Background and Originality Content
Spirocyclic scaffolds are widely present in natural products,[1, 2] marketed drugs, and drug candidates (Figure 1).[3-5] Compared with planar compounds, the incorporation of a spirocyclic framework makes it easier for organic molecules to adopt the optimal conformation to bind to the target proteins.[6] Additionally, the presence of chiral centers at spirocyclic atoms provides more opportunities to discover chiral drugs.[7-9]However, the synthesis of spirocyclic compounds has been greatly limited due to their complex synthetic steps and challenging selectivity issues.[10, 11] Therefore, it is particularly important to develop green and efficient synthetic strategies to prepare various spirocyclic skeletons efficiently.
Oxidative dearomatization is one of the most straightforward means to transform aromatic compounds to spirocyclic compounds.[12] The traditional synthesis strategy mainly uses stoichiometric oxidants[13-16] or the recently developed photochemical means.[17] In recent years, electrochemical synthesis has been emerging as a green and sustainable synthetic alternative.[18-20] Compared with traditional chemical methods, electrochemical synthesis merits good selectivity control, mild reaction conditions,
and prospect for sustainability.[21-26] While most electrochemical dearomative spirocyclizations are carried out in batch reactors,[27-36] there are relatively few cases of using electrochemical continuous-flow syntheses.[37-40] Compared with batch reactors, continuous-flow electrochemical microreactors are easy to scale up in short reaction time. Since the distance between two electrodes in an electrochemical continuous-flow cell is short and adjustable, the use of supporting electrolytes can be reduced or even eliminated in certain circumstances.[41-44]
Figure 1. Bioactive molecules containing spirocyclic scaffolds.
Besides these advantages, electrochemical continuous-flow synthesis also facilitates the discovery of novel reactions. In our previous work,[45] we have achieved the electrochemical migrative cyclization of N -acylsulfonamides in a batch reactor to afford a series of biologically active benzoxathiazine dioxide derivatives.[46-49] Interestingly, the incorporation of an extra p -methoxyl group in theN -acylsulfonamide intercepts the reaction pathway from the original migratory cyclization to dearomative spirocyclization (Scheme 1a). In addition, we utilize an electrochemical continuous-flow reactor to further explore such a novel reactivity to obtain a multitude of spirodienone scaffolds. Remarkably, upon treatment with FeCl3, an exclusive sulfone migration/rearomatization took place to afford the biologically interesting hydroxylated benzothiazine dioxide which is otherwise impossible or challenging to achieve (Scheme 1b).
Scheme 1 Electrochemical dearomative spirocyclization in flow.
Results and Discussion
Initially, we chose N -((4-methoxyphenyl)sulfonyl)benzamide (1 ) as the model substrate to optimize the electrolysis conditions in an electrochemical continuous-flow cell equipped with a carbon plate anode and a nickel cathode (Table 1). Constant-current electrolysis (I = 130 mA) via the pumping of a solution of (1 ) in MeOH (c 0.04 M) without any additive or supporting electrolyte through the cell at a rate of 0.5 mL min-1 and subsequently quenched with 2.0 M HCl solution gave the desired spirodienone (2 ) in 85% yield (entry 1). The control experiment proved that the target product could not be obtained without passing current (entry 2). When the current was reduced or increased, the yield of the target product decreased to a certain extent (entries 3 and 4). Reducing the reaction flow rate to 0.4 mL min-1, the yield of product (2 ) dropped sharply to 56% (entry 5). Interestingly, the inclusion of supporting electrolyte Me4NBF4 (5 mol%) in the reaction mixture resulted in a reduction in the yield (69%) owing to the low conversion (entry 6). The change of cathode material from Ni to Pt (entry 7) or stainless steel (entry 8) was inferior to this reaction.
Under optimal reaction conditions, the substrate scope of this continuous-flow electrochemical spirocyclization ofN -((4-methoxyphenyl)sulfonyl)benzamide was then investigated (Scheme 2). A wide array of substrates with diverse substituents at thepara positions of the phenyl moiety were well tolerated, including electro-donating methyl (3 , 81%), tert -butyl (4 , 78%), methoxyl (5 , 36%), and electron-withdrawing groups (6 -7 , 56%-68%). In addition, various substrates with electron-donating or electron-withdrawing substituents can also be tolerated in themeta or ortho position of the phenyl of benzoate moiety (8 -16 , 25%-79%). When biphenyl (17 ), thiophene (18 ), and naphthalene ring (19 ) were used to replace the phenyl group, this transformation still proceeded smoothly. In addition, this protocol could also be successfully applied to the late-stage functionalization of a pharmaceutical derivative,i.e. , probenecid (20 ). Next, we found the metasubstituents (MeO, F) of arylsulfonyl moiety can be tolerated (21 -22 , 61-66%). The replacement of the originalpara methoxy to the ortho position was still applicable (23 ).
Table 1 Optimization of reaction conditions[a]
[a] Reaction conditions: graphite anode, Ni cathode, fluorinated ethylene propylene (FEP) foil spacer (0.25 mm thick). 1 (c 0.04 M), 10.0 mL of the outlet solution was collected and analyzed. [b] Isolated yield.
Scheme 2 Substrate scope.a
[a] Reaction conditions: undivided cell, carbon cloth as the anode, Ni cathode, MeOH = 10 mL, room temperature, constant-current electrolysis (130 mA), flow rate = 0.5 mL min-1; [b] I = 70 mA;[c] MeOH:DCE = 8:4 mL.
To verify the practicability of this reaction, we carried out a decagram-scale preparation. Remarkably, the anticipated spirodienone (2 ) was obtained in 61% yield (10.57 g, Scheme 3a) by electrolyzing 63.36 mmol ofN -((4-methoxyphenyl)sulfonyl)benzamide (1 ) at a current of 130 mA. Further synthetic elaborations of the obtained spirodienone were also examined (Scheme 3b). The migrative cyclizedpara -hydroxylated benzoxazine (24 ) was obtained in almost quantitative yield upon treatment with FeCl3, whose chemical structure was confirmed by X-ray diffraction analysis.[50] Upon hydrogenation with Pd/C, the C-O bond of the product was highly selectively cleaved and reduced to the starting material 4-hydroxysulfonamide (25 ). Furthermore, the spirodienone (2 ) proceeded smoothly via Michael addition reaction with vinyl magnesium bromide (26 ). Finally, an O-imine derivative (27 ) was readily obtained in the presence of a phosphoric acid catalysis.
Scheme 3 A decagram-scale synthesis and derivatization of product. Reaction conditions: (a) FeCl3 (0.25 equiv.), DCE, r.t., 2 h; (b) Pd/C (0.2 equiv.), H2, MeOH, r.t., 4 h; (c) C2H3BrMg (1.2 equiv.), THF, r.t., 12 h; (d) O-(4-nitrophenyl)hydroxylamine (1.05 equiv.), diphenyl phosphate (10 mol%), Na2SO4 (2.5 equiv.), DCM, r.t., 11 h.
Scheme 4 Proposed mechanism.
Based on cyclic voltammetry studies (see Figure S5) and literature precedence,[37, 40, 51] a possible reaction mechanism was proposed (Scheme 4). First, (1 ) is directly oxidized at the anode to generate the radical cation intermediate (A ). The subsequent intramolecular spirocyclization forms a radical intermediate (B ), which could be further oxidized at the anode to produce a carbocation intermediate (C ). Finally, the intermediate (C ) is readily nucleophilic captured by MeOH, which is hydrolyzed under acidic conditions to give the target product (2 ). Before the workup, the formation of intermediate (28 ) was isolated in 86% yield under standard conditions,[50] which is quantitatively hydrolyzed upon the workup with aqueous HCl (see Supporting Information ).
Conclusions
In summary, we have developed an electrochemical dearomative spirocyclization ofN -((4-methoxyphenyl)sulfonyl)benzamides without any additives or supporting electrolytes. Biologically interesting benzothiazine dioxide can be obtained by simple treatment of FeCl3 with the above-obtained spirodienone, which makes this method attractive in medical and biological applications. This work demonstrates that continuous-flow electrolysis exhibits great prospects for the discovery of novel reactivity and sustainable synthesis.
Experimental
The electrolysis was conducted with a constant current of 130 mA using an electrochemical continuous-flow cell, which was equipped with a graphite anode and a Ni cathode with a surface area of 10 cm2 and an interelectrode distance of 250 μm. The substrate (c 0.04 M in MeOH) was pumped through the electrochemical continuous-flow cell using a syringe pump with a flow rate of 0.5 mL min-1. In the beginning, the system was stabilized for 2 min. After a steady state was reached, the outlet solution was collected for 20 min (10 mL). The formation of bubbles in the tube can be observed during the reaction. A solution of HCl (2 M, 2 mL) was added and kept stirring for 0.5 h. The reaction mixture was then concentrated in vacuo , and the crude residue was subjected to flash column chromatography on silica gel to yield the desired product.
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
This work was supported by the National Natural Science Foundation of China (No. 22171046) and the Hundred-Talent Project of Fujian (No. 50021113).
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