Regioselective synthesis of rare 3-halomethylphenols based on formal [3+3] cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes

Article abstract of DOI:10.1055/s-2008-1077877

The cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with halo-substituted enones afforded 3-difluorochloromethyl-, 3-difluorobromomethyl- , 3-dichloromethyl-, and 3-trichloromethylphenols with very good regioselectivity. The hydrolysis of the dichloromethyl group gave functionalized 3-formylphenols, which are not readily available by other methods. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1077877

1684
LETTER
Regioselective Synthesis of Rare 3-Halomethylphenols Based on Formal [3+3]
Cyclizations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes
R
egioselective Synthes
a
is of Rar
e
3
t
-Halom
h
ethylpheno
i
ls as Lubbe,a Constantin Mamat,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
E-mail: peter.langer@uni-rostock.de
b
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Received 10 April 2008
arenes.21 Herein, we report, for the first time, the synthesis
of difluorochloromethyl-, difluorobromomethyl-, dichlo-
romethyl-, and trichloromethyl-substituted phenols. The
3-dichlorophenols were transformed into preparatively
Abstract: The cyclization of 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes with halo-substituted enones afforded 3-difluorochlorometh-
yl-, 3-difluorobromomethyl-, 3-dichloromethyl-, and 3-trichloro-
methylphenols with very good regioselectivity. The hydrolysis of
the dichloromethyl group gave functionalized 3-formylphenols, functionalized 3-formylphenols which are not readily
which are not readily available by other methods.
available by other methods. In contrast to the halogena-
tion reactions outlined above, our approach to 3-halo-
methylphenols relies on a building block strategy.
Noteworthy, the starting materials, 3-(halomethyl)prop-2-
en-1-ones, are readily available by condensation of enol
ethers with halomethylacetic acid derivatives.
Key words: arenes, cyclization, regioselectivity, silyl enol ethers
Mixed trihalomethylarenes constitute a small, but impor-
tant group of fluorinated and chlorinated arenes which are
of considerable relevance in medicinal chemistry.1 For ex-
ample, chlorodifluoromethylarenes have been shown to
act as tyrosine kinase inhibitors.2 Chlorodifluoromethyl-
substituted benzene derivatives have been prepared by re-
action of arenes with bis(chlorodifluoroacetyl)peroxide.3
In addition, the UV-mediated reaction of difluoromethyl-
arenes with chlorine has been reported.4 Chlorodifluo-
romethylarenes are also available by reaction of
The reaction of difluorochloroacetic anhydride (2a) with
ethylvinyl ether (1a) afforded the known22 enone 3a
(Scheme 1, Table 1). The reaction of acid chlorides 2b–d
with enol ethers 1a,b gave the difluorobromomethyl-,
dichloromethyl-, and trichloromethyl-substituted enones
3b–e. The synthesis of 3d has been previously reported.23
EtO
EtO
O
O
5
(ethylthio)difluoromethylarenes with BrF3 and by fluori-
i
+
CX2Y
Z
CX2Y
2a–d
nation of trichloromethylarenes (using Olah’s reagent or
KF in ionic liquids).6 Bromodifluoromethylarenes have
only scarcely been reported in the literature to date. They
have been prepared by reaction of tribromomethylarenes
with SbF3,7 and by UV-mediated bromination of difluo-
romethylarenes (using bromine8 or NBS9). Dichlorometh-
yl-substituted arenes have been reported to show
antiasthmatic activity,10 irreversible inhibition of yeast a-
glucosidase,11 and antibiotic activity.12 Most syntheses of
dichloromethylarenes rely on the chlorination of an alde-
hyde group using chlorine/triphenyl phosphite,13 PCl5,14
SOCl2,15 or Ni/Cu/CCl4.16 In addition, the reaction of
arenes with dichlorocarbene has been reported.17 Known
methods for the synthesis of di- or trihalomethylarenes are
limited, despite their utility, by several drawbacks such as
harsh reaction conditions, extremely long reaction times
(up to 42 d),8 and low chemo-14,15 or regioselectivity.3,17
R
R
1a,b
3a–e
Scheme 1 Synthesis of 3a–e. Reagents and conditions: (i) TiCl4,
CH2Cl2, –78 to 20 °C.
The TiCl4-mediated reaction of 3a with 1,3-bis(silyloxy)-
1,3-butadiene 4a, readily available from acetylace-
tone,18,24 afforded 2-acetyl-3-(chlorodifluoromethyl)phe-
nol 5a (Scheme 2).25 During the optimization of this
reaction, it proved to be important that the reaction is car-
ried out in a (highly) concentrated solution. The regiose-
lective formation of 5a can be explained by conjugate
Table 1 Synthesis of 3a–e
1
2
3
Z
R
X
Y
Yield of 3
(%)a
Some years ago, Chan and coworkers developed18 an ele-
gant approach to salicylates based on formal [3+3]
cyclizations19 of 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes.20 Recently, we reported the application of this
method to the synthesis of trifluoromethyl-substituted
a
b
a
a
a
a
b
b
c
a
b
c
ClF2CCO2
H
H
Et
H
H
F
Cl
Br
Br
H
91
71
21
67
54
Cl
Cl
Cl
Cl
F
F
d
Cl
Cl
SYNLETT 2008, No. 11, pp 1684–1686
x
x
.x
x
.2
0
0
8
d
e
Cl
Advanced online publication: 11.06.2008
a Yields of isolated products.
DOI: 10.1055/s-2008-1077877; Art ID: D11608ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Synthesis of Rare 3-Halomethylphenols
1685
Me
Me3SiO
Table 2 Synthesis of 5a–p
OH
O
OSiMe3
4a
TiCl4
CH2Cl2
3
4
5
X
Y
R1
R2
R3
Yield of
5 (%)a
Me
+
O
–78 to 20 °C
20 h
a
a
a
b
b
b
b
b
b
c
a
b
c
a
b
c
d
e
f
F
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
H
H
H
Me
43
50
40
55
53
33
67
47
57
48
34
46
37
50
36b
34
CF2Cl
EtO
CF2Cl
3a
5a
F
OMe
Et
OMe
OMe
OEt
OMe
Me
TiCl4
F
– Me3SiCl
H+, H2O
O
d
e
F
H
O
OH
Me3SiO
EtO
Me
F
nPr
H
Me
a
b
f
F
CF2Cl
– Me3SiCl
CF2Cl
OTiCl2OEt
OTiCl3
g
h
i
F
OMe
Et
OMe
OEt
OMe
OEt
Me
A
C
F
O
Me3SiO
Me
g
f
F
H
– TiCl3OEt
j
F
Et
CF2Cl
O
d
d
d
d
d
e
a
g
h
c
k
l
Cl
Cl
Cl
Cl
Cl
Cl
H
TiCl3OEt
H
H
OMe
Ph
B
m
n
o
p
H
H
Scheme 2 Possible mechanism of the formation of 5a
H
Et
OMe
OMe
OEt
Me3SiO
R2
OSiMe3
R3
O
OH
b
H
OMe
H
R2
R3
CX2Y
d
Cl
i
4a–h
+
a Yields of isolated products.
EtO
O
b Hydrolysis of the CHCl2 group into CHO.
R1
CX2Y
5a–p
R1
O
O
OH
OH
3a–e
i
OEt
CBrF2
OEt
Scheme 3 Synthesis of 5a–p. Reagents and conditions: (i) TiCl4,
CH2Cl2, –78 to 20 °C.
CHF2
5a
6
addition of the terminal carbon atom of the 1,3-bis(silyl
enol ether) to the enone, cyclization by attack of the cen-
tral carbon atom onto the carbonyl group, and subsequent
aromatization.
Scheme 4 Synthesis of 6. Reagents and conditions: (i) Na2S2O4,
NaHCO3, DMF–H2O (4:1), 65 °C, 4 h.
O
O
OH
OH
The TiCl4-mediated reaction of 3a–e with 1,3-bis(silyl-
oxy)-1,3-butadienes 4a–h, readily available from the cor-
responding 1,3-dicarbonyl compounds,18,24 gave the 3-
difluorochloromethyl-, 3-difluorobromomethyl-, 3-di-
chloromethyl-, and 3-trichloromethyl-phenols 5a–p
(Scheme 3, Table 2). The structures of all products were
established by spectroscopic methods.
i
OMe
CHCl2
OMe
H
O
5l
7 (70%)
Scheme 5 Synthesis of 7. Reagents and conditions: (i) 1) NaOMe
(3.0 equiv), MeOH, 48 h, 20 °C; 2) HCl (10%).
The reduction of 3-(bromodifluoromethyl)phenol 5a, fol-
lowing a procedure reported by Dolbier and co-workers,26
afforded the 3-(difluoromethyl)phenol 6 (Scheme 4).
Noteworthy, the direct synthesis of 6 from 4a and the cor-
responding enone failed.
other derivatives also proved to be successful. This trans-
formation is of preparative utility, since functionalized 3-
formyl-phenols are not readily available by other meth-
ods.
In conclusion, we reported a convenient and regioselec-
tive synthesis of 3-difluorochloromethyl-, 3-difluorobro-
The 3-dichloromethylphenols 5k–p also represent useful
synthetic building blocks. For example, the 6-formyl-2-
hydroxybenzoate 6 was prepared in good yield by reaction
of 5l with NaOMe and MeOH and subsequent addition of
hydrochloric acid (Scheme 5). Related transformations of
momethyl-,
3-dichloromethyl-,
and
3-trichloro-
methylphenols. The hydrolysis of the dichloromethyl
group allows for a convenient and regioselective synthesis
Synlett 2008, No. 11, 1684–1686 © Thieme Stuttgart · New York

1686
M. Lubbe et al.
LETTER
(15) Hinds, J. L.; Rajadhyaksha, S. N.; Wander, J. D.
of functionalized 3-formylphenols. The scope of this
method and applications are currently being studied.
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Synthesis 2007, 327.
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
(20) For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.
References and Notes
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(25) General Procedure for the Synthesis of 5a–p
To CH2Cl2 solution (4 mL) of 3a–e (2.0 mmol) and of 4a–i
(2.0 mmol) was added TiCl4 (2.0 mmol) at –78 °C under
argon atmosphere. The temperature of the solution was
allowed to rise to 20 °C during 20 h. The solution was
poured into an aq solution of HCl (10%). The organic and
the aqueous layer were separated and the latter was extracted
(3×) with CH2Cl2. The combined organic layers were dried
(Na2SO4), filtered, and the filtrate was concentrated in
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Methyl 6-(Dichlorofluoromethyl)-2-hydroxy-3-meth-
oxybenzoate (5b)
Starting with 3a (370 mg, 2.0 mmol), 4b (581 mg, 2.0
mmol), and TiCl4 (380 mg, 2.0 mmol), 5b was isolated as a
colorless oil (261 mg, 50%); mp 50–51 °C; Rf = 0.78
(n-heptane–EtOAc = 1:1). 1H NMR (300 MHz, CDCl3):
d = 8.01 (s, 1 H, OH), 7.23 (d, 3J = 8.8 Hz, 1 H, CH), 6.94 (d,
3J = 8.8 Hz, 1 H, CH), 3.97, 3.96 (s, 3 H, OMe). 13C NMR
(63 MHz, CDCl3): d = 167.4 (O–C=O), 149.7, 146.6 (C–O),
126.5 (t, JC,F = 27.0 Hz, C-6), 125.3 (t, JC,F = 289.8 Hz,
CF2Cl), 117.9 (t, JC,F = 7.8 Hz, C-5), 115.2 (t, JC,F = 2.8 Hz,
C-1), 111.5 (C-4), 56.3, 52.7 (OMe). 19F NMR (235 MHz,
CDCl3): d = –45.0 (CF2Cl). IR (KBr): n = 3466 (br, m), 2969
(w), 2843 (w), 1735 (s), 1616 (m), 1590 (m) cm–1. MS (EI,
70 eV): m/z (%) = 268 (21) [M+, 37Cl], 266 (62) [M+, 35Cl],
236 (37), 234 (100), 211 (64), 198 (90). HRMS (EI, 70 eV):
m/z calcd for C10H9F2ClO4 [M+, 35Cl]: 266.01519; found:
266.015398.
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Synlett 2008, No. 11, 1684–1686 © Thieme Stuttgart · New York