Synthesis of α-halo-α,α-difluoromethyl ketones by a trifluoroacetate release/halogenation protocol

Article abstract of DOI:10.1021/jo2017179

Three series of α-halo-α,α-difluoromethyl ketones are prepared from highly α-fluorinated gem-diols by exploiting the facile release of trifluoroacetate, followed by immediate trapping of the liberated α,α-difluoroenolate with an electrophilic chlorine, br

Full text of DOI:10.1021/jo2017179

Note
pubs.acs.org/joc
Synthesis of α-Halo-α,α-difluoromethyl Ketones by a Trifluoroacetate
Release/Halogenation Protocol
Jinu P. John† and David A. Colby*,†,‡
†Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
‡Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
S
* Supporting Information
ABSTRACT: Three series of α-halo-α,α-difluoromethyl ketones
are prepared from highly α-fluorinated gem-diols by exploiting the
facile release of trifluoroacetate, followed by immediate trapping of
the liberated α,α-difluoroenolate with an electrophilic chlorine,
bromine, or iodine source. The products are typically isolated in
good yields, even in the case of sensitive, α-iodo-α,α-
difluoromethyl ketones. Also, we demonstrate that an α-iodo-
α,α-difluoromethyl ketone will participate in a copper-promoted
reaction to forge a new carbon−carbon bond.
luorinated organic compounds have attracted considerable
attention from the pharmaceutical, chemical, and agro-
does not require α,α-difluoroenoxysilanes, their precursors, or
α-halo-α,α-difluoroacetates.
F
chemical industries.1,2 Although multiple synthetic methods are
available to introduce fluorine or a trifluoromethyl group, fewer
methods are available to install a difluoromethylene group.3−7
Typically, α-halo-α,α-difluoroacetates are used as building
blocks to prepare compounds with difluoromethylene
groups.8−11 Unfortunately, there are very few synthetic
methods that can be used to assemble α-halo-α,α-difluor-
oacetates or other α-halo-α,α-difluoro centers adjacent to
carbonyl groups, especially α-halo-α,α-difluoromethyl ke-
tones.8−15 Existing synthetic strategies to assemble α-halo-
α,α-difluoromethyl ketones rely heavily on halogenating α,α-
difluoroenoxysilanes13,14 or adding Grignard reagents into α-
bromo-α,α-difluoroacetates or α-chloro-α,α-difluoroacetates
(Figure 1).8,9 Typically, α,α-difluoroenoxysilanes arise from
The strategy to release trifluoroacetate is based on a report in
1968 that hexafluoroacetone hydrate fragments to eliminate
trifluoroacetate.16 We have recently demonstrated that this
fragmentation can be used to generate α,α-difluoroenolates
from highly α-fluorinated gem-diols under very mild conditions
(i.e., LiBr/Et3N) and subsequently used in aldol reactions.17
The major benefits of using this approach are that it is mild,
versatile, and typically finished after 3 min at room temperature.
The release of trifluoroacetate is rarely explored in synthesis,
but other difficult transformations can be accomplished.18 We
now aim to extend this method and trap the difluoroenolate
with electrophilic halogenation reagents (Figure 2). We
Figure 2. Trifluoroacetate release/halogenation strategy.
hypothesize that this strategy will be compatible with common
halogenation reagents and allow isolation of these sensitive,
highly halogenated products. Herein, we describe a versatile,
high-yielding protocol that can be used to assemble α-halo-α,α-
difluoromethyl ketones that is based on the novel halogenation
of α,α-difluoroenolates generated by the facile release of
trifluoroacetate. Reaction conditions for chlorination, bromina-
Figure 1. Three common methods to prepare α-halo-α,α-difluor-
omethyl ketones.
the silylation of a metalloenolate formed after carbon−halogen
fragmentation on a α-halo-α,α-difluoromethyl group or on a
trifluoromethyl group adjacent to a carbonyl group. Our
synthetic plan is an alternative method to assemble α-halo-α,α-
difluoromethyl ketones by halogenation of the α,α-difluor-
oenolate generated by the facile release of trifluoroacetate and
Received: August 16, 2011
Published: October 13, 2011
© 2011 American Chemical Society
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tion, and iodination are described, and the trihalogenated
products are isolated in good yields. Also, we demonstrate that
an α-iodo-α,α-difluoromethyl ketone, which is a highly sensitive
organic compound, will participate in a copper-promoted
reaction to forge a new carbon−carbon bond.
did not provide a high conversion to the α,α-difluoro-α-
iodomethyl ketone as expected. Instead, the additional
formation of the α,α-difluoromethyl ketone 9 along with the
self-aldol condensation product 10 was observed (eq 1). The
We have previously reported an efficient, two-step synthesis
of highly α-fluorinated gem-diols from methyl ketones.17 This
method was based on the fluorination work of Ley and co-
workers.19 Using the α-fluorinated gem-diols, we discovered
that trifluoroacetate release provided the desired brominated
product after the starting material was treated with LiBr, Et3N,
and Br2. Even though the reagent bromine served to brominate
the difluoroenolate generated in situ, a significant excess of base
(i.e., Et3N) was needed to execute the reaction, likely because
of the presence of acidic impurities in bromine. Therefore, we
surveyed other electrophilic sources of bromine as part of our
optimization efforts but found that the common brominating
reagent, NBS, did not provide a brominated product after
trifluoroacetate release. Ultimately, we identified the protocol of
Shreeve using LiBr/Selectfluor to be an ideal source of
electrophilic bromine.20 Using gem-diols 1−4, the combination
of LiBr/Selectfluor/Et3N routinely provided high yields of the
respective α-bromo-α,α-difluoroketones 5−8 (Table 1).
formation of product 10 demonstrates that the protonation of
the difluoroenolate to 9 and subsequent reaction by additional
difluoroenolate will commence if an appropriate electrophile is
not present. Also, LiI/I2/Et3N gave similar results. However, by
substituting LiBr for LiI and using I2 and Et3N, the gem-diols
1−3 and 11−13 provided the α,α-difluoro-α-iodomethyl
ketones 14−19 in good yields (Table 2). The iodinated
Table 2. Strategy for α,α-Difluoro-α-iodo-methyl Ketones
Table 1. Strategy for α-Bromo-α,α-difluoromethyl Ketones
a
b
Isolated yields. Products are not stable to storage. Synthesized from
11 (see eq 2).
products were not stable to storage, as expected,23 but would
readily participate in subsequent coupling reactions (see
below). During these investigations, additional stability data
for highly α-fluorinated gem-diols was gathered, as the α,β-
unsaturated substrate 11 was reduced in high yield to the
saturated alkyl derivative 12 (eq 2). Although trace amounts of
the ethanol-derived hemiacetal were formed, dilute acid
provided the gem-diol 12 (for subsequent iodination to 18).
a
Isolated yields.
Bromination on the aromatic rings in substrates 1−4 was not
observed under these conditions. Indeed, the substrates have
very limited exposure to the halogen source because
trifluoroacetate release is complete after 30 min at room
temperature. Also, evidence of the exclusive release of
trifluoroacetate from these substrates was obtained, as
trifluoroacetate was observed in the crude reaction mixture by
19F NMR (data not shown).
(2)
For the preparation of α-chloro-α,α-difluoromethyl ketones,
chlorine gas was not investigated because of its hazardous
nature. A survey of alternative reagents to promote the
trifluoroacetate release/chlorination was conducted, and finally,
the combination of LiCl/NCS/Et3N was found to be optimal
(Table 3). This strategy minimized the formation of both the
α,α-difluoromethyl ketone and the self-aldol condensation
Amides with an α,α-difluoro-α-iodomethyl group adjacent to
the carbonyl group are synthetically useful because of their
propensity to participate in metal-mediated reactions.21,22 For
example, in 2010, copper-mediated cross-coupling with
difluoroiodoacetamides was demonstrated by Hu and co-
workers.21 When we attempted trifluoroacetate release/
iodination with 1, the combination of LiI/Selectfluor/Et3N
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be formed under mild reaction conditions with high yields
using a trifluoroacetate release/halogenation protocol. These
data correlate well with our previous findings that trifluor-
oacetate release is a quick, powerful, yet mild reaction to
generate reactive intermediates17 and to synthesize sensitive
compounds.17,18 Also, we have demonstrated that an α-iodo-
α,α-difluoromethyl ketone will participate in a copper-
promoted reaction to forge a new carbon−carbon bond.
Additional studies to elucidate the scope of trifluoroacetate
release are underway and will be reported in due course.
Table 3. Strategy for α-Chloro-α,α-difluoromethyl Ketones
EXPERIMENTAL SECTION
■
Representative Procedure for the Synthesis of α-Bromo-α,α-
difluoromethyl Ketones. To a solution of 2,2,4,4,4-pentafluoro-3,3-
dihydroxy-1-(naphthalen-2-yl)-butan-1-one 117 (30 mg, 0.094 mmol)
in THF (940 μL) was added LiBr (48 mg, 0.56 mmol) followed by
Selectfluor (67 mg, 0.19 mmol). The reaction mixture was stirred for 1
min, and then Et3N (25 μL, 0.19 mmol) was added. After stirring for
30 min at rt, the reaction mixture was quenched with saturated
aqueous NH4Cl (1 mL). The mixture was extracted with EtOAc (1
mL × 2), and the organics were dried over Na2SO4 and concentrated
under reduced pressure. SiO2 flash chromatography (5% Et2O in
hexanes) afforded the 2-bromo-2,2-difluoro-1-(naphthalen-2-yl)-
ethanone 5 as a colorless oil (23 mg) in 87% yield.
a
Isolated yields.
product as previously observed during the iodination studies
(see eq 1). The α-chloro-α,α-difluoromethyl ketones 20−23
were isolated in good yields using this process. However, the
incorporation of two additional chlorines at the other α-
position of the carbonyl group was observed with the alkyl
substrate 12. Clearly, these two protons in 12 are highly acidic;
therefore, enolate formation and subsequent chlorination are
also favorable under these reaction conditions. On the other
hand, overiodination was not prevalent when 12 was subjected
similar conditions (see Table 2), so perhaps other factors, such
as sterics or the nature of the electrophile, may contribute.
Indeed, adding a large excess of I2 along with LiBr and Et3N to
substrate 12 did not promote the formation products from
overiodination (analogous to overchlorination in 23); instead,
benzylic iodination was observed.
2-Bromo-2,2-difluoro-1-(naphthalen-2-yl)ethanone 5. See
representative reaction procedure: 1H NMR (500 MHz, CDCl3) δ
8.74 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.96
(d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.69 (ddd, J = 8.2, 6.9,
1.2 Hz, 1H), 7.61 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 181.4 (t, JCF = 25.6 Hz, 1C), 136.3, 133.5, 132.1,
130.2, 129.9, 128.9, 127.9, 127.3, 126.3, 124.9, 113.7 (t, JCF = 318 Hz,
1C); 19F NMR (282 MHz, CDCl3) δ −58.2 (s, 2F); IR (film) νmax
1705.3, 1626.7, 1152.6, 1119.3 cm−1; HRMS (EI/CI) m/z calcd for
C12H7BrF2O (M)+ 283.9648, found 283.9651.
1-(Benzo[1,3]dioxol-5-yl)-2-bromo-2,2-difluoroethanone 6.
See representative reaction procedure. 1-(Benzo[1,3]dioxol-6-yl)-
2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 217 (10 mg, 0.03
mmol), LiBr (16 mg, 0.19 mmol), Selectfluor (22 mg, 0.063 mmol),
and Et3N (9 μL, 0.06 mmol) were used. SiO2 flash chromatography
(5% Et2O in hexanes) provided the title compound as a colorless oil
(6.4 mg) in 75% yield: 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.3
Hz, 1H), 7.57 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.11 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 179.7 (t, JCF = 25.5 Hz, 1C), 153.6, 148.4,
128.0, 123.3, 113.6 (t, JCF = 319 Hz, 1C), 110.0, 108.4, 102.4; 19F
NMR (282 MHz, CDCl3) δ −57.8 (s, 2F); IR (film) νmax 2924.0,
1678.7, 1455.3, 1266.4, 1070.6 cm−1; HRMS (EI/CI) m/z calcd for
C9H5BrF2O3 (M)+ 277.9390, found 277.9393.
With efficient access to α-halo-α,α-difluoromethyl ketones,
we next sought to explore new synthetic roles for these
compounds. On the basis of previous literature precedent with
α,α-difluoro-α-iodoacetamides21,22 and α-bromo-α,α-difluoroa-
cetates,24 we examined copper-promoted reactions with α-iodo-
α,α-difluoromethyl ketone 14 (Scheme 1). To our knowledge,
Scheme 1. Copper-Mediated Reaction
1-(Benzothiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydrox-
ybutan-1-one 3. To a −78 °C solution of hexamethyldisilazane
(165 mg, 1.01 mmol) in THF (1.5 mL) was added a solution of n-
BuLi (400 μL, 2.5 M in hexanes). The mixture was stirred for 30 min
at −78 °C, and then a solution of 1-(benzothiophen-3-yl)ethanone
(150 mg, 0.85 mmol) in THF (1.5 mL) was added dropwise. After an
additional 1 h at −78 °C, 2,2,2-trifluoroethyl 2,2,2-trifluoroacetate
(250 mg, 1.3 mmol) was added dropwise, and the mixture was stirred
for 30 min at the same temperature. Next, the reaction mixture was
quenched at −78 °C with 0.1 M H2SO4 (3 mL) and allowed to warm
to rt. The mixture was extracted with CH2Cl2 (3 mL × 2). The
combined organics were dried over Na2SO4 and concentrated under
reduced pressure to provide the crude product (230 mg). The crude
product was dissolved in CH3CN (6 mL), treated with Selectfluor
(750 mg, 2.1 mmol), and stirred at rt for 24 h. The reaction mixture
was diluted with EtOAc (6 mL), filtered through a pad of Celite, and
concentrated under reduced pressure. The product was dissolved in
CH2Cl2 (10 mL), washed with H2O (5 mL × 2) and brine (5 mL),
and then concentrated under reduced pressure to provide the 1-
(benzothiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one
3 as a colorless solid (250 mg) in 90% yield: mp 72−74 °C; 1H NMR
(500 MHz, CDCl3) δ 8.90 (t, J = 1.6 Hz, 1H), 8.68 (d, J = 8.2 Hz,
such reactions with copper have not been applied to α-halo-
α,α-difluoromethyl ketones, and only reactions initiated by UV-
irradiation and Pd(Ph3)4 have been described.23,25,26 Upon
treatment of α-iodo-α,α-difluoromethyl ketone 14 and olefin
24 with Cu in DMSO followed by heating, the difluoroketone
25 was isolated as the major isomer in a 6:1 mixture with the
terminal olefin isomer. Although a modest yield of 25 was
obtained (i.e., 50%), this yield correlates well with previous
work with acetamides21 and avoids the isolation of an iodinated
product unlike prior work.23,25,26 Indeed, additional synthetic
strategies for difluoroketones are quite valuable because of the
diverse biological activities of these fluorinated compounds.27
In conclusion, we have successfully demonstrated that
synthetically valuable α-halo-α,α-difluoromethyl ketones can
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1H), 7.94 (d, J = 8.1 Hz, 1H), 7.58 (m, 1H), 7.53−7.49 (m, 1H), 4.74
(br s, 2H); 13C NMR (125 MHz, CDCl3) δ 184.9 (t, JCF = 28.0 Hz,
1C), 144.8 (t, JCF = 10.1 Hz, 1C), 138.7, 136.7, 128.4, 126.8, 126.3,
125.0, 122.5, 120.9 (q, JCF = 287 Hz, 1C), 111.0 (t, JCF = 269 Hz, 1C),
92.8 (qt, J = 27.8, 5.5 Hz, 1C); 19F NMR (282 MHz, CDCl3) δ −81.8
(t, J = 11.0 Hz, 3F), −112.6 (q, J = 10.9 Hz, 2F); IR (film) νmax
3368.3, 1662.9, 1488.3, 1461.0, 1424.5, 1204.7, 1067.2 cm−1; HRMS
(EI/CI) m/z calcd for C12H7F5O3S (M − H2O)+ 307.9931, found
307.9936.
HRMS (EI/CI) m/z calcd for C9H5F2IO3 (M)+ 325.9252, found
325.9259.
1-(Benzothiophen-3-yl)-2,2-difluoro-2-iodoethanone 16.
See representative reaction procedure. 1-(Benzothiophen-3-yl)-
2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 3 (10 mg, 0.03
mmol), LiBr (16 mg, 0.19 mmol), I2 (16 mg, 0.063 mmol), and
Et3N (9 μL, 0.06 mmol) were used. SiO2 flash chromatography (5%
Et2O in hexanes) provided the title compound as a pale yellow oil (8.1
mg) in 79% yield: 1H NMR (500 MHz, CDCl3) δ 8.74−8.71 (m, 2H),
7.92 (dt, J = 8.2, 0.9 Hz, 1H), 7.57 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.49
(ddd, J = 8.2, 7.3, 1.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 177.5
(t, JCF = 23.5 Hz, 1C), 142.0 (t, JCF = 6.8 Hz, 1C), 138.9, 137.2, 126.6,
126.2, 125.4, 124.6, 122.3, 95.6 (t, JCF = 326 Hz, 1C); 19F NMR (282
MHz, CDCl3) δ −54.1 (s, 2F); IR (film) νmax 3116.1, 1678.3, 1488.8,
1459.3, 1360.7, 1228.5, 1096.8 cm−1; HRMS (EI/CI) m/z calcd for
C10H5F2IOS (M)+ 337.9074, found 337.9077.
1-(Benzothiophen-3-yl)-2-bromo-2,2-difluoroethanone 7.
See representative reaction procedure. 1-(Benzothiophen-3-yl)-
2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 3 (10 mg, 0.03
mmol), LiBr (16 mg, 0.19 mmol), Selectfluor (22 mg, 0.063 mmol),
and Et3N (9 μL, 0.06 mmol) were used. Purification by semiprep
HPLC (99.9:0.1 hexanes/EtOAc) provided the title compound as a
1
colorless oil (7.2 mg) in 81% yield: H NMR (500 MHz, CDCl3) δ
(E)-4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-
3-one 11. To a −78 °C solution of hexamethyldisilazane (265 mg,
1.64 mmol) in THF (3 mL) was added a solution of n-BuLi (650 μL,
2.5 M in hexanes). The mixture was stirred for 30 min at −78 °C, and
then a solution of (E)-4-phenylbut-3-en-2-one (200 mg, 1.37 mmol)
in THF (3 mL) was added dropwise. After an additional 1 h at −78
°C, 2,2,2-trifluoroethyl 2,2,2-trifluoroacetate (400 mg, 2.05 mmol) was
added dropwise, and the mixture was stirred for 30 min at the same
temperature. Next, the reaction mixture was quenched at −78 °C with
0.1 M H2SO4 (6 mL) and allowed to warm to rt. The mixture was
extracted with CH2Cl2 (6 mL × 2). The combined organics were dried
over Na2SO4 and concentrated under reduced pressure to provide the
crude product (335 mg). The crude product was dissolved in CH3CN
(5 mL), treated with Selectfluor (1.24 g, 3.50 mmol), and stirred at rt
for 24 h. The reaction mixture was diluted with EtOAc (10 mL),
filtered through a pad of Celite, and concentrated under reduced
pressure. The product was dissolved in CH2Cl2 (20 mL), washed with
H2O (10 mL × 2) and brine (10 mL), and then concentrated under
reduced pressure to provide the 4,4,6,6,6-pentafluoro-5,5-dihydroxy-1-
phenylhex-1-en-3-one 11 as a colorless solid (400 mg) in 99% yield:
8.75−8.72 (m, 2H), 7.93 (dt, J = 8.0, 1.0 Hz, 1H), 7.58 (ddd, J = 8.3,
7.1, 1.1 Hz, 1H), 7.50 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 176.2 (t, JCF = 26.2 Hz, 1C), 142.2 (t, JCF = 6.1 Hz,
1C), 139.0, 137.1, 126.6, 126.3, 125.6, 125.3, 122.4, 113.5 (t, JCF = 319
Hz, 1C); 19F NMR (282 MHz, CDCl3) δ −58.1 (s, 2F); IR (film) νmax
1688.0, 1489.5, 1142.7, 1102.0 cm−1; HRMS (EI/CI) m/z calcd for
C10H5BrF2OS (M)+ 289.9213, found 289.9211.
2-Bromo-1-(4-chlorophenyl)-2,2-difluoroethanone 8. See
representative reaction procedure. 1-(4-Chlorophenyl)-2,2,4,4,4-penta-
fluoro-3,3-dihydroxybutan-1-one 417 (20 mg, 0.07 mmol), LiBr (16
mg, 0.39 mmol), Selectfluor (47 mg, 0.13 mmol), and Et3N (18 μL,
0.13 mmol) were used. SiO2 flash chromatography (5% Et2O in
hexanes) provided the title compound as a colorless oil (12.7 mg) in
1
72% yield: H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.9 Hz, 2H),
7.52 (d, J = 8.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 180.3 (t, JCF
= 26.2 Hz, 1C), 142.0, 132.0 (2C), 129.4 (2C), 127.4, 113.3 (t, JCF
=
318 Hz, 1C); 19F NMR (282 MHz, CDCl3) δ −59.1 (s, 2F); IR (film)
νmax 1713.1, 1589.9, 1489.7, 1276.7, 1159.5 cm−1; HRMS (EI/CI) m/
z calcd for C8H4BrClF2O (M)+ 267.9102, found 267.9100.
Representative Procedure for the Synthesis of α,α-Difluoro-
α-iodomethyl Ketones. To a solution of 2,2,4,4,4-pentafluoro-3,3-
dihydroxy-1-(naphthalen-3-yl)butan-1-one 117 (10 mg, 0.03 mmol) in
THF (310 μL) was added LiBr (16 mg, 0.19 mmol) followed by I2 (16
mg, 0.062 mmol). The reaction mixture was stirred for 1 min, and then
Et3N (9 μL, 0.06 mmol) was added. After stirring for 30 min at rt, the
reaction mixture was quenched with saturated aqueous Na2S2O3 (1
mL). The mixture was extracted in EtOAc (1 mL × 2), and the
organics were dried over Na2SO4 and concentrated under reduced
pressure. Purification by semiprep HPLC (99.9:0.1 hexanes/EtOAc)
afforded the 2,2-difluoro-2-iodo-1-(naphthalen-3-yl)ethanone 14 as a
pale yellow oil (7.6 mg) in 73% yield.
2,2-Difluoro-2-iodo-1-(naphthalen-2-yl)ethanone 14. See
representative reaction procedure: 1H NMR (500 MHz, CDCl3) δ
8.77 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.95
(d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.68 (ddd, J = 8.2, 6.9,
1.3 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 182.4 (t, JCF = 23.1 Hz, 1C), 136.2, 133.6, 132.2,
130.2, 129.9, 128.9, 127.9, 127.3, 125.6, 125.2, 95.8 (t, JCF = 326 Hz,
1C); 19F NMR (282 MHz, CDCl3) δ −54.6 (s, 2F); IR (film) νmax
1697.2, 1468.5, 1280.4, 1143.4, 1116.0 cm−1; HRMS (EI/CI) m/z
calcd for C12H7F2IO (M)+ 331.9510, found 331.9512.
1
mp 68−70 °C; H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 15.9 Hz,
1H), 7.68 (d, J = 7.3 Hz, 2H), 7.53−7.50 (m, 1H), 7.46 (t, J = 7.4 Hz,
2H), 7.28 (d, J = 15.9 Hz, 1H), 4.61 (br s, 2H); 13C NMR (125 MHz,
CDCl3) δ 190.4 (t, JCF = 28.1 Hz, 1C), 150.9, 133.3, 132.6, 129.6
(2C), 129.3 (2C), 120.8 (q, JCF = 288 Hz, 1C), 116.8, 110.0 (t, JCF
=
266 Hz, 1C), 92.6 (qt, J = 27.0, 5.8 Hz, 1C); 19F NMR (282 MHz,
CDCl3) δ −82.3 (t, J = 10.3 Hz, 3F), −120.8 (q, J = 10.1 Hz, 2F); IR
(film) νmax 3398.9, 1697.1, 1594.9, 1575.0, 1451.5, 1206.0, 1072.3
cm−1; HRMS (EI/CI) m/z calcd for C12H9F5O3 (M − H2O)+
278.0366, found 278.0363.
(E)-1,1-Difluoro-1-iodo-4-phenylbut-3-en-2-one 17. See rep-
resentative reaction procedure. (E)-4,4,6,6,6-Pentafluoro-5,5-dihy-
droxy-1-phenylhex-1-en-3-one 11 (10 mg, 0.03 mmol), LiBr (17.5
mg, 0.20 mmol), I2 (17 mg, 0.067 mmol), and Et3N (10 μL, 0.07
mmol) were used. SiO2 flash chromatography (5% Et2O in hexanes)
provided the title compound as a pale yellow oil (7.0 mg) in 67%
yield: 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 15.8 Hz, 1H), 7.65
(dd, J = 7.7, 1.5 Hz, 2H), 7.51−7.44 (m, 3H), 7.09 (dt, J = 15.8, 1.1
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 181.9 (t, JCF = 23.3 Hz, 1C),
149.9, 133.6, 132.1, 129.2 (4C), 114.2, 96.9 (t, JCF = 326 Hz, 1C); 19
F
NMR (282 MHz, CDCl3) δ −60.2 (s, 2F); IR (film) νmax 3055.5,
3032.0, 2923.7, 1703.6, 1608.0, 1496.0, 1449.3, 1343.5, 1206.6, 1053.0
cm−1; HRMS (EI/CI) m/z calcd for C10H7F2IO (M)+ 307.9510,
found 307.9508.
4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhexan-3-one
12. To a solution of (E)-4,4,6,6,6-pentafluoro-5,5-dihydroxy-1-
phenylhex-1-en-3-one 11 (100 mg, 0.34 mmol) in EtOH (3.5 mL)
was added Pd/C (17 mg, 0.17 mmol). The reaction mixture was
stirred under a H2 atmosphere for 12 h. The reaction mixture was then
filtered through a pad of Celite and concentrated under reduced
pressure. The residue was dissolved in 1:1 mixture of THF/0.5 M
H2SO4 (10 mL) and vigorously stirred for 24 h at rt. The reaction
mixture was extracted with EtOAc (5 mL × 2), and the organics were
dried over Na2SO4 and concentrated under reduced pressure to
1-(Benzo[1,3]dioxol-5-yl)-2,2-difluoro-2-iodoethanone 15.
See representative reaction procedure. 1-(Benzo[1,3]dioxol-6-yl)-
2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 217 (10 mg, 0.03
mmol), LiBr (16 mg, 0.19 mmol), I2 (16 mg, 0.063 mmol), and
Et3N (9 μL, 0.06 mmol) were used. Purification by semiprep HPLC
(99.9:0.1 hexanes/EtOAc) afforded the title compound as a pale
yellow oil (6.8 mg) in 65% yield: 1H NMR (500 MHz, CDCl3) δ 7.84
(d, J = 9.3 Hz, 1H), 7.58 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.11 (s,
2H); 13C NMR (125 MHz, CDCl3) δ 180.7 (t, JCF = 22.9 Hz, 1C),
153.5, 148.3, 128.2, 122.5, 110.1, 108.4, 102.3, 95.5 (t, JCF = 326 Hz,
1C); 19F NMR (282 MHz, CDCl3) δ −54.1 (s, 2F); IR (film) νmax
2910.2, 1692.6, 1606.2, 1504.9, 1447.9, 1354.6, 1267.6, 1093.9 cm−1
;
9166
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The Journal of Organic Chemistry
Note
provide the 4,4,6,6,6-pentafluoro-5,5-dihydroxy-1-phenylhexan-3-one
12 as a colorless oil (86.6 mg) in 86% yield: H NMR (500 MHz,
1491.1, 1448.6, 1271.4, 1097.7, 1040.9, 995.4, 744.3 cm−1; HRMS
(EI/CI) m/z calcd for C9H5ClF2O3 (M)+ 233.9895, found 233.9894.
(E)-1-Chloro-1,1-difluoro-4-phenylbut-3-en-2-one 22. See
representative reaction procedure. (E)-4,4,6,6,6-Pentafluoro-5,5-dihy-
droxy-1-phenylhex-1-en-3-one 11 (30 mg, 0.1 mmol), LiCl (26 mg,
0.60 mmol), NCS (27 mg, 0.20 mmol), and Et3N (30 μL, 0.20 mmol)
were used. SiO2 flash chromatography (5% Et2O in hexanes) provided
the title compound as a colorless oil (13.7 mg) in 63% yield: 1H NMR
(500 MHz, CDCl3) δ 8.00 (d, J = 15.9 Hz, 1H), 7.65 (dd, J = 5.2, 3.2
Hz, 2H), 7.51−7.44 (m, 3H), 7.06 (d, J = 15.8 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 180.6 (t, JCF = 29.2 Hz, 1C), 150.2, 133.4, 132.2,
129.2 (4C), 120.2 (t, JCF = 305 Hz, 1C), 115.7; 19F NMR (282 MHz,
CDCl3) δ −68.5 (s, 2F); IR (film) νmax 2919.4, 1715.7, 1610.4, 1577.0,
1450.7, 1339.6, 1145.0 cm−1; HRMS (ESI) m/z calcd for C10H7ClF2O
(M + H)+ 217.0232, found 217.0226.
1
CDCl3) δ 7.33−7.30 (m, 2H), 7.25−7.19 (m, 3H), 4.19 (br s, 2H),
3.18 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 202.6 (t, JCF = 28.8 Hz, 1C), 139.3, 128.7 (2C), 128.3
(2C), 126.6, 120.6 (q, JCF = 288 Hz, 1C), 109.5 (t, JCF = 267 Hz, 1C),
92.3 (qt, J = 27.4, 5.9 Hz, 1C), 39.6, 28.1; 19F NMR (282 MHz,
CDCl3) δ −82.1 (t, J = 10.2 Hz, 3F), −120.8 (q, J = 10.2 Hz, 2F); IR
(film) νmax 3462.1, 1742.2, 1209.8, 1171.9, 1069.0 cm−1; HRMS (EI/
CI) m/z calcd for C12H11F5O3 (M − H2O)+ 280.0523, found
280.0525.
1,1-Difluoro-1-iodo-4-phenylbutan-2-one 18. See representa-
tive reaction procedure. 4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenyl-
hexan-3-one 12 (10 mg, 0.036 mmol), LiBr (17 mg, 0.20 mmol), I2
(17 mg, 0.067 mmol), and Et3N (10 μL, 0.07 mmol) were used. SiO2
flash chromatography (5% Et2O in hexanes) provided the title
1,3,3-Trichloro-1,1-difluoro-4-phenylbutan-2-one 23. See
representative reaction procedure. 4,4,6,6,6-Pentafluoro-5,5-dihy-
droxy-1-phenylhexan-3-one 12 (10 mg, 0.033 mmol), LiCl (9 mg,
0.20 mmol), NCS (18 mg, 0.13 mmol), and Et3N (9 μL, 0.07 mmol)
were used. SiO2 flash chromatography (5% Et2O in hexanes) provided
1
compound as a pale yellow oil (8.6 mg) in 83% yield: H NMR (500
MHz, CDCl3) δ 7.33−7.21 (m, 5H), 3.16 (t, J = 7.5 Hz, 2H), 3.02 (t, J
= 7.4 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 192.3 (t, JCF = 24.6
Hz, 1C), 139.5, 128.7 (2C), 128.4 (2C), 126.6, 94.7 (t, JCF = 334 Hz,
1C), 35.2, 29.1; 19F NMR (282 MHz, CDCl3) δ −62.1 (s, 2F); IR
(film) νmax 2929.2, 1748.0, 1585.3, 1496.5, 1454.7, 1134.6, 1049.9
cm−1; HRMS (ESI) m/z calcd for C10H9F2IO (M + H)+ 310.9744,
found 310.9739.
1
the title compound as a colorless oil (7.0 mg) in 73% yield: H NMR
(500 MHz, CDCl3) δ 7.38−7.34 (m, 5H), 3.72 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 180.6 (t, JCF = 29.6 Hz, 1C), 131.8, 131.7 (2C),
128.3 (3C), 118.9 (t, JCF = 308 Hz, 1C), 82.3, 48.7; 19F NMR (376
MHz, CDCl3) δ −60.0 (s, 2F); IR (film) νmax 2925.3, 2854.6, 1761.7,
1456.0, 1166.9, 1091.7 cm−1; HRMS (ESI) m/z calcd for
C10H7Cl3F2O (M + H)+ 286.9609, found 286.9603.
1-(Adamantan-1-yl)-2,2-difluoro-2-iodoethanone 19. See
representative reaction procedure. 1-Adamantyl-2,2,4,4,4-pentafluoro-
3,3-dihydroxybutan-1-one 1317 (10 mg, 0.030 mmol), LiBr (16 mg,
0.19 mmol), I2 (16 mg, 0.063 mmol), and Et3N (9 μL, 0.06 mmol)
were used. SiO2 flash chromatography (5% Et2O in hexanes) provided
2,2-Difluoro-4,5-dimethyl-1-(naphthalen-2-yl)hex-4-en-1-
one 25. A suspension of 2,2-difluoro-2-iodo-1-(naphthalen-3-yl)-
ethanone 14 (26 mg, 0.078 mmol), Cu powder (20 mg, 0.32 mmol),
and 2,3-dimethyl-2-butene 24 (100 μL, 0.78 mmol) in DMSO (150
μL) was stirred at 60 °C for 15 h. The reaction mixture was cooled to
rt, diluted with H2O (5 mL), and extracted with EtOAc (2 mL × 2).
The organics were dried over Na2SO4 and concentrated under reduced
pressure. SiO2 flash chromatography (5% Et2O in hexanes) provided
1
the title compound as a pale yellow oil (7.0 mg) in 66% yield: H
NMR (500 MHz, CDCl3) δ 2.07−2.05 (m, 9H), 1.75 (q, J = 12.2 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 196.3 (t, JCF = 20.7 Hz, 1C),
97.4 (t, JCF = 331 Hz, 1C), 45.4, 38.2 (3C), 36.2 (3C), 27.7 (3C); 19F
NMR (282 MHz, CDCl3) δ −54.5 (s, 2F); IR (film) νmax 2908.8,
2854.7, 1722.3, 1453.8, 1213.2, 1117.4 cm−1; HRMS (EI/CI) m/z
calcd for C12H15F2IO (M + H)+ 341.0214, found 341.0210.
Representative Procedure for the Synthesis of α-Chloro-α,α-
difluoromethyl Ketones. To a solution of 2,2,4,4,4-pentafluoro-3,3-
dihydroxy-1-(naphthalen-3-yl)butan-1-one 117 (10 mg, 0.031 mmol)
in THF (310 μL) was added LiCl (8 mg, 0.2 mmol) followed by NCS
(8 mg, 0.06 mmol). The reaction mixture was stirred for 1 min, and
then Et3N (9 μL, 0.06 mmol) was added. After stirring for 30 min at rt,
the reaction mixture was quenched with saturated aqueous NH4Cl (1
mL). The mixture was extracted in EtOAc (1 mL × 2), and the
organics were dried over Na2SO4 and concentrated under reduced
pressure. SiO2 flash chromatography (5% Et2O in hexanes) afforded
the 2-chloro-2,2-difluoro-1-(naphthalen-2-yl)ethanone 20 as a color-
less oil (6.0 mg) in 80% yield.
1
the title compound as a colorless oil (11.2 mg) in 50% yield (6:1): H
NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H),
7.98 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 13.8, 8.5 Hz, 2H), 7.64 (ddd, J =
8.2, 6.9, 1.2 Hz, 1H), 7.58 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 3.04 (t, J =
18.7 Hz, 2H), 1.78 (s, 3H), 1.69 (s, 3H), 1.65 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 190.2 (t, JCF = 30.9 Hz, 1C), 135.9, 132.7, 132.3,
132.0, 130.1, 129.6, 129.3, 128.5, 127.8, 126.9, 124.9, 120.1 (t, JCF
=
256 Hz, 1C), 118.3, 39.0 (t, JCF = 22.9 Hz, 1C), 21.2, 20.9, 20.3; 19F
NMR (282 MHz, CDCl3) δ −98.9 (t, J = 18.6 Hz, 2F); IR (film) νmax
2925.6, 1698.2, 1627.9, 1597.1, 1465.9, 1289.7, 1153.7, 1037.2 cm−1
;
HRMS (ESI) m/z calcd for C18H18F2O (M+Na)+ 311.1223, found
311.1233.
ASSOCIATED CONTENT
■
2-Chloro-2,2-difluoro-1-(naphthalen-2-yl)ethanone 20. See
representative reaction procedure: 1H NMR (500 MHz, CDCl3) δ
8.70 (s, 1H), 8.11 (dd, J = 8.7, 1.8 Hz, 1H), 8.02 (dd, J = 8.2, 0.6 Hz,
1H), 7.95 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.2, 0.5 Hz, 1H), 7.69
(ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 181.2 (t, JCF = 28.9 Hz, 1C), 136.3,
S
* Supporting Information
1H, 13C, and 19F NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dcolby@purdue.edu.
■
133.5, 132.1, 130.2, 130.0, 128.9, 127.9, 127.3, 126.5, 124.8, 120.3 (t,
J
CF = 305 Hz, 1C); 19F NMR (282 MHz, CDCl3) δ −61.2 (s, 2F); IR
(film) νmax 1709.0, 1155.0, 989.8, 818.7, 752.5 cm−1; HRMS (EI/CI)
m/z calcd for C12H7ClF2O (M)+ 240.0154, found 240.0153.
ACKNOWLEDGMENTS
■
1-(Benzo[1,3]dioxol-5-yl)-2-chloro-2,2-difluoroethanone
21. See representative reaction procedure. 1-(Benzo[1,3]dioxol-6-yl)-
2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 217 (10 mg, 0.03
mmol), LiCl (8 mg, 0.19 mmol), NCS (8.5 mg, 0.065 mmol), and
Et3N (10 μL, 0.07 mmol) were used. SiO2 flash chromatography (5%
Et2O in hexanes) provided the title compound as a colorless oil (6.2
We kindly acknowledge the National Institute on Aging
(R21AG039718) and the Ralph W. and Grace M. Showalter
Research Trust for funding this work.
REFERENCES
■
1
mg) in 83% yield: H NMR (500 MHz, CDCl3) δ 7.78 (ddt, J = 8.3,
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148.4, 127.9, 123.6, 120.2 (t, J = 305 Hz, 1C), 109.8, 108.4, 102.4; 19
F
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9167
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Note
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