2-Substituted 4-(trifluoromethyl)phenols by directed ortho-lithiation

Article abstract of DOI:10.1055/s-2001-18440

A broad variety of 2-substituted 4-(trifluoromethyl)phenols can be prepared in a large scale by o-lithiation and reaction with electrophiles in good to excellent yields. The key for the selectivity is the superior ortho-directing effect of the THP-protect

Full text of DOI:10.1055/s-2001-18440

PAPER
2259
2-Substituted 4-(Trifluoromethyl)phenols by Directed ortho-Lithiation
2
-Substituted 4-(T
e
riflurometh
r
yl)pheno
v
ls by
D
irecte
é
d
ortho-LithiationGeneste, Bernd Schäfer*
Knoll GmbH, Postfach 210805, 67008 Ludwigshafen, Germany
Fax +49(621)6042290; E-mail: bernd.schaefer@basf-ag.de
Received 4 July 2001; revised 10 September 2001
R
R
Abstract: A broad variety of 2-substituted 4-(trifluoromethyl)phe-
nols can be prepared in a large scale by o-lithiation and reaction
with electrophiles in good to excellent yields. The key for the selec-
tivity is the superior ortho-directing effect of the THP-protected hy-
droxy group (OTHP) as compared to the CF3-group.
O
O
OH
El
BuLi / Ligand
ElX , reagent
O
H+
90 %
CF3
CF3
CF3
Key Words: arylations, electrophilic aromatic substitutions, lithia-
tion, protecting groups, 4-(trifluoromethyl)phenol
2
1b
1a
(R = H, 2-THP)
(R = 2-THP)
Scheme
In the course of the development of new methods for the
synthesis of intermediates for pharmaceuticals we became
interested in 2-substituted 4-(trifluoromethyl)phenols. Al-
though usually rather low, the reactivity of the trifluorom-
ethyl group is greatly enhanced in p-trifluoromethyl-
substituted phenols.1 Traces of hydrogen fluoride or basic
conditions induce polymerization.2 Reaction with aque-
ous ammonia furnishes the corresponding nitrile.3 When
4-(trifluoromethyl)phenol is heated, decomposition is ob-
served at 130 °C.4 Due to conjugation, 1,6-elimination of
hydrogen fluoride and formation of 4-(difluoromethyl-
ene)-2,5-cyclohexadiene-1-one seems to be the most
prominent reaction.5 In most cases this elimination is the
reason why yields of substitution of 4-(trifluorometh-
yl)phenols are poor (< 50%).6,7a,b,8a,b In other cases very
toxic reagents (e.g. anhydrous hydrogen fluoride,7c,d chlo-
romethyl methyl ether8g) are used or the syntheses are te-
dious.8–10
Compound 1b was lithiated with butyllithium at –70 °C or
with butyllithium/TMEDA at –10 °C or –20 °C and sub-
sequently quenched with an electrophile ElX (Table). Al-
though CF3 is a strongly electron-withdrawing group, it
has the least ortho-directing aptitude because of its bulki-
ness. Therefore, the deprotonation occurs at the ortho-po-
sition relative to the O-containing function.8h,14 The
protective group can be removed during workup by addi-
tion of HCl/dioxane (entry 1 and 5), an advantage as com-
pared to the methoxymethyl group, which requires a
supplementary deprotection step.8h,15 Moreover, the meth-
oxymethyl group has to be introduced using a highly toxic
chloro compound. A very efficient and convenient meth-
od for the chlorination of 1b was the addition of hexachlo-
roethane (entry 6).16 For the synthesis of the boronic ester
2g an excess of triisopropyl borate and an inverse se-
quence of addition was important to prevent a subsequent
substitution of a second methoxy group. Transesterifica-
tion with diethanolamine gave a solid product which
could be purified by crystallization (entry 7).17
We became interested in the directed ortho-lithiation, a
general method which offers the possibility of synthesis-
ing all of these derivatives of 4-(trifluoromethyl)phenol
selectively, in good yields, short reaction times and con-
venience of handling. O-Tetrahydropyranyl (OTHP) is a
very efficient ortho-directing group.11 Due to the stabilis-
ing effect, the lithium complexes are stable enough to
avoid very low reaction temperatures.12
In conclusion, we have developed a versatile method for
the synthesis of 2-substituted 4-(trifluoromethyl)phenols
in a large scale by ortho-lithiation and reaction with a
broad variety of electrophiles in good to excellent yields.
Reaction times are short. High yields and high selectivity
(other regioisomeres were not detected), caused by a su-
perior o-directing effect of OTHP compared to the CF3-
group, facilitate the purification of the products, and the
use of highly toxic chemicals can be omitted.
For the preparation of the THP ether 1b we used a modi-
fied procedure.13 By addition of 4-(trifluoromethyl)phe-
nol (1a) to a solution of 3,4-dihyro-2H-pyran (DHP) and
a catalytic amount of HCl/dioxane in dichloromethane the
ether 1b was obtained in 90% yield (Scheme). Due to its
distinct sensitivity to acid, the inverse sequence of addi-
tion of DHP to phenol 1a produced a considerable amount
of insoluble solid.
4-(Trifluoromethyl)phenol (ABCR), trimethyl borate (Aldrich) and
trifluoroborane in Et2O (Aldrich) are commercially available. N-
Methoxy-N-methylpropanamide was a generous gift from Dr. T.
Zierke, BASF AG. Petroleum ether used had bp 50 70 °C.
2-[4-Trifluoromethyl)phenoxy]tetrahydro-2H-pyran (1b)
To a solution of 3,4-dihydro-2H-pyran (525 g, 6.25 mol) and HCl
in dioxane (1 mL, 4 M) in CH2Cl2 (1 L) was added dropwise 4-(tri-
fluoromethyl)phenol (1a; 400 g, 2.47 mol) at r.t. The reaction was
Synthesis 2001, No. 15, 12 11 2001. Article Identifier:
1437-210X,E;2001,0,15,2259,2262,ftx,en;T05401SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2260
H. Geneste, B. Schäfer
PAPER
Table Lithiation of 1b with BuLi, Temperature and Duration of Lithiation, the Electrophiles (ElX) Added, and Yields of Isolated Products 2
Entry
Ligand
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
–
T (°C)
–10
–10
–20
–20
–20
–70
–70
t (min)
45
ElX
Product
2a
El
R
Yield (%)
1
2
3
4
5
6
7
DMFa
CHO
H
75
62
90
83
53
89
68
15
EtCO[NMe(OMe)]
Me3SiCl
PhSSPh
2b
EtCO
Me3Si
PhS
2-THP
2-THP
2-THP
H
30
2c
30
2d
a
30
CO2
2e
CO2H
Cl
30
C2Cl6
2f
2-THP
2-THP
b
–
45
B(OPr-i)3
2g
B(OC2H4)2NH
a Acidic workup.
b Inverse sequence of addition, and subsequent addition of (HOC2H4)2NH.
distinctly exothermic. After stirring overnight, the mixture was ex-
tracted with an aq solution of NaHCO3 (200 mL) and the organic
phase was dried (Na2SO4) and evaporated. The residue (618 g, GC:
90%, 2.28 mol, 92%) was used in the following step without further
purification. It gradually crystallized completely on standing at r.t.;
mp 38–39 °C.
1H NMR (400 MHz, CDCl3): = 7.05 (d, 3J = 9.2 Hz, 1 Harom), 7.75
(dd, 3J = 9.2 Hz, 4J = 1.8 Hz, 1 Harom), 7.85 (d, 4J = 1.8 Hz, 1 Harom),
9.95 (s, 1 H, CHO).
13C NMR (400 MHz, CDCl3): = 118.8 (d, CHarom), 120.0 (s, C–
2
CHO), 122.5 (q, J = 32.8 Hz, C–CF3), 125.1 (q, J = 271.6 Hz,
CF3), 131.2 (d, CHarom), 133.5 (d, CHarom), 164.0 (s, Carom–OH),
196.0 (d, CHO).
–
HRMS: m/z calcd for C7H4OF3 [(M–DHP)–]: 161.0219, found:
161.0220.
1-[2-(Tetrahydro-2H-pyran-2-yloxy)-5-(trifluoromethyl)-
phenyl]propan-1-one (2b)
EI-NMS (70 eV): m/z (%) = 246 ([M+], 0.245).
MS (70 eV): m/z (%) = no [M+], 169 (15), 121 (10), 97 (15), 85 (96),
83 (17), 71 (18), 57 (35), 55 (25), 43 (35), 41 (22), 29 (10), 18 (100),
17 (30).
1H NMR (400 MHz, CDCl3): = 1.57 (m, 3 H, THP), 1.80 (m, 2 H,
THP), 1.95 (m, 1 H, THP), 3.54 (m, 1 H, THP), 3.80 (m, 1 H, THP),
5.45 (m, 1 H, THP), 7.10 (d, 3J = 8.8 Hz, 2 Harom), 7.50 (d, 3J = 8.8
Hz, 2 Harom).
13C NMR (400 MHz, CDCl3): = 18.9 (t, CH2-THP), 25.5 (t, CH2-
THP), 30.5 (t, CH2-THP), 62.4 (t, CH-2-THP), 96.6 (t, CH-THP),
116.7 (2 d, CHarom), 122.4 (q, J = 271.2 Hz, CF3), 124.9 (q, 2J = 33.1
Hz, C–CF3), 127.1 (2 d, CHarom), 160.0 (s, Carom–O).
TMEDA (24 g, 0.207 mol) was placed in a 500 mL round-bottomed
flask and while stirring BuLi in hexane (130 mL, 1.63 M, 0.212
mol) was added dropwise at –10 °C over a period of about 30 min.
After 15 min a melt of 1b (40 g, GC 90%, 0.146 mol) was added
dropwise at –10 °C over a period of 30 min, whereupon the lithium
complex precipitated. After 1 h, N-methoxy-N-methylpropanamide
(24 g, 0.205 mol) was added. A cloudy solution was produced,
which after 1 h was added dropwise to a solution of HCl (32%, 60
mL) in H2O (40 mL). The aqueous phase was separated and extract-
ed with hexane and the organic phases were evaporated. The residue
was recrystallized from hexane at –50 °C. The product 2b (27.3 g,
HPLC 96%, 91 mmol, 62%) was obtained as colorless crystals; mp
54–57 °C.
2-Hydroxy-5-(trifluoromethyl)benzaldehyde (2a)
MS (70 eV): m/z (%) = no [M+], 218 (4), 189 (20), 169 (4), 111 (5),
97 (8), 85 (100), 71 (12), 57 (28), 43 (22), 29 (12), 18 (56).
A 2 L round-bottomed flask was filled with TMEDA (241 g, 2.08
mol) and BuLi in hexane (1.3 L, 1.63 M, 2.12 mol) was added to the
sirred content over a period of 30 min at –10 °C. After 45 min a melt
of 1b (400 g, GC 92%, 1.5 mol) was added dropwise at –10 °C over
a period of 30 min, whereupon the lithium complex precipitated.
After 2 h, DMF (152 g, 2.08 mol) was added. A cloudy solution was
produced, which after 15 min was added dropwise over a period of
30 min to a solution of HCl (38%, 750 mL) in H2O (500 mL) at a
maximum temperature of 45 °C. There was a rapid evolution of gas.
After stirring overnight, the aqueous phase was separated, the or-
ganic phase was treated with an HCl/dioxane solution (4 M, 70 mL)
and the mixture was once again stirred overnight. The product crys-
tallized on cooling to –30 °C (2–3 h). It was filtered by suction,
washed with cold pentane (500 mL) and dried in air to give 2a (220
g GC: 98.3%, 1.13 mol, 75%) as colorless crystals; mp 60–62 °C.
1H NMR (360 MHz, CDCl3): = 1.20 (t, 3J = 7.0 Hz, 3 H,
CH3CH2), 1.75 (m, 6 H, THP), 3.05 (q, 3J = 7.0 Hz, 2 H, CH3CH2),
3.65 (m, 1 H, THP), 3.80 (m, 1 H, THP), 5.65 (m, 1 H, THP) 7.30
(d, 3J = 8.8 Hz, 1 Harom), 7.67 (dd, 3J = 8.8 Hz, 4J = 2.2 Hz, 1 Harom),
7.85 (d, 4J = 2.2 Hz, 1 Harom).
13C NMR (360 MHz, CDCl3): = 8.5 (q, CH3), 18.6 (t, CH2-THP),
24.9 (t, CH2-THP), 30.1 (t, CH2-THP), 37.1 (t, CH3CH2), 62.2 (t,
CH2-THP), 97.0 (d, CH-THP), 115.5 (d, CHarom), 123.8 (q, 2J = 33.3
Hz, C–CF3), 124.0 (q, J = 271.6 Hz, CF3), 127.5 (d, CHarom), 129.1
(s, C–CHO), 129.8 (d, CHarom), 158.2 (s, Carom–O), 202.2 (s, C=O).
Trimethyl[2-(tetrahydro-2H-pyran-2-yloxy)-5-(trifluoro-
methyl)phenyl]silane (2c)
–
HRMS: m/z calcd for C8H4O2F3 [(M–H)–]: 189.0168, found:
To a stirred mixture of TMEDA (2.9 g, 25 mmol) and BuLi in hex-
ane (15.9 mL, 15%, 26 mmol) in a 100 mL round-bottomed flask at
–20 °C was added dropwise a solution of 1b (5.0 g, HPLC: 98%,
19.9 mmol) in THF (10 mL). After 30 min, chloro(trimethyl)silane
(2.63 g, 24 mmol) and after 2 h H2O (5 mL) were added. The mix-
ture was allowed to warm up to 20 °C and the phases were separat-
ed. The organic phase was washed once with brine and the
189.0171.
MS (70 eV): m/z (%) = 190 ([M+], 94), 189 (100), 172 (20), 161
(30), 144 (20), 113 (10), 69 (12), 28 (25), 18 (10).
Synthesis 2001, No. 15, 2259–2262 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
2-Substituted 4-(Trifluoromethyl)phenols by Directed ortho-Lithiation
2261
combined aqueous phases were washed with tert-butyl methyl ether
(3 5 mL). The organic phases were combined, dried (Na2SO4) and
evaporated in vacuo. The residue was purified by column chroma-
tography (silica gel, petroleum ether–tert-butyl methyl ether, 5:1).
The title compound (5.8 g, HPLC: 98%, 17.9 mmol, 90%) was ob-
tained as a colorless solid; mp 43–46 °C.
MS (70 eV): m/z (%) = 206 (53) [M+], 188 (100), 160 (76), 132
(20), 63 (28), 18 (65).
1H NMR (400 MHz, CDCl3): = 7.06 (d, 3J = 8.5 Hz, 1 Harom), 7.67
(dd, 3J = 8.5 Hz, 4J = 2.4 Hz, 1 Harom), 8.16 (d, 4J = 2.4 Hz, 1 Harom),
10.60 (s, 1 H, CO2H).
13C NMR (400 MHz, CDCl3): = 113.0 (s, C–CO2H), 118.0 (d,
MS (70 eV): m/z (%) = no [M+], 251 (5), 219 (5), 203 (7), 169 (7),
85 (100), 67 (6), 57 (12), 41 (7), 18 (17).
2
CHarom), 121.1 (q, J = 33.5 Hz, C–CF3), 124.0 (q, J = 271.2 Hz,
CF3), 128.2 (d, CHarom), 131.8 (d, CHarom), 164.4 (s, Carom–O), 171.8
(s, CO2H).
1H NMR (400 MHz, CDCl3): = 0.35 (s, 9 H, TMS), 1.85 (m, 6 H,
THP), 3.65 (m, 1 H, THP), 3.85 (m, 1 H, THP), 5.50 (m, 1 H, THP),
4
7.17 (d, 3J = 8.5 Hz, 1 Harom), 7.55 (dd, 3J = 8.5 Hz, J = 2.4 Hz, 1
2-[2-Chloro-4-(trifluoromethyl)phenoxy]tetrahydro-2H-pyran
(2f)
Harom), 7.60 (d, 4J = 2.4 Hz, 1 Harom).
To a stirred solution of BuLi in hexane (14.7 mL, 15%, 24 mmol)
in a 100 mL round-bottomed flask at –70 °C was added dropwise a
solution of 1b (5 g, HPLC: 98%, 19.9 mmol) in THF (40 mL). After
30 min, a solution of hexachloroethane (9.5 g, 40 mmol) in THF (20
mL) was added at –70 °C. After 4 h, the mixture was allowed to
warm up to 20 °C and it was evaporated the next day. The residue
was taken up in petroleum ether and the insoluble salts were sepa-
rated by filtration. After evaporation of the solvent from the filtrate,
the product was purified by column chromatography (silica gel, pe-
troleum ether–tert-butyl methyl ether, 9: 1); 5.2 g (HPLC: 95%,
17.6 mmol, 89%); colorless oil.
13C NMR (400 MHz, CDCl3): = –1.0 (q, 3 CH3), 18.5 (t, CH-2-
THP), 25.1 (t, CH-2-THP), 30.1 (t, CH-2-THP), 61.7 (t, CH-2-THP),
96.0 (d, CH--THP), 112.5 (d, CHarom), 123.1 (q, J = 32.0 Hz, C–
2
CF3), 124.7 (q, J = 271.5 Hz, CF3), 128.2 (d, CHarom), 128.8 (s,
Carom–Si), 131.8 (d, CHarom), 164.2 (s, Carom–O).
2-[2-(Phenylsulfanyl)-4-(trifluoromethyl)phenoxy]tetrahydro-
2H-pyran (2d)
To a stirred mixture of TMEDA (2.9 g, 25 mmol) and BuLi in hex-
ane (15.9 mL, 15%, 26 mmol) in a 100 mL round-bottomed flask
was added dropwise a solution of 1b (5.0 g, HPLC: 98%, 19.9
mmol) in THF (10 mL) at –20 °C. After 30 min, (phenyldisulfa-
nyl)benzene (4.8 g, 22 mmol) and after 2 h, H2O (5 mL) were added.
The mixture was allowed to warm up to 20 °C and the phases were
separated. The organic phase was washed once with brine and the
combined aqueous phases were washed with tert-butyl methyl ether
(3 5 mL). The organic phases were combined, dried (Na2SO4) and
evaporated in vacuo. The residue was purified by column chroma-
tography (silica gel, petroleum ether–tert-butyl methyl ether, 24: 1)
to afford 2d (6.35 g (HPLC: 92.3%, 16.6 mmol, 83%) as a colorless
solid; mp 72–73 °C.
MS (70 eV): m/z (%) = 280 (>1) [M+], 198 (30), 196 (100), 177
(34), 146 (16), 132 (18), 85 (39), 84 (34), 55 (22).
1H NMR (400 MHz, CDCl3): = 1.85 (m, 6 H, THP), 3.60 (m, 1 H,
THP), 3.80 (m, 1 H, THP), 5.57 (m, 1 H, THP), 7.26 (d, 3J = 8.5 Hz,
1 Harom), 7.45 (dd, 3J = 8.5 Hz, 4J = 1.8 Hz, 1 Harom), 7.65 (d, 4J = 1.8
Hz, 1 Harom).
13C NMR (400 MHz, CDCl3): = 18.1 (t, CH2-THP), 25.1 (t, CH2-
THP), 30.0 (t, CH2-THP), 61.9 (t, CH2-THP), 96.7 (d, CH-THP),
116.0 (d, CHarom), 122.3 (q, J = 271.5 Hz, CF3), 124.0 (s, Carom–Cl),
124.3 (q, 2J = 33.3 Hz, C–CF3), 125.0 (d, CHarom), 127.5 (d, CHarom),
155.2 (s, Carom–O).
MS (70 eV): m/z (%) = 354 (1) [M+], 270 (85) [M+–THP], 200 (20),
171 (18), 85 (100), 77 (18), 67 (20), 57 (27), 41 (35)29 (25).
1H NMR (400 MHz, CDCl3): = 1.70 (m, 6 H, THP), 3.55 (m, 1 H,
2-(1,3,6,2-Dioxazaborocan-2-yl)-4-(trifluoromethyl)phenyl
Tetrahydro-2H-pyran-2-yl Ether (2g)
THP), 3.70 (m, 1 H, THP), 5.55 (m, 1 H, THP), 7.20 (d, 3J = 8.5 Hz,
3
4
1 Harom), 7.30 (m, 6 Harom), 7.43 (dd, J = 8.5 Hz, J = 1.8 Hz, 1
arom).
To a solution of 1b (5 g, HPLC: 98%, 19.9 mmol) in THF (100 mL)
in a 250 mL round-bottomed flask was added dropwise a solution
of BuLi in hexane (27 mL, 15%, 44 mmol) at –70 °C. After 45 min,
this solution was slowly added dropwise to a mixture of triisopropyl
borate (15.04 g, 80 mmol) and THF (40 mL) at –70 °C. After 1.5 h,
the mixture was allowed to warm up to 20 °C and was evaporated
on a rotary evaporator. The residue was taken up in toluene (100
mL) and the insoluble components were filtered. The filtrate was re-
duced to 50 mL by evaporation and treated with diethanolamine
(2.1 g, 20 mmol). After a short time the product crystallized. The
slurry of crystals was taken up in tert-butyl methyl ether (50 mL),
filtered by suction, washed with tert-butyl methyl ether and dried to
give 2g (4.9 g, HPLC: 98.4%, 13.4 mmol, 68%) as a colorless solid;
mp 192 °C.
H
13C NMR (400 MHz, CDCl3): = 17.9 (t, CH2-THP), 25.0 (t, CH2-
THP), 29.9 (t, CH2-THP), 61.6 (t, CH2-THP), 96.3 (d, CH-THP),
114.3 (d, CHarom), 123.9 (q, 2J = 271.6 Hz, C–CF3), 124.0 (q,
2J = 32.8 Hz, CF3), 125.2 (d, CHarom), 126.7 (s, Carom–S), 127.7 (d,
2 CHarom), 129.4 (d, 2 CHarom), 132.0 (d, 2 CHarom), 133.4 (s, Carom
S), 156.8 (s, Carom–O).
–
2-Hydroxy-5-(trifluoromethyl)isophthalic Acid (2e)
To a stirred mixture of TMEDA (2.9 g, 25 mmol) and BuLi in hex-
ane (15.9 mL, 15%, 26 mmol) in a 100 mL round-bottomed flask
was added dropwise a solution of 1b (5.0 g, HPLC: 98%, 19.9
mmol) in THF (10 mL) at –20 °C. After 30 min, gaseous CO2 dried
by passage through a P2O5 cartridge was bubbled through the mix-
ture for 30 min. The mixture was allowed to warm to 20 °C over-
night and then H2O (5 mL), concd HCl (8 mL) and tert-butyl methyl
ether (10 mL) were added. A small amount of (0.4 g) colorless solid
2-hydroxy-5-(trifluoromethyl)isophthalic acid was filtered off by
suction. The phases were separated, the organic phase washed once
with brine and the combined aqueous phases washed with tert-butyl
methyl ether (3 5 mL). The organic phases were combined, dried
(Na2SO4) and evaporated in vacuo. The residue was purified by col-
umn chromatography (silica gel, petroleum ether–tert-butyl methyl
ether, 95:5, + 0.1 mL AcOH/100 mL of eluent) and extraction under
basic conditions with tert-butyl methyl ether and under acid condi-
tions with CH2Cl2. The product 2e (2.2 g, HPLC: 97,8%, 14.5
mmol, 53%) was obtained as a colorless solid; mp 149–151 °C.
MS (70 eV): m/z (%) = no [M+], 275 (18), 244 (20), 114 (61), 85
(100), 67 (22), 57 (29), 55 (22), 43 (17), 41 (48), 27 (30).
1H NMR (360 MHz, CDCl3): = 1.78 (m, 6 H, THP), 2.80 (m, 2 H,
NCH2CH2), 3.30 (m, 1 H, THP), 3.55 (m, 2 H, NCH2CH2), 3.80 (m,
1 H, THP), 4.00 (m, 4 H, NCH2CH2), 5.20 (m, 1 H, THP), 6.15 (br
3
3
s, 1 H, NH), 7.04 (d, J = 8.8 Hz, 1 Harom), 7.45 (dd, J = 8.5 Hz,
4J = 2.2 Hz, 1 Harom), 7.94 (d, 4J = 2.2 Hz, 1 Harom).
13C NMR (360 MHz, CDCl3): = 21.9 (t, CH2-THP), 25.4 (t, CH2-
THP), 32.0 (t, CH2-THP), 51.7 (t, CH2N), 52.2 (t, CH2N), 63.0 (t,
CH2-THP), 63.4 (t, CH2OB), 66.3 (t, CH2OB), 101.6 (d, CH-THP),
115.6 (d, CHarom), 125.2 (q, J = 271.2 Hz, CF3), 125.8 (q, 2J = 31.7
Hz, C–CF3), 126.3 (d, CHarom), 132.2 (d, CHarom), 132.2 (s, Carom
B), 162.8 (s, Carom–O).
–
Synthesis 2001, No. 15, 2259–2262 ISSN 0039-7881 © Thieme Stuttgart · New York

2262
H. Geneste, B. Schäfer
PAPER
213. (g) Caution: Chloromethyl methyl ether is a cancer
Acknowledgement
suspect reagent (bp 55–57 °C) (h) Marzi, E.; Mongin, F.;
Spitaleri, A.; Schlosser, M. Eur. J. Org. Chem. 2001, 2911.
(9) 2-Chloro-4-(trifluoromethyl)phenol: (a) Wakselman, C.;
Tordeux, M. EP 206951, 1986. (b) Chem. Abstr. 1987, 106,
101853. (c) Blazejewski, J.-C.; Dorme, R.; Wakselman, C.
J. Chem. Soc., Perkin Trans. 1 1987, 1861. (d) Briner, P.
H.; Mason, R. F. EP 188031, 1986. (e) Chem. Abstr. 1986,
105, 152701. (f) Horst, O.; Swithenbank, C.; Yih, R. Y.
German Patent 2311638, 1973. (g) Chem. Abstr. 1974, 80,
3253. (h) Veracini, S. French patent 2529197, 1983.
(i) Chem. Abstr. 1984, 100, 209372. (j) Johnson, W. O. EP
19388, 1980. (k) Chem. Abstr. 1981, 94, 156538. (l) Asahi
Chemical Industries Co Ltd.; Japanese Patent 59139336,
1984. (m) Chem. Abstr. 1984, 101, 230138. (n) Aly, E. A.
US Patent 4548640, 1985. (o) Chem. Abstr. 1986, 104,
168110.
We want to thank Mrs. Kummermehr for her technical skills and the
analytical laboratories of BASF for their valuable help.
References
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(4) DSC: onset temperature: 130 °C, decomposition energy: 760
J/g. Caution: After several months on storage 4-
(10) (a) Aryl-(2-hydroxy-5-(trifluoromethyl)phenyl)ketones:
Kaplan, J. P.; Raizon, B. M. German Patent 2907379, 1979.
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(trifluoromethyl)phenol decomposes spontaneously.
(5) Dyer, R. G.; Turnbull, K. D. J. Org. Chem. 1999, 64, 7988.
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(11) Previous applications of OTHP as ortho-directing group for
the metalation: (a) Parham, W. E.; Anderson, E. L. J. Am.
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