1 3
Topics in Current Chemistry (2018) 376:46
conducted over a running time of 24 h, leading to 1-phenylethanol (R)-40a in 40%
yield (11.5 mmol) and 97:3 er, and the corresponding ester (S)-41a in 88:12 er
(15.2 mmol). The process occurred with 55% conversion of and a selectivity factor
of 28. The excellent robustness of the supported catalyst allowed for investigating
the scope of the resolution process by a “wash and run” approach. Remarkably, the
sequential resolution of nine different alcohol/anhydride combinations were carried
out on 4 mmol scale, observing good conversions (49–63%) and good-to-excellent
selectivity factors (s = 11–200) and high enantioselectivity in products 40 and 41
(Scheme 19). Remarkably, the flow system operated efficiently for more than 100 h.
Bode reported on the use of a continuous flow setup for a parallel kinetic resolution (PKR) of cyclic amines [57]. In a PKR, two kinetic resolution reactions are
simultaneously run, leading to two distinct non-enantiomeric products (D, F in
Scheme 20). If both enantiomers of the starting racemic mixture react with similar
rates, a constant concentration is maintained during the resolution, and both products are formed in significantly enantiopurity. The PKR gives access to two enantioenriched products from a single racemic starting material, under certain precise
resolution conditions. As reported by Dehli and Gotor in their review [58], for a
successful PKR, the resolution reactions should: (1) have similar (ideally identical)
rates kR ≈ kS; (2) occur without mutual interference; (3) have opposite enantioselectivity with respect to the substrate; and (4) yield separable reaction products. For
succeed in this task, Bode developed two immobilized quasienantiomeric acylating
agents 43 and 44 (Scheme 20) that were used in a packed-bed flow reactor and efficiently recovered and reused after PKR. In this case, a different approach was followed, as supported reagents rather than a supported catalyst have been employed. It
was mandatory that the amide products were easily separated and hydrolyzed to the
corresponding amines without detectable epimerization. A solution of the amine 42
in THF was circulated continuously for 18–24 h through the columns at a flow rate
of 2–3 ml min
−1
at 45 °C. After resolution, the system was flushed with THF and
Et 2 O and the resulting amides were collected and separated. De-acylation provided
the enantiopure amines 45a–e and ent-45a–e with selectivity factor up to 100.
5 Use of Supported Organometallic Catalysts in Heterogeneous Flow
Catalysis
In this section, some relevant examples of continuous flow processes involving the
use of supported catalyst including metals will be reported. This topic has been
extensively reviewed and only recently published examples will be described. Most
of the selected examples discusses herein concern the use of organic supports where
a metal (generally a transition metal) can be grafted on. It is worth pointing out that
in striking contrast to supported organcatalysts discussed in the previous session,
supported organometallic catalysts often undergo leaching of the metal species, and
this issue is difficult to prevent and control. This aspect has been critically reviewed
by Kappe, who reported that the mechanism involved in the metal-catalyzed process
needs to be taken into consideration in order to establish if a really heterogenous or
“quasi” homogeneous reaction takes place [59]. It was also made aware that even
47
Reprinted from the journal
Topics in Current Chemistry (2018) 376:46
conducted over a running time of 24 h, leading to 1-phenylethanol (R)-40a in 40%
yield (11.5 mmol) and 97:3 er, and the corresponding ester (S)-41a in 88:12 er
(15.2 mmol). The process occurred with 55% conversion of and a selectivity factor
of 28. The excellent robustness of the supported catalyst allowed for investigating
the scope of the resolution process by a “wash and run” approach. Remarkably, the
sequential resolution of nine different alcohol/anhydride combinations were carried
out on 4 mmol scale, observing good conversions (49–63%) and good-to-excellent
selectivity factors (s = 11–200) and high enantioselectivity in products 40 and 41
(Scheme 19). Remarkably, the flow system operated efficiently for more than 100 h.
Bode reported on the use of a continuous flow setup for a parallel kinetic resolution (PKR) of cyclic amines [57]. In a PKR, two kinetic resolution reactions are
simultaneously run, leading to two distinct non-enantiomeric products (D, F in
Scheme 20). If both enantiomers of the starting racemic mixture react with similar
rates, a constant concentration is maintained during the resolution, and both products are formed in significantly enantiopurity. The PKR gives access to two enantioenriched products from a single racemic starting material, under certain precise
resolution conditions. As reported by Dehli and Gotor in their review [58], for a
successful PKR, the resolution reactions should: (1) have similar (ideally identical)
rates kR ≈ kS; (2) occur without mutual interference; (3) have opposite enantioselectivity with respect to the substrate; and (4) yield separable reaction products. For
succeed in this task, Bode developed two immobilized quasienantiomeric acylating
agents 43 and 44 (Scheme 20) that were used in a packed-bed flow reactor and efficiently recovered and reused after PKR. In this case, a different approach was followed, as supported reagents rather than a supported catalyst have been employed. It
was mandatory that the amide products were easily separated and hydrolyzed to the
corresponding amines without detectable epimerization. A solution of the amine 42
in THF was circulated continuously for 18–24 h through the columns at a flow rate
of 2–3 ml min
−1
at 45 °C. After resolution, the system was flushed with THF and
Et 2 O and the resulting amides were collected and separated. De-acylation provided
the enantiopure amines 45a–e and ent-45a–e with selectivity factor up to 100.
5 Use of Supported Organometallic Catalysts in Heterogeneous Flow
Catalysis
In this section, some relevant examples of continuous flow processes involving the
use of supported catalyst including metals will be reported. This topic has been
extensively reviewed and only recently published examples will be described. Most
of the selected examples discusses herein concern the use of organic supports where
a metal (generally a transition metal) can be grafted on. It is worth pointing out that
in striking contrast to supported organcatalysts discussed in the previous session,
supported organometallic catalysts often undergo leaching of the metal species, and
this issue is difficult to prevent and control. This aspect has been critically reviewed
by Kappe, who reported that the mechanism involved in the metal-catalyzed process
needs to be taken into consideration in order to establish if a really heterogenous or
“quasi” homogeneous reaction takes place [59]. It was also made aware that even
47
Reprinted from the journal