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

Carlos L á zaro-Milla, Hikaru Yanai, and Pedro Almendros*

Letter

Metal-Free C−C/C−N/C−C Bond Formation Cascade for the

Synthesis of (Tri ﬂ uoromethyl)sulfonylated Cyclopenta[b]indolines

Cite This: Org. Lett. 2021, 23, 2921 −2926

Read Online

ACCESS

Metrics & More

Article Recommendations

sı Supporting Information

ABSTRACT: 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.

yclopenta[b]indole/indoline is a privileged scaﬀold

present in various biologically active compounds. This

structural motif is widely found in the molecular structures of

indolines from easily available aniline-derived substrate A with

Tf CCH (Tf = SO CF ), 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

natural indole alkaloids such as ﬁscherindole L, yuehchukene,

and polyveoline (Figure 1 ). Azacyclopenta[b ]indolines,

associated with the reduction of reagents, solvents, and waste.

Additionally, the reaction system presented here, including the

sequential C−C/C−N/C−C bond-forming process, is cer-

tainly 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 [Tf CR]

−

moiety. The [Tf CR] species is known to be a chemically

inert carbanion owing to two triﬂyl groups on the anionic

carbon atom, and C−C bond formation from this species is

limited in speciﬁc cases mediated by highly reactive vinyl-type

carbocation intermediates. Herein, we describe our method-

Figure 1. Bioactive and natural products having the polycyclic

indoline core moiety.

ology, 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

exempliﬁed by physostigmine, also make up an important

family of bioactive alkaloids. Synthetic eﬀorts involving these

polycyclic systems focus on the development of the

dearomatization of indoles either by the electrophilic

activation of indole substrates bearing nucleophilic sites

Received: February 16, 2021

Published: April 1, 2021

(

Scheme 1a) or by dearomative cycloadditions (Scheme

b). The de novo synthesis of polycyclic indolines, chemical

transformations of sophisticated aniline-derived substrates,

despite being interesting, required expensive transition metal

catalysts. Consequently, we were interested in the develop-

ment of a novel cascade reaction to produce the polycyclic

2021 American Chemical Society

921

Org. Lett. 2021, 23, 2921−2926

Organic Letters

Introducing substituents on the allene moiety by replacing the

Letter

Scheme 1. Background and Current Design for

Cyclopenta[b]indolines

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

15,16

obtained as a single cis isomer in a reasonable 62% yield.

We concluded that a carbonyl moiety on the nitrogen was

necessary as benzyl- or sulfonyl-protected allenyl anilines 2

decomposed upon reaction with 1.

The scope of this transformation is summarized in Figure 2.

into the highly functionalized indolines with ﬂuorinated

10,11

substituents, which may yield interesting properties.

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 Tf CCH (Scheme 2). We recently reported that

Scheme 2. Reaction of Carbamate-Derived Substrate 2a

Figure 2. Synthesis of bis(triﬂyl)-containing tricyclic indolines 3a−3o

and [D]-3a. The thermal ellipsoids are shown at 50% probability.

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−

8% yields. The NMR spectra of tricycles 3d and 3o showed

signals of a minor isomer (8% and 12%, respectively, as

estimated by H NMR). As only cis-fused 5,5-systems are

typically observed in any reaction outcome, the trans isomer

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 Tf CCH

should be ruled out and these signals should be ascribed to the

corresponding rotamers. 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

on the terminal carbon atom of the allene moiety.

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

proved through X-ray crystallographic analysis.

Motivated by the results presented above, we decided to

expand the substrate scope by exploring other precursors in

crystallographic analysis. After carefully exploring several

922

Org. Lett. 2021, 23, 2921−2926

Organic Letters

obtained in 64% yield (Figure 3 ). The position and electronic

Letter

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

Scheme 3. Synthetic Transformations of gem-

Bis(triﬂyl)indolines 3 and 7

Figure 3. Synthesis of bis(triﬂyl)-containing tricyclic indolines 7a−7g.

The thermal ellipsoids are shown at 50% probability.

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

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.

unambiguously by single-crystal X-ray diﬀraction analysis.

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

The mechanistic hypothesis for the formation of 3 and 7 is

depicted in Scheme 4. First, electrophilic attack of Tf CCH

(

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

enabled the formation of bis(triﬂyl)ethyl-decorated bicyclic

indolines 10, 11, 13, and 19 under reductive conditions

(

Scheme 3b,c,f). 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

Scheme 4. Tentative Pathway for the Formation of gem-

Bis(triﬂyl)indolines 3 and 7

(

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 stereo-

selectively (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 CF SO H

can be smoothly accomplished in 7a to give alkenyl triﬂone 18

923

Org. Lett. 2021, 23, 2921−2926

Organic Letters

orcid.org/0000-0003-3698-1405

Letter

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

Asociada al CSIC, Facultad de Química, Universidad

Complutense de Madrid, 28040 Madrid, Spain;

Hikaru Yanai − School of Pharmacy, Tokyo University of

Pharmacy and Life Sciences, Tokyo 192-0392, Japan;

orcid.org/0000-0003-4638-5113

H-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 Tf CCH at the PCM(DCE)-M06-2X/6-31+G(d)

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c00557

Notes

level of theory (for details, see the Supporting Information).

−

The authors declare no competing ﬁnancial interest.

For the ﬁrst C−C bond-forming step, 23.1 kcal mol of the

activation barrier was obtained and carbocation INT-1 was

found as the reaction intermediate. The very low barrier (1.5

ACKNOWLEDGMENTS

■

−

kcal mol ) 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

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.

REFERENCES

■

(

INT-4 → 3a).

1) (a) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Simple Indole

In summary, tricyclic gem-bis(triﬂyl)indolines have been

Alkaloids and Those with a Non-Rearranged Monoterpenoid Unit.

Nat. Prod. Rep. 2013, 30, 694−752. (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.

(2) (a) Crich, D.; Banerjee, A. Chemistry of the Hexahydropyrrolo-

2,3-b]indoles: Configuration, Conformation, Reactivity, and Appli-

selectively formed by reaction of easily preparable anilide-

derived substrates with Tf CCH 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 Tf CCH on

[

the double bond, which is followed by intramolecular capture

cations in Synthesis. Acc. Chem. Res. 2007 , 40 , 151 −161. (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−

(

azacyclization) of the carbocation intermediate and subse-

quent 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.

3) (a) Zhang, D.; Song, H.; Qin, Y. R. Total Synthesis of Indoline

204.

Alkaloids: A Cyclopropanation Strategy. Acc. Chem. Res. 2011 , 44 ,

47 −457. (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.

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. (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.

e) Sheng, F.-T.; Wang, J.-Y.; Tan, W.; Zhang, Y.-C.; Shi, F.

Progresses in Organocatalytic Asymmetric Dearomatization Reactions

The Supporting Information is available free of charge at

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.1c00557.

of Indole Derivatives. Org. Chem. Front. 2020 , 7 , 3967 −3998.

Experimental procedures, characterization data of new

compounds, copies of NMR spectra, crystallographic

data, and computational details (PDF)

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.

Accession Codes

CCDC 2056816 −2056819 contain the supplementary crys-

tallographic 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.

(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.

(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. (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,

AUTHOR INFORMATION

Corresponding Author

■

1778 −11782. (d) Han, L.; Liu, C.; Zhang, W.; Shi, X.-X.; You, S.-

Pedro Almendros − Instituto de Química Orgánica General,

IQOG, CSIC, 28006 Madrid, Spain; orcid.org/0000-

L. Dearomatization of Tryptophols via a Vanadium-Catalyzed

Asymmetric Epoxidation and Ring-Opening Cascade. Chem. Commun.

001-6564-2758 ; Email: palmendros@iqog.csic.es

Authors

Carlos Lázaro-Milla − Grupo de Lactamas y Heterociclos

014, 50, 1231−1233. (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. (f) Liu, C.; Yi, J.-C.; Liang, X.-W.; Xu, R.-Q.; Dai, L.-

Bioactivos, Departamento de Química Orgánica, Unidad

924

Org. Lett. 2021, 23, 2921−2926

Organic Letters

X.; You, S.-L. Copper(I)-Catalyzed Asymmetric Dearomatization of

Letter

Indole Acetamides with 3-Indolylphenyliodonium Salts. Chem. - Eur.

J. 2016 , 22 , 10813 −10816. (g) Li, X.; Golz, C.; Alcarazo, M. 5-

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 Indo-

lines. Org. Lett. 2021, 23 , 442 −448.

(Cyano)dibenzothiophenium Triflate: A Sulfur-Based Reagent for

Electrophilic Cyanation and Cyanocyclizations. Angew. Chem., Int. Ed.

019 , 58 , 9496 −9500. (h) Biswas, S.; Kim, H.; Le Anh Cao, K.; Shin,

S. Enantioselective Dearomative Cyclization of Homotryptamines

(7) (a) Tietze, L. F. Domino Reactions in Organic Synthesis. Chem.

Rev. 1996 , 96 , 115 −136. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger,

P. G. Cascade Reactions in Total Synthesis. Angew. Chem., Int. Ed.

2006, 45, 7134−7186. (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. (d) Nicolaou, K. C.; Chen, J.

S. The Art of Total Synthesis through Cascade Reactions. Chem. Soc.

Rev. 2009 , 38 , 2993 −3009. (e) Grondal, C.; Jeanty, M.; Enders, D.

Organocatalytic Cascade Reactions as a New Tool in Total Synthesis.

Nat. Chem. 2010, 2, 167−178. (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. (g) Pellissier, H. Stereo-

controlled Domino Reactions. Chem. Rev. 2013, 113, 442−524.

(h) Tietze, L. F., Ed. Domino Reactions; Wiley-VCH: Weinheim,

Germany, 2013.

(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. (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. (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.

with Allenamides into Indolo[2,3-b]quinolines. Adv. Synth. Catal.

020, 362, 1841−1845. (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. (j) Egami, H.; Hotta, R.; Otsubo, M.; Rouno, T.; Niwa, T.;

Yamashita, K.; Hamashima, Y. Asymmetric Dearomatizing Fluoroa-

midation of Indole Derivatives with Dianionic Phase-Transfer

Catalyst. Org. Lett. 2020, 22, 5656−5660.

(5) (a) Spangler, J. E.; Davies, H. M. J. Am. Chem. Soc. 2013, 135,

802 −278. (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−

323. (c) Wang, Y.; Zhang, P.; Liu, Y.; Xia, F.; Zhang, J.

Enantioselective Gold-Catalyzed Intermolecular [2 + 2] versus [4 +

]-Cycloadditions of 3-Styrylindoles with N-Allenamides: Observa-

tion of Interesting Substituent Effects. Chem. Sci. 2015, 6, 5564−

570. (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,

, 793 −798. (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. (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-

(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.

A.; Glorius, F. Gadolinium Photocatalysis: Dearomative [2 + 2]

2-Nitrovinyl)-1,4-benzoquinone. Chem. Commun. 2020, 56, 4200−

203. (g) Ma, J.; Schäfers, F.; Daniliuc, C.; Bergander, K.; Strassert, C.

Cycloaddition/Ring-Expansion Sequence with Indoles. Angew. Chem.,

Int. Ed. 2020, 59, 9639−9645. (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) (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. (b) Orsi, D. L.; Altman, R. A.

Exploiting the Unusual Effects of Fluorine in Methodology. Chem.

Commun. 2017 , 53 , 7168 −7181. (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. (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. (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.

(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 PtCl -Catalyzed Intramolecular [3 + 2] Cycloaddition.

Angew. Chem., Int. Ed. 2020, 59, 12832−12836. (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,

(11) (a) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Synthetic Methods for

141−8148. (k) Mei, M.-S.; Wang, Y.-H.; Hu, Q.; Li, Q.-H.; Shi, D.-

Compounds Having CF −S Units on Carbon by Trifluoromethyla-

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,

tion, Trifluoromethylthiolation, Triflylation, and Related Reactions.

Chem. Rev. 2015 , 115 , 731 −764. (b) Ni, J.; Jiang, Y.; An, Z.; Lan, J.;

Yan, R. A Convenient Access to Allylic Triflones with Allenes and

6) (a) Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Gold-Catalyzed

6, 10718−10721.

Triflyl Chloride in the Presence of (EtO) P(O)H. Chem. Commun.

2019, 55, 7343−7345 and references therein. (c) Krishnamurti, V.;

Barrett, C.; Prakash, G. K. S. Synthesis and Applications of Fluorinated

Cascade Cyclization of 2-Alkynyl-N -Propargylanilines by Rearrange-

ment of a Propargyl Group. Angew. Chem., Int. Ed. 2015, 54, 7862−

Sulfoxides (RSORF) and Sulfones (RSO RF) In Emerging Fluorinated

7866. The Catellani reaction has been used for the preparation of

Motifs. Synthesis, Properties, and Applications; Cahard, D., Ma, J.-A.,

Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2020; Vol. II, pp

norbornane-fused derivatives: (b) Thansandote, P.; Hulcoop, D. G.;

Langer, M.; Lautens, M. Palladium-Catalyzed Annulation of Haloani-

lines and Halobenzamides Using Norbornadiene as an Acetylene

Synthon: A Route to Functionalized Indolines, Isoquinolinones, and

Indoles. J. Org. Chem. 2009 , 74 , 1673 −1678. (c) Tao, M.; Li, W.;

Zhang, J. Pd/Xiang-Phos-Catalyzed Enantioselective Intermolecular

Carboheterofunctionalization of Norbornene and Norbornadiene.

Chem. Commun. 2020, 56, 13125−13128. The (3+2) cycloaddition

477−550. (d) Marc, M. A.; Kincses, A.; Rácz, B.; Nasim, M. J.;

Sarfraz, M.; Lázaro-Milla, C.; Domínguez-Alvarez, 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. (e) Yanai, H.;

Hoshikawa, S.; Moriiwa, Y.; Shoji, A.; Yanagida, A.; Matsumoto, T. A

Fluorinated Carbanionic Substituent for Improving Water Solubility

925

Org. Lett. 2021, 23, 2921−2926

Organic Letters

Matsumoto, T. 2-(Pyridinium-1-yl)-1,1-bis(triflyl)ethanides: Struc-

Letter

and Lipophilicity of Fluorescent Dyes. Angew. Chem., Int. Ed. 2021,

0, 5168.

12) (a) Yanai, H.; Takahashi, Y.; Fukaya, H.; Dobashi, Y.;

tural Behaviour and Availability as Bis(triflyl)ethylating reagents.

Chem. Commun. 2013, 49, 10091−10093. (b) Yanai, H.; Takahashi,

R.; Takahashi, Y.; Kotani, A.; Hakamata, H.; Matsumoto, T. 2-

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 CH CTf .

(

Pyridinium-1-yl)-1,1-bis(perfluoroalkylsulfonyl)ethan-1-ide: A Prac-

tical Reagent for Synthesis of Strongly Acidic 1,1- Bis-

perfluoroalkylsulfonyl)alkanes. Chem. - Eur. J. 2017, 23, 8203−8211.

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.

(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 e ﬀ ect ” 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 −

2267. (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 ,

54 −269. (c) Barreiro, E. J.; Ku

Methylation Effect in Medicinal Chemistry. Chem. Rev. 2011, 111,

215−5246.

16) The hexahydrocyclopenta[b]indole core of 3a is the key motif

mmerle, A. E.; Fraga, C. A. M. The

(

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. (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. (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. (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−

0429. (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.

(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 LiAlH is facilitated by the highly

polar nature of the HC−CTf 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 ) 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

926