Zinc– and palladium–porphyrin based turnstiles

Abstract

The design and synthesis of two new Zn(II) and Pd(II) strapped-porphyrin based molecular turnstiles have been achieved. These molecules are based on a porphyrin backbone as a stator and a handle as a rotor. The junction between the two parts is ensured by covalent bonds using two opposite meso positions. Both compounds have been characterised in solution by NMR spectroscopy and in the solid state by X-ray diffraction on a single crystal. The dynamic of the two systems have been investigated in solution by 1- and 2-D NMR techniques such as ROESY. The switching between the open and closed states is described. Whereas for the Pd(II) complex, the handle freely rotates around the stator, for the Zn(II) analogue owing to the presence of a water molecule bound to the zinc atom and hydrogen bonded to the pyridyl moiety of the rotor, the rotation is blocked. The unlocking of the rotational movement was achieved using an external agent, mainly dimethylaminopyridine as a strong coordinating ligand.

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Introduction

The design and synthesis of molecular architectures for which intramolecular movements can be controlled by external stimuli are a topic of interest (for review articles see ref. 1–8). Many examples of rotaxanes⁹ and catenanes¹⁰ based systems have been reported. Molecular motors functioning with thermal¹¹ or photochemical¹² processes have been published. Molecular cars¹³ and wheelbarrows¹⁴ have also been described. Among the above-mentioned systems, molecular turnstiles¹⁵ form a class of dynamic architectures subject to rotational processes between a fixed (stator) and a mobile (rotor) part. For this type of molecules, the switching between an open and a closed state by an external stimulus is challenging and of interest. We have previously reported examples of turnstiles based either on Sn–porphyrin derivatives^16,17 or on a strapped-porphyrin for which the rotor comprises a tridentate unit.¹⁸

Here, we report on the design, synthesis, characterization, both in solution and in the crystalline phase, and on the switching between the open and closed states of molecular turnstiles based on strapped-porphyrins¹⁹ composed of a free base meso tetraaryl porphyrin and its zinc²⁰ or palladium complexes and a covalently attached handle bearing a pyridyl moiety as a monodentate coordinating site.

Results and discussion

The turnstile reported here is the strapped porphyrin 1 (Scheme 1). Its design is based on a meso tetraaryl porphyrin as a stator and a strap as a rotor. It should be noted that the designation of the two parts as a stator and as a rotor is arbitrary and the rotational process is a relative movement of one of the two parts around the other. The rational behind the choice of the porphyrin backbone is based on its propensity to bind a large variety of metal centres by its tetraaza macrocyclic core and on available synthetic possibilities to incorporate the strap. Examples of strapped porphyrins bearing a phenanthroline unit as a handle have been reported.²¹ The rotor is a monodentate pyridyl coordinating unit bearing, in a symmetrical fashion, two tetraethyleneglycol moieties at positions 2 and 6. The pyridyl unit and the spacer are interconnected using ether junctions. The connection between the porphyrin and the strap is ensured by two covalent ether groups using the two meso positions 5 and 15 on the porphyrin. For the attachment of the handle to the aryl groups of the porphyrin, one may use the ortho, meta or para position. In order to avoid (i) a rotational barrier induced by the use of the ortho position, (ii) longer spacer units between the porphyrin backbone and the pyridyl moiety resulting from the improper angle imposed by the use of the para position, the junction is achieved in a symmetrical fashion using the meta position on both aryl groups in positions 5 and 15. The remaining two meso positions 10 and 20 are occupied by two benzonitrile groups connected to the porphyrin backbone using the position 4 of the aryl moiety. The nitrile groups at the meso positions were introduced as additional coordinating sites in order to explore the possibility of locking the system by simultaneous binding of external metal cations by both the peripheral site and the pyridyl moiety of the handle. Their presence does not interfere with the present study.

Scheme 1 Strapped porphyrin 1, its Zn(II) and Pd(II) complexes 2 and 3 respectively, and the water complex 2·H₂O and the assignment of H atoms.

The operational design of the turnstile (Fig. 1) is based on: (i) free rotation (open state, Fig. 1a) of the rotor around the stator as a consequence of the absence of specific interactions between the two parts, (ii) introduction of the Zn(II) cation within the macrocyclic coordinating moiety of the strapped porphyrin 1 (Fig. 1b) affording the neutral complex 2 (Scheme 1). Owing to the propensity of Zn²⁺ cation to adopt mainly a square based pyramidal geometry when complexed by the tetraaza core of the porphyrin, the coordination of the pyridyl unit of the rotor should lock the rotation process leading thus to the closed state of the turnstile (Fig. 1b). In order to prove the latter statement, the Zn²⁺ cation may be replaced by Pd(II) (complex 3, Scheme 1) adopting the square planar geometry without extension of its coordination sphere. In that case, the locking process cannot take place and thus the rotation of the rotor around the stator should not be altered (Fig. 1c).

Fig. 1 Schematic representation of strapped-porphyrins: (a) free base (open state), (b) Zn–porphyrin (closed state), (c) Pd–porphyrin (open state).

The synthetic strategy adopted for the preparation of the strapped porphyrin 1 (Scheme 2) was based on the condensation of the dipyrrylmethane 13²² and the α, ω dialdehyde 11. The latter was prepared from the commercially available 3-hydroxybenzaldehyde 14, tetraethyleneglycol 4 and 2,6-pyridine diol 6.

Scheme 2

Compound 4 was first converted at room temperature in the presence of a catalytic amount of pyridinium para-toluenesulfonate (PPTS) into its mono-DHP protected derivative 5²³ upon treatment with dihydropyrane (DHP) in CHCl₃ (34% yield). The latter was then condensed in the presence of NaH in refluxing THF with the dichloro compound 7²⁴ affording the compound 8²⁵ in 54% yield. Compound 7 was prepared in 82% yield in THF at room temperature upon treatment of 6 with SOCl₂. The bis-OTHP derivative 8 was then deprotected under acidic conditions affording the diol 9 in 88% yield. The latter was quantitatively activated into its dimesylate derivative 10. The handle 11 was obtained in the presence of potassium carbonate in 96% yield in refluxing CH₃CN upon reaction with 3-hydroxybenzaldehyde 14.

Dipyrrylmethane 13²² was obtained in 63% yield upon reaction of the aldehyde 12 with pyrrole in the presence of TFA. Condensation, in a CH₂Cl₂–EtOH mixture and in the presence of TFA, of the dialdehyde 11 with dipyrrylmethane 13 followed by oxidation in THF and in the presence of Et₃N using DDQ,²⁶ afforded strapped-porphyrin 1 in 2% yield.

In order to increase the yield of the final step, another synthetic strategy was explored. The compound 11 was converted in 66% into its bisdipyrrylmethane derivative 15 by reaction with an excess of pyrrole in the presence of TFA. Unfortunately, this strategy did not enhance the yield of the porphyrin formation. Indeed, the condensation of 15 in the presence of TFA with the aldehyde 12 in a CH₂Cl₂–EtOH mixture followed by oxidation using DDQ²⁶ in the presence of Et₃N in THF afforded the porphyrin derivative 1 in 1% yield.

The Zn–porphyrin complex 2 was quantitatively obtained in a CH₂Cl₂–MeOH mixture and at room temperature, upon treatment of 1 with Zn(OAc)₂. The Pd–porphyrin complex 3 was obtained in 66% yield in a refluxing CHCl₃–MeOH mixture, upon addition of Pd(OAc)₂ to a solution of the porphyrin 1.

The assignment of all hydrogen atoms of the strapped porphyrins 1–3 was achieved at 25 °C in CD₂Cl₂ by 1- and 2-D NMR COSY and ROESY experiments. Using the same technique, the dynamics of compounds 1–3 in solution (CD₂Cl₂) was also studied at 25 °C.

For both porphyrins 1 and 3, a splitting of hydrogen atoms of the benzonitrile moieties H_a, and H_b into H_a, , and H_b, H_b (Scheme 1) was observed. This differentiation, resulting from the slow rotation of the handle around the porphyrin core within the NMR time scale, is in agreement with a previous study performed on an analogue system.¹⁸ The binding of the Pd(II) cation by the tetraaza core of the porphyrin has almost no influence on the H atoms of the handle. Indeed, when compared to the parent compound 1, signals corresponding to H_r and H_s of the pyridyl unit are only slightly shifted by 0.03 ppm and 0.06 ppm respectively. The same observation holds for H_u and H_v atoms belonging to the tetraethyleneglycol units which are shifted by 0.08 ppm and 0.04 ppm, respectively (Fig. 2a and c). These observations indicate the free rotation of the handle around the porphyrin stator defining thus the open state of the turnstile.

Fig. 2 A portion (2.1–9.1 ppm) of the ¹H-NMR spectra (CD₂Cl₂, 400 MHz, 25 °C) of 1 (a), 2 (b) and 3 (c). * and ¤ correspond to residual CHCl₃ and MeOH, respectively. For assignment of H atoms see Scheme 1.

This statement was further confirmed by a 2-D ROESY experiment at room temperature which revealed only the expected correlations between H_k and H_j and H_g due to spatial proximities resulting from the atomic connectivity in the free strapped porphyrin 1 and its Pd complex 3 (Fig. 3a and b).

Fig. 3 Portions of the 2-D ROESY correlations for 1 (a), 3 (b) and 2 (c and d). * and ¤ correspond to residual chloroform and methanol, respectively. For attribution of H atoms see Scheme 1.

For the Zn–porphyrin turnstile 2, the C_2v symmetry of the molecule is conserved. The ¹H-NMR investigations revealed, as expected, a drastic upfield shift of H_u and H_v atoms by 1.32 ppm and 0.53 ppm, respectively, implying the locking of the handle and the positioning of this portion of the handle within the anisotropic cone of the porphyrin backbone. The observed splitting increase between H_b and signals is another argument in favour of a blocked rotation. However, the pyridine H_r and H_s hydrogen atoms were found to be downfield shifted by 0.35 ppm and 0.85 ppm, respectively (Fig. 2b). This observation is not in agreement with a direct binding of the Zn(II) cation located within the centre of the porphyrin stator by the N atom of the pyridyl unit of the handle. Indeed, if this was the case, one would expect upfield shifts of H_r and H_s signals. Thus, the closed state of the turnstile must result from an indirect interaction between the handle and the stator. The 2-D ROESY sequence at room temperature revealed, in addition to the expected correlations between H_k and H_j and H_g, as also observed for 1 (Fig. 3a) and 3 (Fig. 3b), new correlations between H_g of the meso aromatic groups and H_u, H_v and H_q belonging to the handle (Fig. 3c). Furthermore, it also revealed the presence of correlations between H_u, H_v and H_q and a water molecule (Fig. 3d). This observation is consistent with the coordination of a water molecule by the Zn cation and interacting with the handle through a H-bond with the pyridyl moiety affording the complex 2·H₂O (Scheme 1). This proposal also explains why the proton signals of H_r and H_s of the pyridyl unit are slightly downfield shifted. This hypothesis is substantiated in the crystalline phase by the structural investigation on a single crystal presented hereafter.

The solid state structures of both compound 2 and 3 were studied by X-ray diffraction on single crystals obtained upon slow diffusion of pentane into a CH₂Cl₂ solution of 2 (Fig. 4) or 3 (Fig. 5).

Fig. 4 Solid state structure of compound 2·H₂O. One of the two tetraethyleneglycol units connecting the handle to the porphyrin is found to be disordered. Hydrogen atoms and solvent molecules are omitted for clarity. For bond distances and angles, see text.

Fig. 5 Solid state structure of compound 3. Hydrogen atoms and solvent molecules are omitted for clarity. One of the ethyleneglycol units is found to be disordered. For bond distances and angles, see text.

For the Zn–porphyrin 2·H₂O complex, the structural study revealed that the crystal (triclinic, P1̄) in addition to the complex 2 contains water and dichloromethane molecules (Fig. 4). No noticeable deformation of the porphyrin backbone is observed. The zinc cation is located above the porphyrin mean plane (0.441 Å). The coordination geometry around the metallic centre is a slightly distorted square based pyramid. Its coordination sphere is composed of all four N atoms of the porphyrin core with Zn–N distances in the 2.063(3)–2.083(3) Å range and N–Zn–N angles of 160.02(12)–160.97(12)° (N–Zn–N_trans), 87.67(11)–89.05(11)° (N–Zn–N_cis). The water molecule occupies the apical position with the Zn–O distance of 2.120(3) Å and N–Zn–O angles of 98.53(11)–100.49(11)°. The four meso substituents are not coplanar but tilted with respect to the porphyrin mean plane with CCCC dihedral angles of −67.5° and −71.2° for the aryl units of the bridging handle and of −80.2° and 59.7° for the benzonitrile groups. One of the two tetraethyleneglycol units connecting the handle to the porphyrin is found to be disordered. Interestingly, the water molecule is hydrogen bonded to the pyridine nitrogen atoms of the handle with a O–N bond distance of 2.915(4) Å and NHO angles of 165(4)°.

For the Pd–porphyrin complex 3, the crystal (triclinic, P1̄) is composed of the porphyrin 3, pentane and H₂O solvent molecules (Fig. 5). The latter occupy in the crystal the empty space between compounds 3 without any specific interactions. The porphyrin backbone is not distorted. The palladium cation, located almost in the centre of the porphyrin core, is tetracoordinated. The coordination geometry around the metallic centre is almost square planar with Pd–N distances in the 1.995(9)–2.024(10) Å range and N–Pd–N angles of 178.3(4)–178.6(4)° (N–Pd–N_trans), 89.7(4)–90.6(4)° (N–Pd–N_cis). The meso substituents are tilted with respect to the porphyrin mean plane with CCCC dihedral angle of −65.6° and −57.6° for the aryl units of the bridging handle and −75.0° and 61.0° for the benzonitrile groups. One of the glycol units is found to be disordered over two positions.

In order to unlock the turnstile, 1–10 equivalents of para-dimethylaminopyridine (DMAP), a competitive ligand, was added to 2 and the process monitored by ¹H-NMR in CD₂Cl₂ at 25 °C (Fig. 6). As expected, upon addition of one equivalent of DMAP (Fig. 6b), the open state of the turnstile was restored. Indeed, by considering the “free-base” strapped-porphyrin 1 as a reference (Fig. 6d), the presence of DMAP caused a shift of all proton signals towards those observed for 1. In particular, H_r and H_s hydrogen atoms of the pyridyl moiety were upfield shifted by 0.16 ppm and 0.65 ppm respectively, whereas H_u and H_v signals were downfield shifted by 1.30 ppm and 0.55 ppm respectively. Furthermore, H_b and signals were found to be less differentiated. Upon further addition of DMAP, no additional shift of signals of the turnstile was observed (see Fig. 6c for addition of 2 eq. of DMAP). Dealing with DMAP, due to the fast exchange dynamics, its signals appeared to be broadened. However, for the 1/1 mixture of DMAP/2, in agreement with the coordination of DMAP to the Zn cation, the signal corresponding to the CH₃ groups was found to be upfield shifted by 0.53 ppm. Upon increasing the DMAP/2 ratio from 1 to 10, all signals of DMAP became narrower and downfield shifted.

Fig. 6 Portion of the ¹H NMR spectra (CD₂Cl₂, 300 MHz, 25 °C) of 2·H₂O (a) in the presence of 0 eq. (a), 1 eq. (b) and 2 eq. (c) of DMAP and of the parent compound 1 (d). * corresponds to signals of coordinated DMAP. For assignment of H atoms see Scheme 1.

Conclusion

In conclusion, a new strapped-porphyrin based molecular turnstile was designed, synthesized and characterised both in solution and in the solid state. The turnstile is composed of a porphyrin backbone (stator) equipped with a handle bearing a pyridyl unit as a monodentate coordinating site (rotor). In the absence of Zn(II) cation within the tetraaza core of the porphyrin, the rotor freely rotates around the stator (open state). In the presence of Pd(II) within the porphyrin core and adopting a square planar geometry, again the free rotation of the rotor around the stator is observed. In the presence of Zn(II), adopting a square based pyramidal geometry, in contrast with the initial design based on direct coordination of Zn cation by the pyridyl unit, the rotation was found to be locked (closed state) owing to the formation of a H-bond between a water molecule coordinated to the metal centre and the pyridyl moiety of the handle. The addition of DMAP, a competitive ligand, to the turnstile in its closed state leads to the open state of the turnstile. The use of rotors bearing tridentate binding site and other metal centres either bound to the porphyrin and/or to the rotor is currently under investigation. Furthermore, taking advantage of the presence of the peripheral nitrile coordinating sites, the locking of the turnstile using additional metal centres is also currently explored.

Experimental

General procedure

THF and triethylamine were distilled over sodium and KOH, respectively. Analytical grade of CH₂Cl₂, CHCl₃, EtOH and MeOH was used without further purification. ¹H- and ¹³C-NMR spectra were acquired at 25 °C on either a Bruker AV 300, Bruker AV 400 or a Brucker AV 500 spectrometers. Deuterated solvents were used as the lock and residual non deuterated solvents as the internal references. Mass spectrometry analyses were performed by the Service de Spectrometrie de Masse, University of Strasbourg.

X-ray crystal-structure analysis

Data were collected on a Bruker APEX8 CCD diffractometer equipped with an Oxford Cryosystem liquid N₂ device at 173(2) K using a molybdenum microfocus sealed tube generator with mirror-monochromated Mo-Kα radiation (λ = 0.71073 Å), operated at 50 kV/600 mA. The structure was solved using SHELXS-97 and refined by fullmatrix least-squares on F² using SHELXL-97 with anisotropic thermal parameters for all non-hydrogen atoms.²⁷ The hydrogen atoms were introduced at calculated positions and not refined (riding model).

Crystals of 2 and 3 were obtained in a crystallization tube (0.5 × 20 cm) at room temperature upon slow diffusion of pentane into a solution of the complex in CH₂Cl₂ through a buffer layer of pentane/CH₂Cl₂ (1/1).

Crystallographic data for 2: C_138.5H₁₃₁ClN₁₄O₂₃Zn₂, M = 2525.81, triclinic, P1̄, a = 13.5277(4) Å, b = 15.3111(7) Å, c = 17.7296(5) Å, α = 86.083(3)°, β = 67.796(2)°, γ = 77.863(3)°, U = 3323.7(2) ų, Z = 1, μ = 0.454 mm⁻¹, refls measured: 34 801, independent refls: 14 673 [R_int = 0.0240], final R indices [I > 2σ (I)]: R₁ = 0.0782, wR₂ = 0.2357, R indices (all data): R₁ = 0.0969, wR₂ = 0.2528, GOF on F²: 1.063.

Crystallographic data for 3: C₁₄₈H₁₅₆N₁₄O₂₃Pd₂, M = 2711.67, triclinic, P1̄, a = 14.8196(12) Å, b = 17.1292(15) Å, c = 17.1532(17) Å, α = 63.953(3)°, β = 84.648(3)°, γ = 64.883(3)°, U = 3518.9(5) ų, Z = 1, μ = 0.328 mm⁻¹, refls measured: 12 750, independent refls: 11654 [R_int = 0.0378], final R indices [I > 2σ (I)]: R₁ = 0.1132, wR₂ = 0.2997, R indices (all data): R₁ = 0.1510, wR₂ = 0.3255, GOF on F²: 1.416. Owing to the weak diffraction power of the crystal, the data collection was performed with a theta value of 25°.

Synthesis

Compounds 7²⁴ and 13²² have been prepared following reported procedures.

Compound 1: Method A. In a 500 mL two-necked round-bottom flask, dipyrrylmethane 13 (371 mg, 1.5 mmol, 1 eq.) and compound 11 (1.05 g, 1.5 mmol, 1 eq.) were dissolved in 200 mL of a CH₂Cl₂–EtOH (95/5) mixture. The solution was degassed under argon for 30 min before TFA (335 μL, 4.5 mmol, 3 eq.) was added. The reaction mixture was stirred under argon at room temperature for 5 days. TFA was neutralized by triethylamine (840 μL, 6 mmol, 4 eq.) before a solution of DDQ (511 mg, 2.3 mmol, 1.5 eq.) in 50 mL of THF was added and the reaction mixture was further stirred at room temperature for 16 hours. Solvents were removed under vacuum and the crude product was purified by chromatography (SiO₂, CH₂Cl₂–MeOH 100/0 to 98/2) to afford the compound 1 (34 mg, 2%) as a purple solid.

Method B. In a 100 mL two-necked round-bottom flask, compound 15 (900 mg, 970 μmol, 1 eq.) and 4-cyanobenzaldehyde 12 (253 mg, 1.9 mmol, 2 eq.) were dissolved in 25 mL of a CH₂Cl₂–EtOH (4/1) mixture. The solution was degassed under argon for 15 min before TFA (215 μL, 2.9 mmol, 3 eq.) was added. The reaction mixture was stirred under argon at room temperature for 20 hours. Triethylamine (540 μL, 3.9 mmol, 4 eq.) was added to neutralize TFA and then, a solution of DDQ (330 mg, 1.5 mmol, 1.5 eq.) in 10 mL of THF was added and the reaction mixture was stirred at room temperature for 16 hours. After removal of solvents, the crude product was purified by chromatography (SiO₂, CH₂Cl₂–MeOH 1/0 to 97/3) affording the compound 1 in 1% yield (15 mg) as a purple solid.

¹H-NMR (CD₂Cl₂, 400 MHz) δ (ppm): −2.94 (s, 2H, NH_y), 2.88 (m, 4H, OCH_2v), 3.00 (m, 4H, OCH_2q), 3.14 (m, 4H, OCH_2p), 3.34 (m, 4H, OCH_2o), 3.51 (m, 4H, OCH_2n), 3.57 (s, 4H, OCH_2u), 3.64 (m, 4H, OCH_2m), 3.89 (m, 4H, OCH_2l), 4.31 (m, 4H, OCH_2k), 6.15 (d, 2H, Py_r, ³J = 7.5 Hz), 6.46 (t, 1H, Py_s, ³J = 7.5 Hz), 7.36 (dd, 2H, Ar_j, ³J = 8.5 Hz, ⁴J = 2.0 Hz), 7.69 (t, 2H, Ar_i, ³J = 8.0 Hz), 7.76 (m, 2H, Ar_g), 7.88 (d, 2H, Ar_h, ³J = 7.5 Hz), 8.08 (d, 4H, Ar_a, ³J = 8.5 Hz), 8.33 (m, 4H, Ar_b), 8.76 (d, 4H, β-pyr_c, ³J = 4.5 Hz), 8.94 (d, 4H, β-pyr_d, ³J = 4.5 Hz). ¹³C-NMR (CD₂Cl₂, 100 MHz) δ (ppm): 68.0, 69.7, 69.9, 70.0, 70.4, 70.5, 70.7, 71.0, 73.3, 112.0, 114.5, 119.1, 119.2, 120.7, 122.2, 127.7, 128.0, 130.7, 131.1, 132.3, 135.4, 136.3, 143.1, 147.0, 157.1, 157.7. MS (ESI) for C₆₉H₆₅N₇O₁₀: 1152.30 g mol⁻¹. m/z (M + Na⁺): calculated = 1174.469; measured = 1174.497.

Compound 2. In a 10 mL round-bottom flask, to a CH₂Cl₂ solution (3 mL) of compound 1 (9 mg, 7.8 μmol, 1 eq.) a MeOH solution (3 mL) of zinc acetate (171 mg, 780 μmol, 100 eq.) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was successively washed with water (3 × 10 mL) and a 10% aqueous solution of NaHCO₃ (3 × 10 mL). The organic phase was dried over MgSO₄ and the solvent removed under vacuum. The mixture was dissolved in CH₂Cl₂ (5 mL) and the compound 2 was quantitatively precipitated upon addition of pentane affording after filtration 9.5 mg of a purple powder.

¹H-NMR (CD₂Cl₂, 400 MHz) δ (ppm): 2.25 (s, 4H, OCH_2u), 2.35 (m, 4H, OCH_2v), 2.79 (m, 4H, OCH_2p), 2.81 (m, 4H, OCH_2q), 3.13 (m, 4H, OCH_2o), 3.49 (m, 4H, OCH_2n), 3.65 (m, 4H, OCH_2m), 3.89 (m, 4H, OCH_2l), 4.32 (m, 4H, OCH_2k), 6.50 (d, 2H, Py_r, ³J = 7.5 Hz), 7.31 (m, 3H, Py_s, Ar_j), 7.62 (t, 2H, Ar_i, ³J = 8.0 Hz), 7.68 (br, 2H, Ar_g), 7.77 (d, 2H, Ar_h, ³J = 7.5 Hz), 8.02 (m, 6H, Ar_a,b), 8.29 (d, 2H, Ar_b, ³J = 8.0 Hz), 8.77 (d, 4H, β-pyr_c, ³J = 4.5 Hz), 8.95 (d, 4H, β-pyr_d, ³J = 4.5 Hz). ¹³C-NMR (CD₂Cl₂, 100 MHz) δ (ppm): 68.6, 69.3, 69.6, 69.6, 70.0, 70.5, 70.6, 70.9, 71.0, 111.5, 114.4, 118.7, 119.5, 120.0, 121.1, 122.6, 127.6, 128.1, 130.5, 131.5, 132.8, 135.0, 135.4, 137.8, 144.4, 148.3, 149.6, 150.5, 156.3, 157.5.MS (ESI) for C₆₉H₆₃N₇O₁₀Zn: 1215.66 g mol⁻¹. m/z (M + Na⁺): calculated = 1236.382; measured = 1236.400.

Compound 3. In a 50 mL round-bottom flask, to a solution of the compound 1 (8.8 mg, 7.6 μmol, 1 eq.) dissolved in 20 mL of a CHCl₃–MeOH (95/5) mixture, a CHCl₃ solution (5 mL) of palladium acetate (2.6 mg, 11.4 μmol, 1.5 eq.) was added. Under argon, the mixture was heated at reflux for 16 hours before solvents were removed under vacuum. The crude product was purified by column chromatography (SiO₂, CH₂Cl₂–MeOH, 1/0 to 95/5) affording the compound 3 (6.3 mg, 66%) as an orange solid.

¹H-NMR (CD₂Cl₂, 400 MHz) δ (ppm): 2.92 (m, 4H, OCH_2v), 3.07 (m, 4H, OCH₂), 3.20 (m, 4H, OCH_2p), 3.37 (m, 4H, OCH_2o), 3.53 (m, 4H, OCH_2n), 3.65 (m, 8H, OCH_2u,m), 3.89 (m, 4H, OCH_2l), 4.30 (m, 4H, OCH_2k), 6.18 (d, 2H, Py_r, ³J = 7.5 Hz), 6.52 (t, 1H, Py_s, ³J = 7.5 Hz), 7.35 (dd, 2H, Ar_j, ³J = 8.0 Hz, ⁴J = 2.0 Hz), 7.68 (m, 4H, Ar_g,i), 7.82 (d, 2H, Ar_h, ³J = 7.5 Hz), 8.07 (m, 4H, Ar_a), 8.26 (m, 2H, Ar_b), 8.32 (m, 2H, Ar_b), 8.72 (d, 4H, β-pyr_c, ³J = 5.0 Hz), 8.91 (d, 4H, β-pyr_d, ³J = 5.0 Hz). ¹³C-NMR (CDCl₃, 125 MHz) δ (ppm): 68.0, 69.7, 69.8, 70.0, 70.3, 70.5, 70.7, 70.9, 73.2, 111.5, 114.9, 118.5, 119.2, 119.2, 121.2, 121.5, 127.6, 128.0, 130.8, 130.9, 132.2, 134.7, 136.6, 140.8, 141.0, 142.2, 146.2, 156.5, 157.1. MS (ESI) for C₆₉H₆₃N₇O₁₀Pd: 1255.37 g mol⁻¹. m/z (M + Na⁺): calculated = 1278.359; measured = 1278.358.

Compound 5. In a 2 L two-necked round-bottom flask, tetraethyleneglycol 4 (37 mL, 216 mmol, 3 eq.) and pyridinium para-toluenesulfonate (1.8 g, 7.2 mmol, 0.1 eq.) were dissolved in 1 L of analytical grade CHCl₃. Then, under argon, a solution of DHP (6.6 mL, 72 mmol, 1 eq.) in 300 mL of analytical grade CHCl₃ was added dropwise. The reaction mixture was stirred at room temperature for 2 days. The organic layer was washed with a 10% solution of K₂CO₃ (4 × 400 mL) and brine (400 mL) and dried over MgSO₄. The solvent was removed and the residue dried under vacuum overnight to yield the compound 5 (6.8 g, 34%) as a yellow oil.

¹H-NMR (CDCl₃, 300 MHz) δ (ppm): 1.38–1.85 (m, 6H, CH_2(THP)), 2.83 (br, 1H, OH), 3.40–3.85 (m, 18H, OCH₂, OCH_2(THP)), 4.58 (m, 1H, CH_(THP)). ¹³C-NMR (CDCl₃, 75 MHz) δ (ppm): 19.6, 25.6, 30.7, 61.7, 62.4, 66.8, 70.1, 70.7, 70.8, 73.1, 99.1. Anal.: calculated for C₁₃H₂₆O₆: C = 56.10%; H = 9.42%; found: C = 56.53%; H = 9.23%.

Compound 8. In a dry 500 mL two-necked round-bottom flask, sodium hydride (60% in oil) (900 mg, 22 mmol, 2.2 eq.) was suspended at 0 °C in 150 mL of dry THF. A solution of compound 5 (6.26 g, 22 mmol, 2.2 eq.) in dry THF (50 mL) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 40 min. Then, a solution of compound 7 (1.81 g, 10 mmol, 1 eq.) in dry THF (90 mL) was added dropwise. The reaction mixture was heated at reflux for 5 days. The solvent was removed and the brown oily residue was dissolved in CHCl₃ and washed with water (4 × 100 mL) and brine (2 × 100 mL), dried over MgSO₄ and the solvent removed under reduced pressure. The crude orange oil was purified by chromatography (Al₂O₃, cyclohexane–ethyl acetate 1/1 to 0/1) to yield the compound 8 (3.62 g, 54%) as a yellow oil.

¹H-NMR (CDCl₃, 300 MHz) δ (ppm): 1.47–1.87 (m, 12H, CH_{2 (THP)}), 3.45–3.90 (m, 36H, OCH_2k–v, OCH_{2 (THP)}), 4.62 (m, 2H, CH _(THP)), 4.68 (s, 4H, OCH_2u), 7.39 (d, 2H, Py_r, ³J = 8.0 Hz), 7.72 (t, 1H, Py_s, ³J = 8.0 Hz). ¹³C-NMR (CDCl₃, 75 MHz) δ (ppm): 19.6, 25.6, 30.7, 62.4, 66.8, 70.4, 70.7, 70.8, 70.8, 74.0, 99.1, 120.1, 137.5, 157.9. Anal.: calculated for C₃₃H₅₇NO₁₂: C = 60.07%; H = 8.71%; N = 2.12%; found: C = 59.95%; H = 9.07%; N = 1.88%.

Compound 9. In a 1 L round-bottom flask, compound 8 (3.62 g, 5.5 mmol, 1 eq.) was dissolved in a mixture of MeOH (450 mL) and concentrated HCl (3 mL) and stirred at room temperature for 5 hours. To the mixture, solid NaHCO₃ was added to neutralize the excess of HCl. Solvents were removed under vacuum affording a white solid which was washed with Et₂O (5 × 100 mL), filtered and dried under vacuum to yield the compound 9 (2.37 g, 88%) as a pale yellow oil.

¹H-NMR (CDCl₃, 300 MHz) δ (ppm): 2.83 (br, 2H, OH), 3.58–3.75 (m, 32H, OCH_2k–v), 4.67 (s, 4H, OCH_2u), 7.38 (d, 2H, Py_r, ³J = 8.0 Hz), 7.71 (t, 1H, Py_s, ³J = 8.0 Hz). ¹³C-NMR (CDCl₃, 75 MHz) δ (ppm): 61.8, 70.4, 70.5, 70.7, 70.8, 72.7, 74.0, 120.2, 137.6, 157.9. Anal.: calculated for C₂₃H₄₁NO₁₀ 0.5 C₄H₁₀O: C = 56.80%; H = 8.77%; N = 2.65%; found: C = 56.79%; H = 8.70%; N = 2.62%.

Compound 10. In a dry 250 mL two-necked round-bottom flask, compound 9 (2.37 g, 4.8 mmol, 1 eq.) was dissolved in 100 mL of dry THF. Under argon, freshly distilled Et₃N (2.3 mL, 16 mmol, 3.4 eq.) and mesyl chloride (1.1 mL, 15 mmol, 3 eq.) were added and the reaction mixture stirred at room temperature for 5 hours. After removal of the solvent, the white solid was dissolved in CH₂Cl₂ (100 mL), washed with water (3 × 75 mL) and a 5% solution of NaHCO₃ (3 × 75 mL). The organic layer was dried over MgSO₄, filtered and solvent removed under vacuum to yield quantitatively the compound 10 (3.11 g) as a yellow oil.

¹H-NMR (CDCl₃, 300 MHz) δ (ppm): 3.06 (s, 6H, CH₃), 3.62–3.77 (m, 28H, OCH_2v–l), 4.36 (m, 4H, OCH_2k), 4.68 (s, 4H, OCH_2u), 7.39 (d, 2H, Py_r, ³J = 8.0 Hz), 7.73 (t, 1H, Py_s, ³J = 8.0 Hz). ¹³C-NMR (CDCl₃, 75 MHz) δ (ppm): 37.9, 69.1, 69.4, 70.4, 70.7, 70.8, 73.9, 120.3, 137.8, 157.8. Anal.: calculated for C₂₅H₄₅NO₁₄S₂: C = 46.36%; H = 7.00%; N = 2.16%; found: C = 46.35%; H = 6.87%; N = 2.05%.

Compound 11

In a 500 mL two-necked round-bottom flask, 3-hydroxybenzaldehyde 14 (2.35 g, 19 mmol, 4 eq.) was dissolved in 200 mL of dry CH₃CN. K₂CO₃ (2.65 g, 19 mmol, 4 eq.) was added and the reaction mixture stirred under argon at room temperature for 2 hours. A solution of compound 10 (3.11 g, 4.8 mmol, 1 eq.) in 100 mL of dry CH₃CN was added via cannula. The reaction mixture was heated at reflux for 16 hours. The solvent was removed under vacuum and the oily residue was dissolved in CH₂Cl₂ (300 mL), washed with water (2 × 150 mL) and successively with solutions of NaOH (0.1 M, 150 mL), HCl (0.1 M, 150 mL) and brine (150 mL). The organic layer was dried over MgSO₄ and the solvent removed under vacuum to yield the compound 11 (3.22 g, 96%) as a brown oil.

¹H-NMR (CDCl₃, 300 MHz) δ (ppm): 3.65–3.75 (m, 24H, OCH_2v–m), 3.87 (m, 4H, OCH_2l), 4.18 (m, 4H, OCH_2k), 4.67 (s, 4H, OCH_2u), 7.19 (m, 2H, Ar), 7.35–7.44 (m, 8H, Ar, Py_r), 7.69 (t, 1H, Py_s, ³J = 8.0 Hz), 9.95 (s, 2H, CHO). ¹³C-NMR (CDCl₃, 75 MHz) δ (ppm): 67.9, 69.7, 70.4, 70.7, 70.8, 71.0, 74.0, 113.1, 120.1, 122.2, 123.7, 130.2, 137.9, 157.9, 159.5, 192.2.

Compound 15. In a 50 mL two-necked round-bottom flask, in exclusion of light, a mixture of the compound 11 (2.88 g, 4.4 mmol, 1 eq.) and pyrrole (15 mL, 220 mmol, 50 eq.) was degassed under argon for 15 min before TFA (130 μL, 0.4 mmol, 0.1 eq.) was added and the reaction mixture stirred at room temperature for 40 min. Excess pyrrole was removed under vacuum and the crude product was purified by chromatography (Al₂O₃, petroleum ether–ethyl acetate 1/1 to 0/1) to yield the compound 15 (2.7 g, 66%) as a brown oil.

¹H-NMR (CDCl₃, 300 MHz) δ (ppm): 3.65 (m, 24H, OCH_2v–m), 3.79 (m, 4H, OCH_2l), 4.03 (m, 4H, OCH_2k), 4.62 (s, 4H, OCH_2u), 5.41 (s, 2H, CH), 5.90 (m, 4H, pyr.), 6.12 (q, 4H, pyr., ³J = 3.0 Hz), 6.66 (m, 4H, pyr.), 6.77 (m, 6H, Ar), 7.18 (dd, 2H, Ar, ³J = 9.0 Hz, ³J = 7.5 Hz), 7.35 (d, 2H, Py_r, ³J = 7.5 Hz), 7.69 (t, 1H, Py_s, ³J = 7.5 Hz), 8.15 (br, 4H, NH). ¹³C-NMR (CDCl₃, 75 MHz) δ (ppm): 44.1, 67.4, 69.9, 70.4, 70.6, 70.8, 70.9, 107.2, 108.4, 112.9, 115.2, 117.3, 120.3, 121.2, 129.7, 132.5, 143.9, 157.7, 159.1.

Acknowledgements

We thank the University of Strasbourg, the International Centre for Frontier Research in Chemistry (FRC), Strasbourg, the Institut Universitaire de France (IUF), the Ministry of Education and Research and the CNRS for financial support. Thanks to Dr L. Allouche for NMR studies.

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Footnotes

† This article is included in the All Aboard 2013 themed issue.

‡ CCDC 894032 and 894033. For crystallographic data in CIF or other electronic format see DOI: 10.1039/c2nj40657h

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