An efficient debromination technique using PMHS with a number of ligands containing different functional groups

Herein is described the strategy to debrominate different aryl bromides selectively, using polymethylhydrosiloxane (PMHS) which tolerates a variety of functional groups. Key elements of this approach include the use of catalytic Pd(OAc)2 and the correct equivalents of polymethylhydrosiloxane (PMHS), in conjunction with aqueous KF. The present reaction process provides a strategic tool for the synthesis of a number of medicinally important molecules.


Introduction
Bromine-substituted aryl halides are important targets for further functionalization catalyzed by palladium catalysts or other chemical strategies. 1 Often times a cheap starting aryl bromide can be the lynch pin in the synthesis of new heterocyclic compounds.Replacement of bromine by hydrogen can be carried out using Polymethylhydrosiloxane (PMHS) reported earlier by Ronald et al. 2 It is a mild reducing agent, cost-effective, non-toxic and an easily handled chemical.It can be stored for long periods of time since it is more air and moisture stable than any other silanes. 3PMHS is relatively inert but can transfer the hydride to participate in different metal catalyzed reductions. 4Hydrosilanes are mild reducing agents with a variety of applications. 25,26In addition, some hydrosilanes are compatible with some oxidizing agents and act as selective reducing agents in a one-pot redox cocktail. 27MHS hydrodehalogenates aryl halides when using a palladium catalyst. 2A method to debrominate aryl bromides in the presence of a number of functional groups such as ketones, amides, imines, and esters was developed.We debrominated bromo-benzodiazepines using this method and then nitrated the resulting product to synthesize pharmaceutically active potential drug candidates. 15

Results and Discussion
][8][9][10][11][12][13] We required a suitable system to debrominate different benzodiazepine compounds.The investigation initially revealed Pd(OAc)2 with PMHS in the presence of potassium fluoride reduced chlorobenzene to benzene, 2 and this transformation took place at room temperature.We followed the conditions to debrominate a benzodiazepine which bears a bromo and a chloro functionality.The benzodiazepine 1 was synthesized according to the literature procedure. 14As expected both halogens were reduced by PMHS (Scheme 1).

Scheme 1. Dehalogenation of benzodiazepine.
Based on this result, we started to explore this system to find a better method to selectively debrominate the aryl halide without affecting other functional groups.Initially we investigated conditions to determine the correct equivalents of PMHS and reaction time for selective debromination.We used the substrate 1 for our initial investigation (Scheme 2).Different equivalents of PMHS and different mole% of Pd catalyst were used to identify the best conditions.It was found that bromide 1 could be debrominated chemoselectively by reducing the amount of PMHS in the presence of 5 mole% Pd(OAc)2; although the reaction time was longer, as expected, and the reaction also gave the byproduct 2 in minor amounts.(   *From HPLC (Pinnacle -C18 (2.1 mm × 50 mm, 1.8 μm particle size) column, flow rate of 0.5 mL/min, mobile phase-acetonitrile and water (containing 0.1% formic acid)) ; a Isolated combined yield of (2 and 3); b Ratio of 1 and 3; C Combined yield of (1 and 3) The debromination reaction was also investigated with different benzodiazepines, as shown in Table 2. Benzodiazepine derivatives (4a-h) were subjected to debromination under the same conditions (Scheme 3, Table 2) to furnish the products 5a-h (71%-81%), respectively.We also increased the amount of PMHS to debrominate the substrate 4e to produce 5e (Table 2, entry 5).The debromination occurred smoothly in less reaction time without affecting the amide and imine functionality of the benzodiazepine substrates.A similar trend was also observed in the case of substrate 4h.Here an interesting observation was found.Although the acetate is a labile protecting group to reduction, it survived the debromination reaction process by PMHS.The hydride source did not interfere with the acetate moiety.We, then identified conditions in different benzophenone substrates, as shown in Table 3 (Scheme 4).The treatment of other benzophenone substrates afforded debrominated product 7a-d in good to high yields (Table 3).We also observed that increasing the amounts of PMHS decreased the reaction time in some benzophenone substrates (6a-b), as expected.PMHS did not affect the ketone functionality in any benzophenone substrate (Table 3, entry 1-8), as we hypothesized.Selective debromination over chlorination was also observed in this case (Table 3, entry 3), which is also as expected and, gratifyingly, took place.Furthermore, we attempted the debromination on an imidazodiazepine substrate possessing an ester function (Scheme 5).The imidazodiazepine 8a gave the debrominated product 9a in good yield.The imidazodazepine ester was well tolerated under these reaction conditions confirming the mildness of the PMHS process.Also, upon investigation on a double bond containing aryl substrate, PHMS debrominated the bromine group selectively without interfering with the double bond (Scheme 6, preliminary data, SI)  Anti-schistosomal activity of 8-H benzodiazepines Schistosomiasis, a neglected tropical disease is one of the most dominant infectious diseases worldwide that has serious public health consequences [16][17][18][19] and is characterized by chronic helminthic infection with residual morbidity.Over 240 million people are infected, with 800 million at risk of infection and more than 90% of infections occurring in sub-Saharan Africa where the death rate is approximately 280,000 persons per year. 15chistosomiasis is caused by parasitic blood flukes (trematode worms) of the genus Schistosoma, of which Schistosoma mansoni, Schistosoma japonicum and Schistosoma haematobium cause infections in humans. 20he treatment of schistosomiasis relies only on one broad spectrum drug, praziquantel which is associated with several drawbacks including PZQ's lack of efficacy against immature parasites.Meclonazepam, a benzodiazepine was found to be effective in treatment of schistosomiasis 15 and was able to cure both mature and immature infections.[23][24] Figure 1.Structure of meclonazepam.[1,4]diazepin-2-one and the structure bears a nitro group in one of the benzene rings (Figure 1).We synthesized different benzodiazepines (most of them in this manuscript) which contained 8-H instead of 8-nitro groups and assessed the synthesized compounds in schistosome mobility assays.This assay was done in order to identify the importance of the nitro group in the structure of the benzodiazepines in regard to activity.The results are summarized in Table 4.

Table 4. Anti-schistosomal effect of C-7 H benzodiazepines
The IC50 value of meclonazepam is 160 nM and it causes contractile paralysis of the parasites.The parasites were coiled, dead upon the exposure to the meclonazepam (Table 4).But changing the nitro group to hydrogen resulted in total loss of activity (entry 2, Table 4).Changing the nitro group to a hydrogen atom along with other modifications demonstrated no activity at all (entry 3-7, Table 4).Consequently, a hydrogen atom at the 8position in place of a nitro group is not suitable for anti-schistosomal activity.In order to identify whether the electronic effects of the nitro group or the structure of nitro group itself was responsible for schistocidal activity, we replaced the nitro group with a cyano group and assessed the compound's activity in the schistosome mobility assay.This resulted in total loss of activity.This would argue, although not prove, against a pi stacking interaction with the ring-A aromatic ring in meclonazepam.Modification of different positions without changing the nitro group show various degrees of anti-schistosomal activity and some of these results are described in McCusker P. et al. 2019. 15The nitro group in the structure of meclonazepam is crucial for the damage to the parasite.

Conclusions
It was demonstrated that ketones, amides, esters and imines were all well tolerated under the reduction conditions of PMHS employed here with catalytic Pd(OAc)2 in THF.This is an efficient system for the

Experimental Section
General.All reactions were performed in round-bottom flasks with magnetic stir bars under an argon atmosphere.Organic solvents were purified when necessary by standard methods or purchased from Sigma-Aldrich Chemicals.The reagents and other chemicals were purchased from either Sigma-Aldrich, Oakwood Chemical, Alfa Aesar, Matrix Scientific, Admiral Chemical Company, or Acros Organic.The progress of reactions was visualized with TLC plates from Dynamic Adsorbents, Inc. under a UV light.The flash column chromatography was done for purification of some analogs on silica gel (230-400 mesh, Dynamic Adsorbents).
An Agilent HPLC was used to determine the ratio of some debrominated products.The 1 H NMR and 13 C NMR spectra were obtained on Bruker Spectrospin 500 MHz instrument in CDCl3 and chemical shifts were reported in δ (ppm).Multiplicities are represented as follows: singlet (s), broad signal (br), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), and multiplet (m).The technique employed for HRMS was carried out on a LCMS-IT-TOF at the Milwaukee Institute for Drug Discovery in the Shimadzu Laboratory for Advanced and Applied Analytical Chemistry.
General procedure for the debromination: A three neck round bottom flask was charged with the aromatic halide.Then THF was added and the flask was purged with argon.Palladium acetate was then added under an argon atmosphere, followed by the addition of aq potassium fluoride solution.Then PMHS was added dropwise to the reaction mixture, which resulted in a deep greenish solution.The reaction mixture was then stirred for the required time by monitoring by TLC (see Tables for data).The consumption of starting material was confirmed on a LCMS 2020.The round bottom flask was open to the air at the end of the reaction.2 Grams of alumina was added to the reaction flask and this was allowed to stir for 5 min.The reaction mixture was filtered through a pad of celite to removethe Pd salts; water and ethyl acetate was added to the filtrate.The layers were separated and the aq layer was extracted with ethyl acetate and the combined organic layer was washed with aq 10% NaCl solution (2x), dried over sodium sulfate, concentrated under reduced pressure and purified via silica gel column chromatography.The gradient elution was effected by ethyl acetate and hexane.The purified compounds were characterized by NMR spectroscopy, LCMS and HRMS (individually).
The aq layer was extracted with ethyl acetate (2x10mL) and the combined organic layer was washed with aq 10% sodium chloride solution (2x10mL), dried over Na2SO4 and, concentrated under reduced pressure.The residue was purified by silica gel column chromatography using EtOAc: hexane (35:65).The appropriate fractions were pooled, the solvents were removed under reduced pressure and the residue was dried under vacuum to obtain a white powder 5 (0.49 g, 81% yield).
Then aq potassium fluoride (0.351g, 6 mmol in 2 mL water) solution and PMHS (0.16 mL, 2.65 mmol) were added to the mixture and it was stirred for the time mentioned in Table 2.The flask was then opened to the air, stirred with alumina, and filtered through The aq layer was extracted with ethyl acetate (3x10 mL) and the combined organic layer was washed with aq 10% sodium chloride solution (2x10mL), dried over Na2SO4 and concentrated under reduced pressure.The residue, which resulted, was purified with silica gel chromatography using EtOAc: hexane (35:65).The appropriate fractions were pooled, and the solvents were removed under reduced pressure.The residue was then dried under vacuum to obtain a white powder 5b (0.55g, 73%). 1

Scheme 2 Table 1 .
Effect of different equivalents of PMHS on selective debromination

Table 2 .
Debromination strategy on different benzodiazepines a Isolated yield