Ultrasound-promoted sterically congested Passerini reactions under solvent-free conditions

Article abstract of DOI:10.1039/c2gc36095k

A facile, efficient and environmentally-friendly protocol for the synthesis of α-acyloxy amides has been developed by ultrasound-promoted sterically congested Passerini reactions under solvent-free conditions. This method provides several advantages over current reaction methodologies including a simpler work-up procedure, shorter reaction times and higher yields.

Full text of DOI:10.1039/c2gc36095k

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PAPER
Ultrasound-promoted sterically congested Passerini reactions under
solvent-free conditions†
Can Cui, Cong Zhu, Xiu-Jiang Du, Zhi-Peng Wang, Zheng-Ming Li and Wei-Guang Zhao*
Received 15th July 2012, Accepted 31st August 2012
DOI: 10.1039/c2gc36095k
A facile, efficient and environmentally-friendly protocol for the synthesis of α-acyloxy amides has been
developed by ultrasound-promoted sterically congested Passerini reactions under solvent-free conditions.
This method provides several advantages over current reaction methodologies including a simpler
work-up procedure, shorter reaction times and higher yields.
ultrasound on Passerini reactions has not yet been reported.
Accordingly, this attracted us to investigate whether ultrasound
can accelerate hindered Passerini reactions.
Introduction
Multicomponent reactions have become increasingly popular as
powerful tools for drug discovery1–4 because of their high atom
economy and chemical efficiency, and because they provide
ideal scaffolds for parallel synthesis and combinatorial chemistry.
The Passerini reaction is one of the most used and oldest multi-
component reactions to use isocyanides, and is the best method
for producing α-acyloxy amides, depsides, and depsipeptides.5–8
For example, mandipropamid, a novel fungicide against foliar
diseases caused by Oomycetes, was rapidly discovered using iso-
cyanide-based multicomponent reactions of the Passerini type,9
and bicalutamide, the leading antiandrogen used for the treat-
ment of prostate cancer, can be synthesized via a Passerini reac-
tion.10 Both aromatic and aliphatic aldehydes are usually good
substrates for Passerini reactions. However, with ketones, the
reactions are generally slower or even fail to proceed. An inter-
esting empirical phenomenon is that the use of high pressure sig-
nificantly increases the yields in sterically congested Passerini
reactions.11 Although the synthesis is efficient, the reaction times
are usually long (16.5 h), and it is difficult to achieve sufficiently
high compaction pressures in practice.
Results and discussion
According to the literature, at ambient pressure, hindered Passer-
ini reactions give poor yields; when performed at 300 MPa, the
NMR yield (Table 1, entry 4) increases from 6 to 28% (reaction
time 16.5 h). To determine the effects of ultrasound irradiation
on this reaction, experiments were carried out using a sonic horn
as an ultrasound source, with other conditions the same as those
in the literature.11 The reaction mixture was irradiated at 25 kHz/
1200 W (pulse-on time = 2 s, pulse-off time = 2 s) for 1 h. We
found that the use of ultrasound did indeed accelerate the reac-
tion. The yield (Table 1, entry 4) increased from 6 (NMR yield)
to 41% (isolated yield), and the reaction time was shortened
from 16.5 to 1 h (the reaction time was not monitored closely).
We also investigated the effects of the sizes of R1 (acid), R2
(ketone), and R3 (isocyanide). As expected, most ultrasonic reac-
tions provided higher yields than high-pressure reactions
(Table 1). The Passerini reaction shown in entry 3 was reported
to require 16.5 h at 300 MPa with 3-methyl-2-butanone as
solvent (38% NMR yield). Under ultrasound irradiation, the
product was isolated in 44% yield after only 1 h. The lower
product yields for entries 1 and 2 may be the result of losses
during silica gel column chromatography. Obviously, performing
a reaction under ultrasound irradiation is much more convenient
than performing it at high pressure.
Ultrasound techniques have increasingly been used in organic
synthesis during the last few years. Compared with traditional
methods, this method can give higher yields in shorter reaction
times and under milder conditions.12 As is well known, high-
power ultrasound can generate cavitations within a liquid. Cavi-
tation induces temperatures of several thousand degrees and
pressures in excess of 1000 atm inside bubbles, and enhances
mass transfer and turbulent flow in the liquid.13,14
To achieve more suitable conditions for the synthesis of
Passerini products (4), different reaction conditions were investi-
gated in the reaction of acetic acid, 2,2,2-trifluoro-1-phenyletha-
none, and 1-isocyanato-4-methoxy-2-nitrobenzene, because the
progress of the reaction could be easily monitored using TLC.
The classical Passerini reaction is generally performed in a
low-polarity medium such as dichloromethane (DCM), EtOAc,
diethyl ether, or tetrahydrofuran.15 Although compound 4h
could be obtained in DCM by conventional methods (Table 2,
entry 12), the required reaction time is too long (more than 2
Promotion of Passerini reactions at high pressure provides
further support for this idea and suggests that these reactions
could be accelerated by ultrasound. However, the influence of
State Key Laboratory of Elemento-Organic Chemistry, National
Pesticide Engineering Research Center (Tianjin), Nankai University,
Tianjin 300071, China. E-mail: zwg@nankai.edu.cn;
Fax: +862223505948; Tel: +862223498368
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc36095k
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Table 1 Effect of ultrasound on Passerini reactionsa
Yield (%)
0.1 MPab
Entry
Product
R1
R2
R3
300 MPab
Sonic hornc
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
CH3
n-Bu
i-Bu
t-Bu
t-Bu
4-MePh
4-MePh
Me
Me
Me
Me
Et
Me
Et
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
41
16
9
6
—
17
15
89
51
38
28
—
40
36
68
43
44
41
50
49
45
d
4g
a General reaction conditions: acid (0.4 mmol), isocyanide (0.5 mmol), ketone (reactant and solvent), 25 °C. b The yield determined from relative
intensities of characteristic protons versus methylene protons of the internal standard; reaction time = 16.5 h. c Isolated yield after silica gel column
chromatography; reaction time = 1 h. d Not tested.
Table 2 Effects of solvent and temperature on ultrasound-promoted Passerini reactionsa
Entry
Solvent
Condition
Time
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
DCM
EtOAc
THF
H2O
Sonic hornc
Sonic hornc
Sonic hornc
Sonic hornc
Sonic hornc
Sonic hornc
Sonic hornc
Sonic hornc
Sonic hornc
Stir
3 h
3 h
3 h
3 h
3 h
3 h
50 min
40 min
40 min
24 h
2 weeks
RT
RT
RT
RT
RT
RT
RT
40
0
0
0
0
0
0
49
58
50
52
39
LiCl aq.
Petroleum ether
Solvent-free
Solvent-free
Solvent-free
Solvent-free
DCM
9
10
11
60
RT
RT
Stir
a General reaction conditions: acid (1.5 mmol), isocyanide (1.0 mmol), ketone (1.5 mmol). b Isolated yield after silica gel column chromatography.
c Sonic horn power = 1200 W, irradiation frequency = 25 kHz.
weeks). To address questions concerning solvent effects, this
reaction was examined in DCM, EtOAc, and tetrahydrofuran;
however, ultrasound did not significantly accelerate the reactions
(Table 2, entries 1–3). It has also been reported16 that performing
a Passerini reaction in water or aqueous LiCl is much more con-
venient than performing it at high pressure. However, no reac-
tions occurred in water or aqueous LiCl whether ultrasound was
used or not (Table 2, entries 4 and 5). Under these conditions,
isonitrile was quickly degraded to the corresponding N-substi-
tuted formamide.
Solvent-free reactions have proven to be efficient and environ-
mentally friendly procedures for organic synthesis.17–19 We
decided to change to solvent-free procedures to get rid of
organic solvents or water, which always decrease the chances of
collisions between reactant molecules. For ultrasound irradiation
conditions, at the same temperature and with the power set at
1200 W (pulse-on time = 2 s, pulse-off time = 2 s), compound
4h is obtained in 50 min at a 49% yield (Table 2, entry 7).
Because a self-curing mixture hinders the reaction, the reactions
were carried out in excess phenylethanone as solvent at acid :
ketone : isonitrile ratios of 1.5 : 1 : 1.5. For comparison, we also
examined the same reaction under solvent-free conditions and
conventional conditions; the reaction was completed in 24 h
under solvent-free conditions (52% isolated yield; Table 2, entry
10) and in 2 weeks under conventional conditions (39% isolated
yield; Table 2, entry 11).
The classical Passerini reaction is typically carried out at room
temperature.15 The effects of temperature on Passerini reactions
have not often been studied. We carried out experiments at
different temperatures; the results show that temperature plays a
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role in this process (Table 2). When the reaction was carried out
at 40 °C, after 40 min, the yield had increased to 58% (Table 2,
entry 8). This result shows that an ultrasound-assisted solvent-
free procedure provides an approximately 36-fold acceleration
compared with the solvent-free procedure. However, when the
reaction was carried out at 60 °C, after 40 min, the yield had
decreased to 50%, apparently because of isonitrile decompo-
sition. Motivated by this fact, we carried out the experiments
using petroleum ether, which does not dissolve the raw materials,
as a dispersant. The reaction was still unaffected by ultrasound
irradiation (Table 2, entry 6). We think that the most significant
reason why these reactions could not be accelerated by ultra-
sound irradiation in solution is that ultrasound bubbles may be
generated mainly in the solvent because of the low vaporization
temperature of the solvent; thus, it is difficult for the three com-
ponents to exist simultaneously in the same cavitation bubble.
After optimizing the conditions, the generality of this method
was examined using the reactions of several trifluorophenyletha-
nones, isocyanides, and acetic acid under ultrasound irradiation;
the results are shown in Table 3.
With a view to evaluate the bio-activities of α-hydroxyl
amides, the generality of this method was examined using a con-
venient one-pot Passerini-hydrolysis reaction. After completion
of the Passerini reaction, the reaction mixture was hydrolyzed by
directly adding aqueous sodium hydroxide solution and metha-
nol under ultrasound irradiation for 15 min. The substituent on
the isonitrile (R2) had little or no effect on the reaction yield.
Substituted phenylisonitriles, benzylisonitrile, or phenylethanyliso-
nitrile were suitable for this reaction and gave α-hydroxy amides 5
in good yields (Table 3, entries 5–14). However, the yields were
affected by the presence of electron-donating or electron-withdraw-
ing substituents at the para positions of 2,2,2-trifluoro-1-phenyl-
ethanone. Electron-donating substituents (R1) decreased the yields
(Table 3, entries 15–17), whereas electron-withdrawing substituents
had the opposite effect (Table 3, entry 18).
To determine the influence of ultrasonic irradiation on the
development of the process, following the same work up, the
reaction was developed using an ultrasonic cleaner as an ultra-
sound source. When the reaction flask was located in the cleaner
bath (40 kHz, 100 W), compound 4h was obtained in 3 h in
52% isolated yield. When the reaction was carried out in a
cleaner bath, the reaction rate was significantly accelerated
(Table 3, entries 1–4). Comparable yield of the desired product
was obtained after only 2–3 h, which is approximately eight- to
twelve-fold faster than the reaction performed under solvent-free
conditions (Table 2, entry 10). The reaction time was increased
approximately four-fold to six-fold compared with the reaction
performed using a sonic horn (Table 2, entry 8).This is probably
Under the optimized conditions, the reactions proceeded
smoothly, and good-to-excellent conversions were observed
regardless of whether the isocyanide or the trifluorophenyletha-
none bore electron-withdrawing or electron-donating substituents
(Table 3, entries 1–4). Higher yields and shorter reaction times
were obtained for the benzyl isocyanide (Table 3, entries 3 and
4). Excellent conversions were observed for 4e (Table 3, entry
4); compound 4e was obtained in 15 min in 85% yield.
Table 3 Influence of ultrasonic irradiation source on process developmenta
Sonic hornb
Time (min)
Bath cleanerc
Time (min)
Entry
Product
R1
R2
Yieldd (%)
Yieldd (%)
1
2
3
4
5
6
7
8
4h
4i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
2-NO2-4-MeOPh
2-(PhCO2)Ph
4-MeOPhCH2
4-FPhCH2
40
30
15
15
15
15
15
15
15
15
15
40
40
40
40
40
40
40
58
61
78
85
65
62
72
73
79
72
68
68
80
75
60
47
50
69
180
180
120
120
52
61
76
82
—
—
—
—
—
—
—
—
—
—
—
—
—
—
4d
4e
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
e
PhCH2
—
4-MePhCH2
2-MeOPhCH2
4-MeOPhCH2
4-FPhCH2
2-ClPhCH2
3,4-MeOPhCH2CH2
4-MePh
4-MeOPh
4-ClPh
4-MeOPh
4-MeOPh
—
—
—
—
—
—
—
—
—
—
—
—
—
9
10
11
12
13
14
15
16
17
18
4-MeO
4-PhO
4-Ph
5m
5n
4-MeOPh
4-MeOPh
a General reaction conditions: acid (1.5 mmol), isocyanide (1.0 mmol), ketone (1.5 mmol), 40 °C. b Sonic horn power = 1200 W, irradiation frequency
= 25 kHz. c Bath cleaner power = 100 W, irradiation frequency = 40 kHz. d Isolated yield after silica gel column chromatography. e Not tested.
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because the mixture is exposed to weaker ultrasonic energy.
Nevertheless, both methodologies were more efficient, less time
consuming, and more environmentally friendly than the conven-
tional method, particularly when considering basic green chem-
istry concepts.
temperature for 24 h. The reaction mixture was purified by
column chromatography with silica gel and a mixture of EtOAc–
petroleum ether (1 : 25) as the eluent to give 4h as a yellow
solid; yield 52%.
All the synthesized compounds were characterized using spec-
Ultrasonic irradiation
tral data (HRMS, and 1H and 13C NMR).
Method A: A dry 10 mL flask was charged with a 2,2,2-
trifluoro-1-phenylethanone derivative (1.5 mmol), acetic acid
(1.5 mmol), and isonitrile (1.0 mmol). The reaction mixture was
then sonicated using an ultrasonic probe (ultrasonic power =
1200 W, frequency = 25 kHz, pulse-on time = 2 s, pulse-off time
= 2 s) with a frequency of 25 kHz at 25 or 40 °C for a specified
period of time (see Table 1 or 2, monitored by TLC). The result-
ing crude products were purified by column chromatography
using a mixture of petroleum ether–EtOAc (25 : 1) as the eluent.
The corresponding products (4) were obtained.
Method B: A dry 10 mL flask was charged with a 2,2,2-
trifluoro-1-phenylethanone derivative (1.5 mmol), acetic acid
(1.5 mmol), and isonitrile (1.0 mmol). The mixture was soni-
cated in the water bath of an ultrasonic cleaner (ultrasonic power
= 100 W, frequency = 40 kHz) at 40 °C for a specified period of
time (see Table 3, monitored by TLC). The resulting crude pro-
ducts were purified by column chromatography using a mixture
of petroleum ether–EtOAc (25 : 1) as the eluent to give the
corresponding products 4.
Conclusions
In conclusion, we present an eco-friendly and high-yielding pro-
cedure for sterically congested Passerini reactions under ultra-
sound irradiation at 40 °C in solvent-free conditions. This mild
and time-saving procedure leads to the simple α-acyloxy amides
4 or α-hydroxy amides 5. To the best of our knowledge, this new
procedure provides the first example of an efficient and ultra-
sound-promoted sterically congested Passerini reaction under
solvent-free conditions. This method for the acceleration of
Passerini reactions could also be applied to the parallel synthesis
of Passerini reaction products using a non-contact ultrasonic cell
crusher or cleaner bath.
Experimental
General remarks
1H and 13C NMR spectra were measured on a Bruker AC-P500
instrument using TMS as the internal standard and CDCl3 as
solvent. Melting points were determined on an X-4 binocular
microscope melting point apparatus (Beijing Tech Instruments,
Beijing, China) and were uncorrected. HRMS were recorded on
an Ionspec 7.0 T Fourier-transform ion-cyclotron resonance
(FTICR) mass spectrometer.
The ultrasonic irradiation experiments were carried out in (a) a
Nanjing SL2010-N ultrasonic processor equipped with a 2 mm
wide and 140 mm long probe, which was immersed directly into
the reaction mixture; the operating frequency was 25 kHz and
the output power was manually adjusted to 1200 W; and (b) a
Kunshang KQ-100 ultrasonic cleaner with a frequency of
40 kHz and a nominal power of 100 W. All chemicals and
reagents were purchased from standard commercial suppliers.
1,1,1-Trifluoro-3-((4-methoxy-2-nitrophenyl)amino)-3-oxo-
2-phenylpropan-2-yl acetate (4h)
White solid; m.p.: 115 °C; 1H NMR (400 MHz, CDCl3) δ 10.51
(s, 1H, CONH
̲
), 7.71–7.54 (m,
3H, Ar-H), 7.46–7.33 (m, 3H, Ar-H
̲
̲
4.4 Hz, 1H, Ar-H
̲
̲
̲
13C NMR (100 MHz, CDCl3) δ 165.75, 160.88, 153.68, 135.39,
128.50, 127.96, 126.66, 125.24, 124.98, 122.28, 121.76, 121.34,
118.48, 106.97, 53.94, 19.14; 19F NMR (376 MHz, CDCl3)
−
δ
−72.33; HRMS (ESI) m/z Calcd for C18H13F3N2O6
[M − H]− 411.0809, found 411.0818.
2-(2-Acetoxy-3,3,3-trifluoro-2-phenylpropanamido)phenyl
benzoate (4i)
Classical method
1
White solid; m.p.: 122–123 °C; H NMR (CDCl3) 400 MHz:
Acetic acid (0.07 g, 1.1 mmol), 1-isocyano-4-methoxy-2-nitro-
benzene (0.2 g, 1.1 mmol), and 2,2,2-trifluoro-1-phenylethanone
(0.74 g, 1 mmol) were dissolved in DCM (10 mL). The solution
was stirred at room temperature for 14 d. After completion of the
reaction, the solvent was removed under vacuum. The resulting
crude product was purified by column chromatography with
silica gel and a mixture of EtOAc–petroleum ether (1 : 25) as the
eluent to give 4h as a yellow solid; yield 39%.
δ 9.51 (s, 1H, CONH
Hz, 1H, Ar-H), 7.63–7.40 (m, 6H, Ar-H
J = 1.2 Hz, 2H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H
3H, CH
3); 13C NMR (101 MHz, CDCl3) δ 172.99, 164.33,
161.59, 147.22, 134.26, 130.94, 130.32, 129.95, 128.85, 128.28,
127.16, 124.15, 29.72; 19F NMR (376 MHz, CDCl3) δ −73.21;
HRMS (ESI) m/z Calcd for C24H18F3NO5Na (M + Na)+
480.1029, found 480.1030.
̲
̲
̲
̲
̲
̲
Solvent-free method
1,1,1-Trifluoro-3-((4-methoxybenzyl)amino)-3-oxo-2-
phenylpropan-2-yl acetate (4d)
A dry 10 mL flask was charged with 2,2,2-trifluoro-1-phenyl-
ethanone (1.5 mmol), acetic acid (1.5 mmol), and isonitrile
(1.0 mmol). The reaction mixture was stirred at room
1
White solid; m.p.: 105–106 °C; H NMR (400 MHz, CDCl3)
δ 7.54 (d, J = 7.2 Hz, 2H, Ar-H
̲
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Ar-H
Ar-H), 6.33 (br, 1H, NH
ArCH2), 3.79 (s, 3H, CH3
̲
̲
J = 4.0 Hz, 2H, CH2
̲
NH), 2.33 (s, 3H, Ar-CH3
̲
); 13C NMR
̲
̲
(100 MHz, CDCl3) δ 167.16, 137.69, 134.38, 133.62, 129.59,
129.53, 128.98, 127.39, 126.33, 122.40, 44.30, 21.11; 19F NMR
(376 MHz, CDCl3) δ −73.99, −74.01; HRMS (ESI) m/z Calcd
for C17H16F3NO2H+ [M + H]+ 324.1206, found 324.1210.
̲
̲
(376 MHz, CDCl3) δ −72.84. 13C NMR (100 MHz, CDCl3)
δ 168.05, 163.79, 159.19, 130.90, 129.74, 129.23, 128.50,
127.25, 114.13, 77.36, 77.04, 76.72, 55.31, 43.61, 21.41;
HRMS (ESI) m/z Calcd for C19H18F3NO4H+ [M + H]+
382.1261, found 382.1262.
3,3,3-Trifluoro-2-hydroxy-N-(2-methoxybenzyl)-2-phenylpropan-
amide (5c)
1
White solid; m.p.: 146–147 °C; H NMR (400 MHz, CDCl3)
1,1,1-Trifluoro-3-((4-fluorobenzyl)amino)-3-oxo-2-phenylpropan-
2-yl acetate (4e)
δ 7.69–7. 55 (m, 2H, Ar-H
7.36–7.26 (m, 1H, Ar-H), 7.19 (dd, J = 7.2 Hz, J = 1.2 Hz, 1H,
Ar-H), 6.92 (td, J = 7.2 Hz, J = 0.8 Hz, 1H, Ar-H), 6.86 (d, J =
8.0 Hz, 1H, Ar-H), 6.70 (br, 1H, CONH), 5.04 (s, 1H, OH),
4.61–4.41 (m, 2H, CH2NH), 3.75 (s, 3H, Ar-OCH3
); 13C NMR
̲
̲
̲
1
White solid; M.p.: 101–102 °C; H NMR (400 MHz, CDCl3)
̲
δ 7.53 (d, J = 7.2 Hz, 2H, Ar-H
Ar-H), 7.25–7.14 (m, 2H, Ar-H), 7.01 (t, J = 8.4 Hz, 2H, Ar-H
6.42 (br, 1H, CONH), 4.48 (qd, J = 14.8 Hz, J = 5.6 Hz, 2H,
CH2NH), 2.29 (s, 3H, CH3
); 13C NMR (100 MHz, CDCl3)
̲
̲
̲
̲
̲
̲
̲
(100 MHz, CDCl3) δ 166.89, 157.43, 134.64, 129.61, 129.37,
128.81, 126.39, 125.31, 124.55, 122.47, 120.71, 110.30, 55.12,
41.23; 19F NMR (376 MHz, CDCl3) δ −74.14; HRMS (ESI) m/z
Calcd for C17H16F3NO3H+ [M + H]+ 340.1155, found 340.1158.
̲
̲
δ 168.04, 163.99, 129.82, 129.60, 129.52, 128.54, 127.20,
115.75, 115.53, 43.35, 21.39; 19F NMR (376 MHz, CDCl3)
δ −72.88, −114.52; HRMS (ESI) m/z Calcd for C18H16F4NO3H
(M + H)+ 370.1064, found 370.1063.
3,3,3-Trifluoro-2-hydroxy-N-(4-methoxybenzyl)-2-
phenylpropanamide (5d)
One-pot Passerini-hydrolysis method
White solid; m.p.: 138 °C; 1H NMR (400 MHz, CDCl3)
A dry 10 mL flask was charged with a 2,2,2-trifluoro-1-phenyl-
ethanone derivative (1.5 mmol), acetic acid (1.5 mmol), and iso-
nitrile (1.0 mmol). The reaction mixture was then sonicated
using an ultrasonic probe (ultrasonic power, 1200 W; frequency,
25 kHz; pulse-on time, 2 s; pulse-off time, 2 s) with a frequency
of 25 kHz at 25 °C or 40 °C for a specified period of time. After
completion of the reaction, 4 mL of methanol and 2 mL of 10%
sodium hydroxide were added to the reaction mixture to hydro-
lyze the α-acyloxy amides 4 to α-hydroxyl amides 5 under ultra-
sound irradiation. After irradiation of the mixture for 30 min, the
solvent was evaporated and the residue was extracted several
times with EtOAc. The combined organic phases were washed
with brine, dried over MgSO4, evaporated, and recrystallized
from EtOH to give 5.
δ 7.71–7.56 (m, 2H, Ar-H
J = 8.0 Hz, 2H, Ar-H), 6.83 (d, J = 8.0 Hz, 2H, Ar-H
1H, CONH), 4.89 (s, 1H, OH), 4.42 (ddd, J = 34.8 Hz, J =
14.4 Hz, J = 5.6 Hz, 2H, CH2NH), 3.78 (s, 3H, Ar-OCH3);
̲
̲
̲
̲
̲
̲
̲
13C NMR (100 MHz, CDCl3) δ 167.10, 159.26, 134.37, 129.58,
128.98, 128.83, 128.71, 126.32, 125.24, 122.39, 114.21, 55.31,
44.02; 19F NMR (376 MHz, CDCl3) δ −74.02; HRMS (ESI) m/z
Calcd for C17H16F3NO3H+ [M + H]+ 340.1155, found 340.1158.
3,3,3-Trifluoro-N-(4-fluorobenzyl)-2-hydroxy-2-phenylpropan-
amide (5e)
1
White solid; m.p.: 137–138 °C; H NMR (400 MHz, CDCl3)
δ 7.73–7.55 (m, 2H, Ar-H
J = 8.8 Hz, J = 5.6 Hz, 2H, Ar-H
Ar-H), 6.50 (br, 1H, CONH), 4.82 (s, 1H, OH
14.8 Hz, J = 6.0 Hz, 2H, CH
2NH); 13C NMR (100 MHz,
̲
̲
̲
̲
̲
̲
N-Benzyl-3,3,3-trifluoro-2-hydroxy-2-phenylpropanamide (5a)
̲
1
White solid; m.p.: 138 °C; H NMR (400 MHz, CDCl3) δ 7.64
CDCl3) δ 167.27, 163.57, 161.12, 134.24, 132.59, 132.56,
129.65, 129.16, 129.08, 128.98, 126.28, 126.27, 125.19, 122.35,
115.84, 115.62, 43.65; 19F NMR (376 MHz, CDCl3) δ −74.10,
−114.29; HRMS (ESI) m/z Calcd for C16H13F4NO2H+ [M + H]+
328.0955, found 328.0957.
(d, J = 3.8 Hz, 2H, Ar-H
(m, 3H, Ar-H), 7.15 (d, J = 6.8 Hz, 2H, Ar-H
CONH), 4.85 (s, 1H, OH), 4.51 (ddd, J = 33.6 Hz, J = 15.2 Hz,
J = 6.0 Hz, 2H, CH
2NH); 13C NMR (100 MHz, CDCl3)
̲
̲
̲
̲
̲
̲
̲
δ 167.24, 136.69, 134.33, 129.62, 129.00, 128.87, 127.90,
127.37, 126.31, 44.47; 19F NMR (376 MHz, CDCl3) δ −74.01;
HRMS (ESI) m/z Calcd for C16H14F3NO2H+ [M + H]+
310.1049, found 310.1055.
N-(2-Chlorobenzyl)-3,3,3-trifluoro-2-hydroxy-2-phenylpropan-
amide (5f)
1
White solid; m.p.: 132–133 °C; H NMR (400 MHz, CDCl3)
δ 7.62 (d, J = 2.8 Hz, 2H, Ar-H
(d, J = 6.8 Hz, 2H, Ar-H), 7.26–7.11 (m, 2H, Ar-H
1H, CONH), 4.80 (s, 1H, OH), 4.64–4.50 (m, 2H, CH
̲
̲
3,3,3-Trifluoro-2-hydroxy-N-(4-methylbenzyl)-2-phenylpropan-
amide (5b)
̲
̲
̲
̲
1
White solid; m.p.: 122 °C; H NMR (400 MHz, CDCl3) δ 7.63
13C NMR (100 MHz, CDCl3) δ 167.27, 134.22, 134.12, 133.50,
129.76, 129.67, 129.61, 129.36, 128.97, 127.19, 126.27, 42.55;
19F NMR (376 MHz, CDCl3) δ −74.11; HRMS (ESI) m/z Calcd
for C16H13ClF3NO2H+ [M + H]+ 343.0660, found 343.0651.
(d, J = 4.5 Hz, 2H, Ar-H
7.8 Hz, 2H, Ar-H), 7.03 (d, J = 8.0 Hz, 2H, Ar-H
CONH), 4.88 (s, 1H, OH), 4.45 (ddd, J = 32 Hz, J = 16.0 Hz,
̲
̲
̲
̲
̲
̲
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N-(3,4-Dimethoxyphenethyl)-3,3,3-trifluoro-2-hydroxy-2-
phenylpropanamide (5g)
(s, 3H OCH3
̲
); 13C NMR (100 MHz, CDCl3) δ 167.40, 160.35,
159.27, 128.86, 128.81, 127.81, 126.31, 122.47, 114.26, 114.23,
55.34, 55.30, 43.98; 19F NMR (376 MHz, CDCl3) δ −74.30;
HRMS (ESI) m/z Calcd for C18H17F3NO4− [M − H]− 368.1110,
found 368.1117.
1
Colourless liquid; H NMR (400 MHz, CDCl3) δ 7.68–7.32 (m,
5H, Ar-H
4.86 (s, 1H, OH
3.63–3.50 (m, 2H, CH
̲
̲
),
),
̲
̲
̲
̲
̲
CH2);
13C NMR (100 MHz, CDCl3) δ 167.12, 149.10, 147.84, 134.38,
130.40, 129.43, 128.85, 126.21, 120.62, 111.76, 111.40, 55.92,
55.78, 41.71, 34.73; 19F NMR (376 MHz, CDCl3) δ −74.11;
HRMS (ESI) m/z Calcd for C19H20F3NO4H+ [M + H]+
384.1417, found 384.1419.
3,3,3-Trifluoro-2-hydroxy-N-(4-methoxybenzyl)-2-(4-phenoxy-
phenyl)propanamide (5m)
1
White solid; m.p.: 113–114 °C; H NMR (400 MHz, CDCl3) δ
7.56 (d, J = 8.6 Hz, 2H, Ar-H
7.19–7.07 (m, 3H, Ar-H), 7.01 (t, J = 7.4 Hz, 4H, Ar-H
(d, J = 8.6 Hz, 2H, Ar-H), 6.31 (s, 1H, CONH), 4.78 (s, 1H,
OH), 3.79 (s, 3H, OCH
3); 13C NMR (100 MHz, CDCl3) δ
̲
̲
̲
̲
̲
̲
3,3,3-Trifluoro-2-hydroxy-N-(4-methoxyphenyl)-2-phenylpropan-
amide (5i)
̲
̲
167.15, 159.32, 158.61, 156.16, 129.95, 128.88, 128.75, 128.62,
128.07, 124.10, 119.59, 118.42, 114.25, 55.31, 44.03; 19F NMR
(376 MHz, CDCl3) δ −74.24; HRMS (MALDI) m/z Calcd for
C23H20F3NO4Na+ [M + Na]+ 454.1242, found 454.1240.
Pale yellow solid; m.p.: 165–166 °C; 1H NMR (400 MHz,
CDCl3) δ 7.76 (s, 1H, CONH
7.49–7.43 (m, 3H, Ar-H), 7.38 (d, J = 9.0 Hz, 2H, Ar-H
(d, J = 9.0 Hz, 2H, Ar-H), 4.63 (s, 1H, OH), 3.79 (s, 3H,
OCH
3); 13C NMR (100 MHz, CDCl3) δ 164.82, 157.29, 134.05,
̲
̲
̲
̲
̲
̲
̲
2-([1,1′-Biphenyl]-4-yl)-3,3,3-trifluoro-2-hydroxy-N-(4-methoxy-
benzyl)propanamide (5n)
129.77, 129.33, 129.07, 126.35, 125.21, 122.36, 122.05, 114.29,
55.52; 19F NMR (376 MHz, CDCl3) δ −74.04; HRMS (ESI) m/z
Calcd for C16H13F3NO3− [M − H]− 324.0848, found 324.0861.
1
White solid; m.p.: 158–160 °C; H NMR (400 MHz, CDCl3) δ
7.72–7.55 (m, 6H, Ar-H
8.6 Hz, 2H, Ar-H), 6.84 (d, J = 8.7 Hz, 2H, Ar-H
CONH), 4.86 (s, 1H, OH), 3.78 (s, 3H, OCH
3); 13C NMR
(100 MHz, CDCl3) δ 167.08, 159.30, 142.44, 139.93, 133.25,
128.93, 128.87, 127.89, 127.60, 127.14, 126.82, 114.25, 55.30,
44.07; 19F NMR (376 MHz, CDCl3) δ −74.05; HRMS
(MALDI) m/z Calcd for C23H20F3NO3Na+ [M + Na]+ 438.1293,
found 438.1290.
̲
̲
̲
̲
N-(4-Chlorophenyl)-3,3,3-trifluoro-2-hydroxy-2-
phenylpropanamide (5j)
̲
̲
̲
1
White solid; m.p.: 146–147 °C; H NMR (400 MHz, CDCl3)
δ 8.00 (s, 1H, CONH
̲
̲
5H, Ar-H
̲
̲
̲
13C NMR (100 MHz, CDCl3) δ 164.86, 134.90, 133.60, 130.66,
129.97, 129.22, 126.26, 125.05, 121.44; 19F NMR (376 MHz,
−
CDCl3) δ −74.27; HRMS (ESI) m/z Calcd for C15H10ClF3NO2
Acknowledgements
[M − H]− 328.0352, found 328.0351.
We are grateful for financial support for this work from the
National Natural Science Foundation of China (21172124), the
National Basic Research Science Foundation of China
(2010CB126105), and the National Key Technologies R&D
Program (2011BAE06B05).
2-(4-Ethylphenyl)-3,3,3-trifluoro-2-hydroxy-N-(4-methoxybenzyl)-
propanamide (5k)
1
Colourless liquid; H NMR (400 MHz, CDCl3) δ 7.52 (d, J =
7.6 Hz, 2H, Ar-H
7.6 Hz, 2H, Ar-H), 6.84 (d, J = 7.5 Hz, 2H, Ar-H
CONH), 4.80 (s, 1H, OH
J = 5.2 Hz, 2H, CH2), 3.79 (s, 3H, OCH3
2H), 1.23 (t, J = 7.6 Hz, 3H, CH
3); 13C NMR (100 MHz,
CDCl3) δ 166.31, 158.19, 144.76, 130.60, 127.86, 127.79,
127.37, 125.30, 124.28, 121.43, 113.16, 54.25, 42.83, 27.41,
14.25; 19F NMR (376 MHz, CDCl3) δ −74.18; HRMS
(MALDI) m/z Calcd for C19H20F3NO3Na+ [M + Na]+ 390.1293,
found 390.1288.
̲
̲
̲
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̲
̲
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̲
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Green Chem.