New Developments in EnantioselectiveBrønsted Acid Catalysis
221
5
Enantioselective Reduction of Benzoxazines,
Benzthiazines, and Benzoxazinones:
Remarkably Low Catalyst Loading
in the Asymmetric Brønsted Acid Catalyzed
Transferhydrogenation
To date various highly enantioselective processes based on chiral metalcomplexes have been described. However, so far only few catalysts have
been reported to catalyze the reduction of cyclic imines, such as benzoxazine, benzthiazine and benzoxazinone derivatives (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). This is
surprising as the corresponding dihydro-2H-benzoxazines, dihydro-2Hbenzothiazines and dihydro-2H-benzoxazinones represent the structural
motif of various natural products with interesting biological activities.
These compounds have also been employed as important chiral building blocks in the synthesis of many pharmaceuticals, such as promising anti-depressants, calcium antagonists as well as anti-inflammatory,
anti-nociceptive, anti-bacterial and anti-microbial agents (Brown and
Djerassi 1964; Belattar and Saxton 1992; Krohn et al. 1993; Kleemann
et al. 2001; Achari et al. 2004; Ilas et al. 2005).
Based on our newly developed transfer-hydrogenation of ketoimines
(Rueping et al. 2005b) and quinolines (Rueping et al. 2006c) we believed it might be possible to extend our chiral ion pair catalysis procedure to the enantioselective transfer hydrogenation of benzoxazines
and benzthiazines (Rueping et al. 2006d). We reasoned that, similar
to enzymatic transfer hydrogenations, activation of benzoxazines 12
and benzthiazines 14 by catalytic protonation through Brønsted acid 5
would generate a chiral ion pair A, which would subsequently undergo
a hydride transfer addition from Hantzsch dihydropyridine 2 to give the
desired dihydro-2H-benzoxazine 13 and dihydro-2H-benzothiazines 15
(Fig. 7).
Hence, our initial investigations concentrated on finding the appropriate catalyst and reaction conditions. Again, catalyst 5b showed the
best enantioselectivities and remarkable reactivities. Therefore, we decided to perform a detailed investigation of the catalyst loading(Table 4).
221
5
Enantioselective Reduction of Benzoxazines,
Benzthiazines, and Benzoxazinones:
Remarkably Low Catalyst Loading
in the Asymmetric Brønsted Acid Catalyzed
Transferhydrogenation
To date various highly enantioselective processes based on chiral metalcomplexes have been described. However, so far only few catalysts have
been reported to catalyze the reduction of cyclic imines, such as benzoxazine, benzthiazine and benzoxazinone derivatives (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). This is
surprising as the corresponding dihydro-2H-benzoxazines, dihydro-2Hbenzothiazines and dihydro-2H-benzoxazinones represent the structural
motif of various natural products with interesting biological activities.
These compounds have also been employed as important chiral building blocks in the synthesis of many pharmaceuticals, such as promising anti-depressants, calcium antagonists as well as anti-inflammatory,
anti-nociceptive, anti-bacterial and anti-microbial agents (Brown and
Djerassi 1964; Belattar and Saxton 1992; Krohn et al. 1993; Kleemann
et al. 2001; Achari et al. 2004; Ilas et al. 2005).
Based on our newly developed transfer-hydrogenation of ketoimines
(Rueping et al. 2005b) and quinolines (Rueping et al. 2006c) we believed it might be possible to extend our chiral ion pair catalysis procedure to the enantioselective transfer hydrogenation of benzoxazines
and benzthiazines (Rueping et al. 2006d). We reasoned that, similar
to enzymatic transfer hydrogenations, activation of benzoxazines 12
and benzthiazines 14 by catalytic protonation through Brønsted acid 5
would generate a chiral ion pair A, which would subsequently undergo
a hydride transfer addition from Hantzsch dihydropyridine 2 to give the
desired dihydro-2H-benzoxazine 13 and dihydro-2H-benzothiazines 15
(Fig. 7).
Hence, our initial investigations concentrated on finding the appropriate catalyst and reaction conditions. Again, catalyst 5b showed the
best enantioselectivities and remarkable reactivities. Therefore, we decided to perform a detailed investigation of the catalyst loading(Table 4).