Recent Advances in Pyridinium Salts as Radical Reservoirs in Organic

Subscriber access provided by Macquarie University

Review

Recent Advances in Pyridinium Salts as Radical Reservoirs in Organic Synthesis Fu-Sheng He, Shengqing Ye, and Jie Wu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03084 • Publication Date (Web): 28 Aug 2019 Downloaded from pubs.acs.org on August 28, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Recent Advances in Pyridinium Salts as Radical Reservoirs in Organic Synthesis Fu-Sheng He,† Shengqing Ye,† and Jie Wu*†,‡ School of Pharmaceutical and Materials Engineering & Institute for Advanced Studies, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, China. †

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. ‡

ABSTRACT: Pyridinium salts are valuable building blocks, which have been widely applied in various organic transformations during the past few decades. In particular, N-functionalized pyridinium salts have been explored as convenient radical precursors, which would go through reductive single electron transfer. As a result, the chemistry of such pyridinium compounds for generating carbon-, nitrogen-, and oxygen-centered radicals has been witnessed, and a remarkable progress has been achieved, making it a hot topic over the last five years. This review describes recent advances in the area of pyridinium salts as radical precursors, concerning the development of radical reactions involving pyridinium salts in organic synthesis. KEYWORDS: pyridinium salts, transition metal catalysis, photocatalysis, carbon-centered radicals, nitrogen-centered radicals, oxygen-centered radicals. 1. Introduction Pyridinium salts are privileged structural units that are found in many natural products and biologically active compounds.1 Moreover, pyridinium salts have been extensively considered as valuable building blocks in various organic transformations.2 Continuous efforts focused on the preparation and application of pyridinium salts led to numerous research articles and several reviews. Usually, the bench-stable and readily available pyridinium salts are highly reactive species that undergo various reactions such as nucleophilic addition and 1,3-dipolar addition. On the other hand, it’s not until recent years that pyridinium salts have been applied in radical reactions and immediately have aroused significant attention. To date, a variety of N-functionalized pyridinium salts have been developed for generating radicals including alkyl radicals, trifluoromethyl radical, N-centered radicals, O-centered radicals as well as other related radicals, serving as attractive approaches for the construction of C-C and C-X bonds under transition metal or photoredox catalysis. However, an overview to emphasize the chemistry of pyridinium salts as radical precursors is particularly lacked. The growing number of studies on this subject over the past five years entail a more general review of the field. In this review, we will discuss the most notable developments by using pyridinium salts as radical precursors, including carbon-, nitrogen-, and oxygen-centered radicals, highlighting literature reports mainly from the beginning of 2015 to date (Scheme 1). Generally, the synthesis of Nfunctionalized pyridinium salts mentioned in this review can be achieved by following the strategies shown in Scheme 2.

Pyridinium Salts as Radical Reservoirs

RO CF3

F3CO

R1

Alkyl

ClCF2

N R O

R2 N R3

Ar

O

N

Scheme 1 N-functionalized pyridinium salts as radical precursors R2

TFAA or

BF4

R NH2 + R1

O

Tf2O

R1

or R 3O

R1

+

Tf2O

N

R1

BF4 1 + R

or N

R X or

R

N O

Togni Reagent I or N

I NH2

+

O

ArSO2Cl Ar

Cl

Scheme 2 General methods for the preparation of Nfunctionalized pyridinium salts 2. Pyridinium Salts as Alkyl Radical Precursors The generation of alkyl radicals from naturally abundant and inexpensive feedstocks are highly important for the synthetic community. Over the past years, different alkylation reagents including carboxylic acids, redox-active

ACS Paragon Plus Environment

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

esters, halides, sulfones, 1,4-dihydropyridines, organoboronates, organosilicates and oxalates have been well explored as the sources of alkyl radicals for the C-C and C-X bond-forming reactions. In contrast, the use of abundant alkyl amines as effective carbon sources in radical cross coupling transformations is yet to be developed. To this end, Katritzky salts, which were discovered by Katritzky in 1980s, can become effective alkyl precursors to generate alkyl radicals through facile single-electron reduction and fragmentation.3 The benchstable Katritzky salts 1 can be readily prepared from the condensation of primary amines with commercially available 2,4,6-triphenylpyrylium tetrafluoroborate in a single step. Recently, the deaminative cross-coupling of Katritzky salts 1 via C-N bond activation has received considerable attention. In 2017, Watson and co-workers reported that Katritzky salts 1 could act as alkyl electrophiles in nickel-catalyzed deaminative crosscoupling reactions with boronic acids (Scheme 3).4 The reaction featured a broad substrate scope and functional group tolerance. Based on the mechanistic experiments, the authors proposed that the reaction began with singleelectron transfer between Katritzky salts 1 and a Ni(I) intermediate to generate dihydropyridine radical 3A. The fragmentation of 3A would release 2,4,6-triphenylpyridine 3B to give alkyl radical 3C, which then combined with an arylnickel(II) intermediate to form Ni(III) species 3D. Subsequently, the desired product 2 would be produced via reductive elimination. Ar B(OH)2 BF4 Ph

O

R N

Ph

Ph 1

KOtBu (3.4 equiv) EtOH (5.0 equiv) dioxane, 60 ºC

BF4

R Ar 2 25 examples 46-81% yields

BocN

O

p-Tol

N

NEt2

N Me

Ph 75%

73%

81% F

OEt

TBSO

N

EtO

BocN 48%

N

71%

59%

Ph

Ph

R N

Ph

Ph 1

R

BF4

Ar 2

Ph

or R2

N

O

93%

R LNiI-ArX

-LNiI-X

LNiII-ArX

N Ph

Ar LNIII X R 3D

Ph Ph

3A

Ph R

N

Ph

3B

3C

Scheme 3 Nickel-catalyzed deaminative cross-coupling reactions of Katritzky salts and aryl boronic acids Additionally, the same group extended the above strategy to the nickel-catalyzed deaminative crosscoupling reactions of benzylic pyridinium salts with arylboronic acids or vinylboronic acids (Scheme 4).5 By employing this method, a series of di(hetero)arylmethanes 3 or 1,3-disubstituted allylic products 4 were obtained in good to excellent yields, showing good functional group tolerance.

or Ar1

Ar2 3

R1 R2 4

NO2

NH2

N

Ar1

K3PO4 (3.4 equiv) R1 EtOH (5 equiv), dioxane, 60 ºC

(HO)2B

1

N H

N 92%

67%

N

S N

S

N 80%

72%

50%

Scheme 4 Nickel-catalyzed deaminative cross-coupling reactions of benzylic pyridinium salts with arylboronic acids or vinylboronic acids Soon after, Glorius’s group developed an elegant photoredox catalyzed deaminative alkylation of heteroarenes using Katritzky salts 1 under visible light (Scheme 5).6 The scope of this reaction was quite broad, a range of Katritzky salts derived from alkyl amines, including amino acids, was successfully applied as alkyl radical precursors for the alkylation of different heteroarenes to furnish the corresponding products 5. Ph R N

Ph

Ph

+

R

[Ir(ppy)2(dtbbpy)]PF6 (2.5 mol %)

Het

DMA, rt, 24 h 5 W blue LEDs

BF4

1

Het 5 31 examples 32-91% yields Me

Cy N

N i

Cy 83%

N

Ni(OAc)2• 4H2O (10 mol %) BPhen (24 mol %)

Ph

O

Ph

PhenNi(OAc)2 xH2O (5 mol %)

Ar2 B(OH)2 BF4 +

N

Pr

60%

Cl

78%

Pr

N 61%

H N MeO2C

MeO2C Cy

i

86% Ph

N N

Me

N

66%

N

+

Ph

EtOH, reflux or HOAc, CH2Cl2, rt

O

Ph Ar1

Cy

Ph

R NH2

Page 2 of 21

Me 53%

Me

N Ph

33%

Scheme 5 Photoredox catalyzed deaminative alkylation of heterocycles Alkynes are ubiquitous structural motifs in the field of medicinal chemistry, chemical biology and material science. In 2018, Gryko and co-workers described a metal free visible light-mediated approach for the construction of C(sp3)-C(sp) and C(sp3)-C(sp2) bonds, affording functionalized alkynes and alkenes under mild conditions (Scheme 6).7 The reaction of Katritzky salts 1 with alkynyl p-tolylsulfones or vinyl phenyl sulfones featured a broad substrate scope and high chemoselectivity, and was amenable to scale up. According to the proposed mechanism, the reaction was initiated by a single electron transfer from photoexcited eosin Y (EY*) with Katritzky salts 1 to generate dihydropyridine radical 6A, which would then undergo fragmentation to form alkyl radical and 2,4,6-triphenylpyridine 6B. Subsequently, the addition of alkyl radical to alkynyl p-tolylsulfones would provide intermediate 6C, which would be followed by rapid elimination of arylsulfonyl radical to furnish the corresponding products 6.


Page 3 of 21

ACS Catalysis Ph

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

R N

Ph

Eosin Y (2 mol %) DIPEA

R1

+

MeOH/DCE (3:1) Green LEDs

Ts

Ph 1

R1 R

BF4

Ph

O

Ph

78%

6 >40 examples 34-84% yields

BocN

75%

MeS

I

Ru(bpy)2Cl2 (5 mol %) K2CO3 (2.0 equiv)

Ph

Ph

MeCN, rt, 12 h blue LEDs

BF4 1

Ph

R1 N R 8 26 examples up to 98% yields

N

77%

N

66%

46%

DIPEA

-Ts

Ts

h

Ph

Ph

Ph

N

R

Ph

Ph R

+

8B

R N Ph

BF4

Ph EY

BF4

1

Ph

R•

6B

Ph

Ph

Ph

Ph

6A

R N

Ph

Ph

N

Ph

91%

Ph

N

R1

CO2Me

N

75%

Ts Ph

Ph

94% R1 6

EY EY*

CO2Me

N

Ph

1 6C R

DIPEA

CO2Me

N

R

R

EY

1

R

NC

Ph

HO

R N

Ph R N

+

1

58%

Ph

Ph

Ph

8 through a single electron oxidation, deprotonation and aromatization sequence.

Ru2+*

Ru2+

Ru3+

8A

NC

EY

h

SET

Ph

SET -H

Scheme 6 Visible light-mediated deaminative formation of C(sp3)-C(sp) bonds In 2018, Liu and co-workers realized a visible lightmediated deaminative allylation of Katritzky salts with allyl sulfones (Scheme 7).8 Accordingly, Katritzky salts were employed as the alkyl radical source via a single electron transfer, providing rapid access to the formation of site-specific C(sp3)-C(sp3) bond. This method exhibited a broad substrate scope and good functional group tolerance, giving rise to various alkenes 7 in good yields. Ph Ph +

R N Ph 1

R1

SO2Ph

Ir[(ppy)2(dtbbpy)]PF6 (2 mol %) iPr2NEt (8.0 equiv)

BF4

MeO2C MeO2C

R1 R1 = Ph, 67% BocN R1 = Me, 63% R1 = CN, 64%

DCE/DMA (1:1) blue LEDs, rt

R

7 25 examples 43-93% yields

CO2Et

CO2Et

Ph MeO2C 93%

R1

69%

N 8C

N 8D

R

R

Scheme 8 Photoredox enabled deaminative alkylation of isocyanides In 2019, Aggarwal and co-workers developed a photocatalyst free deaminative strategy for the generation of alkyl radicals to further transformations (Scheme 9).10 Based on their previous work, the authors found that Katritzky salts 1 combined with Hantzsch ester 9 or Et3N could also generate EDA complex, which would undergo a single electron transfer by visible light without a photocatalyst. The resulting alkyl radicals were successfully applied to various transformations including Giese, allylation, vinylation, alkynylation, HAT, and thioetherification reactions, showing a broad substrate scope and high functional group tolerance.

Scheme 7 Visible light-mediated deaminative allylation of allylic sulfones

O

O

EtO

R N

Ph

Ph 1

+

EWG

R1

Ph

Me N 9 H Hantzsch ester (3.0 equiv) DMA, 40 ºC, 16 h blue LEDs

R2

BF4

O

R N

Ph + PhO2S

Ph 1

OMe

Hantzsch ester (1.5 equiv) DMA, 40 ºC, 16 h blue LEDs

BF4

EWG

R2 10 30 examples 23-90% yields O R

OMe

11 21 examples 30-77% yields O OMe

OMe

N

Ph 65%

90%

47% O

O

O OMe

OMe Boc

R1 R

O

CN Boc

OEt

Me

Ph

Thereafter, the same group demonstrated a photoinduced radical alkylation of isocyanides with Katritzky salts towards the synthesis of 6-alkylated phenanthridines 8 (Scheme 8).9 In this transformation, the readily available Katritzky salts 1 derived from amino acids/peptides were used as the alkylating agents to afford the desired products in good to excellent yields. On the basis of experimental studies, a plausible mechanism involving single electron reduction of Katritzky salts 1 with photoexcited Ru2+* was proposed. The alkyl radical and 2,4,6-triphenylpyridine 8B were consequently generated after fragmentation of dihydropyridine radical 8A. This alkyl radical species would add to isocyanide furnishing imidoyl radical 8C, which was then converted to radical 8D via an intramolecular cyclization. Finally, the radical 8D would transfer to the desired 6-alkylated phenanthridines

N 8

R

OMe

N 76%

74%

50%

Scheme 9 Photoinduced deaminative functionalizations of primary amines


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

On the basis of the experimental results, the authors proposed a plausible mechanism for this transformation (Scheme 10). Dihydropyridine radical 10A, generated from EDA complex by photoinduced single electron transfer, would undergo fragmentation to give alkyl radical along with the release of triphenylpyridine 10B. Subsequently, the alkyl radical would add to the electron deficient alkene to furnish intermediate 10C, which would be followed by the conversion to Giese product 10 through hydrogen atom transfer with dihydropyridine radical cation 10D or Hantzsch ester 9, accompanied with the formation of pyridinium 10E or dihydropyridine radical 10F. Ph

O

R N Ph

Ph +

1

h

N H

Ph

Ph R N

Ph

Ph

HN Me

CO2Et

10A

Me

H R

EWG

BF4 10E

Ph

N H

CO2Me

70%

N Me 76% R1 R 2O 2C

Ph

Me

CO2Me

N H

R1

X CO2R2 12 30 examples 31-90% yields

Ph

Me

Me

Me

CO2Me

O

82%

CO2Me

83%

Ph N

Ph

Ph

R

3

BF4

EDA complex

X

R1 Ph N R2O2C Ph

Me

O

R3

Ph

11A

Ph

R1

+

N CO2R2 H H BF4

X 12

11B R 2O 2C

R1

R1 R

R CO2Et

X

3

3

R X 11C

R 2O 2C

1

CO2R

2

Ph

O Ph +

N Ph

BF4

N H

H CO2Et 10F

EWG 10C

10B

Me

Me

or

+

Me

or 9

CO2Et 10D R

N

DMSO, blue LEDs

X

BF4

CO2Et

HN

CO2Et

Ph

Ph

CO2Et

H N

Ph

BF4

morpholine (1.5 equiv)

1

Ph Me

10 Me

Ph

N

CO2Et

BF4

R O 2C

Ph

Me

Ph R N

2

R3

R3 Ph +

N

h or thermal

HN Me

Ph

OEt

9 Me

R1

O

EtO Me

BF4

Page 4 of 21

R• EWG

Scheme 10 Proposed mechanism for the photoexcitation of EDA complexes Meanwhile, Glorius and co-workers utilized a traceless acceptor group strategy to promote C-C bond formation by photoexcitation of EDA complexes from Katritzky salts 1 acceptors and heteroarene or enamine donors under visible light (Scheme 11).11 This methodology showed broad substrate scope and good functional group tolerance, giving rise to the corresponding products in good yields. On the basis of experimental and computational studies, a proposed mechanism revealed the crucial role of EDA complexes. Similar to the previous reports, the alkyl radical was generated through the visible light excitation of EDA complex, which would proceed through a single electron transfer and fragmentation sequence. Addition of alkyl radical to heteroarene would lead to benzylic radical 11C. With the assistance of the pre-coordination of morpholine to the acceptor, the desired product 12 was formed through electron transfer propagation pathway.

Scheme 11 Visible light-mediated C–C bond formation with EDA complexes As their continuous interest in the area of visible light promoted C-C bond formation with Katritzky salts, Glorius and co-workers developed a three-component dicarbofunctionalization of styrenes with benzylic radicals (Scheme 12).12 The reaction proceeded smoothly with pyridine moieties and thioethers, exhibiting a broad substrate scope. Moreover, the robustness of the method was further demonstrated through the preparation of highly challenging all-carbon quaternary centers. According to the mechanistic investigations, a single electron transfer between the excited-state photocatalyst and Katritzky salt 1 would deliver benzylic radical 12A after the fragmentation of dihydropyridine radical. Then the benzylic radical 12A would attack the styrene, thus generating another new radical intermediate 12B. This intermediate 12B would undergo a single electron transfer by the oxidized photocatalyst, giving rise to cation 12C. Finally, cation 12C was trapped by the nucleophilic arene, leading to the dicarbo-functionalized 1,1-diarylalkane 13.


Page 5 of 21

ACS Catalysis Ph

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

[Ir(dtbpy)(ppy)2](PF6) (1.0 mol %)

R1

R N

Ph

+

+

Ar'H

1

BF4

NH

Ar Ar' 13 30 examples 25-95% yields

MeCN, blue LEDs rt, 16 h

Ar Ph

R1 R

Ph

MeO2C i

NH

NH

Pr

Br

56%

OMe

65% OMe

34% h

NH Ph

Ph

*Ir(III)

N Ph

SET

BF4

Ph

Ar

Ir(III)

Ph

SET

Ph

Ir(IV)

13

-H

According to the mechanism proposed by Xiao and coworkers, the radical chain was initiated by a single electron transfer with photoexcited *Ir(III) and Katritzky salt 1 to form the alkyl radical, which would attack to alkene giving a new, more stable radical 14A (Scheme 14). Then the radical 14A would proceed through a single-electron oxidation by the oxidized Ir(IV) and subsequent deprotonation to afford the desired product 14. Additionally, the alkyl radical could be captured to generate acyl radical 14B when carbon monoxide was involved in this reaction. After the addition of acyl radical 14B to alkene, the same single-electron oxidation and deprotonation sequence were appeared to deliver the enone product 15.

12C Ar Ph

Ar

Ph 12A

Ph 12B

R1

N H

Ar

Ph

Ph

N

R2

Ph

R1 R 14A

Scheme 12 Photoexcitated dicarbofunctionalization of styrenes

three-component

(a) Xiao, 2019 R1

R N Ph

Ph 1

+ R

BF4

2

Ph Ph R N

Ph

+ Ph

Ph

1

BF4

Ph

Ph 1

Recently, the deaminative alkyl Heck-type and carbonylative alkyl Heck-type reaction of alkylamines was achieved by Xiao and co-workers through visible lightinduced C-N bond activation, using Katritzky salts 1 as the alkyl radical sources (Scheme 13a).13 This strategy opened the door to the deaminative alkyl Heck-type reaction, which was the complement of palladium-catalyzed Heck reaction, providing the corresponding alkene products 14 and 15 in good yields. Later, Uchiyama and co-workers also reported a similar alkyl Heck-type reaction with Katritzky salts 1 and alkenes (Scheme 13b).14 In this case, the Z/Eselectivity of the reaction was observed by the switch control of photoredox catalyst. Additionally, Fu and coworkers demonstrated that the combination of triphenylphosphine and sodium iodide was efficient photoredox catalytic system, which promoted the deaminative alkyl Heck-type reactions using Katritzky salts 1 as the electron accepting substrates (Scheme 13c).15 Ph

R N

[Ir(4-Fppy)2(bpy)]PF6 (2.5 mol %) DABCO (1.0 equiv)

R1 R

R2 14 29 examples 40-97% yields

2x3 W blue LEDs MeCN, 40 ºC, 48 h [Ir(4-Fppy)2(bpy)]PF6 (2.5 mol %) DABCO (1.0 equiv), CO (80 atm)

O

Ph

BF4

CO

Ir(III)

fac-Ir(ppy)3 (1.0 mol %)

Ph +

R N

H

R1 H

Ph

1

Ru(bpy)3(PF6)2 (1.0 mol %)

BF4

H

R1 Z-selectivity R

16

R

DMSO, blue LEDs rt, 12 h

R1 E-selectivity H

17

(c) Fu, 2019 Ph

R1

R N Ph

Ph 1

BF4

+ R

2

NaI (20 mol %) P(p-anisolyl)3 (20 mol %) DMF, rt, 24 h blue LEDs (456 nm)

Ph

R1 R

O

-e base -H+

R2 14 Ph

R

Ph 15

h

Very recently, the groups of Watson, Martin, Rueping and Han independently developed the nickel-catalyzed reductive cross-couplings of aryl halides with Katritzky salts as electrophilic alkylating reagents. For instance, Watson and co-workers realized the transformation of Katritzky salts and aryl bromides using NiCl2·DME and 4,4’-diOMeBipy as the catalyst with Mn as the reductant (Scheme 15a).16 The reaction in NMP at 80 ºC proceeded readily by employing MgCl2 as the additive. Moreover, Martin and co-workers found that NiCl2·glyme in combination with 4,4’-diOMeBipy would enable the same transformation at 60 ºC in the absence of additive (Scheme 15b).16b In Rueping’s protocol, aryl halides including aryl bromides and aryl iodides were efficiently applied to the synthesis of the corresponding products with Katritzky salts (Scheme 15c).17 In particular, the group of Han demonstrated that aryl iodides, alkynyl bromides or alkyl bromides were well tolerated in nickel-catalyzed reductive cross-electrophile coupling reaction using Zn as the reductant (Scheme 15d). 18

Ph 15 5 examples 60-74% yields

DMSO, blue LEDs rt, 12 h

O R 14B

-e base -H+

Scheme 14 Proposed mechanism for the deaminative alkyl Heck-type reactions

(b) Uchiyama, 2019 Ph

*Ir(III)

+e

R

2x3 W blue LEDs MeCN, 40 ºC, 48 h

Ph

R

Ir(IV)

R2

R1 R


Scheme 13 Photocatalytic deaminative alkyl Heck-type reactions


ACS Catalysis (a) Watson, 2019

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Ph R N

Ph

Ph

BF4

(Het)Ar Br

+

NiCl2•DME (10 mol %) 4,4'-diOMeBipy (12 mol %)

R

Mn (2.0 equiv) MgCl2 (1.0 equiv) NMP, 80 ºC, 24 h

1

Ar(Het) 18

(b) Martin, 2019 Ph R N

Ph

Ph

1

BF4

(Het)Ar Br

+

NiCl2•glyme (10 mol %) 4,4'-diOMeBipy (14 mol %)

R

Mn (1.5 equiv) NMP, 60 ºC, 20 h

Ar(Het) 18

(c) Rueping, 2019 Ph R N Ph

Ph

(Het)Ar X

+

NiCl2•DME (10 mol %) 2,2'-Bipyridine (10 mol %)

R

Mn (2.0 equiv) DMA, rt or 60 ºC

1

BF4

Page 6 of 21

of photoexcited catalyst or a low-valent nickel intermediate, which was intercepted by Ni(0) 17A to form intermediate Ni(I) 17B. Subsequently, the oxidative addition Ni(I) 17B with aryl bromide would lead to the Ni(III) complex 17C. Finally, the reductive elimination of 17C would release the desired product and Ni(I)-Br species 17D. Then Ni(I)-Br species 17D would undergo reduction by the reduced state of [4-CzIPN] － • to facilitate the both catalytic cycles.

Ar(Het) 18

Ph R N

(d) Han, 2019

Ph + (Het)Ar Br

Ph

Ph R N

Ph

Ph

1

BF4

+

Halides

R

Ni salts (10 mol %) Ligand (10 mol %)

Ar(Het)

18

Alkyl

19

R

Zn (2.5 equiv) DMF, 60 ºC

R1

R

1

CN

On the basis of the detailed experimental and computational studies, the proposed pathway for the Nicatalyzed reductive deaminative cross-coupling reactions was outlined in Scheme 16. The reduction of Ni(II) salt to the active Ni(0) catalyst was initiated by Zn. Then, the Ni(0) intermediate would undergo oxidative addition with aryl halide to deliver the intermediate Ar-Ni(II)-X 16A, which was reduced by Zn giving rise to the intermediate Ar-Ni(I) 16B. A single electron transfer would then occur to generate radical intermediate 16C, followed by the formation of Ni(III) complex 16D. Finally, the reductive elimination of 16D would release the desired product 18 and regenerate Ni(I) intermediate. Reduction of the Ni(I) intermediate by Zn would accelerate catalytic cycle. Ni(II) Zn 1/2 ZnX2 Ni(0) Zn

X

Ni(II)

NiX(I)

16A

R

Ar(Het) 18

1/2 ZnX2

Ph

Ar(Het)

(Het)Ar Ni(I) 16B

R N

Ph

Ph

BF4 1

X Ni(III) R

N

N

N O 86%

16D

72%

Ph

Ph 1

BF4

4-CzIPN or Ni0Ln

R

4-CzIPN h

Br NiILn 17D

R

[4-CzIPN]

[4-CzIPN]*

Ar 18

[Et3N]

Et3N

Scheme 17 Ni/photoredox catalyzed deaminative cross coupling reactions

reductive

Additionally, the first example of nickel-catalyzed deaminative alkyl-alkyl cross-couplings employing Katritzky salts as electrophiles was recently developed by Watson and co-workers (Scheme 18).20 In the presence of combined Ni(acac)2·xH2O with ttbtpy or 1-bpp, both primary and secondary alkylpyridinium salts would react with alkyl zinc halides efficiently, exhibiting a broad substrate scope and high functional group tolerance. The reaction was proposed to occur via an alkyl radical intermediate through a single electron transfer from a Ni species to Katritzky salt. Ph +

Ph

Alk ZnX

Ni(acac)2 xH2O (5 mol %) ttbtpy or 1-bpp (6 mol %) THF/DMA (2:1), 60 ºC

BF4

1

Scheme 16 Proposed mechanism for the Ni-catalyzed reductive deaminative arylation

O S

OEt

Me 78%

CN N

67%

59%

C5H11

CF3 BocN

R Alkyl 19 22 examples 38-88% yields

O O

68%

At the same time, Molander and co-workers described the nickel/photoredox dual catalyst promoted deaminative reductive arylation of Katritzky salts with aryl bromides, giving rise to the corresponding products 18 in good yields (Scheme 17).19 According to the putative mechanism, initially, the photoexcited [4-CzIPN]* (E1/2 = +1.35 V vs SCE) was quenched by triethylamine (E1/2 = +1.0 V vs SCE) to form the reduced state [4-CzIPN] －•. The alkyl radical was generated from Katritzky salt via a single electron transfer

Ar R NiIIILn Br 17C

Ni0Ln 17A

R N

16C

61% Ar Br

NiILn

Ph

R (Het)Ar Ni(II)

95% R NiILn 17B

Ph R N

Zn

CF3

Ar(Het)


6

Scheme 15 Ni-catalyzed reductive deaminative arylation of Katritzky salts with aryl halides

(Het)Ar

R

Et3N (3.0 equiv) THF or DMA blue LEDs, rt, 24 h

BF4

O

(Het)Ar X

NiBr2(dtbbpy) (5 mol %) 4-CzIPN (3 mol %)

F3C Cl

57%

N

N

BPin

N 80%

Scheme 18 Ni-catalyzed deaminative alkyl-alkyl crosscoupling of alkylamines Overall, Katritzky salts have been widely explored as the sources of alkyl radicals under transition metal catalysis or visible light. Beyond that, the generation of alkyl radicals


Page 7 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

from redox active pyridinium salt complex through decarboxylation was developed by Stephenson and coworkers (Scheme 19).21 By employing heterocyclic N-oxides as both transient redox auxiliary and coupling partner, alkyl carboxylic acid derivatives were converted to the electron-rich alkyl radicals via photoredox catalyzed SET reduction of N-O bond cleavage. Remarkably, the CF2H radical generated from difluoromethylacetic anhydride could also react smoothly with heterocyclic N-oxides in this system, giving rise to the corresponding difluoromethylated products.

+ N O

R

Cl

[Ir(ppy)2(dtbbpy)]PF6 (1 mol %)

O

MeCN, rt, 12 h blue LEDs 13.2 W

or O

HF2C

O

CF2H

O R

O

Ph

N

N

N


40%

21%

Ph

CF2H

Ph

N 15%

CF2H MeO

55%

t

Bu

N 54%

t

Bu

N

t

Bu

49%

Scheme 19 Visible light-mediated alkylation of heterocyclic N-oxides

N 32%

decarboxylative

Organoboronic esters are valuable reagents and building blocks in organic synthesis and have been widely used in molecular science. In 2018, the groups of Aggarwal and Glorius independently reported the deaminative borylation of alkylamines under visible light without any catalysts or additives (Scheme 20).22 The methods developed by both groups provided rapid access to aliphatic boronic esters 21 in good yields under mild conditions. Moreover, the deaminative strategy was successfully applied in the late-stage functionalization of natural products and drugs. Accordingly, an electron donor-acceptor (EDA) complex, which was formed in both reactions by the combination of Katritzky salt, bis(catecholato)diboron (B2cat2) and DMA, was the key to complete the transformation.

+

Bpin N H 52%

68%

Bpin

O

H O

H H

Bpin


OH

Bpin

S

R

then pinacol, Et3N

R1 = OTBS, 51% R1 = CO2H, 24% R1 = CO2Me, 62%

Bpin

R1

DMA, 25 ºC or 45 ºC blue LEDs

B2cat2 (1.1-3.0 equiv)

BF4

1

H

H 76% (19:1)

(b) Glorius, 2018 Ph Ph

+

B2cat2 (1.2 equiv)

BF4

DMA, 30 ºC or 60 ºC blue LEDs then pinacol, Et3N

1 Bpin

Bpin BocN

R

Bpin


Bpin Bpin

HO 91%

Bu

N

Ph

R

Cl

Ph

t

Ph

Ph

R' N

R'

N

Ph

46%

Ph R N

R N

O R'

(a) Aggarwal, 2018

56% (1:1)

67%

98%

Scheme 20 Visible light mediated deaminative borylation of alkylamines To gain more insights into the mechanism, some control experiments were carried out to confirm the formation of radical intermediates, including radical-trapping experiment with TEMPO and radical-clock experiment with cyclopropyl substrate. Additionally, the quantum yield of the deaminative borylation reaction was determined to be Φ = 7.0 (Aggarwal’s result) or Φ = 27.8 (Glorius’s result), indicating that a radical chain process is involved. Based on the detailed mechanistic investigation, two possible reaction pathways were presented by the groups of Aggarwal and Glorius, respectively (Scheme 21). For both of the reactions, an EDA complex was firstly generated in situ from the Katritzky salt 1, B2cat2 and DMA. Then, the radical chain was initiated by irradiation of EDA complex to give dihydropyridine radical 21A, which would undergo fragmentation to form alkyl radical. According to the proposed mechanism of Aggarwal, the alkyl radical would prefer to react with B2cat2 to deliver radical 21C owing to the lowest energy pathway for homolytic radical substitution. The complexation of radical 21C with DMA would afford intermediate 21D, followed by fragmentation to provide boronic ester 21 and boryl radical 21E. As strong single electron reductants, the boron-centred radical 21E would react with the Katritzky salt 1 to regenerate the alkyl radical (path a). Whereas Glorius and co-workers presented a different borylation process, which the alkyl radical would be coupled with DMA-activated B2cat2 to offer final product 21 and boryl radical 21E (path b).


ACS Catalysis

Page 8 of 21 Ph

N

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

O

Ph Ph + B2cat2•DMA

R N Ph 1

O O B B O O

Ph

R

O O O B B O O

h Ph

N Ph

21B

Ph

N

O O B

21A

BF4

21F O

O O B B O O R 21D

1

path b

21B + 21F

O t

N

Bu

homolysis

t

B

R•

path a

B O

N

B2cat2

N

N t

Bu

Bu

O O

N

B2cat2

t

O B O B O N O t

DMA

t

23E

O B

21

1

O 21E

N

R

O O O B B O O

Bcat 21

Scheme 21 Proposed Mechanism Subsequently, Shi and co-workers reported a Lewis base promoted C–N borylation of Katritzky salts derived from alkylamines, which also used B2cat2 as the boron source (Scheme 22).23 The reaction in the presence of catalytic amount of bipyridine in DMA at 100 ºC worked well to access various alkyl potassium trifluoroborate salts 22 with good functional group compatibility. Ph R N

Ph

+

B2cat2

1) dtbpy (10 mol %) DMA, 100 ºC

1

Bpin

R

2) KHF2 or pinacol

Ph

BF3K

BF3K

Me

BF3K

22 28 examples 44-74% yields Bpin N Me

71% BF3K Me

R

BF3K S

NC 60%

54%

or

21

BF4

Ph

t

21E

57%

H H

Bu

23A

Bu O N B O O N B O

Bu

23B

Scheme 23 Lewis base promoted C–N borylation of alkylamines The incorporation of trifluoromethyl groups into drug candidates often result in an enhancement of their biological activities, such as improving cellular membrane permeability and increasing metabolic stability. Therefore, considerable efforts have been devoted to the introduction of trifluoromethyl groups into organic molecules, along with a large number of trifluoromethylation reagents have been developed. In 2015, Stephenson and co-workers reported a facile approach for the scalable and operationally simple trifluoromethylation of arenes and heteroarenes by using trifluoroacetic anhydride as trifluoromethyl radical source (Scheme 24).24 The reaction would undergo a decarboxylation process to access CF3 radical by using pyridine N-oxide and photoredox catalysis. Notably, the robustness of this protocol was further demonstrated by the large scale trifluoromethylation of NBoc-pyrrole conducted in batch (100 g) and flow (20 g).

55% Me Me

Me MeO

Bu N

O

O

Bu

N

O O N B O O N B O 23C

O Bcat

t

Bu

NMe2

O B

R

t

N O

Bu

O

1

21

+ t

BF4

R

23D

Ph

R N

coupling

Bpin

Me2N

Ph

O O B B O O R 21C

DMA

N

Ph Ph

Ph

Ph

Ph

R N

BF4

R N

H

Bpin

O N

Y

Ru(bpy)3Cl2 (0.1-1 mol %) TFAA (1.1-2.1 equiv)

Y

MeCN, 8-15 h, 25-35 ºC blue LEDs 13.2 W

Z

+ Z

H

X

X 23 22 examples 17-74% yields

73%

Scheme 22 Lewis base promoted C–N borylation of alkylamines A plausible mechanism of this transformation on the basis of the experimental and computational results was shown in Scheme 23. It was shown that dtbpy played a crucial role as a promoter in the formation of aliphatic boronic esters 21 from Katritzky salts 1 and B2cat2. Initially, dtbpy was associated with B2cat2 to generate the Lewis base adduct 23A, which would undergo B-B bond cleavage to form bipyridinylidene intermediate 23B. The complexation of intermediate 23B with DMA would lead to the adduct 23C. Subsequently, electron transfer from 23C to Katritzky salts 1 would deliver the alkyl radical. On the other hand, the radical species DMAc-Bcat 23D and dtbpy-Bcat 23E could be generated in situ from the homolytic cleavage of B-N bond of intermediate 23C. Finally, the desired boronic ester 21 was formed through the radical coupling of alkyl radical and DMAc-Bcat 23D.

CF3

CF3 MeO

O

OMe N

N

MeO2C

30% Br

CF3

F3C

N

O

54% CF3 NC

46% (5:1)

O CF3

56%

CF3

49% N

N O

N Ph

N

N

CF3

54%

Scheme 24 Visible light promoted trifluoromethylation of arenes and heterocycles with trifluoroacetic anhydride Later, the same group found that 4-phenylpyridine Noxide 24 was a more efficient activating reagent for the trifluoromethylation of arenes and heteroarenes, resulting in the synthesis of trifluoromethylated products with satisfactory yields. Additionally, the authors also extended this strategy to synthesize pentafluoroethylated and heptafluoropropylated (hetero)arenes using pentafluoropropionic anhydride or heptafluorobutyryl acid anhydride as radical precursors under photoredox


Page 9 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

catalysis (Scheme 25).25 The mechanism for the trifluoromethylation of (hetero)arenes was proposed. Initially, 4-phenylpyridine N-oxide 24 is acylated in the presence of trifluoroacetic anhydride to give the species 25A, which could readily quench the photoexcited catalyst Ru2+* leading to intermediate 25B. Then the fragmentation of intermediate 25B would extrude CO2 and 4phenylpyridine to generate the CF3 radical. Further sequential addition of CF3 radical to arene and the SET oxidation process would give rise to cation 25D, which would then proceed through deprotonation to furnish the desired product 25. Additionally, the authors also assumed that the combination of the acylated pyridine N-oxide derivative with either an additional equivalent of trifluoroacetic anhydride or with a sufficiently electronrich arene substrate to the formation of EDA complexes might be involved in this transformation to deliver the CF3 radical enabled by photoredox catalyst. H +

N

MeCN, 30-35 ºC blue LEDs 13.2 W

O

24

F3C

N Boc

F3C

O

71%

F3C

+

N

O

O F3C

24

O

Ph

O

CF3

O N

Ru3+

O

CF3

25B

PhPyr CO2

CF3 CF3 SET

-H+

CF3

CF3

H

H

O

N

H

25C

25D Ph

Ph N Ph

or

OCOCF3

colored EDA complex

n

N

Boc

CF3 N3

84% F O N

B

83% F CF3 26 F F B CF3

O N Cu(II)

Cu(I)

26A

CO2Me N +

27

F

CO2Me

B O

F

CF3

CF3

R

R

R 26C

26B

N

25A

Ru2+*

25

OH

H N

59% (1.5:1)

-H+

O N

SET

OMe CF3

CF3

O Ph

Ru2+

OMe

OMe

59%

CF3

h

95%

CF3

CF3

O O

O

O O

F3C

62% (11:1)

OMe

R

B

O

73%

Ph

MeO CF3

Cu(I)*

N

N

R3 R2 27 21 examples 59-95% yields R1

MeO

84% (1.5:1)

CF3

MeO

CO2Me

CF3

MeOH

O

Cu(dap)2PF6 (1 mol %) KHCO3 (2.7 equiv)

CF3

OMe

51%

O O

F

MeOH, blue LED, rt, 1 h

26

Bu

B

B

h


F3C

S

+

CF3

59%

79% (mono:bis = 4.6:1)

O N

R2

O

F3C

t

R

3

Het

OMe CF3

F R1

CO2Me

Ru(bpy)3Cl2 (0.1 mol %) TFAA (1.1-4.1 equiv)

Ph

Het

form a new radical 26B, which would undergo SET oxidation by Cu(II) and deprotonation sequence to afford the CF3-containing product 27.

Scheme 26 Photoinduced methoxytrifluoromethylation of alkenes Another impressive example of accessing the CF3 radical from the low-cost and abundant trifluoromethanesulfonic anhydride by merging photoredox catalysis and pyridine activation was achieved by Qing and co-workers (Scheme 27).27 In general, various (hetero)arenes were compatible in this reaction, furnishing the corresponding CF3-containing compounds 28 in good yields. Notably, by employing this strategy, both of the CF3 and OTf groups in trifluoromethanesulfonic anhydride could be simultaneously introduced into internal alkynes, providing a convenient and atom economic approach to tetrasubstituted trifluoromethylated alkenes 29.

OCOCF3

colored EDA complex

R

pyridine Ru(bpy)3Cl2 (2 mol %)

(CF3SO2)2O

+

LEDs, DCE rt, 6 h

X

Scheme 25 Trifluoromethylation of (hetero)arenes using 4-phenylpyridine N-oxide as activating reagent In 2018, Dilman and co-workers showed that the CF3 radical could be generated from CF3-substituted borate complexes bearing a pyridine-N-oxide ligand to establish the methoxytrifluoromethylation of alkenes (Scheme 26).26 In the presence of Cu(I) photocatalyst under visible light, the cleavage of C-B bond was occurred via a single electron reduction. On the basis of CV measurements and radical trapping studies, a possible mechanism involving the formation of CF3 radical by SET reduction between light activated Cu(I) catalyst and the complex 26 was proposed. Subsequently, the CF3 radical would attack to the alkene to

R +

Ar

O

CF3

O

LEDs, DCE rt, 12 h

61%

B O

R 29 10 examples 35-75% yields HO2C

75% (mono:bis = 5:1)

TfO 75% (E/Z = 90:10)

CF3

O

CF3

CF3 72%

CF3

CF3

CF3


Ar TfO

O B

Cl

X 28 23 examples 43-86% yields

pyridine Ru(bpy)3Cl2 (2 mol %)

(CF3SO2)2O

OMe

CF3 R

TfO

Cl

53% (E/Z = 95:5)

TfO

CO2Me

57% (E/Z = 83:17)

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 27 Photoredox-catalyzed trifluoromethylation of (hetero)arenes and internal alkynes According to the proposed mechanism shown in Scheme 28, pyridinium complex 28A was initially formed in situ from the reaction of Tf2O and pyridine. The fluorescencequenching experiments demonstrated that photoexcited Ru2+* was quenched by complex 28A to give Ru3+ and radical species 28B via a single electron reduction. After that, the fragmentation of radical 28B would generate the electrophilic CF3 radical with the release of pyridine and SO2. Addition of the CF3 radical to arene would give rise to intermediate 28C, which would readily convert into the desired product 28 through a single electron oxidation by Ru3+ and deprotonation. Similarly, the CF3 radical would add to the internal alkyne leading to vinyl radical intermediate 28E. Followed by a single electron oxidation would produce vinylic cation 28F. Finally, vinylic cation 28F would react with OTf anion to afford the corresponding tetrasubstituted trifluoromethylated alkene 29. + N

Ar

O O O O S S F3C O CF3

N

S O O

Ru2+* h

CF3

SET

Ru2+

Ru3+

N CF3 S 28B O O

R 28 -H+

alkyne

CF3 SET CF3

CF3 X 28D

N R3

PG N

N 31 R3 (PG =Tos, Boc) 20 examples 31-96% yields

R Ru2+ Ru3+ CF3

Ar

R1

N N

Ar Ru(bpy)3Cl2 (5 mol %) MeCN, 40 ºC 32 blue LEDs 12 examples

R2

30

46-89% yields

O N

X

R

X 28C

Scheme 28 Proposed mechanism for the trifluoromethylation of (hetero)arenes and internal alkynes 3. Pyridinium Salts as Nitrogen Radical Precursors In the past few years, N-centered radicals have received considerable attention in synthetic chemistry owing to their higher reactivity. Consequently, continuous efforts have been devoted to the development of functionalized pyridinium salts as precursors for generating N-centered radicals under photoredox catalysis. In 2015, Studer and coworkers found that the readily prepared Naminopyridinium salts 30 could be served as the sources of amidyl radicals via single electron reduction using Ru(bpy)3Cl2 as the photocatalyst (Scheme 29).28 The resulting amidyl radicals could be used for the direct radical C−H amination of heteroarenes and arenes without any additives. The mechanism for this transformation was proposed as follows: pyridinium salt 30 would undergo a single electron reduction with photoexcited Ru2+* and fragmentation to provide pyridine and the sulfonamidyl radical. Subsequently, the regioselective addition of sulfonamidyl radical to the α-position of N-methylindole would afford a new radical 29A, and the following single

NPhth

Ar

BF4

Ru(bpy)3Cl2 (5 mol %) MeCN, 40 ºC blue LEDs

N

N

O

Ts

Ts

N

71%

X = O, 46% X = NMe, 68%

BF4 N N 30

NHBoc

CO2Et

Ts

N

N

N

76%

89%

Ru2+ h

Ts SET

+ N

Ts

N

Ru2+

Ru3+ N

SET Ts

29A

CF3

Ar

H

N

N

X

R

R

R

R5

Ts

Ts -H+

N N

N

N

TfO

28F

R4

R5 4

R

28E

R

electron oxidation and deprotonation would generate the desired product 31.

CF3

Py + SO2

CF3 X

28A

TfO 29

Page 10 of 21

29B

31

Scheme 29 Direct radical C−H amidation of heteroarenes and arenes using N-aminopyridinium salts as precursors Later, Akita and co-workers described a photocatalyzed regiospecific aminohydroxylation of olefins to obtain vicinal aminoalcohol derivatives with various functional groups in good yields (Scheme 30).29 During the reaction process, N-protected 1-aminopyridinium salt 33 was both used as an electron acceptor and an amidyl radical precursors under mild reaction conditions with easy handling. On the basis of several controlled experiments, the authors proposed a possible mechanism to clarify the reaction pathway. First, a single electron transfer would occur between excited species Ir(III)* and 1aminopyridinium salt 33 to produce amidyl radical and pyridine. The addition of amidyl radical to the double bond would give rise to a radical intermediate 30A, which would undergo oxidation by the highly oxidizable Ir(IV) species leading to the carbon cation intermediate 30B. Then the intermediate 30B would react with H2O providing the 1,2aminoalcohol product 34.


Page 11 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis N NHTs

fac-Ir(ppy)3 (1 mol %)

R2

+

R3

R1

BF4 33

OH

OH

NHTs

68%

Me

63%

BF4 33 SET

Ir(III)

NHTs + py

Ir(IV)

R2

NHTs

R2

+ H 2O

R2 NHTs

R1

1

R 30A R3

3 30B R

3 34 R

R3

R1

SET OH

NHTs

N NHTs

h

R2

OH

23% (1:1)

*Ir(III)

R1

NHTs

N

Bpin

86%

OH


OH

Ph

NHTs

NHTs AcO

R2 R1

acetone/H2O (9:1), rt, 4 h 425 nm blue LEDs

NHTs

Scheme 30 Visible light-promoted aminohydroxylation of olefins

intermolecular

Furthermore, to address the issue that tosyl group is difficult to remove from the corresponding 2-aminoalcohol scaffolds, the group of Akita also found that N-protected iminopyridinium ylide 35 bearing readily removable protective groups (PG = TFAc, Bz, Boc, Troc or Alloc) was a good substitute to promote the vicinal aminohydroxylation of olefins (Scheme 31).30 The reaction was performed in the presence of Ir photoredox/Sc(OTf)3 catalysis under visible light, furnishing various 1,2aminoalcohol derivatives. The effect of Sc(OTf)3 on the photocatalytic aminohydroxylation was also investigated by means of NMR, CV, and Stern-Volmer plots. The mechanistic studies revealed that the reaction would be initiated with the activation of N-protected iminopyridinium ylides 35 by Sc(OTf)3 for the formation of adduct 31A, followed by SET and fragmentation sequence to generate N-centered radical. The subsequent reaction pathway was similar to their previous work, which involved the addition of N-centered radical to olefin, single electron oxidation and nucleophilic attraction by water. N

N

PG

Sc(OTf)3 (20 mol %) fac-Ir(ppy)3 (1 mol %)

R2

+

R

R1

35

3

R2

OH

H N

N

OH O

Ph

OH

H N

PG R3 36 16 examples 21-85% yields

CF3

O

Ph

O O

CF3

85%

OH

H N

62%

Ph CCl3

N

43% Sc N

Sc N

PG Sc

31A

h

SET

N

Sc N

PG

Ir(IV) N(Sc)PG + py

SET

N 35

31B Ir(III)

O O

54%

*Ir(III)

H N

In 2017, Xu and co-workers reported the first example of visible-light-induced aza-pinacol rearrangement for the synthesis of various cyclobutanimines in moderate to good yields under mild reaction conditions (Scheme 32).31 The reaction tolerated a variety of N-protected 1aminopyridium salts, which served as precursors for generating N-centered radicals. On the basis of the results of fluorescence quenching, Stern−Volmer analyses and TEMPO inhibition experiments, it was postulated that the photoexcited *Ir(III) was quenched by N-protected 1aminopyridinium 38 via SET to give the N-centered radical. The addition of N-centered radical to alkylidenecyclopropanes would produce stabilized radical intermediate 32A, which was oxidized by Ir(IV) to deliver tertiary cation 32B. Finally, 1,2-alkyl migration and deprotonation would enable tertiary cation 32B to afford the desired product 39. R3

O R

R2

1

PG

37

36

R Sc

H 2O

1

R1 N(Sc)PG R3 31D

R

N(Sc)PG

1

R

1

R3

S N O

Ir(ppy)3 (2 mol %) MeCN, rt blue LEDs

R

R1

2

39 27 examples 52-94% yields OMe

NTs

Cl

NTs

CF3

O

O

S N O

F 85%

S N O

89% 87%

71%

N NHSO2Ar 38

*Ir(III)

BF4

h SET

N

+ NHSO2Ar

NSO2Ar Ir(III)

Ir(IV)

R2

R1

39

R1

R2

SET

-H+

37

R2 32A

NHSO2Ar

NSO2Ar

R1

R2 32B

R

NHSO2Ar

Scheme 32 Visible-light-induced rearrangement of alkylidenecyclopropanes

1

R2 32C

aza-pinacol

Later, the same group extended this strategy to the preparation of imidazoline and oxazolidine derivatives using N-protected 1-aminopyridium salts as the Ncentered radical precursors under visible light irradiation (Scheme 33).32 Similar to their previous report,31 the authors presented a plausible mechanism including the formation of N-centered radical, radical addition and formal [3+2] annulation processes.

R2 R1

O H N N S O BF4 38

+

R1

H N

R1

acetone/H2O (9:1) rt, blue LEDs

PG = TFAc, Bz, Boc, Troc or Alloc

Ph

OH

Scheme 31 Dual Ir photoredox/Sc(OTf)3 catalysis introduced aminohydroxylation of olefins with iminopyridinium ylides

R3

R3 31C


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

N NHTs

Me Me O N Ts 1

R Ar

Ir(ppy)2(dtbbpy)PF6 (1 mol %)

33 R1

acetone blue LEDs

2

R 40 11 examples 46-88% yields

BF4 +

Me Me O N Ts

R3 N

Ir(ppy)3 (1 mol %) R1 Ar

R3CN blue LEDs

R2

Ar

Page 12 of 21

Me Me O N Ts

N Ts

R Ar


N N H BF4 42

+

N Ts

Br

60%

49% R1 Ar

R1

NHTs R2 33B

Ar

95%

Me

-H

77% (>20:1) *Ir(III)

N NHTs BF4

R1

SET

Ir(IV)

2

Ir(III)

Ir(IV) Ar

Ir(III)

NHTs 33C

R

SET Ts N

N NHTs h

*Ir(III) 33

+

42

NHTs + py

Ar R

34%

57% (>20:1)

NHTs + py Me

R2

Me

h

R2 33A

Ts N

NC

85%

NHTs

MeCN

R1 N Ar

43 32 examples 23-83% yields Ts N

MeO2C

Bpin

R2

Ar

PG=SO2Ar Ts N

69% (>20:1)

F

K3PO4 (1.5 equiv) CH2Cl2, blue LEDs

Me

N

N Ts

PG N

Ir(ppy)2(dtbbpy)PF6 (1 mol %)

Ts N

Et N

PG

BF4

Ar

43

base R

NHTs

Ar 34B

R

NHTs

Ar 34A

R

Me N R1 Ar

Scheme 34 Photoinduced functionalization of alkenes for the synthesis of substituted aziridines

N Ts R

2

41

Scheme 33 Synthesis of imidazoline and oxazolidine derivatives through photoredox catalyzed radical addition and formal [3+2] annulation Furthermore, by employing the strategy to generate Ncentered radicals from N-protected 1-aminopyridinium salts, Xu and co-workers developed a visible-light-induced alkene functionalization for the synthesis of substituted aziridines (Scheme 34).33 A variety of functional groups were proven to be amenable for this transformation, exhibiting excellent regioselectivity and broad substrate scope. Accordingly, the putative mechanism revealed that the generation of N-centered radicals from N-protected 1aminopyridinium salts was the key to promote the reaction, which would also proceed through radical addition and SET sequence to afford carbon cation intermediate 34B. The formation of aziridine 43 would occur through intramolecular nucleophilic attack and deprotonation in the presence of base.

In 2018, Xu and co-workers disclosed a direct aminofluorination of alkenes towards the synthesis of fluorine-containing compounds 44 by employing commercially available hydrogen fluoride-pyridine as the nucleophilic fluorine source (Scheme 35).34 It was demonstrated that pyridine hydrochloride as the chloride donor was suitable as well for the aminochlorination of alkenes. As before, the readily prepared N-Ts-protected 1aminopyridine salts 33 were chosen as the precursors of Ncentered radicals. Importantly, this method was successfully applied to the efficient synthesis of an LY503430 analogue. As for the possible mechanism, similar to their previous reports, the generation of the N-centered radical would occur through a single electron transfer reduction process. Then, the N-centered radical regioselectively attack the alkene to produce stabilized radical intermediate 35A, which would go through a single electron transfer oxidation by Ir species Ir(IV) or N-Tsprotected 1-aminopyridine salts 33 giving rise to the cationic intermediate 35B. A subsequent reaction of cationic intermediate 35B with hydrogen fluoride-pyridine would provide the final product 44.


Page 13 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis N NHTs pyridine•HCl (1.0 equiv) Ir(ppy)2(dtbbpy)PF6 Cl BF4 (1 mol %) R1 NHTs 1 + Ar R CH2Cl2 R2 blue LEDs 45 Ar R2 4 examples 52-73% yields

pyr•9HF (10 equiv HF) Ir(ppy)2(dtbbpy)PF6 (1 mol %) NHTs R Ar CH2Cl2 R2 blue LEDs 44 20 examples 34-86% yields F

33

1

TsHN F

F

F

NHTs

NHTs

I

Cl NHTs t

F3C 74%

64%

Bu

50% (1.5:1)

73%

N NHTs *Ir(III)

BF4

33

On the basis of some control experiments, a possible mechanism was proposed for this transformation (Scheme 37). First, the pyridinyl radical 37A was generated via a single electron transfer between the photoexcited Ru2+* and pyridinium reagent 46. The fragmentation of radical 37A would result in the formation of pyridinyl radical cation 37B, which would react with arene to produce cyclohexadienyl radical 37C. Further oxidation and deprotonation would give rise to the final N-aryl pyridinium product 47.

h OTf

N OTf 46

SET + NHTs N N

37A

OTf

Ar

h

SET

Ir(III)

Ir(IV)

Ru2+*

Ru2+

Ru3+

SET OTf

F NHTs

Ar

HF

NHTs

Ar

N

44

35B

35A

37B

Ar-H

33

H

NHTs

N NHTs

SET

NHTs

Ar

H

N

HOTf

Ar

Ar

BF4

OTf N

37C

N Ar

37D

47

Scheme 35 Visible light-mediated direct aminofluorination and aminochlorination of styrenes

Scheme 37 Proposed machanism for direct C-H amination of (hetero)arenes

Recently, the group of Togni and Carreira documented that N-sulfonyloxypyridinium reagent 46 could serve as pyridinyl radical cation precursor for the C-H amination of (hetero)arenes, furnishing the corresponding pyridinium salts 47 bearing different functional groups (Scheme 36).35 On the basis of the EPR studies and DFT calculations, it was suggested that the direct C-H amination process involved pyridinyl radical cation as the key intermediate. Additionally, the N-aryl pyridinium products 47 could be further transformed into anilines 48 with piperidine at room temperature for 14 hours. Moreover, the N-arylated piperidines 49 were obtained from the direct hydrogenation of N-aryl pyridinium products in the presence of PtO2.

Almost in the same time, Ritter and co-workers developed a similar approach to prepare primary arylamines 51 by using N-OTf 2-ethylpyridine 50 as the pyridinium radical cation source (Scheme 38).36 The reaction featured a wide substrate scope and gave rise to anilines with structural complexity that could not be readily prepared by other methods.

H +

Ar

N OTf 46

OTf

N

Ru(bpy)3(PF6)2 (2 mol %)

Ar

MeCN, blue LEDs, 1.5 h

OTf

47 18 examples 28-89% yields F F

N

N

OTf

NC OTf

F

57%

N

F

F

76%

Cl

Cl N

N

Cl N

N OTf

Cl 66%

Cl

N

OTf

Me

Cl

N

31%

PtO2 (5 mol %) H2 (1 atm), EtOH, 2 h

OTf N Et OTf

1) Ru(bpy)3(PF6)2 (2 mol %) MeCN, blue LEDs 2) MeCN, 5-15 equiv amine (BuNH2, PrNH2, or piperidine)

NH2 Ar 51 16 examples 37-95% yields

Scheme 38 The generation of a pyridyl radical cation for direct C-H amination of (hetero)arenes Recently, the Ritter group further applied the strategy of generating pyridinium radical cation to access N-aryl-2and 4-pyridones through the direct C-H pyridonation of (hetero)arenes (Scheme 39).37 In this transformation, 2and 4-chloropyridine N-OTf reagents were employed to afford various N-phenyl-chloropyridinium salts, which subsequently subjected to hydrolysis by NaHCO3 or LiOH •H2O in a one-pot sequence, leading to the pyridones in good yields.

OTf

32%

Ar 48

OTf

+

50

NH2

N

47

N

N

piperidine (10 equiv) rt, 14 h

Ar

OTf

60%

H Ar

N Ar 49

Scheme 36 Photoinduced direct C-H amination of (hetero)arenes


ACS Catalysis Cl

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

R1

N OTf OTf 52 1) Ru(bpy)3(PF6)2 (5 mol %) MeCN, 23 W CFL or 2) NaHCO3 or LiOH• H2O

H +

Ar

R1

R1

R1

O

N

N or

Ar 54 16 examples 29-98% yields

OTf Cl N OTf 53

Ar

O 55 2 examples 42-80% yields

O O N

N

Me

92%

Cl

CO2Me

Me

O N

N

S O O

MeO2C

Me

O

Me

N Me

Me

59%

O

98%

80%

Scheme 39 Generation of pyridinyl radical cation for thedirect C-H pyridonation of (hetero)arenes According to the previous reports, a mechanism was proposed, which involved the formation of a pyridinium radical cation 40A by a single electron transfer between 4chloropyridine N-OTf reagent 52 and the excited Ru2+* (Scheme 40). Similarly, the subsequent transformation process included radical addition, single electron transfer oxidation and hydrolysis to provide the corresponding Narylpyridone 54.

Page 14 of 21

mediated intermolecular hydrogen atom transfer (HAT) process (Scheme 41).38 Accordingly, the combination of eosin-Y as a photocatalyst and N-ethoxy-2methylpyridinium 56 as an external oxidant would provide a ground state electron donor-acceptor complex (EDA), affording the corresponding benzo[b]phosphole oxides 57 under metal-free conditions. During the reaction process, the EDA complex played a dual role as the photocatalyst and the formation of the initiating radicals. The plausible mechanism for accessing products 57 involved the generation of ethoxy radical, intermolecular HAT, addition of phosphinoyl radical to alkyne, cyclization, oxidation and deprotonation sequence. R1 R2 R1

+

O R PH + Ph

BF4 N OEt 56

Ph

Ph

Ph P Ph O 78%

Me P Ph O 64%

Et P Ph O 91%

Ru2+* SET

H

40A

Ru

O Ph2PH

Ru2+

3+

N

N

Ar 40C

N Ar 40D

Ph2P R2

Product

P Ph O 41D

[Eosin Y] R2

-H+

56

1 H R

O

R2 41B

P Ph 41C O

R1

EtO + N

Cl

Cl H

EtOH

O R1 Ph2P 41A

SET

Cl

R2 N

N 40B

1 H R

EtO +

h

COOEt P Ph O 76%

56

OTf

N Cl

N OEt Eosin Y

[Eosin Y-56]*

Ar-H

Ph

BF4

Eosin Y-56 Green light

N OTf 52

R2 P R O 57 24 examples 43-91% yields

NaHCO3 (1.2 equiv) DMF, green LEDs

Ph

Cl

Cl

Eosin Y (4 mol %)

Hydrolysis

54

Scheme 41 Ethoxy radical mediated P-H functionalization of phosphine oxides with alkynes

40E

H+

Scheme 40 Proposed mechanism for the direct C-H pyridonation of (hetero)arenes 4. Generation of Alkoxy Radicals from Pyridinium Salts The highly reactive alkoxyl radicals are considered as versatile intermediates that are widely applied in a variety of biological processes and organic transformations. In this case, various precursors including hypohalites, peroxides, nitrites, N-alkoxypyridine-2-thiones, or Nalkoxyphthalimides have been developed for the generation of alkoxyl radicals. However, these reagents usually suffer from several drawbacks such as the inherent toxicity or instability, the use of stoichiometric amounts of radical initiators and the requirement of harsh reaction conditions. To address these issues, considerable progress has been made in the development of readily available and bench stable pyridinium salts to generate alkoxyl radicals enabled by photoinduced single electron reduction in recent years. For example, Lakhdar and co-workers reported the oxidative C-H/P-H functionalization of phosphine oxides with alkynes through ethoxy radical

Subsequently, Hong and co-workers demonstrated a direct phosphonation of quinolinone and coumarin derivatives using N-ethoxy-2-methylpyridinium 56 as the oxidant in the absence of an external photocatalyst (Scheme 42).39a Mechanistic investigation revealed that both starting materials and products could act as photosensitizers, under the irradiation by household CFL bulb, promoting the dissociation of N-O bond in the pyridinium salt via a single electron transfer. The protocol exhibited a broad substrate scope and high functional group tolerance, providing rapid access to 3phosphonylated derivatives 58. Recently, the same group also expanded this strategy to the divergent construction of dihydro- or tetrahydrophenanthridinones, using quinolinone-containing substrates as effective photosensitizer to trigger radical cyclization processes.39b

X

O + Ar PH + O Ar O PPh2

N

O

80%


BF4 N OEt 56 O PPh2

N 70%

O

O PAr2

NaHCO3 (1.2 equiv) 23 W CFL

X 58

O PPh2 Br

F O 74%

O

O

O PPh2 O 68%

O

Page 15 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Scheme 42 Visible light-induced direct phosphonation of quinolinone and coumarin derivatives

Scheme 44 Alkoxyl radical-involved difunctionalization of alkenes under visible light irradiation

Furthermore, the group of Lakhdar described a visiblelight induced α-phosphorylation of N-aryl tertiary amines with phosphine oxides under mild, catalyst-free conditions (Scheme 43).40 Preliminary mechanistic studies, including spectrophotometry, NMR spectroscopy and EPR spectroscopy, showed that the formation of EDA complexes between N-aryl tertiary amines and N-ethoxy2-methylpyridinium tetrafluoroborate 56 was the key to the success of the reaction.

Recently, more and more studies have shown that the alkoxyl radical-mediated direct functionalization of unactivated remote C(sp3)-H bonds via 1,5-hydrogen atom transfer (1,5-HAT) provides a elegant access to C-C or C-X bond formation. For instance, Hong and co-workers developed a visible-light-induced site-selective heteroarylation of remote C(sp3)-H bonds using 3phosphonated quinolones as the photoredox catalysts under metal-free conditions (Scheme 45).42 In this transformation, the designed N-alkoxyheteroarenium salts 63 played a dual role as both alkoxy radical precursors and heteroaryl sources. The reaction was suitable for a variety of functionalized pyridinium salts, giving rise to the corresponding 4-heteroaryl alcohol products 64. Notably, the synthetic applicability of the process was also demonstrated through late-functionalization of complex molecules.

N

H

BF4

O + R1 P H +

R

N OEt 56

R2

O P Ph Ph

N

N

85%

DMF 5 W blue LEDs

O P Ph Ph

N

Br

87%

O P R2 R1

N

NaHCO3 (1.2 equiv) R

59

O P Ph Ph

O P Ph Ph

N

71%

76%

Scheme 43 Visible light-induced α-phosphorylation of Naryl tertiary amines with phosphine oxides In 2018, Dagousset and co-workers presented the regioselective difunctionalization of alkenes using Nalkoxypyridinium salts 60 as precursors of alkoxyl radicals under photoredox catalysis (Scheme 44).41 The reaction proceeded smoothly in an anti-Markovnikov fashion, furnishing a variety of functionalized alkyl alkyl ethers 61 or 62 via hydroxyalkoxylation, dialkoxylation, or aminoalkoxylation process. Additionally, both batch and flow conditions were suitable for this transformation, showing high functional group tolerance. According to the proposed mechanism, the photoexcited Ir(III)* was quenched by N-alkoxypyridinium salt 60 to produce the alkoxyl radical. Then, the addition of alkoxyl radical to the double bond would result in a more stable radical 44A, which would undergo a single electron transfer oxidation by Ir(IV) to give the carbocation 44B. Finally, the carbocation 44B would be trapped by either water, alcohol, or acetonitrile to afford the desired ether 61 or 62. R1 + BF4

NC N

Acetone/R2OH or MeCN blue LEDs

NHAc OR

OR2

fac-Ir(ppy)3 (1 mol %) NaH2PO4 2H2O (1.0 equiv)

OR R1

or R1 62 47 examples 43-83% yields

61

OR

60 OH

Ph

OH

OMe

Ph

NHAc OMe

OMe

OEt

OMe t

F 82%

74%

R1 SET

60

OR

R1

N

Nu OR 44B

R1

R1 R1

CH3CN, rt, blue LEDs

R1 HO

O P Ph Ph

MeO N

3

R R2 64 40 examples 46-95% yields

O

PC N

HO

N

HO 92%

N

HO 90%

N

Ph

HO 81%

95%

Scheme 45 Alkoxyl radical-mediated heteroarylation of unactivated remote C(sp3)-H bonds On the basis of the experimental and computational results, a possible mechanism was proposed as shown Scheme 46. The alkoxyl radical intermediate 46A was firstly generated from the N-alkoxyheteroarenium salt 63 via a single electron transfer reduction by excited PC*, which was followed an intramolecular 1,5-HAT process to give the alkyl radical 46B. Nucleophilic addition of alkyl radical 46B to the pyridinium salt 63 would afford the radical cation 46C with excellent regioselectivity. Subsequently, radical cation 46C would go through a single electron transfer oxidation and deprotonation to furnish the carbon cation intermediate 46D, which would further undergo the same catalytic cycle to deliver the final product 64. Additionally, the measurement experiment of quantum yield respect to the model reactions revealed that a radical-chain pathway might be involved as well.

OR 61 or 62

Ir(IV) RO

PC (2.5 mol %) NaHCO3 (1.2 equiv)

R3

63

SET

BF4

O OTs

Nu

Ir(III)* N

63%

Ir(III)

h

NC

Bu

66%

N R2

OR 44A


ACS Catalysis R2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

R

N

1

O

PC*

63

OTs

PC

R3

1,5-HAT

N

R1 R2

R3

HO 46D

OR N

OR

HO

OTs

65

PC*

R3 R2

OR

RO

R2

O

R3

46A

R

2R

N

R1

R2 R3

R1 RO

48B O

N

Chain Pathway

64

PC

48A

R

+ RO R2

O

R2 R3 H 48C

R

3

O

-H+ 66

R2

O

3

66

48D OR

OR

PC*

O

N

PC

R3

48A

R2 R3

R1

PC SET

O

PC + RO

R3 R2 46C

-H+

H O

h

SET

Chain Pathway 1,5-HAT

PC*

R3

R2 R1

H

R1

R2

O

N

R1

64

SET

R2 46A

HO

OR N

PC

SET

H O

46B

h

R3

Page 16 of 21

3

Scheme 46 Proposed mechanism for the site-selective heteroarylation of unactivated remote C(sp3)-H bonds

Scheme 48 Proposed mechanism for the cascade radical reaction

After that, the same group further disclosed a visiblelight-enabled cascade radical ring-closure and pyridinylation for the synthesis of functionalized tetrahydrofurans 66 (Scheme 47).43 A new class of Nalkenyloxypyridinium salts 65 were well designed and successfully synthesized, and served as both alkoxy radical precursors and heteroaryl sources. This protocol exhibited a broad substrate scope and good functional group tolerance, affording various pyridine-tethered tetrahydrofurans 66 in good to excellent yields. It was also demonstrated that pyridinium salts bearing diene chains were feasible for the photocatalytic radical cascade reaction, which provided a rapid access for the construction of synthetically important bicyclic oxaspiro rings.

In 2019, Zhu and co-workers reported a remote C(sp3)-H functionalization of alcohols in the presence of dual photoredox/copper catalysis (Scheme 49).44 By employing N-alkoxypyridinium salts 67 and readily available silyl reagents (TMSN3, TMSCN, TMSNCS) as the substrates, this method enabled the synthesis of δ-azido, δ-cyano, and δthiocyanato alcohols 68 in high yields. Moreover, it was demonstrated the first example of catalytic enantioselective δ-C(sp3)-H cyanation involving a 1,5-HAT process. According to the proposed mechanism, the alkoxyl radical 49A was firstly generated through the reduction of N-alkoxypyridinium salt 67 by excited Ir(III)*, which would undergo 1,5-HAT to give the C-centered radical 49B. On the other hand, the Cu(I) salt in the presence of TMSX was oxidized by Ir(IV) to afford Cu(II)XOAc with the release of Ir(III) species. The combination of the C-centered radical 49B with Cu(II)XOAc would lead to Cu(III) species 49C, which would go through reductive elimination to afford the final δ-C(sp3)-H functionalized product 68 (route a). Additionally, a Cu-centered redox ligand transfer process could also occur between radical 49B and Cu(II)XOAc, giving rise to product 68 (route b).

R1

N

PC (2.5 mol %) NaHCO3 (1.2 equiv)

R2

O

CH3CN, rt, blue LEDs

R3

OTs 65

O P Ph Ph

MeO N

R1

R2 R3 O

N


O

PC

N

O

O

N

N

Ph 77%

73%

72%

O

O

N Ph

BF4

63%

Scheme 47 Visible light-promoted cascade radical ringclosure and pyridinylation of N-alkenyloxypyridinium salts The mechanism for the formation of product 66 was proposed as follows: the N-O bond cleavage of Nalkoxypyridinium salt 65 would provide alkoxyl radical intermediate 48A via a single electron transfer reduction, which would go through 5-exo-trig radical cyclization to afford radical 48B. Then, nucleophilic addition of radical 48B to the pyridinyl group of 65 would result in the formation of radical cation intermediate 48C, followed by deprotonation and another N-O bond cleavage to furnish the final product 66. A radical-chain pathway was also proposed to be involved in the reaction according to the measurement of quantum yield (Scheme 48).

R2

O

N

R3 R1

+ TMSX

X = N3, CN, SCN

67 N3

CuOAc (20 mol %) 1,10-Phen (30 mol %) fac-Ir(ppy)3 (2 mol %) CH3CN, rt blue LEDs

R3 R2

R1


SCN

CN

CN OH Cl

X HO

OH

OH

OH Me

72%

78%

83%

56% X HO

TMSX Ir(III)

h

BF4

HO

R2

O

R1 R3

R1

68

route a

Ir(III)*

N

R1

Cu(I)OAc

R3 R2

Ir(IV) Cu(II)XOAc

67 H O R1 49A

R3 R2

1,5-HAT

Cu(III)X(OAc) R3 49C R2

route b

HO R1 49B

68 + Cu(I)OAc

R3 R2

Scheme 49 Dual photoredox/copper catalyst promoted remote C(sp3)-H functionalization of alcohols


Page 17 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Recently, the group of Hong successfully demonstrated a visible light-induced site-selective functionalization of pyridinium derivatives 69 for the synthesis of C4phosphonated 70 or C2-carbamoylated products 71 (Scheme 50).45 Under mild, metal-free conditions, phosphinoyl and carbamoyl radicals were generated in situ by using 3-phosphonated quinolinone as the photocatalyst. Interestingly, the regioselectivity for the functionalization of pyridines could be easily controlled by the switch of radical coupling sources. The result showed that phosphinoyl radicals provided C4 products and carbamoyl radicals gave rise to C2 products. This protocol featured a broad substrate scope and could be further applied to the late-stage site-selective functionalization of bisacodyl, vismodegib, and pyriproxyfen. On the basis of the experimental and computational outcomes, a possible mechanism was proposed for this transformation. Firstly, the excited state PC* would undergo reductive quenching by N-ethoxypyridinium derivative 69 to produce the ethoxy radical, which would gom through an intermolecular HAT with phosphine oxide and formamide to produce the corresponding phosphinoyl and carbamoyl radicals (50A), respectively. The subsequent pathway for accessing the final product was similar to the previous reports as described by the same group, involving radical addition, deprotonation, and N-O bond cleavage sequence.

H

PC (1 mol %) K2S2O8 (1.5 equiv) NaHCO3 (1.2 equiv)

R H N BF4 OEt 69

O P Ph Ph N

H

P

R1 R1

R N 70 23 examples 41-81% yields

O

blue LEDs

MeO

O

O 1 H P R R1

NR2

R

NR2

N

71 O 23 examples 38-79% yields

O

PC

PC* R N OEt 69

SET

R

O XH

PC EtO

X O N OEt 50C

69

N

X O

H2CO3

HAT

O X = PAr2, C-NMe2 X 50A

R EtO

HCO3 R N OEt

X O

50B

Scheme 50 Visible light-induced C2 and C4-selective functonalization of pyridinium derivatives 5. Miscellaneous

broad substrate scope compatibility, high regioselectivity, and operational simplicity. Similarly, the pyridinium complex, which came from acylation of pyridine N-oxide and chlorodifluoroacetic anhydride, would enable the generation of chlorodifluoromethyl radical under visible light irradiation. Additionally, the synthetic utility of this method was further demonstrated through the conversion of CF2Cl moiety into the corresponding aryl esters, gemdifluoroenones, and β-keto-esters.

Ar

+ O

N

Cl

O

F

72 >18 examples 25-84% yields

R

O

F

Ar

MeCN, rt, 16 h blue LEDs 13.2 W

R = H or Ph N O

F F

O CF2Cl redox active complex

t

Cl

Cl

Bu

F

O

F

42%

S Cl

F F O

70%

O

O Cl

N Br 40%

N B O O

F F O

62%

O

F

71% N B O O

F F

F

Cl

F F

OMe

O

Me Cl

N Boc

O

69%

Scheme 51 Photoinduced chlorodifluoromethylation of (hetero)arenes

radical

The photoredox-enabled direct C-H aroyloxylation of (hetero)arenes to access phenol derivatives was achieved by Akita and co-workers (Scheme 52).47 By combination of photoredox catalysis and N-3,5bis(trifluoromethyl)phenylcarbonyloxylutidinium salts 73, O-centered aroyloxy radicals were generated under mild conditions without the use of explosive peroxides. As disclosed by their previous work, the mechanism for the outcome involved single electron transfer, radical addition and deprotonation. In situ generated O-centered aroyloxy radicals, from photoexcited species and aroyloxylutidinium salt 73 via a single electron transfer reduction, would trigger the addition of (hetero)arenes. The subsequent oxidation and deprotonation would afford the product 74. Me

ArF

O

N

[Ir(dtbpy)(ppy)2](PF6) (2.0 mol %)

H

O

+

Ar

Me OTf 73 ArF = 3,5-bis(trifluoromethyl)phenyl Me

Contrary to the well developed methodologies for the synthesis of trifluoromethylated compounds, procedures for introducing the difluoromethylene functionality (CF2X) into small molecules are less established. To this end, inspired by their achievement with trifluoromethylation and alkylation, Stephenson and co-workers accomplished the radical chlorodifluoromethylation of (hetero)arenes using commercially available chlorodifluoroacetic anhydride as radical precursors (Scheme 51).46 The reaction worked well in both batch and flow process to provide electron-rich difluoromethylated (hetero)arenes, showing

Cl

Ru(bpy)3Cl2 (1 mol %) (COCF2Cl)2O (1.1-4.1 equiv)

R

ArF

O O Me

Me

ArF

O

Br

52%

O 89%

ArF

O

ArF

O

O

55%

S

ArF

O O

O

O 78% (3:1)

93%

OMe ArF

O

ArF

O

O


OMe

OMe

ArF

O Ar

DCM, blue LEDs rt, 12 h

TMS 52%

45%

ArF

O

O

O 22%

Scheme 52 Direct C-H aroyloxylation of (hetero)arenes enabled by photoredox catalysis


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The installation of trifluoromethoxy (OCF3) group into organic molecules plays a vital role in medicinal chemistry and drug discovery processes. As a consequence, the development of efficient synthetic methodologies to furnish trifluoromethoxylated compounds has attracted significant attention during the past few years. In 2018, Togni and co-workers designed and developed a benchstable and highly electrophilic N-O pyridinium reagent 75 as the source of trifluoromethoxyl radical through a single electron reduction in the presence of photocatalyst under visible light (Scheme 53).48 Moreover, this reactive species could be applied to the direct trifluoromethoxylation of various arenes, giving rise to the corresponding aryl trifluoromethyl ethers 76 in moderate to good yields. The reaction was proposed to occur through an aromatic homolytic substitution pathway. On the basis of the results of photo-induced EPR spectroscopy, control experiments, UV/Vis spectroscopy, kinetic isotope experiments, singlecrystal X-ray diffraction, and DFT calculations, it showed that the reaction was initiated by the excitation of Ru(II) under blue light irradiation. Then, the excited Ru(II)* was quenched by the pyridinium-based trifluoromethoxylating reagent 75 via a single electron transfer reduction to afford radical 53A. The subsequent fragmentation would give rise to trifluoromethoxyl radical and neutral pyridine. The trifluoromethoxyl radical would further go through addition to arene, leading to intermediate 53B. Then intermediate 53B would proceed through a single electron transfer oxidation by Ru(III) and deprotonation, giving rise to the trifluoromethoxylated product 76. OCF3 N

H Ar

+

NTf2

OCF3

[Ru(bpy3)](PF6)2 (5 mol %)

F

F3CO

OCF3

The authors declare no competing financial interests.

OH

OCF3

54% (o/m/p = 2.2/1.0/1.7)

52% (o/m/p = 1.0/1.3/1.3)

O NH2 S O t

Notes

O

TfO

47% (o/m/p = 2.4/2.5/1.0) H N

O P

ACKNOWLEDGMENT

O

Financial support from the National Natural Science Foundation of China (No. 21672037 and 21532001) is gratefully acknowledged.

NH

Bu

OCF3 OCF3

31% (o/m = 1.0/1.6)

66% (o/m/p = 1.0/4.0/1.9)

O F3CO 40% (o/m/p = 1.0/2.5/3.7)

OCF3 N

CN 75 Ru(II)*

REFERENCES F3C

O N

h OCF3

53A CN N

Ru(III)

Ru(II) 76

= Py

PyH+ Py

OCF3

F3CO H

CN

F3CO H C 6H 6 53C

53B

Scheme 53 Photoredox catalyzed trifluoromethoxylation of arenes 6. Conclusion and outlook

AUTHOR INFORMATION [email protected]


CN 75

The presented review summarizes the recent advances in the chemistry of pyridinium salts as radical precursors. In general, a variety of readily available N-functionalized pyridinium salts have been developed as versatile radical sources, including alkyl radicals, trifluoromethyl radical, N-centred radicals, O-centred radicals as well as other ralated radicals. The approaches employing pyridinium salts are promising for the formation of C-C and C-X bonds through radical process. Usually, the reactions involving pyridinium salts can be performed under transition metal catalysis or photocatalyst for the generation of the corresponding radicals. In some cases, the EDA complex is formed in situ under visible light irradiation without the need of photocatalyst to facilitate the reaction. The transformations usually tolerate a broad reaction scope and good functional group under mild conditions. Notably, the first example of catalytic asymmetric remote C(sp3)-H cyanation using pyridinium salts as the alkoxyl radical source has been achieved recently. Despite the remarkable advances in the radical chemistry of pyridinium salts, there are some challenges which still need to be explored. It is anticipated that the asymmetric transformation of functionalized pyridinium salts for the synthesis of optically pure compounds will be developed in the near future, since only one example has been reported so far. Furthermore, owing to its great potential in synthetic community, it is believed that the derivatization of pyridinium salts through radical processes will be continuously appeared.

Corresponding Author

Ar

MeCN (0.035 M) blue LEDs, 1 h

Page 18 of 21

direct

C-H

(1) Sowmiah, S.; Esperança, J. M. S. S.; Rebelo, L. P. N.; Afonso, C. A. M. Pyridinium Salts: from Synthesis to Reactivity and Applications. Org. Chem. Front. 2018, 5, 453-493. (2) Nolsøe, J. M. J.; Aursnes, M.; Tungen, J. E.; Hansen, T. V. Dienals Derived from Pyridinium Salts and Their Subsequent Application in Natural Product Synthesis. J. Org. Chem. 2015, 80, 5377-5385. (3) (a) Bapat, J. B.; Blade, R. J.; Boulton, A. J.; Epsztajn, J.; Katritzky, A. R.; Lewis, J.; Molina-Buendia, P.; Nie, P.-L.; Ramsden, C. A. Pyridines as Leaving Groups in Synthetic Transformations: Nucleophilic Displacements of Amino Groups, and Novel Preparations of Nitriles and Isocyanates. Tetrahedron Lett. 1976, 17, 2691-2694; (b) Katritzky, A. R.; De Ville, G.; Patel, R. C. CarbonAlkylation of Simple Nitronate Anions by N-substituted Pyridiniums. Tetrahedron 1981, 37, 25-30; (c) Katritzky, A. R.; Marson, C. M. Pyrylium Mediated Transformations of Primary Amino Groups into Other Functional Groups. New Synthetic Methods (41). Angew. Chem., Int. Ed. Engl 1984, 23, 420-429.


Page 19 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

(4) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C–N Bond Activation. J. Am. Chem. Soc. 2017, 139, 5313-5316. (5) (a) Liao, J.; Guan, W.; Boscoe, B. P.; Tucker, J. W.; Tomlin, J. W.; Garnsey, M. R.; Watson, M. P. Transforming Benzylic Amines into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts via C–N Bond Activation. Org. Lett. 2018, 20, 3030-3033; (b) Guan, W.; Liao, J.; Watson, M. P. Vinylation of Benzylic Amines via C–N Bond Functionalization of Benzylic Pyridinium Salts. Synthesis 2018, 50, 3231-3237. (6) Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy for the Visible-Light-Mediated Generation of Alkyl Radicals. Angew. Chem., Int. Ed. 2017, 56, 12336-12339. (7) Ociepa, M.; Turkowska, J.; Gryko, D. Redox-Activated Amines in C(sp3)–C(sp) and C(sp3)–C(sp2) Bond Formation Enabled by Metal-Free Photoredox Catalysis. ACS Catal. 2018, 8, 11362-11367. (8) Zhang, M.-M.; Liu, F. Visible-Light-Mediated Allylation of Alkyl Radicals with Allylic Sulfones via a Deaminative Strategy. Org. Chem. Front. 2018, 5, 3443-3446. (9) Zhu, Z.-F.; Zhang, M.-M.; Liu, F. Radical Alkylation of Isocyanides with Amino Acid-/Peptide-Derived Katritzky Salts via Photoredox Catalysis. Org. Biomol. Chem. 2019, 17, 1531-1534. (10) Wu, J.; Grant, P. S.; Li, X.; Noble, A.; Aggarwal, V. K. CatalystFree Deaminative Functionalizations of Primary Amines by Photoinduced Single-Electron Transfer. Angew. Chem., Int. Ed. 2019, 58, 5697-5701. (11) James, M. J.; Strieth-Kalthoff, F.; Sandfort, F.; Klauck, F. J. R.; Wagener, F.; Glorius, F. Visible-Light-Mediated Charge Transfer Enables C−C Bond Formation with Traceless Acceptor Groups. Chem. - Eur. J. 2019, 25, 8240-8244. (12) Klauck, F. J. R.; Yoon, H.; James, M. J.; Lautens, M.; Glorius, F. Visible-Light-Mediated Deaminative Three-Component Dicarbofunctionalization of Styrenes with Benzylic Radicals. ACS Catal. 2019, 9, 236-241. (13) Jiang, X.; Zhang, M.-M.; Xiong, W.; Lu, L.-Q.; Xiao, W.-J. Deaminative (Carbonylative) Alkyl-Heck-type Reactions Enabled by Photocatalytic C−N Bond Activation. Angew. Chem., Int. Ed. 2019, 58, 2402-2406. (14) Yang, Z.-K.; Xu, N.-X.; Wang, C.; Uchiyama, M. Photoinduced C(sp3)−N Bond Cleavage Leading to the Stereoselective Syntheses of Alkenes. Chem. - Eur. J. 2019, 25, 5433-5439. (15) Fu, M.-C.; Shang, R.; Zhao, B.; Wang, B.; Fu, Y. Photocatalytic Decarboxylative Alkylations Mediated by Triphenylphosphine and Sodium Iodide. Science 2019, 363, 1429. (16) (a) Liao, J.; Basch, C. H.; Hoerrner, M. E.; Talley, M. R.; Boscoe, B. P.; Tucker, J. W.; Garnsey, M. R.; Watson, M. P. Deaminative Reductive Cross-Electrophile Couplings of Alkylpyridinium Salts and Aryl Bromides. Org. Lett. 2019, 21, 2941-2946; (b) MartinMontero, R.; Yatham, V. R.; Yin, H.; Davies, J.; Martin, R. Nicatalyzed Reductive Deaminative Arylation at sp3 Carbon Centers. Org. Lett. 2019, 21, 2947-2951. (17) Yue, H.; Zhu, C.; Shen, L.; Geng, Q.; Hock, K. J.; Yuan, T.; Cavallo, L.; Rueping, M. Nickel-Catalyzed C–N Bond Activation: Activated Primary Amines as Alkylating Reagents in Reductive Cross-Coupling. Chem. Sci. 2019, 10, 4430-4435. (18) Ni, S.; Li, C.; Mao, Y.; Pan, Y.; Han, J. Ni-Catalyzed Deaminative Cross-Electrophile Coupling of Katritzky Salts with Halides via C-N Bond Activation. Sci. Adv. 2019, 5, eaaw9516. (19) Yi, J.; Badir, S. O.; Kammer, L. M.; Ribagorda, M.; Molander, G. A. Deaminative Reductive Arylation Enabled by Nickel/Photoredox Dual Catalysis. Org. Lett. 2019, 21, 3346-3351. (20) Plunkett, S.; Basch, C. H.; Santana, S. O.; Watson, M. P. Harnessing Alkylpyridinium Salts as Electrophiles in Deaminative Alkyl–Alkyl Cross-Couplings. J. Am. Chem. Soc. 2019, 141, 22572262.

(21) Sun, A. C.; McClain, E. J.; Beatty, J. W.; Stephenson, C. R. J. Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles. Org. Lett. 2018, 20, 34873490. (22) (a) Wu, J.; He, L.; Noble, A.; Aggarwal, V. K. Photoinduced Deaminative Borylation of Alkylamines. J. Am. Chem. Soc. 2018, 140, 10700-10704; (b) Sandfort, F.; Strieth-Kalthoff, F.; Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Borylation of Aliphatic Amines Enabled by Visible Light Excitation of an Electron Donor– Acceptor Complex. Chem. - Eur. J. 2018, 24, 17210-17214. (23) Hu, J.; Wang, G.; Li, S.; Shi, Z. Selective C−N Borylation of Alkyl Amines Promoted by Lewis Base. Angew. Chem., Int. Ed. 2018, 57, 15227-15231. (24) Beatty, J. W.; Douglas, J. J.; Cole, K. P.; Stephenson, C. R. J. A Scalable and Operationally Simple Radical Trifluoromethylation. Nat. Commun. 2015, 6, 7919. (25) Beatty, J. W.; Douglas, J. J.; Miller, R.; McAtee, R. C.; Cole, K. P.; Stephenson, C. R. J. Photochemical Perfluoroalkylation with Pyridine N-Oxides: Mechanistic Insights and Performance on a Kilogram Scale. Chem 2016, 1, 456-472. (26) Smirnov, V. O.; Maslov, A. S.; Kokorekin, V. A.; Korlyukov, A. A.; Dilman, A. D. Photoredox Generation of the Trifluoromethyl Radical from Borate Complexes via Single Electron Reduction. Chem. Commun. 2018, 54, 2236-2239. (27) Ouyang, Y.; Xu, X.-H.; Qing, F.-L. Trifluoromethanesulfonic Anhydride as a Low-Cost and Versatile Trifluoromethylation Reagent. Angew. Chem., Int. Ed. 2018, 57, 6926-6929. (28) Greulich, T. W.; Daniliuc, C. G.; Studer, A. NAminopyridinium Salts as Precursors for N-Centered Radicals – Direct Amidation of Arenes and Heteroarenes. Org. Lett. 2015, 17, 254-257. (29) Miyazawa, K.; Koike, T.; Akita, M. Regiospecific Intermolecular Aminohydroxylation of Olefins by Photoredox Catalysis. Chem. - Eur. J. 2015, 21, 11677-11680. (30) Miyazawa, K.; Koike, T.; Akita, M. Aminohydroxylation of Olefins with Iminopyridinium Ylides by Dual Ir Photocatalysis and Sc(OTf)3 Catalysis. Tetrahedron 2016, 72, 7813-7820. (31) Liu, W.-D.; Xu, G.-Q.; Hu, X.-Q.; Xu, P.-F. Visible-LightInduced Aza-Pinacol Rearrangement: Ring Expansion of Alkylidenecyclopropanes. Org. Lett. 2017, 19, 6288-6291. (32) Chen, J.-Q.; Yu, W.-L.; Wei, Y.-L.; Li, T.-H.; Xu, P.-F. Photoredox-Induced Functionalization of Alkenes for the Synthesis of Substituted Imidazolines and Oxazolidines. J. Org. Chem. 2017, 82, 243-249. (33) Yu, W.-L.; Chen, J.-Q.; Wei, Y.-L.; Wang, Z.-Y.; Xu, P.-F. Alkene Functionalization for the Stereospecific Synthesis of Substituted Aziridines by Visible-Light Photoredox Catalysis. Chem. Commun. 2018, 54, 1948-1951. (34) Mo, J.-N.; Yu, W.-L.; Chen, J.-Q.; Hu, X.-Q.; Xu, P.-F. Regiospecific Three-Component Aminofluorination of Olefins via Photoredox Catalysis. Org. Lett. 2018, 20, 4471-4474. (35) Rössler, S. L.; Jelier, B. J.; Tripet, P. F.; Shemet, A.; Jeschke, G.; Togni, A.; Carreira, E. M. Pyridyl Radical Cation for C−H Amination of Arenes. Angew. Chem., Int. Ed. 2019, 58, 526-531. (36) Ham, W. S.; Hillenbrand, J.; Jacq, J.; Genicot, C.; Ritter, T. Divergent Late-Stage (Hetero)aryl C−H Amination by the Pyridinium Radical Cation. Angew. Chem., Int. Ed. 2019, 58, 532536. (37) Hillenbrand, J.; Ham, W. S.; Ritter, T. C–H Pyridonation of (Hetero-)Arenes by Pyridinium Radical Cations. Org. Lett. 2019, 21, 5363-5367. (38) Quint, V.; Morlet-Savary, F.; Lohier, J.-F.; Lalevée, J.; Gaumont, A.-C.; Lakhdar, S. Metal-Free, Visible LightPhotocatalyzed Synthesis of Benzo[b]phosphole Oxides: Synthetic and Mechanistic Investigations. J. Am. Chem. Soc. 2016, 138, 7436-7441.


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(39) (a) Kim, I.; Min, M.; Kang, D.; Kim, K.; Hong, S. Direct Phosphonation of Quinolinones and Coumarins Driven by the Photochemical Activity of Substrates and Products. Org. Lett. 2017, 19, 1394-1397; (b) Kim, K.; Choi, H.; Kang, D.; Hong, S. Visible-Light Excitation of Quinolinone-Containing Substrates Enables Divergent Radical Cyclizations. Org. Lett. 2019, 21, 34173421. (40) Quint, V.; Chouchène, N.; Askri, M.; Lalevée, J.; Gaumont, A.C.; Lakhdar, S. Visible-Light-Mediated α-Phosphorylation of Naryl Tertiary Amines through the Formation of Electron-Donor– Acceptor Complexes: Synthetic and Mechanistic Studies. Org. Chem. Front. 2019, 6, 41-44. (41) Barthelemy, A.-L.; Tuccio, B.; Magnier, E.; Dagousset, G. Alkoxyl Radicals Generated under Photoredox Catalysis: A Strategy for anti-Markovnikov Alkoxylation Reactions. Angew. Chem., Int. Ed. 2018, 57, 13790-13794. (42) Kim, I.; Park, B.; Kang, G.; Kim, J.; Jung, H.; Lee, H.; Baik, M.H.; Hong, S. Visible-Light-Induced Pyridylation of Remote C(sp3)−H Bonds by Radical Translocation of N-Alkoxypyridinium Salts. Angew. Chem., Int. Ed. 2018, 57, 15517-15522.

Page 20 of 21

(43) Kim, Y.; Lee, K.; Mathi, G. R.; Kim, I.; Hong, S. Visible-LightInduced Cascade Radical Ring-Closure and Pyridylation for the Synthesis of Tetrahydrofurans. Green Chem. 2019, 21, 2082-2087. (44) Bao, X.; Wang, Q.; Zhu, J. Dual Photoredox/Copper Catalysis for the Remote C(sp3)−H Functionalization of Alcohols and Alkyl Halides by N-Alkoxypyridinium Salts. Angew. Chem., Int. Ed. 2019, 58, 2139-2143. (45) Kim, I.; Kang, G.; Lee, K.; Park, B.; Kang, D.; Jung, H.; He, Y.T.; Baik, M.-H.; Hong, S. Site-Selective Functionalization of Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with Quinolinone. J. Am. Chem. Soc. 2019, 141, 9239-9248. (46) McAtee, R. C.; Beatty, J. W.; McAtee, C. C.; Stephenson, C. R. J. Radical Chlorodifluoromethylation: Providing a Motif for (Hetero)arene Diversification. Org. Lett. 2018, 20, 3491-3495. (47) Miyazawa, K.; Ochi, R.; Koike, T.; Akita, M. Photoredox Radical C–H Oxygenation of Aromatics with Aroyloxylutidinium Salts. Org. Chem. Front. 2018, 5, 1406-1410. (48) Jelier, B. J.; Tripet, P. F.; Pietrasiak, E.; Franzoni, I.; Jeschke, G.; Togni, A. Radical Trifluoromethoxylation of Arenes Triggered by a Visible-Light-Mediated N−O Bond Redox Fragmentation. Angew. Chem., Int. Ed. 2018, 57, 13784-13789.


Page 21 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

R1

R N R

C C C B C N C O ......

Insert Table of Contents artwork here Versatile Radical Reservoirs


21

Recent Advances in Pyridinium Salts as Radical Reservoirs in Organic

Recommend Documents