A new and facile stereocontrolled synthesis of conjugated dienyl trifluoromethyl ketones

Article abstract of DOI:10.1039/b005250g

The stereocontrolled synthesis of conjugated dienyl trifluoromethyl ketones has been achieved by a Horner-Wadsworth-Emmons reaction starting from the key trifluoromethylated building block N-(4-methylphenyl)-trifluoroacetimidoyl iodide. The Royal Society

Full text of DOI:10.1039/b005250g

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A new and facile stereocontrolled synthesis of conjugated dienyl
trifluoromethyl ketones†
Jingbo Xiao, Yanshu Feng and Chengye Yuan*
1
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
Received (in Cambridge, UK) 30th June 2000, Accepted 13th November 2000
First published as an Advance Article on the web 29th November 2000
The stereocontrolled synthesis of conjugated dienyl tri-
fluoromethyl ketones has been achieved by a Horner–
Wadsworth–Emmons reaction starting from the key
trifluoromethylated building block N-(4-methylphenyl)-
trifluoroacetimidoyl iodide.
Organofluorine compounds have gained considerable interest
due to their possibly enhanced biological activities as compared
to the nonfluorinated counterparts.1 In particular, trifluoro-
methyl ketones are potential versatile synthetic precursors
in the preparation of trifluoromethyl-containing compounds.2
They can also serve as transition-state analogue inhibitors for
a variety of hydrolytic enzymes.3 For these reasons, the syn-
thesis of trifluoromethyl ketones has received much attention
and many synthetic routes have been developed in recent
years.4 However, unsaturated trifluoromethyl ketones, as func-
tionalized trifluoromethyl ketones in general, are not very
readily accessible,5 because many procedures that are com-
monly employed in the synthesis of unsaturated ketones are not
applicable to the preparation of the fluorinated counterparts.
As an extension of our research on a one-pot synthesis of
α,β-unsaturated trifluoromethyl ketones,6 herein, we wish to
present a new and facile stereocontrolled synthesis of con-
jugated dienyl trifluoromethyl ketones starting from the key
trifluoromethylated building block N-(4-methylphenyl)-
trifluoroacetimidoyl iodide, which has been widely used in
the synthesis of trifluoromethyl-containing compounds.6,7 Our
synthetic route is based on the following sequence of reactions
as shown in Scheme 1.
Scheme
1
Reaction conditions and reagents: i Pd2(dba)3CH3Cl,
K2CO3, 75 ЊC; ii n-BuLi, RCHO, Ϫ78 ЊC; iii 2 mol dmϪ3 HCl, room
temp.
The key trifluoromethylated building block 1 was readily
prepared by displacement of chlorine of the corresponding
acetimidoyl chloride7c,8 with iodine in the NaI–acetone
system.7a We expected that N-(4-methylphenyl)trifluoro-
acetimidoyl iodide (1) would undergo a palladium-catalyzed
reaction smoothly with diethyl allylphosphonate to afford
stereochemical features of the dienyl part were identified as E-
isomers by 1H NMR. The high stereoselectivity of the products
is probably due to the less hindered threo-diastereoisomers
of the oxyanion intermediates in the course of the Horner–
Wadsworth–Emmons reaction.
diethyl
N-(4-methylphenyl)imino-5,5,5-trifluoropent-2-enyl-
1
phosphonate (3). But the H NMR showed no signals corre-
sponding to the P–CH2 part, although the mass spectra and
elemental analyses confirmed the molecular weight and atom
components. So we deduced that compound 4 might easily
isomerize to compound 3. Thus we treated the important
intermediates 4 with butyllithium at Ϫ78 ЊC which underwent
In conclusion, we have described the utility of N-(4-methyl-
phenyl)trifluoroacetimidoyl iodide (1) as the key trifluoro-
methylated building block for the stereocontrolled synthesis of
a series of conjugated dienyl trifluoromethyl ketones via a
Horner–Wadsworth–Emmons reaction. Compared with some
other synthesis of these compounds such as by a Claisen
rearrangement,9 our method is simpler and more convenient.
a
Horner–Wadsworth–Emmons reaction with aldehydes,
followed by acid hydrolysis to provide moderate to good yield
of the title products 6. The stereochemistry of the two vinyl
moieties in the products were both assigned as E-configuration
on the basis of the vinylic H–H coupling constant (J = 15 Hz).
As demonstrated in Table 1, a variety of aromatic aldehydes
can be converted into conjugated dienyl trifluoromethyl
ketones. But the method was unsuccessful, when aromatic
aldehydes were used instead of alkyl aldehydes and ketones.
All the products showed a singlet in their 19F NMR and the
Experimental
1.1 Synthesis of compound 4
To a 25 cm3 flask purged with N2, was added K2CO3 (4.09
mmol, 564 mg), Pd2(dba)3CHCl3 (0.115 mmol, 119 mg) and
dried toluene (1 cm3). A solution of N-(4-methylphenyl)-
trifluoroacetimidoyl iodide (1) (1.955 mmol, 612 mg) and dried
toluene (0.5 cm3) was added dropwise to the mixture. After
30 min diethyl allylphosphonate (2) (5.87 mmol, 1.044 g) was
added. Stirring was continued at 75 ЊC for 9 h. Completion of
the reaction was monitored by TLC. The mixture was filtered
† Experimental data for compounds 6b–6g are available as supplemen-
tary data. For direct electronic access see http://www.rsc.org/suppdata/
p1/b0/b005250g/
4240
J. Chem. Soc., Perkin Trans. 1, 2000, 4240–4241
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005250g

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Table 1 Conjugated dienyl trifluoromethyl ketonesa
was removed under reduced pressure. Isolation of the product
by column chromatography on silica gel (EtOAc:Petroleum
ether = 50:1) gave compound 6a (40 mg, 67%) as a yellow oil
(Found: 226.06094; C12H9F3O requires 226.06055); δH (300
MHz; CDCl3; Me4Si) 7.74 (1H, dd, J1 15, J2 11), 7.52 (2H, m,
ArH), 7.39 (3H, m, ArH), 7.16 (1H, d, J 15), 6.98 (1H, dd, J1 15,
J2 11), 6.56 (1H, d, J 15); δF (56.4 MHz; CDCl3; TFA) Ϫ0.42 (s);
m/z 226 (Mϩ, base), 157 (67.11%), 129 (36.58%), 180 (29.06%).
Yield
Yield
(%)b
R
(%)b
R
6a
6b
6c
6d
Phenyl
67
61
43
41
6e
6f
6g
4-Chlorophenyl
4-Bromophenyl
4-Nitrophenyl
60
71
47
4-Methylphenyl
4-Methoxyphenyl
4-Fluorophenyl
a Satisfactory spectral and microanalytical data were obtained for all
Acknowledgements
new compounds. b Isolated yields.
We gratefully acknowledge the financial support of National
Natural Sciences Foundation of China (NNSFC), Number
29832050.
and concentrated under reduced pressure. The residue was
subjected to column chromatography on silica gel to give
compound 4 (0.365 g, 51%) as a yellow solid, mp 66–68 ЊC
(Found: C, 52.70; H, 5.83; N, 3.78. C16H21F3NO3P requires
C, 52.89; H, 5.83; N, 3.86%); IR: ν/cmϪ1 3252, 2986, 1515,
1248, 1188, 1026; δH (300 MHz; C6D6; Me4Si) 7.31 (1H,
m), 6.87 (2H, d, J 8, Ph-H), 6.84 (1H, s, NH2), 6.77 (2H, d, J 8,
Ph-H), 5.96 (1H, d, J 11), 5.57 (1H, dd, J1 = J2 18), 3.78 (4H,
q, J 8, 2 × CH2), 2.10 (3H, s, CH3), 1.02 (6H, t, J 8, 2 ×
CH2CH3); δF (56.4 MHz; C6D6; TFA) Ϫ9.3(s); m/z 363 (Mϩ,
19.45%), 364 (Mϩ ϩ 1, 12.80%), 225 (base).
Notes and references
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Chemistry, Kodaansha, Tokyo, 182; (b) N. Ishikawa, Biologically
active Organofluorine Compounds, CMC, Tokyo, 1990.
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Knunyants and G. G. Yakobson, Synthesis of Fluoro-organic
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5 M. Hudlicky, Chemistry of Fluorine Compounds, Ellis Horwood,
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1.2 Synthesis of compound 6a, typical procedure
To a 25 cm3 flask purged with N2, was added dried THF (2 cm3)
and butyllithium (2.0 mol dmϪ3 in hexane; 0.396 mmol, 0.198
cm3). After 10 min, the solution was cooled to Ϫ78 ЊC and
a solution of compound 4 (0.265 mmol, 96 mg) in dried THF
(2 cm3) was added dropwise. After the mixture had been stirred
for 3 h at Ϫ78 ЊC, the freshly distilled phenylaldehyde (0.317
mmol, 33.6 mg) in dried THF (2 cm3) was gradually added at
the same temperature. The mixture was stirred continuously at
Ϫ78 ЊC for another 1 h and then warmed to room temperature
over 2 h and stirred overnight. After addition of 2 mol dmϪ3
aq. HCl to the mixture, it was stirred at room temperature for
5 h and then extracted with diethyl ether (3 × 20 cm3). The
combined organic layers were dried (MgSO4) and the solvent
7 (a) K. Uneyama and H. Watanabe, Tetrahedron Lett., 1991, 32,
1459; (b) H. Watanabe, Y. Hashizume and K. Uneyama, Tetrahedron
Lett., 1992, 33, 4333; (c) K. Tamura, H. Mizukami, K. Maeda,
H. Watanabe and K. Uneyama, J. Org. Chem., 1993, 58, 32; (d) L. S.
Hegedus, J. Organomet. Chem., 1993, 457, 167; (e) K. Tamura,
F. Y. Yan, T. Sakai and K. Uneyama, Bull. Chem. Soc. Jpn., 1994,
67, 300; ( f ) Y. Danoh, H. Matta, J. Uemura, H. Watanabe and
K. Uneyama, Bull. Chem. Soc. Jpn., 1995, 68, 1497; (g) H. B. Yu and
W. Y. Huang, J. Fluorine Chem., 1998, 87, 69.
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(b) K. Uneyama, C. Noritake and K. Sadamune, J. Org. Chem., 1996,
61, 6055; (c) K. Uneyama, J. Fluorine Chem., 1999, 97, 11.
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