A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines

Accepted Manuscript A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines Birgit Wilding, Stefan Faschauner, Norbert Klempier PII: DOI: Reference:

S0040-4039(15)00946-6 http://dx.doi.org/10.1016/j.tetlet.2015.05.104 TETL 46376

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

31 March 2015 21 May 2015 27 May 2015

Please cite this article as: Wilding, B., Faschauner, S., Klempier, N., A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.05.104

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A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines

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Birgit Wilding, Stefan Faschauner, Norbert Klempier* OAc MeOOC H2N

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Tetrahedron Letters journal homepage: www.elsevi er.com

A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines Birgit Wildinga, Stefan Faschaunerb and Norbert Klempiera,b,* a b

Austrian Centre of Industrial Biotechnology (acib) c/o Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria

ARTICLE INFO Article history: Received Received in revised form Accepted Available online Keywords: Thieno[2,3-d]pyrimidine Thiophene Gewald reaction Functionalization

ABSTRACT

The synthesis of 5-hydroxmethyl-, 5-acetoxymethyl-, 5-formyl- and 5-cyanothieno[2,3-d]pyrimidines, the (methyl)-5-carboxylate and the respective amide functionality was accomplished by building up the functionalized molecule starting from appropriately substituted thiophene precursors. A similar strategy starting from the pyrimidine precursor and subsequent direct functionalization (formylation and cyanation) of the thieno[2,3-d]pyrimidine parent compound in position 5 was found to be less feasible.

Thieno[2,3-d]pyrimidine derivatives show a wide variety of biological activities. Thieno[2,3-d]pyrimidines have been evaluated as analgesics, anti-inflammatory, antipyretic, antiviral, antidepressant, antidiabetic, antihistaminic, antibacterial and antihypertensive agents, as pesticides, and also as herbicides, and plant growth regulators. Most important is the inhibition of protein kinase1, dihydrofolate reductase2 and thymidylate synthase.2,3 Expectably, the scientific literature dealing with their synthesis is vast, nevertheless only few review articles have appeared until now.4

compounds.14 Cu, Ni and Pd-catalyzed nucleophilic cyanation of aromatic halides,15 and electrophilic cyanation of reactive organometallic species16 have made tremendous progress in the past few years, and the cyanation of some more acidic heterocycles has been accomplished by C-H-functionalization.17 No cyanation in the thiophene moiety has been reported for thieno[2,3-d]pyrimidines so far.

We have been interested in the biocatalytic synthesis and transformations of nitriles since several years.5 The recent discovery of an unprecedented nitrile bioreduction6 and the investigation concerning their biocatalytic potential for organic synthesis7 has required the synthesis of 5-cyanothieno[2,3d]pyrimidine-4-one. Given the wide variety of other possible biocatalytic (consecutive) transformations besides nitriles, in particular by hydrolytic enzymes,8 we extended our work to the synthesis of other functionalities. Here, we wish to report our results on a general practical approach to 5-functionalized thieno[2,3-d]pyrimidin-4-ones.

Scheme 1. Synthesis of thieno[2,3-d]pyrimidines starting from a pyrimidine precursor. a) NaSH, ethylene glycol, 130°C, b) NaBH4, DMF c), d) NaSH, ethylene glycol, 130°C, then chloroacetaldehyde, aq. K2CO3, 40°C (yield 22% in a two step, one pot procedure), e) pivaloylchloride, DMF, pyridine, Et3N, 0°C to 50°C (yield 33%), f) POCl3, DMF, 55°C (yield 23%).

The general strategy of thienopyrimidine synthesis follows a ring annulation either of pyrimidine9 or thiophene rings10. 2aminothiophene precursors are frequently synthesized by Gewald reaction11 from the corresponding α-methylene carbonyl compound, α-cyanoester and sulfur. Several synthetic routes to synthesize 5-cyano substituted thieno[2,3-d]pyrimidines were investigated, such as the ring annulation using a 3-cyano or 3carboxylate substituted thiophene precursor and the introduction of the cyano group in the 5-unsubstituted thieno[2,3-d]pyrimidine by direct cyanation methods. Besides the classical Sandmeyer12 and Rosenmund - von Braun13 reactions using stoichiometric amounts of CuCN, chlorosulfonylisocyanate has been reported to act efficiently as a cyanation reagent for heterocyclic

In this work, we investigated the synthesis of substituted thieno[2,3-d]pyrimidines starting from pyrimidines as well as from thiophene precursors. As pyrimidine precursor, we chose commercially available 2-amino-6-chloro-4-hydroxypyrimidine (Scheme 1). Reaction to the mercaptopyrimidine with sodium hydrosulfide in ethylene glycol18 was accompanied by dimerization of the mercapto group, which could be avoided by carrying out the reaction under inert conditions and by proceeding with the next synthetic step without isolation of the mercapto compound. We investigated chloroacetaldehyde19 and chloroformyl acetonitrile7a,20 for the formation of the thiophene ring. The condensation reaction of 2-amino-6-mercapto-4hydroxypyrimidine with chloroacetaldehyde was successful with

* Corresponding author. Tel.: 43-316-873-32445; fax: +43-316-873-32402; e-mail: [email protected]

2

Tetrahedron

either KHCO3 in DMF19 or sodium acetate in water (see supporting information). Ethylene glycol as solvent and sodium methoxide as base were reported previously in this reaction.21

Scheme 2. Synthesis of thieno[2,3-d]pyrimidines starting from a commercially available thiophene precursor. a) formamide, ammonium formate, 150°C (yield 57%), b) POCl3, Et3N, acetonitrile, 100°C (yield 70%), c) NaOCH3, methanol, reflux (yield 89%), d) Hg(OAc)2, acetic acid, 100°C, then brine, e) iodine, chloroform, 50°C.

Given the low overall yields of the first two steps we decided to pursue a condensation reaction starting from the commercially available thiophene precursor methyl 2-aminothiophene-3carboxylate (Scheme 2). Condensation with formamide10b in presence of ammonium formate22 occurred straightforward to give thieno[2,3-d]pyrimidine-4-one (4). The next step was the introduction of a substituent to the 5-position of the thieno[2,3d]pyrimidine. A cyano-substituent can be introduced by formylation of the thienopyrimidine, subsequent transformation of the resulting aldehyde into its oxime and dehydratisation of the oxime.23 Formylation reaction on a thieno[2,3-d]pyrimidine could not be found in literature and all attempts to introduce the 5formyl group by using the Vilsmeier reagent24 resulted in the preparation of 4-chlorothieno[2,3-d]pyrimidine (9), even when the 4-hydroxy group was protected as methoxy ether (10). This can be attributed to the ease of substitution of the 4-oxo-position in the pyrimidine ring and to the fact that the Vilsmeier reaction works best with electron rich aromatic heterocycles. Palladium catalyzed reductive formylation was considered as alternative formylation method.25 Following the relative reactivity of aryl halides in palladium catalyzed cross-couplings: I ~ OTf > Br > Cl, 5-iodothieno[2,3-d]pyrimidin-4-one was prepared. Direct iodination of thieno[2,3-d]pyrimidin-4-one with N-iodosuccinimide in THF was not successful, probably due to the limited solubility of the starting material in THF. During the iodination by chloromercuration2a,26 and subsequent substitution with iodine we obtained a mixture of mono-iodinated and diiodinated products in a ratio of 1/0.6. Dibromination was also observed in the bromination of thieno[2,3-d]pyrimidin-4-one using bromine in acetic acid, and selective debromination then gave a mono-bromo-substitution in position 5.27 Palladium catalyzed reductive carbonylation was recently successfully applied to the formylation of pyrrolo[2,3d]pyrimidine nucleosides,28 but a formylation of thienopyrimidines has not been reported so far. Our attempts using bis(dibenzylideneacetone)palladium or tris(dibenzylidene) di-palladium as catalyst were not successful. Optimization of the reaction conditions and ligands of the palladium catalyst for this particular reaction would be necessary. Facing these challenges, we anticipated that a thiophene precursor which carries the cyano group (or any group which can be easily converted into a cyano group) in the appropriate position, and can then be used in the condensation reaction to give the 5-substituted thieno[2,3-d]pyrimidine, would be a more convenient choice. We thus prepared methyl 2-amino-4acetoxymethyl-thiophene-3-carboxylate (12) by the one pot

Gewald reaction from the corresponding keto-compound 3chloro-2-oxopropionyl acetate (11)29, methylcyanoacetate and Na2S30 (Scheme 3). We received a mixture of methyl 2-amino-4acetoxymethyl thiophene-3-carboxylate (12) and its deprotection product methyl 2-amino-4-hydroxymethyl thiophene-3carboxylate (13) in different ratios depending on the base used (triethylamine or morpholine) and the ratio of the reactants in methanol (2/8 in case of the conditions given in ref. 31). Complete deprotection of methyl 2-amino-4-acetoxymethyl thiophene-3-carboxylate (Scheme 3) was achieved by dropwise addition of triethylamine to the reaction mixture and subsequent heating of the reaction mixture to 65°C overnight. Upon ring condensation with formamide and ammonium formate, 5hydroxymethylthieno[2,3-d]pyrimidin-4-one (15) was obtained as the desired precursor for further transformations. Conveniently, the product mixture from the Gewald reaction can also be directly subjected to the following condensation step, since the acetoxy group is cleaved upon condensation with formamide under the high temperature conditions. Oxidation of the alcohol to the aldehyde, formation of the oxime and dehydratization under standard conditions23 gave the desired nitrile, though in an overall unsatisfying yield. Therefore we investigated a different synthetic route, shorter in reaction steps and with the option of an even more versatile 4substituent in the 2-aminothiophene-3-carboxylate precursor.

Scheme 3 Synthesis of thieno[2,3-d]pyrimidines starting from a thiophene precursor. a) potassium acetate, glacial acetic acid, 85°C, 24h, vacuum distillation (bp17mbar 85°C, yield 28%), b) methyl cyanoacetate, Na2S nonahydrate, MeOH, Et3N, 2d, r.t. (yield 80% of 13), c) formamide, ammonium formate, 120°C, 2-3d (yield 21% of 15). See supporting information for experimental details.

We thus synthesized methyl 2-aminothiophene-3,4dicarboxylate (16)31 from methyl-2-oxo-propanoate, methyl cyanoacetate and sulfur (S8) in DMF using triethylamine as base in 71% yield (Scheme 4). The condensation of the Gewald product with formamide and ammonium formate10b resulted in a mixture of acid, amide and ester in position 5, which were then separated by silica gel chromatography. Formation of the amide can likely be attributed to reaction of the ester with the ammonia formed by decomposition of the condensing reagent formamide applied in excess at high temperature. The dehydratization of the amide (19) to the nitrile (20) was accomplished using trifluoroacetic acid anhydride in triethylamine or pyridine (Scheme 4).32 It is noteworthy, that chloro-containing dehydrating agents, such as thionylchloride and PPh3/tetrachloromethane were unusable since they would lead to the undesired 4-chloro substituted thieno[2,3-d]pyrimidine.

Scheme 4. Synthesis of thieno[2,3-d]pyrimidines starting from a thiophene precursor. a) methylpyruvate, sulphur, Et3N, DMF, 75°C, overnight (yield 71%), b) formamide, 120-180°C, 2d (yield 30% of

3 19), c) trifluoroacetic anhydride, pyridine, 0°C to 60°C, 4h (yield 55%). See supporting information for experimental details.

In conclusion, we have accomplished the synthesis of 5hydroxy (acetoxy) methyl-, 5-formyl-, 5-cyanothieno[2,3d]pyrimidines, the 5-carboxylates and the respective amide by building up the functionalized molecule starting from appropriately substituted thiophene precursors. A similar strategy starting from the pyrimidine precursor is less feasible since the respective functionalized condensing agent is usually difficult to synthesize. Direct functionalization (formylation and cyanation) of the thieno[2,3-d]pyrimidine parent compound in position 5 turned out to be unsuccessful. The substituted thieno[2,3d]pyrimidines can be subjected to biocatalytic functional group transformations. Supplementary data Synthetic procedures and characterization data (including graphical NMR spectra) can be found in the supplementary information. Acknowledgments The authors would like to thank Christoph Staudinger and Melanie Zechner for skillful assistance in the laboratory. This work has been supported by the Federal Ministry of Science, Research and Economy (BMWFW), the Federal Ministry of Traffic, Innovation and Technology (bmvit), the Styrian Business Promotion Agency SFG, the Standortagentur Tirol and ZIT Technology Agency of the City of Vienna through the COMETFunding Program managed by the Austrian Research Promotion Agency FFG.

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* Corresponding author. Tel.: 43-316-873-32445; fax: +43-316-873-32402; e-mail: [email protected]

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K.; Betebenner, D. A.; Donner, P. L.; Green, B. E.; Kempf, D. J.; McDaniel, K. F.; Maring, C. J.; Stoll, V. S.; Zhang, R. U. S. Patent 162285, 2004. 31. Berrouard, P.; Grenier, F.; Pouliot, J.-R.; Gagnon, E.; Tessier, C.; Leclerc, M. Org. Lett. 2011, 13, 38-41. 32. Campagna, F.; Carotti, A.; Casini, G. Tetrahedron Lett. 1977, 21, 18131816.