Metal-mediated Reformatsky reaction of bromodifluoromethyl ketone and aldehyde using water as solvent

Article abstract of DOI:10.1016/j.jfluchem.2013.08.012

Water is demonstrated as a suitable solvent for an efficient and environmentally friendly method for the synthesis of α,α- difluorinated β-hydroxy carbonyl compounds through the Reformatsky reaction of bromodifluoromethyl ketones with aldehydes in the pre

Full text of DOI:10.1016/j.jfluchem.2013.08.012

Journal of Fluorine Chemistry 156 (2013) 45–50
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Metal-mediated Reformatsky reaction of bromodifluoromethyl ketone
and aldehyde using water as solvent
*
Hui Yao, Chun-Ru Cao, Min Jiang, Jin-Tao Liu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China
A R T I C L E I N F O
A B S T R A C T
Article history:
Water is demonstrated as a suitable solvent for an efficient and environmentally friendly method for the
Received 28 June 2013
synthesis of
a,a-difluorinated b-hydroxy carbonyl compounds through the Reformatsky reaction of
Received in revised form 23 August 2013
Accepted 24 August 2013
Available online 3 September 2013
bromodifluoromethyl ketones with aldehydes in the presence of Zn/CuCl at room temperature.
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Reformatsky reaction
Bromodifluoromethyl ketone
Aldehyde
Water
Zinc
1. Introduction
organometallic reagents often suffer from difficulties due to
their intrinsic low nucleophilicity and thermal instability [7].
Fluorine-containing compounds have received considerable
attention for many years due to their unique physical, chemical,
and biological properties [1]. Incorporation of fluorine as either a
bioisosteric replacement for hydrogen or an isoelectronic replace-
ment for hydroxy group has profound influence on the metabolic
degradation, lipophilicity and reactivities of organic compounds
[2]. Accordingly, deliberate introduction of fluorinated moieties
into organic molecules has become one of the effective strategies in
Moreover, these classic reactions generally require strict
anhydrous and oxygen-free conditions.
Carrying out organic reaction in aqueous media has significant
advantages from an economic and environmental standpoint [8].
Furthermore, the use of a moisture-resistant radical species would
eliminate the cumbersome operations involved in conventional
ionic reactions [9]. It has been demonstrated that metals, such as
Zn, Sn and Bi, could mediate Reformatsky-type reaction in aqueous
media [10]. For these reactions, a radical mechanism initiated by
electron abstraction from organometallic reagent was proposed.
In-mediated aqueous Reformatsky reaction of chlorodifluoro-
methyl ketones has also been reported, in which the mixture of
organic solvent and water was employed and the scope of
chlorodifluoromethyl ketone is quite limited [11]. Recently, it
was found in our laboratory that the Reformatsky reaction of
bromodifluoromethyl ketones with aldehydes could take place
readily in water in the presence of Zn or In to give the
drug design. Among various fluorinated moieties, a,a-difluoroke-
tone unit has found applications in many inhibitors of HIV-1
protease, elastase, rennin, and human heart chymase [1b,3].
Additionally,
a,a-difluorinated b-hydroxy carbonyl compounds
have been used to synthesize many fluorinated analogs of
biochemically important compounds, such as sugars, nucleosides,
amino acids or fatty acids [4]. Therefore, the development of
practical methods for the introduction of
is of great significance.
a,a-difluoroketone unit
Aldol-type addition reaction of difluoroenol ethers has
proven to be productive for the synthesis of difluorocarbonyl
compounds [3,5]. Additionally, metal-mediated Reformatsky
reactions of halodifluoroacetates and halodifluoroketones afford
another effective approach [4,6]. However, fluorine-containing
corresponding a,a-difluorinated b-hydroxy carbonyl compounds.
The results are reported in this paper.
2. Results and discussion
Initially, bromodifluoromethyl phenyl ketone (1a) was used
as the substrate to investigate the Reformatsky reaction
with benzaldehyde. When the reaction was carried out with
4.0 equiv. of benzaldehyde 2a and 1.3 equiv. of zinc powder in
*
Corresponding author. Tel.: +86 21 54925188.
E-mail address: jtliu@sioc.ac.cn (J.-T. Liu).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.08.012

46
H. Yao et al. / Journal of Fluorine Chemistry 156 (2013) 45–50
Table 1
Reformatsky reaction of 1a and 2a under different conditions.
.
Entrya
X (equiv.)
Y (equiv.)
Solvent
Time (h)
Yield (3a, %)b
1
2
4.0
4.0
4.0
4.0
4.0
4.0
1.3
4.0
2.0
4.0
1.3
1.3
1.3
1.3
1.3
1.3
1.3
0.5
2.0
4.0
THF
4
4
4
4
2
2
2
2
2
2
8
27
39
13
81
65c
60
35
81
90
DMF
3
DCM
THF/H2O (3:1)
H2O
4
5
6
H2O
7
H2O
8
H2O
9
H2O
10
H2O
a
Reaction conditions: 1a (0.5 mmol), 2a (X equiv.), zinc (Y equiv.) in solvent (2.0 mL) at room temperature for 2–4 h.
b
c
Determined by 19F NMR.
The reaction was carried out at 55 8C.
tetrahydrofuran (THF) at room temperature, the desired adduct
Increasing the amount of zinc to 4.0 equiv. improved the yield
significantly (90%, entry 10).
3a was obtained in 8% yield (Table 1, entry 1). 19F NMR
monitoring showed that difluoromethyl phenyl ketone was
formed as major by-product. Other solvents such as N,N-
dimethylformide (DMF) and dichloromethane (DCM) didn’t give
satisfactory result either (entries 2–3). Welch et al. [11a] have
reported that water was essential to the In-mediated Refor-
matsky reaction. And Hammond’s group also present that
difluoropropargyl bromide could react with aldehydes in
aqueous media [12]. Since there are many advantages to carry
out reactions in aqueous media, we next used a mixed solvent of
THF and H2O with a ratio of 3:1 (v/v) and ran the reaction at
room temperature. However, 3a was still obtained in low yield
(13%, entry 4). Surprisingly, when the reaction of 1a and 2a was
carried out in pure water, full conversion was achieved and 3a
was obtained in 81% yield in spite of the occurrence of
defluorination (entry 5). Increasing the temperature to 55 8C
had a negative effect on the reaction, leading to a decreased yield
of 3a (65%, entry 6). Decreasing the amount of benzaldehyde or
zinc resulted in the obvious drop of the yield (entries 7–8).
To investigate the Reformatsky reaction of 1a in the aqueous
media further, various metals were examined next. The results
are summarized in Table 2. Indium could also mediate this
reaction effectively and give 3a in 90% yield (Table 2, entry 2).
When aluminum was used, the reaction was very slow and
undetermined by-products were formed (entry 3). In the case of
magnesium, the reaction was complicated and no desired
adduct was observed (entry 4). We noticed that the Reformatsky
reaction of chlorodifluoromethyl ketones with aldehydes and
ketones in the presence of zinc dust activated in situ by copper
(I) gave adducts in good to excellent yields [4,6d]. So we tried
to add CuCl in the reaction system. To our delight, the addition
of 1.25 equiv. CuCl afforded a clean reaction system (entries
5–9). Other metals such as Ni and Sb failed to promote the
reaction, resulting in full recovery of the starting material
(entries 10–12). There was no distinct difference between zinc
and indium, and zinc was chosen in the following investigation.
Therefore, the optimal conditions were set to 4.0 equiv. of
Table 2
Reformatsky reaction of 1a and 2a in the presence of different metal.
.
Entrya
Metal
Additive (X equiv.)
Yield (3a, %)b
1
2
Zn
In
–
90
90
–
3
Al
–
13
0c
4
Mg
Zn
Zn
In
–
5
CuCl (0.50)
CuCl (1.25)
CuCl (1.25)
CuCl (1.25)
CuCl (1.25)
CuCl (1.25)
CuCl (1.25)
CuCl (1.25)
90
6
>95
>95
44
59
0c
0c
0c
7
8
Mg
Al
9
10
11
12
Ni
Cu
Sb
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mmol), metal (2.0 mmol) and X equiv. of additive in water (2.0 mL) at room temperature for 2 h.
b
c
Determined by 19F NMR.
1a was recovered.

H. Yao et al. / Journal of Fluorine Chemistry 156 (2013) 45–50
47
Table 3
Scope of the Reformatsky reaction in water.
.
Entrya
1, R1
2, R2
Product
Yield (3, %)b
1
2
1a, C6H5
2a, C6H5
3a
3b
3c
3d
3e
3f
83
80
71
72
64
75
0c
1a, C6H5
2b, 3-ClC6H4
2c, 4-ClC6H4
2d, 2,4-(Cl)2C6H3
2e, 4-BrC6H4
2f, 4-FC6H4
2g, 4-NO2C6H4
2h, 4-MeOC6H4
2i, 4-CH3C6H4
2j, 2-Furyl
2k, i-C4H9
3
1a, C6H5
4
1a, C6H5
5
1a, C6H5
6
1a, C6H5
7
1a, C6H5
3g
3h
3i
8
1a, C6H5
71
71
56
65
40
56
86
72
86
40
9
1a, C6H5
10
11
12
13
14
15
16
17
1a, C6H5
3j
1a, C6H5
3k
3l
1a, C6H5
2l, C2H5
1a, C6H5
2m, n-C3H7
2a, C6H5
3m
3n
3o
3p
3q
1b, 4-MeOC6H4
1c, 4-ClC6H4
1d, C6H5(CH2)3–
1e, EtO
2a, C6H5
2a, C6H5
2a, C6H5
a
Reaction conditions: 1 (0.5 mmol), 2 (2.0 mmol), zinc (2.0 mmol), and CuCl (0.625 mmol) in water (2.0 mL) at room temperature for 2 h.
b
c
Isolated yields.
1a was recovered.
Scheme 1. Proposed mechanism for the Reformatsky reaction of bromodifluoromethyl ketone and aldehyde.
aldehyde, 4.0 equiv. of zinc and 1.25 equiv. of CuCl in water at
room temperature.
adduct 3p in 86% yield (entry 16). In the case of bromodifluoroester
1e, the expected product 3q was obtained in only 40% yield and
longer reaction time was required for the reaction to reach full
conversion (entry 17).
Mechanistically, we postulate a reaction pathway based on our
research results and literatures [10,13]. As illustrated in Scheme 1,
bromodifluoromethyl ketone 1 was initiated by zinc (or activated
by copper as in the case of the zinc-copper couple) to form a radical
anion A which generated a radical B, then it attacked the aldehyde
to furnish a radical intermediate C. Subsequent zinc-promoted
reduction of intermediate C and the quenching of thus generated
alkoxide anion D in the presence of water afforded the desired
product 3.
Using the optimized conditions, a variety of aldehydes were
investigated to evaluate the scope of this reaction. The results are
summarized in Table 3. The procedure tolerated a broad range of
functional groups. Halide substituted benzaldehydes reacted well
with 1a to give the corresponding adducts 3b-3f in moderate to
good yields (Table 3, entries 2–6). The use of a bromo substitution
allows further modification of the adduct (entry 5). Reaction of 2g
with a nitro-substitutent failed to promote any adduct resulting in
full recovery of the starting material (entry 7). Electron-rich
benzaldehydes bearing methyl or methoxy-substitution worked
well under the optimal reaction conditions (entries 8–9). 2-
Furylaldehyde could also react with 1a to afford product 3j in 56%
yield (entry 10). Reactions of aliphatic aldehydes were successful
and the expected products 3k-3m were formed in moderate yields
(40–65%, entries 11–13).
3. Conclusion
In summary, we have developed an environmentally friendly
The generality of the reaction was also surveyed with various
bromodifluoro ketones 1 under the standard conditions. Both p-
methoxy and p-chloro substituted phenyl ketones 1b and 1c
reacted readily with benzaldehyde 2a to give the desired products
3n and 3o in good yields (entries 14 and 15). The reaction of alkyl
ketone 1d also proceeded smoothly to afford the corresponding
and efficient synthesis of a,a-difluorinated b-hydroxy carbonyl
compounds under mild conditions. In the presence of Zn/CuCl, the
reaction of various aldehydes and bromodifluoromethyl ketones
took place readily in aqueous media at room temperature to give
the corresponding difluorinated compounds in good yields.
Further studies regarding the scope, mechanism and synthetic

48
H. Yao et al. / Journal of Fluorine Chemistry 156 (2013) 45–50
application of this reaction are currently underway in our
laboratory.
4.2.4. 3-(2,4-Dichlorophenyl)-2,2-difluoro-3-hydroxy-1-
phenylpropan-1-one (3d)
Solid, m.p.: 98–99 8C. IR (neat):
1469 cmÀ1. 1H NMR (300 MHz, CDCl3):
7.70 (m, 2H), 7.51–7.54 (m, 2H), 7.43–7.50 (m, 1H), 7.34–7.37 (m,
1H), 5.95 (ddd, J = 21.1, 4.5, 1.5 Hz, 1H), 3.16 (d, J = 4.5 Hz, 1H). 19
NMR (282 MHz, CDCl3):
À103.9 (d, J = 302.0 Hz, 1F), À118.5 (dd,
J = 302.0, 21.4 Hz, 1F). 13C NMR (100 MHz, CDCl3):
190.13 (t,
J = 31.0 Hz), 135.44, 134.90, 134.61, 131.85, 131.47, 131.05,
130.32, 129.14, 128.78, 127.37, 115.54 (dd, J = 246.4, 257.0 Hz),
68.46 (dd, J = 29.7, 21.8 Hz). ESI-MS (m/z): 353 (M+Na+). Anal.
Calcd for C15H10Cl2F2O2: C, 54.41; H, 3.04. Found: C, 54.42; H, 3.15.
n
3443, 1696, 1600, 1589, 1564,
4. Experimental
d
8.10–8.13 (m, 2H), 7.65–
4.1. General
F
d
1H NMR spectra were recorded in CDCl3 on a Bruker AM-300
spectrometer (300 MHz) with TMS as internal standard. 19F NMR
spectra were taken on a Bruker AM-300 (282 MHz) spectrometer
using CFCl3 as external standard. 13C NMR spectra were recorded in
CDCl3 on a Bruker AM-400 spectrometer (100 MHz) with TMS as
internal standard. IR spectra were obtained with a Nicolet AV-360
spectrophotometer. Mass spectra and high resolution mass spectra
(HRMS) were obtained on a Finnigan GC-MS 4021 and a Finnigan
MAT-8430 spectrometer. Unless otherwise mentioned, solvents
and reagents were purchased from commercial sources and used
as received. Bromodifluoromethyl ketones 1a-1d were prepared
according to the reported procedure [14].
d
4.2.5. 3-(4-Bromophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-
1-one (3e)
Solid, m.p.: 96–97 8C. IR (neat):
n
3431, 1699, 1681, 1596, 1578,
8.07 (d, J = 8.1 Hz, 2H),
1490 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d
7.63–7.68 (m, 1H), 7.47–7.55 (m, 4H), 7.39 (d, J = 8.1 Hz, 2H), 5.36
(dt, J = 19.2, 4.2 Hz, 1H), 3.10 (d, J = 4.2 Hz, 1H). 19F NMR (282 MHz,
CDCl3):
d
À104.5 (dd, J = 296.8, 4.5 Hz, 1F), À117.2 (dd, J = 296.8,
190.71 (t, J = 31.5 Hz),
4.2. Typical procedure
18.6 Hz, 1F). 13C NMR (100 MHz, CDCl3):
d
134.80, 133.71, 132.17, 131.45, 130.27, 129.81, 128.74, 123.20,
115.39 (dd, J = 264.1, 255.6 Hz), 72.62 (dd, J = 28.5, 22.7 Hz). EI-MS
(m/z, %): 341 (M+, 0.24), 185 (41.17), 156 (100.00), 105 (82.21), 77
(78.90), 51 (24.82). Anal. Calcd for C15H11BrF2O2: C, 52.81; H, 3.25.
Found: C, 52.59; H, 3.45.
To a flask containing aldehyde 2 (2.0 mmol), bromodifluor-
omethyl ketone 1 (0.5 mmol) and water (2 mL) were added zinc
powder (2.0 mmol) and CuCl (0.625 mmol) under stirring. The
mixture was stirred at room temperature for 2 h, and then
quenched with saturated aqueous NH4Cl solution. The resulted
mixture was stirred for additional 10 min, and extracted with ethyl
acetate (3Â 15 mL). The organic layer was dried over sodium
sulfate. After the removal of solvent under reduced pressure, the
residue was subjected to column chromatography on silica gel
using ethyl acetate and petroleum ether as eluent to afford the
corresponding product 3.
4.2.6. 2,2-Difluoro-3-(4-fluorophenyl)-3-hydroxy-1-phenylpropan-
1-one (3f)
Solid, m.p.: 73–74 8C. IR (neat):
n
3292, 1699, 1604, 1581, 1512,
8.07–8.10 (m, 2H), 7.64–
1450 cmÀ1. 1H NMR (300 MHz, CDCl3):
d
7.70 (m, 1H), 7.49–7.54 (m, 3H), 7.08–7.14 (m, 3H), 5.96 (dt,
J = 18.9, 4.1 Hz, 1H), 3.70 (d, J = 4.1 Hz, 1H). 19F NMR (282 MHz,
CDCl3):
d
À83.7 (dd, J = 294.4, 18.9 Hz, 1F), À87.7–87.8 (m, 1F),
4.2.1. 2,2-Difluoro-3-hydroxy-1,3-diphenylpropan-1-one (3a)
À96.0 (dd, J = 294.4, 5.4 Hz, 1F). 13C NMR (100 MHz, CDCl3):
d
This is a known compound [3]; colorless oil, IR (neat):
n
3462,
191.13 (t, J = 29.3 Hz), 164.60, 162.14, 134.95, 132.55, 130.78,
130.51, 128.94, 115.60, 116.14 (dd, J = 262.7, 256.6 Hz), 72.82 (dd,
J = 28.9, 23.1 Hz). ESI-MS (m/z): 303 (M+Na+). Anal. Calcd for
1697, 1599, 1581, 1496, 1451 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d
8.04 (d, J = 7.5 Hz, 2H), 7.59–7.64 (m, 1H), 7.38–7.48 (m, 7H), 5.36
(dt, J = 18.9, 4.8 Hz, 1H), 3.12 (d, J = 4.8 Hz, 1H). 19F NMR (282 MHz,
C15H11F3O2: C, 64.29; H, 3.96. Found: C, 64.32; H, 4.01.
CDCl3):
d
À104.6 (dd, J = 292.0, 8.2 Hz, 1F), À116.4 (dd, J = 292.0,
17.8 Hz, 1F). EI-MS (m/z, %): 263 (M+H+, 0.61), 156 (29.79), 105
4.2.7. 2,2-Difluoro-3-hydroxy-3-(4-methoxyphenyl)-1-
(89.89), 77 (100.00), 51 (52.82).
phenylpropan-1-one (3h)
Colorless oil, IR (neat):
n
3450, 1698, 1613, 1599, 1587, 1515,
8.04–8.08 (m, 2H), 7.62–
4.2.2. 3-(3-Chlorophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-
1450 cmÀ1. 1H NMR (300 MHz, CDCl3):
d
1-one (3b)
Colorless oil, IR (neat):
1450 cmÀ1. 1H NMR (300 MHz, CDCl3):
7.67 (m, 1H), 7.46–7.53 (m, 3H), 7.25–7.38 (m, 3H), 5.35 (dt,
J = 19.8, 4.8 Hz, 1H), 3.23 (d, J = 4.8 Hz, 1H). 19F NMR (282 MHz,
7.67 (m, 1H), 7.41–7.51 (m, 4H), 6.92–6.95 (m, 2H), 5.33 (dt,
n
3497, 1694, 1599, 1579, 1558, 1480,
8.05–8.08 (m, 2H), 7.62–
J = 19.2, 4.5 Hz, 1H), 3.83 (s, 3H), 3.09 (d, J = 4.5 Hz, 1H). 19F NMR
d
(282 MHz, CDCl3):
d
-104.5 (dd, J = 292.9, 8.2 Hz, 1F), À115.9 (dd,
191.33 (t,
J = 292.9, 20.3 Hz, 1F). 13C NMR (100 MHz, CDCl3):
d
J = 29.0 Hz), 160.07, 134.43, 132.52, 130.19, 129.32, 128.57,
126.83, 115.90 (dd, J = 262.4, 254.6 Hz), 113.71, 72.95 (dd,
J = 28.3, 23.1 Hz), 55.20. EI-MS (m/z, %): 292 (M+, 0.25), 155
(2.60), 137 (51.60), 105 (55.52), 77 (100.00), 51 (35.63). ESI-HRMS
calcd for C16H14F2NaO3 [M+Na] +: 315.0813, found: 315.0803.
CDCl3):
d
À104.3 (d, J = 296.2 Hz, 1F), À117.3 (dd, J = 296.2,
191.00 (t, J = 29.0 Hz),
16.6 Hz, 1F). 13C NMR (100 MHz, CDCl3):
d
136.69, 134.79, 134.26, 132.14, 130.29, 130.26, 129.47, 129.12,
128.71, 128.28, 115.42 (dd, J = 264.3, 256.1 Hz), 72.53 (dd, J = 29.1,
23.1 Hz). EI-MS (m/z, %): 296 (M+, 1.08), 156 (49.70), 141 (14.42),
105 (100.00), 77 (76.83), 51 (22.83). HRMS calcd for C15H11ClF2O2
[M]+: 296.0416, found: 296.0415.
4.2.8. 2,2-Difluoro-3-hydroxy-1-phenyl-3-p-tolylpropan-1-one (3i)
Solid, m.p.: 72–73 8C. IR (neat):
n
3438, 1687, 1615, 1596, 1516,
8.06 (d, J = 7.5 Hz, 2H),
1448 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d
4.2.3. 3-(4-Chlorophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-
7.61–7.66 (m, 1H), 7.37–7.50 (m, 4H), 7.19–7.25 (m, 2H), 5.34 (dt,
J = 18.9, 4.5 Hz, 1H), 2.96 (d, J = 4.5 Hz, 1H), 2.37 (s, 3H). 19F NMR
1-one (3c)
This is a known compound [5b]; colorless oil, IR (neat):
n
3433,
(282 MHz, CDCl3):
d
À105.2 (dd, J = 291.9, 3.95 Hz, 1F), À1117.2
191.05 (t,
1700, 1682, 1597, 1579, 1491 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d
(dd, J = 291.9, 20.6 Hz, 1F). 13C NMR (100 MHz, CDCl3):
d
8.06 (d, J = 9.0 Hz, 2H), 7.62–7.67 (m, 1H), 7.35–7.51 (m, 6H), 5.36
(dt, J = 19.2, 4.2 Hz, 1H), 3.16 (d, J = 4.2 Hz, 1H). 19F NMR (282 MHz,
J = 29.2 Hz), 138.91, 134.51, 132.54, 131.81, 130.25, 129.05,
128.64, 128.01, 115.90 (dd, J = 262.8, 254.6 Hz), 73.24 (dd,
J = 28.7, 23.2 Hz), 21.24. EI-MS (m/z, %): 276 (M+, 0.23), 156
(23.10), 121 (100.00), 105 (46.47), 77 (46.67), 51 (11.41). Anal.
Calcd for C16H14F2O2: C, 69.56; H, 5.11. Found: C, 69.48; H, 4.82.
CDCl3):
d
À104.0 (dd, J = 295.5, 4.8 Hz, 1F), À116.63 (dd, J = 295.5,
18.6 Hz, 1F). EI-MS (m/z, %): 296 (M+, 1.09), 156 (89.69), 141
(43.32), 105 (92.36), 77 (100.00), 51 (21.45).

H. Yao et al. / Journal of Fluorine Chemistry 156 (2013) 45–50
49
4.2.9. 2,2-Difluoro-3-(furan-2-yl)-3-hydroxy-1-phenylpropan-1-one
8.11 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.58–7.63 (m, 1H),
7.36–7.45 (m, 5H), 5.34 (dd, J = 18.8, 5.7 Hz, 1H). 19F NMR
(3j)
Colorless oil, IR (neat):
n
3477, 1699, 1599, 1581, 1504,
8.06 (d, J = 7.5 Hz, 2H),
(282 MHz, CDCl3):
d
À104.7 (d, J = 282.8 Hz, 1F), À116.2 (dd,
190.20 (t,
1450 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d
J = 282.8, 16.9 Hz, 1F). 13C NMR (100 MHz, CDCl3):
d
7.63–7.68 (m, 1H), 7.44–7.52 (m, 3H), 6.50 (d, J = 3.0 Hz, 1H), 6.40
(dd, J = 3.0, 1.8 Hz, 1H), 5.43 (dt, J = 15.9, 6.9 Hz, 1H), 3.07 (d,
J = 29.1 Hz), 141.29, 134.52, 133.78, 131.63, 130.72, 129.12,
128.33, 128.04, 115.79 (dd, J = 262.8, 255.1 Hz), 73.22 (dd,
J = 28.6, 23.0 Hz). EI-MS (m/z, %): 296 (M+, 0.62), 190 (43.19),
139 (100.00), 111 (49.47), 107 (34.94), 77 (35.15).
J = 6.9 Hz, 1H). 19F NMR (282 MHz, CDCl3):
d
À106.5 (dd, J = 291.7,
8.2 Hz, 1F), À114.5 (dd, J = 291.7, 10.2 Hz, 1F). 13C NMR (100 MHz,
CDCl3):
d 190.23 (t, J = 30.5 Hz), 148.35, 143.20, 134.58, 130.11,
130.05, 128.65, 115.43 (dd, J = 262.5, 256.8 Hz), 110.62, 110.10,
68.06 (dd, J = 28.6, 25.3 Hz). EI-MS (m/z, %): 252 (M+, 0.36), 156
(34.29), 117 (0.59), 105 (100.00), 77 (44.37), 51 (20.27). HRMS
calcd for C13H10F2NaO3 [M+Na]+: 275.0500, found: 275.0490.
4.2.15. 2,2-Difluoro-1-hydroxy-1,6-diphenylhexan-3-one (3p)
Colorless oil, IR (neat):
1686, 1602, 1583, 1496, 1454 cmÀ1
8.15–7.14 (m, 10H), 5.20 (dd, J = 16.8, 8.1 Hz, 1H), 2.66 (m, 4H),
n
3457, 3063, 3026, 2946, 2868, 1738,
.
1H NMR (300 MHz, CDCl3):
d
1.91 (m, 2H). 19F NMR (282 MHz, CDCl3):
d
À113.07 (dd, J = 274.1,
4.2.10. 2,2-Difluoro-3-hydroxy-5-methyl-1-phenylhexan-1-one (3k)
8.7 Hz, 1F), À123.7 (dd, J = 274.1, 14.1 Hz, 1F). 13C NMR (100 MHz,
This is a known compound [3]; colorless oil, IR (neat):
2960, 2874, 1698, 1599, 1581, 1470, 1450 cmÀ1 1H NMR
(300 MHz, CDCl3): 8.13 (d, J = 7.8 Hz, 2H), 7.65–7.70 (m, 1H),
n
3449,
CDCl3): d 202.41 (t, J = 31.0 Hz), 141.21, 134.78, 129.21, 128.48,
.
127.78, 126.10, 114.84 (dd, J = 260.6, 255.3 Hz), 73.14 (dd, J = 28.8,
22.2 Hz), 37.34, 34.71, 23.97. EI-MS m/z: 304 (M+, 1.36), 198
(23.65), 147 (53.76), 77 (23.03). HRMS Calcd for C18H18F2O2 (M+):
304.1275. Found: 304.1279.
d
7.50–7.55 (m, 2H), 4.37–4.34 (m, 1H), 2.53 (d, J = 6.0 Hz, 1H), 1.98–
1.93 (m, 1H), 1.74–1.64 (m, 1H), 1.54–1.47 (m, 1H), 1.04–0.97 (m,
6H). 19F NMR (282 MHz, CDCl3):
d
À107.2 (d, J = 300.3 Hz, 1F),
À116.5 (dd, J = 300.3, 17.2 Hz, 1F). 13C NMR (100 MHz, CDCl3):
d
4.2.16. Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate (3q)
190.94 (t, J = 29.7 Hz), 134.81, 132.59, 130.48, 128.92, 116.93 (dd,
J = 260.6, 256.1 Hz), 69.91 (dd, J = 27.4, 24.0 Hz), 37.73, 24.33,
23.85, 21.50. ESI-MS (m/z): 243 (M+H+).
This is a known compound [5c]; 1H NMR (300 MHz, CDCl3):
d
7.42–7.39 (m, 5H), 5.22–5.13 (m, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.30
(t, J = 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3):
d
À114.3 (dd,
J = 262.4, 8.0 Hz, 1F), À120.43 (dd, J = 262.4, 15.3 Hz, 1F).
4.2.11. 2,2-Difluoro-3-hydroxy-1-phenylpentan-1-one (3l)
This is a known compound [15]; colorless oil, IR (neat):
n 3500,
Acknowledgement
2977, 2883, 1696, 1599, 1451 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d
8.11 (d, J = 7.8 Hz, 2H), 7.62–7.67 (m, 1H), 7.47–7.53 (m, 2H), 4.20–
4.11 (m, 1H), 2.54 (d, J = 6.0 Hz, 1H), 1.87–1.61 (m, 2H), 1.07 (t,
We thank the National Natural Science Foundation of China for
financial support (No. 21172243).
J = 7.8 Hz, 3H). 19F NMR (282 MHz, CDCl3):
d
À108.9 (d,
J = 294.2 Hz, 1F), À116.2 (dd, J = 294.2, 20.30 Hz, 1F). 13C NMR
Appendix A. Supplementary data
(100 MHz, CDCl3):
d 190.01 (t, J = 30.5 Hz), 134.76, 132.40, 130.32,
128.77, 116.74 (dd, J = 260.2, 255.4 Hz), 72.84 (dd, J = 27.6,
23.8 Hz), 22.21, 10.03. EI-MS (m/z, %): 214 (M+, 0.13), 156
(6.25), 105 (100.00), 77 (44.98), 59 (4.84), 51 (11.71).
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.
08.012.
4.2.12. 2,2-Difluoro-3-hydroxy-1-phenylhexan-1-one (3m)
References
This is a known compound [4a]; colorless oil, IR (neat):
2965, 2937, 2877, 1698, 1599, 1581, 1467, 1450 cmÀ1 1H NMR
(300 MHz, CDCl3): 8.11 (d, J = 7.8 Hz, 2H), 7.62–7.67 (m, 1H), 7.47–
7.53 (m, 2H), 4.30–4.21 (m, 1H), 2.55 (d, J = 6.0 Hz, 1H), 1.71–1.42
n 3500,
.
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d
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d
À107.0
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d 190.91 (t, J = 29.9 Hz), 134.51, 132.28, 130.16,
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4.2.13. 2,2-Difluoro-3-hydroxy-1-(4-methoxyphenyl)-3-
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phenylpropan-1-one (3n)
This is a known compound [16]; colorless oil, IR (neat):
1681, 1662, 1600, 1570, 1508, 1454 cmÀ1 1H NMR (300 MHz,
CDCl3): 7.95–8.03 (m, 2H), 7.37–7.41 (m, 2H), 7.27–7.30 (m, 3H),
6.83 (d, J = 8.7 Hz, 2H), 5.26 (dd, J = 19.05, 5.4 Hz, 1H), 3.77 (s, 3H).
19F NMR (282 MHz, CDCl3):
À103.9 (d, J = 291.9 Hz, 1F), À115.9
(dd, J = 291.9, 18.6 Hz, 1F). 13C NMR (100 MHz, CDCl3):
189.41 (t,
n 3448,
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d
d
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d
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128.11, 115.81 (dd, J = 263.0, 257.2 Hz), 113.95, 73.26 (dd,
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1-one (3o)
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n 3488,
1693, 1588, 1487, 1456, 1402 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d

50
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