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Synlett 2023; 34(18): 2220-2226
DOI: 10.1055/a-2126-1750
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Modern Boron Chemistry: 60 Years of the Matteson Reaction

Metal-Free Directed C–H Borylation of Indoles at the Sterically Congested C2 Position

Wang Jiang
a   College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, P. R. of China
b   State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China
,
Jingyi Bai
b   State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China
,
Jiahang Lv
b   State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China
,
Yue Zhao
b   State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China
,
Chaoguo Yan∗
a   College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, P. R. of China
,
Zhuangzhi Shi∗
a   College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, P. R. of China
b   State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China
› Author Affiliations

We thank the National Natural Science Foundation of China (Grants 22025104, 22171134, 21972064 and 21901111), the Fundamental Research Funds for the Central Universities (Grant 020514380254) for their financial support.
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Abstract

During the past few decades, transition metal-catalyzed C–H borylation has been one of the most notable advances in synthetic chemistry and has been widely employed in the preparation of organoboron reagents. Due to economic and heavy-metal-residue concerns, there is significant interest in the development of metal-free processes to mimic metallic systems. Here, we disclose a highly efficient metal-free approach for the directed C–H borylation of C3-substituted indoles at the sterically congested C2 position that uses the inexpensive boron reagent BBr3. Compared with the conventional methods using transition metals, this practical protocol provides an ideal pathway to obtain numerous C2-borylated indoles. The benefit of the synthesis of complex molecules and their applicability to medicinal chemistry is also shown through the construction of key intermediates of (–)-goniomitine and bazedoxifene and by a total synthesis of the drug fluvastatin. Mechanistic experiments demonstrate the site selectivity of this C–H borylation process.


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Key words

C–H bond activation - borylation - indoles - BBr3 - site selectivity - metal-free reaction

The indole ring system is one the most common heterocycles, present in many natural products and pharmaceuticals.[1] The efficient construction of substituted indoles has been an objective of research for more than a century, and a variety of well-established methods are now used.[2] Conventional strategies involve the de novo construction of indole skeletons, but to change substituent groups, considerable synthetic effort is required. Alternatively, many studies have been developed to functionalize indole motifs.[3] Among these efforts, a number of studies have been developed to obtain borylated indoles, allowing diverse downstream modular transformations.[4] In this context, the development of efficient and mild methods for indole borylation has attracted increasing attention for research on the preparation of complex indoles.[5]

C2-Borylated indoles are versatile synthetic intermediates used to build 2,3-disubstituted indole skeletons as key intermediates in total syntheses of natural products and pharmaceuticals (Figure [1]A). They are usually prepared by the substitution of lithium reagents with electrophilic boron species.[6] For example, this conventional method has been used as a key step in the synthesis of fluvastatin.[7] However, it requires large amounts of organometallic species, leading to incompatibilities with many sensitive functional groups. The development of the Miyaura borylation with palladium catalysts has allowed the construction of C2-borylated indoles with good functional breadth.[8] This method has been used in a synthesis of the HCV polymerase inhibitor deleobuvir, in which the indole bromide intermediate needs to be pregenerated.[9] Recently, a C–H borylation strategy using transition-metal catalysts has received significant attention,[10] and the C2-selective C–H borylation of indoles has been applied successfully to the total synthesis of many natural products, such as (–)-goniomitine[11] and (–)-trigonoliimines A and B.[12] To date, the catalysis method used in this strategy has been dominated by complexes of noble metals such as Ir, Rh, or Ru. Due to economic factors and concerns regarding heavy-metal residues, an important trend is the development of metal-free C–H borylation strategies that mimic metallic systems.

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Figure 1 Development of a site-selective C–H borylation of indoles at the sterically congested C2 position: (A) previous studies on the C2-borylation of C3-substituted indoles for total synthesis; (B) BBr3-mediated directed C–H borylation of indoles.
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Figure 2 Investigation of the N-substituents of indoles. Reaction conditions: 1a (0.20 mmol), BBr3 (0.22 mmol), DCM (1.0 mL), rt, 5 min, under Ar; then pyridine (2.0 mmol) and pinacol (0.30 mmol), rt, 2 h, under Ar.

Some elegant studies have recently resulted in the development of C–H borylations of indoles without transition metals.[13] For example, the Fontaine group has developed a metal-free strategy for the selective C–H borylation of heteroarenes, in which the quantitative borylation of N-methylindoles occurs at the most-electron-rich C3 position.[14] Recently, our group[15] and that of Ingleson[16] have discovered a general strategy for aromatic C–H borylation enabled by directing groups, in which BBr3 [17] acts as both a reagent and catalyst (Figure [1]B; left). In our previous study, the installation of a directing group at the N1 or C3 position of an indole selectively delivered the boron species to the C7 or C4 position and allowed a subsequent C–H borylation without the need to use a metal. During further investigation of this chemistry, we were surprised to find that the installation of a substituent at the C3 position of an indole enables C–H borylation at the sterically congested C2 position. Furthermore, some unusual examples of C3-substituted indoles showed reversed C7 selectivity. These discoveries piqued our interest. Herein, we disclose a highly efficient BBr3-mediated approach for the C2-selective C–H borylation of indoles (Figure [1]B; right). The installation of a directing group at the N atom of the C3-substituted indoles selectively delivers the boron species to the C2 position. Based on mechanistic experiments, electronic and steric factors that individually promote selectivity using a BBr3 reagent are demonstrated, for the first time, to be powerful control elements.

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Figure 3 Substrate scope of C3-substituted indoles. Reaction conditions: 1a–24a, 26a–28a (0.20 mmol), BBr3 (0.22 mmol), DCM (1.0 mL), rt, 5 min, under Ar; then pyridine (2.0 mmol), pinacol (0.30 mmol), rt, 2 h under Ar. The ratios of isomers were measured by GC/MS analysis of the crude mixtures. a 25a (0.20 mmol), BBr3 (0.44 mmol), DCM (1.0 mL).

Our investigation commenced by evaluating the reaction of BBr3 with C3-methyl indoles bearing various N-substituents (Figure [2]). In experiments to optimize the reaction, the best results were obtained by using N-(1-adamantanoyl)indole (1a) with BBr3 (1.1 equiv) in dry dichloromethane (DCM) without an additive for five minutes at room temperature; this gave the dibromoborane 1b, which was isolated and its structure confirmed by X-ray analysis.[18] When the intermediate was then allowed to react with pinacol in the presence of pyridine at room temperature for one hour, the C2-borylation product 1c was formed in 77% isolated yield, together with a small amount of the C7-borylated byproduct 1d in a 12:1 ratio. The N-pivaloyl indole 1a-I also exhibited excellent reactivity with BBr3 to generate 1c-I in a 4:1 isomeric ratio. Changing the directing group to a benzoyl motif in indole 1a-II led to a much lower reactivity, affording the corresponding product 1c-II in 35% yield. Further exploration showed that indoles bearing acetyl (1a-III) or methyl (1a-IV) groups did not produce borylation products. These results indicate that the appropriate selection of the N-(1-adamantanoyl) group ensures a high reactivity and selectivity in this transformation.

With these optimized reaction conditions, we explored the substrate scope of the indole (Figure [3]). Indoles bearing ethyl (2a), isopropyl (3a), or phenyl (4a) substituents at the C3 position underwent facile C2-borylation and afforded corresponding products 2c–4c in good yields. Regarding the scope of the indole framework, various electron-neutral and electron-donating substituents, including Me (5a and 6a) and OMe (7a), were well tolerated, showing excellent regioselectivities. In particular, motifs containing halogens such as F (8a), Cl (9a), Br (10a), or I (11a) all worked well. Moreover, substrate 12a with an electron-withdrawing CF3 substituent gave the corresponding product 12c in 81% yield with excellent regioselectivity. Aryl substituents at the C3 position were also investigated, and methyl (13a), methoxy (14a and 15a), Cl (16a), Br (17a), and CF3 (18a) substituents at the para and meta positions were found to be compatible. The treatment of biheteroaryl compound 19a under the standard reaction conditions led to C–H borylation at the C2-position of the indole motif. Moreover, a sterically hindered benzyl group at the C3 position was tolerated, giving rise to product 20c with good site selectivity. Notably, substrates with alkenyl substituents were sensitive to the transition-metal-catalyzed borylation system due to an olefin hydroboration process.[19] In this system, indoles 21a–23a with either internal or terminal olefin motifs formed the C–H borylation products 21c–23c exclusively. In addition to the aforementioned carbon substituents, the tolerance of indole 24a to heteroatoms such as Br at the C3 position can also be leveraged to functionalize C–H bonds at the C2 position. By introducing two N-1-directing groups, the natural product 3,3′-diindolylmethane 25a was subjected to twofold C–H borylation with BBr3 to produce 25c in nearly quantitative yield. 3-Aryl indole 26a with an ortho-substituted OMe group also exhibited efficient C2 selectivity. To our surprise, indole 27a bearing an ortho-substituted methyl group formed a mixture of products 27c and 27d in a 1:2 ratio, favoring reaction at the C7 position. Furthermore, the related Br-containing indole 28a produced the single product 28c almost exclusively through the reaction at the C7 position in an excellent yield.

Although the use of a 1-adamantanoyl group can provide the desired indole C–H borylation products with high reactivity and selectivity, removing the directing group requires additional steps (Figure [4]). To facilitate this operation, a traceless-directing-group strategy[20] can be utilized in this borylation process. By using K2CO3 as a base instead of pyridine with pinacol, indole 1a was directly converted into the N-free borylated indole 1e in 67% yield, and the directing group was removed automatically.

To demonstrate the synthetic utility of the metal-free C–H borylation strategy, a reaction of 5.0 mmol indole 1a was first conducted, enabling the gram-scale synthesis of the desired product 1c in 73% isolated yield, without a notable decrease in the yield (Figure [5]). Mild oxidation of 1c with NaBO3·4H2O provided indoline 29 in 77% yield.[21] The Pd-catalyzed arylation, olefination, heteroarylation, or alkynylation of indole 1c with the corresponding organohalides efficiently gave the desired products 30–33. Furthermore, the cyanation of substrate 1c with TMSCN mediated by Cu2O gave the desired product 34 in 63% yield. In addition, we also used compound 1c to prepare the C2-iodinated product 35.

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Figure 4 Tandem C–H borylation and removal of the directing group
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Figure 5 Gram-scale synthesis and downstream transformations. Reagents and conditions: (a) NaBO3·4H2O (4.0 equiv), NaOH (1.5 equiv), H2O–THF, 3 h, rt; (b) PhI (1.3 equiv), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv), DMF–MeOH, 10 h, 60 °C; (c) [(E)-(2-bromovinyl)]benzene (1.3 equiv), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv), toluene–MeOH, 60 °C, 10 h; (d) 2-bromopyridine (1.3 equiv), Pd(PPh3)4 (5 mol%), t-BuOLi (6.0 equiv), 1,4-dioxane–H2O, 100 °C, 12 h; (e) (bromoethynyl)(triisopropyl)silane (1.3 equiv), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv), toluene–MeOH, 80 °C, 10 h, darkness; (f) TMSCN (1.1 equiv), Cu2O (40 mol%), TMEDA (1.2 equiv), Et3N (3.0 equiv), O2, MeCN, 25 °C, 12 h; (g) NaOH (2.0 equiv), I2 (2.0 equiv), H2O/THF, 3 h, rt.
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Figure 6 Concise routes to various indole alkaloids through metal-free directed C–H borylation. (A) Synthesis of intermediate 38 for (–)-goniomitine. (B) Synthesis of intermediate 42 for bazedoxifene. (C) Concise total synthesis of fluvastatin.

The developed C–H borylation process provides a unique opportunity to obtain C2-borylated indoles by more-convergent synthetic routes. We report some examples to showcase the potential synthetic applications of this strategy (Figure [6]). In the total synthesis of (–)-goniomitine, completed in 11 steps by Jia and co-workers, the key 2-indoleboronate intermediate was produced by an Ir-catalyzed C–H borylation with HBpin.[11] Based on this metal-free strategy, treatment of indole 36 with PivCl formed adduct 37, which produced the key compound 38 through tandem C–H borylation and the removal of Piv groups from the N atom (Figure [6]A). Su and co-workers reported an evolution of the total synthesis of bazedoxifene in which the 2-arylindole 42 was a key intermediate.[22] Alternatively, indole substrate 39 was selective for C–H borylation at the C2 position to yield compound 40, which then underwent Suzuki–Miyaura coupling with compound 41 to produce the related N-free indole 42 in 73% yield (Figure [6]B). In addition, we also applied this method to the rapid construction of fluvastatin, a lipid-lowering agent (Figure [6]C).[23] Subjecting indole 43 to BBr3 under the standard reaction conditions provided the borylated product 44 in 77% yield. Subsequent installation of an alkenyl moiety at the C2 position of 44 with olefin 45 by palladium-catalyzed Suzuki–Miyaura coupling generated the olefination indole 46, which reacted with 2-iodopropane in a one-pot process to furnish the alkylation product 47 in 63% yield. Finally, removal of the protecting group under acidic conditions produced the target product in excellent yield.

We have explored an efficient strategy for the selective C–H borylation of C3-substituted indoles at the sterically congested C2 position using only BBr3.[24] The transformation proceeds without a metal and under mild conditions, displays a broad scope and functional-group tolerance, and produces the desired products with good to excellent site selectivity. This protocol also permits the in situ removal of the directing group during workup. This discovery brings us closer to understanding the reactivity of BBr3-mediated C–H borylation. These results lay the foundation for the development of metal-free directed C–H borylation, avoiding the use of transition-metal catalysts.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2126-1750.
  • Supporting Information

Corresponding Authors

Chaoguo Yan
College of Chemistry and Chemical Engineering, Yangzhou University
Yangzhou
P. R. of China   

Zhuangzhi Shi
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University
Yangzhou
P. R. of China   

Publication History

Received: 22 May 2023

Accepted after revision: 10 July 2023

Accepted Manuscript online:
10 July 2023

Article published online:
18 September 2023

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   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Development of a site-selective C–H borylation of indoles at the sterically congested C2 position: (A) previous studies on the C2-borylation of C3-substituted indoles for total synthesis; (B) BBr3-mediated directed C–H borylation of indoles.
Zoom Image
Figure 2 Investigation of the N-substituents of indoles. Reaction conditions: 1a (0.20 mmol), BBr3 (0.22 mmol), DCM (1.0 mL), rt, 5 min, under Ar; then pyridine (2.0 mmol) and pinacol (0.30 mmol), rt, 2 h, under Ar.
Zoom Image
Figure 3 Substrate scope of C3-substituted indoles. Reaction conditions: 1a–24a, 26a–28a (0.20 mmol), BBr3 (0.22 mmol), DCM (1.0 mL), rt, 5 min, under Ar; then pyridine (2.0 mmol), pinacol (0.30 mmol), rt, 2 h under Ar. The ratios of isomers were measured by GC/MS analysis of the crude mixtures. a 25a (0.20 mmol), BBr3 (0.44 mmol), DCM (1.0 mL).
Zoom Image
Figure 4 Tandem C–H borylation and removal of the directing group
Zoom Image
Figure 5 Gram-scale synthesis and downstream transformations. Reagents and conditions: (a) NaBO3·4H2O (4.0 equiv), NaOH (1.5 equiv), H2O–THF, 3 h, rt; (b) PhI (1.3 equiv), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv), DMF–MeOH, 10 h, 60 °C; (c) [(E)-(2-bromovinyl)]benzene (1.3 equiv), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv), toluene–MeOH, 60 °C, 10 h; (d) 2-bromopyridine (1.3 equiv), Pd(PPh3)4 (5 mol%), t-BuOLi (6.0 equiv), 1,4-dioxane–H2O, 100 °C, 12 h; (e) (bromoethynyl)(triisopropyl)silane (1.3 equiv), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv), toluene–MeOH, 80 °C, 10 h, darkness; (f) TMSCN (1.1 equiv), Cu2O (40 mol%), TMEDA (1.2 equiv), Et3N (3.0 equiv), O2, MeCN, 25 °C, 12 h; (g) NaOH (2.0 equiv), I2 (2.0 equiv), H2O/THF, 3 h, rt.
Zoom Image
Figure 6 Concise routes to various indole alkaloids through metal-free directed C–H borylation. (A) Synthesis of intermediate 38 for (–)-goniomitine. (B) Synthesis of intermediate 42 for bazedoxifene. (C) Concise total synthesis of fluvastatin.