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Home > Visible light-mediated chemistry of indolines
Visible light-mediated chemistry of indolines
Construction of indolines
Preparation of indolines starting from indoles has been mainly described in the ‘‘Dearomatization reactions of indoles’’ section and will not be repeated in this section.
Nickel catalysis combined with photoredox proved to be effective for the preparation of indolines 97 through the interaction of o-iodoacetanilides with alkenes in the presence of Ni(cod)2, N-heterocyclic carbene ligand IPr, and Ru(bpy)3(PF6)2.76 The nickel catalytic cycle comprised the Ni(0)–Ni(II)–Ni(III)–Ni(I)–Ni(0) sequence, with single electron transitions Ni(II)–Ni(III) and Ni(I)–Ni(0) provided by the PC. The oxidation to Ni(III) was necessary to make the reductive elimination step more feasible, and the use of an N-heterocyclic ligand was shown indispensable to avoid the b-hydride elimination, giving undesired Heck reaction products. The scope investigation revealed that the reaction worked smoothly with both electron-donating and electron-withdrawing groups at the 4- or 5-position of anilide, but the substitution at the 3- or 6-position lowered the yields substantially. The study of the alkene coupling partner showed that only terminal alkenes, though highly various in substituents, could be used. No target products were detected, when internal or 1,1-disubstituted alkenes were employed (Scheme 48).
N-Allyl substituted o-iodo(bromo)acetanilides 98 were found to be viable substrates for the preparation of indolines. Firstly, Lee and Kim realized an intramolecular cyclization taking advantage of a reductive quenching cycle of a [Ir(ppy)2(dtbbpy)]PF6 and DIPEA system, giving indolines 99 from bromo- or iodo- substituted N-allylanilides with 97 and 93% yields, respectively.77 Later, a copper catalyzed transformation was developed by Evano and co-workers.78 In this case, N-alkyl or N-Boc indolines 100 could be prepared with fair to good yields, and various substituents at the benzene ring were also well tolerated. Again, the reaction proceeded through a reductive quenching cycle, generating strongly reducing Cu(0) species, capable of donating an electron to an aryliodide. Recently, metal-free cyclization o o-iodoacetanilides 101 has been reported.79 In this work, a tris(trimethylsilyl)silane (TTMSS) additive has been used to form a photoactive electron donor–acceptor (EDA) complex with an o-halo-N-allylanilide substrate (Scheme 49).
Cyclopropylidene-substituted anilines may undergo a cyclo- addition with activated alkynes to furnish cyclobuta[b]indolines
102 . When the reaction is performed under an oxygen atmosphere and irradiated with visible light, the oxidation of indoline takes place, and the spiro-cyclobutane–cyclopropane system is rearranged into cyclopenta[b]indoline 103.80 Variously substituted anilines (R1 = Alk, Ar, Hetaryl) react smoothly, giving products with 40–98% yields. The alkyne component has also been screened, and neither dicarbonyl nor dicarboxyl alkyne succeeded in the transformation.
The mechanistic investigations suggest that initial [2+2] cyclo- addition, followed by Michael addition of an aniline amino-group to the formed activated double bond, generates photoactive cyclo- buta[b]indoline 102. Photoexcitation of compound 102 through irradiation with blue LEDs is followed by oxidation with O2 into a cation radical and ring opening to give an intermediate 104. Cyclopropyl ring opening with subsequent reduction of the free radical with the superoxide anion generates biradical 105, which couples to form a final five-membered ring-annulated indoline 103 (Scheme 50).
The ecologically benign preparation of 2-arylindolines 106 from vinyl bromides has been developed by Reiser and Pagire (Scheme 51).81 The reaction sequence includes the following steps: photoexcited Ir(III)* reductive quenching by DIPEA; single electron reduction of the C–Br bond by Ir(II); 1,6-hydrogen transfer; radical addition to an activated double bond, and hydrogen abstraction from the DIPEA radical cation. The aryl moiety has been found to be capable of bearing electron-donating and electron-withdrawing groups, except for the nitro-group, which is often incompatible with photoredox conditions.
Construction of the tetracyclic core of akuammiline alkaloids through a photocatalytic domino transformation has been reported by Zheng and co-workers.82 The N-aryl-substituted anilines, bearing a functionalized alkene moiety in the ortho-position, undergo single electron oxidation by a highly oxidizing Ru(bpz)3(PF6)2* catalyst and the sterically close alkene group is attacked to furnish a spiro-cyclopentylindoline cation radical intermediate 107. Further deprotonation and oxidation of 107 lead to carbocation 108. Subsequent 1,2-shift, followed by nucleophilic attack of a hydroxyl (or amine) group (X = OH, NHBoc, NCO2Me), finalized the reaction sequence, producing valuable tetracyclic indolines 109 with 21– 84% yields (Scheme 52). For the successful reaction, either the aryl substituent on the aniline nitrogen (Ar = PMP, TMP), or the benzene ring (R1 = OMe) should contain an electron-donating group. The role of pivalic anhydride is presumed to be dual: firstly, it is a residual water scavenger, secondly, the formation of pivalic acid creates an acidic medium to facilitate the reaction.
Functionalization of indolines
Knowles and co-workers reported a photoredox-mediated indo- line 110 dehydrogenation for the synthesis of the elbasvir intermediate, 111. The process is carried out in the presence of an [Ir(dF-CF3-ppy)2(dtbpy)]PF6 photocatalyst and tert-butyl- perbenzoate (t-BPB) as an oxidant in DMA, using a flow reactor (Scheme 53). The reaction proceeds smoothly at a temperature below 0 1C with 94% yield and retention of the enantiomeric purity (ee 499%). It is worth noting that this is a first example of employment of photoredox catalysis for multigram scale synthesis of a pharmaceutically relevant intermediate, capable of producing 100 g of the target compound in a few hours. The reaction mechanism investigation suggests that the reaction proceeds via hydrogen atom transfer by an alkoxy radical.
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