Synthetic Studies on Potent Marine Drugs : Synthesis and the Crystal Structure of 6-tert-butyl-4-phenyl-4 H-chromene-2-carboxylic Acid

4H-Chromene-2-carboxylic acid ester derivatives of renieramycinMmight be of use for the structural-activity relationship studies of antitumor antibiotic tetrahydroisoquinoline natural products. Accordingly, 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylic acid, one key intermediate, was synthesized via the condensation of (3E)-2-oxo-4-phenylbut-3-enoate methyl ester with 4-tertbutylphenol in the presence of AuCl 3 /3AgOTf (5mol%), followed by cyclodehydration and aqueous hydrolysis. The product was unambiguously shown to the 4H-chromene-2-carboxylic acid by spectroscopy and X-ray crystallographic analysis. A packing diagram of the crystal structure shows that aromatic π-stacking interactions and O–H⋅ ⋅ ⋅O hydrogen bond stabilize the structure in the solid.


Materials and Methods
2.1.General Experimental Details.NMR spectra were measured on a Bruker XL-300 ( 1 H, 300 MHz and 13 C, 75 MHz) and a Bruker XL-400 ( 1 H, 400 MHz and 13 C, 100 MHz).Data for 1 H are reported as follows: chemical shift (, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), integration, coupling constant (Hz), and number.Data for 13 C NMR are reported in terms of chemical shift (, ppm).Infrared (IR) spectra were recorded on a Perkin Elmer 500 FTIR spectrophotometer and are reported in terms of frequency of absorption (cm −1 ).Elemental analyses were performed on Carlo-Mod 1102 instrument.The X-ray structure analysis was performed on a Bruker Smart-1000 X-ray Diffraction meter.Melting points were measured using a Beijing-Taike X-4 apparatus.

Results and Discussion
During our ongoing interest aiming at the synthesis of functional heterocycles [31][32][33][34], we have developed several synthetic strategies for the preparation various 2H-chromenes [35][36][37][38].In one case, we isolated a trace of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylate methyl ester (13a) whose structure has been determined by single-crystal X-ray analysis.However, the formation of 13a was not completely finished when the transformation of this 4H-chromene-2-carboxylate methyl ester into the corresponding 2Hchromene took place [36].Thus, herein we use an improved synthetic method for the synthesis of 4H-chromene-2carboxylate methyl ester 13a along with the corresponding acid.
Decreased yields were observed when the reaction was performed in refluxing tetrahydrofuran or acetonitrile, reflecting the temperature factor effect on this reaction (entries 18-19, and entry 1).As expected, increased yields were observed when the reaction was performed in toluene or nitromethane at 83 ∘ C (entries 20-21).When the reaction was performed in refluxing toluene (110 ∘ C), degradation was observed.
With the optimized reaction conditions in hand, the scope of the reaction with respect to various ,-unsaturated -ketoesters 11 and phenols 12 was subsequently investigated (Table 2).Deactivated phenols, such as 4-nitrophenol (12b) and 4-chlorophenol (12c), prevented any reaction (entries 3-4), indicating that there is an electronic effect on this tandem reaction.To our delight, activated phenols, such as 4-tertbutylphenol (12a) and 2-naphthol (12d), could react smoothly with ,-unsaturated -ketoesters.Further condensation of the crude products in the presence of a drop of concentrated sulfuric acid helps to improve the yield of 4H-chromene-2-carboxylate methyl ester 13a (entries 1-2).However, this additional step is of little use when 2-naphthol (12d) was used as one starting material (entries 5-6).By treating 2-naphthol with ,-unsaturated -ketoester 11a in 1,2-dichloroethane under reflux for 6 hours, 4H-chromene-2-carboxylate methyl ester 13b was obtained in 92% yield (entry 6).With a weak electron-donating group such as a methyl group at the para position of the ,-unsaturated -ketoester, ,-unsaturated -ketoester 11b reacted with 12d to afford product 13c in 90% yield (entry 7).With a strong electron-donating group such as a methoxy group at the para position of the ,unsaturated -ketoester, the corresponding reaction under standard conditions afforded the desired product in 87% yield (entry 8).With the para position of the ,-unsaturated ketoester bearing an electron-withdrawing group such as a chloro group, ,-unsaturated -ketoester 11d reacted equally well with 12d to afford 4H-chromene-2-carboxylate methyl ester 13e in an excellent yield (91%, entry 9).
The structure of 4H-chromene-2-carboxylic acid 8a was shown in Figure 2, in which hydrogen atoms are represented by circles of arbitrary size.The molecule contains two planar groups, a trisubstituted benzene ring and a phenyl group.
A packing diagram of the crystal structure of 4Hchromene-2-carboxylic acid 8a was shown in Figure 3, in which dashed lines indicate hydrogen bonds.This diagram showed that aromatic -stacking interactions and O-H⋅ ⋅ ⋅ O hydrogen bond stabilize the structure in the solid state.

Conclusion
In summary, we have reported an efficient synthesis of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylic acid from (3E)-2-oxo-4-phenylbut-3-enoate methyl ester and 4-tertbutylphenol via the processes of Friedel-Crafts alkylation, cyclodehydration, and aqueous hydrolysis.The reactions were found to have high selectivity and the potential byproducts were not detected in these reactions.The product was confirmed from its spectra and by single-crystal X-ray analysis.Our synthesis paves the way for the preparation of 4H-chromene-2-carboxylic acid ester derivatives of renieramycin M, as well as the corresponding structural-activity relationship studies.

Table 1 :
Survey of conditions for the condensation of 11a with 12a a .
a General conditions: The mixture of AuCl 3 (15.2mg, 0.05 mmol) and AgOTf (38.6 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 0.5 hour and then was added with a ,-unsaturated -ketoester 11 (1.0 mmol) and a phenol 12 (1.0 mmol).The resulting mixture was stirred at reflux for 6 hours.b The crude products in 1,2-dichloroethane (5 mL) were filtered through Celite, added with a drop of concentrated sulfuric acid, and stirred at room temperature for 0.5 hour.