Late-Stage C-H Arylation of Thiazolo[5,4- f ]quinazolin-9(8 H)-one Backbone: Synthesis of an Array of Potential Kinase Inhibitors

Article abstract of DOI:10.1055/s-0036-1588434

Driven by the need of structural modification to establish structure-activity relationships, the regioselective C-H bond activation of thiazolo[5,4- f ]quinazolin-9(8 H)-one backbone has been developed to furnish the corresponding C2-arylated valuable scaffold. This strategy provides a synthetically streamlined and useful route for late-stage diversification of this attractive skeleton, required in drug discovery. A more eco-friendly synthesis of thiazolo[5,4- f ]quinazolin-9(8 H)-ones is also described giving access to these aforementioned compounds in a facile manner.

Full text of DOI:10.1055/s-0036-1588434

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
special topic
A
de
F. Couly et al.
Special Topic
Synthesis
Late-Stage C–H Arylation of Thiazolo[5,4-f]quinazolin-9(8H)-one
Backbone: Synthesis of an Array of Potential Kinase Inhibitors
Florence Couly
S
N
Ar
H
N
S
Carole Dubouilh-Benard
Thierry Besson*
Corinne Fruit*
1) NHMe2
DMF
2) HBr
O
S
O
S
Cl
Br
O
N
ArX
Cu/Pd
N
R
R
N
R
N
N
N
MW
MW
N
N
Metal-free
Ligand-free
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA
UMR 6014, 76000 Rouen, France
corinne.fruit@univ-rouen.fr
21–64% yield range
R = Bn, 73%
R = cPr, 71%
3 steps, 19 examples
Appel salt chemistry
thierry.besson@univ-rouen.fr
Dedicated to the memory of Prof. Rolf Appel (25 February
1921 – 30 January 2012)
Published as part of the Special Topic Modern Strategies for
Heterocycles Synthesis
Received: 01.03.2017
Accepted after revision: 02.05.2017
Published online: 12.06.2017
the bioactivity profile compared to the parent compound.
In terms of SAR studies, transition-metal-catalyzed inter-
molecular C–C coupling of this valuable scaffold through di-
rect C–H arylation represents an extremely attractive ap-
proach, circumventing tedious multi-step syntheses.
DOI: 10.1055/s-0036-1588434; Art ID: ss-2017-c0132-st
Abstract Driven by the need of structural modification to establish
structure-activity relationships, the regioselective C–H bond activation
of thiazolo[5,4-f]quinazolin-9(8H)-one backbone has been developed
to furnish the corresponding C2-arylated valuable scaffold. This strate-
gy provides a synthetically streamlined and useful route for late-stage
diversification of this attractive skeleton, required in drug discovery. A
more eco-friendly synthesis of thiazolo[5,4-f]quinazolin-9(8H)-ones is
also described giving access to these aforementioned compounds in a
facile manner.
NH
R1O
O
N
S
R2
N
N
Key words thiazoloquinazolinone, C–H arylation, palladium, micro-
wave irradiation, Appel’s salt, kinase inhibition
R1 = Me
2 = Bn
R1 = Me
R
R
R
1 = Bn
2 = cPr
2 = cPr
R
IC50 CLK1 = 500 nM
IC50 DYRK1A = 300 nM
IC50 GSK3 = 220 nM
IC50 CLK1 = 31 nM
IC50 DYRK1A = 91 nM
IC50 GSK3 = 82 nM
IC50 CLK1 = 60 nM
IC50 DYRK1A = 60 nM
IC50 GSK3 = 100 nM
Carbon–carbon bond formation through a C–H bond ac-
tivation emerged as a powerful tool for the late-stage diver-
sification of valuable scaffolds.1 The main feature of this ex-
panding methodology is the incorporation of structural di-
versity into natural or synthetic complex molecules having
usually several C–H bonds.2 In this context, the synthesis of
a library of drug candidates involving a regioselective C–H
activation as functionalization strategy is fairly appealing.
Driven by the design of an efficient route allowing a direct
transformation of lead molecules identified in our research
group as kinase inhibitors3,4 (Scheme 1) into a panel of ana-
logues, the selective and sequential C2-H and C7-H aryla-
tion of N8-benzylated thiazolo[5,4-f]quinazolin-9(8H)-one
was recently reported by our group.5 Owing to the impor-
tance of multi-target directed ligands of kinases,6 struc-
ture-activity relationship (SAR) studies were considered.
Among the potential chemical transformations, C2 aryla-
tion of the N8-cyclopropylthiazolo[5,4-f]quinazolin-9(8H)-
one was therefore envisioned (Scheme 1). The slight modi-
fication of the structure triggered by the introduction of an
aryl residue upon the skeleton could have a huge impact on
This work:
Ar
H
O
S
S
O
N
ArX
Pd/Cu
R2
R2
N
N
N
N
MW
N
R2 = Bn, cPr
Scheme 1 Structure of lead compounds and design of their analogues
The synthesis of thiazolo[5,4-f]quinazolin-9(8H)-one-2-
carbonitriles 5a and 5b were previously reported by our
group in 5 steps starting from commercially available 5-ni-
troanthranilic acid.3,7 Because of its potential for time and
energy savings, safety, increasing product yields, improved
reproducibility and easy scale-up, microwave-heated
methodology8 was applied to this synthesis. The key steps
are the reaction of the aniline derivative 3 with 4,5-di-
chloro-1,2,3-dithiazolium chloride (Appel’s salt) followed
by the cyclization of the intermediate imine 4 (Scheme 2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
F. Couly et al.
Special Topic
Synthesis
a) DMA-DMF (2.5 equiv)
EtOAc
MW 77 °C, 30 min
O
N
O
N
Br
O
Pd/C 10% (10% w/w)
NH4CO2H (5 equiv)
H2N
O2N
H2N
O2N
CO2H
NH2
NBS (1.1 equiv)
DMF, r.t., 2 h
NR
NR
NR
b) RNH2 (1.5 equiv)
AcOH
EtOH, MW 78 °C
30 min
N
MW 118 °C, 30 min
1a, R = Bn, 65%
1b, R = cPr, 85%
2a, R = Bn, 97%
2b, R = cPr, 85%
3a, R = Bn, 99%
3b, R = cPr, 93%
S
N
H
NC
N
S
Cl
Br
O
N
O
N
S
O
N
S
Appel salt (1.2 equiv)
pyridine (2 equiv)
CuI (1 equiv)
pyridine (0.3 M)
N
N
HBr (0.15–0.30 M)
MW 100 °C, 45 min
NR
NR
NR
MW 115 °C
30 min
CH2Cl2, r.t., 3 h
4a, R = Bn, 86%
4b, R = cPr, 76%
5a, R = Bn, 76%
5b, R = cPr, 91%
6a, R = Bn, 92%
6b, R = cPr, 90%
Scheme 2 Synthesis of N8-benzylthiazolo[5,4-f]quinazolin-9(8H)-one (6a) and N8-cyclopropylthiazolo[5,4-f]quinazolin-9(8H)-one (6b) starting from
5-nitroanthranilic acid
Access to compounds 6a,b was finally obtained by heating
Table 1 Effect of the Additives on the Synthesis of Thiazolo-
[5,4-f]quinazolin-9(8H)-one-2-carbonitrile 5a from 4a
the corresponding precursor 5a,b in HBr. Nevertheless pre-
vious studies on C–H arylation of compound 5a,9 showing
that treatment of this compound with 2 equivalents of
tBuOLi and 50 mol% of CuI for 10 minutes afforded small
quantities of product 6a, allowed us to modify the synthetic
route.
S
N
NC
S
CuI (n equiv)
base (n equiv)
Cl
Br
O
N
O
N
S
N
N
NBn
NBn
DMF (0.4 M)
MW 120 °C
10 min
According to this aforementioned observation, we rea-
soned that compound 6a could be arguably obtained from
the key intermediate 4a in a one-pot cyclization-decyana-
tion process in the presence of tBuOLi, instead of the most
toxic pyridine and an excess of CuI. Unfortunately, no decy-
anation reaction was observed under these conditions, but
we were pleased to find that compound 5a was isolated in
70% yield (Table 1, entry 1). Longer reaction time proved to
be inadequate since degradation was observed instead of
the expected compound 6a (entry 2). Control experimenta-
tions revealed that the cyclization was effective without
copper (entry 3) or base (entry 4). In the first case, the effi-
ciency of the reaction was the same, whereas the yield dra-
matically decreases with copper in the absence of base.
With a view to develop a more eco-friendly reaction, the
metal-free process was preferred to carry on the optimiza-
tion.
Increasing the amount of the base gave 9% of 5a besides
traces of decyanated product 6a but led mainly to the deg-
radation of compound 4a (Table 1, entry 5). Longer reaction
time or decreasing amount of tBuOLi did not affect the cy-
clization step (entries 6–8). More surprisingly, compound
5a was obtained without tBuOLi but in lower yield even
with longer reaction time (entries 9 and 10). We speculated
that the rapid microwave decomposition of DMF leading to
in situ generated dimethylamine10 might render compound
4a more likely to cyclize. In fact, the results observed in en-
tries 8 and 9 are consistent with the recent reported studies
that emphasize highest decomposition rate of DMF in the
presence of a base such as tert-butoxide.11 With regard to
4a
5a
Entry
CuI (n equiv)
Base (n equiv)
5a (%)a
1
2b
3
1.5
1.5
–
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
–
70
45
72
42
9
4
1.5
–
5
tBuOLi (3)
tBuOLi (2)
tBuOLi (1)
tBuOLi (0.5)
–
6b
7
–
73
71
61
15
30
51
59
67
76
64
80
78
–
8
–
9
–
10c
11
12
13
14
15d
16e
17f
–
–
–
DBU (2)
–
NH4OH (2)
NHMe2 (2)
NHMe2 (1)
NHMe2 (1)
NHMe2 (1)
NHMe2 (1)
–
–
–
–
–
a Yield of isolated compound.
b Reaction time: 1 h.
c Reaction time: 5 h.
d Reaction time: 5 min.
e Reaction time: 15 min.
f Reaction time: 30 min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
F. Couly et al.
Special Topic
Synthesis
the effect of additives on the decomposition of DMF,11,12
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)13 and ammoni-
um hydroxide solution14 were tested.
With regard to the need of a late-stage diversification
and SAR studies, a variety of aryl iodides and bromides in-
spired by Topliss’ tree18 was screened as coupling partners
to maximize the chances of synthesizing the most potent
compounds in the series as early as possible. We were
pleased to find that this process was able to transfer a range
of substituted aryl groups to the thiazole nucleus to form
the selective corresponding new C2-arylated compounds
7ah, 7aj, and 7bb–bj in moderate to good yields (Scheme 5).
Unfortunately, compound 5a was isolated in a lower
yield (Table 1, entries 11 and 12). Therefore, we reasoned
that adding dimethylamine to the reaction mixture might
arguably help the cyclization to take place. We were de-
lighted to find that when compound 4a was treated with an
aqueous solution of dimethylamine (entries 13–17) the tri-
cyclic core 5a was obtained in up to 80% yield (entry 16). It
could be noticed that DMF-free reaction led to a mixture of
starting material 4a, compound 5a, and degradation. Apply-
ing the optimized condition reaction to compound 4b gave
the tricyclic product 5b in 79% yield (Scheme 3).
1) DBU (2 equiv)
Ar
H
N
CuI (1 equiv), 10 min
2) Pd(OAc)2 (10 mol%)
Ar–X (2 equiv), 5 h
O
S
O
S
N
R
H
R
H
N
N
DMF (0.4 M), MW 120 °C
N
N
7ab–aj, R = Bn
7bb–bj, R = cPr
6a, R = Bn
6b, R = cPr
S
N
NC
S
O
S
Cl
Br
O
N
Me2N
N
MeO
aq Me2NH (1 equiv)
NR
NR
DMF (0.4 M)
MW 120 °C, 15 min
N
N
5a 80% (82%)a
5b 79%
4a, R = Bn
4b, R = cPr
O
N
S
O
N
S
O
N
S
N
N
R
N
R
R
N
N
N
Scheme 3 Metal-free synthesis of thiazolo[5,4-f]quinazolin-9(8H)-one-
2-carbonitriles 5a,b from 4a,b. a Scale-up; 5 mmol of 4a; reaction time:
30 min.
7ad, 87% X = Br
7bd, 31% X = Br
7ac, 63% X = I
7bc, 76% X = I
7ab, 86% X = Br
7bb, 64% X = I
Following our previous investigation into selective C–H
arylation of quinazolin-4-one derivatives and N8-benzylat-
ed thiazolo[5,4-f]quinazolin-9(8H)-one 6a,5,15 the strategy
was now extended to N8-cyclopropylthiazolo[5,4-
f]quinazolin-9(8H)-one scaffold 6b (Scheme 4), a key struc-
tural unit in the CLK1, GSK-3, and DYRK1 Kinase inhibitor
series. A brief screening of bases under thermal condition
showed that tBuOLi and DBU were the most suitable bases
providing higher yield and selectivity compared to carbon-
ate and acetate bases. Since high temperature and long re-
action time are usually required for the C(sp2)–H activation
of heteroarenes,16 the reactions were conducted under mi-
crowave irradiation.17 Under our reported conditions,5 phe-
nylated product 7ba was isolated in only 19% yield with
tBuOLi as base and in an acceptable yield with DBU
(Scheme 4). Longer reaction time, increased amount of PhI
or addition of ligand did not improve the efficiency of the
reaction.
Cl
F
Cl
Cl
O
N
S
O
N
S
O
N
S
N
R
N
N
R
R
N
N
N
7ag, 62% X = I
7bg, 65% X = I
7af, 59% X = I
7bf, 67% X = I
7ae, 71% X = I
7be, 52% X = I
Cl
Cl
N
N
O
N
S
MeO
O
S
O
N
S
N
R
N
N
R
R
N
N
N
N
7ai, 69% X = I
7bi, 43% X = Ia
7aj, 29% X = I
7bj, 33% X = I
7ah, 64% X = I
7bh, 69% X = I
Scheme 5 Scope of the C2-H arylation of thiazolo[5,4-f]quinazolin-
9(8H)-ones 6a,b with aryl halides. Reagents and conditions: Premixing 6
(1 equiv), DBU (2 equiv) and CuI (1 equiv) at 120 °C for 10 min, before
adding Pd(OAc)2 (10 mol %) and ArI or ArBr (2 equiv) for 5 h. a 1,5,7-
Triazabicyclo[4.4.0]dec-5-ene (TBD)19 was used as base instead of DBU.
1) CuI (1 equiv)
base (2 equiv)
DMF, MW 120 °C
10 min
H
O
N
S
O
N
S
N
N
N
N
2) Pd(OAc)2 (10 mol%)
PhX (2 equiv)
MW 120 °C, 5 h
Electron-neutral and electron-donating substituents
were readily tolerated. More interesting, attractive haloge-
no-derivatives were compatible with present conditions,
thus offering an opportunity for additional functionaliza-
tion, leading to compounds 7ae–h and 7be–h in 52–71%
6b
7ba
tBuOLi, X = Br 19%
DBU, X = I 58%
Scheme 4 C2-H arylation of N8-cyclopropylthiazolo[5,4-f]quinazolin-
9(8H)-one (6b) with phenyl halide
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
F. Couly et al.
Special Topic
Synthesis
yield. The coupling of pyridine motifs was possible and pro-
ceeded smoothly in moderate yields to furnish compounds
7bi–j, enhancing the scope of the reaction. Compounds 7aj
and 7bj are especially of interest since they share strong
structural analogies with the bioactive imidate derivatives
(see Scheme 1).
TLC monitoring was done with silica gel 60 F254 pre-coated alumi-
num plates (0.25 mm). Purifications were carried out by flash column
chromatography system equipped with a dual UV-Vis spectropho-
tometer (200–600 nm), a fraction collector (176 tubes), a dual piston
pump (1 to 200 mL/min, Pmax = 15 bar) allowing quaternary gradients
and an additional inlet for air purge. Samples can be injected in liquid
or solid mode.
To add synthetic value, our attention was then focused
on the challenging cleavage of benzyl protecting group.
Whereas the deprotection failed in the case of N8-benzylat-
ed 2,7-diarylthiazolo[5,4-f]quinazolin-9(8H)-ones,5a it was
noted that AlCl3-mediated debenzylation of 7aa was suc-
cessful under traditional heating7a,20 leading to N8-H-2-
phenylthiazolo[5,4-f]quinazolin-9(8H)-one (8a) in 79%
yield (Scheme 6).
Melting points of solid compounds were measured on a Stuart Melt-
ing Point SMP3 with a precision of ± 1.5 °C. IR spectra were recorded
on a PerkinElmer Spectrum 100 Series FT-IR spectrometer. Liquids
and solids were applied on the Single Reflection Attenuated Total Re-
flectance (ATR) Accessories. Absorption bands are given in cm–1 1H
.
NMR and 13C NMR spectra were recorded at 295 K on a Bruker 300
Avance spectrometer (300 and 75.4 MHz). The coupling constants J
are reported in Hz and the chemical shifts in ppm relative to the re-
sidual solvent signal. Mass spectra (ESI) were obtained using a Waters
LCP 1er XR spectrometer.
6-Amino-3-benzyl-5-bromoquinazolin-4(3H)-one (3a)
O
N
S
O
N
S
A suspension of 6-amino-3-benzylquinazolin-4(3H)-one (2a; 6.478 g,
25.8 mmol) and NBS (5.047 g, 1.1 equiv) in DMF (260 mL, 0.1 M) was
stirred at r.t. for 2 h. The resulting solution was concentrated under
vacuum, diluted in EtOAc, and washed with brine (3 ×). The organic
layer was dried (MgSO4) and the solvent was removed in vacuo to give
3a (8.452 g, 99%) as a brown solid.7a
AlCl3 (5.6 equiv)
N
N
NH
NBn
toluene (0.1 M)
80 °C, 45 min
7aa
8a (79%)
Scheme 6 Deprotection of N8-benzyl-2-phenylthiazolo[5,4-
f]quinazolin-9(8H)-one (7aa)
9-Oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carbonitrile 5;
General Procedure
In conclusion, we have described a modified synthesis
of thiazolo[5,4-f]quinazolin-9(8H)-one carbonitriles using a
more eco-friendly process. According to the need of struc-
tural modification to establish structure–activity relation-
ships, the selective palladium-catalyzed and copper-assist-
ed direct C2-H (hetero)-arylation of the thiazolo[5,4-
f]quinazolin-9(8H)-one backbone was achieved with aryl
halides as coupling partners under microwave irradiation.
This late-stage functionalization strategy give access to a
streamline and rapid synthesis of a range of valuable arylat-
ed compounds that are promising kinase inhibitors. Biolog-
ical evaluation of these new arylated compounds are cur-
rently in progress and will be reported in due course.
A suspension of imine 4 (0.271 mol) and an aq 40% solution of NHMe2
(31 μL, 1.0 equiv) in DMF (0.680 mL, 0.4 M) was irradiated under mi-
crowaves at 120 °C (power input: 300 W) for 15 min. After cooling,
the solvent was removed in vacuo. The crude residue was adsorbed in
silica gel and then purified by column chromatography on silica gel
with EtOAc/CH2Cl2 (0:100 to 20:80, v/v) as eluent to give 5.
N8-Benzyl-9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carbo-
nitrile (5a)
Prepared from 4a (0.126 g); yield: 0.069 g (80%); beige solid;7c Rf =
0.56 (CH2Cl2/EtOAc, 4:1, v/v).
N8-Cyclopropyl-9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-
carbonitrile (5b)
Prepared from 4b (0.113 g); yield: 0.058 g (79%); beige solid;3 Rf =
0.45 (CH2Cl2/EtOAc, 1:1, v/v).
Microwave experiments were conducted in Biotage Initiator+ micro-
wave reactor equipped with a monomode cavity with a microwave
power delivery system ranging from 0 to 850 W allowing pressurized
reactions (0 to 30 bar) to be carried out in sealed glass vials (0.5 to 2
mL) equipped with a snap cap and a silicon septum. The temperature
(0 to 300 °C) was monitored via a contactless infrared sensor and was
calibrated with a Ruby Thermometer. Reaction time indicated corre-
sponds to the time measured when the mixture has reached the pro-
grammed temperature. All C–H arylation reactions were carried out
under argon. DMF was purchased from Acros Organics. NBS was re-
crystallized from H2O. Other reagents were purchased from commer-
cial sources (Sigma Aldrich, Alfa Aesar, Fisher Chemicals, Acros Organ-
ics, Avocado, Maybridge, Lancaster) and were used without further
purification. Appel’s salt was synthesized according to reported pro-
cedure.21 For compounds 1a, 2a and 4a, see reference 7a. For com-
pounds 1b to 4b, see reference 3. For compounds 7ab to 7ag and 7ai,
see reference 5a.
N8-Benzylthiazolo[5,4-f]quinazolin-9(8H)-one (6a)
N8-Benzyl-9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carboni-
trile (5a; 4.392 g, 13.8 mmol) in HBr (0.3 M) was stirred under micro-
wave irradiation at 100 °C in an open vessel for 45 min. The resulting
solution was diluted with CH2Cl2 and neutralized with sat. aq NaHCO3
and Na2CO3 powder. The organic layer was washed with H2O, dried
(MgSO4), and concentrated to afford 6a (3.709 g, 92%) as a white sol-
id.5a
N8-Cyclopropylthiazolo[5,4-f]quinazolin-9(8H)-one (6b)
N8-Cyclopropyl-9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-car-
bonitrile (5b; 1.372 g, 5.11 mmol) in HBr (0.15 M) was stirred under
microwave irradiation at 100 °C in an open vessel for 45 min. The re-
sulting solution was diluted with CH2Cl2 and neutralized with sat. aq
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
F. Couly et al.
Special Topic
Synthesis
NaHCO3 and Na2CO3 powder. The organic layer was dried (MgSO4) and
concentrated to afford 6b (1.119 g, 90%) as a beige solid; mp 262–265
°C; Rf = 0.18 (CH2Cl2/EtOAc, 1:1, v/v).
13C NMR (CDCl3, 75.4 MHz): δ = 165.8 (C), 160.9 (C), 160.2 (C), 152.1
(C), 149.1 (CH), 146.7 (C), 145.8 (CH), 138.0 (CH), 135.6 (C), 133.4 (C),
129.3 (2 × CH), 129.1 (CH), 128.7 (CH), 128.2 (2 × CH), 126.1 (CH),
117.6 (CH), 117.1 (C), 116.8 (C), 54.2 (CH3), 49.9 (CH2).
IR (neat): 3073, 3004, 2110, 1921, 1653, 1588, 1455, 1350, 1291, 982,
852 cm–1
.
HRMS (ESI+): m/z calcd for C22H16N4O2S [M + H]+: 401.1072; found:
401.1068.
1H NMR (CDCl3, 300 MHz): δ = 9.22 (s, 1 H, H2), 8.49 (d, J = 8.7 Hz, 1 H,
H4), 8.26 (s, 1 H, H7), 7.87 (d, J = 8.7 Hz, 1 H, H5), 3.50–3.25 (m, 1 H,
NCH), 1.37–1.17 (m, 2 H, CH), 1.12–0.91 (m, 2 H, CH).
N8-Cyclopropyl-2-phenylthiazolo[5,4-f]quinazolin-9(8H)-one
(7ba)
13C NMR (CDCl3, 75.4 MHz): δ = 161.3 (C), 158.0 (CH), 152.7 (C),
146.7 (C + CH), 130.5 (C), 129.6 (CH), 126.2 (CH), 116.3 (C), 29.8 (CH),
6.7 (2 × CH2).
Prepared from 6b (0.083 g); yield: 0.063 g (58%); yellow solid; mp
233–236 °C; Rf = 0.41 (CH2Cl2/EtOAc, 1:1, v/v).
HRMS (ESI+): m/z calcd for C12H10N3OS: 244.0545; found: 244.0542.
IR (neat): 3356, 3054, 2919, 1667, 1584, 1474, 1441, 1340, 1317,
1164, 830, 762 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.42 (d, J = 8.8 Hz, 1 H, H4), 8.24 (s, 1 H,
H7), 8.22–8.15 (m, 2 H, HAr), 7.84 (d, J = 8.8 Hz, 1 H, H5), 7.58–7.49 (m,
3 H, HAr), 3.44–3.30 (m, 1 H, NCH), 1.37–1.21 (m, 2 H, CH), 1.09–0.99
(m, 2 H, CH).
13C NMR (CDCl3, 75.4 MHz): δ = 171.9 (C), 161.4 (C), 153.6 (C), 146.4
(CH), 146.2 (C), 133.7 (C), 131.8 (C), 131.3 (CH), 129.3 (CH), 129.2
(CH), 127.7 (CH), 126.2 (CH), 116.4 (C), 29.7 (CH), 6.7 (2 × CH2).
Palladium- and Copper-Assisted C–H Arylation of Compounds 6;
Typical Procedure for Products 7 (Schemes 4 and 5)
Thiazolo[5,4-f]quinazolin-9(8H)-one 6 (0.341 mmol), CuI (0.065 g,
0.341 mmol, 1 equiv), and DBU (101 μL, 0.682 mmol, 2.0 equiv) in an-
hyd DMF (850 μL) were added to a 2 mL glass microwave vial. The
mixture was stirred under microwave irradiation at 120 °C for 10
min. Then Pd(OAc)2 (7.6 mg, 0.034 mmol, 10 mol%) and the appropri-
ate aryl halide (0.682 mmol, 2.0 equiv) were added to the mixture.
The reaction mixture was then stirred under microwave irradiation at
120 °C for 5 h. The resulting solution was diluted with CH2Cl2, filtered
through a cotton plug and washed with CH2Cl2 (50 mL). The crude
product obtained by concentration of CH2Cl2 was purified by flash
chromatography on silica gel with EtOAc/CH2Cl2 as eluent (1:0 to 1:1,
v/v, for 7ah–j; 7:3 to 1:4, v/v for 7ba–j) to afford the corresponding
product 7.
HRMS (ESI+): m/z calcd for C18H13N3OS: 320.0858; found: 320.0862.
N8-Cyclopropyl-2-(p-tolyl)thiazolo[5,4-f]quinazolin-9(8H)-one
(7bb)
Prepared from 6b (0.083 g); yield: 0.073 g (64%); yellow solid; mp
282–285 °C; Rf = 0.43 (CH2Cl2/EtOAc, 1:1, v/v).
IR (neat): 3058, 3017, 1667, 1584, 1450, 1342, 1294, 1159, 815 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.39 (d, J = 8.8 Hz, 1 H, H4), 8.22 (s, 1 H,
H7), 8.06 (d, J = 7.8 Hz, 2 H, HAr), 7.81 (d, J = 8.8 Hz, 1 H, H5), 7.32 (d, J =
7.8 Hz, 2 H, HAr), 3.42–3.29 (m, 1 H, NCH), 2.43 (s, 3 H, ArCH3), 1.39–
1.17 (m, 2 H, CH), 1.11–0.96 (m, 2 H, CH).
13C NMR (CDCl3, 75.4 MHz): δ = 172.1 (C), 161.4 (C), 153.6 (C), 146.3
(CH), 146.0 (C), 141.8 (C), 131.6 (C), 131.0 (C), 130.0 (2 × CH), 129.0
(CH), 127.6 (2 × CH), 126.0 (CH), 116.3 (C), 29.7 (CH), 21.7 (CH3), 6.7
(2 × CH2).
N8-Benzyl-2-(3,4-dichlorophenyl)thiazolo[5,4-f]quinazolin-9(8H)-
one (7ah)
Prepared from 6a (0.100 g); yield: 0.095 g (64%); yellow solid; mp
242–245 °C; Rf = 0.47 (CH2Cl2/EtOAc, 4:1, v/v).
IR (neat): 3031, 1662, 1583, 1448, 1344, 1156, 830 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.41 (d, J = 8.8 Hz, 1 H, H4), 8.31 (d, J =
2.0 Hz, 1 H, HAr), 8.25 (s, 1 H, H7), 7.97 (dd, J = 8.4, 2.1 Hz, 1 H, HAr),
7.86 (d, J = 8.8 Hz, 1 H, H5), 7.59 (d, J = 8.4 Hz, 1 H, HAr), 7.46–7.30 (m,
5 H, HAr), 5.32 (s, 2 H, NCH2).
HRMS (ESI+): m/z calcd for C19H15N3OS [M + H]+: 334.1014; found:
334.1013.
13C NMR (CDCl3, 75.4 MHz): δ = 168.9 (C), 160.0 (C), 153.4 (C), 147.0
(C), 146.1 (CH), 135.4 (C), 135.3 (C), 133.8 (C), 133.5 (C), 132.0 (C),
131.3 (CH), 129.4 (CH), 129.3 (2 × CH), 129.2 (CH), 128.7 (CH), 128.4
(2 × CH), 126.7 (CH), 126.6 (CH), 116.8 (C), 50.2 (CH2).
N8-Cyclopropyl-2-(4-methoxyphenyl)thiazolo[5,4-f]quinazolin-
9(8H)-one (7bc)
Prepared from 6b (0.083 g); yield: 0.090 g (76%); beige solid; mp 252–
255 °C; Rf = 0.33 (CH2Cl2/EtOAc, 1:1, v/v).
HRMS (ESI+): m/z calcd for C22H14Cl2N3OS [M + H]+: 438.0235; found:
438.0234.
IR (neat): 3014, 2922, 2851, 2124, 1919, 1657, 1601, 1449, 1335,
1246, 1167, 1025, 835 cm–1
.
N8-Benzyl-2-(2-methoxypyridin-3-yl)thiazolo[5,4-f]quinazolin-
9(8H)-one (7aj)
1H NMR (CDCl3, 300 MHz): δ = 8.36 (d, J = 8.8 Hz, 1 H, H4), 8.21 (s, 1 H,
H7), 8.11 (d, J = 8.8 Hz, 2 H, HAr), 7.81 (d, J = 8.8 Hz, 1 H, H5), 7.02 (d, J =
8.8 Hz, 2 H, HAr), 3.89 (s, 3 H, OCH3), 3.50–3.27 (m, 1 H, NCH), 1.37–
1.12 (m, 2 H, CH), 1.12–0.88 (m, 2 H, CH).
Prepared from 6a (0.100 g); yield: 0.039 g (29%); yellow solid; mp
280–283 °C; Rf = 0.43 (CH2Cl2/EtOAc, 1:1, v/v).
13C NMR (CDCl3, 75.4 MHz): δ = 171.7 (C), 162.2 (C), 161.4 (C), 153.7
(C), 146.2 (CH), 145.8 (C), 131.5 (C), 129.3 (2 × CH), 128.7 (CH), 126.5
(C), 126.0 (CH), 116.3 (C), 114.7 (2 × CH), 55.6 (CH3), 29.7 (CH), 6.7 (2
× CH2).
HRMS (ESI+): m/z calcd for C19H15N3O2S [M + H]+: 350.0961; found:
350.0963.
IR (neat): 3062, 2937, 2113, 1665, 1600, 1576, 1464, 1395, 1339,
1261, 1000, 729 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.85 (dd, J = 7.6, 1.9 Hz, 1 H, HAr), 8.43
(d, J = 8.8 Hz, 1 H, H4), 8.32 (dd, J = 4.9, 1.9 Hz, 1 H, HAr), 8.23 (s, 1 H,
H7), 7.86 (d, J = 8.8 Hz, 1 H, H5), 7.44–7.31 (m, 5 H, HAr), 7.11 (dd, J =
7.6, 4.9 Hz, 1 H, HAr), 5.35 (s, 2 H, NCH2), 4.25 (s, 3 H, OCH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
F. Couly et al.
Special Topic
Synthesis
N8-Cyclopropyl-2-(4-(dimethylamino)phenyl)thiazolo[5,4-f]-
quinazolin-9(8H)-one (7bd)
1H NMR (CDCl3, 300 MHz): δ = 8.45 (d, J = 8.8 Hz, 1 H, H4), 8.32 (d, J =
8.6 Hz, 1 H, HAr), 8.26 (s, 1 H, H7), 7.86 (d, J = 8.8 Hz, 1 H, H5), 7.58 (d, J
= 2.1 Hz, 1 H, HAr), 7.42 (dd, J = 8.6, 2.1 Hz, 1 H, HAr), 3.47–3.27 (m, 1 H,
NCH), 1.41–1.18 (m, 2 H, CH), 1.11–0.97 (m, 2 H, CH).
Prepared from 6b (0.083 g); yield: 0.039 g (31%); yellow solid; mp
245–248 °C; Rf = 0.29 (CH2Cl2/EtOAc, 1:1, v/v).
13C NMR (CDCl3, 75.4 MHz): δ = 167.0 (C), 161.3 (C), 151.7 (C), 146.7
(CH), 146.6 (C), 136.9 (C), 133.6 (C), 132.8 (C), 132.6 (CH), 131.0 (C),
130.8 (CH), 129.4 (CH), 127.8 (CH), 126.4 (CH), 116.2 (C), 29.8 (CH),
6.7 (2 × CH2).
HRMS (ESI+): m/z calcd for C18H11Cl2N3OS [M + H]+: 388.0073; found:
388.0070.
IR (neat): 3530, 3386, 3041, 2897, 2819, 2103, 1655, 1600, 1473,
1449, 1367, 1338, 1290, 1187, 816 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.32 (d, J = 8.7 Hz, 1 H, H4), 8.19 (s, 1 H,
H7), 8.05 (d, J = 8.8 Hz, 2 H, HAr), 7.78 (d, J = 8.7 Hz, 1 H, H5), 6.78 (d, J =
8.8 Hz, 2 H, HAr), 3.42–3.27 (m, 1 H, NCH), 3.08 [s, 6 H, N(CH3)2], 1.32–
1.22 (m, 2 H, CH), 1.07–0.98 (m, 2 H, CH).
13C NMR (CDCl3, 75.4 MHz): δ = 172.7 (C), 161.5 (C), 154.0 (C), 152.4
(C), 145.8 (CH), 145.4 (C), 131.2 (C), 129.0 (2 × CH), 128.3 (CH), 125.7
(CH), 121.4 (C), 116.3 (C), 112.0 (2 × CH), 40.3 (2 × CH3), 29.6 (CH), 6.7
(2 × CH2).
N8-Cyclopropyl-2-(3,4-dichlorophenyl)thiazolo[5,4-f]quinazolin-
9(8H)-one (7bh)
Prepared from 6b (0.083 g); yield: 0.091 g (69%); beige powder; mp
263–266 °C; Rf = 0.45 (CH2Cl2/EtOAc, 1:1, v/v).
HRMS (ESI+): m/z calcd for C18H13N3OS [M + H]+: 363.1274; found:
IR (neat): 3088, 3009, 2913, 2849, 1867, 1666, 1585, 1449, 1344,
363.1268.
1311, 829 cm–1
.
N8-Cyclopropyl-2-(4-fluorophenyl)thiazolo[5,4-f]quinazolin-
9(8H)-one (7be)
1H NMR (CDCl3, 300 MHz): δ = 8.41 (d, J = 8.8 Hz, 1 H, H4), 8.32 (d, J =
2.1 Hz, 1 H, HAr), 8.25 (s, 1 H, HAr), 7.97 (dd, J = 8.4, 2.1 Hz, 1 H, HAr),
7.86 (d, J = 8.8 Hz, 1 H, H5), 7.60 (d, J = 8.4 Hz, 1 H, HAr), 3.46–3.32 (m,
1 H, NCH), 1.37–1.22 (m, 2 H, CH), 1.11–0.98 (m, 2 H, CH).
Prepared from 6b (0.083 g); yield: 0.060 g (52%); yellow solid; mp
274–277 °C; Rf = 0.41 (CH2Cl2/EtOAc, 1:1, v/v).
13C NMR (CDCl3, 75.4 MHz): δ = 169.0 (C), 162.2 (C), 153.4 (C), 146.7
(CH), 135.4 (C), 135.1 (C), 133.8 (C), 133.6 (C), 131.3 (C), 131.3 (CH),
129.3 (CH), 129.2 (CH), 126.6 (CH), 126.6 (CH), 116.4 (C), 29.8 (CH),
6.8 (2 × CH2).
HRMS (ESI+): m/z calcd for C18H11Cl2N3OS [M + H]+: 388.0073; found:
388.0069.
IR (neat): 307, 2112, 1877, 1658, 1585, 1454, 1343, 1229, 1153, 830
cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.38 (d, J = 8.8 Hz, 1 H, H4), 8.23 (s, 1 H,
H7), 8.20–8.09 (m, 2 H, HAr), 7.83 (d, J = 8.8 Hz, 1 H, H5), 7.25–7.15 (m,
2 H, HAr), 3.44–3.28 (m, 1 H, NCH), 1.34–1.23 (m, 2 H, CH), 1.09–0.96
(m, 2 H, CH).
13C NMR (CDCl3, 75.4 MHz): δ = 170.6 (C), 164.7 (d, J = 252.1 Hz, C),
161.3 (C), 153.5 (C), 146.4 (CH), 146.2 (C), 131.7 (C), 130.1 (d, J = 3.4
Hz, C), 129.7 (d, J = 8.7 Hz, 2 × CH), 129.1 (CH), 126.3 (CH), 116.5 (d, J =
22.1 Hz, 2 × CH), 29.7 (CH), 6.7 (2 × CH2)
HRMS (ESI+): m/z calcd for C18H12FN3OS [M + H]+: 338.0758; found:
338.0748.
N8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-
one (7bi)
Prepared from 6b (0.083 g) using TBD (0.095 g) instead of DBU and
CH2Cl2/EtOAc (1:1 to 0:1) as eluent for the flash chromatography on
silica gel; yield: 0.047 g (43%); beige solid; mp 237–240 °C; Rf = 0.10
(EtOAc).
IR (neat): 3059, 3012, 2114, 1659, 1588, 1449, 1344, 1295, 1024, 837
2-(4-Chlorophenyl)-N8-Cyclopropylthiazolo[5,4-f]quinazolin-
9(8H)-one (7bf)
cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 9.41 (d, J = 2.3 Hz, 1 H, HAr), 8.75 (d, J =
4.9 Hz, 1 H, HAr), 8.54–8.38 (m, 2 H, HAr + H4), 8.26 (s, 1 H, H7), 7.88 (d,
J = 8.7 Hz, 1 H, H5), 7.48 (dd, J = 8.0, 4.9 Hz, 1 H, CHAr), 3.45–3.26 (m, 1
H, NCH), 1.36–1.24 (m, 2 H, CH), 1.14–0.96 (m, 2 H, CH).
13C NMR (CDCl3, 75.4 MHz): δ = 168.5 (C), 161.3 (C), 153.4 (C), 151.9
(CH), 148.7 (CH), 146.7 (CH), 146.6 (C), 134.7 (CH), 131.7 (C), 129.8
(C), 129.3 (CH), 126.6 (CH), 124.1 (CH), 116.4 (C), 29.8 (CH), 6.7 (2 ×
CH2).
Prepared from 6b (0.083 g); yield: 0.080 g (67%); yellow solid; mp
276–279 °C; Rf = 0.41 (CH2Cl2/EtOAc, 1:1, v/v).
IR (neat): 3059, 1918, 1665, 1587, 1451, 1347, 1289, 1085, 834 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.40 (d, J = 8.7 Hz, 1 H, H4), 8.24 (s, 1 H,
H7), 8.11 (d, J = 8.3 Hz, 2 H, HAr), 7.84 (d, J = 8.7 Hz, 1 H, H5), 7.50 (d, J =
8.3 Hz, 2 H, HAr), 3.47–3.27 (m, 1 H, NCH), 1.43–1.18 (m, 2 H, CH),
1.14–0.93 (m, 2 H, CH)
13C NMR (CDCl3, 75.4 MHz): δ = 170.5 (C), 161.3 (C), 153.5 (C), 146.5
(CH), 146.3 (C), 137.4 (C), 132.2 (C), 131.7 (C), 129.6 (2 × CH), 129.2
(CH), 128.8 (2 × CH), 126.4 (CH), 116.4 (C), 29.7 (CH), 6.7 (2 × CH2).
HRMS (ESI+): m/z calcd for C17H12N4OS [M + H]+: 321.0807; found:
321.0810.
HRMS (ESI+): m/z calcd for C18H12ClN3OS [M + H]+: 354.0462; found:
354.0470.
N8-Cyclopropyl-2-(2-methoxypyridin-3-yl)thiazolo[5,4-f]-
quinazolin-9(8H)-one (7bj)
Prepared from 6b (0.083 g); yield: 0.039 g (33%); yellow solid; mp
280–283 °C: Rf = 0.20 (CH2Cl2/EtOAc, 1:1, v/v).
N8-Cyclopropyl-2-(2,4-dichlorophenyl)thiazolo[5,4-f]quinazolin-
9(8H)-one (7bg)
IR (neat): 3059, 2945, 2849, 2113, 1665, 1577, 1345, 1305, 1200, 836,
Prepared from 6b (0.083 g); yield: 0.086 g (65%); yellow powder; mp
272–275 °C; Rf = 0.49 (CH2Cl2/EtOAc, 1:1, v/v).
806, 767 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.84 (dd, J = 7.6, 2.0 Hz, 1 H, HAr), 8.41
(d, J = 8.8 Hz, 1 H, H4), 8.31 (dd, J = 4.9, 2.0 Hz, 1 H, HAr), 8.23 s, (1 H,
H7), 7.83 (d, J = 8.8 Hz, 1 H, H5), 7.10 (dd, J = 7.6, 4.9 Hz, 1 H, HAr), 4.24
(s, 3 H, OCH3), 3.45–3.28 (m, 1 H, NCH), 1.33–1.21 (m, 2 H, CH), 1.10–
0.98 (m, 2 H, CH).
IR (neat): 3068, 2961, 1664, 1580, 1476, 1439, 1371, 1349, 1102, 829
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
F. Couly et al.
Special Topic
Synthesis
13C NMR (CDCl3, 75.4 MHz): δ = 165.9 (C), 161.5 (C), 160.9 (C), 152.0
(C), 149.1 (CH), 146.2 (CH), 146.2 (C), 137.9 (CH), 133.2 (C), 128.9
(CH), 126.0 (CH), 117.6 (CH), 117.1 (C), 116.4 (C), 54.1 (CH3), 29.7
(CH), 6.7 (2 × CH2).
HRMS (ESI+): m/z calcd for C18H14N4O2S [M + H]+: 351.0916; found:
351.0912.
(4) For recent papers relating the biological interest of 9-aminothi-
azolo[5,4-f]quinazoline derivatives, see: (a) Chaikuad, A.;
Diharce, J.; Schröder, M.; Foucourt, A.; Leblond, B.; Casagrande,
A.-S.; Désire, L.; Bonnet, P.; Knapp, S.; Besson, T. J. Med. Chem.
2016, 59, 10315. (b) Courtadeur, S.; Benyamine, H.; Delalonde,
L.; de Oliveira, C.; Leblond, B.; Foucourt, A.; Besson, T.;
Casagrande, A.-S.; Taverne, T.; Girard, A.; Pando, M. P.; Désiré, L.
J. Neurochem. 2015, 133, 440. (c) Abbassi, R.; Johns, T. G.;
Kassiou, M.; Munoz, L. Pharmacol. Ther. 2015, 151, 87. (d) Deng,
X.; Hu, J.; Ewton, D. Z.; Friedman, E. Carcinogenesis 2014, 35,
1968. (e) Deng, X.; Mercer, S. E.; Sun, C. Y.; Friedman, E. Genes
Cancer 2014, 5, 337. (f) Deng, X.; Hu, J.; Cunningham, M. J.;
Friedman, E. Genes Cancer 2014, 5, 201. (g) Deng, X.; Mercer, S.
E.; Sun, C. Y.; Friedman, E. Genes Cancer 2014, 5, 22. (h) Leblond,
B.; Casagrande, A.-S.; Désiré, L.; Foucourt, A.; Besson, T. Patent
WO 2013026806, 2013; Chem. Abst. 2013, 158, 390018
(5) (a) Harari, M.; Couly, F.; Fruit, C.; Besson, T. Org. Lett. 2016, 18,
3282. (b) Fruit C., Harari M., Couly F., Besson T.; In Proceedings of
the 20th Int. Electron. Conf. Synth. Org. Chem., 1–30 November
2016, Sciforum Electronic Conference Series Vol. 20; 2016,
b002; doi: 10.3390/ecsoc-20-b002
2-Phenylthiazolo[5,4-f]quinazolin-9(8H)-one (8a)
A suspension of 8-benzyl-2-phenylthiazolo[5,4-f]quinazolin-9(8H)-
one (7aa; 0.050 g, 0.14 mmol), AlCl3 (0.101 g, 5.6 equiv) in toluene
(1.4 mL, 0.1 M) was stirred at 80 °C for 45 min. The resulting solution
was concentrated under vacuo, diluted with H2O, and extracted with
EtOAc (2 ×). The combined organic layers were washed with sat. aq
NaHCO3 (2 ×). Evaporation of solvent gave the crude residue, which
was purified by flash chromatography on silica gel with EtOAc/CH2Cl2
as eluent (1:0 to 0:1, v/v) to afford the product 8a as a white solid;
yield: 0.030 g (79%); mp 315–318 °C; Rf = 0.10 (CH2Cl2/EtOAc, 1:1,
v/v).
IR (neat): 3057, 3024, 2655, 1674, 1616, 1437, 1342, 982, 833, 756
cm–1
.
(6) (a) Rosini, M.; Simoni, E.; Caporaso, R.; Minarini, A. Future Med.
Chem. 2016, 8, 697. (b) Guzior, N.; Wieckowska, A.; Panek, D.;
Malawska, B. Curr. Med. Chem. 2015, 22, 373. (c) Katselou, M. G.;
Matralis, A. N.; Kourounakis, A. P. Curr. Med. Chem. 2014, 21,
2743. (d) Leon, R.; Garcia, A. G.; Marco-Contelles, J. Med. Res.
Rev. 2013, 33, 139. (e) León, R.; Marco-Contelles, J. Curr. Med.
Chem. 2011, 18, 552. (f) Cavalli, A.; Bolognesi, M. L.; Minarini, A.;
Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. J. Med.
Chem. 2008, 51, 347.
1H NMR (DMSO-d6, 300 MHz): δ = 12.84 (s, 1 H, NH), 8.45 (d, J = 8.8
Hz, 1 H, H4), 8.28 (s, 1 H, H7), 8.25–8.11 (m, 2 H, HAr), 7.83 (d, J = 8.8
Hz, 1 H, H5), 7.71–7.44 (m, 3 H, HAr).
13C NMR (DMSO-d6, 75.4 MHz): δ = 170.1 (C), 159.8 (C), 152.3 (C),
147.4 (C), 145.4 (CH), 132.9 (C), 131.4 (CH), 130.4 (C), 129.5 (2 × CH),
128.7 (CH), 127.2 (2 × CH), 126.3 (CH), 116.9 (C).
HRMS (ESI+): m/z calcd for C15H10N3OS [M + H]+: 280.0545; found:
280.0548.
(7) (a) Hédou, D.; Guillon, R.; Lecointe, C.; Logé, C.; Chosson, E.;
Besson, T. Tetrahedron 2013, 69, 3182. (b) Testard, A.; Picot, L.;
Lozach, O.; Blairvac, M.; Meijer, L.; Murillo, L.; Piot, J.-M.; Thiéry,
V.; Besson, T. J. Enz. Inhib. Med. Chem. 2005, 20, 557.
(c) Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.; Besson, T.
Tetrahedron Lett. 2003, 44, 4455.
(8) (a) Leadbeater, N. E. In Comprehensive Organic Synthesis;
Knochel, P.; Molander, G. A., Eds.; Elsevier: Oxford, 2014, 2nd
ed., Vol. 9 234. (b) Bazureau, J. P.; Paquin, L.; Carrie, D.;
L’Helgoual’ch, J.-M.; Guiheneuf, S.; Coulibaly, K.-W.; Burgy, G.;
Komaty, S.; Limanton, E. In Microwaves in Organic Synthesis; de
la Hoz, A.; Loupy, A., Eds.; Wiley-VCH: Weinheim, 2012.
(c) Sharma, A.; Appukkuttan, P.; Van der Eycken, E. Chem.
Commun. 2012, 48, 1623. (d) Dallinger, D.; Kappe, C. O. Chem.
Rev. 2007, 107, 2563. (e) Microwave Methods in Organic Synthe-
sis; Larhed, M.; Olofsson, K., Eds.; Springer: Berlin, 2006.
(f) Microwave-Assisted Organic Synthesis; Lidström, P.; Tierney,
J. P., Eds.; Blackwell: Oxford, 2005. (g) Kappe, C. O. Angew. Chem.
Int. Ed. 2004, 43, 6250.
Acknowledgment
Financial support from the MESR (Ministère de l’Enseignement
Supérieur et de la Recherche) is gratefully acknowledged for the doc-
toral fellowship to F.C. We thank the LABEX SynOrg (ANR-11-LABX-
0029) for financial support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588434.
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