Controlling the cleavage of carbon-carbon bonds to generate α,α-difluorobenzyl carbanions for the construction of difluoromethylbenzenes

Article abstract of DOI:10.1021/acs.joc.9b01595

Controlling the cleavage of carbon-carbon bonds during a chemical reaction is a substantial challenge; however, synthetic methods that accomplish this objective produce valuable and often unexplored reactivity. We have designed a mild process to generate α,α-difluorobenzyl carbanions in the presence of potassium carbonate by exploiting the cleavage of C-C bonds during the release of trifluoroacetate. The initiating reagent is potassium carbonate, which represents an improvement over existing protocols that require a strong base. Fragmentation studies across substituted arenes and heteroarenes were conducted along with computational analyses to elucidate reactivity trends. Furthermore, the mildly generated α,α-difluorobenzyl carbanions from electron-deficient aromatics and heteroaromatic rings can react with aldehydes to create derivatives of difluoromethylbenzenes, which are valuable synthetic targets.

Full text of DOI:10.1021/acs.joc.9b01595

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Article
Controlling the Cleavage of Carbon–Carbon Bonds to Generate #,#-
Difluorobenzyl Carbanions for the Construction of Difluoromethylbenzenes
Hari R. Khatri, Changho Han, Erica Luong, Xiaoliang Pan, Amna
T. Adam, Maali D. Alshammari, Yihan Shao, and David A. Colby
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01595 • Publication Date (Web): 26 Aug 2019
Downloaded from pubs.acs.org on August 31, 2019
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Page 1 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
Controlling the Cleavage of Carbon–Carbon Bonds to Generate
Difluorobenzyl Carbanions for the Construction of Difluoro-
methylbenzenes
a
, -
a
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
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0
1
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3
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8
9
0
1
2
3
4
5
6
7
8
9
0
†
‡
§
§
†,#
Hari R. Khatri, Changho Han, Erica Luong, Xiaoliang Pan, Amna T. Adam, Maali D. Al-
†,#
§
*,†
shammari, Yihan Shao, and David A. Colby
†
Department of BioMolecular Sciences, University of Mississippi, University, Mississippi 38677, United States
‡
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana
7907, United States
4
§
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
ABSTRACT: Controlling the cleavage of carbon–carbon bonds during a chemical reaction is a substantial challenge; how-
ever, synthetic methods that accomplish this objective produce valuable and often unexplored reactivity. We have designed
a mild process to generate a,a-difluorobenzyl carbanions in the presence of potassium carbonate by exploiting the cleavage
of C–C bonds during the release of trifluoroacetate. The initiating reagent is potassium carbonate, which represents an
improvement over existing protocols that require strong base. Fragmentation studies across substituted arenes and het-
eroarenes were conducted along with computational analyses to elucidate reactivity trends. Furthermore, the mildly gen-
erated a,a-difluorobenzyl carbanions from electron-deficient aromatics and heteroaromatic rings can react with aldehydes
to create derivatives of difluoromethylbenzenes, which are valuable synthetic targets.
context of fundamental nucleophile reactivity, only two re-
actions are available to produce a,a-difluorobenzyl car-
The first is confined to a trime-
thylsilyldifluoromethylbenzene as a starting material.
Moreover, few trimethylsilyldifluoromethylbenzenes have
been reported in the literature to participate as nucleo-
philic precursors, because this type of starting material is
The second is a stabilized
transfer reagent produced with the strong base, potassium
INTRODUCTION
1
6,17
The cleavage of carbon–carbon bonds is quite challeng-
ing and rather unexplored, but if these bonds can be bro-
ken with high selectivity, organic molecules can be remod-
banions (Figure 1B).
1
6
1
,2
eled into higher value fine chemicals. Although cutting-
edge innovations in breaking C–C bonds have appeared,
primarily through C–C bond activation, strategies to cleave
these bonds are rare due to the high stability of the C–C
1
6–19
challenging to synthesize.
3–5
2
0
bond. The potential for this process in synthetic chemis-
diisopropylamide, and reported by Szymczak in 2018.
try is substantial, and historically, its utility has originated
Currently, methods to generate these fluorinated carbani-
ons are still needed along with additional studies of the re-
activity and stability of these nucleophiles.
6
from C–C bond rearrangements.
Fluorinated organic molecules are valuable targets in the
pharmaceutical and agrochemical industries, because the
presence of fluorine usually imparts beneficial characteris-
7,8
tics during development. Synthetic methods to create
fluorinated compounds are quite prevalent in the cases of
fluorination and trifluoromethylation, but less developed
9
for difluoromethyl groups (i.e., CF
2
group). In medicinal
2
chemistry, aryldifluoromethyl derivatives (ArCF R) consti-
tute a discrete class of fluorinated compounds, and some
of the representative examples that contain aryldifluoro-
1
0
methyl groups include a nitric oxide synthase inhibitor, a
1
1
12
CCR5 receptor antagonist, a urea transporter B inhibitor,
and an analogue of fenofibrate that serves as a PPARα ac-
1
3
tivator (Figure 1). Some methods are available for the syn-
1
3–15
thesis of difluoromethylbenzenes;
however, in the
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Page 2 of 14
A) Aryldifluoromethyl groups in medicinal chemistry
Generation α,α-Difluoroenolates (Colby 2011)
F
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Me
NH2
O HO OH
O
O
F
O
O
base
N
R
CF3
F
+
CF3CO2
R
CF3
R
F
F
F
F
F
F
H
N
F
N
F
NH
N
O
Generation α,α-Difluorocarboxylates (Guerrero 2005)
F
F
CO2H
HO HO OH
nitric oxide synthase inhibitor
F
HO
HO
O
O
F
O
CCR5 receptor antagonist
O
base
R
CF3
F
R
CF3
R
O
+
CF3
F
F
N
N
F
F
F
Me
N
S
O O
S
This work
R
N
O
O
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
CO2i-Pr
F
+
CF3CO2
NH
F
F
HO OH
CF3
NHBoc
F
S
base
PPARα activator
F
F
urea transporter B inhibitor
O
R
+
CF3
O
B) Two methods for the production of ArCF2-based carbanions
F
F
F
F
F
O
F F
Figure 2. Fragmentations of a-Fluorinated-gem-diols.
F
R1
2
SiMe3
+
R1 R2
R
1
2
OH
RESULTS
R
R
= H, alkyl
= aryl, alkyl
We commenced our study with the synthesis of aryl pen-
tafluoro-gem-diols as substrates for the fragmentation
studies. Our two previous reports of synthetic strategies for
the pentafluoro-gem-diols adjacent to ketones
translate to the aromatic or heteroaromatic class of com-
pounds; therefore, we devised a new preparation, starting
from readily available aryl bromides or iodides (Table 1).
Accordingly, the aryl halide couples to bromodifluoroethyl
acetate in the presence of copper and then intermediate
ester is treated with the Ruppert-Prakash reagent and ce-
O
F
1
. B3N3Me6,
B
N
18-crown-6
N
B
N
B
R1
R2
H
Ph
F
2. KN(i-Pr)2
R
R
1
2
= H, aryl
= aryl, alkyl
9,32
F
do not
Figure 1. (a) Medicinal agents displaying an aryldifluoro-
methyl group. (b) Scope of nucleophilic additions with ar-
yldifluoromethyl-based carbanions.
We have previously designed a mild process to generate
α,α-difluorocarbanions by exploiting the cleavage of C–C
bonds during the fragmentation of pentafluoro-gem-diols
Figure 2). Specifically, our laboratory has shown the pen-
tafluoro-gem-diols adjacent to a carbonyl group can be
33
34
9
sium fluoride. The aryl pentafluoro-gem-diols 1–15 are
(
produced in two-steps with isolated yields of 27–84%. Sub-
stituted benzene, pyridine, naphthalene, and pyrazine par-
ticipate in the process. Nitro, cyano, acetyl, and trifluoro-
methyl substituents are compatible with the transfor-
mations. X-ray structures of compounds 1 and 12 were ob-
tained to define the structures of these novel molecules. To
our knowledge, these X-ray data are the first crystal struc-
tures of aryl pentafluoro-gem-diols. All of these products
will serve to define the role of electron-withdrawing versus
election-donating substituents on the aromatic rings dur-
ing the fragmentation studies.
used to generate difluoroenolates from the release of tri-
9,21,22
fluoroacetate.
This method for the production of fluo-
roenolates has enabled substantial advancement in the
study of the reactivity due to its exceedingly mild condi-
2
3–29
tions (for the fragmentation of a carbon–carbon bond).
Prior to these studies, the Guerrero group demonstrated
that pentafluoro-gem-diols adjacent to secondary alcohols
produce difluoroacetic acids following the release of fluo-
3
0,31
roform.
Herein, we have applied this approach to pro-
duce α,α-difluorobenzyl carbanions and construct difluo-
romethylbenzenes upon electron-deficient aromatics and
heteroaromatic rings. This process can be controlled by the
nature of the substrate as well as the reagents depending
upon if trifluoroacetate or fluoroform is released.
a
Table 1. Synthesis of Aryl Pentafluoro-gem-diols 1–15
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Page 3 of 14
The Journal of Organic Chemistry
O2N
1
. Cu, BrCF
. TMSCF , CsF
(2 steps)
2
CO
2
Et
HO OH
CF
R
R
1
2
3
4
5
6
7
8
9
2
3
H
X
3
F
F
X = Br or I
1–15
F F
O2N
O
O
2
N
O
2
N
F
3
C
OH
HO OH
CF
HO OH
HO OH
CF CO H
3
2
F F
CF3H
3
N
CF
3
N
CF
3
F
F
F
F
F F
X-ray
structure
1
, 44%
2, 37%
3, 77%
t = 10 min, K CO
2
3
O
2
N
O
2
N
C
N
N
HO OH
CF
HO OH
CF
HO OH
CF
O2N
H
3
N
3
3
6 5 3
C H CF
(standard)
HO OH
CF3
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
3
C
F
F
F
F
F
F
F
F
4
, 58%
5, 55%
6, 55%
O
t = 0 min (no base)
NC
NC
HO OH
CF
HO OH
CF
HO OH
CF
3
N
3
3
–
60
–70
–80
–90
–100
–110
–120
F
F
F
F
F F
f1 (ppm)
7, 57%
8, 71%
9, 26%
1
9
Figure 3. Comparison of F NMR data of α-fluorinated-
gem-diol 1 in DMSO at t = 0 min and t = 10 min after treat-
F
3
C
HO OH
HO OH
CF
HO OH
CF
N
CF
3
3
O
2
N
3
2 3
ment with K CO .
F
F
F
F
F F
1
0, 46%
11, 84%
12, 67%
X-ray
structure
Table 2. Fragmentation of Pentafluoro-gem-diol 1 in
Cs CO
H
3
CO
2
3
HO OH
CF
HO OH
CF
HO OH
CF
3
O2N
O2N
F
3
C
3
3
O
F
F
F
F
F
F
Cs2CO3, solvent
60 °C, 10 min
1
H
+
OH
1
3, 36%
14, 27%
15, 67%
F
F
F F
a
Isolated yields.
release of
trifluoroacetate
release of
fluoroform
a
a
entry
solvent
The para-nitrobenzene 1 was selected for the initial base-
1
DMPU
NMP
95
91
88
83
79
49
45
44
42
34
34
18
5
promoted fragmentations. Potassium carbonate and ce-
sium carbonate initiated the cleavage of the α-fluorinated-
gem-diol 1 whereas the usual conditions of a mixture of
lithium bromide and triethylamine only returned unre-
acted starting material.
presence of K CO was analyzed by F NMR, and the 1-
difluoromethyl-4-nitrobenzene and the 2,2-difluoro-2-(4-
nitrophenyl)acetic acid were observed along with trifluoro-
acetate and fluoroform (Figure 3). The unique peaks for
each of the fluorinated compounds had excellent disper-
2
9
3
DMF
12
17
21
51
55
56
58
66
66
82
4
acetone
DMSO
EtOAc
CH3CN
5
9
,22
The fragmentation of 1 in the
1
9
6
2
3
7
8
dioxane
toluene
THF
9
10
11
19
sion across –60 to –120 ppm in the F NMR. Also, the frag-
DCE
mentation of 1 was complete in ten minutes at 60 °C in the
presence of cesium carbonate with many common organic
solvents (Table 2). Highly polar solvents such as DMPU,
DMSO, and DMF primarily favored the release of trifluoro-
acetate and the formation of 1-difluoromethyl-4-nitroben-
zene. On the other hand, less polar organic solvents, such
as dioxane, THF, and trifluorotoluene, caused the produc-
tion of 2,2-difluoro-2-(4-nitrophenyl)acetic acid from the
release of fluoroform.
1
2
trifluorotoluene
a 19
F NMR yields.
Next, the para-trifluoromethylbenzene 11 was subjected
to a similar series of fragmentation experiments using ce-
sium carbonate (Table 3). The results from these experi-
ments show that the primary fragmentation pathway is the
release of fluoroform which creates the difluoroacetic acid.
The difluoromethylarene was a minor product in the most
polar solvents and not observed in the less polar organic
solvents. The choice of solvent plays an important role in
directing the fragmentation of these a-fluorinated-gem-di-
ols; however, the results of the reaction are dependent
upon the nature of the starting material.
Table 3. Fragmentation of Pentafluoro-gem-diol 11 in
2 3
Cs CO
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F3C
F3C
+
O
HO OH
CF3
K2CO3
O
R
R
R
Cs2CO3, solvent
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H
+
1
1
H
OH
DMSO, rt
OH
60 °C, 10 min
1–3,
–15
F
F
F
F
F F
F
F
F F
7
release of
trifluoroacetate
release of
fluoroform
release of
trifluoroacetate
release of
a
a
a
a
entry
solvent
entry
starting material
fluoroform
1
2
3
4
5
6
7
8
9
DMSO
DMPU
NMP
17
14
9
83
1
1 (para-nitrophenyl)
2 (5-nitro-2-pyridyl)
3 (5-CF3-2-pyridyl)
7 (5-cyano-2-pyridyl)
8 (para-cyanophenyl)
9 (para-acetylphenyl)
10 (2-pyridyl)
100
0
86
2
100
100
94
0
91
3
0
DMF
6
94
4
6
THF
2
98
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
54
46
73
86
96
100
100
100
100
CH3CN
DCE
2
98
0
100
100
100
6
27
toluene
0
7
1
4
trifluorotoluene
0
8
11 (para-CF -phenyl)
4
0
0
0
0
3
a 19
F NMR yields.
9
12 (meta-nitrophenyl)
10
13 (meta-CF3-phenyl)
14 (naphthyl)
In order to define the role of substrate in the two com-
peting fragmentation processes, the a-fluorinated-gem-di-
ols 1–3 and 7–15 were cleaved in potassium carbonate in
DMSO at room temperature (Table 4). Potassium car-
bonate in DMSO was chosen because these conditions are
the best potential for integration into a synthetic reaction.
The pentafluoro-gem-diol 1 provides quantitative conver-
11
1
2
15 (para-CH3O-phenyl)
a 19
F NMR yields.
Computational investigations using density functional
35
36,37
38
theory (B3LYP functional
and 6-31+G* basis ) and
sion to the difluoromethylarene 16 in K
compared to 79% in Cs CO in DMSO. Other electron-de-
2 3
CO and DMSO
39
IEF-PCM model yielded rather low (1.5 to 7 kcal/mol) bar-
riers for either the release of trifluoroacetate or fluoroform.
The product selectivity is thus determined mainly by the
reaction energies as shown in Table 5 for gem-diols 1–3 and
7–15. The fragmentation of para-nitrophenyl gem-diol 1
and 5-nitro-2-pyridyl gem-diol 2 was predicted to be exer-
gonic with reaction energies of –39.9 and –44.4 kcal/mol,
respectively. Products from the release of trifluoroacetate
were energetically more favorable than those produced
from the release of fluoroform, which were less exergonic
2
3
ficient substrates, such as 5-nitropyridine 2 and 5-trifluo-
romethylpyridine 3, also provided exclusively the respec-
tive difluoromethylarenes from the release of trifluoroace-
tate. The gem-diols 7–11 formed a mixture of difluoro-
methylarene and difluoroacetic acid. Substrates 29–32
formed only the difluoroacetic acids products 30–32, re-
spectively, from the release of fluoroform. Although gem-
diols 13–15 are considered electron-rich, the meta-nitro-
benzene 12 displays similar reactivity to each of them.
These results provide a unique perspective on the cleavage
of carbon–carbon bonds across a series of similar a-fluori-
nated gem-diols.
(
–32.4 and –32.0 kcal/mol). These data support the experi-
mental observation of only products from the release of tri-
fluoroacetate from the nitroaryl pentafluoro gem-diols 1
and 2. However, the computational data contrasted the ex-
perimental results for 3 in which the release of trifluoro-
acetate was exclusively observed by F NMR. The compu-
tational trend for compounds 7–15 agreed the experimental
data as the production of fluoroform increases.
2 3
Table 4. Fragmentation of compds 1–3 and 7–15 in K CO
1
9
Table 5. Computed reaction energies and free energies (in
kcal/mol) at 298.15 K for the fragmentation of each (doubly
deprotonated) gem-diol 1–3 and 7–15 into anionic prod-
a
ucts
compd
release of
trifluoroace-
tate
release of
fluoroform
difference
∆U
∆G
∆U
∆G
∆∆U
∆∆G
–7.5
–12.4
6.0
1
2
3
7
8
–25.6 –39.9 –15.9
–30.9 –44.4 –16.0
–32.4
–32.0
–33.8
–32.4
–33.2
–9.7
–14.9
3.0
–13.9
–18.2
–12.0
–27.8 –16.9
–32.9
–27.2
–16.5
–16.5
–1.7
4.5
–0.5
5.0
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The Journal of Organic Chemistry
9
–12.2
–10.0
–10.1
–8.9
–8.6
–10.3
–6.2
–27.3
–25.5
–25.5
–24.3
–23.8
–25.1
–21.6
–17.2
–18.3
–17.0
–15.7
–16.9
–32.6
–35.0
–34.8
–32.4
–33.3
5.0
8.3
6.9
6.8
8.3
9.9
12.4
5.3
9.5
9.3
8.1
across the aryl and alkyl aldehydes. Pyrazine 6 reacts with
para-chlorobenzaldehyde to make the difluorinated prod-
uct 30 in 56% isolated yield. The results demonstrate a syn-
thetic application of the selective fragmentation of the
pentafluorinated-gem-diols through the release of tri-
fluoroacetate.
1
2
3
4
5
6
7
10
11
12
13
9.5
10.6
14.1
14
–20.2 –35.7
–18.6 –35.7
Table 6. Fragmentations of 1–6 in the Presence of Alde-
a
15
hydes
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
B3LYP/6-31+G* geometry optimization and vibrational anal-
ysis were performed using the IEFP-PCM model for DMSO
OH
O
K2CO3, 4Å MS
DMSO, 60 °C
R1
1–6
+
R
4
0
H
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solvent within the Q-Chem 5.0 software package.
F F
1
6–30
O2N
O2N
It is noteworthy that a nitro group at the meta position
12) cannot stabilize the fragmentation of trifluoroacetate
OH
OH
(
F
F
F
F
F
as well as a nitro group at the para position (1). As shown
in Figure 4, this difference occurs because the lowest un-
occupied orbital of the meta-nitro group overlaps less with
the highest occupied orbitals on the arylated difluorome-
thyl carbanion, and thus withdraws few electrons. The net
electrostatic-potential-derived (ESP) charges on the nitro
groups in the product derived from the fragmentation of
trifluoroacetate were found to be –0.85 for 1 and –0.23 for
12. This difference leads to a less significant reaction free
energy (–24.3 kcal/mol) for the fragmentation of trifluoro-
acetate from molecule 12. Consequently, the product of 12
derived from the cleavage of trifluoroacetate becomes less
stable than the products produced from the release of fluo-
roform (which retain the same reaction free energy of –32.4
kcal/mol as 1).
16, 92%
17, 64%
Cl
Br
O2N
O2N
OH
OH
F
F
F
F
1
8, 69%
19, 64%
t-Bu
O
O N
2
2
O N
OH
OH
F
F
F
2
0, 57%
21, 53%
OCH3
NO2
O2N
O2N
OH
OH
N
F
F
F
F
t-Bu
2
2, 22%
23, 51%
O2N
H3C
F3C
OH
OH
N
N
A) compd 1
B) compd 12
F
F
F
F
t-Bu
t-Bu
Cl
2
4, 38%
25, 65%
0
.003 e
0
.779 e
F3C
F3C
OH
OH
HOMO (A)
HOMO (A)
N
N
F
F
F F
LUMO (B)
LUMO (B)
2
6, 52%
27, 37%
O
0
.111 e
0.065 e
HOMO-2 (A)
HOMO-2 (A)
F3C
2
O N
OH
OH
Figure 4. Intramolecular charge transfer within the frag-
mentation product of para-nitrophenyl pentafluoro gem-
diol 1 and meta-nitrophenyl pentafluoro gem-diol 12 with
the release of trifluoroacetate using a frontier orbital anal-
N
F
F
3
H C
F
F
2
8, 25%
Cl
N
29, 51%
OH
4
1
N
ysis at the B3LYP/6-31+G* level of theory.
F
F
Cl
The goal of developing a process to form the a,a-
difluorobenzyl carbanions is to use them in synthetic reac-
tions with suitable electrophiles. Aldehydes were deter-
mined to be compatible with this class of carbanion, and
30, 56%
a
Isolated yields.
Additional experiments were performed to probe the
2 3
the optimal conditions were five equivalents of K CO in
mechanism of this synthetic transformation. Although we
hypothesized that the creation of the α,α-difluorobenzyl
carbanions would result from the fragmentation of the
pentafluorinated-gem-diols, we still investigated if the
electron-deficient a,a-difluoromethylarenes could be
deprotonated under the reaction conditions and partici-
pate in coupling with the electrophile. Accordingly, the 1-
difluoromethyl-4-nitrobenzene and para-chlorobenzalde-
the presence of molecular sieves in DMSO at 60 °C (Table
6). The reaction was typically completed in two hours, but
some substrates required up to five hours. The para-nitro-
benzene 1 reacted with many aldehydes with a substantial
range of isolated yields (22–93%) as shown in Table 6. Ben-
zaldehydes with bromo, chloro, tert-butyl, acetyl, meth-
oxy, and nitro-substituents participated with good to ex-
cellent isolated yields for the respective products 16–21. An
alkyl aldehyde, isovaleraldehyde, is compatible but pro-
vided the lowest isolated yield for the product 22 of the se-
ries at 22%. Substituted pyridines (e.g., 2, 3, and 5) display
a similar reactivity profile as the nitrobenzenes 1 and 4
hyde in DMSO was treated with K
2 3
CO and heated to 60 °C
eq 1). After six hours, only unreacted starting material was
(
19
observed by F NMR.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
O
to a solution of ethyl 2,2-difluoroacetate-2-(4-nitro-
phenyl)acetate (96 mg, 0.39 mmol) in CH CN (1.0 mL) at rt
O2N
K2CO3, 4Å MS
DMSO, 60 °C
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(1)
+
H
no reaction
3
H
Cl
was added trifluoromethyltrimethylsilane (88 µL, 0.59
mmol). The mixture was stirred for 3 min and then treated
F
F
These mechanistic data serve to highlight the process of
the release of trifluoroacetate to generate valuable reactive
intermediates, such as α,α-difluorobenzyl carbanions. The
with a solution of CsF (30 mg, 0.2 mmol) in CH
mL). The reaction mixture was stirred for 24 h at rt. Then,
the mixture was quenched with saturated aqueous NH Cl
(2 mL), extracted with CH Cl (2 mL ´ 5), dried over
Na SO , and concentrated under reduced pressure. The
crude reaction mixture was treated with TBAF (0.5 mL, 1.0
M in THF) in CH Cl (1 mL) and stirred for 40 min at rt.
3
CN (2.0
4
2 3
necessity of only the mild base, K CO , is a significant ad-
2
2
vancement, because the usual reagents to create potas-
sium-based carbanions in synthesis are the strong bases
KH or KHMDS.
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
The fluorinated alcohols obtained from the fragmentation
process can be used in the common synthetic reactions of
alcohols. For example, alcohol 16 is esterified to 31 in 93%
yield using DCC and DMAP (eq 2). Also, the alcohol 18 is
oxidized to the ketone 32 using Dess-Martin periodinane
in 82% yield (eq 3). These transformations demonstrate the
additional synthetic potential of these difluorinated alco-
hols.
Next, the mixture was quenched with saturated aqueous
NH Cl (2 mL), extracted with CH Cl (2 mL ´ 5), dried over
4
2
2
Na SO , and concentrated under reduced pressure. SiO
2
4
2
flash chromatography (100% CHCl
3
®8:2 hexanes/EtOAc)
afforded 1,1,1,3,3-pentafluoro-3-(4-nitrophenyl)propane-
2,2-diol as a colorless solid (82 mg) in 44% yield (two
steps).
1,1,1,3,3-Pentafluoro-3-(4-nitrophenyl)propane-2,2-
diol (1). See representative reaction. Recrystallization from
a solution of hexanes and CH2Cl2 (by slow evaporation)
O
O
O2N
CF3
DCC, DMAP
O
CF3
1
6
+
(2)
HO
CH2Cl2, rt, 93%
provided a crystalline solid suitable for X-ray structure
F
F
1
Cl
analysis: H NMR (300 MHz, CDCl
2
3
) δ 8.30 (d, J = 9.0 Hz,
3
1
13
1
H), 7.83 (d, J = 8.9 Hz, 2H), 3.84 (br s, 2H); C{ H} NMR
O2N
O
3
(125 MHz, CDCl ) δ 149.4, 137.6 (t, JCF = 25.0 Hz, 1C), 128.6
Dess-Martin
CH2Cl2, rt, 82%
1
8
(3)
(t, JCF = 6.3 Hz, 2C), 123.2 (2), 121.2 (q, JCF = 286.3 Hz, 1C),
F
F
1
17.1 (t, JCF = 253.8 Hz, 1C), 92.6 (app sextet, JCF = 32.5 Hz,
t-Bu
1
9
3
2
1C); F NMR (282 MHz, CDCl
3
) δ –81.17 (t, JFF = 9.6 Hz, 3F),
–
110.95 (q, JFF = 9.3 Hz, 2F); IR (film) νmax 3391, 1531, 1192,
–
1
9 5 5 3
1177, 1064 cm ; HRMS (CI–Q) m/z calcd for C H F NO
+
(M+H–H
2
O) 270.0184, found 270.0193; mp 86–88 °C.
CONCLUSIONS
1,1,1,3,3-Pentafluoro-3-(5-nitropyridin-2-yl)propane-
In summary, we have demonstrated the cleavage of car-
bon–carbon bonds to generate α,α-difluorobenzyl carban-
ions by the selective release of trifluoroacetate. Our ap-
proach provides a method to synthesize α,α-difluorome-
2,2-diol (2). See representative reaction. The reaction mix-
ture was warmed to 70 °C in an oil bath for 72 h, and ethyl
43
2
,2-difluoro-2-(5-nitropyridin-2-yl)acetate was isolated.
See representative reaction. 4Å molecular sieves were
added prior to treatment with CsF. The reaction mixture
2 3
thyl arenes and heteroarenes using the mild base K CO .
This approach is compatible with electron-deficient aro-
matic and heteroaromatics pentafluoro-gem-diols with al-
kyl and aryl aldehydes. These findings demonstrated an-
other application of the selective release of trifluoroacetate
to access organic compounds that display difluoro-
methylarenes.
2
was stirred –30 °C to 0 °C 1 h. SiO flash chromatography
(
20% EtOAc in hexanes) afforded the title compound 2 as
1
colorless solid (37% yield, two steps): H NMR (500 MHz,
CDCl ) δ 9.46 (d, J = 2.5 Hz, 1H), 8.78 (dd, J = 8.6, 2.5 Hz,
H), 8.08 (dd, J = 8.6, 0.6 Hz, 1H), 5.58 (br s, 2H); C{ H}
NMR (125 MHz, CDCl ) δ 157.1 (t, JCF = 28.4 Hz, 1C), 145.2,
43.9, 133.9, 122.2 (t, JCF = 3.8 Hz, 1C), 121.1 (q, JCF = 287.5 Hz,
C), 112.6 (t, JCF = 255.0 Hz, 1C), 93.3 (qt, JCF = 28.8, 3.8 Hz,
3
13
1
1
3
1
1
1
EXPERIMENTAL SECTION
19
Representative Reaction Procedure for Preparation of
C); F NMR (282 MHz, CDCl
3
) δ –81.9 (t, JFF = 10.8 Hz, 3F),
4
2
Pentafluoro gem-Diols. The copper-mediated coupling
–
113.2 (q, JFF = 10.8 Hz, 2F); IR (film) νmax 3218, 1614, 1539,
–
1
of bromoethyldifluoroacetate with aryl halides was con-
8 3 5 2 3
1361, 1201 cm ; HRMS (EI–BE) m/z calcd for C H F N O
33
+
ducted according to the literature method. Briefly, a mix-
ture of 1-iodo-4-nitrobenzene (500 mg, 2.01 mmol) and
copper (510 mg, 8.03 mmol) in DMSO (5.0 mL) was stirred
at rt, and then ethyl 2-bromo-2,2-difluoroacetate (309 µL,
2.41 mmol) was added. The mixture was warmed to 51 °C in
an oil bath for 9 h, cooled to rt, and quenched with satu-
(M–H
2
O) 270.0058, found 270.0060; mp 66–68 °C.
1,1,1,3,3-Pentafluoro-3-(5-(trifluoromethyl)pyridin-2-
yl)propane-2,2-diol (3). See representative reaction. The
reaction mixture was warmed to 70 °C in an oil bath for 72
2 3
h. SiO flash chromatography (100% CHCl ) afforded ethyl
2
,2-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)acetate as a
rated aqueous NH
with CH Cl (6 mL ´ 5). The organics were dried over
Na SO and concentrated under reduced pressure. SiO
flash chromatography (100% CHCl ) provided the ethyl 2,2-
difluoroacetate-2-(4-nitrophenyl)acetate (445 mg). Next,
4
Cl (6 mL). The mixture was extracted
1
colorless oil: H NMR (500 MHz, CDCl
3
) δ 8.90 (s, 1H), 8.12
2
2
(
dd, J = 8.3, 2.1 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 4.37 (q, J =
2
4
2
13
1
7
.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); C{ H} NMR (125 MHz,
) δ 162.7 (t, JCF = 32.1 Hz, 1C), 155.0 (t, JCF = 28.2 Hz,
1C), 146.5, 134.9, 128.5 (q, JCF = 33.2 Hz, 1C), 122.8 (q, JCF
3
CDCl
3
3
3
=
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Page 7 of 14
The Journal of Organic Chemistry
1
9
2
70.6 Hz, 1C), 120.5, 111.5 (t, JCF = 250.8 Hz, 1C), 63.5, 13.8; F
261.0687, found 261.0683. See representative reaction. 4Å
molecular sieves were added prior to treatment with CsF.
The reaction mixture was stirred –30 °C to 0 °C 1 h. SiO
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (282 MHz, CDCl
(
calcd for C10
3
) δ –63.7 (s, 3F), –106.7 (s, 2F); IR
film) νmax 1779, 1332, 1138, 1017 cm ; HRMS (CI–Q) m/z
–
1
+
H
9
F
5
NO
2
(M+H) , 270.0554, found 270.0551.
flash chromatography
to 1:1 hexanes:EtOAc) afforded the title com-
flash chromatography (20% EtOAc in hexanes) afforded
See representative reaction. SiO
(100% CHCl
pound 3 as colorless solid (77% yield, two steps): H NMR
(500 MHz, CDCl ) δ 8.91 (s, 1H), 8.24 (dd, J = 8.3, 1.9 Hz,
1H), 8.00 (d, J = 8.3 Hz, 1H), 5.74 (br s, 2H); C{ H} NMR
(100 MHz, CDCl ) δ 155.6 (t, JCF = 28.3 Hz, 1C), 145.3 (q, JCF
2
the title compound 5 as colorless solid (55% yield, two
1
3
steps): H NMR (500 MHz, (CD
3 2
) CO) δ 8.60 (d, J = 8.5 Hz,
1
1H), 7.92 (d, J = 8.5 Hz, 1H), 2.96, (br s, 2H), 2.83 (s, 3H);
1
3
1
3
C{ H} NMR (125 MHz, (CD
154.2, 148.4, 135.8, 123.5 (q, JCF = 286.7 Hz, 1C), 122.0 (t, JCF
4.8 Hz, 1C), 116.2 (t, JCF = 256.1 Hz, 1C), 94.3 (qt, J = 28.6, 2.8
3 2
) CO) δ 155.6 (t, JCF = 27.6 Hz),
1
3
1
=
3
1
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
= 3.9 Hz, 1C), 136.1 (q, JCF = 3.4 Hz, 1C), 129.1 (q, JCF = 33.7
Hz, 1C), 122.5 (q, JCF = 271.3 Hz, 1C), 121.4 (t, JCF = 4.9 Hz, 1C),
21.2 (q, JCF = 286.4 Hz, 1C), 112.5 (t, JCF = 254.1 Hz, 1C), 93.2
Hz, 1C), 23.9; F NMR (471 MHz, (CD
3 2
) CO) δ –81.40 (t, JFF
= 11.2 Hz, 3F), –113.78 (q, JFF = 10.8 Hz, 2F); IR (film) νmax 3331,
–
1
1
3105, 2928, 2853, 1741, 1610,1537, 1278, 1207, 1168, 1068 cm ;
1
9
–
(qt, J = 32.5, 4.5 Hz 1C); F NMR (282 MHz, CDCl
3
) δ –63.7
9 6 5 2 4
HRMS (ESI–TOF) m/z calcd for C H F N O [M–H]
(
s, 3F), –82.0 (t, JFF = 11.1 Hz, 3F), –113.4 (q, JFF = 11.0 Hz, 2F);
301.0248, found 301.0233; mp 126–128 °C.
–
1
IR (film) νmax 3392, 1615, 1204, 1083 cm ; HRMS (EI–BE) m/z
1,1,1,3,3-Pentafluoro-3-(pyrazin-2-yl)propane-2,2-diol
(6). See representative reaction. The reaction mixture was
warmed to 55 °C in an oil bath for 16 h and ethyl 2,2-
+
calcd for
94.0168; mp 79–81 °C.
,1,1,3,3-Pentafluoro-3-(2-methyl-4-nitrophenyl)pro-
9 4 8 2
C H F NO (M+H–H O) 294.0160, found
2
4
4
1
difluoro-2-(pyrazin-2-yl)acetate was isolated. See repre-
sentative reaction. 4Å molecular sieves were added prior to
treatment with CsF. The reaction mixture was stirred –30
pane-2,2-diol (4). See representative reaction. The reac-
tion mixture was warmed to 55 °C in an oil bath for 18 h.
SiO
ethyl 2,2-difluoro-2-(2-methyl-4-nitrophenyl)acetate as a
yellow solid: H NMR (500 MHz, CDCl
Hz, 1H), 8.10 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 4.33 (q, J = 7.1
2
flash chromatography (5% Et
2
O in hexanes) afforded
2
°C to 0 °C 1 h. SiO flash chromatography (20% acetone in
hexanes) afforded the title compound 6 as colorless solid
1
1
3
) δ 8.15 (d, J = 8.7
(55% yield, two steps): H NMR (500 MHz, (CD
8.97 (s, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 3.40 (br s, 2H); C{ H}
NMR (125 MHz, (CD CO) δ 147.1 (t, JCF = 27.0 Hz, 1C),
3 2
) CO) δ
1
3
1
1
3
1
Hz, 2H), 2.52 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); C{ H} NMR
125 MHz, CDCl ) δ 163.2 (t, JCF = 34.1 Hz, 1C), 149.3, 138.9,
3 2
)
(
3
146.5, 143.8 (t, JCF = 5.0 Hz, 1C), 143.5, 122.2 (q, JCF = 289.1 Hz,
1C), 115.8 (t, JCF = 255.4 Hz, 1C), 92.6 (app sextet, JCF = 31.4
1
1
1
37.4 (t, JCF = 23.6 Hz, 1C), 127.8 (t, JCF = 9.0 Hz, 1C), 126.6,
21.1, 113.3 (t, JCF = 253.1 Hz, 1C), 63.8, 20.0 (t, JCF = 2.8 Hz,
C), 14.0; F NMR (471 MHz, CDCl
1
9
3 2
Hz, 1C); F NMR (471 MHz, (CD ) CO) δ –81.3 (t, JFF = 10.7
19
3
) δ –103.16 (s, 2F); IR
Hz, 3F), –114.7 (q, JFF = 10.7 Hz, 2F); IR (film) νmax 3199, 2923,
2852, 1665,1583, 1413, 1298, 1204, 1176 cm ; HRMS (ESI–
–1
–1
(film) νmax 1761, 1531, 1351 cm . See representative reaction.
–
4
Å molecular sieves were added prior to treatment with
TOF) m/z calcd for C
243.0203; mp 129–131°C.
,1,3,3,3-Pentafluoro-3-(5-cyanopyridin-2-yl)propane-
,2-diol (7). See representative reaction. The reaction mix-
ture was warmed to 70 °C in an oil bath for 72 h. SiO flash
column chromatography (100% CHCl ) afforded ethyl 2-(5-
cyanopyridin-2-yl)-2,2-difluoroacetate as a colorless oil: H
NMR (300 MHz, CDCl ) δ 8.92 (s, 1H), 8.17 (dd, J = 8.2, 1.8
Hz, 1H), 7.89 (dd, J = 8.1, 0.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H),
7
H
4
F N O
5 2 2
[M–H] 243.0193, found
CsF. The reaction mixture was stirred –30 °C to 0 °C 1 h.
SiO flash chromatography (10–20% EtOAc in hexanes) af-
forded the title compound 4 as colorless solid (58% yield,
two steps): H NMR (500 MHz, (CD
8
2
1
2
1
3 2
) CO) δ 8.02 (s, 1H),
2
.01 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 9.4 Hz, 1H), 7.20 (br s,
3
1
3
1
1
H), 3.81 (br s, 1H), 2.65 (t, J = 3.6 Hz, 3H); C{ H} NMR (100
MHz, (CD CO) δ 147.4, 139.6, 135.6 (t, JCF = 23.6 Hz, 1C),
29.6 (t, JCF = 8.9 Hz, 1C), 124.6, 121.3 (q, JCF = 288.1 Hz, 1C),
18.9 (t, JCF = 257.6 Hz, 1C), 118.3, 91.7 (app sextet, JCF = 31.2
1
3 2
)
3
1
1
13
1
1
(
.33 (t, J = 7.1 Hz, 3H); C{ H} NMR (75 MHz, CDCl
t, JCF = 31.5 Hz, 1C), 154.6 (t, JCF = 28.7 Hz, 1C), 151.9, 141.0,
120.6 (t, JCF = 3.6 Hz, 1C), 115.5, 112.0, 111.1 (t, J = 252.0
3
) δ 162.3
1
9
3
Hz, 1C), 19.3 (t, JCF = 5.1 Hz, 1C); F NMR (471 MHz, CDCl )
δ –81.3 (t, JFF = 10.4 Hz, 3F), –106.4 (q, JFF = 10.3 Hz, 2F); IR
CF
–
1
9
(film) νmax 3390, 2986, 2864, 1525, 1352, 1254, 1163, 1058 cm
Hz, 1C), 63.6, 13.7; F NMR (282 MHz, CDCl ) δ –107.0 (s,
3
1
–
–1
; HRMS (ESI–TOF) m/z calcd for C10
300.0295, found 300.0291; mp 111–113 °C.
,1,1,3,3-Pentafluoro-3-(6-methyl-5-nitropyridin-2-
H
7
F
5
NO
4
[M–H]
2F); IR (film) νmax 2239, 1774, 1120, 1019 cm ; HRMS (CI–Q)
+
m/z calcd for C H F N O (M+H) , 227.0632; found,
1
0
9
2
2
2
227.0639. See representative reaction. SiO
chromatography (100% CHCl to 1:1 hexanes/EtOAc) af-
forded the title compound 7 as colorless solid (57% yield,
2
flash column
1
yl)propane-2,2-diol (5). See representative reaction. The
reaction mixture was warmed to 55 °C in an oil bath for 10
h. SiO
forded ethyl 2,2-difluoro-2-(6-methyl-5-nitropyridin-2-
yl)acetate as a yellow oil: H NMR (400 MHz, CDCl
(d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 4.37 (q, J = 7.2
Hz, 2H), 2.83 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); C{ H} NMR
(100 MHz, CDCl ) δ 162.6 (t, JCF = 32.3 Hz, 1C), 154.4 (t, JCF
28.7 Hz, 1C), 154.1, 146.7, 134.1, 119.1 (t, JCF = 3.5 Hz, 1C), 111.3
3
1
two steps): H NMR (500 MHz, CDCl
3
) δ 8.90 (s, 1H), 8.27
2
flash chromatography (5% EtOAc in hexanes) af-
(dd, J = 8.2, 2.0 Hz, 1H), 7.99 (dd, J = 8.0, 1.0 Hz, 1H), 5.60
1
3
1
1
(
2
J
9
br s, 2H); C{ H} NMR (125 MHz, CDCl
8.4 Hz, 1C), 150.7, 142.2, 121.6 (t, JCF = 3.8 Hz, 1C), 121.1 (q,
CF = 286.3 Hz, 1C), 114.9, 112.6, 112.5 (t, JCF = 253.8 Hz, 1C),
3
) δ 155.4 (t, JCF =
3
) δ 8.41
1
3
1
1
9
3
3.3 (app sextet, J = 28.4 Hz, 1C); F NMR (282 MHz, CDCl )
3
=
δ –81.9 (t, JFF = 11.0 Hz, 3F), –113.7 (q, JFF = 11.0 Hz, 2F); IR
–
1
1
9
(
film) νmax 3368, 2239, 1203, 1118 cm ; HRMS (EI–BE) m/z
(t, JCF = 253.2 Hz, 1C), 63.6, 23.6, 14.0; F NMR (376 MHz,
+
–
1
calcd for C
9 3 5 2 2
H F N O (M–H O) 250.0160, found, 250.0164;
3
CDCl ) δ –106.47 (s, 2F); IR (film) νmax 1774, 1531, 1299 cm ;
HRMS (ESI–TOF) m/z calcd for C10H F N O [M+H]
11 2 2 4
+
mp 90–92 °C.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
1
,1,3,3,3-Pentafluoro-3-(4-cyanophenyl)-propane-2,2-
125.2 (q, JCF = 4.0 Hz, 2C), 123.5 (q, JCF = 271.3 Hz, 1C), 121.3
(q, JCF = 286.4 Hz, 1C), 117.3 (t, JCF = 253.1 Hz, 1C), 92.6 (app
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
diol (8). See representative reaction. The reaction mixture
was warmed to 80 °C in an oil bath for 48 h, and ethyl 2-(4-
1
9
sextet, JCF = 32.0 Hz, 1C); F NMR (282 MHz, CDCl
3
) δ –64.1
4
5
cyanophenyl)-2,2-difluoroacetate was isolated. See repre-
sentative reaction. SiO flash column chromatography
(100% CHCl to 1:1 hexanes/EtOAc) afforded the title com-
pound 8 as colorless solid (71% yield, two steps): H NMR
(500 MHz, CDCl
(125 MHz, CDCl
128.1 (t, JCF = 6.6 Hz, 2C), 121.2 (q, JCF = 286.3 Hz, 1C), 117.1
(s, 3F), –81.3 (t, JFF = 9.6 Hz, 3F), –110.0 (q, JFF = 9.6 Hz, 2F);
–
1
2
IR (film) νmax 3435, 1416, 1329, 1138, 1071 cm ; HRMS (EI–BE)
+
3
6 7 2
m/z calcd for C10H F O (M–F) 291.0251, found 291.0251;
1
mp 56–58 °C.
1
3
1
3
) δ 7.76 (s, 4H), 3.73 (br s, 2H); C{ H} NMR
1
,1,1,3,3-Pentafluoro-3-(3-nitrophenyl)propane-2,2-
diol (12). See representative reaction. The reaction mixture
was warmed to 62 °C in an oil bath for 24 h. SiO flash col-
umn chromatography (100% CHCl ) afforded ethyl 2,2-
difluoro-2-(3-nitrophenyl)acetate as a colorless oil: H
NMR (500 MHz, CDCl ) δ 8.49 (s, 1H), 8.38 (d, J = 8.2 Hz,
1H), 7.96 (d, J = 7.4 Hz, 1C), 7.69 (t, J = 8.0 Hz, 1H), 4.33 (q,
3
) δ 135.9 (t, JCF = 25.0 Hz, 1C), 131.9 (2),
2
(t, JCF = 253.5 Hz, 1C), 115.0, 92.6 (app sextet, J = 32.2 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
9
1
–
1
C); F NMR (282 MHz, CDCl
3
) δ –81.3 (t, JFF = 9.3 Hz, 3F),
1
111.5 (q, JFF = 9.5 Hz, 2F); IR (film) νmax 3272, 2249, 1278,
3
–
1
5 5
195, 1071 cm ; HRMS (EI–BE) m/z calcd for C10H F NO
+
(M+H–H
2
O) 250.0286, found 250.0295; mp 98–100 °C.
13
1
J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); C{ H} NMR (125 MHz,
CDCl ) δ 163.1 (t, J = 34.2 Hz, 1C), 148.2, 134.8 (t, JCF = 26.3
1,1,3,3,3-Pentafluoro-3-(4-acetylphenyl)-propane-2,2-
3
CF
diol (9). See representative reaction. The reaction mixture
was warmed to 80 °C in an oil bath for 48 h, and ethyl 2-(4-
Hz, 1C), 131.5 (t, JCF = 5.8 Hz, 1C), 130.0, 125.9, 121.1 (t, J
6.4 Hz, 1C), 112.1 (t, JCF = 252.5 Hz, 1C), 63.7, 13.8; F NMR
CF
=
1
9
4
6
acetylphenyl)-2,2-difluoroacetate was isolated. See repre-
sentative reaction. SiO flash column chromatography
100% CHCl to 1:1 hexanes/EtOAc) afforded the title com-
pound 9 as colorless solid (26% yield, two steps): H NMR
400 MHz, (CD CO) δ 8.07 (d, J = 8.2 Hz, 2H), 7.77 (d, J =
.3 Hz, 2H), 7.07 (s, 2H), 2.63 (s, 3H); C{ H} NMR (100
MHz, (CD CO) δ 197.7, 139.7, 137.7 (t, JCF = 25.0 Hz, 1C),
28.7 (t, JCF = 6.7 Hz, 2C), 128.4 (2C), 123.5 (q, JCF = 287.7 Hz,
C), 119.6 (t, JCF = 252.5 Hz, 1C), 93.5 (q, JCF = 31.3 Hz, 1C),
(282 MHz, CDCl ) δ –104.9 (s, 2F); IR (film) ν 1769, 1539,
3
max
–
1
2
1353, 1096, 717 cm ; HRMS (EI–BE) m/z calcd for
C H F NO (M+H) , 246.0578, found 246.0576. SiO flash
+
(
3
10 10
2
4
2
1
column chromatography (100% CHCl3 to 8:2 hex-
anes/EtOAc) afforded the title compound 12 as colorless
solid (67% yield, two steps). Recrystallization from a solu-
tion of hexanes and CH2Cl2 (by slow evaporation) pro-
vided a crystalline solid suitable for X-ray structure analy-
(
8
3 2
)
1
3
1
3 2
)
1
1
2
1
sis: H NMR (500 MHz, CDCl ) δ 8.50 (t, J = 1.8 Hz, 1H), 8.40
3
19
6.9; F NMR (376 MHz, (CD
3
)
2
CO) δ –79.9 (t, JFF = 11.1 Hz,
(dd, J = 8.0, 1.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68 (t, J =
1
3
1
3
F), –109.7 (q, JFF = 11.6 Hz, 2F); IR (film) νmax 3391, 1679,
8.0 Hz, 1H), 3.57 (br s, 2H); C{ H} NMR (125 MHz, CDCl )
3
δ 147.9, 133.3 (t, JCF = 26.0 Hz, 1C), 133.1 (t, JCF = 6.3 Hz, 1C),
129.4, 125.9, 122.7 (t, JCF = 7.1 Hz, 1C), 121.2 (q, JCF = 286.4
–1
1277, 1198 cm ; HRMS (CI–Q) m/z calcd for C11
H
8
5
F O
2
+
(M+H–H
2
O) 267.0439, found 267.0448; mp 106–108 °C.
Hz, 1C), 116.9 (t, JCF = 253.5 Hz, 1C), 92.6 (sextet, JCF = 32.3
1,1,1,3,3-Pentafluoro-3-(pyridin-2-yl)propane-2,2-diol
19
3
Hz, 1C); F NMR (282 MHz, CDCl ) δ –81.3 (t, JFF = 9.6 Hz,
(
10). See representative reaction. The reaction mixture was
3
F), –110.6 (q, JFF = 9.6 Hz, 2F); IR (film) νmax 3367, 1534,
warmed to 70 °C in an oil bath for 72 h, and ethyl 2,2-
difluoro-2-(pyridin-2-yl)acetate was isolated. See repre-
–
1
44
1356, 1197, 715 cm ; HRMS (EI–BE) m/z calcd for
C H F NO (M+H–H O) 270.0184, found 270.0193; mp 93–
9 5 5 3 2
+
sentative reaction. SiO
100% CHCl to 7:3 hexanes/EtOAc) afforded the title com-
pound 10 as colorless solid (46% yield, two steps): H NMR
400 MHz, CDCl ) δ 8.60 (d, J = 4.0 Hz, 1H), 7.98 (td, J =
.8, 1.6 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.54 (dd, J = 7.2, 5.2
2
flash column chromatography
95 °C.
(
3
1
1,1,1,3,3-Pentafluoro-3-(3-(trifluoromethyl)phe-
(
7
3
nyl)propane-2,2-diol (13). See representative reaction.
The reaction mixture was warmed to 62 °C in an oil bath
for 48 h, and ethyl 2,2-difluoro-2-(3-(trifluoromethyl)phe-
13
1
Hz, 1H), 6.22 (br s, 1H); C{ H} NMR (100 MHz, CDCl
3
) δ
4
7
152.3 (t, JCF = 28.8 Hz, 1C), 147.8, 138.8, 126.0, 121.4 (t, JCF
=
nyl)acetate was isolated. See representative reaction. SiO
flash column chromatography (100% CHCl to 1:1 hex-
anes/EtOAc) afforded the title compound 13 as colorless oil
2
2
86.6 Hz, 1C), 121.3 (JCF = 4.8 Hz, 1C), 112.6 (t, JCF = 254.5 Hz,
3
1
9
1C), 93.6 (qt, J = 32.3, 4.3 Hz, 1C); F NMR (376 MHz, CDCl
3
)
1
δ –81.0 (t, JFF = 10.9 Hz, 3F), –112.2 (q, JFF = 10.9 Hz, 2F); IR
(film) νmax 3351, 1203, 1169, 1081 cm ; HRMS (EI–BE) m/z
(36% yield, two steps): H NMR (300 MHz, CDCl
3
) δ 7.89
–
1
(s, 1H), 7.81 (t, J = 8.3 Hz, 2H), 7.61 (t, J = 7.9 Hz, 1H), 3.44
+
13
1
calcd for C
mp 47–48 °C.
,1,1,3,3-Pentafluoro-3-(4-(trifluoromethyl)phe-
8
H
4
F
5
NO (M–H
2
O) 225.0208, found 225.0219;
3
(br s, 2H); C{ H} NMR (100 MHz, CDCl ) δ 132.5 (t, JCF =
25.6 Hz, 1C), 130.8 (q, JCF = 32.7 Hz, 1C), 130.5 (t, JCF = 6.8 Hz,
1C), 128.6, 127.7 (m, 1C), 124.3 (m, 1C), 123.6 (q, JCF = 270.7
Hz, 1C), 121.4 (q, JCF = 286.3 Hz, 1C), 117.5 (t, JCF = 252.7 Hz,
1
nyl)propane-2,2-diol (11). See representative reaction.
The reaction mixture was warmed to 80 °C in an oil bath
for 24 h, and ethyl 2,2-difluoro-2-(4-(trifluoromethyl)phe-
nyl)acetate was isolated. See representative reaction. SiO
flash column chromatography (100% CHCl to 1:1 hex-
anes/EtOAc) afforded the title compound 11 as colorless
solid (84% yield, two steps): H NMR (300 MHz, CDCl
7.76 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 3.44 (br s,
2H); C{ H} NMR (125 MHz, CDCl
1
9
1C), 92.5 (q, JCF = 31.9 Hz, 1C); F NMR (282 MHz, CDCl
3
) δ
–
64.4 (s, 3F), –81.8 (t, JFF = 9.7 Hz, 3F), –111.3 (q, JFF = 9.7 Hz,
–
1
4
6
2F); IR (film) νmax 3446, 1339, 1259, 1135 cm ; HRMS (EI–BE)
m/z calcd for C10
2
+
5 8 2
H F O (M+H–H O) 293.0207, found
3
293.0219.
1
3
) δ
1,1,1,3,3-Pentafluoro-3-(naphthalen-1-yl)propane-2,2-
diol (14). See representative reaction. The reaction mixture
was warmed to 60 °C in an oil bath for 96 h, and ethyl 2,2-
1
3
1
3
) δ 134.7 (t, JCF = 25.4 Hz,
4
8
1C), 133.1 (q, JCF = 34.0 Hz, 1C), 127.8 (t, JCF = 6.5 Hz, 2C),
difluoro-2-(naphthalen-1-yl)acetate
was isolated. See
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
representative reaction. SiO
raphy (100% CHCl to 8:2 hexanes/EtOAc) afforded the ti-
tle compound 14 as colorless oil (27% yield, two steps): H
NMR (500 MHz, CDCl ) δ 8.45 (d, J = 9.2 Hz, 1H), 8.06* (d,
2
flash column chromatog-
3
MHz, CDCl ) δ –105.8 (dd, JFF = 252.2, JHF= 9.0 Hz, 1F), –
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
108.2 (dd, JFF = 252.2, JHF = 8.6 Hz, 1F); IR (film) νmax 3515,
1
–1
3115, 2907, 2849, 1608, 1519, 1353, 1074 cm ; HRMS (EI–TOF)
+
3
m/z calcd for C14
348.0004; mp 154–155 °C.
-(4-Bromophenyl)-2,2-difluoro-2-(4-nitro-
H10Cl
2
F
2
NO
3
[M+Cl] 348.0006, found
J = 8.3 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.94* (d, J = 11.0 Hz,
1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (dd, J = 7.4, 1.2 Hz, 1H),
1
1
3
1
7.63–7.53 (m, 3H), 3.35 (br s, 2H); C{ H} NMR (125 MHz,
CDCl ) δ 180.3* (q, JCF = 36.6 Hz, 1C), 134.2, 133.9*, 133.3*,
phenyl)ethan-1-ol (17). See representative reaction. Ben-
zophenone (25 mg, 0.14 mmol) was added, and the reaction
mixture was heated to 60 °C in an oil bath for 5 h. Purifica-
3
132.7, 130.5*, 129.2, 128.8, 128.1 (t, JCF = 9.7 Hz, 1C), 127.2*,
126.7*, 126.3 (2C), 126.2, 126.1*, 126.0*, 124.6, 124.3, 123.6*,
121.7* (q, JCF = 286.8 Hz, 1C), 121.3 (q, JCF = 287.6 Hz, 1C),
3
tion by preparative TLC (5% EtOAc in CHCl ) afforded the
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
title compound 17 as a colorless solid (64%): H NMR (400
MHz, CDCl ) δ 8.19 (d, J = 8.6 Hz, 2H), 7.42 (dd, J = 8.7, 2.6
Hz, 4H), 7.06 (d, J = 8.1 Hz, 2H), 5.13 (td, J = 9.0, 3.4 Hz, 1H),
1
(
7
(
16.3* (t, JCF = 257.0 Hz, 1C), 115.8 (t, JCF = 253.1 Hz, 1C), 93.1
3
1
9
sextet, JCF = 32.3 Hz, 1C); F NMR (282 MHz, CDCl
3.8* (t, JFF = 7.6 Hz, 3F), –81.1 (t, JFF = 11.2 Hz, 3F), –102.5*
q, JFF = 7.3 Hz, 2F), –104.4 (q, JFF = 11.1Hz, 2F); IR (film) νmax
3
) δ –
13
1
3 2
2.61 (d, J = 3.9 Hz, 1H); C{ H} NMR (125 MHz, CD ) CO) δ
150.0, 141.5 (t, JCF = 26.3 Hz, 1C), 137.5, 131.8 (2C), 130.8 (2C),
129.0 (t, JCF = 6.3 Hz, 2C), 123.9 (2C), 122.9, 121.5 (t, JCF = 248.6
–
1
3
519, 1202, 1049, 796 cm ; HRMS (EI–BE) m/z calcd for
+
C
13
H
7
F
5
O (M–H
minor keto-form of the product.
,1,1,3,3-Pentafluoro-3-(4-methoxyphenyl)propane-
,2-diol (15). See representative reaction. The reaction
mixture was warmed to 55 °C in an oil bath for 24 h, and
2
O) 274.0412, found 274.0424.* denotes the
19
Hz, 1C), 75.5 (t, JCF = 30.5 Hz, 1C); F NMR (376 MHz,
3
CDCl ) δ –105.7 (dd, JFF = 252.8, JHF = 9.1 Hz, 1F), –108.2 (dd,
1
2
J
FF = 252.3, JHF = 8.6 Hz, 1F); IR (film) νmax 3521, 2922, 2853,
–
1
1607, 1519, 1489, 1353, 1260, 1072 cm ; HRMS (EI–TOF) m/z
calcd for
+
C
14
H10BrClF
2
NO
3
[M+Cl] 391.9501, found
33
ethyl 2,2-difluoro-2-(4-methoxyphenyl)acetate was iso-
lated. See representative reaction. SiO flash column chro-
matography (100% CHCl to 8:2 hexanes/EtOAc) afforded
the title compound 15 as colorless oil (67% yield, two
391.9507; mp 169–170 °C.
2
1-(4-(tert-Butyl)phenyl)-2,2-difluoro-2-(4-nitro-
3
phenyl)ethan-1-ol (18). See representative reaction. Ben-
zophenone (16 mg, 0.088 mmol) was added, and the reac-
tion mixture was heated to 60 °C in an oil bath for 5 h. Pu-
rification by preparative TLC (20% EtOAc in hexanes) af-
1
3
steps): H NMR (500 MHz, CDCl ) δ 7.55 (d, J = 8.8 Hz, 2H),
1
3
1
6
.97 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.57 (br s, 2H); C{ H}
NMR (125 MHz, CDCl
3
) δ 161.7, 128.7 (t, JCF = 6.4 Hz, 2C),
1
forded the title compound 18 as a colorless solid (69%): H
122.7 (t, JCF = 25.0 Hz, 1C), 121.5 (q, JCF = 286.3 Hz, 1C), 118.20
3
NMR (400 MHz, CDCl ) δ 8.17 (d, J = 8.5 Hz, 2H), 7.44 (d, J
(
t, JCF = 252.5 Hz, 1C), 113.7 (2C), 92.5 (sextet, JCF = 31.3 Hz,
=
8.5 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H),
19
1C), 55.4; F NMR (282 MHz, CDCl
3
) δ –81.2 (t, JFF = 10.2 Hz,
13
1
5
(
1
(
.11 (t, J = 9.4 Hz, 1H), 2.55 (s, 1H), 1.30 (s, 9H); C{ H} NMR
100 MHz, CDCl ) δ 152.3, 148.9, 140.1 (t, JCF = 26.5 Hz, 1C),
32.2, 127.9 (t, JCF = 6.2 Hz, 2C), 127.3 (2C), 125.2 (2C), 122.9
2C), 120.3 (t, JCF = 248.9 Hz, 1C), 76.3 (t, JCF = 30.9 Hz, 1C),
3
F), –109.8 (q, JFF = 10.8 Hz, 2F); IR (film) νmax 3368, 1195,
3
–1
7 5 2
1057, 831 cm ; HRMS (EI–BE) m/z calcd for C10H F O (M–
+
H
2
O) 254.0361, found 254.0372; mp 85–87 °C.
1
9
Representative Reaction Procedure for Preparation
α,α-Difluoromethyl Arenes. A solution of 1,1,1,3,3-pen-
tafluoro-3-(4-nitrophenyl)propane-2,2-diol 1 (10 mg, 0.04
mmol) in DMSO (0.8 mL) at rt was treated with 4Å molec-
3
34.6, 31.2 (3C); F NMR (376 MHz, CDCl ) δ –105.7 (dd, JFF
= 251.3, JHF = 9.5 Hz, 1F), –108.5 (dd, JFF = 251.3, JHF = 9.5 Hz,
1F); IR (film) νmax 3457, 2963, 2905, 2870, 1610, 1528, 1410,
–1
1350, 1076 cm ; HRMS (EI–TOF) m/z calcd for
+
ular sieves (100 mg) and K
2
CO
3
(30 mg, 0.2 mmol). Then, a
C
18
H
19ClF
2
NO
3
[M+Cl] 370.1022, found 370.1028; mp 157–
solution of 4-chlorobenzaldehyde (8.0 mg, 0.06 mmol) in
DMSO (0.2 mL) was added dropwise and the reaction mix-
ture was stirred at rt for 15 min. Next, the reaction mixture
was heated to 60 °C in an oil bath for 2 h, cooled to rt, and
quenched with saturated aqueous NH Cl (2 mL). The mix-
4
ture was diluted with EtOAc (20 mL) and filtered through
celite. The organics were washed with saturated aqueous
159 °C.
2-(4-Acetylphenyl)-1-2,2-difluoro-2-(4-nitro-
phenyl)ethan-1-ol (19). See representative reaction. Puri-
fication by preparative TLC (30% EtOAc in hexanes) af-
1
forded the title compound 19 as a colorless solid (69%): H
3
NMR (400 MHz, CDCl ) δ 8.17 (d, J = 8.5 Hz, 2H), 7.87 (d, J
=
8.3 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz,
13
1
2 4
NaCl (5 mL), dried over Na SO , and concentrated under
2
H), 5.23 (t, J = 9.0 Hz, 1H), 2.85 (s, 1H), 2.59 (s, 3H); C{ H}
NMR (125 MHz, CD CO) δ 197.9, 149.9, 143.1, 141.5 (t, JCF
6.4 Hz, 1C), 138.0, 129.0 (2C), 128.9 (t, JCF = 6.4 Hz, 2C),
28.5 (2C), 123.8 (2C), 121.5 (t, JCF = 249.0 Hz, 1C), 75.3 (t, JCF
reduced pressure. Purification by preparative TLC (15%
EtOAc in hexanes) afforded 1-(4-chlorophenyl)-2,2-
difluoro-2-(4-nitrophenyl)ethan-1-ol as a colorless solid (10
mg, 92%).
3
)
2
=
2
1
19
=
30.4 Hz, 1C), 26.7; F NMR (376 MHz, CDCl
(dd, JFF = 252.3 Hz, JHF = 8.9 Hz, 1F), –108.1 (dd, JFF = 252.4,
HF = 8.4 Hz, 1F); IR (film) νmax 3504, 3117, 2921, 1682, 1609,
3
) δ –105.2
1
-(4-Chlorophenyl)-2,2-difluoro-2-(4-nitro-
phenyl)ethan-1-ol (16). See representative reaction: H
NMR (400 MHz, (CD CO) δ 8.28 (d, J = 8.4 Hz, 2H), 7.65
d, J = 8.7 Hz, 2H), 7.34 (s, 4H), 5.71 (d, J = 5.0 Hz, 1H), 5.31
1
J
–
1
3
)
2
1527, 1411, 1354, 1268, 1072 cm ; HRMS (ESI–TOF) m/z calcd
for C16H F NO [M–H] 320.0740, found 320.0740; mp 166–
12 2 4
–
(
1
3
1
(dd, J = 11.8, 8.2 Hz, 1H); C{ H} NMR (100 MHz, (CD
3
2
) CO)
168 °C.
,2-Difluoro-1-(4-methoxyphenyl)-2-(4-nitro-
phenyl)ethan-1-ol (20). See representative reaction.
δ 149.9, 141.5 (t, JCF = 26.4 Hz, 1C), 137.0, 134.6, 130.5 (2C),
129.0 (t, JCF = 6.6 Hz, 2C), 128.8 (2C), 123.8 (2C), 121.5 (t, JCF
2
1
9
= 246.5 Hz, 1C), 75.4 (t, JCF = 30.6 Hz, 1C); F NMR (376
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
–
1
Benzophenone (36 mg, 0.20 mmol) was added, and the re-
action mixture was heated to 60 °C in an oil bath for 5 h.
Purification by preparative TLC (20% EtOAc in hexanes)
1275, 1179, 1077 cm ; HRMS (EI–TOF) m/z calcd for
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
C H
17 18
F N O
2 2 3
[M] 336.1285, found 336.1285.
-(4-(tert-Butyl)phenyl)-2,2-difluoro-2-(6-methyl-5-ni-
tropyridin-2-yl)ethan-1-ol (24). See representative reac-
tion. Purification by preparative TLC (3% EtOAc in CHCl
afforded the title compound 24 as a colorless oil (38%): H
NMR (400 MHz, CDCl ) δ 8.35 (d, J = 8.4 Hz, 1H), 7.61 (d, J
8.4 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz,
H), 5.44 (dd, J = 16.1, 4.2 Hz, 1H), 3.57 (br s, 1H), 2.94 (s,
H), 1.32 (s, 9H); C{ H} NMR (100 MHz, CDCl
CF = 31.2, 28.2 Hz, 1C), 153.5, 151.9, 146.2, 133.8, 132.4, 127.6
(2C), 125.2 (2C), 119.9 (t, JCF = 4.1 Hz, 1C), 117.2 (dd, JCF
248.7, 245.2 Hz, 1C), 74.7 (dd, JCF = 29.8, 25.5 Hz, 1C), 34.6,
1
afforded the title compound 20 as a pale yellow solid
1
(57%): H NMR (400 MHz, CDCl
3
) δ 8.16 (d, J = 8.5 Hz, 2H),
3
)
1
7.41 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 6.80 (d, J =
8.7 Hz, 2H), 5.09 (t, J = 9.2 Hz, 1H), 3.79 (s, 1H), 2.59 (br s,
3
1
3
1
3 2
1H); C{ H} NMR (125 MHz, (CD ) CO) δ 160.3, 149.3, 141.5
=
(t, JCF = 26.5 Hz, 1C), 129.6, 129.5 (2C), 128.5 (t, JCF = 6.2 Hz,
2C), 123.2 (2C), 121.4 (t, JCF = 247.7 Hz, 1C), 113.6 (2C), 75.3 (t,
2
3
1
3
1
3
) δ 156.7 (dd,
1
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J
(
CF = 30.3 Hz, 1C), 55.1; F NMR (376 MHz, CDCl
3
) δ –105.5
dd, JFF = 250.8, JHF = 9.9 Hz), –107.0 (dd, JFF = 250.7, JHF
J
=
=
8
.7 Hz, 1F); IR (film) νmax 3477, 2916, 1611, 1525, 1514, 1351,
–
1
1252, 1075 cm ; HRMS (EI–TOF) m/z calcd for
19
3
31.3 (3C), 23.8; F NMR (471 MHz, CDCl ) δ –105.6 (d, JFF =
263.4 Hz, 1F), –114.3 (dd, JFF = 263.6, JHF = 15.9 Hz, 1F); IR
(film) νmax 3474, 2928, 2856, 1742, 1602, 1531, 1459, 1370, 1222,
1175, 1052 cm ; HRMS (EI–TOF) m/z calcd for C18
+
15 2 4
C H13ClF NO [M+Cl] 344.0501, found 344.0516; mp 137–
139 °C.
–
1
2,2-Difluoro-1,2-bis(4-nitrophenyl)ethan-1-ol (21). See
representative reaction. Purification by preparative TLC
H
19
F N O
2 2 3
–
[M–H] 349.1369, found 349.1387.
(
3
10% EtOAc in CHCl ) afforded the title compound 21 as a
1-(4-Chlorophenyl)-2,2-difluoro-2-(5-(trifluorome-
1
colorless solid (53%): H NMR (500 MHz, CDCl
J = 8.6 Hz, 2H), 8.16 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.7 Hz,
H), 7.42 (d, J = 8.4 Hz, 2H), 5.30 (t, J = 9.6 Hz, 1H), 2.81 (br
3
) δ 8.20 (d,
thyl)pyridin-2-yl)ethan-1-ol (25). See representative re-
action. The reaction mixture was heated to 60 °C in an oil
bath for 5.5 h. Purification by preparative TLC (20% EtOAc
2
1
3
1
s, 1H); C{ H} NMR (125 MHz, CDCl
3
) δ 149.1, 148.3, 141.9,
in hexanes) afforded the title compound 25 as a colorless
1
138.9 (t, JCF = 26.1 Hz, 1C), 128.5 (2C), 127.7 (t, JCF = 6.0 Hz,
solid (65%): H NMR (400 MHz, CDCl
3
) δ 8.94 (s, 1H), 8.07
2
C), 123.3 (2C), 123.2 (2C), 119.8 (t, JCF = 248.6 Hz, 1C), 75.5
(d, J = 8.9 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.6
Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 5.46 (dd, J = 15.8, 6.4 Hz,
1
9
(t, JCF = 31.3 Hz, 1C); F NMR (282 MHz, CDCl
3
) δ –104.5
1
3
1
(dd, JFF = 253.8, JHF = 8.2 Hz, 1F), –108.6 (dd, JFF = 253.8, JHF
1
H), 3.99 (s, 1H); C{ H} NMR (125 MHz, (CD
3 2
) CO) δ 158.3
–
1
=
9.0 Hz, 1F); IR (film) νmax 3497, 1519, 1347, 1080 cm ;
(dd, JCF = 31.6, 26.6 Hz, 1C), 147.1 (dd, JCF = 6.5, 3,7 Hz, 1C),
+
HRMS (CI–Q) m/z calcd for C14
found, 325.0634; mp 188–190 °C.
,1-Difluoro-4-methyl-1-(4-nitrophenyl)pentan-2-ol
22). See representative reaction. Purification by prepara-
tive TLC (10% EtOAc in CHCl ) afforded the title com-
pound 22 as a colorless oil (22%): H NMR (400 MHz,
CDCl ) δ 8.30 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H),
.09 (m, 1H), 2.04 (br s, 1H), 1.84 (septet, J = 6.8 Hz, 1H),
.32 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz,
11 2 2 5
H F N O [M+H] 325.0636,
1
1
37.1, 135.6 (q, JCF = 3.5 Hz, 1C), 134.5, 130.7 (2C), 128.8 (2C),
28.0 (q, JCF = 33.3 Hz, 1C), 124.4 (q, JCF = 272.5 Hz, 1C), 122.5
1
(
(dd, JCF = 5.9, 3.6 Hz, 1C), 119.6 (dd, JCF = 250.7, 245.6 Hz,
1
9
1C), 73.9 (dd, JCF = 30.7, 24.6 Hz, 1C); F NMR (471 MHz,
CDCl ) δ –62.8 (3F), –104.5 (d, JFF = 266.9, 1F), –133.5 (dd, JFF
= 266.7, JHF = 15.8 Hz, 1F); IR (film) νmax 3332, 2916, 2850,
3
3
1
–
1
3
1610, 1492, 1395, 1328, 1137, 1081 cm ; HRMS (EI–TOF) m/z
+
4
1
calcd for C14
9 5
H ClF NO [M] 337.0293, found 337.0263; mp
105–107 °C.
13
1
3
2
J
H); C{ H} NMR (100 MHz, CDCl
6.6 Hz, 1C), 127.5 (t, JCF = 6.3 Hz, 2C), 123.4 (2C), 120.9 (t,
CF = 247.6 Hz, 1C), 72.3 (t, JCF = 29.7 Hz, 1C), 38.8, 24.1, 23.6.
3
) δ 148.9, 140.7 (t, JCF =
1-(4-(tert-Butyl)phenyl)-2,2-difluoro-2-(5-(trifluoro-
methyl)pyridin-2-yl)ethan-1-ol (26). See representative
reaction. The reaction mixture was heated to 60 °C in an
oil bath for 4.5 h. Purification by preparative TLC (3%
19
2
=
3
1.2; F NMR (376 MHz, CDCl
8.4 Hz), –110.8 (dd, JFF = 253.5, JHF = 10.5 Hz); IR (film) νmax
444, 2959, 2924, 2872, 1719, 1611, 1529, 1469, 1352, 1288 1131,
3
) δ –105.4 (dd, JFF = 253.5, JHF
EtOAc in CHCl
3
) afforded the title compound 26 as a col-
1
orless solid (52%): H NMR (400 MHz, CDCl
3
) δ 8.94 (s, 1H),
.04 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.38 (d, J =
.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 5.44 (dd, J = 16.4, 6.5
–1
2 3
1071 cm ; HRMS (EI–TOF) m/z calcd for C12H15ClF NO
8
8
+
[
M+Cl] 294.0709, found 294.0707.
-(4-(tert-Butyl)phenyl)-2,2-difluoro-2-(5-nitro-
pyridin-2-yl)ethan-1-ol (23). See representative reaction.
Purification by preparative TLC (3% EtOAc in CHCl ) af-
forded the title compound 23 as a colorless oil (51%): H
NMR (400 MHz, (CD CO) δ 9.48 (d, J = 2.5 Hz, 1H), 8.74
dd, J = 8.6, 2.6 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.41 (s, 4H),
13
1
1
Hz, 1H), 3.71 (s, 1H), 1.31 (s, 9H); C{ H} NMR (125 MHz,
(CD
3
)
2
CO) δ 157.3 (t, JCF = 29.5 Hz, 1C), 151.8, 145.9 (q, JCF
=
=
3
3.6 Hz, 1C), 134.6 (q, JCF = 3.4 Hz, 1C), 132.5, 128.1 (q, JCF
1
33.6 Hz, 1C), 127.6 (2C), 125.2 (2C), 122.9 (q, JCF = 273.3 Hz,
1C), 121.4 (t, JCF = 4.2 Hz, 1C), 117.4 (dd, JCF = 250.2, 246.6 Hz,
3 2
)
19
(
5
9
1C), 74.7 (dd, JCF = 30.0, 25.4 Hz, 1C), 34.6, 31.3 (3C); F NMR
.47 (dt, J = 18.4, 6.0 Hz, 1H), 5.40 (d, J = 5.6 Hz, 1H), 1.31 (s,
3
(471 MHz, CDCl ) δ –62.6 (s, 3F), –104.1 (d, JFF = 264.7 Hz,
1F), –114.7 (dd, JFF = 264.4, JHF = 16.5 Hz, 1F); IR (film) νmax
1
3
1
H); C{ H} NMR (100 MHz, (CD
3
2
) CO) δ 159.8 (dd, JCF
=
3
1
1.5, 25.5 Hz, 1C), 151.9, 145.9, 145.4, 135.0, 133.3, 128.8 (2C),
25.6 (2C), 123.0 (dd, JCF = 5.5, 3.5 Hz, 1C), 119.8 (dd, JCF
248.5, 244.5 Hz, 1C), 74.4 (dd, JCF = 31.0, 24.0 Hz, 1C), 62.9,
3318, 2965, 2909, 2874, 1609, 1583, 1392, 1332, 1165, 1139, 1081
–
1
+
=
18 5
cm ; HRMS (EI–TOF) m/z calcd for C18H F NO [M]
359.1309, found 359.1309; mp 135–136 °C.
1
9
3
35.1, 31.6 (3C); F NMR (471 MHz, CDCl ) δ –105.0 (d, JFF =
262.4 Hz, 1F), –114.7 (dd, JFF = 262.3, JHF = 15.7 Hz, 1F); IR
(film) νmax 3416, 2963, 2927, 2867, 1735, 1606, 1532, 1469, 1357,
1-(4-Acetylphenyl)-2,2-difluoro-2-(5-(trifluorome-
thyl)pyridin-2-yl)ethan-1-ol (27). See representative
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
reaction. The reaction mixture was heated to 60 °C in an
oil bath for 4.5 h. Purification by preparative TLC (10%
EtOAc in CHCl ) afforded the title compound 27 as a col-
orless solid (37%): H NMR (500 MHz, CDCl
3 2
NMR (125 MHz (CD ) CO) δ 149.7 (dd, JCF = 30.1, 26.2 Hz,
1C), 147.1, 145.0, 143.5 (dd, JCF = 5.9, 4.3 Hz, 1C), 137.0, 134.5,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
130.7 (2C), 128.8 (2C), 119.7 (dd, JCF = 249.7, 246.1 Hz, 1C),
1
19
3
) δ 8.95 (s, 1H),
73.9 (dd, JCF = 30.8, 25.0 Hz, 1C); F NMR (471 MHz, CDCl
3
)
8.08 (dd, J = 8.2, 2.3 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.73
(d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 5.55 (d, J = 16.2
δ –105.9 (d, JFF = 268.3 Hz, 1F), –114.4 (dd, JFF = 268.0, JHF
=
15.0 Hz, 1F); IR (film) νmax 329, 3084, 2930, 1598, 1492, 1410,
1
3
1
–1
Hz, 1H), 4.09 (s, 1H), 2.61 (s, 3H); C{ H} NMR (125 MHz,
(CD CO) δ 197.8, 158.2 (dd, JCF = 31.3, 26.3 Hz, 1C), 147.1 (q,
CF = 3.8 Hz, 1C), 143.1, 138.1, 135.7 (q, JCF = 3.8 Hz, 1C), 129.3
(2C), 128.6 (2C), 128.0 (q, JCF = 33.1 Hz, 1C), 124.4 (q, JCF
273.0 Hz, 1C), 122.6 (dd, JCF = 5.6, 3.6 Hz, 1C), 119.8 (dd, JCF
250.2, 246.1 Hz, 1C), 74.3 (dd, JCF = 30.8, 24.5 Hz, 1C), 26.8;
1347, 1289, 1195, 11092, 1016 cm ; HRMS (ESI–TOF) m/z
–
3
)
2
calcd for C12
mp 137–138 °C.
-(4-Chlorophenyl)-2,2-difluoro-2-(4-nitrophenyl)
ethyl 3,3,3-trifluoropropanoate (31). To a solution of 16
(9.7 mg, 0.031 mmol) in CH Cl (2 mL) was added dicyclo-
H
8
2 2
ClF N O [M–H] 269.0299, found 269.0316;
J
=
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
2
2
1
9
F NMR (471 MHz, CDCl
64.7 Hz, 1F), –114.7 (dd, JFF = 267.3, JHF = 16.3 Hz, 1F); IR
film) νmax 3392, 3032, 2916, 2846, 1683, 1610, 1579, 1396, 1329,
3
) δ –62.6 (s, 3F), –104.1 (d, JFF =
hexylcarbodiimide (10.2 mg, 0.049 mmol) and 3,3,3-tri-
fluoropropionic acid (0.09 mL, 0.049 mmol), and the reac-
tion mixture was stirred at rt for 15 min. Next, the mixture
was treated with N,N-dimethylaminopyridine (0.76 mg,
6.2 μmol) and stirred at rt for 24 h. Then, the mixture was
diluted with pentane (2 mL), filtered through celite, and
washed with pentane (2 mL). The organics were washed
with water (5 mL ´ 3), 5% aqueous acetic acid solution (10
mL ´ 3), water (15 mL), dried with Na SO , and concen-
2
(
1
–
1
271, 1170, 1135, 1081 cm ; HRMS (EI–TOF) m/z calcd for
+
16 12 5 2
C H F NO [M] 345.0788, found 345.0798; mp 152–154 °C.
1,1-Difluoro-4-methyl-1-(5-(trifluoromethyl)pyridin-2-
yl)pentan-2-ol (28). See representative reaction. Purifica-
tion by preparative TLC (15% EtOAc in hexanes) afforded
1
the title compound 28 as a colorless oil (25%): H NMR (400
2
4
MHz, CDCl
(
(
3
) δ 8.92 (s, 1H), 8.11 (dd, J = 8.3, 2.2 Hz, 1H), 7.84
d, J = 8.3 Hz, 1H), 4.42 (m, 1H), 2.98 (d, J = 6.2 Hz, 1H), 1.93
m, 1H), 1.59–1.53 (m, 2H), 0.98 (d, J = 6.7 Hz, 3H), 0.95 (d,
trated under reduced pressure. Purification by preparative
TLC (30% EtOAc in hexanes) afforded the title compound
1
31 as colorless oil (12 mg, 93%): H NMR (400 MHz, CDCl )
3
1
3
1
J = 6.6 Hz, 3H); C{ H} NMR (125 MHz, CDCl
29.8 Hz, 1C), 145.9 (q, JCF = 3.6 Hz, 1C), 134.8 (q, JCF = 3.4
Hz, 1C), 127.9 (q, JCF = 31.9 Hz, 1C), 122.9 (q, JCF = 271.1 Hz,
3
) δ 157.6 (t, JCF
δ 8.23 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.31 (d, J
= 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.21 (t, J = 10.1 Hz, 1H),
=
1
3
1
3
3.27 (q, J = 9.9 Hz, 2H); C{ H} NMR (100 MHz, CDCl ) δ
1
(
C), 121.3 (t, JCF = 4,0 Hz, 1C), 118.3 (t, JCF = 246.5 Hz, 1C), 71.0
162.1, 149.3, 139.0 (t, JCF = 26.1 Hz, 1C), 136.1, 129.8, 129.4 (2C),
128.9 (2C), 127.6 (t, JCF = 6.2 Hz, 2C), 123.4 (2C), 122.9 (q, JCF
= 274.8 Hz, 1C), 118.5 (t, JCF = 248.9 Hz, 1C), 76.4 (t, JCF = 31.7
1
9
t, JCF = 27.1 Hz, 1C), 38.2, 29.7, 24.1, 23.7; F NMR (376 MHz,
) δ –62.7 (s, 3F), –105.9 (d, JFF = 273.3 Hz, 1F), –115.2
dd, JFF = 266.3, JHF = 15.1 Hz, 1F); IR (film) νmax 3406, 2960,
CDCl
(
3
1
9
Hz, 1C), 39.9 (q, JCF = 31.8 Hz, 1C); F NMR (376 MHz,
CDCl ) δ –63.0 (t, J = 9.9 Hz), –105.2 (dd, JFF = 254.7 Hz,
2
927, 2873, 1722, 1610, 1583, 1469, 1329, 1276, 1169, 1136, 1081
3
HF
–1
+
cm ; HRMS (EI–TOF) m/z calcd for C12
83.0996, found 283.0995.
-(4-Chlorophenyl)-2,2-difluoro-2-(2-methyl-4-nitro-
phenyl)ethan-1-ol (29). See representative reaction. Puri-
fication by preparative TLC (3% EtOAc in CHCl ) afforded
the title compound 29 as a colorless oil (51%): H NMR (500
MHz, CDCl ) δ 8.03 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.38 (d,
J = 8.6 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.3 Hz,
14 5
H F NO [M]
JHF = 9.9 Hz, 1F), –106.3 (dd, JFF = 254.9 Hz, JHF = 9.8 Hz); IR
–1
2
(film) νmax 2922, 1767, 1530, 1353, 1269, 1090 cm ; HRMS
–
(ESI–TOF) m/z calcd for C17
5 4
H10ClF NO [M–H] 422.0213,
1
found 422.0222.
3
1-(4-(tert-Butyl)phenyl)-2,2-difluoro-2-(4-nitro-
phenyl)ethan-1-one (32). A mixture of 18 (10 mg, 0.03
mmol) and DMP (21.2 mg, 0.0435 mmol) in CH CI (1 mL)
1
3
2
2
and H2O (0.017 mL) was stirred for 24 h at rt. The mixture
was quenched with 1 M aqueous NaOH (1 mL) and ex-
2
H), 5.14 (td, J = 10.3, 3.4 Hz, 1H), 2.62 (d, J = 4.1 Hz, 1H),
13
1
3 2
2.38 (t, J = 3.0 Hz, 3H); C{ H} NMR (100 MHz, (CD ) CO)
tracted with CH
over Na SO and concentrated under reduced pressure.
Purification by preparative TLC (1% MeOH in CH CI ) af-
2 2
Cl (3 mL ´ 3). The organics were dried
δ 149.5, 140.2 (t, JCF = 2.3 Hz, 1C), 140.0 (t, JCF = 24.5 Hz, 1C),
2
4
137.1, 134.7, 130.7 (2C), 130.5 (t, JCF = 8.7 Hz, 1C), 128 .8 (2C),
2
2
1
26.9, 122.7 (dd, JCF = 249.2, 247.1 Hz, 1C), 120.9, 75.5 (dd, JCF
forded the title compound 32 as a yellow oil (8.1 mg, 82%):
1
9
1
=
30.8, 28.6 Hz, 1C), 20.8 (t, JCF = 4.6 Hz, 1C); F NMR (471
) δ –103.1 (dd, JFF = 254.9, JHF = 8.6 Hz, 1F), –
04.2 (dd, JFF = 254.7, JHF = 8.1 Hz, 1F); IR (film) νmax 3510,
H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.4 Hz, 2H), 8.01
MHz, CDCl
1
3
(
d, J = 7.9 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.7
13
Hz, 2H), 1.34 (s, 9H); C NMR (100 MHz, CDCl
3
) δ 187.4 (t,
CF = 23.8 Hz, 1C), 159.0, 149.4, 139.4 (t, JCF = 25.4 Hz, 1C),
30.3 (2C), 128.9 (t, JCF = 7.7 Hz, 1C), 127.3 (t, JCF = 6.2 Hz,
C), 125.9 (2C), 123.8 (2C), 116.3 (t, JCF = 254.3 Hz, 1C), 35.4,
–
1
3098, 2926, 2857, 1597, 1527, 1494, 1350, 1240, 1081 cm ;
HRMS (EI–TOF) m/z calcd for C15
J
1
2
+
H12ClF
2
NO
3
[M]
327.0474, found 327.0474.
1
9
1-(4-Chlorophenyl)-2,2-difluoro-2-(pyrazin-2-
30.9 (3C); F NMR (376 MHz, CDCl
(film) νmax 2960, 2927, 2870, 1727, 1699, 1531, 1351, 1250, 1105
cm ; HRMS (APCI–TOF) m/z calcd for C18
3
) δ –97.8 (s, 2F); IR
yl)ethan-1-ol (30). See representative reaction. The reac-
tion mixture was heated to 60 °C in an oil bath for 4 h. Pu-
–
1
–
17 2 3
H F NO [M]
rification by preparative TLC (30% EtOAc in CHCl
forded the title compound 30 as a colorless solid (56%): H
NMR (500 MHz, (CD CO) δ 8.80 (s, 1H), 8.72 (d, J = 12.0
Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H),
3
) af-
333.1176, found 333.1178.
1
ASSOCIATED CONTENT
Supporting Information
3 2
)
1
3
1
5.74 (d, J = 5.4 Hz, 1H), 5.42 (dt, J = 17.1, 6.1 Hz, 1H); C{ H}
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Mangeney, P.; Andriamialisoa, R. Z.; Lallemand, J. Y.;
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ACS Publications website. Spectroscopic data from H, F, and
C NMR spectra and X-ray experiments and data (PDF).
Langlois, N.; Langlois, Y.; Potier, P., 5'-Nor Anhydrovinblastine:
Prototype of a New Class of Vinblastine Derivatives. Tetrahedron
1
3
1
979, 35, 2175−2179.
7) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J.
(
AUTHOR INFORMATION
Corresponding Author
L.; Soloshonok, V. A.; Izawa, K.; Liu, H., Next Generation of Fluo-
rine-Containing Pharmaceuticals, Compounds Currently in Phase
II–III Clinical Trials of Major Pharmaceutical Companies: New
Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116,
422–518.
*
dacolby@olemiss.edu
Present Addresses
‡
(8)
ceuticals: Looking Beyond Intuition. Science 2007, 317, 1881−1886.
9) Han, C.; Kim, E. H.; Colby, D. A., Cleavage of Carbon–
Muller, K.; Faeh, C.; Diederich, F., Fluorine in Pharma-
Vanderbilt Center for Neuroscience Drug Discovery, Van-
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derbilt University, Nashville, Tennessee 37212, United States
(
Author Contributions
Carbon Bonds through the Mild Release of Trifluoroacetate: Gen-
eration of a,a-Difluoroenolates for Aldol Reactions. J. Am. Chem.
Soc. 2011, 133, 5802–5805.
H.R.K. conducted the synthetic experiments and mechanistic
studies. C.H. performed the bond-cleavage experiments and
synthesized the substrates. A.T.A. and M.D.A. performed ad-
ditional synthetic experiments and contributed equally to
(10)
Xue, F.; Li, H.; Delker, S. L.; Fang, J.; Martásek, P.; Ro-
man, L. J.; Poulos, T. L.; Silverman, R. B., Potent, Highly Selective,
and Orally Bioavailable Gem-Difluorinated Monocationic Inhibi-
tors of Neuronal Nitric Oxide Synthase. J. Am. Chem. Soc. 2010,
#
the work. E.L. and X.P. conducted the computational stud-
ies. All authors wrote the manuscript and designed the ap-
proach.
1
32, 14229–14238.
11) Lynch, C. L.; Willoughby, C. A.; Hale, J. J.; Holson, E. J.;
(
Budhu, R. J.; Gentry, A. L.; Rosauer, K. G.; Caldwell, C. G.; Chen,
P.; Mills, S. G.; MacCoss, M.; Berk, S.; Chen, L.; Chapman, K. T.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino, J. A.; Sicil-
iano, S. J.; Cascieri, M. A.; Carella, A.; Carver, G.; Holmes, K.;
Schleif, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger,
J.; Miller, M.; Emini, E. A., 1,3,4-Trisubstituted Pyrrolidine CCR5
Receptor Antagonists: Modifications of the Arylpropylpiperidine
Side Chains. Bioorg. Med. Chem. Lett. 2003, 13, 119–123.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors acknowledge funding for this work from the Na-
tional Institutes of Health (NIH). Its contents are solely the
responsibility of the authors and do not necessarily represent
the official view of the NIH. These studies were funded by the
National Institute on Aging (R21AG039718), the National In-
stitute of General Medical Sciences (P20GM104932), and the
Ralph W. and Grace M. Showalter Research Trust funds. The
computational studies were funded by the Department of En-
ergy Office of Science (DE-SC0011297) and OU startup fund
using resources at the OU Supercomputing Center for Educa-
tion and Research (OSCER). The Mass Spectrometry and Pro-
teomic Facility of the University of Notre Dame and Mass
Spectrometry Facility of the Louisiana State University are
acknowledged for acquisition of high-resolution mass spec-
trometry data. The Purdue X-ray Crystallography Facility is
acknowledged for acquisition of X-ray crystallography data.
(12)
Anderson, M. O.; Zhang, J.; Liu, Y.; Yao, C.; Phuan, P.-
W.; Verkman, A. S., Nanomolar Potency and Metabolically Stable
Inhibitors of Kidney Urea Transporter UT-B. J. Med. Chem. 2012,
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13) Xiao, Y.-L.; Min, Q.-Q.; Xu, C.; Wang, R.-W.; Zhang, X.,
(
Nickel-Catalyzed Difluoroalkylation of (Hetero)Arylborons with
Unactivated 1-Bromo-1,1-difluoroalkanes. Angew. Chem. Int. Ed.
2
016, 55, 5837–5841.
(14) An, L.; Xiao, Y.-L.; Zhang, S.; Zhang, X., Bulky Diamine
Ligand Promotes Cross-Coupling of Difluoroalkyl Bromides by
Iron Catalysis. Angew. Chem. Int. Ed. 2018, 57, 6921–6925.
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fluoromethylaromatics with Unactivated Alkenes. J. Am. Chem.
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Clavel, P.; Lessene, G.; Biran, C.; Bordeau, M.; Roques,
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O
HO OH
CF3
OH
K2CO3, 4Å MS
DMSO, 60 °C
H
R1
R
R
R
F
R1
F
F
F
F F
CF3CO2
mild C–C bond
cleavage
R = electron difficient phenyl or pyridyl
= alkyl, aryl
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