An indirect synthetic approach toward conformationally constrained 20

Oct 15, 2018 - A new protocol for PTC-mediated O-alkylation of the intraannular position of 20-membered unclosed cryptands (UCs) is reported. In contr...
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An Indirect Synthetic Approach toward Conformationally Constrained 20-Membered Unclosed Cryptands via Late-Stage Installation of Intraannular Substituents Janusz Jurczak,* Adam Sobczuk, Kajetan Da̧browa, Marcin Lindner, and Patryk Niedbała Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

J. Org. Chem. 2018.83:13560-13567. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 11/02/18. For personal use only.

S Supporting Information *

ABSTRACT: A new protocol for PTC-mediated O-alkylation of the intraannular position of 20-membered unclosed cryptands (UCs) is reported. In contrast to the classical, “direct” strategy, which requires functionalization of the lariat arm at the beginning of synthesis, this “indirect” approach enables the late-stage introduction of various benzylic substituents after an unfavorable macrocyclization step (11 examples, yields up to 98%). Notably, this method permits preparation of, previously inaccessible, crowded UCs bearing 1-acetylpyrene substituent and dimer joined by p-xylene linker.

S

ince the pioneering work of Pedersen1 and Cram,2 expanded further by Lehn,3 macrocyclic compounds and cryptands have been extensively exploited in the construction of various well-defined host−guest molecules. Among others, these include the calix[n]arenes,4a resorcin[n]arenes,4b pilar[n]arenes,4c cucurbit[n]urils,4d cyclodextrins,4e and cyclophanes.4f Nevertheless, preparation of such structures is often inefficient, requiring a multistep procedure and tedious purification protocols.5 Moreover, the entropically unfavorable closure of the linear intermediate during macrocyclization is often a ratelimiting step within the entire synthetic protocol. In addition, the steric bulkiness of the macrocyclization partners further lowers the cyclization yield due to competing oligomerization.5 The latter effect is of particular concern when a formed macrocyclic skeleton contains a sterically demanding group attached at crowded intraannular position. For such compounds, even the application of well-established cyclizationpromoting strategies, such as conducting the reaction under high-dilution conditions, the addition of a suitable template agent,6 or the utilization of rigid building blocks,7 may prove unsuccessful. This is a serious issue when robust access to an array of derivatives of such structures is required, a situation often encountered in the structure−activity optimization of novel catalysts and drugs.8 In this context, the ability of rapid and cost-effective functionalization of the macrocyclic skeleton after the yieldlimiting macrocyclization step is a highly desirable strategy, but it has so far been exploited mainly at the remote sites of macrocyclic entities.9 In contrast, postsynthetic modification of intraannular substituents has remained a great synthetic © 2018 American Chemical Society

challenge, and to date, only a few methods addressing this problem have been reported.10 During our work on functional supramolecular architectures we have developed a new class of geometrically constrained and well-preorganized macrocyclic assemblies called unclosed cryptands (UCs).11,12 As we designed and investigated the smallest and formally achiral 16-, 19-, and 20-membered UCs, we noticed that they might exhibit a controlled phenomenon of planar chirality in the solid state.11 Atropisomerism, as a driving force, proved to be strictly dependent on the type and bulkiness of the intra-annularly mounted substituent (lariat arm) as well as on the macrocyclic cavity size.11 For example, atropisomerism was not observed for more extended 24-, 25-, and 26-membered analogues which, however, due to their increased flexibility, exhibit high selectivity (comparable to that of common cryptands) toward biologically relevant anions.12b−e In addition, extended UCs readily form crystals with unusually high packing efficiency,13 thus providing a well-suited 3D-framework for studying various supramolecular interactions and assemblies, such as discrete water clusters12a,d and chalcogen−chalcogen interactions.12b For the above reasons, we became even more interested in pursuing the structure−properties relationship of UCs. Therefore, we designed and synthesized a new set of 20-membered UCs with chemically diverse annular substituents, thus taking advantage of an approach typically exploited by our group that is based on the synthesis of an acyclic precursor with a Received: August 21, 2018 Published: October 15, 2018 13560

DOI: 10.1021/acs.joc.8b02160 J. Org. Chem. 2018, 83, 13560−13567

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The Journal of Organic Chemistry prefunctionalized lariat arm and subsequent macrocyclization (i.e., the “direct” approach). Nevertheless, the strategy employed may result in a certain handicap, manifested by a modest and even low macrocyclization efficiency, in particular, for UCs bearing large lariat-arm substituents (Scheme 1a).

Table 1. Synthesis of Target UCs 15−23 via Classical Macrocyclization between α,ω-Diamines and α,ω-Diesters

Scheme 1. Direct and Indirect Strategies Devised for the Assembly of Lariat Arm to the 20-Membered UCs entry

diester

diamine

UC

yield (%)

1 2 3 4 5 6 7 8 9

4 5 6 4 5 6 4 5 6

12 12 12 13 13 13 14 14 14

15 16 17 18 19 20 21 22 23

37 18 26 23 11 27 15 34 21

For example, the highest overall yield is recorded for UCs 15− 17 originating from the least crowded diester 4, but replacing the resorcinol ring with an electron donating group (EDG) considerably lowered the yield (23 and 15% for UCs 18 and 21 bearing the OMe and NMe2 substituents, respectively). Interestingly, the unexpectedly high yield for macrocyclization of UC 22 suggests a favorable π−π stacking interaction between positively and negatively charged surfaces of p-nitrophenyl and 5-NMe2-resorcinol rings, respectively. It is notable that, contrary to previous reports on the synthesis of UCs bearing larger 26-membered macrorings, the employment of hydrochloride salts of α,ω-diamines instead of free amines had no effect improving the macrocyclization yield. The 20-membered macroring may plausibly be too small to accommodate the templating chloride anion that is released under the reaction conditions. This assumption is supported by DFT calculations (B3LYP-D3/146-31G(d)/C-PCM-MeOH) which suggest that chloride is bound outside the macrocyclic cavity for both pseudocyclic intermediate and final cyclized product (see the SI for details). Nevertheless, for this class of macrocyclic host systems, the low yield of the macrocyclization step is mainly related to the compact conformation of the macrocyclic structures, and this is clearly exemplified by the crystal structures of UCs 18, 20, and 23 (Figure 1). The first UC 18 bearing an electron-donating OMe group on the resorcinol fragment crystallized as a methanol solvate in a P21/n space group. The host molecule adopts an S-type conformation with the benzyl arm directed out of the macroring. One NH amide proton is directed toward the macrocyclic cavity, while the carbonyl oxygen atom is engaged in a strong and directional interaction with a methanol molecule (dO···HO = 2.77 Å, ∠NHO = 174°). The remaining NH amide proton is directed outside and is engaged in a weak hydrogen bonding interaction with a carbonyl oxygen atom from the adjacent host molecule (dNH···O = 2.92 Å, ∠NHO = 168°). On the other hand, the host molecules 20 and 23 terminating with −OMe and −NMe2 groups, respectively, form isostructural crystals (P-1 space group) with the 1,3-dichlorobenzylic arm directed toward the interior of the macrocyclic cavity. Both host molecules adopt a C-shaped conformation with both amide NH protons directed inside the macroring. Such an orientation of amide groups facilitates the formation of intramolecular hydrogen bonds with

This obviously could be attributed to steric hindrance generated by the bulky intraannular substituent (lariat arm), which hampers the final cyclization of the linear intermediate obtained after a first amide bond is formed. To circumvent this problem, we selected UCs bearing a relatively small benzyl group which could be readily functionalized after near quantitative deprotection (the “indirect” method). This not only helps to significantly improve the efficiency of the UCs’ preparation but also paves the way to a novel, comprehensive method for the late-stage functionalization of the sterically demanding macrocycles at an intraannular position. Herein, we demonstrate and discuss two approaches (the “direct” and “indirect” approach) to the synthesis of a broad library of sterically demanding UCs. Note that the proposed “indirect” method proceeds through a late-stage benzyl deprotection and thus allows for the highly efficient introduction of various benzylic substituents after an unfavorable macrocyclization step. As is shown in Table 1, the preparation of 20-membered UCs, irrespective of the synthetic route, is initiated from the preparation of suitable α,ω-diesters 4−6 and α,ω-diamines 12−14 (see Schemes S1 and S2). Briefly, diesters 4−6 were readily prepared from inexpensive 1,2,3-trihydroxybenzene (pyrogallol) via consecutive O-alkylation at the 2- and 1,3positions by a suitable benzyl bromide and methyl bromoacetate, respectively (Scheme S1). Consecutively, double Oalkylation of either resorcinol or phloroglucinols 7 and 8 at 1,3-positions by chloroacetonitrile afforded dinitriles 7, 10, and 11 in good yields. The nitrile function was subsequently reduced by a Me2S−BH3 complex in refluxing THF to deliver the diamines 4−6 in near-quantitative yields (Scheme S2). Having all of the required partners for the macrocyclization in hand, we attempted to synthesize the target 20-membered UCs by employing the classical methodology, relying on MeONamediated double amidation in methanol at rt (Table 1). The data presented in Table 1 demonstrate that the target macrocyclic products were obtained in relatively low yields (11−37%), irrespective of the electronic properties of the diamine substrate. In addition, the correlation between bulkiness of the lariat arm and the cyclization yield is not trivial. 13561

DOI: 10.1021/acs.joc.8b02160 J. Org. Chem. 2018, 83, 13560−13567

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Table 2. Synthesis of Macrocycles 15−23 via Postfunctionalization of the Lariat Arm under PTC Conditions (Indirect Approach)

Figure 1. Front (left) and side (right) views of the crystal structures of UCs 18 (a), 20 (b), and 23 (c). Nonacidic protons and solvent molecules omitted for clarity.

entry

phenol

aryl bromide

UC

yield (%)

1 2 3 4 5 6 7 8 9

24 25 26 24 25 26 24 25 26

Ph Ph Ph p-C6H4NO2 p-C6H4NO2 p-C6H4NO2 2,6-C6H4Cl2 2,6-C6H4Cl2 2,6-C6H4Cl2

15 16 17 18 19 20 21 22 23

98 99 98 95 72 86 89 99 72

Scheme 2. Synthesis of UC 27 Bearing a Crowded Acetylopyrene Lariat Arm

neighboring oxygen ether atoms, forcing the flat conformation of the macrocyclic entities (dNH···O = 2.59−2.64 Å). In addition, efficiency of packing UCs 18, 20, and 23 in the crystal lattice is much higher than the mean value for organic molecules (CPk = 0.80−0.81 vs 0.68−0.75),11 which exemplifies a pronounced steric hindrance in these macrocyclic systems. To evaluate the applicability of the indirect approach as a synthetic protocol for the late-stage introduction of the lariat arm, we first attempted to unlock the phenolic function by a detachment of the lariat arm in UCs 15, 18, and 21. We selected an O-benzyl protection group, among others, since it could be easily removable under very mild conditions. The required macrocyclic phenols 24−26 were readily obtained via Pd/C catalyzed reductive cleavage of benzyl protection by H2 (1 atm) in near-quantitative yields (98−99%). Subsequently, the released phenol group was O-alkylated by the corresponding benzyl bromides in a biphasic H2O/CH2Cl2 solvent mixture using a tetrabutylammonium bromide (TBAB) as a phasetransfer catalyst. The yield are generally very high, confirming the potential of this approach (Table 2). Only in two cases (Table 2, entries 5 and 9) was the yield considerably lower, albeit still very good. The established path proceeded irrespective of the size of the moiety that plays the role of the lariat arm, as an electron-rich substituent. To verify whether the indirect approach is a suitable method for the preparation of UCs bearing a bulkier lariat arm, we synthesized UC 27 bearing the 1-O-acetylpyrene moiety. Contrary to the direct approach, which gives only traces of product, we were able to isolate the anticipated macrocyclic product in a good 63% yield (Scheme 2). To further evaluate the indirect protocol, we attempted to synthesize the even more structurally demanding pincer-type UCs 29 and 30 in which two macrocyclic skeletons are joined by 1,4-but-2-ene and p-xylene linkers, respectively. Such C2symmetric structures are most likely inaccessible by a classical direct approach due to the overformation of polymeric side products. First, the macrocyclic phenol 25 was reacted with allyl bromide under PTC conditions to give the O-allyl-terminated

UC 28 in high yield (95%). Attempts to couple these molecules using Grubbs (first and second generation), Hoveyda−Grubbs (first and second generation), as well as Grela catalysts, however, did not provide the anticipated pincer-type product UC 29 (Scheme 3a). Scheme 3. Attempts To Synthesize Pincer-Type UC 29 via Alkene Metathesis (a) and the Crystal Structure of UC 28 (b)

Extensive self-aggregation of UCs 28 probably prevents the access of the metal complex to an alkene tether, as deduced from the corresponding X-ray structure (Scheme 3b). Nevertheless, employing a larger p-xylene linker and conducting the coupling under PTC conditions provided a pincer-type product 30 in a moderate (53%) to a very high (93%) yield, depending on the base and the solvent used 13562

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coupling constants values are reported in Hz. Melting points are uncorrected. High-resolution mass spectra (HRMS) were recorded using ESI-TOF technique on a Mariner mass spectrometer from PerSeptive Biosystem. Elemental analyses were obtained on the PerkinElmer 240 elemental analyzer. The structures of chloride complexes were calculated at DFT/B3LYP-D3/6-31G(d)/C-PCMMeOH level of theory using program Spartan’16 Parallel Suite.15 The crystals suitable for the X-ray measurements were obtained by the slow diffusion of pentane into corresponding methanolic solution of UCs 18, 20, 23, 28, and 30. The crystal packing coefficients (CPk) were calculated using formula 112b,d

(Scheme 4a). The structure of UC 30 was unambiguously confirmed by the X-ray structure analysis (Scheme 4b). Scheme 4. Synthesis of Pincer-Type C2h-Symmetric Dimer UC 30 (a) and Its X-ray Structure (b, c)

CPk = Z · Vmol· Vcell −1

where Z is the number of molecules in the unit cell, Vcell is the volume of the cell taken from the X-ray structure, and Vmol is the volume of the molecule calculated at the DFT/B3LYP-D3/6-31G(d) level of theory using constrained positions of heavy atoms. 5-Methoxyresorcinol 8 is commercially available, compounds 1 and 4 were prepared as previously described,16 and N,N-dimethylresorcinol 9 was prepared by the reaction of phloroglucinol with an aqueous solution of dimethylamine in DMF in 69% yield. The α,ω-diesters 5 and 6 and α,ω-diamines 12−14 were prepared as described in Schemes S1 and S2, respectively. General Procedure A for Obtaining 2-O-Benzylated Pyrogallols 1−3. To a suspension of NaH (26.4 g, 1.1 mol) in anhydrous DMF (400 mL) was slowly added dropwise a solution of pyrogallol (141.5 g, 1.1 mol) in anhydrous DMF (500 mL), keeping the temperature between −10 and −5 °C. The mixture was stirred continuously for 0.5 h, and the corresponding benzyl halide (1.1 mol) was carefully added at t = 0−5 °C. The reaction mixture was stirred for 48 h at rt, and the solvent was evaporated under vacuum to yeild a residue which was diluted with 0.2 M aqueous of HCl (1.2 L) and extracted successively with EA (3 × 0.5 L). The combined organic phases were dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to yield a dark brown oily residue which was purified by silica gel chromatography using gradient of EA in hexanes (5:95 → 1:9, v/v) as eluent. General Procedure B for Obtaining α,ω-Diesters 5 and 6. To the solution of the corresponding 2-O-benzyl-functionalized pyrogallol 2 or 3 (0.4 mol) in anhydrous DMF (1.2 L) was added finely powdered anhydrous K2CO3 (226.0 g, 1.6 mol). After 15 min of stirring, methyl bromoacetate (92.0 mL, 1.0 mol) was slowly added dropwise, and the suspension was heated at 80 °C for 24 h. The inorganic salts were filtered through a plug of Celite, and the solvent was removed under reduced pressure to yield a solid residue which was purified by silica gel chromatography using a gradient of EA in hexanes (5:95 → 1:9, v/v) as eluent. General Procedure C for Obtaining Macrocyclic Compounds 15−23 by Employing a Classical Approach. To a solution of corresponding α,ω-diester 4−6 (10 mmol) and α,ω-diamine 12−14 (10 mmol) in methanol (0.3 L) was added a solution of MeONa (30 mmol) in methanol (0.1 L). The starting material (α,ω-diester) was consumed within 2−7 days as indicated by TLC analysis (MeOH in DCM, 5:95 v/v). Afterward, the solvent was removed under reduced pressure to yield a solid residue which was purified by silica gel chromatography with 100% EA as eluent. General Procedure D for Obtaining Macrocyclic Compounds 15−23, 27, 28, and 30 by Employing the Indirect Approach. The macrocyclic phenol (1.2 mmol) and the corresponding halide (1.4 mmol) in DCM (7 mL) were added to the 2 M aqueous solution of NaOH (3 mL). Subsequently, the PTC catalyst (0.12 mmol, TBAHS or TBAB) was added, and the heterogeneous mixture was vigorously stirred at rt for 1−24 h. After consumption of the starting material (macrocyclic phenol), the organic layer was separated and aqueous layer was extracted successively with DCM (3 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to yield a solid residue which was purified by silica gel chromatography using 100% EA as eluent. General Procedure E for Obtaining Macrocyclic Receptors 24−26. To the solution of 2-O-benzylated macrocycle (10 mmol) in

The solid-state structure reveals that the p-xylene linker is arranged in a Z-shaped conformation forming a C2h-symmetric structure. The pincer-type UCs 30 are involved in multiple π−π interactions between resorcinol···pyrogallol (d = 4.02 Å) and resorcinol···xylene (d = 3.75 Å) rings, respectively, thus forming an infinite 1D tape (Scheme 4c).

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CONCLUSION In conclusion, we discussed two synthetic approaches toward sterically hindered 20-membered Unclosed Cryptands with varying bulkiness of the lariat arm. We demonstrated that a novel “indirect” approach, relying on the consecutive reductive cleavage and PTC-mediated O-alkylation of the intraannular position of benzyl-protected UCs 15, 18, and 21, enables latestage introduction of various benzylic substituents after an unfavorable macrocyclization step (11 examples, yields up to 98%). In contrast, despite the shorter synthetic protocol, the employment of the classical, “direct” approach, which requires prefunctionalization of the lariat arm at the beginning of synthesis, was shown to be less effective or even impractical for UCs bearing particularly bulky lariat arms. The superiority of the indirect approach is exemplified by the straightforward preparation of crowded UC 27 derivatized with a 1-acetylpyrene substituent and UC 30, a dimer joined by the p-xylene linker.

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(1)

EXPERIMENTAL SECTION

Materials and Methods. All of the reagents were used as received. The solvents were dried by distillation over the appropriate drying agents. All reactions were performed avoiding moisture by standard procedures and under a nitrogen atmosphere. Flash column chromatography was performed on silica gel (230−400 mesh), thinlayer chromatography (TLC) was carried out on aluminum sheets precoated with silica gel. 1H NMR and 13C{1H} NMR spectra were recorded on Bruker Mercury 500 and 400 MHz spectrometers. Proton and carbon chemical shifts are reported in ppm (δ) (CDCl3: 1H NMR δ = 7.26 and 13C NMR δ = 77.26; DMSO-d6: 1H NMR δ = 2.50 and 13C NMR δ = 39.52). NMR spectra were processed using MestreNova. J 13563

DOI: 10.1021/acs.joc.8b02160 J. Org. Chem. 2018, 83, 13560−13567

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(mp 103−104 °C). 1H NMR (400 MHz, DMSO-d6): δ 7.36 (t, J = 8.4 Hz, 1H), 6.82−6.75 (m, 3H), 5.18 (s, 4H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 157.5, 130.6, 116.4, 108.6, 102.5, 53.5. HRMS (ESI, MeOH): m/z calcd for C10H8N2O2Na [M + Na]+ 211.0483, found 211.0474. Anal. Calcd for C10H8N2O2: C, 63.83; H, 4.28; N, 14.89. Found: C, 63.92; H, 4.50; N, 14.83. 3,5-Dihydroxy-N,N-(dimethylamino)benzene (9). To the solution of phloroglucinol (99.3 g, 0.77 mol) in a mixture of DMF (1.0 L) and water (0.45 L) was added a 3 M aqueous solution (0.20 L) of dimethylamine (0.6 mol). The mixture was stirred for 24 h. Subsequently, a 3 M aqueous solution (50 mL, 0.15 mol) of dimethylamine was added. The mixture was stirred for 24 h. The crude product was recrystallized from chloroform to yield product (85.0 g, 71%) as light pink crystals (mp 117−119 °C). 1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 2H), 5.60 (s, 3H), 2.78 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 158.7, 152.30, 94.1, 92.0, 91.5. HRMS (ESI, MeOH): m/z calcd for C8H12NO2 [M + H]+ 154.0863, found: 154.0864. 3,5-Bis(cyanomethylenoxy)methoxybenzene (10). Following general procedure F, the product (60.2 g, 69%) was obtained as yellowish crystals (mp 98−99 °C). 1H NMR (400 MHz, DMSO-d6): δ 6.43−6.34 (m, 3H), 5.16 (s, 4H), 3.76 (s, 3H). 13C{1H} NMR (100 MHz, DMSOd6): δ 161.4, 158.2, 116.4, 95.3, 94.8, 55.6, 53.6. HRMS (ESI, MeOH): m/z calcd for C11H10N2O3Na [M + Na]+ 241.0584, found 241.0596. 3,5-Bis(cyanomethylenoxy)-N,N-(dimethylamino)benzene (11). Following general procedure F, the product (55.5 g, 60%) was obtained as yellowish crystals (mp 82−83 °C). 1H NMR (400 MHz, DMSO-d6): δ 6.10 (t, J = 1.9 Hz, 1H), 6.06 (d, J = 2.0 Hz, 2H), 5.13 (s, 4H), 2.91 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 158.2, 152.3, 116.6, 93.3, 90.1, 53.4, 39.9. HRMS (ESI, MeOH): m/z calcd for C12H13N3O2Na [M + Na]+ 254.0905, found: 254.0918. Macrocyclic Compound 15. Following general procedure C, the product (1.8 g, 37%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 117−118 °C). Following general procedure D, the product (0.58 g, 98%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.63 (dd, J = 6.4, 4.9 Hz, 2H), 7.45 (dd, J = 7.7, 1.6 Hz, 2H), 7.37−7.31 (m, 3H), 7.13 (t, J = 8.2 Hz, 1H), 6.59−6.50 (m, 3H), 6.47 (dd, J = 8, 2 Hz, 2H), 6.04 (t, J = 2.3 Hz, 1H), 5.03 (s, 2H), 4.59 (dAB, J = 15.0 Hz, 2H), 4.39 (dAB, J = 15.0 Hz, 2H), 4.01−3.94 (m, 2H), 3.88−3.80 (m, 2H), 3.67−3.57 (m, 2H), 3.32−3.25 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 167.9, 159.5, 151.7, 137.4, 137.1, 129.7, 128.7, 128.1, 127.9, 123.7, 108.1, 106.7, 104.4, 74.8, 68.6, 66.6, 38.0. HRMS (ESI, MeOH): m/z calcd for C27H28N2O7Na [M + Na]+ 515.1794, found 515.1770. Anal. Calcd for C27H28N2O7: C, 65.84; H, 5.73; N, 5.69. Found: C, 65.84; H, 5.84; N, 5.61. Macrocyclic Compound 16. Following general procedure C, the product (1.2 g, 23%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 127−128 °C). Following general procedure D, the product (0.45 g, 69%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.46 (bm, 2H), 7.38 (m, 2H), 7.32 (m, 3H), 6.95 (t, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H), 5.86 (t, J = 2.1 Hz, 1H), 5.81 (d, J = 2.1 Hz, 2H), 4.99 (s, 2H), 4.51 (dAB, J = 15.0 Hz, 2H), 4.40 (dAB, J = 15.0 Hz, 2H), 4.05−4.00 (m, 2H), 3.98−3.94 (m, 2H), 3.93−3.87 (m, 2H), 3.40−3.33 (m, 2H), 2.89 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.1, 160.4, 152.5, 152.3, 138.1, 136.6, 129.4, 128.6, 128.4, 124.8, 108.9, 94.5, 92.6, 76.6, 69.2, 67.0, 40.6, 38.38, 38.36. HRMS (ESI, MeOH): m/z calcd for C27H27N3O9Na [M + Na]+ 560.1645, found 560.1632. Anal. Calcd for C27H27N3O9: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.17; H, 5.13; N, 7.68. Macrocyclic Compound 17. Following general procedure C, the product (0.8 g, 15%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 174−176 °C). Following general procedure D, the product (0.64 g, 95%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.57 (bd, J = 6.1 Hz, 2H), 7.31 (d, J = 8 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H),

methanol (100 mL) was added 10% Pd/C. The suspension was stirred under hydrogen atmosphere, and the reaction progress was monitored using TLC. After 24 h, a 1 M methanolic solution of NaOH (20 mL) was added, and stirring was carried out for 3 h. Subsequently, the catalyst was filtered off, and the solvent was evaporated under vacuum. The solid was dissolved in water (50 mL), and 10 mL of hydrochloric acid was added until pH 5−6. After 30 min of stirring, the resulting precipitate was filtered, washed with cold water, and recrystallized from methanol. General Procedure F for Obtaining α,ω-Dinitriles 7, 10, and 11. To a solution of resorcinol (0.4 mol) in 1000 mL of acetone was added finely powdered anhydrous K2CO3 (165.8 g, 1.2 mol). Then potassium iodide (6.6 g, 40 mmol) and chloroacetonitrile (151.0 g, 2.0 mol) were added. The suspension was refluxed for 24 h. After the inorganic salts were cooled and filteed, the solvent was evaporated in vacuo. The residue was recrystallized from ethanol. General Procedure G for Obtaining α,ω-Diaminoethers 12− 14. To the solution of α,ω-dinitrile 7, 10, or 11 (110 mmol) in 250 mL of anhydrous THF was carefully added dropwise the BH3−Me2S (BMS) complex (41.7 mL, 440 mmol). The mixture was then refluxed for 3 h under argon. Subsequently, after cooling, 20 mL of methanol was added with caution. Then 120 mL of 2 M hydrochloric acid in methanol was added. The mixture was then refluxed for 3 h. Subsequently, the solvents were evaporated under vacuum, and the residue was neutralized with a saturated aqueous solution of K2CO3 (500 mL) and extracted three times with DCM (3 × 200 mL). The combined organic phases were dried over anhydrous MgSO4. The solvent was evaporated under vacuum, and the target diamine was used in the subsequent macrocyclization step without further purification. For later use, the product was stored at 0 °C under argon atmosphere. 2-(4-Nitrobenzyloxy)benzene-1,3-diol (2). Following general procedure A and using 4-nitrobenzyl chloride, the product (188.1 g, 65%) was obtained as a yellowish waxy solid. 1H NMR (400 MHz, DMSOd6): δ 9.05 (s, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.67 (t, J = 8.1 Hz, 1H), 6.31 (d, J = 8.1 Hz, 2H), 4.91 (s, 2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 151.0, 137.7, 134.2, 130.8, 130.2, 123.5, 120.6, 107.4, 72.3. HRMS (ESI, MeOH): m/z calcd for C13H11NO5Na [M + Na]+ 284.0535, found: 284.0524. 2-(2,6-Dichlorobenzyloxy)benzene-1,3-diol (3). Following general procedure A and using 2,6-dichlorobenzyl chloride, the product (146.8 g, 47%) was obtained as colorless waxy solid. 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 2H), 7.48−7.43 (m, 2H), 7.36 (dd, J = 8.8, 7.1 Hz, 1H), 6.65 (t, J = 8.1 Hz, 1H), 6.28 (d, J = 8.1 Hz, 2H), 5.26 (s, 2H). 13 C{1H} NMR (100 MHz, DMSO-d6): δ 151.0, 136.5, 134.3, 133.1, 130.8, 128.4, 123.4, 107.3, 68.1. HRMS (ESI, MeOH): m/z calcd for C13H10Cl2O3Na [M + Na]+: 306.9905 (monoisotopic mass), found: 306.9891. Anal. Calcd for C13H10Cl2O3: C 54.76, H 3.54, Cl 24.87, found: C 54.98, H 3.79, Cl 24.57. Dimethyl 2,2′-((2-(4-nitrobenzyloxy)-1,3-phenylene)-bisoxy-diacetate (5). Following general procedure B, the product (139.4 g, 86%) was obtained as yellowish waxy solid. 1H NMR (400 MHz, DMSO-d6): δ 7.55 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.94 (t, J = 8.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 2H), 4.99 (s, 2H), 4.80 (s, 4H), 3.71 (s, 6H). 13 C{1H} NMR (100 MHz, DMSO-d6): δ 169.1, 151.7, 137.2, 136.7, 130.9, 130.3, 123.6, 120.8, 107.1, 73.2, 65.3, 51.8. HRMS (ESI, MeOH): m/z calcd for C19H19NO9Na [M + Na]+ 428.0952, found 428.0947. Dimethyl 2,2′-((2-(2,6-Dichlorobenzyloxy)-1,3-phenylene)bis(oxy))diacetate (6). Following general procedure B, the product (90.7 g, 53%) was obtained as colorless waxy solid. 1H NMR (400 MHz, DMSO-d6): δ 7.48−7.43 (m, 2H), 7.37 (dd, J = 9.0, 6.9 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.30 (s, 2H), 4.69 (s, 4H), 3.68 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 169.0, 151.9, 136.8, 136.5, 132.6, 130.9, 128.3, 123.8, 107.4, 68.5, 65.5, 51.7. HRMS (ESI, MeOH): m/z [M + Na]+ calcd for C19H18Cl2O7Na [M + Na]+ 451.0327 (monoisotopic mass), found 451.0314. Anal. Calcd for C19H18Cl2O7·(H2O)0.5: C, 52.07; H, 4.37; Cl, 16.18. Found: C, 52.32; H, 4.33; Cl, 16.23. 1,3-Bis(cyanomethylenoxy)benzene (7). Following general procedure F, the product (64.6 g, 86%) was obtained as yellowish crystals 13564

DOI: 10.1021/acs.joc.8b02160 J. Org. Chem. 2018, 83, 13560−13567

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The Journal of Organic Chemistry

Macrocyclic Compound 22. Following general procedure C, the product (1.6 g, 27%) was obtained after recrystallization from a methanol/pentane mixture as yellowish crystals (mp 136−139 °C). Following general procedure D, the product (0.50 g, 72%) was obtained after recrystallization from a methanol/pentane mixture as yellowish crystals. 1H NMR (400 MHz, DMSO-d6): δ 8.14 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.35 (bm, 2H), 7.0 (t, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 5.87 (t, J = 2.1 Hz, 1H), 5.8 (d, J = 2.1 Hz, 2H), 5.06 (s, 2H), 4.59 (dAB, J = 15.1 Hz, 2H), 4.49 (dAB, J = 15.1 Hz, 2H), 4.09−4.04 (m, 2H), 4.02−3.96 (m, 2H), 3.91−3.83 (m, 2H), 3.46−3.39 (m, 2H), 2.91 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 167.6, 160.1, 152.3, 151.6, 147.5, 143.5, 137.5, 128.9, 124.9, 123.2, 108.3, 94.9, 92.3, 74.7, 68.7, 67.1, 40.2, 38.2. HRMS (ESI, MeOH): m/z calcd for C29H32N4O9Na [M + Na]+ 603.2067, found 603.2055. Anal. Calcd for C29H32N4O9: C, 59.99; H, 5.56; N, 9.65. Found: C, 59.70; H, 5.63; N, 9.58. Macrocyclic Compound 23. Following general procedure C the product (1.3 g, 21%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 193−194 °C). Following general procedure D, the product (0.62 g, 86%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.57 (dd, J = 7.4, 3.6 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.37 (dd, J = 8.7, 7.4 Hz, 1H), 6.83 (t, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 2H), 5.78 (d, J = 2.0 Hz, 2H), 5.64 (t, J = 1.9 Hz, 1H), 5.32 (s, 2H), 4.43 (dAB, J = 15.2 Hz, 4H), 4.05−3.99 (m, 2H), 3.87−3.80 (m, 2H), 3.72−3.64 (m, 2H), 3.28−3.21 (m, 2H), 2.82 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 167.7, 160.3, 152.2, 152.1, 137.0, 132.1, 130.3, 128.1, 124.8, 107.9, 94.5, 92.1, 69.3, 68.6, 66.9, 40.3, 38.0. HRMS (ESI, MeOH): m/z calcd for C29H31N3O7Cl2Na [M + Na]+ 626.1437 (monoisotopic mass), found 626.1452. Anal. Calcd for C30H33N3O7Cl4 (C29H31N3O7Cl2·CH2Cl2): C, 57.62; H, 5.17; N, 6.95; Cl, 11.73. Found: C, 57.49; H, 5.07; N, 6.85; Cl, 11.63. Macrocyclic Compound 24. Following general procedure E, the product (3.9 g, 9.8 mmol, 98%) was obtained as a colorless amorphous powder. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.32 (t, J = 5.7 Hz, 2H), 7.06 (t, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.71−6.64 (m, 3H), 6.41 (dd, J = 8.2, 2.2 Hz, 2H), 4.41 (s, 4H), 4.04 (t, J = 4.8 Hz, 4H), 3.56 (dd, J = 10.0, 5.0 Hz, 4H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.0, 160.0, 146.7, 136.9, 129.6, 118.8, 109.9, 107.4, 103.8, 69.5, 67.0, 38.1. HRMS (ESI, MeOH): m/z calcd for C20H22N2O7Na [M + Na]+ 425.1325, found 425.1312. Anal. Calcd for C20H22N2O7: C, 59.70; H, 5.51; N, 6.96. Found: C, 58.14; H, 5.52; N, 6.79. Macrocyclic Compound 25. Following general procedure E, the product (4.3 g, 99%) was obtained as a colorless amorphous powder. 1 H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.32 (t, J = 5.7 Hz, 2H), 7.06 (t, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.71−6.64 (m, 3H), 6.41 (dd, J = 8.2, 2.2 Hz, 2H), 4.41 (s, 4H), 4.04 (t, J = 4.8 Hz, 4H), 3.56 (dd, J = 10.0, 5.0 Hz, 4H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.0, 160.0, 146.7, 136.9, 129.6, 118.8, 109.9, 107.4, 103.8, 69.5, 67.0, 38.1. HRMS (ESI, MeOH): m/z calcd for C21H24N2O8Na [M + Na]+ 455.1430, found 455.1445. Anal. Calcd for C21H24N2O8·(CH3OH)0.5: C, 57.58; H, 5.84; N, 6.25. Found: C, 57.55; H, 5.82; N, 6.31. Macrocyclic Compound 26. Following general procedure E, the product (4.4 g, 98%) was obtained as a colorless amorphous powder. 1 H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.47 (bs, 2H), 6.73 (s, 3H), 6.19 (s, 1H), 5.77 (s, 2H), 4.46 (s, 4H), 4.06 (t, J = 4.4 Hz, 4H), 3.58 (m, 4H), 2.86 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.9, 161.2, 147.5, 137.8, 119.6, 110.9, 107.8, 103.4, 93.5, 70.4, 67.4, 41.7, 39.1. HRMS (ESI, MeOH): m/z calcd for C22H28N3O7 [M + H]+ 446.1922, found 446.1938. Macrocyclic Compound 27. Following general procedure D, the product (0.15 g, 63%) was obtained as a yellowish crystalline powder (mp 105−106 °C). 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J = 9.4 Hz, 1H), 8.28 (dd, J = 11.1, 4.6 Hz, 3H), 8.25−8.15 (m, 3H), 8.14−8.07 (m, 2H), 7.82 (d, J = 4.0 Hz, 2H), 7.05 (t, J = 8.2 Hz, 1H), 6.91 (t, J = 8.4 Hz, 1H), 6.69 (t, J = 2.3 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 6.41 (dd, J = 8.2, 2.3 Hz, 2H), 5.47 (s, 2H), 4.63 (dAB, J = 15.2 Hz, 2H), 4.44 (dAB, J = 15.2 Hz, 2H), 4.22 (m, 2H), 4.09−3.94 (m, 4H), 3.40 (m, 2H). 13 C{1H} NMR (100 MHz, CDCl3): δ 198.4, 168.2, 160.0, 151.7, 138.4,

6.91 (t, J = 8.2 Hz, 1H), 6.49 (d, J = 8.4 Hz, 2H), 6.41 (dd, J = 8.2 Hz, 2.4 Hz, 2H), 6.35 (t, J = 2.3 Hz, 1H), 5.41 (s, 2H), 4.53 (dAB, J = 15.1 Hz, 2H), 4.40 (dAB, J = 15.1 Hz, 2H), 4.18−4.15 (m, 2H), 4.06−3.98 (m, 2H), 3.88−3.81 (m, 2H), 3.44−3.35 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 167.6, 159.5, 152.2, 137.1, 136.8, 132.1, 130.3, 129.6, 128.1, 124.7, 107.6, 106.5, 106.4, 69.3, 68.4, 67.3, 37.8. HRMS (ESI, MeOH): m/z calcd for C27H26N2O7Cl2Na [M + Na]+ 583.1015, found 583.0998. Anal. Calcd for C27H26N2O7Cl2: C, 57.76; H, 4.67; N, 4.99. Found: C, 58.01; H, 4.70; N, 4.92. Macrocyclic Compound 18. Following general procedure C, the product (0.9 g, 18%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 117−118 °C). Following general procedure D, the product (0.62 g, 99%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.45−7.33 (m, 7H), 6.93 (t, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 6.0 (m, 3H), 5.0 (s, 2H), 4.53 (dAB, J = 15.1 Hz, 2H), 4.40 (dAB, J = 15.1 Hz, 2H), 4.03−3.97 (m, 2H), 3.95−3.86 (m, 4H), 3.73 (s, 3H), 3.40−3.30 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.1, 161.6, 160.3, 152.2, 138.1, 136.6, 129.3, 128.6, 128.5, 124.8, 108.8, 98.4, 93.9, 76.7, 69.1, 67.1, 55.4, 38.1. HRMS (ESI, MeOH): m/z calcd for C28H30N2O8Na [M + Na]+ 545.1900, found 545.1912. Anal. Calcd for C28H30N2O8: C, 64.36; H, 5.79; N, 5.79. Found: C, 64.43; H, 5.98; N, 5.42. Macrocyclic Compound 19. Following general procedure C, the product (0.6 g, 11%) was obtained after recrystallization from a methanol/pentane mixture as yellowish crystals (mp 131−133 °C). Following general procedure D, the product (0.49 g, 72%) was obtained after recrystallization from a methanol/pentane mixture as yellowish crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.46 (bm, 2H), 7.38 (m, 2H), 7.32 (m, 3H), 6.95 (t, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H), 5.86 (t, J = 2.1 Hz, 1H), 5.81 (d, J = 2.1 Hz, 2H), 4.99 (s, 2H), 4.51 (dAB, J = 15.0 Hz, 2H), 4.40 (dAB, J = 15.0 Hz, 2H), 4.05−4.00 (m, 2H), 3.98−3.94 (m, 2H), 3.93−3.87 (m, 2H), 3.40−3.33 (m, 2H), 2.89 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.1, 160.4, 152.5, 152.3, 138.1, 136.6, 129.4, 128.6, 128.4, 124.8, 108.9, 94.5, 92.6, 76.6, 69.2, 67.0, 40.6, 38.4. HRMS (ESI, MeOH): m/z calcd for C28H29N3O10Na [M + Na]+ 590.1751, found 590.1745. Anal. Calcd for C28H29N3O10: C, 59.26; H, 5.15; N, 7.40. Found: C, 58.88; H, 5.30; N, 7.37. Macrocyclic Compound 20. Following general procedure C, the product (2.0 g, 34%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 205−207 °C). Following general procedure D, the product (0.59 g, 85%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.54 (bm, 2H), 7.31 (d, J = 8 Hz, 2H), 7.19 (t, J = 8.5 Hz, 2H), 6.94 (t, J = 8.4 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.97 (m, 3H), 5.41 (s, 2H), 4.52 (dAB, J = 15.1 Hz, 2H), 4.40 (dAB, J = 15.1 Hz, 2H), 4.13−4.05 (m, 2H), 4.03−3.97 (m, 2H), 3.89−3.82 (m, 2H), 3.72 (s, 3H), 3.44−3.35 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 167.6, 161.2, 160.1, 152.2, 137.0, 136.9, 132.1, 130.4, 128.1, 124.8, 98.6, 93.4, 69.3, 68.5, 67.2, 55.1, 37.8. HRMS (ESI, MeOH): m/z calcd for C28H28N2O8Cl2Na [M + Na]+ 613.1120, found 613.1130. Anal. Calcd for C28H28N2O8Cl2: C, 56.86; H, 4.77; N, 4.74. Found: C, 56.90; H, 4.79; N, 4.63. Macrocyclic Compound 21. Following general procedure C, the product (1.4 g, 26%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 104−107 °C). Following general procedure D, the product (0.63 g, 98%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.46 (bm, 2H), 7.38 (m, 2H), 7.32 (m, 3H), 6.95 (t, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H), 5.86 (t, J = 2.1 Hz, 1H), 5.81 (d, J = 2.1 Hz, 2H), 4.99 (s, 2H), 4.51 (dAB, J = 15.0 Hz, 2H), 4.40 (dAB, J = 15.0 Hz, 2H), 4.05−4.00 (m, 2H), 3.98−3.94 (m, 2H), 3.93−3.87 (m, 2H), 3.40−3.33 (m, 2H), 2.89 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.1, 160.4, 152.5, 152.3, 138.1, 136.6, 129.4, 128.6, 128.4, 124.8, 108.9, 94.5, 92.6, 76.6, 69.2, 67.0, 40.6, 38.4. HRMS (ESI, MeOH): m/z calcd for C29H33N3O7Na [M + Na]+ 558.2216, found 558.2200. Anal. Calcd for C29H33N3O7: C, 65.03; H, 6.21; N, 7.81. Found: C, 65.03; H, 6.40; N, 7.63. 13565

DOI: 10.1021/acs.joc.8b02160 J. Org. Chem. 2018, 83, 13560−13567

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134.5, 131.0, 130.5, 130.3, 130.2, 130.2, 129.9, 128.7, 128.6, 127.3, 127.0, 126.8, 126.7, 126.5, 126.1, 125.1, 125.0, 124.4, 124.1, 124.0, 108.4, 107.1, 106.0, 77.5, 77.4, 77.0, 76.7, 69.1, 67.3, 38.6. HRMS (ESI, MeOH): m/z calcd for C38H32N2O8Na [M + Na]+ 667.2056, found 667.2051. Anal. Calcd for C38H32N2O8·(H2O)1.5: C, 67.95; H, 5.25; N, 4.18. Found: C, 68.39; H, 5.20; N, 4.23. Results of the elemental as well as HPLC analysis (Figure S27, column: Bionacom Velocity C18-2, i.d. 4.6 × 250 mm, 5 μm, elution: MeOH−H2O (1:1 v/v), time: 30 min, flow: 1 mL/min) indicate high purity (≥95%) of the compound. Therefore, some small peaks that are visible in the aromatic region of the 1H NMR spectrum are attributed to the slow interconversion between atropisomers of the macrocycle in the solvent studied (CDCl3). Macrocyclic Compound 28. Following general procedure D, the product (0.63 g, 98%) was obtained as orange crystals (mp 151−152 °C). 1H NMR (500 MHz, DMSO-d6): δ 7.72 (t, J = 5.5 Hz, 2H), 6.75− 6.70 (m, 1H), 6.63 (d, J = 8.3 Hz, 2H), 6.07−5.97 (m, 1H), 5.83 (d, J = 1.9 Hz, 2H), 5.67 (s, 1H), 5.28 (dd, J = 17.2, 1.4 Hz, 1H), 5.15 (d, J = 10.4 Hz, 1H), 4.60 (dAB, J = 15.0 Hz, 2H), 4.45 (s, 2H), 4.44 (dAB, J = 15.0 Hz, 2H), 4.03−3.97 (m, 2H), 3.93−3.85 (m, 2H), 3.62−3.54 (m, 2H), 3.37−3.32 (m, 2H), 2.84 (s, 6H). 13C {1H} NMR (125 MHz, DMSO-d6): δ 167.9, 160.2, 152.2, 151.7, 137.2, 134.6, 123.9, 117.9, 108.6, 92.9, 92.4, 74.0, 68.7, 66.5, 40.2, 38.1. HRMS (ESI, MeOH): m/ z calcd for C25H32N3O7 [M + H]+ 486.2240, found 486.2241. Macrocyclic Compound 30. Following general procedure D, the product (0.55 g, 51%) was obtained after recrystallization from a methanol/pentane mixture as colorless crystals (mp 203−204 °C). 1H NMR (400 MHz, DMSO-d6): δ 7.67 (t, J = 5.2 Hz, 4H), 7.42 (s, 4H), 7.13 (t, J = 8.2 Hz, 2H), 6.57−6.49 (m, 6H), 6.46 (dd, J = 8.2, 2.3 Hz, 4H), 6.06 (t, J = 2.2 Hz, 2H), 5.02 (s, 4H), 4.59 (dAB, J = 15.0 Hz, 4H), 4.40 (dAB, J = 15.1 Hz, 4H), 4.00−3.93 (m, 4H), 3.88−3.80 (m, 4H), 3.64−3.56 (m, 4H), 3.33−3.27 (m, 4H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.0, 159.5, 151.7, 137.1, 137.0, 129.7, 128.3, 123.7, 108.0, 106.8, 104.4, 74.4, 68.6, 66.6, 38.0. HRMS (ESI, MeOH): m/z calcd for C48H50N4O14Na [M + Na]+: 929.3221, found 929.3188. Anal. Calcd for C48H50N4O14·(H2O)0.5: C, 62.94; H, 5.61; N, 6.12. Found: C, 63.13; H, 5.76; N, 6.12.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02160. 1 H and 13C NMR spectra, Cartesian coordinates of calculated structures, X-ray data for compounds 18, 20, 23, 28, and 30 (PDF) X-ray data for compound 18 (CIF) X-ray data for compound 20 (CIF) X-ray data for compound 23 (CIF) X-ray data for compound 28 (CIF) X-ray data for compound 30 (CIF)

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Note

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Janusz Jurczak: 0000-0002-0351-6614 Kajetan Da̧browa: 0000-0001-7767-5303 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to acknowledge Poland’s National Science Centre (project 2014/15/B/ST5/05038) for financial support. K.D. thanks the National Science Centre (UMO-2016/23/D/ ST5/03301) for financial support. 13566

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