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DOI: 10.1055/s-0030-1258404
Selective Halogenation at Position 3 of 5-Hydroxy-2,7-dimethylchromone and Related Compounds
Publication History
Publication Date:
11 January 2011 (online)
Abstract
The core moiety of several natural products referred in the literature as altechromone A can be selectively brominated or iodinated at position 3 despite the adjacent phenolic moiety. This method is extended to more elaborated 5-hydroxychromones exhibiting additional multiple bonds.
Key words
halogenation - heterocycles - chromones - iodination - bromination
Chromones are very common entities in natural products, [¹] in drug development, [²] as well as in technical applications. [³] In particular, 5-hydroxy-2,7-dimethylchromone (1) is a substructure present in several natural products, which were predominantly isolated from different species of fungi. Figure [¹] displays coniochaeton A (2) from Coniochaeta sacerdoi, which inhibits the growth of coprophilous fungi like Sordaria fimicola or Ascobolus furfuracaeus. [4] Remisporin A (3) was isolated from Remispora maritima [5] and chloromonilicin/bromomonilicin (4) from Monilia fructicola. The latter is a powerful fungicide against Monilia sp. as well as Candida sp. and Trychophyton sp. Additionally, compounds 4 exhibit moderate antibacterial activity. [6]
Figure 1 Natural products possessing the altechromone A scaffold
The chromone 1 was first synthesized in 1976 and characterized by melting point and IR bands. [7] Later it was claimed to be isolated from Alternaria sp. and therefore named as altechromone A. [8] Although the literature frequently referred to this compound, [9] altechromone A was recently revised to be identical with 5,7-dihydroxy-2-methylchromone after the total synthesis of 1 and its isomers. [¹0] However, 1 is an ideal architecture for the construction of the naturally occurring compounds 2-4. For this purpose a leaving functionality has to be selectively installed at position 3. The excellent reactivity of bromo or iodo substituents in metalation reactions or transition-metal-catalyzed transformations promised a synthetic pathway to the target molecules 2-4. Surprisingly, very little is known about the halogenation of chromones at position 3. Studies concerning the bromination of chromones have been performed since the 1920s, [¹¹-¹³] but control of halogenation regioselectivity remains a challenge. Most reactions employing electrophilic reagents or mixtures focused on substituted flavones in which the phenyl substituent in position 2 stabilizes the intermediate positive charge and directs the electrophile to position 3 (chlorination, [¹4] bromination, [¹5] iodination [¹6] ). Such reaction conditions mostly do not work on 2-methylchromones.
Selective chlorination was accomplished using sodium hypochlorite and acetic acid, [¹7a] sulfuryl chloride with benzoyl peroxide, [¹7b] or montmorillonite K-10, [¹7c] or by electrolysis on graphite electrodes, which also affords 3-bromochromone. [¹7c] Bromination was performed with bromine prior to cyclization either starting from the 1,3-diketone [¹8a] [b] or an enamine precursor. [¹8c] For our substrate with its methyl group in position 2, the two-step protocols via an enamine intermediate using pyrrolidine/Br2 or N,N-dimethylacetamide/Br2 did not afford the desired 3-bromochromone. In this transformation, N,N-dimethylacetamide was found to add to the pyrone double bond. Installation of iodine at position 3 was accomplished by electrophile-promoted cyclization of an alkynone precursor employing ICl [¹9a] or iodine and CAN, [¹9b] but synthesis of the alkynone requires several steps including a specific protection group strategy. The surveyed methods failed in particular when electron-rich benzo moieties were involved.
Here, we present reliable protocols for the selective bromination and iodination reaction of 1. The bromination reaction with N-bromosuccinimide in weakly acidic media resulted in the twofold installation of bromo substituents at the phenolic portion of 1. The dibromo derivative 5 was isolated in 71% yield (Scheme [¹] ).
Scheme 1 Selective brominations of 5-hydroxy-2,7-dimethylchromone (1)
The substitution pattern was confirmed by an X-ray analysis of suitable single crystals of 5 (Figure [²] ). Compound 5 crystallizes with three independent molecules in the asymmetric unit. The crystal structure shows weak interactions (weak hydrogen bonds and halogen-halogen interaction) between the molecules (see Supporting Information). A regioselective installation of the bromo functionality at the pyrone section can be achieved by prior deactivation of the adjacent phenol system. O-Acetylation reaction was performed using standard conditions and resulted in 76% yield for 6. Subsequent bromination required elevated temperatures and prolonged reaction times leading to a moderate amount of the 3-bromo derivative. Ester cleavage was almost quantitatively conducted providing 8.
Figure 2 Molecular structures of 5 (left) and 9 (right) obtained by X-ray crystal structure analyses
The introduction of iodo functions on arenes is very sensitive towards the applied conditions. [²0] A selective iodination at position 3 was achieved when acetic acid was replaced by the trifluoro congener and its anhydride. Most probably, an in situ protection and deactivation of the phenolic part had occurred. When N-iodosuccinimide was employed as the iodination reagent, the 3-iodochromone 9 was isolated as the sole product after workup in 78% yield (Scheme [²] ).
Scheme 2 Selective iodination protocols for 1
If 5-acetoxy-2,7-dimethylchromone (6) was subjected to the same protocol, chromone 9 was obtained as well. All analytical data were consistent with the structure. Additionally, X-ray analysis of a suitable single crystal underlined the regioselectivity of iodonation (Figure [²] ). The crystal structure shows weak hydrogen bonds and halogen-halogen interactions similar to 5 between the individual molecules (see Supporting Information). A less acidic iodination medium directs the installation of iodo groups onto the phenolic portion providing 10.
The iodination protocol can be extended onto derivatives of 1, which exhibit additional double bonds. Replacement of the methyl group in position 2 by an acrylic ester fragment was conducted in a two-step procedure. Oxidation of 1 by selenium dioxide afforded the 2-formylchromone 11 in almost quantitative yield. Subsequent Z-selective olefination using the Still-Gennari method [²¹] delivered both olefinic isomers in almost quantitative conversion (Scheme [³] ).
Scheme 3 Olefination of 2-formylchromone 11
The olefinic mixture with a ratio of 6.7:1 for 12a and 12b, respectively, was easily separated by column chromatography providing the pure olefins. For an unequivocal verification of the structure, X-ray analyses of suitable single crystals for the formyl chromone 11 and the Z-olefin 12a were performed. In particular, the molecular arrangement of the Z-isomer of 12a indicates sufficient free space at position 3 for the installation of a bulky iodo moiety. The unusual conformation of 12a avoids repulsion of the lone pairs from acrylic substituent and chromone system (Figure [³] ).
Figure 3 Molecular structures of 11 (left) and 12a (right) obtained by X-ray crystal structure analyses
The carboxylate is almost perpendicular to the chromone system, whereas the acrylic ester double bond is nearly in the plane of the heterocycle. Since a good conjugation for this double bond with the chromone system can be anticipated, the chemoselectivity for the iodination process cannot be predicted. However, when 12a was iodinated with the elaborated protocol, the desired 3-iodochromone 13a was obtained in 59% isolated yield (Scheme [4] ).
Scheme 4 Selective iodination protocols for 12
When the olefinic substrate with E-configuration was subjected to the same protocol, almost no conversion was observed. From the reaction mixture only 5% yield of the 3-iodochromone 13b could be isolated. The spatial restriction by the substituent in position 2 seems to play an important role for the iodination process in the adjacent location. Most remarkably, the double bond was not affected during the iodination reaction and stayed intact.
In conclusion, we have found a reliable and selective method for the installation of bromo- and iodo functions at position 3 of 5-hydroxy-2,7-dimethylchromone. The protocol was successfully expanded to more elaborate chromones exhibiting additional activated double bonds. This exocyclic multiple bond is not attacked by the iodination reagent. A remarkable dependence on the stereochemistry of the exocyclic double bond was found to be crucial for the halogenation process.
All reagents used were of analytical grade. Solvents were desiccated, if necessary, by standard methods. Melting points were determined with a Melting Point Apparatus B-545 (Büchi Labortechnik AG, 9320 Flawil 1, Schweiz) and are uncorrected. Microanalyses were performed with a Vario EL cube (Elementar-Analysensysteme, Hanau, Germany). NMR spectra were recorded with a Bruker ARX 300, AMX 400, DPX300, or DPX400 (Analytische Messtechnik, Karlsruhe, Germany) by calibration on CHCl3 with δ = 7.26 or DMSO-d 6 with δ = 2.50 for ¹H NMR and δ = 77.0 (CHCl3) and δ = 39.51 (DMSO-d 6) for ¹³C NMR, respectively; chemical shifts were expressed in ppm. EI mass spectra were obtained on a MAT8200 (Finnigan, Bremen, Germany). MS50 (Kratos, Manchester, England) or MAT95XL (Finnigan, Bremen, Germany) was used for recording HMRS. All reactions were monitored by TLC, visualization was effected by UV and heating with a 1% aq Ce(SO4)2˙4 H2O containing 2.5% of molybdatophosphoric acid and 6% of H2SO4. Column chromatography was performed on silica gel (particle size 63-200 µm, Merck, Darmstadt, Germany) using mixtures of cyclohexane with EtOAc as eluents.
6,8-Dibromo-5-hydroxy-2,7-dimethylchromone (5)
At r.t., NaOAc (500 mg, 6.10 mmol) was added to a solution of 5-hydroxy-2,7-dimethylchromone (1; [7] [¹0] 380 mg, 2.00 mmol) in Ac2O (3.0 mL) and AcOH (1.0 mL). After 45 min, N-bromosuccinimide (445 mg, 2.50 mmol) and AcOH (2.0 mL) were added and the reaction mixture was stirred for 3 h. A further portion of NaOAc (500 mg, 6.10 mmol) and N-bromosuccinimide (445 mg, 2.50 mmol) were added and the mixture was stirred for 2 h. The resulting precipitate was collected by filtration and washed with H2O (30 mL). Purification of the residue was performed by chromatography on silica gel (20% EtOAc in cyclohexane) to afford 2 as a light yellow solid; yield: 496 mg (71%); mp 178 ˚C; R f = 0.5 (cyclohexane-EtOAc, 3:1).
¹H NMR (400 MHz, CDCl3): δ = 2.47 (d, J = 0.8 Hz, 3 H, 2-CH3), 2.73 (s, 3 H, 7-CH3), 6.18 (q, J = 0.8 Hz, 1 H, H-3), 13.42 (s, 1 H, OH).
¹³C NMR (100 MHz, CDCl3): δ = 20.8 (2-CH3), 25.0 (7-CH3), 101.5 (C-8), 107.6 (C-6), 109.3 (C-3), 109.4 (C-4a), 145.6 (C-7), 152.0 (C-8a), 156.4 (C-5), 168.3 (C-2), 182.4 (C-4).
MS (EI, 70 eV): m/z (%) = 350 (50), 348 (100), 346 (50, [M]+ ˙), 310 (6), 308 (12), 306 (6, [M - C3H4]+ ˙), 280 (4, [M - C4H4O]+ ˙), 241 (2, [M - COBr]+), 227 (2, [M - C2H2OBr]+), 199 (4, [M - C3H2O2Br]+), 173 (4, [M - C5H4O2Br]+).
HRMS-EI: m/z [M]+ ˙ calcd for C11H8 79Br2O3: 345.8840; found: 345.8846.
Anal. Calcd for C11H8Br2O3: C, 37.97; H, 2.32. Found: C, 37.95; H, 2.36.
5-Acetoxy-2,7-dimethylchromone (6)
At r.t., 5-hydroxy-2,7-dimethylchromone (1; [7] [¹0] 2.00 g, 10.5 mmol) was stirred in Ac2O (10 mL) for 10 min. Pyridine (0.5 mL) was added and the solution was stirred overnight at 85 ˚C. After cooling to r.t., the mixture was poured onto ice (50 mL) and stirred for 30 min. A precipitate was formed, which was collected by filtration, and washed with H2O (20 mL). Purification was performed by recrystallization from EtOAc to afford 6 as a light yellow solid; yield: 1.85 g (76%); mp 155-157 ˚C.
¹H NMR (300 MHz, acetone-d 6): δ = 2.28 (s, 3 H, CH3COO), 2.34 (d, J = 0.8 Hz, 3 H, 2-CH3), 2.45 (t, J = 0.7 Hz, 3 H, 7-CH3), 5.98 (q, J = 0.8 Hz, 1 H, H-3), 6.86 (dd, J = 1.6, 0.7 Hz, 1 H, H-8), 7.22 (dq, J = 1.6, 0.7 Hz, 1 H, H-6).
¹³C NMR (75 MHz, acetone-d 6): δ = 20.0 (2-CH3), 21.1 (7-CH3), 21.5 (CH3COO), 111.8 (C-3), 115.3 (C-4a), 116.4 (C-8), 120.9 (C-6), 145.8 (C-7), 150.1 (C-8a), 158.5 (C-5), 166.0 (C-2), 169.6 (COO), 176.5 (C-4).
MS (EI, 70 eV): m/z (%) = 232 (<1, [M]+ ˙), 190 (100, [M - C2H2O]+ ˙), 161 (7, [M - C3H3O2]+), 150 (3, [M - C4H2O2]+ ˙), 122 (3, [C7H6O2]+ ˙).
Anal. Calcd for C13H12O4: C, 67.23; H, 5.21. Found: C, 67.10; H, 5.26.
5-Acetoxy-3-bromo-2,7-dimethylchromone (7)
At r.t., NaOAc (300 mg, 4.29 mmol) was added to a solution of 6 (232 mg, 1.00 mmol) in AcOH (1.5 mL) and Ac2O (1.5 mL). After the addition of N-bromosuccinimide (267 mg, 1.50 mmol), the suspension was stirred at 60 ˚C for 5 h. The stirring was continued overnight at r.t. . Then, ice water (8 mL) was added. After 15 min, the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were washed with H2O (10 mL), sat. aq NaHCO3 (2 × 10 mL), H2O (10 mL), brine (10 mL), and dried (MgSO4). After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel (15-20% EtOAc in cyclohexane) to afford 7 as a light yellow solid; yield: 109 mg (35%); mp 185-187 ˚C; R f = 0.3 (cyclohexane-EtOAc, 3:1).
¹H NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3COO), 2.45 (br s, 3 H, 7-CH3), 2.59 (s, 3 H, 2-CH3), 6.86 (d, J = 1.1 Hz, 1 H, H-8), 7.13 (q, J = 0.7 Hz, 1 H, H-6).
¹³C NMR (75 MHz, CDCl3): δ = 21.3, 21.6, 21.9 (2-CH3, 7-CH3, CH3COO), 110.6 (C-3), 113.1 (C-4a), 115.8 (C-8), 121.0 (C-6), 145.5 (C-7), 149.1 (C-8a), 156.7 (C-5), 162.9 (C-2), 169.9 (COO), 170.7 (C-4).
MS (EI, 70 eV): m/z (%) = 270 (100), 268 (98, [M - C2OH]+), 241 (12), 239 (12, [M - C3H2O2]+), 189 (12, [M - C2H3OBr]+), 161 (12, [M - C3H3O2Br]+), 150 (10, [M - C5H6OBr]+), 121 (10, [M - C5H3O3Br]+), 77 (6, [C6H5]+).
HRMS-ESI: m/z [M]+ calcd for C13H11 79BrO4 + Na: 332.9732; found: 332.9733.
Traces (approx. 3%) of compound 6 were detected in the sample.
3-Bromo-5-hydroxy-2,7-dimethylchromone (8)
At r.t., Na2CO3 (3.0 g) was added to a solution of 7 (900 mg, 2.89 mmol) in MeOH (50 mL). The yellow suspension was stirred overnight and the solvent was evaporated. The residue was dissolved in H2O (20 mL), acidified with aq 2 N HCl and extracted with EtOAc (3 × 20 mL). The combined organic fractions were washed with H2O (20 mL), brine (2 × 15 mL), and dried (MgSO4). After evaporation of the solvent, compound 8 was obtained almost pure (TLC, ¹H NMR). It was not further purified, since chromatography on a silica gel column (10% EtOAc in cyclohexane) was proved to decompose a large amount of product; yield: 743 mg (96%); yellow solid; mp 144 ˚C; R f = 0.5 (cyclohexane-EtOAc, 9:1).
¹H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H, 7-CH3), 2.61 (s, 3 H, 2-CH3), 6.64 (m, 1 H, H-8), 6.68 (m, 1 H, H-6), 12.04 (s, 1 H, OH).
¹³C NMR (100 MHz, CDCl3): δ = 21.7 (7-CH3), 22.5 (2-CH3), 107.2, 107.3, 107.4 (C-3, C-8, C-4a), 112.6 (C-6), 147.6 (C-7), 155.7 (C-8a), 160.0 (C-5), 165.1 (C-2), 177.2 (C-4).
MS (EI, 70 eV): m/z (%) = 270 (100), 268 (98, [M]+ ˙), 241 (6), 239 (6, [M - CHO]+), 189 (6, [M - Br]+), 161 (5, [M - COBr]+), 150 (12, [M - C3H3Br]+ ˙), 121 (9, [M - C5H4O2Br]+), 77 (3, [M - C6H5]+).
HRMS-EI: m/z [M]+ ˙ calcd for C11H9 79BrO3: 267.9735; found: 267.9729.
Anal. Calcd for C11H9BrO3: C, 49.10; H, 3.37. Found: C, 49.11; H, 3.41.
5-Hydroxy-3-iodo-2,7-dimethylchromone (9)
NaOAc (4.20 g, 60.0 mmol) was added to a mixture of trifluoroacetic acid (15 mL) and trifluoroacetic anhydride (15 mL) at 0 ˚C. 5-Hydroxy-2,7-dimethylchromone (1; [7] [¹0] 2.69 g, 14.1 mmol) was added and the mixture was stirred at r.t. for 30 min. After the addition of N-iodosuccinimide (4.72 g, 20.9 mmol), the stirring was continued overnight. The reaction mixture was poured into ice (150 mL) and brought to pH 5 with aq NaHCO3. The aqueous layer was extracted with EtOAc (3 × 50 mL) and the combined organic fractions were washed with H2O (50 mL) and brine (50 mL). After drying (MgSO4), the solvent was evaporated. Purification was accomplished by chromatography on silica gel (4% EtOAc in cyclohexane); yield: 3.48 g (78%); colorless solid; mp 159-161 ˚C; R f = 0.4 (cyclohexane-EtOAc, 9:1).
¹H NMR (400 MHz, CDCl3): δ = 2.39 (br s, 3 H, 7-CH3), 2.72 (s, 3 H, 2-CH3), 6.65 (m, 1 H, H-8), 6.68 (m, 1 H, H-6), 12.08 (s, 1 H, OH).
¹³C NMR (100 MHz, CDCl3): δ = 22.6 (2-CH3), 25.6 (7-CH3), 85.3 (C-3), 106.0 (C-4a), 107.0 (C-8), 112.5 (C-6), 147.6 (C-7), 155.9 (C-8a), 159.7 (C-5), 167.4 (C-2), 178.6 (C-4).
MS (EI, 70 eV): m/z (%) = 316 (100, [M]+ ˙), 189 (6, [M - I]+), 150 (6, [M - C3H3I]+ ˙), 122 (4, [M - C4H3IO]+).
HRMS-EI: m/z [M]+ ˙ calcd for C11H9IO3: 315.9596; found: 315.9600.
Anal. Calcd for C11H9IO3: C, 41.80; H, 2.87. Found: C, 41.64; H, 3.03.
5-Hydroxy-6,8-diiodo-2,7-dimethylchromone (10)
To a solution of 6 (232 mg, 1.00 mmol) and NaOAc (107 mg, 1.53 mmol) in AcOH (2.0 mL) was added ICl (0.1 mL, 1.97 mmol) at 40 ˚C. The suspension was heated to 60 ˚C for 3 h and then stirred overnight at r.t. The mixture was poured onto ice (10 mL) and stirred for 15 min. After saturating with NaCl, the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were washed with sat. aq Na2S2O3 (2 × 10 mL) and brine (2 × 10 mL) and dried (MgSO4). After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel (15% EtOAc in cyclohexane); yield: 168 mg (38%); yellow solid; mp 188-190 ˚C; R f = 0.6 (cyclohexane-EtOAc, 3:1).
¹H NMR (400 MHz, CDCl3): δ = 2.48 (d, J = 0.8 Hz, 3 H, 2-CH3), 2.94 (s, 3 H, 7-CH3), 6.18 (q, J = 0.8 Hz, 1 H, H-3), 13.80 (s, 1 H, OH).
¹³C NMR (100 MHz, CDCl3): δ = 20.7 (2-CH3), 36.3 (7-CH3), 75.8 (C-8), 84.5 (C-6), 108.1 (C-4a), 108.8 (C-3), 151.0 (C-7), 155.2 (C-8a), 159.8 (C-5), 168.2 (C-2), 182.1 (C-4).
MS (EI, 70 eV): m/z (%) = 442 (100, [M]+ ˙), 315 (32, [M - I]+), 247 (4, [M - C4H4IO]+).
HRMS-EI: m/z [M]+ ˙ calcd for C11H8I2O3: 441.8563; found: 441.8563.
5-Hydroxy-7-methyl-4-oxo-4 H -1-benzopyran-2-carboxaldehyde (11)
5-Hydroxy-2,7-dimethylchromone (1; [7] [¹0] 2.00 g, 10.52 mmol) and SeO2 (1.751 g, 15.78 mmol) were suspended in 1,4-dioxane (100 mL) in a tube. The tube was sealed and heated to 165 ˚C for 22 h. After bringing to r.t., the black suspension was filtered over a pad of Celite. The filter cake was rinsed with CHCl3 (100 mL) and the resulting filtrate was concentrated under reduced pressure. If necessary, the crude product can be purified by flash chromatography on silica gel (10% EtOAc in cyclohexane) to afford 10 as a yellow solid; yield: 2.12 g (99%); mp 126 ˚C; R f = 0.1 (cyclohexane-EtOAc, 9:1).
¹H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H, 7-CH3), 6.67 (s, 1 H, H-8), 6.79 (s, 1 H, H-3), 6.84 (m, 1 H, H-6), 9.74 (s, 1 H, CHO), 11.93 (s, 1 H, OH).
¹³C NMR (75 MHz, CDCl3): δ = 22.5 (7-CH3), 108.1 (C-8), 110.2 (C-4a), 113.2 (C-3), 115.1 (C-6), 149.3 (C-7), 155.6 (C-8a), 156.3 (C-5), 160.4 (C-2), 183.0 (C-4), 184.7 (2-CHO).
MS (EI, 70 eV): m/z (%) = 204 (100, [M]+ ˙), 175 (12, [M - CHO]+), 147 (8, [M - C2O2H]+).
HRMS-ESI: m/z [M]+ ˙ calcd for C11H8O4: 204.0495; found: 204.0494.
( Z )-3-(5-Hydroxy-7-methyl-4-oxo-4 H -1-benzopyran-2-yl)propenoic Acid Methyl Ester (12a)
Potassium bis(trimethylsilyl)amide (84 mg, 0.42 mmol) was added to a solution of methyl bis(trifluoroethyl)phosphonoacetate (140 mg, 0.44 mmol) and 18-crown-6 (529 mg, 2.0 mmol) in THF (7.0 mL) at -78 ˚C. The resulting suspension was stirred for 30 min and then 11 (82 mg, 0.40 mmol) was added. The mixture was stirred at -78 ˚C for 4 h, followed by the addition of methyl tert-butyl ether (6 mL) and sat. aq NH4Cl (4 mL). The aqueous layer was extracted with methyl tert-butyl ether (4 × 10 mL). The combined organic fractions were washed with H2O (5 × 40 mL) until neutrality and additionally with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product consists of E- and Z-isomers in the ratio 1:6.7, which could be separated by chromatography on silica gel (cyclohexane-EtOAc, 9:1); yield of 12a: 83 mg (80%); mp 122 ˚C; R f = 0.1 (cyclohexane-EtOAc, 9:1).
¹H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H, 7-CH3), 3.85 (s, 3 H, CO2CH3), 6.29 (d, J = 12.6 Hz, 1 H, H-alkenyl), 6.34 (s, 1 H, H-3), 6.45 (d, J = 12.6 Hz, 1 H, H-alkenyl), 6.59 (s, 1 H, H-8), 6.61 (s, 1 H, H-6), 12.23 (s, 1 H, OH).
¹³C NMR (100 MHz, CDCl3): δ = 22.2 (7-CH3), 52.2 (CO2 CH3), 107.2 (C-8), 108.9 (C-4a), 111.4 (C-3), 112.2 (C-6), 127.9 (C-alkenyl), 128.3 (C-alkenyl), 148.1 (C-7), 156.0 (C-8a), 160.0 (C-5), 160.4 (COO), 166.0 (C-2), 183.0 (C-4).
MS (EI, 70 eV): m/z (%) = 260 (100, [M]+ ˙), 229 (12, [M - CH3O]+), 201 (26, [M - C2H3O2]+).
HRMS-EI: m/z [M]+ ˙ calcd for C14H12O5: 260.0685; found: 260.0689.
( E )-3-(5-Hydroxy-7-methyl-4-oxo-4 H -1-benzopyran-2-yl)propenoic Acid Methyl Ester (12b)
Compound 12b was obtained in the above mentioned protocol as a yellow solid; yield: 12 mg (12%); mp 195 ˚C; R f = 0.2 (cyclohexane-EtOAc, 9:1).
¹H NMR (300 MHz, CDCl3): δ = 2.40 (s, 3 H, 7-CH3), 3.85 (s, 3 H, CO2CH3), 6.31 (s, 1 H, H-3), 6.41 (s, 1 H, H-8), 6.72 (s, 1 H, H-6), 6.80 (d, J = 15.7 Hz, 1 H, H-alkenyl), 7.25 (d, J = 15.7 Hz, 1 H, H-alkenyl), 12.15 (s, 1 H, OH).
¹³C NMR (75 MHz, CDCl3): δ = 22.4 (7-CH3), 52.3 (CO2 CH3), 107.4 (C-8), 109.1 (C-4a), 112.5 (C-3), 112.9 (C-6), 125.9 (C-alkenyl), 135.2 (C-alkenyl), 148.1 (C-7), 155.9 (C-8a), 159.3 (C-5), 160.4 (COO), 165.5 (C-2), 182.9 (C-4).
MS (EI, 70 eV): m/z (%) = 260 (100, [M]+ ˙), 229 (10, [M - CH3O]+), 201 (20, [M - C2H3O2]+ ˙).
HRMS-EI: m/z [M]+ calcd for C14H12O5: 260.0685; found: 260.0689.
( Z )-3-(5-Hydroxy-3-iodo-7-methyl-4-oxo-4 H -1-benzopyran-2-yl)propenoic Acid Methyl Ester (13a)
NaOAc (112 mg, 1.36 mmol) was suspended in a mixture of trifluoroacetic acid (0.4 mL) and trifluoroacetic anhydride (0.4 mL) at 0 ˚C. Compound 12a (83 mg, 0.32 mmol) was added and the mixture was stirred at r.t. for 30 min. N-Iodosuccinimide (108 mg, 0.48 mmol) was added and the stirring was continued for 25 h. Then, the reaction mixture was poured onto ice (5 mL) and the pH was adjusted to 6 with sat. aq NaHCO3. The aqueous layer was extracted with EtOAc (4 × 20mL), and the organic fractions were combined. After washing with H2O (80 mL) and brine (80 mL), the organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification was performed by chromatography on silica gel (cyclohexane-EtOAc, 9:1) to afford 13a as a yellow solid; yield: 73 mg (59%); mp 136 ˚C; R f = 0.2 (cyclohexane-EtOAc, 9:1).
¹H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H, 7-CH3), 3.79 (s, 3 H, CO2CH3), 6.28 (d, J = 12.2 Hz, 1 H, H-alkenyl), 6.61 (s, 1 H, H-8), 6.68 (s, 1 H, H-6), 6.97 (d, J = 12.2 Hz, 1 H, H-alkenyl), 11.95 (s, 1 H, OH).
¹³C NMR (100 MHz, CDCl3): δ = 22.5 (7-CH3), 52.2 (CO2 CH3), 86.8 (C-3), 106.3 (C-4a), 106.8 (C-8), 112.7 (C-6), 129.0 (C-alkenyl), 132.4 (C-alkenyl), 148.3 (C-7), 155.4 (C-8a), 159.7 (C-5), 159.9 (COO), 165.2 (C-2), 178.4 (C-4).
MS (EI, 70 eV): m/z (%) = 386 (38, [M]+ ˙), 259 (12, [M - I]+), 244 (20, [M - CH3I]+), 216 (12, [M - C2H3IO]+), 201 (32, [M - C3H6IO]+), 188 (12, [M - C4H7I]+ ˙).
HRMS-ESI: m/z [M]+ ˙ calcd for C14H11IO5: 386.9724; found: 386.9719.
( E )-3-(5-Hydroxy-3-iodo-7-methyl-4-oxo-4 H -1-benzopyran-2-yl)propenoic Acid Methyl Ester (13b)
The reaction was conducted according to the previous protocol (vide 13a) using 12b; yield: 6 mg (5%); yellow solid; mp 210 ˚C; R f = 0.2 (cyclohexane-EtOAc, 9:1).
¹H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H, 7-CH3), 3.88 (s, 3 H, CO2CH3), 6.69 (d, J = 0.5 Hz, 1 H, H-8), 6.75 (d, J = 0.5 Hz, 1 H, H-6), 6.86 (d, J = 15.6 Hz, 1 H, H-alkenyl), 7.91 (d, J = 15.6 Hz, 1 H, H-alkenyl), 11.88 (s, 1 H, OH).
¹³C NMR (75 MHz, CDCl3): δ = 22.5 (7-CH3), 52.2 (CO2 CH3), 91.3 (C-3), 106.4 (C-4a), 107.0 (C-8), 112.8 (C-6), 128.7 (C-alkenyl), 137.6 (C-alkenyl), 148.7 (C-7), 155.0 (C-8a), 158.3 (C-5), 159.7 (COO), 165.2 (C-2), 178.7 (C-4).
MS (EI, 70 eV): m/z (%) = 386 (60, [M]+ ˙), 259 (100, [M - I]+), 244 (32, [M - CH3I]+), 216 (22, [M - C2H3IO]+), 188 (24, [M - C4H7I]+ ˙).
HRMS-ESI: m/z [M]+ ˙ calcd for C14H11IO5: 386.9724; found: 386.9721.
Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis. Included are crystal structure data of 5, 9, 11, and 12a in CIF. CCDC reference numbers 789797 (5), 789798 (9), 790263 (11) and 790264 (12a).
- Supporting Information for this article is available online:
- Supporting Information
Acknowledgment
The authors highly appreciate the financial support by BASF SE and collaboration with the Kompetenzzentrum der Integrierten Naturstoff-Forschung (University of Mainz).
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Rho HS.Ko B.-S.Kim HK.Ju Y.-S. Synth. Commun. 2002, 32: 1303 - 16a
Zhang FJ.Li YL. Synthesis 1993, 565 - 16b
Costa AMBSRCS.Dean FM.Jones MA.Varma RS. J. Chem. Soc., Perkin Trans. 1 1985, 799 - 17a
Jagadeesh SG.Krupadanam DLD.Srimannarayana G. Synth. Commun. 1998, 28: 3827 - 17b
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Dike SY.Mahalingam M. Synth. Commun. 1989, 19: 3443 - 17d
Yamauchi M.Katayama S.Nakashita Y.Watanabe T. Synthesis 1981, 33 - 18a
Santos CMM.Silva AMS.Cavaleiro JAS. Synlett 2005, 3095 - 18b
Ibrahim SS. Ind. Eng. Chem. Res. 2001, 40: 37 - 18c
Gammill RB. Synthesis 1979, 901 - 18d
Nohara A.Ukawa K.Sanno Y. Tetrahedron 1974, 30: 3563 - 19a
Zhou C.Dubrovsky AV.Larock RC. J. Org. Chem. 2006, 71: 1626 - 19b
Likhar PR.Subhas MS.Roy M.Roy S.Kantam ML. Helv. Chim. Acta 2008, 91: 259 - 20a
Waldvogel SR.Wehming K. In Science of Synthesis Vol. 31:Ramsden CA. Thieme; Stuttgart: 2007. p.235 - 20b
Waldvogel SR. In Science of Synthesis Knowledge Updates Vol. 2010/1:Ramsden CA.Thomas EJ. Thieme; Stuttgart: 2010. p.487 - 21a
Still WC.Gennari C. Tetrahedron Lett. 1983, 24: 4405 - 21b
Motoyoshiya J.Kusaura T.Kokin K.Yokoya S.Takaguchi Y.Narita S.Aoyama H. Tetrahedron 2001, 57: 1715
References
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Saengchantara ST.Wallace TW. Nat. Prod. Rep. 1986, 3: 465 - 1b
Houghton PJ. Stud. Nat. Prod. Chem. 2000, 21: 123 - 1c
Sagrera G.Seoane G. Synthesis 2010, 2776 - 1d
Huang Z.Yang R.Guo Z.She Z.Lin Y. Chem. Nat. Compd. 2010, 46: 15 - 1e
Zhang HW.Song YC.Tan RX. Nat. Prod. Rep. 2006, 23: 753 - 1f
Hepworth JD.Heron MB.Gabutt CD. In Comprehensive Heterocyclic Chemistry II 1st ed., Vol. 5:Katritzky AR.Rees CW.Scriven EFV. Pergamon Press; Oxford: 1996. p.427 - 2a
Horton DA.Bourne GT.Smythe ML. Chem. Rev. 2003, 103: 893 - 2b
Geen GR.Evans JM.Vong AK. In Comprehensive Heterocyclic Chemistry II 1st ed., Vol. 5:Katritzky AR.Rees CW.Scriven EFV. Pergamon Press; Oxford: 1996. p.469 - See, for example:
- 3a
Nakazumi H.Maeda K.Yagi S.Kitao T. J. Chem. Soc., Chem. Commun. 1992, 1188 - 3b
Karapire C.Kolancilar H.Oyman Ü.Icli SJ. Photochem. Photobiol. A 2002, 153: 173 - 3c
Walenzyk T.Carola C.Buchholz H.König B. Tetrahedron 2005, 61: 7366 - 4
Wang H.Gloer JB. Tetrahedron Lett. 1995, 36: 5847 - 5
Kong F.Carter GT. Tetrahedron Lett. 2003, 44: 3119 - 6
Sassa T.Kachi H.Nukina M. J. Antibiot. 1985, 38: 439 - 7
Ahluwalia VK.Kumar D. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1976, 14: 326 - 8
Kimura Y.Mizuno T.Nakajima H.Hamasaki T. Biosci. Biotechnol. Biochem. 1992, 56: 1664 - 9a
Gu W.Ge HM.Song Y. C.Ding H.Zhu HL.Zhao XA.Tan RX. J. Nat. Prod. 2007, 70: 114 - 9b
Shushni MAM.Mentel R.Lindequist U.Jansen R. Chem. Biodiversity 2009, 6: 127 - 9c
Gu W. World J. Microbiol. Biotechnol. 2009, 25: 1677 - 10
Königs P.Rinker B.Maus L.Nieger M.Rheinheimer J.Waldvogel SR. J. Nat. Prod. 2010, 73: 2064 - 11
Arndt F. Ber. Dtsch. Chem. Ges. 1925, 58: 1612 - 12
Offe HA. Ber. Dtsch. Chem. Ges. 1938, 71: 1837 - 13
Winter CW.Hamilton CS. J. Am. Chem. Soc. 1952, 74: 3999 - 14a
Merchant JR.Rege DV. Tetrahedron 1971, 27: 4837 - 14b
Lin C.-F.Duh T.-H.Lu W.-D.Lee J.-L.Lee C.-Y.Chen C.-C.Wu M.-J. J. Chin. Chem. Soc. 2004, 51: 183 - 14c
Kamla C.Rastogi MK.Kapoor RP.Garg CP. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1978, 16: 417 - 15a
Bird TGC.Brown BR.Stuart IA.Tyrrell AWR. J. Chem. Soc., Perkin Trans. 1 1983, 1831 - 15b
Miyake M.Nishino S.Nishimura A.Sasaki M. Chem. Lett. 2007, 36: 522 - 15c
Fitzmaurice RJ.Etheridge ZC.Jumel E.Woolfson DN.Caddick S. Chem. Commun. 2006, 4814 - 15d
Zhou Z.Zhao P.Huang W.Guangfu Y. Adv. Synth. Catal. 2006, 348: 63 - 15e
Mazumdar AKD.Saha GC.Sinha TK.Banerji KD. J. Indian Chem. Soc. 1984, 61: 996 - 15f
Joo YH.Kim JK. Synth. Commun. 1998, 28: 4287 - 15g
Rho HS.Ko B.-S.Kim HK.Ju Y.-S. Synth. Commun. 2002, 32: 1303 - 16a
Zhang FJ.Li YL. Synthesis 1993, 565 - 16b
Costa AMBSRCS.Dean FM.Jones MA.Varma RS. J. Chem. Soc., Perkin Trans. 1 1985, 799 - 17a
Jagadeesh SG.Krupadanam DLD.Srimannarayana G. Synth. Commun. 1998, 28: 3827 - 17b
Zagorevskii VA.Tsvetkova ID.Orlova EK. Chem. Heterocycl. Compd. 1967, 3: 624 - 17c
Dike SY.Mahalingam M. Synth. Commun. 1989, 19: 3443 - 17d
Yamauchi M.Katayama S.Nakashita Y.Watanabe T. Synthesis 1981, 33 - 18a
Santos CMM.Silva AMS.Cavaleiro JAS. Synlett 2005, 3095 - 18b
Ibrahim SS. Ind. Eng. Chem. Res. 2001, 40: 37 - 18c
Gammill RB. Synthesis 1979, 901 - 18d
Nohara A.Ukawa K.Sanno Y. Tetrahedron 1974, 30: 3563 - 19a
Zhou C.Dubrovsky AV.Larock RC. J. Org. Chem. 2006, 71: 1626 - 19b
Likhar PR.Subhas MS.Roy M.Roy S.Kantam ML. Helv. Chim. Acta 2008, 91: 259 - 20a
Waldvogel SR.Wehming K. In Science of Synthesis Vol. 31:Ramsden CA. Thieme; Stuttgart: 2007. p.235 - 20b
Waldvogel SR. In Science of Synthesis Knowledge Updates Vol. 2010/1:Ramsden CA.Thomas EJ. Thieme; Stuttgart: 2010. p.487 - 21a
Still WC.Gennari C. Tetrahedron Lett. 1983, 24: 4405 - 21b
Motoyoshiya J.Kusaura T.Kokin K.Yokoya S.Takaguchi Y.Narita S.Aoyama H. Tetrahedron 2001, 57: 1715
References
Figure 1 Natural products possessing the altechromone A scaffold
Scheme 1 Selective brominations of 5-hydroxy-2,7-dimethylchromone (1)
Figure 2 Molecular structures of 5 (left) and 9 (right) obtained by X-ray crystal structure analyses
Scheme 2 Selective iodination protocols for 1
Scheme 3 Olefination of 2-formylchromone 11
Figure 3 Molecular structures of 11 (left) and 12a (right) obtained by X-ray crystal structure analyses
Scheme 4 Selective iodination protocols for 12