The synthesis of α,α-difluoroacetamides via electrophilic fluorination in the mixed-solvent of water and PEG-400

Article abstract of DOI:10.1016/j.jfluchem.2013.03.016

Under mild conditions, a series of α,α-difluoro-β- ketoamides were synthesized with Selectfluor as the F ⁺ source in the presence of K₂CO₃ in the mixed-solvent of water and PEG-400 (VH₂O:^VPEG-400=3:1), without additional phase-transfer catalyst. By using this approach, most cases examined in this study proceeded in nearly quantitative conversions regardless of the electronic nature of the substituent pattern.

Full text of DOI:10.1016/j.jfluchem.2013.03.016

Journal of Fluorine Chemistry 151 (2013) 45–49
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
The synthesis of
a,
a
-difluoroacetamides via electrophilic fluorination
in the mixed-solvent of water and PEG-400
*
*
Zhiguo Zhang , Jingjing Bi, Qingfeng Liu, Guisheng Zhang
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, College of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang, Henan 453007, PR China
A R T I C L E I N F O
A B S T R A C T
Under mild conditions, a series of a,a-difluoro-b
-ketoamides were synthesized with Selectfluor1 as the
Article history:
F+ source in the presence of K2CO3 in the mixed-solvent of water and PEG-400 ðVH : VPEG
¼ 3 : 1Þ,
Received 11 January 2013
Received in revised form 21 March 2013
Accepted 22 March 2013
Available online 30 March 2013
O
2
-400
without additional phase-transfer catalyst. By using this approach, most cases examined in this study
proceeded in nearly quantitative conversions regardless of the electronic nature of the substituent
pattern.
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Electrophilic fluorination
Selectfluor1
Acetoacetamides
Difluorinated
1. Introduction
The advantage of this strategy is that two C–F bonds can be
introduced simultaneously without undergoing the process of
A ‘‘CF2 center’’ adds significant value to some pharmaceu-
ticals [1] (examples including anaesthetics [2], enzyme inhibi-
tors [3], sugar analogues [4], pesticides [5], herbicides [6], etc.)
and materials [7] because it can bring unique features to the
compounds [8]. Besides, ‘‘CF2 center’’-containing compounds are
also very useful intermediates in organic synthesis [9],
especially in asymmetric synthesis [10], labelling chemistry
[11], radical chemistry [12], and for the preparation of fluorine-
containing heterocyclic compounds [13]. Currently, many
methods are available in the literature for the construction of
a ‘‘CF2 center’’. Firstly, it can be transformed from a variety of
fluorine-containing small organic molecules (Eq. (1)). Among
these examples, a variety of reactions using trifluoromethyl
[12d,14] and gem-difluoromethylene [15] compounds have been
reported. It should be also noted that nucleophilic substitution
reactions of difluoromethylphenylsulfone with primary alkyl
halides [16], the derivatization reaction of the difluoroimine
monofluorination. However, the ‘‘CF2 center’’ often cannot be
freely introduced at any step especially in a multi-step process,
which limited its development to some extent. In contrast, the
most widely used method is the direct electrophilic fluorination
reaction of parent carbonyl compounds or their enolates
(Eq. (2)) [10d,20]. At present, elemental fluorine [21] or all
kinds of electrophilic fluorination agents [22], such as FClO3
[23], NF3O [24], XeF2 [25], CsSO4F [26], fluoroxy compounds
RFOF [27] including CF3OF, CF3CO2F or AcOF (some of them are
generated in situ) [22,28], organofluorine reagents involving
iodine and/or iodo-compounds [29], have been developed as the
reagents for electrophilic fluorination reactions. More recently
much attention has been given to the fluoronitrogen com-
pounds, such as NFSI and Selectfluor1 (stable and readily
available) [30]. In the process of the fluorination of carbonyl
compounds, the substrates are firstly converted into the
a-
monofluorinated derivatives, and thence to the -difluori-
a,a
synthons or the
a
-halo-
a
,
a
-difluoroketones [17], the addition
nated derivatives, and the second step is the rate determining
step [31]. Currently, in the most conversions, an excess of
harmful, unstable or expensive F+ source and various strong
bases (such as NaH, KHMDS, LDA etc.) or metal catalyst, organic
solvents, low temperatures or anhydrous conditions were used
reluctantly in order to avoid the generation of monofluorinated
compounds, shorten the reaction times and increase the yield of
the difluorinated compounds. Additionally, these harsh condi-
tions may limit the conversion in large-scale preparation for
reaction of difluoropropargyl bromide with imines [18], and the
addition of PhSeCF2TMS to aldehydes or imines [19] are recent
achievements for functionalized difluoromethylene compounds.
* Corresponding authors. Fax: +86 373 3325250.
E-mail addresses: zhangzhiguo3030@yahoo.com.cn (Z. Zhang),
zgs6668@yahoo.com (G. Zhang).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.03.016

46
Z. Zhang et al. / Journal of Fluorine Chemistry 151 (2013) 45–49
industrial applications.
demonstrated that the higher temperatures or the more reactive
potassium enolates enhanced the difluorination [34d]. We thereby
deduced that increase in both solubility of the acetoacetamides in
hot water and the their interaction with the base would result in
the smooth production of the products 3. Based on this idea, we
examined water as well as mixed-solvent of water and PEG-400 for
the difluorination of acetoacetamides. After many attempts
(Table 1), we found that the yield of 3a could be significantly
improved from 19% to 97% by increasing the amount of K2CO3 from
0 to 1.0 equiv. along with a noticeably shorter reaction times
(entries 2–4). The yield of 3a was slightly lower (88%) by further
increase of K2CO3 (2.2 equiv.), although it took a shorter time, at
25 8C (entry 5 vs. 4). As shown in entry 4, compared with PEG-400
(entry 1), water would be also one of the best solvents for this
reaction. However, it was found that the reaction time could be
greatly shortened without any affect on the product yield when the
mixed-solvent of water in the ratio of 5 to 1 was used (entry 6 vs.
4). Finally, 3a could be obtained in 99% yield when we treated 3-
oxo-N-(p-tolyl)butanamide 1a with Selectfluor1 (2.2 equiv.),
K2CO3 (1.0 equiv.) in water and PEG-400 (3.0 mL, 3:1 ratio) for
6.0 h at 25 8C (entry 7). Increase in the amount of K2CO3 could
resulted in the higher yield of the di-substituted product (entries 8,
9 vs. 7, and 10 vs. 11). Similarly, the yield of 3a could also be
improved by increasing the proportion of PEG-400 in the mixed-
solvent (entry 6 vs. 7 and 10). The reaction performed much better
in hydrophilic ionic liquids 1-butyl-3-methylimidazolium tetra-
fluoroborate ([BMIM]BF4) than in hydrophobic ionic liquids 1-
butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF6)
(entries 12–15), and the base was necessary for the conversion
from 1a to 3a in ionic liquids. And among them, the best yield of 3a
(91%) was isolated from the [BMIM]BF4 along with 8% 2a at 25 8C
after 20 h (entry 13).
(1)
(2)
In fact, the a,a-difluoroacylacetamide moiety is a key structure
of the human heart chymase inhibitors [32] and renin inhibitors
[33]. The difluoromethylene ketone moiety, by interacting with the
S0 subsite of the enzyme, increases the affinity and selectivity of
human chymase [32]. So far a few cases have focused on the
preparation of
a,a-difluoro-b-ketoamides, in which acetoaceta-
mides are in general as a special case of 1,3-dicarbonyl compounds
[34]. And among them, preparation of 2,2-difluoro-3-oxo-N,3-
diphenylpropanamide in water or solvent-free conditions was
reported only in one case [34c]. To the best of our knowledge, there
is no detailed investigation of the synthesis of
a,a-difluoro-b-
ketoamides to date, especially the consideration of a greener
method such as avoiding the use of rigorous conditions, organic
solvent and minimizing fluoride reagents, etc. Herein, we wish to
report a greener approach on the synthesis of the
ketoamides by using acetoacetamides under mild conditions.
a,a-difluoro-b-
2. Results and discussion
Very recently, combined with our research on acetoacetamides
in recent years [35], we developed a catalyst-free and highly
selective method for the synthesis of
a-monofluorinated acet-
oacetamides via electrophilic fluorination reaction of acetoaceta-
mides 1 in PEG-400 [36]. During that research, we found that 2,2-
difluoro-3-oxo-N-(p-tolyl)butanamide 3a could be isolated in good
yield (97%) by using commercially available Selectfluor1 as the F+
source at 60 8C (Table 1, entry 1), but our further investigation
using various substrates revealed that this procedure employing
the single use of PEG-400 was not suitable to obtain the difluoride
3 in high yield [37]. We are still interested in the high-yield
synthesis of 3 under the widely applicable conditions. Davis et al.
Table 2
The preparation of
a,
a
-difluoro-
b
-ketoamides.a
Entry
Substrate 1
Time
(A/B)b
Product 3
Yield/%c
(A/B)b
Table 1
Survey of reaction conditions.a
1
2
R1 = Me, R2 = 4-Me-Ph
R1 = Me, R2 = 2-Me-Ph
R1 = Me, R2 = 2,4-diMe-Ph
R1 = Me, R2 = 2-MeO-Ph
R1 = Me, R2 = 4-MeO-Ph
R1 = Me, R2 = 4-EtO-Ph
R1 = Me, R2 = Ph
R1 = Me, R2 = 2-Cl-Ph
R1 = Me, R2 = 4-Cl-Ph
R1 = Me, R2 = 5-Cl-2-MeOPh
R1 = Me, R2 = 4-COOEt-Ph
R1 = Me, R2 = 4-MeO-Benzyl
R1 = Me, R2 = Benzyl
R1 = Me, R2 = 4-Cl-Benzyl
R1 = (CH3)2CH, R2 = Ph
R1 = Ph, R2 = 4-Me-Ph
15 h/6 h
17 h/8 h
3a
3b
3c
3d
3e
3f
97/99
99/99
3
29 h/10 h
8 h/4 h
99/98
4
97/98
5
3 d/16 h
10 d/11 h
12 h/5 h
10 h/5 h
6 d/8 h
92/99
6
97d/97
99/99
7
3 g
3 h
3i
Entry
Solvent
Base (equiv.)
T
Time
20 h
Yield (%)b
8
99/98
(8C)c
1a:2a:3a
9
97d/99
98d/98
98/98
10
11
12
13
14
15
16
6 d/10 h
22 h/7 h
3 d/16 h
2 d/10 h
5 d/10 h
7 d/15 h
4 d/2 d
3j
1
2
PEG-400
K2CO3 (0)
60
25
25
25
25
25
25
25
25
25
25
25
25
60
60
0:0:97
49:31:19
0:6:93
3k
3l
H2O
K2CO3 (0)
6 d
8 d
15 h
2.5 h
6 h
90e/92
92d/90
97d/96
40d,f/94
19d,g/93d
3
H2O
K2CO3 (0.5)
K2CO3 (1.0)
K2CO3 (2.2)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (0.5)
K2CO3 (0.3)
K2CO3 (1.0)
K2CO3 (0)
3m
3n
3o
3p
4
H2O
0:0:97
5
H2O
0:0:88
6
H2O:PEG-400 (5:1)
H2O:PEG-400 (3:1)
H2O:PEG-400 (3:1)
H2O:PEG-400 (3:1)
H2O:PEG-400 (1:1)
H2O:PEG-400 (1:1)
[BMIM]BF4
0:6:93
7
6 h
6 h
0:0:99
8
0:18:81
0:28:71
0:0:99
Reactions were carried out with acetoacetamides 1 (0.5 mmol), Selectfluor1
(1.1 mmol), K2CO3 (0.5 mmol), solvent (3.0 mL) at room temperature, unless
otherwise indicated.
a
9
6 h
10
11
12
13
14
15
2 h
2 h
10:53:37
37:63:0
0:8:91
b
A: reactions were performed in H2O, B: reactions were performed in mixed-
K2CO3 (0)
20 h
20 h
20 h
24 h
solvent ðVH : VPEG
¼ 3 : 1Þ.
O
2
-400
[BMIM]BF4
K2CO3 (1.0)
K2CO3 (0)
c
Isolated yield.
[BMIM]PF6
61:38:0
0:71:29
d
60 8C was used.
[BMIM]PF6
K2CO3 (1.0)
e
10% 2l was isolated and difluorinated product 3l could not be promoted by
a
All reactions were carried out with acetoacetamide 1a (0.5 mmol), Selectfluor1
prolonging reaction time.
f
(2.2 equiv.) as the F+ source, unless otherwise indicated.
b
22% 2o and 26% 1o were isolated and difluorinated product 3o could not be
promoted by prolonging reaction time.
Isolated yield.
g
c
The yield of monofluorinated 2p was 22% and 57% substrate 1p was recovered.
Oil bath temperature.

Z. Zhang et al. / Journal of Fluorine Chemistry 151 (2013) 45–49
47
With the optimized conditions in hand, the effect of various
b
-
1; 3:0 mLÞ before Selectfluor1 (390 mg, 2.2 mmol) was added.
Then the reaction mixture was stirred at room temperature for
6.0 h (monitored by TLC), then to the mixture was added water
(10.0 mL), extracted with diethyl ether (15.0 mL ꢀ 3). The solvent
was removed under reduced pressure, and the residue was purified
by a short flash silica gel column chromatography to give
compound 3a (112 mg, 99%) (Eluent: petroleum ether/ethyl
acetate = 5/1).
keto amides were then further evaluated in water and the mixed-
solvent, respectively (Table 1, entries 4 and 7). As shown in Table 2,
in the reactions of N-aryl substituted acetoacetamides in water, the
experiments showed that the electronic effect of the substituents
on the aromatic ring, either electron-donating groups (EDG) (Me,
OMe, OEt; entries 1–6, A) or electron-withdrawing groups (EWG)
(Cl, COOEt; entries 8–11, A) coupled with aryl-unsubstituted
substrate (entry 7, A), did not exert any significant effect on the
difluorination reaction. The desired difluorinated products 3a-k
were isolated in the yields of 92–99%. For benzyl substituted
amides 1l-n, these compounds could also produce the correspond-
ing products 3l-n in excellent yields albeit the reaction periods are
longer (entries 12–14, A). On the other hand, substrates with
isobutyroyl or benzoyl moiety in place of acetyl group (1o, 1p)
afforded the difluorinated products 3o and 3p in much lower yields
in water (entries 15–16, A). This is mainly due to the low enol
content of their molecule at equilibrium in water [34d,38].
Compared with the reactions carried out in water, it should be
4.1.1. 2,2-Difluoro-3-oxo-N-(p-tolyl)butanamide (3a)
Light yellow solid; mp: 67–69 8C; 1H NMR (400 MHz, CDCl3):
d
8.22 (s, 1 H), 7.41 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 2.48 (s,
3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3):
196.33 (t,
d
J = 28.0 Hz), 158.96 (t, J = 26.7 Hz), 135.95, 133.07, 129.79,
120.57, 109.13 (t, J = 264.8 Hz), 25.30, 20.98; 19F NMR (CDCl3,
376.5 MHz):
1110, 950, 814
d
ꢁ114.5; IR (KBr, neat):
v 3349, 1670, 1602, 1544,
4.1.2. 2,2-Difluoro-3-oxo-N-(o-tolyl)butanamide (3b)
White solid; mp: 45–47 8C; 1H NMR (400 MHz, CDCl3):
d 8.08
emphasized herein that by using
VPEG
a
mixed-solvent ðVH
:
O
2
¼ 3 : 1Þ as the reaction media, the reaction for all
(s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.21–7.13 (m, 3H), 2.47 (s, 3H), 2.23
(s, 3H); 13C NMR (100 MHz, CDCl3):
196.26 (t, J = 28.2 Hz),
-
400
substrates including 1o and 1p could complete in a dramatically
shorter time period to provide the corresponding products 2 in
excellent yields at room temperature (entries 1–16, B). It is
deduced that the improved solubility of acetoacetamides in the
mixed-solvent possibly made the difluorination easier to proceed
in the absence of any additional phase-transfer catalyst.
d
159.32 (t, J = 26.7 Hz), 133.11, 130.83, 130.77, 126.92, 126.78,
123.75, 109.13 (t, J = 264.8 Hz), 25.06, 17.19; 19F NMR (CDCl3,
376.5 MHz):
d
ꢁ114.4; HRMS (ESI): calcd for C11H11F2NO2
([(M+1)]+) 228.0836, found 228.0831; IR (KBr, neat):
1673,1540, 1463, 1128, 751
v 3351,
4.1.3. N-(2,4-dimethylphenyl)-2,2-difluoro-3-oxobutanamide (3c)
Light yellow solid; mp: 41–43 8C; 1H NMR (400 MHz, CDCl3):
3. Conclusions
d
7.93 (s, 1H), 7.51 (d, J = 8 Hz, 1H), 7.02 (d, J = 8 Hz, 2H), 2.49 (s, 3H),
2.30 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3):
196.34 (t,
J = 28.0 Hz), 159.14 (t, J = 26.7 Hz), 136.71, 131.43, 130.47, 130.36,
127.42, 123.47, 109.17 (t, J = 264.4 Hz), 25.22, 20.88, 17.28; 19F
In conclusion, the electrophilic fluorination of acetoacetamides
d
for the facile synthesis of
a,a-difluoro-b-ketoamides has been
developed by using Selectfluor1 as the F+ source in the presence of
K2CO3 in the mixed-solvent of water and PEG-400 in the ratio of 3
to 1. As the increase in the efficiency, the present method does not
involve the requirement of the use of additional phase-transfer
catalyst and problematic work-up. The electrophilic fluorination of
other 1,3-dicarbonyl derivatives to form 2,2-difluoro-l,3-dicarbo-
nyl analogues under green conditions are in progress in our lab.
NMR (CDCl3, 376.5 MHz):
C
d
ꢁ114.4; HRMS (ESI): calcd for
12H13F2NO2 ([(M + 1)]+) 242.0993, found 242.0987; IR (KBr,
neat):
v 3299, 1698, 1653, 1540, 1506, 1139, 1116, 875, 808
4.1.4. 2,2-Difluoro-N-(2-methoxyphenyl)-3-oxobutanamide (3d)
Yellow solid; mp: 64–66 8C; 1H NMR (400 MHz, CDCl3):
8.72
d
(s, 1H), 8.28 (d, J = 8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.96 (t,
J = 7.6 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 3.89 (s, 3H), 2.49 (s, 3H); 13C
4. Experimental
All reagents were purchased from commercial sources and used
without further purification, unless otherwise indicated. 1H NMR,
13C NMR and 19F spectra were recorded on a Bruker Avance 400
(1H: 400 MHz, 13C: 100 MHz, 19F: 376.5 MHz at 25 8C). Chemical
shifts are reported in ppm units relative to TMS as internal
standard for 1H and 13C resonances, and CCl3F for the 19F
resonance. Data are represented as follows: chemical shift,
integration, multiplicity (br = broad, s = singlet, d = doublet,
dd = double doublet, t = triplet, q = quartet, m = multiplet), cou-
pling constants in Hertz (Hz). All high-resolution mass spectra
(HRMS) were measured on a Bruker MicroTOF mass spectrometer
Bruker micrOTOF (ESI-oa-TOF). Melting points were measured on a
YuHua X-5 apparatus. IR spectra were recorded on a Bio-Rad FTS-
40 FT-IR spectrophotometer as KBr pellets. All reactions were
monitored by TLC with GF 254 silica gel coated plates. Flash
column chromatography was carried out using 200–300 mesh
silica gel at increased pressure.
NMR (100 MHz, CDCl3): d 195.94 (t, J = 28.1 Hz), 158.55 (t,
J = 26.8 Hz), 148.38, 125.75, 125.36, 121.03, 119.99, 110.27,
107.09 (t, J = 192.7 Hz), 55.85, 25.24; 19F NMR (CDCl3,
376.5 MHz):
d
ꢁ114.4; HRMS (ESI): calcd for C11H11F2NO3
([(M+1)]+) 244.0785, found 244.0780; IR (KBr, neat):
1695, 1565, 1491, 1466, 1253, 1128, 756
v 3408,
4.1.5. 2,2-Difluoro-N-(4-methoxyphenyl)-3-oxobutanamide (3e)
Light yellow solid; mp: 69–71 8C; 1H NMR (400 MHz, CDCl3):
d
8.14 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.79 (s,
3H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3):
196.37 (t,
d
J = 28.1 Hz), 158.89 (t, J = 26.7 Hz), 157.62, 128.64, 122.29,
114.41, 109.19 (t, J = 263.8 Hz), 55.56, 25.36; 19F NMR (CDCl3,
376.5 MHz):
d
ꢁ114.5; HRMS (ESI): calcd for C11H11F2NO3
([(M+H)]+) 244.0785, found 244.0780; IR (KBr, neat):
1683, 1653, 1558, 1540, 1515, 1119, 819
v 3327,
4.1.6. N-(4-ethoxyphenyl)-2,2-difluoro-3-oxobutanamide (3f)
Light yellow solid; mp: 91–94 8C; 1H NMR (400 MHz, CDCl3):
d
4.1. General procedure for the synthesis of
a,
a
-difluoro-
b
-
ketoamides 3 in the mixed-solvent
8.01 (s, 1H), 7.42 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.99 (q,
J = 6.8 Hz, 2H), 2.50 (s, 3H), 1.39 (t, J = 6.8 Hz, 3H); 13C NMR
The mixture of 3-oxo-N-p-tolylbutanamide 1a (96 mg,
0.5 mmol), K2CO3 (69 mg, 0.5 mmol) was well stirred for 1.0 h in
(100 MHz, CDCl3):
157.01, 128.41, 122.29, 114.96, 109.18 (t, J = 264.8 Hz), 63.81,
25.36, 14.82; 19F NMR (CDCl3, 376.5 MHz):
ꢁ114.5; HRMS (ESI):
d 196.40 (t, J = 28.2 Hz), 158.87 (t, J = 26.6 Hz),
the mixed-solvent of water and PEG-400 ðVH : VPEG
¼ 3 :
d
O
2
-400

48
Z. Zhang et al. / Journal of Fluorine Chemistry 151 (2013) 45–49
calcd for C12H13F2NO3 ([(M+1)]+) 258.0942, found 258.0936; IR
(KBr, neat): 3342, 1716, 1684, 1558, 1516, 1252, 1118, 829
NMR (100 MHz, CDCl3):
J = 27.0 Hz), 136.33, 129.03, 128.18, 127.89, 109.22 (t,
J = 264.0 Hz), 43.73, 25.29; 19F NMR (CDCl3, 376.5 MHz):
d 196.38 (t, J = 28.2 Hz), 161.20 (t,
v
d
4.1.7. 2,2-Difluoro-3-oxo-N-phenylbutanamide (3g)
ꢁ114.9; IR (KBr, neat):
v
3306, 1667, 1575, 1424, 1147, 1102,
Light yellow liquid; 1H NMR (400 MHz, CDCl3):
d
8.35 (s, 1H),
1064, 724
7.54 (d, J = 8 Hz, 2H), 7.33 (t, J = 8 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H),
2.47 (s, 3H); 13C NMR (100 MHz, CDCl3):
196.26 (t, J = 28.2 Hz),
159.13 (t, J = 27.1 Hz), 135.61, 129.25, 126.09, 120.60, 109.04 (t,
J = 264.8 Hz), 25.19; 19F NMR (CDCl3, 376.5 MHz):
ꢁ114.4; HRMS
(ESI): calcd for C10H9F2NO2 ([(M+1)]+) 214.0680, found 214.0674;
IR (KBr, neat): 3317, 1691, 1548, 1448, 1135, 1114, 753, 690
d
4.1.14. N-(4-chlorobenzyl)-2,2-difluoro-3-oxobutanamide (3n)
Light yellow solid; mp: 59–62 8C; 1H NMR (400 MHz, DMSO):
d
d
9.75 (br, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.34 (d,
J = 6.4 Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO):
195.97 (t,
d
v
J = 27.7 Hz), 160.82 (t, J = 27.1 Hz), 136.96, 131.80, 129.16, 128.95,
128.39, 128.15, 109.10 (t, J = 262.7 Hz), 41.71, 24.84; 19F NMR
4.1.8. N-(2-chlorophenyl)-2,2-difluoro-3-oxobutanamide (3h)
Light yellow solid; mp: 40–42 8C; 1H NMR (400 MHz, CDCl3):
(DMSO, 376.5 MHz):
C
d
ꢁ119.2; HRMS (ESI): calcd for
d
11H10ClF2NO2 ([(M+Na)]+) 284.0266, found 284.0260.
8.60 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8 Hz, 1H), 7.30 (t,
J = 8 Hz, 1H), 7.144 (t, J = 7.6 Hz, 1H), 2.51 (s, 1H); 13C NMR
4.1.15. 2,2-Difluoro-4-methyl-3-oxo-N-phenylpentanamide (3o)
Light yellow liquid; 1H NMR (400 MHz, CDCl3):
8.30
(100 MHz, CDCl3):
132.44, 129.42, 127.97, 126.58, 123.94, 121.89, 108.85 (t,
J = 264.9 Hz), 25.21; 19F NMR (CDCl3, 376.5 MHz):
ꢁ114.2;
HRMS (ESI): calcd for C10H8ClF2NO2 ([(M+1)]+) 248.0290, found
248.0284; IR (KBr, neat): 3404, 1709, 1652, 1541, 1447, 1127, 755
d
195.77 (t, J = 28.3 Hz), 158.96 (t, J = 27.2 Hz),
d
(s, 1H), 7.55 (d, J = 8 Hz, 2H), 7.34 (t, J = 8 Hz, 2H), 7.19 (t,
J = 7.6 Hz, 1H), 3.25 (h, J = 6.8 Hz, 1H), 1.21 (s, 1H), 1.19 (s, 1H);
d
13C NMR (100 MHz, CDCl3):
d
202.92 (t, J = 26.5 Hz), 159.48 (t,
v
J = 26.9 Hz), 135.73, 129.27, 126.01, 120.52, 109.45 (t,
J = 265.7 Hz), 36.49, 17.89; 19F NMR (CDCl3, 376.5 MHz):
d
4.1.9. N-(4-chlorophenyl)-2,2-difluoro-3-oxobutanamide (3i)
Light yellow solid; mp: 84–86 8C; 1H NMR (400 MHz, CDCl3):
ꢁ113.3; HRMS (ESI): calcd for C12H13F2NO2 ([(M+H)]+)
d
242.0993, found 242.0987; IR (KBr, neat):
1603, 1548, 1448, 1122, 754
v 3323, 1743, 1700,
9.30 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 2.48 (s,
3H); 13C NMR (100 MHz, CDCl3):
196.18 (t, J = 28.3 Hz), 159.36 (t,
J = 27.4 Hz), 134.64, 130.94, 129.13, 122.04, 109.07 (t,
J = 264.9 Hz), 25.20; 19F NMR (CDCl3, 376.5 MHz):
ꢁ114.3;
HRMS (ESI): calcd for C10H8ClF2NO2 ([(M+1)]+) 248.0290, found
d
4.1.16. 2,2-Difluoro-3-oxo-3-phenyl-N-(p-tolyl)propanamide (3p)
Light yellow solid; mp: 117–119 8C; 1H NMR (400 MHz, CDCl3):
d
d
8.32 (s, 1H), 8.17 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.51–
7.45 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 2.32 (s, 3H); 13C NMR
(100 MHz, CDCl3): 187.34 (t, J = 27.0 Hz), 159.28 (t, J = 27.0 Hz),
135.80, 135.10, 133.25, 131.60, 130.48, 129.74, 128.89, 120.50,
248.0284; IR (KBr, neat):
1404, 1123, 830
v 3323, 1757, 1696, 1604, 1548, 1493,
d
4.1.10. N-(5-chloro-2-methoxyphenyl)-2,2-difluoro-3-
oxobutanamide (3j)
110.87 (t, J = 264.9 Hz), 20.98; 19F NMR (CDCl3, 376.5 MHz):
d
ꢁ107.8; HRMS (ESI): calcd for C16H13F2NO2 ([(M+1)]+) 290.0993,
Yellow solid; mp: 46–48 8C; 1H NMR (400 MHz, CDCl3):
d
8.67
found 290.0987; IR (KBr, neat):
1157, 1122, 815
v 3260, 1715, 1673, 1538, 1514,
(s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.09 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H),
6.82 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H), 2.51 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 195.97 (t, J = 28.3 Hz), 158.76 (t, J = 27.2 Hz),
Acknowledgements
146.96, 126.22, 126.17, 125.32, 120.11, 111.15, 108.91 (t,
J = 264.9 Hz), 56.28, 25.38; 19F NMR (CDCl3, 376.5 MHz):
d
We would like to thank the NSFC (21002051, 21172056 and
21272057), PCSIRT (IRT1061), China Postdoctoral Science Founda-
tion funded project (2012M521397), and the Foundation and
Frontier Technology Research Program of Henan Province
(112300410312) for financial supports of this research. Moreover,
we appreciate the editor and the reviewers for their constructive
and helpful suggestions very much.
ꢁ114.4; HRMS (ESI): calcd for C11H10ClF2NO3 ([(M+1)]+)
278.0396, found 278.0390; IR (KBr, neat):
1539, 1484, 1125, 1024, 807, 644
v 3396, 1751, 1706,
4.1.11. Ethyl 4-(2,2-difluoro-3-oxobutanamido)benzoate (3k)
Yellow solid; mp: 52–54 8C; 1H NMR (400 MHz, CDCl3):
d
8.70
(s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 4.34 (q,
J = 7.2 Hz, 2H), 2.46 (s, 3H), 1.36 (t, J = 7.2 Hz, 2H); 13C NMR
Appendix A. Supplementary data
(100 MHz, CDCl3):
d 196.16 (t, J = 26.9 Hz), 166.03, 159.42 (t,
J = 27.2 Hz), 139.84, 130.86, 127.63, 119.86, 108.89 (t,
J = 265.3 Hz), 61.25, 25.25, 14.32; 19F NMR (CDCl3, 376.5 MHz):
d
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.
03.016.
ꢁ114.2; HRMS (ESI): calcd for C13H13F2NO4 ([(M+1)]+) 286.0891,
found 286.0885.
References
4.1.12. 2,2-Difluoro-N-(4-methoxybenzyl)-3-oxobutanamide (3l)
Light yellow solid; mp: 51–53 8C; 1H NMR (400 MHz, CDCl3):
d
[1] I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Blackwell Publish-
ing, Ltd, 2009 http://as.wiley.com/WileyCDA/WileyTitle/productCd-1405167203.
html.
[2] (a) L.A. Rozov, C. Huang, D.F. Halpern, G.G. Vernice, U.S. Patent 5,283,372 (1994).;
(b) D.F. Halpern, M.L. Robin, U.S. Patent 4,996,371 (1991).
[3] (a) Y. Chen, J.N. Freskos, A.F. Gasiecki, M.L. Grapperhaus, D.W. Hansen, R.M.
Heintz, I.K. Khanna, S.A. Kolodziej, S. Mantegani, M.A. Massa, J.J. McDonald,
D.A. Mischke, M.A. Nagy, E. Perrone, M.A. Schmidt, D.P. Spangler, J.J. Talley, M.
Trivedi, T.A. Wynn, D.P. Becker, J.G. Rico, WO/2004/000811, 2003.;
(b) M.F. Parker, K.E. McElhone, R.A. Mate, J.J. Bronson, Y. Gai, C.P. Bergstrom, L.R.
Marcin, J.E. Macor, WO/2003/053912, 2003.
7.18 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 3H), 4.40 (d, J = 5.6 Hz,
2H), 3.78 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3):
196.34
d
(t, J = 28.3 Hz), 161.07 (t, J = 27.0 Hz), 159.48, 129.33, 128.42,
114.36, 109.21 (t, J = 263.6 Hz), 55.36, 43.25, 25.25; 19F NMR
(CDCl3, 376.5 MHz):
d
ꢁ114.9; HRMS (ESI): calcd for C12H13F2NO3
([(M+Na)]+) 280.0761, found 286.0756.
4.1.13. N-benzyl-2,2-difluoro-3-oxobutanamide (3m)
White solid; mp: 74–75 8C; 1H NMR (400 MHz, CDCl3):
[4] (a) J.S. Houlton, W.B. Motherwell, B.C. Ross, M.J. Tozer, D.J. Williams, A.M.Z.
Slawin, Tetrahedron 49 (1993) 8087–8106;
d
7.34–
7.22 (m, 5H), 6.88 (br, 1H), 4.45 (d, J = 6 Hz, 2H), 2.42 (s, 3H); 13C
(b) S. Kaneko, T. Yamazaki, T. Kitazume, J. Org. Chem. 58 (1993) 2302–2312.

Z. Zhang et al. / Journal of Fluorine Chemistry 151 (2013) 45–49
49
[5] (a) K. Otaka, D. Oohira, D. Takaoka, WO/2004/006677, 2004.;
(b) M. Markl, W. Schaper, O. Ort, H. Jakobi, R. Braun, G. Krautstrunk, U. Sanft, W.
Bonin, H. Stark, S. Pasenok, I. Cabrera, WO/2000/007998, 2000.
[6] W.F. Goure, K.L. Leschinsky, S.J. Wratten, J.P. Chupp, J. Agric. Food Chem. 39 (1991)
981–986.
(d) M. Schuler, F. Silva, C. Bobbio, A. Tessier, V. Gouverneur, Angew. Chem. Int. Ed.
47 (2008) 7927–7930.
[18] R. Surmont, G. Verniest, N. De Kimpe, Org. Lett. 11 (2009) 2920–2923.
[19] G. Fourrie`re, N. Van Hijfte, J. Lalot, G. Dutech, B. Fragnet, G. Coadou, J.-C. Quirion, E.
Leclerc, Tetrahedron 66 (2010) 3963–3972.
[7] (a) P. Eyerer, M. Weller, C. Hu¨ bner, Polymers-Opportunities and Risks II:
Sustainability, Product Design and Processing, Springer-Verlag, Berlin/Heidel-
[20] (a) D.W. Konas, J.K. Coward, Org. Lett. 1 (1999) 2105–2107;
(b) S. Bloom, M.T. Scerba, J. Erb, T. Lectka, Org. Lett. 13 (2011) 5068–5071;
(c) W. Peng, J.M. Shreeve, J. Org. Chem. 70 (2005) 5760–5763;
(d) G. Verniest, E. Van Hende, R. Surmont, N. De Kimpe, Org. Lett. 8 (2006) 4767–
4770;
berg,
2010,
http://link.springer.com/book/10.1007/978-3-642-02797-0/
page/1;
(b) G.W. Stachowiak, Wear: Materials, Mechanisms and Practice, John Wiley &
Sons, Inc., 2005
16280. html.
http://as.wiley.com/WileyCDA/WileyTitle/productCd-04700
(e) H. Loghmani-Khouzani, M.R. Poorheravi, M.M.M. Sadeghi, L. Caggiano, R.F.W.
Jackson, Tetrahedron 64 (2008) 7419–7425.
[8] (a) G.A. Griffith, I.H. Hillier, A.C. Moralee, J.M. Percy, R. Roig, M.A. Vincent, J. Am.
Chem. Soc. 128 (2006) 13130–13141;
[21] R.D. Chambers, D.J. Burton, F.G. Drakesmith, J. Hutchinson, T. Kitazume, L. Lu, J.M.
Percy, G. Sandford, T. Yamazaki, Topics in Current Chemistry 193: Organofluorine
Chemistry Techniques and Synthons, Springer, 1997, pp. 1–44. http://link.sprin-
ger.com/book/10.1007/3-540-69197-9/page/1.
(b) G.A. Griffith, I.H. Hillier, J.M. Percy, R. Roig, M.A. Vincent, J. Org. Chem. 71
(2006) 8250–8255;
(c) C. Leriche, X. He, C.-W.T. Chang, H.-W. Liu, J. Am. Chem. Soc. 125 (2003) 6348–
6349;
[22] S.D. Taylor, C.C. Kotoris, G. Hum, Tetrahedron 55 (1999) 12431–12477 (and
references cited therein).
(d) T. Mikami, K. Miyatake, M. Watanabe, ACS Appl. Mater. Interfaces 2 (2010)
1714–1721;
[23] C.E. Inman, R.E. Oesterling, E.A. Tyczkowski, J. Am. Chem. Soc. 80 (1958) 6533–
6535.
(e) J. Fawcett, G.A. Griffith, J.M. Percy, E. Uneyama, Org. Lett. 6 (2004) 1277–1280.
[9] (a) S.H. Kyne, J.A.L. Miles, J.M. Percy, K. Singh, J. Org. Chem. 77 (2011) 991–
998;
[24] O.D. Gupta, J.M. Shreeve, Tetrahedron Lett. 44 (2003) 2799–2801.
[25] B. Zajc, M. Zupan, J. Org. Chem. 47 (1982) 573–575.
[26] S. Stavber, M. Zupan, J. Chem. Soc. Chem. Commun. (1981) 795–796.
[27] S. Rozen, Y. Menahem, Tetrahedron Lett. 20 (1979) 725–728.
[28] (a) W.H. Bailey III, W.J. Casteel Jr., R.G. Syvret, Collect. Czech. Chem. Commun. 67
(2002) 1416–1420;
(b) Z. Chen, J. Zhu, H. Xie, S. Li, Y. Wu, Y. Gong, Org. Biomol. Chem. 9 (2011) 3878–
3885;
(c) J.A. Codelli, J.M. Baskin, N.J. Agard, C.R. Bertozzi, J. Am. Chem. Soc. 130 (2008)
11486–11493;
(d) S. Arimitsu, B. Fernndez, C. del Pozo, S. Fustero, G.B. Hammond, J. Org. Chem.
73 (2008) 2656–2661;
(b) T.B. Patrick, M. Hudlicky, A.E. Pavlath (Eds.), In Chemistry of Organic Fluorine
Compounds II; ACS Monograph 187, American Chemical Society, Washington, DC,
1995, pp. 133–171;
(e) S. Fustero, S. Catala´n, J. Piera, J.F. Sanz-Cervera, B. Ferna´ndez, J.L. Acen˜a, J. Org.
Chem. 71 (2006) 4010–4013;
(f) G. Verniest, F. Colpaert, E. Van Hende, N. De Kimpe, J. Org. Chem. 72 (2007)
8569–8572;
(g) R. Surmont, G. Verniest, F. Colpaert, G. Macdonald, J.W. Thuring, F. Deroose, N.
De Kimpe, J. Org. Chem. 74 (2009) 1377–1380;
(h) R. Surmont, G. Verniest, J.W. Thuring, P. Ten Holte, F. Deroose, N. De Kimpe,
Org. Biomol. Chem. 8 (2010) 4514–4517.
(c) S. Rozen, D. Hebel, J. Org. Chem. 55 (1990) 2621–2623.
[29] (a) S. Hara, M. Sekiguchi, A. Ohmori, T. Fukuhara, N. Yoneda, Chem. Commun.
(1996) 1899–1900;
(b) Y. Norihiko, J. Fluorine Chem. 125 (2004) 7–17 (and references cited therein).
[30] J. Baudoux, D. Cahard, Organic Reactions, vol. 69, John Wiley & Sons, Inc., 2007
http://onlinelibrary.wiley.com/doi/10.1002/0471264180.or069.02/abstract.
[31] (a) Z.-Q. Xu, D.D. DesMarteau, Y. Gotoh, J. Chem. Soc. Chem. Commun. (1991)
179–181;
[10] (a) R. Lin, S. Ding, Z. Shi, N. Jiao, Org. Lett. 13 (2011) 4498–4501;
(b) S. Fustero, M. Sa´nchez-Rosello´, J.L. Acen˜a, B. Ferna´ndez, A. Asensio, J.F. Sanz-
Cervera, C. del Pozo, J. Org. Chem. 74 (2009) 3414–3423;
(c) S. Fustero, M. Sa´nchez-Rosello´, V. Rodrigo, C. del Pozo, J.F. Sanz-Cervera, A.
Simo´n, Org. Lett. 8 (2006) 4129–4132;
(b) Z.-Q. Xu, D.D. DesMarteau, Y. Gotoh, J. Fluorine Chem. 58 (1992) 71–79.
[32] (a) F. Akahoshi, A. Ashimori, H. Sakashita, T. Yoshimura, M. Eda, T. Imada, M.
Nakajima, N. Mitsutomi, S. Kuwahara, T. Ohtsuka, C. Fukaya, M. Miyazaki, N.
Nakamura, J. Med. Chem. 44 (2001) 1297–1304;
(b) M. Eda, A. Ashimori, F. Akahoshi, T. Yoshimura, Y. Inoue, C. Fukaya, M.
Nakajima, H. Fukuyama, T. Imada, N. Nakamura, Bioorg. Med. Chem. Lett. 8
(1998) 919–924;
(c) M. Eda, A. Ashimori, F. Akahoshi, T. Yoshimura, Y. Inoue, C. Fukaya, M.
Nakajima, H. Fukuyama, T. Imada, N. Nakamura, Bioorg. Med. Chem. Lett. 8
(1998) 913–918.
(d) D.W. Konas, J.K. Coward, J. Org. Chem. 66 (2001) 8831–8842;
(e) X. Zhang, H. Xia, X. Dong, J. Jin, W.-D. Meng, F.-L. Qing, J. Org. Chem. 68 (2003)
9026–9033;
(f) P.V. Ramachandran, A. Tafelska-Kaczmarek, K. Sakavuyi, Org. Lett. 13 (2011)
4044–4047.
[11] K.W. Dehnert, B.J. Beahm, T.T. Huynh, J.M. Baskin, S.T. Laughlin, W. Wang, P. Wu,
S.L. Amacher, C.R. Bertozzi, ACS Chem. Biol. 6 (2011) 547–552.
[12] (a) S. Pignard, C. Lopin, G. Gouhier, S.R. Piettre, J. Org. Chem. 71 (2005) 31–37;
(b) A.C. Simmonett, S.E. Wheeler, H.F. Schaefer, J. Phys. Chem. A 108 (2004) 1608–
1615;
(c) T. Itoh, K. Sakabe, K. Kudo, H. Ohara, Y. Takagi, H. Kihara, P. Zagatti, M. Renou, J.
Org. Chem. 64 (1998) 252–265;
(d) A. Suzuki, M. Mae, H. Amii, K. Uneyama, J. Org. Chem. 69 (2004) 5132–5134.
[13] V.A. Petrov, Fluorinated Heterocyclic Compounds. Synthesis, Chemustry and
Applications, John Wiley & Sons, Inc., 2009 http://as.wiley.com/WileyCDA/
WileyTitle/productCd-0470452110.html.
[14] K. Uneyama, H. Amii, J. Fluorine Chem. 114 (2002) 127–131.
[15] (a) T. Yamazaki, S. Hiraoka, J. Sakamoto, T. Kitazume, Org. Lett. 3 (2001) 743–746;
(b) P.E. Harrington, L. Li, M.A. Tius, J. Org. Chem. 64 (1999) 4025–4029.
[16] (a) G.K.S. Prakash, J. Hu, T. Mathew, G.A. Olah, Angew. Chem. Int. Ed. 42 (2003)
5216–5219;
(b) G.K.S. Prakash, J. Hu, Y. Wang, G.A. Olah, Angew. Chem. Int. Ed. 43 (2004)
5203–5206.
[17] (a) R. Surmont, G. Verniest, J.W. Thuring, G. Macdonald, F. Deroose, N. De Kimpe, J.
Org. Chem. 75 (2010) 929–932;
[33] (a) A.M. Doherty, I. Sircar, B.E. Kornberg, J. Quin, R.T. Winters, J.S. Kaltenbronn,
M.D. Taylor, B.L. Batley, S.R. Rapundalo, J. Med. Chem. 35 (1992) 2–14;
(b) J.T. Repine, R.J. Himmelsbach, J.C. Hodges, J.S. Kaltenbronn, I. Sircar, R.W.
Skeean, S.T. Brennan, T.R. Hurley, E. Lunney, J. Med. Chem. 34 (1991) 1935–1943;
(c) S. Thaisrivongs, D.T. Pals, W.M. Kati, S.R. Turner, L.M. Thomasco, W. Watt, J.
Med. Chem. 29 (1986) 2080–2087;
(d) S. Thaisrivongs, D.T. Pals, W.M. Kati, S.R. Turner, L.M. Thomasco, J. Med. Chem.
28 (1985) 1553–1555.
[34] (a) R.E. Banks, N.J. Lawrence, A.L. Popplewell, J. Chem. Soc. Chem. Commun.
(1994) 343–344;
(b) J.-C. Xiao, J.M. Shreeve, J. Fluorine Chem. 126 (2005) 473–476;
(c) G. Stavber, S. Stavber, Adv. Synth. Catal. 352 (2010) 2838–2846;
(d) F.A. Davis, W. Han, C.K. Murphy, J. Org. Chem. 60 (1995) 4730–4737;
(e) D.P. Huber, K. Stanek, A. Togni, Tetrahedron: Asymmetry 17 (2006) 658–664.
[35] (a) Z. Zhang, S. Fang, Q. Liu, G. Zhang, Adv. Synth. Catal. 354 (2012) 927–932;
(b) Z. Zhang, Q. Zhang, S. Sun, T. Xiong, Q. Liu, Angew. Chem. Int. Ed. 46 (2007)
1726–1729;
(c) Z. Zhang, Q. Zhang, Z. Ni, Q. Liu, Chem. Commun. 46 (2010) 1269–1271;
(d) Z. Zhang, Q. Zhang, Z. Yan, Q. Liu, J. Org. Chem. 72 (2007) 9808–9810;
(e) Q. Zhang, Z. Zhang, Z. Yan, Q. Liu, T. Wang, Org. Lett. 9 (2007) 3651–3653;
(f) Z. Zhang, C. Xue, X. Liu, Q. Zhang, Q. Liu, Tetrahedron 67 (2011) 7081–7084.
[36] J. Bi, Z. Zhang, Q. Liu, G. Zhang, Green Chem. 14 (2012) 1159–1162.
[37] Please see supporting information for more information.
[38] K.H. Meyer, Eur. J. Inorg. Chem. 47 (1914) 826–832.
(b) E. Van Hende, G. Verniest, R. Surmont, N. De Kimpe, Org. lett. 9 (2007) 2935–
2937;
(c) G. Verniest, R. Surmont, E. Van Hende, A. Deweweire, F. Deroose, J.W. Thuring,
N. De Kimpe, J. Org. Chem. 73 (2008) 5458–5461;