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Cyclocondensations of (+)-camphor derived enaminones with hydrazine derivatives
Tetrahedron 61 (2005) 3991–3998
Cyclocondensations of (C)-camphor derived enaminones with hydrazine derivatives Urosˇ Grosˇelj, David Bevk, Renata Jaksˇe, Simon Recˇnik, Anton Meden, Branko Stanovnik and Jurij Svete* Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, PO Box 537, 1000 Ljubljana, Slovenia Received 2 November 2004; revised 4 February 2005; accepted 18 February 2005
Dedicated to Professor Lubor Fisˇera, Slovak University of Technology, Bratislava, on the occasion of his 60th anniversary
Abstract—Reactions of 3-[(E)-(dimethylamino)methylidene]-(C)-camphor and (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with hydrazine derivatives were studied. Treatment of 3-[(E)-(dimethylamino)methylidene]-(C)camphor with hydrazines afforded the corresponding fused pyrazoles. Similarly, fused pyrazoles were obtained upon reaction of (1R,5S)-4[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with ortho-unsubstituted phenylhydrazines, while reactions with ortho-substituted phenylhydrazines and with hydrazine hydrochloride resulted in ‘ring switching’ type of transformation to furnish 2-aryl-4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-ones. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction Naturally occurring and synthetic pyrazole derivatives have found widespread use in various applications.1 Similarly, (C)-camphor (1) and its derivatives, are among the most frequently employed types of ex-chiral pool starting materials and building blocks, resolving agents, chiral shift reagents in NMR spectroscopy, and ligands in various asymmetric applications.2 Camphor-functionalized pyrazoles, N-substituted (1R,7S)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0 2,6]deca-2(6),4-dienes (or N-substituted (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methyno1H-indazoles) 2 have been synthesized from 3-formylcamphor and hydrazine derivatives.3 Kotsuki and co-workers prepared various N-(b-hydroxyethyl) substituted (1R,7S)1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4dienes 2k–m and 3k–m, which were successfully employed as chiral ligands for enantioselective addition of diethylzinc to benzaldehyde (Fig. 1).4
various heterocyclic systems, including pyrazole derivatives. Various chiral analogs of 3-dimethylaminopropenoates were also prepared from commercially available enantiopure starting materials, such as a-amino acids and (C)-camphor (1). The a-amino acid derived chiral enaminones were employed as the key-intermediates and reagents in the synthesis of functionalized heterocycles, for example, in the ‘ring switching’ synthesis of 3-heteroarylalanine derivatives and related compounds and in the synthesis of heterocyclic analogs of dipeptides.5,6 Recently, utilization of 3-(dimethylamino)propenoates in combinatorial synthesis has also been reported.7 In connection with (C)camphor (1) derived enaminones 4 and 5, we have previously reported stereoselective synthesis of (1R,3R,4R)-3-(1,2,4triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones,8 and N-substituted (1R,5S)-3-aminomethylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones.9
Recently, a series of alkyl 2-substituted 3-(dimethylamino)propenoates and related enaminones, synthetic equivalents of 1,3-dicarbonyl compounds, have been prepared and used for the preparation of dehydroalanine esters and Keywords: Camphor; Enaminones; Terpenes; Hydrazines; Condensations. * Corresponding author. Tel.: C386 1 2419 100; fax: C386 1 2419 220; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.02.048
Figure 1.
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In continuation of our work in the field of (C)-camphor (1) derived enaminones, we now report cyclocondensations of (1R,4S)-3-[(E)-(dimethylamino)methylidene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4) and (1R,5S)-4-[(E)(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one (5) with hydrazine derivatives 6a–i leading to, either fused pyrazole systems 2 and 7, or to 4[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl] substituted pyrazole derivatives 8 and 9, as products of a ‘ring switching’ type transformation.
2. Results and discussion Starting compounds 48 and 59 were prepared from (C)camphor (1) according to literature procedures. Reaction of 4 with hydrazine hydrochloride (6a) in methanol at rt gave (1R,7S)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2a) in 81% yield. Similarly, treatment of 4 with benzylhydazine dihydrochloride (6b) and 6-chloro-3hydrazinopyridazine (6c) in acetic acid under reflux afforded (1R,7S)-3-benzyl-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2b) and 6-[(1R,7S)1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4dien-3-yl]pyridazin-3(2H)-one (2c) in 63% and 83% yield, respectively. On the other hand, upon reaction of 5 with phenylhydrazine derivatives 6d–j in refluxing n-propanol, two different types of products were formed, either fused pyrazoles 7, or cyclopentyl substituted pyrazolones 8. Thus, treatment of 5 with ortho-unsubstituted phenylhydrazines 6d–f afforded (1S,8R)-5-aryl-8,11,11-trimethyl-7-oxa4,5-diazatricyclo[6.2.1.02,6]undeca-2(6),3-dienes 7d–f in 74–91% yields, while treatment of 5 with ortho-substituted phenylhydrazines 6g–j furnished 2-aryl-4-[(1S,3R)-3hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-ones 8g–j in 56–70% yields. ‘Ring switching’ transformation also took place in the case of the reaction
of 5 with hydrazine hydrochloride (6a), which gave 4[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1H-pyrazol-3-ol (9a) in 81% yield (Scheme 1, Table 1). Formation of pyrazole derivatives 2, 7–9 can be explained according to the formation of pyrazoles from hydrazine derivatives and 1,3-dicarbonyl compounds and their enamino analogs.1 Compound 4, an enamino masked b-keto aldehyde, reacts via initial substitution of the dimethylamino group to give the isomeric enehydrazines 10 and 10 0 . The (Z)-isomer 10 0 then cyclizes into dihydropyrazole 11, followed by elimination of water to give fused pyrazole 2. Similarly, compound 5 as an enamino masked b-keto ester is first transformed into a mixture of isomeric enehydrazines 12 and 12 0 . The (Z)-isomer 12 0 then cyclizes into the bicyclic intermediate 13. From this point on, further reaction can take place in two ways: (a) elimination of water leads to pyrazolo fused lactones 7 (Path A) and (b) elimination of the alcohol moiety leads to ‘ring switched’ pyrazolones of type 8 (Path B) (Scheme 2). So far, we do not have an explanation for chemoselectivity of reactions of 5 with hydrazine derivatives 6a,d–j. In the literature, there are several examples, where treatment of bketo esters with arylhydrazines under acidic conditions afforded 5-alkoxy- and/or 5-hydroxypyrazoles.1 Since elimination of water is generally facilitated by the protonation of the hydroxy group, while elimination of alcohol can be, either acid-catalysed or base-catalysed, steric factors might control selectivity of cyclisation of bicyclic intermediates 13a,d–j into pyrazole derivatives 7d–f, 8g–j, and 9a. Thus, in the case of intermediates 13d–f without ortho-substituent attached to the aromatic ring, the hydroxy group can undergo protonation and, consequently, elimination of water can take place to give fused pyrazoles 7d–f. On the other hand, in intermediates 13g–j, the hydroxy group is hindered by the ortho-substituent attached
Scheme 1. Reaction conditions: (i) NH2NH2$HCl (6a) MeOH, rt; (ii) PhCH2NHNH2$2HCl (6b) or 6-chloro-3-hydrazinopyridazine (6c), AcOH, reflux; (iii) RNHNH2$HCl (6a,d–i) or C6F5NHNH2$1⁄2 H2SO4 (6j), n-PrOH, reflux.
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Table 1. Experimental data for compounds 2, 7–9 Compound
R
Yield (%) 2
2a, 6a, 9a 2b, 6b 6c 2c 6d, 7d 6e, 7e 6f, 7f 6g, 8g 6h, 8h 6i, 8i 6j, 8j
H Benzyl 6-Chloropyridazin-3-yl 6-Oxo-1,6-dihydropyridazin-3-yl Phenyl 3-Methylphenyl 4-Methylphenyl 2-Methylphenyl 2-Chlorophenyl 2-Bromophenyl Pentafluorophenyl
to the aromatic ring. Consequently, protonation of the hydroxy group is disfavoured and elimination of alcohol, that is, opening of the lactone ring, takes place to give the hydroxypyrazoles 9g–j, which then tautomerise into the
Scheme 2.
7
8
81 63
9 83
83 91 74 85 70 61 63 56
pyrazolones 8g–j. In the case of transformation of 5 into 9a, which took place upon reaction of 5 with sterically unhindered hydrazine hydrochloride (6a), opening of the lactone ring is favoured due to stronger basicity of the
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Scheme 3.
primary amino group with respect to the arylamino group (Scheme 3).
the ortho-methyl group in the aryl residue was in agreement with (1S,3R)-configuration (Fig. 2). The structure of compound 7d was determined by X-ray diffraction (Fig. 3).
3. Structure determination The structures of compounds 2, 7–9 were determined by spectroscopic methods (NMR, IR, MS, HRMS) and/or by analyses for C, H, and N. The structure of compound 9a, which was not isolated in analytically pure form, was confirmed by 13C NMR and HRMS. Physical and spectral data of known compounds 2a,b were in agreement with the literature data.3a,e Spectral data for pyrazoles 2, 7–9 were in agreement with the literature data for related pyrazole1 and camphor derivatives.2 IR spectra of compounds 2c and 8d–f exhibited amide C]O absoption bands at 1681 and 1682– 1673 cmK1, respectively, while no C]O absorption was observed in IR spectra of compounds 2a,b, 7d–f, and 9a. In compound 8g, NOE between the OH proton and protons of
Figure 2.
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cyclo[3.2.1]octan-3-one (5),9 and 6-chloro-3-hydrazinopyridazine (6c),10 were prepared according to the procedures described in the literature.
Figure 3. ORTEP view of the asymmetric unit of compound 7d with labeling of nonhydrogen atoms (ellipsoids are drawn at 50% probability level).
4. Conclusion In conclusion, (C)-camphor derived enaminones 4 and 5 are easily available reagents, which are suitable for the preparation of terpene-functionalized pyrazole derivatives. Reactions of (1R,4S)-3-[(E)-(dimethylamino)methylidene]1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4) with hydrazine derivatives 6 lead to 3-substituted (1R,7S)-1,10,10trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-dienes 2. However, in the case of (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3one (5), the chemoselectivity was found to be dependent on the type of hydrazine derivative 6 employed. Reactions of 5 with ortho-unsubstituted phenylhydrazines 6d–f afforded fused pyrazole systems 7d–f, while reactions with hydrazine hydrochloride (6a) and ortho-substituted phenylhydrazines 6g–j led to 4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl] substituted pyrazole derivatives 9a and 8g–j, respectively, as products of a ‘ring switching’ type transformation.
5. Experimental 5.1. General Melting points were determined on a Kofler micro hot stage. The 1H NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H, and 75.5 MHz for 13C nucleus, using DMSO-d6 and CDCl3 as solvents and TMS as the internal standard. Mass spectra were recorded on an AutoSpecQ spectrometer, IR spectra on a Perkin–Elmer Spectrum BX FTIR spectrophotometer. Microanalyses were performed on a Perkin–Elmer CHN Analyser 2400. Column chromatography (CC) was performed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm). Hydrazines 6a,b,d–j are commercially available (Fluka AG). (1R,4S)-3-[(E)-(Dimethylamino)-methylidene]-1,7,7trimethylbicyclo[2.2.1]heptan-2-one (4),8 (1R,5S)-4-[(E)(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabi-
5.1.1. (1R,7S)-1,10,10-Trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2a). A mixture of 4 (0.207 g, 1 mmol), hydrazine hydrochloride (6a, 0.069 g, 1 mmol), and methanol (4 ml) was stirred at rt for 24 h. Water (6 ml) was added and the precipitate was collected by filtration to give 2a. Yield: 0.143 g (81%) of yellowish crystals; mp 143–147 8C, lit.3a mp 149–150 8C; [a]23 DZ C35.8 (cZ0.4, CH2Cl2). 1H NMR (DMSO-d6): d 0.56, 0.91 (6H, 2 s, 1:1, 2Me); 0.98–1.16 (2H, m, CH2); 1.19 (3H, s, Me); 1.75–1.83 (1H, m, 1H of CH2); 1.98–2.07 (1H, m, 1H of CH2); 2.73 (1H, d, JZ3.9 Hz, H–C(7)); 7.16 (1H, s, H– C(5)); 11.62 (1H, s, H–N(3)). 13C NMR (DMSO-d6): d 11.2, 19.7, 20.9, 28.2, 34.1, 47.5, 50.4, 61.4, 120.4, 126.4, 166.5. (Found: C, 74.96; H, 9.36; N, 15.59. C11H16N2 requires: C, 74.96; H, 9.15; N, 15.89.); nmax (KBr): 3415, 3145, 2923, 1586, 1479, 1454, 1415, 1386, 1369, 1286, 1273, 1140, 1084, 1026, 972, 804 cmK1. 5.2. General procedure for the preparation of compounds 2b,c, 7d–f, 8g,h, and 9a A mixture of enaminone 4 or 5 (1 mmol), hydrazine derivative 6 (1 mmol), and appropriate solvent (w5 ml) was heated under reflux for 2–6 h. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (CC). Fractions containing the product were combined and evaporated in vacuo to give 2b,c, 7d–f, 8g,h, and 9a. The following compounds were prepared in this manner: 5.2.1. (1R,7S)-3-Benzyl-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2b). Prepared from 4 (0.207 g, 1 mmol), benzylhydrazine dihydrochloride (6b, 0.195 g, 1 mmol), and acetic acid (100%, 6 ml), reflux for 4 h, CC (diethyl ether–petroleum ether, 1:2). Yield: 0.168 g (63%) of colourless oil, lit.3e oil; [a]22 D ZK14.9 (cZ0.29, CH2Cl2). EI-MS: m/zZ266 (MC). 1H NMR (DMSO-d6): d 0.65, 0.82, 1.13 (9H, 3 s, 1:1:1, 3Me); 0.88–1.00 (2H, m, CH2); 1.61–1.70 (1H, m, 1H of CH2); 1.93–2.01 (1H, m, 1H of CH2); 2.73 (1H, d, JZ3.8 Hz, H–C(7)); 5.24 (1H, d, JZ 16.0 Hz, 1H of CH2N); 5.32 (1H, d, JZ16.0 Hz, 1H of CH2N); 7.05–7.07 (2H, m, 2H of Ph); 7.09 (1H, s, H–C(5)); 7.22–7.34 (3H, m, 3H of Ph). 13C NMR (CDCl3): d 11.7, 20.0, 20.7, 28.2, 33.8, 48.0, 52.7, 54.3, 63.2, 127.0, 127.9, 129.0, 129.5, 131.6, 138.6, 153.9. (Found: C, 80.84; H, 8.71; N, 10.51. C18H22N2 requires: C, 81.16; H, 8.32; N, 10.52.); EI-HRMS: m/zZ266.1796 (MC); C18H22N2O requires: m/zZ266.1783 (MC); nmax (NaCl): 2957, 2872, 1606, 1522, 1496, 1440, 1383, 1362, 1285, 1194, 1117, 1059, 997, 907 cmK1. 5.2.2. 6-[(1R,7S)-1,10,10-Trimethyl-3,4-diazatricyclo[5.2.1.0 2,6]deca-2(6),4-dien-3-yl]pyridazin-3(2H)-one (2c). Prepared from 4 (0.207 g, 1 mmol), 6-chloro-3hydrazinopyridazine (6c, 0.145 g, 1 mmol), and acetic acid (100%, 6 ml), reflux for 4 h, CC (ethyl acetate). Before chromatographic purification, the crude solid product was crystallised from methanol. Yield: 0.124 g (83%) of white
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crystals; mp 213–218 8C (from methanol); [a]20 D ZC9.9 (cZ0.40, CH2Cl2). 1H NMR (DMSO-d6): d 0.71, 0.90 (6H, 2 s, 1:1, 2Me); 0.95–1.03 (1H, m, 1H of CH2); 1.19–1.27 (1H, m, 1H of CH2); 1.32 (3H, s, Me); 1.78–1.86 (1H, m, 1H of CH2); 2.01–2.11 (1H, m, 1H of CH2); 2.81 (1H, d, JZ 3.6 Hz, H–C(7)); 7.05 (1H, d, JZ10.0 Hz, H–C(5 0 )); 7.44 (1H, s, H–C(5)); 7.92 (1H, d, JZ10.0 Hz, H–C(4 0 )); 12.92 (1H, s, NH). 13C NMR (DMSO-d6): d 13.4, 20.4, 21.0, 28.1, 33.5, 47.4, 54.8, 63.8, 129.6, 132.4, 133.1, 134.8, 142.2, 154.0, 160.8. (Found: C, 66.83; H, 7.09; N, 20.47. C15H18N4O requires: C, 66.64; H, 6.71; N, 20.73.); nmax (KBr): 3446, 2961, 1681 (C]O), 1613, 1563, 1475, 1448, 1380, 1308, 1242, 1007, 986, 839 cmK1.
crystals; mp 146–150 8C (from chloroform–n-heptane); 1 [a]21 D ZK27.2 (cZ0.23, CH2Cl2). H NMR (CDCl3): d 0.97, 1.08, 1.42 (9H, 3 s, 1:1:1, 3Me); 1.83–1.95 (1H, m, 1H of CH2); 1.95–2.14 (2H, m, CH2); 2.19–2.28 (1H, m, 1H of CH2); 2.35 (3H, s, Me-Ar); 2.57 (1H, d, JZ4.4 Hz, H– C(1)); 7.19 (2H, br d, JZ8.5 Hz, 2H of Ar); 7.23 (1H, s, H– C(3)); 7.66 (2H, br d, JZ8.5 Hz, 2H of Ar). 13C NMR (CDCl3): d 18.7, 19.5, 21.3, 24.3, 34.0, 38.1, 43.1, 43.9, 94.0, 107.1, 120.1, 129.8, 135.4, 136.3, 137.1, 149.5. (Found: C, 76.29; H, 8.03; N, 9.76. C18H22N2O requires: C, 76.56; H, 7.85; N, 9.92.); nmax (KBr): 2972, 1589, 1526, 1458, 1428, 1076, 973, 882, 855, 818 cmK1.
5.2.3. (1S,8R)-5-Phenyl-8,11,11-trimethyl-7-oxa-4,5-diazatricyclo[6.2.1.02,6]undeca-2(6),3-diene (7d). Prepared from 5 (0.223 g, 1 mmol) and phenylhydrazine hydrochloride (6d, 0.145 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 2 h, CC (ethyl acetate–petroleum ether, 1:3). Yield: 0.224 g (91%) of white crystals; mp 173–177 8C (from ethyl acetate–n-hexane); [a]25 D ZK27.6 (cZ0.25, CH2Cl2). EI-MS: m/zZ268 (MC). 1H NMR (CDCl3): d 0.98, 1.08, 1.44 (9H, 3 s, 1:1:1, 3Me); 1.84–1.91 (1H, m, 1H of CH2); 1.96–2.14 (2H, m, CH2); 2.20–2.29 (1H, m, 1H of CH2); 2.58 (1H, d, JZ4.4 Hz, H–C(1)); 7.19 (1H, tt, JZ1.2, 7.5 Hz, 1H of Ph); 7.25 (1H, s, H–C(3)); 7.36–7.42 (2H, m, 2H of Ph); 7.79–7.81 (2H, m, 2H of Ph). 13C NMR (CDCl3): d 18.7, 19.5, 24.2, 34.0, 38.1, 43.1, 43.9, 94.2, 107.3, 120.0, 125.7, 129.3, 136.6, 139.5, 149.7. (Found: C, 76.23; H, 7.64; N, 10.35. C17H20N2O requires: C, 76.09; H, 7.51; N, 10.44.); EI-HRMS: m/zZ268.1585; C17H20N2O requires: m/zZ268.1576 (MC). Found: nmax (KBr): 2956, 1595, 1516, 1492, 1455, 1418, 1377, 1088, 1057, 970, 847, 760, 690 cmK1.
5.2.6. 4-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]2-(2-methylphenyl)-1,2-dihydro-3H-pyrazol-3-one (8g). Prepared from 5 (0.223 g, 1 mmol), (2-methylphenyl)hydrazine hydrochloride (6g, 0.159 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 4 h, CC (first: ethyl acetate– petroleum ether, 1:4, then ethyl acetate–petroleum ether, 1:2). Yield: 0.210 g (70%) of white crystals; mp 139–145 8C (from chloroform–n-heptane); [a]21 D ZK13.2 (cZ0.39, CH2Cl2). EI-MS: m/zZ300 (MC). 1H NMR (CDCl3): d 1.00, 1.01, 1.31 (9H, 3 s, 1:1:1, 3Me); 1.59–1.67 (1H, m, 1H of CH2); 1.93–2.27 (4H, m, 3H of CH2 and H–C(1 0 )); 2.16 (3H, s, Me-Ar); 5.82 (1H, br s, OH); 6.65 (1H, d, JZ 10.4 Hz, H–C(5)); 6.83 (1H, br t, JZ7.3 Hz, 1H of Ar); 6.87 (1H, br d, JZ7.6 Hz, 1H of Ar); 7.07 (1H, br d, JZ7.3 Hz, 1H of Ar); 7.14 (1H, br t, JZ7.6 Hz, 1H of Ar); 8.97 (1H, d, JZ10.4 Hz, NH). 13C NMR (CDCl3): d 17.4, 18.8, 18.9, 23.8, 31.8, 38.0, 43.8, 50.3, 92.0, 100.0, 112.1, 120.9, 122.2, 127.5, 130.8, 146.7, 151.2, 170.1. (Found: C, 71.94; H, 8.09; N, 9.27. C18H24N2O2 requires: C, 71.97; H, 8.05; N, 9.33.); EI-HRMS: m/zZ300.1846 (MC); C18H24N2O2 requires: m/zZ300.1838 (MC). nmax (KBr): 3452, 3287, 3256, 2970, 1677 (C]O), 1607, 1426, 1219, 1138, 756 cmK1.
5.2.4. (1S,8R)-5-(3-Methylphenyl)-8,11,11-trimethyl-7oxa-4,5-diazatricyclo-[6.2.1.0 2,6 ]undeca-2(6),3-diene (7e). Prepared from enaminone 5 (0.223 g, 1 mmol) and (3-methylphenyl)hydrazine hydrochloride (6e, 0.159 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 3 h, CC (ethyl acetate–petroleum ether, 1:4). Yield: 0.209 g (74%) of light orange crystals; mp 75–79 8C; [a]21 D ZK26.3 (cZ0.74, CH2Cl2). EI-MS: m/zZ282 (MC). 1H NMR (CDCl3): d 0.97, 1.08, 1.43 (9H, 3 s, 1:1:1, 3Me); 1.84–1.91 (1H, m, 1H of CH2); 1.96–2.14 (2H, m, CH2); 2.20–2.29 (1H, m, 1H of CH2); 2.38 (3H, s, Me-Ar); 2.57 (1H, d, JZ 4.5 Hz, H–C(1)); 7.01 (1H, br d, JZ7.5 Hz, 1H of Ar); 7.24 (1H, s, H–C(3)); 7.27 (1H, br t, JZ7.8 Hz, 1H of Ar); 7.59 (1H, br d, JZ8.3 Hz, 1H of Ar); 7.63 (1H, br s, 1H of Ar). 13 C NMR (CDCl3): d 18.7, 19.5, 21.9, 24.2, 34.0, 38.1, 43.1, 43.9, 94.1, 107.2, 117.1, 120.8, 126.5, 129.0, 136.5, 139.3, 139.4, 149.7. (Found: C, 76.28; H, 7.79; N, 10.16. C18H22N2O requires: C, 76.56; H, 7.85; N, 9.92.); EI-HRMS: m/zZ 282.1740 (MC); C18H22N2O requires: m/zZ282.1732 (MC). nmax (KBr): 2960, 1611, 1597, 1516, 1489, 1460, 1414, 1392, 1380, 1142, 1099, 1069, 975, 884, 854 cmK1. 5.2.5. (1S,8R)-5-(4-Methylphenyl)-8,11,11-trimethyl-7oxa-4,5-diazatricyclo-[6.2.1.0 2,6 ]undeca-2(6),3-diene (7f). Prepared from 5 (0.223 g, 1 mmol), (4-methylphenyl)hydrazine hydrochloride (6f, 0.159 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 4 h, CC (ethyl acetate– petroleum ether, 1:4). Yield: 0.240 g (85%) of white
5.2.7. 2-(2-Chlorophenyl)-4-[(1S,3R)-3-hydroxy-2,2,3trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one (8h). Prepared from 5 (0.223 g, 1 mmol), (2-chlorophenyl)hydrazine hydrochloride (6h, 0.179 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 6 h, CC (first: ethyl acetate–petroleum ether, 1:4). Yield: 0.196 g (61%) of white crystals; mp 177–182 8C (from chloroform–n-heptane); [a]21 D ZK9.3 (cZ0.31, CH2Cl2). EI-MS: m/zZ320 (MC). 1H NMR (CDCl3): d 1.00, 1.01, 1.31 (9H, 3 s, 1:1:1, 3Me); 1.59–1.67 (1H, m, 1H of CH2); 1.94–2.27 (4H, m, 3H of CH2 and H–C(1 0 )); 6.41 (1H, br s, OH); 6.62 (1H, d, JZ 10.3 Hz, H–C(5)); 6.82 (1H, dt, JZ1.4, 7.8 Hz, 1H of Ar); 6.94 (1H, dd, JZ1.2, 8.0 Hz, 1H of Ar); 7.18 (1H, br t, JZ 7.8 Hz, 1H of Ar); 7.26 (1H, dd, JZ1.3, 7.9 Hz, 1H of Ar); 8.97 (1H, br d, JZ10.3 Hz, NH). 13C NMR (CDCl3): d 18.8, 18.9, 23.8, 31.7, 38.0, 43.8, 50.3, 92.2, 101.0, 113.8, 118.6, 121.4, 128.3, 129.7, 144.7, 150.6, 170.0. (Found: C, 63.62; H, 6.71; N, 8.45. C17H21ClN2O2 requires: C, 63.65; H, 6.60; N, 8.73.); EI-HRMS: m/zZ320.1301 (MC). C17H21ClN2O2 requires: 320.1292 (MC). nmax (KBr): 3452, 3259, 2983, 1682 (C]O), 1618, 1466, 1215, 1138, 748 cmK1. 5.2.8. 4-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]1H-pyrazol-3-ol (9a). Prepared from 5 (0.223 g, 1 mmol), hydrazine hydrochloride (6a, 0.069 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 5 h, CC (chloroform– methanol, 15:1). Yield: 0.175 g (83%) of white crystals; mp
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203–210 8C; [a]25 D ZC24.4 (cZ0.24, DMSO); C36.2 (cZ 0.12, MeOH). EI-MS m/zZ210 (MC). 1H NMR (DMSOd6): d 0.60, 0.76, 1.13 (9H, 3 s, 1:1:1, 3Me); 1.58–1.81 (4H, m, 2CH2); 2.74 (1H, br t, JZ9.0 Hz, H–C(1 0 )); 4.59 (1H, br s, OH); 7.16 (1H, s, H–C(3)); 9.65 (1H, s, NH); 11.03 (1H, s, HO–C(3)). 13C NMR (DMSO-d6): d 19.8, 25.4, 25.6, 27.5, 38.5, 42.9, 47.5, 81.6, 105.7, 129.4, 159.9. (Found: C, 63.09; H, 8.60; N, 12.90. C11H18N2O2 requires: C, 62.83; H, 8.63; N, 13.32.); EI-HRMS: m/zZ210.1374 (MC); C11H18N2O2 requires: m/zZ210.1368 (MC). nmax (KBr): 3481, 3200, 2979, 1524, 1469, 1368, 1144, 1101, 1078, 932 cmK1. 5.2.9. 2-(2-Bromophenyl)-4-[(1S,3R)-3-hydroxy-2,2,3trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one (8i). A mixture of 5 (0.223 g, 1 mmol), (2-bromophenyl)hydrazine hydrochloride 6i (0.224 g, 1 mmol), and anhydrous n-propanol (5 ml) was heated under reflux for 6 h. The reaction mixture was cooled to rt, the precipitate was collected by filtration, and washed with cold n-propanol (0 8C, 2 ml) to give 8i. Yield: 0.230 g (63%) of white crystals; mp 186–194 8C (from chloroform–n-heptane); [a] 21 D ZK11.2 (cZ0.22, CH 2 Cl 2 ). EI-MS: m/zZ364 (MC). 1H NMR (CDCl3): d 1.00, 1.01, 1.31 (9H, 3 s, 1:1:1, 3Me); 1.59–1.68 (1H, m, 1H of CH2); 1.95–2.27 (4H, m, 3H of CH2 and H–C(1 0 )); 6.39 (1H, br s, OH); 6.62 (1H, d, JZ10.4 Hz, H–C(5)); 6.76 (1H, dt, JZ1.5, 7.8 Hz, 1H of Ar); 6.93 (1H, dd, JZ1.4, 8.2 Hz, 1H of Ar); 7.22 (1H, dt, JZ1.1, 7.8 Hz, 1H of Ar); 7.43 (1H, dd, JZ1.3, 7.9 Hz, 1H of Ar); 8.99 (1H, br d, JZ10.4 Hz, NH). 13C NMR (CDCl3): d 18.8, 18.9, 23.8, 31.7, 38.0, 43.9, 50.3, 92.2, 101.0, 108.1, 114.0, 121.9, 128.9, 132.9, 145.7, 150.6, 170.0. (Found: C, 55.93; H, 5.76; N, 7.38 C17H21BrN2O2 requires: C, 55.90; H, 5.79; N, 7.67.); EI-HRMS: m/zZ364.0799 (MC); C 17H 21BrN 2O 2 requires: m/zZ364.0786 (M C); nmax (KBr): 3436, 3256, 2943, 1679 (C]O), 1616, 1461, 1213, 1134, 750 cmK1. 5.2.10. 2-Pentafluorophenyl-4-[(1S,3R)-3-hydroxy-2,2,3trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one (8j). A solution of sulfuric acid in n-propanol (1 M, 0.5 ml, 0.5 mmol) was added to the solution of enamino lactone 5 (0.223 g, 1 mmol) and pentafluorophenylhydrazine (6j, 0.198 g, 1 mmol) in anhydrous n-propanol (5 ml), and the mixture was heated under reflux for 5 h. Volatile components were evaporated in vacuo and the residue was purified by CC (first: ethyl acetate–petroleum ether, 1:10, then ethyl acetate–petroleum ether, 1:3). Fractions containing the product were combined and evaporated in vacuo to give 8j. Yield: 0.211 g (56%) of white crystals; mp 163– 167 8C (from chloroform–n-heptane, with previous melting and solidifying at 139–145 8C); [a]21 D ZC0.9 (cZ0.316, CH2Cl2). 1H NMR (CDCl3): d 0.97, 1.00, 1.29 (9H, 3 s, 1:1:1, 3Me); 1.57–1.67 (1H, m, 1H of CH2); 1.91–2.23 (4H, m, 3H of CH2 and H–C(1 0 )); 5.92 (1H, br s, OH); 6.75 (1H, d, JZ10.0 Hz, H–C(5)); 9.03 (1H, d, JZ10.0 Hz, NH). (Found: 54.08; H, 4.70; N, 7.19. C17H17F5N2O2 requires: C, 54.26; H, 4.55; N, 7.44.); nmax (KBr): 3331, 3295, 2976, 1673 (C]O), 1627, 1520, 1429, 1141, 1018, 966 cmK1. 5.3. X-ray structure determination Single crystal X-ray diffraction data of compound 7d were collected at room temperature on a Nonius Kappa CCD
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diffractometer using the Nonius Collect Software.11 DENZO and SCALEPACK12 were used for indexing and scaling of the data. The structure was solved by means of SIR97.13 Refinement was done using Xtal3.414 program package and the crystallographic plot was prepared by ORTEP III15. Crystal structure was refined on F values using the full-matrix least-squares procedure. The nonhydrogen atoms were refined anisotropically. The positions of hydrogen atoms were geometrically calculated and their positional and isotropic atomic displacement parameters were not refined. Absorption correction was not necessary. Regina16 weighting scheme was used. The crystallographic data for compound 7d have been deposited with the Cambridge Crystallographic Data Center as supplementary material with the deposition number: CCDC 254054. These data can be obtained, free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html.
Acknowledgements The financial support from the Ministry of Science and Technology, Slovenia through grants P0-0502-0103, P10179, and J1-6689-0103-04 is gratefully acknowledged. The diffraction data for compound 7d were collected on the Kappa CCD Nonius diffractometer in the Laboratory of Inorganic Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. We acknowledge with thanks the financial contribution of the Ministry of Science and Technology, Republic of Slovenia through grants X-2000 and PS-511-103, which thus made the purchase of the apparatus possible.
References and notes 1. For an illustration see: (a) Elguero, J. In Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pyrazoles in Comprehensive Heterocyclic Chemistry II; Elsevier Science: Oxford, 1996; Vol. 3, pp 1–75. (b) Varvounis, G.; Fiamegos, Y.; Pilidis, G. Adv. Heterocycl. Chem. 2001, 80, 73–156. (c) Stanovnik, B.; Svete, J. In Neier, R., Ed.; Pyrazoles in Science of Synthesis, Houben-Weyl Methods of Organic Transformations; Georg Thieme Verlag: Stuttgart, 2002; Vol. 12, pp 15–225. 2. For an illustration see: (a) Money, T. Nat. Prod. Rep. 1985, 2, 253–289. (b) Oppolzer, W. Tetrahedron 1987, 43, 1969–2004. (c) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241–1250. (d) Money, T. In Remote Functionalization of Camphor: Application to Natural Product Synthesis in Organic Synthesis: Theory and Applications, Vol. 3; JAI: Greenwich, 1996; p 1–83. 3. (a) Wallach, O. Liebigs. Ann. Chem. 1903, 329, 109–131. (b) Jacquier, R.; Maury, G. Bull. Soc. Chim. Fr. 1967, 295–297. (c) Nagai, S.; Oda, N.; Ito, I.; Kudo, Y. Chem. Pharm. Bull. 1979, 27, 1771–1779. (d) Nagai, S.; Ueda, T.; Oda, N.; Sakakibara, J. Heterocycles 1983, 20, 995–1000. (e) Watson, A. A.; House, D. A.; Steel, P. J. J. Organomet. Chem. 1986, 311, 387–397. (f) Watson, A. A.; House, D. A.; Steel J. Org. Chem. 1991, 56, 4072–4074. 4. (a) Kotsuki, H.; Hayakawa, H.; Wakao, M.; Shimanouchi, T.;
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6. 7.
8.
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Ochi, M. Tetrahedron: Asymmetry 1995, 11, 2665–2668. (b) Kotsuki, H.; Wakao, M.; Hayakawa, H.; Shimanouchi, T.; Shiro, M. J. Org. Chem. 1996, 61, 8915–8920. For recent reviews see: (a) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433–2480. (b) Svete, J. Monatsh. Chem. 2004, 135, 629–647. (c) Svete, J. Heterocycl. Chem. 2002, 39, 437–454. (d) Stanovnik, B.; Svete, J. Synlett 2000, 1077–1091. (e) Stanovnik, B.; Svete, J. Targets Heterocycl. Syst. 2000, 4, 105–137. (f) Stanovnik, B. J. Heterocycl. Chem. 1999, 36, 1581–1593. Jaksˇe, R.; Svete, J.; Stanovnik, B.; Golobicˇ, A. Tetrahedron 2004, 60, 4601–4608. (a) Pirc, S.; Bevk, D.; Golicˇ Grdadolnik, S.; Svete, J. ARKIVOC 2003 (xiv), 37–48. (b) Westman, J.; Lundin, R. Synthesis 2003, 1025–1030. (c) Cˇebasˇek, P.; Wagger, J.; Bevk, D.; Jaksˇe, R.; Svete, J.; Stanovnik, B. J. Comb. Chem. 2004, 6, 356–362. Grosˇelj, U.; Recˇnik, S.; Svete, J.; Meden, A.; Stanovnik, B. Tetrahedron: Asymmetry 2002, 13, 821–833.
9. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Meden, A.; Pirc, S.; Recˇnik, S.; Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry 2004, 15, 2367–2383. 10. Druey, J.; Meier, K.; Eichenberger, K. Helv. Chim. Acta 1954, 37, 121–133. 11. Collect Software. Nonius, BV, Delft, The Netherlands, 1998. 12. Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307. 13. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Cryst. 1999, 32, 115. 14. Hall, S. R.; King, G. S. D.; Stewart, J. M. The Xtal3.4 User’s Manual; University of Western Australia: Lamb, Perth, 1995. 15. Burnett, M. N.; Johnson, C. K. In ORTEP-III: Oak Ridge Thermal Ellipsoid Plot Program for Crystal Structure Illustrations. Oak Ridge National Laboratory Report ORNL6895, 1996. 16. Wang, H.; Robertson, B. E. In Structure and Statistics in Crystallography; Wilson, A. J. C., Ed.; Adenine: New York, 1985.
Cyclocondensations of (C)-camphor derived enaminones with hydrazine derivatives Urosˇ Grosˇelj, David Bevk, Renata Jaksˇe, Simon Recˇnik, Anton Meden, Branko Stanovnik and Jurij Svete* Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, PO Box 537, 1000 Ljubljana, Slovenia Received 2 November 2004; revised 4 February 2005; accepted 18 February 2005
Dedicated to Professor Lubor Fisˇera, Slovak University of Technology, Bratislava, on the occasion of his 60th anniversary
Abstract—Reactions of 3-[(E)-(dimethylamino)methylidene]-(C)-camphor and (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with hydrazine derivatives were studied. Treatment of 3-[(E)-(dimethylamino)methylidene]-(C)camphor with hydrazines afforded the corresponding fused pyrazoles. Similarly, fused pyrazoles were obtained upon reaction of (1R,5S)-4[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with ortho-unsubstituted phenylhydrazines, while reactions with ortho-substituted phenylhydrazines and with hydrazine hydrochloride resulted in ‘ring switching’ type of transformation to furnish 2-aryl-4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-ones. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction Naturally occurring and synthetic pyrazole derivatives have found widespread use in various applications.1 Similarly, (C)-camphor (1) and its derivatives, are among the most frequently employed types of ex-chiral pool starting materials and building blocks, resolving agents, chiral shift reagents in NMR spectroscopy, and ligands in various asymmetric applications.2 Camphor-functionalized pyrazoles, N-substituted (1R,7S)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0 2,6]deca-2(6),4-dienes (or N-substituted (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methyno1H-indazoles) 2 have been synthesized from 3-formylcamphor and hydrazine derivatives.3 Kotsuki and co-workers prepared various N-(b-hydroxyethyl) substituted (1R,7S)1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4dienes 2k–m and 3k–m, which were successfully employed as chiral ligands for enantioselective addition of diethylzinc to benzaldehyde (Fig. 1).4
various heterocyclic systems, including pyrazole derivatives. Various chiral analogs of 3-dimethylaminopropenoates were also prepared from commercially available enantiopure starting materials, such as a-amino acids and (C)-camphor (1). The a-amino acid derived chiral enaminones were employed as the key-intermediates and reagents in the synthesis of functionalized heterocycles, for example, in the ‘ring switching’ synthesis of 3-heteroarylalanine derivatives and related compounds and in the synthesis of heterocyclic analogs of dipeptides.5,6 Recently, utilization of 3-(dimethylamino)propenoates in combinatorial synthesis has also been reported.7 In connection with (C)camphor (1) derived enaminones 4 and 5, we have previously reported stereoselective synthesis of (1R,3R,4R)-3-(1,2,4triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones,8 and N-substituted (1R,5S)-3-aminomethylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones.9
Recently, a series of alkyl 2-substituted 3-(dimethylamino)propenoates and related enaminones, synthetic equivalents of 1,3-dicarbonyl compounds, have been prepared and used for the preparation of dehydroalanine esters and Keywords: Camphor; Enaminones; Terpenes; Hydrazines; Condensations. * Corresponding author. Tel.: C386 1 2419 100; fax: C386 1 2419 220; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.02.048
Figure 1.
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In continuation of our work in the field of (C)-camphor (1) derived enaminones, we now report cyclocondensations of (1R,4S)-3-[(E)-(dimethylamino)methylidene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4) and (1R,5S)-4-[(E)(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one (5) with hydrazine derivatives 6a–i leading to, either fused pyrazole systems 2 and 7, or to 4[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl] substituted pyrazole derivatives 8 and 9, as products of a ‘ring switching’ type transformation.
2. Results and discussion Starting compounds 48 and 59 were prepared from (C)camphor (1) according to literature procedures. Reaction of 4 with hydrazine hydrochloride (6a) in methanol at rt gave (1R,7S)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2a) in 81% yield. Similarly, treatment of 4 with benzylhydazine dihydrochloride (6b) and 6-chloro-3hydrazinopyridazine (6c) in acetic acid under reflux afforded (1R,7S)-3-benzyl-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2b) and 6-[(1R,7S)1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4dien-3-yl]pyridazin-3(2H)-one (2c) in 63% and 83% yield, respectively. On the other hand, upon reaction of 5 with phenylhydrazine derivatives 6d–j in refluxing n-propanol, two different types of products were formed, either fused pyrazoles 7, or cyclopentyl substituted pyrazolones 8. Thus, treatment of 5 with ortho-unsubstituted phenylhydrazines 6d–f afforded (1S,8R)-5-aryl-8,11,11-trimethyl-7-oxa4,5-diazatricyclo[6.2.1.02,6]undeca-2(6),3-dienes 7d–f in 74–91% yields, while treatment of 5 with ortho-substituted phenylhydrazines 6g–j furnished 2-aryl-4-[(1S,3R)-3hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-ones 8g–j in 56–70% yields. ‘Ring switching’ transformation also took place in the case of the reaction
of 5 with hydrazine hydrochloride (6a), which gave 4[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1H-pyrazol-3-ol (9a) in 81% yield (Scheme 1, Table 1). Formation of pyrazole derivatives 2, 7–9 can be explained according to the formation of pyrazoles from hydrazine derivatives and 1,3-dicarbonyl compounds and their enamino analogs.1 Compound 4, an enamino masked b-keto aldehyde, reacts via initial substitution of the dimethylamino group to give the isomeric enehydrazines 10 and 10 0 . The (Z)-isomer 10 0 then cyclizes into dihydropyrazole 11, followed by elimination of water to give fused pyrazole 2. Similarly, compound 5 as an enamino masked b-keto ester is first transformed into a mixture of isomeric enehydrazines 12 and 12 0 . The (Z)-isomer 12 0 then cyclizes into the bicyclic intermediate 13. From this point on, further reaction can take place in two ways: (a) elimination of water leads to pyrazolo fused lactones 7 (Path A) and (b) elimination of the alcohol moiety leads to ‘ring switched’ pyrazolones of type 8 (Path B) (Scheme 2). So far, we do not have an explanation for chemoselectivity of reactions of 5 with hydrazine derivatives 6a,d–j. In the literature, there are several examples, where treatment of bketo esters with arylhydrazines under acidic conditions afforded 5-alkoxy- and/or 5-hydroxypyrazoles.1 Since elimination of water is generally facilitated by the protonation of the hydroxy group, while elimination of alcohol can be, either acid-catalysed or base-catalysed, steric factors might control selectivity of cyclisation of bicyclic intermediates 13a,d–j into pyrazole derivatives 7d–f, 8g–j, and 9a. Thus, in the case of intermediates 13d–f without ortho-substituent attached to the aromatic ring, the hydroxy group can undergo protonation and, consequently, elimination of water can take place to give fused pyrazoles 7d–f. On the other hand, in intermediates 13g–j, the hydroxy group is hindered by the ortho-substituent attached
Scheme 1. Reaction conditions: (i) NH2NH2$HCl (6a) MeOH, rt; (ii) PhCH2NHNH2$2HCl (6b) or 6-chloro-3-hydrazinopyridazine (6c), AcOH, reflux; (iii) RNHNH2$HCl (6a,d–i) or C6F5NHNH2$1⁄2 H2SO4 (6j), n-PrOH, reflux.
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Table 1. Experimental data for compounds 2, 7–9 Compound
R
Yield (%) 2
2a, 6a, 9a 2b, 6b 6c 2c 6d, 7d 6e, 7e 6f, 7f 6g, 8g 6h, 8h 6i, 8i 6j, 8j
H Benzyl 6-Chloropyridazin-3-yl 6-Oxo-1,6-dihydropyridazin-3-yl Phenyl 3-Methylphenyl 4-Methylphenyl 2-Methylphenyl 2-Chlorophenyl 2-Bromophenyl Pentafluorophenyl
to the aromatic ring. Consequently, protonation of the hydroxy group is disfavoured and elimination of alcohol, that is, opening of the lactone ring, takes place to give the hydroxypyrazoles 9g–j, which then tautomerise into the
Scheme 2.
7
8
81 63
9 83
83 91 74 85 70 61 63 56
pyrazolones 8g–j. In the case of transformation of 5 into 9a, which took place upon reaction of 5 with sterically unhindered hydrazine hydrochloride (6a), opening of the lactone ring is favoured due to stronger basicity of the
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Scheme 3.
primary amino group with respect to the arylamino group (Scheme 3).
the ortho-methyl group in the aryl residue was in agreement with (1S,3R)-configuration (Fig. 2). The structure of compound 7d was determined by X-ray diffraction (Fig. 3).
3. Structure determination The structures of compounds 2, 7–9 were determined by spectroscopic methods (NMR, IR, MS, HRMS) and/or by analyses for C, H, and N. The structure of compound 9a, which was not isolated in analytically pure form, was confirmed by 13C NMR and HRMS. Physical and spectral data of known compounds 2a,b were in agreement with the literature data.3a,e Spectral data for pyrazoles 2, 7–9 were in agreement with the literature data for related pyrazole1 and camphor derivatives.2 IR spectra of compounds 2c and 8d–f exhibited amide C]O absoption bands at 1681 and 1682– 1673 cmK1, respectively, while no C]O absorption was observed in IR spectra of compounds 2a,b, 7d–f, and 9a. In compound 8g, NOE between the OH proton and protons of
Figure 2.
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cyclo[3.2.1]octan-3-one (5),9 and 6-chloro-3-hydrazinopyridazine (6c),10 were prepared according to the procedures described in the literature.
Figure 3. ORTEP view of the asymmetric unit of compound 7d with labeling of nonhydrogen atoms (ellipsoids are drawn at 50% probability level).
4. Conclusion In conclusion, (C)-camphor derived enaminones 4 and 5 are easily available reagents, which are suitable for the preparation of terpene-functionalized pyrazole derivatives. Reactions of (1R,4S)-3-[(E)-(dimethylamino)methylidene]1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4) with hydrazine derivatives 6 lead to 3-substituted (1R,7S)-1,10,10trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-dienes 2. However, in the case of (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3one (5), the chemoselectivity was found to be dependent on the type of hydrazine derivative 6 employed. Reactions of 5 with ortho-unsubstituted phenylhydrazines 6d–f afforded fused pyrazole systems 7d–f, while reactions with hydrazine hydrochloride (6a) and ortho-substituted phenylhydrazines 6g–j led to 4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl] substituted pyrazole derivatives 9a and 8g–j, respectively, as products of a ‘ring switching’ type transformation.
5. Experimental 5.1. General Melting points were determined on a Kofler micro hot stage. The 1H NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H, and 75.5 MHz for 13C nucleus, using DMSO-d6 and CDCl3 as solvents and TMS as the internal standard. Mass spectra were recorded on an AutoSpecQ spectrometer, IR spectra on a Perkin–Elmer Spectrum BX FTIR spectrophotometer. Microanalyses were performed on a Perkin–Elmer CHN Analyser 2400. Column chromatography (CC) was performed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm). Hydrazines 6a,b,d–j are commercially available (Fluka AG). (1R,4S)-3-[(E)-(Dimethylamino)-methylidene]-1,7,7trimethylbicyclo[2.2.1]heptan-2-one (4),8 (1R,5S)-4-[(E)(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabi-
5.1.1. (1R,7S)-1,10,10-Trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2a). A mixture of 4 (0.207 g, 1 mmol), hydrazine hydrochloride (6a, 0.069 g, 1 mmol), and methanol (4 ml) was stirred at rt for 24 h. Water (6 ml) was added and the precipitate was collected by filtration to give 2a. Yield: 0.143 g (81%) of yellowish crystals; mp 143–147 8C, lit.3a mp 149–150 8C; [a]23 DZ C35.8 (cZ0.4, CH2Cl2). 1H NMR (DMSO-d6): d 0.56, 0.91 (6H, 2 s, 1:1, 2Me); 0.98–1.16 (2H, m, CH2); 1.19 (3H, s, Me); 1.75–1.83 (1H, m, 1H of CH2); 1.98–2.07 (1H, m, 1H of CH2); 2.73 (1H, d, JZ3.9 Hz, H–C(7)); 7.16 (1H, s, H– C(5)); 11.62 (1H, s, H–N(3)). 13C NMR (DMSO-d6): d 11.2, 19.7, 20.9, 28.2, 34.1, 47.5, 50.4, 61.4, 120.4, 126.4, 166.5. (Found: C, 74.96; H, 9.36; N, 15.59. C11H16N2 requires: C, 74.96; H, 9.15; N, 15.89.); nmax (KBr): 3415, 3145, 2923, 1586, 1479, 1454, 1415, 1386, 1369, 1286, 1273, 1140, 1084, 1026, 972, 804 cmK1. 5.2. General procedure for the preparation of compounds 2b,c, 7d–f, 8g,h, and 9a A mixture of enaminone 4 or 5 (1 mmol), hydrazine derivative 6 (1 mmol), and appropriate solvent (w5 ml) was heated under reflux for 2–6 h. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (CC). Fractions containing the product were combined and evaporated in vacuo to give 2b,c, 7d–f, 8g,h, and 9a. The following compounds were prepared in this manner: 5.2.1. (1R,7S)-3-Benzyl-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.02,6]deca-2(6),4-diene (2b). Prepared from 4 (0.207 g, 1 mmol), benzylhydrazine dihydrochloride (6b, 0.195 g, 1 mmol), and acetic acid (100%, 6 ml), reflux for 4 h, CC (diethyl ether–petroleum ether, 1:2). Yield: 0.168 g (63%) of colourless oil, lit.3e oil; [a]22 D ZK14.9 (cZ0.29, CH2Cl2). EI-MS: m/zZ266 (MC). 1H NMR (DMSO-d6): d 0.65, 0.82, 1.13 (9H, 3 s, 1:1:1, 3Me); 0.88–1.00 (2H, m, CH2); 1.61–1.70 (1H, m, 1H of CH2); 1.93–2.01 (1H, m, 1H of CH2); 2.73 (1H, d, JZ3.8 Hz, H–C(7)); 5.24 (1H, d, JZ 16.0 Hz, 1H of CH2N); 5.32 (1H, d, JZ16.0 Hz, 1H of CH2N); 7.05–7.07 (2H, m, 2H of Ph); 7.09 (1H, s, H–C(5)); 7.22–7.34 (3H, m, 3H of Ph). 13C NMR (CDCl3): d 11.7, 20.0, 20.7, 28.2, 33.8, 48.0, 52.7, 54.3, 63.2, 127.0, 127.9, 129.0, 129.5, 131.6, 138.6, 153.9. (Found: C, 80.84; H, 8.71; N, 10.51. C18H22N2 requires: C, 81.16; H, 8.32; N, 10.52.); EI-HRMS: m/zZ266.1796 (MC); C18H22N2O requires: m/zZ266.1783 (MC); nmax (NaCl): 2957, 2872, 1606, 1522, 1496, 1440, 1383, 1362, 1285, 1194, 1117, 1059, 997, 907 cmK1. 5.2.2. 6-[(1R,7S)-1,10,10-Trimethyl-3,4-diazatricyclo[5.2.1.0 2,6]deca-2(6),4-dien-3-yl]pyridazin-3(2H)-one (2c). Prepared from 4 (0.207 g, 1 mmol), 6-chloro-3hydrazinopyridazine (6c, 0.145 g, 1 mmol), and acetic acid (100%, 6 ml), reflux for 4 h, CC (ethyl acetate). Before chromatographic purification, the crude solid product was crystallised from methanol. Yield: 0.124 g (83%) of white
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crystals; mp 213–218 8C (from methanol); [a]20 D ZC9.9 (cZ0.40, CH2Cl2). 1H NMR (DMSO-d6): d 0.71, 0.90 (6H, 2 s, 1:1, 2Me); 0.95–1.03 (1H, m, 1H of CH2); 1.19–1.27 (1H, m, 1H of CH2); 1.32 (3H, s, Me); 1.78–1.86 (1H, m, 1H of CH2); 2.01–2.11 (1H, m, 1H of CH2); 2.81 (1H, d, JZ 3.6 Hz, H–C(7)); 7.05 (1H, d, JZ10.0 Hz, H–C(5 0 )); 7.44 (1H, s, H–C(5)); 7.92 (1H, d, JZ10.0 Hz, H–C(4 0 )); 12.92 (1H, s, NH). 13C NMR (DMSO-d6): d 13.4, 20.4, 21.0, 28.1, 33.5, 47.4, 54.8, 63.8, 129.6, 132.4, 133.1, 134.8, 142.2, 154.0, 160.8. (Found: C, 66.83; H, 7.09; N, 20.47. C15H18N4O requires: C, 66.64; H, 6.71; N, 20.73.); nmax (KBr): 3446, 2961, 1681 (C]O), 1613, 1563, 1475, 1448, 1380, 1308, 1242, 1007, 986, 839 cmK1.
crystals; mp 146–150 8C (from chloroform–n-heptane); 1 [a]21 D ZK27.2 (cZ0.23, CH2Cl2). H NMR (CDCl3): d 0.97, 1.08, 1.42 (9H, 3 s, 1:1:1, 3Me); 1.83–1.95 (1H, m, 1H of CH2); 1.95–2.14 (2H, m, CH2); 2.19–2.28 (1H, m, 1H of CH2); 2.35 (3H, s, Me-Ar); 2.57 (1H, d, JZ4.4 Hz, H– C(1)); 7.19 (2H, br d, JZ8.5 Hz, 2H of Ar); 7.23 (1H, s, H– C(3)); 7.66 (2H, br d, JZ8.5 Hz, 2H of Ar). 13C NMR (CDCl3): d 18.7, 19.5, 21.3, 24.3, 34.0, 38.1, 43.1, 43.9, 94.0, 107.1, 120.1, 129.8, 135.4, 136.3, 137.1, 149.5. (Found: C, 76.29; H, 8.03; N, 9.76. C18H22N2O requires: C, 76.56; H, 7.85; N, 9.92.); nmax (KBr): 2972, 1589, 1526, 1458, 1428, 1076, 973, 882, 855, 818 cmK1.
5.2.3. (1S,8R)-5-Phenyl-8,11,11-trimethyl-7-oxa-4,5-diazatricyclo[6.2.1.02,6]undeca-2(6),3-diene (7d). Prepared from 5 (0.223 g, 1 mmol) and phenylhydrazine hydrochloride (6d, 0.145 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 2 h, CC (ethyl acetate–petroleum ether, 1:3). Yield: 0.224 g (91%) of white crystals; mp 173–177 8C (from ethyl acetate–n-hexane); [a]25 D ZK27.6 (cZ0.25, CH2Cl2). EI-MS: m/zZ268 (MC). 1H NMR (CDCl3): d 0.98, 1.08, 1.44 (9H, 3 s, 1:1:1, 3Me); 1.84–1.91 (1H, m, 1H of CH2); 1.96–2.14 (2H, m, CH2); 2.20–2.29 (1H, m, 1H of CH2); 2.58 (1H, d, JZ4.4 Hz, H–C(1)); 7.19 (1H, tt, JZ1.2, 7.5 Hz, 1H of Ph); 7.25 (1H, s, H–C(3)); 7.36–7.42 (2H, m, 2H of Ph); 7.79–7.81 (2H, m, 2H of Ph). 13C NMR (CDCl3): d 18.7, 19.5, 24.2, 34.0, 38.1, 43.1, 43.9, 94.2, 107.3, 120.0, 125.7, 129.3, 136.6, 139.5, 149.7. (Found: C, 76.23; H, 7.64; N, 10.35. C17H20N2O requires: C, 76.09; H, 7.51; N, 10.44.); EI-HRMS: m/zZ268.1585; C17H20N2O requires: m/zZ268.1576 (MC). Found: nmax (KBr): 2956, 1595, 1516, 1492, 1455, 1418, 1377, 1088, 1057, 970, 847, 760, 690 cmK1.
5.2.6. 4-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]2-(2-methylphenyl)-1,2-dihydro-3H-pyrazol-3-one (8g). Prepared from 5 (0.223 g, 1 mmol), (2-methylphenyl)hydrazine hydrochloride (6g, 0.159 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 4 h, CC (first: ethyl acetate– petroleum ether, 1:4, then ethyl acetate–petroleum ether, 1:2). Yield: 0.210 g (70%) of white crystals; mp 139–145 8C (from chloroform–n-heptane); [a]21 D ZK13.2 (cZ0.39, CH2Cl2). EI-MS: m/zZ300 (MC). 1H NMR (CDCl3): d 1.00, 1.01, 1.31 (9H, 3 s, 1:1:1, 3Me); 1.59–1.67 (1H, m, 1H of CH2); 1.93–2.27 (4H, m, 3H of CH2 and H–C(1 0 )); 2.16 (3H, s, Me-Ar); 5.82 (1H, br s, OH); 6.65 (1H, d, JZ 10.4 Hz, H–C(5)); 6.83 (1H, br t, JZ7.3 Hz, 1H of Ar); 6.87 (1H, br d, JZ7.6 Hz, 1H of Ar); 7.07 (1H, br d, JZ7.3 Hz, 1H of Ar); 7.14 (1H, br t, JZ7.6 Hz, 1H of Ar); 8.97 (1H, d, JZ10.4 Hz, NH). 13C NMR (CDCl3): d 17.4, 18.8, 18.9, 23.8, 31.8, 38.0, 43.8, 50.3, 92.0, 100.0, 112.1, 120.9, 122.2, 127.5, 130.8, 146.7, 151.2, 170.1. (Found: C, 71.94; H, 8.09; N, 9.27. C18H24N2O2 requires: C, 71.97; H, 8.05; N, 9.33.); EI-HRMS: m/zZ300.1846 (MC); C18H24N2O2 requires: m/zZ300.1838 (MC). nmax (KBr): 3452, 3287, 3256, 2970, 1677 (C]O), 1607, 1426, 1219, 1138, 756 cmK1.
5.2.4. (1S,8R)-5-(3-Methylphenyl)-8,11,11-trimethyl-7oxa-4,5-diazatricyclo-[6.2.1.0 2,6 ]undeca-2(6),3-diene (7e). Prepared from enaminone 5 (0.223 g, 1 mmol) and (3-methylphenyl)hydrazine hydrochloride (6e, 0.159 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 3 h, CC (ethyl acetate–petroleum ether, 1:4). Yield: 0.209 g (74%) of light orange crystals; mp 75–79 8C; [a]21 D ZK26.3 (cZ0.74, CH2Cl2). EI-MS: m/zZ282 (MC). 1H NMR (CDCl3): d 0.97, 1.08, 1.43 (9H, 3 s, 1:1:1, 3Me); 1.84–1.91 (1H, m, 1H of CH2); 1.96–2.14 (2H, m, CH2); 2.20–2.29 (1H, m, 1H of CH2); 2.38 (3H, s, Me-Ar); 2.57 (1H, d, JZ 4.5 Hz, H–C(1)); 7.01 (1H, br d, JZ7.5 Hz, 1H of Ar); 7.24 (1H, s, H–C(3)); 7.27 (1H, br t, JZ7.8 Hz, 1H of Ar); 7.59 (1H, br d, JZ8.3 Hz, 1H of Ar); 7.63 (1H, br s, 1H of Ar). 13 C NMR (CDCl3): d 18.7, 19.5, 21.9, 24.2, 34.0, 38.1, 43.1, 43.9, 94.1, 107.2, 117.1, 120.8, 126.5, 129.0, 136.5, 139.3, 139.4, 149.7. (Found: C, 76.28; H, 7.79; N, 10.16. C18H22N2O requires: C, 76.56; H, 7.85; N, 9.92.); EI-HRMS: m/zZ 282.1740 (MC); C18H22N2O requires: m/zZ282.1732 (MC). nmax (KBr): 2960, 1611, 1597, 1516, 1489, 1460, 1414, 1392, 1380, 1142, 1099, 1069, 975, 884, 854 cmK1. 5.2.5. (1S,8R)-5-(4-Methylphenyl)-8,11,11-trimethyl-7oxa-4,5-diazatricyclo-[6.2.1.0 2,6 ]undeca-2(6),3-diene (7f). Prepared from 5 (0.223 g, 1 mmol), (4-methylphenyl)hydrazine hydrochloride (6f, 0.159 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 4 h, CC (ethyl acetate– petroleum ether, 1:4). Yield: 0.240 g (85%) of white
5.2.7. 2-(2-Chlorophenyl)-4-[(1S,3R)-3-hydroxy-2,2,3trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one (8h). Prepared from 5 (0.223 g, 1 mmol), (2-chlorophenyl)hydrazine hydrochloride (6h, 0.179 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 6 h, CC (first: ethyl acetate–petroleum ether, 1:4). Yield: 0.196 g (61%) of white crystals; mp 177–182 8C (from chloroform–n-heptane); [a]21 D ZK9.3 (cZ0.31, CH2Cl2). EI-MS: m/zZ320 (MC). 1H NMR (CDCl3): d 1.00, 1.01, 1.31 (9H, 3 s, 1:1:1, 3Me); 1.59–1.67 (1H, m, 1H of CH2); 1.94–2.27 (4H, m, 3H of CH2 and H–C(1 0 )); 6.41 (1H, br s, OH); 6.62 (1H, d, JZ 10.3 Hz, H–C(5)); 6.82 (1H, dt, JZ1.4, 7.8 Hz, 1H of Ar); 6.94 (1H, dd, JZ1.2, 8.0 Hz, 1H of Ar); 7.18 (1H, br t, JZ 7.8 Hz, 1H of Ar); 7.26 (1H, dd, JZ1.3, 7.9 Hz, 1H of Ar); 8.97 (1H, br d, JZ10.3 Hz, NH). 13C NMR (CDCl3): d 18.8, 18.9, 23.8, 31.7, 38.0, 43.8, 50.3, 92.2, 101.0, 113.8, 118.6, 121.4, 128.3, 129.7, 144.7, 150.6, 170.0. (Found: C, 63.62; H, 6.71; N, 8.45. C17H21ClN2O2 requires: C, 63.65; H, 6.60; N, 8.73.); EI-HRMS: m/zZ320.1301 (MC). C17H21ClN2O2 requires: 320.1292 (MC). nmax (KBr): 3452, 3259, 2983, 1682 (C]O), 1618, 1466, 1215, 1138, 748 cmK1. 5.2.8. 4-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]1H-pyrazol-3-ol (9a). Prepared from 5 (0.223 g, 1 mmol), hydrazine hydrochloride (6a, 0.069 g, 1 mmol), and anhydrous n-propanol (5 ml), reflux for 5 h, CC (chloroform– methanol, 15:1). Yield: 0.175 g (83%) of white crystals; mp
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203–210 8C; [a]25 D ZC24.4 (cZ0.24, DMSO); C36.2 (cZ 0.12, MeOH). EI-MS m/zZ210 (MC). 1H NMR (DMSOd6): d 0.60, 0.76, 1.13 (9H, 3 s, 1:1:1, 3Me); 1.58–1.81 (4H, m, 2CH2); 2.74 (1H, br t, JZ9.0 Hz, H–C(1 0 )); 4.59 (1H, br s, OH); 7.16 (1H, s, H–C(3)); 9.65 (1H, s, NH); 11.03 (1H, s, HO–C(3)). 13C NMR (DMSO-d6): d 19.8, 25.4, 25.6, 27.5, 38.5, 42.9, 47.5, 81.6, 105.7, 129.4, 159.9. (Found: C, 63.09; H, 8.60; N, 12.90. C11H18N2O2 requires: C, 62.83; H, 8.63; N, 13.32.); EI-HRMS: m/zZ210.1374 (MC); C11H18N2O2 requires: m/zZ210.1368 (MC). nmax (KBr): 3481, 3200, 2979, 1524, 1469, 1368, 1144, 1101, 1078, 932 cmK1. 5.2.9. 2-(2-Bromophenyl)-4-[(1S,3R)-3-hydroxy-2,2,3trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one (8i). A mixture of 5 (0.223 g, 1 mmol), (2-bromophenyl)hydrazine hydrochloride 6i (0.224 g, 1 mmol), and anhydrous n-propanol (5 ml) was heated under reflux for 6 h. The reaction mixture was cooled to rt, the precipitate was collected by filtration, and washed with cold n-propanol (0 8C, 2 ml) to give 8i. Yield: 0.230 g (63%) of white crystals; mp 186–194 8C (from chloroform–n-heptane); [a] 21 D ZK11.2 (cZ0.22, CH 2 Cl 2 ). EI-MS: m/zZ364 (MC). 1H NMR (CDCl3): d 1.00, 1.01, 1.31 (9H, 3 s, 1:1:1, 3Me); 1.59–1.68 (1H, m, 1H of CH2); 1.95–2.27 (4H, m, 3H of CH2 and H–C(1 0 )); 6.39 (1H, br s, OH); 6.62 (1H, d, JZ10.4 Hz, H–C(5)); 6.76 (1H, dt, JZ1.5, 7.8 Hz, 1H of Ar); 6.93 (1H, dd, JZ1.4, 8.2 Hz, 1H of Ar); 7.22 (1H, dt, JZ1.1, 7.8 Hz, 1H of Ar); 7.43 (1H, dd, JZ1.3, 7.9 Hz, 1H of Ar); 8.99 (1H, br d, JZ10.4 Hz, NH). 13C NMR (CDCl3): d 18.8, 18.9, 23.8, 31.7, 38.0, 43.9, 50.3, 92.2, 101.0, 108.1, 114.0, 121.9, 128.9, 132.9, 145.7, 150.6, 170.0. (Found: C, 55.93; H, 5.76; N, 7.38 C17H21BrN2O2 requires: C, 55.90; H, 5.79; N, 7.67.); EI-HRMS: m/zZ364.0799 (MC); C 17H 21BrN 2O 2 requires: m/zZ364.0786 (M C); nmax (KBr): 3436, 3256, 2943, 1679 (C]O), 1616, 1461, 1213, 1134, 750 cmK1. 5.2.10. 2-Pentafluorophenyl-4-[(1S,3R)-3-hydroxy-2,2,3trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one (8j). A solution of sulfuric acid in n-propanol (1 M, 0.5 ml, 0.5 mmol) was added to the solution of enamino lactone 5 (0.223 g, 1 mmol) and pentafluorophenylhydrazine (6j, 0.198 g, 1 mmol) in anhydrous n-propanol (5 ml), and the mixture was heated under reflux for 5 h. Volatile components were evaporated in vacuo and the residue was purified by CC (first: ethyl acetate–petroleum ether, 1:10, then ethyl acetate–petroleum ether, 1:3). Fractions containing the product were combined and evaporated in vacuo to give 8j. Yield: 0.211 g (56%) of white crystals; mp 163– 167 8C (from chloroform–n-heptane, with previous melting and solidifying at 139–145 8C); [a]21 D ZC0.9 (cZ0.316, CH2Cl2). 1H NMR (CDCl3): d 0.97, 1.00, 1.29 (9H, 3 s, 1:1:1, 3Me); 1.57–1.67 (1H, m, 1H of CH2); 1.91–2.23 (4H, m, 3H of CH2 and H–C(1 0 )); 5.92 (1H, br s, OH); 6.75 (1H, d, JZ10.0 Hz, H–C(5)); 9.03 (1H, d, JZ10.0 Hz, NH). (Found: 54.08; H, 4.70; N, 7.19. C17H17F5N2O2 requires: C, 54.26; H, 4.55; N, 7.44.); nmax (KBr): 3331, 3295, 2976, 1673 (C]O), 1627, 1520, 1429, 1141, 1018, 966 cmK1. 5.3. X-ray structure determination Single crystal X-ray diffraction data of compound 7d were collected at room temperature on a Nonius Kappa CCD
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diffractometer using the Nonius Collect Software.11 DENZO and SCALEPACK12 were used for indexing and scaling of the data. The structure was solved by means of SIR97.13 Refinement was done using Xtal3.414 program package and the crystallographic plot was prepared by ORTEP III15. Crystal structure was refined on F values using the full-matrix least-squares procedure. The nonhydrogen atoms were refined anisotropically. The positions of hydrogen atoms were geometrically calculated and their positional and isotropic atomic displacement parameters were not refined. Absorption correction was not necessary. Regina16 weighting scheme was used. The crystallographic data for compound 7d have been deposited with the Cambridge Crystallographic Data Center as supplementary material with the deposition number: CCDC 254054. These data can be obtained, free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html.
Acknowledgements The financial support from the Ministry of Science and Technology, Slovenia through grants P0-0502-0103, P10179, and J1-6689-0103-04 is gratefully acknowledged. The diffraction data for compound 7d were collected on the Kappa CCD Nonius diffractometer in the Laboratory of Inorganic Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. We acknowledge with thanks the financial contribution of the Ministry of Science and Technology, Republic of Slovenia through grants X-2000 and PS-511-103, which thus made the purchase of the apparatus possible.
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