The stereospecific trifluoromethylation of α-iodo-α,β-unsaturated esters: A novel synthesis of (Z)-α-trifluoromethyl-α,β-unsaturated esters

Article abstract of DOI:10.1016/S0022-1139(00)00400-0

This paper describes simple and successful methods for the preparation of α-iodo-α,β-unsaturated esters. The trifluoromethylation of (Z)-α-iodo-α,β-unsaturated esters stereo-selectively provides (Z)-α-trifluoromethyl-α,β-unsaturated esters.

Full text of DOI:10.1016/S0022-1139(00)00400-0

Journal of Fluorine Chemistry 108 (2001) 79±82
The stereospeci®c tri¯uoromethylation of a-iodo-a,b-unsaturated esters:
a novel synthesis of (Z)-a-tri¯uoromethyl-a,b-unsaturated esters
Xingguo Zhangb, Feng-Ling Qinga,*, Yiyuan Pengb
aLaboratory of Organo¯uorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
bDepartment of Chemistry, Jiangxi Normal University, Jiangxi 330027, PR China
Received 27 June 2000; accepted 27 November 2000
Abstract
This paper describes simple and successful methods for the preparation of a-iodo-a,b-unsaturated esters. The tri¯uoromethylation of (Z)-
a-iodo-a,b-unsaturated esters stereo-selectively provides (Z)-a-tri¯uoromethyl-a,b-unsaturated esters. # 2001 Elsevier Science B.V. All
rights reserved.
Keywords: Tri¯uoromethylation; a,b-Unsaturated esters
1. Introduction
suitable for preparation of a-iodo-a,b-unsaturated esters,
because it is dif®cult to obtain the iodoylide and the a-iodo-
a,b-unsaturated ester was easily dehydroiodogenated under
basic conditions. Recently, Kayser [7] reported a one-pot
procedure preparation of a a-iodo-a,b-unsaturated ester
through the reaction of carboethoxymethylenetriphenylpho-
sphorane, potassium carbonate, N-iodosuccinimide and
aldehyde. We were delighted to observe that compounds
1 could be obtained in high yields by a modi®ed Chenault's
procedure [6]. Treatment of (ethoxycarbonyliodomethyl)-
triphenylphosphonium iodide 2 with aldehyde in the pre-
sence of 1.0 equivalent of potassium carbonate at 408C
provided the (Z)-a-iodo-a,b-unsaturated ester 1 as the major
product (Scheme 1 and Table 1). Compound 2 was obtained
from commercial (ethoxycarbonylmethyl)triphenylpho-
sphonium bromide 3 by direct iodination in methanol in
the presence of potassium carbonate (Scheme 1). The Z- and
E-isomers of compounds 1c±e can be separated by column
chromatography, but other Z- and E-isomers of a-iodo-a,b-
unsaturated esters could not be separated by column chro-
matography and the mixtures were used directly in the next
tri¯uoromethylation reaction.
It is well known that the tri¯uoromethyl group has a great
effect on biological activity and often confers signi®cant
changes in chemical and physical properties. Therefore,
methods for the synthesis of tri¯uoromethylated compounds
have been attracting increasing attention [1,2]. We recently
described a new method for the preparation of a-tri¯uor-
omethyl-a,b-unsaturated esters through the tri¯uoromethy-
lation of a-bromo-a,b-unsaturated esters [3], but the double
bond was isomerized under the tri¯uoromethylation condi-
tions. Herein, we report the synthesis of (Z)-a-tri¯uoro-
methyl-a,b-unsaturated esters via the stereospeci®c
tri¯uoromethylation of a-iodo-a,b-unsaturated esters.
2. Results and discussions
2.1. Preparation of a-iodo-a,b-unsaturated esters 1
a-Halo-a,b-unsaturated esters were usually prepared by
the Wittig reaction of aldehydes with haloylides [4,5] and
the condensation of aldehydes with halophosphonates in the
presence of base [6]. However, these methods were not
2.2. Synthesis of a-trifluoromethyl-a,b-unsaturated esters 4
The synthesis of a-tri¯uoromethyl-a,b-unsaturated esters
4 was based on the tri¯uoromethylation of a-iodo-a,b-
unsaturated esters 1 (Scheme 2). Treatment of a 88:12
mixture of Z- and E-1a with FSO2CF2CO2Me and CuI in
* Corresponding author. Tel.: ‡86-21-64163300;
fax: ‡86-21-64166128.
E-mail address: flq@pub.sioc.ac.cn (F.-L. Qing).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 4 0 0 - 0

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X. Zhang et al. / Journal of Fluorine Chemistry 108 (2001) 79±82
Scheme 1.
DMF/HMPA at 708C gave a 88:12 mixture of Z- and E-4a in
89%. Various iodoalkenes 1 were used for the preparation of
a-tri¯uoromethyl-a,b-unsaturated esters 4 under the same
reaction conditions (Table 1). The con®guration of double
bond in 4 was determined by the chemical shifts of the
alkenyl proton. The alkenyl proton in the Z isomer appeared
at lower ®eld than in the E isomer. The following points
Scheme 2.
Table 1
Synthesis of a-trifluoromethyl-a,b-unsaturated esters 4 via trifluoromethylation of a-iodo-a,b-unsaturated esters 1
Entry
Aldehyde
Intermediate 1 (yield (%)a, Z:Eb)
Product 4 (yield (%)c, Z:Ed)
1
2
3
e
4
5
6
7
a Yields based on aldehydes.
b This ratio was determined by 1H NMR.
c Yields based on 1.
d The ratio was determined by 19F NMR.
e This compound was prepared from the Z-1c.

X. Zhang et al. / Journal of Fluorine Chemistry 108 (2001) 79±82
81
‡
‡
derived from the tri¯uoromethylation are noteworthy: (1)
slow addition via syringe and an excess of FSO2CF2CO2Me
(2.0 eq) were necessary for the total conversion of a-iodo-
a,b-unsaturated esters 1; (2) the con®guration of double
bonds in this reaction remained intact. Only Z-4d
was formed from Z-1d (entry 4). When a mixture of
Z- and E-isomers of compound 1 was used for the tri¯uor-
omethylation, the Z:E ratio of compound 4 did not
change; (3) the carbon-iodide bond was more active than
a carbon-bromine bond, this difference of reactivity has
made the chemoselective tri¯uoromethylation possible with
1g (entry 7).
7:1 Hz, 3H); m/z (EI) 348 (M ‡ 1, 56.42), 347 (M ,
63.53), 302 (20.44), 220 (70.99), 192 (100.00).
(Z)-1d: Oil. IR (thin ®lm): 2982, 1708, 1613, 1258, 1226,
1149 cm 1; dH (CDCl3, 300 MHz) 7.80 (d, J ˆ 9:2 Hz, 1H),
7.68 (m, 2H), 7.40 (m, 3H), 7.15 (d, 2H), 4.35 (q,
J ˆ 7:1 Hz, 2H), 1.38 (t, J ˆ 7:1 Hz, 3H); m/z (EI) 329
‡
‡
(M ‡ 1, 13.35), 328 (M , 40.10), 202 (14.10), 173 (9.52),
129 (100.00), 127 (59.95).
1e: Oil. IR (thin ®lm): 2987, 1720, 1372, 1241, 1062,
1031 cm 1; dH (CDCl3, 300 MHz) 7.38 (d, J ˆ 8:1 Hz,
0.89H), 7.08 (d, J ˆ 8:1 Hz, 0.11H), 4.85 (m, 1H), 4.28
(m, 3H), 3.68 (m, 1H), 1.45±1.25 (m, 9H); m/z (EI) 327
‡
(M ‡ 1, 20.64), 311 (67.20), 269 (100.00), 127 (4.51).
1f: Oil. IR (thin ®lm): 2984, 1722, 1429, 1305, 1189,
1035 cm 1; dH (CDCl3, 300 MHz) 7.78 (d, J ˆ 16:4 Hz,
1H), 7.26 (m, 1H), 7.15 (m, 1H), 6.58 (d, J ˆ 16:4 Hz, 1H),
4.32 (q, J ˆ 7:1 Hz, 1.92H), 4.08 (q, J ˆ 7:1 Hz, 0.08H),
1.38 (t, J ˆ 7:1 Hz, 2.88H), 1.13 (t, J ˆ 7:1 Hz, 0.12H); m/z
3. Experimental
1H NMR spectra were recorded on 300 MHz spectro-
meter with Me4Si as internal standard. 19F NMR spectra
were obtained on a 56.4 MHz spectrometer using tri¯uor-
oacetic acid as external standard, down®eld shifts being
designated as negative. All chemical shifts (d) are expressed
in parts per million, coupling constants (J) are given in
Hertz. Mass spectra were obtained using EI ionization at
70 eV. IR spectra were recorded on a Shimadzu IR-440
spectrometer.
‡
‡
(EI) 373 (M ‡ 2; 2:01), 371 (M , 3.13), 244 (5.54), 181
(100.00), 127 (14.36).
1g: Oil. IR (thin ®lm): 2979, 1711, 1640, 1312, 1179,
1035 cm 1; dH (CDCl3, 300 MHz) 7.70 (s, 1H), 7.50 (m,
2H), 7.25 (m, 1H), 6.48 (d, J ˆ 15:7 Hz, 1H), 4.35 (q,
J ˆ 7:1 Hz, 0.34H), 4.28 (q, J ˆ 7:1 Hz 1.66H), 1.35 (t,
‡
J ˆ 7:1 Hz, 3H); m/z (EI) 382/380 (M , 24.44), 337/335
(8.63), 211 (92.11), 209 (100.00), 127 (3.84).
3.1. General procedure for synthesis of iodo esters 1
3.2. General procedure for the synthesis of esters 4
A suspension of (ethoxycarbonyliodomethyl)triphenyl-
phosphonium iodide (1.21 g, 2 mmol) and aldehyde
(2 mmol) in 20 ml of methanol was stirred at 408C. Potas-
sium carbonate (138 mg, 1 mmol) was added in three por-
tions to the suspension. The color of the mixture turned to
dark brown and the suspension dissolved completely. The
reaction mixture was stirred at 408C for 8 h. After removal
of methanol, the residue was puri®ed by column chromato-
graphy on silica gel and elution with 25:1 hexane ethyl
acetate to gave iodo ester 1.
A solution of FSO2CF2CO2CH3 (0.5 ml, 4 mmol) in DMF
(10 ml) was added dropwise over a period of 3 h to a mixture
of ester 1(2 mmol), CuI(96 mg, 0.5 mmol) and HMPA(1 ml)
in DMF(15 ml) at 658C. The reaction was stirred at 658C for
10 h before being cooled to room temperature. Saturated
aqueous NH4Cl (30 ml) was added and the mixture was
extracted with ether. The extracts were washed with brine
and dried over Na2SO4. The solvent was removed in vacuo.
Puri®cation of the residue by column chromatography on
silica gel and elution with 25:1 hexane ethyl acetate gave
compounds 4.
1a: Oil. IR (thin ®lm): 2981, 1712, 1606, 1511, 1254,
1176 cm 1; dH (CDCl3, 300 MHz) 8.25 (s, 0.88H), 8.04 (d,
J ˆ 8:1 Hz, 0.24H), 7.88 (d, J ˆ 8:1 Hz, 1.76H), 6.95 (d,
J ˆ 8:1 Hz, 2H), 6.94 (s, 0.12H), 4.35 (q, J ˆ 7:1 Hz, 2H),
4a: Oil. IR (thin ®lm): 2982, 1726, 1606, 1514, 1265,
1178 cm 1; dH (CDCl3, 300 MHz) 7.99 (s, 0.88H), 7.41 (d,
J ˆ 9:5 Hz, 2H), 7.25 (s, 0.12H), 6.91 (m, 2H), 4.34 (m,
2H), 3.83 (s, 3H), 1.37 (t, J ˆ 7:1 Hz, 3H); dF (CDCl3,
56.4 MHz) 20.6 (s, 2.64F), 15.2 (s, 0.36F); m/z (EI) 275
‡
3.88 (s, 3H), 1.40 (t, J ˆ 7:1 Hz, 3H); m/z (EI) 333 (M ‡ 1,
‡
47.00), 332 (M , 100.00), 287 (46.44), 205 (40.78), 127
(1.79).
‡
‡
1b: Oil. IR (thin ®lm): 2982, 1717, 1599, 1233,
1035 cm 1; dH (CDCl3, 300 MHz) 8.28 (s, 0.81H), 7.80
(m, 2H), 7.45 (s, 0.19H), 7.32 (m, 1H), 4.35 (q, J ˆ 7:1 Hz,
1.62H), 4.20 (q, J ˆ 7:1 Hz, 0.38H), 1.40 (t, J ˆ 7:1 Hz,
(M ‡ 1, 18.44), 274 (M , 100.00), 205 (8.41), 69 (12.45);
Anal. Calc. for C13H13F3O3: C, 56.94; H, 4.78. Found: C,
56.88; H, 4.74%.
4b: Oil. IR (thin ®lm): 2988, 1733, 1641, 1400,
1279 cm 1; dH (CDCl3, 300 MHz) 8.05 (s, 0.88H), 7.36
(s, 0.14H), 7.35 (s, 5H), 4.26 (q, J ˆ 7:1 Hz, 2H), 1.30 (t,
‡
2.43H), 1.20 (t, J ˆ 7:1 Hz, 0.57H); m/z (EI) 303 (M ‡ 1,
‡
71.31), 302 (M , 100.00), 257 (44.85), 175 (90.98), 127
(3.77).
J ˆ 7:1 Hz, 3H); dF (CDCl3, 56.4 MHz)
19.7 (s,
‡
1c: Solid. IR (KBr): 2987, 1716, 1610, 1520, 1347,
1251 cm 1; dH (CDCl3, 300 MHz) 8.28 (m, 2.52H), 7.85
(d, J ˆ 8:9 Hz, 1.68H), 7.72 (m, 0.48H), 6.58 (d, J ˆ
8:9 Hz, 0.32H), 4.38 (q, J ˆ 7:1 Hz, 2H), 1.42 (t, J ˆ
2.58F), 13.7 (s, 0.42F); m/z (EI) 245 (M ‡ 1, 11.91),
‡
244 (M , 65.47), 199 (100.00), 175 (3.25), 69 (4.95).
4c: Solid. IR (KBr): 2992, 1722, 1639, 1521, 1349,
1282 cm 1; dH (CDCl3, 300 MHz) 8.27 (d, J ˆ 9:0 Hz,

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X. Zhang et al. / Journal of Fluorine Chemistry 108 (2001) 79±82
2H), 8.10 (s, 0.84H), 7.54 (d, J ˆ 9:0 Hz, 2H), 7.53 (s,
0.16H), 4.25 (q, J ˆ 7:0 Hz, 2H), 1.38 (t, J ˆ 7:0 Hz, 3H);
dF (CDCl3, 56.4 MHz) 19.0 (s, 2.52F), 12.6 (s, 0.48F); m/
z (EI) 290 (M ‡ 1, 11.58), 289 (M , 25.70), 244 (100.00),
69 (9.49); Anal. Calc. for C12H10F3NO4: C, 49.83; H, 3.49;
N, 4.84. Found: C, 49.80; H, 3.59; N, 4.84%.
4g: Oil. IR (thin ®lm): 2986, 1733, 1642, 1288, 1267,
1141 cm 1; dH (CDCl3, 300 MHz) 8.15 (s, 1H); 7.58 (m,
2H); 7.30 (m, 1H), 6.48 (d, J ˆ 15:8 Hz, 1H), 4.32 (q,
J ˆ 7:1 Hz, 2H), 1.42 (t, J ˆ 7:1 Hz, 3H); dF (CDCl3,
56.4 MHz) 19.7 (s, 2.46F), 13.0 (s, 0.54F); m/z (EI)
‡
‡
‡
‡
325/323 (M ‡ 1, 0.97), 324/322 (M , 0.78), 279/277
(Z)-4d: Oil. IR (thin ®lm): 2987, 1724, 1623, 1290, 1257,
1140 cm 1; dH (CDCl3, 300 MHz) 7.72 (d, J ˆ 11:9 Hz,
1H), 7.53 (m, 2H), 7.41 (m, 4H), 7.11 (d, J ˆ 15:2 Hz, 1H),
4.33 (q, J ˆ 7:1 Hz, 2H), 1.35 (t, J ˆ 7:1 Hz, 3H); dF
(11.86), 195 (100.00), 69 (2.31).
Acknowledgements
‡
(CDCl3, 56.4 MHz) 20.7 (s, 3F); m/z (EI) 271 (M ‡ 1,
‡
We thank the National Natural Science Foundation of
China for funding this work.
49.49), 270 (M , 100.00), 225 (26.47), 69 (12.31).
4e: Oil. IR (thin ®lm): 2991, 1737, 1375, 1264,
1149 cm 1; dH (CDCl3, 300 MHz) 7.30 (d, J ˆ 7:0 Hz,
1H), 5.10 (m, 1H), 4.27 (m, 3H), 3.72 (m, 1H), 1.48±1.26
(m, 9H); dF (CDCl3, 56.4 MHz) 11.9 (s, 2.70F), 17.6 (s,
References
‡
0.30F); m/z (EI) 269 (M ‡ 1, 9.58), 253 (58.69), 69 (4.09),
42 (100.00); Anal. Calc. for C11H15F3O4: C, 49.25; H, 5.60.
Found: C, 49.22; H, 5.79%.
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4f: Oil. IR (thin ®lm): 2984, 1719, 1645, 1430, 1308,
1189 cm 1; dH (CDCl3, 300 MHz) 7.72 (d, J ˆ 16:4 Hz,
1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.55 (d, J ˆ 16:4 Hz, 1H),
4.25 (q, J ˆ 7:1 Hz, 2H), 1.25 (t, J ˆ 7:1 Hz, 3H); dF
(CDCl3, 56.4 MHz) 19.6 (s, 2.85F), 14.8 (s, 0.15F); m/
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‡
‡
z (EI) 315 (M ‡ 2, 1.57), 313 (M , 1.81), 245 (36.54), 209
(100.00), 69 (3.08).