Trifluoromethylation of ketones and aldehydes with Bu3SnCF 3

Article abstract of DOI:10.1021/jo401099e

The (trifluoromethyl)stannane reagent, Bu₃SnCF₃, was found to react under CsF activation with ketones and aldehydes to the corresponding trifluoromethylated stannane ether intermediates at room temperature in high yield. Only a mildly acidic extraction (aqueous NH ₄Cl) is required to release the corresponding trifluoromethyl alcohol products. The protocol is compatible with acid-sensitive functional groups.

Full text of DOI:10.1021/jo401099e

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Trifluoromethylation of Ketones and Aldehydes with Bu3SnCF3
Italo A Sanhueza, Karl J Bonney, Mads C. Nielsen, and Franziska Schoenebeck
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401099e • Publication Date (Web): 08 Jul 2013
Downloaded from http://pubs.acs.org on July 9, 2013
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Trifluoromethylation of Ketones and Aldehydes with
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Bu3SnCF3
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Italo A. Sanhueza,a,b Karl J. Bonney,a,b Mads C. Nielsen,a Franziska Schoenebecka,b
*
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a Laboratory for Organic Chemistry, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093
Zürich, Switzerland
b New address: Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52056 Aachen, Germany
E-mail address: franziska.schoenebeck@rwth-aachen.de
___________________________________________________________________________
Abstract: The (trifluoromethyl)stannane reagent, Bu3SnCF3, was found to react under CsF activation
with ketones and aldehydes to the corresponding trifluoromethylated stannane ether intermediates at
room temperature in high yield. Only a mildly acidic extraction (aqueous NH4Cl) is required to release
the corresponding trifluoromethyl alcohol products. The protocol is compatible with acid-sensitive
functional groups.
___________________________________________________________________________
The incorporation of fluorine into molecules results in profoundly different
properties and activities of compounds.1 In this context, a promising and relevant
building block is the trifluoromethyl alcohol motif. Figure 1 shows selected examples
of biologically and pharmaceutically potent molecules that contain this motif. The
activities of these compounds range from sleep induction (1),2 to anti-inflammatory
effects in cancer treatment (2),3 and inhibition of the cholesteryl ester transfer protein
relevant to heart disease (3).4 A straightforward route to these compounds involves
the direct addition of CF3 to the corresponding ketone or aldehyde precursors.
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Figure 1. Examples of relevant drugs that bear the trifluoromethyl alcohol motif
(top)2-4 and selected trifluoromethylation methods.5-7,10,11
Trifluoromethylation is most commonly accomplished via in situ activation of
the Ruppert-Prakash reagent, Me3SiCF3,5 with a fluoride source, leading to efficient
addition of CF3 to carbonyl compounds (such as aldehydes,6,7 ketones,5b,7 esters7,8 or
Weinreb amides9).10 The Pfizer drug 3 (Figure 1) is synthesized in this way, for
example.4 However, the protocol requires breakdown of the silyl ether intermediate
that is formed upon formal addition of Me3SiCF3 to the carbonyl group (Figure 1).
This is generally accomplished with acid (stirring in HCl) or with fluoride (TBAF).5b,7
Alternative methods include the use of fluoroform (CF3H).11 However, the latter
method is limited to non-enolizable carbonyl substrates, as the basic CF3-anion is
generated stoichiometrically in the presence of the substrate via exposure to a strong
base, such as KHMDS.11a On the other hand, Dolbier and co-workers developed a
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procedure based on CF3I that generates the nucleophilic CF3-anion via reduction by
TDAE, but the protocol is inefficient for enolisable aldehydes and ketones.12
Given that stannanes are generally softer than silanes,13,14 we anticipated
possibilities for synthetic applications and investigated the potential of stannane
reagents in trifluoromethylation reactions. In this context, we recently demonstrated
that Bu3SnCF3 can be used in Cu-mediated trifluoromethylations of aryl iodides.15,16
In this report, we disclose that Bu3SnCF3 can also be applied in efficient
trifluoromethylation reactions of aldehydes and ketones.
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We began our studies by adding one equivalent of Bu3SnCF3 and a catalytic
amount of CsF (0.1 equiv) to an excess of neat acetophenone at room temperature.
We observed that the stannane reagent was fully consumed within 5 h reaction time at
room temperature, and the corresponding trifluoromethylated derivative had formed
(as judged by 19F-NMR), indicating that trifluoromethylation of ketones using the
stannane reagent is indeed possible. Thus, we subsequently set out to identify a
general and more practical reaction protocol. A solvent screen (Table 1) revealed that
the use of a minimal amount of THF allowed the efficient transformation of 1.0 equiv
of acetophenone to the corresponding trifluoromethylated derivative in 24 h at room
temperature, employing a slight excess of Bu3SnCF3 (1.1 equiv) and a catalytic
amount of CsF (see Table 1). The superior reactivity observed in THF over CH2Cl2,
hexane or alternative ether solvents appeared to primarily be a consequence of the
better solubility of CsF in THF.
Table 1. Optimization of Conditions for the Trifluoromethylation of Acetophenonea
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entry equiv CsF
solvent
yield (%)b
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7
0.1
0.1
0.1
0.1
0.2
0.5
1.0
ethylene glycol diethyl ether
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CH2Cl2
n-hexane
THF
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0
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THF
>95
>95
>95
THF
THF
a
conditions: 0.2 mmol acetophenone used in 0.3 mL solvent, with 1.1 equiv of
nBu3SnCF3; b yield quantified after work-up, by integration of the 19F NMR spectrum
against a known amount of the internal standard, 4,4’-difluorobiphenyl.
With the optimized reaction conditions in hand, we subsequently employed a
variety of ketones under these conditions. Table 2 gives a summary of the results.
Aromatic (entries 1-7) as well as an example of aliphatic (entry 8) ketones reacted
efficiently at room temperature. The overall reaction time decreased with greater
electron deficiency of the ketone. The trifluoromethylations can conveniently be
carried out at ambient temperature and do not require cooling. Moreover, as
manifested in entry 6 (Table 2), selective trifluoromethylation of the ketone functional
group was observed, even in the presence of excess stannane reagent. Additional
experiments on aromatic ester compounds (e.g., methyl benzoate) confirmed that the
stannane reagent is not capable of trifluoromethylating the ester functional group
under these conditions. In contrast, under analogous conditions involving Me3SiCF3,
trifluoromethylations of esters do occur. (Selective trifluoromethylation of a ketone
over ester can be achieved with Me3SiCF3, if the reagent is employed in ≤1.0
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equiv.).7,8 The slightly lower reactivity of the stannane therefore bears potential for
selective and mild trifluoromethylations in the presence of alternative functional
groups.
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Table 2. Trifluoromethylation of Ketonesa
entry
product
time (h)
yield –
19F NMR / isolated (%)b
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24
24
96
15
30
>95 / 53
>95 / 69
66 / --c
77 / 41
>95 / 78
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>95 / 71
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78 / 72
70 / 51d
a
conditions: 0.4 mmol ketone in 0.3 mL THF, 0.2 equiv CsF and 1.1 (entries 1, 3–6
and 8) or 1.3 equiv (entries 2 and 7) nBu3SnCF3; b 19F NMR yield quantified by
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c
integration against a known amount of the internal standard, 4,4’-difluorobiphenyl;
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an isolated yield cannot be reported due to volatility of the compound; two
diastereomers were produced in the reaction in a ratio of 5.5/1.0, the isolated yield
being for the major diastereomer.
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The proposed mechanism for trifluoromethylation involving the stannane
reagent is illustrated in Figure 2. The reaction proceeds via the intermediacy of
stannane ether 5, as we demonstrated separately through isolation and characterization
of adduct 6 that resulted from Bu3SnCF3 addition to anthracene-9-carbaldehyde. We
1
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fully characterized adduct 6 with H- and C-NMR spectroscopic analyses and high
resolution mass spectrometry (that gave the expected molecular ion at [M]+=
566.1811, see supporting information for further information).
Figure 2. Proposed mechanism for trifluoromethylation.
We previously demonstrated that the formation of [CuCF3] intermediates from
Bu3SnCF3 in the presence of CuI and CsF is only marginally less efficient than that
from Me3SiCF3,15 which suggests that the stannane can just as readily release its CF3
group upon activation. We therefore hypothesize that the origin of slower reactivity of
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the stannane observed in the trifluoromethylation of ketones stems primarily from the
lower driving force to form stannane ether intermediate 5 as compared to a silyl ether
analogue (see Figure 2). The O-Sn bond is much more labile than the corresponding
O-Si bond (reported bond dissociation energies are: ΔH(O-Sn) = 548 kJ/mol and
ΔH(O-Si) = 798 kJ/mol).17 Greater electron deficiency around the O-Sn moiety in
turn would be expected to strengthen the bond and increase the thermodynamic
driving force to form 5, in line with the reactivity trend observed in Table 2.
The weakness of the O-Sn bond in the formed stannane ether intermediate 5
(Figure 2) gives the advantage that 5 also readily breaks down to release the final
alcohol product. In hydrolysis studies of the reaction given in entry 1 of Table 2, we
observed that upon addition of water to the corresponding stannane ether intermediate
5, hydrolysis had already taken place to about 60%. In subsequent studies, we
identified that complete conversion to the trifluoromethyl alcohol can be achieved
through a simple, aqueous NH4Cl extraction. The corresponding silyl ether
intermediates (analogous to 5) tend to be more stable and may require stirring in acid
(up to 6 N HCl) over hours (≥3 h) or addition of TBAF to release the final product.5b,7
Thus, the stannane protocol may be advantageous to the synthesis of molecules with
functional groups that are sensitive to stronger acids, nucleophiles or show high
lipophilicity.
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We subsequently expanded our studies to aldehydes (see Table 3). In accord
with the reactivities observed for the ketones above, the electron deficient carbonyl
moiety of the aldehydes showed excellent reactivity toward trifluoromethylation with
Bu3SnCF3. High conversions and good isolated yields were obtained after 8-22 h
reaction time at room temperature (see Table 3). Noteworthy are the successful
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isolations of the trifluoromethylated alcohols in entries 7-9, in which acid-sensitive
protecting groups (THP, trityl and MEM) were tolerated in the trifluoromethylation
and work-up procedure. This highlights the mildness of the stannane protocol.
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Table 3. Trifluoromethylation of Aldehydesa
entry
product
time (h)
yield –
19F NMR / isolated (%)b
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8
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>95 / --c
>95 / 83
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73 / 49
88 / 70
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>95 / 70
>95 / --c
>95 / 64
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>95 / 68d
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>95 / 67
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a
conditions: 0.4 mmol ketone in 0.3 mL THF (0.6 mL THF for entry 2), 0.2 equiv
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CsF and 1.1 (entries 1–5) or 1.3 equiv (entries 6–9) nBu3SnCF3; b 19F NMR yield
quantified by integration against a known amount of the internal standard, 4,4’-
c
difluorobiphenyl; an isolated yield cannot be reported due to volatility of the
compound; d this compound was found to decompose upon standing
In conclusion, we have demonstrated the feasibility of stannanes, such as
Bu3SnCF3, to trifluoromethylate aldehydes and ketones at room temperature in high
yield. The reactions proceed via the intermediacy of stannane ethers that in turn are
readily hydrolyzed through mildly acidic extraction (aqueous NH4Cl). The protocol
was shown to tolerate acid-sensitive functional groups.
Experimental Section
General Procedure for the Screening of Solvents. Solvent (0.3 mL, see Table 1)
and tributyl(trifluoromethyl)stannane (79 mg, 0.22 mmol, 1.1 equiv) were added to a
mixture of acetophenone (24 mg, 0.20 mmol, 1.0 equiv), cesium fluoride (0.1-1.0
equiv, see Table 1) and internal standard 4,4’-difluorobiphenyl (19 mg, 0.10 mmol,
0.5 equiv) in a vial. The reaction mixture was stirred at room temperature for 24 h
after which the reaction mixture was diluted with diethyl ether (2 mL) and quenched
with 2M hydrochloric acid (1 mL). The layers were separated and the organic phase
was used for 19F NMR studies.
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General Procedure for the Trifluoromethylation of Aldehydes and Ketones. THF
(0.3 mL, if not stated otherwise) and tributyl(trifluoromethyl)stannane (1.1-1.3 equiv,
see Tables 2 and 3) were added to a mixture of aldehyde or ketone (0.40 mmol, 1.0
equiv), internal standard 4,4’-difluorobiphenyl (19 mg, 0.10 mmol, 0.25 equiv) and
cesium fluoride (30 mg, 0.20 mmol, 0.5 equiv) in a vial. The reaction mixture was
stirred at room temperature for the requisite time (see Tables 2 and 3). The reaction
mixture was then diluted with diethyl ether (20 mL) and washed with a saturated
aqueous ammonium chloride solution (4 x 5 mL). The combined aqueous layers were
extracted with diethyl ether (20 mL) and the combined organics were then dried over
magnesium sulfate, filtered and the solvent was removed under reduced pressure. The
resulting residue was purified by column chromatography using silica gel
impregnated with potassium fluoride (20% w/w), eluting with 9 : 1 n-hexane : diethyl
ether.
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1
1,1,1-Trifluoro-2-phenylpropan-2-ol (Table 2, Entry 1). 40 mg, 53%; H NMR
(CDCl3, 300 MHz) δ 7.61-7.56 (m, 2H, ArH), 7.44-7.36 (m, 3H, ArH), 2.28 (br s, 1H,
ArH), 1.79 (br s, 3H, CH3); 13C NMR (CDCl3, 100 MHz) δ 138.5, 128.7, 128.4,
126.1, 125.7 (q, J = 285), 75.0 (q, J = 29), 24.1; 19F NMR (CDCl3, 282 MHz) δ -81.5
(s, CF3). This data is consistent with that reported in the literature.11e
2-(4-Chlorophenyl)-1,1,1-trifluoropropan-2-ol (Table 2, Entry 2). 62 mg, 69%; 1H
NMR (CDCl3, 300 MHz) δ 7.54-7.50 (m, 2H, ArH), 7.40-7.35 (m, 2H, ArH), 2.39 (s,
1H, OH), 1.77 (m, 3H, CH3); 13C NMR (CDCl3, 100 MHz) δ 136.9, 134.9, 128.7,
127.8, 125.5 (q, J = 286), 74.7 (q, J = 30), 24.1; 19F NMR (CDCl3, 282 MHz,) δ -81.7
(s, CF3). This data is consistent with that reported in the literature.18
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1,1,1,3,3,3-Hexafluoro-2-phenylpropan-2-ol (Table 2, Entry 3). H NMR (CDCl3,
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400 MHz) δ 7.74-7.71 (m, 2H, ArH), 7.49-7.45 (m, 3H, ArH), 3.55 (s, 1H, OH); C
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NMR (CDCl3, 100 MHz) δ 130.4, 129.5, 128.8, 126.7, 122.8 (q, J = 288), 77.1
(septet, J = 30); 19F NMR (CDCl3, 282 MHz) δ -76.1 (s, CF3). An isolated yield
cannot be reported due to volatility of the compound. This data is consistent with that
reported in the literature.19
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1,1,1-Trifluoro-2-(pyridin-2-yl)propan-2-ol (Table 2, Entry 4). 31 mg, 41%; H
NMR (CDCl3, 300 MHz) δ 8.62-8.57 (m, 1H, ArH), 7.85-7.78 (m, 1H, ArH), 7.55-
7.50 (m, 1H, ArH), 7.40-7.34 (m, 1H, ArH), 6.33 (s, 1H, OH), 1.73 (s, 3H, CH3); 13C
19
NMR (CDCl3, 100 MHz) δ 155.5, 147.4, 137.6, 126.8, 123.9, 121.2, 73.6, 21.9; F
NMR (CDCl3, 282 MHz)  -81.4 (s, CF3). This data is consistent with that reported in
the literature.20
1,1,1-Trifluoro-2-(naphthalen-2-yl)propan-2-ol (Table 2, Entry 5). 75 mg, 78%;
1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H, ArH), 7.92-7.83 (m, 3H, ArH), 7.67 (d, J
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= 8.7, 1H, ArH), 7.55-7.48 (m, 2H, ArH), 2.51 (s, 1H, OH), 1.89 (s, 3H, CH3); C
NMR (CDCl3, 100 MHz) δ 135.8, 133.1, 132.9, 128.5, 128.1, 127.5, 126.7, 126.4,
125.8 (q, J = 285), 125.6, 123.6, 75.1 (q, J = 29), 24.0; 19F NMR (CDCl3, 282 MHz) δ
-81.1 (s, CF3). This data is consistent with that reported in the literature.18
Methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (Table 2, Entry 6). 70
1
mg, 71%; H NMR (CDCl3, 300 MHz) δ 8.10-8.04 (m, 2H, ArH), 7.70-7.64 (m, 2H,
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ArH), 3.93 (s, 3H, OCH3), 2.46 (s, 1H, OH), 1.81 (s, 3H, CH3); C NMR (CDCl3,
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100 MHz) δ 166.8, 143.3, 130.3, 129.5, 126.2, 125.4 (q, J = 285), 74.8 (q, J = 29),
52.3, 23.9; 19F NMR (CDCl3, 282 MHz) δ -81.3 (s, CF3). This data is consistent with
that reported in the literature.21
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1,1,1-Trifluoro-2-(4-methoxyphenyl)propan-2-ol (Table 2, Entry 7). 63 mg, 72%;
1H NMR (CDCl3, 400 MHz) δ 7.50 (d, J = 9.0, 2H, ArH), 6.91 (app d, J = 9.0, 2H,
ArH), 3.82 (s, 3H, OCH3), 2.56 (br s, 1H, OH), 1.77 (s, 3H, CCH3); 13C NMR
(CDCl3, 100 MHz) δ 159.9, 130.8, 127.6, 125.8 (q, J = 285), 113.8, 74.7 (q, J = 29),
55.4, 24.0; 19F NMR (CDCl3, 282 MHz) δ -81.8 (s, CF3). This data is consistent with
that reported in the literature.18
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4-tert-Butyl-1-(trifluoromethyl)cyclohexanol (Table 2, Entry 8). 46 mg, 51%; H
NMR (CDCl3, 300 MHz) δ 2.26-2.19 (m, 2H, CH2), 1.96 (br s, 1H, OH), 1.76-1.68
(m, 2H, CH2), 1.52-1.45 (m, 2H, CH2), 1.38-1.25 (m, 2H, CH2), 1.15-1.05 (m, 1H,
13
CHC(CH3)3), 0.86 (s, 9H, CH3); C NMR (CDCl3, 100 MHz) δ 127.0 (q, J = 286),
19
72.0 (q, J = 27), 46.3, 33.3, 32.3, 27.5, 23.0; F NMR (CDCl3, 282 MHz) δ -78.3 (s,
CF3). This data is consistent with that reported in the literature.22
(1-(Anthracen-9-yl)-2,2,2-trifluoroethoxy)tributylstannane (6). To a mixture of
anthracene-9-carbaldehyde (41.2 mg, 0.20 mmol) and cesium fluoride (30.5 mg, 0.20
mmol) in THF (0.4 mL) was added tributyl(trifluoromethyl)stannane (79.0 mg, 0.22
mmol). The mixture was stirred at RT for 3 h, diluted with Et2O (3 mL) and filtered
through celite. The filtrate was concentrated in vacuo and to the resulting crude
mixture was added hexane (5 mL). The suspension was filtered and the filtrate
1
concentrated to provide the title compound as a yellow oil: 109 mg, 96%; H NMR
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(400 MHz, CD2Cl2) δ 9.35 (d, J = 9.2, 1H, ArH), 8.51 (s, 1H, ArH), 8.23 (d, J = 9.2,
1H, ArH), 8.05 (d, J = 9.2, 1H, ArH), 8.01-7.99 (m, 1H, ArH), 7.59-7.55 (m, 1H,
ArH), 7.50-7.44 (m, 3H, ArH), 6.61-6.53 (m, 1H, CHCF3), 1.33-1.24 (m, 6H, CH2),
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1.14-1.04 (m, 6H, CH2), 0.92-0.84 (m, 6H, CH2), 0.73 (t, J = 11.2, 9H, CH3); C
NMR (100 MHz, CD2Cl2) δ 132.6, 131.9, 131.5, 130.9, 129.9 (2C), 129.4, 129.3 (q, J
= 3.1), 128.9, 127.0, 126.0, 125.4, 125.2, 124.9, 123.2, 73.5 (q, J = 33), 28.0, 27.4,
15.5, 13.7; 19F NMR (CD2Cl2, 282 MHz,) δ -74.3 (d, J = 8.2); ESI HRMS: calculated
for C28H37F3OSn+ 566.1818, found 566.1811.
2,2,2-Trifluoro-1-phenylethanol (Table 3, Entry 1). 1H NMR (CDCl3, 400 MHz) δ
7.44-7.37 (m, 2H, ArH), 7.38-7.33 (m, 3H, ArH), 5.01-4.92 (m, 1H, CHCF3), 2.46 (d,
J = 4.6, 1H, OH); 19F NMR (CDCl3, 282 MHz) δ -78.9 (d, J = 6.7, CF3). An isolated
yield cannot be reported and it was not possible to record a 13C NMR spectrum due to
volatility of the compound. This data is consistent with that reported in the
literature.23
1
1-(Anthracen-9-yl)-2,2,2-trifluoroethanol (Table 3, Entry 2). 92 mg, 83%; H
NMR (CDCl3, 300 MHz) δ 8.96 (br s, 1H, ArH), 8.52 (s, 1H, ArH), 8.11 (br s, 1H,
ArH), 8.02 (d, J = 8.3, 2H, ArH), 7.60-7.45 (m, 4H, ArH), 6.62 (m, 1H, CHOH), 2.98
(d, J = 4.4, 1H, OH); 13C NMR (CDCl3, 100 MHz) δ 131.9, 130.9, 129.5, 127.2,
126.4, 125.6 (q, J = 284), 125.1, 123.9, 122.6, 70.3 (q, J = 34); 19F NMR (CDCl3, 282
MHz) δ -74.5 (d, J = 7.9, CF3). This data is consistent with that reported in the
literature.24
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2,2,2-Trifluoro-1-(4-nitrophenyl)ethanol (Table 3, Entry 3). 43 mg, 49%; 1H NMR
(CDCl3, 300 MHz) δ 8.34-8.23 (m, 2H, ArH), 7.74-7.65 (m, 2H, ArH), 5.18 (q, J =
6.3, 1H, CHCF3), 2.86 (s, 1H, OH); 13C NMR (CDCl3, 100 MHz) δ 148.6, 140.4,
128.5, 123.7, 123.7 (q, J = 282), 71.9 (q, J = 32); 19F NMR (CDCl3, 282 MHz) δ -78.7
(dd, J = 6.1, 3.7, CF3). This data is consistent with that reported in the literature.25
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1-[4-(Dimethylamino)phenyl]-2,2,2-trifluoroethanol (Table 3, Entry 4). 61 mg,
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70%; H NMR (CDCl3, 400 MHz) δ 7.35-7.30 (m, 2H, ArH), 6.74-6.70 (m, 2H,
ArH), 4.91 (qd, J = 6.8, 4.4, 1H, CHOH), 2.98 (s, 6H, NCH3), 2.32 (d, J = 4.5, 1H,
13
OH); C NMR (CDCl3, 100 MHz) δ 151.3, 128.4, 124.6 (q, J = 282), 121.7, 112.3,
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72.7 (q, J = 32), 40.4; F NMR (CDCl3, 282 MHz) δ -79.0 (d, J = 6.7, CF3). This
data is consistent with that reported in the literature.26
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1-(4-Bromophenyl)-2,2,2-trifluoroethanol (Table 3, Entry 5). 75 mg, 70%; H
NMR (CDCl3, 400 MHz) δ 7.58-7.53 (m, 2H, ArH), 7.36 (d, J = 8.7, 2H, ArH), 5.01
13
(q, J = 6.6, 1H, CHCF3), 2.60 (br s, 1H, OH); C NMR (CDCl3, 100 MHz) δ 132.8,
131.8, 129.1, 123.9 (q, J = 282), 123.8, 72.2 (q, J = 32); 19F NMR (CDCl3, 282 MHz)
δ -79.0 (dd, J = 6.7, 2.1, CF3). This data is consistent with that reported in the
literature.27
1
2,2,2-Trifluoro-1-(furan-2-yl)ethanol (Table 3, Entry 6). H NMR (CDCl3, 300
MHz) δ 7.48 (dd, J = 1.9, 0.8, 1H, ArH), 6.54 (d, J = 3.4, 1H, ArH), 6.43 (d, J = 3.4,
1.9 Hz, 1H, ArH), 5.06 (m, 1H, CHOH); 19F NMR (CDCl3, 282 MHz) δ -78.5 (d, J =
6.7, CF3). An isolated yield cannot be reported and it was not possible to record a 13C
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NMR spectrum due to volatility of the compound. This data is consistent with that
reported in the literature.28
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2,2,2-Trifluoro-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanol (Table 3,
Entry 7). Compound was isolated as a white solid, as a 1 : 1 mixture of two
1
diastereomers: 71 mg, 64%; H NMR (CDCl3, 400 MHz)  7.41-7.36 (2 x m, 2H,
ArH), 7.08-7.03 (2 x m, 2H, ArH), 5.45-5.40 (2 x m, 1H, OCHO), 4.97-4.89 (2 x m,
1H, CHCF3), 3.92-3.84 (2 x m, 1H, OCHCH2), 3.64-3.56 (2 x m, 1H, OCH2), 2.90 (1
x d, J = 4.6, 1H OH), 2.88 (1 x d, J = 4.7, 1H, OH), 2.05-1.95 (2 x m, 1H, CH2), 1.88-
13
1.83 (2 x m, 2H, CH2), 1.75-1.55 (2 x m, 3H, CH2); C NMR (CDCl3, 100 MHz) δ
157.9 (2 x C), 128.7 (4 x C), 127.1 (2 x C), 124.3 (2 x C, q, J = 283), 116.5 (2 x C),
116.4 (2 x C), 96.3 (2 x C), 72.5 (1 x C, q, J = 32), 72.4 (1 x C, q, J = 32), 62.1 (2 x
C), 30.3 (2 x C), 25.1 (2 x C), 18.7 (2 x C); 19F NMR (CDCl3, 282 MHz) δ -79.0 (d, J
+
= 7.1, CF3); m.p. 68.1-69.9; MALDI/ESI HRMS: calculated for C13H15F3NaO3
299.0866, found 299.0867.
2,2,2-Trifluoro-1-(4-(trityloxy)phenyl)ethanol (Table 3, Entry 8). Compound was
1
isolated as a colourless oil: 118 mg, 68%; H NMR (CDCl3, 300 MHz) δ 7.46-7.43
(m, 6H, ArH), 7.31-7.21 (m, 9H, ArH), 7.08 (d, J = 8.8, 2H, ArH), 6.74-6.66 (m, 2H,
13
ArH), 4.82-4.80 (m, 1H, CHCF3), 2.31 (br d, J = 4.5, 1H, OH); C NMR (CDCl3,
100 MHz) δ 157.5, 144.0, 129.0, 128.0, 127.9, 127.8, 127.4, 126.7, 124.4 (q, J = 282),
19
90.8, 72.6 (q, J = 33); F NMR (CDCl3, 282 MHz) δ -79.0 (d, J = 6.6, CF3). It was
not possible to acquire mass spectrometry data for this compound using EI, ESI or
MALDI ionization techniques.
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2,2,2-Trifluoro-1-(4-((2-methoxyethoxy)methoxy)phenyl)ethanol (Table 3, Entry
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6
1
9). Compound was isolated as a colourless oil; 75 mg, 67%; H NMR (CDCl3, 400
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MHz) δ 7.41-7.37 (m, 2H, ArH), 7.10-7.06 (m, 2H, ArH), 5.28 (s, 2H, OCH2O), 4.97
(q, J = 6.8, 1H, CHCF3), 3.84-3.80 (m, 2H, OCH2), 3.57-3.53 (m, 2H, OCH2), 3.37 (s,
3H, OCH3), 2.61 (br s, 1H, OH); 13C NMR (CDCl3, 100 MHz) δ 158.3, 130.3, 128.9,
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124.4 (q, J = 283), 116.4, 93.5, 72.6 (q, J = 33), 71.7, 67.9, 59.2; F NMR (CDCl3,
+
282 MHz,) δ -79.0 (d, J = 6.8); ESI HRMS: calculated for C12H15F3NaO4 303.0815,
found 303.0817.
Acknowledgements. This work was supported by ETH Zürich, an ETH Independent
Investigator’s Research Award and the Carlsberg Foundation (postdoctoral fellowship
to M.C.N.).
Supporting Information. General experimental details, 1H NMR spectra of
previously reported compounds, 1D and 2D NMR spectra of new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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