Palladium-Catalyzed Direct Arylation of 2,6-Disubstituted Imidazo[2,1-b][1,3,4]thiadiazoles

Article abstract of DOI:10.1055/s-0035-1561317

This work reports the original synthesis of trisarylimidazo[2,1-b][1,3,4]thiadiazole derivatives using a C-H arylation process. The scope of the reaction demonstrated the critical importance of the electronic effects of each substituent on the efficiency

Full text of DOI:10.1055/s-0035-1561317

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 1091–1095
letter
1091
C. Copin et al.
Letter
Synlett
Palladium-Catalyzed Direct Arylation of 2,6-Disubstituted
Imidazo[2,1-b][1,3,4]thiadiazoles
Chloé Copin
Ar3
Nicolas Henry
sequential or "one-pot" double
R
R
N
N
N
N
Pd-catalyzed reaction
Frédéric Buron
N
Ar2
N
Br
Suzuki–Miyaura
C–H arylation
Sylvain Routier*
S
S
R = Ar1 or H
20 examples
Institut de Chimie Organique et Analytique, ICOA, Univ Orleans,
UMR 7311 CNRS, Rue de Chartres, BP 6759, 45067 Orleans,
France
sylvain.routier@univ-orleans.fr
Received: 18.11.2015
Accepted after revision: 14.12.2015
Published online: 08.01.2016
Our group is interested in the discovery and the func-
tionalization of rare heterocyclic systems and was the first
to develop C–H arylation at the C-2 indole position in order
to build polycyclic indolocarbazole-like bioactive mole-
cules.4 More recently, we have built several fused bicyclic
five-membered heterocycles and investigated their potency
toward organometallic-mediated reactions as well as to-
ward C–H arylations.5
DOI: 10.1055/s-0035-1561317; Art ID: st-2015-d0895-l
Abstract This work reports the original synthesis of trisarylimid-
azo[2,1-b][1,3,4]thiadiazole derivatives using a C–H arylation process.
The scope of the reaction demonstrated the critical importance of the
electronic effects of each substituent on the efficiency of the reaction.
In addition, a double efficient ‘one-pot’ functionalization at the C-2 and
then at the C-5 positions of 2-bromo-6-arylimidazo[2,1-b][1,3,4]thiadi-
azole derivatives was achieved using a sequential Suzuki–Miyaura–C–H
arylation cascade procedure.
The current focus of our research is on the imidazothia-
diazole series due to the lack of versatile methods to obtain
and functionalize them as well as the structure of the imid-
azo[2,1-b][1,3,4]thiadiazole core.6 This series is of great in-
terest in pharmaceutical chemistry and in the design of an-
ticancer,7 antitubercular,8 and analgesic agents.9 This
prompted us to explore a palladium-catalyzed reaction to-
ward C–H arylation in the 5,5-fused bicyclic series.10
There has been much interest in developing efficient
synthetic methodologies to design poly- and regioselective-
ly substituted imidazo[2,1-b][1,3,4]thiadiazoles.11 Recently,
we disclosed a method for the amidification and Suzuki–
Miyaura cross-coupling of 2-bromo-imidazo[2,1-b][1,3,4]-
thiadiazole derivatives A.10 We report herein the use of di-
rect arylation to functionalize 2,6-bisarylimidazo[2,1-b]-
[1,3,4]thiadiazoles B at the C-5 position using aryl bro-
mides. We also present an unprecedented synthesis of
2,5,6-trisaryl-imidazo[2,1-b][1,3,4]thiadiazoles C using a
‘one-pot’ microwave-assisted Suzuki cross-coupling–C–H
arylation process (Scheme 1).
Key words imidazothiadiazole, Suzuki–Miyaura, palladium, C–H ary-
lation, cross-coupling
Among the wide variety of synthetic methods used for
heterocyclic functionalization, direct C–H and Suzuki palla-
dium-catalyzed arylations are recognized as the most effi-
cient strategies and have been well described over the past
years.1 The main advantage of these methodologies is that
they avoid tedious reagent preparation, as compared to
Stille or Negishi cross-couplings, that require the prepara-
tion of stannyl or organozinc derivatives.2 Nevertheless, the
latter methods remain crucial in C–C bond formation, for
which other solutions have proved to be less efficient.
The direct C–H activation mode presents several advan-
tages over Suzuki arylation. In view of the widespread in-
terest in the synthesis of bioactive molecules and organic
materials, the rapidity and easy access to reagents of this
straightforward method heighten its usefulness. This cross-
coupling has been efficiently carried out in many heterocy-
clic series leading to a versatile method compatible with
thiophene, furan, imidazole, indole, pyrrole, pyrazole, imid-
azo[1,2-a]pyrimidine, indolizine, and oxazolo[4,5-b]pyri-
dine skeletons.3
To explore the reactivity of 2,6-bis-substituted imid-
azo[2,1-b][1,3,4]thiadiazole B under C–H activation condi-
tions, a set of reactions involving 1 with bromobenzene as
coupling partner was examined. Pd2(dba)3 or Pd(ddpf)Cl2
were first used as palladium sources, Cs2CO3 as inorganic
base, and dioxane at 150 °C under microwave irradiation;
but only starting materials were recovered (Table 1, entries
1 and 2). A switch to Pd(OAc)2 with an aliphatic phosphine
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 1091–1095

1092
C. Copin et al.
Letter
Synlett
Ar3
N
C-5
Ar1
Ar1
R2B(OH)2, Pd0
Suzuki–Miyaura
Ar1
C-6
R3Br, Pd0
N
N
N
N
N
N
N
Ar2
Ar2
N
Br
C–H arylation
S
S
S
C-2
B
A
C
Pd-catalyzed reaction
one-pot
Scheme 1 Synthesis of tris-substituted imidazo[2,1-b][1,3,4]thiadiazoles
as ligand led to a very low but encouraging amount of prod-
uct 2 (1H NMR analysis of crude material showed the pres-
ence of 2 in approximately 10% yield, Table 1, entry 3). Us-
ing an aromatic phosphine, the desired compound 2 was
formed in higher yield, but contaminated by residual start-
ing material 1 (Table 1, entries 4 and 5) after each attempt
at purification. To circumvent this problem we decided to
find conditions leading to a complete conversion of 1. With
a bidentate palladium complex formed in situ using
Pd(OAc)2 (10 mol%) and Xantphos (20 mol%), the reaction
was complete in one hour. Easier purification and the ab-
sence of byproducts led to the desired product 2 being iso-
lated in a very good yield of 91% (Table 1, entry 6). Toluene
(Table 1, entry 7) could be used instead of dioxane but, with
DMF, byproducts appeared and yields of isolated product
dramatically decreased. Other parameters, such as the
amount of base and reaction time, were screened without
any real benefit in conversion or yield.
bromoaryl derivatives, as iodobenzene coupling partners
produced no additional benefit (Table 2). DMF or toluene
were used as solvents, depending on the solubility of the
starting material. We initiated the construction of the tris-
aryl library using derivatives of type B possessing a tolyl
group in the Ar2 position to prevent any alteration of the re-
sults induced by an additional reactive function. Whatever
the bromobenzene used, replacing the R moiety nitro group
by a strong electron-donating group, such as methoxy,
greatly decreased conversion (Table 2, entries 2–4). It also
appeared that the electronic depletion induced by R substi-
tution was required to ensure C–H activation. This behavior
was demonstrated using 4-nitrobromobenzene as coupling
agent, when 8 was isolated in a very good 80% yield (Table
2, entry 6).
The direct arylation of 2,6-bis-substituted imidazo[2,1-
b][1,3,4]thiadiazole appeared to be more efficient with
electron-deficient aryl bromides, and the best results were
obtained with a nitro group on R. With this further substi-
tution, the nature of the aryl halide did not influence the
conversion rate, and yields of isolated products 8–15 always
With these optimized conditions in hand, we next in-
vestigated the scope of the reaction using a variety of 2,6-
bis-substituted imidazo[2,1-b][1,3,4]thiadiazoles with only
Table 1 Pd-Catalyzed C-5 Arylation of Imidazo[2,1-b][1,3,4]thiadiazolesa
H
NO2
NO2
[Pd] (10 mol%)
Br
N
N
N
N
+
ligand (20 mol%), base
solvent, time
N
N
S
S
MW, 150 °C
1
2
Entry
[Pd]
Pd2(dba)3
Ligand
Base (equiv)
Solvent
Time (h)
Yield of 2 (%)
1
2
3
4
5
6
7
8
–
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMF
1
1
1
1
1
1
1
1
–
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
–
PCy3
10b
PPh3
51b
P(o-tolyl)
Xantphos
Xantphos
Xantphos
62b
100b (91c)
100b (80c)
89b (31c)
a Reaction conditions: 1 (0.24 mmol), bromobenzene (1.5 equiv), [Pd] (10 mol%), ligand (20 mol%), base (3.0 equiv), and solvent (3 mL) at 150 °C under argon.
b Amount of 2 was estimated by 1H NMR spectroscopy.
c Yields are given for isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 1091–1095

1093
C. Copin et al.
Letter
Synlett
reached or exceeded 78% (Table 2, entries 6–14). Addition-
ally the three o-, m-, or p-benzaldehyde substrates under-
went a similar arylation reaction, indicating the negligible
effect of steric hindrance (Table 2, entries 8–10).
To complete this study, we suppressed the substituent
at C-6 (R = H). The reaction was totally regioselective, and
the nitrophenyl group was totally introduced at C-5. This C-5
versus C-6 C–H discrimination led to product 20 with an
impressive 92% yield (Table 2, entry 20). This high level of
selectivity opens novel perspectives that will be validated
in due course.
Next, we decided to explore the formation of 2,5,6-tri-
substituted arylated imidazo[2,1-b][1,3,4]thiadiazoles in a
‘one-pot’ sequential Suzuki–Miyaura–C–H arylation proce-
dure using synthesized 2-bromo-6-(het)arylimidazo[2,1-
b][1,3,4]thiadiazoles (Scheme 2). Recently, we reported the
synthesis of 22 and 23 via a Suzuki–Miyaura reaction under
conditions very similar to those required for the above C-5
heteroarylation,9 albeit with two differences: first, the acti-
vation mode (microwave only for C–H arylation), and sec-
ond, the nature of the coupling agent, namely a boron de-
rivative for the Suzuki reaction instead of an aryl bromide
in the case of C–H arylation.
To check the influence of the aryl group at the C-2 posi-
tion, we prepared derivatives of type B possessing a nitro or
a methoxy substituent on Ar2. When electron-donating
groups were positioned both on R and Ar2, the reaction car-
ried out with deactivated 4-nitrobromobenzene exhibited
full C–H arylation efficiency (Table 2, entries 15 and 16).
Surprisingly, the introduction of a nitro group on Ar2 de-
creased the yields of 18 and 19 (Table 2, entries 17 and 18).
This behavior appears mainly to be due to the high insolu-
bility of the corresponding starting material of type B in
toluene or dioxane. Additionally, further increase in micro-
wave irradiation time led to several unidentified byprod-
ucts.
Table 2 Synthesis of Derivatives 2–19a
Ar3
Ar3-Br
R
N
N
Pd-catalyzed reaction
N
N
R
Ar2
N
Ar2
N
S
S
R = Ar1 or H
B
2–20
Entry
R
Ar2
Ar3
Solvent
Product
Yield (%)c
1
2
4-O2NC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-O2NC6H4
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
H
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
4-MeOC6H4
Ph
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2
3
91
15b
10b
45b
16b
80
90
81
79
78
84
81
80
78
81
81
38
38
92
Ph
3
4-MeOC6H4
Ph
4
4
5
5
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
4-HOCC6H4
3-HOCC6H4
2-HOCC6H4
4-FC6H4
6
6
7
7
8
8
9
9
10
11
12
13
14
15
16
17
18
19
20
10
11
12
13
14
15
16
17
18
19
4-NCC6H4
4-F3CC6H4
4-MeOCC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
a Reaction conditions: 2,6-bisarylimidazo[2,1-b][1,3,4]thiadiazole B (1.0 equiv), bromobenzene (1.5 equiv), Pd(OAc)2 (10 mol%), Xantphos (20 mol%), Cs2CO3
(3.0 equiv) in dioxane or toluene (3 mL for 0.24 mmol) at 150 °C for 1 h under argon.
b Conversion estimated by 1H NMR spectroscopy.
c Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 1091–1095

1094
C. Copin et al.
Letter
Synlett
R3
Suzuki–Miyaura
C–H arylation
ArBr (1.5 equiv)
Pd(OAc)2 (10 mol%)
Xantphos (20 mol%)
ArB(OH)2 (1.1 equiv)
Pd(OAc)2 (10 mol%)
Xantphos (20 mol%)
NO2
NO2
NO2
N
N
N
N
N
N
N
N
N
Cs2CO3 (2.0 equiv)
dioxane
Cs2CO3 (3.0 equiv)
dioxane
Br
S
S
S
R2
R2
22: R2 = Me; R3 = H; 84%
23: R2 = H; R3 = NO2; 81%
2: R2 = Me; R3 = H; 91%
24: R2 = H; R3 = Me; 55%
MW, 150 °C, 30 min
MW, 150 °C, 30 min
21
"One-pot" procedure
R2C6H4B(OH)2 (1.0 equiv), Pd(OAc)2 (10 mol%), Xantphos (20 mol%),
Cs2CO3 (3.0 equiv), dioxane, 150 °C , 30 min
then addition of ArBr (1.5 equiv), MW, 150 °C , 1 h
2: R2 = Me; R3 = H; 78%
24: R2 = H; R3 = Me; 72%
Scheme 2 Synthesis of of trisarylimidazo[2,1-b][1,3,4]thiadiazole by a ‘one-pot’ procedure
Taking advantage of this similarity, we first synthesized
2 and 24 in 76% and 45% overall yields. Next we tried a one-
pot sequential synthesis using Cs2CO3 and 10 mol% of
Pd(PPh3)4 and 20 mol% of Xantphos in dioxane at 150 °C. Af-
ter 30 minutes, reaction was complete (as monitored by
TLC) and the bromo-aryl derivative was added. The reaction
was stirred at 150 °C for an additional hour. This new strat-
egy gave a slight increase in yield, and 2 was obtained in
78% yield. Concerning compound 24, this ‘one-pot’ sequen-
tial reaction gave a real benefit as the yield from 24 rose to
72% instead of 45% by the stepwise synthesis. The high po-
tential of the method proved its efficiency and is currently
being used in our laboratory in other programs aimed at
designing biologically active compounds.
The results achieved in this study enable us to put for-
ward a mechanism for the observed palladium-catalyzed
C–H arylation. In the literature, four main pathways involv-
ing SEAr, CMD (concerted metalation–deprotonation), nC-
MD, and the Heck mechanism, are currently proposed.10 In
order to choose or discard certain possibilities, we first
tried to identify the role of the C-5–H bond acidity with a
deuterium incorporation experiment.12 However, the treat-
ment of disubstituted imidazo[2,1-b][1,3,4]thiadiazoles
with KOH in a mixture of dioxane and D2O did not reveal
any exchange in C-5 position. This result was not sufficient
to determine the mechanism involved in this direct C–H
arylation and therefore to justify the presence of an elec-
tron-donating group in C-2 position and the use of an elec-
trophilic palladium complex containing an electron-with-
drawing aryl group. On this basis, a plausible mechanism is
proposed in Scheme 3; DFT calculations will be needed to
draw firm conclusions.
In conclusion, we have reported here the direct aryla-
tion of 2,5-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles
to obtain a novel class of trisubstituted imidazo[2,1-b]-
[1,3,4]thiadiazole derivatives.13,14 Moderate to excellent
yields were achieved from readily available aryl bromides,
particularly those with an electron-withdrawing substitu-
ent. A study to discriminate between the C-5 and C-6 posi-
tions was carried out and showed a high selectivity for the
C-5 position. Finally, we developed a ‘one-pot’ Suzuki–
Miyaura–C–H arylation procedure at the C-2 and C-5 posi-
tions, respectively. This synthetic pathway gave higher
yields than a stepwise strategy.
Acknowledgment
The authors thank the Ligue Contre le Cancer du Grand Ouest (Comi-
tés des Deux Sèvres, du Finistère, de l’Ile et Vilaine, du Loir-et-Cher,
du Loire Atlantique, du Loiret, de la Vienne), the Région Centre Val de
O– Cs+
Ar3
Ar3
Pd
O
H
N
O
N
N
Ar3PdBr
Cs2CO3
Ar3
Ar2
Pd
N
N
N
N
Ar1
Ar2
H
Ar2
Ar1
Ar1
Ar2
N
S
N
N
S
S
N
Ar1
A
D
S
C
N
B
Scheme 3 Proposed mechanism of C–H arylation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 1091–1095

1095
C. Copin et al.
Letter
Synlett
Loire/FEDER (IMAD and Cosmi programs), the Cancéropôle Grand
Ouest (strand ‘valorisation des produits de la mer’) and the MESR for
their financial support.
Toth, L. M. Tetrahedron Lett. 2004, 45, 7157. (e) Barnish, I. T.;
Cross, P. E.; Dickinson, R. P.; Gadsby, B.; Parry, M. J.; Randall, M.
J.; Sinclair, I. W. J. Med. Chem. 1980, 23, 117.
(7) Terzioglu, N.; Gürsoy, A. Eur. J. Med. Chem. 2003, 38, 781.
(8) Kolavi, G.; Hegde, V.; Khazi, I. a.; Gadad, P. Bioorg. Med. Chem.
2006, 14, 3069.
Supporting Information
(9) Gadad, A. K.; Palkar, M. B.; Anand, K.; Noolvi, M. N.; Boreddy, T.
S.; Wagwade, J. Bioorg. Med. Chem. 2008, 16, 276.
(10) Copin, C.; Henry, N.; Buron, F.; Routier, S. Eur. J. Org. Chem. 2012,
6804.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561317.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(11) (a) Théveau, L.; Querolle, O.; Dupas, G.; Hoarau, C. Tetrahedron
2013, 69, 4375. (b) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev.
2010, 110, 749. (c) Bellina, F.; Rossi, R. Adv. Synth. Catal. 2010,
352, 1223. (d) Fagnou, K. Top. Curr. Chem. 2010, 292, 35.
(e) Bellina, F.; Cauteruccio, S.; Rossi, R. Curr. Org. Chem. 2008,
12, 774. (f) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36,
1173.
(12) (a) Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51,
3066. (b) Le Meur, M.; Bourg, S.; Massip, S.; Marchivie, M.; Jarry,
C.; Guillaumet, G.; Routier, S. Eur. J. Org. Chem. 2014, 3704.
(13) General Procedure
References and Notes
(1) (a) Kazzouli, S. E.; Koubachi, J.; Brahmi, N. E.; Guillaumet, G. RSC
Adv. 2015, 5, 15292. (b) Fischmeister, C.; Doucet, H. Green Chem.
2011, 13, 741. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew.
Chem. Int. Ed. 2009, 48, 9792. (e) McGlacken, G. P.; Bateman, L.
M. Chem. Soc. Rev. 2009, 38, 2447. (f) Seregin, I. V.; Gevorgyan,
V. Chem. Soc. Rev. 2007, 36, 1173. (g) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174.
(2) (a) Sharma, A.; Vacchani, D.; Van der Eycken, E. Chem. Eur. J.
2013, 19, 1158. (b) Joo, J. M.; Guo, P.; Sames, D. J. Org. Chem.
2013, 78, 738. (c) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.;
Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 10236. (d) Chen, D. Y.-
K.; Youn, S. W. Chem. Eur. J. 2012, 18, 9452. (e) Joo, J. M.; Touré,
B. B.; Sames, D. J. Org. Chem. 2010, 75, 4911. (f) Roger, J.;
Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2, 20.
(3) (a) Verrier, C.; Lassalas, P.; Théveau, L.; Quéguiner, G.; Trécourt,
F.; Marsais, F.; Hoarau, C. Beilstein J. Org. Chem. 2011, 7, 1584.
(b) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269.
(4) Routier, S.; Peixoto, P.; Mérour, J.-Y.; Coudert, G.; Dias, N.; Bailly,
C.; Pierré, A.; Léonce, S.; Caignard, D.-H. J. Med. Chem. 2005, 48,
1401.
(5) (a) Le Meur, M.; Bourg, S.; Massip, S.; Marchivie, M.; Jarry, C.;
Guillaumet, G.; Routier, S. Eur. J. Org. Chem. 2014, 3704.
(b) Othman, R. B.; Massip, S.; Marchivie, M.; Jarry, C.;
Vercouillie, J.; Chalon, S.; Guillaumet, G.; Suzenet, F.; Routier, S.
Eur. J. Org. Chem. 2014, 3225.
A solution of 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole
derivative (1.0 equiv), Cs2CO3 (3.0 equiv) and (het)aryl bromide
(1.5 equiv) in dry 1,4-dioxane or toluene (3 mL for 80 mg) was
degassed by argon bubbling for 15 min. Xantphos (0.2 equiv)
and Pd(OAc)2 (0.1 equiv) were then added, and the mixture was
heated to 150 °C for 60 min under microwave irradiation. After
removing the solvent in vacuo, the crude product was purified
by flash chromatography on silica gel.
(14) 2-(4-Methylphenyl)-5-phenyl-6-(4-nitrophenyl)imidazo-
[2,1-b][1,3,4]thiadiazole (2)
The reaction was carried out as described in general procedure
using 1 (80 mg, 0.24 mmol, 1.0 equiv) and bromobenzene (37
μL, 0.36 mmol, 1.5 equiv) in dioxane (3 mL). The crude product
was purified by flash chromatography on silica gel (PE–CH2Cl2,
2:8 to 0:1) to afford 2 as a yellow solid (90 mg, 91%). Rf = 0.36
(PE–CH2Cl2, 2:8); mp >260 °C. IR (ATR diamond): ν = 1593, 1505,
1481, 1338, 1324, 1108, 1084, 971, 856, 816, 739, 708, 681 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 8.7 Hz, 2 H, 2 × HAr),
7.83 (d, J = 8.7 Hz, 2 H, 2 × HAr), 7.77 (d, J = 8.1 Hz, 2 H, 2 × HAr),
7.65 (dd, J = 7.6, 1.5 Hz, 2 H, 2 × HAr), 7.56–7.44 (m, 3 H, 3 × HAr),
7.30 (d, J = 8.1 Hz, 2 H, 2 × HAr), 2.46 (s, 3 H, CH3) ppm. 13C NMR
(101 MHz, CDCl3): δ = 162.6 (Cq), 146.8 (Cq), 145.3 (Cq), 142.8
(Cq), 141.4 (Cq), 140.0 (Cq), 130.1 (2 × CHAr), 129.6 (2 × CHAr),
129.3 (CHAr), 129.2 (2 × CHAr), 128.5 (Cq), 128.0 (2 × CHAr), 127.5
(Cq), 127.0 (2 × CHAr), 126.0 (Cq), 124.0 (2 × CHAr), 21.8 (CH3)
ppm. HRMS (EI-MS): m/z calcd for C23H16N4O2S: 413.10667 [M +
H]+; found: 413.10692.
(6) (a) Khazi, I. A. M.; Gadad, A. K.; Lamani, R. S.; Bhongade, B. A.
Tetrahedron 2011, 67, 3289. (b) Ferrari, S.; Morandi, F.;
Motiejunas, D.; Nerini, E.; Henrich, S.; Luciani, R.; Venturelli, A.;
Lazzari, S.; Calò, S.; Gupta, S.; Hannaert, V.; Michels, P. A. M.;
Wade, R. C.; Costi, M. P. J. Med. Chem. 2011, 54, 211. (c) Jung, K.-
Y.; Kim, S.-K.; Gao, Z.-G.; Gross, A. S.; Melman, N.; Jacobson, K.
A.; Kim, Y.-C. Bioorg. Med. Chem. 2004, 12, 613. (d) Vachal, P.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 1091–1095