A simple route to a pyridinyl[2.2]paracyclophane

Article abstract of DOI:10.1002/ejoc.200400633

4-Acetyl[2.2]paracyclophane (1) is converted into the nitrone 2 by treatment with N-methylhydroxylamine-hydrochloride. When 2 is reacted with (E)-1,2-dibenzoylethene (4) the pyridinyl[2.2]paracyclophane 13 is formed in a novel condensation reaction. The structures of 2 and 13, and the mechanism of formation of the latter are discussed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400633

SHORT COMMUNICATION
A Simple Route to a Pyridinyl[2.2]paracyclophane
Henning Hopf,*[a] Ashraf A. Aly,[a] Vijay Narayanan Swaminathan,[a] Ludger Ernst,[b]
Ina Dix,[a] and Peter G. Jones[c]
Keywords: Nitrones / Dipolar cycloadditions / Chiral cyclophanes / X-ray diffraction / Cycloadditions
4-Acetyl[2.2]paracyclophane (1) is converted into the nitrone
2 by treatment with N-methylhydroxylamine·hydrochloride.
reaction. The structures of 2 and 13, and the mechanism of
formation of the latter are discussed.
When 2 is reacted with (E)-1,2-dibenzoylethene (4) the pyrid- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
inyl[2.2]paracyclophane 13 is formed in a novel condensation
Germany, 2005)
Introduction
analytical methods as described in the Exp. Sect. Of par-
ticular importance, indicating the E-configuration of 2 as
Chiral [2.2]paracyclophanes are growing in importance shown in the Scheme, are the NMR spectroscopic data and
as ligands and auxiliaries in asymmetric synthesis,[1] and the the X-ray structure analysis of this derivative. The H and
1
13C NMR spectra of 2 were fully assigned (apart from the
number of mono- (any monosubstituted [2.2]paracyclo-
phane is chiral) and polysubstituted derivatives of this class
of layered compounds reported in the literature is increas-
ing rapidly.[1Ϫ3]
CH2CH2 bridges) by the use of two-dimensional H,H-
COSY, C,H-HETCOR and C,H-COLOC techniques and
by NOE difference spectra (see Exp. Sect.). The E-configu-
ration of the nitrone group follows from the NOE at 5-H
when the N-methyl signal is saturated.
Having been interested in [2.2]paracyclophanes that carry
heterocyclic substituents for some time,[4] we now report on
the preparation of a pyridyl-substituted [2.2]paracyclo-
phane by a novel and efficient procedure. Considering the
rich chemistry of the pyridine nucleus, we believe that this
combination of carbo- and heterocyclic ring systems offers
numerous perspectives in covalent and supramolecular
chemistry.
As shown by the X-ray structure analysis, the molecular
dimensions of 2 (Figure 1) may be regarded as normal; the
˚
CϪN and NϪO bond lengths are 1.306(2) and 1.308(2) A,
respectively. The nitrone group is essentially planar (mean
˚
deviation of 4 atoms 0.005 A) and its orientation is defined
by the torsion angles C3ϪC4ϪC17ϪN18 (60.6°) and
C4ϪC17ϪN18ϪO (9.4°).
The packing involves two short contacts of the form
Preparation of 2-(4Ј-[2.2]Paracyclophanyl)-6-phenylpyridine
(13)
CϪHmethyl···O: C19ϪH19A···Ο and C20ϪH20A···Ο, with
˚
When a solution of 4-acetyl[2.2]paracyclophane (1)[5] and
N-methylhydroxylamine·hydrochloride in ethanol is re-
fluxed in the presence of potassium hydroxide, the nitrone
2 is obtained in 95% yield (Scheme 1). The structure of this
derivative was established by the usual spectroscopic and
H···O distances of 2.38 and 2.45 A (for CϪH normalized
˚
to 1.08 A) and CϪH···O angles of 162 and 169°. The net
effect is to connect the molecules by the 21 screw axis to
form chains parallel to the y axis (Figure 2).
Nitrones are a well-studied class of 1,3-dipoles that react
with numerous unsaturated systems,[6] among them (E)- (4)
and (Z)-1,2-dibenzoylethene,[7] to yield the corresponding
isoxazolidine derivatives, usually under mild conditions and
in good yield. To our surprise, the reaction between 2 and
4 required three days of reflux in toluene, and yielded a
completely unexpected product: the pyridine derivative 13
(isolated yield 70%), together with a small sample of meth-
ylbenzoate (12, 5%). The structure elucidation of this un-
usual adduct, the formation of which required one equiva-
lent each of 12 and water to be eliminated from its two
[a]
Institut für Organische Chemie, Technische Universität
Braunschweig,
Postfach 3329, 38023 Braunschweig, Germany
Fax (internat.): ϩ 49-(0)531-391-5388
E-mail: h.hopf@tu-bs.de
[b]
NMR-Laboratorium der Chemischen Institute, Technische
Universität Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
Fax (internat.): ϩ 49-(0)531-391-8192
E-mail: l.ernst@tu-bs.de
[c]
Institut für Anorganische und Analytische Chemie, Technische
Universität Braunschweig,
Postfach 3329, 38023 Braunschweig, Germany
Fax (internat.): ϩ 49-(0)531-391-5387
E-mail: p.jones@tu-bs.de
1
starting materials, rests primarily on its H and 13C NMR
spectra, which were fully assigned by the techniques men-
68
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400633
Eur. J. Org. Chem. 2005, 68Ϫ71

A Simple Route to a Pyridinyl[2.2]paracyclophane
SHORT COMMUNICATION
Scheme 1. From the [2.2]paracyclophane nitrone 2 to the pyridyl derivative 13
tioned above. The proton signals of the paracyclophanyl the hydroxylamine 3 by a hydrogen transfer process. Since
moiety were analyzed by iterative fitting of the full band- 3 is also an enamine, it can attack the activated double
shape. The points of attachment of the paracyclophanyl, bond of the dipolarophile 4 in a Michael-fashion to furnish
phenyl and pyridinediyl groups follow from the cross-peaks the intermediate enolate 5. As shown in Scheme 1, the
in the C,H-COLOC spectrum and from the spin-coupling charged oxygen atom could then remove a hydrogen atom
patterns in the proton signals of the disubstituted pyridine of the methylene group in 5 via a six-membered transition
ring.
state to provide the next reaction intermediate: the hy-
droxylamine derivative 6, itself a derivative of its starting
material 3. In the next step of the sequence, intramolecular
cyclization takes place — again involving a six-membered
Mechanism of Formation of the Pyridinylcyclophane 13
To rationalize the formation of 13, we propose the rather transition state — to provide 7, from which the structure of
long, but consistent route summarized in Scheme 1. As a the finally isolated product slowly begins to emerge. To re-
decisive initial step we postulate the isomerization of 2 to move benzoate, intermediate 7 — after reprotonation to
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69

H. Hopf, A. A. Aly, V. N. Swaminathan, L. Ernst, I. Dix, P. G. Jones
SHORT COMMUNICATION
numbered such that C-12 is pseudo-geminal to C-7 etc. Results of
NOE difference experiments are given as irradiated signal Ǟ en-
hanced signal. The spin systems of the aromatic protons of 2 and
13 were analyzed iteratively with Bruker’s WIN-DAISY program.
UV/Vis: Beckman UV 5230.
(E)-N,α-Dimethyl-α-(4Ј-[2.2]paracyclophanyl)nitrone (2): A solution
of N-methylhydroxylamine·hydrochloride (5.00 g, 60 mmol) in
water (20 mL) was added to a gently heated stirred solution of 4-
acetyl-[2.2]paracyclophane (1)[6] (2.50 g, 10 mmol) in ethanol
(400 mL). Subsequently, a solution of potassium hydroxide (3.40 g,
60 mmol) dissolved in a mixture of water (25 mL) and ethanol
(25 mL) was added. The mixture was refluxed whilst stirring for
4 h, while the progress of the reaction was monitored by TLC. After
cooling, the reaction mixture was thoroughly extracted with diethyl
ether (600 mL), and the combined organic phases were washed sev-
eral times with water. After removal of the solvents in vacuo, the
residue was dissolved in dichloromethane and purified by silica gel
column chromatography with dichloromethane (150 mL) as eluent
to provide 0.08 g (3%) of 1. Further elution with absolute ethanol
(400 mL) gave 2, which on recrystallization from toluene gave
(2.65 g, 95%) as colorless needles (Rf ϭ 0.4, CH2Cl2/diethyl ether,
1:1). M.p. 182 °C. IR (KBr): ν˜ ϭ 3007 cmϪ1 (s), 2925 (w), 2890
(m), 2852 (m), 1903 (vs), 1670 (vs), 1664 (vs), 1590 (s), 1566 (m),
1500 (m), 1451 (m), 1435 (m), 1396 (s), 1373 (m), 1269 (s), 1016
(m), 943 (s), 902 (m), 885 (m), 837 (m), 821 (m), 791 (s), 738 (m),
721 (m). UV (CH3CN): λmax. (log ε) ϭ 294 nm (3.10). 1H NMR
(400 MHz, CDCl3): δ ϭ 2.68 (q, 3 H, CMe), 2.87Ϫ3.16 (m, 8 H, 2
CH2CH2; shifts from C,H-HETCOR: 2.92, 2.97, 3.01, 3.07, 3.08,
3.10, 3.11, 3.12), 3.47 (q, 3 H, NMe), 6.38 (dd, 1 H, 16-H), 6.44
(dd, 1 H, 15-H), 6.44 (d, 1 H, 5-H), 6.48 (d, 1 H, 8-H), 6.49 (dd, 1
Figure 1. The molecule of compound 2 in the crystal; ellipsoids
represent 30% probability levels; H atom radii are arbitrary
H, 7-H), 6.63 (dd, 1 H, 13-H), 6.65 ppm (dd, 1 H, 12-H); J5,7
ϭ
1.8, J7,8 ϭ 7.8, J12,13 ϭ 7.8, J12,16 ϭ 2.0, J13,15 ϭ 2.0, J15,16 ϭ 8.0,
JMe,Me ϭ 1.3 Hz. NOEs: NMe Ǟ 5-H; CMe Ǟ 5-H,15-H, 16-H.
The spin systems of the bridge protons could not be analyzed.
Figure 2. Packing of compound 2, showing hydrogen bonds as
dashed lines
1
Hence, chemical shifts for the bridge H and 13C nuclei are unas-
signed. 13C NMR: δ ϭ 20.1 (q, CMe), 33.6, 35.0, 35.2, 35.3 (4 t,
CH2), 47.9 (q, NMe), 130.4 (d, C-5), 131.2 (d, C-15), 132.1 (d, C-
16), 132.2 (d, C-12), 133.0 (d, C-13), 134.4 (s, C-4), 135.0 (d, C-7),
135.2 (d, C-8), 138.4 (s, C-3), 139.1 (s, C-14), 139.4 (s, C-11), 140.0
(s, C-6), 147.3 ppm (s, CϭN). MS (EI): m/z ϭ 279 [Mϩ] (40), 262
(8), 175 (30), 162 (100), 158 (44), 144 (14), 117 (28), 104 (24), 103
8 — undergoes transannular attack of the benzoyl substitu-
ent, and the resulting bicyclic intermediate 9 fragments as
indicated by the arrows in Scheme 1. The resulting com-
pound 10 loses water (the benzoate functions as the elimin-
ation reagent), and the resulting pyridinium salt 11 trans- (20), 77 (6), 56 (10). C19H21NO (279.38): calcd. C 81.68, H 7.58,
N 5.01; found C 81.55, H 7.60, N 5.05.
fers its methyl group thus generating the two isolated prod-
ucts, 12 and 13.
2-(4Ј-[2.2]Paracyclophanyl)-6-phenylpyridine (13): A mixture of 2
(0.279 g, 1 mmol) and (E)-1,2-dibenzoylethene (4, 0.236 g, 1 mmol)
was refluxed in dry toluene (100 mL) under N2 for 3 days. The
solvent was evaporated in vacuo, and the residue was purified by
plate chromatography on silica gel with toluene. The two separated
zones were extracted with acetone. The more slowly migrating zone
contained methyl benzoate (12, 0.007 g, 5%, Rf 0.3, CH2Cl2), which
was identified by comparison with an authentic sample (NMR
spectra). The faster migrating zone contained 13 (Rf 0.5, CH2Cl2),
which was recrystallized from ethanol to give (0.25 g, 70%) as col-
orless plates. M.p. 75 °C. IR (KBr): ν˜ ϭ 3066 cmϪ1 (vs), 3023 (vs),
2962 (vs), 2946 (s), 2926 (m), 2891 (s), 2850 (s), 1586 (m), 1567 (w),
1500 (s), 1457 (m), 1442 (w), 1411 (s), 1377 (s), 1158 (s), 901 (s),
Clearly, to produce other substituent patterns in 13, and
therefore determine the scope of this serendipitous obser-
vation, the nature of the dipolarophile must be varied.
Experimental Section
General: Melting points: Büchi melting point apparatus, uncor-
rected. TLC: MachereyϪNagel Polygram SilG/UV254 and Polyg-
ram Alox N/UV 254. Column chromatography: Merck Kieselgel
60 (70Ϫ230 mesh). IR: PerkinϪElmer 1420 and Nicolet 320 FT-
IR. NMR: Bruker AM-400, 400 MHz (1H) and 101 MHz (13C), 860 (s), 816 (m), 798 (m), 763 (w), 746 (m), 720 (m). UV (CH3CN):
solvent CDCl3, internal standards: TMS for 1H (δ ϭ 0.00 ppm)
and CDCl3 (δ ϭ 77.0 ppm) for 13C. Abbreviations: pc ϭ [2.2]para-
λmax (log ε) ϭ 335 nm (3.20). 1H NMR (400 MHz, CDCl3): δ ϭ
2.70 (mc, 1 H, 1-Hs), 2.87Ϫ3.18 [m, 6 H; shifts from C,H-
cyclophanyl, ph ϭ phenyl, py ϭ pyridinediyl; the subscripts a and HETCOR: 2.89 (1-Ha), 2.90 (2-Ha), 2.99 (9-Hs), 3.01 (10-Ha), 3.09
s indicate bridge protons anti and syn, respectively, relative to the (9-Ha), 3.13 (10-Hs)], 3.80 (mc, 1 H, 2-Hs), 6.51 (dd, 1 H, pc-7-H),
4-substituent at the pc system. Positions in the second pc-ring are
6.52 (dd, 1 H, pc-13-H), 6.548 (d, 1 H, pc-8-H), 6.551 (dd, 1 H, pc-
70
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 68Ϫ71

A Simple Route to a Pyridinyl[2.2]paracyclophane
SHORT COMMUNICATION
12-H), 6.58 (dd, 1 H, pc-16-H), 6.65 (dd, 1 H, pc-15-H), 6.89 (d, 1
H, pc-5-H), 7.32 (dd, 1 H, py-3-H), 7.40 (para-type m, 1 H, ph-4-
CCDC-238142 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
H), 7.49 (meta-type m, 2 H, ph-3,5-H), 7.62 (dd, 1 H, py-5-H), 7.69 www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
(t, 1 H, py-4-H), 8.18 ppm (ortho-type m, 2 H, ph-2,6-H); coupling Crystallographic Data Centre, 12, Union Road, Cambridge
constants: a) py: J3,4 ϭ 7.8, J3,5 ϭ 0.9, J4,5 ϭ 7.8 Hz, b) pc: J5,7
2.0, J7,8 ϭ 7.8, J12,13 ϭ 7.9, J12,16 ϭ 2.2, J13,15 ϭ 2.0, J15,16
ϭ
CB2 1EZ, UK; Fax: (internat.) ϩ44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk].
ϭ
7.8 Hz. NOEs: ph-2,6-H Ǟ py-5-H, ph-3,5-H, pc-15-H, pc-16-H;
pc-5-H Ǟ py-3-H, pc-16-H, pc-9-Hs. 13C NMR: δ ϭ 34.6 (t, pc-C-
2), 35.0 (t, pc-C-1), 35.2 (t, pc-C-9), 35.4 (t, pc-C-10), 117.7 (d, py-
C-5), 122.6 (d, py-C-3), 126.8 (d, 2 C, ph-C-2,6), 128.7 (d, 2 C, ph-
C-3,5), 128.8 (d, ph-C-4), 130.8 (d, pc-C-15), 132.4 (d, 2 C, pc-C-
12,16), 132.8 (d, pc-C-13), 133.0 (d, pc-C-7), 133.1 (d, pc-C-5),
135.9 (d, pc-C-8), 136.8 (d, py-C-4), 138.2 (s, pc-C-3), 139.2 (s, pc-
C-11), 139.5 (s, pc-C-6), 139.7 (s, 2 C, ph-C-1, pc-C-14), 140.6 (s,
pc-C-4), 156.5 (s, py-C-6), 158.7 ppm (s, py-C-2). MS (EI): m/z ϭ
361 [Mϩ] (28), 258 (20), 257 (100), 241 (12), 92 (18), 91 (22), 77(8).
C27H23N (361.49): calcd. C 89.71, H 6.41, N 3.87; found C 89.55,
H 6.40, N 3.80.
Acknowledgments
We thank the DAAD (scholarship for A. A. A.) and the Fonds der
Chemischen Industrie for a dissertation scholarship (V. N. S.) and
the constant support of our studies.
[1]
For recent reviews see: [1a] V. Rozenberg, E. Sergeeva, H. Hopf,
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X-ray Structure Determination of Compound 2. Crystal Data for
[3]
C19H21NO: Monoclinic, space group P21/c, a ϭ 15.736(3), b ϭ
D. C. Braddock, S. M. Ahmad, G. T. Douglas, Tetrahedron
3
˚
˚
7.3166(14), c ϭ 12.540(4) A, β ϭ 97.82(2)°, U ϭ 1430.3 A , Z ϭ 4,
µ(Mo-Kα) ϭ 0.08 mmϪ1, T ϭ Ϫ130 °C. Data collection: A colorless
tablet, approximately 0.7 ϫ 0.6 ϫ 0.16 mm, was used to record
3222 intensities on a Stoe STADI-4 diffractometer to 2θmax. 50°.
Structure refinement: The structure was refined anisotropically on
F2 (program SHELXL-97, G. M. Sheldrick, University of
Göttingen) to wR2 0.130, R1 0.048 for 193 parameters and all 2529
Lett. 2004, 45, 6583Ϫ6585.
[4]
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[6]
[7]
R. Huisgen, H. Hauck, R. Grashey, H. Seidl, Chem. Ber. 1969,
unique reflections; S ϭ 1.07, max. ∆ρ ϭ 0.21 e·AϪ3. Hydrogen
˚
102, 736Ϫ745, cf. H. Seidl, R. Huisgen, R. Knorr, Chem. Ber.
1969, 102, 904Ϫ914.
atoms, identifiable as well-resolved maxima in difference syntheses,
were included using a riding model or as rigid methyl groups.
Received September 6, 2004
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71