Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2021 Apr 1;23(8):2921–2926. doi: 10.1021/acs.orglett.1c00557

Metal-Free C–C/C–N/C–C Bond Formation Cascade for the Synthesis of (Trifluoromethyl)sulfonylated Cyclopenta[b]indolines

Carlos Lázaro-Milla †, Hikaru Yanai ‡, Pedro Almendros §,*
PMCID: PMC8479863  PMID: 33793251

Abstract

graphic file with name ol1c00557_0008.jpg

A bis(triflyl)ethylation [triflyl = (trifluoromethyl)sulfonyl] inserted into a sequential cyclization cascade resulted in the direct formation of gem-bis(triflyl)ated cyclopenta[b]indolines from anilide-derived allenols and alkenols. This catalyst- and irradiation-free sequence facilitated the efficient preparation of functionalized tricyclic indoline cores bearing two contiguous stereocenters. The formed cyclopenta[b]indolines can be easily transformed into a wide variety of triflylated indolines, including the tetracycle ring system found in polyveoline.

Cyclopenta[b]indole/indoline is a privileged scaffold present in various biologically active compounds. This structural motif is widely found in the molecular structures of natural indole alkaloids such as fischerindole L, yuehchukene, and polyveoline (Figure 1).1 Azacyclopenta[b]indolines, exemplified by physostigmine, also make up an important family of bioactive alkaloids.2 Synthetic efforts involving these polycyclic systems focus on the development of the dearomatization of indoles3 either by the electrophilic activation of indole substrates bearing nucleophilic sites (Scheme 1a)4 or by dearomative cycloadditions (Scheme 1b).5 The de novo synthesis of polycyclic indolines, chemical transformations of sophisticated aniline-derived substrates, despite being interesting, required expensive transition metal catalysts.6 Consequently, we were interested in the development of a novel cascade reaction to produce the polycyclic indolines from easily available aniline-derived substrate A with Tf2C=CH2 (Tf = SO2CF3), which exhibits outstanding high electrophilicity (Scheme 1c). In general, the domino reactions consisting of several bond formation steps without the isolation of intermediates are efficient, sustainable, and economically favorable processes in organic synthesis because they are associated with the reduction of reagents, solvents, and waste.7 Additionally, the reaction system presented here, including the sequential C–C/C–N/C–C bond-forming process, is certainly challenging from the following points of view: (1) realization of chemo- and regioselectivities in each reaction step and (2) the difficulty with C–C bond formation through intramolecular nucleophilic substitution by the [Tf2CR]− moiety. The [Tf2CR]− species is known to be a chemically inert carbanion owing to two triflyl groups on the anionic carbon atom,8 and C–C bond formation from this species is limited in specific cases mediated by highly reactive vinyl-type carbocation intermediates.9 Herein, we describe our methodology, applying high-energy species as a reaction partner that does not require the use of any catalyst/activator including photochemical activation. In addition, taking advantage of the chameleonic reactivity of sulfonyl compounds, the gem-bis(triflyl)ated indoline products were successfully derivatized into the highly functionalized indolines with fluorinated substituents, which may yield interesting properties.10,11

Figure 1.

Figure 1

Open in a new tab

Bioactive and natural products having the polycyclic indoline core moiety.

Scheme 1. Background and Current Design for Cyclopenta[b]indolines.

Scheme 1

Open in a new tab

The project began from an unexpected reaction of aniline-derived substrate 2a with 2-(2-fluoropyridinium-1-yl)-1,1-bis(triflyl)ethan-1-ide 1, a reagent developed by Yanai et al. as an easily available, shelf-stable compound to serve as a latent source of Tf2C=CH2 (Scheme 2).12 We recently reported that the reaction of several allenols with Yanai’s reagent 1 smoothly proceeded in acetonitrile at room temperature to give bis(triflyl)enones through electrophilic attack of Tf2C=CH2 on the terminal carbon atom of the allene moiety.13 Surprisingly, when aniline-derived allenol 2a was used as a reaction substrate, tricyclic indoline 3a rather than bis(triflyl)enone 4 or bis(triflyl)ethylated anilide 5 was obtained as the major product (35% yield) along with several unidentified compounds. The structure of 3a was proven through its X-ray crystallographic analysis.14 After carefully exploring several reaction solvents and temperatures, we concluded that the use of 1,2-dichloroethane (DCE) at 130 °C was the optimal reaction condition. In this reaction, use of bench grade solvents did not affect the reaction outcome. Fused indoline 3a was obtained as a single cis isomer in a reasonable 62% yield.15,16 We concluded that a carbonyl moiety on the nitrogen was necessary as benzyl- or sulfonyl-protected allenyl anilines 2 decomposed upon reaction with 1.

Scheme 2. Reaction of Carbamate-Derived Substrate 2a.

Scheme 2

Open in a new tab

The scope of this transformation is summarized in Figure 2. Introducing substituents on the allene moiety by replacing the C-methyl group with C-phenyl and C-aryl groups with different electronic and steric characteristics gave the product indoline (3e–3g) in fair yields and total selectivity. Pleasingly, when halogen (I, Br, and Cl), alkyl (Me), or alkoxy (MeO) substituents were incorporated into the aromatic ring of the anilide moiety, the products (3i–3o) were obtained in 40–68% yields. The NMR spectra of tricycles 3d and 3o showed signals of a minor isomer (8% and 12%, respectively, as estimated by 1H NMR). As only cis-fused 5,5-systems are typically observed in any reaction outcome, the trans isomer should be ruled out and these signals should be ascribed to the corresponding rotamers.17 Interestingly, tetracyclic indoline 3h bearing an extra fused benzene ring was formed in a good 77% yield as a single isomer. Similarly, deuterated gem-bis(triflyl)indoline [D]-3a was smoothly formed through the reaction between aniline-derived allenol 2a and reagent [D]-1. The tricycle structure of 3e and its relative stereochemistry were proved through X-ray crystallographic analysis.14

Figure 2.

Figure 2

Open in a new tab

Synthesis of bis(triflyl)-containing tricyclic indolines 3a–3o and [D]-3a. aThe thermal ellipsoids are shown at 50% probability.

Motivated by the results presented above, we decided to expand the substrate scope by exploring other precursors in place of anilide-derived allenols 2. It is noteworthy that when anilide 6a having an electronically unbiased allylic alcohol was exposed to the standard conditions, desired indoline 7a was obtained in 64% yield (Figure 3). The position and electronic nature of the substituents on the arene core of 6 do not seem to have a decisive influence on the transformation and provided tricyclic gem-bis(triflyl)indolines 7 in a competent way. In addition, chloro substitutions in anilide precursors are well accommodated, which brings about the possibility of postfunctionalization. Sterically bulky substituents, such as the phenyl group in allene precursor 6d, attenuated neither reactivity nor selectivity. However, the diminished yield of tricyclic product 7c, having an acetate instead a carbamate group, showed the pivotal role of the protecting group. Structures of compounds 7d and 7g were determined unambiguously by single-crystal X-ray diffraction analysis.14

Figure 3.

Figure 3

Open in a new tab

Synthesis of bis(triflyl)-containing tricyclic indolines 7a–7g. The thermal ellipsoids are shown at 50% probability.

To showcase the applicability of the protocol, tricyclic indolines 3a–3c and 7a were subjected to further synthetic transformations (Scheme 3). As depicted in Scheme 3a, the derivatization of indoline 3a under basic conditions resulted in dienyl triflone 8, while bromination afforded product 9. The facile transformation of the benzylic position in tricycles 3 and 7 enabled the formation of bis(triflyl)ethyl-decorated bicyclic indolines 10, 11, 13, and 19 under reductive conditions (Scheme 3b,c,f).18 Likewise, N-deprotected indoline 12 could easily be obtained by acid treatment of N-Boc indoline 3c (Scheme 3c). On the contrary, the nucleophilic 1,4-addition of amines and thiols to conjugate diene 8 occurred in one pot from 3a to give the functionalized derivatives 14 and 15 (Scheme 3d). Treatment of iodoindoline 3j under Suzuki–Miyaura conditions resulted in cross-coupled adduct 16 in which detriflylation also occurred, while conjugate diene 8 proved to be an excellent dienophile in the Diels–Alder reaction with 2,3-dimethylbuta-1,3-diene to form 17 stereoselectively (Scheme 3e). Compound 17 bears the tetracyclic core of indole sesquiterpene polyveoline (Figure 1). Though functionalized polycycles 15 and 17 can be directly accessed from 3a, higher yields were observed when dienyl triflone 8 was the immediate precursor. Finally, elimination of CF3SO2H can be smoothly accomplished in 7a to give alkenyl triflone 18 after treatment with potassium carbonate (Scheme 3f). In contrast with indolines 3, the absence of the terminal alkene moiety in 7a directs the elimination toward the formation of the more substituted alkene.

Scheme 3. Synthetic Transformations of gem-Bis(triflyl)indolines 3 and 7.

Scheme 3

Open in a new tab

The mechanistic hypothesis for the formation of 3 and 7 is depicted in Scheme 4. First, electrophilic attack of Tf2C=CH2 (generated in situ along with 2-fluoropyridine from betaine 1) proceeds with 2 or 6 on the β-carbon atom of the alkenol (or allenol) moiety to afford putative zwitterionic intermediate INT-1. Thereafter, key bicyclic intermediate INT-2 was formed by cyclization with the amide nitrogen, which after proton release and further protonation forms species INT-3. Oxonium intermediate INT-3 suffers a dehydration to generate 2H-indol-1-ium INT-4. Finally, INT-4 can react in an intramolecular fashion through an ionic carbocyclization to deliver the required gem-bis(triflyl)indolines 3 and 7. The 2-fluoropyridine liberated in the medium should facilitate the protonation and deprotonation steps. This reaction pathway was supported by DFT simulation of the reaction of allenol 2a with Tf2C=CH2 at the PCM(DCE)-M06-2X/6-31+G(d) level of theory (for details, see the Supporting Information).19 For the first C–C bond-forming step, 23.1 kcal mol–1 of the activation barrier was obtained and carbocation INT-1 was found as the reaction intermediate. The very low barrier (1.5 kcal mol–1) of the following C–N bond-forming step implies that this process rapidly proceeds to give INT-2. Although the cis-fused tricyclic indolines were selectively obtained in the experiment, this stereochemical outcome can be attributed to the kinetically favorable approach of the anionic carbon atom to the C1 atom from the less hindered cis site in the last step (INT-4 → 3a).

Scheme 4. Tentative Pathway for the Formation of gem-Bis(triflyl)indolines 3 and 7.

Scheme 4

Open in a new tab

In summary, tricyclic gem-bis(triflyl)indolines have been selectively formed by reaction of easily preparable anilide-derived substrates with Tf2C=CH2 without catalysts or light irradiation. The cascade reaction presented here for the formation of one C–N bond and two C–C bonds is facilitated by initial intermolecular electrophilic attack of Tf2C=CH2 on the double bond,20 which is followed by intramolecular capture (azacyclization) of the carbocation intermediate and subsequent carbocyclization of the resulting carbanion. This method provides interesting tricyclic indolines bearing the triflyl group, which can endow the nonfluorinated derivatives with interesting properties. The chameleonic reactivity of the triflyl group allowed us to derivatize the indolines toward less accessible fluorinated polycyclic heterocycles, including the tetracycle core found in the alkaloid polyveoline.

Acknowledgments

This work was supported in part by AEI (MICIU), FEDER (Project PGC2018-095025-B-I00), and KAKENHI (20K06947). C.L.-M. thanks MICIU and UCM for a postdoctoral contract.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c00557.

  • Experimental procedures, characterization data of new compounds, copies of NMR spectra, crystallographic data, and computational details (PDF)

Accession Codes

CCDC 2056816–2056819 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.

Supplementary Material

ol1c00557_si_001.pdf (9.1MB, pdf)

References

  1. a Ishikura M.; Abe T.; Choshi T.; Hibino S. Simple Indole Alkaloids and Those with a Non-Rearranged Monoterpenoid Unit. Nat. Prod. Rep. 2013, 30, 694–752. 10.1039/c3np20118j. [DOI] [PubMed] [Google Scholar]; b Vivekanand T.; Satpathi B.; Bankar S. K.; Ramasastry S. V. Recent Metal-Catalysed Approaches for the Synthesis of Cyclopenta[b]indoles. RSC Adv. 2018, 8, 18576–18588. 10.1039/C8RA03480J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. a Crich D.; Banerjee A. Chemistry of the Hexahydropyrrolo[2,3-b]indoles: Configuration, Conformation, Reactivity, and Applications in Synthesis. Acc. Chem. Res. 2007, 40, 151–161. 10.1021/ar050175j. [DOI] [PubMed] [Google Scholar]; b Sun Y.; Li R.; Zhang W.; Li A. Total Synthesis of Indotertine A and Drimentines A, F, and G. Angew. Chem., Int. Ed. 2013, 52, 9201–9204. 10.1002/anie.201303334. [DOI] [PubMed] [Google Scholar]
  3. a Zhang D.; Song H.; Qin Y. R. Total Synthesis of Indoline Alkaloids: A Cyclopropanation Strategy. Acc. Chem. Res. 2011, 44, 447–457. 10.1021/ar200004w. [DOI] [PubMed] [Google Scholar]; b Zi W.; Zuo Z.; Ma D. Intramolecular Dearomative Oxidative Coupling of Indoles: A Unified Strategy for the Total Synthesis of Indoline Alkaloids. Acc. Chem. Res. 2015, 48, 702–711. 10.1021/ar5004303. [DOI] [PubMed] [Google Scholar]; c Zheng C.; You S.-L. Catalytic Asymmetric Dearomatization (CADA) Reaction-Enabled Total Synthesis of Indole-Based Natural Products. Nat. Prod. Rep. 2019, 36, 1589–1605. 10.1039/C8NP00098K. [DOI] [PubMed] [Google Scholar]; d Song C.; Liu K.; Jiang X.; Dong X.; Weng Y.; Chiang C.-W.; Lei A. Electrooxidation Enables Selective Dehydrogenative [4 + 2] Annulation between Indole Derivatives. Angew. Chem., Int. Ed. 2020, 59, 7193–7197. 10.1002/anie.202000226. [DOI] [PubMed] [Google Scholar]; e Sheng F.-T.; Wang J.-Y.; Tan W.; Zhang Y.-C.; Shi F. Progresses in Organocatalytic Asymmetric Dearomatization Reactions of Indole Derivatives. Org. Chem. Front. 2020, 7, 3967–3998. 10.1039/D0QO01124J. [DOI] [Google Scholar]; f Tang S.; Vincent G. Natural Products Originated from the Oxidative Coupling of Tyrosine and Tryptophan: Biosynthesis and Bioinspired Synthesis. Chem. - Eur. J. 2021, 27, 2612–2622. 10.1002/chem.202003459. [DOI] [PubMed] [Google Scholar]
  4. a Lozano O.; Blessley G.; Martínez del Campo T.; Thompson A. L.; Giuffredi G. T.; Bettati M.; Walker M.; Borman R.; Gouverneur V. Organocatalyzed Enantioselective Fluorocyclizations. Angew. Chem., Int. Ed. 2011, 50, 8105–8109. 10.1002/anie.201103151. [DOI] [PubMed] [Google Scholar]; b Zhu S.; MacMillan D. W. C. Enantioselective Copper-Catalyzed Construction of Aryl Pyrroloindolines via an Arylation–Cyclization Cascade. J. Am. Chem. Soc. 2012, 134, 10815–10818. 10.1021/ja305100g. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Zhang Z.; Antilla J. C. Enantioselective Construction of Pyrroloindolines Catalyzed by Chiral Phosphoric Acids: Total Synthesis of (−)-Debromoflustramine B. Angew. Chem., Int. Ed. 2012, 51, 11778–11782. 10.1002/anie.201203553. [DOI] [PubMed] [Google Scholar]; d Han L.; Liu C.; Zhang W.; Shi X.-X.; You S.-L. Dearomatization of Tryptophols via a Vanadium-Catalyzed Asymmetric Epoxidation and Ring-Opening Cascade. Chem. Commun. 2014, 50, 1231–1233. 10.1039/C3CC47921H. [DOI] [PubMed] [Google Scholar]; e Nelson H. M.; Reisberg S. H.; Shunatona H. P.; Patel J. S.; Toste F. D. Chiral Anion Phase Transfer of Aryldiazonium Cations: An Enantioselective Synthesis of C3-Diazenated Pyrroloindolines. Angew. Chem., Int. Ed. 2014, 53, 5600–5603. 10.1002/anie.201310905. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Liu C.; Yi J.-C.; Liang X.-W.; Xu R.-Q.; Dai L.-X.; You S.-L. Copper(I)-Catalyzed Asymmetric Dearomatization of Indole Acetamides with 3-Indolylphenyliodonium Salts. Chem. - Eur. J. 2016, 22, 10813–10816. 10.1002/chem.201602229. [DOI] [PubMed] [Google Scholar]; g Li X.; Golz C.; Alcarazo M. 5-(Cyano)dibenzothiophenium Triflate: A Sulfur-Based Reagent for Electrophilic Cyanation and Cyanocyclizations. Angew. Chem., Int. Ed. 2019, 58, 9496–9500. 10.1002/anie.201904557. [DOI] [PMC free article] [PubMed] [Google Scholar]; h Biswas S.; Kim H.; Le Anh Cao K.; Shin S. Enantioselective Dearomative Cyclization of Homotryptamines with Allenamides into Indolo[2,3-b]quinolines. Adv. Synth. Catal. 2020, 362, 1841–1845. 10.1002/adsc.202000083. [DOI] [Google Scholar]; i Clarke A. K.; Rossi-Ashton J. A.; Taylor R. J. K.; Unsworth W. P. Synthesis of Polycyclic Scaffolds via a Gold-Catalysed Dearomative Cyclisation Cascade. Tetrahedron 2020, 76, 131392. 10.1016/j.tet.2020.131392. [DOI] [Google Scholar]; j Egami H.; Hotta R.; Otsubo M.; Rouno T.; Niwa T.; Yamashita K.; Hamashima Y. Asymmetric Dearomatizing Fluoroamidation of Indole Derivatives with Dianionic Phase-Transfer Catalyst. Org. Lett. 2020, 22, 5656–5660. 10.1021/acs.orglett.0c02026. [DOI] [PubMed] [Google Scholar]
  5. a Spangler J. E.; Davies H. M. J. Am. Chem. Soc. 2013, 135, 6802–278. 10.1021/ja4025337. [DOI] [PubMed] [Google Scholar]; b Jia M.; Monari M.; Yang Q.-Q.; Bandini M. Enantioselective Gold Catalyzed Dearomative [2 + 2]-Cycloaddition between Indoles and Allenamides. Chem. Commun. 2015, 51, 2320–2323. 10.1039/C4CC08736D. [DOI] [PubMed] [Google Scholar]; c Wang Y.; Zhang P.; Liu Y.; Xia F.; Zhang J. Enantioselective Gold-Catalyzed Intermolecular [2 + 2] versus [4 + 2]-Cycloadditions of 3-Styrylindoles with N-Allenamides: Observation of Interesting Substituent Effects. Chem. Sci. 2015, 6, 5564–5570. 10.1039/C5SC01827G. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Lachkar D.; Denizot N.; Bernadat G.; Ahamada K.; Beniddir M. A.; Dumontet V.; Gallard J.-F.; Guillot R.; Leblanc K.; N’nang E. O.; Turpin V.; Kouklovsky C.; Poupon E.; Evanno L.; Vincent G. Unified Biomimetic Assembly of Voacalgine A and Bipleiophylline via Divergent Oxidative Couplings. Nat. Chem. 2017, 9, 793–798. 10.1038/nchem.2735. [DOI] [PubMed] [Google Scholar]; e Qi L.-W.; Mao J.-H.; Zhang J.; Tan B. Organocatalytic Asymmetric Arylation of Indoles Enabled by Azo Groups. Nat. Chem. 2018, 10, 58–64. 10.1038/nchem.2866. [DOI] [PubMed] [Google Scholar]; f Zhao S.; Cheng S.; Liu H.; Zhang J.; Liu M.; Yuan W.; Zhang X. Synthesis of Chiral [2,3]-Fused Indolines through Enantioselective Dearomatization Inverse-Electron-Demand Diels–Alder Reaction/Oxidation of Indoles with 2-(2-Nitrovinyl)-1,4-benzoquinone. Chem. Commun. 2020, 56, 4200–4203. 10.1039/D0CC00693A. [DOI] [PubMed] [Google Scholar]; g Ma J.; Schäfers F.; Daniliuc C.; Bergander K.; Strassert C. A.; Glorius F. Gadolinium Photocatalysis: Dearomative [2 + 2] Cycloaddition/Ring-Expansion Sequence with Indoles. Angew. Chem., Int. Ed. 2020, 59, 9639–9645. 10.1002/anie.202001200. [DOI] [PubMed] [Google Scholar]; h Oderinde M. S.; Mao E.; Ramirez A.; Pawluczyk J.; Jorge C.; Cornelius L. A.; Kempson M. J.; Vetrichelvan M.; Pitchai M.; Gupta A.; Gupta A. K.; Meanwell N. A.; Mathur A.; Dhar T. G. M. Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity. J. Am. Chem. Soc. 2020, 142, 3094–3103. 10.1021/jacs.9b12129. [DOI] [PubMed] [Google Scholar]; i Jia X.; Lei H.; Han F.; Zhang T.; Chen Y.; Xu Z.; Nakliang P.; Choi S.; Guo Y.; Ye T. Asymmetric Total Syntheses of Kopsane Alkaloids via a PtCl2-Catalyzed Intramolecular [3 + 2] Cycloaddition. Angew. Chem., Int. Ed. 2020, 59, 12832–12836. 10.1002/anie.202005048. [DOI] [PubMed] [Google Scholar]; j Magné V.; Sanogo Y.; Demmer C. S.; Retailleau P.; Marinetti A.; Guinchard X.; Voituriez A. Chiral Phosphathiahelicenes: Improved Synthetic Approach and Uses in Enantioselective Gold(I)-Catalyzed [2 + 2] Cycloadditions of N-Homoallenyl Tryptamines. ACS Catal. 2020, 10, 8141–8148. 10.1021/acscatal.0c01819. [DOI] [Google Scholar]; k Mei M.-S.; Wang Y.-H.; Hu Q.; Li Q.-H.; Shi D.-Y.; Gao D.; Ge G.; Lin G.-Q.; Tian P. Enantioselective [3 + 2] Annulation of Isatin-Derived MBH-Carbonates and 3-Nitroindoles Enabled by a Bifunctional DMAP-Thiourea. Chem. Commun. 2020, 56, 10718–10721. 10.1039/D0CC04462H. [DOI] [PubMed] [Google Scholar]
  6. a Tokimizu Y.; Oishi S.; Fujii N.; Ohno H. Gold-Catalyzed Cascade Cyclization of 2-Alkynyl-N-Propargylanilines by Rearrangement of a Propargyl Group. Angew. Chem., Int. Ed. 2015, 54, 7862–7866. 10.1002/anie.201502256. [DOI] [PubMed] [Google Scholar]; The Catellani reaction has been used for the preparation of norbornane-fused derivatives:; b Thansandote P.; Hulcoop D. G.; Langer M.; Lautens M. Palladium-Catalyzed Annulation of Haloanilines and Halobenzamides Using Norbornadiene as an Acetylene Synthon: A Route to Functionalized Indolines, Isoquinolinones, and Indoles. J. Org. Chem. 2009, 74, 1673–1678. 10.1021/jo802604g. [DOI] [PubMed] [Google Scholar]; c Tao M.; Li W.; Zhang J. Pd/Xiang-Phos-Catalyzed Enantioselective Intermolecular Carboheterofunctionalization of Norbornene and Norbornadiene. Chem. Commun. 2020, 56, 13125–13128. 10.1039/D0CC04996D. [DOI] [PubMed] [Google Scholar]; The (3+2) cycloaddition of cyclic enamides with quinone diimides, derived from protected benzene-1,4-diamines, using phosphoric acid catalysis has been reported:; d Ma W.-Y.; Gelis C.; Bouchet D.; Retailleau P.; Moreau X.; Neuville L.; Masson G. Chiral Phosphoric Acid-Catalyzed Enantioselective Construction of 2,3-Disubstituted Indolines. Org. Lett. 2021, 23, 442–448. 10.1021/acs.orglett.0c03947. [DOI] [PubMed] [Google Scholar]
  7. a Tietze L. F. Domino Reactions in Organic Synthesis. Chem. Rev. 1996, 96, 115–136. 10.1021/cr950027e. [DOI] [PubMed] [Google Scholar]; b Nicolaou K. C.; Edmonds D. J.; Bulger P. G. Cascade Reactions in Total Synthesis. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. 10.1002/anie.200601872. [DOI] [PubMed] [Google Scholar]; c Bhar S. S.; Ramana M. M. V.. Novel Domino Reactions for Synthesis of Bioactive Diterpenoids and Alkaloids. In Bioactive Natural Products; Rahman A.-u., Ed.; Elsevier: Amsterdam, 2008; Vol. 35, pp 399–422. [Google Scholar]; d Nicolaou K. C.; Chen J. S. The Art of Total Synthesis through Cascade Reactions. Chem. Soc. Rev. 2009, 38, 2993–3009. 10.1039/b903290h. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Grondal C.; Jeanty M.; Enders D. Organocatalytic Cascade Reactions as a New Tool in Total Synthesis. Nat. Chem. 2010, 2, 167–178. 10.1038/nchem.539. [DOI] [PubMed] [Google Scholar]; f Ruiz M.; López-Alvarado P.; Giorgi G.; Menéndez J. C. Domino Reactions for the Synthesis of Bridged Bicyclic Frameworks: Fast Access to Bicyclo[n.3.1]alkanes. Chem. Soc. Rev. 2011, 40, 3445–3454. 10.1039/c1cs15018a. [DOI] [PubMed] [Google Scholar]; g Pellissier H. Stereocontrolled Domino Reactions. Chem. Rev. 2013, 113, 442–524. 10.1021/cr300271k. [DOI] [PubMed] [Google Scholar]; h Tietze L. F., Ed. Domino Reactions; Wiley-VCH: Weinheim, Germany, 2013. [Google Scholar]
  8. a Yanai H.; Yoshino T.; Fujita M.; Fukaya H.; Kotani A.; Kusu F.; Taguchi T. Synthesis, Characterization, and Applications of Zwitterions Containing a Carbanion Moiety. Angew. Chem., Int. Ed. 2013, 52, 1560–1563. 10.1002/anie.201208809. [DOI] [PubMed] [Google Scholar]; b Yanai H.; Almendros P.; Takahashi S.; Lázaro-Milla C.; Alcaide B.; Matsumoto T. Synthesis and Characterization of Stable Phosphorus Carbabetaines. Chem. - Asian J. 2018, 13, 1956–1961. 10.1002/asia.201800769. [DOI] [PubMed] [Google Scholar]; c Yanai H.; Suzuki T.; Kleemiss F.; Fukaya H.; Dobashi Y.; Malaspina L. A.; Grabowsky S.; Matsumoto T. Chemical Bonding in Polarised Push–Pull Ethylenes. Angew. Chem., Int. Ed. 2019, 58, 8839–8844. 10.1002/anie.201904176. [DOI] [PubMed] [Google Scholar]
  9. Alcaide B.; Almendros P.; Fernández I.; Lázaro-Milla C. Unveiling the uncatalyzed reaction of alkynes with 1,2-dipoles for the room temperature synthesis of cyclobutenes. Chem. Commun. 2015, 51, 3395–3398. 10.1039/C4CC10111A. [DOI] [PubMed] [Google Scholar]
  10. a Gillis E. P.; Eastman K. J.; Hill M. D.; Donnelly D. J.; Meanwell N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315–8359. 10.1021/acs.jmedchem.5b00258. [DOI] [PubMed] [Google Scholar]; b Orsi D. L.; Altman R. A. Exploiting the Unusual Effects of Fluorine in Methodology. Chem. Commun. 2017, 53, 7168–7181. 10.1039/C7CC02341C. [DOI] [PubMed] [Google Scholar]; c Ragni R.; Punzi A.; Babudri F.; Farinola G. M. Organic and Organometallic Fluorinated Materials for Electronics and Optoelectronics: A Survey on Recent Research. Eur. J. Org. Chem. 2018, 2018, 3500–3519. 10.1002/ejoc.201800657. [DOI] [Google Scholar]; d Mei H.; Han J.; Fustero S.; Medio-Simon M.; Sedgwick D. M.; Santi C.; Ruzziconi R.; Soloshonok V. A. Fluorine-Containing Drugs Approved by the FDA in 2018. Chem. - Eur. J. 2019, 25, 11797–19039. 10.1002/chem.201901840. [DOI] [PubMed] [Google Scholar]; e Cheng M.; Guo C.; Gross M. L. The Application of Fluorine-Containing Reagents in Structural Proteomics. Angew. Chem., Int. Ed. 2020, 59, 5880–5889. 10.1002/anie.201907662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. a Xu X.-H.; Matsuzaki K.; Shibata N. Synthetic Methods for Compounds Having CF3–S Units on Carbon by Trifluoromethylation, Trifluoromethylthiolation, Triflylation, and Related Reactions. Chem. Rev. 2015, 115, 731–764. 10.1021/cr500193b. [DOI] [PubMed] [Google Scholar]; b Ni J.; Jiang Y.; An Z.; Lan J.; Yan R. A Convenient Access to Allylic Triflones with Allenes and Triflyl Chloride in the Presence of (EtO)2P(O)H. Chem. Commun. 2019, 55, 7343–7345. and references therein 10.1039/C9CC03096D. [DOI] [PubMed] [Google Scholar]; c Krishnamurti V.; Barrett C.; Prakash G. K. S.. Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF) In Emerging Fluorinated Motifs. Synthesis, Properties, and Applications; Cahard D., Ma J.-A., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2020; Vol. II, pp 477–550. [Google Scholar]; d Marć M. A.; Kincses A.; Rácz B.; Nasim M. J.; Sarfraz M.; Lázaro-Milla C.; Domínguez-Álvarez E.; Jacob C.; Spengler G.; Almendros P. Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenium-Substituted Flavonoids. Pharmaceuticals 2020, 13, 453. 10.3390/ph13120453. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Yanai H.; Hoshikawa S.; Moriiwa Y.; Shoji A.; Yanagida A.; Matsumoto T. A Fluorinated Carbanionic Substituent for Improving Water Solubility and Lipophilicity of Fluorescent Dyes. Angew. Chem., Int. Ed. 2021, 60, 5168. 10.1002/anie.202012764. [DOI] [PubMed] [Google Scholar]
  12. a Yanai H.; Takahashi Y.; Fukaya H.; Dobashi Y.; Matsumoto T. 2-(Pyridinium-1-yl)-1,1-bis(triflyl)ethanides: Structural Behaviour and Availability as Bis(triflyl)ethylating reagents. Chem. Commun. 2013, 49, 10091–10093. 10.1039/c3cc46171h. [DOI] [PubMed] [Google Scholar]; b Yanai H.; Takahashi R.; Takahashi Y.; Kotani A.; Hakamata H.; Matsumoto T. 2-(Pyridinium-1-yl)-1,1-bis(perfluoroalkylsulfonyl)ethan-1-ide: A Practical Reagent for Synthesis of Strongly Acidic 1,1- Bis(perfluoroalkylsulfonyl)alkanes. Chem. - Eur. J. 2017, 23, 8203–8211. 10.1002/chem.201700515. [DOI] [PubMed] [Google Scholar]
  13. Lázaro-Milla C.; Macicior J.; Yanai H.; Almendros P. Trifluorosulfonylation Cascade in Allenols: Stereocontrolled Synthesis of Bis(triflyl)enones. Chem. - Eur. J. 2020, 26, 8983–8989. 10.1002/chem.202001236. [DOI] [PubMed] [Google Scholar]
  14. Deposition numbers 2056816 (3a), 2056817 (3e), 2056818 (7d), and 2056819 (7g) contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk/structures).
  15. Taking into account the fascinating methyl effects in drug discovery, we should note that compound 3a bears a methyl substituent at C3a of the tricyclic indoline core. For the “magic methyl effect” in medicinal chemistry, see:; a Schönherr H.; Cernak T. Profound Methyl Effects in Drug Discovery and a Call for New C–H Methylation Reactions. Angew. Chem., Int. Ed. 2013, 52, 12256–12267. 10.1002/anie.201303207. [DOI] [PubMed] [Google Scholar]; b Chatterjee J.; Rechenmacher F.; Kessler H. N-Methylation of Peptides and Proteins: An Important Element for Modulating Biological Functions. Angew. Chem., Int. Ed. 2013, 52, 254–269. 10.1002/anie.201205674. [DOI] [PubMed] [Google Scholar]; c Barreiro E. J.; Kümmerle A. E.; Fraga C. A. M. The Methylation Effect in Medicinal Chemistry. Chem. Rev. 2011, 111, 5215–5246. 10.1021/cr200060g. [DOI] [PubMed] [Google Scholar]
  16. The hexahydrocyclopenta[b]indole core of 3a is the key motif of several dyes. For selected examples, see:; a Matsui M.; Tsuzuki Y.; Kubota Y.; Funabiki K.; Inuzuka T.; Manseki K.; Higashijima S.; Miura H.; Sato H.; Yoshida T. Novel Indoline Dye Tetrabutylammonium Carboxylates Attached with a Methyl Group on the Cyclopentane Ring for Dye-Sensitized Solar Cells. Tetrahedron 2018, 74, 5867–5878. 10.1016/j.tet.2018.08.006. [DOI] [Google Scholar]; b Wang L.; Liang M.; Zhang Y.; Cheng F.; Wang X.; Sun Z.; Xue S. Influence of Donor and Bridge Structure in D–A−π–A Indoline Dyes on the Photovoltaic Properties of Dye-Sensitized Solar Cells Employing Iodine/Cobalt Electrolyte. Dyes Pigm. 2014, 101, 270–279. 10.1016/j.dyepig.2013.10.016. [DOI] [Google Scholar]; c Ohta N.; Awasthi K.; Okoshi K.; Manseki K.; Miura H.; Inoue Y.; Nakamura K.; Kono H.; Diau E. W.-G. Stark Spectroscopy of Absorption and Emission of Indoline Sensitizers: A Correlation with the Performance of Photovoltaic Cells. J. Phys. Chem. C 2016, 120, 26206–26216. 10.1021/acs.jpcc.6b08531. [DOI] [Google Scholar]; d Huang Z.-S.; Zang X.-F.; Hua T.; Wang L.; Meier H.; Cao D. 2,3-Dipentyldithieno[3,2-f:2′,3′-h]quinoxaline-Based Organic Dyes for Efficient Dye-Sensitized Solar Cells: Effect of π-Bridges and Electron Donors on Solar Cell Performance. ACS Appl. Mater. Interfaces 2015, 7, 20418–20429. 10.1021/acsami.5b06404. [DOI] [PubMed] [Google Scholar]; e Brogdon P.; Giordano F.; Puneky G. A.; Dass A.; Zakeeruddin S. M.; Nazeeruddin M. K.; Grätzel M.; Tschumper G. S.; Delcamp J. H. A Computational and Experimental Study of Thieno[3,4-b]thiophene as a Proaromatic π-Bridge in Dye-Sensitized Solar Cells. Chem. - Eur. J. 2016, 22, 694–703. 10.1002/chem.201503187. [DOI] [PubMed] [Google Scholar]
  17. This hypothesis was corroborated both when just a set of signals was observed in the NMR spectra of tricycle 12 after amide bond cleavage in adduct 3d (Scheme 3) and via NOE experiments (see the Supporting Information).
  18. Although merely speculation at this time, we may postulate that the reduction of 3a and 7a with LiAlH4 is facilitated by the highly polar nature of the HC–CTf2 bond and should involve the hydride addition toward the slightly positive CH moiety with concomitant bond breakage.
  19. In a DFT simulation for dehydration of 2a at the PCM(DCE)-M06-2X/6-31+G(d) level of theory, a very high barrier (>40 kcal mol–1) for o-quinone imine formation was found (see the Supporting Information).
  20. Taking into account the pathway proposed in Scheme 4 and Figure S1, we found carbocation INT-1 as the reaction intermediate for the first C–C bond-forming step. One can argue that internal substitution with Me or Ph in allenols and allyl alcohols is important for the stability of intermediate INT-1 after the entry of CH2=CTf2.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol1c00557_si_001.pdf (9.1MB, pdf)

Articles from Organic Letters are provided here courtesy of American Chemical Society

RESOURCES