Silver-Catalyzed Three-Component Difunctionalization of Alkenes via Radical Pathways: Access to CF3-Functionalized Alkyl-Substituted 1,4-Naphthoquinone Derivatives

Article abstract of DOI:10.1021/acs.joc.8b02997

A silver-catalyzed three-component difunctionalization of alkenes by using 2-amino- and 2-hydroxy-1,4-naphthoquinone derivatives as the radical-trapping reagents is reported. Various alkenes and 2-amino- or 2-hydroxy-1,4-naphthoquinones with diverse struc

Full text of DOI:10.1021/acs.joc.8b02997

Article
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Silver-Catalyzed Three-Component Difunctionalization of Alkenes
via Radical Pathways: Access to CF ‑Functionalized Alkyl-
3
Substituted 1,4-Naphthoquinone Derivatives
†
†
Qijun Wang, Bo Wang, Hao Deng, Yu Shangguan, Yan Lin, Yaqi Zhang, Zheming Zhang, Yumei Xiao,
Hongchao Guo, and Cheng Zhang*
Department of Applied Chemistry, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China
*
S Supporting Information
ABSTRACT: A silver-catalyzed three-component difunctionalization of alkenes by using 2-amino- and 2-hydroxy-1,4-
naphthoquinone derivatives as the radical-trapping reagents is reported. Various alkenes and 2-amino- or 2-hydroxy-1,4-
naphthoquinones with diverse structures and electronic properties are applied to the reaction. The methodology provides an
alternative method to access CF -functionalized alkyl-substituted quinone derivatives which are prevalent structures in bioactive
3
molecules. Furthermore, a plausible radical pathway for the reaction is proposed based on results from primary control
experiments.
4
INTRODUCTION
Quinone-based organic molecules play important roles in
developing therapeutic drugs, agrochemicals, and functional
materials and acting as building blocks in total synthesis.
Notable among these are the 2-hydroxy- and 2-aminoquinone
derivatives bearing alkyl substituents, such as lapachol (Figure
require excess amounts of strong oxidants, albeit with some
■
5
exceptions. Other methods by oxidation of the corresponding
dihydroxybenzene derivatives need both the prefunctionaliza-
tion of substrates and the presence of excessive strong
oxidizing reagents, which are environmentally unfavorable
and labor-intensive. Further, the way to introduce the
1
6
1
), which usually show important bioactivities including
prevalent CF group to such alkyl-substituted 1,4-naphthoqui-
3
none derivatives would be much more difficult. Therefore,
developing concise and environmentally benign methods to
synthesize such 1,4-napthoquinone derivatives is highly
desirable.
Three-component difunctionalization of alkenes via radical
pathways is a highly efficient strategy to construct poly-
functionalized molecules and has gained increasing attention
7
over recent years. In this context, developing new radical
trapping reagents has been an intensively studied field while
Figure 1. Important 2-amino- and 2-hydroxy-1,4-naphthoquinone
structures.
8
9
10
oxygen-based, nitrogen-based, and carbon-based as well as
14
other types of radical trapping reagents have been developed.
Among these, the carbon-based radical trapping reagent has
antibacterial, antiinflammatory, antifungal, and in particular,
anticancer activity. As a result, the development of synthetic
10−13
2
received the most attention. In addition to TMSCN,
other typical carbon-based reagents including N-protected
methods to incorporate functional alkyl groups into 2-hydroxy-
or 2-aminoquinones is of great significance. However, common
tactics to access such compounds encounter several drawbacks.
The prevalent transition-metal-catalyzed method usually works
sluggishly on quinone substrates due to their strong oxidation
11
12
13
indoles, phenyl boronic acids, and alkynyl silanes have
been reported. In these transformations, radical functional
Received: November 23, 2018
Published: December 28, 2018
3
and metal-binding ability, and even feasible examples of these
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02997
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
groups generated first from radical precursors add to alkenes,
forming radical intermediates, and the radical intermediates are
either oxidized to carbon cations followed by trapping with
nucleophiles or directly form organocopper intermediates by
combination of the catalyst and nucleophile followed by
Table 1. Screening for Optimal Reaction Conditions
7d,15
reductive elimination (Scheme 1).
2-Hydroxy- and 2-
Scheme 1. Carbon-Based Three-Component
Difunctionalization of Alkenes via Radical Pathways
entry
[M]
L
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
1,4-dioxane
MeOH
DMF
DCE
yield (%)
1
2
3
4
5
6
7
8
9
CuCl
CuBr
CuI
L1
L1
L1
L1
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
38
13
35
52
41
43
67
80
15
52
55
77
42
21
77
AgOAc
FeCp2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
1
1
1
1
1
1
0
1
2
3
4
5
b
c
DCE
DCE
d
aminoquinones have been reported as nucleophiles in a few
1
6
a
Conditions: 1a (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), 3
0.22 mmol, 1.1 equiv), [M] (0.02 mmol, 10 mol %), L (0.02 mmol,
examples. We therefore envisioned that such quinone
derivatives would also be effective as radical-trapping reagents
in the three-component difunctionalization of alkenes.
(
1
b
0 mol %), in 1.5 mL of solvent, 75 °C, 12 h. Catalyst loading was 5
c
d
mol %. Reaction was performed at room temperature. Reaction was
run for 24 h.
Considering the prevalence of the CF group and quinone
3
17
structures in pharmaceuticals and agrochemicals, and also as
a continuing interest in developing synthetic methods to access
18
quinone-based small molecules in our group, we report here
a concise and highly efficient silver-catalyzed three-component
difunctionalization of alkenes to generate alkyl-substituted 1,4-
naphthoquinone derivatives along with incorporation of the
effect that results from the diphosphine and FeCp motifs
because the sole FeCp also imparts moderate catalytic activity
to the reaction. Using the best ligand and the best metal salt,
we further studied the effects of solvents, and the results show
that either DCE or DMF is a favorable solvent for the reaction
2
2
prevalent CF group.
3
(
entry 12). A lower catalyst loading results in a lower chemical
RESULTS AND DISCUSSION
At the outset of our experiment, we selected 2-phenylamino-
,4-naphthoquinone 1a as the radical-trapping reagent, Tongni
■
1
yield of the product (entry 13). The reaction performs
sluggishly when it is carried out at room temperature, which is
probably due to the poor solubility of the starting material
(entry 14). A longer reaction time lowers the yield of 4aa
slightly (entry 15). After establishing the optimal reaction
conditions, we evaluated its feasibility by testing various
alkenes that bear diverse electronic properties and substitution
patterns in the reaction (Scheme 2). Regarding para-
substituted styrenes, both electron-donating and electron-
withdrawing group substitution on the phenyl ring results in
high yields of products (4aa−aj). Substitution on the phenyl
ring that seems to affect the reaction to some extent is
demonstrated by the 2-chloro-substituted styrene, which yields
less product than the 3- or 4-chloro-substituted styrene (4ae−
ag). The α-vinylnaphthalene affords the corresponding
product (4ak) in lower yield than its styrene analogues.
Notably, vinylheteroarenes are also suitable substrates, as 4al
and 4am were obtained in 61% and 73% yields, respectively.
When the alkyl alkene and internal alkene are subjected to the
I reagent 3 as the radical precursor, and 4-methylstyrene 2a to
evaluate our hypothesis (Table 1). To our delight, we isolated
the desired product 4aa in 38% yield with 10 mol % loading of
CuCl and 1,10-phenanthronline as the catalyst (entry 1), and
the product was further verified by single crystal diffraction.
We are therefore encouraged to optimize the reaction
conditions by screening metal salts, ligands, solvents, and
1
9
temperatures. Among several metal salts, including AgOAc,
FeCp (ferrocene), and different types of copper salts, AgOAc
2
shows the best result when 52% yield of the final product is
obtained (entry 4). Ligand screening indicates diphosphine
ligands (such as race-BINAP and DPPF) are superior to
dinitrogen ligands (such as 1,10-phenanthroline and 2,2′-
dipyridine), Interestingly, DPPF, which contains the FeCp
2
structrual motif, affords the best performance (entry 8). The
superiority of the DPPF ligand might come from a cooperative
B
DOI: 10.1021/acs.joc.8b02997
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The Journal of Organic Chemistry
Article
a
Scheme 2. Substrate Scope for Alkenes
a
Conditions: 1a (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), 3 (0.22 mmol, 1.1 equiv), AgOAc (0.02 mmol, 10 mol %), DPPF (0.02 mmol, 10
mol %), in 1.5 mL of solvent, 75 °C, 12 h.
reaction, the corresponding products 4an, 4ao, and 4ap were
also isolated in good yields, along with good diastereoselectiv-
ities for 4ao and 4ap.
As outlined in Scheme 3, the substrate scope for
naphthoquinones was also examined carefully. Initially, 2-
phenylamino-substituted 1,4-naphthoquinone derivatives were
carefully examined under the optimal reaction conditions
the yield is lower than that in substrate scope expansions
(Scheme 4).
Finally, we carried out several control experiments to gain
further insights into the mechanism. When 1,4-naphthoqui-
none 1l or 2-methyl-1,4-naphthoquinone 1m instead of 2-
amino- or 2-hydroxy-1,4-napthoquinone was subjected to the
reaction, none of the corresponding product was detected, and
2
-benzamido-1,4-naphthoquinone 1n is not a suitable substrate
for the reaction either under the optimal conditions (Scheme
.1). The results indicated that the free amino or hydroxyl
(4ba−ha). Electronically diverse substituents on the phenyl
ring of the phenyl amines show no obvious effects on the yields
of the products while all of the corresponding products were
obtained with high yields. However, the substrate with a strong
electron-rich methoxyl group on the para-position affords the
corresponding product in considerably lower yield compared
to the ortho- or meta-substituted ones (4ba−da). Multi-
substituted phenylamino substrate is also a suitable substrate
for the reaction, as 4ha was isolated in 71% yield. Alkylamino-
derived 1,4-naphthoquinone is also favorable for the reaction,
as 4ia was obtained in high yield. When tertiary amino-derived
substrate is subjected to the reaction, the corresponding
product 4ja is furnished in good yield as well. Notably, the 2-
hydroxy-1,4-naphthoquinone also works well under the
optimal reaction conditions, producing 4ka in 67% yield. In
addition, we also scaled up the synthesis of product 4ga, and
5
group is indispensable for the success of the reaction, and an
enamine or enolate isomerization of the 1,4-naphthoquinone
derivative is probably involved. Moreover, the model reaction
was completely inhibited with the addition of 2 equiv of
TEMPO (Scheme 5.2), which implies that the reaction
involves a radical pathway. Combining the results above, we
propose here a plausible mechanism. Initially, trifluoromethyl
radical was generated via SET (single-electron-transfer)
between the silver complex and Togni I reagent. Addition of
the CF radical to styrene 2a formed radical intermediate A
3
followed by oxidation to carbon cation intermediate B, which
was then trapped by 1a′ to afford the desired product 4aa after
the deprotonation and rearrangement of intermediate C (path
a, Scheme 6). However, a mechanism involving the direct
C
DOI: 10.1021/acs.joc.8b02997
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 3. Substrate Scope for 1,4-Naphthoquinone Derivatives
a
Conditions: 1a (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), 3 (0.22 mmol, 1.1 equiv), AgOAc (0.02 mmol, 10 mol %), DPPF (0.02 mmol, 10
b
mol %), in 1.5 mL of solvent, 75 °C, 12 h. DMF was used as the solvent.
Scheme 4. Scale-up Synthesis of 4ga
Scheme 6. Proposed Mechanism
Scheme 5. Control Experiments
easily handled, and relatively environmentally benign while no
strong oxidant is involved, and the resulting 1,4-naphthoqui-
none products containing a trifluoromethyl group are of great
significance in developing biologically active compounds. We
also propose a plausible radical pathway for the reaction based
on the results from control experiments.
reaction of intermediate A with 1a cannot be ruled out (path b,
Scheme 6).
In summary, we have developed a silver-catalyzed three-
component difunctionalization of alkenes, using the Togni I
reagent and 2-amino- or 2-hydroxy-1,4-naphthoquinone
derivatives as the functional reagents. The process is concise,
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under argon
atmosphere unless otherwise stated. Solvents were all dried before use
according to standard procedures. Commercial reagents were
D
DOI: 10.1021/acs.joc.8b02997
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The Journal of Organic Chemistry
Article
obtained from Infinity Scientific, Beijing Ouhe Technology, and
Aladdin, and they were used without further purification. Flash
chromatography was performed on silica gel 60 (40−63 μm, 60 Å).
Thin layer chromatography (TLC) was performed on glass plates
coated with silica gel 60 with F254 indicator. Proton nuclear magnetic
resonance ( H NMR) spectra were recorded on a Bruker 300 MHz
spectrometer. Chemical shifts for protons are reported in parts per
NMR (300 MHz, CDCl ): δ 8.12−8.05 (m, 2H), 7.74 (td, J = 7.5, 1.4
3
Hz, 1H), 7.64 (td, J = 7.5, 1.4 Hz, 1H), 7.52 (s, 1H), 7.28−7.09 (m,
3H), 7.10−6.97 (m, 6H), 4.15 (t, J = 7.1 Hz, 1H), 3.17−2.98 (m,
1
3
1
2H), 2.29 (s, 3H).; C{ H} NMR (75 MHz, CDCl ): δ 183.8, 182.4,
3
143.6, 139.8, 136.8, 135.8, 134.4, 133.2, 132.1, 129.7, 129.1, 128.6,
1
127.6, 126.2, 126.3 (q, J = 265.2), 125.9. 125.4, 123.3, 120.0, 37.0 (q,
1
9
1
J = 27.0 Hz), 36.7 (q, J = 3.1 Hz), 20.6; F{ H} NMR (282 MHz,
+
million downfield from tetramethylsilane and are referenced to
CDCl ): δ = −64.1. HRMS calcd for C H F NO [M + H] :
3
26 21
3
2
residual protium in the NMR solvent (CHCl = δ 7.26, DMSO = δ
436.1519, found: 436.1518.
3
1
3
2
.52). Carbon nuclear magnetic resonance ( C NMR) spectra were
2-(Phenylamino)-3-(3,3,3-trifluoro-1-(4-methoxyphenyl)propyl)-
1
recorded on a Bruker 75 MHz spectrometer. Chemical shifts for
carbon are reported in parts per million downfield from
tetramethylsilane and are referenced to the carbon resonances of
naphthalene-1,4-dione (4ab). Red solid, 66.8 mg, 74% yield. H
NMR (300 MHz, CDCl ): δ 8.12−8.06 (m, 2H), 7.75 (td, J = 7.5, 1.4
3
Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.51 (s, 1H), 7.28−7.09 (m,
3H), 7.09−6.94 (m, 3H), 6.79−6.66 (m, 1H), 4.11 (t, J = 7.1 Hz,
the solvent (CDCl = δ 77.07, DMSO = 39.9). Data are represented
3
1
3
1
as follows: chemical shift, multiplicity (br = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constants in
hertz (Hz), integration.
1H), 3.75 (s, 3H), 3.19−2.89 (m, 2H). C{ H} NMR (75 MHz,
CDCl ): δ 183.9, 182.4, 157.9, 143.6, 139.8, 134.4, 133.2, 132.2,
3
131.8, 129.7, 129.1, 128.8, 126.3 (q, J = 276.4 Hz), 126.2, 125.9,
Synthesis of Starting Materials. Substrate for 2-amino-1,4-
naphthoquinone 1h (known compound) was synthesized by a
modified method, and other 2-amino-1,4-naphthoquinones are all
known compounds that were synthesized following reported
125.4, 123.3, 120.0, 113.3, 54.9, 37.1 (q, J = 26.9), 36.5 (q, J = 3.0
1
9
1
Hz); F{ H} NMR (282 MHz, CDCl ): δ = −64.2. HRMS calcd for
3
+
C H F NO [M + H] : 452.1468, found: 452.1465.
2
6
21
3
3
2-(1-(4-(tert-Butyl)phenyl)-3,3,3-trifluoropropyl)-3-
20,21
methods.
2-Hydroxy-1,4-naphthoquinone was purchased from
(phenylamino)naphthalene-1,4-dione (4ac). Red solid, 74.5 mg,
1
Energy Chemical (China).
78% yield. H NMR (300 MHz, CDCl ): δ 8.13−8.06 (m, 2H), 7.75
3
Synthesis of 1h. A mixture of 1,4-naphthoquinone (5 mmol, 790
mg, 1 equiv), 2,4,6-trimethylaniline (6 mmol, 811 mg, 1.2 equiv), and
CeCl ·7H O (0.25 mmol, 93 mg, 0.05 equiv) in 10 mL of EtOH. The
(td, J = 7.5, 1.4 Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.48 (s, 1H),
7.24−7.06 (m, 6H), 7.06−6.94 (m, 4H), 4.15 (t, J = 7.1 Hz, 1H),
1
3
1
3.26−2.85 (m, 2H), 1.28 (s, 9H). C{ H} NMR (75 MHz, CDCl ):
3
3
2
reaction mixture was stirred at 75 °C for 24 h. After cooling to room
temperature, to the mixture was added 40 mL of cold water, and
yellow solids were precipitated. The solids were collected by filtration
and washed with the smallest volume of cold ethanol. The final
δ 183.8, 182.4, 149.0, 143.8, 139.8, 136.6, 134.4, 133.2, 132.1, 129.7,
129.0, 127.3, 126.3 (q, J = 265.2), 126.2, 125.9, 125.3, 124.8, 123.4,
1
9
1
120.1, 37.0 (q, J = 26.9), 36.7 (q, J = 2.8 Hz), 34.0, 31.0; F{ H}
NMR (282 MHz, CDCl ): δ = −64.2. HRMS calcd for C H F NO
3
29 27
3
2
1
+
product 1h was obtained as a yellow solid of 466 mg, 32% yield. H
[M + H] : 478.1988, found: 478.1983.
NMR (300 MHz, CDCl ): δ 8.13 (dd, J = 7.5 Hz, 2.0 Hz, 1H), 8.09
2-(Phenylamino)-3-(3,3,3-trifluoro-1-phenylpropyl)naphthalene-
3
1
(
=
3
dd, J = 7.5 Hz, 2.0 Hz, 1H), 7.75 (td, J = 7.5, 1.4 Hz, 1H), 7.66 (td, J
7.5, 1.4 Hz, 1H), 7.03 (s, 1H), 6.95 (s, 2H), 5.38 (s, 1H), 2.31 (s,
H), 2.16 (s, 6H).
Synthesis of 2-Benzamido-1,4-naphthoquinone (1o). To a
5 mL flask were added 1,4-naphthoquinone (5 mmol, 1 equiv),
1,4-dione (4ad). Red solid, 67.4 mg, 80% yield. H NMR (300 MHz,
CDCl
): δ 8.13−8.07 (m, 2H), 7.75 (td, J = 7.6, 1.4 Hz, 1H), 7.66
3
(td, J = 7.5, 1.4 Hz, 1H), 7.54 (s, 1H), 7.24−6.99 (m, 10H), 4.16 (t, J
= 7.1 Hz, 1H), 3.27−2.85 (m, 2H). C{ H} NMR (75 MHz,
CDCl ): δ 183.8, 182.3, 143.9, 139.8, 139.6, 134.5, 133.2, 132.2,
2
2
13
1
2
3
benzhydroxamic acid (5.5 mmol, 1.1 equiv), and iPr NEt (10 mmol, 2
129.7, 129.1, 127.9, 127.7, 126.2, 126.2, 126.3 (q, J = 276.1 Hz),
125.9, 125.5, 123.5, 119.4, 37.1 (q, J = 27.1 Hz), 37.2 (q, J = 2.9 Hz);
2
equiv), followed by addition of 10 mL of acetonitrile. The mixture
was stirred at 70 °C for 4 h. Volatiles were then removed under
vacuum, and the residue was purified on a silica flash column with
AcOEt/petroleum ether to afford the desired product 1o.
1
9
1
F{ H} NMR (282 MHz, CDCl
): δ = −64.2. HRMS calcd for
3
+
C H F NO [M + H] : 422.1362, found: 422.1361.
2
5
19
3
2
2-(1-(2-Chlorophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)-
2
3
1
Alkenes 2k and 2n Were Synthesized by Known Methods.
naphthalene-1,4-dione (4ae). Red solid, 59.3 mg, 65% yield. H
NMR (300 MHz, CDCl ): δ 8.17 (dd, J = 7.7, 1.3 Hz, 1H), 8.11 (dd,
A solution of methyltriphenylphosphonium bromide (36 mmol, 12.9
3
t
g) in 55 mL of anhydrous THF was cooled to 0 °C, KO Bu (36 mmol,
J = 7.6, 1.4 Hz, 1H), 7.78 (td, J = 7.6, 1.4 Hz, 1H), 7.68 (td, J = 7.5,
1.4 Hz, 1H), 7.63 (br, 1H), 7.49−7.45 (m, 1H), 7.20−6.96 (m, 6H),
6.85−6.77 (m, 2H), 4.33 (dd, J = 9.8, 4.5 Hz, 1H), 3.38−3.26 (m,
1
.2 equiv, 4.0 g) was added, and the mixture was stirred for 30 min.
After that, a solution of corresponding aldehyde (30 mmol, 1 equiv, in
1 mL of THF) was prepared and added dropwise into the mixture
1
3
1
2
1H), 2.89−2.72 (m, 1H). C{ H} NMR (75 MHz, CDCl ): δ 184.4,
3
above 0 °C. The mixture was allowed to warm to room temperature
and was stirred overnight. After the reaction was complete, THF was
removed under vacuum and 10 mL of ethyl acetate was added to the
residue followed by dilution with 100 mL of petroleum ether. The
mixture was filtered, the filtrate was concentrated with a rotavapor,
and the residue was purified by column chromatography to get the
desired product.
182.1, 144.8, 138.9, 136.3, 134.6, 134.3, 133.3, 132.2, 130.3, 129.7,
129.0, 128.7, 127.8, 126.3, 126.1 (q, J = 276.6 Hz), 126.0, 125.3,
1
9
1
123.1, 122.6, 116.7, 36.4 (q, J = 3.1 Hz), 34.8 (q, J = 26.8); F{ H}
NMR (282 MHz, CDCl ): δ = −64.4. HRMS calcd for
3
+
C H ClF NO [M + H] : 456.0973, found: 456.0972.
2
5
18
3
2
2-(1-(3-Chlorophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)-
1
naphthalene-1,4-dione (4af). Red solid, 70.2 mg, 77% yield. H
NMR (300 MHz, CDCl
Difunctionalization and Characterization of Alkenes. To a
dried Schlenk tube were added 2-hydroxy- or 2-aminoquinone (1,
3
) δ 8.13−8.08 (m, 2H), 7.77 (td, J = 7.6, 1.4
Hz, 1H), 7.67 (td, J = 7.6, 1.4 Hz, 1H), 7.61 (br, 1H), 7.21−7.11 (m,
0
.22 mmol, 1.1 equiv), Togni reagent (3, 0.22 mmol, 1.1 equiv, 69.5
5H), 7.07−6.91 (m, 4H), 4.08 (td, J = 6.9 Hz, 1H), 3.25−3.03 (m,
1
3
1
mg), silver acetate (0.02 mol, 0.1 equiv, 3.3 mg), and DPPF (0.02
mmol, 0.1 equiv, 11.1 mg). The tube was then sealed and backfilled
with argon, followed by addition of a solution of alkene (2, 0.2 mmol,
1H), 3.03−2.77 (m, 1H). C{ H} NMR (75 MHz, CDCl ): δ 183.7,
3
182.2, 144.3, 142.0, 139.4, 134.6, 133.6, 133.2, 132.3, 129.5, 129.1,
129.0, 128.0, 126.4, 126.3, 126.1 (q, J = 276.1), 126.0, 125.9, 124.0,
1
9
1
1
equiv, in 1 mL of 1,2-dichloroethane or DMF) with a syringe. The
117.9, 37.2 (q, J = 27.4 Hz), 37.1 (q, J = 3.1 Hz); F{ H} NMR (282
MHz, CDCl ): δ = −64.3. HRMS calcd for C25 NO [M +
H] : 456.0973, found: 456.0971.
tube was placed in an oil bath and stirred at 75 °C for 12 h. After
completion, volatiles were removed under vacuum, and the residues
were purified on a silica flash column with AcOEt/hexane eluents
3
H
18ClF
3
2
+
2-(1-(4-Chlorophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)-
1
(
AcOEt/hexane = 1:20 to 1:10) to obtain the final product.
naphthalene-1,4-dione (4ag). Red solid, 70.2 mg, 77% yield. H
Compound 4ka was purified on a silica flash column with AcOEt/
DCM eluents (AcOEt/DCM = 1:2).
NMR (300 MHz, CDCl ) δ 8.11−8.07 (m, 2H), 7.75 (td, J = 7.6, 1.4
3
Hz, 1H), 7.68−7.62 (m, 2H), 7.25−7.09 (m, 5H), 7.08−6.93 (m,
13 1
2
-(Phenylamino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)-
4H), 4.09 (t, J = 7.0 Hz, 1H), 3.19−2.82 (m, 2H). C{ H} NMR (75
1
naphthalene-1,4-dione (4aa). Red solid, 69.7 mg, 80% yield. H
MHz, CDCl ): δ 183.7, 182.2, 144.0, 139.5, 138.5, 134.6, 133.2,
3
E
DOI: 10.1021/acs.joc.8b02997
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
32.3, 132.0, 129.5, 129.2, 129.1, 127.9, 126.2, 126.1 (q, J = 276.3
143.5, 142.9, 139.4, 134.6, 133.2, 132.2, 129.6, 129.2, 126.2, 126.1,
Hz), 126.0, 125.9, 123.8, 118.3, 37.5 (q, J = 27.1 Hz), 36.7 (q, J = 3.0
126.0, 125.9 (q, J = 276.2 Hz), 125.7, 125.4, 124.3, 124.1, 117.9, 38.7
Hz); 19F{ H} NMR (282 MHz, CDCl ): δ = −64.3. HRMS calcd for
1
(q, J = 27.1 Hz), 33.0 (q, J = 3.1 Hz); F{ H} NMR (282 MHz,
19
1
3
+
+
C H ClF NO [M + H] : 456.0973, found: 456.0977.
CDCl ): δ = −64.4. HRMS calcd for C H F NO S [M + H] :
25
18
3
2
3
23 17
3
2
2
-(1-(4-Bromophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)-
428.0927, found: 428.0931.
1
naphthalene-1,4-dione (4ah). Red solid, 81.0 mg, 81% yield. H
2-(Phenylamino)-3-(1,1,1-trifluoro-5-phenylpentan-3-yl)-
1
NMR (300 MHz, CDCl ) δ 8.11−8.07 (m, 2H), 7.76 (td, J = 7.5, 1.5
naphthalene-1,4-dione (4an). Red solid, 68.3 mg, 76% yield. H
3
Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.62 (br, 1H), 7.35−7.27 (m,
NMR (300 MHz, CDCl ) δ 8.10−8.05 (m, 2H), 7.74 (td, J = 7.5, 1.4
3
2
4
H), 7.25−7.12 (m, 3H), 7.09−7.00 (m, 2H), 6.98−6.90 (m, 2H),
Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.43−7.35 (m, 3H), 7.32−
7.19 (m, 3H), 7.19−7.09 (m, 3H), 7.09−7.01 (m, 2H), 2.84−2.14
1
3
1
.06 (t, J = 7.0 Hz, 1H), 3.20−2.80 (m, 2H). C{ H} NMR (75
1
3
1
MHz, CDCl ): δ 183.7, 182.2, 144.0, 139.5, 139.0, 134.6, 133.2,
(m, 5H), 2.02−1.81 (m, 2H). C{ H} NMR (75 MHz, CDCl ): δ
3
3
1
1
3
32.3, 130.9, 129.5, 129.5, 129.2, 126.2, 126.1 (q, J = 276.3 Hz),
183.8, 182.3, 144.2, 141.2, 140.7, 134.4, 133.3, 132.1, 129.7, 129.3,
26.0, 125.9, 123.8, 120.1, 118.2, 37.1 (q, J = 27.1 Hz), 36.8 (q, J =
128.0, 127.9, 126.6 (q, J = 275.8 Hz), 125.9, 125.7, 125.5, 123.9,
.1 Hz); 19F{ H} NMR (282 MHz, CDCl ): δ = −64.3. HRMS calcd
1
19
1
121.0, 35.4 (q, J = 26.9 Hz), 33.9, 33.6, 32.3 (q, J = 2.7 Hz); F{ H}
NMR (282 MHz, CDCl ): δ = −63.9. HRMS calcd for
3
+
for C H BrF NO [M + H] : 500.0468, found: 500.0462.
3
25
18
3
2
+
2
-(Phenylamino)-3-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)-
C
27
H
22
F
3
NO
2
Na[M + Na] : 472.1495, found: 472.1491.
1
naphthalene-1,4-dione (4ai). Red solid, 66.8 mg, 76% yield. H
NMR (300 MHz, CDCl ) δ 8.12−8.07 (m, 2H), 7.76 (td, J = 7.6, 1.4
Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.59 (br, 1H), 7.25−7.10 (m,
2-(Phenylamino)-3-(2-(trifluoromethyl)-2,3-dihydro-1H-inden-1-
1
yl)naphthalene-1,4-dione (4ao). Red solid, 64.1 mg, 74% yield. H
3
NMR (300 MHz, CDCl ): δ 8.16−8.06 (m, 1H), 8.01−7.92 (m, 1H),
3
3
1
1
1
H), 7.08−6.97 (m, 4H), 6.91−6.80 (m, 2H), 4.10 (t, J = 7.0 Hz,
7.73−7.62 (m, 2H), 7.59 (br, 1H), 7.32−7.11 (m, 8H), 7.07−6.95
(m, 1H), 4.47 (d, J = 8.5 Hz, 1H), 3.55−3.43 (m, 1H), 3.36−3.27 (m,
1
3
1
H), 3.22−2.81 (m, 2H). C{ H} NMR (75 MHz, CDCl ): δ 183.8,
3
1
3
1
82.2, 161.2 (d, J = 243.7 Hz), 143.9, 139.6, 135.6 (d, J = 3.2 Hz),
34.6, 133.2, 132.3, 129.6, 129.3 (d, J = 7.9 Hz), 129.1, 126.2, 126.1
1H), 2.99−2.91 (m, 1H). C{ H} NMR (75 MHz, CDCl ): δ 182.6,
3
182.2, 144.9, 142.8, 139.5, 139.4, 134.5, 133.2, 132.1, 129.8, 129.1,
127.6 (q, J = 275.9 Hz), 126.4, 126.4, 126.1, 126.0, 124.3, 124.2,
122.3, 47.8 (q, J = 26.2 Hz), 42.9 (q, J = 2.5 Hz), 32.0 (q, J = 2.8 Hz);
(
q, J = 276.1 Hz), 126.0, 125.8, 123.7, 118.8, 114.6 (d, J = 21.1 Hz),
1
9
1
3
7.4 (q, J = 27.1 Hz), 36.7 (q, J = 3.1 Hz); F{ H} NMR (282 MHz,
1
9
1
CDCl ): δ = −64.3, −116.4. HRMS calcd for C H F NO [M +
H] : 440.1268, found: 440.1267.
F{ H} NMR (282 MHz, CDCl
3
): δ = −70.2. HRMS calcd for
3
25 18
4
2
+
C H F NO [M + H]: 434.1362, found: 434.1359.
2
6
19
3
2
2
-(Phenylamino)-3-(3,3,3-trifluoro-1-(4-(trifluoromethyl)phenyl)-
2-(Phenylamino)-3-(2-(trifluoromethyl)cyclohexyl)naphthalene-
1
propyl)naphthalene-1,4-dione (4aj). Red solid, 71.5 mg, 73% yield.
1,4-dione (4ap). Red solid, 55.1 mg, 69% yield. H NMR (300 MHz,
CDCl ): δ8.08−8.04 (m, 2H), 7.72 (td, J = 7.6, 1.4 Hz, 1H), 7.63 (td,
1
H NMR (300 MHz, CDCl ) δ 8.10 (dd, J = 7.6, 1.4 Hz, 2H), 7.77
3
3
(
td, J = 7.5, 1.4 Hz, 1H), 7.71−7.58 (m, 2H), 7.45−7.42 (m, 2H),
J = 7.5, 1.4 Hz, 1H), 7.51−7.31 (m, 3H), 7.31−7.21 (m, 1H), 7.19−
7.16 (m, 2H), 3.13−2.88 (m, 1H), 2.31−2.23 (m, 1H), 2.06 (qd, J =
13.1, 3.6 Hz, 1H), 1.91−1.82 (m, 1H), 1.65−1.48 (m, 3H), 1.37−
1.17 (m, 1H), 0.77 (qd, J = 13.0, 3.6 Hz, 1H), 0.39 (qt, J = 12.9, 4.0
7
3
1
.24−7.10 (m, 5H), 7.05−7.02 (m, 2H), 4.15 (t, J = 7.0 Hz, 1H),
1
3
1
.15−2.94 (m, 2H). C{ H} NMR (75 MHz, CDCl ): δ 183.7,
3
82.1, 144.3, 144.1, 139.4, 134.7, 133.2, 132.3, 129.5, 129.2, 128.5 (q,
1
3
1
J = 32.3 Hz), 128.0, 126.2, 126.1, 126.1 (q, J = 276.1 Hz), 124.7 (q, J
3.7 Hz), 123.9, 123.8 (q, J = 270.2 Hz), 117.6, 37.1 (q, J = 3.0 Hz),
7.1 (q, J = 27.5 Hz); F{ H} NMR (282 MHz, CDCl ): δ = −64.5,
64.3. HRMS calcd for C H F NO [M + H] : 490.1236, found:
Hz, 1H). C{ H} NMR (75 MHz, CDCl ): δ 184.1, 182.5, 143.3,
3
=
3
−
4
140.7, 134.2, 133.4, 131.9, 129.7, 128.9, 125.7 (q, J = 279.0 Hz),
125.8, 125.8, 125.8, 124.5, 120.7, 42.7 (q, J = 23.5 Hz), 36.9 (q, J =
1
9
1
3
+
19
1
1.8 Hz), 28.2, 25.7 (q, J = 3.1 Hz), 25.4, 24.1. F{ H} NMR (282
MHz, CDCl ): δ = −69.6. HRMS calcd for C23 NO [M + H]:
400.1519, found: 400.1517.
2
6
18
6
2
90.1239.
2
3
H
F
21
3
2
-(Phenylamino)-3-(3,3,3-trifluoro-1-(naphthalen-1-yl)propyl)-
1
naphthalene-1,4-dione (4ak). Red solid, 63.2 mg, 67% yield. H
2-((2-Methoxyphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)-
propyl)naphthalene-1,4-dione (4ba). Red solid, 68.9 mg, 74% yield.
NMR (300 MHz, CDCl ) δ 8.22 (dd, J = 7.8, 1.3 Hz, 1H), 8.11 (dd, J
3
1
=
7
(
2
1
1
1
2
7.7, 1.4 Hz, 1H), 7.90−7.62 (m, 4H), 7.62−7.47 (m, 2H), 7.47−
H NMR (300 MHz, DMSO-d ): δ 8.41 (s, 1H), 7.92−7.85 (m, 2H),
6
.31 (m, 2H), 7.31−7.16 (m, 2H), 6.81−6.70 (m, 2H), 6.70−6.52
7.77 (td, J = 7.5, 1.6 Hz, 1H), 7.70 (td, J = 7.4, 1.5 Hz, 1H), 7.15−
7.07 (m, 4H), 7.06−6.96 (m, 2H), 6.96−6.80 (m, 2H), 4.38 (t, J =
m, 3H), 4.88 (dd, J = 10.2, 3.9 Hz, 1H), 3.72−3.44 (m, 1H), 2.86−
.68 (m, 1H). 13C{ H} NMR (75 MHz, CDCl ): δ 184.6, 182.2,
1
13
1
7.2 Hz, 1H), 3.54 (s, 3H), 3.26−3.02 (m, 2H), 2.20 (s, 3H). C{ H}
3
44.6, 139.0, 134.8, 134.5, 133.4, 133.4, 132.2, 130.9, 129.7, 128.4,
28.3, 127.5, 126.4 (q, J = 276.5 Hz), 126.3, 126.1, 126.0, 125.7,
24.9, 124.8, 123.1, 122.0, 118.6, 35.9 (q, J = 26.4 Hz), 34.8 (q, J =
NMR (75 MHz, DMSO-d ): δ 182.6, 181.6, 152.1, 146.8, 137.8,
6
135.3, 134.5, 132.8, 132.8, 130.7, 130.2, 128.7, 127.6, 127.2 (q, J =
276.2 Hz), 125.9, 125.7, 125.6, 124.7, 120.7, 119.4, 112.1, 55.5, 35.6
.9 Hz); 19F{ H} NMR (282 MHz, CDCl ): δ = −64.4. HRMS calcd
1
19
1
(q, J = 25.9 Hz), 34.8 (q, J = 2.1 Hz), 20.6; F{ H} NMR (282 MHz,
DMSO-d ): δ = −62.6. HRMS calcd for C27 NO [M + H]:
466.1625, found: 466.1622.
3
+
for C H F NO [M + H] : 472.1519, found: 472.1512.
6
H
23
F
3
3
29
21
3
2
2
-(Phenylamino)-3-(3,3,3-trifluoro-1-(pyridin-2-yl)propyl)-
1
naphthalene-1,4-dione (4al). Red solid, 51.5 mg, 61% yield. H
2-((3-Methoxyphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)-
propyl)naphthalene-1,4-dione (4ca). Red solid, 69.8 mg, 75% yield.
NMR (300 MHz, CDCl ) δ 10.4 (br, 1H), 8.58−8.56 (m, 1H), 8.14−
3
1
8
(
7
3
1
1
1
.11 (m, 1H), 7.94 (dd, J = 7.6, 1.4 Hz, 1H), 7.73−7.59 (m, 3H), 7.45
H NMR (300 MHz, CDCl ): δ 8.12−8.06 (m, 2H), 7.74 (td, J = 7.5,
3
d, J = 7.8 Hz, 1H), 7.36−7.20 (m, 4H), 7.11 (t, J = 7.4 Hz, 1H),
1.6 Hz, 1H), 7.65 (td, J = 7.4, 1.5 Hz, 1H), 7.48 (br, 1H), 7.14 (t, J =
8.1 Hz, 1H), 7.00 (s, 4H), 6.71−6.65 (m, 2H), 6.49 (t, J = 2.4 Hz,
1H), 4.16 (t, J = 7.2 Hz, 1H), 3.56 (s, 3H), 3.16−2.95 (m, 2H), 2.27
.01−6.98 (m, 2H), 5.25 (t, J = 7.0 Hz, 1H), 3.32−3.05 (m, 1H),
1
3
1
.05−2.78 (m, 1H). C{ H} NMR (75 MHz, CDCl ): δ 182.2,
3
1
3
1
81.4, 159.8, 148.0, 145.4, 141.6, 137.7, 133.7, 132.4, 132.0, 131.6,
(s, 3H). C{ H} NMR (75 MHz, CDCl ): δ 183.8, 182.3, 160.1,
3
28.8, 126.4 (q, J = 275.5 Hz), 126.1, 126.0, 123.6, 123.4, 122.3,
21.2, 36.5 (q, J = 2.3 Hz), 34.7 (q, J = 27.9 Hz); F{ H} NMR (282
MHz, CDCl ): δ = −64.6.HRMS calcd for C H F N O [M + H] :
23.1315, found: 423.1317.
143.7, 140.9, 136.8, 135.8, 134.4, 133.2, 132.1, 129.8, 129.7, 128.6,
1
9
1
127.6, 126.3 (q, J = 276.2 Hz), 126.2, 125.9, 120.0, 115.7, 111.5,
+
19
1
109.0, 54.7, 37.2 (q, J = 27 Hz), 36.8 (q, J = 2.8 Hz), 20.6; F{ H}
NMR (282 MHz, CDCl ): δ = −64.3. HRMS calcd for C27 NO
[M + H]: 466.1625, found: 466.1623.
3
24 18
3
2
2
4
3
H
23
F
3
3
2
-(Phenylamino)-3-(3,3,3-trifluoro-1-(thiophen-2-yl)propyl)-
1
naphthalene-1,4-dione (4am). Red solid, 62.4 mg, 73% yield. H
2-((4-Methoxyphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)-
propyl)naphthalene-1,4-dione (4da). Red solid, 57.7 mg, 62% yield.
NMR (300 MHz, CDCl ) δ 8.14−8.08 (m, 2H), 7.76 (td, J = 7.6, 1.5
3
1
Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.61 (br, 1H), 7.33−7.16 (m,
H NMR (300 MHz, DMSO-d ): δ 8.71 (s, 1H), 7.98−7.88 (m, 2H),
6
3
3
2
H), 7.16−7.07 (m, 3H), 6.83 (dd, J = 5.2, 3.5 Hz, 1H), 6.52 (dt, J =
7.79 (td, J = 7.5, 1.5 Hz, 1H), 7.71 (td, J = 7.4, 1.5 Hz, 1H), 7.09−
6.97 (m, 7H), 6.80−6.71 (m, 2H), 4.18 (t, J = 7.2 Hz, 1H), 3.67 (s,
.5, 1.1 Hz, 1H), 4.37 (t, J = 6.9 Hz, 1H), 3.25−3.07 (m, 1H), 2.97−
.79 (m, 1H). 13C { H}NMR (75 MHz, CDCl ): δ 183.3, 182.3,
1
3H), 3.29−3.13 (m, 1H), 3.08−2.96 (m, 1H), 2.20 (s, 3H). C{ H}
13
1
3
F
DOI: 10.1021/acs.joc.8b02997
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NMR (75 MHz, DMSO-d ): δ 182.9, 182.4, 156.7, 145.9, 137.7,
7.72 (pd, J = 7.4, 1.6 Hz, 2H), 7.25−7.18 (m, 4H), 7.06 (d, J = 7.8
Hz, 2H), 6.87 (t, J = 7.5 Hz, 1H), 6.76−6.60 (m, 2H), 4.78 (dd, J =
9.4, 5.6 Hz, 1H), 3.56−3.37 (m, 1H), 3.14 (s, 3H), 3.05−2.79 (m,
6
1
35.3, 134.8, 134.3, 133.0, 132.8, 130.4, 128.6, 127.7, 127.1 (q, J =
76.4 Hz), 125.9, 125.7, 125.2, 119.5, 114.2, 55.4, 35.6 (q, J = 25.3
2
1
9
1
13
1
Hz), 35.7 (q, J = 2.6 Hz), 20.6; F{ H} NMR (282 MHz, DMSO-
d ): δ = −62.4. HRMS calcd for C H F NO [M + H]: 466.1625,
1H), 2.29 (s, 3H). C{ H} NMR (75 MHz, CDCl ): δ 185.6, 181.5,
3
150.1, 147.9, 146.0, 136.6, 135.7, 133.6, 133.5, 132.2, 131.4, 129.0,
6
27 23
3
3
found: 466.1621.
128.8, 128.4, 126.3, 126.3 (q, J = 275.8 Hz), 126.2, 119.3, 114.0, 39.4,
1
9
1
2
-((4-Methylphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)-
38.1 (q, J = 3.1 Hz), 36.9 (q, J = 27.2 Hz), 20.6; F{ H} NMR (282
1
+
naphthalene-1,4-dione (4ea). Red solid, 69.2 mg, 77% yield. H
MHz, CDCl ): δ = −64.4. HRMS calcd for C H F NO [M + H] :
3
27 23
3
2
NMR (300 MHz, DMSO-d ): δ 8.76 (s, 1H), 7.91 (dt, J = 7.7, 1.8 Hz,
450.1675, found: 450.1675.
6
H), 7.79 (td, J = 7.5, 1.5 Hz, 1H), 7.18−7.07 (m, 2H), 7.06−6.92
2-Hydroxy-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-
1
dione (4ka). Red solid, 48.3 mg, 67% yield. H NMR (300 MHz,
1
3
1
H), 2.21 (s, 3H), 2.19 (s, 3H). C{ H} NMR (75 MHz, DMSO-
CDCl ): δ 8.11 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.73 (t, J
3
= 7.4 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.11
(d, J = 7.7 Hz, 2H), 4.87 (dd, J = 9.8, 5.2 Hz, 1H), 3.60−3.35 (m,
32.9, 130.6, 129.4, 128.7, 127.7, 127.1 (q, J = 276.1 Hz), 125.9,
1
3
1
25.7, 123.0, 121.6, 35.8 (q, J = 2.8 Hz), 35.4 (q, J = 26.2 Hz), 20.6,
1H), 3.03−2.80 (m, 1H), 2.30 (s, 3H). C{ H} NMR (75 MHz,
1
CDCl
129.0, 128.8, 127.7, 126.7, 126.5 (q, J = 275.8 Hz), 125.8, 123.1, 35.4
): δ 183.5, 181.5, 152.9, 137.3, 136.4, 134.9, 132.7, 132.5,
6
3
+
27
23
3
2
1
9
1
2
-((4-Chlorophenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)-
(q, J = 27.5 Hz), 34.0 (q, J = 3.1 Hz), 20.6; F{ H} NMR (282 MHz,
+
1
CDCl
): δ = −64.8. HRMS calcd for C20H F O [M + H] :
16 3 3
3
361.1046, found: 361.1048.
3
Scale-up Synthesis of Compound 4ga. To a dried Schlenk tube
were added 2-aminoquinone 1g (1.1 mmol, 1,1 equiv, 348.9 mg),
Togni reagent (3, 1.1 mmol, 1.1 equiv, 347.8 mg), silver acetate (0.1
mol, 0.1 equiv, 16.7 mg), and DPPF (0.1 mmol, 0.1 equiv, 55.4 mg).
The tube was then sealed and backfilled with argon, followed by
addition of a solution of alkene 2a (1.0 mmol, 1 equiv, 129.8 mg in 5
mL of DMF) with a syringe. The tube was placed in an oil bath and
stirred at 75 °C for 12 h. After completion, volatiles were removed
under vacuum, and the residues were purified on a silica flash column
with AcOEt/hexane eluent (AcOEt/hexane = 15:1), affording 312 mg
of compound 4ga in 71% yield.
H), 7.06−6.86 (m, 6H), 4.10 (t, J = 7.0 Hz, 1H), 3.30−3.03 (m,
13 1
3
32.3, 130.7, 129.7, 129.0, 128.7, 127.4, 126.6 (q, J = 277.2 Hz),
26.3, 126.0, 124.4, 120.8, 37.2 (q, J = 27.1 Hz), 37.0 (q, J = 2.8 Hz),
0.6; 19F{ H} NMR (282 MHz, CDCl ): δ = −64.3. HRMS calcd for
1
3
26
19
3
2
2
-((4-Trifluoromethylphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)-
6
.87−7.68 (m, 2H), 7.57−7.42 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.2
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02997.
■
7.2 Hz, 1H), 3.48−3.34 (m, 1H), 3.24−3.04 (m, 1H), 2.19 (s, 3H).
*
S
1
C{ H} NMR (75 MHz, DMSO-d ): δ 183.5, 181.6, 147.0, 144.7,
6
36.9, 135.7, 134.6, 133.5, 132.4, 131.0, 130.3, 128.8, 127.7, 127.1 (q,
Reaction conditions optimization, copies of single
6.8 Hz), 20.6; 19F{ H} NMR (282 MHz, DMSO-d ): δ = −60.1;
1
crystallographic data for 4aa, and characterization data
6
1
13
19
62.6. HRMS calcd for C H F NO [M + H]: 504.1393, found:
( H, C, and F NMR) (PDF)
2
7
20
6
2
04.1392.
Crystallographic data for 4aa (CIF)
2
-((2,4,6-Trimethylphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)-
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhangc9711@cau.edu.cn or cheunggilbert@gmail.
com.
■
3
.5, 1.4 Hz, 1H), 7.33 (s, 1H), 6.98−6.85 (m, 3H), 6.75−6.65 (m,
H), 6.59−6.51 (m, 1H), 3.90 (t, J = 7.0 Hz, 1H), 3.32−3.12 (m,
1
3
1
ORCID
3
Hongchao Guo: 0000-0002-7356-4283
Cheng Zhang: 0000-0002-8760-8152
Author Contributions
These authors contributed equally.
Notes
34.9, 134.5, 133.8, 133.6, 131.8, 129.6, 129.1, 128.7, 128.1, 127.9,
26.3 (q, J = 276.3 Hz), 126.1, 125.8, 115.9, 39.0 (q, J = 26.5 Hz),
1
9
1
6.5 (q, J = 3.1 Hz), 20.6, 20.5, 18.0, 17.8; F{ H} NMR (282 MHz,
†
3
29 27
3
2
78.1988, found: 478.1985.
2
-Hexylamino-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-
1
The authors declare no competing financial interest.
,4-dione (4ia). Red solid, 67.4 mg, 76% yield. H NMR (300 MHz,
CDCl ): δ 8.02 (td, J = 7.4, 6.9, 1.4 Hz, 2H), 7.68 (td, J = 7.5, 1.5 Hz,
3
ACKNOWLEDGMENTS
H), 7.58 (td, J = 7.5, 1.4 Hz, 1H), 7.33−7.20 (m, 2H), 7.17−7.05
■
We are grateful to the National Key Research and Develop-
ment Plan of China (2017YFD0200504). This work is also
partly supported by the Start-Up Funds from CAU. Support
from College of Science (CAU) is also gratefully acknowl-
edged.
3
.61−3.28 (m, 3H), 3.16−2.90 (m, 1H), 2.31 (s, 3H), 1.75−1.56 (m,
13 1
2
H), 1.41−1.18 (m, 6H), 0.89 (t, J = 6.6 Hz, 3H). C{ H} NMR (75
MHz, CDCl ): δ 182.7, 182.4, 146.2, 138.8, 135.8, 134.3, 133.4,
3
1
1
2
31.6, 129.8, 128.9, 126.9, 126.9 (q, J = 275.8 Hz), 125.9, 125.7,
14.9, 46.1, 36.6 (q, J = 26.6 Hz), 35.7 (q, J = 2.7 Hz), 30.9, 30.3,
1
9
1
5.9, 22.1, 20.6, 13.6; F{ H} NMR (282 MHz, CDCl ): δ = −64.1.
3
+
REFERENCES
HRMS calcd for C H F NO [M + H] : 444.2145, found:
■
2
6
29
3
2
4
44.2146.
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DOI: 10.1021/acs.joc.8b02997
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