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. 2025 May 29;27(28):7507–7512. doi: 10.1021/acs.orglett.5c01778

Synthesis of 2‑Phosphorus-Substituted Indoles via Ring Expansion of Benzocyclobutenone Oxime Sulfonates

Yusuke Kanno †, Yumi Yamashita †, Akira Sugiyama ‡, Tatsuhiko Kodama §, Juri Sakata †, Hidetoshi Tokuyama †,*
PMCID: PMC12281575  PMID: 40439343

Abstract

A method for the synthesis of 2-phosphorus-substituted indoles via ring expansion of benzocyclobutenone oxime sulfonates, which were prepared via the [2 + 2] cycloaddition of benzynes and ketene acetals, and subsequent oximization and sulfonylation was developed. The reaction occurs by addition of the phosphate anion or phosphine oxide anion to the CN bond of oxime sulfonates, followed by ring expansion to provide 2-phosphorus-substituted indoles. This method was applicable to the synthesis of 2-phosphorus-substituted indoles with a wide variety of substitution patterns on the benzene ring and at the 3-position, as well as to a 2-phosphorus-substituted 4-aza-indole. An indol-2-ylphosphonic acid and a 2-phosphaneylindole were obtained by a transformation of the corresponding products. This protocol was applied to synthesize a duocarmycin SA phosphonate analogue, which exhibited greater cytotoxicity against HeLa S3 and KPL-4 cells than duocarmycin SA.

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Extensive research has focused on the development of a novel method to synthesize functionalized indoles because these compounds are frequently found in natural products, pharmaceuticals, functional materials, and agrochemicals. In particular, 2-phosphorus-substituted indoles have recently attracted considerable attention as scaffolds for the design of pharmaceuticals, functional materials, and ligands for transition metal catalysts (Scheme ). −

1. Utilities of 2-Phosphorus-Substituted Indoles.

1

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For example, indol-2-ylphosphonamidate 1 inhibits the salicylating enzymes involved in siderophore biosynthesis, which affects the virulence of various bacteria, including those causing plague (Scheme a). Therefore, 1 is a potential lead antimicrobial compound for use against the bacteria causing plague (Yersinia pestis) and tuberculosis (Mycobacterium tuberculosis). Phosphole heteroacene 3-DIPO (2) was developed for use in organic electroluminescence, and its efficiency as an organic light-emitting diode was investigated. In addition, various indol-2-ylphosphines have been found to be effective ligands for transition metal catalysts. For example, Beller reported the Pd-catalyzed amination of aryl chloride in the presence of indol-2-ylphosphine ligands 3 (Scheme b), and Franzén developed Pd-catalyzed asymmetric allylic substitution of allyl acetate by using indol-2-ylphosphine having oxazoline unit (4: IndPHOX) (Scheme c).

There are two main strategies to synthesize 2-phosphorus-substituted indoles (Scheme ). − First, a phosphorus functional group can be introduced via reactions involving indole derivatives. For example, the reaction of 2-lithioindoles 6, which can be generated by either halogen–lithium exchange of 2-haloindoles 5 or direct lithiation of indoles bearing an appropriate protecting group at the N1 position, with phosphorus-containing electrophiles such as ClPPh2 affords 2-phosphorus-substituted indoles (Scheme a). However, this reaction, requiring strongly basic conditions, has a narrow substrate scope and poor functional group compatibility. Alternatively, Pd-catalyzed coupling of 5 with phosphite (Scheme a) and oxidative radical addition of a P-centered radical to 2-unsubstituted indoles, which proceed under relatively mild conditions, have been reported (Scheme b). A second strategy to construct 2-phosphorus-substituted indoles involves pyrrole ring formation with simultaneous incorporation of a phosphorus-containing moiety (Scheme c). , For example, Fischer indole synthesis uses acylphosphonate (11) as a counterpart of aryl hydrazine (10). Bisseret reported Pd-catalyzed tandem C–P coupling/intramolecular cyclization of O-(2,2-dibromovinyl)-aniline (12), and Yang described a modified Fukuyama indole synthesis initiated by the generation of a P-centered radical under Ru­(bpy)3Cl2-catalyzed photoirradiation conditions, followed by addition of the P-centered radical to isocyano-2-styrylbenzenes (13) and 5-exo-trig cyclization. Moreover, Yorimitsu and Oshima synthesized 2-indolyl phosphine oxides (16) via Pd-catalyzed annulation of 1-alkynylphosphine oxide (15) with 2-iodoaniline (14).

2. Synthesis of 2-Phosphorus-Substituted Indole.

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Despite these important advances, there remains room to expand the scope of accessible 2-phosphorus-substituted indoles. In this research, we focused on our indole synthesis via ring expansion of benzocyclobutenone oxime sulfonates (Scheme ). This reaction was initiated by the addition of a nucleophile, such as hydride, cyanide, and thiolate, to oxime sulfonates 17 to generate tetrahedral intermediates 18, followed by ring expansion via migration of the C­(sp2)–C­(sp3) bond to the nitrogen atom with concomitant cleavage of the N–O bond, affording 2-substituted indoles 19 (Scheme a). We hypothesized that a phosphorus functional group could be introduced at the 2 position of the indole by adding nucleophilic P-centered anion species 20 to 17 (Scheme b). Herein, we report a novel synthetic method for 2-phosphorus-substituted indoles via ring expansion of benzocyclobutenone oxime sulfonates and the synthesis of an unnatural duocarmycin SA phosphonate analog, demonstrating the utility of this method for the synthesis of highly fused 2-phosphorus-substituted indoles.

3. 2-Substituted Indole Synthesis by Ring Expansion of Oxime Sulfonate.

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First, we tested our working hypothesis by using benzocyclobutenone oxime sulfonate 17a as a test substrate to generate 2-substituted indoles because 17a provided indole products most efficiently in the previously developed reactions using other nucleophiles (Table ). To a 0.1 M THF solution of 17a, which had been prepared via [2 + 2] cycloaddition of a benzyne derivative with dimethyl ketene acetal, and diethyl phosphite 7a (2.5 equiv) was added NaH at room temperature. As expected, 2-phosphorus-substituted indole 21aa was formed in 64% yield (Table , entry 1). When NaH was replaced with t-BuOK, the reaction afforded 21aa in a comparable yield (Table , entry 2). Then, we selected t-BuOK as the base and screened various solvents (Table , entries 3–8). Reactions in DMSO and CH3CN generated the product in slightly increased yields, whereas the reaction provided 21aa in lower yields in 1,4-dioxane, cyclopentyl methyl ether (CPME), DMF, or toluene. Decreasing the temperature or increasing the amount of base and phosphite did not improve the yield (Table , entries 9 and 10).

1. Optimization of the Reaction Conditions.

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entry solvent X (equiv) base Y (equiv) temp (°C) time (h) 21aa (%) recovery of 17a (%)
1 THF 2.5 NaH 2.5 rt 2 64 <23
2 THF 2.5 t-BuOK 2.5 rt 2 66 <10
3 1,4-dioxane 2.5 t-BuOK 2.5 rt 2 57 <10
4 CPME 2.5 t-BuOK 2.5 rt 2 43 <42
5 DMF 2.5 t-BuOK 2.5 rt 2 43 <10
6 DMSO 2.5 t-BuOK 2.5 rt 2 72 <7
7 toluene 2.5 t-BuOK 2.5 rt 2 61 <3
8 CH3CN 2.5 t-BuOK 2.5 rt 2 70 <3
9 CH3CN 2.5 t-BuOK 2.5 0 2 71 <9
10 CH3CN 5.0 t-BuOK 5.0 0 2 69 <6
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a

Reactions were conducted at a concentration of 0.1 M.

b

Isolated yield.

To improve the yield of 21aa, we further investigated the experimental conditions. When t-BuOK was used (Table , entries 2–10), unidentified byproducts were generated. To determine whether these byproducts formed via decomposition of 17a under basic conditions, we conducted a control experiment to evaluate the stability of 17a in the presence of t-BuOK. Treatment of 17a with t-BuOK in CH3CN at 0 °C without 7a resulted in complete decomposition of 17a to the unidentified byproducts. To prevent this decomposition, we investigated the order of addition of the reagents and found that the addition of a solution of phosphonate anion effectively suppressed byproduct generation. Thus, when a freshly prepared CH3CN solution of anionic 20a from 7a (5.0 equiv) and t-BuOK (5.0 equiv) was added to a CH3CN solution of 17a via cannula, the desired reaction proceeded cleanly, generating indole 21aa in 83% yield without byproduct generation (Scheme ).

4. Improved Reaction by Addition of a Stock Solution of the Phosphorous Anion.

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After establishing the reaction protocol, we next investigated the scope of phosphorus nucleophiles and benzocyclobutenone oxime sulfonates (Table ). For the phosphonate, methyl ester 7b, n-butyl ester 7c, i-propyl ester 7d, t-butyl ester 7e, benzyl ester 7f, and phenyl ester 7g were suitable for the reaction, and the corresponding 2- phosphorus-substituted indoles were generated in good yields. In addition, an anionic species generated from diphenylphosphine oxide smoothly reacted with 17a to provide indol-2-ylphosphine oxide 21ah in good yield. Because anionic species 20d, 20e, 20g, and 20h, which were generated from i-propyl, t-butyl, and phenyl esters 7d, 7e, and 7g and diphenylphosphine oxide 7h, were poorly soluble in CH3CN, the reaction was conducted by adding NaH to a CH3CN solution of the phosphite or phosphine oxide (7d–e, 7g–h) and 17a. Next, the generality of benzocyclobutenone oxime sulfonates was examined by using phosphonate anion 20a generated from 7a. Substrates 17a–f, bearing electron-donating groups, including methyl, phenyl, trimethylsilyl (TMS), morpholino, and n-C12H25S groups, at the 7 position of the benzene ring, reacted to form desired products 21ba–fa in good to high yields. Conversely, the reaction of substrates 17g–i, bearing electron-withdrawing groups, such as CF3, Br, and triflate (OTf), afforded 21ga–ia in low to modest yields. Furthermore, unsubstituted (21ja), 6-substituted (21ma and 21na), and 6,7-disubstituted (21oa) compounds were obtained in good to high yields, whereas 5-substituted compounds 21ka and 21la were generated in lower yields. Notably, 3-substituted 2-phosphorus-substituted indoles could be synthesized by this reaction. Thus, products bearing a methyl group (21pa), a tert-butyldimethylsilyl (TBS)-protected hydroxyethyl group (21qa), and even a sterically hindered t-Bu group (21ra) were obtained in high yields.

2. Scope of the Nucleophile and Benzocyclobutenone Oxime Sulfonate.

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a

Isolated yield.

b

Since substrates 20d, 20e, 20g, and 20h have poor solubility in CH3CN generating white suspensions, reactions were conducted by adding NaH to a mixture of 7d, 7e, 7g, 7h,and 17a in CH3CN.

c

The reactions were conducted in DMSO.

d

The reaction was conducted in DMSO/1,4-dioxane (3:1).

e

Additional 20 (2.5 equiv) was required to complete the reaction.

Furthermore, the utility of this reaction was expanded to synthesize a 4-aza-indole derivative, indol-2-ylphosphonic acid, and 2-phosphaneylindole (Scheme a–c). Ring expansion of pyridine-fused cyclobutenone oxime sulfonate 17s, which was prepared via [2 + 2] cycloaddition of 2,3-pyridyne species with dimethyl ketene acetal, proceeded in the presence of 7a and t-BuOK in CH3CN, affording 2-phosphorus-substituted 4-aza-indole 21sa in modest yield (Scheme a). Indol-2-ylphosphonic acid 22 was generated by TMSBr-mediated deethylation of phosphate 21aa (Scheme b). Reduction of indol-2-ylphosphine oxide 21ah by treatment with either LiAlH4 or a combination of trichlorosilane and triethylamine afforded 2-phosphaneylindole 23 (Scheme c).

5. Applications of the 2-Phosphorus-Substituted Indole Synthesis.

5

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Finally, the high functional group compatibility of this 2-phosphorus-substituted indole synthesis was demonstrated by the synthesis of a duocarmycin SA phosphonate analog (Scheme d). Duocarmycin SA and the related compounds, which have been isolated from Streptomyces sp., exhibit extremely potent antitumor activity by alkylating DNA at the dienone cyclopropane moiety in the cyclopropa­[e]­pyrroloindole (CPI) segment. Boger et al. investigated the structure–activity relationships of duocarmycins and their derivatives and found that the methoxy carbonyl group in the CPI segment resulted in enhanced binding and was thus crucial for efficient DNA alkylation. In this study, we designed an unnatural duocarmycin SA derivative by replacing the methoxy carbonyl group in the CPI segment with a phosphonate group, aiming to increase the antitumor activity by enhancing the binding.

The duocarmycin SA phosphonate analog was synthesized via completely regioselective [2 + 2] cycloaddition , of a highly functionalized benzyne intermediate, which had been generated by treatment of a 5-bromotetrahydroquinoline derivative 26 , with lithium tetramethylpiperidide, with ketene silyl acetal, followed by treatment with acetic acid to afford benzocyclobutenone 28. After conversion of 28 to oxime sulfonate 17t in two steps, ring expansion of 17t under standard conditions furnished the desired tricyclic 2-phosphorus-substituted indole 21ta in high yield (89%). Then, the TBS group was replaced with a mesyl (Ms) group, and the tert-butyloxycarbonyl group was removed, affording a cyclic secondary amine, which was then condensed with acid chloride 30 to generate amide 31. Finally, transannular cyclopropanation via one-pot Pd/C-catalyzed debenzylation and treatment of the resulting phenol with triethylamine generated the desired duocarmycin SA phosphonate analog 25. The antitumor activities of 25 and duocarmycin SA (24) were compared via an in vitro assay based on the inhibition of HeLa S3 and KPL-4 cell growth. Interestingly, the IC50 values of 25 for HeLa S3 and KPL-4 cells were 2 and 2.7 times lower (indicating greater potency), respectively, than that of duocarmycin SA (24).

In conclusion, we developed a method to synthesize 2-phosphorus-substituted indoles via ring expansion of benzocyclobutenone oxime sulfonates with broad functional group compatibility. The utility of this protocol was demonstrated by the construction of a highly functionalized piperidine-fused 2-phosphorus-substituted indole derivative, which was converted into an unnatural duocarmycin SA phosphonate analog that exhibited greater antitumor activity than its parent duocarmycin SA. The 2-phosphorus-substituted indoles synthesized by this method are expected to be widely applicable in drug discovery, organic synthesis, and materials science.

Supplementary Material

ol5c01778_si_001.pdf (25.8MB, pdf)

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c01778.

  • Full experimental procedure and 1H and 13C NMR spectra of compounds 17, 21–23, 25, 28, 29, and 31 (PDF)

This work was supported by a Grant-in-Aid for Transformative Research Areas (A) “Latent Chemical Space” [JP24H00591] the Ministry of Education, Culture, Sports, Science and Technology, Japan.This work was financially supported by KAKENHI (JP24H01744, JP21K15217, and JP24K09704) from JSPS and Research Support Project for Life Sciences Research and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED (JP25ama121040). This research was also supported by AMED under Grant JP24am0521003.

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

ol5c01778_si_001.pdf (25.8MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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