Generation of Magnesium Pentafluoropropen-2-olate from Hexafluoroisopropanol and Synthesis of 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones

Article abstract of DOI:10.1021/acs.joc.6b02863

2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones are valuable precursors to difluoroenolates following fragmentation during the release of trifluoroacetate; however, there are few synthetic strategies to prepare this unique class of compound. We addressed this

Full text of DOI:10.1021/acs.joc.6b02863

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Note
Generation of Magnesium Pentafluoropropen-2-
olate from Hexafluoroisopropanol and Synthesis
of 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones
Robert Alan Hazlitt, Que-Lynn Tran, Munia Fakhri Sowaileh, and David A. Colby
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02863 • Publication Date (Web): 20 Jan 2017
Downloaded from http://pubs.acs.org on January 20, 2017
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Generation of Magnesium Pentafluoropropen-2-olate from Hexafluoroisopropanol and
Synthesis of 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones
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Robert A. Hazlitt, Que-Lynn Tran, Munia F. Sowaileh, and David A. Colby*
Department of BioMolecular Sciences, University of Mississippi, University, Mississippi 38677
Table of Contents Graphic
HO
HO OH
CF3
O
O
OMgCl
F
HO OH
CF3
Dess-Martin
periodinane
+
R
R
R
H
F3C
F
F
F
F
F
9 examples
(i-Pr)2NMgCl
(CF3)2CHOH
Abstract
2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones are valuable precursors to difluoroenolates,
following fragmentation during the release of trifluoroacetate; however, there are few synthetic
strategies to prepare this unique class of compound. We have addressed this issue and report a
mild, two-step synthesis of 2,2,4,4,4-pentafluoro-3,3-dihydroxyketones from aldehydes.
Specifically, aldehydes are treated with pentafluoropropen-2-olate, generated from a new
fragmentation of hexafluoroisopropanol with a mixed Mg/Li amide, to give pentafluoroalcohols.
A subsequent oxidation with Dess-Martin periodinane provides the targets in good isolated
yields.
The incorporation of fluorine into organic molecules is essential in the pharmaceutical,
agrochemical, and polymer industries. Major advances in synthetic chemistry have occurred to
enable the production of compounds displaying a fluorine atom1 or a trifluoromethyl group;2,3
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however, methods to assemble difluoromethyl groups are less developed.4,5 In 2011, we reported
an approach to produce difluoroenolates through the release of trifluoroacetate from highly a-
fluorinated gem-diols (Scheme 1).6 These difluoroenolates participate in aldol reactions and
subsequent investigations demonstrated that these intermediates react with activated imines,7–9
trifluoromethyl ketones,10 halogenation reagents,11 and dithianes.12 Moreover, the
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difluoroenolates generated during the release of trifluoroacetate can also be immediately trapped
as difluoromethyl ketones13 or deuterodifluoromethyl ketones14 with H2O or D2O, respectively.
Additionally, this method is compatible with catalytic, asymmetric reactions15 and visible-light
photoredox catalysis.16 Despite the utility of this process and rapid adoption of the method,17 the
requisite highly a-fluorinated gem-diols are not common functional groups in fluorine chemistry
and are predominately accessed by only one synthetic strategy.6
O
trifluoroacetate
release
O
HO OH
CF3
R1 CF2H
R1
H2O
F
F
CF3CO2
O
O
OH
R2
O
O
R2
H
D2O
F
R1
R1
R1 CF2D
R1
F
F
S
R2
F
X
R2
S
O
O
R3
X
O
N
S
R1
R2
F
F
R2 CF3
R2
H
F
F
X = Cl, Br, I
R3
R2
O
O
HN
F
HO CF3
R2
R1
R1
F
F
F
Scheme 1. Synthetic Reactions of Difluoroenolates Generated by the Release of
a
Trifluoroacetate from Highly -Fluorinated gem-Diols
Nearly all highly a-fluorinated gem-diols are accessed through methyl ketones by a two-
step process of trifluoroacetylation followed by difluorination with Selectfluor (Figure 1A).6,17
Even though this strategy enables a quick production of substrates for the release of
trifluoroacetate, we recently had to develop an alternative method to access a glucose-derived
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highly a-fluorinated gem-diol from an aldehyde (Figure 1B).18 Specifically, we exploited an
approach from Qian and Nakai, in which the treatment of hexafluoroisopropanol with n-
butyllithium creates a lithium-based pentafluoroenolate that adds smoothly into aldehydes.19
Next, after the addition of the enolate to the aldehyde, the glucose-derived pentafluorinated
product was oxidized with Dess-Martin periodinane to give the targeted gem-diol.18 In this case,
the two-step approach from an aldehyde was quite effective, and also, it provided an opportunity
to devise an additional method for the synthesis of highly a-fluorinate gem-diols. Herein, we
report that hexafluoroisopropanol can be fragmented with mixed Mg/Li amides of type
R2NMgCl.LiCl and added into aldehydes to produce pentafluorinated products that can be
oxidized to the starting materials for the trifluoroacetate-release process. Additionally, we have
discovered that the difluoroenolates generated from the release of trifluoroacetate can be trapped
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as difluoroenoxysilanes and concomitantly arylated using palladium catalyst.
A)
O
O
OH
O
HO OH
CF3
Selectflour
LiHMDS
R
R
CF3
R
CF3CO2CH2CF3,
THF, –78 °C
CH3CN, rt, 24 h
F
F
B)
BnO
O
BnO HO
O
HO OH
O
(CF3)2CHOH
O
O
H
CF3
n-BuLi, THF,
–78 °C, 52%
F
F
BnO BnO
BnO BnO
Dess-Martin
periodinane,
95%
BnO
O
O
O
HO OH
CF3
F
F
BnO BnO
a
Figure 1. Synthetic Approaches to Highly -Fluorinated gem-Diols. A. Primary synthetic
strategy by trifluoroacetylation and subsequent difluorination. B. Addition of lithium
pentafluoropropen-2-olate and oxidation.
The fragmentation of hexafluoroisopropanol requires two equivalents of n-butyllithium:
one to form the alkoxide, and the second to abstract the methine proton and displace fluoride.19,20
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Even though the fragmentation was also reported to occur with NaH and KH,19 the latter process
is believed to be promoted by the coordination of lithium to fluorine, which assists in the
displacement process. All of the subsequent studies have used n-buyllithium as a base.18,20–25
Although n-butyllitium is a common laboratory reagent, it is quite flammable and the potential
for hazards are increased when multiple equivalents are required. Another limitation of using
organolithium as a base is that very low temperatures are required (i.e., –78 °C). In order to
address the typical limitations of organolithium bases, Knochel and co-workers have pioneered
the development of mixed Mg/Li amides of type R2NMgCl.LiCl.26 Accordingly, we aimed to
develop a new method to produce magnesium pentafluoropropen-2-olate from
hexafluoroisopropanol by using magnesium bases (Table 1). Initial efforts with methyl
magnesium bromide were unproductive, but isopropyl Grignard, with or without added lithium
chloride, generated the pentafluoropropen-2-olate in modest yields (i.e., 37–40%) as observed by
19F NMR (entries 1–4). Exchanging the solvent THF with Et2O or dioxane did not notably
increase conversions (entries 5–6); using cesium chloride instead of lithium chloride also did not
affect the formation of the pentafluoroenolate (entry 7). Using the mixed Mg/Li amide of type (i-
Pr)2NMgCl.LiCl26 at room temperature proved to be superior and provided the
pentafluoropropen-2-olate with 91% conversion (entry 8). The doubling of yield when (i-
Pr)2NMgCl.LiCl was utilized compared to i-PrMgCl.LiCl was a substantial improvement (i.e.,
40% to 91%).
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Table 1. Optimization of the Formation of Magnesium Pentafluoropropen-2-olate from
Hexafluoroisopropanol
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OMgCl
OH
RMgX, additive
F
F3C
solvent, 0 °C to rt
F3C
CF3
F
6
7
8
9
entry
RMgX
solvent
THF
additive
19F NMR yield (%)
1
2
3
4
5
6
7
8
MeMgBr
MeMgBr
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
0
THF
LiCl
LiCl
0
THF
37
40
52
18
48
91
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THF
Et2O
dioxane
THF
CsCl
LiCl
(i-Pr)2NMgCl THF
The next step was to determine if the fluoroenolate generated from (i-Pr)2NMgCl.LiCl
and hexafluoroisopropanol would add to aldehydes. Even though the lithium pentafluoropropen-
2-olate reacts well with aldehydes,18,19,25 the reactivity of the magnesium-counterpart is not
characterized in the literature to our knowledge. Benzaldehydes 1–5, heteroaromatic aldehydes
6–7, a,b-unsaturated aldehyde 8, and aliphatic aldehyde 9 were treated at room temperature with
the pentafluoropropen-2-olate generated with (i-Pr)2NMgCl.LiCl (Table 2). The
pentafluoroalcohol 10 was obtained in 59% isolated yield from addition to 4-ethylbenzaldehyde
1. In the case of 4-bromobenzaldehyde 2, the product 11 was isolated in a lower 33% yield most
likely due to debromination of the benzene. All of the other substrates provided the
pentafluoroalcohols 12–18 in 52–87% isolated yields. Substituted benzene rings, heterocycles,
styrene, and alkyl groups are compatible with the magnesium pentafluoropropen-2-olate.
Moreover, during the analysis of the 19F NMR spectra following workup, two products were
routinely observed: 1) the desired target and 2) the aminal formed by addition of
diisopropylamine to the gem-diol. The latter was readily cleaved during purification by silica gel
flash chromatography. Overall, the conversions with the pentafluoropropen-2-olate generated
from (i-Pr)2NMgCl.LiCl were comparable to the intermediate produced with n-butyllithium.
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Table 2. Addition of Magnesium Pentafluoropropen-2-olate to Aldehydes 1–9.
5
6
7
O
HO
(i-Pr)2NMgCl.LiCl
HO OH
CF3
R
H
R
(CF3)2CHOH, THF, rt
F
F
yielda
8
9
entry
1
substrate
product
HO
O
HO OH
CF3
10
HO OH
CF3
10
11
12
13
14
15
16
17
18
19
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H
59%
F
F
1
O
HO
H
33% (45%)b
2
3
4
5
6
7
8
9
F
F
Br
Br
2
11
HO OH
CF3
O
HO
H
71% (82%)b
77%
F
F
3
12
O
HO
HO OH
CF3
F
F
H
F
F
MeO
MeO
4
13
HO OH
CF3
14
HO OH
CF3
15
HO OH
CF3
16
HO OH
CF3
17
O
HO
68% (78%)b
68%
O
O
O
O
H
F
F
5
O
HO
H
F
F
S
6
S
O
HO
65%
H
F
F
O
O
7
O
HO
52% (67%)b
H
F
F
8
BnO
O
BnO HO
O
O
HO OH
CF3
18
87%
O
O
H
F
F
BnO BnO
BnO BnO
9
a Isolated yields
b Yields determined by 19F NMR
With the fluoroalcohols 10–18 in hand, oxidations to the fluoroketones18 were conducted
using the oxidant, Dess-Martin periodinane (Table 3).27 Only mild oxidants can be considered
for this transformation, because the products will easily eliminate trifluoroacetate in the presence
of basic conditions.6 All of the aromatic, heteroaromatic, alkenyl, and alkyl substrates 10–18
provided the respective fluoroketones 19–27 in good isolated yields of 78–95%. Moreover, some
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conversions were nearly quantitative as observed by 19F NMR. In all cases, the by-products from
fragmentation of the compounds 19–27 by trifluoroacetate release were not observed. The
oxidation of allylic fluoroalcohol 17 to 26 provided a lower isolated yield at 41%. Although
allylic alcohols are typically good substrates for Dess-Martin periodinane,27 allylic
fluoroalcohols are not oxidized as well with this reagent.28 In general, the two-step
addition/oxidation protocol was successful to produce the pentafluoroketones from readily
available aldehydes.
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Table 3. Oxidation of Fluoroalcohols 10–18 to 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones
19–27
HO
O
HO OH
CF3
HO OH
CF3
Dess-Martin
periodinane
R
R
F
F
F F
entry
1
substrate
product
yielda
O
HO OH
CF3
19
HO OH
CF3
10
80%
F
F
O
78% (99%)b
79% (90%)b
88% (100%)b
84% (95%)b
80% (97%)b
79% (88%)b
2
3
4
5
6
7
8
9
11
12
13
14
15
16
17
18
F
F
Br
20
HO OH
CF3
O
F
F
21
O
HO OH
CF3
F
F
F
MeO
22
HO OH
CF3
23
HO OH
CF3
24
HO OH
CF3
25
HO OH
CF3
26
O
O
O
F
F
O
F
F
S
O
F
F
O
O
41% (54%)b
95%c
F
F
BnO
O
O
HO OH
CF3
27
O
F
F
BnO BnO
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a Isolated yields
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b Yields determined by 19F NMR
c Reference 18.
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With a new route to starting materials for trifluoroacetate release, additional studies were
undertaken to expand the role of the pentafluoroketones as precursors to difluoroenolates.
Specifically, difluoroenoxysilanes are valuable fluorinated building blocks20 and we aimed to
devise a new method to access these key targets. Treatment of the highly a-fluorinated gem-diol
286 with the strong base, lithium hexamethyldisilazane, according to the protocol reported by
Wolf,8 promotes the release of trifluoroacetate and unleashes the difluoroenolate which we
immediately trapped with chlorotrimethylsilane (Figure 2). The difluoroenoxysilane 29 was
produced in 70% by 19F NMR; the isolated yield of 29 was 47%. The next step was to convert
the difluoroenoxysilane to a valuable difluoromethyl ketone using the method of Shreeve.29
Indeed, difluoromethyl ketones are excellent structures in medicinal chemistry due to their
propensity to form a stable hydrate.30,31 Accordingly, gem-diol 3013 was treated with LiHMDS
and trapped with TMSCl to the difluoroenoxysilane, which, in turn, was immediately subjected
to palladium-mediated arylation conditions29 in the presence of bromoanisole and the
difluoromethyl ketone 31 was obtained in a good 78% isolated yield.
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O
OTMS
HO OH
CF3
LiHMDS
F
then TMSCl,
47%
F
28
F
F
29
(70% by19F NMR)
7
8
9
O
OTMS
HO OH
CF3
LiHMDS
then TMSCl
F
OMe
F
30
F
F
(66% by19F NMR)
10
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Br
Pd(OAc)2, t-Bu3P,
Bu3SnF, 78%
OMe
O
F
31
F
Figure 2. Conversion of Fluorinated gem-Diols to Difluoroenoxysilanes
In conclusion, this mild, two-step synthesis provides an additional route to 2,2,4,4,4-
pentafluoro-3,3-dihydroxyketones from aldehydes. Moreover, this discovery utilizes a mixed
Mg/Li amide for the fragmentation of hexafluoroisopropanol and eliminates the requirement of
n-butyllithium. These advances have enabled the expansion of the reactivity of difluoroenolates
produced from highly a-fluorinated gem-diols through the release of trifluoroacetate so that
difluoroenoxysilanes as well as arylated difluoromethyl ketones can be prepared. This
advancement will likely enable new reactivity for fluoroenolates to be characterized.
Experimental Section
Representative Reaction Procedure for Preparation of Pentafluorotriols.
Hexafluoroisopropanol (58 µL, 0.55 mmol) was added dropwise at rt to a freshly prepared
solution of (i-Pr2N)2MgCl•LiCl26 (5 mL, 0.44 M in THF) and the mixture was stirred for 2 h.
Then, a solution of 4-ethylbenzaldehyde 1 (113 µL, 0.83 mmol) in THF (1.5 mL) was added over
10 min and the mixture was stirred for 18 h at rt. The resultant mixture was quenched with
saturated aqueous NH4Cl (2 mL), diluted with H2O (2 mL), and extracted with Et2O (3 × 2 mL).
The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. SiO2
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flash chromatography (5:1–3:1 hexanes/EtOAc with 1% AcOH) afforded the product 10 as a
colorless oil (97 mg, 59% yield).
7
8
9
1-(4-Ethylphenyl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 10. See representative
reaction procedure: 1H NMR (400 MHz, (CD3)2CO) δ 7.46 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.2
Hz, 2H), 7.21 (s, 1H), 7.00 (s, 1H), 6.41 (s, 1H), 5.53 (d, J = 22.9 Hz, 1H), 2.69 (q, J = 7.6 Hz,
2H), 1.26 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 145.3, 133.7, 128.9 (2C), 127.9
(2C), 122.7 (q, JCF = 288 Hz, 1C), 116.8 (dd, JCF = 261, 254 Hz, 1C), 93.5 (tq, JCF = 30.5, 27.0
Hz, 1C), 73.0 (dd, JCF = 33.2, 22.2 Hz), 28.7, 15.6; 19F NMR (376 MHz, CDCl3) δ –81.8 (t, J =
11.8 Hz, 3F), –118.0 (dq, J = 264, 12.9 Hz, 1F), –131.4 (ddq, J = 264, 22.1, 10.9 Hz, 1F); IR
(film) νmax 3351, 2967, 1616, 1202, 1159, 1067 cm–1; HRMS (EI) m/z calcd for C12H11F5O2 (M–
H2O)+ 282.0679, found 282.0687.
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1-(4-Bromophenyl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 11. See representative
reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 0.5% AcOH) afforded
the title compound 11 as a colorless solid (64 mg, 33% yield): mp = 96–98 °C; 1H NMR (400
MHz, (CD3)2CO) δ 7.59 (dt, J = 8.7, 2.1 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.90 (br s, 2H), 5.53
(dd, J = 22.1, 2.7 Hz, 1H), 3.12 (br s, 1H);13C NMR (100 MHz, (CD3)2CO) δ 136.5, 131.9 (2C),
131.3 (2C), 123.2, 123.0 (q, JCF = 287 Hz, 1C), 117.2 (dd, JCF = 259, 253 Hz, 1C), 93.8 (tq, JCF
30.5, 26.0 Hz, 1C), 72.9 (dd, JCF = 32.9, 22.2 Hz, 1C) ; 19F NMR (376 MHz, (CD3)2CO) δ –81.7
(dd, J = 13.3, 11.0 Hz, 3F), –117.9 (dqd, J = 264, 13.3, 2.5 Hz, 1F), –130.5 (ddq, J = 264, 22.0,
11.0 Hz, 1F); IR (film) νmax 3423, 3213, 1490, 1404, 1286, 1212, 1151, 1064 cm–1; HRMS (EI)
m/z calcd for C10H6BrF5O2 (M–H–H2O)– 331.9477, found 331.9461.
=
1-(4-(tert-Butyl)phenyl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 12. See representative
reaction procedure. SiO2 flash chromatography (4:1 hexanes/EtOAc with 0.5% AcOH) afforded
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the title compound 12 as a colorless solid (129 mg, 71% yield): mp = 94–96 °C; 1H NMR (400
MHz, (CD3)2CO) δ 7.45 (s, 4H), 7.18 (s, 1H), 6.97 (s, 1H), 6.34 (s, 1H), 5.50 (d, J = 23.3 Hz,
1H), 1.33 (s, 9H); 13C NMR (100 MHz, (CD3)2CO) δ 152.5, 133.9, 129.1 (2C), 125.7 (2C), 123.1
(q, JCF = 287 Hz, 1C), 117.3 (dd, JCF = 259, 252 Hz, 1C), 94.0 (tq, JCF = 31.3, 27.0 Hz, 1C), 73.4
(dd, JCF = 33.5, 22.2 Hz, 1C), 35.1, 31.6 (3C); 19F NMR (376 MHz, (CD3)2CO) δ –81.6 (dd, J =
13.2, 11.2 Hz, 3F), –117.8 (dqd, J = 263, 13.2, 1.5 Hz, 1F), –131.0 (ddq, J = 263, 22.5, 11.2 Hz,
1F); IR (film) νmax 3349, 2966, 1617, 1513, 1205, 1161, 1070 cm–1; HRMS (ESI) m/z calcd for
C14H16F5O2 (M+H–H2O)+ 311.1065, found 311.1080.
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2,2,4,4,4-Pentafluoro-1-(3-fluoro-4-methoxyphenyl)butane-1,3,3-triol 13. See
representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 0.5%
AcOH) afforded the title compound 13 as a colorless solid (135 mg, 77% yield): mp = 125–126
°C; 1H NMR (400 MHz, (CD3)2CO) δ 7.28 (m, 2H), 7.14 (t, J = 8.4 Hz, 1H), 6.92 (br s, 3H),
5.49 (dd, J = 22.3, 2.6 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 152.7 (d, JCF
243 Hz, 1C), 149.0 (d, JCF = 10.6 Hz, 1C), 129.7 (d, JCF = 5.8 Hz, 1C), 125.6 (d, JCF = 3.2 Hz,
1C), 123.1 (q, JCF = 287 Hz, 1C), 117.2 (dd, JCF = 259, 253 Hz, 1C), 116.6 (d, JCF = 71.4 Hz,
=
1C), 113.9 (d, JCF = 1.9 Hz, 1C), 93.9 (tq, JCF = 33.0, 27.5 Hz, 1C) 72.7 (dd, JCF = 33.2, 22.0 Hz,
1C), 56.5; 19F NMR (376 MHz, (CD3)2CO) δ –81.6 (d, J = 13.4, 11.0 Hz, 3F), –117.9 (dq, J =
263, 13.3 Hz, 1F), –131.0 (ddq, J = 263, 22.1, 11.1 Hz, 1F), –137.2 (dd, J = 12.4, 8.6 Hz, 1F); IR
(film) νmax 3240, 1628, 1519, 1441, 1276, 1203, 1153, 1120, 1107, 1071 cm–1; HRMS (EI) m/z
calcd for C11H8F6O3 (M–H–H2O)– 302.0383, found 302.0356.
1-(Benzo[1,3]dioxol-5-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 14. See
representative reaction procedure. SiO2 flash chromatography (2:1 hexanes/EtOAc with 0.5%
AcOH) afforded the title compound 14 as a brown oil (118 mg, 68% yield): 1H NMR (400 MHz,
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(CDCl3) δ 6.99 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.99 (s, 2H), 5.35 (dd,
J = 21.9, 1.8 Hz, 1H), 3.79 (br s, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 149.0, 148.5, 130.6,
123.2, 123.1 (q, JCF = 287 Hz, 1C), 117.2 (dd, JCF = 259, 252 Hz, 1C), 109.4, 108.5, 102.2, 93.9
(tq, JCF = 30.5, 27.0 Hz, 1C), 73.3 (dd, JCF = 33.3, 22.1 Hz, 1C); 19F NMR (376 MHz,
(CD3)2CO) δ –81.7, (dd, J = 13.2, 11.2 Hz, 3F), –117.8 (dqd, J = 263, 13.2, 2.4 Hz, 1F), –131.3
(ddq, J = 263, 22.3, 11.1 Hz, 1F); IR (film) νmax 3394, 2920, 1506, 1493, 1447, 1248, 1205,
1161, 1039 cm–1; HRMS (ESI) m/z calcd for C11H8F5O4 (M–H2O)+ 299.0343, found 299.0356.
1-(Benzothiophen-3-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 15. See representative
reaction procedure. SiO2 flash chromatography (5:2 hexanes/EtOAc with 0.5% AcOH) afforded
the title compound 15 as a colorless oil (122 mg, 68% yield): 1H NMR (400 MHz, (CD3)2CO) δ
8.09–7.91 (m, 2H), 7.87 (s, 1H), 7.49–7.28 (m, 3H), 7.00 (s, 1H), 6.49 (s, 1H), 6.03 (d, J = 22.9
Hz, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 141.1, 139.0, 132.3, 128.3, 125.4, 125.1, 123.8 (t,
JCF = 2.2 Hz, 1C), 123.5, 123.1 (q, JCF = 287 Hz, 1C), 117.8 (dd, JCF = 259, 253 Hz, 1C), 94.0
(tq, JCF = 30.8, 28.0 Hz, 1C), 69.2 (dd, JCF = 33.9, 22.5 Hz, 1C); 19F NMR (376 MHz,
(CD3)2CO) δ –81.6 (dd, J = 13.1, 11.2 Hz, 3F), –118.0 (dq, J = 262, 13.1 Hz, 1F), –129.1 (ddq, J
= 262, 22.5, 11.2 Hz, 1F); IR (film) νmax 3368, 1625, 1428, 1204, 1160, 1070 cm–1; HRMS (ESI)
m/z calcd for C12H9F5O3SNa (M+Na)+ 351.0090, found 351.0086.
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1-(Benzofuran-3-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 16. See representative
reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 1.0% AcOH) afforded
the title compound 16 as a colorless oil (112 mg, 65% yield): 1H NMR (400 MHz, (CD3)2CO) δ
7.67 (ddd, J = 7.7, 1.2, 0.7 Hz, 1H), 7.54, (dd, J = 8.2, 0.8 Hz, 1H), 7.35 (td, J = 7.8, 1.2 Hz, 1H),
7.27 (td, J = 7.4, 0.9 Hz, 1H), 7.06 (s, 1H), 6.84 (br s, 2H), 5.72 (dd, J = 21.2, 2.6 Hz, 1H), 3.26
(s, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 155.9, 153.4, 128.8, 125.7, 123.9, 123.0 (q, JCF = 287
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Hz, 1C), 122.3, 117.4 (dd, JCF = 260, 255 Hz, 1C), 112.0, 107.8, 93.7 (qdd, JCF = 31.2, 29.3, 26.8
Hz, 1C), 68.3 (dd, JCF = 32.7, 22.7 Hz, 1C); 19F NMR (376 MHz, (CD3)2CO) δ –81.7 (dd, J =
12.9, 10.9 Hz, 3F), –119.0 (dqd, J = 261, 13.0, 3.0 Hz, 1F), –128.5 (ddq, J = 261, 21.5, 10.8, 1F);
IR (film) νmax 3368, 1619, 1454, 1205, 1161, 1073 cm–1; HRMS (ESI) m/z calcd for
C12H9F5O4Na (M+Na)+ 335.0319, found 335.0314.
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(E)-1,1,1,3,3-Pentafluoro-6-phenylhex-5-ene-2,2,4-triol 17. See representative reaction
procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 1.0% AcOH) afforded the title
compound 17 as a colorless oil (86 mg, 52% yield). All spectral and characterization data
matched the reported data.25
(5S,6R,7R)-5,6,7-tris(benzyloxy)-7-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1,1,1,3,3-
pentafluoroheptane-2,2,4-triol 18. Hexafluoroisopropanol (8 µL, 0.07 mmol) was added
dropwise at rt to a freshly prepared solution of (i-Pr2N)2MgCl•LiCl26 (0.63 mL, 0.44 M in THF)
and the mixture was stirred for 2 h. Then, a solution of aldehyde 918 (85 mg, 0.17 mmol) in THF
(1.5 mL) was added over 10 min and the mixture was stirred for 18 h at rt. The resultant mixture
was quenched with saturated aqueous NH4Cl (2 mL), diluted with H2O (2 mL), and extracted
with Et2O (3 × 2 mL). The organics were dried over Na2SO4, filtered, and concentrated under
reduced pressure. SiO2 flash chromatography (5:2 hexanes/EtOAc) afforded the title compound
18 as a colorless oil (d.r = 2:1, 39 mg, 87% yield). All spectral and characterization data matched
the reported data.18
Representative Reaction Procedure for Preparation of Pentafluoro-gem-diols. Dess-
Martin periodinane (141 mg, 0.333 mmol) was added to a solution of 10 (40 mg, 0.13 mmol) in
CH2Cl2 (3 mL), and the reaction mixture was stirred for 24 h at rt. Next, the reaction mixture was
diluted with CH2Cl2 (5 mL), filtered through Celite, and concentrated under reduced pressure.
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SiO2 flash chromatography (5:1 hexanes/EtOAc with 1% AcOH) afforded the product 19 as a
colorless oil (32 mg, 80% yield).
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1-(4-Ethylphenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 19. See
representative reaction procedure: 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.34
(d, J = 8.6 Hz, 2H), 3.99 (br s, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 190.9 (t, JCF = 28.7 Hz, 1C), 153.1, 130.9 (t, JCF = 3.5 Hz, 2C), 129.5 (t, JCF
= 2.3 Hz, 1C), 128.4 (2C), 121.4 (q, JCF = 289 Hz, 1C), 111.7 (t, JCF = 268 Hz, 1C), 92.8 (qt, JCF
= 32.5, 26.9 Hz, 1C), 29.2, 14.9; 19F NMR (376 MHz, CDCl3) δ –82.0 (t, J = 11.0 Hz, 3F), –
112.8 (q, J = 10.5 Hz, 2F); IR (film) νmax 3402, 2972, 1685, 1606, 1205, 1066 cm–1; HRMS (EI)
m/z calcd for C12H9F5O2 (M–H2O)+ 280.0523, found 280.0547.
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1-(4-Bromophenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 20. See
representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc) afforded the
title compound 20 as a colorless oil (29 mg, 78% yield). All spectral and characterization data
matched the reported data.16
1-(4-(tert-Butyl)phenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 21. See
representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc) afforded the
title compound 21 as a colorless solid (54 mg, 79% yield): mp = 59–61 °C; 1H NMR (400 MHz,
(CD3)2CO) δ 8.12 (d, J = 8.8 Hz, 2H), 7.60 (dt, J = 8.9, 2.1 Hz, 2H), 7.47 (br s, 1H), 3.16 (br s,
1H), 1.35 (s, 9H); 13C NMR (100 MHz, (CD3)2CO) δ 188.5 (t, JCF = 26.7 Hz, 1C), 159.0, 131.7,
131.5 (t, JCF = 3.5 Hz, 2C), 126.3 (2C), 123.0 (q, JCF = 288 Hz, 1C), 115.8 (t, JCF = 263 Hz, 1C),
93.3 (qt, JCF = 31.5, 28.0 Hz, 1C), 35.8, 31.2 (3C); 19F NMR (376 MHz, CDCl3) δ –81.9 (t, J =
11.1 Hz, 3F), –113.1 (q, J = 11.0 Hz, 2F); IR (film) νmax 3420, 2969, 1687, 1604, 1205, 1067 cm–
1; HRMS (ESI) m/z calcd for C14H15F5O3Na (M+Na)+ 349.0839, found 349.0834.
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2,2,4,4,4-Pentafluoro-1-(3-fluoro-4-methoxyphenyl)-3,3-dihydroxybutan-1-one 22.
See representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 1%
AcOH) afforded the title compound 22 as a colorless oil (44 mg, 88% yield): 1H NMR (400
MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 11.8, 1.9 Hz, 1H), 7.05 (t, J = 8.4 Hz, 1H),
4.89 (br s, 1H), 4.00 (s, 3H), 1.82 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 188.7 (t, JCF = 29.3
Hz, 1C), 154.3 (d, JCF = 10.7 Hz, 1C), 151.9 (d, JCF = 248 Hz, 1C), 129.2 (q, JCF = 3.9 Hz, 1C),
124.7 (d, J = 5.0 Hz, 1C), 121.1 (q, JCF = 286 Hz, 1C), 118.2 (dt, JCF = 20.0, 3.0 Hz, 1C), 112.7,
111.9 (t, JCF = 267 Hz, 1C), 92.9 (qt, JCF = 32.5, 26.9 Hz, 1C), 56.6; 19F NMR (376 MHz,
CDCl3) δ –81.9 (t, J = 11.0 Hz, 3F), –113.0 (q, J = 11.0 Hz, 2F), –134.6 (dd, J = 11.8, 8.2 Hz,
1F); IR (film) νmax 3429, 2950, 1684, 1608, 1520, 1442, 1288, 1205, 1108 cm–1; HRMS (ESI)
m/z calcd for C11H8F6O4Na (M+Na)+ 341.0224, found 341.0229.
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1-(Benzo[1,3]dioxol-5-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 23. See
representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 1%
AcOH) afforded the title compound 23 as a colorless oil (42 mg, 84% yield). All spectral and
characterization data matched the reported data.6
1-(Benzothiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 24. See
representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 1%
AcOH) afforded the title compound 24 as a colorless oil (43 mg, 80% yield). All spectral and
characterization data matched the reported data.11
1-(Benzofuran-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 25. See
representative reaction procedure. SiO2 flash chromatography (5:2 hexanes/EtOAc) afforded the
title compound 25 as a yellow solid (43 mg, 79% yield): mp = 72–74 °C; 1H NMR (400 MHz,
(CD3)2CO) δ 8.09–8.01 (m, 1H), 7.93 (dd, J = 7.9, 0.6 Hz, 1H), 7.75–7.56 (m, 3H), 7.47–7.36
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(m, 1H), 3.21 (br s, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 177.7 (t, JCF = 28.6 Hz, 1C), 156.8,
149.9, 130.7, 127.8, 125.4, 125.3, 123.0 (q, J = 288, 1C), 121.2 (t, JCF = 5.8 Hz, 1C), 115.3 (t,
JCF = 262 Hz, 1C), 113.0, 93.2 (qt, JCF = 32.0, 27.8 Hz, 1C); 19F NMR (376 MHz, (CD3)2CO) δ –
81.6 (t, J = 10.2 Hz, 3F), –116.5 (qd, J = 10.2, 2.0); IR (film) νmax 3406, 1673, 1614, 1546, 1335,
1191, 1127, 1071 cm–1; HRMS (ESI) m/z calcd for C12H7F5O4Na (M+Na)+ 333.0162, found
333.0156.
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(E)-4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-3-one 26. See
representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc) afforded the
title compound 26 as a colorless oil (20 mg, 41% yield). All spectral and characterization data
matched the reported data.11
((2,2-Difluoro-1-(naphthalen-2-yl)vinyl)oxy)trimethylsilane 29. A solution of n-BuLi
(1 mL, 1.8 M in hexanes) was added dropwise to a –78 °C solution of hexamethyldisilazane (3
mL, 0.6 M in THF) and the mixture was stirred for 30 min at –78 °C. Then, a –78 °C solution of
286 (300 mg, 0.94 mmol) in THF (3.6 mL) was added slowly, followed by the rapid addition of
TMSCl (59 µL, 0.47 mmol). The mixture was stirred for 20 min at –78 °C, warmed to rt, and
then concentrated under reduced pressure. The residue was dissolved in hexanes (20 mL),
filtered through Celite, and concentrated under reduced pressure to provide the title compound
29 as a colorless oil (61 mg, 47% yield): 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.87–7.80
(m, 3H), 7.63 (dt, J = 8.7, 1.7 Hz, 1H), 7.53–7.46 (m, 2H), 0.23 (d, J = 0.9 Hz, 9H); 13C NMR
(125 MHz, CDCl3) δ 155.1 (dd, JCF = 286, 284 Hz, 1C), 133.0, 132.7, 130.1 (dd, JCF = 7.2, 1.5
Hz, 1C), 128.2, 127.9, 127.6, 126.3 (2C), 125.2 (dd, JCF = 6.4, 5.0 Hz, 1C), 123.5 (dd, JCF = 7.9,
2.6 Hz, 1C), 114.2 (dd, JCF = 34.2, 19.4 Hz, 1C), 0.2 (d, JCF = 1.2 Hz, 3C); 19F NMR (376 MHz,
CDCl3) δ –99.9 (d, J = 66.7 Hz, 1F), –112.1 (d, J = 66.6 Hz, 1F); IR (film) νmax 3059, 2962,
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1719, 1261, 1252, 1151 cm–1; HRMS (ESI) m/z calcd for C15H16F2OSi (M)+ 278.0938, found
278.0931.
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2,2-Difluoro-2-(4-methoxyphenyl)-1-phenylethan-1-one 31. A solution of n-BuLi (3.1
mL, 1.7 M in hexanes) was added dropwise to a –78 °C solution of hexamethyldisilazane (9 mL,
0.6 M in THF) and the mixture was stirred for 30 min at –78 °C. Then, a solution of 3013 (715
mg, 2.65 mmol) in THF (9.8 mL) was added slowly, followed by the rapid addition of TMSCl
(504 µL, 3.97 mmol). The mixture was stirred for 10 min at –78 °C, warmed to rt, and
concentrated under reduced pressure. The residue was dissolved in hexanes (25 mL), filtered
through Celite, and concentrated under reduced pressure. The residue was immediately dissolved
in toluene (1.2 mL) under an argon atmosphere and 4-bromoanisole (99 µL, 0.79 mmol),
Pd(OAc)2 (9 mg, 0.04 mmol), and Bu3SnF (736 mg, 2.38 mmol) were added. Next, a solution of
t-Bu3P (79 µL, 1.0 M in toluene) was added dropwise and the reaction mixture was heated to 85
°C. After 13.5 h. the reaction mixture was cooled to rt, diluted with EtOAc (16 mL), and
decanted with additional EtOAc (10 mL). The mixture was treated with saturated aqueous KF (5
mL) and stirred for 1 h at rt. Next, the reaction mixture was filtered through Celite and extracted
with EtOAc (3 × 5 mL). The organics were dried over Na2SO4, filtered, and concentrated under
reduced pressure. SiO2 flash chromatography (10:1 hexanes/EtOAc) afforded the title compound
31 as a colorless oil (163 mg, 78%). All spectral and characterization data matched the reported
data.29
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1221/acs.joc.xxxxxxx . 1H, 13C, and 19F NMR of all new compounds (PDF).
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*E-mail: dacolby@olemiss.edu
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Notes
The authors declare no competing financial interests.
Acknowledgements
These studies were funded by the University of Mississippi and the National Institute of
General Medical Sciences (P20GM104932). Its contents are solely the responsibility of the
authors and do not necessarily represent the official view of the National Institutes of Health
(NIH). The Mass Spectrometry and Proteomics Facility of the University of Notre Dame is
acknowledged for acquisition of high-resolution mass spectrometry data. The authors also thank
Joshua S. Sharp and Sandeep Misra for mass spectrometry support.
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