A tandem aza-Friedel-Crafts reaction/Hantzsch cyclization: A simple procedure to access polysubstituted 2-amino-1,3-thiazoles

Article abstract of DOI:10.1016/j.tet.2011.04.090

A tandem aza-Friedel-Crafts reaction/Hantzsch cyclization is described to access various polysubstituted 2-amino-1,3-thiazoles from electron-rich (hetero)-aromatic rings, aldehydes, thiourea and α-chloroketones.

Full text of DOI:10.1016/j.tet.2011.04.090

Tetrahedron 67 (2011) 4897e4904
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Tetrahedron
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A tandem aza-FriedeleCrafts reaction/Hantzsch cyclization: a simple procedure
to access polysubstituted 2-amino-1,3-thiazoles
*
Guihlem Chaubet, Ludovic T. Maillard , Jean Martinez, Nicolas Masurier
ꢀ
ꢀ
Institut des Biomolecules Max-Mousseron, UMR 5247, CNRS, Universites Montpellier I et II, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault,
34093 Montpellier Cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem aza-FriedeleCrafts reaction/Hantzsch cyclization is described to access various polysubstituted
2-amino-1,3-thiazoles from electron-rich (hetero)-aromatic rings, aldehydes, thiourea and a-chloroketones.
Received 21 March 2011
Received in revised form 18 April 2011
Accepted 22 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 5 May 2011
Keywords:
aza-FriedeleCrafts reaction
Hantzsch cyclization
2-Amino-1,3-thiazoles
Imidazo[1,2-a]pyridine
1. Introduction
process without any hazardous purification of the intermediates.
In AFCR, three different molecules including a nitrogen source
(amine, amide, urea), an aldehyde and an electron-rich aromatic ring
(naphtol,15 indole,16 pyrrole17 and furan,18 etc.) are put together to
yield one final product and water asthe only byproduct. It iscatalyzed
by many Brønsted as well as Lewis acids.15e18 More recently, it has
been demonstrated that vitamin B1, also known as Thiamine hy-
drochloride, could catalyze the reaction.19 To the best of our knowl-
edge, although AFCRs are well described on amines, amides or urea
onlyone example of AFCRwith thiourea15i has been reported sofar. In
this case, solid silica sulfuric acid was used as catalyst to condense in
The 2-amino-1,3-thiazoles are biologically important com-
pounds with a broad range of activity like antiviral,1 antifungal,2
antiprion,3 anti-inflammatory4 and antibacterial activities.5 Some
2-amino-1,3-thiazole derivatives have been reported as ligands of
thrombopoietin,6 neuropeptide Y57 and adenosine receptors8 and as
inhibitors of several physiological important enzymes like cyclin-
dependant kinase,9 tyrosine kinases (in the antitumoral agent
dasatinib),10 poly (ADP-Ribose) polymerase,11 urokinase12 etc.
2-amino-1,3-thiazole is also considered as a heterocyclic bioisostere
of the phenol moiety in the widely used anti-parkinsonian agent
pramipexol13 and in morphinan derivatives.14 Due to their broad
utility in the pharmaceutical industry, the development of methods
that give quick access to diverse 2-amino-1,3-thiazole libraries
would provide additional lead molecules for drug discovery.
a solvent-free procedure thiourea, liquid aldehydes, and b-naphthol.
However, the reported condition is hardly compatible with our
second objective, i.e., telescoping two reactions (AFCR and Hantzsch
to heterocyclization) in a one-pot procedure.
This study is devoted to a tandem AFCR/Hantzsch reaction in
a one-pot procedure to quickly access polysubstituted 2-amino-1,3-
thiazoles (Scheme 1). In a first step, an electron-rich aromatic ring
(ArH 1) reacted with an aldehyde 2 and the thiourea 3 to afford
a substituted methylene thiourea 4. In a second step, the thiourea
The Hantzsch reaction of a-halocarbonyl compounds with thio-
ureas is the most commonly used method for the synthesis of
2-amino-1,3-thiazoles. However preparation of diverse mono-
substituted thiourea libraries is time consuming and is often limited
by the low solubility of compounds making them difficult to purify. In
this report, we considered adapting aza-FriedeleCrafts reaction
(AFCR) to access diverse methylene thiourea precursors, that could
react to lead to substituted 2-amino-1,3-thiazoles in a one-pot
intermediate reacted in a one-pot procedure with an
5 to lead to 2-amino-1,3-thiazole 6. Three electron-rich aromatic
rings, i.e., imidazo[1,2-a]pyridine (IP), -naphthol and indole were
a-chloroketone
b
considered as privileged structure because of their association with
a variety of biological activities.20 We were mainly interested by the
IP derivatives since some 4-(2-methylimidazo[1,2-a]pyridin-3-yl)
aminothiazoles have recently been reported as highly potent in-
hibitors of Hedgehog pathway-dependent cell proliferation.20h,i
* Corresponding author. Tel.: þ33 467668182; fax: þ33 467548654; e-mail
address: ludovic.maillard@univ-montp1.fr (L.T. Maillard).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.090

4898
G. Chaubet et al. / Tetrahedron 67 (2011) 4897e4904
However, while IP is considered as an electron-rich aromatic ring,21
no example of AFCR has been reported so far. Therefore, the first
part of this paper is dedicated to the study of the aza-FriedeleCrafts
reaction on the IP heterocycle to access imidazo[1,2-a]pyridin-3-yl
methylene thioureas. The second part deals on the synthesis of pol-
addition of 0.1 equiv TiCl4 inhibited the reaction. We assumed that
it results from a complexation of the titanium salts with the imi-
dazo[1,2-a]pyridin-3-yl methylene thiourea.
Therefore we turned out our attention on the use of Thiamine,
HCl as a promising alternative to TiCl4 for a tandem AFCR/Hantzsch
cyclization. We first controlled that Thiamine, HCl did not inhibit
the Hantzsch reaction of thiourea 4{1,1} and chloroacetone (data
ysubstituted 2-amino-1,3-thiazoles through
a tandem AFCR/
Hantzsch reactionwithout purificationof the thioureaintermediates.
O
Ar
S
Cl
R2
Ar
S
R1
NH
5{1-3}
S
+
R1CHO
ArH
+
R1
NH
NH2
N
H2N
NH2
1{1-3}
2{1-10}
3
R2
4{1-3,1-10,1-3}
6{1-3,1-10,1-3}
1{1-3}
2{1-10}
5{1-3)
O
CHO
CHO
CHO
CHO
CHO
CHO
CHO
N
Cl
1
2
1
2
1
4
5
7
CH3
N
O2N
O
Br
OH
CHO
O
Cl
2
3
8
O
9
(CH2O)n
N
Cl
NHCbz
3
6
3
10
CHO
MeO
Scheme 1. Strategy for the synthesis of polysubstituted 2-amino-1,3-thiazoles. Chemset numbering of compounds 4{x,y} and 6{x,y,z} is standardized as follows: 4{building block 1,
building block 2} and 6{building block 1, building block 2, building block 5}.
2. Results and discussion
Table 1
In order to access imidazo[1,2-a]pyridin-3-yl methylene thio-
aza-FriedeleCrafts reaction on imidazo[1,2-a]pyridine 1{1} using various reaction
conditions
ureas by aza-FriedeleCrafts reaction, we initiated our study by
subjecting 2-methylimidazo[1,2-a]pyridine 1{1}, p-bromo-benzal-
N
dehyde 2{1} and thiourea to various reaction conditions (Table 1).
Several catalysts including Brønsted acids (Table 1, entries 2 and 4)
and Lewis acids (Table 1, entries 5e12) were screened at 10 mol %.
While all tested catalysts provided the desired thiourea 4{1}, the
best results were obtained using TiCl4 (Table 1, entries 10e12). It
appeared that the reaction was highly dependent on temperature
limiting solvents to those having a boiling point higher than 100 ꢀC,
i.e., n-butanol or 1,4-dioxane (Table 1, entries 10e12). Since the
reaction was not performed in anhydrous conditions, TiCl4 could
generate hydrochloride acid. However, when using 0.4 equiv HCl as
catalyst the yield of the AFCR was decreased to 24% (data not
shown) compared to 82% yield obtained with 0.1 equiv TiCl4. This
result suggested a catalytic effect of the titanium species.
We explored the scope of the AFCR on a set of various aromatic
and aliphatic aldehydes, i.e., benzaldehyde 2{2}, o-, m-, p-tol-
ualdehyde 2{3e5}, p-anisaldehyde 2{6}, 4-nitrobenzaldehyde 2{7}
and isovaleraldehyde 2{10} with TiCl4 as catalyst. 1,4-Dioxane was
preferred to n-butanol since in this solvent several compounds
spontaneously precipitated at room temperature. Purities were
higher than 85% determined by analytical HPLC for all thiourea
derivatives. A fraction of each compound was purified by reverse
phase preparative HPLC for characterization (Table 2). Encouraged
by the results obtained from AFCRs, we turned our attention to the
Hantzsch heterocyclization. The cyclization of thiourea 4{1,1} and
chloroacetone occurred at temperature higher than 70 ꢀC in protic
solvents, i.e., ethanol or n-butanol. We were surprised that the
CH3
+
Catalyst
N
N
(0.1 equiv)
CHO
CH3
NH
1{1}
N
(1 equiv)
S
Br
2{1}
NH2
(1 equiv)
S
H2N
NH2
Br
3
4{1,1}
(1.1 equiv)
Entry
Catalyst
Solvent
T (ꢀC)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
None
None
None
p-TSA
BiCl3
AcOH
AcOH
80
117
117
117
117
117
117
117
117
80
117
105
80
120
117
117
105
24
24
24
24
3
3
3
3
3
3
3
3
24
3
3
3
3
0b
22b
22b
43b
52b
53b
31b
39b
35b
0b
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
EtOH
FeCl3
Yb(OTf)3
InCl3
9
SnCl2
TiCl4
TiCl4
10
11
12
13
14
15
16
17
n-BuOH
1,4-Dioxane
EtOH
80b
82b
0b
TiCl4
Thiamine, HCl
Thiamine, HCl
Thiamine, HCl
Thiamine, HCl
Thiamine, HCl
DMF
30b
36b
89c
80c
n-BuOH
n-BuOH
1,4-Dioxane
a
Experimental conditions: see Experimental section 4.2.
Volume of solvent 2 mL; concentration of 1{1}: 0.2 M.
Volume of solvent 0.5 mL; concentration of 1{1}: 0.8 M.
b
c

G. Chaubet et al. / Tetrahedron 67 (2011) 4897e4904
4899
Table 2
0.2 M to 0.8 M (Table 1, entries 15e16). Best results were obtained
at 0.8 M 2-methylimidazo[1,2-a]pyridine in refluxing 1,4-dioxane
or n-butanol with 10 mol % Thiamine, HCl. Although yields of AFCRs
were often lower than with TiCl4 (Table 2), Thiamine, HCl was
chosen as catalyst for the tandem AFCR/Hantzsch procedure. 2-
Methylimidazo[1,2-a]pyridine 1{1}, aldehydes and thiourea were
stirred in refluxing 1,4-dioxane with 10 mol % of Thiamine, HCl.
After 3 h stirring, the mixture was cooled down to 80 ꢀC, then
aza-FriedeleCrafts reaction of aryl and alkyl aldehydes, thiourea and imidazo[1,2-a]
pyridine 1{1}
N
Catalyst
CH
(0.1 equiv)
N
N
1,4-dioxane
105°C
CH
NH
1{1}
N
(1 equiv)
S
R1CHO
+
R1
2{1,(1-7,10)}
NH
(1 equiv)
S
H N
NH
a solution of a-chloroketone in ethanol was added. Addition of
3
4{1,(1-7,10}
ethanol as cosolvent was required for conversion of the methylene
thioureas 4{1,1e5}. Cyclizations were completed after 3.5 h leading
to 2-amino-1,3-thiazole derivatives with 37%e50% yields after
purification (Fig. 1, 6{1,1e5,1-2}).
(1.1 equiv)
Entry
1
Compound
R1
Catalyst
TiCl4
Thiamine, HCl
TiCl4
Thiamine, HCl
TiCl4
Thiamine, HCl
TiCl4
Thiamine, HCl
TiCl4
Thiamine, HCl
TiCl4
Thiamine, HCl
TiCl4
Thiamine, HCl
TiCl4
Isolated yield (%)
4{1,1}
4-BrC6H4
71
64
79
60
73
55
84
35
72
81
63
34
52
NRa
15
NRa
The procedure was tested on two more electron-rich aromatic
2
3
4
5
6
7
8
4{1,2}
4{1,3}
4{1,4}
4{1,5}
4{1,6}
4{1,7}
4{1,10}
C6H5
rings, i.e.,
b-naphtol 1{2} and N-methylindole 1{3}. A variety of
starting materials including 10 aldehydes 2{1e10} and three
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
(CH3)2CHCH2
a
-chloroketones 5{1e3} were used. With b-naphthol 1{2}, the AFCRs
occurred smoothly at 78 ꢀC using Thiamine, HCl or TiCl4. Optimiza-
tion of the experimental conditions of the all process indicated that
ethanol was the best solvent whatever the catalyst used (data not
shown). After cooling the reaction mixture to 40 ꢀC, the Hantzsch
cyclization was performed by simply adding the
a-chloroketone.
With Thiamine, HCl, three different amino-1,3-thiazole derivatives
(Fig. 1, 6{2,1,1}, 6{2,2,1}, 6{2,8,1}) were obtained in low to moderate
yields (31%e53%). This resulted from a long AFCR time (almost one
day) leading to some degradation and making compounds hard to
purify (Fig. 1, 6{2,6,1}, 6{2,7,1}). By using 10 mol % of TiCl4 instead of
Thiamine, HCl, the AFCR time was overall divided by 5 limiting
byproduct formation. The optimized procedure tolerated the use of
aromatic aldehydes, as well as paraformaldehyde (Fig.1, 6{2,9,1}) and
aliphatic aldehydes (Fig. 1, 6{2,10,1}). Such a result was unexpected
since only few examples of AFCRs with aliphatic aldehydes have been
reported so far. The presence of a p-electron donating group on
benzaldehyde led to a decrease in yield (Fig. 1, 6{2,5,1}, 6{2,6,1}),
Thiamine, HCl
a
NR: no reaction.
not shown) then we focused on its catalytic activity for the AFCRs.
Solvent, temperature and concentration effects were investigated.
Like with TiCl4, reaction was highly dependent on temperature
conditions (Table 1, entries 13e17). Reaction concentration showed
to be another crucial parameter: crude yields increased when
changing concentration of 2-methylimidazo[1,2-a]pyridine from
N
N
N
N
N
N
CH3
CH3
NH
CH3
NH
CH3
NH
CH3
NH
CH3
NH
N
N
N
N
N
N
OH
NH
OH
NH
NH
S
S
S
S
S
S
N
N
N
N
N
N
Br
N
S
N
S
Br
Br
6{1,1,1}, 43%a
6{1,2,1}, 50%a
6{1,3,1}, 42%a
6{1,4,1}, 41%a
6{1,5,1}, 41%a
6{1,1,2}
6{2,1,1}, 43%a
6{2,2,1}, 53%a
37%a
47%b
39%b
OH
NH
OH
NH
OH
NH
OH
S
OH
NH
OH
OH
OH
NH
NH
NH
NH
N
S
O
N
S
N
S
O2N
MeO
N
N
S
N
S
N
S
N
S
6{2,3,1}, 41%b
6{2,4,1}, 53%b
6{2,5,1}, 35%b
6{2,6,1}, NIa
6{2,7,1}, NIa
6{2,8,1}, 31%a
6{2,9,1}, 44%b
6{2,10,1},
31%b
65%b
NIb
56%b
N
N
N
N
N
N
OH
NH
OH
NH
OH
NH
NH
NH
NH
NH
NH
NH
O2N
S
O2N
N
S
N
S
N
S
S
N
S
S
S
S
N
N
N
N
N
O
O
Br
6{3,1,1}, 42%b
MeO
O2N
Br
HN
6{3,2,1}, 41%b
6{3,6,1}, 30%b
6{3,7,1}, 31%b
6{2,2,2}, 20%b
6{2,7,2}, 59%b
6{3,1,2}, 71%b
6{3,10,2}, 18%b
6{2,7,3},
62%b
Fig. 1. Library of polysubstituted 2-Amino-1,3-thiazoles (Isolated yield of analytically pure compounds. aMethod A: Thiamine, HCl (0.1 equiv) was used as catalyst. bMethod B: TiCl4
(0.1 equiv) was used as catalyst. NI: not isolated).

4900
G. Chaubet et al. / Tetrahedron 67 (2011) 4897e4904
while a p-electron withdrawing group increased the yield (Fig. 1, 6
{2,1,1}, 6{2,7,1}). The Hantzsch cyclization proceeded with diverse
reaction mixture was stirred for 3e24 h under reflux. Crude yield
was determined by HPLC analysis using 4-hydroxymethylbenzoate
a-
chloroketones like chloroacetone, chloroacetophenone and func-
tionalized reagents (Fig. 1, 6{2,2,2}, 6{2,7,2}, 6{2,7,3}). Finally, the
overall process was also tested on N-methylindole (Fig. 1, 6{3,x,y}).
This electron-rich aromatic ring appeared much more reactive than
as internal standard: 15 mL sample was dissolved in 4 mL methanol
containing 4-hydroxymethylbenzoate (0.1 mg/mL) as internal
standard. Crude yield was determined by quantitative HPLC titra-
tion at 254 nm relatively to the standard.
b
-naphthol and IP. Best results were obtained when performing the
AFCR in THF at 0 ꢀC using TiCl4 as catalyst. However, the formation of
4.3. Synthesis of methylene thiourea derivatives 4{1,x}
the
well-known
3,30-(arylmethylene)bis(1-methyl-1H-indole)
byproduct22 is observed in the range of 10e20% yield. The Hantzsch
cyclization was done at 70 ꢀC with ethanol as cosolvent, leading
to 2-amino-1,3-thiazole derivatives with 18%e71% yields after
purification.
To a solution of 2-methylimidazo[1,2-a]pyridine 1{1} (100 mg;
0.76 mmol) in 1,4-dioxane (1 mL) was added thiourea (64 mg;
1.1 equiv), aldehyde (1.0 equiv) and the catalyst TiCl4 or Thiamine,
HCl (0.1 equiv). The reaction mixture was stirred for 3 h at 105 ꢀC
then cooled down to room temperature. After addition of 10 mL
water, pH was adjusted to 10 by addition of 28% aqueous ammonia.
The precipitate was collected by filtration, dried and washed by
w2 mL of diethylether (purities >85% by HPLC).
3. Conclusion
We developed a new tandem procedure consisting on an aza-
FriedeleCrafts reaction and a Hantzsch cyclization to access poly-
substituted 2-amino-1,3-thiazoles from simple precursors. An
For full characterization, a fraction of each compound was dis-
solved in DMSO/TFA (5% v/v) and purified by semi-preparative re-
ꢁ
electron-rich aromatic ring, i.e., IP,
b
-naphthol or indole reacted
verse phase chromatography (RP-C18 Delta-Pak 15
m
m, 100 A,
with an aldehyde and the thiourea to afford a substituted methy-
lene thiourea intermediate that reacted in a one-pot procedure
with an a-chloroketone to lead to the desired product. To the best of
25ꢁ100 mm; solvent A, water/TFA 1&; solvent B, acetonitrile/TFA
1&; gradient, 5% solvent B to 15% in 5 min then 15%e40% solvent B
in solvent A in 30 min; flow rate, 20 mL minꢂ1).
our knowledge, this is the first time that IP was submitted to AFCRs.
While IP is considered as an aza-indole analogue, it presented some
significant differences in reactivity compared to indole. The key of
the procedure was the choice of the appropriate catalyst for the
4.3.1. N-[(4-Bromophenyl)(2-methylimidazo[1,2-a]pyridin-3-yl)
methyl]thio urea 4{1,1}. White solid. Using TiCl4 as catalyst: isolated
yield: 71%. Using Thiamine, HCl as catalyst: isolated yield: 64%. 1H
AFCR, i.e., Thiamine, HCl for IP and TiCl4 for
b
-naphthol or indole.
NMR (DMSO, 300 MHz):
d
ppm 2.17 (3H, s); 7.31 (1H, d, J¼8 Hz);
The reaction, which was simple and allowed the introduction of at
least three diversity points, has been exemplified on 25 com-
pounds. A following study will be devoted to the development of an
asymmetric version of this process.
7.32 (2H, d, J¼8.5 Hz); 7.51 (1H, td, J¼6.5, 1.5 Hz); 7.64 (2H, d,
J¼8.5 Hz); 7.90e8.00 (2H, m); 8.61 (1H, d, J¼6.5 Hz); 9.10 (1H, d,
J¼8 Hz). 13C NMR (DMSO, 75 MHz):
d ppm 10.6; 51.0; 112.3; 116.8;
118.8; 121.3; 121.5; 126.5; 129.0 (2C); 131.8 (2C); 132.3; 132.4;
136.6; 138.6; 183.1. HPLC, tR¼1.27 min. HPLC, tR¼1.18 min. LCeMS
(ESIþ): m/z 375.0, 377.0 [MþH]þ. HRMS calcd for C16H16N4BrS
375.0279, found 375.0273. FT-IR: nmax (cmꢂ1) 3301; 3055; 1673;
1529; 1449; 1397; 1357; 1199; 1176; 1128; 1024; 1006; 823; 799;
158; 719. Mp: 194.8 ꢀC.
4. Experimental section
4.1. General information
Commercially available reagents and solvents were used with-
out further purification. Reactions were monitored by HPLC using
an analytical Chromolith Speed Rod RP-C18 185 Pm column
4.3.2. N-[(2-Methylimidazo [1,2-a]pyridin-3-yl)(phenyl)methyl]thio-
urea 4{1,2}. White solid. Using TiCl4 as catalyst: isolated yield: 79%.
Using Thiamine, HCl as catalyst: isolated yield: 60%. 1H NMR
(50ꢁ4.6 mm, 5
mm) using a flow rate of 3.0 mL/min, and gradients
of 100/0 to 0/100 eluants A/B over 5 min, in which eluants A¼H2O/
0.1% TFA and BCH3CN/0.1% TFA. Detection was at 214 nm using
a Photodiode Array detector. Retention times are reported as fol-
lows: tR (min). 1H and 13C NMR spectra were recorded at room
(DMSO, 300 MHz):
d
ppm 2.19 (3H,s); 7.27 (1H, d, J¼6 Hz);
7.28e7.50 (7H, m); 7.86e7.97 (2H, m); 8.60 (1H, d, J¼5 Hz); 8.95
(1H, d, J¼6 Hz). 13C NMR (DMSO, 75 MHz):
d ppm 10.7; 51.6; 112.5;
114.9; 116.5; 121.8; 126.3; 126.8 (2C); 128.2; 128.9 (2C); 131.8;
137.0; 138.8; 183.0. HPLC, tR¼1.05 min. LCeMS (ESIþ): m/z 297.2
[MþH]þ. HRMS calcd for C16H17N4S 297.1174, found 297.1172. FT-IR:
nmax (cmꢂ1) 3290; 1672; 1623; 1568; 1529; 1418; 1193; 1130; 836;
799; 760; 748; 721. Mp: 175.3 ꢀC.
temperature in deuterated solvents. Chemical shifts (d) are given in
parts per million relative to TMS or relative to the solvent [1H:
d
(CDCl3)¼7.24 ppm; 13C:
d
(CDCl3)¼77.2 ppm]. The following ab-
breviations are used to designate the signal multiplicities: s (sin-
glet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
Analytical thin-layer chromatography (TLC) was performed using
aluminium-backed silica gel plates coated with a 0.2 mm thickness
of silica gel or with aluminium oxide 60 F254, neutral. LCeMS
spectra (ESI) were recorded on an HPLC using an analytical Chro-
4.3.3. N-[(2-Methylimidazo [1,2-a]pyridin-3-yl)(2-methylphenyl)met-
hyl] thiourea 4{1,3}. White solid. Using TiCl4 as catalyst: isolated
yield: 73%. Using Thiamine, HCl as catalyst: isolated yield: 55%. 1H
NMR (DMSO/TFA, 300 MHz):
d ppm 2.10 (3H, s); 2.28 (3H, s);
molith Speed Rod RP-C18 185 Pm column (50ꢁ4.6 mm, 5
m
m);
7.13e7.33 (5H, m); 7.55 (1H, td, J¼6.5, 1.5 Hz); 7.96 (2H, m); 8.58 (1H,
solvent A, water/HCOOH 1&; solvent B, CH3CN/HCOOH 1&; gra-
dient, 0% solvent B to 100% solvent B in solvent A in 3 min; flow
rate, 3.0 mL minꢂ1. Melting points (mp) are uncorrected and were
recorded on a capillary melting point apparatus.
d, J¼6.5 Hz); 8.87 (1H, d, J¼7.0 Hz). 13C NMR (DMSO, 75 MHz):
d ppm
13.0; 18.9; 50.9; 113.7; 115.9; 118.9; 124.9; 126.2; 126.6 (2C); 128.3;
131.2; 136.4; 137.4; 139.5; 142.6; 183.0. HPLC, tR¼0.84 min. LCeMS
(ESIþ): m/z 311.2 [MþH]þ. HRMS calcd for C17H19N4S 311.1330, found
311.1335. FT-IR: nmax (cmꢂ1) 3284; 3170; 1667; 1620; 1585; 1417;
1188; 1134; 836; 801; 751; 720. Mp: 208.6 ꢀC.
4.2. Condition screening of the aza-FriedeleCrafts reaction
on imidazo[1,2-a]pyridine 1a (Table 1)
4.3.4. N-[(2-Methylimidazo
[1,2-a]pyridin-3-yl)(3-methylphenyl)
To a solution of 2-methylimidazo[1,2-a]pyridine 1{1} (50 mg;
0.38 mmol) were added thiourea (32 mg; 1.1 equiv), p-bromo-
benzaldehyde (70 mg; 1.0 equiv) and the catalyst (0.1 equiv). The
methyl] thiourea 4{1,4}. White solid. Using TiCl4 as catalyst: isolated
yield: 84%. Using Thiamine, HCl as catalyst: isolated yield: 35%. 1H
NMR (DMSO, 300 MHz): d ppm 2.21 (3H, s); 2.31 (3H, s); 7.12e7.34

G. Chaubet et al. / Tetrahedron 67 (2011) 4897e4904
4901
(6H, m); 7.47 (1H, td, J¼6.5, 1 Hz); 7.89e7.97 (2H, m); 8.59 (1H, d,
n-hexane and evaporation of the solvent under reduce pressure
(13 Mbar, 40 ꢀC) allowed complete removal of 1,4-dioxane. The
residue was dissolved in DCM and purified by chromatography on
neutral aluminium oxide gel (30 g aluminium oxide; eluant: DCM).
J¼5 Hz); 8.95 (1H, d, J¼6 Hz). 13C NMR (DMSO, 75 MHz):
d ppm 11.1;
21.5; 52.0; 112.8; 116.9; 124.2; 126.7; 127.7; 129.2 (2C); 132.3;
132.9; 137.4; 138.7; 139.1; 183.5. HPLC, tR¼1.02 min. LCeMS (ESIþ):
m/z 311.2 [MþH]þ. HRMS calcd for C17H19N4S 311.1330, found
311.1323. FT-IR: nmax (cmꢂ1) 3282; 3178; 1672; 1621; 1575; 1416;
1199; 1134; 836; 801; 751; 720. Mp: 162.9 ꢀC.
4.4.1. N-[(4-Bromophenyl)(2-methylimidazo[1,2-a]pyridin-3-yl)
methyl]-4-methyl-1,3-thiazol-2-amine 6{1,1,1}. White solid. re-
covering mass: 136 mg; yield 43%. 1H NMR (CDCl3, 300 MHz):
d ppm
4.3.5. N-[(2-Methylimidazo
[1,2-a]pyridin-3-yl)(4-methylphenyl)
2.09 (3H, s); 2.67 (3H, s); 6.06 (1H, b); 6.21 (1H, s); 7.14e7.19 (3H, m);
7.55 (2H, d, J¼8 Hz); 7.67e7.73 (1H, ddd, J¼9, 7, 1 Hz); 8.13 (1H, dd,
methyl] thiourea 4{1,5}. White solid. Using TiCl4 as catalyst: isolated
yield: 72%. Using Thiamine, HCl as catalyst: isolated yield: 81%. 1H
J¼9, 1 Hz); 8.18 (1H, dd, J¼7, 1 Hz). 13C NMR (CDCl3, 75 MHz):
d ppm
NMR (DMSO, 300 MHz):
d
ppm 2.07 (3H, s); 2.29 (3H, s); 6.85 (1H, t,
10.9; 14.2; 54.6; 101.0; 114.2; 117.1; 117.3; 124.3; 126.6 (2C); 128.0;
131.5; 132.6 (2C); 133.3; 140.0; 141.0; 170.0. HPLC, tR¼1.13 min.
LCeMS (ESIþ): m/z 413.1, 415.1 [MþH]þ. HRMS calcd for
C19H18N4BrS 413.0436, found 413.0432. FT-IR: nmax (cmꢂ1) 3175;
2920; 1636; 1516; 1487; 1439; 1393; 1355; 1301; 1209; 1131; 1072;
1010; 827; 736. Mp: 175 ꢀC.
J¼6.5 Hz); 7.07 (2H, d, J¼8.0 Hz); 7.19 (3H, m); 7.48 (2H, d,
J¼6.5 Hz); 8.05 (1H, d, J¼6.05 Hz); 8.59 (1H, d, J¼7 Hz). 13C NMR
(DMSO, 75 MHz): d ppm 14.6; 21.0; 52.2; 112.3; 116.7; 120.0; 124.2;
124.6; 126.8; 129.7; 136.5; 137.0; 141.3; 143.8; 183.2. HPLC,
tR¼1.10 min. LCeMS (ESIþ): m/z 311.2 [MþH]þ. HRMS calcd for
C17H19N4S 311.1330, found 311.1324. FT-IR: nmax (cmꢂ1) 3280; 3180;
1672; 1618; 1575; 1200; 1134; 840; 811; 753. Mp: 190.1 ꢀC.
4.4.2. N-[(2-Methylimidazo[1,2-a]pyridin-3-yl)(phenyl)methyl]-4-
methyl-1,3-thiazol-2-amine 6{1,2,1}. White solid. m: 127 mg; yield
4.3.6. N-[(4-Methoxyphenyl)(2-methylimidazo [1,2-a]pyridin-3-yl)
methyl]thiourea 4{1,6}. White solid. Using TiCl4 as catalyst: isolated
yield: 63%. Using Thiamine, HCl as catalyst: isolated yield: 34%. 1H
50%. 1H NMR (CDCl3, 300 MHz):
d
ppm 2.09 (3H, d, J¼1.0 Hz); 2.25
(3H, s); 5.98 (1H, q, J¼1.0 Hz); 6.16 (1H, s); 6.58 (1H, td, J¼7.0,
1.5 Hz); 7.06 (1H, ddd, J¼9.0, 7.0, 1.5 Hz); 7.24e7.31 (5H, m); 7.46
(1H, dt, J¼9.0, 1.5 Hz); 7.88 (1H, td, J¼7.0, 1.5 Hz). 13C NMR (CDCl3,
NMR (DMSO, 300 MHz):
d ppm 2.23 (3H, s); 3.76 (3H, s); 6.97 (2H,
d, J¼9.0 Hz); 7.14 (1H, d, J¼5.5 Hz); 7.26 (2H, d, J¼9.0 Hz); 7.47 (1H,
75 MHz): d ppm 14.2; 17.2; 54.8; 102.2; 112.1; 117.0 (2C); 117.4;
td, J¼6.5, 1.5 Hz); 7.88e7.94 (2H, m); 8.58 (1H, d, J¼5.5 Hz); 8.85
124.0; 124.3; 126.7 (2C); 128.2; 129.1 (2C); 136.8; 137.7; 148.8.
HPLC, tR¼1.02 min. LCeMS (ESIþ): m/z 335.3 [MþH]þ. HRMS calcd
for C19H19N4S 335.1330, found 335.1331. FT-IR: nmax (cmꢂ1) 3168;
2963; 2923; 1634; 1556; 1527; 1496; 1441; 1393; 1299; 1275; 1213;
1132; 836; 754; 743; 718; 682. Mp: 166 ꢀC (dec).
(1H, d, J¼5.5 Hz). 13C NMR (DMSO, 75 MHz):
d ppm 10.7; 51.2; 55.2;
112.4; 114.1 (2C); 114.15; 114.5; 116.5; 121.9; 126.3; 128.2 (2C);
131.8; 138.6; 159.11; 183.1. HPLC, tR¼1.15 min. LCeMS (ESIþ): m/z
327.1 [MþH]þ. HRMS calcd for C17H19N4OS 327.1280, found
327.1280. FT-IR: nmax (cmꢂ1) 3358; 3296; 3183; 1671; 1622; 1566;
1513; 1434; 1256; 1205; 1177; 1131; 1034; 834; 798; 748; 722. Mp:
157.9 ꢀC.
4.4.3. N-[(2-Methylimidazo[1,2-a]pyridin-3-yl)(2-methylphenyl)
methyl]-4-methyl-1,3-thiazol-2-amine 6{1,3,1}. White solid. m:
111 mg; yield 42%. 1H NMR (CDCl3, 300 MHz):
d ppm 1.98 (3H, s);
4.3.7. N-[(4-Nitrophenyl)(2-methylimidazo[1,2-a]pyridin-3-yl)
2.09 (3H, d, J¼1.0 Hz); 2.19 (3H, s); 6.01 (1H, q, J¼1.0 Hz); 6.14 (1H,
s); 6.69 (1H, td, J¼7.0, 1.5 Hz); 7.11e7.25 (4H, m); 7.34 (1H, d,
J¼7.5 Hz); 7.50 (1H, dt, J¼9.0, 1.5 Hz); 7.95 (1H, dt, J¼7.0, 1.5 Hz). 13C
methyl]thiourea 4{1,7}. White solid. Using TiCl4 as catalyst: isolated
yield: 52%. 1H NMR (DMSO, 300 MHz):
d ppm 1.95 (3H, s); 6.89 (1H,
td, J¼6.0, 1.0 Hz); 7.23 (1H, td, J¼7.0, 1.0 Hz); 7.35 (1H, d, J¼8.0 Hz);
NMR (CDCl3, 75 MHz): d ppm 14.3; 17.4; 19.1; 53.2; 102.0; 112.5;
7.45e7.52 (3H, m); 8.09 (1H, dd, J¼6.0, 1.0 Hz); 8.21 (2H, d,
116.6; 117.1; 123.9; 124.5; 126.5; 126.6; 128.6; 131.4; 135.8; 136.8;
142.7; 144.9; 149.3; 167.7. HPLC, tR¼0.99 min. LCeMS (ESI þ): 349.1
[MþH]þ, 235.2. HRMS calcd for C20H21N4S 349.1487, found
349.1491. FT-IR: nmax (cmꢂ1) 3163; 2920; 1630; 1559; 1521; 1500;
1395; 1377; 1345; 1299; 1274; 1217; 1140; 837; 734. Mp: 201 ꢀC
(dec).
J¼9.0 Hz); 8.74 (1H, d, J¼8.0 Hz). 13C NMR (DMSO, 75 MHz):
d ppm
14.1; 51.7; 112.2; 116.1; 118.6; 123.8 (2C); 124.3; 124.7; 127.8 (2C);
140.7; 143.3; 146.8; 147.1; 183.2. HPLC, tR¼1.08 min. LCeMS (ESIþ):
m/z 342.2 [MþH]þ. HRMS calcd for C16H16N5O2S 342.1025, found
342.1024. Mp: 174.4 ꢀC.
4.3.8. N-[3-Methyl-1-(2-methylimidazo[1,2-a] pyridin-3-yl)butyl]
4.4.4. N-[(2-Methylimidazo[1,2-a]pyridin-3-yl)(3-methylphenyl)
thiourea 4{1,10}. White solid. Using TiCl4 as catalyst: isolated
methyl]-4-methyl-1,3-thiazol-2-amine 6{1,4,1}. White solid. m:
yield: 15%. 1H NMR (DMSO, 300 MHz):
d
ppm 0.94 (6H, d, J¼6.5 Hz);
109 mg; yield 41%. 1H NMR (CDCl3, 300 MHz):
d ppm 2.13 (3H, d,
1.62e1.71 (2H, m); 1.99e2.05 (1H, m); 2.57 (3H, s); 5.74 (1H, br);
7.36 (2H, br); 7.51 (1H, td, J¼6.5, 1 Hz); 7.87 (1H, m); 8.0 (1H, d,
J¼1.0 Hz); 2.27 (3H, s); 2.41 (3H, s); 6.02 (1H, q, J¼1.0 Hz); 6.14 (1H,
s); 6.63 (1H, td, J¼7.0, 1.0 Hz); 7.05e7.14 (4H, m); 7.20 (1H, d,
J¼8.0 Hz); 7.52 (1H, dt, J¼9.0, 1.0 Hz); 7.94 (1H, dt, J¼7.0, 1.0 Hz). 13C
J¼5 Hz); 8.95 (1H, d, J¼6 Hz). 13C NMR (DMSO, 75 MHz):
d ppm
10.5; 21.7; 22.5; 24.5; 40.4; 47.0; 112.1; 116.6; 123.3; 126.5; 130.5;
131.8; 138.1; 183.1. HPLC, tR¼0.94 min. LCeMS (ESIþ): m/z 277.2
[MþH]þ. HRMS calcd for C14H21N4S 277.1487, found 277.1484. FT-
IR: nmax (cmꢂ1) 3188; 29,955; 1605 (br); 1501; 1397; 1354; 1051;
734. Mp: 201.9 (dec).
NMR (CDCl3, 75 MHz): d ppm 14.2; 17.1; 21.5; 54.8; 102.2; 112.1;
116.9; 117.3; 123.6; 124.1; 124.3; 127.4; 129.0; 129.1; 137.5; 139.0;
142.8; 144.9; 148.7; 167.8. HPLC, tR¼1.03 min. HRMS calcd for
C20H21N4S 349.1487, found 349.1493. FT-IR: nmax (cmꢂ1) 3171;
2921; 1634; 1607; 1560; 1524; 1502; 1449; 1356; 1295; 1275; 1218;
1141; 1130; 785; 748; 734. Mp: 140e146 ꢀC.
4.4. Synthesis of 2-amino-1,3-thiazoles 6{1,x,y}
4.4.5. N-[(2-Methylimidazo[1,2-a]pyridin-3-yl)(4-methylphenyl)
To a solution of 2-methylimidazo[1,2-a]pyridine 1{1} (100 mg;
0.76 mmol) in 1,4-dioxane (1 mL) were added thiourea (64 mg;
1.1 equiv), aldehyde (1.0 equiv) and Thiamine, HCl (26 mg;
0.1 equiv). The reaction mixture was stirred for 3 h at 105 ꢀC then
methyl]-4-methyl-1,3-thiazol-2-amine 6{1,5,1}. White solid. m:
108 mg; yield 41%. 1H NMR (CDCl3, 300 MHz):
d ppm 2.16 (3H, d,
J¼1.0 Hz); 2.32 (3H, s); 2.34 (3H, s); 6.03 (1H, q, J¼1.0 Hz); 6.14 (1H,
s); 6.64 (1H, tt, J¼7.0, 1.5 Hz); 7.10e7.20 (6H, m); 7.52 (1H, d,
J¼9.0 Hz); 7.93 (1H, dt, J¼7.0, 1.5 Hz). 13C NMR (CDCl3, 75 MHz):
cooled down to 80 ꢀC.
A solution of a-chloromethylketone
(0.91 mmol, 1.2 equiv) in 2 mL ethanol was added. The mixture was
d ppm 14.09; 17.1; 21.1; 54.6; 102.2; 112.1; 116.8; 117.4; 124.1; 124.4;
stirred at 80 ꢀC for 3e3.5 h (monitoring by HPLC). Addition of 10 mL
126.6 (2C); 129.8 (2C); 134.5; 138.1; 142.5; 144.7; 148.6; 167.8.

4902
G. Chaubet et al. / Tetrahedron 67 (2011) 4897e4904
HPLC, tR¼1.03 min. LCeMS (ESIþ): 349.1 [MþH]þ, 235.3. HRMS
(CDCl3, 75 MHz): d ppm 17.4; 19.2; 53.5; 100.3; 117.4; 118.9; 121.9;
calcd for C20H21N4S 349.1487, found 349.1496. FT-IR: nmax (cmꢂ1
)
123.5; 125.3; 125.8; 126.6; 127.4; 128.3; 128.4; 129.2; 130.4; 132.7;
136.2 (2C); 139.9; 147.5; 167.8. LCeMS (ESIþ): m/z 361.2 [MþH]þ.
HRMS calcd for C22H21N2OS 361.1375; found 361.1371. FT-IR: nmax
(cmꢂ1) 3346; 2954; 2581; 1735; 1540; 1435; 1331; 1270; 1136; 979;
812; 728; 700. Mp: 174.3 ꢀC.
3170; 2923; 1630; 1610; 1560; 1527; 1500; 1449; 1300; 1275; 1215;
1139. Mp: 135 ꢀC (dec).
4.4.6. N-[(4-Bromophenyl)(2-methylimidazo[1,2-a]pyridin-3-yl)
methyl]-4-phenyl-1,3-thiazol-2-amine 6{1,1,2}. White solid. m:
133 mg; yield 37%. 1H NMR (CDCl3, 300 MHz):
d
ppm 2.69 (3H, s);
4.5.4. N-[(2-Hydroxynaphth-1-yl)(3-methylphenyl)methyl]-4-
6.18 (1H, s); 6.69 (s, 1H); 7.13e7.21 (4H, m); 7.45e7.49 (2H, m); 7.57
(2H, d, J¼8.0 Hz); 7.68e7.71 (3H, m); 8.13 (1H, d, J¼8 Hz); 8.25 (1H,
methyl-1,3-thiazol-2-amine 6{2,4,1}. White solid. m: 265 mg; yield
53%. 1H NMR (CDCl3, 300 MHz):
d ppm 2.21 (3H, s); 2.21 (3H, s);
d, J¼8 Hz). 13C NMR (CDCl3, 75 MHz):
d
ppm 11.1; 54.5; 100.4; 114.1;
6.00 (1H, d, J¼1.2 Hz); 6.53 (1H, s); 6.99 (1H, d, J¼6.4 Hz); 7.07e7.12
(2H, m); 7.20 (1H, s); 7.26e7.31 (2H, m); 7.38 (1H, t, J¼7.5 Hz); 7.69
(1H, d, J¼8.9 Hz); 7.76 (1H, d, J¼8.1 Hz); 7.81 (1H, d, J¼8.6 Hz). 13C
117.8; 117.9; 124.3; 126.3(2C); 126.6; 128.1(2C); 129.6; 130.3(2C);
132.1; 132.4; 133.3(2C); 135.8; 140.8; 145.2; 170.0. HPLC,
tR¼1.61 min. LCeMS (ESIþ): m/z 475.2, 477.2 [MþH]þ. HRMS calcd
NMR (CDCl3, 75 MHz):
d ppm 17.1; 21.7; 58.0; 101.2; 118.6; 118.9;
for C24H20N4BrS 475.0592, found 475.0596. FT-IR: nmax (cmꢂ1
)
122.7; 122.9; 123.8; 126.8; 127.3; 128.2; 128.6; 129.1; 129.3; 130.1;
132.7; 138.3; 140.9; 147.5; 154.6; 170.9. LCeMS (ESIþ): m/z 361.2
[MþH]þ. HRMS calcd for C22H21N2OS 361.1363; found 361.1375. FT-
IR: nmax (cmꢂ1) 3333; 2915; 2554; 1548; 1516; 1437; 1333; 1268;
1134; 1071; 983; 819; 808; 746; 695. Mp: 151.4 ꢀC.
1661; 1528; 1489; 1435; 1188; 1130; 1075; 1010; 829; 797; 747;
719. Mp: 80 ꢀC.
4.5. Synthesis of 2-amino-1,3-thiazoles 6{2,x,y}
To a suspension of
b
-naphtol (1.39 mmol, 200 mg, 1.0 equiv) in
4.5.5. N-[(2-Hydroxynaphth-1-yl)(4-methylphenyl)methyl]-4-
ethanol (2 mL) were added thiourea (3.05 mmol, 233 mg,
2.2 equiv), aldehyde (1.39 mmol, 1.0 equiv) and TiCl4 (0.139 mmol,
methyl-1,3-thiazol-2-amine 6{2,5,1}. White solid. m: 175 mg; yield
35%. 1H NMR (CDCl3, 300 MHz):
d ppm 2.22 (3H, s); 2.26 (3H, s);
15.3
m
L, 0.1 equiv). The heterogeneous mixture was stirred at 78 ꢀC
6.00 (1H, s); 6.50 (1H, s,); 7.02 (2H, d, J¼8.0 Hz); 7.26 (2H, d,
J¼8.0 Hz); 7.28e7.31 (2H, m); 7.40 (1H, t, J¼7.5 Hz); 7.69 (1H, d,
J¼8.9 Hz); 7.76 (1H, d, J¼8.0 Hz); 7.85 (1H, m). 13C NMR (CDCl3,
for 3 h. The reaction mixture was then cooled down to 40 ꢀC and
a
-
chloromethylketone (3.19 mmol, 2.3 equiv) was added and the re-
action was stirred until the complete conversion of the previous
intermediate (monitoring by HPLC). After evaporation of the sol-
vent under reduce pressure (13 Mbar, 40 ꢀC), the residue was dis-
solved in 50 mL DCM/Methanol (9/1 v/v) and extracted with
saturated sodium hydrogenocarbonate solution (3ꢁ50 mL). The
organic layer was dried over Na2SO4, filtered and the solvent is
evaporated in vacuo. The resulting crude mixture was purified by
chromatography on silica gel (DCM, 100%, then DCM/ethyl acetate,
95/5 v/v, DCM/methanol, 98/2 v/v and DCM/methanol, 95/5 v/v).
75 MHz):
d ppm 17.2; 21.2; 58.0; 101.0; 118.5; 119.7; 122.5; 122.9;
126.6 (2C); 126.9; 129.1; 129.2; 129.4 (2C); 130.0; 132.7; 136.9;
138.0; 147.5; 154.4; 171.1. LCeMS (ESIþ): m/z 361.2 [MþH]þ. HRMS
calcd for C22H21N2OS 361.1369; found 361.1375. FT-IR: nmax (cmꢂ1
)
3338; 2917; 2540; 1625; 1531; 1511; 1436; 1375; 1328; 1270; 1254;
1135; 1063; 978; 810; 742; 695. Mp: 139.1 ꢀC.
4.5.6. N-[(4-Methoxyphenyl)(2-hydroxynaphth-1-yl)methyl]-4-
methyl-1,3-thiazol-2-amine 6{2,6,1}. White solid. Using Thiamine,
HCl as catalyst: not isolated. Using TiCl4 as catalyst: m: 162 mg;
4.5.1. N-[(4-Bromophenyl)(2-hydroxynaphth-1-yl)methyl]-4-methyl-
1,3-thiazol-2-amine 6{2,1,1}. White solid. Mp: 94.2 ꢀC. Using Thia-
mine, HCl as catalyst: m: 253 mg; yield 43%. Using TiCl4 as catalyst:
yield 31%. m: 276 mg; yield 47%. 1H NMR (CDCl3, 300 MHz):
d ppm
2.22 (3H, s); 3.71 (3H, s); 6.00 (1H, s); 6.45 (1H, s); 6.75 (2H, d,
J¼9.0 Hz); 7.26e7.32 (4H, m); 7.42 (1H, t, J¼8.0 Hz); 7.69 (1H, d,
J¼9.0 Hz); 7.76 (1H, d, J¼8.0 Hz); 7.90 (1H, m). 13C NMR (CDCl3,
m: 276 mg; yield 47%.1H NMR (CDCl3, 300 MHz):
d ppm 2.21 (3H, s);
5.91 (1H, s); 6.25 (1H, s); 7.10 (1H, d, J¼8.7 Hz); 7.13e7.21 (4H, m);
7.32 (1H, t, J¼7.4 Hz); 7.48 (1H, t, J¼7.8 Hz); 7.71 (1H, d, J¼9.2 Hz);
7.79 (1H, d, J¼8.3 Hz); 7.86 (1H, d, J¼8.7 Hz). 13C NMR (CDCl3,
75 MHz): d ppm 17.2; 55.4; 58.0; 100.9; 114.0; 118.5; 119.6; 122.4;
122.9; 126.9; 128.0; 129.1; 130.0; 131.9; 132.7; 133.1; 147.4; 154.3;
158.9; 171.2. LCeMS (ESIþ): m/z 377.18 [MþH]þ. HRMS calcd for
C22H21N2O2S 377.1328; found 377.1324. FT-IR: nmax (cmꢂ1) 3357;
2916; 2537; 1609; 1508; 1437; 1246; 1175; 1030; 811. Mp: 98.1 ꢀC.
75 MHz):
d ppm 13.8; 58.9; 99.5; 114.3; 119.0; 121.0; 121.9; 123.2;
127.5; 128.3 (2C); 128.7; 129.3; 131.0; 131.7 (2C); 132.4; 137.1; 138.4;
153.4; 169.7. LCeMS (ESIþ): m/z 425.04 [MþH]þ. HRMS calcd for
C21H18N2OSBr 425.0317, found 425.0323. FT-IR: nmax (cmꢂ1) 3115;
1663; 1597; 1438; 1185; 1132; 1010; 816; 720. Mp: 94.2 ꢀC.
4.5.7. N-[(4-Nitrophenyl)(2-hydroxynaphth-1-yl)methyl]-4-methyl-
1,3-thiazol-2-amine 6{2,7,1}. White solid. Using Thiamine, HCl as
catalyst: not isolated. Using TiCl4 as catalyst: m: 353 mg; yield 65%.
4.5.2. N-[(2-Hydroxynaphth-1-yl)(phenyl)methyl]-4-methyl-1,3-
thiazol-2-amine 6{2,2,1}. White solid. Using Thiamine, HCl as cat-
alyst: m: 255 mg; yield 53%. Using TiCl4 as catalyst: m: 187 mg;
1H NMR (CDCl3, 300 MHz):
d ppm 2.26 (3H, s); 6.00 (1H, s); 6.33
(1H, s); 7.11 (1H, d, J¼8.9 Hz); 7.37 (1H, t); 7.46 (2H, d, J¼8.9 Hz);
7.54 (1H, t, J¼7.4 Hz); 7.73 (3H, d, J¼8.9 Hz); 7.82 (1H, d, J¼8.1 Hz);
yield 39%. 1H NMR (CDCl3, 300 MHz):
d
ppm 2.21 (3H, d, J¼1.0 Hz);
6.01 (1H, q, J¼1.0 Hz); 6.63 (1H, s); 7.18e7.36 (6H, m); 7.68e7.77
(3H, m). 13C NMR (CDCl3, 75 MHz):
ppm 17.1; 57.5; 101.5; 122.9;
7.91 (1H, d, J¼8.6 Hz). 13C NMR (CDCl3, 75 MHz):
d ppm 13.6; 58.4;
99.3; 114.0; 118.4; 120.2; 123.1; 123.2; 126.9; 127.6; 128.4; 129.2;
131.0; 131.9; 138.6; 145.1; 146.7; 153.0; 169.6. LCeMS (ESIþ): m/z
392.15 [MþH]þ. HRMS calcd for C21H18N3O3S 392.1067; found
392.1069. FT-IR: nmax (cmꢂ1) 2989; 1667; 1592; 1438; 1344; 1188;
1134; 828. Mp: 123.6 ꢀC.
d
123.0; 126.6; 126.7; 127.3; 127.6; 128.7; 129.2; 129.4; 129.5; 129.6;
130.2; 141.0; 147.5; 154.7; 171.3. LCeMS (ESIþ): m/z 347.18 [MþH]þ.
HRMS calcd for C21H19N2OS 347.1218; found 347.1225. FT-IR: nmax
(cmꢂ1) 3560; 2916; 2537; 1732; 1625; 1538; 1514; 1436; 1331;
1264; 1135; 1064; 1029; 978; 811; 740; 695. Mp: 115.7 ꢀC.
4.5.8. N-[(2-Hydroxynaphth-1-yl)(furanl-2-yl)methyl]-4-methyl-1,3-
thiazol-2-amine 6{2,8,1}. White solid. Using Thiamine, HCl as cat-
alyst: m: 145 mg; yield 31%. Using TiCl4 as catalyst: not isolated. 1H
4.5.3. N-[(2-Hydroxynaphth-1-yl)(2-methylphenyl)methyl]-4-
methyl-1,3-thiazol-2-amine 6{2,3,1}. White solid. m: 205 mg; yield
NMR (CDCl3, 300 MHz):
d
ppm 2.08 (3H, d, J¼0.7 Hz); 6.16 (1H, d,
41%. 1H NMR (CDCl3, 300 MHz):
d
ppm 2.04 (3H, s); 2.17 (3H, s); 6.10
J¼1.0 Hz); 6.21 (1H, d, J¼3.3 Hz); 6.37 (1H, dd, J¼3.3 Hz); 6.94 (1H,
d, J¼5.3 Hz); 7.20 (1H, d, J¼9.0 Hz); 7.26 (1H, t, J¼7.1 Hz); 7.37 (1H, t,
J¼8.1 Hz); 7.48 (1H, s); 7.76 (1H, d, J¼9.0 Hz); 7.79 (1H, d, J¼8.1 Hz);
(1H, s); 6.84 (1H, s); 7.07e7.12 (3H, m) 7.16e7.40 (4H, m); 7.72 (1H,
d, J¼8.9 Hz); 7.76 (1H, d, J¼7.8 Hz); 7.98 (1H, d, J¼8.6 Hz). 13C NMR

G. Chaubet et al. / Tetrahedron 67 (2011) 4897e4904
4903
8.04 (1H, d, J¼8.6 Hz). 13C NMR (CDCl3, 75 MHz):
d
ppm 17.2; 49.3;
1.0 equiv), aldehyde (0.76 mmol, 1.0 equiv) and finally TiCl4
(0.08 mmol, 9 L, 0.1 equiv). The heterogeneous mixture was stir-
red at 0 ꢀC for 3 h. After return to room temperature, a solution of
100.9; 106.3; 110.4; 116.7; 118.6; 122.4; 123.5; 126.1; 128.4; 128.6;
129.6; 132.3; 141.8; 147.1; 153.4; 154.7; 167.7. LCeMS (ESIþ): m/z
337.16 [MþH]þ. HRMS calcd for C19H17N2O2S 337.1011; found
337.1001. FT-IR: nmax (cmꢂ1) 3335; 2914; 2581; 1627; 1539; 1516;
1437; 1265; 1138; 1010; 812; 738; 707. Mp: 122.8 ꢀC.
m
a
-
chloromethylketone (0.91 mmol, 1.2 equiv) in 1 mL ethanol was
added. The reaction was stirred at 70 ꢀC until the complete con-
version of the previous intermediate (monitoring by HPLC). After
evaporation of the solvent under reduced pressure (13 Mbar, 40 ꢀC),
the residue was dissolved in DCM (20 mL) and washed with a so-
lution of KHSO4 1 M in water (2ꢁ20 mL). The organic layer was
dried over Na2SO4, filtered and the solvent was evaporated. The
resulting crude mixture was purified by chromatography on neutral
aluminium oxide gel (30 g aluminium oxide; eluant: DCM and then
DCM/EtOH 99/1 v/v).
4.5.9. N-[(2-Hydroxynaphth-1-yl)methyl]-4-methyl-1,3-thiazol-2-
amine 6{2,9,1}. White solid. m: 165 mg; yield 44%. 1H NMR (CDCl3,
300 MHz):
J¼4.4 Hz); 7.32 (1H, t, J¼6.8 Hz); 7.48 (1H, t, J¼6.8 Hz); 7.71e7.82
(3H, m). 13C NMR (CDCl3, 75 MHz):
ppm 16.9; 40.4; 101.4; 117.1;
d ppm 2.27 (3H, s); 4.90 (2H, s); 5.94 (1H, s); 7.24 (1H, t,
d
121.6 (2C), 123.1; 126.9; 127.9; 129.1; 130.3; 133.5; 146.9; 154.7;
169.4. LCeMS (ESIþ): m/z 271.2[MþH]þ. HRMS calcd for
C15H15N2OS 271.0897; found 271.0905. FT-IR: nmax (cmꢂ1) 3354;
2918; 2556; 1622; 1597; 1531; 1462; 1346; 1304; 1223; 1134; 1071;
1023; 841; 814; 737. Mp: 128.2 ꢀC.
4.6.1. 4-Methyl-N-[(4-bromophenyl)(1-methyl-1H-indol-3-yl)
methyl]-1,3-thiazol-2-amine 6{3,1,1}. Red solid. m: 131 mg; yield
42%; Mp: 199.3 ꢀC. 1H NMR (300 MHz, CDCl3):
d ppm 2.14 (s, 3H);
3.70 (s, 3H); 4.75 (br s, 1H); 5.61 (s, 1H;); 6.58 (s, 1H); 7.00 (ddd, 1H,
J¼8.0, 6.9, 1.2 Hz); 7.15 (d, 2H, J¼8.4 Hz); 7.22 (m, 3H); 7.27 (dd, 1H,
J¼8.0, 1.2 Hz); 7.40 (d, 2H, J¼8.4 Hz). 13C NMR (75 MHz, CDCl3):
4.5.10. N-[3-Methyl-1-(2-hydroxynapht-1-yl)butyl]thiourea 6{2,10,1}
. White solid. m: 253 mg; yield 56%. 1H NMR (CDCl3, 300 MHz):
d
ppm 0.97 (3H, d, J¼6.5 Hz); 1.06 (3H, d, J¼6.5 Hz); 1.66 (1H, m);
d ppm 15.2; 32.9; 40.2; 109.5; 117.3; 119.3; 119.8; 120.6; 122.1;
1.81 (1H, m); 2.22 (3H, s); 2.26 (1H, m); 5.17 (1H, dd, J¼4.9 Hz); 5.98
(1H, s); 7.29 (1H, t, J¼7.5 Hz); 7.35 (1H, d, J¼8.7 Hz); 7.51 (1H, t,
J¼7.5 Hz); 7.64 (1H, d, J¼8.9 Hz); 7.75 (1H, d, J¼8.1 Hz); 8.01 (1H, d,
124.9; 126.9; 128.1; 130.1(2C); 131.7 (2C); 137.6; 142.8; 143.1; 165.3.
HPLC: rt¼1.79 min. LCeMS (ESIþ): m/z 412.1 [MþH]þ, 414.1
[MþHþ2]þ. HRMS calcd for C20H19BrN3Sþ: 412.0483, found
412.091. FT-IR: nmax (cmꢂ1) 3435; 3254; 3056; 2920; 1614; 1523;
1485; 1329; 1261; 1106; 1070; 1010; 799; 760. Mp: 199.3 ꢀC.
J¼8.7 Hz). 13C NMR (CDCl3, 75 MHz):
d ppm 17.1; 22.5; 23.7; 25.4;
43.9; 55.5; 100.2; 118.8; 119.5; 121.4; 122.7; 126.9; 128.5; 129.0;
129.2; 132.6; 147.35; 154.2; 172.5. LCeMS (ESIþ): m/z 327.3 [MþH]þ.
HRMS calcd for C19H23N2OS 327.1533; found 327.1531. FT-IR: nmax
(cmꢂ1) 3336; 2955; 2867; 2540; 1740; 1628; 1542; 1436; 1330;
1258; 1062; 978; 809; 743; 697. Mp: 140.6 ꢀC.
4.6.2. 4-Methyl-N-[(1-methyl-1H-indol-3-yl)(phenyl)methyl]-1,3-
thiazol-2-amine 6{3,2,1}. Orange solid. m: 104 mg; yield 41%. 1H
NMR (300 MHz, CDCl3):
1H); 5.66 (s, 1H); 6.59 (s, 1H); 6.99 (dd, 1H, J¼7.9, 7.0 Hz); 7.16e7.30
(m, 9H). 13C NMR (75 MHz, CDCl3):
ppm 15.2; 32.8; 40.8; 109.4;
d ppm 2.15 (s, 3H); 3.69 (s, 3H); 4.72 (br s,
4.5.11. N-[(2-Hydroxynaphth-1-yl)(phenyl)methyl]
thiazol-2-amine 6{2,2,2}. White solid. m: 113 mg; yield 20% 1H NMR
(CDCl3, 300 MHz): ppm 6.62 (1H, s); 6.62 (1H, s); 7.01 (1H, d,
-4-phenyl-1,3-
d
117.9; 119.1; 119.9; 121.9; 125.7; 126.7; 127.2; 128.1; 128.3 (2C);
128.6 (2C); 137.5; 142.8; 143.7; 165.2. HPLC: rt¼1.61 min. LCeMS
(ESIþ): m/z 334.2 [MþH]þ. HRMS calcd for C20H20N3Sþ 334.1378,
found 334.1372. FT-IR: nmax (cmꢂ1) 3425; 3269; 3057; 2919; 1624;
1523; 1327; 1229; 1113; 910; 790; 760. Mp: 184.8 ꢀC (dec).
d
J¼8.9 Hz); 7.22e7.38 (8H, m); 7.40e7.50 (2H, m); 7.54 (1H, d,
J¼9.0 Hz); 7.60 (2H, dd, J¼7.0 Hz); 7.73 (1H, d, J¼7.9 Hz); 7.95 (1H, d,
J¼9.0 Hz). 13C NMR (CDCl3, 75 MHz):
d ppm 58.4; 101.4; 118.5; 119.7;
122.3; 123.0; 126.4; 126.8; 127.0; 127.5; 128.2; 128.7; 128.8; 129.1;
129.1; 130.1; 132.5; 134.1; 140.9; 150.7; 154.0; 171.5. LCeMS (ESIþ):
m/z 409.20 [MþH]þ. HRMS calcd for C26H21N2OS 409.1375; found
409.1368. FT-IR: nmax (cmꢂ1) 3331; 3060; 1544; 1516; 1436; 1267;
1252; 1049; 1026; 950; 906; 807; 738; 707; 696. Mp: 125.4 ꢀC.
4.6.3. 4-Methyl-N-[(1-methyl-1H-indol-3-yl)(4-methoxyphenyl)
methyl]-1,3-thiazol-2-amine 6{3,6,1}. Red solid. m: 83 mg; yield
30%. 1H NMR (300 MHz, CDCl3):
d ppm 2.15 (s, 3H); 3.69 (s, 3H);
3.77 (s, 3H); 4.78 (br s, 1H); 5.61 (s, 1H); 6.59 (s, 1H); 6.82 (d, 1H,
J¼8.7 Hz); 6.99 (t, 1H, J¼7.8 Hz); 7.22 (m, 6H). 13C NMR (75 MHz,
4.5.12. N-[(4-Nitrophenyl)(2-hydroxynaphth-1-yl)methyl]-4-phenyl-
CDCl3): d ppm 15.2; 32.8; 40.0; 55.4; 109.3; 113.9 (2C); 118.2; 119.1;
1,3-thiazol-2-amine 6{2,7,2}. White solid. m: 371 mg; yield 59%. 1H
120.0; 121.9; 126.1; 127.1; 128.1; 129.3 (2C); 136.0; 137.6; 142.5;
158.4; 165.2. HPLC: tR¼1.78 min. LCeMS (ESIþ): m/z 364.1 [MþH]þ.
HRMS calcd for C21H22N3OSþ 364.1484, found 364.1494. FT-IR: nmax
(cmꢂ1) 3425; 2930; 1608; 1507; 1463; 1327; 1243; 1175; 1108;
1029; 907; 803; 760. Mp: 68.2 ꢀC.
NMR (DMSO-d6; 300 MHz):
d
ppm 5.78 (1H, br); 7.10e8.61 (17H,
ppm 53.3; 102.2; 118.4; 122.6;
m). 13C NMR (DMSO-d6; 75 MHz):
d
123.3 (2C); 123.4; 124.1; 125.6 (2C); 127.2; 127.3 (2C); 128.1; 128.4
(2C); 128.5; 128.6; 128.7; 129.9; 134.7; 145.9; 149.4; 151.3; 153.2;
167.7. LCeMS (ESIþ): m/z 454.10 [MþH]þ. HRMS calcd for
C26H20N3O3S 454.1225; found 454.1221. FT-IR: nmax (cmꢂ1) 3298;
3106; 3062; 2527; 1625; 1598; 1510; 1318; 1246; 1165; 1050; 825;
810; 721; 685. Mp: 199.7 ꢀC.
4.6.4. 4-Methyl-N-[(1-methyl-1H-indol-3-yl)(4-nitrophenyl)
methyl]-1,3-thiazol-2-amine 6{3,7,1}. Yellow solid. m: 89 mg; yield
31%. 1H NMR (300 MHz, CDCl3):
d ppm 2.17 (s, 3H); 3.74 (s, 3H); 4.86
(br s, 1H); 5.78 (s, 1H); 6.62 (s, 1H); 7.03 (dd, 1H, J¼8.0, 7.0 Hz); 7.22
4.5.13. Compound 6{2,7,3}. Mixture of diastereoisomers. m:
(m, 3H); 7.46 (d, 2H, J¼8.7 Hz); 8.16 (d, 2H, J¼8.7 Hz). 13C NMR
543 mg; yield 62%. 1H NMR (CDCl3, 300 MHz):
d
ppm 2.89 (2H, m);
(75 MHz, CDCl3): d ppm 15.2; 33.0; 40.7; 109.7 (2C); 116.4; 119.6
4.73e5.02 (4H, m); 5.87 (1H, d, J¼11 Hz); 6.78e7.95 (21H, m).
LCeMS (ESIþ): m/z 631.2 [MþH]þ. HRMS calcd for C36H31N4O5S
631.2015; found 631.2010. FT-IR: nmax (cmꢂ1) 3322; 3029; 1694;
1627; 1599; 151; 14,154; 1438; 1343; 1229; 1110; 1079; 1028; 852;
817; 739; 696.
(2C); 122.4; 126.6; 123.9; 126.7; 127.1; 128.1; 129.2 (2C); 137.6;
143.6; 151.2; 165.6. HPLC: rt¼1.67 min. LCeMS (ESIþ): m/z 379.2
[MþH]þ. HRMS calcd for C20H19N4O2Sþþ 379.1229, found 379.1221.
FT-IR: nmax (cmꢂ1) 3432; 3259; 3072; 2925; 1618; 1593; 1511; 1342;
1262; 1108; 1013; 858; 823; 798; 750. Mp: 198.2 ꢀC (dec).
4.6. Synthesis of 2-amino-1,3-thiazoles 6{3,x,y}
4.6.5. N-[3-Methyl-1-(1-methyl-1H-indol-3-yl)butyl]-4-phenyl-1,3-
thiazol-2-amine 6{3,10,2}. Yellow solid. m: 52 mg; yield 18%. 1H
To a solution of N-methylindole (0.76 mmol, 100 mg, 96
mL) in
NMR (300 MHz, CDCl3):
J¼6.4 Hz); 1.50 (m, 2H); 1.64 (m, 1H); 3.59 (s, 3H); 4.45 (t, 1H,
d
ppm 0.63 (d, 3H, J¼6.4 Hz); 0.72 (d, 3H,
THF (1 mL) at 0 ꢀC were added thiourea (0.76 mmol, 58 mg,

4904
G. Chaubet et al. / Tetrahedron 67 (2011) 4897e4904
8. (a) van Tilburg, E. W.; van der Klein, P. A. M.; de Groote, M.; Beukers, M. W.;
J¼7.3 Hz); 6.91 (s, 1H); 6.99 (t, 1H, J¼6.8 Hz); 7.19 (m, 6H); 7.33 (m,
2H); 9.39 (br s, 1H). 13C NMR (75 MHz, CDCl3):
ppm 22.1; 22.8;
Ijzerman, A. P. Bioorg. Med. Chem. Lett. 2001, 11, 2017e2019; (b) van Muijlwijk-
d
€
Koezen, J. E.; Timmerman, H.; Vollinga, R. C.; Frijtag von Drabbe Kunzel, J.; de
25.8; 32.4; 32.8; 47.2; 109.6; 116.7; 118.8; 119.2; 121.9; 125.3; 126.4;
126.7; 128.6 (2C); 128.9 (2C); 129.0; 129.2; 139.9; 137.2; 168.6.
HPLC: rt¼1.68 min. LCeMS (ESIþ): m/z 376.2 [MþH]þ. HRMS calcd
for C23H26N3Sþ 376.1847, found 376.1849. FT-IR: nmax (cmꢂ1) 2954;
1601; 1466; 1367; 1330; 1085; 907; 771; 750. Mp: 154.0 ꢀC.
Groote, M.; Visser, S.; Ijzerman, A. P. J. Med. Chem. 2001, 44, 749e762.
9. Kim, K. S.; Kimball, S. D.; Misra, R. N.; Rawlins, D. B.; Hunt, J. T.; Xiao, H.-Y.; Lu,
S.; Qian, L.; Han, W.-C.; Shan, W.; Mitt, T.; Cai, Z.-W.; Poss, M. A.; Zhu, H.; Sack, J.
S.; Tokarski, J. S.; Chang, C. Y.; Pavletich, N.; Kamath, A.; Humphreys, W. G.;
Marathe, P.; Bursuker, I.; Kellar, K. A.; Roongta, U.; Batorsky, R.; Mulheron, J. G.;
Bol, D.; Fairchild, C. R.; Lee, F. Y.; Webster, K. R. J. Med. Chem. 2002, 45,
3905e3927.
10. (a) Borzilleri, R. M.; Bhide, R. S.; Barrish, J. C.; D’Arienzo, C. J.; Derbin, G. M.;
Fargnoli, J.; Hunt, J. T.; Jeyaseelan, R.; Kamath, A.; Kukral, D. W.; Marathe, P.;
Mortillo, S.; Qian, L.; Tokarski, J. S.; Wautlet, B. S.; Zheng, X.; Lombardo, L. J. J.
Med. Chem. 2006, 49, 3766e3769; (b) Das, J.; Chen, P.; Norris, D.; Padmanabha,
R.; Lin, J.; Moquin, R. V.; Shen, Z.; Cook, L. S.; Doweyko, A. M.; Pitt, S.; Pang, S.;
Shen, D. R.; Fang, Q.; de Fex, H. F.; McIntyre, K. W.; Shuster, D. J.; Gillooly, K. M.;
Behnia, K.; Schieven, G. L.; Wityak, J.; Barrish, J. C. J. Med. Chem. 2006, 49,
6819e6832.
11. Zhang, W. T.; Ruan, J. L.; Wu, P. F.; Jiang, F. C.; Zhang, L. N.; Fang, W.; Chen, X. L.;
Wang, Y.; Cao, B. S.; Chen, G. Y.; Zhu, Y. J.; Gu, J.; Chen, J. G. J. Med. Chem. 2009,
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12. Wilson, K. J.; Illig, C. R.; Subasinghe, N.; Hoffman, J. B.; Rudolph, M. J.; Soll, R.;
Molloy, C. J.; Bone, R.; Green, D.; Randall, T.; Zhang, M.; Lewandowski, F. A.;
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4.6.6. 4-Phenyl-N-[(4-bromophenyl)(1-methyl-1H-indol-3-yl)
methyl]-1,3-thiazol-2-amine 6{3,1,2}. White solid. m: 255 mg; yield
71%. 1H NMR (300 MHz, CDCl3):
d ppm 3.71 (s, 3H); 5.16 (br s, 1H);
5.80 (s, 1H); 6.71 (s, 1H); 6.97 (t, 1H, J¼7.3 Hz); 7.08 (d, 1H,
J¼7.8 Hz); 7.17 (d, 2H, J¼8.4 Hz,); 7.20 (dd, 1H, J¼7.8, 7.3 Hz);
7.30(m, 4H); 7.40 (d, 2H, J¼8.4 Hz); 7.50 (m, 2H). 13C NMR (75 MHz,
CDCl3):
d ppm 32.9; 40.9; 109.4; 117.8; 119.3; 119.9; 120.7; 122.1;
126.8; 126.8; 127.8; 128.3; 128.5 (2C); 128.6 (2C); 130.1 (2C); 131.7
(2C); 135.1; 137.6; 143.2; 146.4; 165.9. HPLC: rt¼1.98 min. LCeMS
(ESIþ): m/z 474.0 [MþH]þ, 476.0 [MþHþ2]þ. HRMS calcd for
C25H21BrN3Sþ 474.0640, found 474.0631. FT-IR: nmax (cmꢂ1) 3420;
3115; 2926; 1613; 1525; 1484; 1329; 1068; 1009; 854; 818; 801;
770; 750; 701. Mp: 211.2 ꢀC (dec).
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Acknowledgements
The authors are grateful to L. Bendjeddou and V. Martin. They
thank the IBMM for support.
Supplementary data
Analytical data including NMR data and spectra for all reported
thioureas 4 and polysubstituted 2-amino-1,3-thiazoles 6. Supple-
mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2011.04.090.
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