Facile synthesis of o- and p-(1-trifluoromethyl)-alkylated phenols via generation and reaction of quinone methides

Article abstract of DOI:10.1055/s-2002-20458

Several ortho- and para-(1-chloro-2,2,2-trifluoroethyl) phenols were prepared from the corresponding alcohols and thionyl chloride in the presence of pyridine. They reacted smoothly with sodium borohydride and Grignard reagents under mild conditions, forming 2,2,2-trifluoroethyl- or 1-trifluoromethylalkylphenols in high yields.

Full text of DOI:10.1055/s-2002-20458

LETTER
431
Facile Synthesis of o- and p-(1-Trifluoromethyl)-alkylated Phenols via
Generation and Reaction of Quinone Methides
F
acile Synthesis of
u
o
-
and
p
-(1
e
Trifluorom
f
ethyl)-al
a
kylated Phenols Gong, Katsuya Kato*
National Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimoshidami, Moriyama-ku, Nagoya
463-8560, Japan
E-mail: katsuya-kato@aist.go.jp
Received 11 December 2001
Our recent work shows that 2- and 4-(1-hydroxy-2,2,2-tri-
Abstract: Several ortho- and para-(1-chloro-2,2,2-trifluoroeth-
fluoroethyl)phenols are easily prepared through the reac-
yl)phenols were prepared from the corresponding alcohols and thio-
tion of phenols with trifluoroacetaldehyde ethyl
nyl chloride in the presence of pyridine. They reacted smoothly with
hemiacetal in the presence of ZnI2 or K2CO3.8 We thought
sodium borohydride and Grignard reagents under mild conditions,
forming 2,2,2-trifluoroethyl- or 1-trifluoromethylalkylphenols in that these -trifluoromethyl alcohols might be useful
high yields.
starting materials in the preparation of 2- and 4-fluoro-
alkylated phenols. Based on the process outlined in
Scheme 1, we proposed a possible mechanistic pathway
(Scheme 2) for the selective removal of side-chain hy-
droxyl. The key problem is how to selectively convert the
side-chain hydroxyl into a good leaving group, because si-
multaneously the phenolic hydroxyl and the side-chain
hydroxyl are easily O-acylated in acetic anhydride. We
here report a convenient synthetic method for obtaining 2-
and 4-fluoroalkylated phenols. It consists of selective con-
version of the side-chain hydroxyl to chlorine and subse-
quent nucleophilic replacement.
Key words: trifluoroalkyl, phenol, sodium borohydride, Grignard
reagent, quinone methide
Introduction of fluorine atoms into bioactive organic mol-
ecules is of interest because of the characteristic effect on
their physical-chemical and biological properties.1 Phe-
nols with ortho-functional groups are well-known bioac-
tive compounds and ubiquitous among natural products.
They are usually prepared by regioselective electrophilic
aromatic substitution2 or the Claisen rearrangement,3 but
lithiation or halogenation followed by a metal-mediated
coupling process sometimes is used.4 Formation of ortho-
alkylated phenols also occurs during the reduction of phe-
nolic ketones.5 This reductive removal of the side-chain
oxygen from O-acylated phenones has been used to pre-
pare such mono-alkylated polyhydroxyl aromatics as re-
sorcinols, in which process the generation of reactive
quinone methide intermediate was proposed6 (Scheme 1).
There are few reports, however, on the preparation of flu-
oroalkylated phenols.7 To our knowledge, no convenient
method for introducing a fluoroalkyl group specifically
into the ortho-position of phenol has been reported. De-
velopment of a new way of constructing ortho-fluoroalky-
lated phenols therefore is important.
The 2- and 4-(1-hydroxy-2,2,2-trifluoroethyl)phenols 1a–
10a used are listed in the Figure. Selective chlorination
was first done by refluxing 1a and an excess of SOCl2 un-
der solvent-free conditions. As a consequence, a good
yield of -chlorinated product 2,6-dimethyl-4-(1-chloro-
2,2,2-trifluoroethyl)phenol, 1b,9 was obtained (Table 1,
entry 1). Only about 9% of 4-(1-chloro-2,2,2-trifluoroeth-
yl)phenol 2b, however, was obtained under the same con-
ditions (entry 2) due to formation of a large amount of a
white insoluble precipitate. The addition of hexane as sol-
vent somewhat improved the yield of 2b (entry 3). Alter-
native reaction conditions therefore were tried in the
presence of pyridine. The reaction of 1b with SOCl2 in the
presence of pyridine is exothermic at room temperature.
To avoid a violent reaction, equivalent amount of SOCl2
was dropped into the mixture of 1b and pyridine in tolu-
ene set in an ice water bath. Under these improved condi-
tions, the yield of 2b increased markedly (entry 4). An
ideal yield of 2b was obtained when an excess of SOCl2
was used (entry 5). Therefore, that procedures were fol-
lowed for the corresponding reactions of 1a and 3a–7a,
which gave 2- or 4-(1-chloro-2,2,2-trifluoroethyl)phenols
in high yields (entries 6–11). This method also was used
to prepare the bis-(1-chloro-2,2,2-trifluoroethyl)- and tris-
(1-chloro-2,2,2-trifluoroethyl)phenols, 8b (entry 12) and
9b (entry 13). In addition, 6-methyl-2-(1-chloro-2,2,2-tri-
fluoroethyl)pyridin-3-ol (10b) was obtained in good yield
without additional pyridine (entry 14).
OAc O-
OAc O
O-
OAc
R'
R'
NaBH4
R'
X
X
X
X
O
OH
NaBH4
R'
R'
X
Scheme 1
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0431,0434,ftx,en;Y24001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

432
Y. Gong, K. Kato
LETTER
took place between (1-chloro-2,2,2-trifluoroethyl)ben-
zene and NaBH4, indicative that the SN2 substitution of
chlorine with hydride is difficult. Based on these findings,
we consider that reductive removal of the -chlorine atom
occurred via generation of quinone methide followed by
preferential reaction with hydride, as in Scheme 2.
OH
OH
OH X
H3C
CH3
OH X
CF3
CF3
F3C
X
F3C
X
CH3
1
2
3
4
OH
OH X
X
OH X
OCH3
OH X
H3C
Table 2 Reduction of (1-Chloro-2,2,2-trifluoroethyl)phenol with
NaBH4 in THF
H3C
CF3
F3C
CF3
CF3
F3C
X
Cl
Cl
Entry
Substrate
(mmol)
NaBH4
(mmol)
Conditions
Product
5
6
7
8
(Yield %)a
1
2
1b (2.0)
2b (2.0)
3b (2.0)
4b (2.0)
5b (2.0)
6b (2.0)
7b (2.0)
8b (2.0)
9b (2.0)
10b (2.0)
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4.5
7.0
3.0
r.t., 12 h
r.t., 12 h
r.t., 12 h
r.t., 12 h
r.t., 12 h
r.t., 12 h
r.t., 12 h
r.t., 24 h
r.t., 48 h
r.t., 12 h
1c (97)
2c (95)
3c (89)
4c (94)
5c (88)
6c (93)
7c (93)
8c (91)
9c (80)
10c (95)
O
X
OH X
H3C
CH3
F3C
CF3
OH
CF3
H3C
N
F3C
11
H
F3C
X
X
3
10
4
9
a: X = OH; b: X = Cl; c: X = H; d: X = allyl; e: X = vinyl; f: X = ethyl
5
Figure
6
7
Table 1 Reaction of (2,2,2-Trifluoro-1-hydroxyethyl)phenol with
SOCl2
8
Entry Substrate
(mmol)
SOCl2
(mmol)
Pyridine
(mmol)
Product
9
(Yield %)a
10
1
2
1a (2.0)
2a (2.0)
2a (2.0)
2a (2.0)
2a (2.0)
1a (2.0)
3a (2.0)
4a (2.0)
5a (2.0)
6a (2.0)
7a (2.0)
8a (2.0)
9a (2.0)
10a (2.0)
6.0
6.0
6.0
2.0
2.8
2.8
2.8
2.8
2.8
2.8
2.8
5.6
9.0
2.8
noneb
noneb
nonec
2.0d
1b (76)
2b (9)
a Isolated yields.
3
2b (22)
2b (66)
2b (91)
1b (95)
3b (90)
4b (81)
5b (90)
6b (86)
7b (95)
8b (69)
9b (70)
10b (79)
OH CF3
OH
O
OH CF3
OH CF3
Nu
4
CF
Y
3Nu-
B
5
2.0d
Y = AcO, Cl or Br
6
2.0d
Scheme 2
7
2.0d
8
2.0d
Next, the reactions of 1b–4b and 10b with Grignard re-
agents were examined. An addition of allylmagnesium
bromide (4.0 mL) in ether to 1b (2.0 mmol) in toluene (10
mL) at –10 °C produced the corresponding compound 1d
with -branched alkyl chains and an amount of p-quinone
methide 11 (Table 3, entry 1). Compound 11 was stable
enough to be isolated by silica gel column chromatogra-
phy and identified by spectrometry. Addition of a large
excess of allylmagnesium bromide (6.0 mL) caused the
disappearance of 11 and the formation of 1d in high yield
(entry 2). This finding strongly supports the above sug-
gestion that nucleophilic replacement of the -chlorine
atom proceeded via the mechanistic pathway in
Scheme 3. Under the same conditions, the corresponding
reaction with 2b gave 4-(2,2,2-trifluoroethyl)phenol 2d
but only in 38% yield (entry 3). This low yield mainly was
due to the formation of side products caused by competi-
tive substitution of the -chlorine atom with the phenolate
anion generated in situ during the reaction. In contrast,
high yields of phenols ortho-substituted with -branched
alkyl chains, 3d, 4d and 3e, 4e, were obtained by adding
allylmagnesium bromide (6.0 mL) in ether or vinylmag-
9
2.0d
10
11
12
13
14
2.0d
2.0d
4.0d
6.0d
noned
a Isolated yields.
b No solvent, reflux 4 h.
c Hexane (10 mL), reflux 1 h.
d Toluene (10 mL), 0 °C, 1 h then 70 °C, 2 h.
Reductive removal of the -chlorine atom from 2- or 4-(1-
chloro-2,2,2-trifluoroethyl)phenols 1b–10b was done in
THF with NaBH4 as the reducing reagent. Product analy-
sis indicated the formation of 2- or 4-(2,2,2-trifluoroeth-
yl)phenols 1c–10c in excellent yields, for details see
Table 2. A parallel experiment showed that no reaction
Synlett 2002, No. 3, 431–434 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Facile Synthesis of o- and p-(1-Trifluoromethyl)-alkylated Phenols
433
nesium bromide (6.0 mL) in THF (entries 4, 5 and 7, 8).
In the case of ethylmagnesium bromide, reductive prod-
ucts 3c and 4c were detected besides the normal products
with -branched alkyl chains, 3f and 4f (entries 6 and 9).
In addition, the corresponding reaction of allylmagnesium
bromide with 10b produced 6-methyl-2-(1-trifluorometh-
yl-but-3-enyl)pyridin-3-ol (10d) in moderate yield (entry
10).
References
(1) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(2) (a) Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365.
(b) Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Fava, G.
G.; Belicchi, M. F. J. Org. Chem. 1985, 50, 5018.
(c) Casiraghi, G.; Bigi, F.; Casnati, G.; Sartori, G.; Soncini,
P.; Fava, G. G.; Belicchi, M. F. J. Org. Chem. 1988, 53,
1779.
(3) Rhoads, S. J. Org. React. 1974, 22, 1.
(4) (a) Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Mitchell, R.
H.; Lai, Y.-H.; Williams, R. V. J. Org. Chem. 1979, 44,
4733. (c) Knochel, P.; Majid, T. Tetrahedron Lett. 1990, 31,
4413.
(5) McLoughlin, B. J. J. Chem. Soc., Chem. Commun. 1969,
540.
(6) (a) Mitchell, D.; Doecke, C. W.; Hay, L. A.; Koenig, T. M.;
Wirth, D. D. Tetrahedron Lett. 1995, 36, 5335. (b) Van de
Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T. R. R.
J. Am. Chem. Soc. 2000, 122, 6502. (c) Jones, R. M.; Van
de Water, R. W.; Lindsey, C. C.; Hoarau, C.; Ung, T.; Pettus,
T. R. R. J. Org. Chem. 2001, 66, 3435.
(7) (a) Yoshida, M.; Amemiya, H.; Kobayashi, M.; Sawada, H.;
Hagii, H.; Aoshima, K. J. Chem. Soc., Chem. Commun.
1985, 234. (b) Guan, H.-P.; Hu, C.-M. J. Fluorine Chem.
1996, 78, 101.
Table 3 Reaction of (1-Chloro-2,2,2-trifluoroethyl)phenol with
RMgX in Toluene
Entry Substrate
(mmol)
RMgBra
(mL)
Conditionsb Product
(Yield %)c
1
1b (2.0)
allyl (4.0)
–5 oC, 8 h
1d (57),
11 (29)
1d (88)
2d (38)
3d (83)
3e (70)
2
3
4
5
6
1b (2.0)
2b (2.0)
3b (2.0)
3b (2.0)
3b (2.0)
allyl (6.0)
allyl (6.0)
allyl (6.0)
vinyl (6.0)
ethyl (6.0)
–5 °C, 8 h
–5 °C, 8 h
–5 °C, 8 h
–5 °C, 8 h
–5 °C, 8 h
3f (81),
3c (7)
(8) (a) Gong, Y.; Kato, K.; Kimoto, H. Synlett 1999, 1403.
(b) Gong, Y.; Kato, K.; Kimoto, H. Bull. Chem. Soc. Jpn.
2001, 74, 377.
7
8
9
4b (2.0)
4b (2.0)
4b (2.0)
allyl (6.0)
vinyl (6.0)
ethyl (6.0)
–5 °C, 8 h
–5 °C, 8 h
–5 °C, 8 h
4d (90)
4e (76)
(9) 1b: A colorless oil. 1H NMR (CDCl3): = 7.09 (2 H, s), 4.98
(1 H, q, J = 6.8 Hz), 4.52 (1 H, br, s), 2.25 (6 H, s). 19F NMR
(CDCl3): = 88.68 (3 F, d, J = 6.8 Hz). MS: m/z (%) =
238(32) [M+], 203(100), 169(41), 153(67). HRMS: Calcd:
238.0372; found: 238.0373. 2b: A colorless oil. 1H NMR
(CDCl3): = 7.37 (2 H, d, J = 8.4 Hz), 6.85 (2 H, d, J = 8.4
Hz), 5.76 (1 H, br, s), 5.06 (1 H, q, J = 6.8 Hz). 19F NMR
(CDCl3): = 88.39 (3 F, d, J = 6.8 Hz). MS: m/z (%) =
210(39) [M+], 175(100), 141(42), 125(67), 96(24). HRMS:
Calcd: 210.0059; found: 210.0059. 3b: A colorless oil. 1H
NMR (CDCl3): = 7.59 (1 H, d, J = 7.5 Hz), 7.20 (1 H, m),
7.02 (1 H, m), 6.82 (1 H, d, J = 8.1 Hz), 6.17 (1 H, br, s), 5.82
(1 H, q, J = 7.0 Hz). 19F NMR (CDCl3): = 88.80 (3 F, d,
J = 7.0 Hz). MS: m/z (%) = 210(68) [M+], 175(60), 155(30),
145(60), 141(74), 127(100), 96(39). HRMS: Calcd:
210.0059; found: 210.0061. 1c: Colorless needles, mp 86–
87 °C. 1H NMR (CDCl3): = 6.89 (2 H, s), 4.62 (1 H, s), 3.21
4f (73),
4c (9)
10
10b (2.0)
allyl (6.0)
–5 °C, 8 h
10d (58)
a 1 Mol/L solution (allyl in ether and vinyl and Et in THF).
b Addition made at –10 °C.
c Isolated yields.
In conclusion, we consider selective chlorination of the
side-chain hydroxyl of 2- or 4-(1-hydroxy-2,2,2-trifluoro-
ethyl)phenols followed by nucleophilic replacement with
sodium borohydride or Grignard reagents to be a useful
method for the specific introduction of trifluoroethyl or 1-
trifluoromethylalkyl groups to the ortho- or para- posi-
tions of phenols.
(2 H, q, J = 10.8 Hz), 2.23 (6 H, s). 19F NMR (CDCl3):
95.53 (3 F, t, J = 10.8 Hz). MS. m/z (%) = 204(57) [M+],
135(100), 109(7), 91(25). Anal. Calcd for C10H11F3O: C,
58.82; H, 5.43. Found: C, 58.72; H, 5.42. 2c: Colorless
=
needles, mp 56–58 °C. 1H NMR (CDCl3): = 7.15 (2 H, d,
J = 8.2 Hz), 6.81 (2 H, d, J = 8.2 Hz), 5.95 (1 H, br, s), 3.27
(2 H, q, J = 11.0 Hz). 19F NMR (CDCl3): = 95.48 (3 F, t,
J = 11.0 Hz). MS: m/z (%) = 176(40) [M+], 157(3),
OH
OH
OH
, THF
rt
SOCl2 , Pyridine
NaBH
107(100). Anal. Calcd for C8H7F3O: C, 54.55; H, 4.01.
Found: C, 54.50; H, 4.02. 3c: A colorless oil. 1H NMR
(CDCl3): =7.25 (1 H, d, J = 7.5 Hz), 6.92–7.22 (2 H, m),
6.79 (1 H, d, J = 7.9 Hz), 5.12 (1 H, br, s), 3.46 (2 H, q,
J = 10.8 Hz). 19F NMR (CDCl3): = 96.33 (3 F, t, J = 10.8
Hz). MS: m/z (%) = 176(72) [M+], 156(42), 107(100). Anal.
Calcd for C8H7F3O: C, 54.55; H, 4.01. Found: C, 54.47; H,
4.00. 1d: Colorless needles, mp 109–110 °C. 1H NMR
(CDCl3): = 6.87 (2 H, s), 5.60 (1 H, m), 5.00 (1 H, d,
J = 18.0 Hz), 4.96 (1 H, d, J = 9.2 Hz), 4.67 (1 H, s), 3.14 (1
CH2CF3
0 °C
Toluene, 60-70 °C
RMgX , toluene
F3C
OH
OH
F3C
Cl
-5 °C
F3C
R
H, m), 2.66 (2 H, m), 2.21 (6 H, s). 19F NMR (CDCl3):
=
Scheme 3
91.99 (3 F, d, J = 9.4 Hz). MS: m/z (%) = 244(10) [M+],
203(100), 153(27), 91(12). Anal. Calcd for C13H15F3O: C,
63.93; H, 6.19. Found: C, 63.73; H, 6.16. 11: Colorless
Synlett 2002, No. 3, 431–434 ISSN 0936-5214 © Thieme Stuttgart · New York

434
Y. Gong, K. Kato
LETTER
125(51). Anal. Calcd for C11H11F3O: C, 61.11; H, 5.13.
plates, mp 57–58 °C. 1H NMR (CDCl3): = 6.51 (1 H, s),
5.97 (1 H, s), 5.20 (1 H, q, J = 8.1 Hz), 1.97 (3 H, s), 1.95 (3
H, s). 19F NMR (CDCl3): = 106.96 (3 F, d, J = 8.1 Hz). MS:
m/z (%) = 203(100) [M+], 153(26). Anal. Calcd for
C10H9F3O: C, 59.41; H, 4.49. Found: C, 59.60; H, 4.50. 2d:
A colorless oil. 1H NMR (CDCl3): = 7.15 (2 H, d, J = 8.4
Hz), 6.81 (2 H, d, J = 8.4 Hz), 5.60 (1 H, m), 5.21 (1 H, s),
5.00 (1 H, d, J = 16.9 Hz), 4.96 (1 H, d, J = 10.3 Hz), 3.23 (1
H, m), 2.67 (2 H, m). 19F NMR (CDCl3): = 91.67 (3 F, d,
J = 9.4 Hz). MS: m/z (%) = 216(15) [M+], 175(100), 127(6),
Found: C, 61.03; H, 5.11. 3d: A colorless oil. 1H NMR
(CDCl3): = 7.31 (1 H, d, J = 8.3 Hz), 6.94–7.18 (2 H, m),
6.87 (1 H, d, J = 7.7 Hz), 5.60 (1 H, m), 5.07 (1 H, s), 4.99
(1 H, d, J = 15.4 Hz), 4.95 (1 H, d, J = 9.01 Hz), 4.10 (1 H,
m), 2.70 (2 H, m). 19F NMR (CDCl3): = 92.49 (3 F, d,
J = 9.2 Hz). MS: m/z (%) = 216(39) [M+], 215(44), 195(17),
175(62), 155(61), 127(100), 115(28), 107(31). Anal. Calcd
for C11H11F3O: C, 61.11; H, 5.13. Found: C, 61.09; H, 5.10.
Synlett 2002, No. 3, 431–434 ISSN 0936-5214 © Thieme Stuttgart · New York