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. 2023 Dec 20;9(51):eadk1704. doi: 10.1126/sciadv.adk1704

Ir/Zn-cocatalyzed chemo- and atroposelective [2+2+2] cycloaddition for construction of C─N axially chiral indoles and pyrroles

Jian Yang 1,†, Zhong-Yang Xie 1,†, Yu-Jie Ye 1, Sheng-Bing Ye 1, Yi-Bo Wang 1, Wen-Tao Wang 1, Peng-Cheng Qian 1,2,*, Ren-Jie Song 3, Qing Sun 3,*, Long-Wu Ye 4, Long Li 1,2,4,*
PMCID: PMC10732529  PMID: 38117883

Abstract

Here, an Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition of 1,6-diynes and ynamines was developed, forging various functionalized C─N axially chiral indoles and pyrroles in generally good to excellent yields (up to 99%), excellent chemoselectivities, and high enantioselectivities (up to 98% enantiomeric excess) with wide substrate scope. This cocatalyzed strategy not only provided an alternative promising and reliable way for asymmetric alkyne [2+2+2] cyclotrimerization in an easy handle but also settled the issues of previous [Rh(COD)2]BF4-catalyzed system on the construction of C─N axial chirality such as complex operations, limited substrate scope, and low efficiency. In addition, control experiments and theoretical calculations disclosed that Zn(OTf)2 markedly reduced the barrier of migration insertion to significantly increase reaction efficiency, which was distinctly different from previous work on the Lewis acid for improving reaction yield through accelerating oxidative addition and reductive elimination.

Chemo- and atroposelective synthesis of chiral indoles and pyrroles was reported via Ir/Zn-cocatalyzed [2+2+2] cycloaddition.

INTRODUCTION

Transition metal–catalyzed [2+2+2] cycloaddition of three 2π components has attracted much attention, due to its high efficiency and atom economy for the rapid construction of functionalized six-membered carbo- and heterocycles with high functional group tolerance (1–3). In particular, transition metal–catalyzed inter- and intramolecular asymmetric [2+2+2] cycloadditions of alkynes have been proven as a powerful tool to synthesize valuable benzene-based skeletons bearing central (4, 5), axial (6–9), planar (10, 11), helical chirality (12–16), and chiral belts (17–19), which were well established by Tanaka and others (Fig. 1A). In sharp contrast to other well-explored chirality, the studies of C─N axial chirality via catalytic enantioselective [2+2+2] cyclotrimerization of alkynes were extremely limited and challenging. To our knowledge, the pioneering work was developed by Tanaka and co-workers to prepare the C─N axially chiral amides with high enantioselectivities via [Rh(COD)2]BF4-catalyzed [2+2+2] cycloaddition of 1,6-diynes and trimethylsilylynamides in 2006 (Fig. 1B, top) (20). Using a similar strategy, axially chiral amides with C─N and C─C axis were obtained by Hsung and co-workers in 2007 (Fig. 1B, bottom) (21). Although two encouraged achievements have been made, some challenging issues in this field are still not addressed for nearly two decades, such as the limited substrate scope and low efficiency. Moreover, most research on asymmetric [2+2+2] cycloadditions of alkynes are restricted to using air sensitive [Rh(COD)2]BF4 as a catalyst, resulting in the inconvenient process including glove-box and hydrogen operations, and lack a new catalytic system for the construction of C─N axial chirality. Nevertheless, the exploration of efficient preparation of valuable C─N axial indoles and pyrroles with broad substrate scope, especially based on a new strategy involving catalytic atroposelective [2+2+2] cycloaddition of alkynes in an easy handle way, is still underdeveloped but highly desired.

Fig. 1. Catalytic asymmetric [2+2+2] cycloaddition of alkynes for the synthesis of chirality and C─N axially chiral indole–based skeletons.

Fig. 1.

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(A) Synthesis of chirality via catalytic asymmetric [2+2+2] cycloaddition of alkynes. (B) Synthesis of C─N axially chirality via this strategy. (C) C─N axially chiral indole–based skeletons in natural products and chiral ligands. (D) Construction of C─N axially chiral indole–based skeletons from ynamines. (E) This work: Ir/Zn-cocatalyzed chemo- and atroposelective [2+2+2] cycloaddition.

Asymmetric ynamide transformations (22–25) catalyzed by transition metal catalysts and organocatalysts have been verified to be a reliable approach for the rapid assembly of useful chiral N-heterocycles, which were well developed by Ye (26–30) and others (31–35). However, most of them have been restricted to constructing central chirality, and the explorations on the axial chirality (36–42) were rarely reported (20, 21, 26, 29), especially the C─N axially chiral indoles (43, 44), which widely exist in natural products such as (M)-(+)-murrastifoline F and in chiral ligands (Fig. 1C) (29). As a powerful supplement, ynamines, in particular sterically hindered alkynes linked with an indole, are special alkynes attached to the nitrogen atom without an electron-withdrawing group (45) and have attracted much attention for the efficient construction of C─N axis chiral compounds recently. For example, Li and co-workers demonstrated an elegant protocol, by using indolyl-ynamine as an available atropisomer partner, to prepare multitudinous C─N axially chiral indole frameworks via Pd-catalyzed atroposelective hydrophosphination (46) and Rh(III)-catalyzed asymmetric C─H activation (47–49), respectively (Fig. 1D). Very recently, Xu and co-workers realized a novel Enantioselective-Rh-catalyzed Alkyne-Azide Cycloaddition (E-RhAAC) reaction of indolyl-ynamines and azides for the construction of C─N axially chiral 1,2,3-triazoles with high efficiency and atom economy (Fig. 1D) (50). Despite these remarkable achievements, studies on the synthesis of axial chirality based on ynamines, especially C─N axially chiral indoles and pyrroles, were still quite scarce and full of challenges but great in demand. Inspired by our continued work on the alkyne transformations (51, 52) and above mentions (20, 21), we envision that the indolyl-ynamines would be introduced to undergo atroposelective [2+2+2] cycloaddition with 1,6-diynes, leading to the formation of C─N axially chiral indoles (Fig. 1E).

Here, we describe the realization of practical and atom-economic synthesis of valuable C─N axially chiral indoles and pyrroles in generally good to excellent yields and high enantioselectivities with wide substrate scope via Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition of 1,6-diynes and ynamines. Compared with well-established [Rh(COD)2]BF4-catalyzed asymmetric versions involving inconvenient glove-box and hydrogen operations, this Ir/Zn-cocatalyzed protocol provides an alternative and encouraging approach for the construction of axial chirality via atroposelective alkyne [2+2+2] cyclotrimerization in an easy manner. Except for the generally high efficiency and enantiocontrol, this protocol displays excellent chemoselectivity with ynamines bearing different 2π groups. In addition, Zn(OTf)2 catalyst could accelerate migration insertion to significantly improve the reaction yield, which was strongly supported by control experiments and theoretical calculations.

RESULTS

At the outset, indolyl-ynamine 1 substituted with an ester group as a chelation group (8) was chosen as the model substrate to verify our initial design [2+2+2] cycloaddition with 1,6-diynes 3 in Table 1. Encouraged by Tanaka’s work (8, 20), various chiral ligands were initially used to perform [2+2+2] cyclotrimerization in the presence of [Rh(COD)2]BF4 as a catalyst. Unfortunately, no desired axially chiral product was observed in the well-established Rh(I) system, and the steric hindrance of ynamine 1 probably resulted in the almost side-product 3′ from the self-[2+2+2] cycloaddition of 1,6-diynes (see table S1). Pleasingly, the expected C─N axially chiral indole 4 was obtained in 82% enantiomeric excess (ee) value and 37% yield by the introduction of chiral phosphoramidite ligand L1 and [Ir(COD)Cl]2 (Table 1, entry 1). Although the reaction yield was low and most of 1,6-diyne 1 and ynamine 3 were remaining, this positive result strongly supported the feasibility of our presupposition. Further investigation on the different ligands was carried out, and L7 could provide high enantioselectivity but unsatisfactory yield (Table 1, entries 2 to 8). Then, the replacement of phenol group by the steric 1-naphthol group provided the higher enantiocontrol product 5 (Table 1, entry 9). Afterward, we turned our attention to improving the efficiency of this reaction, and many conditions were screened including catalysts, solvents, and other variations but could not give a better result (see table S2). Enlightened by Dong and others’ work on the Lewis acid as a cocatalyst for significant improvement of reaction yield through accelerating oxidative addition and reductive elimination (53–58), a series of Lewis acids covering Fe(OTf)2, Zn(OTf)2, Cu(OTf)2, and Y(OTf)3 were introduced to elevate the reaction rate via the coordination of the ester group and activation the ynamine (Table 1, entries 10 to 13). Delightfully, Zn(OTf)2 could significantly improve the reaction yield to afford 5 in 85% yield and 94% ee (Table 1, entry 11). Subsequent examination of the loading of cocatalyst indicated that 20 mol % Zn(OTf)2 delivered cycloaddition product 5 in 95% yield and 94% ee under an open-air system without any glove-box operation (Table 1, entry 14). In addition, ynamine 1 substituted with the smaller phenol as an ester group was conducted under the optimal conditions to yield chiral product 4 with a satisfactory yield and enantioselectivity (Table 1, entry 16). rt, room temperature.

Table 1. Optimization of reaction conditions.

Reaction conditions: 1 or 2 (0.1 mmol), 3 (0.05 mmol), [Ir(COD)Cl]2 (2 mol %), ligand (5 mol %), and toluene (1.0 ml) in vials.

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Entry Ligand Reaction conditions Yield(%)* Ee(%)†
1 L1 R = X1, 24 hours 37 82
2 L2 R = X1, 24 hours – –
3 L3 R = X1, 24 hours – –
4 L4 R = X1, 24 hours – –
5 L5 R = X1, 24 hours – –
6 L6 R = X1, 24 hours – –
7 L7 R = X1, 24 hours 35 88
8 L8 R = X1, 24 hours 20 85
9 L7 R = X2, 24 hours 38 92
10 L7 R = X2, Fe(OTf)3 (10 mol %), 24 hours 28 90
11 L7 R = X2, Zn(OTf)2 (10 mol %), 24 hours 85 94
12 L7 R = X2, Cu(OTf)2 (10 mol %), 24 hours – –
13 L7 R = X2, Y(OTf)3 (10 mol %), 24 hours 60 92
14 L7 R = X2, Zn(OTf)2 (20 mol %), 12 hours 95 94
15 L7 R = X2, Zn(OTf)2 (30 mol %), 12 hours 92 94
16 L7 R = X1, Zn(OTf)2 (20 mol %), 12 hours 93 90
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*Yield based on 1H NMR analysis of the crude product using 1,3,5-trimethoxybenzene as an internal standard.

†Ee value based on high-performance liquid chromatography analysis.

With the optimal conditions in hand, we turned our attention to evaluating the substrate scope of this cocatalytic system. As illustrated in Fig. 2, this Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition demonstrated excellent functional group tolerance no matter what substituted ynamines and 1,6-diynes, producing the C─N axially chiral indoles in generally good to excellent yields and enantioselectivities. First, ynamines bearing different ester groups such as phenol and 1-naphthol were performed on the 0.15-mmol reaction scale and smoothly transformed into the final products 4 and 5 in 93% yield, 90% ee, and 95% yield, 94% ee, respectively. Subsequently, the variations of indole ring at the different sites including 5-OMe, 6-Me, 6-BPin, 6-F, 6-Cl, 6-Br, 7-F, 7-OMe, and 5,7-F, F were investigated, delivering the C─N axially chiral products 9 to 13 in 60 to 99% yields and 86 to 98% ees. Meanwhile, the methodology is well tolerated to various electron donating group (EDG) or electron withdrawing group (EWG), yielding atroposelective indoles 14 to 24 and 106 (106; see fig. S4) in 76 to 99% yields and 90 to 96% ees. Afterward, ynamines substituted with thiophenyl and benzo[d][1,3]dioxolyl groups underwent [2+2+2] cycloaddition, forging the corresponding chiral products 25 and 26 in 95 to 99% yields and 90 to 95% ees in an easy fashion. Aliphatic groups covering nC6H13, methylenecyclohexyl, and cyclohexyl, which were not explored in the previous work by Tanaka et al. and Hsung and coworkers (20, 21), were compatible with this reaction and successfully converted into cycloaddition products 27 to 29 in high yields and enantioselectivities. Using ent-L7 as a chiral ligand, the atropisomer 30 with the opposite configuration was isolated in 92% yield and 92% ee. In addition, the complex C─N axially chiral indoles incorporating natural products such as 31 (from sesamol) and 32 (from probenecid) were readily synthesized in 85% yield, 88% ee, and 99% yield, 84% ee, separately, demonstrating that this Ir/Zn-cocatalyzed alkyne [2+2+2] cycloaddition displays great potential for the construction of multifunctional axially chiral products. Then, we turned to assess the universality of a wide range of 1,6-diynes in this reaction, and versatile axially chiral indoles 33 to 40 linked with an assortment of functional groups such as 4-Me, 4-NO2, 4-CF3, 4-tBu, 4-OMe, 4-OCF3, 3-Br, and 4-H on the benzene sulfonyl group were obtained in 81 to 99% yields and 90 to 96% ees. Meanwhile, aliphatic groups like Me, iPr, cyclopropyl, tBu, and 3-methylazetidinyl were suitable substituents for the 1,6-diynes to perform smooth [2+2+2] cycloaddition, leading to the expected products 41 to 45 in 69 to 94% yields and 84 to 96% ees. 1,6-Diynes connected with heterocycles, for instance, thiophene and pyrazole proceeded efficiently in this reaction, affording the desired products 46 and 47 in high yields and enantioselectivities. 1,6-Diynes embedded with celecoxib and dansylamide motifs were available partners for the rapid construction of C─N axially chiral products 48 and 49 in quantitative yields and high enantiocontrols. 1,6-Diyne connected by oxygen was used in this reaction to furnish 50 in high enantiocontrol but low yield. The chiral indole 51 bearing diethyl was successfully gained in this catalytic cycle. Di-1,6-diyne could undergo double [2+2+2] cycloaddition with 2 for the highly efficient and atroposelective preparation of final product 52 containing two chiral C─N axes with excellent diastereoselectivity without observation of meso-isomer.

Fig. 2. Substrate scope of enantioselective [2+2+2] cycloaddition of 1,6-diynes and ynamines.

Fig. 2.

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Standard conditions: 1,6-diynes (0.15 mmol), ynamines (0.3 mmol), [Ir(COD)Cl]2 (2 mol %), L7 (5 mol %), Zn(OTf)2 (20 mol %), and toluene (3 ml) in vials. a, X = OPh. b, [Ir(COD)Cl]2 (5 mol %), L7 (12.5 mol %). c, [Ir(COD)Cl]2 (6 mol %), L7 (15 mol %). rt, room temperature.

Pleasingly, this Ir/Zn-cocatalyzed asymmetric [2+2+2] cycloaddition was successfully expanded to the synthesis of C─N axially chiral pyrroles and gave the satisfactory results in the efficacy and enantioselectivity, as illustrated in Fig. 3. For examples, ynamines substituted with thieno[3,2-b]pyrrole, 2-methyl-pyrrole, and 2-cyclohexyl-pyrrole processed well in this reaction for the construction of desired C─N axially chiral products 53 to 55 in 60 to 99% yields and 90 to 98% ees. Moreover, the chiral pyrrole product 56 containing three substituents around a C─N axis was gained in 87% yield and 90% ee.

Fig. 3. Substrate scope of enantioselective synthesis of CN axially chiral pyrroles.

Fig. 3.

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─ Standard conditions: 1,6-diynes (0.15 mmol), ynamines (0.3 mmol), [Ir(COD)Cl]2 (2 mol %), L7 (5 mol %), Zn(OTf)2 (20 mol %), and toluene (3 ml) in vials. a, [Ir(COD)Cl]2 (5 mol %), L7 (12.5 mol %). rt, room temperature.

Unexpectedly, this new protocol merging Ir and Zn in an atroposelective [2+2+2] cycloaddition was also extended to complex ynamines containing more 2π elements such as alkyne or alkene for the chemo- and enantioselective construction of a wide range of chiral indole motifs linked with a C─N axis. As depicted in Fig. 4, ynamines bearing different allyl ethers were appropriate with this reaction for highly enantioselective preparation of C─N axially chiral indoles 57 to 59 in 54 to 90% yields and 92 to 94% ees with excellent chemoselectivity without the observation of any central chiral products (59–61). Moreover, the chiral indole 60 from geraniol linked with two double bonds, which could not affect this asymmetric [2+2+2] cycloaddition, was obtained with excellent yield and enantioselectivity. Following, both styryl and 2-methylprop-1-enyl, which were directly connected with triple bond of ynamines, were suitable substituents and converted into the final products 61 to 63 in 65 to 99% yield and 90 to 93% ees. Besides, ynamines installed with another alkyne group could smoothly undergo chemo- and atroposelective [2+2+2] cyclotrimerization to afford the expected C─N axially chiral indoles 64 and 65 in 77 to 90% yields and 87 to 91% ees (62, 63). Both the coordination of ester group and activation of triple bond via Zn(OTf)2 together most likely dominated the excellent chemoselectivity in this co-catalytic [2+2+2] cycloaddition. It is noteworthy that this catalytic [2+2+2] alkyne cycloaddition for atroposelective construction of C─N axially chiral indoles and pryrroles not only displayed high efficiency and enantiocontrol but also presented excellent chemoselectivity. This novel Ir/Zn-cocatalyzed strategy was the first applied in the [2+2+2] cycloaddition of alkynes and successfully addressed the issues of low yield, complex operations, and limited substrate scope in traditional [Rh(COD)2]BF4-catalyzed system for the construction of C─N axial chirality.

Fig. 4. Chemo- and enantioselective synthesis of CN axially chiral indoles.

Fig. 4.

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─ Standard conditions: 1,6-diynes (0.15 mmol), ynamines (0.3 mmol), [Ir(COD)Cl]2 (2 mol %), L7 (5 mol %), Zn(OTf)2 (20 mol %), toluene (3 mL) in vials. rt, room temperature.

To study configurational stability of representative products, the corresponding experiments of chiral indole 5 and 18 were performed. As shown in Fig. 5, both 5 and 18 were recovered in high yields with retained enantioselectivities after stirring in mesitylene at 120°C for 24 hours, thus revealing that C─N axially chiral indoles 5 and 18 have high configurational stability with four substituents around a C─N axis. To further demonstrate the synthetic utility of the protocol, a gram-scale reaction was carried out under the standard reaction conditions to produce C─N axially chiral indole 5 in 95% yield that observed a decrease in ee values compared to the small-scale reaction (Fig. 6A). After recrystallization, the chiral indole 5 with 99% ee could be readily reduced into alcohol 66 in 92% yield with 99% ee by the treatment with LiAlH4. Subsequently, 66 could smoothly undergo oxidation and azidation to deliver chiral 67 and 68 in excellent yields and enantiopurities, respectively. Meanwhile, the chiral 2-ethynyl-indole 69, which was synthesized from the Seyferth-Gilbert homologation of 67, could undergo click reaction to afford the chiral 1,2,3-triazole 70 bearing C─N axial chirality in high yield without erosion of the optical purity. The oxazoline-forming reaction of 67 could successfully provide 71 without loss of any enantioselectivity. The ester reaction of 66 produced the chiral indole 72 in 85% yield and 99% ee, which was unambiguously confirmed by x-ray crystallographic analysis, and that of the other products was assigned by analogy (see table S3). In addition, iodination of 5 could efficiently deliver the 3-iodo product 73, which could undergo versatile Pd-catalyzed cross-coupling (50). The functionalization of 66 could furnish chiral organocatalysts 74 and 75 in a rapid and practical way, as shown in Fig. 6B. Then, 70 was used to catalyze asymmetric Mannich-type reaction of phosphorusylide 76 and N-Bocimine 77 followed by the treatment with formal, allowing the expected product 78 in 88% yield and 20% ee. Pleasingly, a new chiral phosphine ligand 80 generated from C─P coupling/reduction of 73 was used to realize asymmetric palladium-catalyzed allylic alkylation, leading to the chiral product 83 in 71% yield with 99% ee (Fig. 6C). Notably, obvious aggregation-induced emission nature of 70 was observed after the exploration of the photophysical properties of these axially chiral indoles and pyrroles (see fig. S1).

Fig. 5. The study configurational stability of representative product.

Fig. 5.

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To investigate the reaction mechanism of this atroposelective [2+2+2] cycloaddition of ynamines and 1,6-diynes catalyzed by Ir (64–67) and Zn, the control experiments were carried out, as described in Fig. 7. First, both ynamines 84 and 85 without an ester group were introduced to react with 1,6-diyne 3 under standard conditions, but no target chiral indoles were observed (Fig. 7A). This result possibly ruled out that Zn(OTf)2 could significantly improve the yield via only the activation of ynamine without the coordination of the ester group, which was strong supported by the experiments on the chemoselective [2+2+2] cycloaddition (Fig. 4, 64 and 65). Subsequently, ynamine 88 linked with an ester group at the 2-position of indole was used to perform this reaction, and the desired product 89 was not discovered (Fig. 7B). These results strongly indicated that the carboxylic ester at the 2-position of indole ring as a chelation group plays an important role in this reaction, which was consistent with Tanaka’s research works (8, 20). To simplify the density functional theory (DFT) calculations, the pyrrolyl-ynamine 90 and 1,6-diyne 91 were prepared to undergo catalytic [2+2+2] cycloaddition, giving the expected results that the yield of the reaction in the presence of Zn(OTf)2 was much higher than that in the absence of Zn(OTf)2 (Fig. 7C). In addition, DFT calculations based on related work were performed using the substrates 90 and 91 as a model to elucidate the mechanistic details (see the Supplementary Materials).

Fig. 6. Gram-scale reaction and product elaborations.

Fig. 6.

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(A) Preparative-scale reaction of 5 and synthetic applications. (B) Synthesis and applications of 75. (C) Synthesis and applications of 80. DMSO, dimethyl sulfoxide. rt, room temperature. Cambridge Crystallographic Data Centre (CCDC), molecular sieve (MS), N-Bromosuccinimide (NBS), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-Dimethylaminopyridine (DMAP), 4-Nitrobenzoic acid (PNBA), Dichloromethane (DCM), Tetrahydrofuran (THF).

On the basis of the above experimental observations and density functional theory (DFT) calculations, a plausible mechanism for the construction of C─N axially chiral indole from Ir/Zn-cocatalyzed [2+2+2] cycloaddition of ynamine and 1,6-diyne was described in Fig. 7D. Initially, chiral iridium–activated 1,6-diyne A was generated, resulting in a release of free energy of 47.5 kcal/mol. After overcoming a moderate activation energy of 14.6 kcal/mol, A via cyclometallation delivered intermediate B with a release of free energy of 19.2 kcal/mol. Subsequently, intermediate B reacted with ynamine 90, aided by the cocatalyst Zn(OTf)2, to afford intermediate C with a free energy release of 30.3 kcal/mol. C then occurred the migratory insertion, which surmounted an energy barrier of 4.6 kcal/mol to form the seven-membered cyclometallatic-Ir species D via the transition state TS2, with an exergonic free energy of 20.5 kcal/mol. Last, reductive elimination within D via the transition state TS3 provided intermediate E following the regeneration of Ir and Zn catalysts and furnished the axially chiral indole 92. The entire process of the Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition is highly exergonic with a free energy release of 122.4 kcal/mol. In addition, the absence of Zn(OTf)2 case for the [2+2+2] cycloaddition was considered; however, the relative free energy profile (red line) was found to be higher compared to that of the case with Zn(OTf)2 assistance. This finding strongly suggests that Zn(OTf)2 as a cocatalyst markedly facilitated migration insertion via reduction of the barrier, leading to a significant enhancement in the reaction yield by coordinating with the ester group of ynamine and activating triple bond. It was markedly different from previous studies on the great improvement of reaction yield through Lewis acid–accelerated oxidative addition and reductive elimination (53–58). Notably, to unravel the origin of enantioselectivity achieved by the chiral Ir complex, the structures of the two enantiomerically controlled migratory insertion (8) transition states TS2 and TS2-1 were carefully explored (Fig. 7E). In TS2-1, the bulky ligand L7 in the chiral Ir complex shows large repulsive interactions with the methyl 2-pyrrolecarboxylate moiety of pyrrolyl-ynamine 90. Whereas in TS2, the corresponding steric repulsion is less significant. As such, TS2 has a lower free energy, giving rise to a preference of 7.9 kcal/mol for the generation of the major enantiomer. In short, the observed enantioselectivity is dominated by steric effects.

Fig. 7. Mechanistic investigations.

Fig. 7.

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(A to C) Control experiments. (D and E) DFT calculations. rt, room temperature.

DISCUSSION

In conclusion, we have realized an Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition of 1,6-diynes and ynamines, leading to the practical and atom-economic synthesis of valuable C─N axially chiral indoles and pyrroles in generally good to excellent yields and high enantioselectivities with wide substrate scope. This protocol not only displayed good efficiency and high enantiocontrol but also exhibited excellent chemoselectivity with ynamines bearing different 2π groups. Notably, this cocatalyzed strategy has been verified as a promising and reliable option for the preparation of axial chirality via asymmetric alkyne [2+2+2] cyclotrimerization in an easy handle and artfully solved the issues of previous [Rh(COD)2]BF4-catalyzed asymmetric construction of C─N axial chirality such as complex operations, limited substrate scope, and low efficiency. Zn(OTf)2 as a cocatalyst increases the reaction efficiency via a marked reduction of the barrier of migration insertion, which is strongly supported by control experiments and theoretical calculations. It is significantly distinct from previous work on the Lewis acid for improving reaction yield through accelerating oxidative addition and reductive elimination. Moreover, this strategy presented the potential application in optical materials and the synthesis of chiral organocatalysts and a new chiral ligand. In addition, further investigation on the synthesis of axial chirality via [2+2+2] alkyne cycloaddition in a cocatalytic system is ongoing in our laboratory.

MATERIALS AND METHODS

Unless otherwise noted, materials were obtained commercially and used without further purification. All the solvents were treated according to general methods. Flash column chromatography was performed over silica gel (300 to 400 mesh). See Supplementary Materials and Methods for experimental details.

1H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AV-400 spectrometer and a Bruker AV-500 spectrometer in chloroform-d3. Chemical shifts are reported in parts per million (ppm) with the internal tet-ramethylsilane (TMS) signal at 0.0 ppm as a standard. The data are being reported as [s, singlet; d, doublet; t, triplet; m, multiplet or unresolved; brs, broad singlet, coupling constant(s) in hertz, integration). 13C NMR spectra were recorded on a Bruker AV-400 spectrometer and a Bruker AV-500 spectrometer in chloroform-d3. Chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard. Mass spectra were recorded with Micromass QTOF2 Quadrupole/Time-of-Flight Tandem mass spectrometer using electron spray ionization.

General procedure for the synthesis of C─N axially chiral indoles and pyrroles

A 5-ml vial was charged with Ir(COD)Cl]2 (2 mol %) and L7 (5 mol %), 1 ml of toluene, and a magnetic stir bar. A separate 5-ml vial was charged with 1,6-diynes (0.15 mmol), ynamines (0.3 mmol), and Zn(OTf)2 (20 mol %), and 2 ml of toluene. The solution from the second vial was added to the precatalyst solution. The reaction mixture of pale yellow was stirred at ambient temperature. The progress of the reaction was monitored by thin-layer chromatography (TLC). Upon completion, the mixture of deep yellow was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: PE/EtOAc) to afford the C─N axially chiral indoles and pyrroles.

Acknowledgments

Funding: We are grateful for financial support from the Zhejiang Provincial Natural Science Foundation of China (LQ23B020002 to L.L.); the National Natural Science Foundation of China (no. 21828102 to P.-C.Q.); the Foundation of Wenzhou Science and Technology Bureau (no. ZY2020027 to P.-C.Q.); the Center of Chemistry for Frontier Technologies and Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province of Westlake University (PSFM 2021-02 to P.-C.Q.); start-up funding from Wenzhou University (to L.L.); the Opening Project of PCOSS, Xiamen University (202004 and 202016 to L.L.); the Opening Project of WZAST, Wenzhou Association for Science and Technology (to P.-C.Q.); the Jiangxi Province Science and Technology Project (no. 20224BAB213013 to Q.S. and no. 20212ACB203007 to P.-C.Q.); and the Jiangxi Provincial Educational Department (no. GJJ210906 to R.-J.S).

Author contributions: J.Y., Z.-Y.X., Y.-J.Y., S.-B.Y., Y.-B.W., and W.-T.W. performed the experiments and analyzed the data. R.-J.S. and P.-C.Q. supported funding. Q.S. performed DFT calculations. L.-W.Y. revised the manuscript. L.L. designed and directed the project and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests: The authors declare that they have no competing interests.

Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. For x-ray crystallographic data for 70 (CCDC 2261544), see table S3.

Supplementary Materials

This PDF file includes:

Materials and Methods

Supplementary Text

Figs. S1 to S5

Tables S1 to S3

Spectral Data

References

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REFERENCES AND NOTES

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Associated Data

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Supplementary Materials

Materials and Methods

Supplementary Text

Figs. S1 to S5

Tables S1 to S3

Spectral Data

References

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