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. 2020 Jun 29;11(1):3263.
doi: 10.1038/s41467-020-17085-9.

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

Wen-Jun Zhou #  1   2 , Zhe-Hao Wang #  3 , Li-Li Liao  1 , Yuan-Xu Jiang  1 , Ke-Gong Cao  1 , Tao Ju  1 , Yiwen Li  3 , Guang-Mei Cao  1 , Da-Gang Yu  4   5
Affiliations

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

Wen-Jun Zhou et al. Nat Commun. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
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
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
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
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
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
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
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
Fig. 8. Mechanistic proposal for the arylcarboxylation of 1.
PC = 4CzIPN.
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