Continuous-Flow Synthesis of (R)-Tamsulosin Utilizing Sequential Heterogeneous Catalysis.

We describe the continuous-flow synthesis of (R)-tamsulosin, a blockbuster therapeutic drug employed for dysuria associated with urinary stones and benign prostatic hyperplasia, by utilizing sequential heterogeneous catalysis. Two heterogeneous catalysts have been developed for the synthesis, and the key step involves reductive amination of nitriles using dimethylpolysilane-modified Pd on activated carbon/calcium phosphate. Overall, (R)-tamsulosin was obtained in 60 % yield and 64 % ee (99 % ee after recrystallization) in a flow stream through four catalytic transformations without the need for the isolation or purification of any intermediates or byproduct.

Reworking Organic Synthesis for the Modern Age: Synthetic Strategies Based on Continuous-Flow Addition and Condensation Reactions with Heterogeneous Catalysts.

While organic synthesis carried out in most laboratories uses batch methods, there is growing interest in modernizing fine chemical synthesis through continuous-flow processes. As a synthetic method, flow processes have several advantages over batch systems in terms of environmental compatibility, efficiency, and safety, and recent advances have allowed for the synthesis of several complex molecules, including active pharmaceutical ingredients (APIs). Nevertheless, due to several reasons related to the difficulties arising from byproduct formation during the flow process, such as lower yields, poor selectivities, clogging of columns due to poor solubility, catalyst poisoning, etc., successful examples of continuous-flow synthesis of complex organic molecules are still limited. In order to solve this bottleneck, the development of selective and atom-economical continuous-flow organic transformations are needed. This perspective highlights examples of atom-economical addition and condensation reactions with heterogeneous catalysts under continuous-flow conditions and their applications for the synthesis of complex organic molecules such as natural products and APIs. In order to realize new continuous-flow methodologies, based on addition and condensation reactions, in place of substitution reactions, the development of novel reactions and heterogeneous catalysts is required.

A Nickel-Diamine/Mesoporous Silica Composite as a Heterogeneous Chiral Catalyst for Asymmetric 1,4-Addition Reactions.

A chiral composite material, derived from the deposition of a chiral nickel-diamine complex via wet impregnation to MCM-41, was shown to be an efficient heterogeneous catalyst for asymmetric 1,4-addition reactions of 1,3-dicarbonyl compounds with nitroalkenes, and of nitromethane with alkylidenemalonates. It was discovered that MCM-41 enhanced the reactivity and improved the stability of the chiral nickel complex that resides within the mesoporous material.

Continuous-flow synthesis using a column reactor packed with heterogeneous catalysts: A convenient production of nitroolefins by using amino-functionalized silicagel.

A continuous-flow synthesis of ß-nitroolefins by using heterogeneous base catalysts has been developed. Although the use of an excess amount of nitro-donor such as nitromethane is required in conventional methods, nearly equimolar amounts of nitro-donors and carbonyl compounds are sufficient for high-yielding production of nitroolefins. Catalysts for this flow protocol are inexpensive and abundant, and high durability and high productivity were also realized by using an appropriate second support.

Sequential Continuous-Flow Synthesis of 3-Aryl Benzofuranones.

A sequential continuous-flow system to produce 3-aryl benzofuranones was developed. Starting from 2,4-di-tert-butylphenol and glyoxylic acid monohydrate, both the initial cyclocondensation and the subsequent Friedel-Crafts alkylation were catalyzed by the same heterogeneous catalyst, Amberlyst-15H. The catalyst has a promising life-time for these two steps, and it was able to be recovered and reused for several runs without deactivation. By using the established flow system, 5,7-di-tert-butyl-3-(3,4-dimethylphenyl)-3H-benzofuran-2-one (Irganox HP-136), which is a commercial antioxidant, was prepared in 88% two-step yield. Reactions with various aromatic compounds proceeded well under flow conditions to afford 3-aryl benzo-furanone derivatives in high yields with good functional group compatibility.

Synthesis of Biginelli dihydropyrimidinone derivatives with various substituents on aluminium-planted mesoporous silica catalyst.

Biginelli reactions were well catalyzed on mesoporous silica MCM-41 (M41) whose activity was much greater than that of amorphous silica. Octane was the most suitable among 6 kinds of solvents examined. The addition of metal ions on M41 enhanced the catalytic activity in the order Al > Ti > Fe = In. Al-planted M41s with Si/Al ratios of 45-35 showed the highest catalytic activity and could be used repeatedly though a small loss of the activity was observed. The catalysis could widely be applied to obtain various substituted dihydropyrimidinones (DHPMs) with high yields, some of which were very difficult to prepare until now. In addition, Biginelli reactions were combined with formyl C-H insertion reactions of diazoester on mesoporous silica; that is, a tandem one-pot four-component DHPM synthesis was attempted. Acetaldehyde, ethyl diazoacetate, p-tolualdehyde, and urea could be condensed and the corresponding DHPM derivative was obtained with 50% yield on Al-planted M41.

Highly ordered aluminium-planted mesoporous silica as active catalyst for Biginelli reaction and formyl C-H insertion reaction with diazoester.

Al-planted MCM-41s (Al-M41s) with regular mesoporous structure and Si/Al ratio of 23-32 were successfully prepared by the template-ion exchange method in which the template/Si molar ratio and Si/Al ratio were adjusted at 1.44 and 5-15, and showed much higher catalytic activity for the titled reactions than the other types of Al-M41s prepared by post-synthesis or sol-gel methods.

Enantioselective Sequential-Flow Synthesis of Baclofen Precursor via Asymmetric 1,4-Addition and Chemoselective Hydrogenation on Platinum/Carbon/Calcium Phosphate Composites.

Continuous-flow synthesis of baclofen precursor (2) was achieved using achiral and chiral heterogeneous catalysts in high yield with high enantioselectivity. The key steps are chiral calcium-catalyzed asymmetric 1,4-addition of a malonate to a nitroalkene and chemoselective reduction of a nitro compound to the corresponding amino compound by using molecular hydrogen. A dimethylpolysilane (DMPS)-modified platinum catalyst supported on activated carbon (AC) and calcium phosphate (CP) has been developed that has remarkable activity for the selective hydrogenation of nitro compounds.

Selective Hydrogenation of Nitriles to Primary Amines Catalyzed by a Polysilane/SiO2-Supported Palladium Catalyst under Continuous-Flow Conditions.

Hydrogenation of nitriles to primary amines with heterogeneous catalysts under liquid-phase continuous-flow conditions is described. Newly developed polysilane/SiO2-supported Pd was found to be an effective catalyst and various nitriles were converted into primary amine salts in almost quantitative yields under mild reaction conditions. Interestingly, a complex mixture was obtained under batch conditions. Lifetime experiments showed that this catalyst remained active for more than 300 h (TON≥10 000) without loss of selectivity and no metal leaching from the catalyst occurred. By using this continuous-flow hydrogenation, synthesis of venlafaxine, an antidepressant drug, has been accomplished.

Synthesis of Nitro-Containing Compounds through Multistep Continuous Flow with Heterogeneous Catalysts.

Synthesis of ß-nitrostyrene derivatives and their following reactions through two-step continuous-flow protocols with heterogeneous catalysts are described. In the first step to provide ß-nitrostyrenes from aromatic aldehydes and nitromethane, readily available amino-functionalized silica gel was employed as a catalyst and gave the products continuously for at least 100 h with high selectivity. In the second step, reactions of ß-nitrostyrenes, solid bases, immobilized bases, solid acids, and chiral supported metals and nonmetals were used as catalysts, and seven kinds of nitro-containing organic compounds could be effectively synthesized through the two-step continuous-flow systems.

Air-stable, storable, and highly selective chiral Lewis acid catalyst.

An air-stable, storable, and highly selective chiral Lewis acid catalyst for asymmetric Mannich-type reactions has been developed. The catalyst can be stored for more than three months in air at room temperature without loss of activity. Moreover, it has also been demonstrated that the catalyst can be recovered and reused. [structure: see text]

Catalytic, asymmetric trans-selective hetero Diels-Alder reactions using a chiral zirconium complex.

[reaction: see text] The first catalytic, asymmetric 2,3-trans-selective hetero Diels-Alder reaction has been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the pyranone derivatives in high yields with high trans-selectivities and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide and (R)-3,3'-diiodobinaphthol or its derivatives, primary alcohol, and a small amount of water. This reaction was applied to the concise synthesis of (+)-prelactone C.

Catalytic Asymmetric Synthesis of Antimalarial Alkaloids Febrifugine and Isofebrifugine and Their Biological Activity.

Antimalarial alkaloids febrifugine (1) and isofebrifugine (2) were efficiently synthesized from simple achiral starting materials on the basis of the catalytic asymmetric synthesis. The first key reaction was performed using the tin(II)-mediated catalytic asymmetric aldol protocol to afford chiral aldehyde 3 in high yield with high diastereo- and enantioselectivities. The second key step, a Mannich-type reaction, did not give satisfactory results according to the conventional methods. We then developed a novel aqueous Mannich-type three-component reaction of an aldehyde, an amine, and a vinyl ether using a Lewis acid-surfactant combined catalyst (LASC), and the key intermediates 16 and 17 were obtained in high yields. The final coupling reactions of bromoacetone 14 with 4-hydroxyquinazoline were carried out using basic conditions, and successive deprotection gave 1 and 2, respectively, without any isomerization. These unambiguous total asymmetric syntheses revealed that the absolute configurations of febrifugine and isofebrifugine were not (2'S,3'R) and (2'R,3'R) as reported previously but (2'R,3'S) and (2'S,3'S), respectively (1' and 2'). Finally, antimalarial activities of the synthesized febrifugine and isofebrifugine, and their antipodes, were examined. It was revealed that the activities and selectivities of natural febrifugine and isofebrifugine were much higher than those of the antipodes.

The First Enantioselective Aza-Diels-Alder Reactions of Imino Dienophiles on Use of a Chiral Zirconium Catalyst.

Chiral dihydropyridone derivatives 3 are obtained in high yields and with good enantioselectivities by the title reaction of aldimines such as 1 with Danishefsky's diene 2. 6,6'-Dibromo-1,1'-binaphthol complexes with Group 4 metals serve as catalysts; zirconium proved to be especially effective.

Catalytic, Enantioselective Synthesis of α-Aminonitriles with a Novel Zirconium Catalyst.

Strecker reactions of aldimines with Bu3 SnCN in the presence of the novel chiral zirconium binuclear catalyst 1 provide α-aminonitriles in good yields and with high enantioselectivities. The reaction can be applied to a wide range of substrates. Since both enantiomers of the chiral sources are readily avaibable, both enantiomers of the α-aminonitriles are easily prepared according to this method. L=N-methylimidazole.

Chiral zirconium catalysts using multidentate BINOL derivatives for catalytic enantioselective Mannich-type reactions; ligand optimization and approaches to elucidation of the catalyst structure.

Catalytic enantioselective Mannich-type reactions of silicon enolates with aldimines were investigated using chiral zirconium catalysts prepared from Zr(O(t)Bu)(4), N-methylimidazole, and newly designed multidentate BINOL derivatives. These new multidentate BINOL ligands were designed on the basis of an assumed transition state structure of a chiral zirconium catalyst derived from two molecules of (R)-6,6'-Br(2)-BINOL. Not only tetradentate BINOL 4 but also tridentate BINOL derivatives were found to be effective, and high enantioselectivities were attained. In a structural study of the most effective zirconium complex prepared from tridentate ligand 6e, several NMR experiments and DFT calculations were carried out. Consequently, the structure of an active catalyst and plausible mechanism of asymmetric induction were elucidated.

Chiral hetero Diels-Alder products by enantioselective and diastereoselective zirconium catalysis. Scope, limitation, mechanism, and application to the concise synthesis of (+)-Prelactone C and (+)-9-deoxygoniopypyrone.

Catalytic asymmetric hetero Diels-Alder (HDA) reactions using a chiral zirconium complex have been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the corresponding pyranone derivatives in high yields with high diastereo- and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide, (R)-3,3'-diiodobinaphthol or its derivative, a primary alcohol, and a small amount of water. It is noted that 2,3-trans-pyranone derivatives were obtained with remarkably high diastereo- and enantioselectivities in the reaction with 4-methyl Danishefsky's diene. This is the first example of catalytic asymmetric trans-selective hetero Diels-Alder reactions of aldehydes. Furthermore, asymmetric HDA reactions with 4-benzyloxy Danishefsky's dienes were conducted to afford 2,3-cis-pyranone derivatives in high selectivities. Isolation of an intermediate of this asymmetric hetero Diels-Alder reaction indicated that the reaction proceeded in a stepwise cycloaddition pathway. Finally, these catalytic, asymmetric hetero Diels-Alder reactions were successfully applied to concise syntheses of biologically important natural pyranone derivatives, (+)-Prelactone C and (+)-9-deoxygoniopypyrone.

Highly anti-selective asymmetric aldol reactions using chiral zirconium catalysts. Improvement of activities, structure of the novel zirconium complexes, and effect of a small amount of water for the preparation of the catalysts.

Catalytic asymmetric aldol reactions of silyl enol ethers with aldehydes (Mukaiyama aldol reactions) have been performed using novel chiral zirconium catalysts. The reactions proceeded in high yields under mild conditions, and anti-adducts were obtained in high diastereo- and enantioselectivities. The catalysts were first prepared from zirconium(IV) tert-butoxide (Zr(O(t)Bu)(4)), (R)-3,3'-diiodo-1,1'-binaphthalene-2,2'-diol ((R)-3,3'-I(2)BINOL), a primary alcohol, and a small amount of water. It was revealed that the primary alcohol played an important role in completing the catalytic cycle and that a small amount of water was essential for obtaining high selectivities. Moreover, activities of the chiral zirconium catalysts were enhanced by using new ligands, (R)-3,3'-I(2)-6,6'-X(2)BINOL (X = Br, I, C(2)F(5)), and it has been shown that even aldol reactions of less reactive substrates proceeded smoothly using the novel zirconium catalysts. Finally, NMR studies of these catalysts were performed, which suggested that the catalyst would form a dimeric structure and that the water affected the catalyst formation.