This is an overview of successes in the realm of catalytic homogeneous asymmetric hydrogenation of substrates primarily of interest in the synthesis of pharmaceuticals in order to identify important ...problems still unsolved. First, tables are provided that list the successful reductions to over 90% enantiomeric excess of prochiral ketones to alcohols, imines to amines, and olefins to saturated carbon centers. Noted in the tables are the metal (including “green” metals Mn, Fe, and Co) or enzyme, the class of ligand, the conditions of the medium, and the scale of reduction, if over 1 kg of product, as well as the nature of the process, whether direct hydrogenation using H2 gas (DH), transfer hydrogenation (TH), or hydrogenation with dynamic kinetic resolution (DKR). Tables of representative pharmaceutical or fine chemicals products are provided for each class of substrate. With this overview, the opportunities for further research and development become clearer.
Chiral amines are key building blocks in synthetic chemistry with numerous applications in the agricultural and pharmaceutical industries. Asymmetric imine hydrogenation, particularly with iridium ...catalysts, is well developed. However, imine reduction still remains challenging in the context of replacing such a precious metal with a cheap, nontoxic, and environmentally friendly substitute such as iron. Here, we report that an unsymmetrical iron P-NH-P′ catalyst that was previously shown to be effective for the asymmetric hydrogenation of aryl ketones is also a very effective catalyst for the asymmetric hydrogenation of prochiral aryl imines activated with N-diphenylphosphinoyl or N-tosyl groups. The P-NH-P′ abbreviation stands for (S,S)-PPh2CHPhCHPhNHCH2CH2P i Pr2. Density functional theory results suggest that, surprisingly, the NH group on the catalyst activates and orients the imine to hydride attack by hydrogen bonding to the PO or SO group on the imine nitrogen, as opposed to the imine nitrogen itself. This may explain why N-Ph and N-Bu imines are not hydrogenated.
Two borane-functionalized bidentate phosphine ligands that vary in tether length have been prepared to examine cooperative metal–substrate interactions. Ni(0) complexes react with aryl azides at low ...temperatures to form structurally unusual κ2-(N,N)-N3Ar adducts. Warming these adducts affords products of N2 extrusion and in one case, a Ni-imido compound that is capped by the appended borane. Reactions with 1-azidoadamantane (AdN3) provide a distinct outcome, where a proposed nickel imido intermediate activates the sp2 C–H bonds of arenes, even in the presence of benzylic C–H sites. Combined experimental and computational mechanistic studies demonstrate that the unique reactivity is a consequence of Lewis-acid-induced polarization of the Ni–NR bond, potentially providing a synthetic strategy for chemoselective reaction engineering.
The use of manganese in homogeneous hydrogenation catalysis has been a recent focus in the pursuit of more environmentally benign base metal catalysts. It has great promise with its unique reactivity ...when coupled with metal-ligand cooperation of aminophosphine pincer ligands. Here, a manganese precatalyst Mn(P-N-P′)(CO)
2
, where P-N-P′ is the amido form of the ligand (
S
,
S
)-PPh
2
CHPhCHPhNHCH
2
CH
2
P
i
Pr
2
, has been synthesized and used for base-free ketone hydrogenation. This catalyst shows exceptionally high enantioselectivity and good activity, with tolerance for base-sensitive substrates. NMR structural analysis of intermediates formed by the reaction of the amido complex with hydrogen under pressure identified a reactive hydride with an NOE contact with the
syn
amine proton. Computational analysis of the catalytic cycle reveals that the heterolytic splitting of dihydrogen across the MnN bond in the amido complex has a low barrier while the hydride transfer to the ketone is the turnover-limiting step. The pro-
S
transition state is found to be usually much lower in energy than the pro-
R
transition state depending on the ketone structure, consistent with the high (
S
) enantiomeric excess in the alcohol products. The energy to reach the transition state is higher for the distortion of the in-coming ketone than that of the hydride complex. In a one-to-one comparison with the similar iron catalyst FeH
2
(CO)(P-NH-P′), the manganese catalyst is found to have higher enantioselectivity, often over 95% ee, while the iron catalyst has higher activity and productivity. An explanation of these differences is provided on the basis of the more deformable iron hydride complex due to the smaller hydride ligands.
Base-free direct hydrogenation of ketones using a Mn(PNP′)(CO)
2
complex is more enantioselective than that of a related base-activated iron complex.
A novel PNN ligand bearing an orthophenylene group and a primary amine was synthesized with the aid of a palladium-catalyzed amination and reacted with phosphonium dimers -PR
CH
CH(OH)-
Br
R = Et, ...iPr, Cy, Ph, xylyl, and
-Tol, and Fe(OH
)
to produce a new series of
-β iron(ii) PNNP' precatalysts
-β-Fe(Br)(CO)(PNNP')BPh
as a pair of diastereomers. The more stable orthophenylene amido group was chosen to imitate and replace the enamido moiety of a highly active iron precatalyst for the asymmetric transfer hydrogenation (ATH) of ketones in an attempt to prevent its deactivation caused by reduction of the enamido group. This objective was partially achieved using the complex with a PEt
group which catalyzed the transfer hydrogenation in isopropanol of 150 000 equivalents of acetophenone to racemic 1-phenylethanol. With a low acetophenone to catalyst ratio of 500 to 1, the catalytic activity was moderate and the enantiomeric excess (ee) of the product 1-phenylethanol ranged surprisingly from 94% (
) to 95% (
) depending on the nature of PR
and whether the precatalyst contained an imine or amine donor. The amine precatalyst with a PEt
-group produced a more stable hydride species when activated, allowing the reaction mixture to be heated to 75 °C to obtain a TON of 8821 for acetophenone while retaining the high ee of 95% (
). The activation pathway in basic isopropanol (iPrOH) was studied for three precatalysts to elucidate that the
-β precatalysts rearrange to form
hydride complexes. The study suggests that the enantioselectivity of these complexes is determined by from which side of the PNNP' plane the hydride transfer occurs.
A novel PNN ligand bearing an orthophenylene group and a primary amine was synthesized with the aid of a palladium-catalyzed amination and reacted with phosphonium dimers -PR
2
CH
2
CH(OH)-
2
Br
2
R ...= Et, iPr, Cy, Ph, xylyl, and
o
-Tol, and Fe(OH
2
)
6
2+
to produce a new series of
cis
-β iron(
ii
) PNNP′ precatalysts
cis
-β-Fe(Br)(CO)(PNNP′)BPh
4
as a pair of diastereomers. The more stable orthophenylene amido group was chosen to imitate and replace the enamido moiety of a highly active iron precatalyst for the asymmetric transfer hydrogenation (ATH) of ketones in an attempt to prevent its deactivation caused by reduction of the enamido group. This objective was partially achieved using the complex with a PEt
2
group which catalyzed the transfer hydrogenation in isopropanol of 150 000 equivalents of acetophenone to racemic 1-phenylethanol. With a low acetophenone to catalyst ratio of 500 to 1, the catalytic activity was moderate and the enantiomeric excess (ee) of the product 1-phenylethanol ranged surprisingly from 94% (
R
) to 95% (
S
) depending on the nature of PR
2
and whether the precatalyst contained an imine or amine donor. The amine precatalyst with a PEt
2
-group produced a more stable hydride species when activated, allowing the reaction mixture to be heated to 75 °C to obtain a TON of 8821 for acetophenone while retaining the high ee of 95% (
S
). The activation pathway in basic isopropanol (iPrOH) was studied for three precatalysts to elucidate that the
cis
-β precatalysts rearrange to form
trans
hydride complexes. The study suggests that the enantioselectivity of these complexes is determined by from which side of the PNNP′ plane the hydride transfer occurs.
A slight change in the iron catalyst structure (amine arm with PEt
2
to imine arm with PPh
2
) results in a complete reversal of the enantioselectivity toward ketone reduction.
A slight change in the iron catalyst structure (amine arm with PEt
2
to imine arm with PPh
2
) results in a complete reversal of the enantioselectivity toward ketone reduction.
A novel PNN ligand ...bearing an orthophenylene group and a primary amine was synthesized with the aid of a palladium-catalyzed amination and reacted with phosphonium dimers –PR
2
CH
2
CH(OH)–
2
Br
2
R = Et, iPr, Cy, Ph, xylyl, and
o
-Tol, and Fe(OH
2
)
6
2+
to produce a new series of
cis
-β iron(
ii
) PNNP′ precatalysts
cis
-β-Fe(Br)(CO)(PNNP′)BPh
4
as a pair of diastereomers. The more stable orthophenylene amido group was chosen to imitate and replace the enamido moiety of a highly active iron precatalyst for the asymmetric transfer hydrogenation (ATH) of ketones in an attempt to prevent its deactivation caused by reduction of the enamido group. This objective was partially achieved using the complex with a PEt
2
group which catalyzed the transfer hydrogenation in isopropanol of 150 000 equivalents of acetophenone to racemic 1-phenylethanol. With a low acetophenone to catalyst ratio of 500 to 1, the catalytic activity was moderate and the enantiomeric excess (ee) of the product 1-phenylethanol ranged surprisingly from 94% (
R
) to 95% (
S
) depending on the nature of PR
2
and whether the precatalyst contained an imine or amine donor. The amine precatalyst with a PEt
2
-group produced a more stable hydride species when activated, allowing the reaction mixture to be heated to 75 °C to obtain a TON of 8821 for acetophenone while retaining the high ee of 95% (
S
). The activation pathway in basic isopropanol (iPrOH) was studied for three precatalysts to elucidate that the
cis
-β precatalysts rearrange to form
trans
hydride complexes. The study suggests that the enantioselectivity of these complexes is determined by from which side of the PNNP′ plane the hydride transfer occurs.
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