Synthesis and stereoisomerization of 2-(1-alkoxyimino-2,2,2-trifluoroethyl) -5-trimethylsilylfurans

Article abstract of DOI:10.1007/s10593-005-0211-7

2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans were synthesized by the condensation of 2-(trifluoroacetyl)-5-trimethylsilylfuran with alkoxyamines. According to ¹H and ¹⁹F NMR spectroscopic data, the alkoxyimino group in the E-isomers descreens the H-3 and H-4 protons of the furan ring more strongly than in the Z-isomers, shifting their signals downfield. The fluorine atoms of the α-trifluoromethyl group in the Z-isomer are characterized by a downfield shift in relation to the E-isomer. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0211-7

Chemistry of Heterocyclic Compounds, Vol. 41, No. 6, 2005
SYNTHESIS AND STEREOISOMERIZATION
OF 2-(1-ALKOXYIMINO-2,2,2-TRIFLUOROETHYL)-
5-TRIMETHYLSILYLFURANS
Yu. Melnik, M. Vorona, G. Veinberg, J. Popelis, L. Ignatovich, and E. Lukevics
2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans were synthesized by the condensation of
2-(trifluoroacetyl)-5-trimethylsilylfuran with alkoxyamines. According to 1H and 19F NMR
spectroscopic data, the alkoxyimino group in the E-isomers descreens the H-3 and H-4 protons of the
furan ring more strongly than in the Z-isomers, shifting their signals downfield. The fluorine atoms of
the α-trifluoromethyl group in the Z-isomer are characterized by a downfield shift in relation to the
E-isomer.
1
Keywords: 2-(1-alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans, syn,anti stereoisomerism, H,
19F spectroscopy.
The presence of furan in various types of organic compounds is a determining factor in their display of
biological activity, the effectiveness of which depends on the structure of substituents at positions 2 and 5 of the
heterocycle. This tendency was observed, in particular, during a comparative study of the toxicity of our
previously synthesized 5-alkyl-, 5-trialkylgermyl-, and 5-trialkylsilyl-2-trifluoroacetylfurans [1].
In order to develop further the synthetic basis for the production of new biologically active substances
based on 2-(trifluoroacetyl)-5-trimethylsilylfuran (1) we realized the alkoxyimination of this compound and
studied the stereoisomerism of the products.
OR
O
H2N
2a–h
R
N
O
3 4
6
2
5
SiMe3
SiMe3
1
O
F3C
F3C
O
3a–h
1
2, 3 a R = Me, b R = Et, c R = n-Pr, d R = i-Pr, e R = n-Bu, f R = n-C8H17,
g R = CH2CH=CH2, h R = CH2Ph
Alkoxyimination of the trifluoroacetyl group in the initial furan 1 with the hydrochlorides of
alkoxyamines 2a-h was carried out in boiling ethanol in the presence of sodium acetate. Compounds 3a-h were
isolated from the reaction mixture by column chromatography with yields of 7-70%. Their chromatomass-
spectrometric analysis indicates that apart from the methoxyimino derivative 3a, which consists of two isomers,
the other alkoxyimino derivatives 3b-g are represented almost entirely by only one isomeric form (Table 1).
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga; e-mail: veinberg@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 834-838, June, 2005. Original article submitted December, 7, 2004.
718
0009-3122/05/4106-0718©2005 Springer Science+Business Media, Inc.

Analysis of the 1H and 19F NMR spectra (Table 2) showed that the trifluoroacetyl group in compound 3a
is arranged in two ways in relation to the C(2)–C(6) bond. Besides each conformer A and B corresponds to fixed
anti-(E) of syn-(Z) arrangement of the methoxy group.
H
RO
N
F3C
6
6
2
2
SiMe3
SiMe3
O
O
F3C
N
OR
B (Z)
A (E)
This could be indicated in the spectrum of the conformer B by the presence of long-range spin–spin
coupling constants for the H-3 proton and fluorine nuclei (5JHF = 1.7-2.2 Hz), due to the W-conformation of the
five chemical bonds situated between them, which absent in the structure of conformer A.
As far as the hydroxyimino group in 2-(α-alkoxyiminoethyl)furans is concerned, it is known that this
group descreens the H-3 and H-4 protons of the furan ring more strongly than in the E-isomers, leading to a
downfield shift of their signals. A similar descreening effect from the methoxyimino group in the Z-isomer
appears in relation to the protons of the α-methyl group, shifting their signals downfield compared with the
E-isomers [2, 3].
According to the above-mentioned data, the chemical shifts of the H-3 protons in the furan ring show
unambiguously that the methoxy group has E-geometry in conformer A of compound (3a) (7.34 ppm) (Table 2)
and Z-geometry in conformer B (6.75 ppm). [With identical spatial orientation for the isomeric alkoxyimines
both in our synthesized compounds and in those described in [2, 3] their nomenclature in the case of 3a-g is
reversed in so far as the replacement of hydrogen atoms by fluorine atoms changes the seniority of the
TABLE 1. The Physicochemical Characteristics of 2-(1-Alkoxyimino-2,2,2-
trifluoroethyl)-5-trimethylsilylfurans 3a-h
Com-
pound
E/Z
isomers
Yield,
%
Rf*
MS-GC, m/z (Irel-,%)
E-3a
Z-3a
0.23
0.23,
93/7
20/80
265 [M+] (25), 250 [M+ –Me] (36), 123 (9),
89 (32), 77 (100)
7
63
0.14*2
265 [M+] (27), 250 [M+ –Me] (30), 123 (7),
89 (41), 77 (100)
E-3b
Z-3b
0.28
>99/<1
279 [M+] (62), 264 [M+ –Me] (39), 236 (17),
103 (55), 77 (100)
58
279 [M+] (33), 264 [M+ –Me] (100), 236 (21),
150 (36), 73 (16)
E-3c
E-3d
E-3e
E-3f
E-3g
0.36
0.26
0.38
0.34
0.32
0.31
>99/<1
100/0
98/2
251 [M+ –C3H6] (4), 236 [M+ –Me] (33),
220 (48), 77 (35), 43 (100)
29
7
251 [M+ –C3H6] (31), 236 [M+–Pr–Me] (76),
123 (10), 75 (100)
307 [M+] (14), 292 [M+ –Me] (7), 236 (52),
220 (66), 123 (14), 77 (100)
23
12
65
28
100/0
98/2
363 [M+] (6), 348 [M+ -Me] (4), 262 (35),
236 (47), 220 (98), 123 (16), 73 (67), 43 (100)
291 [M+] (31), 276 [M+ –Me] (3), 128 (22),
73 (100), 41 (63)
E-3h
98/2
341 [M+] (4), 326 [M+ –Me] (3), 91 (100), 77 (11)
_______
* Data from TLC, 1:10 ethyl acetate–petroleum ether system.
*2 A chromatically inseparable mixture.
719

720

trifluoromethyl group.] The opposite tendency could be observed in the case of the fluorine atoms of the α-
trifluoromethyl group, which unlike the protons of the α-methyl group are characterized by a more downfield
signal (-63.83 ppm) for the Z-isomer than for the E-isomer (-66.12 ppm).
The chemical shifts of the H-3 protons in the other alkoxyimino derivatives of furan 3b-h in the region
of 7.33-7.66 ppm indicate that they are all represented almost entirely by only one A conformer with E-geometry
for the alkoxyimino group (Table 2).
Determination of the cytotoxic characteristics of the synthesized substances in vitro according to the
standard procedure [4] showed that only compounds 3a,d at concentrations of 50-100 µg/ml caused the
destruction of 50% of monolayer tumor cells of the HT-1080 line (human fibrosarcoma). Compounds 3c,d,h did
not exhibit cytotoxic characteristics.
The investigation has made it possible to synthesize low-toxicity alkoxyimino derivatives of
2-(trifluoroacetyl)-5-trimethylsilylfurans 3a-h and also to identify the spatial arrangement of the alkoxy- and
trifluoromethyl groups on the basis of data from 1H and 19F NMR spectroscopy.
EXPERIMENTAL
1
The NMR spectra were recorded on a Varian 200 Mercury spectrometer (200 MHz for H, internal
standard TMS, and 188 MHz for 19F, external standard CFCl3) in CDCl3. The mass spectra were obtained on an
HP6890 GC-MS chromato-mass spectrometer (70 eV). The reaction was monitored by TLC on Merck Kieselgel
plates with development in UV light. Merck Kieselgel silica gel (0.063-0.230 mm) was used for preparative
column chromatography. Reagents and materials from Acros were used in the experiments. The hydrochlorides
of the alkoxyamines 2a-h were synthesized by O-alkylation of N-hydroxysuccinimide with the respective alkyl
halides followed by hydrolysis of the obtained N-alkoxysuccinimides with dilute hydrochloric acid.
Production of 2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans (3a-h) (General
Procedure). Sodium acetate (463 mg, 5.71 mmol) and the alkoxyamine 2a-h hydrochloride (3.17 mmol) were
added to a solution of 2-trifluoroacetyl-5-trimethylsilylfuran (450 mg, 1.90 mmol) in ethanol (15 ml). The
mixture was boiled for 4 h, and the solvent was evaporated under vacuum. The residue was chromatographed on
a column of silica gel in 1:10 ethyl acetate–petroleum ether. In the case of 3a (R = Me) the E-isomer was
isolated from the fraction with Rf 0.23, while a mixture of E/Z-isomers was isolated from the inseparable mixture
of fractions with Rf 0.23 and Rf 0.14 respectively. The fractions from which the other substances 3b-h were
obtained were characterized almost entirely by the presence of only one stereoisomer.
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