A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines

The Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with a range of substituted benzyl nitriles (2a-e) afforded rapid access to a family of α,β-unsaturated nitriles (3a-e) in good yields (67-78%). Flow hydrogenation (ThalesNano H-cube™) at 60 °C, 50 bar H₂ pressure, 1.0 mL/min through a 10% Pd-C catalyst selectively, and quantitatively, hydrogenated the olefin double bond (4a-e). Use of a Raney Nickel catalyst at 70 °C, 70 bar H₂ pressure and flow rates of 0.5-1.0 mL/min afforded quantitative conversion into the corresponding saturated amines with the reduction of both the olefin and nitrile bonds (5a-e). The versatility of this approach was further exemplified by reaction of 5a and 5c with norcantharidin to afford acid amide norcantharidin analogues 7 and 8 as novel protein phosphatase 1 and 2A inhibitors.     

Utilization of microflow reactors to carry out synthetically useful organic photochemical reactions

This review focuses on recent advances that have been made in conducting synthetically useful organic photochemical reactions by using microflow reactors. Attention is given to the utilization of this technique in the “scale-up” of a variety of photochemical processes including intermolecular photocycloadditions, intramolecular photocycloadditions and photocyclizations, photoadditions, photoreductions, photoisomerizations, photosubstitutions, photooxidations, photorearrangements, and heterogeneous photocatalytic reactions. In many examples, the use of the microflow method is compared to those carried out in batch systems. Finally, advantages and disadvantages of microflow photoreactions along with the possible employment of this approach to scale-up industrial photochemical processes are discussed.     

A scalable approach to diaminopyrazoles using flow chemistry

This Letter reports on how the combination of microwave and continuous flow chemistry facilitated the convenient preparation of aminopyrazoles from commercial aryl halides. The method was applied to a variety of substrates with good to excellent yields and further extended toward the complete flow synthesis of 5,7-dimethyl-3-phenylpyrazolo[1,5-a]pyrimidin-2-amine.     

Efficient synthesis of panaxadiol derivatives using continuous-flow microreactor and evaluation of anti-tumor activity

An efficient method has been developed for the synthesis of a series of(20R)-panaxadiol derivatives(4a–w) using a continuous-flow microreactor.The antitumor activities of the newly synthesized compounds were evaluated in vitro in two human prostate adenocarcinoma tumor cell lines(i.e.,PC-3and LNCa P cells),and their cytotoxicities were evaluated using a standard MTT assay.Compounds 4c,4h,4p,4q and 4s exhibited higher antitumor activities toward PC-3 cell line than panaxadiol,which was used as a reference standard.     

Process design methodology for organometallic chemistry in continuous flow systems

This publication summarises the methodology applied in the process design and scale up of fast, exothermic reactions using organometallic reagents for synthesis of intermediates in the production of Active Pharmaceutical Ingredient (API). Process understanding was developed by calculation of the kinetic parameters of the desired reactions and subsequent degradation of the reaction products along with calorimetric understanding. A reaction model, developed in silico, was used to specify process parameters to maximise yield and limit product degradation. The designed process operates with pseudo-adiabatic reaction conditions, from ambient temperatures with negligible impurity formation.     

A generic approach for the catalytic reduction of nitriles

The scope of nickel boride mediated reduction of nitriles has been extended further to allow the preparation of Boc protected amines via a mild catalytic process. It is noteworthy that the toxicity of this procedure is greatly reduced due to its catalytic nature in nickel(II) chloride used in combination with excess sodium borohydride. The protocol is marked by its resilience towards air and moisture and hence an easy and general practical protocol.     

A combination of flow and batch mode processes for the efficient preparation of mGlu2/3 receptor negative allosteric modulators (NAMs)

Benzodiazepinones are privileged scaffolds with activity against multiple therapeutically relevant biological targets. In support of our ongoing studies around allosteric modulators of metabotropic glutamate receptors (mGlus) we required the multigram synthesis of a β-ketoester key intermediate. We report the continuous flow synthesis of tert-butyl 3-(2-cyanopyridin-4-yl)-3-oxopropanoate and its transformation to potent mGlu_2/3 negative allosteric modulators (NAMs) in batch mode.     

Recent topics of functionalized organolithiums using flow microreactor chemistry

Examples in this mini-review illustrate the potential of flow microreactor chemistry in chemical science and chemical production. Flow microreactors provide a powerful method for novel transformations via functional organolithiums that cannot be achieved using a conventional macro batch reactor.     

A simple, efficient, and selective deuteration via a flow chemistry approach

A simple and efficient deuteration methodology has been established for a wide variety of substrates using a continuous flow hydrogenation reactor. The described procedure is many times faster (1 mg min⁻¹) compared to literature methods and the purity of the crude product can be as high as 99%. The deuterium source is D₂O, the consumption of which is very low.     

The accelerated preparation of 1,4-dihydropyridines using microflow reactors

The synthesis of 1,4-dihydropyridines was performed in a continuous-flow microreactor. Elevated temperatures accelerated the reaction rate significantly allowing the reaction to be finished in minutes (6–11 min). Different 1,4-dihydropyridines were prepared in good to excellent isolated yields (45–88% yield). The method was amenable to the preparation of daropidine, a calcium channel blocker which is currently in clinical phase 3 trials.     

A convenient electrolytic process for the reduction of aldehydes

We report an efficient electrolytic procedure for the reduction of aldehydes to primary alcohols in the absence of dimeric products. In this promising approach, based on environmentally friendly chemical synthetic methods, a simple electrolytic undivided cell was designed. Two copper plates served as electrodes and recycled water as the medium. A 6-V battery provided the required energy. Although initially the method was intended for the preparation of 2-aryl-3-hydroxymethyl imidazo[1,2-a]azines, it was successfully extended to reduce other aliphatic and aromatic aldehydes. The attractiveness of this procedure includes its operational simplicity, practical viability, inexpensiveness and good yields. In most cases the results were better than those obtained with the standard reduction procedure using sodium borohydride.     

Reduction of aromatic nitriles to aldehydes with sodium aluminum hydride

Conclusions In the reduction of aromatic aldehydes of the benzene, naphthalene, pyridine, and ferrocene series with NaAlU4 in tetrahydrofuran solution, aldehydes were obtained in 65–85% yield. The reduction of aliphatic nitriles proceeds chiefly to the formation of the amines, while the aldehydes are formed in small yields (15–25%).Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8 pp. 1511–1512, August, 1964     

Straightforward zinc-catalyzed transformation of aldehydes and hydroxylamine hydrochloride to nitriles

In the present study, the zinc-catalyzed dehydration of a range of in situ generated aldoximes, available by the reaction of aldehydes and hydroxylamine hydrochloride, has been explored. After investigating various reaction parameters, with Zn(OTf)₂ an excellent and easily accessible pre-catalyst was obtained. The system was highly active and dehydrated a broad range of aldoximes selectively to the corresponding nitriles under mild reaction conditions.     

A highly efficient electrochemical route for the conversion of aldehydes to nitriles

Using NH4 I as the supporting electrolyte as well as the precursor of an I2 promoter and nitrogen source, a highly efficient electrochemical route was developed to convert aldehydes to nitriles with excellent yields under mild reaction conditions. This electrochemical process could effectively avoid the direct use of NH3 gas, molecular iodine, and oxidants.     

Rapid, simple, and efficient deprotection of benzyl/benzylidene protected carbohydrates by utilization of flow chemistry

A rapid, simple, and efficient deprotection procedure for the deprotection of benzyl- and/or benzylidene protected carbohydrates is described utilizing a continuous flow hydrogenation reactor. The method tolerates both acid- and base sensitive functional groups. The high efficiency, simple work-up, and short reaction time should make this method appealing to researchers working in the fields of carbohydrate chemistry and total synthesis.     

Application of thermal analysis to study smelting reduction kinetics

A thermal analysis study on the reduction of iron oxide rich slags under different conditions is presented in this paper. The effects of important process variables such as time, temperature, lime-silica ratio, FeO level in slag etc. are discussed. It is shown that the mechanism of reduction by externally added graphite is different from that by a carbon saturated bath although the activation energy values are similar.     

Click chemistry for the synthesis of 5-substituted 1H-tetrazoles from boron-azides and nitriles

A novel and metal free catalysis of synthesizing 5-substituted 1H-tetrazoles through 1,3-dipolar cycloaddition of boron-azides and nitriles is reported with broad substrate scope and excellent yields.     

Ni-nanoparticles: an efficient green catalyst for chemoselective reduction of aldehydes

A novel method for reduction of aromatic and heteroaromatic aldehydes with ammonium formate using Ni-nanoparticles is described. The Ni-nanoparticles act as a green catalyst for selective reduction of the aldehydic group in the presence of other functional groups, viz.: -NO₂, -CN and alkenes to give the corresponding alcohols in excellent yields.