Abstract
A general route for the synthesis of biologically important flavones is reported via a two step sequence employing a catalytic Wacker-Cook oxidation4b as the key step.
Keywords: Flavones, Wacker-Cook oxidation, BzR/GABAergic, subtype selectivity of flavones
Flavones are a group of natural products which occur as secondary metabolites in plants and exhibit remarkable biological activity (e.g., anti-malarial, anti-oxidant, anti-inflammatory, insecticidal properties).1 In addition, the core structure of flavones (Figure 1) is also found in several natural products rendering this privileged scaffold interesting from a synthetic point of view.2 Analysis of a recent review indicated flavones bind potently to the benzodiazepine binding site (Bz BS) on γ-aminobutyric acid (A) receptors (GABA-A).3a Importantly, Haeberlein et al. had reported that the steric orientation of the substituents in flavones must lie in a coplanar fashion to the aromatic ring for potent affinity to BzR.3d
Figure 1.
General structure of the flavones.
In order to search for subtype selective flavones3a for BzR simple access to a broad spectrum of these ligands was required. The initial idea for a two step process for the synthesis of various flavones originated from the work of Maldonado et al. who had employed a process they termed, a Wacker-Cook oxidation.4b It had been conceived from a one pot synthesis of enones,4a which had been developed during the synthesis of the alkaloids (−)-alstonerine and 6-oxoalstophylline, as well as for the synthesis of the isoflavone core structure.4b
We wish to report the successful synthesis of a wide variety of flavones via this catalytic approach in a two step process. This new procedure is catalytic in palladium (II) rather than stoichiometric.2
The starting enone for this catalytic oxidation was readily prepared via an aldol condensation of the corresponding o-hydroxyacetophenone II with the required benzaldehyde III to give the α,β unsaturated ketone IV following a literature procedure (Scheme 1).5 Optimization of the oxidation conditions employed in the established method4b was carried out in order to reduce the palladium required to a catalytic amount (10 mol%). The α,β unsaturated ketone IV (R1 = Cl, R4 = NO2) was employed as the model compound to optimize the reaction conditions of the intramolecular oxidation for the synthesis of the substituted flavones. Initial attempts by the application of the original Wacker conditions6a,b provided very poor conversion of the starting unsaturated ketone to the desired flavones (~20 % even after 7 days) as well as the use of stoichiometric amounts of palladium (Table 1, entry 1).6
Scheme 1.
Synthesis of the starting material for the flavones.
Table 1.
Optimization studies of the oxidation process.
 | |||||
|---|---|---|---|---|---|
| Temp. | Catalyst loading |
Oxidizing Agent | Yield | Time | |
| 1 | 80 °C | 1.3 eq. | --- | 33 % | 12 h |
| 2 | 80 °C | 1 eq. |
t-BuOOH (1.3 eq.) |
66 % | 21 h |
| 3 | 80 °C | 40 mol% |
t-BuOOH (1.3 eq.) |
67 % | 20 h |
| 4 | 90 °C | 1 eq. | NMO | 67 % | 5 h |
| 5 | 80 °C | 40 mol% |
t-BuOOH (5 × 1.3 eq.) |
74 % | 7 h |
| 6 | 70 °C | 20 mol% |
t-BuOOH (5 × 1.3 eq.) |
75 % | 8 h |
| 7 | 70 °C | 10 mol% |
t-BuOOH (5 × 1.3 eq.) |
76 % | 8 h |
| 8 | 70 °C | 10 mol% |
t-BuOOH (6 eq.) |
85 % | 4 h |
| 9 | 70 °C | 2 mol% |
t-BuOOH (6 eq.) |
64 % | 16 h |
| 10 | 50 °C | 10 mol% |
t-BuOOH (6 eq.) |
0 % | 24 h |
Addition of t-BuOOH as the oxidizing agent to the reaction mixture4a,b increased the yield but only moderately (Table 1, entry 2). Interestingly, the yield remained constant even when the catalyst loading was reduced or the oxidizing agent was changed to NMO (Table 1, entries 3 and 4). However, better yields were achieved when t-BuOOH was used in excess and added portion wise at one hour intervals to the reaction vessel. The increase in yield was now maintained even when the amount of palladium was again lowered to 10 mol% (Table 1, entries 7 and 8). A further improvement in yield was realized by the addition of the oxidizing agent t-BuOOH in excess in one portion at the beginning of the reaction and 10 mol% of the palladium catalyst was employed (Table 1, entry 8). The complete consumption of the starting material was observed and a higher yield of the desired flavone was obtained. In agreement with previous work,4a,b as well as with the reports of Tsuji6c the palladium (0), so generated, in the catalytic cycle was reoxidized to the active palladium (II) species with t-BuOOH before the palladium (0) was converted to the inactive metallic palladium (0). Again as in the earlier work of Tsuji6c and others,4a,b the key step to form the enone was the palladium hydride elimination set up to generate the flavone core.
Further attempts at a lower catalyst loading or a lower reaction temperature resulted in reduced yields or no conversion of the starting material at all, respectively. It must be pointed out the best solvent ratio and conditions for this oxidation (20 mmolar concentration in t-BuOH/H2O (1:1), 10 mol% Na2PdCl4 • 3 H2O, NaOAc, AcOH, 6 equiv. t-BuOOH) are different from the classical Wacker or Tsuji-Wacker oxidations (see brief experimental for details).
These newly developed oxidation conditions were applied to the synthesis of a number of flavones of interest in good to excellent yields (Table 2). Depicted in Table 2 are the structures and Ki values of flavones that bound to the benzodiazepine receptor of GABA(A)ergic ion channels previously reported on synaptosomal membranes by Haeberlein et al..3d
Table 2.
Synthesis of flavones via the oxidation process (I) and Ki values of flavones that bound to BZR/GABAergic receptors.
 | |||||
|---|---|---|---|---|---|
| R1 | R4 | Yield | time | Ki (nM)3a | |
| 1 | F | NO2 | 89 % | 3.5 h | 182 |
| 2 | Cl | NO2 | 85 % | 4 h | 8.0 |
| 3 | Br | Cl | 83 % | 2.5 h | 17.0 |
| 4 | Cl | Br | 84 % | 4.5 h | 23.0 |
| 5 | Br | Br | 87 % | 2.5 h | 19.1 |
| 6 | NO2 | NO2 | 76 % | 4 h | 12.0 |
| 7 | Br | NO2 | 87 % | 3 h | 1.0 |
Importantly, no byproduct was observed from the Michael addition to generate the dihydroflavone which is very difficult to convert to a flavone in some cases. This oxidation was successful in the presence of a wide variety of functional groups. Key to the general nature of this oxidation, electron donating groups (EDG) nor electron withdrawing groups (EWG) on both aromatic rings of the starting α,β unsaturated ketone IV had little if any impact on the yields (Table 2).
To extend the scope of the newly developed oxidation system a broad spectrum of flavone analogues which contained either an EWD or EDG in the B ring at various positions were synthesized in excellent yields (Table 3). To date, this approach to substituted flavones in ring B has been successful with a variety of substituents. Flavones with ring B which contained highly electron rich substituents (Table 3, entries 1, 4, 7, 8, 10) as well as highly electron poor substituents (Table 3, entries 9, 11, 12, 13) gave good yields consistently. Even substituents which contained a phenolic group in ring B (Table 3, entries 2 and 5) gave good yields in this oxidation without byproduct formation from any intermolecular process.
Table 3.
Synthesis of flavones via the oxidation process (II).
 | ||||||
|---|---|---|---|---|---|---|
| R3 | R4 | R5 | R6 | Yield | Time | |
| 1 | H | OMe | H | OMe | 84 % | 4.5 h |
| 2 | H | OH | H | H | 84 % | 2.5 h |
| 3 | H | OMe | H | H | 89 % | 2.5 h |
| 4 | H | H | t-Bu | H | 97 % | 3 h |
| 5 | H | H | OH | H | 79 % | 4 h |
| 6 | H | H | H | H | 88 % | 3 h |
| 7 | OMe | H | H | OMe | 92 % | 3 h |
| 8 | H | H | OMe | H | 90 % | 4 h |
| 9 | H | CF3 | H | H | 74 % | 3.5 h |
| 10 | H | H | NMe2 | H | 81 % | 5 h |
| 11 | H | H | F | H | 72 % | 2.5 h |
| 12 | H | H | CF3 | H | 78 % | 5 h |
| 13 | H | H | CN | H | 71 % | 3.5 h |
Finally, depicted in Table 4 is a series of flavones prepared via this strategy with an EDG in ring A and with an EDG or EWG in ring B.
Table 4.
Synthesis of flavones via the oxidation process (III).
 | |||||
|---|---|---|---|---|---|
| R2 | R4 | R5 | Yield | time | |
| 1 | OMe | H | F | 81 % | 3 h |
| 2 | OMe | NO2 | H | 77 % | 3.5 h |
| 3 | OMe | H | OMe | 82 % | 2.5 h |
| 4 | OMe | OMe | H | 81 % | 3.5 h |
In summary, a catalytic oxidation procedure has been developed for the synthesis of flavones in high yield. This simple two step process provides the first simple entry into a series of flavones with EDG or EWG in ring A or B at will and should provide a simple route to substituted analogues for SAR studies at BzR.3a
Procedure for the preparation of the starting material for the example in Table 3, entry 4
To a solution of 4-t-butylbenzaldehyde (299 mg, 1.84 mmol, 1.25 eq.) in ethanol (5 mL) at r.t. was added a solution of aqueous NaOH (50 % in H2O, 3 mL) and 5´- hydroxy-2-chloroacetophenone (250 mg, 1.47 mmol, 1 eq.). The mixture which resulted was stirred after which it turned from a yellowish color to red in a few minutes and was stirred for 18h at room temperature. After addition of EtOAc/H2O (1:1, 20 mL), the aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic layers were washed with a saturated solution of NaHCO3(aq) until the color of the organic phase changed to yellow and the organic layer was then washed with a saturated solution of NaCl(aq). The organic phase was dried (MgSO4), filtered and the solvent removed under reduced pressure. The oily residue was purified by flash column chromatography on silica gel using n-hexane:EtOAc (20:1) as the eluent. The α,β unsaturated ketone was obtained as a yellowish solid in 76 % yield (352 mg, 1.12 mmol) present as the trans-isomer as the only product, as expected.
Rf: 0.91 on silica gel (n-hexane:EtOAc 6:1); mp. = 138 °C; 1H-NMR (500 MHz, CDCl3) δ 12.78 (s, 1H), 7.94 (d, J = 15.4 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.61 – 7.63 (m, 2H), 7.53 (d, J = 15.4 Hz, 1H), 7.47 – 7.49 (m, 2H), 7.43 (dd, J = 8.8, 2.5 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 1.36 (s, 9H) ppm; 13C-NMR (125 MHz, CDCl3) δ 192.8, 162.0, 155.1, 146.5, 136.0, 131.6, 128.8, 128.8, 126.1, 123.4, 120.7, 120.2, 118.5, 35.0, 31.1 ppm; HRMS (ESI) (M+H)+ Calcd. for C19H20ClO2 315.1146, found: 315.1140.
Procedure for the oxidation of IV to flavones in Table 3, entry 4
To a mixture of t-BuOH/H2O (1:1, 5 mL) and AcOH (670 µL) were added NaOAc (7.8 mg, 0.095 mmol), the α,β unsaturated ketone IV (30 mg, 0.095 mmol), Na2PdCl4 • 3 H2O (10 mol%, 2.3 mg) and t-BuOOH (70 % in H2O, 6 eq.). The brownish solution which resulted was allowed to warm to 70 °C and stirred for 3 h. The mixture was then cooled to room temperature, after which EtOAc (10 mL) and a saturated solution of NaHCO3(aq) (10 mL) were added carefully. The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed successively with saturated solutions of NaHCO3(aq) and NaCl(aq) after which it was dried (MgSO4). After filtration the solvent was removed under reduced pressure and the solid residue purified by flash column chromatography on silica gel using n-hexane:EtOAc (15:1) as the eluent. The flavone was obtained in 97 % (29 mg, 0.092 mmol) yield.
Rf: 0.51 on silica gel (n-hexane:EtOAc 6:1); mp. = 187 °C; 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J = 2.6 Hz, 1H), 7.82 – 7.85 (m, 2H), 7.62 (dd, J = 9.0, 2.6 Hz, 1H), 7.50 – 7.56 (m, 3H), 6.80 (s, 1H), 1,37 (s, 9H); 13C-NMR (75 MHz, CDCl3) δ 177.2, 163.9, 155.7, 154.5, 133.8, 131.1, 128.5, 126.2, 126.1, 125.1, 124.9, 119.8, 106.9, 35.1, 31.1 ppm; HRMS (ESI) (M+H)+ Calcd. for C19H18ClO2 313.0990, found: 313.0986.
Acknowledgments
We thank Matthew E. Dudley for technical advice and the NIH (in part) as well as The Research Growth Initiative of the University of Wisconsin-Milwaukee for financial support. This catalytic process was developed based on the earlier work of Liao4a and Tsuji.6c
Footnotes
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References
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