Preparation of 3-substituted and 2,3-disubstituted-4,4,4-trifluoro-2-butenoic acids-Perkin condensation of activated aromatic ketones

Article abstract of DOI:10.1016/j.jfluchem.2006.03.004

The Perkin reaction of the activated aromatic ketones (2,2,2-trifluoroacetophenone and its 4′-phenyl-derivative) with various condensing agents (acetic anhydride, propionic anhydride, phenylacetic acid/acetic anhydride) gives the title compounds in good o

Full text of DOI:10.1016/j.jfluchem.2006.03.004

Journal of Fluorine Chemistry 127 (2006) 850–853
www.elsevier.com/locate/fluor
Preparation of 3-substituted and 2,3-disubstituted-4,4,4-trifluoro-2-butenoic
acids—Perkin condensation of activated aromatic ketones
*
Szabolcs Cser e´ nyi, K a´ roly Felf o¨ ldi, Peter Forgo, Istv a´ n P a´ link o´
Department of Organic Chemistry, University of Szeged, D o´ m t e´ r 8, Szeged H-6720, Hungary
Received 10 February 2006; received in revised form 6 March 2006; accepted 12 March 2006
Available online 24 March 2006
Abstract
0
The Perkin reaction of the activated aromatic ketones (2,2,2-trifluoroacetophenone and its 4 -phenyl-derivative) with various condensing agents
acetic anhydride, propionic anhydride, phenylacetic acid/acetic anhydride) gives the title compounds in good or moderate yields, and high E-
(
stereoselectivity. For some derivatives an appreciable amount of the Z isomer was also formed. Several of the resulting butenoic acids and their
methyl esters are synthesised and characterised for the first time.
#
2006 Elsevier B.V. All rights reserved.
Keywords: Trifluoro-activated aromatic ketones; Perkin condensation; Stereoisomers
1
. Introduction
reacts with ethoxycarbonylmethylenetriphenylphosphorane fas-
ter and gives higher yield than acetophenone [4].
Fluoro-containing organic compounds are important mole-
Recently, we have studied the structure-forming properties
of cinnamic acid derivatives in the liquid phase and also in the
solid state [5–9]. In the solid state we have identified
(aromatic)C–Hꢀ ꢀ ꢀO intermolecular hydrogen bonds as super-
structure governing interactions and with methyl esters
(olefinic)C–Hꢀ ꢀ ꢀO intermolecular hydrogen bonds as well
[6,7]. Curiously, this latter interaction type was not found with
the acids. We have explained this with a steric reason, i.e. the
dimers of the acids could not come close enough for the
(olefinic)C–Hꢀ ꢀ ꢀO hydrogen bonding to emerge [7]. For the
esters, since they interact as monomers, steric congestion is
smaller, thus (olefinic)C–Hꢀ ꢀ ꢀO close contacts are identified
as hydrogen bonds. One way of decreasing steric congestion
with the acid is substituting the olefinic hydrogen with a CF3
group. Thereby possible hydrogen bonding sites are removed
from the influence of the phenyl group making them more
accessible for hydrogen bond donors. Indeed (aromatic)C–
Hꢀ ꢀ ꢀF hydrogen bonds could be identified for the acid and
also (methyl)C–Hꢀ ꢀ ꢀF hydrogen bonds were found for the
methyl ester [9]. The syntheses of the model compounds are
now described.
cules for the pharmaceutical as well as agrochemical industries,
because of their often peculiar biological effects. The
trifluoromethylated a,b-unsaturated carboxylic acids are valu-
able intermediates. These compounds are accessible in various
ways, through, e.g. Wittig, Wadswort-Emmons, Reformatszkij,
Suzuki or Heck reactions. Another important reaction type is the
Perkin condensation [1]. Here, aromatic aldehydes react with
acetic acid derivatives under basic conditions, providing
substituted cinnamic acids with high E-selectivity. The Perkin
reaction does not proceed with aromatic ketones, e.g.
acetophenone [1]. A recent paper [2] reported, however, that
2
,2,2-trifluoroacetophenones do react with acetic acid anhydride
in the presence of NaOAc giving 3-phenyl-4,4,4-trifluoro-2-
butenoic acids with good yield and E-selectivity. This is due
obviously to the electron withdrawing effect of the trifluoro-
methyl group resulting in the increased electrophilicity of the
carbonyl carbon atom. This type of activation behaviour can also
be seen in other reactions. The yield of acetophenone
hydrogenation is low over chinchona-modified Pt/Al O
2
3
catalyst, however 2,2,2-trifluoroacetophenone can be hydro-
genated rather well [3]. 2,2,2-Trifluoroacetophenone in toluene
2. Results and discussion
The Perkin reaction with the activated aromatic ketone is
depicted in Scheme 1.
*
Corresponding author. Tel.: +36 62 544 288; fax: +36 62 544 200.
E-mail address: palinko@chem.u-szeged.hu (I. P a´ link o´ ).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.03.004

S. Cser e´ nyi et al. / Journal of Fluorine Chemistry 127 (2006) 850–853
851
Scheme 1. The Perkin reaction with 2,2,2-trifluoroacetophenone and its phenyl-substituted derivative.
Table 1
Perkin reaction of 2,2,2-trifluoroacetophenones
a
Entry
Trifluoroketones
Reagents
Reaction
Method
Isolated yield (%)
E:Z ratio
Time (h)
Temperature (8C)
b
1
2
3
4
5
X = H
X = H
X = Ph
X = H
X = H
Ac
(EtCO)
Ac
2
O
A
A
A
B
B
4
4
4
3
3
170
170
170
100
130
61
59
53
75
97
93:7
2
O
80:20
90:10
2
O
b
PhCH
PhCH
2
CO
CO
2
H, Ac
H, Ac
2
O
O
99:<1
99: < 1
b
2
2
2
a
1
The ratio was determined (as methyl esters) by H NMR and/or GC/MS in the isolated mixture.
b
The Z isomer was not isolated.
Details of the reaction as well as the isolated yields and ratio
of stereoisomers are given in Table 1.
4. Experimental
The reactions usually resulted in mixtures of stereoisomers.
These mixtures were transformed to methyl esters and
separated by column chromatography (entries 2 and 3). Then
the esters were hydrolysed [10] and thus the clean stereo-
isomeric acids were obtained. Among the compounds prepared
the 3-phenyl-4,4,4-trifluoro-2-butenoic acid streoisomers (1E,
Compounds used throughout were Fluka or Aldrich
0
products. The 4 -phenyl-2,2,2-trifluoroacetophenone was
synthesised [14]. The purity and characterisation of the
compounds prepared and the isomer distributions were checked
by TLC (Fluka 60778 silica gel TLC cards), GC/MS method
(Agilent Techn. 6890N GC-5973 MSD, 60 m HP-1 column)
1
1
Z, entry 1), as well as the methyl esters are known [2,10–13],
thus, only the E isomer (1E) was isolated. The other compounds
entries 2–4) and their methyl esters have not been described
and NMR spectroscopy (Bruker Avance 500 spectrometer, H:
1
3
500 MHz, C: 125.8 MHz, in CDCl , the chemical shifts are
3
(
expressed in ppm downfield from internal tetramethylsilane).
The E, Z configuration of the products was determined by
one-dimensional NOE experiments using selective excitation
of 2-Me, 2-COOMe or 2-H (olefin protons). Selective
excitation of the protons in the 2-Me or 2-olefin groups
resulted in enhanced signals of the vicinal phenyl protons in
case of Z isomers. Similar enhancements were determined
when 2-COOMe protons were excited in E isomers. The
chemical shift difference measured for the same functionalities
in different isomers were in good agreement with literature data
[11,12] obtained for similar compounds.
previously. The Z isomer of the 2,3-diphenyl-4,4,4-trifluoro-2-
butenoic acid (entries 4 and 5) could be detected only by GC/
MS. The E isomer of the acid and the ester were isolated,
however.
In some cases substantial amounts of the Z isomers could
be isolated (Table 1, entries 2 and 3). These stereoisomers are
difficult to prepare via the Perkin reaction, thus a lot of their
properties, e.g. their aggregation behaviour, are hardly
known. From now, this and other properties of these
stereoisomers can be investigated, thus, significant gaps
may be filled.
Fluka 60741 Silica gel 60 was used for column chromato-
graphy and Fluka 60752 Silica gel 60 for flash chromatography.
The characterisation data on the compounds (white solids or
colourless oils) are summarised below.
3
. Conclusions
Substituting the methyl hydrogens to fluor in acetophenone
derivatives renders the carbonyl carbon electrophilic enough to
take part in Perkin condensation reaction. The E-selectivity of
the reactions was high, however, in some instances appreciable
quantities of the Z isomer could also be prepared and isolated.
Other electron withdrawing groups possibly also exert similar
activation effect.
4.1. Preparation of E-(2E) and Z-2-methyl-3-phenyl-4,4,4-
trifluoro-2-butenoic acid (2Z) (Method A)
3
A mixture of 1.38 cm (10 mmol) of 2,2,2-trifluoroaceto-
3
phenone, 1.86 cm (14.5 mmol) of propionic anhydride and
0.5 g (3.5 mmol) of anhydrous and powdered K CO was
2
3

852
S. Cser e´ nyi et al. / Journal of Fluorine Chemistry 127 (2006) 850–853
heated and stirred in oil bath at 170 8C for 4 h. The mixture was
cooled and 15 cm of 12% KOH solution was added. The basic
199 (89.4), 198 (17.1), 171 (14.9), 151 (85.3), 102 (24.9), 76
(8.8), 51 (10.8), 28 (21.3).
E-2-methyl-3-phenyl-4,4,4-trifluoro-2-butenoic acid (2E).
3
3
solution was extracted with 3ꢁ 10 cm diethyl ether and the
1
aqueous phase was acidified with cc. HCl. The off-white
precipitate was filtered and dried.
mp: 98–99 8C (hexane); TLC: R 0.82 (EtOAc/MeOH 3:1); H
f
NMR: 11.17 (b, 1H, COOH), 7.36 (m, 3H, ArH), 7.20 (d, 2H,
1
3
The obtained acid mixture (2.1 g) was esterified with
traditional diazomethane method (for details, see Section 4.3),
after evaporation the obtained methyl ester yield was 2.2 g. One
gram of the ester mixturewas separated by flash chromatography
ArH), 2.23 (q, 3H, CH3); C NMR: 174.3, 137.6, 133.9 (q),
133.2, 128.9, 128.9, 128.2, 123.1 (q), 16.3. Anal. Calcd for
C H F O : C, 57.39; H, 3.94. Found: C, 57.47; H, 4.05.
1
1 9 3 2
MethylE-2-methyl-3-phenyl-4,4,4-trifluoro-2-butenoate. Oil;
1
(100 g of silica gel, hexane/acetone 95:5). The separated methyl
esters were hydrolysed on the basis of Ref. [10].
TLC: R 0.42 (hexane/acetone 95:5); H NMR: 7.37 (t, 3H, ArH),
f
1
3
7.24 (m, 2H, ArH), 3.43 (s, 3H, OCH ), 2.27 (q, 3H, CH );
C
NMR: 169.2, 138.9, 133.7, 132.6 (q), 129.0, 128.6, 128.1, 123.3
3
3
4.2. Preparation of E-2,3-diphenyl-4,4,4-trifluoro-2-
butenoic acid (4E) (Method B)
(q), 51.8, 16.5; GC/MS: ret. time 22.3 min, m/z (rel. int.%): 244
+
(M 100), 243 (45), 213 (43), 212 (13), 185 (27), 177 (22.5), 165
(
66), 164 (35), 145 (22), 133 (18), 116 (21.5), 115 (80).
Z-2-methyl-3-phenyl-4,4,4-trifluoro-2-butenoic acid (2Z).
3
A mixture of 3 cm (22 mmol) of 2,2,2-trifluoroacetophe-
3
none, 2.5 g (18.3 mmol) of phenylacetic acid, 5 cm of
mp: 134–135 8C (hexane); TLC: R 0.61 (EtOAc/MeOH 3:1);
f
3
triethylamine and 5 cm of acetic anhydride was stirred and
1
H NMR: 11.58 (b, 1H, COOH), 7.47 (t, 3H, ArH), 7.31 (m, 2H,
13
ArH), 1.94 (m, 3H, CH3); C NMR: 175.2, 135.7, 131.7, 130.1
3
heated at130 8C for 3 h. To the cooled mixturewas added 10 cm
of water and acidified with cc. HCl. The mixture was extracted
(q), 129.3, 129.0, 128.7, 122.3 (q), 18.2. Anal. Calcd for
C H F O : C, 57.39; H, 3.94. Found: C, 57.31; H, 4.05.
3
3
ꢁ 15 cm of diethyl ether, the ethereal phase was washed with
1
1 9 3 2
3
3
1
5 cm of saturated NaCl solution and extracted with 3ꢁ 10 cm
Methyl
Oil; TLC: R 0.35 (hexane/acetone 95:5); H NMR: 7.45 (m,
Z-2-methyl-3-phenyl-4,4,4-trifluoro-2-butenoate.
1
of 5% NaOH solution. The aqueous phase was acidified with
diluted(1:1)HCl, theprecipitatewasextractedwithdiethylether.
Theethereal phasewasdried onsicc. Na SO andthe solventwas
f
3H, ArH), 7.28 (d, 2H, ArH), 3.89 (s, 3H, OCH ), 1.85 (m, 3H,
3
1
3
CH3); C NMR: 168.3, 136.8, 131.9, 129.3, 128.8, 128.6,
122.4 (q), 52.5, 18.2; GC/MS: ret. time 26.8 min, m/z (rel.
+
int.%): 244 (M 100), 243 (38), 213 (61), 185 (27.5), 177 (18.5),
2
4
evaporated. An analytical sample (0.3–0.4 g) was purified by
column chromatography (dichloromethane/methanol 10:1). The
obtained pure E-acid was esterified in diethyl ether with
diazomethane (for details, see Section 4.3).
165 (62), 164 (34), 145 (20), 133 (17), 116 (20.5), 115 (76).
E-3-biphenyl-4-yl-4,4,4-trifluoro-2-butenoic acid (3E). mp:
1
64–165 8C (hexane/acetone); TLC: R 0.53 (EtOAc/MeOH
f
1
3:1); H NMR: 9.8 (b, 1H, COOH), 7.64 (m, 4H, ArH), 7.49 (m,
4.3. Preparation of methyl esters with ethereal solution of
diazomethane [15]
13
2H, ArH), 7.40 (m, 3H, ArH), 6.65 (s, 1H, vinyl H); C NMR:
69.1, 144.5 (q), 142.5, 140.1, 129.0, 128.9, 127.8, 127.1,
127.0, 123.2, 122.5 (q). Anal. Calcd for C H F O : C, 65.75;
1
3
.2 g of the acid was dissolved in 10 cm of dry diethyl ether.
0
1
6 11 3 2
To the stirred and cooled (ice bath) solution ethereal solution of
diazomethane [15] was added in small portions until gas
evolution ceased and the solution acquired pale yellow colour
H, 3.79. Found: C, 65.68; H, 3.90.
Methyl E-3-biphenyl-4-yl-4,4,4-trifluoro-2-butenoate. mp:
1
113–114 8C; TLC: R 0.56 (hexane/dichloromethane 1:1); H
f
(
the reaction was followed by TLC). The solvent was
NMR: 7.65 (t, 4H, ArH), 7.47 (t, 2H, ArH), 7.39 (m, 3H, ArH),
1
6.67 (s, 1H, vinyl H), 3.66 (s, 3H, CH3); C NMR: 164.5, 142.2,
3
evaporated and the methyl ester was collected. It was purified
by either crystallisation or column chromatography.
140.2, 129.6, 128.8, 127.7, 127.1, 126.9, 123.9, 52.0; GC/MS:
+
ret. time 38.27 min, m/z (rel. int.%): 306 (M , 100), 305 (20.5),
4
.4. Characterisation data of the compounds
291 (4.7), 275 (9), 233 (24.1), 227 (22.3), 178 (28.8).
Z-3-biphenyl-4-yl-4,4,4-trifluoro-2-butenoic acid (3Z). mp:
1
E-3-phenyl-4,4,4-trifluoro-2-butenoic acid (1E). mp: 94.5–
5.5 8C (hexane, lit. [2] 95–97 8C); TLC: R 0.68 (EtOAc/
168–170 8C; TLC: R 0.39 (EtOAc/MeOH 3:1); H NMR: 7.62
f
9
(m, 4H, ArH), 7.48 (m, 4H, ArH), 7.40 (t, 1H, ArH), 6.43 (s, 1H,
vinyl H). Anal. Calcd for C H F O : C, 65.75; H, 3.79.
f
1
13
MeOH 3:1); H NMR and C NMR are as described in the
literature [12].
Methyl E-3-phenyl-4,4,4-trifluoro-2-butenoate. Oil; TLC: Rf
1
6 11 3 2
Found: C 65.82, H 3.72.
Methyl Z-3-biphenyl-4-yl-4,4,4-trifluoro-2-butenoate. mp:
1
1
0
.43 (hexane/acetone 95:5); H NMR: 7.39 (m, 3H, ArH), 7.28
56–57 8C; TLC: R 0.47 (hexane/dichloromethane 1:1); H
f
1
3
C
(
m, 2H, ArH), 6.60 (s, 1H, vinyl H), 3.59 (s, 3H, CH3);
NMR: 164.5, 142.8 (q), 138.9, 129.3, 128.6, 128.2, 124.0 (q),
22.5 (q), 51.8; GC/MS: ret. time 23.3 min, m/z (rel. int.%): 230
NMR: 7.62 (m, 4H, ArH), 7.48 (m, 4H, ArH), 7.39 (t, 1H, ArH),
6.41 (s, 1H, vinyl H), 3.87 (s, 3H, CH ); GC/MS: ret. time
3
+
46.2 min, m/z (rel. int.%): 306 (M , 100), 305 (29.4), 291 (4.3),
1
+
(
M , 72.4), 229 (100), 215 (5), 199 (73.5), 198 (16.6), 171
13.4), 151 (76.9), 102 (22.1), 76 (7.8), 51 (9.4), 28 (2.3).
Methyl Z-3-phenyl-4,4,4-trifluoro-2-butenoate. Not iso-
275 (16.7), 233 (38.8), 227 (25), 178 (21.8), 176 (18.9), 77
(16.9), 28 (40.8).
E-2,3-diphenyl-4,4,4-trifluoro-2-butenoic acid (4E). mp:
(
lated; TLC: R 0.34 (hexane/acetone 95:5); GC/MS: ret. time
f
181.5–182.5 8C; TLC: R 0.6 (EtOAc/MeOH 3:1); IR data in
f
+
7 min, m/z (rel. int.%): 230 (M , 71.8), 229 (100), 215 (4.6),
ꢂ1
1
lit. [9]: C–F stretch 1264 cm (solid); H NMR: 8.99 (b, 1H,
2

S. Cser e´ nyi et al. / Journal of Fluorine Chemistry 127 (2006) 850–853
853
1
3
COOH), 7.31 (m, 10H, ArH); C NMR: 171.5, 141.7, 132.9,
32.6, 129.3, 129.2, 129.1, 128.3, 128.2, 128.1, 122.6 (q). Anal.
CalcdforC H F O :C,65.75;H, 3.79.Found:C65.81, H3.87.
References
1
[
1] T. Rosen, The Perkin reaction, in: B.M. Trost (Ed.), Comprehensive
Organic Synthesis, vol. 2, Pergamon Press, Oxford, 1991, pp. 395–
1
6 11 3 2
Methyl E-2,3-diphenyl-4,4,4-trifluoro-2-butenoate. mp: 77–
4
08.
7
stretch 1120 cm (solid); H NMR: 7.45 (m, 2H, ArH), 7.40
9 8C; TLC: R 0.7 (hexane/acetone 5:2); IR data in lit. [9]: C–F
f
[
[
2] D.V. Sevenard, Tetrahedron Lett. 44 (2003) 7119–7120.
ꢂ1
1
3] M. Studer, H.U. Blaser, C. Exner, Adv. Synth. Catal. 345 (2003) 45–65.
1
m, 8H, ArH), 3.38 (s, 3H, CH3); C NMR: 167.4, 142.7,
3
(
[4] Y. Shen, S. Gao, J. Org. Chem. 58 (1993) 4564–4566.
[
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1
1
33.3, 133.0, 132.2 (q), 129.3, 129.1, 128.9, 128.2, 128.24,
27.9, 122.8 (q), 52.2; GC/MS: ret. time 38.5 min, m/z (rel.
2
[
[
+
int.%): 306 (M , 79.8), 285 (20.2), 251 (41.7), 247 (41.8), 225
(
7] J.T. Kiss, K. Felf o¨ ldi, T. K o¨ rtv e´ lyesi, I. P a´ link o´ , Vibr. Spect. 22 (2000) 63–
100), 205 (24.6), 178 (61.4), 176 (28.4), 205 (24.6).
Methyl Z-2,3-diphenyl-4,4,4-trifluoro-2-butenoate. Not iso-
7
3.
[8] E. Talab e´ r, Z. Paksi, I. P a´ link o´ , J. Mol. Struct. Theochem. 620 (2003) 37–
1.
9] J.T. Kiss, K. Felf o¨ ldi, I. P a´ link o´ , J. Mol. Struct. 744–747 (2005) 207–210.
4
lated; GC/MS: ret. time 41.5 min, MS spectrum as above.
Elemental analyses were done only for the acids. The esters
from these acids were prepared with simple reaction and the MS
and NMR data revealed that esterification proceeded indeed.
[
[
10] N. Ohno, N. Fukamiya, M. Okano, K. Tagahara, K.-H. Lee, Bioorg. Med.
Chem. 5 (1997) 1489–1495.
[
[
11] H.J. Wang, W. Ling, L. Lu, J. Fluorine Chem. 111 (2001) 241–246.
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Rafanell, J. Forn, J. Med. Chem. 36 (1993) 2984–2997.
Acknowledgement
[
[
13] V.Y. Sosnovskikh, Zh. Org. Khim. 29 (1993) 895–900.
14] T. Varga, K. Felf o¨ ldi, P. Forg o´ , M. Bart o´ k, J. Mol. Catal., A 216 (2004)
This work was supported by the National Science Fund of
Hungary through grant K62288. The financial help is highly
appreciated.
1
81–187.
[
15] Vogel’s Textbook of Practical Organic Chemistry, 5th ed., Longman
Scientific and Technical, England, 1991, pp. 432–433.