NaH Promoted One-Pot Tandem Reactions of 3-(1-Alkynyl) Chromones to Form 2-Nitrogen-Substituted Xanthones.

A silver-catalyzed dimerization of ethyl isocyanoacetates could trigger the tandem reaction of 3-(1-alkynyl) chromones under the basic condition in a one-pot reaction to afford xanthone skeletons with 2-imidazolyl substitution in an efficient manner. With the control experiment in hand, a mechanism including dimerization of isocyanoacetate/deprotonation/Michael addition/ring-opening/cyclization 1,2-elimination was deduced. Further investigation for the base was carried out, resulting in NaH as an optimal base to avoid the dimerization of 3-(1-alkynyl) chromones. The scope of this methodology was extended on the different substituents of 3-(1-alkynyl)-chromones and the potential of other N-heterocycle glycine ester anions to give the novel functional 2-nitrogen-derived xanthones.

Introduction

Tandem reaction is capable of constructing molecular complexity in an efficient manner using readily available intermediates.[1] Owing to multiple attributes in the reactivity of chromone moieties, our group has been applied 3-(1-alkynyl)chromones for the diversified synthesis of chromone-based scaffolds by the tandem reactions with different nucleophiles.[2] Since the α-hydrogen of isocyanoacetate could be removed to afford an anion as a nucleophile and the terminal carbon of isocyano group could be nucleophilic as well on another aspect, isocyanoacetate employed an excellent component in tandem reactions.[3] Based on the information mentioned above, a cascade process was proposed. The consequent anion acquired by the deprotonation of isocyanoacetate as a nucleophile could initiate the Michael addition to 3-(1-alkynl)-chromone under basic conditions, resulting in the formation of the intermediate A. A could further undergo a transition-metal-assisted ring-closure reaction to generate B. The insertion of a transition metal was then followed by the elimination to form C. An aromatization reaction of C occurred to form a fused heterocycle compound D (Scheme a).

Scheme 1

Proposal for the Process

Result and Discussion

The investigation of the tandem reaction of 3-(1-alkynyl) chromones with ethyl isocyanoacetates commenced by utilizing the reported condition with base and transition-metal salt as catalyst.[4] Most of the conditions resulted in messy reaction systems or recovered starting materials (Table S1). While AgOAc/K2CO3 system was employed in NMP under MW irradiation, a major product 2a was afforded, and the X-ray crystallography data of the chloro-analogue 2i was obtained to confirm the structure[5] (Figure ), which is a xanthone skeleton with a 2-imidazolyl substitution. Besides, the reaction system was meticulously analyzed and a byproduct 3a was identified in moderate amount (ca. 20% yield). Our group previously described the formation of product 3a for a tandem dimerization–salicylic acid–extrusion process.[2e] It was noted that the structure of 2a with an imidazolyl group was formed, illustrating that the dimerization of isocyanoacetates might be involved in the reaction. After reviewed Grigg’s work , ethyl isocyanoacetate could be dimerized in competed AgOAc catalyzed reaction via a formal [3 + 2] dipolar addition (Scheme ).[6], The intermediate I was subsequently deprotonated under basic conditions and then underwent the Michael addition to generate II; II went a ring-opening of pyrone moiety to form III. Afterward, alkyne–allene tautomerism was incorporated to produce IV; intramolecular nucleophilic addition transferred the negative charge from the phenol anion to form a carbanion V, which consecutively underwent 1,2-addition on the ethyl ester. Meanwhile, the ethoxy group was eliminated to deliver VI. An aromatization of VI gave 2a, ending the whole cascade with the construction of xanthone skeleton (Scheme , path A). Notably, the base could be critical for the formation of the byproduct 3a (Scheme , path B).

Figure 1

ORTEP diagram of compound 2i(5) with an ellipsoid contour probability of 50%.

Scheme 2

Plausible Mechanism

To confirm the mechanism of the tandem process, we conducted controlled experiments. Without AgOAc, the formation of 3a was predominant (Scheme a, 55% yield). Treating ethyl isocyanate with AgOAc in dimethylformamide (DMF) formed ethyl 1-(2-ethoxy-2-oxoethyl)-1H-imidazole-4-carboxylate I expeditiously in excellent yield (95%). Under MW irradiation, I could be deprotonated by NaH, and the tandem process was promoted to give the desired product 2a (67% yield) smoothly.

Scheme 3

Control Experiments

Owing the dimerization of ethyl isocyanoacetate involved in the reaction, 2 equiv of isocyanoacetate should be adopted in the tandem process. The removal of NMP is arduous due to its high boiling point. Thus, the solvent was replaced with DMF, and further investigations on bases were carefully performed. Deprotonated intermediate I is a relatively weak nucleophile; therefore, the base might significantly influence the reaction pathway. Among the various bases screened, Et3N showed less activity to this reaction and gave traces of 2a (Table , entry 3), whereas DBU gave a decreased yield of 2a (Table , entry 4). The reaction also provided a lower yield of 2a when the base was changed to BuOK (Table , entry 5). When the base was replaced with MeONa, the yield of 2a was increased obviously (Table , entry 6). The screening of base ended with NaH, which was found to be the best and gave a satisfying yield of 2a (Table , entry 7) without 3a. When the equivalents of NaH were increased from 1.0 to 1.5 in the reaction (Table , entry 8), a higher amount of byproduct 3a (∼30% yield) was observed compared with that in the initial stage. The screening of the solvents was carried out posteriorly, revealing that DMF is appropriate for the tandem reaction (Table , entries 9–12). Finally, the tandem process proceeded aptly with NaH as the base and DMF as the solvent in the one-pot reaction.

Table 1

Optimization for the Reaction Conditionsa

entry	base	solvent	yield (2a) (%)
1b	K2CO3	NMP	23
2	K2CO3	DMF	41
3	Et3N	DMF	trace
4	DBU	DMF	34
5	tBuOK	DMF	25
6	MeONa	DMF	52
7c	NaH	DMF	71
8d	NaH	DMF	30
9	NaH	1,4-dioxane	23
10	NaH	DMSO	19
11	NaH	toluene	trace
12e	NaH	MeCN	23

Unless otherwise noted, the reactions were carried out with 0.5 mmol of 1a and 2 equiv of ethyl isocyanoacetate; 0.2 equiv of AgOAc was first mixed for 10 min, followed by 1 equiv of base in 1.5 mL of solvents under MW irradiation at 130 °C for 10 min.

1 equiv of ethyl isocyanoacetate and 1.5 equiv K2CO3 were added together into solvents; 3a was observed in 20% yield.

No significant amount of 3a was found.

1.5 equiv of NaH was used, and 3a was observed in 30% yield.

The reaction was run at 100 °C.

Recognizing the mechanism of the reaction, we explored the scope of 3-(1-alkynyl) chromones 1 under optimized conditions. Overall, substrates with the R1 substitution of benzene as well as heterocycle, or R2 substitution on chromone moiety yielded 2-imidazolylxanthone 2 in merit (38–85% yield). Electron-withdrawing groups (EWGs) on the terminal aromatic ring were unfavorable for this tandem process (Schemes and b–d,i). It indicates that EWGs could stabilize carbanion V, decreasing its nucleophilicity in the ring-closing process. There was no apparent steric effect in the tandem reaction (Schemes and 2d,g). For those substrates with substitution on chromone moiety, the reaction progressed smoothly to yield similar products (Schemes and 2l,m). Besides, alkyl-substituted alkyn could also achieve a reasonable yield (Schemes and 2n).

Scheme 4

Scope of Various 3-(1-Alkynyl)Chromonesa

Reaction conditions: ethyl isocyanoacetate (1 mmol), 1 (0.5 mmol), NaH (0.5 mmol), AgOAc (0.1 mmol), DMF (1.5 mL), and MW irradiation (130 °C, 10 min).

Additionally, the scope of various heterocyclic N-substituted ethyl acetates (4a–d) was investigated (Scheme ). Due to the lability of ethyl 2-(1H-pyrrol-1-yl)acetate (4a) under the basic condition at high temperature, the tandem process gave a low yield of the corresponding pyrroylxanthone 5a. Ethyl 2-(1H-imidazol-1-yl)acetate (4b) and ethyl 2-(1H-pyrazol-1-yl)acetate (4c) gave the corresponding product 5b and 5c in moderate yield. Ethyl N,N-dimethylglycinate (4d) failed to bring in the N,N-dimethylxanthone scaffold.

Scheme 5

Substrate Scope of Various N-Heterocycle-Substituted Ethyl Acetates

In summary, a strategy has been developed for the synthesis of N-heterocycle functionalized xanthones from 3-(1-alkynyl)-chromones and ethyl isocyanoacetate as substrates. Ethyl isocyanoacetate was dimerized to form imidazole intermediate I, which was subsequently deprotonated and then a tandem Michael addition/ring-opening/cyclization/1,2-addition took place to afford 3-hydroxy-2-(1H-imidazol-1-yl)-xanthone skeleton. Other anions of N,N-disubstituted glycinates were incorporated in the tandem reaction to attempt various N-heterocyclic xanthones. Further investigation of the biological activity of these novel xanthones is in progress.

Experimental Section

General Methods

All reagents were purchased from commercial sources without purification unless mentioned otherwise. Ethyl isocyanoacetate was distilled under reduced pressure prior to use. N,N-Dimethylformamide, 1,4-dioxane, was obtained from Extra-Dry Grade. All reactions were monitored by liquid chromatography–mass spectrometry (LC-MS). The NMR spectrum was recorded on Bruker spectrometers (400, 500, or 600 MHz for 1H, 100, 125, or 150 MHz for 13C, respectively). Chemical shifts are reported in δ parts per million (ppm), and the signals are described as br (broad), s (singlet), d (doublet), t (triplet), q (quartet), and m (multiple). Coupling constants (J values) are given in hertz (Hz). High-resolution mass spectroscopy (HRMS) was performed by a Q-TOF mass spectrometer with ESI resources. Single-crystal X-ray diffraction data were recorded on a Bruker SMART APEX II X-ray diffractometer. Microwave-assisted reactions were performed on a CEM Explorer 48 MW reactor.

Synthesis of the Precursor 3-((3-(Trifluoromethyl)phenyl)ethynyl)-4H-chromen-4-one (1b)

To a mixture of 3-iodo-4H-chromen-4-one (554 mg, 2.0 mmol), 1-ethynyl-3-trifluoromethylbenzene (317 μL, 2.2 mmol, 1.1 equiv), copper iodide (1.9 mg, 0.5 mol %), and PdCl2(PPh3) (14 mg, 1 mol %) in acetonitrile (10 mL) in an argon atmosphere was added N,N-diisopropylethylamine (404 μL, 4.0 mmol, 2.0 equiv). The reaction mixture was stirred overnight. The mixture was then filtered by a silica plug. The filtrate was diluted with ethyl acetate, washed with brine (10 mL × 2), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (10:1 v/v) to afford 1b as a yellow solid (58%). mp (°C): 185.0 (dec.); 1H NMR (400 MHz, CDCl3) δ 8.32–8.26 (m, 2H), 7.84 (s, 1H), 7.76–7.70 (m, 2H), 7.62–7.58 (m, 1H), 7.51–7.44 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 175.2, 158.2, 156.0, 134.9, 134.2, 131.0 (q, JCF = 32.8 Hz), 128.9, 128.6 (q, JCF = 3.6 Hz), 126.3, 125.9, 125.2 (q, JCF = 3.6 Hz), 123.7 (q, JCF = 272 Hz), 123.65, 123.59, 118.3, 111.0, 93.4, 81.2; HRMS (ESI): m/z [M + H]+ calcd. for C18H9F3O2: 315.0633; found: 315.0624.

Synthesis of the Precursor 3-Cyclohexylethynyl-4H-chromen-4-one (1n)

To a mixture of 3-iodo-4H-chromen-4-one (554 mg, 2.0 mmol), cyclohexylethyne (391 μL, 3 mmol, 1.5 equiv), copper iodide (1.9 mg, 0.5 mol %), and PdCl2(PPh3) (14 mg, 1 mol %) in acetonitrile (10 mL) under an argon atmosphere was added N,N-diisopropylethylamine (404 μL, 4.0 mmol, 2.0 equiv). The reaction mixture was stirred overnight. The mixture was then filtered by a silica plug. The filtrate was diluted with ethyl acetate, washed with brine (10 mL × 2), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (10:1 v/v) to afford 1n as an orange amorphous solid (58%); 1H NMR (500 MHz, CDCl3) δ 8.25 (dd, J = 8.1, 1.7 Hz, 1H), 8.09 (s, 1H), 7.66 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.45–7.38 (m, 2H), 2.65 (tt, J = 9.0, 3.8 Hz, 1H), 1.93–1.86 (m, 2H), 1.81–1.73 (m, 2H), 1.60–1.51 (m, 4H), 1.40–1.33 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 175.4, 156.9, 155.5, 133.3, 125.8, 125.0, 123.2, 117.7, 111.4, 100.1, 70.0, 32.0, 29.4, 25.4, 24.4. HRMS (ESI): m/z [M + H]+ calcd. for C17H17O2: 253.1223; found: 253.1224.

General Procedure for the Synthesis of 2a–m, 4a–c

To a 10 mL MW vial with a stir bar, silver acetate (0.1 mmol), DMF (1.5 mL), and ethyl isocyanoacetate (1.0 mmol) were added, and the mixture was stirred for 10 min. Sodium hydride was added and stirred for another 5 min, then the corresponding 3-alkynyl chromones 1 (0.5 mmol) were charged into the vial. The vial was subsequently irradiated under 300 W MW in 130 °C for 10 min. The mixture was diluted with dichloromethane and washed with saturated NH4Cl (aq) twice (20 mL each). The organic layer was collected, and the solvent was removed and further purified by flash chromatography to afford the products.

Characterization Data of 2a–n

Ethyl 1-(3-Hydroxy-4-(4-tolyl)-9-oxo-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2a)

Light yellow solid, 156 mg, 71% yield, eluent ratio (dichloromethane/methanol = 10:1), mp (°C): 284.8 (dec.); 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 8.0, 1.7 Hz, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.67 (dd, J = 8.7, 7.2 Hz, 1H), 7.40 (m, 5H), 7.33–7.29 (d, J = 8.0 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.4, 162.0, 155.6, 153.4, 152.0, 139.1, 138.0, 134.3, 133.5, 130.00, 129.97, 126.2, 125.7, 125.6, 124.0, 122.0, 121.7, 120.8, 118.2, 117.6, 115.3, 60.2, 21.0, 13.9; HRMS (ESI): m/z [M + H]+ calcd. for C26H20N2O5: 441.1450; found: 441.1444.

Ethyl 1-(3-Hydroxy-9-oxo-4-(3-(trifluoromethyl)phenyl)-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2b)

Light yellow amorphous solid, 94 mg, 38% yield, eluent ratio (dichloromethane/methanol = 10:1); 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 7.9 Hz, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.75–7.64 (m, 5H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.7, 161.3, 156.0, 155.0, 154.4, 138.7, 134.9, 134.4, 133.4, 131.8, 130.9 (q, JCF = 32.8 Hz), 129.0, 128.0 (q, JCF = 3.6 Hz), 126.5, 125.8, 125.1, 125.0, 124.0 (q, JCF = 273.4 Hz), 123.9, 122.6, 121.1, 118.7, 118.0, 115.2, 60.8, 14.1; HRMS (ESI): m/z [M + H]+ calcd. for C26H18F3N2O5: 495.1168; found: 495.1164.

Ethyl 1-(3-Hydroxy-9-oxo-4-(4-(trifluoromethyl)phenyl)-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2c)

Light yellow solid, 126 mg, 51% yield, eluent ratio (dichloromethane/methanol = 10:1), mp (°C): 273.4 (dec.); 1H NMR (600 MHz, CDCl3) δ 8.31 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 7.9 Hz, 2H), 7.71–7.63 (m, 3H), 7.40 (dd, J = 7.5, 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 175.8, 161.5, 156.1, 155.1, 154.4, 138.8, 135.01, 134.96, 133.5, 131.5, 130.5 (q, JCF = 33.2 Hz), 126.6, 125.9, 125.5 (q, JCF = 3.8 Hz), 124.6, 124.15, 124.10 (q, JCF = 270.6 Hz), 122.6, 121.2, 119.1, 118.1, 115.4, 60.9, 14.2; HRMS (ESI): m/z [M + H]+ calcd. for C26H18F3N2O5: 495.1168; found: 495.1162.

Ethyl 1-(3-Hydroxy-9-oxo-4-(2-(trifluoromethyl)phenyl)-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2d)

Light yellow solid, 109 mg, 44% yield, eluent ratio (dichloromethane/methanol = 10:1), mp (°C): 249.7–251.0; 1H NMR (400 MHz, acetone-d6) δ 8.16 (m, 2H), 8.07 (d, J = 6.0 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.58 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 7.31 (dd, J = 7.5, 7.5 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, acetone-d6) δ 174.1, 165.2, 163.3, 155.9, 155.3, 139.0, 134.4, 134.0, 133.4, 132.1, 131.7, 130.2 (q, JCF = 29.2 Hz), 127.4, 126.2, 126.0 (q, JCF = 5.7 Hz), 125.8, 125.6, 124.6 (q, JCF = 273.8 Hz), 123.2, 121.8, 120.6, 117.3, 115.6, 107.7, 60.0, 13.8; HRMS (ESI): m/z [M + H]+ calcd. for C26H18F3N2O5: 495.1168; found: 495.1167.

Ethyl 1-(3-Hydroxy-4-(4-methoxyphenyl)-9-oxo-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2e)

Light yellow solid, 153 mg, 67% yield, eluent ratio (dichloromethane/methanol = 10:1), mp (°C): 227.9–228.5; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.1, 1H), 8.26 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.69–7.64 (m, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.39 (dd, J = 7.5, 7.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.1 (d, J = 8.6 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR{1H} (125 MHz, CDCl3) δ 176.0, 162.3, 160.3, 156.2, 154.1, 153.2, 138.5, 134.8, 133.8, 132.0, 126.6, 126.1, 124.4, 122.4, 122.4, 121.4, 121.2, 118.8, 118.1, 115.6, 114.9, 60.9, 55.4, 14.4; HRMS (ESI): m/z [M + H]+ calcd. for C26H21N2O6: 457.1400; found: 457.1392.

Ethyl 1-(3-Hydroxy-4-(3-methoxyphenyl)-9-oxo-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2f)

Light yellow amorphous solid, 128 mg, 56% yield, eluent ratio (dichloromethane/methanol = 10:1); 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.67 (dd, J = 8.7, 7.2 Hz, 1H), 7.50 (dd, J = 9.2, 7.2 Hz, 1H), 7.39 (dd, J = 7.5, 7.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.12–7.02 (m, 3H), 4.32 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 175.9, 162.4, 160.4, 156.1, 153.9, 152.9, 138.4, 134.8, 133.8, 130.9, 130.6, 126.6, 126.1, 124.5, 122.7, 122.4, 121.2, 118.8, 118.1, 116.3, 115.7, 114.9, 60.7, 55.4, 14.4; HRMS (ESI): m/z [M + H]+ calcd. for C26H21N2O6: 457.1400; found: 457.1396.

Ethyl 1-(3-Hydroxy-4-(2-methoxyphenyl)-9-oxo-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2g)

Light yellow amorphous solid, 157 mg, 69% yield, eluent ratio (dichloromethane/methanol = 10:1); 1H NMR (400 MHz, CDCl3) δ 8.33–8.28 (m, 2H), 7.99 (s, 1H), 7.85 (s, 1H), 7.67–7.60 (m, 1H), 7.55–7.48 (m, 1H), 7.42–7.35 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.18–7.10 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 175.6, 162.2, 157.0, 155.7, 154.0, 138.1, 134.1, 132.8, 132.3, 130.4, 126.0, 125.8, 123.7, 122.6, 121.7, 120.80, 120.76, 118.4, 117.54, 115.5, 114.6, 111.2, 60.2, 55.4, 13.8; HRMS (ESI): m/z [M + H]+ calcd. for C26H21N2O6: 457.1400; found: 457.1396.

Ethyl 1-(3-Hydroxy-9-oxo-4-phenyl-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2h)

Beige solid, 181 mg, 85% yield, eluent ratio (dichloromethane/methanol = 10:1), mp (°C): 251.0 (dec.); 1H NMR (400 MHz, CDCl3) δ 8.40–8.18 (m, 2H), 7.92 (s, 1H), 7.80 (s, 1H), 7.70–7.52 (m, 6H), 7.39 (t, J = 7.5, 7.5 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.4, 161.9, 155.8, 153.4, 152.2, 138.0, 134.4, 130.3, 130.2, 129.2, 129.0, 126.2, 125.6, 124.1, 122.4, 121.8, 120.8, 118.4, 117.8, 115.3, 60.3, 13.9; HRMS (ESI): m/z [M + H]+ calcd. for C25H19N2O5: 427.1294; found: 427.1289.

Ethyl 1-(4-(4-Chlorophenyl)-3-hydroxy-9-oxo-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2i)

Beige solid, 87 mg, 38% yield, eluent ratio (dichloromethane/methanol = 10:1), mp (°C): 257.4–258.1; 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 7.9 Hz, 1H), 8.26 (s, 1H), 7.78 (s, 1H), 7.73–7.68 (m, 2H), 7.57–7.51 (s, 4H), 7.44–7.39 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.9, 161.8, 156.1, 154.6, 154.3, 138.7, 134.9, 134.7, 133.4, 132.4, 129.2, 129.1, 126.6, 126.0, 124.5, 123.4, 122.7, 121.2, 118.8, 118.1, 115.3, 60.8, 14.3; HRMS (ESI): m/z [M + H]+ calcd. for C25H18ClN2O5: 461.0904; found: 461.0904.

Ethyl 1-(3-Hydroxy-9-oxo-4-(pyridin-4-yl)-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2j)

Light red solid, 88 mg, 41% yield, eluent ratio (dichloromethane/methanol = 5:1), mp (°C): 267.3–268.1; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.24 (s, 1H), 8.17–8.12 (m, 2H), 8.07 (s, 1H), 8.01–7.86 (m, 2H), 7.79–7.72 (m, 1H), 7.49–7.37 (m, 2H), 4.27 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, 1:20 v/v CD3OD in DMSO-d6)[7] δ 173.9, 162.3, 155.2, 154.3, 139.0, 134.6, 132.3, 127.2, 125.6, 125.4, 124.3, 122.5, 121.0, 117.9, 59.6, 14.4; HRMS (ESI): m/z [M + H]+ calcd. for C24H18N3O5: 428.1246; found: 428.1246.

Ethyl 1-(3-Hydroxy-9-oxo-4-(pyrimidin-5-yl)-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2k)

Light red solid, 109 mg, 51% yield, eluent ratio (dichloromethane/methanol = 5:1), mp (°C): >300; 1H NMR (600 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.98 (s, 2H), 8.25 (s, 1H), 8.17 (s, 1H), 8.08 (d, J = 7.8, 1H), 7.91 (s, 1H), 7.64 (dd, J = 7.5, 7.5 Hz, 1H), 7.34 (dd, J = 7.5, 7.5 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR{1H} (150 MHz, DMSO-d6) δ 173.3, 169.0, 163.0, 158.7, 155.6, 155.5, 155.4, 138.8, 133.7, 131.7, 130.3, 127.4, 127.0, 125.8, 123.8, 121.9, 120.1, 117.7, 108.7, 104.5, 59.9, 14.8; HRMS (ESI): m/z [M + H]+ calcd. for C23H17N4O5: 429.1199; found: 429.1193.

Ethyl 1-(3-Hydroxy-7-methoxy-9-oxo-4-phenyl-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2l)

Light yellow amorphous solid, 146 mg, 64% yield, eluent ratio (dichloromethane/methanol = 10:1); 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.59–7.48 (m, 5H), 7.26–7.18 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.8, 162.2, 156.3, 154.0, 153.4, 151.0, 138.5, 133.5, 130.9, 130.3, 129.2, 129.0, 126.1, 124.7, 122.7, 122.6, 121.5, 119.5, 119.2, 115.0, 105.8, 60.7, 56.0, 14.3; HRMS (ESI): m/z [M + H]+ calcd. for C26H21N2O6: 457.1400; found: 457.1393

Ethyl 1-(7-Fluoro-3-hydroxy-9-oxo-4-phenyl-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2m)

Yellow amorphous solid, 111 mg, 50% yield, eluent ratio (dichloromethane/methanol = 10:1); 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.71 (dd, J = 8.6, 3.2 Hz, 1H), 7.50–7.43 (m, 3H), 7.40–7.36 (m, 2H), 7.28–7.20 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H);13C {1H} NMR (150 MHz, DMSO-d6) δ 172.0, 162.5, 157.8 (d, JCF = 238.9 Hz), 154.6, 151.5, 138.4, 135.5, 131.4, 131.3, 127.1, 126.6, 125.6, 122.4 (d, JCF = 6.5 Hz), 120.6, 120.5, 119.5 (d, JCF = 9.0 Hz), 118.63, 115.6, 110.0, 109.9, 59.4, 14.4; HRMS (ESI): m/z [M + H]+ calcd. for C25H18FN2O5: 445.1200; found: 445.1201.

Ethyl 1-(4-Cyclohexyl-3-hydroxy-9-oxo-9H-xanthen-2-yl)-1H-imidazole-4-carboxylate (2n)

Yellow solid, 128 mg, 59% yield, eluent ratio (dichloromethane/methanol = 10:1); mp (°C): 255.5. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.73–7.67 (m, 1H), 7.67–7.58 (m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.31–2.18 (m, 2H), 1.85–1.70 (m, 3H), 1.51 (d, J = 12.6 Hz, 2H), 1.37–1.21 (m, 7H). 13C{1H} NMR (150 MHz, DMSO-d6) δ 172.7, 169.2, 162.6, 155.8, 155.2, 138.4, 132.8, 131.0, 126.6, 125.7, 125.3, 122.4, 121.3, 119.7, 117.3, 117.1, 104.0, 59.3, 34.5, 30.1, 27.3, 26.2, 14.4. HRMS (ESI): m/z [M + H]+ calcd. for C25H25N2O5: 433.1759; found: 433.1758.

Characterization Data of 4a–c

4a–c were synthesized in a similar procedure utilizing corresponding N-heterocycle glycinates.

3-Hydroxy-2-(1H-pyrrol-1-yl)-4-(p-tolyl)-9H-xanthen-9-one (4a)

White amorphous solid, 51 mg, 28% yield, eluent ratio (petroleum ether/ethyl acetate = 5:1); 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.67 (dd, J = 8.7, 7.1 Hz, 1H), 7.45 (d, J = 1.6 Hz, 4H), 7.40 (dd, J = 8.0, 7.1, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 2.1 Hz, 2H), 6.43 (t, J = 2.2 Hz, 2H), 6.00 (s, 1H), 2.52 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.8, 155.7, 152.5, 152.1, 138.6, 134.0, 130.1, 129.6, 126.5, 126.1, 125.9, 123.7, 122.2, 121.6, 120.9, 117.6, 117.22, 115.4, 109.8, 13.7; HRMS (ESI): m/z [M + H]+ calcd. for C24H18NO3: 368.1289; found: 369.1281.

3-Hydroxy-2-(1H-imidazol-1-yl)-4-(p-tolyl)-9H-xanthen-9-one (4b)

White amorphous solid, 90 mg, 49% yield, eluent ratio (petroleum ether/ethyl acetate = 5:1). 1H NMR (600 MHz, CDCl3) δ 8.31 (d, J = 7.9 Hz, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.64 (dd, J = 8.7, 7.1 Hz, 1H), 7.44 (d, J = 7.8 Hz, 2H), 7.41–7.35 (m, 3H), 7.29 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 2.48 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 175.6, 155.7, 154.9, 153.5, 138.3, 134.0, 130.3, 129.5, 127.4, 126.5, 126.0, 123.7, 123.0, 121.5, 120.8, 119.6, 118.3, 117.6, 114.0, 21.0; HRMS (ESI): m/z [M + H]+ calcd. for C23H17N2O3: 369.1234; found: 369.1232.

3-Hydroxy-2-(1H-pyrazol-1-yl)-4-(p-tolyl)-9H-xanthen-9-one (4c)

White amorphous solid, 106 mg, 58% yield, eluent ratio (petroleum ether/ethyl acetate = 5:1); 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.6, 7.1, 1H), 7.49–7.43 (m, 2H), 7.38–7.30 (m, 4H), 6.64–6.56 (m, 1H), 2.48 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 176.5, 156.3, 153.5, 152.9, 139.0, 137.7, 134.4, 130.7, 129.0, 128.5, 127.7, 126.5, 124.0, 123.2, 121.2, 119.6, 118.2, 114.4, 113.8, 107.5, 21.4; HRMS (ESI): m/z [M + H]+ calcd. for C23H17N2O3: 369.1234; found: 369.1229.