Convenient one-pot formation of highly functionalized 5-bromo-2-aminothiazoles, potential endocannabinoid hydrolase MAGL inhibitors

Article abstract of DOI:10.1016/j.tetlet.2018.10.055

Highly functionalized 5-bromo-2-amino-1,3-thiazoles bearing various substituents could be easily prepared by a rapid and efficient one-pot method, using simple starting materials and mild conditions while avoiding the use of metal catalysts or inconvenient reagents such as elemental halogens. These useful products can serve as starting materials for other reactions or as pharmacologically interesting compounds. In our work we have shown that the resulting 5-bromothiazole compounds could lead to monoacylglycerol lipase (MAGL) inhibition in the μM range.

Full text of DOI:10.1016/j.tetlet.2018.10.055

Accepted Manuscript
Convenient one-pot formation of highly functionalized 5-bromo-2-aminothia-
zoles, potential endocannabinoid hydrolase MAGL inhibitors
Julien R.C. Prevost, Arina Kozlova, Bouazza Es Saadi, Esra Yildiz, Sara
Modaffari, Didier M. Lambert, Lionel Pochet, Johan Wouters, Eduard Dolusic,
Raphaël Frédérick
PII:
S0040-4039(18)31285-1
https://doi.org/10.1016/j.tetlet.2018.10.055
TETL 50365
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 August 2018
17 October 2018
24 October 2018
Please cite this article as: Prevost, J.R.C., Kozlova, A., Saadi, B.E., Yildiz, E., Modaffari, S., Lambert, D.M., Pochet,
L., Wouters, J., Dolusic, E., Frédérick, R., Convenient one-pot formation of highly functionalized 5-bromo-2-
aminothiazoles, potential endocannabinoid hydrolase MAGL inhibitors, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.10.055
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Convenient one-pot formation of highly functionalized 5-bromo-2-aminothiazoles,
potential endocannabinoid hydrolase MAGL inhibitors.
Julien R. C. Prevost,a Arina Kozlova,a Bouazza Es Saadi,a Esra Yildiz,a Sara Modaffari,b# Didier
M. Lambert,a Lionel Pochet,b Johan Wouters,b Eduard Dolušić,b∞ Raphaël Frédérick*a
1. Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute
(LDRI), Université Catholique de Louvain (UCL), 73 avenue Mounier, B1.73.10, 1200
Brussels, Belgium
2. Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur
(UNamur) 61 rue de Bruxelles, 5000 Namur, Belgium
# This paper is dedicated to the memory of Mrs Sara Modaffari, a very nice and brilliant student,
who passed away in March 9, 2018, aged 34.
∞Present adress: E. Dolušić, Federal agency for medicines and health products (Belgium), 40
Place Victor Horta, 1060 Brussels
* Corresponding author information:
Prof. Raphaël Frédérick
Université Catholique de Louvain
Louvain Drug Research Institute (LDRI)
Medicinal Chemistry Research Group (CMFA)
73 avenue Mounier
B1.73.10
1200 Brussels
Belgium.
Phone: +32 (0)2 764 73 41
raphael.frederick@uclouvain.be
Graphical abstract: The present study describes the optimization of a new method of
synthesis of highly functionalized 5-bromo-2-amino-1,3-thiazoles by a rapid and efficient one-
pot method, using simple starting materials and mild conditions. Interestingly some of the
synthesized compounds demonstrate promising monoacylglycerol lipase inhibition properties.
Abstract: Highly functionalized 5-bromo-2-amino-1,3-thiazoles bearing various substituents
could be easily prepared by a rapid and efficient one-pot method, using simple starting
materials and mild conditions while avoiding the use of metal catalysts or inconvenient
reagents such as elemental halogens. These useful products can serve as starting materials
for other reactions or as pharmacologically interesting compounds. In our work we have shown
that the resulting 5-bromothiazole compounds could lead to monoacylglycerol lipase (MAGL)
inhibition in the μM range.
Key words: electrophilic aromatic substitution, oxidation, halogenation, thiazoles,
monoacylglycerol lipase.
During an attempt to prepare substituted thiazole N-oxides1 in our laboratory, we unexpectedly
found that treatment of 2-aminothiazoles with m-chloroperoxybenzoic acid (mCPBA) in ethanol
did not afforded the desired product 1 (Scheme 1). Spectral analyses proved that the
corresponding 5-bromo-2-amino-thiazole 2 was formed instead in a very good yield (>90%).

Scheme 1. mCPBA-mediated 5-bromo-2-amino-1,3-thiazole formation
This observation can be explained by the fact that the starting compound was, in fact, obtained
as a hydrobromide salt. Thus, rapid oxidative bromination mediated by mCPBA occurred in
the 5-position of the thiazole ring. We decided to explore this interesting transformation in more
detail, especially because thiazoles are present in many natural products possessing biological
activity, such as anti-mycobacterial agents.2–5 A growing body of medicinal chemistry literature
reports thiazole derivatives as candidates for the treatment of various pathologies.6–15 These
heteroaromatics have also found applications in materials science, e.g. as liquid crystals16,17
Furthermore, halogenated thiazoles are useful synthetic intermediates for introducing this
heterocyclic scaffold into more complex molecules.18 The older method of using elemental
bromine for bromination of the thiazole ring19–21 has still occasionally been used in the recent
years.22–24 However, this approach has drawbacks such as toxicity, low atom economy,
corrosiveness, handling issues and a relatively high cost. Apart from the application of N-
halosuccinimides,25 more recent methods for thiazole halogenation include the use of
copper(II) halides,26 metalations of the thiazole ring followed by quenching the reactive
intermediates with electrophiles27 and transition metal catalysis.28 In general, despite the
modern development in aromatic halogenation,29,30 there still remains a need for new
procedures operating under mild conditions. Environmentally friendly and atom-economic
oxidative halogenation holds a lot of promise in this respect.31
We firstly examined the influence of the nature of the oxidant on the yield of bromothiazole 2.
The brominated compound 2 vs. non-brominated compound 3 system was chosen as the
benchmark and the absolute yields of the two thiazoles were determined by LC/MS analysis.
As observed from Table 1, compared to mCPBA (Entry 1), all the other oxidants, such as
hydrogen peroxide (entry 2), sodium hypochlorite (entry 5), and sodium periodate (entry 10)
gave a lower yield of 2. Moreover, even Oxone® (entry 4), which works fine in some other
oxidative halogenations,[32-41] did not give satisfying results in our experiments, permitting a
6% yield on 2.
Table 1. Yield optimization studies for the formation of the bromothiazole 2
ƞ (2)
(%)a
93
6
3
6
58
19
traces
12
ƞ (3)
(%)a
7
93
97
94
25
68
69
entry oxidant
equivalent
1
2
3
4
5
6
7
8
mCPBA
H2O2 50% aq.
UHP*
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Oxone®**
NaClO2
NaBiO3
t-BuOOH
MnO2
64

a
9
10
Na2CO3·1.5 H2O
NaIO4
1.0
1.0
traces
77
74
20
Yields determined by LC/MS
analysis
* Urea hydrogen peroxide adduct
** 2 KHSO5·KHSO4·K2SO4
With the evidence of mCPBA being the best oxidant agent, the next part of this study examined
the amount of oxidant. Adding up to 1 equivalent of mCPBA improved the bromination ratio,
but further increase of its quantity caused a drop in yields. We secondly aimed at exploring the
influence of solvent. As depicted in Table 2, polar solvents such as ethanol and DMF (Table
2, entry 1, and 7) worked best, permitting high yields (>93%). In fact, the highest yield of 5-
bromo derivative 2 is obtained when using DMF (Table 2, entry 7). Using acetone,
dichloromethane, 1,4-dioxane, toluene or acetonitrile lead to poor global yields (Table 2,
entries 2, 4, 5, 6 and 7).
Table 2. Investigation of the solvent and the reaction times for the formation of (5-bromo-4-
phenyl-thiazol-2-yl)-phenylamine 2
a
reaction time
(min, r1 + r2)
10 + 10
ƞ (2)
(%)a
93
ƞ (3)
(%)a
7
Yields determined by LC/MS
entry solvent
analysis
1
2
3
4
5
6
7
7’
7’’
EtOH
acetone
CH2Cl2
Reduction of the r1 and r2 reaction
time was also evaluated using
DMF as solvent (table 2, entry 7,
7’ and 7’’). Reaction times limited
at 5 min per step at room
temperature is sufficient to obtain
the desired compound 2 in a very
good yield (99%). However, a
10 + 10
10 + 10
52
47
43
10
33
>99
99
29
10
22
12
30
<1
1
1,4-dioxane 10 + 10
toluene
MeCN
DMF
DMF
DMF
10 + 10
10 + 10
10 + 10
5 + 5
0 + 10
5
69
one-pot
operation
adding
mCPBA simultaneously with the α-bromoketone and thiourea (table 2, entry 7’’) caused a
sharp drop in the yield of 2, as well as in total thiazole (2+3). In most cases, a maximum of 10
min with mCPBA at room temperature was enough for the completion of the oxidative
bromination reaction. Being more practical to handle than DMF, ethanol was chosen for all
subsequent experiments and the chosen conditions were applied to probe the syntheses of a
range of brominated thiazoles along with their non-brominated counterparts.
A suggested mechanism of the formation of the halogenation products includes the oxidation
of halide to a reactive halogen derivative (scheme 2) after reaction with the m-
chloroperoxybenzoic acid. This in situ formed electrophilic hypobromous acid could then be
attacked by the thiazole ring system in an electrophilic aromatic substitution reaction, giving
the product brominated at C5 after aromatization. In fact, polarity inversion (umpolung) of the
bromine is the key step for the addition-elimination reaction on the nucleophilic position of the
thiazole ring. The formation of the diatomic elemental halogen X2 with radical reaction seems
to not occur due to the strict need of a stoichiometric amount of mCPBA to react with bromine.
13C NMR studies showed easy identification thanks to a chemical shift for the carbon linked
with the bromine in the brominated derivative around 90 ppm, against 115 ppm for none
brominated compound. 2D NMR experiments (COSY, HSQC and HMBC) also led to the same
conclusion.

Scheme 2. suggested mechanism of the 5-bromo derivatives formation.
Various methods of purification were also tried. Because of the very small differences between
the retention values (Rf) for the thiazole and the 5-bromo-thiazole, flash chromatography did
not reveal to be successful. After several attempts, we found that the best way to obtain an
easy and rapid isolation was by precipitation. Briefly, to a solution of the compounds in
methanol or ethanol, addition of water led to the precipitation of the brominated derivative first.
In case of mixture after precipitation, a second recrystallisation allowed to obtain the desired
products in very high purity (>95%).
Finally, using standard conditions (0.3 M of all reagents in ethanol), the syntheses of a range
of brominated thiazoles was undertaken (Table 3). Briefly, mCPBA was added and the mixture
was stirred for 30 min at room temperature to allow completion of the first (Hantzsch) step
reaction. Conversion rates and absolute yields of the brominated vs. non-brominated
derivatives were determined by LC/MS. In all cases, conversion rates proved to be quantitative
with complete disparition (> 99%) of the starting materials. As observed from Table 3, the
absolute yields (non-optimized) ranged from 14% for 12 up to 91 % for 18, most of the
transformation leading to a yield of brominated compounds greater than 50%.
Table 3. Outcomes of syntheses of 5-bromo-thiazoles with various substitution patterns
(Compound, Yielda %)
Cl
F
R2
R1
Cl
Cl
F
F
2
4
5
6
7
8
9
10
11
63%
74%
70%
71%
71%
78%
39%
36% 82%
12
13
14
15
16
17
18
19
20
14%
51%
47%
28%
76%
87%
91%
77% 77%

21
22
23
24
25
26
27
28
29
25%
27%
51%
41%
60%
45%
35%
51% 55%
30
31
32
33
34
35
36
37
38
45%
36%
53%
45%
61%
49%
45%
85% 85%
39
40
41
42
43
44
45
46
47
71%
36%
53%
45%
61%
49%
45%
85% 85%
NC
a Yields determined by LC/MS analysis
To further illustrate the scope of this reaction, the influence of electro-donating groups on R1
and R2 (Table 3) was also investigated. To this end, the 5-bromo-N-(4-methoxyphenyl)-4-
phenylthiazol-2-amine 48, the 5-bromo-4-(4-methoxyphenyl)-N-phenylthiazol-2-amine 49, and
the 5-bromo-N,4-bis (4-methoxyphenyl)-thiazol-2-amine 50, containing a methoxy group on R1
and/or R2 were prepared and yields of, respectively, 86%, 76% and 73% were obtained, thus
corroborating the versatility of this reaction.
In the case of the fluorinated (5) and chlorinated (7) compounds (see Table 3 above), crystals
suitable for X-ray measurements were obtained. X-Ray data analysis unambiguously
confirmed the structures of the newly synthesized molecules and the insertion of the bromine
in the 5-position on the thiazole core.
Figure 1: Solid state crystallographic structures of 5 (left) and 7 (right).
Next, we investigated the potential of 5-bromothiazole as enzyme inhibitors. To this end, the
brominated parent compound 2 was screened on various targets available in our lab and we
found that this compound was interestingly a relatively potent inhibitor of the monoacylglycerol
lipase (MAGL)32 with > 60% inhibition at 100 μM. The compounds displayed in Table 3 were
thus assayed on MAGL and 6 derivatives 6,8,11,14,15 and 19 proved to be more potent than
the initial compound 2 with half maximal inhibitory concentration (IC ) determined to be in
50
the range of 10-55 μM.33–37 Interestingly, the adamantyl and the phenyl on the left part of the
molecules (R1) seem better tolerated. The biological evaluation of these derivatives on MAGL
can be found in the associated contents available.
In conclusion, our work describes a new, original and easy preparation of 5-bromo-thiazoles
that can be synthesized efficiently following a one-pot procedure from simple starting materials,
α-bromomethyl-ketones and thiosemicarbazides, and without using expensive catalysts or
harsh conditions and reagents. The nature of the oxidant to perform the reaction, of the solvent
and of the reaction time was evaluated. The initial compound 2 proved to be potentially
interesting to target monoacylglycerol lipase (MAGL). A small library of 5-bromo-2-amino-

thiazoles was thus elaborated and demonstrated promising although very preliminary inhibitory
potency of MAGL.
Experimental parts
Chemistry and biological evaluation. General information. All chemicals were purchased
from Sigma or Acros Organics and used without further purification. NMR spectra were
recorded on a Bruker Ultrashield Advance II 400 MHz instrument using dimethyl sulfoxide
(DMSO-d6) or chloroform (CDCl3) as deuterated solvent. Chemical shifts are reported in parts
per million (ppm) and referenced to the residual solvent resonance. Coupling constants (J) are
reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s =
singlet, d = doublet, t = triplet, dd = double doublet, q = quartet, m = multiplet, b = broad. Melting
points (m.p.) were determined using an electrothermal apparatus and are reported
uncorrected. LC-MS analyses were performed on an Agilent 6200 series TOF mass
spectrometer equipped with ESI and APCI as ionization sources and TOF (Time Of Flight)
detector, coupled with an Agilent 1200 series LC system with flux of 0.25 mL/min. High-
resolution mass spectra were carried out on a Thermofisher Scientific LTQ-Orbitrap XL hybrid.
X- ray diffraction datas were collected at room temperature on a Gemini Ultra (Rigaku)
diffractometer using Cu Ka (1.54584 ) radiation.
MAGL esterase activity assay. MAGL activity was measured by following [3H]-2-oleoyl glycerol
([3H]-2-OG) hydrolysis, as previously described (cf ref 37, Morera, L.; et al. Bioorganic and
Medicinal Chemistry 2012, 20, 6260-6275). Briefly, 6 ng of pure human MAGL was
preincubated during 30 min at room temperature in the presence of the inhibitor at various
concentrations (Tris buffer 50 mM, BSA 0.15% w/v, pH 8.0, inhibitor dissolved in 10 μL DMSO).
2-OG (10 μM final concentration; [3H]-2-OG 50,000 dpm, American Radiolabeled Chemicals;
200 μL total volume assay) was then added and the tubes were placed at 37°C for 10 min.
The reaction was stopped by adding 400 μL of a cold methanol- chloroform (1-1) mixture and,
after 5 min centrifugation at 700 g, the radioactivity was measured in the organic phase by
liquid scintillation. The dpm value obtained for a blank (containing no enzyme) was
systematically subtracted. Results were then expressed as percent of control activity (without
inhibitor), after which GraphPad prism software was used to treat the data and to analyze the
dose-response curves.
MAGL rapid dilution assay. The reversibility of MAGL inhibition by synthesized compounds
was investigated using the rapid dilution assay. The enzyme (800 ng in 38 μL of a buffer
containing Tris 50 mM, BSA 0.15%, pH 8.0) was incubated during 30 min at room temperature
with 2 μL of compound 19 (concentration of 10-4 M and 10-5 M in the mixture) dissolved in
DMSO. The enzyme-inhibitor mixture was then diluted 300-fold with the buffer. After 15 min of
incubation, the enzyme activity was measured on a 150 μL aliquot (corresponding to 10 ng of
enzyme) according to the above-described standard procedure.
Intermediate thioureas synthesis. To a solution of a (substituted)-phenylisothiocyanate
derivative (0.6 M) in MeCN was added aqueous ammonia (25%, 1.5 eq). The solution was
stirred at room temperature for 3 h. The reaction mixture was then concentrated. Purification
was done by precipitation from a mixture of n-hexane/ethyl acetate mixture (3/2). The pure
product was recovered as a powder after filtration in a quantitative yield.
2-amino-5-bromothiazole derivatives synthesis. To a solution of the intermediate thioureas (1
eq., 0.1 M) in EtOH was added 2-bromoacetophenone (1.25 eq). The solution was stirred at
room temperature until completion of the reaction followed by TLC. Then mCPBA (1 eq., 3M
in EtOH) was added and the solution was stirred until completion. The reaction mixture was
then concentrated. The resulting powder was dissolved in CH2Cl2 and extracted with water.
The organic phases were combined, dried over Na2SO4 and evaporated. Purification by
precipitation was performed: to the resulting powder was added a solution of 10% water in
methanol until obtention of a cloudy solution. After cooling at 4°C, precipitation of the product
occurred over time. Filtration afforded the pure products as powders.
5-bromo-N,4-diphenylthiazol-2-amine 2 / N,4-diphenylthiazol-2-amine 3 system synthesis and
LC/MS analysis procedure. A mixture of the synthesized thiourea and variously substituted
haloketones (0.3 mmol of each) in an appropriate solvent (900 μL) is reacted under the
indicated experimental conditions. The oxidant in ethanol solution (0.3 mmol in 100 μL )) is

added and the mixture is stirred. Then 1 mL of acetone is added and 20 μL of the mixture is
added to 980 μL of acetonitrile. A second dilution with 20 μL of the previously prepared solution
is added to 980 μL of acetonitrile to give a sample from 0 (0% yield) to 60 μM (100% yield) of
either thiazole, which is then analyzed by LC/MS (measurement of UV absorption at 254 nm).
ASSOCIATED CONTENT
*Supporting Information: Experimental procedures and characterization of all new compounds
including NMR spectroscopy data.
Acknowledgments
We are grateful to Arnaud Mars for his contribution to this project, Dr. Marie-France Herent
and Prof. Giulio Muccioli (UCL, LDRI, BPBL) for helpful discussions and assistance with HRMS
and Nikolay Tumanov (PC2 platform, Unamur) for assistance with X-ray diffraction
experiments. This work was supported by the Université catholique de Louvain (UCL-FSR),
the National Fund for Scientific Research in Belgium (F.R.S.-FNRS) from which RF is an
honorary research associate, the Télévie, the Fonds Maisin, the Fonds Spéciaux de
Recherche (FSR), the Actions de Recherche Concertées (ARC) and the Fondatioun
Kriibskrank Kanner (Luxembourg). RF and ED shares the last authorship position.
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Highlights



Convenient one-pot synthesis of highly functionalized 5-bromo-2-amino-1,3-thiazoles
Potential MAGL inhibitors
Safe and efficient bromination reaction