Palladium(II)-catalyzed directed trifluoromethylthiolation of unactivated C(sp3)-H bonds

Article abstract of DOI:10.1021/acs.joc.5b00505

The synthesis of trifluoromethylthiolated aliphatic acid derivatives by Pd-catalyzed C(sp³)-H bond functionalization was developed. Using a bidentate directing group, the direct and selective introduction of a SCF₃ moiety was possible on a range of amides with remarkable selectivity for C(sp³)-centers with an electrophilic SCF₃ source and pivalic acid as an additive. This work constitutes an example of the unactivated C(sp³)-SCF₃ bond formation by C-H activation offering a new access to relevant molecules.

Full text of DOI:10.1021/acs.joc.5b00505

Note
pubs.acs.org/joc
Palladium(II)-Catalyzed Directed Trifluoromethylthiolation of
Unactivated C(sp3)−H Bonds
Heng-Ying Xiong, Tatiana Besset,* Dominique Cahard, and Xavier Pannecoucke
Normandie Universite,
Saint-Aignan Cedex, France
́
COBRA, UMR 6014 et FR 3038; Universite
́
de Rouen; INSA Rouen; CNRS, 1 rue Tesnier
̀
e, 76821 Mont
S
* Supporting Information
ABSTRACT: The synthesis of trifluoromethylthiolated aliphatic acid derivatives by Pd-catalyzed C(sp3)−H bond
functionalization was developed. Using a bidentate directing group, the direct and selective introduction of a SCF3 moiety
was possible on a range of amides with remarkable selectivity for C(sp3)-centers with an electrophilic SCF3 source and pivalic
acid as an additive. This work constitutes an example of the unactivated C(sp3)−SCF3 bond formation by C−H activation
offering a new access to relevant molecules.
ver the past few years, organofluorine chemistry has
remains restricted to highly reactive benzylic derivatives.11a,12 In
Oexperienced a resurgence of interest and consequently a 2012, Daugulis and co-workers pioneered the Cu-promoted
very fast expansion.1 Due to the unique features of the fluorine
ortho-directed trifluoromethylthiolation of benzamides using
the volatile and toxic bis(trifluoromethyl)disulfide: (CF3S)2.9j
atom and fluorinated groups to modify the biological and
physical properties of a molecule,2 their presence is often
Later, Shen and co-workers reported an elegant Pd(II)-
catalyzed trifluoromethylthiolation of an aromatic C−H bond
by using an electrophilic SCF3 source,9k while Huang and co-
workers used a nucleophilic SCF3 source (i.e., AgSCF3) for the
Pd-catalyzed ortho trifluoromethylthiolation of 2-phenylpyr-
idine derivatives.9l With regard to C(sp)−SCF3 bond
formation, Shen and co-workers reported, in 2013, the Cu-
catalyzed trifluoromethylthiolation of terminal alkynes with a
trifluoromethylsulfenate reagent.11b It is worth noting that the
first example of transition-metal catalyzed direct introduction of
the SCF3 group on benzylic C(sp3)−H bonds was recently
developed by the group of Qing.11a This transformation
involved an innate addition of AgSCF3 on the benzylic
C(sp3)−H bond in the presence of a Cu-catalyst. Taking into
account these considerations, the direct introduction of the
SCF3 moiety through a directed metal catalyzed C(sp3)−H
functionalization would be highly valuable and would offer new
routes to access to C(sp3)-trifluoromethylthiolated molecules.
As part of our research program toward the development of
new methods for the direct and selective introduction of
fluorinated building blocks into molecules,13 we herein report
the first C(sp3)−SCF3 bond formation at the β-position of alkyl
amides by means of Pd-catalyzed C(sp3)−H bond functional-
ization, under mild conditions (Scheme 1).
crucial for the discovery and design of new pharmaceuticals and
agrochemicals.3 Quite recently, special attention has been paid
to the trifluoromethylthiolated molecules, making the SCF3
moiety an emerging fluorinated group. Indeed, due to its own
features such as its high electron-withdrawing character4 and its
ability to enhance molecule lipophilicity (Hansch hydrophobic
parameter: π = 1.44),5 this very appealing fluorinated moiety
has demonstrated a high potential for the elaboration of new
agrochemicals, drugs, and materials. As a matter of con-
sequence, it is worth mentioning that SCF3-containing building
blocks are of high interest. It is not surprising that the organic
chemist community showed a strong interest in the quest for
new SCF3-containing reagents as well as novel, straightforward,
and efficient synthetic transformations for its introduction.6
Besides, among all the transition-metal catalyzed methods, C−
H bond functionalization appeared as one of the most elegant
and promising strategies to introduce functional groups directly
in an atom- and step-economical way.7 Despite the inert
character of nonacidic C(sp3)−H bonds, much progress has
been made in the area of transition-metal catalyzed C(sp3)−H
bond transformations to construct new C−C, C−N, and C−O
bonds.8 In sharp contrast, the direct construction of C−S bonds
by transition-metal mediated and catalyzed C−H bond
activation remained underexplored and was often restricted to
aryl derivatives.9 Therefore, the development of catalytic
systems allowing the formation of the difficult-to-access
C(sp3)−S bond by C−H activation represents a formidable
synthetic challenge.10 Moreover, no example of transition-metal
catalyzed C(sp3)−SCF3 on nonactivated C(sp3)−H bonds has
been depicted since the direct formation of such a bond
At the outset of this study, we anticipated that one of the
main synthetic issues to tackle would be the competing
reductive elimination pathways over the desired C(sp3)−SCF3
bond formation. Inspired by several studies,9k,14 we hypothe-
Received: March 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00505
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Scheme 1. Transition-Metal Promoted
Table 1. Optimization of the Reaction Conditions
Trifluoromethylthiolation by C−H Functionalization
+
entry
cd
catalyst
Pd(OAc)2
additive (x equiv) SCF3 reagent yield (%)
b
,
1
2
3
4
5
6
7
8
9
−
−
−
I
8
4
1
cd
,
b
b
Pd(TFA)2
I
cd
,
Pd[CH3CN]2BF4
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
Pd[CH3CN]2Cl2
−
I
cd
,
b
b
b
b
−
I
26
40
44
41
31
e
e
e
f
AcOH (1)
PhCO2H (1)
MesCO2H (1)
p-TSA (2)
PivOH (2)
PivOH (5)
PivOH (10)
PivOH (10)
PivOH (10)
PivOH (10)
PivOH (10)
PivOH (10)
PivOH (2)
I
I
I
I
f
b
I
53, 31
48
10
11
12
13
14
15
16
17
I
I
53
b
II
III
IV
V
VI
I
27
b
<2
b
4
44
sized that the use of a readily available electrophilic SCF3
reagent, which might act as both an oxidant and SCF3 source,
would allow the selective trifluoromethylthiolation event via a
high Pd oxidation state. Our investigation started with the study
of the Pd-catalyzed trifluoromethylthiolation of 1a with the N-
SCF3-phthalimide I (Table 1). To our delight, in the presence
of Pd(OAc)2 as a catalyst, in DMF, the expected product 6a
was detected albeit in very low yield (entry 1). Several catalysts
were then evaluated (entries 2−4), and gratifyingly Pd-
[CH3CN]2Cl2 afforded the expected trifluoromethylthiolated
compound 6a in 26% yield (entry 4).15 Notably, the structure
of 6a was unambiguously confirmed by X-ray crystallographic
analysis.16 These promising results ascertained the regioselec-
tive C−H trifluoromethylthiolation of a primary C(sp3)−H
bond over the C(sp2)−H bond of the directing group. After
intensive investigations, the addition of a Brønsted acid as
additive (entries 5−9) turned out to be highly beneficial for the
success of such C−S coupling reactions, pivalic acid being the
most efficient (entry 9, 31%). Remarkably, the trifluorome-
thylthiolation proceeded smoothly at 70 °C via a mild C−H
activation process. Finally, the stoichiometry of the different
reactants was further fine-tuned, offering the optimal conditions
for the synthesis of 6a in 53% yield (entry 11). Then, a
screening of the electrophilic SCF3 sources was performed
(entries 11−16). No improvement was observed by using II,
III, IV, or VI since poorer yields were obtained (up to 27%),
while V gave 6a in 44% yield. Notably, a control experiment
performed in the absence of a Pd-catalyst revealed that no
trifluoromethylthiolation reaction occurred (entry 17). Finally,
the nature of the directing group was then investigated.
NR
NR
a
+
Reaction conditions: 1a (0.266 mmol), SCF3 reagent (0.2 mmol),
catalyst (20 mol %), additives (x equiv), DMF (2 mL), 70 °C, argon.
b
Determined by 19F NMR on the crude reaction mixture using α,α,α-
c
d
trifluoroacetophenone as an internal standard. 120 °C, 16 h. catalyst
e
f
(10 mol %). 80 °C, 16 h. 85 °C, 16 h. PivOH = pivalic acid, p-TSA =
p-toluenesulfonamide. NR = no reaction.
and moderate yields, respectively. Then, a series of amides
(1c−o) having an α-quaternary center were tested. When α,α-
dimethylated hydrocinnamic acid derivatives (1c−j) were
tested the transformation furnished the corresponding products
in moderate to good yields. In those cases, the activation of the
primary C(sp3)−H bonds via a five-membered palladacycle
intermediate was preferred over the activation of the intrinsi-
cally more reactive benzylic or aromatic C−H bonds. The
reaction proceeded smoothly with aromatic rings bearing either
an electron-donating (OMe, 6d) or an electron-withdrawing
group (halogens, CF3 or CN; 6e−j) showcasing the functional
group tolerance of the process. Moreover, when the α-
quaternary center was substituted by a homobenzylic
substituent, no introduction of the SCF3 group on the benzylic
position was observed, and the desired product 6k was obtained
in 35% yield. The scope has been further extended to another
class of substrates. Several amides prepared from phenylacetic
acid derivatives were evaluated (1l−o), and the expected
products (6l−o) were synthesized in 30−37% yields.
Pleasingly, no trifluoromethylthiolation reaction has been
observed on the aromatic ring. It is worth mentioning that
this transformation was compatible with amides bearing α-C−
The transformation assisted by the 8-aminoquinoline
bidentate chelating group 1a proceeded smoothly, and against
all expectations, other bicoordinating directing groups such as 2
and 3 as well as monocoordinating ones, 4 and 5, were
inefficient under our reaction conditions.
With these optimized reaction conditions in hand, we next
sought to investigate the substrate scope (Scheme 2). A wide
range of aliphatic amides having a primary β-C(sp3)−H bond
with different patterns were evaluated. At first, α,α-dialkyl
substituted amides 1a and 1b were converted into the
corresponding trifluoromethylated products 6a−6b in good
B
DOI: 10.1021/acs.joc.5b00505
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The Journal of Organic Chemistry
Note
a
Scheme 2. Scope of Pd(II)-Catalyzed Trifluoromethylthiolation
a
b
Reaction conditions: 1 (0.266 mmol), I (0.2 mmol), Pd[CH3CN]2Cl2 (20 mol %), PivOH (10 equiv), DMF (2 mL), 70 °C, argon. V was used
c
instead of I as an electrophilic SCF3 reagent. 6d was contaminated with 10% of an inseparable impurity.
H bonds (1p−1q) giving 6p and 6q in 36% and 31% yields,
respectively. Noteworthy, in some cases, the SCF3 reagent V
proved to be more efficient. The versatility of this method was
then further illustrated through the synthesis of the SCF3-
containing analogues of bioactive molecules: Ibuprofen 1r and
Naproxen 1s. The expected products 6r and 6s were obtained
in moderate-to-low yields, 33% and 23%, respectively. These
results appeared as a proof-of-concept for the potential
application of our approach toward the late-stage functionaliza-
tion of complex molecules and would open new valuable
synthetic routes. Finally, under our reaction conditions, highly
challenging secondary C(sp3)−H bonds were functionalized
even though the corresponding products (6t and 6u) were
obtained in low yields.
Scheme 3. Proposed Mechanism
To gain insight into the mechanism, radical trapping
experiments were performed.16 The reaction was carried out
in the presence of the commonly used radical quencher 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO, 40 mol % and 1 equiv)
and 3,5-di-tert-4-butylhydroxytoluene (BHT, 1 equiv). With
TEMPO, the yield decreased in both cases; however, these
observations might be easily explained by a side-reaction
pathway between TEMPO and I.16,17 Besides, in the presence
of BHT, the reaction was slightly slower but no deleterious
effect on the reaction yield was observed (42% vs 53%). Taking
into consideration these observations, a plausible radical
pathway might be thereby ruled out.
On the basis of the previous studies dealing with the
C(sp3)−H bond functionalization18 and transition-metal
catalyzed SCF3 direct introduction on aromatic rings, a
plausible mechanistic pathway has been proposed (Scheme
3).19 First, the chelation of the Pd(II)-catalyst with the
bidentate chelating group (intermediate A) is followed by the
formation of the key palladacycle (intermediate B) after
activation of the β-C(sp3)−H bond according to a concerted
metalation−deprotonation pathway. This latter undergoes an
oxidative addition in the N−SCF3 bond of the electrophilic
reagent I leading to a putative Pd(IV) species C. Finally, a
selective reductive elimination and a final protonation of the
amide intermediate then affords the desired trifluoromethylth-
iolated derivative 6a and regenerates the catalyst. At that stage,
even though the exact role of PivOH in the catalytic process has
not been elucidated so far, we suspected its assistance in the
regeneration of the active catalyst as proposed by Sahoo and
co-workers.18b
This novel strategy offers new possibilities to access other
classes of products since these SCF3-containing building blocks
could easily undergo postfunctionalization. Indeed, the sulfide
6a reacted in the presence of m-CPBA, giving the
corresponding sulfoxide 7 in good yield (40%) taking into
account the competitive oxidation of the quinoline residue and
the possible overoxidation into sulfone.11a To highlight the
synthetic value of our approach and the traceless character of
the directing group, the removal of the 8-aminoquinoline group
on 6a was carried out.20 The corresponding fluorinated
carboxylic acid 8 was thus obtained in 89% yield (Scheme 4).
In summary, we have developed a method for the Pd-
catalyzed trifluoromethylthiolation of the primary and secon-
dary C(sp3)−H bonds on aliphatic acid derivatives. The
combination of an electrophilic SCF3 reagent with a Brønsted
acid (PivOH) using a bidentate directing group allowed the Pd-
C
DOI: 10.1021/acs.joc.5b00505
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The Journal of Organic Chemistry
Note
warm up to room temperature and stirred overnight. Then, the
reaction mixture was diluted with CH2Cl2 and washed with water and
saturated aqueous NaHCO3. The aqueous layers were extracted with
CH2Cl2 (3×). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and evaporated under vacuum. The residue
was purified by flash column chromatography on silica gel to afford the
corresponding amide.
Scheme 4. Postfunctionalizations of Compound 6a
General Procedure C. To a solution of diisopropylamine (DIPA)
(1.25 equiv) in THF (0.4 M) at −78 °C was slowly added n-BuLi (1.6
M in hexane, 1.17 equiv), and the reaction mixture was stirred for 30
min at room temperature. The reaction mixture was then cooled down
to −78 °C, and methyl isobutyrate (1 equiv) was added dropwise at
the same temperature. The reaction mixture was stirred for 1 h at −78
°C. Then, a solution of the corresponding benzyl bromide (1.1 equiv)
in THF (4.5 M) was added dropwise. After the addition, the mixture
was slowly warmed to room temperature and stirred overnight. Then,
the reaction mixture was quenched with water at 0 °C and extracted
with EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and then evaporated under vacuum to give
the corresponding ester. To the obtained ester was added an aqueous
solution of NaOH (2 M) and methanol, and the reaction mixture was
stirred at 60 °C overnight. Once cooled to room temperature,
methanol was removed under vacuum and the mixture was diluted
with water and extracted with CH2Cl2 (3×). Then, the aqueous layer
was acidified with 2 M HCl until pH = 2 and extracted with diethyl
ether (3×). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and evaporated under vacuum to afford the
crude carboxylic acid, which was used directly for the next step without
further purification. To an oven-dried round-bottom flask containing a
carboxylic acid (1.2 equiv) was slowly added SOCl2 (1.2 M). The
reaction mixture was refluxed at 85 °C for 3 h and then evaporated
under vacuum to provide the crude acid chloride, which was used
immediately without further purification. Then, a solution of 8-
aminoquinoline (1 equiv) and Et3N (1.2 equiv) in CH2Cl2 (1.0 M)
was added dropwise at 0 °C to a solution of acid chloride (1 equiv) in
CH2Cl2 (0.3 M). After addition, the reaction mixture was allowed to
warm up to room temperature and stirred overnight. The reaction
mixture was diluted with CH2Cl2 and washed with water and saturated
aqueous NaHCO3. The aqueous layers were extracted with CH2Cl2
(3×). The combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated under vacuum. The residue was
purified by flash column chromatography on silica gel to afford the
corresponding amide.
General Procedure D. To a solution of benzyl cyanide (1 equiv),
MeI (2.2 equiv) in DMSO (2 M) was added a 50 wt % aqueous
solution of NaOH (2.1 equiv) via a syringe pump over 1 h at 45 °C.
After the addition, the reaction mixture was stirred for 1 h. Once
cooled down to room temperature, water was added to the solution
and the aqueous layer was extracted with hexane/Et2O (1:1, 3×). The
combined organic layers were dried over MgSO4, filtered, and
evaporated under vacuum to afford the corresponding dialkylated
product, which was used directly for the next step without further
purification. To a 100 mL three-necked round-bottom flask with a
reflux condenser were added dialkylated benzyl cyanide (1 equiv) and
ethylene glycol/H2O (4:1, 1 M). Solid KOH (3.2 equiv) was added
portionwise to the mixture. The reaction mixture was stirred at 100 °C
for 48 h. Once cooled to room temperature, the mixture was washed
with CHCl3 (3×). Then, the aqueous layer was acidified with 2 M HCl
until pH = 2 and extracted with diethyl ether (3×). The combined
organic layers were washed with brine, dried over MgSO4, filtered, and
evaporated under vacuum to afford the corresponding carboxylic acid,
which was used directly for the next step without further purification.25
The acyl chloride was prepared according to the literature procedure26
with oxalyl chloride and then engaged with 8-aminoquinoline
according to procedure A.
catalyzed direct introduction of a SCF3 moiety on a C(sp3)−H
bond under mild conditions. Various amides were compatible,
and a series of alkyl trifluoromethylated sulfides have been
prepared. The products were obtained in a regiocontrolled
fashion, and this transformation appeared as a synthetic
milestone taking into account the associated synthetic issues
(SCF3 reagent decomposition, sulfur poisoning, and potential
competing reductive eliminations). This approach offered
synthetic disconnections for the preparation of tertiary and
quaternary β-SCF3-containing aliphatic acids. Moreover, this
method was applied to the late-stage functionalization of
relevant biomolecules such as Ibuprofen and Naproxen,
opening avenues toward the synthesis of SCF3-containing
analogues.
EXPERIMENTAL SECTION
■
The trifluoromethylthiolation reactions were carried out in oven-dried
glassware under an argon atmosphere with magnetic stirring bar.
Reaction temperatures are reported as the temperature of the bath
surrounding the vessel. Commercially available chemicals were used as
received unless otherwise stated. Anhydrous DMF was degassed
before using. Analytical TLC was performed on silica gel coated
aluminum plates with F-254 indicator with visualization by UV
irradiation (254 nm). Column chromatography was performed using
0.063−0.200 mm silica gel. NMR spectra were recorded on a 300
MHz spectrometer. Chemical shifts (δ) are quoted in ppm relative to
TMS (1H) and CFCl3 (19F). Coupling constants (J) are quoted in Hz.
The following abbreviations were used to show the multiplicities: s:
singlet, d: doublet, t: triplet, q: quadruplet, dd: doublet of doublet, m:
multiplet. The residual solvent signals were used as references (CDCl3:
δH = 7.26 ppm, δC = 77.00 ppm and CFCl3: δF = 0.00 ppm). High-
resolution mass spectrometry (HRMS) was carried out on an
electrospray ionization mass spectrometer with a micro-TOF analyzer.
The wave numbers (ν) of recorded IR-signals (ATR) are quoted in
cm−1.
The known amides 1 and trifluoromethylated reagents were
prepared following the literature procedures: 1a,21 1c,21 1d,21 1e,21
1f,21,22 1g,21,22 1h,21,22 1k,21,22 1u,21 I,9k II,9k III,23 IV,24 and V.24 No
attempts were made to optimize yields for substrate synthesis.
General Procedure for Synthesis of 1. General Procedure A.
To a solution of 8-aminoquinoline (1 equiv) and Et3N (1.2 equiv) in
CH2Cl2 (C = 0.25 mol·L−1) was slowly added, at 0 °C, the acid
chloride (1.2 equiv), and the reaction mixture was allowed to warm to
room temperature and stirred overnight. Then, the reaction mixture
was diluted with CH2Cl2 and washed with water and saturated
aqueous NaHCO3. The aqueous layers were extracted with CH2Cl2.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated under vacuum. The residue was
purified by flash column chromatography to afford the corresponding
amide.
General Procedure B. To an oven-dried flask containing a
carboxylic acid (1.2 equiv) was slowly added SOCl2 (1.2 M). The
reaction mixture was heated at 85 °C for 3 h and then evaporated
under vacuum to provide the crude acid chloride, which was used
immediately without further purification. CH2Cl2 was added to the
acid chloride (0.4 M). Then, a solution of 8-aminoquinoline (1 equiv)
and Et3N (1.2 equiv) in CH2Cl2 (0.1M) was added dropwise at 0 °C
to the solution of acid chloride. The reaction mixture was allowed to
Preparation and Characterization of Substrates 1. 2,2-
Dimethyl-N-(quinolin-8-yl)hexanamide 1b. By following general
procedure B, 1b was obtained as a colorless oil (1.2 g, 78%) starting
1
from 2,2-dimethylhexanoic acid. Rf (pentane/EtOAc 90:10): 0.42. H
NMR (300.13 MHz, CDCl3): δ 10.16 (broad s, 1H), 8.75−8.67 (m,
D
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The Journal of Organic Chemistry
Note
2H), 8.02 (dd, J = 8.1, 1.5 Hz, 1H), 7.47−7.27 (m, 3H), 1.66−1.55
(m, 2H), 1.30 (s, 6H), 1.27−1.18 (m, 4H), 0.78 (t, J = 6.9 Hz, 3H).
13C{1H} NMR (75.5 MHz, CDCl3): δ 176.6, 148.1, 138.7, 136.2,
134.6, 127.9, 127.4, 121.4, 121.1, 116.1, 43.7, 41.3, 27.1, 25.6, 23.2,
13.9. ATR-FTIR (cm−1): 3367, 2960, 1680, 1523, 1484, 1387, 1325,
1253, 1147, 1009, 790, 680. HRMS (ESI+) m/z: [M + H]+ Calcd for
C17H23N2O 271.1810; Found 271.1802.
3-(4-Cyanophenyl)-2,2-dimethyl-N-(quinolin-8-yl)propanamide
1i. By following general procedure C, 1i was obtained as a pale yellow
vitrous solid (0.31 g, 13% overall yield) starting from 4-
(bromomethyl)benzonitrile. Rf (pentane/EtOAc 90:10): 0.21. 1H
NMR (300.13 MHz, CDCl3): δ 10.11 (broad s, 1H), 8.79 (dd, J = 6.9,
2.1 Hz, 1H), 8.73 (dd, J = 4.2, 1.5 Hz, 1H), 8.16 (dd, J = 8.4, 1.5 Hz,
1H), 7.59−7.51 (m, 2H), 7.49−7.41 (m, 3H), 7.30 (d, J = 8.1 Hz,
2H), 3.08 (s, 2H), 1.44 (s, 6H). 13C{1H} NMR (75.5 MHz, CDCl3): δ
175.0, 148.2, 143.7, 138.6, 136.3, 134.1, 131.8, 130.9, 127.9, 127.3,
121.7, 121.6, 118.9, 116.3, 110.3, 46.9, 45.1, 25.4. ATR-FTIR (cm−1):
3360, 2225, 1672, 1470, 1418, 1379, 1311, 917, 858, 798, 690. HRMS
(ESI+) m/z: [M + H]+ Calcd for C21H20N3O 330.1606; Found
330.1597.
2-(3,4-Dichlorophenyl)-2-methyl-N-(quinolin-8-yl)propanamide
1o. By following general procedure D, 1o was obtained as a pale
yellow oil (0.71 g, 7% overall yield) starting from 3,4-dichloro-
1
phenylacetonitrile. Rf (pentane/EtOAc 82:8): 0.61. H NMR (300.13
MHz, CDCl3): δ 9.95 (broad s, 1H), 8.72 (d, J = 6.9 Hz, 1H), 8.68 (d,
J = 4.2 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H),
7.46−7.45 (m, 3H), 7.44−7.33 (m, 2H), 1.76 (s, 6H). 13C{1H} NMR
(75.5 MHz, CDCl3): δ 174.3, 148.3, 145.3, 138.6, 136.2, 134.3, 132.8,
131.1, 130.6, 128.5, 127.8, 127.3, 126.0, 121.6, 121.6, 116.1, 48.0, 26.8.
ATR-FTIR (cm−1): 2927, 1664, 1526, 1384, 1090, 829, 658. HRMS
(ESI+) m/z: [M + H]+ Calcd for C19H17Cl2N2O 359.0718; Found
359.0713.
2-Phenyl-N-(quinolin-8-yl)propanamide 1p. By following general
procedure B, 1p was obtained as a white vitrous solid (2.0 g, 72%
overall yield) starting from 2-phenylpropionic acid. Rf (petroleum
1
ether/EtOAc 90:10): 0.36. H NMR (300.13 MHz, CDCl3): δ 9.90
(broad s, 1H), 8.77 (dd, J = 7.2, 1.8 Hz, 1H), 8.71 (dd, J = 4.2, 1.8 Hz,
1H), 8.11 (dd, J = 8.1, 1.5 Hz, 1H), 7.55−7.44 (m, 4H), 7.43−7.35
(m, 3H), 7.33−7.27 (m, 1H), 3.94 (q, J = 7.2 Hz, 1H), 1.70 (d, J = 7.2
Hz, 3H). 13C{1H} NMR (75.5 MHz, CDCl3): δ 172.5, 148.0, 141.0,
138.3, 136.0, 134.4, 128.8, 127.7, 127.6, 127.2, 121.3, 116.1, 65.7, 48.5,
18.5, 15.2. ATR-FTIR (cm−1): 3340, 2803, 1741, 1688, 1523, 1482,
1228, 823. HRMS (ESI+) m/z: [M + H]+ Calcd for C18H17N2O
277.1341; Found 277.1334.
3-(2,6-Dichlorophenyl)-2,2-dimethyl-N-(quinolin-8-yl)propana-
mide 1j. By following general procedure C, 1j was obtained as a white
solid (1.6 g, 74% overall yield) starting from 2-(bromomethyl)-1,3-
1
dichlorobenzene. Rf (pentane/EtOAc 90:10): 0.40. H NMR (300.13
MHz, CDCl3): δ 10.22 (s, 1H), 8.82 (dd, J = 7.5, 1.5 Hz, 1H), 8.72
(dd, J = 4.2, 1.5 Hz, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 7.59−7.47 (m,
2H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 (d, J = 3.0 Hz, 1H), 7.23 (s,
1H), 7.05 (dd, J = 8.4, 7.5 Hz, 1H), 3.50 (s, 2H), 1.53 (s, 6H).
13C{1H} NMR (75.5 MHz, CDCl3): δ 175.7, 148.0, 138.8, 137.1,
136.2, 134.8, 134.7, 128.4, 128.0, 127.8, 127.5, 121.4, 121.2, 116.3,
45.6, 40.0, 25.7. ATR-FTIR (cm−1): 3360, 2947, 1671, 1528, 1485,
1142, 1053, 917, 825, 791, 678. HRMS (ESI+) m/z: [M + H]+ Calcd
for C20H19Cl2N2O 373.0874; Found 373.0867.
N-(Quinolin-8-yl)isobutyramide 1q. By following general proce-
dure A, 1q was obtained as a yellow oil (2.0 g, 92%) starting from
isobutyryl chloride. Rf (petroleum ether/EtOAc 91:9): 0.47. 1H NMR
(300.13 MHz, CDCl3): δ 9.90 (broad s, 1H), 8.84−8.76 (m, 2H), 8.15
(dd, J = 8.4, 1.5 Hz, 1H), 7.59−7.40 (m, 3H), 2.85−2.70 (m, 1H),
1.36 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (75.5 MHz, CDCl3): δ 175.7,
148.1, 138.5, 136.3, 134.6, 127.9, 127.4, 121.5, 121.3, 116.4, 37.1, 19.7.
ATR-FTIR (cm−1): 3353, 2968, 1684, 1520, 1483, 1422, 1383, 1322,
1155, 936, 825, 790, 673. HRMS (ESI+) m/z: [M + H]+ Calcd for
C13H15N2O 215.1184; Found 215.1181.
2-Methyl-2-phenyl-N-(quinolin-8-yl)propanamide 1l. By follow-
ing general procedure D, 1l was obtained as a white vitrous solid (1.2
g, 24% overall yield) starting from 2-phenylpropanenitrile. Rf
2-(4-Isobutylphenyl)-N-(quinolin-8-yl)propanamide 1r. By follow-
ing general procedure B, 1r was obtained as a white vitrous solid (2.1
g, 63% overall yield) starting from 2-(4-isobutylphenyl)propanoic acid.
1
(pentane/EtOAc 90:10): 0.33. H NMR (300.13 MHz, CDCl3): δ
1
9.89 (broad s, 1H), 8.74 (dd, J = 7.2, 1.5 Hz, 1H), 8.64 (dd, J = 4.2, 1.5
Hz, 1H), 8.10 (dd, J = 8.4, 1.5 Hz, 1H), 7.63−7.42 (m, 5H), 7.41−
7.32 (m, 3H), 1.76 (s, 6H). 13C{1H} NMR (75.5 MHz, CDCl3): δ
175.1, 148.2, 143.5, 138.6, 136.1, 134.5, 132.9, 128.8, 127.8, 127.3,
121.5, 121.4, 116.0, 48.0, 26.9. One carbon is overlapped. ATR-FTIR
(cm−1): 3340, 2973, 1676, 1524, 1488, 1388, 1324, 1104, 826, 681.
HRMS (ESI+) m/z: [M + H]+ Calcd for C19H19N2O 291.1497; Found
291.1487.
2-(4-Chlorophenyl)-2-methyl-N-(quinolin-8-yl)propanamide 1m.
By following general procedure D, 1m was obtained as a pale yellow
vitrous solid (0.61 g, 23% overall yield) starting from (4-
chlorophenyl)acetonitrile. Rf (pentane/EtOAc 90:10): 0.46. 1H
NMR (300.13 MHz, CDCl3): δ 9.87 (broad s, 1H), 8.77 (d, J = 7.5
Hz, 1H), 8.60 (dd, J = 4.2, 1.5 Hz, 1H), 8.09 (dd, J = 8.1, 1.5 Hz, 1H),
7.57−7.32 (m, 7H), 1.79 (s, 6H). 13C{1H} NMR (75.5 MHz, CDCl3):
δ 175.8, 148.1, 144.8, 138.6, 136.1, 134.7, 128.7, 127.8, 127.3, 127.0,
126.3, 121.4, 121.2, 115.9, 48.4, 27.0. ATR-FTIR (cm−1): 2929, 1666,
1520, 1387, 1090, 829, 656. HRMS (ESI+) m/z: [M + H]+ Calcd for
C19H18ClN2O 324.1029; Found 324.1035.
Rf (pentane/EtOAc 90:10): 0.36. H NMR (300.13 MHz, CDCl3): δ
9.88 (broad s, 1H), 8.78 (dd, J = 7.2, 1.8 Hz, 1H), 8.66 (dd, J = 4.2, 1.8
Hz, 1H), 8.10 (dd, J = 8.1, 1.5 Hz, 1H), 7.54−7.43 (m, 2H), 7.41−
7.35 (m, 3H), 7.17 (d, J = 8.1 Hz, 2H), 3.91 (q, J = 7.2 Hz, 1H), 2.48
(d, J = 7.2 Hz, 2H), 1.95−1.78 (m, 1H), 1.69 (d, J = 7.2 Hz, 3H), 0.91
(d, J = 6.6 Hz, 6H). 13C{1H} NMR (75.5 MHz, CDCl3): δ 173.1,
148.0, 140.8, 138.5, 138.2, 136.2, 134.6, 129.7, 127.8, 127.5, 127.3,
121.4, 121.3, 116.2, 48.3, 45.0, 30.2, 22.4, 18.5. ATR-FTIR (cm−1)
3347, 2953, 1683, 1521, 1484, 1423, 1323, 1161, 922, 825, 790, 755.
HRMS (ESI+) m/z: [M + H]+ Calcd for C22H25N2O 333.1967; Found
333.1980.
(S)-2-(6-Methoxynaphthalen-2-yl)-N-(quinolin-8-yl)propanamide
1s. By following general procedure B, 1s was obtained as a white solid
(1.3 g, 73% overall yield) starting from (S)-2-(6-methoxynaphthalen-
2-yl)propanoic acid. Rf (petroleum ether/EtOAc 86:14): 0.27. 1H
NMR (300.13 MHz, CDCl3): δ 9.96 (broad s, 1H), 8.79 (dd, J = 7.5,
1.5 Hz, 1H), 8.61 (dd, J = 4.2, 1.8 Hz, 1H), 8.09 (dd, J = 8.4, 1.8 Hz,
1H), 7.87 (s, 1H), 7.76 (dd, J = 8.4, 3.0 Hz, 2H), 7.57 (dd, J = 8.4, 1.8
Hz, 1H), 7.54−7.42 (m, 2H), 7.36 (dd, J = 8.4, 4.2 Hz, 1H), 7.18−
7.10 (m, 2H), 4.07 (q, J = 6.9 Hz, 1H), 3.91 (s, 3H), 1.77 (d, J = 6.9
Hz, 3H). 13C{1H} NMR (75.5 MHz, CDCl3): δ 172.8, 157.6, 148.1,
138.4, 136.3, 136.1, 134.5, 133.8, 129.3, 129.1, 127.8, 127.5, 127.3,
126.3, 126.2, 121.4, 121.4, 119.0, 116.2 (s, CH), 105.6 (s, CH), 55.3
(s, CH3), 48.6 (s, CH), 18.7 (s, CH3). ATR-FTIR (cm−1): 3351, 2980,
1687, 1524, 1483, 1384, 1229, 1172, 1026, 855, 791, 649. HRMS
(ESI+) m/z: [M + H]+ Calcd for C23H21N2O2 357.1603; Found
357.1607.
2-(4-Fluorophenyl)-2-methyl-N-(quinolin-8-yl)propanamide 1n.
By following general procedure D, 1n was obtained as a pale yellow
vitrous solid (0.51 g, 15% overall yield) starting from 4-fluorophenyl-
acetonitrile. Rf (pentane/EtOAc 90:10): 0.55. 1H NMR (300.13 MHz,
CDCl3): δ 9.88 (broad s, 1H), 8.76 (dd, J = 7.5, 1.5 Hz, 1H), 8.62 (dd,
J = 4.2, 1.5 Hz, 1H), 8.09 (dd, J = 8.1, 1.5 Hz, 1H), 7.55−7.43 (m,
4H), 7.37 (dd, J = 8.1, 4.2 Hz, 1H), 7.14−7.04 (m, 2H), 1.77 (s, 6H).
13C{1H} NMR (75.5 MHz, CDCl3): δ 175.5, 161.8 (d, J = 246.1 Hz),
148.2, 140.7 (d, J = 3.0 Hz), 138.6, 136.1, 134.5, 128.1 (d, J = 7.6 Hz),
2-Ethyl-N-(quinolin-8-yl)butanamide 1t. By following general
procedure A, 1t was obtained as a colorless oil (2.1 g, 88%) starting
from 2-ethylbutyryl chloride. Rf (petroleum ether/EtOAc 90:10): 0.47.
1H NMR (300.13 MHz, CDCl3): δ 9.75 (broad s, 1H), 8.81−8.64 (m,
2H), 7.99 (d, J = 8.1 Hz, 1H), 7.46−7.24 (m, 3H), 2.27−2.13 (m,
1H), 1.80−1.63 (m, 2H), 1.62−1.45 (m, 2H), 0.89 (t, J = 7.2 Hz, 6H).
127.8, 127.2, 121.5, 121.3, 115.9, 115.5 (d, J = 21.1 Hz), 47.9, 27.1. 19
F
NMR (282.4 MHz, CDCl3): δ −116.5. ATR-FTIR (cm−1): 3320,
2980, 1669, 1511, 1484, 1384, 1324, 1232, 1151, 1097, 821, 785.
HRMS (ESI+) m/z: [M + H]+ Calcd for C19H18FN2O 309.1403;
Found 309.1412.
E
DOI: 10.1021/acs.joc.5b00505
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
13C{1H} NMR (75.5 MHz, CDCl3): δ 174.6, 148.0, 138.3, 136.1,
pale yellow oil (38.7 mg, 45%), Rf (pentane/dichloromethane =
30:70): 0.38. 1H NMR (300.13 MHz, CDCl3): δ 10.14 (broad s, 1H),
8.77 (dd, J = 6.0, 3.0 Hz, 1H), 8.73 (dd, J = 4.2, 1.5 Hz, 1H), 8.15 (dd,
J = 8.4, 1.5 Hz, 1H), 7.58−7.49 (m, 2H), 7.43 (dd, J = 8.4, 4.2 Hz,
1H), 7.16−7.06 (m, 1H), 6.80−6.63 (m, 3H), 3.54 (d, J = 12.6 Hz,
1H), 3.53 (s, 3H), 3.23 (d, J = 13.5 Hz, 1H), 3.03 (d, J = 12.6 Hz, 1H),
2.96 (d, J = 13.5 Hz, 1H), 1.60 (s, 3H). 19F NMR (282.4 MHz,
CDCl3): δ −42.0. 13C{1H} NMR (75.5 MHz, CDCl3): δ 172.7, 159.4,
148.3, 138.6, 137.4, 136.2, 133.7, 131.0 (q, J = 306.5 Hz), 129.1, 127.8,
127.3, 122.5, 121.9, 121.6, 116.5, 115.2, 112.9, 54.9, 48.9, 45.6, 38.1 (q,
J = 1.5 Hz), 21.0. ATR-FTIR (cm−1): 3350, 2934, 1671, 1527, 1487,
1262, 1106, 1043, 825, 789, 755, 695. HRMS (ESI+) m/z: [M + H]+
Calcd for C22H22F3N2O2S 435.1349; Found 435.1352.
2-(4-Bromobenzyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6e. Procedure E was followed, from 1e and
I (40 h). The product was purified by flash chromatography on silica
gel (height 32 cm, width 2 cm, toluene/pentane = 80:20 + 1% Et3N)
as a white vitrous solid (37.8 mg, 39%), Rf (pentane/dichloromethane
= 60:40): 0.40. 1H NMR (300.13 MHz, CDCl3): δ 9.97 (broad s, 1H),
8.70−8.57 (m, 2H), 8.06 (dd, J = 8.4, 1.5 Hz, 1H), 7.47−7.40 (m,
2H), 7.35 (dd, J = 8.4, 4.2 Hz, 1H), 7.21−7.15 (m, 2H), 6.93 (d, J =
8.4 Hz, 2H), 3.40 (d, J = 12.9 Hz, 1H), 3.12 (d, J = 13.2 Hz, 1H), 2.92
(d, J = 12.6 Hz, 1H), 2.80 (d, J = 13.5 Hz, 1H), 1.47 (s, 3H). 19F NMR
(282.4 MHz, CDCl3): δ −42.0 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 172.3, 148.4, 138.6, 136.3, 135.0, 133.6, 131.8, 131.4, 130.9
(q, J = 305.8 Hz), 127.9, 127.3, 122.1, 121.7, 121.1, 116.0, 48.1, 44.8,
38.2 (q, J = 2.3 Hz), 20.8. ATR-FTIR (cm−1): 3348, 2924, 1671, 1528,
1487, 1425, 1385, 1326, 1261, 1103, 1012, 824, 790, 686. HRMS
(ESI+) m/z: [M + H]+ Calcd for C21H19BrF3N2OS 483.0348; Found
483.0353.
2-(4-Chlorobenzyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6f. Procedure E was followed, from 1f and
I (40 h). The product was purified by flash chromatography on silica
gel (height 35 cm, width 2 cm, pentane/dichloromethane = 60:40) as
a pale yellow oil (36.1 mg, 41%), Rf (pentane/dichloromethane =
60:40): 0.50. 1H NMR (300.13 MHz, CDCl3): δ 10.08 (broad s, 1H),
7.79−7.68 (m, 2H), 8.16 (dd, J = 8.1, 1.2 Hz, 1H), 7.59−7.51 (m,
2H), 7.45 (dd, J = 8.1, 4.2 Hz, 1H), 7.19−7.05 (m, 4H), 3.50 (d, J =
12.6 Hz, 1H), 3.24 (d, J = 13.5 Hz, 1H), 3.03 (d, J = 12.6 Hz, 1H),
2.92 (d, J = 13.5 Hz, 1H), 1.57 (s, 3H). 19F NMR (282.4 MHz,
CDCl3): δ −42.0 (s). 13C{1H} NMR (75.5 MHz, CDCl3): δ 172.3,
148.4, 138.5, 136.3, 134.5, 133.6, 133.0, 131.4, 130.9 (q, J = 306.5 Hz),
128.5, 127.8, 127.3, 122.0, 121.7, 116.7, 48.8, 44.7, 38.2 (q, J = 1.5 Hz),
20.8. ATR-FTIR (cm−1): 3347, 1670, 1527, 1487, 1425, 1384, 1325,
1260, 1103, 1016, 825, 790, 684. HRMS (ESI+) m/z: [M + H]+ Calcd
for C21H19ClF3N2OS 439.0853; Found 439.0847.
2-(4-Fluorobenzyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6g. Procedure E was followed, from 1g and
V (86 h). The product was purified by flash chromatography on silica
gel (height 34 cm, width 2 cm, toluene/pentane = 60:40 + 1% Et3N)
as a colorless oil (33.1 mg, 39%), Rf (pentane/dichloromethane =
60:40): 0.44. 1H NMR (300.13 MHz, CDCl3): δ 10.09 (broad s, 1H),
8.77−8.70 (m, 2H), 8.16 (dd, J = 8.4, 1.5 Hz, 1H), 7.57−7.51 (m,
2H), 7.44 (dd, J = 8.4, 4.2 Hz, 1H), 7.17−7.08 (m, 2H), 6.90−6.80
(m, 2H), 3.51 (d, J = 12.6 Hz, 1H), 3.24 (d, J = 13.5 Hz, 1H), 3.02 (d,
J = 12.6 Hz, 1H), 2.93 (d, J = 13.5 Hz, 1H), 1.58 (s, 3H). 19F NMR
(282.4 MHz, CDCl3): δ −42.0 (s), −116.3 (s). 13C{1H} NMR (75.5
MHz, CDCl3): δ 172.4, 162.0 (d, J = 246.1 Hz), 148.3, 138.6, 136.3,
133.6, 131.7 (d, J = 3.0 Hz), 131.6 (d, J = 7.6 Hz), 130.9 (q, J = 305.8
Hz), 127.8, 127.3, 122.0, 121.7, 116.5, 115.2 (d, J = 21.9 Hz), 48.9,
44.6, 38.1 (q, J = 1.5 Hz), 20.8. ATR-FTIR (cm−1): 3348, 2927, 1673,
1528, 1510, 1487, 1224, 1102, 826, 790. HRMS (ESI+) m/z: [M + H]+
Calcd for C21H19F4N2OS 423.1154; Found 423.1147.
134.4, 127.8, 127.2, 121.4, 121.2, 116.3, 52.5, 25.7, 12.0. ATR-FTIR
(cm−1): 3359, 2958, 1677, 1593, 1523, 1484, 1324, 1191, 1175, 827,
794, 682. HRMS (ESI+) m/z: [M + H]+ Calcd for C15H19N2O
243.1497; Found 243.1504.
General Procedure for the Pd(II)-Catalyzed Trifluoromethyl-
thiolation of 1. Procedure E. An oven-dried 10 mL glassware
equipped with a stir bar was charged with Pd[CH3CN]2Cl2 (10.4 g,
0.04 mmol, 0.2 equiv), I (49.6 mg, 0.2 mmol, 1 equiv) or V (41.4 mg,
0.2 mmol, 1 equiv), PivOH (204.2 mg, 2 mmol, 10 equiv), and 2 mL
of DMF under argon. Then, amide derivative 1 (0.266 mmol, 1.33
equiv) was added. The tube was flushed with argon, sealed, and then
placed in an oil bath preheated to 70 °C and stirred rigorously (see
time for each compound). The reaction mixture was cooled to room
temperature and diluted with diethyl ether (20 mL) and water. The
organic layer was washed with saturated aqueous NaHCO3 (3 × 20
mL) and brine (20 mL), dried over MgSO4, filtered, and evaporated
under vacuum. The crude was purified by flash chromatography on
silica gel to give the desired product. Note that, in the case of solid
amides, these are added in the tube before the solvent.
Preparation and Characterization of Products 6. 2,2-
Dimethyl-N-(quinolin-8-yl)-3-(trifluoromethylthio)propanamide 6a.
Procedure E was followed, from 1a and I (70 h). The product was
purified by flash chromatography on silica gel (height 30 cm, width 2
cm, pentane/dichloromethane 60:40) as a pale yellow solid (34.6 mg,
53%), Rf (pentane/dichloromethane = 60:40): 0.35. 1H NMR (300.13
MHz, CDCl3): δ 10.30 (broad s, 1H), 8.83 (dd, J = 4.2, 1.5 Hz, 1H),
8.79−8.69 (m, 1H), 8.17 (dd, J = 8.4, 1.5 Hz, 1H), 7.58−7.50 (m,
2H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H), 3.22 (s, 2H), 1.58 (s, 6H). 19F
NMR (282.4 MHz, CDCl3): δ −42.3 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 174.0, 148.4, 138.7, 136.4, 134.0, 131.1 (q, J = 306.5 Hz),
127.9, 127.4, 121.8, 121.7, 116.6, 44.4, 39.2 (q, J = 2.3 Hz), 25.2, 25.2.
ATR-FTIR (cm−1): 3327, 2927, 1667, 1535, 1464, 1423, 1386 1328,
1293, 1136, 1096, 926, 822, 784, 693, 623. HRMS (ESI+) m/z: [M +
H]+ Calcd for C15H16F3N2OS 329.0930; Found 329.0948.
2-Methyl-N-(quinolin-8-yl)-2-((trifluoromethylthio)methyl)-
hexanamide 6b. Procedure E was followed, from 1b and I (60 h).
The product was purified by flash chromatography on silica gel (height
32 cm, width 2 cm, pentane/dichloromethane 60:40) as a colorless oil
(25.3 mg, 34%), Rf (pentane/dichloromethane = 60:40): 0.55. 1H
NMR (300.13 MHz, CDCl3): δ 10.28 (broad s, 1H), 8.83 (dd, J = 4.2,
1.5 Hz, 1H), 8.79−8.71 (m, 1H), 8.18 (dd, J = 8.4, 1.5 Hz, 1H), 7.58−
7.50 (m, 2H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H), 3.46 (d, J = 12.9 Hz, 1H),
3.04 (d, J = 12.9 Hz, 1H), 1.95−1.82 (m, 1H), 1.81−1.68 (m, 1H),
1.45−1.17 (m, 6H), 0.97−0.76 (m, 4H). 19F NMR (282.4 MHz,
CDCl3): δ −42.1 (s). 13C{1H} NMR (75.5 MHz, CDCl3): δ 173.5,
148.4, 138.7, 136.4, 134.0, 131.1 (q, J = 306.5 Hz, Cquat), 127.9, 127.4,
121.8, 121.7, 116.5, 47.7, 39.3, 37.8 (q, J = 2.3 Hz), 26.6, 23.0, 21. 8,
13.8. ATR-FTIR (cm−1): 3353, 2960, 2932, 1674, 1527, 1487, 1424,
1326, 1146, 1103, 825, 790. HRMS (ESI+) m/z: [M + H]+ Calcd for
C18H22F3N2OS 371.1405; Found 371.1416.
2-Benzyl-2-methyl-N-(quinolin-8-yl)-3-(trifluoromethylthio)-
propanamide 6c. Procedure E was followed, from 1c and V (70 h).
The product was purified by flash chromatography on silica gel (height
32 cm, width 2 cm, pentane/dichloromethane 60:40) as a white
vitrous solid (30.8 mg, 38%), Rf (pentane/dichloromethane = 60:40):
0.43. 1H NMR (300.13 MHz, CDCl3): δ 10.15 (s, 1H), 8.80−8.70 (m,
2H), 8.16 (dd, J = 8.1, 1.5 Hz, 1H), 7.59−7.50 (m, 2H), 7.44 (dd, J =
8.1, 4.2 Hz, 1H), 7.21−7.14 (m, 5H), 3.53 (d, J = 12.9 Hz, 1H), 3.26
(d, J = 13.5 Hz, 1H), 3.00 (d, J = 13.2 Hz, 2H), 1.59 (s, 3H). 19F NMR
(282.4 MHz, CDCl3): δ − 42.0 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 172.7, 148.3, 138.6, 136.2, 135.9, 133.7, 131.0 (q, J = 306.5
Hz), 130.1, 128.3, 127.8, 127.3, 127.0, 121.9, 121.6, 116.5, 48.8, 45.5,
38.0 (q, J = 1.5 Hz), 21.0. ATR-FTIR (cm−1): 3353, 2927, 2853, 1671,
1531, 1485, 1422, 1144, 788, 687. HRMS (ESI+) m/z: [M + H]+
Calcd for C21H20F3N2OS 405.1248; Found 405.1257.
2-Methyl-N-(quinolin-8-yl)-2-(4-(trifluoromethyl)benzyl)-3-
(trifluoromethylthio)propanamide 6h. Procedure E was followed,
from 1h and I (60 h). The product was purified by flash
chromatography on silica gel (height 35 cm, width 2 cm, pentane/
dichloromethane = 60:40) as a pale yellow oil (46.8 mg, 50%), Rf
2-(3-Methoxybenzyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6d. Procedure E was followed, from 1d and
V (61 h). The product was purified by flash chromatography on silica
gel (height 31 cm, width 2 cm, pentane/dichloromethane 30:70) as a
1
(pentane/dichloromethane = 60:40): 0.49. H NMR (300.13 MHz,
CDCl3): δ 9.98 (broad s, 1H), 8.69−8.64 (m, 1H), 8.61 (dd, J = 4.2,
F
DOI: 10.1021/acs.joc.5b00505
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1.5 Hz, 1H), 8.09 (dd, J = 8.4, 1.5 Hz, 1H), 7.50−7.45 (m, 2H), 7.39−
7.30 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 3.45 (d, J = 12.9 Hz, 1H), 3.27
(d, J = 13.2 Hz, 1H), 2.99 (d, J = 12.9 Hz, 1H), 2.92 (d, J = 13.2 Hz,
1H), 1.51 (s, 3H). 19F NMR (282.4 MHz, CDCl3): δ −42.0 (s), −63.1
(s). 13C{1H} NMR (75.5 MHz, CDCl3): δ 172.0, 148.4, 140.2, 138.5,
136.3, 133.5, 130.9 (q, J = 306.5 Hz), 130.4, 129.3 (q, J = 33.2 Hz),
127.8, 127.3, 125.2 (q, J = 3.8 Hz), 124.0 (q, J = 271.8 Hz), 122.1,
121.7, 116.6, 48.9, 45.1, 38.3 (q, J = 2.3 Hz), 20.8. ATR-FTIR (cm−1):
3347, 2927, 2853, 1673, 1529, 1487, 1424, 1385, 1323, 1258, 1105,
1067, 906, 791, 687. HRMS (ESI+) m/z: [M + H]+ Calcd for
C22H19F6N2OS 473.1117; Found 473.1119.
129.3, 128.1, 127.8, 127.2, 122.0, 121.7, 116.3, 51.7, 39.5 (q, J = 1.5
Hz), 22.2. ATR-FTIR (cm−1): 3327, 1664, 1522, 1486, 1327, 1141,
1106, 825, 760. HRMS (ESI+) m/z: [M + H]+ Calcd for
C20H18F3N2OS 391.1086; Found 391.1082.
2-(4-Chlorophenyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6m. Procedure E was followed, from 1m
and V (143 h). The product was purified by flash chromatography on
silica gel (height 31 cm, width 2 cm, toluene/pentane = 50:50 + 1%
Et3N) as a white amorphous solid (31.2 mg, 37%), Rf (toluene/
pentane = 50:50 + 1% Et3N): 0.30. 1H NMR (300.13 MHz, CDCl3): δ
1H NMR (300.13 MHz, CDCl3): δ 9.83 (broad s, 1H), 8.73 (d, J = 7.2
2-(4-Cyanobenzyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6i. Procedure E was followed, from 1i and I
(39 h). The product was purified by flash chromatography on silica gel
(height 35 cm, width 2 cm, dichloromethane) as a pale yellow oil (22.3
mg, 26%), Rf (dichloromethane): 0.48. 1H NMR (300.13 MHz,
CDCl3): δ 9.96 (broad s, 1H), 8.68−8.59 (m, 2H), 8.09 (dd, J = 8.4,
1.5 Hz, 1H), 7.47 (d, J = 4.5 Hz, 2H), 7.41−7.33 (m, 3H), 7.20 (d, J =
7.2 Hz, 2H), 3.44 (d, J = 12.9 Hz, 1H), 3.28 (d, J = 13.2 Hz, 1H), 3.00
(d, J = 12.9 Hz, 1H), 2.88 (d, J = 13.2 Hz, 1H), 1.50 (s, 3H). 19F NMR
(282.4 MHz, CDCl3): δ −41.9 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 171.7, 148.4, 141.7, 138.5, 136.4, 133.3, 132.0, 130.8, 130.8
(q, J = 306.5 Hz), 127.8, 127.2, 122.3, 121.8, 118.6, 116.6, 111.0, 48.9,
45.3, 38.4 (q, J = 1.5 Hz), 20.6. ATR-FTIR (cm−1): 3347, 2228, 1670,
1525, 1487, 1425, 1385, 1103, 826, 790. HRMS (ESI+) m/z: [M + H]+
Calcd for C22H19F3N3OS 430.1195; Found 430.1195.
Hz, 1H), 8.59 (d, J = 4.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.54−7.33
(m, 7H), 3.72 (d, J = 12.9 Hz, 1H), 3.38 (d, J = 12.9 Hz, 1H), 2.03 (s,
3H). 19F NMR (282.4 MHz, CDCl3): δ − 42.6 (s). 13C{1H} NMR
(75.5 MHz, CDCl3): δ 173.5, 148.2, 140.8, 138.5, 136.1, 134.1, 131.1
(q, J = 305.8 Hz), 129.1, 128.1, 127.8, 127.2, 126.6, 121.8, 121.6,
116.2, 52.1, 39.6 (q, J = 2.3 Hz), 22.2. ATR-FTIR (cm−1): 3333, 1672,
1527, 1489, 1135, 1099, 1054, 824, 792. HRMS (ESI+) m/z:
C20H17ClF3N2OS 425.0697; Found 425.0705.
2-(4-Fluorophenyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6n. Procedure E was followed, from 1n and
V (143 h). The product was purified by flash chromatography on silica
gel (height 32 cm, width 2 cm, toluene/pentane = 50:50 + 1% Et3N)
as a white amorphous solid (26.2 mg, 32%), Rf (toluene/pentane =
1
50:50 + 1% Et3N): 0.44. H NMR (300.13 MHz, CDCl3): δ 9.82
(broad s, 1H), 8.71 (dd, J = 6.9, 1.8 Hz, 1H), 8.62 (dd, J = 4.2, 1.2 Hz,
1H), 8.11 (dd, J = 8.1, 1.2 Hz, 1H), 7.55−7.45 (m, 4H), 7.39 (dd, J =
8.1, 4.2 Hz, 1H), 7.12 (t, J = 8.7 Hz, 2H), 3.67 (d, J = 13.2 Hz, 1H),
3.36 (d, J = 13.2 Hz, 1H), 2.01 (s, 3H). 19F NMR (282.4 MHz,
CDCl3): δ −42.5 (s), −114.3 (m). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 173.2, 162.4 (d, J = 248.4 Hz), 148.3, 138.4, 136.6 (d, J =
3.8 Hz), 136.2, 133.9, 131.0 (q, J = 305.8 Hz), 128.6 (d, J = 27.9 Hz),
127.8, 127.2, 121.9, 121.6, 116.3 (d, J = 8.3 Hz), 115.9, 51.6, 39.7 (q, J
= 1.5 Hz), 22.4. ATR-FTIR (cm−1): 3327, 1668, 1527, 1488, 1141,
1100, 826, 790, 691. HRMS (ESI+) m/z: [M + H]+ Calcd for
C20H17F4N2OS 409.0992; Found 409.1012.
2-(2,6-Dichlorobenzyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6j. Procedure E was followed, from 1j and I
(45 h). The product was purified by flash chromatography on silica gel
(height 31 cm, width 2 cm, pentane/dichloromethane = 60:40) as a
white solid (43.1 mg, 46%), Rf (pentane/dichloromethane = 60:40):
1
0.45. H NMR (300.13 MHz, CDCl3): δ 10.08 (broad s, 1H), 8.73
(dd, J = 6.6, 2.1 Hz, 1H), 8.65 (d, J = 4.2 Hz, 1H), 8.14 (d, J = 8.1 Hz,
1H), 7.58−7.48 (m, 2H), 7.41 (dd, J = 8.1, 4.2 Hz, 1H), 7.21 (d, J =
7.8 Hz, 2H), 7.04 (t, J = 7.8 Hz, 1H), 3.66 (t, J = 14.4 Hz, 2H), 3.46
(d, J = 14.1 Hz, 1H), 3.14 (d, J = 12.9 Hz, 1H), 1.71 (s, 3H). 19F NMR
(282.4 MHz, CDCl3): δ −42.3 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 172.3, 148.1, 138.5, 137.1, 136.2, 134.0, 133.0, 131.1 (q, J =
306.5 Hz), 128.6, 128.6, 127.7, 127.4, 121.7, 121.5, 116.6, 49.6, 39.5,
38.8 (q, J = 1.5 Hz), 21.3. ATR-FTIR (cm−1): 3340, 1666, 1532, 1437,
1324, 1112, 781, 760. HRMS (ESI+) m/z: [M + H]+ Calcd for
C21H18Cl2F3N2OS 473.0464; Found 473.0447.
2-(3,4-Dichlorophenyl)-2-methyl-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6o. Procedure E was followed, from 1o and
V (86 h). The product was purified by flash chromatography on silica
gel (height 32 cm, width 2 cm, toluene/pentane = 60:40 + 1% Et3N)
as a colorless oil (27.3 mg, 30%), Rf (pentane/dichloromethane =
1
50:50): 0.68. H NMR (300.13 MHz, CDCl3): δ 9.88 (s, 1H), 8.69
2-Methyl-4-phenyl-N-(quinolin-8-yl)-2-((trifluoromethylthio)-
methyl)butanamide 6k. Procedure E was followed, from 1k and I (40
h). The product was purified by flash chromatography on silica gel
(height 32 cm, width 2 cm, toluene/pentane = 70:30 + 1% Et3N) as a
white vitrous solid (29.1 mg, 35%), Rf (pentane/dichloromethane =
60:40): 0.33. 1H NMR (300.13 MHz, CDCl3): δ 10.29 (broad s, 1H),
8.76 (dd, J = 4.2, 1.8 Hz, 1H), 8.73−8.65 (m, 1H), 8.12 (dd, J = 8.4,
1.5 Hz, 1H), 7.50−7.45 (m, 2H), 7.41 (dd, J = 8.4, 4.2 Hz, 1H), 7.23−
7.04 (m, 5H), 3.45 (d, J = 12.9 Hz, 1H), 3.05 (d, J = 12.9 Hz, 1H),
2.63 (dd, J = 9.6, 7.8 Hz, 2H), 2.22−2.06 (m, 1H), 2.05−1.91 (m,
1H), 1.59 (s, 3H). 19F NMR (282.4 MHz, CDCl3): δ −42.0 (s).
13C{1H} NMR (75.5 MHz, CDCl3): δ 173.0, 148.4, 141.1, 138.7,
136.4, 133.9, 131.0 (q, J = 306.5 Hz), 128.5, 128.3, 127.9, 127.4, 126.1,
121.9, 121.7, 116.6, 47.7, 41.5, 37.8 (q, J = 2.3 Hz), 31.0, 21.9. ATR-
FTIR (cm−1): 3353, 2933, 1673, 1527, 1486, 1469, 1424, 1384, 1326,
1253, 1105, 893, 825, 790, 697. HRMS (ESI+) m/z: [M + H]+ Calcd
for C22H22F3N2OS 419.1399; Found 419.1390.
2-Methyl-2-phenyl-N-(quinolin-8-yl)-3-(trifluoromethylthio)-
propanamide 6l. Procedure E was followed, from 1l and V (143 h).
The product was purified by flash chromatography on silica gel (height
32 cm, width 2 cm, toluene/pentane = 60:40 + 1% Et3N) as a white
vitrous solid (28.4 mg, 36%), Rf (pentane/dichloromethane = 60:40):
0.37. 1H NMR (300.13 MHz, CDCl3): δ 9.83 (broad s, 1H), 8.70 (dd,
J = 6.6, 2.1 Hz, 1H), 8.63 (dd, J = 4.2, 1.5 Hz, 1H), 8.11 (dd, J = 8.4,
1.5 Hz, 1H), 7.55−7.48 (m, 2H), 7.47−7.36 (m, 6H), 3.66 (d, J = 13.2
Hz, 1H), 3.34 (d, J = 13.2 Hz, 1H), 2.00 (s, 3H). 19F NMR (282.4
MHz, CDCl3): δ −42.5 (s). 13C{1H} NMR (75.5 MHz, CDCl3): δ
172.8, 148.4, 139.4, 138.4, 136.2, 134.2, 133.9, 131.0 (q, J = 306.5 Hz),
(dd, J = 6.3, 2.7 Hz, 1H), 8.67 (dd, J = 4.8, 1.8 Hz, 1H), 8.13 (dd, J =
8.4, 1.8 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.55−7.45 (m, 3H), 7.41
(dd, J = 8.4, 4.2 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 3.65 (d, J =
13.2 Hz, 1H), 3.33 (d, J = 13.2 Hz, 1H), 2.00 (s, 3H). 19F NMR
(282.4 MHz, CDCl3): δ −42.5 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 172.0, 148.5, 141.2, 138.4, 136.3, 133.7, 133.3, 132.5, 131.0,
130.8 (q, J = 306.5 Hz), 128.7, 127.8, 127.2, 126.2, 122.1, 121.7, 116.2,
51.7, 39.4 (q, J = 2.3 Hz), 22.1. ATR-FTIR (cm−1): 3327, 1668, 1527,
1488, 1141, 1100, 825, 790, 691. HRMS (ESI+) m/z: [M + H]+ Calcd
for C20H16Cl2F3N2OS 459.0312; Found 459.0305.
2-Phenyl-N-(quinolin-8-yl)-3-(trifluoromethylthio)propanamide
6p. Procedure E was followed, from 1p and I (60 h). The product was
purified by flash chromatography on silica gel (height 32 cm, width 2
cm, pentane/dichloromethane = 60:40) as a pale yellow oil (27 mg,
36%), Rf (pentane/dichloromethane = 60:40): 0.51. 1H NMR (300.13
MHz, CDCl3): δ 9.93 (broad s, 1H), 8.79−8.70 (m, 2H), 8.12 (dd, J =
8.4, 1.8 Hz, 1H), 7.54−7.45 (m, 4H), 7.44−7.32 (m, 4H), 4.13 (dd, J
= 9.0, 6.0 Hz, 1H), 3.76 (dd, J = 14.1, 9.0 Hz, 1H), 3.30 (dd, J = 14.1,
6.0 Hz, 1H). 19F NMR (282.4 MHz, CDCl3): δ −41.8. 13C{1H} NMR
(75.5 MHz, CDCl3): δ 169.4, 148.3, 138.2, 137.4, 136.2, 134.0, 131.2
(q, J = 306.5 Hz), 129.3, 128.3, 127.9, 127.8, 127.2, 121.9, 121.6,
116.5, 54.7, 32.6 (q, J = 2.3 Hz). ATR-FTIR (cm−1): 3340, 2925, 2855,
1688, 1527, 1486, 1462, 1385, 1324, 1276, 1111, 825, 791, 698. HRMS
(ESI+) m/z: [M + H]+ Calcd for C19H16F3N2OS 377.0930; Found
377.0935.
2-Methyl-N-(quinolin-8-yl)-3-(trifluoromethylthio)propanamide
6q. Procedure E was followed, from 1q and V (143 h). The product
was purified by flash chromatography on silica gel (height 32 cm,
G
DOI: 10.1021/acs.joc.5b00505
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
width 2 cm, toluene + Et3N 1%) as pale yellow oil (19.6 mg, 31%), Rf
(toluene + Et3N 1%): 0.28. H NMR (300.13 MHz, CDCl3): δ 9.97
NMR (282.4 MHz, CDCl3): δ −38.1 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 171.5, 148.2, 138.4, 136.4, 134.2, 127.9, 127.4, 121.8, 121.6,
116.8, 52.1, 45.5, 34.5, 31.3, 26.0, 24.5. The CF3-carbon was not
detectable. ATR-FTIR (cm−1): 3347, 2933, 2860, 1683, 1524, 1486,
1325,1099, 790. HRMS (ESI+) m/z: [M + H]+ Calcd for
C17H18F3N2OS 355.1086; Found 355.1091.
1
(broad s, 1H), 8.83 (dd, J = 4.2, 1.5 Hz, 1H), 8.80−8.73 (m, 1H), 8.17
(dd, J = 8.1, 1.5 Hz, 1H), 7.58−7.51 (m, 2H), 7.47 (dd, J = 8.1, 4.2 Hz,
1H), 3.39−3.26 (m, 1H), 3.11−2.95 (m, 2H), 1.47 (d, J = 6.6 Hz,
3H). 19F NMR (282.4 MHz, CDCl3): δ −41.7 (s). 13C{1H} NMR
(75.5 MHz, CDCl3): δ 172.3, 148.3, 138.3, 136.4, 134.0, 131.1 (q, J =
305.8 Hz), 127.9, 127.3, 121.9, 121.7, 116.7, 43.0, 32.8 (q, J = 2.3 Hz),
18.0. ATR-FTIR (cm−1): 3347, 2927, 1688, 1526, 1486, 1457, 1426,
1379, 1323, 1258, 1105, 942, 826, 791, 671. HRMS (ESI+) m/z: [M +
H]+ Calcd for C14H14F3N2OS 315.0773; Found 315.0784.
2-(4-Isobutylphenyl)-N-(quinolin-8-yl)-3-(trifluoromethylthio)-
propanamide 6r. Procedure E was followed, from 1r and V (143 h).
The product was purified by flash chromatography on silica gel (height
32 cm, width 2 cm, toluene/pentane 80:20 + 1% Et3N) as a pale
yellow oil (28.2 mg, 33%), Rf (toluene/pentane 80:20 + 1% Et3N):
0.48. 1H NMR (300.13 MHz, CDCl3): δ 9.91 (broad s, 1H), 8.76 (dd,
J = 6.9, 2.1 Hz, 1H), 8.70 (dd, J = 4.2, 1.5 Hz, 1H), 8.11 (dd, J = 8.1,
1.5 Hz, 1H), 7.54−7.46 (m, 2H), 7.41 (dd, J = 8.4, 4.5 Hz, 1H), 7.37
(d, J = 8.1 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 4.10 (dd, J = 9.0, 6.0 Hz,
1H), 3.76 (dd, J = 13.8, 9.0 Hz, 1H), 3.29 (dd, J = 13.8, 6.0 Hz, 1H),
2.47 (d, J = 7.2 Hz, 2H), 1.91−1.78 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H).
19F NMR (282.4 MHz, CDCl3): δ − 41.8 (s). 13C{1H} NMR (75.5
Further Transformations of the Product 6. Procedure for the
Oxidation of Compound 6a:27 An oven-dried 10 mL flask equipped
with a stir bar was charged with 6a (32.8 mg, 0.1 mmol, 1 equiv) and
distilled CH2Cl2 (1.5 mL), and the reaction mixture was cooled down
to −10 °C. Then, m-CPBA (61.6 mg, 0.25 mmol, 2.5 equiv, assay
ca.70%) was added portionwise while keeping the temperature at −10
°C. The reaction mixture was allowed to warm up to 5 °C and was
stirred for 3 h until complete disappearence of the starting material.
Then, the reaction mixture was diluted with CH2Cl2 (5 mL) and water
(5 mL). The organic layer was washed with sodium sulfite solution (5
mL), aqueous NaHCO3 solution (5 mL), and brine (5 mL), dried over
MgSO4, and concentrated. The residue was purified by column
chromatography (petroleum ether/dichloromethane, 40:60) to afford
the desired product 7 as a pale yellow vitrous solid in 40% yield (13.9
mg). 2,2-Dimethyl-N-(quinolin-8-yl)-3-(trifluoromethylsulfinyl)propana-
mide 7. Rf (pentane/dichloromethane = 30:70): 0.15. 1H NMR
(300.13 MHz, CDCl3): δ 10.41 (broad s, 1H), 8.83 (dd, J = 4.2, 1.5
Hz, 1H), 8.77−8.69 (m, 1H), 8.19 (dd, J = 8.1, 1.5 Hz, 1H), 7.58−
7.52 (m, 2H), 7.49 (dd, J = 8.1, 4.2 Hz, 1H), 3.58 (d, J = 13.5 Hz, 1H),
3.09 (d, J = 13.5 Hz, 1H), 1.78 (s, 3H), 1.67 (s, 3H). 19F NMR (282.4
MHz, CDCl3): δ −74.5 (s). 13C{1H} NMR (75.5 MHz, CDCl3): δ
173.4, 148.5, 138.6, 136.4, 133.7, 127.9, 127.3, 125.6 (q, J = 334.5 Hz),
122.2, 121.8, 116.7, 59.6 (q, J = 3.0 Hz), 42.9, 27.5, 25.2. ATR-FTIR
(cm−1): 3333, 2958, 1670, 1531, 1489, 1328, 1173, 1137, 1064, 791,
695. HRMS (ESI+) m/z: [M + H]+ Calcd for C15H16F3N2O2S
345.0885; Found 345.0887.
Procedure for the Removal of the Directing Group on
Compound 6a:20 An oven-dried 10 mL flask equipped with a stir
bar was charged with 6a (65.6 mg, 0.2 mmol, 1 equiv), NaOH (120
mg, 3 mmol, 15 equiv), and EtOH (1 mL). The resulting mixture was
stirred at 90 °C for 4 days. After completion, the reaction mixture was
cooled to room temperature, water (20 mL) was added, and the
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The pH of the
aqueous layer was adjusted to 2 with HCl (1 M), and the resulting
aqueous layer was extracted with CH2Cl2 (4 × 20 mL), dried over
MgSO4, and filtered, and the solvent was evaporated under vacuum to
afford pure product 8 (34.6 mg, 89%) as a yellow oil. 2,2-Dimethyl-3-
(trifluoromethylthio)propanoic acid 8. 1H NMR (300.13 MHz, CDCl3):
δ 10.21 (broad s, 1H), 3.08 (s, 2H), 1.35 (s, 6H). 19F NMR (282.4
MHz, CDCl3): δ−42.2 (s). 13C{1H} NMR (75.5 MHz, CDCl3): δ
182.4, 130.8 (q, J = 305.8 Hz), 42.9, 38.2 (q, J = 2.3 Hz), 24.3. ATR-
FTIR (cm−1): 2983, 2940, 1702, 1477, 1151, 1099. HRMS (ESI−) m/
z: [M − H]+ Calcd for C6H8F3O2S 201.0197; Found 201.0193.
MHz, CDCl3): δ 169.7, 148.2, 141.9, 138.3, 136.2, 134.6, 134.1, 131.3
(q, J = 306.5 Hz), 130.0, 127.8, 127.6, 127.2, 121.9, 121.6, 54.3, 45.1,
32.6 (q, J = 2.3 Hz), 30.2, 22.3, 22.3. ATR-FTIR (cm−1): 3340, 2953,
2920, 1683, 1525, 1486, 1148, 1104, 825, 790. HRMS (ESI+) m/z: [M
+ H]+ Calcd for C23H24F3N2OS 433.1556; Found 433.1548.
(S)-2-(6-Methoxynaphthalen-2-yl)-N-(quinolin-8-yl)-3-(trifluoro-
methylthio)propanamide 6s. Procedure E was followed, from 1s and
V (143 h). The product was purified by flash chromatography on silica
gel (height 32 cm, width 2 cm, toluene/pentane 90:10 + 1% Et3N) as a
yellow oil (21.2 mg, 23%), Rf (toluene/pentane 80:20 + 1% Et3N):
0.26. 1H NMR (300.13 MHz, CDCl3): δ 9.98 (broad s, 1H), 8.78 (dd,
J = 7.2, 1.8 Hz, 1H), 8.67 (dd, J = 4.2, 1.8 Hz, 1H), 8.10 (d, dd, J = 8.4,
1.8 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.58−7.46 (m,
3H), 7.38 (dd, J = 8.4, 4.2 Hz, 1H), 7.17 (dd, J = 9.0, 2.4 Hz, 1H), 7.12
(d, J = 2.4 Hz, 1H) 4.26 (dd, J = 9.0, 6.0 Hz, 1H), 3.91 (s, 3H), 3.83
(dd, J = 13.8, 9.0 Hz, 1H), 3.37 (dd, J = 13.8, 6.0 Hz, 1H). 19F NMR
(282.4 MHz, CDCl3): δ −41.7 (s). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 169.6, 158.0, 148.2, 138.2, 136.2, 134.3, 134.0, 132.4, 131.3
(q, J = 306.5 Hz), 129.4, 129.0, 128.0, 127.8, 127.2, 127.0, 125.7,
121.9, 121.6, 119.4, 116.5, 105.6, 55.3, 54.6, 32.6 (q, J = 2.3 Hz). ATR-
FTIR (cm−1): 3333, 2923, 1680, 1633, 1525, 1484, 1262, 1099, 1028,
789. HRMS (ESI+) m/z: [M + H]+ Calcd for C24H20F3N2O2S
457.1192; Found 457.1208.
2-Ethyl-N-(quinolin-8-yl)-3-(trifluoromethylthio)butanamide 6t.
Procedure E was followed, from 1t and I (60 h). The product was
purified by flash chromatography on silica gel (height 31 cm, width 1.5
cm, pentane/dichloromethane = 40:60) as a colorless oil (8.3 mg,
12%), Rf (pentane/dichloromethane = 40:60): 0.42. 1H NMR (300.13
MHz, CDCl3): δ 9.92 (broad s, 1H), 8.86−8.74 (m, 2H), 8.18 (dd, J =
8.4, 1.8 Hz, 1H), 7.54 (d, J = 4.5 Hz, 2H), 7.48 (dd, J = 8.4, 4.2 Hz,
1H), 3.63−3.49 (m, 1H), 2.74−2.62 (m, 1H), 2.07−1.94 (m, 1H),
1.92−1.79 (m, 1H), 1.57 (d, J = 6.3 Hz, 3H), 1.08 (t, J = 7.5 Hz, 3H).
19F NMR (282.4 MHz, CDCl3): δ −41.3 (s). 13C{1H} NMR (75.5
ASSOCIATED CONTENT
* Supporting Information
■
S
Radical trapping experiments, spectral data, crystallographic
information (CCDC 1050504 (6j)) and 1050505 (6a)). This
material is available free of charge via the Internet at http://
pubs.acs.org.
MHz, CDCl3): δ 171.5, 148.3, 138.4, 136.4, 133.9, 127.9, 127.4, 121.9,
121.7, 116.8, 55.4, 42.3 (q, J = 306.5 Hz), 23.9, 21.6, 12.0. The CF3-
carbon was not detectable. ATR-FTIR (cm−1): 3347, 2966, 1682,
1524, 1487, 1425, 1324, 1110, 826, 791, 679. HRMS (ESI+) m/z: [M
+ H]+ Calcd for C16H18F3N2OS 343.1086; Found 343.1086.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tatiana.besset@insa-rouen.fr.
■
N-(Quinolin-8-yl)-2-(trifluoromethylthio)cyclohexane-1-carbox-
amide 6u. Procedure E was followed, from 1u and I (60 h). The
product was purified by flash chromatography on silica gel (height 32
cm, width 2 cm, toluene/pentane 94:6 + Et3N 1%) as a colorless oil
Notes
The authors declare no competing financial interest.
1
(5.6 mg, 8%), Rf (pentane/dichloromethane = 40:60): 0.26. H NMR
ACKNOWLEDGMENTS
■
(300.13 MHz, CDCl3): δ 9.87 (broad s, 1H), 8.84−8.76 (m, 2H), 8.17
(dd, J = 8.1, 1.5 Hz, 1H), 7.59−7.50 (m, 2H), 7.47 (dd, J = 8.4, 4.2 Hz,
1H), 3.66−3.47 (m, 1H), 2.69−2.53 (m, 1H), 2.46−2.32 (m, 1H),
2.25−2.11 (m, 1H), 1.93−1.69 (m, 4H), 1.55−1.34 (m, 2H). 19F
This work has been partially supported by INSA de Rouen,
Universite
0029), EFRD and Reg
́
de Rouen, CNRS, LABEX SynOrg (ANR-11-LABX-
́
ion Haute-Normandie (CRUNCh
H
DOI: 10.1021/acs.joc.5b00505
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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Dr. T. Billard (ICBMS-UMR 5246, Universite de Lyon) is
́
acknowledged for the generous gift of VI.
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DOI: 10.1021/acs.joc.5b00505
J. Org. Chem. XXXX, XXX, XXX−XXX