Exploiting the p

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Cite This: J. Org. Chem. 2018, 83, 5947−5953

Exploiting the p‑Bromodienone Route for the Formation and Trapping of Calixarene Oxenium Cations with Enamine Nucleophiles Annunziata Soriente,* Margherita De Rosa, Pellegrino La Manna, Carmen Talotta, Carmine Gaeta,* Aldo Spinella, and Placido Neri Dipartimento di Chimica e Biologia “A. Zambelli”, Università di Salerno, Via Giovanni Paolo II 132, Fisciano, Salerno I-84084, Italy S Supporting Information *

ABSTRACT: This study shows that calixarene p-bromodienone derivatives can act as precursors for the formation of oxenium cations, which can be trapped with enamine Cnucleophiles. When calixarene p-bromodienones were treated with enamines, in the presence of AgClO4, the lower rimsubstituted C−O−C products were obtained by an electrophilic attack of the intermediate calixarene-oxenium cation with a contemporary cone-to-partial-cone inversion of the involved aromatic ring.

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tion of calixarene macrocycles10,14 represents a useful synthetic strategy to obtain new inherently chiral calixarenes.15 In a previous work,10b we have shown that the reaction between calixarene p-bromodienone derivatives11 2a,b and 1,3,5-trihydroxybenzene gives rise to a C−O−C bond between the phloroglucinol moiety and the calixarene oxygen atom at the lower rim (IV in Scheme 1). As highlighted by Abramovitch and co-workers,16 the oxenium cation PhO+ is electrophilic enough to attack aromatic nucleophiles affording the C−O−C bond formation, and on this basis,16 we hypothesized that the formation of IV in Scheme 1 occurs through an electrophilic attack of the calixarene-oxenium R−O+ ion (Scheme 1) to the phloroglucinol ring. Of course, this can be considered as an example of nucleophilic capture of a calixarene-based oxenium R−O+ cation17 from a highly activated π-nucleophile. Oxenium ions17 are a hypovalent species of formula R−O+ in which a monovalent oxygen atom contains two nonbonding electron pairs. Oxenium cations are highly electrophilic and are proposed as intermediates in useful organic reactions, such as the oxidative Hosomi−Sakurai reaction,18 the oxidative Wagner−Meerwin transposition,19 and the electrochemical oxidations of phenols and phenolates.20 Recently, increasing attention has been devoted to the formation and trapping of the oxenium cation17d,21 by novel precursors and in particular by 4disubstituted cyclohexadienone moieties.17c,21d Thus, on the basis of these considerations, we decided to expand our studies on the reaction between calixarene p-bromodienone derivatives 2a,b and highly activated C-nucleophiles, with the aim to explore the probable formation of novel O-alkylated products through the formation and trapping of calixarene-oxenium

INTRODUCTION

After 40 years from their discovery, calixarene1 macrocycles continue to attract a lot of interest thanks to their synthetic and structural versatility. In fact, a plethora of supramolecular hosts have been obtained by modification of calixarene rims through alkylation or esterification of the lower rim (OH groups)1 and electrophilic aromatic substitution of the upper rim (paraposition)1 and meta-positions.2 In this way,1 appropriately modified calixarene derivatives have shown amazing supramolecular properties ranging from molecular recognition3 and synthesis of mechanomolecules4 to catalysis.5 Regarding the upper rim modification of calixarene macrocycles, the more common routes include a range of electrophilic aromatic substitutions,6 Claisen rearrangement route,7 pquinone-methide route,8 and p-chloromethylation route.9 Recently, we introduced the p-bromodienone route10 in which the calixarene upper rim is modified with O- and Cnucleophiles. In other words, through a sort of “aromatic ring umpolung”, the p-bromodienone route allows the direct introduction of alchols,10 carboxylates,10 and glyco-functions at the calixarene upper rim by a silver-mediated nucleophilic substitution of bromine on calixarene p-bromodienone derivatives11 2a,b (Scheme 1).12 When anionic C-nucleophiles such as acetylides and π-nucleophiles10 were reacted with calixarene p-bromodienone derivatives11 2a,b (Scheme 1), then meta-substituted calixarene derivatives10 (Scheme 1) were obtained, in which a new C−C bond was formed through a dienone−phenol rearrangement.13 In detail, the 2,5-cyclohexadienone ring in I (Scheme 1) bearing two alkyl groups at position 4 undergoes a 1,2-migration of one of them (the dienone−phenol rearrangement) to afford meta-substituted calixarene derivatives IIIa,b (Scheme 1). meta-Functionaliza© 2018 American Chemical Society

Received: February 14, 2018 Published: May 9, 2018 5947

DOI: 10.1021/acs.joc.8b00431 J. Org. Chem. 2018, 83, 5947−5953

Article

The Journal of Organic Chemistry Scheme 1. Three Possible Paths of the p-Bromodienone Routea

a

(II) Nucleophilic functionalization of the upper rim through bromine substitution and de-tert-butylation, (III) meta-functionalization through the dienone−phenol rearrangement, and finally (IV) trapping of calixarene-oxenium cation with C-nucleophiles.

cations. In particular, we decided to investigated the reaction with enamines, which are among the stronger nucleophiles in the Mayr scale.22

Scheme 2. Reaction between Calixarene p-Bromodienone Derivatives 2a,b and Enamine 3 Derived from Ethyl Acetoacetate

RESULTS AND DISCUSSION When the mixture of p-bromodienones 2a,b11 was treated with a solution of AgClO4 and the push−pull enamine 3 derived from ethyl acetoacetate, in DME as the solvent, at 25 °C for 24 h (Scheme 2), the calixarene derivatives 4, 5, and 6 were isolated after chromatographic column in 18, 10, and 15% yield, respectively. The structure of derivative 4 was assigned by 1D and 2D NMR and HRMS spectra. A high-resolution ESI(+) FourierTransform ion cyclotron resonance (ESI-FT-ICR) mass spectrum of 4 showed a molecular ion peak [M + Na]+ at 925.5963 m/z (calcd 925.5958), thus confirming its molecular structure. The 1H NMR spectrum of 4 (CDCl3, 600 MHz, 298 K) evidenced the presence of three singlets attributable to calixarene t-Bu groups at 1.12 (18 H), 1.26 (9H), and 1.39 (9H) ppm. The partial cone structure of 4 was confirmed by a close inspection of the methylene region (3−5 ppm) of its 1D and 2D NMR spectra. In detail, a 2D COSY spectrum evidenced the presence of an AX system at 4.27/3.16 ppm, which correlates in the HSQC spectrum with a carbon resonance at 31.08 ppm attributable to the ArCH2Ar group between syn-oriented Ar rings. In addition, an AB system was present at 3.80 and 3.82 ppm, which correlates in the HSQC spectrum with a carbon resonance at 38.4 ppm attributable to the ArCH2Ar group between anti-oriented aromatic rings. The ether linkage between the γ-position of the ethyl 3oxobutanoate moiety and the calixarene oxygen atom was confirmed by the presence in the 1H NMR spectrum of 4 of a diagnostic singlet at 2.55 ppm (2H), which correlates in the HSQC spectrum with a carbon resonance at 75.3 ppm

attributable the calix−O−CH2C(O)CH2COOEt group. The upfield shift of the calix−OCH2C(O)− singlet indicates that it

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DOI: 10.1021/acs.joc.8b00431 J. Org. Chem. 2018, 83, 5947−5953

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The Journal of Organic Chemistry

interactions with an average CH···πcentroid distance of 2.85 Å and an average CH···πcentroid angle of 152.7°. Interestingly, the products 4 and 5 are obtained by an electrophilic attack of the oxenium cation I (Scheme 3), respectively, to the γ- and α-positions of the push−pull enamine 3. Examples have been reported in the literature21 of electrophilic reactions proceeding at the methyl group in γposition of the push−pull enamines. The structure of derivative 6 was analogously confirmed by 1D and 2D NMR and ESI-FT-ICR spectra. The formation of 6 can be explained by the nucleophilic attack of enamine 3 (γattack) to the phenoxonium cation (Scheme 1) to give intermediate I, which undergoes de-tert-butylation to give the rearomatized product 6. When the cyclohexanone-derived enamine 7 was treated with the mixture of calixarene p-bromodienone derivatives11 2a,b, in the presence of AgClO4 in DME as the solvent, then the product of O-alkylation 8 was obtained in 18% yield (Scheme 4). As above-reported for 4 and 5, the structure of 8 was confirmed by 1D and 2D NMR and ESI(+) spectra. The presence of a molecular ion peak at m/z 870.62 in the mass spectrum confirmed the molecular formula of 8. The 1D and 2D NMR spectra of 8 are in accordance with its asymmetric structure, due to presence of the α-CH stereogenic center. In detail, four t-Bu singlets were present at 1.01, 1.08, 1.31, and 1.38 ppm (9H each) and eight meta-coupled doublets were present in the aromatic region of the 1H NMR of 8 (CDCl3, 298 K, 600 MHz) at 6.59, 6.67, 6.75, 6.89, 7.06, 708, 7.12, and 7.21 ppm. Two AX systems were present in the ArCH2Ar region at 4.13/3.05 and 4.11/3.02 ppm, which correlate in the HSQC spectrum 8 with carbon resonances at 30.1 and 30.5 ppm, attributable to ArCH2Ar groups between syn-oriented aromatic rings. Two AB systems were present at 4.04/3.74 and 3.74/3.72 ppm, which correlate in the HSQC spectrum of 8 with carbon resonances at 38.2 and 38.7 ppm, attributable to ArCH2Ar groups between anti-oriented Ar rings of the partial cone structure. Finally, a diagnostic multiplet was present in the 1 H NMR of 8 (CDCl3, 298 K, 600 MHz) at 4.57 ppm attributable to the α-methine group of the cyclohexanone moiety, which correlates in the HSQC spectrum with an oxygenated carbon resonance at 83.4 ppm. The reaction of exo/endo-mixture of 2 was extended to the acetylacetone-derived enammine 9 (Scheme 5), which afforded the product of C-alkylation 10 in 16% yield. The structure of 10 was assigned by means of spectral analysis. In particular, the presence of a pseudomolecular ion peak at m/z 817.15 in the ESI(+) mass spectrum confirmed the molecular formula. The Cs symmetry was confirmed by pertinent signals in the 1H and 13C NMR spectra. In particular, the presence of only two 2:1 tert-butyl singlets at 0.80 and 1.34 ppm, respectively, and of a singlet at 4.66 ppm, attributable to a methine CH group, was a clear indication of the displacement of a t-Bu group from the aromatic moiety and of the C−C linkage between the calixarene carbon atom and the central position of the 2,4-pentandione moiety. In order to test if other nucleophiles, such as enols, were also able to trap the calixarene-oxenium cation, we decided to extend our study to those substrates. In the case of enols, the reaction was performed directly on acetylacetone and ethyl acetoacetate, which contained the equilibrium amount of their corresponding enolic tautomers. Also the corresponding lithium enolates were tested in separate experiments. In all of

is shielded by the calixarene aromatic cavity. At the expected normal value of 2.05 ppm, the calix−O−CH2C(O)CH2COOEt methylene group was found between the two carbonyl groups, which correlates in the HSQC spectrum with a carbon resonance at 43.5 ppm. Finally, the 13C NMR spectrum of 4 showed the diagnostic presence of two resonances at 166.6 and 197.3 ppm, which were attributable to ester and ketone carbonyl groups, respectively. In a similar way, the ESI-FT-ICR mass spectrum of 5 showed a molecular ion peak [M + Na]+ at 925.5993 m/z (calcd 925.5958), thus confirming its molecular structure. The ether linkage between the calixarene oxygen atom and the α-position (methine CH group) of the ethyl 3-oxobutanoate moiety was confirmed by 1D and 2D NMR experiments. In detail, the 1H NMR spectrum of 5 (600 MHz, CDCl3, 298 K) showed the presence of a singlet at 4.75 ppm, which correlates in the HSQC spectrum with a carbon resonance at 82.3 ppm attributable to the methine calixOCH group. The CH singlet at 4.75 ppm shows two 3J correlations in the HMBC spectrum of 5 with carbon resonances at 167.6 and 204.7 attributable to CO groups and a 3J correlation with a carbon resonance at 151.0 ppm attributable to the oxygenated calixarene carbon resonance. The presence of the stereogenic methine carbon makes structure 5 asymmetrical, and this was confirmed by the presence of four t-Bu singlets at 1.15, 1.16, 1.19, and 1.35 ppm (9H each) and eight doublets attributable to ArCH2Ar groups, forming two AX systems at 3.21/4.20 and 3.19/4.37 ppm and two AB systems at 3.76/4.08 and 3.78/4.01 ppm. As expected, these latter correlate in the HSQC spectrum with two carbon resonances at 40.3 and 39.5 ppm attributable to ArCH2Ar groups between anti-oriented Ar rings, thus confirming the partial cone structure of 5. Surprisingly, the methyl group of the ethyl 3-oxobutanoate moiety of 5 resonates in the 1H NMR spectrum, as a singlet at a negative value of chemical shift (−0.11 ppm). This singlet shows a 2J correlation in the HMBC spectrum of 5 with a CO carbon resonance at 204.5 ppm and a 3J correlation with a carbon resonance at 82.5 ppm attributable to the methine calixOCH group. The unusual upfield shift at −0.11 ppm of the methyl group indicates that it is self-included inside the calix cavity of 5, as confirmed by a 2D-ROESY spectrum, which shows the presence of diagnostic dipolar couplings between it and the tBu singlets at 1.15 and 1.19 ppm and with aromatic signals at 7.00, 7.07, and 7.16 ppm. The DFT optimized structure of 5 (Figure 1), at the B3LYP/6-31G(d,p) level of theory, shows the methyl group of the ethyl 3-oxobutanoate moiety included inside the calix cavity to give two stabilizing CH···π

Figure 1. Different views of the DFT-optimized structure of 5 at the B3LYP/6-31G(d,p) level of theory. The methyl group is included inside the calix cavity (green). 5949

DOI: 10.1021/acs.joc.8b00431 J. Org. Chem. 2018, 83, 5947−5953

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The Journal of Organic Chemistry Scheme 3. Proposed Mechanism for the Formation of Derivatives 4 and 5 via the p-Bromodienone Route

Scheme 4. Reaction between Calixarene p-Bromodienone Derivatives 2a,b and Cyclohexanone-Derived Enamine 7

Scheme 5. Reaction between Calixarene p-Bromodienone Derivatives 2a,b and Acetylacetone-Derived Enamine 9.

Scheme 6. Reaction between Calixarene p-Bromodienone Derivatives 2a,b and Acetone Trimethylsilyl Enol Ether 11

the ArCH2Ar bridges. Finally, a typical pattern for aromatic protons was present between 6.40 and 7.20 ppm. Also, in this instance, the absence of O-substituted derivatives could be ascribed to the lower nucleophilicity of the silyl enol ether substrate in comparison with the enamine-based nucleophiles (i.e., 3, 7, and 9).

these instances, no useful derivatives could be traced. This difficulty could be explained by the lower nucleophilicity of the enol-based substrates when compared with the higher reactivity of enamine-based nucleophiles (i.e., 3, 7, and 9). A different behavior was instead observed using acetone trimethylsilyl enol ether as the C-nucleophile. In fact, the reaction led to the formation of calixarene derivative 12 in 10% yield (Scheme 6). The ESI(+) mass spectrum and detailed NMR studies confirmed the presence of the 2-propanone unit as the para-substituent of a free phenolic ring. In particular, the 1 H NMR spectrum showed two singlets at 1.88 and 3.70 ppm relative to CH3CO− and −CH2COCH3 protons, respectively. Four doublets with typical geminal coupling constants were observed at 3.17 (×2), 4.32, and 4.36 ppm, corresponding to

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CONCLUSIONS

In conclusion, in this work, we have shown that calixarene pbromodienone derivatives are able to react with enamine nucleophiles to form lower rim-substituted C−O−C products by trapping of the intermediate electrophilic calixareneoxenium cation. On the basis of these data, it is possible that 5950

DOI: 10.1021/acs.joc.8b00431 J. Org. Chem. 2018, 83, 5947−5953

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The Journal of Organic Chemistry

(overlapped, ArH, 2H), 7.07−7.08 (overlapped, ArH, 2H), 7.09 (d, ArH, J = 2.2 Hz, 1H), 7.16 (d, ArH, J = 2.2 Hz, 1H); 13C NMR (150 MHz, CDCl3, 298 K) δ 10.1, 10.3, 10.5, 14.0, 22.9, 23.0, 23.4, 25.1, 29.9, 30.8, 30.9, 31.5, 31.6, 31.7, 31.75, 34.1, 39.5, 40.3, 61.3, 68.3, 74.6, 74.9, 76.4, 76.9, 77.1, 77.3, 77.9, 82.5, 124.4, 124.7, 124.8, 124.9, 125.0, 125.4, 126.5, 126.8, 127.1, 129.5, 130.9, 131.0, 133.6, 133.7, 134.8, 135.9, 144.7, 145.5, 151.0, 153.0, 154.0, 154.6, 167.6, 204.5; HRMS (ESI) m/z [M + Na]+ calcd for C59H82NaO7 925.5958, found 925.5993. Derivative 6: white solid, 0.15 g, 0.18 mmol, 15% yield; mp 220− 225 °C; 1H NMR (600 MHz, CDCl3, 298 K) δ 0.83 (overlapped, C(CH3)3, 18H), 0.95 (t, OCH2CH2CH3, J = 7.8 Hz, 3H), 1.09 (t, OCH2CH2CH3, J = 7.2 Hz, 6H), 1.22 (t, OCH2CH3, J = 7.2 Hz, 3H), 1.34 (s, C(CH3)3, 9H), 1.86−1.92 (overlapped, OCH2CH2CH3, 4H), 2.33 (m, OCH2CH2CH3, 2H), 3.17 (d, ArCH2Ar, J = 12.6 Hz, 2H), 3.23 (d, ArCH2Ar, J = 13.2 Hz, 2H), 3.36 (s, COCH2CO, 2H), 3.70− 3.76 (overlapped, OCH2CH2CH3 and CH2COCH2CO, 6H), 3.84 (t, OCH2CH2CH3, J = 7.8 Hz, 2H), 4.15 (q, OCH2CH3, J = 7.2 Hz, 2H), 4.31 (d, ArCH2Ar, J = 13.2 Hz, 2H), 4.36 (d, ArCH2Ar, J = 12.6 Hz, 2H), 5.80 (s, OH, 1H), 6.45 (d, ArH, J = 2.2 Hz, 2H), 6.55 (d, ArH, J = 2.2 Hz, 2H), 6.92 (s, ArH, 2H), 7.14 (s, ArH, 2H); 13C NMR (150 MHz, CDCl3, 298 K) δ 9.8, 11.0, 14.2, 22.7, 23.6, 29.9, 31.3, 31.3, 31.5, 31.9, 33.9, 34.3, 47.5, 50.1, 61.5, 76.5, 78.1, 123.4, 124.6, 125.2, 125.8, 129.5, 131.0, 131.4, 132.6, 136.1, 145.4, 145.8, 152.0, 153.0, 154.1, 167.5, 202.0; HRMS (ESI) m/z [M + Na]+ calcd for C55H74NaO7 869.5332, found 869.5383. Derivative 8: white solid, 0.18 g, 0.21 mmol, 18% yield; mp 196− 200 °C; ESI(+) MS m/z 870.62 (MH+); 1H NMR (600 MHz, CDCl3, 298 K) δ 0.74 (t, OCH2CH2CH3, J = 7.2 Hz, 3H), 0.95 (t, OCH2CH2CH3, J = 7.1 Hz, 3H), 0.99 (t, OCH2CH2CH3, J = 7.4 Hz, 3H), 1.01 (s, C(CH3)3, 9H), 1.08 (s, C(CH3)3, 9H), 1.31 (s, C(CH3)3, 9H), 1.38 (s, C(CH3)3, 9H), 1.52−2.02 (overlapped, OCH2CH2CH3 and CH2CHArCH2CO, 7H), 2.29−2.48 (overlapped, CH2CHArCH2CO, 2H), 3.02 (d, ArCH2Ar, J = 12.1 Hz, 1H), 3.05 (d, ArCH 2 Ar, J = 12.1 Hz, 1H), 3.44−3.54 (overlapped, OCH2CH2CH3, 6H), 3.72 (AB, ArCH2Ar, J = 12.2 Hz, 1H), 3.74 (AB, ArCH2Ar, J = 12.2 Hz, 1H), 3.74 (AB, ArCH2Ar, J = 12.1 Hz, 1H), 4.04 (AB, ArCH2Ar, J = 12.1 Hz, 1H), 4.11 (d, ArCH2Ar, J = 12.1 Hz, 1H), 4.13 (d, ArCH2Ar, J = 12.1 Hz, 1H), 6.59 (s, ArH, 1H), 6.67 (s, ArH, 1H), 6.75 (s, ArH, 1H), 6.89 (s, ArH,2H), 7.06 (s, ArH, 1H), 7.08 (s, ArH, 1H), 7.12 (s, ArH, 1H), 7.21 (s, ArH, 1H); 13C NMR (150 MHz, CDCl3, 298 K) δ 9.7, 10.6, 10.8, 22.2, 23.6, 23.7, 23.8, 28.3, 30.1, 30.5, 31.8, 33.8, 33.9, 34.1, 34.2, 34.5, 38.2, 38.7, 41.1, 75.6, 76.2, 83.4, 124.8, 125, 125.2, 125.3, 125.5, 125.9, 126.1, 128,128.3, 131.2, 131.4, 132.2, 132.4, 133.1, 133.5, 135.5, 135.9, 142.8, 143.6, 143.8, 144.9, 153.8, 154.1, 154.2, 208.6. Anal. Calcd for C59H82O5: C, 81.33; H, 9.49. Found: C, 81.35; H, 9.48. Derivative 10: white solid, 0.15 g, 0.17 mmol, 16% yield; mp 188− 197 °C; ESI(+) MS m/z 817.15 (MH+); 1H NMR (600 MHz, CDCl3, 298 K) δ 0.80 (s, C(CH3)3,18H), 0.95 (t, OCH2CH2CH3, J = 7.8 Hz, 3H), 1.09 (t, OCH2CH2CH3, J = 7.3 Hz, 6H), 1.34 (s, C(CH3)3, 9H), 1.88 (s, CH3CO, 3H), 1.93 (s, CH3CO, 3H), 1.88−1.93 (overlapped, OCH2CH2CH3, 4H), 2.38 (m, OCH2CH2CH3, 2H), 3.18 (d, ArCH2Ar, J = 12.3 Hz, 2H), 3.23 (d, ArCH2Ar, J = 13.2 Hz, 2H), 3.73 (t, OCH2CH2CH3, J = 7.4 Hz, 4H), 3.84 (t, OCH2CH2CH3, J = 7.4 Hz, 4H), 4.35 (d, ArCH2Ar, J = 12.3 Hz, 2H), 4.37 (d, ArCH2Ar, J = 13.2 Hz, 2H), 4.66 (s, COCHCO, 1H), 5.69 (s, OH, 1H), 6.44 (s, ArH, 2H), 6.54 (s, ArH,2H), 6.87 (s, ArH, 2H), 7.15 (s, ArH, 2H); 13C NMR (150 MHz, CDCl3, 298 K) δ 9.8, 11.02, 14.3, 22.7, 23.6, 24.2, 24.3, 29.9, 31.2, 31.4, 31.9, 33.8, 34.4, 76.5, 78.2, 115.5, 124.4, 125.3, 125.9, 127.4, 129.9, 130.9, 131.5, 132.7, 136.2, 145.4, 146.0, 152.0, 152.9, 154.1, 191.2, 191.5. Anal. Calcd for C54H72O6: C, 79.37; H, 8.88. Found: C, 79.36; H, 8.86. Derivative 12: white solid, 0.11 g, 0.14 mmol, 10% yield; mp 185− 189 °C; ESI(+) MS m/z 813.52 (MK+); 1H NMR (600 MHz, CDCl3, 298 K) δ 0.82 (s, C(CH3)3, 9H), 0.94 (t, OCH2CH2CH3, J = 7.5 Hz, 3H), 1.07 (t, OCH2CH2CH3, J = 7.4 Hz, 6H), 1.31 (s, C(CH3)3, 9H), 1.33 (s, C(CH3)3, 9H), 1.88−1.93 (overlapped, OCH2CH2CH3 and CH3CO, 7H), 2.37 (m, OCH2CH2CH3, 2H), 3.16 (d, ArCH2Ar, J = 12.7 Hz, 4H), 3.73 (overlapped, OCH2CH2CH3 and CH2COCH3,

calixarene-oxenium chemistry can be further expanded to give interesting and unexpected results.

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EXPERIMENTAL SECTION

General Information. ESI(+)-MS measurements were performed on a triple quadrupole mass spectrometer equipped with an electrospray ion source, using CHCl3 as a solvent. The mass spectra were calibrated externally and a linear calibration was applied. All chemicals were reagent grade and were used without further purification. Anhydrous solvents were used as purchased from the supplier. When necessary compounds were dried in vacuo over CaCl2. Reaction temperatures were measured externally. Reactions were monitored by TLC silica gel plates (0.25 mm) and visualized by UV light or by spraying with H2SO4−Ce(SO4)2. NMR spectra were recorded on a 600 MHz spectrometer [600 (1H) and 150 MHz (13C)], 400 MHz spectrometer [400 (1H) and 100 MHz (13C)], or 300 MHz spectrometer [300 (1H) and 75 MHz (13C)]. Chemical shifts are reported relative to the residual solvent peak (CHCl3 δ 7.26, CDCl3 δ 77.23). Standard pulse programs, provided by the manufacturer, were used for 2D NMR experiments, COSY-45, HSQC, and HMBC. COSY-45 spectra were taken using a relaxation delay of 2 s with 30 scans and 170 increments of 2048 points each. HSQC spectra were performed with the gradient selection, sensitivity enhancement, and phase-sensitive mode using an Echo/AntiechoTPPI procedure. Typically, 20 scans with 113 increments of 2048 points each were acquired General Procedure for the Reaction of Enamines with Calixarene-p-bromodienone 2a,b. A mixture of enamine or enol trimethylsilyl ether (3, 7, 9, or 11) (11.7 mmol) and AgClO4 (2.3 mmol) in DME (5 mL) was cooled at 0 °C, and a solution of calix[4]arene p-bromodienones 2a,b (1.17 mmol) in DME (5 mL) was added. The reaction mixture was allowed to warm at room temperature and stirred for 24 h. The reaction was stopped by the addition of CH2Cl2 (5 mL). The organic phase was washed three times with water and 1 N HCl, dried over Na2SO4, and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel. Derivative 4: white solid, 0.19 g, 0.21 mmol, 18% yield; mp 210− 215 °C; 1H NMR (CDCl3, 600 MHz, 298 K) δ 0.76 (t, OCH2CH2CH3, J = 7.5 Hz, 3H), 0.93 (t, OCH2CH2CH3, J = 7.4 Hz, 6H), 1.12 (overlapped, C(CH3)3, 18H), 1.19 (t, OCH2CH2CH3, J = 7.2 Hz, 3H), 1.26 (s, C(CH3)3, 9H), 1.39 (s, C(CH3)3, 9H), 1.65− 1.85 (overlapped, OCH2CH2CH3, 6H), 2.05 (s, COCH2CO, 2H), 2.55 (s, CH2COCH2CO, 2H), 3.16 (d, ArCH2Ar, J = 12.4 Hz, 2H), 3.48−3.58 (overlapped, OCH2CH2CH3, 4H), 3.71−3.74 (overlapped, OCH2CH2CH3, 2H), 3.80 and 3.82 (AB, ArCH2Ar, J = 12.4 Hz, 4H), 4.06 (q, OCH2CH3, J = 7.1 Hz, 2H), 4.27 (d, ArCH2Ar, J = 12.4 Hz, 2H), 6.88 (s, ArH, 2H), 6.93 (s, ArH, 2H), 7.11 (s, ArH, 2H), 7.20 (s, ArH, 2H); 13C NMR (150 MHz, CDCl3, 298 K) δ 9.5, 9.7, 10.4, 10.6, 14.1, 14.2, 21.8, 21.9, 23.1, 23.5, 31.1, 33.9, 34.0, 34.0, 37.8, 38.4, 43.5, 60.0, 60.7, 70.9, 75.3, 75.4, 75.8, 75.9, 76.1, 76.8, 76.8, 77.2, 89.9, 125.1, 125.1, 125.3, 125.5, 125.6, 125.9, 126.3, 127.7, 128.0, 131.9, 132.6, 133.1, 133.4, 133.5, 143.8, 143.9, 144.2, 145.1, 145.6, 153.4, 153.7, 153.8, 154.3, 166.6, 197.3; HRMS (ESI) m/z [M + Na]+ calcd for C59H82NaO7 925.5958, found 925.5963. Derivative 5: white solid, 0.10 g, 0.12 mmol, 10% yield; mp 200− 205 °C; 1H NMR (CDCl3, 600 MHz, 298 K) δ −0.11 (s, CH3COCH2CO, 3H), 0.82 (t, OCH2CH2CH3, J = 7.3 Hz, 6H), 0.86 (t, OCH2CH2CH3, J = 7.6 Hz, 3H), 0.88 (t, OCH2CH2CH3, J = 7.5 Hz, 3H), 1.08 (t, COOCH2CH3, J = 7.0 Hz, 3H), 1.15 (s, C(CH3)3, 9H), 1.16 (s, C(CH3)3, 9H), 1.19 (s, C(CH3)3, 9H), 1.35 (s, C(CH3)3, 9H), 1.67−1.78 (overlapped, OCH2CH2CH3, 6H), 3.19 (d, ArCH2Ar, J = 11.9 Hz, 1H), 3.21 (d, ArCH2Ar, J = 12.0 Hz, 1H), 3.59−3.69 (overlapped, OCH2CH2CH3, 6H), 4.01−4.12 (overlapped, OCH2CH3, 2H), 3.76 (d, ArCH2Ar, J = 14.8 Hz, 1H), 3.78 (d, ArCH2Ar, J = 16.0 Hz, 1H), 4.01 (d, ArCH2Ar, J = 14.8 Hz, 1H), 4.08 (d, ArCH2Ar, J = 16.0 Hz, 1H), 4.20 (d, ArCH2Ar, J = 12.0 Hz, 1H), 4.37 (d, ArCH2Ar, J = 12.0 Hz, 1H), 4.75 (s, COCHCO, 1H), 6.77 (d, ArH, J = 2.2 Hz, 1H), 7.00 (d, ArH, J = 2.2 Hz, 1H), 7.01−7.02 5951

DOI: 10.1021/acs.joc.8b00431 J. Org. Chem. 2018, 83, 5947−5953

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The Journal of Organic Chemistry 6H), 3.84 (m, OCH2CH2CH3, 2H), 4.32 (d, ArCH2Ar, J = 12.7 Hz, 2H), 4.36 (d, ArCH2Ar, J = 12.7 Hz, 2H), 5.15 (s, OH, 1H), 6.48 (d, J = 2.4 Hz, ArH, 2H), 6.53 (s, J = 2.4 Hz, ArH, 2H), 6.73 (s, ArH, 2H), 7.14 (s, ArH, 2H); 13C NMR (150 MHz, CDCl3, 298 K) δ 9.6, 11.0, 22.7, 23.7, 29.1, 31.4, 31.7, 32.0, 33.8, 34.4, 76.7, 77.7, 78.0, 124.5, 124.8, 125.1, 125.8, 130.9, 131.9, 132.6, 136.4, 145.9, 146.9, 152.3, 153.9, 199.1. Anal. Calcd for C52H70O5: C, 80.58; H, 9.10. Found: C, 80.56; H, 9.08.

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Lett. 2003, 44, 6087−6090. (b) Soriente, A.; De Rosa, M.; Fruilo, M.; Lepore, L.; Gaeta, C.; Neri, P. Study on an aldol reaction catalyzed by Ti(IV)/calix[n]arene complexes. Adv. Synth. Catal. 2005, 347, 816− 824. (c) De Rosa, M.; La Manna, P.; Soriente, A.; Gaeta, C.; Talotta, C.; Neri, P. Exploiting the hydrophobicity of calixarene macrocycles for catalysis under ″on-water″ conditions. RSC Adv. 2016, 6, 91846− 91851. (d) Cafeo, G.; De Rosa, M.; Kohnke, F. H.; Soriente, A.; Talotta, C.; Valenti, L. Calixpyrrole derivatives: ″Multi hydrogen bond″ catalysts forγ-butenolide synthesis. Molecules 2009, 14 (7), 2594−2601. (6) See ref 1. (7) Gutsche, C. D.; Levine, J. Calixarenes. 6. Synthesis of a functionalizable calix[4]arene in a conformationally rigid cone conformation. J. Am. Chem. Soc. 1982, 104, 2652−2653. (8) Gutsche, C. D.; Nam, K. C. Calixarenes. 22. Synthesis, properties, and metal complexation of aminocalixarenes. J. Am. Chem. Soc. 1988, 110, 6153−6162. (9) Almi, M.; Arduini, A.; Casnati, A.; Pochini, A.; Ungaro, R. Chloromethylation of calixarenes and synthesis of new water soluble macrocyclic hosts. Tetrahedron 1989, 45, 2177−2182. (10) (a) De Rosa, M.; Soriente, A.; Concilio, G.; Talotta, C.; Gaeta, C.; Neri, P. Nucleophilic Functionalization of the Calix[6]arene Paraand Meta-Position via p-Bromodienone Route. J. Org. Chem. 2015, 80, 7295−7300 and references cited therein.. (b) Troisi, F.; Pierro, T.; Carratù, M.; Gaeta, C.; Neri, P. Appending aromatic moieties at the para- and meta-position of calixarene phenol rings via p-bromodienone route. Tetrahedron Lett. 2009, 50, 4416−4419. (11) Gaeta, C.; Martino, M.; Neri, P. Synthesis of the first examples of p-bromodienone and transannular spirodienone calixarene derivatives. Tetrahedron Lett. 2003, 44, 9155−9159. (12) Analogously, Varma and co-workers reported the direct introduction of alcohols at the calixarene upper rim starting from calixarene spirodienone derivatives: (a) Thulasi, S.; Bhagavathy, G. V.; Eliyan, J.; Varma, L. R. A novel method for the upper rim alkoxysubstitution of calix[4]arene via a bis(spirodienone) route. Tetrahedron Lett. 2009, 50, 770−772. (b) Thulasi, S.; Babu, J.; Babukuttannair, A.; Sreemathi, V.; Varma, L. R. Direct access to upper rim substituted mono- and diaryloxy calix[4]arenes via bis(spirodienone) route. Tetrahedron 2010, 66, 5270−5276. (13) For a review, see: (a) Miller, B. Too many rearrangements of cyclohexadienones. Acc. Chem. Res. 1975, 8, 245−256. (b) Lukyanov, S. M.; Koblik, A. V. In The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester, UK, 2003; Chapter 11, pp 806−816 and references cited therein. For more recent examples, see: (c) Chen, Y.; Reymond, J.-L.; Lerner, R. A. An antibody-catalyzed 1,2- rearrangement of carbon-carbon bonds. Angew. Chem., Int. Ed. Engl. 1994, 33, 1607− 1609. (d) Sauer, A. M.; Crowe, W. E.; Henderson, G.; Laine, R. A. Conformational control of selectivity in the dienone−phenol rearrangement. Tetrahedron Lett. 2007, 48, 6590−6593. (14) (a) Tlusty, M.; Slavik, P.; Kohout, M.; Eigner, V.; Lhotak, P. Inherently Chiral Upper-Rim-Bridged Calix[4]arenes Possessing a Seven Membered Ring. Org. Lett. 2017, 19, 2933−2936. (b) Slavik, P.; Kohout, M.; Bohm, S.; Eigner, V.; Lhotak, P. Synthesis of inherently chiral calixarenes via direct mercuration of the partial cone conformation. Chem. Commun. 2016, 52, 2366−2369. (c) Slavik, P.; Dudic, M.; Flidrova, K.; Sykora, J.; Cisarova, I.; Bohm, S.; Lhotak, P. Unprecedented Meta-Substitution of Calixarenes: Direct Way to Inherently Chiral Derivatives. Org. Lett. 2012, 14, 3628−3631. (15) (a) Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. Inherent chirality” and curvature. New J. Chem. 2004, 28, 1198−1199. (b) Szumna, A. Inherently chiral concave moleculesfrom synthesis to applications. Chem. Soc. Rev. 2010, 39, 4274−4285. (16) (a) Abramovitch, R. A.; Inbasekaran, M.; Kato, S. Thermolysis of aryloxypyridinium salts. Possible generation of aryloxenium ions. J. Am. Chem. Soc. 1973, 95, 5428−5430. (b) Abramovitch, R. A.; Alvernhe, G.; Bartnik, R.; Dassanayake, N. L.; Inbasekaran, M.; Kato, S. Aryloxenium ions. Generation from N-(aryloxy)pyridinium tetrafluoroborates and reaction with anisole and benzonitrile. J. Am. Chem. Soc. 1981, 103, 4558−4565. (c) Abramovitch, R. A.; Bartnik, R.;

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00431. Copies of 1D and 2D 1H and 13C NMR spectra, HR mass spectra of synthesized compounds, Cartesian coordinates of the optimized structure of 5 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Annunziata Soriente: 0000-0001-6937-8405 Margherita De Rosa: 0000-0001-7451-5523 Carmen Talotta: 0000-0002-2142-6305 Carmine Gaeta: 0000-0002-2160-8977 Placido Neri: 0000-0003-4319-1727 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the Regione Campania (POR CAMPANIA FESR 2007/2013 O.O.2.1, CUP B46D14002660009) for the FT-ICR mass spectrometer facilities and Farma-BioNet (CUP B25C13000230007) and the “Centro di Tecnologie Integrate per la Salute” (CITIS, Project PONa3-00138), Università di Salerno, for the 600 MHz NMR facilities. We are thankful to Dr. Patrizia Oliva and Dr. Patrizia Iannece for instrumental assistance.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00431 J. Org. Chem. 2018, 83, 5947−5953