Efficient construction of functionalized pyrroloindolines through cascade radical cyclization/intermolecular coupling

Pyrroloindolines are important structural units in nature and the pharmaceutical industry, however, most approaches to such structures involve transition-metal or photoredox catalysts. Herein, we describe the first tandem SET/radical cyclization/intermolecular coupling between 2-azaallyl anions and indole acetamides. This method enables the transition-metal-free synthesis of C3a-substituted pyrroloindolines under mild and convenient conditions. The synthetic utility of this transformation is demonstrated by the construction of an array of C3a-methylamine pyrroloindolines with good functional group tolerance and yields. Gram-scale sequential one-pot synthesis and hydrolysis reactions demonstrate the potential synthetic utility and scalability of this approach.


Introduction
][10][11][12] These molecules have gained interest owing to their extensive biological activities, including antitumor, antimicrobial, antinematodal, vasodilating activities, as well as inhibitory activities against cholinesterases and topoisomerases. 13,14onsequently, the efficient and straightforward construction of functionalized pyrroloindolines remains in demand.
Herein, we describe the rst tandem SET/radical cyclization/ intermolecular coupling between 2-azaallyl anions and indole acetamides, which enables the synthesis of C3a-substituted pyrroloindolines under mild and convenient conditions.The synthetic utility of this transformation is demonstrated by the construction of an array of C3a-methylamine pyrroloindolines with good functional group tolerance and yields (33 examples, up to 88% yield).

Results and discussion
We initiated the reaction optimization by choosing indole Naryloxy acetamide 2a as the model substrate.Reaction of 2a was performed with N-benzylketimine 1a in the presence of base in DMSO at room temperature for 3 h.Initially, a series of bases including LiO t Bu, NaO t Bu, KO t Bu, LiN(SiMe 3 ) 2 , NaN(SiMe 3 ) 2 and KN(SiMe 3 ) 2 were evaluated (Table 1, entries 1-6).Among them, NaN(SiMe 3 ) 2 generated the radical cyclization/coupling product 3aa in 89% assay yield (AY, as determined by 1 H NMR integration against an internal standard) and 86% isolated yield (dr = 1.2 : 1, entry 5), while the other ve bases led to product 3aa in 56-65% AY.Next, we then turned our attention to probe the effect of solvent and concentration.Using NaN(SiMe 3 ) 2 as base, we examined a range of solvents [THF, DMF, CPME, MTBE (methyl tert-butyl ether) and MeCN].Surprisingly, no desired products formed in these solvents (entries 7-11).Furthermore, decreasing the concentration to 0.1 M or 0.05 M led to a reduction in the AY to 78% and 68% (entries 12 and 13).When the equiv of base was increased from 1.5 to 2.0 equiv, a decrease in the AY to 72% (entry 14) was observed.Finally, increasing the reaction temperature to 60 °C or decreasing it to 0 °C resulted in a decrease in the AY to 22% or 8%, respectively (entries 15 and  16).
To demonstrate the utility and scalability of our cascade radical cyclization/intermolecular coupling reaction, a gramscale sequential one-pot synthesis and product hydrolysis were conducted.A telescoped gram-scale experiment was performed by employing benzylamine and diphenyl methyl imine in THF at 50 °C for 12 h, followed by solvent removal to afford imine 1a.The unpuried 1a was coupled with indole N-aryloxy acetamide 2a under the standard reaction conditions.The product 3aa was obtained in 74% yield (1.40 g, Scheme 2a).Subsequently, imine hydrolysis of the cyclization product 3aa under mildly acidic conditions furnished the free C3amethylamine pyrroloindoline derivative 4aa in excellent yield (92%, Scheme 2b).
Finally, to gain some information on the reaction mechanism, we carried out control experiments.First, the experiment with the addition of 2.0 equiv of radical scavenger 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) was conducted under the standard conditions.However, no desired product 3aa was detected, only affording TEMPO trapping compounds 5aa and 6aa in 70% and 10% yields (Scheme 3a).A control experiment with 2.0 equiv of TEMPO in the absence of N-benzyl ketimine 1a was carried out under the standard conditions, and radical coupling product 5aa was not observed (Scheme 3b).The lack of
[M] Yield (%) b product formation indicates that NaN(SiMe 3 ) 2 is not the active reductant in this chemistry.Together, these results suggest that the reaction proceeds via a radical pathway, supporting the key SET/radical cyclization/coupling pathway proposed in Scheme 1c.
A plausible mechanism for the reaction is outlined in Scheme 4. Ketimine 1a is deprotonated by the NaN(SiMe 3 ) 2 to afford the 2-azaallyl anion 7. Next, SED 7 undergoes an SET process with acetamides 2a to form azaallyl radical 8 and Ncentered radical 9.The amidyl radical 9 initiates a radical cyclization to generate C3a-pyrroloindoline radical 10.Finally,

Conclusions
In summary, we have developed a unique strategy for constructing functionalized pyrroloindolines in a single synthetic step.Unlike many previous reports, which generally involve transition-metal catalysts or photoredox catalysts, this chemistry utilizes readily generated SED, 2-azaallyl anions.In this transformation, the tandem SET/radical cyclization/ intermolecular coupling between 2-azaallyl anions and indole N-aryloxy acetamides provides the functionalized pyrroloindolines related to biologically active compounds by simple combination of base and DMSO at room temperature.A gram-scale sequential one-pot synthesis and hydrolysis reaction demonstrate the potential synthetic utility and scalability of this approach.It is noteworthy that this method includes a multistep tandem reaction with a rapid increase in molecular complexity.The sustainability of this method enhances its potential utility in the pharmaceutical industry. 50

Table 1
Optimization of coupling of ketimine 1a and amide 2a a,b

Table 2
Scope of Ketimines