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Synthesis 2011(1): 97-103  
DOI: 10.1055/s-0030-1258969
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Organocatalyzed Reactions Involving 3-Formylchromones and Acetylenedicarboxylates: Efficient Synthesis of Functionalized Benzophenones and Polysubstituted Xanthones

Michael A. Terzidis, Vassilios G. Tsiaras, Julia Stephanidou-Stephanatou*, Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, 54124 Macedonia, Greece
Fax: +30(2310)997679; e-Mail: ioulia@chem.auth.gr; e-Mail: tsolerid@chem.auth.gr;

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Publication History

Received 2 August 2010
Publication Date:
09 November 2010 (online)

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Abstract

Organocatalyzed reactions between chromones and acetylenedicarboxylates leading either to xanthone derivatives or to functionalized benzophenones are described. The outcome of the reactions was found to depend both on the nature of the chromone substituents and on the basicity of the organocatalyst.

Key words

DMAP - hetero-Diels-Alder reactions - Friedel-Crafts reactions - organocatalysis - xanthones - zwitterions

One of the rapidly growing areas of research in the field of organic synthesis is that of catalytic transformations utilizing small organic molecules called organocatalysts. [¹] Although, for a long time, organocatalysis was not viewed as a viable alternative to the two main classes of established catalysts (transition-metal complexes and enzymes) a report, which appeared in 2000, completely changed this perception and highlighted the fascinating attributes of small organic molecules as catalysts. [²] Recently, the possibility of carbon-carbon bond formation by intermolecular trapping of 1,4-zwitterionic intermediates generated from pyridine, acting as an organocatalyst, and acetylenedicarboxylates with aldehydes, and also with carbonyl compounds more generally, was studied. [³] An analogous 4-dimethylaminopyridine (DMAP)-catalyzed reaction between dimethyl acetylenedicarboxylates (DMAD) and β-ketoesters has also been reported. [4]

Scheme 1 Reaction of substituted 3-formylchromones 1 with acetylenedicarboxylates 2 in the presence of 4-picoline or DMAP as organocatalysts

In a continuation of the above mentioned literature reports, a hetero-Diels-Alder type reaction between formylchromones and acetylenedicarboxylates was studied, [5] [6] whereupon, by using 4-picoline as organocatalyst, an efficient one-pot approach to a new class of pyrano[4,3-c]chromenes 3 was possible (Scheme  [¹] ). In the course of further studies on chromone organocatalytic reactions involving zwitterionic intermediates, in the present study we extended our investigation by introducing strong electron-withdrawing substituents into the chromone moiety, and found that, by using the same organocatalyst, 4-picoline, the reaction followed a completely different pathway leading to formation of xanthone derivatives 4 in good yields. The same xanthone derivatives 4 were also isolated when DMAP was used as organocatalyst. In contrast, the use of DMAP with chromones bearing electron-donating substituents led to formation of functionalized benzophenones 5 instead of either pyrano[4,3-c]chromenes 3 or xanthones 4.

Functionalized benzophenones are of considerable interest as pharmacologically relevant natural products and natural product analogues, and they represent versatile synthetic building blocks. [7] Since classical synthesis through Friedel-Crafts acylation frequently leads to unsatisfactory results, [8] benzophenone syntheses rely on the reaction of organometallic reagents with aldehydes and subsequent oxidation. [9] More recently, some functionalized benzophenones were also prepared by domino ‘Michael-retro-Michael-aldol’ reactions. [¹0] On the other hand, xanthones are a class of natural products that have been shown to possess a wide range of pharmacological properties, [¹¹] and it has been shown that electron-­withdrawing substituents enhance the antimycobacterial activity of these compounds. [¹²]

Table 1 Effect of the Substituents and Organocatalyst on the Reaction of 3-Formylchromones 1 and Acetylenedicarboxylates 2
Entry R¹ R² R³ R4 Catalyst Product (%)
 1 Br H Br Me 4-picoline 4f (64)
 2 NO2 H H Me 4-picoline 4g (59)
 3 NO2 H H Et 4-picoline 4h (61)
 4 Br H Br Me DMAP 4f (58)
 5 NO2 H H Me DMAP 4g (53)
 6 NO2 H H Et DMAP 4h (55)
 7 H H H Me DMAP 5a (62)
 8 Me H H Me DMAP 5b (61)
 9 i-Pr H H Me DMAP 5c (59)
10 Cl Me H Me DMAP 5d (63)
11 Cl H H Me DMAP 4e (9)
5e (56)
12 H H H Et DMAP 5i (63)
13 Me H H Et DMAP 5j (57)

Scheme 2 Plausible mechanism for the reaction of substituted 3-formylchromones 1 with zwitterions 6, formed from reaction of acetylenedicarboxylates 2 with 4-picoline, to afford compounds 3

Against this literature background, in the present study we wish to report our results in detail. Initially, as a continuation of our previous study, [6] the 6,8-dibromochromone 1f (1.0 mmol) was allowed to react with DMAD (2a; 1.2 mmol) in 1,2-dimethoxyethane (DME; 10 mL) at -18 ˚C by using 4-picoline (1.0 mmol) as catalyst (Scheme  [¹] ). The reaction mixture was allowed to warm to room temperature and then stirred further for 12 hours, whereupon xanthone 4f was isolated as the only reaction product in 64% yield. When less catalyst (0.2 mmol) was used, the reaction proceeded analogously, although much longer reaction times (7 days) were required to complete the reaction. By increasing the molar ratio of DMAD (2.2 mmol) the product yield was decreased and the reaction became turbid due to formation of substantial amounts of polymeric material. The reaction of 6-nitrochromone (1g) with acetylenedicarboxylates 2a and 2b proceeded in the same manner and resulted in the formation of the corresponding xanthones 4g and 4h (Table  [¹] , entries 2 and 3). The reaction was then investigated by changing the catalyst to DMAP, whereupon chromones 1f and 1g reacted analogously to furnish the same xanthones 4f-h, respectively, as summarized in Table  [¹] (entries 4-6). In contrast, when 6-chlorochromone (1e) was used, the xanthone derivative 4e (9% yield) was formed as the minor product together with a second product that was isolated and identified as the benzophenone tricarboxylate 5e (56% yield; Table  [¹] , entry 11).

Functionalized benzophenones 5 were also formed in good yield (Table  [¹] , entries 7-10, 12 and 13) with all chromones bearing electron-donating substituents in the chromone moiety. It is noteworthy that, as was previously reported, [6] the use of 4-picoline with all ‘electron-rich’ chromones resulted in the hetero-Diels-Alder cycloaddition products 3. As a result, product formation proved to be greatly affected not only by the organocatalyst but also by the nature of the chromone substituents. However, when the reaction with ‘electron-rich’ chromones was repeated with slow, dropwise addition of DMAD over two hours, small amounts of pyranochromenes 3 (approximately 5%) were also detected.

Scheme 3 Plausible mechanism for the reaction of substituted 3-formylchromones 1 with zwitterions 9 to afford compounds 4 or 5

Mechanistically, the reaction may be rationalized as involving initial attack of the zwitterion 6, generated from 4-picoline and acetylenedicarboxylate, on the C2 chromone carbon of 1 to give the intermediate 7, which, after ring closure to form 8, yields compound 3 by regeneration of the catalyst (R¹, R² = electron-donating; Scheme  [²] ). However, when R¹ and R³ are electron-­withdrawing, the ring closure to 3 becomes difficult because the negative charge on the formyl oxygen is substantially reduced. In this case, zwitterion 6 preferentially reacts with a second molecule of acetylenic ester 2 to yield zwitterion 9 which, again, most probably, attacks the C2 chromone carbon to furnish intermediate 10. Depending on the nature of the chromone substituents, intermediate 10 can follow two different reaction paths, as shown in Scheme  [³] . When R¹ and R² are electron-withdrawing, it is likely that intermediate 10 reacts further by Path a; thus, after ring closure to 11 and elimination of the catalyst, intermediate 12 is generated, which, by 1,5-H shift, gives 13. By attack of the catalyst on the ester carbon [¹³] at the 1-position of 13, finally the xanthone derivatives 4 are obtained. However, when R¹ and R² are electron-donating and the organocatalyst is DMAP, Path b is followed leading to intermediate 15 through pyran ring opening. Subsequent electrocyclic ring closure to 16 generates the functionalized benzophenone derivatives 5, as depicted in Scheme  [³] .

The assigned molecular structures of all new compounds 4 and 5 are based on rigorous spectroscopic analysis, including IR, NMR (¹H, ¹³C, DEPT, COSY, NOESY, HETCOR and COLOC), MS and elemental analysis data.

Regarding the structure of the xanthones 4, as a representative example the assignment of 4h is described. In the ¹H NMR spectrum, the presence and position of the three chromone aromatic protons was unequivocally identified from their splitting pattern and COLOC correlations (Figure 1). The presence of one more aromatic proton resonating at δ = 8.99 ppm with its carbon at δ = 131.3 ppm and of only three ester ethyl groups were also identified. This proton gave characteristic COLOC correlations with one of the three ester carbonyl carbons at δ = 163.9 ppm, with the chromone carbonyl carbon at δ = 174.1 ppm (the corresponding carbonyl carbon in 1g resonates at δ = 174.5 ppm) and also with the quaternary carbons at δ = 154.5 (C4a) and 140.4 ppm (C3); thus, the whole molecular carbon connectivity was assigned (Figure 1).

Figure 1 Diagnostic COLOC correlations between protons and carbons (via ² J C-H and ³ J C-H) in compounds 4h and 5a

Regarding the structure of the polysubstituted benzophenones, the assignment of 5a is described. The assignment of the four aromatic protons of the hydroxybenzoyl moiety was clear from the splitting patterns, with protons resonating as a doublet at δ = 7.12 ppm, as a doublet of doublets at δ = 7.58 ppm, as a doublet of doublets at δ = 6.93 ppm and as a doublet at δ = 7.44 ppm, and their carbons resonating at δ = 118.9, 137.3, 119.3 and 132.9 ppm, respectively. Moreover, a hydroxyl proton appears in the ¹H NMR spectrum as a singlet at δ = 11.74 ppm that correlates with the quaternary carbons at δ = 118.5 (C3′) and 163.4 ppm (C2′). In addition, the proton at δ = 7.44 ppm shows COLOC correlations with the carbonyl carbon at δ = 198.7 ppm, and also with C2′ and C4′. In addition to the hydroxybenzoyl moiety, the presence of a symmetrically substituted aromatic ring was established as follows. A two-proton singlet appears at δ = 8.50 ppm with its carbon at δ = 134.3 ppm (C4 and C6) showing COLOC correlations with the hydroxybenzoyl carbonyl carbon at δ = 198.7 ppm, the two identical ester carbonyl carbons at δ = 164.3 ppm and also to C2 (δ = 139.3 ppm) bearing the third carbomethoxy group.

In conclusion, a new and efficient protocol for the organocatalytic one-pot synthesis of the otherwise almost inaccessible, functionalized benzophenones and polysubstituted xanthones has been described; their formation depends on the chromone substitution pattern and on the basicity of the catalyst. The isolated products could possess valuable biological activities. The experimental simplicity and metal-free conditions of the synthesis are especially noteworthy.

Melting points were measured with a Kofler hot-stage apparatus and are uncorrected. Petroleum ether (PE) refers to the fraction boiling between 60-80 ˚C. Column chromatography was carried out using Merck silica gel. TLC was performed using precoated silica gel glass plates (0.25 mm) containing fluorescent indicator UV254 purchased from Macherey-Nagel (PE-EtOAc, 3:1). NMR spectra were recorded at r.t. with Bruker AM 300 or AVANCE 300 spectrometers operating at 300 MHz for ¹H and 75 MHz for ¹³C, respectively, using CDCl3 as solvent. Chemical shifts (ppm) are expressed in δ values relative to TMS as internal standard for ¹H and relative to TMS (δ = 0.00 ppm) or to CDCl3 (δ = 77.05 ppm) for ¹³C NMR spectra. Coupling constants (n J) are reported in Hz. Second order ¹H NMR spectra were analyzed by simulation. [¹4] IR spectra were recorded with a Perkin-Elmer 1600 series FTIR spectrometer and are reported in wavenumbers (cm-¹). LC-MS (ESI, 1.65 eV) spectra were recorded with an LCMS-2010 EV system (Shimadzu). Elemental analyses were performed with a Perkin-Elmer 2400-II CHN analyzer.

Reaction of Substituted 3-Formylchromones 1 with Acetylenedicarboxylates 2 Catalyzed by 4-Picoline or DMAP; Typical Procedure

DMAD (2a; 0.170 g, 1.2 mmol) was added to a stirred solution of 3-formylchromone (1a; 0.174 g, 1 mmol) and DMAP (0.025 g, 1.0 mmol) in dimethoxyethane (10 mL) at -18 ˚C. The system was allowed to come to r.t. (˜25 ˚C) and then stirred for 12 h. Distillation of the solvent in vacuo was followed by column chromatography on silica gel (PE-EtOAc, 5:1→3:1) to give either 9-oxo-9H-xanthene-2,3,4-tricarboxylates (4e-h) or 2-hydroxybenzoylbenzene-1,2,3-tricarboxylates (5a-e, 5i and 5j).

In all cases some unreacted chromone was also isolated. The yields were calculated on the basis of acetylene dicarboxylate. In the case of chromones 1f and 1g the reaction also proceeded analogously with 4-picoline leading to formation of xanthones 4.

Trimethyl 5-(2-Hydroxybenzoyl)benzene-1,2,3-tricarboxylate (5a)

Yield: 0.139 g (62%); yellow crystals; mp 141-143 ˚C.

IR (KBr): 1752 (C=O), 1735 (C=O), 1696 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 3.95 (s, 6 H, 1-COOCH3, 3-COOCH3), 4.05 (s, 3 H, 2-COOCH3), 6.93 (ddd, J = 8.1, 7.2, 1.0 Hz, 1 H, H-5′), 7.11 (dd, J = 8.4, 1.0 Hz, 1 H, H-3′), 7.44 (dd, J = 8.1, 1.5 Hz, 1 H, H-6′), 7.58 (ddd, J = 8.4, 7.2, 1.5 Hz, 1 H, H-4′), 8.50 (s, 2 H, H-4, H-6), 11.73 (s, 1 H, OH).

¹³C NMR (CDCl3): δ = 53.1 (1-OCH3, 2-OCH3, 3-OCH3), 118.5 (C1′), 118.9 (C3′), 119.3 (C5′), 129.0 (C5), 132.9 (C6′), 134.3 (C4, C6), 137.3 (C4′), 138.7 (C1, C3), 139.3 (C2), 163.4 (C2′), 164.3 (1-CO, 3-CO), 167.9 (2-CO), 198.7 (5-CO).

LC-MS (ESI, 1.65 eV): m/z (%) = 427 (95) [M+ + Na + MeOH], 395 (100) [M+ + Na].

Anal. Calcd for C19H16O8: C, 61.29; H, 4.33. Found: C, 61.16; H, 4.28.

Trimethyl 5-(2-Hydroxy-5-methylbenzoyl)benzene-1,2,3-tricarboxylate (5b)

Yield: 0.161 g (61%); yellow crystals; mp 127-129 ˚C.

IR (KBr): 1743 (C=O), 1738 (C=O), 1635 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 2.26 (s, 3 H, 5′-CH3), 3.95 (s, 6 H, 1-COOCH3, 3-COOCH3), 4.05 (s, 3 H, 2-COOCH3), 7.02 (d, J = 8.5 Hz, 1 H, H-3′), 7.17 (d, J = 2.1 Hz, 1 H, H-6′), 7.39 (dd, J = 8.5, 2.1 Hz, 1 H, H-4′), 8.48 (s, 2 H, H-4, H-6), 11.55 (s, 1 H, OH).

¹³C NMR (CDCl3): δ = 20.4 (5′-CH3), 53.1 (1-OCH3, 2-OCH3, 3-OCH3), 118.2 (C1′), 118.6 (C3′), 128.5 (C5′), 128.9 (C5), 132.5 (C6′), 134.2 (C4, C6), 138.5 (C4′), 138.9 (C1, C3), 139.0 (C2), 161.4 (C2′), 164.3 (1-CO, 3-CO), 168.0 (2-CO), 198.6 (5-CO).

LC-MS (ESI, 1.65 eV): m/z (%) = 441 (95) [M+ + Na + MeOH], 409 (100) [M+ + Na].

Anal. Calcd for C20H18O8: C, 62.17; H, 4.70. Found: C, 62.05; H, 4.78.

Trimethyl 5-(2-Hydroxy-5-isopropylbenzoyl)benzene-1,2,3-tricarboxylate (5c)

Yield: 0.147 g (59%); yellow crystals; mp 61-63 ˚C.

IR (KBr): 1752 (C=O), 1735 (C=O), 1696 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 1.19 [d, J = 8.5 Hz, 6 H, 5′-CH(CH3)2], 2.84 [sept, J = 8.5 Hz, 1 H, 5′-CH(CH3)2], 3.97 (s, 6 H, 1-OCH3, 3-OCH3), 4.06 (s, 3 H, 2-OCH3), 7.05 (d, J = 8.6 Hz, 1 H, H-3′), 7.29 (d, J = 2.5 Hz, 1 H, H-6′), 7.46 (dd, J = 8.6, 2.5 Hz, 1 H, H-4′), 8.56 (s, 2 H, H-4, H-6), 11.53 (s, 1 H, OH).

¹³C NMR (CDCl3): δ = 20.4 [5′-CH(CH3)2], 33.1 [5′-CH(CH3)2], 52.9 (1-OCH3, 3-OCH3), 53.0 (2-OCH3), 118.2 (C1′), 118.6 (C3′), 128.5 (C5′), 128.9 (C5), 132.5 (C6′), 134.2 (C4, C6), 138.0 (C1, C3), 139.0 (C4′), 139.0 (C2), 161.5 (C2′), 164.2 (1-CO, 3-CO), 167.8 (2-CO), 198.2 (5-CO).

LC-MS (ESI, 1.65 eV): m/z (%) = 437 (100) [M+ + Na].

Anal. Calcd for C22H22O8: C, 63.76; H, 5.35. Found: C, 63.88; H, 5.46.

Trimethyl 5-(2-Hydroxy-4-methyl-5-chlorobenzoyl)benzene-1,2,3-tricarboxylate (5d)

Yield: 0.159 g (63%); yellow crystals; mp 156-158 ˚C.

IR (KBr): 1751 (C=O), 1736 (C=O), 1697 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 2.42 (s, 3 H, 4′-CH3), 3.97 (s, 6 H, 1-OCH3, 3-OCH3), 4.05 (s, 3 H, 2-OCH3), 7.00 (s, 1 H, H-3′), 7.36 (s, 1 H, H-6′), 8.47 (s, 2 H, H-4, H-6), 11.60 (s, 1 H, OH).

¹³C NMR (CDCl3): δ = 21.0 (4′-CH3), 53.2 (1-OCH3, 2-OCH3, 3-OCH3), 117.4 (C1′), 120.8 (C3′), 124.8 (C5′), 129.2 (C5), 132.1 (C6′), 134.1 (C4, C6), 138.3 (C1, C3), 147.0 (C4′), 139.4 (C2), 161.8 (C2′), 164.1 (1-CO, 3-CO), 168.0 (2-CO), 197.4 (5-CO).

LC-MS (ESI, 1.65 eV): m/z (%) = 443/445 (100) [M+ + Na].

Anal. Calcd for C20H17ClO8: C, 57.09; H, 4.07. Found: C, 57.16; H, 4.20.

Trimethyl 7-Chloro-9-oxo-9 H -xanthene-2,3,4-tricarboxylate (4e)

Yield: 0.022 g (9%); yellowish crystals; mp 167-169 ˚C.

IR (KBr): 1743 (C=O), 1728 (C=O), 1671 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 3.96 (s, 3 H, 2-OCH3), 3.97 (s, 3 H, 4-OCH3), 4.02 (s, 3 H, 3-OCH3), 7.50 (d, J = 9.0 Hz, 1 H, H-5), 7.73 (dd, J = 9.0, 2.7 Hz, 1 H, H-6), 8.29 (d, J = 2.7 Hz, 1 H, H-8), 8.99 (s, 1 H, H-1).

¹³C NMR (CDCl3): δ = 53.1 (3-OCH3), 53.4 (2-OCH3, 4-OCH3), 120.2 (C5), 121.8 (C4), 122.3 (C2), 123.0 (C8a), 124.8 (C9a), 126.2 (C8), 131.4 (C7), 131.9 (C1), 135.9 (C6), 139.9 (C3), 154.2 (C10a), 154.8 (C4a), 163.7 (4-CO), 164.4 (2-CO), 166.5 (3-CO), 174.3 (C9).

LC-MS (ESI, 1.65 eV): m/z (%) = 443/445 (60) [M+ + K], 319 (60), 274/276 (100).

Anal. Calcd for C19H13ClO8: C, 56.38; H, 3.24. Found: C, 56.16; H, 3.28.

Trimethyl 5-(2-Hydroxy-5-chlorobenzoyl)benzene-1,2,3-tricarboxylate (5e)

Yield: 0.136 g (56%); yellow crystals; mp 183-185 ˚C.

IR (KBr): 1745 (C=O), 1739 (C=O), 1686 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 3.96 (s, 6 H, 1-OCH3, 3-OCH3), 4.05 (s, 3 H, 2-OCH3), 7.03 (d, J = 9.0 Hz, 1 H, H-3′), 7.51 (dd, J = 9.0, 2.4 Hz, 1 H, H-4′), 7.65 (s, 2 H, H-4, H-6), 8.30 (d, J = 2.4 Hz, 1 H, H-6′), 11.58 (s, 1 H, OH).

¹³C NMR (CDCl3): δ = 53.0 (1-OCH3, 3-OCH3), 53.1 (2-OCH3), 119.2 (C1′), 120.6 (C3′), 124.1 (C6′), 128.5 (C5′), 129.4 (C5), 134.1 (C4, C6), 137.2 (C4′), 138.1 (C1, C3), 139.5 (C2), 161.9 (C2′), 164.1 (1-CO, 3-CO), 167.6 (2-CO), 197.8 (5-CO).

LC-MS (ESI, 1.65 eV): m/z (%) = 406/408 (100) [M+].

Anal. Calcd for C19H15ClO8: C, 56.10; H, 3.72. Found: C, 55.96; H, 3.62.

Trimethyl 5,7-Dibromo-9-oxo-9 H -xanthene-2,3,4-tricarboxylate (4f)

a) 4-Picoline as catalyst.

Yield: 0.203 g (64%); yellowish crystals; mp 211-213 ˚C.

IR (Nujol): 1753 (C=O), 1730 (C=O), 1665 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 3.97 (s, 3 H, 2-OCH3),* 3.99 (s, 3 H, 4-OCH3),* 4.07 (s, 3 H, 3-OCH3), 8.15 (d, J = 2.5 Hz, 1 H, H-6), 8.41 (d, J = 2.5 Hz, 1 H, H-8), 9.00 (s, 1 H, H-1). *The assignments may be interchanged.

¹³C NMR (CDCl3): δ = 53.1 (OCH3), 53.4 (OCH3), 53.6 (OCH3), 113.2 (C5), 118.5 (C8a), 121.4 (C7), 123.4 (C4), 123.5 (C2), 125.3 (C9a), 128.8 (C8), 131.9 (C1), 140.5 (C3), 141.4 (C6), 151.6 (C4a), 154.6 (C10a), 163.8 (4-CO), 164.3 (2-CO), 167.8 (3-CO), 173.8 (C9).

LC-MS (ESI, 1.65 eV): m/z (%) = 581/583/585 (60) [M+ + Na + MeOH], 565/567/569 (100) [M+ + K], 549/551/553 (50) [M+ + Na].

Anal. Calcd for C19H12Br2O8: C, 43.21; H, 2.29. Found: C, 43.11; H, 2.28.

b) DMAP as catalyst.

Yield: 0.184 g (58%).

Trimethyl 7-Nitro-9-oxo-9 H -xanthene-2,3,4-tricarboxylate (4g)

a) 4-Picoline as catalyst.

Yield: 0.166 g (59%); yellow crystals; mp 181-183 ˚C.

IR (KBr): 1748 (C=O), 1740 (C=O), 1732 (C=O), 1688 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 3.98 (s, 6 H, 2-OCH3, 4-OCH3), 4.04 (s, 3 H, 3-OCH3), 7.71 (d, J = 9.1 Hz, 1 H, H-5), 8.62 (dd, J = 9.1, 2.7 Hz, 1 H, H-6), 9.02 (d, J = 2.7 Hz, 1 H, H-8), 9.02 (s, 1 H, H-1).

¹³C NMR (CDCl3): δ = 53.2 (3-OCH3), 53.5 (2-OCH3, 4-OCH3), 120.3 (C5), 121.5 (C4),* 121.7 (C2),* 123.2 (C8a), 123.5 (C8), 125.7 (C9a), 130.0 (C6), 131.9 (C1), 140.6 (C3), 144.8 (C7), 154.6 (C4a), 158.6 (C10a), 163.3 (4-CO), 164.2 (2-CO), 166.2 (3-CO), 174.0 (C9). *The assignments may be interchanged.

LC-MS (ESI, 1.65 eV): m/z (%) = 470 (40) [M+ + MeOH + Na], 448 (15) [M+ + H + MeOH], 416 (60) [M+ + H], 386 (95), 371 (50), 328 (100).

Anal. Calcd for C19H13NO10: C, 54.95; H, 3.16; N, 3.37. Found: C, 55.06; H, 3.28; N 3.46.

b) DMAP as catalyst.

Yield: 0.149 g (53%).

Triethyl 7-Nitro-9-oxo-9 H -xanthene-2,3,4-tricarboxylate (4h)

a) 4-Picoline as catalyst.

Yield: 0.167 g (61%); yellowish crystals; mp 159-161 ˚C.

IR (Nujol): 1752 (C=O), 1735 (C=O), 1696 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 1.40 (t, J = 7.3 Hz, 3 H, 2-OCH2CH3), 1.44 (t, J = 7.3 Hz, 3 H, 4-OCH2CH3), 1.47 (t, J = 7.1 Hz, 3 H, 3-OCH2CH3), 4.43 (q, J = 7.1 Hz, 2 H, 3-OCH2CH3), 4.44 (q, J = 7.3 Hz, 2 H, 2-OCH2CH3), 4.52 (q, J = 7.3 Hz, 2 H, 4-OCH2CH3), 7.69 (d, J = 9.3 Hz, 1 H, H-5), 8.62 (dd, J = 9.3, 2.7 Hz, 1 H, H-6), 8.97 (s, 1 H, H-1), 9.19 (d, J = 2.7 Hz, 1 H, H-8).

¹³C NMR (CDCl3): δ = 13.9 (OCH2CH3), 14.2 (OCH2CH3), 14.2 (OCH2CH3), 62.4 (OCH2CH3), 62.7 (OCH2CH3), 62.8 (OCH2CH3), 120.2 (C5), 121.5 (C4),* 121.6 (C2),* 123.5 (C8), 123.6 (C8a), 126.3 (C9a), 129.9 (C6), 131.3 (C1), 140.4 (C3), 144.7 (C7), 154.4 (C4a), 158.6 (C10a), 163.0 (4-CO), 163.9 (2-CO), 165.6 (3-CO), 174.1 (C9). *The assignments may be interchanged.

LC-MS (ESI, 1.65 eV): m/z (%) = 457 (100) [M+].

Anal. Calcd for C22H19NO10: C, 57.77; H, 4.19; N, 3.06. Found: C, 57.86; H, 4.28; N 3.00.

b) DMAP as catalyst.

Yield: 0.151 g (55%).

Triethyl 5-(2-Hydroxybenzoyl)benzene-1,2,3-tricarboxylate (5i)

Yield: 0.177 g (63%); yellowish crystals; mp 84-86 ˚C.

IR (KBr): 1739 (C=O), 1696 (C=O), 1638 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 1.39 (t, J = 7.2 Hz, 6 H, 1-OCH2CH3, 3-OCH2CH3), 1.43 (t, J = 7.1 Hz, 3 H, 2-OCH2CH3), 4.40 (q, J = 7.2 Hz, 4 H, 1-OCH2CH3, 3-OCH2CH3), 4.50 (q, J = 7.1 Hz, 2 H, 2-OCH2CH3), 6.92 (ddd, J = 8.1, 7.3, 1.5 Hz, 1 H, H-5′), 7.12 (dd, J = 8.4, 0.8 Hz, 1 H, H-3′), 7.44 (dd, J = 8.1, 1.5 Hz, 1 H, H-6′), 7.57 (ddd, J = 8.4, 7.3, 1.5 Hz, 1 H, H-4′), 8.46 (s, 2 H, H-4, H-6), 11.78 (s, 1 H, OH).

¹³C NMR (CDCl3): δ = 13.9 (2-OCH2CH3), 14.1 (1-OCH2CH3, 3-OCH2CH3), 62.2 (2-OCH2CH3), 62.3 (1-OCH2CH3, 3-OCH2CH3), 118.6 (C1′), 118.9 (C3′), 119.3 (C5′), 129.6 (C5), 133.0 (C6′), 134.1 (C4, C6), 137.3 (C4′), 138.5 (C1, C3), 139.2 (C2), 163.5 (C2′), 164.0 (1-CO, 3-CO), 167.4 (2-CO), 198.9 (5-CO).

LC-MS (ESI, 1.65 eV): m/z (%) = 469 (60) [M+ + Na + MeOH], 437 (80) [M+ + Na], 281 (100).

Anal. Calcd for C22H22O8: C, 63.76; H, 5.35. Found: C, 63.66; H, 5.28.

Triethyl 5-(2-Hydroxy-5-methylbenzoyl)benzene-1,2,3-tricarboxylate (5j)

Yield: 0.165 g (57%); yellow crystals; mp 129-131 ˚C.

IR (KBr): 3434 (br, OH), 1747 (C=O), 1729 (C=O), 1712 (C=O), 1633 (C=O) cm-¹.

¹H NMR (CDCl3): δ = 1.39 (t, J = 7.2 Hz, 6 H, 1-OCH2CH3, 3-OCH2CH3), 1.43 (t, J = 6.9 Hz, 3 H, 2-OCH2CH3), 2.26 (s, 3 H, 5′-CH3), 4.41 (q, J = 7.2 Hz, 4 H, 1-OCH2CH3, 3-OCH2CH3), 4.51 (q, J = 6.9 Hz, 2 H, 2-OCH2CH3), 7.02 (d, J = 8.4 Hz, 1 H, H-3′), 7.19 (d, J = 2.1 Hz, 1 H, H-6′), 7.39 (dd, J = 8.4, 2.1 Hz, 1 H, H-4′), 8.45 (s, 2 H, H-4, H-6), 11.60 (s, 1 H, OH).

¹³C NMR (CDCl3): δ = 13.9 (2-OCH2CH3), 14.2 (1-OCH2CH3, 3-OCH2CH3), 20.4 (5′-CH3), 62.2 (2-OCH2CH3), 62.3 (1-OCH2CH3, 3-OCH2CH3), 118.3 (C1′), 118.6 (C3′), 128.6 (C5′), 128.9 (C5), 132.6 (C6′), 134.0 (C4, C6), 138.7 (C1, C3), 138.5 (C4′), 139.1 (C2), 161.4 (C2′), 164.0 (1-CO, 3-CO), 167.5 (2-CO), 198.9 (5-CO).

LC-MS (ESI, 1.65 eV): m/z (%) = 483 (80) [M+ + Na + MeOH], 451 (100) [M+ + Na].

Anal. Calcd for C23H24O8: C, 64.48; H, 5.65. Found: C, 64.32; H, 5.73.

Acknowledgment

The authors thank Professor Philip Kocienski for improving considerably the mechanistic discussion.

14

The multiplicities and chemical shifts of the aromatic protons have been confirmed after simulation with program SpinWorks, version 2.5, available from: ftp://davinci.chem.umanitoba.ca/pub/marat/SpinWorks/

14

The multiplicities and chemical shifts of the aromatic protons have been confirmed after simulation with program SpinWorks, version 2.5, available from: ftp://davinci.chem.umanitoba.ca/pub/marat/SpinWorks/

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Scheme 1 Reaction of substituted 3-formylchromones 1 with acetylenedicarboxylates 2 in the presence of 4-picoline or DMAP as organocatalysts

Scheme 2 Plausible mechanism for the reaction of substituted 3-formylchromones 1 with zwitterions 6, formed from reaction of acetylenedicarboxylates 2 with 4-picoline, to afford compounds 3

Scheme 3 Plausible mechanism for the reaction of substituted 3-formylchromones 1 with zwitterions 9 to afford compounds 4 or 5

Figure 1 Diagnostic COLOC correlations between protons and carbons (via ² J C-H and ³ J C-H) in compounds 4h and 5a