Trifluoromethylation of alkenyl bromides and iodides (including 5-iodouracils) with (CF3)2Hg and Cu (" trifluoromethylcopper")

Article abstract of DOI:10.1021/jo062544a

Bromo- and iodoalkenes undergo trifluoromethylation efficiently in DMA with "CF₃Cu" generated from (CF₃)₂Hg and Cu. Variable stereochemical inversion is observed with substrates having a gem-carbonyl group. Substrates having gem-hydrogen, -alkyl, or -alkenyl groups give products with stereochemical retention.

Full text of DOI:10.1021/jo062544a

procedure3 (and the method of Matsui et al., CF3CO2Na/CuI)6a
gave small quantities of pentafluoroethyl analogues6b that
presumably resulted from difluorocarbene insertion into C-Cu
bonds. Electrochemical generation of CF3Cu produced three
species depending on the nature of the ligand.7
Trifluoromethylation of Alkenyl Bromides and
Iodides (Including 5-Iodouracils) with (CF3)2Hg
and Cu (“Trifluoromethylcopper”)1
Ireneusz Nowak and Morris J. Robins*
A method with a halogen-free environment that does not
generate difluorocarbene is advantageous. Yagupolskii had
reported high-temperature trifluoromethylations of aryl bromides
and iodides with (CF3)2Hg/Cu,8 but such reactions of CF3Cu
with vinyl halides have not been investigated carefully. Coupling
of perfluoroalkylcopper reagents with (E)-1,2-diiodoethene gave
products with retained configurations.9 However, vicinal rather
than gem-disubstituted alkenes had been obtained by analogous
treatment of 1-bromo-1-perfluoroalkylethenes.10 Coupling of
other haloalkenes with CF3Cu has been reported, but the cyclic
and symmetrical alkenes or E/Z mixtures employed did not allow
definitive stereochemical analysis.11 Recently Qing and co-
workers noted that couplings of R-bromo-R,â-unsaturated esters
with FSO2CF2CO2Me/CuI occurred with high E diastereoste-
reoselectivity.12 Sterospecific couplings of R-iodo-R,â-unsatur-
ated esters were claimed, but most were performed with
Z-diastereomer-enriched mixtures.13 We now report couplings
of bromo- and iodoalkenes of defined stereochemistry with CF3-
Cu generated by the halogen-free procedure of Yagupolskii.8
Department of Chemistry and Biochemistry, Brigham Young
UniVersity, ProVo, Utah 84602-5700
morris_robins@byu.edu
ReceiVed December 12, 2006
Bromo- and iodoalkenes undergo trifluoromethylation ef-
ficiently in DMA with “CF3Cu” generated from (CF3)2Hg
and Cu. Variable stereochemical inversion is observed with
substrates having a gem-carbonyl group. Substrates having
gem-hydrogen, -alkyl, or -alkenyl groups give products with
stereochemical retention.
The anticancer/antiviral drug “trifluorothymidine” [2′-deoxy-
5-(trifluoromethyl)uridine] has been used topically for decades.14
Treatment of acetylated 5-iodouracil nucleosides with a large
excess of CF3I/Cu in HMPA had given 5-(trifluoromethyl)uracil
derivatives (38-54%), and solutions obtained by filtration of
CF3I/Cu/HMPA in a glove box under nitrogen gave higher
yields.15 One review quotes a 78% yield using CF3Br/Cu.16
We generated a CF3Cu reagent8 in situ by heating (CF3)2-
Hg17 and “active” copper powder18 at 140 °C for 2 h in N,N-
dimethylacetamide (DMA) (Hg that separates forms an amal-
gam with excess Cu). Solutions of nucleoside derivatives 1
(Scheme 1) in DMA were then added, and heating was
continued at 140 °C for 2 h. The first reaction (compound 1a,
An increasing number of agrochemicals, materials, and
pharmaceutical agents that contain CF3 groups have been
developed. A notable recent example is “fludelone” an anti-
cancer analogue of Epothilone B.2 Therefore, development of
methodology for the efficient and selective synthesis of com-
pounds with trifluoromethyl substituents is a timely goal.
Fluorinated organocopper reagents with reasonable thermal
stabilities are known. “Trifluoromethylcopper” is more important
and interesting than its homologues because of its applications
and reactivity, but it is less thermally stable. Different ap-
proaches have been described for its preparation, but conditions
often are not compatible with medicinal substrates and/or
common laboratory equipment. The elusive nature of “CF3Cu”
represents an additional difficulty.
(6) (a) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981,
1719-1720. (b) Wrobel, J.; Dietrich, A.; Gorham, B. J.; Sestanj, K. J. Org.
Chem. 1990, 55, 2694-2702.
(7) Paratian, J. M.; Labbe´, E.; Sibille, S.; Pe´richon, J. J. Organomet.
Chem. 1995, 489, 137-143.
(8) Kondratenko, N. V.; Vechirko, E. P.; Yagupolskii, L. M. Synthesis
1980, 932-933.
(9) Coe, P. L.; Milner, N. E.; Smith, J. A. J. Chem. Soc., Perkin Trans.
1 1975, 654-656.
Burton reported the presence of three copper species in DMF
solution,3 which were suggested to include CF3CuL (L ) metal
halide), CdI+[(CF3)2Cu]-, and CdI+[(CF3)4Cu]- (a Cu3+ oxida-
tion product).4 The existence of a copper difluorocarbenoid
(F2CdCuF) was postulated more recently.5 A low-temperature
(10) Santini, G.; Le Blanc, M.; Riess, J. G. Tetrahedron 1973, 29, 2411-
2414.
(11) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I. Tetrahedron Lett. 1979,
42, 4071-4072.
(12) (a) Zhang, X.; Qing, F.-L.; Yu, Y. J. Org. Chem. 2000, 65, 7075-
7082. (b) Qing, F.-L.; Zhang, X. Tetrahedron Lett. 2001, 42, 5929-5931.
(13) Zhang, X.; Quing, F.-L.; Peng, Y. J. Fluorine Chem. 2001, 108,
79-82.
(14) Heidelberger, C.; King, D. H. Pharmacol. Ther. 1979, 6, 427-442.
(15) Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano, M.; Kumadaki,
I. J. Chem. Soc., Perkin Trans. 1 1980, 2755-2761.
(16) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555-
6666.
(17) Knunyants, I. L; Komissarov, Y. F.; Dyatkin, B. L.; Lansteva, L.
T. IzV. Acad. Nauk SSSR, Ser. Khim. 1973, 4, 943-944.
(18) Brewster, R. Q.; Groening, T. Organic Syntheses; Blatt, A. H., Ed.;
Wiley: New York, 1943; Collect. Vol. II, p 446.
(1) Nucleic Acid Related Compounds. 142. Paper 141: Nowak, I.;
Cannon, J. F.; Robins, M. J. J. Org. Chem. 2007, 72, 532-537.
(2) (a) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.; Chou,
T.-C.; Dong, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 10913-
10922. (b) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329-
8351.
(3) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1985, 108, 832-
834.
(4) Willert-Porada, M.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc.,
Chem. Commun. 1989, 1633-1634.
(5) Yang, Z.-Y.; Burton, D. J. J. Fluorine Chem. 2000, 102, 89-103.
10.1021/jo062544a CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/03/2007
2678
J. Org. Chem. 2007, 72, 2678-2681

TABLE 2. Trifluoromethylation of 3 to Give 4 and/or 5a
SCHEME 1. Trifluoromethylation of 5-Iodouracil
Nucleosides 1
TABLE 1. Yields of Trifluoromethylation Reactions of 1a
entryb
R
R′
X
yieldc
1 (1a)
2 (1b)
3 (1c)
4 (1d)
Ph
Ph
Ph
MePh
H
Me
Bz
PMB
PhCO2
PhCO2
PhCO2
H
94d
94
49e
90f
a See Supporting Information for the general procedure. b Starting
material in parentheses. c Percent of 2 isolated relative to starting unprotected
nucleoside. d 2′,3′,5′-Tri-O-benzoyluridine (product of C-I reduction).
e Product 2c′ had R′ ) H (Bz group underwent hydrolysis). f Reaction
temperature 110 °C.
SCHEME 2. Trifluoromethylation of Haloolefins 3
entry 1, Table 1) resulted in reduction of the C-I bond to give
2′,3′,5′-tri-O-benzoyluridine (94%). In contrast, the 3-methyl
derivative 1b underwent trifluoromethylation at C5 to give 2b
(94%) (entry 2). The 3-benzoyl derivative 1c underwent loss
of the N-benzoyl protection and gave 49% of the trifluorom-
ethylated product 2c′ (entry 3). Protection of 2′-deoxy-5-iodo-
3′,5′-di-O-(4-methylbenzoyl)uridine at N3 with 4-methoxyben-
zyl chloride gave PMB-derivative 1d, which underwent
trifluoromethylation at 110 °C to give 2d (90%, entry 4). The
lower temperature caused less thermal cleavage of the 2′-
deoxyglycosyl linkage. Copper-assisted nucleophilic aromatic
substitution has been the favored mechanism for couplings of
[CF3CuI]- with haloaromatics,19 but CF3Cu generated in a
halogen-free process might react differently.
We also subjected a number of linear haloalkenes to our
standard (CF3)2Hg/Cu/DMA conditions. Aldehydes 3a and 3b
and ketone 3c provided the E diastereomers 4 as major products
(Scheme 2) (Table 2, entries 1-6). This is in marked contrast
with the stereospecific process reported (without definitive
characterization of products)7 for the reaction of electrochemi-
cally generated CF3Cu and 3a. The E/Z selectivity with our
trifluoromethylation reactions of R-bromoesters 3d-3f varied
with the nature of the aromatic ring and the ester group (entries
5-12). Other vinyl halides we examined (i.e., without a carbonyl
group geminal to the halide) underwent stereospecific coupling
with retention.
a See Supporting Information for the general procedure. b E/Z ratios were
determined by 19F NMR. c Isolated yields. d Temperature was 100 °C. e A
mixture of E/Z (2:1) isomers was used. f Trace contamination with 3g(Z)
occurred during the Wittig reaction.
add to the confusion,20 and the E configuration assigned to 3b
also is erroneous. The only isomer that appears to have been
isolated is 3b(Z).21 Only 3f(E) of the other carbonyl-containing
starting materials 3 was converted into its Z isomer at 140 °C
(∼30 h, neat or in DMA). Starting material stereochemistry was
A critical observation was that the neat E isomers of 3a and
3c were completely converted into their Z diastereomers at
140 °C within 2 h. Isomer 3a(E) was stereochemically labile
even in the dark at ambient temperature and was purified at
low temperature and used immediately or stored in solution.
Incorrect assignments of E stereochemistry to 3a(Z) and 3c(Z)
(20) (a) Marsura, A.; Luu-Duc, C.; Gellon, G. Synthesis 1985, 537-
541. (b) Suzuki, H.; Aihara, M.; Yamamoto, H.; Takamoto, Y.; Ogawa, T.
Synthesis 1988, 236-238. (c) Berteina, S.; De Mesmaeker, A.; Wendeborn,
S. Synlett 1999, 1121-1123. (d) Murphy, J. A.; Scott, K. A.; Sinclair, R.
S.; Martin, C. G.; Kennedy, A. L.; Lewis, N. J. Chem. Soc., Perkin Trans.
1 2000, 2395-2408. (e) Bour, C.; Suffert, J. Eur. J. Org. Chem. 2006,
1390-1395.
(19) Carr, G. E.; Chambers, R. D.; Holmes, T. F. J. Chem. Soc., Perkin
Trans. 1 1988, 921-926.
(21) Coulomb, F.; Roumenstat, M.-L.; Gore, J. Bull. Soc. Chim. Fr. 1973,
3352-3359.
J. Org. Chem, Vol. 72, No. 7, 2007 2679

SCHEME 3. Possible Pathways for Trifluoromethylation of
SCHEME 4. Possible Isomerization Pathways for Vinyl
Vinyl Halides 3 Containing a gem-Carbonyl Group
Halides 3 Containing a gem-Carbonyl Group
with electrophiles via mechanisms involving copper allenoates.26
Esters 3d gave products with e5% inversion (entries 7 and
8). The electron-withdrawing CF3 ligand on copper and/or the
elevated temperature might contribute to a small loss of
stereochemical retention. Increased electron demand by the aryl
group influenced the stereoselectivity with 3e(Z) (entry 9) but
had no effect with 3e(E) (entry 10). Our X-ray crystal structure
of 3g(2E/4Z) shows a 39° twist between the planes of the phenyl
ring and the CdC double bond (presumably resulting from steric
interactions between bromine and an ortho-hydrogen on the
benzene ring). Larger deviations from coplanarity might result
from steric effects in E diastereomers of 3d and 3e with proximal
ester and phenyl groups on the double bond. Such distortions
of the π-system might limit transmission of electronic effects
from the p-nitro group to the reaction center in 3e(E). Increased
electron demand by a proximal trifluoroethoxy group in 3f(Z)
resulted in predominant inversion, and the same E/Z ratio (entry
11) was obtained with a 3f(E)-rich mixture of isomers (entry
12). In contrast, no inversion was observed with 3g, the
vinylogous analogue of 3d, with the carbonyl group farther
separated from the reaction center (entries 13 and 14).
Interactions of CF3Cu species with ortho-substituent groups
(NO2, CHO, COR, CO2R) had been invoked to rationalize
unexpectedly high substitution yields with some chloroaromatic
compounds.27 Treatment of (Z)-(2-bromo-2-nitrovinyl)benzene
by our procedure gave (E)-(2-nitrovinyl)benzene as the major
product. Ligand coupling of a transient organometallic inter-
mediate might have failed, and its protonolysis during aqueous
workup would generate the debrominated compound.
Stereospecific cross-coupling reactions of 3a(Z) and other
R-bromo-R,â-unsaturated carbonyl compounds (catalyzed by
metals including copper) have been reported to occur with
retention of configuration, even at elevated temperatures.28
Inversion observed in some of our examples might result from
equilibration with copper allenoates, with formation promoted
by the electron-withdrawing CF3 ligand. Related equilibration
via allenyl intermediates 8 might explain the noted isomerization
of some vinyl bromides 3 that contain a gem-carbonyl group
(Scheme 4). Such “halotautomerization” of bromide between
assigned from vinyl proton chemical shifts (3c-3g).13 Aromatic
proton signals for the Z isomers also have more complex
patterns,22 and an X-ray crystal structure of 3g(2E,4Z) was
determined (Supporting Information). Configurations of the
products were assigned from 19F NMR chemical shifts (CF3,
65 ( 2 ppm for the E isomers 423 and 58 ( 2 ppm for the Z
isomers 5).
Because most starting materials were thermally stable under
our conditions, different intermediates must be involved with
formation of products 4 and 5 (Scheme 3). CF3Cu might undergo
insertion into the C-Br(I) bond to give intermediates such as
6. Substrates 3h-3j without a gem-carbonyl group might
undergo direct ligand coupling to give trifluoromethyl products
with retention of configuration. Aldehydes 3a(Z) and 3b(Z),
ketone 3c(Z), and esters 3d-3f might undergo initial insertion
followed by dissociation/combination equilibria involving cop-
per allenoates 7(R/S). Relief of steric strain between the arene
and ligated copper in 6(Z) would favor equilibration to 6(E)
and ultimately the thermodynamically stable E isomer 4. It is
noteworthy that a higher E-isomer product selectivity (more
inversion) was observed at a lower temperature (100 °C, entry
3) for the more reactive iodide 3b. The larger steric bulk of the
iodine ligand might also favor formation of 6(E). Structures
analogous to 6 and 7 were recently proposed as intermediates
in a mechanism for copper-catalyzed hydrostannation of acti-
vated alkynes, which gave exclusive syn-stannation of esters
but inversion of stereochemistry for ketones.24 Marino had
previously suggested that (R-carbethoxyvinyl)cuprates25 react
(26) Marino, J. P.; Linderman, R. J. J. Org. Chem. 1983, 48, 4621-
4628.
(27) (a) Clark, J. H.; McClinton, M. A.; Blade, R. J. J. Chem. Soc. Chem.
Commun. 1988, 638-639. (b) Clark, J. H.; Denness, J. E.; McClinton, M.
A.; Wynd, A. J. J. Fluorine Chem. 1990, 50, 411-426.
(28) (a) Zapata, A. J.; Ru´ız, J. J. Organomet. Chem. 1994, 479, C6-
C8. (b) Urdaneta, N.; Ru´ız, J.; Zapata, A. J. J. Organomet. Chem. 1994,
464, C33-C34. (c) Dai, W.-M.; Wu, A.; Hamaguchi, W. Tetrahedron Lett.
2001, 42, 4211-4214. (d) Lautens, M.; Maddess, M. L.; Sauer, E. L.;
Ouellet, S. G. Org. Lett. 2002, 4, 83-86. (e) Banwell, M. G.; Kelly, B. D.;
Kokas, O. J.; Lupton, D. W. Org. Lett. 2003, 5, 2497-2500. (f) Sahli, S.;
Stump, B.; Welti, T.; Schweizer, W. B.; Diederich, F.; Blum-Kaelin, D.;
Aebi, J. D.; Bo¨hm, H.-J. HelV. Chim. Acta 2005, 88, 707-730. (g) Molander,
G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950-3956.
(22) Agoff, J. M.; Cabaleiro, M. C.; Podesta, J. C. Chem. Ind. 1974,
305-306 and references therein.
(23) Furuta, S.; Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc. Jpn. 1999,
72, 805-819.
(24) Leung, L. T.; Leung, S. K.; Chiu, P. Org. Lett. 2005, 7, 5249-
5252.
(25) Marino, J. P.; Floyd, D. M. J. Am. Chem. Soc. 1974, 96, 7138-
7140; These authors reported generation of (R-carbethoxyvinyl)cuprates
from R-bromoacrylate and organocopper reagents.
2680 J. Org. Chem., Vol. 72, No. 7, 2007

214 ([M +] 65%), 213 (100%); HRMS (C11H9F3O) calcd 214.0605,
found 214.0607.
the R-vinyl carbon and carbonyl oxygen would produce enan-
tiomers 8 of equal energy. It is noteworthy that the iodo analogue
3b(E) could not be isolated by the same procedure used for
3a(E), and carbon-iodine/oxygen-iodine bonds are more
polarizable than those with bromine.
(Z)-4-Phenyl-3-(trifluoromethyl)but-3-en-2-one (5c). 1H NMR
δ 2.48 (s, 3H), 7.41 (m, 5H), 7.88 (s, 1H); 19F NMR δ 57.4 (s,
3F); 13C NMR δ 27.8, 122.1 (q, J ) 274.2 Hz), 128.3, 129.4, 130.1
(q, J ) 28.9 Hz), 130.2, 132.4, 146.8 (q, J ) 3.2 Hz), 194.7; EI-
MS m/z 214 ([M +] 40%), 213 (100%); HRMS (C11H9F3O) calcd
214.0605, found 214.0589.
In conclusion, we have employed (CF3)2Hg/Cu/DMA for
trifluoromethylation of bromo- and iodoalkenes (including
protected 5-iodouracil nucleosides). Higher temperatures are
required than for some methods that use CF3Cu generated from
CuX (X ) Br, I), but a variety of vinyl halides give high yields
in DMA at 140 °C. Reactions with E and Z isomers of several
haloalkenes 3 showed that gem-carbonyl groups can alter cross-
coupling stereochemistry in some cases. Insertion of copper
species into carbon-halogen bonds followed by equilibration
involving copper allenoates 7 might rationalize formation of
products with inverted configurations. Our (CF3)2Hg/Cu/DMA
methodology does not require stainless steel reactors, glove box
techniques, syringe-pump reagent additions, or lengthy reaction
times, and no CF2 insertion byproducts have been observed.
NOTE: caution must be exercised when handling volatile and
toxic organomercury compounds.
Methyl (E)-3-Phenyl-2-(trifluoromethyl)prop-2-enoate12a (4d).
1H NMR δ 3.90 (s, 3H), 7.35-7.42 (m, 6H); 19F NMR δ 64.3 (s,
3F); 13C NMR δ 52.5, 122.1 (q, J ) 273.1 Hz), 123.1 (q, J ) 31.5
Hz), 128.6, 129.1, 130.4, 132.1, 140.4 (q, J ) 5.6 Hz), 163.8; EI-
MS m/z 230 ([M +] 100%); HRMS (C11H9F3O2) calcd 230.0554,
found 230.0562.
Methyl (Z)-3-Phenyl-2-(trifluoromethyl)prop-2-enoate12a (5d).
1H NMR δ 3.77 (s, 3H), 7.37-7.43 (m, 5H), 8.11 (s, 1H); 19F NMR
δ 58.5 (s, 3F); 13C NMR δ 52.4, 121.8 (q, J ) 274.1 Hz), 122.1
(q, J ) 32.0 Hz), 128.1, 129.1, 129.9, 132.3, 148.3, 163.5; EI-MS
m/z 230 ([M +] 100%); HRMS (C11H9F3O2) calcd 230.0554, found
230.0554.
Ethyl (E)-3-(4-Nitrophenyl)-2-(trifluoromethyl)prop-2-enoate12a
1
(4e). H NMR δ 1.21 (t, J ) 7.3 Hz, 3H), 4.23 (q, J ) 7.3 Hz,
2H), 7.51 (s, 1H), 7.55 and 8.26 (2 × d, J ) 8.3 Hz, 2 × 2H); 19
F
NMR δ 64.8 (s, 3F); 13C NMR δ 13.4, 62.2, 121.5 (q, J ) 273.7
Hz), 123.4, 126.6 (q, J ) 31.6 Hz), 129.6, 138.4 (q, J ) 5.6 Hz),
138.8, 148.2, 162.0; EI-MS m/z 289 ([M +] 90%), 244 (100%);
HRMS (C12H10F3NO4) calcd 289.0562, found 289.0569.
Experimental Section29
General Procedure for Trifluoromethylation of Alkenyl
Bromides and Iodides. Freshly generated copper powder18
(341 mg, 5.33 mmol) was dried at 140 °C for 1 h under vacuum in
a 30-mL flask equipped with a Teflon valve. After cooling to
ambient temperature, (CF3)2Hg8,17 (452 mg, 1.33 mmol) and dried
N,N-dimethylacetamide (DMA; 2.0 mL) were added under a
nitrogen atmosphere, and the mixture was stirred at 140 °C for 2
h. [CAUTION: bis(trifluoromethyl)mercury is volatile and toxic
and should be used only by experienced researchers with appropriate
safety precautions.] A solution of the vinyl iodide or bromide (1.33
mmol) in DMA was then added to the dark-green suspension, and
stirring was continued for 2 h at 140 °C. The cooled supernatant
was transferred into a vigorously stirred solution of brine (50 mL),
and the mixture was extracted (EtOAc; 3 × 20 mL). Volatiles were
evaporated from the organic layer, and the residue was chromato-
graphed to give the purified product.
Ethyl (Z)-3-(4-Nitrophenyl)-2-(trifluoromethyl)prop-2-enoate12a
1
(5e). H NMR δ 1.40 (t, J ) 7.3 Hz, 3H), 4.39 (q, J ) 7.3 Hz,
2H), 7.53 and 8.27 (2 × d, J ) 8.3 Hz, 2 × 2H), 8.11 (s, 1H); 19
F
NMR δ 58.4 (s, 3F); 13C NMR δ 13.8, 62.3, 121.3 (q, J )
274.7 Hz), 123.3, 125.6 (q, J ) 32.0 Hz), 129.4, 139.1, 145.1 (q,
J ) 2.3 Hz), 148.1, 162.2; EI-MS m/z 289 ([M +] 90%), 244
(100%); HRMS (C12H10F3NO4) calcd 289.0562, found 289.0574.
2,2,2-Trifluoroethyl (E)-3-(4-Nitrophenyl)-2-(trifluorometh-
yl)prop-2-enoate (4f). 1H NMR δ 4.55 (q, J ) 8.1 Hz, 2H), 7.35-
7.55 (m, 2H), 7.73 (s, 1H), 8.26-8.28 (m, 2H); 19F NMR δ 64.7
(s, 3F), 74.0 (t, J ) 8.5 Hz, 3F); 13C NMR δ 60.9 (q, J ) 37.4
Hz), 121.3 (q, J ) 273.9 Hz), 122.3 (q, J ) 276.9 Hz), 123.6,
124.7 (q, J ) 32.3 Hz), 129.5, 138.4, 142.0 (q, J ) 6.1 Hz), 148.5,
160.4; EI-MS m/z 343 ([M + Na+] 100%); HRMS (C12H7F6NO4)
calcd 343.0279, found 343.0293.
2,2,2-Trifluoroethyl (Z)-3-(4-Nitrophenyl)-2-(trifluoromethyl)-
2′-Deoxy-3-(4-methoxybenzyl)-3′,5′-di-O-(4-methylbenzoyl)-
5-(trifluoromethyl)uridine (2d). H NMR δ 2.23 (ddd, J ) 6.8,
1
1
prop-2-enoate (5f). H NMR δ 4.70 (q, J ) 8.1 Hz, 2H), 7.55-
7.57 (m, 2H), 8.21 (s, 1H), 8.29-8.31 (m, 2H); 19F NMR δ 58.6
(s, 3F), 74.2 (t, J ) 8.5 Hz, 3F); EI-MS m/z 343 ([M + Na+] 100%);
13C NMR δ 61.5 (q, J ) 32.8 Hz), 120.9 (q, J ) 275.2 Hz), 121.7
(q, J ) 277.2 Hz), 123.6, 124.2 (q, J ) 32.3 Hz), 129.7, 138.3,
147.4, 148.5, 160.8; HRMS (C12H7F6NO4) calcd 343.0279, found
343.0280.
7.8, 14.2 Hz, 1H), 2.39 (s, 3H), 2.44 (s, 3H), 2.87 (ddd, J ) 1.0,
5.4, 14.2 Hz, 1H), 3.78 (s, 3H), 4.59-4.61 (m, 1H), 4.67-4.75
(m, 2H), 5.00 (d, J ) 13.7 Hz, 1H), 5.06 (d, J ) 13.7 Hz, 1H),
5.59 (d, J ) 6.3 Hz, 1H), 6.33 (dd, J ) 5.4, 8.3 Hz, 1H), 6.82-
7.94 (m, 12H), 8.05 (s, 1H); 19F NMR δ 64.3 (s, 3F); 13C NMR δ
21.3, 21.4, 38.8, 43.7, 54.8, 63.7, 68.7, 74.7, 83.0, 87.0, 104.4 (q,
J ) 32.8 Hz), 113.5, 121.7 (q, J ) 270.2 Hz), 126.0, 127.8, 129.0-
130.8 (ovlp), 137.8 (q, J ) 5.0 Hz), 144.2, 144.3, 149.5, 157.6,
159.1, 165.6, 165.7; FAB-MS m/z 675 ([M + Na+] 100%); HRMS
(C34H31F3N2O8Na) calcd 675.1924, found 675.1923.
Acknowledgment. We gratefully acknowledge NIH grant
GM029332, pharmaceutical company unrestricted gift funds
(M.J.R.), and Brigham Young University for support of this
research and Professor Steven R. Herron for determining the
X-ray crystal structure of 3g(2E,4Z).
(E)-4-Phenyl-3-(trifluoromethyl)but-3-en-2-one (4c). 1H NMR
δ 2.21 (s, 3H), 7.30-7.44 (m, 6H); 19F NMR δ 63.9 (s, 3F); 13C
NMR δ 30.7, 122.1 (q, J ) 274.2 Hz), 128.7, 129.0, 130.3, 131.3
(q, J ) 29.1 Hz), 132.1, 137.0 (q, J ) 6.1 Hz), 198.8; EI-MS m/z
Supporting Information Available: Experimental procedures,
data, X-ray crystal structure of 3g(2E,4Z) in CIF format, and NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) See Supporting Information for general experimental details,
preparation of starting materials, and other trifluoromethyl compounds, data,
and spectra.
JO062544A
J. Org. Chem, Vol. 72, No. 7, 2007 2681