One-Pot Synthesis of Novel Dibenzoxanthenes , Diarylbutanes , and Calix [ 4 ] resorcinarenes via Consecutive Pyrrolidine Ring-Closure / Ring-Opening Reactions

Herein, we report the approach to the otherwise hardly accessible dibenzoxanthenes, diarylbutanes, and calix[4]resorcinarenes possessing urea moieties based on the reaction of N-(4,4-diethoxybutyl)ureas with electron-rich aromatics in strongly acidic media. Unlike the previously developed methods, the proposed approach benefits from one-pot procedure and allows to obtain the target compounds with much higher yields.


Introduction
Diarylmethane derivatives containing two phenolic moieties are of interest due to their wide spectrum biological activity.
At the same time, methods allowing "one-pot" synthesis of the target compounds is of a great importance nowadays due to both their effectiveness and atom economy [29], which are among main principles of green chemistry.us, herein we report the improved one-pot approach to the diarylbutane derivatives containing urea moieties starting from easily accessible N-(4,4-diethoxybutyl)ureas 2.

Results and Discussion
We assumed that pyrrolidine ring opening in strongly acidic media is general for all 2-aryl substituted pyrrolidines.is assumption was supported both by our own observations [27] and synthesis of diphenylbutane derivative upon treatment of N-phenacyl-2-phenylpyrrolidine with triflic acid in benzene solution described by King et al. [30] (Scheme 1(C)).Based on this data, we proposed that carrying out the reaction of N-(4,4-diethoxybutyl)ureas with phenols in strongly acidic media would allow us to obtain appropriate diarylbutanes in one-pot procedure via consecutive pyrrolidine ring closure-ring opening processes.us, the need of preliminary synthesis of 2-(2hydroxynaphthalene-1-yl)pyrrolidines would be eliminated.
First, we studied the reaction of ureas 2a,c with 2naphthol 3.
e reaction was carried out in chloroform solution in the presence of 3-fold excess of trifluoroacetic acid, since these conditions were found to be optimal for the ring opening in 2-(2-hydroxynaphthalene-1-yl)pyrrolidines 1 [27].However, according to NMR data, in this case the yield of target dibenzoxanthenes 5a,c appeared to be rather low.e main products were previously described by us 2naphthylpyrrolidine derivatives 1a,c [24] (Scheme 2).Next, we gradually increased the amount of trifluoroacetic acid used.Upon increasing the excess of trifluoroacetic acid up to 20-fold, the reaction led to the formation of target dibenzoxanthenes with about 80% yield (Table 1, Nos. 1 and 2).Naphthalene-2,7-diol 4 reacted under the same conditions with urea 2b with the formation of previously unknown 2,12-dihydroxydibenzoxanthene derivative 6b containing urea moiety (Table 1, No. 3).
e applicability of this approach to the synthesis of macrocyclic compounds has been demonstrated as well using 2-methylresorcinol as a model substrate.e reaction of this phenol with ureas 2a,d resulted in the appropriate calix [4]resorcinarenes 10a,d formation with up to 70% yield (Scheme 4, Table 1, No. 9, 10).
As seen from Table 1, using N-(4,4-diethoxybutyl)ureas 2 as a starting compounds instead of 2-(2-hydroxynaphthalene-1-yl)pyrrolidines allowed us to increase the yields of the target compounds by 16% in average.Taking into account the losses of the starting material during the preliminary synthesis of 2-(2-hydroxynaphthalene-1-yl)pyrrolidines, the overall gain in yield was more than 20% (Scheme 5).
Taking into consideration previously published data [30,40], we proposed the mechanism of this reaction depicted in Scheme 6. e first stage of the reaction is a protonation of ethoxy group and elimination of ethanol molecule.e oxonium cation A thus formed may further react with phenol molecule, leading to the 2-arylpyrrolidine derivative B as previously described [24].Subsequent pyrrolidine ring opening in the presence of excess of trifluoroacetic acid followed by interaction with another phenol molecule via the mechanism similar to that of 2-(2hydroxynaphthalene-1-yl)pyrrolidines [27] results in the formation of target compounds E.
In principle, the other pathway is also possible.It includes the protonation of urea moiety of the oxonium cation A, leading to the dication F.
e presence of significant positive charge on the nitrogen atom prevents its intramolecular cyclization, and its further reaction with phenol molecule leads to the acyclic intermediate H.Further reaction of this compound with another phenol molecule via the benzylic cation I also results in the formation of final compounds E.
e experimental data present at the moment does not allow us to unequivocally distinguish between these mechanisms.However, taking into account much higher rate of intramolecular cyclization of N- (4,4-diethoxybutyl)ureas 2 compared to their intermolecular interaction with phenols, as well as instability of dicationic species in non-superacidic media, the first pathway seems to be more probable.Additionally, no acyclic intermediates were present in massspectra of the reaction mixture, which may also indicate the preference of the first pathway over second one.

Conclusions
In conclusion, we have developed one-pot approach to the otherwise hardly accessible dibenzoxanthenes, diarylbutanes, and calix [4]resorcinarenes possessing urea moieties via the reaction of N- (4,4-diethoxybutyl)ureas with electron-rich aromatics in strongly acidic media.e  Journal of Chemistry reaction presumably proceeds via consecutive pyrrolidine ring closure-ring opening stages.e proposed approach, in contrast to the previously developed method, does not require an isolation of intermediates and allows to obtain target compounds with much higher yields.

General Method for the Synthesis of Dibenzoxanthenes
5a,c and 6b.To a mixture of 1.17 mmol of naphthol, 5 ml of chloroform and 0.59 mmol of acetal 2, and 2 ml of trifluoroacetic acid were added.
e reaction mixture was stirred for 24 hours at room temperature, the solvent was removed in vacuum, and the residue was washed with diethyl ether and dried in vacuum.

4
Journal of Chemistry carboxamide 1 in 5 ml of dry chloroform, appropriate 0.90 mmol phenol and 2 ml trifluoroacetic acid were added.e mixture was stirred at room temperature for 72 h.Solvent was evaporated in vacuum.Residue was washed with diethyl ether, filtered, and dried in vacuum (1 h, 0.01 Torr) to give the title compound 7a, 8a-c, 9a.

4.4.
General Method for the Synthesis of Diarylbutanes 7a, 8a-c, 9a.To a mixture of 1.82 mmol of phenol, 5 ml of chloroform, and 0.91 mmol of acetal 2, 2 ml of trifluoroacetic acid was added.
e reaction mixture was stirred for 24 hours at room temperature, the solvent was removed in vacuum, and the residue was washed with diethyl ether and dried in vacuum.
to the signals of residual protons of deuterated solvent (DMSO-d 6 ).13CNMR spectra were recorded on a Bruker Avance 600 (150 MHz) spectrometer relative to signals of residual protons of deuterated solvent (DMSO-d 6 ).MALDI mass-spectra are obtained on a mass spectrometer UltraFlex III TOF/TOF (Bruker Daltonik GmbH, Bremen, Germany) in a linear mode.e laser is Nd : YAG, λ � 266 nm.e data were processed with the FlexAnalysis 3.0 program (Bruker Daltonik GmbH, Bremen, Germany).Positively charged ions were fixed, and a metal target was used.2,5-Dihydroxybenzoic acid (DHB) was used as a matrix.Elemental analysis is performed on a Carlo Erba device EA 1108.e melting points are determined in glass capillaries on a Stuart SMP 10 instrument.