Oxidation of α-trifluoromethyl alcohols using a recyclable oxoammonium salt

Article abstract of DOI:10.1021/jo301477s

A simple, mild method for the oxidation of α-trifluoromethyl alcohols to trifluoromethyl ketones (TFMKs) using the oxoammonium salt 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) is described. Under basic conditions, oxidation proceeds rapidly and affords good to excellent yields of TFMKs, without concomitant formation of the hydrate. The byproduct of the oxidation, 4-acetylamino-2,2,6,6-tetramethyl-1- piperidinyloxy (1c), is easily recovered and can be conveniently reoxidized to regenerate the oxoammonium salt.

Full text of DOI:10.1021/jo301477s

Article
pubs.acs.org/joc
Oxidation of α‑Trifluoromethyl Alcohols Using a Recyclable
Oxoammonium Salt
Christopher B. Kelly,† Michael A. Mercadante,† Trevor A. Hamlin,† Madison H. Fletcher,†
and Nicholas E. Leadbeater*,†,‡
†Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269-3060, United States
‡Department of Community Medicine & Health Care, University of Connecticut Health Center, The Exchange, 263 Farmington
Avenue, Farmington, Connecticut 06030, United States
S
* Supporting Information
ABSTRACT: A simple, mild method for the oxidation of α-
trifluoromethyl alcohols to trifluoromethyl ketones (TFMKs)
using the oxoammonium salt 4-acetylamino-2,2,6,6-tetrame-
thylpiperidine-1-oxoammonium tetrafluoroborate (1) is de-
scribed. Under basic conditions, oxidation proceeds rapidly
and affords good to excellent yields of TFMKs, without
concomitant formation of the hydrate. The byproduct of the
oxidation, 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy
(1c), is easily recovered and can be conveniently reoxidized to regenerate the oxoammonium salt.
overwhelming majority of oxidation methodologies employ
the powerful Dess−Martin periodinane (DMP). However,
there are significant drawbacks of using DMP, including its cost
and the fact that spent oxidant cannot be easily recovered.13
Moreover, in the case of α-CF3 alcohols, a large excess of the
oxidant is required to obtain acceptable yields of TFMKs.10,11
Another problem with the use of most current oxidation
methodologies is the concomitant formation of the hydrate of
the TFMK rather than the desired ketone product.
Subsequently, diminished yields of TFMKs are obtained
because of the high degree of solubility of these hydrates in
water and difficulties in dehydrating them back to the TFMK.
To address this, one option is to use polymer-supported
permanganate in conjunction with supported scavengers where
the oxidation can be performed and the product obtained
without the need for an aqueous workup or column
chromatography.14
Seeking an alternative oxidant for α-CF3 alcohols as well as
avoiding formation of the hydrate, our attention turned to the
possibility of using oxoammonium ions to perform this
transformation. TEMPO and its other oxyl analogues
(including AcNH-TEMPO, 1c) are known to be effective
catalysts for the oxidation of a variety of functional groups in
the presence of a stoichiometric terminal oxidant (typically
using commercial bleach containing NaOCl).15 While examples
of oxidation of α-CF3 alcohols using TEMPO-based catalysts
are known,16,17 the reactions are biphasic (typically DCM/basic
water) and hence diminished yields of the TFMK product are
obtained due to hydrate formation. Therefore, TEMPO-based
catalysts have been sparsely employed in the literature to
INTRODUCTION
■
Incorporation of the trifluoromethyl (CF3) group into organic
molecules is known to have profound effects on their physical
and chemical properties.1 One of the most important effects,
enhancement of lipophilicity, is of great utility to medicinal
chemists.1d−f Many recent drugs and drug candidates for
treating a variety of ailments from cancer to viral infections
feature this moiety.1e,2
One class of compounds containing the CF3 group that is of
particular interest is the trifluoromethyl ketone (TFMK).
TMFKs are themselves potent enzyme inhibitors3 and also
serve as critical intermediates in constructing trifluoromethy-
lated heterocycles,4 medicinal compounds,5 and fluorinated
analogues of natural products.6 The importance of this motif is
exemplified in the synthesis of one of the leading antiretroviral
drugs in the treatment of HIV, Efavirenz (Sustiva).7 TFMKs
have also found application in probing enzymatic mechanisms
by mimicking transition states because of their ability to readily
form stable hydrates.8
Despite their importance, the incorporation of TFMKs into
organic molecules is nontrivial. Current methods typically
involve using one of two major routes: acetylation with
trifluoroacetic acid derivatives (via organometallic intermedi-
ates) or oxidation of α-CF3 alcohols.9 Due to the inherent
danger of working with main-group organometallics and their
high degree of reactivity with a variety of functional groups, the
latter route is often preferred.10
Perfluoroalcohols are notoriously difficult to oxidize, a
property that can likely be attributed to their electron-deficient
nature.11 Unlike their hydrocarbon analogues, many traditional
methods for oxidation (metal or DMSO-based) are ill-suited to
oxidize a broad range of α-CF3 alcohols and attempts using
these methods result in poor yields or failure.12 The
Received: July 19, 2012
Published: August 29, 2012
© 2012 American Chemical Society
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a
oxidize these alcohols. Alternatively, we were interested in
determining whether 4-acetamido-2,2,6,6-tetramethyl-1-oxopi-
peridin-1-ium tetrafluoroborate (1; “Bobbitt’s salt”),18 could be
used as a stoichiometric oxidant of α-CF3 alcohols. Such a
methodology would have several advantages over current
methods: (1) oxoammonium salts are extremely mild and
selective oxidants, allowing for a broad functional group
tolerance, (2) oxidations of alcohols using these salts can be
conducted without water, (3) oxoammonium salts are metal-
free, nontoxic, and, most importantly, recyclable, and (4) 1 can
easily be prepared in house on a large scale at minimal expense
($0.50/g on a mole scale).18a,b We report our results here.
Table 1. Oxidation of Aryl-Functionalized Substrates
b
c
entry
substrate
R
Y
product
yield, %
1
2a
2b
2c
2d
2e
2f
4-Me
C−H
C−H
C−H
C−H
C−H
C−H
C−H
C−H
C−H
C−H
N
3a
3b
3c
3d
3e
3f
71
90
89
99
96
78
97
73
96
89
96
2
4-OMe
3-OMe
4-NO2
3-NO2
2-Br, 4-F
3,4-OCH2O-
2-F
3
4
5
RESULTS AND DISCUSSION
■
6
We began our investigation by probing whether oxidation of α-
CF3 alcohols could be achieved using the standard conditions
for stoichiometric oxoammonium-mediated oxidations.18a
Using 2,2,2-trifluoro-1-(p-tolyl)ethanol (2a) as a representative
substrate, prepared via trifluoromethylation of the correspond-
ing aldehyde using the Ruppert−Prakash reagent (TMS-
CF3),19 we attempted oxidation in both neutral and weakly
acidic media.18a However, even after extended reaction times,
the desired product, 3a, was not detected in either case. On the
basis of the posited mechanism of Bailey,18c,g oxidation under
these conditions would result in a highly destabilized α-CF3
carbocation following the required hydride transfer (Figure 1).
7
2g
2h
2i
3g
3h
3i
8
9
2-OMe
2-NO2
H
10
11
2j
3j
2k
3k
a
Conditions unless otherwise noted: α-CF3 alcohol (1 equiv), 1 (2.5
equiv), 2,6-lutidine (2.25 equiv), CH2Cl2 (0.4 M in starting alcohol).
α-CF3 alcohols were prepared via trifluormethylation of the
corresponding aldehydes using TMS-CF3. Isolated yield after
b
c
purification.
In addition to investigating aryl-functionalized substrates, we
also investigated aliphatic, allylic, and propargylic α-CF3
alcohols to see if they too would be compatible with our
oxidation conditions (Table 2). Aliphatic substrates (entries 1−
3) failed to oxidize appreciably under our standard conditions,
affording primarily starting material, despite increased reaction
times and additional oxidant loading. However, when a stronger
base was utilized (1,5-diazabicyclo[4.3.0]non-5-ene, DBN),
Figure 1. Postulation as to why oxidation in neutral and weakly acidic
media was unsuccessful.
Table 2. Oxidation of Alkyl- And Allyl-Functionalized
Substrates
a
Our attempts to oxidize these α-CF3 alcohols likely failed due
to the high activation barrier of this process.18c,g It is known
that β-oxygen compounds, which share electronics similar to
those of α-CF3 alcohols, fail to oxidize readily when treated
with 1 under standard conditions, likely for the same
reason.18d,f
We therefore attempted the base-mediated oxidation of 2a.
To our delight, upon treatment of 2a with 2.5 equiv of 1 and
2.25 equiv of pyridine in dichloromethane, we observed slow
but steady formation of 3a. Seeking to accelerate the rate of
oxidation, we switched to the more basic 2,6-lutidine.20 While
the reaction in the presence of pyridine typically took overnight
to reach completion, in the case of 2,6-lutidine the reaction was
complete within a few hours. Attempts using a stronger base,
2,4,6-collidine,20 were successful, and the rate of the reaction
was dramatically accelerated, but difficulties in purification of
the TFMK product led us to choose 2,6-lutidine as the optimal
base for our methodology.
With reaction conditions in hand, we sought to explore the
substrate scope of the oxidation by first screening a variety of
aryl systems (Table 1). Both electron-rich (entries 1−3, 7, and
9) and electron-poor (entries 4−6, 8, and 10) arenes are well-
tolerated under our oxidation conditions. We attribute the
slightly diminished yield of certain substrates (entries 1 and 8)
to the volatility of their corresponding TFMK products. A
representative pyridyl-functionalized substrate (2k, entry 11) is
equally well-tolerated, affording 3k in excellent yield.
a
α-CF3 alcohols were prepared via trifluormethylation of the
b
corresponding aldehydes using TMS-CF3. Isolated yield after
purification. Conditions: α-CF3 alcohol (1 equiv), 1 (3.0 equiv),
DBN (2.5 equiv), CH2Cl2 (0.1 M in starting alcohol). Conditions: α-
CF3 alcohol (1 equiv), 1 (2.5 equiv), 2,6-lutidine (2.25 equiv), CH2Cl2
c
d
(0.4 M in starting alcohol).
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rapid conversion to the desired TMFK was observed (entries
1−3). We attribute this change in reactivity to a more tightly
bound ion pairing between the now formally deprotonated α-
CF3 alcohol and 1, resulting in a facile hydride transfer. As a
practical matter, additional base and salt were necessary for
optimal conversion, since DBN is slowly oxidized by the
oxoammonium salt. Additionally, because of this degradation of
the base, further purification was necessary, resulting in
diminished isolated yields. When a point of unsaturation was
introduced at the carbon adjacent to the α-CF3 alcohol moiety,
oxidation proceeded smoothly with 2,6-lutidine as the base.
Both conjugated (Table 2, entries 4, 6, and 8) and
nonconjugated (entry 5) allylic alcohols afford excellent yields.
A propargylic substrate (2r, entry 7) is equally well-tolerated
and the reaction proceeds much faster than expected on the
basis of previous propargylic oxidations using 1.18a
Table 3. Relative Rates of Oxidation of α-CF3 Alcohols to
Their Corresponding TFMKs by Oxoammonium Salt
Oxidation
To further demonstrate the power of our oxidation
methodology over current methods and exploit the selectivity
of 1, a substrate (2t) containing both α-CF3 alcohol (Figure 2,
the current model for oxidation by oxoammonium cations
under basic conditions.18c
Finally, to determine if the spent oxidant could be recycled,
crude 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy (1c)
from several runs was dissolved in water and salted out with
sodium chloride to afford an 87% recovery of 1c. This
recovered nitroxide was converted into 1 in the standard
manner in comparable yield (70%) and used for later oxidations
with no detrimental effect on oxidant reactivity and with a
TFMK yield no more than 5% different than that using freshly
made 1.
Figure 2. Chemoselective oxidations based on reaction media.
CONCLUSION
■
We have reported here an effective, mild method for the
oxidation of α-CF3 alcohols to their corresponding TFMKs.
The reaction is compatible with a wide array of substrates,
proceeds rapidly, can be used to affect chemoselective
oxidations, and affords TFMKs in excellent yield. Moreover,
the spent oxidant is easily recovered and recycled.
in blue) and benzyl alcohol (Figure 2, in red) functionalities
was prepared. In the case of most other oxidants, selective
oxidation would be unlikely and hence a protecting group
strategy would need to be used. However, by simple adjustment
of the reaction conditions, chemoselective oxidation was possible.
The unsubstituted alcohol was readily oxidized to 2t′ in
excellent yield under weakly acidic conditions, while the α-CF3
alcohol group remained intact. The α-CF3 alcohol 2t′ could
then be oxidized using the standard basic conditions to afford
3t in good yield.
EXPERIMENTAL SECTION
General Considerations. All chemical transformations requiring
inert atmospheric conditions or vacuum distillation utilized Schlenk
line techniques with a three- or four-port dual-bank manifold.
■
1
Nitrogen was used to provide such an atmosphere. H NMR spectra
obtained in CDCl3 were referenced to residual nondeuterated
chloroform (7.26 ppm) in the deuterated solvent or in deuterated
methanol referenced to TMS (0.00 ppm). 13C NMR spectra obtained
in CDCl3 were referenced to chloroform (77.3 ppm) or in deuterated
methanol referenced to TMS (0.00 ppm). 19F NMR spectra were
referenced to fluorobenzene (−115.3 ppm) or hexafluorobenzene
(−164.9 ppm).22 Reactions were monitored by GCMS, 1H NMR,
and/or TLC on silica gel plates (60 Å porosity, 250 μm thickness).
TLC analysis was performed using hexanes/ethyl acetate as the eluent
and visualized using permanganate stain, p-anisaldehyde stain,
Seebach’s stain, and/or UV light. Flash chromatography and silica
plugs utilized flash silica gel (60 Å porosity, 32−63 μm).
Chemicals. CDCl3 was stored over 4 Å molecular sieves and
anhydrous K2CO3. Unless otherwise specified, all aldehydes were
purchased from commercial sources and used without further
purification. (Trifluoromethyl)trimethylsilane and 2-bromo-4-fluoro-
benzaldehyde were purchased from Synquest Laboratories. 4-Amino-
2,2,6,6-tetramethylpiperidine and sodium tungstate, used to prepare
oxoammonium salt 1, were supplied by Dr. James M. Bobbitt via the
TCI America Corp.
To gain further insight into the reaction, we obtained rate
data for our oxidation using the method of Mullet and
Nodding.21 Unlike the competitive rate studies typically
used,18a we believed that this alternative method would be
more effective for our systems in obtaining this information
because of complications that arose when analyzing 1H and 19
F
NMR spectra. We determined the relative rates of oxidation of
five representative substrates (Table 3).
Aryl-substituted substrates all oxidized at about the same
rate, and therefore, we utilized 2a as our model substrate for
comparison. From the data in Table 3, we theorize that there is
a large steric component to the reaction. We suggest that the
combined electronic repulsion by the highly electron-rich CF3
group and the steric repulsion by any β-substituent contribute
significantly to oxidant/alcohol complexation and hence
successful oxidation. This likely explains the drastic increase
in rate with increasing conjugation as well as the large rate
acceleration observed for 2r over 2a and is in agreement with
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Oxidant Preparation.18a 4-Acetamido-2,2,6,6-tetramethylpiper-
idin-1-ium Acetate (1b). To a 4 L Erlenmeyer flask was added 2,2,6,6-
tetramethylpiperidin-4-amine (1a; 156.27 g, 1 mol, 1 equiv) and
anhydrous Et2O (564 mL, 1.774 M in 1a) along with a large stir bar.
The flask was cooled to 0 °C in a large ice bath. While the mixture was
vigorously stirred, acetic anhydride (306.27 g, 3 mol, 3 equiv) in 138
mL of anhydrous Et2O was added dropwise over 1 h via an addition
funnel. Upon addition of the anhydride, the solution instantaneously
turned white and a precipitate formed. The milk-white mixture was
allowed to react overnight. The next day the white solid was filtered
through a large medium-porosity fritted funnel and washed four times
(150 mL each) with anhydrous Et2O and placed on a large watch glass
to dry overnight to give 1b (242.22 g, 94%), which was carried on
directly to the next step without further purification. (Note: normally
1b was allowed to dry overnight. However, if it was gently warmed by
placing the watch glass on top of an oven, the solid dried much faster
and was usable the same day.)
4-Acetamido-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (1c). In a 6 L
beaker equipped with a large stir bar was added 1b (242.22 g, 0.9375
mol, 1 equiv) and deionized water (1.736 L, 0.54 M in 1b). The
solution was stirred vigorously, and once all of the 1b had dissolved,
Na2CO3 (231.52 g, 2.18 mol, 2.33 equiv) was added in four portions
over 10 min. After addition of Na2CO3 was complete, Na2WO4
(15.426 g, 0.052 mol, 0.056 equiv) and EDTA (12.33 g, 0.0422
mol, 0.045 equiv) were added all at once. After 5 min, 30 wt % H2O2
(300 mL, 99.80 g, 2.934 mol, 3.13 equiv) was added dropwise via an
addition funnel over the course of 2 h. Once the addition was
complete, the solution gradually began to foam and became yellow.
The solution then became a vivid orange while continuing to produce
a small foam layer. The solution was stirred for 72 h. The beaker was
then cooled to 0 °C in a large ice bath for 30−45 min, causing an
orange precipitate to form. The solid was filtered through a large
medium-porosity fritted funnel and washed with ice-cold water. The
orange solid was placed on a watch glass and allowed to dry in the
same way as for 1b. The volume of the filtrate was estimated, and
enough NaCl was added to this aqueous orange liquid to bring it to 3
M in NaCl. This resulted in the immediate “salting out” of the
remaining 1c in this layer. The solid was filtered and washed with a
minimum amount of ice-cold water. This orange solid was also placed
on the watch glass and dried, giving 1c (yield 164.676 g, 82.5%; mp
145−146 °C, lit. mp 145−147 °C).
4-Acetamido-2,2,6,6-tetramethyl-1-oxopiperidin-1-ium Tetra-
fluoroborate (1). In a 2 L beaker, equipped with a large stir bar
,was added 1c (164.676 g, 0.772 mol, 1 equiv) and deionized water
(330 mL, 2.34 M in 1c). While the mixture was stirred vigorously, 48
wt % HBF4 (163.1 g, 0.891 mol, 1.154 equiv) was added dropwise to
the beaker via an addition funnel over the course of 15 min. The
solution turned a light yellow and was stirred for 30 min. Upon
completion of this time, the beaker was cooled to 0 °C for 10 min. At
this time, fresh commercial sodium hypochlorite (Chlorox 6.00 wt %,
28.735 g, 0.386 mol, 0.5 equiv) was added dropwise via an addition
funnel over the course of 1 h. Once completely added, to the yellow-
orange solution was added NaBF4 (84.76 g, 0.772 mol, 1 equiv) and
the reaction mixture was stirred for 3 h (addition of NaBF4 improved
the yield substantially, likely due to reduced solubility of 1 via the
common ion effect). The reaction mixture was then filtered through a
large medium-porosity filter funnel and washed with a minimum
amount of cold CH2Cl2 and cold water. Upon drying, 1 (211.0 g, 91%)
was obtained as a fine yellow powder.
procedure outlined by Kelly et al.24 To a 100 mL round-bottom flask
equipped with a stir bar was added THF (24 mL), p-tolualdehyde
(2.723 g, 0.020 mol, 0.83 M, 1 equiv), and (trifluoromethyl)-
trimethylsilane (3.12 g, 0.022 mol, 1.3 equiv). The flask was sealed
with a rubber septum and placed under a N2 atmosphere via an inlet
needle. The reaction mixture was cooled to 0 °C in an ice−water bath
and stirred via a magnetic stir plate. After approximately 10 min, TBAF
(1 M in THF, 0.2 mL, 0.0002 mol, 0.01 equiv) was added dropwise via
a syringe. Note: on small scales, i.e. <20 mmol, the TBAF could be
added relatively quickly. However, upon scale-up the addition of
TBAF is quite exothermic. Hence, it is recommended that the TBAF
be added as slowly as possible and/or the reaction mixture be cooled
to a temperature lower than 0 °C.
After 10 min, the ice bath was removed and the solution was stirred
for approximately 6 h at room temperature. To cleave the silyl ether
intermediate, the reaction mixture was cooled to 0 °C in an ice bath.
After 10 min, water (2 mL, 0.110 mol, 5.5 equiv) was added via a
syringe. TBAF (1 M in THF, 2 mL, 0.002 mol, 0.1 equiv) was then
added. After 10 min the ice bath was removed and the reaction
mixture was stirred at room temperature. When the cleavage was
judged to be complete (determined by GC-MS or NMR), the contents
of the flask were transferred to a separatory funnel. Note: some of the
silyl ethers were very slow to cleave and required another addition of
TBAF and water. Brine (∼100 mL) and Et2O (∼150 mL) were added,
and the layers were partitioned. The aqueous layer was back-extracted
(3 × ∼50 mL) with Et2O. The combined ether layers were dried with
Na2SO4, and the solvent was removed in vacuo via rotary evaporation
to afford crude 2, which was further purified by vacuum distillation (bp
85−87 °C @ 11.5 mmHg) to give the pure α-CF3 alcohol 2 (2.75 g,
78%) as a colorless oil: 1H NMR (CDCl3, 400 MHz; δ, ppm) 3.79 (br
s, 1 H), 4.95 (q, J = 6.68 Hz, 1 H), 7.40−7.51 (m, 5 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 73.0 (q, JC−C−F = 32.0 Hz, CH), 120.3−
128.8 (q, JC−F = 281.7 Hz, CF3), 127.7 (CH), 127.7 (CH), 128.9
(CH), 129.8 (CH), 134.2 (C); 19F NMR (CDCl3, 377 MHz; δ, ppm)
−78.13 (d, J = 6.81 Hz); GC-MS (EI) 190 ([M]+, 45%), 122 (10%),
121 (100%), 93 (54%), 91 (60%), 77 (35%), 69 (6%), 65 (12%).
2,2,2-Trifluoro-1-(p-tolyl)ethanol25 (2a). The title compound (3.02
g, 79%) was prepared according to the representative procedure from
p-tolualdehyde (2.723 g, 0.020 mol) followed by vacuum distillation
(bp 59−62 °C @ 0.4 mmHg) to give the pure α-CF3 alcohol 2a as a
1
colorless oil: H NMR (CDCl3, 500 MHz; δ, ppm) 2.39 (s, 3 H),
2.84−2.97 (m, 1 H), 4.95 (q, J = 6.52 Hz, 1 H), 7.23 (d, J = 7.57 Hz, 2
H), 7.36 (d, J = 7.57 Hz, 2 H); 13C NMR (CDCl3, 126 MHz; δ, ppm)
21.4 (CH3), 73.0 (q, JC−C−F = 32.1 Hz, CH), 121.4−128.0 (q, JC−F
=
283.2 Hz, CF3), 127.6 (CH), 129.6 (CH), 131.4 (C), 139.8 (C); 19F
NMR (CDCl3, 376 MHz; δ, ppm) −78.25 (d, J = 6.81 Hz); GC-MS
(EI) 190 ([M]+, 45%), 122 (10%), 121 (100%), 93 (54%), 91 (60%),
77 (35%), 69 (6%), 65 (12%).
2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol28 (2b). The title
compound (3.284 g, 80%) was prepared according to the
representative procedure from p-anisaldehyde (2.723 g, 0.020 mol)
followed by vacuum distillation (bp 87−90 °C @ 1 mmHg) to give the
1
pure α-CF3 alcohol 2b as a clear colorless oil: H NMR (CDCl3, 400
MHz; δ, ppm) 3.24−3.37 (m, 1 H), 3.80 (s, 3 H), 4.91 (q, J = 6.85 Hz,
1 H), 6.92 (d, J = 8.80 Hz, 2 H), 7.37 (d, J = 8.80 Hz, 2 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 55.5 (CH3), 72.6 (q, JC−C−F = 31.5 Hz,
CH), 114.3 (CH), 120.4−128.8 (q, JC−F = 281.7 Hz, CF3), 126.5 (d,
JC−C−C−F = 1.5 Hz, CH), 129.1 (C), 160.6 (C); 19F NMR (CDCl3, 377
MHz; δ, ppm) −78.61 (d, J = 6.81 Hz); GC-MS (EI) 206 ([M]+,
37%), 137 (100%), 109 (27%), 94 (28%), 77 (25%), 69 (4%).
2,2,2-Trifluoro-1-(3-methoxyphenyl)ethanol (2c). The title com-
pound (3.405 g, 83%) was prepared according to the representative
procedure from m-anisaldehyde (2.723 g, 0.020 mol) followed by
vacuum distillation (bp 78−80 °C @ 0.5 mmHg) to give the pure α-
CF3 alcohol 2c as a clear colorless oil: 1H NMR (CDCl3, 400 MHz; δ,
ppm) 3.81 (s, 3 H), 4.95 (q, J = 6.85 Hz, 1 H), 6.95 (ddd, J = 8.25,
2.51, 0.98 Hz, 1 H), 7.01−7.06 (m, 2 H), 7.32 (t, J = 7.80 Hz, 1 H);
For enhanced purity, 1 can be recrystallized from boiling deionized
water followed by filtration through coarse filter paper and rapid
cooling to 0 °C in an ice bath. However, this often leads to only 50−
60% recovered of pure 1. In the case of this study, recrystallized 1 did
not have any beneficial effect. In fact, oxidation of α-CF3 alcohols
seemed to occur faster, likely due to the enhanced surface area to
volume when in the powdered form.
Synthesis of α-Trifluoromethyl Alcohols and Aldehyde
Precursors When Applicable: Representative Procedure for
Preparation of α-CF3 Alcohols. Preparation of 2,2,2-Trifluoro-1-
(p-tolyl)ethanol23 (2a). The following is a modification of the
13C NMR (CDCl3, 101 MHz; δ, ppm) 55.6 (CH3), 73.0 (q, JC−C−F
=
32.3 Hz, CH), 113.3 (d, JC−C−C−F = 1.5 Hz, CH), 115.4 (CH), 120.5−
128.7 (q, JC−F = 281.7 Hz, CF3), 120.1 (CH), 130.0 (CH), 135.8 (C),
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159.9 (C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −78.26 (d, J = 6.81
Hz); GC-MS (EI) 206 ([M]+, 80%), 137 (65%), 135 (11%), 109
(100%), 107 (10%), 94 (43%), 77 (39%), 69 (6%), 66 (12%), 64
(11%); HRMS (ESI+) calcd for C9H9F3O2 [M + H]+ 207.0633, found
207.0641.
δ, ppm) 3.87 (br s, 1 H), 5.41 (q, J = 6.60 Hz, 1 H), 7.10 (ddd, J =
10.03, 8.56, 0.98 Hz, 1 H), 7.21 (td, J = 7.58, 0.98 Hz, 1 H), 7.34−7.43
(m, 1 H), 7.61 (t, J = 7.34 Hz, 1 H); 13C NMR (CDCl3, 101 MHz; δ,
ppm) 66.5 (qd, JC−C−F = 33.7, 3.7 Hz, CH), 115.8 (d, JC−C−F = 21.3
Hz, CH), 120.2−128.7 (qd, JC−F = 282.4, 2.2 Hz, CF3), 121.7 (d,
JC−C−F = 11.7 Hz, C), 124.8 (d, JC−C−F = 3.7 Hz, CH), 128.9 (d,
JC−C−C−F = 2.9 Hz, CH), 131.5 (d, JC−C−C−F = 8.8 Hz, CH), 160.7 (d,
JC−F = 248.0 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −118.06
to −117.93 (m, 1 F), −78.45 (t, J = 6.13 Hz, 3 F); GC-MS (EI) 194
([M]+, 27%), 127 (19%), 125 (100%), 123 (13%), 97 (56%), 95
(16%), 77 (36%), 75 (11%), 69 (9%), 51 (10%).
2,2,2-Trifluoro-1-(4-nitrophenyl)ethanol28 (2d). The title com-
pound (2.690 g, 61%) was prepared according to the representative
procedure from p-nitrobenzaldehyde (3.022 g, 0.020 mol) followed by
recrystallization from boiling water to give the pure α-CF3 alcohol 2d
as a light yellow crystalline solid (mp 132−133 °C, lit.28 mp 129−131
°C): 1H NMR (MeOD, 400 MHz; δ, ppm) 5.40 (q, J = 7.09 Hz, 1 H),
7.94 (apparent doublet, J = 8.80 Hz, 2 H), 8.44 (dt, J = 8.80, 2.00 Hz,
2 H); 13C NMR (MeOD, 101 MHz; δ, ppm) 73.5 (q, JC−C−F = 31.5
Hz, CH), 123.1−131.5 (q, JC−F = 281.7 Hz, CF3), 125.7 (CH), 131.3
(CH), 145.5 (C), 151.2 (C); 19F NMR (MeOD, 376 MHz; δ, ppm)
−77.26 (d, J = 6.81 Hz); GC-MS (EI) 221 ([M]+, 7%), 152 (97%),
150 (58%), 127 (16%), 106 (11%), 105 (16%), 104 (26%), 94 (12%),
92 (10%), 78 (11%), 77 (19%), 76 (20%), 75 (11%), 69 (9%), 51
(11%), 50 (15%), 44 (17%), 40 (100%).
2,2,2-Trifluoro-1-(2-methoxyphenyl)ethanol (2i). The title com-
pound (3.520 g, 85%) was prepared according to the representative
procedure from o-methoxybenzaldehyde (2.720 g, 0.020 mol) followed
by vacuum distillation (bp 68−70 °C @ 0.4 mmHg) to give the pure
α-CF3 alcohol 2i as a clear colorless oil: 1H NMR (CDCl3, 500 MHz;
δ, ppm) 3.86 (s, 3 H), 3.96 (br s, 1 H), 5.31 (q, J = 7.30 Hz, 1 H), 6.96
(d, J = 8.20 Hz, 1 H), 7.03 (td, J = 7.57, 1.26 Hz, 1 H), 7.36−7.40 (m,
1 H), 7.42 (d, J = 7.57 Hz, 1 H); 13C NMR (CDCl3, 126 MHz; δ,
ppm) 55.9 (CH3), 69.7 (q, JC−C−F = 32.1 Hz, CH), 111.5 (CH), 121.3
(CH), 121.6−128.3 (q, JC−F = 283.2 Hz, CF3), 122.4 (CH), 129.4
(C), 130.8 (CH), 157.8 (C); 19F NMR (CDCl3, 377 MHz; δ, ppm)
−78.10 (d, J = 6.81 Hz); GC-MS (EI) 206 ([M]+, 46%), 137 (100%),
122 (10%), 121 (25%), 109 (15%), 107 (68%), 94 (14%), 77 (26%),
69 (5%); HRMS (ESI+) calcd for C9H9F3O2 [M + H − H2O]+
189.0527, found 189.0519.
2,2,2-Trifluoro-1-(3-nitrophenyl)ethanol28 (2e). The title com-
pound (4.010 g, 91%) was prepared according to the representative
procedure from m-nitrobenzaldehyde (3.022, 0.020 mol) followed by
filtration through a silica gel plug using anhydrous Et2O as an eluant to
give the pure α-CF3 alcohol 2e as a yellow solid (mp 49−50 °C, lit.28
1
50.6−52.2 °C): H NMR (MeOD, 400 MHz; δ, ppm) 5.42 (q, J =
7.01 Hz, 1 H), 7.83 (t, J = 8.07 Hz, 1 H), 8.08 (dd, J = 7.70, 0.61 Hz, 1
H), 8.43 (ddd, J = 8.31, 2.45, 0.98 Hz, 1 H), 8.58 (s, 1 H); 13C NMR
(MeOD, 101 MHz; δ, ppm) 72.0 (q, JC−C−F = 31.6 Hz, CH), 121.8−
130.2 (q, JC−F = 281.9 Hz, CF3), 123.6 (CH), 124.9 (CH), 135.0
(CH), 139.4 (C), 149.7 (C); 19F NMR (MeOD, 377 MHz; δ, ppm)
−77.78 (d, J = 6.81 Hz); GC-MS (EI) 221 ([M]+, 5%), 152 (100%),
150 (16%), 127 (18%), 106 (11%), 105 (24%), 78 (12%), 77 (20%),
69 (5%).
2,2,2-Trifluoro-1-(2-nitrophenyl)ethanol28 (2j). The title com-
pound (3.340 g, 76%) was prepared according to the representative
procedure from o-nitrobenzaldehyde (3.020 g, 0.020 mol) followed by
vacuum distillation (bp 94−96 °C @ 0.4 mmHg) to give the pure α-
1
CF3 alcohol 2j as a clear yellow oil: H NMR (CDCl3, 500 MHz; δ,
ppm) 3.59 (br s, 1 H), 6.16 (q, J = 6.10 Hz, 1 H), 7.55 (td, J = 7.80,
1.50 Hz, 1 H), 7.71 (td, J = 7.57, 1.26 Hz, 1 H), 7.95 (d, J = 8.20 Hz, 1
H), 7.99 (dd, J = 8.20, 1.26 Hz, 1 H); 13C NMR (CDCl3, 126 MHz; δ,
ppm) 67.0 (q, JC−C−F = 31.2 Hz, CH), 120.7−127.5 (q, JC−F = 282.3
Hz, CF3), 125.2 (CH), 129.2 (C), 129.7 (CH), 130.5 (CH), 134.0
(CH), 148.6 (C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −77.50 (d, J
= 5.45 Hz); GC-MS (EI) 221 ([M]+, 1%), 203 (10%), 152 (45%), 141
(15%), 135 (10%), 134 (87%), 127 (62%), 123 (100%), 121 (70%),
105 (41%), 104 (77%), 97 (14%), 95 (23%), 78 (14%), 77 (75%), 76
(19%), 75 (12%), 74 (10%), 69 (14%), 65 (12%), 51 (31%), 50
(17%).
1-(2-Bromo-4-fluorophenyl)-2,2,2-trifluoroethanol26 (2f). The
title compound (3.960 g, 72%) was prepared according to the
representative procedure from 2-bromo-4-fluorobenzaldehyde (4.06 g,
0.020 mol) followed by vacuum distillation (bp 68−70 °C @ 0.25
1
mmHg) to give the pure α-CF3 alcohol 2f as a clear colorless oil: H
NMR (CDCl3, 400 MHz; δ, ppm) 3.52 (br s, 1 H), 5.56 (q, J = 6.28
Hz, 1 H), 7.10 (td, J = 8.10, 2.20 Hz, 1 H), 7.33 (dd, J = 8.07, 2.69 Hz,
1 H), 7.64 (dd, J = 8.68, 5.99 Hz, 1 H); 13C NMR (CDCl3, 101 MHz;
δ, ppm) 70.8 (q, JC−C−F = 33.0 Hz, CH), 115.5 (d, JC−C−F = 22.0 Hz,
CH), 120.2−128.6 (qd, JC−F = 282.4, 1.5 Hz, CF3), 120.4 (d, JC−C−F
=
2,2,2-Trifluoro-1-(pyridin-2-yl)ethanol29 (2k). The title compound
(2.920 g, 82%) was prepared according to the representative
procedure from picolinaldehyde (2.142 g, 0.020 mol) followed by
vacuum distillation (bp 75−77 °C @ 2.5 mmHg) to give the pure α-
CF3 alcohol 2k as a clear colorless oil: 1H NMR (CDCl3, 400 MHz; δ,
ppm) 5.03 (q, J = 6.60 Hz, 1 H), 5.55 (br s, 1 H), 7.37 (apparent
triplet, J = 5.80 Hz, 1 H), 7.43 (apparent doublet, J = 8.07 Hz, 1 H),
7.78 (tt, J = 7.70, 1.71 Hz, 1 H), 8.61 (dd, J = 4.65, 1.22 Hz, 1 H); 13C
NMR (CDCl3, 101 MHz; δ, ppm) 71.0 (q, JC−C−F = 32.3 Hz, CH),
120.1−128.6 (q, JC−F = 283.9 Hz, CF3), 122.9 (CH), 124.7 (CH),
137.5 (CH), 148.6 (CH), 151.4 (C); 19F NMR (CDCl3, 377 MHz; δ,
ppm) −78.08 (d, J = 6.81 Hz); GC-MS (EI) 177 ([M]+, 1%, 110
(10%), 108 (100%), 106 (40%), 80 (16%), 79 (16%), 78 (87%), 69
(9%), 52 (13%), 51 (21%), 50 (10%).
24.9 Hz, CH), 124.3 (d, JC−C−C−F = 9.5 Hz, CH), 130.1 (dd, JC−C−C−F
= 3.7, 1.5 Hz, C), 130.8 (d, JC−C−C−F = 9.0 Hz, C), 163.0 (d, JC−F
=
253.8 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −109.34 (q, J =
6.81 Hz, 1 F), −77.79 (d, J = 5.45 Hz, 3 F); GC-MS (EI) 274 ([M]+,
20%), 272 ([M]+, 21%), 205 (95%), 203 (100%), 175 (10%), 172
(6%), 123 (21%), 96 (68%), 95 (40%), 94 (14%), 75 (18%), 69
(10%).
1-(Benzo[d][1,3]dioxol-5-yl)-2,2,2-trifluoroethanol27 (2g). The
title compound (3.560 g, 81%) was prepared according to the
representative procedure from piperonal (3.003 g, 0.020 mol) followed
by vacuum distillation (bp 102−105 °C @ 0.6 mmHg) to give the
1
pure α-CF3 alcohol 2g as a clear colorless oil: H NMR (CDCl3, 400
MHz; δ, ppm) 2.95 (s, 1 H), 4.90 (q, J = 6.60 Hz, 1 H), 5.98 (s, 2 H),
6.82 (d, J = 7.83 Hz, 1 H), 6.91 (apparent doublet, J = 7.83 Hz, 1 H),
1,1,1-Trifluorotridecan-2-ol (2l). The title compound (6.470 g,
67%) was prepared according to the representative procedure from
dodecanal (6.920 g, 0.038 mol) followed by vacuum distillation (bp
90−92 °C @ 0.6 mmHg) to give the pure α-CF3 alcohol 2l as a clear
6.96 (s, 1 H); 13C NMR (CDCl3, 101 MHz; δ, ppm) 72.8 (q, JC−C−F
=
32.3 Hz, CH), 101.6 (CH2), 107.9 (d, J = 1.5 Hz, CH), 108.5 (CH),
120.3−128.7 (q, JC−F = 281.7 Hz, CF3), 121.8 (CH), 128.0 (d,
JC−C−C−F = 1.5 Hz, C), 148.2 (C), 148.8 (C); 19F NMR (CDCl3, 377
MHz; δ, ppm) −78.53 (d, J = 6.81 Hz); GC-MS (EI) 220 ([M]+,
80%), 152 (10%), 151 (100%), 149 (24%), 123 (16%), 121 (18%), 93
(100%), 75 (13%), 69 (8%), 65 (58%), 63 (18%), 40 (11%), 39
(11%).
1
colorless oil: H NMR (CDCl3, 400 MHz; δ, ppm) 0.88 (t, J = 7.10
Hz, 3 H), 1.21−1.36 (m, 16 H), 1.57 (qd, J = 9.50, 4.77 Hz, 2 H),
1.65−1.75 (m, 1 H), 2.48 (br s, 1 H), 3.89 (ddd, J = 9.78, 6.60, 3.18
Hz, 1 H); 13C NMR (CDCl3, 101 MHz; δ, ppm) 14.3 (CH3), 22.9
(CH2), 25.1 (CH2), 29.4 (CH2), 29.6 (CH2), 29.6 (CH2), 29.8−29.9
(CH2 × 4), 32.2 (CH2), 70.8 (q, JC−C−F = 30.8 Hz, CH), 121.3−129.7
(q, JC−F = 283.2 Hz, CF3); 19F NMR (CDCl3, 377 MHz; δ, ppm)
−80.12 (d, J = 6.81 Hz); GC-MS (EI) 254 ([M]+, 1%), 208 (6%), 193
(8%), 165 (8%), 155 (13%), 151 (17%), 141 (26%), 137 (21%), 131
(10%), 123 (18%), 117 (10%), 112 (11%), 111 (27%), 98 (18%), 97
2,2,2-Trifluoro-1-(2-fluorophenyl)ethanol7 (2h). The title com-
pound (3.000 g, 77%) was prepared according to the representative
procedure from o-fluorobenzaldehyde (2.480 g, 0.020 mol) followed
by vacuum distillation (bp 49−51 °C @ 1.0 mmHg) to give the pure
α-CF3 alcohol 2h as a clear colorless oil: 1H NMR (CDCl3, 400 MHz;
8135
dx.doi.org/10.1021/jo301477s | J. Org. Chem. 2012, 77, 8131−8141

The Journal of Organic Chemistry
Article
(42%), 85 (29%), 84 (34%), 83 (35%), 82 (10%), 81 (10%), 73
(11%), 71. (43%), 70 (49%), 69 (50%), 97 (15%), 57 (100%), 56
(48%), 55 (59%), 43 (91%), 42 (17%), 41 (65%), 40 (10%), 39
(13%); HRMS (ESI+) calcd for C13H25F3O [M − H]+ 253.1779,
found 253.1793.
(43%), 83 (47%), 81 (34%), 77 (11%), 71 (16%), 70 (67%), 69
(100%), 68 (13%), 67 (24%), 57 (72%), 56 (84%), 55 (86%), 54
(10%), 53 (13%), 43 (92%), 42 (24%), 41 (79%), 39 (27%); HRMS
(ESI+) calcd for C11H19F3O [M − H]+ 223.1310, found 223.1312.
1,1,1-Trifluorodeca-3,5-dien-2-ol (2q). The title compound (3.420
g, 82%) was prepared according to the representative procedure from
trans,trans-2,4-nonadienal (2.764 g, 0.020 mol) followed by vacuum
distillation (bp 63−65 °C @ 0.15 mmHg) to give the pure α-CF3
1,1,1-Trifluoroundec-10-en-2-ol (2m). The title compound (8.020
g, 92%) was prepared according to the representative procedure from
dec-9-enal (6.000 g, 0.0388 mol) followed by vacuum distillation (bp
63−65 °C @ 0.1 mmHg) to give the pure α-CF3 alcohol 2m as a clear
1
alcohol 2q as a clear colorless oil: H NMR (CDCl3, 400 MHz; δ,
1
colorless oil: H NMR (CDCl3, 400 MHz; δ, ppm) 1.21−1.47 (m, 9
ppm) 0.90 (t, J = 7.10 Hz, 3 H), 1.26−1.46 (m, 4 H), 2.11 (q, J = 6.85
Hz, 2 H), 2.89 (br s, 1 H), 4.43 (quin, J = 6.54 Hz, 1 H), 5.54 (dd, J =
15.41, 6.85 Hz, 1 H), 5.84 (dt, J = 15.16, 6.80 Hz, 1 H), 6.07 (dd, J =
14.92, 10.27 Hz, 1 H), 6.42 (dd, J = 15.28, 10.39 Hz, 1 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 14.1 (CH3), 22.5 (CH2), 31.4 (CH2),
H), 1.49−1.75 (m, 3 H), 2.04 (q, J = 7.01 Hz, 2 H), 2.62 (br s, 1 H),
3.88 (br s, 1 H), 4.89−5.05 (m, 2 H), 5.81 (ddt, J = 16.99, 10.21, 6.69,
6.69 Hz, 1 H); 13C NMR (CDCl3 101 MHz): δ ppm 25.2 (CH2), 29.1
(CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.8 (q, JC−C−C−F = 1.0
Hz, CH2) 34.0 (CH2), 70.8 (q, JC−C−F = 31.0 Hz, 7 C), 114.5 (CH2),
125.5 (q, JC−F = 282.0 Hz, 2 C), 139.4 (CH); 19F NMR (CDCl3, 376
MHz; δ, ppm) −83.05 (d, J = 6.81 Hz); GC-MS (EI) 224 ([M]+, 1%),
153, (14%), 150 (14%), 149 (11%), 139 (30%), 136 (25%), 135
(14%), 123 (15%), 113 (12%), 103 (14%), 99 (11%), 97 (22%), 95
(26%), 84 (14%), 83 (32%), 82 (10%), 81 (30%), 79 (18%), 77
(13%), 73 (12%), 71 (10%), 70 (37%), 69 (55%), 68 (24%), 67
(35%), 59 (14%), 57 (25%), 56 (37%), 55 (100%), 54 (20%), 53
(16%), 43 (27%), 42 (21%), 41 (82%), 39 (37%); HRMS (ESI+),
calcd for C11H20F3O [M + H]+ 225.1466, found 225.1451.
32.6 (CH2), 71.7 (q, JC−C−F = 32.3 Hz, CH), 120.4−128.8 (q, JC−F
=
281.7 Hz, CF3), 121.5 (CH), 128.8 (CH), 137.3 (CH), 139.2 (CH);
19F NMR (CDCl3, 377 MHz; δ, ppm) −79.24 (d, J = 6.81 Hz); GC-
MS (EI) 208 ([M]+, 53%), 152 (38%), 148 (14%), 147 (14%), 141
(12%), 139 (22%), 127 (38%), 109 (16%), 103 (11%), 97 (17%), 95
(17%), 91 (13%), 83 (100%), 82 (11%), 81 (20%), 79 (41%), 77
(22%), 69 (22%), 67 (41%), 65 (11%), 55 (38%), 53 (12%), 43
(13%), 41 (29%), 39 (17%); HRMS (ESI+) calcd for C10H15F3O [M
− H]+ 207.0997, found 207.0991.
Synthesis of 1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-yn-
2-ol (2r). 3-(4-Methoxyphenyl)prop-2-yn-1-ol. This procedure is a
modification of the procedure outlined by Krause and Alexakis et al.31
In a 250 mL round-bottom flask equipped with a stir bar was added
Et3N (150 mL) and 1-iodo-4-methoxybenzene (4.680 g, 0.020 mol,
0.134 M, 1 equiv). The solution was placed under a nitrogen
atmosphere via a gas inlet adapter. To this solution was added
PdCl2(PPh3)2 (0.702 g, 0.001 mol, 0.05 equiv) and CuI (0.191 g,
0.001 mol, 0.05 equiv) all at once, turning the solution yellow.
Propargyl alcohol (1.46 g, 0.026 mol, 1.3 equiv) was added at this
time, turning the solution cloudy green. The reaction mixture was
stirred for 18 h at room temperature. Upon completion of this time,
the solution was filtered through Celite, with EtOAc as eluent. The
filtrate was then further diluted with EtOAc (∼50 mL) and deionized
water (∼100 mL), and the layers were separated. The aqueous layer
was extracted three times with EtOAc. The combined organic layers
were dried with Na2SO4, and the solvent was removed in vacuo,
yielding a thick dark liquid. Purification was accomplished by flash
column chromatography (gradient 9/1 to 8/2 Hex/EtOAc), affording
the pure propargyl alcohol as a tan powdery solid (2.750 g, 85% yield,
3-Cyclohexyl-1,1,1-trifluoropropan-2-ol (2n). The title compound
(5.470 g, 71%) was prepared according to the representative
procedure from 2-cyclohexylacetaldehyde (5.000 g, 0.0396 mol)
followed by vacuum distillation (bp 51−53 °C @ 0.25 mmHg) to
1
give the pure α-CF3 alcohol 2n as a clear colorless oil: H NMR
(CDCl3, 400 MHz; δ, ppm) 0.81−0.93 (m, 1 H), 0.94−1.06 (m, 1 H),
1.09−1.34 (m, 3 H), 1.40−1.59 (m, 3 H), 1.61−1.83 (m, 5 H), 3.04
(br s, 1 H), 3.99 (dqd, J = 9.89, 6.65, 6.65, 6.65, 3.42 Hz, 1 H); 13C
NMR (CDCl3 101 MHz; δ, ppm) 26.1 (CH), 26.4 (CH), 26.6 (CH),
32.2 (CH), 33.3 (CH), 34.3 (CH), 37.1 (CH), 68.4 (q, JC−C−F = 30.8
Hz, CH), 121.5−129.9 (q, JC−F = 283.2 Hz, CF3); 19F NMR (CDCl3,
377 MHz; δ, ppm) −80.21 (d, J = 6.81 Hz, 213 F); GC-MS (EI) 196
([M]+, 1%), 178 (8%), 109 (8%), 83 (96%), 82 (100%), 81 (24%), 69
(13%), 67 (33%), 55 (60%), 41 (25%), 39 (12%); HRMS (ESI+)
calcd for C9H15F3O [M − H]+ 195.0997, found 195.1019.
(E)-1,1,1-Trifluoro-4-phenylbut-3-en-2-ol30 (2o). The title com-
pound (3.360 g, 76%) was prepared according to the representative
procedure from trans-cinnamaldehyde (3.045 g, 0.020 mol) followed
by vacuum distillation (bp 65−67 °C @ 1 mmHg) to give the pure α-
CF3 alcohol 2o as a clear oil, which solidified upon standing to give a
mp 62−64 °C, lit.32 mp 65−68 °C): H NMR (CDCl3, 300 MHz; δ,
1
white solid (mp 44−45 °C, lit.33 mp 42−43 °C): H NMR (CDCl3,
1
ppm) 1.65 (t, J = 6.14 Hz, 1 H), 3.81 (s, 3 H), 4.48 (d, J = 6.14 Hz, 2
H), 6.84 (d, J = 9.10 Hz, 2 H), 7.38 (d, J = 8.77 Hz, 2 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 51.9 (CH2), 55.5 (CH3), 85.8 (C), 86.2
(C), 114.2 (CH), 114.9 (C), 133.4 (CH), 156.0 (C); GC-MS (EI)
162 ([M]+, 22%), 161 (11%), 135 (17%), 131 (7%), 89 (8%), 77
(7%), 44 (17%), 40 (100%).
300 MHz; δ, ppm) 2.27 (br s, 1 H), 4.64 (quin, J = 6.50 Hz, 1 H), 6.21
(dd, J = 16.10, 6.59 Hz, 1 H), 6.87 (d, J = 16.10 Hz, 1 H), 7.28−7.52
(m, 5 H); 13C NMR (CDCl3, 101 MHz; δ, ppm) 71.9 (q, JC−C−F
=
32.3 Hz, CH), 120.4−128.8 (q, JC−F = 283.2 Hz, CF3), 120.8 (CH),
127.2 (CH), 128.9 (CH), 129.2 (CH), 135.6 (CH), 136.7 (C); 19F
NMR (CDCl3, 377 MHz; δ, ppm) −78.94 (d, J = 6.81 Hz); GC-MS
(EI) 202 ([M]+, 48%), 134 (12%), 133 (100%), 131 (16%), 115
(43%), 105 (21%), 103 (27%), 91 (19%), 78 (11%), 77 (33%), 69
(6%), 55 (27%), 51 (16%); HRMS (ESI+) calcd for C10H9F3O [M +
H − H2O]+ 185.0578, found 185.0571.
3-(4-Methoxyphenyl)propiolaldehyde. This procedure is a mod-
ification of the procedure outlined by Bobbitt.18a In a 250 mL flask
equipped with a stir bar were added DCM (170 mL), the previously
prepared propargyl alcohol, 3-(4-methoxyphenyl)prop-2-yn-1-ol
(2.750 g, 0.01696 mol, 0.1 M, 1 equiv), and 1 (5.340 g, 0.01780
mol, 1.05 equiv) followed by 2.750 g of SiO2 (1 mass equiv to
substrate), and the mixture was stirred for 24 h at room temperature.
Upon reaction completion (confirmed by TLC, 8/2 Hex/EtOAc), the
solvent was carefully removed in vacuo and the crude residue was
filtered though a medium-porosity fritted funnel filled halfway with
silica gel. The plug was washed several times with diethyl ether. The
solvent was removed in vacuo by rotary evaporation to afford the pure
aldehyde (1.720 g, 63%, mp 42−43 °C, lit.25 mp 48−50 °C) as a tan
solid: 1H NMR (CDCl3, 400 MHz; δ, ppm) 3.83 (s, 3 H), 6.89 (d, J =
8.80 Hz, 2 H), 7.54 (d, J = 8.80 Hz, 2 H), 9.37 (s, 1 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 55.7 (CH3), 89.0 (C), 96.8 (C), 111.3
(C), 114.7 (CH), 135.6 (CH), 162.4 (C), 176.9 (CH); GC-MS (EI)
161 ([M]2+, 11%), 160 ([M]+, 100%), 159 (59%), 144 (13%), 132
(46%), 117 (34%), 116 (11%), 89 (44%), 88 (11%), 63 (20%), 62
1,1,1-Trifluoroundec-3-en-2-ol (2p). The title compound (3.880 g,
86%) was prepared according to the representative procedure from
trans-dec-2-en-1-al (3.045 g, 0.020 mol) followed by vacuum
distillation (bp 69−71 °C @ 0.35 mmHg) to give the pure α-CF3
1
alcohol 2p as a clear pale yellow oil: H NMR (CDCl3, 400 MHz; δ,
ppm) 0.88 (t, J = 6.80 Hz, 3 H), 1.19−1.34 (m, 8 H), 1.35−1.45 (m, 2
H), 2.10 (q, J = 6.80 Hz, 2 H), 2.70 (br s, 1 H), 4.37 (quin, J = 6.72
Hz, 1 H), 5.50 (dd, J = 15.65, 6.85 Hz, 1 H), 5.97 (dt, J = 15.40, 6.80
Hz, 1 H); 13C NMR (CDCl3, 101 MHz; δ, ppm) 14.2 (CH3), 22.8
(CH), 28.8 (CH), 29.0 (CH), 29.5 (CH), 32.0 (CH), 32.5 (CH), 71.9
(q, JC−C−F = 32.1 Hz, CH), 124.4−128.8 (q, JC−F = 281.7 Hz, CF3),
121.9−122.4 (CH), 139.4 (CH); 19F NMR (376 MHz; δ, ppm)
−79.48 (d, J = 6.81 Hz); GC-MS (EI) 224 ([M]+, 1%), 163 (13%),
155 (12%), 153 (16%), 150 (16%), 149 (12%), 139 (22%), 136
(11%), 98 (11%), 97 (26%), 95 (33%), 91 (12%), 85 (13%), 84
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(16%), 44 (10%), 40 (36%); HRMS (ESI+) calcd for C10H9F3O2 [M
+ H]+ 161.0603, found 161.0604.
light yellow solid (mp 86−88 °C, lit.36 mp 92−94 °C); no further
purification was necessary: 1H NMR (MeOD, 400 MHz; δ, ppm) 4.80
(s, 2 H), 5.13 (br s, 1 H), 5.23 (q, J = 7.09 Hz, 1 H), 7.57 (d, J = 8.31
Hz, 2 H), 7.69 (d, J = 8.07 Hz, 2 H); 13C NMR (MeOD, 101 MHz; δ,
ppm) 66.1 (CH2), 74.3 (q, JC−C−F = 32.3 Hz, CH), 123.3−131.7 (q,
1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-yn-2-ol (2r). The title
compound (1.480 g, 55%) was prepared according to the
representative procedure from the previously prepared aldehyde, 3-
(4-methoxyphenyl)propiolaldehyde, (1.860 g, 0.0116 mol) followed
by vacuum distillation (bp 109−111 °C @ 0.1 mmHg) to give the
JC−F = 281.7 Hz, CF3), 129.2 (CH), 130.1 (CH), 137.0 (d, JC−C−C−F
=
1.5 Hz, C), 144.8 (C); 19F NMR (MeOD, 400 MHz; δ, ppm) −79.11
(d, J = 6.81 Hz); GC-MS (EI) 206 ([M]+, 31%), 138 (10%), 137
(100%), 135 (34%), 133 (10%), 109 (15%), 107 (34%), 105 (13%),
91 (31%), 79 (87%), 77 (44%), 69 (7%), 51 (13%), 40 (14%); HRMS
(ESI+) calcd for C9H9F3O2 [M + H − H2O]+ 189.0527, found
189.0521.
1
pure α-CF3 alcohol 2r as a clear colorless oil: H NMR (CDCl3, 400
MHz; δ, ppm) 3.27 (br s, 1 H), 3.81 (s, 3 H), 4.91 (q, J = 5.71 Hz, 1
H), 6.85 (d, J = 8.80 Hz, 2 H), 7.39 (d, J = 8.80 Hz, 2 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 55.6 (CH3), 63.2 (q, JC−C−F = 36.7 Hz,
CH), 79.6 (q, JC−C−C−F = 2.2 Hz, C), 88.2 (C), 113.3 (CH), 114.3
(C), 119.0−127.4 (q, JC−F = 281.0 Hz, CF3), 133.9 (CH), 160.6 (C);
19F NMR (CDCl3, 377 MHz; δ, ppm) −79.38 (dd, J = 5.45, 2.72 Hz);
GC-MS (EI) 230 ([M]+, 74%), 162 (12%), 161 (100%), 133 (15%),
118 (19%), 90 (12%), 89 (16%), 69 (4%); HRMS (ESI+) calcd for
C11H9F3O2 [M + H]+ 231.0633, found 231.0644.
Representative Procedure for the Preparation of α-CF3
Ketones: Preparation of 2,2,2-Trifluoro-1-(4-methylphenyl)-
ethanone (3a). In a one-neck 50 mL round-bottom flask equipped
with stir bar was added DCM (10 mL), the α-CF3 alcohol 2a (0.704 g,
0.004 mol, 0.4 M, 1 equiv), the oxoammonium salt 1 (3.010 g, 0.010
mol, 2.5 equiv), and 2,6-lutidine (0.964 g, 0.009 mol, 2.25 equiv). The
flask was sealed with a rubber septum and stirred overnight at room
temperature. The solvent was removed in vacuo to afford a thick red
residue. Anhydrous diethyl ether (∼30 mL) was added to the flask and
the mixture was stirred for 10 min. This caused immediate
precipitation of the nitroxide 1c (note: it is imperative that the sides
of the flask be scraped to ensure all the 1c precipitates out, releasing
the product into solution). After stirring, the solution was filtered
through a plug of silica (topped with a piece of filter paper to assist in
recovery) and rinsed thoroughly (three to four times) with anhydrous
diethyl ether. The solvent was removed in vacuo by rotary evaporation
in a room-temperature water bath to give the pure α-CF3 ketone 3a
1,1,1-Trifluoro-4-(furan-2-yl)but-3-en-2-ol (2s). The title com-
pound (3.420 g, 89%) was prepared according to the representative
procedure from 3-(furan-2-yl)acrylaldehyde (2.442 g, 0.020 mol)
followed by vacuum distillation (bp 64−67 @ 0.3 mmHg) to give the
1
pure α-CF3 alcohol 2s as a clear colorless oil: H NMR (CDCl3, 400
MHz; δ, ppm) 3.53 (s, 1 H), 4.59 (quind, J = 6.54, 6.54, 6.54, 6.54,
1.22 Hz, 1 H), 6.15 (dd, J = 15.77, 6.48 Hz, 1 H), 6.35 (d, J = 3.42 Hz,
1 H), 6.40 (dd, J = 3.30, 1.83 Hz, 1 H), 6.65 (dd, J = 15.89, 0.98 Hz, 1
H), 7.39 (d, J = 1.47 Hz, 1 H); 13C NMR (CDCl3, 101 MHz; δ, ppm)
71.4 (q, JC−C−F = 32.3 Hz, CH), 110.6 (CH), 111.8 (CH), 119.0 (q,
JC−C−C−F = 2.2 Hz, CH), 120.3−128.7 (q, JC−F = 281.7 Hz, CF3),
124.2 (CH), 143.2 (CH), 151.4 (C); 19F NMR (CDCl3, 376 MHz; δ,
ppm) −78.92 (d, J = 6.81 Hz); GC-MS (EI) 192 ([M]+, 74%), 127
(11%), 123 (100%), 95 (21%), 81 (26%), 77 (17%), 69 (8%), 67
(21%), 65 (17%), 55 (22%), 39 (13%); HRMS (ESI+) calcd for
C8H7F3O2 [M−H2O]+ 175.0371.0633, found 175.0377
1
(0.565 g, 75%) as a clear yellow oil: H NMR (CDCl3, 400 MHz; δ,
ppm) 2.46 (s, 3 H), 7.35 (d, J = 8.07 Hz, 2 H), 7.98 (d, J = 7.83 Hz, 2
H); 13C NMR (CDCl3, 101 MHz; δ, ppm) 22.0 (CH3), 112.6−121.3
(q, JC−F = 292.0 Hz, CF3), 127.6 (C), 130.0 (CH2), 130.4 (CH2),
147.2 (C), 180.3 (q, JC−C−F = 35.9 Hz, C); 19F NMR (CDCl3, 377
MHz; δ, ppm) −71.38; GC-MS (EI) 188 ([M]+, 15%), 119 (100%),
91 (67%), 89 (10%), 69 (5%), 65 (18%); HRMS (ESI+) calcd for
C9H7F3O [M + H]+ 189.0527, found 189.0518.
Synthesis of 2,2,2-Trifluoro-1-(4-(hydroxymethyl)phenyl)-
ethanol (2t). 4-(Hydroxymethyl)benzaldehyde.33 The title com-
pound was prepared via a modification of the procedure of Tanner.34
To a 500 mL round-bottom flask, equipped with stir bar was added
methanol (250 mL) and terephthalaldehyde (10.000 g, 0.07455 mol,
0.29 M, 1 equiv). After complete dissolution of the dialdehyde, NaBH4
(0.700 g, 0.01850 mol, 0.248 equiv) was added all at once to the
yellow-tinged reaction mixture. Within 15 min, the solution went clear
deep-yellow/orange solution. The solution was stirred at room
temperature for 1 h. After this time the solvent was removed in
vacuo by rotary evaporation in a 40 °C water bath to afford a thick
orange residue. The residue was taken up in boiling water (≈200 mL)
causing the water to become cloudy then clear. Upon cooling to room
temperature in a water bath, a crystalline precipitate (starting material)
formed. The precipitate was removed from the aqueous layer by
filtration via a funnel and Kim Wipe. The filtrate was transferred to a
500 mL separatory funnel. The aqueous layer was extracted Et2O (4 ×
100 mL) and the combined organic layers were dried with Na2SO4.
The solvent was removed in vacuo via rotary evaporation and the crude
clear yellow oil was further purified by column chromatography
(gradient 8:2 Hex:EtOAc to 7:3 Hex:EtOAc to 6:4 Hex:EtOAc). After
removal of the solvent, the oil obtained from chromatography
solidified upon standing, giving 4-(hydroxymethyl)benzaldehyde as a
powdery while solid (4.650 g, 46%, mp 43−44 °C, lit. 42 °C).35 1H
NMR (CDCl3, 400 MHz; δ, ppm) 3.17 (br s, 1 H), 4.73 (s, 2 H), 7.46
(d, J = 8.07 Hz, 2 H), 7.79 (d, J = 8.31 Hz, 2 H), 9.90 (s, 1 H); 13C
NMR (CDCl3, 101 MHz; δ, ppm) 64.5 (CH2), 127.1 (CH), 130.2
(CH), 135.6 (C), 148.3 (C), 192.6 (CH); GC-MS (EI) 136 ([M]+,
49%), 135 (32%), 134 (67%), 133 (60%), 108 (13%), 107 (92%), 105
(40%), 91 (11%), 90 (13%), 89 (29%), 79 (87%), 78 (14%), 77
(100%), 76 (10%), 74 (14%), 63 (10%), 51 (38%), 50 (22%), 40
(27%).
2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanone (3b). The title
compound (0.737 g, 90%) was prepared according to the
representative procedure from 2,2,2-trifluoro-1-(4-methoxyphenyl)-
ethanol (2b; 0.825 g, 0.004 mol) to give the pure α-CF3 ketone 3b as a
1
clear yellow oil: H NMR (CDCl3, 400 MHz; δ, ppm) 3.90 (s, 3 H),
6.99 (apparent doublet, J = 9.05 Hz, 2 H), 8.04 (apparent doublet, J =
8.07 Hz, 2 H); 13C NMR (CDCl3, 101 MHz; δ, ppm) 55.9 (CH3),
112.9−121.6 (q, JC−F = 294.2 Hz, CF3), 114.7 (CH), 123.1 (C), 133.0
(q, JC−C−C−C−F =2.2 Hz, CH), 165.7 (C), 179.2 (q, JC−C−F = 34.5 Hz,
C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −71.06; GC-MS (EI) 204
(21%), 135 (100%), 107 (12%), 92 (24%), 77 (26%), 69 (4%), 64
(10%), 63 (10%); HRMS (ESI+) calcd for C9H7F3O2 [M + H]+
205.0476, found 205.0475.
2,2,2-Trifluoro-1-(3-methoxyphenyl)ethanone (3c). The title
compound (0.779 g, 89%) was prepared according to the
representative procedure from 2,2,2-trifluoro-1-(3-methoxyphenyl)-
ethane (2c; 0.825 g, 0.004 mol) to give the pure α-CF3 ketone 3c as a
1
clear yellow oil: H NMR (CDCl3, 400 MHz; δ, ppm) 3.87 (s, 3 H),
7.25 (ddd, J = 8.31, 2.69, 1.00 Hz, 1 H), 7.45 (t, J = 8.07 Hz, 1 H),
7.56 (s, 1 H), 7.65 (dq, J = 7.80, 1.00 Hz, 1 H); 13C NMR (CDCl3,
101 MHz; δ, ppm) 55.7 (CH3), 112.5−121.2 (q, JC−F = 289.8 Hz,
CF3), 114.2 (q, JC−C−C−C−F = 2.2 Hz, CH), 122.5 (CH), 123.0 (q, J =
2.9 Hz, CH), 130.3 (CH), 131.3 (C), 160.2 (C), 180.6 (q, JC−C−F
=
34.5 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −71.26; GC-MS
(EI) 204 ([M]+, 37%), 135 (87%), 107 (36%), 92 (30%), 77 (35%),
69 (6%), 64 (14%), 63 (14%), 44 (11%), 40 (100%); HRMS (ESI+)
calcd for C9H7F3O2 [M + H]+ 205.0476, found 205.0478.
2,2,2-Trifluoro-1-(4-nitrophenyl)ethanone37 (3d). The title com-
pound (0.870 g, 99%) was prepared according to the representative
procedure from 2,2,2-trifluoro-1-(4-nitrophenyl)ethanol (2d; 0.885 g,
0.004 mol) to give the pure α-CF3 ketone 3d as a powdery white solid
(mp 42−44 °C, lit.38 mp 44−46 °C): 1H NMR (MeOD, 400 MHz; δ,
ppm) 8.04 (apparent doublet, J = 9.05 Hz, 2 H), 8.45 (apparent
2,2,2-Trifluoro-1-(4-(hydroxymethyl)phenyl)ethanol (2t). The title
compound (3.790 g, 92%) was prepared according to the
representative procedure for trifluoromethylation from 4-
(hydroxymethyl)benzaldehyde (2.720 g, 0.020 mol, 1 equiv) and an
excess of TMS-CF3 (6.25 g, 0.044 mol, 2.2 equiv) and obtained as an
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Article
doublet, J = 9.05 Hz, 2 H); 13C NMR (MeOD, 101 MHz; δ, ppm)
98.8 (q, J = 31.5 Hz, 2 C), 121.2−129.7 (q, JC−F = 287.6 Hz, CF3),
125.6 (CH), 132.1 (d, JC−C−C−C−F = 1.5 Hz, CH), 144.6 (C), 151.6
(C); 19F NMR (MeOD, 377 MHz; δ, ppm) −71.06; GC-MS (EI) 219
([M]+, 1%), 150 (100%), 104 (40%), 92 (18%), 76 (27%), 75 (13%),
69 (7%), 50 (14%); HRMS (ESI+) calcd for C8H4F3NO3 [M + H +
H2O]+ 238.0327, found 238.0346.
NMR (CDCl3, 400 MHz; δ, ppm) 3.92 (s, 3 H), 7.01−7.10 (m, 2 H),
7.60 (ddd, J = 8.56, 7.34, 1.71 Hz, 1 H), 7.68 (d, J = 7.82 Hz, 1 H);
13C NMR (CDCl3, 101 MHz; δ, ppm) 55.5 (CH3), 111.5−120.2 (q,
JC−F = 290.5 Hz, CF3), 111.8 (CH), 120.3 (CH), 121.3 (C), 130.9 (d,
JC−C−C−C−F = 1.5 Hz, CH), 135.5 (CH), 159.5 (C), 182.6 (q, JC−C−F
=
36.7 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −74.17; GC-MS
(EI) 204 ([M]+, 21%), 136 (20%), 135 (100%), 92 (25%), 77 (35%),
69 (4%); HRMS (ESI+) calcd for C9H7F3O2 [M + H]+ 205.0476,
found 205.0507.
2,2,2-Trifluoro-1-(3-nitrophenyl)ethanone38 (3e). The title com-
pound (0.830 g, 96%) was prepared according to the representative
procedure from 2,2,2-trifluoro-1-(3-nitrophenyl)ethanol (2e; 0.885 g,
0.004 mol) to give the pure α-CF3 ketone 3e as an off-yellow solid
(mp 50−52 °C, lit.39 mp 54−56 °C): 1H NMR (MeOD, 400 MHz; δ,
ppm) 7.86 (t, J = 7.80 Hz, 1 H), 8.17 (dd, J = 7.83, 0.73 Hz, 1 H), 8.47
(ddd, J = 8.25, 2.26, 0.98 Hz, 1 H), 8.62 (d, J = 1.71 Hz, 1 H); 13C
NMR (CDCl3, 101 MHz; δ, ppm) 110.9−119.6 (q, JC−F = 291.2 Hz,
CF3), 123.9 (q, JC−C−C−C−F = 2.2 Hz, CH), 128.8 (CH), 129.9 (CH),
130.2 (C), 134.4 (q, JC−C−C−C−F = 2.2 Hz, CH), 147.7 (C), 177.9 (q,
JC−C−F = 36.7 Hz, C); 19F NMR (MeOD, 377 MHz; δ, ppm) −71.90;
GC-MS (EI) 219 ([M]+, 1%), 204 (40%), 135 (95%), 107 (39%), 92
(33%), 77 (39%), 69 (7%), 64 (15%), 63 (15%), 22 (11%), 40
(100%); HRMS (ESI+) calcd for C8H4F3NO3 [M + H + H2O]+
238.0327, found 238.0344.
2,2,2-Trifluoro-1-(2-nitrophenyl)ethanone (3j). The title com-
pound (0.782 g, 89%) was prepared according to the representative
procedure from 2,2,2-trifluoro-1-(2-nitrophenyl)ethanol (2j; 0.885 g,
1
0.004 mol) to give the pure α-CF3 ketone 3j as a clear yellow oil: H
NMR (CDCl3, 400 MHz; δ, ppm) 7.55 (dd, J = 7.34, 1.22 Hz, 1 H),
7.82 (td, J = 8.10, 1.00 Hz, 1 H), 7.89 (td, J = 7.60, 1.22 Hz, 1 H), 8.31
(dd, J = 8.19, 0.86 Hz, 1 H); 13C NMR (CDCl3, 101 MHz; δ, ppm)
110.4−119.0 (q, JC−F = 290.5 Hz, CF3), 123.8 (CH), 127.9 (CH),
129.2 (C), 132.3 (CH), 134.8 (CH), 145.3 (C), 183.4 (q, JC−C−F
=
38.9 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −75.86; GC-MS
(EI) 218 ([M]+, 1%), 150 (100%), 123 (12%), 95 (15%), 76 (32%),
75 (12%), 74 (10%), 69 (9%), 51 (23%), 50 (18%); HRMS (ESI+)
calcd for C8H4F3NO3 [M + H]+ 220.0222, found 220.0228.
2,2,2-Trifluoro-1-(pyridin-2-yl)ethanone39 (3k). The title com-
pound (0.759 g, 96%) was prepared according to the representative
procedure from 2,2,2-trifluoro-1-(pyridin-2-yl)ethanol (2k; 0.769 g,
0.00433 mol) to give the pure α-CF3 ketone 3k as a powdery yellow
1-(2-Bromo-4-fluorophenyl)-2,2,2-trifluoroethanone (3f). The
title compound (0.847 g, 78%) was prepared according to the
representative procedure from 1-(2-bromo-4-fluorophenyl)-2,2,2-tri-
fluoroethanol (2f; 1.092 g, 0.004 mol) to give the pure α-CF3 ketone
1
solid (mp 81−83 °C, lit.39 mp 84−85 °C): H NMR (MeOD, 400
1
3f as a clear yellow oil: H NMR (CDCl3, 400 MHz; δ, ppm) 7.19
(ddd, J = 8.80, 7.46, 2.57 Hz, 1 H), 7.50 (dd, J = 8.19, 2.57 Hz, 1 H),
7.78 (ddq, J = 8.76, 5.67, 1.30, 1.30, 1.30 Hz, 1 H); 13C NMR (CDCl3,
101 MHz; δ, ppm) 111.6−120.3 (q, JC−F = 292.0 Hz, CF3), 115.2 (d,
JC−C−F = 21.3 Hz, CH), 123.4 (d, JC−C−F = 24.2 Hz, CH), 124.3 (d,
JC−C−C−F = 9.5 Hz, C), 128.3 (d, JC−C−C−C−F = 3.7 Hz, C), 132.7 (dq,
JC−C−C−F = 9.8, JC−C−C−C−F = 3.2 Hz, CH), 164.9 (d, JC−F = 263.4 Hz,
C), 180.8 (q, JC−C−F = 37.4 Hz, C); 19F NMR (CDCl3, 377 MHz; δ,
ppm) −105.06 (q, J = 7.00 Hz, 1 F), −76.13 (s, 3 F); GC-MS (EI) 272
([M]+, 8%), 270 ([M]+, 8%), 203 (97%), 201 (100%), 175 (46%), 173
(46%), 94 (57%), 93 (11%), 74 (11%), 69 (9%); HRMS (ESI+) calcd
for C8H3BrF4O [M + H]+ 270.9382, found 270.9379.
MHz; δ, ppm) 7.61−7.71 (m, 1 H), 7.94−8.03 (m, 1 H), 8.06−8.16
(m, 1 H), 8.74−8.84 (m, 1 H); 13C NMR (MeOD, 101 MHz; δ, ppm)
97.9 (q, JC−C−F = 31.5 Hz, C), 120.7−129.2 (q, JC−F = 286.8 Hz, CF3),
125.4 (CH), 127.1 (CH), 139.9 (CH), 150.3 (CH), 154.7 (C); 19F
NMR (MeOD, 377 MHz; δ, ppm) −81.66; GC-MS (EI) 175 ([M]+,
7%), 106 (70%), 78 (100%), 69 (12%), 51 (24%), 50 (11%); HRMS
(ESI+) calcd for C7H4F3NO [M + H]+ 176.0323, found 176.0300.
(E)-1,1,1-Trifluoro-4-phenylbut-3-en-2-one (3o). The title com-
pound (0.571 g, 72%) was prepared according to the representative
procedure from (E)-1,1,1-trifluoro-4-phenylbut-3-en-2-ol (2o; 0.809 g,
0.004 mol) to give the pure α-CF3 ketone 3o as a clear yellow oil: 1H
NMR (CDCl3, 400 MHz; δ, ppm) 7.02 (dd, J = 16.14, 0.98 Hz, 1 H),
7.40−7.54 (m, 3 H), 7.62−7.67 (m, 2 H), 7.97 (d, J = 16.14 Hz, 1 H);
13C NMR (CDCl3, 101 MHz; δ, ppm) 112.3−121.0 (q, JC−F = 291.2
Hz, CF3), 116.9 (CH), 127.2 (CH), 127.4 (CH), 129.0 (CH), 129.5
(CH), 132.6 (CH), 133.6 (C), 150.4 (d, JC−C−C−F = 1.5 Hz, CH),
180.3 (q, JC−C−F = 35.2 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm)
−77.70; GC-MS (EI) 200 ([M]+, 56%), 199 (12%), 132 (10%), 131
(100%), 103 (81%), 102 (13%), 77 (42%), 69 (6%), 51 (16%);
HRMS (ESI+) calcd for C10H7F3O [M + H]+ 201.0527, found
201.0548.
(E)-1,1,1-Trifluoroundec-3-en-2-one (3p). The title compound
(0.828 g, 93%) was prepared according to the representative
procedure from 1,1,1-trifluoroundec-3-en-2-ol (2p; 0.897 g, 0.004
mol) to give the pure α-CF3 ketone 3p as a clear yellow oil: 1H NMR
(CDCl3, 400 MHz; δ, ppm) 0.89 (t, J = 6.80 Hz, 3 H), 1.23−1.37 (m,
8 H), 1.51−1.56 (m, 2 H), 2.34 (qd, J = 7.60, 1.50 Hz, 2 H), 6.41 (dd,
J = 15.65, 0.98 Hz, 1 H), 7.34 (dt, J = 15.89, 7.10 Hz, 1 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 13.9 (CH3), 22.5 (CH2), 27.6 (CH2),
28.9 (CH2), 29.1 (CH2), 31.6 (CH2), 33.2 (CH2), 111.9−120.6 (q,
1-(Benzo[d][1,3]dioxol-5-yl)-2,2,2-trifluoroethanol (3g). The title
compound (0.833 g, 97%) was prepared according to the
representative procedure from 1-(benzo[d][1,3]dioxol-5-yl)-2,2,2-
trifluoroethanol (2g; 0.881 g, 0.004 mol) to give the pure α-CF3
1
ketone 3g as a clear yellow oil: H NMR (CDCl3, 400 MHz; δ, ppm)
6.08 (d, J = 1.00 Hz, 2 H), 6.89 (d, J = 8.31 Hz, 1 H), 7.44 (d, J = 0.98
Hz, 1 H), 7.67 (d, J = 8.31 Hz, 1 H); 13C NMR (CDCl3, 101 MHz; δ,
ppm) 102.7 (CH2), 108.7 (CH), 109.4 (q, JC−C−C−F = 2.2 Hz, CH),
112.7−121.4 (q, JC−F = 291.2 Hz, CF3), 124.6 (C), 127.8 (q, JC−C−C−F
= 2.9 Hz, CH), 148.9 (C), 154.3 (C), 178.8 (q, JC−C−F = 34.5 Hz, C);
19F NMR (CDCl3, 377 MHz; δ, ppm) −70.76; GC-MS (EI) 218
([M]+, 41%), 149 (100%), 121 (34%), 91 (10%), 69 (5%), 65 (24%),
63 (20%), 62 (10%); HRMS (ESI+) calcd for C9H5F3O3 [M + H]+
219.0269, found 219.0257.
2,2,2-Trifluoro-1-(2-fluorophenyl)ethanone (3h). The title com-
pound (0.563 g, 73%) was prepared according to the representative
procedure from 2,2,2-trifluoro-1-(2-fluorophenyl)ethanol (2h; 0.777 g,
0.004 mol) to give the pure α-CF3 ketone 3h as a clear orange oil: 1H
NMR (CDCl3, 400 MHz; δ, ppm) 7.32 (t, J = 9.00 Hz, 1 H), 7.41 (t, J
= 7.46 Hz, 1 H), 7.78 (d, J = 4.89 Hz, 1 H), 7.99 (t, J = 7.21 Hz, 1 H);
13C NMR (CDCl3, 101 MHz; δ, ppm) 105.7−114.3 (q, JC−F = 289.8
Hz, CF3), 111.9 (d, JC−C−F = 20.5 Hz, C), 113.6 (d, JC−C−C−F = 10.3
Hz, CH), 119.2 (CH), 125.8 (CH), 131.7 (d, JC−C−C−F = 8.8 Hz, CH),
156.1 (d, JC−F = 262.6 Hz, C), 173.2 (q, JC−C−F = 38.1 Hz, C); 19F
NMR (CDCl3, 376 MHz; δ, ppm) −107.72 to −107.48 (m, 1 F),
−74.79 (d, J = 16.35 Hz, 3 F); GC-MS (EI) 192 ([M]+, 7%), 123
(100%), 95 (54%), 75 (22%), 69 (9%); HRMS (ESI+) calcd for
C8H4F4O [M + H]+ 193.0277, found 193.0310.
JC−F = 290.5 Hz, CF3), 121.3 (CH), 156.9 (CH), 179.7 (q, JC−C−F
=
35.2 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −77.66; GC-MS
(EI) 222 ([M]+, 1%), 165 (13%), 153 (81%), 138 (37%), 110 (11%),
97 (23%), 95 (13%), 83 (19%), 81 (29%), 69 (63%), 68 (25%), 67
(18%), 57 (13%), 56 (15%), 55 (100%), 43 (53%), 41 (51%), 40
(22%), 39 (25%); HRMS (ESI+) calcd for C11H17F3O [M + H]+
223.1310, found 223.1316.
1,1,1-Trifluorodeca-3,5-dien-2-one (3q). The title compound
(0.879 g, 99%) was prepared according to the representative
procedure from 1,1,1-trifluorodeca-3,5-dien-2-ol (2q; 0.895 g, 0.0043
mol) to give the pure α-CF3 ketone 3q as a clear orange oil: 1H NMR
(CDCl3, 400 MHz; δ, ppm) 0.92 (t, J = 7.21 Hz, 3 H), 1.30−1.53 (m,
4 H), 2.26 (q, J = 7.17 Hz, 2 H), 6.24−6.50 (m, 3 H), 7.55 (dd, J =
2,2,2-Trifluoro-1-(2-methoxyphenyl)ethanone (3i). The title com-
pound (0.814 g, 96%) was prepared according to the representative
procedure from 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol (2i; 0.825
g, 0.004 mol) to give the pure α-CF3 ketone 3i as a clear orange oil: 1H
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15.28, 10.88 Hz, 1 H); 13C NMR (CDCl3, 101 MHz; δ, ppm) 13.5
0.021 mol) with the following modifications. Addition of 0.5 equiv of 1
(3.15 g, 0.0105 mol) and DBN (1.31 g 0.0105 mol) was carried out
after 4 h to achieve >90% conversion. Further purification was
accomplished by vacuum distillation (bp 71−74 °C @ 10 mmHg) to
give the pure α-CF3 ketone as a clear pale yellow oil: 1H NMR
(CDCl3, 500 MHz; δ, ppm) 0.93−1.04 (m, 2 H), 1.09−1.22 (m, 1 H),
1.22−1.36 (m, 2 H), 1.66−1.75 (m, 5 H), 1.93 (apparent dddt, J =
14.58, 10.96, 7.25, 3.47, 3.47 Hz, 1 H), 2.57 (d, J = 6.94 Hz, 2 H); 13C
NMR (CDCl3, 125 MHz; δ, ppm) 26.2 (CH2), 26.3 (CH2), 33.2
(CH2), 33.2 (CH), 44.1 (CH2), 115.8 (q, JC−F = 292.3 Hz, CF3), 191.3
(q, JC−C−F = 33.9 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm)
−82.75; GC-MS (EI) 194 ([M]+, 0.01%), 125 (100%), 97 (96%), 82
(72%), 69 (31%), 67 (48%), 55 (87%), 41 (33%), 39 (22%); HRMS
(ESI+) calcd for C9H13F3O [M + H]+ 195.0997, found 195.1044.
1,1,1-Trifluoroundec-10-en-2-one (3m). The title compound
(2.937 g, 60%) was prepared according to the representative
procedure from 1,1,1-trifluoroundec-10-en-2-ol (2m; 4.930 g, 0.022
mol) with the following modifications. Addition of 0.5 equiv of 1 (3.15 g,
0.0105 mol) and DBN (1.31 g 0.0105 mol) was carried out after 4 h to
achieve >90% conversion. Further purification was accomplished by
vacuum distillation (bp 60−62 °C @ 1.5 mmHg) to give the pure α-
(CH3), 22.0 (CH2), 30.3 (CH2), 32.9 (CH2), 111.9−120.5 (q, JC−F
=
290.5 Hz, CF3), 118.1 (CH), 128.5 (CH), 150.4 (CH), 151.6 (CH),
180.0 (q, JC−C−F = 37.4 Hz, C); 19F NMR (CDCl3, 377 MHz; δ, ppm)
−77.54; GC-MS (EI) 206 ([M]+, 8%), 149 (100%), 137 (16%), 95
(13%), 81 (32%), 79 (12%), 77 (10%), 69 (9%), 67 (14%), 66 (12%),
56 (11%), 53 (11%), 41 (17%), 39 (11%); HRMS (ESI+) calcd for
C10H13F3O [M + H]+ 207.0997, found 207.0993.
1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-yn-2-one (3r). The title
compound (0.773 g, 85%) was prepared according to the
representative procedure from 1,1,1-trifluoro-4-(4-methoxyphenyl)-
but-3-yn-2-ol (2r; 0.921 g, 0.004 mol) to give the pure α-CF3 ketone
3r as a clear orange oil: 1H NMR (CDCl3, 400 MHz; δ, ppm) 3.92 (s,
3 H), 6.99 (d, J = 8.56 Hz, 2 H), 7.68 (d, J = 8.31 Hz, 2 H); 13C NMR
(CDCl3, 101 MHz; δ, ppm) 55.0 (CH3), 83.5 (C), 101.8 (C), 109.1
(C), 110.0−118.6 (q, JC−F = 289.0 Hz, CF3), 114.2 (CH), 135.7
(CH), 162.6 (C), 166.4 (q, JC−C−F = 42.5 Hz, C); 19F NMR (CDCl3,
376 MHz; δ, ppm) −77.65; GC-MS (EI) 228 ([M]+, 23%), 1620
(12%), 159 (100%), 144 (18%), 116 (15%), 88 (12%), 69 (3%);
HRMS (ESI+) calcd for C11H7F3O2 [M + H]+ 229.0476, found
229.0474.
(E)-1,1,1-Trifluoro-4-(furan-2-yl)but-3-en-2-one (3s). The title
compound (0.518 g, 68%) was prepared according to the
representative procedure from 1,1,1-trifluoro-4-(furan-2-yl)but-3-en-
2-ol (2s; 0.761 g, 0.004 mol) to give the pure α-CF3 ketone 3s as a
clear yellow oil: 1H NMR (CDCl3, 400 MHz; δ, ppm) 6.55−6.63 (m,
1 H), 6.87−6.92 (m, 2 H), 7.62 (s, 1 H), 7.69 (d, J = 15.41 Hz, 1 H);
13C NMR (CDCl3, 101 MHz; δ, ppm) 108.8−117.4 (q, JC−F = 296.4
1
CF3 ketone as a clear colorless oil: H NMR (CDCl3, 500 MHz; δ,
ppm) 1.23−1.47 (m, 8 H), 1.61−1.74 (qint, J = 7.00 Hz, 2 H), 2.04
(q, J = 6.85 Hz, 2 H), 2.70 (t, J = 7.21 Hz, 2 H), 4.88−5.04 (m, 2 H),
5.80 (ddt, J = 16.96, 10.12, 6.76, 6.76 Hz, 1 H); 13C NMR (CDCl3,
125 MHz; δ, ppm) 22.6 (CH2), 29.0 (CH2), 29.1 (CH2), 29.1 (CH2),
29.3 (CH2), 34.0 (CH2), 36.6 (CH2), 115.9 (q, JC−F = 290.0 Hz, CF3),
114.5 (CH2), 139.3 (CH), 191.9 (d, JC−C−F = 35.0 Hz, C); 19F NMR
(CDCl3, 377 MHz; δ, ppm) −82.44; GC-MS (EI) 222 ([M]+, 2%),
153 (14%), 138 (15%), 135 (29%), 110 (30%), 97 (11%), 95 (22%),
93 (11%), 83 (19%), 82 (24%), 81 (34%), 79 (11%), 70 (10%), 69
(87%), 68 (55%), 67 (38%), 56 (19%), 55 (100%), 54 (25%), 53
(15%), 43 (14%), 42 (25%), 41 (88%), 40 (14%), 39 (41%); HRMS
(ESI+) calcd for C11H17F3O [M + H]+ 223.1309, found 223.1299.
Selective Oxidation of 2,2,2-Trifluoro-1-(4-(hydroxymethyl)-
phenyl)ethanol (2t). 4-(2,2,2-Trifluoro-1-hydroxyethyl)-
benzaldehyde (2t′). This procedure is a modification of the procedure
outlined by Bobbitt.18a In a 100 mL flask equipped with a stir bar was
added DCM (20 mL) and 2t (2.060 g, 0.010 mol, 0.5 M, 1 equiv). 1
(3.150 g, 0.0105 mol, 1.05 equiv) was added followed by 2.060 g of
SiO2 (1 mass equiv to substrate), and the mixture was stirred for 24 h
at room temperature. Upon reaction completion (confirmed by TLC,
8/2 Hex/EtOAc), the solvent was carefully removed in vacuo and the
crude residue was filtered though a medium-porosity fritted funnel
filled halfway with silica gel. The plug was washed several times with
diethyl ether. The solvent was removed in vacuo by rotary evaporation
to afford the pure aldehyde 2t′ (1.865 g, 91%) as a powdery off-white
solid (mp 67−69 °C): 1H NMR (CDCl3, 400 MHz; δ, ppm) 3.60 (br
s, 1 H), 5.15 (q, J = 6.36 Hz, 1 H), 7.67 (d, J = 8.07 Hz, 2 H), 7.90 (d,
J = 8.31 Hz, 2 H), 9.99 (s, 1 H); 13C NMR (CDCl3, 101 MHz; δ,
ppm) 72.5 (q, JC−C−F = 30.8 Hz, CH), 120.0−127.7 (q, JC−F = 281.7
Hz, CF3), 128.5 (d, JC−C−C−C−F = 1.5 Hz, CH), 130.1 (CH), 137.1
(C), 140.8 (C), 192.6 (CH); 19F NMR (400 MHz, CDCl3; δ, ppm)
−79.11 (d, J = 6.81 Hz); GC-MS (EI) 204 ([M]+, 29%), 135 (100%),
133 (16%), 127 (11%), 105 (16%), 79 (56%), 77 (41%), 69 (6%), 51
(13%); HRMS (ESI+) calcd for C9H7F3O2 [M + H]+ 205.0476, found
205.0484.
Hz, CF3), 110.5 (2x CH), 117.1 (CH), 131.6 (CH), 144.4 (CH),
147.2 (C), 176.4 (q, JC−C−F = 35.2 Hz, C); 19F NMR (CDCl3, 376
MHz; δ, ppm) −77.74; GC-MS (EI) 190 ([M]+, 35%), 121 (100%),
69 (9%), 65 (49%), 63 (12%), 39 (15%); HRMS (ESI+) calcd for
C8H5F3O2 [M + H]+ 191.0320, found 191.0328.
Representative Procedure for the Preparation of Aliphatic
α-CF3 Ketones: Preparation of 1,1,1-Trifluorododecanone (3l).
In a one-neck 250 mL round-bottom flask equipped with a stir bar was
added DCM (160 mL), the α-CF3 alcohol 2l (4.07 g, 0.016 mol, 1 M,
1 equiv), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN; 5.48 g, 0.044
mol, 2.75 equiv). After the mixture was stirred at room temperature for
about 10 min, the oxoammonium salt 1 (14.41 g, 0.048 mol, 3 equiv)
was added to the flask (Caution! mildly exothermic) and the reaction
mixture immediately began to turn red. The flask was sealed with a
rubber septum with a vent needle and stirred for 4 h at room
temperature. The solvent was removed in vacuo to afford an orange
solid. Anhydrous diethyl ether (∼30 mL) was added to the flask, and
the mixture was stirred for 10 min. Note: it is imperative that the sides
of the flask be scraped to ensure all the nitroxide (1c) precipitates out,
releasing the product into solution. After stirring, the solution was
filtered through a plug of silica (topped with a piece of filter paper to
assist in recovery of 1c) and rinsed thoroughly (three to four times)
with anhydrous diethyl ether. The solvent was removed in vacuo by
rotary evaporation in a room temperature water bath to give the crude
α-CF3 ketone. Further purification was accomplished by vacuum
distillation through a 130 mm Vigreux column (bp 71−74 °C @ 0.10
mmHg) to give the pure α-CF3 ketone 3l (2.010 g, 50%) as a clear
1
colorless oil: H NMR (CDCl3, 400 MHz; δ, ppm) 0.88 (t, J = 7.00
Hz, 3 H), 1.17−1.39 (m, 16 H), 1.67 (quin, J = 7.30 Hz, 2 H), 2.70
(td, J = 7.21, 0.73 Hz, 2 H); 13C NMR (CDCl3, 101 MHz; δ, ppm)
14.4 (CH3), 22.7 (CH2), 23.0 (CH2), 29.0 (CH2), 29.5 (CH2), 29.6
(CH2), 29.6 (CH2), 29.8 (CH2), 29.9 (CH2), 32.2 (CH2), 36.7 (CH2),
111.5−120.2 (q, JC−F = 292.7 Hz, CF3), 191.9 (q, JC−C−F = 34.5 Hz,
C); 19F NMR (CDCl3, 377 MHz; δ, ppm) −82.66; GC-MS (EI) 252
(M+, 0.1%), 223 (3%), 209 (5%), 191.05 (5%), 183 (85%), 163
(10%), 153 (21%), 150 (10%), 139 (28%) 135 (11%), 125 (12%) 111
(31%) 109 (13%), 97 (55%), 83 (52%), 69 (84%), 43 (100%), 41
(95%); HRMS (ESI+) calcd for C13H23F3O [M + H]+ 253.1779,
found 253.1731.
4-(2,2,2-Trifluoroacetyl)benzaldehyde (3t). The title compound
(0.626 g, 78%) was prepared according to the general oxidation
procedure from 4-(2,2,2-trifluoro-1-hydroxyethyl)benzaldehyde (2t′)
1
to give a yellow solid (mp 86−88 °C): H NMR (MeOD, 400 MHz;
δ, ppm) 7.66 (d, J = 7.83 Hz, 2 H), 7.80 (d, J = 7.34 Hz, 2 H), 10.19
(br s, 1 H); 13C NMR (MeOD, 101 MHz; δ, ppm) 98.5 (q, JC−C−F
=
32.3 Hz, C), 120.8−129.4 (q, JC−F = 286.1 Hz, CF3), 128.3 (CH),
129.9 (CH), 137.0 (C), 141.6 (C); 19F NMR (MeOD, 377 MHz; δ,
ppm) −82.40; GC-MS (EI) 202 ([M]+, 5%), 133 (100%), 105 (34%),
77 (26%), 76 (10%), 69 (5%), 51 (12%), 50 (10%); HRMS (ESI+)
calcd for C9H5F3O2 [M + H]+ 203.0320, found 203.0341.
3-Cyclohexyl-1,1,1-trifluoropropan-2-one (3n). The title com-
pound (1.980 g, 49%) was prepared according to the representative
procedure from 3-cyclohexyl-1,1,1-trifluoropropan-2-ol (2n; 4.120 g,
Recovery and Regeneration of Spent Oxidant. The solid
material from each oxidation was saved, and after seven oxidations the
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solid was dissolved in a minimum amount of deionized water (∼300
mL) in a large Erlenmeyer flask. Once completely dissolved, NaCl was
added to bring the solution to ∼3 M in NaCl (approximately 53 g).
The flask was cooled to 0 °C and allowed to stand for 2 h. Over time, a
solid precipitate (1c) appeared and created a top layer. The top layer
was decanted carefully and filtered through a medium-porosity fritted
filter funnel. The orange solid was washed with cold brine and dried
overnight to afford 12.97 g (87% recovery based on seven reactions at
0.010 mol of 1) of 1c (mp 146−148 °C). This nitroxide was then
converted back to the oxoammonium salt 1 via the procedure outlined
in the salt preparation section (12.85 g, 70%).
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ASSOCIATED CONTENT
■
S
* Supporting Information
Text, tables, and figures giving spectroscopic data for the
compounds and details of the relative rate studies of the
oxidation of α-CF3 alcohols. This material is available free of
charge via the Internet at http://pubs.acs.org.
Chandrasekaran, S. Tetrahedron Lett. 2000, 41, 3327.
(13) Plumb, J. B.; Harper, D. J. Chem. Eng. News 1990, 68, 2−3,45.
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High Throughput Screening 2002, 5, 197.
(15) For reviews see: (a) deNooy, A. E. J.; Besemer, A. C.; van
Bekkum, H. Synthesis 1996, 1153. (b) Adam, W.; Saha-Moller, C. R.;
Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499. (c) Sheldon, R. A.;
Arends, I. W. C. E.; ten Brink, G.-J.; Dijksman, A. Acc. Chem. Res.
2002, 35, 774. (d) Ciriminna, R.; Pagliaro, M. Org. Process Res. Dev.
2010, 14, 245.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nicholas.leadbeater@uconn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(16) Abell, A. D.; Pearson, D.; Alexander, N. Chem. Eur. J. 2008, 14,
7358.
(17) Litvinas, N. D.; Brodsky, B. H.; Du Bois, J. Angew. Chem., Int. Ed.
2009, 48, 4513.
This work was supported by the National Science Foundation
(CAREER Award CHE-0847262). We wish to thank TCI-
America for the generous gifts of 4-amino-2,2,6,6-tetramethyl-
piperidine used for the preparation of 1. We especially
acknowledge Dr. James Bobbit for helpful discussions,
troubleshooting assistance, and aid in salt preparation. We
also wish to thank Drs. Martha Morton and You-Jun Fu of the
University of Connecticut for their assistance with NMR
characterization and obtaining mass spectra of various
compounds, respectively. We also acknowledge Nicholas
Eddy, Adam McShane, Meghan Negus, and DiAndra
Rudzinkski of the University of Connecticut and Dr. Leon
Tilley and his research group at Stonehill College for useful
discussions/technical assistance.
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Org. Chem. 2004, 69, 5116. (g) Qui, J.; Pradhan, P. P.; Blanck, N. B.;
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