Synthesis of pentafluorinated β-hydroxy ketones

Article abstract of DOI:10.1021/jo3017583

The LHMDS-promoted in situ generation of difluoroenolates from readily available 1-aryl and 1-alkyl 2,2,4,4,4-pentafluorobutan-1,3-dione hydrates has been used to produce a series of pentafluorinated β-hydroxy ketones in up to 95% yield. The reaction proc

Full text of DOI:10.1021/jo3017583

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Note
Synthesis of Pentafluorinated beta-Hydroxy Ketones
Peng Zhang, and Christian Wolf
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Sep 2012
Downloaded from http://pubs.acs.org on September 23, 2012
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Synthesis of Pentafluorinated β-Hydroxy Ketones
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Peng Zhang and Christian Wolf*
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
cw27@georgetown.edu
Abstract:
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The LHMDS promoted inꢀsitu generation of difluoroenolates from readily available 1ꢀaryl and 1ꢀalkyl
2,2,4,4,4ꢀpentafluorobutanꢀ1,3ꢀdione hydrates has been used to produce a series of pentafluorinated βꢀ
hydroxy ketones in up to 95% yield. The reaction proceeds under mild conditions, tolerates a wide range
of functional groups and is complete within 10 minutes. Reduction towards the corresponding 1,3ꢀdiol
with DIBAL gives quantitative amounts and favors the formation of the synꢀisomer.
Although few naturally occurring organofluorine compounds are known, about 20% of all
pharmaceuticals contain at least one carbonꢀfluorine bond. In 2011, 30% of the 10 bestꢀselling drugs and
20% of newly approved entities contained fluorine.1 The steadily growing popularity of fluorinated
compounds stems from a variety of beneficial effects of the fluorine moiety on the physiochemical
properties and pharmacological profiles of drugs.2 Fluorine incorporation typically increases a
compound’s lipophilicity which improves partitioning into membranes and bioavailability.3 It also
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enhances oxidative and thermal stability and resistance to metabolic degradation due to the strength of the
CꢀF bond. The placement of more than one fluorine atom at the same site can have dramatic effects on
both structure and function of biologically active compounds. The high electronegativity of fluorine often
leads to increased dipole moments, conformational changes, carbonyl hydration and reduced pKa values
of adjacent functionalities.4 The difluoromethylene unit has been recognized as a unique electronic mimic
and bioisostere of an ether function because it places the two fluorine atoms in the same direction as the
lone electron pairs of the ether oxygen and is capable of serving as a weak hydrogen bond acceptor.
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The chemistry of trifluoromethyl ketones has received significant attention in recent years which is
mostly a consequence of the increasing pharmaceutical utility of organofluorines. Several strategies for
the difluoromethylation of aldehydes and ketones, for example with sulfurꢀderived fluoroalkylating
reagents, are known.5 In contrast, a practical synthetic method for the nucleophilic addition of
difluoroenolates to trifluoromethyl ketones,6 which would provide pentafluorinated βꢀhydroxy ketones,
has not been introduced to date. Uneyama and coworkers were able to produce difluoroenolates via
electroreductive defluorination of trifluoromethyl ketones and showed that the silyl enol ether obtained
from α,α,αꢀtrifluoroacetophenone, 1, reacts with another equivalent of 1 to produce 2,2,4,4,4ꢀ
pentafluoroꢀ3ꢀhydroxyꢀ1,3ꢀdiphenylbutanꢀ1ꢀone, 2, in 24% yield.7 In a similar twoꢀstep synthesis Ishihara
et al. prepared 2 with 47% overall yield.8 Generally, few examples of aldol type reactions with
intermediate difluoroenolates have been reported in the literature.9 Prager and Colby, however, have
demonstrated that the mild cleavage of hexafluoroacetone and its derivatives with excess of base, metal
salts and other additives affords fluorinated nucleophiles suitable for effective carbonꢀcarbon bond
formation.10,11 Encouraged by these findings we have developed a method for the fast and highꢀyielding
synthesis of a wide range of pentafluorinated βꢀhydroxy ketones that occurs via mild inꢀsitu formation of
α,αꢀdifluoroenolates (Scheme 1).
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Scheme 1. Synthetic strategies towards pentafluorinated βꢀhydroxy ketones.
As previously demonstrated by Colby, we observed that the hydrate of 1ꢀphenylꢀ2,2,4,4,4ꢀ
pentafluorobutanꢀ1,3ꢀdione, 3, which is easily prepared from diketone 4 by exhaustive fluorination with
Selectfluor, undergoes rapid CꢀC bond scission and concomitant difluoroenolate release when an excess
of a base is added.11 Initial screening of solvent and additives, including a wide range of amines,
organolithium reagents, Schwesinger base, and inorganic salts, showed that the pentafluoro βꢀhydroxy
ketone 2 can be obtained in 68% yield within 10 minutes when the reaction is carried out in the presence
o
of 2 equivalents of KHMDS in THF at 0 C. Because the enolate precursor 3 was fully consumed in this
reaction we decided to investigate the formation of byꢀproducts. Analysis of the reaction mixture revealed
two major byꢀproducts that apparently arise from competing protonation of the intermediate
difluoroenolate 5 towards α,αꢀdifluoroacetophenone, 6, and aldol reaction between 5 and 6 towards the
tetrafluorinated hydroxy ketone 7 (Scheme 2).
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Scheme 2. Formation of 2 and byproducts 6 and 7.
Fortunately, we observed that the formation of 6 and 7 can be reduced when KHMDS is replaced
with LHMDS. Using this base under otherwise identical conditions, the desired product 2 was isolated in
88% yield. We believe that compared to its potassium analogue the use of LHMDS generates a more
stable ionꢀpair with the intermediate difluoroenolate 5 and thus impedes protonation towards 6. Having
optimized the baseꢀpromoted difluoromethylation protocol by controlling the concentration of 6 which
competes with 1 for the reaction with the inꢀsitu generated nucleophile 5, we then continued with the
evaluation of the substrate scope (Table 1).
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Table 1. Transformation of Trifluoromethyl Ketones to Pentafluorinated βꢀHydroxy Ketones
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Entry Enolate Precursor
1
Ketone
Product
Yielda
88
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2
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85
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89
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O
CF3
MeS
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95
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83
95
O
OH
CF3
F
F
Cl
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93
63b
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O
OH
CF3
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F
F
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86
84
aIsolated yields. b2 equiv. of 30 and 2 equiv. of CeCl3 were used.
We were pleased to find that a wide range of pentafluorinated βꢀhydroxy ketones can be generated in
very good yields. The employment of enolate precursor 3, and trifluoromethyl ketones 8, 10 and 12 in our
protocol gave the corresponding products 9, 11 and 13 in 85ꢀ89% yield (entries 2ꢀ4). Similarly, the aldol
products 15, 17, 19, 21 and 23 were obtained from both electronꢀdeficient and electronꢀrich ketones 14,
16, 18, 20 and 22 in 88ꢀ95% yield (entries 5ꢀ9). The tolerance of several functional groups present in the
trifluoromethyl ketones used and the smooth reaction of 2ꢀtrifluoroacetyl thiophene, 24, towards 25 are
noteworthy (entry 10). Alternatively, other enolate precursor such as 26 and 28 can be used without
compromising the results (entries 12 and 13). When we attempted to use 1,1,1ꢀtrifluoroꢀ3ꢀphenylpropanꢀ
2ꢀone, 30, which is highly prone to enolization, we observed a dramatic decrease in yield due to the side
reaction discussed above (Scheme 2). A change in the addition sequence or addition of lithium salts did
not increase yields with this aliphatic trifluoromethyl ketone. Addition of cerium(III) chloride, however,
improved the yields and we were finally able to prepare 31 in 63% yield (entry 13). As expected, the use
of aliphatic enolate precursor 32 is not problematic and the reaction with ketones 1, 8 and 14 produced
pentafluorinated βꢀhydroxy ketones 33ꢀ35 in 84ꢀ93% yield (entries 14ꢀ16).
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The pentafluorinated βꢀhydroxy ketone 2 can be effectively reduced to 2,2,4,4,4ꢀpentafluoroꢀ1,3ꢀ
diphenylꢀ1,3ꢀbutanediol, 36. We first observed that heterogeneous hydrogenation with 10 mol%
palladium on carbon affords the 1,3ꢀdiol in quantitative yields as a 1:1 syn/antiꢀmixture.12 Following a
procedure previously developed by Kuroboshi and Ishihara,13 we were able to improve the
stereoselectivity using DIBAL and produced the two diastereomers in a 3.1:1 ratio in overall 98% yield
(Scheme 3).14 We were able to grow a single crystal of the minor isomer by slow evaporation of a solution
in chloroform. Crystallographic analysis proved that it was antiꢀ36 (see SI).
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Scheme 3. DIBAL reduction of 2.
In summary, we have developed a LHMDS promoted aldol reaction that utilizes readily available
difluoroenolate precursors for fast addition reactions with trifluoromethyl ketones under mild conditions.
The careful inꢀsitu generation of difluoroenolates provides superior results than previously reported
methods and provides practical access to a series of new pentafluoro βꢀhydroxy ketones. With the
exception of aliphatic substrates, the yields generally range from 83 to 95% and the reaction tolerates
several functional groups. The use of enolizable trifluoromethyl ketones is possible in the presence of
cerium chloride but yields drop significantly due to increased protonation of the intermediate
difluoroenolate and subsequent aldol reaction of the corresponding difluoromethyl ketone. The feasibility
of diastereoselective quantitative reduction of these unprecedented ketones with DIBAL favoring
formation of pentafluorinated synꢀ1,3ꢀdiols has also been demonstrated.
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Experimental Section
General Methods.
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All commercially available reagents and solvents were used without further purification. Anhydrous THF
was used as purchased and not dried any further. NMR spectra were obtained at 400 MHz (1H NMR) and
100 MHz (13C NMR) using CDCl3 as solvent. Chemical shifts are reported in ppm relative to TMS.
Reaction products were purified by column chromatography on silica gel (particle size 32ꢀ63 ꢁm).
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General Procedure for the Preparation of Pentafluoro β-Hydroxy Ketones.
To a solution of LiHMDS (0.8 mL 1.0 M in THF, 0.8 mmol) was added 1 mL of anhydrous THF under
nitrogen at 0 oC. Then, a solution of the enolate precursor (0.4 mmol) and the trifluoromethyl ketone (1.2
equivalents, 0.48 mmol) dissolved in 1.5 mL of THF was added dropwise, and the mixture was stirred at
room temperature for 10 minutes. After completion of the reaction, several drops of saturated ammonium
chloride solution were added. The solvents were removed and the crude residue was loaded directly onto
a silica gel column and purified by flash chromatography as described below.
Preparation of 1-Phenyl-2,2,4,4,4-pentafluorobutan-1,3-dione, 3.11
To a solution of diketone 4 (4.32 g, 20 mmol) in 40 mL of acetonitrile was added Selectfluor (15.576 g,
2.2 equivalents, 44 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred
overnight and then filtrated and washed with dichloromethane. The solvents were removed, and the
residue was dissolved in dichloromethane and extracted with brine. The combined organic layers were
concentrated in vacuum. Purification by column chromatography using EtOAc: hexanes=1:3 as mobile
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phase gave 1ꢀphenylꢀ2,2,4,4,4ꢀpentafluorobutanꢀ1,3ꢀdione, 3, (5.157 g, 19.1 mmol) in 96% yield. H
NMR (400 MHz, CDCl3) δ = 4.57 (s, 2H), 7.54 (dd, J = 7.9 Hz, 7.9 Hz, 2H), 7.72 (dd, J = 7.5 Hz, 7.5 Hz,
1H), 8.10 (d, J = 7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ =92.8 (m), 111.5 (t, JCꢀF = 268.6 Hz), 117.3
(q, JCꢀF = 288.4 Hz), 128.8, 130.5, 131.6, 135.6, 191.6 (t, JCꢀF = 29.1 Hz).
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Reduction Procedure.
A solution of 2 (99 mg, 0.3 mmol) in 2 mL of anhydrous THF was cooled to ꢀ78 oC. Then, DIBAL (1.0 M
in THF, 0.9 mL, 0.9 mmol) was added dropwise and the mixture was stirred at this temperature for 1
hour. After completion of the reaction, several drops of saturated ammonium chloride solution were added
and the mixture was allowed to come to room temperature. The solvents were removed, and the residue
was dissolved in dichloromethane and extracted with brine. The combined organic layers were
concentrated in vacuo. Column chromatography using dichloromethane: hexanes=3:2 as mobile phase
gave 74 mg (0.23 mmol) of synꢀ36 and 24 mg (0.08 mmol) of antiꢀ36 as colorless solids in 98% overall
yield.
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2,2,4,4,4-Pentafluoro-3-hydroxy-1,3-diphenylbutan-1-one, 2.7
Chromatographic purification (EtOAc:hexanes = 1:10) gave 123 mg (0.37 mmol, 93%) of a colorless oil.
1H NMR (400 MHz, CDCl3) δ = 4.84 (s, 1H), 7.35ꢀ7.45 (m, 5H), 7.60 (dd, J = 7.4 Hz, 7.4 Hz, 1H), 7.70ꢀ
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7.74 (m, 2H), 8.04 (d, J = 7.6 Hz, 2H). C NMR (100 MHz, CDCl3) δ = 79.0 (m), 113.9 (t, JCꢀF = 269.1
Hz), 123.3 (q, JCꢀF = 287.9 Hz), 127.0, 128.4, 128.7, 129.7, 130.1, 131.5, 132.3, 134.9, 190.8 (t, JCꢀF
=
30.2 Hz).
2,2,4,4,4-Pentafluoro-3-hydroxy-3-(4-tolyl)-1-phenylbutan-1-one, 9.
Chromatographic purification (DCM:hexanes = 1:4 to 1:2) gave 117 mg (0.34 mmol, 85%) of a colorless
oil. 1H NMR (400 MHz, CDCl3) δ = 2.33 (s, 3H), 4.77 (s, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.42 (dd, J = 8.1
Hz, 8.1 Hz, 2H), 7.57ꢀ7.92 (m, 3H), 7.92 (d, J = 7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 21.0, 78.5
(m), 113.8 (t, JCꢀF = 269.0 Hz), 123.4 (q, JCꢀF = 287.6 Hz), 126.8, 128.5, 128.6, 129.2, 130.3, 132.4, 134.9,
139.7, 190.8 (t, JCꢀF = 29.4Hz). Anal. Calcd. for C17H13F5O2: C, 59.31; H, 3.81. Found: C, 59.26; H, 3.77.
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2,2,4,4,4-Pentafluoro-3-hydroxy-3-(3-tolyl)-1-phenylbutan-1-one, 11.
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Chromatographic purification (DCM:hexanes = 1:4 to 2:3) gave 121 mg (0.35 mmol, 88%) of a colorless
oil. 1H NMR (400 MHz, CDCl3) δ = 2.32 (s, 3H), 4.78 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.26 (dd, J = 7.7
Hz, 7.7 Hz, 1H), 7.41 (ddd, J = 1.5 Hz, 7.6 Hz, 7.6 Hz, 2H), 7.48ꢀ7.54 (m, 2H), 7.69 (dddd, J = 1.2 Hz,
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1.2 Hz, 7.5 Hz, 7.5 Hz, 1H), 7.89 (dd, J = 1.2 Hz, 8.5 Hz, 2H). C NMR (100 MHz, CDCl3) δ = 21.5,
78.8 (m), 114.0 (t, JCꢀF = 269.1 Hz), 123.1 (q, JCꢀF = 287.7 Hz), 124.0, 127.6, 128.3, 128.7, 130.2, 130.5,
131.4, 132.4, 134.9, 138.2, 190.8 (t, JCꢀF = 29.3 Hz). Anal. Calcd. for C17H13F5O2: C, 59.31; H, 3.81.
Found: C, 59.14; H, 3.62.
2,2,4,4,4-Pentafluoro-3-hydroxy-3-(4-tert-butylphenyl)-1-phenylbutan-1-one, 13.
Chromatographic purification (DCM:hexanes = 1:4 to 1:1) gave 137 mg (0.36 mmol, 89%) of a white
o
1
solid, mp 68ꢀ69 C. H NMR (400 MHz, CDCl3) δ = 1.29 (s, 9H), 4.76 (s, 1H), 7.35ꢀ7.40 (m, 4H), 7.57
13
(dd, J = 7.5 Hz, 7.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 7.6 Hz, 2H). C NMR (100 MHz,
CDCl3) δ = 31.1, 34.5, 78.5 (m), 114.3 (t, JCꢀF = 268.8 Hz), 123.4 (q, JCꢀF = 287.7 Hz), 125.4, 126.7, 128.3,
128.6, 130.1, 132.5, 134.7, 152.7, 190.7 (t, JCꢀF = 29.1 Hz). Anal. Calcd. for C20H19F5O2: C, 62.17; H,
4.96. Found: C, 61.78; H, 5.04.
2,2,4,4,4-Pentafluoro-3-hydroxy-3-(4-chlorophenyl)-1-phenylbutan-1-one, 15.
Chromatographic purification (DCM:hexanes = 1:5 to 1:1) gave 137 mg (0.38 mmol, 94%) of a colorless
oil. 1H NMR (400 MHz, CDCl3) δ = 5.01 (s, 1H), 7.36 (ddd, J = 2.1 Hz, 2.1 Hz, 8.9 Hz, 2H), 7.45 (dd, J
= 7.8 Hz, 7.8 Hz, 2H), 7.62ꢀ7.69 (m, 3H), 7.94 (dd, J = 1.2 Hz, 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3)
δ = 78.6 (m), 113.5 (t, JCꢀF = 268.2 Hz), 123.1 (q, JCꢀF = 289.3 Hz), 128.6, 128.8, 129.5, 130.0, 132.2,
132.0, 135.2, 136.1, 189.9 (t, JCꢀF = 29.4 Hz). Anal. Calcd. for C16H10ClF5O2: C, 52.69; H, 2.76. Found: C,
52.43; H, 2.46.
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Chromatographic purification (DCM:hexanes = 2:3) gave 126 mg (0.35 mmol, 88%) of a colorless oil. 1H
NMR (400 MHz, CDCl3) δ = 3.78 (s, 3H), 4.82 (s, 1H), 6.89 (d, J = 9.1 Hz, 2H), 7.42 (dd, J = 8.2 Hz, 8.2
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Hz, 2H), 7.58ꢀ7.65 (m, 3H), 7.90 (d, J = 7.5 Hz, 2H). C NMR (100 MHz, CDCl3) δ = 55.2, 78.5 (m),
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113.8, 113.9 (t, JCꢀF = 268.8 Hz), 123.2, 123.4 (q, JCꢀF = 287.6 Hz), 128.4, 128.6, 130.2, 132.4, 134.9,
160.5, 190.9 (t, JCꢀF = 29.2 Hz). Anal. Calcd. for C17H13F5O3: C, 56.67; H, 3.64. Found: C, 56.72; H, 3.56.
2,2,4,4,4-Pentafluoro-3-hydroxy-3-(4-methylthiophenyl)-1-phenylbutan-1-one, 19.
Chromatographic purification (DCM:hexanes = 1:3 to 1:1) gave 140 mg (0.38 mmol, 93%) of a colorless
oil. 1H NMR (400 MHz, CDCl3) δ = 2.45 (s, 3H), 4.87 (s, 1H), 7.23 (d, J = 8.9 Hz, 2H), 7.43 (dd, J = 8.3
Hz, 8.3 Hz, 2H), 7.58ꢀ7.64 (m, 3H), 7.91 (dd, J = 1.1 Hz, 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ =
15.0, 78.6 (m), 113.8 (t, JCꢀF = 269.5 Hz), 123.3 (q, JCꢀF = 287.6 Hz), 125.7, 127.4, 127.8, 128.7, 130.2,
132.3, 135.0, 140.0, 190.8 (t, JCꢀF = 29.4 Hz). Anal. Calcd. for C17H13F5O2S: C, 54.25; H, 3.48. Found: C,
54.08; H, 3.27.
2,2,4,4,4-Pentafluoro-3-hydroxy-3-(4-cyanophenyl)-1-phenylbutan-1-one, 21.
Chromatographic purification (EtOAc:hexanes = 1:8) gave 131 mg (92%, 0.37 mmol) of a white solid,
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mp 101ꢀ102 C. H NMR (400 MHz, CDCl3) δ = 5.30 (s, 1H), 7.50 (dd, J = 7.6 Hz, 7.6 Hz, 2H), 7.67ꢀ
7.73 (m, 3H), 7.90 (d, J = 8.4 Hz, 2H), 7.97 (dd, J = 1.1 Hz, 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
= 78.7 (m), 113.4 (t, JCꢀF = 268.2 Hz), 113.7, 118.0, 122.9 (q, JCꢀF = 291.3 Hz), 128.0, 128.9, 130.3, 131.8,
132.0, 135.4, 136.2, 190.2 (t, JCꢀF = 28.7 Hz). Anal. Calcd. for C17H10F5NO2: C, 57.47; H, 2.84; N, 3.94.
Found: C, 57.47; H, 2.88; N, 3.92 .
2,2,4,4,4-Pentafluoro-3-hydroxy-3-(4-ethoxycarbonylphenyl)-1-phenylbutan-1-one, 23.
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Chromatographic purification (DCM:hexanes = 1:1 to 2:1) gave 152 mg (95%, 0.38mmol) of a colorless
oil. 1H NMR (400 MHz, CDCl3) δ = 1.38 (t, J = 7.1 Hz, 3H), 4.37 (q, J = 7.1 Hz, 2H), 5.25 (s, 1H), 7.44
(dddd, J = 1.8 Hz, 1.8 Hz, 7.6 Hz, 7.6 Hz, 2H), 7.62 (dddd, J = 1.2 Hz, 1.2 Hz, 7.5 Hz, 7.5 Hz, 1H), 7.83
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(d, J = 8.4 Hz, 2H), 7.94 (dd, J = 1.0 Hz, 8.5 Hz, 2H), 8.06 (ddd, J = 1.9 Hz, 1.9 Hz, 8.8 Hz, 2H). C
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NMR (100 MHz, CDCl3) δ = 14.2, 61.3, 78.8 (m), 113.5 (t, JCꢀF = 269.9 Hz), 123.4 (q, JCꢀF = 287.5 Hz),
127.3, 128.7, 129.4, 130.2, 131.6, 132.1, 135.1, 136.3, 166.0, 190.2 (t, JCꢀF = 29.4 Hz). Anal. Calcd. for
C19H15F5O4: C, 56.72; H, 3.76. Found: C, 56.65; H, 3.49.
2,2,4,4,4-Pentafluoro-3-hydroxy-3-(2-thienyl)-1-phenylbutan-1-one, 25.
Chromatographic purification (DCM:hexanes = 1:4 to 1:2) gave 117 mg (0.33 mmol, 83%) of a light
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yellow solid, mp 59ꢀ60 C. H NMR (400 MHz, CDCl3) δ = 5.34 (s, 1H), 7.03 (dd, J = 3.8 Hz, 5.1 Hz,
1H), 7.33 (m, 1H), 7.39 (dd, J = 1.1 Hz, 5.1 Hz, 1H), 7.47 (ddd, J = 1.2 Hz, 7.9 Hz, 7.9 Hz, 2H), 7.65
(ddd, J = 1.2 Hz, 7.5 Hz, 7.5 Hz, 1H), 7.99 (dd, J = 1.2 Hz, 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ =
78.5 (m), 112.7 (t, JCꢀF = 268.0 Hz), 123.7 (q, JCꢀF = 287.5 Hz), 127.4, 127.7, 128.8, 130.0, 132.0, 134.8,
135.2, 191.3 (t, JCꢀF = 29.3 Hz). Anal. Calcd. for C14H9F5O2S: C, 50.00; H, 2.70. Found: C, 50.05; H,
2.52.
2,2,4,4,4-Pentafluoro-3-hydroxy-3-phenyl-1-(4-chlorophenyl)butan-1-one, 27.
Chromatographic purification (EtOAc:hexanes = 1:20 to 1:10) gave 138 mg (0.38 mmol, 95%) of a
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colorless oil. H NMR (400 MHz, CDCl3) δ = 4.65 (s, 1H), 7.35ꢀ7.40 (m, 5H), 7.70 (d, J = 8.8 Hz, 2H),
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7.82 (d, J = 8.8 Hz, 2H). C NMR (100 MHz, CDCl3) δ = 78.6 (m), 114.2 (t, JCꢀF = 268.8 Hz), 123.3 (q,
JCꢀF = 287.6 Hz), 126.9, 128.5, 129.1, 129.9, 130.6, 131.2, 131.6, 141.8, 189.1 (t, JCꢀF = 29.4 Hz). Anal.
Calcd. for C16H10ClF5O2: C, 52.69; H, 2.76. Found: C, 52.53; H, 2.48.
2,2,4,4,4-Pentafluoro-3-hydroxy-3-phenyl-1-(2-naphthyl)butan-1-one, 29.
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Chromatographic purification (DCM:hexanes = 1:3 to 1:1) gave 142 mg (0.37 mmol, 93%) of a light
yellow solid, mp 89ꢀ90 oC. 1H NMR (400 MHz, CDCl3) δ = 4.93 (s, 1H), 7.35ꢀ7.39 (m, 3H), 7.53 (ddd, J
= 1.2 Hz, 6.9 Hz, 6.9 Hz, 1H), 7.61 (ddd, J = 1.2 Hz, 6.9 Hz, 6.9 Hz, 1H), 7.75ꢀ7.89 (m, 6H), 8.47 (s, 1H).
13C NMR (100 MHz, CDCl3) δ = 79.0 (m), 114.2 (t, JCꢀF = 269.2 Hz), 123.3 (q, JCꢀF = 287.4 Hz), 124.9,
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127.0, 127.2, 127.7, 128.5, 128.6, 129.4, 129.7, 129.9, 130.2, 131.7, 132.0, 133.4, 136.2, 190.5 (t, JCꢀF
=
29.0 Hz). Anal. Calcd. for C20H13F5O2: C, 63.16; H, 3.45. Found: C, 63.15; H, 3.26.
2,2-Difluoro-3-hydroxy-1,4-diphenyl-3-trifluoromethyl-butan-1-one, 31.
Procedure was the same as described above but 2 equivalents of CeCl3 were added prior to LHMDS and 2
equivalents of the trifluoromethyl ketone were used. Chromatographic purification (EtOAc:hexanes =
1:20) gave 86 mg (0.25 mmol, 63%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 3.31 (d, J = 14.5
Hz, 1H), 3.48 (d, J = 14.5 Hz, 1H), 4.33 (s, 1H), 7.28ꢀ7.34 (m, 5H), 7.45ꢀ7.52 (m, 2H), 7.65 (dddd, J =
1.2 Hz, 1.2 Hz, 7.5 Hz, 7.5Hz, 1H), 8.02 (d, J = 7.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 35.5, 78.3
(m), 114.0 (t, JCꢀF = 264.4 Hz), 124.3 (q, JCꢀF = 288.5 Hz), 127.7, 128.5, 128.6, 130.4, 131.3, 132.2, 132.5,
134.8, 191.1 (t, JCꢀF = 28.2 Hz). Anal. Calcd. for C17H13F5O2: C, 59.31; H, 3.81. Found: C, 59.11; H, 3.94.
1,1,1-3,3-Pentafluoro-2-hydroxy-2,6-diphenylhexan-4-one, 33.
Chromatographic purification (EtOAc:hexanes = 1:10) gave 134 mg (0.37 mmol, 93%) of a light yellow
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oil. H NMR (400 MHz, CDCl3) δ = 2.35ꢀ2.85 (m, 3H), 2.95 (m, 1H), 4.33 (s, 1H), 7.04 (d, J = 7.6 Hz,
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2H), 7.16ꢀ7.28 (m, 3H), 7.38ꢀ7.47 (m, 3H), 7.68 (d, J = 7.3 Hz, 2H). C NMR (100 MHz, CDCl3) δ =
28.2, 40.0, 77.8 (m), 111.9 (t, JCꢀF = 267.4 Hz), 123.3 (q, JCꢀF = 287.8 Hz), 126.5, 126.7, 128.2, 128.5,
128.6, 130.0, 130.3, 139.5, 200.3 (t, JCꢀF = 29.1 Hz). Anal. Calcd. for C18H15F5O2: C, 60.34; H, 4.22.
Found: C, 60.12; H, 4.13.
1,1,1-3,3-Pentafluoro-2-hydroxy-2-(4-tolyl)-6-phenylhexan-4-one, 34.
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yellow oil. H NMR (400 MHz, CDCl3) δ = 2.33 (s, 3H), 2.63ꢀ2.80 (m, 3H), 2.92 (m, 1H), 4.29 (s, 1H),
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7.02 (d, J = 7.2 Hz, 2H), 7.15ꢀ7.26 (m, 5H), 7.54 (d, J = 8.0 Hz, 2H). C NMR (100 MHz, CDCl3) δ =
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21.2, 28.2, 40.0, 77.8 (m), 112.8 (t, JCꢀF = 267.2 Hz), 123.3 (q, JCꢀF = 287.9 Hz), 126.4, 126.8, 127.5,
128.2, 128.5, 129.4, 139.6, 140.1, 200.2 (t, JCꢀF = 28.7 Hz). Anal. Calcd. for C19H17F5O2: C, 61.29; H,
4.60. Found: C, 61.22; H, 4.79.
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1,1,1-3,3-Pentafluoro-2-hydroxy-2-(4-chlorophenyl)-6-phenylhexan-4-one, 35.
Chromatographic purification (EtOAc:hexanes = 6.7%) gave 132 mg (0.34 mmol, 84%) of a colorless oil.
1H NMR (400 MHz, CDCl3) δ = 2.75ꢀ2.87 (m, 3H), 2.99 (m, 1H), 4.53 (s, 1H), 7.05 (d, J = 6.6 Hz, 2H),
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7.18ꢀ7.30 (m, 3H), 7.34ꢀ7.39 (m, 2H), 7.60 (d, J = 7.8 Hz, 2H). C NMR (100 MHz, CDCl3) δ = 28.2,
40.0, 77.5 (m), 112.0 (t, JCꢀF = 267.2 Hz), 123.1 (q, JCꢀF = 289.7 Hz), 123.1, 126.5, 128.2, 128.5, 128.6,
128.7, 128.8, 136.4, 139.3, 200.5 (t, JCꢀF = 30.4 Hz). Anal. Calcd. for C18H14ClF5O2: C, 55.05; H, 3.59.
Found: C, 55.04; H, 3.62.
syn-2,2,4,4,4-Pentafluoro-1,3-diphenyl-1,3-butanediol, syn-36.
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Mp 83ꢀ84 C. H NMR (400 MHz, CDCl3) δ = 2.99 (d, J = 2.3 Hz, 1H), 5.26 (ddd, J = 3.3 Hz, 3.3 Hz,
22.0 Hz, 1H), 5.45 (s, 1H), 7.30ꢀ7.40 (m, 8H), 7.69ꢀ7.74 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 75.5
(m), 79.6 (m), 115.7 (dd, JCꢀF = 254.0 Hz, 261.2 Hz), 124.2 (q, JCꢀF = 288.2 Hz), 127.3, 128.0, 128.2,
129.4, 129.5, 131.7, 134.9. Anal. Calcd. for C16H13F5O2: C, 57.84; H, 3.94. Found: C, 58.06; H, 3.98.
anti-2,2,4,4,4-Pentafluoro-1,3-diphenyl-1,3-butanediol, anti-36.
Mp 100ꢀ101 oC. 1H NMR (400 MHz, CDCl3) δ = 2.54 (d, J = 2.4 Hz, 1H), 4.71 (dd, J = 2.7 Hz, 22.2 Hz,
1H), 4.82 (s, 1H), 7.31ꢀ7.38 (m, 5H), 7.48ꢀ7.54 (m, 3H), 7.82ꢀ7.89 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ = 74.5 (m), 79.0 (m), 117.6 (dd, JCꢀF = 256.5 Hz, 267.1 Hz), 123.2 (q, JCꢀF = 286.3 Hz), 126.8, 128.1,
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128.3, 128.7, 129.4, 129.8, 133.2, 134.3. Anal. Calcd. for C16H13F5O2: C, 57.84; H, 3.94. Found: C, 57.75;
H, 4.00.
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Acknowledgement. Funding from the National Science Foundation (CHEꢀ0848301) is gratefully
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acknowledged.
Supporting Information Available Crystallography, NMR and Xꢀray spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
1 Ritter, K. S. C&EN, 2012, 90(9), 10ꢀ17.
2 Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27ꢀ33.
3 Muller, N.; J. Pharm. Sci. 1986, 75, 987ꢀ991.
4 Vuluga, D.; Legros, J.; Crousse, B.; Slawin, A. M. Z.; Laurence, C.; Nicolet, P.; BonnetꢀDelpon, D. J.
Org. Chem. 2011, 76, 1126ꢀ1133.
5 For example: (a) Prakash, G. K. S.; Hu, A. J. Acc. Chem. Res. 2007, 40, 921ꢀ930. (b) Hagiwara, T.;
Fuchikami, T. Synlett 1995, 717ꢀ718. (c) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau,
R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572ꢀ1581. (d) Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah,
G. A. Angew. Chem., Int. Ed. 2003, 42, 5216ꢀ5219. (e) Prakash, G. K.S.; Wang, Y.; Hu, J.; Olah, G. A. J.
Fluorine Chem. 2005, 126, 1361ꢀ1367. (f) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465ꢀ
7478. (g) Kashikura, W.; Mori, K.; Akiyama, T. Org. Lett. 2011, 13, 1860ꢀ1863.
6 For the synthesis of trifluoromethyl ketones, see Reeves, J. T.; Song, J. J.; Tan, Z.; Lee, H.; Yee, N. K.;
Senanayake, C. H. J. Org. Chem. 2008, 73, 9476ꢀ9478 and references therein.
7 Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, T. J. Org. Chem. 1999, 64, 6717ꢀ6723.
8 Yamana, M.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1983, 24, 507ꢀ510.
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9 Howarth, J. A.; Owton, W. M.; Percy, J. M. J. Chem. Soc., Chem. Commun. 1995, 757ꢀ758.
10 Prager, J. H.; Ogden, P. H. J. Org. Chem. 1968, 33, 2100ꢀ2102.
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11 (a) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133, 5802ꢀ5805. (b) Han, C.; Kim, E.
H.; Colby, D. A. Synlett 2012, 1559ꢀ1563.
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12 This reaction was performed using the palladium catalyst (30 wt% Pd/C, 10 mol%) under hydrogen
atmosphere (10 bar) in ethanol at room temperature overnight.
13 Kuroboshi, M.; Ishihara, T.; Bull. Chem. Soc. Jpn. 1990, 63, 1185ꢀ1190.
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14 The same dr was obtained at ꢀ78 C. Addition of ZnCl2 and TMEDA to the DIBAL reduction
procedure proved detrimental and decreased both yield and stereoselectivity.
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