Heterocycles

Methods for the flow synthesis of heterocycles 

Flow synthesis of heterocycles – review
In our 2011 Molecular DIversity article [1] we described an overview of recent research studies towards the preparation of heterocyclic compounds especially those of medicinal interest.

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 2 in 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 5HT1B 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. Chem20119, 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. Ed200948, 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. Chem200810, 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 201082, 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 20099, 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. J201016, 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. Lett20068, 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