Exploiting the p-Bromodienone Route for the Formation and Trapping

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00431 • Publication Date (Web): 09 May 2018 Downloaded from http://pubs.acs.org on May 10, 2018

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The Journal of Organic Chemistry

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, I-84084 Fisciano (Salerno), Italy, e-mail: [email protected], [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

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 C-nucleophiles. When calixarene p-bromodienones were treated with enamines, in the presence of AgClO4, the lower-rimACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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substituted C-O-C products were obtained by an electrophilic attack of the intermediate calixareneoxenium cation with a contemporary cone-to-partial-cone inversion of the involved aromatic ring.

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 (para position)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

mechanomolecules,4 to catalysis.5

Scheme 1. The three possible paths of the p-bromodienone route: (II) nucleophilic functionalization of the upper rim through bromine-substitution and de-tert-butylation, (III) meta-functionalization

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through the dienone-phenol rearrangement, and finally (IV) trapping of calixarene-oxenium cation with C-nucleophiles.

Regarding the upper rim modification of calixarene macrocycles, the more common routes include a range of electrophilic aromatic substitutions,6 Claisen rearrangement route,7 p-quinonemethide 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 C-nucleophiles. 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 silvermediated nucleophilic substitution of bromine on calixarene p-bromodienone derivatives11 2a,b (Scheme 1).12 When anionic C-nucleophiles such as acetylides and π-nucleophiles,10 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 dienonephenol rearrangement.13 In detail, the 2,5-cyclohexadienone ring in I (Scheme 1) bearing two alkylgroups 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-functionalization of calixarene macrocycles10,14 represents an 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 coworkers,16 the oxenium cation PhO+ is electrophilic enough to attack aromatic nucleophiles affording the C-O-C bond formation, and on this basis16 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 ACS Paragon Plus Environment


a highly activated π-nucleophile. Oxenium ions17 are 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 electrochemical oxidations of phenols and phenolates.20 Recently an increasing attention has been devoted to the formation and trapping of 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 Oalkylated products through the formation and trapping of calixarene oxenium cations. In particular, we decided to investigated the reaction with enamines, which are among the stronger nucleophiles in the Mayr scale.22

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.


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Scheme 2. Reaction between calixarene p-bromodienone derivatives 2a,b and enamine 3 derived from ethyl acetoacetate.

The structure of derivative 4 was assigned by 1D-2D NMR and HRMS spectra. A HighResolution ESI(+) Fourier-Transform 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 ACS Paragon Plus Environment


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 3-oxobutanoate 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 (2 H) 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 is shielded by the calixarene aromatic cavity. At the expected normal value of 2.05 ppm was found the calix-O-CH2C(O)CH2COOEt methylene group 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 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 3oxobutanoate 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 singlet ACS Paragon Plus Environment

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at 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 t-Bu 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 interactions with an average C-H···πcentroid distance of 2.85 Å and an average C-H···πcentroid angle of 152.7°.

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

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-position of the push-pull enamine 3. Examples have been reported in the literature21 of electrophilic reactions proceeding at the methyl group in γposition of push-pull enamines.



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Scheme 3. Proposed mechanism for the formation of derivatives 4 and 5 via p-bromodienone route. The structure of derivative 6 was analogously confirmed by 1D and 2D NMR and ESI-FTICR 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-tertbutylation to give the re-aromatized product 6. When the cyclohexanone-derived enamine 7 was treated with the mixture of calixarene pbromodienone 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).

Br But But

But

But

But

But

But

O

O

+ O Prn

N

O O O Prn Prn

2a,b

DME, AgClO4 24 h, 25 °C

O O Prn

7

O Prn

O Prn

But

8 (18%)

Scheme 4. Reaction between calixarene p-bromodienone derivatives 2a,b and cyclohexanonederived enamine 7. As above reported for 4 and 5, the structure of 8 was confirmed by 1D, 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 centre. 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


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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 1H 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.

Scheme 5. Reaction between calixarene p-bromodienone derivatives 2a,b and acetylacetonederived enamine 9.

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

13

C 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 evidence 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. ACS Paragon Plus Environment


In order to test if other nucleophiles, such as enols, were also able to trap the calixareneoxenium 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 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 Cnucleophile. In fact, the reaction led to the formation of calixarene derivative 12 in 10% yield. 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 1H 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 (x2), 4.32, and 4.36 ppm, corresponding to 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).

Scheme 6. Reaction between calixarene p-bromodienone derivatives 2a,b and acetone trimethylsilyl enol ether 11.


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Conclusions In conclusion, in this work we have shown that calixarene p-bromodienone derivatives are able to react with enamine nucleophiles to form lower-rim-substituted C-O-C products by trapping of the intermediate electrophilic calixarene-oxenium cation. On the basis, of these data it is envisionable that calixarene oxenium chemistry can be further expanded to give interesting and unexpected results.

Experimental Section General Information. ESI(+)-MS measurements were performed on a triple quadrupole mass spectrometer equipped with electrospray ion source, using CHCl3 as 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 [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, 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 phasesensitive mode using an Echo/Antiecho- TPPI 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) ACS Paragon Plus Environment


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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 addition of CH2Cl2 (5 mL). The organic phase was washed three times with water and 1N 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).

13

C NMR (150 MHz, CDCl3,

298 K): 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,


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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 (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), 1.861.92 (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).

13

C 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),



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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+CH2CHArCH2CO, 7H), 2.29-2.48 (overlapped, CH2CHArCH2CO, 2H), 3.02 (d, ArCH2Ar, J = 12.1 Hz, 1H), 3.05 (d, ArCH2Ar, 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+).

1

HNMR (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).

13

CNMR (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+).

1

HNMR (600 MHz, CDCl3, 298 K): δ 0.82 (s, C(CH3)3,, 9H), 0.94 (t, ACS Paragon Plus Environment

Page 15 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 +CH3CO, 7H), 2.37 (m, OCH2CH2CH3,

2H),

3.16

(d,

ArCH2Ar,

J

=

12.7

Hz,

4H),

3.73

(overlapped,

OCH2CH2CH3+CH2COCH3, 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). 13CNMR (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.

Supporting Information: The supporting information is available free of charge on the ACS Publicatons website. Copies of 1D and 2D 1H and 13C NMR spectra, HR mass spectra of synthesized compounds. Table S20: Cartesian coordinates of the optimzed structure of 5 (PDF) Acknowledgment. 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), the ‟Centro di Tecnologie Integrate per la Salute” (CITIS, Project PONa3_00138), Università di Salerno, for the 600 MHz NMR facilities. Thanks are due to Dr. Patrizia Oliva and Dr. Patrizia Iannece for instrumental assistance.

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Exploiting the p-Bromodienone Route for the Formation and Trapping

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