Access to Isothiazolones from Simple Acrylamides by Pd-Catalyzed C-H Bond Activation

Article abstract of DOI:10.1021/acs.joc.9b01872

A new methodology was developed to access isothiazolone derivatives from simple acrylamides by transition metal catalyzed C-H bond functionalization. This Pd-catalyzed reaction using an electrophilic SCN source offered an efficient tool to access a panel of functionalized isothiazolone derivatives (21 examples, up to 71% yield).

Full text of DOI:10.1021/acs.joc.9b01872

Subscriber access provided by BUFFALO STATE
Note
Access to Isothiazolones from Simple
Acrylamides by Pd-Catalyzed C-H Bond Activation
Mu-Yi CHEN, Xavier Pannecoucke, Philippe Jubault, and Tatiana Besset
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01872 • Publication Date (Web): 01 Aug 2019
Downloaded from pubs.acs.org on August 1, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Access to Isothiazolones from Simple Acrylamides by Pd-Catalyzed C-H
Bond Activation
Mu-Yi Chen, Xavier Pannecoucke, Philippe Jubault, Tatiana Besset*
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France.
E-mail: tatiana.besset@insa-rouen.fr
Abstract A new methodology was developed to access isothiazolone derivatives from simple
acrylamides by transition metal catalyzed C-H bond functionalization. This Pd-catalyzed
reaction using an electrophilic SCN source offered an efficient tool to access a panel of
functionalized isothiazolone derivatives (21 examples, up to 71% yield).
Over the last years, the development of new catalytic systems to tackle unaddressed synthetic
issues aroused the curiosity of the scientific community to imagine and design new tools. As
part of them, the direct functionalization of a simple C-H bond appeared as an efficient way to
accomplish this task and a panel of transition metal catalyzed transformations is now available.1
With these atom- and step-economical synthetic pathways, unprecedented retrodisconnections
were achieved, offering original synthetic routes towards the construction of more complex
2
molecules. However, it is worth mentioning that compared to the tremendous advances made
for the functionalization of aromatic compounds, the transition metal catalyzed
3
functionalization of vinylic derivatives by C-H bond activation is rather limited. In this context,
we turned our attention to the synthesis of isothiazolone derivatives. These underexplored N,S-
heterocycles are of high interest and found applications as antimicrobials, in paint formulation
as well as in hair care products and shampoos. For instance, N-phenylisothiazolones with
various substituents at C4 and C5 positions turned out to be good candidates as inhibitors of the
histone acetyltransferase enzymes.4,5 Usually, N-substituted isothiazolones are prepared by
different approaches (Scheme 1). Pioneer works from the group of Lewis in 1971, followed by
several other research groups, relied on the cyclization of N,N’-bis-aryl-3,3’-
dithiodipropionamide derivatives in the presence of chlorine gas, SOCl or SO Cl (Scheme 1,
2
2
2
6
eq. 1). Isothiazolones were also prepared from 3-aroylpropionic amides upon reaction with
7
thionyl chloride (Scheme 1, eq. 2). An alternative pathway relying on an oxidative addition
with iodine under basic conditions was depicted by Petraitis and co-workers starting from 3-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
aryl-3-mercapto-propenamide derivatives (Scheme 1, eq. 3). Finally, complementary
approaches were developed to access N-substituted-5-aryl/alkyl-substituted-isothiazolones. In
2
009, the group of McDonald developed a Pummerer-like type reaction for the synthesis of N-
4
aryl-5-aryl-isothiazolone and N-aryl-5-alkyl-isothiazolone compounds (Scheme 1, eq. 4). In
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
017, Reddy and co-workers reported a thiocyanation/intramolecular decyanative cyclization
of ynamides leading to the corresponding N-substituted-5-phenyl-isothiazolones (5 examples,
9
Scheme 1, eq. 5). Compared to traditional routes, the development of alternative synthetic
pathways to provide an access to various isothiazolone derivatives with good diversity at the
C4 position from simple starting materials is appealing.
Traditionnal approaches
to isothiazolones
Ref. 6
O
O
R1
Cl , SOCl
2
2
N R2 (eq.1)
NHR2
S
R1
or SO2Cl2
S
2
Ref. 7
O
O
R1
R1
SOCl2
N R2
(eq.2)
S
CONHR2
Ar
ArOC
R1
Ref. 8
O
SH
O
I2, NEt
3
N Ar2
Ar1
NHAr2
(eq.3)
(eq.4)
S
Ar1
R1
Ref. 4
BnOS
O
O
(
Cl CCO) O
3
2
N Ar
R1
NHAr
NHR
R1
S
Ref. 9
O
O
KSCN
N R
(eq.5)
Ph
O
S
Ph
Present work
O
R1
R3
Pd
R1
N
N R3
H
R2
Electrophilic SCN source
H
S
R2
21 examples
up to 71% yield
Large functional group tolerance
Access to an important class of compounds
Scheme 1. Synthesis of isothiazolone derivatives: traditional approaches and present work.
Inspired by our recent investigations on the functionalization of vinylic C-H bond by transition
1
0
metal catalysis, we sought that the reaction of an acrylamide with an electrophilic SCN source
in the presence of a Pd-catalyst could afford the isothiazolone backbone selectively. Herein, we
ACS Paragon Plus Environment

Page 3 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
report the first Pd-catalyzed synthesis of 4-substituted and 4,5-disubstituted isothiazolones from
acrylamide derivatives.
We began our investigation using the acrylamide 1a in presence of the electrophilic SCN source
I under Pd catalysis at 80 °C under air. The corresponding isothiazolone derivative 2a was
selectively obtained in a 44% NMR yield.11 Note that no product resulting from the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
thiocyanation reaction was detected. First, several Pd-catalysts were tried (Table 1, entries 1-
) and PdCl turned out to be the most efficient one in this transformation. Importantly, in the
4
2
absence of Pd-catalyst, no reaction occurred showcasing with this control experiment its key
role in the synthesis of isothiazolones (Table 1, entry 5). When the reaction was performed
under inert atmosphere or in the presence of a catalytic amount of PivOH (25 mol%), similar
results were obtained (Table 1, entries 6 and 7). When the temperature was lowered to 60 °C,
2
a was isolated in only 51% yield (Table 1, entry 8). On the contrary, an increase of the
temperature to 100 °C and 120 °C gave similar results, the reaction at 100 °C being the most
efficient one (Table 1, entries 9 and 10). Finally, when other solvents were evaluated such as
1.4-dioxane, toluene and DCE, a shutdown of the reactivity or lower yields were obtained
(Table 1, entries 11-13).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Optimization of the reaction conditions a
tBu
tBu
O
O
O
catalyst (10 mol%)
N
N
SCN
N
H
solvent (0.1 M)
air, T °C, 16 h
S
N
H
N
O
1a
I
2a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry catalyst
T
solvent
1H
NMR
yield (%)
(°C)
1
Pd(OAc)2
PdBr2
80
80
80
80
80
80
80
60
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
44
2
45
3
Pd(CH CN) Cl
2
55
3
2
4
PdCl2
None
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
81, 63b
NR
5
6c
7d
8
78, 61b
78, 60b
62, 51b
87, 70b
87, 69b
NR
9
100 DMF
1
1
1
1
0
120 DMF
1
2
3
100 1.4-dioxane
100 toluene
100 DCE
55
28
a
Reaction conditions: 1a (0.1 mmol), SCN reagent I (0.3 mmol), catalyst (10 mol%), solvent (0.1 M), T (°C), 16
1
h, air. Yields determined by H NMR on the crude reaction mixture using 1.1.2.2-tetrachloroethane as an internal
standard. Isolated yields. Under Ar atmosphere. Using 25 mol% of PivOH as additive. PivOH = pivalic acid.
DCE = 1.2-dichloroethane. NR = no reaction.
b
c
d
With the best reaction conditions in hand, the scope of the transformation was investigated
under Pd-catalysis. A panel of -aryl acrylamides were functionalized in moderate to good
yields (Scheme 2). Acrylamides with arenes bearing electron-rich substituents (1a-e) and
halogens (1g-i) at the para-position were converted into the corresponding N-quinolyl-4-
arylisothiazolones. The presence of the benzyl alcohol (compound 2d) was a key value added
9
since not tolerated in the previously reported reaction conditions. The substitution pattern on
the aromatic ring did not have any impact on the reaction outcome as observed with 2b, 2j and
2
m or 2h, 2k and 2n. The reaction was tolerant to various substituents such as halogens and
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CF group (2g-i, 2k and 2n-o), and no product resulting from a protodehalogenation reaction
3
was detected. Note that the reaction was easily scaled up and 2g was synthesized in 65% yield
on a 1 mmol scale. Heteroaromatic ring was also tolerated as demonstrated with compound 2r,
although it was obtained in a somehow lower yield (45%). The reaction was not restricted to -
aryl acrylamides and challenging ,-disubstituted acrylamides were also suitable substrates,
offering an access to fully decorated isothiazolone derivatives. -Phenyl-trans-cinnamide 1s
and ,-dimethyl acrylamide 1t were engaged in the standard reaction conditions. The
transformation yielded the corresponding products 2s and 2t in 49% and 51% yields,
respectively, offering an access to other isothiazolone derivatives and demonstrating the
synthetic utility of the reaction. Finally, when the amide derived from 8-amino-5-
methoxyquinoline was used as a directing group, the corresponding product 2u was obtained in
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
0% and 49% yields (on 0.2 and 0.5 mmol scale, respectively). However, trans-cinnamide 1v
was a reluctant substrate, which highlighted the complementary of our approach compared to
9
some previous report. To gain more insight in the transformation, other directing groups were
investigated. No reaction was observed with the amide derived from the N-methyl amide 1w,
highlighting the key role of the NH from the directing group in the reaction. Note that when the
amide derived from the 2-(aminomethyl)pyridine 3 as well as tertiary amides 4 and 5 were used,
no reaction occurred. Unfortunately, all attempts to cleave the directing group in the presence
of CAN to get the free amide failed, and the starting material was fully recovered.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R3
O
O
O
R1
R2
PdCl2 (20 mol%)
R1
R2
R3
N
H
N
SCN
N
DMF, air, 100 °C, 16 h
S
N
H
O
N
1a-u
I
2a-u
tBu
Me
MeO
Ph
O
O
O
HO
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
N
S
S
S
S
S
N
N
N
N
N
2
a, 70%[a]
2b, 59%
2c, 52%[a]
2d, 41%
2e, 50%
F
Cl
I
O
O
O
O
O
Me
N
N
N
N
N
S
S
S
S
S
N
N
N
N
N
2f, 62%
g, 71%, 65%[b]
2h, 60%
2i, 45%
2j, 61%
2
Br
O
O
O
O
O
Cl
F3C
N
N
N
N
N
Me
Cl
R
S
S
S
S
S
N
N
N
N
N
2
k, 51%
2l, 65%
m, 68%[a]
2n, 62%
2o, 65%
2
MeO
MeO
Cl
O
O
O
O
O
O
O
N
OMe
N
N
N
N
S
N
S
S
S
S
R
N
N
N
N
N
2
p, 47%
2q, 48%
2r, 45%
2s, R= Ph, 49%
t, R = Me, 51%
u, 50%, 49%[c]
2
2
Reluctant substrates and directing groups
Me
O
O
O
O
O
N
H
N
N
NEt2
N(iPr)2
Me
H
N
Me
N
N
Ph
H
H
H
3
H
H
1
v
1w
4
5
Scheme 2. Functionalization of acrylamides 1 into the corresponding isothiazolones 2. Reaction conditions: 1 (0.2
mmol), I (0.6 mmol), PdCl (20 mol%), DMF (2 mL), 100 °C, 16 h, air, isolated yields were given. [a] 10 mol%
of PdCl was used. [b] Reaction was performed on a 1 mmol scale using 4 equivalents of I. [c] Reaction was
2
2
performed on a 0.5 mmol scale.
In order to further demonstrate the synthetic utility of the products 2, an additional
transformation was conducted (Scheme 3). The selective chlorination of the 8-aminoquinoline
part was realized, bringing functional group diversity on that part of the molecule too. Indeed,
in the presence of 0.5 equivalent of TCCA, the functionalized isothiazolone 6 was isolated in
55% yield.
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Post-functionnalization reaction
O
O Cl
TCCA (0.5 equiv)
OMe
OMe
N
N
S
S
MeCN, air, 25 °C, 6 h
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2u
6, 55%
Scheme 3. Selective chlorination reaction of the compound 2u
Based on our previous work regarding the functionalization of olefins according to a C-H bond
functionalization via Pd-catalysis10c and the fact that the transformation did not occur without
a Pd-catalyst (Table 1, entry 5), a possible mechanism was suggested (Scheme 4). Subsequent
to the coordination of the Pd(II)-catalyst with the bidentate directing group, which afforded the
species A, the corresponding palladacycle (intermediate B) was formed. This process might
occur via a concerted metalation-deprotonation step. In the presence of the electrophilic SCN
source I, an oxidative addition reaction with the intermediate B led to a Pd(IV) species C. Then,
a final reductive elimination along with the protonation of the nitrogen atom of the amide
regenerated the catalyst and afforded a putative intermediate D, which quickly underwent an
intramolecular decyanative cyclization to provide the desired isothiazolone 2.9
O
intramolecular
R
2
N
H
SCN
decyanative cyclization
N
1
[Pd(II)]
putative intermediate
reductive
elimination
D
-HX
O
L
N
O
R
N
X
SCN
N
Pd
PdII
R
N
H
X
C
A
oxidative
addition
O
N
Pd
I
-HX
N
R
L
B
Scheme 4. Plausible catalytic cycle
Conclusion
In this study, an original synthesis of N-quinolyl-4-arylisothiazolones and N-quinolyl-4,5-
disubstituted isothiazolones was achieved under an air atmosphere. An array of heterocyclic
compounds was obtained in moderate to good yields (21 examples, up to 71% yield) using
simple and neutral reaction conditions. With this approach, not only 4-substituted but also 4,5-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
disubstituted isothiazolone derivatives were obtained. A post-functionalization reaction further
demonstrated the synthetic utility of the depicted approach. We believe that this methodology
will be of high interest for the scientific community, offering a straightforward access to
molecules of interest, and demonstrating further how the direct C-H bond functionalization
might be used to build up more complex molecules.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
All reactions were carried out using oven dried glassware and magnetic stirring under an
atmosphere of air unless otherwise stated. Reaction temperatures are reported as the
temperature of the oil bath surrounding the vessel. Analytical thin layer chromatography was
performed on silica gel aluminium plates with F-254 indicator and visualized by UV light (254
nm) and/or chemical staining with a KMnO solution or a phosphomolybdic acid solution. Flash
4
chromatography was performed on Merck silica gel (40-63 mesh) either by standard technique
or by Biotage Isolera One Flash Purification System (gradient of solvents; PE = petroleum
1
ether, Et O = diethyl ether). H NMR spectra were recorded on a Bruker DXP 300 MHz
2
1
3
19
spectrometer at 300.1 MHz, C spectra at 75.5 MHz, F NMR at 282.4 MHz. Chemical shifts
(δ) are quoted in parts per million (ppm) relative to residual solvent peak for CDCl (δ = 7.26
3
H
ppm; δ = 77.0 ppm; or relative to external CFCl : δ = 0.0 ppm). Coupling constants (J) are
C
3
quoted in Hz. The following abbreviations were used to show the multiplicities: s: singlet, d:
doublet, dd: doublet of doublet, m: multiplet. High-Resolution Mass Spectra (HRMS) were
recorded on Waters LCT Premier. Infrared spectra were recorded on a Perkin Elmer FT-IR
-1
spectrometer Paragon 100 (ATR); the wave numbers (ν) are quoted in cm . Melting points
were recorded on Kofler bench and are uncorrected.
PdCl was purchased from Sigma-Aldrich Ltd. Dry DMF (N,N-Dimethylformamide, in sealed
2
bottle with molecular sieves) was purchased from Acros Organics Ltd. Reagent I was
synthesized according to the literature procedure. Acrylamides 1a, 1b, 1c, 1e-1f,10c
1
3
10c
14
10c
14
10c
14
10c
14
10c
14
10c
15
10c
14
1
g, 1h-1i, 1j, 1k-1l, 1m, 1n, 1p, 1q-1r, 1s, 1t, 1u were synthesized
1
6
16 17
10b
according to the preview reports in the literature. Starting materials 1v, 3, 4 and 5 were
prepared according to literature procedures.
General Procedures for the Preparation of the Starting Materials 1.
General procedure for the synthesis of 2-aryl-N-(quinolin-8-yl)acrylamides 1a-1e, 1g-1r.
o
Oxalyl chloride (0.94 mL,11 mmol, 1.1 equiv) was slowly added at 0 C to a solution of the
corresponding acid (10 mmol, 1.0 equiv) and DMF (3 drops) in freshly distilled CH Cl (15
2
2
mL). After stirring at room temperature for 3 h, the solvent was removed under vacuum and the
residue was dissolved in freshly distilled CH Cl (50 mL). 8-Aminoquinoline (1.44 g, 10 mmol,
2
2
1
equiv) was added and the reaction was followed by TLC until it was completed. Water (100
mL) was added. The aqueous layers were extracted with CH Cl (3  150 mL). Then, the
2
2
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
combined organic layers were dried over MgSO . Removal of the solvent under vacuum and
4
purification of the residue by Biotage afforded the corresponding amide.
The resulting amide derived from 8-aminoquinoline (5 mmol, 1.0 equiv), (CHO) (0.44 g, 15
n
mmol, 3.0 equiv), (nBu) NHSO (0.17 g, 0.5 mmol, 0.1 equiv) and K CO (1.04 g, 7.5 mmol,
4
4
2
3
o
1.5 equiv) were added in toluene (80 mL) and stirred at 80 C. The reaction was followed by
TLC until it was completed. Water (100 mL) was added. The aqueous layers were extracted
with Et O (3  150 mL). Then, the combined organic layers were dried over Na SO . Removal
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
4
of the solvent under vacuum and purification of the residue by Biotage afforded the desired 2-
aryl-N-(quinolin-8-yl)acrylamides 1.
General procedure for the synthesis of 2-Phenyl-N-(quinolin-8-yl)acrylamide 1f, 1s and 1t.
o
Oxalyl chloride (0.47 mL, 5.5 mmol, 1.1 equiv) was slowly added at 0 C to a solution of the
corresponding acid (5 mmol, 1.0 equiv) and DMF (3 drops) in freshly distilled CH Cl (40 mL).
2
2
After stirring at room temperature for 3 h, the solvent was removed under vacuum and the
residue was dissolved in freshly distilled CH Cl (50 mL). 8-Aminoquinoline (0.72 g, 5 mmol,
2
2
1
equiv) was added and the reaction was followed by TLC until it was completed. Water (100
mL) was added. The aqueous layers were extracted with Et O (3  150 mL). Then, the combined
2
organic layers were dried over Na SO . Removal of the solvent under vacuum and purification
2
4
of the residue by Biotage afforded the desired product 1.
N-(5-Methoxyquinolin-8-yl)-2-phenylacrylamide 1u was prepared by using a similar procedure
as the one depicted above for 1f by replacing the 8-aminoquinoline with the 5-methoxy-8-
aminoquinoline.
General procedure for the synthesis of N-methyl-N-(quinolin-8-yl)-2-(o-tolyl)acrylamide 1w.18
To a suspension of sodium hydride (60%) (80 mg, 2 mmol, 2.0 equiv) in dry DMF (5 mL), was
o
added a solution of 1m (288 mg, 1 mmol, 1 equiv) in dry DMF (10 mL) at 0 C. Then, the
reaction mixture was warmed to room temperature and stirred for 0.5 h. Then, methyl iodide
o
(
81 µL, 1.3 mmol, 1.3 equiv) was added dropwise and the reaction was stirred at 25 C for 3 h.
The reaction was diluted with CH Cl (30 mL) and the organic layer was washed with water (3
2
2
x 15 mL), dried over Na SO . Removal of the solvent under vacuum and purification of the
2
4
residue by Biotage afforded the desired product 1w.
Purification and Characterization of the Starting Materials 1.
2
-(4-(Hydroxymethyl)phenyl)-N-(quinolin-8-yl)-acrylamide (1d): Purification by silica gel
column chromatography (Biotage system 25 g, height 80 mm, width 30 mm, eluent: petroleum
ether/diethyl ether, from 100/0 to 50/50). Yield: 45% (684 mg). R (petroleum ether/diethyl
f
o
1
ether, 50/50): 0.41. White solid; m.p.: 96-97 C. H NMR (300.1 MHz, CDCl ): δ 10.25 (brs,
3
1
6
H), 8.87 (d, J = 7.2 Hz, 1H), 8.72-8.59 (m, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.63-7.31 (m, 7H),
.27 (s, 1H), 5.82 (s, 1H), 4.74 (s, 2H). Note that the proton of OH was not visible. C{ H}
1
3
1
NMR (75.5 MHz, CDCl ): δ 165.9, 148.3, 145.6, 141.4, 138.6, 136.2, 135.9, 134.4, 128.4,
3
-1
1
1
3
27.9, 127.3, 127.1, 121.9, 121.9, 121.5, 116.7, 64.9. IR (neat, cm ) : 3455, 3350, 2855, 1670,
+
522, 1485, 1426, 1389, 1166, 1031, 826, 667. HRMS (ESI ): calcd for C H N O m/z
1
9
17
2
2
+
05.1290 [M+H] , found 305.1277 (-4.3 ppm).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
-(2-Bromophenyl)-N-(quinolin-8-yl)-acrylamide (1o): Purification by silica gel column
chromatography (Biotage system 25 g, height 80 mm, width 30 mm, eluent: petroleum
ether/diethyl ether, from 100/0 to 75/25). Yield: 66% (1.18 g). R (petroleum ether/diethyl ether,
50/50): 0.52. Red solid; m.p.: 123-124 C. H NMR (300.1 MHz, CDCl ): δ 9.90 (brs, 1H), 8.69
f
o
1
3
(dd, J = 7.5 Hz, 1.2 Hz, 1H), 8.37-8.32 (m, 1H), 7.90-7.82 (m, 1H), 7.49 (d, J = 7.8, 1H), 7.36-
1
3
1
7
.23 (m, 4H), 7.17-7.09 (m, 2H), 6.44 (d, J = 1.2 Hz, 1H), 5.55 (d, J = 0.9 Hz, 1H). C{ H}
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (75.5 MHz, CDCl ): δ 163.7, 148.2, 145.3, 138.6, 138.3, 136.1, 134.4, 133.0, 131.7, 130.1,
127.8, 127.8, 127.3, 125.7, 123.8, 121.7, 121.5, 116.4. IR (neat, cm ) : 3328, 1675, 1523,
3
-1
+
1
484, 1385, 1325, 1027, 790, 762, 682. HRMS (ESI ): calcd for C H BrN O m/z 353.0290
1
8
14
2
+
[M+H] , found 353.0296 (1.7 ppm).
N-Methyl-N-(quinolin-8-yl)-2-(o-tolyl)-acrylamide (1w): Purification by silica gel column
chromatography (Biotage system 25 g, height 80 mm, width 30 mm, eluent: petroleum
ether/diethyl ether, from 100/0 to 75/25). Yield: 70% (211 mg). R (petroleum ether/diethyl
f
1
ether, 50/50): 0.59. Yellow oil. H NMR (300.1 MHz, CDCl ): δ 8.87-8.73 (m, 1H), 7.99 (dd,
3
J = 8.4 Hz, 1.5 Hz, 1H), 7.67-7.53 (m, 1H), 7.38-7.16 (m, 3H), 6.66-6.50 (m, 2H), 6.57-6.45
1
3
1
(m, 1H), 6.33-6.18 (m, 1H), 6.07 (s, 1H), 5.22 (s, 1H), 3.54 (s, 3H), 2.11 (s, 3H). C{ H} NMR
(75.5 MHz, CDCl ): δ 171.2, 149.7, 146.9, 143.7, 140.4, 136.8, 135.4, 135.1, 129.0, 128.6,
3
-1
128.6, 128.1, 127.7, 126.3, 125.7, 124.6, 123.5, 121.2, 37.8, 19.7. IR (neat, cm ) : 2965, 2932,
+
1
639, 1613, 1391, 1354, 1281, 1197, 1086, 945, 834, 796. HRMS (ESI ): calcd for C H N O
2
0
19
2
+
m/z 303.1497 [M+H] , found 303.1501 (1.3 ppm).
General Procedure for the Synthesis of Derivatives 2.
A dried tube was loaded with PdCl (7.1 mg, 0.04 mmol, 20 mol%), reagent I (122.4 mg, 0.6
mmol, 3.0 equiv) and amide 1 (0.2 mmol, 1.0 equiv). Then DMF (2 mL) was injected. The tube
was sealed with a cap and the suspension was stirred at 100 C (oil bath) for 16 h. After cooling
down, the reaction was diluted with Et O (30 mL). Then, the organic layers were washed by
water (2 x 10 mL), by an aqueous saturated NaHCO solution (10 mL), dried over Na SO , and
solvents were removed under vacuum. The residue was directly purified by silica gel column
chromatography to give the desired product 2. Note that for some compounds (see Scheme 2 in
the manuscript), 10 mol% PdCl were used (3.5 mg, 0.02 mmol).
2
o
2
3
2
4
2
Purification and Characterization of the Isothiazolones 2.
2
-(Quinolin-8-yl)-4-(4-(tert-butyl)phenyl)-isothiazol-3(2H)-one (2a): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
00/0 to 75/25 to 50/50). Yield: 70% (50 mg). R (n-pentane/ethyl acetate, 50/50): 0.39. White
1
f
o
1
solid; m.p.: 244-245 C. H NMR (300.1 MHz, CDCl ): δ 9.00-8.93 (m, 1H), 8.43 (s, 1H), 8.23
3
(d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.94-7.84 (m, 3H), 7.68-7.59 (m, 1H), 7.51-7.42
13
1
(m, 3H), 1.35 (s, 9H). C{ H} NMR (75.5 MHz, CDCl ): δ 167.3, 151.0, 150.6, 143.9, 136.4,
3
1
3
35.2, 134.2, 133.7, 129.8, 129.6, 129.3, 128.9, 126.5, 126.3, 125.5, 123.7, 123.5, 121.8, 34.6,
-1
+
1.3. IR (neat, cm ) : 2960, 1623, 1609, 1500, 1471, 1315, 1267, 831, 786. HRMS (ESI ):
+
calcd for C H N OS m/z 361.1375 [M+H] , found 361.1388 (3.6 ppm).
2
2
21
2
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
-(Quinolin-8-yl)-4-(4-methylphenyl)-isothiazol-3(2H)-one (2b): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 75/25 to 50/50). Yield: 59% (38 mg). R (n-pentane/ethyl acetate, 50/50): 0.37. White
f
o
1
solid; m.p.: 206-207 C. H NMR (300.1 MHz, CDCl ): δ 8.96 (dd, J = 4.2 Hz, 1.8 Hz, 1H),
3
8
3
.42 (s, 1H), 8.22 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 8.04 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 7.93-7.83 (m,
1
3
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 7.67-7.60 (m, 1H), 7.50-7.41 (m, 1H), 7.25-7.20 (m, 2H), 2.38 (s, 3H). C{ H} NMR
(75.5 MHz, CDCl ): δ 167.2, 150.6, 143.9, 137.8, 136.4, 135.0, 133.7, 129.8, 129.6, 129.3,
3
-1
129.2, 128.9, 126.6, 126.2, 123.6, 121.8, 21.3. IR (neat, cm ) : 1647, 1495, 1387, 1267, 1186,
+
+
8
3
28, 793, 615, 529. HRMS (ESI ): calcd for C H N OS m/z 319.0905 [M+H] , found
19 15 2
19.0902 (-0.9 ppm).
2
-(Quinolin-8-yl)-4-(4-methoxyphenyl)-isothiazol-3(2H)-one (2c): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 75/25 to 50/50). Yield: 52% (35 mg). R (n-pentane/ethyl acetate, 50/50): 0.30. Yellow
f
o
1
solid; m.p.: 142-143 C. H NMR (300.1 MHz, CDCl ): δ 9.01-8.92 (m, 1H), 8.37 (s, 1H), 8.22
3
(d, J = 8.1 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.98-7.84 (m, 3H), 7.69-7.58 (m, 1H), 7.50-7.40
1
3
1
(m, 1H), 6.96 (d, J = 8.7 Hz, 2H). 3.83 (s, 3H). C{ H} NMR (75.5 MHz, CDCl ): δ 167.2,
3
1
59.4, 150.7, 144.0, 136.3, 134.0, 133.8, 129.7, 129.3, 128.9, 128.0, 126.2, 125.4, 123.3, 121.8,
-1
113.9, 55.3. IR (neat, cm ) : 2932, 2839, 1642, 1544, 1498, 1387, 1274, 1252, 1178, 1030,
+
+
8
22, 795, 759, 577. HRMS (ESI ): calcd for C H N O S m/z 335.0854 [M+H] , found
19 15 2 2
3
35.0866 (3.6 ppm).
2-(Quinolin-8-yl)-4-(4-(hydroxymethyl)phenyl)-isothiazol-3(2H)-one (2d): Purification by
silica gel column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate,
from 100/0 to 75/25 to 50/50). Yield: 41% (27 mg). R (n-pentane/ethyl acetate, 50/50): 0.22.
f
o
1
Yellow solid; m.p.: 176-177 C. H NMR (300.1 MHz, CDCl ): δ 9.01-8.93 (m, 1H), 8.51 (s,
3
1
H), 8.25 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 8.09-7.89 (m, 4H), 7.72-7.59 (m, 1H), 7.53-7.40 (m,
1
3
1
3H), 4.62 (s, 2H). Note that, the proton of OH is not visible. C{ H} NMR (75.5 MHz, CDCl ):
3
δ 167.0, 150.7, 143.9, 137.0, 136.4, 136.2, 133.6, 132.7, 129.6, 129.3, 129.0, 128.8, 127.0,
-1
1
26.2, 123.0, 121.9, 46.1. IR (neat, cm ) : 3053, 2921, 2850, 1628, 1599, 1497, 1471, 1320,
+
+
1
259, 1203, 1132, 822, 783, 662. HRMS (ESI ): calcd for C H N O S m/z 335.0854 [M+H] ,
19 15 2 2
found 335.0864 (3.0 ppm).
2-(Quinolin-8-yl)-4-([1,1'-biphenyl]-4-yl)-isothiazol-3(2H)-one (2e): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
1
00/0 to 75/25 to 50/50). Yield: 50% (38 mg). R (n-pentane/ethyl acetate, 50/50): 0.33. Yellow
f
o
1
solid; m.p.: 166-167 C. H NMR (300.1 MHz, CDCl ): δ 9.02-8.93 (m, 1H), 8.53 (s, 1H), 8.24
3
(dd, J = 8.4 Hz, 1.5Hz, 1H), 8.11-8.03 (m, 3H), 7.92 (d, J = 7.2 Hz, 1H), 7.71-7.58 (m, 5H),
1
3
1
7
1
1
.50-7.32 (m, 4H). C{ H} NMR (75.5 MHz, CDCl ): δ 167.1, 150.7, 143.9, 140.7, 140.6,
3
36.4, 135.7, 133.6, 131.6, 129.6, 129.3, 129.0, 128.7, 127.3, 127.2, 127.0, 126.2, 123.5, 123.2,
-1
21.9. IR (neat, cm ) : 2921, 1732, 1637, 1495, 1385, 1260, 1081, 823, 794, 765, 606. HRMS
+
+
(ESI ): calcd for C H N OS m/z 381.1062 [M+H] , found 381.1055 (-1.8 ppm).
2
4
17
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
-(Quinolin-8-yl)-4-phenyl-isothiazol-3(2H)-one (2f): Purification by silica gel column
chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from 100/0 to
75/25 to 50/50). Yield: 62% (37 mg). R (n-pentane/ethyl acetate, 50/50): 0.42. Yellow solid;
f
o
1
m.p.: 222-223 C. H NMR (300.1 MHz, CDCl ): δ 8.98-8.91 (m, 1H), 8.47 (s, 1H), 8.20 (dd,
3
1
3
1
J = 7.2 Hz, 1.2 Hz, 1H), 8.06-7.85 (m, 4H), 7.66-7.58 (m, 1H), 7.48-7.30 (m, 4H). C{ H}
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (75.5 MHz, CDCl ): δ 166.6, 150.8, 150.5, 147.5, 143.8, 136.9, 136.5, 136.5, 133.1, 129.6,
3
-1
1
29.4, 127.6, 126.2, 124.1, 122.0, 119.4. IR (neat, cm ) : 3092, 1646, 1596, 1501, 1458, 1316,
+
+
1273, 1104, 823, 784, 613, 477. HRMS (ESI ): calcd for C H N OS m/z 305.0749 [M+H] ,
1
8
13
2
found 305.0756 (2.3 ppm).
2
-(Quinolin-8-yl)-4-(4-fluorophenyl)-isothiazol-3(2H)-one (2g): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
00/0 to 75/25 to 66/34). Yield: 71% (46 mg), 65% (209 mg) on 1 mmol scale. R (n-
1
f
o
1
pentane/ethyl acetate, 50/50): 0.43. Yellow solid; m.p.: 209-210 C. H NMR (300.1 MHz,
CDCl ): δ 9.00-8.93 (m, 1H), 8.44 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H),
3
1
9
7
.99-7.89 (m, 3H), 7.70-7.61 (m, 1H), 7.52-7.43 (m, 1H), 7.15-7.05 (m, 2H). F NMR (282.4
1
3
1
MHz, CDCl ): δ -113.9 to -114.2 (m, 1F). C{ H} NMR (75.5 MHz, CDCl ): δ 167.0, 162.5
3
3
(d, J = 247.6 Hz), 150.7, 144.0, 136.4, 135.5, 133.6, 129.6, 129.3, 129.1, 128.7 (d, J = 3.0 Hz),
-1
128.5 (d, J = 8.3 Hz), 126.2, 122.6, 121.9, 115.4 (d, J = 21.1 Hz). IR (neat, cm ) : 3064, 1635,
1
3
+
551, 1499, 1389, 1215, 1166, 810, 785, 561, 530. HRMS (ESI ): calcd for C H FN OS m/z
1
8
12
2
+
23.0654 [M+H] , found 323.0650 (-1.2 ppm).
2-(Quinolin-8-yl)-4-(4-chlorophenyl)-isothiazol-3(2H)-one (2h): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
1
00/0 to 75/25 to 50/50). Yield: 60% (41 mg). R (n-pentane/ethyl acetate, 50/50): 0.40. Yellow
f
o
1
solid; m.p.: 208-209 C. H NMR (300.1 MHz, CDCl ): δ 9.00-8.93 (m, 1H), 8.49 (s, 1H), 8.24
3
(d, J = 8.1 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.98-7.89 (m, 3H), 7.70-7.61 (m, 1H), 7.52-7.45
1
3
1
(m, 1H), 7.42-7.36 (m, 2H). C{ H} NMR (75.5 MHz, CDCl ): δ 166.9, 150.7, 143.9, 136.4,
3
1
36.0, 133.8, 133.5, 131.0, 129.6, 129.3, 129.1, 128.7, 127.9, 126.2, 122.4, 121.9. IR (neat,
-1
cm ) : 3048, 1721, 1632, 1538, 1470, 1388, 1317, 1279, 1090, 1012, 811, 786, 611, 523, 474.
HRMS (ESI ): calcd for C H ClN OS m/z 339.0359 [M+H] , found 339.0360 (0.3 ppm).
+
+
1
8
12
2
2
-(Quinolin-8-yl)-4-(4-iodophenyl)-isothiazol-3(2H)-one (2i): Purification by silica gel column
chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from 100/0 to
5/25 to 50/50). Yield: 45% (39 mg). R (n-pentane/ethyl acetate, 50/50): 0.37. Yellow solid;
7
f
o
1
m.p.: 215-216 C. H NMR (300.1 MHz, CDCl ): δ 9.00-8.92 (m, 1H), 8.50 (s, 1H), 8.23 (dd,
3
J = 8.4 Hz, 1.5 Hz, 1H), 8.02 (dd, J = 7.2 Hz, 0.9 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1 H), 7.78-7.62
1
3
1
(m, 5H), 7.51-7.43 (m, 1H). C{ H} NMR (75.5 MHz, CDCl ): δ 166.8, 150.7, 143.9, 137.6,
3
1
1)
36.4, 136.1, 133.4, 132.0, 129.6, 129.3, 129.1, 128.3, 126.2, 122.4, 121.9, 93.7. IR (neat, cm-
+
: 3044, 2162, 1630, 1532, 1470, 1388, 1321, 1198, 1004, 827, 799, 609, 523. HRMS (ESI ):
+
calcd for C H IN OS m/z 430.9715 [M+H] , found 430.9708 (-1.6 ppm).
1
8
12
2
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
-(Quinolin-8-yl)-4-(3-methylphenyl)-isothiazol-3(2H)-one (2j): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 75/25 to 50/50). Yield: 61% (39 mg). R (n-pentane/ethyl acetate, 50/50): 0.36. Yellow
f
o
1
solid; m.p.: 180-181 C. H NMR (300.1 MHz, CDCl ): δ 9.00-8.92 (m, 1H), 8.46 (s, 1H), 8.22
3
(dd, J = 8.4 Hz, 1.2 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.83 (s, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.72 (d, J = 7.8 Hz, 1H), 7.67-7.58 (m, 1H), 7.50-7.41 (m, 1H), 7.36-7.27 (m, 1H), 7.20-7.12
1
3
1
(m, 1H), 2.39 (s, 3H). C{ H} NMR (75.5 MHz, CDCl ): δ 167.1, 150.6, 143.9, 138.0, 136.3,
3
135.8, 133.7, 132.5, 129.5, 129.2, 128.9, 128.7, 128.3, 127.3, 126.1, 123.8, 123.6, 121.8, 21.5.
-1
+
IR (neat, cm ) : 3048, 1644, 1496, 1380, 1324, 1278, 1149, 830, 787, 693, 608. HRMS (ESI ):
calcd for C H N OS m/z 319.0905 [M+H] , found 319.0913 (2.5 ppm).
+
19 15
2
2
-(Quinolin-8-yl)-4-(3-chlorophenyl)-isothiazol-3(2H)-one (2k): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 75/25 to 50/50). Yield: 51% (35 mg). R (n-pentane/ethyl acetate, 50/50): 0.39. Yellow
f
o
1
solid; m.p.: 150-151 C. H NMR (300.1 MHz, CDCl ): δ 9.00-8.91 (m, 1H), 8.51 (s, 1H), 8.23
3
(d, J = 8.1 Hz, 1H), 8.06-7.98 (m, 2H), 7.94-7.82 (m, 2H), 7.70-7.59 (m, 1H), 7.50-7.43 (m,
1
3
1
1H), 7.38-7.28 (m, 2H). C{ H} NMR (75.5 MHz, CDCl ): δ 166.8, 150.7, 143.9, 136.7, 136.4,
3
1
34.5, 134.2, 133.4, 129.7, 129.6, 129.3, 129.1, 128.0, 126.6, 126.2, 124.7, 122.1, 121.9. IR
-1
(neat, cm ) : 3064, 1727, 1651, 1596, 1502, 1472, 1319, 1280, 1149, 825, 778, 608. HRMS
+
+
(ESI ): calcd for C H ClN OS m/z 339.0359 [M+H] , found 339.0364 (1.5 ppm).
18 12 2
2
-(Quinolin-8-yl)-4-(3-(trifluoromethyl)phenyl)-isothiazol-3(2H)-one (2l): Purification by
silica gel column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate,
from 100/0 to 75/25 to 50/50). Yield: 65% (48 mg). R (n-pentane/ethyl acetate, 50/50): 0.34.
f
o
1
Yellow solid; m.p.: 140-141 C. H NMR (300.1 MHz, CDCl ): δ 9.01-8.89 (m, 1H), 8.58 (s,
3
H), 8.33-8.10 (m, 3H), 8.06-7.98 (m, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.69-7.43 (m, 4H). 19F
1
1
3
1
NMR (282.4 MHz, CDCl ): δ -63.1 (s, 3F). C{ H} NMR (75.5 MHz, CDCl ): δ 166.8, 150.7,
3
3
143.9, 137.1, 136.4, 133.3, 133.2, 130.1 (q, J = 32.5 Hz), 129.7 (q, J = 1.1 Hz), 129.6, 129.3,
29.2, 128.9, 126.1, 124.4 (q, J = 3.8 Hz), 124.1 (q, J = 277.1 Hz), 123.3 (q, J = 3.8 Hz), 121.9.
1
-1
IR (neat, cm ) : 3053, 1651, 1503, 1473, 1391, 1331, 1262, 1114, 1072, 826, 789. HRMS
+
+
(ESI ): calcd for C H F N OS m/z 373.0622 [M+H] , found 373.0612 (-2.7 ppm).
19 12 3 2
2
-(Quinolin-8-yl)-4-(2-methylphenyl)-isothiazol-3(2H)-one (2m): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
00/0 to 75/25 to 50/50). Yield: 68% (43 mg). R (n-pentane/ethyl acetate, 50/50): 0.36. White
1
f
o
1
solid; m.p.: 156-157 C. H NMR (300.1 MHz, CDCl ): δ 8.98-8.93 (m, 1H), 8.27-8.16 (m,
3
2H), 8.09 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.66-7.57 (m, 1H), 7.49-7.40 (m, 2H),
1
3
1
7
1
1
4
.30-7.19 (m, 3H), 2.44 (s, 3H). C{ H} NMR (75.5 MHz, CDCl ): δ 167.2, 150.3, 143.6,
3
38.2, 137.3, 136.3, 133.9, 132.6, 130.4, 130.2, 129.2, 129.0, 128.5, 128.3, 126.2, 125.8, 125.7,
-1
21.7, 20.3. IR (neat, cm ) : 3064, 2927, 1651, 1592, 1501, 1472, 1312, 1130, 829, 744, 606,
+
+
52. HRMS (ESI ): calcd for C H N OS m/z 319.0905 [M+H] , found 319.0901 (-1.3 ppm).
1
9
15
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
-(Quinolin-8-yl)-4-(2-chlorophenyl)-isothiazol-3(2H)-one (2n): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 75/25 to 50/50). Yield: 62% (42 mg). R (n-pentane/ethyl acetate, 50/50): 0.41. Yellow
f
o
1
solid; m.p.: 84-85 C. H NMR (300.1 MHz, CDCl ): δ 9.01-8.94 (m, 1H), 8.67 (s, 1H), 8.22
3
(dd, J = 8.1 Hz, 1.5 Hz, 1H), 8.11 (dd, J = 7.5 Hz, 1.2 Hz, 1H), 7.88 (dd, J = 8.1 Hz, 0.9 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H), 7.81 (dd, J = 7.5 Hz, 2.1 Hz, 1H), 7.67-7.58 (m, 1H), 7.52-7.44 (m, 2H), 7.36-7.24 (m,
1
3
1
2
H). C{ H} NMR (75.5 MHz, CDCl ): δ 167.1, 150.4, 143.5, 140.5, 136.4, 133.6, 132.9,
3
-1
131.3, 131.2, 130.0, 129.2, 129.1, 129.1, 128.6, 126.7, 126.2, 121.8, 121.2. IR (neat, cm ) :
3
+
053, 2233, 1628, 1498, 1468, 1387, 1320, 907, 823, 723, 564. HRMS (ESI ): calcd for
+
C H ClN OS m/z 339.0359 [M+H] , found 339.0374 (4.4 ppm).
18 12
2
2
-(Quinolin-8-yl)-4-(2-bromophenyl)-isothiazol-3(2H)-one (2o): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 75/25 to 50/50). Yield: 65% (50 mg). R (n-pentane/ethyl acetate, 50/50): 0.38. Yellow
f
o
1
solid. m.p.: 64-65 C. H NMR (300.1 MHz, CDCl ): δ 9.03-8.93 (m, 1H), 8.62 (s, 1H), 8.22
3
(dd, J = 8.4 Hz, 1.5 Hz, 1H), 8.12 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.74-
1
3
1
7.59 (m, 3H), 7.51-7.42 (m, 1H), 7.41-7.32 (m, 1H), 7.24-7.15 (m, 1H). C{ H} NMR (75.5
MHz, CDCl ): δ 167.0, 150.3, 143.5, 140.5, 136.4, 133.6, 133.3, 133.2, 131.6, 129.4, 129.2,
3
-1
129.0, 128.5, 127.3, 126.2, 123.2, 123.1, 121.8. IR (neat, cm ) : 2927, 2233, 1721, 1629,
1
3
+
595, 1498, 1469, 1320, 1283, 823, 723, 607. HRMS (ESI ): calcd for C H BrN OS m/z
1
8
12
2
+
84.9833 [M+H] , found 384.9840 (1.8 ppm).
2-(Quinolin-8-yl)-4-(3,4-dimethoxyphenyl)-isothiazol-3(2H)-one (2p): Purification by silica
gel column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
1
00/0 to 50/50 to 34/66). Yield: 47% (34 mg). R (n-pentane/ethyl acetate, 50/50): 0.15. Yellow
f
o
1
solid; m.p.: 209-210 C. H NMR (300.1 MHz, CDCl ): δ 9.02-8.91 (m, 1H), 8.42 (s, 1H), 8.25
3
(d, J = 8.4 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.82-7.75 (m, 1H), 7.71-
1
3
1
7.61 (m, 1H), 7.54-7.39 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 3.92 (s, 6H). C{ H} NMR (75.5
MHz, CDCl ): δ 167.3, 150.8, 148.9, 148.8, 144.1, 136.4, 134.2, 133.7, 129.9, 129.4, 129.2,
3
-1
1
1
26.3, 125.7, 123.1, 121.9, 119.2, 111.1, 109.9, 55.9, 55.9. IR (neat, cm ) : 2960, 2916, 1643,
+
497, 1330, 1244, 1135, 1022, 795, 593. HRMS (ESI ): calcd for C H N O S m/z 365.0960
2
0
17
2
3
+
[M+H] , found 365.0964 (1.1 ppm).
2-(Quinolin-8-yl)-4-(benzo[d][1,3]dioxol-5-yl)-isothiazol-3(2H)-one (2q): Purification by
silica gel column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate,
from 100/0 to 75/25 to 50/50). Yield: 48% (34 mg). R (n-pentane/ethyl acetate, 50/50): 0.28.
f
o
1
Yellow solid; m.p.: 234-235 C. H NMR (300.1 MHz, CDCl ): δ 9.03-8.91 (m, 1H), 8.36 (s,
3
1
H), 8.24 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.73-7.60 (m,
1
3
1
1
H), 7.56-7.41 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 5.98 (s, 2H). C{ H} NMR (75.5 MHz,
CDCl ): δ 167.0, 150.7, 147.8, 147.4, 144.0, 136.4, 134.5, 133.7, 129.6, 129.3, 129.0, 126.8,
3
-1
1
26.2, 123.2, 121.9, 120.6, 108.4, 107.3, 101.1. IR (neat, cm ) : 3097, 2921, 1628, 1490,
+
1388, 1323, 1257, 1108, 1032, 932, 821, 801, 768, 615. HRMS (ESI ): calcd for C H N O S
1
9
13
2
3
+
m/z 349.0647 [M+H] , found 349.0651 (1.1 ppm).
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
-(Quinolin-8-yl)-4-(6-chloropyridin-3-yl)-isothiazol-3(2H)-one (2r): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 66/34 to 50/50). Yield: 45% (31 mg). R (n-pentane/ethyl acetate, 50/50): 0.22. Yellow
f
o
1
solid; m.p.: 151-152 C. H NMR (300.1 MHz, CDCl ): δ 8.99-8.92 (m, 1H), 8.91-8.83 (m,
3
1
H), 8.61 (s, 1H), 8.40 (dd, J = 8.1 Hz, 2.4 Hz, 1H), 8.25 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 8.02 (d,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 7.5 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.70-7.61 (m, 1H), 7.54-7.45 (m, 1H), 7.38 (d, J =
1
3
1
8
.4 Hz, 1H). C{ H} NMR (75.5 MHz, CDCl ): δ 166.6, 150.8, 150.4, 147.5, 143.8, 136.9,
3
-1
136.5, 136.4, 133.1, 129.6, 129.4, 129.3, 127.6, 126.2, 124.0, 122.0, 119.3. IR (neat, cm ) :
3
+
053, 1651, 1500, 1470, 1318, 1145, 1276, 824, 762, 694, 605. HRMS (ESI ): calcd for
+
C H ClN OS m/z 340.0311 [M+H] , found 340.0308 (-0.9 ppm).
17 11
3
2
-(Quinolin-8-yl)-4,5-diphenyl-isothiazol-3(2H)-one (2s): Purification by silica gel column
chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from 100/0 to
66/34 to 50/50). Yield: 49% (38 mg). R (n-pentane/ethyl acetate, 50/50): 0.31. Yellow solid;
f
o
1
m.p.: 229-230 C. H NMR (300.1 MHz, CDCl ): δ 9.05-8.96 (m, 1H), 8.25 (d, J = 8.4 Hz, 1H),
3
8
.19 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.69-7.61 (m, 1H), 7.52-7.45 (m, 3H), 7.40-
1
3
1
7.27 (m, 8H). C{ H} NMR (75.5 MHz, CDCl ): δ 168.0, 152.9, 150.3, 143.6, 136.5, 133.9,
3
1
32.4, 131.0, 130.1, 130.0, 129.3, 129.0, 128.9, 128.5, 128.3, 128.2, 127.7, 126.3, 121.8, 121.6.
-1
+
IR (neat, cm ) : 2921, 1652, 1502, 823, 779. 695, 601, 508. HRMS (ESI ): calcd for
C H N OS m/z 381.1062 [M+H] , found 381.1078 (4.2 ppm).
+
2
4
17
2
2
-(Quinolin-8-yl)-4,5-dimethyl-isothiazol-3(2H)-one (2t): Purification by silica gel column
chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from 100/0 to
6/34 to 75/25). Yield: 51% (26 mg). R (n-pentane/ethyl acetate, 50/50): 0.12. Yellow solid;
6
f
o
1
m.p.: 200-201 C. H NMR (300.1 MHz, CDCl ): δ 9.02-8.92 (m, 1H), 8.22 (dd, J = 8.4 Hz,
3
1
.5 Hz, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.67-7.56 (m, 1H), 7.49-7.40
1
3
1
(m, 1H), 2.40 (s, 3H), 2.07 (s, 3H). C{ H} NMR (75.5 MHz, CDCl ): δ 169.4, 150.4, 147.4,
3
-1
144.1, 136.3, 134.1, 129.3, 129.3, 128.4, 126.3, 121.7, 118.6, 13.1, 10.7. IR (neat, cm ) :
2
2
+
916, 1634, 1496, 1328, 829, 793. 695, 624, 509. HRMS (ESI ): calcd for C H N OS m/z
1
4
13
2
+
57.0749 [M+H] , found 257.0745 (-1.6 ppm).
2
-(5-Methoxyquinolin-8-yl)-4-phenyl-isothiazol-3(2H)-one (2u): Purification by silica gel
column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
100/0 to 75/25 to 50/50). Yield: 50% (33 mg), 49% (82 mg) on 0.5 mmol scale. R (n-
f
o
1
pentane/ethyl acetate, 50/50): 0.40. Yellow solid; m.p.: 156-157 C. H NMR (300.1 MHz,
CDCl ): δ 9.03-8.84 (m, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.45 (s, 1H), 7.97 (d, J = 7.2 Hz, 2H),
3
1
3
1
7.87 (d, J = 7.8 Hz, 1H), 7.50-7.30 (m, 4H), 6.92 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H). C{ H}
NMR (75.5 MHz, CDCl ): δ 167.2, 155.9, 151.1, 144.9, 135.4, 132.7, 131.2, 130.5, 128.5, 127.9,
3
-1
126.7, 125.9, 123.7, 121.6, 120.9, 103.7, 56.0. IR (neat, cm ) : 3070, 1728, 1656, 1590, 1477,
1
3
+
369, 1276, 1153, 1091, 811, 770, 695, 610. HRMS (ESI ): calcd for C H N O S m/z
1
9
15
2
2
+
35.0854 [M+H] , found 335.0864 (3.0 ppm).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
18
Post-functionalization reaction of the product 2u. In a dried tube was added 2u (33.4 mg,
0
.1 mmol) and TCCA (23.2 mg, 0.1 mmol, 1 equiv) under air. Then acetonitrile (1 mL) was
injected. The tube was sealed with a cap and the suspension was stirred at room temperature for
6 h. The reaction was diluted with acetonitrile (15 mL). Then, the organic layers were washed
by water (2 x 10 mL), by an aqueous saturated NaHCO solution (10 mL), dried over Na SO ,
and solvents were removed under vacuum. The residue was directly purified by silica gel
column chromatography to afford the desired product 6 (20 mg, 55%).
3
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(7-Chloro-5-methoxyquinolin-8-yl)-4-phenyl-isothiazol-3(2H)-one (6): Purification by silica
gel column chromatography (height 18 cm, width 1.5 cm, eluent: n-pentane/ethyl acetate, from
1
00/0 to 75/25). Yield: 55% (20 mg). R (n-pentane/ethyl acetate, 50/50): 0.65. Yellow solid;
f
o
1
m.p.: 166-167 C. H NMR (300.1 MHz, CDCl ): δ 8.99-8.89 (m, 1H), 8.56-8.44 (m, 2 H), 8.08
3
1
3
1
(s, 1H), 7.94 (d, J = 7.5 Hz, 2H), 7.60-7.32 (m, 4H), 4.08 (s, 3H). C{ H} NMR (75.5 MHz,
CDCl ): δ 167.1, 152.1, 150.7, 143.5, 136.0, 132.4, 131.3, 131.1, 130.3, 128.5, 128.1, 126.7,
3
-
1
1
1
3
24.9, 123.6, 123.1, 122.3, 61.9. IR (neat, cm ) : 3064, 3031, 2949, 1645, 1585, 1469, 1367,
257, 1168, 1080, 978, 876, 769, 690, 578. HRMS (ESI ): calcd for C H ClN O S m/z
+
1
9
14
2
2
+
69.0465 [M+H] , found 369.0461 (-1.1 ppm).
Supporting Information: spectral data for all new compounds found in the SI.
Acknowledgments
This work was partially supported by INSA Rouen, Rouen University, CNRS, EFRD, Labex
SynOrg (ANR-11-LABX-0029), Région Normandie (Crunch Network), the French National
Research Agency (ANR-17-CE07-0038-01) and Innovation Chimie Carnot (I2C). T. B. thanks
the European Research Council (ERC) under the European Union’s Horizon 2020 research and
innovation program (grant agreement no. 758710). M.-Y.C. thanks the French National
Research Agency for a doctoral fellowship (ANR-17-CE07-0038-01).
References
1
For selected reviews, see: (a) Lyons, T. M.; Sanford, M. S. Palladium-catalyzed ligand-
directed C−H functionalization reactions. Chem. Rev. 2010, 110, 1147–1169. (b) Jazzar, R.;
Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Functionalization of organic
molecules by transition‐metal‐catalyzed C(sp )-H activation. Chem. Eur. J. 2010, 16, 2654–
672. (c) Engle, K.; Mei, T.-S.; Wasa, M,; Yu, J.-Q. Weak coordination as a powerful means
for developing broadly useful C–H functionalization reactions. Acc. Chem. Res. 2011, 45, 788–
02. (d) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Beyond directing groups:
transition-metal-catalyzed C-H activation of simple arenes. Angew. Chem. Int. Ed.
012, 51, 10236–10254. (e) Chen, Z.-K.; Wang, B.; Zhang, J.-T.; Yu, W.-L.; Liu, Z.-X.; Zhang,
Y.-H. Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing
groups. Org. Chem. Front. 2015, 2, 1107–1295. (f) Pototschnig G.; Maulide N.; Schnurch M.
Direct Functionalization of C-H Bonds by Iron, Nickel, and Cobalt Catalysis. Chem. Eur. J.
3
2
8
2
2
017, 23, 9206–9232. (g) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-Huy, T.;
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zai, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B.
U. W.; Schnurch, M. A comprehensive overview of directing groups applied in metal-catalysed
C–H functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603–6743. (h) Ma, C.; Fang, P.;
Mei, T.-S. Recent advances in C–H functionalization using electrochemical transition metal
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3
catalysis. ACS. Catal. 2018, 8, 7179–7189. (i) Xu, Y.; Dong, G.-B. sp C–H activation via exo-
type directing groups. Chem. Sci. 2018, 9, 1424–1432. (j) Gandeepan, P.; Muller, T.; Zell, D.;
Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals for C–H Activation. Chem. Rev.
2019, 119, 2192–2452. (k) For an issue on C-H bond activation, see: Chem. Rev. 2017, 117,
8
481–9520.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
For selected reviews, see: (a) McMurray, L.; O’Hara, F.; Gaunt, M. J. Recent developments
in natural product synthesis using metal-catalysed C-H bond functionalisation. Chem. Soc. Rev.
011, 40, 1885–1898. (b) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond
functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew.
Chem. Int. Ed. 2012, 51, 8960–9009. (c) Chen, D. Y.-K.; Youn, S. W. C-H Activation: a
complementary tool in the total synthesis of complex natural products. Chem. Eur. J. 2012, 18,
2
9
452–9474. (d) Schonherr, H.; Cernak, T. Profound methyl effects in drug discovery and a call
for new C-H methylation reactions. Angew. Chem. Int. Ed. 2013, 52, 12256–12267. (e) Cernak,
T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The medicinal chemist's toolbox
for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 2016, 45, 546. (f)
Abrams, D. J.; Provencher, P. A.; Sorensen, E. J. Recent applications of C–H functionalization
in complex natural product synthesis. Chem. Soc. Rev. 2018, 47, 8925–8967. For selected
examples, see: (g) Brady, P. B.; Bhat, V. Recent applications of Rh- and Pd-catalyzed C(sp )–
H functionalization in natural product total synthesis. Eur. J. Org. Chem. 2017, 5179–5190. (h)
Dailler, D.; Danoun, G.; Baudoin, O. A general and scalable synthesis of aeruginosin marine
natural products based on two strategic C(sp )-H activation reactions. Angew. Chem. Int. Ed.
3
3
2015, 54, 4919 –4922.
3 Wang, K.; Hu, F.; Zhang, Y.; Wang, J. Directing group-assisted transition-metal-catalyzed
vinylic C-H bond functionalization. Sci. China. Chem. 2015, 58, 1252-1265 and references
therein.
4
Gorsuch, S.; Bavetsias, V.; Rowlands, M. G.; Aherne, G. W.; Workman, P.; Jarman, M.;
McDonald, E. Synthesis of isothiazol-3-one derivatives as inhibitors of histone
acetyltransferases (HATs). Bioorg. Med. Chem. 2009, 17, 467–474.
5
Stimson, L.; Rowlands, M. G.; Newbatt, Y. M.; Smith, N. F.; Raynaud, F. I.; Rogers, P.;
Bavetsias, V.; Gorsuch, S.; Jarman, M.; Bannister, A.; Kouzarides, T.; McDonald, E.;
Workman, P.; Aherne, G. W. Isothiazolones as inhibitors of PCAF and p300 histone
acetyltransferase activity. Mol. Cancer Ther. 2005, 4, 1521–1532.
6
3
5
(a) Lewis, S. N.; Miller, G. A.; Hausman, M.; Szamborski, E. C. Isothiazoles I: 4-Isothiazolin-
-ones. A general synthesis from 3,3’-dithiodipropionamides. J. Heterocyclic. Chem. 1971, 8,
71–580. (b) Weiler, E. D.; Petigara, R. B.; Wolfersberger, M. H.; Miller, G. A. Isothiazoles
IX. Halogenation of 2-substituted-4-isothiazolin-3-ones. J. Heterocycl. Chem. 1977, 14, 627–
30. (c) Bell, A. S.; Fishwick, C. W. G.; Reed, E. J. Facile palladium catalyzed functionalization
of 1,2-isothiazoline-3-ones. Tetrahedron Lett. 1994, 35, 6551–6554. (d) Casoni, A.; Celentano,
G.; Clerici, F.; Contini, A.; Gelmi, M. L.; Mazzeo, G.; Pellegrino, S.; Rosini, C.
Enantioselective synthesis, chiroptical properties and absolute configuration of 3-
aminosubstituted isothiazole S-oxides. Tetrahedron: Asym. 2009, 20, 2247–2256. (e) Csakai,
A.; Smith, C.; Davis, E.; Martinko, A.; Coulup, S.; Yin, H. Saccharin derivatives as inhibitors
of interferon-mediated inflammation. J. Med. Chem. 2014, 57, 5348–5355.
6
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
(a) Goerdeler, J.; Mittler, W. Synthese von 3-Hydroxy-, 3-Alkoxy- und 3-Amino-
isothiazolen. Chem. Ber. 1963, 96, 944–954. (b) Derbala, H. A.; Hamad, A.-S. S.; El Said, W.
A.; Hashem, A. I. Conversion of 3-aryl-5-phenyl-2(3H)-furanones into 3(2H)-isothiazolone
derivatives. Phosphorus, Sulfur Silicon Relat. Elem. 2001, 175, 153–162. (c) Kandeel, K. A.;
Youssef, A. S. A.; Abou-Elmagd, W. S. I.; Hashem, A. I. Behavior of 3-benzylamino-5-aryl-
2
9
(3H)-furanones towards some nitrogen nucleophiles. J. Heterocyclic Chem. 2006, 43, 957–
62. (d) Youssef, A. S. A.; Kandeel, K. A.; Abou-Elmagd, W. S. I.; Hashem, A. I. Conversion
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
of 5-aryl-3-phenylthio-2(3H)-furanones into some nitrogen- and sulphur-containing
heterocycles. Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 85–97.
8 Wright, S. W.; Petraitis, J. J.; Freimark, B.; Giannaras, J. V.; Pratta, M. A.; Sherk, S. R.;
Williams, J. M.; Magolda, R. L.; Arner, E. C. 2,5-Diarylisothiazolone: novel inhibitors of
cytokine-induced cartilage destruction. Bioorg. Med. Chem. 1996, 4, 851–858.
9
Dwivedi, V.; Rajesh, M.; Kumar, R.; Kant, R.; Reddy, M.-S. A stereoselective thiocyanate
conjugate addition to electron deficient alkynes and concomitant cyclization to N,S-
heterocycles. Chem. Commun. 2017, 53, 11060–11063.
10 (a) Xiong, H.-Y.; Besset, T.; Cahard, D.; Pannecoucke, X. Palladium(II)-catalyzed directed
trifluoromethylthiolation of unactivated C(sp )−H bonds. J. Org. Chem. 2015, 80, 4204−4212.
3
(b) Zhao, Q.; Tognetti, V.; Joubert, L.; Besset, T.; Pannecoucke, X.; Bouillon, J.-P.; Poisson,
T. Palladium-catalyzed synthesis of 3-trifluoromethyl-substituted 1,3-butadienes by means of
directed C-H bond functionalization. Org. Lett. 2017, 19, 2106–2109. (c) Zhao, Q.; Poisson,
T.; Pannecoucke, X.; Bouillon, J.-P.; Besset, T. Pd-catalyzed diastereoselective
trifluoromethylthiolation of functionalized acrylamides. Org. Lett. 2017, 19, 5106–5109.
1
1 See the supporting information for details.
1
2 Note that no product resulting either from the formation of a C-N bond with the phthtalimide
or from a direct cyanation was observed.
1
3 Qiu, J.-S.; Karmaker, P. G.; Yin, H.-Q.; Chen, F.-X. Enantioselective organocatalyzed direct
α-thiocyanation of cyclic β-ketoesters by N-thiocyanatophthalimide. Org. Lett. 2018, 20, 1600–
1
603.
1
4 Zhao, Q.; Chen, M.-Y.; Poisson, T.; Pannecoucke, X.; Bouillon, J.-P.; Besset, T. Pd-
catalyzed trifluoromethylthiolation of unsaturated compounds: a general approach. Eur. J. Org.
Chem. 2018, 6167–6175.
2
1
5 Thrimurtulu, N.; Dey, A.; Maiti, D.; Volla, C. M. R. Cobalt-catalyzed sp -C-H activation:
intermolecular heterocyclization with allenes at room temperature. Angew. Chem. Int. Ed. 2016,
5
5, 12361–12365.
1
6 Pan, J.-L.; Chen, C.; Ma, Z.-J.; Zhou, J.; Wang, L.-R.; Zhang, S.-Y. Stereoselective synthesis
2
of Z‑vinylsilanes via palladium-catalyzed direct intermolecular silylation of C(sp )-H bonds.
Org. Lett. 2017, 19, 5216–5219.
17 Renata, H.; Wang, Z. J.; Kitto, R. Z.; Arnold, F. H. P450-catalyzed asymmetric
cyclopropanation of electron-deficient olefins under aerobic conditions. Catal. Sci. Technol.
2
014, 4, 3640–3643.
ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
8 Motati, R. D.; Uredi, D.; Watkins, E. B. A general method for the metal-free, regioselective,
remote C-H halogenation of 8-substituted quinolines. Chem. Sci. 2018, 9, 1782–1788.
TOC Graphic
R3
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd
O
R1
O
H
R3
R1
N
N
S
H
R2
N
R2
N
N SCN
O
Electrophilic SCN source
2
1 examples, up to 71% yield
Additive free
Robust reaction conditions
Access to an important class of compounds
ACS Paragon Plus Environment