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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