Microwave-assisted synthesis of novel N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides inspired by marine topsentines and nortopsentines

Article abstract of DOI:10.1016/j.tet.2014.06.102

We report the synthesis of novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides, which were inspired by marine topsentines and nortopsentines. Condensation of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) with various ortho-halogenated anilines, aminopyridines and aminophenols gave the corresponding aryliminodithiazoles in good to excellent yields. Copper(I)-mediated or nucleophilic-assisted cyclization of aryliminodithiazoles furnished cyano-functionalized benzo[d]thiazoles, thiazolo[4,5-b]- and thiazolo[5,4-b]-pyridines and benzo[d]oxazoles. The latter were condensed with substituted 4-phenylthiazol-2-amines to furnish twenty seven new polyaromatic carboximidamides in moderate to good yields.

Full text of DOI:10.1016/j.tet.2014.06.102

Tetrahedron xxx (2014) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted synthesis of novel N-(4-phenylthiazol-2-yl)-
benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine-
and benzo[d]oxazole-2-carboximidamides inspired by marine
topsentines and nortopsentines
*
Emmanuel Deau, Carole Dubouilh-Benard, Vincent Levacher, Thierry Besson
^
ꢀ
Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Batiment IRCOF, 1 rue Tesniere, 76821 Mont St Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the synthesis of novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]
pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides, which were inspired by
marine topsentines and nortopsentines. Condensation of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel
salt) with various ortho-halogenated anilines, aminopyridines and aminophenols gave the corresponding
aryliminodithiazoles in good to excellent yields. Copper(I)-mediated or nucleophilic-assisted cyclization
of aryliminodithiazoles furnished cyano-functionalized benzo[d]thiazoles, thiazolo[4,5-b]- and thiazolo
[5,4-b]-pyridines and benzo[d]oxazoles. The latter were condensed with substituted 4-phenylthiazol-2-
amines to furnish twenty seven new polyaromatic carboximidamides in moderate to good yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 19 May 2014
Received in revised form 23 June 2014
Accepted 25 June 2014
Available online xxx
Keywords:
Benzo[d]thiazoles
Thiazolopyridines
Benzo[d]oxazoles
Microwave-assisted chemistry
Copper-mediated cyclisation
1. Introduction
sponges, which have received attention of various research groups
because of their potent biological activities.5
The occurrence and properties of the thiazolic ring in various
natural and synthetic products has been the interest of many re-
search groups on account of its useful biological properties.1
Ten years ago our laboratory launched a research program
dealing with the preparation and pharmacological evaluation of
original heterocyclic derivatives bearing a thiazole ring.2
In this context, the reactivity of 4,5-dichloro-1,2,3-dithiazolium
chloride (Appel salt)3 has been extensively studied for the synthesis
of nitrile-bearing benzothiazoles with applications in the synthesis
of functionalized heterocyclic systems.4 To broaden the scope of our
investigations on the synthesis of new molecules able to modulate
the activity of kinases in signal transduction, we decided to explore
the syntheses of benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thia-
zolo[5,4-b]pyridine-, benzo[d]oxazole-2-carbonitriles and their
reactivity towards aromatic amines to access original hetero-
aromatic carboximidamides (Fig. 1). The design of these novel tris-
aromatic structures was largely inspired by topsentines and nor-
topsentines, two bisindoles alkaloids found in several marine
Fig. 1. Structures of marine alkaloids topsentines and nortopsentines, which inspired
the current work on the synthesis of novel benzo[d]thiazole-, thiazolo[4,5-b]pyridine-,
thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides.
This paper relates the development of a reliable synthetic route
allowing access to novel benzo[d]thiazole-, thiazolo[4,5-b]
* Corresponding author. Tel.: þ33 (0) 2 3552 2904; fax: þ33 (0) 2 3552 2962;
e-mail address: thierry.besson@univ-rouen.fr (T. Besson).
http://dx.doi.org/10.1016/j.tet.2014.06.102
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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2
E. Deau et al. / Tetrahedron xxx (2014) 1e9
Table 1
pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]-oxazole-2-
carboximidamides. Most of the chemistry performed in this study
was achieved under microwave irradiation as a continuation of our
global strategy, which consists of developing reactants and tech-
niques offering operational, economic and environmental benefits
over conventional methods.6
Synthesis of ortho-halogenated N-aryliminodithiazoles 1e6
Entry
Product
Hal
X
Y
R1
Yield (%)a
2. Results/discussion
1
2
3
4
5
6
1
2
3
4
5
6
Br
Cl
Br
Cl
Br
Br
CH
CH
CH
N
N
CH
CH
CH
CH
CH
CH
N
H
H
Br
H
H
H
97
98
96
85
87
45
In order to synthesize the desired carboximidamides, we con-
sidered the synthesis from simple commercially available com-
pounds. The general retrosynthetic route depicted in Scheme 1 is
based on previous work on the synthesis of carbonitrile-bearing
benzo[d]thiazoles3b and benzo[d]oxazoles2b and was extended to
novel thiazolo[4,5-b]pyridines and thiazolo[5,4- b]pyridines. Het-
erocyclic carboximidamides (I) would be obtained by the final
condensation of substituted benzo[d]thiazole-, thiazolo[4,5-b]pyr-
idine-, thiazolo[5,4-b]pyridine-, or benzo[d]oxazole-2-carbonitriles
(II) on substituted 4-phenylthiazol-2-amines (III). 4-Phenylthiazol-
2-amines would be synthesized by Hantzsch condensation of
a
Isolated yield.
Once the ortho-halogenated N-aryliminodithiazoles were iso-
lated, they were converted and cyclized into benzothiazoles and
thiazolopyridines in copper-catalyzed conditions.7 Microwave-
assisted irradiation of ortho-halogenated aryliminodithiazoles in
the presence of copper(I) iodide in refluxing pyridine provided
substituted benzo[d]thiazole-, thiazolo [4,5-b]-pyridine, thiazolo
[5,4-b] pyridine-2-carbonitriles 7e9 in moderate to good yields
(Table 2).
thiourea and substituted a-brominated acetophenones (IV). Thia-
zolo- and oxazolo-2-carbonitriles would be isolated after copper(I)-
mediated cyclisation of ortho-halogenated N-aryliminodithiazoles
and nucleophilic cyclization of ortho-hydroxylated N-arylimino-
1,2,3-dithiazoles (V), respectively. Condensation of 4,5-dichloro-
1,2,3-dithiazolium chloride (Appel salt) with various ortho-
substituted anilines and aminopyridines (VI) would provide ac-
cess to the desired N-aryliminodithiazoles.
Table 2 highlights several important results regarding this
copper(I)-mediated cyclization. Comparison of the results estab-
lishes that the use of ortho-brominated N-aryliminodithiazoles
Scheme 1. General retrosynthetic pathway and access to novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine-, benzo[d]
oxazole-2-carboximidamides.
Appel salt was readily synthesized from chloroacetonitrile and
sulfur monochloride in multigram scale and stored on the bench
away from light for months without apparent degradation.3 In or-
der to synthesize benzo[d]thiazole-, thiazolo[4,5-b]pyridine- and
thiazolo[5,4-b]pyridine-2-carbonitriles, we initially carried out the
synthesis of the corresponding ortho-halogenated N-aryliminodi-
thiazoles 1e6.
Condensation of electrophilic Appel salt with various ortho-
haloanilines and aminopyridines in methylene chloride at room
temperature followed by addition of pyridine gave the expected N-
arylimino-1,2,3-dithiazoles 1e6 in good yields (Table 1).
Under the same operating conditions, most aryliminodithia-
zoles are obtained in good to excellent yields except in the case of
compound 6. In this last case, the relative position of the aromatic
nitrogen atom and the deactivated amine function lead to a de-
creased nucleophilicity of 3-bromopyridin-2-amine thus prevent-
ing an effective condensation with Appel salt. On the other hand,
the choice of the halogen atom does not have any influence on the
condensation.
(Entries 1, 2, 4 and 5) had a beneficial effect on the copper(I)-
mediated cyclisation compared to ortho-chlorinated N-arylimino-
dithiazoles. Depending on the position the halogen atom, the pyr-
idine moiety had a significant effect on the copper(I)-mediated
cyclization. Indeed, the nitrogen atom had a favourable effect on
the cyclization when the halogen atom is located at position C2
(Entries 4 and 5), indicating that the electron-deficient carbon-
ehalogen bond assisted the cyclization process. However, the ni-
trogen atom had a deleterious effect on the cyclization when the
halogen atom is positioned at C3 (Entry 6 and 7) suggesting that the
electron-enriched carbonehalogen bond disfavoured the cycliza-
tion of 6 into thiazolo[5,4-b]pyridine-2-carbonitrile 10. In fact, the
complete conversion of 6 into 10 could only be achieved by mi-
crowave irradiation in sealed vials at a higher temperature (Entry
7). Attempts to run the same reaction by microwave irradiation at
atmospheric pressure significantly decreased the cyclization yield
of 6 into 10 and unknown by-products were observed (Entry 6).
In order to increase chemodiversity of the final topsentines and
nortopsentines analogues, benzo[d]oxazole-2-carbonitriles 13 and
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E. Deau et al. / Tetrahedron xxx (2014) 1e9
3
Table 2
Detailed conditions and yields for microwave-assisted copper(I)-mediated cyclisation of ortho-halogenated N-aryliminodithiazoles 1e6 into benzo[d]thiazole-2-carbonitriles
7 and 8, thiazolo[4,5-b]pyridine-2-carbonitrile 9 and thiazolo[5,4-b]pyridine-2-carbonitrile 10
Entry
Starting material
Hal
X
Y
R1
Conditionsa
Product
X
Y
R1
Yield (%)b
1
2
3
4
5
6
7
1
2
3
4
5
6
6
Br
Cl
Br
Cl
Br
Br
Br
CH
CH
CH
N
N
CH
CH
CH
CH
CH
CH
CH
N
H
H
Br
H
H
H
H
115 ꢀC, 30 min, CuI (1 equiv), py
115 ꢀC, 30 min, CuI (1 equiv), py
115 ꢀC, 30 min, CuI (1 equiv), py
115 ꢀC, 30 min, CuI (1 equiv), py
115 ꢀC, 30 min, CuI (1 equiv), py
115 ꢀC, 6 h, CuI (2e4 equiv), pye
130 ꢀC, 1h, CuI (1 equiv), py
7
7
8
9
9
10
10
CH
CH
CH
N
N
CH
CH
CH
CH
CH
CH
CH
N
H
H
Br
H
H
H
H
43
dc
63
31d
72
25e30
45
N
N
a
Entry 1e5 and 6: reactions were conducted in a microwave oven at atmospheric pressure (RotoSYNTHÔ). Entry 7: reaction was conducted in a microwave oven in a sealed
tube (Anton Paar Monowave 300Ô). For details on experimental conditions, see Experimental section/Supplementary data.
b
Isolated yield.
Degradation of starting material.
c
d
The major by-product of this reaction was the 2-chloro-3-isothiocyanatopyridine derived from 4.
In the first trial, another equiv of CuI was added after 3 h of heating; the second experiment was started with 2 equiv of CuI, and 2 equiv were also added after 3 h of
e
irradiation.
14 were synthesized starting from aminophenols with modest
20e61% overall yields (Scheme 2). Condensation of Appel salt with
aminophenols under the same conditions as those described above
provided thermosensitive ortho-hydroxylated aryliminodithiazoles
11 (76% yield) and 12 (not isolated), which quickly cyclized in
refluxing toluene into benzo[d]oxazole-2-carbonitriles 138 and 14,
upon loss of sulfur and hydrogen chloride (Scheme 2).
Different strategies were implemented to effectively perform
the condensation of the newly synthesized heteroaromatic car-
bonitriles 7e10 with substituted 4-phenylthiazole-2-amines
15e18: activation of the carbonitrile function (AlCl3, THF, micro-
wave), activation of the amine function (NaH, DMF, then addition of
carbonitrile), or direct microwave-assisted high-temperature con-
densation. Among these three methods, the last one gave the best
Scheme 2. Synthesis of benzo[d]oxazole-2-carbonitriles 13e14 using 4,5-dichloro-1,2,3-dithiazolium chloride and aminophenols.
The reactivity of aromatic carbonitriles 7e10 and 13e14 was
tested against aromatic substituted 4-phenylthiazol-2-amines
15e18 in order to get a new set of carboximidamides 19e45 with
a potential biological activity. In addition to our wish to find novel
inhibitors of kinases that include thiazole, it may be noted that
recent studies have shown the importance of tris-aromatic struc-
tures with a thiazole moiety in various biological activities, in-
cluding antibacterial, antimicrobial, anti-oxidant, anti-fungal and
antiproliferative.9
results: microwave irradiation of the carbonitrile and the amine
under pressure in DMF for at least 3 h at 180 ꢀC gave the desired
substituted
carboximidamides (19e28), thiazolo[4,5-b]pyridines (29e33),
thiazolo[5,4-b]pyridine- (34e35), benzo[d]oxazole-2-
N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-2-
carboximidamides (36e45) in moderate to satisfactory yields
(Table 4).
The lack of structureeactivity relationship features among the
studied 4-phenyl-thiazol-2-amines 15e18 prompted us to employ
the Topliss scheme for selecting the substitution patterns on the
aromatic substituent of these heterocyclic amines.11 In the case of
Table 3
Yields for the microwave-assisted synthesis of substituted 4-phenylthiazol-2-
amines 15e18 using thiourea and a
-brominated acetophenones10
our study, four substituted
a-bromoacetophenones were chosen
according to Topliss diagram (Table 3) so as to check the interest of
our methodology, while starting building a short list of molecules
with potential biological interest. Although there were only few
commercially available compounds, the synthesis of these hetero-
aromatic amines proved to be very straightforward thanks to an
optimization under microwave. Irradiating a mixture of thiourea
Product
R2
Yield (%)a
15
16
17
18
H
90
91
91
89
4-OMe
4-Cl
2,4-diCl
and substituted
a-bromoacetophenone, in ethanol for 15 min
provided 4-phenylthiazole-2-amines 15e18 in excellent yields
(Table 3).
a
Isolated yield.
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4
E. Deau et al. / Tetrahedron xxx (2014) 1e9
Table 4
Detailed conditions and yields for the microwave-assisted synthesis of novel substituted N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]
pyridine-, benzo[d]oxazole-2-carboximidamides 19e45a
Starting materiala
W
X
Y
R1
R2
Product
Yield (%)b
7
7
7
7
7
8
8
8
8
8
9
9
9
9
9
10
10
13
13
13
13
13
14
14
14
14
14
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
H
H
H
H
H
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
80
72
44
40
50
73
74
82
65
33
56
39
63
38
47
58
77
56
39
63
38
47
56
51
52
44
42
4-Me
4-OMe
4-Cl
2,4-diCl
H
4-Me
4-OMe
4-Cl
2,4-diCl
H
4-Me
4-OMe
4-Cl
2,4-diCl
4-Me
4-OMe
H
4-Me
4-OMe
4-Cl
2,4-diCl
H
H
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
N
N
N
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
S
N
O
O
O
O
O
O
O
O
O
O
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
Br
Br
Br
Br
Br
4-Me
4-OMe
4-Cl
2,4-diCl
a
All reactions were conducted in a microwave oven in a sealed tube (Anton Paar Monowave 300Ô). For details on experimental conditions, see Experimental section/
Supplementary data.
b
Isolated yield.
Biological experiments were performed in order to evaluate the
capacity of the tris-aromatic compounds 19e45 to inhibit a panel of
Ser/Thr and Tyr kinases, which are considered as relevant thera-
peutic targets.12 Unfortunately, whatever the kinase tested, none of
the twenty-seven tested molecules showed a significant effect on
enzymes activity.
Some comments can be made concerning the microwave
procedure as well as the technical and practical aspects. In the
case of the microwave-assisted synthesis, DMF and pyridine
offer the advantage of having good dielectric properties, thus
enabling an efficient heating of the reaction mixture.13 Cop-
per(I)-mediated cyclizations were carried out at atmospheric
pressure on a RotoSYNTHÔ (Milestone S.r.l. Italy), a multimode
cavity, with temperature and power control (except in the case
of 10). Carboximidamides syntheses were performed in sealed
vials in a Monowave 300Ô single-mode reactor (Anton Paar
GmbH, Graz, Austria) under temperature control mode and not
in constant power mode. Temperature was monitored via
contactless-infrared pyrometer, which was calibrated by control
pyridine- (29e33), thiazolo[5,4-b]pyridine- (34, 35) and benzo[d]
oxazole-2-carboximidamide derivatives (36e45) was described.
Appel salt proved to be an effective reagent for the synthesis of
various benzo[d]thiazole-, thiazolo[4,5- or 5,4-b]pyridine- and
benzo[d]oxazole-2-carbonitriles. A study established that the rel-
ative position of the nitrogen and the nature of the halogen atom of
ortho-halogenated aryliminodithiazoles (e.g., 1e6) had an impor-
tant influence on the performance of the copper(I)-assisted
cyclization.
Although Ser/Thr and Tyr kinases have not shown a relevant
affinity for these novel compounds, work is underway to screen the
carboximamides on new biological targets in order to conceive new
useful heterocycles with potential therapeutic applications.
4. Experimental section
4.1. General methods
All reactions were carried out under inert atmosphere of argon
or nitrogen and monitored by thin-layer chromatography with
silica gel 60 F254 pre-coated aluminium plates (0.25 mm). Visual-
ization was performed with a UV light at 254 and 312 nm.
Purifications were carried out on an Armen Instrument Spot 2
Flash System equipped with a dual UVevis spectrophotometer
(200e600 nm), a fraction collector (192 tubes), a dual piston pump
(1e250 mL/min, Pmax¼35 bar/508 psi) allowing quaternary gradi-
ents and an additional inlet for air purge. Samples can be injected in
liquid or solid mode. Purification was edited and monitored on an
integrated panel PC with a touch screen controlled by Armen Glider
experiments
thermometer).
with
a
fiber-optic
thermometer
(Ruby
3. Conclusion
In conclusion, this synthetic work allowed the preparation of
a large range of valuable functionalized heterocyclic scaffolds in
a straightforward and sustainable manner. Thus, the efficient
microwave-assisted synthesis of novel substituted N-(4-
phenylthiazol-2-yl)benzo[d]thiazole- (19e28), thiazolo[4,5-b]
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E. Deau et al. / Tetrahedron xxx (2014) 1e9
5
Flash v3.1d software. Biotage SNAP flash chromatography car-
tridges (KP-Sil, normal phase, 10e340 g) were used for the purifi-
cation process.
134.1, 130.1, 127.7, 119.2, 114.8; HRMS calcd for C8H759BrClN2S2
[MþH]þ 306.8771, found 306.8766.
Melting points of solid compounds were measured on a StuartÔ
melting point apparatus SMP3 and are uncorrected. IR spectra were
recorded on a PerkinElmer Spectrum 100 Series FT-IR spectrometer.
Liquids and solids were applied on the Single Reflection Attenuated
Total Reflectance (ATR) Accessories. Absorption bands are given in
4.2.2. (Z)-2,4-Dibromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)
aniline (3). Yield 96% (7.421 g), yellow solid, mp¼120e122 ꢀC; IR
(cmꢁ1
) ymax 3080, 2963, 1591, 1543, 1513, 1458, 1376, 1257, 1232,
1154, 1130, 1080, 1041, 861, 851, 810, 795, 776, 712, 649, 533; 1H
NMR (300 MHz, DMSO-d6)
d
8.01 (d, J¼2.1 Hz, 1H, H-3), 7.68 (dd,
cmꢁ1
.
J¼8.5, 2.1 Hz, 1H, H-5), 7.22 (d, J¼8.5 Hz, 1H, H-6); 13C NMR
1H, 13C NMR spectra were recorded on a Bruker DXP 300 spec-
trometer at 300 and 75 MHz, respectively. Abbreviations used for
peak multiplicities are s: singlet, br s: broad singlet, d: doublet, t:
triplet, q: quadruplet and m: multiplet. Coupling constants J are in
Hertz and chemical shifts are given in parts per million and cali-
brated with DMSO-d6 (residual solvent signals). Mass spectra
analysis was performed by the Mass Spectrometry Laboratory of
the University of Rouen. Mass spectra (EI) were recorded with
a Waters LCP 1er XR spectrometer.
(75 MHz, DMSO-d6) d 163.6, 150.2, 146.7, 136.0, 133.1, 121.1, 118.5,
116.1; HRMS calcd for C8H749Br2ClN2S2 [MþH]þ 384.7871, found
384.7876.
4.2.3. (Z)-2-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene) pyr-
idin-3-amine
(4). Yielꢁd1 85% (4.490
g), yellow solid,
ymax 3050, 1581, 1565, 1554, 1505, 1442,
mp¼144e146 ꢀC; IR (cm
)
1397, 1206, 1155, 1082, 1065, 869, 795, 779, 742, 707, 662; 1H NMR
(300 MHz, DMSO-d6)
d
8.29 (d, J¼4.0 Hz, 1H, H-6), 7.76 (d, J¼7.6 Hz,
Microwave experiments were conducted in two different com-
mercial microwave reactors especially designed for synthetic
chemistry. Time indicated in the various protocols is the time
measured when the mixtures reached the programmed tempera-
ture after a ramp period of 2 min.
1H, H-4), 7.55 (dd, J¼7.6, 4.0 Hz,1H, H-5); 13C NMR (75 MHz, DMSO-
d6)
d 164.8, 147.0, 146.7, 145.7, 142.0, 128.8, 125.2; HRMS calcd for
C7H4Cl2N3S2 [MþH]þ 263.9224, found 263.9226.
4.2.4. (Z)-2-Bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene) pyr-
idin-3-amine
(5). Yield
87%
(5.335
g),
brown solid,
- RotoSYNTH (Milestone S.r.l. Italy) is a multimode cavity with
a microwave power delivery system ranging from 0 to 1200 W.
Open vessel experiments (atmospheric pressure) were carried
out in round bottom flask (from 25 mL to 4 L) fitted with
a reflux condenser. The temperature was monitored via a con-
tact-less infrared pyrometer (IRT) and fiber-optic contact
thermometer (FO). Temperature, pressure and power profiles
were edited and monitored through the EASY-Control software
provided by the manufacturer.
- Anton Paar Monowave 300 is a monomode cavity with a mi-
crowave power delivery system ranging from 0 to 850 W
allowing pressurized reactions (0e30 bars) to be carried out in
sealed glass vials (4e30 mL) equipped a snap cap and a silicon
septum. The temperature (0e300 ꢀC) was monitored via
a contact-less infrared sensor and a Ruby Thermometer. Tem-
perature, pressure and power profiles were edited and moni-
tored through a touch screen control panel.
mp¼144e146 ꢀC; IR (cmꢁ1
) ymax 3361, 3037, 1585, 1391, 1154, 1068,
1057, 867, 794, 776, 734, 694, 654, 610; 1H NMR (300 MHz, DMSO-
d6)
d
8.25 (dd, J¼4.6,1.7 Hz,1H, H-6), 7.70 (dd, J¼7.9,1.7 Hz,1H, H-4),
7.56 (dd, J¼7.9, 4.6 Hz, 1H, H-5); 13C NMR (75 MHz, DMSO-d6)
d
164.8, 147.7, 147.4, 146.7, 134.9, 128.1, 125.4; HRMS calcd for
C7H749BrClN3S2 [MþH]þ 307.8719, found 307.8716.
4.2.5. (Z)-3-Bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene) pyr-
idin-2-amine
(6). Yield 45% (2.777 g), yellow solid,
mp¼180e182 ꢀC; IR (cmꢁ1
) ymax 3072, 1573, 1551, 1514, 1483, 1413,
1277, 1229, 1170, 1032, 895, 869, 787, 625; 1H NMR (300 MHz,
DMSO-d6)
d
8.69 (dd, J¼4.8, 1.3 Hz, 1H, H-6), 8.36 (dd, J¼7.8, 1.3 Hz,
1H, H-4), 7.37 (dd, J¼7.8, 4.8 Hz,1H, H-5); 13C NMR (75 MHz, DMSO-
d6)
d 160.6, 152.5, 149.2, 144.1, 143.2, 123.7, 118.3; HRMS calcd for
C7H749BrClN3S2 [MþH]þ 307.8719, found 307.8716.
4.3. Microwave-assisted copper(I)-mediated cyclization of
ortho-bromoaryliminodithiazoles (7e10)
A
stirred solution of the appropriate aryliminodithiazole
4.2. Synthesis of ortho-halogenated N-aryliminodithiazoles
using 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt)
(15 mmol) and copper iodide (CuI, 2.857 g,15 mmol) in dry pyridine
(150 mL) was heated under microwave irradiation (400 W) at
115 ꢀC for 30 min at atmospheric pressure. The dark solution was
evaporated in vacuo. The resulting black residue was dissolved in
ethyl acetate and washed with a saturated solution of sodium
thiosulfate and brine. The organic layer was dried over magnesium
sulfate and evaporated in vacuo. Purification of the dark brown
residue by flash chromatography using petroleum ether/methylene
chloride (100:0 to 0:100, v/v) (benzothiazole series) or methylene
chloride/ethyl acetate (100:0 to 0:100, v/v) (thiazolopyridine se-
ries) as eluent afforded the corresponding cyano derivatives.
4,5-Dichloro-1,2,3-dithiazolium chloride (5.421 g, 26 mmol)
was added portionwise to a stirred solution of the appropriate
amine (20 mmol) in freshly distilled methylene chloride (150 mL)
at room temperature. The dark mixture was vigorously agitated for
3 h. Pyridine (40 mmol, 3.23 mL) was added dropwise to the so-
lution, which was further agitated for another 2 h. The reaction
mixture was quenched with water. The organic layer was sepa-
rated and dried over magnesium sulfate and evaporated to dry-
ness in vacuo. Purification of the dark brown residue by flash
chromatography using petroleum ether/methylene chloride (100:0
to 0:100, v/v) as eluent afforded the corresponding
aryliminodithiazoles.
4.3.1. Benzo[d]thiazole-2-carbonitrile (7). Yield 43% (1.032 g), col-
ourless solid, mp¼75e77 ꢀC; IR (cmꢁ1
) ymax 3084, 3066, 2229,1550,
1466, 1455, 1421, 1317, 1242, 1148, 1133, 1122, 874, 759, 726, 702; 1H
NMR (300 MHz, DMSO-d6)
d 8.45e8.32 (m, 1H, Har), 8.31e8.22 (m,
4.2.1. (Z)-2-Bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene) aniline
1H, Har), 7.79e7.64 (m, 1H, Har); 13C NMR (75 MHz, DMSO-d6)
(1). Yield 97% (5.968 g), yellow solid, mp¼80e82 ꢀC; IR (cmꢁ1
)
ymax
d152.2, 137.6, 135.9, 129.2, 128.6, 125.1, 123.6, 113.9; HRMS calcd for
3065, 1691, 1661, 1596, 1583, 1540, 1503, 1463, 1433, 1223, 1150,
C8H5N2S [MþH]þ 161.0173, found 161.0170.
1042, 1024, 856, 848, 771, 720, 673; 1H NMR (300 MHz, DMSO-d6)
d
7.76 (dd, J¼8.0, 0.9 Hz, 1H, H-3), 7.55e7.43 (m, 1H, Har), 7.27e7.13
4.3.2. 6-Bromobenzo[d]thiazole-2-carbonitrile
(8).ꢁY1 ield
63%
ymax 3083,
(m, 2H, Har); 13C NMR (75 MHz, DMSO-d6)
d
163.0, 150.9, 146.8,
(2.259 g), colourless solid, mp¼140e142 ꢀC; IR (cm
)
Please cite this article in press as: Deau, E.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.102

6
E. Deau et al. / Tetrahedron xxx (2014) 1e9
2231, 1581, 1536, 1464, 1389, 1307, 1144, 1075, 861, 815; 1H NMR
(d, J¼8.6 Hz, 1H, H-4), 7.75 (dd, J¼8.6, 1.8 Hz, 1H, H-5); 13C NMR
(300 MHz, DMSO-d6)
d
8.66 (d, J¼1.9 Hz, 1H, H-7), 8.21 (d, J¼8.8 Hz,
(75 MHz, DMSO-d6) d 151.0, 138.8, 138.3, 130.6, 123.4, 122.3, 115.8,
1H, H-4), 7.89 (dd, J¼8.8, 2.0 Hz,1H, H-5); 13C NMR (75 MHz, DMSO-
109.9; HRMS calcd for C8H749BrN2O [MþH]þ 222.9507, found
d6)
d
151.2, 138.7, 137.9, 132.0, 126.5, 126.2, 122.4, 113.6; HRMS calcd
222.9505.
for C8H739BrN2S [MꢁH]ꢁ 238.9279, found 237.9192.
4.5. Microwave-assisted synthesis of substituted 4-
4.3.3. Thiazolo[5,4-b]pyridine-2-carbonitrile (9). Yield 72% (ꢁ11.741 g),
) ymax
phenylthiazol-2-amines (15e18) via Hantzsch condensation
colourless solid, mp¼136e138 ꢀC (lit.,14 135 ꢀC); IR (cm
2925, 2232,1573,1551, 1461, 1438, 1374,1277, 1246, 1166, 1153, 1114,
In a sealed tube, a stirred solution of thiourea (10.91 mmol) and
the appropriate a-bromoacetophenone (10.91 mmol) in ethanol
806, 747, 703, 630; 1H NMR (300 MHz, DMSO-d6)
1.2 Hz, 1H, H-6), 8.72 (dd, J¼8.4, 1.2 Hz, 1H, H-4), 7.82 (dd, J¼8.4,
d
8.91 (dd, J¼4.6,
(15 mL) was irradiated (800 W) at 100 ꢀC for 15 min. The solvent
was evaporated to dryness. The solid residue was neutralized with
a saturated solution of sodium bicarbonate and extracted three
times with methylene chloride. The organic layer was dried over
magnesium sulfate and the solvent was evaporated to dryness. The
solid residue was agitated for 30 min in cyclohexane and filtered off
to afford the 4-phenylthiazol-2-amine in analytically pure form.
4.6 Hz, 1H, H-5); 13C NMR (75 MHz, DMSO-d6)
d 157.8, 152.1, 145.2,
138.0, 133.4, 124.1, 113.5; HRMS calcd for C7H4N3S [MþH]þ
162.0126, found 162.0129.
4.3.4. Thiazolo[4,5-b]pyridine-2-carbonitrile
(10).ꢁY1ield
45%
ymax 3072,
(0.991 g), colourless solid, mp¼140e142 ꢀC; IR (cm
)
2923, 2236,1538,1469,1377,1306,1291,1137, 808, 772, 728, 714; 1H
NMR (300 MHz, DMSO-d6)
d
8.95 (dd, J¼4.4, 1.3 Hz, 1H, H-5), 8.85
4.5.1. 4-Phenylthiazol-2-amine (15). Yield 90%ꢁ(11.730 g), colourless
3156, 3111, 1595, 1515, 1482, 1329, 1037, 909, 845, 772, 712, 665; 1H
(dd, J¼8.3, 1.3 Hz, 1H, H-7), 7.73 (dd, J¼8.3, 4.4 Hz, 1H, H-6); 13C
solid, mp¼151e153 ꢀC (lit.,15 151 ꢀC); IR (cm
) ymax 3432, 3246,
NMR (75 MHz, DMSO-d6)
d
160.2, 149.4, 139.7, 131.8, 128.2, 121.4,
111.7; HRMS calcd for C7H4N3S [MþH]þ 162.0126, found 162.0130.
NMR (300 MHz, DMSO-d6)
d
7.79 (d, J¼7.5 Hz, 2H), 7.36 (t, J¼7.5 Hz,
2H), 7.25 (t, J¼7.2 Hz, 1H), 7.06 (br s, 2H, NH2), 6.99 (s, 1H, Hthiazole);
4.4. Synthesis of benzo[d]oxazole-2-carbonitriles (13 and 14)
13C NMR (75 MHz, DMSO-d6)
d 169.0, 150.6, 135.5, 129.0 (2C), 127.7,
126.1 (2C), 101.9; HRMS calcd for C9H9N2S [MþH]þ 177.0486, found
4,5-Dichloro-1,2,3-dithiazolium chloride (4.066 g, 19.5 mmol)
was added portionwise to a stirred solution of the appropriate
aminophenol (15 mmol) in freshly distilled methylene chloride
(115 mL) at room temperature. The dark mixture was vigorously
agitated for 3 h. Pyridine (30 mmol, 2.42 mL) was added dropwise
to the solution, which was further agitated for another 2 h. The
reaction mixture was quenched with water. The organic layer was
separated and dried over magnesium sulfate and evaporated to
177.0485.
4.5.2. 4-(4-Methoxyphenyl)thiazol-2-amine
(16). Yield
91%
(2.048 g), colourless solid, mp¼208e210 ꢀC (lit.,15 209 ꢀC); IR
(cmꢁ1
) ymax 3427, 3258, 3116, 1622, 1535, 1517, 1490, 1414, 1287,
1242,1176,1032, 833, 735, 696; 1H NMR (300 MHz, DMSO-d6)
d 7.72
(d, J¼8.7 Hz, 2H, H-Ph), 7.00 (br s, 2H, NH2), 6.92 (d, J¼8.7 Hz, 2H, H-
Ph), 6.82 (s, 1H, Hthiazole), 3.76 (s, 3H, Ph-OCH3); 13C NMR (75 MHz,
dryness
in
vacuo.
(Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-
DMSO-d6) d 168.9, 159.3, 150.4, 128.4, 127.4 (2C), 114.3 (2C), 99.7,
ylideneamino)phenol was purified by flash chromatography using
petroleum ether/methylene chloride (100:0 to 0:100, v/v) or di-
rectly engaged in the cyclization step.
55.2; HRMS calcd for
207.0585.
C
10H11N2OS [MþH]þ 207.0592, found
(Z)-2-(4-Chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenol was
dissolved in toluene (50 mL) and vigorously refluxed for 3 h. The
reaction mixture was evaporated in vacuo. Purification of the res-
idue by flash chromatography using petroleum ether/methylene
chloride (100:0 to 0:100, v/v) afforded the corresponding benzo[d]
oxazole-2-carbonitriles.
4.5.3. 4-(4-Chlorophenyl)thiazol-2-amine (17). Yield 91% (2.091 g),
colourless solid, mp¼171e173 ꢀC (lit.,15 168 ꢀC); IR (cmꢁ1
) ymax
3435, 3271, 3089,1631, 1531, 1474, 1399, 1329, 1085, 1035, 1008, 821,
728, 665; 1H NMR (300 MHz, DMSO-d6)
Ph), 7.41 (d, J¼8.5 Hz, 2H, H-Ph), 7.11 (br s, 2H, NH2), 7.07 (s, 1H,
d
7.81 (d, J¼8.5 Hz, 2H, H-
Hthiazole); 13C NMR (75 MHz, DMSO-d6)
d 169.2, 149.3, 134.4, 132.1,
129.0 (2C), 127.8 (2C), 102.7; HRMS calcd for C9H8ClN2S [MþH]þ
4.4.1. (Z)-2-(4-Chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenol
211.0097, found 211.0092.
(11). Yield 76% (3.71 g), yellow solid, mp¼183e185 ꢀC; IR (cmꢁ1
)
ymax 3385, 1661, 1608, 1583, 1472,1444, 1339,1286, 1254, 1219,1135,
4.5.4. 4-(2,4-Dichlorophenyl)thiazol-2-amine
(18). Yield
89%
1033, 951, 854, 807, 744, 730, 674; 1H NMR (300 MHz, DMSO-d6)
(2.38 g), light brown solid, mp¼166e168 ꢀC (lit.,15 163 ꢀC); 1H NMR
d
9.46 (br s, 1H, OH), 7.12e7.03 (m, 1H, Har), 7.02e6.94 (m, 2H, Har),
(300 MHz, DMSO-d6)
d
7.87 (d, J¼8.5 Hz, 1H, H-Ph), 7.64 (d,
6.87 (td, J¼7.8,1.4 Hz,1H, Har); 13C NMR (75 MHz, DMSO-d6)
d
160.7,
J¼2.2 Hz, 1H, H-Ph), 7.45 (dd, J¼8.5, 2.2 Hz, 1H, H-Ph), 7.11 (s, 3H,
148.0, 147.2, 139.4, 127.4, 120.3, 119.8, 117.3; HRMS calcd for
NH2þHthiazole); 13C NMR (75 MHz, DMSO-d6)
d
168.2, 145.9, 133.0,
) ymax 3451, 3269,
C8H5N2O [MþH]þ 244.9610, found 244.9607.
132.9, 132.7, 131.9, 130.3, 127.9, 107.5; IR (cmꢁ1
3111, 1630, 1536, 1461, 1370, 1334, 1194, 1101, 1025, 834, 811, 784,
694; HRMS calcd for C9H7Cl2N2S [MþH]þ 244.9707, found
244.9704.
4.4.2. Benzo[d]oxazole-2-carbonitrile (13). Yield 61% (1.317 g), col-
ourless solid, mp¼102e104 ꢀC; IR (cmꢁ1
) ymax 2249, 1530, 1475,
1443, 1338, 1256, 1169, 1102, 950, 893, 817, 759, 748, 685, 620; 1H
NMR (300 MHz, DMSO-d6)
d
8.00 (d, J¼8.0 Hz, 1H, Har), 7.94 (d,
4.6. Microwave-assisted synthesis of N-(4-phenylthiazol-2-
yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-
b]pyridine-, benzo[d]oxazole-2-carboximidamides (19e45)
J¼8.3 Hz, 1H, Har), 7.74e7.67 (m, 1H, Har), 7.63e7.56 (m, 1H, Har); 13
C
NMR (75 MHz, DMSO-d6)
d 150.6, 139.4, 137.8, 129.9, 127.2, 122.0,
112.4, 110.2. This compound was already described2b,5, spectro-
metric data are consistent with the assigned structure.
In a sealed tube, a stirred solution of carbonitrile (2 mmol) and
the appropriate 4-phenylthiazol-2-amine (2.4 mmol) in dry DMF
(4 mL) was heated under microwave irradiation (800 W) at 180 ꢀC
for 3 h. Evaporation of the solvent gave a crude product, which was
purified by flash chromatography using petroleum ether/methy-
lene chloride (100:0 to 0:100, v/v) as eluent.
4.4.3. 6-Bromobenzo[d]oxazole-2-carbonitrile
(14).ꢁY1 ield
20%
ymax 3086,
(0.665 g), light brown solid, mp¼148e150 ꢀC; IR (cm
)
2249, 1599, 1528, 1412, 1324, 1257, 1190, 954, 908, 857, 820, 689,
594; 1H NMR (300 MHz, DMSO-d6)
d
8.31 (d, J¼1.8 Hz,1H, H-7), 7.93
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E. Deau et al. / Tetrahedron xxx (2014) 1e9
7
4.6.1. N-(4-Phenylthiazol-2-yl)benzo[d]thiazole-2-carboximidamꢁid1e
152.7, 151.7, 151.5, 138.8, 134.5, 130.8, 129.4 (2C), 128.6, 126.3 (2C),
79
(19). Yield 80% (0.536 g), yellow solid, mp¼228e230 ꢀC; IR (cm
)
125.9, 125.7, 120.3, 110.7; HRMS calcd for C
414.9687, found 414.9685.
H
17 12
BrN4S2 [MþH]þ
ymax 3364, 3107, 2914, 1619, 1592, 1537, 1509, 1476, 1318, 1234, 1117,
1044, 818, 766, 754, 726, 619; 1H NMR (300 MHz, DMSO-d6)
d 9.54
(br s, bs, 1H, NH), 9.26 (br s, 1H, NH), 8.25e8.19 (m, 1H, Har), 8.16 (d,
J¼7.5 Hz, 1H, Har), 7.95 (d, J¼7.2 Hz, 2H, H-Ph), 7.84 (s, 1H, Hthiazole),
7.68e7.55 (m, 2H, Har), 7.48 (t, J¼7.5 Hz, 2H, H-Ph), 7.37 (t, J¼7.3 Hz,
4.6.7. 6-Bromo-N-(4-p-tolylthiazol-2-yl)benzo[d]thiazole-2-
carboximidamide (25). Yield 74% (0.635 g), yellow solid,
mp¼265e267 ꢀC; IR (cmꢁ1
) ymax 3369, 2927, 1620, 1599, 1511, 1476,
1H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
d
173.2, 165.6, 153.7, 151.8,
1441, 1301, 1236, 1117, 1049, 858, 817, 736, 491; 1H NMR (300 MHz,
151.7, 136.9, 134.6, 129.4 (2C), 128.7, 127.6, 127.5, 126.3 (2C), 124.2,
123.4, 110.6; HRMS calcd for C17H13N4S2 [MþH]þ 337.0582, found
337.0596.
DMSO-d6)
d
9.38 (br s, 2H, NHþNH), 8.52 (d, J¼1.9 Hz, 1H, H-7), 8.08
(d, J¼8.7 Hz, 1H, H-4), 7.84 (d, J¼8.1 Hz, 2H, H-Ph), 7.79 (d, J¼2.0 Hz,
1H, H-5), 7.77 (s, 1H, Hthiazole), 7.28 (d, J¼8.0 Hz, 2H, H-Ph), 2.35 (s,
3H, Ph-CH3); 13C NMR (75 MHz, DMSO-d6)
d 172.9, 166.6, 152.7,
4.6.2. N-(4-p-Tolylthiazol-2-yl)benzo[d]thiazole-2-carboximidamꢁid1e
151.8, 151.4, 138.8, 138.1, 131.9, 130.8, 130.0 (2C), 126.2 (2C), 125.9,
79
(20). Yield 72% (0.505 g), yellow solid, mp¼199e201 ꢀC; IR (cm
)
125.7, 120.3, 109.9, 20.8; HRMS calcd for C
428.9843, found 428.9864.
H
18 14
BrN4S2 [MþH]þ
ymax 3364, 3107, 2914, 1619, 1592, 1537, 1509, 1476, 1451, 1318, 1234,
1214, 1117, 1044, 818, 754, 726, 619, 488; 1H NMR (300 MHz, DMSO-
d6)
d
9.40 (br s, 2H, NHþNH), 8.22 (d, J¼7.4 Hz, 1H, Har), 8.16 (d,
4.6.8. 6-Bromo-N-[4-(4-methoxyphenyl)thiazol-2-yl]benzo[d]-thia-
J¼7.4 Hz, 1H, Har), 7.84 (d, J¼8.0 Hz, 2H, H-Ph), 7.75 (s, 1H, Hthiazole),
zole-2-carboximidamide (26). Yield 82% (0.730 g), yellow solid,
7.70e7.53 (m, 2H, Har), 7.29 (d, J¼8.0 Hz, 2H, H-Ph), 2.35 (s, 3H, Ph-
mp¼243e245 ꢀC; IR (cmꢁ1
) ymax 3460, 3247, 3067, 2955,1609,1519,
CH3); 13C NMR (75 MHz, DMSO-d6)
d
173.1, 165.6, 153.7, 151.7, 151.6,
1479, 1250, 1232, 831, 735, 693; 1H NMR (300 MHz, DMSO-d6)
138.0, 136.8, 131.9, 129.9 (2C), 127.5, 127.4, 126.2 (2C), 124.2, 123.3,
109.7, 20.7; HRMS calcd for C18H15N4S2 [MþH]þ 351.0738, found
351.0739.
d
9.36 (br s, 2H, NHþNH), 8.51 (d, J¼2.0 Hz, 1H, H-7), 8.07 (d,
J¼8.7 Hz, 1H, H-4), 7.87 (d, J¼8.8 Hz, 2H, H-Ph), 7.77 (dd, J¼8.7,
2.0 Hz, 1H, H-5), 7.66 (s, 1H, Hthiazole), 7.03 (d, J¼8.8 Hz, 2H, H-Ph),
3.80 (s, 3H, Ph-OCH3); 13C NMR (75 MHz, DMSO-d6)
d 172.9, 166.6,
4.6.3. N-[4-(4-Methoxyphenyl)thiazol-2-yl]benzo[d]thiazole-2-
160.0, 152.7, 151.6, 151.4, 138.8, 130.8, 127.7 (2C), 127.3, 125.9, 125.7,
79
carboximidamide (21). Yield 44% (0.349 g), yellow solid,
120.3, 114.7 (2C), 108.7, 55.3; HRMS calcd for C H BrN4OS2
18 14
mp¼249e251 ꢀC; IR (cmꢁ1
)
ymax 3457, 1609, 1598, 1519, 1481, 1301,
[MþH]þ 444.9792, found 444.9792.
1252, 1030, 833, 734, 694, 631, 588, 454; 1H NMR (300 MHz, DMSO-
d6)
d
9.46 (br s, 1H, NH), 9.27 (br s, 1H, NH), 8.24e8.13 (m, 2H, Har),
4.6.9. 6-Bromo-N-(4-(4-chlorophenyl)thiazol-2-yl)benzo[d]-thia-
7.88 (d, J¼8.8 Hz, 2H, H-Ph), 7.66 (s, 1H, Hthiazole), 7.65e7.55 (m, 2H,
zole-2-carboximidamide (27). Yield 65% (0.583 g), yellow solid,
Har), 7.04 (d, J¼8.8 Hz, 2H, H-Ph), 3.81 (s, 3H, Ph-OCH3); 13C NMR
mp¼>300 ꢀC; IR (cmꢁ1
) ymax 3368, 2923, 1620, 1584, 1542, 1509,
(75 MHz, DMSO-d6)
d
173.0, 165.6, 159.9, 153.7, 151.6, 151.5, 136.8,
1471, 1401, 1305, 1237, 1094, 1012, 861, 819, 734, 487; 1H NMR
127.7 (2C), 127.5, 127.4, 127.3, 124.2, 123.3, 114.7 (2C), 108.5, 55.3;
(300 MHz, DMSO-d6)
d
9.34 (br s, 2H, NHþNH), 8.51 (d, J¼2.0 Hz,
HRMS calcd for C18H15N4OS2 [MþH]þ 367.0687, found 367.0690.
1H, H-7), 8.07 (d, J¼8.7 Hz, 1H, H-4), 7.98 (d, J¼8.6 Hz, 2H, H-Ph),
7.90 (s, 1H, Hthiazole), 7.77 (dd, J¼8.7, 2.0 Hz, 1H, H-5), 7.53 (d,
4.6.4. N-(4-(4-Chlorophenyl)thiazol-2-yl)benzo[d]thiazole-2-
J¼8.6 Hz, 2H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
d 173.1, 166.5,
carboximidamide (22). Yield 40% (0.297 g), yellow solid,
152.7, 151.5, 150.5, 138.8, 133.4, 133.1, 130.8, 129.4 (2C), 128.1 (2C),
79
mp¼234e236 ꢀC; IR (cmꢁ1
)
ymax 3362, 3252, 3221, 1622, 1591, 1537,
125.9, 125.7, 120.3, 111.4; HRMS calcd for C
448.9297, found 448.9293.
H
BrClN4S2 [MþH]þ
17 11
1511, 1470, 1449, 1401, 1314, 1230, 1124, 1094, 1013, 867, 832, 754,
727, 609, 515; 1H NMR (300 MHz, DMSO-d6)
d 9.34 (br s, 2H,
NHþNH), 8.24e8.14 (m, 2H, Har), 7.98 (d, J¼8.6 Hz, 2H, H-Ph), 7.89
4.6.10. 6-Bromo-N-(4-(2,4-dichlorophenyl)thiazol-2-yl)benzo[d]-thi-
(s, 1H, Hthiazole), 7.67e7.56 (m, 2H, Har), 7.53 (d, J¼8.6 Hz, 2H, H-Ph);
azole-2-carboximidamideꢁ1(28). Yield 33% (0.317 g), yellow solid,
13C NMR (75 MHz, DMSO-d6)
d
173.3, 165.5, 153.7, 151.8, 150.5,
mp¼225e227 ꢀC; IR (cm
) ymax 3365, 3247, 3202,1620,1579,1542,
136.9, 133.4, 133.1, 129.4 (2C), 128.1 (2C), 127.6, 127.5, 124.2, 123.3,
111.3; HRMS calcd for C17H12ClN4S2 [MþH]þ 371.0192, found
371.0188.
1507, 1464, 1377, 1298, 1242, 1107, 1042, 865, 809, 747, 481; 1H NMR
(300 MHz, DMSO-d6)
d
9.39 (br s, 2H, NHþNH), 8.53 (d, J¼2.0 Hz,
1H, H-7), 8.07 (d, J¼8.7 Hz, 1H), 7.89 (d, J¼8.4 Hz, 1H, H-Ph), 7.81 (s,
1H, Hthiazole), 7.80e7.75 (m, 2H, HarþH-Ph), 7.56 (dd, J¼8.4, 2.2 Hz,
4.6.5. N-(4-(2,4-Dichlorophenyl)thiazol-2-yl)benzo[d]thiazole-2-
1H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
d 172.4, 166.5, 152.7, 151.8,
carboximidamide (23).ꢁY1ield 50% (0.405 g), yellow solid,
1465, 1235, 1101, 1044, 858, 757; 1H NMR (300 MHz, DMSO-d6)
147.5, 138.8, 133.9, 133.1, 132.5, 132.4, 130.8, 130.5, 128.3, 126.0,
BrCl2N4S2 [MþH]þ
79
mp¼212e214 ꢀC; IR (cm
)
ymax 3454, 3257, 3100, 3055,1603,1526,
125.8, 120.4, 116.0; HRMS calcd for C
482.8907, found 482.8906.
H
17 10
d
9.35 (br s, 2H, NHþNH), 8.24e8.13 (m, 2H, Har), 7.89 (d, J¼8.4 Hz,
1H, H-Ph), 7.80 (s, 1H, Hthiazole), 7.76 (d, J¼2.1 Hz, 1H, H-Ph),
4.6.11. N-(4-Phenylthiazol-2-yl)thiazolo[5,4-b]pyridine-2-carbo-xi-
7.68e7.53 (m, 3H, HarþH-Ph); 13C NMR (75 MHz, DMSO-d6)
d
172.5,
midamide (29). Yield 56% (0.374 g), yellow solid, mp¼221e223 ꢀC;
165.4, 153.7, 152.0, 147.4, 136.8, 133.8, 133.0, 132.5, 132.4, 130.5,
128.2,127.5, 127.4, 124.2, 123.3,115.7; HRMS calcd for C17H11Cl2N4S2
[MþH]þ 404.9802, found 404.9802.
IR (cmꢁ1
) ymax 3359, 3185, 3056, 1624, 1476, 1439, 1235, 803, 7716,
682, 495; 1H NMR (300 MHz, DMSO-d6)
d
9.41 (br s, 2H, NHþNH),
8.76 (dd, J¼4.6, 1.5 Hz, 1H, H-6), 8.55 (dd, J¼8.3, 1.5 Hz, 1H, H-4),
8.02e7.91 (m, 2H, H-Ph), 7.87 (s, 1H, Hthiazole), 7.70 (dd, J¼8.3,
4.6 Hz, 1H, H-5), 7.48 (t, J¼7.5 Hz, 2H, H-Ph), 7.37 (t, J¼7.3 Hz, 1H, H-
4.6.6. 6-Bromo-N-(4-phenylthiazol-2-yl)benzo[d]thiazole-2-
carboximidamide (24). Yield 73% (0.606 g), yellow solid,
Ph); 13C NMR (75 MHz, DMSO-d6)
d 172.9, 165.6, 159.1, 151.7, 151.4,
mp¼241e243 ꢀC; IR (cmꢁ1
)
ymax 3367, 2923, 1621, 1512, 1476, 1440,
149.8, 146.8, 134.5, 131.9, 129.4 (2C), 128.6, 126.3 (2C), 123.0, 110.9;
1237, 1075, 819, 743, 709, 685, 501; 1H NMR (300 MHz, DMSO-d6)
HRMS calcd for C16H12N5S2 [MþH]þ 338.0534, found 338.0523.
d
9.39 (br s, 2H, NHþNH), 8.51 (d, J¼2.0 Hz, 1H, H-7), 8.07 (d,
J¼8.7 Hz, 1H, H-4), 7.95 (d, J¼7.2 Hz, 2H, H-Ph), 7.84 (s, 1H, Hthiazole),
7.77 (dd, J¼8.7, 2.0 Hz, 1H, H-5), 7.48 (t, J¼7.5 Hz, 2H, H-Ph), 7.37 (t,
4.6.12. N-(4-p-Tolylthiazol-2-yl)thiazolo[5,4-b]pyridine-2-carbo-xi-
midamide (30). Yield 63% (0.464 g), yellow solid, mp¼233e235 ꢀC;
J¼7.3 Hz, 1H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
d
173.0, 166.6,
IR (cmꢁ1
) ymax 3298, 3163, 3112, 2927, 1618, 1498, 1476, 1443, 1224,
Please cite this article in press as: Deau, E.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.102

8
E. Deau et al. / Tetrahedron xxx (2014) 1e9
795, 741, 615, 591; 1H NMR (300 MHz, DMSO-d6)
d
9.51 (br s, 1H,
(cmꢁ1
1174, 1069, 907, 859, 814, 725, 692, 664, 627, 507; 1H NMR
(300 MHz, DMSO-d6)
9.44 (br s, 2H, NHþNH), 7.98e7.89 (m, 4H,
Har), 7.86 (s, 1H, Hthiazole), 7.63e7.44 (m, 4H, H-Ph), 7.37 (t, J¼7.3 Hz,
1H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
173.3, 158.0, 151.6, 151.3,
) ymax 3343, 1633, 1599, 1560, 1529, 1476, 1437, 1406, 1227,
NH), 9.27 (br s, 1H, NH), 8.75 (dd, J¼4.6, 1.4 Hz, 1H, H-6), 8.54 (dd,
J¼8.3, 1.4 Hz, 1H, H-4), 7.84 (d, J¼8.1 Hz, 2H, H-Ph), 7.78 (s, 1H,
Hthiazole), 7.69 (dd, J¼8.3, 4.6 Hz, 1H, H-5), 7.28 (d, J¼8.1 Hz, 2H, H-
d
Ph), 2.34 (s, 3H, Ph-CH3); 13C NMR (75 MHz, DMSO-d6)
d
172.8,
d
165.6, 159.1, 151.8, 151.3, 149.8, 146.8, 138.1, 131.9, 131.8, 130.0 (2C),
126.2 (2C), 123.0, 110.1, 20.8; HRMS calcd for C17H14N5S2 [MþH]þ
352.0691, found 352.0688.
146.9, 141.0, 134.5, 129.4 (2C), 128.6, 127.9, 126.3 (2C), 126.1, 121.2,
112.2, 111.0; HRMS calcd for C17H13N4OS [MþH]þ 321.0810, found
321.0799.
4.6.13. N-[4-(4-Methoxyphenyl)thiazol-2-yl]thiazolo[5,4-b]pyri-
4.6.19. N-(4-p-Tolylthiazol-2-yl)benzo[d]oxazole-2-carboximidamide
dine-2-carboximidamide (31). Yield 63% (0.463 g), yellow solid,
(37). Yield 47% (0.314 g), light yellow solid, mp¼246e248 ꢀC; IR
mp¼248e250 ꢀC; IR (cmꢁ1
)
ymax 3291, 3225, 3105, 3055, 2993,
(cmꢁ1
) ymax 3349, 1633, 1602, 1558, 1530, 1477, 1408, 1225, 1172,
1610, 1527, 1476, 1445, 1248, 1225, 8832, 739, 616, 579; 1H NMR
824, 740, 732, 696, 616, 498; 1H NMR (300 MHz, DMSO-d6)
d 9.43
(300 MHz, DMSO-d6)
d
9.57 (br s, 1H, NH), 9.27 (br s, 1H, NH), 8.76
(br s, 2H, NHþNH), 7.95e7.89 (m, 2H, Har), 7.84 (d, J¼8.1 Hz, 2H, H-
Ph), 7.78 (s, 1H, Hthiazole), 7.62e7.48 (m, 2H, Har), 7.28 (d, J¼8.1 Hz,
2H, H-Ph), 2.35 (s, 3H, Ph-CH3); 13C NMR (75 MHz, DMSO-d6)
(dd, J¼4.6, 1.5 Hz, 1H, H-6), 8.55 (dd, J¼8.3, 1.5 Hz, 1H, H-4), 7.89 (d,
J¼8.8 Hz, 2H, H-Ph), 7.77e7.64 (m, 2H, H-5þHthiazole), 7.04 (d,
J¼8.8 Hz, 2H, H-Ph), 3.81 (s, 3H, Ph-OCH3); 13C NMR (75 MHz,
d
172.4, 157.3, 151.0, 150.5, 146.1, 140.4, 137.4, 131.3, 129.3 (2C), 127.3,
DMSO-d6)
d
172.8,165.7, 160.0,159.2,151.7, 151.3, 149.8, 146.9, 132.0,
125.7 (2C), 125.5, 120.6, 111.7, 109.7, 20.8; HRMS calcd for
127.8 (2C), 127.3, 123.1, 114.7 (2C), 108.9, 55.3; HRMS calcd for
C
18H15N4OS [MþH]þ 335.0967, found 335.0975.
C
17H14N5OS2 [MþH]þ 368.0640, found 368.0644.
4.6.20. N-[4-(4-Methoxyphenyl)thiazol-2-yl]benzo[d]oxazole-2-
4.6.14. N-[4-(4-Chlorophenyl)thiazol-2-yl]thiazolo[5,4-b]pyri-dine-
carboximidamide (38). Yield 60% (0.420 g), light yellow solid,
2-carboximidamide (32). ꢁY1ield 38% (0.280 g), yellow solid,
mp¼216e218 ꢀC; IR (cmꢁ1
) ymax 3393, 3185, 3112, 2977, 1627, 1603,
mp¼264e266 ꢀC; IR (cm
)
ymax 3309, 3235, 3173, 3128, 3054,
1523, 1479, 1237, 1174, 826, 766, 746, 528; 1H NMR (300 MHz,
1620, 1536, 1503, 1469, 1226, 829, 733, 613; 1H NMR (300 MHz,
DMSO-d6)
d
9.42 (br s, 2H, NHþNH), 7.96e7.91 (m, 2H, Har), 7.88 (d,
DMSO-d6)
d
9.38 (br s, 2H, NHþNH), 8.76 (dd, J¼4.6,1.5 Hz,1H, H-6),
J¼8.8 Hz, 2H, H-Ph), 7.69 (s, 1H, Hthiazole), 7.62e7.47 (m, 2H, Har),
8.55 (dd, J¼8.3, 1.5 Hz, 1H, H-4), 7.99 (d, J¼8.6 Hz, 2H, H-Ph), 7.92 (s,
7.03 (d, J¼8.8 Hz, 2H, H-Ph), 3.81 (s, 3H, Ph-OCH3); 13C NMR
1H, Hthiazole), 7.70 (dd, J¼8.3, 4.6 Hz, 1H, H-5), 7.53 (d, J¼8.6 Hz, 2H,
(75 MHz, DMSO-d6)
d 173.2, 159.9, 158.1, 151.6, 151.3, 146.8, 141.0,
H-Ph); 13C NMR (75 MHz, DMSO-d6)
d
173.1, 165.6, 159.2, 151.4,
127.9, 127.7 (2C), 127.3, 126.1, 121.2, 114.7 (2C), 112.2, 109.0, 55.3;
150.6, 149.9, 146.8, 133.4, 133.2, 132.0, 129.4 (2C), 128.1 (2C), 123.1,
111.7; HRMS calcd for C16H11ClN5S2 [MþH]þ 372.0144, found
372.0131.
HRMS calcd for C18H15N4O2S [MþH]þ 351.0916, found 351.0904.
4.6.21. N-(4-(4-Chlorophenyl)thiazol-2-yl)benzo[d]oxazole-2-
carboximidamide (39). Yield 62% (0.440 g), light yellow solid,
4.6.15. N-[4-(2,4-Dichlorophenyl)thiazol-2-yl]thiazolo[5,4-b]-pyri-
mp¼221e223 ꢀC; IR (cmꢁ1
)
ymax 3352, 1634, 1601, 1533, 1470, 1402,
dine-2-carboximidamide ꢁ(133). Yield 47% (0.382 g), yellow solid,
1231, 1090, 737, 506; 1H NMR (300 MHz, DMSO-d6)
d 9.38 (br s, 2H,
mp¼242e246 ꢀC; IR (cm
)
ymax 3438, 3314, 3163, 3067,1619,1498,
NHþNH), 7.99 (d, J¼8.4 Hz, 2H, H-Ph), 7.95e7.89 (m, 3H, HarþH-
thiazole), 7.62e7.48 (m, 2H, Har), 7.53 (d, J¼8.4 Hz,1H, H-Ph); 13C NMR
1465, 1373, 1228, 1140, 867, 798, 738; 1H NMR (300 MHz, DMSO-d6)
d
9.40 (br s, 2H, NHþNH), 8.76 (dd, J¼4.6, 1.5 Hz, 1H, H-6), 8.54 (dd,
(75 MHz, DMSO-d6) d 173.5, 158.0, 151.2, 150.4, 146.9, 141.0, 133.4,
J¼8.3, 1.5 Hz, 1H, H-4), 7.89 (d, J¼8.4 Hz, 1H, H-Ph), 7.83 (s, 1H,
Hthiazole), 7.76 (d, J¼2.2 Hz, 1H, H-Ph), 7.70 (dd, J¼8.3, 4.6 Hz, 1H, H-
5), 7.56 (dd, J¼8.4, 2.2 Hz, 1H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
133.1, 129.4 (2C), 128.1 (2C), 127.9, 126.1, 121.2, 112.2, 111.7; HRMS
calcd for C17H12ClN4OS [MþH]þ 355.0420, found 355.0437.
d
172.3, 165.5, 159.1, 151.7, 149.9, 147.5, 146.8, 133.9, 133.1, 132.5,
4.6.22. N-[4-(2,4-Dichlorophenyl)thiazol-2-yl]benzo[d]oxazole-2-
132.4,132.0,130.5,128.3,123.1,116.2; HRMS calcd for C16H10Cl2N5S2
carboximidamide (40). Yield 36% (0.280 g), light yellow solid,
[MþH]þ 405.9755, found 405.9756.
mp¼253e255 ꢀC; IR (cmꢁ1
) ymax 3361, 3203, 1636, 1604, 1537, 1464,
1232, 1103, 1042, 867, 755, 739; 1H NMR (300 MHz, DMSO-d6)
4.6.16. N-(4-p-Tolylthiazol-2-yl)thiazolo[4,5-b]pyridine-2-carbo-xi-
d
9.39 (br s, 2H, NHþNH), 7.94e7.87 (m, 3H, Har), 7.82 (s, 1H, Hthia-
midamide (34). Yield 58% (0.411 g), yellow solid, mp¼286e288 ꢀC; IR
zole), 7.74 (d, J¼2.1 Hz, 1H, H-Ph), 7.61e7.48 (m, 3H, Har); 13C NMR
(cmꢁ1
)
ymax 3381, 3271, 3094, 1613,1541, 1518,1475, 1227, 1109, 1028,
(75 MHz, DMSO-d6) d 172.6, 157.9, 151.2, 147.4, 147.2, 141.0, 133.8,
862, 777, 744, 629; 1H NMR (300 MHz, DMSO-d6)
d
9.48 (br s, 2H,
133.0, 132.5, 132.3, 130.5, 128.2, 127.9, 126.1, 121.2, 116.3, 112.2;
NHþNH), 8.83(dd, J¼4.6,1.5Hz,1H, H-5), 8.72 (dd, J¼8.1,1.5Hz,1H, H-
7), 7.85 (d, J¼8.1 Hz, 2H, H-Ph), 7.78 (s, 1H, Hthiazole), 7.60 (dd, J¼8.1,
4.6 Hz, 1H, H-6), 7.29 (d, J¼8.0 Hz, 2H, H-Ph), 2.31 (s, 3H, Ph-CH3);
HRMS calcd for C17H14N5S2 [MþH]þ 352.0691, found 352.0692.
HRMS calcd for C17H11Cl2N4OS [MþH]þ 389.0031, found 389.0025.
4.6.23. 6-Bromo-N-(4-phenylthiazol-2-yl)benzo[d]oxazole-2-car-
boximidamide (41). Yield 56% (0.451 g), yellow solid,
mp¼202e204 ꢀC; IR (cmꢁ1
) ymax 3357, 2914, 1630, 1597, 1556, 1531,
4.6.17. N-[4-(2,4-Dichlorophenyl)thiazol-2-yl]thiazolo[4,5-b]-pyri-
1476, 1440, 1318, 1235, 1073, 1042, 907, 854, 814, 709, 489; 1H NMR
dine-2-carboximidamide ꢁ(135). Yield 77% (0.566 g), yellow solid,
1479, 1450, 1244, 1173, 1023, 818, 779; 1H NMR (300 MHz, DMSO-
(300 MHz, DMSO-d6)
d
9.42 (br s, 2H, NHþNH), 8.26 (d, J¼1.6 Hz,
mp¼290e292 ꢀC; IR (cm
)
ymax 3378, 3236, 3185, 2916,1608,1519,
1H, H-7), 7.94 (d, J¼7.5 Hz, 2H, H-Ph), 7.91e7.83 (m, 2H, H-
4þHthiazole), 7.68 (dd, J¼8.5, 1.6 Hz, 1H, H-5), 7.47 (t, J¼7.5 Hz, 2H, H-
Ph), 7.36 (t, J¼7.3 Hz, 1H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
d6)
d
9.49 (br s, 2H, NHþNH), 8.82 (dd, J¼4.5, 1.3 Hz, 1H, H-5), 8.72
(dd, J¼8.1, 1.3 Hz, 1H, H-7), 7.89 (d, J¼8.7 Hz, 2H, H-Ph), 7.69 (s, 1H,
Hthiazole), 7.60 (dd, J¼8.1, 4.5 Hz, 1H, H-6), 7.04 (d, J¼8.7 Hz, 2H, H-
Ph), 3.81 (s, 3H, Ph-OCH3) HRMS calcd for C17H14N5OS2 [MþH]þ
368.0640, found 368.0642.
d 173.2, 158.6, 151.9, 151.7, 146.5, 140.4, 134.5, 129.4 (2C), 128.7, 126.3
79
(2C), 122.6, 120.0, 115.6, 111.2; HRMS calcd for C
H BrN4OS
17 12
[MþH]þ 398.9915, found 398.9934.
4.6.24. 6-Bromo-N-(4-p-tolylthiazol-2-yl)benzo[d]oxazole-2-car-
4.6.18. N-(4-Phenylthiazol-2-yl)benzo[d]oxazole-2-carboximidamide
(36). Yield 51% (0.327 g), light yellow solid, mp¼235e237 ꢀC; IR
boximidamide (42). Yield 51% (0.430 g), yellow solid,
mp¼226e228 ꢀC; IR (cmꢁ1
) ymax 3351, 3178, 3077, 1631, 1599, 1553,
Please cite this article in press as: Deau, E.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.102

E. Deau et al. / Tetrahedron xxx (2014) 1e9
9
1530, 1476, 1412, 1237, 812, 729; 1H NMR (300 MHz, DMSO-d6)
8.94 (br s, 2H, NHþNH), 7.78 (s, 1H, H-7), 7.43e7.26 (m, 4H, H-
4þHthiazoleþH-Ph), 7.20 (d, J¼8.5 Hz, 1H, H-5), 6.78 (d, J¼7.8 Hz, 2H,
H-Ph), 1.85 (s, 3H, Ph-CH3); 13C NMR (75 MHz, DMSO-d6)
173.1,
158.6, 151.9, 151.8, 146.5, 140.4, 138.1, 131.9, 130.0 (2C), 129.4, 126.3
K. D.; Stevens, M. F. G. Br. J. Cancer 1998, 77, 745e752; (c) Molinski, T. F. Chem.
Rev. 1993, 93, 1825e1838; (d) Gunawardana, G. P.; Kohmoto, S.; Gunasekara, S.
P.; McConnel, O. J.; Koehn, F. E. J. Am. Chem. Soc. 1988, 110, 4856e4858; (e)
Gunawardana, G. P.; Kohmoto, S.; Burres, N. S. Tetrahedron Lett. 1989, 30,
4359e4362.
2. (a) Lamazzi, C.; Chabane, H.; Thiery, V.; Pierre, A.; Leonce, S.; Pfeiffer, B.; Renard,
P.; Guillaumet, G.; Besson, T. J. Enzyme Inhib. Med. Chem. 2002, 17, 397e401; (b)
d
d
ꢁ
ꢁ
79
(2C), 122.7, 120.0, 115.7, 110.4, 20.8; HRMS calcd for C
H BrN4OS
18 14
ꢀ
ꢁ
Frere, S.; Thiery, V.; Bailly, C.; Besson, T. Tetrahedron 2003, 59, 773e779; (c)
[MþH]þ 413.0072, found 413.0078.
ꢁ
ꢁ
Chabane, H.; Pierre, A.; Leonce, S.; Pfeiffer, B.; Renard, P.; Thiery, V.; Guillaumet,
G.; Besson, T. J. Enzyme Inhib. Med. Chem. 2004, 19, 567e575.
3. The first synthesis of 4,5-dichloro-1,2,3-dithiazolium chloride was described in
1985 by R. Appel. It was improved by C.W. Rees and co-workers who described
the use of a phase transfer catalyst, AdogenÒ, used here as a source of chloride.
Its addition improves the quality, but not the yield of the salt. For recent review
see: (a) Foucourt, A.; Chosson, E.; Besson, T. In Targets in Heterocyclic System-
sdChemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Italian Society of
Chemistry: Roma, Italy, 2010; Vol. 14, pp 315e350; For a broad selection of
previous papers on the use of Appel salt see: (b) English, R. F.; Rakitin, O. A.;
Rees, C. W.; Vlasova, O. G. J. Chem. Soc., Perkin Trans. 11997, 201e205; (c) Besson,
T.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1995, 1659e1662 For seminal paper
see: (d) Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985, 118,
1632e1643.
4. For patent literature on the use of Appel salt, see: (a) Wright, A. E.; Mattern, R.;
Jacobs, R. S. Patent WO 2,000,002,857, 2000. (b) McConnell, O. J.; Saucy, G.;
Jacobs, R. U.S. Patent 5,290,777, 1994; Chem. Abstr. 1994, 120, 236178m. (c) Sun,
H. H.; Sakemi, S.; Gunasekera, S.; Kashman, Y.; Lui, M.; Burres, N.; McCarthy, P.
U.S. Patent 4,970,226, 1990; Chem. Abstr. 1991, 115, 35701z. (d) Gunasekera, S. P.;
Cross, S. S.; Kashman, Y.; Lui, M. S.; Rinehart, K. L.; Tsujii, S. U.S. Patent
4,866,084, 1989; Chem. Abstr. 1990, 112, 185775d. (e) Gunasekera, S. P.; Cross, S.
S. Eur. Patent 304,157, 1989; Chem. Abstr. 1989, 111, 160196g. (f) Gunasekera, S.
P.; Cross, S. S.; Kashman, Y.; Lui M. S. Eur. Patent 272,810, 1988; Chem. Abstr.
1988, 109, 129417q.
4.6.25. 6-Bromo-N-[4-(4-methoxyphenyl)thiazol-2-yl]benzo[d]-ox-
azole-2-carboximidamideꢁ1(43). Yield 52% (0.429 g), yellow solid,
mp¼223e225 ꢀC; IR (cm
) ymax 3391, 3190, 3105, 1628, 1598, 1525,
1477, 1412, 1239, 1175, 1112, 1017, 820, 743, 533; 1H NMR (300 MHz,
DMSO-d6)
d
9.43 (br s, 2H, NHþNH), 8.27 (d, J¼1.6 Hz, 1H, H-7),
7.91e7.86 (m, 3H,H-4þH-Ph), 7.73e7.66 (m, 2H, H-5þHthiazole), 7.03
(d, J¼8.8 Hz, 2H, H-Ph), 3.80 (s, 3H, Ph-OCH3); 13C NMR (75 MHz,
DMSO-d6) d 173.1, 160.0, 158.6, 151.9, 151.7, 146.5, 140.4, 129.4, 127.7
(2C),127.3, 122.7,120.0,115.7, 114.7 (2C), 109.2, 55.3; HRMS calcd for
79
C
H
BrN4O2S [MþH]þ 429.0021, found 429.0024.
18 14
4.6.26. 6-Bromo-N-(4-(4-chlorophenyl)thiazol-2-yl)benzo[d]oxa-
zole-2-carboximidamide (44). Yield 44% (0.382 g), yellow solid,
mp¼230e232 ꢀC; IR (cmꢁ1
) ymax 3356, 3202, 3107,1632,1599,1534,
1470, 1402, 1234, 1094, 1064, 1013, 911, 859, 824, 737, 488; 1H NMR
(300 MHz, DMSO-d6)
d
9.40 (br s, 2H, NHþNH), 8.27 (d, J¼1.5 Hz,1H,
H-7), 7.98 (d, J¼8.5 Hz, 2H, H-Ph), 7.93 (s, 1H, Hthiazole), 7.88 (d,
5. For relevant papers on topsentines and their derivatives see: (a) Mal, S. K.;
ꢁ
J¼8.5 Hz, 1H, H-4), 7.69 (dd, J¼8.5, 1.5 Hz, 1H, H-5), 7.52 (d, J¼8.5 Hz,
Bohe, L.; Achab, S. Tetrahedron 2008, 64, 5904e5914; (b) Guinchard, X.; Vallee,
2H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
d 173.3, 158.6, 154.7, 151.9,
Y.; Denis, J.-N. J. Org. Chem. 2007, 72, 3972e3975; (c) For a review on marine
bis(indole)alkaloids, see: Yang, C.-G.; Huang, H.; Jiang, B. Curr. Org. Chem. 2004,
8, 1691e1720 and references cited therein.
6. For latest advances and reviews in microwave-assisted organic synthesis
(MAOS), see: (a) De la Hoz, A.; Loupy, A. In Microwaves in Organic Synthesis
Wiley-VCH: Weinheim, Germany, 2013; (b) Kappe, C. O.; Dallinger, D. Mol. Diversity
2009, 13, 71e193; (c) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65,
3325e3355; (d) Besson, T.; Chosson, E. Comb. Chem. High Throughput Screening
150.5, 146.6, 140.4, 133.4, 133.1, 129.4 (2C), 128.1 (2C), 122.7, 120.0,
79
115.7, 112.0; HRMS calcd for C
found 432.9533.
H
BrClN4OS [MþH]þ 432.9525,
17 11
4.6.27. 6-Bromo-N-(4-(2,4-chlorophenyl)thiazol-2-yl)benzo[d]-ox-
ꢀ
ꢁ
2007, 10, 903e917; (e) Alexandre, F. R.; Domon, L.; Frere, S.; Testard, A.; Thiery,
V.; Besson, T. Mol. Diversity 2003, 7, 273e280.
azole-2-carboximidamide (45). Yield 42% (0.462 g), yellow solid,
mp¼211e213 ꢀC; IR (cmꢁ1
) ymax 3440, 3235, 3100, 1622, 1595, 1554,
7. For the first description of the copper(I)-mediated cyclization of imino-1,2,3-
dithiazoles into benzothiazoles see: Besson, T.; Dozias, M. J.; Guillard, J.; Rees,
C. W. J. Chem. Soc., Perkin Trans. 1 1998, 3925e3926.
1516, 1465, 1238, 1104, 1043, 909, 863, 810, 757; 1H NMR (300 MHz,
DMSO-d6)
d
9.41 (br s, 2H, NHþNH), 8.25 (d, J¼1.7 Hz, 1H, H-7), 7.88
8. Compound 13 was already described in Ref. 2b.
(d, J¼8.4 Hz, 1H, H-Ph), 7.86 (d, J¼8.5 Hz, 1H, H-4), 7.83 (s, 1H,
Hthiazole), 7.74 (d, J¼2.1 Hz, 1H, H-Ph), 7.67 (dd, J¼8.5, 1.7 Hz, 1H, H-
5), 7.54 (dd, J¼8.4, 2.1 Hz, 1H, H-Ph); 13C NMR (75 MHz, DMSO-d6)
9. Recent selected examples: (a) Zheng, S.; Zhong, Q.; Jiang, Q.; Mottamal, M.;
Zhang, Q.; Zhu, N.; Burow, M. E.; Worthylake, R. A.; Wang, G. ACS Med. Chem.
Lett. 2013, 4, 191e196; (b) Hanke, T.; Dehm, F.; Liening, S.; Popella, S.-D.;
Maczewsky, J.; Pillong, M.; Kunze, J.; Weinigel, C.; Barz, D.; Kaiser, A.; Wurglics,
d
172.5, 158.5, 151.9, 147.4, 146.8, 140.4, 133.8, 133.0, 132.5, 132.3,
€
M.; Lammerhofer, M.; Schneider, G.; Sautebin, L.; Schubert-Zsilavecz, M.; Werz,
130.5, 129.4, 128.3, 122.6, 120.0, 116.4, 115.7; HRMS calcd for
O. J. Med. Chem. 2013, 56, 9031e9044; (c) Ali, A. R.; El-Bendary, E. R.; Ghaly, M.
A.; Shehata, I. A. Eur. J. Med. Chem. 2013, 69, 908e919; (d) Wehn, P. M.; Har-
rington, P. E.; Carlson, T. J.; Davis, J.; Deprez, P.; Fotsch, C. H.; Grillo, M. P.; Ying-
Lin Lu, J.; Morony, S.; Pattabiraman, K.; Poon, S. F.; Reagan, J. D.; StJean, D. J., Jr.;
Temal, T.; Wang, M.; Yang, Y.; Henley, C., III; Lively, S. E. Bioorg. Med. Chem. Lett.
2013, 23, 6625e6628; (e) Agrawal, M.; Kharkar, P.; Moghe, S.; Mahajan, T.;
Deka, V.; Thakkar, C.; Nair, A.; Mehta, C.; Bose, J.; Kulkarni-Almeida, A.; Bhedi,
D.; Vishwakarma, R. A. Bioorg. Med. Chem. Lett. 2013, 23, 5740e5743.
79
C
H
BrCl2N4OS [MþH]þ 466.9136, found 466.9125.
17 10
Acknowledgements
We thank the LABEX SynOrg (ANR-11-LABX-0029) and AI-Chem
Channel Program for financial support. We also acknowledge Anton
Paar GmbH (Graz, Austria) for provision of the single-mode mi-
crowave reactor (Monowave 300) and Milestone S.r.l. (Italy) for fi-
nancial and technical support. For kinase screening experiments,
we thank the kinase Inhibitory Specialized Screening facility (KISSf)
platform based in Station Biologique de Roscoff (Dr. S. Ruchaud),
France.
10. Compound 15 and a series of functionalized 2-aminothiazoles were described
in: Kabalka, G. W.; Meredy, A. R. Tetrahedron Lett. 2006, 47, 5171e5172.
11. Topliss, J. G. J. Med. Chem. 1972, 15, 1006e1011 In this paper, proposals are
presented for the stepwise selection for synthesis of analogues of an active
compound. The diagrams are based on a fundamental assumption of the
Hansch method that a particular substituent may modify activity relative to the
parent compound by virtue of resulting changes in hydrophobic, electronic and
steric effects. Using the Topliss scheme allowed to choose certain reagents to
check the interest of a methodology, while starting to build a list of molecules
with potential biological interest.
Supplementary data
12. Kinase screening experiments were performed by the Kinase Inhibitory Spe-
cialized Screening facility (KISSf) platform based in Station Biologique de Roscoff.
13. Dielectric properties are correlated with lost dissipation factor (tan d), which
1H and 13C NMR spectra of all compounds are available. Sup-
plementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.06.102.
expresses the capacity of a molecule or a material to transform electromagnetic
energy into thermal energy. A very high susceptibility to microwaves is char-
acterized by a high value (>0.5) of tan d. For more details see: Gabriel, C.;
Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998,
27, 213e224.
References and notes
14. Bourdais, J.; Abenhaim, D.; Sabourault, B.; Sabourault, A. L. J. Heterocycl. Chem.
1976, 13, 491e496.
15. Dongjian, Z.; Jiuxi, C.; Huilong, X.; Miaochang, L.; Jinchang, D.; Huayue, W. L.
Synth. Commun. 2009, 39, 2895e2906.
1. For relevant papers and reviews see: (a) Wells, G.; Bradshaw, T. D.; Diana, P.;
Seaton, A.; Shi, D.-F.; Westwell, A. D.; Stevens, M. F. G. Bioorg. Med. Chem. Lett.
2000, 10, 513e515; (b) Bradshaw, T. D.; Wrigley, S.; Shi, D.-F.; Schultz, R. J.; Paull,
Please cite this article in press as: Deau, E.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.102