Download PDF
Synthesis 2022; 54(09): 2133-2147
DOI: 10.1055/a-1729-9572
short review

Transition-Metal-Catalyzed Enantioselective Synthesis of Indoles from 2-Alkynylanilines

Zhi-Shi Ye  ∗
,
Jin-Chen Li
,
Gang Wang

Financial support from the National Natural Science Foundation of China (22071014 and 21801036), the Liaoning Revitalization Talents Program (XLYC1907036), and the Fundamental Research Funds for the Central Universities (DUT19LK54 and DUT19TD28) is acknowledged.
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Optically active indole derivatives are ubiquitous in natural products and are widely recognized as privileged components in pharmacologically relevant compounds. Therefore, developing catalytic asymmetric approaches for constructing indole derivatives is highly desirable. In this short review, we summarize methods for the transition-metal-catalyzed enantioselective synthesis of indoles from 2-alkynyl­anilines.

1 Introduction

2 Aminometalation-Triggered Asymmetric Cross-Coupling Reactions/Insertion

2.1 Asymmetric Cross-Coupling Reactions

2.2 Asymmetric Insertion of C=O, C=C and C≡N Bonds

3 Asymmetric Relay Catalysis

4 Conclusion


#

Key words

indoles - 2-alkynylanilines - aminometalation - cross-coupling - insertion - relay catalysis - axial chirality
1

Introduction

Enantiomerically enriched indole derivatives are not only prevalent in a variety of biologically active compounds and natural products, but are also employed as chiral ligands in asymmetric catalysis (Figure [1]).[1] [2] [3] [4] [5] [6] [7] [8] For example, kopsihainanine A (1) was isolated from the leaves and stems of a Chinese medicinal plant, Kopsia hainanensis, and showed inhibitory activity against acetylcholine esterase (AChE).[2] Aspidospermidine (2) is the parent framework of the Aspidosperma alkaloids, which are a subset of monoterpene indole alkaloids with more than 250 members.[3] Stryvomicine (3) was obtained from the seeds of Strychnos nux-vomica, which is widely used for the treatment of rheumatoid arthritis, pain from swelling, trauma, bone fracture, facial nerve paralysis, myasthenia gravis, and poliomyelitis sequela.[4] Furthermore, compound 4 is a potent selective factor IXa inhibitor,[5] whilst compound 5 is a potent and bioavailable MCHR1 antagonist.[6] Bisindoles 6 and 7, possessing axial chirality, were isolated from the marine blue-green alga Rivularia firma.[7] The axial chiral bisindole-phosphine ligand 8 has been successfully applied to asymmetric synthesis.[8] Therefore, it is highly desirable to develop catalytic asymmetric approaches for the synthesis of indole derivatives.

Zoom Image
Zhi-Shi Yewas born in Zhejiang Province, P. R. of China, in 1984. After completing his B.S. and M.S. degrees at Wenzhou University, he continued to pursue his Ph.D. at the Dalian Institute of Chemical Physics (DICP). He subsequently worked with Prof. Mingji Dai at Purdue University from 2013 to 2017 as a postdoctoral fellow. In 2017, he began his independent career at the Dalian University of Technology (DUT). His research interests include the synthesis of heterocyclic compounds, asymmetric synthesis and organometallic chemistry.
Zoom Image
Figure 1 Biologically active compounds, natural products and chiral ligands containing indole skeletons

2-Alkynylanilines are versatile building blocks that can be easily accessed by Sonogashira reaction of 2-aminoaryl halides and terminal alkynes.[9] The transition-metal-catalyzed cyclization of 2-alkynylaniline derivatives can rapidly construct indoles.[10] In 1985, Taylor and McKillop reported the first example of the palladium-catalyzed cyclization of 2-alkynylanilides to give indoles.[11] In addition, a one-step synthesis of indoles via Sonogashira cross-coupling/cyclization of 2-haloanilines and terminal alkynes was developed by Yamanaka and co-workers.[12] Yamanaka’s group have also documented a cyclization method towards indole-3-carboxylates using 2-alkynylanilides in the presence of carbon monoxide and methanol.[13] Cacchi and co-workers developed the palladium-catalyzed cyclization/cross-coupling reaction of 2-alkynylaniline derivatives with aryl, vinyl, or alkynyl halides.[14] Trost and McClory discovered a rhodium-catalyzed cyclization reaction of 2-alkynylanilides that gave 2,3-unsubstituted indoles.[15] Meanwhile, Crabtree and co-workers have disclosed the synthesis of 2-substituted indole derivatives via the iridium-catalyzed cyclization of 2-alkynylanilides.[16] The gold-catalyzed synthesis of 2-substituted indoles via hydroamination of 2-alkynylanilides was reported by Utimoto’s group,[17] whilst Knochel has reported an elegant synthesis of indoles via Brønsted-base-promoted 5-endo-dig cyclization of 2-alkynylanilides.[18] Despite these achievements, the development of asymmetric cyclization/cross-coupling reactions of 2-alkynylaniline derivatives with nucleophiles or electrophiles falls into a dilemma. The major issue is that a transition-metal catalyst should allow the successive construction of C–N and C–X (X = C, O, N, etc.) bonds with stereoselective control.

Zoom Image
Scheme 1 Transition-metal-catalyzed enantioselective synthesis of indoles from 2-alkynylanilines; CPA: chiral phosphoric acid

To address the above formidable issue, two effective and practical strategies have been developed (Scheme [1]): (1) Aminometalation of 2-alkynylaniline derivatives with a chiral metal catalyst generates the indol-3-yl metal species, which can further undergo asymmetric cross-couplings and insertions, and (2) asymmetric relay catalysis. Based on these two control strategies, several impressive advances have been made over the past few years. In the present review, we summarize the progress made on the transition-metal-catalyzed enantioselective synthesis of indoles from 2-alkynylanilines and provide some insights into future developments.


# 2

Aminometalation-Triggered Asymmetric Cross-Coupling Reactions/Insertion

2.1

Asymmetric Cross-Coupling Reactions

Axial chirality has been recognized as a fascinating subclass of chirality and plays a crucial role in Nature.[19] Axially chiral indole-based frameworks exist widely in natural products, privileged chiral ligands and catalysts, as well as in biologically relevant compounds.[7] [20] In 2010, Kitagawa and co-workers accomplished the first catalytic asymmetric construction of N–C axially chiral indoles (Scheme [2]).[21a] With PdCl2/(R)-Segphos as the catalyst and ethanol as the solvent, 5-endo-hydroaminocyclization of various N-aryl-2-alkynylanilines took place smoothly to afford axially chiral N-arylindoles in good yields and up to 83% ee. The R2 substituent had a dramatic influence on the enantioselectivity. A sterically hindered t-butyl ( t Bu) group gave the best result, with 60% ee being obtained. In the case of a 2-methoxy-containing substrate, no enantioselectivity was observed. Additionally, compared to alkyl R1, the presence of ortho-substituted phenyl groups gave higher enantioselectivity. These results indicate that the rotational energy barrier around the 5-6 biaryl axis is lower and that large steric hindrance contributes to controlling the enantioselectivity. Moreover, in order to confirm that 13a has a high rotational energy barrier, this compound was heated in ethanol for 24 hours at 80 °C and no appreciable change in the ee was detected.

Zoom Image
Scheme 2 Asymmetric construction of N–C axially chiral indoles

Kitagawa and co-workers explained that the increased enantioselectivity with an ortho-substituent was likely ascribed to chiral relay through dynamic axial chirality.[21b] Coordination of the PdCl2/(R)-Segphos complex to the triple bond of the 2-alkynylanilines may effectively produce an intermediate with dynamic axial chirality caused by the twisting around the Calkynyl–Cphenyl bond. Thus complex 14 should be more favored than 15 due to less of a steric clash (Scheme [3]).

Zoom Image
Scheme 3 Explanation for the origin of the chirality

Although the enantioselectivities were not excellent, this work was a milestone in the field of catalytic asymmetric construction of atropisomeric indoles. Since then, significant attention has been paid to this area, and a variety of elegant strategies have been developed in recent years.[22]

In 1992, Cacchi’s group pioneered a palladium-catalyzed cyclization/cross-coupling reaction of 2-alkynylanilines with vinyl triflates and aryl halides.[14a] This transformation displayed a broad substrate scope, excellent functional group tolerance, and has been widely applied in the synthesis of functionalized indoles.[23] Recently, Zhu and co-workers reported an asymmetric Cacchi reaction for the synthesis of atropisomeric 2-arylindoles (Scheme [4]).[24] Under conditions utilizing Pd(OAc)2/(R,R)-QuinoxP* as the catalyst, K3PO4 as the base and oxygen as the oxidant, the reactions of N-sulfonyl-2-alkynylanilides with aryl boronic acids provided the corresponding atropisomeric 2-arylindoles in high yields and with good to excellent enantioselectivities. Notably, the nature and the size of the OR group on the naphthyl ring influenced the enantioselectivity. An OBn group gave the best result with up to 93% ee. Reducing the size of the Ar2 group resulted in a significant loss of enantioselectivity. For example, an ee value of only 71% was observed for the atropisomeric 2-arylindole 18d. Interestingly, this strategy could be utilized for the construction of two axially chiral indoles 18j, albeit with 2:1 dr and low enantioselectivity.

Zoom Image
Scheme 4 A palladium-catalyzed enantioselective Cacchi reaction for the synthesis of atropisomeric 2-arylindoles

Mechanistic studies revealed that transmetalation of the palladium complex with the aryl boronic acid should be the initiation step because only 7% ee was obtained for the cyclization of compound 19. Moreover, treatment of PhPd(OAc){(R,R)-QuinoxP} complex 21 with 2-alkynylaniline 22 delivered the desired product 18b in 78% yield and 84% ee, which is consistent with the original system. Based on these results, a possible mechanism is shown in Scheme [4]. Firstly, the aryl boronic acid is activated to form an aryl anionic borate, which undergoes transmetalation with palladium complex 26 to give (L2)ArPdX species 23. Subsequent coordination with the triple bond of 2-alkynylanilide 16 delivers the π-alkyne-palladium complex 24. The axial chirality is generated by twisting around the Calkynyl–Cphenyl bond in this step, with 24a expected to be more favored than 24b due to minimized steric repulsion. The intermediate 24 undergoes trans-aminopalladation and reductive elimination to afford the desired product 18 and a Pd(0) species. Regeneration of Pd(II) is completed via oxidation of the Pd(0) species with O2. Importantly, the authors assumed that the chirality of the product originates from Pd complex 24 via chirality transfer, instead of during the trans-aminopalladation step.

Since the rotational energy barrier of five–five biaryls is lower than that of six–six and five–six biaryls, the asymmetric construction of five–five biaryls is more difficult.[25] In accordance with the judicious design of a catalytic system, Li’s group accomplished the Rh(III)-catalyzed oxidative coupling of indoles and 2-alkynylanilines for the synthesis of axially chiral 2,3′-bisindoles (Scheme [5]).[26] Using (R)-Rh1 as the catalyst, AgOAc/PivOH as the additive and MeOH as the solvent, the oxidative coupling of indoles 27 and 2-alkynylanilines 28 afforded bisindoles 29 in high yields and with excellent enantioselectivities via a C–H activation and nucleophilic cyclization cascade. This strategy could be further extended to the synthesis of benzo[h]quinolone-indole 29e, albeit with a moderate enantioselectivity. According to the racemization studies, the rotational energy barriers of most of the products are relatively low, thus revealing the superiority of this strategy in controlling the enantioselectivity. In addition, the pre-synthesized rhodacyclic complex 30 reacted with 2-alkynylanilines 28 as well, giving comparable results to the original system. Therefore, a plausible mechanism was proposed. The reaction is initiated by rhodium-catalyzed C–H activation to form rhodacyclic complex 30. The triple bond of the 2-alkynylanilide is further activated by 30, which is followed by trans-aminometalation to furnish the intermediate 31. Finally, reductive elimination of intermediate 31 affords product 29.

Zoom Image
Scheme 5 Rh(III)-catalyzed synthesis of axially chiral bisindolyls by merging C–H activation and nucleophilic cyclization; Pym: pyrimidine. Five–five biaryls: two connected five-membered aromatic rings, such as 2,3′-bisindoles.

Very recently, the same group achieved Pd-catalyzed enantioselective Cacchi reactions between aryl bromides 32 and 2-alkynylanilines 33, providing atropisomeric 3-arylindoles 34 with high yields and excellent enantioselectivities (Scheme [6]).[27] The reaction displayed a broad scope with respect to both aryl bromides and 2-alkynylanilines. Different functional groups such as halogens and heteroaryls were well tolerated under the standard conditions. Although this protocol could be extended to the synthesis of atropisomeric 3-naphthylbenzofuran 34l, the yield and enantioselectivity were lower. An electron-deficient carbonyl group at the ortho-position of the aryl bromides is critical for the reaction, likely because this substituent can improve the reactivity of aryl bromides and increases the rotation energy barrier.

Zoom Image
Scheme 6 Synthesis of axially chiral 3-arylindoles bearing a C(3)–C(aryl) chiral axis

On the basis of mechanism studies, Li and co-workers[27] proposed a plausible catalytic cycle for this transformation (Scheme [7]). Oxidative addition of Pd(0) and aryl bromide 32a generates an arylpalladium(II) species 35, which coordinates with the triple bond of 2-alkynylaniline 33a to deliver 36a and 36b. The intermediate 36a should be more stable than 36b because of less steric clash. The intermediates 36a/36b then undergo trans-aminopalladation and reductive elimination to give the 3-arylindole 34a.

Zoom Image
Scheme 7 Proposed mechanism
Zoom Image
Scheme 8 Synthesis of atropisomeric naphthyl-C3-indoles via palladium-catalyzed asymmetric Cacchi reactions

At the same time, Wang’s group independently developed an efficient Pd(OAc)2/(S)-Segphos-catalyzed Cacchi reaction of 2-alkynylanilines with sterically congested naphthyl halides, affording axially chiral naphthyl-C3-indoles 40 in high yields and good to excellent enantioselectivities (Scheme [8]).[28] Interestingly, the N-COCF3 protecting group could be easily removed under the reaction conditions to furnish axially chiral naphthyl-C3-indoles bearing a free NH moiety. In this case, naphthyl halides possessing an electron-donating OR2 group at the 2-position showed high reactivity and enantioselectivity, which complemented the catalytic system of Li’s group.[27] Additionally, this methodology was employed for synthesis of axially chiral 3-naphthylindole-based monophosphine (R)-43.

Zoom Image
Scheme 9 Palladium-catalyzed enantioselective tandem C–C bond activation/Cacchi reaction between cyclobutanones and 2-alkynylanilines
Zoom Image
Scheme 10 Intramolecular-asymmetric-aminopalladation-initiated insertion of a carbonyl group

Xu and co-workers realized a palladium-catalyzed asymmetric tandem C–C bond activation/Cacchi reaction between cyclobutanones and 2-alkynylanilines, providing enantioenriched indanone-substituted indoles bearing an all-carbon quaternary stereocenter. The desired products were obtained in good yields and excellent enantioselectivities (Scheme [9]).[29] Compared with a Ts protecting group, a Ms group gave a higher ee value (46a vs 46b). When R3 was a trifluoroacetyl group, NH-indanone-substituted indole 46c was obtained. Functional groups such as TMS, Cl, F, MeO and thiophene were well tolerated. It is worth noting that this strategy was suitable for the construction of indanone-substituted indoles 46i–n with both central and axial stereogenic elements, albeit with lower dr values. Based on mechanistic studies and their previous report,[30] a possible reaction pathway has been described. Oxidative addition of cyclobutanone 44 and the Pd(0) complex forms arylpalladium species 47. Formation of intermediate 50 can occur via two pathways, including insertion of the carbonyl group and β-carbon elimination (path a), and oxidative addition of the cyclobutanone and reductive elimination (path b). Coordination of intermediate 50 with 2-alkynylaniline 45 gives 51, which undergoes trans-aminopalladation and reductive elimination to afford product 46.

Zoom Image
Scheme 11 Enantioselective synthesis of 1,2,3,4-tetrahydro-β-carbolines via intramolecular-aminopalladation-initiated insertion of a carbonyl group

# 2.2

Asymmetric Insertion of C=O, C=C and C≡N Bonds

Asymmetric addition of carbonyl compounds is regarded as a powerful synthetic tool for the formation of optically active alcohols.[31] In order to construct enantiomerically enriched pentaleno[2,1‑b]indoles, Lu and co-workers developed the first example of an intramolecular-asymmetric-aminopalladation-initiated insertion of a carbonyl group (Scheme [10]).[32] A combination of Pd(OAc)2 and pyridine oxazoline ligand L11 gave product 54 in 89% yield with a moderate ee value. Mechanistically, trans-aminopalladation of 2-alkynylaniline 53 generates the indol-3-yl palladium species 55, which undergoes insertion of the carbonyl group and protonolysis resulting in formation of the desired product 54.

Zoom Image
Scheme 12 Enantioselective synthesis of tetrahydropyrano[3,4-b]indoles via palladium(II)-catalyzed aminopalladation/1,4-addition
Zoom Image
Scheme 13 Asymmetric aminopalladation-triggered intramolecular Heck-type reaction; amphos: di-tert-butyl(4-dimethylaminophenyl)phosphine

Utilizing the same strategy, Lu and co-workers established an efficient approach for the assembly of enantioenriched 1,2,3,4-tetrahydro-β-carbolines, which are widely found in natural products and pharmaceuticals (Scheme [11]).[33] It was found that 1,4-benzoquinone (BQ) was beneficial for the reactivity and that the pyridine oxazoline ligand L12 gave the best enantioselectivity with up to 93% ee. A number of functional groups were tolerated in this reaction, including heterocycles, halides (F, Cl, and Br), cyano, and esters. An alkyl group (R) was also compatible with the protocol. For example, product 58d was delivered in 83% yield and 90% ee. The electronic properties of the substituents on the aminoaryl ring had a remarkable impact on the transformation. Halide (F, Cl, and Br) and trifluoromethyl groups all worked well, whereas a methoxy group had a negative effect on the reactivity and only a 32% yield of 58f was isolated. Introducing an electron-withdrawing substituent (CO2Me) at the 4-position of the aminoaryl ring led to a dramatic decrease in the enantioselectivity (56% ee for 58i).

Zoom Image
Scheme 14 Asymmetric aminopalladation-triggered intermolecular Heck-type reaction of 2-alkynylanilines with prochiral cyclopentenes; X = OAc

1,3,4,9-Tetrahydropyrano[3,4-b]indole and its derivatives are identified as significant and prevalent structural motifs in bioactive natural products and pharmaceutical molecules.[34] Therefore, their synthesis has been an active field of organic chemistry for decades.[35] In 2017, Lu and co-workers documented an enantioselective synthesis of 1,3,4,9-tetrahydropyrano[3,4-b]indoles via a palladium(II)-catalyzed aminopalladation/1,4-addition cascade (Scheme [12]).[36] The use of axially chiral 2,2′-bipyridine ligand L13 led to the best enantioselectivity (up to 96% ee). Cyclohexenone-fused tetrahydropyrano[3,4-b]indoles 60 could be obtained in high yields and excellent enantioselectivities, regardless of whether R1 was an alkyl or an aryl group. The electronic properties of the substituents on the aminoaryl ring had little impact on the reaction. However, this method was not suitable for the synthesis of 60e. The authors proposed that the key intermediate indol-3-yl palladium species 62 was formed by trans-aminopalladation of 2-alkynylanilines, and not by C–H activation of indole 63. As shown in Scheme [12], the palladium complex coordinates with the triple bond of 2-alkynylaniline 59a to form intermediate 61, which undergoes trans-aminopalladation to deliver the indol-3-yl palladium species 62. The desired product 60a is furnished by insertion of the C=C bond and protonolysis.

Zoom Image
Scheme 15 Asymmetric palladium-catalyzed cyclative cross-coupling of 2-alkynylanilines, cyclopentenes and Selectfluor
Zoom Image
Scheme 16 Asymmetric domino-Heck reaction/aminopalladation
Zoom Image
Scheme 17 Asymmetric aminopalladation-triggered intermolecular insertion of a C≡N bond

The Heck reaction is a classical method for C–C coupling, and has proved extremely powerful for the synthesis of organic electronic materials, new drugs, pharmaceuticals and biologically active compounds.[37] As a result of its discovery, Professor Richard F. Heck along with Professor Ei-ichi Negishi and Professor Akira Suzuki won The Nobel Prize in Chemistry in 2010.[38] Recently, an asymmetric aminopalladation-triggered intramolecular Heck-type reaction was disclosed by our group (Scheme [13]).[39] With the aid of Pd(amphos)Cl2 and (S)-Synphos, indole-fused bicyclo[3.2.1]octanes containing an all-carbon quaternary bridgehead stereocenter, which are highly important structural units in natural products and biologically active compounds,[4] [5] were constructed with up to 96% ee. The protecting group R2 played a crucial role in the trans-aminopalladation: An N-sulfonyl protecting group showed high reactivity for cyclization, however, its replacement with a Boc or Ac group resulted in no reactivity. The electronic properties of the 2-alkynylanilines had a dramatic influence on the reactivity and enantioselectivity. For example, only a 43% yield and 74% ee were observed when an electron-withdrawing CF3 group was present. In terms of the R1 substituent, the reaction demonstrated excellent functional group compatibility (e.g. with ester, amide and ether). A mechanism for this aminopalladation-triggered intramolecular Heck-type reaction has been proposed. The palladium complex undergoes coordination and trans-aminopalladation to form indol-3-yl palladium species 69. Intramolecular C=C bond insertion and β-H elimination furnish the desired product 67 and the Pd–H species. The palladium(II) complex is regenerated via reductive elimination and oxidation with O2.

Zhu and co-workers have reported an asymmetric aminopalladation-triggered intermolecular Heck-type reaction of 2-alkynylanilines 71 with prochiral cyclopentenes 72 that proceeded with high diastereo- and enantioselectivities (Scheme [14]).[40] Importantly, the amide group on the cyclopentenes 72 played a crucial role in the reactivity and controlling the enantioselectivity. The reaction failed to produce the desired product without an amide as a directing group.

Zoom Image
Scheme 18 Enantioselective synthesis of tetrahydrocarbazoles via asymmetric relay catalysis using a gold complex and a chiral Brønsted phosphoric acid

Very recently, Zhu and co-workers discovered a new C–C bond activation via dyotropic rearrangement of a Pd(IV) species in the three-component reaction of arylboronic acids, cyclopentenes and Selectfluor (79).[41] However, indol-3-yl boronic acids exhibited poor reactivity. To overcome this limitation, a cyclative cross-coupling of 2-alkynylanilines 78, cyclopentene 72b and Selectfluor (79) was explored (Scheme [15]). Utilizing Pd(OAc)2/L16 as the catalyst, the reaction was conducted smoothly and furnished the products as single isomers in moderate yields and good to excellent enantioselectivities. The proposed reaction sequence involves aminopalladation, enantioselective carbopalladation, β-hydride elimination/reinsertion, oxidation of PdII to PdIV, 1,2-aryl/PdIV dyotropic rearrangement and reductive C–F bond formation.

In 2018, Yao and Lin discovered that alkylpalladium(II) intermediates were able to couple with 2-alkynylanilines via trans-aminopalladation.[42] Inspired by this work, Lautens­ and co-workers developed a palladium-catalyzed asymmetric domino-Heck reaction/aminopalladation using Pd2(dba)3/L17 as the catalyst, and obtained bis-heterocyclic frameworks in generally good yields and excellent enantio­selectivities (Scheme [16]).[43] Mechanistically, alkylpalladium(II) intermediate 90 was achieved by oxidative addition and insertion of the C=C double bond. Coordination of 90 with the triple bond of the 2-alkynylaniline followed by trans-aminopalladation and reductive elimination delivered the product.

Optically pure carbazolone and its derivatives are identified as prominent structural motifs that exist widely in a large family of indole alkaloids.[44] An enantioselective synthesis of carbazolones containing all-carbon quaternary centers via a trans-aminopalladation/desymmetrizing nitrile addition cascade reaction was documented by Liu and co-workers (Scheme [17]).[45] The Ms protecting group played a key role in the reactivity and enantioselectivity, giving product 94a in 88% yield and 94% ee. This reaction displayed a broad scope of substrates and excellent functional group compatibility. As proposed, coordination of the palladium complex with the triple bond of the 2-alkynylaniline followed by trans-aminopalladation and insertion of the C≡N bond delivers intermediate 97. This intermediate undergoes protonation and hydrolysis with acid to provide the product 94a. Additionally, the absolute stereochemistry for the insertion of the C≡N bond was clarified by a density functional theory (DFT) study.


#
# 3

Asymmetric Relay Catalysis

Asymmetric relay catalysis, utilizing two or more catalysts in a one-pot cascade reaction, enables accurate and sequential activation in multiple steps by distinct catalysts.[46] Over the past few decades, asymmetric relay catalysis has received a tremendous amount of attention and has shown great advantages in asymmetric catalysis, including step-economy and achieving inaccessible reactions with a single catalyst, whilst avoiding the separation of active intermediates.

Zoom Image
Scheme 19 Enantioselective synthesis of tricyclic indoles by the combination of asymmetric relay catalysis and borrowing hydrogen methodology

Utilizing asymmetric relay catalysis of a metal complex with a chiral phosphoric acid (CPA), Han and co-workers developed an intramolecular hydroamination/Michael addition cascade reaction of 2-alkynylanilines to afford fused-tetrahydrocarbazole scaffolds in excellent yields and high enantioselectivities (Scheme [18]).[47] An investigation of the mechanism indicated that the gold complex promoted hydroamination of the 2-alkynylanilines to form indoles, whilst the chiral phosphoric acid catalyzed asymmetric Michael addition of the indoles.

Very recently, based on the combination of asymmetric relay catalysis and borrowing hydrogen methodology, Zhao and co-workers described an efficient synthesis of tricyclic indoles from alcohol-containing 2-alkynylanilines (Scheme [19]).[48] In the presence of [Ir(cod)OMe]2/(S)-Segphos as a metal-catalyst and CPA-2 as an organic catalyst, a number of alkyl-substituted tricyclic indoles were prepared in reasonable to high yields and enantioselectivities. However, only a 12% ee and a 50% yield of 105c were obtained in which R was a furan group. Steric hindrance played an important role in the enantioselectivity. For example, a substrate containing a tert-amyl group afforded the desired product 105g with 90% ee. Based on control experiments, a plausible mechanism was proposed. The alcohol-containing indole intermediate 107 was formed by cyclization of the 2-alkynylaniline 104 catalyzed by the cationic iridium complex. Subsequently, the alcohol-containing indole intermediate 107 undergoes iridium-catalyzed dehydrogenation and an acid-catalyzed formal Friedel–Crafts addition and dehydration to furnish α,β-unsaturated ketamine 110 and/or 111. The tricyclic indole product 105 was delivered following asymmetric reduction catalyzed by an iridium-hydride species.


# 4

Conclusion

In summary, transition-metal-catalyzed processes for the enantioselective synthesis of indoles from 2-alkynylanilines have been highlighted in this short review. Despite the elegant progress that has been made, there are several potential challenges that still need to be addressed: (1) The low catalytic efficiency and unsatisfactory enantioselectivity, which requires the development of new chiral ligands, and (2) the development of non-noble metal catalytic systems because existing catalytic systems focus on noble metals including Pd, Rh, Ir and Au. We hope this short review will arouse further research interest in heterocyclic chemistry and encourage chemists to apply the developed methodologies to drug design and natural product synthesis.


#
#

Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Zhi-Shi Ye
Zhang Dayu School of Chemistry, Dalian University of Technology
Dalian 116024
P. R. of China   

Publication History

Received: 19 November 2021

Accepted after revision: 03 January 2022

Accepted Manuscript online:
03 January 2022

Article published online:
22 February 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Zhi-Shi Yewas born in Zhejiang Province, P. R. of China, in 1984. After completing his B.S. and M.S. degrees at Wenzhou University, he continued to pursue his Ph.D. at the Dalian Institute of Chemical Physics (DICP). He subsequently worked with Prof. Mingji Dai at Purdue University from 2013 to 2017 as a postdoctoral fellow. In 2017, he began his independent career at the Dalian University of Technology (DUT). His research interests include the synthesis of heterocyclic compounds, asymmetric synthesis and organometallic chemistry.
Zoom Image
Figure 1 Biologically active compounds, natural products and chiral ligands containing indole skeletons
Zoom Image
Scheme 1 Transition-metal-catalyzed enantioselective synthesis of indoles from 2-alkynylanilines; CPA: chiral phosphoric acid
Zoom Image
Scheme 2 Asymmetric construction of N–C axially chiral indoles
Zoom Image
Scheme 3 Explanation for the origin of the chirality
Zoom Image
Scheme 4 A palladium-catalyzed enantioselective Cacchi reaction for the synthesis of atropisomeric 2-arylindoles
Zoom Image
Scheme 5 Rh(III)-catalyzed synthesis of axially chiral bisindolyls by merging C–H activation and nucleophilic cyclization; Pym: pyrimidine. Five–five biaryls: two connected five-membered aromatic rings, such as 2,3′-bisindoles.
Zoom Image
Scheme 6 Synthesis of axially chiral 3-arylindoles bearing a C(3)–C(aryl) chiral axis
Zoom Image
Scheme 7 Proposed mechanism
Zoom Image
Scheme 8 Synthesis of atropisomeric naphthyl-C3-indoles via palladium-catalyzed asymmetric Cacchi reactions
Zoom Image
Scheme 9 Palladium-catalyzed enantioselective tandem C–C bond activation/Cacchi reaction between cyclobutanones and 2-alkynylanilines
Zoom Image
Scheme 10 Intramolecular-asymmetric-aminopalladation-initiated insertion of a carbonyl group
Zoom Image
Scheme 11 Enantioselective synthesis of 1,2,3,4-tetrahydro-β-carbolines via intramolecular-aminopalladation-initiated insertion of a carbonyl group
Zoom Image
Scheme 12 Enantioselective synthesis of tetrahydropyrano[3,4-b]indoles via palladium(II)-catalyzed aminopalladation/1,4-addition
Zoom Image
Scheme 13 Asymmetric aminopalladation-triggered intramolecular Heck-type reaction; amphos: di-tert-butyl(4-dimethylaminophenyl)phosphine
Zoom Image
Scheme 14 Asymmetric aminopalladation-triggered intermolecular Heck-type reaction of 2-alkynylanilines with prochiral cyclopentenes; X = OAc
Zoom Image
Scheme 15 Asymmetric palladium-catalyzed cyclative cross-coupling of 2-alkynylanilines, cyclopentenes and Selectfluor
Zoom Image
Scheme 16 Asymmetric domino-Heck reaction/aminopalladation
Zoom Image
Scheme 17 Asymmetric aminopalladation-triggered intermolecular insertion of a C≡N bond
Zoom Image
Scheme 18 Enantioselective synthesis of tetrahydrocarbazoles via asymmetric relay catalysis using a gold complex and a chiral Brønsted phosphoric acid
Zoom Image
Scheme 19 Enantioselective synthesis of tricyclic indoles by the combination of asymmetric relay catalysis and borrowing hydrogen methodology