First cyclocondensations of 1,3-bis(trimethylsilyloxy)buta-1,3-dienes with 1,1-dimethoxy-4,4,4-trifluorobut-1-en-3-one

Article abstract of DOI:10.1055/s-2008-1077886

The formal [3+3] cyclocondensation of 1,3-bis(trimethylsilyloxy)buta-1,3- dienes with 1,1-bis(methoxy)trifluoromethyl-1-en-3-ones afforded functionalized 3-methoxy-5-(trifluoromethyl)phenols with very good regioselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1077886

1862
LETTER
First Cyclocondensations of 1,3-Bis(trimethylsilyloxy)buta-1,3-dienes with
1,1-Dimethoxy-4,4,4-trifluorobut-1-en-3-one
S
ynthesis of Functiona
a
lized 3-M
e
t
h
-(trifluorom
ia
henols s Lubbe,a Alina Bunescu,a,b Muhammad Sher,a,b Alexander Villinger,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, Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Received 22 April 2008
they are derived from naturally occurring polyketides.
Herein, we report a new and convenient method for the re-
gioselective synthesis of 4-methoxy-6-(trifluorometh-
yl)salicylates and related compounds by what are, to the
best of our knowledge, the first cyclocondensations of
1,3-bis(silyl enol ethers) with 1,1-bis(methoxy)-1-en-3-
ones. The products are not readily available by other
methods.
Abstract: The formal [3+3] cyclocondensation of 1,3-bis(trimeth-
ylsilyloxy)buta-1,3-dienes with 1,1-bis(methoxy)trifluoromethyl-
1-en-3-ones afforded functionalized 3-methoxy-5-(trifluorometh-
yl)phenols with very good regioselectivity.
Key words: arenes, cyclizations, regioselectivity, silyl enol ethers
Trifluoromethyl-substituted arenes and hetarenes play an
important role in drug discovery.1 On the one hand, the
size of the CF3 group is similar to the methyl group. On
the other hand, its high electronegativity results in a great
change of the reactivity, which can play an important role
in drug-receptor interactions. The increased lipophilicity
of CF3-substituted molecules often results in a better
transport of the drug in vivo. Due to the high chemical and
biological stability of the CF3 group, undesirable metabol-
ic transformations are often reduced. Besides, CF3-substi-
tuted molecules play an important role as ligands2 for
catalytic reactions in fluorous biphasic systems,3 as orga-
nocatalysts,4 and as liquid crystals.5
The reaction of trifluoroacetic anhydride with 1,1,1-tri-
methoxyethane afforded novel 1,1-dimethoxy-4,4,4-tri-
fluorobut-1-en-3-one (1) in 75% yield (Scheme 1).19 The
TiCl4-mediated reaction of 1 with 1,3-bis(silyloxy)buta-
1,3-diene 2a, readily available from methyl acetoace-
tate,16 afforded methyl 4-methoxy-6-(trifluoromethyl)sal-
icylate (3a) in 42% yield (Scheme 2).
OMe
O
O
O
MeC(OMe)3
i
MeO
CF3
F3C
O
CF3
1 (75%)
Scheme 1 Synthesis of 1. Reagents and conditions: (i) pyridine,
CHCl3, 20 °C, 12 h.
Trifluoromethyl-substituted arenes and hetarenes have
been prepared, for example, by reaction of aryl halides
with trifluoromethylcopper.6,7 Trifluoromethylcopper is
rather unstable and rapidly undergoes decomposition in
reactions with ‘difficult’ substrates. In addition, it has to
be taken into consideration that the synthesis of complex
aromatic starting materials is often a difficult task. Anoth-
er approach relies on the transformation of carboxylic ac-
ids or CX3 into CF3 groups. However, these reactions are
often applicable only to specific substrates. An alternative
strategy is based on the use of CF3-containing building
blocks.8 This includes cyclocondensation reactions,9,10 re-
actions of metalated (trifluoromethyl)arenes,11 Diels–
Alder reactions,12 and cyclizations of enamines with
1,1,1,5,5,5-hexafluoroacetylacetone.13 Recently, we have
reported14 the synthesis of CF3-substituted salicylates by
formal [3+3] cyclizations15,16 of 1,3-bis(silyl enol
ethers)17 with 4-ethoxy-1,1,1-trifluoroalk-3-en-2-ones.
Despite its preparative utility, this method is limited by
the fact that the products contain no functional group lo-
cated at carbon atoms C-3 or C-5.18 On the other hand,
most biologically active salicylates and 2-acylphenols do
contain a functional group at one of these positions, since
Me3SiO
OSiMe3
OMe
OH
O
2a
OMe
i
+
OMe
O
MeO
CF3
MeO
CF3
3a
1
TiCl4
Me3SiCl
O
TiCl3(OH)
OH
O
Me3SiO
OMe
OMe
OTiCl3
CF3
OTiCl3
CF3
MeO
MeO
MeO
Me3SiOMe
A
B
Scheme 2 Possible mechanism of the formation of 3a. Reagents
and conditions: (i) TiCl4, CH2Cl2, –78 to 20 °C.
During the optimization, it proved to be important to carry
out the reaction in a highly concentrated solution.20 The
formation of 3a can be explained by TiCl4-mediated 1,4-
addition of the terminal carbon atom of 2a onto 1a to give
SYNLETT 2008, No. 12, pp 1862–1864
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1077886; Art ID: G08708ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

LETTER
Synthesis of Functionalized 3-Methoxy-5-(trifluoromethyl)phenols
1863
Table 2 Synthesis of 3a–t
Table 1 Optimization of the Synthesis of 3a
3
a
b
c
d
e
f
R1
R2
Yield (%) of 3
n (1) (mmol) n (2a) (mmol) V (CH2Cl2) (mL) Yield of 3a (%)a
H
OMe
OEt
42
34
32
36
35
34
31
44
42
41
40
30
30
30
42
38
43
50
57
41
1
1
1
1
1
1
1
1
2
34
38
26
19
40
47
H
1
H
OBn
Oi-Pr
O(CH2)2OMe
OMe
Et
1
5
H
1
10
2
H
1.5
2
Me
2
a Yields of isolated products.
g
h
i
Me
Et
OEt
intermediate A. The latter underwent a cyclization by at-
tack of the central carbon atom of 2a onto the double bond
to give intermediate B, which was finally transformed into
the product by aromatization.
Allyl
n-Pr
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
j
k
l
n-Bu
n-Hex
n-Oct
n-Undec
Bn
The TiCl4-mediated reaction of 1 with 1,3-bis(silyl-
oxy)buta-1,3-dienes 2a–v afforded the 4-methoxy-6-(tri-
fluoromethyl)salicylates 3a–f and 3h–t and the 3-
methoxy-5-(trifluoromethyl)phenol 3g in moderate yields
(Scheme 3, Table 2). Noteworthy, the products are not
readily available by other methods.
m
n
o
p
q
r
s
Me3SiO
R1
OSiMe3
R2
(CH2)2Ph
(CH2)3Ph
OMe
(CH2)3Cl
(CH2)6Cl
OH
O
R1
R2
CF3
2a–t
i
+
MeO
OMe
O
3a–t
MeO
CF3
t
1
a Yields of isolated products.
Scheme 3 Synthesis of 3a–t. Reagents and conditions: (i) TiCl4,
CH2Cl2, –78 to 20 °C.
References and Notes
The structures of the products were confirmed by spectro-
scopic methods. The structure of 3l was independently
confirmed by X-ray crystal structure analysis.21
(1) (a) Fluorine in Bioorganic Chemistry; Filler, R.; Kobayasi,
Y.; Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.
(b) Filler, R. Fluorine-Containing Drugs in Organofluorine
Chemicals and their Industrial Application; Pergamon: New
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(2) (a) Schmidbaur, H.; Kumberger, O. Chem. Ber. 1993, 126,
3. (b) Dinger, M. B.; Henderson, W. J. Organomet. Chem.
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Grützmacher, H. Tetrahedron 2000, 56, 143.
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Bannwarth, W. Multiphase Homogeneous Catalysis;
Cornils, B.; Herrmann, W. A.; Horvath, I. T.; Leitner, W.;
Mecking, S.; Olivier-Booubigou, H.; Vogt, D., Eds.; Wiley-
VCH: Weinheim, 2005, Chap. 4, 346–354. (b) Clarke, D.;
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D.; Bannwarth, W.; Rayner, C. M. Curr. Top. Med. Chem.
2004, 7, 729.
In conclusion, we reported a convenient and regioselec-
tive synthesis of functionalized 4-methoxy-6-(trifluoro-
methyl)salicylates by the first [3+3] cyclocondensations
of 1,3-bis(trimethylsilyloxy)buta-1,3-dienes with 1,1-
dimethoxy-4,4,4-trifluorobut-1-en-3-one. The prepara-
tive scope of our methodology and applications are cur-
rently being studied in our group.
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
(4) (a) Wittkopp, A.; Schreiner, P. R. The Chemistry of Dienes
and Polyenes, Vol. 2; John Wiley and Sons Ltd.: Chichester,
2000. (b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(c) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9,
407. (d) Kleiner, C. M.; Schreiner, P. R. Chem. Commun.
2006, 4315. (e) Kotke, M.; Schreiner, P. R. Synthesis 2007,
Synlett 2008, No. 12, 1862–1864 © Thieme Stuttgart · New York

1864
M. Lubbe et al.
LETTER
779. (f) Review:Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
1701.
(5) Miethchen, R.; Hein, M. Carbohydr. Res. 2000, 327, 169.
(6) Review: McClinton, M. A.; McClinton, D. A. Tetrahedron
1992, 48, 6555.
(18) For the cyclization of 1,3-bis(silyl enol ethers) with acetal-
protected 3-oxoalkanoyl chlorides, see: (a) Chan, T. H.;
Brook, M. A. Tetrahedron Lett. 1985, 26, 2943. (b) Sher,
M.; Langer, P. Synlett 2008, 1050.
(19) The reaction was carried out following the procedure
reported for the synthesis of 1,1-diethoxy-4,4,4-trifluorobut-
1-en-3-one: Hojo, M.; Masuda, R.; Okada, E. Synthesis
1986, 1013.
(20) General Procedure for the Synthesis of 3a–t
To a CH2Cl2 solution (2 mL/1 mmol of 1) of 1 (1.0 mmol)
was added 2 (2.0 mmol) and, subsequently, TiCl4 (0.1 mL,
1.0 mmol) at –78 °C. The temperature of the solution was
allowed to warm to 20 °C during 12–14 h with stirring. To
the solution was added HCl (10%, 10 mL) and the organic
and the aqueous layer were separated. The latter was
extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by
chromatography.
(7) (a) Paratian, J. M.; Sibille, S.; Périchon, J. J. Chem. Soc.,
Chem. Commun. 1992, 53. (b) Tordeux, M.; Langlois, B.;
Wakselman, C. J. Chem. Soc., Perkin Trans. 1 1990, 2293.
(8) Ding, W.; Pu, J.; Zhang, C. Synthesis 1992, 635.
(9) (a) Guan, H.-P.; Hu, C.-M. Synthesis 1996, 1363. (b) Guan,
H.-P.; Hu, C.-M. J. Fluorine Chem. 1996, 78, 101.
(c) Gambaryan, N. P.; Simonyan, L. A.; Petrovskii, P. V. Izv.
Akad. Nauk. SSSR, Ser. Khim. 1967, 918. (d) Hojo, M.;
Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S. Chem.
Lett. 1976, 499. (e) Hojo, M.; Masuda, R.; Sakaguchi, S.;
Takagawa, M. Synthesis 1986, 1016. (f) Colla, A.; Martins,
M. A. P.; Clar, G.; Krimmer, S.; Fischer, P. Synthesis 1991,
483. (g) Hojo, M.; Masuda, R.; Okada, E. Synthesis 1989,
215. (h) Zanatta, N.; Barichello, R.; Bonacorso, H. G.;
Martins, M. A. P. Synthesis 1999, 765.
(10) Reviews: (a) Nenaidenko, V. G.; Sanin, A. V.; Balenkova,
E. S. Russ. Chem. Rev. 1999, 68, 437. (b) Billard, T. Chem.
Eur. J. 2006, 12, 974. (c) Druzhinin, S. V.; Balenkova, E.
S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753.
(11) (a) Marzi, E.; Mongin, F.; Spitaleri, A.; Schlosser, M. Eur.
J. Org. Chem. 2001, 2911. (b) Dmowski, W.; Piasecka-
Maciejewska, K. J. Fluorine Chem. 1996, 78, 59.
(12) (a) Abubakar, A. B.; Booth, B. L.; Suliman, N. N. E.;
Tipping, A. E. J. Fluorine Chem. 1992, 56, 359.
(b) Barlow, M. G.; Suliman, N. N. E.; Tipping, A. E.
J. Fluorine Chem. 1995, 70, 59.
(13) (a) Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.;
Chernega, A. N.; Pinchuk, A. M.; Tolmachev, A. A.
Tetrahedron 2004, 60, 2361. (b) Volochnyuk, D. M.;
Kostyuk, A. N.; Sibgatulin, D. A.; Chernega, A. N.
Tetrahedron 2005, 61, 2839.
(14) (a) Mamat, C.; Pundt, T.; Schmidt, A.; Langer, P.
Tetrahedron Lett. 2006, 47, 2183. (b) Mamat, C.; Pundt, T.;
Dang, T. H. T.; Klassen, R.; Reinke, H.; Köckerling, M.;
Langer, P. Eur. J. Org. Chem. 2008, 492.
(15) For a review of [3+3] cyclizations of 1,3-bis(silyl enol
ethers), see: Feist, H.; Langer, P. Synthesis 2007, 327.
(16) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534.
(17) For a review of 1,3-bis(silyl enol ethers) in general, see:
Langer, P. Synthesis 2002, 441.
Methyl 2-Hydroxy-3,4-dimethoxy-6-(trifluoro-
methyl)benzoate (3r)
Starting with 1 (0.184 g, 1.0 mmol), 2r (0.581 g, 2.0 mmol)
and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), 3r was
isolated as a slightly yellow solid (0.140 g, 50%); mp 60–
62 °C; Rf = 0.67 (n-heptane–EtOAc, 3:2). 1H NMR (300
MHz, CDCl3): d = 3.93, 3.95, 3.96 (s, 3 H, OCH3), 6.90 (s, 1
H, H-5), 10.27 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3):
d = 52.7, 56.1, 60.7 (OCH3), 103.6 (q, JC–F = 6.7 Hz, C-5),
106.9 (C-1), 123.1 (q, JC–F = 271.1 Hz, CF3), 125.3 (q,
JC–F = 32.2 Hz, C-6), 138.8, 154.8, 155.0 (C), 168.8 (CO).
19F NMR (282 MHz, CDCl3): d = –58.2 (CF3). IR (ATR):
n = 2961 (w), 2855 (w), 1683 (m), 1602 (m), 1413 (m), 1256
(s), 1109 (s), 1023 (s), 963 (s), 922 (s), 840 (s), 709 (s) cm–1.
GC-MS (EI, 70 eV): m/z (%): 280 (54) [M+], 249 (39), 248
(83), 247 (14), 220 (100), 219 (44), 205 (35), 189 (15), 188
(34), 93 (15). HRMS (EI, 70 eV): m/z calcd for C11H11F3O5
[M+]: 280.05557; found: 280.05531. Anal. Calcd for
C11H11F3O5 (280.20): C, 47.15; H, 3.96. Found: C, 47.11; H,
3.89.
(21) CCDC-686385 contains all crystallographic details for
compound 3l and is available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(1223)336033 or
deposit@ccdc.cam.ac.uk.
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