Gold-Catalyzed 1,2-Aminoarylation of Alkenes with External Amines

Akash G. Tathe, Urvashi, Amit K. Yadav, Chetan C. Chintawar, and Nitin T. Patil*

Letter

Gold-Catalyzed 1,2-Aminoarylation of Alkenes with External Amines

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sı Supporting Information

ABSTRACT: Reported herein is the gold-catalyzed 1,2-amino-

arylation of alkenes that engages external amine as a coupling

partner. Careful optimization studies revealed a signiﬁcant role of

the concentration of base to achieve highly chemoselective access to

the aminoarylation products over potential C−N cross-coupled

products. Overcoming all the limitations, the current strategy

provided straightforward access to the medicinally relevant 3-

aminochroman, 2-aminotetrahydronaphthalene, and 2-aminoindane

derivatives.

KEYWORDS: gold catalysis, π-activation, oxidative addition, aminoarylation, cross-coupling

he compounds containing 3-aminochroman, 2-

aminotetrahydronaphthalene, and 2-aminoindane moi-

Alkene difunctionalization, the addition of two functional

groups across a C−C double bond, typiﬁes a class of reactions

eties are biologically active and numerously found in many

with outstanding synthetic potential. Notably, gold complexes

drug molecules. For instance, alnespirone (+) S 20499 and

have emerged as a catalyst of choice for selective functionaliza-

robalzotan (NAD-299) which contain 3-aminochroman cores

tion of C−C multiple bonds because of their excellent π-Lewis

show very high aﬃnity and selectivity toward the 5-HT₁_A

serotonin receptor and are commonly used in the treatment of

anxiety and depression (Figure 1 ). Rotigotin (neupro)

acidity. However, owing to the innate reluctance of gold to

oscillate between Au(I)/Au(III) redox cycle, realizing the

alkene difunctionalization reactions under the gold catalysis

portfolio remained highly elusive. As a solution to tackle this

challenge, the use of strong external oxidants and photo-

catalysts came into the practice which subsequently triggered

the development of an array of gold-catalyzed difunctionaliza-

tion reactions by facilitating the Au(I)/Au(III) redox cycle.

However, the need for a superstoichiometric amount of

sacriﬁcial oxidants and highly reactive aryl diazonium salts

hindered the attractiveness of these strategies. Though few

other strategies appeared recently to facilitate the gold redox

catalysis, they mostly remain conﬁned to speciﬁc coupling

partners. Barring all these limitations, our laboratory has

recently developed a suite of redox-neutral interplay mode of

gold catalysis which integrate the cross-coupling reactivity and

π-activation ability of gold complexes to facilitate the selective

Figure 1. Biologically signiﬁcant compounds.

difunctionalization of C−C multiple bonds. The newly

developed strategy mainly relies on the ligand-enabled Au(I)/

Au(III) catalysis which utilizes the hemilabile P,N-bidentate

ligand (i.e., MeDalPhos) to achieve the key oxidative

consisting of a 2-aminotetrahydronaphthalene core is used in

addition of aryl halides on the cationic gold(I) species. We

the treatment of Parkinson’s disease and restless leg

demonstrated the synthetic potential of our strategy by

syndrome. Similarly, 2-aminoindane is also recognized as a

biologically important class of compound and often referred to

Received: February 19, 2021

Revised: March 23, 2021

Published: March 31, 2021

as a designer drug. For example, indantadol (CHF-3381) is

an anticonvulsant agent and used in the treatment of

neuropathic pain, and aprindine displays anesthetic and

antiarrhythmic properties. Thus, the design and synthesis of

these functionalized carbo(hetero)cycles is of prime impor-

tance in medicinal chemistry.

2021 American Chemical Society

576

ACS Catal. 2021, 11, 4576−4582

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Letter

presenting the ﬁrst example of 1,2-diarylation of alkenes under

the Au(III) species. As Au(III) complexes are highly prone to

22,13,16−18

gold catalysis by utilizing aryl alkenes and aryl iodides as

coordinate with C−C multiple bonds,

the cationic

reacting partners (Scheme 1a). In an ensuing work, the

Au(III) complex, instead of undergoing ligand-exchange with

aniline 2 that leads to direct C−N cross-coupled product F,

should selectively intercept with tethered alkene to generate

Au(III)−π complex D. Since, the gold complexes are reluctant

to follow migratory insertion and β-hydride elimination

Scheme 1. Gold-Catalyzed Difunctionalization of Alkenes:

Known and Present Work

pathways which leads to the Heck-type side-product G, the

so-formed intermediate D should trigger the nucleophilic

attack from aniline 2 onto the activated alkene. The

subsequent reductive elimination should selectively deliver

the desired 1,2-aminoarylation product 3. Herein, we unveil

the successful implementation of our hypothesis that provided

a straightforward access to biologically signiﬁcant 3-amino-

chroman, 2-aminotetrahydronaphthalene, and 2-aminoindane

derivatives.

Our initial investigation into this proposed aminoarylation

reaction began with the use of iodoaryl alkene 1a (1.1 equiv),

-aminoacetophenone 2a (1 equiv), MeDalPhosAuCl (5 mol

), AgSbF (1.105 equiv), and K PO (0.5 equiv) in DCE (0.1

M) at 80 °C (Table 1). To our delight, the desired product 3a

a b

Table 1. Optimization of Reaction Conditions

group of Bourissou reported the two-component 1,2-

heteroarylation of alkenes, in which alkenes with tethered

nucleophiles were used as reacting partners along with external

aryl halides (Scheme 1b). Soon after, our group and Shi’s

group reported the more challenging three-component 1,2-

oxyarylation of alkenes based on the same concept (Scheme

c).

As far as the gold-catalyzed 1,2-aminoarylation of alkenes is

concerned only intramolecular versions are known, and to

date there are no reports where external amines are used as

coupling partners. This could be mainly attributed to the fact

that amines, especially anilines, are highly prone to undergo

direct coupling with aryl iodides under Pd, Cu, or Ni

catalysis. Even, our group and soon after Bourissou’s group

reported that such C−N cross-coupling reactions are feasible

under gold catalysis utilizing MeDalPhosAuCl as a catalyst.

Deviation from standard conditions: (i) none, (ii) 1.105 equiv of

, (iii) 1.105 equiv of AgNTf was

AgOTf was used instead of AgSbF

used instead of AgSbF , (iv) 1.105 equiv AgOTs was used instead of

AgSbF , (v) 0.5 equiv of Cs CO was used instead of K PO , (vi)

without K PO , (vii) 1 equiv K PO was used, (viii) 0.3 equiv K PO

3 4 3 4 3

was used, (ix) 0.1 equiv K PO was used, (x) 1.05 equiv AgNTf

15d,e

instead of AgSbF

along with 0.3 equiv K

was used. Reaction

conditions: 0.22 mmol 1a, 0.20 mmol 2a, 5 mol % MeDalPhosAuCl, x

equiv base, 1.105 equiv AgX, DCE (0.1 M), 80 °C, 2 h. Isolated

yields.

Bypassing this highly facile C−N cross-coupling reaction

would be a major hurdle in this type of scenario. Moreover, the

Heck-type reaction which is obvious under transition metal

catalysis would be another challenge that needs to be

considered. Clearly, overcoming these potential side

reactions and achieving the desired aminoarylation products

demands a special catalytic system capable of possessing an

optimally balanced reactivity and selectivity. Based on the prior

knowledge in the ﬁeld of ligand-enabled Au(I)/Au(III)

was formed in 70% yield along with 13% C−N cross-coupled

product 4. In an attempt to improve the yield of 3a, we

screened various other silver salts such as AgOTf, AgNTf , and

AgOTs; however, all of them were found to be inferior as

compared to AgSbF , favoring the undesired C−N cross-

3,17

catalysis,

we wondered that whether it is possible to

coupled product (condition ii, iii, and iv). Given that the

utilize our newly developed “redox-neutral interplay mode” of

gold catalysis to facilitate such highly arduous transformation

in a chemo- and regioselective fashion by circumventing all the

undesired pathways (Scheme 1d). For instance, it was

hypothesized that the MeDalPhosAuCl catalyst should

base holds a signiﬁcant inﬂuence on the 1,2-difunctionalization

13,17

reactions,

a series of bases were evaluated in lieu of K PO ,

3 4

but none was found to be beneﬁcial (see the Supporting

Information (SI)). Most strikingly, we found that varying the

concentration of K PO signiﬁcantly aﬀected the reaction

oxidatively insert into the C(sp )−I bond of iodoaryl alkenes

outcome. For instance, the use of 1 equiv of K PO in

3 4

in the presence of a silver-based halide scavenger to generate

otherwise identical reaction conditions aﬀorded 3a in poor

577

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Letter

Table 2. Scope of Gold-Catalyzed 1,2-Aminoarylation of Alkenes ^,

a b

Reaction conditions: 0.22 mmol 1, 0.20 mmol 2, 5 mol % MeDalPhosAuCl, 1.105 equiv AgSbF , 0.3 equiv K PO , DCE (0.1 M), 80 °C, 2−6 h.

Isolated yields. Unreacted starting material was recovered. No reaction.

yield (20%) along with 57% C−N cross-coupled product 4

condition vii). In contrast, by lowering the base loading to 0.3

TsNH were used. Further, the electron-rich anilines are not

(

suitable under current reaction conditions as a complex

reaction mixture was obtained when 4-OMe-C H NH and

equiv, the yield of 3a was improved to 86% with minimal

formation of 4 (7% yield) (condition viii). This observation is

4-NMe -C H NH were used as substrates.

15d

in line with our previous studies, suggesting that the more

concentration of base favors the formation of C−N cross-

coupled product by facilitating the strong coordination of

amine with the in situ generated Au(III) species. Further,

lowering the base loading to 0.1 equiv had detrimental eﬀect

on the reaction outcome.

Having optimized reaction conditions in hand, we set out to

explore the scope of various anilines 2 in the present 1,2-

aminoarylation reaction using iodoaryl alkene 1a as a model

substrate. As summarized in Table 2, we were delighted to ﬁnd

that our methodology served as a broadly applicable platform

for coupling a wide array of anilines. For instance, various

substituents at ortho, meta, or para positions of aniline were

well tolerated to aﬀord the 2-aminochroman derivatives 3b−

Next, we turned our attention to interrogate the scope of

iodoaryl alkene 1 (Table 2). At ﬁrst, diﬀerently substituted 2-

iodoallyloxybenzene derivatives 1b−1h were tested against 2-

nitroaniline 2n under the optimized reaction conditions, and

all of them were well-reacted to aﬀord the respective 2-

aminochromans 5b−5h in 58−90% yield. The 2-

aminotetrahydronaphthalene derivative 5j could also be

obtained in decent yield (47%) from 1j. Moreover, iodoaryl

alkenes linked through −NTs and −NMs groups provided

corresponding tetrahydroquinoline derivatives 5k and 5l;

albeit, in slightly lower yields (40 and 46%). However,

iodoaryl alkene with an −NAc group 1m remained inert under

the present reaction conditions. Of note, the suitability of

present methodology for the late-stage functionalization was

assessed by successfully evaluating the L-menthol derived

iodoaryl alkene 1q, which aﬀorded the product 5q in 60% yield

(dr 1:1). The current method does not really demand 2-

nitroaniline, as can be judged from the examples 5r−5x where

4-aminoacetophenone 2a also reacted well with various

iodoaryl alkenes.

p in up to 45−96% yield. Notably, the aniline 2q bearing

pseudohalide (−OTf) substituent reacted chemoselectively

with iodoaryl alkene 1a to furnish the desired product 3q in

4% yield. Next, various disubstituted anilines with electron-

donating and withdrawing substituents at ortho and para

position were also found to be compatible, giving products 3r−

3w in 53−98% yield. Moreover, the reactions of fused aniline

2x and heterocyclic aniline 2y aﬀorded products 3x and 3y in

61% and 51% yields, respectively. However, 4-aminopyridine

2z did not produce the desired product 3z, probably due to the

To further expand the horizon of current aminoarylation

reaction, we considered 1-allyl-2-iodobenzenes 6 as potential

substrates to access 2-aminoindane derivatives 7 (Table 3).

Gratifyingly, a series of anilines having diﬀerent substituents at

ortho and para positions worked well to deliver 2-amino-

indanes 7a−7g up to 96% yield. A heterocyclic amine 2y also

reacted well to furnish the corresponding indane derivative 7h

quenching of active Au(I) or Au(III) catalyst by the strong

coordination of pyridine nitrogen. Besides this, direct C−N

cross-coupled products were observed when PhCONH and

578

ACS Catal. 2021, 11, 4576−4582

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Letter

Table 3. Synthesis of 2-Aminoindane Derivatives ^,

a b

Scheme 2. Reaction with Internal Alkenes, Mechanistic

Investigations, and Proposed Catalytic Cycle

Reaction conditions: 0.22 mmol 6, 0.20 mmol 2, 5 mol %

MeDalPhosAuCl, 1.105 equiv AgSbF , 0.3 equiv K PO , DCE (0.1

M), 80 °C, 2 h. Isolated yields. Unreacted starting material was

recovered.

in 42% yield. Moreover, the substituted 2-iodoallyl benzenes

were also tolerated to furnish 7i and 7j in moderate yields

(

56% and 61%).

In the oxyarylation reaction reported by Bourissou and co-

workers, the reversal of regioselectivity was observed in case of

internal alkenes. We wondered that what would be the fate in

our case when internal alkene 8 was utilized as a substrate

(

Scheme 2a). Interestingly, upon treatment of 2-nitroaniline

n, with (E)-8 as well as (Z)-8 provided dihydrobenzofuran

derivatives 9 and 10 instead of regular chromans. In the

current case, the partial positive charge, generated during the

formation of Au(III)−π complex, could be equally stabilized at

both the position of alkene. However, the formation of more

stable 6-membered auracycle H after nucleophilic attack of

aniline onto the Au(III)−π complex leads the reversal of

regioselectivity. The structure of compound 10 was unambig-

uously conﬁrmed by SC-XRD analysis.

It is known that alkenes can greatly aﬀect the rate of

oxidative addition of cationic gold(I) species by generating

the Au(I)−π complex as a catalyst resting state. In the

current scenario, we thought that as alkene is tethered with aryl

iodide, the Au(I)−π complex (cf. B) should in fact bring the

aminoarylation of alkenes is given in Scheme 2d. As suggested

by our P NMR studies, the cationic Au(I) species generated

from the reaction of MeDalPhosAuCl and AgSbF should

Au(I) species in close proximity with C(sp )−I bond and thus

intercept with the iodoaryl alkene 1a to form the Au(I)−π

accelerate the oxidative addition process (Scheme 2b). To

shed light on this phenomenon, a stoichiometric experiment

was performed by using equimolar amounts of MeDalPho-

complex B as a catalyst resting state. The slow dissociation of

active cationic Au(I) species from π-complex B, in the

presence of tethered aryl iodide should facilitate the oxidative

sAuCl and 1a in the presence of AgSbF . Monitoring the

addition with C(sp )−I bond leading to the formation of

reaction with P NMR conﬁrmed the instantaneous formation

of a putative Au(I)−π complex B (59 ppm). However, the

complete conversion of B to Au(III) complex C (78 ppm) was

observed only after 1 h. Such a slow rate of oxidative addition

could be attributed to the lack of vacant coordination sites at

the putative Au(I)−π complex B. As a result, the Au(I) catalyst

has no option rather to dissociate from the alkene for inserting

Au(III) species C. The subsequent iodide abstraction by silver

salt would furnish the coordinatively unsaturated Au(III)

species capable of activating internal alkene (cf. D) toward

nucleophilic attack of aniline 2n. Stereochemically, this step

should follow the anti-addition across alkene as suggested by

our deuterium labeling experiment. The so-formed Au(III)

intermediate E should rapidly undergo concerted inner sphere

into the C(sp )−I bond, which ultimately causes the decrease

reductive elimination to forge a key C(sp )−C(sp ) bond

in the rate of oxidative addition process. Next, the deuterium

labeling experiments revealed the anti-addition of aniline and

aryl group across alkene which is in agreement with the

anticipated π-activation pathway for the current transformation

leading to product 3n.

In summary, we have developed the ﬁrst gold-catalyzed 1,2-

aminoarylation of alkenes that engages external amine as a

nucleophile. The current reactivity was harnessed by exploiting

the potential of our redox-neutral interplay mode of gold

catalysis, which integrates the cross-coupling reactivity and π-

activation ability of gold complexes. Careful optimization

(

Scheme 2c).

Based on the gathered experimental evidence and our

3,17

previous reports,

the catalytic cycle for gold-catalyzed 1,2-

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1994 , 32 , 183 −190. (b) MacSweeney, C. P.; Lesourd, M.; Gandon, J.-

Letter

studies, involving judicious choice of base and halide

scavenger, were found to be the key to achieve highly

chemoselective aminoarylation of alkenes. Barring the

formation of undesired C−N cross-coupling and Heck-type

side-products that are facile under Pd, Cu, or Ni catalysis, the

current methodology oﬀers straightforward access to highly

valuable 3-aminochroman, 2-aminotetrahydronaphthalene, and

M. Antidepressant-Like Effects of Alnespirone (S 20499) in the

Learned Helplessness Test in Rats. Eur. J. Pharmacol. 1998, 345, 133−

137.

(

2) Ross, S. B.; Thorberg, S.-O.; Jerning, E.; Mohell, N.; Stenfors, C.;

Wallsten, C.; Milchert, I. G.; Ojteg, G. Robalzotan (NAD-299), a

Novel Selective 5-HT ₁ _A Receptor Antagonist. CNS Drug Rev. 1999, 5,

3) (a) Sixel-Doring, F.; Trenkwalder, C. Rotigotine Transdermal

13−232.

-aminoindane derivatives. The mechanistic paradigm was

corroborated with several control experiments involving

Delivery for the Treatment of Restless Legs Syndrome. Expert Opin.

Pharmacother. 2010, 11, 649−656. (b) Chen, J. J.; Swope, D. M.;

Dashtipour, K.; Lyons, K. E. Transdermal Rotigotine: A Clinically

Innovative Dopamine-Receptor Agonist for the Management of

Parkinson ’s Disease. Pharmacotherapy 2009, 29, 1452−1467.

NMR, mass spectrometry, and deuterium labeling studies. The

future research work will be directed toward accessing the

library of these valuable compounds for evaluating their

medicinal potential.

(4) (a) Brandt, S. D.; Braithwaite, R. A.; Evans-Brown, M.; Kicman,

A. T. Aminoindane Analogues. In Novel Psychoactive Substances.

Dargan, P. I.; Wood, D. M., Ed.; Academic Press: Boston, 2013;

Chapter 11, pp 261 −283. (b) Iversen, L.; White, M.; Treble, R.

Designer Psychostimulants: Pharmacology and Differences. Neuro-

pharmacology 2014 , 87 , 59 −65. (c) Smith, J. P.; Sutcliffe, O. B.;

Banks, C. E. An Overview of Recent Developments in the Analytical

Detection of New Psychoactive Substances (NPSs). Analyst 2015,

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acscatal.1c00789.

■

Experimental procedures, analytical data, and copies of

H, C NMR spectra of all newly synthesized

40 , 4932 −4948. (d) Pinterova, N.; Horsley, R. R.; Palenicek, T.

compounds (PDF )

Synthetic Aminoindanes: A Summary of Existing Knowledge. Front.

X-ray crystallographic data of 3e (CIF )

X-ray crystallographic data of 7b (CIF )

X-ray crystallographic data of 10 (CIF )

Psychiatry 2017, 8, 236−242.

(5) (a) Villetti, G.; Bregola, G.; Bassani, F.; Bergamaschi, M.;

Rondelli, I.; Pietra, C.; Simonato, M. Preclinical Evaluation of

CHF3381 as a Novel Antiepileptic Agent. Neuropharmacology 2001,

0, 866−878. (b) Villetti, G.; Bergamaschi, M.; Bassani, F.; Bolzoni,

AUTHOR INFORMATION

Corresponding Author

Nitin T. Patil − Department of Chemistry, Indian Institute of

Science Education and Research Bhopal, Bhopal 462 066,

India; orcid.org/0000-0002-8372-2759; Email: npatil@

iiserb.ac.in

■

P. T.; Maiorino, M.; Pietra, C.; Rondelli, I.; Chamiot-Clerc, P.;

Simonato, M.; Barbieri, M. Antinociceptive Activity of the N -Methyl-

D-Aspartate Receptor Antagonist N -(2-Indanyl)-Glycinamide Hydro-

chloride (CHF3381) in Experimental Models of Inflammatory and

Neuropathic Pain. J. Pharmacol. Exp. Ther. 2003, 306, 804−814. (c)

CHF 3381. Drugs R&D; 2004; Vol. 5, p 28; (d) Mathiesen, O.;

Imbimbo, B. P.; Hilsted, K. L.; Fabbri, L.; Dahl, J. B. CHF3381, a N-

Methyl-D-Aspartate Receptor Antagonist and Monoamine Oxidase −

A Inhibitor, Attenuates Secondary Hyperalgesia in a Human Pain

Model. J. Pain 2006, 7, 565−574. (e) Mattia, C.; Coluzzi, F.

Indantadol, A Novel NMDA Antagonist and Nonselective MAO

Inhibitor for the Potential Treatment of Neuropathic Pain. IDrugs

Authors

Akash G. Tathe − Department of Chemistry, Indian Institute

of Science Education and Research Bhopal, Bhopal 462 066,

India

Urvashi − Department of Chemistry, Indian Institute of Science

Education and Research Bhopal, Bhopal 462 066, India

Amit K. Yadav − Department of Chemistry, Indian Institute of

Science Education and Research Bhopal, Bhopal 462 066,

India

(

007, 10, 636−644.

6) Stoel, I.; Hagemeijer, F. Aprindine: A Review. Eur. Heart J. 1980,

, 147−156.

7) Reviews (a) Zeni, G.; Larock, R. C. Synthesis of Heterocycles via

Palladium-Catalyzed Oxidative Addition. Chem. Rev. 2006 , 106 ,

644 −4680. (b) Chemler, S. R.; Fuller, P. H. Heterocycle Synthesis

Chetan C. Chintawar − Department of Chemistry, Indian

Institute of Science Education and Research Bhopal, Bhopal

by Copper Facilitated Addition of Heteroatoms to Alkenes, Alkynes

and Arenes. Chem. Soc. Rev. 2007 , 36 , 1153 −1160. (c) Wolfe, J. P.

Stereoselective Synthesis of Saturated Heterocycles via Palladium-

Catalyzed Alkene Carboetherification and Carboamination Reactions.

Synlett 2008 , 19 , 2913 −2937. (d) Chemler, S. R. The Enantioselective

Intramolecular Aminative Functionalization of Unactivated Alkenes,

Dienes, Allenes and Alkynes for the Synthesis of Chiral Nitrogen

Heterocycles. Org. Biomol. Chem. 2009 , 7 , 3009 −3019. (e) DeLuca,

R. J.; Stokes, B. J.; Sigman, M. S. The Strategic Generation and

Interception of Palladiumhydrides for Use in Alkene Functionaliza-

tion Reactions. Pure Appl. Chem. 2014 , 86 , 395 −408. (f) Garlets, Z. J.;

62 066, India

Complete contact information is available at:

https://pubs.acs.org/10.1021/acscatal.1c00789

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

Generous ﬁnancial assistance by the Science and Engineering

Research Board (SERB), New Delhi (File No. EMR/2016/

07177 and DIA/2018/000016), is gratefully acknowledged.

A.G.T. and U. and A.K.Y. thank IISER Bhopal for the award of

SRF and fellowships respectively, and C.C.C. thanks UGC for

the award of SRF.

■

White, D. R.; Wolfe, J. P. Recent Developments in Pd -Catalyzed

Alkene- Carboheterofunctionalization Reactions. Asian J. Org. Chem.

017 , 6 , 636 −653. (g) Giri, R.; Shekhar, K. C. Strategies toward

Dicarbofunctionalization of Unactivated Olefins by Combined Heck

Carbometalation and Cross-Coupling. J. Org. Chem. 2018, 83, 3013−

3022. (h) Dhungana, R. K.; Shekhar, K. C.; Basnet, P.; Giri, R.

Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated

Olefins. Chem. Rec. 2018 , 18 , 1314 −1340. (i) Ping, Y.; Li, Y.; Zhu, J.;

Kong, W. Construction of Quaternary Stereocenters by Palladium-

Catalyzed Carbopalladation-Initiated Cascade Reactions. Angew.

Chem., Int. Ed. 2019, 58, 1562−1573.

REFERENCES

■

1) (a) Curle, P. F.; Mocaer, E.; Renard, P.; Guardiola, B. Anxiolytic

Properties of (+) S 20499, a Novel Serotonin 5-HT,, Full Agonist, in

the Elevated Plus-Maze and Social Interaction Tests. Drug Dev. Res.

580

ACS Catal. 2021, 11, 4576−4582

ACS Catalysis

A.; Bourissou, D. Catalytic Au(I)/Au(III) Arylation with the

Letter

(

8) (a) Modern Gold-Catalyzed Synthesis; Hashmi, A. S. K., Toste, F.

Am. Chem. Soc. 2018, 140, 7065−7069. (c) Rodríguez, J.; Zeineddine,

A.; Sosa-Carrizo, E. D.; Miqueu, K.; Saffon-Merceron, N.; Amgoune,

Hemilabile MeDalphos Ligand: Unusual Selectivity for Electronrich

Iodoarenes and Efficient Application to Indoles. Chem. Sci. 2019, 10,

7183 −7192. (d) Akram, M. O.; Das, A.; Chakrabarty, I.; Patil, N. T.

Ligand-Enabled Gold-Catalyzed C(sp2)−N Cross-Coupling Reac-

tions of Aryl Iodides with Amines. Org. Lett. 2019, 21, 8101−8105.

(e) Rodriguez, J.; Adet, N.; Saffon-Merceron, N.; Bourissou, D.

Au(I)/Au(III)-Catalyzed C −N Coupling. Chem. Commun. 2020, 56,

94−97. (f) Stauber, J. M.; Qian, E. A.; Han, Y.; Rheingold, A. L.; Král,

P.; Fujita, D.; Spokoyny, A. M. An Organometallic Strategy for

Assembling Atomically Precise Hybrid Nanomaterials. J. Am. Chem.

Soc. 2020, 142, 327−334.

(16) Rigoulet, M.; Thillaye du Boullay, O.; Amgoune, A.; Bourissou,

D. Gold(I)/Gold(III) Catalysis that Merges Oxidative Addition and π

Alkene Activation. Angew. Chem., Int. Ed. 2020, 59, 16625−16630.

(17) Tathe, A. G.; Chintawar, C. C.; Bhoyare, V. W.; Patil, N. T.

Ligand-Enabled Gold-Catalyzed 1,2-Heteroarylation of Alkenes.

Chem. Commun. 2020, 56, 9304−9307.

(18) Zhang, S.; Wang, C.; Ye, X.; Shi, X. Intermolecular Alkene

Difunctionalization via Gold-Catalyzed Oxyarylation. Angew. Chem.,

Int. Ed. 2020, 59, 20470−20474.

(19) For reports on Au-catalyzed intramolecular 1,2-aminoarylation

of alkenes (a) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. Homogeneou

Gold-Catalyzed Oxidative Carboheterofunctionalization of Alkenes. J.

Am. Chem. Soc. 2010, 132, 1474−1475. (b) Brenzovich, W. E., Jr.;

Benitez, D.; Lackner, A. D.; Shunatona, H. P.; Tkatchouk, E.;

Goddard III, W. A.; Toste, F. D. Gold-Catalyzed Intramolecular

Aminoarylation of Alkenes: C-C Bond Formation through Bimo-

lecular Reductive Elimination. Angew. Chem., Int. Ed. 2010 , 49 , 5519 −

5522. (c) Zhang, G.; Luo, Y.; Wang, Y.; Zhang, L. Combining

Gold(I)/Gold(III) Catalysis and C-H Functionalization: A Formal

Intramolecular [3 + 2] Annulation towards Tricyclic Indolines and

Mechanistic Studies. Angew. Chem., Int. Ed. 2011, 50, 4450−4454.

(d) Tkatchouk, E.; Mankad, N. P.; Benitez, B.; Goddard, W. A., III;

Toste, F. D. Two Metals Are Better Than One in the Gold Catalyzed

Oxidative Heteroarylation of Alkenes. J. Am. Chem. Soc. 2011, 133,

14293 −14300. (e) Sahoo, B.; Hopkinson, M. N.; Glorius, F.

Combining Gold and Photoredox Catalysis: Visible Light-Mediated

Oxy- and Aminoarylation of Alkenes. J. Am. Chem. Soc. 2013, 135,

5505−5508.

(20) Reviews (a) Schlummer, B.; Scholz, U. Palladium Catalyzed C-

N and C-O Coupling − A Practical Guide from an Industrial Vantage

Point. Adv. Synth. Catal. 2004 , 346 , 1599 −1626. (b) Bariwal, J.; Van

der Eycken, E. C −N Bond Forming Cross-Coupling Reactions: An

Overview. Chem. Soc. Rev. 2013, 42, 9283−9303. (c) Bhunia, S.;

Pawar, G. G.; Kumar, S. V.; Jiang, Y.; Ma, D. Selected Copper-Based

Reactions for C-N, C-O, C-S, and C-C Bond Formation. Angew.

Chem., Int. Ed. 2017 , 56 , 16136 −16179. (d) Zhu, C.; Yue, H.; Jia, J.;

Rueping, M. Recent Advances in Nickel Catalyzed C-Heteroatom

Cross- Coupling Reactions under Mild Conditions via Facilitated

Reductive Elimination. Angew. Chem., Int. Ed. 2021, DOI: 10.1002/

anie.202013852 . For pertinent reports related to the present work

D., Eds.; Wiley-VCH: Weinheim, 2012. (b) Gold Catalysis: An

Homogeneous Approach; Toste, F. D., Michelet, V., Ed.; Imperial

College Press: London, 2014. (c) Au-Catalyzed Synthesis and

Functionalization of Heterocycles; Bandini, M., Ed.; Springer Interna-

tional Publishing: Switzerland, 2016. For selected recent reviews

d) Huang, B.; Hu, M.; Toste, F. D. Homogeneous Gold Redox

Chemistry: Organometallics, Catalysis, and Beyond. Trends Chem.

020, 2, 707−720. (e) Campeau, D.; León Rayo, D. F.; Mansour, A.;

Muratov, K.; Gagosz, F. Gold-Catalyzed Reactions of Specially

Activated Alkynes, Allenes, and Alkenes. Chem. Rev. 2020,

DOI: 10.1021/acs.chemrev.0c00788 . (f) Chintawar, C. C.; Yadav,

A. K.; Kumar, A.; Sancheti, S. P.; Patil, N. T. Divergent Gold

Catalysis: Unlocking Molecular Diversity through Catalyst Control.

Chem. Rev. 2021, DOI: 10.1021/acs.chemrev.0c00903 .

9) (a) Bratsch, S. G. Standard Electrode Potentials and Temper-

ature Coefficients in Water at 298.15. K. J. Phys. Chem. Ref. Data

989 , 18 , 1 −21. (b) Gorin, D. J.; Toste, F. D. Relativistic Effects in

Homogeneous Gold Catalysis. Nature 2007, 446, 395−403.

10) Reviews (a) Garcia, P.; Malacria, M.; Aubert, C.; Gandon, V.;

(

Fensterbank, L. Gold-Catalyzed Cross-Couplings: New Opportunities

for C-C Bond Formation. ChemCatChem 2010 , 2 , 493 −497.

b) Wegner, H. A.; Auzias, M. Gold for C-C Coupling Reactions:

8247. (c) Hopkinson, M. N.; Gee, A. D.; Gouverneur, V. Au /Au

A Swiss-Army-Knife Catalyst? Angew. Chem., Int. Ed. 2011, 50 , 8236 −

III

Catalysis: An Alternative Approach for C-C Oxidative Coupling.

Chem. - Eur. J. 2011 , 17 , 8248 −8262. (d) Miro, J.; del Pozo, C.

Fluorine and Gold: A Fruitful Partnership. Chem. Rev. 2016 , 116 ,

1924 −11966. (e) Nijamudheen, A.; Datta, A. Gold-Catalyzed Cross-

Coupling Reactions: An Overview of Design Strategies, Mechanistic

Studies, and Applications. Chem. - Eur. J. 2020 , 26 , 1442 −1487.

f) Banerjee, S.; Bhoyare, V. W.; Patil, N. T. Gold and Hypervalent

Iodine(III) Reagents: Liaisons over a Decade for Electrophilic

Functional Group Transfer Reactions. Chem. Commun. 2020 , 56 ,

677 −2690. (g) Rocchigiani, L.; Bochmann, M. Recent Advances in

Gold(III) Chemistry: Structure, Bonding, Reactivity, and Role in

Homogeneous Catalysis. Chem. Rev. 2020, DOI: 10.1021/acs.chem-

rev.0c00552.

Bedi, V.; Patil, N. T. Oxidant-Free Oxidative Gold Catalysis: The

11) Reviews (a) Hopkinson, M. N.; Tlahuext-Aca, A.; Glorius, F.

Merging Visible Light Photoredox and Gold Catalysis. Acc. Chem. Res.

016, 49, 2261−2272. (b) Akram, M. O.; Banerjee, S.; Saswade, S. S.;

New Paradigm in Cross-Coupling Reactions. Chem. Commun. 2018 ,

4 , 11069 −11083. (c) Witzel, S.; Hashmi, A. S. K.; Xie, J. Light in

Gold Catalysis. Chem. Rev. 2021, DOI: 10.1021/acs.chem-

rev.0c00841.

12) (a) Levin, M. D.; Toste, F. D. Gold-Catalyzed Allylation of Aryl

Boronic Acids: Accessing Cross-Coupling Reactivity with Gold.

Angew. Chem., Int. Ed. 2014, 53, 6211−6215. (b) Wang, J.; Zhang, S.;

Xu, C.; Wojtas, L.; Akhmedov, N. G.; Chen, H.; Shi, X. Highly

Efficient and Stereoselective Thioallylation of Alkynes: Possible Gold

Redox Catalysis with No Need for a Strong Oxidant. Angew. Chem.,

Int. Ed. 2018, 57, 6915−6920. (c) Ye, X.; Zhao, P.; Zhang, S.; Zhang,

Y.; Wang, Q.; Shan, C.; Wojtas, L.; Guo, H.; Chen, H.; Shi, X.

Facilitating Gold Redox Catalysis with Electrochemistry: An Efficient

Chemical-Oxidant-Free Approach. Angew. Chem., Int. Ed. 2019, 58,

(e) Rovira, M.; Soler, M.; Guell, I.; Wang, M. − Z.; Gómez, L.; Ribas,

X. Orthogonal Discrimination among Functional Groups in Ullmann-

Type C −O and C −N Couplings. J. Org. Chem. 2016, 81, 7315 −7325.

(f) Ding, X.; Huang, M.; Yi, Z.; Du, D.; Zhu, X.; Wan, Y. Room-

Temperature CuI-Catalyzed Amination of Aryl Iodides and Aryl

Bromides. J. Org. Chem. 2017, 82, 5416 −5423. (g) Du, F.; Zhou, Q.;

Fu, Y.; Chen, Y.; Wu, Y.; Chen, G. Copper(II)-Catalyzed C −N

Coupling of Aryl Halides and N-Nucleophiles Promoted by

Quebrachitol or Diethylene Glycol. Synlett 2019, 30, 2161 −2168.

(21) Reviews (a) Beletskaya, I. P.; Cheprakov, A. V. The Heck

Reaction as a Sharpening Stone of Palladium Catalysis. Chem. Rev.

2000, 100, 3009−3066. (b) Link, J. T. Intramolecular Heck Reaction.

Org. React. 2002, 60, 157−534. (c) Oestreich, M. The Mizoroki-Heck

Reaction; Wiley-VCH, Chichester, 2009. For pertinent reports related

to present work (d) Patel, V. F.; Pattenden, G.; Russell, J. J. Synthesis

7226−17230.

13) Chintawar, C. C.; Yadav, A. K.; Patil, N. T. Gold-Catalyzed 1,2-

Diarylation of Alkenes. Angew. Chem., Int. Ed. 2020, 59, 11808−

1813.

14) Lundgren, R. J.; Hesp, K. D.; Stradiotto, M. Design of New

DalPhos ’ P,N-Ligands: Applications in Transition-Metal Catalysis.

Synlett 2011, 17, 2443−2458.

15) (a) Zeineddine, A.; Estévez, L.; Mallet-Ladeira, S.; Miqueu, K.;

Amgoune, A.; Bourissou, D. Rational Development of Catalytic

‘

(

Au(I)/Au(III) Arylation Involving Mild Oxidative Addition of Aryl

Halides. Nat. Commun. 2017, 8, 565. (b) Messina, M. S.; Stauber, J.

M.; Waddington, M. A.; Rheingold, A. L.; Maynard, H. D.; Spokoyny,

A. M. Organometallic Gold(III) Reagents for Cysteine Arylation. J.

581

ACS Catal. 2021, 11, 4576−4582

ACS Catalysis

of Benzofurans, Indoles and Benzopyrans via Oxidative Free Radical

Letter

Cyclisation Using Cobalt Salen Complexes. Tetrahedron Lett. 1986 ,

7 , 2303 −2306. (e) Patel, V. F.; Pattenden, G. Radical Reactions in

Synthesis. Homolysis of Alkyl Cobalt Salophens in the Presence of

Radical Trapping Agents. Tetrahedron Lett. 1987, 28 , 1451 −1454.

(f) Negishi, E.; Nguyen, T.; O ’Connor, B.; et al. Synthesis of

Benzofurans, Tetrahydrobenzopyrans and Related Cyclic Ethers via

Carbopalladation. Heterocycles 1889, 28, 55−58. (g) Lan, Y.; Liu, P.;

Newman, S. G.; Lautens, M.; Houk, K. N. Theoretical Study of

Pd(0)-Catalyzed Carbohalogenation of Alkenes: Mechanism and

Origins of Reactivities and Selectivities in Alkyl Halide Reductive

Elimination from Pd(II) Species. Chem. Sci. 2012 , 3 , 1987 −1995.

(

22) Blons, C.; Amgoune, A.; Bourissou, D. Gold(III) π Complexes.

Dalton Trans. 2018, 47, 10388−10393.

23) Reviews (a) Schmidbaur, H.; Raubenheimer, H. G.;

Dobrzanska, L. The Gold −Hydrogen Bond, Au −H, and The

Hydrogen Bond to Gold, Au ···H −X. Chem. Soc. Rev. 2014 , 43 ,

45 −380. (b) Joost, M.; Amgoune, A.; Bourissou, D. Reactivity of

(

Gold Complexes towards Elementary Organometallic Reactions.

Angew. Chem., Int. Ed. 2015, 54, 15022−15045. Reports (c) Alcaide,

B.; Almendros, P.; del Campo, T. M.; Fernández, I. Fascinating

Reactivity in Gold Catalysis: Synthesis of Oxetenes through Rare 4-

exo-dig Allene Cyclization and Infrequent β -Hydride Elimination.

Chem. Commun. 2011, 47, 9054−9056. (d) Klatt, G.; Xu, R.;

Pernpointner, M.; Molinari, L.; Hung, T. Q.; Rominger, F.; Hashmi,

A. S. K.; Köppel, H. Are β -H-Eliminations or Alkene Insertions

Feasible Elementary Steps in Catalytic Cycles Involving Gold(I) Alkyl

Species or Gold(I) Hydrides? Chem. - Eur. J. 2013, 19, 3954−3961.

(

24) For more details, see the SI.

(25) (a) Navarro, M.; Toledo, A.; Joost, M.; Amgoune, A.; Mallet-

Ladeira, S.; Bourissou, D. π Complexes of P ∧P and P ∧N Chelated

Gold(I). Chem. Commun. 2019, 55, 7974−7977. (b) Navarro, M.;

Toledo, A.; Mallet-Ladeira, S.; Sosa-Carrizo, E. D.; Miqueu, K.;

Bourissou, D. Versatility and Adaptative Behaviour of the P ∧N

Chelating Ligand MeDalphos within Gold(I) π Complexes. Chem. Sci.

2020, 11, 2750−2758.

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