Facile access to 2-aryl-3-nitro-2 H -chromenes and 2,3,4-trisubstituted chromanes

.


Introduction
5][6] The tandem oxa-Michael-Henry reaction of salicylaldehyde with β-nitrostyrenes is considered to be the most straightforward for preparation of 2-aryl-3-nitro-2H-chromenes.Several reports describe construction of 2-aryl-3-nitro-2H-chromenes in good yields using 1,4-diazabicyclo[2.2.2]octane (DABCO), 7,8 L-pipecolinic acid 9 or C 2 -symmetric pyrrolidine-triazoles 10 as catalysts.The preparation of optically active 2-aryl-3-nitro-2H-chromenes through asymmetric tandem oxa-Michael-Henry reactions has also been realized recently, with chiral pyrrolidine derivatives, 11,12 or cinchona alkaloid-derived bifunctional thioureas 13 as catalysts under mild conditions, respectively.Kinetic resolution of racemic 2-aryl-3-nitro-2H-chromenes can also be used to provide their enantioriched forms. 14,15However, long reaction times (up to 7 days), high catalystloadings (up to 50 mol%) and toxic solvents (usually in toluene) are involved in some of the aforementioned processes.Therefore, a practical and efficient synthesis of 2-aryl-3-nitro-2Hchromenes in good yields under mild conditions is still needed.2,3,4-Trisubstituted chromanes are usually obtained through nucleophilic additions of activated 2H-chromenes with 1,3dicarbonyl compounds, 16,17 pyrrole 18 or indole. 19The activation of all reagents by the combination of two catalysts to afford a single chemical transformation is emerging as a powerful synthetic strategy in recent decades, and it was also highlighted by MacMillan and coworkers. 20In 2007, Córdova and colleagues 21 developed a novel and efficient one-pot synthesis of 2-aryl-3-formyl-2H-chromenes from salicylaldehydes and cinnamic aldehydes using the combination of pyrrolidine and benzoic acid as catalyst.
Herein we report a facile access to 2-aryl-3-nitro-2H-chromenes through tandem oxa-Michael-Henry reactions of various salicylaldehydes and β-nitrostyrenes using the combination of pyrrolidine and benzoic acid as catalyst, and the Michael additions of 2-aryl-3-nitro-2Hchromenes with acetone are firstly performed under the same catalytic combination in brine to provide multi-substituted chromanes in good yields.The structures of 2-aryl-3-nitro-2Hchromenes and 2,3,4-trisubstituted chromanes were confirmed by X-ray single crystal diffraction analysis.Additionally, the reductive amination of a 2,3,4-trisubstituted chromane was also investigated and provided a fused tricyclic amine in high yield.

Results and Discussion
Initially, the tandem oxa-Michael-Henry reaction of salicylaldehyde 1a with β-nitrostyrene 2a was selected as a model reaction (Table 1).It was found that there is no transformation when benzoic acid was used as the sole catalyst, and pyrrolidine was used as sole catalyst to give 2phenyl-3-nitro-2H-chromene 3a in 32% yield (entry 1).The catalytic combination of pyrrolidine and benzoic acid can provide 3a in 74% yield in toluene at 80 °C (entry 2).From an environmental viewpoint, ethanol was investigated as solvent instead of toluene.To our delight, 3a was obtained in 76% yield in refluxing ethanol.Then, combinations of pyrrolidine with various acids were screened (entries 3-8).Interestingly, when salicylic acid was used as cocatalyst, 3a was isolated in low yield (41%, entry 4), thus it seems that the hydroxyl group for one hydrogen-bonding donor in salicylic acid is not helpful to this tandem reaction.The combinations of pyrrolidine with the other acids such as acetic acid (HOAc, entry 5), trifluoroacetic acid (TFA, entry 6) and para-toluenesulfonic acid (PTSA, entry 7) respectively resulted in no reaction under the comparable conditions.Chiral phosphoric acids (CPAs) based on the BINOL-skeleton have been widely used as efficient catalysts for many enantioselective transformations. 22Due to the scarcity of direct enantioselective synthesis of chiral 2-aryl-3-nitro-2H-chromenes, we have used a BINOL-based chiral phosphoric acid as a co-catalyst with pyrrolidine in the tandem oxa-Michael-Henry reaction of salicylaldehyde with β-nitrostyrene (entry 8) hopefully to give enantioriched 3a.Unfortunately, this catalytic combination proved to be useless.The catalyst-loading was also investigated and it was found that the lower catalystloadings resulted in lower yields (entry 3 vs entries 9 and 10).1.1 mmol of salicylaldehyde, 1.0 mmol of β-nitrostyrene and 0.30 mmol of pyrrolidine were used in 2.0 mL of solvent for entries 1 to 8, and the reaction time was within 12 hours; b CPA = (S)-(+)-1,1'-binaphthyl-2,2'-diylhydrogen phosphate; c Isolated yield based on β-nitrostyrene 2a.d The use of pyrrolidine was also decreased to 20 mol%; e The use of pyrrolidine was also decreased to 10 mol%.
After further systematic optimization of the reaction conditions, the tandem oxa-Michael-Henry reactions between various substituted salicylaldehydes 1 and β-nitrostyrenes 2 were explored (Table 2).All salicylaldehydes, regardless of possessing an electron-withdrawing ordonating group, reacted smoothly with β-nitrostyrenes (entries 1-9) to afford 2-phenyl-3-nitro-2H-chromenes 3a-i in moderate to good yields, and the reactions between the salicylaldehydes with electron-withdrawing group and 2a gave the corresponding products in higher yields than those salicylaldehydes with electron-donating groups under the same conditions (entries 4 and 5 vs entries 6, 7 and 9).The substitutents on the β-nitrostyrenes seem to have slight effect on the yields (entry 1 vs entries 2, 3 and 8).Single crystals of 3i were grown from CH 2 Cl 2 , suitable for X-ray diffraction analysis, and the X-ray structure of 3i is shown in Figure 1.In order to show the reliability of this synthetic strategy, the tandem reaction between 1a and 2a in ethanol was performed on a gram scale (10 mmol), and 3a was isolated in 72% yield (1.87 g) after a simple column chromatographic purification.With 3a-i in hand, the Michael reactions between acetone and 2-aryl-3-nitro-2H-chromenes were also performed.At first, 3a was not isolated from the reaction mixture and acetone was directly added to the mixture hopefully to give the 2,3,4-trisubstituted chromane 4a, but the reaction was complex.When pure 3a was used as substrate in acetone, the Michael adduct 4a was obtained in 35% yield after one day using pyrrolidine-benzoic acid as catalyst.Encouraged by this positive result, we continued to search for optimal conditions for this reaction.Many examples of Michael additions in aqueous media have been reported to provide Michael adducts in both excellent yields and enantioselectivities. [23][24][25][26] When the Michael reaction of 3a and acetone was performed in water, 4a was isolated in 52% yield after flash column chromatography purification.The best result was obtained by using a mixture of brine and acetone as reaction medium, and 4a was produced in 82% yield with excellent stereoselectivity (>99%, based on its 1 H NMR spectrum) within eight hours.Under these optimum conditions, the Michael reactions of chromenes 3 and acetone in brine were performed to provide 2,3,4trisubstituted chromanes 4 in good to high yields (Scheme 1).To our delight, a single crystal of 4f was grown from CH 2 Cl 2 , suitable for X-ray diffraction analysis, and the X-ray structure of 4f is shown in Figure 2. The X-ray structure of 4f shows that the 2-aryl and 3-nitro groups are arranged in a cis-configuration on the pyran ring.

Conclusions
A facile synthesis of 2-aryl-3-nitro-2H-chromenes has been realized by using the combination of pyrrolidine and benzoic acid catalyzed tandem oxa-Michael-Henry reactions in refluxing ethanol.This catalytic strategy has also shown good reliability in the Michael reactions between 2-aryl-3-nitro-2H-chromenes and acetone in brine to provide 2,3,4-trisubstituted chromanes in good yields and excellent stereoselectivities.The structures of chromenes and chromanes were confirmed by X-ray diffraction analysis of a typical examples of each type.Additionally, the reductive amination of 2,3,4-trisubstituted chromane was performed smoothly to afford a fused tricyclic amine in high yield.The investigation of enantioselective synthesis of functional chromanes by various organocatalysts is ongoing in our laboratory.

Experimental
General.Melting points are uncorrected and expressed in °C by MRS-2 Melting point apparatus from Shanghai Apparatus Co., Ltd. 1 H NMR and 13 C NMR spectra were measured in CDCl 3 , MeOD or DMSO-d 6 solution on a Bruker AV-400 or AV-500 spectrometer using TMS as an internal reference.Coupling constant (J) values are given in Hz.Multiplicities are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet.High-resolution mass spectra were performed on a Bruker micrOTOF-Q II Mass Spectrometer with ES ionization (ESI).All commercially available reagents were used as received, ethanol (AR, 99.5%) and acetone (AR, 99.5%) was used as solvent or reagent in the preparation of chromenes 3 and chromanes 4, respectively.Thin-layer chromatography on silica (with GF254) was used to monitor all reactions.Products were purified by flash column chromatography on silica gel purchased from Qingdao Haiyang Chemical Co., Ltd.All reactions involving air-or moisture-sensitive species were performed in oven-dried Schlenk tubes under an inert atmosphere.

Procedure for conversion of chromane 4a into 5
Chromane 4a (1.84 g, 5.9 mmol) was suspended in 30 mL of HOAc and heated to 55 o C, Zn powder (3.90 g, 60 mmol) was added to the above suspension in four portions.The reaction mixture was heated to 65 o C and stirred for 2 h under n inert atmosphere (monitored by TLC).When the reaction finished, the solvent HOAc was evaporated under reduced pressure to yield dark-brown oily residue which was diluted by the addition of CH 2 Cl 2 (60 mL), and this solution washed with cold saturated NaHCO 3 (20 mL), water (20 mL) and brine (20 mL).The organic layer was dried over anhydrous Na 2 SO 4 .The solvent was removed under reduced pressure and the residue was purified on a flash column chromatography (eluent: n-hexane/EtOAc/Et 3 N 1:1:0.01,V/V) to afford pure tricyclic compound 5 as a light yellow powder (1.45 g, 92%).

Table 1 .
Optimization of conditions for oxa-Michael-Henry reaction