New Developments in EnantioselectiveBrønsted Acid Catalysis
223
Beginning with 10 mol% of the chiral Brønsted acid catalyst 5b we
were able to decrease the catalyst loading to 0.01 mol% (substrate/
catalyst ratio = 10,000:1) without a considerable loss in reactivity and
selectivity. With just 0.01 mol% of Brønsted acid 5b the corresponding
2H-dihydro-benzoxazine 13a could be isolated in a remarkable 90%
yield and 93% ee and with a TON of 9000 and a TOF 500 h
–1 .
It should be noted that this is, to date, the lowest catalyst loading
reported for an organocatalytic enantioselective transformation. Furthermore, if compared to enantioselective metal-catalyzed reductions of
heterocyclic systems, which employ 0.5–5 mol% (Glorius 2005; Wang
et al. 2003; Lu et al. 2004; Yang and Zhou 2004; Xu et al. 2005; Reetz
and Li 2006; Noyori 1996; Satoh et al. 1998; Zhou et al. 2005), our
metal-free transformation requires the lowest amount of catalyst, demonstrating the high potential of BINOL-phosphates, and Brønsted acid catalysts in general. With the optimized conditions in hand we started to
explore the scope of the Brønsted acid catalyzed transfer hydrogenation of benzoxazines 12a–e and benzthiazines 14a–e (Table 5). In general, differently substituted 3-aryl-dihydro-2H-benzoxazines 13a–e and
-benzthiazines 15a–e bearing either electron withdrawing or electron
donating groups were obtained in good yields and with excellent enantioselectivities (94%–99% ee). Furthermore, the new metal-free procedure shows advantages over the application of most metal catalysts,
which are known to be poisoned by sulfur containing substrates.
Having established a general and highly enantioselective transfer hydrogenation of 12 and benzthiazines 14, we also decided to apply this
efficient methodology to the reduction of benzoxazinones 16 as this
would lead to the valuable cyclic aryl-substituted amino acid derivatives 17. Hence, we applied our organocatalytic enantioselective hydrogenation procedure to 3-aryl-substituted benzoxazinones 16 using the
same reaction conditions (Table 6). Once again, we were able to isolate
the corresponding differently substituted, electron-rich and electrondeficient aryl- and heteroaryl-glycine derivatives 17 in good yields and
with excellent enantioselectivities (90%–99% ee).
The newly developed procedure described represents the first metalfree reduction of benzoxazines and benzthiazines in general, and
provides the corresponding dihydro-2H-benzoxazine and dihydro-2H-
223
Beginning with 10 mol% of the chiral Brønsted acid catalyst 5b we
were able to decrease the catalyst loading to 0.01 mol% (substrate/
catalyst ratio = 10,000:1) without a considerable loss in reactivity and
selectivity. With just 0.01 mol% of Brønsted acid 5b the corresponding
2H-dihydro-benzoxazine 13a could be isolated in a remarkable 90%
yield and 93% ee and with a TON of 9000 and a TOF 500 h
–1 .
It should be noted that this is, to date, the lowest catalyst loading
reported for an organocatalytic enantioselective transformation. Furthermore, if compared to enantioselective metal-catalyzed reductions of
heterocyclic systems, which employ 0.5–5 mol% (Glorius 2005; Wang
et al. 2003; Lu et al. 2004; Yang and Zhou 2004; Xu et al. 2005; Reetz
and Li 2006; Noyori 1996; Satoh et al. 1998; Zhou et al. 2005), our
metal-free transformation requires the lowest amount of catalyst, demonstrating the high potential of BINOL-phosphates, and Brønsted acid catalysts in general. With the optimized conditions in hand we started to
explore the scope of the Brønsted acid catalyzed transfer hydrogenation of benzoxazines 12a–e and benzthiazines 14a–e (Table 5). In general, differently substituted 3-aryl-dihydro-2H-benzoxazines 13a–e and
-benzthiazines 15a–e bearing either electron withdrawing or electron
donating groups were obtained in good yields and with excellent enantioselectivities (94%–99% ee). Furthermore, the new metal-free procedure shows advantages over the application of most metal catalysts,
which are known to be poisoned by sulfur containing substrates.
Having established a general and highly enantioselective transfer hydrogenation of 12 and benzthiazines 14, we also decided to apply this
efficient methodology to the reduction of benzoxazinones 16 as this
would lead to the valuable cyclic aryl-substituted amino acid derivatives 17. Hence, we applied our organocatalytic enantioselective hydrogenation procedure to 3-aryl-substituted benzoxazinones 16 using the
same reaction conditions (Table 6). Once again, we were able to isolate
the corresponding differently substituted, electron-rich and electrondeficient aryl- and heteroaryl-glycine derivatives 17 in good yields and
with excellent enantioselectivities (90%–99% ee).
The newly developed procedure described represents the first metalfree reduction of benzoxazines and benzthiazines in general, and
provides the corresponding dihydro-2H-benzoxazine and dihydro-2H-