Construction of tertiary alcohols bearing perfluoroalkyl chains catalyzed by prolinamide-thioureas

Article abstract of DOI:10.1021/jo2020104

A systematic study to evaluate the ability of various organocatalysts to catalyze the aldol reaction between acetone and 2,2,2-trifluoromethyl-1- phenylethanone was undertaken. Benchmark organocatalysts failed to catalyzethis reaction. However, a prolinam

Full text of DOI:10.1021/jo2020104

Note
pubs.acs.org/joc
Construction of Tertiary Alcohols Bearing Perfluoroalkyl Chains
Catalyzed by Prolinamide-Thioureas
Christoforos G. Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
S
* Supporting Information
ABSTRACT: A systematic study to evaluate the ability of
various organocatalysts to catalyze the aldol reaction between
acetone and 2,2,2-trifluoromethyl-1-phenylethanone was
undertaken. Benchmark organocatalysts failed to catalyze
this reaction. However, a prolinamide-thiourea consisting of
(S)-prolinamide, (1S,2S)-diphenylethylenediamine, and (S)-di-
tert butyl aspartate proved to be an efficient catalyst, providing
tertiary alcohols as the products of the reaction between
ketones and perfluoroalkyl ketones in high to quantitative
yields and high enantioselectivities (up 81% ee) at a catalyst
loading of 2 mol %.
ore than a decade after the rebirth of organocatalalysis,1
its dramatic pace of expansion has constituted it as the
Since little is known for the reaction between acetone and
2,2,2-trifluoromethyl-1-phenylethanone, a screening of a variety
of known organocatalysts was undertaken (Figure 1, Table 1).
M
third major branch of modern asymmetric catalysis.2,3 Since then,
a plethora of catalysts have been developed, synthesized, and
tested for their efficiency in the aldol reaction.4,5 However, the use
of ketones as electrophilic partners, which provides access to chiral
tertiary alcohols, remains still a challenge due to their poor
reactivity and difficulty in differentiating the two faces of the
carbonyl moiety.5 Zhang and co-workers utilized proline in the
reaction between acetone and trifluoromethyl ketones leading to
mediocre enantioselectivities.6 Although the perfluoroalkyl group
is one of the most attractive moieties in organic chemistry because
of its numerous applications in agricultural, medicinal, and material
chemistry,7,8 there have been only sporadic reports of organo-
catalytic aldol reactions employing perfluoroalkyl ketones as
electrophiles.6,9 Furthermore, the construction of quaternary
stereogenic centers, especially those of tertiary alcohols, remains
a great challenge,10,11 although some elegant contributions, namely
by Aggarwal and co-workers,12 have provided milestone solutions
for this long-standing problem. However, for the synthesis of
tertiary alcohols bearing perfluoroalkyl groups, little is known, with
the use of the Ruppert−Prakash reagent (TMSCF3) being the
reagent of choice.13 It has to be highlighted that a variety of
tertiary alcohols bearing trifluoromethyl moieties are of medicinal
interest.14,15 To provide an alternative synthesis of such
compounds, the screening of a variety of catalyst templates was
undertaken for the reaction between ketones and perfluoroalkyl
ketones. While this manuscript was under preparation, Nakamura
and co-workers reported the use of a specifically designed proline
sulfonamide that was highly efficient for the reaction between aryl
trihalomethyl ketones and acetone.16 In their study, 10 mol %
catalyst loading was needed to ensure high yields (>90%), while
the enantioselectivities varied (77−92% ee). Herein, we present
our studies toward the construction of tertiary alcohols bearing
perfluoroalkyl chains via organocatalysis.
Figure 1. Organocatalysts employed in this study.
Initially, proline (1a) was utilized for comparison purposes
(entry 1, Table 1). Although an excellent yield was obtained,
the ee was lower than that reported by Zhang6 and similar to
Received: October 2, 2011
Published: December 20, 2011
© 2011 American Chemical Society
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Note
Initially, the reaction medium was studied (entries 1−5, Table 2).
Among a range of solvents, toluene provided the best results
Table 1. Various Organocatalysts Employed in the
Asymmetric Aldol Reaction between Acetone and 2,
2,2-Trifluoromethyl-1-phenylethanone
Table 2. Optimization of the Reaction Conditions on the
Reaction between Acetone and 2,2,2-Trifluoromethyl-1-
phenylethanone Using Catalyst 2b
a
b
entry
catalyst
yield [%]
ee [%]
c
1
1a
1b
1h
1i
97
30
22
2
98
96
a
b
3
0
entry
catalyst loading (%)
solvent
yield [%]
ee [%]
4
92
15
1
2
3
4
5
6
7
10
10
10
10
10
2
neat
98
93
68
55
60
55
74
74
72
80
69
5
1j
100
90
13
THF
6
1k
1m
1o
1r
1s
1t
34
CH2Cl2
MeCN
toluene
toluene
toluene
toluene
toluene
95
7
68
−11
15
100
97
8
13
9
traces
31
98
10
11
12
13
30
19
62
68
1
98
c
96
8
2
97
c
2a
2b
93
9
0.1
67
98
a
b
Isolated yield after column chromatography. The ee was determined
by chiral HPLC. The reaction was performed at 0 °C.
a
b
c
Isolated yield after column chromatography. The ee was determined
by chiral HPLC. Reaction time: 24 h.
c
(entry 5, Table 2; see also the Supporting Information). The
use of 2 mol % led to quantitative yield and 74% ee (entry 6,
Table 2), whereas with only 1 mol %, the enantioselectivity
dropped (entry 7, Table 2). The catalyst loading can be
successfully reduced to 0.5 mol % without any considerable impact
on both yield and enantioselectivity (see the Supporting
Information). When the reaction was carried out at 0 °C with
2 mol % catalyst loading, an excellent yield (97%) and good
enantioselectivity (80% ee) were obtained (entry 8, Table 2).
When only 0.1 mol % catalyst was applied, the desired product
was isolated in good yield and enantioselectivity (entry 9, Table 2).
The scope and limitations of the current methodology were
also investigated (Scheme 1). The use of substituted aromatic
trifluoromethyl ketones led to similar results as in the model
reaction (3b−d). Once one of the fluorine atoms was replaced
by a chlorine, an excellent yield but lower enantioselectivity
were observed (3e). When the phenyl ring was replaced by a
perfluorophenyl moiety, the enantioselectivity dropped sig-
nificantly (3f). The use of the ethyl ester functionality instead
of the phenyl ring was also well tolerated, leading to a high yield
and good enantioselectivity (3g). Recently, a number of
trifluoromethyl and perfluoroalkyl ketones have been identified
as enzyme inhibitors exhibiting interesting medicinal proper-
ties.25 Perfluoroalkyl ketones can be efficiently synthesized
from the corresponding Weinreb or morpholine amides.26
Unfortunately, when such a ketone, where the phenyl ring is
not adjacent to the carbonyl moiety but rather four carbon
atoms away, was used, a high yield was observed; however, the
enantioselectivity dropped significantly (3h). Interestingly,
other methyl ketones can also be utilized in the place of
acetone. 2-Butanone led to a single regioisomer in a high yield
and good enantioselectivity (3i). It has to be highlighted that in
the same reaction, proline affords a mixture of regioisomers
(data not shown). Acetophenone led to inferior results (21%
yield, 42% ee, after 7 days, data not shown), while cyclo-
hexanone did not lead to the desired product. Furthermore,
when 2-hydroxyacetone was utilized, an inseparable mixture of
two diastereomers was obtained in almost equal amounts in
good yield and good enantioselectivity (3j). In the case of
the results of Nakamura.16 A number of natural acyclic α-amino
acids were also utilized (entry 2, Table 1; see also the
Supporting Information). The replacement of the secondary
amine of the pyrrolidine ring by a primary amine (catalysts 1b−
h) led to high yields but decreased selectivities, highlighting the
necessity of a five-membered-ring secondary amine. From entry
3 (Table 1), it is obvious that the presence of a free carboxylic
group or a moiety able to form hydrogen bonds on the catalyst
scaffold is a requirement. 4-Hydroxy proline (1i), proline
methanesulfonamide (1j),17 and diamine 1k18 led to high to
quantitative yields, but the enantioselectivity was not
significantly improved (entries 4−6, Table 1). The diary-
lprolinols’ family19 as well as MacMillan’s imidazolidinones20
constitute two classes of organocatalysts that are very
frequently employed; however, inferior results were obtained
(entries 7−8, Table 1). Cinchonine, a member of the Cinchona
alkaloids family, did not furnish the desired product (entry 9,
Table 1). Continuing our interest on organocatalysis,21 we
utilized bifunctional organocatalyst 1s;21b however, the reaction
did not reach completion, albeit similar enantioselectivity was
observed as in the case of proline (entry 10, Table 1).
Pyrrolidine-thioxotetrahydropyrimidinone 1t, which is a highly
reactive catalyst for Michael reactions,21d led to an almost
quantitative yield but poor enantiocontrol (entry 11, Table 1).
Recently, the proline scaffold has been successfully combined
with functionalities able to act as hydrogen bond donors.22,23
Our efforts focused on the combination of a prolinamide with a
thiourea moiety. Prolinamide-thiourea 2a has been proven to
be an excellent catalyst for the aldol reaction.21c Catalyst 2a
afforded enhanced enantioselectivity in the model reaction
(entry 12, Table 1). Most recently, we have undertaken a study
in order to understand the features required for such a catalyst
scaffold, concluding that a tripeptide-like compound such as 2b
is an excellent organocatalyst for the aldol reaction.24 When
catalyst 2b was employed, the best enantioselectivity was
obtained (entry 13, Table 1).
With the optimum catalyst in hand, various reaction
conditions were tested to maximize the enantioselectivity.
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Note
Finally, other methyl ketones instead of acetone were
successfully used.
Scheme 1. Direct Asymmetric Aldol Reaction between
Ketones and Various Perfluoroalkyl Ketones Using Catalyst 2b
EXPERIMENTAL SECTION
■
General Remarks. Chromatographic purification of products was
accomplished using forced-flow chromatography. Thin-layer chroma-
tography (TLC) was performed on aluminum backed silica plates
(0.2 mm, 60 F254). Visualization of the developed chromatogram was
performed by fluorescence quenching using phosphomolybdic acid,
anisaldehyde, or ninhydrin stains. IR spectra are reported in terms of
frequency of absorption (cm−1). 1H and 13C NMR spectra are
internally referenced to residual solvent signals (CDCl3). Data for
1H NMR are reported as follows: chemical shift (δ ppm), integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, m =
multiplet, bs = broad signal, bs m = broad signal multiplet), coupling
constant, and assignment. Data for 13C NMR are reported in terms of
chemical shift (δ ppm). For mass spectra, only molecular ions and
major peaks are being reported with intensities quoted as percentages
of the base peak. Chiral high performance liquid chromatography
(HPLC) analyses were performed using Chiralpak AD-H, OD-H, and
AS-H columns. The configuration of the products has been assigned
either by comparison to literature data (compounds 3a, 3b, 3d, and
3m) or by analogy (all other compounds). Catalysts 1a−t and 2a were
either commercially available or prepared following literature
procedures.
General Procedure for the Synthesis of the Catalyst 2b. The
catalyst 2b was first described in reference 24. The same procedure for
its synthesis was followed.
(S)-Di-tert-butyl 2-{3-[(1S,2S)-1,2-Diphenyl-2-[(S)-(pyrrol-
idine-2-carboxamido]-ethyl]thioureido}succinate (2b). White
1
solid: mp 89−91 °C; [α]D = +35.3 (c = 0.88, CHCl3); H NMR
(200 MHz, CDCl3) δ 8.56 (1H, d, J = 8.6 Hz), 8.05−7.87 (1H, br m),
7.46−7.01 (10H, m), 6.92−6.66 (1H, br m), 5.98−5.65 (1H, m),
5.33−5.06 (2H, m), 3.97−3.68 (1H, m), 3.09−2.76 (4H, m), 2.19−
2.03 (1H, m), 1.87−1.55 (4H, m), 1.43 (9H, s), 1.36 (9H, s); 13C
NMR (50 MHz, CDCl3) δ 182.6, 170.4, 170.1, 169.9, 138.7, 138.6,
128.5, 128.3, 128.0, 127.7, 127.5, 127.4, 82.2, 81.4, 64.2, 60.3, 58.8,
54.0, 47.1, 37.8, 30.5, 28.0, 27.9, 25.8.
perfluoroalkylphenyl ketones, lower yields but the same levels
of enantioselectivity were observed (3k−m).
In order to account for the good enantioselectivity of the
reaction, the transition state in Figure 2 is proposed. The
General Procedure for the Aldol Reaction. To a stirring
solution of catalyst 2b (4 mg, 0.007 mmol, 2 mol %) in toluene
(1.0 mL), perfluoroalkyl ketone (0.34 mmol) followed by acetone or
ketone (3.40 mmol) were added at 0 °C. The reaction mixture was left
stirring at 0 °C for 44 h. The solvent was evaporated, and the crude
product was purified using flash column chromatography eluting with
various mixtures of petroleum ether (40−60 °C)/EtOAc to afford the
desired product.
(S)-5,5,5-Trifluoro-4-hydroxy-4-phenylpentan-2-one (3a).16
Data: 78 mg, 99% yield; [α]D = +18.8 (c = 0.4, CHCl3); IR (KBr)
Figure 2. Proposed transition state model for the aldol reaction.
1
3422, 3062, 1707, 1602, 1497, 1246, 1075, 906, 709 cm−1; H NMR
(200 MHz, CDCl3) δ 7.62−7.52 (2H, m), 7.46−7.34 (3H, m), 5.46
(1H, br s), 3.39 (1H, d, J = 17.2 Hz), 3.21 (1H, d, J = 17.2 Hz), 2.22
(3H, s); 13C NMR (50 MHz, CDCl3) δ 209.1, 137.3, 128.7, 128.4,
126.0, 124.4 (q, J = 284.9 Hz), 75.9 (q, J = 29.1 Hz), 44.8, 31.8; 19F
NMR (188 MHz, CDCl3) δ −13.97 (s); HPLC Diacel Chiralpak AS-
H, hexane/iPrOH 95:5, flow rate 0.7 mL/min, retention time = 12.34
(minor) and 17.06 (major).
pyrrolidine functionality activates the methyl ketone through
the formation of an enamine intermediate, while the
trifluoromethyl carbonyl compound may be activated through
multiple hydrogen bonding.
In conclusion, in an effort to broaden the applicability of the
aldol reaction, a variety of the most common organocatalysts
were tested for their activity in the model reaction of acetone
with phenyltrifluoromethyl ketone. Our prolinamide-thiourea
catalyst combining the (S)-prolinamide unit with (1S,2S)-
diphenylethylenediamine and (S)-di-tert butyl aspartate proved
to have the best catalytic activity for the aldol reaction that was
studied. A variety of parameters were scrutinized in order to
find the optimum reaction conditions for this transformation
that provides tertiary alcohols bearing a perfluoroalkyl moiety.
A number of substituted aryl trifluoromethyl ketones and
perfluoroalkyl ketones are well tolerated leading to good to
excellent yields and moderate to high enantioselectivities.
(S)-5,5,5-Trifluoro-4-(4-fluorophenyl)-4-hydroxypentan-2-
one (3b).16 Data: 82 mg, 96% yield; [α]D = +15.2 (c = 1.0, CH2Cl2);
IR (KBr) 3414, 2925, 1708, 1606, 1512, 1422, 1336, 1238, 1168, 1058,
1
916, 838, 736 cm−1; H NMR (200 MHz, CDCl3) δ 7.58−7.51 (2H,
m), 7.08 (2H, t, J = 8.7 Hz), 5.49 (1H, br s), 3.33 (1H, d, J = 17.2 Hz),
3.20 (1H, d, J = 17.2 Hz), 2.21 (3H, s); 13C NMR (50 MHz, CDCl3) δ
208.9, 162.9 (d, J = 248.2 Hz), 133.2 (d, J = 3.2 Hz), 128.1 (d, J = 8.4
Hz), 124.3 (q, J = 283.7 Hz), 115.4 (d, J = 21.6 Hz), 75.7 (q, J = 29.4
Hz), 44.9, 32.1; 19F NMR (188 MHz, CDCl3) δ −14.15 (s), −46.93
(s); HPLC Diacel Chiralpak AS-H, hexane/iPrOH 95:5, flow rate 0.7
mL/min, retention time = 13.32 (minor) and 19.79 (major).
(S)-5,5,5-Trifluoro-4-hydroxy-4-(4-trifluoromethylphenyl)-
pentan-2-one (3c). Data: 78 mg, 76% yield; [α]D = +7.5 (c = 1.0,
CH2Cl2); IR (KBr) 3478, 2929, 1716, 1622, 1416, 1330, 1168, 1100,
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Note
1
994, 839, 760 cm−1; H NMR (200 MHz, CDCl3) δ 7.72 (2H, d, J =
(S)-6,6,6-Trifluoro-5-hydroxy-5-phenylhexan-3-one (3i).
Data: 74 mg, 88% yield; [α]D = +5.7 (c = 1.0, CHCl3); IR (KBr)
3426, 3023, 2921, 1705, 1455, 1217, 1169, 1076, 1011, 762, 705 cm−1;
1H NMR (200 MHz, CDCl3) δ 7.62−7.50 (2H, m), 7.46−7.32 (3H,
m), 5.61 (1H, br s), 3.33 (1H, d, J = 17.0 Hz), 3.18 (1H, d, J = 17.0
Hz), 2.69−2.31 (2H, m), 1.01 (3H, t, J = 7.2 Hz); 13C NMR (50
MHz, CDCl3) δ 211.8, 137.5, 128.8, 128.4, 126.1, 124.5 (q, J = 284.9
Hz), 75.9 (q, J = 29.0 Hz), 44.1, 38.2, 7.1; 19F NMR (188 MHz,
CDCl3) δ −13.85 (s); HRMS exact mass calculated for [M + Na]+
(C12H13F3O2Na) requires m/z 269.0760, found m/z 269.0766; HPLC
Diacel Chiralpak AS-H, hexane/iPrOH 99:1, flow rate 0.5 mL/min,
retention time = 20.07 (minor) and 23.64 (major).
3,4-Dihydroxy-8-phenyl-4-(trifluoromethyl)octan-2-one (3j).
Data: 1:1 mixture of diastereomers, 72 mg, 70% yield; IR (KBr) 3439,
3021, 2924, 1714, 1453, 1362, 1246, 1169, 1076, 1027, 763, 714 cm−1;
1H NMR (200 MHz, CDCl3) δ 7.72−7.62 (4H, m), 7.52−7.36 (6H,
m), 4.84 (1H, br s), 4.65 (1H, br s), 3.72 (2H, br s), 2.17 (3H, s), 1.56
(3H, s); 13C NMR (50 MHz, CDCl3) δ 207.5, 206.0, 134.0, 133.2,
129.5, 129.4, 128.5, 128.0, 126.4, 125.9, 124.6 (q, J = 287.8 Hz), 124.6
(q, J = 288.2 Hz), 78.7, 78.7, 78.4 (q, J = 25.6 Hz), 77.9 (q, J = 27.4
Hz), 29.7, 28.1; 19F NMR (188 MHz, CDCl3) δ −7.61 (s), −8.65 (s);
HRMS exact mass calculated for [M + Na]+ (C11H11F3O3Na) requires
m/z 271.0552, found m/z 271.0549; HPLC Diacel Chiralpak AS-H,
hexane/iPrOH 97:3, flow rate 0.5 mL/min, retention time = major
diastereomer 49.33 (minor) and 55.65 (major), minor diastereomer
67.27 (minor) and 75.53 (major).
9.1 Hz), 7.66 (2H, d, J = 9.1 Hz), 5.63 (1H, br s), 3.36 (1H, d, J = 17.4
Hz), 3.26 (1H, d, J = 17.4 Hz), 2.24 (3H, s); 13C NMR (50 MHz,
CDCl3) δ 208.6, 141.5, 131.1 (q, J = 32.7 Hz), 126.7, 125.5 (q, J = 3.7
Hz), 124.2 (q, J = 285.2 Hz), 123.8 (q, J = 272.1 Hz), 75.9 (q, J = 29.6
Hz), 44.9, 32.0; 19F NMR (188 MHz, CDCl3) δ 3.58 (s), −13.74 (s);
HRMS exact mass calculated for [M + Na]+ (C12H10F6O2Na) requires
m/z 323.0477, found m/z 323.0472; HPLC Diacel Chiralpak AS-H,
hexane/iPrOH 97:3, flow rate 0.7 mL/min, retention time = 10.95
(minor) and 16.83 (major).
(S)-5,5,5-Trifluoro-4-hydroxy-4-p-tolylpentan-2-one (3d).16
Data: 80 mg, 96% yield; [α]D = +9.6 (c = 0.5, CHCl3); IR (KBr)
3468, 3038, 2926, 1714, 1516, 1412, 1160, 990, 808, 733 cm−1; H
1
NMR (200 MHz, CDCl3) δ 7.45 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J =
8.0 Hz), 5.30 (1H, br s), 3.37 (1H, d, J = 17.0 Hz), 3.19 (1H, d, J =
17.0 Hz), 2.36 (3H, s), 2.21 (3H, s); 13C NMR (50 MHz, CDCl3) δ
209.3, 138.9, 134.4, 129.4, 126.4, 124.4 (q, J = 283.4 Hz), 76.1 (q, J =
29.5 Hz), 45.3, 32.3, 21.1; 19F NMR (188 MHz, CDCl3) δ −14.13 (s);
HPLC Diacel Chiralpak AS-H, hexane/iPrOH 95:5, flow rate 0.7
mL/min, retention time = 6.50 (minor) and 9.11 (major).
(S)-5-Chloro-5,5-difluoro-4-hydroxy-4-phenylpentan-2-one
(3e). Data: 81 mg, 96% yield; [α]D = +6.2 (c = 1.0, CHCl3); IR (KBr)
3464, 3065, 1712, 1448, 1368, 1332, 1169, 1118, 1065, 1014, 955, 890,
757, 719 cm−1; H NMR (200 MHz, CDCl3) δ 7.64−7.52 (2H, m),
1
7.44−7.30 (3H, m), 5.19 (1H, br s), 3.46 (1H, d, J = 17.0 Hz), 3.25
(1H, d, J = 17.0 Hz), 2.18 (3H, s); 13C NMR (50 MHz, CDCl3) δ
209.1, 138.0, 130.1 (t, J = 298.9 Hz), 128.8, 128.2, 126.6, 79.4 (t, J =
25.4 Hz), 45.5, 32.2; 19F NMR (188 MHz, CDCl3) δ 2.26 (d, J = 166.3
Hz), 1.10 (d, J = 166.3 Hz); HRMS exact mass calculated for [M +
Na]+ (C11H11F2O2ClNa) requires m/z 271.0308, found m/z 271.0313;
HPLC Diacel Chiralpak AS-H, hexane/iPrOH 95:5, flow rate
0.7 mL/min, retention time = 11.74 (minor) and 16.15 (major).
(S)-2,2,2-Trifluoro-1-(perfluorophenyl)ethanone (3f). Data:
87 mg, 97% yield; [α]D = +10.8 (c = 1.0, CHCl3); IR (KBr) 3465,
2940, 1713, 1654, 1530, 1495, 1419, 1358, 1245, 1170, 1135, 1002,
(S)-5,5,6,6,6-Pentafluoro-4-hydroxy-4-phenyl-hexan-2-one
(3k). Data: 54 mg, 56% yield; [α]D = +7.8 (c = 1.0, CH2Cl2); IR (KBr)
1
3406, 3066, 1707, 1419, 1341, 1222, 1124, 1000, 842, 709 cm−1; H
NMR (200 MHz, CDCl3) δ 7.61−7.51 (2H, m), 7.44−7.34 (3H, m),
5.60 (1H, br s), 3.39 (1H, d, J = 16.9 Hz), 3.24 (1H, d, J = 16.9 Hz),
2.17 (3H, s); 13C NMR (50 MHz, CDCl3) δ 209.6, 137.5, 134.8−
104.2 (m), 128.9, 128.7, 126.1, 76.9 (q, J = 29.4 Hz), 45.1, 32.3;
19F NMR (188 MHz, CDCl3) δ −11.43 (s), −55.1 (m); HRMS exact
mass calculated for [M + Na]+ (C12H11F5O2Na) requires m/z
305.0571, found m/z 305.0576; HPLC Diacel Chiralpak AS-H,
hexane/iPrOH 97:3, flow rate 0.5 mL/min, retention time = 14.18
(minor) and 22.33 (major).
(S)-5,5,6,6,7,7,7-Heptafluoro-4-hydroxy-4-phenyl-heptan-2-
one (3l). Data: 76 mg, 67% yield; [α]D = +7.5 (c = 1.0, CH2Cl2); IR
(KBr) 3407, 3068, 1706, 1419, 1340, 1224, 1121, 1000, 844, 709 cm−1;
1H NMR (200 MHz, CDCl3) δ 7.62−7.54 (2H, m), 7.44−7.32 (3H,
m), 5.69 (1H, br s), 3.36 (1H, d, J = 16.8 Hz), 3.25 (1H, d, J = 16.8
Hz), 2.16 (3H, s); 13C NMR (50 MHz, CDCl3) δ 209.5, 137.6, 136.1−
106.9 (m), 128.7, 128.3, 126.2, 77.3 (q, J = 29.2 Hz), 45.5, 32.3; 19F
NMR (188 MHz, CDCl3) δ −14.49 (t, J = 11.0 Hz), −51.32 (m),
−56.54 (m); HRMS exact mass calculated for [M + Na]+
(C13H11F7O2Na) requires m/z 355.0539, found m/z 355.0545;
HPLC Diacel Chiralpak AS-H, hexane/iPrOH 97:3, flow rate 0.5
mL/min, retention time = 12.25 (minor) and 15.25 (major).
949, 842, 779, 743 cm−1; H NMR (200 MHz, CDCl3) 4.80 (1H, br
1
s), 3.81 (1H, dt, J = 18.3 and 2.7 Hz), 3.14 (1H, dt, J = 18.3 and 3.7
Hz), 2.29 (3H, s); 13C NMR (50 MHz, CDCl3) δ 206.9, 150.0−110.0
(m), 123.6 (q, J = 285.0 Hz), 78.0−75.0 (m), 46.5 (t, J = 6.0 Hz),
30.5; 19F NMR (188 MHz, CDCl3) δ −15.25 (t, J = 8.3 Hz), −71.65
(m), −85.21 (tt, J = 21.4 and 4.2 Hz), −94.36 (m); HRMS exact mass
calculated for [M + Na]+ (C11H6F8O2Na) requires m/z 345.0132,
found m/z 345.0127; HPLC Diacel Chiralpak AS-H, hexane/iPrOH
97:3, flow rate 0.7 mL/min, retention time = 7.47 (minor) and 11.07
(major).
(S)-Ethyl 3-Hydroxy-5-oxo-3-(trifluoromethyl)hexanoate
(3g). Data: 75 mg, 91% yield; [α]D = +10.7 (c = 1.0, CH2Cl2); IR
(KBr) 3399, 3020, 2923, 2853, 1733, 1708, 1464, 1216, 1176, 1113,
761, 699 cm−1; H NMR (200 MHz, CDCl3) δ 5.78 (1H, br s), 4.18
1
(2H, q, J = 7.2 Hz), 3.03 (1H, d, J = 16.2 Hz), 2.95 (1H, d, J = 16.2
Hz), 2.85 (1H, d, J = 15.5 Hz), 2.75 (1H, d, J = 15.5 Hz), 2.29 (3H, s),
1.28 (3H, t, J = 7.2 Hz); 13C NMR (50 MHz, CDCl3) δ 208.2, 170.4,
124.9 (q, J = 286.0 Hz), 73.8 (q, J = 29.0 Hz), 61.4, 43.1, 37.3 (q, J =
1.1 Hz), 32.3, 13.9; 19F NMR (188 MHz, CDCl3) δ −15.88 (s);
HRMS exact mass calculated for [M + Na]+ (C9H13F3O4Na) requires
m/z 265.0658, found m/z 265.0664; HPLC Diacel Chiralpak OD-H,
hexane/iPrOH 99:1, flow rate 0.7 mL/min, retention time = 13.06
(minor) and 15.36 (major).
(S)-5,5,6,6,7,7,8,8,8-Nonafluoro-4-hydroxy-4-phenyl-octan-
2-one (3m).16 Data: 58 mg, 45% yield; [α]D = −3.7 (c = 1.0, CHCl3);
1H NMR (200 MHz, CDCl3) δ 7.63−7.53 (2H, m), 7.44−7.32 (3H,
m), 5.67 (1H, br s), 3.35 (1H, d, J = 16.8 Hz), 3.26 (1H, d, J = 16.8
Hz), 2.16 (3H, s); 13C NMR (50 MHz, CDCl3) δ 209.5, 137.7, 136.1−
106.9 (m), 128.8, 128.5, 126.2, 77.4 (q, J = 29.2 Hz), 45.7, 32.5;
HPLC Diacel Chiralpak AD-H, hexane/iPrOH 99:1, flow rate 1.0
mL/min, retention time = 5.42 (minor) and 5.73 (major).
(R)-4-Hydroxy-8-phenyl-4-(trifluoromethyl)octan-2-one
(3h). Data: 79 mg, 81% yield; [α]D = +2.6 (c = 1.0, CHCl3); IR (KBr)
3397, 3022, 2923, 2855, 1707, 1455, 1217, 1172, 1075, 761, 705 cm−1;
1H NMR (200 MHz, CDCl3) δ 7.35−7.08 (5H, m), 5.38 (1H, br s),
2.85 (1H, d, J = 16.9 Hz), 2.69−2.48 (3H, m), 2.24 (3H, s), 1.82−1.34
(6H, m); 13C NMR (50 MHz, CDCl3) δ 210.4, 142.1, 128.4, 128.3,
125.9 (q, J = 286.8 Hz), 125.8, 75.2 (q, J = 27.6 Hz), 42.3, 35.7, 34.6,
32.1, 31.5, 22.3; 19F NMR (188 MHz, CDCl3) δ −13.97 (s); HRMS
exact mass calculated for [M + Na]+ (C15H19F3O2Na) requires m/z
311.1229, found m/z 311.1226; HPLC Diacel Chiralpak AS-H,
hexane/iPrOH 98:2, flow rate 0.5 mL/min, retention time = 19.90
(major) and 32.33 (minor).
ASSOCIATED CONTENT
■
S
* Supporting Information
Full optimization details, 1H and 13C NMR spectra, and HPLC
data are available. This material is available free of charge via
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ckokotos@chem.uoa.gr.
1134
dx.doi.org/10.1021/jo2020104 | J. Org. Chem. 2012, 77, 1131−1135

The Journal of Organic Chemistry
Note
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