Scholarly article on topic ' ( E )-2-(4-Arylbut-1-en-3-yn-1-yl)chromones as Synthons for the Synthesis of Xanthone-1,2,3-triazole Dyads '

( E )-2-(4-Arylbut-1-en-3-yn-1-yl)chromones as Synthons for the Synthesis of Xanthone-1,2,3-triazole Dyads Academic research paper on "Chemical sciences"

0
0
Share paper
OECD Field of science
Keywords
{""}

Academic research paper on topic " ( E )-2-(4-Arylbut-1-en-3-yn-1-yl)chromones as Synthons for the Synthesis of Xanthone-1,2,3-triazole Dyads "

FULL PAPER_XpurJOQ

of Organic Chemistry

DOI: 10.1002/ejoc.201500448

(£)-2-(4-Arylbut-1-en-3-yn-1-yl)chromones as Synthons for the Synthesis of

Xanthone-1,2,3-triazole Dyads

Hélio M. T. Albuquerque,|a| Clementina M. M. Santos,|a b| José A. S. Cavaleiro,|a| and

Artur M. S. Silva*|a|

Keywords: Cycloaddition / Diels-Alder reaction / Cyclization / Click chemistry / Oxygen heterocycles / Nitrogen heterocycles

Xanthone-1,2,3-triazole dyads have been synthesized by two different approaches, both starting from novel (£)-2-(4-aryl-but-1-en-3-yn-1-yl)chromones, prepared through a base-catalyzed aldol reaction of 2-methylchromone and arylpropar-gyl aldehydes. In the first method, the xanthone moiety is built by Diels-Alder reaction of the referred unsaturated chromones with N-methylmaleimide under microwave irradiation, followed by oxidation of the obtained adducts with

DDQ, whereas the 1,2,3-triazole ring results from the cycloaddition reaction of the acetylene moiety with sodium azide. The second strategy first involves the cycloaddition reaction with sodium azide to provide the 1,2,3-triazole ring, followed by methylation of the triazole NH group prior to Diels-Alder reaction with N-methylmaleimide. The last step in this synthesis of novel xanthone-1,2,3-triazole dyads entails oxidation of the cycloadducts with DDQ.

Introduction

Xanthones or 9#-xanthen-9-ones are one of the most important classes of naturally occurring oxygenated heterocyclic compounds possessing a dibenzo-y-pyrone framework. The parent xanthone has not been reported as a natural product.[1] However, in 2002 Oldenburg et al. described the occurrence of this xanthone in crude oils from offshore Norway. The authors suggest that this product can be formed by oxidation of xanthene in the reservoir or obtained by geosynthesis from aromatic precursors.[2] Natural xanthones often appear as highly substituted derivatives, bearing methoxy, hydroxy, alkyl, isopentenyl and glycosyl groups in their monomeric, dimeric, polycyclic or xanthonolignoide forms.[3] In the past few years, a great number of studies have emphasized the biological and pharmacological properties of both natural and synthetic xanthones,[4] including anti-inflammatory,[5] cancer chemo-preventive,[6] antimalarial,[7] and radical scavenging activities.^ The inhibitory activities of these agents against enzymes such as cyclooxygenase and cholinesterase have also been reported.[4,9]

Likewise, among the nitrogen heterocycles, triazoles have particular relevance due to their application in several research fields such as biochemistry, pharmaceutical and ma-

[a] Department of Chemistry & QOPNA, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal

E-mail: artur.silva@ua.pt

https://sites.google.com/site/artursilvaua/silva-ams

[b] School of Agriculture, Polytechnic Institute of Bragança, Campus de Santa Apolonia, 5301-855 Bragança, Portugal

□ Supporting information for this article is available on the Q WWW under http://dx.doi.org/10.1002/ejoc.201500448.

terial science. Triazoles have been used as drugs,[10] and are known to possess anti-HIV-type I protease,[11] anti-hyper-glycemic,[12] and antimicrobial activities, among others.[13] In terms of medicinal chemistry, it has been demonstrated that 1,4- and 1,5-disubstituted 1,2,3-triazoles can participate in important binding interactions with biological targets, maintaining a good pharmacokinetic profile.[14] In addition, they are commercially used as anticorrosive agents,[15] agrochemicals,[16] photostabilizers and dyes.[17]

Considering the biological properties exhibited by these two classes of heterocycles, the development of new production methods for xanthone-1,2,3-triazole dyads aimed specifically at developing potentially improved therapeutic agents is a high priority. This idea was recently exemplified by a study carried out by Zou et al. in which xanthones bearing a 1,4-disubstituted-1,2,3-triazole moiety showed promising antitumor activity.[18] Another study indicated that 3,6-dihydroxyxanthone, known as a good fluorophore, increased its fluorescence upon triazole formation.[19] With this rational in mind, we designed and synthesized novel chromone derivatives to be used as building blocks in the synthesis of xanthone-1,2,3-triazole dyads. The first reports dealing with the reactivity of chromone derivatives in Diels-Alder (DA) reactions en route to xanthone derivatives have been summarized by our group in 1993.[20] At that time, xanthene adducts were not characterized and were assumed to have the expected 1,2,3,9a-tetrahydroxanthene structure. Subsequently, other studies revealed that the products formed were, in fact, 1,2,3,4-tetrahydroxanthenes.[21] In 2000, 2-vinylchromones were also used as starting materials in [4 + 2] cycloaddition reactions with enamines for the synthesis of new xanthone derivatives.[22] More recently, studies

on DA reactions of 3-styrylchromones under microwave irradiation in solvent-free conditions resulted in a new strategy for the synthesis of novel xanthones.[23] In 2009, 2- and 3-styrylchromones were used in cyclization reactions to afford new polyhydroxylated 2,3-diarylxanthones.[24] Following the previously described studies, 2-(4-arylbuta-1,3-dien-

1-yl)chromones underwent electrocyclization and oxidation processes in order to prepare 1-arylxanthones.[25] In this paper, we disclose our synthesis of new chromone derivatives,

2-(4-arylbut-1-en-3-yn-1-yl)chromones 4a-d, which were further used as synthons to generate new xanthone-1,2,3-triazole dyads. Such chromones 4a-d possess two unsaturated systems (a diene and an alkyne) anticipated to display different reactivities in cycloaddition reactions. Moreover, these new chromones can participate in two consecutive types of cycloaddition reactions; namely, DA and Huisgen azide-alkyne 1,3-dipolar cycloadditions ("click chemistry"). Herein, we present two different synthetic strategies enabling facile access to new chromone-1,2,3-triazole derivatives as well as xanthone-1,2,3-triazole dyads.

Results and Discussion

Syntheses

Novel (E)-2-(4-arylbut-1-en-3-yn-1-yl)chromones 4a-d were obtained in moderate to good yields (52-80%) using a base-catalyzed aldol reaction of 2-methylchromone 1 with arylpropargyl aldehydes 3a-d in ethanolic solutions (Scheme 1).[25] The required starting material 2-methyl-chromone (1) was prepared by a three-step Baker-Venkata-raman sequence in good overall yields.[26] Since arylprop-argyl aldehydes 3b-d are not commercially available, we generated them using a two-step approach: i) palladium-catalyzed cross-coupling reaction of aryl iodides with prop-argyl alcohol[27] in order to prepare the corresponding arylpropargyl alcohols 2b-d, in good yields (79-95%); ii) oxidation of the arylpropargyl alcohols 2b-d with activated MnO2 to afford desired arylpropargyl aldehydes 3b-d, in excellent yields (86-97%). The first step of this methodol-

_EurlOC

European Journal

of Organic Chemistry

ogy was slightly improved by using toluene as solvent in the presence of 1.5equiv. piperidine instead of in neat dieth-ylamine (Scheme 1).

In our first approach to the target xanthone-1,2,3-tri-azole dyads, newly synthesized chromones 4a-d were used as dienes in DA reactions with the poor dienophile N-methyl-maleimide (Scheme 2). The structure of each conjugated diene suggests that it could not be very reactive due to extended electron delocalization. Thus, we tried highly energetic reaction conditions using 1,2,4-trichlorobenzene (TCB) under refluxing conditions (Table 1, Entry 1). No DA reaction took place and after a reaction time of 7 d only degradation of the starting material was observed when using two different derivatives 4a and 4c (Table 1, Entries 1 and 2). Slightly less energetic conditions (DMF at reflux for 48 h) once again failed to produce any DA reaction despite the inclusion of the Lewis acid Sc(OTf)3 (Table 1, Entries 3 and 4). The failure of the normal (or "typical") electron demand DA reaction to produce meaningful results inspired us to attempt the reaction using an electron rich dienophile (dihydropyran) in neat conditions (Table 1, Entry 5). This DA reaction also failed to take place; we postulate that this is a consequence of the low reaction temperature imposed by the low boiling point of dihydropyran.

On the basis of previous findings by our group[23,28] we performed the DA reaction under microwave irradiation (multimode apparatus) conditions. Several experiments were carried out in which reaction times, solvent, Lewis acids, amounts of dienophile and microwave potencies were varied (Table 1, Entries 6-15). The best results were achieved in a reaction time of 20 min, at 160 °C using a few drops of DMF as solvent (Table 1, Entries 6, 16-18). DA adducts 5a-d were obtained in low yields (20-30%) although it is worth noting that a significant amount of starting chromone could be readily recovered (65-70%). Thus, the poor yields can be explained by the competition of the retro-DA reaction, which is often promoted at such tem-peratures.[29] When the reaction of 4c with N-methylmale-imide was performed under the optimized conditions

a: R = H; b: R = CH3; c: R = OCH3; d: R = Br Scheme 1. Synthesis of (E)-2-(4-arylbut-1-en-3-yn-1-yl)chromones 4a-d.

a: R = H, b: R = CH3, c: R = OCH3, d: R = Br Scheme 2. Strategy for the synthesis of xanthone-1,2,3-triazole dyads 7a-d.

Table 1. Optimization of the Diels-Alder reaction conditions for the synthesis of 4-(arylethynyl)-2-methyl/phenyl-3a,4,5,11b-tetra-hydrochromeno[3,2-e]isoindole-1,3,11-triones 5a-d.

Entry Heating method Reactant Solvent Time T [°C] Catalyst Isolated yield [%] Recovered starting material [%]

1 oil bath 4a 1,2,4-TCB 7 d reflux - no reaction -

2 oil bath 4c 1,2,4-TCB 7 d reflux - no reaction -

3 oil bath 4c DMF 48 h reflux Sc(OTf)3 no reaction -

4 oil bath 4c DMF 48 h reflux - no reaction -

5 oil bath 4b _[e] 24 h 80 - no reaction -

6 MW (800 W) 4c DMF[a] 40 min 160 - 30 67

7 MW (800 w) 4c DMF[a] 40 min 160 AlCl3 30 65

8 MW (800 W) 4c DMF[a] 40 min 160 Sc(OTf)3 30 66

9 MW (800 W) 4c DMF[a] 20 min 160 - 30 68

10 MW (800 W) 4c DMF[a] 10 min 160 - 14 76

11 MW (800 W) 4c DMF[c] 40 min 160 - no reaction -

12 MW (800 W) 4c NMP[a] 40 min 160 - no reaction -

13 MW (600 w) 4c NMP[a] 40 min 150 - 5 70

14 MW (600 w) 4c NMP[b] 40 min 150 - no reaction -

15 MW (600 W) 4c DMF[b] 40 min 150 - no reaction -

16 MW (800 W) 4a DMF[a] 20 min 160 - 28 67

17 MW (800 W) 4b DMF[a] 20 min 160 - 20 72

18 MW (800 W) 4d DMF[a] 20 min 160 - 30 66

19 MW (800 W) 4b DMF[d] 40 min 160 - 14 10

[a] A few drops of DMF and 5 equiv. of N-methylmaleimide. [b] 5 mL of solvent and 10 equiv. N-methylmaleimide. [c] Dimethyl acetylene-dicarboxylate. [d] N-phenylmaleimide. [e] Dihydropyran.

(160 °C, using a few drops of DMF as solvent) for 10 min cycloadduct 5c was isolated in 14% yield; reaction times of 20 and 40 min afforded the same yield (30%) (Table 1, Entries 6, 9 and 10). At lower reaction temperature (100 °C), cycloadduct 5c was obtained in 1 % yield and 80 % of the starting material was recovered.

A single attempt to test N-phenylmaleimide as the dienophile led to no improvements in the DA reaction and led to only a 14% yield of cycloadduct 5e and 10% recovered starting material (Table 1, Entry 19, Scheme 2). The DA reaction has also been studied using monomode microwave equipment in solvent-free conditions. As an example, chromone 4c was used in three experiments performed at 5, 10 and 20 min of irradiation at 200 °C. The best results (31 %) were not significantly better than those obtained under the multimode microwave conditions (30%). However, it was possible to achieve similar results in shorter reaction times (10 min). Thus, after 5 min of irradiation it was pos-

sible to isolate 5c in 23% yield; with 10 or 20 min of irradiation the yields increased to 31 %. Applying these optimized conditions to the other derivatives, we can conclude that the yields were slightly improved (36-45%) using this environmentally friendlier technique since the reaction occurs in solvent-free conditions and in a shorter reaction time.

The next step of our first strategy was the oxidation/ aromatization of the DA adducts to afford xanthone derivatives. The reaction was performed in toluene with DDQ and the corresponding xanthone derivatives 6a-d were achieved in good yields (Scheme 2, 57-83%). The synthesized xanthones possess alkyne substitution in position 4 of the heterocycle, which, upon reacting with sodium azide in re-fluxing DMF provided new xanthone-1,2,3-triazole dyads 7a-d in excellent yields (Scheme 2, 88-90%).

In the second strategy an inverse approach was used, starting with the synthesis of the triazole ring and then the xanthone skeleton. First, the 1,3-cycloaddition reaction of

Scheme 3. Strategy for the synthesis of xanthone-1,2,3-triazole dyads 13a-d.

chromones 4a-d with sodium azide afforded the 1,2,3-tri-azole derivatives 8a-d in excellent yields (Scheme 3, 9097%). Subsequently and before the optimization of the DA reaction we protected the NH of the triazole since it could undergo a Michael addition reaction with the N-methyl-maleimide dienophile.[30] N-Protection with the methyl group was achieved using dimethyl sulfate in refluxing acetone and the expected three isomers of 1,2,3-triazoles 9a-d, 10a-d and 11a-d were prepared in good overall yields (Scheme 3): 2'-NCH3 triazoles 9a-d (higher Rf value) were isolated as major isomers (67-82%); whereas 3'-NCH3 triazoles 10a-d together with 1'-NCH3 isomers 11a-d were obtained as an inseparable mixture in low yields (18-33%). Analysis of the NMR spectra of this mixture allowed us to conclude that 1'-NCH3 isomers 11a-d were obtained in trace amounts (see NMR discussion).

At this point and being aware that the DA reaction of chromone 4a-d only occurs under microwave irradiation conditions, the reaction of protected 1,2,3-triazole derivatives 9a-d with N-methylmaleimide was optimized using similar heating conditions. Once more, the lack of reactivity of the diene resulted in moderate yields of cycloadducts 12a-d (30-40%) and 50-64% of recovered 9a-d when the reactions were performed in DMF at 160 °C for 20min, with microwave irradiation (multimode apparatus). The optimization of the reaction using a monomode microwave apparatus was carried out using 1,2,3-triazole derivative 9c, in solvent-free conditions, with irradiation times of 5, 10 and 20 min at 200 °C. The best yield of compound 12c was obtained with a 10 min irradiation; when applying these conditions to the other derivatives, the yields of cycloadducts 12a-d (36-48%) were slightly better than those obtained using multimode microwave equipment. Furthermore, no side products were detected and 37-51% of starting materials 9a-d were recovered from the reaction mixtures. Finally, dehydrogenation of cycloadducts 12a-d lead-

ing to xanthones 13a-d occurred in the presence of DDQ oxidant and with good results (Scheme 3, 57-80%).

Nuclear Magnetic Resonance Spectroscopy

The most important features in the 1H NMR spectra of the (E)-2-(4-arylbut-1-en-3-yn-1-yl)chromones 4a-d are, in each case: i) two doublets, at S = 6.66-6.71 and 6.896.93 ppm corresponding to the vinylic protons a-H and PH respectively, in a trans configuration (JaH,pH 15-16 Hz), and ii) a singlet at S = 6.26-6.28 ppm corresponding to 3-H. HMBC spectra enabled the assignment of the most relevant quaternary carbons: C-T and C-2' at S = 86.7-88.4 and 96.5-98.4 ppm, respectively, C-2 at S = 160.0-160.5 ppm, C-8a and C-4a at S = 155.9 and 124.1 ppm, respectively, and C-4 at S = 178.3 ppm (Figure 1). In the NOESY spectra of compounds 4a-d NOE cross-peaks were observed between the 3-H signal and those of a-H and P-H indicating free rotation around the C2-Ca bond.

The NMR spectra of DA cycloadducts 5a-d, revealed the disappearance of the structural features mentioned for 4a-d. Furthermore, the NMR spectra showed the presence of five new signals: i) two multiplets at S = 3.023.08 ppm and S = 3.70-3.77 ppm, corresponding to 5-H and 4-H; ii) a double doublet at S = 3.28-3.29 ppm, corresponding to 3a-H; iii) a doublet at S = 4.37-4.39 ppm, corresponding to 11b-H; and iv) a singlet at S = 2.962.98 ppm, corresponding to the 2-NC#3 belonging to N-methylmaleimide moiety. All these structural features of compounds 5a-d support the disappearance of structural features characteristic of compounds 4a-d indicating that the DA reaction proceeded thereby affording desired cy-cloadducts 5a-d. Analysis of the 13C NMR spectra enabled assignment of three carbonyl carbons: C-11 from the chromone moiety, and C-1 and C-3 corresponding to N-methyl-

Figure 1. Important connectivities found in the HMBC spectra of the compounds 4a-d, 6a-d, 8a-d and 13a-d.

maleimide. Furthermore, the HMBC spectra of derivatives 5a-d, allowed the assignment of carbons C-1' (S = 83.384.8 ppm) and C-2' (S = 85.7-86.0 ppm) through the connectivity with aliphatic protons and with H-2",6", respectively.

The most important characteristics in the 1H NMR spectra of 4-(arylethynyl)-2-methylchromeno[3,2-£]isoindole-1,3,11(2H)-triones 6a-d are the presence in each case of two singlets, at S = 7.85-7.89 ppm corresponding to the aromatic protons 5-H, and at S = 3.26 ppm corresponding to the protons of the 2-NCH3 group of the N-methylmaleim-ide moiety. Also, the aliphatic protons characteristic of DA adducts 5a-d do not appear in the aliphatic regions of the spectra.

The most relevant structural differences between compounds 6a-d and 7a-d are found in the 13C NMR spectra. In compounds 6a-d the signals corresponding to C-1' and C-2', assigned through HMBC analysis, appear at S = 83.485.0 and 99.0-101.2 ppm, respectively. These signals are not present in the 13C NMR spectra of compounds 7a-d; instead, analysis of their 13C NMR and HMBC spectra showed the presence of two signals at S = 136.3-139.3 ppm and S = 142.1-142.7 ppm, corresponding to C-5' and C-4', respectively, of the 1,2,3-triazole moiety.

The multiplicity of the 1H NMR spectra of the (E)-2-[2-(4-aryl-2H-1,2,3-triazol-5-yl)vinyl]chromones 8a-d is pretty much the same as in (E)-2-(4-arylbut-1-en-3-yn-1-yl)chrom-ones 4a-d. However, the signals of a-H, P-H and 3-H (S = 7.30-7.35, 7.61-7.68 and 6.58-6.61 ppm, respectively) appear at higher frequency than those of the same protons in compounds 4a-d. The deshielding effect of the triazole moiety is more pronounced for a-H and P-H than for the 3-H protons. As in the case of 4a-d, the NOESY spectra of compounds 8a-d present NOE cross-peaks between the signal of 3-H and those of a-H and P-H indicating free rotation around the C2-Ca bond. In the case of the 13C NMR spectra of compounds 8a-d, the most important feature is the set of signals for C-4' and C-5', from 1,2,3-triazole moiety, at S = 137.6-138.3 and 141.8-145.1 ppm, respectively, assigned from HMBC spectra (Figure 1).

In the 1H NMR spectra of (E)-2-[2-(4-aryl-2-methyl-2H-1,2,3-triazol-5-yl)vinyl]chromones 9a-d the most relevant feature is the singlet at S = 4.28-4.29 ppm corresponding to 2'-NCH3 of the methylated 1,2,3-triazole moiety. The unequivocal identification of isomers 9a-d and 10a-d was based on the connectivity found in the HMBC spectra. Thus, 2'-NCH3 protons of isomers 9a-d do not correlate

with any carbon of the 1,2,3-triazole ring. The position of the methyl group in the triazole ring of isomers 10a-d was identified by correlations observed between 2'',6''-H and 3'-NCH3 with C-4' of the 1,2,3-triazole ring. Traces of isomers 11a-d were detected by the presence of less intense signals of the 1'-NCH3 protons and 3-H in the 1H NMR spectra of the mixture containing both 10a-d and 11a-d isomers.

Once again, the 1H NMR spectra of the 4-(4-aryl-2-methyl-2H-1,2,3-triazol-5-yl)-2-methyl-3a,4,5,11b-tetra-hydrochromeno[3,2-£]isoindole-1,3,11(2H)-triones 12a-d do not show the structural features described for compounds 8a-d and 9a-d. Indeed, new signals are present in these spectra: i) two multiplets at S = 2.96-3.24 and 3.793.91 ppm, corresponding to 5-H and 4-H; ii) a double duplet at S = 3.46-3.48 ppm, due to 3a-H; iii) a doublet at S = 4.63-4.64 ppm, assigned to 11b-H; and iv) a singlet at S = 2.81-2.82 ppm, attributed to 2-NCH3 of the N-methyl-maleimide moiety. The key feature in the 1H NMR spectra of 4-(5-aryl-2-methyl-2H-1,2,3-triazol-4-yl)-2-methyl-chromeno[3,2-£]isoindole-1,3,11(2H)-triones 13a-d is that of a singlet at S = 7.83-7.85 ppm assigned to the 5-H aromatic proton in each case. Moreover, the 1H NMR spectra of compounds 13a-d do not show aliphatic protons indicating successful aromatization of DA cycloadducts 12a-d.

Conclusions

We have reported the preparation of novel (E)-2-(4-aryl-but-1-en-3-yn-1-yl)chromone derivatives, which were further used as starting materials in two main synthetic routes to xanthone-1,2,3-triazole dyads. The first strategy involves the Diels-Alder reaction of the chromone derivatives with N-methylmaleimide followed by aromatization of the cycloadducts and reaction with sodium azide to give desired xanthone-1,2,3-triazole dyads. In the second synthetic approach an additional step of 1,2,3-triazole protection is required. Thus, chromone derivatives first react with sodium azide to provide chromone-1,2,3-triazole dyads, in excellent yields. After methylation of the triazole NH group, DA reaction with N-methylmaleimide and subsequent oxidation with DDQ affords the corresponding cycloadducts.

The DA reactions were performed under both monomode and multimode microwave irradiation conditions. The former case appears to be a more sustainable and environmentally friendly process since the reaction occurs in sol-

vent-free conditions, a shorter reaction time and consequently less energy is required. Moreover, yields obtained in this "greener" fashion were slightly improved relative to those obtained from the multimode microwave irradiation conditions.

Experimental Section

General Remarks: Melting points were measured with a Buchi Melting Point B-540 apparatus. NMR spectra were recorded with a Bruker Avance 300 spectrometer (300.13 MHz for 1H and 75.47 MHz for 13C) or Bruker Avance 500 spectrometer (500.13 MHz for 1H and 125.77 MHz for 13C). Chemical shifts (S) are reported in ppm and coupling constants (J) in Hz; the internal standard was TMS. Unequivocal 13C assignments were made with the aid of 2D gHSQC and gHMBC (delays for one-bond and longrange J C/H couplings were optimised for 145 and 7 Hz, respectively) experiments. Positive-ion ESI mass spectra were acquired with a QTOF 2 instrument [dilution of 1 ^L of the sample in chloroform solution (ca. 10-5 m) in 200 ^L of 0.1 % trifluoroacetic acid/methanol solution. Nitrogen was used as nebuliser gas and argon as collision gas. The needle voltage was set at 3000 V, with the ion source at 80 °C and the desolvation temperature at 150 °C. The cone voltage was 35 V]. Other low- and high-resolution mass spectra (EI, 70 eV) were measured with VG Autospec Q and M spectrometers. Elemental analyses were obtained with a LECO 932 CHNS analyser. Preparative thin-layer chromatography was performed with Merck silica gel (60 DGF254). Column chromatography was performed with Merck silica gel (60, 70-230 mesh). All chemicals and solvents used were obtained from commercial sources and used as received or dried by standard procedures. 3-Phenylpropiolaldehyde (3a) was not prepared since it is commercially available (Sigma-Aldrich).

General Procedure for the Synthesis of Arylpropargyl Alcohols 2b-

d: Propargyl alcohol (1.75 mL, 30 mmol) was added to a solution of the appropriate iodobenzene (20 mmol), bis(triphenylphosphine) palladium(II) chloride (280 mg, 0.04 mmol), piperidine (3.96 mL, 40 mmol) and copper iodide (114 mg, 0.6 mmol) in toluene (10 mL), under a nitrogen atmosphere. The mixture was stirred at 60 °C for 2 h and then filtered through Celite 345 and washed with chloroform. The solvent was evaporated and the residue was purified by silica gel column chromatography using CH2Cl2 as eluent. The solvent was evaporated to dryness in each case, and expected 3-arylprop-2-yn-1-ols 2b-d were obtained in good yields (79-95%).

3-(4-Methylphenyl)prop-2-yn-1-ol (2b): Yield 2.31 g (79%). Oil. 'H NMR (300 MHz, CDCl3): S = 2.34 (s, 3 H, 4'-CH3), 4.48 (d, J = 5.2 Hz, 2 H, 1-H), 7.11 (d, J = 7.9 Hz, 2 H, 3',5'-H), 7.33 (d, J = 7.9 Hz, 2 H, 2',6'-H) ppm. 13C NMR (75 MHz, CDCl3): S = 21.4 (4'-CH3), 51.6 (C-1), 85.7 (C-3), 86.5 (C-2), 119.3 (C-1'), 129.0 (C-3',5'), 131.5 (C-2',6'), 138.6 (C-4') ppm. HRMS (ESI+): m/z calcd. for C10H„O [M + H]+ 147.0810, found 147.0801. MS (ESI+): m/z (%) = 147 (100) [M + H]+, 315 (35) [2M + Na]+.

3-(4-Methoxyphenyl)prop-2-yn-1-ol (2c): Yield 2.56 g (79%). This compound showed spectroscopic and analytical data identical to previously reported data.[31]

3-(4-Bromophenyl)prop-2-yn-1-ol (2d): Yield 4.01 g (95%). This compound showed spectroscopic and analytical data identical to previously reported data.[32]

General Procedure for the Synthesis of Arylpropargyl Aldehydes 3b-

d: Activated MnO2 (6.9 g, 79.6 mmol) was added to a solution of the appropriate arylpropargyl alcohols 2b-d (15.9 mmol) in EtOAc

(40 mL). The resulting mixture was then refluxed for 1 h. After that period, the mixture was filtered through Celite 345 and washed with EtOAc and CH2Cl2. After evaporation of the solvent, the residue was purified by silica gel column chromatography using CH2Cl2 as eluent. The solvent was evaporated to dryness to give the expected arylpropynals 3b-d in good yields (86-97%). 3-(4-Methylphenyl)propiolaldehyde (3b): Yield 1.97 g (86%). Oil. !H NMR (300 MHz, CDCl3): S = 2.40 (s, 3 H, 4'-CH3), 7.22 (d, J = 8.0 Hz, 2 H, 3',5'-H), 7.51 (d, J = 8.0 Hz, 2 H, 2',6'-H), 9.41 (s, 1

H, 1-H) ppm. 13C NMR (300 MHz, CDCl3): S = 21.8 (4'-CH3), 88.4 (C-2), 96.0 (C-3), 116.3 (C-1'), 129.5 (C-3',5'), 133.3 (C-2',6'), 142.2 (C-4'), 176.9 (C-1) ppm. HRMS (ESI+): m/z calcd. for C10H9O [M + H]+ 145.0653, found 145.0644. MS (ESI+): m/z (%) = 189 (55) [M + 2Na]+, 145 (30) [M + H]+.

3-(4-Methoxyphenyl)propiolaldehyde (3c): Yield 2.34 g (92%). This compound showed spectroscopic and analytical data identical to previously reported data.[31]

3-(4-Bromophenyl)propiolaldehyde (3d): Yield 3.22 g (97%). This compound showed spectroscopic and analytical data identical to previously reported data.[32]

General Procedure for the Synthesis of 2-(4-Arylbut-1-en-3-yn-1-yl)-4_ff-chromen-4-ones 4a-d: Sodium (0.11 g, 4.8 mmol) was gradually added to 5 mL of dry ethanol and the mixture was stirred until the reaction mixture reached room temperature. 2-Methylchromone 1 (0.2 g, 1.2 mmol) and the appropriate aldehyde 3a-d (1.8 mmol) were added and the reaction mixture allowed to stand at room temperature until complete disappearance of chromone 1. After this period, the solution was poured into ice (20 g) and water (30 mL) and the pH adjusted to 4 with dilute HCl. The solid was removed by filtration, taken in CH2Cl2 and purified by silica gel column chromatography using CH2Cl2 as eluent. The solvent was evaporated to dryness and the residue were recrystallized from eth-anol to give the (E)-2-(4-arylbut-1-en-3-yn-1-yl)-4H-chromen-4-ones 4a-d in good yields (52-80%).

(£)-2-(4-Phenylbut-1-en-3-yn-1-yl)-4_ff-chromen-4-one (4a): Yield 166 mg (52%), m.p. 127-128 °C (recrystallized from ethanol). !H NMR (300 MHz, CDCl3): S = 6.28 (s, 1 H, 3-H), 6.71 (d, J =

15.7 Hz, 1 H, a-H), 6.93 (d, J = 15.7 Hz, 1 H, |-H), 7.35-7.43 (m, 4 H, 6-H, 3'',4'',5''-H), 7.48 (d, J = 7.7 Hz, 1 H, 8-H), 7.48-7.52 (m, 2 H, 2'',6''-H), 7.69 (dt, J = 7.7, 1.7 Hz, 1 H, 7-H), 8.19 (dd, J = 7.9, 1.7 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 87.4 (C-1'), 97.8 (C-2'), 111.1 (C-3), 117.2 (C-|), 117.9 (C-8), 122.4 (C-1''), 124.1 (C-4a), 125.2 (C-6), 125.7 (C-5), 128.5 (C-3'',5''),

129.2 (C-4''), 131.9 (C-2'',6''), 132.1 (C-a), 134.0 (C-7), 155.9 (C-8a), 160.2 (C-2), 178.3 (C-4) ppm. C19H12O2: C, 83.81; H, 4.44; found C, 83.48; H, 4.40. MS (ESI+): m/z (%) = 273 (100) [M + H]+, 295 (54) [M + Na]+.

(£)-2-[4-(4-Methylphenyl)but-1-en-3-yn-1-yl]-4_ff-chromen-4-one (4b): Yield 286 mg (80%), m.p. 148-150 °C (recrystallized from ethanol). !H NMR (300 MHz, CDCl3): S = 2.38 (s, 3 H, 4''-CH3), 6.27 (s, 1 H, 3-H), 6.69 (d, J = 15.8 Hz, 1 H, a-H), 6.93 (d, J =

15.8 Hz, 1 H, |-H), 7.18 (d, J = 8.1 Hz, 2 H, 3'',5''-H), 7.400 (ddd, J = 7.6, 7.5, 1.0 Hz, 1 H, 6-H), 7.402 (d, J = 8.1 Hz, 2 H, 2'',6''-H), 7.48 (dd, J = 7.9, 1.0 Hz, 1 H, 8-H), 7.69 (ddd, J = 7.9, 7.6,

I.7 Hz, 1 H, 7-H), 8.19 (dd, J = 7.6, 1.7 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 21.6 (4''-CH3), 87.0 (C-1''), 98.3 (C-2'), 111.0 (C-3), 117.4 (C-|), 117.9 (C-8), 119.3 (C-1'), 124.1 (C-4a), 125.1 (C-6), 125.7 (C-5), 129.3 (C-3'',5''), 131.6 (C-a), 131.8 (C-2'',6''), 133.9 (C-7), 139.6 (C-4''), 155.9 (C-8a), 160.4 (C-2),

178.3 (C-4) ppm. C20H14O2: C, 83.90; H, 4.93; found C, 83.51; H, 4.91. MS (ESI+): m/z (%) = 287 (100) [M + H]+, 325 (12) [M + K]+, 595 (8) [2M + Na]+.

(£)-2-[4-(4-Methoxyphenyl)but-1 -en-3-yn-1 -yl]-4_ff-chromen-4-one (4c): Yield 302 mg (80%), m.p. 162-163 °C (recrystallized from eth-anol). 1H NMR (300 MHz, CDCl3): S = 3.85 (s, 3 H, 4''-OCH3), 6.26 (s, 1 H, 3-H), 6.66 (d, J = 15.7 Hz, 1 H, a-H), 6.89 (d, J = 8.6 Hz, 2 H, 3",5"-H), 6.93 (d, J = 15.7 Hz, 1 H, ß-H), 7.40 (dd, J = 7.9, 7.8 Hz, 1 H, 6-H), 7.45 (d, J = 8.6 Hz, 2 H, 2",6"-H), 7.48 (d, J = 7.6 Hz, 1 H, 8-H), 7.69 (ddd, J = 7.8, 7.6, 1.6 Hz, 1 H, 7-H), 8.19 (dd, J = 7.9, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 55.4 (4''-OCH3), 86.7 (C-1'), 98.4 (C-2'), 110.8 (C-3), 114.2 (C-3'',5''), 114.4 (C-1''), 117.5 (C-ß), 117.8 (C-

8), 124.1 (C-4a), 125.1 (C-6), 125.7 (C-5), 131.1 (C-a), 133.5 (C-2'',6''), 133.9 (C-7), 155.9 (C-8a), 160.4 (C-4''), 160.5 (C-2), 178.3 (C-4) ppm. C20H14O3: C, 79.46; H, 4.67; found C, 79.61; H, 4.83. MS (ESI+): mlz (%) = 303 (86) [M + H]+, 325 (53) [M + Na]+, 627 (100) [2M + Na]+.

(£)-2-[4-(4-Bromophenyl)but-1-en-3-yn-1-yl]-4_ff-chromen-4-one (4d): Yield 259 mg (59%), m.p. 164-166 °C (recrystallized from eth-anol). 'H NMR (300 MHz, CDCl3): S = 6.28 (s, 1 H, 3-H), 6.71 (d, J = 15.8 Hz, 1 H, a-H), 6.89 (d, J = 15.8 Hz, 1 H, ß-H), 7.36 (d, J = 8.6 Hz, 2 H, 2'',6''-H), 7.40 (dt, J = 7.8, 0.9 Hz, 1 H, 6-H), 7.48 (dd, J = 8.7, 0.9 Hz, 1 H, 8-H), 7.51 (d, J = 8.6 Hz, 2 H, 3'',5''-H), 7.69 (ddd, J =8.7, 7.8, 1.7 Hz, 1 H, 7-H), 8.19 (dd, J = 7.8, 1.7 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 88.4 (C-1'), 96.5 (C-2'), 111.3 (C-3), 116.7 (C-ß), 117.8 (C-8), 121.3 (C-1''), 123.6 (C-4''), 124.1 (C-4a), 125.2 (C-6), 125.7 (C-5), 131.8 (C-3'',5''), 132.5 (C-a), 133.2 (C-2'',6''), 134.0 (C-7), 155.9 (C-8a),

160.0 (C-2), 178.3 (C-4) ppm. C19H„BrO2: C, 64.98; H, 3.16; found C, 64.71; H, 3.23. MS (ESI+): mlz (%) = 351 (39) [M + H]+ (79Br); 353 (37) [M + H]+ (81Br).

General Procedure for the Synthesis of 4-(Arylethynyl)-2-methyl-3a,4,5,11b-tetrahydrochromeno[3,2-e]isoindole-1,3,11(2_H)-triones 5a-e. Method A: A-Methylmaleimide (0.10 g, 0.92 mmol) was added to a solution of the appropriate (E)-2-(4-arylbut-1-en-3-yn-

1-yl)-4H-chromen-4-one (4a-d) (0.18 mmol) in dry DMF (5 цЬ). The mixture was heated at 160 °C under microwave irradiation (multimode apparatus) for 20 min. The residue was dissolved in CH2Cl2 and purified by preparative TLC using CH2Cl2 as eluent to give desired cycloadducts 5a-d: 5a (19.7 mg, 28 %), 5b (19.3 mg, 20%), 5c (22.3 mg, 30%), 5d (25.0 mg, 30%). Adduct 5e was obtained in 14 % using the same methodology, under irradiation for 40 min.

Method B: A-Methylmaleimide (0.10 g, 0.92 mmol) was mixed with the appropriate (E)-2-(4-arylbut-1-en-3-yn-1-yl)-4H-chromen-4-one 4a-d (0.18 mmol) in a closed vessel. The mixture was heated at 200 °C under microwave irradiation (monomode apparatus) for 10 min. The residue was dissolved in CH2Cl2 and purified by preparative TLC using CH2Cl2 as eluent to give desired cycloadducts 5a-d: 5a (25.3 mg, 36%), 5b (40.5 mg, 42%), 5c (23.0 mg, 31 %), 5d (37.5 mg, 45%).

2-Methyl-4-(phenylethynyl)-3a,4,5,11b-tetrahydrochromeno[3,2-e]-isoindole-1,3,11(2_ff)-trione (5a): M.p. 169-171 °C. !H NMR

(300 MHz, CDCl3): S = 2.98 (s, 3 H, CH3), 3.04-3.08 (m, 2 H, 5-H), 3.29 (dd, J =7.6, 5.0 Hz, 1 H, 3a-H), 3.73-3.77 (m, 1 H, 4-H), 4.39 (d, J = 7.6Hz, 1 H, 11b-H), 7.21-7.28 (m, 5 H, 2'',3'',4'',5'',6''-H), 7.39-7.45 (m, 2 H, 7-H, 9-H), 7.67 (ddd, J = 8.6, 7.1, 1.7 Hz, 1 H, 8-H), 8.29 (dd, J = 8.2, 1.7 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 24.8 (NCH3), 27.8 (C-4), 33.2 (C-5), 37.8 (C-11b), 43.2 (C-3a), 84.7 (C-1'), 85.8 (C-2'),

112.1 (C-11a), 117.6 (C-7), 121.7 (C-1''), 123.5 (C-10a), 125.2 (C-

9), 126.4 (C-10), 128.2 (C-2'',6''), 128.6 (C-4''), 131.6 (C-3'',5''), 133.7 (C-8), 155.7 (C-6a), 162.1 (C-5a), 174.2 (C-3 and C-11), 176.1 (C-1) ppm. HRMS (ESI+): mlz calcd. for C24H18NO4 [M + H]+

384.1236, found 384.1218. MS (ESI+): mlz (%) = 384 (32) [M + H]+, 406 (94) [M + Na]+, 789 (100) [2M + Na]+.

2-Methyl-4-[(4-methylphenyl)ethynyl]-3a,4,5,11b-tetrahydro-chromeno[3,2-e]isoindole-1,3,11(2fl)-trione (5b): M.p. 197-199 °C. !H NMR (300 MHz, CDCl3): S = 2.28 (s, 3 H, 4''-CH3), 2.97 (s, 3 H, A-CH3), 3.03-3.07 (m, 1 H, 5-H), 3.28 (dd, J = 7.6, 5.0 Hz, 1

H, 3a-H), 3.72-3.76 (m, 1 H, 4-H), 4.37 (d, J = 7.6 Hz, 1 H, 11b-H), 7.01 (d, J = 7.1 Hz, 2 H, 3'',5''-H), 7.16 (d, J = 7.1 Hz, 2 H, 2'',6''-H), 7.39-7.44 (m, 2 H, 7-H, 9-H), 7.66 (ddd, J = 8.5, 7.1,

I.7 Hz, 1 H, 8-H), 8.29 (dd, J = 8.2, 1.7 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 21.4 (4''-CH3), 24.8 (N-CH3), 27.8 (C-4), 33.2 (C-5), 37.7 (C-11b), 43.3 (C-3a), 84.0 (C-1'), 85.9 (C-2'), 112.1 (C-11a), 117.6 (C-9), 118.6 (C-1''), 123.5 (C-10a), 125.2 (C-7), 126.4 (C-10), 129.0 (C-3'',5''), 131.4 (C-2'',6''), 133.7 (C-8), 138.8 (C-4''), 155.7 (C-6a), 162.2 (C-5a), 174.3 (C-3), 176.2 (C-1 and C-11) ppm. HRMS (ESI+): mlz calcd. for C25H20NO4 [M + H]+ 398.1392, found 398.1372. MS (ESI+): mlz (%) = 398 (100) [M + H]+, 420 (21) [M + Na]+, 817 (27) [2M + Na]+.

4-[(4-Methoxyphenyl)ethynyl]-2-methyl-3a,4,5,11b-tetrahydro-chromeno[3,2-e]isoindole-1,3,11(2fl)-trione (5c): M.p. 203-204 °C. !H NMR (300 MHz, CDCl3): S = 2.97 (s, 3 H, NCH3), 3.02-3.07 (m, 2 H, 5-H), 3.28 (dd, J =7.6, 5.0 Hz, 1 H, 3a-H), 3.71-3.75 (m, 1 H, 4-H), 3.75 (s, 3 H, OCH3), 4.37 (d, J = 7.6 Hz, 1 H, 11b-H), 6.73 (d, J = 8.9 Hz, 2 H, 3'',5''-H), 7.20 (d, J = 8.9 Hz, 2 H, 2'',6''-H), 7.39-7.44 (m, 2 H, 7-H, 9-H), 7.66 (ddd, J = 8.6, 7.1, 1.7 Hz,

1 H, 8-H), 8.29 (dd, J = 8.2, 1.7 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 24.7 (NCH3), 27.8 (C-4), 33.3 (C-5), 37.7 (C-11b), 43.3 (C-3a), 55.2 (OCH3), 83.3 (C-1'), 85.7 (C-2'), 112.1 (C-11a), 113.7 (C-1''), 113.8 (C-3'',5''), 117.6 (C-7), 123.5 (C-10a),

125.2 (C-9), 126.4 (C-10), 133.0 (C-2'',6''), 133.7 (C-8), 155.7 (C-6a), 159.7 (C-4''), 162.3 (C-5a), 174.3 (C-1), 176.2 (C-3 and C-11) ppm. HRMS (ESI+): mlz calcd. for C25H20NO5 [M + H]+ 414.1341, found 414.1329. MS (ESI+): mlz (%) = 414 (22) [M + H]+, 436 (38) [M + Na]+, 849 (100) [2M + Na]+.

4-[(4-Bromophenyl)ethynyl]-2-methyl-3a,4,5,11b-tetrahydro-chromeno[3,2-e]isoindole-1,3,11(2fl)-trione (5d): M.p. 214-215 °C. !H NMR (300 MHz, CDCl3): S = 2.96 (s, 3 H, CH3), 3.03-3.08 (m,

2 H, 5-H), 3.29 (dd, J = 7.6, 5.0 Hz, 1 H, 3a-H), 3.70-3.75 (m, 1 H, 4-H), 4.39 (d, J = 7.6 Hz, 1 H, 11b-H), 7.14 (d, J = 8.5 Hz, 2 H, 2''-H, 6''-H), 7.36 (d, J =8.5 Hz, 2 H, 3''-H, 5''-H), 7.40-7.45 (m, 2 H, 7-H, 9-H), 7.67 (ddd, J = 8.5, 7.1, 1.6 Hz, 1 H, 8-H), 8.29 (dd, J = 8.2, 1.6 Hz, 1 H, 10-H) ppm. 13CNMR (75 MHz, CDCl3): S = 24.8 (NCH3), 27.8 (C-4), 33.0 (C-5), 37.8 (C-11b), 43.2 (C-3a), 84.8 (C-1'), 86.0 (C-2'), 112.1 (C-11a), 117.6 (C-7), 120.6 (C-1''), 123.0 (C-4''), 123.8 (C-10a), 125.3 (C-9), 126.4 (C-10), 131.5 (C-3'' and C-5''), 133.0 (C-2'' and C-6''), 133.8 (C-8), 155.7 (C-6a),

162.3 (C-5a), 175.9 (C-1), 176.0 (C-3 and C-11) ppm. HRMS (ESI+): mlz calcd. for C24H1779BrNO4 [M + H]+ 462.0341, found 462.0325; calcd. for C24H1781BrNO4 [M + H]+ 464.0320, found 464.0302. MS (ESI+): mlz (%) = 462 (35) [M + H]+, 947 (100) [2M + Na + 2H]+.

4-[(4-Methoxyphenyl)ethynyl]-2-phenyl-3a,4,5,11b-tetrahydro-chromeno[3,2-e]isoindole-1,3,11(2fl)-trione (5e): M.p. 164-166 °C. !H NMR (300 MHz, CDCl3): S = 3.10-3.13 (m, 2 H, 5-H), 3.37 (dd, J =7.7, 4.9 Hz, 1 H, 3-H), 3.71 (s, 3 H, 4''-OCH3), 3.87-3.90 (m, 1 H, 4-H), 4.56 (d, J = 4.9 Hz, 1 H, 11b-H), 6.64 (d, J = 6.9 Hz, 2 H, 3'',5''-H), 7.08 (d, J = 6.9 Hz, 2 H, 2'',6''-H), 7.27-7.34 (m, 5 H, 2''',3''',4''',5''',6'''-H), 7.39-7.43 (m, 1 H, 9-H), 7.43 (d, J = 7.7 Hz, 1 H, 7-H), 7.66 (ddd, J = 7.8, 7.7, 1.6 Hz, 1 H, 8-H), 8.28 (dd, J = 8.3, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 27.9 (C-4), 33.8 (C-5), 38.1 (C-11b), 43.0 (C-3a), 55.2 (OCH3), 83.5 (C-1'), 86.5 (C-2'), 112.0 (C-11a), 113.66 (C-1''),

113.73 (C-3'',5''), 117.7 (C-7), 123.6 (C-10a), 125.3 (C-9), 126.4 (C-10), 126.6 (C-2''',6'''), 128.4 (C-4'''), 128.9 (C-3''',5'''), 131.8 (C-1'''), 133.3 (C-2'',6''), 133.7 (C-8), 155.8 (C-6a), 159.7 (C-4''),

162.4 (C-5a), 173.0 (C-3), 175.3 (C-1), 176.2 (C-11)ppm.

General Procedure for the Synthesis of 4-(Arylethynyl)-2-methyl-chromeno[3,2-e]isoindole-1,3,11(2_H)-triones 6a-d: 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) (121 mg, 534 ^mol) was added to a solution of the appropriate 4-(arylethynyl)-2-methyl-3a,4,5,11b-tetrahydrochromeno[3,2-e]isoindole-1,3,11 (2H)-triones 5a-d (178 ^mol) in toluene (10 mL). The mixture was stirred at 100 °C for 1 h. After that period, the solvent was evaporated to dryness and the residue was purified by preparative TLC using CH2Cl2 as eluent to give desired 4-(arylethynyl)-2-methylchromeno[3,2-e] isoindole-1,3,11-triones 6a-d in good yields (57-83%).

2-Methyl-4-(phenylethynyl)chromeno[3,2-e]isoindole-1,3,11(2_ff)-trione (6a): Yield 42.5 mg (63%), m.p. 273-274 °C. 'H NMR (300 MHz, CDCl3): S = 3.26 (s, 3 H, CH3), 7.42-7.47 (m, 4 H, 9-

H, 3'',4'',5''-H), 7.50 (dd, J = 8.3, 0.6 Hz, 1 H, 7-H), 7.71-7.73 (m, 2 H, 2'',6''-H), 7.77 (ddd, J = 8.3, 7.1, 1.6 Hz, 1 H, 8-H), 7.89 (s, 1 H, 5-H), 8.36 (dd, J = 8.0, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 24.5 (NCH3), 84.0 (C-1'), 100.4 (C-2'), 117.6 (C-7), 118.9 (C-11a), 121.8 (C-11b), 123.0 (C-10a), 124.8 (C-4), 125.1 (C-9), 127.0 (C-5), 127.4 (C-10), 128.6 (C-3'',5''), 128.8 (C-3a), 129.9 (C-4''), 132.4 (C-2'',6''), 133.6 (C-1''), 135.5 (C-8), 155.0 (C-6a), 159.6 (C-5a), 164.1 and 165.9 (C-1 and C-3), 174.0 (C-11) ppm. HRMS (ESI): m/z calcd. for C24H14NO4 [M + H]+ 380.0923, found 380.0907. MS (ESI+): m/z (%) = 380 (40) [M + H] +, 402 (21) [M + Na]+, 781 (100) [2M + Na]+, 797 (27) [2M + K]+.

2-Methyl-4-[(4-methylphenyl)ethynyl]chromeno[3,2-e]isoindole-

I,3,11(2fl)-trione (6b): Yield 53.9 mg (77%), m.p. 326-327 °C. !H NMR (300 MHz, CDCl3): S = 2.41 (s, 3 H, CH3), 3.26 (s, 3 H, N-CH3), 7.24 (d, J = 8.0 Hz, 2 H, 3'',5''-H), 7.45 (t, J = 7.8 Hz, 1 H, 9-H), 7.50 (d, J = 8.3 Hz, 1 H, 7-H), 7.62 (d, J = 8.0 Hz, 2 H, 2'',6''-H), 7.77 (ddd, J = 8.3, 7.8, 1.5 Hz, 1 H, 8-H), 7.88 (s, 1 H, 5-H), 8.37 (dd, J = 7.8, 1.5 Hz, 1 H, 10-H) ppm. 13C NMR (500 MHz, CDCl3): S = 21.8 (CH3), 24.5 (NCH3), 83.7 (C-1'), 100.9 (C-2'), 117.6 (C-7), 118.7 (C-1''), 118.8 (C-3a), 123.0 (C-10a), 125.07 (C-11b), 125.12 (C-9), 126.8 (C-5), 127.4 (C-10), 128.7 (C-11a), 129.4 (C-3'',5''), 132.3 (C-2'',6''), 133.6 (C-4), 135.4 (C-8),

140.5 (C-4''), 155.0 (C-6a), 159.7 (C-5a), 164.1 and 166.0 (C-1 and C-3), 174.1 (C-11) ppm. HRMS (ESI+): m/z calcd. for C25H16NO4 [M + H]+ 394.1079, found 394.1060. MS (ESI+): m/z (%) = 394 (40) [M + H]+, 416 (72) [M + Na]+, 432 (33) [M + K]+, 809 (100) [2M + Na]+, 825 (43) [2M + K]+.

4-[(4-Methoxyphenyl)ethynyl]-2-methylchromeno[3,2-e]isoindole-1,3,11(2fl)-trione (6c): Yield 60.5 mg (83%), m.p. 295-297 °C. !H NMR (500 MHz, CDCl3): S = 3.26 (s, 3 H, NCH3), 3.87 (s, 3 H, OCH3), 6.95 (d, J = 8.9 Hz, 2 H, 3'',5''-H), 7.44 (ddd, J =7.8, 7.3, 1.0 Hz, 1 H, 9-H), 7.50 (dd, J = 8.4, 1.0 Hz, 1 H, 7-H), 7.68 (d, J = 8.9 Hz, 2 H, 2'',6''-H), 7.77 (ddd, J = 8.4, 7.3, 1.6 Hz, 1 H, 8-H), 7.85 (s, 1 H, 5-H), 8.37 (dd, J = 7.8, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (126 MHz, CDCl3): S = 24.5 (NCH3), 55.4 (OCH3), 83.4 (C-1'), 101.2 (C-2'), 113.8 (C-1''), 114.3 (C-3'',5''), 117.6 (C-7),

118.6 (C-11a), 123.0 (C-10a), 125.1 (C-9), 125.3 (C-11b), 126.5 (C-5), 127.4 (C-10), 128.5 (C-3a), 133.6 (C-4), 134.2 (C-2'',6''), 135.4 (C-8), 155.0 (C-6a), 159.7 (C-5a), 161.0 (C-4''), 164.2 and 166.1 (C-1 and C-3), 174.1 (C-11) ppm. HRMS (ESI+): m/z calcd. for C25H16NO5 [M + H]+ 410.1028, found 410.1007. MS (ESI+): m/z (%) = 410 (14) [M + H]+, 432 (30) [M + Na]+, 448 (15) [M + K]+, 841 (100) [2M + Na]+, 857 (47) [2M + K]+.

_EurVC

European Journal of Organic Chemistry

4-[(4-Bromophenyl)ethynyl]-2-methylchromeno[3,2-e]isoindole-1,3,11(2fl)-trione (6d): Yield 46.5 mg (57%), m.p. 332-333 °C. !H NMR (500 MHz, CDCl3): S = 3.26 (s, 3 H, NCH3), 7.45 (ddd, J = 8.0, 7.1, 0.9 Hz, 1 H, 9-H), 7.51 (d, J = 8.2 Hz, 1 H, 7-H), 7.567.60 (m, 4 H, 2'',6''-H, 3'',5''-H), 7.78 (ddd, J = 8.2, 7.1, 1.6 Hz,

1 H, 8-H), 7.88 (s, 1 H, 5-H), 8.37 (dd, J = 8.0, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (126 MHz, CDCl3): S = 24.5 (NCH3), 85.0 (C-1'), 99.0 (C-2'), 117.6 (C-7), 119.1 (C-11a), 120.7 (C-1''), 123.0 (C-10a), 124.3 and 124.5 (C-4 and C-11b), 125.2 (C-9), 126.9 (C-5), 127.5 (C-10), 128.8 (C-3a), 132.0 (C-3'',5''), 133.5 (C-4''), 133.7 (C-2'',6''), 135.5 (C-8), 155.0 (C-6a), 159.7 (C-5a), 164.1 and 166.2 (C-1 and C-3), 174.0 (C-11) ppm. HRMS (ESI+): m/z calcd. for C24H1379BrNO4 [M + H]+ 458.0028, found 458.0006; calcd. for C24H1381BrNO4 [M + H]+ 460.0007, found 459.9986. MS (ESI+): m/z (%) = 480 (23) [M + Na]+, 497 (12) [M + K]+, 939 (19) [2M +

General Procedure for the Synthesis of 4-(4-Aryl-2#-1,2,3-triazol-5-yl)-2-methylchromeno[3,2-e]isoindole-1,3,11(2_ff)-triones 7a-d: Sodium azide (43 mg, 660 ^mol) was added to a solution of the appropriate 4-(arylethynyl)-2-methylchromeno[3,2-e ]isoindole-1,3,11(2H)-trione 6a-d (132 ^mol) in dry DMF (5 mL). The mixture was stirred under reflux for 1 h under nitrogen atmosphere. After that period, the solution was poured into ice (30 g) and water (30 mL), and the pH was adjusted to 4 with diluted HCl. The mixture was vigorously stirred for 15 min, the precipitate was removed by filtration, washed with water (3 x 20 mL) and light petroleum (3 x 20 mL), and recrystallized from ethanol to afford desired xanthone-1,2,3-triazole dyads 7a-d in excellent yields (88-90%).

2-Methyl-4-(4-phenyl-2_ff-1,2,3-triazol-5-yl)chromeno[3,2-e]iso-indole-1,3,11(2#)-trione (7a): Yield 49.6 mg (89%), m.p. 304306 °C. !H NMR [500 MHz, (CD3)2SO + TFA]: S = 2.94 (s, 3 H, NCH3), 7.30-7.34 (m, 3 H, 3'',4'',5''-H), 7.47 (dd, J =7.8, 1.7 Hz,

2 H, 2'',6''-H), 7.55 (ddd, J =7.7, 7.3, 0.9 Hz, 1 H, 9-H), 7.68 (d, J = 8.4 Hz, 1 H, 7-H), 7.91 (ddd, J = 8.4, 7.3, 1.5 Hz, 1 H, 8-H), 8.04 (s, 1 H, 5-H), 8.24 (dd, J = 7.7, 1.5 Hz, 1 H, 10-H) ppm. 13C NMR [126 MHz, (CD3)2SO + TFA]: S = 24.2 (NCH3), 118.0 (C-7), 119.4 (C-11a), 122.7 (C-10a), 125.3 (C-9), 126.4 (C-5), 126.5 (C-10), 126.9 (C-2'',6''), 127.5 (C-3a), 128.4 (C-4''), 128.9 (C-3'',5''), 129.9 (C-1''), 133.7 and 133.8 (C-4 and C-11b), 136.0 (C-8), 136.8 (C-5'), 142.7 (C-4'), 154.8 (C-6a), 159.5 (C-5a), 163.9 and 165.4 (C-1 and C-3), 173.6 (C-11) ppm. HRMS (ESI+): m/z calcd. for C24H15N4O4 [M + H]+ 423.1093, found 423.1076. MS (ESI+): m/z (%) = 423 (100) [M + H]+, 445 (10) [M + Na]+.

2-Methyl-4-[4-(4-methylphenyl)-2#-1,2,3-triazol-5-yl]chromeno-[3,2-e]isoindole-1,3,11(2fl)-trione (7b): Yield 51.8 mg (90%), m.p. 318-320 °C. !H NMR [500 MHz, (CD3)2SO + TFA]: S = 2.23 (s, 3 H, CH3), 2.92 (s, 3 H, NCH3), 7.09 (d, J =8.1 Hz, 2 H, 3'',5''-H), 7.32 (d, J = 8.1 Hz, 2 H, 2'',6''-H), 7.49 (t, J = 7.6 Hz, 1 H, 9-H), 7.61 (d, J = 8.0 Hz, 1 H, 7-H), 7.86 (ddd, J = 8.0, 7.6, 1.6 Hz, 1 H, 8-H), 7.96 (s, 1 H, 5-H), 8.21 (dd, J = 7.6, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR [126 MHz, (CD3)2SO + TFA]: S = 20.9 (CH3), 24.3 (NCH3), 118.2 (C-7), 119.7 (C-11a), 123.0 (C-10a), 125.5 (C-9), 126.6 (C-5), 126.8 (C-10), 127.1 (C-2'',6''), 127.2 (C-1''), 127.8 (C-3a), 129.7 (C-3'',5''), 134.0 and 134.2 (C-4 and C-11b), 136.1 (C-8), 136.8 (C-5'), 138.2 (C-4''), 142.6 (C-4'), 155.1 (C-6a), 159.8 (C-5a), 164.2 and 165.7 (C-1 and C-3), 173.9 (C-11) ppm. HRMS (ESI+): m/z calcd. for C25H17N4O4 [M + H]+ 437.1250, found 437.1228. MS (ESI+): m/z (%) = 437 (100) [M + H]+, 459 (71) [M + Na]+, 475 (38) [M + K]+, 895 (78) [2M + Na]+.

4-[4-(4-Methoxyphenyl)-2_ff-1,2,3-triazol-5-yl]-2-methylchromeno-[3,2-e]isoindole-1,3,11(2fl)-trione (7c): Yield 52.5 mg (88%), m.p. 297-299 °C. !H NMR [500 MHz, (CD3)2SO + TFA]: S = 2.93 (s, 3

H, NCH3), 3.69 (s, 3 H, OCH3), 6.84 (d, J = 8.9 Hz, 2 H, 3'',5''-H), 7.36 (d, J = 8.9 Hz, 2 H, 2'',6''-H), 7.50 (ddd, J = 7.8, 7.3, 0.8 Hz, 1 H, 9-H), 7.63 (d, J = 8.3 Hz, 1 H, 7-H), 7.87 (ddd, J = 8.3, 7.3, 1.5 Hz, 1 H, 8-H), 7.97 (s, 1 H, 5-H), 8.22 (dd, J = 7.8,

I.5 Hz, 1 H, 10-H) ppm. 13C NMR [126 MHz, (CD3)2SO + TFA]: S = 24.2 (NCH3), 55.2 (OCH3), 114.5 (C-3'',5''), 118.1 (C-7), 119.5 (C-11a), 122.2 (C-1''), 122.9 (C-10a), 125.4 (C-9), 126.5 (C-5), 126.6 (C-10), 127.7 (C-3a), 128.4 (C-2'',6''), 133.8 and 134.2 (C-4 and C-11b), 136.1 (C-8), 136.3 (C-5'), 142.1 (C-4'), 154.9 (C-6a), 159.6 and 159.7 (C-4'' and C-5a), 164.1 and 165.6 (C-1 and C-3), 173.8 (C-11) ppm. HRMS (ESI+): mlz calcd. for C25H17N4O5 [M + H]+ 453.1199, found 453.1177. MS (ESI+): mlz (%) = 437 (16) [M - CH3]+, 453 (100) [M + H]+, 475 (77) [M + Na]+, 491 (33) [M + K]+, 927 (64) [2M + Na]+.

4-[4-(4-Bromophenyl)-2_ff-1,2,3-triazol-5-yl]-2-methylchromeno-[3,2-e]isoindole-1,3,11(2fl)-trione (7d): Yield 59.5 mg (90%), m.p. 319-320 °C. !H NMR [500 MHz, (CD3)2SO + TFA]: S = 2.92 (s, 3 H, NCH3), 7.39 (d, J = 8.7 Hz, 2 H, 2'',6''-H), 7.47 (d, J = 8.7 Hz, 2 H, 3'',5''-H), 7.51 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H, 9-H), 7.64 (dd, J = 8.2, 0.9 Hz, 1 H, 7-H), 7.88 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, 8-H), 8.02 (s, 1 H, 5-H), 8.22 (dd, J = 7.8, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR [126 MHz, (CD3)2SO + TFA]: S = 24.3 (NCH3), 118.2 (C-7), 119.7 (C-11a), 121.9 (C-4''), 122.9 (C-10a), 125.5 (C-9),

126.6 (C-5), 126.7 (C-10), 127.6 (C-3a), 129.0 (C-2'',6''), 129.7 (C-1''), 132.1 (C-3'',5''), 133.5 and 134.0 (C-4 and C-11b), 136.2 (C-8), 139.3 (C-5'), 142.5 (C-4'), 155.0 (C-6a), 159.8 (C-5a), 164.1 and

165.7 (C-1 and C-3), 173.8 (C-11) ppm. HRMS (ESI+): mlz calcd. for C24H1479BrN4O4 [M + H]+ 501.0198, found 501.0180; calcd. for C24H1481BrN4O4 [M + H]+ 503.0178, found 503.0155. MS (ESI+): mlz (%) = 501 (100) [M + H]+.

General Procedure for the Synthesis of (£)-2-[2-(4-Aryl-2#-1,2,3-triazol-5-yl)vinyl]-4_ff-chromen-4-ones (8a-d): Sodium azide (117 mg, 1.8 mmol) was added to a solution of the appropriate (E)-

2-(4-arylbut-1-en-3-yn-1-yl)-4H-chromen-4-ones 4a-d (367 ^mol) in dry DMF (5 mL). The mixture was stirred under reflux for 1 h under nitrogen atmosphere. After that period, the solution was poured into ice (30 g) and water (30 mL), and the pH was adjusted to 4 with diluted HCl. The mixture was vigorously stirred for 15 min, the precipitate was washed with water (3 x 20 mL) and light petroleum (3 x 20 mL), removed by filtration and recrystallized from ethanol to give (E)-2-[2-(4-aryl-2H-1,2,3-triazol-5-yl) vinyl]-4H-chromen-4-ones 8a-d in excellent yields (90-97%).

(£)-2-[2-(4-Phenyl-2#-1,2,3-triazol-5-yl)vinyl]-4#-chromen-4-one (8a): Yield 0.10 g (90%), m.p. 240-241 °C. !H NMR [300 MHz, (CD3)2SO + TFA]: S = 6.58 (s, 1 H, 3-H), 7.35 (d, J = 15.8 Hz, 1 H, a-H), 7.46 (t, J = 7.7 Hz, 1 H, 6-H), 7.53 (t, J = 7.5 Hz, 1 H, 4''-H), 7.61 (t, J = 7.5 Hz, 2 H, 3'',5''-H), 7.65 (d, J = 8.1 Hz, 1 H, 8-H), 7.68 (d, J = 15.8 Hz, 1 H, ß-H), 7.74 (d, J = 7.5 Hz, 2 H, 2'',6''-H), 7.77 (ddd, J =8.1, 7.7, 1.5 Hz, 1 H, 7-H), 8.06 (dd, J = 7.7, 1.5 Hz, 1 H, 5-H) ppm. 13C NMR [126 MHz, (CD3)2SO + TFA]: S = 111.1 (C-3), 118.7 (C-8), 123.1 (C-a), 123.9 (C-4a), 124.0 (C-ß), 125.3 (C-5), 125.6 (C-6), 128.5 (C-2'',6''), 129.3 (C-1''), 129.4 (C-4''), 129.6 (C-3'',5''), 134.5 (C-7), 138.3 (C-4'), 142.6 (C-5'), 156.0 (C-8a), 161.5 (C-2), 177.7 (C-4) ppm. HRMS (ESI+): mlz calcd. for C19H14N3O2 [M + H]+ 316.1086, found 316.1075. MS (ESI+): mlz (%) = (100) 316 [M + H]+, 653 (22) [2M + Na]+.

(£)-2-{2-[4-(4-Methylphenyl)-2tf-1,2,3-triazol-5-yl]vinyl}-4#-chromen-4-one (8b): Yield 0.12 g (98 %), m.p. 239-240 °C. !H NMR [300 MHz, (CD3)2SO + TFA]: S = 2.42 (s, 3 H, CH3), 6.61 (s, 1 H,

3-H), 7.34 (d, J = 15.8 Hz, 1 H, a-H), 7.41 (d, J = 7.7 Hz, 2 H, 3'',5''-H), 7.48 (t, J = 7.7 Hz, 1 H, 6-H), 7.61 (d, J =7.7 Hz, 2 H, 2'',6''-H), 7.64 (d, J = 15.8 Hz, 1 H, ß-H), 7.70 (d, J = 8.0 Hz, 1

H, 8-H), 7.80 (ddd, J = 8.0, 7.7, 1.4 Hz, 1 H, 7-H), 8.03 (dd, J = 7.7, 1.4 Hz, 1 H, 5-H) ppm. 13C NMR [126 MHz, (CD3)2SO + TFA]: S = 21.0 (CH3), 110.7 (C-3), 118.5 (C-8), 122.4 (C-a), 123.6 (C-P), 123.8 (C-4a), 124.9 (C-5), 125.4 (C-6), 125.7 (C-1"), 128.1 (C-2" and C-6"), 129.9 (C-3" and C-5"), 134.3 (C-7), 137.8 (C-4'), 138.8 (C-4"), 141.8 (C-5'), 155.5 (C-8a), 161.1 (C-2), 177.3 (C-4) ppm. HRMS-EI: mlz calcd. for C20H15O2N3 M+' 329.1164, found 329.1166. MS (ESI+): mlz (%) = 330 (100) [M + H]+, 352 (15) [M + Na]+.

(£)-2-{2-[4-(4-Methoxyphenyl)-2H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (8c): Yield 0.12 g (98%), m.p. 237-238 °C. 'H NMR [500 MHz, (CD3)2SO + TFA]: S = 3.85 (s, 3 H, OCH3), 6.60 (s, 1 H, 3-H), 7.16 (d, J = 8.8 Hz, 2 H, 3'',5''-H), 7.32 (d, J = 15.8 Hz, 1 H, a-H), 7.46 (ddd, J = 7.7, 7.2, 1.0 Hz, 1 H, 6-H), 7.62 (d, J = 15.8 Hz, 1 H, P-H), 7.64 (d, J = 8.8 Hz, 2 H, 2'',6''-H), 7.70 (d, J = 8.1 Hz, 1 H, 8-H), 7.79 (ddd, J = 8.1, 7.2, 1.6 Hz, 1 H, 7-H), 8.01 (dd, J = 7.7, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR [126 MHz, (CD3)2SO + TFA]: S = 55.4 (OCH3), 110.6 (C-3), 114.8 (C-3'',5''), 118.5 (C-8), 120.7 (C-1''), 122.2 (C-a), 123.6 (C-4a), 123.9 (C-P), 124.9 (C-5), 125.4 (C-6), 129.6 (C-2'',6''), 134.3 (C-7), 137.6 (C-4'), 145.1 (C-5'), 155.5 (C-8a), 160.1 (C-4''), 161.2 (C-2), 177.2 (C-4) ppm. HRMS-EI: mlz calcd. for C20H15O3N3 M+' 345.1113, found 345.1116. MS (ESI+): mlz (%) = 346 (100) [M + H]+, 368 (15) [M + Na]+.

(£)-2-{2-[4-(4-Bromophenyl)-2H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (8d): Yield 0.14 g (97%), m.p. 293-294 °C. !H NMR [300 MHz, (CD3)2SO + TFA]: S = 6.58 (s, 1 H, 3-H), 7.30 (d, J = 15.8 Hz, 1 H, a-H), 7.42 (ddd, J = 7.7, 7.4, 1.3 Hz, 1 H, 6-H), 7.61 (d, J = 15.8 Hz, 1 H, P-H), 7.64 (d, J = 8.5 Hz, 2 H, 2'',6''-H), 7.68 (d, J =7.8 Hz, 1 H, 8-H), 7.73-7.78 (m, 1 H, 7-H), 7.75 (d, J = 8.5 Hz, 2 H, 3'',5''-H), 8.00 (dd, J = 7.7, 1.3 Hz, 1 H, 5-H) ppm. 13C NMR [75 MHz, (CD3)2SO + TFA]: S = 111.1 (C-3), 118.8 (C-8), 122.8 (C-4''), 123.5 (C-a, C-P), 123.9 (C-4a), 125.1 (C-5), 125.6 (C-6), 128.7 (C-1''), 130.3 (C-2'',6''), 132.5 (C-3'',5''), 134.5 (C-7), 138.2 (C-4'), 142.2 (C-5'), 155.8 (C-8a), 161.2 (C-2), 177.6 (C-4) ppm. HRMS-EI: mlz calcd. for C19H12O2N379Br M+ 393.0113, found 393.0122; calcd. for C19H12O2N381Br M+ 395.0092, found 395.0106. MS (ESI+): mlz (%) = 394 (39) [M + H]+ (79Br); (37) 396 [M + H]+ (81Br).

General Procedure for the Synthesis of (£)-2-[2-(4-Aryl-2-methyl-2H-1,2,3-triazol-5-yl)vinyl]-4H-chromen-4-ones 9a-d, (E)-2-[2-(4-Aryl-3-methyl-2H-1,2,3-triazol-5-yl)vinyl] -4H-chromen-4-ones 10a-d and (E)-2-[2-(4-Aryl-1-methyl-2H-1,2,3-triazol-5-yl)vinyl]-4H-chromen-4-ones 11a-d: Dimethyl sulfate (0.1 mL, 1.1 mmol) was added dropwise to a solution of the appropriate (E)-2-[2-(4-aryl-2H-1,2,3-triazol-5-yl)vinyl]-4H-chromen-4-one 8a-d (1 mmol) in acetone (10 mL) with potassium carbonate (0.36 g, 3mmol). The mixture was stirred under reflux for 1 h. The inorganic salts were removed by filtration and washed with acetone (3 X 30 mL). The solvent was evaporated to dryness and the residue was purified by silica column chromatography using CH2Cl2 as eluent. Two fractions were obtained: 1,2,3-triazole derivatives 9a-d (higher Rf value) in 67-82% yield and a mixture of 10a-d and 11a-d in 1833% yield.

(£)-2-[2-(2-Methyl-4-phenyl-2H-1,2,3-triazol-5-yl)vinyl]-4H-chromen-4-one (9a): Yield 221 mg (67%), m.p. 169-171 °C. !H NMR (300 MHz, CDCl3): S = 4.29 (s, 3 H, NCH3), 6.34 (s, 1 H, 3-H), 7.12 (d, J = 15.8 Hz, 1 H, a-H), 7.39 (ddd, J = 8.0, 7.1, 0.8 Hz, 1 H, 6-H), 7.47 (dd, J = 8.2, 0.8 Hz, 1 H, 8-H), 7.48-7.57 (m, 3 H, 3'',4'',5''-H), 7.61 (d, J = 15.8 Hz, 1 H, P-H), 7.64-7.70 (m, 3 H, 7-H, 2'',6''-H), 8.19 (dd, J =8.0, 1.5 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 42.2 (NCH3), 111.3 (C-3), 117.9

(C-8), 123.2 (C-a), 124.0 (C-P), 124.1 (C-4a), 125.1 (C-6), 125.7 (C-5), 128.3 (C-2'',6''), 128.9 (C-4''), 129.0 (C-3'',5''), 130.1 (C-1''),

133.8 (C-8), 140.5 (C-5'), 147.4 (C-4'), 155.9 (C-8a), 161.1 (C-2),

178.5 (C-4) ppm. HRMS (ESI+): m/z calcd. for C20H16N3O2 [M + H]+ 330.1243, found 330.1231. MS (ESI+): m/z (%) = 330 (100) [2M + H]+, 659 (7) [2M + H]+.

Mixture of 10a and 11a (86:14): Yield 109mg (33%). (E)-2-[2-(3-Methyl-4-phenyl-1H-1,2,3-triazol-5-yl)vinyl]-4H-chromen-4-one (10a): !H NMR (500 MHz, CDCl3): S = 4.02 (s, 3 H, NCH3), 6.30 (s, 1 H, 3-H), 7.21 (d, J = 15.8 Hz, 1 H, a-H), 7.36 (d, J = 15.8 Hz, 1 H, P-H), 7.38 (ddd, J = 7.7, 7.5, 1.0 Hz, 1 H, 6-H), 7.41-7.43 (m, 3 H, 8-H, 2'',6''-H), 7.61-7.65 (m, 4 H, 7-H, 3'',4'',5''-H), 8.17 (dd, J = 7.5, 1.5 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 35.5 (NCH3), 110.9 (C-3), 117.9 (C-8), 122.0 (C-a), 124.0 (CP), 124.1 (C-4a), 125.0 (C-6), 125.7 (C-5), 126.1 (C-1''), 129.5 (C-2'',6''), 129.6 (C-3'',5''), 130.2 (C-4''), 133.6 (C-7), 137.0 (C-4'),

141.3 (C-5'), 155.9 (C-8a), 161.4 (C-2), 178.5 (C-4) ppm. (E)-2-[2-(1-Methyl-4-phenyl-1H-1,2,3-triazol-5-yl)vinyl]-4H-chromen-4-one (11a): !H NMR (500 MHz, CDCl3): S = 4.27 (s, 3 H, NCH3), 6.27 (s, 1 H, 3-H) ppm.

(E)-2-{2-[2-Methyl-4-(4-methylphenyl)-2H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (9b): Yield 257 mg (75%), m.p. 192-194 °C. !H NMR (300 MHz, CDCl3): S = 2.46 (s, 3 H, CH3), 4.29 (s, 3 H, N-CH3), 6.49 (s, 1 H, 3-H), 7.13, (d, J = 15.8 Hz, 1 H, a-H), 7.34 (d, J = 8.0 Hz, 2 H, 3'',5''-H), 7.42 (ddd, J = 7.7, 7.4, 1.1 Hz, 1 H, 6-H), 7.50 (dd, J = 8.4, 1.1 Hz, 1 H, 8-H), 7.55 (d, J = 8.0 Hz, 2 H, 2'',6''-H), 7.64 (d, J = 15.8 Hz, 1 H, P-H), 7.70 (ddd, J = 8.4, 7.4, 1.6 Hz, 1 H, 7-H), 8.21 (dd, J = 7.7, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 21.4 (CH3), 42.2 (NCH3), 110.8 (C-3), 118.0 (C-8), 122.7 (C-a), 123.6 (C-4a), 124.9 (C-P), 125.3 (C-6), 125.7 (C-5), 127.1 (C-1''), 128.2 (C-2'',6''), 129.8 (C-3'',5''), 134.1 (C-7), 139.1 (C-4'), 140.3 (C-5'), 147.7 (C-4''), 156.0 (C-8a), 161.9 (C-2), 178.5 (C-4) ppm. HRMS (ESI+): m/z calcd. for C21H18N3O2 [M + H]+ 344.1399, found 344.1381. MS (ESI+): m/z (%) = 344 (100) [M + H]+, 687 (11) [2M + H]+.

Mixture of 10b and 11b (81:19): Yield 86 mg (25%). (E)-2-{2-[3-Methyl-4-(4-methylphenyl)-1H -1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (10b): !H NMR (300 MHz, CDCl3): S = 2.51 (s, 3

H, CH3), 4.01 (s, 3 H, NCH3), 6.31 (s, 1 H, 3-H), 7.20 (d, J = 15.9 Hz, 1 H, a-H), 7.30 (d, J = 8.1 Hz, 2 H, 2'',6''-H), 7.32-7.38 (m, 1 H, 6-H), 7.37 (d, J = 15.9 Hz, 1 H, P-H), 7.41-7.45 (m, 3 H, 8-H, 3'',5''-H), 7.64 (ddd, J = 8.5, 7.1, 1.6 Hz, 1 H, 7-H), 8.17 (dd, J = 7.9, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 21.5 (CH3), 35.5 (NCH3), 110.8 (C-3), 117.9 (C-8), 121.8 (C-a), 123.0 (C-4a), 124.0 (C-1''), 124.3 (C-P), 125.0 (C-6), 125.7 (C-5),

129.4 (C-2'',6''), 130.2 (C-3'',5''), 133.7 (C-7), 137.2 (C-4'), 140.6 (C-4''), 141.1 (C-5'), 155.9 (C-8a), 161.6 (C-2), 178.5 (C-4) ppm. (_E)-2-{2-[1-Methyl-4-(4-methylphenyl)-1H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (11b): !H NMR (300 MHz, CDCl3): S = 2.2 (s, 3 H, CH3), 3.97 (s, 3 H, NCH3), 6.40 (s, 1 H, 3-H) ppm.

(£)-2-{2-[4-(4-Methoxyphenyl)-2-methyl-2H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (9c): Yield 280 mg (78%), m.p. 186187 °C. !H NMR (300 MHz, CDCl3): S = 3.90 (s, 3 H, OCH3), 4.28 (s, 3 H, NCH3), 6.34 (s, 1 H, 3-H), 7.06 (d, J = 8.8 Hz, 2 H, 3'',5''-H), 7.10 (d, J = 15.8 Hz, 1 H, a-H), 7.40 (ddd, J = 7.7, 7.3,

I.1 Hz, 1 H, 6-H), 7.48 (d, J = 8.2 Hz, 1 H, 8-H), 7.59 (d, J = 15.8 Hz, 1 H, P-H), 7.59 (d, J =8.8 Hz, 2 H, 2'',6''-H), 7.67 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, 7-H), 8.20 (dd, J = 7.7, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 42.1 (NCH3), 55.4 (OCH3), 111.1 (C-3), 114.4 (C-3'',5''), 117.9 (C-8), 122.5 (C-1''),

122.9 (C-a), 124.1 (C-4a), 124.2 (C-P), 125.0 (C-6), 125.7 (C-5),

129.6 (C-2'',6''), 133.7 (C-7), 140.2 (C-5'), 147.3 (C-4'), 155.9 (C-

_EurVC

European Journal of Organic Chemistry

8a), 160.2 (C-4''), 161.1 (C-2), 178.5 (C-4) ppm. HRMS (ESI+): m/z calcd. for C21H18N3O3 [M + H]+ 360.1348, found 360.1332. MS (ESI+): m/z (%) = 344 (4) [M - CH3]+, 360 (100) [M + H]+, 719 (10) [2M + H]+.

Mixture of 10c and 11c (87:13): Yield 79 mg (22%). (E)-2-{2-[4-(4-Methoxyphenyl)-3-methyl-1H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (10c): !H NMR (300 MHz, CDCl3): S = 3.94 (s, 3 H, OCH3), 4.00 (s, 3 H, NCH3), 6.30 (s, 1 H, 3-H), 7.13 (d, J = 8.8 Hz, 2 H, 3'',5''-H), 7.19 (d, J = 15.9 Hz, 1 H, a-H), 7.33-7.40 (m, 4 H, PH, 6-H, 2'',6''-H), 7.43 (dd, J =8.5, 0.6 Hz, 1 H, 8-H), 7.64 (ddd, J = 8.5, 7.0, 1.6 Hz, 1 H, 7-H), 8.16 (dd, J = 7.9, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 35.4 (NCH3), 55.5 (OCH3), 110.8 (C-3), 115.0 (C-3'',5''), 117.9 (C-8), 121.6 (C-a), 124.1 (C-1''), 124.3 (C-P), 125.0 (C-6), 125.7 (C-5), 130.9 (C-2'',6''), 133.6 (C-7), 137.0 (C-4'), 141.2 (C-5'), 155.9 (C-8a), 161.0 (C-4''), 161.5 (C-2), 178.5 (C-4) ppm. (£)-2-{2-[4-(4-Meth-oxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (11c): !H NMR (300 MHz, CDCl3): S = 3.88 (s, 3 H, OCH3), 4.25 (s, 3 H, NCH3), 6.27 (s, 1 H, 3-H) ppm.

(E)-2-{2-[4-(4-Bromophenyl)-2-methyl-2H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (9d): Yield 335 mg (82%), m.p. 223-224 °C. !H NMR (300 MHz, CDCl3): S = 4.29 (s, 3 H, NCH3), 6.50 (s, 1 H, 3-H), 7.15 (d, J = 15.8 Hz, 1 H, a-H), 7.43 (dt, J = 7.7, 0.8 Hz, 1

H, 6-H), 7.52 (dd, J = 7.6, 0.8 Hz, 1 H, 8-H), 7.54 (d, J = 8.5 Hz, 2 H, 2'',6''-H), 7.58 (d, J = 15.8 Hz, 1 H, P-H), 7.67 (d, J = 8.5 Hz, 2 H, 3'',5''-H), 7.68-7.74 (m, 1 H, 7-H), 8.21 (dd, J = 7.7, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): S = 42.2 (NCH3), 111.1 (C-3), 117.9 (C-8), 123.3 (C-4''), 123.5 (C-P), 123.7 (C-a), 124.1 (C-4a), 125.2 (C-6), 125.7 (C-5), 129.1 (C-1''), 129.8 (C-2'',6''), 132.2 (C-3'',5''), 133.9 (C-7), 140.5 (C-5'), 146.3 (C-4'), 155.9 (C-8a), 160.9 (C-2), 178.5 (C-4) ppm. HRMS (ESI+): m/z calcd. for C20H1579BrN3O2 [M + H]+ 408.0348, found 408.0330; calcd. for C20H1581BrN3O2 [M + H]+ 410.0327, found 410.0306. MS (ESI+): m/z (%) = 408 (100) [M + H]+, 430 (15) [M + Na]+.

Mixture of 10d and 11d (93:7): Yield 73 mg (18%). (E)-2-{2-[4-(4-Bromophenyl)-1-methyl-1H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (10d): !H NMR (500 MHz, CDCl3): S = 4.02 (s, 3 H, NCH3), 6.33 (s, 1 H, 3-H), 7.26-7.31 (m, 2 H, a-H, P-H), 7.30 (d, J = 8.5 Hz, 2 H, 2'',6''-H), 7.38 (ddd, J = 7.9, 7.1, 0.7 Hz, 1 H, 6-H), 7.45 (dd, J = 8.5, 0.7 Hz, 1 H, 8-H), 7.65 (ddd, J = 8.5, 7.1, 1.6 Hz, 1 H, 7-H), 7.77 (d, J = 8.5 Hz, 2 H, 3'',5''-H), 8.18 (dd, J = 7.9,

I.6 Hz, 1 H, 5-H) ppm. 13C NMR (125 MHz, CDCl3): S = 35.5 (NCH3), 111.2 (C-3), 117.9 (C-8), 122.5 (C-P), 123.3 (C-a), 124.1 (C-4a), 124.9 and 125.0 (C-1'' and C-4''), 125.1 (C-6), 125.7 (C-5), 131.1 (C-2'',6''), 132.9 (C-3'',5''), 133.7 (C-7), 135.9 (C-4'), 141.5 (C-5'), 155.9 (C-8a), 161.2 (C-2), 178.4 (C-4) ppm. (E)-2-{2-[4-(4-Bromophenyl)-3-methyl-1H-1,2,3-triazol-5-yl]vinyl}-4H-chromen-4-one (11d): !H NMR (500 MHz, CDCl3): S = 4.03 (s, 3 H, NCH3), 6.30 (s, 1 H, 3-H) ppm.

General Procedure for the Synthesis of 4-(4-Aryl-2-methyl-2H-1,2,3-triazol-5-yl)-2-methyl-3a,4,5,11b-tetrahydrochromeno[3,2-e]isoind-ole-1,3,11(2H)-triones (12a-d). Method A: N-Methylmaleimide (0.10 g, 0.92 mmol) was added to a solution of the appropriate (E)-2-[2-(4-aryl-2-methyl-2H-1,2,3-triazol-5-yl)vinyl]-4H-chromen-4-ones 9a-d (0.18 mmol) in dry DMF (5 ^L). The mixture was heated at 160 °C under microwave irradiation (multimode apparatus) for 20 min. The residue was dissolved in CH2Cl2 and purified by preparative TLC using CH2Cl2/EtOAc (4:1) as eluent to give desired cycloadducts 12a-d in the following yields: 12a (29.3 mg, 37%), 12b (27.0 mg, 33%), 12c (33.9 mg, 40%), 12d (28.0 mg, 30%).

Method B: N-Methylmaleimide (0.10 g, 0.92 mmol) was mixed with the appropriate (E)-2-[2-(4-aryl-2-methyl-2H-1,2,3-triazol-5-yl)

vinyl]-4H-chromen-4-ones 9a-d (0.18 mmol) in a close vessel. The mixture was heated at 200 °C under microwave irradiation (monomode apparatus) for 10 min. The residue was dissolved in CH2Cl2 and purified by preparative TLC using CH2Cl2 EtOAc (4:1) as elu-ent to give desired cycloadducts 12a-d in the following yields: 12a (28.5 mg, 36%), 12b (39.3 mg, 48%), 12c (33.9 mg, 40%), 12d (35.5 mg, 38%).

2-Methyl-4-(2-methyl-4-phenyl-2H-1,2,3-triazol-5-yl)-3a,4,5,11b-tetrahydrochromeno[3,2-e]isoindole-1,3,11(2H)-trione (12a): M.p.

152-153 °C. !H NMR (300 MHz, CDCl3): S = 2.82 (s, 3 H, 2-NCH3), 2.98-3.24 (m, 2 H, 5-H), 3.47 (dd, J = 8.8, 6.4 Hz, 1 H, 3a-H), 3.84-3.91 (m, 1 H, 4-H), 4.18 (s, 3 H, 2'-NCH3), 4.64 (d, J = 8.8 Hz, 1 H, 11b-H), 7.40-7.49 (m, 5 H, 7-H, 9-H, 3'',4'',5''-H), 7.61 (dd, J = 8.1, 1.5 Hz, 2 H, 2'',6''-H), 7.67 (ddd, J = 8.5, 7.1, 1.6 Hz, 1 H, 8-H), 8.30 (dd, J = 8.4, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 24.9 (2-NCH3), 30.6 (C-5), 32.4 (C-4), 37.9 (C-11b), 41.2 (C-3a), 41.7 (2'-NCH3), 113.3 (C-11a), 117.7 (C-7), 123.7 (C-10a), 125.3 (C-9), 126.4 (C-10), 127.7 (C-2'',6''),

128.6 (C-4''), 129.0 (C-3'',5''), 130.9 (C-1''), 133.7 (C-8), 142.3 (C-5'), 145.1 (C-4'), 155.7 (C-6a), 164.1 (C-5a), 174.7 (C-3), 175.2 (C-1), 176.1 (C-11) ppm. HRMS (ESI+): m/z calcd. for C25H21N4O4 [M + H]+ 441.1563, found 441.1539. MS (ESI+): m/z (%) = 441 (100) [M + H]+, 463 (17) [M + Na]+, 479 (10) [M + K]+.

2-Methyl-4-[2-methyl-4-(4-methylphenyl)-2H-1,2,3-triazol-5-yl]-3a,4,5,11b-tetrahydrochromeno[3,2-e]isoindole-1,3,11(2H)-trione (12b): M.p. 143-145 °C. !H NMR (300 MHz, CDCl3): S = 2.40 (s,

3 H, CH3), 2.82 (s, 3 H, 2-NCH3), 2.98-3.24 (m, 2 H, 5-H), 3.48 (dd, J = 8.8, 6.4 Hz, 1 H, 3a-H), 3.82-3.89 (m, 1 H, 4-H), 4.17 (s, 3 H, 2'-NCH3), 4.63 (d, J = 8.8 Hz, 1 H, 11b-H), 7.26 (d, J = 8.0 Hz, 2 H, 3'',5''-H), 7.40-7.45 (m, 1 H, 9-H), 7.41 (d, J = 8.2 Hz, 1 H, 7-H), 7.49 (d, J = 8.0 Hz, 2 H, 2'',6''-H), 7.67 (ddd, J = 8.2, 7.2, 1.5 Hz, 1 H, 8-H), 8.29 (dd, J = 8.2, 1.5 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 21.3 (CH3), 24.9 (2-NCH3), 30.5 (C-5), 32.4 (C-4), 37.9 (C-11b), 41.1 (C-3a), 41.7 (2'-NCH3), 113.3 (C-11a), 117.7 (C-7), 123.7 (C-10a), 125.3 (C-9), 126.4 (C-10), 127.5 (C-2'',6''), 127.9 (C-1''), 129.7 (C-3'',5''),

133.7 (C-8), 138.6 (C-4''), 142.2 (C-5'), 145.1 (C-4'), 155.7 (C-6a), 164.2 (C-5a), 174.8 (C-3), 175.2 (C-1), 176.0 (C-11) ppm. HRMS (ESI+): m/z calcd. for C26H23N4O4 [M + H]+ 455.1719, found 455.1699. MS (ESI+): m/z (%) = 455 (100) [M + H]+, 477 (26) [M + Na]+.

4-[4-(4-Methoxyphenyl)-2-methyl-2H-1,2,3-triazol-5-yl]-2-methyl-3a,4,5,11b-tetrahydrochromeno[3,2-e]isoindole-1,3,11(2H)-trione (12c): M.p. 167-169 °C. !H NMR (300 MHz, CDCl3): S = 2.82 (s, 3 H, 2-NCH3), 2.97-3.23 (m, 2 H, 5-H), 3.48 (dd, J = 8.8, 6.4 Hz, 1 H, 3a-H), 3.79-3.90 (m, 1 H, 4-H), 3.85 (s, 3 H, OCH3), 4.16 (s, 3 H, 2'-NCH3), 4.64 (d, J = 8.8 Hz, 1 H, 11b-H), 6.98 (d, J = 8.8 Hz, 2 H, 3'',5''-H), 7.41 (d, J = 8.2 Hz, 1 H, 7-H), 7.40-7.45 (m, 1 H, 9-H), 7.53 (d, J = 8.8 Hz, 2 H, 2'',6''-H), 7.67 (ddd, J = 8.2, 7.1, 1.6 Hz, 1 H, 8-H), 8.29 (dd, J = 8.4, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 24.9 (2-NCH3), 30.6 (C-5), 32.4 (C-4), 37.9 (C-11b), 41.2 (C-3a), 41.7 (2'-NCH3), 55.3 (OCH3), 113.3 (C-11a), 114.4 (C-3'',5''), 117.7 (C-7), 123.2 (C-1''), 123.6 (C-10a), 125.3 (C-9), 126.4 (C-10), 129.0 (C-2'',6''), 133.7 (C-8), 142.0 (C-4'), 145.0 (C-5'), 155.7 (C-6a), 159.9 (C-4''), 164.1 (C-5a), 174.7 (C-3), 175.2 (C-1), 176.0 (C-11) ppm. HRMS (ESI+): m/z calcd. for C26H23N4O5 [M + H]+ 471.1668, found 471.1645. MS (ESI+): m/z (%) = 471 (100) [M + H]+, 493 (8) [M + Na]+.

4-[4-(4-Bromophenyl)-2-methyl-2H-1,2,3-triazol-5-yl]-2-methyl-3a,4,5,11b-tetrahydrochromeno[3,2-e]isoindole-1,3,11(2H)-trione (12d): M.p. 145-146 °C. !H NMR (300 MHz, CDCl3): S = 2.81 (s, 3 H, 2-NCH3), 2.96-3.24 (m, 2 H, 5-H), 3.46 (dd, J = 8.8, 6.4 Hz,

1 H, 3a-H), 3.82-3.88 (m, 1 H, 4-H), 4.16 (s, 3 H, 2'-NC#3), 4.64 (d, J = 8.8 Hz, 1 H, 11b-H), 7.40-7.45 (m, 1 H, 9-H), 7.41 (d, J = 8.1 Hz, 1 H, 7-H), 7.49 (d, J = 8.6 Hz, 2 H, 2'',6''-H), 7.59 (d, J = 8.6 Hz, 2 H, 3'',5''-H), 7.67 (ddd, J = 8.1, 7.2, 1.6 Hz, 1 H, 8-H), 8.29 (dd, J =8.2, 1.6 Hz, 1 H, 10-H) ppm. 13CNMR (75 MHz, CDCl3): S = 24.9 (2-NCH3), 30.7 (C-5), 32.3 (C-4), 37.9 (C-11b),

41.2 (C-3a), 41.8 (2'-NCH3), 113.3 (C-11a), 117.7 (C-7), 122.9 (C-4''), 123.6 (C-10a), 125.4 (C-9), 126.4 (C-10), 129.3 (C-2'',6''), 129.8 (C-1''), 132.2 (C-3'',5''), 133.8 (C-8), 142.4 (C-5'), 144.1 (C-4'), 155.7 (C-6a), 163.8 (C-5a), 174.6 (C-3), 175.2 (C-1), 175.9 (C-11) ppm. HRMS (ESI+): m/z calcd. for C25H2079BrN4O4 [M + H]+ 519.0668, found 519.0649; calcd. for C25H2081BrN4O4 [M + H] + 521.0647, found 521.0627. MS (ESI+): m/z (%) = 519 (20) [M + H]+, 541 (15) [M + Na]+.

General Procedure for the Synthesis of 4-(5-Aryl-2-methyl-2_ff-1,2,3-triazol-4-yl)-2-methylchromeno[3,2-e]isoindole-1,3,11(2_ff)-trione (13a-d): 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) (121 mg, 534 ^mol) was added to a solution of the appropriate 4-(4-aryl-2-methyl-2H-1,2,3-triazol-5-yl)-2-methyl-3a,4,5,11b-tetrahydro-chromeno[3,2-e]isoindole-1,3,11(2H)-triones 12a-d (178 ^mol) in toluene (10 mL). The mixture was stirred at 100 °C for 1 h. After that period, the solvent was evaporated to dryness. The residue was purified by preparative TLC using CH2Cl2 as eluent to give desired 4-(4-aryl-2-methyl-2H-1,2,3-triazol-5-yl)-2-methylchromeno[3,2-e]-isoindole-1,3,11(2H)-triones 13a-d in good yields (57-80%).

2-Methyl-4-(2-methyl-4-phenyl-2_ff-1,2,3-triazol-5-yl)chromeno-[3,2-e]isoindole-1,3,11(2fl)-trione (13a): Yield 57.5 mg (74%), m.p. 310-312 °C. 'H NMR (300 MHz, CDCl3): S = 3.07 (s, 3 H, 2-NCH3), 4.35 (s, 3 H, 2'-NCH3), 7.28-7.31 (m, 3 H, 3'',4'',5''-H), 7.39-7.43 (m, 2 H, 2'',6''-H), 7.44-7.49 (m, 1 H, 9-H), 7.50 (d, J = 7.3 Hz, 1 H, 7-H), 7.78 (ddd, J = 8.6, 7.3, 1.6 Hz, 1 H, 8-H), 7.85 (s, 1 H, 5-H), 8.40 (dd, J = 8.0, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (75 MHz, CDCl3): S = 24.4 (2-NCH3), 42.1 (2'-NCH3), 117.6 (C-7), 119.7 (C-11a), 123.0 (C-10a), 125.2 (C-9), 126.3 (C-5), 127.0 (C-2'',6''), 127.4 (C-3a), 127.5 (C-10), 128.5 (C-4''), 128.8 (C-3'',5''), 130.3 (C-1''), 134.1 and 134.2 (C-4 and C-11b), 135.5 (C-8), 138.7 (C-5'), 146.5 (C-4'), 155.0 (C-6a), 159.7 (C-5a), 164.4 and 165.4 (C-1 and C-3), 174.3 (C-11) ppm. HRMS (ESI+): m/z calcd. for C25H17N4O4 [M + H]+ 437.1250, found 437.1229. MS (ESI+): m/z (%) = 895 (100) [M + Na]+, 437 (88) [M + H]+, 911 (35) [2M + K]+.

2-Methyl-4-[2-methyl-4-(4-methylphenyl)-2_ff-1,2,3-triazol-5-yl]-chromeno[3,2-e]isoindole-1,3,11(2_ff)-trione (13b): Yield 64.1 mg (80%), m.p. 302-303 °C. !H NMR (300 MHz, CDCl3): S = 2.31 (s, 3 H, CH3), 3.08 (s, 3 H, 2-NCH3), 4.34 (s, 3 H, 2'-NCH3), 7.09 (d, J = 8.1 Hz, 2 H, 3'',5''-H), 7.29 (d, J = 8.1 Hz, 2 H, 2'',6''-H), 7.44-7.49 (m, 1 H, 9-H), 7.50 (d, J = 7.3 Hz, 1 H, 7-H), 7.78 (ddd, J = 8.5, 7.3, 1.6 Hz, 1 H, 8-H), 7.83 (s, 1 H, 5-H), 8.39 (dd, J = 8.0, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (126 MHz, CDCl3): S =

21.3 (CH3), 24.4 (2-NCH3), 42.1 (2'-NCH3), 117.6 (C-7), 119.7 (C-11a), 123.0 (C-10a), 125.2 (C-9), 126.4 (C-5), 126.9 (C-2'',6''), 127.4 (C-3a), 127.5 (C-10), 129.5 (C-3'',5''), 134.1 and 134.4 (C-11b and C-4), 135.5 (C-8), 138.4 (C-5'), 138.5 (C-1'', C-4''), 146.5 (C-4'), 155.0 (C-6a), 159.7 (C-5a), 164.3 and 165.5 (C-1 and C-3), 174.2 (C-11) ppm. HRMS (ESI+): m/z calcd. for C26H19N4O4 [M + H]+ 451.1406, found 451.1382. MS (ESI+): m/z (%) = 451 (100) [M + H]+, 489 (63) [M + K]+, 923 (16) [2M + Na]+, 939 (20) [2M + K]+.

4-[4-(4-Methoxyphenyl)-2-methyl-2_ff-1,2,3-triazol-5-yl]-2-methyl-chromeno[3,2-e]isoindole-1,3,11(2_ff)-trione (13c): Yield 68.9 mg (83%), m.p. 286-288 °C. !H NMR (500 MHz, CDCl3): S = 3.09 (s, 3 H, 2-NCH3), 3.78 (s, 3 H, OCH3), 4.33 (s, 3 H, 2'-NCH3), 6.81

(d, J = 8.9 Hz, 2 H, 3",5"-H), 7.34 (d, J = 8.9 Hz, 2 H, 2",6"-H), 7.46 (ddd, J = 8.0, 7.1, 0.7 Hz, 1 H, 9-H), 7.50 (dd, J = 8.3, 0.7 Hz, 1 H, 7-H), 7.78 (ddd, J = 8.3, 7.1, 1.6 Hz, 1 H, 8-H), 7.84 (s, 1 H, 5-H), 8.40 (dd, J = 8.0, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (126 MHz, CDCl3): ô = 24.4 (2-NCH3), 42.1 (2'-NCH3), 55.3 (OCH3), 114.3 (C-3",5"), 117.6 (C-7), 119.6 (C-11a), 122.8 (C-1"),

123.0 (C-10a), 125.2 (C-9), 126.4 (C-5), 127.4 (C-3a), 127.5 (C-10), 128.3 (C-2",6"), 134.1 and 134.4 (C-4 and C-11b), 135.5 (C-8),

138.1 (C-5'), 146.3 (C-4'), 155.0 (C-6a), 159.76 (C-4"), 159.75 (C-5a), 164.3 and 165.4 (C-1 and C-3), 174.3 (C-11) ppm. HRMS (ESI+): m/z calcd. for C26H19N4O5 [M + H]+ 467.1355, found 467.1332. MS (ESI+): m/z (%) = 467 (100) [M + H]+, 489 (27) [M + Na]+, 505 (20) [M + K]+.

4-[4-(4-Bromophenyl)-2-methyl-2#-1,2,3-triazol-5-ylj-2-methyl-chromeno[3,2-e]isoindole-1,3,11(2fl)-trione (13d): Yield 52.3 mg (57%), m.p. 312-313 °C. 'H NMR (500 MHz, CDCl3): ô = 3.09 (s, 3 H, 2-NCff3), 4.34 (s, 3 H, 2'-NCff3), 7.29 (d, J = 8.6 Hz, 2 H, 2'',6''-H), 7.42 (d, J = 8.6 Hz, 2 H, 3'',5''-H), 7.47 (ddd, J = 8.0, 7.1, 0.7 Hz, 1 H, 9-H), 7.51 (dd, J = 8.3, 0.7 Hz, 1 H, 7-H), 7.79 (ddd, J = 8.3, 7.1, 1.6 Hz, 1 H, 8-H), 7.84 (s, 1 H, 5-H), 8.40 (dd, J = 8.0, 1.6 Hz, 1 H, 10-H) ppm. 13C NMR (126 MHz, CDCl3): ô = 24.5 (2-NCH3), 42.2 (2'-NCH3), 117.6 (C-7), 119.8 (C-11a), 122.7 (C-4''), 123.0 (C-10a), 125.3 (C-9), 126.3 (C-5), 127.2 (C-3a), 127.5 (C-10), 128.4 (C-2'',6''), 129.4 (C-1''), 132.0 (C-3'',5''), 133.8 and 134.1 (C-4 and C-11b), 135.6 (C-8), 138.7 (C-5'), 145.5 (C-4'), 155.0 (C-6a), 159.8 (C-5a), 164.1 and 165.4 (C-1 and C-3), 174.1 (C-11) ppm. HRMS (ESI+): m/z calcd. for C25H1679BrN4O4 [M + H]+ 515.0355, found 515.0330; calcd. for C25H1681BrN4O4 [M + H]+ 517.0334, found 517.0484. MS (ESI+): m/z (%) = 515 (15) [M + H]+, 537 (24) [M + Na]+, 555 (21) [M + K]+.

Acknowledgments

Thanks are due to the Universidade de Aveiro, Instituto Politécnico de Braganfa, the Fundafáo para a Ciencia e Tecnologia (FCT) (PhD grant to H. M. T. A., SFRH/BD/86277/2012), the European Union (EU), the Quadro de Referencia Estratégico Nacional (QREN), the Fundo Europeu de Desenvolvimento Regional (FEDER and COMPETE) for funding the QOPNA Research Unit (project number PEst-C/QUI/UI0062/2013) and the Portuguese National NMR Network.

[1] a) G. J. Bennett, H.-H. Lee, Phytochemistry 1989, 28, 967-998; b) S.-I. Sakai, M. Katsura, H. Takayama, N. Aimi, N. Choke-thaworn, M. Suttajit, Chem. Pharm. Bull. 1993, 41, 958-960.

[2] T. B. P. Oldenburg, H. Wilkes, B. Horsfield, A. C. T. van Duin, D. Stoddart, A. Wilhelms, Org. Geochem. 2002, 33, 595-609.

[3] L. M. Vieira, A. Kijjoa, Curr. Med. Chem. 2005, 12, 24132446.

[4] a) H. R. El-Seedi, M. A. El-Barbary, D.M. El-Ghorab, L. Bohlin, A. K. Borg-Karlson, U. Goransson, R. Verpoorte, Curr. Med. Chem. 2010, 17, 854-901; b) M. M. Pinto, M. E. Sousa, M.S. Nascimento, Curr. Med. Chem. 2005, 12, 25172538.

[5] a) K. H. Park, Y.-D. Park, J.-M. Han, K.-R. Im, B. W. Lee, I. Y. Jeong, T.-S. Jeong, W. S. Lee, Bioorg. Med. Chem. Lett. 2006,16, 5580-5583; b) D. J. Jiang, Z. Dai, Y. J. Li, Cardiovasc. Drug Rev. 2004, 22, 91-102.

[6] a) Y. Na, J. Pharm. Pharmacol. 2009, 61, 707-712; b) G. C. Ee, S. Daud, S. A. Izzaddin, M. Rahmani, J. Asian Nat. Prod. Res. 2008, 10, 475-479.

_Eur OC

European Journal of Organic Chemistry

[7] a) M. Riscoe, J. X. Kelly, R. Winter, Curr. Med. Chem. 2005, 12, 2539-2549; b) C. Portela, C. M. M. Afonso, M. M. M. Pinto, M.J. Ramos, Bioorg. Med. Chem. 2004, 12, 3313-3321.

[8] a) C. M. M. Santos, M. Freitas, D. Ribeiro, A. Gomes, A. M. S. Silva, J. A. S. Cavaleiro, E. Fernandes, Bioorg. Med. Chem. 2010, 18, 6776-6784; b) W. Pothitirat, M. T. Chomna-wang, R. Supabphol, W. Gritsanapan, Fitoterapia 2009, 80, 442-447.

[9] M. T. Khan, I. Orhan, F. S. Senol, M. Kartal, B. Sener, M. Dvorska, K. Smejkal, T. Slapetova, Chem.-Biol. Interact. 2009, 181, 383-389.

[10] a) R. Herbrecht, Int. J. Clin. Pract. 2004, 58, 612-624; b) S. Arikan, J. H. Rex, Curr. Opin. Investig. Drugs 2002, 3, 555-561; c) P. H. Chandrasekar, E. Manavathu, Drugs Today 2001, 37, 135-148.

[11] F. d. C. da Silva, M. C. B. V. de Souza, 1.1. P. Frugulhetti, H. C. Castro, S. L. d. O. Souza, T. M. L. de Souza, D. Q. Rodrigues, A. M. T. Souza, P. A. Abreu, F. Passamani, C. R. Rodrigues, V. F. Ferreira, Eur. J. Med. Chem. 2009, 44, 373-383.

[12] K.-M. Alexacou, J. M. Hayes, C. Tiraidis, S. E. Zographos, D. D. Leonidas, E. D. Chrysina, G. Archontis, N. G. Oikono-makos, J. V. Paul, B. Varghese, D. Loganathan, Proteins Struct., Funct., Bioinf. 2008, 71, 1307-1323.

[13] M. J. Genin, D. A. Allwine, D. J. Anderson, M. R. Barbachyn, D. E. Emmert, S. A. Garmon, D. R. Graber, K. C. Grega, J. B. Hester, D. K. Hutchinson, J. Morris, R. J. Reischer, C. W. Ford, G. E. Zurenko, J. C. Hamel, R. D. Schaadt, D. Stapert, B. H. Yagi, J. Med. Chem. 2000, 43, 953-970.

[14] A. Massarotti, S. Aprile, V. Mercalli, E. Del Grosso, G. Grosa, G. Sorba, G. C. Tron, ChemMedChem 2014, 9, 2497-2508.

[15] N. H. Morgan, vol. EP 437979 A2, 1991, 0724.

[16] W. Fan, Comprehensive Heterocyclic Chem. II, vol. 4, Perga-mon, Oxford, UK, UK, 1996.

[17] R. J. Willis, I. D. Marlow, Eur. Pat. Appl. 400842, 1990; Chem. Abstr. 1991, 114, 164247b.

[18] Y. Zou, Q. Zhao, H. Hu, L. Hu, S. Yu, M. Xu, Q. Wu, Arch. Pharmacol. Res. 2012, 35, 2093-2104.

[19] J. Li, M. Hu, S. Q. Yao, Org. Lett. 2009, 11, 3008-3011.

[20] W. A. Price, A. M. S. Silva, J. A. S. Cavaleiro, Heterocycles 1993, 36, 2601-2612.

[21] a) R. M. Letcher, T. Y. Yue, J. Chem. Res. Synop. 1992, 248; b) R. M. Letcher, T. Y. Yue, J. Chem. Res. Miniprint 1992, 2078.

[22] A. S. Kelkar, R. M. Letcher, K.-K. Cheung, K.-F. Chiu, G. D. Brown, J. Chem. Soc. Perkin Trans. 1 2000, 3732-3741.

[23] D. C. G. A. Pinto, A. M. S. Silva, C. M. Brito, A. Sandulache, J. R. Carrillo, P. Prieto, A. Diaz-Ortiz, A. de la Hoz, J. A. S. Cavaleiro, Eur. J. Org. Chem. 2005, 2973-2986.

[24] C. M. M. Santos, A. M. S. Silva, J. A. S. Cavaleiro, Eur. J. Org. Chem. 2009, 2642-2660.

[25] C. I. C. Esteves, C. M. M. Santos, C. M. Brito, A. M. S. Silva, J. A. S. Cavaleiro, Synlett 2011, 1403-1406.

[26] a) W. Baker, J. Chem. Soc. 1933, 1381-1389; b) H. S. Mahal, K. Venkataraman, J. Chem. Soc. 1934, 1767-1769.

[27] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467-4470.

[28] V. L. M. Silva, A. M. S. Silva, D. C. G. A. Pinto, J. Elguero, J. A. S. Cavaleiro, Eur. J. Org. Chem. 2009, 4468-4479.

[29] S. Kotha, S. Banerjee, RSC Adv. 2013, 3, 7642-7666.

[30] V. L. M. Silva, A. M. S. Silva, D. C. G. A. Pinto, J. A. S. Cava-leiro, Synlett 2006, 1369-1373.

[31] D.H. Wadsworth, S. M. Geer, M. R. Detty, J. Org. Chem. 1987, 52, 3662-3668.

[32] E. V. Tretyakov, A. V. Tkachev, T. V. Rybalova, Y. V. Gatilov, D. W. Knight, S. F. Vasilevsky, Tetrahedron 2000, 56, 1007510080.

Received: April 7, 2015 Published Online: June 10, 2015