We have synthesized the novel 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one which is a precursor of SERMs with a smaller number of steps and good yield. Two methodologies for the synthesis have been worked out. Anhydrous BF3·Et2O catalyzed reaction was found to be selective for product formation while anhydrous AlCl3, FeCl3, and SnCl4 catalyzed ones were nonselective.
Activity of estrogen receptor can be controlled by a class of compounds which is called selective estrogen receptor modulators (SERMs). The modulators have a distinctive feature in different individual tissues by which they can inhibit or stimulate or selectively suppress or excite estrogen-like behavior in different tissues. The structures of few biologically vital SERMs are shown in Figure
Examples of biologically active heterocyclic frameworks.
Coumarin and its derivatives are important compounds due to their presence in numerous natural products along with their wide ranging applications as drugs, pharmaceuticals, and SERMs. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have been described as potential anti-breast-cancer agents. Thus, coumarin derivatives acting as SERMs either stimulate or inhibit the estrogen action, thereby generating the possibility of curing estrogen related problems. Coumarins and their derivatives are common in nature [
Among the oxygen heterocycles coumarins are one of them which are present in various naturally [
Route 1 for the synthesis of coumarin based SERM’s precursors.
Route 2 for the synthesis of coumarin based SERM’s precursors.
Condensation reactions have been amongst the most useful routes for the synthesis of these compounds, particularly catalyzed by Lewis acids. In Scheme
To decrease the product loss and number of steps, the synthetic strategy was modified and Scheme
Probable mechanism related to Scheme
In our early attempts, to synthesize the coumarin based SERMs precursors, we were not successful in converting the reactants to products without the catalyst (BF3·Et2O). The anhydrous AlCl3, FeCl3, and SnCl4 were not able to give the desired intermediate selectively in quantitative yield. This was possibly due to poor Lewis acid character of AlCl3, FeCl3, and SnCl4 compared to BF3. The reaction was investigated carefully and it was observed that the intermediate (benzylic ketones (
13C NMR (Figure S6(b)) also confirmed the formation of 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one; peaks at 119.60, 126.40, 128.38, 129.53, 134.05, and 161.22 show six different types of carbons which are present in 4-aryl-3-phenyl-benzopyrone in addition to the carbons already present in the starting, that is, 2-(4-hydroxy-phenyl)-1-(2-hydroxy phenyl)-ethanone. FTIR spectrum also confirmed the formation of lactone ring; that is, the cyclized product shows carbonyl absorption at a higher wavenumber, that is, at 1707 cm−1 (Figure S6(c)), while it was 1633 cm−1 in the 2-(4-hydroxy-phenyl)-1-(2-hydroxy-phenyl)-ethanone (Figure S2(a)). Mass spectroscopy shows (m + 1) peak at 343 while the molecular weight of (
Finally the single crystal diffraction studies showed the space orientation (Figures
Bond lengths and bond angles of (
S. number | Atoms | Bond lengths | Atoms | Bond angles |
---|---|---|---|---|
1 | O3-C20 | 1.3772( |
C20-O3-C23 | 117.76 |
2 | O3-C23 | 1.3963( |
C8-O1-C7 | 121.71 |
3 | O1-C8 | 1.3848( |
O3-C20-C21 | 115.93 |
4 | O1-C7 | 1.3722( |
O1-C8-C1 | 115.40 |
5 | C5-C6 | 1.3610( |
O3-C20-C19 | 124.73 |
6 | C6-C7 | 1.4647( |
O1-C7-C6 | 117.78 |
7 | O2-C7 | 1.2114( |
C6-C7-O2 | 125.71 |
(a) ORTEP/PLATON structure of (
This new procedure allows facile introduction of substituents at position 4 of the 4-(4-substituted-benzyl)-3-phenyl-chromen-2-one skeleton and gives the flexibility for the construction of novel precursors.
Various derivatives have been prepared with para substituted benzyl chloride with hydroxyl, methoxy, acetoxy, methyl, and ethyl groups as shown in Table
Derivatives of 4-aryl-3-phenyl-coumarin-2-one and their yield (%) for Scheme
S. number | Compound | R | R2 | Time (h) | Yielda (%) |
---|---|---|---|---|---|
1 | ( |
-OH | H | 7 | 74 |
2 | ( |
-OH | -CH3 | 7 | 77 |
3 | ( |
-OH | -OCH3 | 6 | 80 |
4 | ( |
-OH | -C2H5 | 8 | 70 |
5 | ( |
-OCH3 | H | 7 | 75 |
6 | ( |
-OCH3 | -CH3 | 8 | 79 |
7 | ( |
-OCH3 | -OCH3 | 7 | 82 |
8 | ( |
-OCH3 | -C2H5 | 7 | 80 |
9 | ( |
-OAc | H | 6 | 90 |
After the establishment of the protocol for the synthesis of substituted SERMs precursors (4-benzyl-3-phenyl coumarins), we shifted our focus towards the role of solvents like CH2Cl2, CHCl3, acetone, and toluene upon yield and the reaction time. The results illustrated that the reaction in toluene did not give the desired precursors, whereas the reaction in CHCl3 was slow and the yield was low. However, for this cyclization, CH2Cl2 was found to be good in terms of yield and handling but took a slightly longer time to afford the products. Eventually, acetone appeared as a solvent of choice for intermolecular cyclization in very good yield. Intermolecular cyclization was greatly influenced by the base used; therefore, to find out the appropriate base, we examined K2CO3 and triethylamine in the intermolecular cyclization reaction of (
In conclusion, a simple, efficient, and novel method has been developed for an easy access to synthesis of the 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one via Scheme
All the required chemicals are purchased since they are commercially available and used as received without further purification. Commercially available acetone and benzene were further purified and dried following the known procedure. Thin-layer chromatography (TLC) was performed using silica gel 60 F254 precoated plates. Column chromatography was carried out on silica gel 60 (100–200 mesh). Infrared (FTIR) spectra were recorded in KBr, and wavelengths (
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors are thankful to the Department of Chemistry, BHU, for proving NMR, FTIR, and single crystal X-ray data. Financial assistance from CSIR (Grant no. 01(2362)/10/EMR-II), New Delhi, in the form of a project and fellowships to Ambika Srivastava and Pooja Singh and CSIR and UGC, New Delhi, in the form of SRF and UGC Fellowship, respectively, is gratefully acknowledged.