Synthesis of trifluoromethyl-substituted heteroaromatic aldehydes

Article abstract of DOI:10.1007/s11172-006-0020-x

Trifluoromethylation of furfural and thiophene-2-carbaldehyde trifluoroacetates with XeF₂ and CF₃COOH afforded 5-trifluoromethylfuran-2-carbaldehyde and 5-trifluoromethylthiophene-2- carbaldehyde.

Full text of DOI:10.1007/s11172-006-0020-x

1672
Russian Chemical Bulletin, International Edition, Vol. 54, No. 7, pp. 1672—1674, July, 2005
Synthesis of trifluoromethylꢀsubstituted heteroaromatic aldehydes
S. V. Popkovꢀ and A. V. Kuzenkov
D. I. Mendeleev Russian University for Chemical Technology,
9 Miusskaya pl., 125047 Moscow, Russian Federation.
Fax: +7 (095) 200 4204. Eꢀmail: popkovsv@rctu.ru
Trifluoromethylation of furfural and thiopheneꢀ2ꢀcarbaldehyde trifluoroacetates with XeF2
and CF3COOH afforded 5ꢀtrifluoromethylfuranꢀ2ꢀcarbaldehyde and 5ꢀtrifluoromethylꢀ
thiopheneꢀ2ꢀcarbaldehyde.
Key words: 5ꢀtrifluoromethylfuranꢀ2ꢀcarbaldehyde, 5ꢀtrifluoromethylthiopheneꢀ2ꢀcarbꢀ
aldehyde, trifluoromethylation, xenon difluoride.
Compounds containing trifluoromethyl group bound
Out of various ways of introducing trifluoromethyl
groups,8 we chosen the synthesis of 5ꢀtrifluoromethyl
derivative 1a, which is similar to that mentioned in
the patent.4 The reaction of furfural with trifluoroꢀ
acetic acid and xenon difluoride at room temperature in
methylene chloride gave a trifluoromethylation prodꢀ
uct; a mixture of 5ꢀtrifluoromethylfuranꢀ2ꢀcarbaldehyde
bis(trifluoroacetate) 2a and the expected aldehyde 1a was
isolated by extraction. The IR spectrum of the mixture
show characteristic absorption bands of the carbonyl group
of trifluoroacetate at 1795 cm–1. Prolonged acid hydrolyꢀ
sis of the mixture containing bis(trifluoroacetate) 2a afꢀ
forded 5ꢀtrifluoromethyl derivative 1a in 20% yield. Preꢀ
liminary protection of the formyl group by converting it
into a diacylal one virtually did not affect the yield of
aldehyde 1a (19%) with furfural diacetate as an intermeꢀ
diate but substantially increased the yield in the triꢀ
fluoromethylation of bis(trifluoroacetate) 3a preliminarꢀ
ily prepared from furfural (the yield of aldehyde 1a was
increased to 30%). Despite a twoꢀstep synthesis through
bis(trifluoroacetate) 3a, this scheme provides the higher
yield from trifluoromethylation, which makes it possible
to reduce expenditure for comparatively expensive xenon
difluoride. Novel 5ꢀtrifluoromethylthiopheneꢀ2ꢀcarbꢀ
aldehyde (1b) was obtained analogously in a somewhat
lower yield. Note that when distilled in vacuo, acetal 3b
partially decomposes to aldehyde 4b and trifluoroacetic
anhydride, although the reaction of the aldehyde with the
anhydride occurs quantitatively: the IR spectrum of
bis(trifluoroacetate) 3b contains no absorption band charꢀ
acteristic of the carbonyl group in thiopheneꢀ2ꢀcarbꢀ
aldehyde 4b (1680 cm–1). To complete the hydrolysis of
the resulting aldehyde bis(trifluoroacetates) 2a and 2b in
the isolation of the target compounds, a prolonged reacꢀ
tion with water in the presence of trifluoroacetic acid was
required (Scheme 1).
to the aromatic ring are substantial in the synthesis of
biologically active compounds. Introduction of this (both
electronꢀwithdrawing and highly lipophilic) substituent
into a structure is often accompanied by an increase in the
physiological activity. The presence of perfluorinated
groups enhances the penetrating ability of biologically
active compounds owing to a better affinity for both the
lipophilic and aqueous phases. Such an amphiphilic charꢀ
acter1 allows a reactive molecule to reach the target faster.
Aromatic aldehydes are convenient starting reagents for
the synthesis of various derivatives. However, only triꢀ
fluoromethylbenzaldehydes are commercially accessible,
though they are highly expensive; information on triꢀ
fluoromethylꢀsubstituted heteroaromatic aldehydes are
desultory.
5ꢀTrifluoromethylfuranꢀ2ꢀcarbaldehyde (1a) was obꢀ
tained for the first time in six steps from trifluoroꢀ
acetoacetic ester in 11% overall yield.2 A transformation
of the carboxyl group of 5ꢀmethylpyromucic acid into a
trifluoromethyl one under the action of sulfur tetrafluoꢀ
ride in anhydrous HF gave the same aldehyde in three
steps in 33% overall yield.3 A patented procedure4 inꢀ
volves introduction of a trifluoromethyl group into furꢀ
fural with trifluoroacetic acid and xenon difluoride. In
this way, trifluoromethyl derivatives were obtained, mainly
from substituted benzenes.5 The resulting xenon fluoride
trifluoroacetate generates, via its roomꢀtemperature deꢀ
composition, trifluoromethyl radicals which allow introꢀ
duction of a trifluoromethyl group into the aromatic ring
under mild conditions: e.g., trifluoromethylbenzene was
obtained6 under these conditions in 42% average yield.
Xenon difluoride also initiates fluorodecarboxylation of
carboxylic acids, which makes it possible to synthesize
monofluoro derivatives and, with the use of trifluoroacetic
acid, yields carbon tetrafluoride as a byꢀproduct.7
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1623—1625, July, 2005.
1066ꢀ5285/05/5407ꢀ1672 © 2005 Springer Science+Business Media, Inc.

Synthesis of CF3ꢀcontaining heteroaromatic aldehydes Russ.Chem.Bull., Int.Ed., Vol. 54, No. 7, July, 2005
1673
Scheme 1
carbaldehyde thiosemicarbazone 5b proved to be highly
active, being vastly superior to triadimephon with reꢀ
spect to three pathogenic fungi: Venturia inaequalis,
Rhizoctonia solani, and Helminthosporium sativum.
Experimental
IR spectra were recorded on a Specord Mꢀ80 instrument
(Nujol for solids and thin film for liquids). NMR spectra were
recorded on a Bruker AC 200 spectrometer (200 (1H), 50.3 (13C),
and 188.3 MHz (19F)) in CDCl3 and (CD3)2SO with Me4Si and
CFCl3, respectively, as external standards. The course of the
reaction was monitored and the purity of the compounds obꢀ
tained was checked by TLC on Silufol UVꢀ254 plates (spots
were visualized under UV light and by treating with a solution of
2,4ꢀdinitrophenylhydrazine).
Furanꢀ2ꢀcarbaldehyde bis(trifluoroacetate) (3a) was obtained
as described for furanꢀ2ꢀcarbaldehyde diacetate.13
Furfural 4a (9.6 g, 0.1 mol) was added dropwise at 10—15 °C
to a stirred mixture of (CF3CO)2O (TFAA) (21.9 g, 0.104 mol)
and CF3COOH (TFA) (0.015 g, 0.13 mmol). The reaction mixꢀ
ture was stirred for 1 h and AcONa (0.013 g, 0.156 mmol) was
added. The mixture was twice fractionated in vacuo at 56—58 °C
(8 Torr) to give bis(trifluoroacetate) 3a (17.34 g, 57%),
Z = O (a), S (b)
Reagents and conditions: i. (CF3CO)2O, CF3COOH, 10→20 °C;
ii. CF3COOH, XeF2, CH2Cl2, 0→20 °C; iii. H2O, CF3COOH.
19
nD = 1.3725. Found (%): C, 35.38; H, 1.36. C9H4F6O5. Calꢀ
culated (%): C, 35.31; H, 1.32. IR, ν/cm–1: 3140 (CH fur.),1795
(CF3C=O), 1230, 1170, 1110 (CF3). 1H NMR (CDCl3), δ: 6.55
(dd, 1 H, CH fur., J = 3.4 Hz, J = 1.9 Hz); 6.78 (d, 1 H,
CH fur., J = 3.4 Hz); 7.58 (d, 1 H, CH fur., J = 1.3 Hz); 7.86 (s,
1 H, CH(OCOCF3)2).
It is known that many thiosemicarbazones of aromatic
aldehydes exhibit high biological activity. For instance,
4ꢀacetylaminobenzaldehyde thiosemicarbazone (preparaꢀ
tion thibone9) and 5ꢀethylsulfanylthiopheneꢀ2ꢀcarbꢀ
aldehyde thiosemicarbazone10 show antitubercular activꢀ
ity, while 4ꢀisopropylbenzaldehyde and thiopheneꢀ2ꢀ
carbaldehyde thiosemicarbazones have fungicidal propꢀ
erties and have been proposed as seed disinfectants.11 The
thiosemicarbazones of the synthesized trifluoromethyl
derivatives of heterocyclic aldehydes (5a,b) were tested
in vitro for fungicidal activity with potato agar against
phytopathogenic fungi according to a generally accepted
procedure12 with the widely used fungicide triadimephon
as a standard (Table 1). The activity of trifluoromethylꢀ
furancarbaldehyde thiosemicarbazone 5a was lower than
that of the standard, while trifluoromethylthiopheneꢀ
5ꢀTrifluoromethylfuranꢀ2ꢀcarbaldehyde (1a). Xenon diꢀ
fluoride (4.23 g, 25 mmol) was added in portions under argon at
0 °C for 30 min to a stirred solution of bis(trifluoroacetate) 3a
(7.65 g, 25 mmol) and TFA (2.85 g, 25 mmol) in CH2Cl2 (50 mL)
in a teflon reaction vessel. The reaction mixture was allowed to
stand for 16 h, poured into ice water (50 mL), and stirred for 1 h.
The organic phase was separated and the product from the aqueꢀ
ous phase was extracted with CH2Cl2 (2×20 mL). The comꢀ
bined organic phases were washed with a solution of NaHCO3
and dried with MgSO4. The solvent was removed and the resiꢀ
due was distilled in vacuo. A fraction with b.p. 49—50 °C
25
(25 Torr) was collected, nD = 1.4239 (cf. Ref. 2: b.p. 66 °C
25
(40 Torr), nD = 1.4256). The yield of aldehyde 1a was 1.27 g
(30%). IR, ν/cm–1: 3140 (CH fur.), 2850 (CHO), 1685 (C=O),
1
1300, 1182, 1140, 1110 (CF3). H NMR (CDCl3), δ: 6.99 (d,
Table 1. Growth suppression of the mycelium of pathogenic
fungi in vitro by thiosemicarbazones 5a and 5b (c = 30 mg L–1
1 H, CH fur., J = 3.2 Hz); 7.31 (d, 1 H, CH fur., J = 3.3 Hz);
9.77 (s, 1 H, CHO). 19F NMR, δ: –64.38.
)
5ꢀTrifluoromethylfuranꢀ2ꢀcarbaldehyde
thiosemicarbꢀ
Comꢀ
pound
Growth suppression of microorganisms (%)
azone 5a, m.p. 163—164 °C (from C6H6) (cf. Ref. 2: m.p.
162—164 °C (from C6H6)). H NMR ((CD3)2SO), δ: 7.09 (d,
1 H, CH fur., J = 3.1 Hz); 7.18 (d, 1 H, CH fur., J = 3.1 Hz);
7.74 (br.s, 1 H, NH2); 7.98 (s, 1 H, CH=N); 8.33 (br.s, 1 H,
NH2); 11.61 (br.s, 1 H, NH—N=).
1
V.i.
R.s.
F.o.
F.m.
H.s.
S.s.
5a
5b
Triadiꢀ
mephon
30
97
53
16
84
54
19
51
72
21
77
90
57
82
45
11
45
59
Thiopheneꢀ2ꢀcarbaldehyde bis(trifluoroacetate) (3b) was obꢀ
tained as described for bis(trifluoroacetate) 3a. The yield of
19
compound 3b was 98%, nD = 1.4061. Found (%): C, 33.71;
Note: V.i. stands for Venturia inaequalis, R.s. for Rhizoctonia
solani, F.o. for Fuzarium oxysporum, F.m. for Fuzarium
maniliforme, H.s. for Helminthosporium sativum, and S.s. for
Sclerotinia sclerotiorum.
H, 1.36; S, 9.73. C9H4F6O4S. Calculated (%): C, 33.55; H, 1.25;
S, 9.95. When distilled in vacuo (b.p. 70—72 °C (2 Torr),
35—38 °C (0.2 Torr)), bis(trifluoroacetate) 3b partially decomꢀ
poses to compound 4b. IR, ν/cm–1: 3120 (CH thioph.), 1798

1674
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 7, July, 2005
Popkov and Kuzenkov
(CF3C=O), 1230, 1175, 1110 (CF3). 1H NMR (CDCl3), δ: 7.11
(dd, 1 H, CH thioph., J = 5.1 Hz, J = 3.7 Hz); 7.44 (dd, 1 H,
CH thioph., J = 3.7 Hz, J = 1.2 Hz); 7.55 (dd, 1 H, CH thioph.,
J = 5.1 Hz, J = 1.2 Hz); 8.06 (s, 1 H, CH(OCOCF3)2). 19F NMR,
δ: –75.37.
cyclic Compounds: Synthesis and Application], Nauka,
Novosibirsk, 2001, p. 6 (in Russian).
2. R. E. Bambury, H. K. Yaktin, and K. K. Wyckoff,
J. Heterocycl. Chem., 1968, 5, 95.
3. R. V. Grigorash, V. V. Lyalin, L. A. Alekseeva, and L. M.
Yagupol´skii, Khim. Geterotsikl. Soedin., 1977, 1607 [Chem.
Heterocycl. Compd., 1977, 13, 1280 (Engl. Transl.)].
4. Jpn Pat. 63 66131; Chem. Abstr., 1988, 109, 128541.
5. Y. Tanabe, N. Matsuo, and N. Ohno, J. Org. Chem., 1988,
53, 4582.
6. T. B. Patrick, S. Khazaeli, S. Nadji, K. HeringꢀSmith, and
D. Reif, J. Org. Chem., 1993, 58, 705.
7. V. K. Brel´, N. Sh. Perkuliev, and N. S. Zefirov, Usp. Khim.,
2001, 70, 262 [Russ. Chem. Rev., 2001, 70, 231 (Engl.
Transl.)].
8. T. Umemoto, Preparation and Function of Fluorine Comꢀ
pounds, Ed. N. Ishikawa, CMC Co. Ltd., Tokyo, 1987,
339 pp.
9. M. D. Mashkovskii, Lekarstvennye sredstva. Posobie dlya
vracha [Drugs. A Reference Book for a Doctor], 14th ed.,
revised and supplemented, Novaya Volna, Moscow, 2000,
Ch. 1 (in Russian).
5ꢀTrifluoromethylthiopheneꢀ2ꢀcarbaldehyde (1b) was obꢀ
tained as described for aldehyde 1a. Compound 1b contains an
impurity of the starting aldehyde 4b. Aldehyde 1b was isoꢀ
lated by column chromatography on Acros Organics silica gel
(0.030—0.070 mm) with CH2Cl2 as an eluent. The yield of
compound 1b was 24%, b.p. 75—78 °C (20 Torr), nD20 = 1.4694.
Found (%): C, 39.81; H, 1.73; S, 17.69. C6H3F3OS. Calcuꢀ
lated (%): C, 40.00; H, 1.68; S, 17.80. IR, ν/cm–1: 3115
(CH thioph.), 2840 (CHO), 1670 (C=O), 1285, 1210, 1165,
1130 (CF3). 1H NMR (CDCl3), δ: 7.55 (d, 1 H, CH thioph., J =
4.0 Hz); 7.76 (d, 1 H, CH thioph., J = 4.0 Hz); 10.01 (s, 1 H,
1
CHO). 13C NMR, δ: 121.8 (q, CF3, JC,F = 266 Hz); 128.8
2
(C(4)); 133.7 (C(3)); 134.8 (q, C(5), JC,F = 144 Hz); 146.1
(C(2)); 182.9 (COH). 19F NMR, δ: –56.28.
5ꢀTrifluoromethylthiopheneꢀ2ꢀcarbaldehyde thiosemicarbꢀ
azone 5b, m.p. 161—162 °C (from C6H6). Found (%): C, 33.41;
H, 2.62; N, 16.37. C7H6F3N3S. Calculated (%): C, 33.20;
H, 2.39; N, 16.59. 1H NMR ((CD3)2SO), δ: 7.53 (d, 1 H,
CH thioph., J = 3.8 Hz); 7.81 (d, 1 H, CH thioph., J = 3.8 Hz);
7.84 (br.s, 1 H, NH2); 8.23 (s, 1 H, CH=N); 8.34 (br.s, 1 H,
NH2); 11.67 (br.s, 1 H, NH—N=). 19F NMR, δ: –54.25.
10. L. N. Pavlov, O. O. Makeeva, Ya. L. Danyushevskii, Yu. B.
Vol´kenshtein, N. E. Danilina, and Ya. L. Gol´dfarb, Khim.
Geterotsikl. Soedin., 1967, 176 [Chem. Heterocycl. Compd.,
1967, 3, 136 (Engl. Transl.)].
11. Fr Pat. 2 305 128; Chem. Abstr., 1976, 87, 48908.
12. Metodicheskie rekomendatsii po opredeleniyu fungitsidnoi
aktivnosti novykh soedinenii [Methodological Recommendaꢀ
tions for Determination of the Fungicidal Activity of Novel Comꢀ
pounds], NIITEKhIM, Cherkassy, 1984 (in Russian).
13. Organic Syntheses, 33, Wiley, New York, 1953, 39.
We are grateful to B. V. Sokolov (Russian Scientific
Center "Kurchatov Institute") for providing xenon diꢀ
fluoride.
References
1. G. G. Furin, Ftorsoderzhashchie geterotsiklicheskie
soedineniya: sintez i primenenie [FluoroꢀContaining Heteroꢀ
Received July 7, 2004;
in revised form January 11, 2005