α-trifluoromethylation of secondary and sterically hindered carboxylates with use of BrF3

Article abstract of DOI:10.1021/jo048864g

Secondary esters and those with sterical hindrance at the β carbon were reacted with base, carbon disulfide, and methyl iodide to produce methyl 2-carboalkoxydithioalkenoate (2). These compounds were reacted with BrF ₃, forming the correspondin

Full text of DOI:10.1021/jo048864g

r-Tr iflu or om eth yla tion of Secon d a r y a n d Ster ica lly Hin d er ed
Ca r boxyla tes w ith Use of Br F 3
Aviv Hagooly and Shlomo Rozen*
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University,
Tel-Aviv 69978, Israel
rozens@post.tau.ac.il
Received J uly 5, 2004
Secondary esters and those with sterical hindrance at the â carbon were reacted with base, carbon
disulfide, and methyl iodide to produce methyl 2-carboalkoxydithioalkenoate (2). These compounds
were reacted with BrF3, forming the corresponding R-trifluoromethyl esters (3) along with 1,1-
difluoro-2-trifluoromethyl-2-alkyl ethers (4). The products of type 4 have been transformed to
derivatives of type 3, thus raising the overall yields of the target respective R-trifluoromethyl esters
to 65-80%. The reaction is tolerant to different functional groups such as halogens, protected
alcohols, esters, and lactones.
SCHEME 1. Syn th esis of Str a igh t-Ch a in
Frequently, the biological activity of organic substrates
is strongly influenced by the trifluoromethyl group. This
phenomenon is usually explained by the increased lipo-
philicity and hydrolytic stability of the corresponding
organic substrates. Many articles and reviews are de-
voted to compounds possessing this group. They deal with
the whole spectrum of properties, from pharmacological
aspects to synthetic methods devised for the incorpora-
tion of the CF3 moiety into various specific sites of organic
molecules.1
r-Tr iflu or om eth yl Ca r boxyla tes9
A general method for introducing the trifluoromethyl
group into the R position of carboxylic acids was, however,
conspicuously missing. Only a few unique R-trifluoro-
methyl carboxylates have been described. Purrington
achieved trifluoromethylation of malonic acids using CF2-
Br2 followed by nucleophilic displacement of bromine by
fluoride.2 Tellier performed some sigmatropic shifts with
vinyl alcohols and 2H perfluoropropene,3 Lassaletta
developed a route for constructing R-alkoxy-R-trifluoro-
methyl acids,4 and Allmendinger prepared R-trifluoro-
methyl-R,â-unsaturated acids.5 Kitazume reacted methyl
â,â,â-trifluoropropionate with allylic carbamates obtain-
ing eventually some functionalized R-trifluoromethyl
carboxylates.6 Recently Cahard described a procedure for
electrophilic trifluoromethylation on the highly nucleo-
philic carbon of â-ketocarboxylates.7 Attempting R-alky-
lation of â,â,â-trifluoropropionates was proved to be
impractical since a facile defluorination takes place even
at -78 °C: CF3CH2COOR + B- f CF2dCHCOOR.8 Re-
cently, we developed a general method for constructing
straight-chain R-trifluoromethyl carboxylates using CS2
and BrF3 (Scheme 1).9 These two reagents are the
cornerstone also for the present work, which describes a
general preparation of secondary, as well as sterically
hindered, R-trifluoromethyl carboxylic acids. Although
the reaction with this family of compounds proceeds
differently from what is described in Scheme 1, the basic
roles of the reagents remained the same. The carbon
atom of the CF3 group originated in carbon disulfide,
while BrF3 was the supplier of the fluorine atoms.
Most specific reactions with BrF310 were made possible
because of the tendency of the soft acidic electrophilic
bromine to complex itself with soft basic heteroatoms,
such as nitrogen and sulfur, bringing the naked nucleo-
* Address correspondence to this author. Fax: 972-3-6409293.
(1) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b)
Singh, R. P.; Shreeve, J . M. Tetrahedron 2000, 56, 7613. (c) Lin, P.;
J iang, J . Tetrahedron 2000, 56, 3635. (d) Langlois, B. R.; Billard, T.
Synthesis 2003, 185. (e) Chen, G.; Li, Y.; Missert, J . R.; Rungta, A.;
Dougherty, T. J .; Grossman, R Z.; Pandey, D. K. J . Chem. Soc., Perkin
Trans. 1 1999, 1785. (f) Hilborn, J . W.; Lu, Z. H.; J urgens, A. R.; Fang,
Q. K.; Byers, P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2001,
42, 8919.
(2) Everett, T. S.; Purrington, S. T.; Bumgardner, C. L. J . Org. Chem.
1984, 49, 3702.
(3) Tellier, F.; Audouin, M.; Sauvetre, R. J . Fluorine Chem. 2002,
113, 167.
(4) Fernandez, R.; Zamora, E. M.; Pareja, C.; Vazquez, J .; Diez, E.;
Monge, A.; Lassaletta, J . M. Angew. Chem., Int. Ed. 1998, 37, 3428.
(5) Allmendinger, T.; Lang, R. W. Tetrahedron Lett. 1991, 32, 339.
(6) Komatsu, Y.; Sakamoto, T.; Kitazume, T. J . Org. Chem. 1999,
64, 8369.
(7) Ma, J . A.; Cahard, D. J . Org. Chem. 2003, 68, 8726.
(8) Yokozawa, T.; Nakai, T.; Ishikawa, N. Tetrahedron Lett. 1984,
25, 3987.
(9) Hagooly, A.; Rozen, S. Chem. Commun. 2004, 594.
10.1021/jo048864g CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/18/2004
J . Org. Chem. 2004, 69, 7241-7245
7241

Hagooly and Rozen
SCHEME 2. Gen er a l Mech a n ism of Br F 3 Rea ctin g
w ith Electr on -Rich Cen ter s
SCHEME 4. Th e P r op osed Rea ction Mech a n ism
SCHEME 3
addition to the CF3 group, an R,R-difluoro ether moiety
shown in Scheme 4. In the past we have made intention-
ally similar R,R-difluoro ethers by reacting bromine
trifluoride with thioesters.12 At that time we found that
these ethers are not very stable and tend to decompose
slowly back to the corresponding esters. To facilitate this
last transformation, we treated 4a with an aqueous-
alcoholic mixture of HCl/HF for a few hours regenerating
the ester moiety in higher than 80% yield, raising the
overall yield of 3a to 70% (see also Scheme 3).
Similarly, the aliphatic ethyl 2-propylpentanoate (1b)
was converted to methyl 2-carboethoxy-2-propyldithio-
pentanoate (2b), which was then reacted with BrF3. Both
ethyl 2-propyl-2-trifluoromethylpentanoate (3b ) and
1-ethoxy-1,1-difluoro-2-propyl-2-trifluoromethylpentane
(4b) were formed. The latter was converted to 3b in good
yield (see Table 1). Primary esters with strong steric
hindrance at the â-position can also be manipulated as
described above. Butyl neopentanoate (1c) and methyl
2-norbornyl acetate (1d ) gave, after treatment with base,
CS2 and MeI, the corresponding 2c and 2d . Reacting
these compounds with BrF3 resulted in the respective
R-trifluoromethyl esters 3c and 3d accompanied by the
pentafluoro derivatives 4c and 4d . Here too, these
pentafluoro compounds were transformed back to 3c and
3d , considerably increasing the overall yield of the
desired R-trifluoromethyl esters.
philic fluorides near the reaction center. This proximity
reduces undesirable radical reactions and enables rela-
tively clean substitution of the heteroatoms for fluorides
(Scheme 2). It should be noted that the soft bromine will
not complex itself with hard oxygen atoms. No specific
reactions were observed when BrF3 was brought in
contact with any type of carbonyl, including malonates,
which resemble compounds of type 2 (see below).
Resu lts a n d Discu ssion
The chain of reactions that starts with ethyl cyclohep-
tylcarboxylate (1a ) can serve as an illustrative example
for introducing the CF3 group at the R-position of second-
ary acid derivatives. When 1a was reacted with LDA,
CS2, and MeI, methyl 2-carboethoxydithiocyclohep-
tanoate (2a ) was obtained in very good yield. Unlike the
intermediate A in Scheme 1, no carbon-carbon double
bond could be formed around which the usual first step
of most reactions with BrF3 takes place. Still, we found
that this reagent reacted successfully with 2a although
a larger excess of up to 5 mol equiv was needed. After a
few seconds the desired ethyl 2-trifluoromethylcyclohep-
tanoate (3a ) was formed, although in 35% yield only. It
was accompanied by additional major product (45% yield)
that proved to be 1-(difluoromethylene ethyl ether)-1-
trifluoromethylcycloheptane (4a ) (Scheme 3).
To explore the scope and limitations of this method we
repeated the above chain of reactions with compounds
bearing additional functionalities. It seems that the
presence of common aromatic rings is not compatible with
the reaction since BrF3 readily brominates these rings.13
Other functional groups, however, are tolerated. While
it is known that BrF3 can substitute chlorine with
fluorine14 we found that the reaction at the sulfur center
is much faster. 3-Chloropropyl cyclohexylcarboxylate (1e)
was easily converted to 2e. This compound was reacted
These results indicate that the reaction mechanism is
somewhat similar to the one described for the reaction
of BrF3 with nitriles.11 While the electrophilic bromine
is complexed around the sulfur atoms the nucleophilic
fluorides get close to the adjacent carbonyl forming, in
(10) For some recent reactions with the still rarely used BrF3 see:
(a) Rozen, S.; Mishani, E.; Bar-Haim, A. J . Org. Chem. 1994, 59, 2918.
(b) Rozen, S.; Ben-David, I. J . Org. Chem. 2001, 66, 496. (c) Sasson,
R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769. (d) Hagooly, A.;
Sasson, R.; Rozen, S. J . Org. Chem. 2003, 68, 8287. (e) Hagooly, A.;
Ben-David, I.; Rozen, S. J . Org. Chem. 2002, 67, 8430.
(11) Rozen, S.; Rechavi, D.; Hagooly, A. J . Fluorine Chem. 2001,
111, 161.
(12) Rozen, S.; Mishani, E. J . Chem. Soc., Chem. Commun. 1993,
1761.
(13) Rozen, S.; Lerman, O. J . Org. Chem. 1993, 58, 239.
(14) Rozov, L. A.; Huang, C. G.; Halpern, D. F.; Vernice, G. G.; Ramig
K. Tetrahedron: Asymmetry 1997, 8, 3023.
7242 J . Org. Chem., Vol. 69, No. 21, 2004

R-Trifluoromethylation of Carboxylates
TABLE 1.
SCHEME 5
In conclusion, this work, along with that described in
ref 9, covers the general preparation of the whole
spectrum of the potentially important R-trifluoromethyl
carboxylic acid derivatives. In addition it should be
stressed once again that when properly used, bromine
trifluoride can serve as an excellent fluorinating agent
for hard to prepare fluorinated compounds.
Exp er im en ta l Section
1H NMR spectra were recorded on a 200-MHz spectrometer
with CDCl3 as a solvent and Me4Si as an internal standard.
Only the relevant and characteristic peaks are reported. The
19F NMR spectra were measured at 188.1 MHz and are
reported upfield from CFCl3, serving as an internal standard.
The proton broad-band decoupled 13C NMR spectra were
recorded at 50.2 MHz. Here too, CDCl3 served as a solvent
and Me4Si as an internal standard. IR spectra were recorded
in CHCl3 solution on a FTIR spectrophotometer. Silica gel 60H
(Merck) and petroleum ether/ethyl acetate were used in the
flash chromatography when the purification of the product was
desired. Most compounds described in this work were purified
and their spectral data recorded. However, only the R-triflu-
oromethyl carboxylates were analytically purified. Their purity
was confirmed also by elemental microanalysis.
P r ep a r in g a n d Ha n d lin g Br F 3. Although commercially
available, we usually prepare our own BrF3 by passing 0.6 mol
of pure fluorine through 0.2 mol of bromine placed in a copper
reactor and cooled to 0-10 °C. Under these conditions the
higher oxidation state, BrF5, will not be formed in any
appreciable amount. The product can be stored in Teflon
containers indefinitely. BrF3 is a strong oxidizer and tends to
react very exothermically with water and oxygenated organic
solvents such as acetone or THF. Alkanes, like petroleum
ether, cannot serve as solvents either since they also react fast
with BrF3. Any work with BrF3 should be conducted in a well-
ventilated area, and caution and common sense should be
exercised. It is recommended that a face shield and comfort-
able, yet heavy-duty gloves should be wear when working with
this reagent.
Gen er a l P r oced u r e for th e P r ep a r a tion of Meth yl
2-Ca r boa lk oxyd ith ioa lk en oa te Der iva tives 2.16 A 10-
mmol sample of the ester 1 was dissolved in 100 mL of dry
THF and cooled to -78 °C. Lithium diisopropylamide (12.5
mmol) (LDA, 1.5 M solution in cyclohexane) was added, the
cooling bath was removed, and the mixture was stirred for
2 h. The reaction was cooled again to -78 °C and carbon
disulfide (about 40 mmol) was added. The brown solution was
stirred for another hour and cooled again to -78 °C, then
methyl iodide (about 40 mmol) was added. After another 2 h
the reaction was warmed to room temperature, poured into
water, extracted with ether, and dried over MgSO4, then the
solvent was removed. The product (of type 2) was isolated by
flash chromatography as a brown-orange oil.
a
b
Total overall yield. Yield before converting 4 to 3.
with bromine trifluoride to give the desired 3-chloropro-
pyl 2-trifluoromethylcyclohexanoate (3e) along with the
pentafluoro derivative 4e. The crude reaction mixture
was heated with 3-chloropropanol/HF/HCl to give 3e in
high yield. Alcohols are easily oxidized by BrF3 to the
corresponding acyl fluorides,15 but when protected the
reaction proceeds smoothly. Thus, the hydroxy group of
ethyleneglycyl 2-methylbutanoate was protected as a
pivaloate 1f. The reason for choosing this protecting
group is the absence of any acidic hydrogen R to the
carbonyl, a necessity when a strong base is applied.
Methyl 2-(2-pivaloylcarboethoxy)-2-methyldithiobutanoate
(2f) was thus obtained in very good yield and after the
reaction with bromine trifluoride the pentafluoro deriva-
tive 4f was found to be the major product. The crude
reaction mixture was treated with HCl/HF and we
obtained the 2-pivaloylethyl 2-methyl-2-trifluorometh-
ylbutanoate 3f in good yield. It should be noted that
unlike the carbonyl near the dithioesters that was
attacked by the nucleophilic fluorine atoms of the re-
agent, the remote carbonyl of the pyvaloyl group was not
affected by BrF3, another support for the proposed mech-
anism of the reaction as presented in Schemes 2 and 4.
Lactones are also suitable derivatives for this reaction
and R-methyl-γ-butyrolactone (5) can serve as an ex-
ample. The preparation of the dithioester R-methyl-R-
(methyldithioformate)-γ-butyrolactone (6) proceeded as
usual, but when reacted with BrF3 the only compound
isolated was the desired R-methyl-R-trifluoromethyl-γ-
butyrolactone (7) in 65% yield (Scheme 5). While we do
not have a solid explanation for the absence of the
corresponding pentafluoro derivative in this case, a
probable factor may be the greater distance of the methyl
dithioester from the carbonyl moiety compared with other
2-carboalkoxydithioalkanoates.
Gen er a l P r oced u r e for Rea ctin g 2 w ith Br F 3: Th e
P r ep a r a tion of 2-Tr iflu or om eth yl Ester s 3. The methyl
(16) Konen, D. A.; Pfeffer, P. E.; Silbert, L. S. Tetrahedron 1976,
32, 2507.
(15) Rozen, S.; Ben-David, I. J . Fluorine Chem. 1996, 76, 145.
J . Org. Chem, Vol. 69, No. 21, 2004 7243

Hagooly and Rozen
2-carboalkoxydithioalkenoate derivative 2 (usually 1 mmol)
was dissolved in 10-15 mL of dry CFCl3 and cooled to 0 °C.
About 5 mmol of BrF3 was dissolved in 10 mL of the same
solvent, cooled to 0 °C, and added dropwise, over 1-2 min, to
the above solution. Upon completion, the reaction was quenched
with saturated aqueous Na2SO3 and washed until colorless.
The aqueous layer was extracted with CH2Cl2 and the organic
layer dried over MgSO4. Evaporation of the solvent followed
by purification by flash chromatography gave the desired
product 3 in 25-45% yields and 4 in 45-60% yields. All
compounds of type 4 can be transformed to alkyl 2-trifluoro-
methyl esters (3) by heating them (100 °C, oil bath) for 6-14
h in 10 mL of the same alcohol as the alcoholic part of the
ester (R′′OH) and 5 mL of water containing 0.5 mL of HCl
(32%) and 0.5 mL HF (40%). The regeneration of the ester was
monitored by GC and stopped at about 90% conversion. The
aqueous layer was extracted with ether, the organic solvent
dried over MgSO4 and evaporated, and the residue purified
by flash chromatography. The desired products 3 were ob-
tained in 65-90% yields (based on the pentafluoro derivative)
increasing the overall yields of 3 to 65-80%.
7 Hz), 0.90 ppm (3 H, t, J ) 7 Hz); 19F NMR δ -68.1 (3 F, t,
J ) 11 Hz), -76.5 ppm (2 F, q, J ) 11 Hz); 13C NMR δ 126.4
(q, J ) 285 Hz), 124.4 (t, J ) 270 Hz), 59.3 (t, J ) 8 Hz),
54.4 (six, J ) 23 Hz), 31.3, 16.9, 14.8 ppm; MS (CI) m/z 261
(M - H)+. 4b was transformed to 3b as described above (10 h
of heating in EtOH/H2O/HCl/HF) in 75% yield.
1-Bu t oxy-1,1-d iflu or o-3,3-d im et h yl-2-t r iflu or om et h -
ylbu ta n e (4c) was obtained from 2c as described above in 45%
1
yield: oil; H NMR δ 3.93 (2 H, t, J ) 7 Hz), 2.81-2.53 (1 H,
m), 1.18 (9 H, s), 0.91 ppm (3 H, t, J ) 7 Hz); 19F NMR δ -60.1
(3 F, qm, J ) 11 Hz), -62.5 to -68.5 ppm (2 F, m); 13C NMR
δ 125.4 (q, J ) 282 Hz), 123.2 (t, J ) 268 Hz), 63.0 (t, J ) 7
Hz), 57.4 (six, J ) 25 Hz), 32.7, 31.0, 29.4, 19.0, 13.4 ppm. 4c
was transformed to 3c as described above (6 h of heating in
BuOH/H2O/HCl/HF) in 85% yield.
1,1-Diflu or o-1-m et h oxy-2-n or b or n yl-2-t r iflu or om et h -
yleth a n e (4d ) was obtained from 2d as described above. The
two diastereoisomers were obtained in 50% yield: oil; 19F NMR
δ -63.4 and -64.1 (3 F, qm, J ) 11 Hz), -71.5 to -75.6 ppm
(2 F, m); MS (CI) m/z 257 (M - H)+. 4d was transformed to
3d as described above (14 h of heating in BuOH/H2O/HCl/HF)
in 80% yield.
1-(3-Ch lor op r op oxy)-1,1-d iflu or o-2-tr iflu or om eth ylcy-
cloh exa n e (4e) was obtained from 2e as described above in
60% yield: oil; 1H NMR δ 4.07 (2 H, t, J ) 7 Hz), 3.63 ppm (2
H, t, J ) 7 Hz); 19F NMR δ -69.1 (3 F, t, J ) 13 Hz), -78.7
ppm (2 F, q, J ) 13 Hz); 13C NMR δ 126.6 (q, J ) 283 Hz),
124.5 (t, J ) 272 Hz), 60.1 (t, J ) 8 Hz), 49.8 (six, J ) 23 Hz),
40.8, 32.0, 24.7, 24.1, 20.8 ppm; MS (CI) m/z 293 (M - H)+. 4e
was transformed to 3e as described above (10 h of heating in
3-chloropropanol/H2O/HCl/HF) in 90% yield.
1,1-Diflu or o-2-m et h yl-1-(2-p iva loylet h oxy)-2-t r iflu o-
r om eth ylbu ta n e (4f) was prepared from 2f as described
above in 55% yield: oil; 1H NMR δ 4.28-4.02 (4 H, m), 1.80 (2
H, q, J ) 7 Hz), 1.27 (3 H, s), 1.21 (9 H, s), 0.95 ppm (3 H, t,
J ) 7 Hz); 19F NMR δ -71.4 (3 F, t, J ) 11 Hz), -79.7 to -80.1
ppm (2 F, m); 13C NMR 178.2, 126.4 (q, J ) 283 Hz), 124.3 (t,
J ) 270 Hz), 61.9, 61.5 (t, J ) 7 Hz), 50.4 (six, J ) 25 Hz),
38.7, 27.0, 24.1, 14.0, 8.4 ppm; MS (CI) m/z 321 (MH)+. 4f was
transformed to 3f as described above (6 h of heating in ethylene
glycol/H2O/HCl/HF) in 65% yield.
Eth yl 2-tr iflu or om eth ylcycloh ep ta n oa te (3a ) was pre-
pared from 2a as described above in 70% overall yield: oil; IR
1731 cm-1; 1H NMR δ 4.22 (2 H, q, J ) 7 Hz), 1.24 ppm (3 H,
t, J ) 7 Hz); 19F NMR δ -73.3 ppm (s); 13C NMR δ 170.2, 127.7
(q, J ) 283 Hz), 61.6, 55.8 (q, J ) 23 Hz), 30.4, 30.0, 23.3,
13.8 ppm; HRMS (CI) (m/z) calcd for C11H18F3O2 239.1258
(MH)+, found 239.1262. Anal. Calcd for C11H17F3O2: C, 55.45;
H, 7.19. Found: C, 54.98; H, 7.10.
Meth yl 2-ca r boeth oxyd ith iocycloh ep ta n oa te (2a ) was
prepared from 1a as described above in 90% yield: oil; IR 1724
1
cm-1; H NMR δ 4.12 (2 H, q, J ) 7 Hz), 2.58 (3 H, s), 1.18
ppm (3 H, t, J ) 7 Hz); 13C NMR δ 241.6, 172.7, 70.2, 61.0,
38.1, 29.4, 24.1, 19.9, 13.7 ppm.
Meth yl 2-ca r boeth oxy-2-p r op yld ith iop en ta n oa te (2b)
was prepared from 1b as described above in 90% yield: oil;
IR 1725 cm-1; 1H NMR δ 4.12 (2 H, q, J ) 7 Hz), 2.60 (3 H, s),
1.18 (3 H, t, J ) 7 Hz), 0.89 ppm (3 H, t, J ) 7 Hz); 13C NMR
δ 239.9, 172.3, 69.3, 61.0, 37.9, 19.8, 17.4, 14.4, 13.7 ppm.
Meth yl 2-car bobu toxy-3,3-dim eth yldith iobu tan oate (2c)
was prepared from 1c as described above in 90% yield: oil;
1
IR 1737 cm-1; H NMR 4.26 (1 H, s), 4.08 (2 H, t, J ) 7 Hz),
2.62 (3 H, s), 1.16 (9 H, s), 0.89 ppm (3 H, t, J ) 7 Hz); 13C
NMR δ 229.8, 168.2, 75.2, 64.7, 35.1, 30.3, 28.1, 20.7, 19.0,
13.5 ppm.
Meth yl 2-ca r bom eth oxy-2-n or bor n yld ith ioeth a n oa te
(2d ) was prepared from 1d as described above. The two
diastereoisomers were obtained in 90% yield: oil; IR 1736
1
cm-1; H NMR δ 4.01 and 3.95 (1 H, d, J ) 2 Hz), 3.72 and
3.69 (3 H, s), 2.67 and 2.64 ppm (3 H, s); 13C NMR (only the
relevant picks) δ 231.3 and 230.2, 169.1 and 168.7, 71.2 and
70.9, 52.4 ppm.
Meth yl 2-(3-ch lor ocar bopr opoxy)dith iocycloh exan oate
(2e) was prepared from 1e as described above in 90% yield:
oil; IR 1723 cm-1; 1H NMR δ 4.28 (2 H, t, J ) 7 Hz), 3.55 (2 H,
t, J ) 7 Hz), 2.61 ppm (3 H, s); 13C NMR δ 240.4, 171.3, 67.5,
61.8, 41.2, 36.1, 31.3, 25.2, 23.5, 19.9 ppm.
Meth yl 2-(2-p iva loylca r boeth oxy)-2-m eth yld ith iobu -
ta n oa te (2f) was prepared from 1f as described in about 90%
Eth yl 2-p r op yl-2-tr iflu or om eth ylp en ta n oa te (3b) was
prepared from 2b as described above in 70% overall yield: oil;
IR 1734 cm-1; 1H NMR δ 4.23 (2 H, q, J ) 7 Hz), 1.34 (3 H, t,
J ) 7 Hz), 0.90 ppm (3 H, t, J ) 7 Hz); 19F NMR δ -68.6 ppm
(s); 13C NMR δ 169.6, 126.4 (q, J ) 284 Hz), 61.3, 55.6 (q, J )
24 Hz), 34.5, 17.5, 14.5, 13.9 ppm; HRMS (CI) (m/z) calcd for
1
yield: oil; IR 1728 cm-1; H NMR δ 4.29-4.23 (4 H, m), 2.62
(3 H, s), 2.21 (2 H, q, J ) 7 Hz), 1.65 (3 H, s), 1.20 (9 H, s),
0.91 ppm (3 H, t, J ) 7 Hz); 13C NMR δ 239.9, 178.1, 172.5,
66.4, 62.9, 61.8, 32.5, 27.0, 23.5, 20.9, 19.9, 9.0 ppm.
C
C
11H20F3O2 241.1415 (MH)+, found 241.1412. Anal. Calcd for
11H19F3O2: C, 54.99; H, 7.97. Found: C, 54.43; H, 7.65.
Bu t yl 3,3-d im et h yl-2-t r iflu or om et h ylbu t a n oa t e (3c)
r-Meth yl-r-(m eth yl d ith iofor m a te)-γ-bu tyr ola cton e (6)
was prepared from 5 as described above in 90% yield: oil; IR
1769 cm-1 1H NMR δ 4.36-4.29 (2 H, m), 3.21-2.95 (1 H,
;
m), 2.64 (3 H, s), 2.51-2.28 (1 H, m), 1.79 ppm (3 H, s); 13C
NMR δ 235.9, 176.5, 65.5, 62.4, 39.1, 24.9, 20.4 ppm.
1-(Diflu or om eth ylen e eth yl eth er )-1-tr iflu or om eth yl-
cycloh ep ta n e (4a ) was obtained from 2a as described above
in 45% yield: oil; 1H NMR δ 3.90 (2 H, q, J ) 7 Hz), 1.20 ppm
(3 H, t, J ) 7 Hz); 19F NMR δ -72.2 (3 F, t, J ) 11 Hz), -80.5
ppm (2 F, q, J ) 11 Hz); 13C NMR 127.2 (q, J ) 284 Hz), 125.5
(t, J ) 271 Hz), 59.5 (t, J ) 7 Hz), 53.7 (six, J ) 24 Hz), 31.9,
29.4, 24.1, 14.7 ppm; MS (CI) m/z 259 (M - H)+. 4a was
transformed to 3a as described above (6 h of heating in EtOH/
H2O/HCl/HF) in 80% yield.
was prepared from 2c as described above in 75% overall
1
yield: oil; IR 1739 cm-1; H NMR δ 4.17 (2 H, t, J ) 7 Hz),
3.02 (1 H, q, J ) 9 Hz), 1.14 (9 H, s), 0.92 ppm (3 H, t, J ) 7
Hz); 19F NMR δ -61.7 ppm (d, J ) 9 Hz); 13C NMR 167.2,
125.1 (q, J ) 282 Hz), 65.1, 59.3 (q, J ) 25 Hz), 32.8, 30.4,
28.5, 19.0, 13.5 ppm; HRMS (CI) (m/z) calcd for C11H20F3O2
241.1415 (MH)+, found 241.1406. Anal. Calcd for C11H19F3O2:
C, 54.99; H, 7.97. Found: C, 54.71; H, 7.88.
Meth yl 2-n or bor n yl-2-tr iflu or om eth yleth a n oa te (3d )
was prepared from 2d as described above. The two diastereo-
isomers were obtain in 75% overall yield: oil; IR 1746 cm-1
;
1-Eth oxy-1,1-d iflu or o-2-p r op yl-2-tr iflu or om eth ylp en -
ta n e (4b) was obtained from 2b as described above in 55%
yield: oil; 1H NMR δ 3.95 (2 H, q, J ) 7 Hz), 1.28 (3 H, t, J )
1H NMR δ 3.80 and 3.75 (3 H, s), 3.07-2.89 ppm (1 H, m); 19
F
NMR δ -65.4 and -65.5 ppm (d, J ) 8 Hz); 13C NMR (only
the relevant picks) δ 168.1 and 167.8, 125.0 and 124.4 (q, J )
7244 J . Org. Chem., Vol. 69, No. 21, 2004

R-Trifluoromethylation of Carboxylates
282 Hz), 55.5 and 55.2 (q, J ) 24 Hz), 52.3 ppm; HRMS (CI)
(m/z) calcd for C11H16F3O2 237.1102 (MH)+, found 237.1100.
Anal. Calcd for C11H15F3O2: C, 55.93; H, 6.40. Found: C, 55.81;
H, 6.37.
283 Hz), 63.3, 61.7, 52.7 (q, J ) 25 Hz), 38.6, 26.9, 26.1, 16.1,
8.5 ppm; HRMS (CI) (m/z) calcd for C13H22F3O4 299.1470
(MH)+, found 299.1470. Anal. Calcd for C13H21F3O4: C, 52.34;
H, 7.10. Found: C, 51.89; H, 6.86.
r-Meth yl-r-tr iflu or om eth yl-γ-bu tyr olacton e (7) was pre-
pared from 6 as described above in 65% yield (the pentafluoro
derivative was not formed at all): oil; IR 1782 cm-1; 1H NMR
δ 4.41-4.30 (2 H, m), 2.81-2.51 (1 H, m), 2.40-2.17 (1 H, m),
1.52 ppm (3 H, s); 19F NMR δ -75.3 ppm (s); 13C NMR δ 175.0,
127.4 (q, J ) 282 Hz), 66.7, 49.8 (q, J ) 28 Hz), 32.7, 19.3
ppm; HRMS (CI) (m/z) calcd for C6H8F3O2 169.0476 (MH)+,
found 169.0474. Anal. Calcd for C6H7F3O2: C, 42.87; H, 4.20.
Found: C, 42.67; H, 4.39.
(3-Ch lor opr opyl) 2-tr iflu or om eth ylcycloh exan oate (3e)
was prepared from 2e as described above in 80% overall
1
yield: oil; IR 1737 cm-1; H NMR δ 4.36 (2 H, t, J ) 7 Hz),
3.61 ppm (3 H, t, J ) 7 Hz); 19F NMR δ -75.2 ppm (s); 13C
NMR δ 168.6, 125.8 (q, J ) 283 Hz), 62.2, 53.1 (q, J ) 24 Hz),
40.8, 31.2, 27.3, 24.6, 22.2 ppm; HRMS (CI) (m/z) calcd for
C
11H17ClF3O2 273.0869 (MH)+, found 273.0868; Anal. Calcd for
C11H16ClF3O2: C, 48.45; H, 5.91; Cl, 13.00; F, 20.90. Found:
C, 48.31; H, 5.93; Cl, 13.11; F, 20.72.
(2-P iva loyleth yl) 2-m eth yl-2-tr iflu or om eth ylbu ta n oa te
(3f) was prepared from 2f as described above in 65% overall
yield: oil; IR 1744 and 1728 cm-1; 1H NMR δ 4.38-4.21 (4 H,
Ack n ow led gm en t. This work was supported by the
USA-Israel Binational Science Foundation (BSF), J eru-
salem, Israel.
m), 1.36 (3 H, s), 1.19 (9 H, s), 0.92 ppm (3 H, t, J ) 7 Hz); 19
F
NMR δ -73.4 ppm (s); 13C NMR δ 178.1, 169.4, 126.2 (q, J )
J O048864G
J . Org. Chem, Vol. 69, No. 21, 2004 7245