Synthesis of α,α-difluoro-β-hydroxy ketone via the La(OTf)3-catalyzed aldol reaction of carbonyl compounds with difluoroenol O-Boc esters

Article abstract of DOI:10.1016/j.jfluchem.2016.10.017

We herein present an efficient method for the construction of α,α-difluoro-β-hydroxy ketones. The La(OTf)₃-catalyzed aldol reaction between difluoroenol O-Boc (Boc?=?tert-butyloxycarbonyl) esters and carbonyl compounds affords α,α-difluoro-β-hy

Full text of DOI:10.1016/j.jfluchem.2016.10.017

Journal of Fluorine Chemistry 192 (2016) 78–85
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of
a,a-difluoro-b-hydroxy ketone via the La(OTf)3-catalyzed
aldol reaction of carbonyl compounds with difluoroenol O-Boc esters
*
Shigeru Sasaki , Tatuo Suzuki, Toshihiro Uchiya, Shigenobu Toyota, Akira Hirano,
Mao Tanemura, Hiroyoshi Teramoto, Takayasu Yamauchi, Kimio Higashiyama
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
We herein present an efficient method for the construction of
a,a-difluoro-b-hydroxy ketones. The La
Received 1 September 2016
Received in revised form 25 October 2016
Accepted 25 October 2016
Available online 29 October 2016
(OTf)3-catalyzed aldol reaction between difluoroenol O-Boc (Boc = tert-butyloxycarbonyl) esters and
carbonyl compounds affords -difluoro- -hydroxy ketones in good yield. The key reagents of this
a
,a
b
reaction are the difluoroenol O-Boc esters, which are easily synthesized from trifluoromethyl alcohols in
two steps.
Keywords:
ã 2016 Elsevier B.V. All rights reserved.
Aldol reaction
Difluoroenol O-Boc ester
a
,a-Difluoro-b-hydroxy ketone
lyzed reaction
1. Introduction
We herein report a novel catalytic difluoroalkylation method to
give
a
,
a
-difluoro-
b
-hydroxy ketones 4 from the aldol reaction of
with difluoroenol O-Boc (Boc = tert-
Organic fluorine compounds often show unique bioactivities
and behavior compared with their non-fluorinated counterparts
[1]. Currently, approximately 20–30% of agrochemicals and
pharmaceuticals owe their effectiveness to the presence of one
or more fluorine atoms in their structure. Therefore, various
biologically active organic fluorine compounds are used in or
under development for application in these areas. In particular,
carbonyl compounds
3
butyloxycarbonyl) esters 2 (Scheme 1).
2. Results and discussion
We first demonstrated the synthesis of difluoroenol O-Boc
esters from 1-phenyl-2,2,2-trifluoroethanol 5 [10] in two steps.
Protection of the hydroxyl group of 5 as an O-Boc ester was by
treatment with Boc2O and a catalytic amount (10 mol%) of 4-
dimethylaminopyridine (DMAP) in CH3CN at room temperature, to
give Boc-protected alcohol 6. Compound 6 subsequently under-
a
,
a
-difluoro-
tention due to their unique biological properties. For example,
introduction of the -difluoro- -hydroxy ketone unit into a
peptide can give renin inhibitors [2]. In addition, Hockerman et al.
reported that -difluoro- -hydroxy ketone 1 is an agonist of the
-aminobutyric acid type (GABAB) receptor (Fig. 1) [3].
b-hydroxy ketones have received considerable at-
a,
a
b
a
,a
b
went b-elimination of fluoride when treated with 1.5 eq. of lithium
g
B
diisopropylamide (LDA) in tetrahydrofuran (THF) at À78 ꢀC, giving
Furthermore, numerous bioactive compounds containing the
difluoromethylene ketone unit are inhibitors of enzymes such as
HIV-1 protease [4], elastase [5], and human heart chymase [6].
The aldol reaction is one of the most important and useful
reactions for carbon–carbon bond formation in organic synthesis,
and significant efforts have focused on the development of this
compound 7 in 87% yield (Scheme 2).
We then chose to expand the scope of our synthetic method for
a variety of different trifluoromethyl alcohols [11] using the
optimized conditions as outlined in Table 1. The desired
difluoroenol O-Boc esters 10a-g were formed from 8 via 9 in
moderate to high yields, with the exception of 1-aryl-2,2,2-
trifluoroethanol derivatives containing the strongly electron-
withdrawing trifluoromethyl group in the para position of the
aromatic ring. In this case, a complex mixture was obtained instead
of the desired product (entry 5).
reaction [7]. In general, synthetic routes to
a,a-difluoro-b-hy-
droxy ketones are based on difluoroenol silyl ethers [8], although a
number of other routes have been developed by numerous
research groups [9].
We then used our optimized aldol reaction conditions (1.5 eq.
(7) to benzaldehyde 11) to screen Lewis acid catalysts (Table 2). In
the presence of Cu(OTf)2 (20 mol%, OTf = CF3SO3) in
* Corresponding author.
E-mail address: s-sasaki@hoshi.ac.jp (S. Sasaki).
http://dx.doi.org/10.1016/j.jfluchem.2016.10.017
0022-1139/ã 2016 Elsevier B.V. All rights reserved.

S. Sasaki et al. / Journal of Fluorine Chemistry 192 (2016) 78–85
79
Table 1
Synthesis of difluoroenol O-Boc esters.
Entry
R
Yield of 9 (%)a
Yield of 10 (%)a
1
2
3
4
4-MeO-C6H4
97 (9a)
90 (9b)
91 (9c)
94 (9d)
84 (9e)
91 (9f)
76 (9g)
99 (9h)
64 (10a)
80 (10b)
69 (10c)
78 (10d)
decomposed
65 (10e)
95 (10f)
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
4-CF3-C6H4
2-furyl
5
Fig. 1. The GABAB agonist
a,a-difluoro-b-hydroxy ketone 1.
6
7b
8c
c-C6H11
1-adamantyl
85 (10g)
a
Isolated yield.
The reaction was performed with 2 eq. of LDA.
The reaction was performed with 3 eq. of LDA.
b
c
aldol reaction involved treatment of the difluoroenol O-Boc ester
and carbonyl compounds with 1 mol% La(OTf)3 in DCE under reflux.
To expand the scope of our novel difluoroalkylation reaction, we
then investigated the reaction of 1.5 eq. of the difluoroenol O-Boc
esters (7) with various aldehydes under the optimized conditions
(Table 3).
The effect of substituents on the substrate aromatic ring was
first investigated (entries 1–6). In all cases, the aldol reaction
proceeded successfully and the desired adducts were obtained in
good yield. For substrates containing aromatic oxygen or sulfur
heterocycles, the desired adducts were recovered in good yield
(entries 7 and 8). However, the presence of a nitrogen-based
aromatic heterocycle had a detrimental effect on the reaction, with
no trace of the desired product being detected (entries 9 and 10).
We also applied the aldol reaction to aliphatic substrates (entries
11 À14), with the reaction between heptanal and compound 7
giving the desired product in good yield (entry 11). Furthermore,
Scheme 1. Difluoroalkylation via the aldol reaction of 2 with 3.
dichloromethane (DCM) at r. t. for 24 h, the reaction yielded the
desired product 12 in 50% yield (entry 1). In addition, when treated
with TiCl4 (20 mol%), 12 was obtained in 82% yield (entry 2).
However, the use of Sn(OTf)2 gave the desired product 12 along
with the
a,a-difluoro-b-hydroxy ketone tert-butyl ether 13 as a
byproduct (entry 3; total aldol type product in 81% yield). Then, we
also attempted the aldol reaction in the presence of La(OTf)3,
because lanthanum atom has the large ionic radius and high
oxophilicity [12], to give both 12 and 13 in considerably higher
yields (entry 4; total aldol type product ꢁ99% yield). The general
mechanism of the Boc deprotection involves coordination of the
Lewis acid to the carbonyl oxygen atom of the tert-butyl carbamate,
which results in degradation, initially producing carbon dioxide.
The highly reactive tert-butyl cation can then decompose to
isobutylene [13]. We therefore examined implementation of a
higher reaction temperature to allow removal of isobutylene from
the reaction system. In the presence of La(OTf)3 (20 mol%) in DCM
under reflux for 6 h, the desired product 12 was obtained as the
sole product (entry 5). In addition, performing the reaction in 1,2-
dichloroethane (DCE) under reflux for 20 min gave 12 alone in
excellent yield (entry 6). We then examined the possibility of
reducing the amount of catalyst, which resulted in slightly longer
reaction times, but yielded the desired product in quantitative
yield (entries 7 and 8). We could therefore conclude that the
optimal reaction conditions for the catalytic difluoroalkylation
the reaction also proceeded smoothly for
aldehydes (entries 12 and 13). However, using the
-disubstituted aliphatic pivalaldehyde, the reaction did not
a-branched aliphatic
a,a
proceed due to steric hindrance (entry 14).
We continued to investigate the scope and limitations of the
optimized aldol reaction by applying variety of different ketones
16, as shown in Table 4.
The reaction of alkyl aromatic ketones with compound 7
provided the corresponding adduct in moderate to high yields
(entries 1 and 2). However, using a di-aromatic ketone, the reaction
did not proceed (entry 3). Furthermore, we explored the aldol
Scheme 2. Synthesis of difluoroenol O-Boc ester 7 from trifluoromethyl alcohol 5.
Table 2
Optimization of the reaction conditions.
Entry
Cat.
Amount of cat. (mol%)
Solvent
Temp. (ꢀC)
Reaction time
Yield of 12 (%)a
Yield of 13 (%)a
1
2
3
4
5
6
7
8
Cu(OTf)2
TiCl4
20
20
20
20
20
20
2.5
1
DCM
DCM
DCM
DCM
DCM
DCE
r.t.
r.t.
r.t.
r.t.
reflux
reflux
reflux
reflux
24 h
12 h
24 h
12 h
50
82
56
63
81
96
99
99
N. D.b
N. D.b
25
Sn(OTf)2
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
37
6 h
N. D.b
N. D.b
N. D.b
N. D.b
20 min
40 min
50 min
DCE
DCE
a
Isolated yield.
N. D.; Not detected.
b

80
S. Sasaki et al. / Journal of Fluorine Chemistry 192 (2016) 78–85
Table 3
Table 6
Aldol reaction of 7 with a range of aldehydes.
Synthesis of GABAB agonist 11.
Entry
R
Reaction time (h)
Yield of 15 (%)a
Entry
Catalyst X (mol%)
Yield of 1 (%)a
1
2
3
4
5
6
7
8
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-furyl
2-thionyl
2-pyrrolyl
2-pyridyl
n-C6H13
1.5
3.5
3.5
2
1
1
72 (15a)
85 (15b)
71 (15c)
70 (15d)
92 (15e)
78 (15f)
77 (15g)
73 (15h)
N. D.b
1
2
1
5
29
99
a
Isolated yield.
in the formation of the desired product in low yield (entry 1). As
substrate 19 contains two carbonyl oxygen atoms, we expect that
the Lewis acid was being consumed in coordination with the
carbonyl groups. An increase in the amount of catalyst used (from 1
to 5 mol%) confirmed this, with the yield of 1 increasing to 99%
(entry 2).
2
4.5
24
24
0.5
1.2
1.5
24
9
b
10
11
12
13
14
N. D.
80 (15i)
87 (15j)
79 (15k)
c-C5H9
c-C6H11
t-Bu
b
N. D.
a
3. Conclusion
Isolated yield.
N. D.; Not detected.
b
In conclusion, we successfully developed a catalytic difluor-
oalkylation method to give
a,a-difluoro-b-hydroxy ketones from
carbonyl compounds and difluoroenol O-Boc esters using 1 mol%
La(OTf)3 catalyst. The current methodology is particularly well
suited to the introduction of a difluoromethylene moiety to a wide
range of carbonyl compounds in short reaction times. These
structural classes enjoy significant application in the fields of
biochemical, biomedical, and pharmaceutical research and it is
envisaged that the current methodologies will be of significant use
to researchers in these areas. In ongoing work, we are exploring the
asymmetric aldol reaction of difluoroenol O-Boc esters with
carbonyl compounds. In addition, we are screening catalysts with
complexes of La(OTf)3 and optically active ligands.
Table 4
Aldol reaction of 7 with a range of ketones.
Entry
R1
R2
Reaction time (h)
Yield of 17(%)a
1
2
3
4
5
6
7
Ph
Ph
Ph
Me
Me
Et
Ph
Me
Me
3.5
3
81 (17a)
49 (17b)
N. D.c
52 (17c)
74 (17c)
Trace
24
2.5
0.3
24
0.5
b
Me
À(CH2)4-
À(CH2)5-
99 (17d)
a
Isolated yield.
The reaction was performed with 10 eq. of 16.
N. D.; Not detected.
b
c
4. Experimental
4.1. General
reaction of an aliphatic ketone, namely acetone, which gave the
desired product but in low yield due to the volatility of the ketone
(entry 4). Increasing the amount of acetone from 1 to 10 eq., the
yield of 17c was increased to 81% (entry 5). We then explored the
reactivity of cyclic ketones of different ring sizes, as cyclohexanone
generally exhibits higher reactivity compared to cyclopentanone in
carbonyl addition reactions [14]. Indeed, when cyclopentanone
was used as the substrate, the reaction was unsuccessful (entry 6).
However, when cyclohexanone was used, the reaction proceeded
smoothly to afford the corresponding adduct in excellent yield
(entry 7).
The aldol reaction of various difluoroenol O-Boc esters was also
investigated to generalize the reaction using 11 as the model
substrate (Table 5).
In all cases, the reaction of 10 with 11 was successful, giving the
desired product 18a-g in good to high yields with short reaction
times (entries 1–7).
All reactions were carried out under a nitrogen atmosphere. La
(OTf)3 was purchased from Tokyo Chemical Industry CO., LTD.
Other reagents were obtained from commercial sources, and used
as received. Anhydrous solvents were purified by usual methods.
Melting points were measured using a Yanagimoto micro melting-
point apparatus without correction. 1H, 13C, and 19F NMR spectra
were measured on a BRUKER BioSpin AVANCE-III-400 spectrome-
ter at 400, 100, and 376 MHz, respectively. Chemical shifts were
reported downfield from TMS (0 ppm) for 1H NMR. For 13C NMR,
chemical shifts were reported relative to CDCl3 (77.0 ppm). For 19
F
NMR, chemical shifts were reported relative to CF3C6H5 (À63.7
ppm). Infrared spectra were measured on a Perkin-Elmer Spectrum
Two. Mass spectra were recorded on a JEOL JMS 600 mass
spectrometer by either electron impact (EI) or chemical ionization
(CI) methods. For electrospray ionization (ESI) a JEOL JMS-T100LP
mass spectrometer was used. Purification was by column
Using this procedure, we successfully prepared the GABAB
agonist 1 (Table 6). However, the reaction of 10g with 4-
acetylbenzaldehyde 19 in the presence of 1 mol% catalyst resulted
chromatography using 63-210 mm silica gel 60N (Kanto Chemical
Co. Ltd.) or Chromatorex1 NH-silica gel (NH-DM1020, Fuji Silysia
Chemical Ltd.).
Table 5
4.2. Typical procedure for Boc protection of trifluoromethyl alcohols
Aldol reaction of 11 with various difluoroenol O-Boc esters.
Entry
R
Reaction time (h)
Yield of 18 (%)a
To a stirred solution of the desired 2,2,2-trifluoro-1-phenyl-
ethanol 5 (5.0 mmol) and DMAP (61.1 mg, 0.5 mmol) in dry CH3CN
(12.5 mL) was added (Boc)2O (1.64 g, 7.5 mmol) in dry CH3CN
(5.4 mL). The reaction mixture was stirred at room temperature for
20 h, after which time the mixture was concentrated in vacuo.
Finally, the residue was purified by silica gel column chromatog-
raphy (chloroform/n-hexane = 1: 2) to give product 6.
1
2
3
4
5
6
7
4-MeO-C6H4
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
2-furyl
1.5
2
0.3
3.5
2
72 (18a)
99 (18b)
86 (18c)
75 (18d)
96 (18e)
80 (18f)
88 (18 g)
c-C6H11
1-adamantyl
2
1.5
a
Isolated yield.

S. Sasaki et al. / Journal of Fluorine Chemistry 192 (2016) 78–85
81
4.2.1. 2,2,2-Trifluoro-1-phenylethyl tert-butyl carbonate (6)
Colorless oil; 93% yield; 1H NMR (400 MHz, CDCl3):
9H), 5.91 (q, J = 6.8 Hz,1H), 7.40–7.45 (m, 3H), 7.46–7.51 (m, 2H); 13
NMR (100 MHz, CDCl3): 27.5, 74.6 (q, J = 33.2 Hz), 84.0, 123.1 (q,
J = 280.8 Hz), 127.9, 128.6, 129.9, 131.1, 151.7; 19F NMR (376 Hz,
CDCl3):
À77.3 (d, J = 6.8 Hz, 3F); IR (film): 2983, 1756, 1372, 1255,
1135, 700 cmÀ1 HRMS (CI): calcd. for C13H16O3F3 [M+H+]:
144.2, 144.3, 151.6; 19F NMR (376 Hz, CDCl3): À76.5 (d, J = 6.1 Hz,
3F); IR (film): 2985, 1759, 1256, 1156 cmÀ1; HRMS (CI): calcd. for
C11H14O4F3 [M+H+]: 267.0849, found: 267.0844.
d
1.48 (s,
C
d
4.2.8. 2,2,2-Trifluoro-1-cyclohexylethyl tert-butyl carbonate (9g)
d
Colorless oil; 76% yield; 1H NMR (400 MHz, CDCl3):
d
1.13–1.29
(m, 5H), 1.51 (s, 9H), 1.65–1.68 (m, 1H), 1.75–1.85 (m, 5H), 4.87 (dq,
J = 6.4, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3):
25.5, 25.7, 25.8,
;
277.1046, found: 277.1051.
d
27.3, 27.5, 28.7, 37.2, 76.0 (q, J = 30.7 Hz), 83.3,123.9 (q, J = 282.3 Hz),
152.7; 19F NMR (376 Hz, CDCl3): À74.3 (d, J = 7.5 Hz, 3F); IR (film):
2934, 2859, 1755 cmÀ1; HRMS (CI): calcd. for C13H22O3F3 [M+H+]:
283.1521, found: 283.1538.
4.2.2. 2,2,2-Trifluoro-1-(4-methoxyphenyl)ethyl tert-butyl carbonate
(9a)
Colorless oil; 97% yield; 1H NMR (400 MHz, CDCl3):
d
1.48 (s,
9H), 3.82 (s, 3H), 5.86 (q, J = 6.8 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 7.41
(d, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
27.6, 55.2, 74.3 (q,
J = 33.3 Hz), 83.9, 114.1, 123.1, 123.1 (q, J = 280.4 Hz), 129.4, 152.7,
160.7; 19F NMR (376 Hz, CDCl3):
À77.4 (d, J = 6.8 Hz, 3F); IR (film):
2983, 1754, 1615, 1518, 1254, 1134 cmÀ1; HRMS (CI): calcd. for
14H17O4F3 [M+H+]: 306.1099, found: 306.1079.
d
4.2.9. 2,2,2-Trifluoro-1-(adamantan-1-yl)ethyl tert-butyl carbonate
(9h)
d
Colorless oil; 96% yield; 1H NMR (400 MHz, CDCl3):
d
1.51 (s,
9H), 1.66–1.76 (m, 12H), 2.01 (br s, 3H), 4.67 (q, J = 8.1 Hz, 1H); 13C
C
NMR (100 MHz, CDCl3): d 27.6, 27.9, 35.6, 36.5, 37.5, 78.9 (q,
J = 29.3 Hz), 83.2, 124.2 (q, J = 284.1 Hz), 152.9; 19F NMR (376 Hz,
CDCl3): À70.0 (d, J = 8.2 Hz, 3F); IR (film):3421, 2910, 2854,
1754 cmÀ1; HRMS (CI): calcd. for C17H26O3F3 [M+H+]: 335.1834,
found: 335.1846.
4.2.3. 2,2,2-Trifluoro-1-(4-methylphenyl)ethyl tert-butyl carbonate
(9b)
Colorless oil; 90% yield; 1H NMR (400 MHz, CDCl3):
d
1.48 (s,
9H), 2.37 (s, 3H), 5.88 (q, J = 6.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.37
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
21.1, 27.5, 74.5 (q,
J = 33.1 Hz), 83.8, 123.1 (q, J = 280.7 Hz), 127.9, 128.1, 129.3, 139.9,
d
4.3. Typical procedure for the synthesis of difluoroenol O-Boc esters
151.7; 19F NMR (376 Hz, CDCl3):
d
À77.3 (d, J = 6.8 Hz, 3F); IR (film):
To a solution of the Boc-protected trifluoromethyl alcohol 6
(1.0 mmol) in dry THF (5 mL) at À78 ꢀC was added dropwise a
freshly prepared [15] solution of LDA (0.7 M, 2.14 mL). After stirring
for 1 h at À78 ꢀC, the reaction mixture was stirred for an additional
1 h at room temperature. The reaction mixture was then diluted
with water (10 mL) and extracted with EtOAc (3 Â10 mL), dried
over anhydrous Na2SO4, and the solvent evaporated to give a
residue. Finally, the residue was purified by NH-silica gel
chromatography (n-hexane) to give product 7.
1618, 1755, 2984 cmÀ1; HRMS (CI): calcd. for C14H18O3F3 [M+H+]:
291.1208, found: 291.1220.
4.2.4. 2,2,2-Trifluoro-1-(4-fluorophenyl)ethyl tert-butyl carbonate
(9c)
Colorless oil; 96% yield; 1H NMR (400 MHz, CDCl3):
d
1.48 (s,
9H), 5.89 (q, J = 6.7 Hz,1H), 7.08-7.15 (m, 2H), 7.47 (dd, J = 5.3, 8.7 Hz,
2H); 13C NMR (100 MHz, CDCl3):
27.4, 73.9 (q, J = 33.4 Hz), 84.1,
d
115.8 (d, J = 21.9 Hz), 123.0 (q, J = 280.6 Hz),127.1 (d, J = 3.1 Hz),130.0
(d, J = 8.5 Hz),151.6,163.6 (d, J = 249.3 Hz); 19F NMR (376 Hz, CDCl3):
4.3.1. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-phenylethene (7)
d
À77.4 (d, J = 6.1 Hz, 3F), À112.0 (tt, J = 5.1, 8.1 Hz, 1F); IR (KBr):
Colorless oil; 87% yield; 1H NMR (400 MHz, CDCl3):
d
1.51 (s, 9H),
2989, 1757, 1515, 1160, 1137 cmÀ1; HRMS (CI): calcd. for C13H15O3F4
[M+H+]: 295.0978, found: 295.0957.
7.30–7.34 (m, 1H), 7.38–7.46 (m, 4H); 13C NMR (100 MHz, CDCl3):
d
27.4, 84.4, 112.9 (dd, J = 19.1, 38.9 Hz), 125.3 (dd, J = 3.6, 6.4 Hz),
128.4, 128.6, 129.2 (d, J = 6.5 Hz), 150.8 (t, J = 2.7 Hz), 154.8 (dd,
4.2.5. 2,2,2-Trifluoro-1-(4-chlorophenyl)ethyl tert-butyl carbonate
(9d)
J = 289.9, 291.7 Hz); 19F NMR (376 Hz, CDCl3):
d
À93.6 (d, J = 47.3 Hz,
1F), À104.7 (d, J = 47.3 Hz, 1F); IR (film): 2984, 1769, 1745, 1272,
1255, 1133 cmÀ1 HRMS (CI): calcd. for C13H15O3F2 [M+H+]:
Colorless oil; 94% yield; 1H NMR (400 MHz, CDCl3):
d
1.48 (s,
9H), 5.88 (q, J = 7.0 Hz, 1H), 7.38–7.44 (m, 4H); 13C NMR (100 MHz,
CDCl3): 27.6, 73.9 (q, J = 33.5 Hz), 84.3, 122.8 (q, J = 280.9 Hz),
129.0, 129.3, 129.6, 136.1, 151.5; 19F NMR (376 Hz, CDCl3):
;
257.1009, found: 257.0989.
d
d
À77.3
4.3.2. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-(4-methoxyphenyl)
ethene (10a)
(d, J = 6.8 Hz, 3F); IR (film): 3464, 2986, 1760, 1739, 1258, 1140,
822 cmÀ1; HRMS (CI): calcd. for C13H15O3F3Cl [M+H+]: 311.0685,
found: 311.0662.
White solid (mp 53–54 ꢀC); 64% yield; 1H NMR (400 MHz,
CDCl3):
d
1.51 (s, 9H), 3.82 (s, 3H), 6.94 (d, J = 8.9 Hz, 2H), 7.37 (d,
27.5, 55.2, 84.2, 112.8
J = 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
4.2.6. 2,2,2-Trifluoro-1-[4-(trifluoromethyl)phenyl]ethyl tert-butyl
carbonate (9e)
(dd, J = 19.6, 39.7 Hz), 114.1, 121.2 (d, J = 6.0 Hz), 127.0 (t, J = 4.4 Hz),
150.8, 154.5 (dd, J = 288.4, 289.8 Hz), 159.6; 19F NMR (376 Hz,
Colorless oil; 84% yield; 1H NMR (400 MHz, CDCl3):
d
1.49 (s,
9H), 5.97 (q, J = 6.6 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz,
2H); 13C NMR (100 MHz, CDCl3):
27.5, 73.9 (q, J = 33.5 Hz), 84.6,
CDCl3):
d
À95.7 (d, J = 52.4 Hz, 1F), À106.8 (d, J = 52.4 Hz, 1F); IR
(KBr): 2983, 2938, 2841, 1768, 1612, 1517 cmÀ1; HRMS (CI): calcd.
for C14H17O4F2 [M+H+]: 287.1076, found: 287.1095.
d
122.7 (q, J = 280.9 Hz), 123.7 (q, J = 272.3 Hz), 125.7 (q, J = 3.7 Hz),
128.4, 132.1 (q, J = 32.8 Hz), 135.0, 151.5; 19F NMR (376 Hz, CDCl3):
À63.8 (s, 3F), À79.4 (d, J = 6.8 Hz, 3F); IR (film): 2987, 2295, 1759,
4.3.3. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-(4-methylphenyl)
ethene (10b)
850, 830 cmÀ1
;
HRMS (CI): calcd. For C14H15O3F6 [M+H+]:
White solid (mp 30–33 ꢀC); 80% yield; 1H NMR (400 MHz,
345.0950, found: 345.0925.
CDCl3):
d
1.51 (s, 9H), 2.36 (s, 3H), 7.20 (d, J = 8.1 Hz, 2H), 7.33 (d,
21.2, 27.5, 84.3, 113.0
J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
4.2.7. 2,2,2-Trifluoro-1-(furan-2-yl)ethyl tert-butyl carbonate (9f)
(dd, J = 19.1, 39.4 Hz), 125.3 (dd, J = 3.6, 6.3 Hz), 126.3 (d, J = 6.5 Hz),
129.3, 138.4, 150.8 (dd, J = 2.3, 3.6 Hz),154.6 (dd, J = 289.1, 291.3 Hz);
Colorless oil; 91% yield; 1H NMR (400 MHz, CDCl3):
d
1.50 (s,
9H), 6.07 (q, J = 6.6 Hz, 1H), 6.43 (dd, J = 1.8, 3.4 Hz, 1H), 6.62 (d,
J = 3.4 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
27.3, 68.3 (q, J = 35.2 Hz), 84.2, 110.7, 112.0, 122.3 (q, J = 280.7 Hz),
19F NMR (376 Hz, CDCl3):
d
À94.5 (d, J = 49.1 Hz, 1F), À105.5 (d,
J = 49.1 Hz, 1F); IR (KBr): 3007, 2987, 2935, 1769, 1749, 1613 cmÀ1
HRMS (CI): calcd. for C14H17O3F2 [M+H+]: 271.1146, found: 271.1157.
d
;

82
S. Sasaki et al. / Journal of Fluorine Chemistry 192 (2016) 78–85
4.3.4. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-(4-fluorophenyl)
ethene (10c)
a residue. Finally, the residue was purified by silica gel column
chromatography (n-hexane/AcOEt = 7: 1) to give product 12.
Colorless oil; 69% yield; 1H NMR (400 MHz, CDCl3):
d
1.51 (s, 9H),
7.10 (t, J = 8.7 Hz, 2H), 7.36–7.47 (m, 2H); 13C NMR (100 MHz,
CDCl3): 27.5, 84.7,112.3 (dd, J = 19.8, 40.0 Hz),115.8 (d, J = 22.0 Hz),
4.4.1. 2,2-Difluoro-3-hydroxy-1,3-diphenylpropan-1-one (12)
d
99% yield; 1H NMR (400 MHz, CDCl3):
d 3.04 (brs, 1H), 5.39 (dd,
125.3 (dd J = 3.5, 6.4 Hz), 127.5 (ddd, J = 3.7, 6.2, 8.4 Hz), 150.7 (dd,
J = 2.2, 3.3 Hz), 154.7 (ddd, J = 1.8, 289.0, 290.9 Hz), 162.5 (td, J = 1.8,
J = 5.4, 18.8 Hz, 1H), 7.37–7.43 (m, 3H), 7.45–7.54 (m, 4H), 7.61-7.66
(m, 1H), 8.03–8.08 (m, 2H). The 1H NMR spectrum matched that
reported in the literature [16].
248.7 Hz); 19F NMR (376 Hz, CDCl3):
d
À94.0 (dd, J = 3.4, 49.1 Hz,
1F), À105.4 (d, J = 49.5 Hz,1F), À113.3-–113.4 (m,1F); IR (KBr): 1769,
1608, 1513 cmÀ1 HRMS (CI): calcd. for C14H14O3F3 [M+H+]:
;
4.4.2. 2,2-Difluoro-3-hydroxy-3-(2-methoxyphenyl)-1-
phenylpropan-1-one (15a)
275.0895, found: 275.0869.
Colorless oil; 72% yield; 1H NMR (400 MHz, CDCl3):
d 3.58 (d,
4.3.5. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-(4-chlorophenyl)
ethene (10d)
J = 7.2 Hz, 1H), 3.70 (s, 3H), 5.66 (td, J = 7.2, 17.2 Hz, 1H), 6.87 (d,
J = 8.3 Hz, 1H), 7.04 (dt, J = 0.9, 7.5 Hz, 1H), 7.32–7.37 (m, 1H), 7.45–
7.49 (m, 3H), 7.60–7.64 (m, 1H), 8.04–8.06 (m, 2H); 13C NMR
Colorless oil; 78% yield; 1H NMR (400 MHz, CDCl3):
d
1.54 (s,
9H), 7.37 (s, 4H); 13C NMR (100 MHz, CDCl3):
d
27.4, 84.7, 112.3 (dd,
(100 MHz, CDCl3): d 55.2, 70.1 (dd, J = 24.4, 28.2 Hz),110.8,116.8 (dd,
J = 19.8, 39.0 Hz),126.6 (dd, J = 3.7, 6.5 Hz),127.8 (d, J = 6.7 Hz),128.9,
134.7 (t, J = 1.8 Hz), 150.6 (dd, J = 2.1, 3.4 Hz), 154.8 (dd, J = 290.4,
J = 258.0, 261.4 Hz), 120.9, 122.8, 128.5, 129.5, 130.0 (t, J = 3.4 Hz),
130.1, 132.8, 134.1, 157.2, 190.0 (dd, J = 28.2, 29.5 Hz); 19F NMR
292.7 Hz); 19F NMR (376 Hz, CDCl3):
d
À92.7 (d, J = 45.6 Hz, 1F),
(376 Hz, CDCl3):
d
À107.8 (dd, J = 6.8, 275.2 Hz, 1F), À115.9 (dd,
À103.8 (d, J = 45.6 Hz, 1F); IR (film): 2984, 1770, 1744, 1274 cmÀ1
;
J = 17.0, 275.2 Hz, 1F); IR (film): 3492, 2941, 1698, 1599 cmÀ1; HRMS
HRMS (CI): calcd. for C13H14O3F2Cl [M+H+]: 290.0573, found:
291.0599.
(CI): calcd. for C16H15O3F2 [M+H+]: 293.0948, found: 293.0989.
4.4.3. 2,2-Difluoro-3-hydroxy-3-(3-methoxyphenyl)-1-
phenylpropan-1-one (15b)
4.3.6. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-(furan-2-yl)ethene
(10e)
Colorless oil; 85% yield; 1H NMR (400 MHz, CDCl3):
d 2.98 (brs,
Colorless oil; 65% yield; 1H NMR (400 MHz, CDCl3):
d
1.53 (s,
9H), 6.42 (dd, J = 0.5, 3.4 Hz,1H), 6.45 (dd, J = 1.8, 3.4 Hz,1H), 7.46 (d,
J = 0.5, 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
27.1 (d, J = 5.0 Hz),
1H), 3.82 (s, 3H), 5.36 (dd, J = 5.4, 18.6 Hz, 1H), 6.91–6.94 (m, 1H),
7.05–7.09 (m, 2H), 7.31 (t, J = 8.2 Hz,1H), 7.48 (t, J = 7.9 Hz, 2H), 7.61–
7.66 (m, 1H), 8.06 (dd, J = 1.0, 8.5 Hz, 1H); 13C NMR (100 MHz,
d
84.5 (d, J = 5.1 Hz), 107.3 (dd, J = 23.5, 42.5), 108.6 (t, J = 5.2 Hz),111.2,
CDCl3): d 55.2, 73.1 (dd, J = 23.0, 28.6 Hz), 113.4, 14.7, 115.8 (dd,
142.7 (d, J = 8.2 Hz), 142.9, 150.4, 154.1 (t, J = 292.0 Hz); 19F NMR
J = 256.5, 264.6 Hz), 120.4, 128.6, 129.2, 130.1 (t, J = 3.2 Hz), 132.4 (t,
J = 2.2 Hz), 134.5, 136.2 (d, J = 1.0 Hz), 159.4, 190.9 (dd, J = 28.7,
(376 Hz, CDCl3):
(film): 2985, 1772, 1278, 1258, 1135 cmÀ1; HRMS (CI): calcd. for
11H13O4F2 [M+H+]: 247.0803, found: 247.0782.
d
À95.6 (d, J = 42.2 Hz), À102.3 (d, J = 42.2 Hz); IR
31.5 Hz); 19F NMR (376 Hz, CDCl3):
1F), À117.4 (dd, J = 18.4, 290.5 Hz, 1F); IR (film): 3488, 1706,
1597 cmÀ1; HRMS (CI): calcd. for C16H14O3F2 [M+H+]: 293.0964,
found: 293.0989.
d
À105.8 (dd, J = 5.5, 290.5 Hz,
C
4.3.7. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-cyclohexylethene
(10f)
Colorless oil; 95% yield; 1H NMR (400 MHz, CDCl3):
d
1.10–1.41
(m, 5H), 1.51 (s, 9H), 1.65–1.79 (m, 5H), 2.20–2.34 (m, 1H); 13C NMR
(100 MHz, CDCl3): 25.4, 25.8, 27.1, 29.1 (t, J = 2.3 Hz), 36.5 (d,
J = 2.4 Hz), 83.1, 115.7 (dd, J = 12.7, 44.1 Hz), 150.8 (t, J = 2.8 Hz), 153.8
(dd, J = 280.8, 288.9 Hz); 19F NMR (376 Hz, CDCl3):
4.4.4. 2,2-Difluoro-3-hydroxy-3-(4-methoxyphenyl)-1-
phenylpropan-1-one (15c)
d
71% yield; 1H NMR (400 MHz, CDCl3):
d 2.96 (d, J = 4.6 Hz, 1H),
3.82 (s, 3H), 5.33 (ddd, J = 4.6, 5.5, 18.5 Hz, 1H), 6.90–6.95 (m, 2H),
7.43 (d, J = 8.3 Hz, 2H), 7.45–7.51 (m, 2H), 7.61–7.66 (m, 1H), 8.03–
8.08 (m, 2H). The 1H NMR spectrum matched that reported in the
literature [16].
d
À99.2 (d,
J = 64.7 Hz,1F), À112.4 (dd, J = 2.7, 64.7 Hz,1F); IR (film): 2934, 2858,
1766 cmÀ1; HRMS (CI): calcd. for C13H21O3F2 [M+H+]: 263.1459,
found: 263.1463.
4.4.5. 2,2-Difluoro-3-hydroxy-3-(2-nitrophenyl)-1-phenylpropan-1-
one (15d)
4.3.8. 1-(tert-Butoxycarbonyloxy)-2,2-difluoro-1-(adamantan-1-yl)
ethene (10g)
Yellow solid (mp 106–107 ꢀC); 70% yield; 1H NMR (400 MHz,
Colorless oil; 85% yield; 1H NMR (400 MHz, CDCl3):
d
1.50 (s,
9H),1.70 (brs, 6H),1.82 (brs, 6H), 2.01 (brs, 3H); 13C NMR (100 MHz,
CDCl3): 27.5, 28.0, 35.2 (d, J = 4.0 Hz), 38.7 (dd, J = 1.4, 4.1 Hz), 83.5,
119.0 (dd, J = 13.0, 36.3 Hz),151.2 (t, J = 2.8 Hz),154.5 (t, J = 287.2 Hz);
CDCl3): d 3.26 (d, J = 5.0 Hz, 1H), 6.57 (ddd, J = 2.0, 5.0, 20.4 Hz, 1H),
7.48–7.52 (m, 2H), 7.54–7.59 (m, 1H), 7.64–7.69 (m, 1H), 7.73 (dd,
d
J = 1.2, 7.7 Hz, 1H), 7.99-8.01 (m, 2H), 8.08–8.11 (m, 2H); 13C NMR
(100 MHz, CDCl3):
d 66.7 (dd, J = 21.6, 28.8 Hz), 115.2 (dd, J = 258.9,
19F NMR (376 Hz, CDCl3):
d
À95.5 (d, J = 66.1 Hz, 1F), À107.9 (d,
266.7 Hz),124.6,128.8, 129.4, 129.6,130.3,130.3 (d, J = 3.3 Hz),131.6
(t, J = 2.8 Hz), 133.1, 135.0, 148.9, 189.8 (t, J = 27.6 Hz); 19F NMR
(376 Hz, CDCl3): À104.3 (dd, J = 1.4, 303.1 Hz, 1F), À118.5 (dd,
J = 20.4, 303.1 Hz, 1F); IR (KBr): 3497, 1706, 1531 cmÀ1; HRMS (CI):
calcd. for C15H11O4NF2 [M+H+]: 308.0744, found: 308.0734.
J = 66.1 Hz, 1F); IR (film): 3435, 2909, 2854, 1764 cmÀ1; HRMS (CI):
calcd. for C17H24O3F2 [M+H+]: 315.1786, found: 315.1772.
4.4. Typical procedure for the aldol reaction
To a solution of La(OTf)3 (1.5 mg, 2.6
m
mol) and aldehyde
4.4.6. 2,2-Difluoro-3-hydroxy-3-(3-nitrophenyl)-1-phenylpropan-1-
one (15e)
(0.26 mmol) in dry DCE (2 mL) was added difluoroenol O-Boc ester
(1.5 eq., 0.39 mmol) at room temperature. The reaction mixture
was then heated to reflux, and stirred until the disappearance of
difluoroenol O-Boc ester was observed by TLC. The reaction
mixture was then quenched with saturated aqueous NH4Cl
solution (2 mL) and the organic layer separated. Th aqueous layer
was extracted with chloroform (3 Â 5 mL), and the combined
organic layer dried with anhydrous Na2SO4 and evaporated to give
Yellow solid (mp 80.5-81.5 ꢀC); 92% yield; 1H NMR (400 MHz,
CDCl3):
2H), 7.60 (t, J = 8.0 Hz, 1H), 7.65-7.71 (m, 1H), 7.87 (d, J = 7.7 Hz, 1H),
8.09–8.13 (m, 2H), 8.27 (ddd, J = 1.0, 2.3, 8.2 Hz,1H), 8.42 (s,1H); 13
NMR (100 MHz, CDCl3): 72.0 (dd, J = 23.1, 28.8 Hz), 115.1 (dd,
d 3.30 (brs, 1H), 5.53 (dd, J = 3.7, 19.5 Hz, 1H), 7.49–7.54 (m,
C
d
J = 257.4, 266.6 Hz), 123.1, 123.8, 128.7, 129.1, 130.2 (t, J = 3.2 Hz),
131.8 (t, J = 2.6 Hz),134.2,135.0, 136.8 (d, J = 1.0 Hz),148.0,190.3 (dd,

S. Sasaki et al. / Journal of Fluorine Chemistry 192 (2016) 78–85
83
J = 29.1, 31.8 Hz); 19F NMR (376 Hz, CDCl3):
303.5 Hz,1F), À118.0 (dd, J = 19.1, 303.5 Hz,1F); IR (KBr): 3516,1689,
1596, 1533 cmÀ1; HRMS (CI): calcd. for C15H11O4NF2 [M+H+]:
308.0715, found: 308.0734.
d
À104.4 (dd, J = 3.4,
130.0 (t, J = 3.2 Hz), 132.5, 134.2, 190.8 (dd, J = 28.9, 31.4 Hz); 19F
NMR (376.5 MHz, CDCl3):
À106.0 (dd, J = 6.1, 290.2 Hz, 1F), À115.6
d
(dd, J = 20.4, 290.2 Hz, 1F); IR (film): 3453, 2928, 2854, 1698 cmÀ1
;
HRMS (ESI+): calcd. for C15H19F2O2 [M+H+]: 269.1353, Found:
269.1332.
4.4.7. 2,2-Difluoro-3-hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-
one (15f)
4.4.13. 2,2-Difluoro-3-hydroxy-1,3-diphenylbutan-1-one (17a)
White solid (mp 74–75 ꢀC); 81% yield; 1H NMR (400 MHz,
78% yield; 1H NMR (400 MHz, CDCl3):
d 3.31 (d, J = 4.2 Hz, 1H),
5.55 (td, J = 4.2, 19.4 Hz, 1H), 7.51–7.56 (m, 2H), 7.67–7.77 (m, 3H),
8.12 (dd, J = 1.1, 8.5 Hz, 2H), 8.27–8.32 (m, 2H). The 1H NMR
spectrum matched that reported in the literature [16].
CDCl3):
7.39-7.45 (m, 2H), 7.51–7.62 (m, 3H), 7.92 (dd, J = 1.1, 8.5 Hz, 2H); 13
NMR (100 MHz, CDCl3): 24.0 (t, J = 3.0 Hz), 76.4, (t, J = 24.6 Hz),
d 1.83 (t, J = 1.5 Hz, 3H), 3.53 (brs, 1H), 7.27–7.38 (m, 3H),
C
d
116.4 (t, J = 263.6 Hz), 126.3, 128.0, 128.1, 128.4, 130.2 (t, J = 3.6 Hz),
4.4.8. 2,2-Difluoro-3-(furan-2-yl)-3-hydroxy-1-phenylpropan-1-one
(15g)
133.1 (t, J = 2.2 Hz), 134.3, 140.2, 191.6 (t, J = 30.8 Hz); 19F NMR
(376 Hz, CDCl3):
d
À108.6 (s, 2F); IR (KBr): 3510, 1684, 1596 cmÀ1
;
77% yield; 1H NMR (400 MHz, CDCl3):
d
2.96 (d, J = 7.1 Hz, 1H),
HRMS (CI): calcd. for C16H15O2F2 [M+H+]: 277.1066, found:
277.1040.
5.43 (td, J = 7.1, 16.0 Hz, 1H), 6.41 (dd, J = 1.9, 3.4 Hz, 1H), 6.52 (d,
J = 3.4 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.48–7.54 (m, 2H), 7.63–7.69
(m, 1H), 8.06-8.12 (m, 2H). The 1H NMR spectrum matched that
reported in the literature [16].
4.4.14. 2,2-Difluoro-3-hydroxy-1,3-diphenylpentan-1-one (17b)
Colorless oil; 49% yield; 1H NMR (400 MHz, CDCl3):
d 0.78 (t,
J = 7.4 Hz, 3H), 2.14–2.38 (m, 2H), 3.45 (brs, 1H), 7.27–7.37 (m, 3H),
7.40 (t, J = 7.9 Hz, 2H), 7.51 (d, J = 7.3 Hz, 2H), 7.54–7.61 (m,1H), 7.86–
4.4.9. 2,2-Difluoro-3-(thien-2-yl)-3-hydroxy-1-phenylpropan-1-one
(15h)
7.94 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 6.6, 27.3 (t, J = 2.5 Hz),
White solid (mp 56–58 ꢀC); 73% yield; 1H NMR (400 MHz,
79.1 (t, J = 23.5 Hz), 116.7 (t, J = 264.2 Hz), 126.8, 127.8, 128.1, 128.3,
130.2 (t, J = 3.5 Hz), 133.2 (t, J = 2.1 Hz), 134.2, 137.6, 191.9 (t,
CDCl3):
d 3.07 (d, J = 5.5 Hz, 1H), 5.66 (td, J = 5.5, 17.2 Hz, 1H), 7.05
(dd, J = 3.5, 5.1 Hz, 1H), 7.20 (d, J = 3.5 Hz, 1H), 7.39 (dd, J = 1.1, 5.1 Hz,
1H), 7.50 (t, J = 7.8 Hz, 2H), 7.63–7.69 (m, 1H), 8.09 (d, J = 7.4 Hz, 2H);
J = 30.9 Hz); 19F NMR (376 Hz, CDCl3):
d
À108.8 (s); IR (film): 3521,
1691, 1452 cmÀ1
;
HRMS (CI): calcd. for C17H17O2F2 [M+H+]:
13C NMR (100 MHz, CDCl3):
d
70.1 (dd, J = 24.2, 29.4 Hz), 115.1 (dd,
291.1199, found: 291.1196.
J = 257.7, 264.8 Hz), 126.7, 126.8, 127.5, 128.7, 130.2 (t, J = 3.2 Hz),
132.2 (t, J = 2.6 Hz),134.7, 137.1, 190.5 (dd, J = 29.2, 31.5 Hz); 19F NMR
4.4.15. 2,2-Difluoro-3-hydroxy-3-methyl-1-phenylbutan-1-one (17c)
(376 Hz, CDCl3):
d
À106.0 (dd, J = 5.5, 293.6 Hz, 1F), À116.7 (dd,
Colorless oil; 74% yield; 1H NMR (400 MHz, CDCl3):
d
1.45 (t,
J = 1.4 Hz, 6H), 2.88 (brs, 1H), 7.48–7.52 (m, 2H), 7.63–7.67 (m, 1H),
8.12 (dd, J = 1.0, 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
23.6 (t,
J = 17.7, 293.6 Hz, 1F); IR (KBr): 3420, 1669, 1596 cmÀ1; HRMS (ESI–
): calcd. for C13H10O2F2S [MÀH+]: 267.02913, found: 267.03222.
d
J = 2.9 Hz), 73.3 (t, J = 24.7 Hz), 117.1 (t, J = 261.7 Hz), 128.6, 130.4 (t,
4.4.10. 2,2-Difluoro-3-hydroxy-1-phenylnonan-1-one (15i)
J = 3.6 Hz), 133.1 (t, J = 2.6 Hz), 134.4, 191.2 (t, J = 31.7 Hz); 19F NMR
Colorless oil; 65% yield; 1H NMR (400 MHz, CDCl3):
d
0.90 (t,
(376 Hz, CDCl3):
d
À111.6 (s, 2F); IR (film): 3503, 2994, 1694,
J = 3.4 Hz, 3H), 1.24–1.48 (m, 7H), 1.59–1.76 (m, 3H), 2.41 (d,
J = 6.2 Hz, 1H), 4.18–4.29 (m, 1H), 7.48-7.55 (m, 2H), 7.64–7.68 (m,
1598 cmÀ1; HRMS (CI): calcd. for C11H13O2F2 [M+H+]: 215.0890,
found: 215.0883.
1H), 8.12 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 14.0, 22.6,
25.3, 28.8 (dd, J = 1.5, 2.7 Hz), 29.0, 31.7, 71.4 (dd, J = 24.2, 27.2 Hz),
116.6 (dd, J = 257.2, 261.5 Hz), 128.7, 130.2 (t, J = 3.3 Hz), 132.3 (t,
J = 2.6 Hz), 134.6, 190.6 (dd, J = 30.1, 31.6 Hz); 19F NMR (376 Hz,
4.4.16. 2,2-Difluoro-2-(1-hydroxycyclohexyl)-1-phenylethan-1-one
(17d)
Colorless oil; 99% yield; 1H NMR (400 MHz, CDCl3):
d 1.14-1.35
CDCl3):
d
À108.8 (ddd, J = 1.0, 5.5, 296.0 Hz, 1F), À118.1 (dd, J = 17.0,
(m, 2H), 1.57–1.77 (m, 6H), 1.81–1.95 (m, 2H), 2.53 (brs, 1H), 7.49 (t,
296.0 Hz, 1F); IR (film): 3435, 2928, 1696, 1598 cmÀ1; HRMS (CI+):
J = 7.5 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 8.11 (d, J = 7.5 Hz, 2H); 13C NMR
calcd. for C15H21O2F2 [M+H+]: 271.1509, found: 271.1492.
(100 MHz, CDCl3):
d 20.4, 25.2, 29.9 (t, J = 2.8 Hz), 74.2 (t,
J = 23.7 Hz), 117.4 (t, J = 261.3 Hz), 128.5, 130.4 (t, J = 3.9 Hz), 133.4
4.4.11. 3-Cyclopentyl-2,2-difluoro-3-hydroxy-1-phenylpropan-1-one
(15j)
(t, J = 2.5 Hz), 134.2, 191.4 (t, J = 31.3 Hz); 19F NMR (376 Hz, CDCl3):
d
À113.7 (s, 2F); IR (film): 3514, 2939, 2863, 1692, 1598 cmÀ1; HRMS
Colorless oil; 87% yield; 1H NMR (400 MHz, CDCl3):
d
1.38–1.62
(CI): calcd. for C14H16F2O2 [M+H+]: 255.1196, Found: 255.1199.
(m, 4H), 1.63–1.73 (m, 2H), 1.80–1.94 (m, 2H), 2.23–2.35 (m, 1H),
2.39 (d, J = 6.1 Hz, 1H), 4.19 (qd, J = 6.1, 19.4 Hz, 1H), 7.49–7.53 (m,
2H), 7.63–7.67 (m, 1H), 8.10–8.12 (m, 2H); 13C NMR (100 MHz,
4.4.17. 2,2-Difluoro-3-hydroxy-1-(4-methoxyphenyl)-3-
phenylpropan-1-one (18a)
CDCl3):
d
25.0, 25.3, 27.9, 29.4 (d, J = 2.7 Hz), 39.6, 74.0 (dd,
White solid (mp 68–69 ꢀC); 72% yield; 1H NMR (400 MHz,
J = 23.7 Hz, J = 26.8 Hz), 117.3 (dd, J = 257.2 Hz, J = 262.5 Hz), 128.6,
130.1 (t, J = 3.3 Hz), 132.5, 134.4, 190.9 (dd, J = 29.0 Hz, J = 31.5 Hz);
CDCl3):
1H), 6.92–6.96 (m, 2H), 7.36-7.43 (m, 3H), 7.48–7.54 (m, 2H), 8.04–
8.10 (m, 2H); 13C NMR (100 MHz, CDCl3):
55.6, 73.3 (dd, J = 23.1,
d 3.22 (d, J = 4.6 Hz,1H), 3.89 (s, 3H), 5.37 (td, J = 4.6,19.2 Hz,
19F NMR (376.5 MHz, CDCl3):
d
À106.3 (dd, J = 5.5, 289.5 Hz, 1F),
d
À117.1 (dd, J = 19.1, 289.5 Hz, 1F); IR (film): 3467, 2957, 2870, 1698,
1598 cmÀ1; HRMS (CI): calcd. for C14H17F2O2 [M+H+]: 255.1196,
Found: 255.1207.
28.6 Hz), 114.0, 115.8 (dd, J = 256.9, 264.8 Hz), 125.1 (t, J = 2.6 Hz),
128.1, 128.2, 128.9, 132.9 (t, J = 3.3 Hz), 134.8, 164.8, 189.1 (dd,
J = 29.2, 31.3 Hz); 19F NMR (376 Hz, CDCl3):
294.6 Hz,1F), À117.0 (dd, J = 19.1, 294.6 Hz,1F); IR (KBr): 3429,1669,
1594 cmÀ1; HRMS (CI): calcd. for C16H15O3F2 [M+H+]: 293.0991,
found: 293.0989.
d
À104.9 (dd, J = 4.8,
4.4.12. 3-Cyclohexyl-2,2-difluoro-3-hydroxy-1-phenylpropan-1-one
(15k)
Colorless oil; 79% yield; 1H NMR (400 MHz, CDCl3):
d 1.12–1.43
(m, 6H),1.64–1.90 (m, 4H),1.94–2.02 (m,1H), 2.29 (d, J = 6.4 Hz,1H),
4.01–4.12 (m, 1H), 7.47–7.54 (m, 2H), 7.62–7.68 (m, 1H), 8.07–8.14
4.4.18. 2,2-Difluoro-3-hydroxy-1-(4-methylphenyl)-3-phenylpropan-
1-one (18b)
(m, 2H); 13C NMR (100 MHz, CDCl3):
d
25.8, 26.0, 26.1, 27.2, 29.9,
White solid (mp 126–127 ꢀC); 99% yield; 1H NMR (400 MHz,
38.0, 74.6 (dd, J = 23.0, 26.5 Hz), 117.8 (dd, J = 257.8, 262.8 Hz), 128.5,
CDCl3): d 2.43 (s, 3H), 3.05 (d, J = 4.7 Hz,1H), 5.38 (td, J = 4.7,18.9 Hz,

84
S. Sasaki et al. / Journal of Fluorine Chemistry 192 (2016) 78–85
1H), 7.2–7.31 (m, 2H), 7.37–7.44 (m, 3H), 4.47–7.54 (m, 2H), 7.97 (d,
J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
21.8, 73.2 (dd, J = 23.3,
J = 2.2 Hz), 73.1 (dd, J = 23.4, 27.5 Hz), 116.5 (dd, J = 259.5, 266.5 Hz),
128.0, 128.2, 128.9, 135.0, (d, J = 2.1 Hz), 205.7 (dd, J = 26.0, 29.0 Hz);
19F NMR (376 Hz, CDCl3): À108.4 (dd, J = 7.5, 286.1 Hz, 1F), À119.0
(dd, J = 18.4, 286.1 Hz, 1F); IR (film): 3498, 2907, 2850, 1711,
1700 cmÀ1; HRMS (CI): calcd. for C19H23F2O2 [M+H+]: 321.1666,
found: 321.1676.
d
28.6 Hz), 115.7 (dd, J = 256.7, 264.7 Hz), 128.1, 128.2, 128.9, 129.3,
129.8 (t, J = 2.5 Hz), 130.4 (t, J = 3.2 Hz), 134.7, 145.9, 190.4 (dd,
J = 29.0, 31.3 Hz); 19F NMR (376 Hz, CDCl3):
293.9 Hz, 1F), À117.4 (dd, J = 19.1, 293.9 Hz, 1F); IR (KBr): 3460,
1685 cmÀ1; HRMS (CI): calcd. for C16H15O2F2 [M+H+]: 277.1040,
found: 277.1028.
d
À105.5 (dd, J = 5.5,
4.4.24. GABAB agonist (1)
99% yield; 1H NMR (400 MHz, CDCl3):
d 1.65–1.80 (m, 6H), 1.90
4.4.19. 2,2-Difluoro-3-hydroxy-1-(4-fluorophenyl)-3-phenylpropan-
1-one (18c)
(brs, 6H),1.99–2.06 (m, 3H), 2.62 (s, 3H), 3.00 (d, J = 4.9 Hz,1H), 5.33
(td, J = 4.9, 18.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.94–8.00 (m, 2H).
The NMR data matched that reported in the literature [17].
White solid (mp 103–104 ꢀC); 86% yield; 1H NMR (400 MHz,
CDCl3):
J = 8.7 Hz, 2H), 7.38–7.44 (m, 3H), 7.47-7.53 (m, 2H), 8.07–8.14 (m,
2H); 13C NMR (100 MHz, CDCl3):
73.2 (dd, J = 23.0, 28.6 Hz), 115.7
d 2.98 (d, J = 4.7 Hz, 1H), 5.37 (td, J = 4.7, 13.8 Hz, 1H), 7.15 (t,
References
d
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(dd, J = 256.6, 264.5 Hz), 115.9 (d, J = 22.0 Hz), 128.1, 128.3, 128.8 (q,
J = 2.7 Hz), 129.1, 133.2 (ddd, J = 2.9, 4.0, 9.8 Hz), 134.5, 166.5 (d,
J = 258.2 Hz),189.4 (dd, J = 29.2, 32.1 Hz); 19F NMR (376 Hz, CDCl3):
d
À102.5 (tt, J = 5.5, 8.2 Hz, 1F), À105.6 (dd, J = 5.5, 292.5 Hz, 1F),
À117.3 (dd, J = 19.1, 292.5 Hz); IR (KBr): 3467, 3079, 2938, 1691,
1598 cmÀ1; HRMS (CI): calcd. for C15H11O2F3 [M+H+]: 280.0711,
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White solid (mp 112–113 ꢀC); 75% yield; 1H NMR (400 MHz,
CDCl3):
7.38–7.52 (m, 7H), 7.99 (d, 2H, J = 8.7 Hz); 13C NMR (100 MHz,
CDCl3): 73.3 (dd, J = 23.1, 28.7 Hz), 115.7 (dd, J = 256.3, 264.0 Hz),
128.1,128.4,129.0,129.1,130.7,131.6 (t, J = 3.3 Hz),134.5,141.3,189.8
(d, J = 29.4 Hz); 19F NMR (376 Hz, CDCl3):
d 2.97 (d, J = 4.6 Hz, 1H), 5.37 (td, 1H, J = 4.6, 18.6 Hz, 1H),
d
d
À105.9 (dd, J = 6.1,
291.9 Hz,1F), À117.5 (dd, J = 18.4, 291.9 Hz,1F); IR (KBr): 3486, 2882,
1694, 1588 cmÀ1; HRMS (CI): calcd. for C15H12O2F2Cl [M+H+]:
297.0513, found: 297.0494.
4.4.21. 2,2-Difluoro-1-(furan-2-yl)-3-hydroxy-3-phenylpropan-1-one
(18e)
White solid (mp 68–69 ꢀC); 96% yield; 1H NMR (400 MHz,
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a,a-difluorostatone
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3.7 Hz, 1H), 7.35–7.44 (m, 4H), 7.44–7.50 (m, 2H), 7.73 (d, J = 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3):
72.9 (dd, J = 23.7, 28.3 Hz), 115.8
d 3.12 (s, 1H), 5.34 (dd, J = 6.6, 17.6 Hz, 1H), 6.57 (dd, J = 1.6,
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(dd, J = 254.9, 261.5 Hz),124.2 (dd, J = 3.9, 7.8 Hz), 127.6, 127.8, 128.6,
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À109.4 (dd, J = 5.8, 277.6 Hz, 1F), À120.5
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HRMS (CI): calcd. for C13H11O3F2 [M+H+]: 253.0692, found:
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1H), 2.75 (m, 1H), 5.19 (ddd, J = 4.8, 7.7, 16.6 Hz, 1H), 7.37–7.46 (m,
5H); 13C NMR (100 MHz, CDCl3):
25.1, 25.2, 25.4, 27.6, 27.8, 45.8,
d 1.17–1.46 (m, 6H), 1.65–1.84 (m, 4H), 2.65 (d, J = 4.8 Hz,
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d
À113.6 (dd, J = 7.5, 273.2 Hz, 1F), À123.4 (dd, J = 17.0,
273.2 Hz, 1F); IR (KBr): 3497, 2939, 2857, 1718 cmÀ1; HRMS (ESI +):
calcd. for C15H19F2O2 [M+H+]: 269.1353, Found: 269.1332.
defluorination route to
a-fluoro-a,b-unsaturated ketones from
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hydroxypropan-1-one (18g)
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White solid (mp 88–89 ꢀC); 88% yield; 1H NMR (400 MHz,
CDCl3):
2.76 (d, J = 5.1 Hz, 1H), 5.25 (ddd, J = 5.1, 7.1, 17.4 Hz, 1H) 7.35–7.45
(m, 5H); 13C NMR (100 MHz, CDCl3):
27.5, 36.3, 36.7, 46.7 (t,
d 1.64–1.77 (brm, 6H), 1.84–1.91 (brm, 6H), 2.01 (brs, 3H),
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