Access to 3-amino-carbazoles from CF₃-3-indolylmethanols via Sc(OTf)₃-catalyzed C2-defluorinative allylation and DBN-promoted defluorinative annulation

Abstract

A novel method for constructing 3-(2-allyl)-indolyl substituted gem-difluoroalkenes that relies on a Sc(OTf)₃-catalyzed C2-selective allylation/defluorination cascade of trifluoromethylated 3-indolylmethanols has been realized. This diazo-free protocol features exclusive regioselectivity and broad substrate scope. In addition, the application of this protocol has been demonstrated by the one-step transformation of the obtained gem-difluoroalkenes into valuable and functionalized 3-amino-carbazole skeletons through DBN-promoted defluorinative annulation under catalyst-free conditions.

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Introduction

Carbazoles are privileged scaffolds that are widely encountered in numerous natural products, pharmaceuticals, and biologically active molecules.^1–5 For instance, murrayanine, isolated from Murraya koenigii, shows prominent antimicrobial and cytotoxic properties against human pathogenic fungi.² Carazolol and carprofen are commonly utilized as antihypertensive and nonsteroidal anti-inflammatory drugs, respectively (Fig. 1, top).³ As an important subclass, 3-amino-carbazoles are commonly occurring heterocycles present in a variety of biologically active molecules (Fig. 1, bottom).⁴ Furthermore, 3-amino-carbazole derivatives are widely used in functional materials science due to their distinctive tunable π-extended electronic and structural features.⁵ Despite their attractive features, general methods for preparing 3-amino-carbazoles are still in their infancy. Only very scattered examples have been developed, including transition-metal-catalyzed Ullmann or Buchwald–Hartwig-type cross coupling reactions of 3-halocarbazoles with nitrogen-based nucleophiles,^5e–h two-step procedures involving nitration/reduction from carbazole precursors,⁶ and electro-chemical intramolecular C–N coupling of amino-2-(2-aminoaryl)phenols.⁷ Therefore, the development of novel and versatile methods for the assembly of such skeletons from readily accessible precursors is highly desirable.

Fig. 1 Representative bioactive carbazole derivatives.

gem-Difluoroalkenes are readily accessible and versatile building blocks with unique modes of reactivity owing to the highly polarized nature of the C–C double bond. The activation and functionalization of gem-difluoroalkenes has been proved to be the most promising and appealing protocol, facilitating access to various complex and valuable fluorine-containing and non-fluorinated scaffolds.⁸ Specifically, gem-difluoroalkenes could undergo nucleophilic addition–elimination (S_NV) reactions with diverse nitrogen,⁹ oxygen,¹⁰ sulfur,¹¹ even carbon- and P(V)-based nucleophiles¹² under basic conditions to provide the monofluoroalkenes (Scheme 1a).¹³ Inspired by these elegant studies and as part of our ongoing efforts towards the synthesis and application of indolyl-substituted gem-difluoroalkenes,¹⁴ we envisioned that the preformed or in situ generated 3-(2-allyl)-indolyl gem-difluoroalkenes¹⁵ might be prone to undergo a defluorinative amination/alkene isomerization/6π annulation cascade by taking advantage of the ambiphilic reactivity (as an N-nucleophile and a strong base) of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),^16,17 enabling straightforward access to densely functionalized 3-amino-carbazoles (Scheme 1b). Herein, we disclose the details of this chemistry that provides an unprecedented and novel approach for the assembly of 3-amino-carbazoles from CF₃-containing 3-indolylmethanols via triple C–F bond cleavage¹⁸ by combining Sc(OTf)₃-catalyzed C2-selective defluorinative allylation and DBN-mediated S_NV-type defluorinative annulation.

Scheme 1 Base-mediated defluorinative functionalization of gem-difluoroalkenes.

Results and discussion

We commenced our study by utilizing 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-phenylethanol (1a) as the model substrate to determine the optimum reaction conditions (Table 1). Initially, treatment of 1a and allylTMS 2a (2 equiv.) with 10 mol% of Sc(OTf)₃ in isopropyl ether (IPE) at 80 °C for 18 h furnished the desired 3-(2-allyl)-indolyl substituted gem-difluoroalkene 3a along with the competitive 3,5′-bis(indolyl)methane product 4a in 14% and 52% yields (entry 1).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst (X mol%)	2 (m equiv.)	Solvent	Time (h)	Yield^b (%)
					3a	4a	1a ^c
a Reaction conditions: 1a (0.2 mmol), allyl reagents 2 (0.4–2 mmol), and 10–50 mol% catalyst in 2 mL of solvent at 80 °C. b Isolated yield. c Values in parentheses denote isolated recovered yields of 1a. d No reaction based on TLC analysis and ^1H NMR measurements of the crude reaction mixture. e Decomposition. f Reaction was performed at 100 °C.
1	Sc(OTf)3 (10)	2a (2)	IPE	18	14	52	(0)
2	Sc(OTf)3 (10)	2a (5)	IPE	18	21	40	(0)
3	Sc(OTf)3 (10)	2a (10)	IPE	18	33	39	(0)
4	Sc(OTf)3 (10)	2b (4)	IPE	18	12	0	(85)
5	Sc(OTf)3 (10)	2c (4)	IPE	18	—^d	—	(99)
6	Sc(OTf)3 (10)	2d (4)	IPE	18	—^e	—	(—)
7	Sc(OTf)3 (30)	2b (4)	IPE	18	30	0	(61)
8	Sc(OTf)3 (50)	2b (4)	IPE	12	62	0	(11)
9	Ga(OTf)3 (50)	2b (4)	IPE	13	7	0	(90)
10	Sn(OTf)3 (50)	2b (4)	IPE	15	25	0	(70)
11	Al(OTf)3 (50)	2b (4)	IPE	24	16	0	(80)
12	Dy(OTf)3 (50)	2b (4)	IPE	12	30	0	(63)
13	TfOH (50)	2b (4)	IPE	15	25	0	(60)
14	Sc(OTf)3 (50)	2b (4)	PhF	18	39	0	(50)
15	Sc(OTf)3 (50)	2b (4)	PhMe	24	67	0	(25)
16^f	Sc(OTf)3 (50)	2b (4)	PhMe	24	81	0	(0)

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The formation of the 3,5′-bis(indolyl)methane product 4a might be attributed to further C6-selective Friedel–Crafts alkylation of the resulting 3a with 1a under the Sc(OTf)₃-catalyzed conditions due to the electron-rich nature of 3a. However, varying the amount of allylTMS 2a from 2 to 5 and 10 equivalents (in order to reduce the competitive by-product 4a formation) still resulted in the formation of 4a as the major product in 40% and 39% yields (entries 2 and 3). To improve the chemoselectivity and the yield of 3a, other commercially available allyl reagents such as allylSnBu₃ (2b), allylBF₃K (2c) and allylBpin (2d) were examined (entries 4–6). Among them, allylSnBu₃ was found to furnish the desired product 3a as the only product, albeit in a poor yield of 12% and with the recovery of the substrate 1a in 85% yield. AllylBF₃K (2c) or allylBpin (2d) was shown to be markedly less effective, with either no reaction or decomposition observed (entries 5 and 6). Encouraged by these promising results, we next examined the catalyst loading of Sc(OTf)₃ in an attempt to further improve the yield of 3a. Pleasingly, higher conversion of 1a and good yields of 3a were observed when 30 mol% or 50 mol% of Sc(OTf)₃ was used (entries 7 and 8). However, reactions mediated by other Lewis acid catalysts, such as Ga(OTf)₃, Sn(OTf)₂, Al(OTf)₃, Dy(OTf)₃ or Brønsted acid TfOH, exhibited inferior catalytic efficiency and produced 3a in 7–30% yields (entries 9–13). Our studies subsequently showed that reactions mediated by 50 mol% of Sc(OTf)₃ in PhMe at 100 °C for 24 h gave the best results, providing 3a as the only product in 81% yield (entries 14–16).

With the optimized Sc(OTf)₃-catalyzed reaction conditions established, the generality of this protocol was next evaluated (Table 2). First, we were pleased to find that the reaction of 1a (2 mmol) could be easily scaled up under the optimized conditions (shown in Table 1, entry 16) to furnish the desired product 3a in 78% yield. Notably, our studies subsequently showed that substrates possessing various electron-withdrawing functional groups under the optimized conditions (shown in Table 1, entry 16) gave either poorer results or no reaction; instead, better outcomes were observed under the conditions described in Table 1, entry 2, presumably due to the instability nature of the carbocation species B (see Scheme 3 mechanism section for details). Therefore, two sets of optimal conditions were employed as shown in Table 1, entries 2 and 16, for electron-withdrawing and electron-donating substrates, respectively. Similarly, the reaction of 1b (2 mmol) with 2a could also be scaled up under conditions A, providing the desired product 3b in 80% yield. In addition, the reactions of substrates possessing a diverse range of electron-withdrawing (1c, 1e–i, 1m–p and 1s–u, under conditions A) or electron-donating (1d, 1j–l, 1q–r and 1v–w, under conditions B) functional groups at the C4–C7 positions of the indole moiety were shown to proceed efficiently, giving the corresponding 3-(2-allyl)-indolyl substituted gem-difluoroalkenes 3c–w in 30–88% yields. Likewise, the presence of various electron-withdrawing (1x, 1ab and ac) or -donating (1y–1aa) substituted aryl groups or a sterically demanding 2-naphthyl (1ad) at the carbinol carbon center was found to have little influence on the outcome of the reaction under the optimized reaction conditions B, with 3x–ad obtained in 81–95% yields. In addition, substrates containing a pendant 2-thienyl (1ae) or methyl (1aj) moiety at the R² position or the N-alkyl trifluoromethylated 3-indolylmethanols (1af–ai) were also found to work well, affording the corresponding products 3ae–aj in 40–90% yields under either conditions A or B.

Table 2 Substrate scope for the synthesis of 3-(2-allyl)-indolyl substituted gem-difluoroalkenes^a

a Unless otherwise specified, all reactions were carried out with 1 (0.5 mmol) at 80 or 100 °C under the listed conditions A or conditions B. Values in parentheses denote isolated product yields.

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By taking advantage of the allyl and gem-difluorovinyl functionalities incorporated in the products, a diverse array of densely functionalized 3-amino-carbazoles 5a–5ag could be accessed in moderate to good yields simply by treating them with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) under the optimized catalyst-free conditions (Table 3, also see Table S1 in the SI for details of the optimization conditions). Notably, substrates with a pendant 2-thienyl motif (3ae) or N-alkyl protected gem-difluoroalkenes (3af and 3ag) were also shown to react efficiently to deliver the corresponding products 5ae–5ag in 38–43% yields. In addition, the structure of compound 5o was unambiguously ascertained by X-ray crystallographic analysis (CCDC 2491918).¹⁹ Unfortunately, no reaction was observed when methyl-substituted gem-difluoroalkene 3aj was employed, presumably due to the electron-rich nature of the substrate, making the gem-difluoroalkene moiety less electrophilic toward DBN-nucleophilic addition.

Table 3 Substrate scope for the synthesis of 3-amino-carbazoles^a

a All reactions were carried out with 3 (0.2 mmol) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN, 0.6 mmol) in toluene at 120 °C for 12–24 h. Values in parentheses denote isolated product yields. b No reaction based on TLC analysis and ¹H NMR measurements of the crude reaction mixture.

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Encouraged by these promising results, we attempted to further explore the robustness and synthetic utility of the present protocol by performing the reactions in a one-pot two-step manner (Table 4). The one-pot synthesis of 3-aminocarbazoles 5b, 5f, 5n, 5p and 5r in 35–44% yields by subjecting 1 (0.5 mmol) to the Sc(OTf)₃-catalyzed conditions followed by DBN-mediated defluorinative annulation was found to be possible.

Table 4 One-pot synthesis of 3-amino-carbazoles^a,b

a Conditions 1: 1 (0.5 mmol), allylTMS (2.5 mmol) and Sc(OTf)₃ (10 mol%) in ⁱPr₂O (5 mL) at 80 °C for 6 h, then solvent was concentrated and further treated with DBN (1.5 mmol) and PhMe (5 mL) at 120 °C for 12 h; Conditions 2: 1 (0.5 mmol), allylSnBu₃ (2.0 mmol) and Sc(OTf)₃ (50 mol%) in PhMe (5 mL) at 100 °C for 15 h, then DBN (1.5 mmol) was added and stirred at 120 °C for 12 h. b Isolated yield over two steps from 1.

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To gain a better understanding of the DBN-mediated defluorinative annulation mechanism, some control experiments were performed (Scheme 2). Replacing DBN with more sterically hindered and slightly less basic and nucleophilic DBU was found to provide the 3-amino-carbazole 5b′, 3-fluorocarbazole 6b, and alkene isomerization products E-7b and Z-7b in 13, 26, 21 and 21% yields, respectively (Scheme 2a).¹⁶ However, subjecting 6b to the optimized DBN-mediated conditions for 12 h was shown to result in no reaction being observed and the recovery of 6b in a nearly quantitative yield (Scheme 2b). In addition, treatment of either E-7b or Z-7b with DBN furnished the 3-amino-carbazole 5b in 31% yield for both cases (Scheme 2c). These results clearly corroborated that E-7b or Z-7b might be involved as the intermediate and the possibility of an alternative pathway through the intermediacy of 6b could be ruled out. Finally, the reaction of 3b with DBN under the optimal conditions in the presence of 2 equiv. of D₂O was found to give the corresponding d₄-5b in 51% yield with roughly 30% and 4% deuterium incorporation at the α-position of the cyclic amide and methyl moiety based on HRMS, ¹H and ²D NMR measurements (Scheme 2d). Unknown and lower deuterium incorporation at the NH and methyl moiety of the adduct might be attributed to the presence of residual water in the reaction medium and/or fast deuterium/hydrogen exchange.

Scheme 2 Control experiments.

A plausible mechanism for the Sc(OTf)₃-catalyzed C2-defluorinative allylation and DBN-promoted defluorinative annulation is outlined in Scheme 3. This could initially involve activation of the hydroxyl group of the substrate by Sc(OTf)₃ to generate the Sc-coordinated species A, which triggers elimination to provide the carbocation species B or its delocalized vinyliminium ion species B′.²⁰ The subsequent C2-selective allylation with either 2a or 2b would deliver the intermediate C, which undergoes spontaneous elimination of HF driven by rearomatization to afford the gem-difluoroalkene 3. In the presence of DBN, an ensuing regioselective intermolecular nucleophilic addition of the amidine to 3 followed by the β-fluoride elimination from D would provide intermediate E,^9–12 which might be intercepted by a molecule of residual water in the reaction medium to give the unstable hemiaminal-type intermediate F. DBN-promoted deprotonation of F would provide intermediate G along with the generation of DBN-H⁺. Subsequent ring-opening of F and concomitant proton transfer might ensure production of H, which undergoes DBN-catalyzed or mediated alkene isomerization, leading to intermediate I. This is followed by 6π annulation to afford the intermediate J. Finally, DBN-assisted or spontaneous elimination of HF driven by rearomatization would afford the 3-amino-carbazole product 5. Alternatively, a possible pathway involving the alkene isomerization product E-7 or Z-7 followed by similar transformations to those aforementioned to afford 5 also could not be ruled out.

Scheme 3 Proposed mechanism.

Conclusions

In summary, we have developed a novel and efficient approach for the construction of 3-(2-allyl)-indolyl substituted gem-difluoroalkenes through a Sc(OTf)₃-catalyzed C2-selective allylation/defluorination cascade from readily available trifluoromethylated 3-indolylmethanols and allylTMS/allylSnBu₃. In addition, the application of this protocol was demonstrated by the transformation of the obtained gem-difluoroalkenes into valuable and highly functionalized 3-amino-carbazoles through DBN-mediated defluorinative annulation under catalyst-free conditions. Notably, the synthetic potential of the present defluorinative annulation cascade protocol was also further showcased by one-pot, two-step synthesis of 5 examples.

Author contributions

W. R. conceived and directed the project. Q. L. and W. R. designed the experiments and analysed the data. Q. L. and X. L. performed all the experiments. All the authors contributed to the preparation and writing of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures, spectral data, and crystallographic data. See DOI: https://doi.org/10.1039/d6qo00163g.

CCDC 2491918 (5o) contains the supplementary crystallographic data for this paper.¹⁹

Acknowledgements

We are grateful for the financial support from the Jiangsu Specially Appointed Professor Plan (to W. R.).

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17. (a) R. Herzog, I. Agrawal, H. F. von Köller, K. Kloiber and D. B. Werz, Stereospecific Insertion of Cyclic Amidines into Aryl-Substituted Cyclopropanones: Access to Complex Spirocyclic Aminals, Org. Lett., 2025, 27, 8299–8303; (b) Z.-Y. Zhu, C.-Q. Qin, D.-S. Deng, Y.-B. Xu, G.-S. Chen, D.-X. Xie and Y.-L. Liu, Synthesis of Tricyclic Azepine Derivatives and ε-Caprolactam-Tethered β-Diaminoacrylates and Guanidines via Reactions of DBU with Ketenimines or Carbodiimides, Org. Lett., 2025, 27, 8701–8705; (c) A. C. Santhoshkumar, B. Durugappa, S. V. Doddamani, A. Siby, P. K. Valmiki and S. B. Somappa, Diastereoselective Synthesis of Fused Tricyclic Pyridopyrimidines via Tandem Cyclization of Allenoates and Cyclic Amidines, Org. Lett., 2023, 25, 7711–7715; (d) Z. Luo, J. Chen, M. Li and G. C. Tsui, Three-Component Domino Acylation/Trifluoromethylation of Bicyclic Amidines, Org. Lett., 2023, 25, 5656–5660; (e) T. P. Reddy, J. Gujral, P. Roy and D. B. Ramachary, Catalytic Ynone−Amidine Formal [4 + 2]-Cycloaddition for the Regioselective Synthesis of Tricyclic Azepines, Org. Lett., 2020, 22, 9653–9657; (f) D. Peixoto, G. Malta, H. Cruz, S. Barroso, A. L. Carvalho, L. M. Ferreira and P. S. Branco, N-Heterocyclic Olefin Catalysis for the Ring Opening of Cyclic Amidine Compounds: A Pathway to the Synthesis of ε-Caprolactam-and γ-Lactam-Derived Amines, J. Org. Chem., 2019, 84, 3793–3800.
18. For selected examples of triple C–F bond defluorofunctionalization of trifluoromethylated derivatives, see: (a) T. L. Cheung, Y. Li, P. Zhang, Z. Yang, Y. Quan and H. Lyu, Electrochemical defluorinative Matteson-type homologation, Nature, 2026, 650, 621–628; (b) X.-Y. Huang, S.-J. Gao, D. Ge, M. Ma, Z.-L. Shen and X.-Q. Chu, Modular Synthesis of Furans with Four Nonidentical Substituents by Aqueous Defluorinative Reaction of Trifluoromethyl Enones with Two Nucleophiles, Org. Lett., 2025, 27, 462–469; (c) S.-J. Gao, X.-Y. Huang, X.-Y. Li, D. Ge, M. Ma, Z.-L. Shen and X.-Q. Chu, Three-Component Sulfonylation and Heteroannulation Enabled by 3-Fold Defluorofunctionalization of Trifluoromethyl Enones, J. Org. Chem., 2025, 90, 3373–3383; (d) Y.-J. Yu, F.-L. Zhang, T.-Y. Peng, C.-L. Wang, J. Cheng, C. Chen, K.-N. Houk and Y.-F. Wang, Sequential C–F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts, Science, 2021, 371, 1232–1240.
19. CCDC 2491918: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2pn1gw.
20. For reviews, see: (a) G.-J. Mei and F. Shi, Indolylmethanols as Reactants in Catalytic Asymmetric Reactions, J. Org. Chem., 2017, 82, 7695–7707; (b) L. Wang, Y. Chen and J. Xiao, Alkylideneindoleninium Ions and Alkylideneindolenines: Key Intermediates for the Asymmetric Synthesis of 3-Indolyl Derivatives, Asian J. Org. Chem., 2014, 3, 1036–1052.

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