Palladium-catalyzed ring-opening reactions of cyclopropanated 7-oxabenzonorbornadiene with alcohols

Palladium-catalyzed ring-opening reactions of cyclopropanated 7-oxabenzonorbornadiene derivatives using alcohol nucleophiles were investigated. The optimal conditions were found to be 10 mol % PdCl2(CH3CN)2 in methanol, offering yields up to 92%. The reaction was successful using primary, secondary and tertiary alcohol nucleophiles and was compatible with a variety of substituents on cyclopropanated oxabenzonorbornadiene. With unsymmetrical C1-substituted cyclopropanated 7-oxabenzonorbornadienes, the regioselectivity of the reaction was excellent, forming only one regioisomer in all cases.

While the nucleophilic ring openings of oxabenzonorbornadiene 1 have been extensively studied, no examples of a metalcatalyzed ring opening of cyclopropanated compound 8 have been reported in the literature. Oxabenzonorbornadiene 1 and its derivatives are first cyclopropanated with diazomethane under palladium catalysis to afford 8 in good to excellent yields [29]. Cyclopropanated 8 has been predicted to undergo three distinct ring-opening mechanisms (Scheme 3). The first ringopening type (type 1) involves the attack of the nucleophile at bridgehead carbon A, resulting in cleavage of the C-O bond. Through deprotonation at the bridgehead position and an internal rearrangement, 2-methyldihydronaphthalen-1-ols 9 could be formed. This type 1 ring opening has been accomplished by our group through the use of organocuprate nucleophiles [30]. The second type of predicted ring opening (type 2) involves the attack of the nucleophile at the external cyclopropane carbon B, resulting in the cleavage of the cyclopropane C-C bond followed by a C-O bond cleavage to produce 2-substituted dihydronaphthalenols 10. Under thermal conditions, the dihydronaphthalenols can fully aromatize to form various substituted naphthalene derivatives 11. This has been accomplished through acid catalysis with various alcohol nucleophiles [31]. The last type of predicted ring opening (type 3) which has not yet been observed involves the attack of the nucleophile at the internal cyclopropane carbon C, which could induce ring expansion to form seven-membered ring 12 .
In this paper, we aim to explore the use of a palladium catalyst with an alcohol nucleophile on the ring opening of cyclopropanated oxabenzonorbornadiene with the goal of determining which type of ring-opening pathway it follows. This complements previous studies by our group involving the ring opening of cyclopropanated oxabenzonorbornadiene through the novel use of a transition metal catalyst. Using a transition metal catalyst could reveal new ring-opening pathways and provide further insight into the reactivity of strained cyclopropanated oxabicyclic compounds.
A variety of solvents were next screened including polar aprotic, polar protic, and aromatic solvents ( Table 2). The polar aprotic solvents DMSO, DMF, and acetonitrile (  ( Table 2, entry 8). The polar protic solvent methanol was investigated since it is also a nucleophile and showed a high yield of 89% (Table 2, entry 11). Using methanol, the effect of temperature was investigated. Decreasing the temperature to 40 °C resulted in a reduction of yield to 70% ( Table 2, entry 12) while further lowering the temperature resulted in no reaction ( Table 2, entry 13).
The scope of the reaction was expanded to include type 2 ring openings of symmetrical substituted cyclopropanated 7-oxabenzonorbornadiene ( Table 3). The effect of substituents at both bridgehead positions was first investigated. With a methyl group at both bridge head positions, the yield was decreased to 40% at 90 °C ( Table 3, entry 1). Substitution on the arene portion of cyclopropanated oxabenzonorbornadiene 8a was in-vestigated. p-Methoxy-substituted 8c underwent minimal conversion to the ring-opened product with a yield of only 5% (Table 3, entry 2). While no starting material was recovered, a complex mixture of products were observed. o-Methoxy-substituted 8d was able to undergo ring opening to produce 11d in a moderate yield of 46% (Table 3, entry 3). The effect of a halide substitution on the arene was also investigated in the ortho position which decreased the yield to 37% (Table 3, entry 4).
The scope of the reaction was then extended to include examples of unsymmetrical functionalized substrates 8f-j bearing substituents at the C1 position. With a substituent at the C1 position, the formation of two regioisomers is possible (Scheme 4). The bridgehead-oxygen bond can break in two different directions (a or b), creating either a tertiary or secondary cation which after the nucleophilic ring opening creates two different regioisomers. In all cases, the regioselectivity of this reaction is excellent, forming only one regioisomer. Compared with the reaction of unsubstituted 8a, substitution at the C1 position significantly decreased the yield (Table 4). When the size of the substituent increases, the general trend is that the yield of the reaction decreases. Unexpectedly, with a methyl group at the C1 position, however, the yield was lower than with larger substituents at the C1 position with starting material still being recovered after one week. The reaction was repeated multiple times both at 60 °C (Table 4, entry 1) and 90 °C (Table 4, entry 2) and showed yields of only 27% and 41%, respectively. With an ethyl substituent at the C1 position, the yield decreased to 58% at 60 °C (Table 4, entry 3) or was marginally enhanced in toluene at 90 °C with a 65% yield though the reaction took almost twice as long (Table 4, entry 4). Increasing the steric bulk at the C1 position to a tert-butyl group decreased the yield further to 47% (Table 4, entry 5). Electron-withdrawing groups were then investigated at the C1 position and led to an appreciable reduction in conversion of 8a to the corresponding ringopened product. An acyl group at the C1 position caused the yield to decrease to 29% (Table 4, entry 6) while a methyl ester substituent at the C1 position further decreased the yield to 23% (Table 4, entry 7).
The scope of this reaction was also expanded to include different alcohol nucleophiles (Table 5). By using a primary alcohol nucleophile, a decrease in reactivity was seen with increasing chain length (Me < Et < n-Bu; Table 5, entries 1, 2 and 3) while maintaining reasonable yields in a short period of time. When 2-methoxyethanol was used, a good yield of 80% was observed, although the reaction took much longer to complete (Table 5, entry 4). Similarly, when isobutanol was investigated, the conversion to ring-opened product 11n took 10 days but was still able to achieve a moderate yield of 60% (Table 5, entry 5). Using a secondary alcohol as the nucleophile resulted in an incomplete conversion to ring-opened product 11o even after 25 days, with 8a still recovered as an inseparable mixture (Table 5, entry 6). Unexpectedly, using a tertiary alcohol proceeded quicker than a secondary alcohol and resulted in complete conversion to ring-opened product 11p in a moderate yield of 56% (Table 5, entry 7). Cyclic alcohol nucleophiles were also investigated, starting with cyclohexanol, which resulted in a moderate yield of 63% after only 1 day (Table 5, entry 8). When benzyl alcohol was used, no reaction occurred ( Table 5, entry 9) and similarly when phenol was used, no reaction occurred and 8a was recovered ( Table 5, entry 10).

Conclusion
In conclusion, we have demonstrated the first examples of palladium-catalyzed type 2 ring-opening reactions of cyclopropanated oxabenzonorbornadienes with alcohols. The optimized conditions include PdCl 2 (CH 3 CN) 2 with the alcohol nucleophile as the solvent at 60 °C or with toluene added at 90 °C to produce 2-substituted dihydronaphthalenols. The scope of the reaction was successfully expanded to include the ring opening of various symmetrical substituted cyclopropanated oxabenzonorbornadienes. When unsymmetrical substrates were investigated, the regioselectivity of the reaction was excellent, forming only one regioisomer in all cases. The scope of the reaction was also successfully expanded to include various primary, secondary, and tertiary alcohol nucleophiles.

Supporting Information
Experimental procedures and copies of 1 H and 13 C NMR spectra for compounds 11d, g-i, m, n.