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 paracyclophanylheterocycles (Figure 1), 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 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 fivemembered 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 3benzilic acid hydrazone. 13 More specifically, acylhydrazidebased 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.  (6) and N-(4′- [2.2]Paracyclophanyl)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 1. 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 NaN 3 /acetone to give compound 4 24 (Scheme 1). Heating 4 in toluene at 80°C provided the corresponding isothionate 5 24 in 70% yield (Scheme 1). Second, fusion of 5 with benzylamine gave the corresponding urea 6 in 87% yield (Scheme 1). Based on NMR, IR, mass spectra, as well as HRMS, the structure of compound 6 was satisfactorily proved. As the 1 H NMR spectrum indicated the appearance of the CH 2 protons of compound 6 as a doublet at δ H = 4.26 (J = 6.0 Hz). Whereas, the two NH protons appeared as two singlets at δ H = 7.73 and 6.75 ppm. In 13 C NMR, the CH 2 and the carbonyl carbon signals resonated at δ C = 42.9 and 158.1 ppm, respectively. On subjecting 5 with hydrazines by the procedure mentioned in Scheme 1, N-(4′- [2.2]paracyclophanyl)hydrazinecarboxamides 7a and 7b were obtained in very good yields (Scheme 1). 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 1 H NMR spectrum exhibited the NH-2 and NH-1 protons at δ H = 7.59 and 6.88 ppm, respectively. In addition, the characteristic hydrazine-NH 2 resonated in the 1 H NMR spectrum at δ H = 4.72 ppm. The 13 C NMR spectrum displayed the carbonyl-carbon at δ C = 157.3, whereas the four distinctive CH 2 -bridged carbons of PC resonated at δ C = 35.4, 35.1, 32.9, and 32.3 ppm. HRMS proved the chemical formula of 7a as C 17 For compound 7b, HRMS confirmed the molecular formula of compound 7b as C 23 H 23 N 3 O. The 1 H NMR spectrum revealed the NH protons as three singlets at δ H = 8.36 (for NH-2), 7.97 (for NH-1), and 6.60 ppm for (NH-3). The 13 C NMR spectrum of compound 7b revealed the carbonyl carbon at δ C = 155.8, whereas the carbon signal of C-Ph was observed at δ C = 149.1 ppm (see the Experimental Section). The four carbon signals of the CH 2 −CH 2 appeared at δ C = 36.4, 36.1, 35.7, and 32.2 ppm.
2.2. 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 2). HRMS confirmed the molecular formula of 9 as C 23 H 25 N 3 O 5 indicating the addition reaction of compound 7a to 8a proceeded without elimination of a MeOH molecule. To discriminate between the possible structures 9 and 9′, we analyzed the NMR spectrum. As, the hydrazano-NH appeared in the 1 H NMR spectrum as a singlet at δ H = 11.01, whereas the PC-NH at δ H = 8.45. The two methyl-ester protons appeared as two very close singlets at δ H = 3.90 and 3.75 ppm. The 1 H NMR did not reveal any proton for the ethylenic-H, which excluded the formation of the isomeric product 9′ (Figure 2). The CH 2 carbon and its protons attached to the ester group resonated at the same region of the ethylenic-CH 2 of PC. The 13 C NMR spectrum revealed the two methyl-esters at δ C = 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 3.
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 2). 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 1 H NMR spectrum revealed two singlets at δ H = 8.99 (NH-1) and 7.50 ppm (NH-3). The ethyl protons   were detected in the 1 H NMR spectrum as a quartet at δ H = 3.61 (for CH 2 , J = 7.2 Hz) and as a double-triplet at δ H = 1.08 ppm (for CH 3 , J = 13.2, 7.1 Hz). The 13 C NMR spectrum presented the CS and the ethyl carbon signals at δ C = 180.2, 56.5 (CH 2 -ethyl) and 14.9 ppm (CH 3 -ethyl), respectively. HRMS confirmed the molecular formula of 11d as C 19 H 22 N 2 S. Finally, X-ray structure analysis confirmed the structure of compound 11d as shown in Figure 4.
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 3). 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 3). Upon heating, N 2 and CO would then be eliminated, as shown in Scheme 3, to produce 11 (Scheme 3).
2.3. 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 1 H NMR spectrum via the appearance of the aromatic protons as two multiplets at δ H = 7.58−7.27 (for 5H) and at δ H = 6.66−6.22 ppm (6H), whereas the vinylproton of the exocyclic double bond resonated as a singlet δ H = 6.78 ppm. A quartet at δ H = 5.22 (J = 8.2 Hz, for CH 2 ) and as a triplet (3H) at δ H = 1.20 (J = 6.9 Hz, CH 3 ) appeared to indicate the ethyl ester protons. The benzyl protons are clearly resonated as a double-doublet at δ H = 4.17 ppm (J = 14.3, 6. 8 Hz). The 13 C NMR spectrum supported the structure of compound of 14b via the appearance of the carbonyl carbon signals at δ C = 150.3 and at 147.5 ppm. The ester carbons and the benzyl carbon signals appeared at δ C = 61.4 (ester-CH 2 ), 13.90 (ester-CH 3 ), and 45.9 ppm (CH 2 -benzyl).
In the way to synthesize 1,3,4-oxazole derivative 16, one example, such as 12e, was chosen (Scheme 4). The disappearance of the carbonyl and CS carbons in the IR and 13 C NMR indicated that cyclization occurred (Scheme 4). The 1 H NMR spectrum of 16 showed the two NH protons as two singlets at δ H = 9.41 and 8.44 ppm (see the Experimental Section). The allyl protons appeared as a doublet at δ H = 6.76 (J = 1.4 Hz), besides two multiplets at δ H = 5.98−5.90 and at δ H = 5.35 and 5.25. According to the 13 C NMR spectrum of compound 16, three carbons were distinguished for the allyl carbons at δ C = 46.3 (CH 2 ), 115.8 (CH 2 ), and 132.3 ppm (CH−), respectively.

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 1 H NMR and 101 MHz for 13 C NMR; the references used were the 1 H and 13 C peaks of the solvents, d 6 -dimethyl sulfoxide ((CD 3 ) 2 SOd 6 ): 2.50 ppm for 1 H NMR and 39.4 ppm for 13 C 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: H Ar = aromatic-CH, H Pc = [2.2]paracyclophane-CH 2 . Signals of the 13 C 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), C q = 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.
3.1. General Procedures. Compounds 2−5 were prepared according to the literature. 23 3.2. 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.