FULL PAPER DOI: 10.1002/chem.201201039 Establishing a Flow Process to Coumarin-8-Carbaldehydes as Important Synthetic Scaffolds Jaroslav Zak,[a, c] David Ron,[b] Elena Riva,*[a] Heather P. Harding,[b] Benedict C. S. Cross,[b] and Ian R. Baxendale[a] Abstract: Despite their usefulness as fluorophores and synthetic precursors, effi- cient and reliable routes to coumarin-8-carbaldehydes are lacking. We describe Keywords: coumarins · flow here a high-yielding continuous flow synthesis that requires no manual intermedi- chemistry · heterocycles · micro- ate purification or work-up, giving access to multigram quantities of the aldehyde reactors · solid-supported reagents product. Introduction the ultraviolet region and exhibiting potent fluorescence and luminescence.[2] In addition, they possess a wide range Coumarins are a general structural class of aromatic hetero- of biological activities and have long been considered attrac- cycle defined by the naturally occurring parent compound tive drug scaffolds being used in the treatment of viral infec- (Figure 1), which was first isolated in 1822 from Tonka tions,[3] neurodegenerative diseases,[4] oedema,[5] inflamma- beans (Dipteryx odorata).[1] Molecules possessing the 2H- tion, and as hepatoprotective agents and antioxidants.[6] chromen-2-one core display a diverse range of interesting Indeed, several coumarins derivatives[7] (Figure 1) have al- properties—many are highly coloured, absorbing strongly in ready found pharmaceutical application as vitamin K antag- onists (Warfarin), anticoagulants (Phenprocoumon), antibi- otics (Novobiocin) and antispasmodics (Hymecromone). Furthermore, their utilisation in the fight against cancer is another prominent area, with both natural and synthetic coumarins showing promising activity in in vivo rat models and importantly against malignant human cell lines.[8] Apart from their medicinal applications, coumarins have also found use as sunscreen ingredients,[9] microbiological mark- ers,[10] textile and laser dyes,[11] fluorescent labels[12] and, more recently, as solar cell sensitisers. As a consequence of their general functionality many synthetic methods for their preparation have been reported.[13] However, one particular functional pattern that despite its Figure 1. Coumarin and coumarin derivatives of pharmaceutical impor- simple chemical architecture has proven challenging to tance. access reliably is the 7-hydroxycoumarin-8-carbaldehyde (e.g., 5a, Scheme 1).[14] This is an important structure motif with the juxtaposed formyl and phenoxy groups imparting [a] J. Zak, Dr. E. Riva, Dr. I. R. Baxendale Department of Chemistry enhanced fluorescent characteristics and enabling easy as- University of Cambridge sembly of Schiff base Salen ligands which have found many Lensfield Road, Cambridge, CB2 1EW (UK) applications in diagnostic and detection systems.[15] Histori- E-mail: [email protected] cally, installation of the formyl unit is achieved through [b] Prof. D. Ron, Dr. H. P. Harding, Dr. B. C. S. Cross functionalization of the corresponding 7-hydroxycoumarin University of Cambridge Metabolic Research Laboratories [16] [17] Level 4, Institute of Metabolic Science using a Gattermann–Koch, Reimer–Tiemann, Vilsmei- [18] [14] Box 289, Addenbrookes Hospital er–Haack or Duff reaction. Unfortunately, these meth- Cambridge, CB2 0QQ ods all suffer from poor conversion and often require exten- [c] J. Zak sive work-up leading to further loss of yield and resulting in Current address: Ludwig Institute for Cancer Research an overall inefficient process (Table 1). Requiring access to University of Oxford large quantities of 5a as a biological probe[23] we decided to Old Road Campus Research Building Oxford, OX3 7DQ (UK) evaluate alternative synthesis protocols. Supporting information for this article is available on the WWW We have found that the application of flow processing under http://dx.doi.org/10.1002/chem.201201039. technologies[24] offers several advantages for the synthesis of Chem. Eur. J. 2012, 18, 9901 – 9910 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 9901 streams can be readily facilitated by the incorporation of fixed bed supported reagent cartridges and in-line scaveng- ing columns.[26] Such an approach appeared to us to be ideal for achieving a fast, reliable and readily scalable route to various coumarin carbaldehydes. Results and Discussion Having considered several potential routes we selected two complementary strategies (Scheme 1) which we believed would deliver high yields of the desired products and gain significant efficiencies by adoption of flow processing tech- nologies. However, in order to first facilitate a direct com- parison of the routes against the pre-existing literature methods both proposed sequences were evaluated using standard batch conditions. The basic route development and reaction optimisation was thus conducted on the basic target structure 5a.The first step of both synthetic pathways is common and involves the formation of the coumarin core. This was achieved using [27] Scheme 1. Proposed routes to 7-hydroxy-4-methyl-2-oxo-2H-chromene-8- a Pechmann condensation reaction. A protocol using tri- carbaldehyde (5a). fluoroacetic acid (TFA) as a catalyst was identified being both high-yielding and a generic method of preparation from simple readily available starting materials; resorcinols and acetoacetate derivatives. From this reaction numerous Table 1. Data of comparative yields for the synthesis of 7-hydroxy- coumarin structures. coumarin derivatives were prepared in good yields and ex- cellent regioselectivity (Table 2) when heated at 1008C for Product Reaction Yield [%] Ref. 1 h under microwave irradiation. Using this protocol, only one coumarin derivative failed to form with the anticipated Duff reaction[a] 22 [19] regiocontrol. Thus attempts to prepare the corresponding 2H-chromen-2-one from orcinol and ethyl acetoacetate [28] 5a (Table 2, entry 7) gave compound 1g instead of the ex- 5a Duff reaction[a] 20 [14d]ACHTUNGRE pected 7-hydroxy-4,5-dimethyl-2H-chromen-2-one; the [a] 5a Duff reaction 15 [20] structure of 1g was unambiguously confirmed by X-ray crys- [a] 5a Duff reaction 15 [21] tallography (see the Supporting Information). This is an in- 5a Duff reaction[a] 22 [14b]ACHTUNGRE teresting result as under many alternative reaction condi- tions 7-hydroxy-4,5-dimethyl-2H-chromen-2-one is the only [a] Duff reaction 60 [22] product isolated often in exceptionally high yield.[29] Indeed, [30] following a similar protocol but using H2SO4 as the acid catalyst we also isolated the 7-hydroxy coumarin derivative 1g. Vilsmeier reaction[b] 54 [18a]ACHTUNGRE Following the Pechmann cyclisation the two pathways di- verge (Scheme 1). In Route A the installation of the formyl group is provided for through alkene 4a acting as a latent Vilsmeier reaction[b] 84 [18b]ACHTUNGRE carbonyl group revealed by ozonolysis. The proceeding alke- nylation of the aryl ring occurs by a standard allylation of the phenol (1a!2) followed by a Claisen rearrangement Reaction conditions: [a] 1) hexamethylene tetramine, glacial acetic acid, and metal catalysed isomerisation to yield the necessary 60–808C, 2) HCl. [b] N-methylformanilide, POC13, dichloroethane, 70– conjugated alkene 4a. Alternatively Route B involved an 758C. aminoalkylation of the coumarin followed by N-oxidation and a regioselective Polonovski reaction leading to an inter- complex natural products and their derivatives.[25] Of partic- mediate benzylic iminium species. Direct iminium hydrolysis ular value is the possibility of carrying out two or more se- would then furnish the corresponding aldehyde 5a. Each quential reactions with no or minimal intermediate workup transformation of both sequences was high yielding and fur- and purification between transformations. Indeed, the con- nishes adequately clean material for further processing with- tinuous processing and downstream clean-up of reaction out the need for extensive purification. 9902 www.chemeurj.org 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 9901 – 9910 Flow Process to Coumarin-8-Carbaldehydes FULL PAPER Table 2. Synthesized coumarin-carbaldehydes and their synthetic intermediates. Entry Starting Starting Pechmann Mannich N-Oxidation Polonovski material material reaction product reaction product reaction product reaction product 1 1a (quantitative yield) 6a (86%) 7a (31%) 5a (44 %) 2 1b (92%) 6b (70 %) 7b (57%) 5b (41%) 3 1c (quantitative yield) 6c (74 %) 7c (53%) 5c (52%) 4 1d (quantitative yield) 6d (77 %) 7d (71%) 5d (79%) 5 1e (97%) 6e (99%) 7e (36%) 5e (67 %) 6 No reaction 1f(96%) 7 No reaction 1g (72%) Route A batch conditions: The allylation step proceeded and then the resulting THF solution directly subjected to smoothly in essentially quantitative yield using K2CO3 in the ozonolysis conditions. Treatment with ozone gave acetone under mild conditions (608C, 1 h), aqueous extrac- a rapid and clean conversion to the corresponding aldehyde tion to remove inorganic salts was the only work-up necessa- 5a in 20 min as determined by TLC analysis. The intermedi- ry. The subsequent [3,3]-sigmatropic rearrangement was ate ozonide was subsequently cleaved by treatment with found to require elevated temperatures (2008C) and gener- a polymer-supported triphenylphosphine equivalent (PS- ated a mixture of two isomers (3a/3b 9:2) albeit these could PPh2, 3 equiv) giving the desired product in 91% isolated be readily separated by column chromatography (note that yield after filtration