Abstract
A novel and efficient microwave-assisted one-pot reaction was developed to synthesize angular 2,2-dimethyl-2H-chromone containing compounds, which is the first and key step in the synthesis of potent DCK and DCP anti-HIV agents. The newly developed microwave synthesis conditions dramatically shortened the reaction time from 2 days to 4 hours with improved yields.
Keywords: Microwave reaction, Angular 2, 2-dimethyl-2H-chromone, One-pot reaction, Anti-HIV
Introduction
Suksdorfin (1), isolated from Lomatium suksdorfii, was discovered in early 1994 to exhibit anti-HIV activity.1 Continuing research led to the discovery of (3’R, 4’R)-(+)-cis-khellacone (DCK) analogs and (3’R, 4’R)-di-O-(-)-camphanoyl-2’,2’-dimethyldihydropyrano[2,3-f] chromone (DCP) analogs, some of which demonstrated much more significant anti-HIV activity than 1.2-5 4-MDCK (2) and 2-EDCP (3) are potent representatives of these two series and were selected as lead compounds for further modification to develop more potent and selective anti-HIV agents as possible clinical trial candidates. The skeletons of 1, 2 and 3 share a similar motif, a 2,2-dimethyl-2H-chromene (rings B and C shown in Figure 1). Because the synthesis of the 2,2-dimethyl-2H-chromone motif is the first and key step in the preparation of both DCK and DCP series, the efficiency of this reaction dramatically affects the synthesis of the desired final products.
Figure 1.
Structures of Suksdofin (1), 4-MDCK (2) and 2-EDCP (3)
In our prior studies, the C-ring was constructed by different methods. For DCK compounds, a two-step reaction sequence involved nucleophilic substitution with 3-chloro-3-methyl-1-butyne, followed by Claisen rearrangement and cyclization in N,N-diethylaniline at reflux temperature over 200 °C.3 This transformation generally needed over 48 hours and the yield averaged below 40%. For DCP analogues, a successful one-pot synthesis involved gradual addition of 4,4-dimethoxy-2-methyl-2-butanol into a refluxing solution of 1-(2,4-dihydroxyphenyl)ethanone in pyridine (at approximately 140 °C) to accomplish both alkylation and cyclization.5 However, the maximum yield of the desired product still remained low (< 40%) even with a 48-hour reaction time. Both conventional syntheses of the 2,2-dimethyl-2H-chromone were not time- or yield-efficient, partially attributable to the formation of a linear by-product (b-series, such as 5b shown in Scheme 1). Therefore, for scale-up synthesis of DCK and DCP compounds, a more efficient synthetic approach was needed to shorten the reaction time, increase the yield of the desired product (a-series), and better control the formation of the linear byproduct.
Scheme 1.
Synthesis of 15 a-b, Reagents and conditions: (i) 4,4-dimethoxy-2methyl-2-butanol, pyridine, microwave condition.
Microwave (MW) synthesis was considered to be a useful approach to accomplish these goals. One benefit of MW synthesis is to manage the desired reaction under appropriate conditions (time, temperature, and pressure) to achieve the desired product in a reasonably high yield. In this paper, we report herein our recent study to design and conduct MW synthesis with varying reaction duration, temperature, and reagent, in order to optimize the synthesis of angular 2,2-dimethyl-2H-chromenes (a-series), as key and desired intermediates in synthesis of DCK and DCP analogs.
Results
In our previous report, the 2,2-dimethyl-2H-chromene 15a in Scheme 1 was synthesized by reaction of 1-(2,4-dihydroxyphenyl)ethanone with 4,4-dimethoxy-2-methyl-2-butanol in pyridine. The best reported yield of 15a by this conventional method was 38% with a reaction temperature of 140 °C and reaction time of 48 hours. However, the by-product 15b was also obtained in 6.4% yield under these conditions (Scheme 1). A possible mechanism is proposed in Scheme 2, which illustrates the formation of the desired angular product 15a and the undesired by-product 15b. The activated alkylating reagent, 4,4-dimethoxy-2-methyl-2-butanol, initially attacks at the electron-rich position-3 or -5 of the starting ethanone. Subsequently, cyclization occurs between the lone-pair electrons of the ketone at position-4 and the electrophilic carbon of the butene, and CH3OH is lost to form the angular (a-series from position-3 attack) or linear (b-series from position-5 attack) product. Using the same reagent, experiments were designed and conducted using MW initiation to find better conditions to selectively produce 15a. The results are listed in Table 1. The reaction temperature was varied from 140 °C to 240 °C with 20 °C intervals, and the reaction duration was extended from 2 hours to 8 hours with two-hour intervals. At a set reaction time, the yields of both 15a and 15b increased at higher temperatures, but reached a maximum at 220 °C. At this reaction temperature, the highest yield (57.4%) of the desired 15a occurred at a reaction duration of 4 hours. Although the yield of the undesired 15b also increased slightly (6.40% vs. 7.32%) under these conditions (220°C/4h), the MW synthesis was still a significant improvement compared with the best reported conventional reaction conditions (57.4% versus 38% yield of 15a, respectively).
Scheme 2.
Possible Mechanism for Observed Transformations
Table 1.
Yields of 15a and 15b under Varied Microwave Conditions
| temperature (°C) | yield of 15a (%) | yield of 15b (%) | ||||||
|---|---|---|---|---|---|---|---|---|
| 2 h | 4h | 6h | 8 h | 2 h | 4 h | 6 h | 8 h | |
| 140 °C | ---a | 3.38 | ---a | ---a | ---a | 0.49 | ---a | ---a |
| 160 °C | ---a | 15.2 | 23.1 | 23.8 | ---a | 1.40 | 2.33 | 2.47 |
| 180 °C | ---a | 35.5 | 41.5 | 41.9 | ---a | 4.11 | 5.02 | 7.76 |
| 200 °C | ---a | 45.7 | 49.3 | 54.0 | ---a | 6.06 | 6.27 | 7.14 |
| 220 °C | 52.7 | 57.4 | 54.0 | ---a | 6.4 | 7.32 | 8.05 | ---a |
| 240 °C | ---a | 38.0 | 35.8 | ---a | ---a | 5.92 | 5.60 | ---a |
reaction not performed
To verify the optimized MW conditions, a second series of reactions was conducted using 3-hydroxy-9H-xanthane-9-one (10) as starting material to make the corresponding tetracyclic product (21a). The reaction temperatures, times, and yields are listed in Table 2. The best yield (55.7%) of the desired produce 21a was again reached at 220 °C for 4 hours, and was about 10 times better than the yield obtained from the conventional method with the same alkylating reagent (4.34%, Table 4, entry 7), suggesting that 220°C/4h may be widely applicable to efficiently produce different dimethylchromene-related products, including 8,8-dimethyl-8H-pyrano[2,3-f]chromenes, 3,3-dimethyl-pyrano[2,3-c]xanthen-7(3H)-ones or other compounds, such as 3,3,12-trimethyl-3H-pyrano[2,3-c]acridin-7(12H)-one.
Table 2.
Yields of 21a and 21b under Varied Microwave Conditions
| temperature (°C) | yield of 21a (%) | yield of 21b (%) | ||
|---|---|---|---|---|
| 4 h | 6 h | 4 h | 6 h | |
| 180 | 38.4 | 44.8 | 2.94 | 2.14 |
| 200 | 49.7 | ---a | 3.62 | ---a |
| 220 | 55.7 | ---a | 4.08 | ---a |
| 240 | 52.6 | ---a | 4.58 | ---a |
reaction not performed
Table 4.
Comparisons of Conventional and Microwave Syntheses
| Entry # in Table 3 / Products | Conventional heating system (140 °C/48h for entries 1, 5–7) (%)a | MW condition (220°C/4h) (%)a | ||
|---|---|---|---|---|
| Angular product a | Linear product b | Angular product a | Linear product b | |
| 1 / 15 | 38.0 | 6.40 | 57.4 | 7.32 |
| 5 / 19 | 13.6 | N/A | 40.3 | N/A |
| 6 / 20 | 23.9 | 2.55 | 31.6 | 5.47 |
| 7 / 21 | 4.34 | 1.20 | 55.7 | 4.08 |
| 8 / 226, b | 12.5 | 6.30 | 38.9 | 27.2 |
| 14 / 257, c | 20 | ---d | 36.2 | 4.33 |
alkylating reagent: 2,2-dimethoxy-2-methyl-2-butanol.
alkylating reagent: 2-chloro-2-methylbutyne, two-step reaction.
alkylating reagent: 2-methyl-3-butyn-2-ol, two-step reaction.
not available in the reference.
Next, different substances containing a phenolic ring were reacted with 4,4-dimethoxy-2-methyl-2-butanol under the optimized MW conditions. The results are listed in Table 3. Most reactions generated two new products, the desired angular a-product and an undesired linear b-product, plus differing amounts of recovered starting materials. The exceptions were entries 3 and 5 (Table 3), in which only the desired a-products were observed by TLC and MS. In all cases, the desired angular a-products were predominant compared with the undesired linear b-products, implying that the MW reaction conditions are efficient and applicable to the synthesis of diverse dimethylchromene-related products. The a- and b-products could be separated by silica gel chromatography and identified by NMR spectroscopy.
Table 3.
| Entry | Starting Material | Angular product a | Linear product b | Yield of a | Yield of b |
|---|---|---|---|---|---|
| 1 |
|
|
|
57.4 | 7.32 |
| 2 |
|
|
|
66.4 | 9.54 |
| 3 |
|
|
|
72.6 | N/A |
| 4 |
|
|
|
63.5 | 2.65 |
| 5 |
|
|
|
40.3 | N/A |
| 6 |
|
|
|
31.6 | 5.47 |
| 7 |
|
|
|
55.7 | 4.08 |
| 8 |
|
|
|
38.9 | 27.2 |
| 9 |
|
|
|
42.6 | 17.4 |
| 10 |
|
|
|
38.1 | 7.05 |
| 11 |
|
|
|
36.2 | 4.33 |
Adding a methyl or ethyl group at the 6-position of 1-(2,4-dihydroxyphenyl)ethanone (Table 3, entries 1–3) generated better yields of the desired products [57.4% 15a (6-H), 66.4% 16a (6-CH3), 72.6% 17a (6-CH2CH3). Although the yield of the undesired 16b was slightly higher than that of 15b, interestingly, the undesired 17b was not detected under the applied reaction conditions. With approximately 25% of the starting material 6 recovered, this result suggested a stereo-favorable cyclization toward the 3-position. With 1-(2,4-dihydroxyphenyl)propan-1-one (7) as starting material (Table 3, entry 4), the desired 18a was obtained in 63.5% yield, which was 6% higher than the yield of 15a from 1-(2,4-dihydroxyphenyl)ethanone (4) (Table 3, entry 1). In addition, the undesired 18b was obtained in 5% lower yield than the undesired product 15b, leading to a much higher ratio of desired/undesired product. Both bi- (8, 9) or tri-cyclic (10–13) compounds (Table 3, entries 5-10) were also treated with 4,4-dimethoxy-2-methyl-2-butanol under the established MW reaction conditions. The yields of the desired a-products were generally lower (31.6–55.7%, Table 3, entries 5–11) relative to those obtained with single ring reactants (57.4–72.6%, Table 3, entries 1–4). However, they were much higher than those obtained with conventional reaction conditions utilizing the same alkylating reagent. For example, the yields of the desired products 19a, 20a, and 21a were only 13.5%, 23.9%, and 4.34%, respectively, with conventional synthesis but 40.3%, 31.6%, and 55.7% with MW synthesis (Table 4). Unexpectedly, 19b was not detected under either set of reaction conditions; however, the yields of 19a were not comparably high, and the starting material 8 was mainly recovered. Compound 22a was prepared previously by reaction of 1,3-dihydroxy-xanthen-9-one (11) with 2-chloro-2-methylbutyne. After a two-step reaction sequence, the desired product was obtained in a low yield of 12.5% (Table 4).6 Under the MW conditions, the yield of 22a increased to 38.9%. A substantial quantity of 22b by-product was also obtained (27.2%), suggesting that the meta-hydroxy group may play a role in assisting the formation of the linear b-type compound. Compounds 12 and 13 with a methyl substituent at the 6- or 7-position yielded lower amounts of b-products (23b and 24b) relative to 22b, although the yields of the desired a-products (23a and 24a) were not significantly changed compared with 22a. Compound 25a was synthesized previously from 2-methyl-3-butyn-2-ol through either two- or multiple-step reactions, in a total yield of less than 20% (Table 4).7, 8 Under the optimized MW conditions, we successfully synthesized 25a from 3-hydroxy-10-methylacridin-9(10H)-one (14) in an improved yield of 36.2%.
Discussion and Conclusions
In this research, we were able to successfully utilize a microwave initiation method to synthesize desired angular 2,2-dimethyl-2H-chromenes that are key intermediates in the syntheses of anti-HIV DCP and DCK analogs. Through alkylation and cyclization between an appropriate starting compound and alkylating reagent, a series of desired 2,2-dimethyl-2H-chromene products, including 8,8-dimethyl-8H-pyrano[2,3-f]chromenes, 3,3-dimethyl-pyrano[2,3-c]xanthen-7(3H)-ones, and other products, such as 3,3,12-trimethyl-3H-pyrano[2,3-c]acidin-7(12H)-one, were obtained in a one-pot reaction. Compared to literature reported methods, the newly developed microwave-assisted conditions dramatically shortened the reaction time from 2 days to 4 hours with much higher to comparable yields. Increasing the reaction temperature from 140 to 220 °C and extending the reaction time favored the formation of both a- and b-products; however, with a lower fold increase in the undesired b-product. Although the yields of the desired products are still not ideal, the current optimized MW conditions significantly improve selective synthesis of the desired products in comparison to literature reports with conventional heating conditions.
We also analyzed the factors that might affect yield and regioselectivity in this reaction. Reaction yield and regioselectivity were influenced by electronic effects on the phenolic ring. Electron-donating groups, such as alkyl groups at the 6-postion of 1-(2,4-dihydroxyphenyl)ethanone, should increase the electron density at the 3-position, which consequently enhanced alkylation reactivity at this position and relative percentage of the desired a-product. In contrast, a lone electron-pair on a hydroxy group introduced at the 1-position of xanthenone (Table 3, entries 8-10) results in higher electron density at the 2-position and, therefore, reduced the regioselectivity between a- and b-products. In addition, steric effects of ring substituents may also play a role in the alkylation and cyclization. Introducing an ethyl group at the 6-postion (6, Table 3, entry 3) blocked alkylation from occurring at the 5-position, which led exclusively to the desired product 17a.
This study demonstrates a significant advancement because this MW method, under optimized conditions, can be widely utilized with diverse ring systems, including phenone, chromenone, xanthenone, and acridinone. Therefore, this synthetic methodology dramatically broadens the possibility of efficiently exploring structurally diverse DCK and DCP analogs as novel anti-HIV agents. This work is currently ongoing in the authors’ laboratories, and the results will be reported shortly.
Acknowledgement
This investigation was supported by grant AI 33066 from the National Institute of Allergy and Infectious Disease (NIAID) awarded to K. H. Lee.
Footnotes
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References and notes
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- 9.Sample procedure for microwave-assisted synthesis of 2,2-dimethyl-2H-Chromones. Synthesis of 16a and 16b (Table 3, entry 2): 2',4'-Dihydroxy-6'-methyl-acetophenone (5) (200.0 mg, 1.20 mmol), 4,4-dimethoxy-2-methyl-2-butanol (0.37 mL, 2.40 mmoL), and anhydrous pyridine (2 mL) were added into 2–5 mL microwave vial and sealed. After pre-stirring for 20 sec, the reaction temperature was increased to 220 °C for 4 h under high microwave absorption condition. At completion, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed separately with aqueous HCl (10%) and brine. The organic layer was collected, and the solvent was removed under vacuum. The residue was purified by column chromatography (hexanes:EtOAc = 97:3) to afford 16a in 66.4% yield and 16b in 9.54 % yield. Compound 16a: MS (ESI+) m/z (%) 233 (M++1, 100); 1H NMR (CDCl3, 300 MHz) δ (ppm) 6.69 (1H, d, J = 9.9 Hz, H-4), 6.19 (1H, s, H-8), 5.52 (1H, d, J = 9.9 Hz, H-3), 3.31 (3H, s, COCH3-6), 2.53 (3H, s, CH3-7), 1.43 (6H, s, CH3-2,2). Compound 16b: MS (ESI+) m/z (%) 233 (M++1, 100); 1H NMR (CDCl3, 300 MHz) δ (ppm) 6.52 (1H, d, J = 10.2 Hz, H-4), 6.27 (1H, s, H-8), 5.65 (1H, d, J = 10.2 Hz, H-3), 2.60 (3H, s, COCH3-6), 2.49 (3H, s, CH3-5), 1.42 (6H, s, CH3-2,2).
- 10.Microwave initiator utilized to synthesize 2H-chromones (15–25) is Biotage Initiator (300 watt).