Efficient Synthesis of Various Substituted (Thio)Ureas, Semicarbazides, Thiosemicarbazides, Thiazolidones, and Oxadiazole Derived from [2.2]Paracyclophane.

The strategies of the syntheses of various (thio)ureas, semicarbazides, thiosemicarbazides, thiazolidones, and oxadiazole derived from the [2.2]paracyclophane molecule are achieved starting with 4-(2.2]paracyclophanyl)isocyanate. The structures of the obtained products were elucidated by NMR, mass spectrometry, and infrared (IR) spectroscopy in addition to high-resolution mass spectrometry (HRMS). X-ray structure analysis was also used to prove the assigned structure.

Introduction

[2.2]Paracyclophane (PC) chemistry has evolved from the functional molecules to functional materials and from the synthetic curiosity to emerging applications in asymmetric synthesis, energy materials, π-stacked polymers, and functional parylene coatings (i.e. polymer made by polymerization of PC induced by vapor-phase pyrolysis).[1−4] [2.2]Paracyclophane is also described as a rigid molecule within the interior of the conjugated segment with an otherwise similar aspect ratio to the phenylene unit. The intermolecular interactions in PC involving aromatic rings are the key processes in both chemical and biological recognition.[5]

Recently, it has been shown that connecting heterocycles with the PC moiety showed anticancer activity as in the case of paracyclophanyl-dihydronaphtho[2,3-d]thiazoles and paracyclophanyl-thiazolium bromides.[6] Among the following three assigned series I−III of the synthesized paracyclophanyl-heterocycles (Figure ), series I having 1,4-dihydronaphthoquinone, was found as more active as antiproliferative agents than their naphthalene-containing congeners (series II and III) toward the SK-MEL-5 melanoma cell line.[6]

Figure 1

Different series of paracyclophanyl-thiazole derivatives (I−III) as anticancer agents.

Previously, we reported the various classes of connection between PC and heterocycle moieties.[7] Aly et al. synthesized heterocycles conjugated to [2.2]paracyclophane such as five-membered rings (i.e., imidazolinone,[8] pyrrole,[9] triazolethiones, and substituted oxadiazoles[10]) together with six-membered rings (i.e., pyridine).[11,12]

It was reported that some marketed drugs had been found to contain the N-acylhydrazone motif in their structures, e.g., azumolene, carbazochrome, dantrolene, nitrofurantoin, nitrofurazone, nifuroxazide, and testosterone 17-enanthate 3-benzilic acid hydrazone.[13] More specifically, acylhydrazide-based compounds have shown antioxidant activities.[14] Hydrazides and carbohydrazides have been described as useful building blocks for the assembly of various heterocyclic rings.[15−19] Ureas and thioureas in combination with benzothiazoles were reported that they produced DNA topoisomerase or HIV reverse transcriptase inhibitors.[20−22] 1,3,4-Oxadiazole heterocyclic ring is one of the most important heterocyclic moieties due to its versatile biological actions.[23] Based upon the aforementioned, we are encouraged to incorporate a PC molecule to (thio)urea, semicarbazides, thiosemicarbazide, thiazolidone, and oxadiazole groups.

Results and Discussion

Synthesis of 1N-Benzyl-3-N-[2.2]paracyclophanylurea (6) and N-(4′-[2.2]Paracyclo-phanyl)hydrazinecarboxamides 7a, 7b

The strategy of preparing compounds 6, 7a, and 7b was divided into two parts: First, starting with the parent hydrocarbon 1 as a commercial product, which was then converted into the acid chloride derivative 3(24) by the procedure described in Scheme . At the beginning, compound 1 was converted into 2 during reaction with oxalyl chloride/aluminum trichloride. Then, heating 2 in refluxing chlorobenzene caused decarbonylation to give 3. Subsequently, the resulting acid chloride 3 was subjected toward NaN3/acetone to give compound 4(24) (Scheme ). Heating 4 in toluene at 80 °C provided the corresponding isothionate 5(24) in 70% yield (Scheme ). Second, fusion of 5 with benzylamine gave the corresponding urea 6 in 87% yield (Scheme ). Based on NMR, IR, mass spectra, as well as HRMS, the structure of compound 6 was satisfactorily proved. As the 1H NMR spectrum indicated the appearance of the CH2 protons of compound 6 as a doublet at δH = 4.26 (J = 6.0 Hz). Whereas, the two NH protons appeared as two singlets at δH = 7.73 and 6.75 ppm. In 13C NMR, the CH2 and the carbonyl carbon signals resonated at δC = 42.9 and 158.1 ppm, respectively. On subjecting 5 with hydrazines by the procedure mentioned in Scheme , N-(4′-[2.2]paracyclophanyl)hydrazinecarboxamides 7a and 7b were obtained in very good yields (Scheme ). The structure of the newly prepared compound 7a was established by IR, NMR, mass spectra, as well as HRMS. The IR spectrum revealed a diagnostic broad band at ṽ = 3352–3214 for NH groups, whereas the carbonyl group appeared at ṽ = 1632 cm–1. The 1H NMR spectrum exhibited the NH-2 and NH-1 protons at δH = 7.59 and 6.88 ppm, respectively. In addition, the characteristic hydrazine-NH2 resonated in the 1H NMR spectrum at δH = 4.72 ppm. The 13C NMR spectrum displayed the carbonyl-carbon at δC = 157.3, whereas the four distinctive CH2-bridged carbons of PC resonated at δC = 35.4, 35.1, 32.9, and 32.3 ppm. HRMS proved the chemical formula of 7a as C17H19N3O.

Scheme 1

Synthesis of 1N-Benzyl-3-N-[2.2]paracyclophanylurea (6) and N-(4′-[2.2]Paracyclophanyl)hydrazinecarboxamides 7a and 7b

Reagents and conditions: (A) (COCl)2/AlCl3, −10 to 5 °C, 20 min; (B) PhCl, Δ, 40 h; (C) NaN3, acetone/water, r.t., 2 h; (D) toluene, 80 °C, 1 h; (E) PhCH2NH2/fusion, 100 °C, 10 h; (F) NH2NH2 as a solvent, Δ, 20 h; (G) PhNHNH2, toluene, 20 h.

For compound 7b, HRMS confirmed the molecular formula of compound 7b as C23H23N3O. The 1H NMR spectrum revealed the NH protons as three singlets at δH = 8.36 (for NH-2), 7.97 (for NH-1), and 6.60 ppm for (NH-3). The 13C NMR spectrum of compound 7b revealed the carbonyl carbon at δC = 155.8, whereas the carbon signal of C-Ph was observed at δC = 149.1 ppm (see the Experimental Section). The four carbon signals of the CH2–CH2 appeared at δC = 36.4, 36.1, 35.7, and 32.2 ppm.

Reaction of Compound 7a with Dimethyl Acetylenedicarboxylate (8a) and Substituted Isothiocyanates 10a–10e

In extension to the aforesaid strategy and taking compound 7a, as an example, in the reaction between 7a and dimethyl acetylenedicarboxylate (8a), the reaction gave compound 9 in 80% yield (Scheme ). HRMS confirmed the molecular formula of 9 as C23H25N3O5 indicating the addition reaction of compound 7a to 8a proceeded without elimination of a MeOH molecule.

Scheme 2

Strategy of Various Reactions of N-(4′-[2.2]Paracyclophanyl)hydrazinecarboxamide (7a)

Reagents and conditions: (H) EtOH, reflux 4 h; (I) oil path EtOH, 70 °C, reflux 4–8 h.

To discriminate between the possible structures 9 and 9′, we analyzed the NMR spectrum. As, the hydrazano-NH appeared in the 1H NMR spectrum as a singlet at δH = 11.01, whereas the PC-NH at δH = 8.45. The two methyl-ester protons appeared as two very close singlets at δH = 3.90 and 3.75 ppm. The 1H NMR did not reveal any proton for the ethylenic-H, which excluded the formation of the isomeric product 9′ (Figure ). The CH2 carbon and its protons attached to the ester group resonated at the same region of the ethylenic-CH2 of PC. The 13C NMR spectrum revealed the two methyl-esters at δC = 52.5 and 52.1 ppm (see the Experimental Section). The structure of 9 was unambiguously proved by X-ray structure analysis as shown in Figure .

Figure 2

Additive products 9 and 9′ from the reaction between 7a and 8a.

Figure 3

Molecular structure of compound 9 (displacement parameters are drawn at the 50% probability level).

X-ray structure analysis of compound 9 showed different bond lengths of the C–N bonds, as the bond lengths of C16–N17 and C18–N19 are 1.413 and 1.384 Å, respectively. The lengths of the double bonds assigned to the C=O and N=C as in C18–O18 and N20–C21 are 1.225 and 1.272 Å, respectively. Whereas the lengths of the C–C bond assigned to the C21–C22 and C22–C23 are 1.496 and 1.510 Å, respectively.

Surprisingly, when compound 7a was subjected to substituted isothiocyanates 10a–10e, the unexpected substituted thiourea derivatives 11a–11e were obtained in 50–60% yields as the major products, whereas the expected products results in the addition reaction of 7a to 10a–10e were obtained in 20–30% yields (Scheme ). Both products were separated by column chromatography using ethyl acetate–hexane, 10:1. The IR spectrum of compound 11d, as an example, revealed absorptions at ṽ = 3296–3206 (NH, s), 3091 (aryl-H), 2925 (aliph.-CH), and 1456 cm–1 (C=S). Additionally, the 1H NMR spectrum revealed two singlets at δH = 8.99 (NH-1) and 7.50 ppm (NH-3). The ethyl protons were detected in the 1H NMR spectrum as a quartet at δH = 3.61 (for CH2, J = 7.2 Hz) and as a double-triplet at δH = 1.08 ppm (for CH3, J = 13.2, 7.1 Hz). The 13C NMR spectrum presented the C=S and the ethyl carbon signals at δC = 180.2, 56.5 (CH2-ethyl) and 14.9 ppm (CH3-ethyl), respectively. HRMS confirmed the molecular formula of 11d as C19H22N2S. Finally, X-ray structure analysis confirmed the structure of compound 11d as shown in Figure .

Figure 4

Molecular structure of one of the crystallographic independent molecules of compound 11d (displacement parameters are drawn at the 50% probability level).

The structures of compounds 12a–12e were identified as thiamido derivatives of 11a–11e (Scheme ). As for example, compound 12d was proved as N-(4′-[2.2]paracyclophanyl)-2-(ethylcarbamothioyl)hydrazine-1-carboxamide. In the 1H NMR spectrum, compound 12d supported the structure, since four singlets for NH protons appeared at δH = 9.29 (NH-3), 8.37 (NH-2), 8.29 (NH-4), and 7.59 ppm (NH-1). The ethyl protons resonated in the 1H NMR spectrum as a quartet at δ = 3.61 (CH2, J = 7.2 Hz) and as a triplet for CH3 at δH = 1.12 ppm (J = 7.1 Hz). The 13C NMR spectrum confirmed the structure of 12d by the appearance of the C=S carbon signal at δC = 182.6, in addition to a signal at δC = 155.0 ppm for the carbonyl carbon signal. The ethyl carbon signals were distinguished at δC = 39.0 (CH2-ethyl) and at δC = 14.9 ppm (CH3-ethyl). Mass spectrometry showed the molecular ion peak at m/z (%) = 368 (20). Besides that, HRMS proved the molecular formula of 12d to be C20H24N3OS.

The mechanism describes the formation of compounds 11a–11e and 12a–12e could be explained as due to the addition of the NH lone pair to the electrophilic center in 10a–10d in the C=S to form compound 11 (Scheme ). Rearrangement of 11 involved addition of the NH-PC via the bond between NH-PC and C=O to the electrophilic carbon of C=S accompanied by the oxidation process to give the intermediate 12 (Scheme ). Upon heating, N2 and CO would then be eliminated, as shown in Scheme , to produce 11 (Scheme ).

Scheme 3

Mechanism Describing the Formation of Compounds 11a–11e and 12a–12e

Reaction of Compounds 11a–11e and 12a–12e with Diethyl Acetylenedicarboxylate (8b) and Preparation of 1,3,4-Oxazole Derivative 17

Further investigation was done toward compounds 11a–11e and 12a–12e through their reactions with diethyl acetylenedicarboxylate (8b). The corresponding oxothiazoles 14a–14e and 15a–15e were obtained and were identified by IR and NMR spectra in addition to HRMS. For example, the structure of compound 14b was elucidated by 1H NMR spectrum via the appearance of the aromatic protons as two multiplets at δH = 7.58–7.27 (for 5H) and at δH = 6.66–6.22 ppm (6H), whereas the vinyl-proton of the exocyclic double bond resonated as a singlet δH = 6.78 ppm. A quartet at δH = 5.22 (J = 8.2 Hz, for CH2) and as a triplet (3H) at δH = 1.20 (J = 6.9 Hz, CH3) appeared to indicate the ethyl ester protons. The benzyl protons are clearly resonated as a double-doublet at δH = 4.17 ppm (J = 14.3, 6.8 Hz). The 13C NMR spectrum supported the structure of compound of 14bvia the appearance of the carbonyl carbon signals at δC = 150.3 and at 147.5 ppm. The ester carbons and the benzyl carbon signals appeared at δC = 61.4 (ester-CH2), 13.90 (ester-CH3), and 45.9 ppm (CH2-benzyl).

The structure of compound 14b was totally confirmed by X-ray analysis as shown in Figure . X-ray structure analysis also proved the structure of the other thiazole named (rac)-ethyl-(E)-2-((E)-2-(4′-[2.2]paracyclophanylimino)-3-cyclopropyl-4-oxothiazolidin-5-ylidene)acetate (Figure ).

Figure 5

Molecular structure of compound 14b (minor disordered parts omitted for clarity, displacement parameters are drawn at 50% probability level).

Figure 6

Molecular structure of compound 14e (displacement parameters are drawn at 50% probability level).

On the other side, compound 15c was obtained in 75% yield and it was identified as (rac)-ethyl-(E)-2-((E)-2-(2-(4′-[2.2]paracyclophanylcarbamoyl)-hydrazineylidene)-3-allyl-4-oxothiazolidin-5-ylidene)acetate. The 1H NMR spectrum indicated the NH protons as two singlets at δH = 9.25 (NH-2) and 8.53 ppm (NH-1). The vinyl proton resonated as a singlet at δH = 6.80. The allyl protons appeared at δH = 6.08 as ddd (CH-allyl, J = 22.4, 10.3, 5.2 Hz), at δH = 5.12–4.93 as a multiplet for CH2-allyl, and at δH = 4.29 ppm as a doublet (J = 5.3 Hz). Finally the ethyl protons appeared, as expected, as a quartet at δH = 4.18 (CH2, J = 7.1 Hz), and triplet at δH = 1.14 ppm (CH3, J = 7.1 Hz). Three distinguished carbonyl carbon signals in the 13C NMR spectrum were present at δC = 165.3 (CO), 165.1 (CO), and 162.9 ppm. Besides that, the allyl carbons are shown at δC = 132.8 (=CH), 117.6 (=CH2), and at 44.5 ppm (CH2−).

In the way to synthesize 1,3,4-oxazole derivative 16, one example, such as 12e, was chosen (Scheme ). The disappearance of the carbonyl and C=S carbons in the IR and 13C NMR indicated that cyclization occurred (Scheme ). The 1H NMR spectrum of 16 showed the two NH protons as two singlets at δH = 9.41 and 8.44 ppm (see the Experimental Section). The allyl protons appeared as a doublet at δH = 6.76 (J = 1.4 Hz), besides two multiplets at δH = 5.98–5.90 and at δH = 5.35 and 5.25. According to the 13C NMR spectrum of compound 16, three carbons were distinguished for the allyl carbons at δC = 46.3 (CH2), 115.8 (=CH2), and 132.3 ppm (=CH−), respectively.

Scheme 4

Synthesis of Thiazoles 14a–14e and 15a–15e in Addition to 1,3,4-Oxadiazole Derivative 16

Reagents and conditions: (K) EtOH, reflux; (L) NaOH (2 N), EtOH, reflux 3 h.

Experimental Section

Uncorrected melting points were taken in a Gallenkamp melting point apparatus (Weiss-Gallenkamp, Loughborough, U.K.). The infrared spectra were determined with a Bruker Alpha ATR instrument. The NMR spectra of the title compounds described herein were recorded on a Bruker Avance 400 NMR instrument at 400 MHz for 1H NMR and 101 MHz for 13C NMR; the references used were the 1H and 13C peaks of the solvents, d6-dimethyl sulfoxide ((CD3)2SO-d6): 2.50 ppm for 1H NMR and 39.4 ppm for 13C NMR. For the characterization of centrosymmetric signals, the signal’s median point was chosen; for multiplets, the signal range was given. The following abbreviations were used to describe the proton splitting pattern: d = doublet, t = triplet, m = multiplet, dd = doublet of a doublet. The following abbreviations were used to distinguish between signals: HAr = aromatic-CH, HPc = [2.2]paracyclophane-CH2. Signals of the 13C NMR spectra were assigned with the help of DEPT90 and DEPT135 and were specified in the following way: + = primary or tertiary carbon atoms (positive DEPT signal), – = secondary carbon atoms (negative DEPT signal), Cq = quaternary carbon atoms (no DEPT signal). Mass spectra observed by fast atom bombardment (FAB) experiments were recorded using a Finnigan, MAT 90 (70 eV) instrument. TLC silica plates coated with fluorescence indicator from Merck (silica gel 60 F254, thickness 0.2 mm) were used to purify the crude products; flash chromatography with silica gel 60 (0.040 mm × 0.063 mm, Merck) was used.

General Procedures

Compounds 2–5 were prepared according to the literature.[23]

Synthesis of Compound 6

Isocyanato[2.2]paracyclophane (5)[23] (1.00 g, 4.1 mmol, 1.00 equiv) was fused with benzylamine (5 mL) at 100 °C for 10 h. The reaction mixture was then cooled to room temperature until a precipitate was formed (24 h). The precipitate of 6 was filtered and washed with 150 mL of hexane (three times) and then was dried.

(rac)-1-(4′-[2.2]Paracyclophanyl))-3-benzylurea (6)

R = 0.30 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (EtOH), 310 mg (87%). Mp: 150–152 °C. 1H NMR (400 MHz, DMSO-d6): δH = 7.73 (s, 1H, NH1), 7.44–7.17 (m, 5H, HAr), 6.75 (s, 1H, NH2), 6.55–6.22 (m, 7H, HAr), 4.24 (d, J = 6.0 Hz, 2H, CH2benzyl), 3.09–2.81 (m, 7H, HPc), 2.67–2.62 ppm (m, 1H, HPc). 13C NMR (101 MHz, DMSO-d6): δC = 158.1 (Cq, CO), 155.1 (Cq, CAr), 140.9 (Cq, CAr), 140.4 (Cq, CAr), 139.9 (Cq, CAr), 138.8 (Cq, CAr), 138.5 (+, CHAr), 134.6 (+, CHAr), 132.9 (+, CHAr), 131.8 (+, CHAr), 128.6 (+, CHAr), 128.3 (+, CHAr), 128.2 (+, CHAr), 127.7 (Cq, CAr), 127.1 (+, CHAr), 126.7 (+, CHAr), 126.5 (+, CHAr), 126.0 (+, CHAr), 125.2 (+, CHAr), 42.9 (−, CH2benzyl), 34.7 (−, CH2), 34.6 (−, CH2), 33.1 (−, CH2), 32.6 ppm (−, CH2). IR (ATR): ṽ = 3340–3210 (br), 3186 (w), 2910 (s), 2856 (m), 1630 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 357 (60) [M + H]+, 356 (30) [M]+. HRMS (FAB, 3-NBA, C24H25N2O, [M + H]+) calcd, 357.1967; found, 357.1960.

Synthesis of Compound 7a

Under an argon atmosphere, a mixture of isocyanato[2.2]paracyclophane (5)[23] (5.00 g, 20.1 mmol, 1.00 equiv) was dissolved in 25 mL of hydrazine monohydrate and heated under reflux for 20 h. The reaction mixture was then cooled to room temperature until a precipitate was formed (24 h). Product 7a was then filtered and washed with 150 mL of hexane (three times) and then dried.

(rac)-N-(4′-[2.2]Paracyclophanyl)hydrazinecarboxamide (7a)

R = 0.27 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (EtOH), 5 g (89%). Mp: 170–172 °C. 1H NMR (400 MHz, DMSO-d6): δH = 7.59 (s, 1H, NH2), 6.88 (s, 1H, NH1), 6.82 (dd, J = 7.7, 1.7 Hz, 1H, HAr), 6.62–6.50 (m, 1H, HAr), 6.47–6.29 (m, 3H, HAr), 6.74 (d, J = 1.4 Hz, 1H, HAr), 6.15–5.93 (m, 1H, HAr), 4.72 (s, 2H, NH2) 3.29–2.80 (m, 7H, HPc), 2.80–2.66 ppm (m, 1H, HPc). 13C NMR (101 MHz, DMSO-d6): δC = 157.3 (Cq, CO), 140.3 (Cq, CAr), 139.3 (Cq, CAr), 139.1 (Cq, CAr), 138.6 (Cq, CAr), 135.3 (+, CHAr), 133.6 (+, CHAr), 133.3 (+, CHAr), 132.4 (+, CHAr), 131.8 (+, CHAr), 126.9 (+, CHAr), 121.9 (+, CHAr), 120.7 (Cq, CAr), 35.4 (−, CH2), 35.1 (−, CH2), 32.9 (−, CH2), 32.3 (−, CH2), 21.0 ppm (+, CH3). IR (ATR): ṽ = 3352–3214 (br), 3196 (w), 2927 (s), 2848 (m), 1632 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 282 (50) [M + H]+, 281 (30) [M]+. HRMS (FAB, 3-NBA, C17H20N3O, [M + H]+) calcd, 282.1606; found, 282.1603.

Synthesis of Compound 7b

Under an argon atmosphere, a mixture of isocyanato[2.2]paracyclophane (5)[23] (0.249 g, 1.00 equiv) was added to phenylhydrazine (0.108 g, 1.00 equiv) in 100 mL of toluene and was refluxed for 20 h. The reaction mixture was then cooled to room temperature until a precipitate was formed (24 h). Product 7b was then filtered and washed with 50 mL of hexane (three times) and then dried.

(rac)-N-(4′-[2.2]Paracyclophanyl)-2-phenylhydrazine-1-carboxamide (7b)

R = 0.20 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (EtOH), 321 mg (94%). Mp: 147–149 °C. – 1H NMR (400 MHz, DMSO-d6): δH = 8.36 (s, 1H, NH2), 7.97 (br, 1H, NH1), 7.89 (s, 1H, HAr), 7.26 (t, J = 7.6 Hz, 3H, HAr), 6.73 (s, 2H, HAr), 6.60 (s, 1H, NH3), 6.48 (dd, J = 7.8, 1.7 Hz, 2H, HAr), 6.33 (ddd, J = 28.8, 7.6, 2.1 Hz, 4H, HAr), 3.20–2.78 (m, 6H, HPc), 2.63 ppm (ddd, J = 17.0, 10.6, 6.4 Hz, 2H, HPc). 13C NMR (101 MHz, DMSO-d6): δC = 155.8 (Cq, CO), 149.1 (Cq, CAr), 140.7 (Cq, CAr), 139.3 (Cq, CAr), 139.2 (Cq, CAr), 138.6 (Cq, CAr), 132.4 (+, 2 × CHAr), 131.4 (+, 2 × CHAr), 129.4 (+, 2 × CHAr), 128.1 (+, CHAr), 127.8 (Cq, CAr), 127.3 (+, CHAr), 124.0 (+, CHAr), 120.3 (+, CHAr), 116.1 (+, 2 × CHAr), 36.4 (−, CH2), 36.1 (−, CH2), 35.7 (−, CH2), 32.2 ppm (−, CH2). IR (ATR): ṽ = 3372–3314 (br), 3200 (w), 2927 (s), 2868 (m), 1642 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 358 (55) [M + H]+, 357 (20) [M]+. HRMS (FAB, 3-NBA, C23H24N3O, [M + H]+) calcd, 358.1919; found, 358.1920.

Synthesis of Compound 9

A mixture of [2.2]paracyclophanyl hydrazinecarboxamide (7a, 0.281 g, 1.00 mmol, 1.00 equiv) and dimethyl acytelenedicarboxylate (8a, 0.142 g, 1.00 mmol, 1.00 equiv) in absolute ethanol (40 mL) was refluxed for 4 h (the reaction was monitored by thin-layer chromatography). After removal of the solvent under reduced pressure, the crude product was purified by column chromatography using cyclohexane/EtOAc 10:1 to afford racemic-9.

(rac)-Dimethyl (Z)-2-(2-(4′-[2.2]paracyclophanyl-carbamoyl)hydrazineylidene)succinate (9)

R = 0.25 (dichloromethane/methanol, 10:1). Pale yellow crystals (EtOH), 338 mg (80%). Mp: 208–210 °C. 1H NMR (400 MHz, DMSO-d6): δH = 11.01 (s, 1H, NH2), 8.45 (s, 1H, NH1), 6.82 (s, 1H, HAr), 6.72–6.60 (m, 1H, HAr), 6.55–6.40 (m, 5H, HAr), 3.90 (s, 3H, CH3), 3.75 (s, 3H, CH3), 3.35–3.20 (m, 5H, HPc), 3.05 (s, 2H, CH2vinyl), 2.95–2.64 ppm (m, 3H, HPc). 13C NMR (101 MHz, DMSO-d6): δC = 168.3 (Cq, CO), 164.1 (Cq, CO), 151.5 (Cq, CO), 140.6 (Cq, C=N), 138.7 (Cq, CAr), 138.4 (Cq, CAr), 136.9 (Cq, CAr), 134.8 (Cq, CAr), 133.3 (+, CHAr), 132.9 (+, CHAr), 132.2 (+, CHAr), 131.5 (+, CHAr), 129.0 (+, CHAr), 127.3 (+, CHAr), 127.2 (+, CHAr), 125.2 (Cq, CAr), 52.5 (+, CH3), 52.1 (+, CH3), 34.6 (−, CH2), 34.4 (−, CH2), 32.6 (−, CH2), 32.1 (−, CH2), 31.9 ppm (−, CH2vinyl). IR (ATR): ṽ = 3300 (w), 3206 (w), 3070 (w), 2920 (w), 2808 (vw), 1640 (w), 1601 (m), 1547 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 424 (45) [M + H]+, 423 (35) [M]+. HRMS (FAB, 3-NBA, C23H26O5N3, [M + H]+) calcd, 424.1872; found, 424.1870.

Synthesis of Compounds 11a–11e and 12a–12e

A mixture of [2.2]paracyclophanehydrazinecarboxamide (7a, 1.00 equiv) and the substituted isothiocyanates (10, 1.00 equiv) in 60 mL of ethanol was refluxed 80 °C for 4–8 h (the reaction was monitored by thin-layer chromatography). After removal of the solvent under reduced pressure, the crude residue was purified by column chromatography using ethyl acetate/hexane 5:1 to give compounds 11a–11e and 12a–12e.

(rac)-2′(4′-[2.2]Paracyclophanyl)-16-yridinedin-3-yl)hydrazine-1-carbothioamide (11a)

R = 0.42 (dichloromethane/methanol, 10:1). Buff crystals (EtOH), 223 mg (60%). Mp: 155–157 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.64 (s, 1H, NH1), 9.05 (s, 1H, NH3), 7.51–7.30 (m, 2H, HAr), 7.21–7.08 (m, 2H, HAr), 6.63–6.27 (m, 6H, HAr), 6.20–6.06 (m, 1H, HAr), 3.12–2.93 (m, 6H, HPc), 2.91–2.85 (m, 1H, HPc), 2.81–2.64 (m, 1H, HPc), 2.35–2.19 ppm (m, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): δC = 179.98 (Cq, CS), 140.50 (Cq, CAr), 139.79 (Cq, CAr), 139.22 (Cq, CAr), 137.98 (Cq, CAr), 137.56 (Cq, CAr), 136.11 (Cq, CAr), 135.3 (+, CHAr), 134.05 (+, CHAr), 134.02 (+, CHAr), 133.56 (+, CHAr), 133.21 (+, CHAr), 132.69 (+, CHAr), 130.9 (+, CHAr), 130.2 (Cq, CAr), 129.24 (+, 2 × CHAr), 124.24 (+, 2 × CHAr), 35.2 (−, CH2), 34.8 (−, CH2), 34.5 (−, CH2), 33.7 (−, CH2), 21.0 ppm (+, CH3). IR (ATR): ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 1659 (vs), 1594 (m), 1577 (m), 1538 (vs), 1516 (vs), 1494 (vs), 1455 (m), 1436 cm–1 (w). MS (FAB, 3-NBA): m/z (%) = 373 (100) [M + H]+, 372 (50) [M]+. HRMS (FAB, 3-NBA, C24H25N232S1, [M + H]+) calcd, 373.1738; found, 373.1740.

(rac)-1-(4′-[2.2]Paracyclophanyl)-3-benzylthiourea (11b)

R = 0.40 (dichloromethane/methanol, 10:1). Buff crystals (EtOH), 185 mg (50%). Mp: 165–167 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.06 (s, 1H, NH1), 7.99 (s, 1H, NH3), 7.34 (d, J = 4.4 Hz, 4H, HAr), 7.25 (dt, J = 5.1, 4.2 Hz, 1H, HAr), 6.86 (d, J = 5.3 Hz, 1H, HAr), 6.53 (dd, J = 7.8, 1.7 Hz, 1H, HAr), 6.49–6.39 (m, 4H, HAr), 6.16 (d, J = 1.1 Hz, 1H, HAr), 4.72 (ddd, J = 19.8, 14.7, 5.7 Hz, 2H, CH2benzyl), 3.16–3.07 (m, 1H, HPc), 3.02–2.86 (m, 6H, HPc), 2.65 (ddd, J = 13.5, 10.1, 5.9 Hz, 1H, HPc) ppm. 13C NMR (100 MHz, DMSO-d6): δC = 181.2 (Cq, CS), 140.8 (Cq, CAr), 139.7 (Cq, CAr), 139.7 (Cq, CAr), 139.2 (Cq, CAr), 137.5 (Cq, CAr), 136.0 (+, CHAr), 133.5 (+, CHAr), 133.3 (+, CHAr), 133.1 (+, CHAr), 132.9 (+, CHAr), 130.1 (+, CHAr), 130.3 (+, CHAr), 129.2 (+, CHAr), 128.7 (+, 2 × CHAr), 128.1 (Cq, CAr), 127.8 (+, CHAr), 127.4 (+, CHAr), 48.0 (−, CH2benzyl), 35.2 (−, CH2), 34.8 (−, CH2), 34.4 (−, CH2), 33.5 ppm (−, CH2). IR (ATR) ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 (s), 1456 (s), 1279 (m), 1129 (vs), 795 (w), 725 (m), 613 (vs), 514 cm–1 (w). MS (FAB, 3-NBA): m/z (%) = 373 (100) [M + H]+, 372 (50) [M]+. HRMS (FAB, 3-NBA, C24H25N232S1, [M + H]+) calcd, 373.1738; found, 373.1737.

(rac)-1-(4′-[2.2]Paracyclophanyl)-3-allylthiourea (11c)

R = 0.39 (dichloromethane/methanol, 10:1). Buff crystals (EtOH), 167 mg (52%). Mp: 160–162 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.04 (s, 1H, NH1), 7.67 (s, 1H, NH3), 6.87 (dd, J = 7.7, 1.2 Hz, 1H, HAr), 6.60–6.40 (m, 5H, HAr), 6.15 (d, J = 1.4 Hz, 1H, HAr), 5.96–5.84 (m, 1H, CHallyl), 5.26–5.06 (m, 2H, CH2allyl), 4.28–4.00 (m, 2H, CH2allyl), 3.19–3.06 (m, 1H, HPc), 3.01–2.87 (m, 6H, HPc), 2.70 ppm (ddd, J = 13.5, 10.1, 5.9 Hz, 1H, HPc). 13C NMR (100 MHz, DMSO-d6): δC = 180.9 (Cq, CS), 140.8 (Cq, CAr), 139.7 (Cq, CAr), 139.2 (Cq, CAr), 137.5 (Cq, CAr), 136.0 (+, CHAr), 135.5 (+, 2 × CHAr), 133.4 (+, CHAr), 133.1 (+, CHallyl), 132.8 (+, CHAr), 130.9 (+, CHAr), 130.2 (+, CHAr), 129.2 (Cq, CAr), 116.2 (−, CH2allyl), 46.9 (−, CH2allyl), 35.2 (−, CH2), 34.8 (−, CH2), 34.5 (−, CH2), 33.5 ppm (−, CH2). IR (ATR): ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 (s), 1456 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 323 (100) [M + H]+, 322 (55) [M]+. HRMS (FAB, 3-NBA, C20H23N232S1, [M + H]+) calcd, 323.1582; found, 323.1583.

(rac)-1-(4′-[2.2]Paracyclophanyl)-3-ethylthiourea (11d)

R = 0.35 (dichloromethane/methanol, 10:1). Buff crystals (MeOH), 179 mg (58%). Mp: 168–170 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.99 (s, 1H, NH1), 7.50 (s, 1H, NH3), 6.86 (dd, J = 7.7, 1.7 Hz, 1H, HAr), 6.55 (dd, J = 7.8, 1.8 Hz, 1H, HAr), 6.51–6.40 (m, 4H, HAr), 6.12 (d, J = 1.5 Hz, 1H, HAr), 3.61 (q, 2H, J = 7.2 Hz, CH2ethyl), 3.12–3.02 (m, 1H, HPc), 3.01–2.88 (m, 6H, HPc), 2.70 (ddd, J = 13.4, 10.0, 5.9 Hz, 1H, HPc), 1.08 ppm (dt, J = 13.2, 7.1 Hz, 3H, CH3ethyl). 13C NMR (100 MHz, DMSO-d6): δC = 180.2 (Cq, CS), 140.9 (Cq, CAr), 139.7 (Cq, CAr), 139.1 (Cq, CAr), 137.4 (Cq, CAr), 136.2 (+, CHAr), 135.6 (+, CHAr), 133.4 (+, CHAr), 133.0 (+, CHAr), 132.9 (+, CHAr), 130.8 (+, CHAr), 129.9 (+, CHAr), 129.2 (Cq, CAr), 56.5 (−, CH2ethyl), 35.2 (−, CH2), 34.8 (−, CH2), 34.5 (−, CH2), 33.5 (−, CH2), 14.9 ppm (+, CH3ethyl). IR (ATR): ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 (s), 1456 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 311 (65) [M + H]+, 310 (30) [M]+. HRMS (FAB, 3-NBA, C19H23N232S1, [M + H]+) calcd, 311.1582; found, 311.1584.

(rac)-1-(4′-[2.2]Paracyclophanyl)-3-cyclopropylthiourea (11e)

R = 0.35 (dichloromethane/methanol, 10:1). Buff crystals (MeOH), 173 mg (54%). Mp: 168–170 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.36 (s, 1H, NH1), 8.32 (s, 1H, NH3), 6.85 (dd, J = 7.8, 1.7 Hz, 2H, HAr), 6.57–6.06 (m, 5H, HAr), 3.12 (dd, J = 20.4, 9.9 Hz, 1H, HPc), 3.07–2.81 (m, 7H, HPc), 2.75–2.62 (m, 1H, CHcyclo), 0.75–0.69 (m, 2H, CH2cyclo), 0.65–0.47 ppm (m, 2H, CH2cyclo). 13C NMR (100 MHz, DMSO-d6): δC = 182.2 (Cq, CS), 140.6 (Cq, CAr), 139.7 (Cq, CAr), 139.2 (Cq, CAr), 135.8 (Cq, CAr), 135.2 (+, CHAr), 133.5 (+, CHAr), 133.3 (+, CHAr), 133.1 (+, CHAr), 132.7 (+, CHAr), 130.6 (+, CHAr), 130.1 (+, CHAr), 128.8 (Cq, CAr), 35.2 (−, CH2), 34.8 (−, CH2), 34.3 (−, CH2), 33.7 (−, CH2), 26.8 (+, CHcyclo.), 7.1 ppm (−, 2 × CH2cyclo). IR (ATR): ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 (s), 1456 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 323 (55) [M + H]+, 322 (20) [M]+. HRMS (FAB, 3-NBA, C20H23N232S1, [M + H]+) calcd, 323.1582; found, 323.1583.

(rac)-N-(4′-[2.2]Paracyclophanyl)-2-(p-tolylcarbamothioyl)hydrazine-1-carboxamide (12a)

R = 0.17 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (MeOH), 129 mg (30%). Mp: 190–192 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.87 (s, 1H, NH3), 9.58 (s, 1H, NH2), 8.52 (s, 1H, NH4), 7.81 (s, 1H, NH1), 7.48–7.32 (m, 2H, HAr), 7.15 (d, J = 8.2 Hz, 3H, HAr), 6.90 (dd, J = 7.7, 1.5 Hz, 1H, HAr), 6.74 (d, J = 1.4 Hz, 1H, HAr), 6.62–6.25 (m, 4H, HAr), 3.15–2.79 (m, 7H, HPc), 2.69 (dt, J = 13.8, 9.4 Hz, 1H, HPc), 2.29 ppm (s, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 180.0 (Cq, CS), 155.0 (Cq, CO), 140.6 (Cq, CAr), 139.3 (Cq, CAr), 139.2 (Cq, CAr), 139.0 (Cq, CAr), 138.2 (Cq, CAr), 137.0 (+, CHAr), 135.2 (+, 2 × CHAr), 133.5 (+, CHAr), 133.2 (+, CHAr), 132.4 (+, CHAr), 129.6 (+, CHAr), 129.2 (Cq, CAr), 129.1 (Cq, CAr), 128.8 (+, CHAr), 127.3 (+, CHAr), 125.8 (+, CHAr), 124.2 (+, CHAr), 35.2 (−, CH2), 35.1 (−, CH2), 33.4 (−, CH2), 33.0 (−, CH2), 21.0 ppm (+, CH3). IR (ATR): ṽ = 3980 (vw), 3954 (vw), 3922 (vw), 3903 (vw), 3870 (vw), 3852 (vw), 3412 (vw), 3352 (vw), 2978 (w), 2925 (w), 2884 (w), 1720 (s), 1696 (m), 1616 (m), 1592 cm–1 (vs). MS (FAB, 3-NBA): m/z (%) = 431 (85) [M + H]+, 430 (20) [M]+. HRMS (FAB, 3-NBA, C25H27O1N432S1, [M + H]+) calcd, 431.1906; found, 431.1905.

(rac)-N-(4′-[2.2]Paracyclophanyl)-2-(benzylcarbamothioyl)hydrazine-1-carboxamide (12b)

R = 0.16 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (EtOH), 163 mg (38%). Mp: 186–188 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.43 (s, 1H, NH3), 8.76 (s, 1H, NH2), 8.44 (s, 1H, NH4), 7.68 (s, 1H, NH1), 7.32 (dt, J = 19.4, 7.6 Hz, 4H, HAr), 7.23 (t, J = 7.2 Hz, 1H, HAr), 6.85 (dd, J = 7.7, 1.2 Hz, 1H, HAr), 6.71 (d, J = 1.5 Hz, 1H, HAr), 6.51–6.31 (m, 5H, HAr), 4.80 (ddd, J = 40.4, 15.1, 5.8 Hz, 2H, CH2benzyl), 3.26–3.18 (m, 1H, HPc), 3.02–2.83 (m, 6H, HPc), 2.67 ppm (dt, J = 13.7, 8.3 Hz, 1H, HPc). 13C NMR (101 MHz, DMSO-d6): δC = 183.6 (Cq, CS), 155.0 (Cq, CO), 140.6 (Cq, CAr), 139.7 (Cq, CAr), 139.3 (Cq, CAr), 139.0 (Cq, CAr), 138.1 (Cq, CAr), 135.2 (+, CHAr), 133.5 (+, CHAr), 133.2 (+, CHAr), 132.3 (+, CHAr), 129.6 (+, CHAr), 128.8 (+, CHAr), 128.5 (Cq, CAr), 128.4 (Cq, CAr), 127.7 (+, CHAr), 127.6 (+, CHAr), 127.4 (+, CHAr), 127.1 (+, CHAr), 125.8 (+, CHAr), 47.2 (−, CH2benzyl), 35.2 (−, CH2), 35.1 (−, CH2), 33.3 (−, CH2), 32.9 ppm (−, CH2). IR (ATR): ṽ = 3060 (w), 2983 (w), 2975 (w), 2925 (w), 1715 (s), 1697 (s), 1687 (m), 1628 (m), 1596 cm–1 (vs). MS (FAB, 3-NBA): m/z (%) = 431 (90) [M + H]+, 430 (30) [M]+. HRMS (FAB, 3-NBA, C25H27O1N432S1, [M + H]+) calcd, 431.1906; found, 431.1904.

(rac)-N-(4′-[2.2]Paracyclophanyl)-2-(allylcarbamothioyl)hydrazine-1-carboxamide (12c)

R = 0.18 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (EtOH), 148 mg (39%). Mp: 180–182 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.35 (s, 1H, NH3), 8.40 (s, 1H, NH2), 8.09 (s, 1H, NH4), 7.66 (s, 1H, NH1), 6.85 (d, J = 7.7 Hz, 1H, HAr), 6.71 (d, J = 1.2 Hz, 1H, HAr), 6.50 (dd, J = 7.8, 1.6 Hz, 1H, HAr), 6.42–6.35 (m, 3H, HAr), 6.31 (dd, J = 7.7, 1.6 Hz, 1H, HAr), 5.86 (dddt, J = 27.4, 17.1, 10.3, 5.1 Hz, 1H, CHallyl), 5.21–5.02 (m, 2H, CH2allyl), 4.16 (dd, J = 20.8, 15.8 Hz, 2H, CH2allyl), 3.23 (dd, J = 10.8, 6.2 Hz, 1H, HPc), 3.03–2.86 (m, 6H, HPc), 2.72–2.64 ppm (m, 1H, HPc). 13C NMR (101 MHz, DMSO-d6): δC = 182.8 (Cq, CS), 154.9 (Cq, CO), 140.6 (Cq, CAr), 139.3 (Cq, CAr), 139.0 (Cq, CAr), 138.1 (Cq, CAr), 135.4 (+, CHAr), 135.2 (+, CHAr), 133.5 (+, CHAr), 133.2 (+, CHallyl), 132.3 (+, CHAr), 129.5 (+, CHAr), 128.8 (+, CHAr), 127.3 (Cq, CAr), 125.8 (+, CHAr), 115.0 (−, CH2allyl), 46.4 (−, CH2allyl), 35.2 (−, CH2), 35.1 (−, CH2), 33.4 (−, CH2), 32.9 ppm (−, CH2). IR (ATR): ṽ = 3241 (m), 3233 (m), 3109 (m), 2925 (m), 2846 (w), 1646 (w), 1608 (m), 1591 (m), 1560 (vs), 1487 (vs), 1436 (vs) cm–1. MS (FAB, 3-NBA): m/z (%) = 381 (100) [M + H]+, 380 (20) [M]+. HRMS (FAB, 3-NBA, C21H25O1N432S1, [M + H]+) calcd, 381.1749; found, 381.1750.

(rac)-N-(4′-[2.2]Paracyclophanyl)-2-(ethylcarbamothioyl)hydrazine-1-carboxamide (12d)

R = 0.15 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (MeOH), 117 mg (32%). Mp: 176–178 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.29 (s, 1H, NH3), 8.37 (s, 1H, NH2), 8.29 (s, 1H, NH4), 7.59 (s, 1H, NH1), 6.85 (dd, J = 7.7, 1.3 Hz, 1H, HAr), 6.71 (d, J = 1.2 Hz, 1H, HAr), 6.50 (dd, J = 7.8, 1.6 Hz, 1H, HAr), 6.42–6.28 (m, 4H, HAr), 3.61 (q, 2H, J = 7.2 Hz, CH2-ethyl), 3.27–3.17 (m, 1H, HPc), 3.05–2.83 (m, 6H, HPc), 2.68 (ddd, J = 13.8, 10.0, 7.5 Hz, 1H, HPc), 1.12 ppm (t, J = 7.1 Hz, 3H, CH3ethyl). 13C NMR (101 MHz, DMSO-d6): δC = 182.6 (Cq, CS), 155.0 (Cq, CO), 140.6 (Cq, CAr), 139.2 (Cq, CAr), 139.0 (Cq, CAr), 138.0 (Cq, CAr), 135.2 (+, CHAr), 133.5 (+, CHAr), 133.2 (+, CHAr), 132.3 (+, CHAr), 129.4 (+, CHAr), 128.7 (+, CHAr), 127.3 (Cq, CAr), 125.7 (+, CHAr), 39.0 (−, CH2ethyl), 35.2 (−, CH2), 35.0 (−, CH2), 33.3 (−, CH2), 32.9 (−, CH2), 14.9 ppm (+, CH3ethyl). IR (ATR): ṽ = 3241 (m), 3233 (m), 3109 (m), 2925 (m), 2846 (w), 1646 (w), 1608 (m), 1591 (m), 1560 (vs), 1487 cm–1 (vs). MS (FAB, 3-NBA): m/z (%) = 369 (50) [M + H]+, 368 (20) [M]+. HRMS (FAB, 3-NBA, C20H25O1N332S1, [M + H]+) calcd, 369.1749; found, 369.1750.

(rac)-N-(4′-[2.2]Paracyclophanyl)-2-(cyclopropylcarbamothioyl)hydrazine-1-carboxamide (12e)

R = 0.18 (cyclohexane/ethyl acetate, 4:1). Colorless crystals (DMF/EtOH), 140 mg (37%). Mp: 191–193 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.36 (s, 1H, NH3), 8.31 (s, 1H, NH2), 8.25 (s, 1H, NH4), 7.63 (s, 1H, NH1), 6.97–6.78 (m, 1H, HAr), 6.78–6.65 (m, 1H, HAr), 6.49 (dt, J = 31.4, 15.7 Hz, 1H, HAr), 6.42–6.23 (m, 4H, HAr), 3.30–3.18 (m, 1H, HPc), 3.05–2.83 (m, 6H, HPc), 2.70–2.58 (m, 1H, HPc), 1.26–1.14 (m, 1H, CHcyclo), 0.76–0.68 (m, 2H, CH2cyclo), 0.67–0.60 ppm (m, 2H, CH2cyclo). 13C NMR (101 MHz, DMSO-d6): δC = 184.7 (Cq, CS), 156.2 (Cq, CO), 140.6 (Cq, CAr), 139.3 (Cq, CAr), 139.0 (Cq, CAr), 138.2 (Cq, CAr), 135.2 (+, CHAr), 133.5 (+, CHAr), 133.2 (+, CHAr), 132.3 (+, CHAr), 129.4 (+, CHAr), 128.8 (+, CHAr), 127.2 (Cq, CAr), 125.6 (+, CHAr), 35.2 (−, CH2), 35.1 (−, CH2), 33.3 (−, CH2), 32.9 (−, CH2), 26.8 (+, CHcyclo), 6.8 ppm (−, 2 × CH2cyclo). IR (ATR): ṽ = 3271 (w), 2927 (w), 1751 (m), 1718 (w), 1694 (m), 1656 (vs), 1618 (m), 1601 (m), 1578 (s), 1553 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 381 (45) [M + H]+,380 (20) [M]+. HRMS (FAB, 3-NBA, C21H25O1N332S1, [M + H]+) calcd, 381.1749; found, 381.1750.

Synthesis of Thiazoles 14a–14e

A mixture of N-substituted [2.2]paracyclophanylthioureas (11a–11e, 1.00 mmol, 1.00 equiv) and 8b (0.170 g, 1.00 mmol, 1.00 equiv) in absolute ethanol (40 mL) was refluxed for 3–4 h (the reaction was monitored by thin-layer chromatography). After removal of the solvent under reduced pressure, the crude product was purified by column chromatography using EtOAc/hexane, 5:1 to give compounds 14a–14e.

(rac)-(E)-2-((E)-2-(4′-[2.2]Paracyclophanylimino)-4-oxo-3-(p-tolyl)thiazolidin-5-ylidene)acetate (14a)

R = 0.25 (dichloromethane/methanol, 10:1). Yellow crystals (DMF/EtOH), 401 mg (81%). Mp: 238–240 °C. 1H NMR (400 MHz, DMSO-d6): δH = 8.82 (s, 1H, HAr), 8.16 (s, 1H, HAr), 7.77 (s, 1H, Hvinyl), 7.30 (d, J = 8.4 Hz, 1H, HAr), 7.02 (d, J = 8.3 Hz, 1H, HAr), 6.84 (dd, J = 7.7, 1.5 Hz, 1H, HAr), 6.75–6.62 (m, 2H, HAr), 6.50–6.20 (m, 4H, HAr), 3.37 (dd, J = 12.4, 10.4 Hz, 2H, CH2), 3.11–2.76 (m, 6H, HPc), 2.75–2.54 (m, 2H, HPc), 2.17 (s, 3H, CH3phenyl), 0.98 ppm (t, J = 7.0 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 152.3 (Cq, CO), 151.9 (Cq, CO), 140.0 (Cq, C=N), 138.8 (Cq, C=C), 138.7 (Cq, CAr), 138.6 (Cq, CAr), 138.1 (Cq, CAr), 138.0 (Cq, CAr), 137.4 (Cq, CAr), 134.8 (Cq, CAr), 134.6 (+, CHAr), 133.0 (+, CHAr), 132.8 (+, CHAr), 132.7 (+, CHAr), 131.8 (+, CHAr), 130.3 (+, CHAr), 129.9 (+, CHAr), 129.2 (+, CHAr), 128.0 (+, CHAr), 126.8 (+, CHAr), 126.6 (+, CHAr), 125.7 (Cq, CAr), 118.0 (+, CHvinyl), 61.2 (+, CH2), 34.7 (−, CH2), 34.5 (−, CH2), 33.3 (−, CH2), 33.1 (−, CH2), 32.6 (+, CH3phenyl), 20.3 ppm (+, CH3). IR (ATR): ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 497 (45) [M + H]+, 496 (30) [M]+. HRMS (FAB, 3-NBA, C30H29O3N232S1, [M + H]+) calcd, 497.1899; found, 497.1891.

(rac)-(E)-2-((E)-2-(4′-[2.2]Paracyclophanylimino)-3-benzyl-4-oxothiazolidin-5-ylidene)acetate (14b)

R = 0.20 (cyclohexane/ethyl acetate, 4:1). Yellow crystals (EtOH), 226 mg (86%). Mp: 230–232 °C. 1H NMR (400 MHz, DMSO-d6): δH = 7.58–7.27 (m, 5H, HAr), 6.78 (s, 1H, Hvinyl), 6.66–6.22 (m, 6H, HAr), 5.82 (s, 1H, HAr), 5.22 (q, J = 8.2 Hz, 2H, CH2), 4.17 (dd, J = 14.3, 6.8 Hz, 2H, CH2benzyl), 3.12–2.59 (m, 8H, HPc), 1.20 ppm (t, J = 8.0 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 150.3 (Cq, CO), 147.5 (Cq, CO), 141.4 (Cq, C=N), 139.0 (Cq, C=C), 138.6 (Cq, CAr), 136.0 (Cq, CAr), 134.8 (Cq, CAr), 133.7 (Cq, CAr), 133.1 (Cq, CAr), 132.5 (+, CHAr), 132.0 (+, CHAr), 131.7 (+, CHAr), 130.5 (+, CHAr), 129.7 (+, CHAr), 129.2 (+, CHAr), 128.8 (+, CHAr), 128.6 (+, CHAr), 127.6 (+, CHAr), 127.1 (+, CHAr), 126.6 (+, CHAr), 122.4 (+, CHAr), 121.2 (Cq, CAr), 115.5 (+, CHvinyl), 61.4 (−, CH2), 45.9 (−, CH2benzyl), 34.6 (−, CH2), 34.4 (−, CH2), 33.3 (−, CH2), 31.8 (−, CH2), 13.9 ppm (+, CH3). IR (ATR): ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 497 (65) [M + H]+, 496 (35) [M]+. HRMS (FAB, 3-NBA, C30H29O3N232S1, [M + H]+) calcd, 497.1899; found, 497.1896.

(rac)-Ethyl-(E)-2-((E)-2-(4′-[2.2]paracyclophanylimino)-3-allyl-4-oxothiazolidin-5-ylidene)acetate (14c)

R = 0.17 (cyclohexane/ethyl acetate, 4:1). Yellow crystals (EtOH), 379 mg (85%). Mp: 241–243 °C. 1H NMR (400 MHz, DMSO-d6): δH = 6.92 (dd, J = 7.7, 1.6 Hz, 1H, HAr), 6.74 (s, 1H, Hvinyl), 6.61–6.32 (m, 5H, HAr), 6.08 (ddd, J = 22.4, 10.3, 5.2 Hz, 1H, CHAllyl), 5.84 (d, J = 1.0 Hz, 1H, HAr), 5.42–5.27 (m, 2H, CH2Allyl), 4.64 (d, J = 5.1 Hz, 2H, CH2Allyl), 4.17 (q, J = 7.1 Hz, 2H, CH2), 3.24–3.12 (m, 1H, HPc), 3.08–2.88 (m, 6H, HPc), 2.68–2.55 (m, 1H, HPc), 1.20 ppm (t, J = 7.1 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 165.2 (Cq, CO), 163.7 (Cq, CO), 147.1 (Cq, C=N), 144.8 (Cq, C=C), 141.5 (Cq, CAr), 140.8 (Cq, CAr), 139.1 (Cq, CAr), 138.6 (Cq, CAr), 134.8 (+, CHAr), 133.2 (+, CHAr), 132.7 (+, CHAr), 132.5 (+, CHAllyl), 131.7 (+, CHAr), 131.5 (+, CHAr), 129.6 (+, CHAr), 129.3 (+, CHAr), 126.7 (Cq, CAr), 117.1 (−, CH2Allyl), 115.2 (+, CHvinyl), 61.4 (−, CH2), 44.8 (−, CH2Allyl), 34.7 (−, CH2), 34.3 (−, CH2), 33.4 (−, CH2), 32.1 (−, CH2), 13.9 ppm (+, CH3). IR (ATR): ṽ = 3421 (vw), 3303 (w), 3063 (w), 2945 (w), 2925 (w), 2851 (w), 1697 (s), 1655 (s), 1602 (vs), 1538 cm–1 (m). MS (FAB, 3-NBA): m/z (%) = 447 (100) [M + H]+, 446 (40) [M]+. HRMS (FAB, 3-NBA, C26H27O3N232S1, [M + H]+) calcd, 447.1747; found, 447.1737.

(rac)-Ethyl-(E)-2-((E)-2-(4′-[2.2]paracyclophanylimino)-3-ethyl-4-oxothiazolidin-5-ylidene)acetate (14d)

R = 0.14 (cyclohexane/ethyl acetate, 4:1). Yellow crystals (EtOH), 381 mg (88%). Mp: 220–222 °C. 1H NMR (400 MHz, DMSO-d6): δH = 6.94 (d, J = 6.6 Hz, 1H, HAr), 6.71 (s, 1H, Hvinyl), 6.60–6.32 (m, 5H, HAr), 5.85 (s, 1H, HAr), 4.16 (q, J = 7.1 Hz, 2H, CH2), 4.06 (q, J = 7.1 Hz, 2H, CH2ethyl), 3.25–3.21 (m, 1H, HPc), 3.04–2.90 (m, 6H, HPc), 2.69–2.61 (m, 1H, HPc), 1.40 (t, J = 6.7 Hz, 3H, CH3ethyl), 1.19 ppm (t, J = 7.0 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 165.2 (Cq, CO), 163.8 (Cq, CO), 147.4 (Cq, C=N), 145.0 (Cq, C=C), 141.7 (Cq, CAr), 140.8 (Cq, CAr), 139.1 (Cq, CAr), 138.7 (Cq, CAr), 134.8 (+, CHAr), 133.2 (+, CHAr), 132.6 (+, 2 × CHAr), 131.7 (Cq, CAr), 129.6 (+, CHAr), 129.2 (+, CHAr), 126.8 (+, CHAr), 114.9 (+, CHvinyl), 61.3 (−, CH2), 38.0 (−, CH2ethyl), 34.6 (−, CH2), 34.3 (−, CH2), 33.5 (−, CH2), 32.2 (−, CH2), 13.9 (+, CH3), 12.5 ppm (+, CH3ethyl). IR (ATR): ṽ = 3163 (vw), 3030 (vw), 2929 (w), 2815 (w), 2628 (vw), 1694 (s), 1649 (m), 1606 (vs), 1545 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 435 (100) [M + H]+, 434 (90) [M]+. HRMS (FAB, 3-NBA, C25H27O3N232S1, [M + H]+) calcd, 435.1742; found, 435.1743.

(rac)-Ethyl-(E)-2-((E)-2-(4′-[2.2]paracyclophanylimino)-3-cyclopropyl-4-oxothiazolidin-5-ylidene)acetate (14e)

R = 0.55 (cyclohexane/ethyl acetate, 1:1). Yellow crystals (EtOH), 370 mg (83%). Mp: 180–182 °C. 1H NMR (400 MHz, DMSO-d6): δH = 7.01 (d, J = 7.3 Hz, 1H, HAr), 6.65 (s, 1H, Hvinyl), 6.60–6.34 (m, 5H, HAr), 5.82 (s, 1H, HAr), 4.14 (q, J = 7.1 Hz, 2H, CH2), 3.29–3.18 (m, 1H, HPc), 3.12–2.91 (m, 7H, HPc), 2.70–2.58 (m, 1H, CHcyclo), 1.17–1.14 (m, 4H, 2 × CH2cyclo), 1.06 ppm (t, J = 6.8 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 165.3 (Cq, CO), 164.4 (Cq, CO), 148.2 (Cq, C=N), 145.5 (Cq, C=C), 142.0 (Cq, CAr), 140.8 (Cq, CAr), 139.2 (Cq, CAr), 138.6 (Cq, CAr), 134.7 (+, CHAr), 133.2 (+, CHAr), 132.5 (+, CHAr), 132.4 (+, CHAr), 131.8 (+, CHAr), 129.3 (Cq, CAr), 129.2 (+, CHAr), 126.8 (+, CHAr), 114.4 (+, CHvinyl), 61.2 (−, CH2), 34.7 (−, CH2), 34.3 (−, CH2), 33.4 (−, CH2), 32.2 (−, CH2), 25.6 (+, CHcyclo), 13.9 (+, CH3ethyl), 6.4 (−, CH2cyclo), 6.3 ppm (−, CH2cyclo). IR (ATR): ṽ = 3315 (vw), 3187 (vw), 3013 (w), 2927 (m), 2851 (w), 1714 (s), 1697 (s), 1653 (s), 1606 (vs), 1545 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 447 (70) [M + H]+, 446 (35) [M]+. HRMS (FAB, 3-NBA, C26H27O3N232S1, [M + H]+) calcd, 447.1742; found, 447.1739.

Synthesis of Thiazoles 15a–15e

A mixture of N-substituted [2.2]paracyclophanylhydrazinecarbothioamides (12a–12e, 1.00 mmol, 1.00 equiv) and diethyl acetylenedicarboxylate (DEAD) (8b, 0.170 g, 1.00 mmol, 1.00 equiv) in absolute ethanol (40 mL) was refluxed for 3–6 h (the reaction was monitored by thin-layer chromatography). After removal of the solvent under reduced pressure, the crude product was purified by column chromatography using EtOAc/hexane, 5:1 to afford 15a–15e.

(rac)-Ethyl-(E)-2-((E)-2-(2-(4′-[2.2]paracyclophanylcarbamoyl)hydrazineylidene)-4-oxo-3-(p-tolyl)thiazolidin-5-ylidene)acetate (15a)

R = 0.30 (dichloromethane/methanol, 10:1). Yellow crystals (EtOH), 387 mg (70%). Mp: 268–270 °C. 1H NMR (400 MHz, DMSO-d6) δH = 11.32 (s, 1H, NH2), 10.75 (s, 1H, NH1), 7.65–7.40 (m, 4H, HAr), 7.30–7.22 (m, 1H, HAr), 7.07–6.90 (m, 1H, HAr), 6.80 (s, 1H, Hvinyl), 6.75–6.62 (m, 1H, HAr), 6.59–6.40 (m, 3H, HAr), 3.37 (dd, J = 12.4, 10.4 Hz, 2H, CH2), 3.25–2.70 (m, 8H, HPc), 2.18 (s, 3H, CH3phenyl), 1.40 ppm (t, J = 7.0 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6) δC = 165.4 (Cq, CO), 160.4 (Cq, CO), 152.0 (Cq, CO), 141.0 (Cq, C=N), 140.2 (Cq, C=C), 139.6 (Cq, CAr), 139.4 (Cq, CAr), 139.3 (Cq, CAr), 138.9 (Cq, CAr), 137.7 (Cq, CAr), 135.0 (Cq, CAr), 134.0 (+, CHAr), 132.6 (+, CHAr), 132.4 (+, CHAr), 132.2 (+, CHAr), 132.1 (+, CHAr), 131.2 (+, CHAr), 129.6 (+, CHAr), 129.5 (+, CHAr), 129.0 (+, CHAr), 128.1 (+, CHAr), 125.2 (+, CHAr), 120.5 (Cq, CAr), 118.0 (+, CHvinyl), 52.6 (+, CH2), 34.7 (−, CH2), 34.5 (−, CH2), 34.3 (−, CH2), 34.2 (−, CH2), 32.5 (+, CH3phenyl), 20.9 ppm (+, CH3). IR (ATR) ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 (s), 1456 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 555 (65) [M + H]+, 554 (30) [M]+. HRMS (FAB, 3-NBA, C31H31O4N432S1, [M + H]+) calcd, 555.2066; found, 555.2063.

(rac)-Ethyl-(E)-2-((E)-2-(2-(4′-[2.2]Paracyclophanylcarbamoyl)hydrazineylidene)-3-benzyl-4-oxothiazolidin-5-ylidene)acetate (15b)

R = 0.34 (cyclohexane/ethyl acetate, 4:1). Yellow crystals (ethanol), 415 mg (75%). Mp: 280–282 °C. 1H NMR (400 MHz, DMSO-d6) δH = 10.88 (s, 1H, NH2), 8.40 (s, 1H, NH1), 7.58–7.20 (m, 5H, HAr), 6.78 (s, 1H, Hvinyl), 6.86–6.20 (m, 7H, HAr), 5.19 (q, J = 15.2 Hz, 2H, CH2), 4.18 (dd, J = 14.3, 6.8 Hz, 2H, CH2benzyl), 3.12–2.50 (m, 8H, HPc), 1.21 ppm (t, J = 6.9 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 165.9 (Cq, CO), 161.5 (Cq, CO), 154.4 (Cq, CO), 140.5 (Cq, C=N), 139.1 (Cq, C=C), 138.6 (Cq, CAr), 137.8 (Cq, CAr), 135.2 (Cq, CAr), 132.5 (Cq, CAr), 132.4 (Cq, CAr), 132.3 (+, CHAr), 132.2 (+, CHAr), 131.6 (+, CHAr), 131.3 (+, CHAr), 131.2 (+, CHAr), 128.5 (+, 2 × CHAr), 128.2 (+, CHAr), 127.8 (+, CHAr), 127.3 (+, CHAr), 127.2 (+, 2 × CHAr), 127.0 (Cq, CAr), 116.6 (+, CHvinyl), 60.4 (−, CH2), 45.8 (−, CH2benzyl), 34.8 (−, CH2), 34.6 (−, CH2), 34.5 (−, CH2), 34.2 (−, CH2), 13.8 ppm (+, CH3). IR (ATR): ṽ = 3296 (w), 3206 (w), 3091 (w), 2925 (w), 2839 (vw), 1645 (w), 1604 (m), 1557 (s), 1456 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 555 (75) [M + H]+, 554 (20) [M]+. HRMS (FAB, 3-NBA, C31H31O4N432S1, [M + H]+) calcd, 555.2066; found, 555.2063.

(rac)-Ethyl-(E)-2-((E)-2-(2-(4′-[2.2]paracyclophanylcarbamoyl)hydrazineylidene)-3-allyl-4-oxothiazolidin-5-ylidene)acetate (15c)

R = 0.37 (cyclohexane/ethyl acetate, 4:1). Yellow crystals (EtOH), 368 mg (73%). Mp: 291–293 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.25 (s, 1H, NH2), 8.53 (s, 1H, NH1), 6.80 (s, 1H, Hvinyl), 6.76–6.55 (m, 2H, HAr), 6.36–5.89 (m, 4H, HAr), 6.08 (ddd, J = 22.4, 10.3, 5.2 Hz, 1H, CHallyl), 5.84 (d, J = 1.0 Hz, 1H, HAr), 5.12–4.93 (m, 2H, CH2allyl), 4.29 (d, J = 5.3 Hz, 2H, CH2allyl), 4.18 (q, J = 7.1 Hz, 2H, CH2), 3.05–2.70 (m, 7H, HPc), 2.56 (dd, J = 17.6, 8.3 Hz, 1H, HPc), 1.14 ppm (t, J = 7.1 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 165.3 (Cq, CO), 165.1 (Cq, CO), 162.9 (Cq, CO), 161.8 (Cq, C=N), 154.5 (Cq, C=C), 153.0 (Cq, CAr), 147.0 (Cq, CAr), 140.6 (Cq, CAr), 140.0 (Cq, CAr), 139.0 (+, CHAr), 138.4 (+, CHAr), 134.9 (+, CHAr), 132.8 (+, CHAllyl), 132.0 (+, CHAr), 130.8 (+, CHAr), 128.6 (+, CHAr), 127.7 (+, CHAr), 126.0 (Cq, CAr), 117.6 (−, CH2Allyl), 116.1 (+, CHvinyl), 61.5 (−, CH2), 44.5 (−, CH2Allyl), 34.7 (−, CH2), 34.5 (−, CH2), 33.0 (−, CH2), 32.9 (−, CH2), 14.0 ppm (+, CH3). IR (ATR): ṽ = 3291 (w), 3285 (w), 3271 (w), 2980 (w), 2966 (w), 2927 (w), 2851 (w), 1742 (m), 1707 (s), 1693 (s), 1660 (vs), 1613 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 505 (55) [M + H]+, 504 (25) [M]+. HRMS (FAB, 3-NBA, C27H29O4N432S1, [M + H]+) calcd, 505.1910; found, 505.1906.

(rac)-Ethyl-(E)-2-((E)-2-(2-(4′-[2.2]paracyclophanylcarbamoyl)hydrazineylidene)-3-ethyl-4-oxothiazolidin-5-ylidene)acetate (15d)

R = 0.34 (cyclohexane/ethyl acetate, 4:1). Yellow crystals (EtOH), 374 mg (76%). Mp: 285–287 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.46 (s, 1H, NH2), 8.45 (s, 1H, NH1), 6.90 (d, J = 6.6 Hz, 1H, HAr), 6.74 (s, 1H, Hvinyl), 6.45–6.20 (m, 6H, HAr), 4.18 (q, J = 7.1 Hz, 2H, CH2), 4.02 (q, J = 7.1 Hz, 2H, CH2ethyl), 3.04–2.80 (m, 6H, HPc), 2.68–2.65 (m, 1H, HPc), 1.25 (t, J = 6.7 Hz, 3H, CH3ethyl), 1.15 ppm (t, J = 7.0 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δC = 164.8 (Cq, CO), 161.3 (Cq, CO), 153.9 (Cq, CO), 146.5 (Cq, C=N), 140.1 (Cq, C=C), 139.5 (Cq, CAr), 138.5 (Cq, CAr), 137.9 (Cq, CAr), 136.6 (Cq, CAr), 134.3 (+, CHAr), 132.3 (+, CHAr), 131.5 (+, 2 × CHAr), 130.2 (Cq, CAr), 128.1 (+, CHAr), 127.1 (+, CHAr), 125.4 (+, CHAr), 115.6 (+, CHvinyl), 61.0 (−, CH2), 40.7 (−, CH2ethyl), 34.2 (−, CH2), 34.0 (−, CH2), 32.5 (−, CH2), 32.4 (−, CH2), 14.0 (+, CH3), 13.4 ppm (+, CH3ethyl). IR (ATR) v = 3163 (vw), 3030 (vw), 2929 (w), 2815 (w), 2628 (vw), 1694 (s), 1649 (m), 1606 (vs), 1545 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 493 (100) [M + H]+, 492 (30) [M]+. HRMS (FAB, 3-NBA, C26H29O4N432S1, [M + H]+) calcd, 493.1910; found, 493.1905.

(rac)-Ethyl-(E)-2-((E)-2-(4′-[2.2]paracyclophanyl-carbamoyl)hydrazineylidene)-3-cyclopropyl-4-oxothiazolidin-5-ylidene)acetate (15e)

R = 0.37 (cyclohexane/ethyl acetate, 1:1). Yellow crystals (EtOH), 363 mg (72%). Mp: 260–262 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.36 (s, 1H, NH2), 8.43 (s, 1H, NH1), 6.87 (s, 1H, Hvinyl), 6.80–6.70 (m, 1H, HAr), 6.49 (d, J = 7.8 Hz, 2H, HAr), 6.45–6.27 (m, 4H, HAr), 4.29 (q, J = 6.9 Hz, 2H, CH2), 3.31–3.20 (m, 1H, HPc), 3.09–2.80 (m, 7H, HPc), 2.72–2.55 (m, 1H, CHcyclo), 1.29 (t, J = 7.0 Hz, 3H, CH3), 1.03–0.86 (m, 2H, CH2cyclo), 0.79–0.66 ppm (m, 2H, CH2cyclo). 13C NMR (101 MHz, DMSO-d6): δC = 165.2 (Cq, CO), 161.5 (Cq, CO), 152.8 (Cq, CO), 145.8 (Cq, C=N), 140.0 (Cq, C=C), 138.9 (Cq, CAr), 138.7 (Cq, CAr), 138.5 (+, CHAr), 137.5 (Cq, CAr), 136.9 (Cq, CAr), 134.9 (+, CHAr), 132.7 (+, CHAr), 132.1 (+, CHAr), 131.6 (+, CHAr), 128.7 (Cq, CAr), 127.9 (+, CHAr), 126.2 (+, CHAr), 115.7 (+, CHvinyl), 61.5 (−, CH2), 34.7 (−, CH2), 34.5 (−, CH2), 34.4 (−, CH2), 34.1 (−, CH2), 33.1 (+, CHcyclo), 14.0 (+, CH3ethyl), 8.1 ppm (−, 2 × CH2cyclo). IR (ATR): ṽ = 3315 (vw), 3187 (vw), 3013 (w), 2927 (m), 2851 (w), 1714 (s), 1697 (s), 1653 (s), 1606 (vs), 1545 (s), 1436 cm–1 (m). MS (FAB, 3-NBA): m/z (%) = 505 (90) [M + H]+, 504 (25) [M]+. HRMS (FAB, 3-NBA, C27H29O4N432S1, [M + H]+) calcd, 505.1910; found, 505.1905.

Synthesis of Compound 16

A stirring mixture of N-allyl [2.2]paracyclophanylhydrazinecarbothioamides (12e, 0.380 g, 1.00 mmol, 1.00 equiv) and 10 mL of sodium hydroxide (1.00 mmol, as a 2 N solution) dissolved in 40 mL of ethanol was refluxed for 3 h. After cooling, the solution was acidified with 10 mL of hydrochloric acid (6 M) and the formed precipitate was filtered.

N2-(4′-[2.2]Paracyclophanyl)-N5-allyl-1,3,4-oxadiazole-2,5-diamine (16)

R = 0.46 (dichloromethane/methanol, 10:1), colorless crystals (CHCl3/EtOH), 207 mg (60%). Mp: 206–208 °C. 1H NMR (400 MHz, DMSO-d6): δH = 9.41 (s, 1H, NH), 8.44 (s, 1H, NH), 7.72 (s, 1H, HAr), 6.91 (dd, J = 7.7, 1.3 Hz, 1H, HAr), 6.91 (dd, J = 7.7, 1.3 Hz, 1H, HAr), 6.76 (d, J = 1.4 Hz, 1H, CHallyl), 6.56–6.35 (m, 4H, HAr), 5.98–5.90 (m, 2H, CH2allyl), 5.75–5.25 (m, 2H, CH2allyl), 3.10–2.89 ppm (m, 8H, HPc). 13C NMR (101 MHz, DMSO-d6): δC = 155.0 (Cq, CAr), 140.6 (Cq, CAr), 139.7 (Cq, CAr), 139.3 (Cq, CAr), 139.0 (Cq, CAr), 138.1 (Cq, CAr), 135.4 (+, CHAr), 135.2 (+, CHAr), 133.5 (+, CHAr), 133.2 (+, CHAr), 132.3 (+, CHallyl), 129.5 (+, CHAr), 128.8 (+, CHAr), 127.3 (+, CHAr), 125.8 (Cq, CAr), 115.8 (−, CH2allyl), 46.3 (−, CH2allyl), 35.5 (−, CH2), 35.2 (−, CH2), 33.4 (−, CH2), 32.9 ppm (−, CH2). IR (ATR) ṽ = 3214 (w), 3156 (w), 3013 (w), 2946 (m), 2925 (m), 2888 (m), 2856 (w), 1717 (w), 1653 (vs), 1623 (vs), 1595 cm–1 (s). MS (FAB, 3-NBA): m/z (%) = 347 (100) [M + H]+, 346 (50) [M]+. HRMS (FAB, 3-NBA, C21H23O1N4, [M + H]+) calcd, 347.1872; found, 347.1870.

Crystal Structure Determinations

The single-crystal X-ray diffraction study were carried out on a Bruker D8 Venture diffractometer with a PhotonII detector at 123(2) K or 173(2) K using Cu–Kα radiation (λ = 1.54178 Å). Dual space/intrinsic methods[25] were used for structure solution, and refinement was carried out using SHELXL-2014 (full-matrix least-squares on F2).[26] Hydrogen atoms were localized by difference electron density determination and refined using a riding model (H(N) free). Semiempirical absorption corrections were applied. For 14b, an extinction correction was applied. In 14b, the ethyl moiety is disordered (see the cif files for details). 14e was refined as a twin with two domains.

9: Yellow crystals, C23H25N3O5, Mr = 423.46, crystal size 0.16 × 0.12 × 0.04 mm3, monoclinic, space group P21/n (no. 14), a = 13.3388(5) Å, b = 8.1948(3) Å, c = 19.9695(8) Å, β = 106.989(2)°, V = 2087.58(14) Å3, Z = 4, ρ = 1.347 Mg/m–3, μ(Cu–Kα) = 0.79 mm–1, F(000) = 896, T = 123 K, 2θmax = 144.6°, 32299 reflections, of which 4117 were independent (Rint = 0.035), 288 parameters, 2 restraints, R1 = 0.071 (for 3572I > 2σ(I)), wR2 = 0.213 (all data), S = 1.05, largest diff. peak/hole = 1.00/–0.20 e Å–3.

11d: Colorless crystals, C19H22N2S, Mr = 310.44, crystal size 0.16 × 0.06 × 0.04 mm3, triclinic, space group P-1 (no. 2), a = 11.3925(3) Å, b = 12.0321(3) Å, c = 13.4654(4) Å, α = 88.526(1)°, β = 65.296(1)°, γ = 76.086(1)°, V = 1621.79(8) Å3, Z = 4, ρ = 1.271 Mg/m–3, μ(Cu–Kα) = 1.74 mm–1, F(000) = 664, T = 123 K, 2θmax = 144.8°, 30263 reflections, of which 6380 were independent (Rint = 0.029), 409 parameters, 4 restraints, R1 = 0.038 (for 5802I > 2σ(I)), wR2 = 0.107 (all data), S = 1.05, largest diff. peak/hole = 0.41/–0.27 e Å–3.

14b: Yellow crystals, C30H28N2O3S, Mr = 496.60, crystal size 0.16 × 0.04 × 0.02 mm3, monoclinic, space group P21/c (no. 14), a = 10.0473(4) Å, b = 34.0461(14) Å, c = 7.5093(3) Å, β = 100.286(2)°, V = 2527.43(18) Å3, Z = 4, ρ = 1.305 Mg/m–3, μ(Cu–Kα) = 1.42 mm–1, F(000) = 1048, T = 173 K, 2θmax = 144.6°, 18990 reflections, of which 4720 were independent (Rint = 0.053), 325 parameters, 2 restraints, R1 = 0.045 (for 4229I > 2σ(I)), wR2 = 0.122 (all data), S = 1.04, largest diff. peak/hole = 0.51/–0.51 e Å–3.

14e: Yellow crystals, C26H26N2O3S, Mr = 446.55, crystal size 0.21 × 0.15 × 0.03 mm3, monoclinic, space group P21/c (no. 14), a = 24.6864(10) Å, b = 7.8388(3) Å, c = 11.4055(5) Å, β = 91.995(1)°, V = 2205.76(16) Å3, Z = 4, ρ = 1.345 Mg/m–3, μ(Cu–Kα) = 1.56 mm–1, F(000) = 944, T = 173 K, 2θmax = 144.6°, 16496 reflections, of which 4306 were independent (Rint = 0.043), 290 parameters, R1 = 0.096 (for 3868I > 2σ(I)), wR2 = 0.278 (all data), S = 1.04, largest diff. peak/hole = 1.48/–0.52 e Å–3.

CCDC-2128196 (9), CCDC-2128197 (11d), CCDC-2128199 (14b), and CCDC-2128199 (14e) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

Conclusion

In the current study, a novel series assembly of thio(ureas), semicarbazides, thiosemicarbazides, thiazoles, and oxadiazole derived from [2.2]paracyclophane were effectively synthesized. Therefore, it would be potentially applied to the symmetrical disubstituted PC. We are encouraging to synthesize numerous new heterocycles derived from [2.2]paracyclophanes aiming to increase attention on that important asymmetric molecule toward biological activity. Previous reports have dealt with effective biological activities resulting from conjugation between paracyclophane and heterocycle molecules. That might led to the discovery of promising novel hybrids of interesting heterocyclic/paracyclophanes as a starting point in medicinal chemistry art that warrants further research and development as potential biological active candidates.