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Oct 162017
 

 

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Renzo Luisi Ph.D.

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Leonardo Degennaro at Università degli Studi di Bari Aldo Moro

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

How to cite this article:
Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Beilstein J. Org. Chem. 2017, 13, 520–542. doi:10.3762/bjoc.13.51

Department of Pharmacy – Drug Sciences, University of Bari “A. Moro”, FLAME-Lab – Flow Chemistry and Microreactor Technology Laboratory, Via E. Orabona 4, 70125, Bari. Italy

  1.  Corresponding author email

This article is part of the Thematic Series “Green chemistry”.

Guest Editor: L. Vaccaro
Beilstein J. Org. Chem. 2017, 13, 520–542. doi:10.3762/bjoc.13.51
Received 14 Nov 2016, Accepted 20 Feb 2017, Published 14 Mar 2017

Abstract

Microreactor technology and flow chemistry could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chemistry, catalysis, hazardous chemistry and continuous flow processing are described. Selected examples highlight the role that flow chemistry could play in the near future for a sustainable development.

Keywords: flash chemistry; flow chemistry; green chemistry; microreactor technology; sustainable synthesis

 

Introduction

Green chemistry’s birth was driven by the necessity to consider and face the urgent question of sustainability. Chemical production concerns an extended range of fields such as textiles, construction, food, cosmetic components, pharmaceuticals and so forth. An innovative approach to the chemistry world requires new strategies and criteria for an intelligent chemistry. It is understood that all this matter has big implications in economy and politics. Recent studies predicted a growth of green chemical processing up to $100 billion in 2020 (Pike Research study) [1]. All this offers important and arduous challenges expressed in terms of new synthetic strategies using sustainable, safe, and less toxic materials. On green chemistry we can read Paul Anastas and John Warne’s 12 principles, set up in 1998, which illustrate the characteristics of a greener chemical process or product [2]. Microreactor technology and flow chemistry could play a pivotal role in the context of sustainable development. In fact, flow chemistry is becoming a new technique for fulfilling several of the twelve green chemistry principles. The microreactor approach, could provide protection, preserves atom economy, guarantees less hazardous chemical synthesis and allows the use of safer solvents and auxiliaries. Furthermore, it pushes towards designing of chemistry with a lower environmental and economic impact, enhance the importance of catalysis, allows real-time analysis for pollution prevention and provides inherently safer chemistry (Figure 1[3]. Without claiming to be exhaustive, in this review we report recently published representative synthetic applications that demonstrate the growing contribution of flow chemistry and microreactor technology in green and sustainable synthesis [4-7].

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Figure 1: Microreactor technologies and flow chemistry for a sustainable chemistry.

 

 

Review

 

Flow microreactors: main features

The peculiar properties of microreactors [8] derive from their small size and can be ascribed mainly to the following characteristics: a) fast mixing: in a flow microreactor, in striking contrast to batch conditions, mixing takes place by molecular diffusion so that a concentration gradient can be avoided; b) high surface-to-volume ratio: the microstructure of microreactors allows for a very rapid heat transfer enabling fast cooling, heating and, hence, precise temperature control; c) residence time: it is the period of time the solution of reactants spend inside the reactor, and it gives a measure of the reaction time. The residence time is strictly dependent on the characteristics of the reactor (i.e., length of the channels, volume), and on the flow rate. The residence time is one of the crucial factors to be considered in optimizing flow reactions, especially when unstable or short-lived reactive intermediates are concerned. Microreactor technology provides also several benefits. Safety benefits, because of the high efficiency in heat exchange, and avoided accumulation of unstable intermediates. Economy benefits, due to lower manufacturing and operating costs, reduced work-up procedures, use of less raw materials and solvents and reduced waste. Chemistry benefits associated to the use of microreactor technology are the improved yields and selectivities, the possibility to conduct reactions difficult or even impossible to perform in batch, and the use of reaction conditions that allow exploring new chemical windows [9].

 

Contribution of flash chemistry to green and sustainable synthesis

The concept of flash chemistry as a “field of chemical synthesis using flow microreactors where extremely fast reactions are conducted in a highly controlled manner to produce desired compounds with high selectivity” was firstly introduced by Yoshida [10]. Flash chemistry can be considered a new concept in both organic and sustainable synthesis involving chemical transformations that are very difficult or practically impossible to conduct using conventional batch conditions. With the aim to show how flow microreactor technology and flash chemistry could contribute to the development of a sustainable organic synthesis, very recent examples have been selected and will be discussed here. In the context of green chemistry [11], protecting-group free organic synthesis has received particular attention in the last years, because of atom economy [12-15] and reduction of synthetic steps [16]. It has been demonstrated by Yoshida that protecting-group-free synthesis could be feasible using flash chemistry and microreactor technology [17,18]. Recently, Yoshida and co-workers developed flash methods for the generation of highly unstable carbamoyl anions, such as carbamoyllithium, using a flow microreactor system [19]. In particular, they reported that starting from different substituted carbamoyl chloride 1 and lithium naphthalenide (LiNp) it was possible to generate the corresponding carbamoyllithium 2, that upon trapping with different electrophiles provided several amides and ketoamide 3(Scheme 1).

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Scheme 1: A flow microreactor system for the generation and trapping of highly unstable carbamoyllithium species.

The use of an integrated microflow system allowed the preparation of functionalized α-ketoamides by a three-component reaction between carbamoyllithium, methyl chloroformate and organolithium compounds bearing sensitive functional groups (i.e., NO2, COOR, epoxide, carbonyl) (Scheme 2).

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Scheme 2: Flow synthesis of functionalized α-ketoamides.

It should be stressed that this kind of sequential transformations are practically impossible to perform using conventional batch chemistry because of the incompatibility of sensitive functional groups with organolithiums, and because of the high chemical and thermal instability of the intermediates.

In 2015 Yoshida reported another remarkable finding on the use of protecting-group-free organolithium chemistry. In particular, the flash chemistry approach was exploited for generating benzyllithiums bearing aldehyde or ketone carbonyl groups [20]. This reaction could be problematic for two reasons: a) the competing Wurtz-type coupling, (i.e., the coupling of benzyllithiums with the starting benzyl halides); b) the nucleophilic attack of organolithium species to aldehyde or ketone carbonyl groups (Scheme 3).

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Scheme 3: Reactions of benzyllithiums.

The authors reported that the extremely fast micromixing avoided undesired Wurtz-type coupling [21,22]. It is well known, that competitive reactions can be controlled or even avoided under fast micromixing [23-27]. Moreover, high-resolution residence time control was essential for survival of carbonyl groups. In fact, this transformation can be achieved only with a residence time of 1.3 ms at −78 °C. Under these flow conditions, the aldehyde or ketone carbonyl moiety can survive the nucleophilic organolithium attack. Remarkably, the flow microreactor system allowed also the generation of benzyllithiums at 20 °C, rather than under cryogenic (−95 °C) conditions adopted with a conventional batch protocol. In addition, THF could be used in place of mixed solvents (Et2O/THF/light petroleum). Under the optimized conditions, the reactions of benzyllithiums with different electrophiles, gave adduct products in good yields (Scheme 4).

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Scheme 4: Trapping of benzyllithiums bearing carbonyl groups enabled by a flow microreactor. (Adapted with permission from [18], copyright 2015 The Royal Society of Chemistry).

Another useful aspect of the flash chemistry relies on the possibility to generate highly reactive intermediates, such as halomethyllithium carbenoids, that need to be used under internal-quenching technique in batch mode. In 2014, the first example of effective external trapping of a reactive chloromethyllithium (CML) has been reported [28]. α-Haloalkyllithiums are a useful class of organometallic reagents widely employed in synthetic chemistry. In fact, they allow the direct homologation of carbonyl compounds and imines leading to β-halo-alcohols and amines that are useful building blocks [29-31]. This work represents a remarkable example of flash chemistry, and has elements of sustainability considering that in batch macroreactors, in order to avoid metal-assisted α-elimination, in situ quenching, an excess of reagents, and very low temperature are required [32,33].

Running the reaction in a flow system at −40 °C, by using residence times between 0.18–0.31 s high yields of homologated products have been obtained under external quenching conditions (Scheme 5).

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Scheme 5: External trapping of chloromethyllithium in a flow microreactor system.

The results described above nicely show the potential, as green technology, of flow microreactor systems for synthetic processes involving highly unstable intermediates. Another nice example on the use of microreactor technology for the development of sustainable chemical processes, is represented by the direct introduction of the tert-butoxycarbonyl group into organometallic reagents [34]. The reaction between organolithium reagents and di-tert-butyl dicarbonate run under flow conditions, allowed a straightforward preparation of several tert-butyl esters. The use of a flow process resulted more efficient, versatile and sustainable compared to batch. Moreover, this operationally simple procedure complements well with the already available strategies for the preparation of tert-butyl esters, avoiding the use of inflammable and explosive gaseous isobutylene [35], the use of harsh conditions [36], the use of peroxides [37], the use of toxic gas such as CO or transition metals [38-42]. The flow process, for the direct C-tert-butoxycarbonylation of organolithiums, has been optimized in a green solvent such as 2-MeTHF by a precise control of the residence time, and without using cryogenic conditions (Scheme 6). In addition, many organolithiums were generated from the corresponding halo compounds by a halogen/lithium exchange reaction using hexyllithium as a more sustainable base [43,44].

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Scheme 6: Scope for the direct tert-butoxycarbonylation using a flow microreactor system.

The concept of flash chemistry has been successfully employed for outpacing fast isomerization reactions. The accurate control of the residence time, realized in a microreactor, could suppress or avoid isomerization of unstable intermediates. This is often unavoidable when the same reactions are run in batch mode [45-47].

Yoshida and Kim recently provided an astonishing example on the potential of flash chemistry in controlling fast isomerization of organolithiums [48]. The authors designed a chip microreactor (CMR), able to deliver a reaction time in the range of submilliseconds (0.33 ms) under cryogenic conditions. By using such an incredible short residence time, it was possible to overtake the very rapid anionic Fries rearrangement, and chemoselectively functionalize ortho-lithiated aryl carbamates (Scheme 7).

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Scheme 7: Control of anionic Fries rearrangement reactions by using submillisecond residence time. (Adapted with permission [43], copyright 2016 American Association for the Advancement of Science).

This CMR has been developed choosing a fluoroethylene propylene–polymide film hybrid for fabrication because this material offers exceptional physical toughness at low temperature and high pressure as well as chemical inertness. The most relevant aspect of this microreactor, concerns the 3D design of the mixing zone (Figure 2). The mixing efficiency was evaluated on the basis of computational fluids dynamics (CFD). The simulation results showed that serpentine 3D-structured channels (Figure 2), possessing five turns after each mixing point in a total length of 1 mm, was able to deliver the highest mixing efficiency. The inner volume for the reactor was of 25 μL. This CMR provides mixing efficiency levels of 95% with a total flow rates of 7.5 mL/min corresponding to a residence time of about 0.3 milliseconds.

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Figure 2: Chip microreactor (CMR) fabricated with six layers of polyimide films. (Reproduced with permission from [43], copyright 2016 American Association for the Advancement of Science).

To show the potential use of this microdevice in organic synthesis, the synthesis of Afesal [49], a biologically active compound having anthelmintic activity was reported as application.

This outstanding result by Yoshida and Kim, demonstrates how microdevices and flash chemistry could contribute to the development of new sustainable synthetic strategies, and how microreactor technology could help in taming the reactivity of unstable species [50].

 

Contribution of continuous-flow metal-, organo-, and photocatalysis in green chemistry

The development of continuous-flow catalysis is appealing because it combines the advantages of a catalytic reaction with the benefits of flow microreactors. Under homogeneous conditions a soluble catalyst, which flows through the reactor together with the reactants, is employed. At the end of the process, a separation step would be required in order to remove the catalyst and byproducts. On the other hand, heterogeneous catalysis is widely used in the synthesis of bulk and fine chemicals. In a continuous-flow process, the catalyst can be fixed on a suitable hardware, and the reaction mixture allowed to flow through the system. The use of recyclable catalysts in continuous-flow conditions represents an innovative strategy for the development of more environmentally friendly synthesis. In the last decade, organic photochemistry got a sort of renaissance, emerging as useful approach in modern sustainable and green synthesis.

Concerning the heterogeneous catalysis with palladium, practical procedures for recovering and reusing of the catalysts have been recently reported [51-53]. A versatile Pd-catalysed synthesis of polyfunctionalized biaryls, using a flow microreactor, has been recently reported by Yoshida [54]. Using the integrated microflow system reported in Scheme 8, arylboronic esters were prepared by a lithiation/borylation sequence, and used in a Suzuki–Miyaura coupling in a monolithic reactor. A remarkable aspect of the process was the use of an integrated supported monolithic Pd(0) catalyst that allowed to perform cross-coupling reactions in continuous flow mode (Scheme 8).

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Scheme 8: Flow microreactor system for lithiation, borylation, Suzuki–Miyaura coupling and selected examples of products.

This integrated microflow system allow to handle the borylation of aryl halides (Ar1X), and the subsequent Suzuki–Miyaura coupling using different aryl halide (Ar2X). Without requiring the protection of sensitive functionalities, running the flow system using a residence time (tR) of about 4.7 min at a temperature above 100 °C, high yields of coupling products were obtained. Noteworthy, the Suzuki–Miyaura coupling did not require the use of a base. The authors applied the presented method to the synthesis of adapalene, used in the treatment of acne, psoriasis, and photoaging.

Fluorinated aromatic compounds are extremely important in agrochemical, pharmaceutical and medicinal fields [55-58]. Buchwald and co-workers suggested a telescoped homocatalysis procedure consisting of a three-step sequence (metalation, zincation and Negishi cross-coupling) which furnishes an easy access to a variety of functionalized 2-fluorobiaryl and heteroaryl products (Scheme 9[59]. This strategy is rightfully considered green because it guarantees the employment of readily available and cheap starting materials, the safe handling of highly thermally unstable or dangerous intermediates, and the use of higher temperature with respect to the batch mode in which the proposed reactions have to be carried out at −78 °C.

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Scheme 9: Experimental setup for the flow synthesis of 2-fluorobi(hetero)aryls by directed lithiation, zincation, and Negishi cross-coupling. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

The use of 2-MeTHF as greener solvent, contributes to further validate the green procedure. The 2-MeTHF solutions of fluoroarenes 4 together with the hexane solution of n-BuLi were pumped into the flow system at −40 °C. The generated organozinc intermediate meets the solution of haloarenes and the catalyst, leading to the formation of the desired products 5a–j (Scheme 9). Noteworthy, the homogeneous catalysis requires only 1% of the XPhos-based palladium catalyst. A sonication bath was employed to prevent clogging and the reaction required a residence time of 15 min.

Next, they turned their attention to the arylation of fluoro-substituted pyridines. The regioselective lithiation of halopyridines with lithium diisopropylamide (LDA) was conducted under mild conditions on substrate 6(Scheme 10). The addition of a little amount of THF was necessary in order to avoid clogging and the tendency of the lithiated intermediate to eliminate.

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Scheme 10: Experimental setup for the coupling of fluoro-substituted pyridines. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

The optimized conditions were suitable for the functionalization of 2-fluoropyridine, 2,6- difluoropyridine and 4-(trifluoromethyl)pyridine leading to products 7a–g reported in Scheme 10. Another promising field is the sustainable flow organocatalysis, and recently Pericàs reported an interesting synthesis and application of a recyclable immobilized analogue of benzotetramisole (BMT) used in a catalytic enantioselective Michael addition/cyclization reactions under continuous-flow conditions (Scheme 11[60].

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Scheme 11: Continuous flow process setup for the preparation of 11 (Reproduced with permission from [54], copyright 2015 American Chemical Society).

Resin-bound catalyst 10 was swollen with dichloromethane in a medium-pressure chromatography column used as a reactor. Dichloromethane solutions of substrate 9 reacted with the mixed phenylacetic pivalic anhydride (deriving from phenylacetic acetic (8) and pivaloyl chloride) inside the catalytic reactor producing the expected products 11. This ingenious system was equipped with an in-line FTIR probe, for monitoring the transformation, and an in line liquid–liquid separator to avoid tedious work-up procedures, thus saving solvents, resources and optimizing work times. This system was demonstrated to work for 11 h with higher conversion and enantioselectivity (er >99.9%) in comparison to the batch mode [61]. Pericàs and co-workers taking advantage of the high catalytic activity, robustness and recyclability of the supported catalyst, performed also straightforward gram synthesis of target compounds.

In the context of photocatalysis and oxidations using flow microreactors [62,63], Noël reported a metal-free photocatalytic aerobic oxidation of thiols to disulfides under continuous-flow conditions [64]. Disulfides are useful molecules employed as drugs, anti-oxidants or pesticides as well as rubber vulcanizating agents [65]. Symmetric disulfides are generally obtained by oxidative coupling of thiols [66]. Noël and co-workers set up a microflow system equipped with a mass flow controller (MFC) able to introduce pure oxygen as the oxidant to oxidize a solution of thiol containing 1% of Eosin Y. The flow stream was exposed to white LED light in order to activate the reaction, and a dilution with pure EtOH was needed at the output to avoid clogging (Scheme 12). The residence time of 20 min guaranteed a limited irradiation time and high purity of the products.

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Scheme 12: Continuous-flow photocatalytic oxidation of thiols to disulfides.

The disulfides were obtained with excellent yields, and the process was executed on challenging thiols as in the case of disulfide 12 (Scheme 12), used as food flavour additive [67]. To demonstrate the usefulness of the flow methodology, and its applicability, the photocatalytic aerobic oxidation of a peptide to obtain oxytocin in continuous flow was reported (Scheme 12). Full conversion was achieved in water with 200 s of residence time.

Noël optimized, for the first time, a trifluoromethylation of aromatic heterocycles by continuous-flow photoredox catalysis. The process benefited from the use of microreactor technology and readily available photocatalysts. The process was also employable for perfluoroalkylation. The developed process occurred in less time with respect to batch mode, and under milder conditions. The set-up of the reactor allowed for the use of gaseous CF3I by means of a mass flow controller. Selected examples of trifluoroalkylated products are reported in Scheme 13 [68].

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Scheme 13: Trifluoromethylation by continuous-flow photoredox catalysis.

Tranmer reported a “traceless reagents” chemistry with the continuous-flow photosynthesis of 6(5H)-phenanthridinones, poly(ADP-ribose) polymerase (PARP) inhibitors [69]. The relevance of the work resides in the use of green solvents, the absence of heavy metals, the use of convenient temperatures, and the increased safety by eliminating UV-exposure locating the UV lamp within the microreactor. Hazard of fires caused by the hot UV lamps approaching the auto-ignition temperature of flammable solvents, very often underestimated, is totally prevented thanks to a specific cooling system. 2-Halo-N-arylbenzamides were converted into 6(5H)-phenanthridinones by a photocyclization reaction. In order to run this step, a flow system with a photochemical reactor equipped with a medium pressure Hg lamp and 10 mL reactor coil, was employed. Good yields were obtained from different 2-chlorobenzamides disclosing that either electron-donating or electron withdrawing ortho-substituents were tolerated (Scheme 14).

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Scheme 14: Flow photochemical synthesis of 6(5H)-phenanthridiones from 2-chlorobenzamides.

A metal- and catalyst-free arylation procedure carried out under continuous-flow conditions was recently reported by Fagnoni [70]. This photochemical process allowed for the preparation of a wide range of synthetic targets by Ar–Csp3, Ar–Csp2 and Ar–Csp bond-forming reactions. The use of a photochemical flow reactor, consisting of a polyfluorinated tube reactor wrapped around a 500 W Hg lamp, allowed to overcome batch limitations paving the way for metal-free arylation reactions via phenyl cations. Derivatives 14a–g were prepared with this greener flow approach (Scheme 15) starting from mesitylene 13, and haloarenes using short irradiation times (<6 h), and a 5:1 MeCN/H2O mixture.

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Scheme 15: Synthesis of biaryls 14a–g under photochemical flow conditions.

The reported results show how photochemistry hold the potential to become a green tool for the development of sustainable photochemical flow synthesis.

 

Hazardous chemistry by using green and sustainable continuous-flow microreactors

We have already shown how continuous-flow technology could play an important role in improving chemical processes [5,71], providing different advantages over traditional batch mode. However, the hazardous nature of some chemicals makes handling at conventional lab or industrial scale difficult. The use of microreactors and continuous-flow chemistry offers the possibility to perform reactions using dangerous or hazardous materials that cannot be used in batch mode. In other word, syntheses previously “forbidden” for safety reasons, such as those involving diazo compounds, hydrazine, azides, phosgene, cyanides and other hazardous chemicals could be performed with relatively low risk using flow technology [72-76].

Several research groups investigated this aspect, as highlighted by several available reviews [77,78]. Here we describe very recent reports with the aim to highlight the potential of flow chemistry in the field of hazardous chemistry under a greener perspective.

Diazo compounds are recognized as versatile reagents in organic synthesis. Nevertheless, diazo compounds are also considered highly energetic reagents [79,80]. For this reason, the in situ generation of such reagents has been investigated under flow conditions. Moody and co-workers reported a new method for the in situ generation of diazo compounds as precursors of highly reactive metal carbenes (Scheme 16[81].

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Scheme 16: Flow oxidation of hydrazones to diazo compounds.

As reported in Scheme 16, diazo species 18 could be generated from simple carbonyls 15 and hydrazine (16). Intermediate hydrazones 17 can be converted into the corresponding diazo compounds by oxidation using a recyclable oxidant based on N-iodo-p-toluenesulfonamide potassium salt. The possibility to regenerate a functionalized resin by simple washing with aqueous KI3/KOH solution makes the process more sustainable. This method produces KI solution as waste, and it is an alternative way for the direct oxidation of hydrazones, that often requires the use of heavy metals such as HgO, Pb(OAc)4 and AgO [82,83].

The diazo compounds could be collected as solution in dichloromethane at the output of the flow system, and obtained sufficiently pure for further use without requiring handling or isolation. Further mixing of solutions containing diazo derivatives to a solution containing a Rh(II) catalyst, and reactants such as amines, alcohols or aldehydes led to a wide range of products as reported in Scheme 17.

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Scheme 17: Synthetic use of flow-generated diazo compounds.

Ley’s group developed several continuous-flow approaches for generating diazo species from hydrazones [84,85]. Under flow conditions, diazo compounds were reacted with boronic acids in order to generate reactive allylic and benzylic boronic acids further employed for iterative C–C bond forming reactions [86]. The generation of unstable diazo species was possible using a cheap, recyclable and less toxic oxidant, MnO2. The flow stream was accurately monitored by in-line FTIR spectroscopy in order to maximize the formation of the diazo compound (Scheme 18[87].

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Scheme 18: Ley’s flow approach for the generation of diazo compounds.

Starting from this initial investigation, Ley and co-workers developed an elegant application of this strategy for a sequential formation of up to three C–C bonds in sequence, by an iterative trapping of boronic acid species. The sequence starts with the reaction of diazo compound 20, generated under flow conditions, and boronic acid 19 (Scheme 19). Further sequential coupling with diazo compounds 21 and 22 led to boronates 23 or protodeboronated products 24 at the end of the sequence (Scheme 19).

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Scheme 19: Iterative strategy for the sequential coupling of diazo compounds.

With the aim to exploit the versatility of this approach, Ley and co-workers reported the allylations of carbonyl electrophiles such as aldehydes using the above reported strategy for the generation of allylboronic acids. The flow protocol considers the reaction of diazo compounds 25 (generated in flow) with boronic acid 26 and aldehyde 27 (Scheme 20). By this new iterative coupling it was possible to obtain alcohols as products. The usefulness of the method was demonstrated with the preparation in good yield (60%) of a precursor of the natural product bakuchiol 28 (Scheme 20[88].

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Scheme 20: Integrated synthesis of Bakuchiol precursor via flow-generated diazo compounds.

The microreactor technology offers the advantage to handle hazardous components such as hydrazine and molecular oxygen, which represent alternative reagents for selective reduction of C=C double bonds. In fact, combination of hydrazine hydrate (N2H4·H2O) and O2 provide diimide (HN=NH) as reducing agent. Nevertheless, this strategy is rarely used in traditional batch chemistry for safety reason. Kappe and co-workers recently developed a reduction of the alkene to the corresponding alkane, by a catalyst-free generation of diimide by oxidation of hydrazine monohydrate (N2H4·H2O) with molecular oxygen [89,90]. The flow system set-up is reported in Scheme 21, and consists in a HPLC pump for delivering the alkene and hydrazine monohydrate, while O2 was delivered by a mass-flow controller (MFC) from a standard compressed-gas cylinder. After combination of the reagent streams, the resulting segmented flow was pumped through a heated residence unit (RTU) consisting in a fluorinated tube with low gas permeability (Scheme 21).

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Scheme 21: Kappe’s continuous-flow reduction of olefines with diimide.

The flow system reported in Scheme 21 was able to reduce alkenes with high yields and selectivity by using residence times in the range of 10 to 30 min at 100 °C, and by employing a slight excess of hydrazine. Importantly, this strategy is compatible with sensitive functional groups such as silyl ether, halogenes, and benzyl groups. A very nice application of this approach was the highly selective reduction of artemisinic acid to dihydroartemisinic acid, which are of interest in the synthesis of the antimalarial drug artemisinin. This industrially relevant reduction was executed by using O2 at 20 bar, four residence units at 60 °C and consecutive feedings with N2H4·H2O in order to obtain full conversion in dihydroartemisinic acid (29, DHAA, Scheme 22).

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Scheme 22: Multi-injection setup for the reduction of artemisinic acid.

 

Continuous-flow sustainable production of APIs

With the aim to demonstrate the potential of microreactor technology and flow chemistry in sustainable synthesis, recent outstanding “proof of concepts” will be described. Kobayashi and co-workers reported a multistep continuous-flow synthesis of a drug target via heterogeneous catalysis. The developed process not requiring any isolation of intermediates, separation of the catalyst or other work-up procedures can be considered sustainable [91]. The syntheses of (S)-rolipram and a γ-aminobutyric acid (GABA) derivative were accomplished. Readily available starting materials and columns containing chiral heterogeneous catalysts to produce enantioenriched materials were employed. It is worth mentioning that this work represents a very nice example on the use of chiral catalysis in a multistep flow synthesis of a drug target on gram scale. The multistep synthesis of (S)-rolipram reported in Scheme 23 begins from a benzaldehyde derivative which undergoes a Henry-type reaction with nitromethane in the first flow step (Flow I). The resulting nitroalkene undergoes an asymmetric addition catalyzed by a supported PS–(S)-pybox–calcium chloride catalyst at 0 °C using two columns (Flow II). This is the enantio-determining step of the process. The stereochemistry of the adduct can be simply switched to the opposite enantiomer, by using the enantiomeric supported catalyst PS–(R)-pybox–calcium chloride. The enantiomeric excess of the products was about 96%. Two more steps consisting in a Pd-catalyzed hydrogenation reaction and a decarboxylation (Flow III and Flow IV) led to the target (S)-rolipram in 50% overall yield. The systems was designed in order to keep the level of the palladium in solution as low as possible (<0.01 ppm).

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Scheme 23: Flow reactor system for multistep synthesis of (S)-rolipram. Pumps are labelled a, b, c, d and e; Labels A, B, C, D, E and F are flow lines. X are molecular sieves; Y is Amberlyst 15Dry; Z is Celite. (Reproduced with permission from [84], copyright 2015 Nature Publishing Group).

Another outstanding proof of concept, which demonstrates the potential of flow chemistry for sustainable pharmaceutical manufacturing, has been recently reported by Jensen and his research team. The research team set up a compact and reconfigurable manufacturing platform for the continuous-flow synthesis and formulation of active pharmaceutical ingredients (APIs) [92]. The “mini” plant (reported in Figure 3) was very compact in size [1.0 m × 0.7 m × 1.8 m, (W × L × H)], and low-weighing (about 100 kg) and was able to perform complex multistep synthesis, work-up procedures as well as purification operations such as crystallization. This platform was also equipped with devices for real-time monitoring and final formulation of high purity APIs. For the preparation of target molecules, commercially available starting materials were employed. The platform was tested for the production and supply of hundreds to thousands doses per day of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam and fluoxetine hydrochloride.

Remarkably, for future applications of the platform, the produced medicines also met the U.S. Pharmacopeia standards.

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Figure 3: Reconfigurable modules and flowcharts for API synthesis. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).

The future use of this kind of platform would concern the “on-demand” production or the “instantaneous” production of short-lived pharmaceuticals (Figure 4). Other advantageous concerns of this reconfigurable platform are the lower production costs, the higher safety, the automation (computer controlled processes), the reduced waste (production could be done where is needed and in the right amount).

[1860-5397-13-51-4]

Figure 4: Reconfigurable system for continuous production and formulation of APIs. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).

 

 

Conclusion

Flow chemistry and manufacturing engineering have become largely acknowledged as viable and very often superior alternative to batch processing. Continuous-flow techniques offer increased safety, scalability, reproducibility, automation, reduced waste and costs, and accessibility to a wide range of new chemical possibilities, seldom not accessible through classic batch chemistry. All those benefits are even more noteworthy and outstanding than what they might seem, because they widely fulfil most of the green chemistry principles. In this short overview, we tried to highlight progresses and potential of flow chemistry in the field of sustainable synthesis. Thus, it is expected that flow chemistry and microreactor technology could deeply change the way to perform sustainable chemical production in the near future [93].

 

References

  1. Navigant Pike Research Study. http://www.navigantresearch.com/research/green-chemistry (accessed May 13, 2014).
    Return to citation in text: [1]
  2. Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301–312. doi:10.1039/B918763B
    Return to citation in text: [1]
  3. Reschetilowski, W., Ed. Microreactors in Preparative Chemistry; Wiley-VCH: Weinheim, 2013.
    Return to citation in text: [1]
  4. Nagaki, A.; Yoshida, J.-I. Top. Organomet. Chem. 2015, 57, 137–175. doi:10.1007/3418_2015_154
    Return to citation in text: [1]
  5. Ley, S. V. Chem. Rec. 2012, 12, 378–390. doi:10.1002/tcr.201100041
    Return to citation in text: [1] [2]
  6. Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456–1472. doi:10.1039/c3gc40374b
    Return to citation in text: [1]
  7. Professor Jun-ichi Yoshida firstly introduced the concept of “micro + flow = green” during a plenary lecture at the 14th IMRET conference held in Beijing (China) in Septembeer 2016.
    Return to citation in text: [1]
  8. Yoshida, J.-i.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4, 331–340. doi:10.1002/cssc.201000271
    Return to citation in text: [1]
  9. Hessel, V.; Schouten, J. C.; Renken, A.; Wang, Y.; Yoshida, J.-i., Eds. Handbook of Micro Reactors; Wiley-VCH: Weinheim, 2009.
    Return to citation in text: [1]
  10. Yoshida, J.-i. Flash Chemistry: Fast Organic Synthesis in Microsystems; Wiley-VCH: Weinheim, 2008. doi:10.1002/9780470723425
    Return to citation in text: [1]
  11. Poliakoff, M.; Fitzpatrick, J. M.; Ferren, T. R.; Anastas, P. T. Science 2002, 297, 807–810. doi:10.1126/science.297.5582.807
    Return to citation in text: [1]
  12. Trost, B. M. Science 1991, 254, 1471–1477. doi:10.1126/science.1962206
    Return to citation in text: [1]
  13. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281. doi:10.1002/anie.199502591
    Return to citation in text: [1]
  14. Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233–1246. doi:10.1351/pac200072071233
    Return to citation in text: [1]
  15. Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705. doi:10.1021/ar010068z
    Return to citation in text: [1]
  16. Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40–49. doi:10.1021/ar700155p
    Return to citation in text: [1]
  17. Kim, H.; Nagaki, A.; Yoshida, J.-i. Nat. Commun. 2011, 2, No. 264. doi:10.1038/ncomms1264
    Return to citation in text: [1]
  18. Nagaki, A.; Yoshida, J.-i. Microreactor Technology in Lithium Chemistry, in: Lithium Compounds in Organic Synthesis from Fundamentals to Applications. Luisi, R.; Capriati, V., Eds.; Wiley-VCH: Weinheim, 2014; pp 491–512. doi:10.1002/9783527667512.ch17
    Return to citation in text: [1] [2]
  19. Nagaki, A.; Takahashi, Y.; Yoshida, J.-i. Angew. Chem., Int. Ed. 2016, 55, 5327–5331. doi:10.1002/anie.201601386
    Return to citation in text: [1]
  20. Nagaki, A.; Tsuchihashi, Y.; Haraki, S.; Yoshida, J.-i. Org. Biomol. Chem. 2015, 13, 7140–7145. doi:10.1039/C5OB00958H
    Return to citation in text: [1]
  21. Rys, P. Acc. Chem. Res. 1976, 10, 345–351. doi:10.1021/ar50106a001
    Return to citation in text: [1]
  22. Rys, P. Angew. Chem., Int. Ed. Engl. 1977, 16, 807–817. doi:10.1002/anie.197708073
    Return to citation in text: [1]
  23. Nagaki, A.; Togai, M.; Suga, S.; Aoki, N.; Mae, K.; Yoshida, J.-i. J. Am. Chem. Soc. 2005, 127, 11666–11675. doi:10.1021/ja0527424
    Return to citation in text: [1]
  24. Yoshida, J.-i. Basics of Flow Microreactor Synthesis; SpringerBriefs in Molecular Science; Springer: Tokyo, 2015. doi:10.1007/978-4-431-55513-1
    Return to citation in text: [1]
  25. Yoshida, J.-i.; Nagaki, A.; Iwasaki, T.; Suga, S. Chem. Eng. Technol. 2005, 28, 259–266. doi:10.1002/ceat.200407127
    Return to citation in text: [1]
  26. Nagaki, A.; Takabayashi, N.; Tomida, Y.; Yoshida, J.-i. Org. Lett. 2008, 18, 3937–3940. doi:10.1021/ol8015572
    Return to citation in text: [1]
  27. Nagaki, A.; Ichinari, D.; Yoshida, J.-i. Chem. Commun. 2013, 49, 3242–3244. doi:10.1039/c3cc40392k
    Return to citation in text: [1]
  28. Degennaro, L.; Fanelli, F.; Giovine, A.; Luisi, R. Adv. Synth. Catal. 2015, 357, 21–27. doi:10.1002/adsc.201400747
    Return to citation in text: [1]
  29. Pace, V.; Holzer, W.; De Kimpe, R. Chem. Rec. 2016, 16, 2061–2076. doi:10.1002/tcr.201600011
    Return to citation in text: [1]
  30. Gessner, V. H. Chem. Commun. 2016, 52, 12011–12023. doi:10.1039/C6CC05524A
    Return to citation in text: [1]
  31. Pace, V. Aust. J. Chem. 2014, 67, 311–313. doi:10.1071/CH13416
    Return to citation in text: [1]
  32. Emerson, C. R.; Zakharov, L. N.; Blakemore, P. R. Chem. – Eur. J. 2013, 19, 16342–16356. doi:10.1002/chem.201302511
    See for a tactic to prolong the life-time of carbenoids consisting in the introduction of anion-stabilizing groups and see references cited therein.
    Return to citation in text: [1]
  33. Kupper, C.; Molitor, S.; Gessner, V. H. Organometallics 2014, 33, 347–353. doi:10.1021/om4010862
    See for examples of “stabilized” chloro carbenoids stable at room temperature and references cited therein.
    Return to citation in text: [1]
  34. Degennaro, L.; Maggiulli, D.; Carlucci, C.; Fanelli, F.; Romanazzi, G.; Luisi, R. Chem. Commun. 2016, 52,9554–9557. doi:10.1039/C6CC04588J
    Return to citation in text: [1]
  35. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Wiley: New York, 1989; p 1266.
    Return to citation in text: [1]
  36. Dawar, P.; Raju, M. B.; Ramakrishna, R. A. Tetrahedron Lett. 2011, 52, 4262–4265. doi:10.1016/j.tetlet.2011.04.100
    Return to citation in text: [1]
  37. Zhu, Y.; Wei, Y. RSC Adv. 2013, 3, 13668–13670. doi:10.1039/c3ra40246k
    Return to citation in text: [1]
  38. Zhang, H.; Shi, R.; Ding, A.; Lu, L.; Chen, B.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 12542–12545. doi:10.1002/anie.201206518
    Return to citation in text: [1]
  39. Majek, M.; Jacobi von Wangelin, A. Angew. Chem., Int. Ed. 2015, 54, 2270–2274. doi:10.1002/anie.201408516
    Return to citation in text: [1]
  40. Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177–2250. doi:10.1021/cr100346g
    Return to citation in text: [1]
  41. Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114–4133. doi:10.1002/anie.200900013
    Return to citation in text: [1]
  42. Xin, Z.; Gøgsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. Org. Lett. 2012, 14, 284–287. doi:10.1021/ol203057w
    Return to citation in text: [1]
  43. Zenzola, M.; Degennaro, L.; Trinchera, P.; Carroccia, L.; Giovine, A.; Romanazzi, G.; Mastrorilli, P.; Rizzi, R.; Pisano, L.; Luisi, R. Chem. – Eur. J. 2014, 20, 12190–12200. doi:10.1002/chem.201403141
    Return to citation in text: [1] [2] [3]
  44. Parisi, G.; Capitanelli, E.; Pierro, A.; Romanazzi, G.; Clarkson, G. J.; Degennaro, L.; Luisi, R. Chem. Commun. 2015, 51, 15588–15591. doi:10.1039/C5CC06323J
    Return to citation in text: [1]
  45. Giovine, A.; Musio, B.; Degennaro, L.; Falcicchio, A.; Nagaki, A.; Yoshida, J.-i.; Luisi, R. Chem. – Eur. J.2013, 19, 1872–1876. doi:10.1002/chem.201203533
    Return to citation in text: [1]
  46. Tomida, Y.; Nagaki, A.; Yoshida, J.-i. J. Am. Chem. Soc. 2011, 133, 3744–3747. doi:10.1021/ja110898s
    Return to citation in text: [1]
  47. Nagaki, A.; Matsuo, C.; Kim, S.; Saito, K.; Miyazaki, A.; Yoshida, J.-i. Angew. Chem., Int. Ed. 2012, 51,3245–3248. doi:10.1002/anie.201108932
    Return to citation in text: [1]
  48. Kim, H.; Min, K.-I.; Inoue, K.; Im, D. J.; Kim, D.-P.; Yoshida, J.-i. Science 2016, 352, 691–694. doi:10.1126/science.aaf1389
    Return to citation in text: [1]
  49. Semple, J. E.; Rossignol, J.-F. Pharmaceutical compositions and methods of use of salicylanilides for treatment of hepatitis viruses. PCT Int. Appl. WO2012058378 A1, May 3, 2012.
    Return to citation in text: [1]
  50. Degennaro, L.; Carlucci, C.; De Angelis, S.; Luisi, R. J. Flow Chem. 2016, 6, 136–166. doi:10.1556/1846.2016.00014
    Return to citation in text: [1]
  51. Pavia, C.; Ballerini, E.; Bivona, L. A.; Giacalone, F.; Aprile, C.; Vaccaro, L.; Gruttadauria, M. Adv. Synth. Catal. 2013, 355, 2007–2018. doi:10.1002/adsc.201300215
    Return to citation in text: [1]
  52. de M. Muñoz, J.; Alcázar, J.; de la Hoz, A.; Díaz-Ortiz, A. Adv. Synth. Catal. 2012, 354, 3456–3460. doi:10.1002/adsc.201200678
    Return to citation in text: [1]
  53. Mennecke, K.; Sodolenko, W.; Kirschning, A. Synthesis 2008, 1589–1599. doi:10.1055/s-2008-1072579
    Return to citation in text: [1] [2] [3]
  54. Nagaki, A.; Hirose, K.; Moriwaki, Y.; Mitamura, K.; Matsukawa, K.; Ishizuka, N.; Yoshida, J.-i. Catal. Sci. Technol. 2016, 6, 4690–4694. doi:10.1039/C5CY02098K
    Return to citation in text: [1] [2]
  55. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd ed.; Wiley-VCH: Weinheim, 2013. doi:10.1002/9783527651351
    Return to citation in text: [1]
  56. Wang, J.; Sànchez-Rosellò, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432–2506. doi:10.1021/cr4002879
    Return to citation in text: [1]
  57. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315–8359. doi:10.1021/acs.jmedchem.5b00258
    Return to citation in text: [1]
  58. Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11. doi:10.1016/S0022-1139(01)00375-X
    Return to citation in text: [1]
  59. Roesner, S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2016, 55, 10463–10467. doi:10.1002/anie.201605584
    Return to citation in text: [1]
  60. Izquierdo, J.; Pericas, M. A. ACS Catal. 2016, 6, 348–356. doi:10.1021/acscatal.5b02121
    Return to citation in text: [1]
  61. Izquierdo, J.; Ayats, C.; Henseler, A. H.; Pericàs, M. A. Org. Biomol. Chem. 2015, 13, 4204–4209. doi:10.1039/C5OB00325C
    Return to citation in text: [1]
  62. Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Chem. Rev. 2016, 116, 10276–10341. doi:10.1021/acs.chemrev.5b00707
    Return to citation in text: [1]
  63. Gemoets, H. P. L.; Su, Y.; Shang, M.; Hessel, V.; Luque, R.; Noël, T. Chem. Soc. Rev. 2016, 45, 83–117. doi:10.1039/C5CS00447K
    Return to citation in text: [1]
  64. Talla, A.; Driessen, B.; Straathof, N. J. W.; Milroy, L.-G.; Brunsveld, L.; Hessel, V.; Noël, T. Adv. Synth. Catal. 2015, 357, 2180–2186. doi:10.1002/adsc.201401010
    Return to citation in text: [1]
  65. Cremlyn, R. J. An Introduction to Organosulfur Chemistry; Wiley–VCH: New York, 1996.
    Return to citation in text: [1]
  66. Witt, D. Synthesis 2008, 2491–2509. doi:10.1055/s-2008-1067188
    Return to citation in text: [1]
  67. Blank, I.; Pascual, E. C.; Devaud, S.; Fay, L. B.; Stadler, R. H.; Yeretzian, C.; Goodman, B. A. J. Agric. Food Chem. 2002, 50, 2356–2364. doi:10.1021/jf011329m
    Return to citation in text: [1]
  68. Straathof, N. J. W.; Gemoets, H. P. L.; Wang, X.; Schouten, J. C.; Hessel, V.; Noël, T. ChemSusChem2014, 7, 1612–1617. doi:10.1002/cssc.201301282
    Return to citation in text: [1]
  69. Fang, Y.; Tranmer, G. K. Med. Chem. Commun. 2016, 7, 720–724. doi:10.1039/C5MD00552C
    Return to citation in text: [1]
  70. Bergami, M.; Protti, S.; Ravelli, D.; Fagnoni, M. Adv. Synth. Catal. 2016, 358, 1164–1172. doi:10.1002/adsc.201600019
    Return to citation in text: [1]
  71. Wiles, C.; Watts, P. Green Chem. 2012, 14, 38–54. doi:10.1039/C1GC16022B
    Return to citation in text: [1]
  72. Yoshida, J.-i. Flash Chemistry: Fast Organic Synthesis in Microsystems; John Wiley & Sons: Chichester, UK, 2008. doi:10.1002/9780470723425
    Return to citation in text: [1]
  73. Yoshida, J.-i. Chem. Commun. 2005, 4509–4516. doi:10.1039/b508341a
    Return to citation in text: [1]
  74. Yoshida, J.-i.; Nagaki, A.; Yamada, T. Chem. – Eur. J. 2008, 14, 7450–7459. doi:10.1002/chem.200800582
    Return to citation in text: [1]
  75. Yoshida, J.-i. Chem. Rec. 2010, 10, 332–341. doi:10.1002/tcr.201000020
    Return to citation in text: [1]
  76. Nieuwland, P. J.; Koch, K.; van Harskamp, N.; Wehrens, R.; van Hest, J. C. M.; Rutjes, F. P. J. T. Chem. – Asian J. 2010, 5, 799–805. doi:10.1002/asia.200900705
    Return to citation in text: [1]
  77. Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem., Int. Ed. 2015, 54, 6688–6728. doi:10.1002/anie.201409318
    Return to citation in text: [1]
  78. Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. Chem. Soc. Rev. 2016, 45, 4892–4928. doi:10.1039/C5CS00902B
    Return to citation in text: [1]
  79. Clark, J. D.; Shah, A. S.; Peterson, J. C.; Patelis, L.; Kersten, R. J. A.; Heemskerk, A. H.; Grogan, M.; Camden, S. Thermochim. Acta 2002, 386, 65–72. doi:10.1016/S0040-6031(01)00760-2
    Return to citation in text: [1]
  80. Hosmane, R. S.; Liebman, J. F. Struct. Chem. 2002, 13, 501–503. doi:10.1023/A:1020573723147
    Return to citation in text: [1]
  81. Nicolle, S. M.; Hayes, C. J.; Moody, C. J. Chem. – Eur. J. 2015, 21, 4576–4579. doi:10.1002/chem.201500118
    Return to citation in text: [1]
  82. Regitz, M.; Maas, G. Diazo Compounds Properties and Synthesis; Academic Press: Orlando, Florida, 1986.
    Return to citation in text: [1]
  83. Soldi, C.; Lamb, K. N.; Squitieri, R. A.; González-López, M.; Di Maso, M. J.; Shaw, J. T. J. Am. Chem. Soc.2014, 136, 15142–15145. doi:10.1021/ja508586t
    See for a recent example of hydrazone oxidation using manganese dioxide.
    Return to citation in text: [1]
  84. Roda, N. M.; Tran, D. N.; Battilocchio, C.; Labes, R.; Ingham, R. J.; Hawkins, J. M.; Ley, S. V. Org. Biomol. Chem. 2015, 13, 2550–2554. doi:10.1039/C5OB00019J
    Return to citation in text: [1] [2]
  85. Poh, J.-S.; Tran, D. N.; Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Angew. Chem., Int. Ed. 2015, 54, 7920–7923. doi:10.1002/anie.201501538
    Return to citation in text: [1] [2] [3]
  86. Battilocchio, C.; Feist, F.; Hafner, A.; Simon, M.; Tran, D. N.; Allwood, D. M.; Blakemore, D. C.; Ley, S. V. Nat. Chem. 2016, 8, 360–367. doi:10.1038/nchem.2439
    Return to citation in text: [1]
  87. Tran, D. N.; Battilocchio, C.; Lou, S.-B.; Hawkins, J. M.; Ley, S. V. Chem. Sci. 2015, 6, 1120–1125. doi:10.1039/C4SC03072A
    Return to citation in text: [1]
  88. Esumi, T.; Yamamoto, C.; Fukuyama, Y. Synlett 2013, 24, 1845–1847. doi:10.1055/s-0033-1338968
    Return to citation in text: [1]
  89. Pieber, B.; Martinez, S. T.; Cantillo, D.; Kappe, C. O. Angew. Chem., Int. Ed. 2013, 125, 10431–10434. doi:10.1002/ange.201303528
    Return to citation in text: [1]
  90. Pieber, B.; Glasnov, T.; Kappe, C. O. Chem. – Eur. J. 2015, 21, 4368–4376. doi:10.1002/chem.201406439
    Return to citation in text: [1]
  91. Tsubogo, T.; Oyamada, H.; Kobayashi, S. Nature 2015, 520, 329–332. doi:10.1038/nature14343
    Return to citation in text: [1]
  92. Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.; Monbaliu, J.-C. M.; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.; Weeranoppanant, N.; Wong, S. Y.; Zhang, P. Science 2016, 352, 61–67. doi:10.1126/science.aaf1337
    Return to citation in text: [1]
  93. Hessel, V.; Kralisch, D.; Kockmann, N., Eds. Novel Process Windows: Innovative Gates to Intensified and Sustainable Chemical Processes; Wiley-VCH: Weinheim, 2015.
    Return to citation in text: [1]

How to cite this article:
Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Beilstein J. Org. Chem. 2017, 13, 520–542. doi:10.3762/bjoc.13.51

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io

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As an organic chemist I’m involved in the development of new sustainable synthetic methodologies for the construction of new molecules with defined stereochemistry and functional properties.

Jointly with my coworkers we are involved in three main research themes:

1. Heterosubstituted Organolithiums. We mainly explore the reactivity of lithiated 3,4,5,6-membered N,S,O-heterocycles (aziridines, azetidines, oxazetidines, thietanes, oxazolines, piperazines, morfolines) and their utility in stereoselective synthesis. Our approach is focused in establishing the chemical and configurational stability of the lithiated intermediates as well as their structure in solution by using modern spectrometric and spectroscopic techniques such as in line -IR, in line-MS, NMR and DOSY.


2. Microreactor Technology and Flow-Chemistry. With the aim to design more sustainable synthetic processes, we set up, at the Depatment of Pharmacy, a well equipped “flow chemistry laboratory” named FLAME-Lab, for the development of continuous-flow microreactor-mediated organometallic and organocatalytic synthesis in both homegenous and heterogenous conditions.

3. Molecular DynamicsAs a “curiosity driven” research activity, we investigate the dynamic behavior of small molecules that could function as molecular switches with “on-off” states and as versatile scaffolds useful in catalysis and in “dynamic-controlled and predictable reactivity”.

Leonardo Degennaro at Università degli Studi di Bari Aldo Moro
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Sep 272017
 

 

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC02261A, Communication
Shawn Parisien-Collette, Corentin Cruche, Xavier Abel-Snape, Shawn K. Collins
Polycyclic heterocycles can be formed in good to excellent yields via photochemical conversion of the corresponding substituted aryl azides under irradiation with purple LEDs in a continuous flow reactor.

Photochemical intramolecular amination for the synthesis of heterocycles

 Author affiliations

Abstract

Polycyclic heterocycles can be formed in good to excellent yields via photochemical conversion of the corresponding substituted aryl azides under irradiation with purple LEDs in a continuous flow reactor. The experimental set-up is tolerant to UV-sensitive functional groups while affording diverse carbazoles, as well as an indole and pyrrole framework, in short reaction times. The photochemical method is presumed to progress through a mechanism differing from the other methods of azide activation involving transition metal catalysis.

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Methyl 9H-carbazole-2-carboxylate (9): Following the Photodecomposition Procedure A, starting from Methyl 2’-azido-[1,1’-biphenyl]-4-carboxylate, the crude mixture was purified by silica gel column chromatography (100 % hexanes → 10 % ethyl acetate in hexanes), to afford the desired product as a white solid (24.3 mg, 72 % yield). Following the Photodecomposition Procedure B, starting from Methyl 2’-azido-[1,1’- biphenyl]-4-carboxylate, the crude mixture was purified by silica gel column chromatography (100 % hexanes → 10 % ethyl acetate in hexanes), to afford the desired product as a white solid (27.7 mg, 82 % yield). NMR data was in accordance with what was previously reported.16

16 Takamatsu, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2014, 16, 2892-2895

NEXT…………..

STR2 str3

4-Isopropyl-9H-carbazole (14): Following the Photodecomposition Procedure A, starting from 2-azido-2’-isopropyl-1,1’-biphenyl, the crude mixture was purified by silica gel column chromatography (100 % hexanes → 10 % ethyl acetate in hexanes), to afford the desired product as a yellow solid (16.6 mg, 53 % yield). Following the Photodecomposition Procedure B, starting from 2-azido-2’-isopropyl-1,1’-biphenyl and using ethyl acetate as the solvant, the crude mixture was purified by silica gel column chromatography (100 % hexanes → 10 % ethyl acetate in hexanes), to afford the desired product as a yellow solid (16.0 mg, 51 % yield).

1H NMR (400 MHz, DMSO-d6) δ = 11.29 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.39-7.31 (m, 3H), 7.19- 7.15 (m, 1H), 7.08-7.03 (m, 1H), 3.92-3.82 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H);

13C NMR (100 MHz, DMSO-d6) δ = 143.9, 140.3, 140.1, 126.0, 125.2, 122.8, 122.2, 119.9, 119.1, 114.9, 111.2, 108.9, 30.2, 22.8 (2C);

HRMS (ESI) m/z calculated for C15H15N [M-H]- 208.1130; found 208.1126.

///////////http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC02261A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

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Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions

 FLOW CHEMISTRY, flow synthesis  Comments Off on Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions
Jul 172017
 

Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions

Green Chem., 2017, 19,3006-3013
DOI: 10.1039/C7GC00657H, Paper
Nelly Ntumba Tshibalonza, Jean-Christophe M. Monbaliu
Highly selective flash deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions.

Green Chemistry

Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions

Abstract

The deoxydehydration (DODH) of glycerol towards allyl alcohol was revisited under continuous-flow conditions combining a microfluidic reactor setup and a unique reactive dynamic feed solution approach. Short reaction times, high yield and excellent selectivity were achieved at high temperature and moderate pressure in the presence of formic acid, triethyl orthoformate, or a combination of both. Triethyl orthoformate appeared as a superior reagent for the DODH of glycerol, with shorter reaction times, lower reaction temperatures and more robust conditions. In-line IR spectroscopy and computations provided different perspectives on the unique reactivity of glycerol O,O,O-orthoesters.

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Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

 FLOW CHEMISTRY, flow synthesis  Comments Off on Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene
Jun 052017
 

 

 

Abstract Image

The first continuous flow synthesis of C8–C16 alkane fuel precursors from biobased platform molecules is reported. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) was found to be a recyclable and highly efficient organic base catalyst for the aldol condensation of furfural with carbonyl compounds, and the selectivity of mono- or difuryl product can be easily regulated by adjusting the molar ratio of substrates. By means of flow technique, a shorter reaction time, satisfactory output, and continuous preparation are achieved under the present procedure, representing a significant advance over the corresponding batch reaction conditions.

Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

Tao Shen, Jingjing Tang, Chenglun Tang, Jinglan Wu, Linfeng Wang, Chenjie Zhu*§ , and Hanjie Ying§
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
National Engineering Technique Research Center for Biotechnology, Nanjing 211816, China
§Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing 211816, China
State Key Laboratory of Motor Vehicle Biofuel Technology, Nanyang 473000, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00141

 

*E-mail: zhucj@njtech.edu.cn. Phone/Fax: +86 25 58139389.
1-(furan-2-yl)-2-methylpent-1-en-3-one
1a
3-pentanone (100 mmol, 8.6 g) and furfural (100 mmol, 9.6 g) were diluted with MeOH-H2O to 40 mL in stream 1, catalyst TBD (10 mmol, 1.39 g) were diluted with MeOH-H2O (v/v = 1/1) to 40 mL in stream 2, the two streams was purged in a 0.2 mL/min speed into slit plate mixer and at the 353 K passed tubing reactor. Finally, the product was extracted with EtOAc and water, the obtained organic layer was evaporated and purified by silica gel flash chromatography (25:1 hexane-EtOAc) to provide the analytically pure product for further characterization, the aqueous phase was collected and reused.According to the general procedure afforded 14.92 g (91%) of product 1a, isolated as pale yellow oil;
1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 1.4 Hz, 1H), 7.29 (s, 1H), 6.71 (d, J = 3.5 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 2.71 (q, J = 7.3 Hz, 2H), 2.05 (s, 3H), 1.04 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CD3OD) δ 203.5, 153.0, 145.8, 133.8, 126.8, 116.6, 113.3, 31.1, 13.2, 9.2.
STR1 STR2 str3
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Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

 FLOW CHEMISTRY, flow synthesis, phase 1  Comments Off on Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement
Jan 212017
 

STR1

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03123D, Paper
Maurice A. Marsini, Frederic G. Buono, Jon C. Lorenz, Bing-Shiou Yang, Jonathan T. Reeves, Kanwar Sidhu, Max Sarvestani, Zhulin Tan, Yongda Zhang, Ning Li, Heewon Lee, Jason Brazzillo, Laurence J. Nummy, J. C. Chung, Irungu K. Luvaga, Bikshandarkoil A. Narayanan, Xudong Wei, Jinhua J. Song, Frank Roschangar, Nathan K. Yee, Chris H. Senanayake
A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03123D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

*Corresponding authors
aDepartment of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, USA
E-mail: maurice.marsini@boehringer-ingelheim.com
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03123D

 

Capture STR0 STR1

 

STR0 STR1

1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

m.p. = 140-144 °C;

1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 9.43 (s, 1H), 8.95 (s, 1H), 8.70 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.93 (s, J1 = 8.8 Hz, J2 = 4.7 Hz, 1H), 7.82 (s, 1H), 7.54 (d, J = 4.1 Hz, 1H), 7.49 (t, J = 8.7 Hz, 1H), 3.29 (s, 3H), 1.61 (bs, 4H);

13C NMR (100 MHz, CDCl3) δ 166.1, 162.7, 160.3, 158.4, 156.9, 150.6, 139.2, 138.2, 135.8, 135.6, 125.4 (d, JC-F = 8.8 Hz), 123.3, 121.9, 117.2 (d, JC-F = 23.1 Hz), 116.4, 40.2, 34.9, 20.9;

HRMS: calcd for C22H19FN5O3S [M + H+ ]: 452.1187. Found: 452.1189.

 

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STR0

//////////BI-638683, BI 638683, CCR1 antagonist, 295298-26-8, US2012270870, Boehringer Ingelheim Pharmaceuticals, phase 1

CS(=O)(=O)c1nccc(c1)C2(CC2)NC(=O)c5cncc3c5cnn3c4ccc(F)cc4

SCHEMBL1670702.png

Molecular Formula: C22H18FN5O3S
Molecular Weight: 451.476 g/mol

CCR1 antagonist

cas 295298-26-8

US2012270870

maybe BI-638683, not sure

In September 2010, a randomized, double-blind, placebo-controlled, phase I study (NCT01195688; 1279.1; 2010-021187-15) was initiated in healthy male volunteers (expected n = 64) in Germany, to assess the safety, pharmacokinetics and pharmacodynamics of BI-638683. The study was completed in December 2010 . In June 2014, data were presented at the EULAR 2014 Annual Meeting in Paris, France. A dose of 75-mg showed maximal inhibition of mRNA expression of the four-CC chemokine receptor type-I dependent marker genes. chemokine ligand -2  and Peroxisome proliferator-activated receptor gamma-mRNAs by doses of 300 mg and higher, and for Ras-related protein rab-7b mRNA by doses of 500 mg and higher

Boehringer Ingelheim was developing BI-638683, a CCR1 antagonist, for the potential oral treatment of rheumatoid arthritis. A phase I trial was completed in December 2010 . Phase I data was presented in June 2014

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011049917&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Inventors Brian Nicholas Cook, Daniel Kuzmich, Can Mao, Hossein Razavi
Applicant Boehringer Ingelheim International Gmbh

Chemotactic Cytokine Receptor 1 (CCRl) belongs to a large family (>20) of chemotactic cytokine (chemokine) receptors that interact with specific chemokines (>50) to mediate leukocyte trafficking, granule exocytosis, gene transcription, mitogenic effects and apoptosis. Chemokines are best known for their ability to mediate basal and inflammatory leukocyte trafficking. The binding of at least three chemokines (MIP-1 alpha/CCL3, MCP3/CCL7 and RANTES/CCL5) to CCRl is responsible for the trafficking of monocytes, macrophages and THl cells to inflamed tissues of rheumatoid arthritis (RA) and multiple sclerosis (MS) patients (Trebst et al. (2001) American J of Pathology 159 p. 1701). Macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage chemoattractant protein 3 (MCP-3) and regulated on activation, normal T-cell expressed and secreted (RANTES) are all found in the CNS of MS patients, while MIP-1 alpha and RANTES are found in the CNS in the experimental autoimmune encephalomyelitis (EAE) model of MS (Review: Gerard

and Rollins (2001) Nature Immunology). Macrophages and Thl cells in the inflamed synovia of RA patients are major producers of MIP-1 alpha and RANTES, which continuously recruit leukocytes to the synovial tissues of RA patients to propagate chronic inflammation (Volin et al. (1998) Clin. Immunol. Immunopathology; Koch et al. (1994) J. Clin. Investigation; Conlon et al. (1995) Eur. J. Immunology). Antagonizing the interactions between CCR1 and its chemokine ligands is hypothesized to block chemotaxis of monocytes, macrophages and Thl cells to inflamed tissues and thereby ameliorate the chronic inflammation associated with autoimmune diseases such as RA and MS.

Evidence for the role of CCR1 in the development and progression of chronic inflammation associated with experimental autoimmune encephalitis (EAE), a model of multiple sclerosis, is based on both genetic deletion and small molecule antagonists of CCR1. CCR1 deficient mice were shown to exhibit reduced susceptibility (55% vs. 100%) and reduced severity (1.2 vs. 2.5) of active EAE (Rottman et al. (2000) Eur. J. Immunology). Furthermore, administration of small molecule antagonist of CCR1, with moderate affinity (K; = 120 nM) for rat CCR1, was shown to delay the onset and reduce the severity of EAE when administered intravenously (Liang et al. (2000) /. Biol. Chemistry). Treatment of mice with antibodies specific for the CCR1 ligand MIP- 1 alpha have also been shown to be effective in preventing development of acute and relapsing EAE by reducing the numbers of T cells and macrophages recruited to the CNS (Karpus et al. (1995) /. Immunology; Karpus and Kennedy (1997) /. Leukocyte Biology). Thus, at least one CCR1 ligand has been demonstrated to recruit leukocytes to the CNS and propagate chronic inflammation in EAE, providing further in vivo validation for the role of CCR1 in EAE and MS.

In vivo validation of CCR1 in the development and propagation of chronic inflammation associated with RA is also significant. For example, administration of a CCR1 antagonist in the collagen induced arthritis model (CIA) in DBA/1 mice has been shown to be effective in reducing synovial inflammation and joint destruction (Plater-Zyberk et al. (1997) Immunology Letters). Another publication described potent antagonists of murine CCR1 that reduced severity (58%) in LPS-accelerated collagen-induced arthritis (CIA), when administered orally {Biorganic and Medicinal Chemistry Letters 15, 2005, 5160-5164). Published results from a Phase lb clinical trial with an oral CCRl antagonist demonstrated a trend toward clinical improvement in the absence of adverse side effects (Haringman et al. (2003) Ann. Rheum. Dis.). One third of the patients achieved a 20% improvement in rheumatoid arthritis signs and symptoms (ACR20) on day 18 and CCRl positive cells were reduced by 70% in the synovia of the treated patients, with significant reduction in specific cell types including 50% reduction in CD4+ T cells, 50% reduction in CD8+ T cells and 34% reduction in macrophages.

Studies such as those cited above support a role for CCRl in MS and RA and provide a therapeutic rationale for the development of CCRl antagonists.

STR1

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Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

 FLOW CHEMISTRY, flow synthesis  Comments Off on Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions
Jan 022017
 

Abstract Image

Over the last 20 years organic carbamates have found numerous applications in pesticides, fungicides, herbicides, dyes, pharmaceuticals, cosmetics, and as protecting groups and intermediates for polyurethane synthesis. Recently, in order to avoid phosgene-based synthesis of carbamates, many environmentally benign and alternative pathways have been investigated. However, few examples of carbamoylation of aniline in continuous-flow apparatus have been reported. In this work, we report a high-yielding, dimethyl carbonate (DMC)-mediated carbamoylation of aniline in a fixed-bed continuously fed reactor employing basic zinc carbonate as catalyst. Several variables of the system have been investigated (i.e. molar ratio of reagents , flow rate, and reaction temperature) to optimize the operating conditions of the system.

Figure

Figure

Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

Department of Environmental Sciences, Informatics and Statistics, Ca’ Foscari University of Venice, Dorsoduro 2137, 30123 Venezia, Italia
Org. Process Res. Dev., 2013, 17 (4), pp 679–683
*Tel.: (+39) 041 234 8642. Fax: (+39) 041 234 8620. E-mail: tundop@unive.it.

PIETRO TUNDO

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Tundo300X292

Profile:

PIETRO R. TUNDO is Professor of Organic Chemistry at Ca’ Foscari University of Venice (Italy).
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).
He is Member of the Bureau of IUPAC.

P: Tundo is author of about 300 scientific publications, 40 patents and many books.
His scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry, heteropolyacids, and finally safe alternatives to harmful chemicals.
He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731). He founded and was Chairman (2004-2016) of the Working Party on “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

Founder of the IUPAC International Conferences Series on Green Chemistry, he was awarded by American Chemical Society on 1983 (Kendall Award, with Janos Fendler), and by Federchimica (Italian association of chemical industries) on 1997 (An Intelligent Future).

P. Tundo coordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia, Italy) sponsored by the EU, UNESCO and NATO.
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).

He is holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731) and author of about 260 scientific publications and 30 patents.

Scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry and finally, heteropolyacids.

He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and presently is Chairman of Working Party of “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

Founder of the IUPAC International Conferences Series on Green Chemistry, he was awarded by American Chemical Society on 1983 (Kendall Award, with Janos Fendler), and by Federchimica (Italian association of chemical industries) on 1997 (An Intelligent Future).

P. Tundo co-ordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia), the latter sponsored by the EU, UNESCO and NATO.

Contact:

Professor of Organic Chemistry
Ca’ Foscari University of Venice
IUPAC Bureau Member
Tel. +39 041 2348642
Mob. +39 349 3486191
E-mail: tundop@unive.it

Phone 041 234 8642 / Lab .: 041 234 8669
E-mail tundop@unive.it
green.chemistry@unive.it – 6th IUPAC Conference on Green Chemistry
unescochair@unive.it – TUNDO Pietro
Fax 041 234 8620
Web www.unive.it/persone/tundop

////////Carbamoylation of Aniline, Dimethyl Carbonate, Continuous-Flow Conditions, flow synthesis

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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Continuous-Flow Diazotization

 FLOW CHEMISTRY, flow synthesis  Comments Off on Continuous-Flow Diazotization
Nov 242016
 

str1

 

Figure

Characterization Data of Compound 7

Mp: 118–120 °C. MS (M + H+): 314.
HRMS (ESI) m/z: Calcd for C16H15N3NaO4, (M + Na+): 336.0960. Found: 336.0899.
IR (KBr) ν/cm–1: 3447, 3339, 1717, 1714, 1699, 1594.
1H NMR (CDCl3, 400 MHz) δ/ppm: 8.50 (s, 1H, Ar–H), 7.88 (d, J = 8.8 Hz, 1H, Ar–H), 7.76 (d, J = 7.6 Hz, 1H, Ar–H), 7.60 (d, J = 8.0 Hz, 1H, Ar–H), 7.54 (t, J = 7.2 Hz, 1H, Ar–H), 7.41 (t, J = 7.2 Hz, 1H, Ar–H), 6.71 (d, J = 9.2 Hz, 1H, Ar–H), 6.28 (br s, 2H, −NH2), 3.91 (s, 3H, −CH3), 3.89 (s, 3H, −CH3).
13C NMR (CDCl3, 100 MHz) δ/ppm: 168.2, 168.0, 152.9, 151.6, 143.4, 131.7, 131.2, 129.4, 128.8, 128.0, 126.3, 118.9, 117.1, 109.8, 52.3, 51.9.

 

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Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions

National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00238
Publication Date (Web): November 17, 2016
Copyright © 2016 American Chemical Society
*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

Abstract

Abstract Image

An expeditious process for the highly efficient synthesis of methyl 2-(chlorosulfonyl)benzoate was described, which involved the continuous-flow diazotization of methyl 2-aminobenzoate in a three-inlet flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side reaction such as hydrolysis was decreased eminently from this continuous-flow process even at a high concentration of hydrochloric acid. The mass flow rate of methyl 2-aminobenzoate was 4.58 kg/h, corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.

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Diphenhydramine Hydrochloride, Use of Flow Synthesis

 flow synthesis  Comments Off on Diphenhydramine Hydrochloride, Use of Flow Synthesis
Sep 062016
 
Image result for Diphenhydramine hydrochloride
Diphenhydramine Hydrochloride
Image result for Diphenhydramine Hydrochloride
Image result for Diphenhydramine Hydrochloride
REGULAR SYNTHESIS
Figure
FLOW SYNTHESIS
 Image result for Diphenhydramine Hydrochloride
Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.
In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1).
In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.
The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.
Image result for Diphenhydramine hydrochloride
REF

Snead, D. R.; Jamison, T. F. Chem. Sci. 2013, 4, 2822, DOI: 10.1039/c3sc50859e

Image result for 10.1039/c3sc50859e
A CLIP

In 2013 the Jamison group reported the flow synthesis of the important H1-antagonist diphenhydramine·HCl (92) showcasing the potential of modern flow chemistry to adhere to green chemistry principles (minimal use of organic solvents, atom economy etc.) . The synthetic strategy relied on reacting chlorodiphenylmethane (93) with an excess of dimethylaminoethanol (94) via a nucleophilic substitution reaction (Scheme ).

[1860-5397-11-134-i16]
Scheme : Flow synthesis of diphenhydramine.HCl (92).

As both starting materials are liquid at ambient temperature the use of a solvent could be avoided allowing direct generation of the hydrochloride salt of 92 in a high temperature reactor (175 °C) with a residence time of 16 min. Conveniently at the same reaction temperature the product was produced as a molten paste (m.p. 168 °C) which enabled the continued processing of the crude product circumventing any clogging of the reactor by premature crystallisation. Analysis of the crude extrude product revealed the presence of minor impurities (<10%) even when stoichiometric amounts of 94 were used, consequently an in-line extraction process was developed. Additional streams of aqueous sodium hydroxide (3 M, preheated) and hexane were combined with the crude reaction product followed by passage through a membrane separator. The hexane layer was subsequently collected and treated with hydrochloric acid (5 M in IPA) leading to the precipitation of diphenhydramine hydrochloride (92) in high yield (~90%) and purity (~95%). Furthermore, options to further reduce waste generated during the purification sequence are presented by combining hot IPA with the crude flow stream leading to the isolation of the target compound (92·HCl) by direct crystallisation in the collection vessel (yield 71–84%, purity ~93%, productivity 2.42 g/h).

 

STR1

 

David Snead

David Snead

    dsnead at mit dot edu
Ph.D. The University of Florida, 2010
with Prof. Sukwon Hong
B.S. The University of North Carolina at Chapel Hill, 2005
with Prof. Joseph DeSimone

 

Image result for Timothy F. Jamison

Timothy F. Jamison

Professor of Chemistry
Massachusetts Institute of Technology
Department of Chemistry
77 Massachusetts Ave., Bldg 18-590
Cambridge, MA 02139

Phone: (617) 253-2135
Fax: (617) 324-0253
Email: tfj at mit dot edu

Curriculum Vitae
Tim Jamison was born in San Jose, CA and grew up in neighboring Los Gatos, CA. He received his undergraduate education at the University of California, Berkeley. A six-month research assistantship at ICI Americas in Richmond, CA under the mentorship of Dr. William G. Haag was his first experience in chemistry research. Upon returning to Berkeley, he joined the laboratory of Prof. Henry Rapoport and conducted undergraduate research in his group for nearly three years, the majority of which was under the tutelage of William D. Lubell (now at the University of Montreal). A Fulbright Scholarship supported ten months of research in Prof. Steven A. Benner’s laboratories at the ETH in Zürich, Switzerland, and thereafter he undertook his PhD studies at Harvard University with Prof. Stuart L. Schreiber. He then moved to the laboratory of Prof. Eric N. Jacobsen at Harvard University, where he was a Damon Runyon-Walter Winchell postdoctoral fellow. In July 1999, he began his independent career at MIT, where his research program focuses on the development of new methods of organic synthesis and their implementation in the total synthesis of natural products.

 

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Image result for Diphenhydramine Hydrochloride

IR

 

MASS

13C NMR

RAMAN

 

//////////////////////Diphenhydramine Hydrochloride,  Flow Synthesis, FLOW CHEMISTRY
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The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

 flow synthesis  Comments Off on The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?
Aug 132016
 

A key pharmaceutical intermediate (1) for production of edivoxetine·HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solventcomposition, stoichiometry, and operations temperature were optimized to produce 12 g h−1crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h−1 production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000–6000 L batch reactors.

 

A continuous flow Barbier reaction was employed for the production of a key pharmaceutical intermediate (1) in the synthesis of edivoxetine·HCl (a highly selective norepinephrine re-uptake inhibitor).

US scientists from Eli Lilly and Company and D&M Continuous Solutions, led by Michael Kopach, report the development of a continuous Barbier reaction which preserves chirality and the product obtained in >99% ee.  The team ran the process in a series of continuous stirred tank reactors, where residence time, solvent composition, stoichiometry and operations temperature were optimised to produce 12 g per hour of the ketone precursor to 1 with 98% ee and 88% in situ yield for 47 hours total flow time.  Continuous salt formation and isolation of 1 could then be achieved from the ketone solution with >99% purity.

This process offers up several significant advantages over a traditional Grignard batch process.  This continuous flow method gave greater than 30% reduced process mass intensity and magnesium usage relative to the batch method.  Equally, the flow process resulted in >100 x less excess magnesium to quench and >100 x less diisobutylaluminum hydride to initiate giving significant safety benefits.  The authors expect that the maximum long-term scale of the process is 50 L which would replace 4000-6000 L batch reactors.

 

Continuous Flow Barbier Reaction

Figure 2. Continuous Barbier Laboratory Setup

For 100 years, Grignard reactions have been one of the most powerful and effi cient organic chemistry methodologies for C-C bond formation. However, Grignard reactions are also among the most challenging reactions from both operational and potential safety issues due to initiation diffi culties and runaway potential. A close variation to the Grignard reaction is the Barbier reaction wherein the Grignard reagent is prepared in the presence of an electrophile resulting in the immediate consumption of the Grignard. A Barbier reaction using a CSTR was developed for a key pharmaceutical intermediate in production of edivoxetine·HCl (Scheme 4) [9]. In the fl ow setup (Figure 2), solid magnesium is sequestered in the fi rst tank where the Grignard initiation event takes place. CSTR 2 was used as an aging tank and CSTR 3 was the quench tank. CSTRs were used for Grignard reaction rather than a PFDR because of the solid Mg reagent.

Scheme 4: Barbier Reaction to form Ketone 15

Continuous reaction improved process safety, product quality, and process greenness. The continuous reaction achieved >99% ee in situ versus 95% ee batch because of immediate conversion of unstable intermediate. Solvent volumes were reduced 30%. The safety hazards were reduced by decreasing the reactor size by 50X, which reduced chemical potential and also increased heat transfer surface area per unit volume by 4X. DIBAL-H initiating agent was reduced by more than 100X, and excess Mg that must be quenched at the end of reaction was almost eliminated. When run continuously, the commercial scale Grignard formation reactor was expected to be 50L, which replaces 4000-6000L batch reactor.

The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

*Corresponding authors
aChemical Product Research and Development, Eli Lilly and Company, Indianapolis, USA
E-mail: kopach_michael@lilly.com
bD&M Continuous Solutions, Indianapolis, USA
Green Chem., 2012,14, 1524-1536

DOI: 10.1039/C2GC35050E

http://pubs.rsc.org/en/Content/ArticleLanding/2012/GC/C2GC35050E#!divAbstract

Three vessel Grignard CSTR process train.

Grignard synthesis of compound 1.

 

Retrosynthesis of edivoxetine·HCl.

Flow diagram for the whole continuous process from amide 3 to product 1.

 

Continuous crystallization of compound 1.

Distillation and continuous crystallization of compound 1.

Entry, Rxn temp. (°C), Vol. ratio THF–toluene (%), Conversion (%), ee (%)

//////////The continuous flow,  Barbier reaction,  improved environmental alternative,  Grignard reaction, FLOW SYNTHESIS

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Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

 flow synthesis  Comments Off on Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material
Aug 132016
 

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Abstract Image

Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank reactors (CSTRs). The lithiation utilized a hybrid approach where plug flow reactors (PFRs) were used for the metal halogen exchange and Bouveault formylation steps, while the reduction and workup steps were performed in CSTRs. Relative to traditional batch processing, both approaches offer significant advantages. Both processes were high-yielding and produced the product in high purity. The two main processes were directly compared from a number of perspectives including reagent and operational safety, fouling potential, process footprint, need for manual operation, and product yield and purity.

Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States
Org. Process Res. Dev., Article ASAP

 

 

//////////Flow Grignard,  Lithiation, Screening Tools,  Development, Continuous Processes,  Benzyl Alcohol, Starting Material

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