Cycloadditions of α-(4-[2.2]paracyclophanyl)-N-methyl nitrone

Tetrahedron 62 (2006) 4498–4505

Cycloadditions of a-(4-[2.2]paracyclophanyl)-N-methyl nitrone Ashraf A. Aly,a,* Henning Hopf,b,† Peter G. Jonesc,‡ and Ina Dixc a

Chemistry Department, Faculty of Science, El-Minia University, 61519-El-Minia, Egypt Institut fu¨r Organische Chemie, Technische Universita¨t Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany c Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t Braunschweig, Postfach 3329, Hagenring 30, D-38023 Braunschweig, Germany b

Received 12 October 2005; revised 3 February 2006; accepted 16 February 2006 Available online 13 March 2006

Abstract—Cycloadditions of the newly synthesized a-(4-[2.2]paracyclophanyl)-N-methyl nitrone (9) with selected dipolarophiles such as phenyl isocyanate (10), styrene (13), dimethyl acetylenedicarboxylate (15) and methylene sulfene (17) are reported. Two isolated diastereomeric oxadiazolones 11 and 12 are obtained by the reaction of 9 with 10, whereas the reaction of 9 with either 13 and/or 15 gives only one diastereomer isoxazole 14 and/or 16. 4-([2.2]Paracylophanyl)-N-methylamine (20) was obtained by the reaction of 9 with 17. The structure of compounds 9, 11 and 14 are assigned by X-ray structural analysis. q 2006 Elsevier Ltd. All rights reserved.

1. Introduction For a long time, [2.2]paracyclophane ([PC]) and its derivatives were mostly studied because of their unusual geometry, their steric, transannular, and ring strain effects as well as the electronic interaction between their aromatic rings.1,2 Recently, the stereochemical properties of these systems especially their planar chirality have been the focus of studies in this field. In particular [2.2]-paracyclophanes carrying a nitrogen atom in the 4-position are of growing interest as auxiliaries.3,4 PC derivatives having substituted amino functions have also been shown to be useful as effective photoconductive components.5 Since isoxazoles are nitrogen heterocycles, which have often been encountered in molecules of medicinal interest,6 a simple and efficient procedure for their synthesis would be a welcome advance. Additionally, examination of the electronic properties of isoxazoles has recently become an interesting field of research.7 Cycloaddition reactions still play an important part in the synthesis of various classes of polycyclic and/or heterocyclic compounds derived and/or fused to the [2.2]paracyclophane moiety.8 Our initial studies on the chemistry of nitrones have dealt with the synthesis of 2-(4 0 [2.2]paracyclophanyl)-6-phenylpyridine (3) formed by Keywords: Cyclophanes; Dipolarophiles; Diastereomers; Cycloadditions; X-ray structure analyses. * Corresponding author. Tel./fax: C2 86 2346876; e-mail: [email protected] † Fax: C49 531 391 5388. ‡ Fax: C49 531 391 5387. 0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2006.02.047

the reaction of (E)-N,a-dimethyl-a-(4-[2.2]paracyclophanyl)nitrone (1) with dibenzoylethylene (2) (Scheme 1).9a Furthermore, 1 yields various classes of five-member heterocyclic rings (imidazole, isoxazole and pyrrole derivatives of PC), when it is allowed to react with other dipolarophiles.9b Encouraged by these results, we decided to investigate the chemical behavior of another class of nitrones viz. a-(4-[2.2]paracyclophanyl)-N-methyl nitrone (9) towards different types of dipolarophiles.

2. Results and discussion Isomerization10 of aromatic aldoximes is a well-established method of synthesizing nitrones. We therefore prepared the aldoxime 611 (derived from 4-formyl-[2.2]paracyclophane (4)12) and reacted it with dimethyl sulfate in ethanolic potassium hydroxide solution. The reaction was completed within 10 min but provided the O-ether derivative 7 (95%) rather than the nitrone 9 (Scheme 2). A successful alternative strategy involved treatment of 4 with N-methylhydroxylamine hydrochloride (8) in alcoholic potassium hydroxide leading to product 9 in 92% yield (Scheme 2). The structure of 9 was established by conventional spectroscopic methods (see Section 3) as well as elemental analysis. Moreover, that 9 is the Z-diastereomer was established by X-ray structural analysis (Fig. 1, Table 1). The 1H NMR spectrum revealed slight differences in the d values between compounds 7 and 9; for example the methyl protons in compound 9 appear at dZ3.94, whereas in 7, they appeared at dZ4.02. In the 13C NMR spectra the methyl group signal (19-C) in 9 resonates at dZ54.9, whereas in 7 it

A. A. Aly et al. / Tetrahedron 62 (2006) 4498–4505

4499

Me N + Me

O

N

+ PhCOCH=CHCOPh 2

1

toluene reflux, 3d

3 (70%)

Scheme 1. Reaction of (E)-N,a-dimethyl-a-(4-[2.2]paracyclophane)nitrone (1) with dibenzoylethylene (2); synthesis of 2-(4 0 -[2.2]paracyclophanyl)-6phenylpyridine (3).

Scheme 2. Synthesis of a-(4-[2.2]paracyclophane)-N-methyl nitrone (9).

appears at dZ61.9. The UV spectrum showed an absorption for 9 at lmaxZ322 nm, whereas it exhibits absorption at lmaxZ278 nm for 7. 2.1. Reaction of 9 with phenyl isocyanate (10)

Figure 1. The structure of compound 9 in the crystal. Ellipsoids represent ˚ ) and angles (8): N18–O 30% probability levels. Selected bond lengths (A 1.294(3), C17–N18 1.302(3), N18–C19 1.467(3); O–N18–C17 125.9(2), O–N18–C19 114.4(2), C17–N18–C19 119.7(2).

The reaction of phenyl isocyanate (10) with 9 gives, after 3 d of refluxing in benzene, the two diastereomers 3 0 R*,4R*-3 0 (H)2 0 -methyl-4 0 -phenyl-(4-[2.2]-paracyclophanyl)-1 0 ,2 0 ,4 0 -oxadiazole-5 0 -one (11) and 3 0 R*,4S*-3 0 (H)-2 0 -methyl-4 0 -phenyl(4-[2.2]-paracyclophanyl)-1 0 ,2 0 ,4 0 -oxadiazole-5 0 -one (12) in 1:1 ratio (Scheme 3). The formation of products 11 and 12 is mostly caused by the presence of the nitrone 9, during the course of reaction, in equilibration between its Z and E forms. Consequently, each form reacts with 10 to form the diastereomers 11 and 12, respectively. The structures of 11 and 12 were established on the basis of the 1H, 13C NMR-, IR-, and MS-spectra as well as elemental analyses. Mass spectra and elemental analyses established the molecular formula of the both diastereomers as C25H24N2O2. The IR spectra showed the carbonyl group for both compounds at nmaxZ1750 cmK1. These carbonyl groups appeared, at dZ 155.2 for 11 and at dZ155.0 for 12, in the 13C NMR spectra.

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connected to 4-C. The relative configuration of 11 was secured by X-ray diffraction (Fig. 2, Table 1), hence the other of 12 follows from the indication of NMR spectra is of identical constitution.

Table 1. Details of X-ray structural analyses of 9, 11 and 14 Compound

9

Formula C18H19NO 265.34 Mr Habit Colorless tablet Crystal size 0.8!0.44!0.04 (mm) Crystal system Monoclinic Space group P21/c Cell constants: ˚) a (A 13.538(4) ˚) b (A 9.314(3) ˚) c (A 11.440(4) a (8) 90 b (8) 109.98(3) g (8) 90 ˚ 3) 1355.8 V (A Z 4 1.300 Dx (mg mK3) K1 0.08 m (mm ) F(000) 568 T (8C) K130 50 2qmax No. of reflections: Measured 2810 Independent 2397 0.033 Rint Parameters 182 wR(F2, all refl.) 0.150 R(F, O4s(F)) 0.056 S 1.02 0.19 Max. Dr/e ˚ K3) (A

11

14

C25H24N2O2 384.46 Colorless tablet 0.8!0.4!0.16

C26H27NO 369.49 Colorless prism 0.8!0.38!0.32

Monoclinic P21/c

Monoclinic P21/n

8.310(2) 10.996(3) 21.434(4) 90 90.06(2) 90 1958.6 4 1.304 0.08 816 K130 50

7.538(2) 13.372(3) 19.779(4) 90 91.59(2) 90 1992.9 4 1.231 0.07 792 K120 56

3749 3463 0.027 263 0.135 0.052 1.05 0.23

13105 4830 0.021 254 0.169 0.063 1.05 0.58

2.2. Reaction of 9 with styrene (13) Reaction of 9 with styrene (13) gives 14 as the only diastereomer in 68% yield (Scheme 4). The 1H NMR spectrum of compound 14 showed two unresolved doubledoublets (apparent pseudo triplets), one at dZ5.25 (JZ 8.0 Hz) arising from 5-H and the other at dZ4.06 (JZ 7.8 Hz) coupled with 3-H. One of the CH2 protons of 4-C appears as a multiplet at dZ2.05–1.95, whereas the other is superimposed with the ethano protons of the paracyclophane moiety (see Section 3). In the 13C NMR spectrum the 5-, 4- and 3-C signals absorb at dZ78.2, 69.7, and 46.4, respectively. The X-ray structural analysis (Fig. 3, Table 1) confirms the structure of 14 as illustrated in Scheme 4. 2.3. Reaction of 9 with dimethyl acetylenedicarboxylate (15) The reaction of 9 with dimethyl acetylenedicarboxylate (15) yields the cycloadduct 16 in 61% yield (Scheme 4). The NMR spectra confirmed the structural features of the obtained diastereomer 16, which was identified as dimethyl 2-methyl-5-(4 0 -[2.2]paracyclophanyl)-3H-isoxazole-4,5dicarboxylate. For example, the 13C NMR spectrum displays five distinctive signals at dZ162.5, 159.5, 149.6, 110.5 and 77.0 corresponding to 6-, 7-, 5-, 4- and 3-C (the 1 H NMR spectrum revealed 3-H at dZ5.20), respectively. In addition, the 4-C 0 and the NMe signals resonate at dZ 149.6 and 47.8, respectively (see Section 3).

Compounds 11 and 12 had 1H NMR spectra with surprisingly different chemical shifts for a number of corresponding protons. The most characteristic difference was noted in the chemical shifts of 15-H and 5-H. Proton 15H in 11 resonates at dZ6.83, whereas for 12 it appears at dZ6.43. Moreover, proton 5-H in 11 is deshielded by 0.9 ppm relative to its position in 12 (dZ5.65). Therefore, they were initially believed to be constitutionally different. However, all signal multiplicities and 2D correlations, importantly also those based on nJCH (nZ2, 3), are analogous for both isomers, which proves them to be diastereoisomers that differ in the relative configurations of the planar-chiral cyclophane system and the chiral center O-

2.4. Reaction of 9 with methylene sulfene (17) It has been reported that aromatic nitrones react in situ with the reactive methylene sulfene 17 species to provide azasulfone derivatives.13 Surprisingly, the reaction of 9 with methylene sulfene (17), generated from methanesulfonyl chloride and triethylamine, gives mainly 4[2.2]paracyclophanyl-N-methylamine (20)14 in 80% yield (Scheme 5). The preparation of compound 20 by such

Me + N O

+ N Me

Ph-N=C=O 10

15 11

2

H

H

3

benzene, reflux, 3 d

4

1 5

Z-9

6/

15

E-9

Me

11

2 3

Me

1/

N O

O +

4/

4 5

H

N 11/

N O

5

/

12/

O H

N

16/ 15/

11 (45%)

12 (45%)

Scheme 3. Stereoselective formation of oxadiazolones 11 and 12 during the reaction of nitrone 9 with phenyl isocyanate (10).

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˚ ) and angles (8): O1 0 –N2 0 1.464(3), Figure 2. The structure of compound 11 in the crystal. Ellipsoids represent 30% probability levels. Selected bond lengths (A N4 0 –C5 0 1.359(3), N4 0 –C3 0 1.460(3), O1 0 –C5 0 1.372(3), N2 0 –C3 0 147.6(3); C5 0 -O1 0 –N2 0 108.7(2), O1 0 –N2 0 –C3 0 102.2(2), O2 0 –C5 0 –N4 0 130.2(2), N4 0 –C5 0 – O1 0 108.1(2), C5 0 –N4 0 –C3 0 109.9(2), N4 0 –C3 0 –N2 0 102.3(2), O2 0 –C5 0 –O1 0 121.7(2).

11/ 15/

11/ 9/

1/

15/

5/ 4/

Me N 3

H

H4 H 14 (68%)

H3CO2C

15

6 16

13 9

1

O

benzene/ reflux, 3 d 11

5

H

12

CO2CH3

6

1/

15 benzene/ reflux, 1 d

Me

5/

N

4/

3

H 7

O 11

4

MeO2C

1

5

CO2Me 8

16 (61%)

Scheme 4. Stereospecific formation of isoxazoles 14 and 16 during the reaction of nitrone 9 with styrene (13) and dimethyl acetylenedicarboxylate (15).

˚ ) and angles (8): C5–O1 1.438(3), Figure 3. The structure of compound 14 in the crystal. Ellipsoids represent 30% probability levels. Selected bond lengths (A C4–C5 1.539(3), N2–O1 1.440(2), N2–C3 1.487(2), C3–C4 1.547(3); C5–O1–N2 107.8(2), O1–N2–C3 104.2(2), N2–C3–C4 106.5(2), C3–C4–C5 103.3(2), C4–C5–O1 104.4(2).

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Scheme 5. Synthesis of 4-([2.2]paracyclophanyl)-N-methyl amine (20).

a simple method is a viable alternative for its known synthesis that suffers from a long procedure taking place in overall poor yield.14 The mechanism rationalizing the formation of compound 20, as shown in Scheme 5, is based upon formation of cycloadduct 18. Subsequently, the intermediate 18 undergoes ring opening followed by intramolecular rearrangement involving the migration of the paracyclophane anion concerted with the proton loss to form the iminium–enamine nitrogen as in intermediate 19 (this is more favorable under acidic conditions). Elimination of acetylene and sulfur trioxide from 19 produces the stable corresponding amine 20 (Scheme 5). The formal proposed mechanism is supported by the reported literature, which indicated that isoxazole can be prepared by the addition of triethylamine and acetylene to (Z)-2-chloro-2-arylethenol.15

3. Experimental 3.1. General remarks Melting points were determined on Kofler hot stage and they are uncorrected. NMR: were recorded on Bruker AM400, solvent: CDCl3, internal standards: TMS (dZ0.00) for 1 H, CDCl3 (dZ77.05) for 13C. The results of NOE difference experiments are given in the form: irradiated signal/enhanced signal. When a complex 1H multiplet comprising several protons was not analyzed, the individual proton chemical shifts obtained from the C,H-HETCOR spectra are given in the parentheses following the d-range of the multiplet. Chromatography columns were packed with silica gel 7714 (Merck). For preparative layer chromatography (PLC), glass plates (20 cm!48 cm) were covered with slurry of silica gel Merck PF254 and air-dried using the solvents listed for development. Zones were detected by the quenching of indicator fluorescence upon exposure to 254-nm UV light. Elemental analyses were performed in the Institut fu¨r Anorganische Chemie, Technische Universita¨t Braunschweig. Mass spectra were carried out on Finnigan MAT 8430 spectrometer at 70 eV. IR spectra were recorded on Nicolet 320 FT-IR using KBr pellets. 3.1.1. 4-([2.2]Paracyclophanyl)-N-methoxy-ylideneamine (7). To a solution of N-hydroxylimino-4-[2.2]paracyclophane (6)11 (251 mg, 1 mmol) in absolute ethanol (20 mL), a solution of sodium hydroxide (5 mL, 0.2 M) was added followed by dimethyl sulfate (252 mg, 2 mmol). The mixture was stirred at room temperature for 10 min. The organic layer was extracted with dichloromethane,

washed several times with water and dried over MgSO4. The solvent was concentrated under vacuum and the residue was purified by column chromatography (silica gel) with dichloromethane. Compound 7 was obtained (253 mg, 95%) as colorless plates (benzene), mp 93 8C; 1 H NMR (400 MHz, CDCl3) d 8.04 (s, 1H, 17-H), 6.77 (d, 1H, 5-H, JZ1.7 Hz), 6.62–6.45 (m, 6H), 4.02 (s, 3H, 19-H), 3.64–3.58 (m, 1H, ethano bridge), 3.08–2.80 (m, 7H, ethano bridge); 13C NMR (400 MHz, CDCl3) d 147.9 (17-C), 141.1, 139.4, 139.2, 139.1, 139.0 (C), 135.3, 133.8, 132.1, 132.6, 132.1, 131.9, 130.0 (CH), 61.9 (19-C), 35.3, 34.9, 34.8, 33.9 (all t, ethano bridge carbons); IR nmax (KBr): 3060–2900 cmK1 (Ar-CH, s), 2860–2850 (aliph.-CH, m), 1600 (C]N, s), 1010 (OCH3, s), 1210 (w), 980 (m); UV (CH3CN): lmax (log 3)Z278 nm (2.98); m/z (%): 265 [MC] (54), 234 (12), 160 (50), 149 (60), 130 (100), 104 (30), 103 (20), 77 (16), 57 (18). Anal. Calcd for C18H19NO (265.36): C, 81.48; H, 7.22; N, 5.28. Found: C, 81.35; H, 7.20; N, 5.32. 3.1.2. a-(4-[2.2]Paracyclophanyl)-N-methyl nitrone (9). To a refluxing stirred solution of 4-formyl-[2.2]paracyclophane (4,12 2.36 g, 10 mmol) in ethanol (200 mL), a solution of N-methylhydroxylamine hydrochloride (8, 2.50 g, 30 mmol) in water (10 mL) was added, followed by a solution of potassium hydroxide (2.50 g, 35 mmol) in water (5 mL) and ethanol (10 mL). The mixture was refluxed for 4 h, and then extracted with diethyl ether (500 mL). The organic layer was washed several times with water and dried over MgSO4. The solvent was removed in vacuo and the residue was subjected to column chromatography (silica gel) with diethyl ether–EtOH (1/1) to give compound 9 (2.45 g, 92%) as colorless needles (toluene), mp 150 8C; 1H NMR (400 MHz, CDCl3) d 8.31 (s, 1H, 17H), 7.34 (s, 1H, 5-H), 6.60 (dd, 1H, 12-H, JZ7.8, 2.0 Hz), 6.52 (dd, 1H, 13-H, JZ7.8, 2.0 Hz), 6.49 (dd, 1H, 7-H, JZ7.8, 1.8 Hz), 6.46 (d, 1H, 8-H, JZ1.8 Hz), 6.44 (dd, 1H, 15-H, JZ8.0, 1.8 Hz), 6.38 (dd, 1H, 16-H, JZ8.0, 1.8 Hz), 3.94 (s, 3H, NMe), 3.55–2.85 [m, 8H, 2CH2CH2; shifts from C,H-HETCOR: 3.55, 3.34, 3.28, 3.20, 3.12, 3.00, 2.90, 2.85]; NOEs: 17-H/5-H; 13C NMR (400 MHz, CDCl3) d 148.2 (s, 17-C), 139.8 (s, 6-C), 138.5 (s, 11-C), 138.3 (s, 14C), 134.6 (s, 3-C), 134.3 (d, 8-C), 133.2 (d, 7-C), 132.5 (s, 4C), 132.3 (d, 13-C), 131.6 (d, 12-C), 130.5 (d, 16-C), 130.2 (d, 15-C), 130.0 (d, 5-C), 54.9 (q, 19-C), 35.3, 35.1, 34.2, 34.00 (all t, ethano bridge carbons); IR nmax (KBr): 3080– 2960 cmK1 (Ar-CH, s), 2990–2851 (aliph.-CH, m), 1588 (C]N, s), 1167 (N–O, s); UV (CH3CN): lmax (log 3)Z 322 nm (3.10); m/z (%): 265 [MC] (48), 234 (18), 160 (32), 148 (22), 130 (100), 104 (24), 103 (18), 77 (42), 57 (16).

A. A. Aly et al. / Tetrahedron 62 (2006) 4498–4505

Anal. Calcd for C18H19NO (265.36): C, 81.48; H, 7.22; N, 5.28. Found: C, 81.25, H, 7.20; N, 5.35. 3.1.3. Reaction of nitrone 9 with phenyl isocyanate (10). A mixture of 9 (530 mg, 2 mmol) and phenyl isocyanate (10, 238 mg, 2 mmol) was heated under reflux in absolute benzene (100 mL) for 3 d. The solvent was evaporated under vacuum and the residue was separated by preparative thin-layer chromatography (silica gel) with toluene. Two zones were isolated, the fastest-moving one contained compound 11, while the slowest contained compound 12. 3.1.4. 3 0 R*,4R*-3 0 (H)-2 0 -Methyl-4 0 -phenyl-(4-[2.2]paracyclophanyl)-1 0 ,2 0 ,4 0 -oxadiazole-5 0 -one (11). (344 mg, 45%) as colorless needles (ethanol), RfZ0.5, toluene, mp 192 8C; 1H NMR (400 MHz, CDCl3) d 7.20–7.12 (m, 4H, 12 0 -,16 0 -,13 0 -,15 0 -H), 7.07–7.02 (m, 1H, 14 0 -H), 6.83 (dd, 1H, 15-H, JZ8.0, 2.0 Hz), 6.55 (s, 1H, 5-H), 6.48 (d, 1H, 8H, JZ7.8 Hz), 6.45 (dd, 1H, 12-H, JZ7.7, 2.1 Hz), 6.44– 6.39 (m, 3H, 7-,13-,16-H), 5.66 (s, 1H, 3 0 -H), 3.22 (s, 3H, NMe), 3.15–2.84 (m, 7H, ethano bridge), 3.37–3.32 (m, 1H, ethano bridge); 13C NMR (400 MHz, CDCl3) d 155.2 (s, 5 0 C), 141.0 (s, 4-C), 139.5 (s, 3-C), 138.7 (s, 14-C), 137.7 (s, 11-C), 137.3 (s, 6-C), 136.2 (s, 11 0 -C), 135.7 (d, 8-C), 134.2 (d, 7-C), 133.1 (d, 13-C), 132.7 (d, 5-C), 132.3 (d, 16-C), 131.8 (d, 15-C), 129.1 (d, 2C, 13 0 -,15 0 -C), 128.8 (d, 12-C), 125.0 (d, 14 0 -C), 120.2 (d, 2C, 12 0 ,16 0 -C), 81.3 (s, 3 0 -C), 46.7 (q, 6 0 -C), 35.4, 35.2, 35.1, 32.8 (all t, ethano bridge carbons); IR nmax (KBr): 3032–2994 cmK1 (Ar-CH, s), 2955–2851 (aliph.-CH, m), 1750 (C]O, vs), 1600, 1127 (N–O, s); UV (CH3CN): lmax (log 3)Z254 nm (2.76); m/z (%): 385 [MC1] (28), 384 [MC] (100), 367 (34), 341 (28), 340 (64), 339 (76), 325 (38), 311 (22), 265 (38), 236 (24), 218 (12), 206 (18), 161 (48), 144 (90), 119 (28), 104 (26), 91 (18), 77 (8). Anal. Calcd for C25H24N2O2 (384.48): C, 78.10; H, 6.29; N, 7.29. Found: C, 77.90; H, 6.19; N, 7.15. 3.1.5. 3 0 R*,4S*-3 0 (H)-2 0 -Methyl-4 0 -phenyl-(4-[2.2]paracyclophanyl)-1 0 ,2 0 ,4 0 -oxadiazole-5 0 -one (12). (344 mg, 45%) as colorless needles (ethanol), RfZ0.4, toluene, mp 168 8C; 1H NMR (400 MHz, CDCl3) d 7.58–7.40 (m, 4H, 12 0 -,16 0 -,13 0 -,15 0 -H), 7.26–7.22 (m, 1H, 14 0 -H), 6.55–6.49 (m, 3H, 7-,12-,13-H), 6.43 (dd, 1H, 15-H, JZ7.8, 1.8 Hz), 6.41 (dd, 1H, 16-H, JZ7.8, 2.0 Hz), 6.37 (d, 1H, 8-H, 7.8 Hz), 5.72 (s, 1H, 3 0 -H), 5.65 (d, 1H, 5-H, JZ1.8 Hz), 3.39–3.32 (m, 1H, ethano bridge), 3.17 (s, 3H, NMe), 3.13– 2.78 (m, 7H, ethano bridge); 13C NMR (100.6 MHz, CDCl3) d 155.0 (s, 5 0 -C), 140.0 (s, 4-C), 139.4 (3-C), 139.0 (s, 14C), 138.3 (s, 11-C), 136.7 (s, 6-C), 134.5 (s, 11 0 -C), 134.3 (d, 8-C), 132.9 (d, 7-C), 132.7 (d, 13-C), 131.9 (d, 16-C), 130.8 (d, 15-C), 129.7 (d, 12-C), 129.3 (d, 2C, 13 0 -,15 0 -C), 126.0 (d, 14 0 -C), 125.8 (d, 5-C), 122.0 (d, 2C, 12 0 -,16 0 -C), 84.3 (s, 3 0 -C), 46.9 (q, 6 0 -C), 35.2, 35.0, 34.9, 32.6 (all t, ethano bridge carbons); IR nmax (KBr): 3007–2990 cmK1 (Ar-CH, s), 2960–2854 (aliph.-CH, m), 1750 (C]O, vs), 1595, 1127 (N–O, s); UV (CH3CN): lmax (log 3)Z248 nm (2.70); m/z (%): 385 [MC1] (28), 384 [MC] (100), 367 (30), 341 (20), 340 (42), 339 (56), 325 (28), 311 (14), 265 (24), 236 (24), 206 (32), 161 (24), 144 (88), 119 (16), 104 (20), 91 (12), 77 (8). Anal. Calcd for C25H24N2O2 (384.48): C, 78.10; H, 6.29; N, 7.29. Found: C, 77.94; H, 6.22; N, 7.20.

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3.1.6. 3(4 0 -[2.2]Paracyclophanyl)-3,4,4,5-tetrahydro-2methyl-5-phenyl-isoxazole (14). A mixture of 9 (530 mg, 2 mmol) and styrene (13, 342 mg, 3 mmol) was refluxed in absolute benzene (200 mL) for 3 days. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel with toluene. (480 mg, 68%) of 14 was obtained as colorless crystals (ethanol), mp 138 8C; 1H NMR (400 MHz, CDCl3) d 7.30 (dd, 1H, JZ8.0, 2.0 Hz), 7.20–7.00 (m, 4H), 6.80 (br s, 1H, 5 0 -H), 6.64 (dd, 1H, 13 0 -H, JZ7.8, 1.8 Hz), 6.56 (dd, 1H, 12 0 -H, JZ8.0, 1.8 Hz), 6.54 (dd, 1H, 7 0 -H, JZ8.0, 1.8 Hz), 6.48 (d, 1H, 8 0 H, JZ7.8, 2.0 Hz), 6.42 (dd, 1H, 16 0 -H, JZ8.0, 1.8 Hz), 6.22 (dd, 1H, 15 0 -H, JZ7.8, 1.8 Hz), 5.25 (t, 1H, JZ8.0 Hz, 5-H), 4.06 (t, 1H, JZ7.8 Hz, 3-H), 3.32–2.60 (m, 12H, ethano bridge, 4-H, NMe), 2.05–1.95 (m, 1H, 4-H); 13C NMR (400 MHz, CDCl3) d 140.5 (s, 4 0 -C), 139.9 (s, 14 0 -C), 138.9 (s, 6 0 -C), 138.4 (s, 11 0 -C), 135.0 (d, 8 0 -C), 135.3, 134.8, 133.4, 133.3, 132.9 (C), 132.4 (d, 13 0 -C), 131.5 (d, 12 0 -C), 129.6 (s, 11-C), 129.0 (d, 2C, 13-,15-C), 128.3 (d, 2C, 12-,16-C), 127.7 (d, 14-C), 78.2 (5-C), 69.7 (3-C), 46.4 (4-C), 45.6 (q, 6-C), 35.4, 35.2, 34.4, 33.2 (all t, ethano bridge carbons); IR nmax (KBr): 3024–2975 cmK1 (Ar-CH, s), 2946–2852 (aliph.-CH, s), 1592 (s), 1490 (m), 1455 (s), 916 (m); UV (CH3CN): lmax (log 3)Z320 nm (3.34); m/z (%): 370 [MC1] (30), 369 [MC] (100), 338 (10), 323 (20), 265 (52), 250 (12), 222 (10), 219 (18), 159 (48), 144 (70), 129 (24), 91 (24), 77 (20). Anal. Calcd for C26H27NO (369.51): C, 84.45; H, 7.36; N, 3.79. Found: C, 84.35; H, 7.30; N, 3.68. 3.1.7. Dimethyl 2-methyl-5-(4 0 -[2.2]paracyclophanyl)3H-isoxazole-4,5-dicarboxylate (16). A mixture of 9 (530 mg, 2 mmol) and dimethyl acetylenedicarboxylate (15, 284 mg, 2 mmol) was heated under reflux in absolute benzene (100 mL) for 1 d. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel with toluene. 16 was obtained (500 mg, 61%) as pale yellow crystals (ethanol), mp 105 8C; 1H NMR (400 MHz, CDCl3) d 7.00 (d, 1H, 5 0 -H, JZ1.8 Hz), 6.72 (dd, 1H, 12 0 -H, JZ8.0, 2.0 Hz), 6.62 (d, 1H, 8 0 -H, JZ8.0 Hz), 6.58 (dd, 1H, 13 0 -H, JZ8.0, 1.8 Hz), 6.50 (dd, 1H, 7 0 -H, JZ8.0, 1.8 Hz), 6.50–6.30 (m, 2H, 15 0 -,16 0 -H), 5.20 (s, 1H, 3-H), 3.85 (s, 3H, Me, 8-H), 3.52 (s, 3H, Me, 9-H), 3.20 (s, 3H, NMe), [m, 2H, shifts: 3.22–3.00 (2 0 -,1 0 -H)], 2.90–2.78 [m, 2H, shifts: 3.13 (2!9 0 -H)], 2.70–2.45 [(m, 4H, (2!10 0 )-,1 0 -,2 0 -H)]; 13C NMR (400 MHz, CDCl3) d 162.5 (s, 7-C), 159.5 (s, 6-C), 149.6, (s, 5-C), 143.2 (s, 4 0 -C), 140.6 (s, 14 0 -C), 140.4 (s, 11 0 C), 139.6 (s, 6 0 -C), 139.5 (s, 3 0 -C), 138.8 (d, 8 0 -C), 138.0 (d, 15 0 -C), 137.1 (d, 7 0 -C), 136.3 (d, 16 0 -C), 134.9 (d, 13 0 -C), 133.0 (s, 12 0 -C), 132.0 (d, 5 0 -C), 110.5 (d, 4-C), 77.0 (s, 3-C), 52.3 (q, 9-Me), 51.7 (q, 8-Me), 47.8 (q, NMe), 35.3 (t, 10 0 -C), 35.0 (t, 9 0 -C), 34.9 (t, 1 0 -C), 33.54 (t, 2 0 -C); IR nmax (KBr): 3030–2988 cmK1 (Ar-CH, s), 2880–2850 (aliph.-CH, m), 1597 (C]N, m), 1730 (CO, s), 1560 (C]C, s), 1280 (m), 980 (m), 760 (s); UV (CH3CN): lmax (log 3)Z360 nm (380); m/z (%): 407 [MC] (14), 349 (24), 348 (84), 347 (26), 321 (18), 320 (76), 303 (10), 276 (38), 265 (78), 264 (100), 236 (42), 104 (80), 78 (14). Anal. Calcd for C24H25NO5 (407.47): C, 70.75; H, 6.18; N, 3.44. Found: C, 70.55; H, 6.10; N, 3.40. 3.1.8. 4-([2.2]Paracyclophanyl)-N-methylamine (20). A solution of 9 (530 mg, 2 mmol) in dry benzene (100 mL) was prepared under nitrogen in a three-necked flask

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equipped with two dropping funnels. Equivalent amounts of methylenesulfonyl chloride (229 mg, 2 mmol) and fresh anhydrous triethylamine (182 mg, 2 mmol), each in dry benzene (30 mL), were added simultaneously over a period of 15 min. The reaction was further warmed to 60 8C for 1 h. Triethylammonium chloride precipitated during this period, and the color became more intensely yellow. The precipitate was filtered off and the residue was subjected to column chromatography (silica gel) with toluene. Compound 20 was obtained (250 mg, 80%) as pale red crystals (ethanol), mp 105 8C (lit.14 105 8C); NMR spectroscopic data is in a good agreement with that reported in Ref. 14.

˚ and C–H/O 1508. In 11, the molecules are linked in 2.40 A inversion–symmetric pairs by the contacts C12 0 –H12 0 /O1 0 ˚ , C–H/O 1558] and C6 0 –H6 0 3/O2 0 [H/O [H/O 2.55 A ˚ 2.50 A, C–H/O 1438]. In 14, the molecules are again linked in inversion–symmetric pairs by the contact C5 0 – ˚ , C–H/O 1478]; within the pair and H5 0 /O1 [H/O 2.40 A between pairs there are also C–H/p contacts involving ring centroids (‘Cent’) [C10–H10B/Cent (C11-16) with ˚ , C–H/Cent 1568 and C4–H4B/Cent H/Cent 2.79 A ˚ , C–H/Cent 1528, (C12 0 ,13 0 ,15 0 ,16 0 ) with H/Cent 2.61 A respectively] (Figs. 3 and 4). 3.3. Data collection and reduction

3.2. X-ray structure determinations The structures of compounds 9, 11 and 14 were confirmed by X-ray analysis (Figs. 1–3). Bond lengths and angles are normal (see Figure captions for important values). The fivemembered rings of compounds 11 and 14 display envelope conformations, in which N2 0 (11) lies 0.44 and O1 (14) ˚ out of the plane of the other four atoms (mean 0.51 A ˚ , respectively). deviations 0.02, 0.01 A Some intermolecular contacts are significant. In 9, there is a short contact C19–H19A/O via the 21 axis, with H/O

Crystals were mounted in inert oil on glass fibres and transferred to the cold gas stream of the diffractometer (9, 11: Stoe STADI4; 14: Siemens SMART area detector). Measurements were performed with monochromatic Mo Ka radiation. Structure refinement: the structures were refined anisotropically against F2 (Sheldrick G. M. SHELXL-97: program, University of Go¨ttingen). H atoms were included with a riding model or with rigid methyl groups. Complete Crystallographic data (excluding structure factors) has been deposited in Cambridge Crystallographic Data under the numbers 23138 (9), 238139 (11),

Figure 4. Packing diagram of compound 14. C–H/O interactions are indicated by thin and C–Hp interactions by thick dashed lines.

A. A. Aly et al. / Tetrahedron 62 (2006) 4498–4505

238140 (14). Copies may be requested free of charge from the director, CCDC, 12 Union Road, Cambridge CB2 1EZ, England (e-mail: [email protected]). 4.

Acknowledgements Prof. Dr. Ashraf A. Aly thanks the DAAD for financial support. 5.

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