Copper-free direct C-H trifluoromethylation of acetanilides with sodium trifluoromethanesulfinate

Article abstract of DOI:10.1021/jo501221h

A copper-free direct C-H ortho trifluoromethylation of electron-deficient 4-substituted acetanilides using Langlois reagent (NaSO₂CF₃) as the CF₃ source in the presence of tert-butyl hydroperoxide (tBuOOH, TBHP) was developed.

Full text of DOI:10.1021/jo501221h

Article
pubs.acs.org/joc
Copper-Free Direct C−H Trifluoromethylation of Acetanilides with
Sodium Trifluoromethanesulfinate
Mingxi Wu,† Xinfei Ji,† Wenpeng Dai,† and Song Cao*,†,‡
†Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST),
Shanghai 200237, China
‡Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China
S
* Supporting Information
ABSTRACT: A copper-free direct C−H ortho trifluorome-
thylation of electron-deficient 4-substituted acetanilides using
Langlois reagent (NaSO2CF3) as the CF3 source in the
presence of tert-butyl hydroperoxide (tBuOOH, TBHP) was
developed.
for the synthesis of the CF3-substituted aniline derivatives
INTRODUCTION
■
(Scheme 1a−c).8 However, the high cost of the trifluorome-
Over the last few decades, the introduction of the
trifluoromethyl group (CF3) into organic compounds has
attracted ever-increasing interest in organic synthesis.1 Up to
now, numerous methods for nucleophilic, electrophilic, and
radical trifluoromethylation have been developed.2 Although
the present methods exhibit remarkable reactivity and broad
applicability toward diverse molecules, generally they suffer
from the use of expensive trifluoromethylating reagents (e.g.,
Ruppert−Prakash reagent: about 2000 €/mol; Umemoto
reagent: about 43 000 €/mol; Togni reagent: about 144 000
€/mol),3 the transition metal catalysts or the requirement for
harsh reaction conditions. Consequently, these disadvantages
restrict their widespread use in organic synthesis. Among the
commercially available trifluoromethylating reagents, Langlois
reagent (sodium trifluoromethanesulfinate, NaSO2CF3, about
930 €/mol) has drawn much attention in recent years largely as
a result of their availability, relatively low cost, and ease of
handling.4 However, compared to the development of other
trifluoromethylating reagents, direct trifluoromethylation re-
action using Langlois reagent as the CF3 source still remains
underdeveloped.5
Scheme 1. Trifluoromethylation of Acetanilide or Pivanilide
Derivatives
thylating reagents, the use of transition metal catalysts (Pd and
Cu), and relatively harsh reaction conditions limit their
application on a large scale.
Despite these groundbreaking advances in trifluoromethyla-
tion of aniline or acetanilides derivatives, there is still great
demand for the development of direct C−H trifluoromethyla-
tion approaches that perform under simple and mild
conditions. In this paper, we developed a novel and efficient
method for the synthesis of valuable building blocks of o-CF3
acetanilides by the reaction of electron-deficient 4-substituted
The trifluoromethylated anilines and their derivatives are a
class of useful and valuable fluorinated building blocks for the
synthesis of pharmaceuticals, agrochemicals, and advanced
organic materials.6 Traditionally, such trifluoromethylated
anilines are synthesized from the corresponding aryl
trichlorides by exchange of chloride for fluoride using F2 or
HF as fluorinating agents in the presence of Lewis acid.7
Although these methods are still used in industrial applications,
they have some drawbacks such as serious environmental
problems, severe experimental conditions requirements, and
the formation of other fluorinated sideproducts. Recently,
trifluoromethylation of acetanilides or pivanilides with different
trifluoromethylating reagents has provided an attractive method
Received: May 31, 2014
Published: September 4, 2014
© 2014 American Chemical Society
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acetanilides with Langlois reagent in the presence of tert-butyl
hydroperoxide (Scheme 1d).
reaction furnished a satisfactory yield of trifluoromethylated
aniline (90%, GC-MS), a mixture of regioisomers (ortho-,
meta-, or para-substituted aniline) was obtained. Unfortunately,
these trifluoromethylated products were isolated as an
inseparable mixture of regioisomers. To avoid the formation
of regioisomers, the reaction of 4-methylaniline (1y) with
NaSO2CF3 and tBuOOH was examined; however, only a trace
amount of expected products were observed.
RESULTS AND DISCUSSION
■
In 2011, Baran reported an efficient method for the
trifluoromethylation of heterocycles by using a simple
combination of sodium trifluoromethanesulfinate salt (Na-
SO2CF3) and tert-butyl hydroperoxide (TBHP) in the mixed
solvent of CH2Cl2/H2O, affording the pure products or a
mixture of regioisomers in moderate to good yields.9
Encouraged by the results obtained by Baran and Langlois,
and in our continuing efforts to develop novel methods toward
CF3-containing compounds,10 we envisaged that this radical
oxidation trifluoromethylation protocol might be applied for
the introduction of a CF3 group into the readily available
acetanilides and anilines.
When N-(4-methylphenyl)acetamide 1a was used, the
expected products 2a and 2a′ were formed in 10% yield.
Inspired by this promising result, we chose 1a as the model
substrate to optimize the reaction conditions (Table 1).
Langlois reported trifluoromethylation of N-phenylacetamide
with NaSO2CF3 and tBuOOH in the presence of a catalytic
amount of Cu(II) salt. Thus, initially, we performed the
reaction in the presence of Cu(II) salt (entries 1, 2); however,
trace amounts of the desired products were detected. When
CH2Cl2 was replaced with DMSO or CH3CN, the formation of
2a and 2a′ were almost not observed (entries 3, 4). The
reaction time has a significant impact on the process of reaction
and the yield of product (entries 5−8). A long reaction time
was required for a moderate yield. When the reaction time was
shortened, the yield of 2a was obviously decreased. The
amounts of NaSO2CF3 and tBuOOH used were also varied.
Too little or too much NaSO2CF3 or tBuOOH led to a lower
conversion of 1a to the trifluoromethylated products 2a and 2a′
(entries 9−12). Note that because tert-butyl hydroperoxide
(tBuOOH) should be stored in 2−8 °C, the reaction must be
performed at 0 °C at the beginning of the reaction. It is
unfavorable for the reaction when performed at higher reaction
temperature (e.g., 25 °C).
Langlois and co-workers first reported trifluoromethylation
of electron-rich aromatics such as anilines and phenols. Thus,
we began our investigation by examining the trifluoromethy-
lation of aniline (1x) with NaSO2CF3 and tBuOOH using
CH2Cl2/H2O (2.5/1) as solvent (Scheme 2). Although the
Scheme 2. Reaction of Aniline Derivatives with NaSO2CF3
and tBuOOH
With the optimum reaction conditions in hand (Table 1,
entry 8), we next investigated the scope of this C−H
trifluoromethylation reaction with a variety of different 4-
substituted acetanilides (Table 2, 3). The acetanilides having
electron-donating groups such as methyl or ethyl group at the
para position of the acetamino group afforded mixtures of
isomeric C−H trifluoromethylation products in moderate
yields (2a and 2a′, 2b and 2b′), which were separated by
column chromatography on silica gel using a petroleum ether/
ethyl acetate (2:1) mixture as eluent. The replacement of the
Table 1. Optimization of the Reaction Conditions
a
entry
NaSO2CF3 (equiv)
tBuOOH (equiv)
catalyst (5 mol %)
solvent
time
yield (2a+2a′)
1
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4.0
2.0
3.0
3.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
4.0
3.0
CuCl2
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
DMSO:H2O = 2.5:1
CH3CN:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
CH2Cl2:H2O = 2.5:1
12 h
12 h
12 h
12 h
12 h
1 d
trace
trace
trace
trace
10
2
CuSO4
3
−
−
−
−
−
−
−
−
−
−
4
5
6
33
7
3 d
40
8
5 d
51
9
5 d
50
10
11
12
5 d
46
5 d
45
5 d
28
a
Yields (2a and 2a′) determined by GC analysis and based on 1a.
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were obtained as sole products. The analytical data (1H, 13C,
and 19F NMR) of isolated products 2a, 2c, 2d, 2e, 2f, 2j, and
2m match those of compounds given in the literature.8c
Furthermore, the 13C NMR chemical shifts and three-bond C−
F coupling constants (3JCF) of C atom 3 of 2a, 2c−f, 2j, and 2m
(C atom 2 of 2j) are similar to those reported by Shi.8c
In addition, strong electron-withdrawing groups such as CF3,
CN, and NO2 (2g, 2h, and 2i) are more favorable for this
conversion than weak electron-withdrawing groups. On the
basis of the above observations, we assumed that the yields
were substantially affected by the electron density of the
benzene ring. Increasing the acetanilides’ electron density
resulted in some lower reaction efficiency.
Table 2. Trifluoromethylation of 4-Methyl (or Ethyl)
Acetanilides
ab
,
Finally, to investigate the limitations of the radical
trifluoromethylation reaction, we attempted the trifluorome-
thylation of anilines bearing electron-withdrawing groups at the
4-position directly without the assistance of an acetamino group
(Table 4). The reactions of 4-substituted anilines (3b−e) with
NaSO2CF3 did not proceed efficiently, affording the desired
products in poor yields. Other 4-substituted anilines such as 4-
(trifluoromethoxy)aniline, 1-(4-aminophenyl)ethanone, 4-
((trifluoromethyl)thio)aniline, and 4-(methylsulfonyl)aniline
failed to give the ortho-trifluoromethylated products. Fortu-
nately, those 4-substituted anilines having a strong electron-
withdrawing group still furnished appreciable yields of the
expected products (4a, 4f, and 4g). The spectral data (1H, 13C,
and 19F NMR) of 4a−d, 4f, and 4g match those of compounds
given in the literature.11−14
Although aniline (1x) has been converted into the
corresponding ArCF3 in high yield (90%), when the para
position of the amino group was substituted by another
substituent, no matter whether it is an electron-withdrawing
group (Table 4, 3a−g) or an electron-donating group (Scheme
2, 1y), the trifluoromethylation reaction proceeded slowly and
inefficiently. This result might be due to steric hindrance in the
para position to the amino group, which decreased the reaction
efficiency somewhat, and is consistent with the reported
observation that ·CF3 radical is very sensitive to steric
hindrance.5e
a
Reaction conditions: 1a,b (1 mmol), CH2Cl2 + H2O = 7 mL.
Isolated yield.
b
acetyl group by a benzoyl group did not make much difference
in the yields of the products (GC and GC-MS).
Direct trifluoromethylation of C−H bonds of electron-
deficient anilides or acetanilides, especially for those bearing
strong electron-withdrawing substituents, has not been ex-
plored and still remains a great challenge. We next turned our
attention to the trifluoromethylation of acetanilides bearing an
electron-withdrawing group at the para position of the
acetamino group. As shown in Table 3, most substrates were
Table 3. Trifluoromethylation of Acetanilides Bearing an
Electron-Withdrawing Group
a b
,
According to the Shi and Xi’s reports, the acetamino group
and pivalamido group were considered as ortho-directing
groups for trifluoromethylation of acetanilides and pivanilides
in the presence of palladium and copper catalysts. However, in
this work, the effect of the acetamino group is different. To
probe the role of the acetamino group, an additional
experiment was conducted. When p-nitrotoluene was used as
the substrate, no reaction was observed. This indicated that
only the existence of a strong electron-withdrawing group on
the aryl ring without the assistance of an acetamino or amino
group could not make the reaction proceed smoothly. Although
the acetamino group might play a particularly important role in
altering the distribution of the π electron density of the
benzene ring, it also acted as an ortho-directing group.
However, the influence on the reaction of the former is more
obvious than that of the latter. The presence of a strong
electron-withdrawing group at the para position to the
acetamino or amino group is favorable for the formation of
ortho-trifluoromethylated products.
a
Reaction conditions: acetanilides 1c−n (1 mmol), CH2Cl2 + H2O =
b
7 mL. Isolated yield.
converted into the expected products in moderate yields (42−
65%). However, the reaction did not proceed to completion
and gave a mixture of starting materials and the expected
products. A small amount of products were lost during column
chromatography, and the starting materials were recovered.
The results indicated that these electron-withdrawing groups
aided this transformation, affording the desired products 2c−n
in reasonable yields. Much to our delight, o-CF3 acetanilides
On the basis of a related published paper in this field,8a,9 the
mechanism of the trifluoromethylation of arenes and
heteroarenes with NaSO2CF3 and tBuOOH might involve the
CF3 radical. In our cases, the trifluoromethylation of
acetanilides or anilines might also proceed via the CF3 transient
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a b
,
Table 4. Trifluoromethylation of Anilines Bearing an Electron-Withdrawing Group
a
b
Reaction conditions: anilines 3a−g (1 mmol), CH2Cl2 + H2O = 7 mL. Yields determined by GC analysis and based on 3a−g, isolated yields in
parentheses.
substituted anilines (3a−g, 1.0 mmol) and NaSO2CF3 (0.468g, 3.0
mmol, 3.0 equiv) in dichloromethane (5 mL) and water (2 mL) at
0 °C. After the mixture was stirred for 1 h, the temperature was slowly
raised to 15 °C and the reaction mixture was stirred at 15 °C for about
3−4 days. After the reaction was completed (monitored by TLC or
GC), the mixture was extracted with dichloromethane (3 × 10 mL).
The organic layer was washed with brine and dried over Na2SO4. The
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluting with
petroleum ether/ethyl acetate (2:1) to afford the pure target
compounds.
radical intermediate. To validate this assumption, 1 or 4 equiv
of TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy), a radical
scavenger, was added into the reaction system under the
standard conditions, respectively; no expected trifluoromethy-
lated product was observed, and an observable amount of
TEMPO−CF3 adduct was detected in the crude mixture. These
results clearly indicated that the reaction can go through a
radical pathway.
In summary, we have developed a practical and efficient
metal-free direct C−H ortho trifluoromethylation of a variety of
electron-deficient 4-substituted acetanilides. The reaction could
be carried out at near room temperature under ambient
conditions using stable, inexpensive, and readily available
Langlois reagent (NaSO2CF3) as the trifluoromethylating
reagent. Furthermore, the reaction shows high tolerance to
moisture and good functional group compatibility. This method
provides a simple and straightforward approach to prepare a
variety of useful 4-substituted ortho-trifluoromethylated
acetanilides or anilines, which can be used as remarkably
versatile building blocks in synthetic organic chemistry and
important intermediates in the fine chemical industry.
N-(4-Methyl-2-(trifluoromethyl)phenyl)acetamide (2a, CAS:
1416085-70-5).8c yield 25% (54.3 mg), white solid; mp 116.7−
1
117.8 °C; H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 7.52 (s,
1H), 7.45 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 2.36 (s, 3H),
2.05 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 169.6, 136.7, 133.7,
133.5, 130.7, 126.8 (q, 3JCF = 4.4 Hz), 125.2 (q, 2JCF = 29.0 Hz), 124.1
1
(q, JCF = 271.6 Hz), 23.2, 20.7; 19F NMR (376 MHz, DMSO-d6): δ
−59.5 (s, 3F).
N-(4-Methyl-3-(trifluoromethyl)phenyl)acetamide (2a′, CAS:
22957-86-4).7a yield 26% (56.4 mg), white solid; mp 116.6−
1
117.3 °C; H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 7.99
(s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 2.36 (s,
3H), 2.05 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 168.5, 137.5,
2
1
132.4, 129.8, 127.4 (q, JCF = 29.1 Hz), 124.4 (q, JCF = 272.0 Hz),
122.1, 115.8 (q, JCF = 5.9 Hz), 23.8, 18.0; 19F NMR (376 MHz,
3
EXPERIMENTAL SECTION
■
DMSO-d6): δ −60.7 (s, 3F).
General Comments. All reagents were of analytical grade,
N-(4-Ethyl-2-(trifluoromethyl)phenyl)acetamide (2b). yield 23%
obtained from commercial suppliers, and used without further
1
1
purification. H NMR and 13C{1H} NMR spectra were recorded on
(53.2 mg), white solid; mp 122.0−123.5 °C; H NMR (400 MHz,
1
a 400 spectrometer (400 MHz for H and 100 MHz for 13C) using
DMSO-d6): δ 9.49 (s, 1H), 7.54 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.37
(d, J = 8.4 Hz, 1H), 2.68 (q, J = 7.5 Hz, 2H), 2.05 (s, 3H), 1.20 (t, J =
7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 169.7, 142.9, 133.7,
132.6, 130.8, 125.7 (q, 3JCF = 4.9 Hz), 125.3 (q, 2JCF = 33.0 Hz), 124.1
TMS as internal standard. The 19F NMR spectra were obtained using a
400 spectrometer (376 MHz). DMSO-d6 was used as the NMR
solvent in all cases. The GC and GC-MS were calibrated by authentic
standards. High-resolution mass spectra (HRMS) were acquired in the
electron-impact mode (EI) using a TOF mass analyzer.
1
(q, JCF = 271.7 Hz), 27.9, 23.3, 15.8; 19F NMR (376 MHz, DMSO-
d6): δ −59.4 (s, 3F); HRMS (EI) calcd for C11H12F3NO ([M]+)
231.0871, found 231.0872.
Synthesis of Compounds 1a−n. Substrates 1a−n were synthesized
according to literature procedures.8c
N-(4-Ethyl-3-(trifluoromethyl)phenyl)acetamide (2b′). yield 22%
1
(50.8 mg), white solid; mp 122.2−123.3 °C; H NMR (400 MHz,
Synthesis of Compounds 2a−n. TBHP (70% solution in water,
0.68 mL, 5.0 mmol, 5.0 equiv) was slowly added to a solution of
substituted acetanilide (1a−n, 1.0 mmol) and NaSO2CF3 (0.468g, 3.0
mmol, 3.0 equiv) in dichloromethane (5 mL) and water (2 mL) at
0 °C. After the mixture was stirred for 1 h, the temperature was slowly
raised to 15 °C and the reaction mixture was stirred at 15 °C for 4−5
days. After the reaction was completed (monitored by TLC), the
mixture was extracted with dichloromethane (3 × 10 mL). The
organic layer was washed with brine and dried over Na2SO4. The
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel, eluting with
petroleum ether/ethyl acetate (2:1) to afford the pure compounds.
Synthesis of Compounds 4a−g. TBHP (70% solution in water,
0.68 mL, 5.0 mmol, 5.0 equiv) was slowly added to a solution of
DMSO-d6): δ 10.18 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 8.4
Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 2.69 (q, J = 7.3 Hz, 2H), 2.05 (s,
3H), 1.17 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ
2
1
169.1, 137.9, 136.8, 131.7, 127.2 (q, JCF = 28.9 Hz), 125.0 (q, JCF
=
272.3 Hz), 123.0, 116.2 (q, JCF = 6.0 Hz); 19F NMR (376 MHz,
DMSO-d6): δ −58.9 (s, 3F); HRMS (EI) calcd for C11H12F3NO
([M]+) 231.0871, found 231.0873.
3
N-(4-Fluoro-2-(trifluoromethyl)phenyl)acetamide (2c, CAS: 393-
23-7).8c yield 55% (121.6 mg), white solid; mp 117.8−118.7 °C; H
1
NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 7.63−7.49 (m, 3H), 2.05
1
(s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 169.9, 160.0 (d, JCF
=
3
243.8 Hz), 133.4 (d, JCF = 8.3 Hz), 132.5, 127.5−127.1 (m), 123.1
(qd, JCF = 280.4 Hz, 3JCF = 8.1 Hz), 120.3 (d, 2JCF = 21.9 Hz), 114.0
1
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2
3
(dq, JCF = 26.1 Hz, JCF = 5.0 Hz), 23.2. 19F NMR (376 MHz,
(376 MHz, DMSO-d6): δ −42.2 (s, 3F), −59.8 (s, 3F); HRMS (EI)
calcd for C10H7F6NOS ([M]+) 303.0153, found 303.0155.
DMSO-d6): δ −60.1 (s, 3F), −114.1 (s, 1F).
N-(4-Chloro-2-(trifluoromethyl)phenyl)acetamide (2d, CAS: 344-
N-(4-Acetyl-2-(trifluoromethyl)phenyl)acetamide (2m, CAS:
97760-75-3).8c yield 50% (122.5 mg), white solid; mp 121.9−
122.6 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 8.16 (dd, J
= 8.4, 1.6 Hz, 1H), 8.12 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 2.57 (s, 3H),
2.05 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 196.6, 169.7, 139.9,
134.3, 132.9, 129.8, 126.4 (q, 3JCF = 5.2 Hz), 123.9 (q, 2JCF = 28.3 Hz),
53-6).8c yield 59% (139.8 mg), white solid; mp 134.5−135.4 °C; H
1
NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 7.77 (d, J = 2.0 Hz, 1H),
7.74 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 2.06 (s, 3H); 13C
NMR (100 MHz, DMSO-d6): δ 169.8, 135.1, 133.3, 132.5, 131.2,
126.8, 126.6 (q, JCF = 5.2 Hz), 123.1 (q, JCF = 272.2 Hz), 23.3; 19F
3
1
1
123.5 (q, JCF = 271.7 Hz), 27.1, 23.5. 19F NMR (376 MHz, DMSO-
NMR (376 MHz, DMSO-d6): δ −59.9 (s, 3F).
N-(4-Bromo-2-(trifluoromethyl)phenyl)acetamide (2e, CAS:
29124-62-7).8c yield 53% (148.9 mg), white solid; mp 165.2−
166.1 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 7.88−7.86
(m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 2.06 (s, 3H); 13C NMR (100 MHz,
d6): δ −54.8 (s, 3F).
N-(4-(Methylsulfonyl)-2-(trifluoromethyl)phenyl)acetamide (2n).
1
yield 47% (132.1 mg), white solid; mp 161.0−162.2 °C; H NMR
(400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.19 (s, 1H), 8.17 (d, J = 8.4
Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 3.29 (s, 3H), 2.09 (s, 3H); 13C
NMR (100 MHz, DMSO-d6): δ 169.7, 140.5, 138.2, 131.9, 130.5,
125.9 (q, 3JCF = 5.1 Hz), 124.3, 123.0 (q, 1JCF = 272.2 Hz), 43.5, 23.4;
19F NMR (376 MHz, DMSO-d6): δ −59.7 (s, 3F); HRMS (EI) calcd
for C10H10F3NO3S ([M]+) 281.0333, found 281.0336.
3
DMSO-d6): δ 169.8, 136.3, 135.5, 132.7, 129.4 (q, JCF = 5.2 Hz),
126.9 (q, 2JCF = 29.6 Hz), 123.0 (q, 1JCF = 272.4 Hz), 119.1, 23.3; 19
NMR (376 MHz, DMSO-d6): δ −59.8 (s, 3F).
F
N-(4-Iodo-2-(trifluoromethyl)phenyl)acetamide (2f, CAS: 97760-
98-0).8c yield 48% (157.9 mg), white solid; mp 161.5−162.7 °C; H
1
4-Fluoro-2-(trifluoromethyl)aniline (4a, CAS: 393-39-5).11 yield
NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.02−7.99 (m, 2H), 7.32
(d, J = 8.4 Hz, 1H), 2.06 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ
1
40% (71.6 mg), colorless oil; H NMR (400 MHz, DMSO-d6): δ
3
169.2, 141.6, 135.4, 134.4 (q, JCF = 5.1 Hz), 132.0, 126.1, 122.4 (q,
7.14−7.11 (m, 2H), 6.89 (d, J = 4.4 Hz, 1H), 5.44 (s, 2H); 13C NMR
1JCF = 272.2 Hz), 90.9, 22.9; 19F NMR (376 MHz, DMSO-d6): δ
−59.7 (s, 3F).
(100 MHz, DMSO-d6): δ 152.9 (d, 3JCF = 226.3 Hz), 142.8, 124.1 (qd,
1JCF = 274.8 Hz, 4JCF = 2.2 Hz), 120.1, 118.4, 118.3, 111.8 (dq, 2JCF
=
N-(2,4-Bis(trifluoromethyl)phenyl)acetamide (2g). yield 60%
25.0 Hz, 3JCF = 5.7 Hz); 19F NMR (376 MHz, DMSO-d6): δ −62.5 (s,
3F), −129.4 (s, 1F); HRMS (EI) calcd for C7H5F4N ([M]+) 179.0358,
found 179.0357.
1
(162.6 mg), white solid; mp 122.6−123.5 °C; H NMR (400 MHz,
DMSO-d6): δ 9.79 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.84
(d, J = 8.4 Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ
169.9, 139.9, 130.9, 130.4−130.3 (m), 126.9 (q, 2JCF = 33.0 Hz), 124.8
4-Chloro-2-(trifluoromethyl)aniline (4b, CAS: 455-03-4).12 yield
18% (35.1 mg), colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 7.33
(s, 2H), 6.89 (d, J = 5.6 Hz, 1H), 5.79 (s, 2H); 13C NMR (100 MHz,
2
3
1
(q, JCF = 30.4 Hz), 124.0 (q, JCF = 4.4 Hz), 123.7 (q, JCF = 291.4
Hz), 123.1 (q, JCF = 293.3 Hz), 23.5; 19F NMR (376 MHz, DMSO-
1
3
1
DMSO-d6): δ 145.2, 132.7, 125.2 (q, JCF = 5.1 Hz), 124.2 (q, JCF
=
d6): δ −59.8 (s, 3F), −61.2 (s, 3F); HRMS (EI) calcd for C10H7F6NO
270.6 Hz), 118.5, 118.3, 111.5 (q, JCF = 28.9 Hz); 19F NMR (376
MHz, DMSO-d6): δ −62.3 (s, 3F); HRMS (EI) calcd for C7H5ClF3N
([M]+) 195.0063, found 195.0062.
2
([M]+) 271.0432, found 271.0433.
N-(4-Cyano-2-(trifluoromethyl)phenyl)acetamide (2h). yield 65%
1
(148.2 mg), white solid; mp 181.2−182.3 °C; H NMR (400 MHz,
4-Bromo-2-(trifluoromethyl)aniline (4c, CAS: 455-02-3).12 yield
DMSO-d6): δ 9.75 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.12 (dd, J = 8.4,
1
25% (59.7 mg), colorless oil; H NMR (400 MHz, DMSO-d6): δ
1.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 2.12 (s, 3H); 13C NMR (100
7.43−7.41 (m, 2H), 6.82 (d, J = 6.8 Hz, 1H), 5.81 (s, 2H); 13C NMR
(100 MHz, DMSO-d6): δ 145.5, 135.5, 127.9 (q, 3JCF = 5.4 Hz), 124.1
(q, 1JCF = 270.7 Hz), 118.9, 112.0 (q, 2JCF = 29.8 Hz), 105.1; 19F NMR
(376 MHz, DMSO-d6): δ −62.2 (s, 3F); HRMS (EI) calcd for
C7H5BrF3N ([M]+) 238.9557, found 238.9556.
MHz, DMSO-d6): δ 169.4, 139.8, 141.8, 136.6, 133.4, 130.9 (q, 3JCF
=
1
2
5.3 Hz), 130.8, 125.2 (q, JCF = 272.3 Hz), 124.0 (q, JCF = 30.4 Hz),
108.6, 23.1; 19F NMR (376 MHz, DMSO-d6): δ −59.8 (s, 3F); HRMS
(EI) calcd for C10H7F3N2O ([M]+) 228.0510, found 228.0509.
N-(4-Nitro-2-(trifluoromethyl)phenyl)acetamide (2i). yield 57%
Ethyl 4-amino-3-(trifluoromethyl)benzoate (4d, CAS: 688020-69-
1
(141.4 mg), yellow solid; mp 137.8−138.7 °C; H NMR (400 MHz,
1).13 yield 15% (34.9 mg), yellow solid; mp 124.2−125.1; H NMR
1
DMSO-d6): δ 9.86 (s, 1H), 8.50 (d, J = 8.8 Hz,1H), 8.45, 7.99 (d, J =
(400 MHz, DMSO-d6): δ 7.96, 7.86 (d, J = 8.4 Hz, 1H), 6.92 (d, J =
8.8 Hz, 1H), 6.49 (s, 2H), 4.27 (q, J = 6.8 Hz, 2H), 1.31 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, DMSO-d6): δ 164.9, 150.1, 133.7, 128.1
8.8 Hz, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 169.5,
2
1
143.9, 141.4, 129.5, 127.7, 123.1 (q, JCF = 31.0 Hz), 122.4 (q, JCF
=
272.1 Hz), 122.0 (q, JCF = 5.4 Hz), 23.2; 19F NMR (376 MHz,
DMSO-d6): δ −59.9 (s, 3F); HRMS (EI) calcd for C9H7F3N2O3
([M]+) 248.0409, found 248.0408.
3
3
1
(q, JCF = 5.2 Hz), 124.5 (q, JCF = 270.2 Hz), 116.2, 115.8, 109.6 (q,
2JCF= 29.9 Hz), 60.0, 14.1; 19F NMR (376 MHz, DMSO-d6): δ −62.4
(s, 3F); HRMS (EI) calcd for C10H10F3NO2 ([M]+) 233.0664, found
233.0665.
Ethyl 4-acetamido-3-(trifluoromethyl)benzoate (2j, CAS:
1416085-72-7).8c yield 53% (145.8 mg), white solid; mp 119.5−
120.5 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 8.20−8.18
(m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.12 (s,
3H), 1.33 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ
169.8, 164.6, 140.3, 133.8, 129.9, 127.6, 127.4 (q, 3JCF = 5.2 Hz), 124.0
2,4-Bis(trifluoromethyl)aniline (4e, CAS: 367-71-5). yield 28%
1
(64.1 mg), yellow oil; H NMR (400 MHz, DMSO-d6): δ 7.61 (s,
2H), 7.05−7.03 (m, 1H), 6.40 (s, 2H); 13C NMR (100 MHz, DMSO-
d6): δ 149.3, 129.5, 124.4 (q, 1JCF = 268.2 Hz), 124.2 (q, 1JCF = 270.2
Hz), 123.4, 116.8, 114.9 (q, 2JCF = 30.3 Hz), 109.7 (q, 2JCF = 28.9 Hz);
19F NMR (376 MHz, DMSO-d6): δ −60.2 (s, 3F), −62.9 (s, 3F);
HRMS (EI) calcd for C8H5F6N ([M]+) 229.0326, found 229.0325.
4-Nitro-2-(trifluoromethyl)aniline (4f, CAS: 121-01-7).14 yield 42%
(q, JCF = 29.9 Hz), 123.5 (q, JCF = 271.8 Hz), 61.7, 23.6, 14.5; 19F
2
1
NMR (376 MHz, DMSO-d6): δ −59.8 (s, 3F).
N-(4-(Trifluoromethoxy)-2-(trifluoromethyl)phenyl)acetamide
1
(2k). yield 45% (129.2 mg), white solid; mp 102.7−103.7 °C; H
1
(86.5 mg), yellow solid; mp 90.7−91.8 °C; H NMR (400 MHz,
NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 7.71−7.65 (m, 3H), 2.08
(s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 169.9, 146.0, 135.4,
DMSO-d6): δ 8.19−8.14 (m, 2H), 7.14 (s, 2H), 6.95 (d, J = 6.4 Hz,
1H); 13C NMR (100 MHz, DMSO-d6): δ 151.7, 134.9, 128.4, 123.6
(q, 1JCF = 270.5 Hz), 123.5, 116.3, 109.0 (q, 2JCF = 31.3 Hz); 19F NMR
(376 MHz, DMSO-d6): δ −63.2 (s, 3F); HRMS (EI) calcd for
C7H5F3N2O2 ([M]+) 206.0303, found 206.0302.
2
1
132.9, 126.7 (q, JCF = 30.0 Hz), 126.0, 122.9 (q, JCF = 271.9 Hz),
120.4 (q, JCF = 255.7 Hz), 119.8 (q, JCF = 5.0 Hz), 23.2; 19F NMR
(376 MHz, DMSO-d6): δ −57.6 (s, 3F), −60.3 (s, 3F); HRMS (EI)
calcd for C10H7F6NO2 ([M]+) 287.0381, found 287.0383.
1
3
4-Amino-3-(trifluoromethyl)benzonitrile (4g, CAS: 327-74-2).12
yield 54% (100.5 mg), yellow solid; mp 62.1−63.3 °C; 1H NMR (400
MHz, DMSO-d6): δ 7.75 (s, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 6.90
(d, J = 8.8 Hz, 1H), 6.62 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ
N-(2-(Trifluoromethyl)-4-((trifluoromethyl)thio)phenyl)acetamide
1
(2l). yield 42% (127.3 mg), white solid; mp 88.1−89.5 °C; H NMR
(400 MHz, DMSO-d6): δ 9.75 (s, 1H), 8.02−8.00 (m, 2H), 7.77 (d, J
= 8.4 Hz, 1H), 2.11 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ
3
3
1
169.3, 140.5, 138.6, 133.9 (q, JCF = 5.3 Hz), 130.8, 127.8, 124.9 (q,
149.6, 136.0, 131.2 (q, JCF = 5.3 Hz), 123.9 (q, JCF = 270.5 Hz),
2JCF = 30.2 Hz), 122.7 (q, JCF = 272.3 Hz), 120.7, 23.0; 19F NMR
119.1, 117.0, 110.4 (q, JCF = 30.6 Hz), 95.8; 19F NMR (376 MHz,
1
2
8988
dx.doi.org/10.1021/jo501221h | J. Org. Chem. 2014, 79, 8984−8989

The Journal of Organic Chemistry
Article
DMSO-d6): δ −62.8 (s, 3F); HRMS (EI) calcd for C8H5F3N2 ([M]+)
(5) (a) Cui, L.; Matusaki, Y.; Tada, N.; Miura, T.; Uno, B.; Itoh, A.
Adv. Synth. Catal. 2013, 355, 2203. (b) Deb, A.; Manna, S.; Modak, A.;
Patra, T.; Maity, S.; Maiti, D. Angew. Chem., Int. Ed. 2013, 52, 9747.
(c) Patra, T.; Deb, A.; Manna, S.; Sharma, U.; Maiti, D. Eur. J. Org.
Chem. 2013, 5247. (d) Lu, Y.; Li, Y.-M.; Zhang, R.; Jin, K.; Duan, C.-Y.
J. Fluorine Chem. 2014, 161, 128. (e) Langlois, B. R.; Laurent, E.;
186.0405, found 186.0403.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 19F NMR spectra and HRMS (EI) spectra of
Roidot, N. Tetrahedron Lett. 1992, 33, 1291. (f) Ye, Y.-D.; Kunzi, S. A.;
̈
compounds 2b, 2b′, 2g−i, 2k−l, 2n, 4a−g, and H, 13C, and
1
Sanford, M. S. Org. Lett. 2012, 14, 4979. (g) Landelle, G.; Panossian,
A.; Pazenok, S.; Vors, J.; Leroux, F. R. Beilstein J. Org. Chem. 2013, 9,
2476. (h) Yang, Y.-D.; Lwamoto, K.; Tokunaga, E.; Shibata, N. Chem.
Commun. 2013, 49, 5510.
19F NMR spectra of compounds 2a, 2a′, 2c−f, 2j, 2m. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(6) (a) Ma, D.-W.; Geng, Q.; Zhang, H.; Jiang, Y.-W. Angew. Chem.,
Int. Ed. 2010, 49, 1291. (b) Endeshaw, M. M.; Li, C.; de Leon, J.; Yao,
N.; Latibeaudiere, K.; Premalatha, K.; Morrissette, N.; Werbovetz, K.
A. Bioorg. Med. Chem. Lett. 2010, 20, 5179. (c) Degani, I.; Fochi, R.;
Magistris, C.; Migliaccio, M. Synthesis 2009, 5, 801. (d) Watanabe, E.;
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H. J. Agric. Food Chem. 2000, 48, 5124. (e) Satyanarayana, K.; Srinivas,
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(7) (a) Debarge, S.; Violeau, B.; Bendaoud, N.; Jouannetaud, M.;
Jacquesy, J. Tetrahedron Lett. 2003, 44, 1747. (b) Debois, M. 1988. U.
S. Patent, 4,748,277. (c) Appel, W.; Siegemund, G. US Patent,
5,471,002, 1995.
(8) (a) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett.
1991, 32, 7525. (b) Cai, S.-J.; Chen, C.; Sun, Z.-L.; Xi, C.-J. Chem.
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B.-J.; Luo, S.; Guo, Q.-Y.; Wei, J.-B.; Shi, Z.-J. Org. Lett. 2013, 15, 10.
(9) Ji, Y.-N.; Brucekl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su,
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AUTHOR INFORMATION
Corresponding Author
*Tel: +86-21-64253452. E-mail: scao@ecust.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (grant nos. 21472043, 21272070,
21072057), the National Basic Research Program of China
(973 Program, 2010CB126101), and the Twelfth Five-year
Plan of China (2011BAE06B01-15).
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