A new method for the synthesis of silicon-and germanium-containing 2-acetylfurans and 2-acetylthiophenes

Article abstract of DOI:10.1007/s10593-007-0024-y

A new method was developed for the synthesis of silicon-and germanium-containing acetylfurans and acetylthiophene by metallation of 2-acetylfuran or 2-acetylthiophene with n-BuLi at low temperature after protection of the carbonyl group with lithium N-methylpiperazide and reaction of the lithium derivative with various trialkyl-, alkylphenyl-, and cycloalkylchlorosilanes or trialkylchloro(bromo)germanes. The cytotoxic activity of the new compounds was studied, and it was established that the silicon-and germanium-containing acetylfurans and acetylthiophenes are substances with low toxicity (LD₅₀ 312->2000 mg/kg) and have low cytotoxicity toward HT-1080 and MG-22A tumor cells.

Full text of DOI:10.1007/s10593-007-0024-y

Chemistry of Heterocyclic Compounds, Vol. 43, No. 2, 2007
A NEW METHOD FOR THE SYNTHESIS OF SILICON-
AND GERMANIUM-CONTAINING 2-ACETYLFURANS
AND 2-ACETYLTHIOPHENES
E. Lukevics, L. Ignatovich, I. Sleiksha, V. Romanov,
S. Grinberga, J. Popelis, and I. Shestakova
A new method was developed for the synthesis of silicon- and germanium-containing acetylfurans and
acetylthiophene by metallation of 2-acetylfuran or 2-acetylthiophene with n-BuLi at low temperature
after protection of the carbonyl group with lithium N-methylpiperazide and reaction of the lithium
derivative with various trialkyl-, alkylphenyl-, and cycloalkylchlorosilanes or trialkylchloro-
(bromo)germanes. The cytotoxic activity of the new compounds was studied, and it was established that
the silicon- and germanium-containing acetylfurans and acetylthiophenes are substances with low
toxicity (LD50 312->2000 mg/kg) and have low cytotoxicity toward HT-1080 and MG-22A tumor cells.
Keywords: 2-acetyl-5-alkylphenylsilylthiophenes, 2-acetyl-5-alkylphenylsilylfurans, 2-acetyl-5-sila-
cycloalkylthiophenes, 2-acetyl-5-silacycloalkylfurans, 2-acetyl-5-trialkylsilyl(germyl)thiophenes, 2-acetyl-
5-trialkylsilyl(germyl)furans, synthesis, toxicity, cytotoxicity, 1H, 13C, 29Si NMR.
The presence of a heterocycle in various types of organic compounds plays a significant role in their
manifestation of biological activity [1, 2]. The type and effectiveness of the biological action depend both on the
nature of the heterocycle and on the structure and position of the substituents in the ring. Thus, many
preparations contain a furan ring: Ranitidine and lupitidine (for the treatment of stomach ulcers) furosemide and
mefruside (diuretics), bufetol, prazosin, tetrazosin, and alfuzosin (antihypertensive agents), furodazole
(antihelminthic preparation), dantrolene (muscle relaxant), furagin and solafur (antibacterial preparations),
naftidrofuril (vasodilator), ipomeanols and ftorafur (antitumor agents). 2-Furyloxocarboxylic acid was used in
the synthesis of the cephalosporin antibiotic cerufoxime, and thienylacetic acid was used in the synthesis of
cefalotine [1]. It is interesting to note that if there is a 4-nitrophenyl group at position 5 of the furan ring the
product from condensation with aminohydantoin – dantrolene – can be used as a muscle relaxant; however, if the
nitro group is directly attached to the furan ring the antibacterial agent nitrofurantoin is obtained.
It is known that the presence of a silyl or germyl group in an organic compound substantially increases
the lipophilicity of the substance, i.e., its ability to pass through cell membranes, which in many cases
substantially increases the biological activity of the compound compared with the carbon analogs [3].
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga, Latvia; e-mail: ign@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 2, pp. 192-199, February, 2007. Original article submitted November 11,
2006.
0009-3122/07/4302-0143©2007 Springer Science+Business Media, Inc.
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Comparative study of the toxicity of our synthesized 5-alkyl-, 5-trialkylgermyl-, and 5-trialkylsilyl-
2-trifluoroacetylfurans and their oximes also showed a definite dependence of the toxicity on the substituents at
position 5 [4]. Thus, modification in the organic substituent, condensation of the carbonyl group in
2-trifluoroacetyl-5-trimethylsilylfuran with hydroxylamine, leads to a compound with cytotoxicity for two lines
of tumor cells HT-1080 and MG-22A (LC50 0.3 and 0.8 µg/ml respectively) [5], while further transformation of
the oxime to an alkoxyimine group leads to total loss of cytotoxicity by the compound [6].
In order to develop further the synthetic base for the production of new biologically active substances
based on 2-acetylfuran and 2-acetylthiophene we worked out a new method for the synthesis of silicon- and
germanium-containing acetylfurans and acetylthiophenes and studied their biological activity.
The acyl derivatives of furan and thiophene are usually obtained by acylation of the respective
heterocycle with acetic anhydride in the presence of catalytic amounts of iodine or phosphoric acid [7, 8].
Recently Bowman analyzed and summarized published data on the acylation of thiophene over the last 60 years
[9]. Kinetic investigations showed that the α-position of furan is 7·104 times more reactive than the β-position
[10].
The presence of the silicon- or germanium-containing substituent in the heterocycle significantly
complicates the classical Friedel–Crafts acylation since it is accompanied by ipso substitution of the
heteroatomic substituent. This reaction is widely used in organic synthesis for the selective introduction of
a substituent into an aromatic or heteroaromatic ring [11].
However, the authors in [12] were able to realize the acylation of 2-trimethylsilylfuran and
2-trimethylsilylthiophene with acetic anhydride in the presence of iodine and obtain 2-acetyl-5-
trimethylsilylfuran and 2-acetyl-5-trimethylsilylthiophene with small yields (25 and 13% respectively).
We developed a new method for the synthesis of silyl- and germyl-substituted acetylfurans and
acetylthiophenes by metallation of commercially available 2-acetylfuran and 2-acetylthiophene with n-BuLi at
low temperature after first protecting the carbonyl group with lithium N-methylpiperazide (LiNMP) in situ and
reaction of the obtained lithium derivative with the corresponding chloro(bromo)silane or
chloro(bromo)germane. By the proposed method we were able to obtain a wide range of silicon- and
germanium-substituted acetylfurans and acetylthiophenes with yields of 27-78% and to study their cytotoxic
activity.
1. LiNMP / THF
2. n-BuLi
3. R3MY
+
4. H2O (H )
Me
C
O
R3M
X
X
C
O
Me
1–14
X = O, S; Y = Cl, Br
The yields and physicochemical characteristics of the synthesized compounds are given in Table 1. The
IR and 13C and 29Si NMR spectra are given in Table 2.
Comparison of the δ29Si chemical shifts of the organosilicon derivatives of furan 1, 2, and 5-7 and their
thiophene analogs 8, 9, and 12-14 shows that the 29Si signals of all the furan derivatives appear in the upfield
region (by 3.22-3.85) from the signals of the corresponding thiophene derivatives.
To determine the effect of the nature of the heteroatomic substituent in the ketones 1-14 on the antitumor
activity we studied their cytotoxicity (Table 3) for two lines of tumor cells: HT-1800 (human
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fibrosarcoma) and MG-22A (mouse hepatoma). For comparison we studied the cytotoxicity of these compounds
for normal NIH 3T3 cells (the normal fibroblasts of mouse embryos) and their toxicity (LD50, mg/kg). The
investigation showed that all the studied ketones 1-14 are weakly toxic substances with lethal doses (LD50) in the
range of 312->2000 mg/kg (Table 3). It is interesting to note that 2-acetyl-5-triethylsilylthiophene 9 was -4 times
more toxic than the furan analog 2. Substitution of one methyl group in 2-acetyl-5-trimethyl-silylthiophene by
phenyl [compound 12] reduces the toxicity of the compound by half. Substitution of the trimethylsilyl
substituent by trimethylgermyl substantially reduces the toxicity of the compound both in the thiophene and in
the furan series [compounds 1 and 3 and 8 and 10]. Unfortunately, compounds 1-14 hardly exhibited any
cytotoxic activity against HT-1080 and MG-22A tumor cells and proved toxic against normal NIH 3T3 cells.
Only 2-acetyl-5-triethylsilylthiophene 9 proved moderately cytotoxic against tumor and normal cells. It also had
the highest NO generating activity.
EXPERIMENTAL
1
13
29
The H, C, and Si NMR spectra were recorded on a Varian Mercury-200 spectrometer (200, 50, and
1
40 MHz respectively) in CDCl3 with standards HMDS (δ 0.055 ppm) for H, TMS (external) for 29Si, and the
signal of the residual proton of the solvent (δ 77.05 ppm) for 13C. The mass spectra were recorded on a GC-MS
HP 6890 mass spectrometer with 70 eV ionizing electrons. The 2-acetylthiophene and 2-acetylfuran were
obtained from Acros. The N-methylpiperazine and THF were dried over CaH2 and distilled.
The cytotoxicity of compounds 1-14 (Table 3) was determined by the procedure described in [13]. The
acute toxicity (LD50, mg/kg) on a culture of 3T3 cells (alternative LD50 in an in vivo test) was determined
according to protocols [14].
2-Acetyl-5-trimethylsilylfuran (1) and 2-Acetyl-5-trimethylsilylthiophene (8). These compounds
were obtained from the corresponding acetyl derivatives by the method described in [13].
2-Acetyl-5-triethylgermylthiophene (11). In a three-necked flask fitted with a reflux condenser,
a thermometer, a magnetic stirrer, and a rubber stopper in a stream of argon we placed 2.0 g (20 mmol) of
freshly distilled N-methylpiperazide, dissolved in 40 ml of absolute TFH. The flask with the solution was cooled
to -78°C, and 9.1 ml (20 mmol) of a 2.2 N solution of n-BuLi in hexane was slowly added drop by drop with a
syringe so that the temperature in the flask did not exceed -78°C. When all the n-BuLi had been added the
mixture was stirred for 15 min at -78°C, and 2.27 g (20 mmol) of 2-acetylthiophene in 7 ml of THF was added
drop by drop. When all the 2-acetylthiophene had been added the mixture was stirred for 20 min, and 9.1 ml
(20 mmol) of a 2.2 N solution of n-Buli in hexane was added drop by drop. When all the butyllithium had been
added the temperature was raised to -20°C, and the mixture was stirred at this temperature for 4 h 30 min. The
mixture was cooled to -78°C, and a solution of 4.7 g of triethylbromogermane in 10 ml of THF was slowly
added drop by drop. After the addition of the triethylbromogermane the mixture was stirred at -78°C for 15 min,
the temperature was slowly raised to room temperature, and the mixture was stirred for 10 h. The reaction
mixture was hydrolyzed with 120 ml of 1 M HCl at 0°C for 10 min and neutralized with a saturated solution of
sodium carbonate. The product was extracted with ether (50 ml×3), and the extracts were combined and dried
over magnesium sulfate. The mixture was passed through a layer of Al2O3, and the ether was evaporated to
dryness. The residue was distilled under vacuum at 130-132°C (5 mm Hg), and 4.0 g (78%) of the ketone 11 was
obtained.
The ketones 2-7, 9, 10, and 12-14 were obtained similarly.
The authors express their gratitude to Dr. Chem. M. Petrova for recording the IR spectra.
The work was carried out with financial support from the Latvian Council of Science (grant 1771).
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