A general strategy for construction of a difluoromethyl compound library and its application in synthesis of pseudopeptides bearing a terminal difluoromethyl group

Article abstract of DOI:10.1039/c000835d

We describe the development of a novel synthesis strategy that uses common reaction conditions to transform a collection of simple building blocks into complex molecules bearing a terminal difluoromethyl group. The core of this approach is the conscious design and synthesis of new difluorinated building blocks which contain inactive and reactive groups on each side of the CF ₂ group. The strategy is illustrated by application to the synthesis of CF₂H-bearing pseudopeptides via Ugi reaction.

Full text of DOI:10.1039/c000835d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A general strategy for construction of a difluoromethyl compound library and
its application in synthesis of pseudopeptides bearing a terminal
difluoromethyl group†
Jingjing Wu, Song Cao,* Nianjin Liu, Li Shen, Jinlong Yu, Jian Zhang, Hui Li and Xuhong Qian
Received 15th January 2010, Accepted 5th March 2010
First published as an Advance Article on the web 17th March 2010
DOI: 10.1039/c000835d
We describe the development of a novel synthesis strategy that uses common reaction conditions to
transform a collection of simple building blocks into complex molecules bearing a terminal
difluoromethyl group. The core of this approach is the conscious design and synthesis of new
difluorinated building blocks which contain inactive and reactive groups on each side of the CF2 group.
The strategy is illustrated by application to the synthesis of CF2H-bearing pseudopeptides via Ugi
reaction.
In this paper, we report a new and efficient strategy for the
Introduction
construction of functionalized small molecules bearing CF2H in
Much attention has been drawn in recent years towards the
one process. Our overall strategy is outlined in Fig. 1. Ethyl
difluoromethyl group (CF2H) due to its special physical and
bromodifluoroacetate was used as a starting material. Due to
chemical properties.1 Some CF2H-containing derivatives have
its relatively higher reactivity, which can lead to undesirable
been reported to exhibit herbicidal,2 potential antitumor3 and an-
tileishmanial activity.4 Although difluoromethylated compounds
have significant applications in drug and pesticide discovery, only
a limited number of them are available for evaluation of bioactivity
compared to their CF3 analogues.
side reactions,12 the bromine atom attached to the right side
of difluoromethyl group was replaced by an inactive group
such as PhS–, PhSO2– (or referred to as “protected group”).
These protected CF2 derivatives are stable to a wide variety of
conditions including strong base. Subsequently, the ester group
on the left side of the difluoromethyl unit is converted into
the desired reactive functional group such as isocyano, azide
or carboxylic group by conventional synthetic methods. These
protected functionalized CF2 building blocks can further undergo
many useful reactions such as multicomponent reaction and
click reaction. After the construction of the initial scaffolds of
target compounds and removal of the inactive groups by the
different suitable reducing reagents such as Bu3SnH/AIBN,13
As a result of the relative novelty of these difluoromethyl
compounds, the synthesis of them has been of interest to syn-
thetic chemists. Different methods for the preparation of CF2H-
containing compounds have been developed in recent years.5
For example, the commercialization of several straightforward
fluorinating agents, such as DAST, SF4,6 SeF4,7 TBAF8 and
BrF3,9 has paved the way for the synthesis of various difluo-
rinated compounds. The nucleophilic, radical, and electrophilic
(phenylsulfonyl)difluoromethylations stand out as other novel
and promising synthetic methods to access CF2H-containing
molecules.10 However, the purpose of the present methods is
only to difluorinate the specific positions or groups of the target
compounds. These methods are limited to the preparation of
relatively simple CF2H-containing compounds and just allow
the generation of a single specimen. The procedures tend to be
lengthy and tedious and require multistep reactions to prepare
CF2H-containing compounds individually if the target fluorinated
compounds contain other reactive groups. In addition, the CF2H
groups are not stable to strong organic bases and can undergo
dehydrofluorination.11 Therefore, there is a clear demand for the
development of a novel and general strategy to introduce CF2H
groups and appropriate functional groups into the final molecules
in a controlled fashion.
Na/Hg/Na2HPO4 or Mg0/HOAc/NaOAc,15 structurally com-
14
plex and diverse molecules with –CF2H terminal groups can be
obtained efficiently and simultaneously in one process (Fig. 1, left).
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chem-
ical Technology, School of Pharmacy, East China University of Science
and Technology, Shanghai, 200237, (China). E-mail: scao@ecust.edu.cn;
Fax: (+86) 21-6425-2603
† Electronic supplementary information (ESI) available: NMR and high
resolution mass spectra. See DOI: 10.1039/c000835d
Fig. 1 General strategy for the construction of diverse molecules
containing the terminal CF2H functionality.
Isocyanide-based multicomponent reactions (IMCRs) have
attracted considerable interest.16 The most famous IMCR is the
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Ugi four component reaction which involves the reaction of
amines, aldehydes, carboxylic acids and isocyanides to form pep-
tidomimetic derivatives. It was reported that some pseudopeptides
bearing a CF2H unit have good bioactivity17 (Fig. 2). However, the
number of examples reported in the literature dealing with flexible
and practical syntheses of pseudopeptides bearing a CF2H unit is
scarce.18
LiAlH4 gave a very low yield of the expected product; the major
unexpected product was 2-phenylsulfanyl-ethylamine. To improve
the yields, the reduction of amide 2 was carried out with LiAlH4
at room temperature or 0 ◦C, the yield of amine 3 increased to
20% and 30%, respectively. Finally, moderate isolated yield (up to
45%) was achieved through the replacement of anhydrous THF
with anhydrous diethyl ether at 0 ◦C. The reaction of amine 3
with ethyl formate yielded formamide, which then reacted with
◦
PPh3/CCl4 and NEt3 at 60 C in anhydrous CH2Cl2 successfully
afforded the desired novel isocyanide 4 in good yield.22
With the PhS-protected difluorinated isocyanide building block
in hand, we turned our attention to demonstrate its capability
to synthesize the structural diversity of fluorine-containing pseu-
dopeptides via Ugi reaction. Thus, several different aldehydes,
amines, acids and thi◦s novel isocyanide were reacted under solvent-
free conditions at 60 C which we reported previously.23 In all cases,
the reaction proceeded smoothly to give the difluoromethylene
compounds in moderate to high yields. Aromatic aldehydes and
acids afforded the higher yields of the desired compounds than
aliphatic aldehydes and acids (Scheme 2).
Fig. 2 Two examples of bioactive pseudopeptides bearing the CF2H
group.
In recent years, we have focused on the multicomponent re-
actions including fluoro-containing building blocks.19 To demon-
strate the potential of the above-mentioned new strategy, in this
paper, we described the synthesis of difluoromethyl-containing
pseudopeptides via Ugi reaction using new difluorinated building
block which comprise inactive and active group (phenylthio
and isocyano, respectively) on each side of the CF2 group. The
terminal CF2H functionality has been swiftly incorporated into
pseudopeptides by using this new strategy.
Scheme 2 Synthesis of pseudopeptides bearing the CF2 unit via Ugi
reaction.
Results and discussion
Hu has reported that the reductive cleavage of the weak C–S bond
of PhSCF2R to the corresponding CF2H-bearing compounds
could be achieved easily in the presence of Bu3SnH/AIBN.20 Thus,
we first explored the possibility of using a phenylthio group to
block the left of CF2 group before it was transformed to highly
reactive functionality, isocyano group (Fig. 1, right).
The synthesis of 2,2-difluoro-2-phenylsulfanyl-ethyl-isocyanide
4, the key building block to realize this strategy, is illustrated in
Scheme 1. Ethyl 2,2-difluoro-2-(phenylthio)acetate 1 was readily
prepared by the reaction of ethyl 2-bromo-2,2-difluoroacetate
with benzenethiol according to the method described in the
literature.12b The quasi-quantitative amidation then occurred to
give the corresponding 2,2-difluoro-2-(phenylthio)acetamide 2 by
treatment of 1 with ammonia in methanol. Although amides
can very easily be reduced with various reductants to give
corresponding amines,21 in case of compound 2, the reduction
reaction was found to hardly proceed due to the presence of two
fluorine atoms. Among several reductants tested, no reaction was
observed when NaBH4 and BH3 were used as reducing agents
in refluxing anhydrous THF under argon atmosphere, whereas
At the final stage of the strategy, we tried to remove the inactive
protection group (PhS) using Bu3SnH/AIBN according to the
literature method.20 The deprotection of 5a was studied as a model
reaction. After stirring at 90 ◦C for 24 h in toluene, the desired
product 6a was isolated in only about 20% yield. Several attempts
have been put forth to improve yields including prolonging the
reaction time and elevating the reaction temperature, but failed to
enhance the yield of 6a above 40%. In the end, the good result
(75% isolated yield) for this reaction was achieved by adding
two equivalent of Bu3SnH to the solution in approximately two
equal portions over a period of 16 h. Thus, the PhS group on
Ugi products 5b–k could be cleaved smoothly using the reaction
conditions optimized for 5a and the final target compounds 6b–k
were obtained in good yields (Scheme 3).
Scheme 3 Synthesis of pseudopeptides containing CF2H group.
Conclusion
In summary, we have presented a general and efficient synthesis
strategy that uses common reaction conditions to transform
relatively simple and similar substrates into more and complex
Scheme 1 Synthesis of 2,2-difluoro-2-phenylsulfanyl-ethyl-isocyanide 4.
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molecules having terminal CF2H functionality. The core of this
approach is the conscious design and synthesis of new difluo-
rinated building blocks which contain an inactive group (easily
introduced and removed) and a reactive group on each side of
the CF2 group. To explore the validity and feasibility of this
protocol, we reported the realization of this strategy by detailing
the first example of Ugi four component reaction for the synthesis
of CF2H-bearing pseudopeptides using phenylthio as protecting
group and Bu3SnH/AIBN for PhS removal at the beginning and
end of the route, respectively. The synthesis of more complex CF2-
bearing molecules and the evaluation and optimization of this
strategy with new difluorinated building blocks are in progress
and will be reported in due course.
stirred for 30 more minutes and filtered. The filtrate was diluted
with ethyl acetate, washed successively with H2O and brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to leave the crude product. The resultant crude residue
was purified by chromatography to obtain the product 3. Yield:
45%, light-yellow liquid, 1H NMR: d = 7.63 (d, J = 7.3 Hz, 2H),
7.47-7.38 (m, 3H), 3.13 (t, J = 12.6 Hz, 2H), 1.49 (s, 2H); 13C
NMR: d = 136.2, 129.9, 129.4 (t, 1JCF = 279.4 Hz), 129.2, 126.7,
2
48.6 (t, JCF = 27.5 Hz); 19F NMR: d = -82.2 (t, J = 12.5 Hz);
GC-MS: m/z = 189, 160, 109, 77.
(1,1-Difluoro-2-isocyanoethyl)(phenyl)sulfane (4). The amine
3 (0.95 g, 5.00 mmol) and 20 mL ethyl formate were added
into a flask and the mixture was stirred 12 h (GC-MS) at
room temperature and then concentrated in vacuo, a light-yellow
liquid product N-(2,2-difluoro-2-(phenylthio)ethyl) formamide
was obtained quantitatively. The resultant liquid was directly used
for the next step without further purification. N-(2,2-difluoro-
2-(phenylthio)ethyl)formamide (1.08 g, 5 mmol), PPh3 (2.60 g,
10 mmol), CCl4 (1.0 mL, 10 mmol), triethylamine (1.4 mL,
10 mmol) and dry CH2Cl2 (20 mL) were added into a flask
and the mixture was stirred at 40 ◦C for about 1.5 h (GC-
MS). Then, the dark brown reaction mixture was cooled to room
temperature. Subsequently, the mixture was poured into cool water
and extracted with CH2Cl2 (50 mL ¥ 3). The organic layer was
washed successively with H2O (50 mL) and brine (50 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to get the crude product. The resultant crude residue was
purified by chromatography, and isocyanide 4 was obtained. Yield:
70%, light-yellow liquid, 1H NMR: d = 7.67 (d, J = 7.5 Hz, 2H),
7.52 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 3.87 (t, J =
11.0 Hz, 2H); 13C NMR: d = 162.7, 136.5, 130.9, 129.7, 125.1,
Experimental
General methods
All reagents were of analytical grade, and obtained from com-
mercial suppliers and used with further purification. Melting
points were measured in an open capillary using Bu¨chi melting
1
point B-540 apparatus and are uncorrected. H NMR and 13C
NMR spectra were recorded on a Bruker AM-400 spectrometer
(400 MHz and 100 MHz, respectively) using TMS as internal
standard. The 19F NMR were obtained using a Bruker AM-400
spectrometer (376 MHz) and measured with external CF3CO2H
as the standard. CDCl3 was used as the NMR solvent in all
cases. Gas chromatography-mass spectra (GC-MS) were recorded
on HP 5973 MSD with 6890 GC. High resolution mass spectra
(HRMS) were recorded under electron impact conditions using
a MicroMass GCT CA 055 instrument and recorded on a
MicroMass LCTTM spectrometer. Column chromatography was
carried out with Merck 60 (230-400 mesh) silica gel.
1
2
124.7 (t, JCF = 281.7 Hz), 47.3 (t, JCF = 33.3 Hz); 19F NMR:
d = -80.6 (t, J = 11.0 Hz); GC-MS: m/z = 199, 159, 135, 117,
109, 77. HRMS (EI): calcd for C9H7F2NS (M+): 199.0267, found:
199.0263.
Ethyl 2,2-difluoro-2-(phenylthio)acetate (1). NaH (0.26 g,
11 mmol) was added to a solution of thiophenol (1.10 g,
10 mmol) in DMSO (10 mL) at room temperature. After the
mixture was stirred for 1 h, ethyl bromodifluoroacetate (2.23 g,
11 mmol) was added to the solution. The mixture was stirred at
the same temperature for 15 h (TLC), quenched with aqueous
NH4Cl solution and extracted with Et2O. The organic layer was
washed successively with water and brine, dried over anhydrous
Na2SO4, and evaporated under reduced pressure. The residue was
chromatographed on a silica gel column to give 1. Yield: 87%.
GC-MS: m/z = 232, 159, 109, 77.
2,2-Difluoro-2-(phenylthio)acetamide (2). Ammonia was bub-
bled through a solution of acetate 1 (1.16 g, 5 mmol) in methanol
(10 mL) for 1 h (TLC) and then the mixture was concentrated in
vacuo, a white solid product 2 was obtained. The resultant solid
was directly used for the next step without further purification.
Yield: 98%. Mp = 114.4–115.0 ◦C. GC-MS: m/z = 203, 159, 110,
77.
General procedure for compounds 5a–k
To a stirred amine (1 mmol), aldehyde (1 mmol) was added in
portions for about 5 min. The mixture was stirred for 30 min again
at room temperature. Then, the reaction mixture was heated to
60 ◦C and the isocyanide 4 (1 mmol) and carboxylic acid (1 mmol)
◦
were added. Stirring was continued at 60 C for 1 h (TLC). The
crude residue was purified by chromatography to give the desired
products 5.
N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-2-oxo-1-phenyl-
ethyl)-N-phenylbenzamide (5a). White solid. Yield: 84%. Mp:
◦
1
155.2–156.3 C, H NMR: d = 7.59 (d, J = 7.3 Hz, 2H), 7.46-
7.28 (m, 10H), 7.23-7.12 (m, 3H), 7.06-7.01 (m, 5H), 6.58 (t, J =
6.0 Hz, 1H), 6.25 (s, 1H), 4.07-3.85 (m, 2H);13C NMR: d = 171.4,
169.9, 141.3, 136.4, 135.7, 134.0, 130.1, 130.0, 130.0, 129.7, 129.2,
128.6, 128.5, 128.5, 127.6 (t, 1JCF = 280.3 Hz), 127.3, 125.9, 67.0,
44.8 (t, 2JCF = 28.7 Hz); 19F NMR: d = -78.9 (dt, JF–F = 212.4 Hz,
JH–F = 12.5 Hz, 1F), -79.5 (dt, JF–F = 212.4 Hz, JH–F = 12.5 Hz,
1F).
2,2-Difluoro-2-(phenylthio)ethanamine (3). A solution of the
amide 2 (1.12 g, 5 mmol) in dry diethyl ether (10 mL) was
added dropwise to a suspension of lithium aluminium hydride
(0.38 g, 10 mmol) in dry diethyl ether (10 mL) at 0 ◦C under
argon atmosphere. The reaction mixture was then stirred at 0 ◦C
for 1 h, and quenched with H2O (1 mL) in order to destroy the
excess of lithium aluminium hydride. The resulting suspension was
N-(1-(benzo[d][1,3]dioxol-5-yl)-2-(2,2-difluoro-2-(phenylthio)-
ethylamino)-2-oxoethyl)-N-phenylbenzamide (5b). White solid.
Yield: 82%. Mp: 133.2–134.1 ◦C, 1H NMR: d = 7.60 (d, J = 7.5 Hz,
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2H), 7.46-7.31 (m, 5H), 7.22-7.02 (m, 8H), 6.81 (d, J = 8.7 Hz,
2H), 6.71 (d, J = 7.8 Hz, 1H), 6.51 (t, J = 6.0 Hz, 1H), 6.14
(s, 1H), 5.94 (s, 2H), 4.01-3.90 (m, 2H); 13C NMR: d = 171.4,
169.8, 147.8, 147.7, 141.2, 136.4, 135.7, 130.1, 129.6, 129.2, 128.6,
27.4, 22.3, 13.8; 19F NMR: d = -78.9 (dt, JF–F = 212.2 Hz, JH–F
12.3 Hz, 1F), -79.5 (dt, JF–F = 212.0 Hz, JH–F = 12.6 Hz, 1F).
=
N-benzyl-N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-2-oxo-1-
p-tolylethyl)pentanamide (5h). White solid. Yield: 63%. Mp:
127.6 (t, 1JCF = 279.9 Hz), 127.4, 125.9, 124.2, 110.5, 108.2, 101.2,
◦
1
94.1–95.2 C, H NMR: d = 7.56 (d, J = 7.3 Hz, 2H), 7.45-
7.34 (m, 3H), 7.24-7.14 (m, 5H), 7.08 (d, J = 7.7 Hz, 2H), 7.03 (d,
J = 7.0 Hz, 2H), 6.17 (t, J = 5.8 Hz, 1H), 5.87 (s, 1H), 4.72 (d,
J = 17.3 Hz, 1H), 4.50 (d, J = 17.5 Hz, 1H), 3.97-3.76 (m, 2H),
2.33-2.21 (m, 4H), 1.69-1.54 (m, 3H), 1.27 (dd, J = 14.4, 7.3 Hz,
2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR: d = 175.2, 170.1, 138.6,
137.5, 136.4, 130.1, 129.7, 129.5, 129.2, 128.6 (t, 1JCF = 279.9 Hz),
128.4, 127.0, 126.2, 120.2, 63.3, 50.3, 44.9 (t, 2JCF = 28.6 Hz), 33.7,
27.3, 22.4, 21.1, 13.8; 19F NMR: d = -78.9 (dt, JF–F = 212.1 Hz,
JH–F = 12.5 Hz, 1F), -79.5 (dt, JF–F = 212.1 Hz, JH–F = 12.8 Hz,
1F).
2
66.5, 44.9 (t, JCF = 28.8 Hz); 19F NMR: d = -78.9 (dt, JF–F
212.0 Hz, JH–F = 12.6 Hz, 1F), -79.5 (dt, JF–F = 212.3 Hz, JH–F
12.7 Hz, 1F).
=
=
N -(2-(2,2-difluoro-2-(phenylthio)ethylamino)-1-(4-methoxy-
phenyl)-2-oxoethyl)-N-◦phenylbenzamide (5c). White solid. Yield:
80%. Mp: 162.1–163.0 C, 1H NMR: d = 7.59 (d, J = 7.5 Hz, 2H),
7.46-7.32 (m, 5H), 7.23-6.99 (m, 10H), 6.79 (d, J = 8.6 Hz, 2H),
6.48 (t, J = 5.8 Hz, 1H), 6.25 (s, 1H), 4.06-3.85 (m, 2H), 3.78 (s,
3H); 13C NMR: d = 171.4, 170.0, 159.8, 141.1, 136.4, 135.8, 131.6,
130.2, 130.1, 129.6, 129.2, 128.6, 128.5, 127.6 (t, 1JCF = 280.2 Hz),
127.3, 125.9, 113.9, 66.0, 55.2, 44.9 (t, 2JCF = 28.7 Hz); 19F NMR:
d = -78.9 (dt, JF–F = 212.5 Hz, JH–F = 12.6 Hz, 1F), -79.5 (dt,
JF–F = 212.0 Hz, JH–F = 12.7 Hz, 1F).
N-(1-(2,2-difluoro-2-(phenylthio)ethylamino)-3-methyl-1-oxo-
butan-2-yl)-N-phenylbenzamide (5i). White solid. Yield: 55%.
Mp: 98.3–99.5 ◦C, 1H NMR: d = 8.06 (s, 1H), 7.66-7.64 (m, 2H),
7.48-7.37 (m, 3H), 7.31-7.29 (m, 2H), 7.26-7.13 (m, 8H), 4.40 (d,
J = 11.1 Hz, 1H), 4.04-3.82 (m, 2H), 2.84-2.73 (m, 1H), 1.16 (d,
J = 6.5 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H); 13C NMR: d = 172.7,
171.1, 136.4, 136.0, 130.1, 129.9, 129.2, 129.1, 128.6, 128.5, 127.8
N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-2-oxo-1-p-tolyl-
ethyl)-N-phenylbenzamide (5d). White solid. Yield: 79%. Mp:
◦
1
125.0–125.8 C, H NMR: d = 7.59 (d, J = 7.4 Hz, 2H), 7.46-
7.33 (m, 5H), 7.22-7.02 (m, 12H), 6.51 (t, J = 6.0 Hz, 1H), 6.20 (s,
1H), 4.02-3.89 (m, 2H), 3.32 (s, 3H); 13C NMR: d = 171.4, 169.9,
141.5, 138.5, 136.4, 135.8, 131.0, 130.1, 130.0, 129.9, 129.6, 129.3,
1
(t, JCF = 280.5 Hz), 127.4, 126.1, 44.3 (t, 2JCF = 28.9 Hz), 26.8,
20.2, 19.9; 19F NMR: d = -79.1 (t, J = 12.1 Hz).
129.2, 128.6, 128.5, 127.6 (t, 1JCF = 280.0 Hz), 127.3, 125.9, 66.7,
N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-2-oxo-1-phenyl-
ethyl)-N-(4-methoxyph◦enyl)pentanamide (5j). White solid. Yield:
62%. Mp: 128.0–128.9 C, 1H NMR: d = 7.56 (d, J = 7.5 Hz, 2H),
7.44-7.13 (m, 10H), 6.70 (s, 2H), 6.32 (s, 1H), 6.14 (s, 1H), 4.00-
3.79 (m, 2H), 3.75 (s, 3H), 2.20-1.99 (m, 2H), 1.60-1.52 (m, 2H),
1.26-1.17 (m, 2H), 0.80 (t, J = 7.31 Hz, 3H); 13C NMR: d = 174.6,
170.1, 159.1, 136.4, 134.0, 132.7, 131.3, 130.5, 130.1, 129.2, 128.4,
128.3, 127.6 (t, 1JCF = 280.3 Hz), 125.9, 114.0, 64.9, 55.3, 44.8 (t,
2JCF = 29.1 Hz), 34.4, 27.4, 22.3, 13.8; 19F NMR: d = -78.8 (dt,
JF–F = 211.9 Hz, JH–F = 12.4 Hz, 1F), -79.5 (dt, JF–F = 211.7 Hz,
JH–F = 12.6 Hz, 1F).
2
44.8 (t, JCF = 28.9 Hz), 21.1; 19F NMR: d = -78.9 (dt, JF–F
212.3 Hz, JH–F = 12.3 Hz, 1F), -79.5 (dt, JF–F = 212.4 Hz, JH–F
12.0 Hz, 1F).
=
=
N-butyl-N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-2-oxo-1-
phenyl◦ethyl)benzamide (5e). White solid. Yield: 74%. Mp: 119.0–
120.0 C, 1H NMR: d = 7.62 (d, J = 7.4 Hz, 2H), 7.48-7.37 (m,
13H), 6.98 (s, 1H), 5.77 (s, 1H), 4.02-3.86 (m, 2H), 3.36-3.24 (m,
2H), 1.44 (s, 1H), 1.09-0.97 (m, 3H), 0.63 (s, 3H); 13C NMR: d =
172.9, 170.1, 136.4, 134.7, 130.1, 129.7, 129.3, 129.0, 128.9, 128.6,
128.5, 127.6 (t, 1JCF = 280.3 Hz), 126.6, 125.9, 66.3, 44.7 (t, 2JCF
=
28.8 Hz), 31.3, 31.1, 19.8, 13.3; 19F NMR: d = -79.2 (s).
N-benzyl-N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-1-(4-
methoxyphenyl)-2-oxoethyl)benzamide (5k). White solid. Yield:
77%. Mp: 53.5–54.2 ◦C, 1H NMR: d = 7.59 (d, J = 7.3 Hz, 2H),
7.53-7.37 (m, 10H), 7.24-7.19 (m, 3H), 7.11 (d, J = 6.7 Hz, 2H),
6.86 (d, J = 6.7 Hz, 2H), 6.22 (s, 1H), 5.50 (s, 1H), 4.78 (d, J =
16.6 Hz, 1H), 4.47 (d, J = 16.4 Hz, 1H), 3.95-3.85 (m, 2H), 3.82
(s, 3H); 13C NMR: d = 173.2, 169.8, 159.9, 136.4, 135.9, 131.1,
N-benzyl-N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-2-oxo-1-
phenyl◦ethyl)benzamide (5f). White solid. Yield: 78%. Mp: 120.2–
1
121.1 C, H NMR: d = 7.57 (d, J = 7.5 Hz, 2H), 7.52 (d, J =
7.2 Hz, 2H), 7.46-7.33 (m, 11H), 7.21-7.16 (m, 3H), 7.09 (d, J =
7.1 Hz, 2H), 6.35 (s, 1H), 5.57 (s, 1H), 4.79 (d, J = 16.5 Hz, 1H),
4.51 (d, J = 16.5 Hz, 1H), 3.91-3.83 (m, 2H); 13C NMR: d = 173.3,
169.5, 136.4, 135.9, 134.2, 130.1, 130.0, 129.5, 129.2, 128.9, 128.8,
128.5, 128.4, 127.5 (t, 1JCF = 280.4 Hz), 127.1, 127.0, 126.8, 125.9,
130.2, 130.0, 129.3, 128.5, 128.4, 127.5 (t, 1JCF = 280.0 Hz), 127.1,
2
127.1, 126.8, 126.0, 125.9, 114.3, 64.1, 60.4, 55.3, 44.8 (t, JCF
=
28.7 Hz); 19F NMR: d = -79.2 (d, J = 11.9 Hz, 1F), -79.3 (d, J =
65.1, 60.4, 44.8 (t, 2JCF = 28.9 Hz); 19F NMR: d = -78.9 (dt, JF–F
212.6 Hz, JH–F = 12.5 Hz, 1F), -79.5 (dt, JF–F = 212.7 Hz, JH–F
12.4 Hz, 1F).
=
=
11.6 Hz, 1F).
General procedure for compounds 6a–k
N-(2-(2,2-difluoro-2-(phenylthio)ethylamino)-2-oxo-1-phenyl-
ethyl)-N-phe◦nylpentanamide (5g). White solid. Yield: 65%. Mp:
107.0–108.0 C, 1H NMR: d = 7.57 (d, J = 7.4 Hz, 2H), 7.45-7.35
(m, 4H), 7.23-7.15 (m, 9H), 6.34 (s, 1H), 6.11 (s, 1H), 3.98-3.84
(m, 2H), 2.10-2.05 (m, 2H), 1.60-1.56 (m, 2H), 1.27-1.17 (m, 2H),
0.80 (t, J = 7.3 Hz, 3H); 13C NMR: d = 174.1, 170.0, 140.2,
136.4, 133.9, 130.2, 130.1, 129.2, 129.0, 128.5, 128.3, 128.2, 127.6
To a solution of 5 (0.5 mmol) in dry toluene (1 mL) was
added Bu3SnH (150 mg, 0.5 mmol) under argon atmosphere.
Deoxygenation was continued for 5 min. Azo-bis-isobutryonitrile
(AIBN) (13 mg, 0.08 mmol) was added and the solution was
heated at 90 ◦C for 8 h. Another portion of Bu3SnH (150 mg,
0.5 mmol) was added and stirring was continued for 8 h (TLC).
The mixture was concentrated under reduced pressure and the
residue was dissolved in EtOAc (5 mL). The solution was stirred
1
2
(t, JCF = 284.1 Hz), 125.9, 65.3, 44.8 (t, JCF = 28.9 Hz), 34.5,
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overnight with KF/H2O (15 mg/0.15 mL) and extracted with
EtOAc (20 mL ¥ 3). The organic phase was washed successively
with water (20 mL) and brine (20 mL), and dried over anhydrous
Na2SO4. After solvent removal, the crude product was purified by
chromatography to give desired products 6.
(d, J = 16.6 Hz, 1H), 4.41 (d, J = 16.1 Hz, 1H), 3.68-3.53 (m,
2H); 13C NMR: d = 173.1, 170.0, 135.7, 134.3, 130.1, 129.4, 129.1,
129.0, 128.6, 127.4, 127.0, 126.8, 113.5 (t, 1JCF = 241.6 Hz), 67.7,
65.0, 42.0 (t, 2JCF = 26.9 Hz); 19F NMR: d = -122.8 (d, J = 55.4
Hz); HRMS (ESI): calcd for C24H22F2N2O2 ([M+H]+): 409.1728,
found: 409.1715.
N-(2-(2,2-difluoroethylamino)-2-oxo-1-phenylethyl)-N-phenyl-
benzamide (6a). White solid. Yield: 65%. Mp: 122.2–123.0 ◦C,
1H-NMR: d = 7.31-7.28 (m, 7H), 7.19-6.97 (m, 8H), 6.27 (s, 1H),
N-(2-(2,2-difluoroethylamino)-2-oxo-1-phenylethyl)-N-phenyl-
pentanamide (6g). White solid. Yield: 51%. Mp: 88.0–89.1 ◦C,
1H NMR: d = 7.25-7.13 (m, 10H), 6.09 (s, 1H), 5.98 (s, 1H), 5.87
(tt, J = 56.0, 4.1 Hz, 1H), 3.73-3.62 (m, 2H), 2.09-2.04 (m, 2H),
6.08 (s, 1H), 5.90 (tt, J = 56.0, 3.9 Hz, 1H), 3.80-3.60 (m, 2H); 13
C
NMR: d = 171.3, 170.3, 141.5, 135.6, 134.1, 129.9, 129.8, 129.7,
128.8, 128.7, 128.6, 128.5, 127.6, 127.3, 113.5 (t, 1JCF = 241.6 Hz),
1.59-1.55 (m, 2H), 1.27-1.19 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H); 13
C
2
67.4, 42.1 (t, JCF = 26.8 Hz); 19F NMR: d = -122.8 (dt, J =
NMR: d = 174.1, 170.6, 140.3, 134.0, 130.2, 130.1, 129.0, 128.6,
128.5, 128.2, 113.5 (t, 1JCF = 241.6 Hz), 65.6, 42.0 (t, 2JCF = 26.7
Hz), 34.5, 27.4, 22.3, 13.8; 19F NMR: d = -122.8 (dt, J = 56.0, 14.8
Hz); HRMS (ESI): calcd for C21H24F2N2O2 ([M+H]+): 375.1884,
found: 375.1873.
56.7, 14.8 Hz); HRMS (ESI): calcd for C23H20F2N2O2 ([M+H]+):
395.1571, found: 395.1555.
N-(1-(benzo[d][1,3]dioxol-5-yl)-2-(2,2-difluoroethylamino)-2-
oxoethyl)-N-phenylbenzamide (6b). White solid. Yield: 67%. Mp:
62.3–63.0 ◦C, 1H NMR: d = 7.31 (d, J = 7.1 Hz, 2H), 7.22-6.98
(m, 8H), 6.82-6.70 (m, 3H), 6.25 (s, 1H), 5.96 (s, 1H), 5.95 (s, 2H),
5.91 (tt, J = 56.0, 4.2 Hz, 1H), 3.78-3.65 (m, 2H); 13C NMR: d =
171.3, 170.3, 148.0, 147.9, 141.5, 135.6, 129.9, 129.7, 128.6, 128.5,
127.8, 127.6, 127.4, 124.0, 113.5 (t, 1JCF = 241.6 Hz), 110.2, 108.3,
101.3, 67.0, 42.1 (t, 2JCF = 26.7 Hz); 19F NMR: d = -122.8 (dt, J =
56.2, 14.7 Hz); HRMS (ESI): calcd for C24H20F2N2O4 ([M+H]+):
439.1469, found: 439.1455.
N-benzyl-N-(2-(2,2-difluoroethylamino)-2-oxo-1-p-tolyl◦ethyl)-
pentanamide (6h). White solid. Yield: 54%. Mp: 63.0-63.9 C, 1H
NMR: d = 7.27-7.18 (m, 4H), 7.11-7.08 (m, 4H), 6.30 (s, 1H),
5.84 (tt, J = 56.1, 4.0 Hz, 1H), 5.74 (s, 1H), 3.73-3.62 (m, 2H),
4.73 (d, J = 17.6 Hz, 1H), 4.47 (d, J = 18.6 Hz, 1H), 3.69-3.53
(m, 2H), 2.38-2.26 (m, 4H), 1.83-1.58 (m, 3H), 1.29 (dd, J = 14.2,
7.8 Hz, 2H), 0.86 (t, J = 7.3 Hz, 2H); 13C NMR: d = 175.1,
170.7, 138.7, 137.4, 131.5, 129.6, 129.5, 128.5, 127.1, 126.2, 113.6
1
2
(t, JCF = 241.5 Hz), 63.3, 50.3, 41.9 (t, JCF = 26.9 Hz), 33.7,
27.3, 22.4, 21.1, 13.8; 19F NMR: d = -122.7 (dt, J = 56.1, 14.6
Hz); HRMS (ESI): calcd for C23H28F2N2O2 ([M+H]+): 403.2197,
found: 403.2189.
N -(2-(2,2-difluoroethylamino)-1-(4-methoxyphenyl)-2-oxo-
ethyl)-N-phenylbenzamide (6c). White solid. Yield: 69%. Mp:
◦
1
136.5–137.2 C, H NMR: d = 7.31 (d, J = 7.3 Hz, 2H), 7.21-
6.97 (m, 10H), 6.80 (d, J = 8.6 Hz, 2H), 6.25 (s, 1H), 6.08 (s, 1H),
5.91 (tt, J = 56.1, 4.1 Hz, 1H), 3.78 (s, 3H), 3.76-3.60 (m, 2H); 13
C
N-(1-(2,2-difluoroethylamino)-3-methyl-1-oxobutan-2-yl)-N-
phenylbenzamide (6i). White solid. Yield: 64%. Mp: 94.0–
94.9 ◦C, 1H NMR: d = 7.85 (s, 1H), 7.35-7.29 (m, 2H), 7.28-7.08
(m, 8H), 5.90 (tt, J = 56.1, 4.0 Hz, 1H), 4.41 (d, J = 11.3 Hz,
1H), 3.76-3.66 (m, 2H), 2.80-2.74 (m, 1H), 1.17 (d, J = 6.50 Hz,
NMR: d = 171.3, 170.6, 159.8, 141.3, 135.8, 131.5, 130.1, 129.6,
128.5, 127.6, 127.3, 126.1, 114.0, 113.6 (t, 1JCF = 241.5 Hz), 66.3,
2
55.2, 42.1 (t, JCF = 26.7 Hz); 19F NMR: d = -122.8 (dt, J =
56.0, 14.8 Hz); HRMS (ESI): calcd for C24H22F2N2O3 ([M+H]+):
425.1677, found: 425.1673.
3H), 1.07 (d, J = 6.60 Hz, 3H); 13C NMR: d = 172.7, 171.5, 142.6,
1
135.9, 130.0, 129.1, 128.6, 128.3, 127.9, 127.4, 113.5 (t, JCF
=
N-(2-(2,2-difluoroethylamino)-2-oxo-1-p-tolylethyl)-N-phenyl-
benzamide (6d). White solid. Yield: 70%. Mp: 111.5–112.3 ◦C, 1H
NMR: d = 7.32 (d, J = 7.1 Hz, 2H), 7.22-7.05 (m, 10H), 6.99-6.98
(m, 2H), 6.25 (s, 1H), 6.04 (s, 1H), 5.91 (tt, J = 56.1, 4.1 Hz, 1H),
3.75-3.64 (m, 2H), 2.32 (s, 3H); 13C NMR: d = 171.3, 170.6, 141.5,
138.7, 135.8, 131.1, 129.9, 129.8, 129.6, 129.4, 128.6, 127.6, 127.3,
241.7 Hz), 41.6 (t, 2JCF = 26.1 Hz), 26.9, 20.1, 19.9; 19F NMR: d =
-122.9 (dt, J = 25.6, 15.4 Hz, 1F), -123.1 (dt, J = 24.7, 15.2 Hz,
1F); HRMS (ESI): calcd for C20H22F2N2O2 ([M+H]+): 361.1728,
found: 361.1726.
N-(2-(2,2-difluoroethylamino)-2-oxo-1-phenylethyl)-N-(4-meth-
oxyphenyl)pentanamide (6j). Light-yellow viscous liquid. Yield:
1
2
113.6 (t, JCF = 241.5 Hz), 110.6, 67.1, 42.1 (t, JCF = 26.8 Hz),
21.1; 19F NMR: d = -122.8 (dt, J = 56.3, 14.3 Hz); HRMS (ESI):
calcd for C24H22F2N2O2 ([M+H]+): 409.1728, found: 409.1719.
1
52%. H NMR: d = 7.28-7.12 (m, 7H), 6.83-6.71 (m, 2H), 6.34
(d, J = 6.0 Hz, 1H), 6.08 (s, 1H), 5.86 (tt, J = 56.1, 4.2 Hz, 1H),
3.76(s, 3H), 3.70-3.60 (m, 2H), 2.08-2.03 (m, 2H), 1.57-1.52 (m,
2H), 1.29-1.19 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H); 13C NMR: d =
174.6, 170.8, 159.0, 134.2, 132.7, 131.3, 130.3, 128.5, 128.4, 114.0,
N-butyl-N-(2-(2,2-difluoroethylamino)-2-oxo-1-phenylethyl)-
benzamide (6e). White solid. Yield: 70%. Mp: 104.0–105.2 ◦C,
1H NMR: d = 7.42-7.38 (m, 10H), 6.70 (s, 1H), 5.88 (tt, J = 56.1,
3.6 Hz, 1H), 5.66 (s, 1H), 3.69-3.58 (m, 2H), 3.31-3.21 (m, 2H),
1.37-1.31 (m, 1H), 1.06-1.02 (m, 3H), 0.60 (s, 3H); 13C NMR: d =
172.9, 170.6, 136.3, 134.8, 129.7, 129.0, 128.9, 128.7, 128.5, 126.5,
113.5 (t, 1JCF = 241.6 Hz), 64.2, 49.1, 41.9 (t, 2JCF = 26.6 Hz), 31.1,
19.7, 13.3; 19F NMR: d = -122.8 (d, J = 53.2 Hz); HRMS (ESI):
calcd for C21H24F2N2O2 ([M+H]+): 375.1884, found: 375.1877.
1
2
113.6 (t, JCF = 241.6 Hz), 65.1, 55.3, 42.0 (t, JCF = 26.7 Hz),
34.4, 27.4, 22.3, 13.8; 19F NMR: d = -122.7 (dt, J = 56.0, 14.8
Hz); HRMS (ESI): calcd for C22H26F2N2O3 ([M+H]+): 405.1990,
found: 405.1980.
N-benzyl-N-(2-(2,2-difluoroethylamino)-1-(4-methoxyphenyl)-
2-oxoethyl)benzamide (6k). White solid. Yield: 72%. Mp: 137.5-
138.4 ◦C, 1H NMR: d = 7.53 (d, J = 6.7 Hz, 2H), 7.44-7.35 (m,
5H), 7.27-7.20 (m, 5H), 6.88 (d, J = 8.4 Hz, 2H), 6.05 (s, 1H),
5.89 (t, J = 62.3 Hz, 1H), 5.23 (s, 1H), 4.77 (d, J = 16.6 Hz, 1H),
4.39 (d, J = 15.9 Hz, 1H), 3.83 (s, 3H), 3.71-3.53 (m, 2H); 13C
N-benzyl-N-(2-(2,2-difluoroethylamino)-2-oxo-1-phenyl◦ethyl)-
benzamide (6f). White solid. Yield: 76%. Mp: 112.0–113.0 C, 1H
NMR: d = 7.52 (d, J = 7.6 Hz, 2H), 7.41-7.35 (m, 8H), 7.25-7.18
(m, 5H), 6.12 (s, 1H), 5.86 (t, J = 56.1 Hz, 1H), 5.32 (s, 1H), 4.78
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NMR: d = 173.1, 170.3, 160.0, 136.8, 136.7, 135.7, 131.0, 130.1,
128.6, 127.3, 127.0, 126.8, 126.2, 114.5, 113.5 (t, 1JCF = 241.8 Hz),
64.3, 60.4, 53.4, 42.0 (t, 2JCF = 26.9 Hz); 19F NMR: d = -122.8 (d,
J = 56.0 Hz); HRMS (ESI): calcd for C25H24F2N2O3 ([M+H]+):
439.1833, found: 439.1828.
10 J. Hu, J. Fluorine Chem., 2009, 130, 1130–1139.
11 (a) G. K. S. Prakash, J. Hu, T. Mathew and G. A. Olah, Angew.
Chem., Int. Ed., 2003, 42, 5216–5219; (b) X. Qiu, W. Meng and F.
Qing, Tetrahedron, 2004, 60, 5201–5206; (c) W. Wan, Y. H. Gao, H. Z.
Jiang and J. Hao, J. Fluorine Chem., 2008, 129, 510–514.
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Eto, Y. Kaneko, S. Takeda, M. Tokizawa, S. Sato, K. Yoshida, S.
Namiki, M. Ogawa, K. Maebashi, K. Ishida, M. Matsumoto and T.
Asaoka, Chem. Pharm. Bull., 2001, 49, 173–182.
Acknowledgements
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(b) V. Reutrakul, T. Thongpaisanwong, P. Tuchinda, C. Kuhakarn and
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We are grateful for financial supports from the National Basic
Research Program of China (973 Program, 2010CB126101),
Shanghai Foundation of Science of Technology (09391911800),
the National High Technology Research and Development Pro-
gram of China (863 Program, 2006AA10A201), and the Shanghai
Leading Academic Discipline Project (B507).
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2386–2391 | 2391
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