Regioselective substitution of phenols with trifluoroacetaldehyde ethyl hemiacetal

Article abstract of DOI:10.1246/bcsj.74.377

2,2,2-Trifluoroethanols are of great interest because of their unique physical, chemical, and biological properties. Trifluoroacetaldehyde is a very efficient reagent for obtaining 2,2,2-trifluoroethanols. Because it is unavailable commercially, its hemia

Full text of DOI:10.1246/bcsj.74.377

© 2001 The Chemical Society of Japan
377
Bull. Chem. Soc. Jpn., 74, 377–383 (2001)
Regioselective Substitution of Phenols with Trifluoroacetaldehyde Ethyl
Hemiacetal
Yuefa Gong,* Katsuya Kato, and Hiroshi Kimoto
National Industrial Research Institute of Nagoya, Hirate-cho, Kita-ku, Nagoya 462-8510
(Received October 2, 2000)
Phenol did not react directly with trifluoroacetaldehyde ethyl hemiacetal. In the presence of catalytic amounts of an-
hydrous potassium carbonate, however, the reaction readily occurred. The p-substituted product 4-(2,2,2-trifluoro-1-hy-
droxyethyl)phenol predominated. In contrast, the reaction catalyzed by zinc halide predominantly produced the o-substi-
tuted product. Corresponding reactions of several phenols were studied under the same catalytic conditions.
2,2,2-Trifluoroethanols are of great interest because of their
unique physical, chemical, and biological properties.1 The de-
velopment of new preparation methods therefore continues to
be an important area of research. Useful synthetic methods re-
ported include the reduction of trifluoromethyl ketones,2 addi-
tion of trifluoromethanide anion reagents to carbonyl com-
pounds,3 and electrochemical trifluoromethylation of carbonyl
compounds.4 Trifluoroacetaldehyde is a very efficient reagent
for obtaining 2,2,2-trifluoroethanols.5 Because it is unavailable
commercially, its hemiacetal has been usually used to react
with enamines,6 enolates,7 olefins,8 alkylmetals9 or arenes,10
sometimes using Lewis acid catalyst.
We found that trifluoroacetaldehyde ethyl hemiacetal
(TFAE) readily reacts with the various electron-rich heteroare-
nes, forming 1-hetereoaryl-2,2,2-trifluoroethanols in good
yields.11 In our continuing investigations, substitution reactions
of TFAE with electron-rich benzene derivatives, in particularly
phenol, have been used to prepare 1-(hydroxyphenyl)-2,2,2-tri-
fluoroethanols.12 4-(2,2,2-Trifluoro-1-hydroxyethyl)phenol (1)
is an important intermediate used in ferroelectric liquid crys-
tals. Usually it is prepared by the Grignard reaction of trifluoro-
acetic acid, with subsequent demethylation and reduction2c,13
(Scheme 1). We recently succeeded in achieving regioselective
substitutions of phenols with TFAE by using potassium car-
bonate or zinc halide as the catalyst. This method provides a
most convenient route to 1-(hydroxyphenyl)-2,2,2-trifluoroeth-
anols (Chart 1). Details of the procedure are described hereaf-
ter.
Results
When a mixture of equimolar amounts of phenol and TFAE
was heated at 120 °C for 8 h, no detectable substitution product
was determined by TLC, but in the presence of 0.05 molar
amount of anhydrous potassium carbonate, phenol readily re-
acted with TFAE even at 60 °C, giving a good yield of the p-
substituted product 4-(2,2,2-trifluoro-1-hydroxyethyl)phenol
(1) and a small amount of the o-substituted product 2-(2,2,2-
trifluoro-1-hydroxyethyl)phenol (2).12 Further experiments
clearly showed that the ratio of 1/2 is comparatively low and
that the disubstituted product (3), purified as its triacetylated
product (4) (Chart 1), is generated simultaneously when the re-
action takes place at a high temperature (Scheme 2). Moreover,
the addition of a large excess of TFAE led to the formation of
the trisubstituted product 2,4,6-tris(2,2,2-trifluoro-1-hydroxy-
ethyl)phenol (5) in an excellent yield. The yields obtained are
given in Table 1 (Entries 1–4).
Next the reaction of phenol with TFAE was studied with a
Lewis acid as the catalyst. The first experiment done at 70 °C
in the presence 0.05 molar amount of zinc chloride gave no
substitution product, but when the temperature was raised to
130 °C, the reaction readily proceeded (Scheme 2). Product
analysis by GC showed preferential formation of o-substituted
product (2) rather than p-substituted product (1) (Table 1, Entry
6). In addition, about 5% of the corresponding ether, 2- or 4-(1-
ethoxy-2,2,2-trifluoroethyl)phenol (6), was detected by GC/
MS, but the product was not purified further. Similar results
Scheme 1.

378 Bull. Chem. Soc. Jpn., 74, No. 2 (2001)
Substitution of Phenol with Trifluoroacetaldehyde
Chart 1.
Scheme 2.
Table 1. Reaction of Phenol with TFAE
Entry
Molar ratioa)
Catalystb)
Conditions
Product (Yield/%)
1
2
1
1
none
K2CO3
120 ◦C, 8 h
none
60 ◦C, 12 h
1 (65) 2(10) c)
1 (85) 2(15) d)
1 (48) 2(20) 3 (7) c)
1 (55) 2(30) 3 (10) d)
5 (92) c)
3
1
K2CO3
120 ◦C, 6 h
4
5
6
7
8
5
K2CO3
ZnCl2
ZnCl2
ZnI2
BF3• Et2O
120 ◦C, 6 h
70 ◦C, 6 h
130 ◦C, 8 h
130 ◦C, 8 h
45 ◦C, 8 h
1.1
1.1
1.1
1.1
none
1 (1)
2(46) d)
2(83) d)
1 (4)
1 (10) d)
a) TFAE/Phenol. b) Catalytic amounts: K2CO3 (0.05 mol amt.), ZnX2 (0.05 mol amt.) and BF3• Et2O
(0.1 mol amt.). c) Isolated yields. d) GC yields .

Y. Gong et al.
Bull. Chem. Soc. Jpn., 74, No. 2 (2001) 379
were obtained when 0.05 molar amount of zinc iodide was
used, but the catalytic activity was much higher than that of
zinc chloride (Entry 7). In contrast, p-substitution occurred
with low conversion when the reaction was catalyzed by boron
trifluoride–diethyl ether, indicative of low catalytic efficiency
(Entry 8). For this reason, the reactions of other phenols were
studied using potassium carbonate or zinc halide as the cata-
lyst.
The reaction of 2,6-dimethylphenol catalyzed by potassium
carbonate afforded only the p-substituted product 2,6-dimeth-
yl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (7), whereas that
of 4-methylphenol gave the o-substituted product 4-methyl-2-
(2,2,2-trifluoro-1-hydroxyethyl)phenol (8), both in high yields
(Table 2, Entries 1–2).12 With 2-methoxyphenol, mainly the p-
substituted product 2-methoxy-4-(2,2,2-trifluoro-1-hydroxy-
ethyl)phenol (9) was formed together with small amounts of
the o-substituted and disubstituted products, 2-methoxy-6-
(2,2,2-trifluoro-1-hydroxyethyl)phenol (10) and 2-methoxy-
4,6-bis(2,2,2-trifluoro-1-hydroxyethyl)phenol (11) (Entry 3).
The yields of (10) and (11) somewhat increased when the reac-
tion temperature was raised to 120 °C (Entry 4). In the case of
4-phenylphenol, only the o-substituted products 4-phenyl-2-
(2,2,2-trifluoro-1-hydroxyethyl)phenol (12) and 4-phenyl-2,6-
bis(2,2,2-trifluoro-1-hydroxyethyl)phenol (13) were obtained
(Entry 5), but no product substituted in the other phenyl ring
was detected.
nol, disubstitution being markedly decreased (Entry 6) as com-
pared with the reaction catalyzed by potassium carbonate (Ta-
ble 2, Entry 5). The reaction promoted by boron trifluoride was
also assessed. Only the o-substituted products (12) and (13)
were produced under the conditions (Entry 7). Like phenol, 2-
methylphenol reacted with TFAE, giving a high yield of the o-
substituted product 2-methyl-6-(2,2,2-trifluoro-1-hydroxyeth-
yl)phenol (17), but there was no detectable p-substituted prod-
uct (Entry 4). The reaction of 2-methoxyphenol proceeded
with relatively low regioselectivity, the o-substituted product
(10) still being the main product (Entry 5).
As reported, zinc chloride also catalyzed the reaction of
TFAE with phenol, but with relatively poor catalytic activity.
For this reason, in the reaction with phenols we used a high
molar ratio of zinc chloride. In the presence of 0.5 molar
amount of zinc chloride, the reaction with phenol proceeded
smoothly at 130 °C. Crude product analysis, however, clearly
showed that very complicated products were afforded under
those conditions, mainly because of successive condensation
between 1-aryl-2,2,2-trifluoroethanols 1–3 and phenol. Similar
results were obtained for the reactions with 4-methylphenol
and with 2-methoxyphenol. In contrast, bisphenolic compound
(14) was the main product in the corresponding reaction with
2,6-dimethylphenol, and it was easily purified by column chro-
matography (Table 3, Entry 2). The corresponding reaction
with 1- or 2-naphthols was also investigated. In the presence of
0.05 molar amount of zinc iodide, the reaction with 2-naphthol
gave only the 1-substituted product 1-(2,2,2-trifluoro-1-hy-
droxyethyl)-2-naphthol (18) (Table 4, Entry 1), whereas that of
1-naphthol afforded complicated products. Similar results
were observed when 0.5 molar amount of zinc chloride was
used instead (Table 4, Entry 2). In addition, the reaction with 1-
or 2-naphthols carried out in the presence of 0.05 molar
amount of potassium carbonate at 90 °C provided quite com-
plicated products.
These phenols were also used to study the reaction catalyzed
by 0.05 molar amount of zinc iodide. Results are given in Table
3. With 2,6-dimethylphenol, p-substituted product (7) was the
main product (Entry 1), and a small amount of 4,4′-(2,2,2-trif-
luoroethylidene)bis(2,6-dimethylphenol) (14) was detected by
19F NMR and MS. 4-Methylphenol, however, always gave the
o-substitution (Entry 3). Besides the main product (8), small
amounts of condensation products (15) and (16) were detected.
Only o-substitution occurred in the reaction with 4-phenylphe-
Table 2. Reaction of Substituted Phenols Catalyzed by K2CO3
Entry
Substituent
Conditions
Products (Yield/%a))
1
2
3
4
5
2,6-di-Me
4-Me
2-MeO
2-MeO
4-Ph
120 ◦C, 6 h
120 ◦C, 6 h
60 ◦C, 72 h
120 ◦C, 6 h
120 ◦C, 30 h
7 (95)
8 (91)
9 (48) 10 (3)
9 (33) 10 (11) 11 (12)
12 (43) 13 (22)
11 (6)
a) Isolated yields based on the substrate
Table 3. Reaction of Substituted Phenols Catalyzed by Lewis Acid at 130 ◦C
Entry
Substituent
Catalysta)
Time /h
Product (Yield/%b))
1
2
3
4
5
6
7
2,6-di-Me
2,6-di-Me
4-Me
ZnI2
ZnCl2
ZnI2
ZnI2
ZnI2
ZnI2
BF3
8
8
8
8
8
7 (92) 14 (3)
7 (19) 14 (78)
8 (86)
2-Me
17 (92)
2-MeO
9 (16) 10 (46)
12 (63) 13 (5)
12 (21) 13 (2)
4-Phc)
12
12
4-Phc)
a) Catalyst: ZnI2 (0.05 mol amt.), ZnCl2 (0.5 mol amt.), BF3 (0.2 mol amt.). b) Isolated yields based on
the substrate. c) Toluene was the solvent.

380 Bull. Chem. Soc. Jpn., 74, No. 2 (2001)
Substitution of Phenol with Trifluoroacetaldehyde
Table 4. Reaction of Other Typical Arenes with TFAE
Entry
Substrate
Catalysta)
Conditions
Product (Yield/%b))
1
2
3
4
5
6
7
2-naphthol
2-naphthol
PhNMe2
p-MePhNMe2
PhOMe
ZnI2
130 ◦C, 8 h
130 ◦C, 8 h
120 ◦C, 6 h
120 ◦C, 30 h
130 ◦C, 8 h
130 ◦C, 8 h
130 ◦C, 8 h
18 (14)
18 (57)
19 (95)
20 (58)
21 (10)
21 (21)
trace
ZnCl2
none
none
ZnI2
ZnCl2
ZnCl2
PhOMe
PhNHAc
a) Catalytst: ZnI2 (0.05 mol amt.), ZnCl2 (0.5 mol amt.). b) Isolated yields based on the substrate.
Next we extended our study to other typical benzene deriva-
mechanism is not clearly understood, apparently some kind of
a complex is formed between the reactants.14 In fact, potassium
phenoxide, which is less likely to form such a complex, is
chiefly attacked in the para position.15 Therefore in the case of
potassium carbonate, the reaction may have proceeded along
the route shown in Scheme 3. Potassium carbonate, a strong
Brønsted base, easily removed the weakly acidic proton of phe-
nol, generating the much more reactive potassium phenoxide.
Potassium phenoxide is mainly attacked by TFAE in the para
position, affording an unstable intermediate 22, which was
quickly converted into the substituted phenolate anion 23. This
anion was consumed in the following ways: (a) abstracting one
proton from phenol to form the final product (1) and a new phe-
nolate anion; and (b) successive reaction with TFAE to form
disubstituted or trisubstituted products. Eventually, trisubsti-
tuted product 5 was obtained in high yield when a large excess
of TFAE was used.
Lewis acids are widely used in the Friedel−Crafts reaction
of TFAE with olefinic compounds.8 Their catalytic effect is the
enhancement of the reactivity of electrophile by coordination
with one oxygen atom of TFAE. The catalytic role of zinc ha-
lide in the reaction with phenol can be considered similar. The
preference for the o-substitution suggests that this reaction pro-
ceeds through a six-membered transition state involving a zinc
halide (Scheme 4), as reported in the reactions of phenol or 1-
naphthol with aldehydes catalyzed by aluminium or titanium
complexes.16 Moreover, preferential formation of 1-aryl-2,2,2-
trifluoroethanol, rather than the corresponding ether 6, indi-
cates that the pathway (A) is much more important than path-
tives. N,N-dimethylaniline reacted smoothly with TFAE with
no catalyst present at 120 °C, yielding 4-(2,2,2-trifluoro-1-hy-
droxyethyl)-N,N-dimethylaniline (19) in a high yield (Table 4,
Entry 3). A similar reaction with N,N-dimethyl-p-toluidine
provided a good yield of 4-methyl-2-(2,2,2-trifluoro-1-hydro-
xyethyl)-N,N-dimethylaniline (20) (Entry 4).12 Acetanilide,
however, did not react with TFAE, and only a trace amount of
substituted product was detected in the presence of zinc chlo-
ride (Entry 7). The reaction with anisole proceeded in the pres-
ence of 0.05 molar amount of zinc iodide with formation of
4,4′-(2,2,2-trifluoroethylidene)dianisole (21) (Entry 5), and the
yield of (21) was markedly enhanced by using 0.5 molar
amount of zinc chloride as the catalyst (Entry 6).
Discussion
As reported above, direct substitution of TFAE with phenol
did not occur due to the relatively low reactivity of phenol, but
the reaction readily took place in the presence of a catalytic
amount of potassium carbonate or zinc halide. The reaction
catalyzed by potassium carbonate mainly produced p-substi-
tuted product (1), whereas that catalyzed by zinc halide prefer-
entially formed o-substituted product (2). Moreover, bisphe-
nolic compounds are mainly generated when a large amount of
zinc chloride was used.
In interpreting these results, one must consider the role of
the catalyst used. As known to us, o-substitution was usually
preferred in some aromatic substitution reaction of sodium
phenoxide such as in the Kolbe−Schmitt reaction. Although the
Scheme 3.

Y. Gong et al.
Bull. Chem. Soc. Jpn., 74, No. 2 (2001) 381
Scheme 4.
Scheme 5.
mmol) of trifluoroacetaldehyde ethyl hemiacetal and 0.48 g (1.5
mmol) of zinc iodide was heated with stirring at 130 °C for the pe-
riods given in Tables 1 and 3. After being cooled, the mixture was
dissolved in ethyl acetate (20 ml), and washed with water. The or-
ganic phase was dried over anhydrous sodium sulfate. The solvent
was removed by evaporation under reduced pressure. The residue
was isolated by column chromatography eluted with hexane/ethyl
acetate (v/v: 5/1 to 5/2).
way (B) in the reaction. An alternative explanation for the pref-
erential removal of ethoxy group in the presence of a Lewis
acid has been already proposed by HSAB theory.10b Further-
more, formation of bisphenolic compounds, e.g. (14), may be
due to a successive substitution of 1-aryl-2,2,2-trifluoroethanol
with phenol; a possible pathway for this is suggested in
Scheme 5. This means that the coordination of zinc halide may
greatly weaken the C−O bond of 1-aryl-2,2,2-trifluoroethanol,
and may eventually lead to the generation of a reactive species
such as 1-aryl-2,2,2-trifluoroethyl cation.
In the case of 4-phenylphenol, about 10 ml of toluene dried over
4 Å molecular sieves was added to the mixture.
4-(2,2,2-Trifluoro-1-hydroxyethyl)phenol (1). Mp 123.5–125
1
°C, white needles. H NMR (acetone-d6) δ 2.95 (2H, br, s), 5.06
Experimental
(1H, q, J = 7.4 Hz), 6.86 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.5
Hz). 19F NMR (acetone-d6) δ 85.73 (3F, d, J = 7.4 Hz); MS m/z
192 (M+, 38), 123 (100). HRMS Found: m/z 192.0398, Calcd for
C8H7O2F3: 192.0398.
1H NMR spectra were recorded at 90 MHz on a Hitachi R-90H
FT spectrometer with tetramethylsilane (TMS) as an internal stan-
dard. 19F NMR spectra were recorded at 84.7 MHz on the same
spectrometer with hexafluorobenzene as an internal standard.
Mass spectra (70 eV) were determined on a Hitachi M-80 instru-
ment. Melting points were measured in a glass capillary on a heat-
ing block and are uncorrected. High-resolution mass spectra were
recorded on a JEOL JMS-SX102A MS spectrometer.
Reaction with Phenol Catalyzed by K2CO3 (General Proce-
dure): A mixture of 2.82 g (30 mmol) of phenol, 4.32 g (30
mmol) of trifluoroacetaldehyde ethyl hemiacetal and 0.21 g (1.5
mmol) of anhydrous potassium carbonate was heated with stirring
at the temperatures and for the periods given in Tables 1 and 2. Af-
ter being cooled, the mixture was dissolved in ethyl acetate (20
ml), and washed with aqueous ammonium chloride and distilled
water, then dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure. The residue was isolated by
silica gel column chromatography (hexane/ethyl acetate, v/v: 5:1
to 5:2) to give products (1) and (2).
2-(2,2,2-Trifluoro-1-hydroxyethyl)phenol (2). Mp 118–118.5
1
°C, white needles. H NMR (acetone-d6) δ 2.87 (2H, br, s), 5.57
(1H, q, J = 7.4 Hz), 6.91 (2H, m), 7.17 (1H, dd, J = 7.0, 2.0 Hz),
7.50 (1H, d, J = 7.0 Hz). 19F NMR (acetone-d6) δ 85.94 (3F, d, J =
7.4 Hz); MS m/z 192 (M+, 55), 174 (18), 146 (40), 123 (95), 77
(100). HRMS Found: m/z 192.0378, Calcd for C8H7O2F3:
192.0398.
2,4-Bis(1-acetoxy-2,2,2-trifluoroethyl)phenyl Acetate (4).
1
Mp 109–110 °C, white plates. H NMR (CDCl3) δ 2.17 (3H, s),
2.20 (3H, s), 2.37 (3H, s), 6.19 (1H, q, J = 6.8 Hz), 6.51 (1H, q, J =
6.8 Hz), 7.27 (1H, dd, J = 8.1, 2.8 Hz), 7.58 (1H, d, J = 8.1 Hz),
7.65 (1H, d, J = 2.8 Hz). 19F NMR (CDCl3) δ 85.84 (3F, d, J = 6.8
Hz), 86.25 (3F, d, J = 6.8 Hz); MS m/z 416 (M+, 12), 374 (100),
357 (13), 332 (76), 294 (17). HRMS Found: 416.0693, Calcd for
C16H14O6F6: 416.0695.
2,4,6-Tris(2,2,2-trifluoro-1-hydroxyethyl)phenol (5). A col-
orless liquid. 1H NMR (acetone-d6) δ 3.30 (2H, br, s), 5.18 (1H, q,
J = 7.3 Hz), 5.63 (2H, q, J = 7.3 Hz), 6.60 (1H, br,s), 7.64 (2H, s),
Reaction of Phenol Catalyzed by Lewis Acid (General Pro-
cedure): A mixture of 2.82 g (30 mmol) of phenol, 4.75 g (33

382 Bull. Chem. Soc. Jpn., 74, No. 2 (2001)
Substitution of Phenol with Trifluoroacetaldehyde
8.90 (1H, br, s). 19F NMR (acetone-d6) δ 85.69 (9F, d, J = 7.3 Hz);
MS m/z 388 (M+, 26), 319 (39), 301 (100), 281 (15). HRMS
Found: m/z 388.0359, Calcd for C12H9O4F9: 388.0357.
graphy eluted with hexane/ethyl acetate (v/v 3:1). Mp 139–140
°C, white needles. H NMR (acetone-d6) δ 5.10 (2H, br, s), 6.29
1
(1H, q, J = 7.9 Hz), 7.18 (1H, d, J = 9.1 Hz), 7.45 (2H, m), 7.84
(2H, m), 8.27 (1H, m). 19F NMR (acetone-d6) δ 87.68 (3F, d, J =
7.9 Hz); MS m/z 242 (M+, 52), 196 (26), 173 (100), 127 (59).
HRMS Found: m/z 242.0554, Calcd for C12H9O2F3: 242.0555.
4-(2,2,2-Trifluoro-1-hydroxyethyl)-N,N-dimethylaniline (19).
A mixture of 3.63 g (30 mmol) of N,N-dimethylaniline and 4.32 g
(30 mmol) of trifluoroacetaldehyde ethyl hemiacetal was heated
with continuous stirring at 120 °C for 6 h. After being cooled, the
mixture became a solid cake. The crude product was then recrys-
tallized from dichloromethane to give 6.24 g (95%) of the pure
2,6-Dimethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (7).
1
Mp 136–138 °C, white solid. H NMR (CDCl3) δ 2.25 (6H, s),
4.88 (1H, q, J = 7.2 Hz), 5.12 (2H, br, s), 7.07 (2H, s). 19F NMR
(CDCl3) δ 85.91 (3F, d, J = 7.2 Hz); MS m/z 220 (M+, 60), 151
(100). HRMS Found: m/z 220.0711, Calcd for C10H11O2F3:
220.0711.
4-Methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (8). Mp
1
106–107.5 °C, white needles. H NMR (CDCl3) δ 2.26 (3H, s),
4.51 (2H, br, s), 5.16 (1H, q, J = 6.7 Hz), 6.75 (1H, d, J = 8.1 Hz),
7.02 (2H, m). 19F NMR (CDCl3) δ 83.49 (3F, d, J = 6.7 Hz); MS m/
z 206 (M+, 39), 188 (21), 137 (20), 108 (100). HRMS Found: m/z
206.0551, Calcd for C9H9O2F3: 206.0555.
1
product (19). Mp 98–99 °C, white needles. H NMR (CDCl3) δ
2.55 (1H, s), 2.94 (6H,s), 4.85 (1H, q, J = 6.5 Hz), 6.70 (2H, d, J =
8.7 Hz), 7.29 (2H, d, J = 8.7 Hz). 19F NMR (acetone-d6) δ 85.81
(3F, d, J = 6.5 Hz); MS m/z 219 (M+, 94), 150 (100). HRMS
Found: m/z 219.0871, Calcd for C10H12NOF3: 219.0871.
2-Methoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (9). Mp
83–85 °C, white grains. 1H NMR (CDCl3) δ 2.85 (1H, br, s), 3.89
(3H, s), 4.92 (1H, q, J = 6.6 Hz), 5.70 (1H, br, s), 6.92 (2H, s), 6.99
(1H, s). 19F NMR (CDCl3) δ 83.46 (3F, d, J = 6.6 Hz); MS m/z 222
(M+, 100), 204 (19), 184 (66), 153 (59), 124 (26), 93 (37). HRMS
m/z Found: 222.0499, Calcd for C9H9O3F3: 222.0504.
4-Methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)-N,N-dimethy-
laniline (20). A mixture of 4.05 g (30 mmol) of N,N-dimethyl-p-
toluidine and 4.32 g (30 mmol) of trifluoroacetaldehyde ethyl
hemiacetal was heated with continuous stirring at 120 °C for 30 h.
After being cooled, the mixture was distilled under reduced pres-
sure, giving 4.05 g (58%) of the product (20), Bp 124–126 °C/ 9
mm Hg, a yellowish liquid. 1H NMR (CDCl3) δ 2.31 (3H, s), 2.66
(6H, s), 2.88 (1H, s), 5.04 (1H, q, J = 7.5 Hz), 6.99 (1H, d, J = 1.8
Hz), 7.20 (1H, d, J = 1.8 Hz), 7.27 (1H, s). 19F NMR (CDCl3) δ
83.67 (3F, d, J = 7.5 Hz); MS m/z 233 (M+, 100), 218 (12), 164
(58), 162 (55), 134 (30). HRMS Found: m/z 233.1025, Calcd for
C11H14NOF3: 233.1027.
4,4′-(2,2,2-Trifluoroethylidene)dianisole (21). The product
was purified by column chromatography eluted with hexane/ethyl
acetate (v/v: 9:1). A colorless liquid. 1H NMR (acetone-d6) δ 3.78
(6H, s), 4.90 (1H, q, J = 10.5 Hz), 6.92 (4H, d, J = 8.8 Hz), 7.38
(4H, d, J = 8.8 Hz). 19F NMR (acetone-d6) δ 97.69 (3F, d, J = 10.5
Hz); MS m/z 296 (M+, 26), 227 (100), 165 (14), 137 (36), 107 (15).
HRMS Found: m/z 296.1019, Calcd for C16H15O2F3: 296.1024.
2-Methoxy-6-(2,2,2-trifluoro-1-hydroxyethyl)phenol (10).
A
colorless liquid. 1H NMR (CDCl3) δ 3.64 (1H, br, s), 3.90 (3H, s),
5.29 (1H, q, J = 7.0 Hz), 6.10 (1H, br, s), 6.91 (3H, s). 19F NMR
(CDCl3) δ 83.75 (3F, d, J = 7.0 Hz); MS m/z 222 (M+, 79), 204
(19), 184 (100), 153 (15), 133 (13). HRMS Found: m/z 222.0504,
Calcd for C9H9O3F3: 222.0504.
2-Methoxy-4,6-bis(2,2,2-trifluoro-1-hydroxyethyl)phenol (11).
A colorless liquid. 1H NMR (CDCl3) δ 2.85 (1H, br, s), 3.89 (3H,
s), 4.91 (1H, q, J = 6.2 Hz), 5.34 (1H, q, J = 6.2 Hz), 5.70 (2H, br,
s), 7.04 (1H, s), 7.10 (1H, s). 19F NMR (CDCl3) δ 83.52 (6F, d, J =
6.2 Hz); MS m/z 320 (M+, 100), 303 (37), 282 (32), 251 (38).
HRMS Found: m/z 320.0492, Calcd for C11H10O4F6: 320.0483.
4-Phenyl-2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (12). Mp
93–94 °C, white grains. 1H NMR (CDCl3) δ 5.10 (1H, br, s), 5.28
(1H, q, J = 6.9 Hz), 6.94 (1H, d, J = 7.3 Hz), 7.30 (1H, d, J = 7.3
Hz), 7.45 (6H, m). 19F NMR (CDCl3) δ 83.49 (3F, d, J = 6.9 Hz);
MS m/z 268 (M+, 100), 303 (37), 250 (69), 222 (33), 181 (28), 153
(14). HRMS Found: m/z 268.0703, Calcd for C14H11O2F3:
268.0711.
References
1
a) R. Filler, Y. Kobayashi, and L. M.Yagupolskii, “Organo-
4-Phenyl-2,6-bis(2,2,2-trifluoro-1-hydroxyethyl)phenol (13).
Mp 102–104 °C, white solid. 1H NMR (CDCl3) δ 5.31 (2H, q, J =
6.8 Hz), 7.42 (5H, m), 7.47 (2H, s). 19F NMR (CDCl3) δ 83.64 (6F,
d, J = 6.8 Hz); MS m/z 366 (M+, 100), 348 (34), 328 (17), 279 (82),
259 (32). HRMS Found: m/z 366.0680, Calcd for C16H12O3F6:
366.0691.
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1
Mp 85–86 °C, colorless needles. H NMR (CDCl3) δ 2.22 (12H,
s), 4.40 (1H, q, J = 10.3 Hz), 4.60 (2H, br, s), 6.95 (4H, s).
19F NMR (CDCl3) δ 95.67 (3F, d, J = 10.3 Hz); MS m/z 324 (M+,
36), 255 (100). HRMS Found: m/z 324.1344, Calcd for
C18H19O2F3: 324.1337.
3
a) C. Mispelaere and N. Roques, Tetrahedron Lett., 40,
2-Methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)phenol (17).
A
colorless liquid. 1H NMR (CDCl3) δ 2.24 (3H, s), 4.20 (2H, br, s),
5.17 (1H, q, J = 7.3 Hz), 6.80 (1H, t, J = 7.2 Hz), 6.98 (1H, d, J =
7.2 Hz), 7.15 (1H, d, J = 7.2 Hz). 19F NMR (CDCl3) δ 83.46 (3F, d,
J = 7.3 Hz); MS m/z 206 (M+, 100), 189 (5), 168 (62), 137 (39),
109 (27), 91 (38). HRMS Found: m/z 206.0555, Calcd for
C9H9O2F3: 206.0555.
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