Application of Sonogashira and Baylis-Hillman reactions with β-trifluoromethylated acroleins

Article abstract of DOI:10.3184/030823409X12608085606117

The reaction of alkynes with 2-phenyl-3-iodo-4,4,4-trifluorobut-2-enal in the presence of palladium (0) is reported (Sonogashira reaction). Moreover, 2-(hydroxytrifluoromethylalkenyl)cyclohexenones have been prepared by the reaction of cyclohexenone and β

Full text of DOI:10.3184/030823409X12608085606117

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 5
JANUARY, 5–7
Application of Sonogashira and Baylis–Hillman reactions with
β-trifluoromethylated acroleins
Emna Zouaoui* and Mohamed Moncef El Gaïed
Laboratoire de chimie organique, Faculté des Sciences deTunis, Campus University, 1060Tunis, Tunisia
The reaction of alkynes with 2-phenyl-3-iodo-4,4,4-trifluorobut-2-enal in the presence of palladium (0) is reported (Sono-
gashira reaction). Moreover, 2-(hydroxytrifluoromethylalkenyl)cyclohexenones have been prepared by the reaction of cyclo-
hexenone and β-trifluromethylacroleins in the presence of N-methylimidazole catalysis.
Keywords: β- trifluoromethylenynes, palladium (0), cyclohexenone, N-methylimidazol catalysis, Baylis–Hillman adducts
synthetic method to form densely functionalised precursors.20,21
Their versatility has made these multifunctionalised com-
pounds valuable synthetic intermediates22,23 and has also
stimulated their utilisation as substrates for chemical trans-
formation mediated by palladium, especially for Heck
reactions.24,25
In continuation of our study on α-functionalisation of cyclic
enones, we now report our results on the N-methylimidazole
mediated Baylis–Hillman reaction between cyclic enones and
trifluoromethylated acroleins 5a–f). We have found the 2-(hyd
roxytrifluoromethylalkenyl)cycloxenones 6a–f) (Scheme 2).
In conclusion, we describe in this work the synthesis of
trifluoromethylated enynes 3a–c) by palladium catalysis cou-
pling reaction. The products obtained can be precursors for the
synthesis of biological heterocyclic such as Neocarzinstatine
which has antitumor activity.26
Organofluorine compounds have found increasing use in the
areas of agrochemicals, pharmaceuticals, polymers and new
materials.1−5 The fluorine atom brings specific chemical and
physical properties to molecules in the pharmaceutical field.
Molecules containing CF2 or CF3 can offer a significant change
in biological activity, compared to their non fluorinated
analogues. For example, the enzyme inhibitory activity of tri-
fluoromethylketones has been widely proved.6 The interest in
molecules containing the CF3 group entailed the development
of new and efficient synthetic methodologies.
In particular, the formation of C–C bond and the transfor-
mation of functional groups are fundamental processes for
organic synthesis. Recently, the catalysis by the transition
metals and Baylis–Hillman reaction have been the focus of
research.7−13
In connection with our interest in the synthesis and the
reactivity of trifluoromethylated Vilsmeir adducts,14,15 we con-
sidered the Sonogashira reaction with the acrolein 116 and
the Baylis–Hillman reaction towards trifluoromethylated
acroleins 5a–f.17,18
The Baylis–Hillman adducts 6–f can be used as inter-
mediates in the synthesis of natural products.27 However, we
have varied the operation conditions to ameliorate yields and
to reduce the reaction time.
Palladium-catalysed coupling reaction; synthesis of trifluo-
romethylatedenynes (3a–c): This reaction is useful for the
preparation of biological polymers.19 It consists of introducing
an sp2 hybrid organic substratum to acetylenic one: (sp2-sp
coupling). The utilisation of a co-catalysis (CuI) expedites the
acetylenic substratum easing the reaction with the palladium
complex (0). By utilising Sonogashira coupling, the reaction
of the acrolein 1 with alkynes 2a–c has given trifluoromethyl-
ated enynes 3a–c; each one formed as a mixture of Z and E
diastereomeres. We have observed that the E:Z ratios of these
compounds depend on the nature of the alkynes and can be
determined by 19F NMR spectroscopy. An anisotropic effect
for the phenyl moiety on to the CF3 group was observed in the
case of the (Z)-3 diastereomers (Scheme 1).
Experimental
All reactions progress was monitored by TLC analysis (Merck Kiesel-
gel 60 F254). All compounds were purified by chromatography column
(Silica gel 60. 70–230 mesh ASTM). IR spectra were obtained on
Perkin-Elmer Paragon 1000 PC. 1H NMR spectra were recorded on a
Bruker AC-300 (300 MHz) spectrometer using tetramethylsilane
(TMS, δH, 0) as internal standard. 13C NMR spectra were recorded on
Bruker AC-300 (75 MHz) spectrometer with proton decoupling. For
19F NMR spectra, C6F was used as reference and they were performed
on a Bruker AC-300 (6282.36 MHz). Mass spectra were carried out on
a Hewlett-Packard model (70 eV) by the staff of the Faculty of Medi-
cine, Department of Biochemistry, Monastir, Tunisia, under electronic
impact (EI). Elemental analyses were performed by the microanalyses
service of the Centre of Pharmaceutical Studies, Châtenay-Malabry.
Coupling constants (J values) are given in Hertz and spin multiplici-
ties are indicated by the following symbols: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet).
N-Methylimidazole-catalysed
Baylis–Hilman
reactions:
synthesis of 2-(hydroxytrifluoromethylalkenyl)cyclohexenon
es from β-trifluromethylated acroleins and cyclochexenone
The Baylis–Hillman reaction is a useful and general σ C–C
bond-forming reaction providing a straight forward single-step
Typical procedure for the synthesis of compound 3a–c
To a solution of the acrolein 1 (3x10−4 mol) in the benzene, we are
added under argon atmosphere and at room temperature,the Pd0(PPh3)4
Scheme 1
* Correspondent. E-mail: zouaoui_amna@yahoo.fr

6
JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
(5%), CuI (10%), Et3N (6x10−4 mol) and the alkynes 2a–c). The
mixture was stirred at room temperature the evolution of the reaction
was followed by gaseous phase chromatography and quenched with
NH4Cl. The organic layer was separated and the aqueous phase was
extracted with ether (3x15 mL) and dried over Na2SO4. The solvent
was removed under reduced pressure. The product was purified by
column chromatography, filled with silica gel and elution with ethyl
ether-petroleum ether (20/80).
2-(3-ethylsulfanyl-4,4,4-trifluoro-1-hydroxy-2-phenylbut-2-enyl)
cyclohex-2-en-1-one (6c): Colourless oil. Yield: 55%. 22 days. IR ν
1
(cm−1): 3406 (OH); 1669 (CO); 1167 (CF3); H NMR (400 MHz,
CDCl3): 0.85 (t, 3H); 2 (q, 2H); 2.38 (m, 6H); 6.1 (t, 1H); 3.9 (s, 1H);
4.6 ( , OH); 7.3 (m, 5H); 13C NMR(75,47 MHz, CDCL3): 14.15; 22.3;
26.22; 30.31; 37.78; 60.4; 127.40; 129.48; 136.91; 146.3; 200.65; 19
F
NMR (282.4 MHz; CDCl ): δ 106.84; MS (m/z): 356 (M+, 60); 231
(42); 126(31); 77(25); 613(30)F;: 57(10). Anal Calcd for C18H19F3O2S:
C, 60.65; H, 5.37. Found C, 60.52; H, 5.45%.
2-phenyl-3-trifluoromethyl-5-trimethylsilanylpent-2-en-4-ynal
(3a): Colourless oil. Yield: 80%. IR ν (cm−1): 1692 (CO); 1155–1148
2-(4,4,4-trifluoro-1-hydroxy-2-phenyl-3-propylsulfanylbut-2-enyl)
1
(CF3); H NMR (400 MHz, CDCl3): 0.2 (2s, 9H); 7.3 (m, 5H); 10
cyclohex-2-en-1-one (6d): Colourless oil. Yield: 50%. 28 days. IR ν
(q, 1H); 10.3 (s, 1H); 13C NMR (75,47 MHz, CDCl ): 14.2–14.6
(2s, CH3); 122.1–122.6 (2q, CF3); 128–130.3 (m, C6H53); 192–191.7
(2s, CHO); 19F NMR (282.4 MHz; CDCl3): E:Z: 5/95. δF: 109 (s, CF3);
111 (s, CF3). Anal Calcd for C15H15F3OSi: C, 60.78; H, 5.10 . Found:
C, 60.72; H, 5.28%.
1
(cm−1): 3394 (OH); 1658 (CO); 1152 (CF ); H NMR (400 MHz,
CDCl ): 0.83 (t, 3H); 1.56 (m, 2H); 1.99 (t,32H); 2.18 (m, 6H); 5.92
(t, 1H3); 3.6 (s, 1H); 4.1 ( OH); 7.1 (m, 5H); 13C NMR (75,47 MHz,
CDCL ): 14.12; 14.25; 21.88; 26.11; 30.28; 37.41; 60.1; 127.38;
128.783; 135.98;144.8;200.65; 19F NMR (282.4 MHz; CDCl3):
2,5-diphenyl-3-trifluoromethylpent-2-en-4-ynal (3b): Yellow oil.
δ
106.78 Anal Calcd for C19H21F3O2S: C, 61.59; H, 5.71. Found C,
1
Yield: 85 %. IR. ν (cm−1): 1690 (CO); 1148–1185 (CF3); H NMR
6F1:.59; H, 5.43%.
(400 MHz, CDCl3): 7.5 (m, 10H); 10.3 (q, 1H); 10.6 (s,1H); 13C NMR
(75,47 MHz, CDCL ): 122.8–122.3 (2q, CF ); 128.15–131.5 (m,
2C6H5); 137 (CCF3);3147.31 (C–C–CF3); 192.36–191.83 (2s, CHO);
19F NMR(282.4 MHz; CDCl3): E:Z= 13/87. δ 103.5 (s, CF3); 109
(s, CF ). Anal Calcd for C18H11F3O: C, 71.98; HF,: 3.69. Found C, 71.7;
H, 3.238%.
2-[3(dimethylamino)-4,4,4-trifluoro-1-hydroxy-2-phenylbut-2-
enyl]cyclohex-en-1-one (6e): Colourless oil. Yield: 47%. 32 days. IR
1
ν (cm−1): 3547 (OH); 1690 (CO); 1163 (CF ); H NMR(400 MHz,
CDCl3): 2.09 (s, 6H); 2.6 (m, 6H); 4 (s, 1H); 53.8 (OH); 7.2 (t, 1H); 7.6
(m, 5H); 13C NMR(75,47 MHz, CDCL3): 21.32; 26.43; 29.72; 43.02;
127.95; 129.23; 129.64; 129.89; 130.24; 131.28; 135.13; 172.06;
19F NMR (282.4 MHz; CDCl ): δF: 80.93; MS (m/z): 339 (M+, 10);
282 (35); 224 (68); 97 (100). 3Anal Calcd for C18H20F3NO2: C, 63.68;
H, 5.94; N = 4.13. Found C, 63.64; H, 5.73; N = 4.55%.
2-phenyl-3-trifluoromethylnon-2-en-4-ynal (3c): Colourless oil.
Yield: 78%. IR. ν (cm−1): 1698 (CO); 1158.17–1134 (CF3); 1H NMR
(400 MHz, CDCl3):0.7 (t, 3H); 1.4 (m, 4H); 2.1 (m, 2H); 7.3 (m, 5H);
10.4 (s, 1H); 13C NMR (75,47 MHz, CDCL3): 13.58–14.8 (m,
(CH2)2CH3); 47.53–48.7 (2s, CH2); (121.7; 122) (2q, CF3, 1JCF = 282.7
2-[3(diethylamino)-4,4,4-trifluoro-1-hydroxy-2-phenylbut-2enyl]
2
cyclohex-2-en-1-one (6f): Colourless oil. Yield: 45%. 30 days. IR ν
Hz); 127.3–130.2 (m, C6H5); 134 (q, CCF3, JCF = 30.18 Hz); 145.22
1
(cm−1): 3557 (OH); 1688 (CO); 1151 (CF3); H NMR (400 MHz,
(C–C–CF3); (191.7; 190.6) (2s, CHO); 19F NMR (282.4 MHz; CDCl ):
E:Z = 10/90. δF: 108.8 (s,CF3); 110.5 (s,CF ).Anal Calcd for C16H15F33O:
C, 68.54; H, 5.39. Found C, 68.78; H, 5.433%.
CDCl3): 2 (t, 6H); 2.6 (q, 4H); 2.4 (m, 6H); 5.4 (OH); 3.9 (s, 1H); 6.1
(t, 1H); 7.4 (m, 5H); 13C NMR (75,47 MHz, CDCL3): 13.58; 22.77;
25.69; 38.25; 47.53; 60.76; 128.49; 128.5; 128.47; 128.83; 131;
138.44; 146.77; 200.38; 19F NMR (282.4 MHz; CDCl3): δ 81; M
S(m/z): 126 (60); 111 (29); 97 (44); 77 (78); 71 (18); 56 (4F0: ). Anal
Calcd for C20H24F3NO2: C, 65.36; H, 6.59; N = 3.81. Found: C, 65.41;
H, 6.52; N, 3.67%.
Preparation of 2-(3-chloro-4,4,4-trifluoro-1-hydroxy-2-phenylbut-
2-enyl)-cyclohex-2-en-1-one (6a): A 50 mL round-bottomed flask was
charged with cyclohexenone (0.48, 5mmol), 10 mmol of the acrolein
5a 3mL of THF and 3mL of H2O and N-methylimidazole (0.05g,
0.5mmol). The resulting mixture was stirred for 40 days at 60 °C.
When the reaction, followed by TLC was finished, the mixture
was acidified with aqueous HCl (1.5M) and extracted with methylene-
chloride. After the usual work up, chromatography of crude product
on silica gel, using ether as eluent, gave pure 2-(3-chloro-4,4,4-
trifluoro-1-hydroxy-2-phenylbut-2-enyl)-cyclohex-2-en-1-one 6a.
2-(3-chloro-4,4,4-trifluoro-1-hydroxy-2-phenylbut-2-enyl)-
cyclohex-2-en-1-one (6a): Yellow oil. Yield: 45%. 40 days. IR ν
Received 22 October 2009; accepted 1 December 2009
Paper 090836 doi: 10.3184/030823409X12608085606117
Published online: 20 January 2010
References
1
(cm−1): 3397 OH); 1686 (CO); H NMR (400 MHz, CDCl3): 1.2 (m,
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5
6
7
8
9
2-(4,4,4-trifluoro-1-hydroxy-3-iodo-2-phenylbut-2-enyl)-cyclohex-
2-en-1-one (6b): Yellow oil. Yield: 44%. 45 days. IR ν (cm−1): 3383
1
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Anal Calcd for C16H14F3IO2: C, 45.49; H, 3.34. Found C,F:45.53;
H, 3.26%.

JOURNAL OF CHEMICAL RESEARCH 2010
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