catalytic influence of Ni° complexes 31a-e of 1,2-diol phosphinites that are derived from readily available mono- and di-saccharides. The sugar backbone and substitution of the phosphorus-attached aryl groups have a pronounced effect on the reaction pathway. It is shown that electron-withdrawing groups on the aryl ligands dramatically increase the stereoselectivity. As much as 85% ee was obtained when... 

The coupling of ethylene with 6-methoxy-2-bromonaphthalene (eq. (16)) is efficiently catalyzed by palladacycles 4. The ethylene reacts only once, thus yielding 6-methoxy-2-vinylnaphthalene in excellent selectivity and yield [57]. This elegant reaction is being developed as an industrial process by the former Hoechst AG, possibly the first industrial Heck coupling after the 30 years during which this type of reaction has been in existence. 

An unfortunate consequence of this polarization was a set-back to a steroid synthesis along these lines. Citraconic anhydride (239) reacted with the 1-vinylnaphthalene (238) to give the adduct (240) and not the adduct (241) which would have been useful for a steroid synthesis.195 The polarization of the LUMO of citraconic anhydride has been explained earlier (p. 137) and plainly leads to the observed product. Evidently the methoxy group in 238 has not changed the relative sizes of the coefficients from that shown in 235. For a sequel to this set-back, see p. 164. 

Another impressive exanqtle for the importance of electronic asymmetry in the design of chelating chiral ligands was reported by RajanBabu and Casalnuovo for the asymmetric hydrocyanation reaction . As chiral ligands 3,4-phosphinites from D-fructofiiranoside derivatives were synthesized. The unsymmetrical phosphinite with the more electron-deficient phosphorous at the C4-position of fiuctose gave superior enantioselectivities for the hydrocyanation of 6-methoxy-2-vinylnaphthalene. 

Similarly hydrovinylation of 4-isobutylstyrene or 6-methoxy-2-vinylnaphthalene, ozonolysis and oxidation gives ibuprofen (11) and naproxen (12) with high ee values5. 

Asymmetric hydroesterification of styrenes is suggested as an alternative route to optically active 3-arylbutanoic acids, a series of nonsteroidal anti-inflammatory drugs18. Thus, with palladium(0)bis(dibenzylideneacetone) in the presence of NMDPP and trifluoroacetic acid 6-methoxy-2-vinylnaphthalene gives the pharmaceutically interesting methyl (— )-2-(6-methoxy-2-naphthvl)propanoate (naproxen) with 42% ee20. 

I) Dependence of the second excimer to monomer intensities ratio 1 d z /I m of poly(methoxy-4-vinylnaphthalene)(PMVN) in polystyrene matrix on the... 

Recently, ee s of 85-90% have been obtained for the asymmetric hydrocyanation of 6-methoxy-2-vinylnaphthalene using nickel complexes of chiral bidentate phosphinites derived from glucose (abbreviated PP, equation 12). This reaction is of great interest to the pharmaceutical industry because the S) enantiomer of the product nitrile is a useful precursor for the widely marketed antiinflammatory drug naproxen (equation 13). The same reaction can be applied to a number of other vinyl aromatic compounds, including the precursor for the antiinflammatory drug ibuprofen (6) however, the ee is not as high. 

---