Acquisition of a manageable isolated yield was the first objective to be achieved when running this aza-Henry addition in an asymmetric fashion. This was done primarily by prolonging the reaction time and increasing the equivalents of nucleophile. When subjecting ketimine 82 to 2 equivalents of nitromethane and 50 mol% of PBAM (19) in toluene (0.1 M) at ambient temperature, minimal conversion to adduct 87 was seen after a 5 day reaction period (Scheme 51). Yet when the amount of nitromethane nucleophile was increased from 2 equivalents to 20 equivalents, the desired product was acquired in 26% isolated yield and -7% ee according to HPLC analysis. Although it is evident that more equivalents of nucleophile leads to product, no promising degree of enantioselection was observed with this new Boc-protected trifluoromethyl ketimine electrophile.
The next variable that was examined for this reaction system was the influence of added Brønsted acid. Previous studies have shown that the introduction of an acid salt to PBAM results in similar or increased levels of selectivity for a number of aza-Henry addition systems. When the triflic acid salt of PBAM (19•HOTf) was used as the catalyst for this system, adduct 87 was obtained in 31% yield and 45% ee, a considerably higher degree of enantioselectivity relative to PBAM free base (19) (Scheme 52). Upon submission of the triflimidic acid salt (PBAM•HNTf2),
the desired adduct was furnished in 38% yield and 51% ee, the highest enantioselection achieved to this point. These results show that the introduction of an acid not only reverses the direction of selectivity, it also results in a much higher level of enantioselection as well.
Additionally, one of the most optimal asymmetric amidine-amide catalysts, 3,5(CF
3)2BenzAM (78a), was tested in this aza-Henry system. For this particular case however, the
catalyst did not fare as well as the traditional bis(amidine) catalysts as adduct 87 was acquired in
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33% yield and -25% ee (Scheme 52). Needless to say, PBAM•HNTf2 was the catalyst chosen to
be carried onto further studies.
The effects of concentration and catalyst loading were the next two variables that were examined. Up to this point, acquisition of adduct 87 in 38% yield and 51% ee was the optimal result. This was achieved with a 50 mol% catalyst loading of PBAM•HNTf2 and a 0.1 M
concentration of toluene. When the solvent concentration was increased to 0.25 M, adduct 87 was furnished in 64% yield and 48% ee (Table 6, entry 2) indicating that increased concentrations lead to higher yields, but slightly diminished ee. Conversely, lowering the catalyst loading to 20 mol% results in a decrease in yield and a slight enhancement in selectivity as the desired adduct was afforded in 56% yield and 49% ee (entry 3). The reaction conditions used in entry 3 were carried into further studies.
With a 20 mol% catalyst loading of PBAM•HNTf2, a more in-depth solvent concentration
study was conducted. When increasing the concentration of toluene from 0.25 M to 0.5 M, a decrease in both yield and enantioselection was observed (Table 7, entry 2). Further increasing the concentration to 1 M resulted in a considerable increase in yield but a continued diminishment in ee as adduct 87 was acquired in 71% yield and 42% ee (entry 3). Due to the gradual decrease in
Scheme 52. Effects of Counterions and Asymmetric Catalysts
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enantioselection upon increasing the concentration, 0.25 M was still considered to be the most optimal concentration at this point.
A more in-depth nucleophile equivalence study was also conducted. Although it was previously determined that going from 2 to 20 equivalents of nitromethane resulted in isolatable yields (Scheme 51), there was still the possibility that 20 equivalents of nucleophile may not be optimal as such an excess may result in catalyst deactivation by nitroalkane binding (e.g. solvation). Therefore, lesser amounts of nucleophile were examined to see if both yield and ee could be enhanced. When dropping the amount of nitromethane from 20 equivalents to 10 equivalents, a slight increase of enantioselection was achieved. In this same run however, a considerable drop in yield was also observed (Table 7, entry 5). Dropping the equivalents further to 5 equivalents of nitromethane resulted in lower yield and no change in enantioselection as adduct 87 was furnished in 29% yield and 51% ee (entry 6). Since the minimal increase in ee cannot account for the larger loss in yield, 20 equivalents of nitromethane was still considered to be the optimal amount of nucleophile at this point.
Other BAM catalysts with more Brønsted basic character were also tested to see if reactivity and selectivity could be enhanced. As previously mentioned, 8(MeO)PBAM was determined to be the most reactive catalyst for the tosyl ketimine aza-Henry system. When 8(MeO)PBAM was subjected to the trifluoromethly ketimine aza-Henry addition, no improvement was seen as the intended product was obtained in only 42% yield and -7% ee (Scheme 53). Other available BAM catalysts of higher Brønsted basicity, such as 6(MeO)PBAM and 6,7(MeO)2PBAM,
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performed worse relative to 8(MeO)PBAM as the adduct was acquired in lower yields and minimal ee.
Studies continued with the examination of additional counterions. After submitting a number of sulfonic acid salts of PBAM to the aza-Henry system, none gave superior results relative to PBAM•HNTf2 as the most optimal sulfonic acid salt, nonafluorosulfonic acid, afforded adduct
87 in 27% yield and 43% ee (Scheme 54). The bis(triflyl)methane salt (PBAM•CH2Tf2) appeared
to be the only salt comparable to PBAM·HNTf2 as this catalyst furnished the desired product in
44% yield and 50% ee. While the lithium triflimide analog (PBAM•LiNTf2) gave a comparable ee
value relative to the triflimidic acid salt (45% ee), a significant drop in yield was observed as the adduct was obtained in only 19% yield. The bis(triflyl)methane salt, along with PBAM•HNTf2,
was carried onto further studies due to similarity in catalyst behavior.
The next variable that was altered was temperature. Traditionally, lowering the temperature results in an increase in enantioselection. This trend held true for this particular reaction system. When the reaction temperature was lowered from room temperature to 0 °C, an increase in enantioselectivity was observed at the expense of decreased yield (Table 8, entry 2). Lowering the
Scheme 53. Application of More Brønsted Basic BAM Catalysts
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temperature to -20 ºC had little effect on reactivity relative to 0 ºC, yet higher enantioselection was observed as adduct 87 was afforded in 34% yield and 66% ee (entry 3). Unfortunately, when running this reaction at -78 ºC, reactivity was inhibited as minimal conversion was seen over the course of 5 days (entry 4). However, when repeating this run at a higher concentration (0.5 M), the desired product was obtained in 6% isolated yield and 80% ee (entry 5). Although this was the highest degree of selectivity observed for this system, -20 ºC was chosen as this temperature provided a more fruitful and manageable yield. Thus, the most optimal reaction conditions up to date include a 20 mol% catalyst loading of PBAM•HNTf2, 20 equivalents of nitromethane, a 0.25
M solvent concentration, and a temperature of -20 ºC.
Before this aza-Henry addition was conducted on a larger scale, it had to be reaffirmed that PBAM•HNTf2, was the best catalyst under the chosen conditions, As previously shown,
PBAM•CH2Tf2 showed comparable results at room temperature (Scheme 54). Yet when
submitting the same catalyst under more chilled conditions, adduct 87 was afforded in only 20% yield and 65% ee, which proved to be inferior relative to PBAM•HNTf2 (Scheme 55). Additionally,
it had to be verified that the cyclohexane backbone of PBAM•HNTf2 was indeed ideal. Upon
subjecting a catalyst with a stilbene backbone, StilbPBAM•HNTf2 (88•HNTf2), to the aza-Henry Table 8. Effects of Temperature
59
system, the intended product was furnished in 15% yield and 16% ee. These results confirm that PBAM·HNTf2 is the best catalyst for this particular reaction.
A great degree of consistency was exhibited upon scaling up this aza-Henry addition. When using 20 mg of substrate, the desired adduct is acquired in 34% yield and 66% ee. The same degree of reactivity and selectivity is seen upon a 50 fold increase of electrophile. When submitting 1 gram of the ketimine, adduct 87 is furnished in 33% yield and 66% ee (Scheme 56). This consistency indicates that the aza-Henry adduct can be taken on to its corresponding Nutlin analog in gram quantities.