Scissoring Enaminone C=C Double Bond by Free Radical Process for the Synthesis of α-Trifluoromethyl Ketones with CF3SO2Na

Article abstract of DOI:10.1021/acs.joc.0c02431

The C=C double bond cleavage on tertiary enaminones, enabling the formation of a new C-CF3 bond, has been realized as a practical method for the synthesis of α-trifluoromethyl ketones with only the promotion of TBHP and ambient heating. Control experiments support that the reactions proceed via a featured free radical process. The deuterium labeling experiment employing D2O indicates that water participated in the product formation by donating the hydrogen atom for the newly generated α-C-H bond in the product.

Full text of DOI:10.1021/acs.joc.0c02431

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Note
Scissoring Enaminone CC Double Bond by Free Radical Process
for the Synthesis of α‑Trifluoromethyl Ketones with CF3SO2Na
Lu Gan, Qing Yu, Yunyun Liu, and Jie-Ping Wan*
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ABSTRACT: The CC double bond cleavage on tertiary enaminones, enabling the formation of a new C−CF3 bond, has been
realized as a practical method for the synthesis of α-trifluoromethyl ketones with only the promotion of TBHP and ambient heating.
Control experiments support that the reactions proceed via a featured free radical process. The deuterium labeling experiment
employing D2O indicates that water participated in the product formation by donating the hydrogen atom for the newly generated
α-C−H bond in the product.
are yet desirable to develop a complementary method for the
synthesis of α-trifluoromethyl ketones.
he trifluoromethyl group is a well-documented moiety
Tthat is capable of providing new biological functions or
enhancing the bioactivity of organic molecules, which finds
widespread application in the discovery of pharmaceuticals and
lead compounds.1 Owing to the scarce availability of
trifluoromethyl in the natural world, the synthesis of CF3-
functionalized molecules via a trifluoromethylation reaction
thus constitutes the predominant tool to access trifluorometh-
yl-functionalized organic compounds.2 Under the driving force
of the high application potential and promise of trifluor-
omethyl compounds, a great number of different trifluor-
omethyl-functionalized products have been synthesized over
the past decades.3 Among the numerous trifluoromethyl
compounds reported in the literature, the α-trifluoromethyl
ketones are inarguably a class of highly important and useful
compounds for not only the versatile biological profiles
associated with them but also their distinctive utilities in the
synthesis of other diverse trifluoromethylated molecules by
acting as the key building blocks.4 Typically, the trifluor-
omethylation of activated ketones such as silyl enol ethers,5
enol acetates/triflates,6 α-haloketones,7 and α-ketocarboxylic
acids8 has been proven to be applicable methods for α-
trifluoromethyl ketone synthesis. In addition, the direct C−H
trifluoromethylation of methyl ketones9 and the difunctional-
ization of alkynes,10 alkenes,11 or their functionalized
derivatives12 have also been developed. Generally, the
employment of a noble metal catalyst or expensive or sensitive
trifluoromethyl reagent and/or the requirement of prior
functionalization to activate the ketone substrates are yet the
restrictions in known methods, which implies that more efforts
As easily available and highly useful organic substrates,
enaminones have in recent years exhibited widespread
applications in organic synthesis.13 Particularly, the featured
CC double bond cleavage of enaminones has been identified
as a powerful tool toward the synthesis of structurally diverse
products. Under proper reaction conditions, such CC
double bond cleavage takes place via different pathways and
leads to the synthesis of α-aminoesters,14 1,2-diketones,15 α-
ketoamides/thioamides/ketoesters,16 carbamoyl-functionalized
enaminones,17 amidines, and diazoketones18 as well as ketones
bearing various heteroatom functional structures.19 With the
encouragement for these successful examples on the diverse
products initiated by the enaminone CC bond cleavage as
well as our longstanding interest in enaminone chemistry, we
envisage that a new method for the synthesis of α-
trifluoromethyl ketones by employing enaminone CC
double bond functionalization should be feasible. Herein, we
report our recent results on the α-trifluoromethyl ketone
synthesis via the TBHP-promoted reactions of N,N-dimethy-
lenaminones with cheap CF3SO2Na as the trifluoromethyl
Received: October 14, 2020
https://dx.doi.org/10.1021/acs.joc.0c02431
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

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Note
source by stirring at 35 °C without employing any transition
metal reagent.
To start the synthetic investigation, the reaction of p-
bromophenyl-functionalized enaminone 1a and CF3SO2Na 2a
was conducted under a variety of different conditions (Table
1). Whereas the employment of TBHP (2 equiv) in DMSO
ing products with a yield (3b and 3c, Table 2) generally lower
than that of equivalent reactions using electron withdrawing
group functionalized phenyl enaminones. The electron with-
drawing effect in the phenyl of enaminones might enhance the
addition selectivity of the electrophilic CF3 free radical to the
nucleophilic enaminone α-site (see Scheme 1) by making the
electron in the CC double bond more polar, which
improved product yield from related entries. In addition, the
enaminones featured with monosubstituted phenyl at the meta-
site (3l−3p, Table 2) and the disubstituted (3q−3t, Table 2)
and trisubstituted (3u, Table 2) phenyls were also utilized as
substrates for the practical synthesis of related α-trifluor-
omethyl ketones with moderate to good yields. Furthermore,
the fused aryl, such as naphthyl-functionalized enaminone (3v,
Table 2) and heteroaryl-functionalized enaminone (3w, Table
2), was also well tolerated, indicating the general applicability
of this method for the titled transformation on aryl-
functionalized enaminones. More notably, the enaminone
derived from the natural product progesterone was also
successfully transformed into corresponding α-trifluoromethyl
progesterone with this method (3x, Table 2), further
demonstrating the important application of the present
protocol. The reaction using a methyl-based enaminone
(Table 2, R3 = Me) and CF3SO2Na did not provide a
corresponding product. As additional efforts, the reactions of
enaminones containing a methyl substituent at the α- or β-site
with 2a were also run, but the expected trifluoromethylation
was not observed in both entries (Table 2). Furthermore,
performing the model experiment at the scale of 4 mmol 1a
gave product 3a in 38% yield. In the synthesized products, 3j,
3p, 3r−3u, and 3x were new compounds which had not been
previously reported in other synthetic methods.
a
Table 1. Optimization of Reaction Conditions
b
entry
variation
yield (%)
1
2
3
no
36
20
trace
0
DTBP as oxidant
H2O2 as oxidant
PhI(OAc)2 as oxidant
4
5
K2S2O8 as oxidant
0
6
no oxidant
0
7
8
DMF as medium
toluene as medium
25
0
9
1,4-dioxane as medium
0
10
11
12
13
14
15
16
17
18
19
MeCN as medium
with 1 equiv of TBHP
with 1.5 equiv of TBHP
1.5 equiv of TBHP, 16 h
1.5 equiv of TBHP, 22 h
1.5 equiv of TBHP, 16 h, 60 °C
1.5 equiv of TBHP, 16 h, 35 °C
1.5 equiv of TBHP, 16 h, 35 °C, 0.2 mmol 2a
1.5 equiv of TBHP, 16 h, 35 °C, 0.6 mmol 2a
1.5 equiv of TBHP, 16 h, 35 °C, 0.8 mmol 2a
0
38
41
43
38
44
58
49
70
57
Following the work on the synthesis of different α-
trifluoromethyl ketones, an array of control experiments were
then conducted. At first, the model reaction was performed
under the standard conditions in the presence of additionally
employed free radical scavenger. In the reactions independ-
ently employing TEMPO and BHT, no target product (eqs 1
a
General conditions: 1a (0.2 mmol), 2a (0.4 mmol), oxidant (0.4
b
mmol) in 2 mL of solvent and stirred at 80 °C for 12 h. Isolated
yield.
and 80 °C heating gave product 3a in 36% yield (entry 1,
Table 1), the variation on oxidant species (entries 2−5, Table
1) and oxidant-free (entry 6, Table 1) operation proved that
TBHP was the most proper oxidant. In addition, altering the
reaction medium to DMF, toluene, dioxane, or MeCN led to
no observation of better medium (entries 7−10, Table 1). An
improved result was obtained by varying the TBHP loading to
1.5 equiv (entries 11 and 12, Table 1). Later, slightly increasing
the reaction time (entries 13 and 14, Table 1) and modifying
the reaction temperature to 35 °C (entries 15 and 16, Table 1)
gave further enhanced product yield. Finally, when the loading
of substrate 2a was utilized at 3 equiv, the yield of 3a was
increased to 70% (entries 17−19, Table 1).
Following the efforts at optimizing the reaction conditions,
we then turned to investigate the application scope of this
synthetic method toward different α-trifluoromethyl ketones.
According to the results from this section, this CC double
bond cleavage protocol was found to be widely applicable in
the synthesis α-trifluoromethyl ketones. For benzene-derived
enaminone substrates, the functional groups of varied proper-
ties, including alkyl, halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxyl, as well as sulfonyl (3a−3t, Table 2) all
displayed fine tolerance to the synthesis. According to the
results given by those enaminones bearing para-substituted
phenyl structure, the unsubstituted and electron donating
group functionalized phenyl enaminones provided correspond-
and 2), demonstrating that key free radical generation and
transformations were involved in the reactions. On the other
hand, when this reaction was conducted under standard
conditions with additionally added D2O (0.3 mL), the α-
deuterium-labeled product 3a-d1 was observed as the only
compound in the chromatography purified sample (eq 3). On
the contrary, stirring product 3a under identical conditions did
not provide, such a deuterium-labeled product, confirming that
water had participated in the reactions forming α-trifluor-
omethyl ketones.
B
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a,b
Table 2. Scope of the Synthesis of α-Trifluoromethyl Ketones
a
b
c
General conditions: 1 (0.2 mmol), 2a (0.6 mmol), TBHP (0.3 mmol), 2 mL of DMSO, 35 °C, 16 h, under air. Isolated yield. The yield from the
reaction of 4 mmol (1.012 g) 1a.
cooperation of this cation with water then leads to the CF3-
functionalized N,O-acetal intermediate C. A typical 1,5-proton
transfer in C takes place to promote the decomposition of the
α,β-C−C bond in this species and yields the CF3-function-
alized enone D accompanied by the release of DMF (see
Supporting Information for the detection of DMF with GC).
The α-trifluoromethyl ketones were provided via enone−
ketone tautomerization.
Scheme 1. Proposed Reaction Mechanism
In conclusion, by means of a free-radical-initiated CC
bond cleavage, we have disclosed a new method for the
synthesis of α-trifluoromethyl ketones via the reactions of N,N-
dimethylenaminones and simple CF3SO2Na. In addition to
enabling the synthesis of highly diverse CF3-functionalized
ketones with this cheap and stable trifluoromethyl source, this
method possesses several additional advantages such as the
transition-metal-free catalysis, tolerance to moisture, and
applicability in the synthesis of deuterium-labeled α-trifluor-
omethyl ketones and CF3-elaborated natural product.
Based on the results given by the control experiments, the
reaction mechanism involving the free radical addition to the
CC double bond and water-assisted C−C bond decom-
position is proposed (Scheme 1). Initially, the reaction of
TBHP and CF3SO2Na provides a CF3 free radical, and this free
radical adds to the CC double bond in enaminones to afford
free radical intermediate A. In the presence of oxidant
(TBHP), this free radical can be oxidized to cation
intermediate B via single electron transfer (SET). The quick
EXPERIMENTAL SECTION
■
General Experimental Information. All experiments were
carried out under air atmosphere. Enaminones 1 were prepared
using methyl ketones via a simple one-step process following a
literature process.20 All other chemicals and solvents used in the
experiments were acquired from commercial sources and used directly
C
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Note
1
without further treatment. The H NMR, 13C NMR, and 19F NMR
H), 3.80 (q, J = 10.0 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ
189.7, 135.8, 134.2, 128.9, 128.3, 124.0 (d, 1JC−F = 275.3 Hz), 42.1 (q,
2JC−F = 28.7 Hz); 19F NMR (376 MHz, CDCl3) δ −62.05.
spectra were recorded on a 400 MHz spectrometer using CDCl3 or
DMSO-d6 as solvent and TMS as the internal standard, and the
chemical shifts are reported in parts per million. High-resolution mass
spectrometry (HRMS) data for all new products were obtained under
ESI model in an apparatus equipped with a TOF analyzer. The
melting points were tested with X-4A apparatus without correcting
the temperature. Thin-layer chromatography was performed on
GF254 plates.
3,3,3-Trifluoro-1-p-tolylpropan-1-one (3c):11e White solid (14
mg, 35% yield); mp 46−47 °C; 1H NMR (400 MHz, CDCl3) δ 7.83
(d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 3.77 (q, J = 10.1 Hz, 2
H), 2.44 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.3, 145.3,
133.4, 129.6, 128.5, 124.1 (d, 1JC−F = 275.2 Hz), 42.0 (q, 2JC−F = 28.2
Hz), 21.7; 19F NMR (376 MHz, CDCl3) δ −62.00.
3,3,3-Trifluoro-1-(4-fluorophenyl)propan-1-one (3d):11c Pale yel-
(E)-1-(4-Chloro-3-nitrophenyl)-3-(dimethylamino)prop-2-en-1-
one (1r): Brown solid (reaction at 10 mmol scale, 57% yield, 1.45 g);
mp 149−150 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.0 Hz,
1 H), 7.98 (dd, J = 8.4, 2.0 Hz, 1 H), 7.81 (d, J = 12.0 Hz, 1 H), 7.51
(d, J = 8.4 Hz, 1 H), 5.56 (d, J = 12.0 Hz, 1 H), 3.14 (s, 3 H), 2.91 (s,
3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.7, 155.1, 141.5,
133.9, 131.7, 131.2, 129.1, 118.7, 112.3, 91.2, 45.3, 37.5; HRMS (ESI)
1
low solid (21 mg, 51% yield); mp 32−33 °C; H NMR (400 MHz,
CDCl3) δ 7.99−7.96 (m, 2 H), 7.19 (t, J = 8.5 Hz, 2 H), 3.78 (q, J =
9.9 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.1, 166.4 (d,
1JC−F = 255.5 Hz), 132.3, 131.1 (d, 3JC−F = 9.5 Hz), 123.9 (q, 1JC−F
275.1 Hz), 116.2 (d, 2JC−F = 20.0 Hz), 42.1 (q, 2JC−F = 28.2 Hz); 19
NMR (376 MHz, CDCl3) δ −62.03, −102.92.
=
F
+
m/z calcd for C11H12ClN2O3 [M + H]+ 255.0531, found 255.0551.
1-(4-Chlorophenyl)-3,3,3-trifluoropropan-1-one (3e):11c Yellow
solid (28 mg, 63% yield); mp 46−47 °C; 1H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 7.6 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 2 H), 3.69 (q,
J = 9.9 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.5, 140.9,
134.1, 129.7, 129.3, 123.8 (d, 1JC−F = 275.2 Hz), 42.1 (q, 2JC−F = 28.4
Hz); 19F NMR (376 MHz, CDCl3) δ −61.98.
(E)-3-(Dimethylamino)-1-(4-methoxy-3-nitrophenyl)prop-2-en-
1-one (1s): Yellow solid (reaction at 10 mmol scale, 65% yield, 1.63
g); mp 173−174 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.0
Hz, 1 H), 8.17 (dd, J = 8.8, 2.0 Hz, 1 H), 7.84 (d, J = 12.0 Hz, 1 H),
7.12 (d, J = 8.8 Hz, 1 H), 5.66 (d, J = 12.0 Hz, 1 H), 4.01 (s, 3 H),
3.18 (s, 3 H), 2.97 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
184.6, 154.8, 139.0, 133.5, 132.8, 125.0, 113.0, 90.7, 56.7, 45.2, 37.5;
HRMS (ESI) m/z calcd for C12H15N2O4+ [M + H]+ 251.1026, found
251.1039.
(E)-3-(Dimethylamino)-1-(3,4,5-trifluorophenyl)prop-2-en-1-one
(1u): Yellow solid (reaction at 10 mmol scale, 62% yield, 1.43 g); mp
125−126 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 12.0 Hz, 1
H), 7.62−7.46 (m, 2 H), 5.57 (d, J = 12.0 Hz, 1 H), 3.19 (s, 3 H),
2.96 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.1, 155.2,
1-(4-Iodophenyl)-3,3,3-trifluoropropan-1-one (3f):6b Yellow solid
1
(41 mg, 65% yield); mp 83−84 °C; H NMR (400 MHz, CDCl3) δ
7.88 (d, J = 8.4 Hz, 2 H), 7.63 (d, J = 8.4 Hz, 2 H), 3.75 (q, J = 9.9
Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.1, 138.3, 135.1,
1
2
129.6, 123.8 (q, JC−F = 276.4 Hz), 102.5, 42.1 (q, JC−F = 28.4 Hz);
19F NMR (376 MHz, CDCl3) δ −61.98.
3,3,3-Trifluoro-1-(4-nitrophenyl)propan-1-one (3g):11c Yellow
solid (25 mg, 54% yield); mp 96−97 °C; 1H NMR (400 MHz,
CDCl3) δ 8.37 (d, J = 8.4 Hz, 2 H), 8.12 (d, J = 8.4 Hz, 2 H), 3.88 (q,
J = 9.8 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.4, 150.9,
140.0, 129.5, 124.1, 123.5 (q, 1JC−F = 275.9 Hz), 42.7 (q, 2JC−F = 28.7
Hz); 19F NMR (376 MHz, CDCl3) δ −61.94.
1
2
3
150.9 (ddd, JC−F = 252.7, JC−F = 10.4, JC−F = 3.4 Hz), 140.2 (t,
2JC−F = 15.1), 136.3 (t, JC−F = 4.7), 111.7 (m), 90.6, 45.3, 37.4;
3
HRMS (ESI) m/z calcd for C11H11F3NO+[M + H]+ 230.0787, found
230.0801.
3,3,3-Trifluoro-1-(4-(trifluoromethyl)phenyl)propan-1-one
General Procedure for the Synthesis of α-CF3 Ketones.
Enaminone 1 (0.2 mmol), CF3SO2Na 2 (0.6 mmol), TBHP (0.3
mmol, 70 wt % aqueous solution), and DMSO (2 mL) were charged
in a 25 mL round-bottom flask equipped with stirring bar. Then the
mixture was stirred at 35 °C under air atmosphere for 16 h. After
being cooled to room temperature, 5 mL of water was added, and the
resulting mixture was extracted with ethyl acetate (3 × 10 mL). The
organic phases were collected and washed with a small amount of
water three times. After being dried with anhydrous Na2SO4, the solid
was filtered and the solvent was removed at reduced pressure. The
residue obtained therein was subjected to flash silica gel column
chromatography to provide pure products with the elution of mixed
petroleum ether/ethyl acetate (v/v = 50:1).
(3h):6b White solid (29 mg, 57% yield); mp 59−60 °C; H NMR
1
(400 MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0 Hz, 2
H), 3.83 (q, J = 9.7 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ
2
3
188.8, 138.4, 135.4 (d, JC−F = 32.6 Hz), 128.7, 126.0 (q, JC−F = 3.7
Hz), 123.7 (d, J = 275.5 Hz), 123.3 (d, 1JC−F = 271.4 Hz), 42.5 (q, J =
28.5 Hz); 19F NMR (376 MHz, CDCl3) δ −62.00, −63.37.
4-(3,3,3-Trifluoropropanoyl)benzonitrile (3i):11c White solid (26
1
mg, 61% yield); mp 132−133 °C; H NMR (400 MHz, CDCl3) δ
8.04 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 3.83 (q, J = 9.7 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.5, 138.6, 132.8, 128.8,
1
2
123.6 (q, JC−F = 275.4 Hz), 117.5, 117.5, 42.5 (q, JC−F = 28.7 Hz);
19F NMR (376 MHz, CDCl3) δ −61.96.
3,3,3-Trifluoro-1-(4-(methylsulfonyl)phenyl)propan-1-one (3j):
Procedure for the Synthesis of 3a at 4 mmol Scale.
Enaminone 1a (4 mmol, 1.012g), CF3SO2Na (12 mmol, 1.970g),
TBHP (6 mmol, 70 wt % aqueous solution), and DMSO (15 mL)
were charged in a 50 mL round-bottom flask equipped with stirring
bar. Then the mixture was stirred at 35 °C under air atmosphere for
16 h. After being cooled to room temperature, 45 mL of water was
added, and the resulting mixture was extracted with ethyl acetate (3 ×
30 mL). The organic phases were collected and washed with a small
amount of water three times. After being dried with anhydrous
Na2SO4, the solid was filtered and the solvent was removed at reduced
pressure. The resulting residue was subjected to flash silica gel column
chromatography to provide 3a (404 mg, 38% yield) with the elution
of mixed petroleum ether and ethyl acetate (v/v = 50:1).
1
White solid (26 mg, 49% yield); mp 168−169 °C; H NMR (400
MHz, DMSO-d6) δ 8.23 (d, J = 8.4 Hz, 2 H), 8.12 (d, J = 8.4 Hz, 2
H), 4.52 (q, J = 10.6 Hz, 2 H), 3.31 (s, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 191.1 (d, 3JC−F = 2.6 Hz), 145.4, 139.6, 129.7, 127.9,
125.3 (q, JC−F = 274.7 Hz), 43.6, 42.6 (q, JC−F = 26.8 Hz); 19F
NMR (376 MHz, CDCl3) δ −61.11; HRMS (ESI) m/z calcd for
C10H10F3O3S+ [M + H]+ 267.0297, found 267.0306.
1
2
3,3,3-Trifluoro-1-(4-(trifluoromethoxy)phenyl)propan-1-one
(3k):21 Yellow liquid (37 mg, 68% yield); 1H NMR (400 MHz,
CDCl3) δ 8.06−7.92 (m, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 3.79 (q, J =
9.9 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.2, 153.4 (d,
3JC−F = 17.0 Hz), 133.9, 130.5,123.8 (q, JC−F = 275.3 Hz), 120.6,
1
1
2
120.2 (q, JC−F = 257.8 Hz), 42.2 (q, JC−F = 28.4 Hz); 19F NMR
1-(4-Bromophenyl)-3,3,3-trifluoropropan-1-one (3a):11e White
1
(376 MHz, CDCl3) δ −57.66, −62.03.
solid (37 mg, 70%); mp 67−68 °C; H NMR (400 MHz, CDCl3)
1-(3-Chlorophenyl)-3,3,3-trifluoropropan-1-one (3l):6b Yellow
liquid (25 mg, 56% yield); 1H NMR (400 MHz, CDCl3) δ 7.91
(br s, 1 H), 7.81 (d, J = 7.6 Hz, 1 H), 7.61 (d, J = 8.8 Hz, 1 H), 7.46
(t, J = 7.9 Hz, 1 H), 3.78 (q, J = 9.8 Hz, 2 H); 13C{1H} NMR (100
MHz, CDCl3) δ 188.5, 137.3, 135.4, 134.1, 130.3, 128.4, 126.4, 123.7
δ 7.79 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 3.77 (q, J = 9.9
Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.8, 134.5, 132.3,
129.8, 123.8 (q, JC−F = 275.2 Hz), 42.1 (q, JC−F = 28.3 Hz); 19F
1
2
NMR (376 MHz, CDCl3) δ −62.01(t, J = 3.0 Hz).
3,3,3-Trifluoro-1-phenylpropan-1-one (3b):11e White solid (19
mg, 51% yield); mp 38−39 °C; 1H NMR (400 MHz, CDCl3) δ 7.94
(d, J = 7.0 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 2
1
2
(q, JC−F = 275.3 Hz), 42.3 (q, J = 29.0 Hz); 19F NMR (376 MHz,
CDCl3) δ −62.04.
D
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1-(3-Bromophenyl)-3,3,3-trifluoropropan-1-one (3m):11c Yellow
liquid (36 mg, 68% yield); 1H NMR (400 MHz, CDCl3) δ 8.06 (br s,
1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.41 (d, J =
3,3,3-Trifluoro-1-(naphthalen-2-yl)propan-1-one (3v):11c Pale
yellow solid (20 mg, 42% yield); mp 79−80 °C; 1H NMR (400
MHz, CDCl3) δ 8.41 (s, 1 H), 8.02−7.89 (m, 4 H), 7.67−7.57 (m, 2
H), 3.93 (q, J = 10.0 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ
189.6, 136.0, 133.2, 132.4, 130.6, 129.7, 129.2, 128.9, 127.9, 127.2,
8.0 Hz, 1 H), 3.78 (q, J = 9.8 Hz, 2 H); 13C{1H} NMR (100 MHz,
1
CDCl3) δ 188.4, 137.4, 137.1, 131.3, 130.5, 126.9, 123.8 (q, JC−F
=
2
1
2
275.5 Hz), 123.3, 42.2 (q, JC−F = 28.4 Hz); 19F NMR (376 MHz,
123.5, 124.1 (d, JC−F = 275.2 Hz), 42.3 (q, JC−F = 28.9 Hz); 19F
CDCl3) δ −62.04.
NMR (376 MHz, CDCl3) δ −61.90.
3,3,3-Trifluoro-1-(3-nitrophenyl)propan-1-one (3n):6d Yellow
solid (26 mg, 56% yield); mp 81−82 °C; 1H NMR (400 MHz,
CDCl3) δ 8.75 (s, 1 H), 8.52 (d, J = 8.0 Hz, 1 H), 8.30 (d, J = 7.6 Hz,
1 H), 7.77 (t, J = 8.0 Hz, 1 H), 3.90 (q, J = 9.7 Hz, 2 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 187.8, 148.6, 136.9, 133.8, 130.4, 128.4,
3,3,3-Trifluoro-1-(thiophen-2-yl)propan-1-one (3w):11c Brown
1
liquid (22 mg, 57% yield); H NMR (400 MHz, CDCl3) δ 7.77−
7.73 (m, 2 H), 7.19 (dd, J = 4.9, 3.9 Hz, 1 H), 3.71 (d, J = 10.0 Hz, 2
H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.2, 143.2, 135.7, 133.4,
1
2
128.5, 123.7 (d, JC−F = 275.6 Hz), 43.0 (q, JC−F = 28.6 Hz); 19F
1
2
123.2, 123.6 (q, JC−F = 275.5 Hz), 123.3, 42.5 (q, JC−F = 28.8 Hz);
NMR (376 MHz, CDCl3) δ −61.95.
19F NMR (376 MHz, CDCl3) δ −61.97.
(8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(3,3,3-trifluoropropano-
yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-
cyclopenta[a]phenanthren-3-one (3x): White solid (15 mg, 20%
3,3,3-Trifluoro-1-(3-(trifluoromethyl)phenyl)propan-1-one
(3o):11c White solid (29 mg, 57% yield); mp 41−42 °C; H NMR
1
1
yield); mp 102−103 °C; H NMR (400 MHz, CDCl3) δ 5.74 (s, 1
(400 MHz, CDCl3) δ 8.19 (s, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 7.90 (d,
J = 7.6 Hz, 1 H), 7.68 (t, J = 7.8 Hz, 1 H), 3.84 (q, J = 9.8 Hz, 2 H);
13C{1H} NMR (100 MHz, CDCl3) δ 188.5, 136.3, 131.9, 131.5, 130.6
H), 3.20 (qd, J = 10.2, 3.0 Hz, 2 H), 2.57 (t, J = 8.8 Hz, 1 H), 2.45−
2.13 (m, 6 H), 2.07−2.00 (m, 2 H), 1.90−1.84 (m, 1 H), 1.77−1.71
(m, 3 H), 1.60−1.56 (m, 1 H), 1.50−1.43 (m, 2 H), 1.34−1.25 (m, 2
(d, 3JC−F = 3.4 Hz), 129.7, 125.2 (q, 3JC−F = 3.8 Hz), 123.7 (d, 1JC−F
275.7 Hz), 123.4 (d, 1JC−F = 270.9 Hz), 42.4 (q, 2JC−F = 28.5 Hz); 19
NMR (376 MHz, CDCl3) δ −62.00, −62.97.
=
F
H), 1.19 (s, 3 H), 1.09−0.96 (m, 2 H), 0.71 (s, 3 H); 13C{1H} NMR
1
(100 MHz, CDCl3) δ 200.6, 199.3, 170.5, 124.0, 123.6 (d, JC−F
=
275.3 Hz), 63.3, 56.1, 53.5, 47.0 (q, 2JC−F = 27.2 Hz), 44.6, 38.6, 38.5,
3-(3,3,3-Trifluoropropanoyl)benzonitrile (3p): White solid (26
mg, 61% yield); mp 80−81 °C; 1H NMR (400 MHz, CDCl3) δ 8.23
(s, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.70 (t, J
35.7, 35.5, 33.9, 32.7, 31.8, 24.3, 22.9, 21.0, 17.4, 13.5; 19F NMR (376
+
MHz, CDCl3) δ −62.24; HRMS (ESI) m/z calcd for C22H30F3O2
[M + H]+ 383.2192, found 383.2207.
= 7.8 Hz, 1 H), 3.85 (q, J = 9.8 Hz, 2 H); 13C{1H} NMR (100 MHz,
1
CDCl3) δ 188.0, 137.0, 136.5, 132.2, 132.0, 130.1, 123.6 (d, JC−F
=
275.4 Hz), 117.5, 113.7, 42.3 (q, JC−F = 28.6 Hz); 19F NMR (376
MHz, CDCl3) δ −61.99; HRMS (ESI) m/z calcd for C10H7F3NO+
[M + H]+ 214.0474, found 214.0474.
2
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02431.
■
sı
1-(3,4-Dichlorophenyl)-3,3,3-trifluoropropan-1-one (3q):6b
White solid (31 mg, 61% yield); mp 58−59 °C; 1H NMR (400
MHz, CDCl3) δ 8.01 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.60 (d, J =
8.4 Hz, 1 H), 3.76 (q, J = 9.8 Hz, 2 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 187.6, 139.1, 135.3, 133.9, 131.1, 130.3, 127.3, 123.6 (d,
1H NMR spectrum of the D-labeled compound 3a-d1,
1H, 13C NMR spectra for all products and new
enaminone substrates, 19F NMR spectra for all CF3-
functionalized products, and the GC chromatograms on
DMF detection (PDF)
1JC−F = 275.5 Hz), 42.3 (q, JC−F = 28.6 Hz); 19F NMR (376 MHz,
2
CDCl3) δ −61.99.
1-(4-Chloro-3-nitrophenyl)-3,3,3-trifluoropropan-1-one (3r):
1
Brown solid (25 mg, 47% yield); mp 152−153 °C; H NMR (400
AUTHOR INFORMATION
Corresponding Author
MHz, CDCl3) δ 8.42 (d, J = 2.0 Hz, 1 H), 8.08 (dd, J = 8.4, 2.2 Hz, 1
H), 7.75 (d, J = 8.4 Hz, 1 H), 3.83 (q, J = 9.7 Hz, 2 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 186.8, 134.9, 133.2, 132.9, 132.1, 129.9,
■
Jie-Ping Wan − College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang 330022,
P.R. China; orcid.org/0000-0002-9367-8384;
Email: wanjieping@jxnu.edu.cn
1
2
125.4, 123.4 (q, JC−F = 275.5 Hz), 42.5 (q, JC−F = 28.8 Hz); 19F
NMR (376 MHz, CDCl3) δ −61.89; HRMS (ESI) m/z calcd for
+
C9H6ClF3NO3 [M + H]+ 267.9983, found 267.9981.
3,3,3-Trifluoro-1-(4-methoxy-3-nitrophenyl)propan-1-one (3s):
Yellow solid (27 mg, 51% yield); mp 115−116 °C; H NMR (400
1
Authors
MHz, CDCl3) δ 8.39 (d, J = 2.4 Hz, 1 H), 8.18 (dd, J = 8.8, 2.4 Hz, 1
H), 7.22 (d, J = 9.2 Hz, 1 H), 4.07 (s, 3 H), 3.79 (q, J = 9.9 Hz, 2 H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.7, 157.0, 139.5, 134.2,
128.2, 126.3, 123.7 (q, 1JC−F = 275.5 Hz), 113.7, 42.1 (q, 2JC−F = 28.6
Hz); 19F NMR (376 MHz, CDCl3) δ −61.92; HRMS (ESI) m/z
calcd for C10H8F3NO4Na+ [M + Na]+ 286.0298, found 286.0299.
1-(3,5-Bis(trifluoromethyl)phenyl)-3,3,3-trifluoropropan-1-one
Lu Gan − College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P.R. China;
School of Science, Nanchang Institute of Technology,
Nanchang 330029, P.R. China
Qing Yu − College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P.R. China
Yunyun Liu − College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P.R. China;
orcid.org/0000-0002-5553-1672
1
(3t): Pale yellow liquid (40 mg, 62% yield); H NMR (400 MHz,
CDCl3) δ 8.37 (s, 2 H), 8.15 (s, 1 H), 3.89 (q, J = 9.6 Hz, 2 H);
13C{1H} NMR (100 MHz, CDCl3) δ 187.2, 137.1, 132.9 (q, JC−F
=
2
34.0 Hz), 128.3 (d, 3JC−F = 4.0 Hz), 127.3 (q, 1JC−F = 3.5 Hz), 123.4
1
1
2
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02431
(q, JC−F = 275.5 Hz), 122.6 (q, JC−F = 271.4 Hz), 42.5 (q, JC−F
=
28.9 Hz); 19F NMR (376 MHz, CDCl3) δ −62.03, −63.13; HRMS
(ESI) m/z calcd for C11H6F9O+ [M + H]+ 325.0269, found 325.0287.
3,3,3-Trifluoro-1-(3,4,5-trifluorophenyl)propan-1-one (3u): Pale
Notes
1
yellow liquid (27 mg, 56% yield); H NMR (400 MHz, CDCl3) δ
The authors declare no competing financial interest.
7.60 (t, J = 6.2 Hz, 2 H), 3.74 (qd, J = 9.7, 1.6 Hz, 2 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 186.3, 151.4 (ddd, 1JC−2F = 252.7, 2JC−F
=
ACKNOWLEDGMENTS
3
1
■
10.4, JC−F = 3.4 Hz), 142.9 (dt, JC1−F = 260.9, JC−F = 15.2 Hz),
3
This work is financially supported by the National Natural
Science Foundation of China (21861019, 21562025) and
Natural Science Foundation of Jiangxi Province
(20202ACBL203006).
131.3 (d, JC−F = 3.9 Hz), 123.4 (q, JC−F = 275.5 Hz), 113.1 (m),
2
42.2 (q, JC−F = 28.9 Hz); 19F NMR (376 MHz, CDCl3) δ −62.04,
−130.88, −130.93, −149.80 (t, JF−H = 20.3 Hz); HRMS (ESI) m/z
calcd for C9H5F6O+ [M + H]+ 243.0239, found 243.0241.
E
https://dx.doi.org/10.1021/acs.joc.0c02431
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
2011, 50, 6119−6122. (b) Jacquet, J.; Blanchard, S.; Derat, E.;
Desage-El Murr, M.; Fensterbank, L. Redox-ligand sustains controlled
generation of CF3 radicals by well-defined copper complex. Chem. Sci.
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