electrochemical/photochemical aminations based on ...€¦ · 2.1.2 sulfonamides or sulfonimides as...

83

H. Zhang, A. Lei Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2019, 51, 83–96short reviewen

Electrochemical/Photochemical Aminations Based on Oxidative Cross-Coupling between C–H and N–HHeng Zhanga 0000-0003-4823-4167 Aiwen Lei*a,b 0000-0001-8417-3061

a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. of China

b State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of [email protected]

Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

X

YN

R

(X, Y = N or C) O

NNH2R

NS

Ar

O

O

R1

O

NR2 NN

R NH2

R1

R2

Ar1 Ar2

HH

HH

H H

H

H

C

N

H

C N

Ar HR

O

H

H2[Ox] or H2

R3

HR2

R1

+

or

+

ArH

R RH

OO H

with or without oxidant

Received: 16.10.2018Accepted: 18.10.2018Published online: 15.11.2018DOI: 10.1055/s-0037-1610380; Art ID: ss-2018-z0696-sr

License terms:

Abstract The construction of nitrogen-containing molecules remainsat the cutting edge of organic synthesis because of its wide applicationin various areas. Instead of prefunctionalized substrates, using free C–Hand N–H bonds in the starting materials can supply a more sustainableavenue to the C–N bond-forming reactions. Compared with the well-developed transition-metal-catalyzed protocols, the strategy of intro-ducing optical or electrical energy into reactions is fantastic and appeal-ing. As a result, visible light or electricity mediated amination transfor-mations have continued to develop over the past several years. In thisshort review, recent progress of carbon–nitrogen bond-forming reac-tions based on the oxidative cross coupling between C(sp2, sp3)–H andN–H are summarized.1 Introduction2 C(sp2)–H/N–H Oxidative Cross Coupling2.1 Aryl C(sp2)–H as C Nucleophiles2.1.1 Azoles as N Nucleophiles2.1.2 Sulfonamides or Sulfonimides as N Nucleophiles2.1.3 NH3 as N Nucleophile2.1.4 Morpholine as N Nucleophile2.1.5 Diaryl Amines as N Nucleophiles2.1.6 Primary Amines as N Nucleophiles2.1.7 Imides as N Nucleophiles2.1.8 Imines as N Nucleophiles2.2 Alkenyl C(sp2)–H as C Nucleophiles2.3 Aldehydic C(sp2)–H as C Nucleophiles3 C(sp3)–H/N–H Oxidative Cross Coupling3.1 Benzylic C(sp3)–H as C Nucleophiles3.2 α-C(sp3)–H as C Nucleophiles4 Conclusions and Outlook

Key words oxidative cross coupling, amination, C–H bond functional-ization, electrochemistry, photochemistry

1 Introduction

Nitrogen-containing molecules form the cornerstone ofmany disciplines including medicine, material science, and

agrochemicals. As a result, relevant research on C–N bond-forming reactions remains at the cutting edge of organicsynthesis. It is clear that transition-metal-catalyzed C–Nbond-forming reactions have played an important roleduring the past several decades. The palladium-catalyzedBuchwald–Hartwig amination reactions, the copper cata-lyzed Chan–Evans–Lam coupling, and Ullmann type reac-tions have been extensively employed in the constructionof various nitrogen-containing pharmaceuticals, organicoptoelectronic materials, and so forth.1 Despite the greataccomplishments that have been achieved in this realm,

Heng Zhang received his Bachelor’s degree (2000) and his Ph.D. (2005) from Wuhan. Upon completion of his graduate studies, he be-came a lecture of Wuhan University and was promoted to associate professor in 2009. He joined Prof. William D. Jones group (University of Rochester) as a visiting scholar from 2015 to 2016. His current research interests focus on physical organic chemistry.

Aiwen Lei obtained his Ph.D. (2000) under the supervision of Prof. Xi-yan Lu at the Shanghai Institute of Organic Chemistry, Chinese Acade-my of Sciences (CAS). He then moved to Pennsylvania State University, USA, and worked with Prof. Xumu Zhang as a postdoctoral fellow. He joined Stanford University (2003), working with Prof. James P. Collman as a research associate. He then became a full professor (2005) at the College of Chemistry and Molecular Sciences, Wuhan University, China. He was Fellow of the Royal Society of Chemistry, FRSC (2015). His re-search focuses on novel approaches and understanding of bond-forma-tion processes.

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 83–96

http://orcid.org/0000-0003-4823-4167

http://orcid.org/0000-0001-8417-3061

84


more efforts are still needed to make it sustainable and en-vironmentally benign.

Prefunctionalized building blocks are normally the pre-requisites of many C–N bond-forming protocols. However,this is a double-edged sword because the improvement ofreactivity and selectivity is accompanied by a loss of atomeconomy. From the view point of retrosynthetic analysis, itis conspicuous that this obstacle can be overcome by the di-rect utilization of easily available ‘C–H’ and ‘N–H’ in thestarting materials. Compared with the classical C–N cou-pling between electrophiles and nucleophiles, this idea isoxidative cross-coupling based on two nucleophiles: ‘C–H’and ‘N–H’, which have been utilized extensively in bondformations.2 Formally, two hydrogen atoms must be re-moved to drive the reaction to proceed and therefore sacri-ficial oxidant is usually required in this chemistry. Althoughthis strategy has been successfully applied in transition-metal-catalyzed C–N bond-forming reactions, there remainsome limitations; namely, the harsh reaction conditions re-quired to compensate for the low reactivity of nonprefunc-tionalized substrates, and the low atom economy caused bythe introduction of stoichiometric amount of oxidants.3

The involvement of visible light or electricity in chemi-cal reactions is not a novel idea; indeed, the history of manyreactions driven by visible light or electricity dates back tothe early times of modern chemistry. In theory, the integra-tion of optical or electrical energy with a chemical transfor-mation can circumvent the restrictions of the second law ofthermodynamics to make many unimaginably fantastic re-actions feasible.

In addition, the renaissance of radical chemistry hasdrawn the attention of increasing numbers of chemists tothe areas of electrosynthesis and photosynthesis.4 Photonsand electrons can be deemed as traceless reagents, whichcan not only reduce the concomitant by-product but alsosimplify the work up process. Moreover, the consumptionof electricity or visible light can be negligible comparedwith the price of chemicals. Mild reaction conditions arecharacteristic features of these processes. The introductionof visible light or electricity can supply a promising avenue

to the development of oxidative amination based on C–H/N–H.

For the visible-light-mediated aminations, many report-ed studies are based on photoredox catalysis. Ru/Ir-basedpolypyridyl complexes and organic dyes are frequently usedphotoredox catalysts, which supply many choices to matchthe needs of different substrates. Besides numerous chemi-cal oxidants, air or oxygen can be employed as direct oxi-dant or terminal oxidant. This chemistry can be ameliorat-ed with the help of dihydrogen producing catalyst, such asgraphene-supported RuO2 nanocomposite5 or cobaloxime.6With this modification, sacrificial external oxidant can beomitted and dihydrogen is the sole side product. In someother cases, no photosensitizer is needed as the oxidant(DDQ, K2S2O8, etc.) can be excited directly by visible light orthe weak bond (C-I) can be broken just in the presence ofvisible light.

In principle, electrochemical oxidative cross couplingbetween C–H/N–H normally works in the anodic oxidationmode. Generally speaking, no external oxidant is neededand the surplus hydrogens are evolved in the form of dihy-drogen. With the choice of appropriate anode, cathode andother reaction conditions, some transformations can be at-tained just through direct electrolysis. More flexible op-tions can be provided if electrocatalytic amination is em-ployed. Redox mediator (Br–, I–, etc.), transition-metal com-plexes are commonly used catalysts. Divided or undividedcells are another variable in the setup, with the more com-plex former being able to separate the reactive intermedi-ates and avoid the reduction of transition-metal catalystphysically. Compared with the easily available constant-current electrolysis, constant potential electrolysis can con-trol the activation of substrates and supply another way toinhibit the reduction of transition-metal catalyst.

Electrochemical or photochemical amination reactionsestablished on the C–H and N–H nucleophiles are unques-tionable hot topics nowadays. A case in point is the consid-erable research work summarized herein which has beenpublished in the past one or two years, and many analogousworks are reported nearly at the same time back to back.

Scheme 1 The scope of this short review

or

with or without oxidant

X

YN

R

(X, Y = N or C) O

NNH2R

NS

Ar

O

O

R1

O

NR2 NN

R NH2

R1

R2

Ar1 Ar2

HH

HH

H H

H

H

C

N

H

C N

Ar HR

O

H

H2[Ox] or H2

R3

HR2

R1

++

ArH

R RH

OO H


85


Many insightful reviews have been published on related do-mains or from different perspectives.7 This short reviewconcentrates on the C(sp2, sp3)–H/N–H oxidative cross-cou-pling reactions mediated by visible light or electricity(Scheme 1). The achievements of the past six years are re-viewed, especially focusing on the latest progress.

2 C(sp2)–H/N–H Oxidative Cross Coupling

2.1 Oxidative Cross Coupling between Aryl C(sp2)–H and N–H

2.1.1 Azoles as N Nucleophiles

Photoinduced electron transfer is an efficient method toyield arene radical cations. In 2015, the Nicewicz group re-ported a pioneering work on a visible-light-mediated areneC–H amination reaction based on this strategy (Scheme 2).8Acridinium was chosen as the photoredox catalyst, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was the cocatalystand dioxygen was the terminal oxidant. For substrates suchas mesitylene or xylene, a stoichiometric amount of TEMPOand anaerobic conditions should be used to avoid the ben-zylic oxidation. Besides azoles, ammonium carbamate couldalso be used as nitrogen source for the synthesis of aniline.Regioisomers were observed for most of the transforma-tions, which may be due to the complex interplay betweenelectronic and steric effects.

Scheme 2 Photochemical amination between arene and pyrazole

The oxidative cross coupling between electron-richarenes and azoles were also realized based on photoredoxcatalysis (Scheme 3).9 9-Mesityl-10-methylacridinium per-chlorate (Acr+-MesClO4

–) was used as the photoredox cata-lyst. No external oxidant was required in the presence of co-baloxime catalyst, which was proposed to replenish thephotoredox catalyst, oxidize radical adduct intermediateand release dihydrogen. This assembly was superior to thecombination of photoredox catalyst plus dioxygen becauselow yield and concomitant aldehyde formation were ob-served for the latter.

Scheme 3 Photochemical amination between arene and pyrazole with and without external oxidant

Pandey et al. reported the visible-light-mediated amina-tion between electron-rich arenes and benzotriazole(Scheme 4).10 In this case, Selectfluor was chosen as oxidantand 2,6-lutidine was used as base after screening. The deli-cate match between the Ru photoredox catalyst and thearenes was crucial for the success of this transformation.

Scheme 4 Photochemical amination between arene and benzotriazole

2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ), awell-known organic oxidant, can also be used as photosen-sitizer. The Lei group realized the amination of thiopheneby using a catalytic amount of DDQ and tert-butyl nitrite(TBN) (Scheme 5).11 TBN could be considered as a bridge toconnect DDQ and terminal oxidant O2. The scope of the re-action with respect to nitrogen sources was limited to vari-ous azoles.

Scheme 5 Photochemical amination between thiophene and pyrazole

Heteroaryl C(sp2)–H/N–H dehydrogenative cross cou-pling was reported with and without external oxidant insequence. Acr+-MesClO4

– was chosen as the photoredox cat-

N

HNNH3CO

H3CON

H3CO N

N

N

Ph

BF4

+

(0.5 mmol) (1 mmol) Yield: 88% (p + o)p/o = 6.7:1

PC (5 mol%), light

TEMPO (20 mol%), CH2ClCH2Cl (5 mL)O2, r.t., 20 h

+

PC: N

O•

TEMPO:

Light: blue LED lamp (λ = 440–460 nm)

N

HNN

NPC (7 mol%), light

Co cat. (8 mol%), CH3CN (5 mL)r.t., 24 h

(1 mmol) (0.3 mmol) Yield: 70%

+ H2+

N

HNN

N++

HO

(1 mmol) (0.3 mmol) Yield: 27% Yield: 11%

PC (7 mol%), light

CH3CN (5 mL), O2, r.t., 24 h

Light: 3 W blue LEDs Co cat.: Co

Cl

Cl

N

N

N

N

O

O

O

O

H

H

H

N

ClO4PC:

Acr+-Mes ClO4–

NH

NN

N

H3CO

OCH3

(1 mmol) (1.5 mmol)

Yield: 78%

PC (1.5 mol%), light

Selectfluor® (1.5 mmol), 2,6-lutidine (1.5 mmol)

CH3CN (5 mL), r.t.

+

OCH3

OCH3

RuN

NN

NN

N

2 Cl–

PC: Light: 3 W blue LED NN

Cl

HF2 BF4

–Selectfluor®:

N

N

S

N

HN ClS N

N

Cl

DDQ: TBN:OO

CN

CNNC

NC

ON

O

DDQ (15 mol%), TBN (15 mol%), light

CH2ClCH2Cl (3 mL), air, r.t., 4 h


+

Light: 3 W blue LEDs


86


alyst for both works. Adimurthy and coworkers used K2S2O8as oxidant (Scheme 6a).12 The cobaloxime catalyst was usedby Lei, Zhang and coworkers to make this transformationexternal-oxidant free (Scheme 6b).13 Both protocols werelimited by the substrate scope of both heteroarenes and ni-trogen sources.

Scheme 6 Photochemical amination between heteroarene and pyra-zole with external oxidant (a) or with cobaloxime catalyst (b)

2.1.2 Sulfonamides/Sulfonimides as N Nucleophiles

By using [Ir(ppy)2(dtbbpy)]PF6 as photocatalyst andNaClO as oxidant, N-methylindole could be aminated withN-methylsulfonamide in only 30 minutes by Yu and Zhanget al. (Scheme 7).14 According to the authors’ proposal, anN-centered radical was the key reactive intermediate in thereaction, which was proved by trapping experiments using2,6-di-tert-butyl-4-methylphenol (BHT). Although N-chlo-rosulfonamide can be formed when N-methylsulfonamidereacts with NaClO, control experiments demonstrated thatN-chlorosulfonamide was not involved in the reaction path-way, which proposed that the N-centered radical did notoriginate from N-chlorosulfonamide.

Scheme 7 Photochemical amination between indole and sulfonamide

Nearly at the same time, König et al. achieved the 2-am-ination of N-methylpyrrole by using Acr+-MesClO4

– as pho-toredox catalyst and O2 as oxidant (Scheme 8).15 However,5–20 equivalents of N-substituted pyrroles should be usedto operate this transformation. However, the desired cou-pling product was not obtained when pyrrole was substi-tuted with other heterocycles such as furan, thiophene andindole. The N-methylpyrrole radical cation was formedupon the oxidation by the excited state photoredox catalyst

according to the proposed mechanism. N-Alkyl-substitutedsulfonamide was deprotonated by sodium hydroxide toyield the corresponding anion nucleophile. The distinctionbetween these two similar works may originate from theoxidizing ability of the excited-state photoredox catalysts.

Scheme 8 Photochemical amination between pyrrole and sulfon-amide

Aryl sulfonimidation was achieved by Itami andMurakami et al. using DDQ both as photosensitizer and asoxidant (Scheme 9a).16 However, the substrate scope of thereaction with respect to arenes was quite limited, and itwas postulated that unreactive arenes might be thequenchers of photoexcited DDQ. This transformation wasdeveloped by the same group using [Ru(bpy)3]Cl2·6H2O asphotoredox catalyst and a special hypervalent iodine re-agent (IBB) as oxidant (Scheme 9b).17 The superiority of thismethodology was that only an equimolar amount of areneand sulfonamide were needed. Cyclic voltammetry (CV) ex-periments illustrated that an N-centered radical was gener-ated upon oxidation by Ru photoredox catalyst. The addi-tion of the N-centered radical to the arene and the follow-ing oxidation and deprotonation could yield the targetcross-coupling product.

Scheme 9 Photochemical amination between naphthalene and sul-fonimide with different photosensitizers

Cyclic sulfonamides were synthesized through intramo-lecular aryl C–H functionalization by the Muñiz group(Scheme 10).18 This methodology was also compatible withsilicon-tethered arenes, which could be removed easily bytreatment with tBu4NF under mild conditions. Based on theproposed mechanism, an N-centered radical was generatedupon irradiation of the N-I intermediate formed in situ. Theaddition of the N-centered radical and the following single-electron oxidation and deprotonation gave the target prod-uct.

N

HN+ + H2

Yield: 96%

PC (5 mol%), light

Co cat. (5 mol%), CH2ClCH2Cl (3 mL)r.t., 24 h

Light: 3 W blue LEDsPC: Acr+-Mes ClO4– Co cat.: Co

Cl

Cl

N

N

N

N

O

O

O

O

H

H

N

N N

N

N N

H(0.25 mmol) (0.5 mmol)

N

HN+

Yield: 82%

PC (5 mol%), light

K2S2O8 (0.4 mmol), CH2ClCH2Cl (2.5 mL)r.t., 28 h

Light: 12 W blue LED strips

PC: Acr+-Mes ClO4–

N

N N

N

N N

(0.2 mmol) (0.4 mmol)

(a)

(b)

PC (2 mol%), light

NaClO (0.3 mmol)1,4-dioxane (2 mL), r.t., 30 min

Ir

PF6 Yield: 81%

PC: Light: 5 W white LEDs

NN

NN t-Bu

t-Bu

NN S

H O

O

NN

SO

O+

(0.1 mmol) (0.2 mmol)

PC (10 mol%), light

NaOH (2 equiv), O2, r.t.CH3CN/H2O(3:1, 2 mL)

Yield: 84%

Light: 455 nm

N SH O

O+N

N S

O

O

N


(0.2 mmol)

HNSO2Ph

SO2Ph

NSO2PhPhO2S

+

Yield: 79%


DCE, 40 °C, IBB(2 equiv), 12 h

OI

O

On-Bu

IBB:PC: [Ru(bpy)3]Cl2•6H2O

Light: three 2.88 W blue LED strips

HNSO2Ph

SO2Ph

NSO2PhPhO2S

+

quantitative yield

DDQ (1.5 equiv), light

DCE, 40 °C, 12 h

(0.2 mmol) (0.2 mmol)

(a)

(b)

(0.2 mmol) (0.2 mmol)


87


Scheme 10 Intramolecular aryl C(sp2)–H/N–H amination mediated by visible light

The photoredox and transition-metal catalysis were in-tegrated in the intramolecular C–H amination for the syn-thesis of carbazoles (Scheme 11).19 The substrate scopecould be extended from sulfonamides to acetamides. Ac-cording to the proposed mechanism, both the C–H and N–Hactivation process were achieved by Pd catalyst. The pho-toredox catalyst took part in the following product-formingstep, which may be run through Pd(III)/Pd(I) orPd(IV)/Pd(II) cycle.

Scheme 11 Preparation of carbazole by photoredox and Pd catalysis

2.1.3 NH3 as N Nucleophile

The classical procedures for the preparation of anilinesare nitration and subsequent reduction, which runs counterto the idea of sustainable chemistry because relatively largeamounts of byproduct are formed. In 2010, Yoshida et al. re-ported a direct aniline synthesis from benzene and ammo-nia using Pt/TiO2 as photocatalyst with dihydrogen evolu-tion at the same time (Scheme 12).20 Later, the same groupcarried out a mechanistic study of this process.21 Ammoniawas oxidized by the photoinduced hole on the TiO2 surfaceto yield an amide radical (·NH2), which was detected byelectron paramagnetic resonance (EPR). Aniline was formedby subsequent addition and elimination steps. The dihydro-gen was liberated through simultaneous proton reductionby the photo formed electron.

Scheme 12 Photosynthesis of aniline from benzene and ammonia

The same transformation was also realized by the Wugroup in 2016 using organic photoredox catalyst QuH+

(Scheme 13).22 According to their proposal, a benzene radi-

cal cation was formed through single-electron oxidizationby the excited-state photocatalyst, and ammonia was acti-vated through the formation of BF3·NH3, which was quitedifferent to the mechanism proposed by Yoshida. Given thatbenzene (Eox = 2.48 V vs. SCE) is not easily oxidized, thechoice of a suitable photocatalyst QuH+ [Ered(excited state)=2.46 V vs. SCE] insures the success of this methodology. Nofurther amination occurred because of the rapid back-elec-tron transfer.

Scheme 13 Photosynthesis aniline from benzene and ammonia

2.1.4 Morpholine as N Nucleophile

Zeng, Little and co-workers reported the electrochemi-cal oxidative amination of benzoxazoles using iodide aselectroredox catalyst (Scheme 14).23 The reactions werecarried out in an undivided electrolytic cell at constant cur-rent mode. HOAc acted both as ring-opening promoter ofbenzoxazole and as supporting electrolyte. The desired cou-pling product could still be obtained in 53% yield throughdirect electrolysis in the absence of halide. Besides morpho-line, the N nucleophile substrates could be extended to bothcyclic and acyclic secondary amines. However, primaryamines and phthalimide were not compatible with thismethodology.

Scheme 14 Electrochemical amination between benzoxazole and morpholine mediated by iodide

Very recently, the same reaction was also accomplishedthrough direct electrolysis by the Ackermann group(Scheme 15).24 A reticulated vitreous carbon (RVC) anodeand a platinum plate cathode were employed. Cobalt cata-lyst was used in the initial screening, but later experimental

O2S

NH

O2S

NH

O2S

N

NSO2

I2 (5 mol%), PhI(O2CAr)2* (1.1 equiv)

CH2ClCH2Cl (2 mL), visible light, r.t., 12 hYield: 99%

Yield: 95%

* Ar = 3-ClC6H4

(0.45 mmol)

(0.45 mmol)

NHSO2PhN

SO2Ph

Ir

PF6

PC: Light: 7 W blue LEDs

Yield: 94%N

N

NF

F

NF

F

PC (1 mol%), Pd(OAc)2 (10 mol%), light

DMSO (1.5 mL), 80 °C, O2

(0.3 mmol)

NH3 NH3 + H2

Pt (0.1 wt%) /TiO2 (0.2 g), light

r.t., 3 h+

(4.5 μmol)92% select.

(1 mL) (1 mL)(aqueous)

Light: 365 20 nm 30 mW/cm2

NH3 NH2 + H2

PC (10 mol%), light

Co cat. (3 mol%), BF3·Et2O (5 mol%)CH3CN (10 mL), r.t., 5 h

Light: 500 W high pressure mercury lamp with glass water cooling jacket ( λ > 300 nm)

+

NPC:

N NO OCo

N NO OB B

F

F

F

F

N

N

CCH3

CCH3

Co cat.:

20% conv., 80% select.(0.1 mmol)(0.06 mmol)(1.5 mL)

O

NOHN

O

NN O

Yield: 91%

+

undivided cell, glassy carbon anodeFe plate cathode, 6 mA/cm2

n-Bu4NI (10 mol%), HOAc (5 mmol)CH3CN (20 mL), r.t.(1 mmol) (2 mmol)

Scheme 15 Electrochemical amination between benzoxazole and morpholine

O

NOHN

O

NN O

Yield: 94%

+

undivided cell, RVC anodePt plate cathode, 4 mA

HOAc (2.4 equiv), CH3CN (10 mL)r.t., 18 h(1 mmol) (2 mmol)


88


results indicated that it was not indispensable. Besides arylC(sp2)–H, benzylic C(sp3)–H could also be aminated. The re-action was proposed to initiate through anodic oxidation ofamine.

In an undivided cell, electrochemical amination was re-alized by the Ackermann group using a cobalt catalyst(Scheme 16).25 An N,O-bidentate directing group was cru-cial for this methodology. No external oxidant was neededand dihydrogen was the only byproduct. The scope of nitro-gen sources was restricted to the cyclic alkylamines. Theproposed mechanism involved a Co(III)/Co(I) catalytic cyclewhich was based on the common organometallics notion.The anodic oxidation and cathodic reduction fulfilled therecycling of Co catalyst and dihydrogen evolution, respec-tively.

Scheme 16 Cobalt-catalyzed electrochemical amination between arene and morpholine

The directing group strategy was also applied by the Leigroup to achieve a similar transformation at nearly thesame time (Scheme 17).26 N-(Quinolin-8-yl)carboxamidewas installed as directing group in this case. No desiredproduct could be obtained when an undivided cell wasused, which may be because of reduction of Co at the cath-ode. According to an analogous mechanism, the regenera-tion of Co catalyst was attained through anodic oxidation.

Besides the normally used organic and transition-metalphotoredox catalysts, supramolecular ensembles of Cunanoparticles can also be employed as photosensitizer inthe C(sp2)–H amination and alkynylation reactions (Scheme18).27 The supramolecular ensemble 4:CuNPs was preparedin situ by mixing CuCl2 and 3 (triazole-appended perylenebisimide derivative), in which 3 was oxidized to the N-oxidespecies 4. The latter acted as both stabilizer of CuNPs andantenna to harvest light. Benzamide substituted with oxaz-oline as directing group was indispensable for this method-ology. The authors also showed that the directing group canbe easily removed through hydrolysis to yield the corre-sponding benzoic acid under alkaline conditions.

Scheme 18 Photochemical amination between arene and morpholine mediated by a supramolecular ensemble

2.1.5 Diaryl Amines as N Nucleophiles

In 2016, the Xia group demonstrated the direct couplingbetween phenols and cyclic anilines mediated by visiblelight (Scheme 19).28 No photocatalyst was needed becausethe oxidant (K2S2O8) could be activated by visible light di-rectly. Although dioxygen may not act as oxidant, the reac-tion could be promoted slightly in air atmosphere, whichalso simplified the operation. The relative low yield of thecoupling product might be due to its decomposition and theoxidation of 4-methoxyphenol to 1,4-benzoquinone. Goodto excellent yields could be obtained when other electron-rich phenols were employed. The authors proposed a C rad-ical/N radical cross-coupling mechanism.

Scheme 19 Photochemical amination between phenol and phenothi-azine

Two years later, the Lei group achieved the same trans-formation using direct electrolysis (Scheme 20).29 No exter-nal oxidant was needed and dihydrogen was liberated.However, only 20% yields were obtained when phenothi-azine was replaced with acyclic diaryl amines. According tothe proposed mechanism, the phenothiazine was anodized

OHN

Yield: 77%

+NH

O

N

O

NH

O

N

ON

O

GVL:OO

undivided cell, RVC anodePt plate cathode, 2.5 mA

Co(OAc)2•4H2O (10 mol%), KOAc (3 equiv)n-Bu4NPF6, GVL (2 mL), 40 °C, 24 h

(0.5 mmol) (1 mmol)

Scheme 17 Cobalt-catalyzed electrochemical amination between arene and morpholine

OHN

Yield: 61%

+NH

O

N

O

divided cell, carbon cloth anode Ni plate cathode, 10 mA, 65 °C, 3.5 h

anode: Co(OAc)2•4H2O (20 mol%), NaOPiv•H2O (1 equiv) n-Bu4NBF4 (2 equiv), CH3CN (10 mL)cathode: NaOPiv•H2O (2 equiv), HOPiv (8 equiv) CH3OH (10 mL)

NNH

O

N

(0.25 mmol) (0.5 mmol)

OHN

Yield: 87%

+4 (5 mol%):CuNPs, light

K2CO3 (2 mmol), DMSO (2 mL)air, r.t., 4 h

NH

O

N

OO

N

NH

O

ON

Light: 60 W tungsten filament bulb

N OO

n-C12H25

NO O

n-C12H25

O

O

NN

N

NN

N

n-C6H11

n-C6H11

O

NN

N

N N

Nn-C6H11

n-C6H113

4: CuNPs was prepared in situ by mixing 3 with CuCl2

(1 mmol) (1 mmol)

Yield: 32%

+K2S2O8 (0.6 mmol), light

CH3CN (4 mL), air, r.t., 2 hS

HN

OH

OCH3 S

N

HO

OCH3

Light: 8 W blue LED strips(0.4 mmol) (0.2 mmol)


89


to its radical cation to initiate the reaction. Subsequentelectrophilic addition to the phenol, oxidation and depro-tonation gave the desired coupling product.

Scheme 20 Electrochemical amination between phenol and phenothi-azine

A little later, the substrate scope of N nucleophiles wasenlarged to acyclic diaryl anilines by the Xia group (Scheme21).30 Although comparable yields could be obtained whenacridinium was used, 2,4,6-triphenylpyrylium tetrafluoro-borate was used as photoredox catalyst because of its easypreparation. One trick of this methodology was the choiceof oxidant; ammonium persulfate was significantly superi-or to potassium persulfate. At least one electron-donatinggroup should be installed in the aromatic ring because lessthan 5% yield was obtained when diphenylamine was test-ed. The mechanistic experiments still supported a C(radi-cal)/N(radical) cross-coupling pathway.

Scheme 21 Photochemical amination between phenol and diaryl ani-line

2.1.6 Primary Amines as N Nucleophiles

The combination of DDQ and TBN was also applied byKönig and co-workers to achieve benzene amination usingBocNH2 (Scheme 22).31 According to the mechanistic stud-ies, the reactivity of arenes can be divided into two catego-ries: arenes that can form charge-transfer complexes withDDQ and those that cannot. More nucleophilic amines canreact with the former, whereas the latter can react withvarious amines. However, the arenes (such as N-methylin-dole) and amines (such as aniline) that can react with DDQdirectly are not suitable for this methodology.

Scheme 22 Photochemical amination between benzene and BocNH2

Acridinium photoredox catalyst was also used by theNicewicz group to realize benzene amination with valinemethyl ester hydrochloride (Scheme 23).32 Although the ox-idation of amine to its radical cation by the excited-stateacridinium was proposed, the formation of an arene radicalcation could not be precluded for the electron-rich arenes.Later, a predictive model was constructed by the samegroup to rationalize the regioselectivity of the aryl amina-tion reactions based on the experimental results and onDFT calculations.33

Scheme 23 Photochemical amination between benzene and valine derivatives

The formal aryl amination using primary alkylamineswas achieved by the Yoshida group by using a three-stepprocess.34 As shown in Scheme 24, 2-methyl-5-phenyloxaz-oline was first synthesized. Subsequent anodic oxidationresulted in the formation of a cationic intermediate, whichcould be treated with ethylenediamine to yield the targetmolecule.

Scheme 24 Indirect electrosynthesis of aryl amine from arene and pri-mary alkylamine

2.1.7 Imides as N Nucleophiles

Amination of heteroarenes (indoles, pyrroles and ben-zothiophene) using phthalimide as N nucleophiles with aphotoredox catalyst was reported by Itoh and co-workers(Scheme 25).35 The reaction was inhibited in the presenceof TEMPO, and the TEMPO adduct could be isolated. A plau-

Yield: 93%

+

undivided cell, graphite rod anodeNi plate cathode, constant current 7 mA

n-Bu4NBF4 (0.1 mmol), r.t., 100 minCH3CN/CH3OH (8 mL:4 mL)

S

HN

OH

OCH3S

N

HO

OCH3

(0.24 mmol) (0.20 mmol)

HN

OH

OCH3

N

OH

H3CO

O

Ph

Ph Ph

BF4

+


(NH4)2S2O8 (0.6 mmol)CH2Cl2 (3 mL), r.t., 5 h

(0.3 mmol)(0.6 mmol) Yield: 38%

Light: 8 W blue LED strips

PC:

OH2N

O

ONH

ODDQ (20 mol%)/TBN (1:1), light

CH3CN (3 mL), air, r.t., 24 h+

Yield: 68%Light: 455 nm blue LEDs(1 mmol) (0.5 mmol)

HN

O

OPC (5 mol%), light

TEMPO (40 mol%), O2, r.t., 15 hCH2ClCH2Cl:C6H6:pH 8 phosphate buffer

(0.4 mL:0.4 mL:0.2 mL)Yield: 40%(0.4 mL)

H2N

O

OHCl

+

(1 equiv)

N

Ph

BF4PC: Light: blue LED lamp (λ = 440–460 nm)

HN

OH

N

O

H2N

OH

N

O

H2N

NH2

+

Yield: 67%

divided cell: carbon felt anode, platinum plate cathode constant current 8 mAanodic chamber: substrates, LiClO4/CH3CN (0.3 M, 10 mL)cathodic chamber: CF3SO2OH (150 μL) LiClO4/CH3CN (0.3 M, 10 mL)

(0.2 mmol) (1 mmol)

anodic oxidation

0 °C

ZnCl2C6H5Cl140 °C, 24 h

70 °C3 h


90


sible mechanism may start with deprotonation of thephthalimide and then single-electron oxidation by the ex-cited photoredox catalyst. The addition of the generated N-centered radical to arene and subsequent oxidation can re-sult in the formation of the cross-coupling product. Howev-er, another possibility that the arenes quench the excitedphotoredox catalyst could not yet be excluded.

Scheme 25 Photochemical amination between heteroarene and phthalimide

Intramolecular amination was realized through electrol-ysis using one equivalent of NaBr as redox mediator(Scheme 26).36 After screening, pivaloxyloxy group (OPiv)was found the best substituent of the amide. The substratewas deprotonated with electrogenerated methoxide andthen reacted with bromine to yield the N–Br species in situ.The N-acyloxy amidyl as the key intermediate was formedthrough N–Br bond homolytic cleavage. Subsequent radicaladdition, oxidation, and deprotonation would yield the tar-get molecule.

Scheme 26 Intramolecular electrochemical amination to prepare lact-am

2.1.8 Imines as N Nucleophiles

The Xu group synthesized tetracyclic benzimidazolesthrough intramolecular cyclization by direct electrolysis(Scheme 27).37 This process was metal- and external-oxi-dant-free and the only byproduct was dihydrogen. Sincethis reaction was an anode oxidation process, the choice ofanode material was crucial; no reaction occurred when Ptanode was used and the yields decreased significantlywhen the RVC anode was replaced with a graphite rod. Con-trol experiments suggested that an N-centered radical wasinvolved in the reaction pathway.

Scheme 27 Intramolecular electrochemical amination to prepare tet-racyclic benzimidazole

2.2 Oxidative Cross-Coupling between Vinyl C(sp2)–H and N–H

In 2012, Zheng et al. reported the synthesis of N-arylin-doles through the intramolecular C–H/N–H oxidative cross-coupling of styryl aniline (Scheme 28).38 For the diaryl-amine substrates, one phenyl should be installed with a p-alkoxy group in order for the reaction to proceed. It is inter-esting to note that the involvement of silica gel increasedthe yield significantly, which was proposed to increase thesolubility of dioxygen and supply protons. With elongationof the reaction time, the reaction can be enlarged to gramscale without a significant decrease in yield. As to the reac-tion mechanism, the replacement of Ru photocatalyst withtetraphenylporphyrin resulted in no formation of the targetproduct, which indicated the absence of singlet oxygen inthe reaction pathway.

Scheme 28 Intramolecular photochemical alkenyl C(sp2)–H/N–H cou-pling to prepare N-arylindole

When a combination of Acr+-MesClO4– and cobaloxime

catalyst was applied to alkenes and azoles, N-vinylazolescan be synthesized directly without external oxidant

PC (10 mol%), light

K2CO3 (60 mol%), DMF (3 mL)4 Å MS (50 mg), air, 20 h

Yield: 82%

NNH

O

O N

N

O

O

Light: 21 W fluorescent lamp

O

O

PC:

+

(0.6 mmol) (0.3 mmol)

ONH

OO

N

O

undivided cell, Pt anode & cathodeconstant current 20 mA

NaBr (0.3 mmol), r.t., 2 h CH3CN/CH3OH (7 mL:0.5 mL)

Yield: 93%(0.3 mmol)

Yield: 94%

+

undivided cell, RVC anodePt plate cathode, constant current 10 mA

Et4NPF6 (0.3 mmol), CH3OH (9 mL), reflux, 3 h

N

N

NH

O

N

NO

N

H2

(0.3 mmol)

N

OMe

NH

OMe

PC (4 mol%), light

CH3CN (12 mL), silica gel (500 mg)air, r.t., 5 h

Ru

NN

N

NNN

NN

N

N NN

(PF6)2

Yield: 73%PC:

Light: 18 W white-light LED

(0.2 mmol)

Scheme 29 Photochemical amination between aryl alkene and pyra-zole

N

HN+ + H2

Yield: 70%

NNPC (3 mol%), light

Co cat. (3 mol%), r.t., 24 hCH2ClCH2Cl (2 mL)

Light: 3 W blue LED

PC: Acr+-Mes ClO4– Co cat.: Co

Cl

N

N

N

N

N

O

O

O

O

H

H

(0.2 mmol) (0.4 mmol)


91


(Scheme 29).39 However, only aryl alkenes were reportedand the N–H nucleophiles could not be extended to aniline,diphenylamine, and so forth.

Recently, Guan and He et al. reported the synthesis of N-vinylazoles from cross coupling between electron-deficientalkenes and azoles (Scheme 30).40 Rose Bengal (RB) waschosen as photoredox catalyst and air was used as oxidant.It is interesting to note that a compact fluorescent lamp(CFL) was superior to a green light-emitting diode (LED),which is normally to mate with RB. Although 1O2 can beproduced by RB through energy-transfer pathways, the pos-sible involvement of singlet oxygen was eliminated becausethe reaction was not inhibited by singlet oxygen quencher,cysteine. When radical scavenger TEMPO or BHT was mixedin the reaction system, the reaction was inhibited, andhigh-resolution MS indicated the formation of radical spe-cies. Control experiments demonstrated the Michael addi-tion between electron-deficient alkenes and azoles was nota possible pathway.

Scheme 30 Photochemical amination between electron-deficient alkene and benzotriazole

2.3 Oxidative Cross-Coupling between Aldehydic C(sp2)–H and N–H

The synthesis of amides can also be achieved by directoxidative coupling between aldehyde and amine. Leowdemonstrated this feasibility by using (hetero)aryl alde-hydes and secondary amines (Scheme 31).41 Various transi-tion-metal and organic photoredox catalysts were tested,and phenazine ethosulfate was found to perform best. Anegative effect was observed when the inhibitor was not re-moved from the solvent tetrahydrofuran (THF). However,only one acyclic secondary amine (nBuNHMe) was reportedwith 56% isolated yield. According to the author’s proposal,H2O2 was formed during the photocatalytic cycle and theamide was yielded through the oxidation of hemiaminal byH2O2. Besides acting as reactant, amine was oxidized toimine to finish the photocatalytic cycle; excess amines weretherefore used in this transformation. It is interesting tonote that the reductive amination product can also be pre-pared through photoredox catalysis between aromatic alde-hydes and cyclic amines, as described by Molander et al.42

Having accomplished the oxidative esterification medi-ated by N-heterocyclic carbene using a microfluidic elec-trolysis cell, the Brown group applied the same strategy toprepare amide from aldehydes and amines (Scheme 32).43

The key point to the success of this method was the forma-tion of Breslow intermediate between aldehyde and the N-heterocyclic carbene formed in situ before mixing withamine. When the current was increased to 510 mA, thetemperature of the heating chip was kept at 110 °C, the pro-ductivity of this system was as high as 2.5 g/h, which sug-gested the suitability of this methodology for scaling up.Various (hetero)aryl aldehydes and aliphatic or benzylicprimary amines could be accommodated with good to ex-cellent yields. Only one aliphatic aldehyde (n-C12H25CHO)was reported with 71% yield.

Scheme 32 Flow electrochemical amidation of aldehyde mediated by N-heterocyclic carbene

3 C(sp3)–H/N–H Oxidative Cross Coupling

3.1 Benzylic C(sp3)–H as C Nucleophiles

Isoquinolino[2,1-a]quinazoline derivatives were syn-thesized through intramolecular benzylic C(sp3)–H/N–Hcoupling by the Xiao group (Scheme 33).44 Both transition-metal and organic photoredox catalysts could be successful-ly employed in the gram-scale preparation with goodyields.

The benzylic C(sp3)–H amination using amide as N nu-cleophiles was reported by Pandey et al. (Scheme 34).45 Theamides must be methoxy substituted; no reaction occurredwhen N-phenylacetamide or diphenylamine was employedin this protocol. No clear decay of the photoredox catalyst9,10-dicyanoanthracene (DCA) was observed after 12–15

CN

CN

Ph NH

NN

CN

CN

Ph

N

NN

PC (3 mol%), light

acetone (1 mL), air, r.t., 24 h+

PC:

Light: 12 W compact fluorescent lamp

Cl

Cl

COOHCl

Cl

O O

I

HO

I I

I

Yield: 79%(0.4 mmol) (0.2 mmol)

Rose Bengal (RB)

Scheme 31 Photochemical amide synthesis from aldehyde and amine

BrO

H

HN

N

N

EtEtOSO3–

O

N

Br

+

PC:Yield: 81%

PC (1 mol%), light

THF (inhib. free, 1.2 mL), air, r.t., 20 h

Light: 24 W compact fluorescent lamp

(0.12 mmol) (0.3 mmol)

MeOO

H

MeO

MeO

O

NH

MeO

Yield: 99%

MeO

OMe

NS

H

Mes

DBU

NH2

anodicoxidation

heating60 °C

constant current103–105 mA

(1 equiv, 0.1 M)

(1 equiv, 0.1 M)

(1 equiv, 0.05 M)

(1.5 equiv, 0.15 M)single pass

solvent: DMF

N

N

DBU:


92


hours of photolysis. According to the results of control ex-periments, the benzylic carbocation and radical were prob-ably involved in the reaction pathway.

Scheme 34 Photochemical amination between arene and amide

Later, the same group reported the benzylic C(sp3)–Hamination using benzotrizole as the N nucleophile (Scheme35).46 [Ir{dF(CF3)ppy}2(dtbpy)]PF6 was the photoredox cata-lyst and BrCCl3 was the oxidant. The scope of N nucleophileswas quite limited because pyrrole, TsNH2, and (Boc)2NHwere not compatible. A tentative proposed mechanisminvolved an oxidative quench of the excited Ir catalyst byBrCCl3, which resulted in the formation of Ir(IV) and ·CCl3radical. The arene radical cation was produced through thesingle-electron oxidation by Ir(IV). Then the benzylic carbo-cation was generated through hydrogen abstraction by ·CCl3radical. The reaction between benzylic carbocation and Nnucleophile could yield the target coupling product.

Scheme 35 Photochemical amination between arene and benzotrizole

Hofmann–Löffler–Freytag reaction is a powerful meth-od to the construction of pyrrolidines. However, harsh reac-tion conditions (high temperature, strong acid and base) arerequired for this transformation. The development of thisreaction has been ongoing. For example, much milder reac-tion conditions could be employed when 1 equivalent of I2

and 3 equivalents of PhI(OAc)2 were used.47 With the aid ofvisible light or electrolysis, Muñiz, Reiher, Nagib, Lei and co-workers improved this process prominently in recent sever-al years. As shown in Scheme 36a, only 2.5 mol% I2 wasneeded, and the key to the success was the choice ofPhI(mCBA)2 as iodine(III) reagent.48 The loading of I2 couldbe reduced to as low as 0.5 mol%. The screening of the visi-ble-light wavelength illustrated that 400 nm was the opti-mum. Daylight was used in the end to simplify operationsas no clear loss in yield occurred. As shown in Scheme 36b,N-iodosuccinimide (NIS) was found to be the optimalchoice after screening of a series of halogen promoters suchas N-bromosuccinimide (NBS), N-bromophthalimide (NBP)and so forth.49 The reaction could be run just using 2 equiv-alents of NIS under visible light at room temperature. Fourequivalents of NaI and PhI(OAc)2 were employed in themethod developed by the Nagib group (Scheme 36c).50 Theformation of triiodide between I2 and a large excess iodidecan solve the unproductive oxidations mediated by I2. Thestrategy of the integration of I2 and photoredox catalyst wasalso applied in this transformation (Scheme 36d).51 Thecrucial factors of this methodology were the ratio of iodineand photoredox catalyst, air and a trace amount of water.The light irradiation functioned both in the excitation ofphotoredox catalyst and in the activation of the N–I bondformed in situ. An iodine-free protocol was also developedwhen nBu4NBr was used as catalyst and m-chloroperoxy-benzoic acid (mCPBA) acted as terminal oxidant (Scheme36e).52 The reaction still worked when the catalytic amountof nBu4NBr was replaced with I2 (Scheme 36f).53 Very re-cently, this transformation was also achieved through directelectrolysis with the liberation of dihydrogen concomitant-ly (Scheme 36g).54 Similar electrolysis conditions were alsodeveloped by the Lei group at nearly the same time(Scheme 36h).55 Compared with the photochemical meth-ods, much higher atomic economy was realized in the elec-trochemical method because no halogen or external oxi-dant was needed. In contrast to the above visible light me-diated protocols, which were speculated to proceed through1,5-hydrogen atom transfer, the benzylic carbon radical wasproposed by Muñiz and coworkers to be involved in the re-action pathway rather than the N-centered radical. Al-though many reported reactions occurred at benzylic sites,the substrate scope of this chemistry could also extend tothose without benzylic C–H.

The synthesis of piperidine derivatives has also beenachieved by the Muñiz group through both photochemi-cal56 and electrochemical54 methods (Scheme 37). The com-bination of a catalytic amount of iodine and a stoichiomet-ric amount of NBS was used in the photochemical transfor-mation. Direct constant-current electrolysis could also beemployed to do the same reaction.

The triiodide protocol developed by the Nagib groupwas also tactfully applied in the synthesis of β-amino alco-

Scheme 33 Photochemical intramolecular benzylic C(sp3)–H/N–H coupling

N

HN

SO

O

N

NS

O

O

Reaction conditions

(a) [Ir(ppy)2(dtbbpy)]PF6 (0.5 mol%), 36 W fluorescent light t-BuOK (2 equiv), CH3OH/CH2Cl2 (1:1), air, r.t., 36 h, 82% yield(b) Eosin Y (0.5 mol%), 36 W fluorescent light t-BuOK (2 equiv), CH3OH/CH2Cl2 (1:1), air, r.t., 25 h, 85% yield

(2.5 mmol)

O

NH

OCH3 N

O

O

+

(2 mmol) (3 mmol)


CH3CN (50 mL), r.t., 12 h

Yield: 55%CN

CN

PC:Light: 410 nm, with filter from 450 W medium pressure mercury lamp

DCA

NH

NN N

NN

H3CO

OCH3

Ir

PF6

PC:N

Nt-Bu

t-Bu

NF

F

CF3

NF

F

CF3


PC (1 mol%), light

BrCCl3 (1.5 mmol), K2CO3 (1.5 mmol)CH3CN (5 mL), r.t.

+

Light: 3 W blue LED


93


hol (Scheme 38).57 Three steps were involved in the wholeprocess, in which the intramolecular photochemical cy-clization of the imidate was pivotal. The desired productcould be obtained conveniently just by hydrolysis of theformed dihydrooxazole derivatives without further purifi-cation.

3.2 α C(sp3)–H as C Nucleophiles

The strategy of C–H functionalization via intermediateperoxides was used in the amination of tetrahydrocarbazolederivatives by Klussmann et al. (Scheme 39).58 In essence,this was a two-step process. The first step was the genera-tion of the corresponding hydroperoxide in the presence ofphotosensitizer (Rose Bengal) and dioxygen mediated byvisible light. The second step was Brønsted acid catalyzednucleophilic substitution. Given that no oxidative condi-tions were involved in the amination step, aniline could beused as N nucleophile directly. The reactions could be runin three modes without obvious yield change: two stepwith isolation of hydroperoxide, one pot with solvent ex-change and one pot without solvent exchange. Later, a de-tailed experimental and theoretical study was carried outon this reaction.59

Scheme 39 Photochemical amination of tetrahydrocarbazole

The cross coupling between tetrahydrofuran and azoleshas been achieved by the Lei group through both photore-dox catalysis60 and direct electrolysis61 (Scheme 40). Com-pared with the photochemical method, the reaction timewas sharply reduced in the electrochemical method. Bothstudies proposed that the N-centered radical, originatingfrom oxidation, was the key intermediate.

Scheme 36 Photochemical and electrochemical modified Hofmann–Löffler–Freytag reaction

NS

HN

SO

O

O

O

NI

O

O

(g) undivided cell, graphite rod anode, platinum mesh cathode, constant current 2.5 mA sulfonamide (0.2 mmol), n-Bu4NBF4 (1 mmol), (CF3)2CHOH (10 mL) r.t., 280 min, 85% yield

(b) sulfonamide (0.1 mmol), NIS (0.2 mmol), visible light CH2Cl2 (2 mL), r.t., 5 h, 95% yield

Reaction conditions

ClO

O OH

(e) sulfonamide (0.22 mmol), n-Bu4NBr (0.044 mmol), m-CPBA (0.44 mmol) visible light, CH3CN (2 mL), r.t., 12 h, 95% yield

m-CPBA:

NIS:

(d) sulfonamide (0.3 mmol),TPT (1 mol%), I2 (5 mol%), blue LED (CF3)2CHOH/CH2ClCH2Cl (1:1, 3 mL), air, r.t., 18 h, 90% yield

O

Ph

Ph Ph

BF4TPT:

PhI(m-CBA)2:

O IO

O

O

(a) sulfonamide (0.22 mmol), PhI(m-CBA)2 (0.22 mmol), I2 (2.5 mol%) visible light, CH2ClCH2Cl (1.5 mL), r.t., 12 h, 98% yield

(c) sulfonamide* (0.2 mmol), PhI(OAc)2 (4 equiv), NaI (4 equiv) visible light, CH3CN (2 mL), r.t., 93% yield

HN

SO

Osulfonamide*:

ClCl

(f) sulfonamide (0.22 mmol), I2 (15 mol%), m-CPBA (0.33 mmol) visible light, CH3CN/t-BuOH (1:1, 1 mL), r.t., 12 h, 95% yield

(h) undivided cell, carbon rod anode, platinum plate cathode, constant current 15 mA sulfonamide (0.4 mmol), n-Bu4NOAc (0.4 mmol), (CF3)2CHOH/CH2ClCH2Cl (4 mL/8 mL) r.t., 4 h, 98% yield

Scheme 37 Preparation of a piperidine from intramolecular photo-chemical and electrochemical amination

NS

O

O

NH

SO

O

Reaction conditions

(b) undivided cell, graphite rod anode, platinum mesh cathode, constant current 2.5 mA sulfonamide (0.2 mmol), n-Bu4NBF4 (1 mmol), (CF3)2CHOH (10 mL) r.t., 280 min, 53% yield

NBr

O

O

(a) sulfonamide (0.2 mmol), I2 (5 mol%), NBS (0.4 mmol) CH2Cl2 (1.5 mL), visible light, r.t., 4 h, 80% yield

NBS:

Scheme 38 Indirect β-amination of alcohol through photochemical cyclization of an imidate intermediate

NHCl3C

O

OCH3

NO

OCH3

Cl3C

HO

OCH3

NH2

(0.4 mmol) yield: 99%

yield: 80%

PhI(OAc)2 (1.2 mmol), NaI (1.2 mmol)

CH3CN (4 mL), r.t., 2 h23 W compact fluorescent light

HO

OCH3

2 M HCl (0.8 mL)CH3OH (4 mL), 2 h

Cl3CCN (1.5 equiv)DBU (0.1 equiv), CH2Cl2

PC: Rose Bengal (RB)

NH

NH NH

O2N

NH2

NO2

NH

OOH

(0.5 mmol) (0.5 mmol)

CF3COOH (0.05 mmol)

CH3OH (0.5 mL), r.t., 2 h

Yield: 86%

+

Light: 23 W lampPC (0.7 mol%), lightC6H5CH3, O2, r.t., 3 h


94


Scheme 40 Photochemical and electrochemical amination between tetrahydrofuran and azole

Zeng, Sun and co-workers reported the electrochemicalsynthesis of α-amino ketones mediated by iodide (Scheme41).62 After optimization of the reaction conditions, NH4Iwas found to be a good choice of redox catalyst. The sub-strate scope of N nucleophiles was restricted to secondaryamines; no desired product could be obtained in the pres-ence of primary amines. The radical pathway was preclud-ed because α-cyclopropyl substituted acetophenone couldbe tolerated in this protocol without ring opening. The pro-posed mechanism suggested that α-iodo ketone was thekey reactive intermediate, which could be generated by thereaction between ketone and I2 formed in situ. Subsequentnucleophilic substitution by the amine resulted in the tar-get coupling product.

Scheme 41 Electrochemical synthesis of α-amino ketones mediated by iodide

Huang and co-workers reported the direct electrochem-ical coupling between N-methyl pyrrolidone and anilines(Scheme 42).63 Besides electron-deficient anilines, anilinesinstalled with electron-donating groups could still be com-patible, albeit with lower yields. It was interesting to notethat the efficiency of this transformation was very sensitiveto the geometric dimensions of the Pt wire anode. As a sho-no-type oxidation, the reaction was initiated by the anodicoxidation of N-methyl pyrrolidone to its iminum cation.Subsequent trapping of the iminum cation by aniline couldgenerate the target coupling product.

Scheme 42 Electrochemical oxidative cross coupling between γ-lac-tam and aniline

4 Conclusions and Outlook

Although no general mechanism can be drawn from thereactions discussed above, radical intermediates are pro-posed to be involved in most transformations. The reactionscan be initiated from oxidation of either ‘C–H’ or ‘N–H’.Photoredox catalysis and anodic oxidation provide a mildway to generate radicals because most reactions can be runat room temperature. Quite a lot of reported reactions canbe realized through both photochemical and electrochemi-cal approaches. Due to the essence of oxidative cross cou-pling, oxidant should be an indispensable component.However, external oxidant can be removed if the photore-dox catalyst is accompanied by a cobaloxime catalyst.Moreover, no external oxidant is needed in electrolysis be-cause the surplus hydrogens are evolved as dihydrogen. Ingeneral, less time is consumed in electrochemical processthan photochemical methods to transform an identicalamount of substrate. This may be rationalized by two con-siderations: (a) the low quantum yield of photochemical re-actions, and (2) the productivity of electrochemical reac-tions is determined by the Faraday’s laws of electrolysis.From the inspection of the substrate scope of both C–H andN–H nucleophiles, it can be seen that the success of manyprotocols are based on the delicate match of limited start-ing material. Broadening of the substrate scope may be-come an urgent need in the near future. Many intermolecu-lar reactions are run on 1 versus n (n>1) molar ratio to at-tain better yields, which count against the principle ofatomic economy and post treatment. Enabling the reactionsto run on a 1:1 molar ratio is another target for future ef-forts.

For the photochemical aminations, the development ofnovel photocatalysts may be the most efficient way to im-prove the reactions. The involvement of redox mediator orelectrocatalyst and modification of the electrode can supplymore opportunities for the electrochemical aminations.The idea of combining photochemical and electrochemicalprocess in the same reaction is challenging but may provideanother avenue for the amination reactions.

Compared with the transition-metal catalyzed C–Nbond-forming reactions, electrochemical or photochemicaloxidative cross coupling between C–H and N–H have goodpotential for further application in industry. The reactionscan be easily controlled to start and stop. When running oncontinuous flow mode, the productivity can be scaled upconveniently. Considerations such as current efficiency, en-ergy efficiency, and quantum yield, which are not import-ant in the laboratory, may be crucial factors for industrialmanufacture.

O NHNNN

O

+

Light: 3 W blue LEDs


(3 mL) (0.2 mmol)

PC (3 mol%), light

air, r.t., 24 h

Yield: 82%

(a)

undivided cell, Pt anode & cathodeconstant current 12 mA

n-Bu4NBF4 (0.2 mmol), CH3CN (8 mL)80 °C, 5 h

O NHNNN

O

+

(2 mL) (0.3 mmol) Yield: 91%

(b) + H2

O

HN

O

N

(1 mmol) (3 mmol) Yield: 65%

+

undivided cell, graphite plate anode & cathodeconstant current 48 mA

NH4I (0.5 mmol), LiClO4 (2 mmol)CH3CN (20 mL), r.t.

N

ONH2

Br

undivided cell, Pt wire anode & Pt foil cathodeconstant current 20 mA

NH4ClO4 (1.2 mmol), r.t., 2.5 h CH3CN (5 mL)

HN

Br

NO

Yield: 81%(5.2 mmol) (0.25 mmol)

+


95


Funding Information

This work was supported by the National Natural Science Foundationof China (21390402, 21520102003, 21272180) and the Natural Sci-ence Foundation of Hubei Province (2017CFA010, 2016CFB571). TheProgram of Introducing Talents of Discipline to Universities of China(111 Program) is also appreciated.National Natural Science Foundation of China (21390402)National Natural Science Foundation of China (21520102003)National Natural Science Foundation of China (21272180)Natural Science Foundation of Hubei Province (2017CFA010)Natural Science Foundation of Hubei Province (2016CFB571)

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