The generation and handling of organic azides using traditional batch methods brings with it a number of safety concerns, particularly on scale, which can limit the use of these important compounds. We have therefore developed several flow procedures to provide flexible working methods for the safe generation of a range of aryl and alkyl azides. These compounds can either be isolated as final products or more often progressed for further transformations without isolation within the contained flow system.

Generation and purification of aryl azides
We have developed a protocol that enables facile generation and purification of aryl azides in flow, providing safe and efficient access to clean aryl azides as intermediates or final products [1].

Monolithic reactor for azide generation
We have developed the use of a monolithic azide reagent for flow chemistry applications [2]. While the reagent is more generally applicable, it was originally developed to conduct Staudinger aza-Wittig reactions in flow to afford imines. But more recently it has been useful in the conversion of alkyl bromides to amines.

We have also used these monolithic reactor devices as immobilised azide sources for the conversion of acid chlorides under Curtius rearrangements (below) [3].

However, the first time we used azides in a flow synthesis was during our synthesis of the natural product, oxomaritidine in 2006 [4]. In the first step of the synthesis 4-(2-bromoethyl)phenol was quantitatively was converted to its corresponding azide. We accomplished by packing a glass column with an azide exchange resin (azide on Amberlite^¬Æ IRA-400) and flowing a solution of the bromide through the supported reagent using a Syrris AFRICA^¬Æ flow reactor system (below).

Publications

1. Fully automated, multistep flow synthesis of 5-Amino-4-cyano-1,2,3-triazoles
C.J. Smith, I.R. Baxendale, H. Lange, S.V. Ley
Org. Biomol. Chem. 2011, 9, 1938-1947

2. Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent
C.J. Smith, C.D. Smith, N. Nikbin, S.V. Ley, I.R. Baxendale
Org. Biomol. Chem. 2011, 9, 1927-1937

3. Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions
M. Baumann, I.R. Baxendale, S.V. Ley, N. Nikbin, C.D. Smith
Org. Biomol. Chem. 2008, 6, 1587-1593

4. A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly
I.R. Baxendale, J. Deeley, C.M. Griffiths-Jones, S.V. Ley, S. Saaby, G. Tranmer
Chem. Commun. 2006, 2566-2568

We have prepared an azide-containing monolithic reactor and used it as a flow chemistry device for conducting Curtius rearrangementreactions via acid chloride inputs [1]. We extended the work to the trapping of the intermediate isocyanates with various other nucleophiles [2].

1. Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions
M. Baumann, I.R. Baxendale, S.V. Ley, N. Nikbin, C.D. Smith
Org. Biomol. Chem. 2008, 6, 1587-1593

2. A modular flow reactor for performing Curtius rearrangements as a continuous flow process
M. Baumann, I.R. Baxendale, S.V. Ley, N. Nikbin, C.D. Smith, J.P. Tierney
Org. Biomol. Chem. 2008, 6, 1577-1586

Fluorinated molecules are found in many commercially important products. This is because fluorination can dramatically improve the properties of compounds especially against metabolic degradation in pharmaceutical or in agrochemical applications. However, the introduction of fluorine is not always straightforward and can add considerably to the cost of goods owing to the hazardous and aggressive nature of the reagents used to introduce fluorine or the inherent expense of specific fluorinated building blocks.

We have developed several methods to incorporate fluorine into various substrates using flow micro-reactor devices often using immobilized reagents and scavengers to effect product clean-up and isolation. In particular, fluorination using N,N-diethylaminosuflur trifluoride (DAST), trifluoromethylation (Ruppert’s reagent) and electrophilic fluorination (Selectfluour) in continuous-flow microreactors [1]. Special attention was given to the use of in-line scavenging procedures to avoid exposure to hazardous by-products such as HF  [2].

Publications

1. The use of diethylaminosulfur-trifluoride (DAST) for the fluorination in a continuous flow reactor
M. Baumann, I.R. Baxendale, S.V. Ley
Synlett 2008, 14, 2111-2114

2. Development of fluorination methods using continuous-flow microreactors
M. Baumann, I.R. Baxendale, L.J. Martin, S.V. Ley
Tetrahedron 2009, 65, 6611-6625

The increasing demand for clean and environmentally-benign processes is driving the way we develop and deliver our chemistry. We believe that heterogeneous catalysis in flow can make the difference in reducing the environmental footprint. The development of heterogeneous flow protocol may represent a new industrial breakthrough for the implementation of sustainable processes.

We have disclosed a diverse range of processes using this concept to carryout transfer hydrogenation of carbonyl compounds [1] and cross coupling reactions [2]. We are currently working on different processes to broaden the spectrum of applications.

Furthermore we are working on the idea of using solid reagents within the flow setup to speed up synthetic procedures and reduce the usage of solvents and the production of waste materials.

Publications

1. A mild and efficient flow procedure for the transfer hydrogenation of ketones and aldehydes using hydrous zirconia C. Battilocchio, J.M. Hawkins, S.V. Ley, Org. Lett. 2013, 15, 2278-2281.

2. Flow based, cerium oxide enhanced, low level palladium Sonogashira and Heck coupling reactions by perovskite catalysts C. Battilocchio, B. N. Bhawal, R. Chorghade, B. J. Deadman, J.M. Hawkins, S.V. Ley, Isr. J. Chem., 2013, ASAP.

Triazoles
We devised a general protocol for the in-line preparation and purification of aryl azide intermediates from which a series of 5-amino-4-cyano-1,2,3-triazoles from anilines were prepared in a fully automated fashion. In this work we also evaluated the use of an infrared flow device (the ReactIR 45m) as a tool for real-time monitoring of potentially hazardous intermediates [2].

In another route to triazoles, we have also used the Seyferth-Gilbert reagent 1 in a flow system to synthesise terminal alkynes and employed these in the preparation of triazoles such as 3 from alcohol 2in a three-step oxidation/homologation/copper(I)-catalyzed azide-alkyne cycloaddition sequence without isolation of intermediates [3].

Thiazoles and Imidazoles
A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles using a modular flow microreactor has been devised [4]. The process makes use of microfluidic reaction chips and packed immobilized reagent columns to effect bifurcation of the reaction pathway to afford the different products in a selective fashion.

Pyrrolidines
We have synthesised a series of trisubstituted drug-like pyrrolidines [5] via an efficient use of microreactors to bring about useful cycloaddition processes.

Nitropyrrolidines and nitropyrroles
We have further reported on the dipolar cycloaddition reactions with unstabilized azomethine ylids and nitro alkenes to generate 3-nitropyrrolidines using flow chemistry methods [6]. In later work we describe the development of a three-component coupling reaction between glycine esters, aldehydes and nitro alkenes. In order to demonstrate the utility of flow technology in concert with heterogeneous reagents and scavengers for complex reaction sequences an in-line oxidation resulting in the conversion of tetra-substituted pyrrolidines to their pyrrole congeners was also developed [7].

In other work we have devised novel pyrrole syntheses using flow reactors by combining tosyl isocyanide and ethyl chloroformate with nitrostyrenes to afford nitro-substituted pyrroles in a single step. Catch-and-release protocols were used to purify the products following their synthesis [8].

Yne-ones
We have also reported on the palladium-catalysed acylation of terminal alkynes for the preparation of yne-ones which, after in-line reagent stream-splitting, gave various heterocycles [9].

Oxazoles
A multipurpose mesofluidic flow reactor capable of producing multi-gram quantities of material has been developed as an automated synthesis platform for the rapid on-demand synthesis of key building blocks and small exploratory libraries [10]. The reactor was configured to provide the maximum flexibility for screening of reaction parameters that incorporated on-chip mixing and columns of solid supported reagents to expedite the chemical syntheses.

Quinoxalines
A flow method for the synthesis of aliphatic and aromatic diazoketones from acyl chloride precursors has been developed and used to prepare quinoxalines in a multistep sequence without isolation of the potentially explosive diazoketone building blocks. The protocol showcases an efficient in-line purification using supported scavengers with time-saving and safety benefits and in particular a reduction in the operator’s exposure to carcinogenic phenylenediamines [11].

Imidazopyridazines
In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle chemical inputs [12].

Butane-2,3-diacetals
The continuous flow synthesis of butane-2,3-diacetal protected derivatives has been achieved using commercially available flow chemistry microreactors in concert with solid supported reagents and scavengers to provide in-line purification systems [13]. The BDA protected products are all obtained in superior yield to the corresponding batch processes and can then be used as important starting materials for various natural product synthesis programmes.

Quinolones
The quinolone derivative shown below is a potent 5HT_1B antagonist developed by AstraZeneca. The continuous flow synthesis (the final steps shown below) of this pharmaceutical agent was completed using a combination of flow microreactors, while incorporating polymer-supported reagents and scavengers to aid reaction telescoping and purification [14]. The result is encouraging, as it clearly demonstrates that multi-step sequences can be incorporated into flow chemistry platforms leading to polyfunctional molecules of biological interest. Moreover, we were able to improve on the overall yield via a batch method using the new reactors.

Publications

1. The flow synthesis of heterocycles for natural products and medicinal chemistry applications
M. Baumann, I.R. Baxendale, S.V. Ley
Mol. Div. 2011, 15, 613-630

2. Fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles
C.J. Smith, I.R. Baxendale, H. Lange, S.V. Ley
Org. Biomol. Chem. 2011, 9, 1938-1947

3. MultiStep synthesis using modular flow reactors: Bestmann-Ohira reagent for the formation of alkynes and triazoles
I.R. Baxendale, S.V. Ley, A.C. Mansfield, C.D. Smith
Angew. Chem. Int. Ed. 2009, 48, 4017-4021

4. A bifurcated pathway to thiazoles and imidazoles using a modular flow microreactor
I.R. Baxendale, S.V. Ley, C.D. Smith, L. Tamborini, A.F. Voica
J. Comb. Chem. 2008, 10, 851-857

5. Synthesis of a drug-like focused library of trisubstituted pyrrolidines using integrated flow chemistry and batch methods
M. Baumann, R.E. Martin, C. Kuratli, J. Schneider, I.R. Baxendale, S.V. Ley
A.C.S. Comb. Sci. 2011, 13, 405-413

6. Synthesis of nitropyrrolidines via dipolar cycloaddition reactions using a modular flow reactor
M. Baumann, I.R. Baxendale, S.V. Ley
Synlett 2010, 749-752

7. Synthesis of highly substituted 3-nitropyrrolidines and 3-nitropyrroles by a multicomponent multi-step flow sequence
M. Baumann, I.R. Baxendale, J. Wegner, A. Kirschning, S.V. Ley
Heterocycles 2010, 82, 1297-1316

8. A base-catalysed, one pot, three component coupling reaction leading to nitrosubstituted pyrroles
I.R. Baxendale, C.D. Buckle, S.V. Ley, L. Tamborini
Synthesis 2009, 9, 1485-1493

9. Multi-step synthesis using modular flow reactors: the preparation of yne-ones and their use in heterocycle synthesis
I.R. Baxendale, S.C. Schou, J. Sedelmeier, S.V. Ley
Chem. Eur. J. 2010, 16, 89-94

10. A fully automated continuous flow synthesis of 4,5-disbustituted oxaxoles
M. Baumann, I.R. Baxendale, S.V. Ley, C.D. Smith, G.K. Tranmer
Org. Lett. 2006, 8, 5231-5234

11. Safe and reliable synthesis of diazoketones and quinoxalines in a continuous flow reactor
L. J. Martin, A.L. Marzinzik, S.V. Ley, I.R. Baxendale
Org. Lett. 2011, 13, 320-323

12. Application of flow chemistry microreactors in the preparation of casein kinase I inhibitors
F. Venturoni, N. Nikbin, S.V. Ley and I.R. Baxendale
Org. Biomol. Chem. 2010, 8, 1798-1806

13. The continuous flow synthesis of butane 2,3-diacetal protected building blocks using microreactors
C.F. Carter, I.R. Baxendale, J.B.J. Pavey, S.V. Ley
Org. Biomol. Chem. 2010, 8, 1588-1595

14. A flow process using microreactors for the preparation of a quinolone derivative as a potent 5HTIB antagonist
Z. Qian, I. R. Baxendale, S.V. Ley
Synlett 2010, 505-508