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DOI: 10.1055/s-0032-1316564
Simple Ultrasound-Assisted Synthesis of 3,4-Dihydropyrimidin-2(1H)-one and 3,4-Dihydropyrimidine-2(1H)-thione-Fused Steroidal Derivatives by a Three-Component Reaction
Publication History
Received: 26 April 2012
Accepted after revision: 30 May 2012
Publication Date:
13 July 2012 (online)
Abstract
Compounds containing fused 3,4-dihydropyrimidin-2(1H)-one or 3,4-dihydropyrimidine-2(1H)-thione moieties were prepared by three-component reactions of a steroidal or nonsteroidal ketone, an alkyl or aryl aldehyde, and urea or thiourea in the presence of sodium ethoxide. The products were isolated in good yields after short reaction times under mild conditions.
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Dihydropyrimidinones and dihydropyrimidinethiones are important classes of bioactive molecules that can exhibit a wide range of properties, such as antiviral, antitumor, antibacterial, or antiinflammatory activities.[ 1 ] These compounds can also act as calcium-channel blockers, antihypertensives, anticancer agents, neuropeptide Y antagonists, and α1a adrenergic antagonists.[ 2 ] The biological activity of some recently isolated alkaloids has been attributed to the presence of a dihydropyrimidinone moiety,[1a] [3] the most prominent of these alkaloids being the batzalladine alkaloids, which are potent inhibitors of HIV-gp-120-CD4.[ 3a ]
The synthesis of dihydropyrimidinones and their thione analogues was first reported by Biginelli in 1893.[ 4 ] Improved procedures and new Biginelli-like scaffolds have been reported over the past decade, and considerable efforts have been made to develop new methods for the synthesis of such compounds because of their therapeutic and pharmacological properties.[2c] [5] There are several reports on the synthesis of derivatives of dihydropyrimidinone and dihydropyrimidinethione by using protic acids,[ 6 ] Lewis acids,[ 7 ] triflates,[ 8 ] microwave irradiation,[ 9 ] ionic liquids,[ 10 ] metallic salts,[ 11 ] Dowex-50W,[ 12 ] or polyaniline, tetrafluoroboric acid, and dodecyl hydrogen sulfate.[ 13 ] Unfortunately, many of these methods suffer from major or minor limitations, such as harsh reaction conditions, low yields, expensive or toxic reagents, stoichiometric requirements for catalysts, strongly acidic conditions, long reaction times, or incompatibility with various functional groups. Therefore, the development of a milder, faster, eco-friendly, and high-yielding protocol for the synthesis of compounds containing a 3,4-dihydropyrimidin-2(1H)-one or a 3,4-dihydropyrimidine-2(1H)-thione moiety remains of great importance and represents a considerable challenge.
The recent development of synthetic protocols that use ultrasound irradiation has led to epoch-making changes in organic chemistry, as it permits the activation of substrates that have low reactivities.[ 14 ] Among the notable features of ultrasound-promoted reactions that are recognized as having value in green chemistry[14c] [d] are enhanced reaction rates, the formation of purer products in improved yields, greater ease of manipulation, improved energy conservation, and minimization of wastes.[ 15 ]
a US: Ultrasound irradiation; MW: Microwave irradiation; TH: thermal heating.
b Isolated yield of isolated product.
Multicomponent reactions form an important class of reactions that are related to tandem reactions and that can be used to generate vast libraries of compounds with great rapidity. The highly flexible and selective nature of multicomponent reactions makes them convenient tools for the construction of many heterocyclic compounds.[ 16 ] It is known that the Biginelli reaction catalyzed by acids such as hydrochloric, trifluoroacetic, or aminosulfonic acid is accelerated by ultrasound.[ 17 ] Even Bignelli reactions catalyzed by ceric ammonium nitrate, ionic liquids, iodine, ammonium chloride, silica, or magnesium perchlorate are promoted by ultrasound.[ 18 ] However, there are few reports on base-catalyzed Biginelli reactions[ 19 ] and, the best of our knowledge, there is no report of an ultrasound-assisted, base-mediated, one-pot, Biginelli-type, three-component reaction of a cyclic ketone, an aldehyde, and urea or thiourea. In a continuation of our studies on heterosteroids,[ 20 ] we present a very simple, mild, economic, and efficient strategy for the synthesis of dihydropyrimidinone- or dihydropyrimidinethione-fused steroids and nonsteroids through an ultrasound-promoted, three-component, one-pot condensation of a ketone, an aldehyde, and thiourea or urea in the presence of an equimolar amount of base using 2-propanol as an environmentally benign solvent.[ 21 ]
a Yield of the isolated product.
We began our study by investigating the reaction of cholestan-3-one (1a) with benzaldehyde (2a) and urea (3a) in presence of an equimolar amount of sodium ethoxide as the base (Scheme [1]). We performed an extensive optimization of the three-component reaction to determine the best condition for the synthesis of the 3,4-dihydropyrimidine-2(1H)one-fused steroid product 4a (Table [1]). Initially, we examined the synthesis of 4a by three different methods involving ultrasound irradiation (US), microwave irradiation (MW), and conventional thermal heating (TH), respectively. We selected the protic solvents ethanol, 2-propanol, and water as media for the reaction. When the three-component reaction was carried in ethanol or 2-propanol under thermal condition for six hours, the product 4a was obtained in 56 and 65% yield, respectively (Table [1], entries 3 and 6, respectively). Similarly, the microwave-mediated reaction of 1a, 2a, and 3a in protic solvent under basic condition gave 4a in 50–63% yield (entries 2 and 5), whereas the solid-phase three-component reaction with microwave heating for 15 minutes gave a 39% yield of 4a (entry 8). Our initial attempt to carry out the three-component reaction with ultrasonication in water as the solvent gave a poor yield (33%) of 4a (entry 7). However, we observed that the use of isopropanol as a cosolvent (20%) improved the yield of 4a to 70% (entry 9). The best yield (94%) was, however, obtained by conducting the three-component reaction with ultrasound irradiation in 2-propanol as the solvent (entry 4).
Next, we examined the three-component reaction of cholestan-3-one (1a) with various aromatic or aliphatic aldehydes 2b–g and urea (3a) or thiourea (3b) under our optimized reaction conditions (Table [2]). The corresponding products 4b–n were obtained in in 86–93% yields.
To evaluate the scope and limitations of the reaction further, we extended it to the steroidal A-ring conjugated ketone 1b, the D-ring oxo steroid 1c, the B-ring conjugated ketone 1d, and the nonsteroidal cyclic ketones 1e–f under our optimized condition, and we obtained products 4o–x in 85–91% yields (Table [3]).
a Yield of the isolated product.
The fused steroids and nonsteroids 4a–x were characterized by means of 1H and 13C NMR spectroscopy and GC/MS.
In relation to the mechanism, we believe that the initial condensation of benzaldehyde (2a) on the α-position of ketone 1a under basic condition leads to the formation of the intermediate exo-α,β-unsaturated ketone A; this readily undergoes a Michael addition reaction with thiourea to afford intermediate B. This intermediate then undergoes dehydrative cyclization to give the product 4h. To substantiate this mechanism, we independently prepared the stable intermediate 2-benzylidenecholestan-3-one (A) by condensation of cholestan-3-one (1a) with benzaldehyde (2a), and we treated intermediate A with thiourea under ultrasound to give the fused derivative 4h in high yield (88%). The most probable reason for the increase in the efficiency of the reaction in the presence of ultrasound is that cavitation creates bubbles that collapse, inducing mechanical stress that can be transmitted to a target bond.[ 22 ]
In summary, we have developed a simple, rapid, and efficient base-catalyzed one-pot procedure for the annulation of a 3,4-dihydropyrimidin-2(1H)-one or 3,4-dihydropyrimidine-2(1H)-thione moiety onto the A-, B-, or D-ring of a steroid by a three-component reaction of a steroidal ketone, an aromatic or aliphatic aldehyde, and urea or thiourea. We have compared the ultrasound-promoted Biginelli-type reaction with the corresponding reactions under conventional heating or microwave heating, and we have shown that the ultrasound-mediated reaction produces the best results. The reaction provides a new method for the preparation of A-, B- and D-ring-fused steroidal 3,4-dihydropyrimidin-2(1H)-ones and 3,4-dihydropyrimidin-2(1H)-thiones from keto steroids or endocyclic conjugated keto steroids. This new method provides significant advantages in comparison to previous methods[6] [7] [8] [9] [10] [11] [12] [13] for synthesizing 3,4-dihydropyrimidin-2(1H)-ones and 3,4-dihydropyrimidin-2(1H)-thiones, in that the reaction is easy to perform and can be conducted at ambient temperature with short reaction times and very simple workup to give good yields (85–94%) of the required products.
Melting points were measured with a Buchi B-540 melting-point apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer FTIR-2000 spectrometer by using KBr pellets. NMR spectra were recorded on a Bruker Avance DPX 300-MHz FT-NMR spectrometer with TMS as the internal standard. Mass spectra were recorded on a Trace DSQ GCMS instrument. All the commercially available regents were used as received. All experiments were monitored by TLC on pre-coated silica gel plates (Merck). Column chromatography was performed on silica gel (60–120 mesh, Merck Chemicals). Sonication was carried in round-bottom flasks immersed in a standard ultrasonic bath producing sound waves at 44.2 kHz. All microwave reactions were carried out in a Synthos 3000 (Anton Paar) microwave reactor.
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3,4-Dihydropyrimidin-2′(1H)-ones and 3,4-Dihydropyrimidine-2′(1H)-thiones; General Procedures
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Method I (Ultrasound)
A mixture of the ketone (1 mmol), aldehyde (1 mmol), urea or thiourea (1 mmol), and NaOEt (1 mmol) in i-PrOH (10 mL) was irradiated with ultrasound for 15 min. The solvent was removed in a rotatory evaporator, and the crude residue was purified by column chromatography [silica gel, EtOAc–hexane (1:10)].
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Method II (Microwave Heating)
A mixture of the ketone (1 mmol), aldehyde (1 mmol), urea or thiourea (1 mmol), and NaOEt (1 mmol) in i-PrOH (10 mL) was irradiated with microwaves in a closed vessel in a Synthos 3000 microwave reactor at 450 W (90 °C and 11 bar) for 15 min. The solvent was removed in a rotatory evaporator, and the crude residue was purified by column chromatography [silica gel, EtOAc–hexane (1:10)].
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Method III (Thermal)
A mixture of the ketone (1 mmol), aldehyde (1 mmol), urea or thiourea (1 mmol), and NaOEt (1 mmol) was refluxed in i-PrOH (10 mL) for 6 h. The solvent was removed in a rotatory evaporator, and the crude residue was purified by column chromatography [silica gel, EtOAc–hexane (1:10)].
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4′-Phenyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestan-2′(1′H)-one (4a)
Yield: 485 mg (94%); light-yellow solid; mp 174–176 °C.
IR (KBr): 3237, 2930, 2868, 1686, 1466, 1220, 770, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.43–7.02 (m, 6 H), 5.32 (s, 1 H), 4.74 (s, 1 H), 2.00–0.50 (m, 44 H).
13C NMR (75 MHz, CDCl3): δ = 154.8, 143.2, 128.8, 128.7, 127.9, 127.3, 127.0, 126.9, 103.7, 61.7, 56.3, 53.3, 42.4, 40.9, 40.1, 39.8, 39.5, 36.1, 35.8, 35.4, 35.0, 31.5 (2C), 29.7, 28.2, 28.0, 24.2, 23.8 (2C), 22.8, 22.6, 21.0, 18.7 12.0, 11.9.
MS (EI): m/z = 516 [M]+.
Anal. Calcd for C35H52N2O: C, 81.34; H, 10.14; N, 5.42. Found: C, 81.19; H, 10.27; N, 5.73.
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4′-(4-Tolyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestan-2′(1′H)-one (4b)
Yield: 477 mg (90%); light-yellow solid; mp 202–204 °C.
IR (KBr): 3237, 2931, 2869, 1687, 1467, 1219, 770, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.45–6.88 (m, 5 H), 5.26 (s, 1 H), 4.71 (s, 1 H), 2.38–0.52 (m, 47 H).
13C NMR (75 MHz, CDCl3): δ = 155.0, 143.1, 129.3, 128.3 (2C), 128.0, 127.1 (2C), 105.1, 61.1, 56.3 (2C), 53.5, 42.3, 41.1, 40.1, 39.8 (2C), 39.4, 36.1, 35.7, 35.4, 34.1, 31.8 (2C), 28.2, 28.0, 24.2, 23.8 (2C), 22.8, 22.7, 21.0, 18.7, 12.1, 12.0.
MS (EI): m/z = 530.4 [M+].
Anal. Calcd for C36H54N2O: C, 81.46; H, 10.25; N, 5.28. Found: C, 81.19; H, 10.21; N, 5.33.
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4′-(4-Fluorophenyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestan-2′(1′H)-one (4c)
Yield: 497 mg (93%); light-yellow solid; mp 228–229 °C.
IR (KBr): 3237, 2930, 2868, 1687, 1467, 1218, 772, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.45–6.76 (m, 5 H), 5.38 (s, 1 H), 4.75 (s, 1 H), 2.27–0.64 (m, 44 H).
13C NMR (75 MHz, CDCl3): δ = 154.7, 142.9, 129.4, 128.5 (2C), 128.2, 127.2 (2C), 105.0, 61.1, 56.2 (2C), 53.4, 42.4, 40.9, 40.1, 39.8, 39.5, 36.2, 35.7, 35.4, 34.1, 31.8 (2C), 28.2, 28.1, 24.1, 23.7 (2C), 22.8, 22.7, 21.1, 18.7, 12.1, 11.9.
MS (EI): m/z = 534.4 [M+].
Anal. Calcd for C35H51FN2O: C, 78.61; H, 9.61; N, 5.24. Found: C, 78.66; H, 9.73; N, 5.50.
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4′-(3-Bromophenyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestan-2′(1′H)-one (4d)
Yield: 511 mg (86%); light-yellow solid; mp 232–234 °C.
IR (KBr): 3236, 2930, 2869, 1686, 1467, 1219, 770, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.43–6.69 (m, 5 H), 5.37 (s, 1 H), 4.71 (s, 1 H), 2.28–0.54 (m, 44 H).
13C NMR (75 MHz, CDCl3): δ = 154.5, 144.0, 130.0, 128.5, 128.2, 127.4, 126.6, 126.4, 104.3, 61.0, 56.2, 53.5, 42.4, 41.0, 40.1, 39.8, 39.5 (2C), 36.1, 35.8, 35.4, 34.1, 31.8 (2C), 28.2, 28.0, 24.2, 23.8 (2C), 22.9, 22.6, 21.1, 18.7, 12.1, 12.0.
MS (EI): m/z = 516.4 [M – Br]+.
Anal. Calcd for C35H51BrN2O: C, 70.57; H, 8.63; N, 4.70. Found: C, 70.77; H, 8.69; N, 4.75.
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4′-Propyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestan-2′(1′H)-one (4e)
Yield: 439 mg (91%); light-yellow solid; mp 183–184 °C.
IR (KBr): 3249, 2929, 2868, 1715, 1467, 1222, 771 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.05 (s, 1 H), 5.67 (s, 1 H), 3.73 (m, 1 H), 2.19–0.66 (m, 51 H).
13C NMR (75 MHz, CDCl3): δ = 153.2, 142.2, 105.4, 56.9, 56.3 (2C), 54.2, 44.6, 42.4, 39.8, 39.5 (2C), 36.2, 35.8, 35.4, 35.3, 31.8 (2C), 31.5, 29.8, 28.2, 28.0 (2C), 24.2 (2C), 23.9 (2C), 22.5, 18.7, 14.2, 11.9, 11.8.
MS (EI): m/z = 482.4 [M+].
Anal. Calcd for C32H54N2O: C, 79.61; H, 11.27; N, 5.80. Found: C, 79.82; H, 11.30; N, 5.73.
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4′-Butyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestan-2′(1′H)-one (4f)
Yield: 437 mg (88%); light-yellow solid; mp 187 °C.
IR (KBr): 3249, 2929, 2868, 1716, 1467, 1222, 771 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.04 (s, 1 H), 5.66 (s, 1 H), 3.74 (m, 1 H), 2.20–0.68 (m, 53 H).
13C NMR (75 MHz, CDCl3): δ = 153.2, 142.2, 105.4, 56.9, 56.3 (2C), 54.3, 44.8, 42.4, 39.8, 39.5 (2C), 36.1, 35.8, 35.4, 35.3, 31.8 (2C), 31.5, 29.7, 28.2, 28.0 (2C), 24.2 (2C), 23.8 (2C), 23.3, 22.6, 18.7, 14.1, 11.9, 11.8.
MS (EI): m/z = 496.4 [M+].
Anal. Calcd for C33H56N2O: C, 79.78; H, 11.36; N, 5.64. Found: C, 79.83; H, 11.20; N, 5.79.
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4′-Pentyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestan-2′(1′H)-one (4g)
Yield: 449 mg (88%); light-yellow solid; mp 194–195 °C.
IR (KBr): 3249, 2929, 2868, 1716, 1467, 1221, 771 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.03 (s, 1 H), 5.70 (s, 1 H), 3.79 (s, 1 H), 2.19–0.66 (m, 55 H).
13C NMR (75 MHz, CDCl3): δ = 153.3, 142.2, 105.4, 56.9, 56.2 (2C), 54.4, 44.9, 42.4, 39.9, 39.5 (2C), 36.1, 35.8, 35.4, 35.3, 31.8 (2C), 31.5, 29.7, 28.2, 28.0 (2C), 24.2 (2C), 23.9 (2C), 23.3, 22.9, 22.6, 18.7, 14.2, 11.9, 11.8.
MS (EI): m/z = 510.4 [M+].
Anal. Calcd for C34H58N2O: C, 79.94; H, 11.44; N, 5.48. Found: C, 79.78; H, 11.25; N, 5.72.
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4′-Phenyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4h)
Yield: 479 mg (90%); light-yellow solid; mp 201–203 °C.
IR (KBr): 3190, 2928, 2868, 1567, 1468, 1208, 758, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.13 (m, 6 H), 6.48 (s, 1 H), 4.77 (s, 1 H), 1.87–0.63 (m, 44 H).
13C NMR (75 MHz, CDCl3): δ = 172.3, 141.8, 130.1, 129.8, 128.9, 128.4, 127.2, 126.0, 107.0, 61.3, 56.3, 53.3, 42.4, 41.8, 39.8 (2C), 36.1, 35.8, 35.4, 35.3, 31.5 (2C), 29.8, 28.2, 28.0, 24.2, 23.8 (2C), 22.8, 22.6, 21.1, 18.7, 12.1, 12.0, 11.9.
MS (EI): m/z = 532.4 [M+].
Anal. Calcd for C35H52N2S: C, 78.89; H, 9.84; N, 5.26. Found: C, 78.95; H, 9.90; N, 5.23.
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4′-(4-Tolyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4i)
Yield: 475 mg (87%); light-yellow solid; mp 212–214 °C.
IR (KBr): 3192, 2929, 2869, 1570, 1490, 1220, 756, 666 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.27 (s, 1 H) 7.38–7.01 (m, 5 H), 4.55 (s, 1 H), 1.99–0.43 (m, 47 H).
13C NMR (75 MHz, CDCl3): δ = 173.1, 141.6, 129.0, 128.1 (2C), 127.1 (2C), 125.5, 106.8, 61.9, 56.3 (2C), 53.3, 42.4, 40.9, 39.8 (2C), 39.5, 36.1, 35.8, 35.0, 31.4, 30.0, 28.1, 28.0 (2C), 24.2 (2C), 23.8 (2C), 22.8, 22.6, 21.0, 18.6, 12.0, 11.9.
MS (EI): m/z = 546 [M+].
Anal. Calcd for C36H54N2S: C, 79.06; H, 9.95; N, 5.12. Found: C, 78.85; H, 9.80; N, 5.36.
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4′-(4-Fluorophenyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4j)
Yield: 484 mg (88%); light-yellow solid; mp 221–223 °C.
IR (KBr): 3192, 2926, 2868, 1570, 1493, 1219, 762, 664 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.27 (s, 1 H) 7.67–6.96 (m, 5 H), 4.55 (s, 1 H), 1.99–0.43 (m, 44 H).
13C NMR (75 MHz, CDCl3): δ = 173.1, 141.7, 129.1, 128.2 (2C), 127.2 (2C), 125.4, 106.9, 61.4, 56.1 (2C), 54.0, 42.8, 41.9, 39.9 (2C), 39.5, 36.1, 35.7, 34.8, 31.5, 30.0, 28.6, 28.0 (2C), 24.9, 23.1, 30.0, 22.6, 21.1, 18.5, 12.7, 12.0, 11.9.
MS (EI): m/z = 550 [M+].
Anal. Calcd for C35H51FN2S: C, 76.31; H, 9.33; N, 5.09. Found: C, 76.55; H, 9.54; N, 5.16.
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4′-(3-Bromophenyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4k)
Yield: 537 mg (88%); light-yellow solid; mp 231–232 °C.
IR (KBr): 3186, 2932, 2869, 1570, 1471, 1219, 770, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.74 (s, 1 H), 7.46–7.19 (m, 4 H), 6.87 (s, 1 H), 4.73 (s, 1 H), 1.90–0.55 (m, 44 H).
13C NMR (75 MHz, CDCl3): δ = 172.4, 144.0, 131.5, 130.6, 130.2, 126.6, 126.4, 122.9, 106.3, 60.8, 59.5, 56.2, 53.5, 53.2, 42.4, 40.9, 40.1, 39.8, 39.5, 36.1, 35.8, 35.4, 35.0, 31.4, 28.2, 28.0, 24.2, 23.8, 22.9, 22.6, 21.1, 18.7, 12.1, 12.0, 11.9.
MS (EI): m/z = 531.4 [M – Br]+.
Anal. Calcd for C35H51BrN2S: C, 68.72; H, 8.40; N, 4.58. Found: C, 68.70; H, 8.20; N, 4.21.
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4′-Propyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4l)
Yield: 449 mg (90%); light-yellow solid; mp 187 °C.
IR (KBr): 3162, 2929, 2868, 1587, 1465, 1221, 772 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.34 (s, 1 H), 6.58 (s, 1 H), 3.81 (m, 1 H), 2.17–0.64 (m, 51 H).
13C NMR (75 MHz, CDCl3): δ = 173.2, 126.1, 106.4, 71.3, 56.9, 56.2 (2C), 54.3, 44.8, 41.9, 39.8, 39.5 (2C), 36.2, 35.7, 35.4, 35.3, 31.7, 31.5, 29.0, 28.2, 28.2, 24.2, 23.8 (2C), 23.3, 22.8, 22.6, 18.7, 14.1, 12.0, 11.7.
MS (EI): m/z = 498.4 [M+], 455.4 [M – C3H7]+.
Anal. Calcd for C32H54N2S: C, 77.05; H, 10.91; N, 5.62. Found: C, 77.35; H, 10.98; N, 5.75.
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4′-Butyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4m)
Yield: 466 mg (91%); light-yellow solid; mp 192 °C.
IR (KBr): 3172, 2928, 2868, 1583, 1467, 1222, 771 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.64 (s, 1 H), 6.96 (s, 1 H), 3.51 (m, 1 H), 2.56–0.58 (m, 53 H).
13C NMR (75 MHz, CDCl3): δ = 173.2, 126.0, 106.5, 71.3, 56.8, 56.2 (2C), 54.4, 44.7, 42.4, 39.5 (2C), 39.1, 36.3, 35.8, 35.4, 35.2, 31.8, 31.5, 29.7, 28.2, 28.0 (2C), 24.2, 23.8 (2C), 23.3, 22.8, 22.6, 18.7, 14.2, 11.8, 11.6.
MS (EI): m/z = 512.4 [M+], 455.4 [M – C4H9]+.
Anal. Calcd for C33H56N2S: C, 77.28; H, 11.01; N, 5.46. Found: C, 77.39; H, 10.94; N, 5.25.
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4′-Pentyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4n)
Yield: 489 mg (93%); light-yellow solid; mp 188–190 °C.
IR (KBr): 3171, 2929, 2868, 1583, 1467, 1222, 770 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38 (s, 1 H), 6.64 (s, 1 H), 3.82 (m, 1 H), 2.17–0.64 (m, 55 H).
13C NMR (75 MHz, CDCl3): δ = 173.3, 126.1, 106.4, 71.3, 56.9, 56.3 (2C), 54.3, 44.8, 42.4, 39.9, 39.5 (2C), 36.2, 35.8, 35.4, 35.3, 31.8 (2C), 31.5, 29.7, 28.2, 28.0 (2C), 24.2, 23.8 (2C), 23.3, 22.8, 22.6, 18.7, 14.2, 12.0, 11.8.
MS (EI): m/z = 526.4 [M+], 455.4 [M – C5H11]+.
Anal. Calcd for C34H58N2S: C, 77.50; H, 11.10; N, 5.32. Found: C, 77.48; H, 11.03; N, 5.27.
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4′-Phenyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholest-4-en-2′(1′H)-one (4o)
Yield: 463 mg (90%); light-yellow solid; mp 202–204 °C.
IR (KBr): 3189, 2929, 2869, 1600, 1569, 1467, 1208, 759, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.72–7.19 (m, 6 H), 6.82 (s, 1 H), 5.31(s, 1 H), 4.98 (s, 1 H), 2.03–0.61 (m, 41 H).
13C NMR (75 MHz, CDCl3): δ = 154.2, 142.1, 137.8, 129.1, 128.9, 128.2, 128.0, 127.0, 126.7, 120.4, 107.9, 57.1, 56.1, 48.4, 47.9, 42.3, 39.7, 39.5, 36.2, 35.8, 35.4, 31.9, 31.1, 28.2, 28.0, 24.1, 23.8, 22.8, 22.7, 21.2, 19.0, 18.7, 18.6, 11.9, 11.8.
MS (EI): m/z = 530.4 [M]+.
Anal. Calcd for C35H50N2O: C, 81.66; H, 9.79; N, 5.44. Found: C, 81.78; H, 9.73; N, 5.47.
#
4′-Pentyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholest-4-en-2′(1′H)-one (4p)
Yield: 442 mg (87%); white solid; mp 180–181 °C.
IR (KBr): 3249, 2928, 2867, 1716, 1467, 1221, 771 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.78 (s, 1 H), 6.90 (s, 1 H), 5.33 (s, 1 H), 4.96 (s, 1 H), 2.23–0.61 (m, 52 H).
13C NMR (75 MHz, CDCl3): δ = 154.0, 144.1, 126.0, 122.0, 107.5, 71.3, 56.8, 56.1 (2C), 54.4, 44.7, 42.4, 39.6 (2C), 39.1, 36.3, 35.8, 35.4 35.2, 31.8, 31.5, 29.7, 28.2, 28.0, 24.4, 23.8 (2C), 23.3, 22.8, 22.6, 18.7, 14.2, 11.8, 11.7.
MS (EI): m/z = 508.4 [M]+.
Anal. Calcd for C34H56N2O: C, 80.26; H, 11.09; N, 5.51. Found: C, 80.28; H, 11.14; N, 5.57.
#
4′-Phenyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholest-4-ene-2′(1′H)-thione (4q)
Yield: 477 mg (90%); white solid; mp 209–210 °C.
IR (KBr): 3189, 2929, 2869, 1600, 1569, 1467, 1208, 759, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.72–7.19 (m, 6 H), 6.82 (s, 1 H), 5.31 (s, 1 H), 4.98 (s, 1 H), 2.03–0.61 (m, 41 H).
13C NMR (75 MHz, CDCl3): δ = 172.0, 142.1, 137.8, 129.1, 128.9, 128.2, 128.0, 127.0, 126.7, 120.4, 107.9, 57.1, 56.1, 48.4, 47.9, 42.3, 39.7, 39.5, 36.2, 35.8, 35.4, 31.9, 31.1, 28.2, 28.0, 24.1, 23.8, 22.8, 22.6, 21.2, 19.0, 18.7, 18.6, 11.9, 11.8.
MS (EI): m/z = 530.4 [M]+.
Anal. Calcd for C35H50N2S: C, 79.19; H, 9.49; N, 5.28. Found: C, 79.38; H, 9.41; N, 5.54.
#
4′-(3-Bromophenyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholest-4-ene-2′(1′H)-thione (4r)
Yield: 553 mg (91%); yellow solid; mp 226–228 °C.
IR (KBr): 3186, 2931, 2869, 1571, 1471, 1219, 771, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.73 (s, 1 H), 7.40–7.18 (m, 4 H), 6.86 (s, 1 H), 5.30 (s, 1 H), 4.78 (s, 1 H), 2.01–0.65 (m, 41 H).
13C NMR (75 MHz, CDCl3): δ = 172.4, 143.9, 137.5, 130.2, 129.2, 128.0, 127.0, 126.6, 126.4, 122.9, 106.3, 56.2, 53.5, 53.2, 42.4, 40.9, 40.1, 39.8, 39.5, 36.1, 35.8, 35.4, 35.0, 31.4, 28.2, 28.0, 24.2, 23.9, 22.8, 22.6, 21.0, 18.7, 12.1, 12.0, 11.9.
MS (EI): m/z = 529.4 [M – Br]+.
Anal. Calcd for C35H49BrN2S: C, 68.94; H, 8.10; N, 4.59. Found: C, 68.74; H, 8.18; N, 4.33.
#
4′-(4-Tolyl)-3′,4′-dihydropyrimidino[6′,5′:2,3]cholest-4-ene-2′(1′H)-thione (4s)
Yield: 485 mg (89%); light-yellow solid; mp 208–210 °C.
IR (KBr): 3192, 2929, 2867, 1569, 1490, 1220, 756, 666 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.36–7.04 (m, 5 H), 5.31 (s, 1 H), 4.56 (s, 1 H), 1.98–0.43 (m, 44 H).
13C NMR (75 MHz, CDCl3): δ = 173.1, 141.6, 137.2, 129.0, 128.1 (2C), 127.1 (2C), 125.5, 120.0, 106.8, 56.3 (2C), 53.1, 42.4, 40.9, 39.9 (2C), 39.8, 39.5, 36.2, 35.8, 34.9, 31.4, 30.0, 28.1, 28.0 (2C), 24.1, 23.8, 22.8, 22.5, 21.0, 18.5, 12.0, 11.9.
MS (EI): m/z = 544 [M+].
Anal. Calcd for C36H52N2S: C, 79.35; H, 9.62; N, 5.14. Found: C, 79.70; H, 9.78; N, 5.10.
#
3β-Acetoxy-3′,4′-dihydropyrimidino[6′,5′:16,17]androst-5-en-2′(1′H)-one (4t)
Yield: 400 mg (87%); gum.
IR (KBr): 2928, 2853, 1732, 1612, 1245, 1037 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.85–7.03 (m, 7 H), 6.73 (d, J = 6.0 Hz, 1 H), 5.50–5.33 (m, 1 H), 4.63–4.50 (m, 1 H), 2.50–0.85 (m, 26 H).
13C NMR (75 MHz, CDCl3): δ = 172.9, 154.6, 139.9, 137.1, 129.5, 128.4 (2C), 127.8 (2C), 125.2, 122.0, 73.7, 51.7, 50.1, 47.5, 38.1, 36.9 (2C), 35.9, 31.5, 30.8, 29.7, 27.7, 21.9, 21.4, 20.3, 19.6, 13.6, 11.6.
MS (EI): m/z = 400.6 [M – CH3COOH]+.
Anal. Calcd for C29H36N2O3: C, 75.62; H, 7.88; N, 6.08. Found: C, 75.72; H, 7.74; N, 6.16.
#
3β-Acetoxy-3′,4′-dihydropyrimidino[6′,5′:16,17]androst-5-ene-2′(1′H)-thione (4u)
Yield: 429 mg (90%); gum.
IR (KBr): 2929, 2856, 1738, 1666, 1246, 1031 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.89–7.00 (m, 7 H), 6.71 (d, J = 6.0 Hz, 1 H), 5.50–5.30 (m, 1 H), 4.63–4.50 (m, 1 H), 2.47–0.85 (m, 26 H).
13C NMR (75 MHz, CDCl3): δ = 173.4, 170.6, 140.1, 137.4 (2C), 129.7, 128.2 (2C), 127.8 (2C), 125.1, 122.4, 73.9, 51.5, 50.1, 47.7, 38.8, 36.8, 35.8, 31.8, 30.5, 29.7, 27.4, 21.9, 21.4, 20.1, 19.7, 13.5, 11.4.
MS (EI): m/z = 416.6 [M – CH3COOH]+, 359.2.
Anal. Calcd for C29H36N2O2S: C, 73.07; H, 7.61; N, 5.88. Found: C, 73.32; H, 7.74; N, 5.93.
#
3β-Acetoxy-4′-phenyl-3′,4′-dihydropyrimidino[6′,5′:6,7]cholest-4-ene-2′(1′H)-thione (4v)
Yield: 506 mg (86%); white solid; mp 182 °C.
IR (KBr): 2950, 2932, 2868, 1706, 1566, 1450, 1381, 1238, 765 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.70–7.08 (m, 8 H), 6.15 (m, 1 H), 4.23 (m, 1 H), 2.82–0.6 (m, 42 H).
13C NMR (75 MHz, CDCl3): δ = 172.5, 170.8, 141.2, 133.5, 130.2, 129.7, 129.2, 128.6 (2C), 128.2, 127.0 (2C), 82.0, 65.3, 56.1, 44.1, 42.9, 41.5, 39.5 (2C), 37.4, 36.1, 35.7, 31.0 (2C), 29.7, 28.0 (2C), 27.7 (2C), 23.8, 22.8, 22.6, 21.7, 18.7, 14.2, 11.7.
MS (EI): m/z = 528.4 [M – CH3COOH]+.
Anal. Calcd for C37H52N2O2S: C, 75.46; H, 8.90; N, 4.76. Found C, 75.68; H, 8.82; N, 4.56.
#
4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4w)
Yield: 251 mg (86%); gum.
IR (KBr): 2927, 1692, 1566, 1493, 1453, 1192, 1026 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 9.79 (s, 1 H), 9.12 (s, 1 H), 7.96 (d, J = 9.0 Hz, 1 H), 7.82–6.54 (m, 8 H), 4.96 (d, J = 2.4 Hz, 1 H), 2.62 (t, J = 7.2 Hz, 2 H), 2.08 (t, J = 7.0 Hz, 2 H).
13C NMR (75 MHz, DMSO-d 6): δ = 174.5, 143.2, 135.9, 129.7, 129.1, 128.5 (2C), 128.3, 128.1, 128.0, 127.4, 126.9 (2C), 121.8, 111.7, 58.9, 27.7, 23.0.
MS (EI): m/z = 292 [M]+.
Anal. Calcd for C18H16N2S: C, 73.94; H, 5.52; N, 9.58. Found: C, 73.75; H, 5.72; N, 9.68.
#
8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4x)
Yield: 274 mg (85%); gum.
IR (KBr): 2927, 1692, 1601, 1538, 1493, 1251 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 9.72 (s, 1 H), 9.06 (s, 1 H), 8.20–6.50 (m, 8 H), 4.92 (s, 1 H), 3.5 (s, 3 H), 2.68 (t, J = 7.2 Hz, 2 H), 2.14 (t, J = 7.2 Hz, 2 H).
13C NMR (75 MHz, DMSO-d 6): δ = 174.7, 142.8, 135.5, 129.9, 129.6, 128.1, 128.6 (2C), 128.0 (2C), 127.1 (2C), 127.0, 121.9, 111.8, 59.4, 55.9, 27.5, 23.3.
MS (EI): m/z = 322.0 [M]+.
Anal. Calcd for C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found: C, 70.42; H, 5.70; N, 8.78.
#
2-Benzylidenecholestan-3-one (A)
A mixture of ketone 1a (400 mg, 1.04 mmol), PhCHO (110 mg, 1.04 mmol), and NaOEt (71 mg, 1.04 mmol) in i-PrOH (10 mL) was irradiated with ultrasound for 10 min. The solvent was removed in a rotatory evaporator and the crude residue was purified by column chromatography [silica gel, EtOAc–hexane (1:10)] to give a light-yellow solid; yield: 443 mg (90%); mp 176 °C.
IR (KBr): 2929, 1678, 1445, 1193, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.60–7.28 (m, 5 H), 7.26 (s, 1 H), 3.13–3.08 (m, 2 H), 2.49–0.64 (m, 42 H).
13C NMR (75 MHz, CDCl3): δ = 201.7, 137.1, 135.7, 135.4, 129.7, 129.6, 128.9, 128.6, 128.4, 66.7, 66.3, 56.4, 53.6, 42.9, 42.4, 39.9, 39.5 (2C), 36.2, 35.9, 35.8, 35.4, 31.5 (2C), 28.7, 28.3, 24.3, 23.9 (2C), 22.9, 21.4, 18.7, 12.0, 11.9.
MS (EI): m/z = 474.4 [M]+.
Anal. Calcd for C34H50O: C, 86.01; H, 10.62. Found: C, 86.27; H, 10.75.
#
Conversion of 2-Benzylidenecholestan-3-one (A) into 4′-Phenyl-3′,4′-dihydropyrimidino[6′,5′:2,3]cholestane-2′(1′H)-thione (4h)
A mixture of ketone A (200 mg, 0.42 mmol) and thiourea (32 mg, 0.42 mmol) in i-PrOH (10 mL) was irradiated with ultrasound for 5 min. The solvent was removed in a rotatory evaporator and the crude residue was purified by column chromatography [silica gel, EtOAc–hexane (1:10)] to give 4h; yield: 195 mg (87%). The analytical and spectral data for this compound were similar to those reported above.
#
#
Acknowledgment
We thank the Department of Science and Technology, New Delhi, for financial support. M.D. thanks CSIR, New Delhi, for the award of a senior research fellowship (SRF). We are grateful to the Director of CSIR-NEIST for his keen interest.
-
References
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- 4 Biginelli P. Ber. Dtsch. Chem. Ges. 1893; 26: 447
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- 18a Yadav JS, Subba Reddy BV, Bhaskar Reddy K, Raj KS, Prasad AR. J. Chem. Soc., Perkin Trans. 1 2001; 1939
- 18b Wang J.-S, Li J.-T, Lin Z.-P. Lett. Org. Chem. 2006; 3: 523
- 18c Stefani HA, Oliveira CB, Almeida RB, Pereira CM. P, Braga RC, Cella R, Borges VC, Savegnago L, Nogueira CW. Eur. J. Med. Chem. 2006; 41: 513
- 18d Chattejee NR, Sharma DC, Choudhary YD, Deshpande AD. Indian J. Heterocycl. Chem. 2007; 16: 293
- 18e Zhang X, Li Y, Wang J. J. Mol. Catal. A: Chem. 2006; 253: 207
- 19a Li J.-T, Lin Z.-P, Han J.-F, Li T.-S. Synth. Commun. 2004; 34: 2623
- 19b Li J.-T, Han J.-F, Lin Z.-P, Li T.-S. Youji Huaxue 2004; 24: 675 ; Chem. Abstr. 2004, 141, 260681z
- 20a Barthakur MG, Gogoi S, Dutta M, Boruah RC. Steroids 2009; 74: 730
- 20b Saikia A, Barthakur MG, Borthakur M, Saikia CJ, Bora U, Boruah RC. Tetrahedron Lett. 2006; 47: 43
- 20c Bora U, Saikia A, Boruah RC. Org. Lett. 2003; 5: 435
- 21 Yilgor E, Atilla EG, Ekin A, Kurt P, Yilgor I. Polymer 2003; 44: 7787
- 22 Mason TJ, Lorimer JP. Applied Sonochemistry: The Uses of Power Ultrasound in Chemistry and Processing. Wiley-VCH; Weinheim: 2002
-
References
- 1a Snider BB, Shi Z. J. Org. Chem. 1993; 58: 3828
- 1b Overman LE, Rabinowitz MH, Renhowe PA. J. Am. Chem. Soc. 1995; 117: 2657
- 1c Amr AE, Ashraf MM, Salwa FM, Nagla AA, Hammam AG. Bioorg. Med. Chem. 2006; 14: 5488
- 1d Kappe CO. Eur. J. Med. Chem. 2000; 35: 1043 ; and references cited therein
- 2a Atwal KS, Swanson BN, Unger SE, Floyd DM, Moreland S, Hodberg A, O’Reilly BC. J. Med. Chem. 1991; 34: 806
- 2b Atwal KS, Rovnyak GC, Kimball SD, Floyd DM, Moreland S, Swanson BN, Gougoutas JZ, Schwartz J, Smillie KM, Malley MF. J. Med. Chem. 1990; 33: 2629
- 2c Kidwai M, Bhatnagar D, Kumar R, Luthra PM. Chem. Pharm. Bull. 2010; 58: 1320
- 3a Rao RA. V, Gurjar MK, Vasudevan J. J. Chem. Soc., Chem. Commun. 1995; 13: 1369
- 3b Patil AD, Kumar NV, Kokke WC, Bean MF, Freyer AJ, De Brosse C, Mai S, Truneh A, Faulkner DJ, Carte B, Breen AL, Hertzberg RP, Johnson RK, Westley JW, Potts BC. M. J. Org. Chem. 1995; 60: 1182
- 4 Biginelli P. Ber. Dtsch. Chem. Ges. 1893; 26: 447
- 5a Kappe CO. Tetrahedron 1993; 49: 6937
- 5b Abelman MM, Smith SC, James DR. Tetrahedron Lett. 2003; 44: 4559
- 5c Lin H, Zhao Q, Xu B, Wang X. J. Mol. Catal A: Chem. 2007; 268: 221
- 5d Shen Z.-L, Xu X.-P, Ji S.-J. J. Org. Chem. 2010; 75: 1162
- 6a Bussolari JC, McDonnell PA. J. Org. Chem. 2000; 65: 6777
- 6b Atwal KS, O’Reilly BC, Gougoutas JZ, Malley MF. Heterocycles 1987; 26: 1189
- 7a Tu S, Fang F, Zhu S, Li T, Zhang X, Zhang Q. Synlett 2004; 537
- 7b Gohain M, Prajapati D, Sandhu JS. Synlett 2004; 235
- 7c Sabita G, Reddy GS. K. K, Reddy KB, Yadav JS. Tetrahedron Lett. 2003; 44: 6497
- 8a Ma Y, Qian CT, Wang LM, Yang M. J. Org. Chem. 2000; 65: 3864
- 8b Adapa SR, Alam MM, Varala R. Synlett 2003; 67
- 9a Mirza-Aghayan M, Bolourtchian M, Hosseini M. Synth. Commun. 2004; 34: 3335
- 9b Legeay J.-C, Eynde JJ. V, Bazureau JP. Tetrahedron 2005; 61: 12386
- 10 Peng J, Deng Y. Tetrahedron Lett. 2001; 42: 5917
- 11a Liu C, Wang J, Li Y. J. Mol. Catal. A: Chem. 2006; 258: 367
- 11b Surya K, Gibbs A. Synthesis 2005; 1748
- 11c Liang B, Wang X, Wang J.-X, Du Z. Tetrahedron 2007; 63: 1981
- 12 Singh K, Arora D, Singh S. Tetrahedron Lett. 2006; 47: 4205
- 13 Palaniappan S, John A. J. Mol. Catal. A: Chem. 2005; 233: 9
- 14a Cravotto G, Cintas P. Chem. Soc. Rev. 2006; 35: 17
- 14b Xu H, Liao W.-M, Li HF. Ultrason. Sonochem. 2007; 14: 779
- 14c United States Environmental Protection Agency; Green Chemistry; http://www.epa.gov/opptintr/greenchemistry/index.html
- 14d Cella R, Stefani H. Tetrahedron 2009; 65: 2619
- 15 Wang SY, Ji SJ, Loh TP. Synlett 2003; 2377
- 16a Armstrong RW, Combs AP, Tempest PA, Brown SD, Keating TA. Acc. Chem. Res. 1996; 29: 123
- 16b Ugi I. Pure Appl. Chem. 2001; 73: 187
- 17a Zhidovinova MS, Fedorova OV, Rusinov GL, Ovchinnikova IG. Russ. Chem. Bull. 2003; 52: 2527
- 17b Singh K, Singh S, Kaur P. Lett. Org. Chem. 2006; 3: 201
- 17c Li J.-T, Han J.-F, Yang J.-H, Li T.-S. Ultrason. Sonochem. 2003; 10: 119
- 18a Yadav JS, Subba Reddy BV, Bhaskar Reddy K, Raj KS, Prasad AR. J. Chem. Soc., Perkin Trans. 1 2001; 1939
- 18b Wang J.-S, Li J.-T, Lin Z.-P. Lett. Org. Chem. 2006; 3: 523
- 18c Stefani HA, Oliveira CB, Almeida RB, Pereira CM. P, Braga RC, Cella R, Borges VC, Savegnago L, Nogueira CW. Eur. J. Med. Chem. 2006; 41: 513
- 18d Chattejee NR, Sharma DC, Choudhary YD, Deshpande AD. Indian J. Heterocycl. Chem. 2007; 16: 293
- 18e Zhang X, Li Y, Wang J. J. Mol. Catal. A: Chem. 2006; 253: 207
- 19a Li J.-T, Lin Z.-P, Han J.-F, Li T.-S. Synth. Commun. 2004; 34: 2623
- 19b Li J.-T, Han J.-F, Lin Z.-P, Li T.-S. Youji Huaxue 2004; 24: 675 ; Chem. Abstr. 2004, 141, 260681z
- 20a Barthakur MG, Gogoi S, Dutta M, Boruah RC. Steroids 2009; 74: 730
- 20b Saikia A, Barthakur MG, Borthakur M, Saikia CJ, Bora U, Boruah RC. Tetrahedron Lett. 2006; 47: 43
- 20c Bora U, Saikia A, Boruah RC. Org. Lett. 2003; 5: 435
- 21 Yilgor E, Atilla EG, Ekin A, Kurt P, Yilgor I. Polymer 2003; 44: 7787
- 22 Mason TJ, Lorimer JP. Applied Sonochemistry: The Uses of Power Ultrasound in Chemistry and Processing. Wiley-VCH; Weinheim: 2002
