A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• ., benzaldehydes) and low-molecular-weight enolate nucleophiles, therefore, temperature regulation is vital for selectivity. This requirement for strict temperature control makes aldol reactions highly suited to flow processing conditions. In 2008, Tanaka et al. [96] disclosed several examples of aldol reaction in

• doravirine (49) in an overall 52% yield. The use of an interrupted flow sequence with intermediate batch collection of the output is an easy way of overcoming one of the problematic issues in flow processing; that being assimilating the different residence time requirements in sequential downstream

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• utilizing electron-poor alkenes as the reaction partners that would undergo aza-Michael addition reactions on the Cbz-carbamates (Scheme 4). Driven by the desire to develop readily scalable routes towards the target products 8, continuous flow processing was again exploited. In a first approach the use of

• carbamate group allowing for further use of the resulting N-protected amino acid species (e.g., 9d) in synthetic elaborations. Conclusion In conclusion, a new strategy in continuous flow processing that combines challenging high-energy transformations with downstream impurity tagging facilitated by

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• specific characteristics of nanoreactors should be employed more effectively. Physical protection and separation of catalytic species will allow the performance of multistep conversions in one-pot reactors. This would then enable continuous flow processing, as intermediate work-up steps and solvent

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• with unstable intermediates or reagents can be overcome with the use of continuous-flow chemistry. Continuous-flow processing has demonstrated to be an ideal tool for the development of uninterrupted multistep reactions [35][36][37]. The integration of several sequential steps can be readily achieved

• ) resulted in fully homogeneous conditions suitable for flow processing (Table 3, entry 3). Continuous-flow experiments Azirine formation. With the optimal conditions for the three reaction steps in hand, we translated the process to continuous-flow conditions. For that purpose, individual continuous-flow

Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

• Imane Nekkaa,
• Márta Palkó,
• István M. Mándity and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2018, 14, 318–324, doi:10.3762/bjoc.14.20

• addition, they are present in several natural frameworks [42][43][44]. We wanted to exploit the benefits of flow processing for reaction optimization and synthesis and develop novel sustainable synthetic methodologies with possible useful applications for the pharmaceutical industry. Our results show that

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

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• 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

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

• Arno Verlee,
• Thomas Heugebaert,
• Tom van der Meer,
• Pavel I. Kerchev,
• Frank Van Breusegem and
• Christian V. Stevens

Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

• suitable hit is identified on the other hand, the synthetic prerequisites change completely, and a robust and scalable protocol is needed. Over the past few years, flow chemistry has emerged as a potential solution to these conflicting prerequisites [3][4][5][6][7][8][9][10][11]. Flow processing is

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• -type continuous-flow reactor and a batch stirred tank. The use of continuous-flow processing allows for an efficient synthesis of large quantities of the Diels–Alder adduct and we managed to scale-up the reaction of myrcene (1) with acrylic acid (2b) inside the 105 mL flow reactor to a throughput of

• . Results and Discussion The solution-phase Diels–Alder reactions presented herein follow the general reaction pathway shown in Scheme 1. The conjugated diene myrcene (1) was reacted with a series of dienophiles 2 to form the Diels–Alder adducts 3. Before investigating this reaction for continuous-flow

• processing, we first undertook a series of batch experiments to explore the reactivity of the different dienophiles shown in Scheme 1. These experiments were carried out on a batch microwave-reactor system (see experimental section) at temperatures between 100 and 140 °C, and the results are presented in

Dinuclear thiazolylidene copper complex as highly active catalyst for azid–alkyne cycloadditions

• Anne L. Schöffler,
• Ata Makarem,
• Frank Rominger and
• Bernd F. Straub

Beilstein J. Org. Chem. 2016, 12, 1566–1572, doi:10.3762/bjoc.12.151

• bioactive surfaces [8][14], imaging of biochemical processes [15], localization of bioactive compounds inside living cells [16], syntheses of small-molecule screening libraries [17], catenane and rotaxane syntheses [18], in reactions under continuous flow processing [19], polymer and surface science [20][21

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• Marcus Baumann Ian R. Baxendale Department of Chemistry, Durham University, South Road, DH1 3LE Durham, United Kingdom 10.3762/bjoc.11.134 Abstract The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our

• order to surmount these obstacles and for us to achieve the vision of true continuous manufacture of pharmaceuticals. Review Early flow processing approaches The first published examples of flow chemistry applied to the synthesis of pharmaceutically active molecules emerged in the early 2000s when

• company. An excellent illustration would be the adoption of microwave reactors which have become primary heating methods in many medicinal chemistry labs. This is also being seen in the adoption of flow processing technologies where all the major pharmaceutical companies have internal teams working on

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

Beilstein J. Org. Chem. 2014, 10, 405–424, doi:10.3762/bjoc.10.38

• more of these limitations are experienced in every batch operation it is necessary to check their feasibility for continuous flow processing. Such transformations from batch to flow have been carried out for a lot of reactions and many continuous nitration plants of commercial scale exist. However, the

Flow synthesis of phenylserine using threonine aldolase immobilized on Eupergit support

• Jagdish D. Tibhe,
• Hui Fu,
• Timothy Noël,
• Qi Wang,
• Jan Meuldijk and
• Volker Hessel

Beilstein J. Org. Chem. 2013, 9, 2168–2179, doi:10.3762/bjoc.9.254

• were carried out to estimate the yield of phenylserine formation and reaction time which can principally be achieved. Flow processing, and in particular its productivity highly depends on achieving a complete transformation in a very short time, ideally within a few minutes or less. After 20 minutes, a

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• -substituted propargyl aldehydes undergo Hantzsch dihydropyridine synthesis in preference to Bohlmann–Rahtz reaction in a very high yielding process that is readily transferred to continuous flow processing. Keywords: Bohlmann–Rahtz; continuous flow processing; ethynyl ketones; flow chemistry; Hantzsch

• -mediated reactions still poses a number of challenges, in particular as a result of a lack of uniform heating [9]. Scale-up using batch methodologies in open reaction vessels can give excellent yields but might not be appropriate for certain volatile or toxic reagents whereas continuous flow processing

• , providing the reaction mixture is homogeneous, allows transfer from small-scale sealed vessel conditions to mesoscale production often without any modification of reaction conditions or loss in product yield [10]. The transfer from microwave batch reaction to continuous flow processing can offer many

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• Trevor A. Hamlin Nicholas E. Leadbeater Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, USA 10.3762/bjoc.9.215 Abstract An apparatus is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability

• means of a calibration curve, determine product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy. Keywords: flow processing; Raman spectroscopy; reaction monitoring; α,β-unsaturated carbonyl; Introduction Continuous-flow processing is used in the chemical

• describe here an apparatus for real-time Raman monitoring of reactions performed using continuous-flow processing. We assess its capability by studying four reactions. We find that it is possible to monitor reactions and also, by means of a calibration curve, determine product conversion from Raman

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• emerged [59]. The main driving forces behind these CF methodologies are the safety aspects associated with the handling of azides and the inherent scalability of flow processing. Moreover, when organic azides are formed in situ, operational safety can be further improved [55][57]. We envisioned that it

Controlled synthesis of poly(3-hexylthiophene) in continuous flow

• Helga Seyler,
• Jegadesan Subbiah,
• David J. Jones,
• Andrew B. Holmes and
• Wallace W. H. Wong

Beilstein J. Org. Chem. 2013, 9, 1492–1500, doi:10.3762/bjoc.9.170

• film quality. This will almost certainly create problems with the performance consistency of large-area roll-to-roll printed devices. To this end, we have started to examine some key reactions in the synthesis of organic electronic materials using continuous-flow processing [11][12][13]. Continuous

• reaction conditions for P3HT synthesis to continuous-flow processing. The polymerization step in flow was examined first with the thiophene Grignard monomer prepared in batch. Good solubility and solvent compatibility in the polymerization are essential factors to be evaluated for the translation into flow

• initiated with this complex showed lower defect levels [23][24]. After successfully experimenting with this catalyst in batch conditions, the reagent was applied in flow processing for the synthesis of P3HT (Scheme 1b). The thiophene Grignard reagent 2 was prepared by traditional batch chemistry and the

The application of a monolithic triphenylphosphine reagent for conducting Appel reactions in flow microreactors

• Kimberley A. Roper,
• Heiko Lange,
• Anastasios Polyzos,
• Malcolm B. Berry,
• Ian R. Baxendale and
• Steven V. Ley

Beilstein J. Org. Chem. 2011, 7, 1648–1655, doi:10.3762/bjoc.7.194

• and reaction safety [1][2][3][4][5][6]. Further benefits can be realised when flow processing techniques are combined with the use of solid-supported reagents and scavengers, which allow telescoping of reactions or in-line removal of byproducts to both increase the purity profile of the output product

Triple-channel microreactor for biphasic gas–liquid reactions: Photosensitized oxygenations

• Ram Awatar Maurya,
• Chan Pil Park and
• Dong-Pyo Kim

Beilstein J. Org. Chem. 2011, 7, 1158–1163, doi:10.3762/bjoc.7.134

• context triple-channel microreactors could be quite useful as they comprise all the required elements for photosensitized oxygenations, namely continuous-flow processing, large gas–liquid interfacial area, short molecular diffusion distances, and very high surface illumination homogeneity. The middle