477-Chromene, formation

With an effective catalytic resolution of allylic styrene ethers in hand, we focused our attention on the Ru-catalyzed reaction of disubstituted styrenyl ethers (e.g., 49). When we treated (S)-49 with 10 mol% la under an atmosphere of Ar (Scheme 12), we found chromene formation to be sluggish 25-30% of dimer (S,S)-50 was isolated after 48 h at 45°C, together with substantial amounts of oligomeric materials. 

In contrast to the reaction carried under an Ar atm, when (S)-49 was treated with 10 mol% la under an atmosphere of ethylene (22°C, CH2C12,24 h), (S)-41 was obtained in 81% isolated yield and >98% ee (Scheme 12). As expected, the use of ethylene atmosphere proved to be necessary for preferential monomer formation (10% of the derived dimer was also generated). These results indicate that the presence of ethylene is imperative for efficient metal-catalyzed chromene formation as well for processes involving disubstituted styrenyl ethers (25-30% yield of dimer 50 under argon). 

As was mentioned previously, certain disubstituted styrene ethers can be efficiently resolved through the Zr-catalyzed kinetic resolution. As illustrated in Eq. 7, optically pure cycloheptenyl ether 64c is obtained by the Zr-catalyzed process. The successful catalytic resolution makes the parent alcohol and the derived benzyl ether derivatives 64a and 64b accessible in the optically pure form as well. However, this approach cannot be successfully applied to all the substrates shown in Table 1. Lor example, under identical conditions, cyclopentenyl susbstrate 60b is recovered in only 52% ee after 60% conversion. Cycloheptenyl substrates shown in entry 4 undergo significant decomposition under the Zr-catalyzed carbomagnesation conditions. These observations indicate that future work should perhaps be directed towards the development of a chiral metathesis catalyst that effects the chromene formation and resolves the two styrene ether enantiomers simultaneously. 

C. W. Johannes, M. S. Visser, G. S. Weatherhead, A H. Hoveyda Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (SJUUD-Nebivolol J. Am Chem Soc 1998, 120, 8340-8347. For development of the enantioselective methodology, see M. S. Visser, J. P. A. Harrity, A. H. Hoveyda Zirconium-Catalyzed Kinetic Resolution of Cyclic Allylic Ethers. An Enantioselective Route to Unsaturated Medium Ring Systems , J. Am Chem Soc 1996,118, 3779-3780. 

The pyridine-catalyzed aromatic proton exchange with deuterium provides a simple indication of the ability of a phenol to participate in chromene formation. Only those phenols which undergo exchange react with the unsaturated carbonyl compound, the attack occurring at the positions of deuteration (64JA2084). 

Chromene formation also results from the reaction of DDQ with the isomeric but-l-enyl derivatives (104). Similar structural restrictions are apparent. Thus, 2-(3-methylbut-l-enyI)phenol affords the chromene, whereas the unsubstituted compound does not cyclize. 

Cyclocondensation of phenols with a, fi-unsaturated carbonyl compounds Chromene formation is catalyzed by base, aldehydes are favoured as cyclocondensation components. 

In intramolecular reactions, both exo- and endo-mode cyclizations may be observed. In a study of chromene formation, endo-cyclization giving the chromene 6.194 was generally the preferred pathway the observation of the 5-exo product 6.193 was attributed to fragmentation of the organogold intermediate 6.191 prior to protonation, to give an allenic intermediate 6.192, followed by cyclization (Scheme 6.90). ... 

Banderanayake, M., M.J. Begeley, B.O. Brown, D.G. Clarke, L. Crombie, and D.A. Whiting Synthesis of Acridone and Carbazole Alkaloids Involving Pyridine Catalysed Chromene Formation Crystal and Molecular Structure of Dibromocanna-bicyclol and Its Bearing on the Structures of Cyclol Alkaloids. J. Chem. Soc. Perkin I, 999 (1974). 

As expected, the formation of a carbonyl group is not possible with tert-allylic alcohols. Although the aromatic ring bears electron-donating groups, the 2,2-disubstituted chromene 119 was formed smoothly with the tert-allylic alcohol 118[100]. 

R] (a) Hauser, C. R. Swamer, F. W. Adams, J. T. Org. React. 1954, 8, 59. [R] (b) Ellis, G. P., Chromenes, Chromanones, and Chromones from The Chemistry of Hetereocylic Compounds, Weissberger, A. and Taylor, E. C., eds John Wiley Sons, 1977, vol. 31, New York, p.495. Note The author in the former reference refers to the formation of chromones, coumarins, and flavones as the Kostanecki acylation while the latter author calls the formation of chromones and coumarins the Kostanecki-Robinson reaction. 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

Scheme 12. In the Ru-catalyzed conversion of disubstituted styrenyl ethers to chromenes the presence of ethylene is required for reaction efficiency as well as high yield of monomer formation...

Catalytic reactions of disubstituted styrenyl substrates diminish oligomeric product formation because of the presence of ethylene. That is, if the initial transformation of the Ru-carbene occurs with the undesired regiochemis-try (e.g., 49->52 in contrast to 49->51, Scheme 13), dimerization and oligomerization may predominate, particularly in situations where reclosure of the carbocyclic ring is relatively slow (e.g., cycloheptenyl substrates). In contrast, as illustrated in Scheme 14, in the presence of ethylene atmosphere, the unwanted metal-carbene isomer 52 may rapidly be converted to triene 53. The resulting triene might then react with LnRu=CH2 to afford metal-carbene 51 and eventually chromene 41. 

An advantage of the metal-catalyzed conversion of styrenyl ethers to chromenes is that control of relative stereochemistry on the carbocyclic substrate before catalytic synthesis of chromenes can lead to the formation of various functionalized heterocycles that are diastereomerically pure (Table 1). 

The photochromic mechanism for the chromenes is very similar to that for spiropyrans given in Figure 1.1. Under the influence of UV the C-0 bond in the pyran ring is broken to give either the zwitterionic form or, more likely, the cis- and fran.y-quinoidal forms (Figure 1.6). Studies suggest that formation of the cis-quinoidal species occurs in picoseconds, followed by generation of the trans-form in nanoseconds. 

The formation of the chromene caibamate 21 from resorcinol dicarbamate involves directed ortho metallation and an intramolecular 0- 0 carbamoyl transfer. Further manipulation utilising directed metallation and transition metal catalysed reactions allows the synthesis of plicadin, a naturally occurring coumestan <99AG(E)1435>. 

An effective method for the regioselective formation of chromenes has been reported by Subburaj et al. using base-catalyzed conditions (Equation 38) <1997J(P1)1875>. Trost < / /. have shown that pyranocoumarins can be synthesized using palladium catalysis, although regioselectivity problems are encountered (Equation 39 Table 7) <2003JA4518>. 

The chromenes and benzofurans are rather simple compounds built from acetate and Isoprene metabolites. Heterocyclic ring formation gives rise to 2,2-dlmethyl chromene or 2-isoprophenyl benzofurans. The majority of known chromenes and benzofurans exhibit a methyl ketone moiety at a position para to the oxygen of the heterocyclic ring. Constituents esterified with phenolic acids or lacking methyl ketones are rare. 

Very recently, Fujii and Ohno developed a route for the synthesis of dihydroquinoline and chromene derivatives under mild reaction conditions. Hydroarylation leads to a highly selective formation of six-membered rings, depending on the carbon (terminal or central allenic) that reacts with the aryl moiety [50]. 

Another reaction which requires o-quinoneallides as intermediates is the synthesis of chromenes from benzyne and ,/3-unsaturated aldehydes (Scheme 5).189 The formation of the unstable benzoxete was confirmed by isotope labeling. Yields are in the range 4—40%. 

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