Homologative trifluoromethylation of acetals

Article abstract of DOI:10.1055/s-0033-1338485

Trifluoroethyl α-insertion of acetals has been developed. Aromatic, heteroaromatic, and alkenyl acetals react with in situ generated (trifluoromethyl)diazomethane in the presence of antimony(V) chloride to furnish α-trifluoromethyl acetals. A stereoselective version of this transformation exploiting the acetal as a chiral auxiliary is also presented. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338485

PAPER
▌1857
pHapoermologative Trifluoromethylation of Acetals
Homologative Trifluoromethylation of Acetals
James Y. Hamilton, Bill Morandi,1 Erick M. Carreira*
Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland
Fax +41(1)6321328; E-mail: carreira@org.chem.ethz.ch
Received: 01.05.2013; Accepted: 02.05.2013
We dedicate this manuscript to Prof. Dr. Scott E. Denmark in honor of his 60th birthday.
We have recently described the use of F3CCHN2 for the
generation of synthetically useful building blocks via
metal-catalyzed (Fe, Rh, Co) cyclopropanation and cyclo-
propenation,7 as well as Lewis acid mediated processes.8
Abstract: Trifluoroethyl α-insertion of acetals has been developed.
Aromatic, heteroaromatic, and alkenyl acetals react with in situ
generated (trifluoromethyl)diazomethane in the presence of antimo-
ny(V) chloride to furnish α-trifluoromethyl acetals. A stereoselec-
tive version of this transformation exploiting the acetal as a chiral As a part of this ongoing effort, we recently disclosed a
auxiliary is also presented.
strategy for aldehyde homologation/trifluoromethylation
and cyclic ketone insertion to provide access to α-trifluo-
romethyl ketones.9 Although aliphatic aldehydes may be
converted into the homologated ketones cleanly, difficul-
ties were encountered when aromatic aldehydes were em-
ployed as substrates (Scheme 2). In this respect, the fact
that arenes display greater migratory aptitude than hy-
drides leads to a homologated trifluoromethylated alde-
hyde product which in turn participates in a second
homologation, giving hexafluorinated ketones.
Key words: antimony, acetals, insertion, diazo compounds, trifluo-
romethyl group
Unique properties of fluorinated compounds in pharma-
ceutical, agrochemical, and materials industry2 have stim-
ulated recent development of methods to incorporate
fluorine into organic scaffolds.3 Despite the many impres-
sive advances in this discipline, the introduction of tri-
fluoromethyl groups onto aliphatic chains remains
challenging. Previously reported approaches to access this
moiety rely mainly on reactions of enolates via pathways
involving organic halides, as electrophiles, or precursors
to radical or organometallic intermediates.4–6 The use of
diazoalkane intermediates provides an alternative means
to access these valuable compounds, yet relatively little
has appeared involving these reactive species. Herein, we
report a method for the introduction of trifluoroethyl
groups into aromatic, heteroaromatic, and alkenyl acetals
with in situ generated (trifluoromethyl)diazomethane
(F3CCHN2), circumventing its handling and isolation
(Scheme 1). A key feature of our protocol is the use of a
strong Lewis acid, under conditions compatible with
F3CCHN2 formation and the aqueous medium. This en-
ables, for the first time, the direct synthesis of homologat-
ed trifluoromethyl-substituted acetals from acetals
precursors.
previous work: aldehyde addition
O
O
R
R
F3C
I
H
H
Scheme 2 Problem formulation and proposed solution
CF3
this work: acetal insertion
O
The observation of uncontrolled sequential migration for
aromatic aldehydes prompted us to investigate other syn-
thetic equivalents for the insertion reaction. Attributing
the uncontrolled second homologation (Scheme 2,
II → III) to the increased electrophilicity of trifluoro-
methylated aldehyde II, we envisioned that employment
of acetals as synthetic equivalents of aldehydes could pre-
vent the undesired second reaction. It was postulated that
after the first insertion reaction of aromatic acetals
(Scheme 2, IV → VI), subsequent formation of oxonium
O
R
H
O
C
O
R
F3C
NH3Cl
CF3
NaNO2
then SbCl5
Scheme 1 Comparison of work herein with prior tactics
SYNTHESIS 2013, 45, 1857–1862
Advanced online publication: 06.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338485; Art ID: SS-2013-E0327-OP
© Georg Thieme Verlag Stuttgart · New York

1858
J. Y. Hamilton et al.
PAPER
Table 2 Substrate Scopea
VII would be disfavored due to the destabilizing effect of
the trifluoromethyl group (kf < kr). Accordingly, we set
out to investigate whether acetals would be suitable sub-
strates for the homologative trifluoromethylation inser-
tion reaction.
1)
F3C
NH3Cl
NaNO2, CH2Cl2/H2O (30:1)
0 °C, 1 h
O
O
R
O
O
R
2) SbCl5, −78 °C, 1 h
To our surprise, despite the rich chemistry of diazoal-
kanes, there is a single report by Doyle and co-workers of
homologation of acetals with ethyl diazoacetate in the
presence of BF3·OEt2,10 in which for all but two aldehydes
examined mixtures of C–C and C–H migration products
were observed, as well as cyclopropane products. More-
over, to the best of our knowledge, there are no examples
involving fluorinated diazoalkanes.
CF3
5
6
Entry
6
R
Yieldb (%)
69
1
6a
OMe
F
We began by examining 2-phenyl-1,3-dioxolane with
F3CCHN2, generated in situ, and BF3·OEt2. Although the
initial experimentation proved fruitful with electron-rich
acetals, the procedure did not prove general, especially
with more electron-deficient substrates.
2
3
4
5
6b
6c
6d
6e
76
62
65
57
A second screening was conducted with 2-(2-chlorophe-
nyl)-1,3-dioxolane (3) with several Lewis acids, which
led to the identification of SbCl5 as optimal (Table 1). A
control experiment with HCl was also conducted, as HCl
could arise from a hydrolytic decomposition of SbCl5, but
no product formation was observed (Table 1, entry 7).
With a convenient protocol11 in hand, the substrate scope
of this reaction was next examined (Table 2). Both elec-
tron-rich and electron-poor aryl acetals smoothly afforded
Cl
Br
6
6f
63
Table 1 Lewis Acid Screeninga
NaNO2
NH3Cl
51c
82
CH2Cl2/H2O
7
8
6g
6h
0 °C, 1 h
CF3
1
N2
CF3
2
TsN
O
9
6i
6j
76
70
O
O
Lewis acid
−78 °C
CF3 Cl
O
Cl
NTs
3
4
10
Entry
Lewis acid
Yieldb (%)
1
2
3
4
5
6
7
BF3·OEt2
AlCl3
ZrCl4
SnCl4
SbCl5
TiCl4
n.r.c
26
11
12
6k
6l
81
52d
28
a Reaction conditions: F3CCH2NH3Cl (3.0 equiv), NaNO2 (3.6 equiv),
CH2Cl2–H2O (30:1), stirring, 0 °C, 1 h; then, substrate (0.22 mmol,
1.0 equiv), SbCl5 (1.0 equiv), –78 °C.
76
64
b Isolated yield after purification by flash chromatography.
c Performed with SbCl5 (1.5 equiv).
HCl
n.r.c
d Lower yield due to product volatility.
a Reaction conditions: F3CCH2NH3Cl (3.0 equiv), NaNO2 (3.6 equiv),
CH2Cl2–H2O (30:1), stirring, 0 °C, 1 h; then, substrate (0.22 mmol,
1.0 equiv), Lewis acid (1.8 equiv), –78 °C.
the α-insertion products in good yields (Table 2, entries 1–
5). Sterically hindered phenyl groups were also tolerated
as substrates (Table 2, entry 6). We were pleased to find
b Yield determined by 19F NMR integration relative to (trifluorometh-
yl)benzene as the internal standard.
c n.r. = no reaction.
Synthesis 2013, 45, 1857–1862
© Georg Thieme Verlag Stuttgart · New York

PAPER
Homologative Trifluoromethylation of Acetals
1859
Unless otherwise noted, reagents were purchased from commercial
suppliers and used without further purification, and all reactions
were carried out under an atmosphere of argon. Reaction tempera-
tures are reported as the temperature of the bath surrounding the
vessel. Analytical thin-layer chromatography (TLC) was performed
on Merck silica gel 60 F254 TLC glass plates which were visualized
with 254 nm light and KMnO4 staining solutions followed by heat-
ing. Purification of reaction products was carried out by flash chro-
matography using Brunschwig silica gel 32–63, 60 Å and technical
grade pentane–Et2O, which were distilled prior to use, as eluent
with 0.3–0.5 bar pressure. Acetals were prepared by the reaction of
the corresponding aldehyde with ethylene glycol and catalytic p-tol-
uenesulfonic acid monohydrate in benzene with azeotropic removal
of water. Analytical data were in accordance with previously report-
ed values.15 1H NMR spectra were recorded at r.t. on a Varian Mer-
cury 300 MHz or a Bruker AV 400 MHz spectrometer and are
reported in ppm with the solvent resonance employed as the internal
standard (CDCl3 at 7.26 ppm). 13C NMR spectra were recorded with
1H decoupling on a Varian Mercury 300 or a Bruker AV 400 spec-
trometer (at 75 MHz and 100 MHz, respectively) with the solvent
resonance employed as the internal standard (CDCl3 at 77.0 ppm).
Infrared spectra were measured neat on a Perkin-Elmer Spectrum
BX FT-IR spectrometer. The peaks are reported as absorption max-
ima (ν, cm–1). Mass spectral data were obtained at the mass spec-
trometry service operated by the Laboratory of Organic Chemistry
at the ETHZ on a VG-TRIBRID instrument for electron impact ion-
ization (EI). The enantiomeric excess was determined by supercrit-
ical-fluid chromatography (SFC) on a Jasco 2080 Plus system. The
optical rotation was measured with a Jasco DID-1000 Polarimeter
(10 cm, 2 mL cell). The absolute configuration was determined by
comparison with a reported [α]D value.
that the reaction could be extended to heteroaromatics,
with reactions of 2-pyrrole and 3-indole acetals proceed-
ing well under the standard reaction conditions (Table 2,
entries 9 and 10). The method was also applicable to alke-
nyl acetals, where alkene migration took place to furnish
the α-trifluoromethyl-substituted β,γ-unsaturated acetals
(Table 2, entries 11 and 12). These results were particular-
ly interesting since convenient methods to construct an al-
lylic trifluoromethyl functionality are scarce.12
Application of this strategy to introduce the trifluorometh-
yl group in a stereoselective manner exploiting a chiral
acetal auxiliary was envisioned (Scheme 3).13 In this re-
spect, we disclose our preliminary observations toward
this endeavor. Acetal 7, derived from optically active stil-
bene diol and benzaldehyde, was prepared and investigat-
ed. For this case, TiCl4 proved to be a superior Lewis acid,
yielding the desired product 8 in good diastereoselectivity
(dr 9:1) and yield (83%). Hydrogenolytic cleavage of 8
furnished enantioenriched α-trifluoromethyl aldehyde
without racemization, which was immediately reduced for
the purpose of isolation and characterization.14
1)
F3C
NH3Cl
NaNO2, CH2Cl2/H2O (30:1)
0 °C, 1 h
Ph
Ph
O
O
2) TiCl4 (1.8 equiv)
–78 °C, 1 h
Ph
Ph
O
O
Lewis Acid Screen (Table 1); General Procedure
To a stirred soln of F3CCH2NH3Cl (3.0 equiv), CH2Cl2 (3 mL), and
H2O (0.1 mL) in a sealed Schlenk tube at 0 °C was added NaNO2
(3.6 equiv), and the resulting mixture was stirred at 0 °C for 1 h. The
reaction mixture was then cooled to –78 °C by stirring in a dry ice–
acetone bath for 10 min, which was followed by addition of the sub-
strate (0.22 mmol, 1.0 equiv) and the Lewis acid (1.8 equiv). The
mixture was stirred for 3 h, then the reaction was quenched by the
addition of MeOH (3 mL) and then sat. aq NaHCO3 (10 mL). The
mixture was warmed to r.t. and extracted with CH2Cl2 (3 × 10 mL).
The combined extracts were dried over Na2SO4, filtered, and con-
CF3
83%
9:1 dr
7
8
–
Ph
OTiCl4
H
F3C
Ph
Ph
N2
O
H
+
N2
centrated under reduced pressure. The yield was determined by 19
F
O+
Ph
NMR analysis with (trifluoromethyl)benzene as the internal stan-
dard.
OTiCl4
CF3
–
Scheme 3 Formal enantioselective trifluoroethyl α-insertion
Trifluoroethyl α-Insertion (Table 2); General Procedure
To a stirred soln of F3CCH2NH3Cl (3.0 equiv), CH2Cl2 (3 mL), and
H2O (0.1 mL) in a sealed Schlenk tube at 0 °C was added NaNO2
(3.6 equiv), and the resulting mixture was stirred at 0 °C for 1 h. The
reaction mixture was then cooled to –78 °C by stirring in a dry ice–
acetone bath for 10 min, which was followed by addition of the sub-
strate (0.22 mmol, 1.0 equiv) and SbCl5 (1.0 equiv). The mixture
was stirred for 1 h, then the reaction was quenched by the addition
of MeOH (3 mL) and then sat. aq NaHCO3 (10 mL). The mixture
was warmed to r.t. and extracted with CH2Cl2 (3 × 10 mL). The
combined extracts were dried over Na2SO4, filtered, and concentrat-
ed under reduced pressure. The crude product was purified via the
respective described method.
In summary, we have disclosed an insertion strategy using
in situ generated F3CCHN2 to furnish α-trifluoromethyl
acetals, which can be readily cleaved to yield the corre-
sponding aldehydes. This methodology is complementary
to other existing strategies to access these useful com-
pounds, as it employs F3CCH2NH2 instead of CF3I. Im-
portantly, the observations we describe represent the first
example of the use of acetals as starting materials for the
introduction of fluorinated fragments. The ability to use
heteroaromatic and alkenyl substrates has important im-
plications in medicinal chemistry. A preliminary result to
obtain enantioenriched α-trifluoromethyl aldehydes using
a chiral acetal has also been presented. Further investiga-
tion along this front will be reported in due course.
2-(2,2,2-Trifluoro-1-phenylethyl)-1,3-dioxolane (6a)
The crude product was purified via flash chromatography (pentane–
Et2O, 29:1) to afford 6a as a colorless oil; yield: 35 mg (69%).
IR (neat): 2956, 2895, 1498, 1457, 1401, 1365, 1251, 1163, 1145,
1106, 1048, 1032, 943, 875, 805 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37 (m, 5 H), 5.44 (d, J = 4.3 Hz,
1 H), 3.89–3.76 (m, 4 H), 3.58 (qd, J = 9.8, 4.3 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1857–1862

1860
J. Y. Hamilton et al.
PAPER
13C NMR (100 MHz, CDCl3): δ = 131.0 (q, J = 1.9 Hz), 130.1,
128.5, 128.4, 127.4 (q, J = 280.7 Hz), 101.8 (q, J = 2.5 Hz), 65.3,
65.2, 54.2 (q, J = 25.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –65.4 (d, J = 9.7 Hz).
HRMS (EI): m/z [M – H]+ calcd for C11H9BrF3O2: 308.9733; found:
308.9739.
19F NMR (376 MHz, CDCl3): δ = –65.2 (d, J = 9.7 Hz).
2-(2,2,2-Trifluoro-1-mesitylethyl)-1,3-dioxolane (6f)
The crude product was purified via flash chromatography (pentane–
Et2O, 49:1) to afford 6f as a white, amorphous solid; yield: 38 mg
(63%).
HRMS (EI): m/z [M – H]+ calcd for C11H10F3O2: 231.0627; found:
231.0621.
2-(2,2,2-Trifluoro-1-(4-methoxyphenyl)ethyl)-1,3-dioxolane
(6b)
The crude product was purified via flash chromatography (pentane–
Et2O, 14:1) to afford 6b as a white solid; yield: 44 mg (76%).
IR (neat): 2971, 2950, 2895, 2356, 2323, 1613, 1575, 1485, 1453,
1247, 1169, 1133, 1103, 1059, 1020, 943, 850, 823, 682 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.91 (d, J = 3.3 Hz, 2 H), 5.70 (d,
J = 6.8 Hz, 1 H), 4.20–3.98 (m, 3 H), 3.96–3.88 (m, 1 H), 3.87–3.78
(m, 1 H), 2.43 (s, 3 H), 2.37 (s, 3 H), 2.27 (s, 3 H).
IR (neat): 3007, 2962, 2929, 2902, 2837, 2361, 1883, 1616, 1519,
1305, 1273, 1244, 1162, 1118, 1031, 997, 939, 871, 816, 682 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.31 (dm, J = 8.7 Hz, 2 H), 6.90
(dm, J = 8.8 Hz, 2 H), 5.41 (d, J = 4.2 Hz, 1 H), 3.90–3.76 (m, 7 H),
3.54 (qd, J = 9.8, 4.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.8, 137.7, 137.3, 131.2, 129.5,
126.4 (q, J = 2.0 Hz), 126.0 (q, J = 281.5 Hz), 101.0 (q, J = 2.0 Hz),
65.3, 64.9, 51.2 (q, J = 26.4 Hz), 21.8, 21.6 (q, J = 3.5 Hz), 20.7.
13C NMR (75 MHz, CDCl3): δ = 159.2, 130.9, 125.2 (q, J = 279.4
Hz), 122.7, 113.7, 101.6, 65.3, 55.2, 53.4 (q, J = 25.4 Hz).
19F NMR (282 MHz, CDCl3): δ = –65.4 (d, J = 9.8 Hz).
19F NMR (376 MHz, CDCl3): δ = –62.1 (d, J = 10.5 Hz).
HRMS (EI): m/z [M]+ calcd for C14H17F3O2: 274.1181; found:
274.1169.
HRMS (EI): m/z [M]+ calcd for C12H13F3O3: 262.0812; found:
262.0810.
1,4-Bis(1-(1,3-dioxolan-2-yl)-2,2,2-trifluoroethyl)benzene (6g)
Following the general procedure using SbCl5 (1.5 equiv), the crude
product was purified via flash chromatography (pentane–Et2O, 4:1)
to afford 6g as a white, amorphous solid; yield: 44 mg (51%).
2-(2,2,2-Trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dioxolane (6c)
The crude product was purified via flash chromatography (pentane–
Et2O, 39:1) to afford 6c as a colorless oil; yield: 34 mg (62%).
IR (neat): 2956, 2902, 2847, 2359, 1522, 1401, 1321, 1245, 1127,
1100, 1055, 1025, 943, 853, 814 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38 (s, 4 H), 5.43 (d, J = 3.9 Hz,
1 H), 5.42 (d, J = 3.9 Hz, 1 H), 3.92–3.71 (m, 8 H), 3.60 (qd, J = 9.8,
3.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 131.1, 130.2, 125.2 (q, J = 280.8
Hz), 101.6 (q, J = 2.4 Hz), 65.3, 65.3, 53.7 (q, J = 25.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –65.1 (d, J = 9.8 Hz), –65.1 (d,
J = 9.8 Hz).
IR (neat): 2956, 2895, 2360, 2335, 1609, 1513, 1262, 1227, 1165,
1145, 1110, 1046, 944, 825 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37 (dd, J = 8.7, 5.4 Hz, 2 H),
7.05 (tm, J = 8.7 Hz, 2 H), 5.41 (d, J = 3.9 Hz, 1 H), 3.92–3.71 (m,
4 H), 3.60 (qd, J = 9.8, 3.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.8 (d, J = 247.4 Hz), 131.9 (d,
J = 8.1 Hz), 126.6, 125.2 (q, J = 279.9 Hz), 115.4 (d, J = 21.5 Hz),
101.5 (q, J = 2.1 Hz), 65.3, 65.2, 53.3 (q, J = 25.6 Hz).
19F NMR (376 MHz, CDCl3): δ = –65.5 (d, J = 9.7 Hz), –113.6.
HRMS (EI): m/z [M – H]+ calcd for C16H15F6O4: 385.0869; found:
HRMS (EI): m/z [M – H]+ calcd for C11H9F4O2: 249.0533; found:
385.0873.
249.0497.
2-(2,2,2-Trifluoro-1-(naphthalen-2-yl)ethyl)-1,3-dioxolane (6h)
The crude product was purified via flash chromatography (hexane–
Et2O, 9:1) to afford 6h as a pale yellow, amorphous solid; yield: 51
mg (82%).
2-(1-(4-Chlorophenyl)-2,2,2-trifluoroethyl)-1,3-dioxolane (6d)
The crude product was purified via flash chromatography (pentane–
Et2O, 39:1) to afford 6d as a colorless oil; yield: 38 mg (65%).
IR (neat): 3064, 2956, 2893, 1601, 1510, 1408, 1372, 1326, 1265,
1102, 1039, 1016, 822, 749, 675 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.91–7.83 (m, 4 H), 7.55–7.48 (m,
3 H), 5.55 (d, J = 4.1 Hz, 1 H), 3.90–3.73 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 132.9, 129.7, 128.2, 127.9, 127.5,
127.2, 126.3, 126.2, 125.3 (q, J = 280.3 Hz), 101.7, 65.3, 54.3 (q,
J = 25.4 Hz).
IR (neat): 2961, 2894, 2359, 2335, 1599, 1495, 1254, 1164, 1145,
1114, 1104, 1093, 1039, 1016, 943, 876, 819, 806, 728, 678 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.30 (m, 4 H), 5.41 (d,
J = 3.8 Hz, 1 H), 3.91–3.72 (m, 4 H), 3.59 (qd, J = 9.7, 3.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 134.6, 131.5, 129.3 (q, J = 1.7
Hz), 128.6, 125.1 (q, J = 280.6 Hz), 101.4 (q, J = 2.5 Hz), 65.4,
65.2, 53.5 (q, J = 25.7 Hz).
19F NMR (282 MHz, CDCl3): δ = –64.9 (d, J = 9.7 Hz).
HRMS (EI): m/z [M]+ calcd for C15H13F3O2: 282.0868; found:
19F NMR (376 MHz, CDCl3): δ = –65.4 (d, J = 9.6 Hz).
HRMS (EI): m/z [M – H]+ calcd for C11H9ClF3O2: 265.0238; found:
282.0861.
265.0243.
2-(1-(1,3-Dioxolan-2-yl)-2,2,2-trifluoroethyl)-1-tosyl-1H-pyr-
2-(1-(4-Bromophenyl)-2,2,2-trifluoroethyl)-1,3-dioxolane (6e)
The crude product was purified via flash chromatography (pentane–
Et2O, 49:1) to afford 6e as a colorless oil; yield: 39 mg (57%).
role (6i)
The crude product was purified via flash chromatography (pentane–
Et2O, 9:1) to afford 6i as a white, amorphous solid; yield: 63 mg
(76%).
IR (neat): 2956, 2892, 2359, 2335, 1594, 1492, 1252, 1163, 1145,
1114, 1104, 1037, 1012, 943, 814, 724, 674 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.51 (dm, J = 8.6 Hz, 2 H), 7.28
(d, J = 8.4 Hz, 2 H), 5.41 (d, J = 3.8 Hz, 1 H), 3.90–3.73 (m, 4 H),
3.58 (qd, J = 9.7, 3.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 131.8, 131.6, 129.8 (q, J = 1.9
Hz), 125.0 (q, J = 280.5 Hz), 122.8, 101.3 (q, J = 2.5 Hz), 65.4,
65.2, 53.5 (q, J = 25.7 Hz).
IR (neat): 3128, 2996, 2891, 1595, 1469, 1402, 1366, 1359, 1303,
1251, 1143, 1049, 881, 810, 750, 701, 669 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.4 Hz, 2 H), 7.38 (dd,
J = 3.4, 1.7 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.47 (br, 1 H), 6.30
(t, J = 3.4 Hz, 1 H), 5.32 (d, J = 4.2 Hz, 1 H), 4.70 (qd, J = 9.2, 4.2
Hz, 1 H), 3.83–3.73 (m, 3 H), 3.71–3.61 (m, 1 H), 2.40 (s, 3 H).
Synthesis 2013, 45, 1857–1862
© Georg Thieme Verlag Stuttgart · New York

PAPER
Homologative Trifluoromethylation of Acetals
1861
13C NMR (100 MHz, CDCl3): δ = 145.1, 136.3, 129.8, 126.9, 124.4
(q, J = 280.4 Hz), 124.0, 123.9 (q, J = 2.3 Hz), 116.5, 111.8, 101.6
(q, J = 2.2 Hz), 65.3, 65.2, 44.7 (q, J = 26.5 Hz), 21.6.
19F NMR (376 MHz, CDCl3): δ = –66.3 (d, J = 9.2 Hz).
HRMS (EI): m/z [M]+ calcd for C16H16F3NO4S: 375.0752; found:
(4R,5R)-4,5-Diphenyl-2-((R)-2,2,2-trifluoro-1-phenylethyl)-1,3-
dioxolane (8)
Following the general procedure using TiCl4 (1.8 equiv), the crude
product was purified via flash chromatography (pentane–Et2O, 4:1)
to afford 8 as a viscous oil; yield: 70 mg (83%). The product was
obtained as an inseparable mixture of diastereomers (dr 9:1).
375.0751.
IR (neat): 3033, 2894, 2361, 2335, 1496, 1454, 1351, 1315, 1265,
1167, 1137, 1115, 1046, 1026, 761 cm–1.
3-(1-(1,3-Dioxolan-2-yl)-2,2,2-trifluoroethyl)-1-tosyl-1H-indole
(6j)
The crude product was purified via flash chromatography (pentane–
Et2O, 4:1) to afford 6j as a white, amorphous solid; yield: 66 mg
(70%).
1H NMR (400 MHz, CDCl3): δ = 7.59–7.52 (m, 2 H), 7.45–7.38 (m,
3 H), 7.33–7.19 (m, 6 H), 7.17–7.09 (m, 2 H), 7.04* (dd, J = 7.5, 2.0
Hz, 0.2 H), 6.90 (dd, J = 8.0, 1.4 Hz, 1.8 H), 6.02 (d, J = 2.4 Hz, 0.9
H), 5.99* (d, J = 3.2 Hz, 0.1 H), 4.72* (d, J = 8.3 Hz, 0.1 H), 4.68
(d, J = 8.3 Hz, 0.9 H), 4.43* (d, J = 8.2 Hz, 0.1 H), 4.38 (d, J = 8.3
Hz, 0.9 H), 3.86 (qd, J = 10.0, 2.5 Hz, 1 H); assignable peaks of the
minor isomer are marked with asterisks.
13C NMR (100 MHz, CDCl3): δ = 137.2*, 137.1, 135.4, 135.3*,
130.7 (q, J = 1.7 Hz), 130.6, 128.6, 128.6, 128.5, 128.5, 128.5,
128.3, 126.8, 126.3, 125.45 (q, J = 280.7 Hz), 102.4 (q, J = 2.4 Hz),
102.2* (q, J = 2.4 Hz), 87.0*, 86.6, 85.4, 84.9*, 54.3 (q, J = 25.5
Hz); assignable peaks of the minor isomer are marked with aster-
isks.
IR (neat): 2976, 2899, 1596, 1444, 1370, 1258, 1165, 1112, 1090,
1073, 1038, 812, 736, 665 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 8.2 Hz, 1 H), 7.79–
7.73 (m, 3 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.38–7.19 (m, 4 H), 5.50
(d, J = 2.9 Hz, 1 H), 3.98 (qd, J = 9.6, 2.8 Hz, 1 H), 3.91–3.75 (m,
3 H), 3.64–3.55 (m, 1 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 135.1, 134.5, 130.8, 129.8,
126.8, 126.5, 125.1 (q, J = 280.4 Hz), 124.9, 123.5, 119.5, 113.6,
111.5, 101.0 (q, J = 2.5 Hz), 65.7, 65.1, 45.2 (q, J = 26.6 Hz), 21.5.
19F NMR (376 MHz, CDCl3): δ = –64.4* (d, J = 9.9 Hz, 0.3 F),
–64.8 (d, J = 10.0 Hz, 2.7 F).
HRMS (EI): m/z [M – H]+ calcd for C23H18F3O2: 383.1253; found:
19F NMR (376 MHz, CDCl3): δ = –66.3 (d, J = 9.7 Hz).
HRMS (EI): m/z [M]+ calcd for C20H18F3NO4S: 425.0909; found:
425.0900.
383.1252.
2-((E)-1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)-1,3-dioxolane
(6k)
(R)-3,3,3-Trifluoro-2-phenylpropan-1-ol
To a stirred soln of (4R,5R)-4,5-diphenyl-2-((R)-2,2,2-trifluoro-1-
phenylethyl)-1,3-dioxolane (8; 70 mg, 0.18 mmol) in MeOH (1.6
mL) was added 10% Pd/C (95 mg, 0.090 mmol), and the mixture
was stirred for 12 h under an atmosphere of H2. The reaction mix-
ture was then filtered, with MeOH (2.0 mL) washing. The filtrate
was cooled to –78 °C, NaBH4 (140 mg, 3.6 mmol) was added, and
the mixture was stirred at –78 °C for 1 h. Then, the reaction was
quenched by the addition of sat. aq NH4Cl (2 mL). The resulting
mixture was warmed to r.t. and diluted with sat. aq NaHCO3 (10
mL), which was followed by extraction with CH2Cl2 (3 × 10 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was puri-
fied via flash chromatography (pentane–Et2O, 9:1) to afford the
product as a white, amorphous solid; yield: 24 mg (69%). Analyti-
cal data were in accordance with reported values14 and the absolute
stereochemistry was determined as R by a comparison of [α]D val-
ues.
The crude product was purified via flash chromatography (pentane–
Et2O, 19:1) to afford 6k as a white, amorphous solid; yield: 46 mg
(81%).
IR (neat): 2959, 2895, 1450, 1394, 1325, 1257, 1149, 1100, 1039,
972, 948, 870, 748, 692 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.39 (m, 2 H), 7.38–7.24 (m,
3 H), 6.67 (d, J = 16.0 Hz, 1 H), 6.14 (dd, J = 16.0, 9.4 Hz, 1 H),
5.29 (d, J = 2.8 Hz, 1 H), 4.22–3.64 (m, 4 H), 3.33–3.17 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 137.8, 136.0, 128.5, 128.1, 126.5,
125.2 (q, J = 280.0 Hz), 116.8 (q, J = 2.3 Hz), 101.0 (q, J = 2.7 Hz),
65.8, 65.2, 52.0 (q, J = 25.4 Hz).
19F NMR (282 MHz, CDCl3): δ = –67.3 (d, J = 9.2 Hz).
HRMS (EI): m/z [M – H]+ calcd for C13H12F3O2: 257.0784; found:
257.0777.
[α]D21 +29.5 (c 0.50, CHCl3) [Lit.14 [α]D28 +33.3 (c 0.6, CHCl3)].
SFC [Daicel Chiralcel OJ-H, CO2–MeOH (98:2), 2 mL·min–1,
2-(1,1,1-Trifluoro-4-methylpent-3-en-2-yl)-1,3-dioxolane (6l)
The crude product was purified via flash chromatography (pentane–
Et2O, 79:1) to afford 6l as a colorless oil; yield: 24 mg (52%).
25 °C, 200 nm]: 83% ee [tR = 7.5 min (minor), 8.2 min (major)].
IR (neat): 2971, 2892, 2359, 1679, 1446, 1402, 1326, 1256, 1160,
1149, 1103, 1051, 1037, 1018, 876 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.18–5.13 (m, 1 H), 5.15 (d,
J = 3.5 Hz, 1 H), 4.00–3.84 (m, 4 H), 3.37–3.25 (m, 1 H), 1.80 (d,
J = 1.4 Hz, 3 H), 1.69 (d, J = 1.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 140.8, 125.7 (q, J = 280.5 Hz),
112.4 (q, J = 2.3 Hz), 101.6 (q, J = 2.8 Hz), 65.5, 65.2, 47.1 (q,
J = 25.1 Hz), 26.1, 18.5.
IR (neat): 3359, 2956, 2360, 2335, 1493, 1454, 1361, 1318, 1254,
1156, 1112, 1028, 873, 795, 701 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.31 (m, 5 H), 4.20 (ddd,
J = 11.5, 7.6, 5.8 Hz, 1 H), 4.04 (ddd, J = 11.5, 7.7, 5.6 Hz, 1 H),
3.62–3.50 (m, 1 H), 1.54 (dd, J = 7.6, 5.6 Hz, 1 H, OH).
13C NMR (100 MHz, CDCl3): δ = 132.5 (q, J = 2.1 Hz), 129.1,
129.0, 128.7, 126.1 (q, J = 280.4 Hz), 61.4 (q, J = 2.8 Hz), 52.6 (q,
J = 25.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –67.5 (d, J = 9.2 Hz).
HRMS (EI): m/z [M – H]+ calcd for C9H12F3O2: 209.0784; found:
19F NMR (376 MHz, CDCl3): δ = –67.4 (d, J = 9.4 Hz).
HRMS (EI): m/z [M]+ calcd for C9H9F3O: 190.0605; found:
209.0776.
190.0597.
(4R,5R)-2,4,5-Triphenyl-1,3-dioxolane (7)
Compound 7 was obtained by following a reported procedure.16 An-
alytical data were in accordance with reported values.
Acknowledgment
We are grateful to the ETH Zürich for financial support.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1857–1862

1862
J. Y. Hamilton et al.
PAPER
Tetrahedron Lett. 2008, 49, 3558. (b) Sato, K.; Yuki, T.;
Yamaguchi, R.; Hamano, T.; Tarui, A.; Omote, M.;
Kumadaki, I.; Ando, A. J. Org. Chem. 2009, 74, 3815.
(c) Tomita, Y.; Itoh, Y.; Mikami, K. Chem. Lett. 2008, 37,
1080. (d) Sato, K.; Higashinagata, M.; Yuki, T.; Tarui, A.;
Omote, M.; Kumadaki, I.; Ando, A. J. Fluorine Chem. 2008,
129, 51.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
References
(1) Present address: Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
CA 91125, USA.
(7) (a) Morandi, B.; Carreira, E. M. Angew. Chem. Int. Ed.
2010, 49, 938. (b) Morandi, B.; Carreira, E. M. Angew.
Chem. Int. Ed. 2010, 49, 4294. (c) Morandi, B.;
Mariampillai, B.; Carreira, E. M. Angew. Chem. Int. Ed.
2011, 50, 1101. (d) Morandi, B.; Cheang, J.; Carreira, E. M.
Org. Lett. 2011, 13, 3080. (e) Morandi, B.; Dolva, A.;
Carreira, E. M. Org. Lett. 2012, 14, 2162. (f) Morandi, B.;
Carreira, E. M. Science 2012, 335, 1471.
(8) (a) Morandi, B.; Carreira, E. M. Org. Lett. 2011, 13, 5984.
(b) Künzi, S. A.; Morandi, B.; Carreira, E. M. Org. Lett.
2012, 14, 1900.
(9) Morandi, B.; Carreira, E. M. Angew. Chem. Int. Ed. 2011,
50, 9085.
(2) For general reviews on fluorine chemistry, see: (a) Kirsch, P.
Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications; Wiley-VCH: Weinheim, 2004. (b) Schlosser,
M. Angew. Chem. Int. Ed. 2006, 45, 5432. (c) Müller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320. (e) Isanbor, C.; O’Hagan, D. J. Fluorine
Chem. 2006, 127, 303. (f) Jeschke, P. ChemBioChem 2004,
5, 570. (g) Babudri, F.; Farinola, G. M.; Naso, F.; Ragni, R.
Chem. Commun. 2007, 1003.
(3) For general reviews on fluorination and fluoromethylation,
see: (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(b) Dawood, K. M. Tetrahedron 2004, 60, 1435.
(10) Doyle, M. P.; Trudell, M. L.; Terpstra, J. W. J. Org. Chem.
1983, 48, 5146.
(c) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475. (d) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
2011, 473, 470. (e) Hu, J.; Zhang, W.; Wang, F. Chem.
Commun. 2009, 7465.
(11) Further experimentation allowed reduction of the SbCl5
loading (1.8 → 1.0 equiv) and the reaction time (3 → 1 h)
without any discernible deterioration to the yield.
(12) For recent examples of trifluoromethylation of olefins, see:
(a) Parsons, A. T.; Buchwald, S. L. Angew. Chem. Int. Ed.
2011, 50, 9120. (b) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.;
Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Liu, L. J. Am. Chem. Soc.
2011, 133, 15300. (c) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.;
Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133,
16410.
(13) For a review on chiral acetals in asymmetric synthesis, see:
Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990,
1, 477.
(14) Konno, T.; Takehana, T.; Mishima, M.; Ishihara, T. J. Org.
Chem. 2006, 71, 3545.
(4) For electrophilic trifluoromethylation, see: (a) Kieltsch, I.;
Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46,
754. (b) Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.;
Shiro, M. Eur. J. Org. Chem. 2008, 3465. (c) Umemoto, T.;
Adachi, K. J. Org. Chem. 1994, 59, 5692. (d) Umemoto, T.;
Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156. For a recent
example of organocatalytic enantioselective
trifluoromethylation of aldehydes, see: (e) Allen, A. E.;
Macmillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986.
(f) Nagib, D. A.; Scott, M. E.; Macmillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 10875.
(5) For radical trifluoromethylation, see: (a) Itoh, Y.; Mikami,
K. J. Fluorine Chem. 2006, 127, 539. (b) Mikami, K.;
Tomita, Y.; Ichikawa, Y.; Amikura, K.; Itoh, Y. Org. Lett.
2006, 8, 4671. (c) Itoh, Y.; Mikami, K. Org. Lett. 2005, 7,
4883. (d) Tomita, Y.; Ichikawa, Y.; Itoh, Y.; Kawada, K.;
Mikami, K. Tetrahedron Lett. 2007, 48, 8922. (e) Itoh, Y.;
Houk, K. N.; Mikami, K. J. Org. Chem. 2006, 71, 8918.
(f) Petrik, V.; Cahard, D. Tetrahedron Lett. 2007, 48, 3327.
(6) For metal-catalyzed trifluoromethylation, see: (a) Sato, K.;
Yuki, T.; Tarui, A.; Omote, M.; Kumadaki, I.; Ando, A.
(15) (a) Gregg, B. T.; Golden, K. C.; Quinn, J. F. Tetrahedron
2008, 64, 3287. (b) Barbasiewicz, M.; Mąkosza, M. Org.
Lett. 2006, 8, 3745. (c) Müller, P.; Nury, P.; Bernardinelli,
G. Eur. J. Org. Chem. 2001, 4137. (d) Kmentová, I.; Toma,
S. Collect. Czech. Chem. Commun. 2002, 67, 1616. (e) Jang,
Y.-J.; Shih, Y.-K.; Liu, J.-Y.; Kuo, W.-Y.; Yao, C.-F. Chem.
Eur. J. 2003, 9, 2123.
(16) Superchi, S.; Contursi, M.; Rosini, C. Tetrahedron 1998, 54,
11247.
Synthesis 2013, 45, 1857–1862
© Georg Thieme Verlag Stuttgart · New York