treated sequentially. Alkylation of sodium phenolate was slightly more selective for 114 than with potassium phenolate. Lithium phenolates reacted slower than their sodium counterparts. Interestingly, the use of potassium in polar media with allyl chloride results in clean ether formation.130 In contrast, sodium phenolates were more problematic substrates for the reaction with an allyl halide. Calculation of charge densities for phenol and its alkali metal salts at the B3LYP level shows that the partial negative charge at C(2) increases monotonically moving down the group (Scheme 55). Greater O-alkylation over ether formation would be expected as a consequence, in contrast to the observed trend. However, these calculations were performed in the gas phase. The aggregation of phenols in nonpolar media may alter the relative reactivities of these enolates. The strongly coodinating nature of Li-ate complexes in nonpolar media probably attenuates the reactivity of the phenolate anion. Furthermore, coordination of the oxygen can both sterically encumber and electronically deactivate it, favoring C- over O-alkylation.
Scheme 55
Indeed, changes in the solvent had a great effect on the site of alkylation. Thus, whereas high selectivity for 114 was observed in ether, the reaction in THF afforided primarily the undesired isomer 115. These results were in agreement with previous results for ethereal solvents.109 Thus, the alkylation was performed in highly nonpolar solvents. Under these conditions the reaction is usually heterogenous, as the phenoxide ion can crash out of solution.
NaH was significantly more effective at deprotonating the phenol. Deposition of phenolate on the metal surface can retard the further formation of anions in dissolving metal deprotonations. Alkali metals can also undergo SET reactions with chlorinated and aromatic solvents. The clean reactivity profile of NaH led to it being the best choice for this reaction.
The alkylation of phenols under these conditions resulted in the formation of two major isomers. High selectivity for the desired isomer 114 was observed, the SN2' alkylation product was difficult to remove from the reaction mixture. Although a number of conditions were tested, its production could not be fully suppressed. The relative ratio of 114/115 appears to be better in highly nonpolar solvents. The SN2' alkylation of cinnamyl chloride would require the phenolate to approach a secondary methine as opposed to a primary methylene for SN2 alkylation. Thus, the formation of aggregates may actually be beneficial. Increased nucleophile size as a consequence of aggregation would then favor attack at the less hindered position of cinnamyl chloride. Unfortunately, even under the optimized conditions, the production of isomer 115 could not be fully suppressed. The separation of 114 and 115 was not possible on silica. Thus, new purification techniques needed to be developed. Unfortunately, the sacrificial reaction with K2OsO4/NMO, which had previously been successfully employed in these laboratories did not fully remove the minor isomer.131 Finally, AgNO3 on SiO2 (10% w/w) was found to separate the two isomers. The operational overhead on the direct alkylation of phenols proved to be considerable.
4.5.2. Synthesis of 2-Substituted Phenols. The synthesis of phenols with more than one methylene linker was successful only after numerous different attempts. The initial failure of 2nd generation Hoveyda-Grubbs led fruitless efforts at either geometrically constructing the (E)- alkene in a geometrically pure manner or disconnecting somewhere else in the tether. After much effort, the efforts came full circle, and the alkene could be constructed in >50:1 E/Z selectivity using 1st generation Grubbs catalyst 134
The success of 134 over 135 is comment worthy. NHC ligands are known to decrease the reactivity of the Ru center, while substantially increasing catalyst stability. In the current system, no reactivity was observed with 130 at room temperature. If the Ru center is insufficiently reactive, the initial [2+2] addition to form the [Ru(substrate)] complex can not take place. As a result, starting material is recovered. The selectivity of the two catalysts was also different. Whereas 135 gave a mixture of homo- and heterocoupling products, 134 afforded
primarily the heterocoupling product. The reactivity of terminal alkenes in cross-metathesis reactions is greater than styrenes, therefore an initial addition to form the homocoupling product is plausible. However, the carbene complex derived from 134 can add back into the dimer 136 to reform starting material and the [Ru(substrate)] complex. The mixture observed for 135 suggests that the carbene derived from 135 can either not add back into the internal alkene or that this addition is much slower than the initial rate of reaction with the terminal alkene in solution. Either way, catalyst 134 was much better suited to the reaction. However, the low stability of 134 required two portions of catalyst to be added over the timeframe of the reaction. Since the overall total catalyst loading is still 3-4 mol %, this was not particularly problematic. The effect of the hydroxyl group was not prominent.
The low selectivity of intermolecular metathesis reactions is a result of the low energy difference between alkyl substituted (E)- and (Z)-alkenes. In light of the difficulties encountered with the aforementioned methods of making geometrically pure (E)-alkenes, a different approach was tested. The palladium catalyzed opening of 2-vinylchroman proceeded with very high (E)- selectivity. The original proposal for the selectivity is the preference for the Pd-allyl complex that forms upon opening of vinyl chroman to adopt a preferentially trans configuration. Subsequent displacement of the Pd-allyl complex by malonate preserves the high (E)-selectivity on account of an outer-shell SE2-type transition state that is formally related to the Tsuji-Trost process.132
4.5.3. Optimization of the Phenoxysulfenylation Reaction. The systematic variation of reaction conditions, phenol substituents, tether length and functional groups enabled a more thorough understanding of the factors governing the sulfenofunctionalization process. In this section, the influences of each of these components on observable reaction outcomes such as rate, enantioselectivity and site-selectivity will be discussed in turn.
4.5.3.1. Catalyst. The optimization of the sulfenofunctionalization reaction focused on two main variables, the catalyst and the loading of the Brønsted acid. Of the three best catalysts for sulfenofunctionalization, optimum selectivity was achieved with 62e. The high selectivity for this catalyst can be traced to the increased steric encumbrance provided by the N,N-diisopropyl substituents, accentuating the degree to which the catalyst backbone must distort to accommodate the alkene.40 Conversion across all catalysts was comparable.
4.5.3.2. Brønsted Acid. The kinetic studies established that for an alcohol nucleophile, the υmax was reached with 0.6 equiv of methanesulfonic acid (MsOH).40 Further increases in the Brønsted acid loading led to decreases in reaction rate. Two major factors need to be considered for optimal MsOH loading: (1) the amount of acid necessary to fully transform the catalyst into active complex 95, (2) the effective acidity of the reaction mixture as a result of solvation effects in nonpolar reaction media. In the proposed mechanistic cycle, the acid is present only in cocatalytic amounts, therefore only 1.0 equiv of acid with respect to catalyst should be necessary. However, titration studies with ethanesulfonic acid together with 56 and 62d established that up to 4 equiv of acid are needed before full conversion to the sulfenylated species is observed.87 In the case of cyclizations of phenolic hydroxyl groups, high conversion could be achieved with as little as 2.5 equiv of MsOH with respect to catalyst. Small differences in the pKa values of MsOH and ethanesulfonic acid as well as the pKb values of 62d and 62e may account for the reduced acid loading necessary for good reactivity. In contrast to alcohols, the phenolic hydroxyl group does not appear to act as a proton buffer.
The cyclization of 142a was complete within 24 h at -20 oC, compared to 93% after 24 h at the same temperature for the corresponding alcohol substrate.20 Thus, the rate of phenol cyclization is comparable to that of the alcohols. In the prior set of experiments a large excess (10 equiv with respect to catalyst) of MsOH was employed, which led to rates slower than υmax. The decrease in rate at high MsOH concentrations was ascribed to protonation of the substrate by excess acid.40 In the case of phenols, no substantial changes in rate were observed as a result of increased acid concentration in the range of 2.5 to 7.5 equiv of MsOH with respect to catalyst. The substantially lower Brønsted basicity of phenols (pKa of PhOH2+: -6.5, pKa EtOH2+: -2.2)66 implies that a much smaller fraction of substrate is protonated even in the presence of an excess of acid. Thus similar reaction rates are observed over a much broader range of acid stoichiometry.
4.5.4. Structural Effects on Rate and Selectivity. 4.5.4.1. Influence of the Nucleophile.