Reductive dearomative arylcarboxylation of indoles with CO2 via visible-light photoredox catalysis

Abstract

Catalytic reductive coupling of two electrophiles and one unsaturated bond represents an economic and efficient way to construct complex skeletons, which is dominated by transition-metal catalysis via two electron transfer. Herein, we report a strategy of visible-light photoredox-catalyzed successive single electron transfer, realizing dearomative arylcarboxylation of indoles with CO₂. This strategy avoids common side reactions in transition-metal catalysis, including ipso-carboxylation of aryl halides and β-hydride elimination. This visible-light photoredox catalysis shows high chemoselectivity, low loading of photocatalyst, mild reaction conditions (room temperature, 1 atm) and good functional group tolerance, providing great potential for the synthesis of valuable but difficultly accessible indoline-3-carboxylic acids. Mechanistic studies indicate that the benzylic radicals and anions might be generated as the key intermediates, thus providing a direction for reductive couplings with other electrophiles, including D₂O and aldehyde.

Fig. 1. Strategies for tandem reductive couplings.

a Widely investigated transition-metal-catalyzed reductive coupling via two electron transfer process. (i) ipso reductive coupling, (ii) tandem reductive cyclization/coupling, (iii) β-hydride elimination or isomerization as other side reactions. b Rarely investigated radical-type reductive coupling via successive single-electron transfer process. O.A. oxidative addition, SET single-electron transfer. The gray square represents common organic structure. The pink circle represents organic electrophiles.

Fig. 2. Reductive dearomative difunctionalization of indoles.

a Tandem Ni-catalyzed asymmetric reductive dearomative functionalization of indoles by using proton or alkyl bromides as another electrophile. b Visible-light-promoted reductive dearomative arylcarboxylation of indoles with CO₂ via SSET process, in which carbon centered benzylic radical and benzylic anion as key intermediate. PC photocatalyst.

Fig. 3. Scope of substrates with substituents on indoles.

The standard reaction conditions were used, as shown in Table 1, entry 1. Isolated yields are presented.

Fig. 4. Scope of substrates bearing unactivated aryl bromides and iodides.

Reaction conditions: Indole derivatives (0.2 mmol), Ir-catalyst (0.002 mmol), Cs₂CO₃ (0.6 mmol), DIPEA (1.3 mmol), DMSO (2 mL), 1 atm of CO₂, 30 W blue LEDs, RT, 24 h, isolated yield.

Fig. 5. Synthetic applications.

a Synthesis of 6-membered and 7-membered ring-bearing products under the standard conditions. b Gram-scale synthesis of 2. c Transformations of the product 2. (i) bromination with Br₂ and AcOH. (ii) selective reduction of the C3-ester group by borane. (iii) reduction of amide and ester groups by LiAlH₄.

Fig. 6. Preliminary mechanistic studies.

a Trapping experiment by radical scavenger 2,2,6,6-tetramethyl-piperidinyloxyl (TEMPO), supporting that radical process might be involved. b Isotopic labeling experiments in DMSO-d₆ or in the presence of different amounts of deuterated water, suggesting that benzylic anion was involved. c 4-fluorobenzaldehyde was used as an electrophile instead of CO₂, further indirectly confirming the formation of benzylic anion intermediate.

Fig. 7. Optical experiment with fluorescence spectrum.

a Steady-state Stern–Volmer experiment of 4CzIPN and DIPEA, the luminescence of 4CzIPN was readily quenched by DIPEA. b Stern–Volmer fluorescence quenching experiments using 4CzIPN with DIPEA, 1 as well as 1 and Cs₂CO₃.

Fig. 8. Mechanistic proposal for the arylcarboxylation of 1.

PC = 4CzIPN.