Acid-catalyzed reaction of 1-(2,2-dimethoxyethyl)ureas with phenols as an effective approach to diarylethanes and dibenzoxanthenes

A one-pot synthesis of urea-substituted diarylethanes and dibenzoxanthenes starting from 1-(2,2-dimethoxyethyl)ureas and phenols has been developed. The approach uses readily available reagents and catalysts, requires mild reaction conditions and provides the target compounds in good to high yields


Introduction
Diarylethanes containing urea fragments are known for their pharmacological activity.According to the literature, these compounds exhibit antibacterial activity, [1][2][3] may act as inhibitors of lysine-specific histone demethylase 1 (LSD1) 4 and antagonists of muscarinic acetylcholine 5 and chemokine type 3 receptors (CCR3) 6 .Additionally, some of them can be used in malaria 7 and sclerosis 8 treatment (Figure 1, A).The main synthetic approach to urea-containing diarylethanes is based on the reaction of amines with isocyanates (Figure 1, B).While from a technical point of view the approach is simple, it suffers from hard to access starting amines and/or isocyanates.As a result, varying the target urea substituents is a complex and cumbersome task.0][11][12] The main reason for this, is the presence of both nucleophilic nitrogen and electrophilic α-carbon atoms leading to a diverse array of potential reactions.Moreover, nitrogen-containing acetals serve as valuable reagents for the synthesis of various biologically active compounds, both natural and synthetic.For example, Erythroxylon coca alkaloids were obtained with high enantioselectivity via acid-catalyzed cyclization of 2,2'-{[1,9-di(1,3-dioxan-2-yl)nonane-3,7diyl]bis(azanediyl)}bis(2-phenylethan-1-ol). 131-[2-(1,3-Dioxolan-2-yl)ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline was used as starting compound in the synthesis of S-(-)-crispin A. 14,15 Similarly, N-(2,2methoxyethyl)-1H-indole-2-carboxamide was employed in the synthesis of carbolines. 16Kuehne et al. 17 described a synthesis of 18-methoxycoronaridine from methyl 5-[1-(1,3-dioxolan-2-yl)-3-methoxypropyl]-1,2,3,4,5,6,7,8-octahydroazonino [5,4-b]indole-7-carboxylate.2,2-Dimethoxyethan-1-amine is used in one stage of the synthesis of the anthelmintic drug praziquantel. 18Recently, we successfully used N-substituted 4,4-diethoxybutane-1-amines to prepare pyrazolyl-substituted nicotine analogues. 19erein, we describe results obtained during our ongoing research of nitrogen-containing acetal chemistry and report the employment of 2,2-dimethoxyethane-1-amines in the synthesis of urea-containing diarylethanes and dibenzoxanthenes.Next, we carried out the reaction of the synthesized acetals 2a,b with 4-chlororesorcinol and sesamol.The reaction proceeded smoothly at room temperature in the presence of trifluoroacetic acid and resulted in the diarylethanes 3a,b with fairly good yield (Table 1, entries 1 and 2).4][25] Thus, 2-naphthol and 2,7naphthalenediol were used in the reaction with acetals 2a,b in the presence of an excess of trifluoroacetic acid (Scheme 2).As a result, dibenzoxanthenes 4a-d were obtained in good yields (Table 1, entries 3-6).Notably, no influence of substituents at the nitrogen atom on target compound yields was detected (cf.The bond lengths, valence and torsion angles taken from a single crystal x-ray structure of compound 4c were in the ranges typical for every bond type as proved by X-ray analysis.The conformation of molecule 4c is folded and stabilized by CH(Ph)…π and π…π interactions (Figure 1).The crystal packing of compound 4c involves a large number of non-covalent interactions.Infinite chains are formed by the hydrogen bonds with additional stabilization of Lp…π interactions.Folded layers are formed perpendicular to them due to stacking and CH…π interactions (Figure 2).
The proposed reaction mechanism is similar to that previously described for formation of polyphenols from N-(4,4-diethoxybutyl)sulfonylamides (Scheme 3). 24The key step of the reaction is the elimination of methanol from acetal 2, which affords oxonium ion A. The next stage is the interaction of this species with phenolic nucleophile.Depending on the phenol used, the reaction can lead either to dibenzoxanthenes 4 or diarylethanes 3. The use of naphthol leads to an intermediate compound B; and subsequent stages result in dibenzoxanthenes 4 according to the previously described mechanism. 24

Conclusions
In conclusion, we have developed a convenient one-pot protocol for the synthesis of otherwise hard to access diarylethanes and dibenzoxanthenes via metal-free acid-catalyzed reaction of phenols with 1-(2,2dimethoxyethyl)ureas.

Experimental Section
General. 1 H NMR spectra were recorded on Bruker MSL 400 spectrometer (working frequency 400.13 MHz) in CDCl 3 and (CD 3 ) 2 SO relative to the residual solvent protons. 13C NMR spectra were recorded on Bruker Avance 600 spectrometer (working frequency 150.90 MHz).The MALDI-TOF mass spectra were recorded on a Bruker ULTRAFLEX III TOF/TOF instrument (with 2,5-dihydroxybenzoic acid matrix).IR spectra were obtained with a Bruker Vector 22 spectrometer.Elemental analysis was performed on Carlo Erba EA 1108 instrument.Schöniger method was applied for chlorine determination. 28Melting points were determined in glass capillaries with a Stuart SMP 10 apparatus.Single-crystal X-ray diffraction analysis was performed at 295(2) K on Smart Apex II automatic diffractometer using graphite monochromated radiation.All solvents were purified and dried according to standard procedures.
The X-ray diffraction data for the crystal of 4с were collected on a Smart Apex II automatic diffractometer using graphite monochromated radiation.The structures were solved by direct methods and refined by fullmatrix least-squares using the SHELXL97 26 program.All the non-hydrogen atoms were refined with anisotropic atomic displacement parameters.All figures were made using the program OLEX2 27 .Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Center (deposit number is 1950456).

General method for the synthesis of ureas 2a,b.
To a solution of 2,2-dimethoxyethan-1-amine (0.90 g, 8.60 mmol) and triethylamine (1.74 g, 17.21 mmol) in benzene (15 mL) was added dropwise with cooling (5-7 °C), carbamoyl chloride (8.60 mmol).The reaction mixture was stirred under cooling for 2 hours.The precipitate was filtered off, the filtrate was evaporated in vacuum to afford the oily product.

Figure 1
Figure 1 Molecular structure of compound 4c in the crystalline state.Ellipsoids are shown with 50% probability.
When 4-bromoresorcinol or sesamol are used as nucleophiles, diarylethanes 3 are formed through the intermediate E and benzylic cation F.

Figure 2 Scheme 3 .
Figure 2 Fragment of H-bonded chain in crystal packing of compound 4c.