O

BrNH

S

H2N

F

N

S

NH

F

.HBr

mCPBA

N

S

NH

F

O

N

S

NH

FBr

EtOH

Molecular Weight: 286,32

Molecular Weight: 349,22

1

CH2Cl2

1) (a) Jin, Zh. Nat. Prod. Rep. 2006, 23, 464; (b) Turner, G. L. et al, Angew. Chem. Int. Ed. 2007, 46, 7996; (c) Bagley, M. C. et al, Chem. Rev. 2005, 105, 685; (d) Altmann, K.-H. et al, ChemMedChem 2007, 2, 396.2) (a) Huang, W. H. et al, Curr. Med. Chem. 2009, 16, 1806; (b) Matulenko, M. A. et al, Curr. Top. Med. Chem. 2009, 9, 362; (c) McInnes, C., Drug Discov. Today 2008, 13, 875; (d) Cabrera, D. G. et al, J. Med. Chem. 2011, 54, 7713.3) (a) Kiryanov, A. A., et al, J. Org. Chem. 2001, 66, 7925; (b) Mori, A., et al, J. Am. Chem. Soc. 2003, 125, 1700.4) (a) Kaye, P. T., et al, J. Chem. Soc. Perkin Trans. 1, 1981, 2335; (b) Begtrup, M. and Hansen, L. B. L., Acta Chem. Scand. 1992, 46, 372; (c) Grubb, A. M., et al, Synthesis 2012, 44, 1026.5) (a) Altman, M. D., et al, 2011, WO2011075515 (A1); (b) Siméon, F. G., et al, J. Org. Chem. 2009, 74, 2578; (c) Dunst, C. and Knochel, P., J. Org. Chem. 2011, 76, 6972.6) (a) Krishna Mohan Kandepi, V. V. and Narender, N., Synthesis 2012, 44, 15; (b) Rothenberg, G. and Clark, J. H.; Green Chemistry 2000, 2, 248.7) Lagoja, I., et al, Eur. J. Pharm. Sci. 2011, 43, 386.This work is supported by the FNRS and the Walloon Region (BioWin project CANTOL: Convention n° 5678).

O

Br

NH

S

H2N

NS

HN'5-Br'

1.

2. oxidant, room. temp.

Br

solvent, room. temp.0 - 10 min

5 - 10 min

+

NS

HN'5-H'

entry solvent rt [min] ƞ (5-Br) [%] ƞ (5-H) [%]

1 ethanol 10 + 10 93 7

1’ ethanol 5 + 10 93 7

2 acetone 10 + 10 52 29

3 DMF 10 + 10 >99 <1

3’ DMF 5 + 5 99 1

3’’ DMF 0 + 10 5 69

4 CH2Cl2 10 + 10 47 10

5 1,4-dioxane 10 + 10 43 22

6 toluene 10 + 10 10 12

7 MeCN 10 + 10 33 30

4. References

1. Introduction

2. Synthesis and its scope

NAMEDIC

CONVENIENT ONE-POT FORMATION OF HIGHLY FUNCTIONALIZED 5-HALOTHIAZOLES

Eduard Dolušić, Sara Modaffari, Lionel Pochet, Johan Wouters, Bernard Masereel and Raphaël Frédérick

NAmur MEDIcine Center (NAMEDIC), NARILIS, 61 rue de Bruxelles, B-5000 Namur, Belgium

Scheme 1. mCPBA-mediated 5-bromothiazole formation

Halogenated thiazoles are useful synthetic intermediates for introducing this scaffold into more complex molecules. Older methods for thiazole halogenation in the 5-position, which rely on the use of elemental halogens,4a,b are still in use today4c despite halogen toxicity and low atom economy of the transformation. Some recent alternatives include the

application of N-halosuccinimides,5a copper(II) halides5b or metalations of the thiazole ring followed by quenching the reactive intermediates with electrophiles.5c However, all these methods are based on transformations of pre-formed 1,3-thiazoles and often include relatively lengthy reaction times or silylated starting thiazoles.

Figure 1. LC/MS chromatogram of 5-bromothiazole 1

We next aimed at exploring an one-pot operation, i. e. adding mCPBA directly to the thiazole forming reaction mixture (Scheme 2). The ‘5-Br’ / ‘5-H’ was chosen as the model system and the absolute yields of the two thiazoles were determined by LC/MS analysis. Ethanol and DMF worked best as solvents, with reaction times as short as 5 min at room temp. per step (Table 1). However, adding mCPBA simultaneously with the a-

bromoketone and thiourea (entry 3’’) caused a sharp drop in the 5-Br yield. Being more practical to handle than DMF, ethanol was chosen for most subsequent experiments. All other oxidants investigated were inferior to mCPBA in terms of 5-Br yield (Table 2), including Oxone® in MeCN, a system working fine in a number of other oxidative halogenations.6a Adding more than 1 equivalent mCPBA could improve the bromination yield

up to a certain extent, but increasing its quantity further caused the yields to drop again (Table 3; acetone was chosen as solvent because the formation of both 5-Br and 5-H could clearly be observed).

Scheme 2. General synthetic

scheme for (5-bromo-4-phenyl-

thiazol-2-yl)-phenylamine and its 5-H derivative

Finally, the chosen conditions (0.3 M of all reagents in ethanol) were applied to probe the syntheses of a range

of brominated thiazoles (Table 4). mCPBA was added upon completion of the first (Hantzsch) step as judged

by TLC. In some cases, the Hantzsch step required extended reaction times or microwave heating. In most cases, max. 10 min with mCPBA at room temperature

was enough for the completion of the oxidative bromination reaction. The final products were typically obtained by trituration with cyclohexane, filtration and

drying. No chromatography on silica was usually necessary. The ratio of the brominated vs. non-

brominated compound was determined by LC/MS.

The reaction scope was successfully extended to 5-chlorination in a model reaction (Scheme 3).

The exact reaction mechanism is not completely clear at this point, although in situ formation of the active

halogenating species by oxidation of X- with mCPBA can be assumed with great probability.

In attempted preparations of substituted thiazole N-oxides in our laboratory, treatment of 2-aminothiazoles with m-chloroperoxybenzoic acid (mCPBA) in dichloromethane did not afford the desired products (Scheme 1). Spectral analyses (NMR, not shown; LC/MS, Figure 1) proved that corresponding 5-

bromothiazoles were formed instead in very good yields. This can be explained by the fact that the starting compounds had, in fact, been obtained as hydrobromide salts. Rapid oxidative bromination mediated by mCPBA then occurred in the 5-position of the thiazole ring. We decided to explore this

interesting transformation in more detail.

Table 1. Evaluation of the solvent and reaction times; oxidant = 1 mol. eq. mCPBA

mol. eq. mCPBA

ƞ (5-Br) [%] ƞ (5-H) [%]

1,0 53 34

1,5 69 15

2,0 47 9

Table 3. Evaluation of the mCPBA quantity;

solvent = acetone; rt = 10’ + 10’

entry oxidant solvent ƞ (5-Br) [%]

ƞ (5-H) [%]

1 H2O2 50% aq. ethanol 6 93

2 UHP* ethanol 3 97

3 Oxone®** ethanol 6 94

3’ Oxone® MeCN traces 73

3’’ Oxone® DMF 50 52

4 NaClO2 ethanol 58 25

5 NaBiO3 ethanol 19 68

6 tBuOOH ethanol - 69

7 MnO2 ethanol 12 64

8 Na2CO3.1.5H2O ethanol - 74

9 NaIO4 ethanol 77 20

Table 2. Evaluation of the oxidant (1 mol. eq.); rt = 10’ + 10’; *) urea hydrogen peroxide; **) 2 KHSO5·KHSO4·K2SO4

Scheme 3. One-pot5-chlorothiazole synthesis

O

Cl

NH

S

H2N

NS

HN2 52%

isolated

1.

2. 2 mol. eq. m-CPBA, r. t, 5'

Cl

EtOH, W (120°C), 5'

Highly functionalized 5-halothiazoles could be prepared quickly and efficiently in an one-pot operation from simple starting materials and without using catalysts and harsh conditions or reagents. This methods fits into the modern developments of environmentally friendly and

biomimetic methods of oxyhalogenations, which have so far only been described for a limited range of aromatic substrates.6

Attempts are in progress to further functionalize these 5-halothiazoles by known chemical methods to give rise to pharmacologically interesting products (e. g. Scheme 4).

O

Br

NH

S

H2N

3; 65%

1.

2. m-CPBA, r. t, 10'

1. DMF, room temp, 10'

S

N NH

Br

BF3K

Pd cat.

S

N NH

4

Scheme 4. Envisaged synthesis of anti-Alzheimer's compound 4.7

Thiazoles are an important class of heterocycles. They are present in many natural products possessing biological activity.1 A growing body of medicinal chemistry literature reports thiazole derivatives in the treatment of various

pathologies.2 These heteroaromatics have also found applications in materials science, e. g. as liquid crystals.3

Table 4. Reaction conditions and outcomes of syntheses of (bromo)thiazoles with various substitution patterns.

ƞ = overall yield of the thiazole products, followed by the relative yield of the 5-brominated product;

N. D. = not done

3. Conclusions and perspectives