Synthesis of trifluoromethyl-substituted arenes, cyclohexenones and pyran-4-ones by cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-one: Influence of the Lewis acid on the product distribution

Article abstract of DOI:10.1021/jo900702u

(Chemical Equation Presented) The TiCl₄-mediated formal [3 + 3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-one afforded a variety of functionalized 4-methoxy-6-(trifluoromethyl) s

Full text of DOI:10.1021/jo900702u

Synthesis of Trifluoromethyl-Substituted Arenes, Cyclohexenones
and Pyran-4-ones by Cyclocondensation of
1,3-Bis(silyloxy)-1,3-butadienes with
4,4-Dimethoxy-1,1,1-trifluorobut-3-en-2-one: Influence of the Lewis
Acid on the Product Distribution
Alina Bunescu,†,‡ Sebastian Reimann,†,‡ Mathias Lubbe,† Anke Spannenberg,‡ and
Peter Langer*,†,‡
Institut fu¨r Chemie, UniVersita¨t Rostock, Albert-Einstein-Strausse 3a, 18059 Rostock, Germany, and
Leibniz-Institut fu¨r Katalyse e. V. an der UniVersita¨t Rostock, Albert-Einstein-Strausse 29a,
18059 Rostock, Germany
peter.langer@uni-rostock.de
ReceiVed April 3, 2009
The TiCl4-mediated formal [3 + 3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-one afforded a variety of functionalized 4-methoxy-6-(trifluo-
romethyl)salicylates and 3-methoxy-5-(trifluoromethyl)phenols with very good regioselectivity. The
Me3SiOTf-mediated cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes, containing no substituent
located at carbon atom C-4 of the diene (R1 ) H), resulted in the formation of trifluoromethyl-substituted
pyran-4-ones. In contrast, trifluoromethylated cyclohexenones were formed when dienes were employed
which do contain a substituent located at carbon C-4 (R1 * H).
Introduction
of the CF3 group, undesirable metabolic transformations are
often reduced. Besides, CF3-substituted molecules play an
important role as ligands2 for catalytic reactions in fluorous
biphase systems,3 as organocatalysts,4 and as liquid crystals.5
Trifluoromethyl-substituted arenes and hetarenes are of
considerable importance in the field of medicinal chemistry.1
While the sizes of the CH3 and CF3 groups are similar, the high
electronegativity of the latter results in a dramatic change of
the reactivity and polarity. The increased lipophilicity of CF3-
substituted molecules often results in a better transport of the
drug in vivo which can play an important role in drug-receptor
interactions. Due to the high chemical and biological stability
(2) (a) Schmidbaur, H.; Kumberger, O. Chem. Ber. 1993, 126, 3. (b) Dinger,
M. B.; Henderson, W. J. Organomet. Chem. 1998, 560, 233. (c) Liedtke, J.;
Loss, S.; Widauer, C.; Gru¨tzmacher, H. Tetrahedron 2000, 56, 143.
(3) See for example. (a) Schneider, S.; Tzschucke, C. C.; 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; Chapter 4, pp 346-354. (b) Clarke, D.; Ali, M. A.;
Clifford, A. A.; Parratt, A.; Rose, P.; Schwinn, D.; Bannwarth, W.; Rayner,
C. M. Curr. Top. Med. Chem. 2004, 7, 729.
* To whom correspondence should be addressed. Fax: 00 49 381 49864112.
Tel: 0049 381 4986410.
† Institut fu¨r Chemie.
(4) (a) Wittkopp, A.; Schreiner, P. R. The chemistry of dienes and polyenes,
Vol. 2; John Wiley & Sons Ltd: New York, 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, 779. (f) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701.
‡ Leibniz-Institut fu¨r Katalyse e. V.
(1) (a) Fluorine in Bioorganic Chemistry; Filler, R.; Kobayasi, Y.; Yagupol-
skii, L. M., Eds.; Elsevier: Amsterdam, 1993. (b) Filler, R. Fluorine Containing
Drugs in Organofluorine Chemicals and their Industrial Application; Pergamon:
New York, 1979; Chapter 6. (c) Hudlicky, M. Chemistry of Organic Compounds;
Ellis Horwood: Chichester, 1992.
(5) Miethchen, R.; Hein, M. Carbohydr. Res. 2000, 327, 169.
5002 J. Org. Chem. 2009, 74, 5002–5010
10.1021/jo900702u CCC: $40.75  2009 American Chemical Society
Published on Web 05/29/2009

Influence of the Lewis Acid on the Product Distribution
SCHEME 1. Synthesis of 1a,ba
Trifluoromethyl-substituted arenes and hetarenes are available,
for example, by reaction of aryl halides with trifluoromethyl-
copper.6,7 However, this reagent is rather unstable and can
decompose in reactions with “difficult” substrates. In addition, the
synthesis of the required aromatic starting materials can be a
difficult task. Other syntheses rely on the transformation of
carboxylic acids or CX3 into CF3 groups, but these reactions often
work only for specific substrates. An alternative strategy relies on
the employment of suitable CF3-containing building blocks.8 In
this context, cyclocondensations,9,10 condensations of metalated
(trifluoromethyl)arenes,11 Diels-Alder reactions,12 and cyclizations
of enamines with 1,1,1,5,5,5-hexafluoroacetylacetone have been
developed.13 We have recently reported14 the synthesis of CF3-
substituted salicylates by formal [3 + 3] cyclizations15,16 of 1,3-
bis(silyloxy)-1,3-butadienes17 with 4-ethoxy-1,1,1-trifluoroalk-3-
en-2-ones. Despite its preparative utility, the scope of this method
is limited to products containing no functional group located at
carbon atoms C3 or C-5.18 However, biologically active molecules
often contain a hydroxy or methoxy group at one of these positions,
because they are related to naturally occurring polyketides.
Recently, we have reported the TiCl4-mediated cyclocondensation
of 1,3-bis(silyloxy)-1,3-butadienes with 4,4-dimethoxy-1,1,1-trif-
luorobut-3-en-2-one.19 These reactions provide a convenient and
regioselective approach to 4-methoxy-6-(trifluoromethyl)salicylates.
Herein, we report full details of this study. In addition, we report,
for the first time, the influence of the Lewis acid on the product
distribution. The Me3SiOTf-mediated cyclization of 1,3-bis(trim-
ethylsilyloxy)-1,3-butadienes, containing no substituent located at
carbon atom C-4 of the diene (R1 ) H), resulted in the formation
of trifluoromethyl-substituted pyran-4-ones. In contrast, trifluo-
romethylated cyclohexenones were formed when dienes were
employed which do contain a substituent located at carbon C-4
(R1 * H). The synthesis of pyran-4-ones from 1,3-bis(trimethyl-
a Conditions: i, pyridine, CHCl3, 20 °C, 12 h.
SCHEME 2. Possible Mechanism of the Formation of 3aa
a Conditions: i, TiCl4, CH2Cl2, -78 f 20 °C.
TABLE 1. Optimization of the Synthesis of 3a
n (1) [mmol]
n (2a) [mmol]
V (CH2Cl2) [mL]
yield (3a)a [%]
1
1
1
1
1
1
1
1
1
1
1.5
2
1
2
5
10
2
2
34
38
26
19
40
47
(6) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(7) (a) Paratian, J. M.; Sibille, S.; Pe´richon, 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.
a Yields of isolated products.
(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) Hojo, M.; Masuda, R.; Kokuryo,
Y.; Shioda, H.; Matsuo, S. Chem. Lett. 1976, 499. (d) Hojo, M.; Masuda, R.;
Sakaguchi, S.; Takagawa, M. Synthesis 1986, 1016. (e) Colla, A.; Martins,
M. A. P.; Clar, G.; Krimmer, S.; Fischer, P. Synthesis 1991, 483. (f) Hojo, M.;
Masuda, R.; Okada, E. Synthesis 1989, 215. (g) 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.
silyloxy)-1,3-butadienes has, to the best of our knowledge, not been
previously reported.
Results and Discussion
The reactions of trifluoroacetic anhydride with 1,1,1-tri-
methoxy- and triethoxyethane afford 4,4-dimethoxy-1,1,1-
trifluorobut-3-en-2-one (1a) and 4,4-diethoxy-1,1,1-trifluorobut-
3-en-2-one (1b) (Scheme 1).20 1,3-Bis(silyloxy)-1,3-butadienes
2a-t are prepared according to the literature from the corre-
sponding ꢀ-ketoesters in two steps.16,21,22
The TiCl4-mediated reaction of 1a with 1,3-bis(silyloxy)-1,3-
butadiene 2a affords 4-methoxy-6-(trifluoromethyl)salicylate 3a
in 47% yield (Scheme 2). During the optimization (Table 1),
the concentration, the temperature and the stoichiometry play
an important role. The best yield is obtained when the solution
is slowly warmed from -78 to 20 °C, when the reaction is
(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.; Ko¨ckerling, 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.
(18) For the cyclization of 1,3-bis(silyl enol ethers) with acetal-protected
3-oxoalkanoyl chlorides, see:Chan, T. H.; Brook, M. A. Tetrahedron Lett. 1985,
26, 2943.
(20) 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, 12, 1013.
(21) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993, 115, 830.
(22) Nguyen, V. T. H.; Bellur, E.; Appel, B. Synthesis 2006, 2865.
(19) Lubbe, M.; Bunescu, A.; Villinger, A.; Langer, P. Synlett 2008, 1862.
J. Org. Chem. Vol. 74, No. 14, 2009 5003

Bunescu et al.
SCHEME 4. Possible Mechanism of the Formation of 4a
SCHEME 3. Synthesis of 3a-ta
a Conditions: i, TiCl4, CH2Cl2, -78 f 20 °C.
TABLE 2. Synthesis of 3a-t
1
2
3
R1
R2
R3
yield (3) [%]a
a
b
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
a
a
a
H
H
H
H
H
H
Me
Me
Et
Allyl
nPr
nBu
nHex
OMe
OMe
OEt
OBn
OiPr
O(CH2)2OMe
OMe
Et
Me
Et
47
31
34
32
36
35
34
31
44
42
41
40
30
30
30
38
43
50
33
57
a
b
c
d
e
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
f
g
h
i
j
k
l
m
n
o
p
q
q
r
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
nOct
nUndec
(CH2)2Ph
(CH2)3Ph
OMe
OMe
(CH2)3Cl
SCHEME 5. Synthesis of 4a-g and 5g-pa
t
Me
a Yields of isolated products.
carried out in a highly concentrated solution, and when an excess
(2.0 equiv) of 2a is employed.
The formation of 3a can be explained by reaction of 1a with
TiCl4 to give A containing an allylic carbon unit. The attack of
the terminal carbon atom of 2a onto A affords intermediate B.
The elimination of Me3SiOMe (intermediate C) and subsequent
cyclization gives intermediate D (Scheme 2). The elimination
of titanium hydroxide (before or during the aqueous workup)
and aromatization results in the formation of product 3a. Product
3a, containing the CF3 group located ortho to the ester group,
is formed with excellent regioselectivity. The formation of the
other regioisomer, containing the CF3 group located para to
the ester group, is not observed. The moderate yield can be
explained by TiCl4-mediated oxidative dimerization of the diene.
This type of process has been previously reported.23
a Conditions: i, Me3SiOTf, CH2Cl2, -78 f 20 °C.
The reaction of 1a with 1,3-bis(silyloxy)-1,3-butadiene 2a,
carried out in the presence of Me3SiOTf (1.0 equiv) rather than
TiCl4, results in the formation of pyran-4-one 4a in 63% yield
(Scheme 4).
The formation of 4a presumably proceeds by formation of
allylic cation E. The attack of the terminal carbon atom of 2a
onto E gives intermediate F. The elimination of Me3SiOMe
(intermediate G) and subsequent cyclization via the oxygen
rather than the carbon atom gives intermediate H. The elimina-
tion of silanol (before or during the aqueous workup) results in
the formation of pyran-4-one 4a. The formation of product 3a
is not observed.
The TiCl4-mediated reactions of 1a,b with 1,3-bis(silyloxy)-
1,3-butadienes 2a-r afford the 4-methoxy-6-(trifluoromethyl)-
salicylates 3a-f and 3h-t and the 3-methoxy-5-(trifluorom-
ethyl)phenol 3g in moderate yields (Scheme 3, Table 2). The
products are not readily available by other methods. Better yields
are obtained for enone 1a than for 1b (3a and 3b, 3r and 3s).
The yields also depend on the type of diene employed. However,
no clear trend is observed.
The Me3SiOTf-mediated reactions of 1a with 1,3-bis(sily-
loxy)-1,3-butadienes 2a-e and 2s, all containing no substituent
located at carbon atom C-4 of the diene (R1 ) H), afford pyran-
4-ones 4a-f in 32-69% yield (Scheme 5, Table 3). The reaction
conditions have been optimized for the synthesis of derivative
4d (Table 4). The best yield is obtained when an excess of 2d
is employed. In contrast to the TiCl4-mediated syntheses of
salicylates 3, which are carried out in a highly concentrated
solution, the yield of 4d can be significantly improved when
the reaction is carried out in a more dilute solution.
The structures of the products are confirmed by spectroscopic
methods. The structure of 3e is independently confirmed by
X-ray crystal structure analysis (see Supporting Information).
(23) (a) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J. Can.
J. Chem. 1983, 61, 688. (b) Hirai, K.; Ojima, I. Tetrahedron Lett. 1983, 24,
785.
5004 J. Org. Chem. Vol. 74, No. 14, 2009

Influence of the Lewis Acid on the Product Distribution
TABLE 3. Synthesis of 4a-g and 5g-p
TABLE 5. Optimization of the Synthesis of 4g and 5g
n (1a) (mmol) n (2f) (mmol) V (CH2Cl2) (mL) yield (4g) (%)a yield (5g) (%)a
2
4,5
R1
R2
yield (4) (%)a yield (5) (%)a
1
1
1
1
1
1
1
1
2
3
2
2
2
10
10
10
5
10
9
12
10
24
12
15
20
38
12
19
26
a
b
c
d
e
s
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
H
H
H
H
H
H
OMe
OEt
OBn
OiPr
O(CH2)2OMe
OiBu
OMe
OMe
OMe
OEt
OEt
63
69
32
64
40
64
12
0
0
0
0
0
0
0
0
0
0
15
0
f
t
Me
Et
Cl
n-Pent
n-Hep
n-Oct
n-Non
n-Dodec
n-Hexadec OMe
(CH2)2iPr OMe
38
50
44
39
35
62
57
58
54
55
a Yields of isolated products.
u
v
w
m
x
y
z
SCHEME 7. Relative Configuration of 5g and 5i
OMe
OMe
OMe
0
0
0
0
aa
a Yields of isolated products.
4 is not observed. This might be explained by the steric influence
of the ethyl group (R1 ) Et) which results in a change of the
conformation of intermediate J with regard to G (allylic strain).
In contrast to the formation of salicylates 3, no elimination of
the hydroxyl group and aromatization occurs. This result is
surprising since the aromatization should be a facile process. It
might be explained by the assumption that intermediate D,
containing a titanium alkoxide moiety, readily undergoes an
elimination of TiCl3OH and aromatization before the aqueous
work up (Vide supra). In contrast, intermediate K, containing a
silanolate moiety, is more stable and no elimination occurs. The
addition of hydrochloric acid (10%) (aqueous work up) results
in cleavage of Si-O bond, but no elimination and aromatization
occurs. The stability of compounds 5 might be explained by
the presence of the electron-withdrawing CF3 group. The rate
of the acid-mediated elimination of water is decreased because
a cation located next to the CF3 group is expected to be unstable
and an elimination requires more drastic conditions.
TABLE 4. Optimization of the Synthesis of 4d
n (1a) (mmol) n (2d) (mmol) V (CH2Cl2) (mL) yield (4d) (%)a
1
1
1
1
1
2
2
2
2
1
1
2
10
15
15
42
50
64
60
31
a Yields of isolated products.
SCHEME 6. Possible Mechanism of the Formation of 5h
The cyclization of 1a with diene 2f is of special interest
because both pyran-4-one 4g (12%) and cyclohexenone 5g
(38%) can be isolated. This might be explained by the fact that
the steric influence of the methyl group (R1 ) Me) is relatively
small. The influence of the reaction conditions on the product
distribution has been studied for this reaction (Table 5). The
best yield of 5g is observed when 2.0 equiv of 2f is used and
when the cyclization is carried out in a relatively dilute solution.
The yield decreases when 1.0 or 3.0 equiv of the diene is
employed.
The structures of all products are confirmed by spectroscopic
methods. The structure of 4a is independently confirmed by
X-ray crystal structure analysis (see Supporting Information).
The structures of 5g, and 5i are independently confirmed by
X-ray crystal structure analyses (see Supporting Information).
The X-ray structures of 5g, and 5i allow to unambiguously prove
the relative configuration of these molecules. The hydroxyl and
the ester group are located cis to eachother and an intramolecular
hydrogen bond O-H· · ·O is present (Scheme 7). In solution,
only one major isomer is present. In some cases, a small amount
of the minor isomer can be detected.
Under the conditions of mass spectrometry (EI, electron
ionization), elimination of water from cyclohexenones 5 is
observed and only the molecular ions of the aromatized products
can be detected. The correct molecular ions are observed when
the measurements are carried out using the milder ESI technique
(electrospray ionization).
The Me3SiOTf-mediated reactions of 1a with 1,3-bis(sily-
loxy)-1,3-butadienes 2m and 2t-aa, which contain an alkyl or
a chloride group located at carbon C-4 of the diene moiety (R1
* H), afford the cyclohexenones 5g-p in 38-62% yield
(Scheme 5, Table 3). The formation of product 5h can be
explained by a mechanism related to the one suggested for the
formation of products 4 (Scheme 6). The reaction of diene 2t
with intermediate E affords intermediate I which is transformed
into intermediate J. Intermediates I and J are closely related to
intermediates F and G (Vide supra). The cyclization of J
proceeds via the carbon atom. The formation of pyran-4-ones
J. Org. Chem. Vol. 74, No. 14, 2009 5005

Bunescu et al.
(M+, 40), 219 (39), 218 (100), 190 (42), 175 (36), 147 (13). Anal.
Calcd for C10H9F3O4 (250.17): C, 48.01; H, 3.63. Found: C, 48.28;
H, 3.62.
Conclusions
In conclusion, we report the TiCl4-mediated formal [3 + 3]
cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes
with 4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-one. These reac-
tions allow for a convenient synthesis of a variety of function-
alized 4-methoxy-6-(trifluoromethyl)salicylates with very good
regioselectivity. The Me3SiOTf-mediated cyclizations of 1,3-
bis(trimethylsilyloxy)-1,3-butadienes, containing no substituent
located at carbon atom C-4 of the diene (R1 ) H), result in a
cyclization via the oxygen atom and formation of pyran-4-ones.
The reasons for the influence of the Lewis acid on the
regioselectivity of cyclization remain unclear at present. Tri-
fluoromethyl-substituted cyclohexenones are formed in the
Me3SiOTf-mediated cyclization of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes which contain a substituent located at carbon
C-4 (R1 * H).
Methyl 2-Hydroxy-4-ethoxy-6-(trifluoromethyl)benzoate (3b).
Starting with 1b (213 mg, 1.0 mmol), 2a (0.521 g, 2.0 mmol) and
TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product3b was isolated
as a colorless solid (0.082 g, 31%); mp ) 62-63 °C; RF ) 0.78
(heptane/EtOAc ) 1:1). 1H NMR (250 MHz, CDCl3): δ ) 1.44 (t,
3
3J ) 7.0 Hz, 3H), 3.95 (s, 3H), 4.07 (q, J ) 7.0 Hz, 2H), 6.59,
6.89 (s, 1H), 11.45 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 14.4,
52.5, 64.2, 102.8, 104.0, 109.7 (q, JC-F ) 7.1 Hz), 123.1 (q, JC-F
) 273.4 Hz), 131.8 (q, JC-F ) 31.9 Hz), 162.9, 165.1, 169.8. 19F
NMR (235 MHz, CDCl3): δ ) -59.3. IR (ATR, cm-1): ν˜ ) 2986
(w), 2957 (w), 2902 (w), 2857 (w), 1664 (s), 1618 (s), 1585 (s),
1438 (s). MS (EI, 70 eV): m/z (%): 264 (M+, 58), 233 (27), 232
(100), 205 (31), 204 (99), 176 (67). Anal. Calcd for C11H11F3O4
(264.20): C, 50.01; H, 4.20. Found: C, 50.33; H, 4.20.
Ethyl 2-Hydroxy-4-methoxy-6-(trifluoromethyl)benzoate (3c).
Starting with 1a (0.184 g, 1.0 mmol), 2b (0.549 g, 2.0 mmol) and
TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product 3c was isolated
as a white solid (0.090 g, 34%); mp ) 83-84 °C; RF ) 0.64 (n-
heptane/EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3): δ ) 1.40 (t,
3J ) 7.2 Hz, 3H), 3.85 (s, 3H), 4.41 (q, 3J ) 7.1 Hz, 2H), 6.60 (d,
Experimental Section
General Comments. All solvents were dried by standard
methods and all reactions were carried out under an inert atmo-
sphere. For 1H and 13C NMR spectra the deuterated solvents
indicated were used. Mass spectrometric data (MS) were obtained
by electron ionization (EI, 70 eV), chemical ionization (CI,
isobutane) or electrospray ionization (ESI). For preparative scale
chromatography silica gel 60 (0.063-0.200 mm, 70-230 mesh)
was used. 1,3-Bis(silyloxy)-1,3-butadienes 2a-aa were prepared
according to the literature from the corresponding ꢀ-ketoesters in
two steps.16,21,22
4,4-Dimethoxy-1,1,1-trifluorobut-3-en-2-one (1a). To a stirred
dichloromethane solution (10 mL) of trimethyl orthoacetate (1.202
g, 10.0 mmol) and pyridine (1.820 g, 23.0 mmol) was dropwise
added trifluoroacetic acid anhydride (4.201 g, 20 mmol) at 0 °C,
and the mixture was subsequently stirred for 24 h at 20 °C. The
mixture was washed with an aqueous solution of sodium carbonate
(5%, 20 mL>). The organic layer was dried (sodium sulfate), filtered
and the solvent and the pyridine were removed in vacuo to give 1a
as a light-yellow solid (1.350 g, 74%); mp ) 52-53 °C. 1H NMR
(300 MHz, CDCl3): δ ) 3.93 (s, 3H), 3.97 (s, 3H), 4.98 (s, 1H).
13C NMR (75 MHz, CDCl3): δ ) 55.5, 57.7, 72.1, 116.8 (q, JC-F
) 292.4 Hz), 172.3, 175.9 (q, JC-F ) 32.9 Hz). 19F NMR (282
MHz, CDCl3): δ ) -77.3. MS (EI, 70 eV): m/z (%): 184 (M+, 8),
139 (3), 115 (100), 103 (5), 69 (88), 59 (10). HRMS (EI, 70 eV):
Calcd for C6H7F3O3 (M+) 184.03394, found 184.034018.
The synthesis of 1b has been previously reported.20
4
4J ) 2.4 Hz, 1H), 6.89 (d, J ) 2.4 Hz, 1H), 11.59 (s, 1H). 13C
NMR (75 MHz, CDCl3): δ ) 13.5, 55.7, 62.1, 103.3, 103.6, 109.3
(q, JC-F ) 7.2 Hz), 123.1 (q, JC-F ) 271.5 Hz), 131.8 (q, JC-F
)
32.0 Hz), 163.4, 165.2, 169.3. 19F NMR (282 MHz, CDCl3): δ )
-58.1. IR (ATR, cm-1): ν˜ ) 2984 (w), 1650 (m), 1618 (m), 1591
(m), 1467 (w), 1447 (w), 1424 (m), 1371 (m), 1282 (s), 1238 (s),
1207 (s), 1125 (s), 1038 (s), 985 (s), 869 (s), 803 (s), 711 (s). GC-
MS (EI, 70 eV): m/z (%): 264 (M+, 31), 219 (32), 218 (100), 190
(35), 175 (22). Anal. Calcd for C11H11F3O4 (264.20): C, 50.01; H,
4.20. Found: C, 50.15; H, 4.22.
Benzyl 2-Hydroxy-4-methoxy-6-(trifluoromethyl)benzoate (3d).
Starting with 1a (0.184 g, 1.0 mmol), 2c (0.673 g, 2.0 mmol) and
TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product 3d was
isolated as a slightly yellow solid (0.100 g, 32%); mp ) 44-46
1
°C; RF ) 0.60 (n-heptane/EtOAc ) 3:2). H NMR (300 MHz,
CDCl3): δ ) 3.79 (s, 3H), 5.35 (s, 2H), 6.56 (d, 4J ) 2.5 Hz, 1H),
4
6.84 (d, J ) 2.5 Hz, 1H), 7.32-7.42 (m, 5H), 11.50 (s, 1H). 13C
NMR (75 MHz, CDCl3): δ ) 55.7, 67.9, 103.0, 103.6, 109.4 (q,
JC-F ) 7.1 Hz), 123.0 (q, JC-F ) 271.9 Hz), 128.5, 128.6, 128.8,
131.7 (q, JC-F ) 32.0 Hz), 134.5, 163.6, 165.4, 169.1. 19F NMR
(282 MHz, CDCl3): δ ) -58.1. IR (ATR, cm-1): ν˜ ) 3074 (w),
2969 (w), 1655 (m), 1620 (m), 1372 (m), 1322 (m), 1274 (m),
1210 (s), 1127 (s), 985 (s), 863 (s), 799 (m), 741 (s). GC-MS (EI,
70 eV): m/z (%): 326 (M+, 14), 91 (100). HRMS (EI, 70 eV): calcd
for C16H13F3O4 (M+) 326.07604, found 326.07538.
General Procedure for the Synthesis of 3a-t. To a CH2Cl2
solution (2 mL/1 mmol of 1a,b) of 1a,b (1.0 mmol) was added
2a-r (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.
Isopropyl 2-Hydroxy-4-methoxy-6-(trifluoromethyl)-benzoate
(3e). Starting with 1a (0.184 g, 1.0 mmol), 2d (0.577 g, 2.0 mmol)
and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product 3e was
isolated as a slightly yellow solid (0.100 g, 36%); mp ) 45-47
1
°C; RF ) 0.69 (n-heptane/EtOAc ) 3:2). H NMR (300 MHz,
CDCl3): δ ) 1.36 (s, 3H), 1.38 (s, 3H), 3.84 (s, 3H), 5.22-5.35
4
4
(m, 1H), 6.59 (d, J ) 2.5 Hz, 1H), 6.88 (d, J ) 2.5 Hz, 1H),
11.70 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 21.3, 55.7, 70.5,
103.6, 103.7, 109.2 (q, JC-F ) 7.2 Hz), 123.1 (q, JC-F ) 271.7
Hz), 131.7 (q, JC-F ) 32.0 Hz), 163.3, 165.2, 168.8. 19F NMR (282
MHz, CDCl3): δ ) -57.6. IR (ATR, cm-1): ν˜ ) 2978 (w), 1654
(m), 1618 (m), 1590 (w), 1467 (w), 1446 (w), 1426 (w), 1365 (s),
1278 (s), 1207 (s), 1125 (s), 1037 (s), 985 (s), 803 (s), 713 (s).
GC-MS (EI, 70 eV): m/z (%): 278 (M+, 14), 236 (16), 219 (29),
218 (100). Anal. Calcd for C12H13F3O4 (278.22): C, 51.80; H, 4.71.
Found: C, 51.55; H, 4.58.
Methyl 2-Hydroxy-4-methoxy-6-(trifluoromethyl)benzoate (3a).
Starting with 1a (0.184 g, 1.0 mmol), 2a (0.521 g, 2.0 mmol) and
TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product 3a was
isolated as a light-yellow solid (0,117 g, 47%); mp ) 66-67 °C;
1
RF ) 0.73 (heptane/EtOAc ) 1:1). H NMR (250 MHz, CDCl3):
δ ) 3.85, 3.95 (s, 3H), 6.62, 6.69 (s, 1H), 11.41 (s, 1H). 13C NMR
(63 MHz, CDCl3): δ ) 52.5, 55.8, 103.0, 103.6, 109.3 (q, JC-F
)
2-Methoxyethyl 2-hydroxy-4-methoxy-6-(trifluoromethyl)-ben-
zoate (3f). Starting with 1a (0.184 g, 1.0 mmol), 2e (0.609 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3f was isolated as a white solid (0.103 g, 35%); mp ) 57-58 °C;
RF ) 0.49 (n-heptane/EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3):
7.3 Hz), 123.0 (q, JC-F ) 273.3 Hz), 131.8 (q, JC-F ) 32.5 Hz),
163.6, 165.1, 169.7. 19F NMR (235 MHz, CDCl3): δ ) -59.3. IR
(ATR, cm-1): ν˜ ) 2985 (w), 2960 (w), 2923 (w), 2856 (w), 1662
(s), 1615 (s), 1593 (s), 1440 (s). MS (EI, 70 eV): m/z (%): 250
5006 J. Org. Chem. Vol. 74, No. 14, 2009

Influence of the Lewis Acid on the Product Distribution
3
δ ) 3.40 (s, 3H, OCH3), 3.72 (t, J ) 4.8 Hz, 2H), 3.85 (s, 3H),
CDCl3): δ ) -58.3. IR (ATR, cm-1): ν˜ ) 2956 (w), 1667 (m),
1608 (m), 1439 (m), 1404 (m), 1293 (s), 1245 (s), 1203 (s), 1127
(s), 1004 (m), 845 (m), 715 (m). GC-MS (EI, 70 eV): m/z (%):
290 (M+, 26), 270 (12), 259 (20), 258 (37), 243 (100), 230 (16),
215 (37). HRMS (EI, 70 eV): calcd for C13H13F3O4 (M+) 290.07604,
found 290.07604.
3
4
4.49 (t, J ) 4.8 Hz, 2H), 6.60 (2 × d, J ) 2.7 Hz, 1H), 6.89 (2
× d, 4J ) 2.7 Hz, 1H), 11.28 (s, 1H). 13C NMR (75 MHz, CDCl3):
δ ) 55.7, 58.9, 64.7, 69.6, 103.3, 103.6, 109.3 (q, JC-F ) 7.0 Hz),
123.1 (q, JC-F ) 272.0 Hz), 131.7 (q, JC-F ) 32.0 Hz), 163.5,
164.9, 168.9. 19F NMR (282 MHz, CDCl3): δ ) -58.3. IR (ATR,
cm-1): ν˜ ) 3096 (w), 2935 (w), 2824 (w), 1650 (m), 1598 (m),
1431 (m), 1376 (s), 1336 (s), 1285 (s), 1244 (s), 1212 (s), 1128
(s), 1025 (s), 986 (s), 891 (s), 808 (s), 715 (s). GC-MS (EI, 70
eV): m/z (%): 294 (M+, 20), 236 (19), 219 (71), 218 (100), 190
(22), 171 (15), 59 (19). Anal. Calcd for C12H13F3O5 (294.22): C,
48.99; H, 4.45. Found: C, 48.72; H, 4.46.
Methyl 2-Hydroxy-4-methoxy-3-methyl-6-(trifluoromethyl)-ben-
zoate (3g). Starting with 1a (0.184 g, 1.0 mmol), 2f (0.549 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3g was isolated as a white solid (0.091 g, 34%); mp ) 65-67 °C;
RF ) 0.88 (n-heptane/EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3):
δ ) 2.14 (s, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 6.86 (s, 1H), 11.26 (s,
1H). 13C NMR (100 MHz, CDCl3): δ ) 8.3, 52.5, 55.8, 102.5 (q,
JC-F ) 7.0 Hz), 104.0, 117.7, 123.5 (q, JC-F ) 271.6 Hz), 128.9
(q, JC-F ) 31.6 Hz), 160.7, 161.3, 170.1. 19F NMR (282 MHz,
CDCl3): δ ) -58.1. IR (ATR, cm-1): ν˜ ) 2959 (w), 2866 (w),
1657 (s), 1607 (w), 1586 (w), 1439 (m), 1286 (s), 1248 (s), 1121
(s), 999 (s), 842 (s), 713 (s). GC-MS (EI, 70 eV): m/z (%): 264
(M+, 72), 233 (45), 232 (100), 231 (14), 214 (16), 212 (60), 204
(68), 203 (18), 202 (28), 185 (15). Anal. Calcd for C11H11F3O4
(264.20): C, 50.01; H, 4.20. Found: C, 50.06; H, 4.22.
Methyl 2-Hydroxy-4-methoxy-3-propyl-6-(trifluoromethyl)-ben-
zoate (3k). Starting with 1a (0.184 g, 1.0 mmol), 2j (0.605 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3k was isolated as a slightly yellow solid (0.120 g, 41%); mp )
1
43-45 °C; RF ) 0.77 (n-heptane/EtOAc ) 3:2). H NMR (300
MHz, CDCl3): δ ) 0.94 (t, 3J ) 7.3 Hz, 3H), 1.46-1.59 (m, 2H),
2.66 (t, 3J ) 7.6 Hz, 2H), 3.89 (s, 3H), 3.94 (s, 3H), 6.86 (s, 1H),
11.19 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 14.2, 21.6, 24.9,
52.5, 55.7, 102.7 (q, JC-F ) 7.0 Hz), 104.2, 122.2, 123.5 (q, JC-F
) 271.5 Hz), 129.0 (q, JC-F ) 31.7 Hz), 160.7, 161.3, 170.2. 19F-
NMR (282 MHz, CDCl3): δ ) -58.2. IR (ATR, cm-1): ν˜ ) 2961
(w), 2866 (w), 1659 (m), 1611 (w), 1582 (w), 1441 (m), 1405 (m),
1320 (m), 1246 (s), 1127 (s), 1000 (m), 849 (s), 715 (s). GC-MS
(EI, 70 eV): m/z (%): 292 (M+, 53), 261 (28), 260 (72), 245 (29),
243 (17), 232 (71), 231 (100), 229 (17), 212 (13), 204 (23), 201
(15), 181 (31). Anal. Calcd for C13H15F3O4 (292.25): C, 53.43; H,
5.17. Found: C, 53.54; H, 5.17.
Methyl 3-Butyl-2-hydroxy-4-methoxy-6-(trifluoromethyl)-ben-
zoate (3L). Starting with 1a (0.184 g, 1.0 mmol), 2k (0.633 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3l was isolated as a white solid (0.102 g, 40%); mp ) 29-30 °C;
RF ) 0.71 (n-hexane/CH2Cl2 ) 3:2). 1H NMR (300 MHz, CDCl3):
3-Methyl-2-hydroxy-4-methoxy-6-(trifluoromethyl)-propiophe-
none (3h). Starting with 1a (0.184 g, 1.0 mmol), 2g (0.545 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3h was isolated as a slightly yellow solid (0.080 g, 30%); mp )
3
3
δ ) 0.92 (t, J ) 7.2 Hz, 3H), 1.29-1.57 (m, 4H), 2.68 (t, J )
7.6 Hz, 2H), 3.89 (s, 3H), 3.94 (s, 3H), 6.86 (s, 1H), 11.19 (s, 1H).
13C NMR (75 MHz, CDCl3): δ ) 14.0, 22.8, 22.9, 30.5, 52.5, 55.7,
102.7 (q, JC-F ) 7.0 Hz), 104.2, 122.5, 123.5 (q, JC-F ) 271.2
Hz), 129.0 (q, JC-F ) 31.7 Hz), 160.7, 161.2, 170.2. 19F-NMR (282
MHz, CDCl3): δ ) -58.2. IR (ATR, cm-1): ν˜ ) 2958 (w), 2938
(w), 2860 (w), 1664 (m), 1586 (w), 1436 (m), 1403 (m), 1320 (m),
1250 (s), 1125 (s), 850 (s), 808 (s), 715 (m). GC-MS (EI, 70 eV):
m/z (%): 306 (M+, 39), 275 (15), 257 (15), 245 (23), 243 (52), 232
(100), 231 (78), 212 (18), 204 (25), 181 (24). Anal. Calcd. for
C14H17F3O4 (306.28): C, 54.90; H, 5.59. Found: C, 55.02; H, 5.64.
Methyl 3-Hexyl-2-hydroxy-4-methoxy-6-(trifluoromethyl)-ben-
zoate (3m). Starting with 1a (0.184 g, 1.0 mmol), 2 L (0.689 g,
2.0 mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL),
product3m was isolated as a white solid (0.100 g, 30%); mp )
1
95-98 °C; RF ) 0.64 (n-heptane/EtOAc ) 3:2). H NMR (300
MHz, CDCl3): δ ) 1.18 (t, 3 ) 7.2 Hz, 3H), 2.13 (s, 3H), 2.88 (q,
3J ) 7.3 Hz, 2H), 3.90 (s, 3H), 6.76 (s, 1H), 9.76 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ ) 8.4, 9.1, 36.9 (q, JC-F ) 5 Hz),
55.8, 101.6 (q, JC-F ) 5.6 Hz), 115.7, 117.9, 124.0 (q, JC-F
)
271.6 Hz), 126.9 (q, JC-F ) 31.3 Hz), 157.0, 159.9, 208.5. 19F-
NMR (282 MHz, CDCl3): δ ) -54.7. IR (ATR, cm-1): ν˜ ) 3338
(w), 2931 (w), 1679 (m), 1606 (m), 1587 (m), 1455 (w), 1408 (w),
1347 (s), 1241 (s), 1117 (s), 837 (s), 705 (m). GC-MS (EI, 70 eV):
m/z (%): 262 (M+, 13), 233 (100), 185 (17). Anal. Calcd for
C12H13F3O3 (262.23): C, 54.96; H, 5.00. Found: C, 54.88; H, 5.34.
Ethyl 3-Ethyl-2-hydroxy-4-methoxy-6-(trifluoromethyl)-ben-
zoate (3i). Starting with 1a (0.184 g, 1.0 mmol), 2h (0.605 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3i was isolated as a white solid (0.130 g, 44%); mp ) 50-51 °C;
RF ) 0.77 (n-heptane/EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3):
1
34-35 °C; RF ) 0.74 (n-hexane/CH2Cl2 ) 3:2). H NMR (300
MHz, CDCl3): δ ) 0.88 (t, 3J ) 6.7 Hz, 3H), 1.25-1.56 (m, 8H),
3
2.67 (t, J ) 7.5 Hz, 2H), 3.89 (s, 3H), 3.94 (s, 3H) 6.86 (s, 1H),
11.19 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 14.1, 22.6, 23.0,
28.3, 29.4, 31.7, 52.5, 55.7, 102.7 (q, JC-F ) 7.0 Hz), 104.1, 122.5,
123.5 (q, JC-F ) 271.5 Hz), 128.9 (q, JC-F ) 31.7 Hz), 160.7,
161.2, 170.2. 19F-NMR (282 MHz, CDCl3): δ ) -58.2. IR (ATR,
cm-1): ν˜ ) 2931 (w), 2851 (w), 1671 (m), 1601 (m), 1501 (w),
1439 (m), 1404 (m), 1306 (s), 1246 (s), 1148 (s), 1117 (s), 1001
(m), 933 (m), 845 (s), 717 (m). GC-MS (EI, 70 eV): m/z (%): 334
(M+, 31), 303 (14), 285 (12), 271 (64), 245 (18), 232 (100), 231
(89), 212 (17), 204 (23), 181 (24). Anal. Calcd for C16H21F3O4
(334.33): C, 57.48; H, 6.33. Found: C, 57.43; H, 6.25.
3
3
δ ) 1.09 (t, J ) 7.5 Hz, 3H), 1.39 (t, J ) 7.0 Hz, 3H), 2.70 (q,
3J ) 7.4 Hz, 2H), 3.90 (s, 3H), 4.41 (q, 3J ) 7.1 Hz, 2H), 6.86 (s,
1H), 11.32 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 12.8, 13.5,
16.4, 55.7, 62.1, 102.7 (q, JC-F ) 7.2 Hz), 104.5, 123.6, 123.6 (q,
JC-F ) 271.5 Hz), 129.0 (q, JC-F ) 31.7 Hz), 160.4, 161.2, 169.7.
19F-NMR (282 MHz, CDCl3): δ ) -57.2. IR (ATR, cm-1): ν˜ )
2984 (m), 2950 (m), 1655 (s), 1609 (w), 1584 (w), 1468 (w), 1451
(w), 1398 (m), 1321 (s), 1247 (s), 1123 (s), 1021 (m), 846 (s), 808
(s), 713 (s). GC-MS (EI, 70 eV): m/z (%): 292 (M+, 54), 247 (39),
246 (100), 231 (29), 226 (48), 218 (77), 208 (16), 200 (15), 175
(17). Anal. Calcd for C13H15F3O4 (292.25): C, 53.43; H, 5.17.
Found: C, 53.25; H, 5.05.
Methyl 2-Hydroxy-4-methoxy-6-(trifluoromethyl)-3-octyl-ben-
zoate (3n). Starting with 1a (0.184 g, 1.0 mmol), 2m (0.754 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3n was isolated as a white solid (0.110 g, 30%); mp ) 38-39 °C;
RF ) 0.62 (n-hexane/CH2Cl2 ) 3:2). 1H NMR (300 MHz, CDCl3):
Methyl 3-Allyl-2-hydroxy-4-methoxy-6-(trifluoromethyl)-ben-
zoate (3j). Starting with 1a (0.184 g, 1.0 mmol), 2i (0.601 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3j was isolated as a colorless oil (0.123 g, 42%); RF ) 0.78 (n-
3
3
δ ) 0.87 (t, J ) 6.7 Hz, 3H), 1.26-1.56 (m, 12H), 2.66 (t, J )
7.5 Hz, 2H), 3.89 (s, 3H), 3.94 (s, 3H) 6.86 (s, 1H), 11.18 (s, 1H).
13C NMR (75 MHz, CDCl3): δ ) 14.1, 22.6, 23.0, 28.3, 29.2, 29.4,
29.7, 31.9, 52.5, 55.7, 102.6 (q, JC-F ) 7.0 Hz), 104.1, 122.5, 123.5
(q, JC-F ) 271.5 Hz), 128.9 (q, JC-F ) 31.5 Hz), 160.6, 161.2,
170.1. 19F-NMR (282 MHz, CDCl3): δ ) -58.2. IR (ATR, cm-1):
ν˜ ) 2918 (m), 2849 (m), 1656 (m), 1611 (w), 1584 (w), 1463 (w),
1441 (m), 1320 (s), 1250 (s), 1207 (s), 1126 (s), 1010 (w), 933
1
heptane/EtOAc ) 3:2). H NMR (400 MHz, CDCl3): δ ) 3.45
3
(dt, J ) 6.1 Hz, 2H), 3.90 (s, 3H), 3.94 (s, 3H) 4.96-5.04 (m,
2H), 5.87-5.97 (m, 1H), 6.88 (s, 1H), 11.24 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ ) 27.2, 52.6, 55.9, 102.8 (q, JC-F ) 7.0
Hz), 104.4, 115.1, 119.4, 123.4 (q, JC-F ) 271.6 Hz), 129.7 (q,
JC-F ) 31.6 Hz), 134.9, 160.7, 161.2, 170.0. 19F-NMR (282 MHz,
J. Org. Chem. Vol. 74, No. 14, 2009 5007

Bunescu et al.
(m), 717 (s). GC-MS (EI, 70 eV): m/z (%): 362 (M+, 28), 331
(15), 313 (12), 299 (69), 245 (17), 233 (12), 232 (100), 231 (87),
212 (15), 204 (20), 181 (19). HRMS (EI, 70 eV): calcd for
C18H25F3O4 (M+) 362.16995, found 362.16995.
205 (35), 189 (15), 188 (34), 93 (15). Anal. Calcd for C11H11F3O5
(280.20): C, 47.15; H, 3.96. Found: C, 47.11; H, 3.89.
Methyl 2-Hydroxy-4-ethoxy-3methoxy-6-(trifluoromethyl)-ben-
zoate (3s). Starting with 1b (213 mg, 1.0 mmol), 2q (0.581 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3s was isolated as a colorless solid (0.097 mg, 33%); mp ) 61-62
°C; RF ) 0.68 (heptane/EtOAc ) 1:1). 1H NMR (250 MHz, CDCl3):
δ ) 1.48 (t, 3J ) 7.1 Hz, 3H), 3.94, 3.95 (s, 3H), 4.17 (q, 3J ) 7.1
Hz, 2H), 6.88 (s, 1H), 10.11 (s, 1H). 13C NMR (75 MHz, CDCl3):
δ ) 14.7, 52.7, 60.7, 64.9, 104.8 (q, JC-F ) 7.1 Hz), 107.0, 123.3
(q, JC-F ) 272.9 Hz), 125.2 (q, JC-F ) 32.5 Hz), 139.1, 154.2,
154.9, 168.8. 19F NMR (235 MHz, CDCl3): δ ) -58.7. IR (ATR,
cm-1): ν˜ ) 2986 (w), 2947 (w), 2899 (w), 2852 (w), 1665 (s),
1600 (s), 1573 (m), 1436 (s). MS (EI, 70 eV): m/z (%): 294 (M+,
63), 263 (45), 262 (100), 247 (16), 234 (67), 233 (63), 206 (74),
205 (83). Anal. Calcd for C12H13F3O5 (294.22): C, 48.99; H, 4.45.
Found: C, 49.32; H, 4.77.
Methyl 2-Hydroxy-4-methoxy-6-(trifluoromethyl)-3-undecylben-
zoate (3o). Starting with 1a (0.184 g, 1.0 mmol), 2n (0.829 g, 2.0
mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3o was isolated as a white solid (0.120 g, 30%); mp ) 55-56 °C;
RF ) 0.50 (n-hexane/CH2Cl2 ) 3:1). 1H NMR (300 MHz, CDCl3):
3
3
δ ) 0.87 (t, J ) 6.7 Hz, 3H), 1.25-1.55 (m, 18H), 2.66 (t, J )
7.6 Hz, 2H), 3.89 (s, 3H), 3.94 (s, 3H), 6.86 (s, 1H), 11.18 (s, 1H).
13C NMR (75 MHz, CDCl3): δ ) 14.1, 22.6, 23.0, 28.3, 29.3, 29.5,
29.6, 29.6, 29.7, 29.8, 31.9, 52.5, 55.7, 102.6 (q, JC-F ) 7.0 Hz),
104.1, 122.5, 123.5 (q, JC-F ) 271.5 Hz), 128.9 (q, JC-F ) 31.5
Hz), 160.6, 161.2, 170.1. 19F-NMR (282 MHz, CDCl3): δ ) -58.1.
IR (ATR, cm-1): ν˜ ) 2914 (m), 2894 (m), 1656 (m), 1610 (w),
1584 (w), 1465 (w), 1441 (m), 1316 (s), 1251 (s), 1207 (s), 1127
(s), 933 (m), 716 (s). GC-MS (EI, 70 eV): m/z (%): 404 (M+, 24),
373 (12), 355 (13), 342 (14), 341 (67), 245 (16), 233 (14), 232
(100), 231 (87), 212 (14), 204 (18), 181 (18). Anal. Calcd for
C21H31F3O4 (404.21): C, 62.36; H, 7.73. Found: C, 62.19; H, 7.93.
Methyl 3-(Chloropropyl)-2-hydroxy-4-methoxy-6-(trifluorom-
ethyl)benzoate (3t). Starting with 1a (0.184 g, 1.0 mmol), 2r (0.674
g, 2.0 mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL),
product 3t was isolated as a white solid (0.185 g, 57%); mp )
1
46-50 °C; RF ) 0.68 (n-heptane/EtOAc ) 3:2). H NMR (300
Methyl 2-Hydroxy-4-methoxy-3-phenethyl-6-(trifluoromethyl)-
benzoate (3p). Starting with 1a (0.184 g, 1.0 mmol), 2o (0.729 g,
2.0 mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product
3p was isolated as a white solid (0.136 g, 39%); mp ) 62-63 °C;
RF ) 0.61 (n-hexane/CH2Cl2 ) 3:2). 1H NMR (300 MHz, CDCl3):
MHz, CDCl3): δ ) 1.95-2.04 (m, 2H), 2.82 (t, 3J ) 7.3 Hz, 2H),
3.54 (t, 3J ) 7.0 Hz, 2H), 3.91 (s, 3H), 3.95 (s, 3H), 6.87 (s, 1H),
11.27 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 20.7, 31.4, 44.8,
52.6, 55.8, 102.6 (q, JC-F ) 7.2 Hz), 104.3, 120.4, 123.3 (q, JC-F
) 271.7 Hz), 129.6 (q, JC-F ) 32.0 Hz), 160.8, 161.3, 170.0. 19F-
NMR (282 MHz, CDCl3): δ ) -58.3. IR (ATR, cm-1): ν˜ ) 3010
(w), 2961 (w), 2854 (w), 1660 (m), 1605 (w), 1438 (m), 1398 (w),
1247 (s), 1142 (s), 1125 (s), 1102 (s), 1004 (s), 848 (s), 714 (s).
GC-MS (EI, 70 eV): m/z (%): 326 (M+, 14), 260 (12), 259 (100),
232 (25), 231 (21). HRMS (EI, 70 eV): calcd for C13H14ClF3O4
(M+) 326.05272, found 326.05208.
3
3
δ ) 2.77 (t, J ) 8.1 Hz, 2H), 2.99 (t, J ) 8.1 Hz, 2H), 3.81 (s,
3H), 3.95 (s, 3H), 6.84 (s, 1H), 7.18-7.28 (m, 5H), 11.27 (s, 1H).
13C NMR (75 MHz, CDCl3): δ ) 25.2, 34.3, 52.6, 55.7, 102.7 (q,
JC-F ) 7.2 Hz), 104.2, 121.3, 123.4 (q, JC-F ) 271.5 Hz), 125.8,
128.1, 128.5, 129.3 (q, JC-F ) 32.0 Hz), 142.3 (Ph), 160.7, 161.3,
170.1. 19F-NMR (282 MHz, CDCl3): δ ) -58.2. IR (ATR, cm-1):
ν˜ ) 3085 (w), 3027 (w), 2947 (w), 2861 (w), 1668 (m), 1600 (m),
1496 (w), 1440 (m), 1404 (m), 1317 (s), 1247 (s), 1127 (s), 997
(m), 844 (s), 656 (s). GC-MS (EI, 70 eV): m/z (%): 354 (M+, 15),
263 (23), 232 (11), 231 (100), 181 (12), 91 (15). Anal. Calcd for
C18H17F3O4 (354.32): C, 61.02; H, 4.84. Found: C, 61.16; H, 4.87.
General Procedure for the Synthesis of 4a-g and 5g-p. To a
CH2Cl2 solution (10 mL/1 mmol of 1) of 1 (1 mmol) was added 2
(2 mmol) and, subsequently, Me3SiOTf (0.18 mL, 1 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 hydro-
chloric acid (10%, 20 mL) and the organic and the aqueous layer
were separated. The latter was extracted with CH2Cl2 (2 × 15 mL).
The combined organic layers were dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography.
Methyl 2-(6-(Trifluoromethyl)-4-oxo-4H-pyran-2-yl)acetate (4a).
Starting with 1a (0.184 g, 1.0 mmol), 2a (0.520 g, 2.0 mmol) and
Me3SiOTf (0.18 mL, 1.0 mmol) in CH2Cl2 (10 mL), product 4a
was isolated as a yellow solid (0.148 g, 63%); mp ) 83-85 °C;
RF ) 0.22 (n-heptane/EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3):
δ ) 3.63 (s, 2H), 3.78 (s, 3H), 6.38 (d, 4J ) 2.2 Hz, 1H), 6.69 (d,
4J ) 2.2 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ ) 38.8, 52.9,
114.6 (q, JC-F ) 2.5 Hz), 117.5, 118.2 (q, JC-F ) 271.9 Hz), 152.8
(q, JC-F ) 39.5 Hz), 161.3, 166.9, 177.3. 19F NMR (282 MHz,
CDCl3): δ ) -71.2. IR (ATR, cm-1): ν˜ ) 3056 (w), 2969 (w),
2940 (w), 1726 (s), 1672 (s), 1626 (s), 1440 (m), 1415 (m), 1342
(m), 1201 (s), 1139 (s), 1090 (s), 979 (s), 917 (s), 719 (m). GC-
MS (EI, 70 eV): m/z (%): 236 (M+, 100), 205 (10), 192 (65), 189
(13), 149 (68), 123 (17), 99 (29), 95 (19), 69 (55), 59 (98), 39
(13). Anal. Calcd for C9H7F3O4 (236.14): C, 45.78; H, 2.90. Found:
C, 45.83; H, 3.03.
Methyl 2-Hydroxy-4-methoxy-3-(phenylpropyl)-6-(trifluorom-
ethyl)benzoate (3q). Starting with 1a (0.184 g, 1.0 mmol), 2p (0.757
g, 2.0 mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL),
product 3q was isolated as a slightly yellow solid (0.160 g, 43%);
1
mp ) 50-52 °C; RF ) 0.59 (n-hexane/CH2Cl2 ) 3:2). H NMR
(300 MHz, CDCl3): δ ) 1.78-1.89 (m, 2H), 2.65-2.77 (m, 4H),
3.87 (s, 3H), 3.94 (s, 3H), 6.85 (s, 1H), 7.13-7.29 (m, 5H), 11.21
(s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 22.9, 29.7, 35.9, 52.6,
55.7, 102.6 (q, JC-F ) 7.0 Hz), 104.2, 121.9, 123.4 (q, JC-F
)
271.5 Hz), 125.6, 128.1, 128.3, 129.1 (q, JC-F ) 31.7 Hz), 142.5,
160.7, 161.2, 170.0. 19F-NMR (282 MHz, CDCl3): δ ) -58.2. IR
(ATR, cm-1): ν˜ ) 3029 (w), 2971 (w), 2930 (w), 2863 (w), 1667
(m), 1606 (w), 1579 (w), 1511 (w), 1441 (m), 1320 (s), 1249 (s),
1125 (s), 998 (m), 847 (s), 697 (s). MS (EI, 70 eV): m/z (%): 368
(M+, 100), 337 (35), 336 (37), 245 (77), 244 (42), 233 (32), 232
(96), 231 (89), 224 (67), 212 (44), 209 (36), 204 (51), 181 (22),
118 (31), 105 (51), 104 (22), 92 (13), 91 (46). Anal. Calcd for
C19H19F3O4 (368.35): C, 61.95; H, 5.20. Found: C, 62.29; H, 5.32.
Methyl 2-Hydroxy-3,4-dimethoxy-6-(trifluoromethyl)-benzoate
(3r). Starting with 1a (0.184 g, 1.0 mmol), 2q (0.581 g, 2.0 mmol)
and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (2 mL), product 3r was
isolated as a slightly yellow solid (0.140 g, 50%); mp ) 60-62
Ethyl 2-(6-(Trifluoromethyl)-4-oxo-4H-pyran-2-yl)acetate (4b).
Starting with 1a (0.184 g, 1.0 mmol), 2b (0.549 g, 2.0 mmol) and
Me3SiOTf (0.18 mL, 1.0 mmol) in CH2Cl2 (10 mL), 4b was isolated
as a yellow solid (0.172 g, 69%); mp ) 73-75 °C; RF ) 0.31
(n-heptane/EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3): δ ) 1.29
(t, 3J ) 7.2 Hz, 3H), 3.62 (s, 2H), 4.24 (q, 3J ) 7.3 Hz, 2H), 6.38
1
°C; RF ) 0.67 (n-heptane/EtOAc ) 3:2). H NMR (300 MHz,
CDCl3): δ ) 3.93 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 6.90 (s, 1H),
10.27 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 52.7, 56.1, 60.7,
103.6 (q, JC-F ) 6.7 Hz), 106.9, 123.1 (q, JC-F ) 271.1 Hz), 125.3
(q, JC-F ) 32.2 Hz), 138.8, 154.8, 155.0, 168.8. 19F NMR (282
MHz, CDCl3): δ ) -58.2. IR (ATR, cm-1): ν˜ ) 2961 (w), 2855
(w), 1683 (m), 1602 (m), 1413 (m), 1256 (s), 1109 (s), 1023 (s),
963 (s), 922 (s), 840 (s), 709 (s). GC-MS (EI, 70 eV): m/z (%):
280 (M+, 54), 249 (39), 248 (83), 247 (14), 220 (100), 219 (44),
4
4
(d, J ) 2.3 Hz, 1H), 6.69 (d, J ) 2.2 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ ) 14.0, 39.2, 62.1, 114.6 (q, JC-F ) 2.6 Hz),
117.5, 120.0 (q, JC-F ) 272.3 Hz), 152.6 (q, JC-F ) 39.7 Hz),
161.6, 166.4, 177.5. 19F NMR (282 MHz, CDCl3): δ ) -71.2. IR
5008 J. Org. Chem. Vol. 74, No. 14, 2009

Influence of the Lewis Acid on the Product Distribution
(ATR, cm-1): ν˜ ) 3056 (w), 2990 (w), 2974 (w), 2936 (w), 1722
(s), 1673 (s), 1627 (s), 1414 (m), 1367 (s), 1334 (s), 1282 (s), 1143
(s), 916 (s), 719 (s). GC-MS (EI, 70 eV): m/z (%): 250 (M+, 56),
205 (25), 203 (10), 178 (100), 177 (13), 149 (52), 139 (22), 99
(22), 69 (50), 39 (10). Anal. Calcd for C10H9F3O4 (250.17): C, 48.01;
H, 3.63. Found: C, 48.16; H, 3.79.
(39), 39 (12), 29 (15). Anal. Calcd for C12H13F3O4 (278.22): C,
51.80; H, 4.71. Found: C, 51.84; H, 4.82.
Methyl 6-(Trifluoromethyl)-6-hydroxy-4-methoxy-3-methyl-2-
oxocyclohex-3-enecarboxylate (5g). Starting with 1a (0.184 g, 1.0
mmol), 2f (0.549 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), product 5g was isolated as a light-yellow solid
(0.107 g, 38%); mp ) 123-126 °C; RF ) 0.49 (n-heptane/EtOAc
Benzyl 2-(6-(Trifluoromethyl)-4-oxo-4H-pyran-2-yl)acetate (4c).
Starting with 1a (0.184 g, 1.0 mmol), 2c (0.673 g, 2.0 mmol) and
Me3SiOTf (0.18 mL, 1.0 mmol) in CH2Cl2 (10 mL), product 4c
was isolated as a yellow oil (0.099 g, 32%); RF ) 0.30 (n-heptane/
1
) 3:2). H NMR (300 MHz, CDCl3): δ ) 1.72-1.74 (m, 3H),
2.78 (brd, 2J ) 17.6 Hz, 1H), 2.95 (d, 2J ) 17.5 Hz, 1H), 3.69 (s,
0.5 H), 3.70 (s, 0.5H), 3.88 (s, 3H), 3.89 (s, 3H), 5.49 (s, 0.5H),
5.50 (s, 0.5H). 13C NMR (100 MHz, CDCl3): δ ) 7.3, 30.4, 52.9,
53.1, 55.7, 74.1 (q, JC-F ) 29.1 Hz), 113.4, 124.5 (q, JC-F ) 286.4
Hz), 166.4, 171.3, 188.4. 19F-NMR (282 MHz, CDCl3): δ ) -81.2.
IR (ATR, cm-1): ν˜ ) 3428 (w), 3013 (w), 2965 (w), 2926 (w),
2867 (w), 1739 (s), 1648 (m), 1613 (s), 1461 (w), 1440 (w), 1164
(s), 1117 (s), 1063 (s), 972 (s), 688 (m). GC-MS (EI, 70 eV): m/z
(%): 282 (M+, 4), 264 (100), 233 (16), 232 (41), 220 (32), 212
(18), 207 (27), 205 (40), 204 (22), 189 (16), 181 (31), 175 (14), 83
(20), 69 (36) 59 (20), 43 (15). Anal. Calcd for C11H13F3O5 (282.21):
C, 46.81; H, 4.64. Found: C, 46.88; H, 4.63.
1
EtOAc ) 3:2). H NMR (300 MHz, CDCl3): δ ) 3.65 (s, 2H),
5.20 (s, 2H), 6.36, (d, 4J ) 2.2 Hz, 1H), 6.67 (d, 4J ) 2.2 Hz, 1H),
7.31-7.40 (m, 5H). 13C NMR (75 MHz, CDCl3): δ ) 39.0, 67.7,
114.6 (q, JC-F ) 2.5 Hz), 117.6, 118.1 (q, JC-F ) 272.2 Hz), 128.3,
128.6, 128.7, 134.6, 153.0 (q, JC-F ) 39.5 Hz), 161.2, 166.2, 177.3.
19F NMR (282 MHz, CDCl3): δ ) -71.1. IR (ATR, cm-1): ν˜ )
3070 (w), 2938 (w), 1740 (m), 1674 (s), 1641 (m), 1619 (m), 1498
(w), 1362 (w), 1274 (s), 1147 (s), 1083 (s), 968 (m), 877 (m), 696
(s). GC-MS (EI, 70 eV): m/z (%): 312 (M+, 0.71), 178 (59), 91
(100), 65 (10). HRMS (EI, 70 eV): calcd for C15H11F3O4 (M+)
312.06039, found 312.06008.
Methyl 6-(Trifluoromethyl)-3-ethyl-6-hydroxy-4-methoxy-2-oxo-
cyclohex-3-enecarboxylate (5 h). Starting with 1a (0.184 g, 1.0
mmol), 2t (0.577 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), 5h was isolated as a white solid (0.146 g, 50%);
mp ) 106-110 °C; RF ) 0.42 (n-heptane/EtOAc ) 3:2). 1H NMR
(300 MHz, CDCl3): δ ) 0.93 (t, 3J ) 7.4 Hz, 3H), 1.21-2.48 (m,
Isopropyl 2-(6-(Trifluoromethyl)-4-oxo-4H-pyran-2-yl)acetate
(4d). Starting with 1a (0.184 g, 1.0 mmol), 2d (0.577 g, 2.0 mmol)
and Me3SiOTf (0.18 mL, 1.0 mmol) in CH2Cl2 (10 mL), product
4d was isolated as a yellow oil (0.170 g, 64%); RF ) 0.33 (n-
1
heptane/EtOAc ) 3:2). H NMR (300 MHz, CDCl3): δ ) 1.25(s,
4
2
2
3H), 1.28 (s, 3H), 3.60 (s, 2H), 5.04-5.13 (m, 1H), 6.37 (d, J )
2H), 2.78 (brd, J ) 17.7 Hz, 1H), 2.94 (d, J ) 17.7 Hz, 1H),
3.68 (s, 0.5H), 3.70 (s, 0.5H), 3.89 (s, 3H), 5.50 (s, 0.5H), 5.51 (s,
0.5H). 13C NMR (75 MHz, CDCl3): δ ) 12.8, 15.6, 30.3, 52.9,
53.1, 55.7, 74.1 (q, JC-F ) 28.7 Hz), 119.6, 124.5 (q, JC-F ) 279.0
Hz), 166.3, 171.4, 188.0. 19F-NMR (282 MHz, CDCl3): δ ) -81.2.
IR (ATR, cm-1): ν˜ ) 3437 (w), 3021 (w), 2963 (w), 2942 (w),
2879 (w), 1741 (s), 1649 (m), 1611 (s), 1441 (w), 1413 (w), 1250
(s), 1165 (s), 1132 (s), 1120 (s), 986 (s), 659 (m). GC-MS (EI, 70
eV): m/z (%):296 (M+, 2), 278 (30), 246 (14), 220 (11), 219 (100),
195 (13), 83 (13), 69 (19). Anal. Calcd for C12H15F3O5 (396.24):
C, 48.65; H, 5.10. Found: C, 48.70; H, 5.12.
2.1 Hz, 1H), 6.69 (d, 4J ) 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3):
δ ) 21.6, 39.6, 70.0, 114.7 (q, JC-F ) 2.7 Hz), 117.5, 118.2 (q,
JC-F ) 272.0 Hz), 153.1 (q, JC-F ) 39.5 Hz), 161.9, 166.0, 177.5.
19F NMR (282 MHz, CDCl3): δ ) -71.3. IR (ATR, cm-1): ν˜ )
3076 (w), 2985 (w), 2940 (w), 1735 (m), 1674 (s), 1643 (m), 1410
(w), 1361 (m), 1274 (s), 1201 (s), 1148 (s), 1083 (s), 961 (m), 876
(m), 721 (w). GC-MS (EI, 70 eV): m/z (%): 264 (M+, 9), 205 (38),
178 (36), 177 (11), 149 (38), 99 (11), 69 (19), 43 (100), 41 (19).
Anal. Calcd for C11H11F3O4 (264.20): C, 50.01; H, 4.20. Found: C,
50.16; H, 4.55.
2-Methoxyethyl 2-(6-(trifluoromethyl)-4-oxo-4H-pyran-2-yl)ac-
etate (4e). Starting with 1a (0.183 g, 1.0 mmol), 2e (0.549 g, 2.0
mmol) and Me3SiOTf (0.18 mL, 1.0 mmol) in CH2Cl2 (10 mL),
product4e was isolated as a yellow oil (0.112 g, 40%); RF ) 0.36
(n-heptane/EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3): δ ) 3.84
Methyl 6-(Trifluoromethyl)-3-chloro-6-hydroxy-4-methoxy-2-
oxocyclohex-3-enecarboxylate (5i). Starting with 1a (0.184 g, 1.0
mmol), 2u (0.589 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), product5i was isolated as a light-yellow solid
(0.134 g, 44%); mp ) 108-109 °C; RF ) 0.34 (n-heptane/EtOAc
3
3
1
2
(s, 3H), 3.61 (t, J ) 4.5 Hz, 2H), 3.67 (s, 2H), 4.34 (t, J ) 4.5
Hz, 2H), 6.39 (d, 4J ) 2.1 Hz, 1H), 6.69 (d, 4J ) 2.1 Hz, 1H). 13
NMR (75 MHz, CDCl3): δ ) 39.0, 59.0, 64.1, 70.2, 114.7 (q, JC-F
) 3:2). H NMR (300 MHz, CDCl3): δ ) 2.93 (d, J ) 17.7 Hz,
2
C
1H), 3.09 (d, J ) 17.4 Hz, 1H), 3.81 (s, 1H), 3.91, 4.04 (s, 3H),
5.53 (brs, 1H). 13C NMR (75 MHz, CDCl3): δ ) 32.2, 53.6, 53.6,
57.2, 75.4 (q, JC-F ) 29.3 Hz), 109.6, 124.4 (q, JC-F ) 285.8 Hz),
166.0, 170.1, 181.8. 19F-NMR (282 MHz, CDCl3): δ ) -81.0. IR
(ATR, cm-1): ν˜ ) 3430 (m), 3018 (w), 2962 (w), 2937 (m), 2873
(w), 1733 (s), 1661 (m), 1591 (s), 1349 (w), 1265 (m), 1341 (m),
1185 (s), 955 (s), 845 (m), 664 (s). GC-MS (EI, 70 eV): m/z (%):
302 (M+, 2), 286 (16), 284 (52), 242 (27), 240 (100), 227 (17),
212 (12), 210 (11), 197 (22), 174 (17), 131 (10), 103 (11), 69 (56),
59 (44). HRMS (ESI): calcd for C18H28F3O5 (M+H+) 303.02416,
found 303.02477.
) 2.3 Hz), 117.7, 118.2 (q, JC-F ) 271.5 Hz), 152.9 (q, JC-F
)
39.0 Hz), 161.4, 166.6, 177.5. 19F NMR (282 MHz, CDCl3): δ )
-71.2. IR (ATR, cm-1): ν˜ ) 3057 (w), 2928 (w), 2897 (w), 2849
(w), 2825 (w), 1741 (s), 1675 (s), 1642 (m), 1620 (w), 1362 (m),
1275 (s), 1199 (m), 1150 (s), 1084 (s), 1032 (m), 974 (m), 877 (s),
722 (s). GC-MS (EI, 70 eV): m/z (%): 280 (M+, 2), 250 (15), 222
(20), 178 (87), 161 (11), 149 (56), 99 (19), 69 (29), 58 (33), 45
(100), 43 (11), 29 (16). Anal. Calcd for C11H11F3O5 (280.02): C,
47.15; H, 3.96. Found: C, 47.14; H, 4.31.
Isobutyl 2-(6-(Trifluoromethyl)-4-oxo-4H-pyran-2-yl)acetate (4f).
Starting with 1a (0.184 g, 1.0 mmol), 2s (0.605 g, 2.0 mmol) and
Me3SiOTf (0.18 mL, 1.0 mmol) in CH2Cl2 (10 mL), product 4d
was isolated as a brownish oil (0.178 g, 64%); RF ) 0.40 (n-heptane/
EtOAc ) 3:2). 1H NMR (300 MHz, CDCl3): δ ) 0.91(s, 3H), 0.93
Ethyl 6-(Trifluoromethyl)-6-hydroxy-4-methoxy-2-oxo-3-pen-
tylcyclohex-3-enecarboxylate (5j). Starting with 1a (0.184 g, 1.0
mmol), 2v (0.689 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), 5j was isolated as a yellow solid (0.138 g,
1
39%); mp ) 73-75 °C; RF ) 0.42 (n-heptane/EtOAc ) 3:2). H
3
(s, 3H), 1.88-2.01 (m, 1H), 3.63 (s, 2H), 3.96 (d, J ) 6.6 Hz,
NMR (300 MHz, CDCl3): δ ) 0.86 (t, 3J ) 6.9 Hz, 3H), 1.25-1.38
4
4
2
2H), 6.38 (d, J ) 2.4 Hz, 1H), 6.69 (d, J ) 2.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ ) 18.8, 27.5, 39.2, 72.0, 114.6 (q,
JC-F ) 1.9 Hz), 117.5, 118.2 (q, JC-F ) 272.1 Hz), 152.8 (q, JC-F
) 39.6 Hz), 161.6, 166.4, 177.4. 19F NMR (282 MHz, CDCl3): δ
) -71.1. IR (ATR, cm-1): ν˜ ) 3076 (w), 2965 (w), 2878 (w),
1740 (m), 1675 (s), 1644 (m), 1620 (w), 1471 (w), 1361 (m), 1274
(s), 1201 (s), 1150 (s), 1084 (s), 973 (m), 876 (m), 721 (m). GC-
MS (EI, 70 eV): m/z (%): 278 (M+, 2), 223 (100), 205 (24), 178
(60), 177 (12), 149 (64), 99 (17), 69 (24), 57 (51), 56 (15), 41
(m, 9H), 2.19-2.34 (m, 2H), 2.77 (brd, J ) 17.4 Hz, 1H), 2.94
(d, 2J ) 17.4 Hz, 1H), 3.64 (s, 1H), 3.87 (s, 3H), 4.35 (q, 3J ) 7.2
Hz, 2H), 5.59 (s, 0.5H), 5.60 (s, 0.5H). 13C NMR (75 MHz, CDCl3):
δ ) 13.9, 14.0, 22.1, 22.4, 27.9, 30.3, 31.7, 52.9, 55.6, 62.5, 74.1
(q, JC-F ) 28.5 Hz), 118.4, 124.6 (q, JC-F ) 285.0 Hz), 166.3,
171.0, 188.3. 19F-NMR (282 MHz, CDCl3): δ ) -81.2. IR (ATR,
cm-1): ν˜ ) 3439 (w), 2959 (w), 2932 (w), 2873 (w), 2849 (w),
1735 (s), 1648 (m), 1612 (s), 1463 (w), 1414 (w), 1336 (m), 1250
(m), 1171 (s), 1122 (s), 1024 (s), 946 (m), 657 (m). GC-MS (EI,
J. Org. Chem. Vol. 74, No. 14, 2009 5009

Bunescu et al.
70 eV): m/z (%):352 (M+, 1), 334 (13), 314 (12), 257 (20), 233
(15), 232 (24), 231 (22), 206 (15), 205 (100), 69 (11). Anal. Calcd
for C16H23F3O5 (352.35): C, 54.54; H, 6.58. Found: C, 54.64; H,
6.64.
Methyl 6-(Trifluoromethyl)-3-dodecyl-6-hydroxy-4-methoxy-2-
oxocyclohex-3-enecarboxylate (5n). Starting with 1a (0.184 g, 1.0
mmol), 2y (0.857 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), 5n was isolated as a yellow solid (0.252 g,
1
58%); mp ) 74-76 °C; RF ) 0.63 (n-heptane/EtOAc ) 3:2). H
Ethyl 6-(Trifluoromethyl)-3-heptyl-6-hydroxy-4-methoxy-2-oxo-
cyclohex-3-enecarboxylate (5k). Starting with 1a (0.184 g, 1.0
mmol), 2w (0.754 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), 5k was isolated as a slightly yellow solid (0.133
g, 35%); mp ) 20-25 °C; RF ) 0.58 (n-heptane/EtOAc ) 3:2).
NMR (400 MHz, CDCl3): δ ) 0.87 (t, 3J ) 6.8 Hz, 3H), 1.24-1.29
2
(m, 20H), 2.20-2.32 (m, 2H), 2.77 (brd, J ) 17.6 Hz, 1H), 2.94
(d, 2J ) 17.6 Hz, 1H), 3.68 (s, 0.5H), 3.70 (s, 0.5H), 3.87 (s, 3H),
3.88 (s, 3H), 5.49 (s, 0.5H), 5.50 (s, 0.5H). 13C NMR (75 MHz,
CDCl3): δ ) 14.1, 22.2, 22.6, 28.2, 29.3, 29.4, 29.6 (m), 30.3, 31.9,
3
1H NMR (300 MHz, CDCl3): δ ) 0.86 (t, J ) 6.8 Hz, 3H),
52.9, 53.1, 55.6, 74.1 (q, JC-F ) 28.7 Hz), 118.4, 124.7 (q, JC-F
)
1.25-1.38 (m, 13H), 2.19-2.31 (m, 2H), 2.77 (brd, 2J ) 17.7 Hz,
284.9 Hz), 166.3, 171.4, 188.2. 19F-NMR (282 MHz, CDCl3): δ )
-81.2. IR (ATR, cm-1): ν˜ ) 3413 (w), 2953 (w), 2916 (m), 2848
(m), 1734 (m), 1656 (m), 1614 (s), 1463 (w), 1439 (w), 1245 (s),
1160 (s), 1140 (s), 1119 (s), 664 (m). ESI: calcd for C22H36F3O5
(M+H+) 437.2509, found 437.2510; calcd for C22H35F3NaO5
(M+Na+) 459.2328, found 459.2327. Anal. Calcd for C22H35F3O5
(436.51): C, 60.53; H, 8.08. Found: C, 60.74; H, 8.08.
2
1H), 2.94 (d, J ) 17.4 Hz, 1H), 3.64 (s, 1H), 3.87 (s, 3H), 4.35
(dq, 3J ) 7.2 Hz, 2H), 5.59 (s, 0.5H), 5.60 (s, 0.5H). 13C NMR (75
MHz, CDCl3): δ ) 13.9, 14.0, 22.1, 22.6, 28.3, 29.1, 29.5, 30.3,
31.8, 52.9, 55.6, 62.5, 74.1 (q, JC-F ) 28.7 Hz), 118.4, 124.6 (q,
JC-F ) 285.0 Hz), 166.3, 171.0, 188.3. 19F-NMR (282 MHz,
CDCl3): δ ) -81.2. IR (ATR, cm-1): ν˜ ) 3427 (w), 2960 (w),
2927 (w), 2856 (w), 1722 (m), 1638 (w), 1605 (s), 1446 (w), 1426
(w), 1375 (m), 1245 (s), 1171 (s), 1122 (s), 1016 (m), 656 (m).
GC-MS (EI, 70 eV): m/z (%):380 (M+, 1), 362 (21), 342 (15), 285
(31), 233 (17), 232 (50), 231 (37), 206 (16), 205 (100), 204 (12),
29 (10). ESI: calcd for C18H28F3O5 (M+H+) 381.1883, found
381.1884; calcd for C18H27F3NaO5 (M+Na+) 403.1702, found
403.1705. Anal. Calcd for C18H27F3O5 (380.40): C, 56.83; H, 7.15.
Found: C, 56.89; H, 7.19.
Methyl 6-(Trifluoromethyl)-3-hexadecyl-6-hydroxy-4-methoxy-
2-oxocyclohex-3-enecarboxylate (5o). Starting with 1a (0.184 g, 1.0
mmol), 2z (0.969 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), 5o was isolated as a yellow solid (0.264 g,
1
54%); mp ) 82-84 °C; RF ) 0.69 (n-heptane/EtOAc ) 3:2). H
NMR (400 MHz, CDCl3): δ ) 0.88 (t, 3J ) 6.8 Hz, 3H), 1.24-1.31
2
(m, 28H), 2.20-2.32 (m, 2H), 2.77 (brd, J ) 18.0 Hz, 1H), 2.94
2
(d, J ) 17.6 Hz, 1H), 3.68 (s, 1H), 3.86 (s, 3H), 3.88 (s, 3H),
5.49 (s, 0.5H), 5.50 (s, 0.5H). 13C NMR (75 MHz, CDCl3): δ )
14.1, 22.2, 22.6, 28.2, 29.3, 29.4, 29.6 (m), 30.3, 31.9, 52.9, 53.1,
55.6, 74.1 (q, JC-F ) 28.7 Hz), 118.4, 124.5 (q, JC-F ) 285.0 Hz),
166.3, 171.4, 188.2. 19F-NMR (282 MHz, CDCl3): δ ) -81.2. IR
(ATR, cm-1): ν˜ ) 3413 (w), 2952 (w), 2916 (s), 2847 (s), 1735
(m), 1655 (m), 1613 (s), 1462 (m), 1439 (m), 1245 (s), 1161 (s),
1140 (s), 1120 (s), 664 (m). GC-MS (EI, 70 eV): m/z (%):492 (M+,
1), 475 (11), 474 (48), 454 (15), 423 (15), 411 (55), 474 (48), 442
(22), 411 (55), 263 (16), 233 (25), 232 (100), 231 (83), 205 (83).
ESI: calcd for C26H44F3O5 (M+H+) 493.3135, found 493.3134;
calcd for C26H43F3NaO5 (M+Na+) 515.2954, found 515.2955. Anal.
Calcd for C26H43F3O5 (492.61): C, 63.39; H, 8.80. Found: C, 63.71;
H, 8.87.
Methyl 6-(Trifluoromethyl)-6-hydroxy-4-methoxy-3-octyl-2-oxo-
cyclohex-3-enecarboxylate (5 L). Starting with 1a (0.184 g, 1.0
mmol), 2m (0.745 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), 5 L was isolated as a yellow solid (0.236 g,
1
62%); mp ) 77-79 °C; RF ) 0.62 (n-heptane/EtOAc ) 3:2). H
NMR (300 MHz, CDCl3): δ ) 0.87 (t, 3J ) 6.7 Hz, 3H), 1.24-1.31
2
(m, 12H), 2.21-2.31 (m, 2H), 2.77 (brd, J ) 17.6 Hz, 1H), 2.94
(d, 2J ) 17.6 Hz, 1H), 3.68 (s, 0.5H), 3.70 (s, 0.5H), 3.87 (s, 3H),
3.88 (s, 3H), 5.50 (s, 0.5H), 5.51 (s, 0.5H). 13C NMR (100 MHz,
CDCl3): δ ) 14.0, 22.2, 22.6, 28.2, 29.2, 29.4, 29.5, 30.3, 31.8,
53.0, 53.1, 55.6, 74.1 (q, JC-F ) 29.0 Hz), 118.4, 124.5 (q, JC-F
)
285.0 Hz), 166.3, 171.4, 188.2. 19F-NMR (282 MHz, CDCl3): δ )
-81.2. IR (ATR, cm-1): ν˜ ) 3438 (m), 3025 (w), 2958 (w), 2928
(m), 2854 (w), 1739 (s), 1650 (m), 1612 (s), 1461 (w), 1438 (m),
1341 (m), 1258 (s), 1166 (s), 1123 (s), 1069 (m), 974 (m), 659
(m). GC-MS (EI, 70 eV): m/z (%):380 (M+, 1), 362 (28), 342 (17),
232 (27), 219 (18), 205 (100), 69 (17). ESI: calcd for C18H28F3O5
(M+H+) 381.1883, found 381.1880; calcd for C18H27F3NaO5
(M+Na+) 403.1702, found 403.1704. Anal. Calcd for C18H27F3O5
(380.40): C, 56.83; H, 7.15. Found: C, 56.84; H, 7.12.
Methyl 6-(Trifluoromethyl)-6-hydroxy-3-isopentyl-4-methoxy-
2-oxocyclohex-3-enecarboxylate (5p). Starting with 1a (0.184 g, 1.0
mmol), 2aa (0.661 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0
mmol) in CH2Cl2 (10 mL), 5p was isolated as a yellow solid (0.193
g, 55%); mp ) 90-92 °C; RF ) 0.60 (n-heptane/EtOAc ) 3:2).
1H NMR (300 MHz, CDCl3): δ ) 0.87 (s, 3H), 0.89 (s, 3H),
1.14-1.28 (m, 2H), 1.45-1.54 (m, 1H), 2.22-2.32 (m, 2H), 2.77
(brd, 2J ) 17.7 Hz, 1H), 2.94 (d, 2J ) 17.7 Hz, 1H), 3.68 (s, 0.5H),
3.70 (s, 0.5H), 3.87 (s, 3H), 3.88 (s, 3H), 5.50 (s, 0.5H), 5.51 (s,
0.5H). 13C NMR (75 MHz, CDCl3): δ ) 20.2, 22.4, 22.5, 28.1,
30.3, 37.3, 53.0, 53.1, 55.6, 74.1 (q, JC-F ) 28.7 Hz), 118.6, 124.5
(q, JC-F ) 284.7 Hz), 166.3, 171.4, 188.2. 19F-NMR (282 MHz,
CDCl3): δ ) -81.2. IR (ATR, cm-1): ν˜ ) 3435 (w), 2959 (w),
2933 (w), 2876 (w), 2853 (w), 1740 (s), 1650 (m), 1612 (s), 1452
(w), 1439 (w), 1342 (m), 1249 (s), 1168 (s), 1140 (s), 1124 (s),
1041 (m), 978 (m), 658 (m). GC-MS (EI, 70 eV): m/z (%):338
(M+, 2), 320 (32), 300 (17), 288 (11), 273 (10), 263 (16), 261 (18),
260 (11), 251 (13), 245 (16), 244 (18), 237 (14), 233 (14), 232
(73), 231 (35), 219 (17), 206 (12), 205 (100), 181 (10), 159 (15),
153 (10), 69 (23), 59 (15), 43 (12), 41 (11). Anal. Calcd for
C15H21F3O5 (338.32): C, 53.25; H, 6.26. Found: C, 53.37; H, 6.61.
Methyl 6-(Trifluoromethyl)-6-hydroxy-4-methoxy-3-nonyl-2-
oxocyclohex-3-enecarboxylate (5m). Starting with 1a (0.184 g, 1.0
mmol), 2x (0.745 g, 2.0 mmol) and Me3SiOTf (0.18 mL, 1.0 mmol)
in CH2Cl2 (10 mL), 5m was isolated as a yellow solid (0.225 g,
1
57%); mp ) 63-64 °C; RF ) 0.53 (n-heptane/EtOAc ) 3:2). H
NMR (300 MHz, CDCl3): δ ) 0.87 (t, 3J ) 6.7 Hz, 3H), 1.24-1.31
2
(m, 14H), 2.25-2.27 (m, 2H), 2.77 (brd, J ) 17.7 Hz, 1H), 2.94
(d, 2J ) 17.6 Hz, 1H), 3.68 (s, 0.5H), 3.70 (s, 0.5H), 3.87 (s, 3H),
3.88 (s, 3H), 5.50 (s, 0.5H), 5.51 (s, 0.5H). 13C NMR (100 MHz,
CDCl3): δ ) 14.1, 22.2, 22.6, 28.2, 29.3, 29.4, 29.5, 29.6, 30.3,
31.8, 53.0, 53.1, 55.6, 74.1 (q, JC-F ) 28.9 Hz), 118.4, 124.5 (q,
JC-F ) 286.9 Hz), 166.3, 171.4, 188.2. 19F-NMR (282 MHz,
CDCl3): δ ) -81.2. IR (ATR, cm-1): ν˜ ) 3439 (m), 3025 (w),
2958 (w), 2925 (m), 2855 (w), 1739 (s), 1651 (m), 1613 (s), 1461
(w), 1438 (w), 1248 (s), 1167 (s), 1123 (s), 975 (m), 659 (m). GC-
MS (EI, 70 eV): m/z (%):394 (M+, 1), 376 (41), 356 (23), 345
(15), 313 (70), 263 (16), 259 (15), 245 (18), 233 (17), 232 (100),
231 (84), 219 (21), 212 (15), 205 (99), 204 (19), 181 (19), 69 (16).
ESI: calcd for C19H30F3O5 (M+H+) 395.2039, found 395.2042;
calcd for C19H29F3NaO5 (M+Na+) 417.1859, found 417.1860. Anal.
Calcd for C19H29F3O5 (394.20): C, 57.86; H, 7.41. Found: C, 57.78;
H, 7.30.
Acknowledgment. Financial support from the State of
Mecklenburg-Vorpommern is gratefully acknowledged.
Supporting Information Available: Copies of NMR spectra,
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO900702U
5010 J. Org. Chem. Vol. 74, No. 14, 2009