Design, synthesis, and structure-activity relationship studies of 6<i>H</i>-benzo[<i>b</i>]indeno[1,2-<i>d</i>]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors.
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Abstract
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Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors†
Abstract
A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i–k (IC50 = 35–116 nM) and the 5-methoxy derivative 4e (IC50 = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k. In addition, the most active compound 4k, having an ATP-competitive mechanism of action, proved to be also a potent inhibitor of CLK1/CLK4 (IC50 = 20 and 26 nM) and, to a lesser extent, of haspin (IC50 = 76 nM) kinases. In silico docking studies within the DYRK1A, CLK1/CLK4 and haspin ATP binding sites were carried out to understand the interactions of our tetracyclic derivatives 4 with these targets. Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a–m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.
Introduction
Since the approval of imatinib in 20011 and the clinical successes of this first rationally-designed kinase inhibitor (KI) for the treatment of chronic myelogenous leukemia2 and gastrointestinal stromal tumors,3 many KIs have been developed for the treatment of various cancers,4 also addressing the problems of selectivity and resistance phenomena to KI treatments.5 To date, more than 70 KIs have been clinically approved in the U.S.,6 with different mechanisms of action, mainly targeting the ATP binding site (with few molecules acting as allosteric modulators). Currently, the main applications of KIs focus on oncology,5 which remains one of the most challenging public health issues and a leading cause of death for the World population.7
In this context, the search for new therapeutic/druggable protein kinase targets remains a tremendous area of research and KIs were also developed by industrial and academic research groups for potential applications not only in cancer but also in infectious diseases,8–13 auto-immune pathologies such as multiple sclerosis,14 Parkinson's15,16 and Alzheimer's diseases.17,18 More specifically, the dual-specificity tyrosine regulated kinase 1A (DYRK1A) has gained considerable attention due to its involvement in numerous diseases19 such as diabetes,20,21 viral infections22,23 and central nervous disorders like Down syndrome and Alzheimer's disease.24–26
Many DYRK1A inhibitors, both from natural and synthetic origins, were developed,27,28 such as harmine, INDY, its acetylated prodrug Pro-INDY or its methylated derivative 1 (also known as TG003), PST-001,29 7-azaindole DANDY-5a,30 the tetracyclic derivative 231 or leucettinibs, the most advanced and selective DYRK1A inhibitors reported to date.32
While being in some cases very active, some off-target cross-inhibition was sometimes observed for these molecules,33,34 which stimulated the scientific community to develop new chemical entities with enhanced potency and selectivity.
Inspired by the structure of chromeno[3,4-b]indoles 335 (Fig. 2), we planned on synthesizing the original 9-thia-indeno[1,2-a]inden-10-ones 4, after chromene ring contraction to indenone and isoelectronic NH substitution by a sulfur atom. These original structures are also constrained analogs of the corresponding “open form”, benzothiophenyl-acetophenones 5 (Fig. 2), known DYRK1A/CLK1 dual inhibitors, acting as pre-mRNA splicing modulators.36,37
In the work described herein, we wish to report the synthesis and biological evaluations of a series of these new derivatives 4a–m, initially designed to inhibit DYRK1A.
Results and discussion
Chemistry
The syntheses of the target products 4a–m relied on a palladium-catalyzed annulation reaction of precursors 6a–m. These substrates were prepared after oxidation of the corresponding alcohols 7a–m, which were itself obtained using the addition of 2-benzothiophenyl lithium anions from 9a–c onto methoxy ortho-iodobenzaldehydes 8a–e (Fig. 3).
Functionalized benzo[b]thiophenes 9 were prepared by acidic cyclization of diethoxy acetals 10a, b, obtained from corresponding para-thiophenols 11a, b38–41 (Scheme 1) and a subsequent BBr3-mediated demethylation on 9a/silylation sequence for the preparation of silyl derivative 9c (R5 = OTBDMS).42,43
Ortho-Iodobenzaldehydes 8a–e were prepared according to various protocols: electrophilic iodination of meta-methoxy anisaldehyde 12 into 8d44 or pyridinium dichromate PDC (Cornforth reagent) mediated oxidation of ortho-iodobenzyl alcohols 13a–c, e45 into 8a–c, e (Schemes 2 and and3).3). Whereas aldehyde 8a was obtained after PDC/silica oxidation of commercially available 2-iodobenzyl alcohol 13a in 98% yield (Scheme 3), compound 8b was obtained from 3-methoxy 2-iodobenzyl alcohol 13b, first synthesized using a nucleophilic iodination (n-BuLi/I2) on 3-methoxy benzyl alcohol 14 (Scheme 2).46
The other benzylic alcohols were prepared using a two steps sequence:45 diazotation/diazonium iodination on 4- and 6-methoxy anthranilic acids 15a, b, followed by reduction of the benzoic acid functions of 16a, b into an alcohol using BH3, yielding the iodo compounds 13c, e (Scheme 3).
The two key partners were then engaged in the next step: the lithium anion was generated at position 2 of benzo[b]thiophene 9a–c, after deprotonation using n-BuLi at low temperature, and was trapped by ortho-iodobenzaldehydes 8a–e to give carbinols 7a–m in 20–91% yield (Scheme 3). Yield disparities were indeed noticed: although good to very good yields for the preparation of most alcohols were observed, low yields were especially observed when using the ortho,ortho′-disubstituted aldehyde 8e. Steric hindrance resulting from the presence of both iodo and methoxy groups on this electrophile may be responsible for the low 20% and 38% yields (Scheme 4).
The bis(het)arylcarbinols 7 were hereafter oxidized into the corresponding ketones 6 using stoichiometric amounts of manganese dioxide in 67–96% yield (Scheme 5 and Table 1). These substrates 6 then underwent a palladium-catalyzed annulation reaction,47 thus leading to the desired tetracycles 4a–m in good to very good yields (Scheme 5 and ESI† Table S2).
| Entry |
| % inhibitiona,b at 1 μM | IC50 for DYRK1Aa,b in nM | ||
|---|---|---|---|---|---|
| 1 | 4a | R5 = H | R′′ = 10-OMe | DYRK1A <5% | nd |
| DYRK1B <5% | |||||
| 2 | 4b | R5 = H | R′′ = 9-OMe | DYRK1A <5% | nd |
| DYRK1B <5% | |||||
| 3 | 4c | R5 = H | R′′ = 8-OMe | DYRK1A <5% | nd |
| DYRK1B <5% | |||||
| 4 | 4d | R5 = H | R′′ = 7-OMe | DYRK1A 23% | nd |
| DYRK1B 7% | |||||
| 5 | 4e | R5 = OMe | R′′ = H | DYRK1A 91% | 52 |
| DYRK1B 68% | |||||
| 6 | 4f | R5 = OMe | R′′ = 10-OMe | DYRK1A 28% | nd |
| DYRK1B <5% | |||||
| 7 | 4g | R5 = OMe | R′′ = 9-OMe | DYRK1A 25% | nd |
| DYRK1B <5% | |||||
| 8 | 4h | R5 = OMe | R′′ = 8-OMe | DYRK1A <5% | nd |
| DYRK1B <5% | |||||
| 9 | 4i | R5 = OH | R′′ = H | DYRK1A 98% | 105 |
| DYRK1B 89% | |||||
| 10 | 4j | R5 = OH | R′′ = 9-OMe | DYRK1A 99% | 116 |
| DYRK 1B 93% | |||||
| 11 | 4k | R5 = OH | R′′ = 8-OMe | DYRK1A 97% | 35 |
| DYRK1B 78% | |||||
| 12 | 4l | R5 = OH | R′′ = 7-OMe | DYRK1A 93% | 54 |
| DYRK1B 78% | |||||
| 13 | 4m | R5 = F | R′′ = 8-OMe | DYRK1A <5% | nd |
| DYRK1B <5% | |||||
Inhibitory properties towards DYRK1A/DYRK1B and R5/R′′ structure–activity relationship studies
A primary screening of the tetracyclic derivatives 4a–m inhibitory properties was first carried out on DYRK1A, together with its off-target DYRK1B, at a 1 μM concentration, using a radiometric assay with Woodtide substrate peptide.48
As shown above (Table 1), some interesting hits were identified, indicating a sharp structure–activity relationship depending on the molecular diversity brought by R5 (H, OMe, OH and F) and R′′ (H or OMe) substitution on the tetracyclic scaffold.
Low DYRK1A inhibitions were observed with compounds 4a–d, without any substituent on R5 of the benzo[b]thiophene ring (Table 1, entries 1–4).
On the other hand, compounds 4f and 4g bearing methoxy groups on R5 displayed fairly low 25–32% inhibition at 1 μM (Table 1, entries 6 and 7), whereas no inhibition was detected for compound 4h (Table 1, entry 8). Surprisingly, compound 4e exhibited significant 91% DYRK1A inhibition at 1 μM, meaning that the introduction of a methoxy group at this position without any other substitution on the indenone ring could be useful to have a potent inhibitor (IC50 for DYRK1A = 52 nM, Table 1, entry 5). It should be noted that 4e was the sole active derivative without a hydroxy group.
DYRK1A inhibitory activity for hydroxy compounds 4i–l was higher than 90% at 1 μM (Table 1, entries 9–12) and these results encouraged us to determine their IC50s. We were pleased to see that the potencies of compounds 4k and 4l against DYRK1A were quite high (IC50 = 35 and 54 nM, respectively) and, to a lesser extent, that the same tendency was observed for 4i and 4j (IC50 = 105 and 116 nM, respectively). These results demonstrated that higher potencies can be reached by introducing a hydroxyl group at R5 position, in combination with a methoxy group at position 5 of the indenone moiety (Table 1, entry 11). The presence of a phenolic moiety on DYRK1A inhibitors was already reported in the literature49,50 as for example INDY, DANDY-5a (Fig. 1), derivatives 3b (R′ = OH) and 5 (Fig. 2).
A comparison of the “open form” 5c activity (R3 = R4 = H, IC50 (DYRK1A) = 2000 nM, Fig. 2) with its rigidified analog 4i (IC50 (DYRK1A) = 105 nM) showed that constraining the third cycle was a successful strategy to improve DYRK1A inhibition.
Finally, compound 4m was synthesized to explore an isosteric replacement of the hydroxyl by a fluorine atom.51–53 However, 4m displayed a complete lack of activity against DYRK1A (Table 1, entry 13).
For all the compounds 4a–m, residual DYRK1B activity was determined at 1 μM concentration and, across the five most active compounds 4e, i–l (IC50s for DYRK1A ranged from 35 to 116 nM), a marked DYRK1B cross-inhibition was observed (68 to 93%, Table 1, entries 5, 9–12). However, the most potent derivative 4k against DYRK1A was amongst the least active DYRK1B co-inhibitors of this series (78% inhibition at 1 μM, Table 1, entry 11).
ATP competition of 4k was evaluated by measuring residual DYRK1A activity upon treatment with increasing concentrations of ATP, in the presence of a 50 nM concentration of 4k. Inhibition decreases with increasing ATP concentration as shown in ESI† Fig. S1, clearly indicating an ATP-competitive mechanism of action, as described for other literature compounds (Fig. 1).
Kinase selectivity study
In order to evaluate the off-target activity of our lead compound 4k, a complementary kinase profiling was then carried out at a 0.35 μM concentration (Table 2), i.e. 10-fold its IC50. As significant disparities have been noted in the literature between fluorescence resonance energy transfer (FRET)-based and radiometric assays,28 some of the kinase activities were quantified by both techniques, operated by ThermoScientific/Invitrogen and Eurofins/CEREP, respectively.
| Kinase | % inhibition/(IC50 [nM]) | Kinase | % inhibition/(IC50 [nM]) |
|---|---|---|---|
| CDK5/p25 | 8a | EGFR (ErbB1) | 0a |
| CLK1 | 16a (1080a) 93d (20d) | GSK3B (GSK3 beta) | 2a |
| CLK2 | 34a | GSG2 (haspin) | 95b (28b) 88d (76d) |
| CLK3 | 7a | MLCK (MLCK2) | 15c |
| CLK4 | 95c (14c) 91d (26d) | HIPK1 (Myak) | 0a |
| CSNK1D (CK1 delta) | 2a | NTRK2 (TRKB) | 0a |
| CSNK2A1 (CK2 alpha 1) | 2a | PIM1 | 0a |
| STK17A (DRAK1) | 42c | SRPK1 | 6a |
| DYRK1B | 57a (206a) 47d | SRPK2 | 0a |
| DYRK2 | 66c (186c) | STK33 | 8c |
| DYRK3 | 5a |
Using the FRET-based kinase assays (Z'-LYTE™/Adapta® activity assays or LanthaScreen europium kinase binding assay, see Table 2 footnotes), four hits with more than 50% inhibition were observed amongst the 21 selected kinases for our study: CLK4, DYRK1B, DYRK2 and haspin (Table 2).
Cross-inhibition for DYRK1A inhibitors was frequently observed with CLK1 and CLK4;28 hence, the low inhibition of CLK1 by 4k (16% inhibition at 0.35 μM, confirmed by its modest 1080 nM IC50 value) appeared suspicious, prompting us to evaluate the inhibition of this protein kinase, using a radiometric activity assay. This second technique allowed us to demonstrate that compound 4k was in fact a potent CLK1 inhibitor, too, with a very low 20 nM IC50 value.
Our first hypothesis to tentatively explain this difference is that the 6H-benzo[b]indeno[1,2-d]thiophen-6-one scaffold displays intrinsic fluorescent properties that could interfere with the FRET measurements. Nonetheless, as no “warnings flags” indicating such an interference were detected during the “test compound interference” evaluation, we can assume that the marked difference could be attributed by different assay conditions (e.g. protein kinase and substrate concentrations), as previously outlined in the literature.28
For the three other impacted protein kinases (cross-validation was not realized for DYRK2, IC50 = 186 nM), results obtained by FRET techniques were corroborated by the radiometric activity assays.
The inhibitory effect of compound 4k against DYRK1B was proved to be moderate, both determined with Z'-LYTE FRET activity assay (IC50 = 206 nM) and functional radiometric test (47% inhibition of kinase activity at 0.35 μM). Furthermore, compound 4k is a moderate DYRK2 inhibitor but also a strong haspin inhibitor, as attested by both the FRET LanthaScreen Eu binding assay (IC50 = 28 nM) and the activity radiometric evaluation (IC50 = 76 nM). As expected, 4k also strongly inhibits CLK4 in addition to CLK1, with low IC50 values of 14 nM (FRET-based binding assay) and 26 nM (functional radiometric test), respectively (Table 2).
Altogether, the selectivity profiling proved that compound 4k was a mixed DYRK1A/CLK1/CLK4/haspin inhibitor, thus corroborating trends already observed with similar molecular architectures and these DYRK1A off-targets.36,50,54,55 In contrast, none of the other challenging off-targets in the screening panel was significantly inhibited, suggesting a reasonable “group selectivity” for the identified targets.
On the other side, dual/multiple kinase inhibitors could emerge as interesting approaches to cure cancers,56–58 and could involve DYRK/CLK protein kinases59 such as CLK1,60–63 CLK462–64 or the relatively underexplored but promising haspin kinase.65
Given that DYRK1A was previously identified as a promising target for a potential glioblastoma treatment,49,66–69 we have chosen to evaluate some of our most potent compounds on these specific cell lines.
Antiproliferative effects on glioblastoma cells
The cellular effects of the most potent inhibitor 4k were determined by measuring growth inhibition following treatment with this compound in comparison to the less active derivative 4i and the reference compound harmine.70 Dose–response curves allowed us to determine the IC50 on the two cell lines U37367,68 and U8768,70–73 (see ESI†), as DYRK1A proved to play a crucial role for cell proliferation and invasion of glioblastoma cells.49,69,71,73
These studies showed that compound 4i (DYRK1A IC50 = 105 nM) had no significant effect on cell proliferation towards both glioblastoma cell lines U373 and U87 (Table 3, entry 1) whereas our most potent inhibitor 4k (DYRK1A IC50 = 35 nM) exhibited a moderate anti-proliferative activity (Table 3, entry 2). Harmine also showed a moderate activity in both cell lines as well (Table 3, entry 3).
| Entry | Compound | U373a | U87a |
|---|---|---|---|
| 1 | 4i | >100 μM | >100 μM |
| 2 | 4k | 32.8 ± 5.0 μMb | 45.9 ± 3.8 μMb |
| 3 | Harmine | 19.6 ± 4.7 μMc | 16.0 ± 5.1 μMc |
Harmine has a similar kinase selectivity profile as our compound 4k, and their effects on U87 and U373 cell lines growth require further exploration to discern whether they are mainly caused by DYRK1A inhibition alone or by cross-inhibition of DYRK1A, CLK1, CLK4, and haspin.
Microsomal stability
In order to evaluate the potential druggability of this new family of DYRK/CLK/haspin inhibitors, we assessed their in vitro stability using rat liver microsomes (Table 4).
| Entry | Compound | t½ (min) | CLint (μL min−1 mg−1) |
|---|---|---|---|
| 1 | 4a | 6.5 ± 0.5 | 355.5 ± 26.2 |
| 2 | 4b | 33.7 ± 2.8 | 68.8 ± 5.7 |
| 3 | 4c | 24.4 ± 0.8 | 94.8 ± 3.0 |
| 4 | 4d | <5.0 | >500 |
| 5 | 4e | 21.7 ± 1.1 | 106.5 ± 5.2 |
| 6 | 4f | <5.0 | >500 |
| 7 | 4g | 25.3 ± 3.0 | 92.4 ± 10.8 |
| 8 | 4h | 18.9 ± 0.5 | 122.0 ± 2.9 |
| 9 | 4i | <5.0 | >500 |
| 10 | 4j | —a | —a |
| 11 | 4k | <5.0 | >500 |
| 12 | 4l | <5.0 | >500 |
| 13 | 4m | 16.8 ± 1.2 | 93.9 ± 32.7 |
One can observe that 7- and 10-methoxy derivatives of 6H-benzo[b]indeno[1,2-d]thiophen-6-one scaffold are rapidly metabolized as shown with 4a, 4d, 4f and 4l. 2-Hydroxy substitutions (4i–l) showed poor stability with fast conversion in our assay system whereas their methoxy equivalents were less sensitive to microsomal degradation as for 4e, 4g and 4h, except for 4d and 4l, bearing methoxy in 7- or 10-positions. Introduction of a 2-fluoro substituent (4m) did not improve stability against microsomal digestion. Interestingly, 4j was rapidly degraded to 50% of its initial amount then plateaued for the rest of the assay, suggesting an inhibitory mechanism by 4j (or its metabolite) against microsomes.
Docking studies
To gain insights into the binding mode of the synthesized compounds, molecular docking was performed using one of the described X-ray structures of DYRK1A (PDB ID: 5AIK). Prior to docking, every ligands, cofactors and additional interacting proteins were removed from the structure, and preparation of the protein was done using Molecular Operating Environment (MOE).74 Each tested ligand (4a–m) was prepared for docking using MOE. Docking was performed using HERMES-GOLD.75
The DYRK1A surfaces were generated and a superposition of the docking results for all the synthesized compounds 4a–m was established (Fig. S2†). The comparison between all compounds showed significant positional homology, with the exception of compound 4b, which was flipped compared to the others (Fig. S2 and S3†).
A comparative study of the interaction modes of the five best ligands was carried out (Fig. 4). From these results, four protein residues were identified as stabilizing the ligand–protein complex, namely: Ile165, Glu203, Glu239 and Leu241. These similarities are consistent with the observed biological activities of the prepared compounds. The interactions between the molecular tetracyclic scaffolds with Glu239 and Leu241 are the most preserved over all structures. The carbonyl group is engaged with Leu241 by a strong H-bond, and the sulfur atom connects with the Glu239 backbone oxygen through a sigma* interaction. Surprisingly, the usual observed H-bonding with Lys18876,77 in DYRK1A was not observed with compounds 4a–m. This could be explained by the tandem sulfur–carbonyl sigma* and carbonyl-Leu214-NH strong interactions. For some of the structures bearing a hydroxyl group on the benzothiophene moiety, more interactions can be observed with Glu203 (4i and 4j, Fig. 4B and C). Depending on the position of a methoxy group on the indenone ring, another weak interaction can occasionally be detected with Ile165, as observed with compounds 4j and 4k (Fig. 4C and D). Surprisingly, the most active compound 4k did not show any interaction between the phenol group and Glu203.
Additionally, the best hit 4k was overlaid with known ligands from the literature (harmine, INDY and compound 3a (R′ = OH)) in order to better understand its position in the protein pocket (Fig. 5). The consistency on the heteroatoms' positions showed a similarity in the fitting mode in the protein pocket.
As mentioned above, the most potent compound 4k showed crossed inhibition with three off-target kinases: CLK1, CLK4 and haspin. In order to evaluate similarities of the ligand/protein interactions, compound 4k was docked within the four protein X-ray structures (Fig. 6). Some homologies in the binding mode were established. The H-bond interaction observed with Leu241 in DYRK1A (Fig. 6A) can also be shown with Leu244 in CLK1 (Fig. 6B) and CLK4 (Fig. 6C), and a similar H-bond is present with Gly608 in haspin (Fig. 6D). The sulfur atom sigma* interaction with Glu239 in DYRK1A can also be shown with Glu242 in CLK1 and CLK4, respectively, and with Glu606 for haspin. A similar weak interaction as Ile165 in DYRK1A can also be observed with Leu167 in CLK1 and CLK4. In haspin, two more interactions were identified: 1) a weak interaction of Gly609 with the methoxy group on the indanone side, 2) a H-bond between Lys511 and the hydroxyl group of 4k. The latter could be explained by the smaller distance between Lys188 amino group and 4k phenol moiety (Fig. 6D).
Conclusion
The goal of this study was to modulate the structure of known DYRK1A inhibitors with marked modifications, i.e. a ring contraction and an isosteric NH to S modification, thus leading to original 6H-benzo[b]indeno[1,2-d]thiophen-6-ones 4.
Our pharmacomodulation study also aimed at exploring the molecular diversity on this scaffold: this was achieved by investigating the influence of grafting different moieties such as methoxy/hydroxy/fluorine substitution onto the benzothiophene ring and the presence of a methoxy group on different positions of the indanone part of tetracyclic derivatives 4a–m.
First designed as a DYRK1A inhibitor, the most active compound 4k of this series proved to be a potent multiple CLK1/CLK4/DYRK1A/haspin inhibitor, with interesting IC50 values (20/26/35/76 nM, respectively). Such a cross inhibition was already reported in the literature for DYRK1A inhibitors but was quite surprising, regarding the pronounced structural modifications, compared to the parent scaffolds.
The antiproliferative effects of the most active compound 4k were also evaluated on two different glioblastoma cell lines. Surprisingly and given the broad inhibitory profile of this compound, the observed impact was only moderate.
The docking study of the entire set of molecules 4a–m on DYRK1A crystal structure has provided a very interesting insight into the ligands–protein interactions of the most active derivatives 4e, i–l, demonstrating key interactions between the benzo[b]thiophene ring sulfur atom and the indenone oxygen atom with residues Glu242 and Leu244 respectively. Comparison of docking poses of the most active DYRK1A inhibitor 4k with CLK1, CLK4 and haspin showed similarities of protein ligand interactions for DYRK1A, CLK1 and CLK4 whereas interactions within the haspin ATP pocket relied on different residues.
Lastly, as a preliminary approach to evaluate the druggability of these tetracyclic derivatives, microsomal stability studies have shown the fast degradation of the most active compound 4k, thus impeding its further development in its present form. To overcome this issue, a carbamate78 prodrug of the phenol group79,80 is currently under investigation to increase compound half-life, which could also be relevant for enhancing blood–brain barrier crossing81 or compound targeting,82–85 before considering further in vivo studies.
Experimental section
Chemistry – general
All moisture/air-sensitive reactions were carried out under a positive pressure of argon and with oven-dried glassware. Melting points were measured on a Büchi B-540 melting point apparatus and are uncorrected. Infra-red spectra (IR) were recorded on a Perkin Elmer Spectrum Two apparatus, equipped with an attenuated total reflectance sampling module: absorption bands are reported in cm−1. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on Bruker DRX400 and AV500 Fourier transform spectrometers, using an internal deuterium lock, operating at 400 or 500 MHz. Chemical shifts are reported in parts per million (ppm) relative to internal standards (tetramethylsilane, δH = δC = 0.00; CDCl3, δH = 7.26 and δC = 77.16; DMSO-d6, δH = 2.50 and δC = 39.52; acetone-d6, δH = 2.05 and δC = 29.84).86 Data are presented as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet t = triplet, q = quadruplet, dd = doublet of doublet, m = multiplet, br = broad), coupling constant, integration. Atom numbering refers to benzo[b]thiophene or aromatic compounds nomenclature.
Agilent UHPLC/MS consists of a 1290 Infinity system with a binary pump, degasser, autosampler, thermostated column compartment, 1260 diode array detector and 6120 single quadrupole mass spectrometer. The entire system was controlled by Chemstation software (Agilent Technologies). The column was an Agilent Poroshell 120 SB-C18, 2.7 μm, 2.1 × 50 mm. The samples were analysed in the positive ion mode of the electro spray ionisation (ESI) source, whose conditions were as follow: gas temperature, 350 °C, drying gas at 12.0 l min−1, nebulizer gas at 35 psig, Vcap at 3000 V, fragmentor at 60 V.
High-resolution mass spectra were recorded on a Bruker QTOF Impact II mass spectrometer (ESI mode).
Reactions were monitored with analytical thin layer chromatography (TLC), which was carried out using Merck commercial aluminium sheets coated (0.2 mm layer thickness) with Kieselgel 60 F254, with visualization by ultraviolet and acidic anisaldehyde staining solution. Proportions of solvents used for TLC are by volume. Product purification by flash column chromatography was performed using Merck Kieselgel 60 Å (40–63 mm) or using pre-packed silica gel columns. Proportions of solvents used for column chromatography are by volume. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) (Acroseal®, over molecular sieves) were purchased from Acros Organics. For extraction/purification, diethyl ether, dichloromethane (DCM), cyclohexane and ethyl acetate (AcOEt) were of reagent grade. All other chemical reagents were used as received. Commercial n-BuLi solutions in hexanes were titrated using N-benzylbenzamide.87
5-Methoxybenzo[b]thiophene 9a,38,39 5-fluorobenzo[b]thiophene 9b,40,41 (benzo[b]thiophen-5-yloxy)-tert-butyl-dimethyl-silane 9c,42,43 (2-iodo-3-methoxyphenyl)methanol 13b,46 (2-iodo-4-methoxyphenyl) methanol 13c,88 (2-iodo-6-methoxyphenyl) methanol 13e45 and 2-iodo-5-methoxybenzaldehyde 8d44 were prepared according to literature procedures.
Synthetic procedures
Preparation of aldehydes 8a–c,e45
The 2-iodobenzyl alcohol was dissolved in dichloromethane (0.2 M) with silica gel (1 g mmol−1). The slurry was stirred at rt followed by the addition of PDC (2 equiv.). The reaction was stirred until the starting material was consumed by TLC typically 6 h. The crude was filtered through a silica gel pad, washing with ethyl acetate. The crude aldehyde was purified if required by flash column chromatography using ethyl acetate and cyclohexane.
2-Iodobenzaldehyde 8a
Scale: 2-iodobenzylic alcohol 13a (0.998 g, 4.27 mmol), silica (4.285 g), PDC (3.232 g, 8.60 mmol). Compound 8a (0.973 g, 98%) was obtained as a pale yellow solid and was used without further purification.
Spectral data were identical to those reported in the literature.89
2-Iodo-3-methoxybenzaldehyde 8b
Scale: (2-iodo-3-methoxyphenyl)methanol 13b (1.423 g, 5.39 mmol), silica (5.400 g), PDC (4.063 g, 10.80 mmol). The residue was purified by flash chromatography (20% of EtOAc in cyclohexane) to afford compound 8b as a white solid (1.070 g, 76%).
Spectral data were identical to those reported in the literature.90
2-Iodo-4-methoxybenzaldehyde 8c
Scale: (2-iodo-4-methoxyphenyl) methanol 13c (1.711 g, 6.48 mmol), silica (6.520 g), PDC (4.879 g, 12.97 mmol). The residue was purified by flash chromatography (20% of EtOAc in cyclohexane) to afford compound 8c as a white solid (1.512 g, 89%).
Spectral data were identical to those reported in the literature.91
2-Iodo-6-methoxybenzaldehyde 8e
Scale: (2-iodo-6-methoxyphenyl) methanol 13e (1.240 g, 4.70 mmol), silica (4.200 g), PDC (3.136 g, 8.34 mmol). The residue was purified by flash chromatography (20% of EtOAc in cyclohexane) to afford compound 8e as a white solid (0.750 g, 61%).
Spectral data were identical to those reported in the literature.45
General procedure A for the preparation of alcohols 7 using n-butyl lithium 2-deprotonation of benzo[b]thiophene 9 and subsequent electrophile addition of ortho-iodoaldehydes 8
To a solution of benzo[b]thiophene 9 (1.60 mmol) in THF (5 mL) under an argon atmosphere at – 78 °C was added dropwise n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol). The mixture was stirred at −78 °C for 1 h. A solution of 2-iodobenzaldehyde 8 (1.95 mmol) in THF (7 mL) was added then added dropwise. The stirring of the mixture was continued at – 78 °C for 1 h and at room temperature for 4 h. Subsequently, the mixture was quenched with brine (20 mL) and ethyl acetate (20 mL) was then added. After decantation, the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown residue. The crude product was purified by flash chromatography (gradient of EtOAc in cyclohexane) to afford the desired alcohol 7.
Benzo[b]thiophen-2-yl(2-iodo-3-methoxy phenyl)methanol 7a
According to general procedure A, scale: benzo[b]thiophene (0.205 g, 1.53 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodo-3-methoxybenzaldehyde (0.515 g, 1.96 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7a as a white solid (0.452 g, 75%), m.p. 48.0–49.2 °C. IR: 3532, 3357, 3057, 3002, 2962, 2936, 2835, 2329, 1699, 1585, 1566, 1463, 1425, 1365, 1333, 1262, 1184, 1155, 1105, 1088, 1068, 1009, 936, 893, 859, 834, 793, 767, 745, 725, 668, 657, 590, 553, 480. 1H NMR (400 MHz, acetone-d6) δ = 7.86–7.81 (m, 1H), 7.75–7.71 (m, 1H), 7.43–7.37 (m, 2H), 7.33–7.26 (m, 2H), 7.18 (s, 1H), 6.95 (dd, J = 7.1, 2.4 Hz, 1H), 6.45 (dd, J = 4.6, 1.1 Hz, 1H), 5.52 (d, J = 4.6 Hz, 1H), 3.90 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 158.68(C), 149.82(C), 148.68(C), 140.61(C), 140.47(C), 130.34(CH), 124.97(CH), 124.90(CH), 124.32(CH), 123.05(CH), 122.15(CH), 121.17(CH), 111.16(CH), 90.97(C), 76.45(CH), 56.92(CH3). LC/MS (retention time 4.21 min) m/z (ESI+) 379.00 (MH+–H2O, 100%), 418.90 (MNa+, 20.7%). HRMS (ESI+): m/z calcd for C16H12IOS+ [MH+–H2O]: 378.9648; found: 378.9648.
Benzo[b]thiophen-2-yl(2-iodo-4-methoxy phenyl)methanol 7b
According to general procedure A, scale: benzo[b]thiophene (0.203 g, 1.51 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodo-4-methoxybenzaldehyde (0.517 g, 1.97 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7b as a yellow oil (0.442 g, 74%). IR: 3376, 3055, 3002, 2959, 2936, 2894, 2834, 1702, 1594, 1562, 1484, 1457, 1436, 1395, 1363, 1305, 1282, 1228, 1179, 1154, 117, 1091, 1065, 1026, 1015, 938, 852, 343, 784, 745, 726, 708, 667, 591, 552, 529, 482. 1H NMR (400 MHz, acetone-d6) δ = 7.84 (ddt, J = 7.0, 1.6, 0.9 Hz, 1H), 7.77–7.71 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.34–7.26 (m, 2H), 7.17 (t, J = 1.0 Hz, 1H), 7.07 (dd, J = 8.7, 2.6 Hz, 1H), 6.25 (d, J = 4.5 Hz, 1H), 5.46 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 160.49(C), 150.40(C), 140.66(C), 140.58(C), 139.01(C), 129.47(CH), 125.03(CH), 124.92(CH), 124.75(CH), 124.36(CH), 123.08(CH), 121.93(CH), 115.60(CH), 98.40(C), 75.82(CH), 55.95(CH3). LC/MS (retention time 4.38 min) m/z (ESI+) 379.00 (MH+–H2O, 100%), 418.90 (MNa+, 17.5%). HRMS (ESI+): m/z calcd for C16H12IOS+ [MH+–H2O]: 378.9648; found: 378.9644.
Benzo[b]thiophen-2-yl(2-iodo-5-methoxy phenyl)methanol 7c
According to general procedure A, scale: benzo[b]thiophene (0.205 g, 1.53 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodo-4-methoxybenzaldehyde (0.511 g, 1.95 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7c as an orange oil (0.410 g, 68%). IR: 3443, 3073, 3049, 2959, 2931, 2850, 2831, 1590, 1564, 1458, 1437, 1411, 1397, 1281, 1271, 1224, 1156, 1115, 1052, 1024, 1001, 929, 881, 865, 836, 808, 791, 745, 726, 666, 633, 588, 556, 518, 457. 1H NMR (400 MHz, acetone-d6) δ = 7.85 (dd, J = 6.4, 2.1 Hz, 1H), 7.75 (dd, J = 8.8, 3.0 Hz, 2H), 7.39 (d, J = 3.1 Hz, 1H), 7.34–7.22 (m, 2H), 7.19 (s, 1H), 6.75 (dd, J = 8.7, 3.1 Hz, 1H), 6.23 (d, J = 4.5 Hz, 1H), 5.56 (d, J = 4.6 Hz, 1H), 3.81 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 161.43(C), 149.44(C), 147.90(C), 140.70(C), 140.66(CH), 140.49(C), 125.06(CH), 125.03(CH), 124.44(CH), 123.10(CH), 122.40(CH), 116.69(CH), 114.78(CH), 86.42(C), 76.09(CH), 55.77(CH3). LC/MS (retention time 4.38 min) m/z (ESI+) 379.00 (MH+–H2O, 100%), 418.90 (MNa+, 10.8%). HRMS (ESI+): m/z calcd for C16H12IOS+ [MH+–H2O]: 378.9648; found: 378.9645.
Benzo[b]thiophen-2-yl(2-iodo-6-methoxy phenyl)methanol 7d
According to general procedure A, scale: benzo[b]thiophene (0.137 g, 1.02 mmol), n-BuLi 2.5 M in hexanes (0.48 mL, 1.20 mmol), 2-iodo-6-methoxybenzaldehyde (0.340 g, 1.30 mmol). The residue was purified by flash chromatography (0 to 100% of MeOH in H2O, using a reversed phase C18 column) to afford compound 7d as a white solid (0.153 g, 38%), m.p. 109.8–110.7 °C. IR: 3529, 3095, 3059, 3043, 3013, 2970, 2940, 2922, 2853, 2839, 1582, 1566, 1458, 1432, 1404, 1324, 1296, 1262, 1231, 1194, 1176, 1154, 1140, 1098, 1083, 1011, 935, 889, 862, 845, 831, 788, 772, 744, 728, 706, 677, 657, 585, 556, 506, 462. 1H NMR (400 MHz, acetone-d6) δ 7.87–7.83 (m, 1H), 7.71 (dd, J = 6.7, 2.1 Hz, 1H), 7.57 (dd, J = 7.7, 1.2 Hz, 1H), 7.30 (ddd, J = 7.2, 5.2, 1.6 Hz, 2H), 7.13 (dd, J = 16.4, 7.6 Hz, 2H), 7.02 (s, 1H), 6.42–6.36 (m, 1H), 5.09 (d, J = 10.7 Hz, 1H), 3.82 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 158.95(C), 150.19(C), 140.85(C), 140.54(C), 133.71(C), 133.09(CH), 131.67(CH), 124.97(CH), 124.69(CH), 124.15(CH), 123.00(CH), 120.59(CH), 113.39(CH), 99.89(C), 77.99(CH), 56.35(CH3). LC/MS (retention time 4.52 min) m/z (ESI+) 379.00 (MH+–H2O, 100%), 419.00 (MNa+, 16.6%). HRMS (ESI+): m/z calcd for C16H12IOS+ [MH+–H2O]: 378.9648; found: 378.9643.
(2-Iodophenyl)(5-methoxy benzo[b]thiophen-2-yl)methanol 7e
According to general procedure A, scale: 5-methoxy benzo[b]thiophene (0.246 g, 1.50 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodobenzaldehyde (0.454 g, 1.96 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7e as a yellow oil (0.523 g, 88%). IR: 3527, 3387, 3059, 2999, 2948, 2935, 2902, 2830, 1700, 1600, 1584, 1533, 1456, 1434, 1363, 1331, 1298, 1279, 1216, 1151, 1113, 1069, 1047, 1021, 1007, 943, 855, 832, 802, 746, 730, 718, 668, 649, 619, 597, 561, 537, 492. 1H NMR (400 MHz, acetone-d6) δ = 7.88 (dd, J = 7.9, 1.1 Hz, 1H), 7.79 (dd, J = 7.8, 1.7 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.51–7.45 (m, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.12 (s, 1H), 7.08 (td, J = 7.6, 1.7 Hz, 1H), 6.94 (dd, J = 8.8, 2.5 Hz, 1H), 6.30 (d, J = 4.3 Hz, 1H), 5.56 (d, J = 4.5 Hz, 1H), 3.81 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 158.47(C), 150.75(C), 146.84(C), 141.52(C), 140.03(CH), 132.82(C), 130.44(CH), 129.47(CH), 129.00(CH), 123.68(CH), 122.22(CH), 115.12(CH), 106.53(CH), 98.37(C), 76.25(CH), 55.66(CH3). LC/MS (retention time 4.28 min) m/z (ESI+) 379.00 (MH+–H2O, 100%), 418.90 (MNa+, 15.5%). HRMS (ESI+): m/z calcd for C16H12IOS+ [MH+–H2O]: 378.9648; found: 378.9646.
(2-Iodo-3-methoxyphenyl)(5-methoxy benzo[b]thiophen-2-yl)methanol 7f
According to general procedure A, scale: 5-methoxybenzo[b]thiophene (0.252 g, 1.53 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodo-3-methoxybenzaldehyde (0.519 g, 1.98 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7f as a white solid (0.392 g, 60%), m.p. 133.0–135.4 °C. IR: 3566, 3530, 3068, 3000, 2970, 2934, 2905, 2834, 1584, 1598, 1564, 1526, 1455, 1428, 1357, 1332, 1284, 1276, 1264, 1246, 1211, 1173, 1116, 1068, 1010, 939, 859, 821, 794, 765, 725, 669, 679, 627, 583. 1H NMR (400 MHz, acetone-d6) δ = 7.69 (d, J = 8.8 Hz, 1H), 7.43–7.36 (m, 2H), 7.26 (d, J = 2.4 Hz, 1H), 7.09 (s, 1H), 6.97–6.90 (m, 2H), 6.42 (dd, J = 4.7, 1.1 Hz, 1H), 5.48 (d, J = 4.6 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 158.67(C), 158.50(C), 150.99(C), 148.75(C), 141.57(C), 132.83(C), 130.31(CH), 123.66(CH), 122.14(CH), 121.18(CH), 115.06(CH), 111.14(CH), 106.52(CH), 90.98(C), 76.50(CH), 56.93(CH3), 55.68(CH3). LC/MS (retention time 4.15 min) m/z (ESI+) 409.00 (MH+–H2O, 100%), 449.00 (MNa+, 30.0%). HRMS (ESI+): m/z calcd for C17H14IO2S+ [MH+–H2O]: 408.9754; found: 408.9752.
(2-Iodo-4-methoxyphenyl)(5-methoxybenzo[b]thiophen-2-yl)methanol 7g
According to general procedure A, scale: 5-methoxybenzo[b]thiophene (0.210 g, 1.28 mmol), n-BuLi 2.5 M in hexanes (0.60 mL, 1.50 mmol), 2-iodo-4-methoxybenzaldehyde (0.428 g, 1.63 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7g as a yellow oil (0.447 g, 82%). IR: 3389, 3062, 3000, 2956, 2936, 2899, 2833, 1703, 1595, 1563, 1534, 1484, 1456, 1436, 1363, 1330, 1281, 1219, 1180, 1151, 1070, 1029, 943, 850, 803, 730, 718, 893, 657, 595, 563, 530. 1H NMR (400 MHz, acetone-d6) δ = 7.69 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.09–7.04 (m, 2H), 6.93 (dd, J = 8.8, 2.5 Hz, 1H), 6.22 (d, J = 4.4 Hz, 1H), 5.42 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H), 3.82 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 160.45(C), 158.55(C), 151.56(C), 141.66(C), 139.07(C), 132.85(C), 129.45(CH), 124.71(CH), 123.70(CH), 121.90(CH), 115.56(CH), 115.05(CH), 106.55(CH), 98.39(C), 75.85(CH), 55.94(CH3), 55.69(CH3). LC/MS (retention time 4.30 min) m/z (ESI+) 409.00 (MH+–H2O, 100%), 449.00 (MNa+, 23.4%). HRMS (ESI+): m/z calcd for C17H14IO2S+ [MH+–H2O]: 408.9754; found: 408.9749.
(2-Iodo-5-methoxyphenyl)(5-methoxy benzo[b]thiophen-2-yl) methanol 7h
According to general procedure A, scale: 5-methoxybenzo[b]thiophene (0.247 g, 1.50 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodo-5-methoxybenzaldehyde (0.510 g, 1.95 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7h as a yellow oil (0.582 g, 91%). IR: 3428, 3062, 3001, 2973, 2935, 2910, 2883, 2832, 1599, 1584, 1564, 1532, 1456, 1447, 1406, 1370, 1331, 1294, 1278, 1263, 1240, 1204, 1150, 1137, 1111, 1069, 1045, 1019, 997, 943, 935, 924, 890, 859, 811, 802, 778, 756, 721, 697, 664, 631, 621, 590, 568, 521, 454. 1H NMR (400 MHz, acetone-d6) δ = 7.74 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.11 (s, 1H), 6.94 (dd, J = 8.8, 2.5 Hz, 1H), 6.74 (dd, J = 8.7, 3.1 Hz, 1H), 6.21 (d, J = 4.1 Hz, 1H), 5.53 (d, J = 4.6 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 161.42(C), 158.57(C), 150.61(C), 147.97(C), 141.58(C), 140.62(CH), 132.90(C), 123.72(CH), 122.38(CH), 116.66(CH), 115.21(CH), 114.77(CH), 106.60(CH), 86.43(C), 76.13(CH), 55.77 (CH3), 55.69(CH3). LC/MS (retention time 4.31 min) m/z (ESI+) 409.00 (MH+–H2O, 100%), 449.00 (MNa+, 32.4%), 450.10 (7.8), 451.00 (2.6). HRMS (ESI+): m/z calcd for C17H14IO2S+ [MH+–H2O]: 408.9754; found: 408.9751.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodophenyl) methanol 7i
According to general procedure A, scale: (benzo[b]thiophen-5-yloxy)(tert-butyl)dimethylsilane (0.400 g, 1.51 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodobenzaldehyde (0.452 g, 1.95 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7i as a yellow oil (0.481 g, 64%). IR: 3436, 3054, 2962, 2929, 2880, 2858, 1594, 1566, 1535, 1463, 1444, 1390, 1364, 1342, 1311, 1288, 1257, 1207, 1143, 1113, 1092, 1066, 1049, 1008, 959, 939, 870, 853, 835, 811, 784, 745, 730, 720, 701, 680, 676, 659, 637, 623, 605, 590, 560, 543, 485. 1H NMR (400 MHz, acetone-d6) δ = 7.88 (dd, J = 7.9, 1.1 Hz, 1H), 7.77 (dd, J = 7.8, 1.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.48 (td, J = 7.5, 1.0 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.11–7.07 (m, 2H), 6.90 (dd, J = 8.6, 2.4 Hz, 1H), 6.27 (d, J = 4.5 Hz, 1H), 5.53 (d, J = 4.5 Hz, 1H), 1.00 (s, 9H), 0.22 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 153.96(C), 150.94(C), 146.92(C), 141.81(C), 140.10(CH), 133.83(C), 130.51(CH), 129.54(CH), 129.09(CH), 123.76(CH), 122.02(CH), 119.32(CH), 114.35(CH), 98.36(C), 76.32(CH), 26.07(CH3), 18.79(C), −4.32(CH3). LC/MS (retention time 5.89 min) m/z (ESI+) 479.10 (MH+–H2O, 100%). HRMS (ESI+): m/z calcd for C21H24IOSSi+ [MH+–H2O]: 479.0356; found: 479.0347.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-4-methoxyphenyl)methanol 7j
According to general procedure A, scale: (benzo[b]thiophen-5-yloxy)(tert-butyl)dimethylsilane (0.322 g, 1.22 mmol), n-BuLi 2.5 M in hexanes (0.60 mL, 1.50 mmol), 2-iodo-4-methoxybenzaldehyde (0.421 g, 1.60 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7j as a yellow oil (0.581 g, 91%). IR: 3386, 2954, 2929, 2893, 2856, 1705, 1595, 1563, 1531, 1486, 1471, 1462, 1445, 1390, 1361, 1313, 1282, 1254, 1226, 1181, 1151, 1093, 1068, 1027, 1013, 967, 939, 855, 837, 800, 779, 737, 720, 674, 591, 563. 1H NMR (400 MHz, acetone-d6) δ = 7.69 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.09–7.04 (m, 2H), 6.89 (dd, J = 8.6, 2.4 Hz, 1H), 6.22 (d, J = 4.4 Hz, 1H), 5.41 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H), 1.00 (s, 9H), 0.22 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 160.47(C), 153.94(C), 151.68(C), 141.88(C), 139.05(C), 133.82(C), 129.48(CH), 124.71(CH), 123.74(CH), 121.68(CH), 119.22(CH), 115.60(CH), 114.31(CH), 98.39(C), 75.87(CH), 55.95(CH3), 26.07(CH3), 18.79 (C), −4.31 (CH3). LC/MS (retention time 5.86 min) m/z (ESI+) 509.10 (MH+–H2O, 100%). HRMS (ESI+): m/z calcd for C22H26IO2SSi+ [MH+–H2O]: 509.0462; found: 509.0461.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanol 7k
According to general procedure A, scale: (benzo[b]thiophen-5-yloxy)(tert-butyl)dimethylsilane (0.404 g, 1.52 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodo-5-methoxybenzaldehyde (0.513 g, 1.95 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7k as a yellow oil (0.434 g, 54%). IR: 3418, 3054, 3002, 2954, 2928, 2884, 2856, 1704, 1595, 1567, 1532, 1463, 1445, 1414, 1362, 1312, 1287, 1255, 1226, 1148, 1114, 1068, 1047, 1034, 1003, 967, 939, 873, 837, 804, 780, 740, 720, 677, 635, 587, 521, 486. 1H NMR (400 MHz, acetone-d6) δ = 7.74 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.09 (s, 1H), 6.90 (dd, J = 8.6, 2.4 Hz, 1H), 6.74 (dd, J = 8.7, 3.2 Hz, 1H), 6.20 (dd, J = 4.6, 1.2 Hz, 1H), 5.52 (d, J = 4.6 Hz, 1H), 3.81 (s, 3H), 1.00 (s, 9H), 0.22 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 161.42(C), 153.96(C), 150.70(C), 147.93(C), 141.80(C), 140.62(CH), 133.85(C), 123.77(CH), 122.15(CH), 119.35(CH), 116.66(CH), 114.79(CH), 114.37(CH), 86.42(C), 76.14(CH), 55.77(CH3), 26.07(CH3), 18.79 (C), −4.31 (CH3). LC/MS (retention time 5.87 min) m/z (ESI+) 509.10 (MH+–H2O, 100%), 549.10 (MNa+, 6.3%). HRMS (ESI+): m/z calcd for C22H26IO2SSi+ [MH+–H2O]: 509.0462; found: 509.0462.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-6-methoxyphenyl)methanol 7l
According to general procedure A, scale: (benzo[b]thiophen-5-yloxy)(tert-butyl)dimethylsilane (0.271 g, 1.03 mmol), n-BuLi 2.5 M in hexanes (0.45 mL, 1.13 mmol), 2-iodo-6-methoxybenzaldehyde (0.343 g, 1.31 mmol). The residue was purified by flash chromatography (0 to 100% of MeOH in H2O, using a reversed phase C18 column) afford compound 7l as a white solid (0.110 g, 20%), m.p. 124.6–125.6 °C. IR: 3533, 3097, 3054, 3008, 2958, 2917, 2852, 1595, 1567, 1535, 1445, 1432, 1408, 1362, 1326, 1310, 1290, 1256, 1219, 1176, 1153, 1139, 1099, 1082, 1068, 1012, 965, 938, 867, 832, 818, 787, 760, 735, 729, 713, 678, 659, 636, 613, 588, 563, 538, 512, 459. 1H NMR (400 MHz, acetone-d6) δ = 7.69 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 7.7, 1.3 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 8.3, 1.2 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.92 (dd, J = 1.3, 0.6 Hz, 1H), 6.88 (dd, J = 8.6, 2.4 Hz, 1H), 6.34 (s, 1H), 5.05 (s, 1H), 3.83 (s, 3H), 1.00 (s, 9H), 0.22 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 158.97(C), 153.92(C), 151.46(C), 142.17(C), 133.73(C), 133.71(C), 133.11(CH), 131.65(CH), 123.66(CH), 120.42(CH), 118.97(CH), 114.13(CH), 113.42(CH), 99.90(C), 78.11(CH), 56.38(CH3), 26.08(CH3), 18.79 (C), −4.30 (CH3). LC/MS (retention time 6.03 min) m/z (ESI+) 509.10 (MH+–H2O, 100%), 549.10 (MNa+, 8.2%). HRMS (ESI+): m/z calcd for C22H26IO2SSi+ [MH+–H2O]: 509.0462; found: 509.0456.
(5-Fluorobenzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanol 7m
According to general procedure A, scale: 5-fluoro benzo[b]thiophene (0.229 g, 1.50 mmol), n-BuLi 2.5 M in hexanes (0.72 mL, 1.80 mmol), 2-iodo-5-methoxybenzaldehyde (0.511 g, 1.95 mmol). The residue was purified by flash chromatography (0 to 30% of EtOAc in cyclohexane) to afford compound 7m as a yellow oil (0.317 g, 51%). IR: 3385, 3068, 3000, 2959, 2935, 2905, 2835, 1702, 1589, 1567, 1535, 1464, 1442, 1413, 1401, 1286, 1228, 1201, 1163, 1140, 1125, 1043, 1002, 954, 864, 798, 772, 746, 716, 687, 660, 628, 566, 521, 469. 1H NMR (400 MHz, acetone-d6) δ = 7.87 (dd, J = 8.8, 4.9 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 9.8, 2.5 Hz, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.20 (s, 1H), 7.13 (td, J = 9.0, 2.6 Hz, 1H), 6.76 (dd, J = 8.7, 3.1 Hz, 1H), 6.25–6.21 (m, 1H), 5.63 (d, J = 4.6 Hz, 1H), 3.81 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 161.65(C, d, J = 240.4 Hz), 161.46(C), 152.46(C), 147.74(C), 141.62(C, d, J = 10.1 Hz), 140.71(CH), 136.27(C), 124.65(CH, d, J = 9.1 Hz), 122.13(CH, d, J = 4.1 Hz), 116.78(CH), 114.79(CH), 113.51(CH, d, J = 25.3 Hz), 109.72(CH, d, J = 23.2 Hz), 86.37(C), 76.06(CH), 55.78(CH3). 19F NMR (376 MHz, acetone-d6) δ = −120.45. LC/MS (retention time 4.45 min) m/z (ESI+) 397.00 (MH+–H2O, 100%), 437.15 (MNa+, 5.3%). HRMS (ESI+): m/z calcd for C16H11FIOS+ [MH+–H2O]: 396.9554; found: 396.9550.
General procedure B for the preparation of ketones 6 by an oxidation reaction of alcohols 7
To a solution of alcohol 7 (0.54 mmol) in ACN (12.5 mL) under an argon atmosphere at room temperature was added MnO2 (0.142 g, 1.63 mmol) and, after a 2 h stirring at rt, a second portion of MnO2 (0.142 g, 1.63 mmol) was added. After stirring for 4 h at room temperature, the reaction mixture was filtered over a pad of silica gel and washed with ACN (2 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (0 to 20% gradient of EtOAc in cyclohexane) to afford the desired ketone 6.
Benzo[b]thiophen-2-yl(2-iodo-3-methoxyphenyl)methanone 6a
According to general procedure B, scale: benzo[b]thiophen-2-yl(2-iodo-3-methoxyphenyl)methanol 7a (0.229 g, 0.58 mmol) and MnO2 (0.304 g, 3.50 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6a as a white solid (0.198 g, 87%), m.p. 121.1–122.3 °C. IR: 3059, 3011, 2943, 2921, 2842, 2328, 1640, 1592, 1562, 1511, 1464, 1417, 1333, 1308, 1262, 1248, 1202, 1184, 1143, 1099, 1049, 1012, 939, 915, 868, 841, 802, 776, 750, 732, 718, 709, 664, 601, 580, 547, 489, 483. 1H NMR (400 MHz, acetone-d6) δ = 8.06 (dq, J = 8.3, 0.9 Hz, 1H), 8.00 (dt, J = 8.0, 1.0 Hz, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.58–7.53 (m, 2H), 7.46 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.18 (dd, J = 8.3, 1.3 Hz, 1H), 7.10 (dd, J = 7.5, 1.3 Hz, 1H), 3.98 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 191.41(C), 159.32(C), 147.21(C), 143.89(C), 143.15(C), 140.13(C), 134.69(CH), 130.77(CH), 128.91(CH), 127.47(CH), 126.15(CH), 123.91(CH), 120.91(CH), 113.01(CH), 84.70(C), 57.09(CH3). LC/MS (retention time 4.56 min) m/z (ESI+) 395.00 (MH+, 100%), 416.90 (MNa+, 18.8%), 810.90 (2MNa+, 21.9%). HRMS (ESI+): m/z calcd for C16H12IO2S+ [MH+]: 394.9597; found: 394.9596.
Benzo[b]thiophen-2-yl(2-iodo-4-methoxyphenyl)methanone 6b
Following general procedure B, scale: benzo[b]thiophen-2-yl(2-iodo-4-methoxyphenyl)methanol 7b (0.313 g, 0.79 mmol) and MnO2 (0.418 g, 4.80 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6b as a colorless oil (0.272 g, 87%). IR: 3261, 3064, 3062, 3046, 2999, 2961, 2935, 2907, 2886, 2830, 2551, 1635, 1591, 1558, 1517, 1481, 1455, 1433, 1424, 1391, 1336, 1313, 1299, 1286, 1266, 1250, 1223, 1183, 1160, 1149, 1121, 1032, 1021, 952, 883, 871, 849, 815, 791, 760, 748, 726, 691, 660, 622, 572, 555, 522, 478. 1H NMR (400 MHz, acetone-d6) δ = 8.06 (dq, J = 8.2, 0.9 Hz, 1H), 8.01 (dt, J = 8.1, 1.1 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.59–7.54 (m, 3H), 7.47 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.15 (dd, J = 8.5, 2.5 Hz, 1H), 3.93 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 190.79(C), 162.19(C), 143.79(C), 143.76(C), 140.13(C), 136.82(C), 134.46(CH), 130.90(CH), 128.79(CH), 127.42(CH), 126.30(CH), 126.12(CH), 123.85(CH), 114.45(CH), 93.69(C), 56.24(CH3). LC/MS (retention time 4.72 min) m/z (ESI+) 395.00 (MH+, 100%), 417.00 (MNa+, 14.7%), 810.90 (2MNa+, 26.7%). HRMS (ESI+): m/z calcd for C16H12IO2S+ [MH+]: 394.9597; found: 394.9595.
Benzo[b]thiophen-2-yl(2-iodo-5-methoxyphenyl)methanone 6c
According to general procedure B, scale: benzo[b]thiophen-2-yl(2-iodo-5-methoxyphenyl)methanol 7c (0.335 g, 0.84 mmol) and MnO2 (0.441 g, 5.07 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6c as a yellow oil (0.302 g, 90%). IR: 3062, 3005, 2937, 2923, 2894, 2850, 2828, 2353, 2328, 1638, 1582, 1567, 1507, 1459, 1426, 1383, 1335, 1321, 1262, 1230, 1172, 1159, 1133, 1100, 1047, 1011, 951, 918, 861, 845, 807, 792, 761, 750, 721, 730, 663, 593, 576, 552, 470. 1H NMR (400 MHz, acetone-d6) δ 8.07 (dd, J = 8.3, 0.9 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 1.0 Hz, 1H), 7.58 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.48 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.18 (d, J = 3.1 Hz, 1H), 6.97 (dd, J = 8.8, 3.1 Hz, 1H), 3.88 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 191.07(C), 160.75(C), 145.93(C), 143.96(C), 143.03(C), 141.35(C), 140.18(CH), 135.09(CH), 129.00(CH), 127.58(CH), 126.20(CH), 123.92(CH), 118.86(CH), 114.99(CH), 80.62(C), 56.12(CH3). LC/MS (retention time 4.75 min) m/z (ESI+) 395.00 (MH+, 100%), 417.00 (MNa+, 20.6%), 810.90 (2MNa+, 26.3%). HRMS (ESI+): m/z calcd for C16H12IO2S+ [MH+]: 394.9597; found: 394.9594.
Benzo[b]thiophen-2-yl(2-iodo-6-methoxyphenyl)methanone 6d
According to general procedure B, scale: benzo[b]thiophen-2-yl(2-iodo-6-methoxyphenyl)methanol 7d (0.115 g, 0.29 mmol) and MnO2 (0.300 g, 3.45 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) afford compound 6d as a colorless oil (0.110 g, 96%). IR: 3288, 3080, 2964, 2937, 2835, 1927, 1646, 1580, 1562, 1512, 1456, 1425, 1360, 1331, 1281, 1258, 1180, 1159, 1147, 1112, 1060, 1022, 945, 910, 878, 840, 817, 777, 748, 721, 697, 671, 605, 581, 552, 530, 491, 477, 458. 1H NMR (400 MHz, acetone-d6) δ = 8.05 (dq, J = 8.2, 0.9 Hz, 1H), 8.00–7.97 (m, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.58–7.54 (m, 2H), 7.48–7.44 (m, 1H), 7.29–7.23 (m, 2H), 3.77 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 190.13(C), 158.27(C), 143.77(C), 143.52(C), 140.20(C), 134.61(C), 133.34(CH), 132.96(CH), 131.85(CH), 128.76(CH), 127.36(CH), 126.10(CH), 123.94(CH), 112.35(CH), 93.12(C), 56.54(CH3). LC/MS (retention time 4.56 min) m/z (ESI+) 395.00 (MH+, 100%), 416.90 (MNa+, 11.5%), 810.90 (2MNa+, 24.1%). HRMS (ESI+): m/z calcd for C16H12IO2S+ [MH+]: 394.9597; found: 394.9601.
(2-Iodophenyl)(5-methoxy benzo[b]thiophen-2-yl)methanone 6e
According to general procedure B, scale: (2-iodophenyl)(5-methoxybenzo[b]thiophen-2-yl)methanol 7e (0.311 g, 0.79 mmol) and MnO2 (0.420 g, 4.83 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6e as a yellow oil (0.256 g, 83%). IR: 3255, 3059, 2962, 2930, 2845, 2826, 2633, 1635, 1598, 1580, 1558, 1511, 1448, 1421, 1341, 1293, 1253, 1220, 1185, 1156, 1124, 1070, 1040, 1023, 943, 878, 854, 836, 809, 773, 745, 715, 681, 660, 636, 593, 555, 487. 1H NMR (400 MHz, acetone-d6) 8.04 (dd, J = 7.9, 1.2 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.64–7.59 (m, 2H), 7.57 (dd, J = 7.6, 1.8 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.39–7.33 (m, 1H), 7.21 (dd, J = 8.9, 2.6 Hz, 1H), 3.85 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 191.30(C), 159.06(C), 145.11(C), 144.02(C), 141.23(C), 140.59(CH), 136.63(C), 134.60(CH), 132.42(CH), 129.11(CH), 128.99(CH), 124.61(CH), 120.10(CH), 108.19(CH), 92.49(C), 55.84(CH3). LC/MS (retention time 4.63 min) m/z (ESI+) 395.00 (MH+, 100%), 416.90 (MNa+, 16.1%), 810.90 (2MNa+, 20.8%). HRMS (ESI+): m/z calcd for C16H12IO2S+ [MH+]: 394.9597; found: 394.9594.
(2-Iodo-3-methoxyphenyl)(5-methoxy benzo[b]thiophen-2-yl)methanone 6f
According to general procedure B, scale: (2-iodo-3-methoxyphenyl) (5-methoxybenzo[b]thiophen-2-yl)methanol 7f (0.242 g, 0.57 mmol) and MnO2 (0.299 g, 3.44 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6f as a yellow solid (0.172 g, 71%), m.p. 129.1–130.6 °C. IR: 3076, 3059, 3008, 2959, 2926, 2839, 2826, 2350, 1632, 1600, 1560, 1515, 1449, 1418, 1341, 1307, 1262, 1223, 1192, 1179, 1160, 1056, 1023, 912, 876, 834, 807, 784, 763, 747, 715, 663, 613, 495. 1H NMR (400 MHz, acetone-d6) δ = 7.92 (dt, J = 8.9, 0.6 Hz, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.55 (dd, J = 8.3, 7.5 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.22–7.16 (m, 2H), 7.08 (dd, J = 7.5, 1.3 Hz, 1H), 3.98 (s, 3H), 3.85 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 191.30(C), 159.31(C), 159.06(C), 147.34(C), 144.05(C), 141.25(C), 136.58(C), 134.36(CH), 130.74(CH), 124.62(CH), 120.88(CH), 119.99(CH), 112.94(CH), 108.18(CH), 84.72(C), 57.09(CH3), 55.83(CH3). LC/MS (retention time 4.54 min) m/z (ESI+) 425.00 (MH+, 100%), 446.80 (MNa+, 15.7%), 870.90 (2MNa+, 24.7%). HRMS (ESI+): m/z calcd for C17H14IO3S+ [MH+]: 424.9703; found: 424.9704.
(2-Iodo-4-methoxyphenyl)(5-methoxy benzo[b]thiophen-2-yl)methanone 6g
According to general procedure B, scale: according to general procedure 2, scale: (2-iodo-4-methoxyphenyl)(5-methoxybenzo[b]thiophen-2-yl)methanol 7g (0.286 g, 0.62 mmol) and MnO2 (0.360, 4.14 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6g as a yellow oil (0.249 g, 95%). IR: 3074, 3002, 2959, 2935, 2834, 2777, 1710, 1638, 1586, 1556, 1510, 1485, 1451, 1437, 1421, 1386, 1342, 1296, 1284, 1217, 1180, 1157, 1121, 1070, 1019, 945, 868, 807, 764, 756, 715, 696, 676, 661, 621, 580, 572, 530, 486. 1H NMR (400 MHz, acetone-d6) δ = 7.92 (dt, J = 8.9, 0.7 Hz, 1H), 7.66 (d, J = 1.0 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.20 (dd, J = 8.9, 2.6 Hz, 1H), 7.15 (dd, J = 8.6, 2.4 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 190.74(C), 162.16(C), 159.06(C), 144.67(C), 141.26(C), 136.99(C), 136.49(C), 134.15(CH), 130.82(CH), 126.23(CH), 124.59(CH), 119.87(CH), 114.45(CH), 108.17(CH), 93.66(C), 56.25(CH3), 55.85(CH3). LC/MS (retention time 4.70 min) m/z (ESI+) 425.00 (MH+, 100%), 447.00 (MNa+, 17.3%), 870.90 (2MNa+, 52.4%). HRMS (ESI+): m/z calcd for C17H14IO3S+ [MH+]: 424.9703; found: 424.9698.
(2-Iodo-5-methoxyphenyl)(5-methoxy benzo[b]thiophen-2-yl)methanone 6h
According to general procedure B, scale: according to general procedure 2, scale: (2-iodo-5-methoxyphenyl)(5-methoxybenzo[b]thiophen-2-yl)methanol 7h (0.294 g, 0.69 mmol) and MnO2 (0.367 g, 4.22 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6h as a yellow oil (0.233 g, 80%). IR: 3065, 3002, 2392, 2934, 2832, 1710, 1644, 1602, 1586, 1582, 1509, 1451, 1422, 1401, 1390, 1342, 1318, 1295, 1265, 1231, 1213, 1178, 1155, 1106, 1070, 1044, 1023, 1008, 946, 916, 888, 800, 765, 714, 698, 680, 657, 607, 566, 560, 530, 490, 456. 1H NMR (400 MHz, acetone-d6) δ 7.93 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 1.0 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 8.9, 2.4 Hz, 1H), 7.16 (d, J = 3.1 Hz, 1H), 6.96 (dd, J = 8.8, 3.1 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H). 13C NMR (101 MHz, acetone-d6) δ = 190.97(C), 160.71(C), 159.08(C), 146.02(C), 143.89(C), 141.30(CH), 141.28(C), 136.65(C), 134.74(CH), 124.62(CH), 120.10(CH), 118.77(CH), 114.94(CH), 108.24(CH), 80.62(C), 56.12(CH3), 55.85(CH3). LC/MS (retention time 4.70 min) m/z (ESI+) 425.00 (MH+, 100%), 447.00 (MNa+, 18.1%), 870.90 (2MNa+, 33.5%). HRMS (ESI+): m/z calcd for C17H14IO3S+ [MH+]: 424.9703; found: 424.9699.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodophenyl) methanone 6i
According to general procedure B, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodophenyl)methanol 7i (0.420 g, 0.85 mmol) and MnO2 (0.443 g, 5.10 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6i as a yellow oil (0.358 g, 85%). IR: 3059, 2954, 2928, 2885, 2856, 1712, 1648, 1599, 1583, 1549, 1510, 1471, 1462, 1437, 1390, 1361, 1324, 1288, 1256, 1222, 1158, 1126, 1108, 1069, 1040, 1016, 968, 939, 878, 868, 838, 813, 780, 741, 716, 704, 673, 642, 632, 616, 592, 552, 529, 487. 1H NMR (400 MHz, acetone-d6) δ = 8.04 (ddd, J = 7.9, 1.1, 0.5 Hz, 1H), 7.94 (dt, J = 8.8, 0.7 Hz, 1H), 7.63 (d, J = 0.9 Hz, 1H), 7.61 (dd, J = 7.2, 1.1 Hz, 1H), 7.58–7.54 (m, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.35 (ddd, J = 8.1, 7.3, 2.0 Hz, 1H), 7.18 (dd, J = 8.7, 2.4 Hz, 1H), 1.00 (s, 9H), 0.24 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 191.35(C), 154.65(C), 145.11(C), 144.20(C), 141.45(C), 140.61(CH), 137.34(C), 134.56(CH), 132.44(CH), 129.12(CH), 129.00(CH), 124.75(CH), 123.87(CH), 116.47(CH), 92.46(C), 26.01(CH3), 18.78(C), −4.36 (CH3). LC/MS (retention time 6.14 min) m/z (ESI+) 495.10 (MH+, 100%), 517.10 (MNa+, 4.4%). HRMS (ESI+): m/z calcd for C21H24IO2SSi+ [MH+]: 495.0306; found: 495.0302.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-4-methoxyphenyl)methanone 6j
According to general procedure B, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-4-methoxyphenyl)methanol 7j (0.338 g, 0.64 mmol) and MnO2 (0.336 g, 3.86 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6j as a yellow oil (0.225 g, 67%). IR: 3070, 3005, 2954, 2929, 2893, 2858, 1712, 1644, 1588, 1557, 1511, 1486, 1471, 1462, 1436, 1390, 1361, 1324, 1285, 1255, 1220, 1182, 1158, 1120, 1069, 1020, 968, 936, 880, 856, 838, 803, 780, 757, 740, 717, 696, 676, 625, 604, 590, 572, 529, 489. 1H NMR (400 MHz, acetone-d6) δ = 7.92 (d, J = 9.5 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.15 (ddd, J = 8.6, 7.7, 2.5 Hz, 2H), 3.92 (s, 3H), 1.01 (s, 9H), 0.25 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 190.73(C), 162.13(C), 154.58(C), 144.80(C), 141.43(C), 137.19(C), 136.91(C), 134.07(CH), 130.80(CH), 126.24(CH), 124.68(CH), 123.63(CH), 116.37(CH), 114.41(CH), 93.64(C), 56.23(CH), 26.02(CH3), 18.78(C), −4.35 (CH3). LC/MS (retention time 6.16 min) m/z (ESI+) 525.20 (MH+, 100%), 527.20 (MNa+, 1.9%). HRMS (ESI+): m/z calcd for C22H26IO3SSi+ [MH+]: 525.0411; found: 525.0413.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanone 6k
According to general procedure B, scale: according to general procedure 2, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanol 7k (0.330 g, 0.63 mmol) and MnO2 (0.326 g, 3.76 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6k as a yellow oil (0.292 g, 89%). IR: 3059, 3002, 2954, 2929, 2885, 2856, 1711, 1651, 1599, 1564, 1549, 1510, 1461, 1437, 1402, 1390, 1361, 1324, 1287, 1257, 1232, 1213, 1182, 1155, 1106, 1069, 1046, 1009, 968, 939, 917, 883, 838, 802, 780, 741, 716, 679, 637, 617, 587, 490. 1H NMR (400 MHz, acetone-d6) δ = 7.93 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 0.9 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.20–7.12 (m, 2H), 6.96 (dd, J = 8.7, 3.0 Hz, 1H), 3.88 (s, 3H), 1.01 (s, 9H), 0.25 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 191.01(C), 160.73(C), 154.66(C), 146.02(C), 144.06(C), 141.50(C), 141.31(CH), 137.36(C), 134.70(CH), 124.75(CH), 123.87(CH), 118.77(CH), 116.51(CH), 114.95(CH), 80.60(C), 56.11(CH), 26.02(CH3), 18.79(C), −4.36(CH3). LC/MS (retention time 6.14 min) m/z (ESI+) 525.20 (MH+, 100%), 547.20 (MNa+, 3.5%). HRMS (ESI+): m/z calcd for C22H26IO3SSi+ [MH+]: 525.0411; found: 525.0404.
(5-((Tert-Butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-6-methoxyphenyl)methanone 6l
According to general procedure B, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-6-methoxyphenyl)methanol 7l (0.084 g, 0.16 mmol) and MnO2 (0.165 g, 1.90 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6l as a yellow solid (0.070 g, 83%), m.p. 124.8–125.5 °C. IR: 3535, 2953, 2928, 2856, 1660, 1585, 1566, 1513, 1456, 1428, 1325, 1288, 1257, 1221, 1159, 1114, 1064, 1025, 966, 938, 870, 838, 822, 776, 752, 742, 717, 674, 640, 613, 588, 562, 500, 465. 1H NMR (400 MHz, acetone-d6) δ = 7.92 (dt, J = 8.8, 0.7 Hz, 1H), 7.62 (d, J = 0.7 Hz, 1H), 7.55 (dd, J = 7.5, 1.3 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.31–7.23 (m, 2H), 7.19–7.14 (m, 1H), 3.77 (s, 3H), 1.01 (s, 9H), 0.24 (s, 6H). 13C NMR (101 MHz, acetone-d6) δ = 190.07(C), 158.28(C), 154.61(C), 144.57(C), 141.55(C), 137.16(C), 134.71(C), 132.94(CH), 132.92(CH), 131.85(CH), 124.77(CH), 123.61(CH), 116.36(CH), 112.34(CH), 93.13(C), 56.54(CH), 26.03(CH3), 18.79(C), −4.35 (CH3). LC/MS (retention time 5.99 min) m/z (ESI+) 525.10 (MH+, 100%), 547.00 (MNa+, 11.3%). HRMS (ESI+): m/z calcd for C22H26IO3SSi+ [MH+]: 525.0411; found: 525.0406.
(5-Fluorobenzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanone 6m
According to general procedure B, scale: (5-fluoro benzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanol 7m (0.206 g, 0.50 mmol) and MnO2 (0.259 g, 2.97 mmol). The residue was purified by flash chromatography (0 to 20% of EtOAc in cyclohexane) to afford compound 6m as a yellow oil (0.180 g, 88%). IR: 3089, 3073, 3000, 2935, 2845, 1647, 1585, 1570, 1515, 1461, 1437, 1437, 1389, 1330, 1319, 1289, 1268, 1234, 1204, 1186, 1149, 1138, 1105, 1069, 1036, 1008, 956, 881, 805, 769, 754, 724, 713, 673, 653, 600, 584, 488, 463. 1H NMR (400 MHz, acetone-d6) δ = 8.16–8.08 (m, 1H), 7.90–7.84 (m, 1H), 7.81–7.71 (m, 2H), 7.47–7.39 (m, 1H), 7.21–7.16 (m, 1H), 7.00–6.95 (m, 1H), 3.89–3.87 (m, 3H). 13C NMR (101 MHz, acetone-d6) δ = 190.99(C), 161.86(C, d, J = 240.4 Hz), 160.76(C), 145.67(C), 145.36 (C), 141.39(CH), 141.19(C, d, J = 9.1 Hz), 139.66(C), 134.47(CH, d, J = 5.1 Hz), 125.79(CH, J = 9.1 Hz), 118.95(CH), 117.89(CH, d, J = 26.3 Hz), 115.04(CH), 112.28(CH, d, J = 23.2 Hz), 80.54(C), 56.13(CH3). 19F NMR (376 MHz, acetone-d6) δ = −118.54. LC/MS (retention time 4.78 min) m/z (ESI+) 412.90 (MH+, 100%), 434.90 (MNa+, 30.0%), 844.00 (2MNa+, 26.5%). HRMS (ESI+): m/z calcd for C16H11FIO2S+ [MH+]: 412.9503; found: 412.9494.
General procedure C for the palladium-catalysed cyclisation of iodoketone 6 into tetracyclic derivative 4
In a sealable tube was added iodoketone 6 (0.30 mmol) in DMF (4 mL) under an argon atmosphere. Then Pd(OAc)2 (0.004 g, 0.018 mmol), Cy3P·HBF4 (0.012 g, 0.03 mmol) and K2CO3 (0.084 g, 0.61 mmol) were added successively. After stirring for 15 min at room temperature, the tube was sealed and heated during 16 h at 130 °C. After cooling, the reaction mixture was filtered through a sintered-glass funnel. Water (10 mL) and DCM (10 mL) were added, the aqueous layer was separated and extracted with ethyl acetate (2 × 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (DCM or MeOH/DCM) to afford the desired product.
10-Methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4a
According to general procedure C, scale: benzo[b]thiophen-2-yl(2-iodo-3-methoxyphenyl)methanone 6a (0.124 g, 0.31 mmol), Pd(OAc)2 (0.004 g, 0.018 mmol), Cy3P·HBF4 (0.012 g, 0.03 mmol), K2CO3 (0.087 g, 0.63 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4a as a red solid (0.068 g, 82%), m.p. 187.0–189.4 °C. IR: 3100, 3000, 2954, 2922, 2845, 1929, 1697, 1600, 1487, 1467, 1435, 1411, 1388, 1328, 1260, 1201, 1182, 1163, 1087, 1052, 985, 838, 828, 857, 801, 770, 762, 750, 731, 682, 628, 599, 551, 520, 498, 463. 1H NMR (500 MHz, DMSO-d6) δ = 8.60–8.52 (m, 1H), 8.09–8.02 (m, 1H), 7.54–7.48 (m, 2H), 7.27 (dt, J = 5.1, 2.6 Hz, 2H), 7.09 (td, J = 4.6, 2.5 Hz, 1H), 4.02 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 186.14(C), 152.54(C), 151.44(C), 147.18(C), 137.44(C), 134.10(C), 131.65(C), 130.51(CH), 127.62(CH), 126.51(CH), 125.69(CH), 125.62(C), 124.32(CH), 120.00(CH), 116.57(CH), 55.81(CH3). LC/MS (retention time 4.72 min) m/z (ESI+) 267.10 (MH+, 100%), 289.10 (MNa+, 7.7%). HRMS (ESI+): m/z calcd for C16H11O2S+ [MH+]: 267.0474; found: 267.0465.
9-Methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4b
According to general procedure C, scale: benzo[b]thiophen-2-yl(2-iodo-4-methoxyphenyl)methanone 6b (0.165 g, 0.42 mmol), Pd(OAc)2 (0.005 g, 0.02 mmol), Cy3P·HBF4 (0.016 g, 0.04 mmol), K2CO3 (0.116 g, 0.84 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4b as an orange solid (0.098 g, 88%), m.p. 201.8–203.3 °C. IR: 3054, 998, 2352, 1890, 1719, 1691, 1599, 1499, 1467, 1428, 1413, 1383, 1293, 1270, 1241, 1222, 1165, 1147, 1072, 1019, 965, 942, 865, 856, 828, 770, 761, 730, 706, 691, 648, 667, 621, 509, 491, 482. 1H NMR (500 MHz, DMSO-d6) δ = 8.38–8.36 (m, 1H), 8.14–8.05 (m, 1H), 7.58–7.53 (m, 2H), 7.42 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.73 (dd, J = 8.1, 2.2 Hz, 1H), 3.92 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 186.97(C), 164.55(C), 150.28(C), 146.75(C), 141.56(C), 137.55(C), 131.13(C), 128.35(C), 127.47(CH), 125.99(CH), 125.32(CH), 124.55(CH), 124.11(CH), 110.26(CH), 109.00(CH), 55.75(CH3). LC/MS (retention time 4.61 min) m/z (ESI+) 267.10 (MH+, 100%), 289.10 (MNa+, 4.2%), 555.10 (2MNa+, 3.5%). HRMS (ESI+): m/z calcd for C16H10O2S+ [MH+]: 267.0474; found: 267.0475.
8-Methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4c
According to general procedure C, scale: benzo[b]thiophen-2-yl(2-iodo-5-methoxyphenyl)methanone 6c (0.197 g, 0.50 mmol), Pd(OAc)2 (0.006 g, 0.03 mmol), Cy3P·HBF4 (0.018 g, 0.05 mmol), K2CO3 (0.140 g, 1.01 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4c as a red solid (0.117 g, 88%), m.p. 159.4–161.0 °C. IR: 3092, 3059, 3013, 2951, 2842, 2328, 1696, 1618, 1593, 1494, 1468, 1435, 1387, 1330, 1288, 1261, 1221, 1191, 1157, 1139, 1086, 1057, 1019, 944, 909, 892, 832, 817, 770, 742, 726, 710, 681, 631, 573, 542, 500. 1H NMR (500 MHz, DMSO-d6) δ = 8.32–8.25 (m, 1H), 8.09 (ddd, J = 7.1, 3.9, 3.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.55 (qt, J = 9.4, 5.5, 4.7 Hz, 2H), 7.02 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 8.0, 2.5 Hz, 1H), 3.81 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 186.10(C), 160.06(C), 153.77(C), 147.62(C), 138.48(C), 134.27(C), 131.29(C), 131.15(C), 128.28(CH), 126.29(CH), 124.97(CH), 124.69(CH), 121.48(CH), 116.39(CH), 112.01(CH), 55.72(CH3). LC/MS (retention time 4.68 min) m/z (ESI+) 267.10 (MH+, 100.0%), 289.0 (MNa+, 8.7%), 555.20 (2MNa+, 3.6%). HRMS (ESI+): m/z calcd for C16H10O2S+ [MH+]: 267.0474; found: 267.0465.
7-Methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4d
According to general procedure C, scale: benzo[b]thiophen-2-yl(2-iodo-6-methoxyphenyl)methanone 6d (0.056 g, 0.14 mmol), Pd(OAc)2 (0.002 g, 0.01 mmol), Cy3P·HBF4 (0.005 g, 0.02 mmol), K2CO3 (0.040 g, 0.28 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4d as an orange solid (0.025 g, 67%), m.p. 178.6–183.7 °C. IR: 3372, 3263, 3067, 3002, 2978, 2923, 2847, 2839, 1662, 1690, 1597, 1501, 1478, 1460, 1435, 1415, 1386, 1279, 1246, 1200, 1165, 1138, 1069, 1049, 975, 881, 851, 825, 794, 783, 774, 758, 732, 702, 681, 647, 580, 503. 1H NMR (500 MHz, DMSO-d6) δ = 8.32–8.28 (m, 1H), 8.15–8.10 (m, 1H), 7.58–7.51 (m, 2H), 7.49 (dd, J = 8.7, 7.1 Hz, 1H), 7.43–7.35 (m, 1H), 7.02 (d, J = 8.6 Hz, 1H), 3.88 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 184.56(C), 157.22(C), 150.16(C), 146.80(C), 141.14(C), 137.09(CH), 136.81(C), 131.53(C), 127.69(CH), 126.37(CH), 125.02(CH), 124.20(CH), 120.00(C), 114.88(CH), 113.76(CH), 55.75(CH3). LC/MS (retention time 4.20 min) m/z (ESI+) 267.10 (MH+, 100%), 289.00 (MNa+, 13.0%), 555.10 (2MNa+, 51.1%). HRMS (ESI+): m/z calcd for C16H11O2S+ [MH+]: 267.0474; found: 267.0474.
2-Methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4e
According to general procedure C, scale: (2-iodophenyl)(5-methoxybenzo[b]thiophen-2-yl)methanone 6e (0.213 g, 0.54 mmol), Pd(OAc)2 (0.006 g, 0.03 mmol), Cy3P·HBF4 (0.020 g, 0.05 mmol), K2CO3 (0.151 g, 1.09 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4e as an orange solid (0.119 g, 83%), m.p. 168.7–170.7 °C. IR: 3062, 3049, 3000, 2956, 2931, 2826, 1719, 1688, 1606, 1502, 1455, 1435, 1419, 1378, 1331, 1310, 1287, 1272, 1232, 1204, 1188, 1130, 1074, 1058, 1023, 973, 936, 877, 857, 824, 810, 766, 758, 721, 696, 653, 615, 566, 540, 482. 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J = 9.0 Hz, 1H), 7.80 (dt, J = 7.3, 0.8 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.47 (td, J = 7.5, 1.1 Hz, 1H), 7.42 (dt, J = 7.2, 0.9 Hz, 1H), 7.25 (ddd, J = 8.0, 7.2, 0.9 Hz, 1H), 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 3.92 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 186.49(C), 158.45(C), 152.05(C), 140.11(C), 139.36(C), 136.92(C), 136.23(C), 134.37(CH), 132.44(C), 128.43(CH), 125.65(CH), 123.55(CH), 120.66(CH), 118.89(CH), 105.55(CH), 55.76(CH3). LC/MS (retention time 4.63 min) m/z (ESI+) 267.10 (MH+, 100%), 289.20 (MNa+, 5.2%), 555.20 (2MNa+, 1.9%). HRMS (ESI+): m/z calcd for C16H10NaO2S+ [MNa+]: 289.0294; found: 289.0299.
2,10-Dimethoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4f
According to general procedure C, scale: (2-iodo-3-methoxyphenyl)(5-methoxybenzo[b]thiophen-2-yl)methanone 6f (0.116 g, 0.27 mmol), Pd(OAc)2 (0.003 g, 0.02 mmol), Cy3P·HBF4 (0.010 g, 0.03 mmol), K2CO3 (0.076 g, 0.55 mmol). The residue was purified by flash chromatography (DCM) to afford compound 8 cycle as a red solid (0.070 g, 86%), m.p. 198.0–205.8 °C. IR: 3122, 2981, 2943, 2918, 2899, 2838, 1728, 1690, 1599, 1491, 1444, 1414, 1376, 1337, 1307, 1266, 1224, 1199, 1180, 1160, 1123, 1064, 1027, 973, 927, 851, 815, 799, 742, 679, 640, 569, 550, 485. 1H NMR (500 MHz, DMSO-d6) δ = 8.07 (d, J = 2.6 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.31–7.23 (m, 2H), 7.14 (dd, J = 8.9, 2.6 Hz, 1H), 7.09 (q, J = 4.6, 4.0 Hz, 1H), 4.03 (s, 3H), 3.89 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 186.04(C), 157.65(C), 151.93(C), 151.21(C), 139.85(C), 137.40(C), 135.15(C), 132.76(C), 130.30(CH), 125.68(C), 124.88(CH), 119.86(CH), 118.26(CH), 116.56(CH), 107.63(CH), 55.91(CH3), 54.94(CH3). LC/MS (retention time 4.76 min) m/z (ESI+) 297.10 (MH+, 100%), 319.00 (MNa+, 9.6%), 615.20 (2MNa+, 15.5%). HRMS (ESI+): m/z calcd for C17H13O3S+ [MH+]: 297.0580; found: 297.0578.
2,9-Dimethoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4g
According to general procedure C, scale: (2-iodo-4-methoxyphenyl)(5-methoxybenzo[b]thiophen-2-yl)methanone 6g (0.169 g, 0.40 mmol), Pd(OAc)2 (0.005 g, 0.02 mmol), Cy3P·HBF4 (0.015 g, 0.04 mmol), K2CO3 (0.114 g, 0.82 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4g as an orange solid (0.100 g, 84%), m.p. 194.2–196.0 °C. IR: 3106, 3070, 3019, 2983, 2926, 2902, 2861, 2826, 2358, 2326, 1694, 1595, 1500, 1452, 1439, 1409, 1369, 1341, 1312, 1282, 1237, 1204, 1169, 1147, 1122, 1084, 1061, 1018, 976, 913, 851, 822, 813, 807, 793, 760, 737, 700, 691, 664, 655, 632, 619, 565, 509, 484. 1H NMR (500 MHz, DMSO-d6) δ = 7.93 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 9.0, 2.5 Hz, 1H), 6.66 (dd, J = 8.1, 2.2 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 184.70(C), 164.42(C), 158.23(C), 149.42(C), 141.39(C), 139.27(C), 138.62(C), 132.16(C), 128.34(C), 125.01(CH), 124.97(CH), 117.75(CH), 109.61(CH), 109.17(CH), 105.81(CH), 55.51(2 × CH3). LC/MS (retention time 4.66 min) m/z (ESI+) 297.10 (MH+, 100%), 319.00 (MNa+, 4.9%), 615.10 (2MNa+, 11.9%). HRMS (ESI+): m/z calcd for C17H13O3S+ [MH+]: 297.0580; found: 297.0580.
2,8-Dimethoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4h
According to general procedure C, scale: (2-iodo-5-methoxyphenyl)(5-methoxybenzo[b]thiophen-2-yl)methanone 6h (0.164 g, 0.39 mmol), Pd(OAc)2 (0.004 g, 0.02 mmol), Cy3P·HBF4 (0.014 g, 0.04 mmol), K2CO3 (0.108 g, 0.78 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4h as a brown solid (0.080 g, 70%), m.p. 192.4–193.9 °C. IR: 3383, 2975, 3956, 2935, 2877, 2850, 2826, 1885, 1720, 1700, 1606, 1502, 1487, 1469, 1458, 1445, 1432, 1416, 1375, 1328, 1310, 1278, 1269, 1234, 1200, 1132, 1073, 1057, 1020, 971, 884, 833, 822, 809, 787, 768, 761, 738, 657, 645, 583, 580, 541, 474. 1H NMR (500 MHz, DMSO-d6) δ = 7.94 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 9.0, 2.5 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.0, 2.5 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 185.47(C), 159.73(C), 158.16(C), 152.54(C), 139.96(C), 138.18(C), 135.18(C), 131.96(C), 131.23(C), 125.04(CH), 120.91(CH), 118.25(CH), 116.37(CH), 111.40(CH), 105.90(CH), 55.47(CH3), 55.38(CH3). LC/MS (retention time 4.73 min) m/z (ESI+) 297.10 (MH+, 100%), 319.00 (MNa+, 9.1%), 616.10 (2MNa+, 13.7%). HRMS (ESI+): m/z calcd for C17H13O3S+ [MH+]: 297.0580; found: 297.0574.
2-Hydroxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4i
According to general procedure C, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodophenyl)methanone 6i (0.235 g, 0.48 mmol), Pd(OAc)2 (0.005 g, 0.02 mmol), Cy3P·HBF4 (0.018 g, 0.05 mmol), K2CO3 (0.132 g, 0.96 mmol). The residue was purified by flash chromatography (DCM/MeOH: 99/1) to afford compound 4i as a red solid (0.088 g, 74%), m.p. 265.4–270.8 °C. IR: 3372, 3321, 3054, 2921, 2847, 2328, 1720, 1680, 1607, 1504, 1455, 1424, 1402, 1364, 1328, 1279, 1237, 1201, 1141, 1130, 1075, 1056, 980, 883, 859, 848, 818, 802, 788, 759, 724, 694, 654, 614, 563, 543, 512. 1H NMR (500 MHz, DMSO-d6) δ = 9.95 (s, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.57 (dt, J = 7.3, 0.8 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.48 (td, J = 7.5, 1.1 Hz, 1H), 7.43 (dt, J = 7.2, 0.9 Hz, 1H), 7.28–7.23 (m, 1H), 7.09 (dd, J = 8.9, 2.4 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ = 186.55(C), 156.48(C), 151.75(C), 139.55(C), 138.64(C), 136.74(C), 136.34(C), 134.50(CH), 132.72(C), 128.37(CH), 125.66(CH), 123.61(CH), 120.03(CH), 119.02(CH), 108.27(CH). LC/MS (retention time 3.71 min) m/z (ESI+) 253.00 (MH+, 100%), 275.00 (MNa+, 14.2%), 527.00 (2MNa+, 5.0%). HRMS (ESI+): m/z calcd for C15H9O2S+ [MH+]: 253.0318; found: 253.0325.
2-Hydroxy-9-methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4j
According to general procedure C, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-4-methoxyphenyl)methanone 6j (0.141 g, 0.27 mmol), Pd(OAc)2 (0.003 g, 0.02 mmol), Cy3P·HBF4 (0.010 g, 0.03 mmol), K2CO3 (0.074 g, 0.54 mmol). The residue was purified by flash chromatography (DCM/MeOH: 99/1) to afford compound 4j as a brown solid (0.060 g, 79%), m.p. 288.8–292.4 °C. IR: 3345, 3226, 3008, 2925, 2850, 2828, 1673, 1601, 1504, 1460, 1417, 1363, 1343, 1298, 1242, 1198, 1181, 1156, 1143, 1131, 1074, 1056, 1024, 982, 926, 846, 802, 765, 739, 699, 662, 624, 603, 567, 506, 487. 1H NMR (500 MHz, DMSO-d6) δ = 9.89 (s, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.07 (dd, J = 8.9, 2.4 Hz, 1H), 6.68 (dd, J = 8.1, 2.2 Hz, 1H), 3.89 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 185.43(C), 164.59(C), 156.42(C), 149.58(C), 141.96(C), 138.55(C), 138.10(C), 132.70(C), 128.53(C), 125.62(CH), 125.54(CH), 118.57(CH), 110.15(CH), 108.68(CH), 108.23(CH), 55.96(CH3). LC/MS (retention time 3.77 min) m/z (ESI+) 283.00 (MH+, 100%), 305.10 (MNa+, 7.1%), 587.10 (2MNa+, 17.2%). HRMS (ESI+): m/z calcd for C16H11O3S+ [MH+]: 283.0423; found: 283.0421.
2-Hydroxy-8-methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4k
According to general procedure C, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanone 6k (0.195 g, 0.37 mmol), Pd(OAc)2 (0.004 g, 0.02 mmol), Cy3P·HBF4 (0.014 g, 0.04 mmol), K2CO3 (0.103 g, 0.74 mmol). The residue was purified by flash chromatography (DCM/MeOH: 99/1) to afford compound 4k as a dark brown solid (0.060 g, 57%), m.p. 224–229.7 °C. IR: 3319, 3002, 2962, 2397, 2921, 2853, 2834, 2350, 1906, 1700, 1674, 1621, 1600, 1498, 1471, 1462, 1421, 1363, 1338, 1260, 1242, 1222, 1198, 1189, 1140, 1056, 1029, 979, 926, 917, 880, 848, 823, 808, 796, 770, 741, 693, 657, 647, 625, 576, 512. 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.9, 2.4 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 6.92 (dd, J = 8.1, 2.5 Hz, 1H), 3.80 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 186.12(C), 159.86(C), 156.35(C), 152.78(C), 138.77(C), 138.52(C), 135.12(C), 132.49(C), 131.51(C), 125.59(CH), 120.87(CH), 119.06(CH), 116.35(CH), 112.01(CH), 108.35(CH), 55.69(CH3). LC/MS (retention time 3.86 min) m/z (ESI+) 283.00 (MH+, 100%), 305.00 (MNa+, 10.3%). HRMS (ESI+): m/z calcd for C16H11O3S+ [MH+]: 283.0423; found: 283.0429.
2-Hydroxy-7-methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4l
According to general procedure C, scale: (5-((tert-butyldimethylsilyl)oxy)benzo[b]thiophen-2-yl)(2-iodo-6-methoxyphenyl)methanone 6l (0.050 g, 0.10 mmol), Pd(OAc)2 (0.001 g, 0.01 mmol), Cy3P·HBF4 (0.004 g, 0.01 mmol), K2CO3 (0.026 g, 0.19 mmol). The residue was purified by flash chromatography (DCM/MeOH: 99/1) to afford compound 4l as a brown solid (0.014 g, 51%), m.p. 264.7–269.9 °C. IR: 3369, 3324, 3097, 3065, 2924, 2853, 1739, 1683, 1600, 1508, 1468, 1424, 1361, 1341, 1288, 1254, 1231, 1177, 1160, 1135, 1077, 1053, 994, 930, 867, 855, 790, 782, 733, 692, 676, 652, 583, 528, 511. 1H NMR (500 MHz, DMSO-d6) δ = 9.91 (s, 1H), 7.90 (dd, J = 8.9, 3.5 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.51–7.48 (m, 1H), 7.21 (d, J = 7.0 Hz, 1H), 7.08–7.05 (m, 1H), 7.03 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 184.77(C), 157.38(C), 156.60(C), 149.37(C), 141.53(C), 138.01(C), 137.80(C), 137.27(CH), 133.03(C), 125.82(CH), 120.20(C), 118.54(CH), 114.82(CH), 113.37(CH), 108.17(CH), 55.90(CH3). LC/MS (retention time 3.33 min) m/z (ESI+) 283.10 (MH+, 100%), 305.10 (MNa+, 10.4%), 587.20 (2MNa+, 47.4%). HRMS (ESI+): m/z calcd for C16H11O3S+ [MH+]: 283.0423; found: 283.0425.
2-Fluoro-8-methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one 4m
Following general procedure C, scale: (5-fluorobenzo[b]thiophen-2-yl)(2-iodo-5-methoxyphenyl)methanone 6m (0.139 g, 0.34 mmol), Pd(OAc)2 (0.004 g, 0.02 mmol), Cy3P·HBF4 (0.013 g, 0.04 mmol), K2CO3 (0.097 g, 0.70 mmol). The residue was purified by flash chromatography (DCM) to afford compound 4m as a purple solid (0.083 g, 87%), m.p. 196.6–198.7 °C. IR: 3092, 3032, 2994, 2956, 1703, 1618, 1599, 1499, 1468, 1438, 1418, 1371, 1333, 1288, 1260, 1225, 1181, 1143, 1120, 1056, 1016, 976, 922, 876, 854, 820, 797, 768, 740, 653, 640, 573, 504. 1H NMR (500 MHz, DMSO-d6) δ 8.16–8.07 (m, 2H), 7.74–7.67 (m, 1H), 7.42 (tdt, J = 9.1, 2.2, 1.0 Hz, 1H), 7.04 (dt, J = 2.9, 1.5 Hz, 1H), 6.94 (ddt, J = 8.0, 2.5, 1.2 Hz, 1H), 3.83 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 185.58(C), 160.83(C, J = 243.2 Hz), 159.93(C), 152.70(C, J = 5.0 Hz), 143.03(C), 137.89(C), 136.56(C), 131.78 (C, J = 10.1 Hz), 130.88(C), 126.38(CH, J = 8.8 Hz), 121.32(CH), 116.55(CH, J = 26.5 Hz), 116.54(CH), 111.78(CH), 109.52(CH, J = 22.7 Hz), 55.52(CH3), 19F NMR (471 MHz, DMSO-d6) δ = −115.51 (td, J = 9.0, 4.7 Hz). LC/MS (retention time 4.77 min) m/z (ESI+) 285.10 (MH+, 100%), 307.10 (MNa+, 24.3%), 591.10 (2MNa+, 6.0%). HRMS (ESI+): m/z calcd for C16H9FO2S+ [MH+]: 285.0386; found: 285.0387.
Biological evaluations
DYRK1A/DYRK1B kinases inhibition assays
Human Dyrk1A was expressed and purified as described earlier.48 Dyrk1B were purchased from Life Technologies.50 Woodtide substrate peptide for Dyrk1A and Dyrk1B (KKISGRLSPIMTEQ) were custom synthesized at the Department of Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany. Kinase inhibition assays for Dyrk1A and Dyrk1B were performed as described previously, in the presence of 15 mM ATP.48 The calculated IC50 values are representative of at least two independent determinations and 3,3′-(2,4-thienediyl)dipyridine was used as the positive control.
The larger panel of kinases shown in Table 2 was screened by the SelectScreen Kinase Profiling Service, Thermo Fisher Scientific, Madison, USA and the Kinase Profiler service, Eurofins/CEREP Celle L'Evescault, France. For each kinase, ATP concentrations were set at ATP Km.
Cell viability of compounds – MTT protocol
Cell viability is evaluated through the MTT colorimetric assay. The MTT assay is based on protocol described by Mosmann.92 The assay was optimized for cell line used in the experiment. U-87MG cells or U373MG cells (human malignant gliomas, respectively HTB14 and HTB17 ATCC) are plated at a density of 10000 cells per well into 96 well culture plates. Cells are incubated overnight at 37 °C in 5% CO2 in MEM (modified Eagle's medium) media supplemented with 10% FBS (fetal bovine serum). The following day, cells are treated in triplicated with the compounds (1–200 μM) in 1% DMSO or with vehicle control (1% DMSO). After 72 h, the cells are incubated with 20 μL of MTT at 5 mg mL−1 (Sigma Aldrich M2128) for 3 h at 37 °C. The medium is the removed and 100 μl of 0.1 N HCl in isopropanol is added in each well for 15 min. Absorbance is measured by a plate reader at 570 nm and the value measured at 690 nm was subtracted. Data are the mean ± SD of at least three independent experiments.
Microsomal stability assays
Protocol for metabolic stability was adapted from different published procedures.93–95
Compounds (10 μM) were preincubated with phosphate buffer (pH 7.4, 0.1 M) and rat liver microsomes (0.15 mg) for 10 min at 37 °C then NADPH (1 mM) was added to start the reaction. Final concentration of DMSO was 0.5% and total reaction volume was 500 μL. Aliquots (50 μL) were taken at desired timepoints (0, 5, 15, 30, 45, 60 min) and diluted with a solution of cold acetonitrile to stop the reaction (100 μL, containing 0.5 mg mL−1 BHT as internal standard). After centrifugation, supernatants were analyzed by gradient UHPLC-MS method using Agilent 1290 series (Agilent POROSHELL 120 SB-C18 column, 2.7 μm, 2.1 × 50 mm) with the following parameters: injection volume: 10 μl, flow rate: 0.5 mL min−1, column temperature: 30 °C, solvents: A (0.1% HCO2H in ACN) and B (0.1% HCO2H in H2O), t = 0–0.5 min, 10% A; t = 0.5–5.5 min, 10 → 90% A then t = 5.5–6 min, 90% A. Areas recorded at 254 nm were ratioed with internal standard peak area (BHT). Remaining compound was ratioed with t = 0 peak area and the natural logarithm of the remaining compound ratio was plotted against time. Linear fit of the curve allowed us to determine t1/2 for tested compound and microsomal intrinsic clearance (CLint, in μL min−1 mg−1 protein) was calculated using this equation as previously described:
In silico docking studies
Each protein (DYRK1A (PDB ID: 5AIK), CLK1 (PDB ID: 6RAA), CLK4 (PDB ID: 6FYV), haspin (PDB ID: 3IQ7)) has been setup and protonated (pH = 7) using MOE software (Molecular Operating Environment, 2022.2). The docking procedures were performed with GOLD software (version 2020.2.0) using the HERMES interface. GOLD scores have been optimized following variation of different parameters (solvated/unsolvated protein, co-crystallized structure origin, scoring and rescoring algorithms (Chemscore, Goldscore, PLP)).
The following parameters has showed the best correlations between biologics assays and fitness scoring: using protonated, unsolvated unminimized protein with a spherical site (10 Å radius) centered on the previously co-crystallized ligands, the GOLD template chemscore_kinase, Goldscore scoring and chemscore rescoring without using the “allow termination” option with a genetic algorithm (GA) search efficiency 100%.
Data were extracted as “.csv” extension and computed with excel.
Best and consistent results were extracted as “mol2” extension complexes and visualized with PyMOL (1.8.6.2) and MOE softwares to generate superposition, ligand interactions and images generation.
Data availability
The data used for the manuscript entitled “Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors” will be included in a ESI† file, available online on RSC Medicinal Chemistry web site.
Author contributions
Conceptualization: TL and RB. Formal analysis: TL and ME. Funding acquisition: TL and FH. Investigation: AF, AA, FH, JR, MA, VD, CVD, AM, MS, AE, T-NP, AB. Methodology: TL, RB and ME. Project administration: TL. Resources: TL, MLB, RT. Supervision: TL. Validation: TL and AA. Visualization: TL, VD, JR and FH. Writing – original draft: TL, VD and FH. Writing – review & editing: FH, ME, AF and TL.
Acknowledgments
AF and JR thank the Ministère de l'Enseignement Supérieur, de la Recherche et de l'innovation for PhD fellowships. CVD would like to thank the University of Science and Technology of Hanoi (USTH) for a PhD fellowship. FH thanks the Université Claude Bernard Lyon 1 (SENS 2022) and Agence Nationale de la Recherche (ANR-22-CE18-0004 – SINGE) for financial support. The Common Centre of Mass Spectrometry CCSM and Common Centre of NMR CCRMN of CNRS UMR 5246 research unit are gratefully acknowledged for the promptness and accuracy of their analyses.
Notes
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra of synthesis intermediate alcohols 7a–m, ketones 6a–m, and final tetracyclic compounds 4a–m, effect/dose curves for complementary kinase profiling, anti-proliferative effects (U373 and U87 glioblastoma cells) for compound 4k and molecular modelling data. See DOI: https://doi.org/10.1039/d4md00537f
Notes and references
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Protein structures in PDBe (2)
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